HK1086006B - Diamine derivatives - Google Patents

Description

Diamine derivatives

Technical Field

The present invention relates to a novel compound which inhibits activated blood coagulation factor ten (hereinafter abbreviated as FXa), exhibits a potent anticoagulant effect, and can be administered orally, or a blood coagulation inhibitor or a prophylactic and/or therapeutic agent for thrombosis or embolism, which comprises the compound as an active ingredient.

Background

Unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary embolism, thromboangiitis obliterans, deep venous Thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve replacement, reocclusion after blood flow reconstruction, thrombus formation during extracorporeal circulation, and the like, and thus excellent anticoagulants having excellent dose responsiveness, persistence, low bleeding risk, few side effects, and sufficient effects immediately upon oral administration are required (Thrombosis Research, volume 68, page 507, 512, 1992).

In studies of anticoagulants based on various mechanisms of action, the possibility that FXa inhibitors will become good anticoagulants has been suggested. The blood coagulation system is a series of reactions that undergo an amplification process by a multistage enzymatic reaction to produce a large amount of thrombin and produce insoluble fibrin. In the endogenous system, after the activation of the contact factor, the multistage reaction is continued, and then the activated factor ninth activates the factor tenth on the phospholipid membrane in the presence of the activated factor eighth and calcium ions. In addition, the activated seventh factor activates factor ten in the presence of tissue factor in the exogenous system. That is, activation of FXa by the tenth factor in the coagulation system is a reaction necessary for thrombin generation. The activated tenth factor (FXa) in both systems is restricted to break down prothrombin to thrombin. Since the produced thrombin activates the upstream coagulation factor, the generation of thrombin is further amplified. As described above, since the coagulation system upstream of FXa is divided into an intrinsic system and an extrinsic system, inhibition of coagulation system enzymes upstream of FXa does not sufficiently inhibit FXa production, and as a result, thrombin is generated. Furthermore, since the coagulation system is a self-amplifying reaction, more effective inhibition of the coagulation system can be achieved by inhibition of FXa located upstream than inhibition of thrombin generated (Thrombosis Research, Vol.15, pp.617-629, 1979). Another advantage of FXa inhibitors is that there is a large deviation between the effective dose in the thrombus model and the dose that extends the bleeding time in the experimental bleeding model, and from the results of this experiment, it is considered that FXa inhibitors are anticoagulants with a low risk of bleeding.

Various compounds have been reported as FXa inhibitors, but it is known that antithrombin III, antithrombin III-dependent pentasaccharide and the like do not inhibit prothrombinase complex having a practical effect on thrombus formation in vivo (Thrombosi Research, Vol. 68, pp. 507-512, 1992, Journal of Clinical Investigation, Vol. 71, pp. 1383-1389, 1983, Mebio, Vol. 14, pp. 8, pp. 92-97) in general, and that oral administration does not show any effectiveness. Tick Anticoagulant Peptide (TAP) (Science, volume 248, page 593-. Therefore, development of an orally administrable low-molecular FXa inhibitor that directly inhibits an antithrombin III-independent coagulation factor has been carried out.

Disclosure of The Invention

Accordingly, an object of the present invention is to provide a novel compound which has a potent FXa inhibitory effect and can rapidly exhibit a sufficient and sustained antithrombotic effect when administered orally.

The present invention has studied the synthesis and pharmacological effects of a novel FXa inhibitor and found a diamine derivative, a salt thereof, a solvate thereof or an N-oxide thereof which exhibits a potent FXa inhibitory effect and a potent anticoagulation effect. Further, oral administration of these compounds has been found to be useful as a prophylactic or therapeutic agent for various diseases caused by thrombosis or embolism, because they inhibit FXa immediately, continuously and effectively and exhibit potent anticoagulant and antithrombotic effects.

Namely, the present invention provides the general formula (1)

Q¹-Q²-T⁰-N(R¹)-Q³-N(R²)-T¹-Q⁴(1)

A compound represented by (i), a salt thereof, a solvate thereof or an N-oxide thereof;

in the formula, R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q¹represents 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 saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q²represents 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 alkynylene group having 2 to 6 carbon atoms, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a 2-valent saturated or unsaturated 5-to 7-membered heterocyclic group which may have a substituent, a 2-valent saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a 2-valent saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q³from the following groups

Represents Q in the group⁵Is C1-8 alkylene, C2-8 alkenylene or- (CH) ₂)m-CH₂-A-CH₂-(CH₂)_n(in the group, m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-)；

R³And R⁴In the presence of Q⁵Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an optionally substituted C, N or SAcylamino, alkoxyimino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylamino, carboxyalkylamino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carbamoyl, N-alkylcarbamoyl which may have a substituent on the alkyl group, N-dialkylcarbamoyl which may have a substituent on the alkyl group, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbonylalkyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbonylalkyl, n-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonylalkyl, 3-to 6-membered heterocyclic carbonyl which may have a substituent, carbamoylalkyl, N-alkylcarbamoylalkyl which may have a substituent on the alkyl group, N-dialkylcarbamoylalkyl which may have a substituent on the alkyl group, carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, 3-to 6-membered heterocyclic carbonylalkyl which may have a substituent, 3-to 6-membered heterocyclic carbonyloxyalkyl which may have a substituent, aryl, aralkyl, 3-to 6-membered heterocyclic group which may have a substituent, 3-to 6-membered heterocyclic alkyl which may have a substituent, substituted or unsubstituted, Alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, aralkoxy, carboxyalkoxy, alkoxycarbonylalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3 to 6-membered heterocyclic sulfonyl which may have a substituent A heterocyclic oxy group, an N-alkylacylamino group, an N, N-dialkylaminoacyl group, an N, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group, an alkylsulfonylacyl group, an N-arylcarbamoyl group, an N-3-to 6-membered heterocyclic carbamoyl group, an N-alkylN-arylcarbamoyl group, an N-alkyl-N-3-to 6-membered heterocyclic carbamoyl group, an N-arylcarbamoylalkyl group, an N-3-to 6-membered heterocyclic carbamoylalkyl group, an N-alkyl-N-arylcarbamoylalkyl group, an N-alkyl-N-3-to 6-membered heterocyclic carbamoylalkyl group, a carbothioformyl group (carbothioyl group), N-alkylaminothioformyl, N-dialkylaminothioformyl, alkoxyalkyl (thiocarbonyl), alkylthioalkyl or N-acyl-N-alkylaminoalkyl or R³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group or a carbonyldioxy group having 1 to 5 carbon atoms;

Q⁴represents 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 heteroarylalkenyl group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused heterocyclic group which may have a substituent;

T⁰Represents a carbonyl group or a thiocarbonyl group;

T¹represents a carbonyl group, a sulfonyl group, a group-C (═ O) -C- (═ O) -N (R ') -, a group-C (═ S) -C (═ O) -N (R ') -, a group-C (═ O) -C (═ S) -N (R ') -, a group-C (═ S) -N (R ') -, wherein R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, a group-C (═ O) -a¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein 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) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³-C(＝O) -NH- (A in the radical)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group, R^bRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, the group-C (═ NOR)^c)-C(＝O)-N(R^d) - (R in the radical)^cRepresents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, R^dRepresents 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) - (R in the radical)^eAnd R^fEach independently represents a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl group (thiocarbonyl group), R ^gRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -NH-C (═ O) -, the group-C (═ S) -NH-C (═ O) -, the group-C (═ O) -NH-C (═ S) -, the group-C (═ S) -NHC (═ S) -, the group-C (═ O) -NH-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl.

The present invention also provides a pharmaceutical agent containing the compound represented by the above general formula (1), a salt thereof, a solvate thereof, or an N-oxide thereof, in particular, an activated coagulation factor viii inhibitor, a coagulation inhibitor, a preventive and/or therapeutic agent for thrombus or embolism, and a preventive and/or therapeutic agent for cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve/joint replacement, thrombus formation and reocclusion after blood flow reconstruction, Systemic Inflammatory Response Syndrome (SIRS), Multiple Organ Dysfunction Syndrome (MODS), thrombus formation during extracorporeal circulation, or blood coagulation during blood collection.

In addition, the present invention provides an intermediate for producing the compound (1) represented by the general formula (1).

The present invention also provides the use of a compound represented by the above general formula (1), a salt thereof, a solvate thereof, or an N-oxide thereof for the production of a pharmaceutical.

The present invention also provides a method for treating thrombosis or embolism, which is characterized by 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.

The cyclic diamine derivative of the present invention exhibits a potent inhibitory activity against activated blood coagulation factor ten, and therefore is useful as a pharmaceutical product, an activated blood coagulation factor ten inhibitor, a blood coagulation inhibitor, a preventive and/or therapeutic agent for thrombus or embolism, a preventive and/or therapeutic agent for thrombotic diseases, and a preventive and/or therapeutic agent for cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve/joint replacement, thrombus formation and reocclusion after blood flow reconstruction, Systemic Inflammatory Response Syndrome (SIRS), Multiple Organ Dysfunction Syndrome (MODS), thrombus formation during extracorporeal circulation, or blood coagulation during blood collection.

Best Mode for Carrying Out The Invention

The substituents in the diamine derivative of the present invention represented by the general formula (1) are described below.

(with respect to group Q)⁴)

Group Q ⁴Represents 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 heteroarylalkenyl group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused heterocyclic group which may have a substituent.

Group Q⁴The aryl group in the above formula means an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group and a phenanthryl group. Arylalkenyl representsExamples of the group comprising an aryl group having 6 to 14 carbon atoms and an alkenylene group having 2 to 6 carbon atoms include styryl. The arylalkynyl group represents 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 phenylethynyl groups.

The heteroaryl group represents an aromatic 1-valent group having at least 1 hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and the total number of ring atoms is 5 or 6, and examples thereof include a pyridyl group, a pyridazinyl group, a pyrazinyl group, a furyl group, a thienyl group, a pyrrolyl group, a thiazolyl group, an oxazolyl group, a pyrimidinyl group, and a tetrazolyl group. The heteroarylalkenyl group represents a group composed of the above-mentioned heteroaryl group and an alkenylene group having 2 to 6 carbon atoms, and may, for example, be a thienylvinyl group or a pyridylvinyl group.

The saturated or unsaturated 2-or 3-membered fused hydrocarbon group represents a 1-valent group formed by a saturated or unsaturated 2-or 3-membered fused hydrocarbon, and the saturated or unsaturated 2-or 3-membered fused hydrocarbon is a 2-or 3-membered fused hydrocarbon formed by fusing 2 to 3 identical or different saturated or unsaturated 5-to 6-membered cyclic hydrocarbons. Examples of the saturated or unsaturated 5-to 6-membered cyclic hydrocarbon include cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, benzene, and the like. Specific examples of the saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group include indenyl, indanyl, tetrahydronaphthyl, and naphthyl. To saturated or unsaturated 2-or 3-ring fused hydrocarbon group with T in the general formula (1)¹The bonding position of (3) is not particularly limited.

The saturated or unsaturated 2-or 3-membered fused heterocyclic group is a 1-valent group formed from a saturated or unsaturated 2-or 3-membered fused heterocyclic ring shown in the following 1) to 3).

1) 2-3 homologous or heterologous saturated or unsaturated 5-7 membered heterocyclic rings are fused to form a 2-or 3-membered fused heterocyclic ring;

2) a 2-or 3-membered fused heterocyclic ring formed by fusing 1 to 2 saturated or unsaturated 5-to 7-membered heterocyclic rings and 1 to 2 saturated or unsaturated 5-to 6-membered cyclic hydrocarbons; and

3)2 saturated or unsaturated 5-7 membered heterocyclic rings and 1 saturated or unsaturated 5-6 membered cyclic hydrocarbon are fused to form a 3-membered fused heterocyclic ring.

T in the general formula (1) for the above saturated or unsaturated 2-or 3-ring fused heterocyclic group¹The bonding position of (3) is not particularly limited.

The saturated or unsaturated 5-to 7-membered heterocyclic ring represents a heterocyclic ring having at least 1 hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and specific examples thereof include furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazan, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine, oxadiazine, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazole, triazole, triazine, thiadiazine, oxadiazine, aza-nitrogenDiaza derivativesTriazaSulfur complexOxygen oxideThe saturated or unsaturated 5-to 6-membered cyclic hydrocarbon is the same compound as the saturated or unsaturated 5-to 6-membered cyclic hydrocarbon exemplified in the description of the saturated or unsaturated 2-or 3-membered fused hydrocarbon group. Specific examples of the saturated or unsaturated 2-or 3-membered fused heterocyclic group may include benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, indolyl, substituted or unsubstituted heteroaryl, Quinolyl, dihydroquinolyl, 4-oxodihydroquinolyl (dihydroquinolin-4-one), tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, chromenyl, chromanyl, isochromanyl, 4H-4-oxobenzopyranyl, 3, 4-dihydro-4H-4-oxobenzopyranyl, 4H-quinolizinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, tetrahydroquinoxalinyl, cinnolinyl, indolizinyl, tetrahydroindolizinyl, benzothiazolyl, tetrahydrobenzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, naphthyridinyl, tetrahydronaphthyridinyl, thienopyridyl, tetrahydrothienopyridyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl, quinoxalinyl, and a, Thiazolopyridazinyl, tetrahydrothiazolopyridazinyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, tetrahydropyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, pyridoquinazolinyl, dihydropyridinoquinazolinyl, pyridopyrimidinyl, tetrahydropyridopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl, furopyridinyl, tetrahydrofuropyridinyl, oxazolopyridinyl, tetrahydrooxazolopyridinyl, oxazolopyridazinyl, tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolinyl, thienopyrrolyl, thiazolopyrimidinyl, 4-oxotetrahydrocinnolinyl, 1, 2, 4-benzothiadiazinyl, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 1, 2, 4-benzoxazediinyl, cyclopentapyranyl, thienofuryl, furopyranyl, pyridooxazinyl, pyrazolooxazolyl, imidazothiazolyl, imidazopyridinyl, tetrahydroimidazopyridinyl, pyrazinopyridazinyl, benzisoquinolyl, furocinnolinyl, pyrazolothiazolopyridazinyl, tetrahydropyrazolothiazolopyridazinyl, hexahydrothiazolopyridazinyl, imidazotriazinyl, oxazolopyridyl, benzoxaxoxazinyl Radical, benzazepineTetrahydro benzazepineRadical, benzodiazepineRadical, benzotriazazepineAryl, thienoazaAryl, tetrahydrothienoazepineAryl, thienodiazepinesAryl, thienotriazaThiazolyl and thiazolyl azaTetrahydro-thiazoloazepineA 4, 5, 6, 7-tetrahydro-5, 6-tetramethylenethiazolopyridazinyl group, a 5, 6-trimethylene-4, 5, 6, 7-tetrahydrothiazolopyridazinyl group, or the like.

The condensed form of the condensed heterocyclic group is not particularly limited, and examples thereof include a naphthyridinyl group which may be any of 1, 5-, 1, 6-, 1, 7-, 1, 8-, 2, 6-or 2, 7-naphthyridinyl group, a thienopyridyl group which may be thieno [2, 3-b ] group]Pyridyl, thieno [2, 3-c ]]Pyridyl, thieno [3, 2-b ]]Pyridyl, thieno [3, 2-c]Pyridyl radicalThieno [3, 4-b ]]Pyridyl, thieno [3, 4-c]Any of the pyridyl groups, thienopyrrolyl, may be thieno [2, 3-b ]]Pyrrolyl, thieno [2, 3-b ]]Any of the pyrrolyl groups, thiazolopyridyl, may be thiazolo [4, 5-b ]]Pyridyl, thiazolo [4, 5-c ]]Pyridyl, thiazolo [5, 4-b ]]Pyridyl, thiazolo [5, 4-c ]]Pyridyl, thiazolo [3, 4-a ] ]Pyridyl, thiazolo [3, 2-a ]]Any of the pyridyl groups, thiazolopyridazinyl, may be thiazolo [4, 5-c ]]Pyridazinyl, thiazolo [4, 5-d ]]Pyridazinyl, thiazolo [5, 4-c ]]Pyridazinyl, thiazolo [3, 2-b ]]Any one of the pyridazinyl groups, pyrrolopyridinyl, may be pyrrolo [2, 3-b ]]Pyridyl, pyrrolo [2, 3-c]Pyridyl, pyrrolo [3, 2-b]Pyridyl, pyrrolo [3, 2-c]Pyridyl, pyrrolo [3, 4-b]Pyridyl, pyrrolo [3, 4-c]Any of the pyridyl groups, pyridopyrimidyl groups, can be pyrido [2, 3-d]Pyrimidinyl, pyrido [3, 2-d ]]Pyrimidinyl, pyrido [3, 4-d ]]Pyrimidinyl, pyrido [4, 3-d ]]Pyrimidinyl, pyrido [1, 2-c ]]Pyrimidinyl, pyrido [1, 2-a ]]Any one of pyrimidinyl, pyranothiazolyl, can be pyrano [2, 3-d ]]Thiazolyl, pyrano [4, 3-d ]]Thiazolyl, pyrano [3, 4-d ]]Thiazolyl, pyrano [3, 2-d ]]Any of the thiazolyl, furopyridinyl, may be furo [2, 3-b ]]Pyridyl, furo [2, 3-c ]]Pyridyl, furo [3, 2-b ]]Pyridyl, furo [3, 2-c ]]Pyridyl, furo [3, 4-b ]]Pyridyl, furo [3, 4-c ] ]Any of the pyridyl groups, oxazolopyridyl, may be oxazolo [4, 5-b]Pyridyl, oxazolo [4, 5-c]Pyridyl, oxazolo [5, 4-b]Pyridyl, oxazolo [5, 4-c)]Pyridyl, oxazolo [3, 4-a ]]Pyridyl, oxazolo [3, 2-a ] s]Any of the pyridyl groups, oxazolopyridazinyl, may be oxazolo [4, 5-c]Pyridazinyl, oxazolo [4, 5-d ]]Pyridazinyl, oxazolo [5, 4-c ]]Pyridazinyl, oxazolo [3, 4-b ]]Any one of the pyridazinyl groups, pyrrolothiazolyl, may be pyrrolo [2, 1-b ]]Thiazolyl, pyrrolo [1, 2-c ]]Thiazolyl, pyrrolo [2, 3-d ]]Thiazolyl, pyrrolo [3, 2-d ]]Thiazolyl, pyrrolo [3, 4-d ]]Any one of thiazolyl, pyrrolooxazolyl, may be pyrrolo [2, 1-b]Oxazolyl, pyrrolo [1, 2-c ] s]Oxazolyl, pyrrolo [2, 3-d]Oxazolyl, pyrrolo [3, 2-d]Oxazolyl, pyrrolo [3, 4-d]Any of oxazolyl, benzazepineThe radical may be 1H-1-benzazepine1H-2-benzazepine radical1H-3-benzazepine radicalAny of the radicals, 4, 5-dihydro-1-oxo-1H-2-benzazepineThe radicals being benzazepines of the dihydro-oxo derivative typeRadical, benzodiazepine The radical may be 1H-1, 3-benzodiazepineRadical, 1H-1, 4-benzodiazepinesRadical, 1H-1, 5-benzodiazepinesAny of the radicals, e.g. 4, 5-dihydro-4-oxo-1H-1, 3-benzodiazepineBenzodiazepines of the dihydro-oxo derivative typeRadical, benzotriazazepineThe radical may be 1H-1, 3, 4-benzotriazazepine1H-1, 3, 5-benzotriazazepineAny of the radicals, e.g. 4, 5-dihydro-5-oxo-1H-1, 3, 4-benzotriazaRadicals, which may be benzotriazazepines of the dihydro-oxo derivative typeAryl, thienoazaA group which may be thieno [2, 3-b ]]Aza derivativesAlkyl, thieno [2, 3-c ]]Aza derivativesAlkyl, thieno [2, 3-d ]]Aza derivativesAlkyl, thieno [3, 2-c]Aza derivativesAlkyl, thieno [3, 2-b ]]Aza derivativesAny of the radicals, e.g. 5, 6, 7, 8-tetrahydro-4-oxo-4H-thieno [3, 2-c]Aza derivativesBy radicals, which may be thienoazepines of the dihydro-oxo derivative typeRadical, thienodiazepineAryl or thienotriazaThe radicals may likewise be any of the condensed types, or may be of the dihydro-oxo derivative type, benzothioxaThe radical may be 1H-1-benzothiepin1H-2-benzothiepins1H-3-benzothiepins Any of the radicals, e.g. 4, 5-dihydro-1-oxo-1H-2-benzothioxaThe radicals, being benzothioxas, being of the dihydro-oxo derivative typeRadical, benzoxaThe radical may be 1H-1-benzoxaxolRadical, 1H-2-benzoxaxolRadical, 1H-3-benzoxaxolAny of the radicals, e.g. 4, 5-dihydro-1-oxo-1H-2-benzoxaxolThe radicals being benzoxas of the dihydro-oxo derivative typeThe groups may be in forms other than these fused forms.

The above-mentioned aryl group, heteroaryl group, arylalkenyl group, heteroarylalkenyl group, saturated or unsaturated 2-or 3-membered fused hydrocarbon group and saturated or unsaturated 2-or 3-membered fused heterocyclic group may each have 1 to 3 substituents, which may, for example, be a halogen atom such as a hydroxyl group, fluorine atom, chlorine atom, bromine atom and iodine atom, a haloalkyl group having 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, an amino group, a cyano group, an aminoalkyl group, a nitro group, a hydroxyalkyl group (e.g., hydroxymethyl group, 2-hydroxyethyl group and the like), an alkoxyalkyl group (e.g., methoxymethyl group, 2-methoxyethyl group and the like), a carboxyl group, a carboxyalkyl group (e.g., carboxymethyl group, 2-carboxyethyl group and the like), an alkoxycarbonylalkyl group (e.g., methoxycarbonylmethyl group, ethoxycarbonylmethyl group and the like), an acyl group (e.g., formyl group, Alkanoyl groups such as acetyl group and 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 or ethyl group), linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms (for example, methoxy group or ethoxy group), linear, branched or cyclic amidino group substituted with alkyl group having 1 to 6 carbon atoms (for example, imino (methylamino) methyl group or the like), linear, branched or cyclic amidino group substituted with alkoxy group having 1 to 6 carbon atoms (for example, amino (methoxyimino) methyl group or the like), linear, branched or cyclic amidino group substituted with alkoxycarbonyl group having 2 to 7 carbon atoms (for example, amino (methoxycarbonylimino) methyl group, amino (ethoxycarbonylimino) methyl group or the like), a linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms (e.g., vinyl, allyl, etc.), a linear or branched alkynyl group having 2 to 6 carbon atoms (e.g., ethynyl, propynyl, etc.), a linear, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), a carbamoyl group, a mono-or dialkylcarbamoyl group substituted with a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, ethylmethylcarbamoyl, etc.), a mono-or dialkylamino group substituted with a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (e.g., ethylamino, dimethylamino, methylethylamino), and a 5 to 6-membered nitrogen-containing heterocyclic group (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like).

Group Q represented by the above group⁴Of these, the following 12 groups (a) to (1) are preferred. That is, preferred groups are exemplified by

[ in the group, R⁵And R⁶Each independently represents a hydrogen atom, a cyano group, a halogen atom, an alkyl group, a hydroxyalkyl group, an alkoxy group, an alkoxyalkyl group, a carboxyl group, a carboxyalkyl group, an acyl group, an alkoxy groupAlkylcarbonyl, alkoxycarbonylalkyl or phenyl which may be substituted by cyano, hydroxy, halogen, alkyl or alkoxy, R⁷And R⁸Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group]，

[ in the group, R⁹And R¹⁰Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group ]，

[ in the group, R¹¹、R¹²And R¹³Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group]，

[ in the group, X¹Represents CH₂CH, NH, NOH, N, O or S, R¹⁴、R¹⁵And R¹⁶Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group]，

[ in the group, X²Represents NH, N, O or S, X³Denotes N, C or CH, X⁴Denotes N, C or CH, R¹⁷And R¹⁸Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, X ³And X⁴In the case of a combination of C and CH and in the case of C or CH]，

[ in the group, N represents R¹⁹1 or 2 of the carbon atoms of the substituted ring being substituted by nitrogen atoms, R¹⁹、R²⁰And R²¹Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group]，

[ in the group, X⁵Represents CH₂CH, N or NH, Z1 represents N, NH or O, Z²Represents CH₂CH, C or N, Z³Represents CH₂、CH、S、SO₂Or C ═ O, X⁵-Z²Represents X⁵And Z²By a single or double bond, R²²And R²³Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, R²⁴Represents a hydrogen atom or an alkyl group]，

[ in the group, X⁶Represents O or S, R²⁵And R ²⁶Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group]，

[ in the group, R²⁷And R²⁸Each independently represents a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkaneAlkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, carboxyl, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N-dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkyl]，

[ group, E¹And E²Each independently represents N or CH, R²⁹And R³⁰Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group ]，

[ in the group, Y¹Represents CH or N, Y²represents-N (R)³³) - (in the radical, R)³³Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), O or S, R³¹And R³²Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group]And the following groups

[ groupWherein 1 to 8 are each a number representing a position, each of N represents any one of 1 to 4 carbon atoms and any one of 5 to 8 carbon atoms is substituted by 1 nitrogen atom, and R is³⁴、R³⁵And R³⁶Each independently represents 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, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkylalkyl group]。

These groups are described below.

R in the above radicals⁵～R³⁶Wherein the halogen atom in the description represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, the alkyl group represents a linear, branched or cyclic group having 1 to 6 carbon atoms, the alkenyl group represents a linear, branched or cyclic group having 2 to 6 carbon atoms, the alkynyl group represents a linear or branched group having 2 to 6 carbon atoms, and the hydroxyalkyl group represents the C-atom ₁～C₆Alkyl is a group substituted with 1 hydroxyl group, alkoxy represents a linear, branched or cyclic group having 1 to 6 carbon atoms, and alkoxyalkyl represents the above-mentioned C₁～C₆Alkyl having 1 of the above-mentioned C₁～C₆Alkoxy-substituted radical, carboxyalkyl representing the above-mentioned C₁～C₆Alkyl is substituted by 1 carboxyl, acyl represents C1-6 alkanoyl (including formyl), benzoyl or naphthoyl, or C₁～C₆Alkanoyl having the above-mentioned C₆～C₁₄Aryl-substituted arylalkanoyl, N-alkylcarbamoyl representing the above-mentioned C₁～C₆Carbamoyl substituted by alkyl on the nitrogen atom, N, N-dialkylcarbamoyl representing 2 of the above-mentioned C₁～C₆Carbamoyl substituted by alkyl on the nitrogen atom, alkoxycarbonyl represented by the above-mentioned group C₁～C₆Alkoxy and carbonyl, alkoxycarbonylalkyl representing C₁～C₆Alkyl having 1 of the above-mentioned C₁～C₆Alkoxycarbonyl-substituted radical, haloalkyl representing the above-mentioned C₁～C₆The alkyl group has 1 to 3 halogen atom-substituted groups. In the above description, the substitution position is not particularly limited.

The following groups

[ in the group, R⁵、R⁶、R⁷、R⁸As mentioned above, the numbers 1-6 represent positions]Wherein R is⁵And R⁶Each independently preferably represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. R ⁵And R⁶More preferably a hydrogen atom or an alkyl group, and in the case of an alkyl group, a methyl group is more preferred. R⁷And R⁸One 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 halogenated alkyl 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 preferably an ethynyl group. Specific examples of the group represented by the above formula include chlorostyryl, fluorostyryl, bromostyryl, ethynylstyryl and the like, and the substitution position of the halogen atom, alkyl or alkynyl in these groups is not particularly limited, but the 4-position in the above formula is particularly preferable, and specific examples include 4-chlorostyryl, 4-fluorostyryl, 4-bromostyryl, 4-ethynylstyryl and the like.

The following groups

[ in the group, R⁹And R¹⁰As mentioned above, the number of 1 ~ 6 represents the bitDevice for placing]Wherein R is⁹And R¹⁰Each independently preferably represents a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. More preferably R⁹Is a hydrogen atom, R¹⁰Is 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 preferably an ethynyl group. Specific examples of the group represented by the above formula may include chlorophenylethynyl, fluorophenylethynyl, bromophenylethynyl and ethynylphenylethynyl groups, and the substitution position of the halogen atom, alkyl group or alkynyl group in these groups is not particularly limited, but the 4-position in the above formula is particularly preferable, and specific examples may include 4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl and 4-ethynylphenylethynyl groups.

The following groups

[ in the group, R¹¹、R¹²And R¹³As mentioned above, the numbers 1-8 represent positions]Wherein R is¹¹、R¹²And R¹³Each independently preferably represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. R¹¹More preferred are a hydrogen atom, an alkyl group, a halogen atom and a hydroxyl group, and particularly preferred is a hydrogen atom. R¹²And R¹³More preferably, one is a hydrogen atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably, the other is a hydrogen atom, halogen atom, alkyl group or 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, 2-naphthyl is more preferable than 1-naphthyl, and in the case of 2-naphthyl, the position of substitution with a halogen atom, alkyl group or alkynyl group is not particularly limited, but is preferably the 6-position or 7-position in the above formula, and most preferably the 6-position. More preferably, these naphthyl groups are substituted with a chlorine atom, a fluorine atom, a bromine atom, an alkynyl group or the likeThe group (b) is particularly preferably a group substituted with a chlorine atom, fluorine atom, bromine atom, alkynyl group or the like. Specific preferable examples thereof include 6-chloro-2-naphthyl, 6-fluoro-2-naphthyl, 6-bromo-2-naphthyl, 6-ethynyl-2-naphthyl, 7-chloro-2-naphthyl, 7-fluoro-2-naphthyl, 7-bromo-2-naphthyl and 7-ethynyl-2-naphthyl.

The following groups

[ in the group, X¹、R¹⁴、R¹⁵And R¹⁶As mentioned above, the numbers of 4-7 represent positions]Wherein X is¹NH, NOH, N, O and S are preferred, and NH, O and S are more preferred. R¹⁴Preferred are a hydrogen atom, a halogen atom, an acyl group, an N-alkylcarbamoyl group, an N, N-dialkylcarbamoyl group, an alkyl group, R¹⁵And R¹⁶Each independently preferably represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. R¹⁵And R¹⁶In this case, one is preferably 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 halogenated alkyl group, particularly preferably 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 preferably an ethynyl group. The substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, and is preferably the 4-, 5-or 6-position in the above formula. Specific examples of the group represented by the above formula may include 5-chloroindolyl, 5-fluoroindolyl, 5-bromoindolyl, 5-ethynylindolyl, 5-methylindolyl, 5-chloro-4-fluoroindolyl, 5-chloro-3-fluoroindolyl and 5-fluoro-3-chloroindolyl, 5-ethynyl-3-fluoroindolyl, 5-chloro-3- (N, N-dimethylcarbamoyl) indolyl, 5-fluoro-3- (N, N-dimethylcarbamoyl) indolyl, 5-chloro-3-formylindolyl, 5-fluoro-3-formylindolyl, 6-chloroindolyl, 6-fluoroindolyl, 6-bromoindolyl. 6-ethynylindolyl, 6-methylindolyl, 5-chlorobenzothienyl, 5-fluorobenzothienyl, 5-bromobenzothiophenyl, 5-ethynylbenzothiophenyl, 5-methylbenzothienyl, 5-chloro-4-fluorobenzothienyl, 6-chlorobenzothienyl, 6-fluorobenzothienyl, 6-bromobenzothiophenyl, 6-ethynylbenzothiophenyl, 6-methylbenzothienyl, 5-chlorobenzofuranyl, 5-fluorobenzofuranyl, 5-bromobenzofuranyl, 5-ethynylbenzofuranyl, 5-methylbenzofuranyl, 5-chloro-4-fluorobenzofuranyl, 6-chlorobenzofuranyl, 6-fluorobenzofuranyl, 6-bromobenzofuranyl, 6-ethynylbenzofuranyl, 6-methylbenzofuranyl and the like. For these substituents and T¹The binding position of (d) is not particularly limited, but it is preferably the 2-position or 3-position in the above formula (d), and specifically, it may, for example, be 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, etc, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-bromo-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-ethynyl-3- (N, n-dimethylcarbamoyl) indol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chloroindol-3-yl, 5-fluoroindol-3-yl, 5-bromoindol-3-yl, 5-ethynylindol-3-yl, 5-methylindol-3-yl, 5-chloro-4-fluoroindol-3-yl, 6-chloroindol-3-yl, 6-fluoroindol-3-yl, 6-bromoindol-3-yl, 6-chloroindol-2-yl, 6-fluoroindol-3-yl, 6-bromoindol-3-yl, 6-chloroindol-2-yl, 6-chloroindol-, 6-ethynylindol-3-yl, 6-methylindol-3-yl, 5-chlorobenzothien-2-yl, 5-fluorobenzothien-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothien-2-yl, 5-methylbenzothien-2-yl, 5-chloro-4-fluorobenzothien-2-yl, 6-chlorobenzothien-2-yl, 6-fluorobenzothien-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothien-2-yl, 6-methylbenzothien-2-yl, 5-chlorobenzothien-2-yl Benzothien-3-yl, 5-fluorobenzothien-3-yl, 5-bromobenzothiophen-3-yl, 5-ethynylbenzothien-3-yl, 5-methylbenzothien-3-yl, 5-chloro-4-fluorobenzothien-3-yl, 6-chlorobenzothien-3-yl, 6-fluorobenzothien-3-yl, 6-bromobenzothiophen-3-yl, 6-ethynylbenzothien-3-yl, 6-methylbenzothien-3-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromobenzofuran-3-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl, 5-chlorobenzofuran-3-yl, 5-fluorobenzofuran-3-yl, 5-bromobenzofuran-3-yl, 5-ethynylbenzofuran-3-yl, 5-methylbenzofuran-3-yl, 5-chloro-4-fluorobenzofuran-3-yl, 6-chlorobenzofuran-3-yl, 6-fluorobenzofuran-3-yl, 6-bromobenzofuran-3-yl, 6-ethynylbenzofuran-3-yl, 6-methylbenzofuran-3-yl and the like; particularly preferred are 5-chloroindol-2-yl, 5-fluoroindol-2-yl, 5-bromoindol-2-yl, 5-ethynylindol-2-yl, 5-methylindol-2-yl, 5-chloro-4-fluoroindol-2-yl, 6-chloroindol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5-chloro-3-fluoroindol-2-yl, 3-bromo-5-chloroindol-2-yl, 3-chloro-5-fluoroindol-2-yl, 3-bromo-5-fluoroindol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formylindol-2-yl, 5-bromo-3-formylindol-2-yl, 5-ethynyl-3-formylindol-2-yl, 5-chloro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-fluoro-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-bromo-3- (N, n-dimethylcarbamoyl) indol-2-yl, 5-ethynyl-3- (N, N-dimethylcarbamoyl) indol-2-yl, 5-chlorobenzothien-2-yl, 5-fluorobenzothien-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothien-2-yl, 5-methylbenzothien-2-yl, 5-chloro-4-fluorobenzothien-2-yl, 6-chlorobenzothien-2-yl, 6-fluorobenzothien-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothien-2-yl, m, 6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran Pyran-2-yl, 5-bromobenzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chlorobenzofuran-2-yl, 6-fluorobenzofuran-2-yl, 6-bromobenzofuran-2-yl, 6-ethynylbenzofuran-2-yl, 6-methylbenzofuran-2-yl.

The following groups

[ in the group, X²、X³、X⁴、R¹⁷And R¹⁸As mentioned above, the numbers of 4-7 represent positions]Wherein X is²Preferably NH, O or S, X³And X⁴One of them is preferably CH or C, and particularly preferably one is C. R¹⁷And R¹⁸Each independently preferably represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. R¹⁷And R¹⁸One is preferably a hydrogen atom, and the other is preferably a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably a hydrogen atom, halogen atom, alkyl group or 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 of substitution with the halogen atom, alkyl group or alkynyl group is not particularly limited, and is preferably the 5-position or 6-position in the above formula. Preferred examples of the specific group represented by the above formula include 5-chloroindazolyl, 5-fluoroindazolyl, 5-bromoindazolyl, 5-ethynylindazolyl, 6-chloroindazolyl, 6-fluoroindazolyl, 6-bromoindazolyl, 6-ethynylindazolyl, 5-chlorobenzimidazolyl, 5-fluorobenzimidazolyl, 5-bromobenzimidazolyl, 5-ethynylbenzimidazolyl, 6-chlorobenzimidazolyl, 6-fluorobenzimidazolyl, 6-bromobenzimidazolyl, 6-ethynylbenzimidazolyl, 5-chlorobenzothiazolyl, 5-fluorobenzothiazolyl, 5-bromobenzothiazolyl, 5-ethynylbenzothiazolyl, 6-chlorobenzothiazolyl, 6-fluorobenzothiazolyl, 6-bromobenzothiazolyl, 6-ethynylbenzothiazolyl, 5-chlorobenzoxazolyl, 5-fluorobenzooxazolyl, 5-bromobenzooxazolyl, 5-ethynylbenzoxazolyl, 6-chlorobenzoxazolyl, 6-fluorobenzooxazolyl, 6-bromobenzooxazolyl, 6-ethynylbenzoxazolyl, 5-chlorobenzoisothiazolyl, 5-fluorobenzoisothiazolyl, 5-bromobenzoisothiazolyl, 5-ethynylbenzisothiazolyl, 6-chlorobenzoisothiazolyl, 6-fluorobenzoisothiazolyl, 6-bromobenzoisothiazolyl, 6-ethynylbenzisothiazolyl, 5-chlorobenzoisoxazolyl, 5-fluorobenzoisoxazolyl, 5-bromobenzoisoxazolyl, 5-ethynylbenzisoxazolyl, 6-chlorobenzoisoxazolyl, 6-fluorobenzoisoxazolyl, 6-bromobenzoisoxazolyl, 6-ethynylbenzisoxazolyl and the like, and the substituents and T¹The binding position of (A) is not particularly limited, but preferred examples thereof include 5-chloroindazol-3-yl, 5-fluoroindazol-3-yl, 5-bromoindazol-3-yl, 5-ethynylindazol-3-yl, 6-chloroindazol-3-yl, 6-fluoroindazol-3-yl, 6-bromoindazol-3-yl, 6-ethynylindazol-3-yl, 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chlorobenzimidazol-3-yl, 5-fluorobenzimidazol-3-yl, 5-fluoroindazol, 6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl, 5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl, 5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl, 6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl, 6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl, 5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl, 5-bromobenzooxazol-2-yl, 5-ethynylbenzoxazol-2-yl, 5-ethynylbenzimidazol-2-yl, 5-chlorobenzothiazol-2-yl, 5-chlorobenzothia, 6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl, 6-bromobenzooxazol-2-yl, 6-ethynylbenzoxazol-2-yl, 5-chlorobenzoisothiazol-3-yl, 5-fluorobenzoisothiazol-3-yl, 5-bromobenzoisothiazol-3-yl, 5-ethynylbenzisothiazol-3-yl, 6-chlorobenzoisothiazol-3-yl, 6-fluorobenzoisothiazol-3-yl, 6-bromobenzoisothiazol-3-yl, 6-ethynylbenzisothiazol-3-yl, 5-chlorobenzoisothiazol-3-yl, 5-fluorobenzoisoxazol-3-yl, 3-yl, 5-bromobenzisoxazol-3-yl, 5-ethynylbenzisoxazol-3-yl, 6-chlorobenzoisoxazol-3-yl, 6-fluorobenzoisoxazol-3-yl, 6-bromobenzisoxazol-3-yl, 6-ethynylbenzisoxazol-3-yl, particularly preferred Is 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl, 6-chlorobenzimidazol-2-yl, 6-fluorobenzimidazol-2-yl, 6-bromobenzimidazol-2-yl, 6-ethynylbenzimidazol-2-yl, 5-chlorobenzothiazol-2-yl, 5-fluorobenzothiazol-2-yl, 5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl, 6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl, 5-bromobenzothiazol-2-yl, 5-ethynylbenzothiazol-2-yl, 6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl, 6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2-yl, 5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl, 5-bromobenzooxazol-2-yl, 5-ethynylbenzoxazol-2-yl, 6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl, 6-bromobenzooxazol-2-yl, 6-ethynylbenzoxazol-2-yl, most preferred are 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazol-2-yl, 5-ethynylbenzimidazol-2-yl.

The following groups

[ in the group, N represents R¹⁹1 or 2 of the carbon atoms of the substituted ring being substituted by nitrogen atoms, R¹⁹、R²⁰And R²¹As mentioned above, the numbers of 5 ~ 8 represent the position]Wherein R is¹⁹、R²⁰And R²¹Each independently preferably represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. R ¹⁹Particularly preferably a hydrogen atom, R²⁰And R²¹One is preferably a hydrogen atom, and the other is preferably a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably a hydrogen atom, halogen atom, alkyl group or alkynyl group. In this case, the halogen atom is 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 substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, and is preferably the 6-position or 7-position in the above formula. Specific examples of the group represented by the above formula include quinolyl, isoquinolyl and cinnolinyl, and 6-chloroquinoline is preferredA group such as a phenyl group, a 6-fluoroquinolyl group, a 6-bromoquinolyl group, a 6-ethynylquinolyl group, a 6-chloroisoquinolyl group, a 6-fluoroisoquinolyl group, a 6-bromoisoquinolyl group, a 6-ethynylisoquinolyl group, a 7-chlorocinnolinyl group, a 7-fluorocinnolinyl group, a 7-bromocinnolinyl group, and a 7-ethynylcinnolinyl group. Particularly preferred are 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 6-chloroquinolin-3-yl, 6-fluoroquinolin-3-yl, 6-bromoquinolin-3-yl, 6-ethynylquinolin-3-yl, 7-chloroquinolin-2-yl, 7-fluoroquinolin-2-yl, 7-bromoquinolin-2-yl, 7-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-bromoquinolin-2-yl, 6-bromoquinolin-3-, 6-chloroisoquinolin-3-yl, 6-fluoroisoquinolin-3-yl, 6-bromoisoquinolin-3-yl, 6-ethynylisoquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 7-ethynylcinnolin-3-yl and the like. Among them, the most preferable are 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 7-bromoisoquinolin-3-yl, 7-ethynylisoquinolin-3-yl, 7-chlorocinnolin-3-yl, 7-fluorocinnolin-3-yl, 7-bromocinnolin-3-yl, 7-ethynylcinnolin-3-yl.

The following groups

In the [ base, the number of 5 to 8 represents the position, X⁵Represents CH₂CH, N or NH, Z1 represents N, NH or O, Z²Represents CH₂CH, C or N, Z³Represents CH₂、CH、S、SO₂Or C ═ O, X⁵-Z²Represents X⁵And Z²By a single or double bond, R²²、R²³And R²⁴As described above]Wherein R is²²And R²³Independently of one another, preferably hydrogen atom, cyanogenA halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group. R²²And R²³One is preferably a hydrogen atom, and the other is preferably a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably a hydrogen atom, halogen atom, alkyl group or alkynyl group. In this case, the halogen atom is 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 substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, and is preferably the 6-position or 7-position in the above formula. R²⁴A hydrogen atom or an alkyl group is preferred, and a methyl group is preferred as the alkyl group. R²⁴Particularly preferred is a hydrogen atom. Specific examples of the group represented by the above formula include 4-oxodihydroquinolinyl, tetrahydroquinolinyl, 4-oxodihydroquinazolin-2-yl, 4-oxotetrahydrocinnolinyl, 4-oxobenzopyranyl, 4-oxobenzothiadiazinyl, 1-dioxido-4-oxobenzothiadiazinyl, and benzoxazadiazinyl. More specific examples of the group include 6-chloro-4-oxodihydroquinolinyl, 6-fluoro-4-oxodihydroquinolinyl, 6-bromo-4-oxodihydroquinolinyl, 6-ethynyl-4-oxodihydroquinolinyl, 7-chloro-4-oxodihydroquinolinyl, 7-fluoro-4-oxodihydroquinolinyl, 7-bromo-4-oxodihydroquinolinyl, 7-ethynyl-4-oxodihydroquinolinyl, 6-chloro-4-oxo-1, 4-dihydroquinazolinyl, 6-fluoro-4-oxo-1, 4-dihydroquinazolinyl, 6-bromo-4-oxo-1, 4-dihydroquinazolinyl, and the like, 6-ethynyl-4-oxo-1, 4-dihydroquinazolinyl, 7-chloro-4-oxo-1, 4-dihydroquinazolinyl, 7-fluoro-4-oxo-1, 4-dihydroquinazolinyl, 7-bromo-4-oxo-1, 4-dihydroquinazolinyl, 7-ethynyl-4-oxo-1, 4-dihydroquinazolinyl, 6-chloro-1, 2, 3, 4-tetrahydroquinolinyl, 6-fluoro-1, 2, 3, 4-tetrahydroquinolinyl, 6-bromo-1, 2, 3, 4-tetrahydroquinolinyl, 6-ethynyl-1, 2, 3, 4-tetrahydroquinolinyl, 7-chloro-1, 2, 3, 4-tetrahydroquinolyl, 7-fluoro-1, 2, 3, 4-tetrahydroquinolyl, 7-bromo-1, 2, 3, 4-tetrahydroquinolyl, 7-ethynyl-1, 2, 3, 4-tetrahydroquinolyl, 6-chloro-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 7-chloro-1, 2, 3, 4-tetra-tetrahydrocinnolinyl Hydrogen-4-oxocinnolinyl, 7-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 7-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 7-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolinyl, 6-chloro-4H-4-oxobenzopyranyl, 6-fluoro-4H-4-oxobenzopyranyl, 6-bromo-4H-4-oxobenzopyranyl, 6-ethynyl-4H-4-oxobenzopyranyl, 7-chloro-4H-4-oxobenzopyranyl, 7-fluoro-4H-4-oxobenzopyranyl, 7-bromo-4H-4-oxobenzopyranyl, 7-ethynyl-4H-4-oxobenzopyranyl, 6-chloro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 6-fluoro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 6-bromo-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 6-ethynyl-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 7-chloro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 7-fluoro-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 7-bromo-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 7-ethynyl-1, 1-dioxo-2H-1, 2, 4-benzothiadiazinyl, 6-chloro-2H-1, 2, 4-benzoxazodiazinyl, 6-fluoro-2H-1, 2, 4-benzoxazodiazinyl, 6-bromo-2H-1, 2, 4-benzoxazodiazinyl, 6-ethynyl-2H-1, 2, 4-benzoxazodiazinyl, 7-chloro-2H-1, 2, 4-benzodioxazinyl, 7-fluoro-2H-1, 2, 4-benzoxazediyl, 7-bromo-2H-1, 2, 4-benzoxazediyl, 7-ethynyl-2H-1, 2, 4-benzoxazediyl, and the like. Particularly preferred are 6-chloro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinolin-2-yl, 6-ethynyl-4-oxo-1, 4-dihydroquinolin-2-yl, 7-chloro-4-oxo-1, 4-dihydroquinolin-2-yl, 7-fluoro-4-oxo-1, 4-dihydroquinolin-2-yl, 7-bromo-4-oxo-1, 4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydro, 7-ethynyl-4-oxo-1, 4-dihydroquinolin-2-yl, 6-chloro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-ethynyl-4-oxo-1, 4-dihydroquinazolin-2-yl, 7-chloro-4-oxo-1, 4-dihydroquinazolin-2-yl, 7-fluoro-4-oxo-1, 4-dihydroquinazolin-2-yl, 4-fluoro-1, 4-dihydroquinazolin-2-yl, and pharmaceutically acceptable salts thereof, 7-bromo-4-oxo-1, 4-dihydroquinazolin-2-yl, 7-ethynyl-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-chloro-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-fluoro-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-bromo-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-ethynyl-1, 2, 3, 4-tetrahydroquinolin-2-yl, 6-chloro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-chloro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-fluoro-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-bromo-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 7-ethynyl-1, 2, 3, 4-tetrahydro-4-oxocinnolin-2-yl, 6-chloro-4H-4-oxochromen-2-yl, 6-fluoro-4H-4-oxochromen-2-yl, 6-bromo-4H-4-oxochromen-2-yl, 6-ethynyl-4H-4-oxochromen-2-yl, 2-fluoro-4H-oxochromen-2-yl, 7-chloro-4H-4-oxochromen-2-yl, 7-fluoro-4H-4-oxochromen-2-yl, 7-bromo-4H-4-oxochromen-2-yl, 7-ethynyl-4H-4-oxochromen-2-yl, 6-chloro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-fluoro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-bromo-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-ethynyl-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-chloro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-fluoro-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-bromo-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 7-ethynyl-1, 1-dioxido-2H-1, 2, 4-benzothiadiazin-3-yl, 6-chloro-2H-1, 2, 4-benzothiadiazin-3-yl, 6-fluoro-2H-1, 2, 4-benzoxadiazin-3-yl, 6-bromo-2H-1, 2, 4-benzoxadiazin-3-yl, 6-ethynyl-2H-1, 2, 4-benzoxadiazin-3-yl, 7-chloro-2H-1, 2, 4-benzoxadiazin-3-yl, 7-fluoro-2H-1, 2, 4-benzoxadiazin-3-yl, 7-bromo-2H-1, 2, 4-benzoxadiazin-3-yl, 7-ethynyl-2H-1, 2, 4-benzoxadiazin-3-yl, and the like. Of these, the most preferable are 6-chloro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinolin-2-yl, 6-ethynyl-4-oxo-1, 4-dihydroquinolin-2-yl, 6-chloro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-fluoro-4-oxo-1, 4-dihydroquinazolin-2-yl, 6-bromo-4-oxo-1, 4-dihydroquinazolin-2-yl, and the like, 6-ethynyl-4-oxo-1, 4-dihydroquinazol -an-lin-2-yl group.

The following groups

[ in the group, X⁶Represents O or S, R²⁵And R²⁶As mentioned above, the numbers of 5 ~ 8 represent the position]Wherein X is⁶Preferably O, R²⁵And R²⁶Each independently preferably represents a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group. R²⁵And R²⁶One is preferably a hydrogen atom, and the other is preferably a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably a hydrogen atom, halogen atom, alkyl group or alkynyl group. In this case, the halogen atom is 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 substitution position of the halogen atom, alkyl group or alkynyl group is not particularly limited, and is preferably the 6-position or 7-position in the above formula. Specific examples of the group include 6-chloro-2H-chromen-3-yl, 6-fluoro-2H-chromen-3-yl, 6-bromo-2H-chromen-3-yl, 6-ethynyl-2H-chromen-3-yl, 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl. Particularly preferred are 7-chloro-2H-chromen-3-yl, 7-fluoro-2H-chromen-3-yl, 7-bromo-2H-chromen-3-yl and 7-ethynyl-2H-chromen-3-yl groups.

The following groups

[ in the group, R²⁷And R ²⁸As mentioned above, the numbers 1-6 represent positions]Wherein R is²⁷And R²⁸It is preferred that one is a hydrogen atom or a halogen atom and the other is a hydrogen atom, cyano group, nitro group, amino group, halogen atom, alkyl group, alkenyl group, alkynyl group, halogenoalkyl group or N, N-di-alkyl groupAmong these, particularly preferred is an alkylcarbamoyl group, the other of which is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. In this case, the halogen atom is 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. Specific examples of the group represented by the above formula may include phenyl, chlorophenyl, fluorophenyl, bromophenyl, ethynylphenyl, chlorophenyl and the like, and the position of substitution with a halogen atom, alkyl group or alkynyl group in these groups is not particularly limited, and when the number of the substituents is 1, the 3-position and the 4-position in the above formula are particularly preferred, and when the number of the substituents is 2, the combination of the 4-position and the 2-position or the 3-position in the above formula is particularly preferred. Specific examples thereof may include phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-ethynylphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-bromophenyl, 3-ethynylphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 2, 4-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-dibromophenyl, 4-chloro-3-methylphenyl, 4-fluoro-3-methylphenyl, 4-bromo-3-methylphenyl, 4-ethynylphenyl, 3-chlorophenyl, 4-bromophenyl, 4-ethynylphenyl, 3-chlorophenyl, 4-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-bromo-2-methylphenyl, 3, 4-dichlorophenyl, 3, 4-difluorophenyl, 3, 4-dibromophenyl.

The following groups

[ group, E¹、E²、R²⁹And R³⁰As mentioned above, the numbers 1-6 represent positions]Wherein R is²⁹And R³⁰One is preferably a hydrogen atom or a halogen atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably the other is a hydrogen atom, halogen atom, alkyl group or alkynyl group. In this case, the halogen atom is 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. Specific examples of the group represented by the above formula include pyridyl, pyrimidyl and pyridazinyl, and halogen atom, alkyl and alkyne in these groupsThe substitution position of the group is not particularly limited, and the group T¹When the above-mentioned (B) is bonded to the 2-position in the above-mentioned formula, particularly preferred are the 4-position and the 5-position in the above-mentioned formula. Specific preferable examples thereof may include 2-pyridyl, 3-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 4-chloro-3-pyridyl, 4-ethynyl-2-pyridyl, and the like, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 5-chloro-2-pyrimidinyl, 5-fluoro-2-pyrimidinyl, 5-bromo-2-pyrimidinyl, 5-ethynyl-2-pyrimidinyl, 4-chloro-3-pyridazinyl, 4-fluoro-3-pyridazinyl, 4-bromo-3-pyridazinyl, 4-ethynyl-3-pyridazinyl, 6-chloro-3-pyridazinyl, 6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl, 6-ethynyl-3-pyridazinyl and the like. Particularly preferred are 2-pyridyl, 3-pyridyl, 4-chloro-2-pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-pyridyl, 4-ethynyl-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-3-pyridyl, 4-bromo-3-pyridyl, 4-ethynyl-3-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 4-chloro-3-pyridyl, 4-fluoro-2-pyridyl, and the like, 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-pyridazinyl group. Among them, preferred is 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 4-chloro-3-pyridazinyl, 4-fluoro-3-pyridazinyl, 4-bromo-3-pyridazinyl, 4-ethynyl-3-pyridazinyl.

Further, the following groups

[ in the group, Y¹、Y²、R³¹And R³²As mentioned above, the numbers 1-5 represent positions]Wherein R is³¹And R³²One is preferably a hydrogen atom or a halogen atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably the other is a hydrogen atom, halogen atom, alkyl group or alkynyl group. In this case, the halogen atom is 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. Specific examples of the group represented by the above formula include thienyl, pyrrolyl, furyl, oxazolyl and thiazolyl, and the substitution position of the halogen atom, alkyl or alkynyl in these groups is not particularly limited, and particularly preferred are the 4-position and the 5-position in the above formula. Specifically, it may be mentioned 4-chloro-2-thienyl, 4-fluoro-2-thienyl, 4-bromo-2-thienyl, 4-ethynyl-2-thienyl, 4-chloro-2-pyrrolyl, 4-fluoro-2-pyrrolyl, 4-bromo-2-pyrrolyl, 4-ethynyl-2-pyrrolyl, 4-chloro-2-furyl, 4-fluoro-2-furyl, 4-bromo-2-furyl, 4-ethynyl-2-furyl, 5-chloro-2-thienyl, 5-fluoro-2-thienyl, 5-bromo-2-thienyl, 5-ethynyl-2-thienyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl, 5-ethynyl-2-thiazolyl, 5-chloro-2-oxazolyl, 5-fluoro-2-oxazolyl, 5-bromo-2-oxazolyl, 5-ethynyl-2-oxazolyl, and the like. Particularly preferred are 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl, and 5-ethynyl-2-thiazolyl groups.

The following groups

In the [ radical, the number of 1 to 8 represents a position, each N represents any one of carbon atoms of 1 to 4 and any one of carbon atoms of 5 to 8 is substituted by 1 nitrogen atom, R³⁴～R³⁶As described above]Wherein each nitrogen atom may be in any position, R³⁴Preferably a hydrogen atom or a halogen atom, R³⁵And R³⁶One is preferably a hydrogen atom or a halogen atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group or halogenoalkyl group, and particularly preferably the other is a hydrogen atom, halogen atom, alkyl group or 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 preferably an ethynyl group. The position of substitution with a halogen atom, an alkyl group or an alkynyl group is not particularly limited, and specific examples of the group represented by the above formula include 6-chloro-1, 5-naphthyridin-2-yl, 6-fluoro-1, 5-naphthyridin-2-yl, 6-bromo-1, 5-naphthyridin-2-yl, 6-ethynyl-1, 5-naphthyridin-2-yl, 7-chloro-1, 5-naphthyridin-2-yl, 7-fluoro-1, 5-naphthyridin-2-yl, 7-bromo-1, 5-naphthyridin-2-yl, 7-ethynyl-1, 5-naphthyridin-2-yl, 6-chloro-1, 5-naphthyridin-3-yl, 6-bromo-1, 5-naphthyridin-3-yl, 6-fluoro-1, 5-naphthyridin-3-yl, 6-bromo-1, 5-naphthyridin-3-yl, 6-ethynyl-1, 5-naphthyridin-3-yl, 7-chloro-1, 5-naphthyridin-3-yl, 7-fluoro-1, 5-naphthyridin-3-yl, 7-bromo-1, 5-naphthyridin-3-yl, 7-ethynyl-1, 5-naphthyridin-3-yl, 6-chloro-1, 7-naphthyridin-2-yl, 6-fluoro-1, 7-naphthyridin-2-yl, 6-bromo-1, 7-naphthyridin-2-yl, 6-ethynyl-1, 7-naphthyridin-2-yl, 6-chloro-1, 7-naphthyridin-3-yl, 6-fluoro-1, 7-naphthyridin-3-yl, 6-bromo-1, 7-naphthyridin-3-yl, 6-ethynyl-1, 7-naphthyridin-3-yl, 6-chloro-1, 8-naphthyridin-2-yl, 6-fluoro-1, 8-naphthyridin-2-yl, 6-bromo-1, 8-naphthyridin-2-yl, 6-ethynyl-1, 8-naphthyridin-2-yl, 7-chloro-1, 8-naphthyridin-2-yl, 7-fluoro-1, 8-naphthyridin-2-yl, 7-naphthyridin-3-yl, 7-bromo-1, 8-naphthyridin-2-yl, 7-ethynyl-1, 8-naphthyridin-2-yl, 6-chloro-1, 8-naphthyridin-3-yl, 6-fluoro-1, 8-naphthyridin-3-yl, 6-bromo-1, 8-naphthyridin-3-yl, 6-ethynyl-1, 8-naphthyridin-3-yl, 7-chloro-1, 8-naphthyridin-3-yl, 7-fluoro-1, 8-naphthyridin-3-yl, 7-bromo-1, 8-naphthyridin-3-yl, 7-ethynyl-1, 8-naphthyridin-3-yl, 6-chloro-2, 5-naphthyridin-3-yl, 6-fluoro-2, 5-naphthyridin-3-yl, 6-bromo-2, 5-naphthyridin-3-yl, 6-ethynyl-2, 5-naphthyridin-3-yl, 7-chloro-2, 5-naphthyridin-3-yl, 7-fluoro-2, 5-naphthyridin-3-yl, 7-bromo-2, 5-naphthyridin-3-yl, 7-ethynyl-2, 5-naphthyridin-3-yl, 7-chloro-2, 6-naphthyridin-3-yl, 7-fluoro-2, 6-naphthyridin-3-yl, 7-bromo-2, 6-naphthyridin-3-yl, 7-ethynyl-2, 6-naphthyridin-3-yl, 6-chloro-2, 8-naphthyridin-3-yl, 6-fluoro-2, 8-naphthyridin-3-yl, 6-bromo-2, 8-naphthyridin-3-yl, 6-ethynyl-2, 8-naphthyridin-3-yl, 7-chloro-2, 8- Naphthyridin-3-yl, 7-fluoro-2, 8-naphthyridin-3-yl, 7-bromo-2, 8-naphthyridin-3-yl, 7-ethynyl-2, 8-naphthyridin-3-yl, 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 of the above (a) to (1), a thienopyrrolyl group which may have a substituent is preferred. The substituent(s) may have 1 to 3 substituents, and examples of the substituent(s) include 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 haloalkyl 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 and an alkoxycarbonylalkyl group, and among these, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group and a haloalkyl group are preferable. Specific preferable examples thereof include 2-chlorothieno [2, 3-b ] pyrrol-5-yl, 2-fluorothieno [2, 3-b ] pyrrol-5-yl, 2-bromothieno [2, 3-b ] pyrrol-5-yl, and 2-ethynylthieno [2, 3-b ] pyrrol-5-yl.

[ with respect to the group Q¹]

In the present invention, Q¹Represents 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 saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent.

The saturated or unsaturated 5 to 6-membered cyclic hydrocarbon group may, for example, be cyclopentyl, cyclopentenyl, cyclohexyl, cyclopentenyl or phenyl, preferably cyclopentyl, cyclohexyl or phenyl, more preferably phenyl.

The saturated or unsaturated 5-to 7-membered heterocyclic group represents a 1-valent group formed by a heterocyclic ring having at least 1 hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom, and may, for example, be furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl or thiazoleLinyl, thiadiazolyl, furazanyl, pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazolyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl, triazinyl, aza-azadiazinylRadical diazaRadical and triazaAnd the like. Among them, preferred are thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, furazanyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, thiadiazinyl and triazolyl. More preferred are thienyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, piperazinyl, and piperidinyl. Further, of these heterocyclic groups, a nitrogen-containing heterocyclic group may be formed as an N-oxide.

A saturated or unsaturated 2-or 3-membered fused hydrocarbon group and Q of the general formula (1)⁴The saturated or unsaturated 2-or 3-ring fused hydrocarbon group described in the above description has the same meaning, and specific examples thereof include indenyl, indanyl, naphthyl, tetrahydronaphthyl, anthryl, phenanthryl, etc., and preferred are indenyl, indanyl, naphthyl and tetrahydronaphthyl.

A saturated or unsaturated 2-or 3-ring fused heterocyclic group and Q of the general formula (1)⁴The saturated or unsaturated 2-or 3-membered fused heterocyclic group described in the description above has the same meaning, and specific examples thereof may include benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, quinolyl, dihydroquinolyl, 4-oxodihydroquinolyl (dihydroquinolin-4-one), tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, chromenyl, phenylalkenyl, and the likeA chromanyl group, an isochromanyl group, a 4H-4-oxobenzopyranyl group, a 3, 4-dihydro-4H-4-oxobenzopyranyl group, a 4H-quinolizinyl group, a quinazolinyl group, a dihydroquinazolinyl group, a tetrahydroquinazolinyl group, a quinoxalinyl group, a tetrahydroquinoxalinyl group, a cinnolinyl group, a tetrahydrocinnolinyl group, a indolizinyl group, a tetrahydroindolizinyl group, a benzothiazolyl group, a tetrahydrobenzothiazolyl group, a benzoxazolyl group, a benzisothiazolyl group, a benzisoxazolyl group, a benzimidazolyl group, a naphthyridinyl group, a tetrahydronaphthyridinyl group, a thienopyridyl group, a tetrahydrothienopyridyl group, a thiazolopyridinyl group, a thiazolopyridazinyl group, a tetrahydrothiazolopyridazinyl group, a pyrrolopyridyl group, a dihydropyrrolopyridyl group, a tetrahydropyrrolopyridinyl group, a pyrimidyl group, a dihydropyrrolopyrimidyl group, Pyridoquinazolinyl, dihydropyridinoquinazolinyl, pyridopyrimidinyl, tetrahydropyridopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl, furopyridinyl, tetrahydrofuropyridinyl, oxazolopyridinyl, tetrahydrooxazolopyridinyl, oxazolopyridinyl, tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolyl, thienopyrrolyl, thiazolopyrimidinyl, dihydrothiazolopyrimidinyl, 4-oxotetrahydrocinnolinyl, 1, 2, 4-benzothiadiazinyl, 1-dioxido-2H-1, 2, 4-benzothiadiazinyl, 1, 2, 4-benzoxazodiazinyl, cyclopentopyranyl, thienofuranyl, furopyranyl, pyridooxazinyl, Pyrazolooxazolyl, imidazothiazolyl, imidazopyridinyl, tetrahydroimidazopyridinyl, pyrazinopyridazinyl, benzisoquinolinyl, furocinnolinyl, pyrazolothiazolopyridazinyl, tetrahydropyrazolothiazolopyridazinyl, hexahydrothiazolopyridazinyl, imidazotriazinyl, oxazolopyridyl, benzoxaxoxazinyl Radical, benzazepineTetrahydro benzazepineRadical, benzodiazepineRadical, benzotriazazepineAryl, thienoazaAryl, tetrahydrothienoazepineAryl, thienodiazepinesAryl, thienotriazaThiazolyl and thiazolyl azaTetrahydro-thiazoloazepineA 4, 5, 6, 7-tetrahydro-5, 6-tetramethylenethiazolopyridazinyl group, a 5, 6-trimethylene-4, 5, 6, 7-tetrahydrothiazolopyridazinyl group, or the like. Among them, preferred are benzothiazolyl, tetrahydrobenzothiazolyl, thienopyridyl, tetrahydrothienopyridyl, thienopyrrolyl, thiazolopyridinyl, tetrahydrothiazolopyridinyl, thiazolopyridazinyl, tetrahydrothiazolopyridazinyl, pyrrolopyrimidyl, dihydropyrrolopyrimidyl, pyranothiazolyl, dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridinyl, oxazolopyridinyl, tetrahydrooxazolopyridinyl, pyrrolopyridyl, dihydropyrrolopyridyl, thiazolopyridinyl,tetrahydropyrrolopyridinyl, oxazolopyridazinyl, tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolyl, thiazolopyrimidinyl, dihydrothiazolopyrimidinyl, benzazepine Tetrahydro benzazepineThiazolyl and thiazolyl azaTetrahydro-thiazoloazepineAryl, thienoazaAryl, tetrahydrothienoazepineA 4, 5, 6, 7-tetrahydro-5, 6-tetramethylenethiazolopyridazinyl group, a 5, 6-trimethylene-4, 5, 6, 7-tetrahydrothiazolopyridazinyl group. Particularly preferred are tetrahydrobenzothiazolyl, tetrahydrothienopyridyl, tetrahydrothiazolopyridinyl, tetrahydrothiazolopyridazinyl, dihydropyrrolopyrimidinyl, dihydropyranothiazolyl, tetrahydrooxazolopyridinyl, dihydropyrrolothiazolyl, 4, 5, 6, 7-tetrahydro-5, 6-tetramethylenethiazolopyridazinyl, 5, 6-trimethylene-4, 5, 6, 7-tetrahydrothiazolopyridazinyl.

The condensed form of the above-mentioned condensed heterocyclic group is not particularly limited, and for example, thienopyridine may be thieno [2, 3-b ]]Pyridine, thieno [2, 3-c ]]Pyridine, thieno [3, 2-b ]]Pyridine, thieno [3, 2-c ]]Pyridine, thieno [3, 4-b ]]Pyridine, thieno [3, 4-c ]]Any of pyridines, preferably thieno [2, 3-c ]]Pyridine and thieno[3，2-c]Pyridine. Thienopyrroles, which may be thieno [2, 3-b ]]Pyrrole, thieno [3, 2-b ]]Any of pyrrole. Thiazolopyridines, which may be 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, thiazolo [3, 2-a ]]Any of pyridines, preferably thiazolo [4, 5-c ]]Pyridine and thiazolo [5, 4-c]Pyridine. Thiazolopyridazines, which may be thiazolo [4, 5-c]Pyridazine, thiazolo [4, 5-d ]]Pyridazine, thiazolo [5, 4-c ]]Pyridazine, thiazolo [3, 2-b ]]Pyridazine is preferably thiazolo [4, 5-d ]]Pyridazine. Pyrrolo-pyridines, which may be pyrrolo [2, 3-b ]]Pyridine, pyrrolo [2, 3-c ]]Pyridine, pyrrolo [3, 2-b ]]Pyridine, pyrrolo [3, 2-c]Pyridine, pyrrolo [3, 4-b ]]Pyridine, pyrrolo [3, 4-c]Any of pyridines, preferably pyrrolo [2, 3-c ]]Pyridine and pyrrolo [3, 2-c]Pyridine. Pyrrolopyrimidines, which may be pyrrolo [3, 4-d]Pyrimidine, pyrrolo [3, 2-d]Pyrimidine, pyrrolo [2, 3-d]Any of the pyrimidines, preferably pyrrolo [3, 4-d]A pyrimidine. Pyridopyrimidines, which may be pyrido [2, 3-d ]]Pyrimidine, pyrido [3, 2-d ]]Pyrimidine, pyrido [3, 4-d ]]Pyrimidine, pyrido [4, 3-d ]]Pyrimidine, pyrido [1, 2-c ]]Pyrimidine, pyrido [1, 2-a ] ]Any of the pyrimidines, preferably pyrido [3, 4-d ]]Pyrimidines and pyrido [4, 3-d]A pyrimidine. Pyranothiazoles, which may be pyrano [2, 3-d ]]Thiazole, pyrano [4, 3-d ]]Thiazole, pyrano [3, 4-d ]]Thiazole, pyrano [3, 2-d ]]Any of the thiazoles, preferably pyrano [4, 3-d ]]Thiazole, pyrano [3, 4-d ]]And (b) a thiazole. Furopyridines, e.g. 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 ]]Any of pyridines, preferably furo [2, 3-c ]]Pyridine and furo [3, 2-c ]]Pyridine. An oxazolopyridine which may be 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, oxazolo [3, 2-a ]]Any of pyridines, preferably oxazolo [4, 5-c ]]Pyridine and oxazolo [5, 4-c ]]Pyridine. Oxazolopyridazines, which may beOxazolo [4, 5-c]Pyridazine, oxazolo [4, 5-d ]]Pyridazine, oxazolo [5, 4-c ]]Pyridazine, oxazolo [3, 4-b ]]Any of pyridazines, preferably oxazolo [4, 5-d ]]Pyridazine. Pyrrolothiazoles, which may be pyrrolo [2, 1-b ] ]Thiazole, pyrrolo [1, 2-c ]]Thiazole, pyrrolo [2, 3-d]Thiazole, pyrrolo [3, 2-d]Thiazole, pyrrolo [3, 4-d]Any of the thiazoles is preferably pyrrolo [3, 4-d ]]And (b) a thiazole. Pyrrolo-oxazole, which can be 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, preferably pyrrolo [3, 4-d]Oxazole. Benzazepine compoundsMay be 1H-1-benzazepine1H-2-benzazepine1H-3-benzazepineAny of these, preferably 1H-3-benzazepineThiazolo [4, 5-c ]]Aza derivativesCan be 4H-thiazolo [4, 5-c ]]Aza derivatives4H-thiazolo [4, 5-d]Aza derivatives4H-thiazolo [5, 4-c ]]Aza derivativesAny of these, preferably 4H-thiazolo [4, 5-d ]]Aza derivativesThieno [2, 3-c]Aza derivativesMay be 4H-thieno [2, 3-d ]]Aza derivatives4H-thieno [3, 2-c]Aza derivativesAny of these is preferably 4H-thieno [2, 3-d ]]Aza derivatives

Of these heterocyclic groups, the nitrogen-containing heterocyclic group may be formed as an N-oxide. To the above substituents and Q²The bonding position of (3) is not particularly limited.

The saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group, saturated or unsaturated 5-to 7-membered heterocyclic group, saturated or unsaturated 2-or 3-membered fused hydrocarbon group or saturated or unsaturated 2-or 3-membered fused heterocyclic group may have 1 to 3 substituents, respectively, which may, for example, be a hydroxyl group, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a haloalkyl group substituted with 1 to 3 halogen atoms, an amino group, a cyano group, an amidino group, a hydroxyamidino group, a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms (hereinafter referred to as C) ₁～C₆Alkyl represents linear, branched or cyclic alkyl, for example, methyl, ethyl, isopropyl, tert-butyl or other linear or branched C₁～C₆C such as alkyl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl and the like₃～C₆Cycloalkyl) C₃～C₆Cycloalkyl radical C₁～C₆Alkyl radical (example)E.g., cyclopropylmethyl, etc.), hydroxy C₁～C₆Alkyl (e.g., hydroxyethyl, 1-dimethyl-2-hydroxyethyl, etc.), C₁～C₆Alkoxy (e.g., methoxy, ethoxy, etc.), C₁～C₆Alkoxy radical C₁～C₆Alkyl, carboxyl, C₂～C₆Carboxyalkyl (e.g., carboxymethyl, etc.), C₂～C₆Alkoxycarbonyl radical C₁～C₆Alkyl (e.g., methoxycarbonylmethyl, tert-butoxycarbonylmethyl, etc.), C₂～C₆Alkoxycarbonyl-substituted amidino group, C₂～C₆Alkenyl (e.g., vinyl, allyl, etc.), C₂～C₆Alkynyl (e.g., ethynyl, propynyl, etc.), C₂～C₆Alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), amino C₁～C₆Alkyl (e.g., aminomethyl, aminoethyl, etc.), C₁～C₆Alkylamino radical C₁～C₆Alkyl (e.g., N-methylaminomethyl, N-ethylaminomethyl, etc.), di (C)₁～C₆Alkyl) amino C₁～C₆Alkyl (e.g., N, N-dimethylaminomethyl, N, N-diethylaminomethyl, N-ethyl-N-methylaminoethyl, etc.), C ₂～C₆Alkoxycarbonylamino C₁～C₆Alkyl (e.g., methoxycarbonylaminoethyl, tert-butoxycarbonylaminoethyl, etc.), C₁～C₆Alkanoyl (e.g., formyl, acetyl, methylpropanoyl, cyclopentanecarbonyl, etc.), C₁～C₆Alkanoylamino C₁～C₆Alkyl (e.g., acetylaminomethyl, etc.), C₁～C₆Alkylsulfonyl (e.g., methylsulfonyl, etc.), C₁～C₆Alkylsulfonylamino C₁～C₆Alkyl (e.g., methylsulfonylaminomethyl, etc.), carbamoyl, C₁～C₆Alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, t-butylcarbamoyl, etc.), N, N-di (C)₁～C₆Alkyl) carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl, etc.), C₁～C₆Alkylamino (e.g., N-methylamino, N-ethylamino, etc.), di (C)₁～C₆Alkyl) amino (e.g., N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, etc.), aminosulfonyl, arylsulfonyl (e.g., phenylsulfonyl, etc.), arylcarbonyl (e.g., benzoyl, 4-fluorobenzoyl, etc.) which may be substituted with a halogen atom or the like, C₂～C₆Alkoxycarbonyl (C)₁～C₆Alkyl) amino C₁～C₆Alkyl (e.g., methoxycarbonyl (methyl) aminomethyl, tert-butoxycarbonyl (methyl) aminomethyl, etc.), C ₁～C₆Alkylsulfonyl radical C₁～C₆Alkyl (e.g., methylsulfonylmethyl, etc.), 5-to 6-membered heterocyclic group containing 1, the same or different 2 nitrogen, oxygen or sulfur atoms (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, pyrimidinyl, tetrahydropyranyl, etc.), the above-mentioned 5-to 6-membered heterocyclic group-C₁～C₄Alkyl (e.g., morpholinomethyl, etc.), the above 5-to 6-membered heterocyclyl-carbonyl (e.g., pyrrolidinylcarbonyl, etc.), the above 5-to 6-membered heterocyclyl-amino-C₁～C₄Alkyl (e.g., N- (oxazol-2-yl) aminomethyl, etc.), the above-mentioned 5-to 6-membered heterocyclic-amino (e.g., pyridylamino, etc.), the above-mentioned 5-to 6-membered heterocyclic-oxy (e.g., 4-pyridyloxy, (1-methyliminopiperidin-4-yl) oxy, etc.), 3-to 6-membered heterocyclic-carbonyl-C₁～C₄Alkyl (e.g., (4, 4-dioxothiomorpholin-1-yl) carbonylmethyl), and the above 5-to 6-membered heterocyclic group (C)₁～C₆Alkyl) amino-C₁～C₄Alkyl (e.g., N- (4, 5-dihydro-1, 3-oxazol-2-yl) -N-methylaminomethyl, etc.) and the like.

Q¹Specific examples of (3) include 5-to 6-membered cyclic hydrocarbon groups such as 2-aminosulfonylphenyl, 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ]]Pyridin-2-yl, 4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ]Pyridin-2-yl, 5-cyclopropyl-4, 5, 6, 7-tetrahydroThiazolo [5, 4-c ]]Pyridin-2-yl, 5-carboxymethyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridin-2-yl, 5-butyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridin-2-yl, 5- (4-pyridinyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridin-2-yl, 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c]Pyridin-2-yl, 6-methyl-4, 5, 6, 7-tetrahydrothieno [2, 3-c ]]Pyridin-2-yl, 5-methyl-4, 5, 6, 7-tetrahydrooxazolo [5, 4-c ]]Pyridin-2-yl, 5-methyl-4, 6-dihydro-5H-pyrrolo [3, 4-d]Thiazol-2-yl, 5, 7-dihydro-6-methylpyrrolo [3, 4-d ]]Pyrimidin-2-yl, 5, 6-dimethyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-d ]]Pyridazin-2-yl, 5, 6-dimethyl-4, 5, 6, 7-tetrahydrooxazolo [4, 5-d ]]Pyridazin-2-yl, 5-dimethylamino-4, 5, 6, 7-tetrahydrobenzo [ d]Thiazol-2-yl, 5- (4-pyridyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl, 6, 7-dihydro-4H-pyrano [4, 3-d ] s]2-cyclic heterocyclic group such as thiazol-2-yl, pyridyl group such as 4-pyridyl or 2-pyridyl, dihydrooxazolyl group such as 4, 5-dihydrooxazol-2-yl, 4- [ N- (4, 5-dihydrooxazol-2-yl) -N-methylaminomethyl group ]Thien-2-yl, 4- [ N- (4, 5-dihydrooxazol-2-yl) -N-methylaminomethyl]5-to 6-membered heterocyclic groups such as-3-chlorothien-2-yl, 5- (N-methylaminomethyl) thiazol-2-yl, 5- (N-methylaminomethyl) thien-2-yl, 5- (N, N-dimethylaminomethyl) thiazol-2-yl, 5- (N, N-dimethylaminomethyl) thien-2-yl, and 5- (N, N-dimethylaminomethyl) pyridin-2-yl. However, these examples do not limit Q¹。

[ with respect to the group Q²]

Group Q²Represents 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 alkynylene group having 2 to 6 carbon atoms, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a 2-valent saturated or unsaturated 5-to 7-membered heterocyclic group which may have a substituent, a 2-valent saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a 2-valent saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent.

Group Q²In the above formula, the linear or branched alkylene group having 1 to 6 carbon atoms may, for example, be a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group or a hexamethylene group.

Examples of the linear or branched alkenylene group having 2 to 6 carbon atoms include vinylene, propenylene, butenylene and pentenylene. 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 ethynylene, propynyl, butynyl, pentynyl and hexynyl. The binding position of the triple bond is not particularly limited.

The 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group is Q in the general formula (1)⁴Specific examples of the saturated or unsaturated 2-valent group of the 5-to 6-membered cyclic hydrocarbon described in the above paragraph include cyclohexylene, cyclohexenylene and phenylene, and cyclohexylene and phenylene are preferred.

The 2-valent saturated or unsaturated 5-to 7-membered heterocyclic group is Q in the general formula (1)⁴The saturated or unsaturated 2-valent group of a 5-to 7-membered heterocycle described in the above. Specific examples thereof include furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furazan, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine, oxadiazine, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazole, triazole, triazine, and aza-diaza Diaza derivativesTriazaThe 2-valent group may, for example, be pyrazole, imidazole, oxazole, thiazole, thiadiazole, furazan or pyrazinePyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, triazole, triazine, azaDiaza derivativesTriazaA 2-valent group of (1).

The 2-or 3-membered saturated or unsaturated 2-or 3-membered fused hydrocarbon group is Q in the general formula (1)⁴Specific examples of the 2-valent group of the saturated or unsaturated 2-or 3-cyclic condensed hydrocarbon described in the above paragraph include 2-valent groups such as indene, indan, naphthalene, tetrahydronaphthalene, anthracene and phenanthrene, and preferable examples include 2-valent groups of indan and naphthalene.

The 2-or 3-membered saturated or unsaturated 2-or 3-membered fused heterocyclic group is Q in the general formula (1)⁴Specific examples of the saturated or unsaturated 2-or 3-membered fused heterocyclic group described in the description of (a) 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, thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridine, thiazolopyridazine, tetrahydrothiazolopyridazine, pyrrolopyridine, dihydropyrrolopyridine, tetrahydropyrrolopyridine, pyrrolopyrimidine, dihydropyrrolopyrimidine, dihydropyridoquinazoline, pyranothiazole, dihydropyranothiazole, furopyridine, tetrahydrofuropyridine, oxazolopyridine, naphthoxazoline, naphthoxazine, and naphthoxazine, Tetrahydrooxazolopyridine, oxazolopyridazine, tetrahydrooxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole, pyrrolooxazole, dihydropyrrolooxazole, benzazepine Examples of the 2-valent group include 2-valent groups of benzofuran, benzothiophene, indole, indazole, quinoline, isoquinoline, tetrahydroisoquinoline, benzothiazole, naphthyridine, thienopyridine, thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine, pyrrolopyridine, tetrahydropyrrolopyridine, pyridopyrimidine, pyranothiazole, dihydropyranothiazole, furopyridine, oxazolopyridine, oxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole, pyrrolooxazole and dihydropyrrolooxazole. The condensed form of the condensed heterocyclic group is not particularly limited, and for example, naphthyridine may be any of 1, 5-, 1, 6-, 1, 7-, 1, 8-, 2, 6-or 2, 7-naphthyridine, thienopyridine may be thieno [2, 3-b ]]Pyridine, thieno [2, 3-c ]]Pyridine, thieno [3, 2-b ]]Pyridine, thieno [3, 2-c ]]Pyridine, thieno [3, 4-b ]]Pyridine, thieno [3, 4-c ]]Any of the pyridines, thiazolopyridines, may be 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, thiazolo [3, 2-a ] ]Any of the pyridines, thiazolopyridazines, may be thiazolo [4, 5-c ]]Pyridazine, thiazolo [4, 5-d ]]Pyridazine, thiazolo [5, 4-c ]]Pyridazine, thiazolo [3, 2-b ]]Any one of pyridazine, pyrrolopyridine, may be pyrrolo [2, 3-b ]]Pyridine, pyrrolo [2, 3-c ]]Pyridine, pyrrolo [3, 2-b ]]Pyridine, pyrrolo [3, 2-c]Pyridine, pyrrolo [3, 4-b ]]Pyridine, pyrrolo [3, 4-c]Any of the pyridines, pyrrolopyrimidines, may be pyrrolo [3, 4-d]Pyrimidine, pyrrolo [3, 2-d]Pyrimidine, pyrrolo [2, 3-d]Any of the pyrimidines, pyridopyrimidines, may be pyrido [2, 3-d ]]Pyrimidine, pyrido [3, 2-d ]]Pyrimidine, pyrido [3, 4-d ]]Any of the pyrimidines, pyranothiazoles, may be pyrano [2, 3-d ]]Thiazole, pyrano [4, 3-d ]]Thiazole, pyrano [3, 4-d ]]Thiazole, pyrano [3, 2-d ]]Any one of the thiazoles, furopyridines, may be 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 ]]Any one of the pyridines, oxazolopyridines, may be oxazolo [4, 5-b]Pyridyl, oxazolo [4, 5-c ]Pyridine, oxazolo [5, 4-b ]]Pyridine, oxazolo [5, 4-c ]]Pyridine, oxazolo [3, 4-a ]]Pyridine, oxazolo [3, 2-a ]]Any one of pyridine, oxazolopyridazine, may be oxazolo [4, 5-c ]]Pyridazine, oxazolo [4, 5-d ]]Pyridazine, oxazolo [5, 4-c ]]Pyridazine, oxazolo [3, 4-b ]]Any one of pyridazine, pyrrolothiazole, may be pyrrolo [2, 1-b ]]Thiazole, pyrrolo [1, 2-c ]]Thiazole, pyrrolo [3, 2-d]Thiazole, pyrrolo [3, 4-d]Any one of the thiazoles, pyrrolooxazoles, may be 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 one of oxazole. In addition, these may be in forms other than the fused form.

The above-mentioned saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group having a valence of 2, a saturated or unsaturated 5-to 7-membered heterocyclic group having a valence of 2, a saturated or unsaturated 2-or 3-membered fused hydrocarbon group and the saturated or unsaturated 2-or 3-membered fused heterocyclic group having a valence of 2, a saturated or unsaturated 2-or 3-membered fused heterocyclic group may each have 1 to 3 substituents, which may, for example, be a halogen atom such as a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a haloalkyl 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 and the like), a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms (for example, methoxy group, ethoxy group and the like), a linear, branched or cyclic amidino group substituted with an alkoxycarbonyl group having 2 to, methoxycarbonylamidino group, ethoxycarbonylamidino group, etc.), a linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms (for example, vinyl group, allyl group, etc.), a linear or branched alkynyl group having 2 to 6 carbon atoms (for example, ethynyl group, propynyl group, etc.), a linear, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms (for example, methoxycarbonyl group, ethoxycarbonyl group, etc.), a carbamoyl group, etc.

Above Q²Of these, the preferred isA bond, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a 2-valent saturated or unsaturated 5-to 7-membered heterocyclic group which may have a substituent, and a 2-valent saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent, wherein a single bond, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group, and a 2-valent saturated or unsaturated 5-to 7-membered heterocyclic group are more preferable.

Group Q¹When it is a saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent, the group Q²Preferably a single bond. In the above combination, Q²When it is a single bond, formula (1)

Q¹-Q²-T⁰-N(R¹)-Q³-N(R²)-T¹-Q⁴(1)

[ in the formula, R¹、R²、Q¹、Q²、Q³、Q⁴、T⁰And T¹As described above]

Is represented by the following general formula (1').

Q¹-T⁰-N(R¹)-Q³-N(R²)-T¹-Q⁴(1′)

[ wherein Q¹Represents the above-mentioned 2-or 3-membered fused hydrocarbon group or 2-or 3-membered fused heterocyclic group, R¹、R²、Q³、Q⁴、T⁰And T¹As described above]

More preferably the group Q¹Is a thienopyridyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent, a thiazolopyridyl group which may have a substituent, 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 dihydropyranothiazolyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent A furopyridyl group of the group, a tetrahydrofuropyridyl group which may have a substituent, an oxazolopyridyl group which may have a substituent, a tetrahydrooxazolopyridyl group which may have a substituent, a pyrrolopyridyl group which may have a substituent, a dihydropyrrolopyridyl group which may have a substituent, a tetrahydropyrrolopyridyl group which may have a substituent, a pyrrolopyrimidyl group which may have a substituent, a dihydropyrrolopyrimidyl group which may have a substituent, an oxazolopyridazinyl group which may have a substituent, a tetrahydrooxazolopyridazinyl group which may have a substituent, a pyrrolothiazolyl group which may have a substituent, a dihydropyrrolothiazolyl group which may have a substituent, a pyrrolooxazolyl group which may have a substituent, a benzothiazolyl group which may have a substituent, a tetrahydrobenzothiazolyl group which may have a substituent, a thiazolopyrimidinyl group which may have a substituent, Optionally substituted dihydrothiazolopyrimidinyl group, optionally substituted benzazepine groupRadical, tetrahydrobenzazepine which may have substituentsA thiazoloazepine which may have a substituentSubstituted or unsubstituted tetrahydrothiazoloazepineA group, a thienoazepine which may have a substituent Substituted tetrahydrothienoazepinesA 4, 5, 6, 7-tetrahydro-5, 6-tetramethylenethiazolopyridazinyl group which may have a substituent(s)5, 6-trimethylene-4, 5, 6, 7-tetrahydrothiazolopyridazinyl radical, group Q²Is a single bond.

Group Q¹When the group 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 group which may have a substituent, the group Q²Preferably a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent or a 2-valent saturated or unsaturated 5-to 7-membered heterocyclic group which may have a substituent as the group Q¹-Q²Examples of the "phenyl" may include 4- (4-pyridyl) phenyl, 4- (2-pyridyl) phenyl, 5- (4-pyridyl) thiazolyl, 1- (4-pyridyl) piperidinyl, 4-hydroxy-1- (4-pyridyl) piperidin-4-yl, biphenyl, 4- (2-aminosulfonylphenyl) phenyl, 4- (2-amidinophenyl) phenyl, 4- (2-methylsulfonylphenyl) phenyl, 4- (2-aminomethylphenyl) phenyl, 4- (2-carbamoylphenyl) phenyl, 4- (2-imidazolyl) phenyl, 4- (1-methyl-2-imidazolyl) phenyl, and the like, 4- (2, 3, 4, 5-tetrahydropyrimidin-2-yl) phenyl, 4- (1-methyl-2, 3, 4, 5-tetrahydropyrimidin-2-yl) phenyl, 4- (5-tetrazolyl) phenyl, 1- (4-pyridyl) piperidin-4-yl, 3- (4-piperidyl) isoxazolin-5-yl, 3- (4-amidinophenyl) isoxazolin-5-yl, 3- (4-piperidyl) isoxazolidin-5-yl, 3- (4-amidinophenyl) isoxazolidin-5-yl, 2- (4-piperidyl) -1, 3, 4-thiadiazol-5-yl, 2- (4-aminophenyl) -1, 3, 4-oxadiazol-5-yl, 4- (4-piperidinyl) piperidin-1-yl, 4- (4-piperidinyl) piperazin-1-yl, 4- (4-piperazinyl) piperazin-1-yl, 1- (4-pyrimidinyl) piperidin-1-yl, 1- (2-methylpyrimidin-4-yl) piperidin-4-yl, 1- (4-pyrimidinyl) pyrrolidin-3-yl, 1- (4-methylpyrimidin-6-yl) piperazin-4-yl, 1- (2-methylpyrimidin-4-yl) pyrrolidin-4-yl, 1- (6-chloropyrimidin-4-yl) piperidin-4-yl, and mixtures thereof, 5- (4-chlorophenyl) thiophen-2-yl, 2- (4-chlorophenyl) thiazol-4-yl, 3- (4-chlorophenyl) -1H-pyrrol-2-yl, 4- (4-pyrimidinyl) phenyl, 4- (4-imidazolyl) phenyl, 5- (pyridin-4-yl) pyrimidin-2-yl, 2' - [ (dimethylamino) methyl ][1, 1' -Biphenyl]-4-yl, 4- [2- (hydroxymethyl) pyridin-4-yl]Phenyl, 4- [2- (aminomethyl) pyridin-4-yl]Phenyl, 2 '- (aminosulfonyl) [1, 1' -biphenyl ] s]-4-yl, 4- (3-oxomorpholin-4-yl) phenyl and the like.

[ with respect to the group Q³]

Group Q³From the following groups

Is represented by the group, Q⁵Represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nWherein m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-, 1 and 2 represent positions);

R³and R⁴In the presence of Q⁵Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an alkoxyimino group, a hydroxyimino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylamino group, a carboxyalkylamino 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, an N, N-dialkylaminoalkyl group which may have a substituent, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl, alkyl group Sulfonylalkyl, 3-to 6-membered heterocyclic carbonyl which may have a substituent, carbamoylalkyl, N-alkylcarbamoylalkyl which may have a substituent on the alkyl, N-dialkylcarbamoylalkyl which may have a substituent on the alkyl, carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, 3-to 6-membered heterocyclic carbonylalkyl which may have a substituent, 3-to 6-membered heterocyclic carbonyloxyalkyl which may have a substituent, aryl, aralkyl, 3-to 6-membered heterocyclic group which may have a substituent, 3-to 6-membered heterocyclic alkyl which may have a substituent, alkylsulfonyloxy, arylsulfonylamino, alkylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkylcarbonylalkyl, Arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkoxy group, alkoxycarbonylalkoxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkoxycarbonyl group, hydroxyacyl group, alkoxyacyl group, haloacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3 to 6-membered heterocyclic sulfonyl group which may have a substituent(s), 3 to 6-membered heterocyclic oxy group which may have a substituent(s), N-alkylaminoacyl group, N-dialkylaminoacyl group, N-dialkylcarbamoylacyl group which may have a substituent(s) on the alkyl group, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent(s) on the alkyl group, N-dialkyl, Alkylsulfonylacyl, N-arylcarbamoyl, N-3-to 6-membered heterocyclic carbamoyl, N-alkyl-N-arylcarbamoyl, N-alkyl-N-3-to 6-membered heterocyclic carbamoyl, N-arylcarbamoylalkyl, N-3-to 6-membered heterocyclic carbamoylalkyl, N-alkyl-N-arylcarbamoylalkyl, N-alkyl-N-3-to 6-membered heterocyclic carbamoylalkyl, aminothiocarbonyl, N-alkylaminothioformyl, N-dialkylaminothiosulfonyl, alkoxyalkyl (thiocarbonyl), alkylthioalkyl or N-acyl-N-alkylaminoalkyl or R ³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, a carbon atom number2 to 5 alkenylene groups, and 1 to 5 alkylenedioxy or carbonyldioxy groups.

The following groups will be described in detail.

[ in the group, Q⁵、R³And R⁴As mentioned above, table 1 and 2 are not positions]

Containing the above-mentioned group Q⁵The cyclic structure of (a) is a 3-to 10-membered 2-valent cyclic hydrocarbon group which may have 1 double bond or a 5-to 12-membered 2-valent heterocyclic group which may have 1 to 2 hetero atoms, preferably a 3-to 8-membered 2-valent cyclic hydrocarbon group or a 5-to 8-membered 2-valent heterocyclic group, more preferably a 5-to 7-membered 2-valent cyclic hydrocarbon group or a 5-to 7-membered 2-valent heterocyclic group. Wherein Q is⁵Preferably an alkylene group having 3 to 6 carbon atoms or a group- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n- (where m and n are each independently 0 or 1, A is as defined above), Q⁵Particularly preferred is an alkylene group having 4 carbon atoms.

Further, the cyclic hydrocarbon group or heterocyclic group can have a cis-or trans-structure in the relationship between the 1-and 2-positions, and is preferably a 5-membered one, and more preferably a cis-or trans-structure in the case of 6-to 7-membered one.

For the above substituent R³And R⁴A detailed description will be given. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples of the "alkyl" may include straight-chain, branched or cyclic C ₁～C₆Examples of the alkyl group (e.g., methyl, cyclopropyl, isobutyl, etc.) and the haloalkyl group may include those wherein the alkyl group is substituted with 1 to 3 halogen atoms (e.g., chloromethyl, 1-bromoethyl, trifluoromethyl, etc.). Cyanoalkyl is exemplified by the above-mentioned C₁～C₆The alkyl group is a group substituted with 1 cyano group (for example, cyanomethyl group, 1-cyanoethyl group, etc.). Examples of the "alkenyl" may include straight-chain or branched-chain carbon atoms having 1 double bondA group having a sub-number of 2 to 6 (e.g., vinyl group, allyl group, etc.). Examples of the "alkynyl" group may include linear or branched groups having 1 triple bond and having 2 to 6 carbon atoms (for example, ethynyl, propynyl and the like). Examples of the acyl group may include C.sub.1 to C.sub.6 alkanoyl (e.g., formyl, acetyl, etc.), benzoyl, naphthoyl, etc₇～C₁₅Aroyl or C above₁～C₆Alkanoyl having 1C₆～C₁₄Aryl-substituted arylalkanoyl (e.g., phenylacetyl, and the like). Examples of the "acylalkyl" may include the above-mentioned C₁～C₆The alkyl group has 1 of the above-mentioned acyl group-substituted groups (for example, acetylmethyl group and the like). Examples of the "alkoxy" may include straight, branched or cyclic C₁～C₆Alkoxy (e.g., methoxy, cyclopropoxy, isopropoxy, etc.). The alkoxyalkyl group may, for example, be C as described above₁～C₆Alkyl having 1 of the above-mentioned C₁～C₆Alkoxy-substituted groups (e.g., methoxymethyl, ethoxymethyl, etc.). Hydroxyalkyl is exemplified by the above-mentioned C ₁～C₆The alkyl group has a 1-hydroxy-substituted group (for example, hydroxymethyl, 1-hydroxyethyl, etc.). The carboxyalkyl group may, for example, be C as described above₁～C₆The alkyl group has a group substituted with 1 carboxyl group (for example, carboxymethyl, 1-carboxyethyl, etc.). Alkoxycarbonyl is exemplified by the above-mentioned C₁～C₆Alkoxy group and carbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group and the like). Examples of the "alkoxycarbonylalkyl" may include the above-mentioned C₁～C₆Alkyl groups substituted with 1 of the above alkoxycarbonyl groups (for example, methoxycarbonylethyl, ethoxycarbonylethyl and the like). Carbamoylalkyl is exemplified by the above-mentioned C₁～C₆Alkyl groups substituted with carbamoyl (e.g., carbamoylmethyl, carbamoylethyl).

The 3-to 6-membered heterocyclic group which may have a substituent(s) represents a saturated or unsaturated 3-to 6-membered heterocyclic group which may contain 1 to 3 hetero atoms (nitrogen atom, oxygen atom, sulfur atom, etc.), and the heterocyclic group may have a hydroxyl group, a halogen atom, an amino group, C₁～C₆Alkyl, oxo, haloalkyl and the like, and the 3-to 6-membered heterocyclic group is pyrrolyl or thiopheneExamples of the substituent include a group selected from the group consisting of a pyrazolyl group, an imidazolyl group, a pyrazolinyl group, an oxazolyl group, an oxazolinyl group, an oxadiazolyl group, an oxazolidinyl group, a thiazolyl group, a thiazolinyl group, a thiadiazolyl group, a furazanyl group, a pyranyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrrolidinyl group, a piperazinyl group, a piperidyl group, an oxazinyl group, an oxadiazolyl group, a morpholinyl group, a thiazinyl group, a thiadiazinyl group, a thiomorpholinyl group, a tetrazolyl. Specifically, the compound may include thiazolyl, 4, 5-dihydrothiazolyl, oxazolyl, 4, 5-dihydrooxazolyl, 5-methyloxazolyl, imidazolyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxothiomorpholinyl, tetrahydropyranyl, pyridinyl, 1, 2, 4-oxadiazolyl, 3-methyl-1, 2, 4-oxadiazolyl, 5-methyl-1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 5-methyl-1, 3, 4-oxadiazolyl, 5- (trifluoromethyl) -1, 3, 4-oxadiazolyl, 1, 3-oxazolyl, 1, 3, 4-thiadiazolyl, 5-methyl-1, 3, 4-thiadiazolyl, 1, 3-oxazolidinyl, and the like. Examples of the 3-to 6-membered heterocycloalkyl group which may have a substituent(s) may include alkyl groups substituted with 1 of the above 3-to 6-membered heterocyclic groups which may have a substituent(s) (e.g., thiazolylmethyl, 4, 5-dihydrothiazolylmethyl, morpholinylmethyl, 1-dioxothiomorpholinylmethyl, etc.). Examples of the aryl group may include a group having 6 to 14 carbon atoms such as phenyl and naphthyl, and the aryl group may be selected from the group consisting of the above-mentioned groups C ₁～C₆Alkyl group, the above-mentioned C₁～C₆Alkanoyl group, hydroxy group, nitro group, cyano group, halogen atom, the above-mentioned C₂～C₆Alkenyl radical, above C₂～C₆Alkynyl group, the above-mentioned C₁～C₆Haloalkyl, the above-mentioned C₁～C₆Alkoxy, carboxy, carbamoyl, the above-mentioned C₁～C₆1 to 3 groups such as alkoxycarbonyl groups. Aralkyl is exemplified by the above-mentioned C₁～C₆Alkyl having 1 of the above-mentioned C₆～C₁₄Aryl-substituted groups (e.g., benzyl, phenethyl, and the like). In the above description, the substitution position is not particularly limited. Examples of the "acylamino" which may have a substituent(s) may include the above-mentioned C₁～C₆Acyl-substituted amino group (e.g., formylamino, acetylamino, etc.)) The acyl group has 1 to several halogen atoms, hydroxyl groups, C₁～C₆Alkoxy, acyl, N-C₁～C₆Alkylamino, N-di-C₁～C₆Alkylamino, carboxyl, C₂～C₆And substituted acyl groups such as alkoxycarbonyl groups (for example, 2-methoxyacetylamino group, 3-aminopropionylamino group, etc.). Examples of the acylaminoalkyl group may include the above-mentioned C₁～C₆Acylamino substituted for the above C₁～C₆Alkyl groups (e.g., formylaminomethyl, acetylaminomethyl, etc.). The aminoalkyl group may, for example, be C as described above₁～C₆The alkyl group is a group substituted with 1 amino group (for example, aminomethyl group, 1-aminoethyl group, etc.). The N-alkylaminoalkyl group may, for example, be exemplified by amino-C ₁～C₆Having 1C on the nitrogen atom of the alkyl group₁～C₆Examples of the alkyl-substituted group (e.g., N-methylaminomethyl group, N-methylaminoethyl group and the like) and the N, N-dialkylaminoalkyl group may include amino-C₁～C₆Having 2C atoms on the nitrogen atom of the alkyl group₁～C₆Alkyl-substituted groups (e.g., N, N-dimethylaminomethyl, N-ethyl-N-methylaminomethyl, etc.). Examples of the "N-alkenylcarbamoyl" group may include straight-chain or branched-chain ones₂～C₆Alkenyl groups substituted for carbamoyl groups (e.g., allylcarbamoyl and the like). Examples of the "N-alkenylcarbamoylalkyl" group may include the aforementioned N-C₂～C₆Substituted by alkenylcarbamoyl₁～C₆Alkyl groups (e.g., allylcarbamoylethyl, etc.). Examples of the N-alkenyl-N-alkylcarbamoyl group may include the above-mentioned N-C₂～C₆The alkenylcarbamoylalkyl group having a straight or branched C atom₁～C₆Alkyl-substituted groups (e.g., N-allyl-N-methylcarbamoylmethyl, and the like). Examples of the N-alkenyl-N-alkylcarbamoylalkyl group may include the above-mentioned N-C₂～C₆The alkenylcarbamoyl group having a straight or branched C group on the nitrogen atom₁～C₆Alkyl-substituted groups (e.g., N-allyl-N-methylcarbamoyl, etc.). Examples of the "N-alkoxycarbamoyl" group may include straight or branched C ₁～C₆Alkoxy groups substituted for carbamoyl groups (e.g., methoxycarbamoyl and the like). Examples of the "N-alkoxycarbamoylalkyl" may include the aforementioned N-C₁～C₆Straight or branched chain C of alkoxycarbamoyl₁～C₆A group substituted on an alkyl group (for example, methoxycarbamoylmethyl group, etc.). Examples of the "N-alkyl-N-alkoxycarbamoyl" group may include straight-chain or branched-chain C₁～C₆Alkoxy and C₁～C₆A group in which an alkyl group is substituted on a carbamoyl group (for example, N-ethyl-N-methoxycarbamoyl group and the like). Examples of the N-alkyl-N-alkoxycarbamoylalkyl group may include the above-mentioned N-C₁～C₆alkyl-N-C₁～C₆Straight or branched chain C of alkoxycarbamoyl₁～C₆A group substituted on an alkyl group (for example, N-ethyl-N-methoxycarbamoylmethyl group and the like). Examples of the carbazolyl group which may be substituted with 1 to 3 alkyl groups include 1 to 3 straight-chain or branched C₁～C₆Alkyl-substituted carbazolyl groups (e.g., 1-methylcarbazolyl group, 1, 2-dimethylcarbazolyl group, etc.). Examples of the "alkylsulfonyl" may include straight-chain, branched or cyclic C₁～C₆Alkylsulfonyl (e.g., methylsulfonyl, etc.). Examples of the alkylsulfonylalkyl group may include the above-mentioned C₁～C₆Alkylsulfonyl substituted straight or branched C₁～C₆Alkyl groups (e.g., methylsulfonylmethyl, etc.). The alkoxyimino group may, for example, be C ₁～C₆Alkoxyimino groups (e.g., methoxyimino, ethoxyimino, etc.). The alkoxycarbonylalkylamino group may be exemplified by amino groups having 1 of the above-mentioned C₁～C₆Alkoxycarbonylalkyl substituted groups (e.g., methoxycarbonylmethylamino, ethoxycarbonylpropylamino, etc.). The carboxyalkylamino group may be exemplified by amino groups having 1 of the above carboxyl groups C₁～C₆Alkyl-substituted groups (e.g., carboxymethylamino, carboxyethylamino, etc.). The alkoxycarbonylamino group may be exemplified by amino having 1 of the above-mentioned C₁～C₆Alkoxycarbonyl-substituted groups (e.g., methoxycarbonylamino, tert-butoxycarbonylamino, and the like). Alkoxycarbonyl radicalThe aminoalkyl group may be exemplified by the alkyl groups mentioned above having 1 of the above C₁～C₆An alkyl ethyl carbonylamino-substituted group (e.g., methoxycarbonylaminomethyl, tert-butoxycarbonylaminoethyl, etc.). The N-alkylcarbamoyl group which may have a substituent(s) on the alkyl group represents a linear, branched or cyclic C group which may have a substituent(s)₁～C₆Alkyl-substituted carbamoyl, and the substituent may, for example, be hydroxy, amino or N-C₁～C₆Alkylamino, amidino, halogen, carboxyl, cyano, carbamoyl, C₁～C₆Alkoxy radical, C₁～C₆Alkanoyl radical, C₁～C₆Alkanoylamino, C₁～C₆Examples of the alkylsulfonylamino group include an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-isopropylcarbamoyl group, an N-cyclopropylcarbamoyl group, an N- (2-hydroxyethyl) carbamoyl group, an N- (2-fluoroethyl) carbamoyl group, an N- (2-cyanoethyl) carbamoyl group, an N- (2-methoxyethyl) carbamoyl group, an N-carboxymethylcarbamoyl group, an N- (2-aminoethyl) carbamoyl group and an N- (2-amidinoethyl) carbamoyl group. The N, N-dialkylcarbamoyl group which may have a substituent(s) on the alkyl group represents a linear, branched or cyclic C group which may have 2 substituents ₁～C₆Alkyl-substituted carbamoyl, and the substituent may, for example, be hydroxy, amino or N-C₁～C₆Alkylamino, amidino, halogen, carboxyl, cyano, carbamoyl, C₁～C₆Alkoxy radical, C₁～C₆Alkanoyl radical, C₁～C₆Alkanoylamino, C₁～C₆Examples of the alkylsulfonylamino group include an N, N-dimethylcarbamoyl group, an N, N-diethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group, an N-isopropyl-N-methylcarbamoyl group, an N- (2-hydroxyethyl) -N-methylcarbamoyl group, an N, N-bis (2-hydroxyethyl) carbamoyl group, n, N-bis (2-fluoroethyl) carbamoyl, N- (2-cyanoethyl) -N-methylcarbamoyl, N- (2-methoxyethyl) -N-methylcarbamoyl, N-carboxymethyl-N-methylcarbamoyl, N-bis (2-aminoethyl) amino.Formyl and the like. Examples of the "N-alkylcarbamoylalkyl" which may have a substituent on the alkyl group may include the above-mentioned C₁～C₆Straight or branched C substituted with N-alkylcarbamoyl which may have a substituent on the alkyl group₁～C₆Alkyl groups (e.g., N-methylcarbamoylmethyl, N- (2-hydroxyethyl) carbamoylmethyl, etc.). Examples of the N, N-dialkylcarbamoylalkyl group which may have a substituent on the alkyl group include the above-mentioned C ₁～C₆Straight or branched C substituted by N, N-dialkylcarbamoyl which may have a substituent on the alkyl group₁～C₆Alkyl groups (e.g., N, N-dimethylcarbamoylmethyl, N- (2-hydroxyethyl) -N-methylcarbamoylmethyl, etc.). Examples of the 3-to 6-membered heterocyclic carbonyl group which may have a substituent include groups composed of the above 3-to 6-membered heterocyclic group which may have a substituent and a carbonyl group (for example, aziridinylcarbonyl, azetidinylcarbonyl, 3-hydroxyazetidinylcarbonyl, 3-methoxyazetidinylcarbonyl, pyrrolidinylcarbonyl, 3-hydroxypyrrolidinylcarbonyl, 3-fluoropyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-dioxothiomorpholinylcarbonyl, tetrahydropyranylcarbonyl, pyridylcarbonyl, furoyl, thiophenecarbonyl and the like). The 3-to 6-membered heterocyclic carbonylalkyl group which may have a substituent is one wherein 1 of the above 3-to 6-membered heterocyclic carbonyl groups which may have a substituent is substituted for the above C₁～C₆Alkyl groups (e.g., azetidinylcarbonylmethyl, pyrrolidinylcarbonylethyl, and the like). The 3-to 6-membered heterocyclic carbonyloxyalkyl which may have a substituent may be exemplified by 1 in which the C is substituted with a 3-to 6-membered heterocyclic carbonyloxy group consisting of the above 3-to 6-membered heterocyclic carbonyl which may have a substituent and an oxygen atom ₁～C₆Alkyl groups (e.g., piperidinylcarbonyloxyethyl, morpholinylcarbonyloxymethyl, and the like). Carbamoyloxyalkyl is exemplified by 1 carbamoyloxy group consisting of 1 carbamoyl group and an oxygen atom substituted by the above-mentioned C₁～C₆Alkyl groups (e.g., carbamoyloxymethyl, carbamoyloxyethyl, etc.). Examples of the "N-alkylcarbamoyloxyalkyl" may include 1 or more of the above-mentioned C₁～C₆May have substitution on alkylBy substitution of the above-mentioned C by an N-alkylcarbamoyloxy group consisting of an N-alkylcarbamoyl group and an oxygen atom₁～C₆Alkyl groups (e.g., N-methylcarbamoyloxymethyl, N-methylcarbamoyloxyethyl, etc.). Examples of the "N, N-dialkylcarbamoyloxyalkyl" group may include 1 or more of the above-mentioned C₁～C₆The above-mentioned C is substituted with an N, N-dialkylcarbamoyloxy group consisting of an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group and an oxygen atom₁～C₆Alkyl groups (e.g., N, N-dimethylcarbamoyloxymethyl, N-ethyl-N-methylcarbamoyloxyethyl, etc.). The alkylsulfonylamino group may, for example, be 1 having the above-mentioned C₁～C₆Alkylsulfonyl of alkyl groups in place of amino groups (for example, methylsulfonylamino, isopropylsulfonylamino and the like). Examples of the arylsulfonylamino group include 1 group (for example, phenylsulfonylamino group, naphthylsulfonylamino group and the like) having an arylsulfonyl group-substituted amino group as described above. Examples of the "alkylsulfonylaminoalkyl" group may include 1 or more of the above-mentioned C ₁～C₆Alkylsulfonylamino substituted by said C₁～C₆Alkyl groups (e.g., methylsulfonylaminomethyl, methylsulfonylaminoethyl, etc.). Examples of the arylsulfonylaminoalkyl group include the above-mentioned C₁～C₆Alkyl groups substituted with 1 of the above-mentioned arylsulfonylamino groups (for example, phenylsulfonylaminomethyl groups, naphthylsulfonylaminoethyl groups, etc.). Examples of the alkylsulfonylaminocarbonyl group may include the above-mentioned C₁～C₆Alkyl sulfonyl amino group and carbonyl group (for example, methyl sulfonyl amino carbonyl, isopropyl sulfonyl amino carbonyl group). Examples of the arylsulfonylaminocarbonyl group include those composed of the arylsulfonylamino group and a carbonyl group (for example, phenylsulfonylaminocarbonyl group, naphthylsulfonylaminocarbonyl group and the like). Examples of the "alkylsulfonylaminocarbonylalkyl" group may include the above-mentioned C₁～C₆Alkylsulfonylaminocarbonyl group substituted for the above C₁～C₆Alkyl groups (e.g., methylsulfonylaminocarbonylmethyl, isopropylsulfonylaminocarbonylmethyl, and the like). Examples of the arylsulfonylaminocarbonylalkyl group may include the above-mentioned arylsulfonylaminocarbonyl group substituted by the above-mentioned C₁～C₆Alkyl radicals (e.g. phenylsulphonylaminocarbonylmethyl, naphthylsulphonamide)Alkylcarbonylmethyl, and the like). Examples of the alkoxycarbonylalkoxy group may include those wherein the above-mentioned alkoxycarbonyl group is substituted for the above-mentioned C₁～C₆The alkoxy group (for example, methoxycarbonylmethoxy group) and the acyloxy group represent a group composed of the above-mentioned acyl group and an oxygen atom (for example, formyloxy group, acetyloxy group, etc.). Examples of the acyloxyalkyl group may include those wherein the above acyloxy group is substituted for the above C ₁～C₆Alkyl groups (e.g., formyloxymethyl, acetoxymethyl, etc.). The aralkyloxy group may be a substituted aryl group of the above-mentioned C₁～C₆Alkoxy groups (e.g., benzyloxy, naphthylmethoxy, and the like). The carboxyalkoxy group may, for example, be a group obtained by substituting the above alkoxy group with a carboxyl group (for example, carboxymethoxy group, carboxyethoxy group, etc.).

The arylsulfonyl group may, for example, be C₆～C₁₄Arylsulfonyl (e.g., phenylsulfonyl, naphthylsulfonyl, and the like). Examples of the alkoxycarbonylalkylsulfonyl group may include the above-mentioned C₁～C₆Alkoxycarbonylalkyl and sulfonyl (for example, methoxycarbonylethylsulfonyl, ethoxycarbonylethylsulfonyl and the like). Examples of the carboxyalkylsulfonyl group may include groups composed of the above carboxyalkyl group and a sulfonyl group (for example, carboxymethylsulfonyl group, carboxyethylsulfonyl group and the like). Examples of the "alkoxycarbonylacyl" group may include the groups consisting of the aforementioned alkoxycarbonylalkyl group and carbonyl group (for example, methoxycarbonylmethylcarbonyl group, ethoxycarbonylmethylcarbonyl group and the like). The alkoxyalkoxycarbonyl group may include 1 or more of the above-mentioned C₁～C₆Alkoxy groups substituted for the above alkoxycarbonyl groups (for example, methoxymethoxycarbonyl group, methoxyethoxycarbonyl group, etc.). Examples of the "hydroxyacyl" group may include 1 hydroxyl group substituted for the above-mentioned acyl group (including C) ₁～C₆Alkanoyl and aroyl) (e.g., glycoloyl, propanooyl, diphenoxyoyl, etc.). The alkoxyacyl group may, for example, be 1 of the above-mentioned C₁～C₆Alkoxy groups substituted for the above acyl groups (for example, methoxyacetyl, ethoxyacetyl, etc.). Examples of the "haloacyl" group may include groups composed of the above-mentioned haloalkyl group and a carbonyl group (for example, chloromethylcarbonyl group, trifluoromethylcarbonyl group and the like). The carboxyacyl group may, for example, be a group obtained by substituting 1 carboxyl group for the above acyl group (for example, carboxyl group)Acetoacetyl, 2-carboxypropionyl, etc.). The aminoacyl group may be exemplified by 1 amino substituted with the above acyl group (including C)₁～C₆Alkanoyl and aroyl) (e.g., aminomethylcarbonyl, 1-aminoethylcarbonyl, etc.). Examples of the acyloxyacyl group may include groups composed of the acyloxyalkyl group and a carbonyl group (for example, formyloxymethylcarbonyl group, acetyloxymethylcarbonyl group and the like). Examples of the acyloxyalkylsulfonyl group may include those composed of the acyloxyalkyl group and a sulfonyl group (e.g., formyloxymethylsulfonyl group, acetyloxymethylsulfonyl group and the like). Examples of the hydroxyalkylsulfonyl group may include the above-mentioned C₁～C₆Hydroxyalkyl group and sulfonyl group (for example, hydroxymethylsulfonyl group, 1-hydroxyethylsulfonyl group and the like). The alkoxyalkylsulfonyl group may, for example, be C ₁～C₆Alkoxyalkyl groups and sulfonyl groups (for example, methoxymethylsulfonyl group, ethoxyethylsulfonyl group and the like). Examples of the 3-to 6-membered heterocyclic sulfonyl group which may have a substituent include groups composed of a 3-to 6-membered heterocyclic ring having the above substituent and a sulfonyl group (for example, aziridinylsulfonyl group, azetidinylsulfonyl group, pyrrolidinylsulfonyl group, piperidinylsulfonyl group, piperazinylsulfonyl group, morpholinylsulfonyl group, tetrahydropyranylsulfonyl group and the like). Examples of the 3-to 6-membered heterocyclic oxy group which may have a substituent include the groups composed of the 3-to 6-membered heterocyclic ring which may have a substituent and an oxygen atom (for example, tetrahydrofuryloxy group and the like). Examples of the N-alkylaminoacyl group may include those having 1 of the above-mentioned C on the nitrogen atom of the aminoacyl group₁～C₆Alkyl-substituted groups (e.g., N-methylaminoacetyl, N-ethylaminoacetyl, etc.). Examples of the N, N-dialkylaminoacyl group may include those wherein 2 of the above-mentioned C are present on the nitrogen atom of the aminoacyl group₁～C₆Alkyl-substituted groups (e.g., N, N-dimethylaminoacetyl, N-ethyl-N-methylaminoacetyl, etc.). Examples of the N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group may include the above-mentioned C₁～C₆The group in which the above-mentioned acyl group is substituted with an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group (for example, N, N-dimethylcarbamoylacetyl group, N, N-diethylcarbamoylacetyl group, N-ethyl-N-methylcarbamoylacetoacetyl group Etc.). Examples of the N, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group may include the above-mentioned C₁～C₆A group composed of an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group and a sulfonyl group (for example, N, N-dimethylcarbamoyl methylsulfonyl, N- (2-hydroxyethyl) -N-methylcarbamoyl methylsulfonyl, etc.). Examples of the alkylsulfonylacyl group may include 1 having the above-mentioned C₁～C₆Alkyl sulfonyl of alkyl group in place of acyl group (for example, methylsulfonylacetyl, isopropylsulfonylacetyl and the like).

Examples of the "N-arylcarbamoyl" group may include the above-mentioned aryl-substituted carbamoyl groups (for example, phenylcarbamoyl group, naphthylcarbamoyl group and the like). Examples of the N-3-to 6-membered heterocyclic carbamoyl group may include substituted carbamoyl groups with the above-mentioned 3-to 6-membered heterocyclic group which may have a substituent (for example, pyridylcarbamoyl group, thienylcarbamoyl group and the like). Examples of the "N-alkyl-N-arylcarbamoyl" may include the aforementioned N-arylcarbamoyl having a straight or branched C atom on the nitrogen atom₁～C₆Alkyl-substituted groups (e.g., N-methyl-N-phenylcarbamoyl, etc.). Examples of the N-alkyl-N-3-to 6-membered heterocyclic carbamoyl group may include the above-mentioned N-3-to 6-membered heterocyclic carbamoyl group having a straight or branched C atom ₁～C₆Alkyl-substituted groups (e.g., N-methyl-N-thienylcarbamoyl, etc.). Examples of the "N-arylcarbamoylalkyl" may include the straight-chain or branched-chain C substituted with the aforementioned N-arylcarbamoyl group₁～C₆Alkyl groups (e.g., phenylcarbamoylmethyl, etc.). Examples of the "N-3-to 6-membered heterocyclic carbamoylalkyl group" may include the straight-chain or branched C-substituted heterocyclic carbamoyl group having 3 to 6 members₁～C₆Alkyl groups (e.g., pyridylcarbamoylmethyl, etc.). Examples of the "N-alkyl-N-arylcarbamoylalkyl" may include the ones mentioned above which have a straight or branched C atom on the nitrogen atom₁～C₆Alkyl-substituted groups (e.g., N-methyl-N-phenylcarbamoylmethyl, and the like). Examples of the "N-alkyl" -N-3-to 6-membered heterocyclic carbamoylalkyl group may include the aforementioned N-3-to 6-membered heterocyclic carbamoylalkyl groupThe nitrogen atom of the acylalkyl group having a straight-chain or branched C₁～C₆Alkyl-substituted groups (e.g., N-methyl-N-thienylcarbamoylmethyl, and the like).

Aminothiocarbonyl is-C (═ S) -NH₂The "N-alkylaminothiocarbonyl" group represents an aminothiocarbonyl group substituted by 1 alkyl group, and examples thereof include a (methylamino) thiocarbonyl group and an (ethylamino) thiocarbonyl group. The N, N-dialkylaminothiocarbonyl group represents an aminothiocarbonyl group substituted with 2 alkyl groups, and examples thereof include a (dimethylamino) thiocarbonyl group, a (diethylamino) thiocarbonyl group, and an (ethylmethylamino) thiocarbonyl group. Examples of the "alkoxyalkyl" (thiocarbonyl) "and" alkylthioalkyl "may include straight-chain, branched or cyclic C ₁～C₆Alkylthio substituted straight, branched or cyclic C₁～C₆Alkyl groups (e.g., methylthiomethyl, 1-methylthioethyl, etc.). The N-acyl-N-alkylaminoalkyl group may be exemplified by amino-C₁～C₆Having C on the nitrogen atom of the alkyl group₁～C₆Alkyl and acyl substituted groups (e.g., N-acetyl-N-methylaminomethyl, etc.). Examples of the "alkyl" group include a phenyl group, a naphthyl group, a anthryl group, a.

The alkylene group represents 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 1 double bond and having 2 to 5 carbon atoms, and examples thereof include a vinylene group and a propenylene group. Examples of the alkylenedioxy group include a group having 1 to 5 carbon atoms such as a methylenedioxy group, an ethylenedioxy group, and a propylenedioxy group. Carbonyldioxy is a group represented by-O-C (═ O) -O-. In the above description, the substitution position is not particularly limited.

R³And R⁴Among the substituents represented herein, preferred are a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, an amino group, a hydroxyimino group, an alkoxyimino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, and an acylamino group which may have a substituent Acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyl, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carbamoyl, N-alkylcarbamoyl which may have a substituent on the alkyl group, N-dialkylcarbamoyl which may have a substituent on the alkyl group, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkylcarbamoyl, N-alkyl-N-alkoxycarbamoylalkyl, N-alkoxycarbam, Carbazolyl, alkylsulfonyl, alkylsulfonylalkyl, 3-to 6-membered heterocyclic carbonyl which may be substituted by 1 to 3 alkyl groups, 3-to 6-membered heterocyclic carbonyloxyalkyl which may be substituted, 3-to 6-membered heterocyclic group which may be substituted, carbamoylalkyl, carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, N-alkylcarbamoylalkyl which may be substituted on the alkyl group, N-dialkylcarbamoylalkyl which may be substituted on the alkyl group, alkylsulfonylamino, alkylsulfonylaminoalkyl, oxo, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, carboxyacyloyl, alkoxyalkoxycarbonyl, alkoxycarbonylalkyl, Haloacyl, N-dialkylaminoacyl, acyloxyacyl, alkoxyacyl, alkoxyalkylsulfonyl, N-dialkylcarbamoylacyl, N-dialkylcarbamoylalkylsulfonyl, alkylsulfonylacyl, carbonothioyl, N-alkylaminothioyl, N-dialkylaminothioyl or alkoxyalkyl (thiocarbonyl), etc., and further, R is preferable ³And R⁴Together represent an alkylene group, an alkenylene group, an alkylenedioxy group, a carbonyldioxy group, or the like.

Preferably, R is³And R⁴R in (1)³Is a hydrogen atom, R⁴The substituents mentioned above as preferred groups are exemplified. Then as R⁴Is morePreferable examples of the group 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, an acylamino group which may have a substituent, 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, an N-alkylcarbamoyl group which may have a substituent on an alkyl group, an N, N-dialkylcarbamoyl group which may have a substituent on an alkyl group, an N-alkenylcarbamoyl group, an N-alkenylcarbamoylalkyl group, an N-alkenyl-N-alkylcarbamoyl group, an N-alkenyl-N-alkylcarbamoylalkyl group, an N-alkoxycarbamoyl group, an N-alkyl-N, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonylalkyl, 3-to 6-membered heterocyclic carbonyl which may have substituents, 3-to 6-membered heterocyclic carbonyloxyalkyl which may have substituents, 3-to 6-membered heterocyclic alkyl which may have substituents, carbamoylalkyl, N-dialkylcarbamoyloxyalkyl, N-alkylcarbamoylalkyl which may have substituents on the alkyl group, N-dialkylcarbamoylalkyl which may have substituents on the alkyl group, alkylsulfonylamino, alkylsulfonylaminoalkyl, acyloxy, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, carboxyacyl, alkoxyalkoxycarbonyl, haloacyl, N, n-dialkylaminoacyl, acyloxyacyl, hydroxyacyl, alkoxyacyl, alkoxyalkylsulfonyl, N-dialkylcarbamoylacyl, N-dialkylcarbamoylalkylsulfonyl, alkylsulfonylacyl, carbonothioyl, N-alkylaminothioyl, N-dialkylaminothioyl, alkoxyalkyl (thiocarbonyl), or the like.

Of these groups, as R⁴Particularly preferred examples of the group (b) include a hydrogen atom, a hydroxyl group, an alkyl group, an N, N-dialkylaminoalkyl group, an acylamino group which may have a substituent, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylamino group, and ammoniaCarbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, 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-alkyl-N-alkoxycarbamoyl group, carbazolyl group which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl group, alkylsulfonylalkyl group, 3 to 6-membered heterocyclic carbonyl group which may have a substituent, 3 to 6-membered heterocyclic group which may have a substituent, N-dialkylcarbamoyloxyalkyl group, N-alkylcarbamoylalkyl group which may have a substituent on the alkyl group, N which may have a substituent on the alkyl group, n-dialkylcarbamoylalkyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, acyloxy, acyl, alkoxyalkoxycarbonyl, haloacyl, N-dialkylaminoacyl, hydroxyacyl, alkoxyacyl, carbonothioyl, N-alkylaminothioyl, N-dialkylaminothioyl, alkoxyalkyl (thiocarbonyl), or the like.

R³And R⁴Examples of the preferable specific substituent include a hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, an isopropyl group, an N, N-dimethylaminomethyl group, an N, N-dimethylaminoethyl group, an N, N-diethylaminomethyl group, an acetylamino group, a methoxyacetylamino group, an acetylaminomethyl group, an acetylaminoethyl group, a methoxy group, an ethoxy group, a methoxymethyl group, a methoxyethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a methoxycarbonylamino group, an ethoxycarbonylamino group, an N-allylcarbamoyl group, an N-allylcarbamoylmethyl group, an N-allyl-N-methylcarbamoyl group, an N-allyl-N-methylcarbamoylmethyl group, an N-allyl-N-methylcarbamoyl, N-methoxy-N-methylcarbamoyl, N, N-dimethylcarbazolyl, N, N, N' -trimethylcarbazolyl, methanesulfonyl, methanesulfonylmethyl, ethanesulfonylmethyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclopropylmethylcarbamoylA base, an N- (1-ethoxycarbonylcyclopropyl) carbamoyl group, an N- (2-hydroxyethyl) carbamoyl group, an N- (2-fluoroethyl) carbamoyl group, an N- (2-methoxyethyl) carbamoyl group, an N- (carboxymethyl) carbamoyl group, an N- (2-aminoethyl) carbamoyl group, an N- (2-amidinoethyl) carbamoyl group, an N, N-dimethylcarbamoyl group, an N, N-diethylcarbamoyl group, an N-ethyl-N-methylcarbamoyl group, an N-isopropyl-N-methylcarbamoyl group, an N-methyl-N-propylcarbamoyl group, an N- (2-hydroxyethyl) -N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-isopropyl-N-methylcarbamoyl group, an N-methyl-N-, N- (2-fluoroethyl) -N-methylcarbamoyl, N-bis (2-hydroxyethyl) carbamoyl, N-bis (2-fluoroethyl) carbamoyl, N- (2-methoxyethyl) -N-methylcarbamoyl, N-carboxymethyl-N-methylcarbamoyl, N-bis (2-aminoethyl) carbamoyl, azetidinylcarbonyl, 3-methoxyazetidinylcarbonyl, 3-hydroxyazetidiylcarbonyl, pyrrolidinylcarbonyl, 3-hydroxypyrrolidinylcarbonyl, 3-fluoropyrrolidinylcarbonyl, 3, 4-dimethoxypyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, (tetrahydropyran-4-yl) carbonyl, tetrahydropyran-4-yl, Benzoyl, pyridylcarbonyl, thiazolyl, 4, 5-dihydrothiazolyl, oxazolyl, 4, 5-dihydrooxazolyl, 5-methyloxazolyl, imidazolyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxothiomorpholinyl, tetrahydropyranyl, pyridyl, 1, 2, 4-oxadiazolyl, 3-methyl-1, 2, 4-oxadiazolyl, 5-methyl-1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 5-methyl-1, 3, 4-oxadiazolyl, 5- (trifluoromethyl) -1, 3, 4-oxadiazolyl, 1, 3-oxazolyl, 1, 3, 4-thiadiazolyl, and the like, 5-methyl-1, 3, 4-thiadiazolyl, 1, 3-oxazolidinyl, N-methylcarbamoylmethyl, N-methylcarbamoylethyl, N-ethylcarbamoylmethyl, N- (2-fluoroethyl) carbamoylmethyl, N- (2-methoxyethyl) carbamoylmethyl, N-dimethylcarbamoylmethyl, N-dimethylcarbamoylethyl, N- (2-fluoroethyl) -N-methylcarbamoylmethyl, N- (2-methoxyethyl) -N-methylcarbamoylmethyl, N-dimethylcarbamoyloxymethyl, 2- (N-ethyl-N-methylcarbamoylmethyl) Carbamoyloxy) ethyl group, methylsulfonylamino group, ethylsulfonylamino group, methylsulfonylaminomethyl group, methylsulfonylaminoethyl group, acetyl group, propionyl group, isobutyryl group, 2-methoxyethoxycarbonyl group, trifluoroacetyl group, N-dimethylaminoacetyl group, N-ethyl-N-methylaminoacetyl group, hydroxyacetyl group, 1-dimethyl-2-hydroxyethylcarbonyl group, methoxyacetyl group, 1-dimethyl-2-methoxyethylcarbonyl group, aminothiocarbonyl group, (dimethylamino) thiocarbonyl group, 2-methoxythioacetyl group and the like.

As previously described, R³And R⁴Is preferably R³Is a hydrogen atom, R⁴The above-mentioned specific substituents and the like. Particularly preferred is an N, N-dialkylcarbamoyl group which may have a substituent on the alkyl group, and among these, an N, N-dimethylcarbamoyl group is more preferred. R³And R⁴These substituents are not limited to these specific substituents.

[ regarding the group T⁰]

Group T⁰Represents a carbonyl group or thiocarbonyl group, but more preferably a carbonyl group.

[ regarding the group T¹]

Group T¹Represents a carbonyl group, a sulfonyl group, a group-C (═ O) -C- (═ O) -N (R ') -, a group-C (═ S) -C (═ O) -N (R ') -, a group-C (═ O) -C (═ S) -N (R ') -, a group-C (═ S) -N (R ') -, wherein R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, a group-C (═ O) -a ¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein 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) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³-C (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group, R^bRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, the group-C (═ NOR)^c)-C(＝O)-N(R^d) - (R in the radical)^cRepresents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, R^dRepresents 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) - (R in the radical)^eAnd R^fEach independently represents a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl group (thiocarbonyl group), R^gRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -NH-C (═ O) -, the group-C (═ S) -NH-C (═ O) -, the group-C (═ O) -NH-C (═ S) -, the group-C (═ S) -NHC (═ S) -, the group-C (═ O) -NH-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl.

In the above groups, A¹、A²And A³The alkylene group having 1 to 5 carbon atoms in the above-mentioned formula represents a linear, branched or cyclic alkylene group having 1 to 5 carbon atoms, and examples thereof include a methylene group, an ethylene group, a propylene group, a cyclopropylene group, a 1, 3-cyclopentylene group and the like. R ', R', R^a、R^b、R^c、R^d、R^e、R^fAnd R^gThe alkyl group in (3) is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group and an ethyl group. Examples of the "alkoxy" may include straight-chain, branched-chain or cyclic alkoxy having 1 to 6 carbon atoms, and examples thereof may include methoxy and ethoxy.

R^a、R^c、R^eAnd R^fThe alkanoyl group in (1) represents a group consisting of a straight-chain, branched or cyclic alkyl group having 1 to 6 carbon atoms and a carbonyl group, and may, for example, be an acetyl group or a propionyl group.

R^cThe aryl group in (A) represents a group having 6 to 14 carbon atoms, and examples thereof include phenyl and naphthyl. The aralkyl group represents a group in which an aryl group having 6 to 14 carbon atoms is substituted for a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a benzyl group and a phenethyl group.

Group T¹More preferred are carbonyl, the radical-C (═ O) -C- (═ O) -N (R ') -, the radical-C (═ S) -C (═ O) -N (R') -, the radical-C (═ O) -C (═ S) -N (R ') -, the radical-C (═ S) -N (R') -, and the radical-C (═ O) -CH-₂-N (R ' -, particularly preferably carbonyl, the radical-C (═ O) -C- (═ O) -N (R ') -, the radical-C (═ S) -C (═ O) -N (R ') -, the radical-C (═ O) -C (═ S) -N (R ') -, the radical-C (═ S) -N (R ') -.

[ with respect to the group R¹And R²]

R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, but is preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom.

R¹And R²In the above formula, the alkyl group is 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 is a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group and an ethoxy group. R¹And R²Preferably, each independently represents a hydrogen atom or an alkyl group, and more preferably, both are hydrogen atoms.

T¹Is carbonyl or sulfonyl, the radical Q³Q in (1)⁵When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q⁴It is preferred that (b), (f), (g), (h), (i), (j), (k) and (l) among the aforementioned 12 groups (in the group (f), N represents R¹⁹2 carbon atoms of the substituted ring are substituted with nitrogen atoms).

Furthermore, T¹Is carbonyl or sulfonyl, the radical Q³Q in (1)⁵When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q⁵The substituent(s) is preferably an N-alkylcarbamoyl group or an N, N-dialkylcarbamoyl group.

T¹Is a radical-C (═ O) -C- (═ O) -N (R ') -, a radical-C (═ S) -C (═ O) -N (R') -, a radical-C (═ O) -C (═ S) -N (R ') -, or a radical-C (═ S) -N (R') -, a radical Q ³Q in (1)⁵When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q⁴Preferred are (i), (j) and (k) among the above 12 groups.

Furthermore, T¹Is a radical-C (═ O) -C- (═ O) -N (R ') -, a radical-C (═ S) -C (═ O) -N (R') -, a radical-C (═ O) -C (═ S) -N (R ') -, or a radical-C (═ S) -N (R') -, a radical Q³Q in (1)⁵When the group is an alkylene group having 1 to 8 carbon atoms or an alkenylene group having 2 to 8 carbon atoms, Q⁵The substituent(s) is preferably an N-alkylcarbamoyl group or an N, N-dialkylcarbamoyl group.

The compound represented by the general formula (1), a salt thereof, a solvate thereof or an N-oxide thereof of the present invention is represented by the group T¹And a group Q³The combination (a) has characteristics, and the following 2 cases ((I) and (II)) are approximately obtained.

(I)T¹Represents a carbonyl, sulfonyl, 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-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl, Q³Represents a group represented by the following formula (I),

in the basic formula, Q⁵Represents a radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nWherein m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO ₂-NH-).

(II)T¹Represents a group-C (═ O) -C- (═ O) -N (R ') -, a group-C (═ S) -C (═ O) -N (R ') -, a group-C (═ O) -C (═ S) -N (R ') -, a group-C (═ S) -N (R ') -, where R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ O) -a¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein 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) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³- (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group, R^bRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, the group-C (═ NOR)^c)-C(＝O)-N(R^d) - (R in the radical)^cRepresents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, R^dRepresents 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) - (R in the radical)^eAnd R^fEach independently represents a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl group (thiocarbonyl group), R ^gRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -NH-C (═ O) -, the group-C (═ S) -NH-C (═ O) -, the group-C (═ O) -NH-C (═ S) -, the group-C (═ S) -NHC (═ S) -, the group-C (═ O) -NH-SO₂-, yl-SO₂-NH-, group-C (═ NCN) -NH-C (═ O) -, group-C (═ S) -C (═ O) -or thiocarbonyl, Q³Represents a group represented by the following formula (I),

in the basic formula, Q⁵Represents an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or a group- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nWherein m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-).

Of the above (I) and (II), the following (I) and (II) are preferred examples.

(i) Radical R¹And a radical R²Each independently of the others, is a hydrogen atom or an alkyl group, a group Q¹Is a saturated or unsaturated 2-or 3-ring fused hydrocarbon group which may have a substituent or a saturated or unsaturated 2-or 3-ring fused heterocyclic group which may have a substituent, a group Q²Is a single bond, group Q³Q in (1)⁵Is a radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n- (where m and n are each independently 0 or 1, A is as defined above) and a group Q⁴9 groups selected from the group consisting of (a) to (h) and (1) among the above 12 groups, group T ⁰Is a carbonyl or thiocarbonyl group, the group T¹Is carbonyl or sulfonyl.

