CN1751025A - Diamine derivatives - Google Patents

Abstract

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 or the like; q¹Represents a saturated or unsaturated 5-to 6-membered cyclic hydrocarbon group which may have a substituent, or the like; q²Represents a single bond or the like, Q³Represented by the following group (2), wherein Q⁵An alkylene group having 1 to 8 carbon atoms; t is⁰And T¹Represents a carbonyl group or the like. Used as cerebral infarction, cerebral embolism and myocardial infarctionThe prophylactic and/or therapeutic agent is useful for thrombosis in extracorporeal circulation or blood coagulation in blood collection, or for thrombosis in extracorporeal circulation, or for pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombosis after prosthetic valve/joint replacement, thrombosis and reocclusion after blood flow reconstruction, Systemic Inflammatory Response Syndrome (SIRS), Multiple Organ Dysfunction Syndrome (MODS), or the like.

Description

Diamine derivatives

technical field

The present invention relates to a novel compound that inhibits activated blood coagulation factor ten (hereinafter abbreviated as FXa), exhibits strong anticoagulation effect, orally, or a blood coagulation inhibitor containing it as an active ingredient, or prevention of thrombus or embolism and/or therapeutic agent.

Background technique

Unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep vein thrombosis, disseminated intravascular coagulation syndrome, thrombosis after artificial valve replacement, blood flow remodeling Hypercoagulation is one of the important causes of subsequent reocclusion and thrombosis during extracorporeal circulation. Therefore, it is necessary to have excellent dose-responsiveness, persistence, low risk of bleeding, and few side effects. A good anticoagulant drug (Thrombosis Research, volume 68, pages 507-512, 1992).

In studies of anticoagulants based on various mechanisms of action, the possibility of FXa inhibitors being good anticoagulants has been suggested. The blood coagulation system is a series of reactions in which a large amount of thrombin is produced and insoluble fibrin is produced through a multi-stage enzymatic reaction and amplified process. In the endogenous system, after the activation of the contact factor, the multi-stage reaction continues, and then in the presence of the activated factor VIII, calcium ions, the activated factor IX activates the tenth factor on the phospholipid membrane. In addition, activated factor VII activates factor X in the presence of tissue factor in an exogenous system. That is, the activation of factor 10 in the blood coagulation system to FXa is a reaction necessary for the generation of thrombin. The activated tenth factor (FXa) in the two systems is restricted to decompose prothrombin to generate thrombin. Thrombin generation is further amplified because the generated thrombin activates upstream coagulation factors. As described above, the coagulation system upstream of FXa is divided into the intrinsic system and the extrinsic system, so inhibition of coagulation system enzymes upstream of FXa does not sufficiently inhibit the production of FXa, resulting in the generation of thrombin. Furthermore, since the blood coagulation system is a self-amplifying reaction, inhibition of the upstream FXa can achieve more effective inhibition of the blood coagulation system than inhibition of generated thrombin (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 prolongs the bleeding time in the experimental bleeding model. From the results of this experiment, it can be considered that FXa inhibitors are anticoagulants with less risk of bleeding medicine.

Various compounds have been reported as FXa inhibitors, but it is known that general antithrombin III and antithrombin III-dependent pentasaccharides do not inhibit the prothrombinase complex ( Thrombosis Research, Volume 68, Pages 507-512, 1992, Journal of Clinical Investigation, Volume 71, Pages 1383-1389, 1983, Mebio, Volume 14, August Issue, Pages 92-97), and oral administration does not appear to be effective sex. Tick anticoagulant peptide (TAP) (Science, volume 248, pages 593-596, 1990) and hirudin (AST) isolated from mites and leeches as blood-sucking animals (Journal of Biological Chemistry, volume 263, 10162-10167 Pages, 1988) also have inhibitory effect on FXa, from venous thrombosis model to arterial thrombosis model all show antithrombotic effect, but they are all high molecular weight peptides, oral ineffective. Therefore, the development of an orally available low-molecular-weight FXa inhibitor that directly inhibits antithrombin III-independent blood coagulation factors has been pursued.

disclosure of invention

Therefore, the object of the present invention is to provide a novel compound that has a potent FXa inhibitory effect and can quickly exhibit sufficient and sustained antithrombotic effect when administered orally.

After discussing the synthesis and pharmacological effects of the new FXa inhibitors, the present invention finds diamine derivatives, their salts, their solvates or their N-oxides that exhibit strong FXa inhibitory and anticoagulant effects. In addition, since oral administration of these compounds immediately, continuously, and effectively inhibits FXa and exhibits strong anticoagulant and antithrombotic effects, it has been found that they are useful as preventive and therapeutic agents for various diseases based on thrombosis and embolism, thereby completing the invention.

That is, the present invention provides general formula (1)

Q ¹ -Q ² -T ⁰ -N(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (1)

The indicated compounds, their salts, their solvates or their N-oxides;

In the formula, R ¹ and R ² are each independently representing a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q ¹ represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5-7 membered heterocyclic group which may have a substituent, a saturated or unsaturated 2-membered hydrocarbon group which may have a substituent A cyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have substituents;

Q ² represents 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 chain Alkynylene groups with 2 to 6 carbon atoms, divalent saturated or unsaturated 5 to 6-membered cyclic hydrocarbon groups that may have substituents, divalent saturated or unsaturated 5 to 7-membered heterohydrocarbon groups that may have substituents A cyclic group, a divalent saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated bicyclic or tricyclic fused heterohydrocarbon group which may have a substituent ring group;

Q ³ consists of the following groups

means that Q ⁵ in this group is an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or a group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -( m and n in the group are independent, representing an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O -NH-, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-);

R ³ and R ⁴ are substituted on the carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁵ , each independently representing a hydrogen atom, hydroxyl, alkyl, alkenyl, alkynyl, halogen atom, haloalkyl, Cyano, cyanoalkyl, amino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, optionally substituted acylamino, alkoxy Imino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl Amino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and which may have a substituent on the alkyl group N, N-dialkylcarbamoyl, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoyl Base-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 substituents , carbamoylalkyl, N-alkylcarbamoylalkyl that may have substituents on the alkyl, N, N-dialkylcarbamoylalkyl that may have substituents on the alkyl, carbamoyloxy Alkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, 3-6 membered heterocyclic carbonylalkyl which may have substituents, may have substituents 3-6 membered heterocyclic carbonyloxyalkyl groups, aryl groups, aralkyl groups, 3-6 membered heterocyclic groups that may have substituents, 3-6 membered heterocycloalkyl groups that may have substituents, alkylsulfonium Amino, arylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, aryl Sulfonylaminocarbonylalkyl, oxo, carbamoyloxy, aralkoxy, carboxyalkoxy, alkoxycarbonylalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, Alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxy Acyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may have a substituent, 3- to 6-membered heterocyclic epoxy group which may have a substituent group, N-alkylacylamino group, N,N-dialkylaminoacyl group, N,N-dialkylcarbamoylacyl group which may have substituents on the alkyl group, N,N-dialkylcarbamoyl group which may have substituents on the alkyl group -Dialkylcarbamoylalkylsulfonyl, alkylsulfonylacyl, N-arylcarbamoyl, N-3 to 6-membered heterocyclic carbamoyl, N-alkyl-N-arylcarbamoyl , N-Alkyl-N-3～6 membered heterocyclic carbamoyl, N-arylcarbamoyl alkyl, N-3～6 membered heterocyclic carbamoyl alkyl, N-alkyl-N-aryl Carbothioyl, N-alkyl-N-3-6 membered heterocyclic carbamoyl alkyl, carbothioyl, N-alkylcarbamoyl, N, N-two Alkylaminothioformyl, alkoxyalkyl (thiocarbonyl), alkylthioalkyl or N-acyl-N-alkylaminoalkyl or ^R3 and ^R4 together represent 1 to 5 carbon atoms An alkylene group, an alkenylene group with 2 to 5 carbon atoms, an alkylenedioxy group or a carbonyldioxy group with 1 to 5 carbon atoms;

^Q represents an optionally substituted aryl group, an optionally substituted arylalkenyl group, an optionally substituted arylalkynyl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl chain Alkenyl, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group that may have a substituent, a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have a substituent;

T ⁰ represents carbonyl or thiocarbonyl;

T ¹ represents carbonyl, sulfonyl, group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C(=O)-N(R')- , base-C(=O)-C(=S)-N(R')-, base-C(=S)-C(=S)-N(R')-(R' in the group represents Hydrogen atom, hydroxyl group, alkyl or alkoxy group), group -C(=O)-A ¹ -N(R")-(A ¹ in the group represents a C1-5 carbon atom that may have a substituent Alkylene, R" represents a hydrogen atom, hydroxyl, alkyl or alkoxy), group -C(=O)-NH-, group -C(=S)-NH-, group -C(=O)- NH-NH-, group-C(=O)-A ² -C(=O)-(A in the group represents a single bond or an alkylene group with 1 to 5 carbon atoms), ^group -C(= O)-A ³ -C(=O)-NH-(A ³ in the group represents an alkylene group with 1 to 5 carbon atoms), group-C(=O)-C(=NOR ^a )-N (R ^b )-, group-C(=S)-C(=NOR ^a )-N(R ^b )-(R ^a in the group represents a hydrogen atom, an alkyl group or an alkanoyl group, and R ^b represents a hydrogen atom, hydroxy, alkyl or alkoxy), group-C(=O)-N=N-, group-C(=S)-N=N-, group-C(=NOR ^c )-C(=O) -N(R ^d )-(R ^c in the group represents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, and R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), group-C (=NN-(R ^e )(R ^f ))-C(=O)-N(R ^g )-(R ^e and R ^f in the group are independently hydrogen atom, alkyl, alkanoyl, alkane Group (thiocarbonyl), R ^g represents a hydrogen atom, hydroxyl, alkyl or alkoxy), group-C(=O)-NH-C(=O)-, group-C(=S)-NH- C(=O)-, group-C(=O)-NH-C(=S)-, group-C(=S)-NHC(=S)-, group-C(=O)-NH-SO ₂ -, -SO ₂ -NH-, -C(=NCN)-NH-C(=O)-, -C(=S)-C(=O)- or thiocarbonyl.

In addition, the present invention also provides pharmaceuticals containing the compounds represented by the above general formula (1), their salts, their solvates or their N-oxides, in particular, activated blood coagulation factor ten inhibitors, blood coagulation Inhibitors, prophylactic and/or therapeutic agents for thrombosis or embolism, cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep vein thrombosis, disseminated intravascular Coagulation syndrome, thrombosis after prosthetic valve/joint replacement, thrombosis and reocclusion after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombosis during cardiopulmonary bypass or a prophylactic and/or therapeutic agent for coagulation during blood collection.

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

The present invention also provides the use of the compounds represented by the above general formula (1), their salts, their solvates or their N-oxides in the preparation of pharmaceuticals.

The present invention also provides a method for treating thrombus or embolism, which is characterized by administering an effective amount of the compound represented by the above general formula (1), its salt, their solvate or their N-oxide.

Since the cyclic diamine derivative of the present invention exhibits a strong inhibitory effect on activated blood coagulation factor ten, it can be used as a medicine, an activated blood coagulation factor ten inhibitor, a blood coagulation inhibitor, and the prevention and/or prevention of thrombus or embolism. or therapeutic agents, prophylactic and/or therapeutic agents for thrombotic diseases, and can also be used as cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep vein thrombosis, diffuse vascular Internal coagulation syndrome, thrombosis after prosthetic valve/joint replacement, thrombosis and reocclusion after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombosis during cardiopulmonary bypass A prophylactic and/or therapeutic agent for coagulation during formation or blood collection.

The best way to practice the invention

Hereinafter, the substituent in the diamine derivative of this invention represented by General formula (1) is demonstrated.

(with respect to group Q ⁴ )

Group ^Q represents 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 heteroaryl group which may have a substituent an alkenyl group, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group which may have a substituent, a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent.

In the group ^Q4 , the aryl group refers to an aryl group having 6 to 14 carbon atoms, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, etc. can be mentioned. The arylalkenyl group represents a group composed of an aryl group having 6 to 14 carbon atoms and an alkenylene group having 2 to 6 carbon atoms, for example, a styryl group. 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, for example, a phenylethynyl group and the like.

The heteroaryl group represents an aromatic monovalent group having at least one heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom, and a heteroaryl group having a total ring atom number of 5 or 6, for example, pyridyl, Pyridazinyl, pyrazinyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrimidinyl, tetrazolyl, etc. The heteroarylalkenyl group means a group composed of the above-mentioned heteroaryl group and an alkenylene group having 2 to 6 carbon atoms, and examples thereof include thienylvinyl, pyridylvinyl and the like.

A saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group represents a monovalent group formed of a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon, and the saturated or unsaturated bicyclic or The tricyclic condensed hydrocarbon is a bicyclic or tricyclic condensed hydrocarbon formed by condensing two or three of the same or different saturated or unsaturated 5- to 6-membered cyclic hydrocarbons. The saturated or unsaturated 5-6 membered cyclic hydrocarbon may, for example, be cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene or benzene. Specific examples of the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group include indenyl, indanyl, tetrahydronaphthyl, naphthyl and the like. The binding position of the saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group to ^T1 in the general formula (1) is not particularly limited.

A saturated or unsaturated bicyclic or tricyclic fused heterocyclic group is a monovalent group formed by a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic ring, and the saturated or unsaturated 2 Cyclic or tricyclic fused heterocycles are shown in 1) to 3) below.

1) A 2- or 3-ring fused heterocycle formed by the fusion of 2 to 3 saturated or unsaturated 5- to 7-membered heterocycles of the same or different species;

2) A 2- or 3-membered condensed heterocycle formed by the fusion of one saturated or unsaturated 5-7 membered heterocycle and 1-2 saturated or unsaturated 5-6-membered cyclic hydrocarbons; and

3) A tricyclic condensed heterocycle formed by condensing two saturated or unsaturated 5- to 7-membered heterocycles and one saturated or unsaturated 5- to 6-membered cyclic hydrocarbon.

There is no particular limitation on the bonding position of the saturated or unsaturated bicyclic or tricyclic fused heterocyclic group to ^T1 in the general formula (1).

The aforementioned saturated or unsaturated 5- to 7-membered heterocyclic ring means a heterocyclic ring having at least one heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom. Specific examples thereof include furan, pyrrole, thiophene, pyrazole, imidazole, Oxazole, oxazolidine, thiazole, thiadiazole, furoxan, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, oxazine, oxadiazine, morpholine, thiazine, thiadi Oxazine, thiomorpholine, tetrazole, triazole, triazine, thiadiazine, oxadiazine, aza_, diaza_, triaza_, thia_, oxa_. In addition, the saturated or unsaturated 5-6 membered cyclic hydrocarbon is the same as the saturated or unsaturated 5-6-membered cyclic hydrocarbon exemplified in the description of the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group. compound of. Specific examples of saturated or unsaturated bicyclic or tricyclic fused heterocyclic groups include benzofuryl, isobenzofuryl, benzothienyl, indolyl, indolinyl, iso Indolyl, isoindolinyl, indazolyl, quinolinyl, dihydroquinolinyl, 4-oxodihydroquinolinyl (dihydroquinolin-4-one), tetrahydroquinolinyl, Isoquinolyl, tetrahydroisoquinolyl, chromenyl, chromanyl, isochromanyl, 4H-4-oxobenzopyranyl, 3,4-di Hydrogen-4H-4-oxobenzopyranyl, 4H-quinazinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, tetrahydroquinoxalinyl , cinnolinyl, indolizyl, tetrahydroindolizyl, benzothiazolyl, tetrahydrobenzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzo Imidazolyl, naphthyridyl, tetrahydronaphthyridyl, thienopyridyl, tetrahydrothienopyridyl, thiazolopyridyl, tetrahydrothiazolopyridyl, thiazolopyridazinyl, tetrahydrothiazolopyridazinyl , pyrrolopyridyl, dihydropyrrolopyridyl, tetrahydropyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, pyridoquinazolinyl, dihydropyrrolopyridinyl, pyrido Pyrimidinyl, tetrahydropyridopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl, tetrahydrooxazolopyridyl, oxazole Pyridazinyl, tetrahydrooxazolopyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolyl, thienopyrrolyl, thiazolopyrimidinyl, 4-oxotetrahydrocinnolinyl, 1,2,4-benzothiadiazinyl, 1,1-dioxide-2H-1,2,4-benzothiadiazinyl, 1,2,4 -Benzoxadiazinyl, cyclopentadienopyranyl, thienofuryl, furopyranyl, pyridoxazinyl, pyrazolooxazolyl, imidazothiazolyl, imidazopyridyl , Tetrahydroimidazopyridyl, pyrazinopyridazinyl, benzisoquinolinyl, furanocinnolinyl, pyrazolothiazolopyridazinyl, tetrahydropyrazolothiazolopyridazinyl, hexahydro Thiazolopyridazinopyridazinyl, imidazotriazinyl, oxazolopyridyl, benzoxepinyl, benzazepinyl, tetrahydrobenzazepinyl, benzodiazepine_ Base, benzotriazepine-base, thiezoazepine-base, tetrahydrothiezoazepine-base, thienodiazepine-base, thienotriazepine-base, thiazoloazepine-base, tetrahydrothiezepine-base, Hydrogenthiazoloazepine-yl, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl, 5,6-trimethylene-4,5,6,7-tetra Hydrothiazolopyridazinyl, etc.

There is no particular limitation on the fused form of the above-mentioned fused heterocyclic group, for example, naphthyridinyl, which can be 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7 - any of naphthyridyl, thienopyridyl, may be thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-b] Any of pyridyl, thieno[3,2-c]pyridyl, thieno[3,4-b]pyridyl, thieno[3,4-c]pyridyl, thienopyrrolyl, can It is any one of thieno[2,3-b]pyrrolyl, thieno[2,3-b]pyrrolyl, thiazolopyridyl, it can be thiazolo[4,5-b]pyridyl, thiazole And[4,5-c]pyridyl, thiazolo[5,4-b]pyridyl, thiazolo[5,4-c]pyridyl, thiazolo[3,4-a]pyridyl, thiazolo[ Any of 3,2-a]pyridyl, thiazolopyridazinyl, can be thiazolo[4,5-c]pyridazinyl, thiazolo[4,5-d]pyridazinyl, thiazolo Any one of [5,4-c]pyridazinyl, thiazolo[3,2-b]pyridazinyl, pyrrolopyridyl, 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 , any of 4-c]pyridyl, pyridopyrimidinyl, can be pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4 Any of -d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[1,2-c]pyrimidinyl, pyrido[1,2-a]pyrimidinyl, pyrano Thiazolyl, which can be pyrano[2,3-d]thiazolyl, pyrano[4,3-d]thiazolyl, pyrano[3,4-d]thiazolyl, pyrano[3, Any of 2-d]thiazolyl, furopyridyl, can be furo[2,3-b]pyridyl, furo[2,3-c]pyridyl, furo[3,2- b] Any of pyridyl, furo[3,2-c]pyridyl, furo[3,4-b]pyridyl, furo[3,4-c]pyridyl, oxazolopyridine The base can be oxazolo[4,5-b]pyridyl, oxazolo[4,5-c]pyridyl, oxazolo[5,4-b]pyridyl, oxazolo[5,4 Any one of -c]pyridyl, oxazolo[3,4-a]pyridyl, oxazolo[3,2-a]pyridyl, oxazolopyridazinyl, may be oxazolo[ 4,5-c]pyridazinyl, oxazolo[4,5-d]pyridazinyl, oxazolo[5,4-c]pyridazinyl, oxazolo[3,4-b]pyridazinyl Any of the bases, pyrrolothiazolyl, can be pyrrolo[2,1-b]thiazolyl, pyrrolo[1,2-c]thiazolyl, pyrrolo[2,3-d]thiazolyl, Any one of pyrrolo[3,2-d]thiazolyl, pyrrolo[3,4-d]thiazolyl, pyrrolooxazolyl, can be pyrrolo[2,1-b]oxazolyl, Pyrrolo[1,2-c]oxazolyl, pyrrolo[2,3-d]oxazolyl, pyrrolo[3,2-d]oxazolyl, pyrrolo[3,4-d]oxazole Any of the bases, benzazepin-base, can be in 1H-1-benzazepin-base, 1H-2-benzazepin-base, 1H-3-benzazepin-base Either, 4,5-dihydro-1-oxo-1H-2-benzazepin-yl, may be dihydro-oxo derivative type benzazepin-yl, benzodiazepine _, can be any of 1H-1,3-benzodiazepin-base, 1H-1,4-benzodiazepine-base, 1H-1,5-benzodiazepine-base Species, such as 4,5-dihydro-4-oxo-1H-1,3-benzodiazepin-yl, can be benzodiazepin-yl of dihydro-oxo derivative type, benzo Triazepin-yl, can be any one of 1H-1,3,4-benzotriazepin-yl, 1H-1,3,5-benzotriazepin-yl, such as 4,5- Dihydro-5-oxo-1H-1,3,4-benzotriazepin-yl, which may be dihydro-oxo derivative type benzotriazepin-yl, thienoazepin-yl, Can be thieno[2,3-b]azepin-yl, thieno[2,3-c]azepin-yl, thieno[2,3-d]azepin-yl, thieno[3,2 -c] any of azepine-base, thieno [3,2-b] azepine-base, such as 5,6,7,8-tetrahydro-4-oxo-4H-thieno [3 , 2-c] azepine-base, can be thienoazepin-base of dihydro-oxo derivative type, thienodiazepine-base or thienotriazepine-base, can be any of the same Fused type, or dihydro-oxo derivative type, benzothia-yl, can be 1H-1-benzothia-yl, 1H-2-benzothia-yl, 1H - Any of the 3-benzothiapinyls, such as 4,5-dihydro-1-oxo-1H-2-benzothiapinyl, may be of the dihydro-oxo derivative type Benzothiapin-yl, benzoxepin-yl, can be in 1H-1-benzoxepin-yl, 1H-2-benzoxepin-yl, 1H-3-benzoxepin-yl Either, such as 4,5-dihydro-1-oxo-1H-2-benzoxepinyl, can be a benzoxepinyl of the dihydro-oxo derivative type, and can also be these Forms other than fused forms.

The above-mentioned aryl group, heteroaryl group, arylalkenyl group, heteroarylalkenyl group, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group and saturated or unsaturated bicyclic or tricyclic The condensed heterocyclic group can have 1 to 3 substituents, such as hydroxyl, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, and the number of carbon atoms substituted by 1 to 3 halogen atoms 1-6 haloalkyl, amino, cyano, aminoalkyl, nitro, hydroxyalkyl (for example, hydroxymethyl, 2-hydroxyethyl, etc.), alkoxyalkyl (for example, methoxymethyl , 2-methoxyethyl, etc.), carboxyl, carboxyalkyl (for example, carboxymethyl, 2-carboxyethyl, etc.), alkoxycarbonylalkyl (for example, methoxycarbonylmethyl, ethoxy carbonylmethyl, etc.), acyl (for example, alkanoyl such as formyl, acetyl, propionyl, etc.), amidino, hydroxyamidino (amino (hydroxyimino) methyl), linear, branched or cyclic Alkyl groups with 1 to 6 carbon atoms (for example, methyl, ethyl, etc.), linear, branched or cyclic alkoxy groups with 1 to 6 carbon atoms (for example, methoxy, ethyl, etc.) Oxy group, etc.), linear, branched or cyclic amidino group substituted with an alkyl group having 1 to 6 carbon atoms (for example, imino (methylamino) methyl, etc.), linear, branched Alkoxy-substituted amidino groups (for example, amino(methoxyimino)methyl, etc.) with a carbon number of 1 to 6 in shape or cyclic, straight-chain, branched or cyclic with 2 carbon atoms Alkoxycarbonyl-substituted amidinos of ~7 (for example, amino(methoxycarbonylimino)methyl, amino(ethoxycarbonylimino)methyl, etc.), linear, branched or cyclic Alkenyl groups with 2 to 6 carbon atoms (for example, vinyl, allyl, etc.), linear or branched alkynyl groups with 2 to 6 carbon atoms (for example, ethynyl, propynyl, etc. ), a straight-chain, branched or cyclic alkoxycarbonyl group with 2 to 6 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, etc.), carbamoyl, with a straight chain on the nitrogen atom Shaped, branched or cyclic C1-6 alkyl substituted mono- or dialkylcarbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, ethylmethylcarbamoyl, etc.), mono- or dialkylamino (for example, ethylamino, dimethylamino , methylethylamino) and 5-6 membered nitrogen-containing heterocyclic groups (for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.) and the like.

Among the groups Q ⁴ represented by the above groups, the following 12 types of groups (a) to (l) are preferred. That is, better groups can be exemplified

[In the group, ^R5 and ^R6 are each independently representing 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 group Carbonyl, alkoxycarbonylalkyl or phenyl which may be substituted by cyano, hydroxyl, halogen atom, alkyl or alkoxy, R ⁷ and R ⁸ each independently represent a hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylaminomethyl group Acyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkyl],

[In the group, ^R9 and ^R10 are each independently representing a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, Alkoxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkane base],

[In the group, R ¹¹ , R ¹² and R ¹³ are each independently representing a hydrogen atom, hydroxyl, nitro, amino, cyano, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkane Oxy, alkoxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxy Cylcarbonylalkyl],

[In the group, X ¹ represents CH ₂ , CH, NH, NOH, N, O or S, R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently representing a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, Alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N, N -dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkyl],

[In the group, X ² represents NH, N, O or S, X ³ represents N, C or CH, X ⁴ represents N, C or CH, R ¹⁷ and R ¹⁸ are each independently representing a hydrogen atom, hydroxyl, nitro, Amino, cyano, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alk Carbamoyl group, N,N-dialkylcarbamoyl group, alkoxycarbonyl group, amidino group or alkoxycarbonylalkyl group, X ³ and X ⁴ are the combination of C and CH and are C or CH exception],

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

[In the group, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, Z ³ represents CH ₂ , CH, S, SO ₂ or C=O, X ⁵ -Z ² means that X ⁵ and Z ² are combined with a single bond or a double bond, R ²² and R ²³ are independent, representing a hydrogen atom, hydroxyl, nitro, amino, cyano, halogen atom, alkyl , alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N, N-di Alkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkyl, R ²⁴ represents a hydrogen atom or an alkyl],

[In the group, ^X6 represents O or S, and ^R25 and ^R26 are each independently representing a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyl group Alkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, amidine group or alkoxycarbonylalkyl],

[In the group, R ²⁷ and R ²⁸ are each independently representing a hydrogen atom, a hydroxyl group, a nitro group, an amino group, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, Alkoxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkane base],

[In the group, ^E1 and ^E2 are each independently representing N or CH, ^R29 and ^R30 are independently representing a hydrogen atom, hydroxyl, nitro, amino, cyano, halogen, alkyl, alkenyl, alkyne group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyalkyl group, acyl group, carbamoyl group, N-alkylcarbamoyl group, N,N-dialkylcarbamoyl group, Alkoxycarbonyl, amidino or alkoxycarbonylalkyl],

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

[In the group, the numbers from 1 to 8 represent positions, each N represents any one of 1 to 4 carbon atoms and any one of 5 to 8 carbon atoms is replaced by a nitrogen atom, R ³⁴ , R ³⁵ and R ³⁶ Each independently represents hydrogen atom, hydroxyl group, nitro group, amino group, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, carboxyl group, carboxyl group Alkyl, acyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, amidino or alkoxycarbonylalkyl].

These groups are described below.

The halogen atom in the description of R ⁵ to R ³⁶ in the above group represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and an alkyl group represents a linear, branched or cyclic group having 1 to 6 carbon atoms. Group, alkenyl means a straight-chain, branched or cyclic group with 2 to 6 carbon atoms, alkynyl means a straight-chain or branched group with 2 to 6 carbon atoms, hydroxyalkane The group represents the above-mentioned C ₁ to C ₆ alkyl group substituted with one hydroxyl group, the alkoxy group represents a linear, branched or cyclic group with 1 to 6 carbon atoms, and the alkoxyalkyl group represents The aforementioned C ₁ -C ₆ alkyl groups are substituted by one of the aforementioned C ₁ -C ₆ alkoxy groups; carboxyalkyl means the aforementioned C ₁ -C ₆ alkyl groups are substituted by one carboxyl group; acyl means carbon atoms Aroyl groups such as alkanoyl (including formyl), benzoyl or naphthoyl with the number 1 to 6, or aryl alkanoyl with the above C ₁ to C ₆ alkanoyl substituted by the aforementioned C ₆ to C ₁₄ aryl, N- Alkylcarbamoyl means the carbamoyl group in which the above-mentioned C ₁ -C ₆ alkyl group is substituted on the nitrogen atom, and N,N-dialkylcarbamoyl group means that 2 of the above-mentioned C ₁ -C ₆ alkyl groups are substituted on the nitrogen atom carbamoyl, alkoxycarbonyl means a group formed by the above C ₁ to C ₆ alkoxy and carbonyl, alkoxycarbonylalkyl means that the above C ₁ to C ₆ alkyl has one of the above C ₁ to C A group substituted with ₆ alkoxycarbonyl groups, and a haloalkyl group means a group in which the aforementioned C ₁ -C ₆ alkyl groups are substituted with 1 - 3 halogen atoms. In the above description, there is no particular limitation on the substitution position.

The following groups

[In the group, R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as described above, and the numbers from 1 to 6 represent positions], wherein R ⁵ and R ⁶ are each independently, preferably a hydrogen atom, a cyano group, or a halogen atom , alkyl, alkenyl, alkynyl or haloalkyl. More preferably, R ⁵ and R ⁶ are a hydrogen atom or an alkyl group, and when they are an alkyl group, they are preferably a methyl group. Preferably, one of R ^{and R} is a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, or a haloalkyl group, and it is particularly desirable that the other side is hydrogen atom, halogen atom, alkyl or alkynyl. In this case, the halogen atom is preferably a fluorine atom, chlorine atom and bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. Preferable examples of the specific groups represented by the above formula can be exemplified by chlorostyryl, fluorostyryl, bromostyryl, ethynylstyryl, etc., for the halogen atom, alkyl or alkynyl in these groups The substitution position of is not particularly limited, but it is particularly desirable to be the 4-position in the above formula. Specific preferred examples include 4-chlorostyryl, 4-fluorostyryl, 4-bromostyryl, 4- Ethynyl styryl etc.

The following groups

[In the group, R ⁹ and R ¹⁰ are as described above, and the numbers from 1 to 6 represent positions], wherein R ⁹ and R ¹⁰ are each independently, preferably a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. More preferably, ^R9 is a hydrogen atom, and ^R10 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, chlorine atom and bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. Preferable examples of specific groups represented by the above formula may include chlorophenylethynyl, fluorophenylethynyl, bromophenylethynyl, ethynylphenylethynyl, etc., for halogen atoms, alkyl or alkynyl groups in these groups The substitution position of is not particularly limited, but the 4-position in the above formula is particularly ideal. Specific and better examples include 4-chlorophenylethynyl, 4-fluorophenylethynyl, 4-bromophenylethynyl , 4-ethynylphenylethynyl, etc.

The following groups

[In the group, R ¹¹ , R ¹² and R ¹³ are as described above, and the numbers from 1 to 8 represent positions], wherein R ¹¹ , R ¹² and R ¹³ are each independently, preferably a hydrogen atom, a cyano group, or a halogen atom , alkyl, alkenyl, alkynyl or haloalkyl. R ¹¹ is more preferably a hydrogen atom, an alkyl group, a halogen atom or a hydroxyl group, particularly preferably a hydrogen atom. Preferably, one of ^R12 and ^R13 is a hydrogen atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, and particularly preferably the other is a hydrogen atom. , halogen atom, alkyl or alkynyl. In this case, the halogen atom is preferably a fluorine atom, chlorine atom and bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The above-mentioned naphthyl, 2-naphthyl is more ideal than 1-naphthyl, and when it is 2-naphthyl, there is no special limitation on the substitution position of halogen atom, alkyl or alkynyl, but it is preferably the 6-position or 7 bits, the best is 6 bits. More preferably, these naphthyl groups are substituted by a chlorine atom, a fluorine atom, a bromine atom, an alkynyl group, etc., particularly preferably a chlorine atom, a fluorine atom, a bromine atom, an alkynyl group, or the like. group. Specific preferred examples 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, 7-ethynyl-2-naphthyl and the like.

The following groups

[In the group, X ¹ , R ¹⁴ , R ¹⁵ and R ¹⁶ are as described above, and the numbers from 4 to 7 indicate positions], wherein X ¹ is preferably NH, NOH, N, O and S, more preferably NH , O and S. R ¹⁴ is preferably a hydrogen atom, a halogen atom, an acyl group, an N-alkylcarbamoyl group, a N,N-dialkylcarbamoyl group, an alkyl group, R ¹⁵ and R ¹⁶ are each independently, preferably a hydrogen atom, a cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl. Preferably, one of ^R15 and ^R16 is a hydrogen atom or a halogen atom, preferably a fluorine atom or a chlorine atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkane Among them, it is particularly preferable that 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, chlorine atom and bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. There is no particular limitation on the substitution position of the halogen atom, the alkyl group or the alkynyl group, but it is preferably the 4-position, 5-position or 6-position in the above formula. Preferable examples of specific groups represented by the above formulas include 5-chloroindolyl, 5-fluoroindolyl, 5-bromoindolyl, 5-ethynylindolyl, and 5-methylindolyl , 5-chloro-4-fluoroindolyl, 5-chloro-3-fluoroindolyl, 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-formylindole Base, 5-fluoro-3-formylindolyl, 6-chloroindolyl, 6-fluoroindolyl, 6-bromoindolyl, 6-ethynylindolyl, 6-methylindolyl , 5-chlorobenzothienyl, 5-fluorobenzothienyl, 5-bromobenzothienyl, 5-ethynylbenzothienyl, 5-methylbenzothienyl, 5-chloro-4-fluoro Benzothienyl, 6-chlorobenzothienyl, 6-fluorobenzothienyl, 6-bromobenzothienyl, 6-ethynylbenzothienyl, 6-methylbenzothienyl, 5-chloro Benzofuryl, 5-fluorobenzofuryl, 5-bromobenzofuryl, 5-ethynylbenzofuryl, 5-methylbenzofuryl, 5-chloro-4-fluorobenzofuryl , 6-chlorobenzofuryl, 6-fluorobenzofuryl, 6-bromobenzofuryl, 6-ethynylbenzofuryl, 6-methylbenzofuryl, etc. The binding position of these substituents to ^T1 is not particularly limited, but it is preferably the 2-position or 3-position in the above formula (d), specifically 5-chloroindol-2-yl, 5-fluoroindole -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-fluoro Indol-2-yl, 5-bromo-3-chloroindol-2-yl, 5-bromo-3-fluoroindol-2-yl, 5-chloro-3-formylindol-2-yl, 5-fluoro-3-formyl indol-2-yl, 5-bromo-3-formyl indol-2-yl, 5-ethynyl-3-formyl indol-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-chloro Indol-2-yl, 6-fluoroindol-2-yl, 6-bromoindol-2-yl, 6-ethynylindol-2-yl, 6-methylindol-2-yl, 5 -Chlorindol-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-ethynyl indol Indol-3-yl, 6-methylindol-3-yl, 5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl, 5-methylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl, 6-bromobenzothiophen-2-yl, 6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl, 5-chlorobenzene thiophen-3-yl, 5-fluorobenzothiophen-3-yl, 5-bromobenzothiophen-3-yl, 5-ethynylbenzothiophen-3-yl, 5-methylbenzothiophen-3 -yl, 5-chloro-4-fluorobenzothiophen-3-yl, 6-chlorobenzothiophen-3-yl, 6-fluorobenzothiophen-3-yl, 6-bromobenzothiophen-3-yl , 6-ethynylbenzothiophen-3-yl, 6-methylbenzothiophen-3-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-2-yl, 5-bromo Benzofuran-2-yl, 5-ethynylbenzofuran-2-yl, 5-methylbenzofuran-2-yl, 5-chloro-4-fluorobenzofuran-2-yl, 6-chloro Benzofuran-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, etc.; particularly preferred are 5-chloroindol-2-yl, 5- Fluorindol-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 Indol-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-formylindole -2-yl, 5-fluoro-3-formyl indol-2-yl, 5-bromo-3-formyl indol-2-yl, 5-ethynyl-3-formyl indol-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- Base, 5-chlorobenzothiophen-2-yl, 5-fluorobenzothiophen-2-yl, 5-bromobenzothiophen-2-yl, 5-ethynylbenzothiophen-2-yl, 5-methyl ylbenzothiophen-2-yl, 5-chloro-4-fluorobenzothiophen-2-yl, 6-chlorobenzothiophen-2-yl, 6-fluorobenzothiophen-2-yl, 6-bromobenzene Dithiophen-2-yl, 6-ethynylbenzothiophen-2-yl, 6-methylbenzothiophen-2-yl, 5-chlorobenzofuran-2-yl, 5-fluorobenzofuran-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, X ² , X ³ , X ⁴ , R ¹⁷ and R ¹⁸ are as described above, and the numbers from 4 to 7 indicate positions], wherein X ² is preferably NH, O or S, and X ³ and X ⁴ Either one of is preferably CH or C, particularly preferably one of them is C. R ¹⁷ and R ¹⁸ are each independently, preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. Preferably, one of ^R17 and ^R18 is a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, and it is particularly preferable that the other side is a hydrogen atom, a halogeno group, or a hydrogen atom. atom, alkyl or alkynyl. In this case, the halogen atom is preferably a fluorine atom, chlorine atom and bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. There is no particular limitation on the substitution position of a halogen atom, an alkyl group or an alkynyl group, but it is preferably the 5-position or 6-position in the above formula. Preferable examples of specific groups 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-ethynyl Benzimidazolyl, 6-chlorobenzoimidazolyl, 6-fluorobenzoimidazolyl, 6-bromobenzoimidazolyl, 6-ethynylbenzoimidazolyl, 5-chlorobenzothiazolyl, 5-fluorobenzene Thiazolyl, 5-bromobenzothiazolyl, 5-ethynylbenzothiazolyl, 6-chlorobenzothiazolyl, 6-fluorobenzothiazolyl, 6-bromobenzothiazolyl, 6-ethynylbenzene Thiazolyl, 5-chlorobenzoxazolyl, 5-fluorobenzoxazolyl, 5-bromobenzoxazolyl, 5-ethynylbenzoxazolyl, 6-chlorobenzoxazolyl, 6-fluorobenzoxazolyl, 6-bromobenzoxazolyl, 6-ethynylbenzoxazolyl, 5-chlorobenzisothiazolyl, 5-fluorobenzisothiazolyl, 5-bromobenzene Benzisothiazolyl, 5-ethynylbenzisothiazolyl, 6-chlorobenzisothiazolyl, 6-fluorobenzisothiazolyl, 6-bromobenzisothiazolyl, 6-ethynylbenzisothiazolyl Base, 5-chlorobenzisoxazolyl, 5-fluorobenzisoxazolyl, 5-bromobenzisoxazolyl, 5-ethynylbenzisoxazolyl, 6-chlorobenzisoxazolyl Azolyl, 6-fluorobenzisoxazolyl, 6-bromobenzisoxazolyl, 6-ethynylbenzisoxazolyl, etc., there is no particular limitation on the binding positions of these substituents and ^T1 , but Preferred are 5-chloroindazol-3-yl, 5-fluoroindazol-3-yl, 5-bromoindazol-3-yl, 5-ethynyl indazol-3-yl, 6-chloroindazol -3-yl, 6-fluoroindazol-3-yl, 6-bromoindazol-3-yl, 6-ethynyl indazol-3-yl, 5-chlorobenzimidazol-2-yl, 5-fluoro Benzimidazol-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, 6-bromobenzothiazole- 2-yl, 6-ethynylbenzothiazol-2-yl, 5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl, 5-bromobenzoxazol-2- Base, 5-ethynylbenzoxazol-2-yl, 6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl, 6-bromobenzoxazol-2-yl , 6-ethynylbenzoxazol-2-yl, 5-chlorobenzisothiazol-3-yl, 5-fluorobenzisothiazol-3-yl, 5-bromobenzisothiazol-3-yl, 5-ethynylbenzisothiazol-3-yl, 6-chlorobenzisothiazol-3-yl, 6-fluorobenzisothiazol-3-yl, 6-bromobenzisothiazol-3-yl, 6 -Ethynylbenzisothiazol-3-yl, 5-chlorobenzisoxazol-3-yl, 5-fluorobenzisoxazol-3-yl, 5-bromobenzisoxazol-3-yl , 5-ethynylbenzisoxazol-3-yl, 6-chlorobenzisoxazol-3-yl, 6-fluorobenzisoxazol-3-yl, 6-bromobenzisoxazol-3-yl 3-yl, 6-ethynylbenzisoxazol-3-yl, especially 5-chlorobenzimidazol-2-yl, 5-fluorobenzimidazol-2-yl, 5-bromobenzimidazole -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-ethynylbenzene Andthiazol-2-yl, 6-chlorobenzothiazol-2-yl, 6-fluorobenzothiazol-2-yl, 6-bromobenzothiazol-2-yl, 6-ethynylbenzothiazol-2- Base, 5-chlorobenzoxazol-2-yl, 5-fluorobenzoxazol-2-yl, 5-bromobenzoxazol-2-yl, 5-ethynylbenzoxazol-2-yl , 6-chlorobenzoxazol-2-yl, 6-fluorobenzoxazol-2-yl, 6-bromobenzoxazol-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 that one or two of the carbon atoms of the ring substituted by R ¹⁹ is replaced by a nitrogen atom, R ¹⁹ , R ²⁰ and R ²¹ are as described above, and the numbers from 5 to 8 represent positions], wherein, R ¹⁹ , R ²⁰ and R ²¹ are each independently, preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. R ¹⁹ is particularly preferably a hydrogen atom, R ²⁰ and R ²¹ are preferably a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, and particularly preferably is the other side is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. The halogen atom in this case is a fluorine atom, a chlorine atom and a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. There is no particular limitation on the substitution position of the halogen atom, the alkyl group or the alkynyl group, but it is preferably the 6-position or the 7-position in the above formula. The specific group represented by the above formula can be exemplified by quinolinyl, isoquinolyl, cinnolinyl, preferably 6-chloroquinolyl, 6-fluoroquinolyl, 6-bromoquinolyl, 6-ethynyl Quinolinyl, 6-chloroisoquinolinyl, 6-fluoroisoquinolinyl, 6-bromoisoquinolinyl, 6-ethynylisoquinolinyl, 7-chlorocinnolinyl, 7-fluorocinnolinyl Base, 7-bromocinnolinyl, 7-ethynylcinnolinyl, etc. 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 - Base, 7-bromoquinolin-2-yl, 7-ethynylquinolin-2-yl, 7-chloroquinolin-3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3 -yl, 7-ethynylquinolin-3-yl, 6-chloroisoquinolin-3-yl, 6-fluoroisoquinolin-3-yl, 6-bromoisoquinolin-3-yl, 6-ethynyl Base isoquinolin-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, etc. The best of these are 6-chloroquinolin-2-yl, 6-fluoroquinolin-2-yl, 6-bromoquinolin-2-yl, 6-ethynylquinolin-2-yl, 7-chloroquinolin-2-yl, 3-yl, 7-fluoroquinolin-3-yl, 7-bromoquinolin-3-yl, 7-ethynylquinolin-3-yl, 7-chloroisoquinolin-3-yl, 7-fluoroiso Quinolin-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 group, the numbers from 5 to 8 represent positions, X ⁵ represents CH ₂ , CH, N or NH, Z ¹ represents N, NH or O, Z ² represents CH ₂ , CH, C or N, Z ³ represents CH ₂ , CH, S, SO ₂ or C=O, X ⁵ -Z ² means that X ⁵ and Z ² are combined with a single bond or a double bond, R ²² , R ²³ and R ²⁴ are as described above], wherein, R ²² and R ²³ are each independently, preferably a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. Preferably, one of ^R22 and ^R23 is a hydrogen atom, and the other is a hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, and it is particularly preferable that the other side is a hydrogen atom, a halogeno group, or a hydrogen atom. atom, alkyl or alkynyl. The halogen atom in this case is a fluorine atom, a chlorine atom and a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. There is no particular limitation on the substitution position of the halogen atom, the alkyl group or the alkynyl group, but it is preferably the 6-position or the 7-position in the above formula. R ²⁴ is preferably a hydrogen atom or an alkyl group, and the alkyl group is preferably a methyl group. R ²⁴ is particularly preferably a hydrogen atom. The specific group represented by the above formula can be exemplified by 4-oxodihydroquinolinyl, tetrahydroquinolinyl, 4-oxodihydroquinazolin-2-yl, 4-oxotetrahydrocinnolinyl, 4-oxobenzopyranyl group, 4-oxobenzothiadiazinyl group, 1,1-dioxy-4-oxobenzothiadiazinyl group, benzoxadiazinyl group and the like. More specific groups include 6-chloro-4-oxodihydroquinolyl, 6-fluoro-4-oxodihydroquinolyl, 6-bromo-4-oxodihydroquinolyl, 6-ethynyl-4-oxodihydroquinolinyl, 7-chloro-4-oxodihydroquinolinyl, 7-fluoro-4-oxodihydroquinolinyl, 7-bromo-4-oxo Substituted dihydroquinolinyl, 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, 6-ethynyl-4-oxo-1,4-dihydroquinazole Linyl, 7-chloro-4-oxo-1,4-dihydroquinazolinyl, 7-fluoro-4-oxo-1,4-dihydroquinazolinyl, 7-bromo-4-oxo Generation-1,4-dihydroquinazolinyl, 7-ethynyl-4-oxo-1,4-dihydroquinazolinyl, 6-chloro-1,2,3,4-tetrahydroquinoline Base, 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-tetrahydroquinolinyl, 7-fluoro-1,2,3,4-tetrahydroquinolinyl, 7-bromo-1,2 , 3,4-tetrahydroquinolinyl, 7-ethynyl-1,2,3,4-tetrahydroquinolinyl, 6-chloro-1,2,3,4-tetrahydro-4-oxoquinolinyl Linyl, 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-tetrahydro-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-oxobenzopyranyl, 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-dioxide-2H-1,2,4-benzothiadiazinyl, 6-fluoro-1,1-dioxide-2H-1,2,4-benzothiadiazinyl, 6- Bromo-1,1-dioxide-2H-1,2,4-benzothiadiazinyl, 6-ethynyl-1,1-dioxide-2H-1,2,4-benzothiadiazinyl , 7-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazinyl, 7-fluoro-1,1-dioxide-2H-1,2,4-benzothiadiazinyl Azinyl, 7-bromo-1,1-dioxide-2H-1,2,4-benzothiadiazinyl, 7-ethynyl-1,1-dioxide-2H-1,2,4-benzene Thiadiazinyl, 6-chloro-2H-1,2,4-benzoxadiazinyl, 6-fluoro-2H-1,2,4-benzoxadiazinyl, 6-bromo-2H- 1,2,4-benzoxadiazinyl, 6-ethynyl-2H-1,2,4-benzoxadiazinyl, 7-chloro-2H-1,2,4-benzoxadiazinyl Base, 7-fluoro-2H-1,2,4-benzoxadiazinyl, 7-bromo-2H-1,2,4-benzoxadiazinyl, 7-ethynyl-2H-1,2 , 4-benzoxadiazinyl, etc. 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 Generation-1,4-dihydroquinolin-2-yl, 7-fluoro-4-oxo-1,4-dihydroquinolin-2-yl, 7-bromo-4-oxo-1,4- Dihydroquinolin-2-yl, 7-ethynyl-4-oxo-1,4-dihydroquinolin-2-yl, 6-chloro-4-oxo-1,4-dihydroquinazoline -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, 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 - Base, 6-chloro-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl, 6-fluoro-1,2,3,4-tetrahydro-4-oxocinnoline -2-yl, 6-bromo-1,2,3,4-tetrahydro-4-oxocinnolin-2-yl, 6-ethynyl-1,2,3,4-tetrahydro-4-oxo Suboxocinnolin-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-tetra Hydrogen-4-oxocinnolin-2-yl, 6-chloro-4H-4-oxobenzopyran-2-yl, 6-fluoro-4H-4-oxobenzopyran-2-yl , 6-bromo-4H-4-oxobenzopyran-2-yl, 6-ethynyl-4H-4-oxobenzopyran-2-yl, 7-chloro-4H-4-oxo Benzopyran-2-yl, 7-fluoro-4H-4-oxobenzopyran-2-yl, 7-bromo-4H-4-oxobenzopyran-2-yl, 7-acetylene Base-4H-4-oxobenzopyran-2-yl, 6-chloro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl, 6-fluoro- 1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl, 6-bromo-1,1-dioxide-2H-1,2,4-benzothiadiazine- 3-yl, 6-ethynyl-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl, 7-chloro-1,1-dioxide-2H-1,2 , 4-benzothiadiazin-3-yl, 7-fluoro-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl, 7-bromo-1,1- Dioxide-2H-1,2,4-benzothiadiazin-3-yl, 7-ethynyl-1,1-dioxide-2H-1,2,4-benzothiadiazin-3-yl , 6-chloro-2H-1,2,4-benzoxadiazin-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-benzoxadio Oxazin-3-yl, 7-ethynyl-2H-1,2,4-benzoxadiazin-3-yl, etc. Among them, 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, 6-ethynyl-4-oxo-1,4-dihydroquinazolin-2-yl.