(ii) In the general formula (1), the group R¹And a radical R²Each independently of the others, is a hydrogen atom or an alkyl group, a group Q¹Is a saturated or unsaturated 2-or 3-ring fused hydrocarbon group which may have a substituent or a saturated or unsaturated 2-or 3-ring fused heterocyclic group which may have a substituent, a group Q²Is a single bond, group Q³Q in (1)⁵Is C3-6 alkylene or- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n- (where m and n are each independently 0 or 1, A is as defined above) and a group Q⁴The group T being 3 of the aforementioned 12 groups selected from (i), (j) and (k)⁰Is a carbonyl or thiocarbonyl group, the group T¹Is a radical-C (═ O) -C- (═ O) -N (R ') -, a radical-C (═ S) -C (═ O) -N (R') -, a radical-C (═ O) -C (═ S) -N (R ') -, or a radical-C (═ S) -N (R') -.

The compound represented by the general formula (1) of the present invention may exist as stereoisomers or optical isomers derived from chiral carbon atoms, and these stereoisomers, optical isomers and mixtures thereof are included in the scope of 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 pharmaceutically acceptable, and specific examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate and sulfate, organic sulfonic acid salts such as benzoate, methanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate, and organic carboxylic acid salts such as acetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and mandelate. When the compound represented by the general formula (1) has an acidic group, a salt may be formed with an alkali metal ion or an alkaline earth metal ion. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specifically, a hydrate, an ethanolate, and the like may be mentioned. In addition, N-oxide species may also be formed in the presence of nitrogen atoms in the general formula (1).

The compound of the present invention is particularly preferably a compound or a salt of the compound shown in examples described below, or the following compound or a salt thereof.

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 (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 ] pyridin-2-yl) carbonyl ] amino } cyclohexyl) -4a, 8 a-dihydro-4H-1, 2, 4-benzoxadiazine-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- [ (dimethyl-ammonia)Yl) 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-benzotriazazepine -2-carboxamides

6) 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-3, 4-dihydro-2 (1H) -1, 2, 4-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-propionyl ] amino } -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 group]Cyclohexyl } -6-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d)]Aza derivatives-2-carboxamides

11) 5-chloro-N- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- ({ [5- (3-pyrrolidino) thiazol-2-yl ] carbonyl } amino) cyclohexyl ] indole-2-carboxamide

12)N¹- (4-chlorophenyl) -N ²- ((1S, 2R) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

13)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

14)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R) -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

15)N¹- (4-chlorophenyl) -N²- ((1S, 2R) -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

16)N¹- (5-chloropyridin-2-yl) -N²- ((1R, 2R) -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclopentyl) oxalamides

17)N¹- (4-chlorophenyl) -N²- ((1R, 2R) -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclopentyl) oxalamides

18)N¹- (4-chlorophenyl) -N²- ((1R, 2R) -2- [ [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cycloheptyl) oxalamides

19)N¹- (5-chloropyridin-2-yl) -N²- ((1R, 2R) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cycloheptyl) oxalamides

20)N¹- (5-chloropyridin-2-yl) -N²- ((1R, 2R) -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cycloheptyl) oxalamides

21)N¹- (4-chlorophenyl) -N²- ((1R, 2R) -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cycloheptyl) oxalamides

22)N¹- (5-chloro-6-methylpyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

23)N¹- (5-chloro-3-methylpyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

24)N¹- (5-chloro-4-methylpyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

25)N¹- (4-chloro-3-hydroxyphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

26)N¹- (4-chloro-2-hydroxyphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group ]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

27)N¹- [ 4-chloro-2- (fluoromethyl) phenyl group]-N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

28)N¹- [ 4-chloro-2- (methoxymethyl) phenyl group]-N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

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)N¹- (5-chloropyridin-2-yl) -N²- ((1R, 2R, 4R) -4- (hydroxymethyl) -2- { [ (5-methyl)-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridin-2-yl) carbonyl]Amino } cyclopentyl) oxalamides

31)N¹- (5-chloropyridin-2-yl) -N²- ((1R, 2R, 4S) -4- (hydroxymethyl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclopentyl) oxalamides

32)N¹- ((3R, 4S) -1-acetyl-3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c) ]Pyridin-2-yl) carbonyl]Amino } piperidinyl-4-yl) -N²- (5-chloropyridin-2-yl) ethanediamide

33)N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (methylsulfonyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidinyl-4-yl) oxalamides

34)N¹- { (1S, 2R, 4S) -2- { [ (3-chlorobenzothien-2-yl) carbonyl]Amino } -4- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide

35)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) thiocarbonyl)]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

36)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) thiocarbonyl]Amino } cyclohexyl) oxalamides

37)N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-Methoxythioacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

38)N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) thiocarbonyl ]Amino } piperidin-4-yl) ethylDiamides

39) N- [ (3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

40) N- [ (3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-thioacetyl } amino) -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

41)N¹- (4-chlorophenyl) -N²- ((3R, 4S) -1- (2-Methoxythioacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

42)N¹- (4-chlorophenyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) thiocarbonyl]Amino-piperidin-4-yl-oxalamides

43) N- [ (3R, 4S) -4- { [2- (4-Chloroanilino) -2-oxothioacetyl ] amino } -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

44) N- [ (3R, 4S) -4- ({2- [ (4-chlorophenyl) amino ] -2-thioacetyl } amino) -1- (2-methoxyacetyl) piperidin-3-yl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

45)N¹- ((1S, 2R, 4S) -4- (1-azetidinylcarbonyl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (5-chloropyridin-2-yl) ethanediamide

46)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1-pyrrolidinylcarbonyl) cyclohexyl]Oxalamides

47)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1-piperidinylcarbonyl) cyclohexyl]Oxalamides

48)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (4-morpholinylcarbonyl) cyclohexyl]Oxalamides

49)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (methylamino) carbonyl)]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

50) N- { (1R, 2S, 5S) -2- ({2- [ (6-Chloropyridazin-3-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

51)N¹- (4-bromophenyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamides

52)N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-Methoxyacetyl) -3- { [4- (pyridin-4-yl) benzoyl]Amino-piperidin-4-yl-oxalamides

53)N¹- (5-chloropyridin-2-yl) -N²- [ (3R, 4S) -1- (2-Methoxyacetyl) -3- ({ [2- (pyridin-4-yl) pyrimidin-5-yl)]Carbonyl } amino) piperidin-4-yl]Oxalamides

54)N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- ({ [2- (pyridin-4-yl) pyrimidin-5-yl]Carbonyl radical]Amino) cyclohexyl]Oxalamides

55) N- { (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) -2-oxoethane (methoxy) imino ] 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-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

57)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (4, 4, 5-trimethyl-5, 6-dihydro-4H-pyrrolo [3, 4-d) ]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

58)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (4, 4-ethylene-5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

59) N- { (1R, 2S, 5S) -2- ({ [ (E) -2- (4-chlorophenyl) ethenyl ] 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-tetrahydrothiazolo [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-Chloropyrimidin-2-yl) amino ] -2-oxothioacetyl } 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-oxothioacetyl } amino) -5- [ (dimethylamino) 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-oxothioacetyl } 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-oxothioacetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

66)N¹- (4-chlorothiazol-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

67)N¹- ((1S, 2R, 4S) -5- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (3-fluorophenyl) oxalamides

68)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²-Phenyloxalamides

69)N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (pyridin-2-yl) ethanediamides

70)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5, 6, 6-trimethyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

71)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (4, 4, 5, 6, 6-pentamethyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

72)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2-{[ 2-methyl-2, 3-dihydrothiazolo [5, 4-d ]]Isoxazol-5-yl) carbonyl]Amino } cyclohexyl) oxalamides

73)N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (2-methyl-2, 3-dihydrothiazolo [4, 5-d)]Isoxazol-5-yl) carbonyl]Amino } cyclohexyl) oxalamides

74)N¹- (5-chloro-2-furyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

75)N¹- (5-chlorooxazol-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

76)N¹- (5-chloro-1H-imidazol-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

77) N- { (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) -1-ethoxyimino-2-oxoethyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [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-Benzyloxyiimino-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-oxoethyl ] 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-Thioacetylhydrazono) -2-oxoethyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [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

The process for producing the diamine derivative (1) of the present invention will be described below.

[ 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.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹And R²As mentioned above, T¹Is a carbonyl group]

Compound (1) of the present invention can be obtained by deriving carboxylic acid (3) as a mixed acid anhydride, acid halide, active ester or the like, reacting diamine (2) with the compound (4) to obtain compound (4), and reacting the compound (4) thus obtained with carboxylic acid (5) under the same conditions. In the reaction of each step, a reaction reagent and conditions generally used for peptide synthesis may be used. The mixed acid anhydride can be produced, for example, by reacting a chloroformate such as ethyl chloroformate or isobutyl chloroformate with carboxylic acid (3) in the presence of a base. The acid halide can be obtained by treating carboxylic acid (3) with an acid halide such as thionyl chloride or oxalyl chloride. The active ester can be obtained by reacting a phenol such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide, and the like with the carboxylic acid (3) using a condensing agent such as N, N' -dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The active ester can also be produced by a reaction between a carboxylic acid (3) and pentafluorophenyl trifluoroacetate or the like, a reaction between a carboxylic acid (3) and 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate, a reaction between a carboxylic acid (3) and diethyl cyanophosphonate (salt-addition method), a reaction between a carboxylic acid (3) and triphenylphosphine and 2, 2' -dipyridyl disulfide (Mount-John method), or the like. Compound (4) can be produced by reacting the mixed acid anhydride, acid halide or active ester of carboxylic acid (3) obtained above with diamine (2) in the presence of an appropriate base in an inert solvent at-78 ℃ to 150 ℃. Compound (1) of the present invention can be obtained 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 those in the reaction of the diamine (2) and the carboxylic acid (3).

Specific examples of the base used in each step include carbonates, alkali metal alkoxides, alkali metal hydroxides or hydrides of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, organometallic bases typified by alkyllithium such as N-butyllithium or dialkylaminolithium such as diisopropylaminolithium, organometallic bases of disilylamine such as bis (trimethylsilyl) aminolithium, and organic bases such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] undecene-7 (DBU).

The inert solvent used in the reaction may, for example, be a halogenated alkyl solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether solvent such as tetrahydrofuran, 1, 2-dimethoxyethane or dioxane, an aromatic solvent such as benzene or toluene, an amide solvent such as N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidin-2-one, or a sulfoxide solvent such as dimethylsulfoxide or sulfolane, or a ketone solvent such as acetone or methyl ethyl ketone.

[ production method 2]

The compound (1) of the present invention can also be produced by the following method.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹And R²As mentioned above, T¹For carbonyl, Boc is tert-butoxycarbonyl and Boc-ON is 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile]

Compound (1) of the present invention can be obtained by treating diamine (2) with Boc-ON (6) as described above to prepare compound (7) having one of 2 amino groups protected with tert-butoxycarbonyl, reacting the obtained compound (7) with carboxylic acid (5) to obtain compound (8), treating with an acid to obtain compound (9), and reacting (9) with carboxylic acid (3). The compound (7) can be produced by reacting in a solvent such as methylene chloride in the presence of triethylamine at-10 ℃ to 40 ℃. Compound (8) can be obtained by reacting compound (7) with a mixed acid anhydride, acid halide or active ester of carboxylic acid (5) under the reagents and reaction conditions described in preparation Process 1. The resulting compound (8) can be treated with trifluoroacetic acid or the like at-20 ℃ to 70 ℃ to obtain amine (9). In the reaction of the obtained amine (9) and carboxylic acid (3), the same reagents and reaction conditions as those described in preparation Process 1 can be employed.

However, the tert-butoxycarbonyl group of compound (7) may be replaced with another amino-protecting group. In this case, the reagent (6) is also replaced with another reagent, and reaction conditions and the like corresponding thereto must be employed. Examples of the other amino-protecting group include an alkanoyl group such as an acetyl group, an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group, an arylmethoxycarbonyl group such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group or a p- (or o-) nitrobenzyloxycarbonyl group, an arylmethyl group such as a benzyl group or a trityl group, an aroyl group such as a benzoyl group, and an arylsulfonyl group such as a 2, 4-dinitrobenzenesulfonyl group or an o-nitrobenzenesulfonyl group. These protecting groups may be selected according to the nature of the compound protecting the amino group, and even when these protecting groups are cleaved, reagents and reaction conditions corresponding to the protecting groups may be selected.

[ production method 3]

The compound (1) of the present invention can be produced by reacting the diamine (2) with the sulfonyl halide (10) and then condensing the reaction product with the carboxylic acid (5).

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹And R²As mentioned above, T¹Is sulfonyl, X is halogen]

The compound (4) can be obtained by reacting the diamine (2) with the sulfonyl halide (10) in an inert solvent in the presence of a base such as triethylamine at-10 ℃ to 30 ℃. The inert solvent and the base can be appropriately selected and used from those described in preparation Process 1. Compound (1) of the present invention can be obtained by condensing the resulting (4) with carboxylic acid (5) using the reagents and reaction conditions described in preparation Process 1. The sulfonyl halide (10) can be synthesized by a known method (WO 96/10022, WO 00/09480) or a method based thereon in the presence of an appropriate base.

[ production method 4]

The compound (1) of the present invention can also be prepared by the following method.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And X is as defined above, T¹Is a sulfonyl group]

That is, the compound (1) can be obtained by reacting the amine (9) with the sulfonyl halide (10) in an inert solvent in the presence of a base at-10 ℃ to 30 ℃. The inert solvent and the base can be appropriately selected from those described in preparation Process 1.

[ production method 5]

Q of Compound (1) of the present invention ³When the moiety (c) is a group as described below,

[ group, R³、R⁴And Q⁵As previously mentioned, the numbers of 1 and 2 represent positions]

The trans and cis geometric isomers may exist in the relationship between position 1 and position 2. The following describes a method for producing the cis-and trans-form compounds (1).

[ Process for producing Trans-form ]

[ wherein Q⁵、R³And R⁴As described above]

As a preparation example of the trans diol (12a) from the cyclic ene (11), for example, a conversion from cyclohexene to trans cyclohexanediol (Organic Synthesis, 1955, volume III, page 217) and the like are known. Further, as a preparation example of the conversion from trans diol (12a) to trans diamine (2a), the conversion from trans cyclopentanediol to trans cyclopentanediamine (WO 98/30574) and the like have been reported. According to these reports, trans diamine (2a) can be obtained from cyclic alkene (11).

Trans-diamine (2a) produced by the above-mentioned process can be further subjected to the above-mentioned production processes 1 to 4 to obtain trans-compound (1).

[ Process for producing cis-form ]

[ wherein Q⁵、R³And R⁴As described above]

As a preparation example of the cis-diol (12b) from the cyclic alkene (11), for example, conversion from cyclohexene to cis-cyclohexanediol (J.org.chem, 1998, volume 63, page 6094) and the like are known. Further, as a preparation example of the cis-diol (12b) converted into the cis-diamine (2b), a conversion of cis-cyclopentanediol into cis-cyclopentanediamine (WO 98/30574) and the like have been reported. According to these reports, cis-diamine (2b) can be produced.

The cis-diamine (2b) produced by the above-mentioned method can be used to produce the cis-compound (1) by the above-mentioned production methods 1 to 4.

[ preparation method 6]

As described above, Q of Compound (1) of the present invention³The moiety (A) may have trans and cis forms, and may have geometrical isomers, and further may have optical isomers, respectively. The following describes a method for producing an optically active substance.

[ formula (II) Q⁵、R¹、R²、R³And R⁴As previously described, R⁵⁰Being protecting groups for amino groups]

As a method for producing the optically active 1, 2-trans aminoalcohol derivative (15), for example, a method for producing optically active 1, 2-trans-2-aminocyclopentanol from cyclopentene oxide or a method for producing optically active 1, 2-trans-2-aminocyclohexanol from cyclohexene oxide are known (Tetrahedron: Asymmetry, 1996, Vol.7, p.843; J.Org.Chem., 1985, Vol.50, p.4154; J.Med.Chem., 1998, Vol.41, p.38). The compound (16) can be obtained by reacting the amino group of the optically active aminoalcohol derivative (15) obtained by the known method or by using the method with an appropriate protecting agent. With R in the compound (16)⁵⁰Among the conventional acyl-type protecting groups, preferred are an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group, an arylmethoxycarbonyl group such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group or a p- (or o-) nitrobenzyloxycarbonyl group, and an arylsulfonyl group such as a 2, 4-dinitrobenzenesulfonyl group or an o-nitrobenzenesulfonyl group. For example, when the protection is performed by t-butoxycarbonyl group, compound (16) can be obtained by reacting aminoalcohol derivative (15) with di-t-butyl dicarbonate in an inert solvent at-78 ℃ to 50 ℃. The inert solvent can be suitably selected from the solvents described in preparation Process 1.

Compound (17) can be obtained by reacting compound (16) with methanesulfonyl chloride in the presence of a base at-78 to 50 ℃ in an inert solvent. The inert solvent can be suitably selected from the solvents described in preparation Process 1. The base is preferably an organic base such as pyridine, 2, 6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undecene-7 (DBU), etc.

Compound (18) can be obtained by reacting compound (17) with sodium azide in an appropriate solvent at-10 ℃ to 150 ℃. The solvent is preferably an amide solvent such as N, N-dimethylformamide, N-dimethylacetamide, or N-methylpyrrolidin-2-one, an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran, 1, 2-dimethoxyethane, or dioxane, a benzene solvent such as toluene, a halogenated carbon such as dichloromethane, chloroform, or carbon tetrachloride, acetone, dimethylsulfoxide, or a mixed solvent of these solvents and water.

Examples of the method for converting the azide derivative (18) into the compound (7a) include a method of hydrogenation using a palladium catalyst, a raney nickel catalyst or a platinum catalyst, a method of reaction using a reducing agent such as lithium aluminum hydride, sodium borohydride or zinc borohydride, a method of reaction using zinc in the presence of nickel chloride or cobalt chloride, a method of reaction using triphenylphosphine, and the like, and appropriate reaction conditions can be selected depending on the properties of the compound. For example, the compound (7a) can be obtained from the azide compound (18) by hydrogenation at a temperature of-10 to 70 ℃ in an appropriate solvent using 1 to 20% palladium on carbon as a catalyst. The hydrogen pressure can be raised above atmospheric pressure. The solvent is preferably an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran, 1, 2-dimethoxyethane or dioxane, an amide solvent such as N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidin-2-one, an ester solvent such as ethyl acetate, acetic acid, hydrochloric acid, water or a mixed solvent of these solvents.

According to the above production method 2, the optically active compound (1) can be obtained from the optically active amine (7a) produced by the above method. Furthermore, the enantiomer (1) of the optically active form (1) can be obtained from the optically active amine (7a) by the same method.

Further, the optically active compound (1) can also be obtained by separating the racemate (1) through a column formed from an optically active carrier. The optically active compound (1) can also be obtained by separating the intermediate (2), (4), (7), (8) or (9) of the racemic modification (1) using a column formed of an optically active carrier, isolating the optically active compound (2), (4), (7), (8) or (9), and then carrying out the preparation methods 1 to 4. The isolation method of (1), (2), (4), (7), (8) or (9) having optical activity may be 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.

[ production method 7]

Hereinafter, Q in the compound (1) of the present invention is shown³The process for producing the compound (1c) containing a hetero atom is described in detail.

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 Q¹、Q²、Q⁴、R³、R⁴A, m and n are as previously described, T¹Represents a carbonyl group]

Compound (1c) of the present invention can be obtained by deriving carboxylic acid (3) as a mixed acid anhydride, acid halide, active ester or the like, reacting compound (2c) with compound (4c) to obtain compound (4c), and reacting compound (4c) obtained with carboxylic acid (5) under the same conditions.

In the reaction of each step, a reaction reagent and conditions generally used for peptide synthesis may be used. The mixed acid anhydride can be produced, for example, by reacting a chloroformate such as ethyl chloroformate or isobutyl chloroformate with carboxylic acid (3) in the presence of a base. The acid halide can be obtained by treating carboxylic acid (3) with an acid halide such as thionyl chloride or oxalyl chloride. The active ester can be obtained by reacting a phenol such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide with the carboxylic acid (3) using a condensing agent such as N, N' -Dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The active ester can also be produced by a reaction between a carboxylic acid (3) and pentafluorophenyl trifluoroacetate or the like, a reaction between a carboxylic acid (3) and 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate, a reaction between a carboxylic acid (3) and diethyl cyanophosphonate (salt-addition method), a reaction between a carboxylic acid (3) and triphenylphosphine and 2, 2' -dipyridyl disulfide (Mount-John method), or the like. Compound (4c) can be produced by reacting the mixed acid anhydride, acid halide or active ester of carboxylic acid (3) obtained above with compound (2c) in the presence of an appropriate base in an inert solvent under cooling to heating. Compound (1c) of the present invention can be obtained by reacting the obtained compound (4c) 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 (4c) and the carboxylic acid (5) are the same as those in the reaction of the compound (2c) and the carboxylic acid (3).

Specific examples of the base used in each step include carbonates of alkali metals or alkaline earth metals such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium ethoxide and potassium butoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium hydride, or alkali metal hydrides, or organic bases such as alkyllithium such as N-butyllithium, or dialkylaminolithium such as diisopropylaminolithium, or organic bases such as bis-silylamines such as bis (trimethylsilyl) aminolithium, or organic bases such as pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, and diazabicyclo [5.4.0] undecene-7 (DBU).

Examples of the inert solvent used in the reaction include halogenated alkyl solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran and 1, 4-dioxane, aromatic solvents such as benzene and toluene, and amide solvents such as N, N-dimethylformamide. In addition, sulfoxide solvents such as dimethyl sulfoxide, ketone solvents such as acetone, and the like may be used depending on the case.

In the above-mentioned production steps, the compound (1c) of the present invention can be produced by the operation of addition and removal of an appropriate protecting group or conversion of a functional group.

As the protecting group for an amino group, there may be used a protecting group commonly used in peptide synthesis in the synthesis of organic compounds, and specific examples thereof include an alkoxycarbonyl group such as a tert-butoxycarbonyl group, a methoxycarbonyl group and an ethoxycarbonyl group, an arylmethoxycarbonyl group such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group and a p- (or o-) nitrobenzyloxycarbonyl group, an arylmethyl group such as a benzyl group, a 4-methoxybenzyl group and a trityl group, an alkanoyl group such as a formyl group and an acetyl group, an aroyl group such as a benzoyl group, and an arylsulfonyl group such as a 2, 4-dinitrobenzenesulfonyl group and an o-nitrobenz.

As the protecting group for a hydroxyl group, a protecting group for a hydroxyl group which is generally used in the synthesis of organic compounds can be used, and specific examples thereof include an alkoxymethyl group such as a methoxymethyl group, an arylmethyl group such as a benzyl group, a 4-methoxybenzyl group and a trityl group, an alkanoyl group such as an acetyl group, an aroyl group such as a benzoyl group, a tert-butyldiphenylsilyloxy group and the like. The carboxyl group can be protected by forming 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 addition and removal of the above-mentioned protecting group can be carried out according to a conventional method.

The compound in the compound (1c) of the present invention can form various derivatives by changing the functional group of the compound. For example, a common organic chemical method is a method of acylating a compound in which a is an unsubstituted nitrogen atom with a mixed acid anhydride, an acid halide, an active ester or the like to form an amide compound, reacting the amide compound with a sulfonyl halide or the like to produce a sulfonamide compound, reacting the sulfonamide compound with an alkyl halide to produce an N-alkyl compound, reacting an aryl halide or the like to produce an N-aryl compound, and reacting an isocyanate to produce a urethane compound. A is a compound having an unsubstituted nitrogen atom, and can be produced, for example, by preparing a compound (1c) from a diamine (2c) in which A is protected with a tert-butoxycarbonyl group according to preparation Process 7, and subjecting the compound (1c) to acid treatment.

The compound of the present invention obtained as above can be isolated and purified by a known method such as extraction, precipitation, differential chromatography, fractional crystallization, recrystallization, etc. In addition, the compounds of the present invention can form desired salts by ordinary salt-forming reactions.

In addition, the compounds of the present invention have optical isomers due to having chiral carbons. These optical isomers can be produced by a method of preparing from the optically active diamine (2c), a method of forming a salt of a racemic modification with an optically active amine or acid and then performing fractional crystallization, or a method of separating by using a column or the like which uses an optically active carrier.

Further, T can be produced by substituting the carboxylic acid (3) with a sulfonyl halide (10) in the reaction of the compound (2c) and the carboxylic acid (3)¹Compound (1c) which is a sulfonyl group.

[ production method 8]

The compound (1c) of the present invention can also be produced by the following method.

[ wherein Q¹、Q²、Q⁴、R³、R⁴A, m and n are as previously described, T¹Represents a carbonyl group, R⁵¹And R⁶¹A protecting group representing an amino group]

The protecting group R of the compound (19) obtained by removing the amino group of the compound (2c)⁶¹Compound (21) can be obtained. Here, as R⁵¹And R ⁶¹Exemplary AmmoniaThe protecting group of the group is not particularly limited as long as it is a group generally used for protecting an amino group, and typical examples thereof include the protecting group of an amino group described in preparation Process 7. In this case, R⁵¹And R⁶¹Must be a protecting group that can be removed by different methods or conditions. For example, R may be mentioned⁵¹Is tert-butoxycarbonyl, R⁶¹A combination of benzyloxycarbonyl groups, and the like. These protecting groups may be optionally selected depending on the nature of the compound protecting the amino group, and when these protecting groups are removed, reagents and reaction conditions corresponding to the protecting groups may be selected.

Further, compound (21) can be also obtained by converting the hydroxyl group of aminoalcohol body (20) into an amino group. Examples of the production of aminoalcohol (20) include conversion from methionine to 3-hydroxy-4-aminothiopyran-1, 1-dioxide (Tetrahedron lett., 37, page 7457, 1996), and the like.

Examples of the method for converting the hydroxyl group of the aminoalcohol compound (20) into the amino group include a method in which the aminoalcohol compound (20) is reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride or the like, and then reacted with ammonia, primary aralkylamines such as benzylamine, p-methoxybenzylamine and 2, 4-dimethoxybenzylamine, secondary aralkylamines such as dibenzylamine, hydroxylamines such as N-benzylhydroxylamine and N, O-dibenzylhydroxylamine or the like, and the benzyl group or the like is removed if necessary, to obtain the diamine (21). The aminoalcohol (20) can be obtained as the diamine (21) by a reaction (yamamoto method) in which treatment with triphenylphosphine and ethyl azodicarboxylate is performed, a reaction with phthalimide or succinimide, and then treatment with hydrazine, N-methylhydrazine, or the like. In addition, A in the formula is SO ₂And N is 0, the aminoalcohol (20) is reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride or the like, the aminoalcohol (20) is treated with an appropriate base or directly treated with triphenylphosphine and ethyl azodicarboxylate, the resulting α, β -unsaturated cyclic sulfone is added with primary aralkylamines such as ammonia, benzylamine, p-methoxybenzylamine, 2, 4-dimethoxybenzylamine or the like, secondary aralkylamines such as dibenzylamine or the like, hydroxylamines such as N-benzylhydroxylamine, N, O-dibenzylhydroxylamine or the like, and the benzyl group or the like is removed to obtain diamine(21)。

The resulting diamine compound (21) and carboxylic acid (3) are reacted to prepare compound (22), and then protecting group R is removed⁵¹After obtaining the compound (4c), the compound (4c) is reacted with the carboxylic acid (5) to obtain the compound (1c) of the present invention. In the reaction of the compound (21) with the carboxylic acid (3) and the reaction of the compound (4c) with the carboxylic acid (5), the same reagents and reaction conditions as described in preparation Process 7 were used.

Similarly, T can be produced by substituting the carboxylic acid (3) with a sulfonyl halide (10) in the reaction of the compound (21) and the carboxylic acid (3)¹Compound (1c) which is a sulfonyl group.

[ production method 9]

A typical production method of the production intermediate (2c) described in production method 7 will be described.

[ in the formula, R³、R⁴A, m and n are as previously described]

Examples of the diol (23) include 1, 2, 3, 6-tetrahydropyridine converted into 1-benzyloxycarbonyl-3, 4-cis-dihydroxypyrrolidine (Japanese patent laid-open No. Hei 7-138264), L-tartaric acid converted into (R, R) -tetrahydrofuran diol or (R, R) -N-benzylpyrrolidine diol (Tetrahedron: Asymmetry, volume 8, page 1861, 1997), and the like. By these known methods or by using the methods, a diol body (23) can be produced by removing a protecting group or converting a functional group as required.

Compound (24) can be produced by reacting diol (23) with methanesulfonyl chloride in the presence of a base in an inert solvent at a temperature of from cooling to room temperature. The inert solvent can be suitably selected from the solvents described in preparation Process 7, and particularly preferred are halogenated alkyl solvents such as methylene chloride and chloroform, and ether solvents such as tetrahydrofuran and 1, 4-dioxane. As the base, organic bases such as pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] undecene-7 (DBU) are preferred.

The azide (25) can be obtained by reacting the compound (24) with sodium azide in an appropriate solvent under cooling to heating. As the solvent, 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, aromatic solvents such as benzene and toluene, halogenated alkyl solvents such as dichloromethane and chloroform, dimethylsulfoxide, acetone, and the like are preferable. Mixtures of the above-mentioned conventional solvents and water may also be used.

Examples of the method for converting azide (25) into compound (2c) include hydrogenation using a palladium catalyst, raney nickel catalyst or platinum catalyst, reaction using a reducing agent such as lithium aluminum hydride or sodium borohydride, reaction using zinc in the presence of nickel chloride or cobalt chloride, and reaction using triphenylphosphine. The hydrogen pressure can be raised above atmospheric pressure. The solvent is preferably an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or 1, 4-dioxane, an amide solvent such as N, N-dimethylformamide or N-methylpyrrolidin-2-one, an ester solvent such as ethyl acetate, acetic acid, hydrochloric acid, water or a mixed solvent of these solvents. The compound (1c) of the present invention can be obtained by the diamine compound (2c) obtained by the above-mentioned method according to the above-mentioned preparation method 7.

The diol (23) is an optically active substance such as trans-3, 4-dihydroxytetrahydrofuran or trans-1-substituted-3, 4-dihydroxypyrrolidine. From these optically active diol bodies (23), optically active diamine bodies (2c) can be obtained, and the optically active compound (1c) of the present invention can be obtained according to preparation Process 7.

[ production method 10]

A typical production method of optically active compounds (30), (31) and (32) contained in compound (19) described in production method 8 will be described. The configuration of the chiral carbon shown in the following preparation scheme is shown as 1 example.

[ wherein m, n, R³、R⁵¹And R⁶¹As previously described, R⁷¹A protecting group representing a carboxyl group]

The optically active α, β -unsaturated ester compound (26) can be produced by a method described in the literature (J.org.chem., vol.61, p. 581, 1996; J.org.chem., vol.57, p. 6279, 1992, etc.) or by applying the method. Diastereoisomers (27a) and (27b) can be obtained by reacting an optically active α, β -unsaturated ester compound (26) with an amine in an appropriate solvent under cooling to heating. The amine can be suitably selected from those described in the above-mentioned production method 8. As the solvent, an organic solvent which does not react with the substrate, the product, the reagent, or the like can be used, and particularly, an alcohol-based solvent such as methanol or ethanol, or an ether-based solvent such as tetrahydrofuran, 1, 2-dimethoxyethane, or 1, 4-dioxane is preferable. Diastereoisomers (27a) and (27b) can also be obtained by reacting an α, β -unsaturated ester (26) with an organometallic base such as N-benzyl (trimethylsilyl) aminolithium and the like, using a method described in the literature (j. org. chem., volume 63, page 7263, 1998). By separating the diastereomer, (27a) can be used for the subsequent reaction, for example.

Compound (28) can be obtained by subjecting compound (27a) to acid treatment in an appropriate solvent under cooling to heating. Examples of the acid to be used include Lewis acids such as hydrochloric acid, sulfuric acid and boron trifluoride, trifluoroacetic acid and p-toluenesulfonic acid. As the solvent used in the reaction, water, and an alcohol solvent such as methanol and ethanol can be used. Mixtures of the above solvents and water may also be employed. In addition, a protecting group R for amino group is present in the reaction⁶¹A condition of being cut off. In this case, the amino group-protecting agent may be added as requiredAnd carrying out reaction.

The compound (28) is subjected to an acid treatment in a solvent under cooling to heating, whereby an optically active compound (30) can be obtained. The acid to be used may be suitably selected from the above-mentioned acids, and particularly preferred are Lewis acids such as boron trifluoride and p-toluenesulfonic acid. As the solvent used for the reaction, ether solvents such as 1, 4-dioxane and tetrahydrofuran, and aromatic solvents such as benzene and toluene can be used. Further, compound (30) can also be produced from azide (29). Examples of the preparation of the optically active azide (29) include conversion from L-aspartic acid to (R, R) - (3S, 4S) -3-amino-4-azido-5-oxotetrahydrofuran (Can, j.chem., volume 71, page 1407, 1993) and the like. By this known method or application of this method, an azide (29) having optical activity can be produced by removing a protecting group or converting a functional group as required. Compound (30) can be obtained by reducing the azide group of azide (29) to form an amino group and then reacting the amino group with an appropriate amino group-protecting reagent. Reduction of the azide group can be carried out under the same reaction conditions and using the same reagents as described in the process for converting azide (25) into compound (2c) of production Process 9.

Compound (31) can be obtained by converting the hydroxyl group moiety of compound (28) into an amino group and then treating it with a base. The method for converting the hydroxyl group of the compound (28) into an amino group can be carried out, for example, according to the above-mentioned production method 8. Alternatively, compound (31) can be obtained by treating alcohol (28) with an oxidizing agent and then reductively aminating the obtained aldehyde. Specific examples of the oxidizing agent used in the above reaction are preferably pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), sulfur trioxide pyridinium complex, and the like. Examples of the amine include primary alkylamines such as ammonia, methylamine and ethylamine, and primary aralkylamines such as benzylamine, p-methoxybenzylamine and 2, 4-dimethoxybenzylamine. The reduction method may be a method of hydrogenation using a palladium catalyst, a raney nickel catalyst or a platinum catalyst, a reaction using a reducing agent such as sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, or the like, and reagents and conditions may be selected depending on the nature of the compound or the like. Further, the base used in the above step can be appropriately selected from those described in preparation Process 7. Compound (31) can be produced by using compound (30) and an amine according to the method described in the literature (Tetrahedron, Lett., vol. 41, p. 1141, 2000; Heterocycles, vol. 53, p. 173, 2000) or by applying the method. Examples of the amine to be used include primary alkylamines such as ammonia, methylamine and ethylamine, primary aralkylamine such as benzylamine and p-methoxybenzylamine, and aniline.

Compound (32) can be obtained by treating compound (31) with a reducing agent in a solvent under cooling to heating. The reducing agent may, for example, be a reducing agent such as borane/tetrahydrofuran complex, borane/methyl sulfide complex or lithium aluminum hydride, and the reagents and reaction conditions may be selected according to the properties of the compound. As the solvent, an organic solvent which does not react with the substrate, the product, the reagent, or the like can be used, and tetrahydrofuran, 1, 4-dioxane, or the like is particularly preferable.

The optically active form (1c) of the compound of the present invention can be obtained by the above-mentioned production method 8 using the compounds (30), (31) and (32) obtained by the above-mentioned methods.

The above-mentioned production steps are exemplified for 1 type of optically active substance, and optically active substances having different steric configurations can be produced by the same steps as long as starting materials having different steric configurations are used.

[ production method 11]

T¹Compound (1) which is a-CO-N (R ') -group (R' in the group is as defined above) can be obtained by the following procedure.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CO-N (R ') -group (R' in the group is as defined above)]

That is, the compound (1) of the present invention can be obtained by deriving the carboxylic acid (33) into an acid halide, an active ester, or the like, reacting the compound with the diamine (2) to obtain the compound (4), and reacting the obtained compound (4) with the carboxylic acid (5) under the same conditions. In the reaction of each step, a reaction reagent and conditions generally used for peptide synthesis may be used. The acid halide can be obtained by treating carboxylic acid (33) with an acid halide such as thionyl chloride or oxalyl chloride. The active ester can be obtained by reacting a phenol such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide, and the like with the carboxylic acid (33) using a condensing agent such as N, N' -dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. Further, the active ester can be also produced by a reaction of a carboxylic acid (33) with pentafluorophenyl trifluoroacetate or the like, a reaction of a carboxylic acid (33) with 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate, a reaction of a carboxylic acid (33) with diethyl cyanophosphonate (salt-addition method), a reaction of a carboxylic acid (33) with triphenylphosphine and 2, 2' -dipyridyl disulfide (Mount-Johnson method), or the like. Compound (4) can be produced by reacting the mixed acid anhydride, acid halide or active ester of carboxylic acid (33) obtained above with diamine (2) in the presence of an appropriate base in an inert solvent at-78 ℃ to 150 ℃. Compound (1) of the present invention can be obtained 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 those in the reaction of the diamine (2) and the carboxylic acid (3 osmium). The base and the solvent used in each step described above can be appropriately selected from those described in production Process 1.

In addition, in the preparation of Q³Is a group represented by the following formula (I),

[ group, R³、R⁴And Q⁵As previously mentioned, the numbers of 1 and 2 represent positions]Relationship between 1 and 2 bitsIn the case of the trans-and cis-form of the compound (1), the diamine (2a) or (2b) described in preparation Process 5 can be used.

In addition, in the preparation of Q⁵In the case of the compound (1) containing a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom, the carboxylic acid (3) may be replaced with the carboxylic acid (33) in the reaction of the compound (2c) described in the production process 7 with the carboxylic acid (3). That is, Q can be produced by the following procedure⁵The compound (1) containing a hetero atom, i.e., the compound (1 c).

[ formula (II) Q¹、Q²、Q⁴、R³、R⁴R', A, m and n are as previously described, T¹Is a-CO-N (R ') -group (R' in the group is as defined above)]

[ production method 12]

T¹Compound (1) which is a-CO-N (R ') -group (R' in the group is as defined above) can also be prepared by the following procedure.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CO-N (R ') -group (R' in the group is as defined above)]

In the reaction of amine (9) and carboxylic acid (33), the same reagents and reaction conditions as those described in preparation Process 1 can be employed.

The amine (9) used herein can be produced, for example, by a step as a production step of the amine (41) described below, in addition to the step described in the production method 2.

[ in the formula, R³、R⁴、Q¹、Q²And Q⁵As previously described, R⁵²A protecting group representing an amino group]

The compound (34) in the above production step can be obtained by treating a cycloolefin with perbenzoic acid or a derivative thereof in a solvent such as dichloromethane and epoxidizing the treated product. The reaction conditions may be those conventional for the epoxidation of alkenes. Further, the compound (34) can be produced by the method described in J.org.chem., 61, 8687-8691 (1996) or a method based thereon.

Compound (36) can be obtained by catalytically reducing azide (35) obtained by treating compound (34) with sodium azide or the like and then protecting the amino group according to a conventional method. Examples of the protecting group of the amino group in this case may include those described in preparation Process 2. Compound (39) can be produced by forming azide (38) from compound (36) and then removing the amino-protecting group in the same manner as described in production Process 5. Compound (41) can be produced by reacting compound (39) with carboxylic acid (5) to give compound (40), and then subjecting the reaction product to catalytic reduction.

[ production method 13]

T can also be produced by changing the reaction of the compound (9) with the carboxylic acid (3) in the step described in production Process 2 to the reaction of the compound (9) with the carboxylic acid (33)¹Compound (1) which is a-CO-N (R ') -group (R' in the group is as defined above).

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CO-N (R') -radical (of the group)R' is as defined above)]

The reaction conditions may be the conditions described in preparation Process 2.

In addition, in the preparation of Q³Is a group represented by the following formula (I),

[ group, R³、R⁴And Q⁵As previously mentioned, the numbers of 1 and 2 represent positions]

Q⁵In the case of the compound (1) containing a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom, the carboxylic acid (3) may be replaced with the carboxylic acid (33) in the reaction of the compound (21) with the carboxylic acid (3) described in the production process 8. That is, Q can be produced by the following procedure⁵The compound (1) containing a hetero atom, i.e., the compound (1 c).

[ formula (II) Q¹、Q²、Q⁴、R³、R⁴R', A, m and n are as previously described, T¹Is a-CO-N (R ') - (where R' is as defined above) group, R is⁵¹A protecting group representing an amino group]

[ production method 14]

Reacting the compound (9) and Q described in the production method 2 in an inert solvent at-50 to 50 ℃ using a condensing agent⁴-N(R”)-A¹-CO₂H (42) reaction to obtain T¹is-CO-A¹-N (R ') -group (wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, A¹An alkylene group having 1 to 5 carbon atoms which may have a substituent(s). Examples of the condensing agent may include N, N' -dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbon Diimine hydrochloride, and the like. 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, and amide solvents such as N, N-dimethylformamide.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹is-CO-A¹-N (R ') -group (wherein R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, A¹Represents an alkylene group of a carbon atom acid 1 to 5 which may have a substituent]

For example, the compound (42) described in the above production method can be produced by reacting an ester of an aromatic amine such as 4-chloroaniline and a bromoalkanoic acid in a solvent such as acetonitrile or N, N-dimethylformamide in the presence of a base such as potassium carbonate at 40 to 120 ℃, and then hydrolyzing the ester with a base such as lithium hydroxide, potassium hydroxide or sodium hydroxide. The potassium salt of compound 42 and the like can be used directly for the reaction.

[ production method 15]

Reacting the compound (9) described in the production method 2 and an isocyanate (Q) in an inert solvent at-20 to 50 DEG C⁴-N ═ C ═ O) or isothiocyanates (Q)⁴-N ═ C ═ S) to give T¹Compound (1) which is-C (═ O) -NH-or-C (═ S) -NH-group. The inert solvent may, for example, be the solvent described in preparation Process 14. When the isocyanate or isothiocyanate to be used is not commercially available, it can be prepared by a conventional method as a method for preparing isocyanate or isothiocyanate.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹And R²As mentioned above, T¹is-C (═ O) -NH-group or-C (═ S) -NH-group]

[ preparation method 16]

The compound (9) and Q described in the production method 2 are reacted at room temperature to 150 ℃ in an inert solvent in the presence of a base as required⁴-NH-NH-CO₂Ph (43) reaction to obtain T¹A compound (1) which is a-CO-NH-group. As the inert solvent, in addition to acetonitrile or N, N-dimethylformamide, the solvent described in preparation Process 14 can be exemplified as a typical example. Examples of the base may include pyridine, 2, 6-dimethylpyridine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0 ]]Undecene-7 (DBU).

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹And R²As mentioned above, T¹is-CO-NH-NH-group, Ph is phenyl]

For example, compound (43) described in the above production method can be produced by reacting an arylhydrazine such as 4-chlorophenylhydrazine with diphenyl carbonate in a solvent such as acetonitrile, N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, 1, 2-dimethoxyethane, dioxane, benzene, toluene, or the like at room temperature to 120 ℃.

[ production method 17]

Reacting the compound (9) and Q of Process 2 in an inert solvent at-50 to 50 ℃ using a condensing agent ⁴-CO-A²-CO₂H (44) reacting to obtain T¹is-CO-A²-CO-group (in the formula, A)²Is a single bond or alkylene having 1 to 5 carbon atomsGroup) of the compound (1). Examples of the condensing agent include N, N' -dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The solvent may, for example, be the solvent described in preparation Process 16.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹And R²As mentioned above, T¹is-CO-A²-CO-group (in the formula, A)²Is a single bond or an alkylene group having 1 to 5 carbon atoms)]

In A²When the bond is a single bond, for example, a base such as lithium hydroxide, potassium hydroxide or sodium hydroxide, an aromatic heterocycle such as an aromatic hydrocarbon such as chlorobenzene or thiophene, and ethyl chlorooxoacetate (for example, ClCO-CO)₂Et) Friedel-crafts reaction of the compounds (e.g., Q)⁴-CO-CO₂Et) to obtain compound (44) described in the above production method.

Furthermore, A²In the case of methylene, for example, arylformyl chlorides such as 4-chlorobenzoyl chloride and heteroarylformyl chlorides such as thiophenoyl chloride are reacted with potassium malonate-monocarboxylate in the presence of magnesium chloride and triethylamine to obtain ketoester derivatives (e.g., Q)⁴-CO-CH₂-CO₂Et), and then hydrolyzing the derivative with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, or the like, to obtain compound (44). The carboxylic acid obtained by hydrolysis of the carbonyl group of the above ketoester derivative after glycolation can also be used for the reaction with the compound (9). Furthermore, A ²When the alkylene group has 2 or more carbon atoms, a ketone ester derivative (e.g., Q) obtained by Friedel-crafts reaction of an aromatic hydrocarbon such as benzene or an aromatic heterocycle such as thiophene with an alkylene dicarboxylic acid monoester monoacid chloride with a base such as lithium hydroxide, potassium hydroxide, or sodium hydroxide is used⁴-CO-A²-CO₂Et) to prepare compound (44).

[ preparation method 18]

Reacting the compound (9) and Q of Process 2 in an inert solvent at-50 to 50 ℃ using a condensing agent⁴-NH-CO-A³-CO₂H (45) reaction to obtain T¹is-CO-A³-CO-NH-yl (in the formula, A)³An alkylene group having 1 to 5 carbon atoms). 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, and amide solvents such as N, N-dimethylformamide.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹And R²As mentioned above, T¹is-CO-A³-CO-group (in the formula, A)³Is an alkylene group having 1 to 5 carbon atoms)]

In an inert solvent, a condensing agent is used, and the temperature is-50 to 50 ℃ so that the temperature is equivalent to Q ⁴-NH₂By reacting an aromatic amine such as 4-chloroaniline or a heteroaromatic amine such as aminopyridine with a potassium salt of an alkylenedicarboxylic acid monoester monocarboxylic acid⁴-NH-CO-A³-CO₂Et), and then the compound is hydrolyzed with a base such as lithium hydroxide, potassium hydroxide, or sodium hydroxide to obtain compound (45).

[ preparation method 19]

T¹Compound (1) which is a-CS-CO-N (R ') -group (wherein R' is as defined above) can be prepared according to the following procedure.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CS-CO-N (R ') -group (where R' is as defined above)]

That is, the compound (1) of the present invention can be produced by dissolving or suspending sodium thiosulfate (46) and the compound (9) in a solvent and heating. The reaction temperature is preferably from 80 to 200 ℃ and particularly preferably around 150 ℃. Examples of the solvent used in the reaction include water, alcohols such as methanol and ethanol, basic solvents such as pyridine and N-methylmorpholine, halogenated alkyl solvents such as methylene chloride and chloroform, ether solvents such as tetrahydrofuran, 1, 2-dimethoxyethane and dioxane, and amide solvents such as N, N-dimethylformamide. These solvents may be used in combination as appropriate, and examples of the mixed solvent include a mixed solvent of methanol and methylene chloride. In this reaction, the solvent is not necessarily refluxed, and for example, when a mixed solvent of methanol and methylene chloride is used, the reaction solution (or the reaction mixture) is heated to an external temperature of 150 ℃ and the solvent is distilled off, and then the residue is further heated at the same temperature.

[ production method 20]

T¹Compound (1) which is a-CO-CS-N (R ') -group (wherein R' is as defined above) can be prepared according to the following procedure.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CO-CS-N (R ') -radical (where R' is as defined above)]

I.e. in the presence of a baseNext, after the compound (47) is obtained by reacting the compound (9) with chloroacetyl chloride, the compound (47) and sodium thiosulfate are heated in a solvent, whereby a sodium thiosulfate derivative (48) can be obtained. For the above obtained (48) and the amine, i.e. NH (R') -Q⁴The compound (1) of the present invention can be obtained by heating.

The reaction conditions and the solvent and the like for preparing compound (47) from compound (9) can employ those generally used in the reaction of an amine and an acid chloride. When compound (48) is produced from compound (47), it may be refluxed with sodium thiosulfate in a solvent such as ethanol for about 1 hour. When the compound (47) is a salt such as hydrochloric acid, the reaction can be carried out in the presence of a base such as sodium hydrogencarbonate. The conditions for producing the compound (48) are not limited to those described herein, and the temperature, the type of solvent, and the type of base may be appropriately changed. Compound (48) and NH (R') -Q⁴The reaction conditions of (a) are the same as those described in preparation Process 19.

[ preparation method 21]

T⁰Compound (1) which is a thiocarbonyl (-CS-yl) group can be obtained by the following procedure.

[ wherein Q¹、Q²、Q³、Q⁴And R²As mentioned above, T¹is-SO₂-group, -CO-NH-group, -CS-NH-group, -CO-NH-NH-group, -CO-CO-N (R ') -group (wherein R' is as defined above), -CO-CS-N (R ') -group (wherein R' is as defined above), -CS-CO-N (R ') -group (wherein R' is as defined above), -CS-CS-N (R ') -group (wherein R' is as defined above), -CO-A¹-N (R') -yl (where A is¹And R' is as defined above), -CO-A²-CO-group (in which A is²As described above), -CO-A³-CO-NH-yl (where A³As described above), -CO-A³-CO-group (in which A is³As described above)]

That is, compound (1) of the present invention can be obtained by subjecting compound (49) and amine (50) to dehydration reaction in the presence of an acid catalyst such as p-toluenesulfonic acid to obtain compound (51), and then heating the compound (51) together with sulfur powder in a solvent such as a methanol/dichloromethane mixed solution. The conditions for preparing compound (51) from compound (49) and amine (50) can employ those generally used in the preparation of Schiff bases. Specifically, the compound can be refluxed with benzene or toluene in the presence of an acid catalyst under the condition of removing water from the reaction system by using a dean-Stark apparatus or the like. In addition, in the case of removing water from the reaction system, a molecular sieve may also be used.

[ preparation method 22]

T¹Compound (1) which is a-CS-CO-N (R ') -group (wherein R' is as defined above) can be prepared according to the following procedure.

[ wherein Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CS-CO-N (R ') -group (where R' is as defined above)]

In an inert solvent such as N, N-dimethylformamide or a basic solvent such as pyridine at-78 to 150 ℃ to give a solution corresponding to HN (R') Q⁴The aromatic amine such as 4-chloroaniline or the like or the heteroaromatic amine such as aminopyridine or the like is reacted with dichloroacetyl chloride to obtain the compound (52). In addition, dichloroacetic acid and HN (R') Q equivalent were reacted under the reagents and conditions described in preparation Process 1⁴Compound (52) can also be obtained by the amine reaction of (a).

The compound (52) and sulfur powder are suspended in a solvent, and a base such as diisopropylethylamine or triethylamine and the diamine (9) are added and reacted at a reaction temperature of 0 to 200 ℃ to obtain the compound (1) more efficiently. The amount of sulfur powder used for the reaction is preferably 1N. The reaction temperature is preferably from 60 ℃ to 160 ℃, particularly preferably from 90 ℃ to 140 ℃. Examples of the solvent used in the 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 and water.

[ production method 23]

T¹Compound (1) which is a-CS-CO-N (R ') -group (wherein R' is as defined above) can be prepared according to the following procedure.

[ wherein Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CS-CO-N (R ') -group (where R' is as defined above)]

In an inert solvent such as N, N-dimethylformamide or a basic solvent such as pyridine at-78 to 150 ℃ to give a solution corresponding to HN (R') Q⁴The aromatic amine such as 4-chloroaniline or the like or the heteroaromatic amine such as aminopyridine or the like is reacted with chloroacetyl chloride to obtain the compound (53). Furthermore, monochloroacetic acid and the equivalent HN (R') Q are reacted under the reagents and conditions described in preparation Process 1⁴Compound (53) can also be obtained by the amine reaction of (2).

The compound (53) and sulfur powder are suspended in a solvent, and after adding a base such as diisopropylethylamine or triethylamine and stirring for 5 minutes to 8 hours, diamine (9) and a condensing agent are added to carry out a reaction, thereby obtaining a compound (1). The amount of the sulfur powder used for the reaction is preferably 2N or more. The reaction temperature is preferably from 0 ℃ to 80 ℃. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and N, N' -dicyclohexylcarbodiimide. Examples of the solvent used in the reaction include amide solvents such as N, N-dimethylformamide, basic solvents such as N-methylmorpholine and pyridine, halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as dioxane, and acetonitrile. Further, the reaction may be carried out without a condensing agent to obtain the compound (1). In this case, in addition to the above-mentioned solvent, alcohols such as methanol and ethanol, water, and the like can be used.

[ production method 24]

T¹Compounds (1) which are the-CS-CO-N (R ') -radical (where R' is as defined above) can also be prepared by reaction of the corresponding compounds with T¹The following procedure for the preparation of compound (4) which is a-CS-CO-N (R ') -group (wherein R' is as defined above).

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹Is a-CS-CO-N (R ') -group (where R' is as defined above)]

That is, the compound (1) of the present invention can be obtained by reacting a dichloroacetamide (52) or a chloroacetamide (53), sulfur powder and an amine (7) in a solvent in the presence of a base, removing the protecting group to obtain a compound (4), and condensing the obtained compound (4) with a carboxylic acid (5). The compound (52) and sulfur powder are suspended in a solvent, and a base such as diisopropylethylamine or triethylamine and an amine (7) are added to carry out a reaction at a reaction temperature of 0 to 200 ℃ to more efficiently produce the compound (54). The amount of sulfur powder used for the reaction is preferably 1N. The reaction temperature is preferably from 60 ℃ to 160 ℃, particularly preferably from 90 ℃ to 140 ℃. The solvent used in the reaction may, for example, be an amide solvent such as N, N-dimethylformamide, an alkaline solvent such as N-methylmorpholine and pyridine, an alcohol such as ethanol and butanol, an ether solvent such as dioxane, acetonitrile and water. Alternatively, the compound (54) can be prepared by suspending the 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 the amine (7) and a condensing agent to react. The amount of the sulfur powder used for the reaction is preferably 2N or more. The reaction temperature is preferably from 0 ℃ to 80 ℃. Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and N, N' -dicyclohexylcarbodiimide. Examples of the solvent used in the reaction include amide solvents such as N, N-dimethylformamide, basic solvents such as N-methylmorpholine and pyridine, halogenated alkyl solvents such as dichloromethane and chloroform, ether solvents such as dioxane, and acetonitrile. Further, the reaction may be carried out without a condensing agent to obtain compound (54). In this case, in addition to the above-mentioned solvent, alcohols such as methanol and ethanol, water, and the like can be used. Compound (54) can also be produced by reacting sodium thiosulfate salt (46) with amine (7) under the reaction conditions described in preparation Process 19. Compound (4) can be obtained by treating compound (54) with trifluoroacetic acid or the like at-20 ℃ to 70 ℃.

The above prepared T is prepared by the method described in preparation method 1¹Compound (4) which is a-CS-CO-N (R ') -group (wherein R' is as defined above) is reacted with carboxylic acid (5) to give compound (1) of the present invention.

The tert-butoxycarbonyl group of compound (7) may be replaced with another amino-protecting group as described in preparation Process 2. The type of the protecting group may be selected depending on the nature of the compound, etc., and when the protecting group is cleaved, the reagent and reaction conditions may be selected depending on the protecting group.

[ production method 25]

T¹Compound (1) which is a-CO-N (R ') -CO-group (wherein R' is as defined above) can be prepared according to the following procedure.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹is-CO-N (R ') -CO-yl (where R' is as defined above)]

Namely, the equivalent of NH (R') COQ⁴(55) Aryl amides such as 4-chlorobenzamide and heteroaryl amides such as picolinamideCompound (1) of the present invention can be obtained by reacting an acyl isocyanate intermediate with amine (7) to give compound (54), deprotecting the compound (54), and condensing the resulting compound (4) with carboxylic acid (5).

For example, the compound (54) can be produced by reacting an amide (55) with oxalyl chloride in an inert solvent at a reaction temperature of 20 to 100 ℃ to produce an acyl isocyanate derivative, and reacting the derivative with an amine (7) at a reaction temperature of 0 to 100 ℃. Examples of the inert solvent used in the reaction include halogenated alkyl solvents such as dichloromethane, chloroform and dichloroethane, ether solvents such as tetrahydrofuran and dioxane, aromatic solvents such as benzene and toluene, amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and acetonitrile.

Compound (4) can be obtained by treating compound (54) with trifluoroacetic acid or the like at-20 ℃ to 70 ℃.

The above-obtained T was reacted by the method described in preparation Process 1¹Compound (4) which is a-CO-N (R ') -CO-group (wherein R' is as defined above) is reacted with carboxylic acid (5) to give compound (1) of the present invention.

The tert-butoxycarbonyl group of compound (7) may be replaced with another amino-protecting group as described in preparation Process 2. The type of the protecting group may be selected depending on the nature of the compound, etc., and when the protecting group is cleaved, the reagent and reaction conditions may be selected depending on the protecting group.

[ preparation method 26]

T¹is-SO₂Compound (1) of the group-N (R ') - (wherein R' is as defined above) can be prepared by the following procedure.

[ formula (II) Q¹、Q²、Q³、Q⁴、R¹、R²And R' is as previously described, T¹is-SO₂-N (R ') -yl (where R' is as defined above)]

Reacting HN (R') Q in an inert solvent at a reaction temperature of-78 ℃ to 30 DEG C⁴An amine such as 4-chloroaniline is reacted with chlorosulfonic acid to give an aminosulfonic acid derivative, and the derivative is activated with a reagent such as phosphorus pentachloride and then reacted with an amine (9) to give a compound (1). As the agent for activating the sulfamic acid derivative, a condensing agent such as 1, 1-carbonyldiimidazole may be used in addition to a halogenating agent such as phosphorus pentachloride or phosphorus oxychloride. In this reaction, when a halogenating agent such as phosphorus pentachloride or phosphorus oxychloride is used for activation, it is preferable to heat the reaction mixture at 50 to 120 ℃. Examples of the inert solvent used in the reaction include halogenated alkyl solvents such as dichloromethane, chloroform and dichloroethane, ether solvents such as tetrahydrofuran and dioxane, aromatic solvents such as benzene and toluene, amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and acetonitrile.

Hereinafter, important intermediates described in the production methods 1 to 21 of the compound (1) of the present invention will be described.

1) The compound represented by the following general formula (4) described in the above production methods 1, 3 and 11 is an important production intermediate of the compound (1) of the present invention.

HN(R¹)-Q³-N(R²)-T¹-Q⁴(4)

[ in the formula, R¹、R²、Q³And Q⁴As mentioned above, T¹Is carbonyl, sulfonyl or-CO-N (R ') -group (where R' is as defined above)]

Among the above intermediates, T is preferred¹A compound represented by the formula-C (═ O) -N (R ') - (where R' is a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), and T in the formula¹Is carbonyl, Q³Is the following group

(wherein R is³And R⁴As previously described, Q⁵Represents a radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nWherein m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-).

2) The compounds represented by the following general formula (9) described in production methods 2, 4 and 12 are important intermediates of the compound (1) of the present invention.

Q¹-Q²-C(＝O)-N(R¹)-Q³-NHR²(9)

[ in the formula, R¹、R²、Q¹、Q²And Q³As described above]

Among the above intermediates, Q is preferred³Is the following group

(wherein R is³And R⁴As previously described, Q⁵Represents a radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nWherein m and n are each independently 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-, -S-NH-, -SO-NH-or-SO₂-NH-).

3) The following compound (4c) described in production methods 7, 11 and 13 is an important production intermediate of the compound (1) of the present invention.

[ formula (II) Q⁴、R³、R⁴A, m and n are as previously described, T¹Is carbonyl, sulfonyl or-CO-N (R ') -group (where R' is as defined above)]

Among the above intermediates, T in the above formula is preferred¹A compound which is a-CO-CO-N (R ') -group (where R' is as defined above), and T¹Is a carbonyl group, A is an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-.

4) The following compound (22) described in production methods 8 and 13 is an important intermediate for producing the compound (1) of the present invention.

[ formula (II) Q⁴、R³、R⁴A, m and n are as previously described, T¹Is carbonyl, sulfonyl or a-CO-CO-N (R ') -group (wherein R' is as defined above), R⁵¹Being protecting groups for amino groups]

Among the above intermediates, T in the above formula is preferred¹A compound which is a-CO-CO-N (R ') -group (where R' is as defined above), and T¹Is a carbonyl group, A is an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO ₂-NH-.

5) The following optically active compound (7a) described in production process 6 is an important production intermediate of the compound (1) of the present invention.

[ formula (II) Q⁵、R¹、R²、R³And R⁴As previously described, R⁵⁰Being protecting groups for amino groups]

Among the above intermediates, Q in the above formula is preferred⁵Represents a radical- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_nWherein m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-).

6) The following compound (21) described in production process 8 is an important production intermediate of the compound (1) of the present invention.

[ in the formula, R³、R⁴A, m and n are as previously described, R⁵¹Being protecting groups for amino groups]

In the above intermediate, A in the above formula is preferably an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-.

7) The following compounds described in preparation Process 10 are important production intermediates of the compound (1) of the present invention.

Namely, the following trans-compounds (30), (31) and (32) having optical activity,

[ in the formula, R³M and n are as described above, and,R⁵¹and R⁶¹Being protecting groups for amino groups]

Enantiomers (30a), (31a) and (32a) of the above-mentioned compound were also obtained,

[ in the formula, R³M and n are as defined above, R⁵¹And R⁶¹Being protecting groups for amino groups]

Cis-compounds (30b), (31b), (32b),

[ in the formula, R³M and n are as defined above, R⁵¹And R⁶¹Being protecting groups for amino groups]

And their enantiomers (30c), (31c), (32c),

[ in the formula, R³M and n are as defined above, R⁵¹And R⁶¹Being protecting groups for amino groups]Is very important as a production intermediate of the compound (1) of the present invention.

The diamine derivative of the present invention exhibits a potent inhibitory activity against activated blood coagulation factor ten, and is therefore useful as a pharmaceutical agent for mammals including humans, in particular, an activated blood coagulation factor ten inhibitor, a blood coagulation inhibitor, a preventive and/or therapeutic agent for thrombus or embolism, a preventive and/or therapeutic agent for thrombotic diseases, a preventive and/or therapeutic agent for cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, thrombosis and reocclusion after blood flow reconstruction, Systemic Inflammatory Response Syndrome (SIRS), Multiple Organ Dysfunction Syndrome (MODS), thrombosis in extracorporeal circulation, or blood coagulation at the time of blood collection.

When the compound of the present invention is used as a human pharmaceutical, the dose is 1mg to 1g, preferably 10mg to 300mg, per 1 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, and the type and degree of the pathogenic bacteria of infection, and the dose for 1 day generally corresponds to 0.1mg to 200mg, preferably 0.5mg to 100mg, per 1kg of the animal body weight. The 1-day dosage can be administered 1 time or 2-4 times per day. The dose for 1 day may be more than the above amount as required.

The pharmaceutical composition containing the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and preparing it by a common method for preparing various preparations. The dosage form of the pharmaceutical composition containing the compound of the present invention as a main ingredient may, for example, be tablets, powders, granules, capsules, solutions, syrups, elixirs, oily to aqueous suspensions, etc., which are oral preparations.

As an injection, a stabilizer, a preservative and a cosolvent are used in a preparation, and a solution containing these adjuvants is filled in a container and then freeze-dried to prepare a further preparation for use as a solid preparation. Further, 1 dose may be contained in one container, or a plurality of doses may be contained in one container.

Examples of the external preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays, patches, and the like.

The solid preparation may contain pharmaceutically acceptable additives in addition to the compound of the present invention, and for example, fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants and the like may be optionally mixed and then formulated.

The liquid preparation may, for example, be a solution, a suspension, an emulsion or the like, and the additive may, for example, be a suspension or an emulsifier.

Examples of the compound of the present invention include the following compounds (a) to (E).

(A) General formula (1)

Q¹-C(＝O)-N(R¹)-Q²-N(R²)-T¹-Q³(1)

A compound represented by (i), a salt thereof, a solvate thereof or an N-oxide thereof;

in the formula, R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q¹represents a saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5-to 6-membered heterocyclic group which may have a substituent, a saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q²represents a group represented by the following formula (I),

Q in the group⁴Is C1-8 alkylene, C2-8 alkenylene or- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n(in the group, m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-, 1 and 2 represent positions);

R³and R⁴In the presence of Q⁴Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an alkoxyimino group, a hydroxyimino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylamino group, a carboxyalkylamino 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, an N, N-dialkylaminoalkyl group which may have a substituent, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonylalkyl, 3 to 6-membered heterocyclic carbonyl which may have a substituent, carbamoylalkyl, N-alkylcarbamoylalkyl which may have a substituent on the alkyl group, N-dialkylcarbamoylalkyl which may have a substituent on the alkyl group, carbamoyloxyalkyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, n-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, 3 to 6-membered heterocyclic carbonylalkyl which may have a substituent, 3 to 6-membered heterocyclic carbonyloxyalkyl which may have a substituent, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, aralkyloxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyloxyacyl A group, a haloacyl group, a carboxyacyl group, an aminoacyl group, an acyloxyacyl group, an acyloxyalkylsulfonyl group, a hydroxyalkylsulfonyl group, an alkoxyalkylsulfonyl group, a 3-to 6-membered heterocyclic sulfonyl group which may have a substituent, an N-alkylaminoacyl group, an N, N-dialkylaminoacyl group, an N, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, an N, N-dialkylcarbamoylalkylsulfonyl group which may have a substituent on the alkyl group, an alkylsulfonylacyl group or the like, or R³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group or a carbonyldioxy group having 1 to 5 carbon atoms;

Q³represents 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 saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused heterocyclic group which may have a substituent; t is¹Represents a carbonyl group or a sulfonyl group.

(B) General formula (1)

Q¹-Q²-C(＝O)-N(R¹)-Q³-N(R²)-T¹-Q⁴(1)

A compound represented by (i), a salt thereof, a solvate thereof or an N-oxide thereof;

in the formula, R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q¹Represents a saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5-to 6-membered heterocyclic group which may have a substituent, a saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q²represents a single bond, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, and may haveA substituted 2-valent saturated or unsaturated 5-to 6-ring heterocyclic group, a 2-valent saturated or unsaturated 2-or 3-ring fused hydrocarbon group which may have a substituent, or a 2-valent saturated or unsaturated 2-or 3-ring fused heterocyclic group which may have a substituent;

Q³represents a group represented by the following formula (I),

q in the group⁵Is C1-8 alkylene, C2-8 alkenylene or- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n(in the group, m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-)；

R³And R⁴In the presence of Q⁵Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an alkoxyimino group, a hydroxyimino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylamino group, a carboxyalkylamino 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, an N, N-dialkylaminoalkyl group which may have a substituent, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoyl A formylalkyl group, an N-alkyl-N-alkoxycarbamoylalkyl group, a carbazolyl group which may be substituted with 1 to 3 alkyl groups, an alkylsulfonyl group, an alkylsulfonylalkyl group, a 3-to 6-membered heterocyclic carbonyl group which may have a substituent, 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 carbamoyloxyalkyl group, an N-alkylcarbamoyloxyalkyl group, an N, N-dialkylcarbamoyloxyalkyl group, a 3-to 6-membered heterocyclic carbonylalkyl group which may have a substituent, a 3-to 6-membered heterocyclic carbonyloxyalkyl group which may have a substituent, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, an alkylsulfonylamino group, an arylsulfonylamino group, an alkylsulfonylaminoalkyl group, an arylsulfonylaminoalkylalkyl group, Alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, aralkoxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3-to 6-membered heterocyclic sulfonyl which may have a substituent(s), N-alkylaminoacyl, N-dialkylaminoacyl, N-dialkylcarbamoylacyl which may have a substituent(s) on the alkyl, N-dialkylcarbamoylalkylsulfonyl which may have a substituent(s) on, Alkylsulfonylacyl radicals and the like or R ³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group or a carbonyldioxy group having 1 to 5 carbon atoms;

Q⁴represents 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 saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused heterocyclic group which may have a substituent;

T¹represents a carbonyl group, a sulfonyl group or a group-C (═ O) -C- (═ O) -N (R ') - (where R' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group).

(C) General formula (1)

Q¹-Q²-C(＝O)-N(R¹)-Q³-N(R²)-T¹-Q⁴(1)

A compound represented by (i), a salt thereof, a solvate thereof or an N-oxide thereof;

in the formula, R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q¹represents 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 saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q²Represents a single bond, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a 2-valent saturated or unsaturated 5-to 7-membered cyclic heterocyclic group which may have a substituent, a 2-valent saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a 2-valent saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q³represents a group represented by the following formula (I),

q in the group⁵Is C1-8 alkylene, C2-8 alkenylene or- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n- (in which m and n are each independently 0, 1 to3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-)；

R³And R⁴In the presence of Q⁵Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an alkoxyimino group, a hydroxyimino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylamino group, a carboxyalkylamino 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, an N, N-dialkylaminoalkyl group which may have a substituent, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonylalkyl, 3 to 6-membered heterocyclic carbonyl which may have a substituent, carbamoylalkyl, N-alkylcarbamoylalkyl which may have a substituent on the alkyl group, N-dialkylcarbamoylalkyl which may have a substituent on the alkyl group, carbamoyloxyalkyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, n-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, 3-to 6-membered heterocyclic carbonylalkyl which may have a substituent, 3-to 6-membered heterocyclic carbonyloxyalkyl which may have a substituent, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, Oxo, carbamoyloxy, aralkyloxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3-to 6-membered heterocyclic sulfonyl group which may have a substituent, N-alkylaminoacyl, N-dialkylaminoacyl group which may have a substituent on the alkyl group, N-dialkylcarbamoylacyl group which may have a substituent on the alkyl group, N-dialkylcarbamoylalkylsulfonyl or alkylsulfonylacyl group which may have a substituent on the alkyl group, or R³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group or a carbonyldioxy group having 1 to 5 carbon atoms;

Q⁴represents 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 heteroarylalkenyl group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused heterocyclic group which may have a substituent;

T¹Represents a carbonyl group, a sulfonyl group, a group-C (═ O) -C- (═ O) -N (R ') - (where R' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group-C (═ O) -A¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein 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) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³-C (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms) or a thiocarbonyl group.

(D) General formula (VII)

Q¹-Q²-T⁰-N(R¹)-Q³-N(R²)-T¹-Q⁴(1)

A compound represented by (i), a salt thereof, a solvate thereof or an N-oxide thereof;

in the formula, R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q¹represents 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 saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q²represents a single bond, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a 2-valent saturated or unsaturated 5-to 7-membered cyclic heterocyclic group which may have a substituent, a 2-valent saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a 2-valent saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q³Represents a group represented by the following formula (I),

q in the group⁵Is C1-8 alkylene, C2-8 alkenylene or- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n(in the group, m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-)；

R³And R⁴In the presence of Q⁵Is substituted on a carbon atom, a nitrogen atom or a sulfur atom of the ring (a), each independentlyRepresents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an alkoxyimino group, a hydroxyimino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylamino group, a carboxyalkylamino group, an alkoxycarbonylamino 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, an N-alkenylcarbamoyl group, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted with 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonylalkyl, 3 to 6-membered heterocyclic carbonyl which may have a substituent, carbamoylalkyl, N-alkylcarbamoylalkyl which may have a substituent on the alkyl group, N-dialkylcarbamoylalkyl which may have a substituent on the alkyl group, carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N-alkoxycarbamoyloxyalkyl, 3-to 6-membered heterocyclic carbonylalkyl group which may have a substituent, 3-to 6-membered heterocyclic carbonylaminoalkyl group which may have a substituent, aryl group, aralkyl group, heteroaryl group, heteroarylalkyl group, alkylsulfonylamino group, arylsulfonylamino group, alkylsulfonylaminoalkyl group, arylsulfonylaminocarbonyl group, alkylsulfonylaminocarbonylalkyl group, arylsulfonylaminocarbonylalkyl group, oxo group, carbamoyloxy group, aralkyloxy group, carboxyalkoxy group, acyloxy group, acyloxyalkyl group, arylsulfonyl group, alkoxycarbonylalkylsulfonyl group, carboxyalkylsulfonyl group, alkoxycarbonylacyl group, alkoxyalkoxycarbonyl group, hydroxyacyl group, alkoxyacyl group, haloacyl group, carboxyacyl group, aminoacyl group, acyloxyacyl group, acyloxyalkanyl group Alkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, optionally substituted 3-to 6-membered heterocyclic sulfonyl, N-alkylaminoacyl, N-dialkylaminoacyl, optionally substituted N, N-dialkylcarbamoylacyl, optionally substituted N, N-dialkylcarbamoylalkylsulfonyl or alkylsulfonylacyl, or R³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group or a carbonyldioxy group having 1 to 5 carbon atoms;

Q⁴represents 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 heteroarylalkenyl group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused heterocyclic group which may have a substituent;

T⁰represents a carbonyl group or a thiocarbonyl group;

T¹represents a carbonyl group, a sulfonyl group, a group-C (═ O) -C- (═ O) -N (R ') -, a group-C (═ S) -C- (═ O) -N (R ') -, a group-C (═ O) -C- (═ S) -N (R ') -, a group-C (═ S) -C- (═ S) -N (R ') -, wherein R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, a group-C (═ O) -a ¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein 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) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³- (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group, R^bRepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, or a thiocarbonyl group.

(E) General formula (1)

Q¹-Q²-T⁰-N(R¹)-Q³-N(R²)-T¹-Q⁴(1)

A compound represented by (i), a salt thereof, a solvate thereof or an N-oxide thereof;

in the formula, R¹And R²Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q¹represents 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 saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q²Represents a single bond, a 2-valent saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, a 2-valent saturated or unsaturated 5-to 7-membered cyclic heterocyclic group which may have a substituent, a 2-valent saturated or unsaturated 2-or 3-membered fused hydrocarbon group which may have a substituent, or a 2-valent saturated or unsaturated 2-or 3-membered fused heterocyclic group which may have a substituent;

Q³represents a group represented by the following formula (I),

q in the group⁵Is C1-8 alkylene, C2-8 alkenylene or- (CH)₂)_m-CH₂-A-CH₂-(CH₂)_n(in the group, m and n are each independently an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO₂-, -NH-, -O-NH-, -NH-, -S-NH-, -SO-NH-or-SO₂-NH-)；

R³And R⁴In the presence of Q⁵Each independently represents a hydrogen atom, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, a halogen atom, a haloalkyl group, a cyano group, a cyanoalkyl group, an amino group, an aminoalkyl group, an N-alkylaminoalkyl group, an N, N-dialkylaminoalkyl group, an acyl group, an acylalkyl group, an acylamino group which may have a substituent, an alkoxyimino group, a hydroxyimino group, an acylaminoalkyl group, an alkoxy group, an alkoxyalkyl group, a hydroxyalkyl group, a carboxyl group, a carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkylamino group, a carboxyalkylamino 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, an N, N-dialkylaminoalkyl group which may have a substituent, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonylalkyl, 3 to 6-membered heterocyclic carbonyl which may have a substituent, carbamoylalkyl, N-alkylcarbamoylalkyl which may have a substituent on the alkyl group, N-dialkylcarbamoylalkyl which may have a substituent on the alkyl group, carbamoyloxyalkyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkoxycarbamoylalkyl, N-alkyl-N-alkoxycarbamoylalkyl, n-alkylcarbamoyloxyalkyl, N-dialkylcarbamoyloxyalkyl, 3 to 6-membered heterocyclic carbonylalkyl which may have a substituent, 3 to 6-membered heterocyclic carbonyloxyalkyl which may have a substituent, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, aralkyloxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylaminocarbonyl Acyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, optionally substituted 3-to 6-membered heterocyclic sulfonyl, N-alkylaminoacyl, N-dialkylaminoacyl, optionally substituted N, N-dialkylcarbamoylacyl, optionally substituted N, N-dialkylcarbamoylalkylsulfonyl or alkylsulfonylacyl, or R³And R⁴Together represent an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 to 5 carbon atoms, an alkylenedioxy group or a carbonyldioxy group having 1 to 5 carbon atoms;

Q⁴represents 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 heteroarylalkenyl group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated 2-or 3-cyclic fused heterocyclic group which may have a substituent;

T⁰represents a carbonyl group or a thiocarbonyl group;

T¹represents a carbonyl group, a sulfonyl group, a group-C (═ O) -C- (═ O) -N (R ') -, a group-C (═ S) -C- (═ O) -N (R ') -, a group-C (═ O) -C- (═ S) -N (R ') -, a group-C (═ S) -C- (═ S) -N (R ') -, wherein R ' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, a group-C (═ O) -a ¹-N (R') - (A in the group)¹Represents an optionally substituted alkylene group having 1 to 5 carbon atoms, wherein 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) -A²-C (═ O) - (a in the group)²A single bond or an alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -A³-C (═ O) -NH- (a in the group)³An alkylene group having 1 to 5 carbon atoms), a group-C (═ O) -C (═ NOR)^a)-N(R^b) -, C (-S) -C (-NOR)^a)-N(R^b) - (R in the radical)^aRepresents a hydrogen atom, an alkyl group or an alkanoyl group,R^brepresents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C (═ O) -N ═ N-, the group-C (═ S) -N ═ N-, or a thiocarbonyl group.

Examples

The present invention will be described below with reference to examples

[ reference example 1] pyridin-4-ylcarbamic acid tert-butyl ester

4-aminopyridine (10g) was dissolved in tetrahydrofuran (500ml), and di-tert-butyl dicarbonate (25.5g) was added to stir at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the precipitated solid was washed with hexane to obtain the title compound (16.9 g).

¹H-NMR(CDCl₃)δ：1.53(9H，s)，6.86(1H，br.s)，7.30(2H，dd，J＝1.5，4.9Hz)，8.44(2H，dd，J＝1.5，4.9Hz).

MS(FAB)m/z：195(M+H)⁺.

[ reference example 2] 3-mercaptopyridin-4-yl carbamic acid tert-butyl ester

The compound (61.6g) obtained in referential example 1 was dissolved in tetrahydrofuran (2000ml), and the mixture was stirred at-78 ℃ for 10 minutes. N-butyllithium (1.59N hexane solution, 500ml) was added dropwise to the reaction mixture, and after stirring for 10 minutes, the mixture was stirred for 2 hours under ice-cooling. After the reaction mixture was cooled to-78 ℃, sulfur powder (12.2g) was added thereto, and the mixture was stirred for 1 hour after warming to room temperature. Water (1000ml) was added to the reaction mixture for liquid separation. And adding 3N hydrochloric acid into the water layer to adjust the pH to 3-4, and then adding dichloromethane 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 silica gel column chromatography (dichloromethane: methanol 50: 1) to obtain the title compound (33.2 g).

¹H-NMR(DMSO-d₆)δ：1.52(9H，s)，7.89(1H，d，J＝6.4Hz)，7.99(1H，d，J＝6.4Hz)，8.20(1H，s)，9.91(1H，br.s).

MS(FAB)m/z：227(M+H)⁺.

[ reference example 3] Thiazolo [5, 4-c ] pyridine

The compound (33.2g) obtained in referential example 2 was dissolved in formic acid (250ml), and heated under reflux for 3 days. The reaction mixture was concentrated under reduced pressure, and a 5N aqueous solution (100ml) of potassium hydroxide and diethyl ether were added to the residue to conduct liquid separation. 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 (dichloromethane: methanol 25: 1) to obtain the title compound (9.03 g).

¹H-NMR(CDCl₃)δ：8.05(1H，d，J＝5.4Hz)，8.70(1H，d，J＝5.4Hz)，9.23(1H，s)，9.34(1H，s).

MS(FAB)m/z：137(M+H)⁺.

[ reference example 4] 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

The compound (1.61g) obtained in referential example 3 was dissolved in N, N-dimethylformamide (50ml), and after methyl iodide (1.50ml) was added, it was stirred with heating at 80 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (100ml), followed by addition of sodium borohydride (1.53g) and stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous potassium carbonate solution and diethyl ether were added to the residue to conduct 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 column chromatography (dichloromethane: methanol ═ 25: 1) to obtain the title compound (1.28 g).

¹H-NMR(CDCl₃)δ：2.52(3H，s)，2.83(2H，t，J＝5.9Hz)，2.98(2H，t，J＝5.9Hz)，3.70(2H，s)，8.63(1H，s).

MS(FAB)m/z：155(M+H)⁺.

[ reference example 5] lithium 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylate

The compound (6.43g) obtained in referential example 4 was dissolved in anhydrous tetrahydrofuran (200ml), and N-butyllithium (1.47N in hexane, 34.0ml) was added dropwise thereto at-78 ℃ and stirred for 40 minutes. After carbon dioxide gas was introduced into the reaction mixture at-78 ℃, the temperature was raised to room temperature, and the reaction mixture was concentrated under reduced pressure to obtain the title compound (9.42 g).

¹H-NMR(DMSO-d₆)δ：2.37(3H，s)，2.64-2.77(4H，m)，3.54(2H，s).

MS(FAB)m/z：199(M+H)⁺.

[ reference example 6] 2-amino-6, 7-dihydrothiazolo [5, 4-c ] pyridine-5 [4H ] -carboxylic acid tert-butyl ester

1-t-butoxycarbonyl-4-piperidone (40.0g) was dissolved in cyclohexane (80ml), and p-toluenesulfonic acid 1 hydrate (191mg) and pyrrolidine (17.6ml) were added to the solution, which was dehydrated with a dean-Stark apparatus and heated under reflux for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (60ml), and sulfur powder (6.42g) was added. A methanol solution (10ml) of cyanamide (8.44g) was slowly dropped under ice cooling, and the mixture was stirred at room temperature for 5 hours. The precipitated solid was collected by filtration to obtain the title compound (31.0 g).

¹H-NMR(DMSO-d₆)δ：1.41(9H，s)，2.44(2H，t，J＝5.6Hz)，3.57(2H，t，J＝5.6Hz)，4.29(2H，s)，6.79(2H，s).

MS(EI)m/z：255(M⁺).

[ reference example 7] 2-bromo-6, 7-dihydrothiazolo [5, 4-c ] pyridine-5 [4H ] -carboxylic acid tert-butyl ester

Copper bromide (1.05g) was suspended in N, N-dimethylformamide (20ml), and tert-butyl nitrite (0.696ml) and the compound (1.00g) obtained in reference example 6 were added under ice cooling, followed by stirring the reaction mixture at 40 ℃ for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 5) to obtain the title compound (568 mg).

¹H-NMR(CDCl₃)δ：1.48(9H，s)，2.85(2H，br.s)，3.72(2H，br.s)，4.56(2H，br.s).

MS(FAB)m/z：319(M+H)⁺.

[ reference example 8] 2-bromo-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine trifluoroacetate

The compound (890mg) obtained in referential example 7 was dissolved in methylene chloride (2ml), and trifluoroacetic acid (15ml) was added to stir at room temperature for 30 seconds. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue to collect the precipitated solid by filtration to obtain the title compound (867 mg).

¹H-NMR(DMSO-d₆)δ：2.98(2H，t，J＝6.1Hz)，3.45(2H，t，J＝6.1Hz)，4.35(2H，s)，9.53(2H，br.s).

MS(FAB)m/z：219(M+H)⁺.

[ reference example 9] 2-bromo-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

The compound (422mg) obtained in referential example 8 was suspended in methylene chloride (10ml), and after triethylamine (0.356ml) was added to dissolve it, acetic acid (0.216ml), an aqueous formaldehyde solution (35% solution, 0.202ml), and sodium triacetoxyborohydride (428mg) were successively added, followed by stirring at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution (100ml), dichloromethane (100ml) and a 3N aqueous sodium hydroxide solution (3ml), and the liquid separation was performed. 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 (dichloromethane: methanol 100: 3) to obtain the title compound (286 mg).

¹H-NMR(CDCl₃)δ：2.49(3H，s)，2.79(2H，t，J＝5.7Hz)，2.85-2.93(2H，m)，3.58(2H，t，J＝1.8Hz).

MS(FAB)m/z：233(M+H)⁺.

[ reference example 10] lithium 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylate

The compound (531mg) obtained in referential example 9 was dissolved in anhydrous ether (20ml), and N-butyllithium (1.54N in hexane, 1.63ml) was added dropwise at-78 ℃ and stirred for 30 minutes under ice cooling. Carbon dioxide gas was introduced into the reaction mixture at-78 ℃ 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).

¹H-NMR(DMSO-d₆)δ：2.37(3H，s)，2.64-2.85(4H，m)，3.54(2H，s).

[ reference example 11]2- [ (E) -2-Phenylvinyl ] oxazole-4-carboxylic acid ethyl ester

Synthesized according to the report of Panek et al (j. org. chem., 1996, volume 61, page 6496). Sodium hydrogencarbonate (22.8g) and ethyl bromopyruvate (10.5ml) were added to a tetrahydrofuran (250ml) solution of cinnamamide (10.0g) at room temperature, and the mixture was refluxed for 48 hours. The reaction mixture was naturally cooled to room temperature, filtered through celite, and concentrated under reduced pressure to obtain a residue. Trifluoroacetic anhydride (30ml) was added to a tetrahydrofuran (30ml) solution of the residue at 0 ℃ and the temperature was slowly raised to room temperature. After stirring for 63 hours, a saturated aqueous sodium hydrogencarbonate solution (500ml) and ethyl acetate (150ml) were added to the reaction mixture to separate the mixture, and the aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layers were washed with saturated brine (150ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1 → 3: 1) to obtain the title compound (10.9 g).

¹H-NMR(CDCl₃)δ：1.41(3H，t，J＝7.0Hz)，4.42(2H，q，J＝7.0Hz)，6.96(1H，d，J＝16.6Hz)，7.30-7.40(3H，m)，7.53(2H，d，J＝6.8Hz)，7.63(1H，d，J＝16.6Hz)，8.20(1H，s).

[ reference example 12]2- [ (E) -2-Phenylvinyl ] oxazole-4-carbaldehyde

Diisobutylaluminum hydride (1.0N in hexane, 66ml) was added dropwise to a dichloromethane (80ml) solution of the compound (8.57g) obtained in referential example 11 at-78 ℃. After stirring for 15 minutes, methanol (11ml) was added dropwise and the temperature was raised to room temperature over 1 hour. The reaction mixture was filtered through celite, the resulting paste was dissolved in ethyl acetate (200ml) and saturated aqueous ammonium chloride (200ml), and the aqueous layer was extracted with dichloromethane (2X 100ml) after separation. The organic layers were combined, washed with a saturated aqueous sodium hydrogencarbonate solution (100ml) and a saturated brine (100ml), and the filtrates obtained by filtration through Celite were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 5: 1 → dichloromethane: methanol ═ 10: 1) to obtain the title compound (5.86 g).

¹H-NMR(CDCl₃)δ：6.96(1H，d，J＝16.6Hz)，7.35-7.45(3H，m)，7.56(2H，d，J＝6.4Hz)，7.67(1H，d，J＝16.6Hz)，8.26(1H，s)，9.98(1H，s).

MS(FAB)m/z：200(M+H)⁺.

[ reference example 13]2- [ (E) -2-phenylvinyl ] -4-vinyloxazole

N-butyllithium (1.54N in hexane, 14.2ml) was added dropwise to a tetrahydrofuran (80ml) solution of (methyl) triphenylphosphonium bromide (8.16g) at 0 ℃ and stirred at room temperature for 30 minutes. The reaction mixture was again cooled to 0 ℃ and a solution of the compound (3.64g) obtained in referential example 12 in tetrahydrofuran (20ml) was added to warm to room temperature. After stirring for 2 hours, water (200ml) and ethyl acetate (100ml) were added thereto, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100ml), 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).

¹H-NMR(CDCl₃)δ：5.33(1H，dd，J＝1.5，10.7Hz)，5.98(1H，dd，J＝1.5，17.6Hz)，6.56(1H，dd，J＝10.7，17.6Hz)，6.95(1H，d，J＝16.6Hz)，7.31-7.42(3H，m)，7.49-7.56(4H，m).

MS(FAB)m/z：198(M+H)⁺.

[ reference example 14]2- {2- [ (E) -2-Phenylvinyl ] oxazol-4-yl } -1-ethanol

9-Borabicyclo [3.3.1] nonane (0.5N in tetrahydrofuran, 158ml) was added to a tetrahydrofuran (500ml) solution of the compound (13.0g) obtained in referential example 13 at 0 ℃ and stirred at room temperature for 15 hours. Water (10ml), a 3N aqueous solution of sodium hydroxide (80ml) and an aqueous solution of hydrogen peroxide (80ml) were added dropwise to the reaction mixture in this order at 0 ℃ and the mixture was stirred at room temperature for 6 hours. After water (600ml) and ethyl acetate (200ml) were added to the reaction mixture to separate the phases, the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers were washed with saturated brine (200ml), 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 → ethyl acetate only) to obtain the title compound (14.1 g).

¹H-NMR(CDCl₃)δ：2.69(1H，br.s)，2.80(2H，t，J＝5.6Hz)，3.90-3.97(2H，m)，6.91(1H，d，J＝16.6Hz)，7.30-7.42(4H，m)，7.43-7.56(3H，m).

MS(FAB)m/z：216(M+H)⁺.

[ reference example 15]2- (2- {2- [ (E) -2-Phenylvinyl ] oxazol-4-yl } ethyl) -1H-isoindole-1, 3(2H) -dione

Phthalimide (200mg), triphenylphosphine (357mg) and diethyl azodicarboxylate (0.214ml) were added to a tetrahydrofuran (15ml) solution of the compound (292mg) obtained in referential example 14 at room temperature, and the mixture was 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).

¹H-NMR(CDCl₃)δ：2.98(2H，t，J＝7.2Hz)，4.03(2H，t，J＝7.2Hz)，6.88(1H，d，J＝16.6Hz)，7.28-7.45(5H，m)，7.48(2H，d，J＝7.3Hz)，7.71(2H，dd，J＝2.9，5.4Hz)，7.84(2H，dd，J＝2.9，5.4Hz).

MS(FAB)m/z：345(M+H)⁺.

[ reference example 16] tert-butyl 2- {2- [ (E) -2-phenylvinyl ] oxazol-4-yl } ethylcarbamate

Hydrazine 1 hydrate (1.50ml) was added to an ethanol (150ml) solution of the compound (6.40g) obtained in referential example 15 at room temperature, and after stirring for 1 hour, hydrazine 1 hydrate (0.500ml) was added again at room temperature, and the mixture was stirred for 2 hours. Then, methylene chloride (150ml), a saturated aqueous sodium hydrogencarbonate solution (150ml) and di-tert-butyl dicarbonate (13.4g) were added to the reaction mixture at room temperature. After stirring for 30 minutes, the layers were separated and the aqueous layer was extracted with dichloromethane (50 ml). The combined organic layers were 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).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，2.75(2H，t，J＝6.6Hz)，3.46(2H，dt，J＝5.9，6.6Hz)，4.92(1H，br.s)，6.91(1H，d，J＝16.6Hz)，7.29-7.45(4H，m)，7.48(1H，d，J＝16.6Hz)，7.52(2H，d，J＝7.3Hz).

MS(FAB)m/z：315(M+H)+，259(M-isobutene+H)+，315(M-Boc+H)⁺.

[ reference example 17] tert-butyl 2- [ (E) -2-phenylvinyl ] -6, 7-dihydrooxazolo [5, 4-c ] pyridine-5 (4H) carboxylate

Polyoxymethylene (54.5mg) and p-toluenesulfonic acid (7.2mg) were added to a toluene (15ml) solution of the compound (190mg) obtained in referential example 16 at room temperature. After the mixture was refluxed for 1 hour, the mixture was naturally cooled, and ethyl acetate (15ml) and a saturated aqueous sodium bicarbonate solution (15ml) were added to the reaction mixture to separate the mixture. After the aqueous layer was extracted with ethyl acetate (10ml), the organic layers were combined, 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 3: 1 → 2: 1) to obtain the title compound (153 mg).

¹H-NMR(CDCl₃)δ：1.50(9H，s)，2.67(2H，br.s)，3.73(2H，br.s)，4.55(2H，s)，6.90(1H，d，J＝16.1Hz)，7.29-7.42(3H，m)，7.46(1H，d，J＝16.1Hz)，7.52(2H，d，J＝7.3Hz).

MS(FAB)m/z：327(M+H)+，271(M-isobutene+H)+，227(M-Boc+H)⁺.

[ reference example 18] 2-formyl-6, 7-dihydrooxazolo [5, 4-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

Acetone (8.0ml), water (4.0ml), N-methylmorpholine-N-oxide (577mg) and a 0.039 molar aqueous solution of osmium tetraoxide (3.20ml) were added to a tetrahydrofuran (16ml) solution of the compound (803mg) obtained in referential example 17 at room temperature, and the mixture was stirred overnight. After ethyl acetate (50ml) and a 10% aqueous solution (50ml) of sodium thiosulfate were added to the reaction mixture to separate the reaction mixture, the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methanol (8.0ml), water (8.0ml) and sodium metaperiodate (790mg) were added to a tetrahydrofuran (16ml) solution of the residue at room temperature. After stirring for 3 hours, ethyl acetate (30ml) and water (50ml) were added to the reaction mixture to separate the mixture, and the aqueous layer was extracted with ethyl acetate (20 ml). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate (50ml), 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 4: 1 → 2: 1) to obtain the title compound (234 mg). The aldehyde is unstable and is therefore immediately used for the subsequent reaction.

¹H-NMR(CDCl₃)δ：1.49(9H，s)，2.77(2H，br.s)，3.77(2H，br.s)，4.62(2H，s)，9.70(1H，s).

[ reference example 19]6, 7-Dihydrooxazolo [5, 4-c ] pyridine-2, 5(4H) -dicarboxylic acid 5- (tert-butyl) 2-methyl ester

Sodium cyanide (220mg) and manganese dioxide (780mg) were added to a methanol (9.0ml) solution of the compound (225mg) obtained in referential example 18 at room temperature, and after stirring for 30 minutes, the mixture was filtered through celite with ethyl acetate. The filtrate was washed with water (50ml) and saturated brine (50ml), 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).

¹H-NMR(CDCl₃)δ：1.49(9H，s)，2.73(2H，br.s)，3.74(2H，br.s)，4.01(3H，s)，4.59(2H，s).

MS(FAB)m/z：283(M+H)⁺.

[ reference example 20] methyl 5-methyl-4, 5, 6, 7-tetrahydrooxazolo [5, 4-c ] pyridine-2-carboxylate

Trifluoroacetic acid (15ml) was added to a dichloromethane (15ml) solution of the compound (500mg) obtained in referential example 19 at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (20ml), triethylamine (0.495ml), acetic acid (205ml), formalin (0.230ml) and sodium triacetoxyborohydride (570mg) were added to the resulting residue at room temperature. After stirring for 15 minutes, methylene chloride (20ml) and a saturated aqueous solution (50ml) of sodium hydrogencarbonate were added to the reaction mixture to separate the mixture, and the aqueous layer was extracted with methylene chloride (3X 20 ml). The combined organic layers were 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).

¹H-NMR(CDCl₃)δ：2.52(3H，s)，2.72-2.78(2H，m)，2.78-2.83(2H，m)，3.61(2H，t，J＝1.7Hz)，4.00(3H，s).

MS(FAB)m/z：197(M+H)⁺，165(M-OCH₃)⁺.

[ reference example 21] lithium 5-methyl-4, 5, 6, 7-tetrahydrooxazolo [5, 4-c ] pyridine-2-carboxylate

Water (6.0ml) and lithium hydroxide (99.7mg) were added to a tetrahydrofuran (24ml) solution of the compound (800mg) obtained in referential example 20 at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (825 mg).

¹H-NMR(DMSO-d₆)δ：2.37(3H，s)，2.47(2H，t，J＝5.6Hz)，2.64(2H，t，J＝5.6Hz)，3.43(2H，s).

[ reference example 22] 5-chloro-6-fluoroindole-2-carboxylic acid methyl ester

A mixture of methyl 3-chloro-4-fluoro-. alpha. -azidocinnamate (Japanese patent laid-open No. Hei 7-149723) (1.85g) and xylene (140ml) was heated under reflux for 1 hour, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (dichloromethane), whereby the title compound (491mg) was obtained.

¹H-NMR(CDCl₃)δ：3.95(3H，s)，7.13-7.15(1H，m)，7.20(1H，dd，J＝9.3，0.49Hz)，7.71(1H，d，J＝7.3Hz)，8.93(1H，br.s).

MS(FAB)m/z：227(M⁺).

[ reference example 23] 5-chloro-6-fluoroindole-2-carboxylic acid

The compound (461mg) obtained in referential example 22 was dissolved in a mixed solvent of tetrahydrofuran (15ml), methanol (10ml) and water (10m1), and lithium hydroxide (283mg) was added thereto and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, 1N hydrochloric acid was added to the residue to adjust the mixture to be weakly acidic, and the obtained powder was collected by filtration and dried to obtain the title compound (422 mg).

¹H-NMR(CDCl₃)δ：7.08-7.10(1H，m)，7.34(1H，d，J＝9.5Hz)，7.88(1H，d，J＝7.6Hz)，12.04(1H，s)，13.16(1H，s).

MS(FAB)m/z：213(M⁺).

[ reference example 24]5- (pyridin-4-yl) 4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

1) Phosphorus pentasulfide (500g) was suspended in formamide (3000ml) under ice cooling, and stirred overnight. Water and ether were added to the reaction mixture to conduct a liquid separation operation. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oil. This was dissolved in n-butanol (350ml), ethyl 3-chloro-4-oxo-1-piperidinecarboxylate (150g) synthesized according to the literature method (Tetrahedron, 1983, vol.39, page 3767) was added, and the mixture was stirred at 100 ℃ for 2.5 hours. The reaction mixture was filtered through celite, and the filtrate was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, respectively, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane to ethyl acetate: hexane: 1: 2) to give ethyl 6, 7-dihydrothiazolo [5, 4-c ] pyridine-5 (4H) -carboxylate (79.0 g).

¹H-NMR(CDCl₃)δ：1.30(3H，t，J＝7.3Hz)，2.96(2H，br.s)，3.82(2H，br.s)，4.19(2H，q，J＝7.3Hz)，4.73(2H，br.s)8.68(1H，s).

MS(FAB)m/z：213(M+H)⁺.

2) To the product (33.5g) was added a 3.5N aqueous solution (250ml) of sodium hydroxide, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, di-tert-butyl dicarbonate (103g) was added under ice cooling, and the mixture was stirred at room temperature overnight. Adding 3N hydrochloric acid into the reaction solution, adjusting the pH to 1-2, and then adding dichloromethane for liquid separation. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine in this order, and then 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) to obtain tert-butyl 6, 7-dihydrothiazolo [5, 4-c ] pyridine-5 (4H) -carboxylate (21.1 g).

¹H-NMR(CDCl₃)δ：1.49(9H，s)，2.94(2H，br.s)，3.76(2H，br.s)，4.68(2H，s)，8.67(1H，s).

MS(FAB)m/z：241(M+H)⁺.

3) Trifluoroacetic acid (25ml) was added to a dichloromethane (25ml) solution of the compound (5.00g) obtained in the above 2) at room temperature. After stirring for 10 minutes, the reaction mixture was concentrated under reduced pressure. 4-bromopyridine (5.20g), N-dimethylformamide (30ml) and triethylamine (15.5ml) were added to the residue at room temperature, and the mixture was stirred at 150 ℃ for 2 days, followed by cooling to room temperature. The resulting colorless precipitate was filtered off, the filtrate was concentrated under reduced pressure, and then methylene chloride (50ml) and a saturated aqueous sodium bicarbonate solution (100ml) were added to saturate the aqueous layer with sodium chloride. After separation, the aqueous layer was extracted with dichloromethane (5X 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20: 1 → 8: 1) to obtain the title compound (2.97 g).

¹H-NMR(CDCl₃)δ：3.07(2H，t，J＝5.9Hz)，3.81(2H，t，J＝5.9Hz)，4.61(2H，s)，6.74(2H，t，J＝6.5Hz)，8.30(2H，t，J＝6.5Hz)，8.70(1H，s).

MS(ESI)m/z：218(M+H)⁺.

[ reference example 25] 2-chloro-6, 7-dihydro-4H-pyrano [4, 3-d ] thiazole

1) tetrahydro-4H-pyran-4-one (5.0g) was dissolved in cyclohexane (20ml), and pyrrolidine (4.35ml) and p-toluenesulfonic acid 1 hydrate (48mg) were added to the solution, and the mixture was refluxed for 70 minutes while removing water with a dean-Stark apparatus. After the reaction solution was cooled to room temperature, the supernatant was separated and concentrated under reduced pressure. The residue was dissolved in methanol (15ml), and sulfur powder (1.60g) was added with cooling water, and after 15 minutes, a methanol solution (10ml) of cyanamide (2.10g) was added dropwise over 20 minutes, followed by stirring for 3 days. The solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane: methanol ═ 20: 1 → 10: 1 → 4: 1) to give 6, 7-dihydro-4H-pyrano [4, 3-d ] thiazol-2-ylamine (3.97 g).

¹H-NMR(CDCl₃)δ：2.66-2.70(2H，m)，3.97(2H，t，J＝5.6Hz)，4.63(2H，s)，4.94(2H，br.s).

MS(FAB)m/z：157(M+H)⁺.

2) Copper chloride (4.10g) was dissolved in acetonitrile (50ml), and tert-butyl nitrite (3.93g) was added in one portion under water cooling. After 10 minutes, the compound (3.97g) obtained in the above reaction was added over about 1 hour and stirred at room temperature for 1 hour. Then, the reaction solution was heated to 65 ℃ and stirred for 2 hours. After silica gel (20g) was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 3: 1) to obtain the title compound (1.78 g).

¹H-NMR(CDCl₃)δ：2.85-2.89(2H，m)，4.02(2H，t，J＝5.6Hz)，4.73(2H，s).

MS(FAB)m/z：175(M+H)⁺.

[ reference example 26] lithium 6, 7-dihydro-4H-pyrano [4, 3-d ] thiazole-2-carboxylate

1) The compound (1.78g) obtained in referential example 25 was dissolved in methanol (30ml), and 10% palladium on carbon (300mg) and sodium acetate (830mg) were added to stir under a hydrogen flow of 5 atm for 5 days. The catalyst was filtered off, the solvent was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to give 6, 7-dihydro-4H-pyrano [4, 3-d ] thiazole (1.14 g).

¹H-NMR(CDCl₃)δ：2.97-3.01(2H，m)，4.04(2H，t，J＝5.6Hz)，4.87(2H，s)，8.69(1H，s).

MS(FAB)m/z：142(M+H)⁺.

2) The product (1.14g) was dissolved in diethyl ether (30ml), cooled to-78 ℃ and then 1.6N butyllithium (6.6ml) was added thereto and stirred. After 20 minutes, carbon dioxide gas was introduced over 15 minutes. After the temperature of the reaction solution was returned to room temperature, the reaction solution was concentrated under reduced pressure to obtain the title compound (1.65 g).

¹H-NMR(DMSO-d₆)δ：2.83(2H，t，J＝5.6Hz)，3.92(2H，t，J＝5.6Hz)，4.73(2H，s).

[ reference example 27] Thiazolo [4, 5-c ] pyridine

3- (tert-Butoxycarbonylamino) -4-mercaptopyridine (Japanese patent laid-open No. Hei 4-321691) (9.20g) was dissolved in formic acid (60ml) and heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and a 5N aqueous solution (100ml) of potassium hydroxide and diethyl ether were added to the residue to conduct liquid separation. 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 obtain the title compound (3.97 g).

¹H-NMR(CDCl₃)δ：7.93(1H，d，J＝5.4Hz)，8.60(1H，d，J＝5.4Hz)，9.07(1H，s)，9.46(1H，s).

[ reference example 28] 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c ] pyridine

The title compound was obtained from the compound obtained in referential example 27 in the same manner as in referential example 4.

¹H-NMR(CDCl₃)δ：2.52(3H，s)，2.77(2H，t，J＝5.4Hz)，2.92-3.00(2H，m)，3.69(2H，t，J＝2.0Hz)，8.61(1H，s).

MS(FAB)m/z：155(M+H)⁺.

[ reference example 29] lithium 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c ] pyridine-2-carboxylate

The title compound was obtained from the compound obtained in referential example 28 in the same manner as in referential example 5.

¹H-NMR(DMSO-d₆)δ：2.38(3H，s)，2.64(2H，br.s)，2.80(2H，br.s)，3.44(2H，br.s).

[ reference example 30] 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, volume 77, page 1256) (2.0g) was dissolved in methanol (100ml), and ammonium acetate (8.2g) and sodium cyanoborohydride (4.0g) were added and the mixture was refluxed for 20 hours. Hydrochloric acid was added to the reaction solution to decompose excess sodium cyanoborohydride, the solvent was removed under reduced pressure, the reaction solution was made alkaline with 1N sodium hydroxide solution, and then extracted with dichloromethane. 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 (50ml), and aqueous formaldehyde (4.29g) and sodium cyanoborohydride (3.49g) were added thereto at room temperature, followed by stirring for 12 hours. The solvent was distilled off under reduced pressure, methylene chloride was added, and the mixture was washed with a saturated sodium hydrogencarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 10: 1) to obtain the title compound (740 mg).

¹H-NMR(CDCl₃)δ：1.71-1.78(1H，m)，2.10-2.19(1H，m)，2.35(6H，s)，2.66-2.94(5H，m).

MS(FAB)m/z：217(M+H)⁺.

[ reference example 31]6- (dimethylamino) -4, 5, 6, 7-tetrahydrobenzothiazole-2-carboxylic acid lithium salt

The compound (750mg) obtained in referential example 30 was dissolved in diethyl ether (15ml), cooled to-78 ℃ and then 1.5N t-butyllithium (3.5ml) was added, and after stirring for 20 minutes, carbon dioxide gas was introduced over about 15 minutes. After the reaction solution was warmed to room temperature, it was concentrated under reduced pressure to obtain the title compound.

¹H-NMR(DMSO-d₆)δ：1.75-1.78(1H，m)，1.98-2.07(1H，m)，2.50(6H，s)，2.64-2.88(5H，m).

[ reference example 32] tert-butyl 2-amino-4, 6-dihydro-5H-pyrrolo [3, 4-d ] thiazole-5-carboxylate

1-t-butoxycarbonyl-3-pyrrolidone (1.58g) was dissolved in cyclohexane (10ml), and p-toluenesulfonic acid 1 hydrate (8.12mg) and pyrrolidine (607mg) were added to the solution, which was then dehydrated with a dean-Stark apparatus and heated under reflux for 1.5 hours. The supernatant was separated, concentrated under reduced pressure, and the residue was dissolved in methanol (5ml), followed by addition of sulfur powder (274mg), followed by stirring under ice cooling for 15 minutes. A methanol solution (2ml) of cyanamide (377mg) was slowly dropped into the reaction mixture, and the mixture was stirred at room temperature overnight. Then, the mixture was refluxed for 2 hours, and the reaction mixture was concentrated, and then methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added to dry the organic layer over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 39) to obtain the title compound (248 mg).

¹H-NMR(CDCl₃)δ1.50(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] tert-butyl 2-bromo-4, 6-dihydro-5H-pyrrolo [3, 4-d ] thiazole-5-carboxylate

Copper bromide (445mg) was suspended in N, N-dimethylformamide, and tert-butyl nitrite (256mg) was added dropwise at room temperature. A solution of the compound (400mg) obtained in referential example 32 in N, N-dimethylformamide (1ml) was added under ice cooling, and the reaction mixture was stirred at 60 ℃ for 1.5 hours. To the reaction mixture were added diethyl ether and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 4) to obtain the title compound (174 mg).

¹H-NMR(CDCl₃)δ：1.51(9H，s)，4.52-4.55(1H，m)，4.57-4.67(3H，m).

MS(FAB)m/z：305(M+H)⁺.

[ reference example 34] lithium 5- (tert-butoxycarbonyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylate

The title compound was obtained from the compound obtained in referential example 7 in the same manner as in referential example 10.

¹H-NMR(DMSO-d₆)δ：1.42(9H，s)，2.69-2.77(2H，m)，3.60-3.68(2H，m)，4.51-4.58(2H，m).

[ reference example 35] methyl 2-bromo-4- (2-methoxy-2-oxoethyl) thiazole-5-carboxylate

Copper bromide (26.8g) was added in one portion to a solution of tert-butyl nitrite (15.5g) in acetonitrile (500ml) under ice cooling. To the reaction mixture was added dropwise a solution (500ml) of methyl 2-amino-5-methoxycarbonyl-4-thiazoleacetate (J.Pharmacol., 1966, vol. 86, p. 300) (23.0g) in acetonitrile over 45 minutes, and the mixture was stirred under ice cooling for 1 hour and then at room temperature for 30 minutes. The reaction solution was concentrated, 10% hydrochloric acid and ether were added to the residue, and 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).

¹H-NMR(CDCl₃)δ：3.73(3H，s)，3.87(3H，s)，4.21(2H，s).

[ reference example 36]2- [5- (hydroxymethyl) thiazol-4-yl ] -1-ethanol

A tetrahydrofuran (500ml) solution of the compound (23.4g) obtained in referential example 35 was added dropwise to a tetrahydrofuran (500ml) suspension of lithium aluminum hydride (9.03g) over 1 hour under ice-cooling. After stirring for 1 hour under ice-cooling, water (9ml), a 35% aqueous sodium hydroxide solution (9ml) and water (27ml) were added in this order, and the mixture was stirred at room temperature for 1 hour. After anhydrous magnesium sulfate was added to the reaction solution and stirred, insoluble matter was removed by filtration through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (methanol: dichloromethane: 7: 93) to obtain the title compound (8.64 g).

¹H-NMR(CDCl₃)δ：3.01(2H，t，J＝5.5Hz)，3.30(1H，br.s)，3.57(1H，br.s)，3.90(2H，br.s)，4.75(2H，br.s)，8.66(1H，s).

MS(ESI)m/z：160(M+H)⁺.

[ reference example 37] methanesulfonic acid 2- (5- { [ (methylsulfonyl) oxy ] methyl } thiazol-4-yl) ethyl ester

The compound (8.64g) obtained in referential example 36 and triethylamine (45.4ml) were dissolved in dichloromethane (500ml), and a dichloromethane solution of methanesulfonyl chloride (12.6ml) was added dropwise to the solution at-78 ℃ over 20 minutes. Stirring at-78 deg.C for 15 min, stirring at 0 deg.C for 1 hr, adding water, separating organic layer, and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (13.4 g).

¹H-NMR(CDCl₃)δ：2.93(3H，s)，3.03(3H，s)，3.28(2H，t，J＝6.3Hz)，4.61(2H，t，J＝6.3Hz)，5.44(2H，s)，8.84(1H，s).

[ reference example 38]5- (1-methylcyclopropyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

1-methylcyclopropylamine hydrochloride (J.org.chem., 1989, vol. 54, p. 1815) (1.89g) was added to dichloromethane (20ml) containing the compound (4.46g) obtained in reference example 37 under ice cooling, and stirred at room temperature overnight. Then, 1-methylcyclopropylamine hydrochloride (1.89g) was added thereto, and the mixture was stirred at room temperature for 20 hours, and then heated under reflux and stirred for 5 hours. Methylene chloride and water were added to the reaction mixture, and 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 (methanol: dichloromethane ═ 1: 49) to obtain the title compound (944 mg).

¹H-NMR(CDCl₃)δ：0.40-0.50(2H，m)，0.68-0.73(2H，m)，1.16(3H，s)，2.88-2.94(2H，m)，3.03(2H，t，J＝5.7Hz)，3.89(2H，br.s)，8.60(1H，s).

MS(ESI)m/z：195(M+H)⁺.

[ reference example 39] lithium 5- (1-methylcyclopropyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylate

The title compound was obtained from the compound obtained in referential example 38 in the same manner as in referential example 5.

¹H-NMR(DMSO-d₆)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

The title compound was obtained from the compound obtained in referential example 37 and 2-amino-2-methyl-1-propanol by the same process as referential example 38.

¹H-NMR(CDCl₃)δ：1.15(6H，s)，2.91(4H，s)，3.45(2H，s)，3.87(2H，s)，8.63(1H，s).

[ reference example 41]5- (2- { [ tert-butyl (diphenyl) silyl ] oxy } -1, 1-dimethylethyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

tert-Butylchlorodiphenylsilane (1.93g) and imidazole (994mg) were added to a solution of the compound (1.24g) obtained in referential example 40 in N, N-dimethylformamide (5ml) at room temperature, and the mixture was stirred overnight. Water and ether were added to the reaction mixture, and 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 (hexane: ethyl acetate 1: 2) to obtain the title compound (2.46 g).

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.15(6H，s)，2.83-2.90(2H，m)，2.93-3.00(2H，m)，3.63(2H，s)，3.97(2H，s)，7.35-7.48(6H，m)，7.63-7.70(4H，m)，8.58(1H，s).

MS(ESI)m/z：451(M+H)⁺.

[ reference example 42] lithium salt of 5- (2- { [ tert-butyl (diphenyl) silyl ] oxy } -1, 1-dimethylethyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid

The title compound was obtained from the compound obtained in referential example 41 in the same manner as in referential example 5.

¹H-NMR(DMSO-d₆)δ：1.01(9H，s)，1.11(6H，s)，2.55-2.65(2H，m)，2.80-2.90(2H，m)，3.57(2H，s)，3.80(2H，br.s)，7.40-7.52(6H，m)，7.60-7.65(4H，m).

[ reference example 43]4, 7, 8, 10-tetrahydro-6H-pyrazolo [1, 2-a ] thiazolo [4, 5-d ] pyridazine

1) 4, 5-dimethylthiazole (5.00g), N-bromosuccinimide (15.7g) and α, α' -azobisisobutyronitrile (362mg) were dissolved in dichloroethane (500ml) at room temperature and heated under reflux for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ether ═ 1: 4) to give 4, 5-bis (bromomethyl) thiazole (5.24 g).

¹H-NMR(CDCl₃)δ：4.64(2H，s)，4.74(2H，s)，8.75(1H，s).

2) 4, 5-bis (bromomethyl) thiazole (1.37g) and 1, 2-trimethylenehydrazine hydrochloride (WO9532965) (732mg) were suspended in ethanol (15ml) under ice-cooling, and triethylamine (2.82ml) was added dropwise over 5 minutes. After stirring at room temperature for 2 hours, the solvent was distilled off, methylene chloride (50ml) and a saturated aqueous sodium bicarbonate solution were added to the residue, 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: dichloromethane ═ 3: 47) to obtain the title compound (358 mg).

¹H-NMR(CDCl₃)δ：2.10-2.25(2H，m)，3.01(4H，br.s)，3.95(2H，s)，3.99(2H，br.s)，8.64(1H，s).MS(FAB)m/z：182(M+H)⁺.

[ reference example 44] lithium 4, 7, 8, 10-tetrahydro-6H-pyrazolo [1, 2-a ] thiazolo [4, 5-d ] pyridazine-2-carboxylate

The title compound was obtained from the compound obtained in referential example 43 in the same manner as in referential example 5.

¹H-NMR(DMSO-d₆)δ：1.90-2.10(2H，m)，2.60-3.10(4H，br.s)，3.65-4.00(4H，m).

[ reference example 45]4, 6, 7, 8, 9, 11-hexahydropyridazino [1, 2-a ] thiazolo [4, 5-d ] pyridazine

The title compound was obtained from 4, 5-bis (bromomethyl) thiazole (2.20g) obtained in 1) of referential example 43 and 1, 2-tetramethylenehydrazine hydrochloride (U.S. Pat. No. 5726126) in the same manner as in referential example 43.

¹H-NMR(CDCl₃)δ：1.77(4H，br.s)，2.20-3.50(4H，br)，3.92(4H，br.s)，8.65(1H，s).

MS(FAB)m/z：196(M+H)⁺.

[ reference example 46] lithium 4, 6, 7, 8, 9, 11-hexahydropyridazino [1, 2-a ] thiazolo [4, 5-d ] pyridazine-2-carboxylate

The title compound was obtained from the compound obtained in referential example 45 in the same manner as in referential example 5.

[ reference example 47] tert-butyl 2- (methylthio) -5, 7-dihydro-6H-pyrrolo [3, 4-d ] pyridazine-6-carboxylate

1- (tert-butoxycarbonyl) -3-pyrrolidone (4.57g) and N, N-dimethylformamide dimethyl acetal (30ml) were added thereto at room temperature, and the mixture was heated at 140 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Hexane was added to the residue, and the precipitated yellow powder was collected by filtration, dissolved in ethanol (100ml), and to the solution were added methylisothiourea sulfate (9.24g) and sodium ethoxide (4.52g) at room temperature, followed by heating and refluxing for 24 hours. Saturated brine and ether were added to the reaction mixture to separate the solution, and the organic layer was dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 99) to obtain the title compound (1.10 g).

¹H-NMR(CDCl₃)δ：1.51(9H，s)，2.57(3H，m)，4.15-4.45(4H，m)，8.39(1/2H，s)，8.43(1/2H，s).

MS(FAB)m/z：268(M+H)⁺.

[ reference example 48] tert-butyl 2- (methylsulfonyl) -5, 7-dihydro-6H-pyrrolo [3, 4-d ] pyrimidine-6-carboxylate

To a dichloromethane solution (20ml) of the compound (1.08g) obtained in referential example 47 was added m-chloroperbenzoic acid (1.99g) under ice cooling, and the mixture was stirred for 5 hours. To the reaction mixture were added a saturated aqueous sodium sulfite solution, a saturated aqueous sodium bicarbonate solution and dichloromethane, followed by liquid separation, and then 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).

¹H-NMR(CDCl₃)δ：1.53(9H，s)，3.36(3H，m)，4.77-4.90(4H，m)，8.77(1/2H，s)，8.81(1/2H，s).

MS(FAB)m/z：300(M+H)⁺.

[ reference example 49] tert-butyl 2-cyano-5, 7-dihydro-6H-pyrrolo [3, 4-d ] pyrimidine-6-carboxylate

Tetrabutylammonium cyanide (1.04g) was added to a dichloromethane (30ml) solution of the compound (1.05g) obtained in referential example 48 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: acetone ═ 20: 1) to obtain the title compound (776 mg).

¹H-NMR(CDCl₃)δ：1.52(9H，s)，4.70-4.85(4H，m)，8.68-8.77(1H，m).

MS(FAB)m/z：247(M+H)⁺.

[ reference example 50]5, 7-dihydro-6H-pyrrolo [3, 4-d ] pyrimidine-2, 6-dicarboxylic acid 6- (tert-butyl) 2-methyl ester

Concentrated hydrochloric acid (5ml) was added to a methanol (10ml) solution of the compound (776mg) obtained in referential example 49 at room temperature, and the mixture was stirred at 100 ℃ for 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10ml), triethylamine (2.20ml) and di-tert-butyl dicarbonate (1.37g) were added thereto at room temperature, followed by stirring for 1 hour. The mixture was concentrated under reduced pressure, and methylene chloride and a saturated saline solution were added to separate the mixture, and then 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: dichloromethane ═ 3: 97) to obtain the title compound (317 mg).

¹H-NMR(CDCl₃)δ：1.53(9H，s)，4.09(3H，s)，4.75-4.85(4H，m)，8.81(1/2H，s)，8.85(1/2H，s).

MS(FAB)m/z：280(M+H)⁺.

[ reference example 51] lithium 5, 6-dimethyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-d ] pyridazine-2-carboxylate

1) 4, 5-bis (bromomethyl) thiazole (600mg) obtained in 1) of reference example 43 was dissolved in ethanol (20ml), and after 1, 2-dimethylhydrazine hydrochloride (294mg) was added under ice cooling, triethylamine (1.23ml) was added in one portion, and the mixture was stirred at room temperature for 30 minutes and then at 50 ℃ for 30 minutes. The solvent was distilled off, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 19) to give 5, 6-dimethyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-d ] pyridazine (90 mg).

¹H-NMR(CDCl₃)δ：2.43(3H，s)，2.56(3H，s)，3.92(2H，s)，4.06(2H，br.s)，8.68(1H，s).MS(FAB)m/z：170(M+H)⁺.

2) The title compound was obtained from 5, 6-dimethyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-d ] pyridazine by the same method as in reference example 5.

¹H-NMR(DMSO-d₆)δ：2.28(3H，s)，2.39(3H，s)，3.66(2H，br.s)，3.88(2H，br.s).

[ reference example 52] 5-chloroindole-2-carboxylic acid 4-nitrophenyl ester

5-Chloroindole-2-carboxylic acid (20g) was suspended in methylene chloride (1500ml), and after N, N-dimethylformamide (2ml) was added, thionyl chloride (11ml) was added dropwise at room temperature. The reaction mixture was refluxed overnight under heating, and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (1000ml), and triethylamine (8.47ml) was added thereto under ice cooling, followed by addition of p-nitrophenol (14.2g), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and 0.2N hydrochloric acid were added to the residue to conduct a liquid separation operation. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (29.9 g).

¹H-NMR(CDCl₃)δ：7.35(1H，dd，J＝9.0，1.7Hz)，7.39-7.42(2H，m)，7.45(2H，dd，J＝7.3，1.7Hz)，7.73(1H，d，J＝1.0Hz)，8.35(2H，dd，J＝7.3，1.7Hz)，9.09(1H，br.s).

MS(FD)m/z：316(M⁺).

[ reference example 53] 6-chloro-2-quinolinecarbonitrile

6-chloroquinoline (2.50g) was dissolved in methylene chloride (25ml), and m-chloroperbenzoic acid (3.71g) was added under ice cooling to stir at room temperature for 1 hour. After dilution with dichloromethane, the mixture was 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, and the residue was dissolved in methylene chloride (40ml), and trimethylsilyl cyanide (2.0ml) and N, N-dimethylcarbamoyl chloride (1.50ml) were added thereto and the mixture was refluxed for 9 hours. Then, trimethylsilyl cyanide (1.0ml) and N, N-dimethylcarbamoyl chloride (0.80ml) were added, and after refluxing under heating for 16 hours, the mixture was diluted with methylene chloride, and a 10% aqueous potassium carbonate solution (40ml) was added and stirred for 30 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Methylene chloride was added to the residue, and the precipitated crystals were collected by filtration to obtain the title compound (1.77 g). Then, the mother liquor was concentrated and purified by silica gel column chromatography (dichloromethane) to obtain the title compound (0.80 g).

¹H-NMR(DMSO-d₆)δ：7.94(1H，dd，J＝9.0，2.2Hz)，8.09(1H，d，J＝8.5Hz)，8.15(1H，d，J＝9.0Hz)，8.29(1H，d，J＝2.2Hz)，8.63(1H，d，J＝8.5Hz).

MS(FAB)m/z：189(M+H)⁺.

[ reference example 54] 6-chloro-2-quinolinecarboxylic acid

The compound (1.73g) obtained in referential example 53 was dissolved in concentrated hydrochloric acid (40ml), and heated under reflux for 19 hours. After the temperature was lowered to room temperature, the precipitate was filtered off and washed with water to obtain the title compound (1.81 g).

¹H-NMR(DMSO-d₆)δ：7.87(1H，dd，J＝9.0，2.4Hz)，8.10-8.20(2H，m)，8.24(1H，d，J＝2.2Hz)，8.52(1H，d，J＝8.5Hz).

MS(FAB)m/z：208(M+H)⁺.

[ reference example 55] methyl 3- (4-chlorophenyl) -2- (formylamino) propionate

(. + -.) - (4-chlorophenyl) alanine methyl ester hydrochloride (2.00g) was dissolved in methylene chloride (20ml), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.60g), 1-hydroxybenzotriazole 1 hydrate (1.23g), N-methylmorpholine (1.90ml) and formic acid (0.30ml) were added thereto, followed by stirring for 15 minutes, followed by addition of formic acid (0.30ml), stirring for 15 minutes, and this operation was repeated 3 times, followed by diluting the reaction solution with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 40: 1) to obtain the title compound (1.21 g).

¹H-NMR(CDCl₃)δ：3.10(1H，dd，J＝13.9，5.6Hz)，3.18(1H，dd，J＝13.9，5.9Hz)，3.75(3H，s)，4.95(1H，m)，6.07(1H，br)，7.05(2H，d，J＝8.3Hz)，7.27(2H，d，J＝8.3Hz)，8.18(1H，s).

MS(FAB)m/z：242(M+H)⁺.

[ reference example 56] 7-chloro-3-isoquinolinecarboxylic acid methyl ester

The compound (1.45g) obtained in referential example 55 was dissolved in methylene chloride (40ml), and oxalyl chloride (0.57ml) was added dropwise. After stirring at room temperature for 30 minutes, ferric chloride (1.17g) was added at an external temperature of about-10 ℃ and stirred at room temperature for 4 days. 1N hydrochloric acid was added, and the mixture was diluted with methylene chloride, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in methanol (38ml), followed by addition of concentrated sulfuric acid (2ml) and heating under reflux for 20 hours. Aqueous sodium bicarbonate was added, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The solvent was evaporated 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).

¹H-NMR(CDCl₃)δ：4.07(3H，s)，7.74(1H，dd，J＝8.8，2.0Hz)，7.94(1H，d，J＝8.8Hz)，8.06(1H，d，J＝2.0Hz)，8.59(1H，s)，9.28(1H，s).

[ reference example 57] 7-chloro-3-isoquinoline carboxylate salt

The compound (0.23g) obtained in referential example 56 was dissolved in concentrated hydrochloric acid (10ml), and heated under reflux for 18 hours. After the reaction solution was allowed to warm to room temperature, the precipitate was filtered off and washed with water to obtain the title compound (0.21 g).

¹H-NMR(DMSO-d₆)δ：7.96(1H，m)，8.29(1H，d，J＝8.5Hz)，8.44(1H，s)，8.72(1H，s)，9.45(1H，d，J＝6.6Hz).

MS(FAB)m/z：208(M+H)⁺.

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

(3R) -1-benzyl-3-hydroxypyrrolidine (500. mu.l) and imidazole (466mg) were dissolved in N, N-dimethylformamide (15ml), and tert-butyldiphenylsilyl chloride (1.57ml) was added under ice cooling, followed by stirring at room temperature for 9 days. The solvent was distilled off under reduced pressure, methylene chloride and water were added to the residue to conduct a liquid separation operation, and then 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 on silica gel (hexane: ethyl acetate 3: 1) to obtain the title compound (1.27 g).

¹H-NMR(CDCl₃)δ：1.05(9H，s)，1.70-1.85(1H，m)，1.90-2.00(1H，m)，2.45-2.65(3H，m)，2.70-2.80(1H，m)，3.50-3.70(2H，m)，4.35-4.45(1H，m)，7.20-7.45(11H，m)，7.60-7.70(4H，m).

MS(ESI)m/z：416(M+H)⁺.

[ reference example 59 ]]N-[(1R^*，2S^*) -2-aminocyclopropyl radical]-5-chloroindole-2-carboxamide

1-hydroxybenzotriazole 1 hydrate (377mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (642mg) and isopropylethylamine (1.95ml) were added to a solution of cis-1, 2-cyclopropyldiamine hydrochloride (J.Med.chem., 1998, 41, 4723, 4732) (405mg) and 5-chloroindole-2-carboxylic acid (546mg) in N, N-dimethylformamide (10ml) at room temperature, followed by stirring for 50 hours. The reaction mixture was concentrated under reduced pressure, and then methylene chloride (50ml) and a saturated aqueous sodium bicarbonate solution (200ml) were added to the mixture, followed by filtration of the precipitated colorless solid. The filtrate was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a residue. The resulting residue was purified by flash column chromatography on silica gel (dichloromethane: methanol ═ 100: 7 → 10: 1) to obtain the title compound (110 mg).

¹H-NMR(DMSO-d₆)δ：0.44(1H，dd，J＝10.7，4.4Hz)，1.11(1H，dd，J＝14.0，7.4Hz)，2.63-2.70(1H，m)，3.07-3.16(1H，m)，6.77(1H，s)，6.97(1H，br.s)，7.23(1H，dd，J＝8.9，1.8Hz)，7.36(1H，d，J＝8.9Hz)，7.60(1H，s)，9.32(1H，s).

MS(FAB)m/z：250(M+H)⁺.

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

The title compound was obtained from cis-1, 2-cyclobutanediamine hydrochloride (J, am. chem. Soc., 1942, vol.64, page 2696-2700) in the same manner as in reference example 59.

¹H-NMR(DMSO-d₆)δ：1.55-2.20(4H，m)，3.52-3.62(1H，m)，4.35-4.50(1H，m)，7.16(1H，dd，J＝8.7，2.1Hz)，7.19(1H，s)，7.42(1H，d，J＝8.7Hz)，7.70(1H，d，J＝2.1Hz)，8.36(1H，d，J＝7.8Hz)，11.77(1H，br.s).

MS(ESI)m/z：264(M+H)⁺.

[ reference example 61](1R^*，2R^*) -2-Aminocyclopentylcarbamic acid tert-butyl ester

(. + -.) -trans-1, 2-cyclopentediamine (WO 98/30574) (692mg) was dissolved in methylene chloride (10ml), and triethylamine (1.1ml) and 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (493mg) were added thereto at 0 ℃ and the mixture was stirred at 0 ℃ for 1 hour. Then, 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (493mg) was added thereto, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was separated by water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol ═ 9: 1) to obtain the title compound (395 mg).

¹H-NMR(CDCl₃)δ：1.25-1.40(2H，m)，1.49(9H，s)，1.59-1.77(2H，m)，1.92-2.08(1H，m)，2.10-2.17(1H，m)，2.98(1H，q，J＝7.2Hz)，3.48-3.53(1H，m)，4.49(1H，br.s).

MS(ESI)m/z：201(M+H)⁺.

[ reference example 62]N-[(1R^*，2R^*) -2-aminocyclopentyl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The compound (175mg) obtained in referential example 61 was dissolved in N, N-dimethylformamide (3ml), and lithium salt (purity 90%, 258mg) of 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylic acid, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (252mg), 1-hydroxybenzotriazole 1 hydrate (60mg) were added to stir at room temperature for 2 days. The solvent was evaporated under reduced pressure by a pump, and methylene chloride and a saturated aqueous sodium bicarbonate solution were added to the residue to separate the mixture. 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 (dichloromethane: methanol 47: 3). The resulting pale yellow oil was dissolved in ethanol hydrochloride (5ml), and after stirring at room temperature for 1 hour, ethyl acetate was added, and the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (120 mg).

¹H-NMR(DMSO-d₆)δ：1.63-1.73(4H，m)，1.99-2.06(2H，m)，2.91(3H，s)，3.09-3.14(1H，m)，3.25-3.70(4H，m)，4.27-4.32(1H，m)，4.42-4.46(1H，m)，4.68-4.71(1H，m)，8.20-8.23(3H，m)，9.09(1H，d，J＝8.3Hz)，11.82-12.01(1H，m).

MS(ESI)m/z：281(M+H)⁺.

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

The compound (1.40g) obtained in referential example 61 was dissolved in N, N-dimethylformamide (15ml), and 5-chloroindole-2-carboxylic acid (1.64g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.68g) and 1-hydroxybenzotriazole 1 hydrate (473mg) were added to stir at room temperature for 23 hours. The solvent was evaporated under reduced pressure, and methylene chloride and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to filter the precipitate. The precipitate was washed with ethyl acetate, dichloromethane and methanol. On the other hand, the filtrate was subjected to liquid separation, and the organic layer was separated, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol 19: 1) to obtain a pale yellow solid. The pale yellow solids and the precipitate obtained by filtration were combined, dissolved in methylene chloride (10ml), and trifluoroacetic acid (10ml) was added to stir at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and methylene chloride and a 1N aqueous solution of sodium hydroxide were added to the residue to collect a precipitate by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. To the solution was added the precipitate obtained by filtration, and a 4N dioxane hydrochloride solution (20ml) was further added, and the solvent was distilled off under reduced pressure. To the residue were added dichloromethane (10ml) and 4N dioxane hydrochloride solution (10ml), and the solvent was distilled off again under reduced pressure. Ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (1.83 g).

¹H-NMR(DMSO-d₆)δ：1.60-1.75(4H，m)，2.05-2.10(2H，m)，3.49(1H，q，J＝7.6Hz)，4.27(4H，quintet，J＝7.6Hz)，7.17(1H，d，J＝8.6Hz)，7.19(1H，s)，7.42(1H，d，J＝8.6Hz)，7.70(1H，s)，8.24(3H，br.s)，8.85(1H，d，J＝7.3Hz)，11.91(1H，s).

MS(ESI)m/z：278(M+H)⁺.

[ reference example 64](1R^*，2R^*) -2-Aminocyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from (. + -.) -trans-1, 2-cyclohexanediamine in the same manner as in referential example 61.

Melting point: 79 to 81 DEG C

¹H-NMR(CDCl₃)δ：1.05-1.34(4H，m)，1.45(9H，s)，1.68-1.75(2H，m)，1.92-2.02(2H，m)，2.32(1H，dt，J＝10.3，3.9Hz)，3.08-3.20(1H，m)，4.50(1H，br.s).

MS(FAB)m/z：215(M+H)⁺.

[ reference example 65]N-[(1R^*，2R^*) -2-aminocyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide trifluoroacetate (and hydrochloride)

The title compound was obtained from the compound obtained in referential example 64 in the same manner as in referential example 62.

¹H-NMR(DMSO-d₆)δ：1.10-1.80(7H，m)，1.95-2.05(1H，m)，2.97(3H，s)，3.00-3.20(3H，m)，3.63(2H，br.s)，3.72-3.88(1H，m)，4.61(2H，br.s)，7.98(3H，s)，8.89(1H，d，J＝9.2Hz).

MS(FAB)m/z：295(M+H)⁺.

The hydrochloride salt was also obtained.

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

The title compound was obtained from cis-1, 2-cyclohexanediamine in the same manner as in referential example 61.

¹H-NMR(CDCl₃)δ：1.30-1.70(17H，m)，2.98-3.05(1H，m)，3.60(1H，br.s)，4.98(1H，br.s).

MS(FAB)m/z：215(M+H)⁺.

[ reference example 67]N-[(1R^*，2S^*) -2-aminocyclohexyl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride (and trifluoroacetate salt)

The title compound was obtained from the compound obtained in referential example 66 in the same manner as in referential example 62.

¹H-NMR(DMSO-d₆)δ：1.30-1.90(8H，m)，2.92(3H，s)，3.05-3.79(5H，m)，4.23(1H，br.s)，4.34-4.79(2H，m)，8.01-8.34(3H，m)，8.30-8.49(1H，m)，11.90-12.30(1H，m).

MS(FAB)m/z：295(M+H)⁺.

The trifluoroacetate salt is likewise obtained.

Reference example 68](1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester

To a solution of the compound (3.00g) obtained in referential example 64 in N, N-dimethylformamide (10ml) were added 5-chloroindole-2-carboxylic acid (2.88g), 1-hydroxybenzotriazole 1 hydrate (2.08g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.95g) at room temperature. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and methylene chloride (30ml), a saturated aqueous sodium hydrogencarbonate solution (150ml) and water (150ml) were added to the resulting residue to filter a resulting colorless precipitate, followed by drying to obtain the title compound (5.21 g).

¹H-NMR(DMSO-d₆)δ：1.10-1.45(4H，m)，1.21(9H，s)，1.68(2H，d，J＝8.1Hz)，1.86(2H，t，J＝16.2Hz)，3.22-3.42(1H，m)，3.69(1H，br.s)，6.66(1H，d，J＝8.5Hz)，7.02(1H，s)，7.15(1H，dd，J＝8.5，2.0Hz)，7.41(1H，d，J＝8.5Hz)，7.67(1H，d，J＝2.0Hz)，8.15(1H，d，J＝8.1Hz)，11.73(1H，br.s).

MS(ESI)m/z：392(M+H)⁺.

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

To a dichloromethane (100ml) solution of the compound (5.18g) obtained in referential example 68 was added an ethanol hydrochloride solution (100ml) at room temperature. After stirring for 2 days, the reaction mixture was concentrated under reduced pressure, and diethyl ether (300ml) was added to the resulting residue to collect a colorless precipitate by filtration and then dried to obtain the title compound (4.30 g).

¹H-NMR(DMSO-d₆)δ：1.20-1.36(2H，m)，1.36-1.50(2H，m)，1.60(2H，br.s)，1.90(1H，d，J＝13.0Hz)，2.07(1H，d，J＝13.7Hz)，3.06(1H，br.s)，3.83-3.96(1H，m)，7.15-7.24(2H，m)，7.45(1H，d，J＝8.6Hz)，7.73(1H，s)，8.00(3H，br.s)，8.60(1H，d，J＝8.3Hz)，11.86(1H，s).

MS(ESI)m/z：292(M+H)⁺

Reference example 70](1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 66 in the same manner as in referential example 68.

¹H-NMR(DMSO-d₆)δ：1.20-1.45(11H，m)，1.45-1.70(4H，m)，1.70-1.85(2H，m)，3.76(1H，br.s)，4.08(1H，br.s)，6.64(1H，d，J＝7.6Hz)，7.12(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.43(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.0Hz)，7.85(1H，d，J＝6.9Hz)，11.80(1H，br.s).