The following groups

[In the group, X ⁶ represents O or S, R ²⁵ and R ²⁶ are as described above, and the numbers from 5 to 8 represent positions], wherein X ⁶ is preferably O, R ²⁵ and R ²⁶ are independently, preferably A hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group. Preferably, one of ^R25 and ^R26 is a hydrogen atom, and the other is a hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl, and particularly preferably the other is a hydrogen atom, halogen atom, alkyl or alkynyl. The halogen atom in this case is a fluorine atom, a chlorine atom and a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. There is no particular limitation on the substitution position of the halogen atom, the alkyl group or the alkynyl group, but it is preferably the 6-position or the 7-position in the above formula. Specific groups 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, 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, 7-ethynyl-2H- Chrom-3-yl.

The following groups

[In the group, R ²⁷ and R ²⁸ are as described above, and the numbers from 1 to 6 indicate the position], wherein, R ²⁷ and R ²⁸ are preferably one hydrogen atom or a halogen atom, and the other is a hydrogen atom, cyano group, Nitro, amino, halogen, alkyl, alkenyl, alkynyl, haloalkyl or N,N-dialkylcarbamoyl, where the other is preferably a hydrogen atom, halogen, alkyl or alkyne base. The halogen atom in this case is a fluorine atom, a chlorine atom and a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. Preferable examples of specific groups represented by the above formulas include phenyl, chlorophenyl, fluorophenyl, bromophenyl, ethynylphenyl, chlorofluorophenyl, etc., for halogen atoms, alkane, etc. in these groups The substitution position of the radical or alkynyl group is not particularly limited, and when there is one substituent, it is particularly preferably the 3rd and 4th positions in the above formula, and when there are two substituents, it is particularly preferably the 4th and 2nd positions in the above formula or a combination of 3 bits. Specific examples 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-chloro-2-methylphenyl, 4-fluoro-2-methylphenyl, 4-bromo-2-methylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dibromophenyl.

The following groups

[In the group, E ¹ , E ² , R ²⁹ and R ³⁰ are as described above, and the numbers from 1 to 6 represent positions], wherein, R ²⁹ and R ³⁰ are preferably one of hydrogen atom or halogen atom, and the other is A hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, wherein the other is particularly preferably a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. The halogen atom in this case is a fluorine atom, a chlorine atom and a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The specific group represented by the above formula can be exemplified by pyridyl, pyrimidyl, pyridazinyl, etc., the substitution position of the halogen atom, alkyl or alkynyl in these groups is not particularly limited, and the combination with the group ^T1 is When the 2-position in the above formula is used, particularly preferably the 4-position and 5-position in the above-mentioned formula. Specific preferred examples include 2-pyridyl, 3-pyridyl, 4-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, 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-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 Base, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 5-chloro-4-fluoro -2-pyridyl, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 6-chloro-3-pyridyl Azinyl, 6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl, 6-ethynyl-3-pyridazinyl, 4-chloro-3-pyridazinyl, 4-fluoro-3- Pyridazinyl, 4-bromo-3-pyridazinyl, 4-ethynyl-3-pyridazinyl. The best of these are 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-chloro-2-pyridyl, 5-fluoro-2-pyridyl, 5-bromo-2-pyridyl, 5-ethynyl Base-2-pyridyl, 5-chloro-4-fluoro-2-pyridyl, 4-chloro-5-fluoro-2-pyridyl, 4-chloro-3-pyridazinyl, 4-fluoro-3-pyridyl azinyl, 4-bromo-3-pyridazinyl, 4-ethynyl-3-pyridazinyl.

In addition, the following groups

[In the group, Y ¹ , Y ² , R ³¹ and R ³² are as described above, and the numbers from 1 to 5 represent positions], wherein, R ³¹ and R ³² are preferably one of hydrogen atom or halogen atom, and the other is A hydrogen atom, a cyano group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, wherein the other is particularly preferably a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. The halogen atom in this case is a fluorine atom, a chlorine atom and a bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. The specific group represented by the above formula can be thienyl, pyrrolyl, furyl, oxazolyl, thiazolyl, etc., and the substitution position of halogen atom, alkyl or alkynyl in these groups is not particularly limited, especially 4 and 5 in the above formula. Specifically, 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-thiophene Base, 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.

The following groups

[In the group, the numbers from 1 to 8 represent positions, each N represents any one of 1 to 4 carbon atoms and any one of 5 to 8 carbon atoms is replaced by a nitrogen atom, and R ³⁴ to R ³⁶ are as described above described], wherein, the position of each nitrogen atom can be any position, ^R34 is preferably a hydrogen atom or a halogen atom, ^R35 and ^R36 are preferably one of a hydrogen atom or a halogen atom, and the other is a hydrogen atom, a cyanogen A group, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or a haloalkyl group, and it is particularly preferable that the other one is a hydrogen atom, a halogen atom, an alkyl group or an alkynyl group. The halogen atom is preferably a fluorine atom, chlorine atom and bromine atom, the alkyl group is preferably a methyl group, and the alkynyl group is preferably an ethynyl group. There is no special limitation on the substitution positions of halogen atoms, alkyl groups or alkynyl groups. Specific groups represented by the above formulas include 6-chloro-1,5-naphthyridin-2-yl, 6-fluoro-1,5-naphthalene Pyridine-2-yl, 6-bromo-1,5-naphthyridin-2-yl, 6-ethynyl-1,5-naphthyridin-2-yl, 7-chloro-1,5-naphthyridin-2- Base, 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-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-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-naphthyridine -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, etc. Particularly preferred are 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 and the like.

In addition to the 12 types of groups (a) to (l) above, a thienopyrrolyl group which may have a substituent is preferred. It may have 1 to 3 substituents, such as hydroxyl, nitro, amino, cyano, halogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, alkane Oxyalkyl, carboxy, carboxyalkyl, acyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, alkoxycarbonyl, amidino and alkoxycarbonylalkyl , Among them, cyano group, halogen atom, alkyl group, alkenyl group, alkynyl group and haloalkyl group are preferred. Specific preferred examples 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 or 2-ethynylthieno[2,3-b]pyrrol-5-yl, etc.

[About group Q ¹ ]

In the present invention, ^Q represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5-7 membered heterocyclic group that may have a substituent, a saturated or unsaturated cyclic hydrocarbon group that may have a substituent An unsaturated bicyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have a substituent.

The above-mentioned saturated or unsaturated 5-6 membered cyclic hydrocarbon groups can be exemplified by cyclopentyl, cyclopentenyl, cyclohexyl, cyclopentenyl, phenyl, etc., preferably cyclopentyl, cyclohexyl and phenyl , more preferably phenyl.

A saturated or unsaturated 5- to 7-membered heterocyclic group represents a monovalent group formed by a heterocyclic ring having at least one heteroatom selected from an oxygen atom, a sulfur atom, and a nitrogen atom, and examples include furyl, pyrrolyl, and thiophene Base, pyrazolyl, imidazolyl, pyrazolyl, oxazolyl, oxazolyl, thiazolyl, thiazolinyl, thiadiazolyl, furazanyl, pyryl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl , triazinyl, azepinyl, diazepinyl and triazepinyl, etc. Among them, 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. In addition, among these heterocyclic groups, nitrogen-containing heterocyclic groups may be N-oxides.

The saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group has the same meaning as the saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group described in the description of Q ⁴ of the general formula (1), Specific examples include indenyl, indanyl, naphthyl, tetrahydronaphthyl, anthracenyl, phenanthrenyl, etc., preferably indenyl, indanyl, naphthyl and tetrahydronaphthyl.

A saturated or unsaturated bicyclic or tricyclic fused heterocyclic group and a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group described in the description of Q ⁴ of the general formula (1) have the same meaning, and specific examples can include benzofuryl, isobenzofuryl, benzothienyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, quinolyl, Linyl, dihydroquinolinyl, 4-oxodihydroquinolinyl (dihydroquinolin-4-one), tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, chromenyl , chromanyl, isochromanyl, 4H-4-oxochromanyl, 3,4-dihydro-4H-4-oxochromanyl, 4H -Quinazinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, tetrahydroquinoxalinyl, cinnolinyl, tetrahydrocinnolinyl, indolizine , Tetrahydroindolizyl, benzothiazolyl, tetrahydrobenzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, naphthyridinyl, tetrahydro Naphthyridyl, Thienopyridyl, Tetrahydrothienopyridyl, Thiazolopyridyl, Tetrahydrothiazolopyridyl, Thiazolopyridazinyl, Tetrahydrothiazolopyridazinyl, Pyrrolopyridyl, Dihydropyrrole pyridyl, tetrahydropyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, pyridoquinazolinyl, dihydropyridoquinazolinyl, pyridopyrimidinyl, tetrahydropyridopyrimidinyl , pyranothiazolyl, dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridyl, oxazolopyridyl, tetrahydrooxazolopyridyl, oxazolopyridazinyl, tetrahydrooxazole Pyridazinyl, pyrrolothiazolyl, dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrrolooxazolyl, thienopyrrolyl, thiazolopyrimidinyl, dihydrothiazolopyrimidinyl, 4- Oxytetrahydrocinnolinyl, 1,2,4-benzothiadiazinyl, 1,1-dioxide-2H-1,2,4-benzothiadiazinyl, 1,2,4-benzene Oxadiazinyl, cyclopentadienopyranyl, thienofuryl, furopyranyl, pyridoxazinyl, pyrazolooxazolyl, imidazothiazolyl, imidazopyridyl, tetra Hydrogenimidazopyridyl, pyrazinopyridazinyl, benzisoquinolinyl, furanocinnolinyl, pyrazolothiazolopyridazinyl, tetrahydropyrazolothiazolopyridazinyl, hexahydrothiazolo Pyridazinopyridazinyl, imidazotriazinyl, oxazolopyridyl, benzoxepinyl, benzazepinyl, tetrahydrobenzazepinyl, benzodiazepinyl, Benzotriazepin-yl, thiezoazepin-yl, tetrahydrothieazepine-yl, thienodiazepin-yl, thienotriazepin-yl, thiazoazepin-yl, tetrahydrothiazole Azepin-yl, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl, 5,6-trimethylene-4,5,6,7-tetrahydrothiazole And pyridazinyl, etc. Among them, benzothiazolyl, tetrahydrobenzothiazolyl, thienopyridyl, tetrahydrothienopyridyl, thienopyrrolyl, thiazolopyridyl, tetrahydrothiazolopyridyl, thiazopyridyl are preferred. Azinyl, tetrahydrothiazolopyridazinyl, pyrrolopyrimidinyl, dihydropyrrolopyrimidinyl, pyranothiazolyl, dihydropyranothiazolyl, furopyridyl, tetrahydrofuropyridyl, oxazolo Pyridyl, tetrahydrooxazolopyridyl, pyrrolopyridyl, dihydropyrrolopyridyl, tetrahydropyrrolopyridyl, oxazolopyridazinyl, tetrahydrooxazolopyridazinyl, pyrrolothiazolyl , Dihydropyrrolothiazolyl, pyrrolooxazolyl, dihydropyrroloxazolyl, thiazolopyrimazinyl, dihydrothiazolopyrimazinyl, benzazepin-yl, tetrahydrobenzazepine- Base, thiazoloazepine-base, tetrahydrothiazoazepine-base, thienoazepine-base, tetrahydrothienoazepine-base, 4,5,6,7-tetrahydro-5,6-tetrahydro Methylenethiazolopyridazinyl, 5,6-trimethylene-4,5,6,7-tetrahydrothiazolopyridazinyl. Particularly preferred are tetrahydrobenzothiazolyl, tetrahydrothienopyridyl, tetrahydrothiazolopyridyl, tetrahydrothiazolopyridazinyl, dihydropyrrolopyrimidinyl, dihydropyranothiazolyl, tetrahydro Oxazolopyridyl, dihydropyrrolothiazolyl, 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl, 5,6-trimethylene-4,5, 6,7-Tetrahydrothiazolopyridazinyl.