MS(ESI)m/z：392(M+H)⁺.

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

The title compound was obtained from the compound obtained in referential example 70 in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：1.30-1.50(2H，m)，1.55-1.95(6H，m)，3.41(1H，br.s)，4.32(1H，br.s)，7.19(1H，dd，J＝8.7，2.0Hz)，7.33(1H，s)，7.45(1H，d，J＝8.7Hz)，7.60-7.90(4H，m)，8.17(1H，d，J＝7.1Hz)，11.91(1H，s).

MS(FAB)m/z：292(M+H)⁺.

[ reference example 72](1R^*，2R^*) -1, 2-cycloheptanediol

Cycloheptene (3.85g) was added to 30% aqueous hydrogen peroxide (45ml) and 88% formic acid (180ml) in small amounts at a time, and the mixture was stirred at 40 to 50 ℃ for 1 hour and then stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and a 35% aqueous solution of sodium hydroxide was added to the residue to adjust the mixture to alkaline. After stirring the reaction solution at 40 to 50 ℃ for 10 minutes, ethyl acetate was added to separate the reaction solution, and extraction was performed from the water layer 4 times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (4.56 g).

¹H-NMR(CDCl₃)δ：1.44-1.56(6H，m)，1.63-1.70(2H，m)，1.83-1.91(2H，m)，2.91(2H，br.s)，3.40-3.44(2H，m).

MS(FAB)m/z：131(M+H)⁺.

[ reference example 73](1R^*，2R^*) -1, 2-cycloheptanediamine hydrochloride

The compound (4.56g) obtained in referential example 72 was dissolved in methylene chloride (35ml), and triethylamine (29ml) was added to cool to-78 ℃. Methanesulfonyl chloride (8.13ml) was added dropwise thereto. Dichloromethane (10ml) was added thereto, and the mixture was stirred at the same temperature for 20 minutes and then at 0 ℃ for 1.5 hours. The reaction mixture was separated by water, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil. This oil was dissolved in N, N-dimethylformamide (90ml), and sodium azide (13.65g) was added to stir at 65 ℃ for 18 hours. To the reaction mixture were added diethyl ether and water for liquid separation, and the diethyl ether layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil.

The oily substance was dissolved in ethanol (70ml), 10% palladium on carbon (containing 50% water, 4g) was added thereto, and the mixture was stirred under an atmosphere of hydrogen (3.5 atm) for 4 days. 10% Palladium on carbon was filtered, and 1N ethanol hydrochloride solution (70ml) 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 again distilled off under reduced pressure. The resulting precipitate was collected by filtration to obtain the title compound (3.57 g).

¹H-NMR(DMSO)δ：1.44(4H，br.s)，1.73-1.81(6H，m)，3.43(2H，br.s)，8.63(6H，br.s).MS(ESI)m/z：129(M+H)⁺.

Reference example 74]N-[(1R^*，2R^*) -2-aminocycloheptyl radical]-5-chloroindole-2-carboxamide

The title compound was obtained from the compound obtained in referential example 73 in the same manner as in referential example 59.

¹H-NMR(DMSO-d₆)δ：1.49-1.52(4H，m)，1.72-1.91(6H，m)，4.04-4.10(1H，m)，7.17-7.23(2H，m)，7.44(1H，d，J＝8.8Hz)，7.72(1H，d，J＝2.0Hz)，7.96(2H，br.s)，8.75(1H，d，J＝8.5Hz)，11.89(1H，br.s).

MS(ESI)m/z：306(M+H)⁺.

[ reference example 75](1R^*，2S^*) -1, 2-cyclooctanediol hydrochloride

Cyclooctene (4.41g) was dissolved in acetonitrile (45ml) and water (15ml), and N-methylmorpholine-N-oxide (5.15g) and microencapsulated osmium tetroxide (1g, containing 10% osmium tetroxide) were added and stirred at 40 to 50 ℃ for 21 hours. Insoluble microencapsulated osmium tetroxide was filtered off and washed with acetonitrile. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexane: ethyl acetate 1: 1) to obtain the title compound (4.97 g).

¹H-NMR(CDCl₃)δ：1.48-1.58(6H，m)，1.64-1.75(4H，m)，1.86-1.96(2H，m)，2.28(2H，d，J＝2.9Hz)，3.90(2H，d，J＝8.3Hz).

MS(FAB)m/z：145(M+H)⁺.

Reference example 76](1R^*，2S^*) -1, 2-diazido cyclooctane

Cis-1, 2-cyclooctadiene (4.82g) was dissolved in methylene chloride (60ml), triethylamine (27.7ml) was added to the solution, the gas in the vessel was replaced with argon, the solution was cooled to-78 ℃ and methanesulfonyl chloride (7.7ml, 100mmol) was added dropwise. After stirring at the same temperature for 1 hour in total, the reaction mixture was stirred at 0 ℃ for 1 hour, the aqueous solution was added to the reaction mixture, and the organic layer was washed with water, a 0.5N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (80ml), and sodium azide (13.0g) was added to stir at 65 ℃ for 19 hours. To the reaction mixture were added diethyl ether and water for liquid separation, and the diethyl ether layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexane: ethyl acetate 6: 1) to obtain the title compound (4.85 g).

¹H-NMR(CDCl₃)δ：1.49-1.64(6H，m)，1.67-1.78(2H，m)，1.81-1.97(4H，m)，3.74-3.76(2H，m).

[ reference example 77](1R^*，2S^*) -1, 2-cyclooctadiene hydrochloride

The compound (4.85g) obtained in referential example 76 was dissolved in ethanol (55ml), and 10% palladium on carbon (containing 50% of water, 3.0g) was added and stirred for 21 hours under an atmosphere of hydrogen (4.5 atm). The catalyst was filtered off, 1N ethanol hydrochloride solution (50ml) was added to the filtrate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (4.14 g).

¹H-NMR(DMSO)δ：1.51(6H，br.s)，1.69(2H，br.s)，1.79-1.99(4H，m)，3.68-3.70(2H，m)，8.66(6H，br.s).

MS(ESI)m/z：143(M+H)⁺.

Reference example 78]N-[(1R^*，2S^*) -2-aminocyclooctyl group]-5-chloroindole-2-carboxamide

The title compound was obtained from the compound obtained in referential example 77 in the same manner as in referential example 59.

MS(ESI)m/z：320(M+H)⁺.

[ reference example 79](1R^*，2R^*) 4-methoxy-1, 2-cyclopentanediol (mixture of stereoisomers in position 4)

3-Cyclopenten-1-ol (1.68g) and methyl iodide (1.25ml) were dissolved in tetrahydrofuran (20ml), and to the solution was added 60% sodium hydride (800mg) in small amounts each under ice cooling, followed by stirring overnight at room temperature. To the reaction mixture, water and ether were added for liquid separation, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure under ice cooling to obtain crude 4-methoxy-1-cyclopentene.

88% formic acid (90ml) and 30% hydrogen peroxide (3.17ml) were added to the obtained 4-methoxy-1-cyclopentene at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a 35% aqueous solution of sodium hydroxide was added to the residue to make the reaction mixture alkaline, followed by stirring at 50 ℃ for 10 minutes. After cooling to room temperature, the mixture was 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: dichloromethane ═ 1: 19) to obtain the title compound (1.21 g).

¹H-NMR(CDCl₃)δ：1.65-1.85(2H，m)，2.15-2.30(2H，m)，3.28(3H，s)，3.90-4.00(2H，m)，4.26(1H，br.s).

Reference example 80](1R^*，2R^*) -1, 2-diazide-4-methoxycyclopentane (mixture of stereoisomers in position 4)

The compound (1.21g) obtained in referential example 79 and triethylamine (7.66ml) were dissolved in methylene chloride (20ml), and methanesulfonyl chloride (2.13ml) was added dropwise over 20 minutes at-78 ℃. After the completion of the dropwise addition, the temperature was raised to 0 ℃ and the mixture was stirred for 80 minutes to obtain crude (1R)^*，2R^*) -1, 2-bis (methylsulfonyloxy) -4-methoxycyclopentane. This was dissolved in N, N-dimethylformamide (20ml), and sodium azide (3.57g) was added to the solution, followed by stirring at 65 ℃ for 22 hours. Then, sodium azide (3.57g) was added thereto, and the mixture was stirred at 70 ℃ for 2 days. The reaction solution was naturally cooled, separated with water and ether, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to obtain the title compound (584 mg).

¹H-NMR(CDCl₃)δ：1.65-1.80(2H，m)，2.05-2.18(1H，m)，2.25-2.40(1H，m)，3.21(3H，s)，3.55-3.65(1H，m)，3.75-3.90(2H，m).

[ reference example 81](1R^*，2R^*) 4-methoxy-1, 2-cyclopentediamine hydrochloride (mixture of stereoisomers in position 4)

The compound (584mg) obtained in referential example 80 was dissolved in ethanol, 10% palladium on carbon (321mg) was added, and hydrogenation was carried out at normal temperature and pressure for 2 days. The catalyst was filtered off, and the mixture was concentrated, and 1N ethanol hydrochloride solution and ethyl acetate were added to the residue to obtain the title compound (488 mg).

¹H-NMR(CDCl₃)δ：1.72-1.83(1H，m)，1.91-2.03(1H，m)，2.07-2.18(1H，m)，2.37-2.50(1H，m)，3.19(3H，s)，3.55-3.75(2H，br)，3.85-3.95(1H，m)，8.60-8.90(6H，br).

MS(ESI)m/z：261(2M+H)⁺.

Reference example 82]N-[(1R^*，2R^*) -2-amino-4-methoxycyclopentyl]-5-chloroindole-2-carboxamide (mixture of stereoisomers in position 4)

The compound (470mg) obtained in referential example 81 was suspended in N, N-dimethylformamide (5ml), and triethylamine (0.966ml) and p-nitrophenyl 5-chloroindole-2-carboxylate (805mg) were added to stir at room temperature for 4 days. The solvent was evaporated under reduced pressure, methylene chloride and a saturated aqueous sodium bicarbonate solution were added to separate the layers, 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: dichloromethane ═ 1: 9) to obtain the title compound (268 mg).

[ reference example 83](1R^*，2R^*) -4- [ (benzyloxy) methyl group]1, 2-cyclopentanediol (mixture of stereoisomers in position 4)

The title compound was obtained by benzylating 4-hydroxymethyl-1-cyclopentene (j. heterocyclic. chem., 1989, volume 26, page 451) with benzyl bromide and then using formic acid-hydrogen peroxide in the same manner as in reference example 79.

¹H-NMR(CDCl₃)δ：1.44-1.52(1H，m)，1.77-1.85(1H，m)，1.89-1.97(1H，m)，2.25-2.35(1H，m)，2.46-2.58(1H，m)，3.40-3.50(2H，m)，3.89(1H，br.s)，4.08(1H，br.s)，4.54(2H，s)，7.27-7.39(5H，m).

MS(FAB)m/z：223(M+H)⁺.

Reference example 84](1R^*，2R^*) -4- [ (benzyloxy) methyl group]1, 2-cyclopentediamine (mixture of stereoisomers in position 4)

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

[ reference example 85]N-{(1R^*，2R^*) -2-amino-4- [ (benzyloxy) methyl group]Cyclopentyl } -5-chloroindole-2-carboxamide (mixture of stereoisomers in position 4)

The title compound was obtained from the compound in referential example 84 by the same method as referential example 59.

¹H-NMR(DMSO-d₆)δ：1.07-1.15(0.5H，m)，1.26-1.35(0.5H，m)，1.47-1.55(0.5H，m)，1.61-1.79(1H，m)，1.83-1.92(0.5H，m)，1.99-2.10(0.5H，m)，2.12-2.20(0.5H，m)，2.27-2.40(1H，m)，3.10-3.20(1H，m)，3.33-3.39(2H，m)，3.81-3.92(1H，m)，4.48(2H，s)，7.13-7.20(2H，m)，7.22-7.39(5H，m)，7.43(1H，d，J＝8.5Hz)，7.69(1H，d，J＝2.2Hz)，8.34(1H，t，J＝7.1Hz).

MS(FAB)m/z：398(M+H)⁺.

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

Will be (1R)^*，4R^*，5R^*) -4-iodo-6-oxabicyclo [3.2.1]Octane-7-one (J.org.chem., 1996, vol.61, 8687) (14.3g) was dissolved in ethanol (130ml), and a 2N aqueous solution (34.5ml) of sodium hydroxide was added thereto under ice cooling, followed by stirring at room temperature for 7 hours. After the solvent was distilled off under reduced pressure, the residue was extracted with dichloromethane by adding water and dried over anhydrous sodium sulfate. The solvent was evaporated 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).

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝7.1Hz)，1.50-1.70(2H，m)，1.71-1.82(1H，m)，2.08-2.28(4H，m)，3.16(2H，s)，4.12(2H，q，J＝7.1Hz).

[ reference example 87](1R^*，3S^*，4S^*) -3-azido-4-hydroxycyclohexanecarboxylic acid ethyl ester

The compound (13.6g) obtained in referential example 86 was dissolved in N, N-dimethylformamide (100ml), and ammonium chloride (6.45g) and sodium azide (7.8g) were added in this order at room temperature, followed by stirring at 75 ℃ for 12 hours. The solvent was concentrated to about 1/3, 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 4) to obtain the title compound (15.8 g).

¹H-NMR(CDCl₃)δ：1.28(3H，t，J＝7.1Hz)，1.37-1.67(2H，m)，1.86-1.95(1H，m)，2.04-2.18(2H，m)，2.32-2.43(1H，m)，2.68-2.78(1H，m)，3.40-3.60(2H，m)，4.17(2H，q，J＝7.1Hz).

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

The compound (100mg) obtained in referential example 87 and di-tert-butyl dicarbonate (133mg) were dissolved in ethyl acetate (12ml), and a catalytic amount of 10% palladium on carbon was added and the mixture was stirred at room temperature for 12 hours under a hydrogen stream. After insoluble matter 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 obtain the title compound (145 mg).

¹H-NMR(CDCl₃)δ：1.28(3H，t，J＝7.1Hz)，1.45(9H，s)，1.38-1.57(2H，m)，1.86-1.95(1H，m)，2.05-2.17(1H，m)，2.29-2.39(2H，m)，2.61-2.68(1H，m)，3.25-3.66(3H，m)，4.17(2H，q，J＝7.1Hz)，4.53(1H，br.s).

[ reference example 89](1R^*，3S^*，4R^*) -4-azido-3- [ (tert-butoxycarbonyl) amino group]Cyclohexanecarboxylic acid ethyl ester and (1R)^*，3S^*，4S^*) -4-azido-3- [ (tert-butoxycarbonyl) amino group]Cyclohexanecarboxylic acid ethyl ester

The compound (16g) obtained in referential example 88 and triethylamine (38ml) were dissolved in methylene chloride (150ml), and after cooling to-78 ℃, methanesulfonyl chloride (13ml) was added dropwise at the same temperature. Then, the mixture was stirred at the same temperature for 15 minutes, heated to 0 ℃ and stirred for 30 minutes, and further stirred at room temperature for 2 hours. After 0.1N hydrochloric acid was added and the mixture was diluted with methylene chloride, the organic layer was separated, washed with a saturated aqueous sodium hydrogencarbonate 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 group]-4- [ (methylsulfonyl) oxy group ]Cyclohexanecarboxylic acid ethyl ester

The product was dissolved in N, N-dimethylformamide (100ml), and sodium azide (18g) was added thereto at room temperature, and the mixture was stirred for 12 hours after the temperature was raised to 75 ℃. The solvent was concentrated to about 1/3, 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 evaporated 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^*) Body, 6.74g]And [ (1R)^*，3S^*，4S^*) Body, 1.32g]。

(1R^*，3S^*，4R^*) Body:

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.1Hz)，1.45(9H，s)，1.38-2.33(6H，m)，2.57-2.68(1H，m)，3.77-4.20(4H，m)，4.63(1H，br.s).

(1R^*，3S^*，4S^*) Body:

¹H-NMR(CDCl₃)δ：1.27(3H，t，J＝7.1Hz)，1.46(9H，s)，1.53-2.30(6H，m)，2.50-2.65(1H，m)，3.42-3.72(2H，m)，4.15(2H，q.J＝7.1Hz)，4.67(1H，br.s).

reference example 90](1R^*，3S^*，4R^*) -4-amino-3- [ (tert-butoxycarbonyl)Radical) amino]Cyclohexanecarboxylic acid ethyl ester

(1R) obtained in referential example 89^*，3S^*，4R^*) -4-azido-3- [ (tert-butoxycarbonyl) amino group]Ethyl cyclohexanecarboxylate (5.4g) was dissolved in a mixed solvent of ethanol (10ml) and ethyl acetate (10ml), and a catalytic amount of 10% palladium on carbon was added thereto, followed by stirring under a hydrogen stream at room temperature for 20 hours. After insoluble matter was filtered, the solvent was distilled off under reduced pressure to obtain the title compound (4.7 g).

[ reference example 91](1R^*，3S^*，4R^*) -3- [ (tert-butoxycarbonyl) amino group]-4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid ethyl ester

The compound (4.62g) obtained in referential example 90 was dissolved in methylene chloride (50ml), and 5-chloroindole-2-carboxylic acid (3.63g), 1-hydroxybenzotriazole 1 hydrate (2.43g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.45g) were added to stir at room temperature for 12 hours. After 0.1N aqueous hydrochloric acid solution was added to the reaction mixture and extracted with dichloromethane, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine 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 ═ 2: 3) to obtain the title compound (5.3 g).

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.1Hz)，1.43(9H，s)，1.35-2.46(7H，m)，3.91-4.02(1H，m)，4.10-4.22(2H，m)，4.79(1H，br.s)，6.79(1H，s)，7.18-7.40(2H，m)，7.59(1H，s)，8.00(1H，br.s)，9.13(1H，br.s).

[ reference example 92] (1S, 3S, 6R) -7-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, vol.61, p 8687) (89.3g) was suspended in ethanol (810ml), and a 2N aqueous solution (213ml) of sodium hydroxide was added thereto, followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water was added to the residue, followed by extraction with dichloromethane and drying over anhydrous magnesium sulfate. The solvent was evaporated 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 (41g) obtained in referential example 92 was dissolved in N, N-dimethylformamide (300ml), and after ammonium chloride (19.3g) and sodium azide (23.5g) were added in this order at room temperature, stirring was carried out at 76 ℃ for 13 hours. Filtering the reaction solution, concentrating the filtrate, adding the previous filtrate into the residue, and dissolving in water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (51.5 g).

[α]_D ²⁵Not 2 ° (c not 1.0, chloroform)

[ reference example 94] (1S, 3R, 4R) -3- [ (tert-butoxycarbonyl) amino ] -4-hydroxycyclohexanecarboxylic acid ethyl ester

The compound (51.2g) obtained in referential example 93 and di-tert-butyl dicarbonate (68.1g) were dissolved in ethyl acetate (1000ml), and 5% palladium on carbon (5.0g) was added at room temperature at 7kg/cm²The mixture was stirred overnight under hydrogen pressure. After insoluble matter was filtered, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1 → 3: 1), followed by addition of hexane for solidification to obtain the title compound (46.9 g).

[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 (53.5g) obtained in referential example 94 and triethylamine (130ml) were dissolved in methylene chloride (500ml), and methanesulfonyl chloride (42ml) was added dropwise over 20 minutes under cooling at-10 to-15 ℃. After stirring at the same temperature for 20 minutes, the temperature was raised to room temperature over 2 hours. The reaction mixture was cooled to 0 ℃ and 0.5N hydrochloric acid (800ml) was added dropwise thereto, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude ethyl (1S, 3R, 4R) -3- [ (tert-butoxycarbonyl) amino ] -4- [ (methylsulfonyl) oxy ] cyclohexanecarboxylate.

The crude compound was dissolved in N, N-dimethylformamide (335ml), and sodium azide (60.5g) was added thereto, followed by stirring at 67 to 75 ℃ for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and 250ml of the solvent was distilled off. The residue and the previous filtrate 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 (ethyl acetate: hexane ═ 1: 4) to obtain (1S, 3R, 4S) body (18.4g) as the title compound and (1S, 3R, 4R) body (3.3g) as the title compound. (1S, 3R, 4S) form: [ alpha ] to]_D ²⁵(c ═ 1.0, chloroform), (1S, 3R, 4R) body: [ alpha ] to]_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 (4.0g) obtained in referential example 95 was dissolved in a mixed solvent of ethanol (150m) and ethyl acetate (150ml), and 5% palladium on carbon (0.5g) was added under a hydrogen atmosphere (5 kg/cm)²) Stirred at room temperature for 17 hours. After insoluble matter was filtered off, the solvent was distilled off under reduced pressure to obtain 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 (4.2g) obtained in referential example 96 was dissolved in methylene chloride (50ml), and 5-chloroindole-2-carboxylic acid (3.33g), 1-hydroxybenzotriazole 1 hydrate (2.52g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.15g) were added to stir at room temperature for 12 hours. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution, and after extraction with dichloromethane, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, 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: 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 group]-4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid ethyl ester

The title compound was obtained from the compound obtained in referential example 90 and the compound obtained in referential example 10 in the same manner as in referential example 91.

[ reference example 99] benzyl 3-cyclohexene-1-carboxylate

(. + -.) -3-cyclohexene-1-carboxylic acid (50g) was dissolved in N, N-dimethylformamide (550ml), and triethylamine (170ml) and benzyl bromide (61ml) were added under ice cooling, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated 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).

¹H-NMR(CDCl₃)δ：1.66-1.76(1H，m)，2.00-2.13(3H，m)，2.27-2.29(2H，m)，2.58-2.65(1H，m)，5.13(2H，s)，5.66(2H，br.s)，7.29-7.38(5H，m).

Reference example 100](1R^*，3S^*，6S^*) -7-oxabicyclo [4.1.0]Heptane-3-carboxylic acid benzyl ester

The compound (40g) obtained in referential example 99 was dissolved in methylene chloride (500ml), and m-chloroperbenzoic acid (86g) was added under ice cooling to stir for 2 hours. After stirring with 10% aqueous sodium thiosulfate solution 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 evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 9) to give the title compounds (23.4g) and (1R)^*，3R^*，6S^*) -7-oxabicyclo [4.1.0]Heptane-3-carboxylic acid benzyl ester (12.1 g).

¹H-NMR(CDCl₃)δ：1.39-1.49(1H，m)，1.75-1.82(1H，m)，1.90-2.04(3H，m)，2.30(1H，dd，J＝14.9，4.9Hz)，2.54-2.61(1H，m)，3.12-3.14(1H，m)，3.22-3.24(1H，m)，5.12(2H，s)，7.30-7.39(5H，m).

MS(FAB)m/z：233(M+H)⁺.

[ reference example 101](1R^*，3S^*，4S^*) -4-StackN-3-Hydroxycyclohexanecarboxylic acid benzyl ester

The compound (52.3g) obtained in referential example 100 was dissolved in N, N-dimethylformamide (1000ml), and ammonium chloride (21.9g) and sodium azide (18.1g) were added to heat at 70 ℃ and stir for 24 hours. The solvent was evaporated under reduced pressure, the residue was extracted with ethyl acetate and water was added thereto, and 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).

¹H-NMR(CDCl₃)δ：1.51-1.66(2H，m)，1.91-1.98(1H，m)，2.07-2.10(1H，m)，2.27-2.32(1H，m)，2.51-2.52(1H，m)，2.81-2.86(1H，m)，3.30-3.36(1H，m)，3.70-3.75(1H，m)，5.13(2H，s)，7.30-7.39(5H，m).

Reference example 102](1R^*，3S^*，4S^*) -4- [ (tert-butoxycarbonyl) amino group]-3-Hydroxycyclohexanecarboxylic acid benzyl ester

The compound (5.27g) obtained in referential example 101 was dissolved in tetrahydrofuran (25ml), and triphenylphosphine (5.53g) and water (0.55ml) were added to stir at room temperature for 20 hours. Di-tert-butyl dicarbonate (4.82g) was added to the reaction mixture, and stirring was continued for 2 hours. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to obtain the title compound (6.22 g).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.59-1.66(2H，m)，1.88-2.00(2H，m)，2.29-2.32(1H，m)，2.80-2.85(1H，m)，3.02(1H，br.s)，3.42(1H，br.s)，3.59-3.65(1H，m)，4.56(1H，br.s)，5.12(2H，q，J＝12.5Hz)，7.30-7.38(5H，m).

MS(FAB)m/z：350(M+H)⁺.

[ reference example 103](1R^*，3S^*，4S^*) -4- [ (tert-butoxycarbonyl) amino group]-3-Hydroxycyclohexanecarboxylic acid methyl ester

The compound (2.54g) obtained in referential example 102 was dissolved in ethyl acetate (15ml), and a catalytic amount of 10% palladium on carbon was added, followed by stirring at room temperature for 20 hours under a hydrogen stream. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give (1R) as a colorless oil^*，3S^*，4S^*) -4- [ (tert-butoxycarbonyl) amino group]-3-hydroxycyclohexanecarboxylic acid. This was dissolved in a mixed solution of methanol (8ml) and toluene (15ml), and a 2N trimethylsilyl diazomethane hexane solution (10ml) was added under ice cooling, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to obtain the title compound (1.82 g).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.36-2.32(7H，m)，2.74-2.82(1H，m)，3.04(1H，br.s)，3.33-3.47(1H，m)，3.55-3.65(1H，m)，3.68(3H，s)，4.56(1H，br.s).

MS(FAB)m/z：274(M+H)⁺.

Reference example 104](1R^*，3R^*，4S^*) -3-azido-4- [ (tert-butoxycarbonyl) amino group]Cyclohexanecarboxylic acid methyl ester and (1R)^*，3S^*，4S^*) -3-azido-4- [ (tert-butoxycarbonyl) amino group]Cyclohexanecarboxylic acid methyl ester

The compound (1.81g) obtained in referential example 103 was dissolved in methylene chloride (36ml), and triethylamine (4.6ml) and methanesulfonyl chloride (1.63ml) were added at-78 ℃ and, after 30 minutes, the temperature was raised to 0 ℃ and further stirred for 30 minutes. 1N hydrochloric acid was added thereto, the mixture was extracted with dichloromethane, and 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 group]-3- [ (methylsulfonyl) oxy group]Cyclohexane carboxylic acid methyl ester. The crude compound was dissolved in N, N-dimethylformamide (23ml), and sodium azide (1.29g) was added thereto, followed by heating at 70 ℃ and stirring for 12 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine 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 ═ 3: 17) to give (1R)^*，3S^*，4S^*) -3-azido-4- [ (tert-butoxycarbonyl) amino group]Cyclohexanecarboxylic acid methyl ester (85mg) and (1R)^*，3R^*，4S^*) -3-azido-4- [ (tert-butoxycarbonyl) amino group]Cyclohexanecarboxylic acid methyl ester (590 mg).

(1R^*，3R^*，4S^*) Body:¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.35-2.35(7H，m)，2.45-2.55(1H，m)，3.73(3H，s)，3.67-3.84(2H，m)，4.70(1H，br.s).

MS(FAB)m/z：299(M+H)⁺.

(1R^*，3S^*，4S^*) Body:¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.56-2.25(7H，m)，2.68-2.80(1H，m)，3.70(3H，s)，3.48-3.68(2H，m)，4.56(1H，br.s).

MS(FAB)m/z：299(M+H)⁺.

[ reference example 105](1R^*，3R^*，4S^*) -3-amino-4- [ (tert-butoxycarbonyl) amino group]Cyclohexanecarboxylic acid methyl ester

(1R) obtained in referential example 104^*，3R^*，4S^*) The compound (230mg) was dissolved in ethyl acetate (8ml), and a catalytic amount of 10% palladium on carbon was added thereto, followed by stirring under a hydrogen flow for 20 hours. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (220 mg).

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

The title compound was obtained from the compound obtained in referential example 105 and the compound obtained in referential example 10 in the same manner as in referential example 91.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.53-1.95(5H，m)，2.17-2.24(1H，m)，2.50(3H，s)，2.50-2.53(1H，m)，2.80-2.96(4H，m)，3.67(3H，s)，3.69-3.74(1H，m)，4.10(2H，br.s)，4.88(1H，br.s).

MS(FAB)m/z：453(M+H)⁺.

Reference example 107](1R^*，3R^*，4S^*) -4- [ (tert-butoxycarbonyl) amino group]-3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid methyl ester

The title compound was obtained from the compound obtained in referential example 105 in the same manner as in referential example 91.

¹H-NMR(CDCl₃)δ：1.33(9H，s)，1.42-2.47(6H，m)，2.78-2.88(1H，m)，3.70(3H，s)，3.86-4.15(2H，m)，4.65-4.75(1H，m)，6.86(1H，br.s)，7.18-7.38(2H，m)，7.57-7.61(1H，m)，8.32(1H，br.s).MS(ESI)m/z：450(M+H)⁺.

[ reference example 108] (1S, 3R, 6R) -7-oxabicyclo [4.1.0] heptane-3-carboxylic acid benzyl ester

1) Benzyl (1R) -3-cyclohexene-1-carboxylate was obtained from (1R) -3-cyclohexene-1-carboxylate (J.Am.chem.Soc, 1978, Vol.100, p.5199) in the same manner as in reference example 99.

2) The title compound was obtained from the above product by the same method as in reference example 100.

MS(FAB)m/z：233(M+H)⁺.

[ reference example 109] (1R, 3S, 4S) -4- [ (tert-butoxycarbonyl) amino ] -3-hydroxycyclohexanecarboxylic acid benzyl ester

1) Benzyl (1R, 3S, 4S) -4-azido-3-hydroxycyclohexanecarboxylate was obtained from the compound obtained in referential example 108 in the same manner as in referential example 101.

2) The title compound was prepared from the above product by the same method 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

The title compound was obtained from the compound obtained in referential example 109 in the same manner as in referential example 104.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.52-1.66(2H，m)，1.83-2.01(3H，m)，2.20-2.28(1H，m)，2.51-2.54(1H，m)，3.77(2H，br.s)，4.70(1H，br.s)，5.15(2H，ABq，J＝12.2Hz)，7.33-7.38(5H，m).

MS(FAB)m/z：375(M+H)⁺.

[ reference example 111] (1R, 3R, 4S) -3-azido-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid methyl ester

The compound (3.5g) obtained in referential example 110 was dissolved in tetrahydrofuran (130ml) and water (16ml), and lithium hydroxide (291mg) was added under ice cooling, and after 10 minutes, the temperature was returned to room temperature and stirring was carried out for 20 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 20) to give (1R, 3R, 4S) -3-azido-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid (3.34g) as a pale yellow oil. This was dissolved in methanol (18ml) and toluene (64ml), and a 2-molar trimethylsilyl diazomethane hexane solution (6.1ml) was added under ice cooling, and after 10 minutes, the temperature was returned to room temperature and stirred for 2 hours. 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 (3.35 g).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.57-1.63(2H，m)，1.82-1.85(1H，m)，1.95-1.99(2H，m)，2.20-2.28(1H，m)，2.48-2.51(1H，m)，3.73(3H，s)，3.78(2H，br.s)，4.70-4.72(1H，m).

MS(FAB)m/z：299(M+H)⁺.

[ reference example 112] (1R, 3R, 4S) -4- [ (tert-butoxycarbonyl) amino ] -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylic acid methyl ester

1) Methyl (1R, 3R, 4S) -3-amino-4- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylate was prepared from the compound obtained in referential example 111 in the same manner as in referential example 105.

2) The title compound was obtained from the above-mentioned product and the compound obtained in referential example 10 in the same manner as in referential example 106.

MS(FAB)m/z：453(M+H)⁺.

[ reference example 113](1R^*，2S^*，5S^*) -5-aminocarbonyl-2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester

The compound (590mg) obtained in referential example 91 was dissolved in a mixed solvent of ethanol (3ml) and tetrahydrofuran (6ml), and a 1N aqueous solution (2.5ml) of sodium hydroxide was added thereto at room temperature, followed by stirring for 12 hours. Evaporating the solvent to obtain (1R)^*，3S^*，4R^*) -3- [ (tert-butoxycarbonyl) amino group]-4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid sodium salt. This was suspended in N, N-dimethylformamide (4ml), and di-tert-butyl dicarbonate (654mg) and ammonium hydrogencarbonate (1g) were added at room temperature and stirred for 18 hours. The solvent was distilled off under reduced pressure, water was added thereto, and extraction was performed with chloroform, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: 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-yl-carbamic acid benzyl ester

4-cyclohexene-1, 2-diamine hydrochloride (4.0g) was dissolved in a mixed solvent of water (20ml) and acetonitrile (20ml), and benzyl chloroformate (7.66ml) and potassium carbonate (14.9g) were added thereto, followed by stirring at room temperature for 3 days. The reaction mixture was poured into water, extracted with dichloromethane, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain the title compound (8.22 g).

¹H-NMR(CDCl₃)δ：2.03(2H，m)，2.53(2H，d，J＝17.1Hz)，3.77(2H，m)，5.03(2H，q，J＝12.3Hz)，5.09(2H，q，J＝12.3Hz)，5.59(2H，s)，7.32(10H，m).

MS(ESI)m/z：381(M+H)⁺.

Reference example 115](1R^*，2S^*) -2- { [ (benzyloxy) carbonyl]Amino } -5-hydroxycyclohexyl-carbamic acid benzyl ester

The compound (10g) obtained in referential example 114 was dissolved in anhydrous tetrahydrofuran (70ml), and borane dimethyl sulfide complex (7.4ml) was added at 0 ℃ to stir the solution for 14 hours after slowly raising the temperature to room temperature. Ice was added to the reaction solution to decompose excess borane, and a 1N aqueous solution of sodium hydroxide (80ml) and 30% aqueous hydrogen peroxide (80ml) were added thereto, followed by direct stirring for 1 hour. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to obtain the title compound (9.2 g).

¹H-NMR(CDCl₃)δ：1.98(1H，m)，2.08(1H，m)，2.30(1H，m)，3.43(2H，m)，3.73(1H，m)，5.06(6H，m)，7.32(10H，s).

MS(ESI)m/z：399(M+H)⁺.

Reference example 116](1R^*，2S^*) -2- { [ (benzyloxy) carbonyl]Amino } -5-oxocyclohexylcarbamic acid benzyl ester

Dimethyl sulfoxide (8.2ml) was added to a solution of oxalyl chloride (9.9ml) in methylene chloride (90ml) while stirring at-60 ℃ and then a solution of the compound (9.2g) obtained in referential example 115 in tetrahydrofuran (90ml) was added one by one. After 1 hour the temperature was raised to-40 ℃ and triethylamine (26ml) was added in one portion. The mixture was directly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 1) to obtain the title compound (8.0 g).

¹H-NMR(CDCl₃)δ：2.27-2.43(4H，m)，2.78(1H，dd，J＝14.4，3.9Hz)，3.86(2H，m)，5.08(4H，m)，5.22(2H，m)，7.32(10H，m).

MS(ESI)m/z：397(M+H)⁺.

Reference example 117](1R^*，2S^*) -2- { [ (benzyloxy) carbonyl]Amino } -5, 5-dimethoxycyclohexyl-carbamic acid benzyl ester

The compound (3.89g) obtained in referential example 116 was dissolved in a mixed solvent of methanol (15ml) and tetrahydrofuran (15ml), and 2, 2-dimethoxypropane (10.7ml) and p-toluenesulfonic acid (187mg) were added to stir at room temperature for 3 hours. The solution was concentrated, and saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction 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 (ethyl acetate: hexane ═ 1: 2) to obtain the title compound (3.54 g).

¹H-NMR(CDCl₃)δ：1.30-1.41(4H，m)，1.93(1H，m)，2.38(1H，m)，3.19(6H，s)，3.46(1H，m)，3.59(1H，m)，5.03(2H，q，J＝12.5Hz)，5.09(2H，q，J＝12.5Hz)，7.32(10H，s).

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

The compound (1.45g) obtained in referential example 117 was dissolved in methanol (12ml), and 10% palladium on carbon (290mg) was added to stir at room temperature for 20 hours in a hydrogen atmosphere. 10% Palladium on carbon (290mg) and methanol (10ml) were added thereto, and the mixture was stirred for 8 hours. The reaction mixture was filtered through Celite, and after concentrating the mother liquor, the residue was dissolved in N, N-dimethylformamide (10ml), and 5-chloroindole-2-carboxylic acid (320mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (377mg), 1-hydroxybenzotriazole 1 hydrate (301mg) and N-methylmorpholine (360ml) were added thereto and stirred at room temperature for 14 hours. The reaction mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (dichloromethane: methanol 93: 7) to obtain N- [ (1R)^*，2S^*) -2-amino-4, 4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide (orN-[(1R^*，2S^*) -2-amino-5, 5-dimethoxycyclohexyl]-5-Chloroindole-2-carboxamide) (98mg) 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).

N-[(1R^*，2S^*) -2-amino-4, 4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide:

¹H-NMR(CDCl₃)δ：1.45-1.50(2H，m)，2.06-2.10(2H，m)，2.34(1H，d，J＝13.1Hz)，2.78(1H，dt，J＝2.9，13.1Hz)，3.18(3H，s)，3.23(3H，s)，3.75-3.77(1H，m)，6.24(1H，d，J＝8.3Hz)，6.79(1H，s)，7.23(1H，dd，J＝8.8，2.0Hz)，7.35(1H，d，J＝8.8Hz)，7.60(1H，d，J＝8.8Hz)，9.53(1H，br.s).

MS(ESI)m/z：352(M+H)⁺.

N-[(1R^*，2S^*) -2-amino-5, 5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide:

¹H-NMR(CDCl₃)δ：1.83-1.87(1H，m)，1.97-2.01(1H，m)，2.39(1H，br，J＝13.2Hz)，2.86-2.90(1H，m)，3.22-3.28(10H，m)，4.00-4.02(1H，m)，6.77(1H，s)，7.23(1H，d，J＝8.5Hz)，7.37(1H，d，J＝8.5Hz)，7.61(1H，s)，9.49(1H，br.s).

MS(ESI)m/z：352(M+H)⁺.

[ reference example 119](7R^*，8S^*) -7- { [ (benzyloxy) carbonyl]Amino } -1, 4-dioxaspiro [4.5 ]]Decyl-8-ylcarbamic acid benzyl ester

The compound (4.0g) obtained in referential example 116 was dissolved in anhydrous tetrahydrofuran (30ml), and ethylene glycol (5.6ml) and p-toluenesulfonic acid (192mg) were added to stir at room temperature for 17 hours. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 1) to obtain the title compound (4.23 g).

¹H-NMR(CDCl₃)δ：1.65-1.71(4H，m)，2.00(1H，m)，2.11(1H，m)，3.49(1H，m)，3.73(1H，m)，3.93(4H，s)，5.03(2H，q，J＝12.2Hz)，5.08(2H，q，J＝12.2Hz)，7.32(10H，s).

MS(ESI)m/z：441(M+H)⁺.

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

N- [ (7R) was obtained from the compound obtained in referential example 119 in the same manner as in referential example 118 ^*，8S^*) -7-amino-1, 4-dioxaspiro [4.5 ]]Decan-8-yl]-5-chloroindole-2-carboxamide or (N- [ (7R)^*，8S^*) -8-amino-1, 4-dioxaspiro [4.5 ]]Decan-7-yl]-5-chloroindole-2-carboxamide) and N- [ (7R)^*，8S^*) -8-amino-1, 4-dioxaspiro [4.5 ]]Decan-7-yl]-5-chloroindole-2-carboxamide (or N- [ (7R)^*，8S^*) -7-amino-1, 4-dioxaspiro [4.5 ]]Decan-8-yl]-5-chloroindole-2-carboxamide).

N-[(7R^*，8S^*) -8-amino-1, 4-dioxaspiro [4.5 ]]Decan-7-yl]-5-chloroindole-2-carboxamide (or N- [ (7R)^*，8S^*) -7-amino-1, 4-dioxaspiro [4.5 ]]Decan-8-yl]-5-chloroindole-2-carboxamide):

¹H-NMR(CDCl₃)δ：1.68-1.81(4H，m)，2.11(2H，m)，2.87(1H，td，J＝3.9，11.2Hz)，3.77(1H，m)，3.97(4H，s)，6.27(1H，d，J＝7.6Hz)，6.80(1H，s)，7.24(1H，d，J＝9.0Hz)，7.35(1H，d，J＝9.0Hz)，7.61(1H，s)，9.47(br.s，1H).

MS(ESI)m/z：350(M+H)⁺.

N-[(7R^*，8S^*) -8-amino-1, 4-dioxaspiro [4.5 ]]Decan-7-yl]-5-chloroindole-2-carboxamide (or N- [ (7R)^*，8S^*) -7-amino-1, 4-dioxaspiro [4.5 ]]Decan-8-yl]-5-chloroindole-2-carboxamide):

¹H-NMR(CDCl₃)δ：1.65(2H，m)，1.88(1H，m)，1.96(1H，m)，2.31(1H，dd，J＝12.9，3.2Hz)，2.96(1H，m)，3.98(1H，m)，4.02(4H，s)，4.12(1H，m)，6.77(1H，s)，7.06(1H，br.s)，7.23(1H，dd，J＝8.8，2.0Hz)，7.37(1H，d，J＝8.8Hz)，7.62(1H，d，J＝2.0Hz)，9.49(1H，br.s).

MS(ESI)m/z：350(M+H)⁺.

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

Cis-4-cyclohexene-1, 2-diamine hydrochloride (4.0g) was dissolved in water (40ml) and acetonitrile (40ml), and di-tert-butoxycarbonate (11.8g) and triethylamine (12ml) were added to stir at room temperature for 4.5 hours. The reaction mixture was poured into water, extracted with dichloromethane, and the dichloromethane layer was washed with saturated brine and dried over anhydrous sodium 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 (6.12 g).

¹H-NMR(CDCl₃)δ：1.44(18H，s)，1.98(2H，dd，J＝9.3，15.9Hz)，2.48(2H，br.d，J＝15.9Hz)，3.66(2H，br.s)，4.88(2H，br.s)，5.58(2H，d，J＝2.7Hz).

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

The compound (6.1g) obtained in referential example 121 was dissolved in anhydrous tetrahydrofuran (40ml), and borane-dimethyl sulfide complex (2.22ml) was added under ice cooling to stir for 16 hours while slowly raising the temperature to room temperature as it is. Ice was added to the reaction solution, and a 1N aqueous solution of sodium hydroxide and a 30% aqueous solution of hydrogen peroxide (50ml) were added thereto, followed by stirring at room temperature for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated 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).

¹H-NMR(CDCl₃)δ：1.42(9H，s)，1.43(9H，s)，1.83-1.67(5H，m)，2.15(1H，m)，2.22(1H，s)，3.34(1H，m)，3.78(1H，m)，4.15(1H，s)，4.98(1H，q，J＝9.0Hz)，5.02(1H，q，J＝9.0Hz).

MS(ESI)m/z：331(M+H)⁺.

[ reference example 123](1R^*，2S^*) -2- [ (tert-butoxycarbonyl) amino group]-5-Oxocyclohexylcarbamic acid tert-butyl ester

Oxalyl chloride (8.2ml) and dimethyl sulfoxide (6.8ml) were dissolved in methylene chloride (100ml), cooled to-60 ℃ and a solution of the compound (mixture of stereoisomers) (6.32g) obtained in referential example 122 in tetrahydrofuran (80ml) was added in one portion and stirred for 1 hour. The temperature was raised to-40 ℃ and triethylamine (21ml) was added, the temperature was raised to room temperature and after 3 hours water was added. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 1) to obtain the title compound (3.8 g).

¹H-NMR(CDCl₃)δ：1.43(9H，s)，1.44(9H，s)，2.24-2.36(3H，m)，2.39-2.44(2H，m)，2.75(1H，dd，J＝14.6，2.9Hz)，3.66-3.81(2H，m)，4.95-4.90(1H，m)，4.97-5.03(1H，m).

MS(ESI)m/z：329(M+H)⁺.

[ reference example 124](1R^*，2S^*) -2- [ (tert-butoxycarbonyl) amino group]-5- (Methoxyimino) cyclohexyl carbamic acid tert-butyl ester

The compound (1.5g) obtained in referential example 123 was dissolved in methanol (30ml), and O-methylhydroxylamine hydrochloride (572mg) and pyridine (737ml) were added to stir at room temperature for 17 hours. The reaction mixture was concentrated, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium 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 (1.52 g).

¹H-NMR(CDCl₃)δ：1.44(18H，s)，1.64(1H，m)，2.16(2H，m)，2.44(1H，m)，3.45-3.63(3H，m)，3.82(3H，s)，4.93(1H，m).

MS(ESI)m/z：358(M+H)⁺.

Reference example 125](1R^*，2S^*) -2- [ (tert-butoxycarbonyl) amino group]-5- { [ tert-butyl (diphenyl) silyl]Oxy } cyclohexyl carbamic acid tert-butyl ester (stereoisomer A)

The title compound was obtained from the compound (mixture of stereoisomers) obtained in referential example 122 in the same manner as in referential example 58. Furthermore, (1R) is recovered^*，2S^*) -2- [ (tert-butoxycarbonyl) amino group]-5-Hydroxycyclohexylcarbamic acid tert-butyl ester (stereoisomer B).

¹H-NMR(CDCl₃)δ：1.03(9H，s)，1.39(9H，s)，1.40(9H，s)，1.72(1H，m)，1.86(1H，m)，2.13(1H，m)，3.24(2H，m)，3.65(1H，m)，4.83(1H，m)，7.37(10H，m).

Reference example 126](1R^*，2S^*) -2- { [ (benzyloxy) carbonyl]Amino } -5-hydroxy-5-methylcyclohexyl-carbamic acid benzyl ester

Anhydrous cerium chloride (6.4g) was suspended in tetrahydrofuran (50ml) and cooled to-78 ℃ under a stream of argon. To the suspension was added methyllithium solution (1.14N in ether, 22.5ml) and the mixture was stirred at-78 ℃ for 30 minutes. A tetrahydrofuran solution (50ml) of the mixture (3.0g) obtained in referential example 116 was added dropwise at-78 ℃ and stirred for 30 minutes. The reaction mixture was poured into a 3% aqueous solution (100ml) of acetic acid, and diethyl ether (50ml) was added thereto, followed by stirring at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform: 0: 100 to 1: 19) 2 times to obtain the title compound (stereoisomer a) (780mg) and the title compound (stereoisomer B) (1.1 g).

Stereoisomer a:

¹H-NMR(CDCl₃)δ：1.26(3H，s)，1.27-2.08(6H，m)，3.48(1H，br.s)，3.59(1H，br.s)，5.02-5.09(5H，m)，5.33(1H，br.s)，7.30-7.32(10H，s)

MS(FAB)m/z：413(M+H)⁺.

stereoisomer B:

¹H-NMR(CDCl₃)δ：1.25(3H，s)，1.29-2.07(6H，m)，3.39(1H，br.s)，3.82(1H，br.s)，5.02-5.23(6H，m)，7.30(10H，s)

MS(FAB)m/z：413(M+H)⁺.

[ reference example 127](3R^*，4S^*) -3, 4-diamino-]-methylcyclohexanol (stereoisomer A)

10% Palladium on carbon (350mg) was suspended in a methanol solution (100ml) of the compound (stereoisomer A) (780mg) obtained in referential example 126, and the mixture was stirred for 5 hours under a hydrogen stream. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride (100ml), which was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound (stereoisomer A) (190 mg).

¹H-NMR(CDCl₃)δ：1.22(3H，s)，1.25-2.48(11H，m)，2.62(1H，br.s)，2.78(1H，br.s).

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

The title compound was obtained from the compound (stereoisomer A) obtained in referential example 127 and 5-chloroindole-2-carboxylic acid by the same method as referential example 59.

¹H-NMR(CDCl₃)δ：1.32(3H，s)，1.34-2.29(6H，m)，4.42-4.70(4H，br)，7.13(2H，s)，7.50(2H，s)，8.00(1H，s)，11.0(1H，br).

[ reference example 129](1R^*，2R^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (hydroxymethyl) cyclohexyl-carbamic acid tert-butyl ester

1) (1R) obtained in referential example 89^*，3S^*，4S^*) (1R) was obtained in the same manner as described in reference examples 90 to 91^*，3S^*，4S^*) -3- [ (tert-butoxycarbonyl) amino group]-4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid ethyl ester.

¹H-NMR(CDCl₃)δ：1.22-1.72(6H，m)，2.15-2.28(2H，m)，2.41-2.49(1H，m)，2.85(1H，brs)，3.62-3.75(1H，m)，3.78-3.92(1H，m)，4.12-4.28(2H，m)，4.56-4.63(1H，m)，6.88(1H，brs)，7.20(1H，dd，J＝8.8and 2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.52-7.57(1H，m)，7.59(1H，d，J＝2.0Hz)，9.24(1H，s).

MS(ESI)m/z：464(M+H)⁺.

2) The product (735mg) was dissolved in methylene chloride (10ml), and a 1N hexane solution (5ml) of diisobutylaluminum hydride was added thereto at-78 ℃ to stir the mixture for 3 hours, followed by stirring at 0 ℃ for 30 minutes. Saturated aqueous ammonium chloride was added thereto at-78 ℃, followed by extraction with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 19: 1) to obtain the title compound (480 mg).

¹H-NMR(CDCl₃)δ：1.20-2.30(7H，m)，3.60-3.86(4H，m)，4.64(1H，br.s)，6.87(1H，s)，7.20-7.48(3H，m)，9.15(1H，br.s).

MS(ESI)m/z：422(M+H)⁺.

Reference example 130](1R^*，3R^*，6S^*) -3- (methoxymethyl) oxabicyclo [4.1.0]Heptane (Heptane)

1) Will be (1R)^*，4R^*，5R^*) -4-iodo-6-oxabicyclo [3.2.1]Octane-7-one (2.8g) was dissolved in a mixed solvent of tetrahydrofuran (27ml) and water (3ml), and concentrated hydrochloric acid (0.1ml) was added thereto and the mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure to obtain (1R) as a colorless solid^*，3R^*，4R^*) -3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g).

2) The product (3.22g) obtained by the above reaction was dissolved in tetrahydrofuran (50ml), and borane-dimethylsulfide complex (2 mol tetrahydrofuran solution, 47ml) was added under ice cooling, followed by stirring at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in isopropanol (10ml), and a 1N aqueous solution (12ml) of sodium hydroxide was added thereto at room temperature, followed by stirring for 12 hours. The solvent was concentrated to about 1/5, diluted with water and dichloromethane, and stirred for 10 minutes. The organic layer was separated, successively saturated with a saturated aqueous ammonium chloride solution and saturated Washed with brine 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: 2) to give (1R) as a colorless oil^*，3R^*，6S^*) -7-oxabicyclo [4.1.0]Hept-3-ylmethanol (1.25 g).

3) The product (4.63g) obtained by the reaction of 2) above was dissolved in tetrahydrofuran (50ml), and potassium bis (trimethylsilyl) amide (0.5N in toluene, 80ml) was added at-78 ℃ and after stirring at the same temperature for 10 minutes, methyl iodide (2.93ml) was added. After warming to 0 ℃ and stirring for 1 hour, saturated aqueous ammonium chloride solution was added and diluted with ether. The organic layer was separated, washed with saturated brine, 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 (3.7 g).

¹H-NMR(CDCl₃)δ：0.89-1.63(5H，m)，1.80-2.05(2H，m)，1.89-3.06(4H，m)，3.16(3H，s).

[ reference example 131](1R^*，2R^*，4S^*) -2-azido-4- (methoxymethyl) cyclohexanol

The title compound was obtained from the compound obtained in referential example 130 in the same manner as in referential example 87.

¹H-NMR(CDCl₃)δ：1.45-1.70(5H，m)，1.77-1.95(2H，m)，1.98-2.08(1H，m)，3.30(2H，d，J＝6.8Hz)，3.35(3H，s)，3.45-3.65(2H，m).

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

The title compound was obtained from the compound obtained in referential example 131 in the same manner as in referential example 88.

¹H-NMR(CDCl₃)δ：1.35-2.01(16H，m)，3.05(1H，br.s)，3.32(2H，d，J＝7.1Hz)，3.34(3H，s)，3.44-3.62(2H，m)，4.59(1H，br.s).

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

The title compound was obtained from the compound obtained in referential example 132 via its mesylate by the same procedure as referential example 89.

¹H-NMR(CDCl₃)δ：1.31-1.93(16H，m)，3.27(2H，d，J＝6.4Hz)，3.32(3H，s)，3.57-3.70(1H，m)，3.67(1H，br.s)，3.95(1H，br.s).

Reference example 134](1R^*，2S^*，5S^*) -2-amino-5- (methoxymethyl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 133 by the same method as referential example 90.

Reference example 135](1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (methoxymethyl) cyclohexyl-carbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 134 and 5-chloroindole-2-carboxylic acid by the same method as referential example 91.

¹H-NMR(CDCl₃)δ：1.12-2.31(16H，m)，3.14-3.30(2H，m)，3.34(3H，s)，3.92(1H，br.s)，4.13(1H，br.s)，4.88(1H，br.s)，6.82(1H，s)，7.21(1H，br.d，J＝8.8Hz)，7.33(1H，d，J＝8.8Hz)，7.60(1H，s)，8.09(1H，br.s)，9.42(1H，br.s).

MS(ESI)m/z：436(M+H)⁺.

Reference example 136](1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- (hydroxymethyl) cyclohexyl-carbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 91 in the same manner as in referential example 129.

¹H-NMR(CDCl₃)δ：0.78-2.30(16H，m)，3.41-3.59(3H，m)，3.86-3.95(1H，m)，4.12-4.20(1H，m)，4.82-4.91(1H，m)，6.81(1H，s)，7.17-7.40(2H，m)，7.60(1H，s)，8.03(1H，br.s)，9.18(1H，br.s).

MS(ESI)m/z：422(M+H)⁺.

[ reference example 137 ]](1R^*，2S^*，5S^*) -5- (azidomethyl) -2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 136 in the same manner as in referential example 80.

[ reference example 138] tert-butyl 3-cyclohexen-1-ylcarbamate

3-cyclohexene-1-carboxylic acid (25.3g) was dissolved in tert-butanol (250ml), triethylamine (28ml) and diphenylphosphoryl azide (43.0ml) were added, and the mixture was stirred at room temperature for 1 hour and then at 90 ℃ for 2 days. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) and then further purified by silica gel column chromatography (hexane: ethyl acetate: 20: 1) to obtain the title compound (24.9 g).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.45-1.60(1H，m)，1.80-1.90(2H，m)，2.05-2.20(2H，m)，2.35-2.45(1H，m)，3.78(1H，br)，4.56(1H，br)，5.55-5.65(1H，m)，5.65-5.75(1H，m).

[ reference example 139](3R^*，4S^*) -3, 4-Dihydroxycyclohexylcarbamic acid tert-butyl ester

The compound (1.24g) obtained in referential example 138 was dissolved in a mixed solvent of acetonitrile (15ml) and water (5ml), and N-methylmorpholine-N-oxide (0.90g) and microencapsulated 10% osmium tetroxide (1g) were added and stirred at about 80 ℃ for 1 day. After insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20: 1) to obtain the title compound (1.28 g).

¹H-NMR(CDCl₃)δ：1.15-1.30(1/2H，m)，1.35-2.00(15H，m)，2.15-2.30(3/2H，m)，2.40-2.60(1H，m)，3.64(1H，br)，3.75-3.90(3/2H，m)，4.00(1/2H，br).

MS(FAB)m/z：232(M+H)⁺.

Reference example 140](3R^*，4S^*) -3, 4-Diazidocyclohexylcarbamic acid tert-butyl ester (stereoisomers A and B)

The title compound (stereoisomer a and stereoisomer B) was prepared from the compound obtained in referential example 139 by the same method as referential example 80.

Stereoisomer a:

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.40-1.55(1H，m)，1.55-1.80(3H，m)，1.95-2.15(2H，m)，3.53(1H，m)，3.59(1H，br)，3.80(1H，m)，4.70(1H，br).

stereoisomer B:

¹H-NMR(CDCl₃)δ：1.27(1H，m)，1.44(9H，s)，1.40-1.55(1H，m)，1.80-2.00(2H，m)，2.00-2.15(1H，m)，2.21(1H，m)，3.48(1H，m)，3.77(1H，br)，3.89(1H，br)，4.34(1H，br).

[ reference example 141] (1R, 3R, 4S) -4- { [ (benzyloxy) carbonyl ] amino } -3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid ethyl ester

The compound (3.10g) obtained in referential example 96 was dissolved in tetrahydrofuran (50ml), and a saturated aqueous sodium hydrogencarbonate solution (50ml) was added. Benzyloxycarbonyl chloride (1.71ml) was added dropwise to the reaction mixture under ice cooling, followed by stirring at room temperature for 4 days. Ethyl acetate (200ml) and water (200ml) were added to the reaction mixture to conduct a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to obtain the title compound (3.24 g).

¹H-NMR(CDCl₃)δ：1.24(3H，t，J＝7.1Hz)，1.29-1.44(1H，m)，1.44(9H，s)，1.51-1.64(1H，m)，1.72-2.10(4H，m)，2.27-2.43(1H，m)，3.60-3.73(1H，m)，4.00-4.18(3H，m)，4.62(1H，br.s)，5.01-5.13(2H，m)，5.26(1H，br.s)，7.27-7.38(5H，m).

[ reference example 142] (1S, 3R, 4S) -4- { [ (benzyloxy) carbonyl ] amino } -3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid

The compound (620mg) obtained in referential example 141 was dissolved in tetrahydrofuran (20ml), and an aqueous solution (10ml) of lithium hydroxide 1 hydrate (93mg) was added to stir at room temperature for 16 hours. Lithium hydroxide 1 hydrate (217mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours, then neutralized by adding 1N hydrochloric acid aqueous solution, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound (600 mg).

¹H-NMR(CDCl₃)δ：1.22-2.20(6H，m)，1.44(9H，s)，2.45(1H，br.s)，3.60-3.80(1H，br)，4.09(1H，br.s)，4.66(1H，br.s)，5.00-5.20(2H，m)，5.26(1H，br.s)，7.20-7.40(5H，m).

MS(ESI)m/z：393(M+H)⁺.

[ reference example 143] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid benzyl ester

After the compound (600mg) obtained in referential example 142 and dimethylamine hydrochloride (240mg) were suspended in methylene chloride (50ml), an appropriate amount of tetrahydrofuran was added to form a solution. To the solution were added triethylamine (0.41ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (422mg) and 1-hydroxybenzotriazole 1 hydrate (338mg), and the mixture was stirred at room temperature for 1 hour. Dimethylamine hydrochloride (480mg) and triethylamine (0.82ml) were added to the reaction mixture, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was poured into water, and the organic layer was separated, washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 3: 47 → 2: 23) to obtain the title compound (620 mg).

¹H-NMR(CDCl₃)δ：1.20-1.50(2H，m)，1.44(9H，s)，1.50-2.10(4H，m)，2.60(1H，br.t，J＝11.6Hz)，2.93(3H，s)，3.02(3H，s)，3.70(1H，br.s)，4.14(1H，br.s)，4.65(1H，br.s)，5.00-5.30(3H，m)，7.26-7.40(5H，m).

MS(ESI)m/z＝420(M+H)⁺.

[ reference example 144] (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

10% Palladium on carbon (57g) was added to a methanol (8000ml) solution of the compound (190g) obtained in referential example 143, and the mixture was stirred under a hydrogen gas atmosphere of 7 atm for 3 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. After toluene was added to the residue and the mixture was concentrated under reduced pressure, hexane (2500ml) was added to the residue to solidify, and the resultant mixture was filtered and dried to obtain the title compound (121 g).

¹H-NMR(CDCl₃)δ：1.20-1.77(6H，m)，1.45(9H，s)，2.20-2.35(1H，br)，2.63-2.74(1H，m)，2.92(3H，s)，3.02(3H，s)，3.02-3.11(2H，m)，3.74-3.82(1H，m)，4.88-5.00(1H，br)MS(ESI)m/z：286(M+H)⁺.

[ reference example 145] (1R, 2S, 5S) -2- { [ (6-chloroquinolin-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 54 in the same manner as in referential example 91.

¹H-NMR(CDCl₃)δ：1.41(9H，br)，1.50-1.70(1H，m)，1.75-1.95(2H，m)，1.95-2.25(3H，m)，2.65-2.80(1H，m)，2.96(3H，s)，3.07(3H，s)，4.15-4.30(1H，m)，4.30-4.40(1H，m)，4.95(1H，br)，7.66(1H，d，J＝8.8Hz)，7.84(1H，s)，8.00(1H，d，J＝8.8Hz)，8.19(1H，d，J＝8.6Hz)，8.30(1H，d，J＝8.6Hz).

MS(FAB)m/z：475(M+H)⁺.

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

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 57 in the same manner as in referential example 91.

¹H-NMR(CDCl₃)δ：1.30-1.65(10H，br)，1.75-1.90(2H，m)，1.90-2.25(3H，m)，2.65-2.90(1H，br)，2.96(3H，s)，3.08(3H，s)，4.20-4.30(1H，m)，4.30-4.40(1H，m)，4.93(1H，br)，7.68(1H，m)，7.90(1H，br)，7.99(1H，s)，8.35-8.70(2H，m)，9.01(1H，br).

MS(FAB)m/z：475(M+H)⁺.

[ reference example 147] 2-bromo-5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

The title compound was obtained from the compound obtained in referential example 8 in the same manner as in referential example 9.

¹H-NMR(CDCl₃)δ：1.13(6H，d，J＝6.5Hz)，2.86(4H，s)，2.89-3.00(1H，m)，3.70(2H，s).

[ reference example 148] lithium 5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylate

The title compound was obtained from the compound obtained in referential example 147 in the same manner as in referential example 10.

¹H-NMR(DMSO-d₆)δ：1.05(6H，d，J＝6.4Hz)，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

The title compound was obtained from the compound obtained in referential example 10 and p-nitrophenol in the same manner as in referential example 52.

¹H-NMR(CDCl₃)δ：2.55(3H，s)，2.88(2H，t，J＝5.7Hz)，3.06-3.12(2H，m)，3.80(2H，s)，7.46(2H，d，J＝9.3Hz)，8.32(2H，d，J＝9.3Hz).

MS(ESI)m/z：320(M+H⁺).

[ reference example 150] benzyl 3-oxocyclobutanecarboxylate

Triethylamine (2.0ml) and benzyl bromide (1.2ml) were added to a solution of 3-oxocyclobutanecarboxylic acid (J.org.chem., 53, 3841-3843, 1981) (995mg) in tetrahydrofuran (5.0ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, 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).

¹H-NMR(CDCl₃)δ：3.22-3.33(3H，m)，3.37-3.48(2H，m)，5.19(2H，s)，7.31-7.42(5H，m).MS(FAB)m/z：205(M+H⁺).

[ reference example 151] benzyl 3-hydroxycyclobutanecarboxylate

To a mixed solution of the compound (781mg) obtained in referential example 150 in tetrahydrofuran (10ml) and methanol (0.5ml) was added sodium borohydride (76mg), and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate 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 (ethyl acetate: hexane ═ 1: 2) to obtain the title compound (770 mg).

¹H-NMR(CDCl₃)δ：2.13-2.27(3H，m)，2.55-2.71(3H，m)，4.14-4.23(1H，m)，5.12(2H，s)，7.28-7.39(5H，m).

MS(FAB)m/z：207(M+H⁺).

[ reference example 152] 3-Hydroxycyclobutanecarboxylic acid

10% Palladium on carbon (108mg) was added to an ethanol (10ml) solution of the compound (706mg) obtained in referential example 151, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After filtering the catalyst with celite, the filtrate was concentrated under reduced pressure to obtain the title compound (399 mg).

¹H-NMR(CD₃OD)δ：2.00-2.21(2H，m)，2.41-2.61(3H，m)，4.01-4.13(1H，m).

[ reference example 153] benzyl 3-methoxycyclobutanecarboxylate

To a solution of the compound (317mg) obtained in referential example 151 in N, N-dimethylformamide (3.0ml) were added methyl iodide (194. mu.l) and silver oxide (237mg), and the mixture was stirred at 45 ℃ for 1 hour. To the reaction mixture were added methyl iodide (194. mu.l) and silver oxide (226mg), and the mixture was stirred at 45 ℃ for 16 hours. After the catalyst was filtered off, 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).

¹H-NMR(CDCl₃)δ：2.14-2.24(2H，m)，2.44-2.54(2H，m)，2.59-2.72(1H，m)，3.21(3H，s)，3.73-3.81(1H，m)，5.11(2H，s)，7.22-7.39(5H，m).

MS(ESI)m/z：221(M+H⁺).

[ reference example 154] 3-Methoxycyclobutanecarboxylic acid

The title compound was obtained from the compound obtained in referential example 153 in the same manner as in referential example 152.

¹H-NMR(CDCl₃)δ：2.17-2.27(2H，m)，2.48-2.58(2H，m)，2.62-2.73(1H，m)，3.25(3H，s)，3.76-3.86(1H，m)，8.60-9.30(1H，br).

[ reference example 155] methyl 3-methoxy-2- (methoxymethyl) propionate

Sodium methoxide (1.21g) was added to a solution of methyl 2- (bromomethyl) acrylate (1.0ml) in methanol (10ml), and the mixture was refluxed for 26 hours. The reaction solution was cooled, diluted with 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).

¹H-NMR(CDCl₃)δ：2.90-2.96(1H，m)，3.34(6H，s)，3.57(2H，dd，J＝9.3，5.9Hz)，3.64(2H，dd，J＝9.3，6.6Hz)，3.73(3H，s).

¹³C-NMR(CDCl₃)δ：172.71，70.31，59.91，46.49.

MS(ESI)m/z：163(M+H⁺).

[ reference example 156] tetrahydro-2H-pyran-4-carboxylic acid

To dimethyl tetrahydro-4H-pyran-4, 4-dicarboxylate (4.04g) was added 20% hydrochloric acid (20ml), and the mixture was refluxed for 19 hours. The reaction mixture was extracted with ether and 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).

¹H-NMR(CDCl₃)δ：1.75-1.95(4H，m)，2.55-2.65(1H，m)，3.40-3.52(2H，m)，3.93-4.05(2H，m).

[ reference example 157] methyl 3- { [ tert-butyl (diphenyl) silyl ] oxy } -2, 2-dimethylpropionate

The title compound was obtained from methyl 2, 2-dimethyl-3-hydroxypropionate in the same manner as in reference example 41.

¹H-NMR(CDCl₃)δ：1.03(9H，s)，1.20(6H，s)，3.64-3.68(5H，m)，7.38-7.44(6H，m)，7.63-7.65(4H，m).

[ reference example 158]3- { [ tert-butyl (diphenyl) silyl ] oxy } -2, 2-dimethylpropanoic acid

Water (0.24ml) was added to a suspension of potassium tert-butoxide (5.32g) and diethyl ether (100ml) under ice cooling, and the mixture was stirred for 5 minutes. To this was added the compound (2.22g) obtained in referential example 157, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the solution was acidified with 1N aqueous hydrochloric acid solution and extracted with ether 3 times. 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).

¹H-NMR(CDCl₃)δ：1.04(9H，d，J＝0.7Hz)，1.22(6H，s)，3.65(2H，s)，7.36-7.45(6H，m)，7.64-7.66(4H，m).

[ reference example 159] methyl 3-methoxy-2, 2-dimethylpropionate

To a suspension of 60% sodium hydride (8.32g) and tetrahydrofuran (100ml) suspended in oil, a tetrahydrofuran (300ml) solution of methyl 3-hydroxy-2, 2-dimethyl-propionate (25.0g) was added dropwise under ice cooling, and the mixture was stirred at 60 ℃ for 1 hour. To the reaction solution was added methyl iodide (53.7g), and the mixture was stirred at room temperature for another 2 hours. Water was carefully added, extraction was performed with dichloromethane 2 times, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting oil was distilled to obtain the title compound (12.8 g).

Boiling point: 140 to 142 ℃ (normal pressure)

¹H-NMR(CDCl₃)δ：1.19(6H，d，J＝1.0Hz)，3.33(3H，d，J＝1.0Hz)，3.38(2H，d，J＝1.0Hz)，3.69(3H，d，J＝1.0Hz).

[ reference example 160] 3-methoxy-2, 2-dimethylpropionic acid

The title compound was obtained by treating the compound obtained in referential example 159 in the same manner as in referential example 158.

¹H-NMR(CDCl₃)δ：1.22(6H，d，J＝0.7Hz)，3.38(3H，d，J＝0.7Hz)，3.40(2H，d，J＝0.7Hz).

[ reference example 161]1- (methoxycarbonyl) cyclopropanecarboxylic acid

Dimethyl 1, 1-cyclopropanedicarboxylate (25g) was dissolved in methanol (250ml) and cooled with ice. Then, a 1N aqueous solution (158ml) of sodium hydroxide was added dropwise thereto, and the temperature was returned to room temperature, followed by stirring overnight. After methanol was evaporated, the reaction solution was washed with chloroform, the aqueous layer was cooled with ice, the pH was adjusted to 2 with a concentrated aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (16.8 g).

¹H-NMR(CDCl₃)δ：1.76-1.80(2H，m)，1.82-1.88(2H，m)，3.79(3H，s)，12.73(1H，br).

[ reference example 162] methyl 1- (hydroxymethyl) cyclopropanecarboxylate

The compound (9.0g) produced in referential example 161 and triethylamine (9.7ml) were dissolved in tetrahydrofuran (180ml), which was cooled to-10 ℃ and isobutyl chloroformate (9.1ml) was added dropwise and the mixture was stirred for 1 hour. On the other hand, sodium borohydride (7.1g) was dissolved in tetrahydrofuran (100ml) -water (25ml) and cooled with ice. The solution was added dropwise while insoluble matter was filtered off, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a cold 10% citric acid aqueous 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).

¹H-NMR(CDCl₃)δ：0.87-0.93(2H，m)，1.28-1.30(2H，m)，3.63(2H，s)，3.70(3H，s).

[ reference example 163] methyl 1- (bromomethyl) cyclopropanecarboxylate

Triphenylphosphine (10g) and carbon tetrabromide (16g) were added to a dichloromethane solution (168ml) of the compound (4.20g) obtained in referential example 162 under a nitrogen atmosphere at room temperature, and after 2 minutes, a saturated aqueous sodium bicarbonate solution 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).

¹H-NMR(CDCl₃)δ：1.00-1.05(2H，m)，1.52-1.59(2H，m)，3.61(2H，s)，3.73(3H，s).

[ reference example 164] (4S) -4- [ (E) -3-ethoxy-3-oxo-1-propenyl ] -2, 2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester

A mixed solution of tert-butyl (4R) -4-formyl-2, 2-dimethyl-1, 3-oxazolidine-3-carboxylate (11.7g), triphenylphosphorane (20.7g) and toluene (100ml) was stirred with heating at 100 ℃ for 18 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 8: 1) to obtain the title compound (17 g).

¹H-NMR(CDCl₃)δ：1.29(3H，t，J＝6.6Hz)，1.43-1.56(15H，m)，3.80(1H，dd，J＝9.0，2.4Hz)，4.09(1H，dd，J＝9.0，6.6Hz)，4.11-4.23(2H，m)，4.30-4.61(1H，m)，5.83-6.02(1H，m)，6.74-6.89(1H，m).

[ reference example 165] (4S) -4- [1- (benzylamino) -3-ethoxy-3-oxopropyl ] -2, 2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester

A mixed solution of the compound (22.2g) obtained in referential example 164, benzylamine (16g) and ethanol (100ml) was refluxed for 2 days. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 8: 1) to obtain the title compound (26 g).

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝6.6Hz)，1.42-1.63(15H，m)，2.24-2.33(0.5H，m)，2.40-2.50(1H，m)，2.63-2.74(0.5H，m)，3.41-3.52(1H，m)，3.67-3.80(1H，m)，3.83(2H，s)，3.89-4.00(1H，m)，4.03-4.22(4H，m)，7.23-7.45(5H，m).

[ reference example 166] (4S) -4- (1-amino-3-ethoxy-3-oxopropyl) -2, 2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester

10% Palladium on carbon (10g) was added to an ethanol (200ml) solution of the compound (13.6g) obtained in referential example 165, and the mixture was stirred for 2 days under a hydrogen atmosphere. Insoluble matter was filtered off through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the title compound (10.5 g).

¹H-NMR(DMSO-d₆)δ：1.19(1.5H，t，J＝6.6Hz)，1.20(1.5H，t，J＝6.6Hz)，1.32-1.50(15H，m)，2.63-2.81(2H，m)，3.22-3.34(2H，m)，3.93(1H，dd，J＝10.0，6.8Hz)，4.08(2H，q，J＝6.6Hz)，4.20-4.30(1H，m).

[ reference example 167] (4S) -4- (1- { [ (benzyloxy) carbonyl ] amino } -3-ethoxy-3-oxopropyl) -2, 2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester

The compound (3.0g) obtained in referential example 166 was suspended in a 9% aqueous sodium hydrogencarbonate solution (56ml), and a solution of N- (benzyloxycarbonyloxy) succinimide (2.3g) in dioxane (12ml) was added dropwise under ice cooling, followed by stirring for 3 hours while gradually returning the temperature to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, 10% citric acid aqueous 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).

¹H-NMR(CDCl₃)δ：1.23(3H，t，J＝6.6Hz)，1.48(9H，s)，1.56(6H，s)，2.40-2.51(2H，m)，2.63-2.70(2H，m)，3.92-4.04(1H，m)，4.06-4.10(2H，m)，4.14-4.22(1H，m)，5.09(2H，s)，7.30-7.43(5H，m).

[ reference example 168] (3S, 4S) -3- { [ (benzyloxy) carbonyl ] amino } -4- [ (tert-butoxycarbonyl) amino ] -5-hydroxypentanoic acid ethyl ester (low-polar compound) and (3R, 4S) -3- { [ (benzyloxy) carbonyl ] amino } -4- [ (tert-butoxycarbonyl) amino ] -5-hydroxypentanoic acid ethyl ester (high-polar compound)

Low-polarity compound and high-polarity compound

Trifluoroacetic acid (100ml) was added dropwise to a dichloromethane (100ml) solution of the compound (30g) obtained in referential example 167 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 the solution were added dropwise triethylamine (20ml) and a dichloromethane (100ml) solution of di-tert-butyl dicarbonate (19g) successively under ice cooling, and the mixture was stirred for 4 hours while gradually returning to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to obtain the title low-polar compound (7.6g) and the title high-polar compound (10 g).

Low polarity compounds:

¹H-NMR(CDCl₃)δ：1.24(3H，t，J＝6.6Hz)，1.42(9H，s)，2.63(2H，d，J＝4.4Hz)，3.30-3.41(1H，m)，3.50(1H，t，J＝9.7Hz)，3.65(1H，t，J＝9.7Hz)，3.75(1H，d，J＝11.7Hz)，3.90-4.00(1H，m)，4.03-4.23(2H，m)，5.12(2H，s)，5.13-5.25(1H，m)，5.79-6.02(1H，m)，7.32-7.41(5H，m).

highly polar compounds:

¹H-NMR(CDCl₃)δ：1.22(3H，t，J＝6.6Hz)，1.41(9H，s)，2.50-2.70(2H，m)，3.20-3.31(1H，m)，3.43-3.51(1H，m)，3.56-3.70(1H，m)，3.74-3.78(1H，m)，4.00-4.19(2H，m)，4.23-4.30(1H，m)，4.78-4.89(1H，m)，5.10(2H，s)，5.56-5.67(1H，m)，7.31-7.40(5H，m).

[ reference example 169] methanesulfonic acid (3R, 4S) -4- [ (methylsulfonyl) oxy ] tetrahydro-3-furan ester

Triethylamine (12.0ml) and methanesulfonyl chloride (3.6ml) were sequentially added dropwise to a dichloromethane (50ml) solution of 1, 4-anhydroerythritol (5.0g) under ice cooling, and stirred for 10 minutes under ice cooling. The reaction mixture was diluted with dichloromethane and washed with a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (9.2 g).

¹H-NMR(CDCl₃)δ：3.15(6H，s)，3.99(2H，dd，J＝11.2，2.5Hz)，4.16(2H，dd，J＝11.2，4.6Hz)，5.10-5.20(2H，m).

[ reference example 170] (3R, 3S) -3, 4-diazidotetrahydrofuran

The compound (9.2g) obtained in referential example 169 was dissolved in N, N-dimethylformamide (50ml), and sodium azide (18g) was added and stirred at 100 ℃ for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (3.8 g).

¹H-NMR(CDCl₃)δ：3.83(2H，dd，J＝8.6，2.0Hz)，3.96-4.12(4H，m).

[ reference example 171] (3R, 4S) -tetrahydro-3, 4-furandiamine 2 hydrochloride

The compound (3.8g) obtained in referential example 170 was dissolved in ethanol (50ml), and 10% palladium on carbon (1.0g) was added to stir for 18 hours under a hydrogen atmosphere. Insoluble matter was filtered off through a Celite pad, and the filtrate was concentrated under reduced pressure. After 1N ethanol hydrochloride solution was added to the obtained residue to form hydrochloride, recrystallization was performed with a mixed solvent of ethanol and diethyl ether to obtain the title compound (2.0 g).

¹H-NMR(CDCl₃)δ：3.90(2H，dd，J＝9.0，3.7Hz)，4.01-4.13(4H，m)，8.84(6H，s).

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

5-Chloroindole-2-carboxylic acid (0.29g), 1-hydroxybenzotriazole (0.2g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.6g) were added in this order to a solution of the compound (0.5g) obtained in referential example 171 in N, N-dimethylformamide (10ml) at room temperature, and the mixture was stirred at 50 ℃ for 1 day. The reaction mixture was concentrated, and the resulting residue was diluted with a mixed solvent of chloroform and methanol (9: 1) and washed with a saturated aqueous sodium bicarbonate solution and a 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: methanol 95: 5) to obtain the title compound (0.2 g).

¹H-NMR(CDCl₃)δ：1.80-1.92(1H，m)，3.62(1H，dd，J＝9.3，4.2Hz)，3.68-3.80(2H，m)，4.06(1H，dd，J＝9.3，5.6Hz)，4.21(1H，dd，J＝9.3，6.8Hz)，4.36-4.52(2H，m)，6.87(1H，s)，7.24(1H，dd，J＝8.8，2.0Hz)，7.36(1H，d，J＝8.8Hz)，7.44-7.56(1H，m)，7.62(1H，d，J＝2.0Hz)，9.41(1H，s).

[ reference example 173] (4R) -4- [ (E) -3-ethoxy-3-oxo-1-propenyl ] -2, 2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester

The title compound was obtained from tert-butyl (4S) -4-formyl-2, 2-dimethyl-1, 3-oxazolidine-3-carboxylate in the same manner as in reference example 164.

¹H-NMR(CDCl₃)δ：1.29(3H，t，J＝6.6Hz)，1.40-1.60(15H，m)，3.80(1H，dd，J＝9.0，2.4Hz)，4.09(1H，dd，J＝9.0，6.6Hz)，4.11-4.21(2H，m)，4.32-4.64(1H，m)，5.78-6.01(1H，m)，6.67-6.89(1H，m).

[ reference example 174] (4R) -4- [1- (benzylamino) -3-ethoxy-3-oxopropyl ] -2, 2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 173 in the same manner as in referential example 165.

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝6.6Hz)，1.40-1.61(15H，m)，2.21-2.32(0.5H，m)，2.40-2.51(1H，m)，2.61-2.72(0.5H，m)，3.43-3.50(1H，m)，3.67-3.80(1H，m)，3.83(2H，s)，3.90-4.03(1H，m)，4.04-4.22(4H，m)，7.20-7.40(5H，m).

[ reference example 175] (4R) -4- (1- { [ (5-chloroindol-2-yl) carbonyl ] amino } -3-ethoxy-3-oxopropyl) -2, 2-dimethyl-1, 3-oxazolidine-3-carboxylic acid tert-butyl ester

The title compound was obtained by catalytically reducing the compound obtained in referential example 174 in the same manner as in referential example 166, removing the benzyl group, and then condensing the resulting product with 5-chloroindole-2-carboxylic acid in the same manner as in referential example 172.

¹H-NMR(CDCl₃)δ：1.23(1.5H，t，J＝6.6Hz)，1.25(1.5H，t，J＝6.6Hz)，1.50(4.5H，s)，1.54(4.5H，s)，1.62(6H，s)，2.50-2.70(1.5H，m)，2.86(0.5H，dd，J＝16.4，5.5Hz)，3.80-3.90(0.5H，m)，4.00-4.31(5H，m)，4.41-4.67(0.5H，m)，6.85(0.5H，s)，6.87(0.5H，s)，7.10-7.20(1H，m)，7.34(0.5H，d，J＝8.8Hz)，7.38(0.5H，d，J＝8.8Hz)，7.57(0.5H，s)，7.63(0.5H，s)，7.88(0.5H，d，J＝7.6Hz)，8.54(0.5H，d，J＝7.6Hz)，9.40(0.5H，s)，9.54(0.5H，s).

[ reference example 176] (3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -6-oxotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (low-polarity compound) and (3R, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -6-oxotetrahydro-2H-pyran-3-ylcarbamic acid tert-butyl ester (high-polarity compound)

Low-polarity compound and high-polarity compound

To an ethanol (20ml) solution of the compound (1.0g) obtained in referential example 175 was added a 1N aqueous solution (4.0ml) of sodium hydroxide, and the mixture was stirred for 4 hours. Citric acid was added to the reaction solution to adjust the pH to 4.0, followed by extraction 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 resulting residue was dissolved in methanol (50ml), and toluenesulfonic acid 1 hydrate (0.1g) was added thereto and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a 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: methanol 99: 1) to obtain the title low-polar compound (0.3g) and high-polar compound (0.3 g).

Low polarity compounds:

¹H-NMR(CDCl₃)δ：1.45(9H，s)，2.70(1H，dd，J＝16.5，4.9Hz)，2.85(1H，dd，J＝16.5，4.6Hz)，3.50-3.61(1H，m)，3.71-3.81(2H，m)，4.30-4.40(1H，m)，5.30(1H，d，J＝9.5Hz)，6.89(1H，s)，7.23(1H，dd，J＝8.8，2.0Hz)，7.38(1H，d，J＝8.8Hz)，7.62(1H，d，J＝2.0Hz)，7.93(1H，d，J＝9.5Hz)，9.30(1H，s).

highly polar compounds:

¹H-NMR(CDCl₃)δ：1.39(9H，s)，2.75(1H，dd，J＝16.5，4.9Hz)，2.82(1H，dd，J＝16.5，4.6Hz)，3.41-3.52(2H，m)，3.71-3.82(1H，m)，3.85-3.94(1H，m)，5.03(1H，d，J＝9.3Hz)，6.99(1H，s)，7.22-7.31(1H，m)，7.34(1H，d，J＝8.8Hz)，7.61(1H，d，J＝2.0Hz)，7.83(1H，d，J＝9.3Hz)，9.28(1H，s).

[ reference example 177] tert-butyl 1, 1, 3-trioxohexahydro-1-thiopyran-4-ylcarbamate

A tetrahydrofuran (900ml) solution of N-t-butoxycarbonyl-L-methionine sulfomethyl ester (60.2g) was cooled to-78 ℃ and 0.5M potassium bis (trimethylsilyl) amide (toluene solution, 900ml) was added dropwise thereto, followed by stirring at-78 ℃ for 2 hours and at room temperature for 4 and a half hours. 1M aqueous ammonium chloride solution was added thereto and stirred. After the reaction mixture was separated, 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 resulting solid was collected by filtration to obtain the title compound (12.4 g). The aqueous layer separated previously was extracted 2 times with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the water 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 obtain the title compound (27.7g) (total amount of the title compound: 40.1 g).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.85-1.96(1H，m)，2.76-2.78(1H，m)，3.34-3.46(2H，m)，4.05(1H，dd，J＝13.5，3.7Hz)，4.14(1H，d，J＝13.5Hz)，4.38-4.44(1H，m)，5.46(1H，br).

MS(ESI)m/z：262(M-H)^-.

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

To a suspension of the compound (10.1g) obtained in referential example 177 in methanol (200ml) was added sodium borohydride (2.17g), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue were added ethyl acetate and a saturated aqueous sodium bicarbonate solution, and after separation, the aqueous layer was extracted 2 times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (9.96 g).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，2.21-2.36(2H，m)，3.03-3.17(2H，m)，3.26-3.28(2H，m)，3.77-3.80(2H，m)，4.26-4.28(1H，m)，5.05-5.07(1H，m).

MS(ESI)m/z：264[(M-H)^-].

[ reference example 179](3R^*，4R^*) -3-amino-1, 1-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 (highly polar compound)

Low-polarity compound and high-polarity compound

(racemate)

Diethyl azodicarboxylate (6.96g) was added to a tetrahydrofuran (150ml) solution of the compound (9.66g) obtained in referential example 178 and triphenylphosphine (10.5g), and the mixture was stirred at room temperature for 4 hours and a half. After the reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the resulting solid was collected by filtration. The collected solid was purified by silica gel column chromatography (hexane: ethyl acetate 7: 3) to obtain a mixture (7.25g) containing tert-butyl 1, 1-dioxo-1, 2, 3, 4-tetrahydrothiopyran-4-ylcarbamate as a colorless solid. Then, the mother liquor was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 7: 3) to obtain a mixture (9.18g) containing tert-butyl 1, 1-dioxo-1, 2, 3, 4-tetrahydrothiopyran-4-ylcarbamate as a colorless solid (total amount: 16.4 g). The resulting mixture was dissolved in dioxane (60ml), 28% aqueous ammonia (60ml) was added, and the mixture was stirred in a sealed tube at 60 ℃ for 4 hours and a half. After natural cooling, the reaction mixture was concentrated under reduced pressure. After evaporation of dioxane, extraction was performed 5 times with dichloromethane. The organic layers were combined and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (dichloromethane: methanol 96: 4) to obtain the title low-polar compound (2.31g) and high-polar compound (4.31 g).

Low polarity compounds:

¹H-NMR(CDCl₃)δ：1.44(9H，s)，2.14-2.28(2H，m)，3.01-3.08(3H，m)，3.23(1H，dd，J＝13.8，3.9Hz)，3.47-3.49(1H，m)，3.71-3.76(1H，m)，5.32(1H，d，J＝7.3Hz).

MS(ESI)m/z：265(M+H⁺).

highly polar compounds:

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.94-2.01(1H，m)，2.37-2.44(1H，m)，2.91(1H，dd，J＝11.2，14.1Hz)，3.04-3.07(2H，m)，3.12-3.19(1H，m)，3.26-3.30(1H，m)，3.39-3.42(1H，m)，4.62(1H，br).

MS(ESI)m/z：265(M+H⁺).

[ reference example 180] (2S, 3S) -2, 3-bis (methoxymethyloxy) -1, 4-butanediol

Chloromethyl methyl ether (4.8ml) was added dropwise to a mixed solution of diethyl L-tartrate (8.6g), diisopropylethylamine (40ml) and dichloromethane (40ml) under ice cooling, and the mixture was stirred for 18 hours while gradually warming to room temperature. The reaction mixture was concentrated, and the resulting residue was diluted with ethyl acetate and washed with a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated brine. After 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 solution was added dropwise to a tetrahydrofuran suspension of lithium aluminum hydride (2.2g) under ice cooling, and the mixture was stirred under ice cooling for 2 hours. Under ice cooling, 10% aqueous sodium hydrogen sulfate solution was carefully added, and after stirring for 1 hour, the mixture was diluted with saturated brine and ethyl acetate was extracted. 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).

¹H-NMR(CDCl₃)δ：1.55-1.64(2H，m)，3.44(6H，s)，3.70-3.81(6H，m)，4.70(2H，d，J＝6.9Hz)，4.76(2H，d，J＝6.9Hz).

[ reference example 181] (3S, 4S) -3, 4-bis (methoxymethyloxy) tetrahydrofuran

Diethyl azodicarboxylate (2.64ml) was added dropwise to a mixed solution of the compound (3.0g) obtained in referential example 180, triphenylphosphine (4.5g), tetrahydrofuran (10ml) and toluene (40ml), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated, and a mixed solvent (160ml) of hexane and diethyl ether (1: 1) was added to the obtained residue, followed by stirring for 3 hours, followed by filtration of the insoluble matter deposited. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound (1.95 g).

¹H-NMR(CDCl₃)δ：3.38(6H，s)，3.80(2H，dd，J＝9.2，1.7Hz)，4.00(2H，dd，J＝9.2，4.4Hz)，4.23(2H，dd，J＝4.4，1.7Hz)，4.67(2H，d，J＝6.9Hz)，4.71(2H，d，J＝6.9Hz).

[ reference example 182] (3S, 4S) tetrahydro-3, 4-furandiol

Concentrated hydrochloric acid (2.1ml) was added to a methanol (6.0ml) solution of the compound (1.95g) obtained in referential example 181, and the mixture was stirred for 18 hours. The reaction solution was concentrated, and the resulting residue was diluted with chloroform, dried over potassium carbonate, and the solvent was evaporated under reduced pressure to obtain the title compound (0.52 g).

¹H-NMR(CDCl₃)δ：1.77(2H，d，J＝4.7Hz)，3.73(2H，d，J＝10.2Hz)，4.08(2H，dd，J＝10.2，3.7Hz)，4.18-4.34(2H，m).

[ reference example 183] (3S, 4S) tetrahydro-3, 4-furandiamine

The title compound was obtained from the compound obtained in referential example 182 by the same method as that described in referential examples 169 to 171.

¹H-NMR(CDCl₃)δ：1.35-1.46(4H，m)，3.19(2H，dd，J＝5.6，4.1Hz)，3.50(2H，dd，J＝9.0，4.1Hz)，4.09(2H，dd，J＝9.0，5.6Hz).

[ reference example 184] (2R, 3R) -2, 3-bis (methoxymethyloxy) -1, 4-butanediol

The title compound was obtained from diethyl D-tartrate in the same manner as in referential example 180.

¹H-NMR: in accordance with reference example 180 as enantiomer.

[ reference example 185] (3R, 4R) -3, 4-bis (methoxymethyloxy) tetrahydrofuran

The title compound was obtained from the compound obtained in referential example 184 in the same manner as in referential example 181.

¹H-NMR: in accordance with reference example 181 as enantiomer.

[ reference example 186] (3R, 4R) tetrahydro-3, 4-furandiol

The title compound was obtained from the compound obtained in referential example 185 in the same manner as in referential example 182.

¹H-NMR: in accordance with reference example 182 as an enantiomer.

[ reference example 187] (3R, 4R) tetrahydro-3, 4-furandiamine

The title compound was obtained from the compound obtained in referential example 186 in the same manner as in referential example 183.

¹H-NMR: in accordance with reference example 183 as enantiomer.

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

L-tartaric acid (30g) and benzylamine (22ml) were added to xylene (150ml) using a dean-Stark dehydration unit at 150 deg.F. Reflux at 3 deg.C for 3 hours. After the reaction solution was naturally cooled overnight, the crystals were collected by filtration and washed with acetone. The obtained crude body was recrystallized from ethanol to obtain the title compound (23.2 g).

¹H-NMR(DMSO-d₆) δ: 4.36-4.40(2H, m), 4.55 (each 1H, AB type d, J ═ 15Hz), 6.26-6.30(2H, m), 7.25-7.35(5H, m).

[ reference example 189] (3S, 4S) -1-benzyl-3, 4-pyrrolidinediol

The compound (11g) obtained in referential example 188 was dissolved in tetrahydrofuran (110ml) under ice-cooling, and lithium aluminum hydride (5.69g) was added in small amounts each time. After the temperature is raised to room temperature, the mixture is heated and refluxed for 1 hour, and then the heating and refluxing are continued for one night. After cooling naturally, the mixture was cooled with ice, and water (5.7ml), a 15% aqueous solution of sodium hydroxide (5.7ml) and water (17.1ml) were added in this order to return the temperature to room temperature and stirred for 1 hour. The precipitate was filtered through celite, and the mother liquor was concentrated and then recrystallized from ethyl acetate to obtain the title compound (6.35 g).

¹H-NMR(CDCl₃) δ: 2.40-2.44(2H, m), 2.88-2.92(2H, m), 3.58 (each 1H, AB type d, J ═ 7.8Hz), 4.04(2H, t, J ═ 4.2Hz), 7.25-7.34(5H, m).

[ reference example 190] methanesulfonic acid (3S, 4S) -1-benzyl-4- [ (methylsulfonyl) oxy ] pyrrolidinyl ester

The title compound was obtained from the compound obtained in referential example 189 in the same manner as in referential example 169.

¹H-NMR(CDCl₃)δ：2.76(2H，dd，J＝11，4.6Hz)，3.08(6H，s)，3.64(2H，d，J＝2.5Hz)，3.68-3.75(2H，m)，5.12-5.15(2H，m)，7.27-7.35(5H，m).

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

The compound (1.57g) obtained in referential example 190 was dissolved in 1, 2-dichloroethane (16ml), and 1-chloroethyl chloroformate (0.73ml) was added at room temperature to reflux for 4 hours. After the solvent was distilled off under reduced pressure, methanol (16ml) was added to the resulting residue, and the mixture was refluxed for 1 hour, naturally cooled and concentrated, and the crystals were collected by filtration with ethyl acetate to obtain (3S, 4S) -3, 4-bis [ (methylsulfonyl) oxy ] pyrrolidine hydrochloride (1.30g) as colorless crystals. To a solution of the obtained hydrochloride and triethylamine (1.40ml) in dichloromethane (26ml) was added di-tert-butyl dicarbonate (1.15ml), and the mixture was stirred overnight at room temperature. After concentration, the 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 silica gel column chromatography (ethyl acetate: hexane: 1: 9 to 1: 1) to obtain the title compound (1.40 g).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，3.12(6H，s)，3.70-3.73(2H，m)，3.79(1H，d，J＝4.5Hz)，3.82(1H，d，J＝4.5Hz)，5.19(2H，br).

[ reference example 192] (3R, 4R) -3, 4-diazido-1-pyrrolidinecarboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 191 in the same manner as in referential example 170.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，3.37-3.46(2H，m)，3.64-3.71(2H，m)，3.96(2H，t，J＝3.2Hz).

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

The title compound was obtained from the compound obtained in referential example 192 by the same method as that described in referential examples 171 and 172.

¹H-NMR(DMSO-d₆)δ：1.39(9H，s)，2.95-3.00(1H，m)，3.09-3.13(1H，m)，3.52(1H，dd，J＝10，6.5Hz)，3.68(1H，dd，J＝10，7.8Hz)，4.04-4.09(2H，m)，7.16(1H，s)，7.18(1H，s)，7.42(1H，d，J＝8.5Hz)，7.69(1H，d，J＝1.5Hz)，8.50(1H，d，J＝6.5Hz)，11.77(1H，br).

[ reference example 194] (3S) -5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester

To a solution of benzyl (3S) - (-) -tetrahydro-5-oxo-3-furanylcarbamate (3.3g) in tetrahydrofuran (20ml) were added di-tert-butyl dicarbonate (4.1g) and 10% palladium on carbon (0.4g), and the mixture was stirred for 1 day under a hydrogen atmosphere. Insoluble matter was filtered off 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 obtain the title compound (1.5 g).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，2.45(1H，dd，J＝17.8，2.7Hz)，2.86(1H，dd，J＝17.8，7.3Hz)，4.12-4.23(1H，m)，4.54-4.62(2H，m)，4.85-4.95(1H，m).

[ reference example 195] (3S, 4S) -4-azido-5-oxotetrahydro-3-furanylcarbamic acid tert-butyl ester

To a tetrahydrofuran (20ml) solution of the compound (0.87g) obtained in referential example 194 was added dropwise 1M potassium bis (trimethylsilyl) amide (tetrahydrofuran solution, 8.65ml) at-78 ℃ and stirred for 30 minutes. Then, a tetrahydrofuran (10ml) solution of p-toluenesulfonylazide (1.02g) was added, and after stirring for 5 minutes, trimethylchlorosilane (1.7ml) was added, and the mixture was stirred for 2 hours while gradually returning the temperature to room temperature. The reaction mixture was diluted with ether, washed with a 10% aqueous hydrochloric acid solution, a 5% saturated aqueous sodium bicarbonate solution and a 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 obtain the title compound (0.62 g).

¹H-NMR(CDCl₃)δ：1.46(9H，s)，4.09(1H，dt，J＝15.3，7.6Hz)，4.12-4.23(1H，m)，4.37-4.50(1H，m)，4.54(1H，dd，J＝9.0，7.6Hz)，4.81-4.90(1H，m).

[ reference example 196] (3S, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5-oxotetrahydro-3-furanyl carbamic acid tert-butyl ester

The title compound was prepared from the compound of referential example 195 by the same method as that described in referential examples 90 and 91.

¹H-NMR(CDCl₃)δ：1.44(9H，s)，4.01-4.13(1H，m)，4.20-4.36(1H，m)，4.78-4.93(2H，m)，6.15(1H，s)，6.93(1H，s)，7.03-7.11(1H，m)，7.20-7.28(1H，m)，7.30(1H，d，J＝8.8Hz)，7.61(1H，s)，9.27(1H，s).

[ reference example 197] (3S, 4S) -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } -5-oxotetrahydro-3-furanyl carbamic acid tert-butyl ester

The title compound was obtained by reacting the compound obtained in referential example 10 with tert-butyl (3S, 4S) -4-amino-5-oxotetrahydro-3-furanylcarbamate prepared from the compound obtained in referential example 195 in the same manner as in referential example 90 under the reaction conditions of referential example 91.

¹H-NMR(CDCl₃)δ：1.44(9H，s)，2.52(3H，s)，2.83(2H，t，J＝5.9Hz)，2.79-3.02(2H，m)，3.74(2H，s)，4.03-4.12(1H，m)，4.21-4.36(1H，m)，4.80-4.95(2H，m)，6.14-6.24(1H，m)，7.76-7.85(1H，m).

[ reference example 198] Ethyl 2- [ ((3S) -3- [ (tert-butoxycarbonyl) amino ] -2- { [ (5-chloroindol-2-yl) carbonyl ] amino } -4-hydroxybutyryl) amino ] acetate

The compound (0.4g) obtained in referential example 196, ethyl glycinate hydrochloride (1.0g) and triethylamine (1.0ml) were added to ethanol (20ml), and the mixture was refluxed at 60 ℃ for 18 hours. The reaction mixture was diluted with chloroform and washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium chloride. 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: methanol 98: 2) to obtain the title compound (0.31 g).

¹H-NMR(DMSO-d₆)δ：1.17(3H，t，J＝7.0Hz)，1.34(6H，s)，1.36(3H，s)，3.51-3.63(0.6H，m)，3.72-3.80(2H，m)，4.06(2H，q，J＝7.0Hz)，4.11-4.23(1.4H，m)，4.67-4.82(1H，m)，4.85-4.91(1H，m)，6.48(0.4H，d，J＝9.5Hz)，6.80(0.6H，d，J＝9.5Hz)，7.10-7.22(2H，m)，7.42(1H，d，J＝8.8Hz)，7.72(0.4H，d，J＝2.0Hz)，7.73(0.6H，d，J＝2.0Hz)，8.23-8.31(0.6H，m)，8.34-8.41(0.4H，m)，8.43-8.50(1H，m)，11.83(1H，s).

[ reference example 199] Ethyl 2- ((4R) -4-amino-3- { [ (5-chloroindol-2-yl) carbonyl ] amino } -2-oxopyrrolidin-1-yl) acetate hydrochloride

The title compound was obtained by converting the compound obtained in referential example 198 into a pyrrolidone derivative under the reaction conditions described in referential example 181 and then removing the tert-butoxycarbonyl group in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：1.17(2H，t，J＝7.0Hz)，1.23(1H，t，J＝7.0Hz)，3.31-3.40(0.6H，m)，3.57(0.4H，d，J＝11.2Hz)，3.90-4.23(4H，m)，4.42(0.6H，dd，J＝12.0，6.1Hz)，4.50-4.60(0.4H，m)，4.62(0.6H，dd，J＝12.0，3.9Hz)，5.12-5.23(0.4H，m)，7.17(0.4H，s)，7.20(0.4H，dd，J＝8.8，2.0Hz)，7.28(0.6H，dd，J＝8.8，2.0Hz)，7.30(0.6H，s)，7.44(0.4H，d，J＝8.8Hz)，7.50(0.6H，d，J＝8.8Hz)，7.75(1H，d，J＝2.0Hz)，8.20-8.33(1H，m)，8.71-8.94(3.6H，m)，9.22-9.35(0.4H，m)，11.97(0.4H，s)，12.44(0.6H，s).

[ reference example 200] (3R, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -1-methyl-5-oxopyrrolidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained by treating the compound obtained by reacting the compound obtained in referential example 196 with methylamine (40% methanol solution) in the same manner as in referential example 198 under the same conditions as in referential example 181.

¹H-NMR(CDCl₃)δ：1.43(9H，s)，2.90(3H，s)，4.26(1H，br.s)，4.36(2H，m)，4.51-4.52(1H，m)，5.35(1H，br.s)，6.95-6.99(2H，m)，7.22-7.32(3H，m)，7.63(1H，s)，8.95(1H，br.s)

[ reference example 201] N- [ (3S, 4R) -4-amino-1-methyl-2-oxopyrrolidin-3-yl ] -5-chloroindole-2-carboxamide

The title compound was obtained by treating the compound obtained in referential example 200 in the same manner as in referential example 69.

¹H-NMR(CDCl₃)δ：2.95(3H，d，J＝5.1Hz)，3.91-3.93(1H，m)，4.19(1H，d，J＝3.7Hz)，4.36(1H，dd，J＝11，1.7Hz)，4.48(1H，dd，J＝11，2.0Hz)，6.90-6.97(2H，m)，7.21-7.33(2H，m)，7.62(1H，d，J＝2.0Hz)，8.90(1H，s)

[ reference example 202] tert-butyl 3, 6-dihydro-1 (2H) -pyridinecarboxylate

To a mixture of 1, 2, 3, 6-tetrahydropyridine (2.50g) and 10% aqueous sodium carbonate (3.0ml) was added di-tert-butyl dicarbonate (6.55g), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (5.08 g).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，2.12(2H，br.s)，3.48(2H，t，J＝5.6Hz)，3.88(2H，br.s)，5.60(1H，br.s)，5.78-5.90(1H，m).

Reference example 203](3R^*，4S^*) -3, 4-dihydroxy-1-piperidinecarboxylic acid tert-butyl ester

The compound (18.45g) obtained in referential example 202 was dissolved in acetonitrile (200ml), and water (38ml), a 0.039 mol aqueous solution (82ml) of osmium tetroxide, and N-methylmorpholine N-oxide (23.13g) were added and the mixture was stirred at room temperature for 17 hours. The excess oxidant was treated with saturated aqueous sodium sulfite solution and extracted with ethyl acetate. The organic layer was washed with water, 0.5N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 3) to obtain the title compound (15.0 g).

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.60-1.73(1H，m)，1.77-1.90(1H，m)，2.68(1H，br.s)，2.80-3.20(1H，br)，3.22-3.32(1H，m)，3.42(1H，dd，J＝14.3，3.4Hz)，3.50-3.62(2H，m)，3.77(1H，brs)，3.81-3.92(1H，m).

[ reference example 204](3R^*，4S^*) -3, 4-bis [ (methylsulfonyl) oxy)]-1-Piperidinecarboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 203 in the same manner as in referential 169.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.85-1.97(1H，m)，2.08-2.20(1H，m)，3.00-4.20(4H，m)，3.12(6H，s)，4.85(1H，br.s)，4.94(1H，br.s).

Reference example 205](3R^*，4S^*) -3, 4-Diazido-1-piperidinecarboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 204 in the same manner as in referential example 170.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.70-1.80(1H，m)，1.90-2.00(1H，m)，3.05-4.00(6H，m).

Reference example 206](3R^*，4S^*) -3, 4-diamino-1-piperidinecarboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 205 in the same manner as in referential example 171.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.48-1.60(2H，m)，1.80-2.10(4H，br)，2.85-2.91(2H，m)，2.97(1H，br.s)，3.09(1H，dd，J＝13.6，2.7Hz)，3.74(1H，dd，J＝13.6，4.2Hz)，3.81(1H，s).

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

The compound (3.23g) obtained in referential example 206 was dissolved in N, N-dimethylformamide (100ml), and triethylamine (2.08ml) and the compound (3.80g) obtained in referential example 52 were added to stir at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with methylene chloride. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 20: 1 to 10: 1) to obtain the title compound (2.70 g).

¹H-NMR(DMSO-d₆)δ：1.40-1.58(3H，m)，1.41(9H，s)，1.75-1.90(1H，m)，2.95(1H，br.s)，2.98-3.05(1H，m)，3.19-3.28(1H，m)，3.74(1H，dd，J＝19.5，15.4Hz)，3.79(1H，br.s)，4.04-4.12(1H，m)，7.17(1H，dd，J＝8.7，1.9Hz)，7.21(1H，s)，7.42(1H，d，J＝8.7Hz)，7.68(1H，d，J＝1.9Hz)，8.00(1H，br.d，J＝7.6Hz)，11.80(1H，s).

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

The compound (3.23g) obtained in referential example 206 was dissolved in N, N-dimethylformamide (100ml), and triethylamine (2.08ml) was added. Then, the compound (3.83g) obtained in referential example 149 was added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with methylene chloride. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate 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 (dichloromethane: methanol 10: 1 to 5: 1) to obtain the title compound (2.27 g).

¹H-NMR(CDCl₃)δ：1.30-1.62(3H，m)，1.47(9H，s)，1.78-1.88(1H，m)，2.51(3H，s)，2.81(2H，t，J＝5.9Hz)，2.85-2.98(3H，m)，3.00-3.15(2H，m)，3.71(2H，s)，3.80-4.15(3H，m)，7.79(1H，br.s).

Reference example 209](3R^*，4S^*) -3-amino-4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1-piperidinecarboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 206 and 5-fluoroindole-2-carboxylic acid in the same manner as in referential example 172.

¹H-NMR(CDCl₃)δ：1.40-1.70(3H，m)，1.48(9H，s)，2.79-2.92(1H，m)，2.99-3.14(1H，m)，4.00-4.23(3H，m)，6.85(1H，s)，7.04(1H，td，J＝9.0，2.4Hz)，7.07-7.20(1H，br)，7.27(1H，dd，J＝9.0，2.4Hz)，7.35(1H，d，J＝9.0，4.4Hz)，9.25-9.50(1H，br).

MS(ESI)m/z：377(M+H)⁺.

[ reference example 210] (3S, 4R) -5-azido-3- { [ (benzyloxy) carbonyl ] amino } -4- [ (tert-butoxycarbonyl) amino ] pentanoic acid ethyl ester

Triethylamine (4.80ml) and methanesulfonyl chloride (1.55mml) were sequentially added dropwise to a dichloromethane (100ml) solution of the (3S, 4S) -compound (low-polar compound) (7.1g) obtained in referential example 168 under ice-cooling, and stirred for 30 minutes under ice-cooling. The reaction mixture was diluted with chloroform and washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain methanesulfonyl compound (9.20 g). A mixed solution of the resulting methanesulfonyl compound, sodium azide (5.64g) and N, N-dimethylformamide (100ml) was stirred at 80 ℃ 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).

¹H-NMR(CDCl₃)δ：1.24(3H，t，J＝7.1Hz)，1.43(9H，s)，2.56-2.68(2H，m)，3.48-3.60(2H，m)，3.88-3.97(1H，m)，4.04-4.20(3H，m)，4.88-4.97(1H，br)，5.10(2H，s)，5.60-5.75(1H，br)，7.30-7.40(5H，m).

MS(ESI)m/z：436(M+H)⁺.

[ reference example 211] (4S, 5R) -5- [ (tert-butoxycarbonyl) amino ] -2-oxopiperidin-4-ylcarbamic acid benzyl ester

A Lindlar catalyst (2.71g) was added to a mixed solution of the compound (5.42g) obtained in referential example 210 in ethanol (150ml) and tetrahydrofuran (10.0ml), and the mixture was stirred under a hydrogen atmosphere for 3 hours and then under nitrogen for 14 hours. Insoluble matter was filtered off through a Celite pad, and after concentrating the filtrate under reduced pressure, the resulting residue was dissolved in tetrahydrofuran (30ml), and triethylamine (3.0ml) was added thereto and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate 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: methanol ═ 25: 1) to obtain the title compound (2.50 g).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，2.30-2.50(1H，br)，2.65-2.90(1H，br)，3.15-3.30(1H，br)，3.35-3.65(1H，br)，4.00-4.25(2H，br)，5.11(2H，s)，5.55-5.60(1H，br)，5.65-5.90(1H，br)，6.25-6.55(1H，br)，7.28-7.40(5H，m).

MS(ESI)m/z：364(M+H)⁺.

[ reference example 212] (3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] piperidin-4-ylcarbamic acid benzyl ester

Under ice-cooling, 1 mol of borane-tetrahydrofuran complex (tetrahydrofuran solution, 34.0ml) was added dropwise to a tetrahydrofuran (70ml) solution of the compound (2.49g) obtained in reference example 211, and the mixture was stirred for 20 hours while gradually raising the temperature to room temperature. Methanol (100ml) was added to the reaction solution, and the solvent was distilled off under reduced pressure. To the resulting residue were added ethanol (45ml), water (5ml) and triethylamine (10ml), and the mixture was refluxed for 24 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol: water 7: 3: 1, lower layer) to obtain the title compound (1.61 g).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.65-1.72(2H，m)，2.67(1H，t，J＝12.0Hz)，2.82(12H，d，J＝12.0Hz)，2.90-3.10(1H，br)，3.60-3.80(2H，m)，3.90-4.00(1H，m)，5.00-5.20(2H，m)，5.40-5.60(2H，br)，7.25-7.74(5H，m).MS(FAB)m/z：350(M+H)⁺.

[ reference example 213] (3R, 4S) -1-acetyl-4- { [ (benzyloxy) carbonyl ] amino } piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained by reacting the compound obtained in referential example 212 with acetyl chloride in methylene chloride in the presence of triethylamine.

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.85-2.15(2H，m)，2.07(1.5H，s)，2.14(1.5H，s)，2.75-2.90(1H，m)，3.10-3.20(0.5H，m)，3.25-3.35(0.5H，br.d，J＝14.2Hz)，3.65-4.05(3H，m)，4.38-4.47(0.5H，br.d，J＝13.0Hz)，4.5，4-4.63(0.5H，m)，4.69-4.83(1H，br)，4.98-5.20(2.5H，m)，5.90-6.05(0.5H，br)，7.30-7.40(5H，m).

MS(ESI)m/z：392(M+H⁺).

[ reference example 214] (3R, 4S) -1-acetyl-4- { [ (5-chloroindol-2-yl) carbonyl ] amino } piperidin-3-ylcarbamic acid tert-butyl ester

10% Palladium on carbon (532mg) was added to a solution of the compound (745mg) obtained in referential example 213 in ethanol (50ml), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After insoluble matter was removed by filtration through celite, the filtrate was concentrated under reduced pressure. The obtained residue was treated with 5-chloroindole-2-carboxylic acid (467mg) in the same manner as in reference example 68 to obtain the title compound (650 mg).

¹H-NMR(CDCl₃)δ：1.52(9H，s)，1.60-1.80(2H，m)，2.12(1H，s)，2.16(2H，s)，2.30-2.45(0.5H，m)，2.67-2.82(0.3H，m)，2.89(0.7H，d，J＝13.7Hz)，3.23(0.7H，t，J＝12.9Hz)，3.37(0.3H，d，J＝13.7Hz)，3.81-3.95(1H，m)，4.05-4.33(2H，m)，4.62-4.72(0.3H，br)，4.77(0.7H，d，J＝13.7Hz)，5.10-5.27(1H，m)，6.81(0.3H，br.s)，6.85(0.7H，s)，7.21(1H，br.d，J＝8.8Hz)，7.34(1H，d，J＝8.8Hz)，7.57(0.3H，br.s)，7.61(0.7H，s)，8.55-8.65(0.5H，br)，9.43-9.53(0.7H，br)，9.60-9.70(0.3H，br).

MS(ESI)m/z：435(M+H⁺).

[ reference example 215] (3R, 4R) -5-azido-3- { [ (benzyloxy) carbonyl ] amino } -4- [ (tert-butoxycarbonyl) amino ] pentanoic acid ethyl ester

The title compound was obtained from the (3R, 4S) -compound (highly polar compound) obtained in referential example 168 in the same manner as in referential example 210.

¹H-NMR(CDCl₃)δ：1.23(3H，t，J＝6.6Hz)，1.42(9H，s)，2.51-2.63(2H，m)，3.43-3.50(2H，m)，3.84-3.92(1H，m)，4.03-4.23(3H，m)，5.10(2H，s)，5.11-5.24(1H，m)，5.54-5.60(1H，m)，7.32-7.44(5H，m).

[ reference example 216] (4R, 5R) -5- [ (tert-butoxycarbonyl) amino ] -2-oxopiperidin-4-ylcarbamic acid benzyl ester

The title compound was obtained by treating the compound obtained in referential example 215 in the same manner as in referential example 211.

¹H-NMR(DMSO-d₆)δ：1.35(9H，s)，2.19(1H，dd，J＝17.4，9.1Hz)，2.41-2.51(1H，m)，2.97(1H，t，J＝9.1Hz)，3.00-3.11(1H，m)，3.51-3.64(1H，m)，3.67-3.73(1H，m)，5.00(2H，s)，6.71-6.80(1H，m)，7.20-7.30(5H，m)，7.44-7.52(1H，m)，8.30(1H，s).

[ reference example 217] (3R, 4R) -3- [ (tert-butoxycarbonyl) amino ] piperidin-4-ylcarbamic acid benzyl ester

The title compound was obtained by treating the compound obtained in referential example 216 in the same manner as in referential example 212.

¹H-NMR(CDCl₃)δ：1.39(9H，s)，2.05(2H，d，J＝12.9Hz)，2.40(1H，t，J＝11.0Hz)，2.63(1H，t，J＝12.0Hz)，3.09(1H，d，J＝12.0Hz)，3.31(1H，d，J＝11.0Hz)，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 title compound was obtained by treating the compound obtained in referential example 217 in the same manner as in referential example 213.

¹H-NMR(CDCl₃)δ：1.42(9H，s)，1.53-1.67(1H，m)，1.89-2.00(1H，m)，2.09(1.5H，s)，2.15(1.5H，s)，2.57(1H，t，J＝12.0Hz)，2.78(1H，t，J＝12.0Hz)，3.20-3.30(1H，m)，3.40-3.56(2H，m)，4.23-4.31(1H，m)，4.45-4.56(1H，m)，5.01-5.08(1H，m)，5.10(2H，s)，7.32-7.44(5H，m).

[ reference example 219] (3R, 4R) -1-acetyl-4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained by treating the compound obtained in referential example 218 in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.35(9H，s)，1.42-1.56(2H，m)，2.00-2.10(1H，m)，2.12(1.5H，s)，2.17(1.5H，s)，2.31-2.43(1H，m)，2.67-3.00(1H，m)，3.55-3.63(1H，m)，3.78-4.00(1H，m)，4.03-4.21(1H，m)，4.78-5.24(2H，m)，6.91(0.5H，s)，6.92(0.5H，s)，7.22-7.32(1H，m)，7.33(1H，d，J＝8.8Hz)，7.58(1H，s)，9.45(0.5H，s)，9.51(0.5H，s).

[ reference example 220] (3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -1- (2-methoxyacetyl) piperidin-4-ylcarbamic acid benzyl ester

The title compound was obtained from the compound obtained in referential example 212 and methoxyacetyl chloride in the same manner as in referential example 213.

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.70-2.15(2H，m)，2.70-2.85(1H，m)，2.90-3.30(1H.m)，3.35-3.70(1H，m)，3.43(3H，s)，3.75-3.90(2H，m)，3.90-4.25(3H，m)，4.40-4.80(1H，m)，5.05-5.09(1H，m)，5.10(2H，br.s)，7.30-7.40(5H，m).

MS(ESI)m/z：322(M+H⁺).

[ reference example 221] (3R, 4S) -4- { [ (5-chloroindol-2-yl) carbonyl ] amino } -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 220 in the same manner as in referential example 214.

¹H-NMR(CDCl₃) δ: 1.52(9H, s), 1.60-1.80(1H, m), 2.20-2.40(1H, m), 2.70-2.80(0.6H, m), 2.90-3.00(0.4H, m), 3.15-3.30(0.4H, m), 3.32-3.40(0.6H, m), 3.46, 3.49 (all 3H, s 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, 2.0Hz), 7.33(1H, d, J ═ 8.7, 7.8H, 1H, 8.41 Hz), 7.33(1H, 8.7, 8.8H, 8.41 Hz), 8.41H, 1H, 8.41 Hz).

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

The title compound was obtained from the compound obtained in referential example 217 and methoxyacetyl chloride in the same manner as in referential example 213.

¹H-NMR(CDCl₃)δ：1.41(9H，s)，1.45-1.67(1H，m)，2.01-2.14(1H，m)，2.63(1H，t，J＝12.0Hz)，2.75(1H，t，J＝12.0Hz)，3.20-3.30(1H，m)，3.32-3.41(5H，m)，3.44-3.56(2H，m)，4.21-4.32(1H，m)，4.50-4.63(1H，m)，5.03-5.08(1H，m)，5.09(2H，s)，7.32-7.40(5H，m).

[ reference example 223] (3R, 4R) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 222 and 5-chloroindole-2-carboxylic acid in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.35(9H，s)，1.41-1.56(2H，m)，2.11-2.23(0.5H，m)，2.34-2.50(0.5H，m)，2.78-2.89(0.5H，m)，3.01-3.12(0.5H，m)，3.42(5H，s)，3.45-3.56(1H，m)，3.78-3.89(1H，m)，4.00-4.21(2H，m)，4.78-5.21(2H，m)，6.91(0.5H，s)，6.93(0.5H，s)，7.23(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.59(1H，s)，9.37(0.5H，s)，9.54(0.5H，s).

[ reference example 224] (3R, 4S) -3- { [ (benzyloxy) carbonyl ] amino } -4- [ (tert-butoxycarbonyl) amino ] -5- { [ tert-butyl (diphenyl) silyl ] oxy } pentanoic acid ethyl ester

Triethylamine (0.47ml), imidazole (0.19g) and tert-butylchlorodiphenylsilane (0.7ml) were added to a solution of the (3R, 4S) -compound (highly polar compound) (0.74g) obtained in referential example 168 in this order in N, N-dimethylformamide (30ml) under ice-cooling, and the mixture was stirred for 4 days while gradually returning to room temperature. The reaction mixture was diluted with ethyl acetate, washed with a 10% citric acid aqueous solution and a saturated sodium chloride solution, 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).

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.19(3H，t，J＝7.4Hz)，1.40(9H，s)，2.40-2.50(1H，m)，2.60(1H，dd，J＝15.9，4.5Hz)，3.56-3.67(1H，m)，3.74(1H，dd，J＝11.2，4.5Hz)，3.78-3.89(1H，m)，4.08(2H，q，J＝7.4Hz)，4.21-4.30(1H，m)，4.99-5.13(3H，m)，5.41-5.52(1H，m)，7.40-7.53(6H，m)，7.60-7.72(4H，m).

[ reference example 225] (3R, 4S) -4- [ (tert-butoxycarbonyl) amino ] -5- { [ tert-butyl (diphenyl) silyl ] oxy } -3- { [ (5-chloroindol-2-yl) carbonyl ] amino } pentanoic acid ethyl ester

The title compound was obtained by removing the benzyloxycarbonyl group of the compound obtained in referential example 224 and condensing it with 5-chloroindole-2-carboxylic acid in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.10(9H，s)，1.20(3H，t，J＝7.4Hz)，1.32(9H，s)，2.40-2.52(1H，m)，2.71(1H，dd，J＝15.9，4.5Hz)，3.67-3.81(2H，m)，4.00-4.20(2H，m)，4.56-4.74(1H，m)，5.00-5.11(1H，m)，6.81(1H，s)，7.21(1H，dd，J＝8.8，2.0Hz)，7.32(1H，d，J＝8.8Hz)，7.40-7.50(6H，m)，7.58(1H，d，J＝8.5Hz)，7.63-7.74(5H，m)，9.01-9.14(1H，m).

[ reference example 226](3R^*，4R^*) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

(3R) obtained in referential example 179 in the same manner as in referential example 68^*，4R^*) Compound (low-polar compound) and the compound obtained in reference example 10 the title compound was prepared.

¹H-NMR(CDCl₃)δ：1.43(9H，s)，2.30-2.37(2H，m)，2.51(3H，s)，2.82-2.85(2H，m)，2.92-2.95(2H，m)，3.17-3.20(4H，m)，3.40-3.43(1H，m)，3.69-3.77(2H，m)，3.97-3.98(1H，m)，4.98(1H，br)，5.25(1H，br).

[ reference example 227]N-(3R^*，4R^*) -4-amino-1, 1-dioxohexahydro-1-thiopyran-3-yl]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 226 in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：2.29-2.33(2H，m)，2.93(3H，s)，3.16(2H，br)，3.40(2H，br)，3.52(2H，br)，3.69-3.76(3H，m)，4.48(1H，br)，4.71-4.82(2H，m)，8.34(2H，br)，8.82(1H，br).

MS(ESI)m/z：345(M+H)⁺.

Reference example 228](3R^*，4R^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

The title compound was prepared from the (3R, 4R) -compound (low-polar compound) obtained in referential example 179 and 5-chloroindole-2-carboxylic acid in the same manner as in referential example 68.

¹H-NMR(DMSO-d₆)δ：1.34(9H，s)，2.09(2H，br)，3.07(1H，d，J＝12.6Hz)，3.24-3.28(1H，m)，3.48(2H，br)，4.12(1H，br)，4.53(1H，br)，7.04(1H，s)，7.16-7.18(2H，m)，7.44(1H，d，J＝8.7Hz)，7.67(1H，s)，8.37(1H，br)，11.81(1H，s).

MS(ESI)m/z：442(M+H)⁺.

[ reference example 229]N-[(3R^*，4R^*) -4-amino-1, 1-dioxohexahydro-1-thiopyran-3-yl]-5-chloroindole-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 228 in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：2.24-2.33(2H，m)，3.43-3.55(3H，m)，3.60-3.66(1H，m)，3.77(1H，br)，4.75-4.79(1H，m)，7.18-7.21(2H，m)，7.46(1H，d，J＝8.8Hz)，7.72(1H，d，J＝1.7Hz)，8.39(2H，br)，8.58(1H，d，J＝6.8Hz)，11.93(1H，s).

MS(ESI)m/z：342(M+H⁺).

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

(3R) obtained in referential example 179 in the same manner as in referential example 98^*，4S^*) Compound (highly polar compound) and the compound obtained in reference example 10 the title compound was prepared.

¹H-NMR(CDCl₃)δ：1.32(9H，s)，2.14-2.24(1H，m)，2.33-2.38(1H，m)，2.50(3H，s)，2.78-2.83(2H，m)，2.86-2.95(2H，m)，3.08-3.14(3H，m)，3.55(1H，d，J＝13.4Hz)，3.68(1H，d，J＝15.5Hz)，3.72(1H，d，J＝15.5Hz)，3.86-3.88(1H，m)，4.45-4.53(1H，m)，4.75(1H，d，J＝8.5Hz)，7.76(1H，d，J＝8.3Hz).

MS(ESI)m/z：445(M+H)⁺.

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

The title compound was obtained by treating the compound obtained in referential example 230 in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：2.03-2.12(1H，m)，2.51(1H，br)，2.93(3H，s)，3.14(2H，d，J＝12.2Hz)，3.28(2H，br)，3.33(2H，br)，3.48(3H，br)，3.72(2H，br)，4.49(2H，br)，4.71-4.74(1H，m)，8.38(2H，br)，9.21-9.24(1H，m).

MS(ESI)m/z：345(M+H⁺).

[ reference example 232](3R^*，4R^*) -3- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1, 1-dioxohexahydro-1-thiopyran-4-ylcarbamic acid tert-butyl ester

(3R) obtained in referential example 179 in the same manner as in referential example 68^*，4R^*) Compound (low polarity compound) and 5-fluoroindole-2-carboxylic acid the title compound was prepared.

¹H-NMR(DMSO-d₆)δ：1.37(9H，s)，2.10-2.13(2H，m)，3.06(1H，br)，3.37-3.49(3H，m)，4.13(1H，br)，4.57(1H，br)，6.95-7.01(2H，m)，7.14(1H，br)，7.30(1H，d，J＝8.5Hz)，7.41(1H，dd，J＝8.8，4.5Hz)，8.28(1H，br)，11.68(1H，s).

MS(ESI)m/z：426(M+H⁺).

[ reference example 233]N-[(3R^*，4R^*) -4-amino-1, 1-dioxohexahydro-1-thiopyran-3-yl]-5-fluoroindole-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 232 in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：2.25-2.31(1H，m)，2.47(1H，br)，3.30(1H，br)，3.49-3.53(2H，m)，3.60-3.66(1H，m)，3.78(1H，br)，4.79(1H，br)，7.01-7.05(1H，m)，7.21(1H，s)，7.38(1H，d，J＝9.0Hz)，7.44(1H，dd，J＝8.8，4.4Hz)，8.40(2H，br)，8.56(1H，br)，11.81(1H，s).

MS(ESI)m/z：326(M+H⁺).

[ reference example 234] (3R) -3- { [ (benzyloxy) carbonyl ] amino } -4- [ (tert-butoxycarbonyl) amino ] -5-oxopentanoic acid ethyl ester

Sulfur trioxide pyridine complex salt (1.5g) was slowly added to a mixed solvent of the (3R, 4S) -compound (highly polar compound) (0.5g) obtained in referential example 168, dimethyl sulfoxide (6.8ml) and triethylamine (2.6ml) at room temperature, and the mixture was stirred for 20 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and a 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 (hexane: ethyl acetate 3: 1) to obtain the title compound (0.51 g).

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝7.4Hz)，1.44(9H，s)，2.51-2.70(2H，m)，4.01-4.23(2H，m)，4.45-4.67(1H，m)，5.00-5.23(2H，s)，5.24-5.42(1H，m)，7.23-7.43(5H，m)，9.63(0.5H，s)，9.67(0.5H，s).

[ reference example 235] (4R) -5- [ (tert-butoxycarbonyl) amino ] -1-methyl-2-oxopiperidin-4-ylcarbamic acid benzyl ester

Acetic acid (0.27ml) and 2M methylamine (tetrahydrofuran solution, 1.0ml) were sequentially added to an ethanol (10ml) solution of the compound (0.51g) obtained in referential example 234 under ice cooling, and stirred for 1 hour while slowly returning to room temperature, and sodium cyanoborohydride (0.15g) was added and stirred for 18 hours. The reaction mixture was diluted with chloroform and washed with a saturated aqueous sodium bicarbonate solution and a 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 the solution was added triethylamine (2ml), the mixture was refluxed for 2 hours, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol 98: 2) to obtain the title compound (0.28 g).

¹H-NMR(DMSO-d₆)δ：1.36(3.6H，s)，1.38(5.4H，s)，2.22-2.43(1H，m)，2.44-2.61(1H，m)，2.72(1.2H.s)，2.80(1.8H.s)，3.10(0.5H，dd，J＝12.5，8.3Hz)，3.21-3.30(0.5H，m)，3.33-3.45(1H，m)，3.56-3.82(1H，m)，3.89-4.00(1H，m)，4.94(1H，d，J＝8.1Hz)，5.00(1.2H.s)，5.01(0.8H，s)，6.89-7.02(0.5H，m)，7.23-7.44(5.5H，m).

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

The title compound was obtained from the compound obtained in referential example 235 and 5-chloroindole-2-carboxylic acid in the same manner as in referential example 214.

¹H-NMR(DMSO-d₆)δ：1.24(5.4H，s)，1.35(3.6H，s)，2.43-2.56(2H，m)，2.80(3H，s)，3.10-3.20(1H，m)，3.30-3.52(1H，m)，3.83-3.91(0.4H，m)，4.02-4.10(0.6H，m)，4.20-4.31(0.6H，m)，4.43-4.54(0.4H，m)，6.94(0.6H，d，J＝8.1Hz)，7.08(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.0Hz)，8.30(0.4H，s)，8.36(0.4H，d，J＝7.3Hz)，8.43(0.6H，d，J＝8.3Hz)，11.75(0.6H，s)，11.78(0.4H，s).

[ reference example 237]4- (pyridin-4-yl) benzoic acid hydrochloride

4-bromopyridine hydrochloride (11.7g) and 4-carboxyphenylboronic acid (10.0g) were dissolved in a mixed solvent of toluene (250ml) -water (250ml), and tetrakis (triphenylphosphine) palladium (0) (5.0g) and anhydrous sodium carbonate (25.4g) were sequentially added, followed by heating and refluxing at 120 ℃ for 19 hours. After cooling to room temperature, ethyl acetate was added, extraction was performed with water, and concentrated hydrochloric acid was added to the water layer to make it acidic. The aqueous layer was washed with ethyl acetate, and the aqueous layer was concentrated to collect the precipitated solid by filtration to prepare the title compound (8.37 g).

¹H-NMR(DMSO-d₆)δ：8.11(2H，d，J＝8.8Hz)，8.14(2H，dJ＝8.8Hz)，8.35(2H，d，J＝6.6Hz)，8.97(2H，d，J＝6.6Hz).

MS(FAB)m/z：200(M+H)⁺.

[ reference example 238] methyl 4- (pyridin-4-yl) benzoate

The compound (12.4g) obtained in referential example 237 was dissolved in methanol (200ml), and concentrated sulfuric acid (5ml) was added at room temperature, followed by heating under reflux for 3 hours. After completion of the reaction, the solvent was evaporated, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with ethyl acetate, followed by drying over anhydrous sodium sulfate. The solvent was distilled off, and hexane was added to the residue to solidify, thereby obtaining the title compound (9.86 g).

¹H-NMR(CDCl₃)δ：3.96(3H，s)，7.54(2H，d，J＝5.9Hz)，7.71(2H，dJ＝8.3Hz)，8.16(2H，d，J＝8.3Hz)，8.71(2H，d，J＝5.9Hz).

[ reference example 239]4- [4- (methoxycarbonyl) phenyl ] pyridine N-oxide

The compound (1.49g) obtained in referential example 238 was dissolved in methylene chloride (30ml), and 70% m-chloroperbenzoic acid (3.46g) was added to stir at room temperature for 1 hour. An aqueous sodium sulfite solution was added to separate the organic layer, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.33 g).

¹H-NMR(DMSO)δ：3.88(3H，s)，7.86(2H，d，J＝7.2Hz)，7.94(2H，d，J＝8.3Hz)，8.05(2H，d，J＝8.3Hz)，8.30(2H，d，J＝7.2Hz).

MS(FAB)m/z：230(M+H)⁺.

[ reference example 240]4- (4-carboxyphenyl) pyridine N-oxide

The compound (802mg) obtained in referential example 239 was dissolved in dioxane (20ml), and a 1N aqueous solution (5ml) of sodium hydroxide was added to reflux for 1 hour, followed by stirring at room temperature for 2 hours. 1N aqueous hydrochloric acid (5ml) was added thereto for neutralization, water (5ml) was further added thereto, and the resulting precipitate was collected by filtration to obtain the title compound (627 mg).

¹H-NMR(DMSO)δ：7.85(2H，d，J＝7.2Hz)，7.91(2H，d，J＝8.3Hz)，8.03(2H，d，J＝8.3Hz)，8.30(2H，d，J＝7.2Hz).

[ 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.

¹H-NMR(DMSO-d₆)δ：7.41-7.45(2H，m)，7.65-7.69(1H，m)，7.94(2H，d，J＝8.3Hz)，8.02(2H，d，J＝8.3Hz)，8.34-8.38(1H，m)，13.09(1H，s).

MS(FAB)m/z：216(M+H)⁺.

[ reference 242] Ethyl 2- (4-chloroanilino) -2-oxoacetate

Triethylamine (1.52ml) and ethyl chlorooxoacetate (1.11ml) were added successively to a solution of 4-chloroaniline (1.16g) and methylene chloride (26ml) under ice cooling, and the mixture was stirred at room temperature for 14 hours. After a saturated aqueous sodium bicarbonate solution was added to the reaction mixture to carry out a liquid separation operation, the organic layer was washed with a 10% aqueous citric acid solution and a saturated brine in this order, 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 then filtered off and dried to obtain the title compound (1.89 g).

¹H-NMR(CDCl₃)δ：1.43(3H，t，J＝7.1Hz)，4.42(2H，q，J＝7.1Hz)，7.34(2H，d，J＝8.8Hz)，7.60(2H，d，J＝8.8Hz)，8.86(1H，br.s).

MS(ESI)m/z：228(M+H)⁺.

[ reference example 243] methyl 2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetate

2-amino-5-chloropyridine (1.16g) and triethylamine (1.51ml) were dissolved in methylene chloride (26ml), and ethyl chlorooxoacetate (1.10ml) was added under ice cooling to stir at room temperature for 14 hours. After a saturated aqueous sodium bicarbonate solution was added to the reaction mixture to conduct 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 (hexane: ethyl acetate 3: 1). The resulting pale yellow solid was dissolved in methanol (20ml) and stirred at 50 ℃ for 11 hours. The reaction mixture was concentrated under reduced pressure, and precipitated crystals were collected by filtration and dried to obtain the title compound (0.43 g).

¹H-NMR(CDCl₃)δ：3.99(3H，s)，7.73(1H，dd，J＝8.8，2.2Hz)，8.24(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.2Hz)，9.39(1H，br.s).

MS(ESI)m/z：215(M+H)⁺.

[ reference example 244] (1S) -3-cyclohexene-1-carboxylic acid

(R) - (+) - α -methylbenzylamine salt of (1S) -3-cyclohexene-1-carboxylic acid (J.Am.chem.Soc., 1978, Vol.100, p. 5199-5203) (95.0g) was dissolved in ethyl acetate (1.61) and 2N hydrochloric acid (1.61), and after separating the organic layer, the aqueous layer was extracted with ethyl acetate (500 ml. times.2), the organic layers were combined, washed with saturated brine (300 ml. times.2), and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (200ml), and the organic layer was washed with saturated brine (100ml), and all the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (48.3 g).

[α]²⁵ _D-104 ° (c ═ 1, chloroform).

¹H-NMR(CDCl₃)δ：1.66-1.77(1H，m)，2.00-2.20(3H，m)，2.20-2.38(2H，m)，2.57-2.65(1H，m)，5.65-5.75(2H，m).

[ reference example 245] (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octan-7-one

To a mixture of the compound (48.0g) obtained in referential example 244, methylene chloride (580ml), potassium iodide (82.1g), sodium hydrogencarbonate (42.0g) and water (530ml) at an internal temperature of 5 ℃ was added iodine (125.4g), and the mixture was stirred at room temperature for 3 hours. After a 1N aqueous solution (800ml) of sodium thiosulfate was added to the reaction mixture, the mixture was extracted with dichloromethane (1L, 500ml), and the organic layer was washed with an aqueous solution (300ml) of sodium hydrogencarbonate, water (500ml) and saturated brine (300ml), dried over anhydrous magnesium sulfate and concentrated. The precipitated crystal was collected by filtration, washed with hexane and dried to obtain the title compound (89.5 g).

Melting point: 130-131 deg.C

[α]²⁵ _D= 41 ° (c ═ 1, chloroform)

¹H-NMR(CDCl₃)δ：1.78-1.96(2H，m)，2.12(1H，dd，J＝16.5Hz，5.2Hz)，2.35-2.50(2H，m)，2.65-2.70(1H，m)，2.80(1H，d，J＝12.2Hz)，4.45-4.55(1H，m)，4.77-4.87(1H，m).

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

A2N aqueous solution (213ml) of sodium hydroxide was added to a suspension of the compound (89.3g) obtained in referential example 245 in ethanol (810ml) while stirring at room temperature, and the mixture was stirred for 3 hours. After the reaction mixture was concentrated under reduced pressure at a bath temperature of 35 ℃, water (500ml) was added to the obtained oily substance, followed by extraction with methylene chloride (500ml and 300 ml). The organic layer was washed with water (300ml), 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 obtain the title compound (41.3 g).

[α]²⁵ _D-58 ° (c ═ 1, chloroform).

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝7.2Hz)，1.50-1.70(2H，m)，1.71-1.82(1H，m)，2.08-2.28(4H，m)，3.16(2H，s)，4.12(2H，q，J＝7.2Hz).