The condensed form of the above-mentioned fused heterocyclic group is not particularly limited, for example, thienopyridine, which can be thieno[2,3-b]pyridine, thieno[2,3-c]pyridine, thieno[3,2 Any one of -b]pyridine, thieno[3,2-c]pyridine, thieno[3,4-b]pyridine, thieno[3,4-c]pyridine, preferably thieno[ 2,3-c]pyridine and thieno[3,2-c]pyridine. Thienopyrrole may be any one of thieno[2,3-b]pyrrole and thieno[3,2-b]pyrrole. Thiazolopyridine, which can be thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine, Any one of thiazolo[3,4-a]pyridine and thiazolo[3,2-a]pyridine, preferably thiazolo[4,5-c]pyridine and thiazolo[5,4-c] ] Pyridine. Thiazolopyridazine, which may be thiazolo[4,5-c]pyridazine, thiazolo[4,5-d]pyridazine, thiazolo[5,4-c]pyridazine, thiazolo[3,2- b] Any of pyridazines, preferably thiazolo[4,5-d]pyridazine. pyrrolopyridine, which may be pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine, Any one of pyrrolo[3,4-b]pyridine and pyrrolo[3,4-c]pyridine, preferably pyrrolo[2,3-c]pyridine and pyrrolo[3,2-c] ] Pyridine. Pyrrolopyrimidine, can be any one of pyrrolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-d]pyrimidine, preferably pyrrolo [3,4-d]pyrimidine. pyridopyrimidine, which may be pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, Any of pyrido[1,2-c]pyrimidine and pyrido[1,2-a]pyrimidine, preferably pyrido[3,4-d]pyrimidine and pyrido[4,3-d ] pyrimidine. pyranothiazole, which can be pyrano[2,3-d]thiazole, pyrano[4,3-d]thiazole, pyrano[3,4-d]thiazole, pyrano[3,2 Any one of d]thiazoles, preferably pyrano[4,3-d]thiazole and pyrano[3,4-d]thiazole. Furopyridine, which can be furo[2,3-b]pyridine, furo[2,3-c]pyridine, furo[3,2-b]pyridine, furo[3,2-c]pyridine, Any one of furo[3,4-b]pyridine and furo[3,4-c]pyridine, preferably furo[2,3-c]pyridine and furo[3,2-c] pyridine. Oxazolopyridine, which can be oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4 Any one of -c]pyridine, oxazolo[3,4-a]pyridine, oxazolo[3,2-a]pyridine, preferably oxazolo[4,5-c]pyridine and oxazolo[4,5-c]pyridine Azolo[5,4-c]pyridine. Oxazolo[4,5-c]pyridazine, which can be oxazolo[4,5-c]pyridazine, oxazolo[4,5-d]pyridazine, oxazolo[5,4-c]pyridazine, oxazolo Any of [3,4-b]pyridazine, preferably oxazolo[4,5-d]pyridazine. pyrrolothiazole, which may be pyrrolo[2,1-b]thiazole, pyrrolo[1,2-c]thiazole, pyrrolo[2,3-d]thiazole, pyrrolo[3,2-d]thiazole, Any of pyrrolo[3,4-d]thiazoles, preferably pyrrolo[3,4-d]thiazole. Pyrroloxazole, which can be pyrrolo[2,1-b]oxazole, pyrrolo[1,2-c]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2- d] Any one of oxazole and pyrrolo[3,4-d]oxazole, preferably pyrrolo[3,4-d]oxazole. Benzazepine_, can be any of 1H-1-benzazepine_, 1H-2-benzazepine_, 1H-3-benzazepine_, preferably 1H-3- Benzazepine_. Thiazolo[4,5-c]azepine-, can be 4H-thiazolo[4,5-c]azepine-, 4H-thiazolo[4,5-d]azepine-, 4H-thiazolo[ Any of 5,4-c]aza_, preferably 4H-thiazolo[4,5-d]aza_. Thieno[2,3-c]azepine_, can be any one of 4H-thieno[2,3-d]azepine, 4H-thieno[3,2-c]azepine, Preferably it is 4H-thieno[2,3-d]azepine_.

Among these heterocyclic groups, nitrogen-containing heterocyclic groups may be N-oxides. There is no particular limitation on the bonding position of the above-mentioned substituents to Q ² .

The above-mentioned saturated or unsaturated 5-6 membered cyclic hydrocarbon group, saturated or unsaturated 5-7 membered heterocyclic group, saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group or saturated or unsaturated bicyclic or The tricyclic condensed heterocyclic group may have 1 to 3 substituents, such as hydroxyl, halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, and those substituted by 1 to 3 halogen atoms. Haloalkyl, amino, cyano, amidino, hydroxyamidino, linear, branched or cyclic alkyl with 1 to 6 carbon atoms (hereinafter referred to as C ₁ to C ₆ alkyl means straight chain Shaped, branched and cyclic alkyl groups, such as methyl, ethyl, isopropyl, tert-butyl and other straight-chain or branched C ₁ -C ₆ alkyl groups, cyclopropyl, cyclobutyl, Cyclopentyl, 1-methylcyclopropyl and other C ₃ -C ₆ cycloalkyl), C ₃ -C ₆ cycloalkyl C ₁ -C ₆ alkyl (for example, cyclopropylmethyl, etc.), hydroxyl C ₁ -C ₆ alkyl (for example, hydroxyethyl, 1,1-dimethyl-2-hydroxyethyl, etc.), C ₁ -C ₆ oxy (for example, methoxy, ethoxy, etc.), C ₁ ~ C ₆ alkoxy C ₁ ~ C ₆ alkyl, carboxy, C ₂ ~ C ₆ carboxyalkyl (for example, carboxymethyl, etc.), C ₂ ~ C ₆ alkoxycarbonyl C ₁ ~ C ₆ alkyl (eg, methoxycarbonylmethyl, tert-butoxycarbonylmethyl, etc.), C ₂ -C ₆ alkoxycarbonyl substituted amidinyl, C ₂ -C ₆ alkenyl (eg, vinyl, allyl group, etc.), C ₂ to C ₆ alkynyl (for example, ethynyl, propynyl, etc.), C ₂ to C ₆ alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl etc.), amino C ₁ -C ₆ alkyl (for example, aminomethyl, aminoethyl, etc.), C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl (for example, N-methylaminomethyl, N-ethylaminomethyl, etc.), di(C ₁ ~C ₆ alkyl)amino C ₁ ~C ₆ alkyl (for example, N,N-dimethylaminomethyl, N,N-ethylamino methyl, N-ethyl-N-methylaminoethyl, etc.), C ₂ -C ₆ alkoxycarbonylamino C ₁ -C ₆ alkyl (for example, methoxycarbonylaminoethyl, tert-butoxy carbonylaminoethyl, etc.), C ₁ -C ₆ alkanoyl (for example, formyl, acetyl, methylpropionyl, cyclopentanecarbonyl, etc.), C ₁ -C ₆ alkanoylamino C ₁ -C ₆ alkyl (eg, acetylaminomethyl, etc.), C ₁ -C ₆ alkylsulfonyl (eg, methylsulfonyl, etc.), C ₁ -C ₆ alkylsulfonylamino C ₁ -C ₆ alkyl (eg, methyl sulfonylaminomethyl, etc.), carbamoyl, C ₁ -C ₆ alkylcarbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert-butylcarbamoyl etc.), N,N-di(C ₁ ~C ₆ alkyl)carbamoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl, etc.), C ₁ ~ C ₆ alkylamino (for example, N-methylamino, N-ethylamino, etc.), di(C ₁ ~C ₆ alkyl)amino (for example, N,N-dimethylamino, N,N-di ethylamino, N-ethyl-N-methylamino, etc.), aminosulfonyl, arylsulfonyl (e.g., phenylsulfonyl, etc.), arylcarbonyl which may be substituted by a halogen atom, etc. (e.g., benzyl Acyl, 4-fluorobenzoyl, etc.), C ₂ ~C ₆ alkoxycarbonyl (C ₁ ~C ₆ alkyl)amino C ₁ ~C ₆ alkyl (such as 1 methoxycarbonyl (methyl) aminomethyl group, tert-butoxycarbonyl (methyl) aminomethyl group, etc.), C ₁ to C ₆ alkylsulfonyl C ₁ to C ₆ alkyl group (for example, methylsulfonylmethyl, etc.), containing one or the same 5-6 membered heterocyclic groups of 2 nitrogen, oxygen or sulfur atoms of one or different species (for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrimidinyl, tetrahydropyranyl group, etc.), the above-mentioned 5-6 membered heterocyclic group-C ₁ -C ₄ alkyl group (for example, morpholinomethyl group, etc.), the above-mentioned 5-6 membered heterocyclic group-carbonyl group (for example, pyrrolidinylcarbonyl group, etc.) , the above-mentioned 5-6 membered heterocyclyl-amino-C ₁ -C ₄ alkyl (for example, N-(oxazol-2-yl) aminomethyl, etc.), the above-mentioned 5-6 membered heterocyclyl-amino (for example , pyridylamino, etc.), the above-mentioned 5-6 membered heterocyclyl-oxyl groups (for example, 4-pyridyloxy, (1-methyliminopiperidin-4-yl)oxy, etc.), 3-6 membered Heterocyclyl-carbonyl-C ₁ -C ₄ alkyl (for example, (4,4-dioxothiomorpholin-1-yl) carbonylmethyl, etc.), and the above-mentioned 5-6 membered heterocyclyl (C ₁ -C ₆ alkyl)amino-C ₁ -C ₄ alkyl (for example, N-(4,5-dihydro-1,3-oxazol-2-yl)-N-methylaminomethyl, etc.) wait.

Specific examples of ^Q1 include 5- to 6-membered cyclic hydrocarbon groups such as 2-aminosulfonylphenyl, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine -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-pyridyl)-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-tetrahydro Hydrothieno[2,3-c]pyridin-2-yl, 5-methyl4,5,6,7-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 2-cyclic heterocyclic groups such as ]thiazol-2-yl, pyridyl such as 4-pyridyl and 2-pyridyl, dihydrooxazolyl such as 4,5-dihydrooxazol-2-yl, 4-[N -(4,5-dihydrooxazol-2-yl)-N-methylaminomethyl]thiophen-2-yl, 4-[N-(4,5-dihydrooxazol-2-yl)- N-methylaminomethyl]-3-chlorothiophene-2-yl, 5-(N-methylaminomethyl)thiazol-2-yl, 5-(N-methylaminomethyl)thiophene-2- Base, 5-(N,N-dimethylaminomethyl)thiazol-2-yl, 5-(N,N-dimethylaminomethyl)thiophen-2-yl, 5-(N,N-two A 5- to 6-membered heterocyclic group such as methylaminomethyl)pyridin-2-yl. However, these examples do not limit Q ¹ .

[About group Q ² ]

The group ^Q2 represents a single bond, a straight-chain or branched alkylene group with 1 to 6 carbon atoms, a straight-chain or branched alkenylene group with 2 to 6 carbon atoms, a straight-chain or A branched alkynylene group having 2 to 6 carbon atoms, a divalent saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group that may have a substituent, a divalent saturated or unsaturated 5- to 7-membered hydrocarbon group that may have a substituent A membered heterocyclic group, a divalent saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group that may have a substituent, or a divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group that may have a substituent Heterocyclyl.

In the group ^Q2 , the linear or branched alkylene group having 1 to 6 carbon atoms may, for example, be methylene, ethylene, trimethylene, propylene, tetramethylene, or pentamethylene Methyl, hexamethylene, etc.

The linear or branched alkenylene group having 2 to 6 carbon atoms may, for example, be ethenylene, propenylene, butenylene or pentenylene. In addition, the position of the double bond is not particularly limited.

The linear or branched C 2-6 alkynylene group may, for example, be ethynylene, propynylene, butynylene, pentynylene or hexynylene. The bonding position of the triple bond is not particularly limited.

The divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group is a divalent group of a saturated or unsaturated 5-6-membered cyclic hydrocarbon group described in the description of Q ⁴ in the general formula (1), specific examples Examples thereof include cyclohexylene, cyclohexenylene, and phenylene, among which cyclohexylene and phenylene are preferred.

The divalent saturated or unsaturated 5- to 7-membered heterocyclic group is a divalent saturated or unsaturated 5- to 7-membered heterocyclic group described in the description of Q ⁴ in the general formula (1). Specific examples include furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, oxazolidine, thiazole, thiadiazole, furan, pyran, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine , oxazine, oxadiazine, morpholine, thiazine, thiadiazine, thiomorpholine, tetrazole, triazole, triazine, aza_, diaza_, triaza_, etc. Among them, better examples can exemplify pyrazole, imidazole, oxazole, thiazole, thiadiazole, furazan, pyridine, pyrimidine, pyridazine, pyrrolidine, piperazine, piperidine, triazole, triazine, The divalent group of aza_, diaza_, triaza_.

The divalent saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon group is a saturated or unsaturated bicyclic or tricyclic condensed hydrocarbon described in the description of Q ⁴ in the general formula (1) Specific examples of the divalent group include divalent groups of indane, indane, naphthalene, tetrahydronaphthalene, anthracene, and phenanthrene, and preferable examples include divalent groups of indane and naphthalene.

The divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group is a saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group described in the description of Q ⁴ in the general formula (1). Divalent groups of heterocycles, specific examples include benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, quinoline, Azoline, dihydroquinazoline, tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline, cinnoline, tetrahydrocinnoline, indolizine, tetrahydroindolizine, benzothiazole, tetrahydrobenzene Thiazole, naphthyridine, tetrahydronaphthyridine, thienopyridine, tetrahydrothienopyridine, thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine, tetrahydrothiazolopyridazine, pyrrolopyridine, dihydropyrrole Pyridine, tetrahydropyrrolopyridine, pyrrolopyrimidine, dihydropyrrolopyrimidine, dihydropyridoquinazoline, pyranothiazole, dihydropyranothiazole, furopyridine, tetrahydrofuropyridine, oxazolo Pyridine, tetrahydrooxazolopyridine, oxazolopyridazine, tetrahydrooxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole, pyrroloxazole, dihydropyrroloxazole, benzazepine_ and other divalent groups, better examples include benzofuran, benzothiophene, indole, indazole, quinoline, isoquinoline, tetrahydroisoquinoline, benzothiazole, naphthyridine, thieno Pyridine, thiazolopyridine, tetrahydrothiazolopyridine, thiazolopyridazine, pyrrolopyridine, tetrahydropyrrolopyridine, pyridopyrimidine, pyranothiazole, dihydropyranothiazole, furopyridine, oxazolo Divalent groups of pyridine, oxazolopyridazine, pyrrolothiazole, dihydropyrrolothiazole, pyrroloxazole and dihydropyrroloxazole. There is no particular limitation on the condensed form of the above-mentioned fused heterocyclic group, for example, naphthyridine can be 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2, Any of the 7-naphthyridines, thienopyridines, may be thieno[2,3-b]pyridine, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thiophene Any one of [3,2-c]pyridine, thieno[3,4-b]pyridine, thieno[3,4-c]pyridine, thiazolopyridine, can 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 Any of the [3,2-a]pyridines, thiazolopyridazine, may be thiazolo[4,5-c]pyridazine, thiazolo[4,5-d]pyridazine, thiazolo[5, Any of 4-c]pyridazine, thiazolo[3,2-b]pyridazine, pyrrolopyridine, may be pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c] Any of pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,4-b]pyridine, pyrrolo[3,4-c]pyridine , pyrrolopyrimidine, can be any one of pyrrolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-d]pyrimidine, pyridopyrimidine, can be Is any one of pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyranothiazole, can be pyrano[ Any of 2,3-d]thiazole, pyrano[4,3-d]thiazole, pyrano[3,4-d]thiazole, pyrano[3,2-d]thiazole, furan pyridine, which can be furo[2,3-b]pyridine, furo[2,3-c]pyridine, furo[3,2-b]pyridine, furo[3,2-c]pyridine, furan Any one of [3,4-b]pyridine, furo[3,4-c]pyridine, oxazolopyridine, can 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, Any of 2-a]pyridines, oxazolopyridazines, can be oxazolo[4,5-c]pyridazine, oxazolo[4,5-d]pyridazine, oxazolo[5 , any one of 4-c] pyridazine, oxazolo[3,4-b] pyridazine, pyrrolothiazole, can be pyrrolo[2,1-b]thiazole, pyrrolo[1,2- c] Any one of thiazole, pyrrolo[3,2-d]thiazole, pyrrolo[3,4-d]thiazole, pyrroloxazole, which can be pyrrolo[2,1-b]oxazole, Any of pyrrolo[1,2-c]oxazole, pyrrolo[2,3-d]oxazole, pyrrolo[3,2-d]oxazole, pyrrolo[3,4-d]oxazole A sort of. In addition, forms other than these condensed forms are also possible.

The above-mentioned divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon groups, divalent saturated or unsaturated 5-7 membered heterocyclic groups, divalent saturated or unsaturated 2- or 3-membered fused hydrocarbon groups and The divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group can have 1 to 3 substituents, such as hydroxyl, fluorine atom, chlorine atom, bromine atom and iodine atom, etc. Halogen atom, haloalkyl group substituted with 1 to 3 halogen atoms, amino group, cyano group, aminoalkyl group, amidino group, hydroxyamidino group, linear, branched or cyclic alkyl group with 1 to 6 carbon atoms (for example, methyl, ethyl, etc.), straight-chain, branched or cyclic alkoxy groups with 1 to 6 carbon atoms (for example, methoxy, ethoxy, etc.), straight-chain, branched Chain or cyclic alkoxycarbonyl-substituted amidinos with 2 to 7 carbon atoms (for example, methoxycarbonylamidino, ethoxycarbonylamidino, etc.), linear, branched or cyclic Alkenyl groups with 2 to 6 carbon atoms (for example, vinyl, allyl, etc.), linear or branched alkynyl groups with 2 to 6 carbon atoms (for example, ethynyl, propynyl, etc. ), a straight-chain, branched or cyclic alkoxycarbonyl group having 2 to 6 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl, etc.), carbamoyl and the like.

Among the above ^Q2 , a single bond, a divalent saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group which may have a substituent, and a divalent saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent are preferred and a divalent saturated or unsaturated bicyclic or tricyclic condensed heterocyclic group which may have a substituent, more preferably a single bond, a divalent saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group, A divalent saturated or unsaturated 5- to 7-membered heterocyclic group.

The group ^Q1 is a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group which may have a substituent or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have a substituent When, the group Q ² is preferably a single bond. In the above-mentioned combination, when Q ² is a single bond, general formula (1)

Q ¹ -Q ² -T ⁰ -N(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (1)

[wherein, R ¹ , R ² , Q ¹ , Q ² , Q ³ , Q ⁴ , T ⁰ and T ¹ are as described above] are represented by the following general formula (1′).

Q ¹ -T ⁰ -N(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (1′)

[wherein, Q ¹ represents the above-mentioned bicyclic or tricyclic fused hydrocarbon group or bicyclic or tricyclic fused heterocyclic group, R ¹ , R ² , Q ³ , Q ⁴ , T ⁰ and T ¹ as previously stated]

More preferably, the group ^Q1 is 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 tetrahydrothiazolo group which may have a substituent Pyridyl, optionally substituted thiazolopyridazinyl, optionally substituted tetrahydrothiazolopyridazinyl, optionally substituted pyranothiazolyl, optionally substituted dihydropyranothiazinyl , optionally substituted furopyridyl, optionally substituted tetrahydrofuropyridyl, optionally substituted oxazolopyridyl, optionally substituted tetrahydrooxazolopyridyl, optionally substituted Pyrrolopyridyl, optionally substituted dihydropyrrolopyridyl, optionally substituted tetrahydropyrrolopyridyl, optionally substituted pyrrolopyrimidinyl, optionally substituted dihydropyrrolopyrimidinyl , oxazolopyridazinyl which may have a substituent, tetrahydrooxazolopyridazinyl which may have a substituent, pyrrolothiazolyl which may have a substituent, dihydropyrrolothiazolyl which may have a substituent, Substituent pyrrolooxazolyl, optionally substituted dihydropyrrolooxazolyl, optionally substituted benzothiazolyl, optionally substituted tetrahydrobenzothiazolyl, optionally substituted Thiazolopyrimidinyl, dihydrothiazopyrimidinyl which may have substituents, benzazepine-yl which may have substituents, tetrahydrobenzazepin-yl which may have substituents, thiazolo which may have substituents Aza-based, tetrahydrothiazoazepin-yl which may have substituents, thieno-azepin-yl which may have substituents, tetrahydrothiezo-azepin-yl which may have substituents, and which may have substituents 4,5,6,7-tetrahydro-5,6-tetramethylenethiazolopyridazinyl or 5,6-trimethylene-4,5,6,7-tetrahydrothiazolo which may have substituents Pyridazinyl, group Q ² is a single bond.

When the group Q ¹ is a saturated or unsaturated 5-6 membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5-7 membered heterocyclic group which may have a substituent, the group Q ² preferably may have a substitution A divalent saturated or unsaturated 5-6-membered cyclic hydrocarbon group or a divalent saturated or unsaturated 5-7-membered heterocyclic group that may have substituents. As the group Q ¹ -Q ² -, a better example can be Exemplary 4-(4-pyridyl) phenyl, 4-(2-pyridyl) phenyl, 5-(4-pyridyl) thiazolyl, 1-(4-pyridyl) piperidyl, 4-( 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 Base, 4-(2-imidazolyl)phenyl, 4-(1-methyl-2-imidazolyl)phenyl, 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)piperidine -4-yl, 3-(4-piperidinyl) isoxazolin-5-yl, 3-(4-amidinophenyl) isoxazolin-5-yl, 3-(4-piperidinyl ) isoxazolidin-5-yl, 3-(4-amidinophenyl) isoxazolidin-5-yl, 2-(4-piperidinyl)-1,3,4-thiadiazole-5 -yl, 2-(4-aminophenyl)-1,3,4-oxadiazol-5-yl, 4-(4-piperidinyl)piperidin-1-yl, 4-(4-piperidine Base) piperazin-1-yl, 4-(4-piperazinyl)piperazin-1-yl, 1-(4-pyrimidinyl)piperidin-1-yl, 1-(2-methylpyrimidine-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, 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 Base]-4-yl, 4-(3-oxomorpholin-4-yl)phenyl, etc.