[ reference example 247] (1S, 3R, 4R) -3-azido-4-hydroxycyclohexanecarboxylic acid ethyl ester

A mixture of the compound (41.0g) obtained in referential example 246, N-dimethylformamide (300ml), ammonium chloride (19.3g) and sodium azide (23.5g) was stirred at 76 ℃ for 13 hours. After insoluble matter was collected by filtration, the filtrate was concentrated under reduced pressure without drying, and the residue was added to the previous filtrate and dissolved in water (500 ml). Extraction was performed with ethyl acetate (500ml, 300ml), which was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (51.5 g).

[α]²⁵ _D= 8 ° (c ═ 1, chloroform)

¹H-NMR(CDCl₃)δ：1.28(3H，t，J＝7.1Hz)，1.37-1.64(3H，m)，1.86-1.95(1H，m)，2.04-2.16(1H，m)，232-2.41(1H，m)，2.44(1H，br.s)，2.68-2.78(1H，m)，3.45-3.60(2H，m)，4.17(2H，q，J＝7.1Hz).

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

Hydrogen pressure (7 kg/cm)²) A mixture of the compound (51.2g) obtained in referential example 247, di-tert-butyl dicarbonate (68.1g), 5% palladium on carbon (5.0g) and ethyl acetate (1000ml) was stirred overnight at room temperature. The reaction mixture was filtered, concentrated, and the resulting oil was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1 → 3: 1).Crystallization from hexane gave the title compound (46.9 g). 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).

¹H-NMR(CDCl₃)δ：1.28(3H，t，J＝7.1Hz)，1.38-1.57(3H，m)，1.45(9H，s)，1.86-1.95(1H，m)，2.05-2.17(1H，m)，2.29-2.39(1H，m)，2.61-2.68(1H，m)，3.34(1H，br.s)，3.39-3.48(1H，m)，3.53-3.64(1H，m)，4.10-4.24(2H，m)，4.54(1H，br.s).

[ reference example 249] (1S, 3R, 4S) -4-azido-3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid ethyl ester

Methanesulfonyl chloride (42ml) was added dropwise to a solution of the compound (53.5g) obtained in referential example 248, methylene chloride (500ml) and triethylamine (130ml) over 20 minutes at-10 ℃ to-15 ℃. The temperature was allowed to rise to room temperature over 2 hours and stirred for 2 hours. 0.5N hydrochloric acid (800ml) was added dropwise to the reaction mixture at 0 ℃ to make the solution acidic, followed by extraction with dichloromethane (500ml, 300 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crystals were dissolved in N, N-dimethylformamide (335ml), and sodium azide (60.5g) was added thereto, followed by stirring at 67 to 75 ℃ for 16 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to remove 250ml of the solvent by evaporation. The residue and the previous filtrate were combined, dissolved in water (500ml) and extracted with ethyl acetate (11 and 300 ml). The organic layer was washed with saturated brine (400ml, 200ml), dried over anhydrous magnesium sulfate, concentrated, and the resulting crystals were purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound (18.4 g).

[α]²⁵ _D+62 ° (c-1, chloroform).

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.1Hz)，1.35-2.00(15H，s)，2.60-2.68(1H，m)，3.80-3.96(2H，m)，4.15(2H，q，J＝7.1Hz)，4.61(1H，br.s).

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

Lithium hydroxide (102mg) and water (5ml) were added to a tetrahydrofuran (25ml) solution of the compound (1.0g) obtained in referential example 249, and after stirring for 17 hours, lithium hydroxide (50mg) was further added and stirred for 4 hours. 1N aqueous hydrochloric acid (6.3ml) was added to the reaction mixture, which was extracted with ethyl acetate. After the organic layer was dried, the solvent was distilled off under reduced pressure to obtain the title compound (980 mg).

¹H-NMR(CDCl₃)δ：1.30-2.20(6H，m)，1.45(9H，s)，2.70-2.80(1H，m)，3.94(2H，br.s)，4.73(1H，br.s).

[ reference example 251] (1R, 2S, 5S) -2-azido-5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The compound (4.77g) obtained in referential example 250 was dissolved in methylene chloride (150ml), and dimethylamine hydrochloride (3.26g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.60g), 1-hydroxybenzotriazole 1 hydrate (3.24g) and N-methylmorpholine (8.09g) were added to stir at room temperature for 18 hours. After adding a saturated aqueous sodium bicarbonate solution to the reaction mixture to separate the reaction mixture, the organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 50) to obtain the title compound (4.90 g).

¹H-NMR(CDCl₃)δ：1.30-1.90(4H，m)，1.45(9H，s)，1.97-2.18(2H，m)，2.75-2.85(1H，m)，2.92(3H，s)，3.02(3H，s)，3.68-3.80(1H，m)，4.05-4.20(1H，m)，4.55-4.75(1H，m).

[ reference example 252] N- { (1R, 2S, 5S) -2-azido-5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

The compound (9.13g) obtained in referential example 251 was dissolved in methylene chloride (100ml), and an ethanol solution (100ml) of hydrochloric acid was added to stir at room temperature for 1 minute. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in N, N-dimethylformamide (200ml), and the compound (7.75g) obtained in referential example 10, 1-hydroxybenzotriazole 1 hydrate (4.47g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.2g) and triethylamine (2.02ml) were added to stir at room temperature overnight. Subsequently, the compound (2.38g) obtained in referential example 10 and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.60g) were added to stir the mixture for 3 days. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added to the residue to separate the mixture, and the obtained 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 (dichloromethane: methanol 47: 3) to obtain the title compound (7.38 g).

¹H-NMR(CDCl₃)δ：1.72-1.97(4H，m)，2.10-2.27(2H，m)，2.51(3H，s)，2.77-3.05(11H，m)，3.68(1H，d，J＝15.4Hz)，3.74(1H，d，J＝15.4Hz)，3.86-3.93(1H，m)，4.54-4.60(1H，m)，7.25(1H，d，J＝7.6Hz).

[ REFERENCE 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 methanol (300ml) solution of the compound (9.0g) obtained in referential example 252 was added 10% palladium on carbon (6.0g), and the mixture was vigorously stirred at room temperature for 11 hours under 4 hydrogen pressures. The catalyst was filtered off, and the filtrate was concentrated to obtain the title compound (7.67 g).

¹H-NMR(CDCl₃)δ：1.42-1.54(1H，m)，1.66-1.89(5H，m)，2.30-2.40(1H，m)，2.51(3H，s)，2.68-3.05(6H，m)，2.92(3H，s)，3.00(3H，s)，3.10-3.18(1H，m)，3.65-3.77(2H，m)，4.21-4.28(1H，m)，7.52(1H，d，J＝6.1Hz).

[ reference example 254] methyl 2- (4-Fluoroanilino) -2-oxoacetate

The title compound was obtained from 4-fluoroaniline and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：3.98(3H，s)，7.00-7.14(2H，m)，7.55-7.68(2H，m)，8.85(1H，br.s).

MS(ESI)m/z：198(M+H)+.

[ reference example 255] methyl 2- (4-bromoanilino) -2-oxoacetate

The title compound was obtained from 4-bromoaniline and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：3.98(3H，s)，7.49(2H，d，J＝9.0Hz)，7.55(2H，d，J＝9.0Hz)，8.85(1H，br.s).

MS(FAB)m/z：258M⁺.

[ reference example 256] methyl 2- (4-chloro-2-methylanilino) -2-oxoacetate

The title compound was obtained from 4-chloro-2-methylaniline and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：2.31(3H，s)，3.99(3H，s)，7.15-7.30(2H，m)，7.98(1H，d，J＝8.8Hz)，8.77(1H，br).

MS(FAB)m/z：228(M+H)⁺.

[ reference example 257] methyl 2- [ (4-chloro-3-methylanilino) -2-oxoacetate

The title compound was obtained from 4-chloro-3-methylaniline and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：2.39(3H，s)，3.98(3H，s)，7.33(1H，d，J＝12.5Hz)，7.44(1H，dd，J＝12.5，2.5Hz)，7.53(1H，d，J＝2.5Hz)，8.81(1H，br.s).

MS(ESI)m/z：228(M+H)⁺.

[ reference example 258] methyl 2- (4-chloro-2-fluoroanilino) -2-oxoacetate

The title compound was obtained from 4-chloro-2-fluoroaniline and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：3.99(3H，s)，7.15-7.24(2H，m)，8.33(1H，t，J＝8.4Hz)，9.05(1H，br.s).

MS(ESI)m/z：232(M+H)⁺.

[ reference example 259] methyl 2- (2, 4-difluoroanilino) -2-oxoacetate

The title compound was obtained from 2, 4-difluoroaniline and methyl chlorooxoacetate by a method similar to that described in referential example 242.

¹H-NMR(CDCl₃)δ：3.99(3H，s)，6.87-7.00(2H，m)、8.29-8.38(1H，m)，8.99(1H，br.s).

MS(ESI)m/z：215M⁺.

[ reference example 260] methyl 2- (3, 4-difluoroanilino) -2-oxoacetate

The title compound was obtained from 3, 4-difluoroaniline and methyl chlorooxoacetate by a method similar to that described in referential example 242.

¹H-NMR(CDCl₃)δ：3.98(3H，s)，7.10-7.28(2H，m)，7.67-7.78(1H，m)，8.83(1H，br.s).

MS(ESI)m/z：215M⁺.

[ reference example 261] 2-oxo-2- (pyridin-4-ylamino) acetic acid methyl ester

The title compound was obtained from 4-aminopyridine and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：3.99(3H，s)，7.58(2H，dd，J＝4.8，1.6Hz)，8.60(2H，dd，J＝4.8，1.6Hz)，9.04(1H，br.s).

MS(ESI)m/z：181(M+H)⁺.

[ reference example 262] methyl 2- [ (5-bromopyridin-2-yl) amino ] -2-oxoacetate

The title compound was obtained from 2-amino-5-bromopyridine and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：3.99(3H，s)，7.87(1H，dd，J＝8.8，2.4Hz)，8.19(1H，d，J＝8.8Hz)，8.41(1H，d，J＝2.4Hz)，9.38(1H，br.s).

MS(FAB)m/z：259M⁺.

[ reference example 263] Ethyl 2- [ (6-chloropyridin-3-yl) amino ] -2-oxoacetate

5-amino-2-chloropyridine (386mg) was dissolved in N, N-dimethylformamide (8ml), and potassium 2-ethoxy-2-oxoacetate (469mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (863mg) and 1-hydroxybenzotriazole 1 hydrate (203mg) were added thereto, followed by stirring at room temperature for 2 days. The solvent was distilled off under reduced pressure, methylene chloride and a saturated aqueous sodium bicarbonate solution were added to separate the phases, and then 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: ethyl acetate 2: 1) to obtain a residue (200mg) containing the title compound.

¹H-NMR(CDCl₃)δ：1.43(3H，t，J＝7.2Hz)，4.44(2H，q，J＝7.2Hz)，7.36(1H，d，J＝8.7Hz)，8.24(1H，dd，J＝8.7，2.7Hz)，8.55(1H，d，J＝2.7Hz)，9.03(1H，br.s).

[ reference example 264] methyl 2- [ (6-chloropyridazin-3-yl) amino ] -2-oxoacetate

3-amino-6-chloropyridazine (516mg) was dissolved in pyridine (26ml), and triethylamine (665. mu.l) and methyl chlorooxoacetate (441. mu.l) were successively added under ice cooling, followed by stirring at room temperature for 14 hours. After water was added to the reaction mixture, the mixture was separated, 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).

¹H-NMR(CDCl₃)δ：4.03(3H，s)，7.59(1H，d，J＝9.3Hz)，8.52(1H，d，J＝9.3Hz)，9.88(1H，br.s).

MS(FAB)m/z：215M⁺.

[ reference example 265] methyl 2- [ (5-chlorothiazol-2-yl) amino ] -2-oxoacetate

The title compound was obtained from 2-amino-5-chlorothiazole and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：4.02(3H，s)，7.48(1H，s)，11.03(1H，br.s).

MS(ESI)m/z：221(M+H)⁺.

[ reference example 266] lithium 2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetate

Water (5.0ml) and lithium hydroxide (128mg) were added to a tetrahydrofuran solution (20ml) of the compound (1.12g) obtained in referential example 243, and the mixture was stirred for 5 hours at room temperature. The solvent was distilled off under reduced pressure, hexane (30ml) was added to the resulting white solid, and the mixture was stirred for 30 minutes, and after the solid was collected by filtration, the title compound (1.02g) was obtained by drying.

¹H-NMR(DMSO-d₆)δ：7.90(1H，dd，J＝8.9，2.6Hz)，8.12(1H，d，J＝8.9Hz)，8.34(1H，d，J＝2.6Hz)，10.18(1H，s).

[ reference example 267] Ethyl 2- (4-chloroanilino) acetate

4-chloroaniline (2.0g) was dissolved in acetonitrile (20ml), and ethyl bromoacetate (2.1g) and lithium carbonate (2.2g) were added to stir at 60 ℃ 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).

¹H-NMR(CDCl₃)δ：1.30(3H，t，J＝7.3Hz)，3.86(2H，s)，4.24(2H，q，J＝7.3Hz)，4.26-4.35(1H，m)，6.53(2H，dd，J＝6.6，2.2Hz)，7.14(2H，dd，J＝6.6，2.2Hz).

[ reference example 268] Ethyl 2- (4-chloro-2-fluoroanilino) acetate

The title compound was obtained from 4-chloro-2-fluoroaniline and ethyl bromoacetate by the same method as that described in referential example 267.

¹H-NMR(CDCl₃)δ：1.29(3H，t，J＝7.3Hz)，3.91(2H，s)，4.22(2H，q，J＝7.3Hz)，4.42-4.51(1H，m)，6.49(1H，t，J＝8.8Hz)，6.98(1H，dt，J＝8.8，2.5Hz)，7.01(1H，dd，J＝11.3，2.5Hz).

[ reference example 269] Ethyl 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-oxoacetate

The compound (1.5g) obtained in referential example 253 was dissolved in N, N-dimethylformamide (15ml), and 2-ethoxy-2-oxoacetic acid potassium salt (962mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.18g) and 1-hydroxybenzotriazole 1 hydrate (277mg) were added to stir at room temperature for 14 hours. The solvent was evaporated under reduced pressure, and an aqueous sodium hydrogencarbonate solution and methylene chloride were added to the residue to separate the mixture. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol ═ 47: 3) to obtain the title compound (1.13 g).

¹H-NMR(CDCl₃)δ：1.37(3H，t，J＝7.1Hz)，1.55-2.15(6H，m)，2.52(3H，s)，2.77-2.89(3H，m)，2.94(5H，br.s)，3.06(3H，s)，3.71(1H，d，J＝15.5Hz)，3.73(1H，d，J＝15.5Hz)，4.06-4.13(1H，m)，4.32(2H，q，J＝7.1Hz)，4.60-4.63(1H，m)，7.39(1H，d，J＝8.3Hz)，7.83(1H，d，J＝7.6Hz).

MS(ESI)m/z：466(M+H)⁺.

[ REFERENCE EXAMPLE 270] lithium 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-oxoacetate

The compound (1.13g) obtained in referential example 269 was dissolved in tetrahydrofuran (20ml), methanol (10ml) and water (10ml), and lithium hydroxide (58mg) was added to stir at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (1.10 g).

¹H-NMR(DMSO-d₆)δ：1.41-1.73(4H，m)，2.00-2.07(2H，m)，2.39(3H，s)，2.74-2.99(11H，m)，3.67(2H，s)，3.82-3.88(1H，m)，4.28-4.30(1H，m)，8.66-8.70(2H，m).

[ reference example 271] N- { (1S, 2S, 5S) -2-azido-5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole-2-carboxamide

The title compound was obtained from the compound obtained in referential example 293 and the compound obtained in referential example 251 in the same manner as in referential example 252.

¹H-NMR(CDCl₃)δ：1.73-1.87(4H，m)，2.11-2.20(2H，m)，2.67(3H，s)，2.85-2.90(1H，m)，2.93(3H，s)，3.00(3H，s)，3.90-4.10(5H，m)，4.57-4.62(1H，m)，7.20-7.22(1H，m).

MS(FAB)m/z：378(M+H)⁺.

[ reference example 272] N- { (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole-2-carboxamide

The title compound was obtained from the compound obtained in referential example 271 by the same method as that described in referential example 253.

¹H-NMR(CDCl₃)δ：1.67-1.97(6H，m)，2.36-2.40(1H，m)，2.67(3H，s)，2.92(3H，s)，3.00(3H，s)，3.07-3.18(1H，m)，3.92-3.95(2H，m)，4.02-4.06(2H，m)，4.23-4.26(1H，m)，7.50-7.52(1H，m).

[ reference example 273] 5-chloro-4-fluoroindole-2-carboxylic acid methyl ester

Ethanol (100ml) was added to sodium hydride (containing 60%, 4.7g) at 0 ℃ under argon atmosphere and stirred for 10 minutes. After 2-nitropropane (11ml) was added to the reaction mixture and stirred for 10 minutes, 1- (bromomethyl) -3-chloro-2-fluorobenzene (10g) was added thereto and stirred at room temperature for 3.5 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between ether and water, and the organic layer was washed successively with a 1N aqueous solution of sodium hydroxide, 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 give crude 3-chloro-2-fluorobenzaldehyde (5.5g) as a pale yellow oily compound. Methanol (20ml) was added to sodium hydride (containing 60%, 1.6g) at 0 ℃ under argon atmosphere and stirred for 10 minutes. The reaction mixture was cooled to-20 ℃ and a solution of crude 3-chloro-2-fluorobenzaldehyde (5.5g) and methyl 2-azidoacetate (5.0g) in methanol (10ml) was added over 20 minutes. The reaction mixture was warmed to 0 ℃ and stirred for 2.5 hours, followed by addition of water (40 ml). The reaction mixture was concentrated under reduced pressure, and the residue was extracted with a mixture of dichloromethane and ethyl acetate. The extract 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 (toluene: hexane ═ 3: 17) to obtain crude methyl 2-azido-3- [ (3-chloro-2-fluoro) phenyl ] acrylate (2.6 g). The resulting solution was dissolved in xylene (50ml), and the mixture was stirred at 130 to 140 ℃ for 3 hours. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane) and recrystallized from ether-hexane to obtain the title compound (440 mg).

¹H-NMR(DMSO-d₆)δ：4.08(3H，s)，7.20(1H，s)，7.31-7.38(2H，m).

MS(FAB)m/z：228(M+H)⁺.

[ reference example 274] 5-chloro-4-fluoroindole-2-carboxylic acid

The compound (440mg) obtained in referential example 273 was dissolved in tetrahydrofuran (10ml), and an aqueous solution (5ml) of lithium hydroxide (160mg) was added to stir at room temperature for 3 hours. An aqueous solution (5ml) of lithium hydroxide (240mg) was added to the reaction solution, and after stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The residue was neutralized with 1N aqueous hydrochloric acid, and extracted 3 times with ethyl acetate. The combined organic layer was 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).

¹H-NMR(DMSO-d₆)δ：6.79(1H，s)，7.16-7.26(2H，m)

MS(FAB)m/z：214(M+H)⁺.

[ reference example 275] 1-benzyl-5-chloroindole-2-carboxylic acid ethyl ester

Ethyl 5-chloroindole-2-carboxylate (1.4g) was dissolved in N, N-dimethylformamide (30ml), and potassium carbonate (2.9g) and benzyl chloride (2.4ml) were added thereto, followed by heating and stirring at a bath temperature of 100 ℃ for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 19), and crystallized from ether-hexane to obtain the title compound (1.6 g).

¹H-NMR(CDCl₃)δ：1.36(3H，t，J＝7.1Hz)，4.33(2H，q，J＝7.1Hz)，5.83(2H，s)，7.00-7.02(2H，d)，7.20-7.38(6H，m)，7.67(1H，d，J＝1.7Hz).

[ reference example 276] 1-benzyl-5-chloro-3-fluoroindole-2-carboxylic acid ethyl ester

To a dichloromethane solution (30ml) of the compound (2.2g) obtained in referential example 275 was added 1-fluoro-2, 6-dichloropyridinium trifluoromethanesulfonate (4.4g), and the mixture was refluxed for 3 days. The reaction solution was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with 1N hydrochloric acid, water and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated, 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 which was purified by preparative silica gel thin layer chromatography to give the title compound.

¹H-NMR(DMSO-d₆)δ：1.25(3H，t，J＝7.1Hz)，4.29(2H，q，J＝7.1Hz)，5.77(2H，s)，6.97-6.99(2H，m)，7.18-7.28(3H，m)，7.39(1H，dd，J＝9.0，2.1Hz)，7.69(1H，dd，J＝9.0，2.1Hz)，7.78(1H，d，J＝2.1Hz)

[ reference example 277] 5-chloro-3-fluoroindole-2-carboxylic acid ethyl ester

The crude compound (1.4g) obtained in referential example 276 was dissolved in anisole (30ml), and aluminum chloride (2.9g) was added in small amounts each under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, and then aluminum chloride (2.9g) was added thereto and stirred for 18 hours. To the reaction mixture was added aluminum chloride (8.0g), and the mixture was stirred for 5 hours and then added water. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, 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 (dichloromethane) to obtain the title compound (470 mg).

¹H-NMR(CDCl₃)δ：1.43(3H，t，J＝7.2Hz)，4.45(2H，q，J＝7.2Hz)，7.25-7.31(2H，m)，7.66(1H，d，J＝0.73Hz)，8.53(1H，br.s).

MS(FAB)m/z：242(M+H)⁺.

[ reference example 278] 5-chloro-3-fluoroindole-2-carboxylic acid

The title compound was obtained from the compound obtained in referential example 277 by the same method as referential example 274.

¹H-NMR(DMSO-d₆)δ：7.31(1H，dd，J＝8.8，1.9Hz)，7.42(1H，dd，J＝8.8，1.9Hz)，7.70(1H，d，J＝1.9Hz)，11.78(1H，s)

MS(FAB)m/z：214(M+H)⁺.

[ reference example 279] (tert-butyl 1R, 2S, 5S) - { [ (5-chloro-3-fluoroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamate

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 278 in the same manner as in referential example 97.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.73-2.11(6H，m)，2.65(1H，br.s)，2.96(3H，s)，3.07(3H，s)，4.20(1H，br.s)，4.28(1H，br.s)，4.78(1H，br)，7.23-7.30(3H，m)，7.58(1H，s)，9.03(1H，s).

MS(FAB)m/z：481(M+H)⁺.

[ reference example 280] 3-bromo-5-chloroindole-2-carboxylic acid ethyl ester

N-bromosuccinimide (440mg) was added to a solution of ethyl 5-chloroindole-2-carboxylate (500mg) in N, N-dimethylformamide (10ml) under ice-cooling. The reaction mixture was stirred at room temperature for 18 hours, and then 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 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 (ethyl acetate: hexane ═ 1: 9), and the resulting white powder was washed with hexane to obtain the title compound (680 mg).

¹H-NMR(CDCl₃)δ：1.42-1.48(3H，m)，4.43-4.49(2H，m)，7.30-7.32(2H，m)，7.65(1H，d，J＝0.74Hz)，9.11(1H，s)

MS(FAB)m/z：303(M+H)⁺.

[ reference example 281] 3-bromo-5-chloroindole-2-carboxylic acid

The title compound was obtained from the compound obtained in referential example 280 in the same manner as in referential example 274.

¹H-NMR(DMSO-d₆)δ：7.35(1H，dd，J＝8.8，2.0Hz)，7.48-7.53(2H，m)，12.33(1H，s)

MS(FAB)m/z：275(M+H)⁺.

[ reference example 282] (1R, 2S, 5S) -2- { [ (3-bromo-5-chloroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 281 in the same manner as referential example 97.

¹H-NMR(CDCl₃)δ：1.42(9H，s)，1.58-2.17(6H，m)，2.70(1H，br.s)，2.96(3H，s)，3.07(3H，s)，4.23-4.28(2H，m)，4.83(1H，br)，7.34-7.41(3H，m)，7.52(1H，s)，9.76(1H，s).

MS(FAB)m/z：542(M+H)⁺.

[ reference example 283] 3-chloro-5-fluoroindole-2-carboxylic acid ethyl ester

Ethyl 5-fluoroindole-2-carboxylate (2.0g) was dissolved in N, N-dimethylformamide (20ml), and a solution of N-chlorosuccinimide (1.4g) in N, N-dimethylformamide (10ml) was added dropwise under ice cooling, followed by stirring at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, 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 (hexane: ethyl acetate 5: 1) to obtain the title compound (1.9 g).

¹H-NMR(CDCl₃)δ：1.45(3H，t，J＝7.4Hz)，4.46(2H，q，J＝7.4Hz)，7.14(1H，dt，J＝8.0，2.7Hz)，7.32-7.36(2H，m)，8.91(1H，br).

[ reference example 284] 3-chloro-5-fluoroindole-2-carboxylic acid

The title compound was obtained from the compound obtained in referential example 283 by the same method as referential example 274.

¹H-NMR(DMSO-d₆)δ：7.20(1H，dt，J＝8.8，2.4Hz)，7.31(1H，dd，J＝8.8，2.4Hz)，7.46(1H，dd，J＝8.8，4.4Hz)，12.12(1H，br).

[ reference example 285] 5-chloro-3-formylindole-2-carboxylic acid ethyl ester

Phosphorus oxychloride (2.0ml) was added to N-methyl-N-formanilide (2.9g), and after stirring for 15 minutes, 1, 2-dichloroethane (50ml) and ethyl 5-chloroindole-2-carboxylate (4.0g) were added and the mixture was refluxed for 1 hour. The reaction mixture was poured into an aqueous solution (28ml) of sodium acetate (14g) under ice cooling, stirred for 18 hours, and then the insoluble matter was collected by filtration. After washing it with water and diethyl ether in this order, the title compound (3.56g) was obtained.

¹H-NMR(DMSO-d₆)δ：1.38(3H，t，J＝7.1Hz)，4.44(2H，q，J＝7.1Hz)，7.38(1H，dd，J＝8.0，1.4Hz)，7.56(1H，d，J＝8.0Hz)，8.19(1H，d，J＝1.4Hz)，10.53(1H，s).

[ reference example 286] 5-chloro-3-formylindole-2-carboxylic acid

The compound (1.0g) obtained in referential example 285 was dissolved in ethanol (10ml), and a 1N aqueous solution (10ml) of sodium hydroxide was added dropwise, followed by stirring at 50 ℃ for 2 hours. 1N aqueous hydrochloric acid (11ml) was added to the reaction mixture, and insoluble matter deposited was filtered off with stirring to obtain the title compound (0.86 g).

¹H-NMR(DMSO-d₆)δ：7.39(1H，d，J＝8.0Hz)，7.55(1H，d，J＝8.0Hz)，8.20(1H，s)，10.58(1H，s)，12.90(1H，br).

[ reference example 287] 5-chloro-2-ethoxycarbonylindole-3-carboxylic acid

The compound (1.5g) obtained in referential example 286 and sulfamic acid (1.7g) were dissolved in tert-butanol (30ml) -water (30ml), and sodium chlorite (1.6g) was added thereto and stirred for 8 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, washed successively with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether-hexane to obtain the title compound (0.7 g).

¹H-NMR(DMSO-d₆)δ：1.34(3H，t，J＝7.1Hz)，4.38(2H，q，J＝7.1Hz)，7.33(1H，dd，J＝8.0，1.4Hz)，7.52(1H，d，J＝8.0Hz)，7.97(1H，d，J＝1.4Hz)，12.75(1H，br).

[ reference example 288] 5-chloro-3- [ (dimethylamino) carbonyl ] indole-2-carboxylic acid ethyl ester

The compound (0.7g) obtained in referential example 287 was dissolved in N, N-dimethylformamide (10ml), and dimethylamine hydrochloride (0.26g), 1-hydroxybenzotriazole 1 hydrate (0.43g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.0g) were further added to stir at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, 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 of isopropyl ether-hexane to obtain the title compound (0.6 g).

¹H-NMR(DMSO-d₆)δ：1.29(3H，t，J＝7.1Hz)，2.78(3H，s)，3.04(3H，s)，4.30(2H，q，J＝7.1Hz)，7.31(1H，dd，J＝8.0，1.4Hz)，7.45(1H，d，J＝1.4Hz)，7.48(1H，d，J＝8.0Hz)，12.29(1H，s).

[ reference example 289] 5-chloro-3- [ (dimethylamino) carbonyl ] indole-2-carboxylic acid

The title compound was obtained from the compound obtained in referential example 288 by the same method as in referential example 286.

¹H-NMR(DMSO-d₆)δ：2.91(6H，s)，7.29(1H，d，J＝8.0Hz)，7.44(1H，d，J＝8.0Hz)，7.47(1H，s)，12.16(1H，s).

[ reference example 290]5- (phenylsulfonyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole

Benzenesulfonamide (638mg) and 4, 5-bis (bromomethyl) thiazole (M.Al. Hariri, O.Galley, F.Pautet, H.Filion, Eur.J.Org.Chem.1998, 593-594) (1.10g) were dissolved in N, N-dimethylformamide (10ml) under ice-cooling, and sodium hydride (60% oily, 357mg) was added dropwise and stirred at room temperature for 3 hours. Water and dichloromethane were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate 9: 1) to obtain the title compound (137 mg).

¹H-NMR(CDCl₃)δ：4.60-4.63(2H，m)，4.70-4.73(2H，m)，7.52-7.64(3H，m)，7.88-7.92(2H，m)，8.71(1H，s).

MS(FAB)m/z：267(M+H)⁺.

[ reference example 291]5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole 2 hydrobromide

A mixture of the compound (800mg) obtained in referential example 290, phenol (800. mu.l) and 47% aqueous hydrobromic acid (5.00ml) was heated under reflux for 2 hours. After cooling to room temperature, ethyl acetate and water were added to separate the phases, and the solvent was evaporated from the aqueous layer under reduced pressure. To the residue was added ethyl acetate, and the precipitate was collected by filtration and dried to obtain the title compound (521 mg).

¹H-NMR(DMSO-d₆)δ：4.42(2H，br s)，4.56(2H，br s)，9.14(1H，s).

MS(FAB)m/z：127(M+H)⁺.

[ reference example 292] 5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole

The title compound was obtained from the compound obtained in reference example 291 by the same method as that described in reference example 9.

¹H-NMR(CDCl₃)δ：2.67(3H，s)，3.95-3.99(2H，m)，4.01-4.05(2H，m)，8.69(1H，s).

MS(ESI)m/z：141(M+H)⁺.

Reference example 293 lithium 5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole-2-carboxylate

The title compound was obtained from the compound obtained in referential example 292 by the same method as that described in referential example 5.

¹H-NMR(DMSO-d₆)δ：2.52(3H，s)，3.73(2H，t，J＝3.2Hz)，3.87(2H，t，J＝3.2Hz).

[ reference example 294] (1R, 2S, 5S) -2- [ (6-chloro-2-naphthoyl) amino ] -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 144 and 6-chloronaphthalene-2-carboxylic acid (Eur.J.chem-Chim.Ther., 1984, vol.19, p.205-214) in the same manner as in referential example 97.

¹H-NMR(CDCl₃)δ：1.30-2.00(15H，m)，2.60-2.80(1H，m)，2.96(3H，s)，3.09(3H，s)，4.00-4.20(1H，m)，4.20-4.30(1H，m)，4.75-4.95(1H，m)，7.44(1H，d，J＝9.0Hz)，7.70-7.95(5H，m)，8.31(1H，s).

MS(FAB)m/z：474(M+H)⁺.

[ reference example 295] (E) -3- (morpholin-4-yl) -2-propenoic acid ethyl ester

Ethyl propionate (2.0ml) was dissolved in dichloromethane (20ml), morpholine (1.70ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane: methanol 20: 1) to obtain the title compound (3.72 g).

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.1Hz)，3.21(4H，t，J＝5.1Hz)，3.71(4H，t，J＝5.1Hz)，4.14(2H，q，J＝7.1Hz)，4.70(1H，d，J＝13.4Hz)，7.36(1H，d，J＝13.4Hz).

MS(FAB)m/z：186(M+H)⁺.

[ reference example 296] 3-Chlorobiazinyltetrafluoroborate

3-chloroaniline (2.0g) was dissolved in a mixed solvent of water (30ml) and concentrated hydrochloric acid (3.5ml), and sodium nitrite (1.30g) was added thereto under ice cooling and stirred for 10 minutes. Then, concentrated hydrochloric acid (5.3ml) and sodium tetrafluoroborate (6.90g) were added thereto, and the mixture was stirred under ice cooling for 30 minutes, and then the precipitate was collected by filtration and washed with water, methanol and ether to obtain the title compound (2.63 g). It was used directly in the subsequent reaction.

[ reference example 297] 7-Chlorcinnoline-3-carboxylic acid ethyl ester

The compound (1.45g) obtained in referential example 295 was dissolved in acetonitrile (100ml), and the compound (1.73g) obtained in referential example 296 was added to stir at room temperature for 1 hour and then heated under reflux for 7 days. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane → dichloromethane: ethyl acetate 10: 1, then hexane: ethyl acetate 4: 1 → 1: 1) to obtain the title compound (0.25 g).

¹H-NMR(CDCl₃)δ：1.53(3H，t，J＝7.1Hz)，4.62(2H，q，J＝7.1Hz)，7.80(1H，dd，J＝8.8，2.0Hz)，7.95(1H，d，J＝8.8Hz)，8.64(1H，s)，8.68(1H，d，J＝2.0Hz).

[ reference example 298] 7-Chlorcinnoline-3-carboxylic acid

The title compound was obtained from the compound obtained in referential example 297 by a similar method to referential example 286.

¹H-NMR(DMSO-d₆)δ：8.02(1H，dd，J＝8.8，2.0Hz)，8.34(1H，d，J＝8.8Hz)，8.70(1H，s)，8.90(1H，s).

MS(FAB)m/z：209(M+H)⁺.

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

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 298 by the same method as referential example 97.

¹H-NMR(CDCl₃)δ：1.36(9H，s)，1.80-2.20(5H，m)，2.72(1H，m)，2.96(3H，s)，3.07(3H，s)，3.49(1H，d，J＝3.7Hz)，4.30-4.45(2H，m)，4.87(1H，br)，7.77(1H，dd，J＝8.8，2.0Hz)，7.96(1H，d，J＝8.8Hz)，8.59(2H，br)，8.72(1H，s).

MS(FAB)m/z：476(M+H)⁺.

[ reference example 300] (1R, 2S, 5S) -2- { [ (5-chloro-1H-benzimidazol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

10% Palladium on carbon (50mg) was added to a tetrahydrofuran (5.0ml) solution of the compound (235mg) obtained in referential example 143, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and 1-hydroxybenzotriazole 1 hydrate (100mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (171mg) were added to a solution of the obtained product and 5-chlorobenzimidazole-2-carboxylic acid (Bull. chem. Soc. Jpn., 1989, vol. 62, p. 2668) (165mg) in N, N-dimethylformamide (5.0ml) at room temperature, followed by stirring for 4 days. After the reaction mixture was concentrated, dichloromethane, an aqueous sodium bicarbonate solution and water were added to separate the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol 10: 1) to obtain the title compound (250 mg).

¹H-NMR(DMSO-d₆)δ：1.01-2.00(6H，m)，1.34(9H，s)，2.79(3H，s)，2.80-2.95(1H，m)，2.98(3H，s)，3.89-4.06(2H，m)，7.08(1H，d，J＝6.6Hz)，7.31(1H，d，J＝8.5Hz)，7.62(2H，br.s)，8.47(1H，d，J＝8.5Hz)，13.46(1H，br.s).

MS(ESI)m/z：466(M+H)⁺.

[ reference example 301] methyl 3- (4-fluorophenyl) -2- { [ (4-methylphenyl) sulfonyl ] amino } propanoate

Methyl 2-amino-3- (4-fluorophenyl) propionate (2.01g), p-toluenesulfonyl chloride (2.25g) and 4-dimethylaminopyridine (309mg) were dissolved in chloroform (30ml), and pyridine (3.0ml) was added to the solution, and the mixture was refluxed for 4.5 hours. 92.20g of p-toluenesulfonyl chloride was added thereto, and the mixture was refluxed for 3.5 hours. The reaction mixture was poured into ice and 1N hydrochloric acid (17ml) to separate the solution, and then the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order and dried over anhydrous sodium sulfate. The solvent was evaporated 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).

¹H-NMR(CDCl₃)δ：2.41(3H，s)，2.90-3.10(2H，m)，3.51(3H，s)，4.10-4.20(1H，m)，5.04(1H，d，J＝9.0Hz)，6.85-6.95(2H，m)，7.00-7.10(2H，m)，7.20-7.30(2H，m)，7.60-7.70(2H，m).

MS(ESI)m/z：352(M+H)⁺.

[ reference example 302] methyl 7-fluoro-2- [ (4-methylphenyl) sulfonyl ] -1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylate

The compound (1.50g) obtained in referential example 301 and paraformaldehyde (207mg) were dissolved in chloroform (40ml) and replaced with argon. Then, trifluoroborane-diethyl ether complex (1.20ml) was added thereto, and the mixture was stirred at room temperature for 7.5 hours. The reaction solution was poured into ice or a saturated aqueous sodium bicarbonate solution to separate the solution, and then 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 (hexane: ethyl acetate 3: 1) to obtain the title compound (1.45 g).

¹H-NMR(CDCl₃)δ：2.42(3H，s)，3.15(2H，d，J＝3.9Hz)，3.46(3H，s)，4.45(1H，d，J＝15.9Hz)，4.69(1H，d，J＝15.9Hz)，5.01(1H，t，J＝4.4Hz)，6.70-6.80(1H，m)，6.80-6.90(1H，m)，7.00-7.10(1H，m)，7.29(2H，d，J＝8.1Hz)，7.72(2H，d，J＝8.3Hz).

MS(ESI)m/z：364(M+H)⁺.

[ reference example 303] 7-fluoroisoquinoline-3-carboxylic acid methyl ester

The compound (1.45g) obtained in referential example 302 was dissolved in N, N-dimethylformamide (40 ml). Oxygen was introduced into the reaction solution, and the mixture was stirred at 100 ℃ for 3.5 hours. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to the residue to separate the solution, and then the organic layer was washed with a 10% aqueous citric acid solution and saturated brine in this order and dried over anhydrous sodium sulfate. 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 (0.59 g).

¹H-NMR(CDCl₃)δ：4.07(3H，s)，7.55-7.65(1H，m)，7.65-7.75(1H，m)，8.00-8.05(1H，m)，8.61(1H，s)，9.30(1H，s).

MS(ESI)m/z：206(M+H)⁺.

[ reference example 304] 7-fluoroisoquinoline-3-carboxylate

The compound (1.45g) obtained in referential example 303 was dissolved in concentrated hydrochloric acid (18ml), and heated under reflux for 2.5 hours. The reaction mixture was cooled, and the precipitated crystal was collected by filtration, washed with water, and dried to obtain the title compound (0.46 g).

¹H-NMR(DMSO-d₆)δ：7.90-8.00(1H，m)，8.15-8.25(1H，m)，8.40-8.50(1H，m)，8.82(1H，s)，9.55(1H，s).

MS(FAB)m/z：192(M+H)⁺.

[ reference example 305] 7-chloro-2H-chromene-3-carboxylic acid ethyl ester

4-chloro-2-hydroxybenzaldehyde (acta. chem. Scand., 1999, 53 vol., 258 p.) (510mg) was dissolved in tetrahydrofuran (40ml), and sodium hydride (60% oily, 157mg) was added and stirred at room temperature for 2 hours. Then, a tetrahydrofuran solution (10ml) of ethyl 2-diethylphosphonoacrylate (J.org.chem.1978, 43 vol., 1256 p.) (769mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours and then refluxed overnight. After the reaction solution was cooled to room temperature, water and ether were added to separate the reaction solution. 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 (hexane: ethyl acetate 10: 1) to obtain the title compound (247 mg).

¹H-NMR(DMSO-d₆)δ：1.33(3H，t，J＝7.1Hz)，4.27(2H，q，J＝7.1Hz)，4.99(2H，d，J＝1.2Hz)，6.85(1H，d，J＝1.2Hz)，6.89(1H，dd，J＝8.1，2.0Hz)，7.04(1H，d，J＝8.1Hz)，7.38(1H，d，J＝1.0Hz).

MS(EI)m/z：238(M⁺).

[ reference example 306] 7-chloro-2H-chromene-3-carboxylic acid

The title compound was obtained from the compound obtained in referential example 305 by the same method as referential example 274.

¹H-NMR(DMSO-d₆)δ：4.92(1H，d，J＝2.0Hz)，6.95(1H，d，J＝2.0Hz)，7.01(1H，dd，J＝8.1，2.2Hz)，7.35(1H，d，J＝8.1Hz)，7.44(1H，s).MS(EI)m/z：210(M)⁺.

[ reference example 307] (1R, 2S, 5S) -2- { [ (E) -3- (4-chlorophenyl) -2-acryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 144 and 4-chlorocinnamic acid by the same process as referential example 97.

¹H-NMR(CDCl₃)δ：1.30-1.55(3H，m)，1.48(9H，s)，1.60-2.30(4H，m)，2.57-2.70(1H，m)，2.95(3H，s)，3.06(3H，s)，4.01(1H，br s)，4.10-4.20(1H，m)，4.78(1H，br.s)，6.30(1H，d，J＝15.6Hz)，7.02(1H，s)，7.31(2H，d，J＝8.5Hz)，7.40(2H，d，J＝8.5Hz)，7.52(1H，d，J＝15.6Hz).

MS(ESI)m/z：450(M+H)⁺.

[ reference example 308] 6-chloro-4-oxo-1, 4-dihydroquinoline-2-carboxylic acid methyl ester

Dimethyl acetylenedicarboxylate (13.5ml) was added to a methanol (150ml) solution of 4-chloroaniline (12.76g) and heated under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in diphenyl ether (70ml), which was then stirred at 240 ℃ for 4 hours. After the reaction solution was cooled, a mixed solvent of hexane and diethyl ether was added, and the precipitated crystals were collected by filtration and washed to obtain the title compound (11.09 g).

¹H-NMR(DMSO-d₆)δ：3.97(3H，s)，7.76(1H，dd，J＝9.0，2.5Hz)，7.90-8.05(2H，m)，12.28(1H，br.s).

MS(ESI)m/z：238(M+H)⁺.

[ reference example 309] 6-chloro-4-oxo-1, 4-dihydroquinoline-2-carboxylic acid

The title compound was obtained from the compound obtained in referential example 308 in the same manner as in referential example 286.

¹H-NMR(DMSO-d₆)δ：6.90-7.05(1H，m)，7.90-8.05(2H，m)，10.10-10.30(1H，m)，12.13(1H，br.s).

MS(ESI)m/z：224(M+H)⁺.

[ reference example 310] (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

To a tetrahydrofuran (40ml) solution of the compound (5.00g) obtained in referential example 97 were added water (10ml) and lithium hydroxide (263mg), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was concentrated, and to the resulting residue and a solution of dimethylamine hydrochloride (1.85g) in N, N-dimethylformamide (100ml), 1-hydroxybenzotriazole 1 hydrate (1.75g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.32g) and diisopropylethylamine (11.3ml) were added at room temperature, followed by stirring for 2 days. After the reaction mixture was concentrated, dichloromethane, an aqueous sodium bicarbonate solution and water were added to separate the reaction mixture, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: acetone ═ 2: 1 → 1: 1) to obtain the title compound (4.59 g).

¹H-NMR(CDCl₃)δ：1.60-1.76(2H，m)，1.73(9H，s)，1.76-1.87(1H，m)，1.93(1H，br.s)，2.14(1H，br.s)，2.28(1H，br.s)，2.65(1H，br.s)，2.95(3H，s)，3.05(3H，s)，4.01(1H，br.s)，4.21(1H，br.s)，4.84(1H，br.s)，6.81(1H，br.s)，7.20(1H，dd，J＝8.8，1.9Hz)，7.36(1H，d，J＝8.8Hz)，7.59(1H，br.s)，8.02(1H，br.s)，10.06(1H，br.s).

MS(FAB)m/z：465(M+H)⁺.

[ reference example 311] (1R, 2S, 5S) -2- { [ (5-Fluoroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

1) Ethyl (1R, 3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -4- { [ (5-fluoroindol-2-yl) carbonyl ] amino } cyclohexanecarboxylate was obtained from the compound obtained in referential example 96 and 5-fluoroindole-2-carboxylic acid in the same manner as in referential example 91

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.1Hz)，1.52(9H，s)，1.67-2.41(7H，m)，3.97(1H，br.s)，4.15(2H，q，J＝7.1Hz)，4.08-4.22(1H，m)，6.83(1H，s)，7.00-7.05(1H，m)，7.32-7.36(1H，m)，8.02(1H，s)，9.51(1H，s).

MS(FAB)m/z：448(M+H)⁺.

2) The title compound was obtained from the above compound by the same method as in reference example 310.

¹H-NMR(CDCl₃)δ：1.52(9H，s)，1.57-1.79(2H，m)，1.79-2.00(2H，m)，2.14(1H，br.s)，2.31(1H，br.s)，2.65(1H，br.s)，2.95(3H，s)，3.07(3H，s)，4.02(1H，br.s)，4.17-4.25(1H，m)，4.80(1H，br.s)，6.82(1H，br.s)，7.02(1H，dt，J＝2.3，9.0Hz)，7.24(1H，br.s)，7.35(1H，dd，J＝9.0，4.3Hz)，7.91(1H，br.s)，9.49(1H，br.s).

MS(FAB)m/z：447(M+H)⁺.

[ reference example 312] 2-amino-6, 6-dimethyl-6, 7-dihydrothiazolo [4, 5-c ] pyridine-5 (4H) -carboxylic acid ethyl ester

Copper (I) cyanide (918mg) was dissolved in tetrahydrofuran (50ml) under an argon stream, cooled to-20 ℃ and then N-butyllithium (1.56N hexane solution, 6.41ml) was added dropwise over 5 minutes, followed by stirring at-20 ℃ for 30 minutes. After the reaction solution was cooled to-50 ℃, diisobutylaluminum hydride (1.00 mol in hexane) was added dropwise over 20 minutes, and the mixture was stirred at-50 ℃ for 1 hour. To the reaction mixture was added dropwise a solution of ethyl 2, 2-dimethyl-5-oxo-5, 6-dihydro-2H-pyridine-1-carboxylate (Helv. Chim. acta, 1998, volume 81, p. 303) (986mg) in tetrahydrofuran (5ml) over 5 minutes, and the mixture was stirred at-50 ℃ for 2 hours. After the temperature was raised to-20 ℃, bromine (4.90ml) was added dropwise at one time, and the mixture was stirred at-20 ℃ for 30 minutes. Water and ethyl acetate were added to the reaction mixture to separate the reaction mixture, and the organic layer was washed with a saturated aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was dissolved in N, N-dimethylformamide (10ml), followed by addition of thiourea (760mg) and stirring at 50 ℃ overnight. After the solvent was distilled off, methylene chloride and a saturated aqueous sodium bicarbonate solution were added to separate the organic layer, and 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).

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝7.1Hz)，1.54(6H，s)，2.65-2.67(2H，m)，4.09(2H，q，J＝7.1Hz)，4.44-4.46(2H，m)，4.78(2H，br.s).

[ reference example 313] 2-bromo-6, 6-dimethyl-6, 7-dihydrothiazolo [4, 5-c ] pyridine-5 (4H) -carboxylic acid ethyl ester

Copper bromide (431mg) was suspended in acetonitrile (8ml), and tert-butyl nitrite (249mg) was added dropwise thereto at room temperature. An acetonitrile solution (8ml) of the compound (412mg) obtained in referential example 312 was added to the reaction mixture under ice cooling, and the mixture was stirred at 50 ℃ for 15 minutes. The solvent was distilled off, ether and 10% hydrochloric acid were added to the residue to separate a liquid, 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).

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.1Hz)，1.55(6H，s)，2.79-2.81(2H，m)，4.10(2H，q，J＝7.1Hz)，4.65-4.67(2H，m).

MS(ESI)m/z：319(M+H)⁺.

[ reference example 314] Ethyl 6, 6-dimethyl-6, 7-dihydrothiazolo [4, 5-c ] pyridine-5 (4H) -carboxylate

To an ether solution (5ml) of the compound (432mg) obtained in referential example 313 was added N-butyllithium (1.56N in hexane, 1.04ml) at-78 ℃ and the mixture was stirred at-78 ℃ for 30 minutes. To the reaction mixture, water and ether were added to separate a liquid, and an organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (307 mg).

¹H-NMR(CDCl₃)δ：1.28(3H，t，J＝7.1Hz)，1.55(6H，s)，2.90(2H，s)，4.12(2H，q，J＝7.1Hz)，4.75(2H，m)，8.63(1H，s).

[ reference example 315]6, 6-dimethyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c ] pyridine

The compound (307mg) obtained in referential example 314 was dissolved in a mixed solvent of water (5ml), ethanol (5ml) and dioxane (5ml), and lithium hydroxide (598mg) was added to the reaction solution, followed by heating and refluxing for 7 days. After the mixture was allowed to stand at room temperature, water and methylene chloride were added to separate the mixture, and the aqueous layer was extracted with methylene chloride 6 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound (207 mg).

¹H-NMR(CDCl₃)δ：1.23(6H，s)，2.71-2.73(2H，m)，4.09-4.11(2H，m)，8.61(1H，s).

MS(ESI)m/z：168(M⁺).

[ reference example 316]6, 6-dimethyl-6, 7-dihydrothiazolo [4, 5-c ] pyridine-5 (4H) -carboxylic acid tert-butyl ester

The compound (207mg) obtained in referential example 315 was dissolved in methylene chloride (5ml), and di-tert-butyl dicarbonate (404mg) and 4- (N, N-dimethylamino) pyridine (151mg) were added to stir at room temperature for 2 hours. Then, di-tert-butyl dicarbonate (404mg) was further added thereto and stirred at room temperature overnight, followed by further addition of di-tert-butyl dicarbonate (1.00g) and stirring for 1 hour. Dichloromethane and 10% aqueous hydrochloric acid were added to separate the solution, and the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to obtain the title compound (95.4 mg).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.52(6H，s)，2.87(2H，s)，4.69(2H，s)，8.62(1H，s).

MS(ESI)m/z：269(M+H)⁺.

[ reference example 317] lithium 4-chloro-5- (1, 3-dioxolan-2-yl) thiazole-2-carboxylate

2, 4-dichlorothiazole-5-carbaldehyde ethylene glycol (J. chem. Soc. Perkin Trans.1, 1992, page 973) (2.26g) was dissolved in tetrahydrofuran (15ml), and N-butyllithium (1.5N hexane solution, 6.8ml) was added under cooling with dry ice-acetone, and after stirring for 20 minutes, carbon dioxide was introduced at the same temperature. From this state, the temperature was gradually raised to room temperature over 1.5 hours, and then the mixture was concentrated under reduced pressure, and hexane was added to the mixture to obtain a powder, which was collected by filtration, suspended in ethyl acetate, and collected by filtration again to obtain the title compound (1.65g).

[ reference example 318] 4-chloro-5- (1, 3-dioxolan-2-yl) thiazole-2-carboxylic acid ethyl ester

The compound (242mg) obtained in referential example 317 and ethanol (0.2ml) were dissolved in N, N-dimethylformamide (2ml), and 1-hydroxybenzotriazole 1 hydrate (136mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250mg) were added to stir at room temperature overnight. The solvent was concentrated under reduced pressure, and the organic layer was separated by adding diethyl ether and dilute hydrochloric acid. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (170 mg).

¹H-NMR(CDCl₃)δ：1.43(3H，t，J＝7.3Hz)，4.00-4.10(2H，m)，4.10-4.20(2H，m)，4.48(2H，q，J＝7.3Hz)，6.15(1H，s).

MS(ESI)m/z：264(M+H)⁺.

[ reference example 319] 4-chloro-5-formylthiazole-2-carboxylic acid ethyl ester

The compound (132mg) obtained in referential example 318 was dissolved in diethyl ether (5ml), and 20% aqueous hydrochloric acid (0.3ml) was added and the mixture was stirred at room temperature for 7 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, extracted with ether, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (110 mg).

¹H-NMR(CDCl₃)δ：1.46(3H，t，J＝7.1Hz)，4.52(2H，q，J＝7.1Hz)，10.12(1H，s).

[ reference example 320] 4-azido-5-formylthiazole-2-carboxylic acid ethyl ester

The compound (5.15g) obtained in referential example 319 was dissolved in dimethyl sulfoxide (30ml), and sodium azide (1.52g) was added and stirred at room temperature for 2.5 hours. Ice water was added to the reaction mixture, which was extracted with ether, washed with water 2 times, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 24: 1) to obtain the title compound (1.78 g).

¹H-NMR(CDCl₃)δ：1.45(3H，t，J＝7.1Hz)，4.50(2H，q，J＝7.1Hz)，9.95(1H，s).

[ reference example 321] 6-methyl-6, 7-dihydrothiazolo [4, 5-d ] pyridine-2-carboxylic acid ethyl ester

The compound (1.56g) obtained in referential example 320 was dissolved in methylene chloride (20ml), and acetic acid (2ml), methylamine (2N in tetrahydrofuran, 21ml) and sodium triacetoxyborohydride (2.98g) were added to stir. After 1 hour, sodium triacetoxyborohydride (2.98g) was added and stirring was continued for another 4.5 hours. To the reaction mixture was added 0.5N aqueous sodium hydroxide (100ml) to make it basic, followed by extraction with dichloromethane and drying 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 (50ml), and 10% palladium on carbon (2.0g) was added to conduct hydrogenation reaction at normal temperature and pressure. After 2.5 hours, the catalyst was filtered off, the filtrate was concentrated, and the residue was dissolved in methylene chloride (30ml), and trimethyl orthoformate (0.7ml) and boron trifluoride-diethyl ether complex (0.3ml) were further added to stir at room temperature for 15 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane and drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 97: 3) to obtain the title compound (100 mg).

¹H-NMR(CDCl₃)δ：1.41(3H，t，J＝7.1Hz)，2.95(3H，s)，4.44(2H，q，J＝7.1Hz)，4.87(2H，s)，7.06(1H，s).

MS(ESI)m/z：226(M+H)⁺.

[ reference example 322] 6-methyl-6, 7-dihydrothiazolo [4, 5-d ] pyrimidine-2-carboxylic acid lithium salt

The compound (463mg) obtained in referential example 321 was dissolved in tetrahydrofuran (20ml), and lithium hydroxide (54.1mg) and water (4ml) were added and the mixture was stirred at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure, and dried by vacuum pump to obtain the title compound (460 mg).

¹H-NMR(DMSO-d₆)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

Condensation of the compound obtained in referential example 250 with ethylmethylamine was conducted to obtain the title compound.

¹H-NMR(CDCl₃) δ: 1.08, 1.18(3H, 7.1Hz for each t, J), 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, s) 3.32, 3.39(2H, 7.1Hz for each q, J), 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 (1.44g) obtained in referential example 323 was dissolved in methanol (20ml), and 10% palladium on carbon (150mg) was added thereto and stirred under a hydrogen stream. After 24 hours the catalyst was filtered off and the solvent was concentrated under reduced pressure to give a colorless oil which was used directly in the following reaction.

This oily substance was dissolved in methylene chloride (30ml), and the compound (850mg) obtained in referential example 57, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.27g), 1-hydroxybenzotriazole 1 hydrate (900mg) and N-methylmorpholine (1.34g) were added to stir at room temperature. After 17 hours, dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture to separate the reaction mixture, the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 50) to obtain the title compound (1.61 g).

¹H-NMR(CDCl₃) δ: 1.10, 1.22(3H, 7.1Hz for each t, J), 1.43(9H, s), 1.84-2.17(6H, m), 2.66(1H, br.s), 2.92, 3.03(3H, s), 3.35-3.44(2H, m), 4.20-4.30(2H, m), 5.30(1H, br.s), 7.70(1H, d, J8.6 Hz),7.92(1H，d，J＝8.6Hz)，8.00(1H，s)，8.40(1H，br.s)，8.56(1H，s)，9.03(1H，s).

MS(FAB)m/z：489(M+H)⁺.

[ reference example 325] N- ((1S, 2R, 4S) -2-amino-4- [ (7-chloroisoquinolin-3-yl) carbonyl ] -4- { [ ethyl (methyl) amino ] carbonyl } cyclohexyl) -7-chloroisoquinoline-3-carboxamide

The compound (1.60g) obtained in referential example 324 was dissolved in an ethanol hydrochloride solution (25ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and methylene chloride and a 1N aqueous solution of sodium hydroxide were added to the residue to separate the residue. The aqueous layer was extracted with dichloromethane, the combined organic layers were dried over potassium carbonate, and the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the precipitate was collected by filtration to obtain the title compound (1.22 g).

¹H-NMR(DMSO-d₆) δ: 1.10, 1.23(3H, 7.1Hz for each t, J), 1.26(2H, br.s), 1.69-2.11(6H, m), 2.89(1H, br.s), 2.93, 3.05(3H, s), 3.38-3.45(2H, m), 3.52(1H, s), 4.18(1H, br.s), 7.70(1H, dd, J-8.8, 2.0Hz), 7.94(1H, d, J-8.8 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 group]-4- { [ tert-butyl (diphenyl) silyl]Oxy } cyclohexanecarboxylic acid ethyl ester

The compound (28.0g) obtained in referential example 88 was dissolved in N, N-dimethylformamide (500ml), and tert-butyldiphenylsilyl chloride (63.5ml) and imidazole (19.9g) were added. After stirring at room temperature for 10 hours, ethyl acetate and water were added to the reaction mixture to separate the mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed 2 times with water. After drying over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 1: 0 → 47: 3), to give the title compound (52.5g) mixed with 0.4 molecule of N, N-dimethylformamide.

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.27(3H，t，J＝7.1Hz)，1.38(9H，s)，1.43-1.59(3H，m)，1.63-1.67(1H，m)，1.92-1.98(1H，m)，2.25-2.32(1H，m)，2.37-2.42(1H，m)，3.66(1H，br.s)，3.80(1H，br.s)，4.16(2H，q，J＝7.1Hz)，4.32(1H，d，J＝8.1Hz)，7.34-7.46(6H，m)，7.65-7.73(4H，m).

[ reference example 327](1R^*，2R^*，5S^*) -2- { [ tert-butyl (diphenyl) silyl]Oxy } -5- (hydroxymethyl) cyclohexanecarboxylic acid tert-butyl ester

Lithium aluminum hydride (7.11g) was suspended in dry diethyl ether (100ml) at 0 ℃ under argon replacement, and a diethyl ether solution (500ml) of the compound (52.5g) obtained in referential example 326 was added dropwise over 30 minutes. After stirring at 0 ℃ for 30 minutes, methanol (100ml) was added dropwise to the reaction mixture. The resulting slurry was filtered off with celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 3: 1) to obtain the title compound (29.6 g).

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.32-1.74(16H，m)，1.87(1H，t，J＝10.4Hz)，3.35-3.55(2H，m)，3.71(1H，br.s)，3.79(1H，br.s)，4.36(1H，br.s)，7.34-7.44(6H，m)，7.65-7.72(4H，m).

Reference example 328]Methanesulfonic acid ((1R)^*，3S^*，4S^*) -3- [ (tert-butoxycarbonyl) amino group]-4- { [ tert-butyl (diphenyl) silyl]Oxy } cyclohexyl) methyl ester

The compound (29.5g) obtained in referential example 327 was dissolved in methylene chloride (200ml) and pyridine (20ml), and methanesulfonyl chloride (9.5ml) was added to stir at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue to separate the solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water 2 times and dried over anhydrous sodium sulfate. 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 (29.8 g).

¹H-NMR(CDCl₃)δ：1.08(9H，s)，1.38(9H，s)，1.43-1.61(5H，m)，1.86-1.89(2H，m)，3.02(3H，s)，3.77(1H，br.s)，3.81(1H，br.s)，4.10(2H，d，J＝5.4Hz)，4.32(1H，br.s)，7.35-7.45(6H，m)，7.64-7.68(4H，m).

MS(ESI)m/z：562(M+H)⁺.

[ reference example 329](1R^*，2R^*，5S^*) -2- { [ tert-butyl (diphenyl) silyl]Oxy } -5- (cyanomethyl) cyclohexanecarboxylic acid tert-butyl ester

The compound (29.8g) obtained in referential example 328 was dissolved in N, N-dimethylformamide (400ml), and sodium cyanide (3.64g) was added and stirred at 80 ℃ for 11 hours. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the mixture. The aqueous layer was extracted 2 times with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated 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).

¹H-NMR(CDCl₃)δ：1.08(9H，s)，1.38(9H，s)，1.43-1.68(5H，m)，1.79-1.85(1H，m)，1.88-1.95(1H，m)，2.32(2H，d，J＝7.1Hz)，3.77(1H，br.s)，3.82(1H，br.s)，4.32(1H，br.d，J＝6.8Hz)，7.35-7.45(6H，m)，7.65-7.71(4H，m).

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

The compound (2.00g) obtained in referential example 329 was dissolved in anhydrous dichloromethane (20ml), which was then replaced with argon, followed by cooling to-78 ℃. To this was added dropwise diisobutylaluminum hydride (0.95M hexane solution, 8.55ml), followed by warming to room temperature and stirring for 3 hours. After the reaction mixture was cooled to 0 ℃, methanol (10ml) was added dropwise. The resulting slurry was filtered off with celite, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 1: 0 → 49: 1) to obtain the title compound (1.45 g).

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.38(9H，s)，1.43-1.54(5H，m)，1.82-1.88(1H，m)，2.06(1H，br.s)，2.42-2.43(2H，m)，3.72(1H，br.s)，3.77(1H，br.s)，4.38(1H，br.s)，7.34-7.44(6H，m)，7.65-7.68(4H，m)，9.77(1H，t，J＝1.7Hz).

MS(FAB)m/z：496(M+H)⁺.

[ reference example 331]2-((1R^*，3S^*，4S^*) -3- [ (tert-butoxycarbonyl) amino group]-4- { [ tert-butyl (diphenyl) silyl]Oxy } cyclohexyl) acetic acid

The compound (8.40g) obtained in referential example 330 was dissolved in a mixed solvent of water (33ml) and tert-butanol (120ml), and 2-methyl-2-butene (8.08ml), sodium dihydrogenphosphate dihydrate (2.64g) and sodium chlorite (3.45g) were further added to stir at room temperature for 1.5 hours. Dichloromethane and water were added to the reaction mixture to dilute the mixture, and the aqueous layer was adjusted to pH 4 with 1N aqueous hydrochloric acid. After separation, the aqueous layer was extracted 2 times with dichloromethane. The organic layers were combined, dried over anhydrous magnesium 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 (7.62 g).

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.22-1.63(15H，m)，1.82(1H，br.s)，2.17(1H，br.s)，2.27-2.33(1H，m)，3.69(1H，br.s)，3.84(1H，br.s)，7.00(1H，br.s)，7.33-7.42(6H，m)，7.63-7.65(4H，m).MS(ESI)m/z：512(M+H)⁺.

Reference example 332](1R^*，2R^*，5S^*) -2- { [ tert-butyl (diphenyl) silyl]Oxy } -5- [2- (dimethylamino) -2-oxoethyl]Cyclohexanecarboxylic acid tert-butyl ester

The compound (7.62g) obtained in referential example 331 was dissolved in N, N-dimethylformamide (150ml), and dimethylamine hydrochloride (6.07g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.56g), 1-hydroxybenzotriazole 1 hydrate (1.01g) and triethylamine (10.3ml) were added to stir at room temperature for 4 days. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added to the residue to conduct liquid separation. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1), the solvent was evaporated, hexane was added, and the resulting white precipitate was collected by filtration to obtain the title compound (6.42 g).

¹H-NMR(CDCl₃)δ：1.08(9H，s)，1.38(9H，br.s)，1.43-1.55(5H，m)，1.79-1.86(1H，m)，2.03(1H，br.s)，2.21-2.32(2H，s)，2.94(3H，s)，3.03(3H，s)，3.74(1H，br.s)，3.80(1H，br.s)，4.49(1H，br.s)，7.33-7.44(6H，m)，7.64-7.69(4H，m).

MS(ESI)m/z：539(M+H)⁺.

[ reference example 333](1R^*，2R^*，5S^*) -5- [2- (dimethylamino) -2-oxoethyl]-2-Hydroxycyclohexanecarboxylic acid tert-butyl ester

The compound (6.36g) obtained in referential example 332 was dissolved in tetrahydrofuran (50ml), and tetrabutylammonium fluoride (1N solution in tetrahydrofuran, 17.85ml) was added and stirred at room temperature for 13 hours. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane: methanol ═ 24: 1) to obtain the title compound (3.49 g).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.46-1.60(4H，m)，1.79-1.84(2H，m)，2.28-2.35(3H，s)，2.82(1H，br.s)，2.95(3H，s)，3.01(3H，s)，3.56(2H，br.s)，4.67(1H，br.s).

MS(ESI)m/z：301(M+H)⁺.

Reference example 334]Methanesulfonic acid (1R)^*，2R^*，4S^*) -2- [ (tert-butoxy)Alkylcarbonyl) amino]-4- [2- (dimethylamino) -2-oxoethyl]Cyclohexyl esters

The compound (8.05mg) obtained in referential example 333 was dissolved in methylene chloride (50ml), cooled to-78 ℃ under an argon atmosphere, and methanesulfonyl chloride (2.70ml) was added dropwise. After warming to 0 ℃ and stirring for 30 minutes, the mixture was stirred at room temperature for 2 hours. The reaction mixture was separated by adding water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexane: ethyl acetate ═ 1: 1 → 0: 1) to obtain the title compound (3.63 g).

¹H-NMR(CDCl₃)δ：1.43(9H，s)，1.59-1.74(4H，m)，1.85-2.30(5H，m)，2.95(3H，s)，3.00(3H，s)，3.10(3H，s)，3.79-3.83(1H，m)，4.72(1H，br.s)，4.91(1H，br.s).

MS(ESI)m/z：379(M+H)⁺.

Reference example 335](1R^*，2S^*，5S^*) -2-azido-5- [2- (dimethylamino) -2-oxoethyl]Cyclohexanecarboxylic acid tert-butyl ester

The compound (3.62g) obtained in referential example 334 was dissolved in N, N-dimethylformamide (20ml), and after adding sodium azide (3.11g), the mixture was stirred at 75 ℃ for 17 hours. The reaction solution was poured into a mixture of water and ethyl acetate to separate the solution. The aqueous layer was extracted with ethyl acetate 2 times, and the combined organic layers were washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate) to give the title compound (1.30 g).

¹H-NMR(CDCl₃)δ：1.14-1.21(1H，m)，1.33-1.40(1H，m)，1.45(9H，s)，1.61-1.71(1H，m)，1.78-1.91(3H，m)，2.22-2.27(3H，m)，2.94(3H，s)，3.00(3H，s)，3.60-3.62(1H，m)，3.97(1H，br.s)，4.76(1H，br.s).

MS(ESI)m/z：326(M+H)⁺.

Reference example 336]N-{(1R^*，2S^*，4S^*) -2-amino-4- [2- (dimethylamino) -2-oxoethyl]Cyclohexyl } -5-chloroindole-2-carboxamide hydrochloride

The title compound was obtained by subjecting the compound obtained in referential example 335 to catalytic reduction in the same manner as in referential example 324 and then condensing it with 5-chloroindole-2-carboxylic acid to the same treatment as in referential example 69.

¹H-NMR(DMSO-d₆)δ：1.16-1.19(1H，m)，1.51-1.56(1H，m)，1.70-1.73(1H，m)，1.81-1.91(2H，m)，1.99-2.03(1H，m)，2.19-2.30(3H，m)，2.83(3H，s)，2.99(3H，s)，3.63(1H，br.s)，4.08(1H，br.s)，7.19(1H，dd，J＝8.7，1.7Hz)，7.35(1H，s)，7.44(1H，d，J＝8.7Hz)，7.69(1H，d，J＝1.7Hz)，8.22(3H，br.s)，8.62(1H，d，J＝7.1Hz)，11.91(1H，s).MS(ESI)m/z：377(M+H)⁺.

[ reference example 337] (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- (hydroxymethyl) cyclohexanecarboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 97 by the same method as in 2) of referential example 129.

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

The compound (500mg) obtained in referential example 337 and triethylamine (329ml) were dissolved in tetrahydrofuran (8ml) -dichloromethane (8ml), and cooled at-78 ℃. After methanesulfonyl chloride (138ml) was added dropwise to the solution, the temperature of the solution was gradually raised to-5 ℃ and stirred at the same temperature for 15 hours. After the reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with dichloromethane 3 times. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (654 mg).

¹H-NMR(CDCl₃)δ：1.57(9H，s)，1.84-2.01(4H，m)，2.28-2.31(1H，m)，3.04(3H，s)，3.68(1H，s)，3.74-3.75(1H，m)，3.91-3.93(1H，m)，4.02-4.12(2H，m)，4.18-4.20(1H，m)，4.85(1H，br.s)，6.81(1H，s)，7.21(1H，dd，J＝2.0，8.8Hz)，7.34(1H，d，J＝8.8Hz)，7.60(1H，s)，8.02(1H，br.s)，9.27(1H，br.s).

MS(ESI)m/z：500(M+H)⁺.

[ reference example 339] (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (methylthio) methyl ] cyclohexanecarboxylic acid tert-butyl ester

The compound (654mg) obtained in referential example 338 was dissolved in N, N-dimethylformamide (8ml), and a 15% aqueous solution (1.8ml) of sodium thiomethoxide was added to stir at room temperature for 4 hours. The reaction solution was poured into water, and extracted 3 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 (dichloromethane: methanol 24: 1) to obtain the title compound (492 mg).

¹H-NMR(CDCl₃)δ：1.52(9H，s)，1.87-3.04(13H，m)，3.91-3.94(1H，m)，4.12-4.15(1H，m)，4.95(1H，br.s)，6.81(1H，s)，7.19(1H，dd，J＝8.8，1.2Hz)，7.35(1H，d，J＝8.8Hz)，7.57(1H，s)，9.82(1H，br.s).

MS(ESI)m/z：452(M+H)⁺.

[ reference example 340] (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (methylsulfonyl) methyl ] cyclohexanecarboxylic acid tert-butyl ester

The compound (300mg) obtained in referential example 339 was dissolved in methylene chloride (10ml), and m-chloroperbenzoic acid (70%, 400mg) was added with stirring at 0 ℃. After directly stirring for 1 hour, the reaction solution was poured into water and extracted 3 times with dichloromethane. 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 (dichloromethane: methanol 24: 1), and after separating by saturated aqueous sodium bicarbonate and ethyl acetate, the organic layer was concentrated to obtain the title compound (254 mg).

¹H-NMR(CDCl₃)δ：1.44-2.19(13H，m)，2.22-2.30(2H，m)，2.89-3.25(7H，m)，3.93-4.15(2H，m)，4.98(1H，br.s)，6.82(1H，s)，7.21(1H，dd，J＝8.8，2.0Hz)，7.34(1H，d，J＝8.8Hz)，7.60(1H，br.s)，9.54(1H，br.s).

[ reference example 341] (5-chlorothien-3-yl) methanol

5-chlorothiophene-3-carboxylic acid (Monatsh. chem., 1989, 120, p. 53) (6.93g) was dissolved in tetrahydrofuran (750ml), and triethylamine (27.3ml) and ethyl chloroformate (18.7ml) were added thereto and the mixture was stirred at room temperature for 2 and half hours. Then, an aqueous solution (41ml) of sodium borohydride (19.3g) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 18.5 hours. Acetic acid was added to the reaction mixture to make it acidic, and then the solvent was distilled off under reduced pressure. After the residue was separated by adding water and methylene chloride, the organic layer was washed with water and a saturated aqueous sodium hydrogencarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate: hexane ═ 1: 4) to obtain the title compound (5.17 g).

¹H-NMR(CDCl₃)δ：1.63(1H，t，J＝5.8Hz)，4.59(2H，d，J＝5.3Hz)，6.91(1H，d，J＝1.7Hz)，6.98-6.99(1H，m).

[ reference example 342] 5-chlorothiophene-3-carbaldehyde

The compound (5.17g) obtained in referential example 341 was dissolved in methylene chloride (400 mD), manganese dioxide (51.3g) was further added, and the mixture was stirred at room temperature for 15 hours, and after the reaction solution was filtered, the solvent was distilled off under reduced pressure to obtain the title compound (2.84 g).

¹H-NMR(CDCl₃)δ：7.35(1H，d，J＝1.7Hz)，7.88(1H，d，J＝1.7Hz)，9.75(1H，s).

[ reference example 343] 2-azido-3- (5-chlorothien-3-yl) acrylic acid ethyl ester

Ethanol (15ml) was added to a 20% sodium ethoxide ethanol solution (10.7ml), and after cooling at 0 ℃ a mixture of the compound (1.01g) obtained in referential example 342 and ethyl azidoacetate (3.55g) was added dropwise over 30 minutes, followed by stirring at 0 ℃ for 3 hours. To the reaction solution was added a cold aqueous ammonium chloride solution, and the mixture was extracted with ether 3 times. The organic layers were combined and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: hexane ═ 1: 49) to obtain the title compound (1.04 g).

¹H-NMR(CDCl₃)δ：1.38(3H，t，J＝7.1Hz)，4.34(2H，q，J＝7.1Hz)，6.75(1H，s)，7.39(1H，d，J＝1.7Hz)，7.54(1H，d，J＝1.7Hz).

[ reference example 344] 2-chloro-6H-thieno [2, 3-b ] pyrrole-5-carboxylic acid ethyl ester

The compound (0.97g) obtained in referential example 343 was dissolved in xylene (20ml), and was refluxed for 30 minutes. After cooling, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the resultant solid was collected by filtration to obtain the title compound (0.608 g).

¹H-NMR(CDCl₃)δ：1.38(3H，t，J＝7.0Hz)，4.35(2H，q，J＝7.0Hz)，6.90(1H，s)，7.00(1H，d，J＝1.9Hz)，9.32(1H，br).

[ reference example 345] 2-chloro-6H-thieno [2, 3-b ] pyrrole-5-carboxylic acid

The title compound was obtained from the compound obtained in referential example 344 in the same manner as in referential example 274.

¹H-NMR(CD₃OD)δ：3.35(1H，s)，6.94(1H，s)，6.96(1H，s).

MS(ESI)m/z：200(M-H)^-.

[ reference example 346] 1-chloro-4- (2, 2-dibromovinyl) benzene

4-chlorobenzaldehyde (2.81g) was dissolved in methylene chloride (300ml), and carbon tetrabromide (13.3g) and triphenylphosphine (21.0g) were added to stir at room temperature for 90 minutes. The insoluble matter precipitated was filtered off, 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).

¹H-NMR(CDCl₃)δ：7.33(2H，d，J＝8.5Hz)，7.43(1H，s)，7.47(2H，d，J＝8.5Hz).

MS(EI)m/z：296(M⁺).

[ reference example 347]3- (4-chlorophenyl) -2-propiolic acid

The compound (1.0g) obtained in referential example 346 was dissolved in tetrahydrofuran (30ml), and N-butyllithium (1.59N in hexane, 4.46ml) was added dropwise at-78 ℃ under a stream of argon gas. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was cooled to-78 ℃ again, stirred under a stream of carbon dioxide for 2 minutes, and then warmed to room temperature. After the reaction mixture was concentrated under reduced pressure, saturated brine and ethyl acetate were added to the residue to separate the mixture. 3N hydrochloric acid was added to the aqueous layer to make it acidic, extraction was performed with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (453 mg).

¹H-NMR(DMSO-d₆)δ：7.55(2H，d，J＝8.5Hz)，7.66(2H，d，J＝8.5Hz)，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

Ethyl chlorooxoacetate (2.0ml) was added to a pyridine (15ml) solution of 2-amino-5-chlorobenzamide (2.50g), 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 (50ml), followed by addition of acetic anhydride (5.0ml) and heating under reflux for 16 hours. The solvent was evaporated under reduced pressure, ethanol was added to the residue, and the precipitated crystal was collected by filtration and washed to obtain the title compound (2.71 g).

¹H-NMR(DMSO-d₆)δ：1.35(3H，t，J＝7.1Hz)，4.38(2H，q，J＝7.1Hz)，7.85(1H，d，J＝8.6Hz)，7.91(1H，dd，J＝8.6，2.3Hz)，8.10(1H，d，J＝2.3Hz)，12.85(1H，br.s).

MS(ESI)m/z：253(M+H)⁺.

[ reference example 349] 6-chloro-4-oxo-1, 4-dihydroquinazoline-2-carboxylic acid

To a mixed solution of the compound (1.26g) obtained in referential example 348 in water (5ml) -tetrahydrofuran (15ml) was added lithium hydroxide (263mg), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized with 1N hydrochloric acid (11ml) under ice-cooling, and stirred for 1 hour. The precipitated crystals were collected by filtration and washed with water to obtain the title compound (0.96 g).

¹H-NMR(DMSO-d₆)δ：7.50-8.20(3H，m)，12.44(1H，br.s).

MS(ESI)m/z：265(M+H+CH₃CN)⁺.

[ reference example 350] 2-chloro-N- (4-chlorophenyl) acetamide

P-chloroaniline (3.82g) was dissolved in ethyl acetate (30ml), and chloroacetyl chloride (2.39ml) was added thereto at room temperature, followed by stirring for 1 hour. The reaction mixture was stirred at 60 ℃ for 3.5 hours, and then the precipitated crystals were collected by filtration to obtain the title compound (4.78 g). Then, the filtrate was concentrated to about 1/4, and the precipitated crystals were collected by filtration to obtain the title compound (1.01 g).

¹H-NMR(CDCl₃)δ：4.19(2H，s)，7.33(2H，d，J＝9.0Hz)，7.51(2H，d，J＝9.0Hz)，8.22(1H，br.s).

[ reference example 351] S- [2- (4-Chloroanilino) -2-oxoethyl ] thiosulfuric acid sodium salt

The compound (5.79g) obtained in referential example 350 was dissolved in ethanol (140ml), and an aqueous solution (140ml) of sodium thiosulfate 5 hydrate (7.04g) was added in one portion with stirring at 70 ℃ and heated under reflux for 1.5 hours. The reaction mixture was concentrated to about 1/10, and the precipitated powder was collected by filtration to obtain the title compound (8.20 g).

¹H-NMR(DMSO-d₆)δ：3.73(2H，s)，7.35(2H，d，J＝8.8Hz)，7.57(2H，d，J＝8.8Hz)，10.30(1H，s).

[ reference example 352] 2-chloro-N- (5-chloropyridin-2-yl) acetamide hydrochloride

2-amino-5-chloropyridine (3.85g) was dissolved in ethyl acetate (60ml), and chloroacetyl chloride (2.39ml) was added thereto at room temperature and stirred for 1 hour. After the reaction mixture was heated and stirred at 60 ℃ for 30 minutes, chloroacetyl chloride (0.5ml) was added thereto, and the mixture was further stirred at 60 ℃ for 1 hour. The precipitated powder was collected by filtration to obtain the title compound (6.18 g).

¹H-NMR(DMSO-d₆)δ：4.36(2H，s)，7.94(1H，dd，J＝8.8，2.7Hz)，8.09(1H，d，J＝8.8Hz)，8.40(1H，d，J＝2.7Hz)，11.03(1H，s).

[ reference example 353] S- {2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoethyl } thiosulfuric acid sodium salt

To a solution of the compound (6.18g) obtained in referential example 352 in ethanol (130ml) was added, while stirring at 80 ℃ an aqueous solution (130ml) in which sodium thiosulfate 5 hydrate (6.35g) and sodium hydrogencarbonate (2.15g) were dissolved, at once, and the mixture was heated under reflux at an external temperature of 110 ℃ for 2 hours. Concentrating under reduced pressure to dry, adding ethanol (500ml) into the residue, heating, and extracting for 2 times. The extract was concentrated to about 1/20, diethyl ether was added, and insoluble matter precipitated was collected by filtration to obtain the title compound (6.65 g).

¹H-NMR(DMSO-d₆)δ：3.77(2H，s)，7.89(1H，dd，J＝9.0，2.7Hz)，8.09(1H，d，J＝9.0Hz)，8.34(1H，d，J＝2.7Hz)，10.57(1H，s).

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

The compound (100mg) obtained in referential example 253 was dissolved in ethyl acetate (10ml), and chloroacetyl chloride (21.6. mu.l) was added, followed by heating and stirring at 60 ℃ for 30 minutes. After cooling, insoluble matter was filtered off, and dissolved in methylene chloride-methanol, and the solvent was distilled off under reduced pressure to obtain the crude title compound (112 mg).

¹H-NMR(DMSO-d₆)δ：1.35-1.50(1H，m)，1.55-2.00(5H，m)，2.78(3H，s)，2.98(3H，s)，3.00-3.25(5H，m)，3.17(3H，s)，3.80-3.90(1H，m)，3.96(1H，d，J＝12.9Hz)，4.00-4.15(1H，m)，4.02(1H，d，J＝12.9Hz)，4.45-4，70(2H，m)，7.85-8.00(1H，br)，8.12(1H，d，J＝7.3Hz)，8.35(1H，d，J＝8.3Hz).

MS(ESI)m/z：442(M+H)⁺.

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

The compound (106mg) obtained in referential example 354 was dissolved in ethanol (1.5ml), and an aqueous solution (1.5ml) in which sodium thiosulfate 5 hydrate (55mg) and sodium hydrogencarbonate (18.6mg) were dissolved were added in one portion at 90 ℃ with stirring and heated under reflux for 1 hour. Concentrated to a dry solid under reduced pressure, and ethanol (10ml) was added to the residue to conduct extraction with heating. The extract was concentrated to about 1/2, isopropyl ether (10ml) was added, and insoluble matter deposited was collected by filtration to obtain the title compound (72 mg).

¹H-NMR(DMSO-d₆)δ：1.35-1.50(1H，m)，1.55-1.90(5H，m)，2.40(3H，s)，2.78(3H，s)，2.80-3.10(5H，m)，2.96(3H，s)，3.44(1H，d，J＝14.2Hz)，3.50(1H，d，J＝14.2Hz)，3.68(2H，s)，3.75-3.90(1H，m)，4.45-4.50(1H，m)，8.01(1H，d，J＝7.4Hz)，8.15(1H，d，J＝8.3Hz).

[ reference example 356] methyl 2- [ (5-chlorothien-2-yl) amino ] -2-oxoacetate

Triethylamine (1.25ml) and diphenylphosphoryl azide (1.55ml) were added to a suspension of 5-chlorothiophene-2-carboxylic acid (0.99g) in toluene (20ml), and the mixture was stirred at 80 ℃ for 1 hour. After the reaction mixture was cooled to room temperature, t-butanol (2ml) was added thereto, and the mixture was refluxed for 19 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (200ml) was added to the resulting residue, which was washed with distilled water, a 10% citric acid aqueous solution, distilled water, a saturated sodium bicarbonate aqueous solution, and a saturated brine in this order, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give tert-butyl 5-chloro-2-thienylcarbamate (1.05 g).

¹H-NMR(CDCl₃)δ：1.51(9H，s)，6.21(1H，d，J＝3.1Hz)，6.60(1H，d，J＝3.1Hz)，6.91(1H，br.s).

MS(ESI)m/z：234(M+H)⁺.

The product (1.87g) was added to a 4N dioxane hydrochloride solution (40ml), stirred at room temperature for 4 hours, and then the solvent was distilled off under reduced pressure. The residue was suspended in tetrahydrofuran (50ml), and sodium hydrogencarbonate (2.02g) and methyl chlorooxoacetate (0.883ml) were added under ice cooling to stir at room temperature for 18 hours. The solvent was evaporated under reduced pressure, water and dichloromethane were added to the residue to separate the solution, and 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: ethyl acetate 3: 1), and the solvent was evaporated to obtain the title compound (1.44 g).

¹H-NMR(CDCl₃)δ：3.98(3H，s)，6.61(1H，d，J＝4.2Hz)，6.75(1H，d，J＝4.2Hz)，9.42(1H，br.s).

MS(FAB)m/z：220(M+H)⁺.

[ reference example 357] methyl 2- [ (5-Fluoropyridin-2-yl) amino ] -2-oxoacetate

The title compound was obtained from 2-amino-5-fluoropyridine and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：3.99(3H，s)，7.48-7.53(1H，m)，8.21(1H，d，J＝2.9Hz)，8.27-8.31(1H，m)，9.41(1H，br.s).

MS(FAB)m/z：198(M+H)⁺.

[ reference example 358] methyl 2- [ 4-chloro-2- (trifluoromethyl) anilino ] -2-oxoacetate

The title compound was obtained from 4-chloro-2-trifluoroaniline and methyl chlorooxoacetate by the same method as that described in referential example 242.

¹H-NMR(CDCl₃)δ：4.01(3H，s)，7.58(1H，dd，J＝8.8，2.2Hz)，7.65(1H，d，J＝2.2Hz)，8.34(1H，d，J＝8.8Hz)，9.30(1H，br.s).

MS(EI)m/z：281(M+H)⁺.

[ reference example 359]2- [ 4-chloro-2- (trifluoromethyl) anilino ] -2-oxoacetic acid

Lithium hydroxide (28mg) was added to a mixed solution of the compound (297mg) obtained in referential example 358 in tetrahydrofuran (7ml) and water (3ml), and the mixture was stirred at room temperature for 2 hours. 1N hydrochloric acid (8ml) and methylene chloride (20ml) were added to the reaction solvent to conduct a liquid separation operation. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated and dried under reduced pressure to obtain the title compound (291 mg).

¹H-NMR(CDCl₃)δ：7.61(1H，dd，J＝8.8，2.5Hz)，7.68(1H，d，J＝2.5Hz)，8.26(1H，d，J＝8.8Hz)，9.36(1H，br.s).

MS (ESI, anionic) m/z: 267(M-H)^-.

[ reference example 360] 5-chloro-N, N-dimethyl-2-nitrobenzamide

The title compound was obtained by condensation of 5-chloro-2-nitrobenzoic acid and dimethylamine in the same manner as in referential example 143.

¹H-NMR(CDCl₃)δ：2.86(3H，s)，3.16(3H，s)，7.38(1H，d，J＝2.2Hz)，7.51(1H，dd，J＝8.8，2.2Hz)，8.15(1H，d，J＝8.8Hz).

[ reference example 361] 2-amino-5-chloro-N, N-dimethylbenzamide

To a mixed solution of the compound (2.8g) obtained in referential example 360 in N, N-dimethylformamide (80ml) -water (40ml) were added ferric trichloride 6 hydrate (9.93g) and zinc powder (8.01g), and the mixture was refluxed for 20 minutes. The reaction solution was filtered through celite 545, and ethyl acetate (200ml) was added to the filtrate to conduct a liquid separation operation. The aqueous layer was washed with ethyl acetate (100 ml. times.2), and the combined organic layers were washed with distilled water (100ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: hexane ═ 1: 1 → 1: 0 → methanol: dichloromethane ═ 1: 100) to obtain the title compound (2.41 g).

¹H-NMR(CDCl₃)δ：3.13(6H，s)，4.33(2H，br)，6.65(1H，d，J＝8.5Hz)，7.07(1H，d，J＝2.2Hz)，7.11(1H，dd，J＝8.5，2.2Hz).

MS(ESI)m/z：240(M+MeCN)⁺.

[ reference example 362] methyl 2- { 4-chloro-2- [ (dimethylamino) carbonyl ] anilino } -2-oxoacetate

The title compound was obtained from the compound obtained in referential example 361 and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：3.09(6H，br)，3.96(3H，s)，7.30(1H，d，J＝2.4Hz)，7.41(1H，d，J＝8.8，2.4Hz)，8.34(1H，d，J＝8.8Hz)，10.46(1H，br).

MS(ESI)m/z：285(M+H)⁺.

[ reference example 363] 4-chloro-2-methoxyaniline

The title compound was obtained from 5-chloro-2-nitrobenzyl ether in the same manner as in referential example 361.

¹H-NMR(CDCl₃)δ：3.65-3.95(2H，br)，3.87(3H，s)，6.61(1H，d，J＝8.8Hz)，6.74-6.78(2H，m).

MS(ESI)m/z：199(M+MeCN+H)⁺.

[ reference example 364] methyl 2- (4-chloro-2-methoxyanilino) -2-oxoacetate

The title compound was obtained from the compound obtained in referential example 363 and methyl chlorooxoacetate in the same manner as referential example 242.

¹H-NMR(CDCl₃)δ：3.92(3H，s)，3.97(3H，s)，6.90(1H，d，J＝2.2Hz)，6.98(1H，dd，J＝8.8，2.2Hz)，8.35(1H，d，J＝8.8Hz)，9.33-9.44(1H，br).

MS(ESI)m/z：244(M+H)⁺.

[ reference example 365] Ethyl 2- (4-chloroanilino) -2- (hydroxyimino) acetate

The title compound was prepared from 4-chloroaniline (3.03g) and ethyl 2-chloro-2-hydroxyiminoacetate using the same method as described in literature (Cilchrist, t.l.; Peek, m.e.; Rees, c.w.; j.chem.soc.chem.commun., 1975, 913.).

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.1Hz)，1.60-1.80(1H，br)，4.28(2H，q，J＝7.1Hz)，6.85(2H，d，J＝8.6Hz)，7.24(2H，d，J＝8.6Hz)，8.15-8.45(1H，br).

MS(ESDm/z：243(M+H)⁺.

[ reference example 366] (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) -2- (hydroxyimino) acetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

To a solution of the compound (350mg) obtained in referential example 365 in ethanol (5.0ml) was added the compound (597mg) obtained in referential example 144, and the mixture was stirred at 70 ℃ for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol: 30: 1) to obtain the title compound (180 mg).

¹H-NMR(CD₃OD)δ：1.46(9H，s)，1.47-1.84(6H，m)，1.88-1.95(1H，m)，2.90(3H，s)，3.08(3H，s)，3.90-3.97(1H，m)，4.11-4.17(1H，m)，6.84(2H，d，J＝8.8Hz)，7.18(2H，d，J＝8.8Hz).

MS(ESI)m/z：504(M+Na)⁺.

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

The title compound was obtained from the compound obtained in referential example 374 and the compound obtained in referential example 220 in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.55-1.75(1H，br)，1.94-2.07(1H，br)，2.70-3.00(1H，m)，3.10-3.37(1H，m)，3.44(3H，s)，3.88-4.22(4H，m)，4.55-4.69(1H，br)，4.80-4.90(0.5H，br)，5.36-5.48(0.5H，br)，7.20-7.30(1H，br)，7.32(2H，d，J＝8.8Hz)，7.62(2H，d，J＝8.8Hz)，8.20-8.40(1H，br)，9.15-9.25(1H，br).

MS(ESI)m/z：469(M+H)⁺.

[ reference example 368] (3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 266 and the compound obtained in referential example 220 in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.65-2.30(2H，br)，2.68-3.02(1H，m)，3.10-3.35(1H，m)，3.44(3H，s)，3.80-4.25(4H，m)，4.45-4.70(1H，m)，5.05-5.20(0.5H，m)，5.80-5.93(0.5H，m)，7.30-7.40(1H，br)，7.71(1H，brd，J＝8.7Hz)，7.95-8.05(0.3H，br)，8.19(1H，br d，J＝8.8Hz)，8.31(1H，br.s)，8.38-8.53(0.7H，br)，9.74-9.84(1H，br).

MS(ESI)m/z：470(M+H)⁺.

[ reference example 369] (3R, 4S) -4- ({2- [ (5-Bromopyridin-2-yl) amino ] -2-oxoacetyl } amino) -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 375 and the compound obtained in referential example 220 in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.50-1.75(1H，m)，1.95-2.13(1H，br)，2.70-2.98(1H，m)，3.05-3.36(1H，m)，3.45(3H，s)，3.80-4.24(4H，m)，4.57-4.73(1H，br)，4.85-4.95(0.25H，br)，5.10-5.15(0.25H，br)，5.45-5.58(0.5H，br)，7.30-7.38(1H，m)，7.84(1H，dd，J＝8.8，2.2Hz)，8.16(1H，d，J＝8.8Hz)，8.30-8.55(1H，br)，8.40(1H，d，J＝2.2Hz)，9.68(1H，br.s).

[ reference example 370] Ethyl 3- (4-chloroanilino) -3-oxopropanoate

Ethyl malonate potassium salt (3.2g), 1-hydroxybenzotriazole (2.1g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.5g) were added successively to a solution of 4-chloroaniline (2.0g) in N, N-dimethylformamide (20ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, a 10% aqueous citric acid solution and a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (4.0 g).

¹H-NMR(CDCl₃)δ：1.33(3H，t，J＝7.3Hz)，3.47(2H，s)，4.26(2H，q，J＝7.3Hz)，7.29(2H，d，J＝8.8Hz)，7.51(2H，d，J＝8.8Hz)，9.32(1H，br.s).

[ reference example 371]3- (4-Chloroanilino) -3-oxopropanoic acid

To a solution of the compound (1.0g) obtained in referential example 370 in ethanol (10ml) was added dropwise a 1N aqueous solution (10ml) of sodium hydroxide at room temperature, and the mixture was stirred for 2 hours. 1N aqueous hydrochloric acid (10ml) was added to the reaction mixture, and after stirring, the insoluble matter deposited was filtered to obtain the title compound (0.5 g).

¹H-NMR(DMSO-d₆)δ：3.34(2H，s)，7.35(2H，d，J＝8.8Hz)，7.59(2H，d，J＝8.8Hz)，10.26(1H，s)，12.66(1H，br.s).

[ reference example 372] ethyl 3- (3-chloroanilino) -3-oxopropanoate

The title compound was obtained by condensation of 3-chloroaniline and potassium ethyl malonate in the same manner as in referential example 370.

¹H-NMR(CDCl₃)δ：1.33(3H，t，J＝7.3Hz)，3.47(2H，s)，4.26(2H，q，J＝7.3Hz)，7.09(1H，d，J＝8.8Hz)，7.22-7.26(1H，m)，7.39(1H，d，J＝8.8Hz)，7.69(1H，s)，9.35(1H，br.s).

[ reference example 373]3- (3-Chloroanilino) -3-oxopropanoic acid

The title compound was obtained from the compound obtained in referential example 372 in the same manner as in referential example 371.

¹H-NMR(DMSO-d₆)δ：3.35(2H，s)，7.11(1H，d，J＝8.8Hz)，7.33(1H，t，J＝8.8Hz)，7.39(1H，d，J＝8.8Hz)，7.78(1H，s)，10.31(1H，s)，12.67(1H，br.s).

[ reference example 374]2- (4-Chloroanilino) -2-oxoacetic acid

The title compound was obtained from the compound obtained in referential example 242 in the same manner as referential example 359.

¹H-NMR(DMSO-d₆)δ：7.37(2H，d，J＝8.8Hz)，7.79(2H，d，J＝8.8Hz)，10.66(1H，s).

[ reference example 375]2- [ (5-Bromopyridin-2-yl) amino ] -2-oxoacetic acid

The title compound was obtained from the compound obtained in referential example 262 by the same method as referential example 359.

¹H-NMR(DMSO-d₆)δ：7.95-8.00(1H，m)，8.08(1H，dd，J＝8.8，2.0Hz)，8.50(1H，d，J＝2.0Hz)，10.74(1H，s).

[ reference example 376] 4-chloro-3-fluorobenzoic acid

Sodium chlorite (17g) was added in small amounts to a mixed solution of 4-chloro-3-fluorobenzaldehyde (10g), sulfamic acid (18g), tert-butanol (50ml) and water (50ml) under ice cooling, and the mixture was stirred for 4 days while slowly raising the temperature 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 evaporated under reduced pressure, and the resulting residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g).

¹H-NMR(DMSO-d₆)δ：7.72(1H，dt，J＝8.3，1.5Hz)，7.77(1H，dt，J＝8.3，1.6Hz)，7.82(1H，dt，J＝9.7，1.5Hz)，13.45(1H，s).

[ reference example 377] methyl 2- (4-chloro-3-fluoroanilino) -2-oxoacetate

The title compound was obtained by condensation of the compound obtained in referential example 376 with methyl chlorooxoacetate after undergoing a coulter rearrangement reaction in the same manner as in referential example 356.

¹H-NMR(CDCl₃)δ：3.99(3H，s)，7.25-7.27(1H，m)，7.39(1H，t，J＝8.5Hz)，7.72(1H，dd，J＝10.4，2.4Hz)，8.90(1H，br.s).

[ reference example 378]2- (4-chloro-3-fluoroanilino) -2-oxoacetic acid

The title compound was obtained from the compound obtained in referential example 377 by the same method as referential example 359.

¹H-NMR(DMSO-d₆)δ：7.52(1H，t，J＝8.8Hz)，7.63(1H，dd，J＝8.8，2.2Hz)，7.88(1H，dd，J＝12.0，2.2Hz)，10.83(1H，br.s).

[ reference example 379] ethyl 3- (4-chlorophenyl) -3-oxopropanoate

Triethylamine (17ml) and magnesium chloride (5.5g) were added to a suspension of potassium ethyl malonate (8.2g) in ethyl acetate (100ml) under ice cooling, and the mixture was stirred for 18 hours while slowly warming to room temperature. Separately, a suspension of 4-chlorobenzoic acid (5.0g), thionyl chloride (12ml), N-dimethylformamide (1 drop) and toluene (100ml) was refluxed for 1 hour, and then the reaction solution was concentrated. The obtained residue was dissolved in ethyl acetate, and added dropwise to the above reaction solution under ice cooling, and stirred for 18 hours while slowly raising the temperature to room temperature. After a 10% citric acid aqueous solution was added to the reaction mixture and stirred for 30 minutes, the organic layer was separated, washed with 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 (chloroform), and purified to obtain the title compound (6.4 g).

¹H-NMR(CDCl₃)δ：1.26(3H，t，J＝7.3Hz)，3.96(2H，s)，4.21(2H，q，J＝7.3Hz)，7.46(2H，d，J＝8.8Hz)，7.89(2H，d，J＝8.8Hz).

[ reference example 380] ethyl 3- (4-chlorophenyl) -3-hydroxypropionate

Sodium borohydride (0.2g) was added to a tetrahydrofuran (10ml) solution of the compound (1.0g) obtained in referential example 379 in small amounts each under ice cooling, and the mixture was stirred for 2 hours while slowly warming to room temperature. A10% citric acid aqueous solution was added to the reaction mixture, followed by extraction 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).

¹H-NMR(CDCl₃)δ：1.27(3H，t，J＝7.3Hz)，2.70(1H，d，J＝7.8Hz)，2.71(1H，d，J＝3.4Hz)，3.37(1H，d，J＝3.4Hz)，4.18(2H，q，J＝7.3Hz)，5.09-5.13(1H，m)，7.30-7.35(5H，m).

[ reference example 381]3- (4-chlorophenyl) -3-hydroxypropionic acid

The title compound was obtained from the compound obtained in referential example 380 in the same manner as referential example 359.

¹H-NMR(DMSO-d₆)δ：3.25-3.32(1H，m)，4.89-4.95(1H，m)，5.45-5.53(1H，m)，7.35-7.36(5H，m)，12.11-12.18(1H，m).

MS (ESI, anionic) m/z: 198(M-H)^-.

[ reference example 382] (1R, 2S, 5S) -2- { [3- (4-chlorophenyl) -3-hydroxypropionyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by condensation of the compound obtained in referential example 144 and the compound obtained in referential example 381 in the same manner as in referential example 91.

¹H-NMR(CDCl₃)δ：1.21-1.44(2H，m)，1.46(9H，s)，1.76-1.92(2H，m)，1.95-2.10(2H，m)，2.40-2.55(2H，m)，2.55-2.68(1H，m)，2.94(3H，s)，3.05(3H，s)，3.82-3.96(1H，m)，4.02-4.17(1H，m)，4.65-4.80(2H，m)，5.03-5.13(1H，m)，7.28-7.33(5H，m).

MS(ESI)m/z：468(M+H)⁺.

[ reference example 383] (1R, 2S, 5S) -2- { [3- (4-chlorophenyl) -3-oxopropanoyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

Manganese dioxide (0.47g) was added to a solution of the compound (0.5g) obtained in referential example 382 in 1, 4-dioxane (20ml) at room temperature, and the mixture was stirred for 4 days. Insoluble matter was filtered off through a Celite pad, and the obtained filtrate was concentrated under reduced pressure to obtain the title compound (0.46 g).

¹H-NMR(DMSO-d₆)δ：1.28-1.39(1H，m)，1.40(9H，s)，1.41-1.63(3H，m)，2.25-2.42(2H，m)，2.76(3H，s)，2.90-2.97(1H，m)，2.98(3H，s)，3.56(2H，s)，3.89-3.97(1H，m)，4.88-4.98(1H，m)，6.65-6.70(1H，m)，7.30-7.35(4H，m)，7.33(1H，dd，J＝2.9，1.7Hz).

MS (ESI, anionic) m/z: 464(M-H)^-.

[ reference example 384] (1R, 3R, 4R) -4-azido-3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid ethyl ester

The title compound was obtained from the compound obtained in referential example 248 by the same method as referential example 249.

[α]²⁵ _D+62 ° (c ═ 1, chloroform)

¹H-NMR(CDCl₃)δ：1.27(3H，t，J＝7.1Hz)，1.46(9H，s)，1.61(1H，s)，1.61-1.71(2H，m)，1.81-1.90(1H，m)，1.97-2.03(1H，m)，2.22-2.28(1H，m)，2.56-2.60(1H，m)，3.54(1H，br.s)，3.63-3.68(1H，m)，4.16(2H，q，J＝7.1Hz)，4.58(1H，br.s)，

[ reference example 385] (1R, 2R, 5S) -2-azido-5- [ (dimethylamino) carbonyl ] cyclohexanecarboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 384 in the same manner as in referential example 250 and referential example 251.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.40-2.20(6H，m)，2.70-2.80(1H，m)，2.93(3H，s)，3.03(3H，s)，3.60-3.78(1H，m)，3.83-3.95(1H，m)，4.65(1H，d，J＝7.2Hz).

[ reference example 386] (1R, 2R, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) -2-oxoacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was prepared by converting the azide group of the compound obtained in referential example 385 into an amino group in the same manner as in referential example 90 and then condensing the compound obtained in referential example 266 in the same manner as in referential example 91.

¹H-NMR(CDCl₃)δ：1.13-2.25(16H，m)，2.94(3H，s)，3.03(3H，s)，3.60-3.78(1H，m)，4.13-4.31(1H，m)，4.45-4.65(1H，m)，7.80(1H，dd，J＝8.8，2.4Hz)，8.03(1H，br.s)，8.21(1H，d，J＝8.8Hz)，8.29(1H，d，J＝2.4Hz)，9.71(1H，s).

MS(ESI)m/z：468(M+H)⁺.

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

The title compound was obtained from the compound obtained in referential example 385 and the compound obtained in referential example 10 in the same manner as in referential example 252.

¹H-NMR(CDCl₃)δ：1.75-2.08(6H，m)，2.20-2.32(1H，m)，2.51(3H，s)，2.75-2.97(4H，m)，2.95(3H，s)，3.04(3H，s)，3.65-3.80(3H，m)，4.27-4.39(1H，m)，7.17-7.28(1H，m).

MS(ESI)m/z：392(M+H)⁺.

[ reference example 388] tert-butyl 4- [ (2-methoxy-2-oxoacetyl) amino ] piperidine-1-carboxylate

The title compound was obtained from (4-amino-N-tert-butoxycarbonyl) piperidine and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(DMSO-d₆)δ：1.46(9H，s)，1.34-1.51(2H，m)，1.89-1.98(2H，m)，2.82-2.96(2H，m)，3.91(3H，s)，3.88-4.14(3H，m)，6.96-7.07(1H，m).

MS(FAB)m/z：287(M+H)⁺.

[ reference example 389] tert-butyl 4- { [2- ({ (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } amino) -2-oxoacetyl ] amino } piperidine-1-carboxylate

The title compound was obtained from the compound obtained in referential example 310 and the compound obtained in referential example 388 by the same method as referential example 191.

¹H-NMR(DMSO-d₆)δ：1.46(9H，s)，1.35-2.28(11H，m)，2.70-3.18(9H，m)，3.80-4.57(4H，m)，6.78(1H，s)，7.15-8.12(6H，m)，9.45(1H，s).

MS(FAB)m/z：617(M+H)⁺.

[ reference example 390] methyl 2- [ (5-chloropyridin-2-yl) (methyl) amino ] -2-oxoacetate

The title compound was obtained from 5-chloro-N-methyl-2-pyridylamine and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：3.43(3H，s)，3.81(3H，s)，7.08(1H，br.s)，7.68-7.78(1H，m)，8.27(1H、br.s).

MS(ESI)m/z：229(M+H)⁺.

[ reference example 391] methyl 2- [ (5-chloro-pyrimidin-2-yl) amino ] -2-oxoacetate

The title compound was obtained from 2-amino-5-chloropyrimidine and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：4.00(3H，s)，8.63(2H，s)，9.58(1H，br.s).

MS(ESI)m/z：215(M+H)⁺.

[ reference example 392] N- ((1R, 2S, 5S) -2-azido-5- { [ ethyl (methyl) amino ] carbonyl } cyclohexyl) -5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole-2-carboxamide

The title compound was obtained from the compound obtained in referential example 323 and the compound obtained in referential example 293 in the same manner as in referential example 252.

¹H-NMR(CDCl₃) δ: 1.08, 1.15(3H, 7.1Hz for each t, J), 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, s), 3.28-3.43(2H, m), 3.91-4.10(5H, m), 4.60-4.62(1H, m), 7.21(1H, d, J), 7.6Hz).

MS(ESI)m/z：392(M+H)⁺.

[ reference example 393] methyl 2- (4-chloro-3-methoxyanilino) -2-oxoacetate

The title compound was obtained by reducing 2-chloro-5-nitrobenzyl ether to give an amino group in the same manner as in referential example 361 and then condensing the amino group with methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：3.93(3H，s)，3.98(3H，s)，7.00(1H，dd，J＝8.5，2.4Hz)，7.33(1H，d，J＝8.5Hz)，7.57(1H，d，J＝2.4Hz)，8.89(1H，br.s).

[ reference example 394]2- (4-chloro-3-methoxyanilino) -2-oxoacetic acid

The title compound was obtained by hydrolyzing the compound obtained in referential example 393 in the same manner as in referential example 359.

¹H-NMR(DMSO-d₆)δ：3.81(3H，s)，7.36(1H，d，J＝8.7Hz)，7.43(1H，d，J＝8.7Hz)，7.65(1H，d，J＝2.2Hz)，10.79(1H，s).

MS (ESI, anionic) m/z: 288(M-H)^-.

Reference example 395]N¹- { (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (4-chloro-3-methoxyphenyl) ethanediamide

The title compound was obtained by condensing the compound obtained in referential example 144 with the compound obtained in referential example 394 in the same manner as in referential example 97, then treating with hydrochloric acid and neutralizing with a 1N aqueous solution of sodium hydroxide in the same manner as in referential example 69.

¹H-NMR(CDCl₃)δ：1.48-2.00(8H，m)，2.84-2.93(1H，m)，2.95(3H，s)，3.08(3H，s)，3.33-3.35(1H，m)，3.89-3.94(4H，m)，7.06(1H，dd，J＝8.5，2.2Hz)，7.32(1H，d，J＝8.5Hz)，7.56(1H，d，J＝2.2Hz)，8.05(1H，d，J＝8.5Hz)，9.43(1H，br.s).

MS(ESI)m/z：397(M⁺).

[ reference example 396] methyl 2- (4-ethynylanilino) -2-oxoacetate

The title compound was obtained from 4-ethynylaniline and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：3.09(1H，s)，3.98(3H，s)，7.50(2H，d，J＝8.4Hz)，7.62(2H，d，J＝8.4Hz)，8.89(1H，br.s).

[ reference example 397]2- (4-ethynylanilino) -2-oxoacetic acid sodium salt

The title compound was obtained by hydrolyzing the compound obtained in referential example 396 with sodium hydroxide in the same manner as in referential example 266.

¹H-NMR(DMSO-d₆)δ：4.06(1H，s)，7.39(2H，d，J＝8.4Hz)，7.80(2H，d，J＝8.4Hz)，10.33(1H，br.s).

[ reference example 398] methyl 2- [ (5-chloropyrazin-2-yl) amino ] -2-oxoacetate

The title compound was prepared from 2-amino-5-chloropyrazine synthesized according to the literature (Sato, Nobuhiro et al, J.heterocyclic. chem.1982, 19(3), 673-4) and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：4.02(3H，s)，8.35(1H，d，J＝1.5Hz)，9.37(1H，d，J＝1.5Hz)，9.41(1H，br.s).

MS(FAB)m/z：216(M+H)⁺.

[ reference example 399]2- [ (5-chloropyrazin-2-yl) amino ] -3-oxoacetic acid

The title compound was obtained from the compound obtained in referential example 398 by the same method as referential example 359.

¹H-NMR(DMSO-d₆)δ：8.62(1H，s)，9.02(1H，br.s)，11.30(1H，s).

MS(EI)m/z：201M⁺.

[ reference example 400]2- (4-chloro-3-nitroanilino) -2-oxoacetic acid

The title compound was obtained by condensing 4-chloro-3-nitroaniline and methyl chlorooxoacetate in the same manner as in referential example 242 and then hydrolyzing in the same manner as in referential example 359.

¹H-NMR(DMSO-d₆) δ: 7.76(1H, dd, J ═ 8.8Hz), 8.04(1H, dd, J ═ 8.8, 2.4Hz), 8.55(1H, d, J ═ 2.4Hz), 11.24(1H, s).

MS(EI)m/z：244M⁺.

[ reference example 401]2- (4-chloro-2-nitroanilino) -2-oxoacetic acid sodium salt

The title compound was obtained by condensing 4-chloro-2-nitroaniline and methyl chlorooxoacetate in the same manner as in referential example 242, hydrolyzing the resultant in the same manner as in referential example 266, dissolving the residue in methanol, adding a 1N aqueous solution of sodium hydroxide, and filtering the resulting precipitate.

¹H-NMR(DMSO-d₆)δ：7.84(1H，dd，J＝9.0，2.5Hz)，8.20(1H，d，J＝2.5Hz)，8.67(1H，d，J＝9.0Hz)，11.89(1H，s).

[ reference example 402] 6-chloro-4-methyl-3-pyridineamine

2-chloro-4-methyl-5-nitropyridine (173mg) was dissolved in ethanol (5ml), and a catalytic amount of raney nickel was added thereto, followed by stirring at room temperature for 9 hours under a hydrogen atmosphere. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 3: 2) to obtain the title compound (113 mg).

¹H-NMR(CDCl₃)δ：2.13(3H，s)，3.85(2H，br.s)，6.96(1H，s)，7.74(1H，s).

MS(EI)m/z：142M⁺.

Reference example 403]N¹- (2-aminophenyl) -N²- (4-chlorophenyl) ethanediamide

The title compound was obtained by condensation of 1, 2-phenylenediamine and the compound obtained in referential example 374 in the same manner as in referential example 59.

¹H-NMR(DMSO-d₆)δ：5.00(2H，s)，6.59-6.63(1H，m)，6.78(1H，dd，J＝8.1，1.2Hz)，6.96-7.01(1H，m)，7.25(1H，dd，J＝7.8，1.2Hz)，7.44(2H，d，J＝8.8Hz)，7.91(2H，d，J＝8.8Hz)，10.04(1H，s)，10.91(1H，s).

MS(FAB)：290(M+H)⁺.

[ reference example 404] N- ((1R, 2S, 5S) -2-azido-5- { [ ethyl (methyl) amino ] carbonyl } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

The title compound was obtained by treating the compound obtained in referential example 323 with hydrochloric acid in the same manner as in referential example 252, deprotecting, and then condensing with the compound obtained in referential example 10.

¹H-NMR(CDCl₃)δ：1.08(1/2 of 3H，t，J＝7.2Hz)，1.14(1/2 of 3H，t，J＝7.2Hz)，1.70-1.90(4H，m)，2.10-2.25(2H，m)，2.52(3H，s)，2.78-3.00(8H，m)，3.25-3.45(2H，m)，3.69(1H，d，J＝13.4Hz)，3.73(1H，d，J＝13.4Hz)，3.87-3.95(1H，m)，4.55-4.62(1H，m)，7.26(1H，d，J＝7.6Hz).

[ reference example 405] phenyl 2- (4-chlorophenyl) -1-hydrazinocarboxylate

(4-chlorophenyl) hydrazine hydrochloride (3.00g) was dissolved in tetrahydrofuran (50ml), diethyl ether (50ml) and a saturated aqueous sodium hydrogen carbonate solution, and after separating an organic layer, it was dried over anhydrous sodium sulfate and concentrated to obtain (4-chlorophenyl) hydrazine as a brown solid. After dissolving it in benzene (15ml), it was refluxed, and a benzene (8.0ml) solution of diphenyl carbonate (5.22g) was added dropwise thereto over 30 minutes. After refluxing for 19 hours, it was naturally cooled to room temperature, concentrated, and then benzene (15ml) was added, and it was suspended by ultrasonic wave, hexane (50ml) was added, and after stirring for 30 minutes, insoluble matter was filtered off and dried to obtain the title compound (1.05 g).

¹H-NMR(CDCl₃)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＝7.7Hz).

MS(ESI)m/z：263(M+H)⁺.

[ reference example 406] lithium 5-tert-butoxycarbonyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole-2-carboxylate

The title compound was obtained from the compound obtained in referential example 33 in the same manner as in referential example 10.

¹H-NMR(DMSO-d₆)δ：1.46(9H，s)，4.30-4.70(4H，m).

[ reference example 407] benzyl 1-Hydroxycyclopropanecarboxylate

Triethylamine (1.0ml) and benzyl bromide (650. mu.l) were added to a tetrahydrofuran (3.0ml) solution of 1-hydroxycyclopropanecarboxylic acid (409mg), and the mixture was stirred at room temperature for 23 hours. Methylene chloride and a 1N hydrochloric acid aqueous solution were added to the reaction mixture, and the mixture was divided into 2 layers. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a 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).

¹H-NMR(CDCl₃)δ：1.16(2H，dd，J＝7.9，4.9Hz)，1.32(2H，dd，J＝7.9，4.9Hz)，3.09(0.5H，s)，3.11(0.5H，s)，5.17(2H，s)，7.30-7.39(5H，m).

MS(FAB)m/z：192(M+H)⁺.

[ reference example 408] benzyl 1-Methoxycyclopropanecarboxylate

To a tetrahydrofuran (5.0ml) solution of the compound (600mg) obtained in referential example 407 were added 60% oily sodium hydride (345mg) and methyl iodide (900. mu.l), and the mixture was refluxed for 28 hours. Ethyl acetate and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was divided into 2 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).

¹H-NMR(CDCl₃)δ：1.16(2H，dd，J＝7.9，4.8Hz)，1.31(2H，dd，J＝7.9，4.8Hz)，3.42(3H，s)，5.18(2H，s)，7.30-7.39(5H，m).

MS(FAB)m/z：207(M+H)⁺.

[ reference example 409] 1-Methoxycyclopropanecarboxylic acid

The title compound was obtained from the compound obtained in referential example 408 in the same manner as in referential example 152.

¹H-NMR(CDCl₃)δ：1.23(2H，dd，J＝8.0，4.9Hz)，1.38(2H，dd，J＝8.0，4.9Hz)，3.45(3H，s)，8.80-9.00(1H，br).

[ reference example 410] (3R, 4S) -4- { [ (7-chloroisoquinolin-3-yl) carbonyl ] amino } -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 220 and the compound obtained in referential example 57 in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.46(9H，br s)，1.62-1.80(1H，m)，2.04-2.22(1H，m)，2.95-3.32(1H，m)，3.38-3.53(1H，m)，3.46(3H，s)，3.84-3.95(1H，m)，4.02-4.27(3H，m)，4.30-4.65(2H，m)，4.87-4.98(0.5H，br)，5.32-5.43(0.5H，br)，7.71(1H，dd，J＝8.8，2.0Hz)，7.94(1H，d，J＝8.8Hz)，8.02(1H，s)，8.55-8.66(0.7H，br)，8.58(1H，s)，8.73-8.85(0.3H，br)，9.14(1H，br s).

MS(ESI)m/z：477(M+H)⁺.

[ reference example 411] (3R, 4S) -4- { [2- (4-chloro-3-fluoroanilino) -2-oxoacetyl ] amino } -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained by condensation of the compound obtained in referential example 220 and the compound obtained in referential example 377 in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.60-1.75(1H，m)，1.92-2.08(1H，m)，2.68-2.80(0.5H，m)，2.88-3.03(0.5H，m)，3.06-3.24(0.5H，m)，3.27-3.36(0.5H，m)，3.45(3H，s)，3.90-4.22(5H，m)，4.56-4.71(1H，m)，4.80-4.92(0.3H，br)，5.44-5.54(0.7H，br)，7.24(1H，d，J＝12.9Hz)，7.35(1H，t，J＝8.3Hz)，7.72(1H，dd，J＝8.3，2.3Hz)，8.20-8.

42(1H，br)，9.18-9.28(1H，br).

MS(ESI)m/z：487(M+H)⁺.

[ reference example 412] (3R, 4S) -4- ({2- [ (5-chloro-2-thienyl) amino ] -2-oxoacetyl } amino) -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained by hydrolyzing the lithium salt of the obtained carboxylic acid from the compound obtained in referential example 220 and the compound obtained in referential example 356 in the same manner as in referential example 214.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.55-1.75(1H，br)，1.90-2.10(1H，br)，2.68-2.80(0.7H，m)，2.90-3.03(0.3H，br)，3.07-3.22(0.3H，br)，3.25-3.35(0.7H，br)，3.45(3H，s)，3.83-4.22(5H，m)，4.55-4.70(1H，br)，4.80-4.90(0.2H，br)，5.07-5.14(0.2H，br)，5.44-5.55(0.6H，br)，6.58-6.64(1H，br)，6.73(1H，d，J＝3.9Hz)，8.05-8.27(1H，br)，9.65-9.88(1H，br).

MS(FAB)m/z：475(M+H)⁺.

[ reference example 413] 5-methyl-5H-pyrrolo [3, 4-d ] thiazolo-2-carboxylic acid ethyl ester

1) Ethyl 2-thioacetate (26.75g) was added to a solution of 3-bromo-2-butanone (26.36g) in ethanol (250ml), and the mixture was refluxed for 14 hours. The reaction mixture was cooled, concentrated under reduced pressure, and ethyl acetate and saturated brine were added to the residue to separate the mixture into 2 layers. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and 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: 6: 1) to give ethyl 4, 5-dimethylthiazole-2-carboxylate (19.53 g).

¹H-NMR(CDCl₃)δ：1.42(3H，t，J＝7.1Hz)，2.42(3H，s)，2.44(3H，s)，4.45(2H，q，J＝7.1Hz).

2) To a solution of the above product (19.53g) in 1, 2-dichloroethane (500ml) were added N-bromosuccinimide (62.42g) and 2, 2' -azobisisobutyronitrile (227mg), and the mixture was refluxed for 42 hours. After the reaction solution was cooled, water and methylene chloride were added to separate the reaction solution into 2 layers, and the organic layer was washed with saturated brine and then concentrated under reduced pressure to obtain a crude product (40.54g) as a dark brown oil. Triethylamine (8.0ml) and a 2-molar methylamine tetrahydrofuran solution (11.0ml) were added to an acetonitrile solution (400ml) of the resulting crude product (8.41g) at 0 ℃ and stirred at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, methylene chloride and saturated brine were added to the residue to separate the mixture into 2 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).

¹H-NMR(CDCl₃)δ：1.45(3H，t，J＝7.1Hz)，3.91(3H，s)，4.48(2H，q，J＝7.1Hz)，6.73(1H，d，J＝1.7Hz)，7.30(1H，d，J＝1.7Hz).

MS(ESI)m/z：211(M+H)⁺.

[ reference example 414] 6-chloro-4-oxo-4H-chromene-2-carboxylic acid ethyl ester

Oily about 60% sodium hydride (1.68g) was added to ethanol (10ml) under argon gas replacement, and the mixture was stirred at room temperature for 10 minutes. After diethyl oxalate (3.36ml) was added, an ethanol solution (20ml) of 5 '-chloro-2' -hydroxyacetophenone (2.82g) was added dropwise thereto, and ethanol (40ml) was added thereto, and the mixture was refluxed for 1 hour and then stirred at 50 ℃ for 14 hours. Concentrated sulfuric acid (1.5ml) and ethanol (10ml) 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 a 1N aqueous solution (15ml) of sodium hydroxide were added to the concentrate. The mixture was extracted 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), and the resulting solid was washed with hexane to obtain the title compound (1.20 g).

¹H-NMR(CDCl₃)δ：1.44(3H，t，J＝7.1Hz)，4.47(2H，q，J＝7.1Hz)，7.12(1H，s)，7.58(1H，d，J＝9.0Hz)，7.69(1H，dd，J＝9.0，2.7Hz)，8.16(1H，d，J＝2.7Hz).

MS(ESI)m/z：293(M+MeCN+H)⁺.

[ reference example 415] 6-chloro-4-oxo-4H-chromene-2-carboxylic acid

The title compound was obtained from the compound obtained in referential example 414 in the same manner as referential example 359.

¹H-NMR(CDCl₃)δ：7.12(1H，s)，7.60(1H，d，J＝8.8Hz)，7.69(1H，dd，J＝8.8，2.7Hz)，8.15(1H，d，J＝2.7Hz).

MS(FAB)m/z：225(M+H)⁺.

[ reference example 416] (1S, 3R, 4S) -4-amino-3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid ethyl ester

The title compound was obtained from the compound obtained in referential example 249 in the same manner as in referential example 90.

¹H-NMR(CDCl₃)δ：1.20-1.80(4H，m)，1.25(3H，t，J＝7.3Hz)，1.46(9H，s)，1.85-2.00(1H，m)，2.10-2.20(1H，m)，2.30-2.45(1H，m)，2.90-3.00(1H，m)，3.84(1H，br s)，4.12(2H，q，J＝7.3Hz)，4.75(1H，br s).

[ reference example 417] (1R, 2S, 5S) -2- { [ (6-chloro-4-oxo-4H-chromen-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

To a solution of the compound (213mg) obtained in referential example 415 in thionyl chloride (2.0ml) was added N, N-dimethylformamide (0.02ml), and the mixture was refluxed for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4.0ml), to which triethylamine (500. mu.l) and the compound (294mg) obtained in referential example 144 were added, followed by stirring at room temperature for 15 minutes. Ethyl acetate and a 10% citric acid aqueous solution were added to the reaction mixture, and the mixture was separated into 2 layers. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 30: 1) to obtain the title compound (230 mg).

¹H-NMR(CDCl₃)δ：1.33-1.77(3H，m)，1.50(9H，s)，1.81-2.34(3H，m)，2.63-2.80(1H，m)，2.95(3H，s)，3.10(3H，s)，3.90-4.04(1H，br)，4.18-4.31(1H，br)，4.93-5.12(1H，br)，7.13(1H，s)，7.55(1H，d，J＝8.8Hz)，7.66(1H，dd，J＝8.8，2.4Hz)，8.14(1H，d，J＝2.4Hz)，8.77-8.92(1H，br).

MS(ESI)m/z：492(M+H)⁺.

[ reference example 418] (3R, 4S) -4- { [ (7-chlorocinnolin-3-yl) carbonyl ] amino } -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 220 and the lithium salt of the carboxylic acid obtained by hydrolysis of the ester described in referential example 297 by the same procedure as referential example 214.

¹H-NMR(CDCl₃)δ：1.38(9H，s)，1.65-1.90(1H，m)，1.90-2.15(1H，m)，2.80-3.00(0.6H，m)，3.00-3.15(0.4H，m)，3.20-3.50(1H，m)，3.46(3H，s)，3.80-4.70(6H，m)，4.87(0.4H，br s)，5.30(0.6H，br s)，7.78(1H，d，J＝8.8Hz)，7.97(1H，d，J＝8.8Hz)，8.61(1H，s)，8.62-8.90(1H，br)，8.73(1H，s).

MS(ESI)m/z：478(M+H)⁺.

[ reference example 419] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by condensing the compound obtained in referential example 144 with the compound obtained in referential example 266 in the same manner as referential example 68.

¹H-NMR(CDCl₃)δ：1.35-1.65(1H，m)，1.45(9H，s)，1.65-1.89(2H，m)，1.90-2.10(3H，m)，2.56-2.74(1H，br)，2.95(3H，s)，3.06(3H，s)，3.94-4.01(1H，m)，4.18-4.27(1H，m)，4.70-4.90(0.7H，br)，5.80-6.20(0.3H，br)，7.68(1H，dd，J＝8.9，2.6Hz)，7.83(1H，brs)，8.14(1H，br d，J＝7.8Hz)，8.30(1H，s)，9.72(1H，s).

MS(ESI)m/z：468(M+H)⁺.

Reference example 420]N¹- { (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide hydrochloride

The title compound was obtained from the compound obtained in referential example 419 by the same method as referential example 69.

¹H-NMR(DMSO-d₆)δ：1.38-1.51(1H，m)，1.65-1.85(3H，m)，1.96-2.10(2H，m)，2.81(3H，s)，3.07(3H，s)，3.23-3.33(1H，m)，3.74(1H，br s)，3.84-3.92(1H，m)，8.02(1H，dd，J＝9.0，2.5Hz)，8.07(1H，d，J＝9.0Hz)，8.34(3H，br s)，8.46(1H，d，J＝2.5Hz)，8.96(1H，d，J＝6.6Hz)，10.34(1H，s).

MS(ESI)m/z：368(M+H)⁺.

[ reference example 421]2- [ ({ (1R, 2S, 5S) -2- ({2- [ (5-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 title compound was obtained by condensing the compound obtained in referential example 420 with 5- (tert-butoxycarbonyl) -4, 5, 6, 7-tetrahydrothiazolo [3, 2-c ] pyridine-2-carboxylic acid (WO 94/21599).

¹H-NMR(CDCl₃)δ：1.50(9H，s)，1.73-1.95(3H，m)，1.95-2.06(1H，m)，2.08-2.20(2H，m)，2.82(3H，br s)，2.94(3H，s)，3.03(3H，s)，3.60-3.80(2H，m)，3.96-4.08(1H，m)，4.44(2H，br s)，4.66(1H，br s)，6.74(1H，br s)，7.20-7.32(1H，m)，7.66(1H，dd，J＝9.0，2.4Hz)，8.13(1H，d，J＝9.0Hz)，8.13-8.25(1H，m)，8.28(1H，d，J＝2.4Hz)，9.75(1H，s).

MS(ESI)m/z：633(M+H)⁺.

[ reference example 422] 2-chloro-N- (4-fluorophenyl) acetamide

The title compound was obtained from p-fluoroaniline by the same method as in reference example 350.

¹H-NMR(CDCl₃)δ：4.19(2H，s)，7.05(2H，t，J＝8.6Hz)，7.51(2H，dd，J＝9.1，4.7Hz)，8.19(1H，br s).

[ reference example 423] S- [2- (4-Fluoroanilino) -2-oxoethyl ] thiosulfuric acid sodium salt

The title compound was obtained from the compound obtained in referential example 422 by the same method as referential example 351.

¹H-NMR(DMSO-d₆)δ：3.72(2H，s)，7.14(2H，t，J＝9.0Hz)，7.56(2H，dd，J＝9.0，5.1Hz)，10.21(1H，s).

[ reference example 424] (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- { [2- (4-fluoroanilino) -2-oxothioacetyl ] amino } cyclohexylcarbamic acid tert-butyl ester

The compound (1.1g) obtained in referential example 144 and the compound (1.24g) obtained in referential example 423 were dissolved in N-methylmorpholine (20ml), and the bath temperature was raised from room temperature to 140 ℃ over 15 minutes, followed by stirring with heating at the same temperature for 15 minutes. After cooling naturally, ice water was added to the reaction solution, and the insoluble matter was collected by filtration. The obtained insoluble matter was purified by silica gel column chromatography (dichloromethane: methanol ═ 200: 1 → 197: 3) to obtain the title compound (1.43 g).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.70-2.10(5H，m)，2.10-2.30(1H，m)，2.60-2.80(1H，m)，2.96(3H，s)，3.07(3H，s)，4.30-4.50(2H，m)，4.65-4.85(1H，m)，7.06(2H，t，J＝8.5Hz)，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 by the same method as in referential example 352.

¹H-NMR(DMSO-d₆)δ：4.35(2H，s)，7.74-7.82(1H，m)，8.10(1H，dd，J＝9.0，4.2Hz)，8.36(1H，d，J＝2.9Hz)，(1H，br s).

MS(ESI)m/z：188(M+H)⁺.

[ reference example 426] S- {2- [ (5-Fluoropyridin-2-yl) amino ] -2-oxoacetyl } thiosulfuric acid sodium salt

The title compound was obtained from the compound obtained in referential example 425 in the same manner as in referential example 353.

¹H-NMR(DMSO-d₆)δ：3.75(2H，s)，7.67-7.77(1H，m)，8.07(1H，dd，J＝9.2，4.2Hz)，8.28(1H，d，J＝2.9Hz)，10.48(1H，s).

[ reference example 427] (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexylcarbamic acid tert-butyl ester

A pyridine (70ml) solution of the compound (1.20g) obtained in referential example 144 was heated at 120 ℃ and the compound (2.42g) obtained in referential example 426 was added thereto, followed by stirring for 30 minutes, cooling to room temperature naturally and evaporating the solvent under reduced pressure. To the resulting residue were added dichloromethane (100ml), saturated aqueous sodium bicarbonate (100ml) and water (50ml) to separate the mixture, and then the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane: tetrahydrofuran 1: 1), and the obtained solid was slurried with isopropyl ether (40ml) for 1 hour, filtered off, and dried to obtain the title compound (920 mg).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.70-2.10(5H，m)，2.27(1H，br s)，2.70(1H，br s)，2.96(3H，s)，3.08(3H，s)，4.34-4.44(2H，m)，4.77(1H，br s)，7.44-7.51(1H，m)，8.18-8.27(2H，m)，9.90(1H，br s)，10.57(1H，s).

MS(ESI)m/z：468(M+H)⁺.

[ reference example 428] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 353 in the same manner as in referential example 427.

¹H-NMR(CDCl₃)δ：1.43(9H，s)，1.65-2.35(6H，m)，2.70(1H，br s)，2.95(3H，s)，3.09(3H，s)，4.30-4.60(2H，m)，4.87(1/2H，br s)，6.92(1/2H，br s)，7.69(1H，dd，J＝8.9，2.6Hz)，7.95-8.20(1H，br)，8.29(1H，s)，9.67(1/2H，br s)，9.93(1/2H，br s)，10.54(1H，br s).

[ reference example 429] 2-chloro-4, 5, 6, 7-tetrahydrobenzothiazol-6-ylcarboxamide

Ammonium acetate (18.58g) and sodium cyanoborohydride (10.68g) were added to a methanol (200ml) solution of 2-chloro-5-oxo-4, 5, 6, 7-tetrahydrobenzo [ d ] thiazole (Helv. Cim. acta., 1994, volume 77, page 1256) (4.53g), and the mixture was refluxed. After 19 hours, hydrochloric acid was added to decompose the excess reagent, the reaction solution was concentrated under reduced pressure, made alkaline with a 1N aqueous solution of sodium hydroxide, and then separated with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane: methanol 20: 1), and the solvent was distilled off to obtain a pale yellow oil (2.42 g). The oily substance was dissolved in methylene chloride (100ml), and formic acid (530. mu.l), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.68g), 1-hydroxybenzotriazole (2.60g) and N-methylmorpholine (3.88g) were added thereto and the mixture was stirred at room temperature. After 20 hours, dichloromethane and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the mixture. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20: 1) to obtain the title compound (2.21 g).

¹H-NMR(CDCl₃)δ：1.93-2.11(2H，m)，2.63-2.69(1H，m)，2.83-2.89(2H，m)，3.

13(1H，dd，J＝16.2，4.4Hz)，4.46-4.48(1H，m)，5.76(1H，br s)，8.17(1H，s).

[ reference example 430] tert-butyl N- (2-chloro-4, 5, 6, 7-tetrahydrobenzothiazol-6-yl) -N-methylcarbamate

To a tetrahydrofuran (50ml) solution of the compound (2.11g) obtained in referential example 429 was added a 1M borane-tetrahydrofuran complex tetrahydrofuran solution (14.6ml), and the mixture was refluxed. After 15 hours, a 1M tetrahydrofuran solution (6.0ml) of borane-tetrahydrofuran complex was added thereto, and the mixture was refluxed. After 4 hours, ethanol (10ml) and 1N hydrochloric acid (15ml) were added thereto and the mixture was refluxed. After 3 hours, the reaction mixture was concentrated under reduced pressure, a 1N aqueous solution of sodium hydroxide and methylene chloride were added, the organic layer after liquid separation was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in methylene chloride (50ml), and triethylamine (1.28g) and di-tert-butyl dicarbonate (2.21g) were added to stir at room temperature. After 30 minutes, dichloromethane and 1N hydrochloric acid were added to separate the solution, and the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to obtain the title compound (2.26 g).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.96-1.98(2H，m)，2.80-2.96(7H，m)，4.40-4.50(1H，m).

MS(FAB)m/z：303(M+H)⁺.

[ reference example 431] tert-butyl 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-methylcarbamate

To a solution of the compound (1.0g) obtained in referential example 430 in diethyl ether (10ml) -tetrahydrofuran (5ml) was added a 1.6N pentane solution of t-butyllithium (3.1ml) cooled to-78 ℃, and after stirring for 20 minutes, carbon dioxide gas was introduced over 20 minutes. After the reaction mixture was warmed to room temperature, it was concentrated under reduced pressure to obtain 6- [ (tert-butoxycarbonyl) (methyl) amino ] -4, 5, 6, 7-tetrahydrobenzothiazole-2-carboxylic acid lithium salt.

To a solution of the compound (490.5mg) obtained in referential example 420 in N, N-dimethylformamide (20ml) were added the lithium salt of a carboxylic acid (350.2mg) obtained in the above-mentioned reaction, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (287.6mg), 1-hydroxybenzotriazole (202.7mg) and N-methylmorpholine (0.319ml), and the mixture was stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, water and dichloromethane were added to the residue to separate the organic layer, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order. After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure, and the product was purified by silica gel column chromatography (dichloromethane: methanol ═ 40: 1 → 20: 1) to obtain the title compound (323.9 mg).

¹H-NMR(CDCl₃) δ: 1.48, 1.49 (all 9H, each s), 1.60-1.92(4H, m), 1.95-2.20(6H, m), 2.78-3.10(3H, m), 2.83(3H, s), 2.95(3H, s), 3.06, 3.07 (all 3H, each s), 4.05-4.15(1H, m), 4.20-4.60 (1H，m)，4.63-4.73(1H，m)，7.39(1H，d，J＝8.6Hz)，7.68(1H，dt，J＝8.8，2.6Hz)，7.95-8.10(1H，m)，8.13-8.22(1H，m)，8.30-8.35(1H，m)，9.72(1H，brs).

MS(ESI)m/z：662(M+H)⁺.

[ reference example 432] N- { (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl ] cyclohexyl } -5-chloroindole-2-carboxamide hydrochloride

The title compound was obtained by deprotecting the compound obtained in referential example 310 in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：1.43-1.56(0.5H，m)，1.72-1.97(4.5H，m)，2.82(3H，s)，3.06(3H，s)，3.11-3.26(1H，m)，3.75-3.84(1H，m)，4.07-4.14(1H，m)，4.22-4.41(1H，m)，7.19(1H，dd，J＝2.0，8.8Hz)，7.29(1H，d，J＝2.0Hz)，7.45(1H，d，J＝8.8Hz)，7.72(1H，s)，8.07(3H，br)，8.47(1H，m)，11.85(1H，br).

[ reference example 433] lithium 2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetate

Methyl chlorooxoacetate (78.7ml) was added dropwise to a suspension of 2-amino-5-chloropyridine (100g) and sodium hydrogencarbonate (78.4g) in tetrahydrofuran (2000ml) at 0 ℃ and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a mixture of diethyl ether (2000ml), ammonium chloride (62.4g) and water (1000ml) with stirring, followed by liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure and dried to obtain methyl 2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetate (162 g). To this ester (160g) in tetrahydrofuran (1800ml) were added water (450ml) and lithium hydroxide (18.2 g). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and hexane (3000ml) was added to the resulting residue and stirred for 3 hours. The solid was collected by filtration, and after drying, acetonitrile (1000ml) was added to the resulting solid (190g), and after stirring for 1 hour, the resultant solid was collected by filtration, washed with diethyl ether (500ml) and dried to obtain the title compound (158 g).

¹H-NMR(DMSO-d₆)δ：7.92(1H，dd，J＝9.1，2.7Hz)，8.13(1H，dd，J＝9.1，0.5Hz)，8.36(1H，dd，J＝2.7，0.5Hz)，10.19(1H，s).