[About group Q ³ ]

Group Q ³ consists of the following groups

In the group, Q ⁵ represents an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or a group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(In the group, m and n are each independently representing an integer of 0, 1 to 3, and A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH -, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-, 1 and 2 represent positions);

R ³ and R ⁴ are substituted on the carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁵ , each independently representing a hydrogen atom, hydroxyl, alkyl, alkenyl, alkynyl, halogen atom, haloalkyl, Cyano, cyanoalkyl, amino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, optionally substituted acylamino, alkoxy Imino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl Amino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and which may have a substituent on the alkyl group N, N-dialkylcarbamoyl, 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 substituents, Carbamoylalkyl, N-alkylcarbamoylalkyl which may have a substituent on the alkyl, N,N-dialkylcarbamoylalkyl which may have a substituent on the alkyl, carbamoyloxy Alkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, 3- to 6-membered heterocyclic carbonylalkyl which may have substituents, optionally substituted 3-6 membered heterocyclic carbonyloxyalkyl, aryl, aralkyl, 3-6 membered heterocyclic group which may have substituent, 3-6 membered heterocycloalkyl group which may have substituent, alkylsulfonyl Oxygen, arylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, aryl Sulfonylaminocarbonylalkyl, oxo, carbamoyloxy, aralkoxy, carboxyalkoxy, alkoxycarbonylalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, Alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkoxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxy Acyl group, acyloxyalkylsulfonyl group, hydroxyalkylsulfonyl group, alkoxyalkylsulfonyl group, 3- to 6-membered heterocyclic sulfonyl group which may have a substituent, 3- to 6-membered heterocyclic epoxy group which may have a substituent group, N-alkylaminoacyl group, N, N-dialkylaminoacyl group, N, N-dialkylcarbamoyl acyl group that may have substituents on the alkyl group, N, N that may have substituents on the alkyl group -Dialkylcarbamoylalkylsulfonyl, alkylsulfonylacyl, N-arylcarbamoyl, N-3 to 6-membered heterocyclic carbamoyl, N-alkyl-N-arylcarbamoyl , N-Alkyl-N-3～6 membered heterocyclic carbamoyl, N-arylcarbamoyl alkyl, N-3～6 membered heterocyclic carbamoyl alkyl, N-alkyl-N-aryl Carbamoyl alkyl, N-alkyl-N-3-6 membered heterocyclic carbamoyl alkyl, carbamoyl, N-alkylcarbamoyl, N, N-dialkylamino Thiosulfonyl, alkoxyalkyl (thiocarbonyl), alkylthioalkyl or N-acyl-N-alkylaminoalkyl or ^R3 and ^R4 together represent an alkylene group with 1 to 5 carbon atoms group, alkenylene group having 2 to 5 carbon atoms, alkylenedioxy group or carbonyldioxy group having 1 to 5 carbon atoms.

The following groups are described in detail.

[In the group, Q ⁵ , R ³ and R ⁴ are as described above, and 1 and 2 represent positions]

The part of the cyclic structure containing the above-mentioned group ^Q5 is a 3-10-membered divalent cyclic hydrocarbon group that may have one double bond or a 5-12-membered divalent heterocyclic group that has 1-2 heteroatoms , preferably a 3-8-membered divalent cyclic hydrocarbon group or a 5-8-membered divalent heterocyclic group, more preferably a 5-7-membered divalent cyclic hydrocarbon group or a 5-7-membered divalent cyclic hydrocarbon group heterocyclyl. Among them, Q ⁵ is preferably an alkylene group with 3 to 6 carbon atoms or a group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(In the group, m and n are independently, represents 0 or 1, A is as described above), and Q ^is particularly preferably an alkylene group having 4 carbon atoms.

In addition, the cyclic hydrocarbon group or heterocyclic group can obtain cis and trans structures in the relationship between the 1-position and the 2-position. When it is 5-membered, it is preferably cis-form, and when it is 6-7 members, it is best to be cis-form. The formula can also be trans.

The above substituents R ³ and R ⁴ will be described in detail. The halogen atom represents a fluorine atom, chlorine atom, bromine atom or iodine atom. The alkyl group can be exemplified by linear, branched or cyclic C ₁ -C ₆ alkyl groups (for example, methyl, cyclopropyl, isobutyl, etc.), and the haloalkyl group can be exemplified by the above-mentioned alkyl groups with 1- A group substituted with 3 halogen atoms (for example, chloromethyl, 1-bromoethyl, trifluoromethyl, etc.). The cyanoalkyl group may, for example, be a group in which the above-mentioned C ₁ -C ₆ alkyl group is substituted with one cyano group (for example, cyanomethyl group, 1-cyanoethyl group, etc.). The alkenyl group may, for example, be a linear or branched group having 2 to 6 carbon atoms having one double bond (for example, vinyl group, allyl group, etc.). The alkynyl group may, for example, be a linear or branched C2-6 group having one triple bond (for example, ethynyl, propynyl, etc.). The acyl group can be, for example, an alkanoyl group with 1 to 6 carbon atoms (for example, formyl, acetyl, etc.), a benzoyl group or a naphthoyl group such as a C ₇ -C ₁₅ aroyl group, or the above-mentioned C ₁ -C ₆ alkanoyl group. C ₆ -C ₁₄ aryl substituted aryl alkanoyl (for example, phenylacetyl, etc.). The acylalkyl group may, for example, be a group in which the above-mentioned C ₁ -C ₆ alkyl group is substituted with one of the above-mentioned acyl groups (for example, acetylmethyl group, etc.). The alkoxy group may, for example, be a linear, branched or cyclic C ₁ -C ₆ alkoxy group (for example, methoxy, cyclopropoxy, isopropoxy, etc.). The alkoxyalkyl group may, for example, be a group in which the above-mentioned C ₁ -C ₆ alkyl group is substituted with one of the above-mentioned C ₁ -C ₆ alkoxy groups (for example, methoxymethyl group, ethoxymethyl group, etc.). The hydroxyalkyl group may, for example, be a group in which the above-mentioned C ₁ -C ₆ alkyl group is substituted with one hydroxy group (for example, hydroxymethyl group, 1-hydroxyethyl group, etc.). The carboxyalkyl group may, for example, be a group in which the above-mentioned C ₁ -C ₆ alkyl group is substituted with one carboxy group (for example, carboxymethyl group, 1-carboxyethyl group, etc.). The alkoxycarbonyl group may, for example, be a group composed of the aforementioned C ₁ -C ₆ alkoxy group and a carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, etc.). The alkoxycarbonylalkyl group may, for example, be a group in which the aforementioned C ₁ -C ₆ alkyl group is substituted with one of the aforementioned alkoxycarbonyl groups (for example, methoxycarbonylethyl, ethoxycarbonylethyl, etc.). The carbamoylalkyl group may, for example, be a group in which the aforementioned C ₁ -C ₆ alkyl group is substituted with a carbamoyl group (for example, carbamoylmethyl group, carbamoylethyl group).

The 3-6 membered heterocyclic group that may have a substituent means a saturated or unsaturated 3-6-membered heterocyclic group that may contain 1 to 3 heteroatoms (nitrogen atom, oxygen atom, sulfur atom, etc.), and the heterocyclic group may Substituents such as hydroxyl, halogen atom, amino group, C ₁ ~C ₆ alkyl group, oxo group, haloalkyl group, etc., and 3-6 membered heterocyclic groups are pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazole Linyl, oxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiazolyl, thiazolinyl, thiadiazolyl, furazanyl, pyranyl, pyridyl, pyrimidinyl, pyridazine Base, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and Triazinyl etc. Specific examples include thiazolyl, 4,5-dihydrothiazolyl, oxazolyl, 4,5-dihydrooxazolyl, 5-methyloxazolyl, imidazolyl, pyrrolidinyl, 3-hydroxypyrrolidine Base, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, tetrahydropyranyl, pyridyl, 1,2,4-oxadio Azolyl, 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-oxadiazolyl, 1,3,4-thiadiazolyl , 5-methyl-1,3,4-thiadiazolyl, 1,3-oxazolidinyl, etc. The 3- to 6-membered heterocycloalkyl group which may have a substituent may be, for example, a group in which the alkyl group is substituted with one of the above-mentioned 3- to 6-membered heterocyclic group which may have a substituent (for example, thiazolylmethyl, 4,5- dihydrothiazolylmethyl, morpholinylmethyl, 1,1-dioxothiomorpholinylmethyl, etc.). The aryl group can be, for example, a group with 6 to 14 carbon atoms such as phenyl and naphthyl, and the aryl group can be selected from the above-mentioned C ₁ to C ₆ alkyl group, the above-mentioned C ₁ to C ₆ alkanoyl group, hydroxyl group, nitro group, cyano group, halogen atom, the above-mentioned C ₂ -C ₆ alkenyl group, the above-mentioned C ₂ -C ₆ alkynyl group, the above-mentioned C ₁ -C ₆ haloalkyl group, the above-mentioned C _{1 -C 6} alkoxy group, carboxyl group, carbamoyl group, 1 to 3 groups such as the aforementioned C ₁ to C ₆ alkoxycarbonyl are substituted. Examples of the aralkyl group include groups in which the above-mentioned C ₁ -C ₆ alkyl group is substituted with one of the above-mentioned C ₆ -C ₁₄ aryl groups (for example, benzyl, phenethyl, etc.). In the above description, there is no particular limitation on the substitution position. As the acylamino group which may have a substituent, there may be mentioned C ₁ -C ₆ acyl groups substituted for the amino group (for example, formylamino, acetylamino, etc.), and the acyl group has 1 to several halogen atoms, hydroxyl, C ₁ to C ₆ alkoxy, acyl, NC ₁ to C ₆ alkylamino, N,N-di C ₁ to C ₆ alkylamino, carboxyl, C ₂ to C ₆ alkoxycarbonyl and other substituted acyl groups (eg , 2-methoxyacetylamino, 3-aminopropionylamino, etc.). The acylaminoalkyl group may, for example, be a group in which the above-mentioned C ₁ -C ₆ acylamino group is substituted for the above-mentioned C ₁ -C ₆ alkyl group (for example, formylaminomethyl group, acetylaminomethyl group, etc.). The aminoalkyl group may, for example, be a group in which the aforementioned C ₁ -C ₆ alkyl group is substituted with one amino group (for example, aminomethyl group, 1-aminoethyl group, etc.). N-Alkylaminoalkyl can be exemplified by amino-C ₁ ～C ₆ alkyl nitrogen atoms with 1 C ₁ ～C ₆ alkyl substituted groups (for example, N-methylaminomethyl, N- methylaminoethyl, etc.), N,N-dialkylaminoalkyl can be exemplified by amino-C ₁ -C ₆ alkyl nitrogen atoms with two C ₁ -C ₆ alkyl substituted groups (for example , N, N-dimethylaminomethyl, N-ethyl-N-methylaminomethyl, etc.). Examples of the N-alkenylcarbamoyl group include linear or branched C ₂ -C ₆ alkenyl substituted carbamoyl groups (for example, allylcarbamoyl group, etc.). The N-alkenylcarbamoylalkyl group may, for example, be a group in which the above-mentioned NC ₂ -C ₆ alkenylcarbamoyl group is substituted for a C ₁ -C ₆ alkyl group (for example, allylcarbamoylethyl group, etc.). The N-alkenyl-N-alkylcarbamoyl group can be exemplified by the above-mentioned NC ₂ to C ₆ alkenylcarbamoyl alkyl having a linear or branched C ₁ to C ₆ alkyl group on the nitrogen atom Substituted groups (eg, N-allyl-N-methylcarbamoylmethyl, etc.). N-alkenyl-N-alkylcarbamoylalkyl can be exemplified by the above-mentioned NC ₂ -C ₆ alkenylcarbamoyl having a linear or branched C ₁ -C ₆ alkyl group on the nitrogen atom Substituted groups (eg, N-allyl-N-methylcarbamoyl, etc.). The N-alkoxycarbamoyl group may, for example, be a linear or branched C ₁ -C ₆ alkoxy-substituted carbamoyl group (for example, methoxycarbamoyl group, etc.). The N-alkoxycarbamoyl alkyl group can be, for example, a group in which the above-mentioned NC ₁ to C ₆ alkoxycarbamoyl group is substituted on a linear or branched C ₁ to C ₆ alkyl group (for example, methyl Oxycarbamoylmethyl, etc.). The N-alkyl-N-alkoxycarbamoyl group can be, for example, a linear or branched C ₁ -C ₆ alkoxy group and a C ₁ -C ₆ alkyl group substituted on the carbamoyl group ( For example, N-ethyl-N-methoxycarbamoyl, etc.). N-Alkyl-N-alkoxycarbamoylalkyl can be exemplified by the above-mentioned NC ₁ to C ₆ alkyl-NC ₁ to C ₆ alkoxycarbamoyl in straight or branched C ₁ to A group substituted on C ₆ alkyl (for example, N-ethyl-N-methoxycarbamoylmethyl, etc.). The carbazolyl that may be substituted by 1 to 3 alkyl groups includes, in addition to the carbazolyl, carbazolyl that is substituted by 1 to 3 linear or branched C ₁ -C ₆ alkyl groups ( For example, 1-methylcarbazolyl, 1,2-dimethylcarbazolyl, etc.). The alkylsulfonyl group may, for example, be linear, branched or cyclic C ₁ -C ₆ alkylsulfonyl (for example, methylsulfonyl, etc.). The alkylsulfonylalkyl group may, for example, be a group in which the above-mentioned C ₁ -C ₆ alkylsulfonyl group is substituted for a linear or branched C ₁ -C ₆ alkyl group (for example, methylsulfonylmethyl group, etc.). The alkoxyimino group may, for example, be a C ₁ -C ₆ alkoxyimino group (for example, methoxyimino group, ethoxyimino group, etc.). Alkoxycarbonylalkylamino can be, for example, a group in which the amino group is substituted by one of the above-mentioned C ₁ -C ₆ alkoxycarbonylalkyl groups (for example, methoxycarbonylmethylamino, ethoxycarbonylpropylamino, etc.) . Carboxyalkylamino may, for example, be a group in which the amino group is substituted with one of the aforementioned carboxy C ₁ -C ₆ alkyl groups (for example, carboxymethylamino, carboxyethylamino, etc.). The alkoxycarbonylamino group may, for example, be a group in which the amino group is substituted with one of the aforementioned C ₁ -C ₆ alkoxycarbonyl groups (for example, methoxycarbonylamino, tert-butoxycarbonylamino, etc.). The alkoxycarbonylaminoalkyl group can be, for example, a group in which the above-mentioned alkyl group is substituted by one of the above-mentioned C ₁ -C ₆ alkylethylcarbonylamino groups (for example, methoxycarbonylaminomethyl, tert-butoxycarbonylaminoethyl wait). The N-alkylcarbamoyl group that may have a substituent on the alkyl group represents a carbamoyl group substituted by a linear, branched or cyclic C ₁ -C ₆ alkyl group that may have a substituent, and the substituent may be Examples include hydroxyl, amino, NC ₁ -C ₆ alkylamino, amidino, halogen, carboxyl, cyano, carbamoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkanoyl, C ₁ - C ₆ alkanoylamino, C ₁ -C ₆ alkylsulfonylamino, etc., specific examples thereof include N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N -Cyclopropylcarbamoyl, N-(2-hydroxyethyl)carbamoyl, N-(2-fluoroethyl)carbamoyl, N-(2-cyanoethyl)carbamoyl, N- (2-methoxyethyl)carbamoyl, N-carboxymethylcarbamoyl, N-(2-aminoethyl)carbamoyl, N-(2-amidinoethyl)carbamoyl, and the like. The N,N-dialkylcarbamoyl group that may have a substituent on the alkyl group means a carbamoyl group substituted by two straight-chain, branched-chain or cyclic C1 _{- C6} alkyl groups that may have substituents , the substituent can be exemplified by hydroxyl, amino, NC ₁ -C ₆ alkylamino, amidino, halogen, carboxyl, cyano, carbamoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkane Acyl, C ₁ -C ₆ alkanoylamino, C ₁ -C ₆ alkylsulfonylamino, etc. Specific examples thereof include N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl , N-ethyl-N-methylcarbamoyl, N-isopropyl-N-methylcarbamoyl, N-(2-hydroxyethyl)-N-methylcarbamoyl, N, N- Bis(2-hydroxyethyl)carbamoyl, N,N-bis(2-fluoroethyl)carbamoyl, N-(2-cyanoethyl)-N-methylcarbamoyl, N-( 2-methoxyethyl)-N-methylcarbamoyl, N-carboxymethyl-N-methylcarbamoyl, N,N-bis(2-aminoethyl)carbamoyl, etc. The N-alkylcarbamoyl alkyl group that may have a substituent on the alkyl group may be substituted with the above-mentioned N-alkylcarbamoyl group that may have a substituent on the C ₁ to C ₆ alkyl group. Linear or branched A C ₁ -C ₆ alkyl group (for example, N-methylcarbamoylmethyl, N-(2-hydroxyethyl)carbamoylmethyl, etc.). The N,N-dialkylcarbamoyl alkyl group that may have a substituent on the alkyl group may include the N,N-dialkylcarbamoyl group that may have a substituent on the above-mentioned C ₁ to C ₆ alkyl group. C ₁ -C ₆ alkyl groups (for example, N,N-dimethylcarbamoylmethyl, N-(2-hydroxyethyl)-N-methylcarbamoylmethyl) base, etc.). The 3-6 membered heterocyclic carbonyl group which may have a substituent may, for example, a group composed of the above-mentioned 3-6 membered heterocyclic group which may have a substituent and a carbonyl group (for example, aziridinylcarbonyl, azetidinyl Carbonyl, 3-hydroxyazetidinylcarbonyl, 3-methoxyazetidinylcarbonyl, pyrrolidinylcarbonyl, 3-hydroxypyrrolidinylcarbonyl, 3-fluoropyrrolidinylcarbonyl, piperidinyl Carbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1,1-dioxothiomorpholinylcarbonyl, tetrahydropyranylcarbonyl, pyridylcarbonyl, furoyl, thiophenecarbonyl wait). The 3-6 membered heterocyclic carbonylalkyl group which may have a substituent is a group in which one of the above-mentioned 3-6-membered heterocyclic carbonyl group which may have a substituent is substituted for the above-mentioned C ₁ -C ₆ alkyl group (for example, azetidine carbonylmethyl, pyrrolidinylcarbonylethyl, etc.). The 3- to 6-membered heterocyclic carbonyloxyalkyl group which may have a substituent may be exemplified by a 3- to 6-membered heterocyclic carbonyloxy group consisting of the above-mentioned 3-6-membered heterocyclic carbonyl group which may have a substituent and an oxygen atom in place of the above-mentioned A C ₁ -C ₆ alkyl group (for example, piperidinylcarbonyloxyethyl, morpholinylcarbonyloxymethyl, etc.). The carbamoyloxyalkyl group can be exemplified by a carbamoyloxy group consisting of a carbamoyl group and an oxygen atom substituting the above-mentioned C ₁ -C ₆ alkyl groups (for example, carbamoyloxymethyl, carbamoyl acyloxyethyl, etc.). The N-alkylcarbamoyloxyalkyl group includes one N-alkylcarbamoyl group that may have a substituent on the above-mentioned C ₁ -C ₆ alkyl group and an N-alkylcarbamoyloxy group composed of an oxygen atom. A group substituting the above-mentioned C ₁ -C ₆ alkyl group (for example, N-methylcarbamoyloxymethyl group, N-methylcarbamoyloxyethyl group, etc.). The N,N-dialkylcarbamoyloxyalkyl group includes one N,N-dialkylcarbamoyl group which may have a substituent on the above-mentioned C ₁ -C ₆ alkyl group and N consisting of an oxygen atom, N-dialkylcarbamoyloxy group substituting the above-mentioned C ₁ -C ₆ alkyl groups (for example, N, N-dimethylcarbamoyloxymethyl, N-ethyl-N-methylamino formyloxyethyl, etc.). The alkylsulfonylamino group may, for example, be one amino group substituted with an alkylsulfonyl group having the aforementioned C ₁ -C ₆ alkyl group (for example, methylsulfonylamino, isopropylsulfonylamino, etc.). As the arylsulfonylamino group, one of the above-mentioned arylsulfonylamino groups having an aryl group substituted for an amino group (for example, phenylsulfonylamino, naphthylsulfonylamino, etc.) may be mentioned. The alkylsulfonylaminoalkyl group can be exemplified by one of the above-mentioned C ₁ -C ₆ alkylsulfonylamino groups replacing the above-mentioned C ₁ -C ₆ alkyl groups (for example, methylsulfonylaminomethyl, methylsulfonyl aminoethyl, etc.). The arylsulfonylaminoalkyl group can be, for example, a group in which the above-mentioned C ₁ -C ₆ alkyl group is substituted with one of the above-mentioned arylsulfonylamino groups (for example, phenylsulfonylaminomethyl, naphthylsulfonylaminoethyl, etc. ). The alkylsulfonylaminocarbonyl group may, for example, be a group composed of the above C ₁ -C ₆ alkylsulfonylamino and carbonyl groups (for example, methylsulfonylaminocarbonyl, isopropylsulfonylaminocarbonyl, etc.). The arylsulfonylaminocarbonyl group may, for example, be a group composed of the above-mentioned arylsulfonylaminocarbonyl group and a carbonyl group (eg, phenylsulfonylaminocarbonyl, naphthylsulfonylaminocarbonyl, etc.). Alkylsulfonylaminocarbonylalkyl can be exemplified by the above-mentioned C ₁ -C ₆ alkylsulfonylaminocarbonyl group substituting the above-mentioned C ₁ -C ₆ alkyl group (for example, methylsulfonylaminocarbonylmethyl, isopropyl sulfonylaminocarbonylmethyl, etc.). The arylsulfonylaminocarbonylalkyl group may, for example, be a group in which the above-mentioned arylsulfonylaminocarbonyl is substituted for the above-mentioned C ₁ -C ₆ alkyl (for example, phenylsulfonylaminocarbonylmethyl, naphthylsulfonylaminocarbonylmethyl, wait). Alkoxycarbonylalkoxy may, for example, be a group in which the aforementioned alkoxycarbonyl is substituted for the aforementioned C ₁ -C ₆ alkoxy (for example, methoxycarbonylmethoxy, etc.), and acyloxy means the aforementioned acyl and an oxygen atom. Constituent groups (for example, formyloxy, acetoxy, etc.). The acyloxyalkyl group may, for example, be a group in which the aforementioned acyloxy group is substituted for the aforementioned C ₁ -C ₆ alkyl group (for example, formyloxymethyl, acetoxymethyl, etc.). The aralkoxy group may, for example, be a group in which the above-mentioned aryl is substituted for the above-mentioned C ₁ -C ₆ alkoxy (for example, benzyloxy, naphthylmethoxy, etc.). The carboxyalkoxy group may, for example, be a group in which the above-mentioned alkoxy group is substituted with a carboxy group (for example, carboxymethoxy, carboxyethoxy, etc.).

The arylsulfonyl group may, for example, be a C ₆ -C ₁₄ arylsulfonyl group (for example, phenylsulfonyl, naphthylsulfonyl, etc.). The alkoxycarbonylalkylsulfonyl group may, for example, be a group composed of the above-mentioned C ₁ -C ₆ alkoxycarbonylalkyl and sulfonyl groups (for example, methoxycarbonylethylsulfonyl, ethoxycarbonylethylsulfonyl, wait). The carboxyalkylsulfonyl group may, for example, be a group composed of the above-mentioned carboxyalkyl group and a sulfonyl group (for example, carboxymethylsulfonyl group, carboxyethylsulfonyl group, etc.). The alkoxycarbonylacyl group may, for example, be a group composed of the above-mentioned alkoxycarbonylalkyl group and a carbonyl group (eg, methoxycarbonylmethylcarbonyl, ethoxycarbonylmethylcarbonyl, etc.). The alkoxyalkoxycarbonyl group can be exemplified by one of the above-mentioned C ₁ -C ₆ alkoxy groups substituting the above-mentioned alkoxycarbonyl group (for example, methoxymethoxycarbonyl, methoxyethoxycarbonyl, etc.) . The hydroxyacyl group may, for example, be a group in which one hydroxyl group is substituted for the above-mentioned acyl groups (including C ₁ -C ₆ alkanoyl groups and aroyl groups) (for example, glycoloyl, propanoyl, diphenylglycoloyl, etc.). The alkoxyacyl group may, for example, be a group in which one of the aforementioned C ₁ -C ₆ alkoxy groups is substituted for the aforementioned acyl group (for example, methoxyacetyl, ethoxyacetyl, etc.). The haloacyl group may, for example, be a group composed of the above-mentioned haloalkyl group and a carbonyl group (for example, chloromethylcarbonyl, trifluoromethylcarbonyl, etc.). The carboxyacyl group may, for example, be a group in which one carboxyl group is substituted for the aforementioned acyl group (for example, carboxyacetyl, 2-carboxypropionyl, etc.). The aminoacyl group may, for example, be a group in which one amino group is substituted for the aforementioned acyl groups (including C ₁ -C ₆ alkanoyl groups and aroyl groups) (for example, aminomethylcarbonyl, 1-aminoethylcarbonyl, etc.). The acyloxyacyl group may, for example, be a group composed of the above-mentioned acyloxyalkyl group and a carbonyl group (eg, formyloxymethylcarbonyl, acetoxymethylcarbonyl, etc.). The acyloxyalkylsulfonyl group may, for example, be a group composed of the above-mentioned acyloxyalkyl group and a sulfonyl group (for example, formyloxymethylsulfonyl group, acetoxymethylsulfonyl group, etc.). The hydroxyalkylsulfonyl group may, for example, be a group composed of the aforementioned C ₁ -C ₆ hydroxyalkyl group and a sulfonyl group (for example, hydroxymethylsulfonyl group, 1-hydroxyethylsulfonyl group, etc.). The alkoxyalkylsulfonyl group may, for example, be a group composed of the above-mentioned C ₁ -C ₆ alkoxyalkyl group and a sulfonyl group (for example, methoxymethylsulfonyl group, ethoxyethylsulfonyl group, etc.). The 3-6 membered heterocyclic sulfonyl group which may have a substituent may, for example, a group composed of a 3-6-membered heterocyclic ring which may have the above-mentioned substituent and a sulfonyl group (for example, aziridinylsulfonyl, azetidinyl, alkylsulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, piperazinylsulfonyl, morpholinosulfonyl, tetrahydropyranylsulfonyl, etc.). The 3-6 membered heterocyclic ring which may have a substituent is mentioned the group which consists of the said 3-6 membered heterocyclic ring which may have a substituent, and an oxygen atom (for example, tetrahydrofuryloxy group etc.). The N-alkylaminoacyl group can be, for example, a group substituted with one of the above-mentioned _C1 - _C6 alkyl groups on the nitrogen atom of the above-mentioned aminoacyl group (for example, N-methylaminoacetyl group, N-ethylaminoacetyl group, etc. ). The N,N-dialkylaminoacyl group can be, for example, a group substituted by two of the above-mentioned C ₁ -C ₆ alkyl groups on the nitrogen atom of the above-mentioned aminoacyl group (for example, N,N-dimethylaminoacetyl, N- ethyl-N-methylaminoacetyl, etc.). The N,N-dialkylcarbamoyl acyl group which may have a substituent on the alkyl group may be, for example, one in which the above-mentioned acyl group is substituted by the N,N-dialkylcarbamoyl group which may have a substituent on the C ₁ -C ₆ alkyl group. group (eg, N,N-dimethylcarbamoylacetyl, N,N-diethylcarbamoylacetyl, N-ethyl-N-methylcarbamoylacetyl, etc.). The N,N-dialkylcarbamoylalkylsulfonyl group that may have a substituent on the alkyl group may, for example, be the N,N-dialkylcarbamoyl group that may have a substituent on the above-mentioned C ₁ to C ₆ alkyl group and A group consisting of a sulfonyl group (for example, N,N-dimethylcarbamoylmethylsulfonyl, N-(2-hydroxyethyl)-N-methylcarbamoylmethylsulfonyl, etc.). Examples of the alkylsulfonyl acyl group include one alkylsulfonyl-substituted acyl group having the aforementioned C ₁ -C ₆ alkyl group (for example, methylsulfonylacetyl, isopropylsulfonylacetyl, etc.).

The N-arylcarbamoyl group may, for example, be the aforementioned aryl-substituted carbamoyl group (for example, phenylcarbamoyl group, naphthylcarbamoyl group, etc.). The N-3-6 membered heterocyclic carbamoyl group may, for example, be a carbamoyl group substituted by the above-mentioned 3-6 membered heterocyclic group which may have a substituent (for example, pyridylcarbamoyl, thienylcarbamoyl, etc.) . The N-alkyl-N-arylcarbamoyl group can be, for example, a group substituted with a straight-chain or branched _C1 - _C6 alkyl group on the nitrogen atom of the above-mentioned N-arylcarbamoyl group (for example, N-methyl-N-phenylcarbamoyl, etc.). N-Alkyl-N-3-6 membered heterocyclic carbamoyl can be exemplified by the above-mentioned N-3-6 membered heterocyclic carbamoyl having a straight-chain or branched _C1 - _C6 alkane on the nitrogen atom A group substituted with a group (eg, N-methyl-N-thienylcarbamoyl, etc.). The N-arylcarbamoylalkyl group may, for example, be a group in which the above-mentioned N-arylcarbamoyl is substituted for a linear or branched C ₁ -C ₆ alkyl group (for example, phenylcarbamoylmethyl, etc. ). The N-3 to 6-membered heterocyclic carbamoyl alkyl group can be exemplified by the above-mentioned N-3 to 6-membered heterocyclic carbamoyl group substituting a linear or branched C ₁ to C ₆ alkyl group (such as , pyridylcarbamoylmethyl, etc.). The N-alkyl-N-arylcarbamoylalkyl group can be, for example, a group in which the nitrogen atom of the above-mentioned N-arylcarbamoylalkyl group is substituted with a straight-chain or branched _C1 - _C6 alkyl group. group (eg, N-methyl-N-phenylcarbamoylmethyl, etc.). N-Alkyl-N-3 to 6-membered heterocyclic carbamoyl alkyl can be exemplified by straight-chain or branched _C1 on the nitrogen atom of the above-mentioned N-3 to 6-membered heterocyclic carbamoyl alkyl -C ₆ alkyl substituted groups (eg, N-methyl-N-thienylcarbamoylmethyl, etc.).

Aminothiocarbonyl is a group represented by -C(=S)-NH ₂ , and N-alkylaminothiocarbonyl represents an aminothiocarbonyl substituted by 1 alkyl, for example (methylamino)thio Carbonyl, (ethylamino)thiocarbonyl, etc. N, N-dialkylaminothiocarbonyl means aminothiocarbonyl substituted by 2 alkyl groups, such as (dimethylamino)thiocarbonyl, (diethylamino)thiocarbonyl, (ethyl Methylamino) thiocarbonyl, etc. Alkoxyalkyl (thiocarbonyl), alkylthioalkyl can be exemplified by linear, branched or cyclic C ₁ -C ₆ alkylthio substituted linear, branched or cyclic C ₁ -C ₆ alkyl groups (for example, methylthiomethyl, 1-methylthioethyl, etc.). N-acyl-N-alkylaminoalkyl can be exemplified by amino-C ₁ -C ₆ alkyl nitrogen atoms with C ₁ -C ₆ alkyl and acyl substituted groups (for example, N-acetyl-N -methylaminomethyl, etc.). It represents a group composed of the above-mentioned alkoxyalkyl group and thiocarbonyl group, and examples thereof include 2-ethoxythioacetyl group and the like.

The alkylene group represents a straight-chain or branched-chain alkylene group having 1 to 5 carbon atoms, and examples thereof include methylene, ethylene, and propylene. The alkenylene group is an alkenylene group having 2 to 5 carbon atoms having one double bond, and may, for example, be ethenylene or propenylene. The alkylenedioxy group may, for example, be a group having 1 to 5 carbon atoms such as methylenedioxy, ethylenedioxy, or propylenedioxy. Carbonyldioxy is a group represented by -O-C(=O)-O-. In the above description, there is no particular limitation on the substitution position.

Among the substituents represented by ^R3 and ^R4 , hydrogen atom, hydroxyl group, alkyl group, alkenyl group, alkynyl group, halogen atom, haloalkyl group, amino group, hydroxyimino group, alkoxyimino group, aminoalkyl group are preferred , N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, acylamino which may have a substituent, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxy Alkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carbamoyl, N- Alkylcarbamoyl, N,N-dialkylcarbamoyl which may have a substituent on the alkyl group, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkene Base-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, alkylsulfonylalkane Group, 3-6 membered heterocyclic carbonyl group which may have substituent, 3-6 membered heterocyclic carbonyloxyalkyl group which may have substituent, 3-6 membered heterocyclic group which may have substituent, carbamoylalkyl group , carbamoyloxyalkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, N-alkylaminomethyl that may have substituents on the alkyl Acylalkyl, N,N-dialkylcarbamoylalkyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, oxo, acyloxy, acyloxy that may have substituents on the alkyl Alkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, carboxyacyl, alkoxyalkoxycarbonyl, haloacyl, N,N-dioxane Aminoacyl, acyloxyacyl, alkoxyacyl, alkoxyalkylsulfonyl, N,N-dialkylcarbamoylacyl, N,N-dialkylcarbamoylalkylsulfonyl, alkane Sulfonyl acyl, aminothioformyl, N-alkylaminothioformyl, N, N-dialkylaminothioformyl or alkoxyalkyl (thiocarbonyl), etc., in addition, preferably R and ^R together represent an alkylene group, an alkenylene group, an alkylenedioxy group, a carbonyldioxy group ^, and the like.

In a preferred situation, R ³ among R ³ and R ⁴ is a hydrogen atom, and R ⁴ is a substituent exemplified above as a preferred group. At ^this time, the better group as R can be exemplified by hydrogen atom, hydroxyl group, alkyl group, halogen atom, hydroxyimino group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, acyl group, Acylamino group, acylaminoalkyl group, alkoxy group, alkoxyalkyl group, hydroxyalkyl group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylamino group, carbamoyl group which may have a substituent , N-alkylcarbamoyl which may have a substituent on the alkyl, N,N-dialkylcarbamoyl which may have a substituent on the alkyl, N-alkenylcarbamoyl, N-chain Alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenyl-N-alkylcarbamoylalkyl, N-alkoxycarbamoyl, N-alkane Base-N-alkoxycarbamoyl, N-alkyl-N-alkoxycarbamoylalkyl, carbazolyl which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl, alkylsulfonyl Alkyl, 3- to 6-membered heterocyclic carbonyl which may have substituents, 3- to 6-membered heterocyclic carbonyloxyalkyl which may have substituents, 3- to 6-membered heterocycloalkyl which may have substituents, carbamoyl Alkyl, N,N-dialkylcarbamoyloxyalkyl, N-alkylcarbamoylalkyl which may have substituents on alkyl, N,N-dioxane which may have substituents on alkyl Carbamoylalkyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, acyloxy, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl , carboxyacyl, alkoxyalkoxycarbonyl, haloacyl, N,N-dialkylaminoacyl, acyloxyacyl, hydroxyacyl, alkoxyacyl, alkoxyalkylsulfonyl, N,N -Dialkylcarbamoyl acyl, N,N-dialkylcarbamoylalkylsulfonyl, alkylsulfonyl acyl, aminothioformyl, N-alkylcarbamoylthiol, N,N- Dialkylcarbamoyl or alkoxyalkyl (thiocarbonyl) and the like.

Among these groups, particularly desirable groups for ^R include hydrogen atoms, hydroxyl groups, alkyl groups, N,N-dialkylaminoalkyl groups, acylamino groups that may have substituents, acylaminoalkyl groups, alkyl groups, etc. Oxygen, alkoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkoxycarbonylamino, carbamoyl, N-alkylcarbamoyl which may have a substituent on the alkyl, Substituent N,N-dialkylcarbamoyl, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N -alkenyl-N-alkylcarbamoylalkyl, N-alkyl-N-alkoxycarbamoyl, carbazolyl which may be substituted by 1 to 3 alkyl groups, alkylsulfonyl, alkyl Sulfonylalkyl, 3-6 membered heterocyclic carbonyl that may have substituents, 3-6 membered heterocyclic groups that may have substituents, N,N-dialkylcarbamoyloxyalkyl, N-alkylcarbamoylalkyl with substituents, N,N-dialkylcarbamoylalkyl with optional substituents on the alkyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, acyl Oxy, acyl, alkoxyalkoxycarbonyl, haloacyl, N,N-dialkylaminoacyl, hydroxyacyl, alkoxyacyl, aminothioformyl, N-alkylaminothioformyl , N, N-dialkylcarbamoyl or alkoxyalkyl (thiocarbonyl) and the like.

Examples of preferred specific substituents for R ^{and R} include hydrogen atoms, hydroxyl groups, methyl groups, ethyl groups, isopropyl groups, N, N-dimethylaminomethyl, N, N-dimethyl Aminoethyl, N, N-diethylaminomethyl, acetylamino, methoxyacetylamino, acetylaminomethyl, acetylaminoethyl, methoxy, ethoxy, methoxy Methyl, methoxyethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylamino, ethoxycarbonyl Amino, N-allylcarbamoyl, N-allylcarbamoylmethyl, N-allyl-N-methylcarbamoyl, N-allyl-N-methylcarbamoylmethyl Base, N-methoxy-N-methylcarbazolyl, N,N-dimethylcarbazolyl, N,N,N'-trimethylcarbazolyl, methanesulfonyl, methanesulfonylmethyl , Ethanesulfonylmethyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopropylcarbamoyl, N-cyclopropylmethylcarbamoyl, N-(1-ethoxycarbonylcyclopropyl)carbamoyl, N-(2-hydroxyethyl)carbamoyl, N-(2-fluoroethyl)carbamoyl, N-(2-methoxyethyl)carbamoyl, N-(carboxymethyl)carbamoyl, N-(2-aminoethyl)carbamoyl Acyl, N-(2-amidinoethyl)carbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-ethyl-N-methylcarbamoyl , N-isopropyl-N-methylcarbamoyl, N-methyl-N-propylcarbamoyl, N-(2-hydroxyethyl)-N-methylcarbamoyl, N-(2 -Fluoroethyl)-N-methylcarbamoyl, N,N-bis(2-hydroxyethyl)carbamoyl, N,N-bis(2-fluoroethyl)carbamoyl, N-(2 -Methoxyethyl)-N-methylcarbamoyl, N-carboxymethyl-N-methylcarbamoyl, N,N-bis(2-aminoethyl)carbamoyl, azetidine Alkylcarbonyl, 3-methoxyazetidinylcarbonyl, 3-hydroxyazetidinylcarbonyl, pyrrolidinylcarbonyl, 3-hydroxypyrrolidinylcarbonyl, 3-fluoropyrrolidinylcarbonyl, 3 , 4-dimethoxypyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, (tetrahydropyran-4-yl)carbonyl, benzoyl, pyridylcarbonyl, thiazolyl, 4,5-dihydrothiazolyl, oxazolyl, 4,5-dihydrooxazolyl, 5-methyloxazolyl, imidazolyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, piperidinyl, piperidine Azinyl, morpholinyl, thiomorpholinyl, 1,1-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, 5-methyl-1 , 3,4-thiadiazolyl, 1,3-oxazolidinyl, N-methylcarbamoylmethyl, N-methylcarbamoylethyl, N-ethylcarbamoylmethyl, N -(2-fluoroethyl)carbamoylmethyl, N-(2-methoxyethyl)carbamoylmethyl, N,N-dimethylcarbamoylmethyl, N,N-dimethyl N-(2-fluoroethyl)-N-methylcarbamoylmethyl, N-(2-methoxyethyl)-N-methylcarbamoylmethyl, N , N-dimethylcarbamoyloxymethyl, 2-(N-ethyl-N-methylcarbamoyloxy) ethyl, methylsulfonylamino, ethylsulfonylamino, methylsulfonyl Acylaminomethyl, methylsulfonylaminoethyl, acetyl, propionyl, isobutyryl, 2-methoxyethoxycarbonyl, trifluoroacetyl, N,N-dimethylaminoacetyl, N -Ethyl-N-methylaminoacetyl, hydroxyacetyl, 1,1-dimethyl-2-hydroxyethylcarbonyl, methoxyacetyl, 1,1-dimethyl-2-methoxy Ethylcarbonyl, aminothioformyl, (dimethylamino)thioformyl, 2-methoxythioacetyl and the like.

As mentioned above, a preferred case of ^R3 and ^R4 is that ^R3 is a hydrogen atom, and ^R4 is the specific substituent mentioned above. Particularly preferred is an N,N-dialkylcarbamoyl group which may have a substituent on the alkyl group, and among them, N,N-dimethylcarbamoyl group is more preferable. R ³ and R ⁴ are not limited to these specific substituents.

[About group T ⁰ ]

The group T ⁰ represents carbonyl or thiocarbonyl, but more preferably carbonyl.

[About group T ¹ ]

Group ^T represents carbonyl, sulfonyl, group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C(=O)-N(R' )-, group-C(=O)-C(=S)-N(R')-, group-C(=S)-C(=S)-N(R')-(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 ¹ in the group represents 1 to 1 carbon atoms that may have a substituent The alkylene group of 5, R" represents a hydrogen atom, hydroxyl, alkyl or alkoxy), group -C(=O)-NH-, group -C(=S)-NH-, group -C(=O )-NH-NH-, group-C(=O)-A ² -C(=O)-(A ² in the group represents a single bond or an alkylene group with 1 to 5 carbon atoms), group-C (=O)-A ³ -C(=O)-NH-(A ³ in the group represents an alkylene group with 1 to 5 carbon atoms), group-C(=O)-C(=NOR ^a ) -N(R ^b )-, group-C(=S)-C(=NOR ^a )-N(R ^b )-(R ^a in the group represents hydrogen atom, alkyl or alkanoyl, R ^b represents hydrogen atom, hydroxyl, alkyl or alkoxy), group-C(=O)-N=N-, group-C(=S)-N=N-, group-C(=NOR ^c )-C(= O)-N(R ^d )-(R ^c in the group represents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, and R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group -C(=NN-(R ^e )(R ^f ))-C(=O) ^-N (R ^g )-(Re and R ^f in the group are independently hydrogen atom, alkyl, alkanoyl , alkyl (thiocarbonyl), R ^g represents a hydrogen atom, hydroxyl, alkyl or alkoxy), group-C(=O)-NH-C(=O)-, group-C(=S)- NH-C(=O)-, group-C(=O)-NH-C(=S)-, group-C(=S)-NHC(=S)-, group-C(=O)-NH -SO ₂ -, -SO ₂ -NH-, -C(=NCN)-NH-C(=O)-, -C(=S)-C(=O)- or thiocarbonyl.