[ reference example 434] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 433 by the same method as referential example 91.

¹H-NMR(CDCl₃)δ：1.25-1.55(1H，m)，1.45(9H，s)，1.60-2.15(5H，m)，2.56-2.74(1H，br)，2.95(3H，s)，3.06(3H，s)，3.90-4.01(1H，m)，4.18-4.27(1H，m)，4.70-4.85(0.7H，br)，5.70-6.00(0.3H，br)，7.70(1H，dd，J＝8.8，2.4Hz)，7.75-8.00(1H，br)，8.16(1H，br d，J＝8.8Hz)，8.30(1H，d，J＝2.4Hz)，9.73(1H，s).

MS(ESI)m/z：468(M+H)⁺.

[ reference example 435]N¹- { (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide hydrochloride

The title compound was obtained from the compound obtained in referential example 434 by the same method as referential example 69.

¹H-NMR(DMSO-d₆)δ：1.38-1.51(1H，m)，1.65-1.85(3H，m)，1.92-2.09(2H，m)，2.80(3H，s)，3.06(3H，s)，3.20-3.32(1H，m)，3.55-4.40(2H，br)，8.02(1H，dd，J＝9.1，2.5Hz)，8.07(1H，d，J＝9.1Hz)，8.15-8.40(3H，br)，8.45(1H，d，J＝2.5Hz)，8.96(1H，d，J＝6.6Hz)，10.33(1H，s).

[ reference example 436] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- [ (methylamino) carbonyl ] cyclohexylcarbamic acid benzyl ester

The title compound was obtained from the compound obtained in referential example 142 and methylamine hydrochloride by the same method as referential example 143.

¹H-NMR(DMSO-d₆)δ：1.39(9H，s)，1.40-1.61(4H，m)，1.63-1.73(1H，m)，1.75-1.85(1H，m)，2.23-2.48(1H，m)，2.53(3H，d，J＝4.6Hz)，3.48(1H，br.s)，3.80-3.91(1H，m)，5.01(1H，1/2ABq，J＝12.1Hz)，5.03(1H，1/2ABq，J＝12.1Hz)，6.28-6.40(1H，m)，6.82-6.98(1H，m)，7.25-7.40(5H，m)，7.50-7.60(1H，m).

MS(FAB)m/z：406(M+H)⁺.

[ reference example 437] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- [ (methylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 436 in the same manner as in referential example 144 and then condensing the amine thus obtained with the compound obtained in referential example 433 in the same manner as in referential example 91.

¹H-NMR(DMSO-d₆)δ：1.35-1.75(3H，m)，1.39(9H，s)，1.75-1.86(2H，m)，1.87-1.95(1H，m)，2.30-2.40(1H，m)，2.55(3H，d，J＝4.6Hz)，3.79-3.90(2H，m)，6.73-6.90(1H，m)，7.58-7.70(1H，m)，8.00-8.13(2H，m)，8.46(1H，dd，J＝2.2，1.0Hz)，8.67(1H，d，J＝7.6Hz)，10.26(1H，s).

MS (ESI:: anion) m/z: 452[ (M-H)^-，C^l35]，454[(M-H)^-，C^l37]

[ reference example 438] 2-chloro-N- (5-methylpyridin-2-yl) acetamide hydrochloride

The title compound was obtained from 2-amino-5-methylpyridine by the same method as in referential example 425.

¹H-NMR(DMSO-d₆)δ：2.30(3H，s)，4.40(2H，s)，7.83(1H，d，J＝8.8Hz)，7.91(1H，d，J＝8.5Hz)，8.21(1H，s)，11.40(1H，s).

[ reference example 439] S- {2- [ (5-methylpyridin-2-yl) amino ] -2-oxoethyl } thiosulfuric acid sodium salt

The title compound was obtained from the compound obtained in referential example 438 by the same method as in referential example 353.

¹H-NMR(DMSO-d₆)δ：2.24(3H，s)，3.74(2H，s)，7.59(1H，d，J＝8.5Hz)，7.94(1H，d，J＝8.3Hz)，8.12(1H，s)，10.26(1H，s).

[ reference example 440] (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-methylpyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 144 and the compound obtained in referential example 439 by the same method as in referential example 427.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.60-2.10(5H，m)，2.15-2.35(1H，m)，2.31(3H，s)，2.60-2.80(1H，m)，2.95(3H，s)，3.07(3H，s)，4.30-4.45(2H，m)，4.65-4.85(1H，m)，7.54(1H，dd，J＝8.5，2.0Hz)，8.06(1H，br.d)，8.18(1H，s)，9.70-9.90(1H，m)，10.48(1H，s).

MS(ESI)m/z：464(M+H)⁺.

[ reference example 441] (3R, 4S) -4- { [2- (4-Chloroanilino) -2-oxothioacetyl ] amino } -1- (2-methoxyacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 220 by catalytic reduction in the same manner as referential example 214 and then condensing the obtained amine with the compound obtained in referential example 351 in the same manner as referential example 427.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.59-1.84(1H，m)，2.10-2.33(1H，m)，2.68-2.81(0.7H，m)，2.94-2.04(0.3H，m)，3.15-3.40(1H，m)，3.44(3H，s)，3.91-4.32(4H，m)，4.45-4.58(1H，m)，4.60-4.77(1H，m)，5.15-5.30(0.3H，br)，5.84-5.94(0.7H，m)，7.32(2H，d，J＝8.6Hz)，7.61(2H，d，J＝8.6Hz)，10.12(1H，s)，10.19-10.33(1H，br).

MS(FAB)m/z：485[(M+H)⁺，C^l35]，487[(M+H)⁺，C^l37].

[ reference example 442] (1R, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- [ (dimethylamino) carbonyl ] cyclohexanecarboxylic acid 9H-fluoren-9-ylmethyl ester

The compound (856mg) obtained in referential example 144 was dissolved in acetone (10ml), and 9-fluorenylmethyl pentafluorophenylcarbamate (1.34g) and sodium hydrogencarbonate (302mg) were added to stir at room temperature for 2.5 hours. Then, 9-fluorenylmethyl pentafluorophenyl carbamate (609mg) and sodium hydrogencarbonate (151mg) were added thereto, and the mixture was refluxed for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (SI-40B, dichloromethane: methanol 93: 7) using silica gel as a carrier to obtain the title compound (1.47 g).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.30-2.05(6H，m)，2.63(1H，br.s)，2.94(3H，s)，3.04(3H，s)，3.69(1H，br.s)，4.15(1H，br.s)，4.21(1H，br.s)，4.37(2H，br.s)，4.73(1H，br.s)，5.41(1H，br.s)，7.29(2H，t，J＝7.3Hz)，7.39(2H，t，J＝7.3Hz)，7.57(2H，d，J＝7.3Hz)，7.75(2H，d，J＝7.3Hz).

MS(ESI)m/z：508(M+H)⁺.

[ reference example 443] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- [ (dimethylamino) thiocarbonyl ] cyclohexylcarbamic acid 9H-fluoren-9-ylmethyl ester

The compound (1.26g) obtained in referential example 442 was dissolved in toluene (50ml), and ロ - ソン reagent (1.00g) was added to stir at 60 ℃ for 1 hour. Insoluble matter was filtered off, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (50ml), and di-tert-butyl dicarbonate (541mg) and sodium hydrogencarbonate (208mg) were added. After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography using silica gel as a carrier (hexane: ethyl acetate ═ 1: 1 → dichloromethane: methanol ═ 9: 1). The title compound (609mg) was obtained as a white solid.

¹H-NMR(CDCl₃)δ：1.43(9H，s)，1.43-2.10(6H，m)，2.92(1H，br.s)，3.31(3H，s)，3.47(3H，s)，3.74(1H，br.s)，4.09-4.19(2H，m)，4.38(2H，br.s)，4.75(1H，br)，5.29(1H，br.s)，7.29(2H，t，J＝7.3Hz)，7.38(2H，t，J＝7.3Hz)，7.55(2H，br.s)，7.75(2H，d，J＝7.3Hz).

[ reference example 444] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- [ (dimethylamino) thiocarbonyl ] cyclohexylcarbamic acid tert-butyl ester

The compound (1.11g) obtained in referential example 443 was dissolved in N, N-dimethylformamide (30ml), and piperazine (3.0ml) was added and stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue to separate the solution. The aqueous layer was extracted 2 times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (629mg) was obtained by condensing the residue with the compound obtained in referential example 433 in the same manner as in referential example 91.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.48-2.23(6H，m)，2.98(1H，br.s)，3.36(3H，s)，3.49(3H，s)，3.98-4.04(1H，m)，4.22-4.25(1H，m)，4.75(1H，br.s)，7.70(1H，dd，J＝8.8，2.7Hz)，7.85(1H，br.s)，8.16(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.7Hz)，9.73(1H，s).

MS(FAB)m/z：484[(M+H)⁺，C^l35]，486[(M+H)⁺，C^l37].

[ reference example 445]N¹- { (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) thiocarbonyl]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide dihydrochloride

The title compound was obtained from the compound obtained in referential example 444 in the same manner as in referential example 69.

¹H-NMR(DMSO-d₆)δ：1.66-2.11(6H，m)，3.38(3H，s)，3.42(3H，s)，3.52(1H，br.s)，3.75(1H，br.s)，3.88(1H，br.s)，8.03-8.09(2H，m)，8.21(3H，br.s)，8.48(1H，d，J＝2.2Hz)，9.06(1H，d，J＝6.8Hz)，10.34(1H，s).

MS(FAB)m/z：384[(M+H)⁺，C^l35]，386[(M+H)⁺，C^l37].

[ reference example 446] (3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -1- (2-methoxyacetyl) piperidin-4-ylcarbamic acid 9H-fluoren-9-ylmethyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 220 by catalytic reduction in the same manner as referential example 214 and then treating the amine thus obtained in the same manner as referential example 442.

¹H-NMR(CDCl₃)δ：1.48(9H，s)，1.55-1.80(1H，m)，1.92-2.20(1H，m)，2.70-3.35(2H，m)，3.44(3H，s)，3.77-4.90(10H，m)，5.29-5.45(0.6H，br)，5.75-5.90(0.4H，br)，7.26-7.34(2H，m)，7.39(2H，t，J＝7.6Hz)，7.55-7.65(2H，m)，7.76(2H，d，J＝7.6Hz).

MS(FAB)m/z：510(M+H)⁺.

[ reference example 447] (3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -1- (2-methoxythioacetyl) piperidin-4-ylcarbamic acid 9H-fluoren-9-ylmethyl ester

The title compound was obtained from the compound obtained in referential example 446 in the same manner as in referential example 443.

¹H-NMR(CDCl₃)δ：1.48(9H，s)，1.50-1.80(1H，m)，2.07-2.23(1H，m)，3.04-3.18(0.5H，m)，3.25-3.37(0.5H，m)，3.44(1.5H，s)，3.47(1.5H，s)，3.88-4.75(9H，m)，5.00-5.70(2H，br)，5.98-6.23(1H，br)，7.26-7.29(2H，m)，7.39(2H，t，J＝7.3Hz)，7.55-7.68(2H，m)，7.77(2H，d，J＝7.3Hz).

MS(FAB)m/z：526(M+H)⁺.

[ reference example 448] (3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -1- (2-methoxythioacetyl) piperidin-3-ylcarbamic acid tert-butyl ester

The title compound was obtained by treating the compound obtained in referential example 447 with diethylamine to deprotect it and then condensing it with the compound obtained in referential example 433 in the same manner as in referential example 444.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.73-1.88(1H，m)，2.07-2.22(1H，m)，3.05-3.15(1H，m)，3.27-3.42(1H，m)，3.45(1H，s)，3.48(2H，s)，4.10-4.54(5H，m)，5.12-5.21(0.3H，br)，5.48-5.56(0.7H，br)，5.61-5.74(1H，br)，7.70(1H，dd，J＝8.5，2.0Hz)，8.21(1H，d，J＝8.5Hz)，8.31(1H，d，J＝2.0Hz)，8.42-8.60(1H，br)，9.72(1H，br.s).

MS(ESI)m/z：486[(M+H)⁺，C^l35]，488[(M+H)⁺，C^l37].

[ 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 (10.0g) obtained in referential example 141 in tetrahydrofuran (40ml) and ethanol (40ml) was added 10% palladium on carbon catalyst (10.2g), and the mixture was stirred at room temperature for 63 hours under a hydrogen atmosphere. After the catalyst was filtered through celite, the filtrate was concentrated under reduced pressure. The resulting colorless oil was dissolved in tetrahydrofuran (25ml), pyridine (2.3ml) was added thereto at room temperature, and allyl chloroformate (2.70ml) was added dropwise thereto at 0 ℃ and stirred for 20 minutes. Ice and ethyl acetate were added to the reaction mixture, and after stirring for 5 minutes, a 10% citric acid aqueous solution was added to make the mixture acidic. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate 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 (dichloromethane: methanol 40: 1) to obtain the title compound (6.03 g).

¹H-NMR(CDCl₃)δ：1.25(3H，t，J＝7.1Hz)，1.31-1.40(1H，m)，1.45(9H，s)，1.51-1.65(1H，m)，1.72-1.86(1H，m)，1.89-2.10(3H，m)，2.25-2.50(1H，br)，3.63-3.72(1H，m)，4.03-4.15(1H，br)，4.13(2H，q，J＝7.1Hz)，4.49-4.59(2H，m)，4.60-4.75(1H，m)，5.20(1H，d，J＝10.5Hz)，5.22-5.32(1H，br)，5.29(1H，dd，J＝17.1，1.7Hz)，5.85-5.97(1H，m).

MS(ESI)m/z：371(M+H)⁺.

[ reference example 450] (1S, 3R, 4S) -4- { [ (allyloxy) carbonyl ] amino } -3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid

The title compound was obtained from the compound obtained in referential example 449 in the same manner as in referential example 142.

¹H-NMR(CDCl₃)δ：1.35-2.15(6H，br)，1.45(9H，s)，2.35-2.65(1H，br)，3.65-3.75(1H，m)，4.00-4.15(1H，br)，4.48-4.63(2H，m)，4.63-4.80(1H，br)，5.03-5.33(1H，br)，5.21(1H，d，J＝10.3Hz)，5.29(1H，dd，J＝17.1，1.5Hz)，5.86-5.97(1H，m).

MS(ESI)m/z：343(M+H)⁺.

[ reference example 451] (1S, 3R, 4S) -4- { [ (allyloxy) carbonyl ] amino } -3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid 2, 2, 2-trichloroethyl ester

To a solution of the compound (5.93g) obtained in referential example 450 in N, N-dimethylformamide (40ml) were added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.99g), 1-hydroxybenzotriazole (2.81g), 2, 2, 2-trichloroethanol (4.15ml) and 4-dimethylaminopyridine (4.15g), and the mixture was stirred at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 40: 1) to obtain the title compound (8.88 g).

¹H-NMR(CDCl₃)δ：1.35-1.50(1H，m)，1.46(9H，s)，1.55-1.73(1H，m)，1.77-2.22(4H，m)，2.50-2.65(1H，br)，3.66-3.75(1H，m)，4.05-4.20(1H，m)，4.50-4.60(2H，m)，4.60-4.80(1H，br)，4.71(1H，d，J＝11.8Hz)，4.77(1H，d，J＝11.8Hz)，5.18-5.34(1H，br)，5.20(1H，d，J＝10.5Hz)，5.30(1H，dd，J＝17.4，1.0Hz)，5.86-5.97(1H，m).

MS(ESI)m/z：473[(M+H)⁺，3×C^l35]，475[(M+H)⁺，2×C^l35，C^l37]，477[(M+H)⁺，C^l35，2×C^l37].

[ reference example 452] (1S, 3R, 4S) -4-amino-3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid 2, 2, 2-trichloroethyl ester

To a tetrahydrofuran (35ml) solution of the compound (8.83g) obtained in referential example 451, diethylamine (20ml), tetrakis (triphenylphosphine) palladium (719mg) were added, and the mixture was stirred at room temperature for 2.5 hours under argon. 10% citric acid aqueous solution (250ml) was added to the reaction mixture to make it acidic, and diethyl ether was added thereto. The aqueous layer was washed with diethyl ether, made alkaline by adding sodium carbonate and extracted with dichloromethane. The dichloromethane layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (4.35 g).

¹H-NMR(CDCl₃)δ：1.20-1.50(3H，m)，1.46(9H，s)，1.58-1.69(1H，m)，1.70-1.81(2H，m)，1.98-2.07(1H，m)，2.22-2.31(1H，m)，2.55-2.66(1H，m)，2.97-3.04(1H，m)，3.79-3.93(1H，br)，4.70(1H，d，J＝12.0Hz)，4.75-4.85(1H，br)，4.78(1H，d，J＝12.0Hz).

MS(ESI)m/z：389[(M+H)⁺，3×C^l35]，391[(M+H)⁺，2×C^l35，C^l37]，393[(M+H)⁺，C^l35，2×C^l37].

[ 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

The title compound was obtained by condensation of the compound obtained in referential example 452 and the compound obtained in referential example 433 in the same manner as referential example 91.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.50-1.63(1H，m)，1.65-1.79(2H，m)，1.87-2.08(2H，m)，2.10-2.22(2H，m)，2.50-2.70(1H，br)，3.94-4.02(1H，m)，4.17-4.30(1H，br)，4.73(1H，d，J＝12.0Hz)，4.78(1H，d，J＝12.0Hz)，7.70(1H，dd，J＝8.8，2.4Hz)，7.90-8.07(1H，br)，8.18(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，9.72(1H，br.s).

MS(ESI)m/z：571[(M+H)⁺，3×C^l35]，573[(M+H)⁺，2×C^l35，C^l37]，575[(M+H)⁺，C^l35，2×C^l37].

[ reference example 454] methyl 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) acetate

The compound (435mg) obtained in referential example 144 and methyl 2- (methoxyimino) -2- (methylsulfonyl) acetate (WO 99/67209) (233mg) were dissolved in tetrahydrofuran (5ml), and triethylamine (332. mu.l) was added to the solution, followed by stirring at 70 ℃ overnight. The reaction mixture was concentrated under reduced pressure, methylene chloride and a saturated aqueous sodium bicarbonate solution were added to separate the reaction mixture, and the oil layer was dried over anhydrous sodium sulfate. After concentration, the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 91; 9) to obtain the title compound (111 mg).

¹H-NMR(CDCl₃)δ：1.42-2.10(6H，m)，2.52(3H，s)，2.70-3.10(11H，m)，3.71(2H，br.s)，3.83(3H，s)，3.84(3H，s)，4.22-4.35(1H，m)，4.55-4.65(1H，m)，5.16(1H，d，J＝8.8Hz)，7.25-7.30(1H，m).

MS(ESI)m/z：481(M+H)⁺.

[ reference example 455]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- {5- [2- (trimethylsilyl) ethynyl group]Pyridin-2-yl oxalamides

The compound (658mg) obtained in example 204 was dissolved in tetrahydrofuran (10ml), N-dimethylformamide (10ml) and triethylamine (20ml), and triphenylphosphine (87mg), trimethylsilylacetylene (471. mu.l) and palladium acetate (50mg) were added to stir at 80 ℃ for 14 hours under an argon atmosphere. The reaction solution was filtered through celite, and washed thoroughly with dichloromethane. Water was added to the filtrate to separate a liquid, and the organic layer was decolorized with activated carbon (about 3g) and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 93: 7) to obtain the title compound (360 mg).

¹H-NMR(CDCl₃)δ：0.25(9H，s)，1.66-2.13(6H，m)，2.52(3H，s)，2.78-2.96(8H，m)，3.05(3H，s)，3.70(1H，d，J＝15.4Hz)，3.73(1H，d，J＝15.4Hz)，4.08-4.15(1H，m)，4.66-4.69(1H，m)，7.42(1H，d，J＝8.4Hz)，7.77(1H，dd，J＝8.4，2.1Hz)，8.03(1H，d，J＝8.1Hz)，8.13(1H，d，J＝8.8Hz)，8.43(1H，d，J＝2.1Hz)，9.74(1H，s).

MS(ESI)m/z：610(M+H)⁺.

[ reference example 456] 5-methyl-5, 6-dihydro-4H-thieno [2, 3-c ] pyrrole-2-carboxylic acid methyl ester

Methyl 4, 5-bis (chloromethyl) -2-thiophenecarboxylate (D.J.Zwanenburg and Hans wynberg, J.org.chem., 34, 333-. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 1: 0 → 19: 1) to obtain the title compound (176 mg).

¹H-NMR(CDCl₃)δ：2.63(3H，s)，3.82-3.83(2H，m)，3.86(3H，s)，3.97-3.99(2H，m)，7.51(1H，s).

MS(ESI)m/z：198(M+H)⁺.

[ reference example 457] 2-chloro-N- (6-chloropyridazin-3-yl) acetamide

3-amino-6-chloropyridazine (10.4g) was dissolved in N, N-dimethylformamide (200ml), and chloroacetyl chloride (7.48ml) was added and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the residue. The precipitated solid was collected by filtration, washed with ethyl acetate and water to obtain the title compound (9.39 g).

¹H-NMR(CDCl₃)δ：4.30(2H，s)，7.56(1H，d，J＝9.3Hz)，8.51(1H，d，J＝9.3Hz)，9.68(1H，br.s).

[ reference example 458] S- {2- [ (6-Chloropyridazin-3-yl) amino ] -2-oxoethyl } thiosulfuric acid sodium salt

The title compound was obtained from the compound obtained in referential example 457 by the same method as referential example 353.

¹H-NMR(DMSO-d₆)δ：3.84(2H，s)，7.87(1H，d，J＝9.4Hz)，8.36(1H，d，J＝9.4Hz)，11.21(1H，br.s).

[ reference example 459] (1R, 2S, 5S) -2- ({2- [ (6-Chloropyridazin-3-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 458 and the compound obtained in referential example 144 in the same manner as in referential example 427.

¹H-NMR(CDCl₃)δ：1.35-1.58(10H，m)，1.71-1.80(1H，m)，1.86-1.94(2H，m)，2.09(1H，br.s)，2.30(1H，br.s)，2.96(3H，s)，3.08(3H，s)，4.36(2H，br.s)，4.79(1H，br.s)，5.30(1H，br.s)，7.54(1H，d，J＝9.0Hz)，8.47(1H，d，J＝9.0Hz)，10.03(1H，br.s)，11.03(1H，s).

[ reference example 460] (1S, 3R, 4S) -3-amino-4- ({2- [ (6-chloropyridazin-3-yl) ] amino ] -2-oxothioacetyl } amino) -N, N-dimethylcyclohexanecarboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 459 by the same method as referential example 69.

¹H-NMR(DMSO-d₆)δ：1.45-1.53(1H，m)，1.73-1.85(3H，m)，2.03-2.07(1H，m)，2.15-2.24(1H，m)，2.82(3H，s)，3.08(3H，s)，3.32-3.37(1H，m)，4.06(1H，br.s)，4.39(1H，br.s)，8.01(1H，d，J＝9.3Hz)，8.37(1H，d，J＝9.3Hz)，8.43(3H，br.s)，11.11(1H，d，J＝6.6Hz)，11.37(1H，s).

MS(FAB)m/z：385[(M+H)⁺，C^l35]，387[(M+H)⁺，C^l37].

[ reference example 461] 2-chloro-N- (6-chloropyridin-3-yl) acetamide

The title compound was obtained from 5-amino-2-chloropyridine by the same method as in referential example 457.

¹H-NMR(CDCl₃)δ：4.22(2H，s)，7.34(1H，d，J＝8.5Hz)，8.14(1H，dd，J＝8.5，2.7Hz)，8.30(1H，br.s)，8.45(1H，d，J＝2.7Hz).

[ reference example 462] S- {2- [ (6-Chloropyridin-3-yl) amino ] -2-oxoethyl } thiosulfuric acid sodium salt

The title compound was obtained from the compound obtained in referential example 461 by the same method as referential example 353.

¹H-NMR(DMSO-d₆)δ：3.77(2H，s)，7.47(1H，d，J＝8.8Hz)，8.04(1H，dd，J＝8.8，2.7Hz)，8.57(1H，d，J＝2.7Hz)，10.51(1H，s).

[ reference example 463] (1R, 2S, 5S) -2- ({2- [ (6-Chloropyridin-3-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 462 and the compound obtained in referential example 144 in the same manner as in referential example 427.

¹H-NMR(CDCl₃)δ：1.46(9H，br.s)，1.60-2.23(6H，m)，2.68(1H，br.s)，2.96(3H，s)，3.08(3H，s)，4.34-4.38(2H，m)，4.78(1H，m)，7.33(1H，d，J＝8.5Hz)，8.09(1H，br.s)，8.63(1H，s)，9.91(1H，br.s)，10.24(1H，s).

MS(ESI)m/z：506[(M+Na)⁺，C^l35]，508[(M+Na)⁺，C^l37].

[ reference example 464] (1S, 3R, 4S) -3-amino-4- ({2- [ (6-chloropyridin-3-yl) amino ] -2-oxothioacetyl } amino) -N, N-dimethylcyclohexanecarboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 463 by the same method as referential example 69.

¹H-NMR(DMSO-d₆)δ：1.46-1.49(1H，m)，1.79-1.81(3H，m)，1.99-2.03(1H，m)，2.14-2.16(1H，m)，2.82(3H，s)，3.06(3H，s)，3.25-3.28(1H，m)，3.99(1H，br.s)，4.30-4.60(1H，br)，7.55(1H，d，J＝8.7Hz)，8.26(1H，dd，J＝8.7，2.4Hz)，8.38(3H，br.s)，8.85(1H，d，J＝2.4Hz)，10.90(1H，d，J＝6.8Hz)，11.07(1H，s).

MS(FAB)m/z：384[(M+H)⁺，C^l35]，386[(M+H)⁺，C^l37].

[ reference example 465]2 '-aminosulfonyl-1, 1' -biphenyl-4-carboxylic acid

2-bromobenzenesulfonamide (800mg) and 4-carboxyphenylboronic acid (563mg) were suspended in a mixed solvent of toluene (5ml) and water (5 ml). To the reaction solution were added tetrakis (triphenylphosphine) palladium (392mg) and anhydrous sodium carbonate (1.08g) in this order, and the mixture was heated under reflux overnight. After cooling to room temperature, diethyl ether and water were added for liquid separation, and the organic layer was extracted with water 2 times. All the aqueous layers obtained were combined, and 12N aqueous hydrochloric acid was added to the solution to make the solution acidic. The mixture was concentrated under reduced pressure to about 20ml, 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：277M⁺.

[ reference example 466] methyl 2- [ (5-methylpyridin-2-yl) amino ] -2-oxoacetate

The title compound was obtained from 2-amino-5-methylpyridine and methyl chlorooxoacetate in the same manner as in referential example 242.

¹H-NMR(CDCl₃)δ：2.33(3H，s)，3.98(3H、s)，7.57(1H，dd，J＝8.4，2.0Hz)，8.14(1H，d，J＝8.4Hz)，8.17(1H，d，J＝2.0Hz).

MS(ESI)m/z：195(M+H)⁺.

[ referential example 467] lithium 2- [ (5-methylpyridin-2-yl) amino ] -2-oxoacetate

The title compound was obtained from the compound obtained in referential example 466 by the same method as referential example 266.

¹H-NMR(DMSO-d₆)δ：2.25(3H，s)，7.63(1H，d，J＝8.2Hz)，8.00(1H，d，J＝8.2Hz)，8.15(1H，s)，10.00(1H，br.s).

MS(FAB)m/z：181(M-Li+2H)⁺.

[ reference example 468] methyl 2-oxo-2- (4-methylanilino) acetate

The title compound was obtained from p-toluidine and methyl chlorooxoacetate in the same manner as in referential example 242.

MS(ESI)m/z：194(M+H)⁺.

[ reference example 469] (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- { [ 2-oxo-2- (4-methylanilino) acetyl ] amino } cyclohexylcarbamic acid tert-butyl ester

The title compound was prepared by condensing the lithium salt of the carboxylic acid obtained by hydrolyzing the ester described in reference example 468 with the compound obtained in reference example 144 in the same manner as in reference example 91.

MS(ESI)m/z：447(M+H)⁺.

[ reference example 470] 4-bromomethyl-3-chlorothiophene-2-carboxylic acid methyl ester

N-bromosuccinimide (3.56g) and α, α' -azobisisobutyronitrile (200mg) were added to a solution of methyl 3-chloro-4-methyl-2-thiophenecarboxylate (3.81g) in carbon tetrachloride (40ml), and the mixture was refluxed for 2.5 hours. After insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 19 → 1: 9) to obtain the title compound (2.92g) as a yellow oil.

¹H-NMR(CDCl₃)δ：3.91(3H，s)，4.46(2H，s)，7.59(1H，s).

MS(ESI)m/z：269(M+H)⁺.

[ reference example 471]4- { [ (tert-butoxycarbonyl) (methyl) amino ] methyl } -3-chloro-2-thiophenecarboxylic acid

To a tetrahydrofuran (30ml) solution of methylamine (2 mol/l, tetrahydrofuran solution, 27ml), a tetrahydrofuran (50ml) solution of the compound (2.92g) obtained in referential example 470 was added dropwise over 30 minutes. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to about half of the reaction mixture, and di-tert-butyl dicarbonate (3.0g) was added and stirred at room temperature for 75 minutes. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue to be left overnight. The organic layer was separated with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 99: 1 → 19: 1) to give a colorless oil (4.0 g). To a solution of this oil (4.0g) in methanol (35ml), water (5ml) and sodium hydroxide (1.2g) were added, 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, which was then acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and hexane was added thereto for crystallization to obtain the title compound (2.67g) as a colorless powder.

¹H-NMR(CDCl₃)δ：1.48(9H，s)，2.74(3H，br.s)，4.14(2H，br.s)，7.40(0.5H，br.s)，7.48(0.5H，br.s).

[ reference example 472] (1R, 2S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by condensation of tert-butyl (1R, 2S) -2-aminocyclohexylcarbamate (WO01/74774) and the compound obtained in referential example 266 in the same manner as in referential example 68.

¹H-NMR(CDCl₃)δ：1.35-1.90(8H，m)，1.46(9H，s)，3.97(1H，br.s)，4.00-4.12(1H，m)，4.73-4.82(1H，m)，7.69(1H，dd，J＝8.8，2.5Hz)，7.90(1H，br。s)，8.17(1H，dd，J＝8.8，0.55Hz)，8.29(1H，dd，J＝2.5，0.55Hz)，9.76(1H，br.s).

MS(ESI)m/z：397(M+H)⁺.

[ reference example 473]5- [ (4-Methylphenyl) sulfonyl group]-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c]Aza derivatives-2-Amines

In the presence of 3-bromo-1- [ (4-methylphenyl) sulfonyl]Thiourea (1.44g) was added to an N, N-dimethylformamide (100ml) solution of (E) -4-azaheptanone (J.chem.Soc.Perkin Trans., 1995, volume 1, page 2355) (6.54g), and the mixture was heated and stirred at 60 ℃ overnight. After the solvent was distilled off under reduced pressure, methylene chloride (100ml) and a saturated aqueous sodium bicarbonate solution (100ml) were added to the residue to separate the mixture. The aqueous layer was extracted with dichloromethane (100ml), combined with the organic layer obtained previously and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, ethyl acetate (100ml) was added to the obtained residue, and the precipitated pale yellow powder was collected by filtration to obtain 5- [ (4-methylphenyl) sulfonyl group as a crude purified product]-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c]Aza derivatives-2-ylcarboxamide (1.86 g). The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 19) to obtain 5- [ (4-methylphenyl) sulfonyl group ]-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c]Aza derivatives2-Methylformamide and the title compound (4.01 g). The mixture and the crude product were combined, suspended in dioxane (50ml), and 3N hydrochloric acid (50ml) was added to the mixture and heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, methylene chloride (250ml) and a saturated aqueous sodium carbonate solution (200ml) were added to separate the layers, and the oil layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off. Diisopropyl ether (100ml) was added to the residue, and the precipitated pale yellow powder was collected by filtration to obtain the title compound (4.47 g).

¹H-NMR(CDCl₃)δ：1.75-1.87(2H，m)，2.40(3H，s)，2.62(2H，t，J＝5.7Hz)，3.53(2H，t，J＝5.7Hz)，4.37(2H，s)，4.73(2H，br.s)，7.25(2H，d，J＝8.5Hz)，7.61(2H，d，J＝8.5Hz).

MS(ESI)m/z：324(M+H)⁺.

Reference example 474]5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c ]]Aza derivatives-2-Aminoamine hydrobromide salt

The title compound was obtained by treating the compound obtained in referential example 473 in the same manner as in referential example 291.

¹H-NMR(DMSO-d₆)δ：1.95(2H，br.s)，2.70-2.90(2H，m)，3.38(2H，br.s)，4.56(2H，br.s)，9.07(3H，br.s).

MS(ESI)m/z：170(M+H)⁺.

[ reference example 475]5-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c]Aza derivatives-2-Amines

The compound (2.73g) obtained in referential example 474 was suspended in methanol, and triethylamine (2.30ml), acetic acid (453. mu.l), a 37% aqueous formaldehyde solution (668. mu.l) and sodium cyanoborohydride (544mg) were added to the suspension under ice cooling. After stirring overnight at room temperature, a saturated aqueous sodium bicarbonate solution (20ml) was added, and the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (methanol: dichloromethane: 3: 17). Methanol (100ml) and anhydrous sodium carbonate (20g) were added to the crude purified product, and the mixture was stirred at room temperature for 30 minutes, followed by filtration of insoluble matter. After the filtrate was concentrated under reduced pressure, methylene chloride (250ml) and methanol (50ml) were added to the residue, and insoluble matter was filtered off. After the filtrate was concentrated under reduced pressure, the resulting pale yellow powder was washed with acetonitrile (100ml) to obtain the title compound (1.23 g).

¹H-NMR(CDCl₃)δ：1.70-1.85(2H，s)，2.38(3H，s)，2.77(2H，t，J＝5.6Hz)，2.97(2H，t，J＝5.6Hz)，3.65(2H，s)，4.68(2H，br.s).

MS(ESI)m/z：184(M+H)⁺.

[ reference example 476]2-bromo-5-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c]Aza derivatives

The compound (1.13g) obtained in referential example 475 was suspended in water (10ml), and a 48% aqueous hydrobromic acid solution (7.0ml) was added to stir under ice-cooling. To the reaction solution, an aqueous solution (3.0ml) containing sodium nitrite (639mg) was carefully added dropwise. After the addition was complete, the suspension was stirred at room temperature overnight. Under ice-cooling, methylene chloride (100ml) was added to the reaction solution and while stirring, saturated aqueous sodium carbonate solution was added to neutralize the reaction solution. After separation, the aqueous layer was extracted with methylene chloride (100ml), and the organic layers were combined and dried over anhydrous sodium sulfate. Then, the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 3: 47) to obtain the title compound (582mg) as a pale orange oil.

¹H-NMR(CDCl₃)δ：1.70-1.85(2H，s)，2.38(3H，s)，2.95-3.05(4H，m)，3.79(2H，s).

MS(ESI)m/z：247(M+H)⁺.

[ reference example 477]5-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c]Aza derivatives-2-carboxylic acid lithium salt

The title compound was obtained from the compound obtained in referential example 476 by the same method as referential example 10.

¹H-NMR(DMSO-d₆)δ：1.65(2H，br.s)，2.23(3H，s)，2.80-2.97(4H，m)，3.75(2H，s).

[ reference example 478]4, 4, 5-trimethyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazol-2-ylamine

Pyrrolidine (1.31ml) and p-toluenesulfonic acid 1 hydrate (7.48mg) were sequentially added to a cyclohexane (5ml) solution of 1, 2, 2-trimethylpyrrolidin-3-one (1.00g), and the mixture was refluxed for 3 days. After allowing to stand at room temperature, it was concentrated under reduced pressure to obtain crude 1, 2, 2-trimethyl-3- (pyrrolidin-1-yl) -2, 5-dihydro-1H-pyrrole (972 mg). To a solution of this compound in dimethylformamide (10ml) was added formamidine disulfide hydrochloride (1.20g), and the mixture was stirred at room temperature for 4 days. After concentration under reduced pressure, methanol (50ml) and anhydrous sodium carbonate (20g) were added to the residue, and the mixture was stirred at room temperature for 1 hour, and insoluble matter was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 99 → 1: 9) to obtain the title compound (580 mg).

¹H-NMR(CDCl₃)δ：1.25(6H，s)，2.48(3H，s)，3.83(2H，s)，4.83(2H，br.s).

MS(ESI)m/z：184(M+H)⁺.

[ reference example 479] 2-bromo-4, 4, 5-trimethyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole

The title compound was obtained from the compound obtained in referential example 478 by the same method as referential example 476.

¹H-NMR(CDCl₃)δ：1.30(6H，s)，2.49(3H，s)，3.91(2H，s).

MS(ESI)m/z：247(M+H)⁺.

[ reference example 480]2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridine-6-carboxylic acid

Ethyl 2- [ (4-methylphenyl) sulfonyl ] -2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridine-6-carboxylate (chem. commun., 2001, page 1102) was treated in the same manner as in reference example 291 to obtain the title compound.

¹H-NMR(CDCl₃)δ：4.60-4.75(4H，m)，8.17(1H，s)，8.78(1H，s)，9.69(2H，br.s).

MS(ESI)m/z：165(M+H)⁺.

[ referential example 481] lithium 2- (tert-butoxycarbonyl) -2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridine-6-carboxylate

Thionyl chloride (3.0ml) was added to a methanol (100ml) solution of the compound (1.66g) obtained in referential example 480, and the mixture was refluxed overnight. After the mixture was allowed to stand at room temperature, the solvent was distilled off under reduced pressure, and methylene chloride (100ml) and a saturated aqueous sodium bicarbonate solution (100ml) were added to the residue to separate the mixture. To the aqueous layer were added methylene chloride (100ml) and di-tert-butyl dicarbonate (1.40g), and the mixture was stirred at room temperature for 2 hours. After the liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane (50ml) was added to the residue, and the precipitated pale yellow powder was collected by filtration to obtain crude methyl 2- (tert-butoxycarbonyl) -1, 3-dihydro-2H-pyrrolo [3, 4-c ] pyridine-6-carboxylate (602 mg). To a solution of the crude product (564mg) in methanol (10ml), a 1N aqueous solution (2.20ml) of lithium hydroxide was added, and the mixture was stirred at room temperature overnight. Concentration to a dry solid under reduced pressure gave the title compound (591mg) as a pale brown solid.

¹H-NMR(DMSO-d₆)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 title compound was obtained by esterifying a compound formed from pyridin-4-ylboronic acid and 5-bromopyrimidine-2-carboxylic acid with methanol and thionyl chloride by the method described in reference example 237.

¹H-NMR(CDCl₃)δ：4.12(3H，s)，7.57(2H，d，J＝6.1Hz)，8.83(2H，d，J＝6.1Hz)，9.18(2H，s).

MS(ESI)m/z：216(M+H)⁺.

[ reference example 483] lithium 5- (pyridin-4-yl) pyrimidine-2-carboxylate

The title compound was obtained from the compound obtained in referential example 482 in the same manner as in referential example 322.

¹H-NMR(DMSO-d₆)δ：7.85(2H，d，J＝6.0Hz)，8.69(2H，d，J＝6.0Hz)，9.12(2H，s).

MS(ESI)m/z：202(M-Li+2H)⁺.

[ reference example 484]2 '-methyl- [1, 1' -biphenyl ] -4-carbaldehyde

The title compound was obtained from 2-bromotoluene and 4-formylphenylboronic acid in the same manner as in referential example 237.

¹H-NMR(CDCl₃)δ：2.28(3H，s)，7.20-7.33(4H，m)，7.50(2H，d，J＝8.2Hz)，7.94(2H，d，J＝8.2Hz)，10.07(1H，s).

MS(ESI)m/z：197(M+H)⁺.

[ reference example 485]2 '-methyl- [1, 1' -biphenyl ] -4-carboxylic acid

The compound (1.51g) obtained in referential example 484 was suspended in water (100ml), and tert-butanol (10ml), 2-methyl-2-butene (20ml), sodium chlorite (3.67g) and sodium dihydrogenphosphate dihydrate (3.62g) were added to the suspension in this order, followed by stirring overnight at room temperature. Diisopropyl ether (200ml) was added to the reaction mixture to separate the mixture, 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 obtain the title compound (1.43g) as a colorless powder.

¹H-NMR(CDCl₃)δ：2.29(3H，s)，7.20-7.35(4H，m)，7.65(2H，d，J＝8.1Hz)，8.18(2H，d，J＝8.1Hz).

MS(ESI)m/z：213(M+H)⁺.

[ reference example 486]2 '-methyl- [1, 1' -biphenyl ] -4-carboxylic acid methyl ester

The compound (1.42g) obtained in referential example 485 was suspended in methanol, and thionyl chloride (1ml) was added to the suspension and heated under reflux for 2 hours. After the reaction mixture was allowed to stand at room temperature, a saturated aqueous sodium bicarbonate solution (100ml) and methylene chloride (100ml) were added thereto to separate the mixture. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (1.51g) as a colorless oil.

¹H-NMR(CDCl₃)δ：2.26(3H，s)，3.94(3H，s)，7.20-7.35(4H，m)，7.40(2H，d，J＝7.8Hz)，8.08(2H，d，J＝7.8Hz).

MS(ESI)m/z：227(M+H)⁺.

[ reference example 487]2 '- [ (dimethylamino) methyl ] - [1, 1' -biphenyl ] -4-carboxylic acid methyl ester

The compound (663mg) obtained in referential example 486 was dissolved in 1, 2-dichloroethane (30ml), and N-bromosuccinimide (521mg) and 2, 2' -azobisisobutyronitrile (48.1mg) were added to the solution and the mixture was refluxed for 1 hour. After completion of the reaction, the mixture was cooled to 0 ℃, dimethylamine (40% aqueous solution, 0.99ml) was added, and the mixture was stirred at room temperature for 3 days. To the mixture were added water (100ml) and methylene chloride (100ml) to separate the mixture, 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 column chromatography (methanol: dichloromethane ═ 1: 25) to obtain the title compound (607mg) as a colorless oil.

¹H-NMR(CDCl₃)δ：2.13(6H，s)，3.31(2H，s)，3.95(3H，s)，7.23(1H，dd，J＝7.4，1.5Hz)，7.31(1H，dt，J＝1.5，7.4Hz)，7.37(1H，dt，J＝1.5，7.4Hz)，7.46(2H，d，J＝8.2Hz)，7.52(1H，dd，J＝7.4，1.5Hz)，8.07(2H，d，J＝8.2Hz).

MS(ESI)m/z：270(M+H)⁺.

[ referential example 488]2 '- [ (dimethylamino) methyl ] - [1, 1' -biphenyl ] -4-carboxylic acid lithium salt

The title compound was obtained from the compound obtained in referential example 487 in the same manner as in referential example 322.

¹H-NMR(DMSO-d₆)δ：2.06(6H，s)，3.29(2H，s)，7.20-7.38(5H，m)，7.49(1H，d，J＝7.3Hz)，7.88(2H，d，J＝8.0).

MS(ESI)m/z：256(M-Li+2H)⁺.

[ reference example 489]4- [4- (methoxycarbonyl) phenyl ] -2-methyl-1-pyridine N-oxide

The title compound was obtained from methyl 4- (2-methylpyridin-4-yl) benzoate (Japanese patent laid-open No. 2000-143623) by the method described in referential example 239.

¹H-NMR(CDCl₃)δ：2.60(3H，s)，3.96(3H，s)，7.42(1H，dd，J＝6.8，2.7Hz)，7.53(1H，d，J＝2.7Hz)，7.66(2H，d，J＝8.2Hz)，8.14(2H，d，J＝8.2Hz)，8.3

3(1H，d，J＝6.8Hz).

MS(FAB)m/z：244(M+H)⁺.

[ reference example 490] methyl 4- {2- [ (acetoxy) methyl ] pyridin-4-yl } benzoate

A solution of the compound (980mg) obtained in referential example 489 in acetic anhydride (25ml) was stirred at 130 ℃ for 30 minutes. After cooling to 90 ℃, methanol (50ml) was added and stirred for 1 hour. After dichloromethane (50ml) and saturated aqueous sodium bicarbonate (150ml) were added to the reaction solution, solid sodium bicarbonate was added until the reaction solution became basic. After stirring for 3 hours, the layers were separated and the aqueous layer was extracted with dichloromethane (2X 50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 40: 1 → 10: 1) and then by medium pressure column chromatography using silica gel as a carrier (hexane: ethyl acetate ═ 2: 1 → 1: 1), whereby the title compound (749mg) was obtained as a white solid.

¹H-NMR(CDCl₃)δ：2.19(3H，s)，3.96(3H，s)，5.29(2H，s)，7.47(1H，dd，J＝5.1，1.7Hz)，7.57-7.60(1H，m)，7.70(2H，d，J＝8.5Hz)，8.15(2H，d，J＝8.5Hz)，8.68(1H，d，J＝5.1Hz).MS(ESI)m/z：286(M+H)⁺.

[ reference example 491] methyl 4- (2- { [ (tert-butoxycarbonyl) amino ] methyl } pyridin-4-yl) benzoate

To a solution of the compound (532mg) obtained in referential example 490 in tetrahydrofuran (4.0ml) were added water (1.0ml) and lithium hydroxide (137mg) at room temperature. After stirring for 24 hours, tetrahydrofuran was distilled off under reduced pressure, and water (4.0ml) and 1N hydrochloric acid (5.65ml) were added. The resulting solid was collected by filtration, washed with water, and dried to obtain a white solid (400 mg). A portion (272mg) of the solid was suspended in tetrahydrofuran (10ml), and methanol (2.0ml) and trimethylsilyldiazomethane (2.0M in hexane, 890. mu.l) were added at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure. To a solution of the obtained solid in dichloromethane (10ml) were added ethyl acetate (5.0ml), trimethylamine hydrochloride (12mg), methanesulfonyl chloride (140. mu.l) and triethylamine (252. mu.l) at room temperature. After stirring for 3 hours, a saturated aqueous sodium hydrogencarbonate solution (20ml) and methylene chloride (20ml) were added to separate the mixture, and the aqueous layer was extracted with methylene chloride (2X 15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the resulting reddish-purple oil in N, N-dimethylformamide (5.0ml) was added sodium azide (155mg) at room temperature. After stirring for 1 hour, water (100ml) and methylene chloride (30ml) were added to separate the solution, and the aqueous layer was extracted with methylene chloride (3X 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, added with dioxane (5.0ml), and concentrated under reduced pressure to about 5 ml. Tetrahydrofuran (5.0ml), di-tert-butyl dicarbonate (400mg) and 10% palladium on carbon (100mg) were added to the brown solution, and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: acetone 20: 1) to give the title compound (270mg) as a pale yellow oil.

¹H-NMR(CDCl₃)δ：1.48(9H，s)，3.96(3H，s)，4.52(2H，d，J＝5.4Hz)，4.94(0.5H，br.s)，5.59(0.5H，br.s)，7.42(1H，dd，J＝5.1，1.7Hz)，7.51(1H，br.s)，7.69(2H，d，J＝8.3Hz)，8.15(2H，d，J＝8.3Hz)，8.61(1H，d，J＝5.1Hz).

MS(ESI)m/z：343(M+H)⁺.

[ reference example 492]1- (phenylsulfonyl) piperidine-4-carboxylic acid ethyl ester

Triethylamine (1.40ml) was added to a tetrahydrofuran (10ml) solution of ethyl hexahydroisonicotinate (1.08ml), and benzenesulfonyl chloride (1.02ml) was added thereto at 0 ℃ and stirred at room temperature for 21 hours. Then, ice was added thereto and the mixture was stirred for 10 minutes, and ethyl acetate and 0.5N hydrochloric acid were further added to separate the reaction mixture into 2 layers. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and then 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 (1.66g) as a white solid.

¹H-NMR(CDCl₃)δ：1.21(3H，t，J＝7.1Hz)，1.76-1.87(2H，m)，1.92-2.01(2H，m)，2.20-2.29(1H，m)，2.49(2H，dt，J＝2.9，11.4Hz)，3.59-3.67(2H，m)，4.10(2H，q，J＝7.1Hz)，7.51-7.63(3H，m)，7.74-7.78(2H，m).

MS(ESI)m/z：298(M+H)⁺.

[ reference example 493]1- (phenylsulfonyl) piperidine-4-carboxylic acid

The title compound was obtained from the compound obtained in referential example 492 in the same manner as in referential example 274.

¹H-NMR(CDCl₃)δ：1.74-1.90(2H，m)，1.90-2.04(2H，m)，2.23-2.33(1H，m)，2.39-2.54(2H，m)，3.58-3.72(2H，m)，7.48-7.64(3H，m)，7.67-7.80(2H，m).

MS(ESI)m/z：270(M+H)⁺.

[ referential example 494] Ethyl 1- (4-fluorobenzoyl) piperidine-4-carboxylate

The title compound was prepared from ethyl hexahydroisonicotinate and p-fluorobenzoyl chloride in the same manner as in reference example 492.

¹H-NMR(CDCl₃)δ：1.27(3H，t，J＝7.1Hz)，1.60-2.10(4H，br)，2.54-2.62(1H，m)，2.95-3.13(2H，m)，3.55-3.90(1H，br)，4.16(2H，q，J＝7.1Hz)，4.30-4.70(1H，br)，7.09(2H，t，J＝8.8Hz)，7.41(2H，dd，J＝8.8，5.4Hz).

MS(ESI)m/z：280(M+H)⁺.

[ reference example 495]1- (4-fluorobenzoyl) piperidine-4-carboxylic acid

The title compound was obtained from the compound obtained in referential example 494 in the same manner as in referential example 274.

¹H-NMR(CDCl₃)δ：1.60-2.20(4H，br)，2.57-2.68(1H，m)，2.98-3.20(2H，m)，3.55-4.00(1H，br)，4.25-4.65(1H，br)，7.09(2H，t，J＝8.5Hz)，7.40(2H，dd，J＝8.5，5.4Hz).

MS(ESI)m/z：252(M+H)⁺.

[ reference example 496] methyl 4- (pyrrolidin-1-ylcarbonyl) benzoate

The title compound was obtained from pyrrolidine and monomethylterephthaloyl chloride by the same method as in referential example 492.

¹H-NMR(CDCl₃)δ：1.85-1.93(2H，m)，1.94-2.01(2H，m)，3.38(2H，t，J＝6.6Hz)，3.66(2H，t，J＝6.6Hz)，3.94(3H，s)，7.57(2H，d，J＝8.6Hz)，8.07(2H，d，J＝8.6Hz).

MS(ESI)m/z：234(M+H)⁺.

[ reference example 497]4- (pyrrolidin-1-ylcarbonyl) benzoic acid

The title compound was obtained from the compound obtained in referential example 496 by the same method as in referential example 274.

¹H-NMR(CDCl₃)δ：1.85-2.03(4H，m)，3.43(2H，t，J＝6.6Hz)，3.67(2H，t，J＝6.6Hz)，7.61(2H，d，J＝8.6Hz)，8.14(2H，d，J＝8.6Hz).

MS(ESI)m/z：220(M+H)⁺.

[ reference example 498] methyl 4- (pyrrolidin-1-ylmethyl) benzoate

The title compound was obtained by subjecting the compound obtained in referential example 496 to the same treatment as in referential example 212.

¹H-NMR(CDCl₃)δ：1.75-1.84(4H，m)，2.47-2.56(4H，m)，3.37(2H，s)，3.90(3H，s)，7.41(2H，d，J＝8.3Hz)，7.98(2H，d，J＝8.3Hz).

MS(ESI)m/z：220(M+H)⁺.

[ reference example 499] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- [ (methylamino) carbonyl ] cyclohexanecarboxylic acid 9H-fluoren-9-ylmethyl ester

To a methanol (20ml) solution of the compound (823mg) obtained in referential example 436 was added a 10% palladium on carbon catalyst (117mg), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The catalyst was filtered through a glass filter, and the filtrate was concentrated under reduced pressure. To a solution of the obtained colorless viscous oil (622mg) in 1, 2-dimethoxyethane (15ml) were added a saturated aqueous sodium hydrogencarbonate solution (5ml), water (2ml) and fluoren-9-ylmethyl succinimidyl carboxylate (867mg), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate, and water was added to separate into 2 layers. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After the residue was washed with a slurry containing ethyl acetate, a white powder was collected by filtration. Further, the mother liquor was concentrated under reduced pressure, washed with diethyl ether, and filtered to obtain a white powder. The filtered powder was dissolved in ethyl acetate, mixed, the solvent was evaporated under reduced pressure, and dried by a vacuum pump to obtain the title compound (939mg) as a white powder.

¹H-NMR(CDCl₃)δ：1.46(9H，br.s)，1.60-1.74(1H，m)，1.78-1.92(2H，m)，1.92-2.07(2H，m)，2.10-2.26(1H，m)，2.81(3H，d，J＝4.9Hz)，3.62-3.77(1H，br)，3.85-4.63(5H，m)，5.30-5.67(2H，br)，7.24-7.33(2H，m)，7.39(2H，t，J＝7.6Hz)，7.58(2H，br.d，J＝7.1Hz)，7.76(2H，d，J＝7.6Hz).

MS(ESI)m/z：394(M-COOtBu)⁺.

[ reference example 500] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- [ (methylamino) thiocarbonyl ] cyclohexanecarboxylic acid 9H-fluoren-9-ylmethyl ester

The title compound was obtained from the compound obtained in referential example 499 in the same manner as in referential example 443.

¹H-NMR(CDCl₃)δ：1.46(9H，br.s)，1.55-2.10(6H，m)，2.45-2.72(1H，br)，3.17(3H，d，J＝4.4Hz)，3.65-3.77(1H，br)，3.78-3.88(0.5H，m)，4.00-4.65(4H，br)，4.75-5.25(0.5H，br)，5.30-5.60(0.5H，br)，6.85-7.00(0.5H，br)，7.25-7.34(2H，m)，7.39(2H，t，J＝7.6Hz)，7.42-7.53(0.5H，br)，7.58(2H，br.d，J＝6.6Hz)，7.75(2H，d，J＝7.6Hz)，7.80-7.90(0.5H，br).

MS(ESI)m/z：410(M-COOtBu)⁺.

[ reference example 501] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- [ (methylamino) thiocarbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 500 in the same manner as in referential example 444.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.50-1.70(1H，m)，1.80-2.16(5H，m)，2.60-2.75(1H，br)，3.19(3H，d，J＝4.9Hz)，3.94-4.05(1H，br)，4.10-4.28(1H，br)，4.80-5.00(0.8H，br)，5.75-5.90(0.2H，br)，7.40-7.55(1H，br)，7.68(1H，dd，J＝8.8，2.2Hz)，7.96-8.07(1H，br)，8.17(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.0Hz)，9.76(1H，s).

MS(ESI)m/z：414(M-tBu+H)⁺.

[ reference example 502]2, 2-dichloro-N- (5-chloropyrimidin-2-yl) acetamide

Dichloroacetic acid chloride (1.44ml) and sodium hydrogencarbonate (1.26g) were added to a solution of 2-amino-5-chloropyrimidine (1.30g) in N, N-dimethylformamide (30ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and methylene chloride and water were added to the residue to conduct liquid separation. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated 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 washed with a slurry of a mixed solvent of hexane-diethyl ether (4: 1) and then filtered to obtain the title compound (1.24g) as a white solid.

¹H-NMR(CDCl₃)δ：6.43(1H，br.s)，8.65(2H，s)，9.07(1H，br.s).

MS(ESI)m/z：240(M+H)⁺.

[ reference example 503] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyrimidin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The compound (8.03g) obtained in referential example 144, the compound (6.76g) obtained in referential example 502 and sulfur (947mg) were added to N, N-dimethylformamide (90ml), and the mixture was heated at 120 ℃ and diisopropylethylamine (9.57ml) 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 insoluble matter was removed by filtration through celite. The filtrate was separated by adding water, and the organic layer was washed with water. The crude purified product was purified by flash column chromatography on silica gel (dichloromethane: methanol ═ 19: 1), dissolved in dichloromethane, and the solid was filtered off by adding hexane to obtain the title compound (940mg) as a pale yellow solid. Further, the filtrate was purified by silica gel column chromatography to obtain the title compound (940mg) containing N, N-dimethylformamide as a pale brown solid.

¹H-NMR(DMSO)δ：1.28-2.22(15H，m)，2.71(1H，br.s)，2.96(3H，s)，3.07(3H，s)，4.25-4.42(2H，m)，8.62(2H，s)，9.88(1H，br.s)，10.89(1H，s).

[ reference example 504] 2-chloro-N- (4-chloro-3-nitrophenyl) acetamide

The title compound was obtained from 4-chloro-3-nitroaniline and chloroacetyl chloride in the same manner as in referential example 502.

¹H-NMR(CDCl₃)δ：4.23(2H，s)，7.54(1H，d，J＝8.8Hz)，7.74(1H，dd，J＝8.8，2.4Hz)，8.22(1H，d，J＝2.4Hz)，8.39(1H，br.s).

[ reference example 505] (1R, 2S, 5S) -tert-butyl 2- { [2- (4-chloro-3-nitroanilino) -2-oxothioacetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamate

To a solution of the compound (498mg) obtained in referential example 504 in N, N-dimethylformamide (4ml) were added sulfur (128mg) and triethylamine (833. mu.l), and the mixture was stirred at room temperature for 1 hour. The compound (571mg) obtained in referential example 144 and 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (767mg) were added to a reaction solution, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, methylene chloride and aqueous solution were added to the residue, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification by flash column chromatography on silica gel (ethyl acetate) afforded the title compound (688mg) as a yellow solid.

¹H-NMR(CDCl₃)δ：1.47(9H，m)，1.48-1.59(1H，m)，1.72-1.81(1H，m)，1.86-1.95(2H，m)，2.04(1H，br.s)，2.23(1H，br.s)，2.69(1H，br.s)，2.96(3H，s)，3.09(3H，s)，4.34-4.39(2H，m)，4.78(1H，br.s)，7.52(1H，d，J＝8.6Hz)，7.69(1H，d，J＝8.6Hz)，8.39(1H，br.s)，9.95(1H，br.s)，10.37(1H，s).

MS(ESI)m/z：528(M+H)⁺.

[ reference example 506] (1S, 3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -4- { [ (7-chlorocinnolin-3-yl) carbonyl ] amino } cyclohexanecarboxylic acid ethyl ester

The title compound was obtained by condensing the compound obtained in referential example 96 with the compound obtained in referential example 298 in the same manner as in referential example 97.

¹H-NMR(CDCl₃)δ：1.28(3H，t，J＝7.2Hz)，1.36(9H，s)，1.53-2.16(6H，m)，2.48(1H，br.s)，4.17(2H，q，J＝7.2Hz)，4.30-4.35(2H，m)，4.86(1H，br.s)，7.78(1H，dd，J＝8.8，2.0Hz)，7.97(1H，d，J＝8.8Hz)，8.59-8.60(1H，m)，8.64(1H，d，J＝8.6Hz)，8.73(1H，s).

MS(ESI)m/z：477(M+H)⁺.

[ reference example 507] (1S, 3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -4- { [ (7-chlorocinnolin-3-yl) thiocarbonyl ] amino } cyclohexanecarboxylic acid ethyl ester

The title compound was obtained from the compound obtained in referential example 506 by the same method as referential example 443.

¹H-NMR(CDCl₃)δ：1.28(3H，t，J＝7.1Hz)，1.37(9H，br.s)，1.59-2.26(6H，m)，2.49(1H，br.s)，4.17(2H，q，J＝7.1Hz)，4.54(1H，br.s)，4.83-4.87(2H，m)，7.76(1H，dd，J＝8.7，1.8Hz)，7.97(1H，d，J＝8.7Hz)，8.57(1H，s)，9.20(1H，s)，10.64(1H，br.s).

MS(ESI)m/z：493(M+H)⁺.

[ reference example 508] (1R, 2S, 5S) -2- { [ (7-chlorocinnolin-3-yl) thiocarbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by hydrolyzing the compound obtained in referential example 507 and condensing the resulting carboxylic acid with dimethylamine hydrochloride in the same manner as in referential example 251.

¹H-NMR(CDCl₃)δ：1.37(9H，br.s)，1.66(1H，br.s)，1.82-2.05(4H，m)，2.29-2.32(1H，m)，2.76(1H，br.s)，2.97(3H，s)，3.09(3H，s)，4.56-4.59(1H，m)，4.90(2H，br.s)，7.75(1H，dd，J＝8.7，2.0Hz)，7.97(1H，d，J＝8.7Hz)，8.56(1H，s)，9.19(1H，br.s)，10.60(1H，d，J＝7.8Hz).

MS(ESI)m/z：492(M+H)⁺.

[ reference example 509] (1S, 3R, 4S) -3-amino-4- { [ (7-chlorocinnolin-3-yl) thioformyl ] amino } -N, N-dimethylcyclohexanecarboxamide

The title compound was obtained from the compound obtained in referential example 508 in the same manner as in referential example 325.

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

Oxalyl chloride (435. mu.l) was added to a solution of p-chlorobenzamide (311mg) in dichloroethane (20ml), and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, and an acetonitrile (10ml) solution of the residue was added dropwise to an acetonitrile (20ml) solution of the compound (571mg) obtained in referential example 144, followed by stirring at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue to collect a solid by filtration, whereby the title compound was obtained as a white solid.

¹H-NMR(CDCl₃)δ：1.42(9H，s)，1.52-2.01(6H，m)，2.68(1H，br.s)，2.95(3H，s)，3.08(3H，s)，3.95(1H，br.s)，4.29(1H，br.s)，4.84(1H，br.s)，7.41(2H，d，J＝8.3Hz)，7.88(2H，br.s)，8.92(1H，d，J＝7.6Hz)，9.78(1H，s).

MS(ESI)m/z：489(M+Na)⁺.

[ reference example 511] (1S, 3R, 4S) -3-amino-4- ({ [ (4-chlorobenzoyl) amino ] carbonyl } amino) -N, N-dimethylcyclohexanecarboxamide

The title compound was obtained from the compound obtained in referential example 510 in the same manner as in referential example 325.

¹H-NMR(CDCl₃)δ：1.51(2H，br.s)，1.67-1.96(6H，m)，2.90(1H，br.s)，2.95(3H，s)，3.08(3H，s)，3.44(1H，br.s)，3.93(1H，br.s)，7.47(2H，d，J＝8.5Hz)，7.86(2H，d，J＝8.5Hz)，8.85(1H，br.s)，8.93(1H，d，J＝7.3Hz).

MS(ESI)m/z：367(M+H)⁺.

[ reference example 512] (E) -3- (5-Chloropyridin-2-yl) -2-propenoic acid methyl ester

To a tetrahydrofuran (30ml) solution in which sodium hydride (60% oil, 580mg) was suspended was added dropwise a tetrahydrofuran (30ml) solution of methyl 2- (dimethoxyphosphoryl) acetate (2.35ml) at-30 ℃. After stirring at the same temperature for 30 minutes, tetrahydrofuran (10ml) and a solution of 5-chloropyridine-2-carbaldehyde (J.Med.chem.1970, volume 13, page 1124) (1.96g) in tetrahydrofuran (15ml) were added. After slowly warming to room temperature over 1 hour, water (100ml) and ether (50ml) were added to separate the layers, and the aqueous layer was extracted with ether (50 ml). The organic layers were combined, washed with saturated brine (50ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane (30ml) was added to the resulting white solid, and the mixture was stirred for 30 minutes and then filtered to obtain the title compound (1.89g) as a white solid.

¹H-NMR(CDCl₃)δ：3.82(3H，s)，6.91(1H，dd，J＝15.7，0.9Hz)，7.36(1H，d，J＝8.3Hz)，7.64(1H，d，J＝15.7Hz)，7.68(1H，ddd，J＝8.3，2.4，0.9Hz)，8.59(1H，d，J＝2.4Hz).

MS(ESI)m/z：197(M⁺).

[ reference example 513] (1R, 2S, 5S) -2- { [ (E) -3- (5-Chloropyridin-2-yl) acryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by hydrolyzing the obtained compound with the compound obtained in referential example 512 in the same manner as in referential example 97 and condensing the lithium salt of the obtained carboxylic acid with the compound obtained in referential example 144.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.65-1.88(3H，m)，1.88-2.00(2H，m)，2.05-2.22(1H，m)，2.65(1H，br.s)，2.94(3H，s)，3.05(3H，s)，4.05(1H，br.s)，4.10-4.18(1H，m)，4.78(1H，br.s)，6.71(1H，br.s)，6.89(1H，d，J＝15.4Hz)，7.30(1H，d，J＝8.3Hz)，7.54(1H，d，J＝15.4Hz)，7.65(1H，dd，J＝8.3，2.4Hz)，8.53(1H，d，J＝2.4Hz).

MS(ESI)m/z：451(M+H)⁺.

[ reference example 514] Ethyl 3- (4-chlorophenyl) -2-fluoro-3-hydroxypropionate

To a solution of 4-chlorobenzaldehyde (141mg) in benzene (20ml), zinc powder (1.96g) was added, and a catalytic amount of iodine was added while heating under reflux. A benzene solution (2.5ml) of ethyl bromofluoroacetate (185mg) was added dropwise thereto, and the mixture was stirred for 2.5 hours. The reaction mixture was cooled with ice, 1N hydrochloric acid (12.5ml) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. Water and ethyl acetate were added for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound (117mg) as a mixture of diastereomers as a colorless oil.

¹H-NMR(CDCl₃)δ：1.16-1.24(3H，m)，3.35(1H，br.d，J＝51.9Hz)，4.15-4.25(2H，m)，4.89-5.11(2H，m)，7.31-7.33(4H，m).

MS(EI)m/z：246(M⁺).

[ referential example 515] (Z) -3- (4-chlorophenyl) -2-fluoroacrylic acid ethyl ester

Pyridine (100. mu.l) was added to a dichloromethane (1.0ml) solution of the compound (51mg) obtained in referential example 514, and the mixture was cooled at 0 ℃ and added with thionyl chloride (20. mu.l) and stirred at 0 ℃ for 20 minutes. A1N aqueous hydrochloric acid solution and ethyl acetate were added to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (2ml), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (34. mu.l) was added to stir at room temperature for 3.5 hours. 1N hydrochloric acid and dichloromethane were added to separate a liquid, and an aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 4: 1) to give the title compound (22mg) as a pale yellow solid.

¹H-NMR(CDCl₃)δ：1.38(3H，t，J＝7.2Hz)，4.35(2H，q，J＝7.2Hz)，6.87(1H，d，J＝34.9Hz)，7.37(2H，d，J＝8.3Hz)，7.57(2H，d，J＝8.3Hz).

[ reference example 516] (Z) -3- (4-chlorophenyl) -2-fluoroacrylic acid

The title compound was obtained from the compound obtained in referential example 515 by the same method as referential example 274.

¹H-NMR(DMSO-d₆)δ：7.06(1H，d，J＝36.4Hz)，7.52(2H，d，J＝8.2Hz)，7.72(2H，d，J＝8.2Hz).

MS (ESI-anion) 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

2, 2, 2-Trichloroethyl chloroformate (10.6ml) was added dropwise to a pyridine (175ml) solution of the compound (10.0g) obtained in referential example 144, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, methylene chloride and a 0.5N aqueous hydrochloric acid solution were added to separate the layers, and the resulting organic layer was washed 2 times with a 0.5N aqueous hydrochloric acid solution and then 1 time with a saturated saline solution. 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, and hexane was added to filter a solid. This was washed with diethyl ether to give the title compound (13.6g) as a white solid.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.62-1.97(6H，m)，2.67(1H，br.s)，2.94(3H，s)，3.05(3H，s)，3.71-3.76(1H，m)，4.16(1H，br.s)，4.64-4.86(3H，m)，5.62(1H，d，J＝7.3Hz).

MS(ESI)m/z：460(M+H)⁺.

[ reference example 518] (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydro [1, 3] thiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexylcarbamic acid 2, 2, 2-trichloroethyl ester

The title compound was obtained by treating the compound obtained in referential example 517 with hydrochloric acid in the same manner as in referential example 252, deprotecting, and then condensing with the compound obtained in referential example 10.

¹H-NMR(CDCl₃)δ：1.53-2.17(6H，m)，2.52(3H，s)，2.74-2.93(8H，m)，3.03(3H，s)，3.72(2H，br.s)，3.83-3.90(1H，m)，4.62-4.79(3H，m)，5.65(1H，br.d，J＝6.8Hz)，7.36(1H，br.d，J＝8.5Hz).

MS(ESI)m/z：540(M+H)⁺.

[ reference example 519] (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-4, 5, 6, 7-tetrahydro [1, 3] thiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexylcarbamic acid tert-butyl ester

The compound (5.01g) obtained in referential example 518 was dissolved in a mixed solvent of ethanol (100ml) and water (5ml), and zinc (6.06g) and ammonium chloride (2.48g) were added to stir at 40 ℃ for 4.5 hours. After zinc was removed by Celite filtration, sodium hydrogencarbonate (7.78g) and di-tert-butyl dicarbonate (6.08g) were added to the filtrate, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, methylene chloride and water were added to the residue to separate the solution, and the aqueous layer was extracted with methylene chloride 2 times. The combined organic layers were dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate: methanol: 7: 3) and by preparative HPLC (japanese analytical industrial LC908-C60, columns: JAIGEL 1H-40 and 2H-40, solvent: chloroform) to give the title compound (2.30g) as a pale yellow solid.

¹H-NMR(CDCl₃)δ：1.43(9H，s)，1.48-2.07(6H，m)，2.52(3H，s)，2.70-2.96(8H，m)，3.00(3H，s)，3.68-3.77(3H，m)，4.57-4.60(1H，m)，4.94(1H，br.s)，7.33(1H，br.s).

MS(ESI)m/z：466(M+H)⁺.

[ reference example 520]2, 2-dichloro-N- (5-chloropyridin-2-yl) acetamide

The title compound was obtained from 2-amino-5-chloropyridine by the same method as in referential example 457.

¹H-NMR(CDCl₃)δ：6.06(1H，s)，7.73(1H，dd，J＝8.8，2.4Hz)，8.15(1H，dd，J＝9.0，0.5Hz)，8.30(1H，dd，J＝2.5，0.5Hz)，8.78(1H，s).MS(ESI)m/z：239(M+H)⁺.

[ reference example 521] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (methylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

To a methanol (50ml) solution of the compound (1.01g) obtained in referential example 436 was added 10% palladium on carbon catalyst (0.35g), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5.0ml), and the compound (600mg) obtained in referential example 520, diisopropylethylamine (5.0ml) and sulfur (80.3g) were added to stir at 120 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with dichloromethane (200ml) 2 times by adding water. The organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (dichloromethane: methanol ═ 50: 1 → 30: 1) to obtain the title compound (812mg) as a yellow glassy solid.

¹H-NMR(CDCl₃)δ：1.25-2.50(7H，m)，1.46(9H，s)，2.82(3H，d，J＝4.9Hz)，4.23-4.43(2H，m)，4.80-5.10(0.8H，br)，5.50-5.80(1H，br)，580-6.05(0.2H，br)，7.69(1H，dd，J＝8.8，22.4Hz)，8.02(1H，s)，8.10-8.23(1H，m)，8.31(1H，d，J＝2.4Hz)，9.50-9.85(0.2H，br)，9.85-10.15(0.8H，br)，10.56(1H，s).

MS(ESI)m/z：470(M+H)⁺.

[ reference example 522] (1S, 3R, 4S) -3-amino-4- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -N, N-dimethylcyclohexanecarboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 427 by the same method as referential example 69.

¹H-NMR(DMSO-d₆)δ：1.42-1.55(1H，m)，1.72-1.90(3H，m)，2.00-2.09(1H，m)，2.11-2.28(1H，m)，2.82(3H，s)，3.08(3H，s)，3.27-3.40(1H，m)，4.03(1H，br.s)，4.35-4.45(1H，m)，7.89(1H，dt，J＝2.9，9.0Hz)，8.14(1H，dd，J＝9.0，4.2Hz)，8.33(3H，br.s)，8.44(1H，d，J＝2.9Hz)，10.64(1H，s)，10.97(1H，d，J＝7.1Hz).

MS(ESI)m/z：368(M+H)⁺.

[ reference example 523] ethyl 3-amidinobenzoate hydrochloride

Hydrogen chloride gas was introduced into a solution of 3-cyanobenzoic acid (5g) in ethanol (100ml) while stirring with ice-cooling to saturate the solution. Ethanol (400ml) was added to the resulting suspension to dissolve it, and the mixture was allowed to warm to room temperature and then sealed for 18 hours. The mixture was concentrated to a dry solid under reduced pressure, ethanol (100ml) was added to the obtained residue to dissolve the residue, and ammonia gas was introduced under ice-cooling stirring to saturate the solution. After warming to room temperature, the mixture was sealed and left for 18 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified with a synthetic adsorbent HP-20 (water → acetonitrile: water 1: 4). The crude purified product was dissolved in methanol/dichloromethane (1/4), insoluble matter was filtered off, and the product was purified by silica gel column chromatography (methanol/dichloromethane (1: 4)) to obtain the title compound (5.53g) as a colorless powder.

¹H-NMR(DMSO-d₆)δ：1.36(3H，t，J＝7.0Hz)，4.38(2H，q，J＝7Hz)，7.78(1H，t，J＝7.8Hz)，8.11(1H，dd，J＝7.8，1.0Hz)，8.27(1H，d，J＝7.8Hz)，8.38(1H，d，J＝1.5Hz)，9.41(1H，br.s)，9.61(1H，br.s).

MS(FAB)m/z：193(M+H)⁺

[ reference example 524] Ethyl 3- [ [ (tert-butoxycarbonyl) amino ] (imino) methyl ] benzoate

To a methanol (5.0ml) solution of the compound (250mg) obtained in referential example 523 was added diisopropylethylamine (952. mu.l) and di-t-butoxycarbonate (480 mg). After stirring for 3 days, the solvent was evaporated under reduced pressure, and the resulting residue was purified by medium-pressure column chromatography using silica gel as a carrier (dichloromethane: methanol 25: 1) to obtain the title compound (285mg) as a white foamy solid.

¹H-NMR(CDCl₃)δ：1.41(3H，t，J＝7.2Hz)，1.56(9H，s)，4.41(2H，q，J＝7.2Hz)，7.52(1H，t，J＝7.8Hz)，8.14(1H，d，J＝7.8Hz)，8.19(1H，d，J＝7.8Hz)，8.43(1H，s).

MS(ESI)m/z：293(M+H)⁺.

[ reference example 525] (1R, 2S, 5S) -2- [ (3-cyanobenzoyl) amino ] -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamic acid tert-butyl ester

Diisopropylethylamine (730. mu.l) was added to a solution of the compound (800mg) obtained in referential example 144 and 3-cyanobenzoyl chloride (560mg) in methylene chloride (30ml) at room temperature. After stirring for 4 hours, water and a saturated aqueous ammonium chloride solution were added to separate the aqueous layer, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (dichloromethane: acetone ═ 5: 1 → 1: 1) to obtain the title compound (1.15g) as a white foamy solid.

¹H-NMR(CDCl₃)δ：1.40-1.78(2H，m)，1.47(9H，s)，1.78-1.94(2H，m)，2.08-2.40(2H，m)，2.60-2.70(1H，m)，2.96(3H，s)，3.09(3H，s)，3.94-4.08(1H，m)，4.16-4.34(1H，m)，4.79-4.88(1H，m)，7.55(1H，t，J＝7.9Hz)，7.75(1H，d，J＝7.9Hz)，8.0

6-8.16(3H，m).

MS(ESI)m/z：415(M+H)⁺.

[ reference example 526] Ethyl 3- [ [ (ethoxycarbonyl) amino ] (imino) methyl ] benzoate

To the compound (250mg) obtained in referential example 523 were added dichloromethane (10ml), diisopropylethylamine (952. mu.l) and ethyl chloroformate (160. mu.l). After stirring for 8 hours, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to separate the solution, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by medium-pressure column chromatography using silica gel as a carrier (dichloromethane: methanol 25: 1) to obtain the title compound (270mg) as a white solid.

¹H-NMR(CDCl₃)δ：1.36(3H，t，J＝7.1Hz)，1.40(3H，t，J＝7.1Hz)，4.23(2H，q，J＝7.1Hz)，4.39(2H，q，J＝7.1Hz)，6.84(1H，br.s)，7.51(1H，t，J＝7.8Hz)，8.10-8.25(2H，m)，8.45(1H，s)，9.63(1H，br.s).

MS(ESI)m/z：265(M+H)⁺.

[ reference example 527]2, 2-dichloro-N- (5-fluoropyridin-2-yl) acetamide

Dichlorochloroacetyl chloride (279. mu.l) was added to a solution of 2-amino-5-fluoropyridine (250mg) in ethyl acetate (10ml) at room temperature, followed by stirring at 60 to 70 ℃ for 2.5 hours. After cooling the reaction solution, a saturated aqueous sodium bicarbonate solution was added thereto, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude title compound (438 mg).

¹H-NMR(CDCl₃)δ：6.05(1H，s)，7.45-7.55(1H，m)，8.15-8.25(2H，m)，8.72(1H，s).

MS(ESI)m/z：223(M+H)⁺.

[ reference example 528] (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexylcarbamic acid tert-butyl ester

To the compound (112mg) obtained in referential example 527, the compound (143mg) obtained in referential example 144 and sulfur (17mg) were added N, N-dimethylformamide (1.0ml) and diisopropylethylamine (1.0ml), and the mixture was stirred at 130 ℃ for 20 minutes. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue to conduct extraction with methylene chloride. The solution was purified by silica gel column chromatography (dichloromethane: methanol 99: 1) and washed with diisopropyl ether to obtain the title compound (121 mg). NMR data were completely in agreement with the compound of reference example 424.

[ reference example 529] methyl 4-morpholinobenzoate

Thionyl chloride (436. mu.l) was added dropwise to methanol (10ml) under ice cooling. To the solution was added 4-morpholinobenzoic acid (207mg), and after heating under reflux for 1.5 hours, the solvent was distilled off under reduced pressure. Methylene chloride and an aqueous solution were added to the residue, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.

¹H-NMR(CDCl₃)δ：3.28(4H，t，J＝4.9Hz)，3.84-3，87(7H，m)，6.86(2H，dt，J＝9.6，2.5Hz)，7.94(2H，dt，J＝9.6，2.4Hz).

MS(EI)m/z：222(M+H)⁺.

[ reference example 530] methyl 4- (3-oxomorpholin-4-yl) benzoate

To a dichloromethane (10ml) solution of the compound (207mg) obtained in referential example 529 were added benzyltriethylammonium chloride (639mg) and potassium permanganate (222mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with a saturated aqueous solution of sodium bisulfite to separate the reaction mixture, and the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (hexane: ethyl acetate 1: 2) using silica gel as a carrier to give the title compound (41 mg).

¹H-NMR(CDCl₃)δ：3.80-3.83(2H，m)，3.92(3H，s)，4.03-4.07(2H，m)，4.36(2H，s)，7.47(2H，dt，J＝9.0，2.2Hz)，8.08(2H，dt，J＝9.0，2.2Hz).

MS(EI)m/z：236(M+H)⁺.

[ reference example 531]4- (3-oxomorpholin-4-yl) benzoic acid

The title compound was obtained from the compound obtained in referential example 530 in the same manner as in referential example 274.

¹H-NMR(DMSO-d₆)δ：3.78-3.82(2H，m)，3.97-4.01(2H，m)，4.23(2H，s)，7.57(2H，dt，J＝9.1，2.2Hz)，7.96(2H，dt，J＝9.1，2.2Hz)，12.97(1H，br.s)

[ reference example 532]3- (5-chlorothien-2-yl) -2-fluoro-3-hydroxypropionic acid ethyl ester

Zinc powder (19.6g) was added to a solution of 5-chlorothiophene-2-carbaldehyde (1.07ml) in benzene (200ml) and the mixture was refluxed. To this was added a catalytic amount of iodine, followed by dropwise addition of a solution of ethyl bromofluoroacetate (3.70g) in benzene (25 ml). After heating and refluxing for 1.5 hours, a catalytic amount of iodine was added, and the mixture was heated and refluxed for 3.5 hours. After the reaction solution was cooled naturally, 1N aqueous hydrochloric acid (125ml) was added thereto under ice cooling, and the mixture was stirred for 1 hour. The insoluble matter 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 evaporated 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).

¹H-NMR(CDCl₃)δ：1.24-1.31(3H，m)，3.09-3.21(1H，m)，4.21-4.31(2H，m)，4.97-5.12(1H，m)，5.21-5.28(1H，m)，6.79-6.86(2H，m).

MS(EI)m/z：252(M⁺).

[ reference example 533] (Z) -3- (5-chlorothien-2-yl) -2-fluoroacrylic acid ethyl ester

Pyridine (4.70ml) and thionyl chloride (849. mu.l) were added to a dichloromethane (50ml) solution of the compound (2.46g) obtained in referential example 532 under ice cooling, and stirred at 0 ℃ for 30 minutes and at room temperature for 1 hour. 1N hydrochloric acid aqueous solution was added to the reaction mixture to separate the solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with a 1N hydrochloric acid aqueous solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (150ml), and 1, 8-diazabicyclo [5.4.0] undec-7-ene (1.60ml) was added to stir at room temperature for 1 hour. The solvent was evaporated under reduced pressure and purified by flash column chromatography on silica gel (hexane: ethyl acetate 7: 1) to obtain the title compound (1.05 g).

¹H-NMR(CDCl₃)δ：1.37(3H，t，J＝7.1Hz)，4.34(2H，q，J＝7.1Hz)，6.90(1H，dd，J＝3.9，2.0Hz)，7.06(1H，d，J＝33.7Hz)，7.08-7.10(1H，m).

MS(FAB)m/z：235(M+H)⁺.

[ reference example 534] (Z) -3- (5-chlorothien-2-yl) -2-fluoroacrylic acid

The title compound was obtained from the compound obtained in referential example 533 by the same method as referential example 274.

¹H-NMR(DMSO-d₆)δ：7.22(1H，dd，J＝3.9，2.0Hz)，7.35-7.40(2H，m)，13.76(1H，br.s).

MS(ESI-neg.)m/z：205(M-H)^-.

[ reference example 535]6-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d]Aza derivatives-2-Amines

Prepared by the same method as described in reference example 475 as 5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d ]]Aza derivatives-2-Amylamine (Japanese patent laid-open No. Hei 2-45489) to obtain the title compound.

¹H-NMR(CDCl₃)δ：2.44(3H，s)，2.66-2.69(2H，m)，2.71(4H，s)，2.80-2.83(2H，m)，4.66(2H，s).

MS(ESI)m/z：184(M+H)⁺.

[ reference example 536]2-bromo-6-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d]Aza derivatives

The title compound was obtained from the compound obtained in referential example 535 by the same method as referential example 476.

¹H-NMR(CDCl₃)δ：2.45(3H，s)，2.66-2.72(4H，m)，2.85-2.88(2H，m)，3.03-3.06(2H，m).

MS(ESI)m/z：247(M+H)⁺.

[ reference example 537)]6-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d]Aza derivatives-2-carboxylic acid lithium salt

The title compound was obtained from the compound obtained in referential example 536 in the same manner as in referential example 10.

¹H-NMR(DMSO-d₆)δ：2.33(3H，s)，2.56-2.63(4H，m)，2.77-2.93(4H，m)

MS(ESI)m/z：213(M+H)⁺.

[ reference example 538]5, 6, 7, 8-tetrahydro [1, 6] naphthyridine-2-carbonitrile hydrochloride

To a solution of tert-butyl 2-cyano-7, 8-dihydro-5H- [1, 6] naphthyridine-6-carboxylate (WO 00/09480) (3.74g) in dichloromethane (5.0ml) was added a 4N hydrochloric acid-dioxane solution (14ml), and the mixture was stirred at room temperature for 65 minutes and at 40 ℃ for 40 minutes. A4N hydrochloric acid-dioxane solution (8ml) was added to the reaction mixture, and the mixture was stirred at 45 ℃ for 75 minutes. Ethyl acetate was added to the reaction mixture, and the precipitated powder was collected by filtration to obtain the title compound (3.20g) as a colorless powder.

¹H-NMR(DMSO-d₆)δ：3.14(2H，t，J＝6.4Hz)，3.50-3.70(2H，m)，4.40(2H，s)，7.93(1H，s)，8.30(1H，s)，9.49(1H，br.s).

[ reference example 539] 6-methyl-5, 6, 7, 8-tetrahydro [1, 6] naphthyridine-2-carbonitrile

The title compound was obtained by reacting the compound obtained in referential example 538 in the same manner as in referential example 9.

¹H-NMR(CDCl₃)δ：2.49(3H，s)，2.81(2H，q，J＝6.0Hz)，3.10(2H，t，J＝6.0Hz)，3.71(2H，s)，7.44(1H，d，J＝8.1Hz)，7.47(1H，d，J＝7.8Hz).

[ reference example 540] 6-methyl-5, 6, 7, 8-tetrahydro [1, 6] naphthyridine-2-carboxylate hydrochloride

Concentrated hydrochloric acid (12ml) was added to the compound (2.46g) obtained in referential example 539, and the mixture was heated at 100 to 110 ℃ for 5.5 hours. The reaction mixture was concentrated under reduced pressure with water, and then water was added thereto, and the mixture was made alkaline with a 1N aqueous solution of sodium hydroxide. After concentrating the solution to about half, it was neutralized with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. Adding ethanol to the residue, heating at 40-50 deg.C, and filtering off insoluble substances with diatomaceous earth. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethanol, 1N hydrochloric acid-ethanol (18ml) was added, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and insoluble matter was collected by filtration to obtain the crude title compound (2.33 g).

¹H-NMR(DMSO-d₆)δ：2.93(3H，s)，3.16(1H，d，J＝16.4Hz)，3.37-3.80(3H，m)，4.35-4.47(1H，m)，4.59(1H，d，J＝16.8Hz)，7.83(1H，d，J＝8.1Hz)，7.93(1H，d，J＝8.1Hz).

[ reference example 541] (1S, 3R, 4S) -4- { [ (benzyloxy) carbonyl ] amino } -3- [ (tert-butoxycarbonyl) amino ] cyclohexanecarboxylic acid tert-butyl ester

The compound (7.15g) obtained in referential example 142 was dissolved in methylene chloride (100ml), and 2-methyl-2-propanol (4.88ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.89g) and 4-dimethylaminopyridine (2.08g) were added to stir at room temperature for 19 hours. The reaction mixture was diluted with methylene chloride (200ml), washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: acetone → 30: 1 → 20: 1) to obtain the title compound (7.07 g).

¹H-NMR(CDCl₃)δ：1.20-2.09(6H，m)，1.43(9H，s)，1.44(9H，s)，2.26(1H，br.s)，3.62-3.72(1H，m)，4.10(1H，br.s)，4.52-5.40(4H，m)，7.27-7.38(5H，m).

MS(FAB)m/z：449(M+H)⁺.

[ reference example 542] (1S, 3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -4- ({2- [ (5-chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexanecarboxylic acid tert-butyl ester

To a methanol (7.0ml) -tetrahydrofuran (7.0ml) solution of the compound (700mg) obtained in referential example 541 was added a 10% palladium on carbon catalyst (wet, 350mg), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (10ml), and sulfur (65mg), the compound (374mg) obtained in referential example 520 and diisopropylethylamine (0.816ml) were added to stir at 120 ℃ for 8 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride was added to the residue, which was washed successively with a 10% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate 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 (dichloromethane: methanol ═ 100: 1 → 50: 1) to obtain the title compound (373 mg).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.48(9H，s)，1.49-1.70(2H，m)，1.80-2.40(5H，m)，4.26-4.39(2H，m)，4.79(1H，br.s)，7.70(1H，dd，J＝9.0，2.4Hz)，8.19(1H，d，J＝9.0Hz)，8.32(1H，d，J＝2.4Hz)，10.01(1H，br.s)，10.58(1H，s).

MS(ESI)m/z：513(M+H)⁺.

[ referential example 543] (1S, 3R, 4S) -3-amino-4- ({2- [ (5-chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexanecarboxylic acid tert-butyl ester hydrochloride

To an ethyl acetate (3.90ml) solution of the compound (530mg) obtained in referential example 542 was added a 1N hydrochloric acid-ethyl acetate solution (1.30ml), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (284 mg).

¹H-NMR(DMSO-d₆)δ：1.42(9H，s)，1.49-1.61(1H，m)，1.71-1.88(2H，m)，1.88-2.03(1H，m)，2.04-2.26(2H，m)，2.71-2.85(1H，m)，3.84-4.12(1H，m)，4.44(1H，br.s)，8.00-8.29(5H，m)，8.44-8.51(1H，m)，10.67(1H，s)，10.91(1H，d，J＝6.8Hz).

MS(ESI)m/z：413(M+H)⁺.

[ reference example 544] (1S, 3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -4- ({2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) cyclohexanecarboxylic acid tert-butyl ester

To a methanol (20ml) -tetrahydrofuran (20ml) solution of the compound (1.00g) obtained in referential example 541 was added a 10% palladium on carbon catalyst (wet, 500mg), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, the resulting residue was dissolved in N, N-dimethylformamide (10ml), and the compound (231mg) obtained in referential example 266, 1-hydroxybenzotriazole (139mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288mg) were successively added to the solution, followed by stirring overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and a 10% citric acid aqueous solution were added to the residue to separate the mixture. The oil layer was washed with saturated brine, aqueous sodium hydrogencarbonate solution and saturated brine. The oil layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (364 mg).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.46(9H，s)，1.54-2.09(6H，m)，2.20-2.38(1H，m)，3.83-3.98(1H，m)，4.08-4.29(1H，m)，4.71(1H，br.s)，7.69(1H，dd，J＝8.9，2.6Hz)，8.00(1H，br.s)，8.18(1H，d，J＝8.9Hz)，8.31(1H，d，J＝2.5Hz)，9.72(1H，br.s).

MS(ESI)m/z：441(M-tBu)⁺.

[ reference example 545] methyl 2-methyl-1, 2, 3, 4-tetrahydro-6-isoquinolinecarboxylate

Trifluoroacetic acid (3ml) was added to a solution of 2- (tert-butyl) 3, 4-dihydro (1H) isoquinoline-2, 6-dicarboxylic acid 2- (tert-butyl) ester 6-methyl ester (WO 00/09480) (344mg) in methylene chloride (6ml) under ice cooling, and the mixture was stirred for 30 minutes. The concentrated reaction solution was diluted with chloroform, neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with chloroform/methanol (4/1). The obtained organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol ═ 20: 1 → 1: 1) to give methyl 1, 2, 3, 4-tetrahydroisoquinoline-6-carboxylate (154 mg). This compound was dissolved in dichloromethane (5ml), and formalin (90.6. mu.l) was added at room temperature. After stirring for 10 minutes, acetic acid (46. mu.l) and sodium triacetoxyborohydride (269mg) were added under ice cooling. After stirring at room temperature for 105 minutes, the mixture was neutralized with a saturated aqueous sodium bicarbonate 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).

¹H-NMR(CDCl₃)δ：2.47(3H，s)，2.70(2H，dd，J＝6.0Hz)，2.96(2H，dd，J＝6.0Hz)，3.62(2H，s)，3.90(3H，s)，7.08(1H，d，J＝7.6Hz)，7.78(1H，d，J＝7.6Hz)，7.80(1H，s).

MS(ESI)m/z：206(M+H)⁺.

[ reference example 546] (1R, 2R, 4S) -4- (aminocarbonyl) -2- [ (tert-butoxycarbonyl) amino ] cyclohexylcarbamic acid fluoren-9-ylmethyl ester

The compound (1.92g) obtained in referential example 142 was dissolved in N, N-dimethylformamide (30ml) under ice-cooling, and ammonium chloride (523mg), 1-hydroxybenzotriazole (661mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.41g) and diisopropylethylamine (1.70ml) were successively added to the solution, followed by standing until the temperature returned to room temperature and stirring for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a 10% citric acid aqueous solution were added to the residue to separate the mixture. The oil layer was washed with saturated brine, aqueous sodium hydrogencarbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and hexane was added to the resulting residue to solidify it, whereby crude tert-butyl (1R, 2S, 5S) -5- (aminocarbonyl) -2- { [ (benzyloxy) carbonyl ] amino } cyclohexylcarbamate (1.66g) was obtained. A mixture of the crude (1.65g), 10% palladium on carbon catalyst (400mg) and methanol (150ml) was stirred overnight at room temperature under a hydrogen atmosphere. After the catalyst was filtered off, the solvent was evaporated under reduced pressure, and 9-fluorenylmethyl succinimidyl carboxylate (2.13g), 1, 2-dimethoxyethane (130ml) and a saturated aqueous sodium bicarbonate solution (130ml) were added to the resulting residue, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate, saturated brine and water, followed by liquid separation, and the obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain the title compound (1.99 g).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.53-2.08(6H，m)，2.30(1H，br.s)，3.71(1H，br.s)，4.07-4.15(1H，m)，4.21(1H，br.s)，4.37(2H，br.s)，4.70-5.80(4H，m)，7.26-7.33(2H，m)，7.39(2H，t，J＝7.3Hz)，7.53-7.61(2H，m)，7.76(2H，d，J＝7.3Hz).

MS(ESI)m/z：502(M+Na)⁺.

[ reference example 547] (1S, 2R, 4S) -4- (Thiocarboxoyl) -2- [ (tert-butoxycarbonyl) amino ] cyclohexylcarbamic acid fluoren-9-ylmethyl ester

The compound (1.98g) obtained in referential example 546 was dissolved in tetrahydrofuran (200ml), and ロ - ソン reagent (1.22g) was added to the solution, followed by stirring at room temperature for 4 days. Thereafter, ロ - ソン reagent (0.50g) was added to the reaction solution and stirred overnight. Silica gel was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 2: 1). To the resulting oil was added diethyl ether and stirred, and the precipitated powder was collected by filtration to obtain the title compound (1.25 g).

¹H-NMR(CDCl₃)δ：1.45(9H，br.s)，1.57-2.10(6H，m)，2.69(1H，br.s)，3.71(1H，br.s)，4.06-4.27(2H，m)，4.36(2H，br.s)，4.89(1H，br.s)，5.46(1H，br.s)，7.11(1H，br.s)，7.26-7.34(2H，m)，7.39(2H，t，J＝7.3Hz)，7.57(3H，br.s)，7.76(2H，d，J＝7.1Hz).

MS(ESI)m/z：518(M+Na)⁺.

[ reference example 548] (1R, 2S, 5S) -5- (Thiocarbamoyl) -2- ({2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) cyclohexylcarbamic 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 (4.64g) obtained in referential example 547 was dissolved in N, N-dimethylformamide (50ml), and piperidine (2.78ml) was added to the solution, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane ═ 3: 47 → 3: 17) to obtain crude tert-butyl (1R, 2S, 5S) -2-amino-5- (carbonothioyl) cyclohexylcarbamate (2.17 g). This compound was dissolved in N, N-dimethylformamide (100ml), and the compound (1.78g) obtained in referential example 266, 1-hydroxybenzotriazole (1.07g) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.28g) were successively added to this solution and stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, dichloromethane and a 10% citric acid aqueous solution were added to the residue to conduct liquid separation. The oil layer was washed with saturated brine, aqueous sodium hydrogencarbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound having a cyano group at the 5-position (427mg) and the title compound having a thiocarbamoyl group at the 5-position (718 mg).

5-cyano group:¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.56-1.66(1H，m)，1.74-1.87(1H，m)，1.90-2.23(4H，m)，2.72(1H，br.s)，4.02-4.23(2H，m)，4.71(1H，br.s)，7.71(1H，dd，J＝8.8，2.4Hz)，7.85(1H，br.s)，8.15(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，9.69(1H，br.s).

5- (carbothioformyl) body:¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.74-2.17(6H，m)，2.70(1H，s)，3.94-4.04(1H，m)，4.23(1H，br.s)，4.86(1H，br.s)，6.97(1H，br.s)，7.50(1H，br.s)，7.70(1H，dd，J＝8.8，2.4Hz)，7.98(1H，br.s)，8.18(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，9.72(1H，s).

MS(ESI)m/z：456(M+H)⁺.

[ reference example 549] (1R, 2S, 5RS) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (thiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

The compound having a thiocarbamoyl group at the 5-position (72mg) obtained in referential example 548 and bromoacetaldehyde dimethylacetal (20.4. mu.l) were dissolved in N, N-dimethylformamide (5ml), and the mixture was stirred at 50 ℃ for 8 hours. Then, bromoacetaldehyde dimethylacetal (80. mu.l) was added thereto, stirred for 13 hours, and allowed to stand at room temperature. To the reaction mixture were added di-tert-butyl dicarbonate (34.5mg) and anhydrous sodium hydrogencarbonate (200mg), and the mixture was stirred at room temperature for 1 hour, then triethylamine (97. mu.l) was added, and the mixture was stirred for 2 hours. Ethyl acetate and a 10% citric acid aqueous solution were added to the reaction mixture to separate the reaction mixture, and the organic layer was washed with a saturated saline solution, a saturated sodium bicarbonate aqueous solution and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to obtain the title compound (37.5 mg).

¹H-NMR(CDCl₃)δ：1.40-1.51(9H，m)，1.75-2.16(5H，m)，2.19-2.39(1H，m)，3.10-3.38(1H，m)，3.91-4.08(1H，m)，4.21-4.40(1H，m)，4.80-4.94(0.5H，m)，5.61-5.90(0.5H，m)，7.24-7.26(1H，m)，7.66-7.74(2H，m)，7.80-7.90(0.5H，m)，8.02-8.11(0.5H，m)，8.16-8.22(1H，m)，8.27-833(1H，m)，9.66-9.80(1H，m).

MS(ESI)m/z：480(M+H)⁺.

[ reference example 550] (1R, 2S, 5S) -2- ({2- [ (5-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 the 5-position (427mg) obtained in referential example 548 and anhydrous sodium hydrogencarbonate (84.9mg) were suspended in ethanol, and hydroxylamine sulfate (82.9mg) was added to the suspension, which was then heated at 60 ℃ and stirred for 6 days. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 9) to obtain crude tert-butyl (1R, 2S, 5S) -5- [ amino (hydroxyimino) methyl ] -2- ({2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) cyclohexylcarbamate (183 mg). To this compound were added methyl orthoformate (5ml) and boron trifluoride etherate (1 drop) at room temperature, followed by heating at 55 ℃ and stirring for 20 minutes. After the mixture was allowed to stand at room temperature, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 9) to obtain the title compound (57.6 mg).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.53-1.70(1H，m)，1.73-1.94(1H，m)，1.95-2.30(4H，m)，3.03(1H，br.s)，4.00-4.11(1H，m)，4.27(1H，br.s)，4.87(1H，br.s)，7.70(1H，dd，J＝8.9，2.4Hz)，8.04(1H，s)，8.19(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，8.66(1H，s)，9.74(1H，br.s).

MS(ESI)m/z：463(M-H)^-.

[ reference example 551] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (5-methyl-1, 2, 4-oxadiazol-2-yl) cyclohexylcarbamic acid benzyl ester

The compound (4.0g) obtained in referential example 142 was dissolved in N, N-dimethylformamide (100ml), and to the solution, hydrazine 1 hydrate (765mg), 1-hydroxybenzotriazole (1.38g) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.93g) were added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and methylene chloride and an aqueous solution of sodium hydrogencarbonate were added to the residue to separate the mixture. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, silica gel (25g) and methanol (15ml) were added to the obtained filtrate and stirred, and insoluble matter was filtered off. The solvent was distilled off under reduced pressure to obtain crude benzyl (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (hydrazinocarbonyl) cyclohexylcarbamate (3.71 g). To the obtained crude product (1.73g) were added methyl orthoacetate (10ml) and boron trifluoride etherate (2 drops), and the mixture was heated at 70 ℃ and stirred overnight. After the mixture was allowed to stand at room temperature, the solvent was evaporated under reduced pressure, and methylene chloride and an aqueous solution of sodium hydrogencarbonate were added to the obtained residue to separate the mixture. After the aqueous layer was extracted with dichloromethane, the resulting organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (methanol: dichloromethane ═ 1: 19) gave the title compound (1.10 g).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.68-2.27(6H，m)，2.50(3H，s)，2.95-3.09(1H，m)，3.66-3.86(1H，m)，4.08-4.24(1H，m)，4.76(1H，br.s)，5.04-5.16(2H，m)，5.27-5.36(1H，m)，7.29-7.39(5H，m).

MS(ESI)m/z：431(M+H)⁺.

[ reference example 552] (1R, 2S, 5S) -2- ({2- [ (5-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 (1.10g) obtained in referential example 551, a 10% palladium on carbon catalyst (300mg) and methanol (50ml) was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the catalyst was filtered off, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in N, N-dimethylformamide (50 ml). To the solution were added the compound (632mg) obtained in referential example 266, 1-hydroxybenzotriazole (381mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (810mg) in this order, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a 10% citric acid aqueous solution were added to the residue to separate the mixture. The oil layer was washed with saturated brine, aqueous sodium hydrogencarbonate 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).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.58-1.88(2H，m)，1.92-2.31(4H，m)，2.52(3H，s)，3.04(1H，br.s)，3.98-4.09(1H，m)，4.27(1H，br.s)，4.83(1H，br.s)，7.71(1H，dd，J＝8.8，2.4Hz)，8.02(1H，br.s)，8.19(1H，d，J＝8.8Hz)，8.32(1H，d，J＝2.4Hz)，9.72(1H，br.s).

MS(ESI)m/z：479(M+H)⁺.

[ reference example 553] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (1, 3, 4-oxadiazol-2-yl) cyclohexylcarbamic acid benzyl ester

The title compound was obtained by condensing the compound obtained in referential example 142 with hydrazine and then subjecting the condensed product to cyclization reaction with methyl orthoformate in the same manner as in referential example 551.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.71-2.30(6H，m)，3.04-3.15(1H，m)，3.80(1H，br.s)，4.17(1H，br.s)，4.75(1H，br.s)，5.05-5.15(2H，m)，5.25(1H，s)，7.30-7.38(5H，m)，8.35(1H，s).

MS(ESI)m/z：417(M+H)⁺.

[ reference example 554] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (1, 3, 4-oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 553 and then condensing it with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.59-1.92(2H，m)，2.00-2.33(4H，m)，3.02-3.22(1H，m)，3.94-4.10(1H，m)，4.27(1H，br.s)，4.83(1H，br.s)，7.71(1H，dd，J＝8.9，2.6Hz)，8.00(1H，br.s)，8.19(1H，d，J＝8.9Hz)，8.32(1H，d，J＝2.6Hz)，8.37(1H，br.s)，9.72(1H，s).

MS(ESI)m/z：465(M+H)⁺.

[ reference example 555] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- { [ (2-hydroxyethyl) amino ] carbonyl } cyclohexylcarbamic acid benzyl ester

The title compound was obtained by condensing the compound obtained in referential example 142 with 2-aminoethanol in the same manner as in referential example 143.

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.50-2.07(6H，m)，2.28-2.39(1H，m)，3.26-3.49(1H，m)，3.45-3.63(1H，m)，3.65-3.84(3H，m)，3.90-4.07(1H，m)，5.02-5.28(4H，m)，6.21-6.35(1H，m)，7.28-7.39(5H，m).

MS(ESI)m/z：436(M+H)⁺.

[ reference example 556] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (1, 3-oxazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

Dimethyl sulfoxide (3.47ml) was added dropwise to a dichloromethane (50ml) solution of oxalyl chloride (2.85ml) cooled to-60 ℃ under a nitrogen atmosphere, and then a dichloromethane (20ml) solution of the compound (3.55g) obtained in referential example 555 was added dropwise over 15 minutes. After stirring at-60 ℃ for 45 minutes, triethylamine (11.4ml) was added dropwise thereto, and the mixture was further stirred for 30 minutes. Water was added to the reaction mixture at-60 ℃ to return the temperature to room temperature, followed by extraction with chloroform and drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol ═ 50: 1 → 10: 1) to obtain a yellow solid (2.43 g). To a solution of triphenylphosphine (4.41g) in dichloromethane (25ml), hexachloroethane (3.32g), triethylamine (4.69ml) and a solution of the resulting yellow solid (2.43g) in dichloromethane (35ml) were added in this order, and the mixture was stirred at room temperature for 20 hours. After adding a saturated aqueous sodium bicarbonate solution and stirring for 30 minutes, the reaction mixture was extracted with chloroform, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting concentrated residue was purified by silica gel column chromatography (chloroform: methanol: 50: 1) to obtain a mixture of an oxazole cyclic compound and triphenylphosphine oxide. The resulting mixture was dissolved in methanol (30ml), and 10% palladium on carbon catalyst (2.08g) was added to stir at room temperature for 14 hours under a hydrogen atmosphere. 10% Palladium on carbon catalyst (1.02g) was added, and after stirring for another 6 hours under a hydrogen atmosphere, the catalyst was filtered, and the filtrate was concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (chloroform: methanol ═ 50: 1 → 10: 1), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (872mg) and 1-hydroxybenzotriazole 1 hydrate (461mg) were added to a solution of the obtained compound and the compound (612mg) obtained in referential example 266 in N, N-dimethylformamide (15ml) at room temperature. After the reaction mixture was stirred for 12 hours, chloroform was added to the reaction mixture, which was washed with water and a protected aqueous sodium bicarbonate solution in this order, and then dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography (methanol: chloroform ═ 50: 1) to obtain the title compound (390 mg).

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.54-2.30(6H，m)，2.90-3.07(1H，m)，3.97-4.08(1H，m)，4.15-4.30(1H，m)，4.91-5.10(1H，m)，7.03(1H，s)，7.58(1H，s)，7.70(1H，dd，J＝8.8，2.4Hz)，7.98-8.11(1H，m)，8.25(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，9.75(1H，s).

MS(ESI)m/z：464(M+H)⁺.

[ reference example 557] (1S, 3R, 4S) -3- [ (tert-butoxycarbonyl) amino ] -4- ({ [2- (trimethylsilyl) ethoxy ] carbonyl } amino) cyclohexanecarboxylic acid

A mixture of the compound (4.20g) obtained in referential example 141, a 10% palladium on carbon catalyst (1.0g) and ethanol (100ml) was stirred at room temperature for 5 hours under a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. To the resulting residue were added dioxane (50ml), water (50ml) and triethylamine (2.09ml), and the mixture was cooled with ice. To the mixture was added 1- [2- (trimethylsilyl) ethoxycarbonyloxy ] pyrrolidine-2, 5-dione (2.85g), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and a 10% citric acid aqueous solution were added to the residue to separate the solution. The oil layer was washed with saturated saline, aqueous sodium hydrogencarbonate and saturated saline in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a pale yellow oil (4.46 g). To a tetrahydrofuran (50ml) solution of the oily substance were added water (10ml) and lithium hydroxide (479mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and ethyl acetate and a 10% citric acid aqueous solution were added to the residue to separate the solution. The oil layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained colorless powder was washed with hexane to obtain the title compound (3.51 g).

¹H-NMR(CDCl₃)δ：0.06(9H，s)，0.97(2H，t，J＝7.8Hz)，1.46(9H，br.s)，1.52-2.22(6H，m)，2.47(1H，br.s)，3.68(1H，s)，3.97-4.24(3H，m)，4.69(0.5H，br.s)，4.95(0.5H，br.s)，5.18(0.5H，br.s)，6.42(0.5H，br.s).

MS(ESI)m/z：401(M-H)^-].

[ reference example 558] N-Hydroxyacetamidine

Hydroxylamine (50% water, 661mg) was dissolved in acetonitrile (10ml) and stirred at 60 ℃ 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).

¹H-NMR(DMSO-d₆)δ：1.62(3H，s)，5.33(2H，br.s)，8.66(1H，br.s).

[ reference example 559] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (3-methyl-1, 2, 4-oxadiazol-5-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The compound (201mg) obtained in referential example 557 and the compound (37mg) obtained in referential example 558 were suspended in 1, 2-dimethoxyethane (5ml), and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (115mg) was added to the suspension, followed by stirring overnight at room temperature. Then, molecular sieves (MS-4A, powder, 1.0g) were added to the reaction solution, and the mixture was heated under reflux overnight. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to obtain the title compound (96.5 mg).

¹H-NMR(CDCl₃)δ：0.04(9H，s)，0.98(2H，t，J＝8.4Hz)，1.46(9H，s)，1.60-1.83(2H，m)，1.87-2.28(4H，m)，2.38(3H，s)，3.04(1H，br.s)，3.76(1H，br.s)，4.07-4.22(3H，m)，4.72(1H，br.s)，5.14(1H，br.s).

MS(ESI)m/z：341(M-Boc+2H)⁺.

[ reference example 560] (1S, 2R, 4S) -4- (3-methyl-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

A solution of the compound (96.5mg) obtained in referential example 559 in ethanol (10ml) was added with p-toluenesulfonic acid (45.8mg) at room temperature. The reaction solution was heated to 60 ℃ and stirred overnight. After standing at room temperature, the solvent was evaporated under reduced pressure to obtain a colorless powder. To the powder were added the compound (67mg) obtained in referential example 10 and N, N-dimethylformamide (5 ml). To the solution were added 1-hydroxybenzotriazole (44.5mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (84mg), and the mixture was stirred at room temperature overnight. After the solvent was distilled off under reduced pressure, methylene chloride and an aqueous sodium bicarbonate solution were added to the residue to separate the mixture, and 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 column chromatography (methanol: dichloromethane ═ 3: 47) to obtain the title compound (110 mg).

¹H-NMR(CDCl₃)δ：0.02(9H，s)，0.97(2H，dd，J＝9.9，7.0Hz)，1.57-1.72(1H，m)，1.79-1.92(1H，m)，2.06-2.37(4H，m)，2.38(3H，s)，2.53(3H，s)，2.84-2.89(2H，m)，2.93-2.99(2H，m)，3.12-3.23(1H，m)，3.76(2H，br.s)，3.85-3.94(1H，m)，4.14(2H，dd，J＝9.9，7.0Hz)，4.60-4.69(1H，m)，5.23(1H，d，J＝7.6Hz)，7.41(1H，d，J＝8.3Hz).

MS(ESI)m/z：521(M+H)⁺.

[ reference example 561] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (1, 3, 4-thiadiazol-2-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The compound (1.0g) obtained in referential example 557 was dissolved in N, N-dimethylformamide (20ml), and to the solution were added formylhydrazine (149mg), 1-hydroxybenzotriazole (335mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (713mg) in this order, followed by stirring overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and a 10% citric acid aqueous solution were added to the residue to separate the mixture. The oil layer was washed with saturated brine, aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless powder (1.12 g). Toluene (50ml) and ロ - ソン reagent (2.0g) were added to the powder at room temperature, followed by heating and refluxing for 1 hour. After the mixture 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 column chromatography (hexane: ethyl acetate ═ 1: 1 → 0: 1) to obtain the title compound (511 mg).

¹H-NMR(CDCl₃)δ：0.04(9H，s)，0.99(2H，t，J＝8.4Hz)，1.46(9H，s)，1.59-1.85(2H，m)，1.91-2.02(1H，m)，2.05-2.14(1H，m)，2.18-2.27(1H，m)，2.29-2.40(1H，m)，3.31-3.44(1H，m)，3.69-3.86(1H，m)，4.09-4.23(3H，m)，4.71-4.93(1H，m)，5.07-5.34(1H，m)，9.05(1H，s).

MS(ESI)m/z：443(M+H)⁺.

[ reference example 562] (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } -4- (1, 3, 4-thiadiazol-2-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The title compound was obtained by treating the compound obtained in referential example 561 with p-toluenesulfonic acid in the same manner as in referential example 560, deprotecting the treatment, and then condensing the deprotected compound with the compound obtained in referential example 10.

¹H-NMR(CDCl₃)δ：0.03(9H，s)，0.97(2H，t，J＝8.5Hz)，1.63-1.75(1H，m)，1.81-1.93(1H，m)，2.01-2.22(2H，m)，2.25-2.37(1H，m)，2.42-2.51(1H，m)，2.52(3H，s)，2.81-2.89(2H，m)，2.92-2.99(2H，m)，3.47-3.57(1H，m)，3.73(2H，s)，3.86-3.96(1H，m)，4.14(2H，t，J＝8.5Hz)，4.61-4.69(1H，m)，5.21-5.28(1H，m)，7.41-7.53(1H，m)，9.06(1H，s).

MS(ESI)m/z：523(M+H)⁺.

[ reference example 563] (1S, 3R, 4S) -3-amino-4- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -N, N-dimethylcyclohexanecarboxamide hydrochloride

To a dioxane (350ml) -methanol (200ml) suspension of the compound (73.3g) obtained in reference example 427 was added dropwise a 4N hydrochloric acid-dioxane solution (350ml) over 5 minutes, and after stirring in ice water for 10 minutes, the mixture was stirred at room temperature for 2 and half hours. The reaction solution was concentrated under reduced pressure, azeotroped with dioxane and tetrahydrofuran, and dried to obtain the title compound (76.4 mg).

¹H-NMR(DMSO-d₆)δ：1.34-1.55(1H，m)，1.64-1.84(3H，m)，1.97-2.11(1H，m)，2.11-2.30(1H，m)，2.80(3H，br.s)，3.06(3H，br.s)，3.20-3.58(1H，m)，3.91-4.07(1H，m)，4.22-4.42(1H，m)，7.74-7.91(1H，m)，8.00-8.16(1H，m)，8.25-8.60(4H，m)，10.64(1H，d，J＝11.9Hz)，10.89-10.99(1H，m).

MS(ESI)m/z：367(M+H)⁺.

[ reference example 564] 5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxylate hydrochloride

To the compound (3.00g) obtained in referential example 10 was added a 1N ethanol hydrochloride solution (36ml), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, and washed with ethanol (9 ml). The wet body was dried under reduced pressure at room temperature to obtain the title compound (2.76 g).

¹H-NMR(D₂O)δ：4.82-4.88(1H，d，J＝16.0Hz)，4.51-4.57(1H，d，J＝16.0Hz)，3.88-3.96(1H，m)，3.60-3.70(1H，m)，3.22-3.33(2H，m)，3.15(3H，s).

[ reference example 565] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (5-methyl-1, 3, 4-thiadiazol-2-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The title compound was obtained by condensing the compound obtained in referential example 557 with acethydrazide, reacting with ロ - ソン reagent and heating in the same manner as in referential example 561.

¹H-NMR(CDCl₃)δ：0.04(9H，s)，0.98(2H，t，J＝8.5Hz)，1.46(9H，s)，1.61-1.75(1H，m)，1.80-2.00(3H，m)，2.11-2.20(1H，m)，2.22-2.31(1H，m)，2.75(3H，s)，3.17-3.32(1H，m)，3.61-3.88(1H，m)，4.07-4.22(3H，m)，4.82(1H，br.s)，5.24(1H，br.s).

MS(ESI)m/z：457(M+H)⁺.

[ reference example 566] (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } -4- (5-methyl-1, 3, 4-thiadiazol-2-yl) cyclohexanecarboxylic acid 2- (trimethylsilyl) ethyl ester

The title compound was obtained by treating the compound obtained in referential example 565 with p-toluenesulfonic acid in the same manner as in referential example 560, deprotecting the treatment, and condensing with the compound obtained in referential example 564.

¹H-NMR(CDCl₃)δ：0.02(9H，s)，0.97(2H，t，J＝7.8Hz)，1.59-1.73(1H，m)，1.74-1.87(1H，m)，1.97-2.08(1H，m)，2.08-2.20(1H，m)，2.20-2.31(1H，m)，2.36-2.45(1H，m)，2.52(3H，s)，2.75(3H，s)，2.84(2H，t，J＝5.5Hz)，2.95(2H，t，J＝5.5Hz)，3.35-3.49(1H，m)，3.73(2H，br.s)，3.89(1H，br.s)，4.14(2H，t，J＝7.8Hz)，4.58-4.69(1H，m)，5.29(1H，br.s)，7.47(1H，d，J＝8.1Hz).

MS(ESI)m/z：537(M+H)⁺.

[ reference example 567] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (1, 3-oxazol-5-yl) cyclohexylcarbamic acid benzyl ester

N-methylformamide (0.99ml) was added dropwise to a mixture of quinoline (8.00ml) and p-toluenesulfonyl chloride (4.84g) under reduced pressure at 75 ℃. The resulting gas was cooled to a liquid by a Liebig condenser, and collected in an eggplant type flask cooled to-78 ℃ to obtain methyl isocyanide (553 mg). N-butyllithium (1.57M in hexane, 6.95ml) was added to a solution of methyl isocyanide (349mg) in tetrahydrofuran (10ml) under a nitrogen atmosphere at-78 ℃ and stirred for 15 minutes. A tetrahydrofuran (10ml) solution of the compound (1.02g) obtained in referential example 141 was dropped into the reaction mixture at-78 ℃ and stirred for 30 minutes. The reaction mixture was heated to 0 ℃ and stirred for 15 minutes, then cooled again to-78 ℃ and acetic acid (0.62ml) was added thereto. The reaction mixture was stirred at 0 ℃ for another 45 minutes, diluted with ether, washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography using silica gel as a carrier (methanol: dichloromethane ═ 1: 49 → 3: 97) to obtain the title compound (663 mg).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.50-2.20(6H，m)，2.75-2.88(1H，m)，3.69-3.81(1H，m)，4.19-4.23(1H，m)，4.65-4.84(1H，m)，5.05-5.18(2H，m)，6.78(1H，s)，7.30-7.45(6H，m)，7.77(1H，s).

MS(ESI)m/z：416(M+H)⁺.

[ reference example 568] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (1, 3-oxazol-5-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 567 and then condensing the deprotected compound with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.53-1.68(1H，m)，1.70-1.92(2H，m)，1.94-2.24(3H，m)，2.78-2.95(1H，m)，3.94-4.05(1H，m)，4.16-4.30(1H，m)，4.88-5.04(1H，m)，6.78(1H，s)，7.69(1H，dd，J＝8.8，2.4Hz)，7.78(1H，s)，7.95-8.10(1H，m)，8.17(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.4Hz)，9.74(1H，s).

MS(ESI)m/z：464(M+H)⁺.

[ reference example 569] (1S, 2R, 4S) -4- (aminocarbonyl) -2- [ (tert-butoxycarbonyl) amino ] cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The title compound was obtained by condensing the compound obtained in referential example 557 with ammonium chloride in the same manner as referential example 143.

¹H-NMR(CDCl₃)δ：0.04(9H，s)，0.97(2H，t，J＝8.3Hz)，1.45(9H，s)，1.62-2.07(6H，m)，2.33(1H，br.s)，3.69(1H，br.s)，4.00-4.21(3H，m)，4.93(1H，br.s)，5.15(1H，br.s)，5.60(1H，br.s)，5.75(1H，br.s).

MS(ESI)m/z：302(M-Boc)⁺.

[ reference example 570] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4-cyanocyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The compound (1.48g) obtained in referential example 569 and triethylamine (1.04ml) were dissolved in methylene chloride (25ml), and trifluoroacetic anhydride (0.790ml) was added to the solution under ice-cooling. After stirring at room temperature for 1 hour, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to the solution to separate the solution. 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 to solidify, to obtain the title compound (1.18 g).

¹H-NMR(DMSO-d₆)δ：0.01(9H，s)，0.91(2H，dd，J＝9.0，7.1Hz)，1.38(9H，s)，1.48-1.64(3H，m)，1.65-1.77(1H，m)，1.81(2H，t，J＝5.9Hz)，3.03(1H，br.s)，3.62(1H，br.s)，3.78(1H，br.s)，4.02(2H，dd，J＝9.0，7.1Hz)，6.54(1H，br.s)，6.74(1H，br.s).

MS(ESI)m/z：406(M+Na)⁺，328(M-tBu)⁺，284(M-Boc)⁺.

[ reference example 571] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (5-methyl-1, 2, 4-oxadiazol-3-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The title compound was obtained by reacting the compound obtained in referential example 570 with hydroxylamine and then cyclizing it with trimethyl orthoacetate in the same manner as in referential example 550.

¹H-NMR(CDCl₃)δ：0.03(9H，s)，0.98(2H，t，J＝8.4Hz)，1.35-2.18(6H，m)，1.45(9H，s)，2.56(3H，s)，2.81-2.96(1H，m)，3.65-3.79(1H，m)，4.05-4.23(3H，m)，4.65-4.83(1H，m)，5.10-5.30(1H，m).

[ reference example 572] (1S, 2R, 4S) -4- (5-methyl-1, 2, 4-oxadiazol-3-yl) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

The title compound was obtained by treating the compound obtained in referential example 571 with p-toluenesulfonic acid in the same manner as in referential example 560, deprotecting, and then condensing with the compound obtained in referential example 10.

¹H-NMR(CDCl₃)δ：0.02(9H，s)，0.96(2H，t，J＝8.4Hz)，1.52-1.66(1H，m)，1.73-1.90(1H，m)，2.00-2.29(4H，m)，2.56(3H，s)，2.58(3H，s)，2.85-3.11(5H，m)，3.73-3.93(3H，m)，4.13(2H，t，J＝8.4Hz)，4.59-4.68(1H，m)，5.15-5.26(1H，m)，7.34-7.45(1H，m).

MS(ESI)m/z：521(M+H)⁺.

[ reference example 573] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- ({ [2- (trimethylsilyl) ethoxy ] carbonyl } amino) cyclohexylcarbamic acid benzyl ester

Triethylamine (1.67ml) and diphenylphosphoryl azide (2.06ml) were added to a toluene (60ml) solution of the compound (3.14g) obtained in referential example 142, and the mixture was stirred at 80 ℃ for 2 hours. After cooling to room temperature, trimethylsilylethanol (4.59ml) was added and stirred at 90 ℃ for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate. The solution was washed with a 10% citric acid aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated brine in this order, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 50: 1), and hexane was added to the obtained solid to obtain the title compound (2.72 g).

¹H-NMR(CDCl₃)δ：0.03(9H，s)，0.91-1.01(2H，m)，1.23-1.64(3H，m)，1.44(9H，s)，1.90-2.08(3H，m)，3.51-3.75(2H，m)，4.04-4.18(3H，m)，4.49(1H，br.s)，4.78(1H，br.s)，5.03-5.14(2H，m)，5.36(1H，br.s)，7.28-7.38(5H，m).

MS(ESI)m/z：508(M+H)⁺.

[ reference example 574] (1S, 2R, 4S) -4-amino-2- [ (tert-butoxycarbonyl) amino ] cyclohexylcarbamic acid benzyl ester

To a tetrahydrofuran (6.0ml) solution of the compound (1.02g) obtained in referential example 573 was added a 1N tetrahydrofuran solution (6.0ml) of tetrabutylammonium, and the mixture was stirred at room temperature for 3 days. Ethyl acetate was added to the reaction mixture, which was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol: concentrated aqueous ammonia 100: 10: 1) to obtain the title compound (660 mg).

¹H-NMR(CDCl₃)δ：1.19-1.63(3H，m)，1.44(9H，s)，1.80-2.06(3H，m)，2.79-2.91(1H，m)，3.63-3.72(1H，m)，4.11(1H，br.s)，4.68(1H，br.s)，5.03-5.14(2H，m)，5.27(1H，br.s)，7.28-7.38(5H，m).

MS(ESI)m/z：363(M+H)⁺.

[ reference example 575] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) -4- (4H-1, 2, 4-triazol-4-yl) amino ] cyclohexylcarbamic acid benzyl ester

To a pyridine (3.0ml) solution of the compound (182mg) obtained in referential example 574, 1, 2-diformylhydrazide (154mg), triethylamine (0.464ml) and chlorotrimethylsilane (0.952ml) were added, and the mixture was stirred at 80 ℃ for 6 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to separate the reaction mixture, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by flash column chromatography (dichloromethane: methanol 30: 1 → 10: 1) using silica gel as a carrier to obtain the title compound (127 mg).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.54-1.91(3H，m)，1.91-2.15(2H，m)，2.21(1H，d，J＝12.5Hz)，2.37(1H，d，J＝12.9Hz)，3.82(1H，br.s)，4.24(1H，br.s)，4.36(1H，br.s)，5.05-5.16(2H，m)，5.35(1H，d，J＝7.6Hz)，7.30-7.40(5H，m)，8.26(2H，s).

MS(ESI)m/z：416(M+H)⁺.

[ reference example 576] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (4H-1, 2, 4-triazol-4-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 575 and then condensing it with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.60-1.98(2H，m)，2.05-2.20(2H，m)，2.25-2.35(1H，m)，2.36-2.45(1H，m)，4.03-4.13(1H，m)，4.37(1H，br.s)，4.47(1H，br.s)，5.42(1H，br.s)，7.71(1H，dd，J＝8.8，2.4Hz)，8.04(1H，br.s)，8.17(1H，d，J＝8.8Hz)，8.31-8.33(3H，m)，9.71(1H，s).

MS(ESI)m/z：464(M+H)⁺.

[ reference example 577] (1R, 2S, 5S) -2-amino-5- (5-methyl-1, 3, 4-oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

The compound (5.74g) obtained in referential example 551 was dissolved in methanol (110ml), and a 10% palladium on carbon catalyst (1.22g) was added to stir at room temperature for 17 hours in a hydrogen atmosphere. The catalyst was filtered off, and the solvent was evaporated under reduced pressure to obtain the title compound (3.95 g).

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.65-2.45(6H，m)，2.51(3H，s)，3.03-3.60(3H，m)，4.12-4.35(1H，m)，5.45-5.76(1H，m)，6.86-7.17(1H，m).

MS(ESI)m/z：297(M+H)⁺.

[ reference example 578] lithium 2- [ (5-bromopyridin-2-yl) amino ] -2-oxoacetate

The title compound was obtained from the compound obtained in referential example 262 by the same method as referential example 266.

¹H-NMR(DMSO-d₆)δ：8.03(1H，dd，J＝8.8，2.4Hz)，8.09(1H，d，J＝8.8Hz)，8.44(1H，d，J＝2.4Hz)，10.18(1H，s).

[ reference example 579] (1R, 2S, 5S) -2- ({2- [ (5-Bromopyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (5-methyl-1, 3, 4-oxadiazol-2-yl) cyclohexanecarboxylic acid tert-butyl ester

To a solution of the compound (900mg) obtained in referential example 577 in N, N-dimethylformamide (40ml) were added the compound (1.24g) obtained in referential example 578, 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (1.17g) and 1-hydroxybenzotriazole (205mg), and the mixture was stirred at 40 ℃ for 7 hours. Ethyl acetate and the aqueous solution were added to the reaction mixture, and the organic layer was washed with water, 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 (dichloromethane: methanol ═ 19: 1) to obtain the title compound (1.51 g).

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.56-2.31(6H，m)，2.52(3H，s)，3.01-3.12(1H，m)，4.00-4.08(1H，m)，4.26(1H，br.s)，4.92(1H，br.s)，7.84(1H，dd，J＝8.8，2.5Hz)，8.03(1H，d，J＝2.9Hz)，8.14(1H，d，J＝8.8Hz)，8.41(1H，d，J＝2.5Hz)，9.72(1H，s).

[ reference example 580] (1R, 2S, 5S) -2- { [ (7-chlorocinnolin-3-yl) carbonyl ] amino } -5- (5-methyl-1, 3, 4-oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by hydrolyzing the compound obtained in referential example 297 and condensing the resulting lithium salt of a carboxylic acid with the compound obtained in referential example 577 in the same manner as in referential example 579.

¹H-NMR(CDCl₃)δ：1.37(9H，s)，1.68-1.82(1H，m)，1.82-1.99(1H，m)，2.01-2.37(4H，m)，2.53(3H，s)，3.12(1H，br.s)，4.40(2H，br.s)，4.96(1H，br.s)，7.79(1H，dd，J＝8.8，1.8Hz)，7.98(1H，d，J＝8.8Hz)，8.61(1H，s)，8.69(1H，d，J＝7.8Hz)，8.74(1H，s).

MS(ESI)m/z：487(M+H)⁺.

[ reference example 581] (1R, 2S, 5S) -2- { [ (7-chloroisoquinolin-3-yl) carbonyl ] amino } -5- (5-methyl-1, 3, 4-oxadiazol-2-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by condensing the compound obtained in referential example 577 with the compound obtained in referential example 57 in the same manner as in referential example 579.

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.57-1.74(1H，m)，1.79-2.49(5H，m)，2.53(3H，s)，3.00-3.16(1H，m)，4.24-4.38(2H，m)，5.00(1H，br.s)，7.71(1H，dd，J＝8.8，1.7Hz)，7.90-7.97(1H，m)，8.02(1H，d，J＝1.7Hz)，8.45-8.62(2H，m)，9.05(1H，s).

MS(ESI)m/z：486(M+H)⁺.

[ reference example 582] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (1, 2, 4-oxadiazol-5-yl) cyclohexylcarbamic acid 2- (trimethylsilyl) ethyl ester

A mixture of the compound (994mg) obtained in referential example 569 and dimethyl acetal (10ml) of N, N-dimethylformamide was stirred at 120 ℃ for 2 hours. After the reaction mixture was left at room temperature, the reaction mixture was concentrated under reduced pressure, and hexane was added to the residue to obtain a colorless powder. To the powder were added 70% aqueous acetic acid (10ml) and hydroxylamine (containing 50% water, 197mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the obtained residue to separate the mixture. 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 (hexane: ethyl acetate ═ 2: 1) to obtain the title compound (759 mg).

¹H-NMR(CDCl₃)δ：0.04(9H，s)，0.91-1.04(2H，m)，1.46(9H，s)，1.61-2.44(6H，m)，2.98-3.49(1H，m)，3.73(1H，br.s)，4.03-4.25(2H，m)，4.85(1H，br.s)，5.30(1H，br.s)，6.70(1H，br.s)，8.34(1H，s).

MS(ESI)m/z：449(M+Na)⁺，327(M-Boc)⁺.

[ reference example 583] (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } -4- (1, 2, 4-oxadiazol-5-yl) cyclohexanecarboxylic acid 2- (trimethylsilyl) ethyl ester

The title compound was obtained by treating the compound obtained in referential example 583 with p-toluenesulfonic acid to deprotect it and then condensing it with the compound obtained in referential example 564 in the same manner as in referential example 560.

¹H-NMR(CDCl₃)δ：0.02(9H，s)，0.97(2H，dd，J＝9.9，7.0Hz)，1.58-1.94(2H，m)，2.07-2.20(2H，m)，2.21-2.30(1H，m)，2.35-2.44(1H，m)，2.53(3H，s)，2.85(2H，t，J＝5.6Hz)，2.95(2H，t，J＝5.6Hz)，3.20-3.32(1H，m)，3.74(2H，s)，3.90(1H，br.s)，4.14(2H，dd，J＝9.9，7.0Hz)，4.62-4.69(1H，m)，5.19(1H，br.s)，7.39(1H，d，J＝8.1Hz)，8.35(1H，s).

MS(ESI)m/z：507(M+H)⁺.

[ reference example 584] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- { [2- (2, 2, 2-trifluoroacetyl) hydrazino ] carbonyl } cyclohexyl carbamic acid benzyl ester

To a solution of the compound (4.00g) obtained in referential example 142 in N, N-dimethylformamide (100ml) were added hydrazine 1 hydrate (765mg), 1-hydroxybenzotriazole (1.38g) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.93g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and methylene chloride and an aqueous sodium bicarbonate solution were added to the residue to separate the mixture. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, silica gel (25g) and methanol (15ml) were added to the obtained filtrate, followed by stirring and filtration of insoluble matter. The solvent was distilled off under reduced pressure to obtain crude benzyl (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (hydrazinocarbonyl) cyclohexylcarbamate (3.71g) as a colorless oily substance. To the resulting colorless oily substance (306mg), dichloromethane (10ml) and triethylamine (115. mu.l) were added, and trifluoroacetic anhydride (116. mu.l) was added to the mixture under ice cooling, followed by stirring at room temperature for 5 hours. Then, triethylamine (115. mu.l) and trifluoroacetic anhydride (116. mu.l) were added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was separated by adding dichloromethane and water, the aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 19) to obtain the title compound (283 mg).

¹H-NMR(CDCl₃)δ：1.41(9H，s)，1.52-2.06(6H，m)，2.53(1H，br.s)，3.73(1H，br.s)，4.09(1H，br.s)，4.99-5.15(3H，m)，5.34(1H，d，J＝7.3Hz)，7.27-7.36(5H，m)，8.92-9.36(1H，m).

MS(ESI)m/z：525(M+Na)⁺，403(M-Boc)⁺.

[ REFERENCE EXAMPLE 585] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- [5- (trifluoromethyl) -1, 3, 4-oxadiazol-2-yl ] cyclohexylcarbamic acid benzyl ester

Triphenylphosphine (392mg) was dissolved in methylene chloride (10ml), and hexachloroethane (296mg) and triethylamine (416. mu.l) and the compound (250mg) obtained in referential example 584 were added in this order in methylene chloride (5ml) under ice cooling. After stirring overnight at room temperature, dichloromethane and a 10% aqueous solution of citric acid were added to the reaction mixture to separate the mixture. The organic layer was washed with saturated brine, aqueous sodium hydrogencarbonate 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 column chromatography (hexane: ethyl acetate 1: 1) to obtain the title compound (204 mg).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.51-1.62(1H，m)，1.71-1.90(1H，m)，1.92-2.16(2H，m)，2.16-2.25(1H，m)，2.28-2.38(1H，m)，3.16(1H，br.s)，3.81(1H，br.s)，4.20(1H，br.s)，4.56-4.84(1H，m)，5.04-5.16(2H，m)，5.20-5.28(1H，m)，7.29-7.39(5H，m).

MS(ESI)m/z：429(M-tBu)⁺，385(M-Boc)⁺.

[ reference example 586] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- [5- (trifluoromethyl) -1, 3, 4-oxadiazol-2-yl ] cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 585 and then condensing it with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.55-1.66(1H，m)，1.79-1.94(1H，m)，1.98-2.19(2H，m)，2.23-2.32(1H，m)，2.32-2.41(1H，m)，3.18(1H，br.s)，4.00-4.10(1H，m)，4.29(1H，br.s)，4.86(1H，br.s)，7.71(1H，dd，J＝8.8，2.4Hz)，7.98(1H，br.s)，8.18(1H，d，J＝8.8Hz)，8.32(1H，d，J＝2.4Hz)，9.72(1H，s).

MS(ESI)m/z：477(M-tBu)⁺，433(M-Boc)⁺.

[ reference example 587] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- { [ (2-chloroethoxy) carbonyl ] amino } cyclohexyl carbamic acid benzyl ester

To a solution of the compound (872mg) obtained in referential example 574 in methylene chloride (30ml) were added chloroethyl chloroformate (323. mu.l) and triethylamine (499. mu.l) under ice cooling, and the mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was added with water, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (hexane: ethyl acetate 3: 2) using silica gel as a carrier to give the title compound (1.03 g).

¹H-NMR(CDCl₃)δ：1.24-1.70(12H，m)，1.99-2.03(3H，m)，3.59-3.73(4H，m)，4.06-4.13(1H，m)，4.29(2H，t，J＝5.5Hz)，4.82(1H，br.s)，4.86(1H，br.s)，5.05-5.12(2H，m)，5.41(1H，br.s)，7.28-7.36(5H，m).

MS(ESI)m/z：492(M+Na)⁺.

[ reference example 588] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (2-oxo-1, 3-oxazolidin-3-yl) cyclohexylcarbamic acid benzyl ester

A solution of the compound (926mg) obtained in referential example 587 in N, N-dimethylformamide (5.0ml) was added to a suspension of 60% sodium hydride (87mg) in N, N-dimethylformamide (5.0ml), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture to separate the reaction solution, and the organic layer was 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 flash column chromatography using silica gel as a carrier (hexane: ethyl acetate 2: 3) to obtain the title compound (680 mg).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.45-2.08(6H，m)，3.44-3.54(2H，m)，3.64(1H，br.s)，3.77-3.87(1H，m)，4.20(1H，br.s)，4.29-4.36(2H，m)，4.84(1H，br.s)，5.05-5.13(2H，m)，5.37(1H，br.s)，7.27-7.36(5H，m).

MS(ESI)m/z：434(M+H)⁺.

[ reference example 589] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (2-oxo-1, 3-oxazolidin-3-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 588 and then condensing the same with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.58-1.65(2H，m)，1.79-2.05(4H，m)，3.47-3.55(2H，m)，3.84-3.93(2H，m)，4.29(1H，br.s)，4.33-4.39(2H，m)，5.08(1H，br.s)，7.70(1H，dd，J＝8.8，2.5Hz)，8.10(1H，br.s)，8.19(1H，dd，J＝8.8，0.7Hz)，8.31(1H，dd，J＝2.5，0.7Hz)，9.71(1H，s).

MS(ESI)m/z：504(M+Na)⁺.

[ reference example 590] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (formylamino) cyclohexylcarbamic acid benzyl ester

To a dichloromethane (5ml) solution of the compound (200mg) obtained in referential example 574 were added formic acid (31.1. mu.l), 1-hydroxybenzotriazole (108mg), triethylamine (115. mu.l) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (210mg), and the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue to conduct extraction with methylene chloride, followed by drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 49: 1 → 97: 3) to obtain the title compound (100 mg).

¹H-NMR(CDCl₃)δ：1.27-1.50(2H，m)，1.44(9H，s)，1.94-2.07(4H，m)，3.66-3.74(1H，m)，3.97-4.07(1H，m)，4.08-4.15(1H，m)，4.80-4.88(1H，m)，5.05(1H，d，J＝12.2Hz)，5.10(1H，d，J＝12.0Hz)，5.33-5.41(1H，m)，5.43-5.50(1H，m)，7.30-7.37(5H，m)，8.12(1H，s).

MS(ESI)m/z：392(M+H)⁺.

[ referential example 591] (1R, 2S, 5S) -2- [ (benzyloxycarbonyl) amino ] -5- (tetrazol-1-yl) cyclohexylcarbamic acid tert-butyl ester

Chloroform chloroformate (268. mu.l) was added dropwise to a dichloromethane (10ml) solution of the compound (792mg) obtained in referential example 590 and pyridine (1.63ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was allowed to come to room temperature and stirred for 15 minutes, and trimethylsilyl azide (295. mu.l) was added thereto and stirring was continued for 22 hours. The solvent was evaporated under reduced pressure, an aqueous sodium hydrogencarbonate solution was added to the residue, insoluble materials were collected by filtration, and the resulting solid was washed with water and purified by silica gel column chromatography (dichloromethane: methanol: 199: 1 → 49: 1) to obtain the title compound (60 mg).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.55-1.59(1H，m)，2.02-2.14(2H，m)，2.21-2.32(2H，m)，2.41-2.49(1H，m)，3.84-3.92(1H，m)，4.20-4.25(1H，m)，4.65-4.76(1H，m)，5.07-5.16(3H，m)，5.21-5.28(1H，m)，7.32-7.38(5H，m)，8.68(1H，s).

MS(ESI)m/z：417(M+H)⁺.

[ reference example 592] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (tetrazol-1-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 591 and then condensing with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.73-1.92(1H，m)，2.07-2.21(2H，m)，2.28-2.41(2H，m)，2.45-2.53(1H，m)，4.10-4.19(1H，m)，4.33-4.40(1H，m)，4.71-4.89(1H，m)，4.99-5.14(1H，m)，7.71(1H，dd，J＝8.8，2.4Hz)，7.96-8.04(1H，m)，8.17(1H，d，J＝8.8Hz)，8.32(1H，d，J＝2.4Hz)，8.69(1H，s)，9.71(1H，s).

MS(ESI)m/z：465(M+H)⁺.

[ reference example 593] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (1H-pyrrol-1-yl) cyclohexylcarbamic acid benzyl ester

To a mixture of the compound (200mg) obtained in referential example 574, 2, 5-dimethoxytetrahydrofuran (71.3. mu.l), water (10ml) and 1, 2-dichloroethane (10ml) was added 1N hydrochloric acid (550. mu.l), and the mixture was stirred at 80 ℃ for 2.5 hours. After the reaction mixture was allowed to stand at room temperature, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to separate the reaction mixture. 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 (hexane: ethyl acetate ═ 4: 1 → 1: 1) to obtain the title compound (84 mg).

¹H-NMR(CDCl₃)δ：1.45(9H，s)，1.71-2.20(5H，m)，2.22-2.31(1H，m)，3.78(1H，br.s)，3.99(1H，br.s)，4.22(1H，br.s)，4.73(1H，br.s)，5.04-5.16(2H，m)，5.29(1H，br.s)，6.15(2H，t，J＝2.2Hz)，6.70(2H，t，J＝2.2Hz)，7.29-7.39(5H，m).

MS(ESI)m/z：436(M+Na)⁺.

[ reference example 594] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (1H-pyrrol-1-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 593 and then condensing it with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.80-2.33(6H，m)，3.92-4.08(2H，m)，4.31(1H，br.s)，4.89(1H，br.s)，6.17(2H，t，J＝2.0Hz)，6.71(2H，t，J＝2.0Hz)，7.69(1H，dd，J＝8.8，2.2Hz)，8.02(1H，br.s)，8.17(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.2Hz)，9.72(1H，br.s).

MS(ESI)m/z：462(M+H)⁺.

[ reference example 595] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- ({ [ (dimethylamino) methylidene ] amino } carbonyl) cyclohexylcarbamic acid benzyl ester

Ammonium chloride (409mg), 1-hydroxybenzotriazole (516mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.03g) and triethylamine (1.06ml) were added to a solution of the compound (1.50g) obtained in referential example 142 in N, N-dimethylformamide (100ml), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a 10% citric acid aqueous solution were added to the residue to separate the mixture. The organic layer was washed with saturated brine, aqueous sodium hydrogencarbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting powder was suspended in dimethyl acetal of N, N-dimethylformamide (30ml), and stirred at 120 ℃ for 2 hours. After standing at room temperature, the precipitated colorless powder was collected by filtration and washed with diethyl ether to obtain the title compound (957 mg).

¹H-NMR(CDCl₃)δ：1.25-1.40(1H，m)，1.44(9H，s)，1.53-1.66(1H，m)，1.73-2.08(4H，m)，2.32-2.46(1H，m)，3.07(3H，s)，3.11(3H，s)，3.63-3.75(1H，m)，4.13(1H，br.s)，4.59-4.75(1H，m)，5.07(1H，d，J＝12.2Hz)，5.12(1H，d，J＝12.2Hz)，5.30-5.45(1H，m)，7.28-7.37(5H，m)，8.40(1H，s).

MS(ESI)m/z：447(M+H)⁺.

[ reference example 596] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (1, 2, 4-triazol-5-yl) cyclohexylcarbamic acid benzyl ester

To a solution of the compound (400mg) obtained in referential example 595 in acetic acid (10ml) was added hydrazine 1 hydrate (51.9. mu.l), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and an aqueous sodium hydrogencarbonate solution and ethyl acetate were added to the obtained residue to separate the mixture. 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).

¹H-NMR(DMSO-d₆)δ：1.39(9H，s)，1.48-1.62(2H，m)，1.62-1.75(2H，m)，1.88-2.06(2H，m)，3.06(1H，br.s)，3.56(1H，br.s)，3.95(1H，br.s)，4.95-5.10(2H，m)，6.62(1H，br.s)，7.00(1H，br.s)，7.27-7.38(5H，m)，13.59(1H，br.s).

MS(ESI)m/z：416(M+H)⁺.

[ reference example 597] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (1, 2, 4-triazol-5-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 596 and then condensing the deprotected compound with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(DMSO-d₆)δ：1.39(9H，s)，1.50-2.03(5H，m)，2.05-2.17(1H，m)，2.94-3.20(1H，m)，3.85-3.99(2H，m)，7.06(1H，br.s)，7.80(0.5H，br.s)，8.03(1H，dd，J＝8.8，2.2Hz)，8.06(1H，d，J＝8.8Hz)，8.39(0.5H，s)，8.47(1H，d，J＝2.2Hz)，8.56-8.69(1H，m)，10.27(1H，s)，13.59-13.66(1H，m).

MS(ESI)m/z：464(M+H)⁺.

[ reference example 598] (1S, 2R, 4S) -2- [ (tert-butoxycarbonyl) amino ] -4- (1-methyl-1H-1, 2, 4-triazol-5-yl) cyclohexylcarbamic acid benzyl ester

To a solution of the compound (400mg) obtained in referential example 595 in acetic acid (10ml) was added methylhydrazine (56.9. mu.l), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the obtained residue to separate the mixture. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 19) to obtain the title compound (224 mg).

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.53-1.80(2H，m)，1.88-2.18(4H，m)，2.77-2.89(1H，m)，3.71-3.83(1H，m)，3.86(3H，s)，4.17(1H，br.s)，4.74(1H，br.s)，5.08(1H，d，J＝12.2Hz)，5.12(1H，d，J＝12.2Hz)，5.25-5.42(1H，m)，7.29-7.39(5H，m)，7.91(1H，s).

MS(ESI)m/z：430(M+H)⁺.

[ reference example 599] (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -5- (1-methyl-1H-1, 2, 4-triazol-5-yl) cyclohexylcarbamic acid tert-butyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 598 and then condensing the deprotected compound with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.50-1.65(1H，m)，1.72-1.87(1H，m)，1.95-2.22(4H，m)，2.81-2.94(1H，m)，3.87(3H，s)，3.97-4.06(1H，m)，4.25(1H，br.s)，4.91(1H，d，J＝8.8Hz)，7.70(1H，dd，J＝8.8，2.4Hz)，7.93(1H，s)，8.06(1H，br.s)，8.20(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，9.74(1H，s).

MS(ESI)m/z：478(M+H)⁺.

[ reference example 600] (3R, 4S) -4- [ (benzyloxycarbonyl) amino ] -3- [ (tert-butoxycarbonyl) amino ] piperidine-1-carbamic acid 2-trimethylsilylethyl ester

To a dioxane (50ml) solution of the compound (5.98g) obtained in referential example 212 was added a 9% aqueous solution (150ml) of sodium hydrogencarbonate, and after cooling to 0 ℃, a dioxane (20ml) solution of 1- [ (2-trimethylsilyl) ethoxycarbonyloxy ] pyrrolidine-2, 5-dione (4.83g) was added and stirred at room temperature for 20 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution, a 10% aqueous citric acid solution, and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated 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.

¹H-NMR(CDCl₃)δ：0.00(9H，s)，0.96(2H，t，J＝8.3Hz)，1.36-1.53(1H，m)，1.41(9H，s)，1.82-2.00(1H，m)，2.85(1H，t，J＝12.1Hz)，3.01(1H，d，J＝13.4Hz)，3.66-3.81(1H，m)，3.87-4.25(5H，m)，4.63-4.81(1H，m)，5.06(2H，br.s)，5.22-5.69(1H，br)，7.23-7.40(5H，m).

ESI-MSm/z：394(M-Boc)⁺.

[ reference example 601] (3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -3- [ (tert-butoxycarbonyl) amino ] piperidine-1-carbamic acid 2-trimethylsilylethyl ester

The title compound was obtained by deprotecting the compound obtained in referential example 600 and then condensing it with the compound obtained in referential example 266 in the same manner as in referential example 552.

¹H-NMR(CDCl₃)δ：0.05(9H，s)，0.84-0.92(2H，m)，1.47(9H，s)，1.51-1.70(1H，m)，1.98(1H，d，J＝11.2Hz)，2.84-2.98(1H，m)，3.07(1H，d，J＝13.9Hz)，3.94-4.29(6H，m)，4.81-4.95(1H，br)，7.70(1H，d，J＝9.0Hz)，8.09-8.34(1H，br)，8.20(1H，d，J＝9.0Hz)，8.31(1H，s)，9.69(1H，s).

MS(ESI)m/z：442(M-Boc)⁺，486(M-tBu)⁺.

[ reference example 602] (3R, 4S) - [4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) piperidin-3-yl ] carbamic acid tert-butyl ester

To a tetrahydrofuran (90ml) solution of the compound (6.92g) obtained in referential example 601 was added a 1.0mmol/l tetrabutylammonium fluoride solution in tetrahydrofuran (40ml), and the mixture was stirred at room temperature for 5 days. To the reaction mixture were added ethyl acetate and a saturated aqueous solution of sodium chloride. The aqueous layer was extracted with ethyl acetate and dichloromethane, and the combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol: 30: 1 → 20: 1 → 10: 1) to obtain a crude purified product (7.96 g). Ethyl acetate was added to the crude purified product, and insoluble matter was collected by filtration to obtain the title compound (466 mg). Further, water was added to the filtrate, and the mixture was extracted with ethyl acetate and methylene chloride, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (4.86g) of the title compound containing about 30% tetrabutylammonium fluoride.

¹H-NMR(CDCl₃)δ：1.47(9H，s)，1.55-1.72(2H，m)，1.84-1.99(1H，m)，2.71(1H，t，J＝10.7Hz)，2.85(1H，d，J＝11.2Hz)，3.03(2H，t，J＝12.7Hz)，3.85-3.98(1H，m)，3.98-4.09(1H，m)，5.40-5.71(1H，m)，7.70(1H，dd，J＝8.8，2.4Hz)，8.13(1H，br.s)，8.21(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，9.75(1H，s).

MS(ESI)m/z：398(M+H)⁺.

[ reference example 603] (3R, 4S) - [4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) -1- (thiazol-2-yl) piperidin-3-yl ] carbamic acid tert-butyl ester

To a toluene (4ml) solution of the mixture of tetrabutylammonium fluorides (401mg) obtained in referential example 602 were added 2-bromothiazole (115. mu.l), sodium tert-butoxide (91mg), (S) - (-) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (65mg), and tris (dibenzylideneacetone) dipalladium (0) (28mg), and the mixture was stirred at 80 ℃ for 3 days under an argon atmosphere. After the reaction solution was cooled, ethyl acetate was added thereto, insoluble materials were filtered off through celite, and a saturated aqueous sodium chloride solution was added to the filtrate. After extraction with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride solution. 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).

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.78-1.93(1H，m)，2.07-2.18(1H，m)，3.05-3.19(1H，m)，3.27(1H，dd，J＝13.2，1.7Hz)，3.98(1H，br.d，J＝12.9Hz)，4.04-4.15(2H，m)，4.18-4.29(1H，br)，5.04-5.34(1H，m)，6.65(1H，d，J＝3.7Hz)，7.21(1H，d，J＝3.7Hz)，7.70(1H，dd，J＝8.8，2.4Hz)，8.21(1H，d，J＝8.8Hz)，8.23-8.33(1H，br)，8.31(1H，d，J＝2.4Hz)，9.73(1H，br.s).

MS(ESI)m/z：481(M+H)⁺.

[ 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

1-hydroxybenzotriazole 1 hydrate (71mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100mg) were added to a solution of the compound (108mg) obtained in referential example 59 and the compound (124mg) obtained in referential example 10 in N, N-dimethylformamide (3ml) at room temperature, followed by stirring for 8 days. After the reaction mixture was concentrated under reduced pressure using a vacuum pump, water (50ml) and a saturated aqueous sodium hydrogencarbonate solution (50ml) were added to conduct extraction with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (dichloromethane: methanol ═ 10: 1). To the obtained amorphous substance, 1N ethanol hydrochloride solution, dichloromethane and methanol were added and concentrated to obtain the title compound (72 mg).

¹H-NMR(DMSO-d₆)δ：1.15-1.35(2H，m)，2.88(3H，s)，2.95-3.25(4H，m)，3.35-3.75(2H，m)，4.32-4.45(1H，m)，4.68(1H，br，J＝15.4Hz)，7.08(1H，s)，7.17(1H，dd，J＝8.6，2.1Hz)，7.41(1H，d，J＝8.6Hz)，7.70(1H，s)，8.50(1H，br，J＝11.0Hz)，8.56(1H，br.s)，11.56(1H，br，J＝19.3Hz)，11.86(1H，s).

MS(FAB)m/z：430(M+H)⁺.

[ example 2]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclobutyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The compound (117mg) obtained in referential example 60 was dissolved in N, N-dimethylformamide (5ml), and the compound (136mg) obtained in referential example 10, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (255mg) and 1-hydroxybenzotriazole 1 hydrate (90mg) were added to stir at room temperature overnight. The solvent was evaporated under reduced pressure by a vacuum pump, and methylene chloride and a saturated aqueous sodium bicarbonate solution were added to the residue to separate the mixture. 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: dichloromethane ═ 7: 93). To the obtained compound, ethyl acetate and a 1N ethanol hydrochloride solution were added to make the reaction solution acidic, and the solvent was concentrated under reduced pressure. Ethyl acetate was again added to the residue, and the resulting precipitate was collected by filtration and dried to obtain the title compound (56 mg).

¹H-NMR(DMSO-d₆)δ：2.00-2.35(4H，m)，2.88(3H，s)，3.10(2H，br.s)，3.20-3.75(3H，m)，4.20-4.85(3H，m)，7.09(1H，s)，7.16(1H，d，J＝8.8Hz)，7.38(1H，d，J＝8.8Hz)，7.71(1H，s)，8.63(1H，d，J＝8.3Hz)，8.85(1H，d，J＝8.6Hz)，10.85-11.20(1H，br)，11.81(1H，s).

MS(FAB)m/z：444(M+H)⁺.

[ example 3]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclopentyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The compound (120mg) obtained in referential example 62 was dissolved in N, N-dimethylformamide (5ml), and 5-chloroindole-2-carboxylic acid (80mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (98mg), 1-hydroxybenzotriazole 1 hydrate (23mg) and triethylamine (141. mu.l) were added to stir at room temperature for 3 days. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous sodium bicarbonate solution were added to the residue to separate the mixture. 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 (dichloromethane: methanol: 93: 7). To the resulting pale yellow solid were added methylene chloride (5ml) and 1N ethanol hydrochloride solution (282. mu.l). Then, ethyl acetate was added, the solvent was concentrated under reduced pressure, and the resulting precipitate was collected by filtration to obtain the title compound (109 mg).

¹H-NMR(DMS0-d₆)δ：1.64-1.74(4H，m)，1.98-2.02(2H，m)，2.89(3H，s)，3.14(2H，br.s)，3.47-3.65(2H，m)，4.29-4.63(4H，m)，7.10(1H，d，J＝1.5Hz)，7.14(1H，dd，J＝8.5，2.0Hz)，7.38(1H，d，J＝8.5Hz)，7.68(1H，d，J＝2.0Hz)，8.55(1H，d，J＝8.5Hz)，8.91(1H，d，J＝8.5Hz)，11.49(1H，br.s)，11.76(1H，s).

MS(ESI)m/z：458(M+H)⁺.

[ example 4 ]]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) sulfonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The compound (400mg) obtained in referential example 67 was suspended in methylene chloride (10ml), and triethylamine (0.514ml) and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (Japanese patent laid-open No. 2000-119253) (319mg) were added to stir at room temperature for 15 minutes. After a liquid separation operation was performed by adding water to the reaction mixture, 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 (dichloromethane: methanol 100: 3) to obtain a pale yellow foamy substance. This material was dissolved in tetrahydrofuran (3ml), and methanol (2ml) and a 1N aqueous solution (1.5ml) of sodium hydroxide were added to the solution, followed by heating and refluxing for 2 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a 1N aqueous hydrochloric acid solution were added to the residue to conduct a liquid separation operation. 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 (dichloromethane: methanol 100: 3). To the resultant product, 1N hydrochloric acid (1ml) was added and the mixture was concentrated under reduced pressure to obtain the title compound (108 mg).

¹H-NMR(DMSO-d₆)δ：1.20-1.78(8H，m)，2.94(3H，s)，3.13(2H，br.s)，3.22-3.40(1H，m)，3.44-3.70(3H，m)，3.83-3.95(1H，m)，4.20-4.70(1H，m)，6.78(1H，s)，7.18-7.30(2H，m)，7.44(1H，s)，7.69(1H，br.s)，8.09(1H，br.s)，11.92(1H，s).

MS(FAB)m/z：508(M+H)⁺.

[ example 5]N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The compound (300mg) obtained in referential example 65 was dissolved in N, N-dimethylformamide (20ml), and 5-chloroindole-2-carboxylic acid (109mg), 1-hydroxybenzotriazole 1 hydrate (9mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (321mg) and triethylamine (0.232ml) were added to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure using a vacuum pump, methylene chloride and water were added to the residue to separate, 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 25: 1) to obtain a colorless foamy substance. 1N hydrochloric acid (1ml) was added thereto, and concentrated under reduced pressure to obtain the title compound (203 mg).

¹H-NMR(DMSO-d₆)δ：1.25-1.40(2H，m)，1.46-1.81(4H，m)，1.88-1.98(2H，m)，2.89(3H，s)，3.00-3.76(5H，m)，3.86-3.97(1H，m)，4.00-4.10(1H，m)，4.25-4.72(1H，m)，7.03(1H，s)，7.12(1H，dd，J＝8.5，1.2Hz)，7.38(1H，d，J＝8.5Hz)，7.64(1H，s)，8.28(1H，d，J＝8.5Hz)，8.54(1H，d，J＝8.5Hz)，11.70(1H，s).

MS(FAB)m/z：472(M+H)⁺.

[ example 6]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 67 and 5-chloroindole-2-carboxylic acid by the same process as in example 5.

¹H-NMR(DMSO-d₆)δ：1.35-1.70(6H，m)，1.80-2.06(2H，m)，2.89(3H，s)，3.00-3.27(2H，m)，3.35-3.51(1H，m)，3.57-3.82(1H，m)，4.15-4.30(2H，m)，4.32-4.48(1H，m)，4.60-4.74(1H，m)，7.15(1H，s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.6Hz)，7.70(1H，d，J＝2.0Hz)，8.14(1H，br.s)，8.36-8.48(1H，m)，11.51(1H，br.s)，11.86(1H，s).

MS(FAB)m/z：472(M+H)⁺.

[ 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

The compound (275mg) obtained in referential example 67, 6-chloronaphthalene-2-carboxylic acid (Eur.J.chem.Chim.Ther., 1984, 19: 205-214) (148mg), triethylamine (0.298ml) and 1-hydroxybenzotriazole 1 hydrate (11mg) were dissolved in N, N-dimethylformamide (20ml) by the same method as in example 5, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (412mg) was added to react them to obtain the title compound (186 mg).

¹H-NMR(DMSO-d₆)δ：1.40-1.56(2H，m)，1.57-1.77(4H，m)，1.90-2.10(2H，m)，2.90(3H，s)，3.13(2H，br.s)，3.28-3.74(2H，m)，4.26(2H，br.s)，4.30-4.74(2H，m)，7.59(1H，d，J＝8.6Hz)，7.90(1H，d，J＝8.6Hz)，7.98(1H，d，J＝8.3Hz)，8.03-8.11(2H，m)，8.25-8.58(3H，m)，11.52(1H，br.s).

MS(FAB)m/z：483(M+H)⁺.

[ example 8]N-((1R^*，2R^*) -2- { [ (6-chloro-1-benzothien-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound (239mg) was obtained by dissolving the compound (255mg) obtained in referential example 65, 6-chlorobenzo [ b ] thiophene-2-carboxylic acid (Japanese patent laid-open No. 2000-119253) (141mg), triethylamine (0.276ml) and 1-hydroxybenzotriazole 1 hydrate (10mg) in N, N-dimethylformamide (20ml) and adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (382mg) in the same manner as in example 5.

¹H-NMR(DMSO-d₆)δ：1.20-1.98(8H，m)，2.88(3H，s)，3.00-3.72(4H，m)，3.84-4.09(2H，m)，4.20-4.75(2H，m)，7.41(1H，dd，J＝8.6，1.7Hz)，7.91(1H，d，J＝8.6Hz)，7.99(1H，s)，8.12(1H，s)，8.54-8.67(2H，m)，11.53(1H，br.s).

MS(FAB)m/z：489(M+H)⁺.

[ example 9]N-((1R^*，2R^*) -2- { [ (5-fluoroindol-2-yl) carbonyl ]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 65 and 5-fluoroindole-2-carboxylic acid by the same process as in example 5.

¹H-NMR(DMSO-d₆)δ：1.20-1.38(2H，m)，1.40-1.57(1H，m)，1.54-1.68(1H，m)，1.71(2H，d，J＝7.3Hz)，1.88(2H，d，J＝12.0Hz)，2.86(3H，s)，2.95-3.24(2H，m)，3.40(1H，br.s)，3.63(1H，br.s)，3.90(1H，br.s)，3.97-4.10(1H，m)，4.20-4.44(1H，m)，4.53-4.70(1H，m)，6.98(1H，dd，J＝9.2，2.3Hz)，7.01(1H，s)，7.31-7.39(2H，m)，8.26(1H，d，J＝8.6Hz)，8.59(1H，d，J＝8.4Hz)，11.21(1/2H，br.s)，11.42(1/2H，br.s)，11.60(1H，s).

MS(ESI)m/z：456(M+H)⁺.

[ example 10]N-((1R^*，2R^*) -2- { [ (5-fluoro-6-fluoroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 65 and the compound obtained in referential example 23 in the same manner as in example 5.

¹H-NMR(DMSO-d₆)δ：1.20-1.40(2H，m)，1.40-1.80(4H，m)，1.80-2.00(2H，m)，2.87(3H，s)，3.01(2H，br.s)，3.30-3.80(2H，m)，3.81-3.97(2H，m)，4.20-4.80(2H，m)，7.06(1H，s)，7.28(1H，d，J＝10.0Hz)，7.86(1H，d，J＝7.3Hz)，8.32(1H，d，J＝8.5Hz)，8.59(1H，d，J＝8.5Hz)，11.77(1H，s).

MS(FAB)m/z：490(M+H)⁺.

[ example 11]N-((1R^*，2S^*) -2- { [ (5-bromoindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 67 and 5-bromoindole-2-carboxylic acid by the same process as in example 5.

¹H-NMR(DMSO-d₆)δ：1.43(2H，br.s)，1.61(4H，br.s)，1.80-2.10(2H，m)，2.88(3H，s)，3.00-3.26(2H，m)，3.40(1H，br.s)，3.65(1H，br.s)，4.22(1H，br.s)，4.26(1H，br.s)，4.41(1H，br.s)，4.67(1H，d，J＝15.6Hz)，7.14(1H，s)，7.28(1H，d，J＝8.7Hz)，7.37(1H，d，J＝8.7Hz)，7.84(1H，s)，8.13(1H，br.s)，8.33-8.52(1H，m)，11.51(1H，br.s)，11.86(1H，s).

MS(ESI)m/z：515(M⁺).

[ example 12]N-((1R^*，2S^*) -2- { [ (5-ethynylindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

Triethylamine (6ml), N-dimethylformamide (5ml), trimethylsilylacetylene (0.250ml) and palladium acetate (20mg) were added to a tetrahydrofuran solution (2ml) of the compound obtained in example 11 (300mg) and triphenylphosphine (70mg) at room temperature. After stirring at 90 ℃ for 2 hours, the reaction mixture was allowed to cool to room temperature, and methylene chloride (20ml) and a saturated aqueous sodium bicarbonate solution (30ml) were added thereto to separate the mixture. The aqueous layer was extracted with dichloromethane (3X 10ml), and the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The resulting residue was purified by preparative silica gel thin layer chromatography (dichloromethane: acetone: methanol ═ 10; 10: 1) to obtain a colorless solid. The solid was dissolved in methanol (6ml), and potassium carbonate (120mg) was added thereto and stirred for 1 hour. Methylene chloride (20ml) and water (20ml) were added to the reaction mixture to separate the mixture, and the aqueous layer was extracted with methylene chloride (2X 15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (dichloromethane: acetone: methanol ═ 10; 10: 1), which was dissolved in water-methanol-dichloromethane and then concentrated to obtain the title compound (72 mg).

¹H-NMR(CDCl₃)δ：1.50-2.25(8H，m)，2.53(3H，s)，2.85(2H，br.s)，2.93(2H，br.s)，3.01(1H，s)，3.74(1H，d，J＝14.1Hz)，3.77(1H，d，J＝14.1Hz)，4.21(1H，br.s)，4.45(1H，br.s)，6.91(1H，s)，7.25-7.42(2H，m)，7.61(1H，br.s)，7.80-7.97(2H，m)，9.72(1H，s).

MS(FAB)m/z：462(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 51 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.35-1.50(2H，m)，1.50-1.75(4H，m)，1.80-2.10(2H，m)，2.70(3H，br.s)，2.79(3H，br.s)，4.10-4.70(6H，m)，7.10-7.27(2H，m)，7.41(1H，d，J＝8.8Hz)，7.70(1H，s)，8.12(1H，d，J＝6.8Hz)，8.47(1H，d，J＝7.6Hz)，11.85(1H，s).

MS(FAB)m/z：487(M+H)⁺.

[ example 14]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -6, 7-dihydro-4H-pyrano [4, 3-d]Thiazole-2-carboxamides

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 26 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.36-1.72(6H，m)，1.90-2.10(2H，m)，2.80-2.87(2H，m)，3.93(2H，t，J＝5.6Hz)，4.20-4.32(2H，m)，4.81(2H，s)，7.12(1H，s)，7.15(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.67(1H，d，J＝1.7Hz)，8.11(1H，d，J＝6.6Hz)，8.36(1H，d，J＝8.3Hz)，11.78(1H，s).

MS(FAB)m/z：459(M+H)⁺.

[ example 15]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [4, 5-c]Pyridine-2-carboxamide saltsAcid salts

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 29 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.32-1.74(6H，m)，1.82-2.10(2H，m)，2.92(3H，s)，3.12-3.50(3H，m)，3.69(1H，br.s)，4.13-4.39(3H，m)，4.51(1H，br.s)，7.10-7.19(2H，m)，7.41(1H，d，J＝8.6Hz)，7.68(1H，s)，8.10(1H，br.s)，8.40(1H，br.s)，11.41(1H，br.s)，11.87(1H，s).

MS(FAB)m/z：472(M+H)⁺.

[ example 16]N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrooxazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 69 and the compound obtained in referential example 21 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.23-1.39(2H，m)，1.40-1.81(4H，m)，1.82-1.98(2H，m)，2.60-3.00(5H，m)，3.20-3.70(2H，m)，3.87-3.96(1H，m)，3.98-4.10(1H，m)，4.12-4.70(2H，m)，7.04(1H，d，J＝1.5Hz)，7.12(1H，dd，J＝8.8，2.0Hz)，7.38(1H，d，J＝8.8Hz)，7.65(1H，d，J＝2.0Hz)，8.33(1H，d，J＝8.6Hz)，8.72(1H，d，J＝8.6Hz)，11.61(1H，br.s)，11.72(1H，s).

MS(FAB)m/z：456(M+H)⁺.

[ 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

The title compound was obtained by condensing the compound obtained in referential example 71 with 5- (tert-butoxycarbonyl) -4, 5, 6, 7-tetrahydrothieno [3, 2-c ] pyridine-2-carboxylic acid (WO 94/21599) and deprotecting it by treatment with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.42(2H，br.s)，1.56-1.76(4H，m)，1.98-2.11(2H，m)，3.04(2H，br.s)，3.32-3.45(2H，m)，4.15(3H，br.s)，4.26(1H，br.s)，7.14(1H，dd，J＝8.8，2.0Hz)，7.23(1H，s)，7.41(1H，d，J＝8.8Hz)，7.62(1H，s)，7.77(1H，s)，8.18-8.30(2H，m)，9.42(2H，br.s)，11.92(1H，s).

MS(FAB)m/z：457(M+H)⁺.

EXAMPLE 18]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothieno [3, 2-c]Pyridine-2-carboxamide hydrochloride

The compound (171mg) obtained in example 17 was suspended in methylene chloride (10ml), and triethylamine (0.104ml) was added to stir at room temperature for 10 minutes. After adding acetic acid (0.059m1) to the reaction mixture, 35% formalin (0.070ml) and sodium triacetoxyborohydride (118mg) were added thereto, and the mixture was stirred at room temperature for 30 minutes. After a 1N aqueous solution (3ml) of sodium hydroxide was added to the reaction mixture, water was added thereto to conduct 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 (dichloromethane: methanol 50: 3) to obtain a colorless foamy substance. After adding 1N hydrochloric acid thereto to suspend, the mixture was concentrated under reduced pressure to obtain the title compound (85 mg).

¹H-NMR(DMSO-d₆)δ：1.40(2H，br.s)，1.50-1.71(4H，m)，1.97-2.05(2H，m)，2.87(3H，s)，2.98-3.20(1H，m)，3.30-3.38(2H，m)，3.54-3.70(1H，m)，4.05-4.42(4H，m)，7.14(1H，d，J＝8.6Hz)，7.23(1H，s)，7.40(1H，d，J＝8.6Hz)，7.63(1H，s)，7.77(1H，s)，8.17-8.27(2H，m)，10.83(1H，br.s)，11.92(1H，s).

MS(FAB)m/z：471(M+H)⁺.

[ example 19]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -6- (dimethylamino) -4, 5, 6, 7-tetrahydrobenzothiazole-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 31 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.44(2H，br.s)，1.52-1.68(4H，m)，1.87-2.08(3H，m)，2.30-2.40(1H，m)，2.65-2.75(1H，m)，2.77(6H，s)，2.95-3.17(2H，m)，3.30-3.70(2H，m)，4.15-4.30(2H，m)，7.10-7.20(2H，m)，7.41(1H，d，J＝8.6Hz)，7.69(1H，s)，8.11(1H，d，J＝5.1Hz)，8.34(1H，d，J＝8.1Hz)，10.95(1H，br.s)，11.83(1H，s).

MS(FAB)m/z：500(M+H)⁺.

Example 20]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl)) Carbonyl radical]Amino } cyclohexyl) -5- (pyridin-4-yl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

To a tetrahydrofuran (3ml) solution of the compound (204mg) obtained in referential example 24 was added dropwise N-butyllithium (1.60N hexane solution, 0.704ml) at-78 ℃ and then, the mixture was stirred at 0 ℃ for 30 minutes. After cooling to-78 ℃ again, the reaction mixture was warmed to room temperature over 20 minutes while introducing carbon dioxide gas, and concentrated under reduced pressure. To a solution of the obtained residue in N, N-dimethylformamide (6ml) were added at room temperature the compound (400mg) obtained in referential example 71, 1-hydroxybenzotriazole 1 hydrate (254mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (360mg) and diisopropylamine (0.491 ml). After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, and methylene chloride (30ml), a saturated aqueous sodium bicarbonate solution (100ml) and water (100ml) were added to the residue to separate the mixture, followed by extraction of the aqueous layer with methylene chloride (4X 15 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20: 1 → 10: 1), and the purified product was dissolved in 1N aqueous hydrochloric acid-methanol-dichloromethane and concentrated to obtain the title compound (245 mg).

¹H-NMR(DMSO-d₆)δ：1.42(2H，br.s)，1.60(4H，br.s)，1.84-1.94(1H，m)，1.94-2.08(1H，m)，2.97(2H，br.s)，3.97-4.13(2H，m)，4.19(1H，br.s)，4.27(1H，br.s)，5.03(2H，s)，7.13(1H，br.s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.32(2H，br.s)，7.40(1H，d，J＝8.8Hz)，7.68(1H，d，J＝2.0Hz)，8.15(1H，br，J＝7.3Hz)，8.31(2H，d，J＝5.9Hz)，8.39(1H，d，J＝8.1Hz)，11.90(1H，s)，14.03(1H，br.s).

MS(ESI)m/z：535(M+H)⁺.

[ example 21]N-((1R^*，2R^*) -2- { [ (5-chloro)Indol-2-yl) carbonyl]Amino } cycloheptyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 74 and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.51-1.55(4H，m)，1.75-1.80(6H，m)，2.88(3H，s)，3.12(1H，br.s)，3.35-3.63(4H，m)，4.10-4.13(1H，m)，4.29-4.61(2H，m)，7.06(1H，s)，7.14(1H，dd，J＝8.8，2.0Hz)，7.39(1H，d，J＝8.8Hz)，7.67(1H，d，J＝2.0Hz)，8.46(1H，d，J＝8.3Hz)，8.77(1H，d，J＝8.3Hz)，11.21-11.35(1H，m)，11.71(1H，s).

MS(ESI)m/z：486(M+H)⁺.

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

The title compound was obtained from the compound obtained in referential example 78 and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(DMSO-d₆) δ: 1.61-2.06(12H, m), 2.90(3H, s), 3.08-3.17(2H, m), 3.43-3.45(1H, m), 3.67(1H, br.s), 4.43(3H, br.s), 4.67(1H, br.s), 7.16-7.18(2H, m), 7.42(1H, d, J ═ 8.8Hz), 7.70(1H, s), 8.24(1H, br.s), 8.58(1H, d, J ═ 8.3Hz), 11.43, 11.63(1H, each br.s), 11.24 (1H, br.s).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

The title compound was obtained by treating the reaction product between the compound obtained in referential example 63 and the compound obtained in referential example 34 with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.60-1.82(4H，m)，1.91-2.15(2H，m)，3.08(2H，s)，3.37-3.49(2H，m)，4.28-4.56(4H，m)，7.13(1H，s)，7.15(1H，d，J＝8.8Hz)，7.40(1H，d，J＝8.8Hz)，7.69(1H，s)，8.61(1H，d，J＝8.3Hz)，8.88(1H，d，J＝8.3Hz)，10.05(2H，br.s)，11.82(1H，s).

MS(FAB)m/z：444(M+H)⁺.

EXAMPLE 24]N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclopentyl) -5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The compound (30mg) obtained in example 23 was suspended in methylene chloride (20ml), and triethylamine (260. mu.l) was added thereto and the mixture was stirred at room temperature for 15 minutes. Acetic acid (179. mu.l) and acetone (920. mu.l) were added to the reaction solution, and the mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (796mg) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. A1N aqueous solution (10ml) of sodium hydroxide was added to the reaction mixture to conduct a liquid separation operation. 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 (dichloromethane: methanol 100: 3) to obtain a colorless foamy substance. This was dissolved in methylene chloride, and 1N ethanol hydrochloride solution (1ml) was added. The solution was concentrated under reduced pressure to obtain the title compound (205 mg).

¹H-NMR(DMSO-d₆)δ：1.27-1.39(6H，m)，1.58-1.80(4H，m)，1.95-2.10(2H，m)，3.00-3.12(1H，m)，3.25-3.45(2H，m)，3.59-3.77(2H，m)，4.25-4.39(1H，m)，4.40-4.55(2H，m)，4.57-4.65(1H，m)，7.10(1H，s)，7.14(1H，d，J＝8.8Hz)，7.38(1H，d，J＝8.8Hz)，7.68(1H，s)，8.56(1H，d，J＝8.8Hz)，8.90(1H，d，J＝8.8Hz)，11.39(1H，br.s)，11.76(0.5H，s)，11.80(0.5H，s).

MS(FAB)m/z：486(M+H)⁺.

EXAMPLE 25]N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclopentyl) -5-ethyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The compound (500mg) obtained in example 23 was dissolved in N, N-dimethylformamide (10ml), and triethylamine (576. mu.l) and ethyl iodide (329. mu.l) were added to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to remove insoluble matter. This was purified by silica gel column chromatography (dichloromethane: methanol 100: 3) to obtain a pale brown foamy substance. This was suspended in 1N hydrochloric acid (2ml), and the solution was concentrated under reduced pressure to obtain the title compound (180 mg).

¹H-NMR(DMSO-d₆)δ：1.32(3H，t，J＝7.1Hz)，1.60-1.80(4H，m)，1.96-2.10(2H，m)，3.20-3.39(5H，m)，3.70-3.80(1H，m)，4.26-4.58(3H，m)，4.68-4.79(1H，m)，7.11(1H，s)，7.15(1H，dd，J＝8.8，2.0Hz)，7.39(1H，d，J＝8.8Hz)，7.69(1H，d，J＝1.5Hz)，8.55(1H，d，J＝8.5Hz)，8.92(1H，d，J＝8.5Hz)，11.38(1H，br.s)，11.70-11.80(1H，m).

MS(FAB)m/z：472(M+H)⁺.

[ reference example 26]N-((1R^*，2R^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclopentyl) -5- (1-methylcyclopropyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 63 and the compound obtained in referential example 39 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：0.81(2H，br.s)，1.20-1.55(5H，br)，1.55-1.80(4H，m)，1.95-2.12(2H，m)，3.05-3.40(2H，br)，3.60-3.80(2H，br)，4.25-4.80(4H，m)，7.10(1H，s)，7.16(1H，d，J＝8.8Hz)，7.39(1H，d，J＝8.8Hz)，7.69(1H，s)，8.53(1H，d，J＝8.6Hz)，8.85-8.95(1H，m)，10.60-10.90(1H，br)，11.73(1H，br.s).

MS(FAB)m/z：498(M+H)⁺.

[ 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)

From the compound (mixture of stereoisomers at position 4) (268mg) obtained in referential example 82, by the same method as in example 2, condensed with the compound obtained in referential example 10 to synthesize a mixture of stereoisomers a and B of the title compound, which was separated by silica gel column chromatography to form a hydrochloride salt, to obtain stereoisomer a (75mg) and stereoisomer B (70mg) of the title compound.

Stereoisomer a:

¹H-NMR(DMSO-d₆)δ：1.70-2.15(4H，m)，2.90(3H，s)，3.00-3.90(8H，m)，4.10-4.80(4H，m)，7.08(1H，s)，7.16(1H，d，J＝8.8Hz)，7.38(1H，d，J＝8.8Hz)，7.69(1H，s)，8.56(1H，d，J＝8.8Hz)，8.88(1H，d，J＝8.3Hz)，10.96(1H，br.s)，11.75(1H，br.s).

MS(FAB)m/z：488(M+H)⁺.

stereoisomer B:

¹H-NMR(DMSO-d₆)δ：1.60-2.10(4H，m)，2.89(3H，s)，3.00-3.70(7H，m)，3.70-3.90(1H，m)，4.20-4.80(4H，m)，7.05-7.20(2H，m)，7.38(1H，d，J＝8.8Hz)，7.68(1H，s)，8.59(1H，d，J＝8.3Hz)，8.90(1H，d，J＝8.5Hz)，11.26(1H，br.s)，11.74(1H，br.s).

MS(FAB)m/z：488(M+H)⁺.

[ 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) was prepared from the compound obtained in referential example 85 and the compound obtained in referential example 42 in the same manner as in example 2^*，2R^*) -4- [ (benzyloxy) methyl group]-2-{ [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclopentyl) -5- (2- { [ tert-butyl (diphenyl) silyl]Oxy } -1, 1-dimethylethyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Stereoisomer a and stereoisomer B of pyridine-2-carboxamide.

Stereoisomer a:

¹H-NMR(CDCl₃) δ: 1.05(9H, s), 1.168, 1.171(6H, each s), 1.53-1.61(1H, m), 1.76-1.88(1H, m), 2.30-2.37(2H, m), 2.78-2.79(2H, m), 2.87-2.90(1H, m), 2.96-3.00(1H, m), 3.37-3.47(2H, m), 3.58(2H, s), 3.96(1H, q, J ═ 13.1Hz), 4.41-4.45(1H, m), 4.51-4.57(2H, m), 6.88(1H, d, J ═ 1.5Hz), 7.17(1H, dd, J ═ 8.8, 2.0), 7.23-7.43(12H, 7.43, 7.52H, 7.6H, 1H, 7, 7.5 Hz), 7.6, br.

Stereoisomer B:

¹H-NMR(CDCl₃)δ：1.05(9H，s)，1.17(6H，s)，1.43-1.47(1H，m)，1.85-1.88(1H，m)，2.09-2.14(1H，m)，2.58-2.63(1H，m)，2.78-2.79(2H，m)，2.86-2.90(1H，m)，2.96-3.00(1H，m)，3.38-3.46(2H，m)，3.59(2H，s)，3.95(1H，q，J＝13.3Hz)，4.15-4.20(1H，m)，4.45-4.56(3H，m)，6.74(1H，d，J＝2.0Hz)，7.16(1H，dd，J＝8.8，2.0Hz)，7.27-7.43(12H，m)，7.57(1H，d，J＝2.0Hz)，9.48(1H，br.s).

2) the stereoisomer A (288mg) was suspended in methylene chloride (20ml), and dimethyl sulfide (1.15ml) and anhydrous aluminum chloride (350mg) were added to stir at room temperature for 1 hour. To the reaction mixture was added a 1N aqueous solution (10ml) of sodium hydroxide, followed by extraction with methylene chloride and drying of the organic layer over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 9: 1) to give 5- (2- { [ tert-butyl (diphenyl) silyl group ]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).

¹H-NMR(CDCl₃)δ：1.04(9H，s)，1.15(6H，s)，1.54-1.62(1H，m)，1.73-1.81(1H，m)，1.99-2.25(2H，m)，2.34-2.38(2H，m)，2.67-2.85(3H，m)，2.92-2.97(1H，m)，3.48-3.62(4H，m)，3.93(1H，q，J＝15.6Hz)，4.20-4.28(1H，m)，4.47-4.56(1H，m)，6.89(1H，s)，7.11-7.18(1H，m)，7.24-7.27(1H，m)，7.32-7.43(6H，m)，7.54(1H，d，J＝1.7Hz)，7.63(4H，dd，J＝7.8，1.5Hz)，7.90-7.92(2H，m)，10.13(1H，br.s).

MS(FAB)m/z：784(M+H)⁺.

3) The stereoisomer (A) (180mg) obtained in the above 2) was dissolved in a 1N tetrahydrofuran solution (2ml) of tetrabutylammonium fluoride, and stirred overnight at room temperature. Methylene chloride, a 1N aqueous solution of sodium hydroxide and sodium chloride were added to the reaction mixture to conduct a liquid separation operation, 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 (dichloromethane: methanol 19: 1), the obtained powder was dissolved in methanol, 1N ethanol hydrochloride solution (229 μ l) was added, and the solvent was concentrated under reduced pressure by adding ethyl acetate to obtain the title compound (63 mg).

¹H-NMR(DMSO-d₆) δ: 1.33-1.50(8H, m), 1.70-1.91(2H, m), 2.07-2.14(1H, m), 2.23-2.24(1H, m), 3.04-3.10(1H, m), 3.27-3.44(4H, m), 3.57-3.70(2H, m), 3.92-3.95(1H, m), 4.29-4.72(4H, m), 5.81(1H, br.s), 7.11(1H, s), 7.15(1H, dd, J ═ 8.6, 2.0Hz), 7.39(1H, d, J ═ 8.6Hz), 7.68(1H, d, J ═ 2.0Hz), 8.53-8.56(1H, m), 8.83(1H, d, J ═ 8.7, 11H, 11.75 (1H, s), 8.83(1H, d, J ═ 8.7.7.7.7, 11H, 75 Hz).

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

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 44 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.35-1.50(2H，m)，1.61(4H，br.s)，1.80-2.00(2H，m)，2.27(2H，br.s)，2.80-4.80(10H，m)，7.14(1H，d，J＝1.5Hz)，7.17(1H，dd，J＝8.5，2.0Hz)，7.41(1H，d，J＝8.5Hz)，7.70(1H，d，J＝2.0Hz)，8.09(1H，d，J＝7.3Hz)，8.44(1H，br.s)，11.81(1H，br.s).

MS(FAB)m/z：499(M+H)⁺.

Example 30]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -4, 6, 7, 8, 9, 11-hexahydropyridazino [1, 2-a]Thiazolo [4, 5-d]Pyridazine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 46 and the compound obtained in referential example 71 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.35-1.55(2H，m)，1.55-2.10(10H，m)，2.80-4.80(10H，m)，7.10-7.25(2H，m)，7.42(1H，d，J＝8.8Hz)，7.72(1H，d，J＝1.7Hz)，8.12(1H，br.s)，8.41(1H，br.s)，11.83(1H，br.s).

MS(FAB)m/z：513(M+H)⁺.

[ example 31]5-chloro-N- { (1R)^*，2S^*) -2- [ (5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-ylcarbonyl) amino]CyclohexaneYl indole-2-carboxamide hydrochloride

The compound (171mg) obtained in referential example 33 was dissolved in diethyl ether (5ml) under an argon atmosphere, and N-butyllithium (1.60N in hexane, 385. mu.l) was added dropwise at-78 ℃. After stirring at-78 ℃ for 10 minutes, carbon dioxide gas was introduced over 20 minutes, and the temperature was raised to room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in N, N-dimethylformamide (10ml), and the compound (184mg) obtained in referential example 71, 1-hydroxybenzotriazole 1 hydrate (76mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (215mg) were added to stir at room temperature for 3 days. After the reaction mixture was concentrated, methylene chloride and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (methanol: dichloromethane 3: 97), an ethanol solution (5ml) of hydrochloric acid was added to the resultant product, and the mixture was stirred at room temperature for 1 hour, followed by concentrating the reaction mixture. To the resulting residue was added ethyl acetate to solidify, and the powder was collected by filtration to obtain the title compound (31 mg).

¹H-NMR(DMSO-d₆)δ：1.35-1.52(2H，m)，1.55-1.80(4H，m)，1.82-2.05(2H，m)，4.22(1H，br.s)，4.28(1H，br.s)，4.38(2H，s)，4.56(2H，s)，7.14-7.20(2H，m)，7.42(1H，d，J＝8.6Hz)，7.71(1H，d，J＝1.7Hz)，8.10(1H，d，J＝7.1Hz)，8.45(1H，d，J＝7.8Hz)，10.10-10.50(2H，br)，11.83(1H，br.s).MS(FAB)m/z：444(M+H)⁺.

[ 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 title compound was obtained by hydrolyzing the compound obtained in referential example 50 with lithium hydroxide and then reacting it with the compound obtained in referential example 71 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.54(9H，s)，1.55-2.30(8H，m)，4.23(1H，br.s)，4.53(1H，br.s)，4.74-4.83(4H，m)，6.99(1H，d，J＝1.5Hz)，7.19(1H，dd，J＝8.8，2.1Hz)，7.34(1H，d，J＝8.8Hz)，7.62(1H，d，J＝2.1Hz)，8.11(1H，br.s)，8.48-8.53(1H，br)，8.70-8.76(1H，br)，9.60-9.70(1H，br).

MS(ESI)m/z：539(M+H)⁺.

[ 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

Trifluoroacetic acid (1ml) was added to a solution prepared by dissolving the compound (34.0mg) obtained in example 32 in methylene chloride (1ml) and stirred at room temperature for 1 hour. Concentrated under reduced pressure, the residue was dissolved in methylene chloride (1ml), and triethylamine (17.6. mu.l), acetic acid (7.21. mu.l), 35% formalin (8.13. mu.l) and sodium triacetoxyborohydride (20.1mg) were added at room temperature to stir for 1 hour. Methylene chloride (10ml) and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, 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: dichloromethane ═ 7: 93), followed by addition of 1N ethanol hydrochloride solution and ethyl acetate to solidify the mixture, and filtration was carried out to obtain the title compound (8.00 mg).

¹H-NMR(DMSO-d₆)δ：1.40-1.55(2H，m)，1.55-1.75(4H，m)，1.80-2.05(2H，m)，2.98(3H，br.s)，4.28(2H，br.s)，4.65(4H，br.s)，7.14-7.20(2H，m)，7.41(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.0Hz)，8.17(1H，d，J＝6.9Hz)，8.65(1H，d，J＝8.3Hz)，8.93(1H，s)，11.73(1H，br.s)，11.82(1H，br.s).

MS(FAB)m/z：453(M+H)⁺.

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

The title compound was obtained by treating the reaction product between the compound obtained in referential example 71 and the compound obtained in referential example 34 with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.39-1.52(2H，m)，1.62(4H，br.s)，1.86-2.09(2H，m)，3.03(2H，br.s)，3.40-3.47(2H，m)，4.17-4.32(2H，m)，4.44(2H，s)，7.15(1H，s)，7.17(1H，dd，J＝8.6，2.0Hz)，7.41(1H，d，J＝8.6Hz)，7.71(1H，s)，8.10-8.15(1H，m)，8.40-8.47(1H，m)，9.69(2H，br.s)，11.85(1H，s).

MS(FAB)m/z：458(M+H)⁺.

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

The title compound was obtained from the compound obtained in example 34 and 2-methoxyethyl bromide by the same method as in example 25.

¹H-NMR(DMSO-d₆)δ：1.44(2H，br.s)，1.62(4H，br.s)，1.85-2.10(2H，m)，2.76-3.21(6H，m)，3.28(3H，s)，3.64(2H，br.s)，4.00-4.52(4H，m)，7.14(1H，s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.70(1H，d，J＝2.0Hz)，8.08-8.20(1H，m)，8.36-8.48(1H，m)，11.84(1H，s).

MS(FAB)m/z：516(M+H)⁺.

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

The title compound was obtained from the compound obtained in example 34 and methyl bromoacetate by the same method as in example 25.

¹H-NMR(CDCl₃)δ：1.52-1.98(7H，m)，2.17(1H，br.s)，2.87-3.10(4H，m)，3.49(2H，s)，3.76(3H，s)，3.93(1H，d，J＝15.4Hz)，3.99(1H，d，J＝15.4Hz)，4.22(1H，br.s)，4.45(1H，br.s)，6.86(1H，d，J＝1.2Hz)，7.18(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.58-7.63(2H，m)，7.87(1H，br.s)，9.88(1H，br.s).

MS(FAB)m/z：530(M+H)⁺.

[ example 37]N-((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in example 34 and acetone by the same method as in example 24.

¹H-NMR(DMSO-d₆)δ：1.18-1.73(8H，m)，1.81-2.10(2H，m)，2.97-3.16(1H，m)，3.20-3.41(2H，m)，3.52-3.80(2H，m)，4.19-4.31(2H，m)，4.34-4.77(2H，m)，7.17(1H，s)，7.18(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.71(1H，d，J＝2.0Hz)，8.15(1H，br.s)，8.28-8.51(1H，m)，11.31(1H，br.s)，11.86(1H，s).

MS(FAB)m/z：500(M+H)⁺.

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

The title compound was obtained from the compound obtained in example 34 and tetrahydro-4H-pyran-4-one by the same method as in example 24.

¹H-NMR(DMSO-d₆)δ：1.30-3.56(19H，m)，3.70-4.01(3H，m)，4.17-4.30(2H，m)，4.32-4.80(1H，m)，7.15(1H，s)，7.17(1H，dd，J＝8.6，2.0Hz)，7.41(1H，d，J＝8.6Hz)，7.71(1H，d，J＝2.0Hz)，8.14(1H，br.s)，8.39(1H，br.s)，11.84(1H，s).

MS(FAB)m/z：542(M+H)⁺.

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

The title compound was obtained from the compound obtained in example 34 and N- (tert-butoxycarbonyl) aminoacetaldehyde (j. org. chem., 1988, vol. 53, p. 3457) by the same method as in example 24.

¹H-NMR(CDCl₃)δ：1.44(9H，s)，1.54-1.98(7H，m)，2.10-2.20(1H，m)，2.74(2H，br.s)，2.92(4H，br.s)，3.34(2H，br.s)，3.84(2H，br.s)，4.21(1H，br.s)，4.45(1H，br.s)，6.86(1H，s)，7.19(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.57-7.63(2H，m)，7.81(1H，br.s)，9.66(1H，br.s).

MS(FAB)m/z：601(M+H)⁺.

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 (450mg) obtained in example 39 was dissolved in methylene chloride (5ml), and an ethanol solution (30ml) of hydrochloric acid was added thereto and 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 obtain the title compound (367 mg).

¹H-NMR(DMSO-d₆)δ：1.38-1.50(2H，m)，1.61(4H，br.s)，1.85-2.08(2H，m)，3.00-4.62(12H，m)，7.14(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.0Hz)，8.12(1H，d，J＝6.6Hz)，8.15-8.68(4H，m)，11.85(1H，s).

MS(FAB)m/z：501(M+H)⁺.

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 obtained in example 40 (110mg) was dissolved in pyridine (3ml), and after methanesulfonyl chloride (30. mu.l) was added, the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a solution of dichloromethane: methanol 85: 15 and water were added to the residue to conduct a liquid separation operation, followed by drying the organic layer over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 100: 3) to obtain a pale yellow foamy substance. This was suspended in 1N hydrochloric acid (0.3ml), and the solution was concentrated under reduced pressure to obtain the title compound (63 mg).

¹H-NMR(DMSO-d₆)δ：1.38-1.50(2H，m)，1.55-1.70(4H，m)，1.86-2.05(2H，m)，2.97(3H，s)，3.02-3.25(2H，m)，3.30-3.60(5H，m)，3.78(1H，br.s)，4.18-4.30(2H，m)，4.45-4.86(2H，m)，7.14(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.40(1H，d，J＝8.8Hz)，7.41(1H，br.s)，7.69(1H，d，J＝2.0Hz)，8.09(1H，br.s)，8.43(1H，br.s)，11.18(1H，br.s)，11.82(1H，s).

MS(FAB)m/z：579(M+H)⁺.

[ 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 (144mg) obtained in example 40 was dissolved in pyridine (3ml), and triethylamine (138. mu.l) was added thereto and the mixture was stirred at room temperature for 5 minutes. To the solution was added dropwise a solution prepared by adding triphosgene (49mg) to tetrahydrofuran (1ml) containing methanol (20. mu.l) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane/methanol (9: 1), and water was added to the solution to separate the 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 (dichloromethane: methanol 100: 3) to obtain a colorless foamy substance. This was suspended in 1N hydrochloric acid (0.2ml), and the solution was concentrated under reduced pressure to obtain the title compound (60 mg).

¹H-NMR(DMSO-d₆)δ：1.38-1.50(2H，m)，1.61(4H，br.s)，1.85-2.04(2H，m)，2.80-3.49(8H，m)，3.52(3H，s)，3.62-4.91(4H，m)，7.14(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.37(1H，br.s)，7.40(1H，d，J＝8.8Hz)，7.70(1H，s)，8.11(1H，d，J＝6.8Hz)，8.40(1H，br.s)，11.05(1H，br.s)，11.82(1H，br.s).

MS(FAB)m/z：559(M+H)⁺.

[ 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 (90mg) obtained in example 40 was dissolved in N, N-dimethylformamide (3ml), and triethylamine (65. mu.l) and acetic anhydride (22. mu.l) were added thereto and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a 0.3N aqueous solution of sodium hydroxide were added to the residue to conduct a liquid separation operation, followed by drying the organic layer over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 100: 3) to obtain a colorless foamy substance. This was suspended in 1N hydrochloric acid (0.3ml), and the solution was concentrated under reduced pressure to obtain the title compound (73 mg).

¹H-NMR(DMSO-d₆)δ：1.39-1.52(2H，m)，1.54-1.70(4H，m)，1.83(3H，s)，1.84-2.06(2H，m)，3.02-3.87(8H，m)，4.16-4.32(2H，m)，4.40-4.52(1H，m)，4.78-4.88(1H，m)，7.14(1H，s)，7.16(1H，d，J＝8.6Hz)，7.40(1H，d，J＝8.6Hz)，7.70(1H，s)，8.07-8.17(1H，m)，8.22-8.30(1H，m)，8.38-8.52(1H，m)，11.14(1H，br.s)，11.83(1H，s).

MS(FAB)m/z：543(M+H)⁺.

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-carboxamides

The title compound was obtained from the compound obtained in example 34 and 2-bromoethanol by the same method as in example 25.

¹H-NMR(DMSO-d₆)δ：1.37-1.69(6H，m)，1.86-2.03(2H，m)，2.54-2.61(2H，m)，2.75-2.86(4H，m)，3.52-3.59(2H，m)，3.75(2H，s)，4.47(1H，t，J＝5.4Hz)，7.12(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.40(1H，d，J＝8.8Hz)，7.70(1H，s)，8.05-8.13(1H，m)，8.28-8.35(1H，m)，11.78(1H，s).

MS(FAB)m/z：502(M+H)⁺.

EXAMPLE 45]5-butyl-N- ((1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -4, 5, 6, 7-tetrahydroThiazolo [5, 4-c ]]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in example 34 and 1-bromobutane by the same method as in example 25.

¹H-NMR(DMSO-d₆)δ：0.88(3H，t，J＝7.2Hz)，1.20-1.70(10H，m)，1.87-2.05(2H，m)，2.55-3.40(8H，m)，4.16-4.30(2H，m)，7.13(1H，s)，7.16(1H，d，J＝8.8Hz)，7.40(1H，d，J＝8.8Hz)，7.69(1H，s)，8.05-8.14(1H，m)，8.35(1H，br.s)，11.81(1H，s).

MS(FAB)m/z：514(M+H)⁺.

EXAMPLE 46]5-acetyl-N- ((1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

The compound (100mg) obtained in example 34 was dissolved in N, N-dimethylformamide (3ml), and triethylamine (84. mu.l) and acetic anhydride (29. mu.l) were added thereto and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and 1N hydrochloric acid were added to the residue to conduct a liquid separation operation, and then 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 (dichloromethane: methanol 100: 3) to obtain the title compound (86 mg).

¹H-NMR(CDCl₃)δ：1.52-1.85(5H，m)，1.91(2H，br.s)，2.10-2.28(4H，m)，2.77-3.00(2H，m)，3.70-4.00(2H，m)，4.19-4.38(1H，m)，4.45(1H，br.s)，4.68-4.99(2H，m)，6.85(1H，s)，7.17-7.22(1H，m)，7.30-7.39(1H，m)，7.50-7.84(3H，m)，9.7

2-10.05(1H，m).

MS(FAB)m/z：500(M+H)⁺.

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-carboxamides

The compound (100mg) obtained in example 34 was dissolved in pyridine (3ml), and triethylamine (168. mu.l) and methanesulfonyl chloride (48. mu.l) were added to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and methylene chloride and 1N hydrochloric acid were added to the residue to separate an organic layer, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 100: 1) to obtain the title compound (79 mg).

¹H-NMR(CDCl₃)δ：1.50-1.82(5H，m)，1.90(2H，br.s)，2.13(1H，br.s)，2.89(3H，s)，2.91-2.98(2H，m)，3.60-3.70(2H，m)，4.30(1H，br.s)，4.44(1H，br.s)，4.58(2H，s)，6.87(1H，s)，7.19(1H，d，J＝8.8Hz)，7.34(1H，d，J＝8.8Hz)，7.61(3H，br.s)，9.91(1H，br.s).

MS(FAB)m/z：536(M+H)⁺.

EXAMPLE 48]5-methyl-N- ((1R)^*，2S^*) -2- { [ (5-methylindol-2-yl) carbonyl]Amino } cyclohexyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 67 and 5-methylindole-2-carboxylic acid by the same process as in example 5.

¹H-NMR(DMSO-d₆)δ：1.35-1.50(2H，m)，1.50-1.80(4H，m)，1.85-2.07(2H，m)，2.36(3H，s)，2.88(3H，s)，3.12(2H，br.s)，3.53(2H，br.s)，4.15-4.30(2H，m)，4.30-4.80(2H，br)，7.00(1H，dd，J＝8.4，1.5Hz)，7.05(1H，d，J＝1.5Hz)，7.30(1H，d，J＝8.4Hz)，7.38(1H，s)，8.00(1H，d，J＝7.3Hz)，8.43(1H，br.s)，11.45(1H，br.s)，11.49(1H，br.s).

MS(FAB)m/z：452(M+H)⁺.

[ 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 (1.40g) obtained in referential example 91 was suspended in ethanol (8ml), and an ethanol solution (10ml) of hydrochloric acid was added thereto at room temperature to stir for 12 hours. Evaporating the solvent under reduced pressure to obtain (1R)^*，3S^*，4R^*) -3-amino-4- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexanecarboxylic acid ethyl ester hydrochloride (1.25 g).

The title compound was obtained from the above product and the compound obtained in reference example 10 by the same method as in example 2.

¹H-NMR(CDCl₃) δ: 1.29(3H, t, J ═ 7.1Hz), 1.52-1.80(2H, m), 2.03-2.37(4H, m), 2.53(3H, s), 2.57-2.71(1H, m), 3.73 and 3.78 (1H, d, J ═ 14.4Hz), 4.08-4.17(1H, m), 4.18(2H, q, J ═ 7.2Hz), 4.55-4.65(1H, m), 6.85(1H, br.s), 7.21(1H, d, H, q, J ═ 7.2Hz), 4.55-4.65(1H, m), 6.85(1H, br.s), 7.21(1H, b, m) d，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.48(1H，d，J＝7.6Hz)，7.63(1H，d，J＝2.0Hz)，7.98(1H，d，J＝7.6Hz)，9.30(1H，s).

MS(ESI)m/z：544(M+H)⁺.

[ example 50] (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 ethyl ester

The compound (4.2g) obtained in referential example 97 was suspended in ethanol (25ml), and an ethanol solution (55ml) of hydrochloric acid was added thereto at room temperature and stirred for 11 hours. The solvent was distilled off under reduced pressure to obtain a colorless solid (4.15 g).

The above-mentioned product (4.15g) was dissolved in N, N-dimethylformamide (40ml), and the compound (2.86g) obtained in referential example 10, 1-hydroxybenzotriazole 1 hydrate (1.72g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.15g) were added at room temperature to stir for 39 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with chloroform and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated 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).

[d]_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 title compound was obtained by treating the compound obtained in referential example 107 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.55-1.80(3H，m)，1.80-2.20(3H，m)，2.60-2.75(1H，m)，2.92(3H，s)，3.15-3.30(1H，m)，3.30-3.50(4H，m)，3.57(3H，s)，3.55-3.70(1H，m)，4.20-4.30(1H，m)，4.30-4.40(1H，m)，7.02(1H，s)，7.17(1H，dd，J＝8.5，2.0Hz)，7.41(1H，d，J＝8.5Hz)，7.71(1H，s)，8.20-8.35(1H，m)，8.35-8.45(1H，m)，11.82(1H，br).

MS(FAB)m/z：530(M+H)⁺.

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 title compound was obtained by treating the compound obtained in referential example 98 with a hydrochloric acid ethanol solution and then condensing it with 5-chloroindole-2-carboxylic acid in the same manner as in example 49.

¹H-NMR(CDCl₃)δ：1.29(3H，t，J＝7.1Hz)，1.82-2.30(6H，m)，2.49(3H，s)，2.62-2.73(1H，m)，3.74-3.85(2H，m)，3.85-3.93(2H，m)，3.71(2H，s)，4.12-4.29(3H，m)，4.49-4.59(1H，m)，6.89(1H，br.s)，7.21(1H，dd，J＝8.8，2.0Hz)，7.32(1H，d，J＝8.8Hz)，7.33(1H，br.s)，7.41(1H，br.s)，7.62(1H，br.s)，9.37(1H，s).

MS(ESI)m/z：544(M+H)⁺.

[ 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 title compound was obtained by treating the compound obtained in referential example 106 with a 4N dioxane hydrochloride solution and then condensing it with 5-chloroindole-2-carboxylic acid in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.65-1.80(3H，m)，1.80-2.10(2H，m)，2.15-2.25(1H，m)，2.55-2.70(1H，m)，2.89(3H，s)，3.05-3.20(1H，m)，3.30-3.50(4H，m)，3.55-3.65(1H，m)，3.62(3H，s)，4.20-4.30(1H，m)，4.35-4.45(1H，m)，7.19(1H，dd，J＝8.8，1.2Hz)，7.23(1H，s)，7.43(1H，d，J＝8.8Hz)，7.73(1H，s)，8.03(1H，d，J＝6.8Hz)，8.73(1H，d，J＝8.5Hz)，11.15-11.38(1H，br)，11.85(1H，s).

MS(FAB)m/z：530(M+H)⁺.

[ example 54] (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

The title compound was obtained by treating the compound obtained in referential example 112 with a 4N dioxane hydrochloride solution and then condensing it with 5-chloroindole-2-carboxylic acid in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.67-1.76(3H，m)，1.88-1.91(1H，m)，2.01(1H，br.s)，2.13-2.22(1H，m)，2.52-2.67(4H，m)，2.86(2H，br.s)，3.04(2H，br.s)，3.33-3.41(1H，m)，3.61(3H，s)，4.22-4.36(3H，m)，7.17-7.22(2H，m)，7.42(1H，d，J＝8.8Hz)，7.72(1H，s)，8.00(1H，d，J＝6.9Hz)，8.68(1H，d，J＝8.6Hz)，11.80(1H，s).

MS(FAB)m/z：530(M+H)⁺.

[ 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-carboxamides

The title compound was obtained by treating the compound obtained in referential example 113 with a 4N dioxane hydrochloride solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 49.

¹H-NMR(CDCl₃)δ：0.78-2.40(7H，m)，2.53(3H，s)，2.80-2.89(1H，m)，2.91-3.00(1H，m)，3.68-3.76(2H，m)，4.08-4.19(1H，m)，4.54-4.65(1H，m)，6.80(1H，br.s)，7.21(1H，dd，J＝8.4，1.6Hz)，7.33(1H，d，J＝8.4Hz)，7.38-7.43(1H，m)，7.49-7.55(1H，m)，7.63(1H，br.s)，9.14(1H，br.s).

MS(ESI)m/z：515(M+H)⁺.

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 acids

The compound (916mg) obtained in example 49 was suspended in a mixed solvent of ethanol (10ml) and tetrahydrofuran (8ml), and a 1N aqueous solution (3.3ml) of sodium hydroxide was added thereto at room temperature, followed by stirring at the same temperature for 12 hours. After 1N ethanol hydrochloride solution (3.3ml) was added, the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (712 mg).

[ example 57]N-{(1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) carbonyl group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamide hydrochloride

Triethylamine (0.25ml), dimethylamine hydrochloride (133mg), 1-hydroxybenzotriazole 1 hydrate (53mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (75mg) were added to a chloroform suspension (10ml) of the compound (168mg) obtained in example 56, and the mixture was stirred for 72 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform and water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 93: 7), the resulting colorless solid (135mg) was suspended in ethanol (5ml), and 1N ethanol hydrochloride solution (0.5ml) was added thereto and stirred for 2 hours. The solvent was distilled off to obtain the title compound (112 mg).

¹H-NMR(DMSO-d₆)δ：1.42-2.07(6H，m)，2.73-3.70(10H，m)，2.88(3H，s)，2.97(3H，s)，4.03-4.20(1H，m)，4.51-4.67(1H，m)，7.04(1H，br.s)，7.16(1H，br，J＝8.8Hz)，7.41(1H，d，J＝8.8Hz)，7.68(1H，br.s)，8.32-8.47(2H，m)，10.76(1H，br.s).

MS(ESI)m/z：543(M+H)⁺.

[ example 58] (1S, 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

The compound (1.6g) obtained in example 50 was suspended in a mixed solvent of ethanol (20ml) and tetrahydrofuran (15ml), and a 1N aqueous solution (5.9ml) of sodium hydroxide was added thereto at room temperature, followed by stirring at the same temperature for 12 hours. After 1N hydrochloric acid (5.9ml) was added, the solvent was distilled off under reduced pressure, and the residue was washed with water and ether to obtain the title compound (1.19 g).

Melting point: 234 to 236 DEG 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

The title compound was obtained from the compound obtained in example 58 and cyclopropylamine by the same method as in example 57.

¹H-NMR(DMSO-d₆)δ：0.32-0.40(2H，m)，0.53-0.63(2H，m)，1.50-2.10(6H，m)，2.25-2.40(1H，m)，2.45-2.70(2H，m)，2.91(3H，s)，3.05-3.80(3H，m)，4.05-4.17(1H，m)，4.30-4.55(2H，m)，4.55-4.80(1H，m)，7.03(1H，d，J＝1.5Hz)，7.16(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.68(1H，d，J＝2.0Hz)，7.86(1H，br，J＝3.4Hz)，8.06(1H，br.s)，8.40(1H，br，J＝7.6Hz)，11.20-11.60(1H，br)，11.79(1H，s).

MS(FAB)m/z：555(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 58 and pyrrolidine by the same method as in example 57.

¹H-NMR(DMSO-d₆)δ：1.45-2.10(10H，m)，2.75-2.90(2H，m)，2.90(3H，s)，3.10-3.70(H，m)，4.05-4.20(1H，m)，4.25-4.80(3H，m)，7.05(1H，s)，7.17(1H，d，J＝8.7Hz)，7.41(1H，d，J＝8.7Hz)，7.69(1H，s)，8.32(1H，br，J＝7.6Hz)，8.38(1H，br，J＝7.1Hz)，11.22(1H，br.s)，11.78(1H，s).

MS(FAB)m/z：569(M+H)⁺.

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

The title compound was obtained from the compound obtained in example 56 and morpholine by the same method as in example 57.

¹H-NMR(DMSO-d₆)δ：1.40-2.05(6H，m)，2.75-3.70(18H，m)，4.02-4.17(1H，m)，4.55-4.69(1H，m)，7.05(1H，br.s)，7.17(1H，br，J＝8.8Hz)，7.41(1H，d，J＝8.8Hz)，7.67(1H，br.s)，8.35(1H，d，J＝7.6Hz)，8.40(1H，d，J＝7.6Hz)，10.79(1H，br.s).

MS(ESI)m/z：585(M+H)⁺.

[ 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 (150mg) obtained in example 58 was dissolved in N, N-dimethylformamide (3ml), and N-ethylamine hydrochloride (119mg), 1-hydroxybenzotriazole 1 hydrate (79mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (112mg) and triethylamine (326. mu.l) were added to stir at room temperature for 4 days. The solvent was evaporated under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to extract with methylene chloride, 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 (dichloromethane: methanol 47: 3). The resulting solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (171. mu.l) 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 obtain the title compound (74 mg).

¹H-NMR(DMSO-d₆)δ：0.99(3H，t，J＝7.2Hz)，1.57-2.02(6H，m)，2.33-2.38(1H，m)，2.92(3H，s)，3.01-3.08(2H，m)，3.17-3.20(2H，s)，3.45-3.70(2H，m)，4.10-4.17(1H，m)，4.40-4.69(3H，m)，7.04(1H，d，J＝2.0Hz)，7.17(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.0Hz)，7.78-7.81(1H，m)，8.08-8.12(1H，m)，8.40(1H，d，J＝8.1Hz)，11.23(1H，br.s)，11.79(1H，br.s).

MS(FAB)m/z：543(M+H)⁺.

[ 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 (900mg) obtained in example 58 was dissolved in N, N-dimethylformamide (50ml), and dimethylamine hydrochloride (304mg), 1-hydroxybenzotriazole 1 hydrate (262mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (369mg), and diisopropylethylamine (1.83ml) were added to stir at room temperature for 12 hours. The solvent was evaporated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 47: 3), and the obtained white solid was dissolved in dichloromethane, 1N ethanol hydrochloride solution (1.49ml) 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 obtain the title compound (777 mg).

[α]_D-53.9 ° (18 °, c ═ 0.505, methanol)

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.70-1.85(3H，m)，1.90-2.05(2H，m)，2.80(3H，s)，2.91(3H，s)，2.95-3.10(1H，m)，2.97(3H，s)，3.10-3.75(4H，m)，4.05-4.15(1H，m)，4.35-4.75(3H，m)，7.05(1H，s)，7.16(1H，dd，J＝8.7，2.1Hz)，7.41(1H，d，J＝8.6Hz)，7.67(1H，s)，8.30-8.45(2H，m)，11.63(1H，br)，11.78(1H，s).

MS(FAB)m/z：543(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 58 by the same method as in example 57.

¹H-NMR(DMSO-d₆) δ: 1.50-1.99(6H, m), 2.80, 3.01(3H, s 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, 2.0Hz), 7.42(1H, d, J ═ 8.8Hz), 7.69(1H, br.s), 8.29-8.41(2H, m), 11.59(1H, br.s), 11.80(1H, br.s).

MS(FAB)m/z：587(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 58 by the same method as in example 57.

¹H-NMR(DMSO-d₆) δ: 1.50-1.55(1H, m), 1.74-1.84(3H, m), 1.94-1.97(2H, m), 2.67, 3.02(3H, s each), 2.91(3H, s), 3.10-3.68(9H, m), 4.11-4.13(1H, m), 4.43-4.66(4H, m), 7.05(1H, s), 7.16(1H, dd, J ═ 8.7, 2.0Hz), 7.41(1H, d, J ═ 8.7Hz), 7.68(1H, s), 8.34-8.40(2H, m), 11.47(1H, br.s), 11.79(1H, s).

MS(FAB)m/z：573(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 58 and azetidine hydrochloride by the same method as in example 57.

¹H-NMR(DMSO-d₆)δ：1.47-1.55(1H，m)，1.65-1.82(3H，m)，1.88-2.01(2H，m)，2.16(2H，quint.，J＝7.6Hz)，3.17-3.67(5H，m)，3.82(2H，t，J＝7.6Hz)，4.02-4.14(3H，m)，4.43-4.67(3H，m)，7.06(1H，s)，7.17(1H，dd，J＝8.7，1.7Hz)，7.41(1H，d，J＝8.7Hz)，7.69(1H，br.s)，8.31(1H，d，J＝7.6Hz)，8.38(1H，d，J＝7.6Hz)，11.41(1H，br.s)，11.80(1H，s).

MS(FAB)m/z：555(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 58 and (S) -3-fluoropyrrolidine (synlett., 1995, page 55) by the same method as in example 57.

¹H-NMR(DMSO-d₆)δ：1.23-3.77(22H，m)，4.11-4.16(1H，m)，4.58-4.51(1H，m)，5.23-5.42(1H，m)，7.05(1H，s)，7.16(1H，d，J＝8.3Hz)，7.42(1H，d，J＝8.3Hz)，7.68(1H，s)，8.34-8.37(2H，m)，11.78(1H，s).

MS(FAB)m/z：587(M+H)⁺.

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 (1.20g) obtained in example 51 was dissolved in tetrahydrofuran (32ml), and lithium hydroxide (60.8mg) and water (4ml) were successively added under ice cooling, followed by stirring at room temperature for 14 hours. The solvent was distilled off under reduced pressure to obtain the title compound (1.12 g).

¹H-NMR(DMSO-d₆)δ：1.55-1.70(2H，m)，1.70-2.05(4H，m)，2.10-2.20(1H，m)，2.25-2.40(4H，m)，2.50-2.80(4H，m)，3.45-3.65(3H，m)，4.10-4.30(2H，m)，7.00-7.20(2H，m)，7.50-7.65(2H，m).

[ example 69]N-{(1R^*，2S^*，4S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl ]Amino } -4- [ (dimethylamino) carbonyl group]Cyclohexyl } -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 68 and dimethylamine hydrochloride by the same method as in example 57.

¹H-NMR(DMSO-d₆)δ：1.40-1.60(2H，m)，1.65-1.80(2H，m)，1.95-2.10(2H，m)，2.84(3H，s)，2.90-3.05(1H，m)，2.92(3H，s)，3.06(3H，s)，3.15-3.75(4H，m)，4.25-4.75(4H，m)，7.02(1H，d，J＝1.5Hz)，7.15(1H，dd，J＝8.8，2.1Hz)，7.41(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.1Hz)，8.05(1H，d，J＝7.7Hz)，8.63(1H，d，J＝7.7Hz)，11.20(1H，br)，11.79(1H，s).

MS(FAB)m/z：543(M+H)⁺.

[ 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 (1.18g) obtained in referential example 58 was dissolved in methanol (12ml), 1N hydrochloric acid (240. mu.l) and palladium hydroxide (221mg) were added, hydrogen gas was introduced, and a catalytic reduction reaction was carried out at room temperature over 4.5 hours under normal pressure. The catalyst was filtered off, and the filtrate was concentrated to a solid under reduced pressure to obtain crude (3R) -3- { [ tert-butyl (diphenyl) silyl ] oxy } pyrrolidine hydrochloride (984 mg).

The resultant (249mg), the compound (295mg) obtained in example 58, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (126mg) and 1-hydroxybenzotriazole 1 hydrate (87mg) were dissolved in N, N-dimethylformamide (10 ml). Diisopropylethylamine (450. mu.l) was added dropwise thereto under ice cooling, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, methylene chloride and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to conduct a liquid separation operation, and then 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 (methanol: dichloromethane ═ 3: 97) to give 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).

¹H-NMR(CDCl₃)δ：1.06(9H，s)，1.50-1.60(1H，m)，1.75-2.10(5H，m)，2.20-2.50(2H，m)，2.54(3H，d，J＝2.8Hz)，2.60-3.00(5H，m)，3.30-3.80(6H，m)，4.10-4.20(1H，m)，4.40-4.70(2H，m)，6.85(1H，s)，7.15-7.25(1H，m)，7.30-7.50(8H，m)，7.60-7.70(5H，m)，7.90-8.00(1H，m)，9.38(1H，s).

MS(FAB)m/z：823(M+H)⁺.

2) The product (240mg) was dissolved in pyridine (10ml), and hydrogen fluoride-pyridine (3.0ml) was added dropwise under ice cooling, followed by stirring at 0 ℃ for 4.5 hours. Ethyl acetate (80ml) was added to the reaction mixture to dilute the mixture under ice-cooling, and the diluted reaction mixture was poured into ice water. After adding sodium hydrogencarbonate to the solution to make it alkaline, a liquid separation operation was performed, 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: dichloromethane ═ 1: 19 → 1: 9). The crude purified product was dissolved in methylene chloride and methanol, 1N ethanol hydrochloride solution (225. mu.l) was added thereto and evaporated to dryness once, and methanol-ether was added to the residue to solidify it, whereby the title compound (114mg) was obtained.

¹H-NMR(DMSO-d₆)δ：1.50-1.60(1H，m)，1.70-2.10(6H，m)，2.75-2.85(1H，m)，2.92(3H，s)，3.10-3.80(8H，m)，4.10-5.10(6H，m)，7.05(1H，d，J＝1.7Hz)，7.16(1H，dd，J＝8.8，1.7Hz)，7.42(1H，d，J＝8.8Hz)，7.68(1H，s)，8.30-8.45(2H，m)，11.10-11.40(1H，m)，11.78(1H，s).

MS(FAB)m/z：585(M+H)⁺.

[ 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-carboxamides 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-carboxamides

The title compound was obtained from the compound obtained in referential example 118 and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：2.11-2.15(1H，m)，2.21-2.25(1H，m)，2.41-2.43(1H，m)，2.46(3H，s)，2.70-2.75(1H，m)，2.81-2.88(1H，m)，3.21(3H，s)，3.24(3H，s)，3.49(1H，s)，3.58(1H，d，J＝15.6Hz)，3.71(1H，d，J＝15.6Hz)，3.87-3.93(1H，m)，4.26-4.29(1H，m)，6.85(1H，d，J＝2.0Hz)，7.19(1H，dd，J＝8.5，2.0Hz)，7.30(1H，d，J＝8.5Hz)，7.62(1H，s)，9.21(1H，s).

[ 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-carboxamides 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-carboxamides

The compound (100mg) obtained in example 71 was dissolved in chloroform (2ml), and trifluoroacetic acid (0.5ml) and water (0.5ml) were added to stir at room temperature for 3.5 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (dichloromethane: methanol ═ 19: 1). The obtained colorless solid was dissolved in methanol (4ml), a 1N ethanol hydrochloride solution (0.38ml) was added, and the solvent was distilled off under reduced pressure to obtain the title compound (35 mg).

¹H-NMR(DMSO-d₆)δ：1.83-1.90(1H，m)，2.08-2.10(1H，m)，2.28-2.32(1H，m)，2.50-2.59(1H，m)，2.87(3H，s)，2.96(1H，t，J＝13.0Hz)，3.06-3.10(2H，m)，3.33-3.36(3H，m)，4.02-4.04(2H，m)，4.55-4.57(2H，m)，7.03(1H，s)，7.15(1H，d，J＝8.8Hz)，7.38(1H，d，J＝8.8Hz)，7.69(1H，s)，8.43(1H，d，J＝8.8Hz)，8.91(1H，d，J＝8.8Hz)，11.75(1H，s).

[ 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-carboxamides 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-carboxamides

The compound (133mg) obtained in example 72 was dissolved in a mixed solvent of pyridine (8ml) and methanol (8ml), and hydroxylamine hydrochloride (30mg) was added thereto and stirred at room temperature for 3 days. The reaction mixture was concentrated, water was added to the residue, which was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 97: 3 → 17: 3) to obtain the title compound (131 mg).

¹H-NMR(CDCl₃) δ: 1.43-1.86(3H, m), 1.98-2.03(1H, m), 2.26-2.30(1H, m), 2.45(3H, s), 2.47-2.51(1H, m), 2.67-2.71(1H, m), 2.78-2.86(3H, m), 3.86-3.43(2H, m), 4.16-4.24(2H, m), 6.85(1H, s), 7.13-7.16(1H, m), 7.20-7.24(1H, m), 7.46, 7.50 (all 1H, s), 7.56-7.64(2H, m), 9.59, 9.62 (all 1H, s).

Example 74]N-((7R^*，8S^*) -8- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1, 4-dioxaspiro [4.5 ]]Decan-7-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides or N- ((7R)^*，8S^*) -7- ([ (5-chloroindol-2-yl) carbonyl]Amino } -1, 4-dioxaspiro [4.5 ]]Decan-8-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

The title compound was obtained from the compound obtained in referential example 120 and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.69-1.87(6H，m)，2.14-2.17(1H，m)，2.30-2.32(1H，m)，2.47(3H，s)，2.70-2.75(1H，m)，2.81-2.89(2H，m)，3.58(1H，d，J＝15.4Hz)，3.72(1H，d，J＝15.4Hz)，3.89-3.91(1H，m)，3.99(4H，s)，4.37-4.40(1H，m)，6.86(1H，d，J＝2.0Hz)，7.19(1H，dd，J＝8.8，2.0Hz)，7.30(1H，d，J＝8.8Hz)，7.38(1H，d，J＝7.3Hz)，7.62(1H，d，J＝2.0Hz)，9.15(1H，s).

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-carboxamides 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-carboxamides

1) The compound (2.21g) obtained in referential example 124 was dissolved in methylene chloride (30ml), and trifluoroacetic acid (6ml) was added to stir at room temperature for 1.5 hours. The concentrated reaction solution was dried by a vacuum pump, dissolved in N, N-dimethylformamide (20ml), and added with 5-chloroindole-2-carboxylic acid (500mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (593mg), 1-hydroxybenzotriazole 1 hydrate (473mg) and N-methylmorpholine (2.8ml), followed by stirring at room temperature for 10 hours. Then, 5-chloroindole-2-carboxylic acid (242mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (237mg) and 1-hydroxybenzotriazole 1 hydrate (189mg) were added to the solution, and the mixture was stirred for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction 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 (dichloromethane: methanol 97: 3 → 4: 1) to obtain N- [ (1R) ^*，2S^*) -2-amino-5- (methoxyimino) cyclohexyl]-5-Chloroindole-2-carboxamide (368mg) and N- [ (1R)^*，2S^*) -2-amino-4- (methoxyimino) cyclohexyl]-5-chloroindole-2-carboxamide (300 mg).

2) Formation obtained by the above reactionN- [ (1R) of one of the compounds^*，2S^*) -2-amino-5- (methoxyimino) cyclohexyl]-5-chloroindole-2-carboxamide or N- [ (1R)^*，2S^*) -2-amino-4- (methoxyimino) cyclohexyl]The title compound (syn and anti isomer mixture of methoxyimino moiety) was prepared from (5-chloroindole-2-carboxamide and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(CDCl₃) δ: 1.84-2.00(3H, m), 2.26-2.56(3H, m), 2.46(3H, s), 2.80-2.83(4H, m), 3.57(1H, q, J ═ 15.4Hz), 3.70(1H, q, J ═ 15.4Hz), 3.84, 3.85 (all 3H, s), 4.08-4.14(1H, m), 4.26-4.30(1H, m), 6.84(1H, s), 7.17(1H, d, J ═ 8.8Hz), 7.27(1H, d, J ═ 8.8Hz), 7.46-7.48(2H, m), 7.56(1H, m), 9.42, 9.55 (all 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-carboxamides (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) Using the same procedure as in 1) of example 75, (1R) obtained in referential example 125 was removed^*，2S^*) After tert-butoxycarbonyl of the body (stereoisomer A), N- ((1R) is obtained by reaction with 5-chloroindole-2-carboxylic acid^*，2S^*) -2-amino-4- { [ tert-butyl (diphenyl) silyl]Oxy } cyclohexyl) -5-chloroindole-2-carboxamide (stereoisomer A) and N- ((1R)^*，2S^*) -2-amino-5- { [ tert-butyl (diphenyl) silyl]Oxy } cyclohexyl) -5-chloroindole-2-carboxamide (stereoisomer a).

2) N- ((1R) was obtained from the product and the mixture obtained in reference example 10 in the same manner as in example 2^*，2S^*) -5- { [ 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-carboxamides (stereoisomer 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).

¹H-NMR(CDCl₃)δ：1.06(9H，s)，1.55-1.61(1H，m)，1.85-1.90(1H，m)，2.18-2.25(1H，m)，2.46(3H，s)，2.51(2H，d，J＝7.6Hz)，2.68-2.76(1H，m)，3.56(1H，s)，3.57(1H，d，J＝15.3Hz)，3.72(1H，d，J＝15.3Hz)，3.71-3.81(1H，m)，3.88-3.95(1H，m)，6.78(1H，s)，7.17(1H，dd，J＝2.0，8.8Hz)，7.37-7.44(7H，m)，7.59(1H，s)，7.65-7.68(6H，m)，9.30(1H，s).

3) The title compound was prepared from the compound obtained by the above reaction by the same method as in 3) of example 28.

¹H-NMR(DMSO-d₆)δ：1.25-1.30(2H，m)，1.45-1.64(2H，m)，1.86(1H，d，J＝9.0Hz)，1.98-2.03(1H，m)，2.33(3H，s)，2.66-2.73(2H，m)，2.75-2.79(2H，m)，3.54(1H，d，J＝15.6Hz)，3.62(1H，d，J＝15.6Hz)，3.96-4.02(2H，m)，4.78(1H，d，J＝4.2Hz)，7.00(1H，s)，7.14(1H，dd，J＝2.0，8.8Hz)，7.38(1H，d，J＝8.8Hz)，7.66(1H，s)，8.20(1H，d，J＝7.8Hz)，8.54(1H，d，J＝7.8Hz)，11.69(1H，s).

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-carboxamides (isomer A1) or N- ((1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4-hydroxy-4-methylcyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides (isomer A2)

The title compound was obtained by reacting the compound obtained in referential example 128 with the compound obtained in referential example 10 in the same manner as in example 2.

Isomer a 1:

¹H-NMR(DMSO-d₆)δ：1.24(3H，s)，1.33-1.82(4H，m)，2.34(3H，s)，2.67-3.64(8H，m)，4.02-4.10(2H，m)，4.67(1H，br.s)，7.02(1H，s)，7.13(1H，d，J＝8.6Hz)，7.38(1H，d，J＝8.6Hz)，7.66(1H，d，J＝2.0Hz)，8.21-8.26(1H，m)，8.59(1H，d，J＝8.1Hz)，11.73(1H，br.s)

MS(FAB)m/z：502(M+H)⁺.

isomer a 2:

¹H-NMR(DMSO-d₆)δ1.25(3H，s)，1.33-1.79(4H，m)，2.33(3H，s)，2.65-3.63(8H，m)，3.88-3.94(1H，m)，4.20-4.25(1H，m)，4.59(1H，br)，7.01(1H，s)，7.13(1H，d，J＝7.8Hz)，7.38(1H，d，J＝8.6Hz)，7.67(1H，s)，8.29(1H，br)，8.43(1H，d，J＝9.3Hz)，11.67(1H，br)

MS(FAB)m/z：502(M+H)⁺.

[ 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-carboxamides

The title compound was obtained by treating the compound obtained in referential example 129 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.42-1.90(5H，m)，2.07-2.26(3H，m)，2.46(3H，s)，2.67-2.95(4H，m)，3.55-3.80(4H，m)，3.80-3.95(1H，m)，4.13-4.25(1H，m)，6.84(1H，br.s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.23-7.35(2H，m)，7.43(1H，d，J＝7.2Hz)，7.58(1H，br.s)，9.29(1H，s).

MS(ESI)m/z：502(M+H)⁺.

[ 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-carboxamides

The title compound was obtained by treating the compound obtained in referential example 135 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 49.

¹H-NMR(CDCl₃)δ：1.20-1.38(1H，m)，1.50-1.67(2H，m)，1.88-2.03(2H，m)，2.03-2.14(1H，m)，2.21-2.32(1H，m)，2.53(3H，s)，2.75-2.95(2H，m)，3.20-3.35(2H，m)，3.37(3H，s)，3.73(1H，d，J＝16.0Hz)，3.76(1H，d，J＝16.0Hz)，4.04-4.13(1H，m)，4.53-4.62(1H，m)，6.85(1H，d，J＝2.0Hz)，7.19(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.54(1H，d，J＝7.2Hz)，7.63(1H，d，J＝2.0Hz)，8.07(1H，d，J＝5.6Hz)，9.49(1H，br.s).

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-carboxamides

1) Reference example 137 toThe obtained compound (437mg) was dissolved in ethanol (5ml), and a 4N dioxane hydrochloride solution (5ml) was added thereto at room temperature, followed by stirring for 13 hours. The solvent was distilled off, and the residue was dissolved in N, N-dimethylformamide (10ml), and triethylamine (0.7ml), the compound (300mg) obtained in referential example 10, 1-hydroxybenzotriazole 1 hydrate (162mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (230mg) were added to stir for 13 hours. The solvent was distilled off under reduced pressure, water was added thereto, and extraction was performed with chloroform, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol: 97: 3) to obtain 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).

¹H-NMR(DMSO-d₆)δ：1.15-2.08(7H，m)，2.33(3H，s)，2.34-2.95(6H，m)，3.64(2H，s)，4.05-4.17(1H，m)，4.36-4.47(1H，m)，7.02(1H，s)，7.15(1H，dd，J＝8.8，2.0Hz)，7.40(1H，d，J＝8.8Hz)，7.67(1H，d，J＝2.0Hz)，8.02(1H，d，J＝7.6Hz)，8.44(1H，d，J＝7.6Hz)，11.8(1H，s).

2) The compound (300mg) obtained in the above reaction was dissolved in ethanol (8ml), and a catalytic amount of 10% palladium on carbon was added thereto, followed by stirring under a hydrogen stream at room temperature for 168 hours. Filtering the insoluble material, evaporating the solvent, and separating the 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 (150mg) was dissolved in chloroform (6ml), and triethylamine (0.2ml) and methanesulfonyl chloride (0.035ml) were added under ice cooling to stir for 13 hours. The solvent was distilled off under reduced pressure, water was added thereto, and extraction was performed with chloroform, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 24: 1) to obtain the title compound (56 mg).

¹H-NMR(CDCl₃)δ：1.18-1.34(2H，m)，1.50-1.75(4H，m)，1.90-2.30(4H，m)，2.53(3H，s)，2.78-2.90(2H，m)，2.90-3.05(6H，m)，3.20-3.30(1H，m)，3.68-3.81(2H，m)，3.98-4.08(1H，m)，4.54-4.62(1H，m)，6.10-6.19(1H，m)，6.86(1H，s)，7.19(1H，dd，J＝8.8，2.0Hz)，7.35(1H，d，J＝8.8Hz)，7.52(1H，d，J＝7.6Hz)，7.62(1H，d，J＝2.0Hz)，8.21(1H，d，J＝5.6Hz)，9.89(1H，s).

MS(ESI)m/z：579(M+H)⁺.

Example 81]N-{(1R^*，2S^*，5S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) methyl group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamide trifluoroacetate salt

The title compound was obtained from the amine obtained in 2) of example 80 by the same method as in example 24.

¹H-NMR(DMSO-d₆)δ：1.15-2.22(7H，m)，2.40-2.65(2H，m)，2.68-2.85(6H，m)，2.92-3.08(5H，m)，3.10-3.18(2H，m)，4.08-4.20(1H，m)，4.35-4.51(2H，m)，7.04(1H，s)，7.14-7.20(1H，m)，7.41(1H，d，J＝8.8Hz)，7.67(1H，s)，8.25-8.42(2H，m)，9.11(1H，br.s)，9.89(1H，s).

MS(ESI)m/z：529(M+H)⁺.

Example 82](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 } cyclohexyl carbamic acid tert-butyl ester (isomer B) and (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 group }Cyclohexylcarbamic acid tert-butyl ester (isomer B)

The compound (stereoisomer B) (1.79g) obtained in referential example 140 was dissolved in tetrahydrofuran (36ml), and 10% palladium on carbon (0.40g) was added to stir at room temperature for 20 hours under a hydrogen stream. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (36ml), and p-nitrophenol 5-chloroindole-2-carboxylate (2.02g) was added thereto and stirred for 16 hours. Concentrating the reaction solution under reduced pressure, adding ethyl acetate and water, filtering off insoluble substances, washing with ethyl acetate to obtain crude (3R)^*，4S^*) -3-amino-4- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester (or (3R)^*，4S^*) -4-amino-3- { [ (5-chloroindol-2-yl) carbonyl]Amino } tert-butyl cyclohexylcarbamate) (isomer B1) (1.49 g). The organic layer of the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 30: 1 → 10: 1) to obtain (3R)^*，4S^*) -4-amino-3- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl carbamic acid tert-butyl ester (or (3R)^*，4S^*) -3-amino-4- { [ (5-chloroindol-2-yl) carbonyl]Amino } tert-butyl cyclohexylcarbamate) (isomer B2) (0.37 g).

One of the title compounds was obtained from the above isomer B1 and the compound obtained in reference example 10 by the same method as in example 2.

¹H-NMR(DMSO-d₆)δ：1.25-1.50(1H，m)，1.37(9H，s)，1.50-1.65(1H，m)，1.75-2.20(4H，m)，2.37(3H，s)，2.70-3.00(4H，m)，3.60-3.80(3H，m)，4.13(1H，br.s)，4.43(1H，br.s)，6.92(1H，d，J＝7.1Hz)，7.05(1H，s)，7.17(1H，dd，J＝8.8，2.2Hz)，7.41(1H，d，J＝8.8Hz)，7.69(1H，s)，8.15(1H，d，J＝7.8Hz)，8.37(1H，d，J＝7.1Hz)，11.78(1H，s).

MS(FAB)m/z：587(M+H)⁺.

In addition, another title compound was obtained from the above isomer B2 in the same manner.

¹H-NMR(DMSO-d₆)δ：1.15-1.30(1H，m)，1.35(9H，s)，1.45-1.60(1H，m)，1.65-1.75(1H，m)，1.85-1.95(1H，m)，2.05-2.20(2H，m)，2.34(3H，s)，2.65-2.85(4H，m)，3.55-3.70(3H，m)，4.05-4.14(1H，m)，4.40(1H，br.s)，6.80(1H，d，J＝7.3Hz)，7.15-7.25(2H，m)，7.43(1H，d，J＝8.8Hz)，7.73(1H，d，J＝2.0Hz)，8.05(1H，d，J＝6.6Hz)，8.51(1H，d，J＝8.8Hz)，11.82(1H，s).

MS(FAB)m/z：587(M+H)⁺.

[ 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) (1.11g) synthesized from isomer B1 in example 82 was suspended in methylene chloride (20ml), and an ethanol solution (20ml) of hydrochloric acid was added to stir at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel filtration (Sephadex LH-20, methanol) to obtain the title compound (1.05 g).

¹H-NMR(DMSO-d₆)δ：1.55-1.65(1H，m)，1.75-1.90(2H，m)，1.95-2.20(2H，m)，2.20-2.40(1H，m)，2.90(3H，s)，3.10-3.20(1H，m)，3.20-3.50(3H，m)，3.65-3.75(1H，m)，4.10-4.20(1H，m)，4.35-4.50(1H，m)，4.55-4.65(1H，m)，4.65-4.75(1H，m)，7.07(1H，s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.69(1H，s)，8.05-8.30(3H，br)，8.40-8.50(2H，m)，11.70-11.90(2H，m).

MS(FAB)m/z：487(M+H)⁺.

EXAMPLE 84]N-[(1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (methylsulfonyl) amino group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamides or N- [ (1R)^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- [ (methylsulfonyl) amino group]Cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c) ]Pyridine-2-carboxamides (stereoisomer B)

The compound (0.20g) obtained in example 83 was suspended in methylene chloride (7ml), and triethylamine (0.16ml) and methanesulfonyl chloride (28. mu.l) were added to stir at room temperature for 20 hours. The reaction solution was diluted with dichloromethane, washed with an aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 30: 1 → 15: 1) to obtain the title compound (67.9 mg).

¹H-NMR(DMSO-d₆)δ：1.40-1.55(1H，m)，1.65-1.85(2H，m)，1.90-2.05(2H，m)，2.15-2.25(1H，m)，2.41(3H，s)，2.75-2.95(4H，m)，2.92(3H，s)，3.55-3.80(3H，m)，4.10-4.20(1H，m)，4.45-4.55(1H，m)，7.08(1H，s)，7.15-7.20(2H，m)，7.41(1H，d，J＝8.8Hz)，7.69(1H，s)，8.27(1H，d，J＝7.3Hz)，8.33(1H，d，J＝8.1Hz)，11.77(1H，s).

MS(FAB)m/z：565(M+H)⁺.

Example 85]N-((1R^*，2S^*) -5- (acetylamino) -2- { [ (5-chloroindazole)Indole-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides or N- ((1R)^*，2S^*) -4- (acetylamino) -2- { [ (5-chloroindol-2-yl) carbonyl]Amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides (stereoisomer B)

The compound (stereoisomer B) (0.20g) obtained in example 83 was suspended in methylene chloride (7ml), and triethylamine (0.16ml) and acetic anhydride (34. mu.l) were added thereto at room temperature, and stirred at room temperature for 20 hours. Methylene chloride and an aqueous solution of sodium hydroxide were added to the reaction mixture, and insoluble matter was collected by filtration. The organic layer of the filtrate was separated, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 15: 1 → 10: 1) to obtain the title compound (0.12 g).

¹H-NMR(DMSO-d₆)δ：1.35-1.50(1H，m)，1.55-1.70(1H，m)，1.80(3H，s)，1.80-2.05(3H，m)，2.05-2.20(1H，m)，2.47(3H，s)，2.80-3.00(4H，m)，3.75-4.00(3H，m)，4.15-4.30(1H，m)，4.45-4.55(1H，m)，7.07(1H，s)，7.17(1H，dd，J＝8.8，1.0Hz)，7.41(1H，d，J＝8.8Hz)，7.69(1H，s)，7.89(1H，d，J＝7.3Hz)，8.24(1H，d，J＝8.1Hz)，8.31(1H，d，J＝7.3Hz)，11.77(1H，s).

MS(FAB)m/z：528(M+H)⁺.

[ 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 (250mg) obtained in example 58 was dissolved in N, N-dimethylformamide (5ml), and N, O-dimethylhydroxylamine hydrochloride (142mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (111mg), 1-hydroxybenzotriazole 1 hydrate (89mg), and N-methylmorpholine (213ml) were added to stir at room temperature for 19 hours. After the reaction mixture was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction 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 (dichloromethane: methanol 47: 3 → 23: 2) to obtain a colorless amorphous solid (179 mg). This solid was dissolved in methanol-tetrahydrofuran, and 1N ethanol hydrochloride solution (960ml) was added to obtain the title compound.

¹H-NMR(DMSO-d₆)δ：1.57-1.91(4H，m)，1.96-2.00(1H，m)，2.10-2.21(1H，m)，2.92(3H，s)，2.93-3.03(2H，m)，3.08(3H，s)，3.10-3.28(2H，m)，4.16-4.19(1H，m)，4.50-4.52(1H，m)，4.69(1H，br.s)，7.06(1H，s)，7.17(1H，dd，J＝8.8，1.5Hz)，7.42(1H，d，J＝8.8Hz)，7.70(1H，s)，8.33(1H，br.s)，8.41(1H，d，J＝7.8Hz)，11.81(1H，br.s).

MS(ESI)m/z：559(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 58 and N, N-dimethylhydrazine in the same manner as in example 57.

¹H-NMR(DMSO-d₆)δ：1.49-1.54(1H，m)，1.76-1.81(2H，m)，1.89-1.93(2H，m)，2.07-2.17(1H，m)，2.33-3.60(14H，m)，4.15-4.19(1H，m)，4.40-4.47(2H，m)，4.70-4.72(1H，m)，7.04(1H，s)，7.17(1H，dd，J＝8.5，2.0Hz)，7.42(1H，d，J＝8.5Hz)，7.70(1H，s)，8.17-8.22(1H，m)，8.41-8.43(1H，m)，11.80(1H，br.s).

MS(ESI)m/z：558(M+H)⁺.

[ 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 title compound was obtained by treating the compound obtained in referential example 145 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.75-1.90(3H，m)，1.90-2.00(1H，m)，2.00-2.20(1H，m)，2.80(3H，s)，2.90(3H，s)，2.99(3H，s)，3.10-3.30(5H，m)，3.56(1H，br)，4.10-4.20(1H，m)，4.40-4.70(2H，m)，7.88(2H，s)，8.15(1H，d，J＝8.6Hz)，8.22(1H，s)，8.52(1H，d，J＝8.6Hz)，8.72(1H，d，J＝8.3Hz)，8.89(1H，d，J＝8.3Hz).

MS(FAB)m/z：555(M+H)⁺.

[ 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

The title compound was obtained by condensing the compound obtained in referential example 144 with the compound obtained in referential example 274 in the same manner as in referential example 91, treating the resulting compound with a 4N dioxane hydrochloride solution, and then condensing the resulting compound with the compound obtained in referential example 10.

¹H-NMR(DMSO-d₆)δ：1.24-1.98(6H，m)，2.33-3.33(6H，m)，2.81(3H，s)，2.90(3H，s)，2.99(3H，s)，4.12(1H，br.s)，4.30-4.70(1H，m)，4.60(1H，br.s)，7.21(1H，s)，7.27(2H，br.s)，8.37(1H，d，J＝8.1Hz)，8.43(1H，d，J＝7.6Hz).12.11(1H，s).

MS(FAB)m/z：561(M+H)⁺.

[ 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 title compound was obtained by treating the compound obtained in referential example 146 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.45-1.65(1H，m)，1.70-1.85(3H，m)，1.95-2.10(1H，m)，2.10-2.20(1H，m)，2.80(3H，s)，2.92(3H，s)，2.96(3H，s)，2.95-3.10(1H，m)，3.10-3.40(3H，m)，3.70-3.80(1H，m)，4.20-4.30(1H，m)，4.40-4.60(2H，m)，4.65-4.80(1H，m)，7.83-7.93(1H，m)，8.26(1H，d，J＝8.8Hz)，8.38(1H，s)，8.60(1H，s)，8.85-9.00(2H，m)，9.30-9.40(1H，m).

MS(FAB)m/z：555(M+H)⁺.

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 (0.12g) obtained in referential example 172 in N, N-dimethylformamide (20ml) were added the compound (0.1g) obtained in referential example 10, 1-hydroxybenzotriazole 1 hydrate (78mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.2g) in this order, and the mixture was stirred at room temperature for 1 day. The reaction solution was concentrated, and the obtained residue was diluted with chloroform: methanol (9: 1), washed with a saturated aqueous sodium hydrogencarbonate solution and a 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 (chloroform: methanol 95: 5) to obtain the free base of the title compound, which was then treated with a hydrochloric acid ethanol solution to obtain the title compound (0.1 g).

¹H-NMR(CDCl₃)δ：2.50(3H，s)，2.70-2.90(4H，m)，3.67(1H，s)，3.70(1H，s)，3.86(1H，dd，J＝9.2，6.3Hz)，3.97(1H，dd，J＝9.7，4.1Hz)，4.15(1H，dd，J＝9.7，5.8Hz)，4.24(1H，dd，J＝9.2，7.0Hz)，4.75-4.89(1H，m)，4.92-5.03(1H，m)，6.88(1H，s)，7.20(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.35-7.43(1H，m)，7.58(1H，d，J＝2.0Hz)，7.64(1H，d，J＝7.1Hz)，9.38(1H，s).

MS(FAB)m/z：460(M+H⁺).

[ 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 referential example 183 by the methods of referential example 172 and example 91.

¹H-NMR(CDCl₃)δ：2.51(3H，s)，2.83(2H，t，J＝5.3Hz)，2.93(2H，t，J＝5.3Hz)，3.72(2H，s)，3.78-3.89(2H，m)，4.31(1H，dd，J＝9.2，7.3Hz)，4.41-4.56(2H，m)，4.63-4.75(1H，m)，6.88(1H，s)，7.22(1H，dd，J＝8.8，2.0Hz)，7.32(1H，d，J＝8.8Hz)，7.35-7.46(1H，m)，7.55(1H，d，J＝7.1Hz)，7.60(1H，d，J＝2.0Hz)，9.38(1H，s).

MS(FAB)m/z：460(M+H⁺).

[ 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 referential example 187 by the methods of referential example 172 and example 91.

¹H-NMR and MS (FAB): in accordance with example 92 as enantiomer.

[ 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 referential example 193 and the compound obtained in referential example 10 by the process of example 91.

Melting point: 190-192 DEG C

¹H-NMR(CDCl₃) δ: 1.45(9H, s), 2.46(3H, s), 2.74-2.81(4H, m), 3.24-3.37(2H, m), 3.54-3.70(2H, m), 3.96-4.00(1H, m), 4.15-4.23(1H, m), 4.50-4.65(1H, m), 4.77-4.82(1H, m), 6.79, 6.87 (all 1H, each s), 7.12-7.95(5H, m), 9.91, 9.97 (all 1H, each s).

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 (170mg) obtained in example 94 was dissolved in methylene chloride (3ml), and trifluoroacetic acid (2ml) was added thereto at room temperature and stirred for 1 hour. After concentration, chloroform and a saturated aqueous solution of sodium hydrogencarbonate were added, and the organic layer was 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: water 7: 3: 1, lower layer), and hydrochloric acid methanol was added to the target product to form a hydrochloride salt, to obtain the title compound (90mg) (NMR measured as a free base).

Melting point: 248 ~ 250 deg.C (decomposition)

¹H-NMR(CDCl₃)δ：2.44(3H，s)，2.70-2.80(4H，m)，2.97-3.05(2H，m)，3.46-3.68(4H，m)，4.49-4.52(1H，m)，4.60-4.65(1H，m)，6.86(1H，s)，7.05-7.08(1H，m)，7.20(1H，d，J＝8.5Hz)，7.44(1H，s)，7.89(2H，br)，10.51(1H，br).

MS(FAB)m/z：459(M+H⁺).

[ example 96] N- ((3S, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -5-oxotetrahydro-furan-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by removing the tert-butoxycarbonyl group of the compound obtained in referential example 196 in the same manner as in referential example 69 and then reacting the compound with the compound obtained in referential example 10 in the same manner as in example 91.

¹H-NMR(DMSO-d₆)δ：2.90(3H，s)，3.02-3.17(2H，m)，3.23-3.34(4H，m)，4.20(1H，t，J＝8.6Hz)，4.61(1H，t，J＝8.6Hz)，4.92-5.01(1H，m)，5.14-5.26(1H，m)，7.09(1H，s)，7.19(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.73(1H，d，J＝2.0Hz)，9.27(1H，d，J＝6.8Hz)，9.35(1H，d，J＝6.8Hz)，11.22-11.33(1H，m)，11.89(1H，s).

MS(FAB)m/z：474(M+H⁺).

[ example 97] N- ((3S, 4S) -4- { [ (5-Chloroindol-2-yl) carbonyl ] amino } -2-oxotetrahydro-furan-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by removing the tert-butoxycarbonyl group of the compound obtained in referential example 197 in the same manner as in referential example 69 and then reacting it with 5-chloroindole-2-carboxylic acid in the same manner as in example 91.

¹H-NMR(DMSO-d₆)δ：2.52(3H，s)，2.83(2H，t，J＝5.9Hz)，2.91-3.00(2H，m)，3.73(2H，s)，4.23(1H，t，J＝8.6Hz)，4.40-4.53(1H，m)，4.96(1H，dd，J＝10.8，5.2Hz)，5.16(1H，dd，J＝9.2，7.3Hz)，7.01(1H，s)，7.25(1H，dd，J＝8.8，2.0Hz)，7.34(1H，d，J＝8.8Hz)，7.52(1H，d，J＝2.0Hz)，8.01(1H，d，J＝5.4Hz)，8.51-8.63(1H，m)，9.22(1H，s).

MS(FAB)m/z：474(M+H⁺).

[ example 98] (3S, 4R) -ethyl 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) acetate hydrochloride

The title compound was obtained from the compound obtained in referential example 199 and the compound obtained in referential example 10 in the same manner as in example 91 (NMR was measured as a free base).

¹H-NMR(DMSO-d₆)δ：1.19(3H，t，J＝7.1Hz)，2.35(3H，s)，2.71-2.84(2H，m)，2.80-2.90(2H，m)，3.40(1H，d，J＝10.3Hz)，3.61(2H，d，J＝10.8Hz)，3.84(1H，dd，J＝10.3，5.6Hz)，4.01-4.23(4H，m)，4.80-4.94(1H，m)，5.04(1H，t，J＝8.6Hz)，7.01(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.40(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.0Hz)，8.73(1H，d，J＝8.6Hz)，8.90(1H，d，J＝8.8Hz)，11.86(1H，s).

MS(FAB)m/z：559(M+H⁺).

[ 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 from the compound obtained in referential example 201 and the compound obtained in referential example 10 in the same manner as in example 91.

¹H-NMR(CDCl₃)δ：2.49(3H，s)，2.77-2.82(2H，m)，2.86-2.91(5H，m)，3.69(2H，d，J＝1.2Hz)，4.39-4.54(3H，m)，4.93-4.98(1H，m)，6.98(1H，d，J＝1.2Hz)，7.05-7.34(3H，m)，7.63(1H，d，J＝2.0Hz)，8.11(1H，d，J＝7.8Hz)，9.00(1H，s)

MS(FAB)m/z：487(M+H⁺).

[ example 100] methyl 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 ] acetate

The compound (230mg) obtained in example 95 and triethylamine (0.10ml) were dissolved in dichloromethane (6.9ml), which was cooled with ice. Then, methoxycarbonylmethanesulfonyl chloride (Synthesis, p. 321, 1975) (105mg) was added to bring the temperature back to room temperature, and the mixture was stirred overnight. After dilution with chloroform, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol 20: 1) and then pulverized with methanol-water to obtain the title compound (150 mg).

¹H-NMR(CDCl₃)δ：2.48(3H，s)，2.76-2.86(4H，m)，3.49-3.73(4H，m)，3.87(3H，s)，3.94-3.98(1H，m)，4.08-4.11(1H，m)，4.13(2H，s)，4.69-4.72(1H，m)，4.88-4.91(1H，m)，6.89(1H，s)，7.12-7.15(1H，m)，7.27-7.28(1H，m)，7.50(1H，s)，7.81-7.86(2H，m)，9.92(1H，s).

MS(FAB)m/z：595(M+H⁺).

[ 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 (100mg) obtained in example 100 was dissolved in tetrahydrofuran (4ml) -water (1ml), and cooled with ice. Then, lithium hydroxide 1 hydrate (7.8ml) was added thereto, and the mixture was allowed to warm to room temperature and stirred for 4 hours. After neutralization with 1N aqueous hydrochloric acid solution and concentration, the precipitate was collected by filtration, washed with water and 50% ethanol, and dried under reduced pressure at 50 ℃ overnight to obtain the title compound (87 mg).

¹H-NMR(DMSO-d₆) δ: 2.50(3H, s), 2.92(4H, s), 3.34-3.43(4H, m), 3.76-3.85(2H, m), 4.27 (each 1H, AB type d, J ═ 14.5Hz), 4.65-4.71(1H, m), 4.78-4.84(1H, m), 7.14(1H, s), 7.18(1H, d, J ═ 8.8Hz), 7.40(1H, d, J ═ 8.8Hz), 7.72(1H, s), 8.87(1H, d, J ═ 7.8Hz), 9.12(1H, d, J ═ 8.2Hz), 11.83(1H, s).

[ example 102] methyl 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) acetate

The compound (230mg) obtained in example 95 and potassium carbonate (90mg) were dissolved in N, N-dimethylformamide (4.6ml), which was cooled with ice. Methyl bromoacetate (0.062ml) was then 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 resulting residue was purified by preparative silica gel thin layer chromatography (chloroform: methanol 10: 1) and then pulverized with methanol-water to obtain the title compound (190 mg).

¹H-NMR(CDCl₃)δ：2.35(2H，s)，2.48(3H，s)，2.73-2.95(4H，m)，3.34-3.42(2H，m)，3.46(2H，q，J＝6.5Hz)，3.67(2H，q，J＝6.5Hz)，3.75(3H，s)，4.57-4.71(2H，m)，6.91(1H，s)，7.10-7.13(1H，m)，7-31(1H，d，J＝9.0Hz)，7.53(1H，s)，7.77(1H，d，J＝8.0Hz)，7.87(1H，d，J＝6.8Hz)，10.22(1H，s).MS(FAB)m/z：531(M+H⁺).

[ 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.

¹H-NMR(DMSO-d₆) δ: 2.42(3H, s), 2.69-2.87(6H, m), 3.13(1H, t, J ═ 9.0Hz), 3.22(1H, t, J ═ 9.0Hz), 3.33 (each 1H, AB type d, J ═ 6.8Hz), 3.72(2H, s), 4.53-4.60(1H, m), 4.65-4.72(1H, m), 7.16-7.20(2H, m), 7.42(1H, d, J ═ 8.8Hz), 7.70(1H, s), 8.85(1H, d, J ═ 7.5Hz), 9.00(1H, d, J ═ 8.3Hz), 11.79(1H, s).

[ example 104] methyl 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) propanoate

The title compound was obtained from the compound obtained in example 95 and methyl 3-bromopropionate in the same manner as in example 102.

¹H-NMR(CDCl₃)δ：1.96-2.20(2H，m)，2.49(3H，s)，2.61-2.96(8H，m)，3.17-3.21(2H，m)，3.62-3.72(2H，m)，3.69(3H，s)，4.46-4.49(1H，m)，4.56-4.61(1H，m)，6.87(1H，s)，7.05-7.14(1H，m)，7.32(1H，d，J＝9.2Hz)，7.53(1H，s)，7.65-7.71(2H，m)，10.02(1H，s).

MS(FAB)m/z：545(M+H⁺).

[ 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) propanoic acid

The title compound was obtained from the compound obtained in example 104 in the same manner as in example 101.

¹H-NMR(DMSO-d₆)δ：2.38(3H，s)，2.39-2.84(10H，m)，2.93(1H，t，J＝8.8Hz)，3.05(1H，t，J＝8.8Hz)，3.65(2H，s)，4.51-4.56(1H，m)，4.63-4.68(1H，m)，7.16-7.19(2H，m)，7.41(1H，d，J＝8.8Hz)，7.69(1H，s)，8.81(1H，d，J＝7.8Hz)，8.97(1H，d，J＝8.3Hz)，11.75(1H，s).

[ example 106] Ethyl 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-oxopropanoate

The title compound was obtained from the compound obtained in example 95 and ethyl malonyl chloride by the same method as in example 100.

¹H-NMR(DMSO-d₆)δ：1.20(3H，t，J＝7.0Hz)，2.37(3H，s)，2.73-2.75(2H，m)，2.82-2.84(2H，m)，3.35-3.38(2H，m)，3.64(2H，s)，3.68-3.83(2H，m)，3.91-4.00(2H，m)，4.10(2H，q，J＝7.0Hz)，4.61-4.84(2H，m)，7.13(1H，s)，7.18(1H，dd，J＝8.5，2.0Hz)，7.41(1H，d，J＝8.5Hz)，7.72(1H，s)，8.73(1H，t，J＝9.0Hz)，9.10(1H，d，J＝9.0Hz)，11.79(1H，s).

[ 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-oxopropanoic acid

The title compound was obtained from the compound obtained in example 106 in the same manner as in example 101.

¹H-NMR(DMSO-d₆)δ：2.39(3H，s)，2.77(2H，s)，2.85(2H，s)，3.29-3.55(4H，m)，3.68(2H，s)，3.82-4.01(2H，m)，4.62-4.68(1H，m)，4.77-4.86(1H，m)，7.14(1H，s)，7.18(1H，d，J＝8.8Hz)，7.41(1H，d，J＝8.8Hz)，7.72(1H，s)，8.75(1H，t，J＝8.8Hz)，9.12(1H，d，J＝7.8Hz)，11.81(1H，s).

[ example 108] methyl 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 ] cyclopropanecarboxylate

The title compound was obtained from the compound obtained in example 95 and methyl 1- (bromomethyl) cyclopropanecarboxylate in the same manner as in example 102.

¹H-NMR(CDCl₃)δ：0.78-0.79(2H，m)，1.24-1.26(2H，m)，2.49(3H，s)，2.62-2.88(6H，m)，3.20-3.28(2H，m)，3.66(3H，s)，3.61-3.75(4H，m)，4.45-4.62(2H，m)，6.86(1H，s)，7.12-7.15(1H，m)，7.24-7.28(1H，m)，7.52(1H，d，J＝8.5Hz)，7.54(1H，s)，7.69(1H，d，J＝8.0Hz)，10.00(1H，s).

MS(ESI)m/z：571(M+H⁺).

[ 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.

¹H-NMR(DMSO-d₆)δ：0.73-0.78(2H，m)，1.04-1.07(2H，m)，2.37(3H，s)，2.65-2.84(6H，m)，3.11-3.20(4H，m)，3.64(2H，s)，4.59-4.74(2H，m)，7.16(1H，s)，7.17(1H，d，J＝8.5Hz)，7.40(1H，d，J＝8.5Hz)，7.70(1H，s)，8.84(1H，d，J＝7.5Hz)，9.12(1H，d，J＝7.5Hz)，11.77(1H，s).

[ 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 from the compound obtained in referential example 193 and the compound obtained in referential example 148 in the same manner as in example 91.

¹H-NMR(CDCl₃) δ: 1.12(6H, d, J ═ 6.6Hz), 1.47(9H, s), 2.83-2.88(4H, m), 2.94-2.99(1H, m), 3.20-3.29(1H, m), 3.31-3.42(1H, m), 3.75-3.81(2H, m), 3.98(1H, t, J ═ 8.5Hz), 4.15-4.35(2H, m), 4.50-4.65(1H, m), 6.85, 6.91 (all 1H, each s), 7.15-7.90(5H, m), 9.41, 9.50 (all 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 from the compound obtained in example 110 in the same manner as in example 95.

¹H-NMR(CDCl₃)δ：1.13(6H，d，J＝6.3Hz)，2.85(4H，br.s)，2.96-3.05(3H，m)，4.51-4.52(1H，m)，4.76-4.80(2H，m)，5.36-5.39(2H，m)，5.53-5.58(1H，m)，7.17-7.19(1H，m)，7.27-7.31(2H，m)，7.57(1H，s)，7.64(2H，br)，9.82(1H，br).

[ example 112] Ethyl 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) propionate

The title compound was obtained from the compound obtained in example 111 and ethyl 3-bromopropionate in the same manner as in example 102.

¹H-NMR(CDCl₃) δ: 1.14(6H, d, J ═ 6.5Hz), 1.26(3H, t, J ═ 7.0Hz), 2.51(3H, t, J ═ 7.0Hz), 2.63(1H, dd, J ═ 9.5, 6.5Hz), 2.73-2.91(6H, m), 2.95-3.02(1H, m), 3.22(2H, q, J ═ 7.0Hz), 3.81 (each 1H, AB type d, J ═ 14.5Hz), 4.16(2H, q, J ═ 7.0Hz), 4.40-4.45(1H, m), 4.52-4.59(1H, m), 6.88(1H, d, J ═ 2.0Hz), 7.17-7.19(1H, m), 7.30-4.59 (1H, 56H, 1H, 62, s ═ 2.0 Hz).

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) propanoic acid

The title compound was obtained from the compound obtained in example 112 in the same manner as in example 101.

¹H-NMR(DMSO-d₆)δ：1.04(6H，d，J＝6.6Hz)，2.40(2H，q，J＝7.0Hz)，2.50(4H，s)，2.60-2.74(4H，m)，2.90-2.94(2H，m)，3.02-3.06(1H，m)，3.20-3.35(2H，m)，4.50-4.53(1H，m)，4.61-4.65(1H，m)，7.15-7.18(2H，m)，7.41(1H，d，J＝8.8Hz)，7.68(1H，s)，8.78(1H，d，J＝7.5Hz)，8.90(1H，d，J＝8.0Hz)，11.73(1H，s).

[ 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 from the compound obtained in example 111 and acetic anhydride in the same manner as in example 100.

Melting point: 254 to 258 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.34-1.37(6H，m)，1.96(3H，s)，3.30-3.55(5H，m)，3.66-3.82(3H，m)，3.95(1H，q，J＝8.3Hz)，4.45-4.82(4H，m)，7.15(1H，s)，7.18(1H，d，J＝9.0Hz)，7.41(1H，d，J＝9.0Hz)，7.71(1H，s)，8.75-8.81(1H，m)，9.21(1H，d，J＝8.0Hz)，11.32(1H，br)，11.83(1H，d，J＝7.3Hz).

MS(FAB)m/z：529(M+H⁺).

[ 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 from the compound obtained in example 111 and methanesulfonyl chloride in the same manner as in example 100.

Melting point: 230 to 235 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.32-1.36(6H，m)，3.32(3H，s)，3.43-3.46(5H，m)，3.68-3.75(4H，m)，4.48(1H，m)，4.62-4.72(2H，m)，4.83(1H，t，J＝5.5Hz)，7.14(1H，s)，7.18(1H，d，J＝8.6Hz)，7.40(1H，d，J＝8.6Hz)，7.72(1H，s)，8.82(1H，br)，9.20(1H，d，J＝8.3Hz)，11.30(1H，br)，11.86(1H，d，J＝7.5Hz).

MS(FAB)m/z：565(M+H⁺).

[ 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 from the compound obtained in example 111 and ethyl chloroformate in the same manner as in example 100.

Melting point: 225 to 228 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.20(3H，t，J＝7.0Hz)，1.31-1.37(6H，m)，3.33-3.45(5H，m)，3.66-3.75(4H，m)，4.05(2H，q，J＝7.0Hz)，4.45-4.77(4H，m)，7.15(1H，s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.71(1H，d，J＝2.0Hz)，8.77(1H，d，J＝7.0Hz)，9.20(1H，d，J＝8.0Hz)，11.30(1H，br)，11.83(1H，d，J＝7.5Hz).

MS(FAB)m/z：559(M+H⁺).

EXAMPLE 117](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 } piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 207 and the compound obtained in referential example 10 in the same manner as in example 91.

Melting point: 152 to 154 ℃ (decomposition)

¹H-NMR(CDCl₃)δ：1.53(9H，s)，1.62-1.80(1H，m)，2.23-2.30(1H，m)，2.52(3H，s)，2.75-3.05(5H，m)，3.10-3.25(1H，m)，3.68-3.82(2H，m)，4.15-4.45(4H，m)，6.89(1H，s)，7.19(1H，dd，J＝8.8，1.8Hz)，7.32(1H，d，J＝8.8Hz)，7.92(1H，d，J＝1.8Hz)，7.75(1H，br.s)，8.21(1H，br.s)，9.39(1H，s).

MS(ESI)m/z：573(M+H)⁺.

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 2 hydrochloride

The title compound was obtained from the compound obtained in example 117 in the same manner as in example 95.

Melting point: 240 to 258 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.85-2.00(1H，m)，2.05-2.20(2H，m)，2.93(3H，s)，3.05-3.60(7H，m)，3.65-3.75(1H，m)，4.10-4.52(2H，m)，4.60-4.75(2H，m)，7.10-7.21(2H，m)，7.43(1H，d，J＝8.6Hz)，7.70(1H，s)，8.50(1H，br.d，J＝7.8Hz)，8.90-9.05(2H，m)，9.27(1H，br.s)，11.9(1H，br.d，J＝13.4Hz).

MS(ESI)m/z：473(M+H)⁺.

Example 119]((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 } piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 208 and 5-chloroindole-2-carboxylic acid in the same manner as in example 91.

Melting point: 187 to 189 deg.C (decomposition)

¹H-NMR(CDCl₃)δ：1.48(9H，s)，1.72-1.90(1H，m)，2.00(1H，br.s)，2.00-2.10(1H，m)，2.45(3H，s)，2.60-2.70(2H，m)，2.70-2.80(2H，m)，3.23(1H，t，J＝10.8Hz)，3.35-3.50(1H，m)，3.50-3.72(2H，m)，3.90-4.20(2H，m)，4.30-4.40(1H，m)，4.45-4.55(1H，m)，6.85(1H，d，J＝1.5Hz)，7.17(1H，dd，J＝8.8，1.9Hz)，7.20-7.30(1H，m)，7.33(1H，d，J＝8.8Hz)，7.58(1H，d，J＝1.9Hz)，10.17(1H，s).

MS(ESI)m/z：573(M+H⁺).

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 2 hydrochloride

The title compound was obtained from the compound obtained in example 119 in the same manner as in example 95.

Melting point: 276 to 278 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.77-1.88(1H，m)，2.40-2.50(2H，m)，2.89(3H，s)，2.90-3.20(4H，m)，3.30-3.50(2H，m)，3.63(1H，br.s)，4.33-4.47(2H，m)，4.62-4.75(2H，m)，7.18(1H，dd，J＝8.8，1.9Hz)，7.42(1H，d，J＝8.8Hz)，7.48(1H，br.s)，7.71(1H，d，J＝1.9Hz)，8.66(1H，br.s)，8.95(1H，d，J＝8.1Hz)，9.20-9.30(1H，m)，9.45-9.70(1H，m)，11.61(1H，s)，11.90(1H，s).

MS(ESI)m/z：473(M+H)⁺.

EXAMPLE 121](3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 209 and the compound obtained in referential example 10 in the same manner as in example 91.

¹H-NMR(CDCl₃)δ：1.53(9H，s)，1.65-1.78(1H，m)，2.23-2.32(1H，br)，2.52(3H，s)，2.78-3.03(5H，m)，3.15-3.24(1H，br)，3.68-3.82(2H，br)，4.16-4.45(4H，br)，6.91(1H，s)，7.02(1H，td，J＝9.0，2.7Hz)，7.30(1H，dd，J＝9.0，2.7Hz)，7.34(1H，dd，J＝9.0，4.4Hz)，7.65-7.90(1H，br)，8.10-8.40(1H，br)，9.31-9.41(1H，br).

MS(ESI)m/z：557(M+H⁺).

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 2 hydrochloride

The title compound was obtained from the compound obtained in example 121 in the same manner as in example 95.

Melting point: 236 to 245 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.85-1.98(1H，br)，2.06-2.18(1H，br)，2.89(3H，s)，3.05-3.75(8H，s)，4.34-4.54(2H，br)，4.60-4.75(2H，br)，7.04(1H，td，J＝9.3，2.4Hz)，7.15(1H，br.s)，7.37-7.44(2H，m)，8.46(1H，d，J＝7.8Hz)，8.88-9.00(1H，br)，9.09-9.27(2H，br)，11.55-11.75(1H，br)，11.76-11.84(1H，br).

MS(FAB)m/z：457(M+H⁺).

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 from the compound obtained in example 118 and acetic anhydride in the same manner as in example 100.

Melting point: 215 to 225 ℃ (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.65-1.85(1H, m), 1.88, 2.06 (all 3H, s 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 ═ 15.6Hz), 7.17(1H, d, J ═ 8.8Hz), 7.41(1H, d, J ═ 8.8Hz), 7.71(1H, s), 8.23-8.53(2H, m), 11.20-11.55(1H, m), 11.85(1H, br, d, J ═ 4.5 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 from the compound obtained in example 120 and acetic anhydride in the same manner as in example 100.

Melting point: 225 to 250 ℃ (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.65-1.80(1H, m), 1.81, 2.05 (all 3H, each s), 2.00-2.20(1H, m), 2.70-2.85(1H, m), 2.89(3H, s), 3.00-3.20(2H, m), 3.20-3.50(2H, m), 3.64(1H, br.s), 3.78-4.30(2H, m), 4.30-4.50(3H, m), 4.55-4.75(1H, m), 7.05-7.23(2H, m), 7.38-7.48(1H, m), 7.70-7.80(1H, m), 7.79, 8.12 (all 1H, each d, J ═ 6.8Hz), 8.73, 8.83 (all 1H, each d, 8J ═ 6.8Hz), 8.73, 8.83 (all 1H, each J ═ 11.92, 11.11H, 11H, 1H, m), all 11H, m).

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 from the compound obtained in example 122 and acetic anhydride in the same manner as in example 100.

Melting point: 202 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.67-1.85(1H，m)，1.87(1.5H，s)，1.87-2.10(1H，m)，2.06(1.5H，s)，2.88-2.96(3H，br.s)，3.05-3.30(2H，m)，3.32-3.83(5H，br)，3.97-4.33(2H，m)，4.35-4.50(2H，br)，4.67-4.78(1H，br)，7.01-7.14(2H，m)，7.38-7.44(2H，m)，8.25-8.50(2H，m)，10.85-11.15(1H，br)，11.72-11.80(1H，br).

MS(FAB)m/z：499(M+H⁺).

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 from the compound obtained in example 118 and methanesulfonyl chloride in the same manner as in example 100.

Melting point: 225 to 23 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.80-1.90(1H，m)，2.05-2.15(1H，m)，2.30-2.80(5H，m)，2.85-3.80(9H，m)，4.20-4.90(4H，m)，7.08(1H，d，J＝1.7Hz)，7.18(1H，dd，J＝8.7，1.7Hz)，7.42(1H，d，J＝8.7Hz)，7.77(1H，s)，8.02-8.20(1H，m)，8.40-8.50(1H，m)，11.00-11.60(1H，m)，11.87(1H，s).

MS(ESI)m/z：551(M+H⁺).

[ 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

From the compound obtained in example 120 and methanesulfonyl chloride, the title compound was obtained in the same manner as in example 100.

Melting point: 228 to 245 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.75-1.85(1H，m)，2.25-2.40(1H，m)，2.40-2.60(2H，m)，2.76(3H，br.s)，2.90(3H，s)，2.93-3.05(3H，m)，3.12(1H，d，J＝10.6Hz)，3.55-3.80(2H，m)，4.25-4.40(4H，m)，7.17(1H，d，J＝1.7Hz)，7.19(1H，dd，J＝8.7，2.0Hz)，7.43(1H，d，J＝8.7Hz)，7.74(1H，d，J＝2.0Hz)，8.03(1H，d，J＝6.6Hz)，8.78(1H，d，J＝7.4Hz)，10.90-11.20(1H，br.s)，11.89(1H，s).

MS(ESI)m/z：551(M+H⁺).

EXAMPLE 128]N-[(3R^*，4S^*) -4- { [ (5-fluoroindol-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 from the compound obtained in example 122 and methanesulfonyl chloride in the same manner as in example 100.

Melting point: 216 to 250 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.80-1.90(1H，m)，2.01-2.12(1H，m)，2.92(3H，s)，2.94(3H，s)，3.00-3.80(8H，m)，4.28-4.53(3H，m)，4.60-4.80(1H，br)，7.01-7.12(2H，m)，7.37-7.44(2H，m)，8.00-8.18(1H，br)，8.39-8.50(1H，br)，11.00-11.60(1H，br)，11.72-11.80(1H，br).

MS(FAB)m/z：535(M+H⁺).

Example 129](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 groupPiperidine-1-carboxylic acid methyl ester hydrochloride

The title compound was obtained from the compound obtained in example 118 and methyl chloroformate in the same manner as in example 100.

Melting point: 248 ~ 253 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.65-1.78(1H，m)，1.88-2.03(1H，m)，2.90(3H，s)，3.00-3.80(9H，m)，3.80-3.90(1H，m)，3.95-4.08(1H，m)，4.20-4.70(4H，m)，7.10(1H，s)，7.17(1H，dd，J＝8.8，1.8Hz)，7.42(1H，d，J＝8.8Hz)，7.71(1H，d，J＝1.8Hz)，8.29(1H，br.s)，8.41(1H，d，J＝8.1Hz)，11.29(1H，br.s)，11.85(1H，s).

MS(ESI)m/z：531(M+H⁺).

EXAMPLE 130](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 } piperidine-1-carboxylic acid ethyl ester hydrochloride

The title compound was obtained from the compound obtained in example 118 and ethyl chloroformate in the same manner as in example 100.

Melting point: 215 to 225 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：0.85-1.30(3H，m)，1.65-1.78(1H，m)，1.90-2.03(1H，m)，2.90(3H，s)，3.10-3.40(4H，m)，3.48(1H，br.s)，3.65(1H，br.s)，3.75-4.15(4H，m)，4.25(1H，br.s)，4.32-4.50(2H，m)，4.66(1H，br.s)，7.09(1H，s)，7.18(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.71(1H，d，J＝2.0Hz)，8.23(1H，br.s)，8.45(1H，br.d，J＝8.1Hz)，11.50(1H，br.s)，11.86(1H，s).

MS(ESI)m/z：545(M+H⁺).

[ example 131](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 } piperidine-1-carboxylic acid 2-methoxyethyl ester hydrochloride

The title compound was obtained from the compound obtained in example 118 and 2-methoxyethyl chloroformate in the same manner as in example 100.

Melting point: 224 to 226 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.68-1.78(1H，m)，1.90-2.03(1H，m)，2.89(3H，s)，3.00-3.75(11H，m)，3.80-3.90(1H，m)，3.95-4.18(3H，m)，4.20-4.70(4H，m)，7.10(1H，s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.71(1H，d，J＝2.0Hz)，8.26(1H，br.s)，8.42(1H，d，J＝7.8Hz)，11.30(1H，br.s)，11.86(1H，s).