Among the above-mentioned groups, the alkylene group having 1 to 5 carbon atoms in A ¹ , A ² and A ³ represents a linear, branched or cyclic alkylene group having 1 to 5 carbon atoms, for example, Examples include methylene, ethylene, propylene, cyclopropylene, 1,3-cyclopentylene and the like. The alkyl groups in R', R", R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g are linear, branched or cyclic alkanes with 1 to 6 carbon atoms Alkoxy group, for example, methyl group, ethyl group, etc. Alkoxy group, for example, a straight chain, branched or cyclic alkoxy group with 1 to 6 carbon atoms, for example, methoxy group, ethoxy group, etc. wait.

The alkanoyl group in R ^a , R ^c , R ^e and R ^f represents a straight-chain, branched or cyclic group consisting of an alkyl group having 1 to 6 carbon atoms and a carbonyl group, examples of which include acetyl, propane Acyl etc.

The aryl group in R ^c represents a group having 6 to 14 carbon atoms, and examples thereof include phenyl, naphthyl and the like. 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 benzyl, phenethyl and the like.

Group T ^is more preferably carbonyl, group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C(=O)-N(R') -, group-C(=O)-C(=S)-N(R')-, group-C(=S)-C(=S)-N(R')- and group-C(=O )-CH ₂ -N(R”)-, particularly preferably carbonyl, group-C(=O)-C-(=O)-N(R’)-, group-C(=S)-C(= O)-N(R')-, group-C(=O)-C(=S)-N(R')-, group-C(=S)-C(=S)-N(R') -.

[Regarding the groups R ¹ and R ² ]

R ¹ and R ² are each independently a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, but are preferably a hydrogen atom or an alkyl group, more preferably a hydrogen atom.

Among ^R1 and ^R2 , 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 straight-chain, branched-chain or cyclic alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy and ethoxy. R ¹ and R ² are each independently preferably a hydrogen atom or an alkyl group, more preferably both are hydrogen atoms.

When ^T1 is a carbonyl group or a sulfonyl group, and ^Q5 in the group ^Q3 is an alkylene group with 1 to 8 carbon atoms or an alkenylene group with 2 to 8 carbon atoms, ^Q4 is preferably the aforementioned 12 groups In (b), (f), (g), (h), (i), (j), (k) and (l) (in group (f), N represents R ¹⁹ on the ring substituted 2 carbon atoms are replaced by nitrogen atoms).

In addition, when ^T1 is a carbonyl group or a sulfonyl group, and ^Q5 in the group ^Q3 is an alkylene group with 1 to 8 carbon atoms or an alkenylene group with 2 to 8 carbon atoms, the substituent on ^Q5 is preferably is N-alkylcarbamoyl or N,N-dialkylcarbamoyl.

T ¹ is group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C(=O)-N(R')-, group-C( ＝O)-C(=S)-N(R')-or group-C(=S)-C(=S)-N(R')-, Q ⁵ in the group Q ³ is the number of carbon atoms In the case of an alkylene group of 1 to 8 or an alkenylene group of 2 to 8 carbon atoms, Q ⁴ is preferably (i), (j) and (k) among the aforementioned 12 groups.

In addition, ^T1 is group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C(=O)-N(R')-, group- C(=O)-C(=S)-N(R')- or group-C(=S)-C(=S)-N(R')-, ^Q5 in group ^Q3 is carbon In the case of an alkylene group having 1 to 8 atoms or an alkenylene group having 2 to 8 carbon atoms, the substituent on Q ⁵ is preferably an N-alkylcarbamoyl group or an N,N-dialkylcarbamoyl group.

The compound represented by the general formula (1) of the present invention, its salt, its solvate or its N-oxide has characteristics in the combination of group ^T1 and group ^Q3 , which are roughly the following two situations ((I ) and (II)).

(I) T represents ^carbonyl , sulfonyl, group-C(=O)-NH-C(=O)-, group-C(=S)-NH-C(=O)-, group-C(= O)-NH-C(=S)-, radical-C(=S)-NHC(=S)-, radical-C(=O)-NH-SO ₂ -, radical-SO ₂ -NH-, radical -C(=NCN)-NH-C(=O)-, group-C(=S)-C(=O)-or thiocarbonyl, ^Q represents the following groups,

In the group, Q ⁵ represents the group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(In the group, m and n are each independently representing an integer of 0, 1 to 3, and A represents oxygen atom, nitrogen atom, sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH -)Case.

(II) T ¹ represents group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C(=O)-N(R')-, group -C(=O)-C(=S)-N(R')-, group -C(=S)-C(=S)-N(R')-(R' in the group represents a hydrogen atom , hydroxyl, alkyl or alkoxy), group -C(=O)-A ¹ -N(R")-(A ¹ in the group represents an alkylene group with 1 to 5 carbon atoms that may have substituents group, R" represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group -C(=O)-NH-, a group -C(=S)-NH-, a group -C(=O)-NH- NH-, group-C(=O)-A ² -C(=O)-(A ² in the group represents a single bond or an alkylene group with 1 to 5 carbon atoms), group-C(=O) -A ³ -(=O)-NH-(A ³ in the group represents an alkylene group with 1 to 5 carbon atoms), group -C(=O)-C(=NOR ^a )-N(R ^b )-, group-C(=S)-C(=NOR ^a )-N(R ^b )-(R ^a in the group represents hydrogen atom, alkyl or alkanoyl, R ^b represents hydrogen atom, hydroxyl, alkane group or alkoxy group), group-C(=O)-N=N-, group-C(=S)-N=N-, group-C(=NOR ^c )-C(=O)-N( R ^d )-(R ^c in the group represents a hydrogen atom, an alkyl group, an alkanoyl group, an aryl group or an aralkyl group, and R ^d represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group-C(=NN -(R ^e )(R ^f ))-C(=O)-N(R ^g )-(The R ^e and R ^f in the group are each independently representing a hydrogen atom, an alkyl group, an alkanoyl group, an alkyl group (sulfur Carbonyl), R ^g represents a hydrogen atom, hydroxyl, alkyl or alkoxy), group-C(=O)-NH-C(=O)-, group-C(=S)-NH-C(= O)-, group-C(=O)-NH-C(=S)-, group-C(=S)-NHC(=S)-, group-C(=O)-NH-SO ₂ -, Group -SO ₂ -NH-, group -C(=NCN)-NH-C(=O)-, group -C(=S)-C(=O)- or thiocarbonyl, Q ³ represents the following group group,

In the group, Q ⁵ represents an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or a group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n - (In the group, m and n are each independently representing an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, - NH-NH-, -S-NH-, -SO-NH- or -SO2-NH-).

Among the above-mentioned (I) and (II), the following (i) and (ii) can be mentioned as preferable examples.

(i) The group ^R1 and the group ^R2 are independently hydrogen atoms or alkyl groups, and the group ^Q1 is a saturated or unsaturated 2-ring or 3-ring condensed hydrocarbon group that may have a substituent or may be A saturated or unsaturated bicyclic or tricyclic fused heterocyclic group with substituents, the group ^Q2 is a single bond, ^{and Q5} in the group ^Q3 is a group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(in the group, m and n are each independently representing 0 or 1, and A is as described above), the group Q ⁴ is selected from (a)～ In the nine types of groups (h) and (l), the group T ⁰ is a carbonyl group or thiocarbonyl group, and the group T ¹ is a carbonyl group or a sulfonyl group.

(ii) In the general formula (1), the group R ¹ and the group R ² are each independently a hydrogen atom or an alkyl group, and the group Q ¹ is a saturated or unsaturated 2-ring or 3-ring that may have substituents. A fused hydrocarbon group or a saturated or unsaturated 2-ring or 3-ring condensed heterocyclic group that may have a substituent, the group ^Q2 is a single bond, and ^Q5 in the group ^Q3 is the number of carbon atoms 3 to 6 alkylene groups or groups -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(In the group, m and n are each independently representing 0 or 1, and A is as described above ), the group ^Q is a group selected from the aforementioned 12 types (i), (j) and (k), the group ^T is carbonyl or thiocarbonyl, and the group T is ^a group- C(=O)-C-(=O)-N(R')-, group-C(=S)-C(=O)-N(R')-, group-C(=O)-C (=S)-N(R')- or group-C(=S)-C(=S)-N(R')-.

The compound represented by the general formula (1) of the present invention may exist stereoisomers or optical isomers from chiral carbon atoms, and these stereoisomers, optical isomers and mixtures thereof are all included in the scope of the present invention Inside.

The salt of the compound represented by the general formula (1) of the present invention is not particularly limited as long as it is a salt allowed in medicine, and specific examples include hydrochloride, hydrobromide, hydroiodide, phosphate, Inorganic acid salts such as nitrate and sulfate, organic sulfonates such as benzoate, methanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate, and acetate, propionate, Organic carboxylic acid salts such as oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate, and almondate. In addition, when the compound represented by the general formula (1) has an acidic group, it can also form a salt with an alkali metal ion or an alkaline earth metal ion. The solvate is not particularly limited as long as it is acceptable in medicine, and specific examples thereof include hydrates, ethanolates, and the like. In addition, N-oxide bodies can also be formed when nitrogen atoms are present in the general formula (1).

The compounds of the present invention are particularly preferably the compounds and salts of the compounds shown in Examples described later, the following compounds, their salts, and the like.

1) 3-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole And[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)[1,6]naphthyridine-7-formamide (carboxamide)

2) 7-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole And[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-tetrahydrothiazole And[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-4a,8a-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-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole And[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-5-oxo-4,5-dihydro-1H-1,3,4-benzotriazepine-2 -Formamide

6) 6-chloro-N-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole And[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-tetrahydrothiazole And[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]cyclohexyl}-6- Methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxamide

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

12) N ¹ -(4-chlorophenyl)-N ² -((1S,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c] pyridin-2-yl) carbonyl] amino} cyclohexyl) oxalamide

13) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 , 4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

14) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3, 4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

15) N ¹ -(4-chlorophenyl)-N ² -((1S,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d ]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

16) N ¹ -(5-chloropyridin-2-yl)-N ² -((1R, 2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3, 4-d]thiazol-2-yl)carbonyl]amino}cyclopentyl)oxalamide

17) N ¹ -(4-chlorophenyl)-N ² -((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d ]thiazol-2-yl)carbonyl]amino}cyclopentyl)oxalamide

18) N ¹ -(4-chlorophenyl)-N ² -((1R,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c] pyridin-2-yl) carbonyl] amino} cycloheptyl) oxalamide

19) N ¹ -(5-chloropyridin-2-yl)-N ² -((1R,2R)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 , 4-c]pyridin-2-yl)carbonyl]amino}cycloheptyl)oxalamide

20) N ¹ -(5-chloropyridin-2-yl)-N ² -((1R, 2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3, 4-d]thiazol-2-yl)carbonyl]amino}cycloheptyl)oxalamide

21) N ¹ -(4-chlorophenyl)-N ² -((1R,2R)-2-{[(5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d ]thiazol-2-yl)carbonyl]amino}cycloheptyl)oxalamide

22) N ¹ -(5-chloro-6-methylpyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

23) N ¹ -(5-chloro-3-methylpyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

24) N ¹ -(5-chloro-4-methylpyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

25) N ¹ -(4-chloro-3-hydroxyphenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

26) N ¹ -(4-chloro-2-hydroxyphenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

27) N ¹ -[4-Chloro-2-(fluoromethyl)phenyl]-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

28) N ¹ -[4-chloro-2-(methoxymethyl)phenyl]-N ² -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{ [(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

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

30) N ¹ -(5-chloropyridin-2-yl)-N ² -((1R, 2R, 4R)-4-(hydroxymethyl)-2-{[(5-methyl-4,5, 6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)oxalamide

31) N ¹ -(5-chloropyridin-2-yl)-N ² -((1R, 2R, 4S)-4-(hydroxymethyl)-2-{[(5-methyl-4,5, 6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)oxalamide

32) N ¹ -((3R,4S)-1-acetyl-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2- Base)carbonyl]amino}piperidinyl-4-yl)-N ² -(5-chloropyridin-2-yl)oxalamide

33) N ¹ -(5-chloropyridin-2-yl)-N ² -((3R,4S)-1-(methylsulfonyl)-3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidinyl-4-yl)oxalamide

34) N ¹ -{(1S, 2R, 4S)-2-{[(3-chlorobenzothiophen-2-yl)carbonyl]amino}-4-[(dimethylamino)carbonyl]cyclohexyl}- N ² -(5-chloropyridin-2-yl)oxalamide

35) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)thiocarbonyl]-2-{[(5-methyl Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

36) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)thiocarbonyl]amino}cyclohexyl)oxalamide

37) N ¹ -(5-chloropyridin-2-yl)-N ² -((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

38) N ¹ -(5-chloropyridin-2-yl)-N ² -((3R, 4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4, 5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)thiocarbonyl]amino}piperidin-4-yl)oxalamide

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

41) N ¹ -(4-chlorophenyl)-N ² -((3R,4S)-1-(2-methoxythioacetyl)-3-{[(5-methyl-4,5 , 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide

42) N ¹ -(4-chlorophenyl)-N ² -((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)thiocarbonyl]amino}piperidin-4-yl)oxalamide

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

45) N ¹ -((1S,2R,4S)-4-(1-azetidinylcarbonyl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(5-chloropyridin-2-yl)oxalamide

46) N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1-pyrrolidinylcarbonyl)cyclohexyl]oxalamide

47) N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1-piperidinylcarbonyl)cyclohexyl]oxalamide

48) N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S,2R,4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)carbonyl]amino}-4-(4-morpholinylcarbonyl)cyclohexyl]oxalamide

49) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(methylamino)carbonyl]-2-{[(5-methyl-4 , 5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

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) N ¹ -(4-bromophenyl)-N ² -((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide

52) N ¹ -(5-chloropyridin-2-yl)-N ² -((3R,4S)-1-(2-methoxyacetyl)-3-{[4-(pyridin-4-yl) )benzoyl]amino}piperidin-4-yl)oxalamide

53) N ¹ -(5-chloropyridin-2-yl)-N ² -[(3R,4S)-1-(2-methoxyacetyl)-3-({[2-(pyridine-4- Base) pyrimidin-5-yl] carbonyl} amino) piperidin-4-yl] oxalamide

54) N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-({[2-(pyridine- 4-yl)pyrimidin-5-yl]carbonyl]amino)cyclohexyl]oxalamide

55) N-{(1R, 2S, 5S)-2-{[2-(4-chloroanilino)-2-oxoethane(methoxy)imino]amino}-5-[(dimethyl Amino)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) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(4,4,5 -Trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

58) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(4,4- Ethyl-5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

59) N-{(1R, 2S, 5S)-2-({[(E)-2-(4-chlorophenyl)vinyl]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-[(two Methylamino)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-oxosulfur Substituted acetyl}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-[(dimethyl Amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

66) N ¹ -(4-chlorothiazol-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

67) N ¹ -((1S,2R,4S)-5-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 , 4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(3-fluorophenyl)oxalamide

68) N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 , 4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -phenyloxamide

69) N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 , 4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(pyridin-2-yl)oxalamide

70) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5,6,6 -Trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

71) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-44(dimethylamino)carbonyl]-2-{[(4,4,5,6 , 6-pentamethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

72) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[2-methyl-2 , 3-dihydrothiazolo[5,4-d]isoxazol-5-yl)carbonyl]amino}cyclohexyl)oxalamide

73) N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(2-methyl- 2,3-Dihydrothiazolo[4,5-d]isoxazol-5-yl)carbonyl]amino}cyclohexyl)oxalamide

74) N ¹ -(5-chloro-2-furyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

75) N ¹ -(5-chlorooxazol-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

76) N ¹ -(5-chloro-1H-imidazol-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

77) N-{(1R, 2S, 5S)-2-{[2-(4-chloroanilino)-1-ethoxyimino-2-oxoethyl]amino}-5-[(two Methylamino)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-[(two Methylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

79) N-{(1R, 2S, 5S)-2-{[1-benzyloxyimino-2-(4-chloroanilino)-2-oxoethyl]amino}-5-[( Dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

80) N-{(1R, 2S, 5S)-2-({2-(4-chloroanilino)-1-hydrazono-2-oxoethyl]amino)-5-[(dimethyl Amino)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 -Formamide

83) N-{(1R, 2S, 5S)-2-{[2-(4-chloroanilino)-1-methylimino-2-oxoethyl]amino}-5-[(dimethyl Amino)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-acryloyl]amino}-5-[(dimethylamino )carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

Hereinafter, the production method of the diamine derivative (1) of this invention is demonstrated.

[Preparation method 1]

The compounds represented by the general formula (1), their salts, their solvates or their N-oxides can be produced, for example, as follows.

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are as described above, and T ¹ is a carbonyl group]

Derivatize carboxylic acid (3) into mixed acid anhydride, acid halide or active ester, etc., make it react with diamine (2) to obtain compound (4), make the obtained compound (4) and carboxylic acid under the same conditions (5) Reaction, the compound (1) of this invention can be obtained. In the reactions of the above-mentioned steps, the reaction reagents and conditions generally used for peptide synthesis may be used. The above mixed acid anhydride can be produced, for example, by reacting chloroformic acid esters such as ethyl chloroformate and isobutyl chloroformate with carboxylic acid (3) in the presence of a base. Acid halides can be prepared by treating carboxylic acid (3) with acid halides such as thionyl chloride and oxalyl chloride. Various esters can be used as active esters, such as N, N'-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·hydrochloride etc. The mixture can be obtained by reacting phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide with carboxylic acid (3). In addition, by reaction of carboxylic acid (3) with pentafluorophenyl trifluoroacetate, etc., reaction of carboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate, carboxylic acid (3) ) and the reaction of diethyl cyanophosphonate (salt-in method), the reaction of carboxylic acid (3) with triphenylphosphine and 2,2'-dipyridyl disulfide (Xiangshan method), etc., can also produce active ester. In the presence of a suitable base, in an inert solvent, react the mixed anhydride, acid halide or active ester of the carboxylic acid (3) obtained above with diamine (2) at -78°C to 150°C to obtain the compound (4). The compound (1) of the present invention can be obtained by reacting the obtained compound (4) with the mixed anhydride, acid halide or active ester of the carboxylic acid (5) under the same conditions. The reagents and reaction conditions in the reaction of compound (4) and carboxylic acid (5) are the same as those in the reaction of diamine (2) and carboxylic acid (3).

The specific alkali used in the above-mentioned steps can for example be carbonates of alkali metals such as sodium carbonate, potassium carbonate, sodium ethylate, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride or alkaline earth metals, Alkali metal alkoxides, alkali metal hydroxides or hydrides, or organometallic bases represented by alkyllithiums such as n-butyllithium, lithium dialkylamides such as lithium diisopropylamide, bis(trimethyl Organometallic bases of bissilylamines such as lithium silyl)amide, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylpyridine Organic bases such as morpholine, diisopropylethylamine, diazabicyclo[5.4.0]undecene-7(DBU), etc.

The inert solvent used in this reaction can be exemplified by halogenated alkyl solvents such as methylene chloride, chloroform, and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, and dioxane, benzene, toluene, and the like. Aromatic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one and other amide solvents, in addition, according to different situations Sulfoxide-based solvents such as dimethylsulfoxide and sulfolane, ketone-based solvents such as acetone and methyl ethyl ketone, and the like can be used.

[Preparation method 2]

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

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are as described above, T ¹ is carbonyl, Boc is tert-butoxycarbonyl, Boc-ON is 2-(tert-butoxy Carbonyloxyimino)-2-phenylacetonitrile]

As mentioned above, diamine (2) is treated with Boc-ON (6) to prepare a compound (7) with two amino groups protected by a tert-butoxycarbonyl group, and the resulting (7) and carboxylic acid (5 ) reaction to obtain compound (8), then treat with acid to obtain compound (9), and then react (9) with carboxylic acid (3) to obtain compound (1) of the present invention. Compound (7) can be produced by reacting at -10°C to 40°C in a solvent such as dichloromethane in the presence of triethylamine. Compound (8) can be prepared by reacting compound (7) with mixed anhydride, acid halide or active ester of carboxylic acid (5) under the reagents and reaction conditions described in Preparation Method 1. The obtained compound (8) can be treated with trifluoroacetic acid or the like at -20°C to 70°C to obtain the amine (9). In the reaction of the obtained amine (9) and carboxylic acid (3), the same reagents and reaction conditions as those described in Production Method 1 can be used.

However, the tert-butoxycarbonyl group of compound (7) can be replaced by other amino-protecting groups. In this case, the reagent (6) is also replaced by other reagents, and corresponding reaction conditions and the like must be adopted. Other amino protecting groups include alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-(or o-) nitro Arylmethoxycarbonyl such as benzyloxycarbonyl, arylmethyl such as benzyl and trityl, aroyl such as benzoyl, or 2,4-dinitrobenzenesulfonyl, o-nitrobenzenesulfonyl and other arylsulfonyl groups. These protecting groups can be selected according to the properties of the compound protecting the amino group, and even when these protecting groups are cleaved, the reagents and reaction conditions corresponding to the protecting groups can be selected.