MS(ESI)m/z：575(M+H⁺).

EXAMPLE 132](3R^*，4S^*) -3- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -4- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-e ]]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid ethyl ester hydrochloride

The title compound was obtained from the compound obtained in example 120 and ethyl chloroformate in the same manner as in example 100.

Melting point: 213 to 225 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：0.75-1.30(3H，m)，1.60-1.72(1H，m)，2.12-2.25(1H，m)，2.89(3H，s)，2.95-3.20(4H，m)，3.40-3.88(4H，m)，3.90-4.10(2H，m)，4.10-4.30(2H，m)，4.30-4.40(1H，m)，4.40-4.80(1H，m)，7.10(1H，s)，7.18(1H，dd，J＝8.8，2.0Hz)，7.43(1H，d，J＝8.8Hz)，7.74(1H，s)，8.03(1H，d，J＝5.6Hz)，8.79(1H，s)，11.37(1H，s)，11.88(1H，s).

MS(ESI)m/z：545(M+H⁺).

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 to 228 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：0.88-1.10(3H，m)，1.70-2.05(2H，m)，2.06-2.60(2H，m)，2.91(3H，s)，3.14(2H，br.s)，3.20-3.90(5H，m)，3.95-4.80(5H，m)，7.09(1H，d，J＝11.0Hz)，7.17(1H，dd，J＝8.8，1.2Hz)，7.41(1H，d，J＝8.8Hz)，7.71(1H，s)，8.20-8.50(2H，m)，11.00-11.40(1H，m)，11.86(1H，s).

MS(ESI)m/z：529(M+H⁺).

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 from the compound obtained in example 118 and isobutyryl chloride in the same manner as in example 100.

Melting point: 266 to 272 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：0.80-1.15(6H，m)，1.70-2.05(2H，m)，2.65-2.80(1H，m)，2.90(3H，s)，2.90-4.80(12H，m)，7.09(1H，d，J＝11.0Hz)，7.17(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.71(1H，s)，8.00-8.30(1H，m)，8.30-8.50(1H，m)，10.95-11.50(1H，m)，11.86(1H，s).

MS(ESI)m/z：543(M+H⁺).

EXAMPLE 135]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2, 2-dimethylpropionyl) piperidin-3-yl radical]-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 trimethylacetyl chloride in the same manner as in example 100.

Melting point: 250 to 255 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.20(9H，s)，1.70-1.81(1H，m)，1.90-2.00(1H，m)，2.88(3H，s)，3.10(2H，br.s)，3.20-3.70(4H，m)，3.95-4.08(1H，m)，4.10-4.20(1H，m)，4.25-4.35(1H，m)，4.35-4.80(3H，m)，7.10(1H，s)，7.16(1H，dd，J＝8.8，1.9Hz)，7.41(1H，d，J＝8.8Hz)，7.69(1H，d，J＝1.9Hz)，8.06(1H，br.s)，8.38(1H，d，J＝7.8Hz)，11.31(1H，br.s)，11.84(1H，s).

MS(ESI)m/z：557(M+H⁺).

EXAMPLE 136]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (3, 3-dimethylbutyryl) 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 and tert-butylacetyl chloride in the same manner as in example 100.

Melting point: 260 to 265 deg.C (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.91, 1.04 (all 9H, s 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, 1.2Hz), 7.41(1H, d, J ═ 8.7Hz), 7.69(1H, d, J ═ 7.6Hz), 7.93-8.18(1H, m), 8.38-8.45(1H, m), 10.95-11.30(1H, m), 11.80-11.90(1H, m).

MS(ESI)m/z：571(M+H⁺).

[ example 137 ]]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2, 2, 2-trifluoroacetyl) 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 and trifluoroacetic anhydride in the same manner as in example 100.

Melting point: 262 to 267 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.82-1.98(1H，m)，2.05-2.21(1H，m)，2.89(3H，s)，3.05-3.20(2H，m)，3.40-3.75(4H，m)，3.85-3.95(1H，m)，4.00-4.07(1H，m)，4.20-4.70(4H，m)，7.10(1H，s)，7.18(1H，dd，J＝8.6，1.9Hz)，7.41(1H，d，J＝8.6Hz)，7.72(1H，s)，8.47(1H，dd，J＝22.4，7.9Hz)，8.60(1H，br)，11.08(1H，br.s)，11.87(1H，s).

MS(ESI)m/z：569(M+H⁺).

EXAMPLE 138]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (cyclopropylcarbonyl) piperidin-3-yl radical]-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 cyclopropanecarbonyl chloride in the same manner as in example 100.

Melting point: 280 to 286 ℃ (decomposition)

¹H-NMR(DMSO-d₆) δ: 0.25-0.80(4H, m), 1.65-2.15(4H, m), 2.91(3H, s), 2.90-3.20(3H, m), 3.35-3.70(2H, m), 4.00-4.80(6H, m), 7.06(1H, s), 7.18(1H, d, J ═ 8.8Hz), 7.42(1H, d, J ═ 8.7Hz), 7.71(1H, s), 8.18(1H, br.s), 8.40, 8.48 (all 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 from the compound obtained in example 118 and cyclobutanecarbonyl chloride in the same manner as in example 100.

Melting point: 271 ~ 275 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.60-2.30(8H，m)，2.89(3H，s)，3.12(2H，br.s)，3.20-3.75(6H，m)，3.75-3.90(1H，m)，4.05-4.80(4H，m)，7.08(1H，s)，7.15(1H，dd，J＝9.0，2.0Hz)，7.39(1H，d，J＝9.0Hz)，7.68(1H，d，J＝2.0Hz)，8.15(1H，br.s)，8.39(1H，br)，11.19(1H，br.s)，11.84(1H，s).

MS(ESI)m/z：555(M+H⁺).

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 from the compound obtained in example 118 and cyclopentanecarbonyl chloride in the same manner as in example 100.

Melting point: 254 to 260 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.30-2.10(10H，m)，2.90(3H，s)，3.00-3.20(2H，m)，3.20-3.75(5H，m)，3.80-4.80(6H，m)，7.09(1H，s)，7.17(1H，dd，J＝8.7，2.0Hz)，7.42(1H，d，J＝8.7Hz)，7.71(1H，s)，7.95-8.30(1H，m)，8.35-8.50(1H，m)，11.23(1H，br.s)，11.85(1H，s).

MS(ESI)m/z：569(M+H⁺).

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 from the compound obtained in example 118 and acetoxyacetyl chloride in the same manner as in example 100.

¹H-NMR(CDCl₃) δ: 1.70-2.00(1H, m), 2.05-2.48(3H, m), 2.51(3H, s), 2.70-3.05(4H, m), 3.05-4.10(5H, m), 4.20-4.48(1H, m), 4.50-5.10(4H, m), 6.87(1H, br.s), 7.10-7.82(4H, m), 7.32(1H, d, J ═ 8.8Hz), 8.35(1H, br.s), 9.34, 9.45 (all 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 (301.8mg) obtained in example 141 was dissolved in tetrahydrofuran (10ml), and a 1N aqueous solution (0.53ml) of sodium hydroxide was added to stir at room temperature for 18 hours. Water was added to the reaction mixture, which was extracted with dichloromethane, and the organic layer was washed successively with water and saturated brine. Drying over anhydrous sodium sulfate, evaporating the solvent under reduced pressure, purifying the residue by silica gel column chromatography (dichloromethane: methanol 20: 1 to 10: 1), and evaporating the solvent under reduced pressure. The purified product was dissolved in ethanol (3ml) and methylene chloride (2ml), and 1N ethanol hydrochloride solution (0.40ml) was added thereto and 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 to 230 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.70-1.80(1H，m)，1.88-2.10(2H，m)，2.68(3H，s)，3.18(2H，s)，3.08-3.70(5H，m)，3.80-3.95(1H，m)，4.00-4.25(3H，m)，4.25-4.50(2H，m)，4.50-4.65(1H，m)，7.09(1H，d，J＝11.0Hz)，7.17(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.71(1H，s)，8.33(1H，br.s)，8.35-8.50(1H，m)，10.80-11.30(1H，br.s)，11.84(1H，br.s).

EXAMPLE 143]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-methoxyacetyl) piperidin-3-yl radical]-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 to 228 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.70-1.80(1H，m)，1.85-2.05(1H，m)，2.90(3H，s)，3.00-3.20(2H，m)，3.16(3H，s)，3.22-3.82(7H，m)，3.88-4.80(5H，m)，7.09(1H，d，J＝9.0Hz)，7.17(1H，dd，J＝8.8，1.9Hz)，7.42(1H，d，J＝8.8Hz)，7.70(1H，d，J＝1.9Hz)，8.29(1H，br.s)，8.40-8.50(1H，m)，11.34(1H，br.s)，11.86(1H，s).

MS(ESI)m/z：545(M+H)⁺.

Example 144]N-[(3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1- (2-methoxyacetyl) piperidin-3-yl radical]-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 122 and methoxyacetyl chloride in the same manner as in example 100.

Melting point: 190 to 208 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.70-1.83(1H，br)，1.85-2.10(1H，m)，2.91(3H，s)，3.00-3.55(10H，m)，3.62-3.85(1H，m)，3.90-4.50(6H，m)，4.63-4.78(1H，br)，7.04(1H，td，J＝9.4，2.4Hz)，7.07-7.13(1H，br)，7.37-7.44(1H，m)，8.16-8.49(2H，m)，11.30-11.70(1H，br)，11.72-11.80(1H，br).

MS(FAB)m/z：529(M+H⁺).

Example 145]N-[(3R^*，4S^*) -1- (3- { [ tert-butyl (diphenyl) silyl]Oxy } -2, 2-dimethylpropionyl) -4- { [ (5-chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

Thionyl chloride (3.0ml) and a catalytic amount of dimethylformamide were added to a chloroform (10ml) solution of the compound (261mg) obtained in referential example 158, and the mixture was stirred overnight at 60 ℃. The reaction solution was concentrated under reduced pressure, and the resulting yellow oil and the compound obtained in example 118 (200mg) were subjected to the same operation as in example 100 to obtain the title compound (241 mg).

Melting point: 153 deg.C

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.39(6H，d，J＝3.9Hz)，1.57(1H，br.s)，2.26(1H，d，J＝10.7Hz)，2.57(3H，s)，2.86(4H，s)，2.97-3.01(2H，m)，3.78(4H，s)，4.20(1H，br.s)，4.33(1H，d，J＝13Hz)，4.42(1H，br.s)，4.67(1H，d，J＝13Hz)，6.88(1H，s)，7.20-7.23(1H，m)，7.32-7.46(7H，m)，7.64-7.65(6H，m)，7.86(1H，d，J＝6.8Hz)，8.23(1H，s)，9.10(1H，s).

EXAMPLE 146]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (3-hydroxy-2, 2-dimethylpropionyl) piperidin-3-yl group]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

Tetrabutylammonium fluoride (1 mol tetrahydrofuran solution, 0.594ml) was added to a tetrahydrofuran (30ml) solution of the compound (241mg) obtained in example 145 under ice cooling, and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the obtained 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 (dichloromethane: methanol ═ 9: 1) to obtain the title compound (116 mg).

Melting point: 220 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.17(6H，d，J＝8.3Hz)，1.79(1H，br.s)，1.91-1.97(1H，m)，2.49(3H，s)，2.87(4H，s)，3.35-3.50(4H，m)，3.81(1H，br.s)，3.97(1H，m)，4.10-4.15(1H，m)，4.32(1H，br.s)，4.42(1H，br.s)，4.52(1H，t，J＝5.7Hz)，7.10(1H，s)，7.16-7.19(1H，m)，7.42(1H，d，J＝8.8Hz)，7.69(1H，s)，8.11(1H，d，J＝8.8Hz)，8.37(1H，d，J＝7.3Hz)，11.8(1H，s).

MS(FAB)m/z：573(M+H⁺).

Example 147]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (3-methoxy-2, 2-dimethylpropionyl) piperidin-3-yl group]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

The title compound was obtained from the compound obtained in example 118 and the compound obtained in reference example 160 in the same manner as in example 145.

Melting point: 240 deg.C (decomposition)

¹H-NMR(CDCl₃)δ：1.34(3H，s)，1.37(3H，s)，1.65-1.77(1H，m)，2.33-2.37(1H，m)，2.53(3H，s)，2.82-3.29(6H，m)，3.34(3H，s)，3.41(1H，d，J＝9.3Hz)，3.56(1H，d，J＝9.3Hz)，3.76(2H，d，J＝5.9Hz)，4.26(1H，m)，4.44-4.53(2H，m)，4.82(1H，d，J＝13.7Hz)，6.88(1H，d，J＝1.5Hz)，7.20-7.23(1H，m)，7.33(1H，d，J＝8.8Hz)，7.64(1H，d，J＝1.5Hz)，7.90(1H，d，J＝7-1Hz)，8.22(1H，d，J＝5.1Hz)，9.18(1H，s).

MS(FAB)m/z：587(M+H⁺).

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 from the compound obtained in example 118 and 2-acetoxyisobutyryl chloride in the same manner as in example 100.

Melting point: 190 deg.C (decomposition)

¹H-NMR(CDCl₃)δ：1.56-1.67(8H，m)，2.08(3H，s)，2.35(1H，d，J＝10.5Hz)，2.52(3H，s)，2.82-2.84(2H，m)，2.90-2.96(2H，m)，3.14(1H，br.s)，3.75(2H，s)，4.25(1H，br.s)，4.40-4.47(1H，m)，4.54(1H，br.s)，4.80(1H，br.s)，6.86(1H，s)，7.20-7.33(3H，m)，7.64(1H，d，J＝1.7Hz)，7.76(1H，d，J＝7.3Hz)，9.11(1H，s).

MS(FAB)m/z：601(M+H⁺).

Example 149]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-hydroxy-2-methylpropionyl) piperidin-3-yl group]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

To a solution of the compound obtained in example 148 (190mg) in methanol (50ml) was added sodium methoxide (76.8mg), which was then stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (dichloromethane: methanol 9: 1) to obtain the title compound (130 mg).

Melting point: 190 deg.C (decomposition)

¹H-NMR(CDCl₃)δ：1.53(3H，s)，1.56-1.78(5H，m)，2.34(1H，d，J＝10.5Hz)，2.53(3H，s)，2.83-2.86(2H，m)，2.91-2.93(2H，m)，3.30(1H，d，J＝12.5Hz)，3.75(2H，s)，4.28(1H，d，J＝5.6Hz)，4.43(1H，s)，4.65(1H，d，J＝13.5Hz)，4.95(1H，d，J＝13.5Hz)，6.92(1H，d，J＝1.5Hz)，7.20-7.23(1H，m)，7.33(1H，d，J＝8.6Hz)，7.65(1H，d，J＝2.0Hz)，8.43(1H，d，J＝5.6Hz)，9.14(1H，s).

MS(FAB)m/z：559(M+H⁺).

EXAMPLE 150]N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (3-hydroxycyclobutyl) carbonyl]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamide hydrochloride

To a mixed solution of the compound (117mg) obtained in referential example 152 in tetrahydrofuran (20ml), dichloromethane (3.0ml) and N, N-dimethylformamide (2.0ml) were added the compound (306mg) obtained in example 118, N-methylmorpholine (200. mu.l), 1-hydroxybenzotriazole 1 hydrate (87mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (197mg), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane and then saturated aqueous sodium bicarbonate solution was added to divide the mixture into 2 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 (dichloromethane: methanol 10: 1) to obtain the free base of the title compound (207 mg). The free base was treated with 1N ethanol hydrochloride solution to obtain the title compound.

Melting point: 200 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.78-2.10(4H，m)，2.24-2.68(3H，m)，2.75-5.20(14H，m)，2.91(3H，s)，7.08(0.5H，s)，7.09(0.5H，s)，7.18(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.70(1H，d，J＝2.0Hz)，8.05-8.28(1H，br)，8.38(0.5H，br.d，J＝7.3Hz)，8.43(0.5H，br.d，J＝8.3Hz)，10.80-11.25(1H，br)，11.84(1H，br.s).

MS(ESI)m/z：571(M+H⁺).

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 from the compound obtained in example 118 and the compound obtained in reference example 154 in the same manner as in example 150.

Melting point: 191 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.69-2.23(4H，m)，2.25-2.40(1H，m)，2.71-2.84(0.5H，m)，2.89-3.93(9.5H，m)，2.91(3H，s)，3.01(1H，s)，3.14(2H，s)，4.05-4.80(5H，m)，7.09(1H，s)，7.18(1H，d，J＝8.4Hz)，7.42(1H，d，J＝8.4Hz)，7.70(1H，s)，8.00-8.30(1H，br)，8.36-8.53(1H，m)，11.25-11.75(1H，br)，11.85(1H，br.s).

MS(ESI)m/z：585(M+H⁺).

EXAMPLE 152]N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (3-methoxy-2- (methoxymethyl) propanoyl group]Piperidin-3-yl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-carboxamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 155 and condensing the resulting carboxylic acid with the compound obtained in example 118 in the same manner as in example 150.

Melting point: 178 to 184 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.69-1.82(1H，m)，1.84-2.04(1H，m)，2.91(3H，s)，3.00-3.75(17H，m)，3.95-4.55(5H，m)，4.60-4.80(1H，m)，7.10(1H，br.s)，7.18(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.69(0.5H，br.s)，7.71(1H，br.s)，8.18-8.28(1H，br)，8.35-8.50(1H，br)，11.83(1H，br.s).

MS(ESI)m/z：603(M+H⁺).

EXAMPLE 153]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (tetrahydro-2H-pyran-4-ylcarbonyl) 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 and the compound obtained in reference example 156 in the same manner as in example 150.

Melting point: 225 to 248 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.55-1.68(4H，m)，1.70-1.85(1H，m)，1.85-2.05(1H，m)，2.60-2.95(1H，m)，2.89(3H，s)，2.95-3.20(3H，m)，3.20-4.00(9H，m)，4.00-4.80(4H，m)，7.08(1H，s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.71(1H，s)，8.00-8.30(1H，m)，8.35-8.50(1H，m)，11.16(1H，br.s)，11.85(1H，s).

MS(ESI)m/z：585(M+H⁺).

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 from the compound obtained in example 118 and benzoyl chloride in the same manner as in example 100.

Melting point: 215 to 225 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.75-1.90(1H，m)，1.90-2.20(1H，m)，2.93(3H，s)，3.10-4.00(8H，m)，4.05-4.80(4H，m)，7.00-7.60(5H，m)，7.08(1H，s)，7.16(1H，dd，J＝8.8，1.6Hz)，7.40(1H，d，J＝8.8Hz)，7.71(1H，d，J＝1.6Hz)，8.31(1H，br.s)，8.46(1H，br.s)，11.39(1H，br.s)，11.86(1H，s).

MS(FAB)m/z：577(M+H⁺).

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 from the compound obtained in referential example 207 and the compound obtained in referential example 42 in the same manner as in example 91.

¹H-NMR(DMSO-d₆)δ：1.00(9H，s)，1.12(6H，s)，1.15-1.50(9H，m)，1.63-1.75(1H，m)，1.82-2.00(1H，m)，2.60-2.80(3H，m)，2.83-2.95(2H，m)，3.12-3.30(1H，m)，3.30(2H，s)，3.58(2H，s)，3.85-4.10(2H，m)，4.19(1H，br.s)，4.37(1H，br.s)，7.04(1H，s)，7.16(1H，d，J＝9.0Hz)，7.30-7.50(7H，m)，7.50-7.65(4H，m)，7.70(1H，s)，7.99(1H，d，J＝6.8Hz)，8.45(1H，br.s)，11.82(1H，s).

MS(ESI)m/z：869(M+H⁺).

EXAMPLE 156]5- (2- { [ tert-butyl (diphenyl) silyl group]Oxy } -1, 1-dimethylethyl) -N- ((3R)^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide 2 hydrochloride

The title compound was obtained by treating the compound obtained in example 155 in the same manner as in example 95.

¹H-NMR(DMSO-d₆) δ: 1.04(9H, s), 1.43, 1.48 (all 6H, s), 1.85-2.00(1H, m), 2.05-2.20(1H, m), 2.95-3.20(2H, m), 3.25-3.60(6H, m), 3.80-3.90(1H, m), 3.95-4.05(1H, m), 4.45-4.55(1H, m), 4.60-4.85(3H, m), 7.10-7.20(2H, m), 7.35-7.55(7H, m), 7.55-7.75(5H, m), 8.52(1H, dd, J ═ 14.4, 7.8Hz), 8.93(1H, br), 9.20-9.40(2H, m), 11.30-11.92 (1H, 11.87H, 11.92), 11.87H, s).

MS(ESI)m/z：769(M+H⁺).

[ example 157]5- (2- { [ tert-butyl (diphenyl) silyl group]Oxy } -1, 1-dimethylethyl) -N- [ (3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-methoxyacetyl } piperidin-3-yl radical]-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamides

The title compound was obtained from the compound obtained in example 156 and methoxyacetyl chloride in the same manner as in example 100.

¹H-NMR(CDCl₃)δ：1.07(9H，s)，1.20(6H，s)，1.60-1.85(1H，m)，2.25-2.40(1H，m)，2.36(2H，s)，2.70-3.20(4H，m)，3.20-3.55(4H，m)，3.55-3.70(2H，m)，3.95-4.10(3H，m)，4.10-4.90(4H，m)，6.90(1H，d，J＝1.5Hz)，7.15-7.30(2H，m)，7.30-7.50(6H，m)，7.60-7.70(5H，m)，8.15-8.22(1H，m)，8.46(1H，d，J＝5.1Hz)，9.28(1H，s).

MS(ESI)m/z：842(M+H)⁺.

EXAMPLE 158]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-methoxyacetyl) piperidin-3-yl radical]-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 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.32(3H，s)，1.40(3H，s)，1.70-1.85(1H，m)，1.85-2.10(1H，m)，2.60-3.35(8H，m)，3.40-3.82(3H，m)，3.85-4.05(3H，m)，4.05-4.35(2H，m)，4.50-4.60(1H，m)，4.55-4.80(2H，m)，5.75-5.85(1H，m)，7.08(1H，br.s)，7.17(1H，d，J＝8.8Hz)，7.41(1H，d，J＝8.8Hz)，7.71(1H，s)，8.20-8.35(1H，m)，8.40-8.55(1H，m)，10.00-10.35(1H，m)，11.87(1H，s).

MS(ESI)m/z：603(M+H)⁺.

[ example 159](3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -3- { [ (5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } piperidine-1-carboxylic acid tert-butyl ester

The title compound was obtained from the compound obtained in referential example 209 and the compound obtained in referential example 148 in the same manner as in example 91.

¹H-NMR(CDCl₃)δ：1.16(6H，d，J＝6.6Hz)，1.53(9H，s)，1.65-1.80(1H，m)，2.23-2.32(1H，m)，2.80-3.10(6H，m)，3.10-3.25(1H，m)，3.80-3.90(2H，m)，4.00-4.50(4H，m)，6.91(1H，s)，6.95-7.05(1H，m)，7.25-7.40(2H，m)，7.74(1H，br.s)，8.21(1H，br.s)，9.30(1H，s).

MS(ESI)m/z：585(M+H)⁺.

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 2 hydrochloride

The title compound was obtained by treating the compound obtained in example 159 in the same manner as in example 95.

¹H-NMR(DMSO-d₆)δ：1.28-1.40(6H，m)，1.85-2.00(1H，m)，2.05-2.20(1H，m)，2.40-2.60(1H，m)，2.95-3.90(8H，m)，4.40-4.55(2H，m)，4.60-4.75(2H，m)，7.00-7.20(2H，m)，7.30-7.50(2H，m)，8.45-8.60(1H，m)，8.85-9.05(1H，m)，9.05-9.50(2H，m)，11.60-11.90(2H，m).

MS(ESI)m/z：485(M+H)⁺.

Example 161]N-[(3R^*，4S^*) -4- { [ (5-fluoroindol-2-yl) carbonyl]Amino } -1- (2-methoxyacetyl) piperidin-3-yl radical]-5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in example 160 and methoxyacetyl chloride in the same manner as in example 100.

Melting point: 214 to 228 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.25-1.40(6H，m)，1.68-1.82(1H，m)，1.85-2.10(1H，m)，2.90-3.60(8H，m)，3.60-3.85(2H，m)，3.85-4.40(5H，m)，4.40-4.55(2H，m)，4.60-4.75(1H，m)，7.00-7.15(2H，m)，7.35-7.50(2H，m)，8.15-8.50(2H，m)，10.80-11.30(1H，m)，11.73(1H，d，J＝6.6Hz).

MS(ESI)m/z：557(M+H)⁺.

[ example 162]N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (dimethylamino) carbonyl group]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 and N, N-dimethylcarbamoyl chloride in the same manner as in example 100.

Melting point: 267 to 270 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：1.65-1.78(1H，m)，1.97-2.10(1H，m)，2.70(6H，s)，2.90(3H，s)，2.95-3.80(8H，m)，4.25-4.80(4H，m)，7.08(1H，s)，7.16(1H，dd，J＝8.8，1.8Hz)，7.41(1H，d，J＝8.8Hz)，7.70(1H，s)，8.31(1H，br.s)，8.40(1H，d，J＝7.3Hz)，11.15-11.60(1H，m)，11.82(1H，s).

MS(ESI)m/z：544(M+H)⁺.

Example 163]N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (dimethylamino) carbonyl group]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 and ethyl isocyanate in the same manner as in example 100.

Melting point: 221 to 235 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：0.98(3H，t，J＝7.1Hz)，1.60-1.70(1H，m)，1.80-1.95(1H，m)，2.90(3H，s)，2.95-3.40(6H，m)，3.40-4.00(4H，m)，4.25-4.80(4H，m)，6.60-6.80(1H，m)，7.09(1H，s)，7.16(1H，dd，J＝8.8，1.9Hz)，7.41(1H，d，J＝8.8Hz)，7.68(1H，d，J＝1.9Hz)，8.02(1H，br.s)，8.35(1H，d，J＝7.1Hz)，11.20-11.70(1H，m)，11.82(1H，s).

MS(FAB)m/z：544(M+H)⁺.

EXAMPLE 164]N-((3R^*，4S^*) -1- [ (tert-butylamino) carbonyl]-4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } piperidin-3-yl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [ 2 ]5，4-c]Pyridine-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in example 118 and tert-butyl isocyanate in the same manner as in example 100.

Melting point: 236 to 238 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.21(9H，s)，1.60-1.70(1H，m)，1.80-1.90(1H，m)，2.87(3H，s)，3.00-3.40(6H，m)，3.49(1H，br.s)，3.80-3.90(1H，m)，3.90-4.00(1H，m)，4.20-4.35(2H，m)，4.47(1H，br.s)，5.90(1H，s)，7.06(1H，s)，7.16(1H，dd，J＝8.8，1.9Hz)，7.41(1H，d，J＝8.8Hz)，7.67(1H，d，J＝1.9Hz)，8.04(1H，d，J＝6.8Hz)，8.34(1H，d，J＝7.3Hz)，11.22(1H，br.s)，11.79(1H，s).

MS(FAB)m/z：572(M+H)⁺.

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 ethyl ester 2 hydrochloride

The title compound was obtained from the mixture obtained in example 118 and methyl bromoacetate in the same manner as in example 102.

Melting point: 253 to 255 ℃ (decomposition)

¹H-NMR(DMSO-d₆，δ：1.95-2.10(1H，m)，2.10-2.25(1H，m)，2.88(3H，s)，3.00-3.73(8H，m)，3.75(3H，s)，3.97-4.15(2H，m)，4.30-4.80(4H，m)，7.08-7.20(2H，m)，7.44(1H，d，J＝8.6Hz)，7.63(1H，d，J＝2.0Hz)，8.42(1H，d，J＝7.3Hz)，8.62(1H，br.s)，11.82(1H，br.s).

MS(ESI)m/z：545(M+H)⁺.

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) acetate acid salt

The title compound was obtained by subjecting the compound obtained in example 165 to the same treatment as in example 101.

Melting point: 234 to 240 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.75-1.95(1H，m)，2.05-2.20(1H，m)，2.88(3H，s)，2.95-3.90(10H，m)，4.20-4.70(4H，m)，7.11(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.66(1H，d，J＝2.0Hz)，8.46(1H，br.d，J＝7.8Hz)，8.65(1H，br.s)，11.60-12.70(2H，br.s)，11.91(1H，br.s).

[ example 167]N-[(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- (2-methoxyethyl) piperidin-3-yl radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ]Pyridine-2-carboxamide 2 hydrochloride

From the compound obtained in example 118 and 2-bromoethyl methyl ether, the title compound (NMR was measured as a free base) was obtained in the same manner as in example 102.

Melting point: 238 to 242 ℃ (decomposition)

¹H-NMR(CDCl₃) δ: 1.75-1.83(2H, m), 2.27-2.39(2H, m), 2.52(3H, s), 2.60-2.66(1H, m), 2.69-2.75(1H, m), 2.81-2.90(2H, m), 2.96-3.07(2H, m), 3.41(3H, s), 3.53-3.60(2H, m), 3.75 (each 1H, AB type d, J15.5 Hz), 4.02-4.05(1H, m), 4.40(1H, br), 6.88(1H, d, J1.5 Hz), 7.18-7.21(1H, m), 7.31-7.33(1H, m), 7.63(1H, d, J ═ 1.5), 8.17H, 17, 17.8H, 1H, 8, 7.9H, 8, 1H, 8H, 1H, 8H, 1H, 26, 8H, 1H, m), 1H, m, 3H, m, 3.9H, m, 3H, m, 3.1H, m, 3.40 (1H, m).

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 radical]-5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c]Pyridine-2-carboxamide 2 hydrochloride

The title compound (NMR was measured as a free base) was obtained by treating the compound obtained in example 118 and 2-fluoroethyl bromide in the same manner as in example 102.

Melting point: 228 to 233 ℃ (decomposition)

₁H-NMR(CDCl₃) δ: 1.77(2H, dq, J ═ 12.5, 4.0Hz), 2.28-2.32(1H, m), 2.41(1H, t, J ═ 12.5Hz), 2.52(3H, s), 2.65(1H, d, J ═ 10.5Hz), 2.76-2.81(1H, m), 2.83-2.86(3H, m), 2.98-3.05(3H, m), 3.75 (each 1H, AB type d, J ═ 15.5Hz), 4.02-4.08(1H, m), 4.45(1H, br), 4.54-4.59(1H, m), 4.64-4.70(1H, m), 6.87(1H, d, J ═ 1.5), 7.19-7.22(1H, 7.22H, 7.8, J ═ 1H, 8, J ═ 1H, J ═ 1.5Hz), 7.8, J ═ 8, J ═ 1H, d, J ═ 15.5Hz, J ═ 1.5, J ═ 1H, 8, J 2.0Hz)，8.11(1H，d，J＝5.5Hz)，8.20(1H，d，J＝7.3Hz)，9.30(1H，br).

MS(FAB)m/z：519(M+H)⁺.

[ 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

To a dioxane solution (15ml) of the compound (630mg) obtained in referential example 214 was added a 4N dioxane hydrochloride solution (7.0ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained yellow solid (590mg) and the compound (379mg) obtained in referential example 10 were used to obtain the free base (330mg) of the title compound in the same manner as in example 91. The free base was treated with a solution of hydrochloric acid in ethanol to give the title compound (NMR measured as free base).

Melting point: 202 to 222 ℃ (decomposition)

¹H-NMR(DMSO-d₆) δ: 1.65-1.85(1H, m), 1.87, 2.06 (all 3H, s 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 (all 1H, s each), 7.18(1H, d, J-8.8 Hz), 7.42(1H, d, J-8.8), 7.81 (1H, 8.8H, 7.81, 8H, 7.8Hz), 7.42(1H, 8.8H, 7.8H, 7.81, 8H, 8Hz), 7.8H, 8, 22.8 Hz, 8H, 22.8 Hz, 8H, 8H, 1.

MS(ESI)m/z：515(M+H)⁺.

[α]_D ²⁵56.0 ° (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

The title compound was obtained from the compound obtained in referential example 219 and the compound obtained in referential example 10 in the same process as in example 169.

Melting point: 221-238 DEG C

¹H-NMR(DMSO-d₆)δ：1.45-1.56(0.5H，m)，1.60-1.70(0.5H，m)，1.89-2.01(1H，m)，2.05(3H，s)，2.51-2.67(1H，m)，2.88(3H，s)，3.00-3.22(3H，m)，3.31-3.40(3H，m)，3.56-3.67(0.5H，m)，3.78-4.02(1.5H，m)，4.22-4.44(2H，m)，4.56-4.72(1H，m)，7.02(1H，s)，7.15(1H，dd，J＝8.8，2.0Hz)，7.37(1H，d，J＝8.8Hz)，7.67(1H，d，J＝2.0Hz)，8.42(1H，d，J＝9.8Hz)，8.67-8.78(1H，m)，11.02-11.14(1H，m)，11.72(0.5H，s)，11.74(0.5H，s).

MS(FAB)m/z：515(M+H)⁺.

[α]_D ²⁵-105.4 ° (c ═ 0.58, methanol)

[ 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

The title compound was obtained from the compound obtained in referential example 221 by the same process as in example 169.

Melting point: 207 to 220 ℃ (decomposition)

¹H-NMR(DMSO-d₆)δ：1.70-1.80(1H，m)，1.85-2.05(1H，m)，2.90(3H，s)，3.00-3.20(2H，m)，3.16(3H，s)，3.22-3.82(7H，m)，3.88-4.80(5H，m)，7.09(1H，d，J＝9.0Hz)，7.17(1H，dd，J＝8.8，1.9Hz)，7.42(1H，d，J＝8.8Hz)，7.70(1H，d，J＝1.9Hz)，8.29(1H，br.s)，8.40-8.50(1H，m)，11.20-11.50(1H，m)，11.85(1H，s).

MS(ESI)m/z：545(M+H)⁺.

[α]_D ²⁵-53.4 ° (c ═ 0.52, methanol)

[ 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

The title compound was obtained from the compound obtained in referential example 223 by the same process as in example 169.

Melting point: 213 to 230 DEG C

¹H-NMR(DMSO-d₆)δ：1.45-1.56(0.5H，m)，1.61-1.70(0.5H，m)，1.89-2.00(1H，m)，2.05(3H，s)，2.45-2.67(1H，m)，2.88(3H，s)，3.00-3.21(4H，m)，3.32-3.56(7H，m)，3.78-3.89(2H，m)，4.00-4.24(2H，m)，4.26-4.43(2H，m)，7.02(1H，s)，7.13(1H，dd，J＝8.8，2.0Hz)，7.37(1H，d，J＝8.8Hz)，7.67(1H，d，J＝2.0Hz)，8.41(1H，d，J＝9.8Hz)，8.74(1H，d，J＝9.8Hz)，10.80-10.90(1H，m)，11.72(1H，s).

MS(FAB)m/z：545(M+H)⁺.

[α]_D ²⁵Equal to-100.3 ° (c equal to 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 by treating the low-polarity compound obtained in referential example 176 and the compound obtained in referential example 10 in the same manner as in example 169.

¹H-NMR(DMSO-d₆)δ：2.41-2.56(2H，m)，2.91(3H，s)，3.01-3.23(1H，m)，3.24-3.56(5H，m)，3.62-3.67(1H，m)，4.21-4.44(1H，m)，4.56-4.78(2H，m)，7.11(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.22(1H，d，J＝8.5Hz)，7.41(1H，d，J＝8.8Hz)，7.69(1H，d，J＝2.0Hz)，8.40-8.50(1H，m)，11.34-11.56(1H，m)，11.82(1H，s).

MS(FAB)m/z：488(M+H)⁺.

[ 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 from the highly polar compound obtained in referential example 176 and the compound obtained in referential example 10 by the same treatment as in example 169.

¹H-NMR(DMSO-d₆)δ：2.41-2.56(2H，m)，2.91(3H，s)，3.23-3.41(2H，m)，3.43-3.50(2H，m)，3.56-3.67(2H，m)，4.37(1H，dd，J＝13.9，7.1Hz)，4.40-4.50(1H，m)，4.56-4.78(2H，m)，7.12(1H，s)，7.17(1H，dd，J＝8.8，2.0Hz)，7.41(1H，d，J＝8.8Hz)，7.71(1H，d，J＝2.0Hz)，8.44(1H，d，J＝8.5Hz)，8.15(1H，d，J＝8.5Hz)，11.42-11.53(1H，m)，11.79(1H，s).

MS(FAB)m/z：488(M+H⁺).

[ 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 } pentanoic acid ethyl ester

The title compound was obtained from the compound obtained in referential example 225 by the same treatment as in example 169.

¹H-NMR(CDCl₃)δ：1.09(9H，s)，1.21(3H，t，J＝7.4Hz)，2.49(3H，s)，2.65(1H，dd，J＝15.9，5.4Hz)，2.67-2.90(5H，m)，3.60(1H，d，J＝14.9Hz)，3.72(1H，d，J＝14.9Hz)，3.78-3.91(2H，m)，4.00-4.21(2H，m)，4.43-4.50(1H，m)，4.78-4.89(1H，m)，6.81(1H，s)，7.20(1H，dd，J＝8.8，2.0Hz)，7.32-7.52(m，7H)，7.63-7.74(6H，m)，7.89-8.01(1H，m)，9.18(1H，s).

[ 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 } pentanoic acid ethyl ester

Hydrogen fluoride-pyridine (0.4ml) was added dropwise to a mixed solution of the compound (0.54g) obtained in referential example 175, pyridine (4.0ml) and tetrahydrofuran (10ml) under ice cooling, and the reaction mixture was stirred for 18 hours while gradually warming to room temperature. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol ═ 9: 1) to obtain the title compound (0.31 g).

¹H-NMR(CDCl₃)δ：1.20(3H，t，J＝7.4Hz)，2.49(3H，s)，2.67-2.90(6H，m)，3.62-3.74(3H，m)，3.78-3.94(1H，m)，4.00-4.20(2H，m)，4.30-4.40(1H，m)，4.80-4.89(1H，m)，6.93(1H，s)，7.23(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.56(1H，d，J＝8.5Hz)，7.61(1H，d，J＝2.0Hz)，7.88(1H，d，J＝8.5Hz)，9.29(1H，s)

[ 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 obtained in example 176 (0.31g) was added a 4N dioxane hydrochloride solution (20ml), and the mixture was refluxed for 4 hours. The reaction solution was concentrated, and the resulting residue was recrystallized from diethyl ether to obtain the title compound (0.23 g).

Melting point: 221 to 238 ℃ (decomposition)

¹H-NMR and MS: in accordance with example 174 as enantiomer

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 title compound was obtained as a free base from the compound obtained in referential example 227 and 5-chloroindole-2-carboxylic acid by the same treatment as in example 91. The free base was treated with a solution of hydrochloric acid in ethanol to obtain the title compound.

Melting point: 241 to 244 DEG C

¹H-NMR(DMSO-d₆)δ：2.14(1H，br)，2.30-2.34(1H，m)，2.92(3H，s)，3.10-3.18(2H，m)，3.41(4H，br)，3.68(2H，br)，4.44(1H，br)，4.63-4.78(3H，m)，7.16-7.18(1H，m)，7.21(1H，s)，7.43(1H，d，J＝8.5Hz)，7.67(1H，d，J＝4.6Hz)，8.39(1H，br)，8.94(1H，br)，11.82(1H，br).

MS(ESI)m/z：522(M+H)⁺.

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 title compound was obtained as a free base from the compound obtained in referential example 227 and 5-fluoroindole-2-carboxylic acid by the same treatment as in example 91. The free base was treated with a solution of hydrochloric acid in ethanol to obtain the title compound.

Melting point: 243-245 DEG C

¹H-NMR(DMSO-d₆)δ：2.14(1H，br)，2.30-2.33(1H，m)，2.92(3H，s)，3.13(2H，br)，3.51(4H，br)，3.63(2H，br)，4.63(3H，br)，4.78(1H，br)，7.01-7.05(1H，m)，7.21(1H，s)，7.37-7.44(2H，m)，8.36(1H，br)，8.93(1H，d，J＝6.8Hz)，11.72(1H，br).

MS(ESI)m/z：506(M+H⁺).

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 from the compound obtained in referential example 229 and the compound obtained in referential example 10 by the same treatment as in example 91. The free base was treated with a solution of hydrochloric acid in ethanol to obtain the title compound.

Melting point: 242-247 deg.C

¹H-NMR(DMSO-d₆)δ：2.16(1H，br)，2.45(1H，br)，2.93(3H，s)，3.13(2H，br)，3.26(4H，br)，3.69(2H，br)，4.45(1H，br)，4.65-4.77(3H，m)，7.01(1H，s)，7.17(1H，dd，J＝8.7，1.4Hz)，7.43(1H，d，J＝8.5Hz)，7.69(1H，s)，8.35-8.40(1H，m)，9.04(1H，br)，11.86(1H，s).

MS(ESI)m/z：522(M+H⁺).

[ 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 title compound was obtained as a free base by treating the compound obtained in referential example 231 and 5-chloroindole-2-carboxylic acid in the same manner as in example 91. The free base was treated with a solution of hydrochloric acid in ethanol to obtain the title compound.

Melting point: 244 to 249 DEG C

¹H-NMR(DMSO-d₆)δ：2.17-2.27(2H，m)，2.90(3H，s)，3.09(1H，br)，3.18-3.21(2H，m)，3.31-3.34(2H，m)，3.60-3.67(3H，m)，4.41-4.49(2H，m)，4.54-4.59(2H，m)，7.04(1H，s)，7.09-7.13(1H，m)，7.39(1H，d，J＝8.5Hz)，7.61(1H，d，J＝9.9Hz)，8.52-8.56(1H，m)，8.83-8.85(1H，m)，11.65(1H，d，J＝11.9Hz).

MS(ESI)m/z：522(M+H⁺).

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 title compound was obtained as a free base by treating the compound obtained in referential example 231 and 5-fluoroindole-2-carboxylic acid in the same manner as in example 91. The free base was treated with a solution of hydrochloric acid in ethanol to obtain the title compound.

Melting point: 236-241 deg.C

¹H-NMR(DMSO-d₆)δ：2.20-2.24(2H，m)，2.89(3H，s)，3.07(1H，br)，3.19-3.22(2H，m)，3.60-3.66(4H，m)，4.43-4.58(5H，m)，6.95-7.00(1H，m)，7.04(1H，s)，7.32-7.38(2H，m)，8.50(1H，d，J＝8.5Hz)，8.83(1H，d，J＝8.5Hz)，11.59(1H，s).

MS(ESI)m/z：506(M+H⁺).

[ 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 from the compound obtained in referential example 233 and the compound obtained in referential example 10 by treating in the same manner as in example 91. The free base was treated with a solution of hydrochloric acid in ethanol to obtain the title compound.

Melting point: 244 to 249 DEG C

¹H-NMR(DMSO-d₆)δ：2.12-2.18(1H，m)，2.50(1H，br)，2.92(3H，s)，3.17(3H，br)，3.50-3.61(5H，m)，4.45(1H，br)，4.62-4.78(3H，m)，6.98-7.03(2H，m)，7.36-7.42(2H，m)，8.30(1H，br)，9.00(1H，d，J＝8.0Hz)，11.74(1H，s).

MS(ESI)m/z：506(M+H⁺).

EXAMPLE 184N- ((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-polar compound) and N- ((3R, 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 (high-polar compound).

Low-polarity compound and high-polarity compound

The title compound was obtained from the compound obtained in referential example 236 and the compound obtained in referential example 10 by the same process as in example 169.

Low polarity compounds:

melting point: 189 to 203 ℃ (decomposition)

¹H-NMR(CDCl₃)δ：2.52(3H，s)，2.59(1H，q，J＝8.8Hz)，2.71-2.78(2H，m)，2.89-3.00(2H，m)，3.03(3H，s)，3.12(1H，dd，J＝17.6，5.4Hz)，3.43(1H，dd，J＝12.7，5.1Hz)，3.70(1H，d，J＝15.2Hz)，3.77(1H，d，J＝15.2Hz)，3.83(1H，dd，J＝12.7，3.9Hz)，4.55-4.67(2H，m)，6.99(1H，s)，7.23(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.65(1H，d，J＝2.0Hz)，8.07(1H，d，J＝5.1Hz)，8.16(1H，d，J＝5.4Hz)，9.43(1H，s).

MS(FAB)m/z：501(M+H⁺).

Highly polar compounds:

melting point: 183 to 195 deg.C (decomposition)

¹H-NMR(DMSO-d₆)δ：2.33(3H，s)，2.41-2.50(1H，m)，2.62-2.73(3H，m)，2.75-2.81(1H，m)，2.82(3H，s)，3.21-3.32(2H，m)，3.34-3.50(2H，m)，3.55(1H，d，J＝15.4Hz)，3.63(1H，d，J＝15.4Hz)，4.30-4.40(0.5H，m)，4.50-4.60(0.5H，m)，7.04(1H，s)，7.15(1H，dd，J＝8.8，2.0Hz)，7.38(1H，d，J＝8.8Hz)，7.67(1H，d，J＝2.0Hz)，8.49(1H，d，J＝8.5Hz)，8.71(1H，d，J＝8.5Hz)，11.74(1H，s).

MS(FAB)m/z：501(M+H⁺).

Example 185]5-chloro-N- ((1R)^*，2S^*) -2- { [4- (pyridin-4-yl) benzoyl]Amino } cyclohexyl) indole-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 237 by the same process as in example 2.

¹H-NMR(DMSO-d₆)δ：1.40-1.52(2H，m)，1.60-1.80(4H，m)，1.96-2.10(2H，m)，4.24-4.39(2H，m)，7.15(1H，dd，J＝8.8，2.0Hz)，7.21(1H，s)，7.40(1H，d，J＝8.8Hz)，7.64(1H，d，J＝2.0Hz)，8.06(4H，s)，8.18(1H，J＝7.3Hz)，8.34-8.42(3H，m)，8.94(2H，d，J＝6.9Hz)，11.91(1H，s).

MS(FAB)m/z：473(M+H)⁺

EXAMPLE 186]4-(4-{[((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) amino]Carbonyl } phenyl) pyridine N-oxides

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 240 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.40-1.52(2H，m)，1.60-1.80(4H，m)，1.88-2.00(2H，m)，4.21-4.36(2H，m)，7.12-7.18(2H，m)，7.41(1H，d，J＝8.6Hz)，7.66(1H，s)，7.80-7.87(4H，m)，7.91(2H，d，J＝8.3Hz)，8.01(1H，d，J＝7.6Hz)，8.09(1H，d，J＝7.3Hz)，8.27(2H，d，J＝6.6Hz)，11.79(1H，s).

MS(FAB)m/z：489(M+H)⁺.

Example 187]5-chloro-N- ((1R)^*，2S^*) -2- { [4- (pyridin-2-yl) benzoyl]Amino } cyclohexyl) indole-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 71 and 4- (2-pyridyl) benzoic acid (Japanese patent laid-open No. 2000-119253) in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.39-1.51(2H，m)，1.60-1.80(4H，m)，1.89-2.00(2H，m)，4.24-4.38(2H，m)，7.12-7.16(2H，m)，7.36-7.39(1H，m)，7.42(1H，d，J＝8.8Hz)，7.66(1H，d，J＝2.0Hz)，7.87-7.90(1H，m)，7.92(2H，d，J＝8.3Hz)，7.98-8.11(3H，m)，8.15(2H，d，J＝8.3Hz)，8.69(1H，d，J＝4.6Hz)，11.80(1H，s).

MS(FAB)m/z：473(M+H)⁺.

[ example 188]2-(4-{[((1R^*，2S^*) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } cyclohexyl) amino]Carbonyl } phenyl) pyridine N-oxides

The title compound was obtained from the compound obtained in referential example 71 and the compound obtained in referential example 241 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.39-1.51(2H，m)，1.60-1.79(4H，m)，1.89-2.00(2H，m)，4.23-4.37(2H，m)，7.12-7.17(2H，m)，7.39-7.43(3H，m)，7.61-7.64(1H，m)，7.67(1H，d，J＝2.0Hz)，7.89(4H，s)，8.00-8.06(1H.m)，8.08-8.02(1H，m)，8.32-8.35(1H，m)，11.79(1H，s).

MS(FAB)m/z：489(M+H)⁺.

[ example 189]5-chloro-N- [ (1R)^*，2R^*) -2- ({ [5- (4-pyridin-2-yl) thiazol-2-yl) ]Carbonyl } amino } cyclohexyl]Indole-2-carboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 69 and lithium 5- (4-pyridyl) thiazole-2-carboxylate salt (Japanese patent laid-open No. 2000-143623) by the same process as in example 2.

¹H-NMR(DMSO-d₆)δ：1.44(2H，br.s)，1.65(4H，br.s)，1.85-2.06(2H，m)，4.23(1H，br.s)，4.30(1H，br.s)，7.14-7.23(2H，m)，7.41(1H，d，J＝8.8Hz)，7.69(1H，s)，8.04-8.13(2H，m)，8.13(1H，d，J＝8.8Hz)，8.59(1H，d，J＝8.0Hz)，8.75-8.87(3H，m)，11.83(1H，s).

MS(ESI)m/z：480(M+H)⁺.

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, volume 44, page 7095) (206mg) was suspended in dichloromethane (50ml), and thionyl chloride (144. mu.l) was added thereto under ice-cooling and stirred for 30 minutes. Triethylamine (969. mu.l) was added to the reaction solution, and the compound (328mg) obtained in referential example 71 was added thereto 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 precipitated precipitate was collected by filtration to obtain the title compound (310 mg).

¹H-NMR(DMSO-d₆)δ：1.30-2.00(10H，m)，2.74(1H，br.s)，3.18(2H，q，J＝12.3Hz)，4.03(1H，br.s)，4.10-4.25(3H，m)，7.15-7.55(4H，m)，7.42(1H，d，J＝8.8Hz)，7.65(1H，s)，7.91(1H，d，J＝8.8Hz)，8.20-8.35(3H，m)，11.91(1H，s)，13.47(1H，br.s).

MS(FAB)m/z：480(M+H)⁺.

[ example 191]N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (288mg) obtained in referential example 242 was dissolved in tetrahydrofuran (8.0ml), and lithium hydroxide (46mg) and water (1.0ml) were successively added to stir at room temperature for 2 hours. The reaction mixture was concentrated to a dry solid under reduced pressure to obtain a crude product (292mg) of lithium 2- (4-chloroanilino) -2-oxoacetate as a colorless solid. This crude product and the compound obtained in referential example 253 were dissolved in N, N-dimethylformamide (15ml), and 1-hydroxybenzotriazole 1 hydrate (164mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (251mg) were added to stir at room temperature for 64.5 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution and methylene chloride were added to the residue to separate a liquid, and then 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 (dichloromethane: methanol 47: 3). The resulting pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.52ml) 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 obtain the title compound (245 mg).

¹H-NMR(DMSO-d₆)δ：1.45-1.55(1H，m)，1.60-1.80(3H，m)，1.95-2.10(2H，m)，2.79(3H，s)，2.80-3.00(1H，m)，2.92(3H，s)，2.94(3H，s)，3.10-3.40(2H，m)，3.40-3.80(2H，m)，3.95-4.05(1H，m)，4.40-4.80(3H，m)，7.40(2H，d，J＝8.8Hz)，7.83(2H，d，J＝8.8Hz)，8.75(1H，d，J＝7.1Hz)，9.00-9.10(1H，br)，10.81(1H，s)，11.45-11.75(1H，m).

MS(FAB)m/z：547(M+H)⁺.

[ example 192]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (240mg) obtained in referential example 243 was dissolved in tetrahydrofuran (8.0ml), and lithium hydroxide (41mg) and water (1.0ml) were added in this order and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated to a solid under reduced pressure to give lithium 2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetate (249 mg).

On the other hand, 10% palladium on carbon (200mg) was added to a methanol (10ml) solution of the compound (293mg) obtained in referential example 252, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. After filtering off palladium on carbon, the filtrate was concentrated under reduced pressure to obtain a crude product (259mg) of N- { (1R, 2S, 5S) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide.

This crude product (259mg) and the above lithium salt (249mg) were added to N, N-dimethylformamide (15ml), and 1-hydroxybenzotriazole 1 hydrate (166mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (235mg) were further added to stir at room temperature for 63.5 hours. The solvent was evaporated under reduced pressure, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to the residue to separate, and the obtained 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 (dichloromethane: methanol 93: 7). The resulting pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.855ml) 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 obtain the title compound (209 mg).

¹H-NMR(DMSO-d₆)δ：1.40-1.57(1H，m)，1.60-1.80(3H，m)，1.95-2.13(2H，m)，2.79(3H，s)，2.80-3.00(1H，m)，2.92(3H，s)，2.94(3H，s)，3.10-3.40(2H，m)，3.40-3.80(2H，m)，3.95-4.05(1H，m)，4.37-4.80(3H，m)，7.90-8.10(2H，m)，8.45(1H，d，J＝2.2Hz)，8.71(1H，d，J＝7.6Hz)，9.10-9.30(1H，br)，10.26(1H，s)，11.30-11.60(1H，br).

MS(FAB)m/z：548(M+H)⁺.

Example 193]N¹- (3-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (222mg) obtained in referential example 270 and 3-chloroaniline (63. mu.l) were dissolved in N, N-dimethylformamide (10ml), and 1-hydroxybenzotriazole 1 hydrate (68mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (144mg) were added to stir at room temperature for 40 hours. The solvent was evaporated under reduced pressure, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to the residue to separate, and then 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 (dichloromethane: methanol ═ 30: 1). The resulting pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (0.50ml) 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 obtain the title compound (174 mg).

¹H-NMR(DMSO-d₆)δ：1.45-1.62(1H，m)，1.65-1.90(3H，m)，1.98-2.20(2H，m)，2.79(3H，s)，2.88-3.10(1H，m)，2.93(3H，s)，2.94(3H，s)，3.15-3.40(2H，m)，3.40-3.90(2H，m)，3.95-4.10(1H，m)，4.40-4.80(3H，m)，7.19(1H，dd，J＝9.3，2.0Hz)，7.37(1H，d，J＝8.2Hz)，7.77(1H，d，J＝8.3Hz)，7.92-8.05(1H，m)，8.75(1H，d，J＝7.3Hz)，8.95-9.20(1H，br)，10.87(1H，s)，11.25-11.45(1H，br).

[ example 194]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (4-fluorophenyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 254, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.40-2.13(6H，m)，2.77(3H，s)，2.93(3H，s)，2.97(3H，s)，3.12-3.82(7H，m)，3.93-4.04(1H，m)，4.38-4.46(1H，m)，4.35-4.75(1H，m)，7.11-7.21(2H，m)，7.72-7.84(2H，m)，8.73(1H，d，J＝7.6Hz)，8.93-9.02(1H，m)，10.70(1H，s).

MS(FAB)m/z：531(M+H)⁺.

EXAMPLE 195]N¹- (4-bromophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (152mg) obtained in referential example 255 was dissolved in tetrahydrofuran (5.0ml), and a 1N aqueous solution (1.20ml) of sodium hydroxide and methanol (5.0ml) were successively added to stir at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride (10ml) and 1N hydrochloric acid (2.0ml) were added to the residue to separate the mixture. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated 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 (280mg) obtained in referential example 253 were dissolved in N, N-dimethylformamide (30ml), and 1-hydroxybenzotriazole 1 hydrate (90mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (226mg) were added to stir at room temperature overnight. The solvent was evaporated under reduced pressure, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to the residue to separate, and then 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 (dichloromethane: methanol 97: 3). The resulting pale yellow solid was dissolved in methylene chloride, 1N ethanol hydrochloride solution (191. mu.l) 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 obtain the title compound (103 mg).

¹H-NMR(DMSO-d₆)δ：1.43-1.57(1H，m)，1.59-1.80(3H，m)，1.97-2.10(2H，m)，2.79(3H，s)，2.84-2.98(7H，m)，3.18(2H，br.s)，3.39-3.72(2H，m)，3.95-4.05(1H，m)，4.20-4.80(3H，m)，7.53(2H，d，J＝8.8Hz)，7.77(2H，d，J＝8.8Hz)，8.75(1H，d，J＝7.3Hz)，8.97-9.09(1H，m)，10.82(1H，s)，11.11(1H，br.s).

MS(FAB)m/z：591(M+H)⁺.

[ example 196]N¹- (4-chloro-2-methylphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 256, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.45-1.55(1H，m)，1.60-1.80(3H，m)，2.00-2.10(2H，m)，2.19(3H，s)，2.79(3H，s)，2.80-3.00(7H，m)，3.31(2H，br.s)，3.40-3.70(2H，br)，3.95-4.05(1H，m)，4.35-4.70(3H，m)，7.20-7.30(1H，m)，7.35(1H，d，J＝2.5Hz)，7.43(1H，d，J＝8.6Hz)，8.76(1H，d，J＝6.6Hz)，9.00-9.15(1H，br)，10.19(1H，s).

MS(FAB)m/z：561(M+H)⁺.

[ example 197]N¹- (4-chloro-3-methylphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 257, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.47-1.53(1H，m)，1.68-1.80(3H，m)，1.98-2.09(2H，m)，2.29(3H，s)，2.79(3H，s)，2.80-3.00(1H，m)，2.95(6H，s)，3.17-3.19(3H，m)，3.40-3.80(1H，m)，3.93-4.02(1H，m)，4.44-4.56(3H，m)，7.38(1H，d，J＝8.8Hz)，7.65(1H，d，J＝8.8Hz)，7.74(1H，s)，8.75(1H，d，J＝7.8Hz)，8.96(1H，d，J＝8.0Hz)，10.69(1H，s).

MS(FAB)m/z：561(M+H)⁺.

[ example 198]N¹- (4-chloro-2-fluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 258, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.40-1.55(1H，m)，1.58-1.80(3H，m)，1.95-2.12(2H，m)，2.77(3H，s)，2.80-3.00(1H，m)，2.91(3H，s)，2.92(3H，s)，3.10-3.40(2H，m)，3.40-3.80(2H，m)，3.95-4.05(1H，m)，4.30-4.80(3H，m)，7.29(1H，d，J＝8.5Hz)，7.52(1H，dd，J＝10.3，2.0Hz)，7.61(1H，t，J＝8.4Hz)，8.72(1H，d，J＝6.8Hz)，9.00-9.20(1H，br)，10.38(1H，s)，11.20-11.45(1H，br).

MS(FAB)m/z：565(M+H)⁺.

[ example 199]N¹- (2, 4-dichlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (300mg) obtained in referential example 270 was dissolved in N, N-dimethylformamide (5ml), and 2, 4-dichloroaniline (165mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (260mg) and 1-hydroxybenzotriazole 1 hydrate (91mg) were added to stir at room temperature for 2 days. The solvent was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to the residue to separate a liquid, an 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 (dichloromethane: methanol ═ 47: 3) to obtain a free base of the title compound. This was dissolved in methylene chloride, 1N ethanol hydrochloride solution (108. mu.l) was added, and 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 performing ultrasonic irradiation, and the resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (60 mg).

¹H-NMR(DMSO-d₆)δ：1.45-1.77(4H，m)，2.03-2.12(2H，m)，2.79(3H，s)，2.92-2.96(7H，m)，3.25(2H，br.s)，3.49(1H，br.s)，3.69(1H，br.s)，3.98-4.04(1H，m)，4.40-4.43(1H，m)，4.45(1H，br.s)，4.69(1H，br.s)，7.48(1H，dd，J＝8.5，2.4Hz)，7.75(1H，d，J＝2.4Hz)，7.89(1H，d，J＝8.5Hz)，8.75(1H，d，J＝6.8Hz)，9.21(1H，br.s)，10.25(1H，s)，11.55(1H，br.s).

MS(FAB)m/z：581(M+H)⁺.

Example 200]N¹- (3, 4-dichlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group ]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

3, 4-dichloroaniline (1.62g) was dissolved in methylene chloride (20ml), and triethylamine (1.67ml) and methyl chlorooxoacetate (1.01ml) were added in this order under ice cooling, followed by stirring at room temperature for 21 hours. After water and dichloromethane were added to the reaction solution to separate the solution, the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in ethanol (50ml), and water (25ml) and lithium hydroxide 1 hydrate (629mg) were added in this order, followed by stirring at room temperature for 12.5 hours. Then, lithium hydroxide 1 hydrate (629mg) was added thereto, and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was concentrated under reduced pressure to dryness. After water and ether were added to the residue to separate the solution, hydrochloric acid was added to the aqueous layer to make it acidic. The resulting solid was collected by filtration to obtain a crude product (1.62g) of 2- (3, 4-dichloroanilino) -2-oxoacetic acid as a colorless solid. This crude product (191mg) and the compound (250mg) obtained in referential example 253 were dissolved in N, N-dimethylformamide (10ml), and 1-hydroxybenzotriazole 1 hydrate (110mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (157mg) were added to stir at room temperature for 67 hours. The solvent was evaporated under reduced pressure, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the residue to separate, and then the aqueous layer was extracted with dichloromethane 3 times. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 95: 5) to obtain the title compound (154 mg).

¹H-NMR(CDCl₃)δ：1.77-1.88(1H，m)，1.91-1.95(1H，m)，2.05-2.10(3H，m)，2.51(3H，s)，2.77-2.99(6H，m)，2.95(3H，s)，3.05(3H，s)，3.68(1H，d，J＝15.5Hz)，3.74(1H，d，J＝15.5Hz)，4.08-4.13(1H，m)，4.69-4.72(1H，m)，7.40(2H，s)，7.41(1H，d，J＝7.7Hz)，7.90(1H，s)，8.01(1H，d，J＝7.7Hz)，9.27(1H，s).

MS(ESI)m/z：581(M+H)⁺.

[ example 201]N¹- (2, 4-difluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

The title compound was obtained by hydrolyzing the compound obtained in referential example 259 and then condensing the product with the compound obtained in referential example 253 in the same manner as in example 191.

¹H-NMR(CDCl₃)δ：1.55-1.62(1H，m)，1.67-1.98(2H，m)，2.01-2.18(4H，m)，2.52(3H，s)，2.77-3.00(4H，m)，2.95(3H，s)，2.99(3H，s)，3.65-3.78(2H，m)，4.06-4.15(1H，m)，4.66-4.73(1H，m)，6.85-6.94(2H，m)，7.38(1H，d，J＝8.5Hz)，7.96(1H，d，J＝7.3Hz)，8.22-8.29(1H，m)，9.36(1H，br).

Example 202]N¹- (3, 4-difluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

The title compound was obtained by hydrolyzing the compound obtained in referential example 260 and then condensing the product with the compound obtained in referential example 253 in the same manner as in example 191.

¹H-NMR(CDCl₃)δ：1.56-1.73(1H，m)，1.77-1.99(2H，m)，2.00-2.18(4H，m)，2.52(3H，s)，2.75-3.00(4H，m)，2.95(3H，s)，3.06(3H，s)，3.64-3.79(2H，m)，4.05-4.14(1H，m)，4.68-4.75(1H，m)，7.09-7.21(2H，m)，7.38(1H，d，J＝8.8Hz)，7.72(1H，ddd，J＝12.0，7.1，2.6Hz)，7.95(1H，d，J＝7.8Hz)，9.22(1H，br).

EXAMPLE 203]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (pyridin-4-yl) ethanediamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 261, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.40-2.10(6H，m)，2.77(3H，s)，2.927(3H，s)，2.933(3H，s)，3.05-4.20(8H，m)，4.40-4.55(1H，m)，8.27(2H，d，J＝6.8Hz)，8.67(1H，d，J＝8.0Hz)，8.71(2H，d，J＝6.8Hz)，9.10-9.30(1H，br)，11.81(1H，s).

MS(FAB)m/z：514(M+H)⁺.

EXAMPLE 204]N¹- (5-bromopyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 262, condensing the hydrolyzed product with the compound obtained in referential example 253 and then treating the product with hydrochloric acid in the same manner as in example 195.

¹H-NMR(DMSO-d₆)δ：1.43-1.57(1H，m)，1.61-1.81(3H，m)，1.98-2.15(2H，m)，2.79(3H，s)，2.86(3H，s)，2.89-3.01(4H，m)，3.18(2H，br.s)，3.50(2H，br.s)，3.95-4.05(1H，m)，4.35-4.62(3H，m)，7.97(1H，d，J＝9.0Hz)，8.12(1H，dd，J＝9.0，2.4Hz)，8.52(1H，d，J＝2.4Hz)，8.70(1H，d，J＝7.5Hz)，9.18(1H，d，J＝7.5Hz)，10.25(1H，br.s).

MS(FAB)m/z：592(M+H)⁺.

Example 205]N¹- (6-chloropyridin-3-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (200mg) obtained in referential example 263 as a crude product was dissolved in methanol (10ml), heated at 50 ℃ and stirred for 5 minutes by adding a 1N aqueous solution (3ml) of sodium hydroxide. To this solution, 1N hydrochloric acid aqueous solution was added to adjust the pH to weak acidity, and the solvent was distilled off under reduced pressure to obtain a residue containing 2- [ (2-chloropyridin-5-yl) amino ] -2-oxoacetic acid. To the residue and the compound (250mg) obtained in referential example 253, N-dimethylformamide (5ml) was added, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (328mg) and 1-hydroxybenzotriazole 1 hydrate (46mg) were further 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 hydrogencarbonate solution and methylene chloride were added to the residue to conduct 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 column chromatography (dichloromethane: methanol ═ 47: 3) to obtain the free base of the title compound as a pale yellow solid. This was dissolved in methylene chloride, 1N ethanol hydrochloride solution (862. mu.l) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, ethyl acetate and diethyl ether were added dropwise while irradiating with ultrasonic waves, and the resulting precipitate was collected by filtration and washed with ethyl acetate to obtain the title compound (229 mg).

¹H-NMR(DMSO-d₆) δ: 1.46-1.75(4H, m), 1.99-2.09(2H, m), 2.79(3H, s), 2.92-2.95(7H, m), 3.12-3.53(3H, m), 3.70(1H, br.s), 3.99-4.06(1H, m), 4.44(2H, br.s), 4.69, 4.73(1H, each s), 7.53(1H, d, J ═ 8.5Hz), 8.23-8.25(1H, m), 8.72-8.77(1H, m), 8.85(1H, s), 9.07, 9.16(1H, each d, J ═ 8.1Hz), 11.09(1H, d, J ═ 8.1Hz), 11.78(1H, br.78).

MS(FAB)m/z：548(M+H)⁺.

Example 206]N¹- (6-chloropyridazin-3-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 264, condensing the hydrolyzed product with the compound obtained in referential example 253 and then treating the condensed product with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.44-1.57(1H，m)，1.62-1.80(3H，m)，2.00-2.10(2H，m)，2.79(3H，s)，2.86(3H，br.s)，2.94(3H，s)，2.95-3.01(1H，m)，3.14-3.23(2H，m)，3.45-3.63(2H，m)，3.96-4.08(1H，m)，4.40-4.60(3H，m)，7.97(1H，d，J＝9.3Hz)，8.26(1H，d，J＝9.3Hz)，8.69(1H，d，J＝7.6Hz)，9.20(1H，d，J＝7.6Hz)，11.06(1H，s).

MS(FAB)m/z：549(M+H)⁺.

EXAMPLE 207]N¹- (5-chlorothiazol-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 265, condensing the hydrolyzed product with the compound obtained in referential example 253 and then treating the condensed product with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.35-2.10(6H，m)，2.77(3H，s)，2.92(3H，s)，2.93(3H，s)，3.05-4.23(8H，m)，4.32-4.80(2H，m)，7.59(1H，s)，8.63(1H，d，J＝7.6Hz)，9.14(1H，d，J＝7.6Hz).

MS(FAB)m/z：554(M+H)⁺.

Example 208]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (210mg) obtained in referential example 266 and the compound (350mg) obtained in referential example 272 were dissolved in N, N-dimethylformamide (15ml), and 1-hydroxybenzotriazole 1 hydrate (205mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (290mg) were added to stir at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution and methylene chloride were added to the residue to conduct liquid separation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane: methanol 20: 1), the resulting pale yellow solid was dissolved in dichloromethane, 1N ethanol hydrochloride solution (0.46ml) 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 obtain the title compound (248 mg).

¹H-NMR(DMSO-d₆)δ：1.47-1.50(1H，m)，1.69-1.76(3H，m)，1.98-2.06(2H，m)，2.79(3H，s)，2.95(3H，s)，2.98-3.05(1H，m)，3.10(3H，s)，3.49-4.62(6H，m)，7.98-8.03(2H，m)，8.45(1H，s)，8.73(1H，d，J＝7.6Hz)，9.10(1H，d，J＝8.0Hz)，10.30(1H，s).

MS(FAB)m/z：534(M+H)⁺.

[ 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 (2.3g) obtained in referential example 267 was dissolved in ethanol (10ml), and a 1N aqueous solution (20ml) of sodium hydroxide was added to stir at room temperature for 2 hours. After 1N aqueous hydrochloric acid (20ml) was added to the reaction mixture, the mixture was diluted with water and stirred for 30 minutes. The insoluble matter thus precipitated was collected by filtration. 2- (4-Chloroanilino) acetic acid (1.05g) was obtained as a colorless solid. This solid and the compound (0.25g) obtained in referential example 253 were dissolved in N, N-dimethylformamide (10ml), and 1-hydroxybenzotriazole 1 hydrate (0.11g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.23g) were added to stir at room temperature for 4 days. The reaction solution was diluted with chloroform, washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol: 97: 3), the resulting pale yellow solid was dissolved in ethanol, a 1N ethanol hydrochloride 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 obtain the title compound (0.15 g).

¹H-NMR(DMSO-d₆)δ：1.35-1.41(1H，m)，1.59-1.80(3H，m)，1.82-1.95(2H，m)，2.76(3H，s)，2.93(3H，s)，2.94(3H，s)，2.99-3.10(1H，m)，3.10-3.22(2H，m)，3.42-3.60(2H，m)，3.60-3.77(2H，m)，3.80-3.90(1H，m)，4.35-4.48(2H，m)，4.68-4.80(1H，m)，6.40(1H，d，J＝6.7Hz)，6.44(1H，d，J＝6.7Hz)，6.90(1H，d，J＝6.7Hz)，7.00(1H，d，J＝6.7Hz)，7.70-7.89(1H，m)，8.35-8.42(1H，m)，11.05-11.38(1H，m).

[ 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

The title compound was obtained by hydrolyzing the compound obtained in referential example 268, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 209.

¹H-NMR(DMSO-d₆)δ：1.35-1.42(1H，m)，1.55-1.78(3H，m)，1.80-2.00(2H，m)，2.76(3H，s)，2.92(3H，s)，2.94(3H，s)，2.99-3.10(1H，m)，3.10-3.22(2H，m)，3.42-3.60(2H，m)，3.60-3.77(2H，m)，3.85-4.00(1H，m)，4.33-4.48(2H，m)，4.65-4.80(1H，m)，6.41(1H，t，J＝8.8Hz)，6.73(1H，dt，J＝8.8，1.2Hz)，7.08(1H，dd，J＝11.7，1.2Hz)，7.78-7.92(1H，m)，8.35-8.42(1H，m)，11.18-11.50(1H，m).

[ 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 title compound was obtained by condensing the compound obtained in referential example 432 with the compound obtained in referential example 34 and then treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.70-2.15(6H，m)，2.80(3H，s)，2.97(3H，s)，2.95-3.15(2H，m)，3.35-3.55(2H，m)，4.05-4.20(1H，m)，4.46(2H，s)，4.50-4.65(1H，m)，7.05(1H，s)，7.16(1H，dd，J ＝8.8，2.2Hz)，7.41(1H，d，J＝8.8Hz)，7.68(1H，s)，8.30-8.45(1H，br)，9.30-9.50(1H，br)，11.78(1H，s).

MS(ESI)m/z：529(M+H)⁺.

[ 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 (250mg) obtained in example 211 was suspended in methylene chloride, and a saturated aqueous solution of sodium hydrogencarbonate was added thereto and the mixture was sufficiently stirred. The organic layer was separated, dried over anhydrous magnesium sulfate, and then triethylamine (0.5ml) and ethyl bromoisocyanate (43. mu.l) were added thereto, followed by stirring at room temperature for 20 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution, and 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 (dichloromethane: methanol 22: 3) to obtain the title compound (227mg).

¹H-NMR(CDCl₃)δ：1.50-2.15(4H，m)，2.15-2.40(2H，m)，2.80-3.00(1H，m)，2.97(3H，s)，3.11(3H，s)，3.70-3.95(4H，m)，4.10-4.30(1H，m)，4.30-4.50(2H，m)，4.60-4.70(1H，m)，4.74(2H，s)，6.85(1H，s)，7.21(1H，dd，J＝8.8，2.2Hz)，7.34(1H，d，J＝8.8Hz)，7.50(1H，br.s)，7.62(1H，s)，7.87(1H，br.s)，9.48(1H，br.s).

MS(ESI)m/z：598(M+H)⁺.

[ 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 (140mg) obtained in referential example 144 was dissolved in N, N-dimethylformamide (10ml), and the compound (100mg) obtained in referential example 274, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (140mg) and 1-hydroxybenzotriazole 1 hydrate (110mg) were added to stir at room temperature for 18 hours. The solvent was evaporated under reduced pressure, the residue was partitioned into water-ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 19) to give tert-butyl (1R, 2S, 5S) -2- { [ (5-chloro-4-fluoroindol-2-yl) carbonyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexylcarbamate (260 mg).

The above powder was dissolved in dichloromethane (5ml) and 4N dioxane hydrochloride solution (1.2ml) was added. The reaction mixture was stirred at room temperature for 3.5 hours, and then the solvent was distilled off under reduced pressure. After dichloromethane (10ml) was added to the residue and the procedure was repeated 3 times, 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. This was dissolved in N, N-dimethylformamide (50ml), and the compound (150mg) obtained in referential example 10, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (140mg) and 1-hydroxybenzotriazole 1 hydrate (110mg) were added to stir at room temperature for 18 hours. The solvent was evaporated under reduced pressure, the residue was partitioned into a water-ethyl acetate-tetrahydrofuran mixture, and the aqueous layer was extracted with ethyl acetate. The combined 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 (methanol: dichloromethane ═ 1: 19) to obtain the free base (270mg) of the title compound. The base was dissolved in methylene chloride (10ml), a 1N ethanol hydrochloride solution (0.72ml) was added thereto, and the mixture was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration to obtain the title compound (200 mg).

¹H-NMR(DMSO-d₆)δ：1.24-1.98(6H，m)，2.33-3.33(6H，m)，2.81(3H，s)，2.90(3H，s)，2.99(3H，s)，4.12(1H，br.s)，4.30-4.70(1H，m)，4.60(1H，br.s)，7.21(1H，s)，7.27(2H，br.s)，8.37(1H，d，J＝8.1Hz)，8.43(1H，d，J＝7.6Hz)，12.11(1H，s).

MS(FAB)m/z：561(M+H)⁺.

[ 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 (250mg) obtained in referential example 279 was dissolved in methylene chloride (60ml), and a 4N dioxane hydrochloride solution (1.3ml) was added. After the reaction mixture was stirred at room temperature for 5.5 hours, a 4N dioxane hydrochloride solution (0.65ml) was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and methylene chloride (10ml) was added to the residue to concentrate, and this operation was repeated 3 times. The residue was dried under reduced pressure, and the resulting crude product was dissolved in N, N-dimethylformamide (50ml), and the compound (160mg) obtained in referential example 10, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (150mg) and 1-hydroxybenzotriazole 1 hydrate (120mg) were added to stir at room temperature for 18 hours. The solvent was evaporated 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 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 2 times by silica gel column chromatography (methanol: dichloromethane ═ 2: 23 → 1: 9) to obtain the free base (260mg) of the title compound. The base was dissolved in methylene chloride, a 1N ethanol hydrochloride solution (0.69ml) was added thereto, 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 diethyl ether and hexane were added to crystallize it, which was then filtered off to obtain the title compound (230 mg).

¹H-NMR(DMSO-d₆)δ：1.50-1.56(1H，m)，1.73-1.78(3H，m)，1.94-2.02(2H，m)，2.33-3.55(6H，m)，2.80(3H，s)，2.92(3H，s)，2.98(3H，s)，4.17(1H，br.s)，4.30-4.80(1H，br)，4.62(1H，br.s)，7.25(1H，d，J＝8.8，1.7Hz)，7.40(1H，d，J＝8.8，1.7Hz)，7.65(1H，d，J＝1.7Hz)，7.72(1H，d，J＝5.9Hz)，8.74(1H，d，J＝8.0Hz)，10.85-11.35(1H，br)，11.71(1H，s).

MS(FAB)m/z：561(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 282 with a 4N dioxane hydrochloride solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.51-2.01(6H，m)，2.33-3.29(7H，m)，2.81(3H，s)，2.88(3H，s)，3.01(3H，s)，4.20(1H，br.s)，4.48(1H，br)，4.70-4.73(1H，m)，7.29(1H，dd，J＝8.9，1.8Hz)，7.45-7.49(2H，m)，7.80(1H，d，J＝7.6Hz)，8.76(1H，d，J＝8.8Hz)，12.31(1H，s).

MS(FAB)m/z：622(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in referential example 253 and the compound obtained in referential example 284 by the same method as in example 5.

¹H-NMR(DMSO-d₆)δ：1.40-1.51(1H，m)，1.75-2.00(5H，m)，2.79(3H，s)，2.92(3H，s)，2.99(3H，s)，3.10-3.21(3H，m)，3.29-3.41(4H，m)，4.11-4.21(1H，m)，4.62-4.75(1H，m)，7.14(1H，dt，J＝8.8，2.4Hz)，7.24(1H，dd，J＝8.8，2.4Hz)，7.45(1H，dd，J＝8.8，4.4Hz)，7.69(1H，d，J＝2.5Hz)，8.79(1H，d，J＝2.5Hz)，12.10(1H，s).

MS(FAB)m/z：561(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in referential example 253 and the compound obtained in referential example 286 by the same process as in example 5.

¹H-NMR(DMSO-d₆)δ：1.40-1.51(1H，m)，1.75-1.89(4H，m)，1.90-2.01(1H，m)，2.80(3H，s)，2.91(3H，s)，3.03(3H，s)，3.05-3.33(3H，m)，3.60-3.71(1H，m)，4.11-4.21(1H，m)，4.32-4.44(1H，m)，4.62-4.75(2H，m)，7.35(1H，dd，J＝8.0，1.4Hz)，7.56(1H，d，J＝8.0Hz)，8.21(1H，d，J＝1.4Hz)，8.65(1H，t，J＝7.4Hz)，9.92(1H，d，J＝6.8Hz)，10.15(1H，t，J＝9.1Hz)，13.00(1H，d，J＝6.4).

MS(FAB)m/z：571(M+H)⁺.

Example 218 ]5-chloro-N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine-2-yl) carbonyl]Amino } cyclohexyl) -N³，N³-dimethylindole-2, 3-dicarboxamide hydrochloride

The title compound was obtained from the compound obtained in referential example 253 and the compound obtained in referential example 289 in the same manner as in example 5.

¹H-NMR(DMSO-d₆)δ：1.40-1.51(1H，m)，1.75-2.01(5H，m)，2.78(9H，s)，2.93(3H，s)，3.01(3H，s)，3.10-3.33(3H，m)，3.40-3.50(1H，m)，3.65-3.75(1H，m)，4.01-4.09(1H，m)，4.32-4.44(1H，m)，4.62-4.75(2H，m)，7.25(1H，d，J＝8.0Hz)，7.40-7.50(2H，m)，8.62(1H，br)，9.08(1H，br)，12.28(1H，br).

MS(FAB)m/z：614(M+H)⁺.

[ 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 (270mg) obtained in referential example 294 was dissolved in methylene chloride (10ml), and 1N ethanol hydrochloride (10ml) was added to stir for 90 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in N, N-dimethylformamide (7ml), and the compound (110mg) obtained in referential example 10, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100mg) and 1-hydroxybenzotriazole 1 hydrate (70mg) were added to stir at room temperature for 23 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the reaction mixture, which was then extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20: 1 → 10: 1) 2 times, and the obtained free base was dissolved in methanol, and 1N ethanol hydrochloride solution (0.30ml) was added. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to obtain the title compound (130 mg).

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.70-1.90(3H，m)，1.90-2.10(2H，m)，2.81(3H，s)，2.91(3H，s)，3.00(3H，s)，3.00-3.22(3H，m)，3.53(2H，br)，4.10-4.20(1H，m)，4.30-4.70(3H，m)，7.59(1H，dd，J＝8.8，2.2Hz)，7.87(1H，d，J＝8.5Hz)，7.96(1H，d，J＝8.5Hz)，8.02(1H，d，J＝8.8Hz)，8.10(1H，d，J＝2.2Hz)，8.33(1H，s)，8.43(1H，d，J＝8.1Hz)，8.52(1H，d，J＝7.3Hz).

MS(FAB)m/z：554(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 299 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 219.

¹H-NMR(CDCl₃)δ：1.50-1.65(1H，m)，1.70-1.90(3H，m)，2.05-2.15(1H，m)，2.15-2.30(1H，m)，2.81(3H，s)，2.85-3.05(8H，m)，3.15-3.25(2H，m)，3.40-3.80(1H，m)，4.25-4.80(4H，m)，8.02(1H，dd，J＝8.8，2.0Hz)，8.38(1H，d，J＝8.8Hz)，8.66(1H，s)，8.91(1H，s)，8.96(1H，d，J＝7.3Hz)，9.53(1H，br).

MS(FAB)m/z：556(M+H)⁺.

[ 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 title compound was obtained by treating the compound obtained in referential example 300 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.60-1.83(3H，m)，2.00-2.20(2H，m)，2.78(3H，s)，2.92(6H，s)，3.00-3.30(3H，m)，3.47(2H，br.s)，4.10-4.75(4H，m)，7.30(1H，d，J＝8.8Hz)，7.62(1H，d，J＝12.5Hz)，7.63(1H，s)，8.75-8.87(1H，m)，9.09(1H，dd，J＝12.5，8.8Hz)，11.20-11.40(1H，m).

MS(FAB)m/z：546(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in referential example 253 and the compound obtained in referential example 304 in the same manner as in example 5.

¹H-NMR(DMSO-d₆)δ：1.50-1.60(1H，m)，1.70-1.85(3H，m)，1.95-2.05(1H，m)，2.10-2.20(1H，m)，2.80(3H，s)，2.90-3.90(5H，m)，2.93(3H，s)，2.96(3H，s)，4.10-4.75(4H，m)，7.75-7.85(1H，m)，8.00-8.05(1H，m)，8.30-8.35(1H，m)，8.61(1H，s)，8.93(2H，d，J＝7.3Hz)，9.31(1H，s).

MS(FAB)m/z：539(M+H)⁺.

[ 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 (220mg) obtained in referential example 252 was dissolved in methanol (10ml), and 10% palladium on carbon (180mg) was added to stir at room temperature for 4 hours in a hydrogen atmosphere. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (30ml), and the compound (108mg) obtained in referential example 306, 1-hydroxybenzotriazole 1 hydrate (78mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (196mg) were added to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added to the residue to separate the mixture, followed by drying the organic layer over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 100: 3) to obtain a pale yellow foamy substance. The resulting foamy substance was dissolved in methylene chloride (2ml), and 1N ethanol hydrochloride solution (363. mu.l) was added thereto. After the solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated precipitate was collected by filtration to obtain the title compound (175 mg).

¹H-NMR(DMSO-d₆)δ：1.40-1.52(1H，m)，1.55-1.96(5H，m)，2.78(3H，s)，2.90(3H，s)，2.98(3H，s)，3.01-3.12(1H，m)，3.13-3.28(2H，m)，3.40-3.85(2H，m)，3.92-4.00(1H，m)，4.35-4.80(3H，m)，4.84(1H，d，J＝14.5Hz)，4.89(1H，d，J＝14.5Hz)，6.92(1H，s)，6.98(1H，dd，J＝8.1，1.7Hz)，7.08(1H，s)，7.17(1H，d，J＝8.3Hz)，8.12(1H，d，J＝8.1Hz)，8.34(1H，d，J＝8.1Hz).

MS(FAB)m/z：558(M+H)⁺.

[ example 224] N- { (1R, 2S, 5S) -2- { [ (E) -3- (4-chlorophenyl) -2-acryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 307 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.35-1.55(1H，m)，1.55-1.90(4H，m)，2.79(3H，s)，2.92(3H，s)，2.99(3H，s)，3.05-3.30(3H，m)，3.40-3.55(1H，m)，3.60-3.75(1H，m)，3.93-4.03(2H，m)，4.35-4.50(1H，m)，4.50-4.60(1H，m)，4.60-4.75(1H，m)，6.65(1H，d，J＝15.7Hz)，7.35(1H，d，J＝15.7Hz)，7.44(1H，d，J＝8.6Hz)，7.55(1H，d，J＝8.6Hz)，8.03(1H，d，J＝8.1Hz)，8.34(1H，br.s)，11.25-11.70(1H，br).

MS(ESI)m/z：530(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in referential example 253 and the compound obtained in referential example 309 in the same manner as in example 5.

¹H-NMR(DMSO-d₆)δ：1.43-1.60(1H，m)，1.65-2.10(3H，m)，2.79(3H，s)，2.92(3H，s)，2.99(3H，s)，3.05-3.20(2H，m)，3.20-3.80(5H，m)，4.08-4.20(1H，m)，4.35-4.50(1H，m)，4.60-4.70(1H，m)，4.70(1H，d，J＝15.6Hz)，6.77(1H，br.s)，7.73(1H，d，J＝8.9Hz)，7.94(1H，d，J＝8.9Hz)，7.97(1H，d，J＝2.2Hz)，8.54(1H，br.s)，8.80-9.00(1H，m)，11.18-11.42(1H，br)，11.70-12.50(1H，br).

MS(ESI)m/z：571(M+H)⁺.

[ example 226] Tert-butyl 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-carboxylate

1) The compound (1.46g) obtained in referential example 310 was dissolved in methylene chloride (10ml), and an ethanol solution (10ml) of hydrochloric acid was added thereto at room temperature and stirred for 1 hour. After completion of the reaction, the solvent was distilled off, ethanol was added to the reaction mixture, the mixture was concentrated, isopropyl ether was added to the residue, and the mixture was solidified and filtered to obtain N- { (1S, 2R, 4S) -2-amino-4- [ (dimethylamino) carbonyl ] cyclohexyl } -5-chloroindole-2-carboxamide hydrochloride.

2) This hydrochloride was dissolved in N, N-dimethylformamide (5ml) at room temperature, and the compound (1.31mg) obtained in referential example 406, 1-hydroxybenzotriazole 1 hydrate (640mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.36g) were added to stir at room temperature for 3 days. The reaction mixture was concentrated, dichloromethane and a saturated aqueous sodium bicarbonate solution were added to separate the reaction mixture, and then 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: dichloromethane ═ 1: 19) to obtain the title compound (1.22 g).

¹H-NMR(CDCl₃)δ：1.53(9H，s)，1.70-2.40(6H，m)，2.80-3.20(7H，m)，4.15-4.25(1H，m)，4.55-4.80(5H，m)，6.83(1H，d，J＝1.5Hz)，7.20(1H，dd，J＝8.8，2.0Hz)，7.33(1H，d，J＝8.8Hz)，7.40-7.50(1H，m)，7.61(1H，br.s)，7.72-7.80(1H，m)，9.41(1H，br.s).

MS(ESI)m/z：615(M+H)⁺.

[ 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 (1.22g) obtained in example 226 was dissolved in methylene chloride (5ml), and an ethanol solution (10ml) of hydrochloric acid was added thereto at room temperature and stirred for 1 hour. After the reaction mixture was concentrated, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to separate the reaction mixture, 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: dichloromethane ═ 1: 9) to obtain the free base of the title compound (636mg) as a colorless glassy solid. The free base (200mg) was dissolved in 1N ethanol hydrochloride solution (1ml), concentrated and then ethyl acetate was added to solidify, and the resulting colorless powder was filtered off and dried to obtain the title compound (195 mg).

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.70-1.90(3H，m)，1.90-2.05(2H，m)，2.80(3H，s)，2.98(3H，s)，2.98-3.15(1H，m)，4.05-4.20(1H，m)，4.44(2H，br.s)，4.58(3H，br.s)，7.05(1H，d，J＝1.5Hz)，7.16(1H，dd，J＝8.7，1.8Hz)，7.42(1H，d，J＝8.7Hz)，7.68(1H，d，J＝1.8Hz)，8.38(1H，d，J＝7.8Hz)，8.42(1H，d，J＝7.8Hz)，10.45-10.65(2H，br)，11.78(1H，br.s).

MS(FAB)m/z：515(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 227 and formalin by the same method as in example 18.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.65-1.90(3H，m)，1.90-2.05(2H，m)，2.80(3H，s)，2.98(3H，s)，2.98-3.06(1H，m)，3.06(3H，s)，4.05-4.20(1H，m)，4.30-5.00(5H，br.s)，7.04(1H，d，J＝1.7Hz)，7.17(1H，dd，J＝8.8，2.1Hz)，7.41(1H，d，J＝8.8Hz)，7.68(1H，d，J＝2.1Hz)，8.36(1H，d，J＝7.8Hz)，8.42(1H，d，J＝8.1Hz)，11.78(1H，br.s)，12.14(1H，br.s).

MS(FAB)m/z：529(M+H)⁺.

[ example 229] tert-butyl 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-carboxylate

The title compound was obtained from the compound obtained in referential example 311 and the compound obtained in referential example 406 in the same manner as in example 226.

¹H-NMR(CDCl₃)δ：1.53(9H，s)，1.60-2.40(6H，m)，2.80-3.20(7H，m)，4.15-4.25(1H，m)，4.55-4.80(5H，m)，6.84-6.87(1H，m)，7.01(1H，dt，J＝2.4，9.1Hz)，7.25-7.30(1H，m)，7.34(1H，dd，J＝9.1，4.3Hz)，7.42-7.49(1H，m)，7.70-7.80(1H，m)，9.37-9.45(1H，m).

MS(ESI)m/z：599(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 229 by the same method as in example 227.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.65-1.90(3H，m)，1.90-2.10(2H，m)，2.80(3H，s)，2.97(3H，s)，2.98-3.15(1H，m)，4.05-4.20(1H，m)，4.35-4.50(2H，m)，4.58(3H，br.s)，6.97-7.10(2H，m)，7.35-7.47(2H，m)，8.34(1H，d，J＝7.8Hz)，8.41(1H，d，J＝8.1Hz)，10.53(2H，br.s)，11.68(1H，br.s).

MS(FAB)m/z：499(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 230 and formalin by the same method as in example 18.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.65-1.90(3H，m)，1.90-2.10(2H，m)，2.80(3H，s)，2.90-3.20(7H，m)，4.05-4.20(1H，m)，4.30-5.00(5H，br.s)，6.95-7.10(2H，m)，7.35-7.50(2H，m)，8.33(1H，d，J＝7.6Hz)，8.41(1H，d，J＝8.1Hz)，11.67(1H，br.s)，12.37(1H，br.s).

MS(FAB)m/z：513(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in referential example 294 and the compound obtained in referential example 293 in the same manner as in example 226.

¹H-NMR(DMSO-d₆)δ：1.48-1.56(1H，m)，1.71-1.84(3H，m)，1.95-2.04(2H，m)，2.81(3H，s)，3.00(3H，s)，3.02(3H，s)，3.06-3.15(2H，m)，4.13-4.14(1H，m)，4.52-4.63(4H，m)，7.60(1H，d，J＝8.5Hz)，7.87(1H，d，J＝8.8Hz)，7.96(1H，d，J＝8.5Hz)，8.01(1H，d，J＝8.8Hz)，8.10(1H，s)，8.32(1H，s)，8.45(1H，d，J＝8.1Hz)，8.51(1H，d，J＝7.3Hz).

MS(FAB)m/z：540(M+H)⁺.

[ 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 (330mg) obtained in referential example 299 in dioxane (3.0ml) -dichloromethane (3.0ml) was added a 4N dioxane solution (3.0ml) of hydrochloric acid, and the mixture was 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 (5.0ml), and the compound (172mg) obtained in referential example 293, 1-hydroxybenzotriazole 1 hydrate (130mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (192mg) were added to stir at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and methylene chloride and a saturated aqueous sodium hydrogencarbonate solution were added to the residue. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 20: 1). To a solution of the obtained highly polar main product in ethanol (4.0ml), 1N ethanol hydrochloride solution (0.35ml) was added, and the solvent was distilled off under reduced pressure. Ethanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to give 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).

¹H-NMR(DMSO-d₆)δ：1.50-1.65(1H，m)，1.70-1.90(3H，m)，2.03-2.12(1H，m)，2.15-2.30(1H，m)，2.81(3H，s)，2.90-3.05(1H，m)，2.96(3H，s)，3.07(3H，s)，4.28-4.37(1H，m)，4.40-4.95(5H，br)，8.02(1H，d，J＝8.8Hz)，8.38(1H，d，J＝8.8Hz)，8.66(1H，s)，8.91(1H，s)，8.97(1H，d，J＝7.1Hz)，9.43-9.57(1H，br)，11.75-11.95(0.5H，br)，12.35-12.55(0.5H，br).

MS(FAB)m/z：542(M+H)⁺.

Further, 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 (98mg) was obtained as a low-polarity by-product by purification by silica gel column chromatography.

¹H-NMR(CDCl₃)δ：1.90-2.25(6H，m)，2.85-3.00(1H，m)，2.95(3H，s)，3.05(3H，s)，3.91(3H，s)，4.43-4.54(1H，m)，4.86-4.95(1H，m)，6.70(1H，d，J＝1.5Hz)，7.19(1H，d，J＝1.5Hz)，7.59(1H，d，J＝8.8Hz)，7.76(1H，d，J＝8.8Hz)，7.95(1H，d，J＝8.8Hz)，8.53(1H，s)，8.64(1H，d，J＝8.0Hz)，8.73(1H，s).

MS(FAB)m/z：540(M+H)⁺.

[ 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 (500mg) obtained in referential example 146 was dissolved in an ethanol solution (5ml) of hydrochloric acid, and stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in N, N-dimethylformamide (7ml), and the compound (299mg) obtained in referential example 293, 1-hydroxybenzotriazole 1 hydrate (71mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (403mg) were added to stir at room temperature overnight. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate and methylene chloride were added to the residue to separate a liquid, and then the aqueous layer was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 93: 7) to obtain the free base of the title compound (260mg) as a pale yellow solid. This solid was dissolved in methylene chloride, a 1N ethanol hydrochloride solution (961. mu.l) was added, and the solvent was distilled off under reduced pressure. To the residue was added a small amount of methanol, and 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).

¹H-NMR(DMSO-d₆)δ：1.47-1.56(1H，m)，1.71-1.75(3H，m)，1.95-1.99(1H，m)，2.12-2.15(1H，m)，2.78(3H，s)，2.95(3H，s)，2.98(1H，br.s)，3.05(3H，s)，4.19-4.22(1H，m)，4.44-4.52(3H，m)，4.74-4.88(2H，m)，7.87(1H，dd，J＝8.8，1.7Hz)，8.24(1H，d，J＝8.8Hz)，8.36(1H，d，J＝1.7Hz)，8.58(1H，s)，8.90-8.92(2H，m)，9.30(1H，s)，12.65-12.75(1H，m).

MS(FAB)m/z：541(M+H)⁺.

[ 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

The compound (95.4mg) obtained in referential example 316 was dissolved in diethyl ether (1ml) under an argon atmosphere, and tert-butyllithium (1.60N in pentane, 244. mu.l) was added dropwise at-78 ℃. After stirring at-78 ℃ for 1 hour, carbon dioxide gas was introduced over 10 minutes. After warming to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (5ml), and the compound (178mg) obtained in referential example 432, 1-hydroxybenzotriazole 1 hydrate (48.0mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (136mg) were successively added to stir at room temperature overnight. The reaction mixture was concentrated, and methylene chloride and a saturated aqueous sodium bicarbonate solution were added to separate the reaction mixture. 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 (methanol: dichloromethane ═ 1: 19) to obtain the title compound (140 mg).

¹H-NMR(CDCl₃)δ：1.50(9H，s)，1.52(3H，s)，1.54(3H，s)，1.70-2.10(4H，m)，2.15-2.45(2H，m)，2.80-3.20(9H，m)，4.10-4.25(1H，br)，4.60-4.75(3H，m)，6.85(1H，br.s)，7.21(1H，dd，J＝8.8，1.8Hz)，7.34(1H，d，J＝8.8Hz)，7.48(1H，d，J＝7.3Hz)，7.61-7.63(1H，m)，7.89(1H，br.s)，9.27(1H，br.s).

MS(ESI)m/z：657(M+H)⁺.

[ 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 the same method as in example 227.

¹H-NMR(DMSO-d₆)δ：1.40(6H，s)，1.45-1.60(1H，m)，1.70-2.05(5H，m)，2.81(3H，s)，2.95-3.15(6H，m)，4.05-4.20(1H，br)，4.25-4.45(2H，m)，4.55-4.65(1H，m)，7.06(1H，d，J＝1.7Hz)，7.17(1H，dd，J＝8.8，2.0Hz)，7.42(1H，d，J＝8.8Hz)，7.68(1H，d，J＝2.0Hz)，8.34-8.39(2H，m)，9.77(1H，br.s)，9.84(1H，br.s)，11.79(1H，br.s).

MS(ESI)m/z：557(M+H)⁺.

[ 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 (1.27g) obtained in referential example 50 was dissolved in tetrahydrofuran (48ml), and lithium hydroxide (117mg) and water (6.0ml) were added to stir at room temperature for 4.5 hours. The reaction solution was evaporated to dryness under reduced pressure to give a crude lithium carboxylate salt (1.24g), which was then condensed with the compound obtained in referential example 432 in the same manner as in 2) of example 226 to prepare the title compound.

¹H-NMR(CDCl₃)δ：1.50-1.70(1H，m)，1.54(9H，s)，1.80-2.10(3H，m)，2.25-2.50(2H，m)，2.85-2.95(1H，m)，2.99(3H，s)，3.14(3H，s)，4.15-4.25(1H，m)，4.65-4.75(1H，m)，4.80-4.90(4H，m)，6.97(1H，s)，7.15-7.25(1H，m)，7.30-7.40(1H，m)，7.60-7.65(1H，m)，8.15-8.25(1H，m)，8.40-8.45(1H，m)，8.75-8.85(1H，m)，9.40-9.45(1H，m).

MS(ESI)m/z：611(M+H)⁺.

[ 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 (367mg) obtained in example 237 was dissolved in dichloromethane (10ml), and trifluoroacetic acid (10ml) was added to stir at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to dryness, and the title compound was obtained from the obtained crude product and formalin by the same method as in example 18.

¹H-NMR(DMSO-d₆)δ：1.50-1.60(1H，m)，1.65-2.10(5H，m)，2.81(3H，s)，2.90-3.00(1H，m)，2.96(3H，s)，3.05(3H，s)，4.10-4.20(1H，m)，4.55-4.65(1H，m)，4.65-4.90(4H，br)，7.06(1H，s)，7.15(1H，dd，J＝8.7，2.1Hz)，7.41(1H，d，J＝8.8Hz)，7.66(1H，d，J＝1.7Hz)，8.35-8.45(1H，m)，8.57(1H，d，J＝8.1Hz)，9.00(1H，s)，11.80(1H，s)，11.90-12.20(1H，m).

MS(FAB)m/z：524(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 146 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 322 in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.50-1.60(1H，m)，1.70-1.90(3H，m)，1.90-2.15(2H，m)，2.81(3H，s)，2.95(3H，s)，2.90-3.05(1H，m)，3.26(3H，s)，4.20-4.55(2H，m)，5.00(2H，s)，7.91(1H，d，J＝8.8Hz)，8.27(1H，d，J＝8.8Hz)，8.37(1H，s)，8.54(1H，s)，8.62(1H，s)，8.79(1H，d，J＝8.3Hz)，8.94(1H，d，J＝8.1Hz)，9.32(1H，s).

MS(ESI)m/z：554(M+H)⁺

[ 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

The title compound was obtained from the compound obtained in referential example 325 and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(DMSO-d₆) δ: 0.98, 1.04(3H, 7.1Hz per t, J), 1.52-1.60(1H, m), 1.74-1.77(3H, m), 1.96-2.05(1H, m), 2.15-2.18(1H, m), 2.77-2.93(8H, m), 3.17-3.32(3H, m), 3.49(1H, br.s), 4.22(1H, br.s), 4.41-4.45(1H, m), 4.51(1H, br.s), 4.69-4.72(1H, m), 7.89(1H, d, J ═ 8.7Hz), 8.26(1H, d, J ═ 8.7Hz), 8.37(1H, s), 8.60(1H, s), 8.91-8.98(2H, m), 9.32(1H, d, J ═ 6.6Hz), 11.39, 11.53(1H, m each).

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

The title compound was obtained from the compound obtained in referential example 336 and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.13-1.22(1H，m)，1.40-1.46(1H，m)，1.68-1.99(5H，m)，2.18-2.29(2H，m)，2.80(3H，s)，2.92(3H，s)，2.96(3H，s)，3.22(2H，br.s)，3.49(1H，br.s)，3.70(1H，br.s)，4.09-4.16(1H，m)，4.42-4.46(2H，m)，4.67(1H，br.s)，7.03(1H，s)，7.16(1H，dd，J＝8.5，1.5Hz)，7.42(1H，d，J＝8.5Hz)，7.67(1H，s)，8.01(1H，d，J＝8.5Hz)，8.40(1H，d，J＝7.8Hz)，11.35-11.58(1H，m)，11.76(1H，br.s).

MS(FAB)m/z：557(M+H)⁺.

[ 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 title compound was obtained by treating the compound obtained in referential example 340 with a hydrochloric acid ethanol solution and then condensing it with the compound obtained in referential example 10 in the same manner as in example 219.

¹H-NMR(DMSO-d⁶)δ：1.35-1.40(1H，m)，1.55-1.62(1H，m)，1.70-1.76(1H，m)，1.88-1.94(1H，m)，2.03-2.07(1H，m)，2.13-2.17(1H，m)，2.30-2.33(1H，m)，2.43-3.48(10H，m)，3.60-3.73(2H，m)，4.11-4.16(1H，m)，4.40-4.42(2H，m)，4.68-4.73(1H，m)，7.05(1H，s)，7.16(1H，dd，J＝2.0，8.8Hz)，7.41(1H，d，J＝8.8Hz)，7.68(1H，s)，8.26(1H，d，J＝7.8Hz)，8.39(1H，d，J＝7.8Hz)，11.78(1H，br.s).

MS(ESI)m/z：564(M+H)⁺.

[ 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 title compound was obtained by catalytically reducing the compound obtained in referential example 252 and then condensing it with the compound obtained in referential example 345 in the same manner as in example 223.

¹H-NMR(CDCl₃)δ：1.56-1.66(1H，m)，1.76-1.93(2H，m)，2.02-2.06(1H，m)，2.19-2.26(1H，m)，2.30-2.34(1H，m)，2.52(3H，s)，2.79-2.88(3H，m)，2.91-2.94(2H，m)，2.96(3H，s)，3.09(3H，s)，3.69-3.77(2H，m)，4.13-4.19(1H，m)，4.58-4.61(1H，m)，6.72(1H，s)，6.84(1H，s)，7.50(1H，d，J＝7.3Hz)，7.60(1H，d，J＝5.8Hz)，10.54(1H，br).

MS(ESI)m/z：549(M+H)⁺.

[ example 244] N- { (1R, 2S, 5S) -2- { [3- (4-chlorophenyl) -2-propynoyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by catalytically reducing the compound obtained in referential example 252 and then condensing it with the compound obtained in referential example 347 in the same manner as in example 223.

¹H-NMR(DMSO-d₆)δ：1.38-1.50(1H，m)，1.58-1.92(4H，m)，2.78(3H，s)，2.90(3H，s)，2.97(3H，s)，3.01-3.24(3H，m)，3.26-3.80(2H，m)，3.90-3.98(1H，m)，4.30-4.78(3H，m)，7.51(1H，d，J＝8.8Hz)，7.57(1H，d，J＝8.8Hz)，8.34(1H，d，J＝8.8Hz)，8.83(1H，d，J＝7.8Hz).

MS(FAB)m/z：528(M+H)⁺.

[ 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 title compound was obtained by catalytically reducing the compound obtained in referential example 252 and then condensing the reduced product with the compound obtained in referential example 349 in the same manner as in example 223.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.70-1.90(3H，m)，1.90-2.20(3H，m)，2.80(3H，s)，2.93(3H，s)，2.97(3H，s)，2.98-3.80(4H，m)，4.05-4.20(2H，m)，4.35-4.80(3H，m)，7.63(1H，d，J＝8.3Hz)，7.90(1H，d，J＝7.3Hz)，8.75-9.00(2H，m)，11.00-11.50(1H，br)，12.53(1H，br.s).

MS(ESI)m/z：573(M+H)⁺.

[ example 246] N- { (1R, 2S, 5S) -2- { [2- (4-Chloroanilino) -2-oxothioacetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

The compound (184mg) obtained in referential example 253 and the compound (150mg) obtained in referential example 351 were dissolved in methanol (1ml) -dichloromethane (4ml), and the mixture was heated under stirring at 150 ℃ to distill off the solvent, followed by heating for further 5 minutes. After the mixture was cooled naturally, the product was purified by silica gel column chromatography (dichloromethane: methanol: 24: 1) to obtain the title compound (59 mg).

¹H-NMR(CDCl₃)δ：1.65-1.90(2H，m)，1.90-2.00(1H，m)，2.00-2.15(2H，m)，2.20-2.30(1H，m)，2.52(3H，s)，2.75-2.95(5H，m)，2.96(3H，s)，3.07(3H，s)，3.68(1H，d，J＝15.2Hz)，3.75(1H，d，J＝15.7Hz)，4.45-4，60(1H，m)，4.80-4.85(1H，m)，7.31(2H，d，J＝8.8Hz)，7.44(1H，d，J＝8.6Hz)，7.60(2H，d，J＝8.8Hz)，9.99(1H，d，J＝7.6Hz)，10.15(1H，s).

MS(ESI)m/z：563(M+H)⁺.

[ example 247] N- { (1R, 2S, 5S) -2- { [2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

The compound (184mg) obtained in referential example 253 and the compound (150mg) obtained in referential example 353 were dissolved in methanol (0.3ml) -dichloromethane (0.3ml), and the mixture was heated under stirring at 150 ℃ to distill off the solvent, followed by heating for further 5 minutes. After the mixture was cooled naturally, the product was purified by silica gel column chromatography (dichloromethane: methanol: 24: 1) to obtain the title compound (52 mg).

¹H-NMR(CDCl₃)δ：1.60-2.00(3H，m)，2.00-2.20(2H，m)，2.25-2.40(1H，m)，2.53(3H，s)，2.80-2.95(5H，m)，2.96(3H，s)，3.08(3H，s)，3.70(1H，d，J＝15.4Hz)，3.75(1H，d，J＝15.4Hz)，4.45-4，60(1H，m)，4.75-4.85(1H，m)，7.45(1H，d，J＝8.3Hz)，7.67(1H，dd，J＝8.8，2.5Hz)，8.18(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.0Hz)，10.06(1H，d，J＝6.3Hz)，10.56(1H，s).

MS(ESI)m/z：564(M+H)⁺.

[ example 248] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-thioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

The compound (72mg) obtained in referential example 355 and 2-amino-5-chloropyridine (100mg) were dissolved in methanol (0.2ml) -dichloromethane (0.2ml), and the mixture was stirred with heating at 150 ℃ and, after the solvent was distilled off, heated for 8 minutes. After natural cooling, the product was purified by preparative silica gel thin layer chromatography (dichloromethane: methanol 23: 2) to obtain the title compound (4 mg).

¹H-NMR(CDCl₃)δ：1.60-2.00(3H，m)，2.00-2.20(3H，m)，2.53(3H，s)，2.75-3.00(5H，m)，2.95(3H，s)，3.05(3H，s)，3.65-3.80(2H，m)，4.05-4.15(1H，m)，4.70-4.80(1H，m)，7.28(1H，d)，7.43(1H，d，J＝9.3Hz)，7.75(1H，dd，J＝8.8，2.7Hz)，8.41(1H，d，J＝2.7Hz)，9.05(1H，d，J＝8.8Hz)，11.56(1H，s).

MS(ESI)m/z：564(M+H)⁺.

[ example 249]N¹- (5-chloro-2-thienyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 356, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.40-1.55(1H，m)，1.60-1.85(3H，m)，1.90-2.15(2H，m)，2.79(3H，s)，2.90-3.15(1H，m)，2.92(3H，s)，2.94(3H，s)，3.15-3.30(2H，m)，3.50-3.80(2H，m)，3.95-4.05(1H，m)，4.35-4.90(3H，m)，6.90(1H，d，J＝4.2Hz)，6.94(1H，d，J＝4.2Hz)，8.72(1H，d，J＝7.3Hz)，9.13(1H，br.s)，11.21(1H，br.s)，12.32(1H，br.s).

MS(ESI)m/z：553(M+H)⁺.

[ 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

To a dichloromethane (2ml) solution of the compound (183mg) obtained in referential example 253 was added 4-chlorophenyl isocyanate (76.8mg), which was then stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20: 1 → 10: 1), and the solvent was distilled off. The residue was dissolved in ethanol (2ml) and methylene chloride (2ml), and a 1N ethanol hydrochloride solution (0.4ml) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (160 mg).

¹H-NMR(DMSO-d₆) δ: 1.35-1.50(1H, m), 1.60-1.90(5H, m), 2.79(3H, s), 2.92(3H, s), 3.00(3H, s), 3.10-3.60(4H, m), 3.60-3.90(2H, m), 4.35-4.80(3H, m), 6.26(1H, br.s), 7.23(2H, d, J ═ 9.0Hz), 7.37(2H, d, J ═ 9.0Hz), 8.53(1H, br.s), 8.72(1H, br.s), 11.35, 11.67 (all 1H, s each).

MS(ESI)m/z：519(M+H)⁺.

Example 251]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c) ]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (5-fluoropyridin-2-yl) ethanediamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 357, condensing the product with the compound obtained in referential example 253 and then treating the product with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.47-1.53(1H，m)，1.68-1.75(3H，m)，1.99-2.10(2H，m)，2.80(3H，s)，2.80-3.00(1H，m)，2.95(6H，s)，3.18-3.21(2H，m)，3.40-3.80(2H，m)，3.87-4.82(4H，m)，7.82-7.85(1H，m)，8.01-8.05(1H，m)，8.40(1H，d，J＝2.9Hz)，8.71(1H，d，J＝7.7Hz)，9.13(1H，d，J＝7.3Hz)，10.27(1H，s).

MS(FAB)m/z：532(M+H)⁺.

EXAMPLE 252]N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained from the compound obtained in referential example 242 and the compound obtained in referential example 272 in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.47-1.51(1H，m)，1.69-1.75(3H，m)，1.98-2.05(2H，m)，2.80(3H，s)，2.95(3H，s)，2.98-3.04(1H，m)，3.10(3H，s)，3.40-4.61(6H，m)，7.41(2H，d，J＝8.8Hz)，7.81(2H，d，J＝8.8Hz)，8.76(1H，d，J＝7.6Hz)，8.95(1H，d，J＝8.3Hz)，10.79(1H，s).

MS(FAB)m/z：533(M+H)⁺.

Example 253]N¹- [ 4-chloro-2- (trifluoromethyl) phenyl group]-N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

Thionyl chloride (1ml) was added to a chloroform solution (10ml) of the compound (269mg) obtained in referential example 359, and the mixture was stirred at 75 ℃ for 30 minutes, the solvent was distilled off under reduced pressure and dried. A dichloromethane solution (7ml) of the compound (286mg) obtained in referential example 253 and pyridine (3ml) were added thereto under ice cooling, and the mixture was stirred for 2 hours while warming to room temperature. After a saturated aqueous solution (10ml) of sodium hydrogencarbonate was added to the reaction mixture to conduct a liquid separation operation, the obtained organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 20: 1) and LH-20 column chromatography (molecular sieve, methanol) to obtain the free base (90mg) of the title compound as a pale yellow amorphous solid. To this were added dichloromethane (5ml), ethanol (5ml) and 1N ethanol hydrochloride solution (1ml), and distillation under reduced pressure was carried out to dryness to obtain the title compound.

¹H-NMR(DMSO-d₆)δ：1.41-1.55(1H，m)，1.59-1.80(3H，m)，1.98-2.13(2H，m)，2.77(3H，s)，2.91(6H，s)，3.12-3.26(2H，m)，3.30-3.58(2H，m)，3.60-3.78(1H，m)，3.94-4.04(1H，m)，4.35-4.63(2H，m)，4.64-4.80(1H，m)，7.73-7.82(2H，m)，7.85(1H，s)，8.68-8.73(1H，m)，9.18(1H，br.s)，10.31(1H，s).

MS(ESI)m/z：615(M+H)⁺.

Example 254]N¹- { 4-chloro-2- [ (dimethylamino) carbonyl group]Phenyl } -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 362, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.42-1.56(1H，m)，1.59-1.82(3H，m)，1.98-2.14(2H，m)，2.79(3H，s)，2.91(3H，s)，2.93(3H，s)，2.95(3H，s)，2.98(3H，s)，3.10-3.30(4H，m)，3.62-3.79(1H，m)，3.92-4.01(1H，m)，4.34-4.50(2H，m)，4.66-4.79(1H，m)，7.52(1H，d，J＝2.4Hz)，7.55(1H，dd，J＝2.4，8.5Hz)，8.05(1H，d，J＝8.5Hz)，8.75(1H，br)，9.10-9.24(1H，m)，10.52(1H，s).

MS(ESI)m/z：618(M+H)⁺.

[ example 255]N¹- [ 4-chloro-2- (hydroxymethyl) phenyl group]-N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 270 with 4-chloro-2-hydroxymethylaniline and then treating with hydrochloric acid in the same manner as in example 199.

¹H-NMR(DMSO-d₆)δ：1.42-1.57(1H，m)，1.58-1.81(3H，m)，1.98-2.14(2H，m)，2.79(3H，s)，2.93(6H，s)，3.12-3.58(4H，m)，3.67-3.80(1H，m)，3.94-4.04(1H，m)，4.37-4.50(1.5H，m)，4.55(2H，s)，4.67-4.80(1H，m)，5.77-5.92(0.5H，m)，7.37(1H，dd，J＝2.4，8.6Hz)，7.42(1H，d，J＝2.4Hz)，7.91(1H，d，J＝8.6Hz)，8.74-8.81(1H，m)，9.03-9.19(1H，m)，10.79(1H，s).

MS(ESI)m/z：577(M+H)⁺.

Example 256]N¹- (4-chloro-2-methoxyphenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 364, condensing it with the compound obtained in referential example 253 and then treating it with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.40-1.55(1H，m)，1.58-1.79(3H，m)，1.94-2.11(2H，m)，2.77(3H，s)，2.92(6H，s)，3.05-3.55(4H，m)，3.65-3.75(1H，br)，3.90(3H，s)，3.91-4.00(1H，m)，4.36-4.47(2H，br)，4.65-4.77(1H，br)，7.04(1H，dd，J＝8.5，2.0Hz)，7.20(1H，d，J＝2.0Hz)，8.06(1H，d，J＝8.5Hz)，8.65-8.80(1H，br)，9.10-9.25(1H，br)，9.74(1H，s)，11.10-11.35(1H，br).

MS(ESI)m/z：577(M+H)⁺.

[ 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

The title compound was obtained by deprotecting the compound obtained in referential example 366 by hydrochloric acid treatment, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.41-1.53(1H，m)，1.57-1.77(3H，m)，1.88-2.04(2H，m)，2.77(3H，s)，2.91(6H，s)，3.00-3.60(4H，m)，3.65-3.74(1H，br)，3.87-3.96(1H，m)，4.37-4.48(2H，m)，4.66-4.76(1H，m)，6.70(2H，d，J＝8.8Hz)，7.04(1H，d，J＝8.8Hz)，7.10(1H，d，J＝8.8Hz)，8.40-8.53(2H，m)，8.57-8.66(1H，m)，10.30-10.47(1H，br)，10.66-10.76(1H，br).

MS(ESI)m/z：562(M+H)⁺.

[ example 258]N¹- (4-chlorophenyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamide hydrochloride

The title compound was obtained by deprotecting the compound obtained in referential example 367 by hydrochloric acid treatment, condensing the deprotected compound with the compound obtained in referential example 10 and then treating the product with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.60-1.72(1H，m)，1.99-2.22(1H，m)，2.90(3H，s)，3.03-4.80(17H，m)，7.40(2H，d，J＝8.8Hz)，7.83(2H，d，J＝8.8Hz)，8.56-8.73(1H，br)，9.14-9.33(1H，br)，10.83(1H，s)，11.20-11.55(1H，br).

MS(ESI)m/z：549(M+H)⁺.

[ example 259]N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamide hydrochloride

The title compound was obtained by deprotecting the compound obtained in referential example 368 by treatment with hydrochloric acid, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.60-1.72(1H，m)，1.98-2.20(1H，m)，2.90(3H，s)，3.00-4.77(17H，m)，7.20-7.35(0.8H，br)，7.48-7.56(0.2H，br)，7.94-8.07(1H，br)，8.40-8.70(1H，br)，8.48-8.70(1H，br)，9.23-9.45(1H，br)，10.21-10.35(1H，br)，11.30-11.70(1H，br).

MS(ESI)m/z：550(M+H)⁺.

[ example 260]N¹- (5-bromopyridin-2-yl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamide hydrochloride

The title compound was obtained by deprotecting the compound obtained in referential example 369 by hydrochloric acid treatment, condensing the deprotected compound with the compound obtained in referential example 10 and then treating the product with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.60-1.73(1H，m)，1.97-2.20(1H，m)，2.90(3H，s)，3.03-3.52(7H，m)，3.64-4.07(5H，m)，4.10-4.50(4H，m)，4.65-4.78(1H，m)，7.28-7.35(0.2H，m)，7.97(1H，d，J＝8.8Hz)，8.11(1H，dd，J＝8.8，2.2Hz)，8.51(1H，d，J＝2.2Hz)，8.55-8.67(1H，m)，9.22-9.41(1H，m)，10.20-10.31(0.8H，m)，11.25-11.70(1H，br).

MS(ESI)m/z：594(M+H)⁺.

EXAMPLE 261]N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } ringHexyl) malonamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 371 with the compound obtained in referential example 253 and then treating with hydrochloric acid in the same manner as in example 5.

¹H-NMR(DMSO-d₆)δ：1.32-1.50(1H，m)，1.55-1.87(5H，m)，2.78(3H，m)，2.92(3H，s)，2.98(3H，s)，2.99-3.00(1H，m)，3.05-3.50(5H，m)，3.65-3.75(1H，m)，3.80-3.92(1H，m)，4.35-4.45(1H，m)，4.45-4.55(1H，m)，4.65-4.80(1H，m)，7.34(2H，d，J＝8.8Hz)，7.58(2H，d，J＝8.8Hz)，8.00-8.10(1H，m)，8.30-8.40(1H，m)，10.29(1H，d，J＝12.5Hz)，12.40(1H，br.s)

MS(FAB)m/z：561(M+H)⁺.

EXAMPLE 262]N¹- (3-chlorophenyl) -N³- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) malonamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 373 and the compound obtained in referential example 253 and then treating them with hydrochloric acid in the same manner as in example 5.

¹H-NMR(DMSO-d₆)δ：1.32-1.50(1H，m)，1.55-1.90(5H，m)，2.77(3H，s)，2.91(3H，s)，2.98(3H，s)，2.99-3.00(1H，m)，3.05-3.50(5H，m)，3.65-3.80(1H，m)，3.80-3.90(1H，m)，4.35-4.50(1H，m)，4.50-4.60(1H，m)，4.65-4.80(1H，m)，7.09(1H，d，J＝8.8Hz)，7.31(1H，d，J＝8.8Hz)，7.38(1H，t，J＝8.8Hz)，7.79(1H，s)，8.00-8.10(1H，m)，8.30-8.40(1H，m)，10.28(1H，d，J＝12.5Hz)，11.67(1H，br.s).

MS(FAB)m/z：561(M+H)⁺.

[ example 263]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

10% Palladium on carbon (0.3g) was added to an ethanol (20ml) solution of the compound (0.33g) obtained in referential example 404, and the mixture was stirred for 24 hours under a hydrogen atmosphere. Insoluble matter was filtered off through celite, and the filtrate was concentrated under reduced pressure. The resulting residue (0.37g) was dissolved in N, N-dimethylformamide (20ml), and the compound (0.3g) obtained in referential example 266, 1-hydroxybenzotriazole 1 hydrate (0.2g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.37g) were successively added at room temperature and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with a mixed solvent of chloroform-methanol (9: 1) and washed with a saturated aqueous sodium bicarbonate solution and a saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol: 95: 5), and the target fraction was concentrated. To the obtained residue was added 1N ethanol hydrochloride solution to form a hydrochloride, and then the mixture was recrystallized from a mixed solvent of methanol and ether to obtain the title compound (0.28 g).

¹H-NMR(DMSO-d₆)δ：0.95(1.5H，t，J＝6.9Hz)，1.42(1.5H，t，J＝6.9Hz)，1.40-1.52(1H，m)，1.60-1.78(3H，m)，1.92-2.11(2H，m)，2.74(3H，s)，2.90(3H，s)，3.10-3.38(5H，m)，3.40-3.52(1H，m)，3.68-3.70(1H，m)，3.96-4.05(1H，m)，4.41(2H，s)，4.70(1H，d，J＝15.9Hz)，8.00-8.01(2H，m)，8.44(1H，s)，8.71(1H，dd，J＝10.1，2.2Hz)，9.14(0.5H，d，J＝7.8Hz)，9.22(0.5H，d，J＝8.3Hz)，10.24(0.5H，s)，10.28(0.5H，s)，11.48(1H，br.s)，11.61(1H，br.s).

MS(FAB)m/z：562(M+H)⁺.

Example 264]N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by converting the compound obtained in referential example 404 into an amine, condensing it with the compound obtained in referential example 374 and treating it with hydrochloric acid in the same manner as in example 263.

¹H-NMR(DMSO-d₆)δ：0.97(1.5H，t，J＝6.9Hz)，1.04(1.5H，t，J＝6.9Hz)，1.40-1.60(1H，m)，1.60-1.80(3H，m)，1.92-2.11(2H，m)，2.74(3H，s)，2.89(3H，s)，3.10-3.32(5H，m)，3.40-3.52(1H，m)，3.65-3.80(1H，m)，3.90-4.05(1H，m)，4.40(2H，s)，4.70(1H，d，J＝15.9Hz)，7.39(2H，d，J＝8.8Hz)，7.82(2H，d，J＝8.8Hz)，8.75(1H，dd，J＝10.1，2.2Hz)，9.00(0.5H，d，J＝7.8Hz)，9.08(0.5H，d，J＝8.3Hz)，10.81(1H，d，J＝4.9Hz)，11.45(1H，br.s).

MS(FAB)m/z：561(M+H)⁺.

[ example 265]N¹- (5-bromopyridin-2-yl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by converting the compound obtained in referential example 404 into an amine, condensing it with the compound obtained in referential example 375 and then treating it with hydrochloric acid in the same manner as in example 263.

¹H-NMR(DMSO-d₆)δ：1.02(1.5H，t，J＝6.9Hz)，1.08(1.5H，t，J＝6.9Hz)，1.49-1.60(1H，m)，1.60-1.86(3H，m)，2.00-2.20(2H，m)，2.81(3H，s)，2.97(3H，s)，3.15-3.42(6H，m)，3.50-3.60(1H，m)，3.70-3.82(1H，m)，4.48(2H，s)，4.77(1H，d，J＝15.9Hz)，8.04(1H，d，J＝8.8Hz)，8.17(1H，d，J＝8.8Hz)，8.58(1H，s)，8.78(1H，dd，J＝10.1，2.2Hz)，9.21(0.5H，d，J＝7.8Hz)，9.29(0.5H，d，J＝8.3Hz)，10.29(0.5H，s)，10.33(0.5H，s)，11.53(0.5H，br.s)，11.65(0.5H，br.s).

MS(FAB)m/z：607(M+H)⁺.

Example 266]N¹- (4-chloro-3-fluorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by converting the compound obtained in referential example 252 into an amine, condensing the amine with the compound obtained in referential example 378 and then treating the resulting product with hydrochloric acid in the same manner as in example 263.

¹H-NMR(DMSO-d₆)δ：1.44-1.52(1H，m)，1.65-1.76(3H，m)，2.01-2.07(2H，m)，2.77(3H，s)，2.93(6H，s)，2.94-3.00(1H，m)，3.10-3.38(3H，m)，3.68-3.70(1H，m)，3.96-4.05(1H，m)，4.42(2H，s)，4.70(1H，d，J＝15.9Hz)，7.56(1H，t，J＝8.8Hz)，7.68(1H，d，J＝8.8Hz)，7.90(1H，dd，J＝11.7，1.5Hz)，8.73(1H，dd，J＝12.5，7.3Hz)，9.06(1H，dd，J＝12.5，8.1Hz)，11.01(1H，d，J＝5.8Hz)，11.30-11.42(1H，m).

MS(FAB)m/z：565(M+H)⁺.

[ 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

The title compound was obtained by deprotecting the compound obtained in referential example 383 by treatment with hydrochloric acid in the same manner as in example 214, then condensing the deprotected compound with the compound obtained in referential example 10 and then treating the product with hydrochloric acid.

¹H-NMR(CDCl₃) (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 ═ 8.3Hz), 7.87(2H, d, J ═ 8.3Hz).

MS(FAB)m/z：546(M+H)⁺.

[ example 268]N¹- (5-chloropyridin-2-yl) -N²- ((1R, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-5H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

The title compound was obtained by deprotecting the compound obtained in referential example 386 by hydrochloric acid treatment and then condensing the same with the compound obtained in referential example 293 in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.00-2.35(7H，m)，2.96(3H，s)，3.04(3H，s)，3.85-3.95(1H，m)，3.88(3H，s)，4.60-4.75(1H，m)，6.68(1H，d，J＝2.0Hz)，7.17(1H，d，J＝2.0Hz)，7.20-7.32(1H，m)，7.67(1H，dd，J＝8.8，2.8Hz)，7.99(1H，d，J＝8.4Hz)，8.21(1H，d，J＝8.8Hz)，8.25(1H，d，J＝2.8Hz)，9.64(1H，s).

HRMS(FAB)m/z：532.1520(M+H)⁺.

(calculated value; C)₂₃H₂₇ClN₇O₄S：532.1534)

[ example 269]N¹- [ (5-Chloropyridin-2-yl) amino]-N²- ((1R, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by reducing the compound obtained in referential example 387 in the same manner as in referential example 253, condensing the compound with the compound obtained in referential example 266 and treating the condensation product with hydrochloric acid in the same manner as in example 208.

¹H-NMR(DMSO-d₆)δ：1.50-1.98(6H，m)，2.82(3H，s)，2.91(3H，s)，2.95(3H，s)，2.86-3.92(7H，m)，4.30-4.81(2H，m)，7.92-8.09(2H，m)，8.39-8.47(1H，m)，8.56-8.72(2H，m)，10.17(1H，s).

MS(ESI)m/z：548(M+H)⁺.

Example 270]N¹- (4-chlorophenyl) -N²- ((1R, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

The title compound was obtained by reducing the compound obtained in referential example 387 in the same manner as in referential example 253, condensing a lithium salt formed by hydrolyzing the compound obtained in referential example 242 in the same manner as in example 191, and treating the condensed product with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.50-1.97(6H，m)，2.82(3H，s)，2.91(3H，s)，2.98(3H，s)，2.83-3.88(7H，m)，4.30-4.79(2H，m)，7.37(2H，d，J＝8.8Hz)，7.89(2H，d，J＝8.8Hz)，8.34(1H，d，J＝8.4Hz)，8.63(1H，d，J＝8.8Hz)，10.72(1H，s).

MS(ESI)m/z：547(M+H)⁺.

[ example 271]N¹- { (1R, 2R, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (pyridin-4-yl) ethanediamide hydrochloride

The title compound was obtained by deprotecting the compound obtained in referential example 310 by hydrochloric acid treatment, condensing lithium 2- [ (pyridin-4-yl) amino ] -2-oxoacetate hydrolyzed from the compound obtained in referential example 261 in the same manner as in example 191, and then treating with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.40-2.01(6H，m)，2.79(3H，s)，3.01(3H，s)，3.00-3.18(1H，m)，4.02-4.19(1H，m)，4.45-4.55(1H，m)，7.09(1H，s)，7.13-7.22(1H，m)，7.41(1H，d，J＝8.4Hz)，7.64(1H，br.s)，8.28(2H，d，J＝6.8Hz)，8.36(1H，d，J＝8.0Hz)，8.62(1H，d，J＝8.8Hz)，8.72(2H，d，J＝6.8Hz)，11.74(1H，s)，11.83(1H，s).

MS(FAB)m/z：511(M+H)⁺.

EXAMPLE 272]N¹- { (1R, 2R, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (pyridin-3-yl) ethanediamide hydrochloride

The title compound was obtained by condensing 3-aminopyridine with methyl 2-chloro-2-oxoacetate in the same manner as described in reference example 242, and using the obtained methyl 2- [ (pyridin-3-yl) amino ] -2-oxoacetate and the compound obtained in reference example 310 as starting materials in the same manner as in example 271.

¹H-NMR(DMSO-d₆)δ：1.40-2.05(6H，m)，2.80(3H，s)，3.02(3H，s)，2.92-3.15(1H，m)，4.02-4.17(1H，m)，4.42-4.58(1H，m)，7.10(1H，s)，7.12-7.19(1H，m)，7.40(1H，d，J＝8.4Hz)，7.62-7.87(2H，m)，8.36-8.64(4H，m)，9.18(1H，s)，11.39(1H，s)，11.79(1H，s).

MS(FAB)m/z：511(M+H)⁺.

[ example 273]N¹- { (1R, 2S, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (piperidin-4-yl) ethanediamide hydrochloride

To a solution of the compound (400mg) obtained in referential example 389 in ethanol (5.0ml) was added a 4N dioxane hydrochloride solution (8.0ml) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The solvent was distilled off under reduced pressure, and after washing with methylene chloride, insoluble matter was washed by filtration to obtain the title compound (320 mg).

¹H-NMR(DMSO-d₆)δ：1.38-1.92(10H，m)，2.77(3H，s)，2.96(3H，s)，2.82-3.35(6H，m)，3.88-4.10(2H，m)，4.34-4.43(1H，m)，7.05(1H，s)，7.11-7.17(1H，m)，7.38(1H，d，J＝8.8Hz)，7.65(1H，s)，8.25(1H，d，J＝8.0Hz)，8.34(1H，d，J＝7.6Hz)，8.89(1H，d，J＝8.4Hz)，11.75(1H，s).

MS(ESI)m/z：517(M+H)⁺.

[ example 274]N¹- { (1R, 2R, 5S) -2- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -5- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (1-methylpiperidin-4-yl) ethanediamide hydrochloride

The title compound was obtained by methylating the compound obtained in example 273 and then treating it with hydrochloric acid in the same manner as described in reference example 9.

¹H-NMR(DMSO-d₆)δ：1.40-2.01(11H，m)，2.67(3H，s)，2.79(3H，s)，2.98(3H，s)，2.85-4.48(7H，m)，7.07(1H，s)，7.16(1H，dd，J＝8.8，2.0Hz)，7.40(1H，d，J＝8.8Hz)，7.68(1H，d，J＝2.0Hz)，8.25-8.35(1H，m)，8.37(1H，d，J＝7.6Hz)，8.90-9.02(1H，m)，9.82(1H，br.s)，11.78(1H，s).

MS(ESI)m/z：531(M+H)⁺.

Example 275]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N¹-methylglyoxal hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 390, condensing the hydrolyzed compound with the compound obtained in referential example 253 and then treating the condensed product with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.32-1.97(6H，m)，2.42-2.51(1H，m)，2.76(3H，s)，2.91(3H，s)，2.93(3H，s)，3.27(3H，s)，3.00-4.80(8H，m)，7.45(1H，br.s)，7.88-7.97(1H，m)，8.25-8.41(2H，m)，8.78-8.91(1H，m).

MS(FAB)m/z：562(M+H)⁺.

Example 276]N¹- (5-chloropyrimidin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 391, condensing with the compound obtained in referential example 253 and then treating with hydrochloric acid in the same manner as in example 191.

¹H-NMR(DMSO-d₆)δ：1.38-2.10(7H，m)，2.77(3H，s)，2.90(3H，s)，2.93(3H，s)，3.04-4.80(8H，m)，8.60-8.70(2H，m)，8.82(2H，s)，9.08(1H，br.s)，10.64(1H，s)，11.57(1H，br.s).

MS(FAB)m/z：549(M+H)⁺.

Example 277]N¹- (4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by reducing the compound obtained in referential example 392 in the same manner as in referential example 253, and condensing the resulting product with a carboxylic acid obtained by hydrolyzing the compound obtained in referential example 242 and treating the resulting product with hydrochloric acid in the same manner as in example 195.

¹H-NMR(DMSO-d₆) δ: 0.96, 1.02(3H, 7.0Hz per t, J), 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, J8.8 Hz), 7.83(2H, d, J8.8 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 ]]N¹- (5-bromopyridin-2-yl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained from the compound obtained in referential example 392 and the compound obtained in referential example 262 in the same manner as in example 277.

¹H-NMR(DMSO-d₆)δ：0.90-1.08(3H，m)，1.40-2.13(6H，m)，2.70-3.53(13H，m)，3.92-4.08(1H，m)，4.35-4.47(1H，m)，7.95(1H，d，J＝8.8Hz)，8.10(1H，dd，J＝8.8，2.4Hz)，8.50-8.55(1H，m)，8.68-8.78(1H，m)，9.12-9.18(1H，m)，10.26(1H，s).

MS(FAB)m/z：592(M+H)⁺.

[ example 279]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- { [ Ethyl (methyl) amino group]Carbonyl } -2- { [ (5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained from the compound obtained in referential example 392 and the compound obtained in referential example 243 in the same manner as in example 277.

¹H-NMR(DMSO-d₆)δ：[0.95(t，J＝7.0Hz)，1.01(t，J＝6.8Hz)，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]N¹- (4-chloro-3-methoxyphenyl) -N ²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 395 with the compound obtained in referential example 10 and then treating the condensation product with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.46-1.54(1H，m)，1.67-1.77(3H，m)，2.01-2.10(2H，m)，2.79(3H，s)，2.92-2.98(7H，m)，3.21(2H，br.s)，3.49(1H，br.s)，3.69(1H，br.s)，3.80(3H，s)，3.98-4.03(1H，m)，4.42-4.50(2H，m)，4.69(1H，br.s)，7.37(1H，d，J＝8.7Hz)，7.48(1H，dd，J＝8.7，2.2Hz)，7.72(1H，d，J＝2.2Hz)，8.75(1H，d，J＝7.3Hz)，9.06(1H，br.s)，10.77(1H，s)，11.44(1H，br.s).

MS(FAB)m/z：577(M+H)⁺.

Example 281]N¹- (4-chlorophenyl) -N²-((1R^*，2R^*) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclopentyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 242, condensing with the compound obtained in referential example 62 and treating with hydrochloric acid in the same manner as in example 195.

₁H-NMR(DMSO-d₆)δ：1.65-1.73(4H，m)，1.91-1.96(2H，m)，2.91(3H，s)，3.15(2H，br.s)，3.49(1H，br.s)，3.66(1H，br.s)，4.32-4.42(3H，m)，4.66(1H，br.s)，7.40(2H，d，J＝8.9Hz)，7.84(2H，d，J＝8.9Hz)，8.92(1H，d，J＝8.5Hz)，9.03(1H，d，J＝8.3Hz)，10.76(1H，s)，11.32(1H，br.s).

MS(FAB)m/z：462(M+H)⁺.

EXAMPLE 282]N¹- (5-chloropyridin-2-yl) -N²-((1R^*，2R^*) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclopentyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 62 with the compound obtained in referential example 266 and then treating the condensation product with hydrochloric acid in the same manner as in example 208.

¹H-NMR(DMSO-d₆)δ：1.71(4H，br.s)，1.96(2H，br.s)，2.90(3H，s)，3.14(1H，br.s)，3.21(1H，br.s)，3.47(1H，br.s)，3.68(1H，br.s)，4.34-4.45(3H，m)，4.66(1H，br.s)，7.99-8.06(2H，m)，8.43-8.44(1H，m)，8.94(1H，d，J＝8.3Hz)，9.20(1H，d，J＝8.5Hz)，10.20(1H，br.s)，11.78(1.1H，br.s).

MS(FAB)m/z：463(M+H)⁺.

[ example 283]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c) ]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (4-ethynylphenyl) ethanediamide

The title compound was obtained by condensing the compound obtained in referential example 252 with the compound obtained in referential example 397 in the same manner as in example 263.

¹H-NMR(CDCl₃) δ: 1.67-2.16(6H, m), 2.51(3H, s), 2.76-2.91(5H, m), 2.94(3H, s), 3.04(3H, s), 3.07(1H, s), [3.65(1H, d, J ═ 15.5Hz), 3.73(1H, d, J ═ 15.5Hz) type AB]，4.09-4.16(1H，m)，4.72-4.75(1H，m)，7.42-7.46(3H，m)，7.58(2H，d，J＝8.5Hz)，8.02(1H，d，J＝8.1Hz)，9.36(1H，s).

MS(FAB)m/z：537(M+H)⁺.

Example 284]N¹- (5-chloropyrazin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 253 with the compound obtained in referential example 399 and then treating the condensation product with hydrochloric acid in the same manner as in referential example 97.

¹H-NMR(DMSO-d₆)δ：1.44-1.52(1H，m)，1.65-1.77(3H，m)，2.00-2.10(2H，m)，2.77(3H，s)，2.91-2.97(7H，m)，3.20(2H，br.s)，3.48(1H，br.s)，3.68(1H，br.s)，3.97-4.02(1H，m)，4.40-4.46(2H，m)，4.68(1H，br.s)，8.64(1H，d，J＝1.2Hz)，8.70(1H，d，J＝7.3Hz)，9.02(1H，s)，9.21(1H，br.s)，10.91(1H，br.s)，11.50(1H，br.s).

MS(FAB)m/z：549(M+H)⁺.

Example 285]N¹- (4-chloro-3-nitrophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 253 with the compound obtained in referential example 400 and then treating the condensation product with hydrochloric acid in the same manner as in referential example 97.

¹H-NMR(DMSO-d₆)δ：1.44-1.53(1H，m)，1.66-1.73(3H，m)，1.97-2.07(2H，m)，2.77(3H，s)，2.89-3.05(7H，m)，3.20(2H，br.s)，3.55(2H，br.s)，4.00(1H，br.s)，4.44(1H，br.s)，4.52(2H，br.s)，7.75(1H，d，J＝8.8Hz)，8.08(1H，d，J＝8.8Hz)，8.59(1H，s)，8.71(1H，d，J＝7.3Hz)，9.07(1H，d，J＝8.0Hz)，11.24(1H，s)，11.58(1H，br.s).

MS(FAB)m/z：592(M+H)⁺.

EXAMPLE 286]N¹- (4-chloro-2-nitrophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 253 with the compound obtained in referential example 401 and then treating the condensation product with hydrochloric acid in the same manner as in example 208.

¹H-NMR(DMSO-d₆)δ：1.46-1.54(1H，m)，1.66-1.77(3H，m)，2.03-2.10(2H，m)，2.79(3H，s)，2.90-2.93(7H，m)，3.17-3.28(2H，m)，3.49(1H，br.s)，3.68(1H，br.s)，3.99-4.04(1H，m)，4.41(1H，br.s)，4.46(1H，br.s)，4.68(1H，br.s)，7.89(1H，d，J＝9.0Hz)，8.20-8.21(2H，m)，8.73(1H，d，J＝6.4Hz)，9.28(1H，br.s)，11.49(1H，br.s)，11.56(1H，s).

MS(FAB)m/z：592(M+H)⁺.

[ example 287]N¹- (3-amino-4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The compound (236mg) obtained in example 285 was dissolved in ethanol (25ml), and a catalytic amount of raney nickel was added to stir at room temperature for 17 hours in a hydrogen atmosphere. Then, a catalytic amount of raney nickel was added thereto and stirred for another 7 hours. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 23: 2) to obtain a pale yellow solid (101 mg). This was dissolved in methylene chloride, and 1N ethanol hydrochloride solution (360. mu.l) 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 with ultrasonic waves. The resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (95 mg).

¹H-NMR(DMSO-d₆) δ: 1.45-1.53(1H, m), 1.66-1.73(3H, m), 1.97-2.10(2H, m), 2.78(3H, s), 2.91-2.94(7H, br.s), 3.11-3.19(1H, m), 3.29(1H, br.s), 3.48(1H, br.s), 3.69(1H, br.s), 3.95-4.02(1H, m), 4.44(2H, br.s), 4.68, 4.72(1H, br.s), 4.86(2.5H, br.s), 6.98(1H, dd, J ═ 8.5, 1.9Hz), 7.14(1H, d, J ═ 8.5Hz), 7.35, 7.38H, 1.38H, 1.77H, 8.7J ═ 8.5Hz, 8.9 Hz, 7.14(1H, 8.5Hz), 8.7.7.8H, 8.7.7.7H, 8J ═ 8.5Hz, 8.7.7.7.7.8, 8, 8.7.8, 8]10.45, 10.47(1H, br.s each), 11.74(1H, br.s).

MS(FAB)m/z：562(M+H)⁺.

EXAMPLE 288]N¹- (2-amino-4-chlorophenyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) group) Carbonyl radical]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained from the compound obtained in example 286 in the same manner as in the method described in example 287.

¹H-NMR(DMSO-d₆) δ: 1.45-1.77(4H, m), 2.06-2.09(2H, m), 2.78(3H, s), 2.92(7H, br.s), 3.12-3.19(1H, m), 3.26-3.28(1H, m), 3.48(1H, br.s), 3.70(1H, br.s), 4.00-4.44(5.7H, m), 4.70, 4.74(1H, each br.s), 6.63-6.66(1H, m), 6.85(1H, br.s), 7.18-7.21(1H, m), 8.77-8.81(1H, m), [8.97(d, J ═ 7.8Hz), 9.06(d, J ═ 8.1Hz), 1H ═ 8.1Hz, 1H, 1Hz, 1H ═ 1H, m), 1H ═ 3.7.7.7, m, 4.6. ]，9.98(1H，s)，11.60(1H，br.s).

MS(FAB)m/z：562(M+H)⁺.

Example 289]N¹- (6-chloro-4-methylpyridin-3-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 270 and the compound obtained in referential example 402 and then treating them with hydrochloric acid in the same manner as in example 199.

¹H-NMR(DMSO-d₆)δ：1.45-1.54(1H，m)，1.65-1.77(3H，m)，2.02-2.08(2H，m)，2.22(3H，s)，2.79(3H，s)，2.89-2.93(7H，m)，3.19(2H，br.s)，3.54(2H，br.s)，3.99-4.04(1H，m)，4.40-4.42(1H，m)，4.50(2H，br.s)，7.49(1H，s)，8.32(1H，s)，8.75(1H，d，J＝7.1Hz)，9.09(1H，d，J＝7.3Hz)，10.48(1H，s)，11.40(0.9H，br.s).

MS(FAB)m/z：562(M+H)⁺.

[ 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 tetrahydrofuran (10ml) solution of the compound (700mg) obtained in referential example 252 was added 10% palladium on carbon (200mg), and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere of 1 atm, then filtered, the filtrate was concentrated, and to an N, N-dimethylformamide (5.0ml) solution of the amine obtained was added the compound (470mg) obtained in referential example 405, and the mixture was stirred at 95 ℃ for 18 hours. The reaction mixture was concentrated, and a saturated aqueous sodium hydrogencarbonate solution (50ml), water (50ml) and methylene chloride (30ml) were added to separate the solution, and the aqueous layer was extracted with methylene chloride (2X 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol 12: 1), followed by treatment with 1N hydrochloric acid to obtain the title compound (100 mg).

¹H-NMR(DMSO-d₆)δ：1.40-1.60(1H，m)，1.65-2.05(5H，m)，2.80(3H，s)，2.91(3H，s)，2.99(3H，s)，3.00-3.20(2H，m)，3.20-3.32(1H，m)，3.43(1H，br.s)，3.69(1H，br.s)，3.95(1H，br.s)，4.45(1H，br.s)，4.60-4.80(2H，m)，7.68(2H，d，J＝8.7Hz)，7.83(2H，d，J＝8.7Hz)，8.41(1H，br.s)，8.68(1H，d，J＝7.6Hz)，11.40-11.80(1H，br).

MS(ESI)m/z：532(M+H)⁺.

[ 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

The title compound was obtained by stirring at 40 ℃ for 3 days under the reaction conditions described in example 290.

¹H-NMR(DMSO-d₆)δ：1.30-1.50(1H，m)，1.50-1.80(3H，m)，1.80-1.97(2H，m)，2.76(3H，s)，2.80-3.05(2H，m)，2.91(6H，s)，3.05-3.30(2H，m)，3.47(2H，br.s)，4.30-4.50(2H，m)，4.72(1H，t，J＝12.8Hz)，6.40-6.60(2H，m)，6.55-6.70(2H，m)，6.95-7.20(2H，m)，7.88(1H，d，J＝11.3Hz)，8.48-8.65(1H，m)，11.48-11.80(1H，br).

MS(ESI)m/z：534(M+H)⁺.

EXAMPLE 292]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 34 and the compound obtained in referential example 420 and then treating them with hydrochloric acid in the same manner as in example 17.

¹H-NMR(DMSO-d₆)δ：1.45-1.55(1H，m)，1.60-1.80(3H，m)，1.95-2.10(2H，m)，2.78(3H，s)，2.85-3.00(4H，m)，3.11(2H，br s)，3.40-3.55(2H，m)，3.95-4.07(1H，m)，4.37-4.45(1H，m)，4.48(2H，br s)，8.00-8.01(2H，m)，8.10(1H，d，J＝7.1Hz)，8.43-8.47(1H，m)，9.16(1H，d，J＝7.8Hz)，9.43(2H，br s)，10.27(1H，s).

MS(FAB)m/z：534(M+H)⁺.

[ example 293]N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (1-hydroxycyclopropyl) carbonyl]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 compound obtained in example 118 with 1-hydroxy-1-cyclopropanecarboxylic acid and then treating with hydrochloric acid in the same manner as in example 150.

¹H-NMR(DMSO-d₆)δ：0.60-0.90(3H，br)，0.92-1.03(1H，m)，1.71-1.84(1H，m)，1.85-2.03(1H，m)，2.91(3H，s)，3.00-3.80(7H，m)，4.05-4.80(5H，m)，6.28-6.42(1H，br)，7.09(1H，s)，7.18(1H，dd，J＝8.8，1.5Hz)，7.42(1H，d，J＝8.8Hz)，7.70(1H，d，J＝1.5Hz)，8.14-8.29(1H，br)，8.41(1H，brd，J＝7.6Hz)，11.83(1H，s).

MS(ESI)m/z：557(M+H)⁺.

[ example 294]N-{(3R^*，4S^*) -4- { [ (5-Chloroindol-2-yl) carbonyl]Amino } -1- [ (1-methoxycyclopropyl) carbonyl ]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 compound obtained in example 118 and the compound obtained in reference example 409 and then treating with hydrochloric acid in the same manner as in example 150.

¹H-NMR(DMSO-d₆)δ：0.65-1.05(4H，m)，1.74-1.88(1H，m)，1.92-2.10(1H，m)，2.91(3H，s)，3.00-3.80(10H，m)，4.05-4.83(6H，m)，7.08(1H，s)，7.18(1H，dd，J＝8.6，2.0Hz)，7.42(1H，d，J＝8.6Hz)，7.71(1H，d，J＝2.0Hz)，8.08-8.30(1H，br)，8.41(1H，br d，J＝7.8Hz)，10.60-10.80(0.5H，br)，10.85-11.05(0.5H，br)，11.84(1H，s).

[ 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

The title compound was obtained by treating the compound obtained in referential example 410 with a 4N dioxane hydrochloride solution for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.60-1.80(1H，m)，2.13-2.38(1H，m)，2.90(3H，s)，3.00-3.87(10H，m)，3.89-4.10(2H，m)，4.15-4.58(4H，m)，4.60-4.78(1H，m)，7.89(1H，d，J＝8.8Hz)，8.25(1H，d，J＝8.8Hz)，8.37(1H，s)，8.61(1H，s)，8.70-8.95(1H，m)，9.05-9.29(1H，m)，9.36(1H，s)，11.20-11.40(0.5H，br)，11.45-11.65(0.5H，br).

MS(ESI)m/z：557(M+H)⁺.

[ example 296 ]]N¹- (4-chloro-3-fluorophenyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 411 with a 4N dioxane hydrochloride solution for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.60-1.72(1H，m)，1.98-2.21(1H，m)，2.91(3H，s)，3.00-3.52(9H，m)，3.56-4.05(3H，m)，4.08-4.50(4H，m)，4.60-4.78(1H，br)，7.56(1H，t，J＝8.8Hz)，7.70(1H，d，J＝9.0Hz)，7.91(1H，dd，J＝8.8，2.3Hz)，8.50-8.72(1H，m)，9.15-9.35(1H，m)，11.02(1H，s)，11.15-11.33(0.5H，br)，11.35-11.50(0.5H，br).

MS(FAB)m/z：567(M+H)⁺.

[ example 297]N¹- (5-chloro-2-ethynyl) -N²- ((3R, 4S) -1- (2-methoxyacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 412 with a 4N dioxane hydrochloride solution for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.60-1.73(1H，m)，1.96-2.19(1H，m)，2.91(3H，s)，3.04-3.54(9H，m)，3.60-4.05(3H，m)，4.07-4.34(3H，m)，4.35-4.54(1H，br)，4.60-4.80(1H，br)，6.89(1H，d，J＝4.2Hz)，6.93(1H，d，J＝4.2Hz)，8.48-8.70(1H，m)，9.18-9.40(1H，m)，12.31(1H，s).

MS(ESI)m/z：555(M+H)⁺.

[ 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

The title compound was obtained by reducing the compound obtained in referential example 252, condensing it with p-chlorophenoxyacetic acid and then treating it with hydrochloric acid in the same manner as in example 223.

¹H-NMR(DMSO-d₆)δ：1.35-1.47(1H，m)，1.55-1.90(5H，m)，2.77(3H，s)，2.92(3H，s)，2.96(3H，s)，2.98-3.10(1H，m)，3.10-3.80(3H，m)，3.85-3.95(1H，m)，4.35-4.50(4H，m)，4.50-4.80(1H，br)，6.85(2H，d，J＝8.5Hz)，7.15-7.35(1H，br)，7.88-8.03(1H，br)，8.46(1H，d，J＝8.8Hz)，11.30-11.65(1H，br).

MS(FAB)m/z：534(M+H)⁺.

[ example 299] 7-chloro-N- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl ] -2- { [ (5-methyl-5H-pyrrolo [3, 4-d ] thiazol-2-yl) carbonyl ] amino } cyclohexyl) -3-isoquinolinecarboxamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 413, condensing a lithium salt of the obtained carboxylic acid with the deprotected compound obtained by acid treatment of the compound obtained in referential example 146, and then treating with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.00-1.11(2H，m)，1.45-1.60(1H，m)，1.65-1.85(1H，m)，1.95-2.06(1H，m)，2.10-2.24(1H，m)，2.78(3H，s)，2.87-3.02(1H，m)，2.94(3H，s)，3.88(3H，s)，4.16-4.27(1H，m)，4.45-4.56(1H，m)，7.03(1H，s)，7.55(1H，s)，7.87(1H，br d，J＝8.3Hz)，8.24(1H，br d，J＝8.8Hz)，8.33(1H，s)，8.59(1H，s)，8.85(1H，br d，J＝7.6Hz)，9.01(1H，br d，J＝7.8Hz)，9.28(1H，s).

MS(ESI)m/z：539(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 417 with a 4N dioxane hydrochloride solution, condensing the resulting compound with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.40-1.53(1H，m)，1.67-2.04(5H，m)，2.40-2.53(1H，m)，2.80(3H，s)，2.92(3H，s)，3.01(3H，s)，3.09-3.22(3H，m)，3.66-3.77(1H，m)，4.01-4.10(1H，m)，4.34-4.49(1H，m)，4.58-4.76(2H，m)，6.80(1H，d，J＝4.9Hz)，7.59-7.70(1H，m)，7.90-8.00(1H，m)，7.96(1H，s)，8.52-8.60(1H，m)，8.80-8.90(1H，m)，11.10-11.25(0.5H，br)，11.40-11.55(0.5H，br).

MS(ESI)m/z：572(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 418 with a 4N dioxane hydrochloride solution, condensing the resulting compound with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.70-1.80(1H，m)，1.85-2.05(1H，m)，2.90(3H，s)，3.00-3.20(2H，m)，3.16(3H，s)，3.22-3.82(7H，m)，3.88-4.80(5H，m)，7.09(1H，d，J＝9.0Hz)，7.17(1H，dd，J＝8.8，1.9Hz)，7.42(1H，d，J＝8.8Hz)，7.70(1H，d，J＝1.9Hz)，8.29(1H，br s)，8.40-8.50(1H，m)，11.20-11.50(1H，br m)，11.85(1H，s).

MS(ESI)m/z：558(M+H)⁺.

Example 302]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothieno [3, 2-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by deprotecting the compound obtained in referential example 421 with hydrochloric acid, methylating it in the same manner as in example 18 and then treating it with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.42-1.58(1H，m)，1.59-1.80(3H，m)，1.83-1.95(1H，m)，1.97-2.10(1H，m)，2.78(3H，s)，2.89(3H，s)，2.96(3H，s)，3.00-3.10(1H，m)，3.10-3.20(2H，m)，3.45-3.80(1H，m)，3.90-4.00(2H，m)，4.00-4.50(3H，m)，7.77(1H，s)，7.95-8.05(3H，m)，8.44(1H，t，J＝1.6Hz)，8.90(1H，d，＝8.6Hz)，10.25(1H，s)，11.12(1H，br s).

MS(ESI)m/z：547(M+H)⁺.

EXAMPLE 303]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-isopropyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 148 and the compound obtained in referential example 420 and then treating the condensed product with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.30-1.40(6H，m)，1.38-1.58(1H，m)，1.59-1.82(3H，m)，1.95-2.13(2H，m)，2.40-2.65(1H，m)，2.49(3H，s)，2.87-3.55(4H，m)，2.49(3H，s)，3.60-3.82(2H，m)，3.93-4.04(1H，m)，4.37-4.55(2H，m)，4.55-4.72(1H，m)，7.94-8.10(2H，m)，8.43(1H，s)，8.64-8.77(1H，m)，9.12(1/2H，d，J＝7.8Hz)，9.24(1/2H，d，J＝7.8Hz)，10.22(1/2H，s)，10.26(1/2H，s)，11.25(1/2H，brs)，11.44(1/2H，br s).

MS(FAB)m/z：578(M+H)⁺.

[ example 304] N- ((1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- { [2- (4-fluoroanilino) -2-oxothioacetyl ] amino } cyclohexyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 424 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.60-1.80(3H，m)，2.00-2.10(1H，m)，2.20-2.35(1H，m)，2.79(3H，s)，2.93(3H，s)，2.95(3H，s)，2.95-3.10(1H，m)，3.10-3.30(2H，m)，3.40-3.60(1H，m)，3.60-3.80(1H，m)，4.35-4.50(1H，m)，4.50-4.60(1H，m)，4.60-4.80(2H，m)，7.20(2H，t，J＝8.8Hz)，7.77(2H，dd，J＝9.0，5.1Hz)，8.80(1H，br)，10.42(1H，s)，10.93(1H，br)，11.28(1H，br).

MS(ESI)m/z：547(M+H)⁺.

EXAMPLE 305N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 427 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.43-1.57(1H，m)，1.64-1.87(3H，m)，2.00(1H，br s)，2.17-2.34(1H，m)，2.78(3H，s)，2.90(3H，s)，2.95(3H，s)，2.95-3.10(1H，m)，3.10-3.30(2H，m)，3.40-3.60(1H，m)，3.68(1H，br s)，4.44(1H，br s)，4.45-4.56(1H，m)，4.60-4.73(2H，m)，7.80-7.90(1H，m)，8.08(1H，dd，J＝9.1，3.9Hz)，8.41(1H，d，J＝2.9Hz)，8.79(1H，d，J＝6.6Hz)，10.49(1H，s)，11.07(1H，brs)，11.69(1H，br).

MS(ESI)m/z：548(M+H)⁺.

[ example 306] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-5H-pyrrolo [3, 4-d ] thiazole-2-carboxamide

The title compound was obtained by deprotecting the compound obtained in referential example 428 by treatment with hydrochloric acid and then condensing it with the compound obtained in referential example 293 in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.45-1.58(1H，m)，1.63-1.73(2H，m)，1.73-1.87(2H，m)，2.00-2.10(1H，m)，2.20-2.35(1H，m)，2.79(3H，s)，2.95(3H，s)，2.96-3.10(1H，m)，3.89(3H，s)，4.48-4.58(1H，m)，4.60-4.70(1H，m)，7.05(1H，d，J＝1.7Hz)，7.55(1H，d，J＝1.7Hz)，8.00(1H，dd，J＝8.9，2.4Hz)，8.05(1H，d，J＝8.9Hz)，8.44(1H，d，J＝2.4Hz)，8.71(1H，d，J＝7.3Hz)，10.57(1H，s)，11.13(1H，d，J＝7.8Hz).

MS(FAB)m/z：548(M+H)⁺.

[ example 307] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 428 with hydrochloric acid for deprotection, condensing it with the compound obtained in referential example 293 under an argon atmosphere, and treating it with hydrochloric acid in the same manner as described in example 219.

¹H-NMR(DMSO-d₆)δ：1.42-1.58(1H，m)，1.65-1.87(3H，m)，1.97-2.10(1H，m)，2.17-2.30(1H，m)，2.80(3H，s)，2.96(3H，s)，2.98-3.10(1H，m)，3.07(3H，s)，4.30-5.00(6H，m)，8.00-8.10(1H，m)，8.46(1H，d，J＝2.4Hz)，8.79(1H，t，J＝7.3Hz)，10.54(1H，s)，11.04(1H，d，J＝7.8Hz)，12.24(1H，br s).

MS(ESI)m/z：550(M+H)⁺.

EXAMPLE 308]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- ({ [6- (dimethylamino) -4, 5, 6, 7-tetrahydrobenzothiazol-2-yl]Carbonyl } amino) cyclohexyl]Oxalamides

The title compound was obtained by treating the compound obtained in referential example 431 with hydrochloric acid to deprotect it, methylating it in the same manner as described in example 18, and then treating it with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.42-1.58(1H，m)，1.59-1.80(3H，m)，1.90-2.12(3H，m)，2.30-2.45(1H，m)，2.70-3.00(11H，m)，2.92(3H，s)，3.00-3.20(2H，m)，3.25-3.45(1H，m)，3.63-3.80(1H，m)，3.88-4.02(1H，m)，4.35-4.47(1H，m)，8.02(1H，s)，8.42-8.55(1H，m)，8.60-8.68(1H，m)，8.93(1H，dd，J＝14.5，8.2Hz)，9.19(1H，dd，J＝17.7，8.2Hz)，10.28(1H，s)，10.91(1H，br s).

MS(ESI)m/z：576(M+H)⁺.

[ 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 dichloromethane (10ml) solution of the compound (328.0mg) obtained in referential example 253 was added 4-chlorophenylsulfonyl isocyanate (148. mu.l), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the residue was purified by preparative silica gel thin layer column chromatography (dichloromethane: methanol ═ 9: 1). The resultant was dissolved in ethanol (2ml) and methylene chloride (2ml), and 1N ethanol hydrochloride solution (0.25ml) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was solidified with diethyl ether to obtain the title compound (104.3 mg).

¹H-NMR(DMSO-d₆)δ：1.25-1.45(1H，m)，1.45-1.80(5H，m)，2.76(3H，s)，2.94(3H，s)，2.97(3H，s)，3.00-3.80(6H，m)，4.35-4.85(3H，m)，6.53(1H，brs)，7.66(2H，d，J＝8.5Hz)，7.86(2H，d，J＝8.5Hz)，8.50-8.82(1H，m)，10.64(1H，br s)，11.10-11.80(1H，br).

MS(ESI)m/z：583(M+H)⁺.

Example 310]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

The title compound was obtained from the compound obtained in referential example 435 and the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.60-1.98(3H，m)，2.00-2.16(3H，m)，2.52(3H，s)，2.78-2.90(3H，m)，2.92-2.98(2H，m)，2.95(3H，s)，3.06(3H，s)，3.69(1H，d，J＝15.4Hz)，3.75(1H，d，J＝15.4Hz)，4.07-4.15(1H，m)，4.66-4.72(1H，m)，7.40(1H，d，J＝8.8，0.6Hz)，7.68(1H，dd，J＝8.8，2.4Hz)，8.03(1H，d，J＝7.8Hz)，8.16(1H，dd，J＝8.8，0.6Hz)，8.30(1H，dd，J＝2.4，0.6Hz)，9.72(1H，s).

MS(ESI)m/z：548(M+H)⁺.

[ example 311]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group ]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide p-toluenesulfonate 1 hydrate

6.2g of the compound obtained in example 310 was dissolved in methylene chloride (120ml), a 1mol/L p-toluenesulfonic acid-ethanol solution (11.28ml) was added, and the solvent was distilled off. To the residue was added 15% aqueous ethanol (95ml), and the mixture was dissolved at 60 ℃ with stirring. Then, the mixture was cooled to room temperature and stirred for 1 day. The precipitated crystal was collected by filtration, washed with ethanol, and dried under reduced pressure at room temperature for 2 hours to obtain the title compound (7.4g).

¹H-NMR(DMSO-d₆)δ：1.45-1.54(1H，m)，1.66-1.78(3H，m)，2.03-2.10(2H，m)，2.28(3H，s)，2.79(3H，s)，2.91-3.02(1H，m)，2.93(3H，s)，2.99(3H，s)，3.13-3.24(2H，m)，3.46-3.82(2H，m)，3.98-4.04(1H，m)，4.43-4.80(3H，m)，7.11(2H，d，J＝7.8Hz)，7.46(2H，d，J＝8.2Hz)，8.01(2H，d，J＝1.8Hz)，8.46(1H，t，J＝1.8Hz)，8.75(1H，d，J＝6.9Hz)，9.10-9.28(1H，br)，10.18(1H，br)，10.29(1H，s).

MS(ESI)m/z：548(M+H)⁺

Elemental analysis: c₂₄H₃₀ClN₇O₄S·C₇H₈O₃S·H₂O

Theoretical value: c; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69

Measured value: c; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79

mp (decomposition): 245-248 DEG C

Example 312]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 437 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219. ¹H-NMR(DMSO-d₆)δ：1.48-1.61(1H，m)，1.61-1.74(2H，m)，1.74-1.82(1H，m)，1.98-2.12(2H，m)，2.29-2.38(1H，m)，2.53(3H，d，J＝4.2Hz)，2.92(3H，s)，3.10-3.40(4H，br)，3.40-3.80(1H，br)，3.97-4.05(1H，m)，4.28-4.34(1H，m)，4.34-4.80(1H，br)，7.70-7.78(1H，m)，7.97-8.07(2H，m)，8.43-8.50(1H，m)，8.49(1H，br.s)，9.27(1H，d，J＝7.8Hz)，10.26(1H，br.s)，11.48(1H，br.s).MS(ESI)m/z：534[(M+H)⁺，Cl³⁵]，535[(M+H)⁺，Cl³⁷].

[ example 313]N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-Methoxyacetyl) -3- { [4- (pyridin-4-yl) benzoyl)]Amino-piperidin-4-yl-oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 368 with a 4N dioxane hydrochloride solution for deprotection, condensing with the compound obtained in referential example 237, and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.62-1.75(1H，m)，2.00-2.20(1H，m)，2.80-4.40(11H，m)，7.90-8.00(4H，m)，8.05-8.13(2H，m)，8.14-8.43(3H，m)，8.40-8.45(1H，m)，8.87-9.04(3H，m)，10.20-10.50(2H，br).

MS(FAB)m/z 551[(M+H)⁺，Cl³⁵]，553[(M+H)⁺，Cl³⁷].

[ example 314] N- { (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-methylpyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 440 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.65-1.90(3H，m)，2.00-2.10(1H，m)，2.20-2.40(1H，m)，2.28(3H，s)，2.80(3H，s)，2.91(3H，s)，2.95-3.10(1H，m)，2.96(3H，s)，3.15-3.30(1H，m)，3.32(2H，s)，3.50-3.80(1H，m)，4.45-4.60(2H，m)，4

.60-4.80(2H，m)，7.72(1H，d，J＝8.5Hz)，7.97(1H，d，J＝8.5Hz)，8.23(1H，s)，8.83(1H，d，J＝7.3Hz)，10.38(1H，s)，11.06(1H，d，J＝7.6Hz)，11.49(1H，br.s).

MS(ESI)m/z：544(M+H)⁺.

[ example 315] N- [ (3R, 4S) -4- { [2- (4-Chloroanilino) -2-oxothioacetyl ] 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 by treating the compound obtained in referential example 441 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.71-1.82(1H，m)，2.18-2.44(1H，m)，2.89(3H，s)，3.00-4.85(17H，m)，7.41(2H，d，J＝8.8Hz)，7.77(2H，d，J＝8.8Hz)，8.48-8.73(1H，m)，10.48(1H，br.s)，10.90-11.06(1H，m)，11.45-11.90(1H，br).

MS(ESI)m/z：565[(M+H)⁺，Cl³⁵]，567[(M+H)⁺，Cl³⁷].

Example 316]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) thiocarbonyl)]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 445 and the compound obtained in referential example 10 and then treating them with hydrochloric acid in the same manner as in example 3.

¹H-NMR(DMSO-d₆)δ：1.66-2.15(6H，m)，2.93(3H，s)，3.15-3.40(9H，m)，3.49(1H，br.s)，3.71(1H，br.s)，3.97-4.01(1H，m)，4.42(2H，br.s)，4.70(1H，br.s)，8.01(2H，br.s)，8.46(1H，br.s)，8.78(1H，d，J＝6.8Hz)，9.24(1H，br.s)，10.28(1H，s)，11.29(1H，br.s).

MS(FAB)m/z：564[(M+H)⁺，Cl³⁵]，566[(M+H)⁺，Cl³⁷].

Example 317]N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -1- (2-Methoxythioacetyl) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino-piperidin-4-yl-oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 448 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.74-1.85(1H，m)，2.13-2.35(1H，m)，2.89(3H，s)，2.95-3.98(9H，m)，4.05-5.33(8H，m)，7.95-8.06(2H，m)，8.43(1H，s)，8.48-8.73(1H，br)，9.29-9.45(1H，br)，10.21-10.34(1H，br)，11.45-11.90(1H，br).

MS(ESI)m/z：566[(M+H)⁺，Cl³⁵]，568[(M+H)⁺，Cl³⁷].

[ 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 referential example 453 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 219.

¹H-NMR(CDCl₃)δ：1.60-1.87(2H，m)，2.04-2.15(2H，m)，2.21-2.32(2H，m)，2.52(3H，s)，2.73-2.89(3H，m)，2.92-2.98(2H，m)，3.71(1H，d，J＝15.4Hz)，3.73(1H，d，J＝15.4Hz)，4.08-4.16(1H，m)，4.66-4.71(1H，m)，4.72(1H，d，J＝12.0Hz)，4.82(1H，d，J＝12.0Hz)，7.37(1H，d，J＝8.8Hz)，7.69(1H，dd，J＝8.8，2.4Hz)，8.05(1H，d，J＝8.1Hz)，8.16(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.4Hz)，9.69(1H，s).

MS(ESI)m/z：651[(M+H)⁺，3×Cl³⁵]，653[(M+H)⁺，2×Cl³⁵，Cl³⁷]，655[(M+H)⁺，Cl³⁵，2×Cl³⁷].

[ 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 (475mg) obtained in example 318 was dissolved in tetrahydrofuran (50ml), and to the solution, zinc (2.85g) and acetic acid (5.7ml) were successively added and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added celite 545(2.85g), insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and then methylene chloride was added to the resulting residue, followed by adding a 1N aqueous solution of sodium hydroxide while stirring to adjust the liquid property to pH 7. After the organic layer was separated, saturated brine (50ml) was added to the aqueous layer, followed by extraction with dichloromethane (10X 50 ml). The resulting organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 95: 5 → 9: 1 → 4: 1) to obtain the title compound (140 mg).

¹H-NMR(DMSO-d₆)δ：1.50-1.80(3H，m)，1.84-1.95(1H，m)，1.95-2.10(1H，m)，2.15-2.30(1H，m)，2.38(3H，s)，2.40-2.50(1H，m)，2.67-2.80(2H，m)，2.80-2.95(2H，m)，3.66(2H，m)，4.03(1H，br.s)，4.33(1H，br.s)，7.97-8.10(2H，m)，8.45(1H，s)，8.53(1H，d，J＝6.8Hz)，9.19(1H，d，J＝8.3Hz)，10.27(1H，br.s).

MS(FAB)m/z：521[(M+H)⁺，³⁵Cl]，523[(M+H)⁺，³⁷Cl].

[ 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

The title compound was obtained by hydrolyzing the ester of the compound obtained in referential example 454 in the same manner as in referential example 142, condensing the product with 4-chloroaniline in the same manner as in referential example 143, and treating the product with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.30-1.17(1H，m)，1.50-1.62(1H，m)，1.62-1.75(2H，m)，1.85-2.00(2H，m)，2.76(3H，s)，2.93(6H，br.s)，3.00-3.10(1H，m)，3.18(1H，br.s)，3.27(1H，br.s)，3.49(1H，br.s)，3.71(1H，br.s)，3.76(3H，s)，3.93(1H，br.s)，4.35-4.50(2H，m)，4.66-4.77(1H，m)，6.09(0.5H，d，J＝7.8Hz)，6.19(0.5H，d，J＝7.8Hz)，7.38(2H，d，J＝8.8Hz)，7.71(2H，d，J＝8.8Hz)，8.70-8.79(1H，m)，10.28(1H，d，J＝11.0Hz)，11.53(0.5H，br.s)，11.45(0.5H，br.s).

MS(FAB)m/z：576[(M+H)⁺，³⁵Cl]，578[(M+H)⁺，³⁷Cl].

Example 321]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- ({ [1- (pyridin-4-yl) piperidin-4-yl]Carbonyl } amino) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 420 with 1- (pyridin-4-yl) piperidine-4-carboxylic acid (WO 96/10022) and treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.35-1.49(1H，m)，1.49-1.78(6H，m)，1.78-1.98(3H，m)，2.75-2.90(1H，m)，2.78(3H，s)，3.02(3H，s)，3.03-3.14(1H，m)，3.14-3.28(2H，m)，3.74-3.85(1H，m)，4.13-4.30(3H，m)，7.18(2H，d，J＝7.3Hz)，7.99(2H，s)，8.10-8.23(3H，m)，8.41(1H，s)，8.50(1H，d，J＝8.1Hz)，10.19(1H，s)，13.73(1H，br.s).

MS(FAB)m/z：556[(M+H)⁺，³⁵Cl]，558[(M+H)⁺，³⁷Cl].

Example 322]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothia-neAzolo [5, 4-c ] s]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (5-ethynylpyridin-2-yl) ethanediamide

The compound (348mg) obtained in referential example 455 was dissolved in tetrahydrofuran (14ml), and tetrabutylammonium fluoride (1N tetrahydrofuran solution, 628. mu.l) was added and stirred at room temperature for 30 minutes. Activated carbon (about 1g) was added to the reaction solution to decolorize, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 93: 7). The residue was dissolved in methylene chloride (about 1ml), hexane (about 10ml) was added, and the resulting precipitate was collected by filtration to obtain the title compound (116 mg).

¹H-NMR(CDCl₃) δ: 1.62-2.14(8H, m), 2.52(3H, s), 2.79-2.95(6H, m), 3.05(3H, s), 3.19(1H, s), [ AB type 3.71(1H, d, J ═ 15.5Hz), 3.74(1H, d, J ═ 15.5Hz)]，4.08-4.14(1H，m)，4.66-4.69(1H，m)，7.41(1H，d，J＝8.6Hz)，7.80(1H，dd，J＝8.6，2.2Hz)，8.03(1H，d，J＝7.6Hz)，8.15(1H，d，J＝8.6Hz)，8.46(1H，d，J＝2.2Hz)，9.75(1H，s).

MS(ESI)m/z538(M+H)⁺.

[ example 323]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-5, 6-dihydro-4H-thieno [2, 3-c)]Pyrrol-2-yl) carbonyl]Amino } cyclohexyl) oxalamides

The title compound was obtained by hydrolyzing the compound obtained in referential example 456 and then condensing the product with the compound obtained in referential example 420 in the same manner as in example 191.

¹H-NMR(CDCl₃)δ：1.80-2.15(6H，m)，2.64(3H，s)，2.76-2.79(1H，m)，2.94(3H，s)，3.03(3H，s)，3.84-3.86(2H，m)，3.94-3.99(3H，m)，4.58-4.59(1H，m)，6.70(1H，d，J＝6.3Hz)，7.31(1H，s)，7.70(1H，dd，J＝8.8，2.3Hz)，8.15-8.18(2H，m)，8.30(1H，d，J＝2.3Hz)，9.72(1H，br.s).

MS(FAB)m/z：533[(M+H)⁺，Cl³⁵]，535[(M+H)⁺，Cl³⁷].

[ example 324] N- { (1R, 2S, 5S) -2- ({2- [ (6-Chloropyridazin-3-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 460 and the compound obtained in referential example 10 and then treating them with hydrochloric acid in the same manner as in example 3.

¹H-NMR(DMSO-d₆)δ：1.48-1.51(1H，m)，1.71-1.79(3H，m)，2.00(1H，br.s)，2.20-2.23(1H，m)，2.78(3H，s)，2.90(3H，s)，2.96(3H，s)，3.05(1H，br.s)，3.16-3.47(3H，m)，3.69(1H，br.s)，4.43(1H，br.s)，4.53(1H，br.s)，4.69(2H，br.s)，7.97(1H，d，J＝9.6Hz)，8.32(1H，d，J＝9.6Hz)，8.73(1H，d，J＝7.3Hz)，11.08(2H，br.s)，11.61-11.75(1H，m).

MS(FAB)m/z：565[(M+H)⁺，Cl³⁵]，567[(M+H)⁺，Cl³⁷].

[ example 325] N- { (1R, 2S, 5S) -2- ({2- [ (6-Chloropyridin-3-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 464 and the compound obtained in referential example 10 and then treating them with hydrochloric acid in the same manner as in example 3.

¹H-NMR(DMSO-d₆)δ：1.47-1.55(1H，m)，1.66-1.78(3H，m)，2.02-2.05(1H，m)，2.21-2.33(1H，m)，2.79(3H，s)，2.91(3H，s)，2.95(3H，s)，2.99-3.04(1H，m)，3.21(2H，br.s)，3.45-3.75(2H，br)，4.40-4.75(4H，m)，7.53(1H，d，J＝8.6Hz)，8.20(1H，dd，J＝8.6，2.6Hz)，8.77(1H，d，J＝7.3Hz)，8.80(1H，d，J＝2.6Hz)，10.73(1H，s)，10.94(1H，br.d，J＝7.6Hz)，11.37(1H，br.s).

MS(FAB)m/z：564[(M+H)⁺，Cl³⁵]，566[(M+H)⁺，Cl³⁷].

EXAMPLE 326]N¹- [ (3R, 4S) -3- ({ [2 '- (aminosulfonyl) [1, 1' -biphenyl)]-4-yl]Carbonyl } amino) -1- (2-methoxyacetyl) piperidin-4-yl]-N²- (5-chloropyridin-2-yl) ethanediamide

The title compound was obtained by treating the compound obtained in referential example 368 with hydrochloric acid for deprotection and then condensing it with the compound obtained in referential example 465 in the same manner as in example 219.

¹H-NMR(CDCl₃)δ：1.59-1.85(1H，m)，2.09-2.23(1H，m)，2.88-3.13(1H，m)，3.29-3.51(4H，m)，4.06-4.20(4H，m)，4.51-4.78(4H，m)，7.09(0.25H，br.s)，7.30(1H，d，J＝7.1Hz)，7.51-7.54(3.75H，m)，7.60(1H，t，J＝7.0Hz)，7.69(1H，dd，J＝8.9，2.2Hz)，7.94-7.96(2H，m)，8.13-8.22(2H，m)，8.30(1H，d，J＝2.2Hz)，8.91(0.75H，br.d，J＝5.9Hz)，9.18(0.25H，br.s)，9.70(1H，s).

MS(FAB)m/z：629[(M+H)⁺，Cl³⁵]，631[(M+H)⁺，Cl³⁷]

[ example 327]N¹- (5-chloropyridin-2-yl) -N²- { (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- [ (thieno [3, 2-b ]]Pyridin-2-ylcarbonyl) amino]Cyclohexyl oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 420 with a thieno [3, 2-b ] pyridine-2-carboxylic acid lithium salt (Japanese patent laid-open No. 2001-294572) and then treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.44-1.57(1H，m)，1.62-1.84(3H，m)，1.86-1.98(1H，m)，2.04-2.19(1H，m)，2.78(3H，s)，2.99(3H，s)，3.11-3.25(1H，m)，3.85-4.10(1H，br)，4.44-4.55(1H，br)，7.51-7.62(1H，m)，7.98(2H，br.s)，8.43(2H，br.s)，8.60(1H，s)，8.66(1H，br.d，J＝8.1Hz)，8.81(1H，br.d，J＝4.2Hz)，9.05(1H，br.d，J＝7.8Hz)，10.24(1H，s).

MS(ESI)m/z：529[(M+H)⁺，Cl³⁵]，531[(M+H)⁺，Cl³⁷].

Example 328]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (5-methylpyridin-2-yl) ethanedi Amide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 467 and the compound obtained in referential example 253 and then treating them with hydrochloric acid in the same manner as in example 208.

¹H-NMR(DMSO-d₆)δ：1.42-1.57(1H，m)，1.60-1.80(3H，m)，1.95-2.15(2H，m)，2.28(3H，s)，2.78(3H，s)，2.90-3.10(1H，m)，2.92(3H，s)，2.94(3H，s)，3.07-3.38(2H，m)，3.40-3.58(1H，br)，3.60-3.80(1H，m)，3.95-4.05(1H，m)，4.36-4.50(2H，m)，4.66-4.80(1H，m)，7.73(1H，d，J＝8.0Hz)，7.90-7.94(1H，m)，8.24(1H，s)，8.70-8.80(1H，m)，9.13(0.5H，d，J＝7.3Hz)，9.21(0.5H，d，J＝8.0Hz)，10.06(1H，s)，11.46(0.5H，br.s)，11.57(0.5H，br.s).

MS(FAB)m/z：528(M+H)⁺.

[ example 329]N¹- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) -N²- (4-methylphenyl) ethanediamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 469 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.42-1.55(1H，m)，1.60-1.80(3H，m)，1.95-2.15(2H，m)，2.26(3H，s)，2.79(3H，s)，2.93(7H，br.s)，3.07-3.35(2H，m)，3.40-3.55(1H，m)，3.65-3.77(1H，m)，3.95-4.06(1H，m)，4.38-4.52(2H，br)，4.67-4.80(1H，m)，7.13(2H，d，J＝8.3Hz)，7.66(2H，d，J＝8.3Hz)，8.72-8.80(1H，m)，8.96(0.5H，d，J＝7.8Hz)，9.04(0.5H，d，J＝8.1Hz)，10.56(1H，d，J＝6.6Hz)，11.30(1H，br.s).

MS(FAB)m/z：527(M+H)⁺.

[ 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

The title compound was obtained by condensing the compound obtained in referential example 471 with the compound obtained in referential example 420 in the same manner as in example 2.

¹H-NMR(CDCl₃) δ: 1.48(9H, s), 1.50-1.70(1H, m), 1.80-2.00(2H, m), 2.00-2.12(2H, m), 2.14-2.22(1H, m), 2.72-2.83(1H, m), 2.88, 2.89 (all 3H, each s), 2.96(3H, s), 3.04(3H, s), 4.05-4.15(1H, m), 4.32-4.50(1H, m), 4.73-4.80(1H, m), 7.22(1H, d, J ═ 8.8Hz), 7.38(1H, br.s), 7.69(1H, dd, J ═ 8.8, 2.6Hz), 7.99(1H, d, J ═ 8.6 Hz), 8.17(1H, 17.8, 17H, 17.6 Hz), 1H, 8, 1H, m).

MS(ESI)m/z：655(M+H)⁺.

[ example 331]N¹- { (1S, 2R, 4S) -2- [ ({ 3-chloro-4- [ (methylamino) methyl group)]-2-thienyl } carbonyl) amino]-4- [ (dimethylamino) carbonyl group]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide

The title compound was obtained from the compound obtained in example 330 by the same method as in example 227.

¹H-NMR(CDCl₃)δ：1.55-1.70(1H，m)，1.75-1.98(2H，m)，2.00-2.22(2H，m)，2.22-2.32(1H，m)，2.52(3H，s)，2.72-2.86(1H，m)，2.96(3H，s)，3.05(3H，s)，3.53-3.82(1H，m)，3.78(2H，s)，4.05-4.16(1H，m)，4.72-4.80(1H，m)，7.27(1H，d，J＝7.8Hz)，7.52(1H，s)，7.67(1H，dd，J＝8.8，2.6Hz)，8.09(1H，d，J＝7.6Hz)，8.09(1H，d，J＝7.6Hz)，8.13(1H，d，J＝8.8Hz)，8.29(1H，d，J＝2.6Hz)，9.90-11.00(1H，br).

MS(ESI)m/z：555(M+H)⁺.

EXAMPLE 332]N¹- { (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 group]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide hydrochloride

Triethylamine (0.735ml) and 2-bromoethyl isocyanate (0.106ml) were added to a dichloromethane (20ml) suspension of the compound (590mg) obtained in example 331, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride and washed with water, 0.5N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and a saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol 20: 1), and the solvent was evaporated under reduced pressure. The resulting crude product was dissolved in methylene chloride (2ml) and ethanol (3ml), and 1N ethanol hydrochloride solution (0.5ml) was added thereto, followed by stirring at room temperature for 30 minutes and then concentration under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration and washed to obtain the title compound (197mg) as a colorless powder.

¹H-NMR(DMSO-d₆)δ：1.45-1.60(1H，m)，1.60-1.83(3H，m)，1.85-2.02(3H，m)，2.80(3H，s)，2.84(3H，s)，2.90-3.01(1H，m)，2.97(3H，s)，3.25-3.40(2H，m)，3.60(2H，t，J＝6.6Hz)，3.95-4.05(1H，m)，4.30-4.45(3H，m)，6.80(1H，t，J＝5.5Hz)，7.51(1H，s)，7.94-8.06(2H，m)，8.10(1H，d，J＝6.8Hz)，8.42-8.50(1H，m)，8.97(1H，d，J＝8.6Hz)，10.27(1H，s).

MS(ESI)m/z：624(M+H)⁺.

[ example 333] [ 4-chloro-5- ({ [ (1R, 2S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxoacetyl } amino) cyclohexyl ] amino } carbonyl) -3-thienyl ] methyl (meth) carbamic acid tert-butyl ester

The title compound was obtained by treating the compound obtained in referential example 472 with hydrochloric acid for deprotection and then condensing it with the compound obtained in referential example 471 in the same manner as in example 214.

¹H-NMR(CDCl₃)δ：1.15-2.00(6H，m)，1.46(9H，s)，2.87(3H，s)，4.15-4.25(1H，m)，4.30-4.45(2H，m)，4.48-4.56(1H，m)，7.20(1H，d，J＝8.1Hz)，7.27-7.32(1H，m)，7.70(1H，dd，J＝8.8，2.2Hz)，8.01(1H，d，J＝8.3Hz)，8.18(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.6Hz)，9.73(1H，br.s).

MS(ESI)m/z：584(M+H)⁺.

Example 334]N¹- { (1S, 2R) -2- [ ({ 3-chloro-4- [ (methylamino) methyl group)]-2-thienyl } carbonyl) amino]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide

The title compound was obtained from the compound obtained in example 333 by the same method as in example 227.

¹H-NMR(CDCl₃)δ：1.48-2.02(8H，m)，2.46(3H，s)，3.72(2H，s)，4.15-4.25(1H，m)，4.45-4.55(1H，m)，7.22(1H，d，J＝8.1Hz)，7.42(1H，s)，7.71(1H，dd，J＝8.8，2.6Hz)，8.03(1H，d，J＝9.3Hz)，8.19(1H，dd，J＝8.8，0.73Hz)，8.31(1H，dd，J＝2.6，0.73Hz).

MS(ESI)m/z：484(M+H)⁺.

EXAMPLE 335]N¹- ((1S, 2R) -2- { [ (3-chloro-4- { [4, 5-dihydro-1, 3-oxazol-2-yl (methyl) amino)]Methyl } -2-thienyl } carbonyl]Amino } cyclohexyl) -N²- (5-chloropyridin-2-yl) ethanediamide

The title compound was obtained from the compound obtained in example 334 by the same method as in example 332.

¹H-NMR(CDCl₃)δ：1.50-2.00(8H，m)，2.94(3H，s)，3.80(2H，t，J＝8.5Hz)，4.17-4.25(1H，m)，4.32(2H，t，J＝8.5Hz)，4.39(1H，d，J＝16.5Hz)，4.41(1H，d，J＝16.5Hz)，4.58-4.67(1H，m)，7.18(1H，d，J＝8.3Hz)，7.40(1H，s)，7.69(1H，dd，J＝8.8，2.4Hz)，8.00(1H，d，J＝8.1Hz)，8.17(1H，d，J＝8.8Hz)，8.29(1H，d，J＝2.4Hz)，9.73(1H，br.s).

MS(ESI)m/z：553(M+H)⁺.

Example 336]N¹- (5-chloropyridin-2-yl) -N²- ((1R, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (5-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c)]Aza derivatives-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 477 and the compound obtained in referential example 420 and then treating them with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.42-1.58(1H，m)，1.60-1.84(3H，m)，1.85-2.15(4H，m)，2.79(6H，br.s)，2.93(4H，br.s)，3.05-3.25(2H，m)，3.49(1H，br.s)，3.63(1H，br.s)，3.95-4.05(1H，m)，4.42(1H，br.s)，4.64(1H，br.s)，4.78(1H，br.s)，8.01(2H，br.s)，8.46(1H，br.s)，8.65(1H，d，J＝7.3Hz)，9.19(1H，d，J＝8.1Hz)，10.29(1H，s)，10.64(1H，br.s).

MS(FAB)m/z：562(M+H)⁺.

EXAMPLE 337]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (4, 4, 5-trimethyl-5, 6-dihydro-4H-pyrrolo [3, 4-d)]Thiazol-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

A lithium salt of 4, 4, 5-trimethyl-5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazole-2-carboxylic acid was prepared from the compound obtained in referential example 479 by the same process as referential example 10. Then, this lithium salt was condensed with the compound obtained in reference example 420 and treated with hydrochloric acid in the same manner as described in example 2 to obtain the title compound.

¹H-NMR(DMSO-d₆)δ：1.45-1.55(4H，m)，1.60-1.85(6H，m)，1.85-2.10(2H，m)，2.78(3H，s)，2.85-3.08(7H，m)，3.93-4.05(1H，br)，4.41-4.53(1H，br)，4.52-4.68(1H，br)，4.70-4.83(1H，br)，8.01(2H，br.s)，8.45(1H，br.s)，8.63(0.5H，d，J＝7.6Hz)，8.68(0.5H，d，J＝7.6Hz)，9.07-9.20(1H，m)，10.29(0.5H，s)，10.26(0.5H，s)，11.83(0.5H，br.s)，11.76(0.5H，br.s).

MS(FAB)m/z：562(M+H)⁺.

[ 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

The title compound was prepared by condensing the compound obtained in referential example 481 with the compound obtained in referential example 420 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.53(4.5H，s)，1.61(4.5H，s)，1.54-2.20(6H，m)，2.76-2.90，(1H，m)，2.96(3H，s)，3.07(3H，s)，4.05-4.15(1H，m)，4.46-4.85(5H，m)，7.67(1H，dd，J＝8.8，2.3Hz)，8.10-8.23(3H，m)，8.30(1H，d，J＝2.3Hz)，8.30-8.40(1H，m)，8.45(0.5H，br.s)，8.49(0.5H，br.s)，9.72(1H，br.s).

MS(ESI)m/z：614(M+H)⁺.

[ example 339 ]N¹- (5-chloro-2-pyridyl) -N²-{(1S，2R，4S) -2- [ (2, 3-dihydro-1H-pyrrolo [3, 4-c)]Pyridin-6-ylcarbonyl) amino]-4- [ (dimethylamino) carbonyl group]Cyclohexyl oxalamide hydrochloride

The title compound was obtained from the compound obtained in example 338 by the same method as in example 227.

¹H-NMR(DMSO-d₆)δ：1.45-1.61(1H，m)，1.62-1.84(3H，m)，1.95-2.10(2H，m)，2.78(3H，s)，2.79-2.90(1H，m)，2.90(3H，s)，3.90-4.15(1H，m)，4.45-4.53(1H，br)，4.55-4.68(4H，m)，8.00(2H，br.s)，8.10(1H，s)，8.45(1H，d，J＝1.5Hz)，8.67(1H，d，J＝7.6Hz)，8.75(1H，s)，9.19(1H，d，J＝8.3Hz)，10.11(2H，br.s)，10.26(1H，br.s).

MS(FAB)m/z：514(M+H)⁺.

Example 340]N¹- (5-chloro-2-pyridyl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (2-methyl-2, 3-dihydro-1H-pyrrolo [3, 4-c)]Pyridin-6-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained from the compound obtained in example 339 and formalin by the same method as in example 18.

¹H-NMR(DMSO-d₆)δ：1.45-1.59(1H，m)，1.60-1.85(3H，m)，1.91-2.10(2H，m)，2.78(3H，br.s)，2.80-2.90(1H，m)，2.90(1.5H，s)，2.92(1.5H，s)，3.01(1.5H，s)，3.02(1.5H，s)，3.90-4.05(1H，m)，4.42-4.60(3H，m)，4.80-5.00(2H，m)，8.00(2H，br.s)，8.11(1H，s)，8.44(1H，d，J＝1.5Hz)，8.60-8.70(1H，m)，8.75(1H，s)，9.18(1H，d，J＝7.8Hz)，10.25(0.5H，s)，10.28(0.5H，s)，11.95(0.5H，s)，12.02(0.5H，s).

MS(FAB)m/z：528(M+H)⁺.

[ example 341]N¹- (5-chloropyridin-2-yl) -N²- { (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- [ (5, 6, 7, 8-tetrahydro [1, 6]]Naphthyridin-2-ylcarbonyl) amino]Cyclohexyl oxalamide hydrochloride

In the same manner as in example 2, methyl 6- (tert-butoxycarbonyl) -5, 6, 7, 8-tetrahydro [1, 6] naphthyridine-2-carboxylate (Japanese patent laid-open No. 2000-119253) was hydrolyzed, the obtained lithium salt of carboxylic acid was condensed with the compound obtained in referential example 420, and the resultant was treated with hydrochloric acid to obtain the title compound.

¹H-NMR(DMSO-d₆)δ：1.45-1.62(1H，m)，1.62-1.87(3H，m)，1.89-2.05(2H，m)，2.80(3H，s)，2.81-2.94(1H，m)，2.95(3H，s)，3.15-3.35(2H，m)，3.51(2H，br.s)，3.90-4.05(1H，m)，4.38(2H，br.s)，4.43-4.55(1H，m)，7.88(2H，br.s)，8.01(2H，br.s)，8.45(1H，d，J＝1.5Hz)，8.51(1H，d，J＝8.3Hz)，9.16(1H，d，J＝7.8Hz)，9.85(1H，br.s)，10.02(1H，br.s)，10.27(1H，br.s).

MS(FAB)m/z：528(M+H)⁺.

Example 342]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group ]-2- { [ (6-methyl-5, 6, 7, 8-tetrahydro [1, 6 ]]Naphthyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained from the compound obtained in example 341 and formalin by the same method as in example 18.

¹H-NMR(DMSO-d₆)δ：1.45-1.62(1H，m)，1.63-1.80(3H，m)，1.86-2.06(2H，m)，2.80(3H，br.s)，2.81-2.96(7H，m)，3.14-3.27(1H，m)，3.11-3.63(2H，m)，3.76(1H，br.s)，3.99(1H，br.s)，4.35-4.52(2H，m)，4.53-4.65(1H，m)，7.84(1H，J＝8.0Hz)，7.89(1H，J＝8.0Hz)，8.00(2H，br.s)，8.40-8.55(2H，m)，9.07(0.4H，d，J＝7.6Hz)，9.19(0.6H，d，J＝8.1Hz)，10.24(0.6H，s)，10.28(0.4H，s)，11.42-11.80(1H，br).

MS(FAB)m/z：542(M+H)⁺.

[ example 343]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- ({ [5- (pyridin-4-yl) pyrimidin-2-yl]Carbonyl } amino) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 420 with the compound obtained in referential example 483 and treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.50-1.63(1H，m)，1.67-1.85(3H，m)，1.95-2.12(2H，m)，2.80(3H，s)，2.86-2.95(1H，m)，2.95(3H，s)，4.00-4.10(1H，m)，4.45-4.55(1H，m)，8.01(2H，br.s)，8.34(2H，d，J＝5.6Hz)，8.44-8.47(1H，m)，8.79(1H，d，J＝7.6Hz)，8.99(2H，d，J＝5.6Hz)，9.08(1H，d，J＝8.3Hz)，9.54(2H，s)，10.31(1H，s).

MS(FAB)m/z：551(M+H)⁺.

EXAMPLE 344]N¹- (5-chloropyridin-2-yl) -N²- { (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- [ ({ 2' - [ (dimethylamino) methyl][1, 1' -Biphenyl]-4-yl } carbonyl) amino]Cyclohexyl oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 420 and the compound obtained in referential example 488 and then treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.45-1.56(1H，m)，1.60-1.85(3H，m)，1.85-2.15(2H，m)，2.40-2.55(6H，m)，2.80(3H，s)，2.99(3H，s)，3.05-3.20(1H，m)，3.93-4.06(1H，m)，4.25-4.33(2H，m)，4.45-4.55(1H，m)，7.30-7.37(1H，m)，7.48(2H，d，J＝8.3Hz)，7.50-7.58(2H，m)，7.84-7.90(1H，m)，7.95-8.05(4H，m)，8.15(1H，d，J＝7.3Hz)，8.46(1H，br.s)，9.20(1H，d，J＝8.3Hz)，10.15-10.29(1H，br)，10.30(1H，br.s).

MS(FAB)m/z：605(M+H)⁺.

Example 345]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- ({4- [2- (hydroxymethyl) pyridin-4-yl]Benzoyl } amino) cyclohexyl]Oxalamide hydrochloride

The title compound was prepared by hydrolyzing the compound of referential example 490, condensing the lithium salt of the resulting carboxylic acid with the compound obtained in referential example 420 and then treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.44-1.58(1H，m)，1.63-1.81(3H，m)，1.89-1.99(1H，m)，1.99-2.13(1H，m)，2.79(3H，s)，2.97(3H，s)，3.06-3.17(1H，m)，3.93-4.02(1H，m)，4.44-4.51(1H，m)，4.89(2H，s)，7.99(2H，s)，8.08(4H，m)，8.19(1H，d，J＝6.3Hz)，8.24(1H，d，J＝7.3Hz)，7.29(1H，s)，8.44-8.46(1H，m)，8.80(1H，d，J＝5.9Hz)，9.01(1H，d，J＝8.3Hz)，10.27(1H，s).

MS(ESI)m/z：579(M+H)⁺.

[ example 346]N¹{ (1S, 2R, 4S) -2- ({4- [2- (aminomethyl) pyridin-4-yl]Benzoyl amino) -4- [ (dimethylamino) carbonyl]Cyclohexyl } -N²- (5-chloropyridin-2-yl) ethanediamide hydrochloride

The title compound was obtained by hydrolyzing the compound of reference example 491, condensing the lithium salt of the obtained carboxylic acid with the compound obtained in reference example 420, and treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.40-1.58(1H，m)，1.58-1.83(3H，m)，1.87-1.98(1H，m)，1.98-2.13(1H，m)，2.78(3H，s)，2.97(3H，s)，3.05-3.17(1H，m)，3.93-4.03(1H，m)，4.17-4.30(2H，m)，4.40-4-50(1H，m)，7.80(1H，dd，J＝5.2，1.6Hz)，7.90-8.06(7H，m)，8.18(1H，d，J＝7.6Hz)，8.43-8.46(1H，m)，8.50(3H，br.s)，8.70(1H，d，J＝5.2Hz)，9.01(1H，d，J＝8.5Hz)，10.27(1H，s).

MS(ESI)m/z：578(M+H)⁺.

[ example 347]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- ({ [1- (phenylsulfonyl) piperidin-4-yl)]Carbonyl } amino) cyclohexyl]Oxalamides

The title compound was prepared by condensing the compound obtained in referential example 420 with the compound obtained in referential example 493 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.60-2.10(10H，m)，2.12-2.21(1H，m)，2.40(2H，br.t，J＝11.2Hz)，2.65-2.77(1H，m)，2.92(3H，s)，2.99(3H，s)，3.77(2H，br.d，J＝11.7Hz)，3.92-4.05(1H，m)，4.42-4.53(1H，m)，6.31(1H，br.d，J＝7.3Hz)，7.53(2H，t，J＝7.3Hz)，7.62(1H，t，J＝7.3Hz)，7.67-7.78(3H，m)，8.01(1H，brd，J＝7.3Hz)，8.16(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.2Hz)，9.72(1H，s).

MS(ESI)m/z：619(M+H)⁺.

[ example 348]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -4- [ (dimethylamino) carbonyl]-2- ({ [1- (4-fluorobenzoyl) piperidin-4-yl]Carbonyl } amino) cyclohexyl]Oxalamides D22-5792

The title compound was obtained by condensing the compound obtained in referential example 420 with the compound obtained in referential example 495 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.60-2.16(10H，m)，2.37-2.48(1H，m)，2.64-2.78(1H，m)，2.80-3.13(2H，m)，2.94(3H，s)，3.02(3H，s)，3.65-4.18(1H，br)，3.93-4.01(1H，m)，4.43-4.80(2H，br)，6.32(1H，br.d，J＝7.1Hz)，7.09(2H，t，J＝8.5Hz)，7.40(2H，dd，J＝8.5，5.4Hz)，7.71(1H，dd，J＝8.8，2.4Hz)，8.04(1H，br.d，J＝7.6Hz)，8.15(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.4Hz)，9.71(1H，s).

MS(ESI)m/z：601(M+H)⁺.

Example 349]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [4- (pyrrolidin-1-ylcarbonyl) benzoyl ]Amino } cyclohexyl) oxalamides

The title compound was obtained by condensing the compound obtained in referential example 420 with the compound obtained in referential example 497 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.68-2.23(9H，m)，2.33(1H，br.d，J＝7.4Hz)，2.85-3.02(1H，m)，2.92(3H，s)，2.98(3H，s)，3.31(2H，t，J＝6.8Hz)，3.61(2H，t，J＝6.8Hz)，4，13-4.22(1H，m)，4.54-4.63(1H，m)，7.28(2H，d，J＝8.1Hz)，7.63-7.69(1H，m)，7.66(2H，d，J＝8.1Hz)7.95(1H，br.d，J＝5.6Hz)，8.05(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.4Hz)，8.54(1H，brd，J＝8.3Hz)，9.76(1H，s).

MS(ESI)m/z：569(M+H)⁺.

Example 350]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [4- (pyrrolidin-1-ylmethyl) benzoyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound described in referential example 498 to condense the lithium salt of the obtained carboxylic acid with the compound obtained in referential example 420 and then treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.43-1.57(1H，m)，1.62-2.10(9H，m)，2.78(3H，s)，2.95(3H，s)，2.96-3.12(3H，m)，3.28-3.50(2H，m)，3.92-4.01(1H，m)，4.35-4.48(3H，m)，7.69(2H，d，J＝8.1Hz)，7.92(2H，d，J＝8.1Hz)，7.99(2H，s)，8.09(1H，br.d，J＝7.6Hz)，8.44(1H，s)，8.99(1H，br.d，J＝8.3Hz)，10.27(1H，s)，10.65-10.80(1H，br).

MS(ESI)m/z：555(M+H)⁺.

Example 351]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) thiocarbonyl)]-2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 501 with a 4N dioxane hydrochloride solution for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.60-2.18(6H，m)，2.70-2.95(4H，m)，2.90(3H，s)，3.06-3.40(2H，m)，3.42-3.54(1H，br)，3.62-3.78(1H，br)，3.96-4.05(1H，m)，4.24-4.34(1H，br)，4.35-4.52(1H，br)，4.60-4.76(1H，m)，7.96-8.04(2H，m)，8.43(1H，s)，8.48-8.60(1H，br)，9.39(1H，br.d，J＝7.8Hz)，9.91-10.03(1H，br)，10.18-10.30(1H，m)，11.72-11.95(1H，br).

MS(ESI)m/z：550(M+H)⁺.

[ 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

Chlorosulfonic acid (146. mu.l) was added to a solution of 4-chloroaniline (255mg) in dichloromethane (15ml) at 0 ℃. After stirring at the same temperature for 1 hour, the mixture was stirred at room temperature for 2 hours. Phosphorus pentachloride (458mg) was added to the reaction solution and the mixture was refluxed for 2 hours. The temperature was returned to room temperature, the compound (731mg) obtained in referential example 253 was added, and triethylamine was added to adjust the pH to neutral. After stirring at room temperature for 17 hours, the reaction mixture was added with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water 2 times and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified 2 times by flash column chromatography on silica gel (dichloromethane: methanol 93: 7) followed by preparative thin layer chromatography (dichloromethane: methanol 9: 1) to give a pale yellow solid (46 mg). The solid was dissolved in dichloromethane and 1N ethanol hydrochloride solution (83. mu.l) was added. The solvent was distilled off under reduced pressure, a small amount of methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (34mg) as a pale yellow solid.

¹H-NMR(DMSO-d₆)δ：1.34-1.69(5H，m)，1.98(1H，br.s)，2.75(3H，s)，2.85-2.94(8H，m)，3.17(2H，br.s)，3.50(1H，br.s)，3.69(1H，br.s)，4.39-4.50(2H，m)，4.69(1H，br.s)，7.08-7.15(4H，m)，7.74(1H，br.s)，7.98(1H，br.s)，9.90(1H，s)，11.35(1H，br.s).

MS(FAB)m/z：555(M+H)⁺.

[ example 353] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyrimidin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 503 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO)δ：1.49-1.54(1H，m)，1.68-1.79(3H，m)，1.99-2.02(1H，m)，2.16-2.22(1H，m)，2.80(3H，s)，2.91(3H，s)，2.97(3H，s)，3.06(1H，br.s)，3.20(2H，br.s)，3.49(1H，br.s)，3.64(1H，br.s)，4.40-4.55(2H，m)，4.70(2H，br.s)，8.68(1H，d，J＝7.1Hz)，8.81(2H，s)，10.87(1H，br.s)，10.99(1H，br.s)，11.47(1H，br.s).

MS(FAB)m/z：565(M+H)⁺.

[ example 354] N- { (1R, 2S, 5S) -2- { [2- (4-chloro-3-nitroanilino) -2-oxothioacetyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 505 with hydrochloric acid for deprotection, then condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO)δ：1.48-1.54(1H，m)，1.67-1.78(3H，m)，1.99-2.03(1H，m)，2.22-2.33(1H，m)，2.79(3H，s)，2.91(3H，s)，2.96(3H，s)，3.01-3.67(5H，m)，4.40-4.80(4H，m)，7.78(1H，d，J＝8.8Hz)，8.05(1H，dd，J＝8.8，1.4Hz)，8.59(1H，d，J＝1.4Hz)，8.75(1H，d，J＝7.6Hz)，10.89-10.92(2H，m)，11.43(1H，br.s).

MS(ESI)m/z：608(M+H)⁺.

[ example 355] N- { (1R, 2S, 5S) -2- { [2- (3-amino-4-chloroanilino) -2-oxothioacetyl ] 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 (458mg) obtained in example 354 in ethanol (30ml) was added 10% palladium on carbon (1.00g), and the mixture was stirred at room temperature for 3 days. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane: methanol: 94: 6), and the resulting yellow solid (137mg) was dissolved in dichloromethane (5ml), followed by addition of 1N ethanol hydrochloride (474 μ l). Additional diethyl ether (20ml) was added, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (144mg) as a yellow solid.

¹H-NMR(DMSO-d₆)δ：1.46-1.54(1H，m)，1.70-1.78(3H，m)，1.98-2.07(1H，m)，2.21-2.23(1H，m)，2.79(3H，s)，2.91(3H，s)，2.96(3H，s)，3.03(1H，br.s)，3.11-3.19(1H，m)，3.30(1H，br.s)，3.47(1H，br.s)，3.69(1H，br.s)，4.10-4.51(4H，m)，4.68(2H，s)，6.95(1H，dd，J＝8.6，2.3Hz)，7.18(1H，d，J＝8.6Hz)，7.31(0.5H，s)，7.33(0.5H，s)8.74-8.80(1H，m)，10.18(1H，d，J＝9.8Hz)，10.83(0.5H，d，J＝7.6Hz)，10.89(0.5H，d，J＝8.0Hz)，11.79(0.5H，br.s)，11.87(0.5H，br.s).

MS(ESI)m/z：578(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 428 with hydrochloric acid for deprotection and then condensing with the compound obtained in referential example 481 in the same manner as in example 219.

¹H-NMR(CDCl₃)δ：1.53(9H，s)，1.56-2.42(6H，m)，2.85-2.94，(1H，m)，2.98(3H，s)，3.10(3H，s)，4.45-4.52(1H，m)，4.70-4.85(5H，m)，7.67(1]，dd，J＝8.8，2.4Hz)，8.18(0.5H，br.s)，8.18(1H，d，J＝8.8Hz)，8.23(0.5H，b.s)，8.31(1H，d，J＝2.4Hz)，8.40-8.52(2H，m)，10.29(1H，br.s)，10.60(1H，r.s).

MS(ESI)m/z：630(M+H)⁺

[ example 357] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl ] amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -2-methyl-2, 3-dihydro-1H-pyrrolo [3, 4-c ] pyridine-6-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in example 356 with hydrochloric acid to deprotect it, methylating it in the same manner as described in example 18, and treating it with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.46-1.61(1H，m)，1.62-1.95(3H，m)，1.95-2.10(1H，m)，2.10-2.30(1H，m)，2.79(3H，br.s)，2.84-2.94(4H，m)，2.95(3H，s)，4.45-4.60(3H，m)，4.75(1H，br.s)，4.80-5.00(2H，m)，7.97-8.13(2H，m)，8.16(1H，br.s)，8.46(1H，br.s)，8.76(2H，br.s)，10.51(0.5H，s)，10.55(0.5H，s)，11.09(1H，br.s)，11.92(0.5H，br.s)，11.99(0.5H，br.s).

MS(FAB)m/z：544(M+H)⁺.

[ example 358] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl ] amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -1- (pyridin-4-yl) -4-piperidinecarboxamide hydrochloride

The title compound was obtained by deprotecting the compound obtained in referential example 428 by treatment with hydrochloric acid in the same manner as in example 219, condensing with 1- (pyridin-4-yl) -4-piperidinecarboxylic acid (Tetrahedron, 1998, volume 44, page 7095) and treating with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.38-1.52(1H，m)，1.52-1.73(4H，m)，1.73-1.88(3H，m)，1.88-2.02(2H，m)，2.80(3H，s)，3.04(3H，s)，3.10-3.40(4H，m)，4.14-4.36(3H，m)，4.48-4.57(1H，m)，7.18(2H，d，J＝6.8Hz)，7.90-8.11(2H，m)，8.11-8.30(3H，m)，8.30-8.45(1H，m)，10.33(1H，s)，10.56(1H，d，J＝7.3Hz)，13.48(1H，br.s).

MS(ESI)m/z：572(M+H)⁺.

[ example 359] N- { (1R, 2S, 5S) -2- { [ (7-Chlorcinnolin-3-yl) thioformyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 509 with the compound obtained in referential example 10 and then treating the condensation product with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.55-1.63(1H，m)，1.72-1.78(1H，m)，1.86-1.89(2H，m)，2.10(1H，br.s)，2.40-2.46(1H，m)，2.81(3H，s)，2.91(3H，s)，2.97(3H，s)，3.04(1H，br.s)，3.15-3.20(1H，m)，3.27(1H，br.s)，3.49(1H，br.s)，3.69(1H，br.s)，4.43(1H，br.s)，4.67(1H，br.s)，4.81(1H，br.s)，4.95(1H，br.s)，8.00(1H，d，J＝8.8Hz)，8.41(1H，d，J＝8.8Hz)，8.65(1H，s)，9.06(1H，br.s)，9.20(1H，s)，11.44(1H，br.s)，11.66(1H，br.s).

MS(ESI)m/z：572(M+H)⁺.

[ 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

The title compound was obtained by condensing the compound obtained in referential example 511 and the compound obtained in referential example 10 and then treating them with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.45-1.50(1H，m)，1.74-1.84(4H，m)，1.87-1.95(1H，m)，2.80(3H，s)，2.92(3H，s)，3.02(3H，s)，3.13-3.35(3H，m)，3.47(1H，br.s)，3.69(1H，br.s)，3.97(1H，br.s)，4.41-4.44(1H，m)，4.62-4.72(2H，m)，7.56(2H，d，J＝8.6Hz)，7.86-7.88(2H，m)，8.68(1H，br.s)，8.83(1H，br.s).

MS(FAB)m/z：547(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 513 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.37-1.52(1H，m)，1.57-1.92(5H，m)，2.77(3H，s)，2.89(3H，s)，2.99(3H，s)，3.04-3.20(2H，m)，3.20-3.38(1H，m)，3.47(1H，br.s)，3.60-3.90(1H，m)，3.90-4.03(1H，m)，4.36-4.48(1H，m)，4.52-4.62(1H，m)，4.67(1H，br.d，J＝16.2Hz)，7.08(1H，d，J＝15.4Hz)，7.38(1H，dd，J＝15.4，3.9Hz)，7.60(1H，d，J＝8.4Hz)，7.94(1H，d，J＝8.4Hz)，8.28(1H，d，J＝7.1Hz)，8.35(1H，d，J＝9.8Hz)，8.59(1H，s)，11.72(0.5，br.s)，11.88(0.5H，br.s).

MS(ESI)m/z：531(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 519 with hydrochloric acid for deprotection, then condensing it with the compound obtained in referential example 516 and then treating it with hydrochloric acid in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.47-1.75(4H，m)，1.97-2.20(2H，m)，2.79(3H，s)，2.92-2.96(7H，m)，3.20(2H，br.s)，3.50(1H，br.s)，3.67(1H，br.s)，4.03(1H，br.s)，4.47(2H，br.s)，4.66(1H，br.s)，6.88(1H，d，J＝38.6Hz)，7.50(2H，d，J＝8.4Hz)，7.66(2H，d，J＝8.4Hz)，8.52-8.56(2H，m)，11.36(1H，br.s).

MS(EI)m/z：547(M⁺).

[ example 363] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (methylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 521 with a 4N dioxane hydrochloride solution to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.48-1.61(1H，m)，1.61-1.72(1H，m)，1.72-1.87(2H，m)，2.02-2.12(1H，m)，2.15-2.30(1H，m)，2.33-3.43(1H，m)，2.52(3H，d，J＝4.4Hz)，2.86(3H，s)，3.17(2H，br.s)，3.50(2H，br.s)，4.35-4.60(4H，m)，7.73-7.80(1H，m)，8.00(1H，dd，J＝9.0，2.4Hz)，8.05(1H，d，J＝9.0Hz)，8.43(1H，d，J＝2.4Hz)，8.51-8.58(1H，m)，10.55(1H，s)，11.13(1H，d，J＝7.8Hz).

MS(ESI)m/z：550(M+H)⁺.

Example 364]N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl]-2- ({2- [ (5-Fluoropyridin-2-yl) amino]-2-oxothioacetyl } amino) cyclohexyl]-5-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-c]Aza derivatives-2-carboxamide hydrochloride

The title compound was obtained by condensing the compound obtained in referential example 522 and the compound obtained in referential example 477 and then treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.43-1.60(1H，m)，1.61-1.90(3H，m)，1.92-2.18(3H，m)，2.18-2.35(1H，m)，2.70-2.88(6H，m)，2.96(3H，br.s)，2.96-3.00(1H，m)，3.05-3.27(2H，m)，3.40-3.52(1H，br)，3.60-3.80(1H，br)，4.45-4.60(1H，m)，4.60-4.75(2H，m)，4.75-4.90(1H，m)，7.87(1H，dt，J＝2.9，9.0Hz)，8.05-8.27(1H，m)，8.43(1H，d，J＝2.9Hz)，8.70-8.82(1H，m)，10.54(1H，s)，11.05-11.30(2H，m).

MS(FAB)m/z：562(M+H)⁺.

[ example 365] (tert-butyl 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) methylcarbamate

Water (1.0ml) and lithium hydroxide (20.5mg) were added to a tetrahydrofuran (3.0ml) solution of the compound (250mg) obtained in referential example 524 at room temperature. After stirring for 15 hours, the mixture was concentrated under reduced pressure. To a solution of the obtained solid and the compound (464mg) obtained in referential example 253 in N, N-dimethylformamide (5.0ml) were added 1-hydroxybenzotriazole (140mg) and 1- [3- (dimethylamino) propyl ] -3-ethylcarbodiimide hydrochloride (330mg) at room temperature. After stirring at the same temperature for 21 hours, the solvent was distilled off under reduced pressure, and after adding methylene chloride, water and a saturated aqueous sodium bicarbonate solution to separate, the aqueous layer was extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was purified by medium-pressure column chromatography using silica gel as a carrier (dichloromethane: methanol 10: 1), whereby the title compound (213mg) was obtained as a pale brown foamy solid.

¹H-NMR(CDCl₃)δ：1.40-2.32(6H，m)，1.56(9H，s)，2.52(3H，s)，2.77-2.90(3H，m)，2.90-3.05(2H，m)，2.96(3H，s)，3.11(3H，s)，3.70(1H，d，J＝15.5Hz)，3.73(1H，d，J＝15.5Hz)，4.15-4.23(1H，m)，4.58-4.64(1H，m)，7.43-7.57(2H，m)，7.91(1H，d，J＝6.1Hz)，7.98(1H，d，J＝6.6Hz)，8.12(1H，d，J＝7.8Hz)，8.23(1H，s)，9.30-10.00(2H，br).

MS(ESI)m/z：612(M+H)⁺.

[ 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 (210mg) obtained in example 365 in dichloromethane (4.0ml) was added a 4N dioxane hydrochloride solution (4.0ml) at room temperature. After stirring for 1 hour, a saturated ethanol hydrochloric acid solution (20ml) was added. After stirring overnight, the solvent was evaporated under reduced pressure. To the resulting residue was added water (4.0ml), and the solvent was distilled off under reduced pressure and dried to obtain the title compound (210mg) as a pale brown solid.

¹H-NMR(DMSO-d₆)δ：1.20-2.10(6H，m)，2.78(3H，s)，2.90-3.20(1H，m)，2.91(3H，s)，2.99(3H，s)，3.20-3.35(1H，m)，3.35-3.80(3H，m)，4.00-4.13(1H，m)，4.35-4.80(3H，m)，7.60-7.75(1H，m)，7.85-8.10(2H，m)，8.10-8.25(1H，m)，8.40-8.53(1H，m)，8.53-8.70(1H，m)，9.25-9.80(4H，m)，11.91(1H，br.s).

MS(ESI)m/z：512(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 525 with a 4N dioxane hydrochloride solution for deprotection and then condensing with the compound obtained in referential example 10 in the same manner as in example 214.

¹H-NMR(CDCl₃)δ：1.50-1.66(1H，m)，1.74-1.88(1H，m)，1.90-2.07(2H，m)，2.22-2.37(2H，m)，2.53(3H，s)，2.79-2.91(3H，m)，2.91-3.03(2H，m)，2.97(3H，s)，3.13(3H，s)，3.73(1H，d，J＝15.4Hz)，3.74(1H，d，J＝15.4Hz)，4.13-4.21(1H，m)，4.58-4.64(1H，m)，7.47(1H，d，J＝7.1Hz)，7.55(1H，t，J＝7.8Hz)，7.74(1H，d，J＝7.8Hz)，8.03(1H，d，J＝5.6Hz)，8.06(1H，d，J＝7.8Hz)，8.12(1H，s).

MS(ESI)m/z：494(M⁺).

[ 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

To the compound (270mg) obtained in example 367, ethanol (5.0ml) and tetrahydrofuran (2.0ml) were added and dissolved, and hydroxylamine hydrochloride (114mg) and triethylamine (230. mu.l) were further added at room temperature. After heating and refluxing for 3 hours, a saturated aqueous sodium bicarbonate solution and dichloromethane were added, and the aqueous layer was extracted with dichloromethane after liquid separation. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography using silica gel as a carrier (dichloromethane: methanol: 7: 1), sephadex column (methanol) and preparative reverse phase high-performance liquid chromatography (acetonitrile-water-formic acid system), then converted to hydrochloride salt with 1N hydrochloric acid, and then purified by sephadex column (methanol) in this order to obtain the title compound (175mg) as a white solid.

¹H-NMR(CD₃OD)δ：1.53-1.67(1H，m)，1.78-1.97(5H，m)，2.84(3H，s)，2.96-3.15(2H，m)，3.00(3H，s)，3.03(3H，s)，3.15-3.26(2H，m)，3.64(2H，br.s)，4.09-4.18(1H，m)，4.55(2H，br.s)，7.55(1H，t，J＝7.8Hz)，7.72(1H，d，J＝7.8Hz)，7.94(1H，d，J＝7.8Hz)，8.01(1H，s)，8.08(1H，d，J＝9.1Hz)，8.45(1H，d，J＝7.6Hz).

MS(ESI)m/z：528(M+H)⁺.

[ example 369] (ethyl 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) methylcarbamate

The title compound was obtained by hydrolyzing the compound described in referential example 526 and condensing the lithium salt of the resulting carboxylic acid with the compound obtained in referential example 253 in the same manner as in example 365.

¹H-NMR(CDCl₃)δ：1.36(3H，t，J＝7.1Hz)，1.55-1.71(1H，m)，1.73-2.05(3H，m)，2.05-2.35(2H，m)，2.52(3H，s)，2.75-3.05(5H，m)，2.97(3H，s)，3.11(3H，s)，3.67-3.80(2H，m)，4.10-4.35(3H，m)，4.55-4.67(1H，m)，7.09(1H，br.s)，7.40-7.60(2H，m)，7.94(1H，d，J＝6.1Hz)，8.03(1H，d，J＝7.8Hz)，8.16(1H，d，J＝7.8Hz)，8.27(1H，s)，9.68(1H，br.s).

MS(ESI)m/z：584(M+H)⁺.

EXAMPLE 370N- [ (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 (400mg) obtained in example 367 was added a saturated ethanol hydrochloride solution (30ml) at room temperature. After stirring for 2 days, concentration was carried out under reduced pressure to obtain a white solid. After the solid was dissolved in methanol (10ml), methylamine (2.0M tetrahydrofuran solution) (30ml) was added at room temperature. After stirring for 2 hours, the mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse phase high performance liquid chromatography (acetonitrile-water-formic acid system) and sephadex column (methanol) in this order to obtain the title compound (152mg) as a white solid.

¹H-NMR(DMSO-d₆)δ：1.40-1.54(1H，m)，1.57-1.71(2H，m)，1.71-1.80(1H，m)，1.90-2.06(2H，m)，2.32(3H，s)，2.45(3H，s)，2.68(2H，d，J＝5.6Hz)，2.75(3H，s)，2.75-2.85(2H，m)，2.91(3H，s)，2.91-3.00(1H，m)，3.42(3H，br.s)，3.59(2H，s)，4.00-4.12(1H，m)，4.43-4.52(1H，m)，7.59(1H，t，J＝7.8Hz)，7.81(1H，d，J＝7.8Hz)，7.96(1H，d，J＝7.8Hz)，8.15(1H，s)，8.34-8.47(2H，m)，8.89(1H，d，J＝7.6Hz).

MS(ESI)m/z：526(M+H)⁺.

[ 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

To the compound (300mg) obtained in example 367 at room temperature was added a saturated ethanol hydrochloric acid solution (30 ml). After stirring for 2 days, concentration was carried out under reduced pressure to obtain a pale yellow solid. After the solid was dissolved in methanol (10ml), O-methylhydroxylamine hydrochloride (1.01g) and triethylamine (1.69ml) were added at room temperature. After stirring for 2 hours, dichloromethane and a saturated aqueous sodium bicarbonate solution were added to separate the mixture, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by medium pressure chromatography on silica gel (dichloromethane: methanol ═ 20: 1 → 7: 1) and preparative reverse phase high performance liquid chromatography (acetonitrile-water-formic acid system) in this order and treated with 1N hydrochloric acid to obtain the title compound (51.8mg) as a white solid.

¹H-NMR(DMSO-d₆)δ：1.44-1.57(1H，m)，1.63-1.88(3H，m)，1.88-2.05(2H，m)，2.79(3H，s)，2.85-3.85(5H，m)，2.90(3H，s)，2.96(3H，s)，3.73(3H，s)，4.04-4.13(1H，m)，4.42(1H，br.s)，4.50-4.60(1H，m)，4.67(1H，br.s)，6.22(2H，br.s)，7.44(1H，t，J＝7.8Hz)，7.75(2H，d，J＝7.8Hz)，7.99(1H，s)，8.33-8.50(2H，m)，11.20-11.60(1H，br).

MS(ESI)m/z：542(M+H)⁺.

Example 372]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [4- (3-oxomorpholin-4-yl) benzoyl]Amino } cyclohexyl) oxalamides

The title compound was obtained by condensing the compound obtained in referential example 531 with the compound obtained in referential example 420 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.72-2.16(6H，m)，2.78-2.88(1H，m)，2.95(3H，s)，3.02(3H，s)，3.76-3.80(2H，m)，4.01-4.08(3H，m)，4.32(2H，s)，4.59-4.65(1H，m)，7.07(1H，d，J＝6.9Hz)，7.38(2H，dt，J＝8.6，2.2Hz)，7.70(1H，dd，J＝8.8，2.5Hz)，7.78(2H，dt，J＝8.6，2.2Hz)，8.16(1H，d，J＝8.8Hz)，8.28-8.31(2H，m)，9.73(1H，s).

MS(FAB)m/z：571(M+H)⁺.

[ example 373] N- { (1R, 2S, 5S) -2- { [ (Z) -3- (5-chlorothien-2-yl) -2-fluoro-2-acryloyl ] amino } -5- [ (dimethylamino) carbonyl ] cyclohexyl } -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 519 with hydrochloric acid for deprotection, then condensing it with the compound obtained in referential example 534 and then treating it with hydrochloric acid in the same manner as in example 49.

¹H-NMR(DMSO-d₆)δ：1.42-2.01(6H，m)，2.79(3H，s)，2.91-3.02(7H，m)，3.19(1H，br.s)，3.25(1H，br.s)，3.49(1H，br.s)，3.70(1H，br.s)，3.98-4.05(1H，m)，4.39-4.50(2H，m)，4.70(1H，br.s)，7.19(1H，dd，J＝3.9，1.7Hz)，7.22(1H，d，J＝37.6Hz)，7.37(1H，d，J＝3.9Hz)，8.50(1H，d，J＝7.3Hz)，8.57(1H，br.s)，11.38-11.53(1H，m).

MS(FAB)m/z：554(M+H)⁺.

Example 374]N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino]-2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl]Cyclohexyl } -6-methyl-5, 6, 7, 8-tetrahydro-4H-thiazolo [5, 4-d)]Aza derivatives2-carboxamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 428 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 537, and then treating with hydrochloric acid in the same manner as in example 219.

¹H-NMR(DMSO-d₆)δ：1.44-1.58(1H，m)，1.62-1.74(1H，m)，1.74-1.88(2H，m)，1.95-2.07(1H，m)，2.15-2.30(1H，m)，2.45-2.65(1H，m)，2.79(3H，s)，2.84-3.08(7H，m)，3.16-3.72(7H，m)，4.45-4.55(1H，m)，4.61-4.70(1H，m)，8.02(1H，dd，J＝8.8，2.4Hz)，8.07(1H，d，J＝8.8Hz)，8.46(1H，d，J＝2.4Hz)，8.59-8.68(1H，m)，10.56(1H，d，J＝4.0Hz)，10.85(1H，br.s)，11.00-11.09(1H，m).

MSm/z：578(M+H)⁺.

[ example 375]N¹- (5-chloropyridin-2-yl) -N²- { (1S, 2R, 4S) -2- [ (6, 7-dihydro-4H-pyrano [4, 3-d)]Thiazol-2-ylcarbonyl) amino]-4- [ (dimethylamino) carbonyl group]Cyclohexyl oxalamides

The title compound was obtained by condensing the compound obtained in referential example 26 and the compound obtained in referential example 420 in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.39-1.56(1H，m)，1.58-1.80(3H，m)，1.97-2.13(2H，m)，2.77(3H，s)，2.92(6H，br.s)，3.90-4.06(3H，m)，4.35-4.45(1H，m)，4.83(2H，s)，7.96-8.06(2H，m)，8.44(1H，br.s)，8.61(1H，d，J＝7.3Hz)，9.22(1H，d，J＝8.1Hz)，10.25(1H，br.s).

MS(FAB)m/z：535(M+H)⁺.

[ example 376] N- { (1R, 2S, 5S) -2- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -5- [ (dimethylamino) carbonyl ] cyclohexyl } -6-methyl-5, 6, 7, 8-tetrahydro [1, 6] naphthyridine-2-carboxamide

The title compound was obtained by treating the compound obtained in referential example 428 with hydrochloric acid for deprotection and then condensing it with the compound obtained in referential example 540 in the same manner as in example 219.

¹H-NMR(CDCl₃)δ：1.50-1.75(2H，m)，1.80-2.10(3H，m)，2.10-2.20(1H，m)，2.30-2.45(1H，m)，2.52(3H，s)，2.75-2.85(2H，m)，2.98(3H，s)，2.95-3.10(2H，m)，3.11(3H，s)，3.66(2H，s)，4.45-4.55(1H，m)，4.65-4.80(1H，m)，7.52(1H，d，J＝7.8Hz)，7.67(1H，dd，J＝8.8，2.4Hz)，8.05(1H，d，J＝7.8Hz)，8.21(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.7Hz)，8.50(1H，d，J＝7.5Hz)，10.49(1H，d，J＝7.3Hz)，10.60(1H，s).

MS(ESI)m/z：558(M+H)⁺.

[ example 377] (1S, 3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylic acid tert-butyl ester

The title compound was obtained by condensing the compound obtained in referential example 543 with the compound obtained in referential example 10 in the same manner as in example 2.

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.58-1.78(2H，m)，1.95-2.33(4H，m)，2.49-2.61(1H，m)，2.52(3H，s)，2.80-2.88(2H，m)，2.93-3.00(2H，m)，3.66-3.79(2H，m)，4.40-4.54(1H，m)，4.71-4.84(1H，m)，7.43(1H，d，J＝8.3Hz)，7.68(1H，dd，J＝8.8，2.4Hz)，8.19(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.4Hz)，10.13(1H，d，J＝7.6Hz)，10.55(1H，s).

MS(ESI)m/z：593(M+H)⁺.

[ example 378] (1S, 3R, 4S) -4- ({2- [ (5-Chloropyridin-2-yl) amino ] -2-oxothioacetyl } amino) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridin-2-yl) carbonyl ] amino } cyclohexanecarboxylic acid hydrochloride

To a dioxane (8.0ml) solution of the compound (293mg) obtained in example 377 was added a 4N hydrochloric acid-dioxane solution (10ml), and the mixture was stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, the residue was suspended in diisopropyl ether and filtered, and the obtained powder was dissolved in water and neutralized with a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with dichloromethane, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added a 1N hydrochloric acid-ethanol solution (0.50ml), which was concentrated under reduced pressure, and the residue was dissolved in water and freeze-dried to obtain the title compound (242 mg).

¹H-NMR(DMSO-d₆)δ：1.50-1.64(1H，m)，1.66-1.86(2H，m)，1.89-2.04(1H，m)，2.16-2.32(2H，m)，2.51-2.64(1H，m)，2.93(3H，s)，3.12-3.58(3H，m)，3.64-3.80(1H，m)，4.36-4.80(4H，m)，8.03(1H，dd，J＝8.8，2.7Hz)，8.08(1H，d，J＝8.8Hz)，8.46(1H，d，J＝2.7Hz)，8.73(1H，br.s)，10.57(1H，s)，10.94-11.45(2H，m).

MS(ESI)m/z：537(M+H)⁺.

[ 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

To the compound (307mg) obtained in referential example 544 was added a 1N hydrochloric acid-ethyl acetate solution (3.09ml), and the resulting suspension was stirred at room temperature for 7 hours. Then, a 2N hydrochloric acid-ethyl acetate solution (40ml) was added to the suspension, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried under reduced pressure. The solid was dissolved in N, N-dimethylformamide (10ml), and the compound (191mg) obtained in referential example 26, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (288mg) and 1-hydroxybenzotriazole (135mg) were added to the solution and stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, and methylene chloride and a saturated aqueous sodium bicarbonate solution were added to the residue to separate the mixture, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by flash column chromatography (methanol: dichloromethane ═ 1: 49) using silica gel as a carrier to obtain the title compound (124 mg).

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.58-1.76(2H，m)，1.90-2.21(4H，m)，2.45-2.55(1H，m)，2.97(2H，t，J＝5.6Hz)，3.99-4.14(3H，m)，4.62-4.71(1H，m)，4.88(2H，br.s)，7.35(1H，d，J＝8.8Hz)，7.69(1H，dd，J＝8.8，2.7Hz)，7.99(1H，d，J＝8.1Hz)，8.17(1H，d，J＝8.8Hz)，8.30(1H，d，J＝2.7Hz)，9.70(1H，br.s).

MS(ESI)m/z：564(M+H)⁺.

[ 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

The title compound was obtained from the compound obtained in example 379 in the same manner as the process described in example 378.

¹H-NMR(DMSO-d₆)δ：1.44-1.80(3H，m)，1.83-2.11(2H，m)，2.17-2.27(1H，m)，2.45-2.54(1H，m)，2.92(2H，br.s)，3.90-4.10(3H，m)，4.33(1H，br.s)，4.84(2H，br.s)，7.98-8.07(2H，m)，8.45(1H，d，J＝2.2Hz)，8.59(1H，d，J＝7.4Hz)，9.19(1H，d，J＝8.1Hz)，10.27(1H，s)，12.23(1H，s).

MS(FAB)m/z：508(M+H)⁺.

Example 381]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -4- [ (dimethylamino) carbonyl group]-2- { [ (2-methyl-1, 2, 3, 4-tetrahydroisoquinolin-6-yl) carbonyl]Amino } cyclohexyl) oxalamide hydrochloride

The title compound was obtained by hydrolyzing the compound obtained in referential example 545, condensing the lithium salt of the obtained carboxylic acid with the compound obtained in referential example 420 and then treating with hydrochloric acid in the same manner as in example 2.

¹H-NMR(DMSO-d₆)δ：1.31-1.46(1H，m)，1.49-1.72(3H，m)，1.75-2.01(2H，m)，2.68(3H，s)，2.80(3H，s)，2.86(3H，s)，2.90-3.06(1H，m)，3.05-3.42(3H，m)，3.49-3.61(1H，m)，3.80-3.92(1H，m)，4.13-4.48(3H，m)，7.20(1H，d，J＝8.0Hz)，7.62(1H，d，J＝8.0Hz)，7.64(1H，s)，7.85-7.95(2H，m)，7.95-8.05(1H，m)，8.34(1H，s)，8.84-8.96(1H，m)，10.16(1H，s)，11.10(1H，br.s).

MS m/z：541(M+H)⁺.

[ example 382]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4R) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (thiazol-2-yl) cyclohexyl]Oxalamide hydrochloride and N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (thiazol-2-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 549 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating the 2 stereoisomers with hydrochloric acid in the same manner as in example 214.

Low polarity compounds:¹H-NMR(DMSO-d₆)δ：1.60-1.84(2H，m)，1.86-1.97(1H，m)，2.00-2.14(2H，m)，2.21-2.34(1H，m)，2.89(3H，br.s)，3.01-3.52(4H，m)，3.61-3.74(1H，m)，4.06-4.49(3H，m)，4.63-4.75(1H，m)，7.63(1H，d，J＝3.2Hz)，7.75(1H，d，J＝3.2Hz)，7.98-8.10(2H，m)，8.44(1H，br.s)，8.78-8.87(1H，m)，9.13-9.29(1H，m)，10.34-10.42(1H，m)，11.66(1H，br.s).

MS(FAB)m/z：560(M+H)⁺

highly polar compounds:¹H-NMR(DMSO-d₆)δ：1.67-1.80(2H，m)，1.89-1.99(1H，m)，2.10-2.25(2H，m)，2.30-2.46(1H，m)，2.90(3H，br.s)，3.08-3.53(4H，m)，3.65-3.76(1H，m)，4.05-4.53(3H，m)，4.64-4.75(1H，m)，7.62(1H，br.s)，7.73(1H，br.s)，7.97-8.10(2H，m)，8.44(1H，br.s)，8.69-8.81(1H，m)，9.18-9.34(1H，m)，10.20-10.35(1H，m)，11.48-11.92(1H，m).

MS(FAB)m/z：560(M+H)⁺.

example 383]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 2, 4-oxadiazol-3-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 550 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.64-1.79(2H，m)，1.84-1.95(1H，m)，2.01-2.22(2H，m)，2.30-2.43(1H，m)，2.91(4H，br.s)，3.19(2H，br.s)，3.34-3.79(2H，m)，4.06-4.17(1H，m)，4.35-4.75(3H，m)，7.97-8.06(2H，m)，8.42(1H，s)，8.81(1H，d，J＝7.1Hz)，9.21(1H，br.s)，9.51(1H，s)，10.28(1H，s).

MS(FAB)m/z：545(M+H)⁺.

[ example 384]N¹- (5-chloropyridin-2-yl) -N²- [ (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-oxadiazol-2-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 552 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 10 and then treating it with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.66-1.80(2H，m)，1.87-1.96(1H，m)，2.04-2.20(2H，m)，2.35-2.43(1H，m)，2.45(3H，s)，2.93(3H，s)，3.16-3.31(2H，m)，3.43-3.57(2H，m)，3.63-3.80(1H，m)，4.08-4.19(1H，m)，4.37-4.52(2H，m)，4.65-4.82(1H，m)，7.99-8.08(2H，m)，8.44-8.48(1H，m)，8.84(1H，d，J＝6.8Hz)，9.22(1H，br.s)，10.30(1H，s)，10.96-11.25(1H，m).

MS(EI)m/z：558(M⁺).

[ example 385]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 3, 4-oxadiazol-2-yl) cyclohexyl]Oxalamides

The title compound was obtained by treating the compound obtained in referential example 554 with hydrochloric acid for deprotection and then condensing with the compound obtained in referential example 10 in the same manner as in example 214.

¹H-NMR(CDCl₃)δ：1.72-2.00(2H，m)，2.13-2.23(2H，m)，2.28-2.36(1H，m)，2.39-2.46(1H，m)，2.53(3H，s)，2.80-2.91(2H，m)，2.93-3.00(2H，m)，3.28-3.38(1H，m)，3.69-3.79(2H，m)，4.14-4.24(1H，m)，4.68-4.77(1H，m)，7.51(1H，d，J＝8.3Hz)，7.70(1H，dd，J＝8.8，2.5Hz)，8.14(1H，d，J＝7.8Hz)，8.18(1H，d，J＝8.8Hz)，8.31(1H，d，J＝2.5Hz)，8.38(1H，s)，9.72(1H，s).

MS(FAB)m/z：545(M+H)⁺.

[ example 386]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 3-oxazol-2-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 556 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.65-1.82(2H，m)，1.85-2.00(1H，m)，2.01-2.22(2H，m)，2.31-2.48(1H，m)，2.94(3H，s)，3.08-3.74(4H，m)，3.65-3.83(1H，m)，4.06-4.20(1H，m)，4.36-4.55(2H，m)，4.65-4.82(1H，m)，7.14(1H，s)，8.00-8.17(3H，m)，8.48(1H，s)，8.77-8.90(1H，m)，9.14-9.34(1H，m)，10.25-10.40(1H，m)，11.35-11.68(1H，m).

MS m/z：544(M+H)⁺.

[ example 387]N¹- (5-chloropyridin-2-yl) -N²-((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) oxalamide hydrochloride

The compound (110mg) obtained in referential example 560 was dissolved in methylene chloride (5ml), and a 4N hydrochloric acid-dioxane solution (5ml) was added to the solution, followed by stirring 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 (5ml), to the solution were added the compound (71.1mg) obtained in referential example 266, 1-hydroxybenzotriazole (42.7mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (80.9mg) in this order, and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, methylene chloride and an aqueous sodium bicarbonate solution were added to the residue to separate the mixture, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 19). To the free body thus obtained was added 1N ethanol hydrochloride solution to concentrate, and further, ether was added, and the precipitated colorless powder was collected by filtration to obtain the title compound (69.8 mg).

¹H-NMR(DMSO-d₆)δ：1.65-1.85(2H，m)，1.89-1.92(1H，m)，2.05-2.22(2H，m)，2.32(3H，s)，2.35-2.46(1H，m)，2.93(3H，br.s)，3.05-3.56(4H，m)，3.65-3.78(1H，m)，4.05-4.18(1H，m)，4.35-4.53(2H，m)，4.65-4.83(1H，m)，7.97-8.10(2H，m)，8.46(1H，br.s)，8.78-8.90(1H，m)，9.15-9.32(1H，m)，10.30(1H，br.s)，10.90-11.30(1H，m).

MS(FAB)m/z：559(M+H)⁺.

[ example 388]N¹- (5-chloropyridin-2-yl) -N²- [ (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) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 562 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 266 and then treating it with hydrochloric acid in the same manner as in example 387.

¹H-NMR(DMSO-d₆)δ：1.68-1.86(2H，m)，1.96-2.08(1H，m)，2.11-2.28(2H，m)，2.38-2.47(1H，m)，2.94(3H，s)，3.10-3.30(1H，m)，3.37-3.62(2H，m)，3.63-3.80(1H，m)，4.11-4.23(1H，m)，4.38-4.51(2H，m)，4.65-4.81(1H，m)，7.99-8.08(2H，m)，8.44-8.48(1H，m)，8.76-8.84(1H，m)，9.20-9.34(1H，m)，9.52(1H，s)，10.29(1H，br.s)，10.99-11.33(1H，m).

MS(ESI)m/z：561(M+H)⁺.

[ example 389] N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide

To a solution of the compound (76.3g) obtained in referential example 563 in N, N-dimethylformamide (1.0L) were added the compound (38.4g) obtained in referential example 10, 1-hydroxybenzotriazole 1 hydrate (28.8g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (37.6g) and diisopropylethylamine (35ml), and the mixture was stirred at room temperature for 63 hours. After the reaction mixture was concentrated under reduced pressure, methylene chloride (1.2L) and an aqueous solution (500ml) of sodium hydrogencarbonate were added to the residue. The aqueous layer was extracted with dichloromethane, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate 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 (dichloromethane: methanol 50: 1 → 10: 1). The resulting powder (77.2g) was dissolved in methylene chloride (500ml), insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. Dichloromethane (250ml) was added again, and diethyl ether (1L) was added dropwise thereto, followed by stirring at 0 ℃ for 30 minutes and filtration to obtain the title compound (71.5 g).

¹H-NMR(CDCl₃)δ：1.61-1.75(1H，m)，1.78-2.21(5H，m)，2.19(3H，s)，2.27-2.37(1H，m)，2.52(3H，s)，2.77-2.95(4H，m)，2.96(3H，s)，3.70(1H，d，J＝15.4Hz)，3.75(1H，d，J＝15.6Hz)，4.48-4.57(1H，m)，4.76-4.85(1H，m)，7.40-7.49(2H，m)，8.21(2H，dd，J＝8.2，4.8Hz)，10.06(1H，br.d，J＝7.6Hz)，10.55(1H，br.s).

MS(ESI)m/z：548(M+H)⁺.

EXAMPLE 390N- [ (1R, 2S, 5S) -5- [ (dimethylamino) carbonyl ] -2- ({2- [ (5-fluoropyridin-2-yl) amino ] -2-oxothioacetyl } amino) cyclohexyl ] -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine-2-carboxamide citrate 1 hydrate

The compound (6.26g) obtained in example 389 was suspended in 100ml of 20% aqueous ethanol, and 11.4ml of a 1M aqueous citric acid solution was added. Dissolving with 20% aqueous ethanol under stirring at 60 deg.C. After hot filtration, the mixture was cooled to room temperature by stirring and left to stand for 1 day. The precipitated crystals were collected by filtration, dried at room temperature under reduced pressure for 2 hours, and left to stand for 1 day to obtain the title compound (6.95 g).

¹H-NMR(DMSO-d₆)δ：1.44-1.56(1H，m)，1.64-1.72(1H，m)，1.74-1.84(2H，m)，2.05(1H，d，J＝14.2Hz)，2.21-2.32(1H，m)，2.47-2.53(1H，m)，2.50(3H，s)，2.71(2H，d，J＝15.1Hz)，2.62(2H，d，J＝15.6Hz)，2.79(3H，s)，2.94-3.01(2H，m)，2.94(3H，s)，4.48-4.56(1H，m)，4.62-4.68(1H，m)，7.86-7.90(1H，dt，J＝8.2Hz)，8.10(1H，dd，J＝9.2，3.7Hz)，8.42(1H，d，J＝2.7Hz)，8.72(1H，d，J＝6.9Hz)，10.53(1H，s)，11.11(1H，d，J＝7.8Hz).

Elemental analysis: c₂₄H₃₀FN₇O₃S₂C₆H₈O₇H₂O

Theoretical value: c; 47.55, H; 5.32, N; 12.94, F; 2.51, S; 8.46

Measured value: c; 47.48, H; 5.10, N; 13.05, F; 2.55, S; 8.61mp (decomposition): 176 to 179

[ example 391]N¹- (5-chloropyridin-2-yl) -N²- [ (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) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 566 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 266 and then treating with hydrochloric acid in the same manner as in example 387.

¹H-NMR(DMSO-d₆)δ：1.67-1.82(2H，m)，1.92-2.03(1H，m)，2.06-2.26(2H，m)，2.35-2.44(1H，m)，2.68(3H，s)，2.94(3H，s)，3.13-3.27(2H，m)，3.40-3.56(2H，m)，3.66-3.80(1H，m)，4.09-4.22(1H，m)，4.37-4.51(2H，m)，4.64-4.82(1H，m)，7.98-8.07(2H，m)，8.44-8.48(1H，m)，8.79(1H，br.s)，9.16-9.34(1H，m)，10.29(1H，s).

MS(ESI)m/z：575(M+H)⁺.

[ example 392]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 3-oxazol-5-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 568 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 214.¹H-NMR(DMSO-d₆)δ：1.50-1.87(3H，m)，1.97-2.40(3H，m)，2.93(3H，s)，2.96-3.83(5H，m)，4.04-4.16(1H，m)，4.30-4.53(2H，m)，4.62-4.80(1H，m)，6.93(1H，s)，7.96-8.10(2H，m)，8.22(1H，s)，8.45(1H，s)，8.66-8.80(1H，m)，9.17-9.37(1H，m)，10.24-10.37(1H，m)，11.20-11.54(1H，m).

MS(ESI)m/z：544(M+H)⁺.

[ example 393]N¹- (5-chloropyridin-2-yl) -N²- ((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) oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 572 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 266 and then treating it with hydrochloric acid in the same manner as in example 387.

¹H-NMR(DMSO-d₆)δ：1.63-1.79(2H，m)，1.80-1.94(1H，m)，1.98-2.24(2H，m)，2.27-2.41(1H，m)，2.56(3H，s)，2.83(3H，s)，3.04-3.88(6H，m)，4.06-4.18(1H，m)，4.29-4.53(2H，m)，7.98-8.10(2H，m)，8.46(1H，d，J＝2.4Hz)，8.79(1H，d，J＝6.8Hz)，9.23(1H，d，J＝8.0Hz)，10.31(1H，s).

MS(ESI)m/z：559(M+H)⁺.

Example 394]N¹- (5-chloropyridin-2-yl) -N²- ((1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (4H-1, 2, 4-triazol-4-yl) cyclohexyl) ethanediamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 576 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 564 and then treating with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.69-1.79(1H，m)，1.87-2.00(1H，m)，2.04-2.14(1H，m)，2.17-2.40(3H，m)，2.92(3H，s)，3.02-3.84(4H，m)，4.13-4.22(1H，m)，4.35-4.83(4H，m)，7.99-8.05(2H，m)，8.45-8.47(1H，m)，8.65(2H，s)，8.69-8.76(1H，m)，9.39(1H，d，J＝8.1Hz)，10.29(1H，s)，11.49(1H，br.s).

MS(ESI)m/z：544(M+H)⁺.

Example 395]N¹- (5-chloropyridin-2-thienyl) -N²- ((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) oxalamide citrate

1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (308mg) and 1-hydroxybenzotriazole (159mg) were added to a solution of a lithium salt of a carboxylic acid (249mg) obtained by hydrolyzing the compound obtained in referential example 356 and a solution of the compound (317mg) obtained in referential example 577 in N, N-dimethylformamide (8ml) at 0 ℃ and stirred at room temperature for 11 hours. The reaction mixture was diluted with ethyl acetate, washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated brine in this order, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the resulting solid was dissolved in dichloromethane (10ml), and a 4N hydrochloric acid-dioxane solution (10ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (8ml), and the compound (262mg) obtained in referential example 10, 1-hydroxybenzotriazole (174mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (308mg) and triethylamine (149. mu.l) were added at room temperature. The reaction mixture was stirred for 19 hours, diluted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (dichloromethane: methanol 10: 1). The resulting compound was dissolved in ethanol, hexane was added, and the precipitated solid was collected by filtration. To the resulting solid (371mg) were added ethanol (15ml) and citric acid 1 hydrate (138mg) to dissolve it, and after concentrating under reduced pressure, water was added thereto, and after azeotropy was carried out 3 times, drying was carried out to obtain the title compound (503 mg).

¹H-NMR(DMSO-d₆)δ：1.69-1.84(2H，m)，1.87-1.99(1H，m)，2.05-2.22(2H，m)，2.35-2.52(1H，m)2.48(3H，s)，2.65(2H，d，J＝15.4Hz)，2.75(2H，d，J＝15.4Hz)，2.98(3H，s)，3.03-3.84(5H，m)，3.84-3.95(2H，m)，4.10-4.21(1H，m)，4.38-4.48(1H，m)，6.93(1H，d，J＝4.4Hz)，6.98(1H，d，J＝4.4Hz)，8.77(1H，d，J＝7.6Hz)，9.22(1H，d，J＝8.4Hz)，12.34(1H，s).

MS(ESI)m/z：564(M+H)⁺.

EXAMPLE 396]N¹- (5-bromo-2-pyridinyl) -N²- ((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) oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 579 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 564 and then treating it with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.70-2.15(5H，m)，2.32-2.43(1H，m)，2.45(3H，s)，2.92(3H，s)，3.10-3.30(3H，m)，3.49(1H，br.s)，3.70(1H，br.s)，4.09-4.17(1H，m)，4.38-4.52(2H，m)，4.69(1H，br.s)，7.99(1H，d，J＝8.8Hz)，8.13(1H，dd，J＝8.8，2.5Hz)，8.53(1H，d，J＝2.5Hz)，8.83(1H，br.s)，9.22(1H，br.s)，10.28(1H，s)，11.43(1H，br.s).

MS(FAB)m/z：603(M+H)⁺.

[ example 397 ]]N¹- (4-chlorophenyl) -N²- ((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) oxalamide citrate

The title compound was obtained by condensing the compound obtained in referential example 577 with the compound obtained in referential example 374, deprotecting the condensed product by treatment with hydrochloric acid, condensing the deprotected product with the compound obtained in referential example 10 and treating the condensed product with citric acid in the same manner as in example 395.

¹H-NMR(DMSO-d₆)δ：1.66-1.82(2H，m)，1.85-1.97(1H，m)，2.02-2.23(2H，m)，2.34-2.48(1H，m)，2.46(3H，s)，2.63(2H，d，J＝15.4Hz)，2.72(2H，d，J＝15.4Hz)，2.95(3H，s)，3.03-3.82(5H，m)，3.84-3.92(2H，m)，4.07-4.20(1H，m)，4.37-4.46(1H，m)，7.42(2H，d，J＝8.8Hz)，7.84(2H，d，J＝8.8Hz)，8.78(1H，d，J＝7.3Hz)，9.13(1H，d，J＝8.1Hz)，10.83(1H，s).

MS(ESI)m/z：558(M+H)⁺.

[ example 398]N¹- (5-chloropyridin-2-yl) -N²- ((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) oxalamide citrate

The title compound was obtained by condensing the compound obtained in referential example 577 with the compound obtained in referential example 266, deprotecting the condensation by treatment with hydrochloric acid, condensing the product with the compound obtained in referential example 540 and then treating the product with citric acid in the same manner as in example 395.

¹H-NMR(DMSO-d₆)δ：1.70-1.87(2H，m)，1.90-2.21(3H，m)，2.29-2.40(1H，m)，2.47(3H，s)，2.59(3H，s)，2.62(2H，d，J＝15.4Hz)，2.71(2H，d，J＝15.4Hz)，2.90-3.80(5H，m)，3.87-3.95(2H，m)，4.08-4.19(1H，m)，4.48-4.58(1H，m)，7.74(1H，d，J＝8.1Hz)，7.84(1H，d，J＝8.1Hz)，7.98-8.07(2H，m)，8.44-8.48(1H，m)，8.59(1H，d，J＝8.1Hz)，9.21(1H，d，J＝7.8Hz)，10.31(1H，s).MS(ESI)m/z：553(M+H)⁺.

[ 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 salt

The title compound was obtained by condensing the compound obtained in referential example 577 with 5-chloroindole-2-carboxylic acid, deprotecting by treatment with hydrochloric acid, further condensing with the compound obtained in referential example 10 and then treating with citric acid in the same manner as in example 395.

¹H-NMR(DMSO-d₆)δ：1.71-1.85(2H，m)，1.90-2.21(3H，m)，2.31-2.43(1H，m)，2.47(3H，s)，2.63(2H，d，J＝15.2Hz)，2.72(2H，d，J＝15.2Hz)，2.94(3H，s)，3.05-3.95(7H，m)，4.20-4.31(1H，m)，4.49-4.58(1H，m)，7.10(1H，d，J＝1.6Hz)，7.19(1H，dd，J＝8.8，2.0Hz)，7.44(1H，d，J＝8.8Hz)，7.70(1H，d，J＝2.0Hz)，8.40(1H，d，J＝7.6Hz)，8.44(1H，d，J＝7.6Hz)，11.79(1H，s).MS(ESI)m/z：554(M+H)⁺.

Example 400]N¹- (5-chloro-2-thienyl) -N²- ((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) oxalamide citrate

The title compound was obtained by condensing the lithium salt of the carboxylic acid obtained by hydrolyzing the compound of referential example 356 with the compound obtained in referential example 577, deprotecting the condensation product by treatment with hydrochloric acid, and then condensing the product with the compound obtained in referential example 540 and then treating the product with citric acid in the same manner as in example 395.

¹H-NMR(DMSO-d₆)δ：1.70-1.86(2H，m)，1.90-2.21(3H，m)，2.27-2.39(1H，m)，2.46(3H，s)，2.58(3H，s)，2.61(2H，d，J＝15.4Hz)，2.71(2H，d，J＝15.4Hz)，2.98-3.95(7H，m)，4.09-4.19(1H，m)，4.47-4.56(1H，m)，6.90(1H，d，J＝4.2Hz)，6.95(1H，d，J＝4.2Hz)，7.74(1H，d，J＝7.8Hz)，7.83(1H，d，J＝7.8Hz)，8.58(1H，d，J＝8.0Hz)，9.15(1H，d，J＝8.0Hz)，12.32(1H，s).

MS(ESI)m/z：558(M+H)⁺.

Example 401]N¹- ((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) -N²- {5- [2- (trimethylsilyl) ethynyl group]Pyridin-2-yl oxalamides

The title compound was obtained from the compound obtained in example 396 by the same method as that described in reference example 455.¹H-NMR(CDCl₃)δ：0.26(9H，s)，1.77-1.92(2H，m)，2.08-2.43(4H，m)，2.52(6H，s)，2.81-2.89(2H，m)，2.93-2.98(2H，m)，3.19-3.28(1H，m)，3.68-3.77(2H，m)，4.13-4.22(1H，m)，4.68-4.74(1H，m)，7.48(1H，d，J＝8.4Hz)，7.78(1H，dd，J＝8.4，2.3Hz)，8.11-8.17(2H，m)，8.44(1H，d，J＝2.3Hz)，9.73(1H，s).MS(FAB)m/z：621(M+H)⁺.

Example 402]N¹- (5-ethynylpyridin-2-yl) -N²- ((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) oxalamides

To a methanol (30ml) solution of the compound (617mg) obtained in example 401 was added potassium fluoride (116mg), and the mixture was 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 to separate the mixture. 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 on silica gel (dichloromethane: methanol 93: 7). The resulting solid was dissolved in methanol, and the solvent was distilled off under reduced pressure by adding water to obtain the title compound (287 mg).

¹H-NMR(CDCl₃)δ：1.81-1.96(2H，m)，2.07-2.19(2H，m)，2.27(1H，br.s)，2.41(1H，d，J＝13.2Hz)，2.52(3H，s)，2.58(3H，s)，2.88-3.07(4H，m)，3.22(1H，s)，3.27(1H，br.s)，3.76-3.92(2H，m)，4.20(1H，s)，4.71-4.76(1H，m)，7.60(1H，d，J＝8.3Hz)，7.79(1H，d，J＝8.3Hz)，8.14(1H，d，J＝8.3Hz)，8.23(1H，d，J＝7.4Hz)，8.45(1H，s)，9.81(1H，s).

MS(FAB)m/z：549(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 580 with hydrochloric acid for deprotection, then condensing it with the compound obtained in referential example 10 and then treating it with citric acid in the same manner as in example 214.¹H-NMR(DMSO-d₆)δ：1.75-1.90(2H，m)，1.91-2.03(1H，m)，2.10-2.22(1H，m)，2.25-2.52(2H，m)，2.47(3H，s)，2.63(2H，d，J＝15.4Hz)，2.73(2H，d，J＝15.4Hz)，2.96(3H，s)，3.00-3.95(7H，m)，4.41-4.58(2H，m)，8.02(1H，ddd，J＝8.8，2.0，2.0Hz)，8.39(1H，dd，J＝8.8，1.6Hz)，8.65-8.70(1H，m)，8.90-8.94(1H，m)，9.00(1H，d，J＝6.8Hz)，9.66(1H，d，J＝8.4Hz).

MS(ESI)m/z：567(M+H)⁺.

[ 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 salt

The title compound was obtained by condensing the compound obtained in referential example 577 with the compound obtained in referential example 516, deprotecting by treatment with hydrochloric acid, further condensing with the compound obtained in referential example 10 and then treating with citric acid in the same manner as in example 395.

¹H-NMR(DMSO-d₆)δ：1.66-1.80(2H，m)，1.85-1.96(1H，m)，2.00-2.16(2H，m)，2.30-2.41(1H，m)，2.46(3H，s)，2.63(2H，d，J＝15.6Hz)，2.72(2H，d，J＝15.6Hz)，2.96(3H，s)，3.10-3.95(7H，m)，4.11-4.22(1H，m)，4.40-4.50(1H，m)，6.90(1H，d，J＝38.8Hz)，7.51(2H，d，J＝8.4Hz)，7.68(2H，d，J＝8.4Hz)，8.54(1H，d，J＝7.2Hz)，8.62(1H，d，J＝7.6Hz).

MS(ESI)m/z：559(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 581 with hydrochloric acid for deprotection and then with the compound obtained in referential example 10 and then with citric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.69-1.86(2H，m)，1.89-2.03(1H，m)，2.05-2.19(1H，m)，2.20-2.34(1H，m)，2.34-2.49(1H，m)，2.47(3H，s)，2.63(2H，d，J＝15.4Hz)，2.72(2H，d，J＝15.4Hz)，2.96(3H，s)，3.00-3.80(5H，m)，3.84-3.91(2H，m)，4.30-4.42(1H，m)，4.47-4.56(1H，m)，7.91(1H，dd，J＝8.8，2.2Hz)，8.27(1H，d，J＝8.8Hz)，8.37-8.41(1H，m)，8.61(1H，s)，8.95(1H，d，J＝7.3Hz)，9.08(1H，d，J＝8.3Hz)，9.36(1H，s).

MS(ESI)m/z：566(M+H)⁺.

[ 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

The title compound was obtained by condensing the compound obtained in referential example 577 with the compound obtained in referential example 349, deprotecting by treatment with hydrochloric acid, condensing with the compound obtained in referential example 10 and then treating with citric acid in the same manner as in example 395.

¹H-NMR(DMSO-d₆)δ：1.71-1.88(2H，m)，1.90-2.02(1H，m)，2.07-2.26(2H，m)，2.34-2.44(1H，m)，2.47(3H，s)，2.63(2H，d，J＝15.4Hz)，2.73(2H，d，J＝15.4Hz)，2.95(3H，s)，3.17-3.94(7H，m)，4.18-4.30(1H，m)，4.46-4.56(1H，m)，7.76(1H，d，J＝8.8Hz)，7.89-7.94(1H，m)，8.08-8.13(1H，m)，8.76-8.85(1H，m)，8.96-9.06(1H，m).

MS(ESI)m/z：583(M+H)⁺.

Example 407]N¹- (5-chloropyridin-2-yl) -N²- [ (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) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 583 with hydrochloric acid for deprotection, then condensing with the compound obtained in referential example 266 and then treating with hydrochloric acid in the same manner as in example 387.

¹H-NMR(DMSO-d₆)δ：1.65-1.85(2H，m)，1.92-2.05(1H，m)，2.09-2.23(2H，m)，2.37-2.50(1H，m)，2.92(3H，s)，3.11-3.57(4H，m)，3.71(1H，br.s)，4.14(1H，br.s)，4.44(2H，br.s)，4.64-4.79(1H，m)，7.98-8.09(2H，m)，8.46(1H，br.s)，8.84(1H，br.s)，8.91(1H，br.s)，9.15-9.33(1H，m)，10.29(1H，br.s)，11.36-11.67(1H，m).

MS(FAB)m/z：545(M+H)⁺.

[ example 408]N¹- (5-chloropyridin-2-yl) -N²- { (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- [5- (trifluoromethyl) -1, 3, 4-oxadiazol-2-yl) cyclohexyl } ethanediamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 586 with hydrochloric acid for deprotection, then condensing with the compound obtained in referential example 10, and then treating with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.70-1.88(2H，m)，1.95-2.06(1H，m)，2.10-2.23(2H，m)，2.42-2.49(1H，m)，2.92(3H，s)，3.09-3.81(5H，m)，4.15(1H，br.s)，4.33-4.56(2H，m)，4.57-4.79(1H，m)，7.99-8.08(2H，m)，8.46(1H，br.s)，8.86(1H，d，J＝7.1Hz)，9.24(1H，br.s)，10.30(1H，s)，11.48(1H，br.s).

MS(ESI)m/z：613(M+H)⁺.

Example 409]N¹- (5-chloro-2-thienyl) -N²- ((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) oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 560 with hydrochloric acid to deprotect it in the same manner as in example 387, then condensing it with a lithium salt of a carboxylic acid obtained by hydrolyzing the compound of referential example 356, and then treating it with hydrochloric acid.

¹H-NMR(DMSO-d₆)δ：1.65-1.82(2H，m)，1.90-1.99(1H，m)，2.06-2.18(2H，m)，2.31(3H，s)，2.36-2.46(1H，m)，2.92(3H，s)，3.21(2H，br.s)，3.32-3.38(1H，m)，3.50(1H，br.s)，3.68(1H，br.s)，4.08-4.16(1H，m)，4.37-4.74(3H，m)，6.91(1H，d，J＝4.2Hz)，6.94(1H，d，J＝4.2Hz)，8.83(1H，d，J＝6.9Hz)，9.15(1H，br.s)，11.43(1H，br.s)，12.31(1H，s).

MS(FAB)m/z：564(M+H)⁺.

Example 410]N¹- (6-chloropyridazin-3-yl) -N²- ((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) oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 560 with hydrochloric acid for deprotection, then condensing with a lithium salt of a carboxylic acid obtained by hydrolyzing the compound of referential example 264 and then treating with hydrochloric acid in the same manner as in example 387.

¹H-NMR(DMSO-d₆)δ：1.69-1.82(2H，m)，1.97-2.03(1H，m)，2.08-2.20(2H，m)，2.32(3H，s)，2.39-2.45(1H，m)，2.81-2.83(4H，m)，3.10-3.53(3H，m)，4.10-4.18(1H，m)，4.36-4.46(4H，m)，7.98(1H，d，J＝9.2Hz)，8.29(1H，d，J＝9.2Hz)，8.79(1H，d，J＝7.1Hz)，9.27(1H，d，J＝7.8Hz)，11.06(1H，s).

MS(FAB)m/z：560(M+H)⁺.

Example 411]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (2-oxo-1, 3-oxan-3-yl) cyclohexyl]Oxalamides

To a methanol (70ml) solution of the compound (696mg) obtained in referential example 589 was added p-toluenesulfonic acid 1 hydrate (301mg), and the mixture was refluxed overnight. To the reaction mixture was added p-toluenesulfonic acid 1 hydrate (82mg), and the mixture was refluxed for 2 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (50ml), and the compound (338mg) obtained in referential example 564, 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (552mg) and 1-hydroxybenzotriazole (97mg) were added to stir at room temperature overnight. Triethylamine (599. mu.l) was added to the reaction mixture, and the mixture was stirred overnight at 45 ℃. Water and ethyl acetate were added to the reaction mixture to separate the reaction solution, and the organic layer was 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 flash column chromatography using silica gel as a carrier (dichloromethane: methanol 93: 7), a part of the objective product was concentrated, ether was added, and the resultant solid was filtered to obtain the title compound (83 mg).

¹H-NMR(CDCl₃)δ：1.46(9H，s)，1.58-1.65(2H，m)，1.79-2.05(4H，m)，3.47-3.55(2H，m)，3.84-3.93(2H，m)，4.29(1H，br.s)，4.33-4.39(2H，m)，5.08(1H，br.s)，7.70(1H，dd，J＝8.8，2.5Hz)，8.10(1H，br.s)，8.19(1H，dd，J＝8.8，0.7Hz)，8.31(1H，dd，J＝2.5，0.7Hz)，9.71(1H，s).

MS(ESI)m/z：562(M+H)⁺.

Example 412]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (tetrazol-1-yl) cyclohexyl]Oxalamides

The title compound was obtained by treating the compound obtained in referential example 592 with hydrochloric acid for deprotection and then condensing it with the compound obtained in referential example 10 in the same manner as in example 214.

¹H-NMR(CDCl₃)δ：1.90-2.02(1H，m)，2.16-2.29(2H，m)，2.40-2.52(2H，m)，2.52(3H，s)，2.59-2.66(1H，m)，2.80-2.91(2H，m)，2.94-2.98(2H，m)，3.68-3.78(2H，m)，4.23-4.32(1H，m)，4.78-4.92(2H，m)，7.55(1H，d，J＝8.1Hz)，7.70(1H，dd，J＝8.9，2.6Hz)，8.05(1H，d，J＝7.6Hz)，8.16(1H，dd，J＝8.9，0.6Hz)，8.32(1H，dd，J＝2.6，0.6Hz)，8.72(1H，s)，9.72(1H，s).

MS(ESI)m/z：545(M+H)⁺.

[ example 413 ]]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1H-pyrrol-1-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 594 with hydrochloric acid for deprotection, condensing the compound with the compound obtained in referential example 564 and then treating the resulting product with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.67-1.78(1H，m)，1.82-1.95(1H，m)，1.97-2.06(1H，m)，2.13-2.31(3H，m)，2.94(3H，s)，3.29-3.39(2H，m)，3.51(1H，br.s)，3.73(1H，br.s)，4.12-4.30(2H，m)，4.43(2H，br.s)，4.66-4.80(1H，m)，5.96(2H，br.s)，6.85(2H，br.s)，7.98-8.06(2H，m)，8.46(1H，br.s)，8.72(1H，br.s)，9.36(1H，br.s)，10.28(1H，br.s)，11.20-11.48(1H，m).

MS(FAB)m/z：542(M+H)⁺.

Example 414]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1, 2, 4-triazol-5-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 597 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 564 and then treating it with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.64-1.79(2H，m)，1.83-1.95(1H，m)，1.97-2.08(1H，m)，2.09-2.21(1H，m)，2.28-2.38(1H，m)，2.89(3H，s)，2.97-3.63(5H，m)，4.04-4.16(1H，m)，4.34-4.62(3H，m)，7.81(1H，br.s)，8.01(1H，dd，J＝8.9，2.3Hz)，8.05(1H，d，J＝8.9Hz)，8.46(1H，d，J＝2.3Hz)，8.74(1H，d，J＝6.Hz)，9.24(1H，br.s)，10.28(1H，s)，13.67(1H，br.s).

MS(FAB)m/z：544(M+H)⁺.

EXAMPLE 415]N¹- (5-chloropyridin-2-yl) -N²- [ (1S, 2R, 4S) -2- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -4- (1-methyl-1H-1, 2, 4-triazol-5-yl) cyclohexyl]Oxalamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 599 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 564 and then treating it with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆)δ：1.60-1.76(2H，m)，1.77-1.88(1H，m)，1.94-2.04(1H，m)，2.05-2.18(1H，m)，2.25-2.36(1H，m)，2.85-2.98(4H，m)，3.15-3.67(4H，m)，3.78(3H，s)，4.08(1H，br.s)，4.31-4.70(3H，m)，7.97-8.08(2H，m)，8.30(1H，s)，8.44(1H，br.s)，8.71(1H，d，J＝6.8Hz)，9.14-9.26(1H，m)，10.27(1H，s).MS(FAB)m/z：558(M+H)⁺.

MS(FAB)m/z：544(M+H)⁺.

[ 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

The title compound was obtained by treating the compound obtained in referential example 560 with hydrochloric acid to deprotect it, condensing it with the compound obtained in referential example 298 and then treating it with hydrochloric acid in the same manner as in example 387.

¹H-NMR(DMSO-d₆)δ：1.76-1.90(2H，m)，1.97-2.06(1H，m)，2.16-2.23(1H，m)，2.28-2.38(4H，m)，2.44-2.52(1H，m)，2.88(3H，s)，3.21(2H，br.s)，3.27-3.42(1H，m)，3.55(2H，br.s)，4.41-4.56(4H，m)，8.01(1H，dd，J＝8.8，1.7Hz)，8.38(1H，d，J＝9.1Hz)，8.67(1H，s)，8.91(1H，s)，9.06(1H，d，J＝6.9Hz)，9.64(1H，d，J＝7.8Hz).

MS(ESI)m/z：567(M+H)⁺.

[ example 417]N¹- (5-chloropyridin-2-yl) -N²- ((3R, 4S) -3- { [ (5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c)]Pyridin-2-yl) carbonyl]Amino } -1- (thiazol-2-yl) piperidin-4-yl) ethanediamide hydrochloride

The title compound was obtained by treating the compound obtained in referential example 603 with hydrochloric acid for deprotection, condensing with the compound obtained in referential example 10 and then treating with hydrochloric acid in the same manner as in example 214.

¹H-NMR(DMSO-d₆) δ: 1.73-1.87(1H, m), 2.21-2.37(1H, m), 2.91(3H, s), 3.03-3.29(2H, m), 3.31-3.52(2H, 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 (all 1H, each d, J ═ 7.8Hz), 10.28, 10.33 (all 1H, each br.s), 11.30-11.64(1H, br).

MS(ESI)m/z：561(M+H)⁺.

[ test example 1]Human FXa Inhibition (IC)₅₀Value) determination

To each well of a 96-well microplate, 10. mu.l of a sample 5% DMSO solution, 40. mu.l of Tris buffer (100mM Tris, 200mM potassium chloride, 0.2% BSA, pH 7.4), and 10. mu.l of 0.0625U/ml human FXa (Enzyme Research laboratories, Inc., dissolved and diluted in Tris buffer) were added at predetermined concentrations at appropriate intervals, 40. mu.l of a 750. mu.M S-2222 aqueous solution (Chromogenix Co.) was added, and the absorbance at 405nm was measured at room temperature for 10 minutes to determine the increase in absorbance (. DELTA.OD/minute). The test article was replaced with Tris buffer in the control group.

The inhibition rate (%) at each final concentration of the test sample obtained by the following formula was plotted on a logarithmic probability paper with the vertical axis and the final concentration of the test sample on the horizontal axis to obtain 50% Inhibition Concentration (IC) ₅₀Value).

Inhibition (%) - (1- Δ OD/min for test article ÷ Δ OD/min for control group) × 100

(results) Table 1 shows that the compounds of the present invention have potent FXa inhibitory action.

TABLE 1

[ test example 2] measurement of anti-FXa Activity in rat plasma after oral administration

(A) Administration and blood sampling

A test sample (10 mg) was orally administered (10ml/kg) to rats as a drug solution (1mg/ml) prepared by dissolving or suspending 10mg of a test sample in 0.5% Methylcellulose (MC). After 0.5, 1, 2, and 4 hours after administration, 0.5ml of blood (blood volume collected: 0.45ml) was collected from the jugular vein using a syringe filled with 50. mu.l of a 3.13% (w/v) aqueous solution of trisodium citrate dihydrate. After the control group rats were administered 0.5% MC solution, blood was collected in the same manner as described above. Each blood sample was centrifuged at 1500 Xg for 10 minutes at 4 ℃ to separate plasma, which was then stored at-40 ℃ until used in the following measurement of anti-FXa activity in plasma.

(B) Measurement of FXa inhibitory Activity in plasma

In the measurement of anti-FXa activity in plasma, S-2222 was used as a substrate. Mu.l of Tris buffer (100mM Tris, 200mM potassium chloride, 0.2% BSA, pH 7.4), 44. mu.l of human FXa (2.5U/ml) and 550. mu.l of water were mixed. The resulting human FXa solution was used for the following experiments. Mu.l of the rat plasma obtained in the above procedure (A) was added to each well of a 96-well microplate, 55. mu.l of the human FXa solution and 40. mu.l of a 750. mu.M aqueous S-2222 solution were sequentially added, and then immediately absorbance at 405nm was measured with an absorption spectrophotometer SPECTRA max340 or 190(Molecular Devices Co., U.S. A.) at room temperature to determine the reaction rate (. DELTA.OD/min).

The anti-FXa activity, i.e., the inhibition (%) was calculated by the following formula.

Inhibition (%) [1- (Δ OD/min of sample divided by Δ OD/min of control) ] × 100

(result) the compounds described in examples 63, 191, 192, 194 and 204 exhibited strong FXa inhibitory activity in plasma of 62% to 96% when orally administered at 10 mg/kg.

Claims (12)

1. A compound which is a compound represented by the formula,

2. a pharmaceutical having an inhibitory activity on activated blood coagulation factor tenth, which comprises the compound according to claim 1 or a salt thereof.

3. An activated blood coagulation factor tenth inhibitor comprising the compound according to claim 1 or a salt thereof.

4. A blood coagulation inhibitor comprising the compound according to claim 1 or a salt thereof.

5. A prophylactic and/or therapeutic agent for thrombosis or embolism, which comprises the compound according to claim 1 or a salt thereof.

6. An agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, thrombosis and reocclusion after blood flow reconstruction, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, thrombosis in extracorporeal circulation, or blood coagulation in blood collection, which comprises the compound or a salt thereof according to claim 1.

7. A pharmaceutical composition having an inhibitory activity on activated blood coagulation factor tenth, which comprises the compound or salt according to claim 1 and a pharmaceutically acceptable carrier.

8. Use of the compound or salt thereof according to claim 1 for the production of a pharmaceutical agent having an inhibitory activity on activated blood coagulation factor ten.

9. Use of the compound of claim 1 or a salt thereof for the preparation of an activated coagulation factor tenth inhibitor.

10. Use of a compound of claim 1 or a salt thereof in the preparation of a coagulation inhibitor.

11. Use of the compound or a salt thereof according to claim 1 for the production of a prophylactic and/or therapeutic agent for thrombosis or embolism.

12. Use of the compound or a salt thereof according to claim 1 for production of an agent for preventing and/or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve/joint replacement, thrombosis and reocclusion after blood flow reconstruction, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, thrombosis during extracorporeal circulation, or blood coagulation during blood collection.