[Preparation method 3]

The compound (1) of the present invention can be produced by reacting diamine (2) with sulfonyl halide (10), followed by condensation with carboxylic acid (5).

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are as described above, T ¹ is a sulfonyl group, and X is a halogen atom]

Compound (4) can be prepared by reacting diamine (2) and sulfonyl halide (10) at -10°C to 30°C in an inert solvent in the presence of a base such as triethylamine. Inert solvent and base The solvents and bases described in Production Method 1 can be appropriately selected and used. The compound (1) of the present invention can be obtained by condensing the obtained (4) with the carboxylic acid (5) using the reagents and reaction conditions described in Preparation Method 1. In addition, 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 a suitable base.

[Preparation method 4]

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

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and X are as described above, and T ¹ is a sulfonyl group]

That is, the compound (1) can be prepared by reacting the amine (9) and the sulfonyl halide (10) at -10°C to 30°C in the presence of a base in an inert solvent. The inert solvent and base can be appropriately selected from those described in Production Method 1 for use.

[Preparation method 5]

When the ^Q3 part of the compound (1) of the present invention is the following group,

[In the group, R ³ , R ⁴ and Q ⁵ are as described above, and the numbers of 1 and 2 indicate positions]

Trans and cis geometric isomers may exist in the relationship between the 1-position and the 2-position. Hereinafter, the production method of the cis-form and trans-form compound (1) will be described.

[Preparation method of trans body]

[wherein, Q ⁵ , R ³ and R ⁴ are as described above]

As a production example for obtaining trans diol (12a) from cyclic alkenes (11), for example, conversion from cyclohexene to trans cyclohexanediol is known (Organic Synthesis, 1955, Vol. III, p. 217) wait. In addition, as a production example of converting trans diol (12a) into trans diamine (2a), 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 alkenes (11).

The trans diamine (2a) obtained by the above method can be further obtained by the method of the above preparation methods 1-4 to obtain the trans compound (1).

[Preparation method of cis-isomer]

[wherein, Q ⁵ , R ³ and R ⁴ are as described above]

As a preparation example for obtaining cis-diol (12b) from cyclic alkenes (11), for example, known conversion from cyclohexene to cis-cyclohexanediol (J.Org.Chem, 1998, Vol. 63, 6094 pages) etc. In addition, as a preparation example of converting cis-diol (12b) to cis-diamine (2b), conversion from cis-cyclopentanediol to cis-cyclopentanediamine (WO 98/30574) and the like have been reported. According to these reports, cis-diamine (2b) can be prepared.

The cis-diamine (2b) obtained by the above method can then be used to obtain the cis-type compound (1) by the method of the above-mentioned preparation methods 1-4.

[Preparation method 6]

As described above, the ^Q3 moiety of the compound (1) of the present invention may exist in trans and cis forms, geometric isomers, and optical isomers may exist, respectively. Hereinafter, a method for producing an optically active body will be described.

[wherein, Q ⁵ , R ¹ , R ² , R ³ and R ⁴ are as described above, and R ⁵⁰ is a protecting group for amino]

Regarding the production method of the optically active substance 1,2-trans-aminoalcohol derivative (15), for example, a production method of obtaining the optically active substance 1,2-trans-2-aminocyclopentanol from cyclopentene oxide is known Or obtain optically active body 1 from cyclohexene oxide, the preparation method of 2-trans-2-aminocyclohexanol (Tetrahedron: Asymmetry, 1996, 7 volumes, 843 pages; J.Org.Chem., 1985 , vol. 50, pp. 4154; J. Med. Chem., 1998, vol. 41, pp. 38). Compound (16) can be prepared by reacting the amino group of the optically active aminoalcohol derivative (15) produced by or by applying this known method with a suitable protecting reagent. The protective group equivalent to R in compound (16) is preferably ^{alkoxycarbonyl} such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, Arylmethoxycarbonyl such as p-methoxybenzyloxycarbonyl, p-(or o-)nitrobenzyloxycarbonyl, etc., arylsulfonyl such as 2,4-dinitrobenzenesulfonyl, ortho-nitrobenzenesulfonyl . For example, when protected by tert-butoxycarbonyl, compound (16) can be obtained by reacting aminoalcohol derivative (15) with di-tert-butyl dicarbonate in an inert solvent at -78°C to 50°C. The inert solvent can be appropriately selected from those described in Production Method 1 for use.

Compound (17) can be prepared by reacting compound (16) with methanesulfonyl chloride at -78°C to 50°C in the presence of a base in an inert solvent. The inert solvent can be appropriately selected from those described in Production Method 1 for use. The base is preferably pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] Undecene-7 (DBU) and other organic bases, etc.

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

The method for converting azide derivative (18) into compound (7a) includes the method of hydrogenation using palladium catalyst, Raney nickel catalyst or platinum catalyst, and the method of using reducing agents such as lithium aluminum hydride, sodium borohydride, zinc borohydride, etc. For the reaction, there are various methods such as the reaction using zinc in the presence of nickel chloride or cobalt chloride, and the reaction using triphenylphosphine, and appropriate reaction conditions can be selected according to the properties of the compound. For example, compound (7a) can be obtained from azide compound (18) by adding hydrogen at a temperature of -10°C to 70°C with 1-20% palladium carbon as a catalyst in a suitable solvent. The hydrogen pressure can be raised above atmospheric pressure. As the solvent, alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, N, N-dimethylformamide, N, N-dimethyl Amide solvents such as acetamide and N-methylpyrrolidin-2-one, ester solvents such as ethyl acetate, acetic acid, hydrochloric acid, water or a mixed solvent of these solvents, etc.

According to the above-mentioned Production Method 2, the optically active compound (1) can be obtained from the optically active amine (7a) produced by the above-mentioned method. Furthermore, the enantiomer (1) of the optically active body (1) can be prepared from the optically active amine (7a) by the same method.

In addition, the optically active compound (1) can also be produced by separating the racemate (1) through a column formed of an optically active carrier. The intermediate (2), (4), (7), (8) or (9) of the racemate (1) is separated and prepared by a column formed by an optically active carrier, and then the optically active (2), ( 4), (7), (8) or (9) is isolated, and then the optically active compound (1) can also be prepared according to Preparation Methods 1-4. As a method of isolating optically active (1), (2), (4), (7), (8) or (9), a method of fractional crystallization of a salt with an optically active carboxylic acid may be used , or conversely, a method for fractional crystallization of salts with optically active bases.

[Preparation method 7]

Hereinafter, the preparation method of the compound (1c) containing a heteroatom in Q ³ in the compound (1) of the present invention will be described in detail.

The compounds represented by the general formula (1c), their salts, their solvates or their N-oxides can be produced, for example, as follows.

[wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , A, m and n are as described above, and T ¹ represents a carbonyl group]

Carboxylic acid (3) is derivatized as mixed acid anhydride, acid halide or active ester etc., makes it react with compound (2c) and makes compound (4c), makes gained compound (4c) and carboxylic acid ( 5) Reaction, the compound (1c) of the present invention can be obtained.

In the reactions of the above-mentioned steps, the reaction reagents and conditions generally used for peptide synthesis may be used. The above mixed acid anhydride can be produced, for example, by reacting chloroformic acid esters such as ethyl chloroformate and isobutyl chloroformate with carboxylic acid (3) in the presence of a base. Acid halides can be prepared by treating carboxylic acid (3) with acid halides such as thionyl chloride and oxalyl chloride. Various esters can be used as active esters, such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·hydrochloric acid Condensing agents such as salts can be obtained by reacting phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide with carboxylic acid (3). In addition, by reaction of carboxylic acid (3) with pentafluorophenyl trifluoroacetate, etc., reaction of carboxylic acid (3) with 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate, carboxylic acid (3) ) and the reaction of diethyl cyanophosphonate (salt-in method), the reaction of carboxylic acid (3) with triphenylphosphine and 2,2'-dipyridyl disulfide (Xiangshan method), etc., can also produce active ester. In the presence of a suitable base, in an inert solvent, under cooling to heating, the mixed anhydride, acid halide or active ester of the carboxylic acid (3) obtained above is reacted with the compound (2c) to obtain the compound ( 4c). The compound (1c) of the present invention can be prepared by reacting the obtained compound (4c) with a mixed anhydride, acid halide or active ester of carboxylic acid (5) under the same conditions. The reagents and reaction conditions in the reaction of compound (4c) and carboxylic acid (5) are the same as those in the reaction of compound (2c) and carboxylic acid (3).

The specific alkali used in the above-mentioned steps can be for example 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 metals such as sodium hydroxide and potassium hydroxide. Hydroxide, sodium hydride, potassium hydride, etc. or alkali metal hydrides, or organometallic bases represented by dialkylamide lithium such as n-butyllithium and diisopropylamide lithium, bis(tri Organometallic bases of bissilylamines such as lithium methylsilyl)amide, or pyridine, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine , diisopropylethylamine, diazabicyclo[5.4.0]undecene-7(DBU) and other organic bases.

The inert solvent used in this reaction can, for example, be haloalkyl-based solvents such as dichloromethane and chloroform, ether-based solvents such as tetrahydrofuran and 1,4-dioxane, aromatic solvents such as benzene and toluene, N,N-dimethyl Amide-based solvents such as formamide. In addition to these, sulfoxide-based solvents such as dimethylsulfoxide, ketone-based 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 adding and removing an appropriate protecting group or switching a functional group.

The protecting group of the amino group can adopt the protecting group commonly used as the protecting group of the amino group in the peptide synthesis in the synthesis of organic compounds, specifically, alkoxycarbonyl groups such as tert-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, benzyl Oxycarbonyl, p-methoxybenzyloxycarbonyl, p-(or o) nitrobenzyloxycarbonyl and other arylmethoxycarbonyl groups, benzyl, 4-methoxybenzyl, trityl and other aryl groups Methyl, alkanoyl such as formyl and acetyl, aroyl such as benzoyl, or arylsulfonyl such as 2,4-dinitrobenzenesulfonyl and o-nitrobenzenesulfonyl, and the like.

As a protecting group for a hydroxyl group, a protecting group for a hydroxyl group commonly used in the synthesis of organic compounds can be used, and specific examples include alkoxymethyl groups such as methoxymethyl, benzyl, 4-methoxybenzyl, triphenyl Arylmethyl groups such as methyl, alkanoyl groups such as acetyl group, aroyl groups such as benzoyl group, tert-butyldiphenylsilyloxy group and the like. A carboxyl group can be protected by forming an ester with an alkyl group such as methyl, ethyl, or tert-butyl, or an arylmethyl group such as benzyl. Addition and removal of the above-mentioned protecting groups can be carried out according to ordinary methods.

Among the compounds (1c) of the present invention, various derivatives can be formed by changing the functional groups of the compounds. For example, the usual organic chemical method uses mixed acid anhydrides, acid halides or active esters to acylate compounds in which A is an unsubstituted nitrogen atom to form an amide compound, which is reacted with a sulfonyl halide to obtain a sulfonamide Compounds, N-alkyl compounds are obtained by reacting with alkyl halides, N-aryl compounds are obtained by reacting aryl halides, etc., and urethane compounds are obtained by reacting isocyanate, etc. A is a compound with an unsubstituted nitrogen atom. For example, the compound (1c) can be prepared according to the preparation method 7 through the diamine (2c) protected by A with a tert-butoxycarbonyl group, and the compound (1c) is subjected to acid treatment. And made.

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

In addition, the compounds of the present invention have optical isomers due to having chiral carbons. In addition to the method of preparing these optical isomers from the optically active diamine (2c), the racemate can be formed into a salt with an optically active amine or acid, followed by fractional crystallization, or It is produced by using a chromatographic column with an optically active carrier, etc. for separation.

In addition, in the reaction of compound (2c) and carboxylic acid (3), sulfonyl halide (10) is used instead of carboxylic acid (3) to obtain compound (1c) whose T ¹ is a sulfonyl group.

[Preparation method 8]

Compound (1c) of the present invention can also be produced according to the following method.

[wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , A, m and n are as described above, T ¹ represents a carbonyl group, and R ⁵¹ and R ⁶¹ represent amino protecting groups]

Compound (21) can be produced by removing the protecting group R ⁶¹ of compound (19) obtained by protecting the amino group of compound (2c). Here, the amino protecting group exemplified as R ⁵¹ and R ⁶¹ is not particularly limited as long as it is a group generally used for protecting an amino group, and a representative example thereof includes the protecting group for an amino group described in Production Method 7. In this case, R ⁵¹ and R ⁶¹ must be protecting groups that can be removed under different methods or conditions. For example, a combination of R ⁵¹ being tert-butoxycarbonyl and R ⁶¹ being benzyloxycarbonyl can be mentioned. These protecting groups can be selected according to the properties of the compound protecting the amino group, etc. When removing these protecting groups, the reagents and reaction conditions corresponding to the protecting groups can also be selected.

In addition, the compound (21) can also be obtained by changing the hydroxyl group of the aminoalcohol (20) to an amino group. As a preparation example of aminoalcohol (20), for example, conversion of methionine to 3-hydroxy-4-aminothiopyran-1,1-dioxide (Tetrahedron Lett., volume 37, page 7457, 1996) et al.

As a method of converting the hydroxyl group of the aminoalcohol (20) to an amino group, the aminoalcohol (20) is reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc., and then reacted with ammonia, Benzylamine, p-methoxybenzylamine, 2,4-dimethoxybenzylamine and other primary aralkylamines, dibenzylamine and other secondary aralkylamines, N-benzyl hydroxylamine, N, O-dibenzyl hydroxylamine A method of preparing diamine (21) by reacting hydroxylamines, etc., and removing benzyl groups, etc., if necessary. In addition, the amino alcohol (20) is treated with triphenylphosphine and ethyl azodicarboxylate (Xiangshan method), etc., and after reacting with phthalimide or succinimide, it is treated with hydrazine or Diamine (21) can be obtained by treating with N-methylhydrazine or the like. In addition, A in the formula is SO ₂ , and when n=0, react the aminoalcohol (20) with methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc., and then treat with an appropriate base or directly use Amino alcohol (20) is treated with triphenylphosphine and ethyl azodicarboxylate, and the resulting α, β-unsaturated cyclic sulfone is mixed with ammonia water, benzylamine, p-methoxybenzylamine, 2,4 -Addition of primary aralkylamines such as dimethoxybenzylamine, secondary aralkylamines such as dibenzylamine, hydroxylamines such as N-benzylhydroxylamine and N,O-dibenzylhydroxylamine, etc., and then remove the benzyl group, etc. , can obtain diamine (21).

react the obtained diamine compound (21) and carboxylic acid (3) to prepare compound (22), then remove the protecting group R ⁵¹ to obtain compound (4c), then react compound (4c) and carboxylic acid (5) , the compound (1c) of the present invention can be obtained. In the reaction of compound (21) and carboxylic acid (3) and the reaction of compound (4c) and carboxylic acid (5), the same reagents and reaction conditions as described in Production Method 7 were used.

Similarly, in the reaction of compound (21) and carboxylic acid (3), substituting sulfonyl halide (10) for carboxylic acid (3), compound (1c) in which T1 is a sulfonyl group can be prepared.

[Preparation method 9]

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

[wherein, R ³ , R ⁴ , A, m and n are as described above]

As a preparation example of diol (23), for example, conversion of 1,2,3,6-tetrahydropyridine to 1-benzyloxycarbonyl-3,4-cis-dihydroxypyrrolidine is known (Japanese patent Patent Kaiping 7-138264), converted from L-tartaric acid to (R, R)-tetrahydrofuran diol or (R, R)-N-benzylpyrrolidine diol (Tetrahedron: Asymmetry, volume 8, page 1861, 1997 )wait. The diol (23) can be prepared by using these known methods or applying the method, removing the protecting group or performing functional group conversion as necessary.

Compound (24) can be prepared by reacting diol (23) with methanesulfonyl chloride in the presence of a base in an inert solvent under cooling to room temperature. The inert solvent can be appropriately selected from the solvents described in Production Method 7, and particularly preferred are haloalkyl-based solvents such as dichloromethane and chloroform, and ether-based solvents such as tetrahydrofuran and 1,4-dioxane. As base, preferably pyridine, 2,6-lutidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo[5.4. 0] Organic bases such as undecene-7 (DBU), etc.

The azide (25) can be obtained by reacting the compound (24) with sodium azide in a suitable solvent under cooling to heating. As the solvent, amide-based solvents such as N,N-dimethylformamide and N-methylpyrrolidin-2-one, alcohol-based solvents such as methanol and ethanol, tetrahydrofuran, 1,4-dioxane, and the like are preferred. Ether solvents, aromatic solvents such as benzene and toluene, halogenated alkyl solvents such as methylene chloride and chloroform, dimethyl sulfoxide, acetone, etc. Mixtures of the usual solvents mentioned above and water may also be used.

The method for converting the azide (25) to the compound (2c) includes the method of hydrogenation using a palladium catalyst, Raney nickel catalyst or platinum catalyst, and the reaction of reducing agents such as lithium aluminum hydride and sodium borohydride. There are various methods such as the reaction using zinc in the presence of nickel chloride or cobalt chloride, and the reaction using triphenylphosphine. Appropriate reagents and reaction conditions can be selected according to the properties of the compound. The hydrogen pressure can be raised above atmospheric pressure. The solvent is preferably alcohol-based solvents such as methanol and ethanol, ether-based solvents such as tetrahydrofuran and 1,4-dioxane, and amide-based solvents such as N,N-dimethylformamide and N-methylpyrrolidin-2-one. The solvent is an ester-based solvent such as ethyl acetate, acetic acid, hydrochloric acid, water, or a mixed solvent of these solvents. Using the diamine (2c) prepared by the above method, the compound (1c) of the present invention can be obtained according to the above preparation method 7.

An optically active substance exists when the diol (23) is trans-3,4-dihydroxytetrahydrofuran, trans-1-substituted-3,4-dihydroxypyrrolidine, or the like. The optically active diamine (2c) can be obtained from these optically active diols (23), and then the optically active compound (1c) of the present invention can be obtained according to Preparation Method 7.

[Preparation method 10]

Typical production methods of the optically active compounds (30), (31) and (32) contained in the compound (19) described in Production Method 8 will be described. The configuration of the chiral carbon shown in the following production route is shown as an example.

[wherein, m, n, R ³ , R ⁵¹ and R ⁶¹ are as described above, and R ⁷¹ represents a carboxyl protecting group]

Optically active α, β-unsaturated ester body (26) can be used in literature (J.Org.Chem., volume 61, page 581, 1996; J.Org.Chem., volume 57, page 6279, 1992 etc.) or prepared by the method described. Diastereoisomers (27a) and (27b) can be obtained by reacting optically active α,β-unsaturated ester (26) with amine in a suitable solvent under cooling to heating. The amine can be appropriately selected from the amines described in Production Method 8 above. Organic solvents that do not react with substrates, products, or reagents can be used as solvents, particularly alcohol-based solvents such as methanol and ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc. Ether solvents. In addition, using the method described in the literature (J.Org.Chem., volume 63, page 7263, 1998), the α, β-unsaturated ester body (26) and N-benzyl (trimethylsilyl) Diastereomers (27a) and (27b) can also be prepared by reacting with organometallic bases such as lithium amides. By separating the diastereoisomers, for example (27a) can be used in the subsequent reaction.

Compound (28) can be prepared by acid-treating compound (27a) in a suitable solvent under cooling to heating. The acid used may, for example, be Lewis acid such as hydrochloric acid, sulfuric acid or boron trifluoride, trifluoroacetic acid or p-toluenesulfonic acid. As the solvent used for the reaction, water, alcoholic solvents such as methanol and ethanol, and the like can be used. Mixtures of the above solvents and water may also be used. In addition, in this reaction, the protecting group R ⁶¹ of the amino group may be cut off. In this case, it can be reacted with an appropriate amino-protecting reagent as needed.

Optically active compound (30) can be obtained by acid-treating compound (28) in a solvent under cooling to heating. The acid to be used can be appropriately selected from the above-mentioned acids, and particularly preferred are Lewis acids such as boron trifluoride, p-toluenesulfonic acid, and the like. 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. In addition, compound (30) can also be prepared from azide (29). As an example of preparation of optically active azide (29), for example, conversion of L-aspartic acid to (R,R)-(3S,4S)-3-amino-4-azido is known. - 5-Oxotetrahydrofuran (Can, J. Chem., Vol. 71, Page 1407, 1993) and the like. The optically active azide (29) can be produced by removing the protective group or converting the functional group as necessary by using or applying this known method. Compound (30) can be obtained by reducing the azido group of the azide (29) to form an amino group, and then reacting with an appropriate amino-protecting reagent. For the reduction of the azido group, the same reaction conditions and reagents as those described in the method of converting the azide (25) to the compound (2c) in Production Method 9 can be used.

Compound (31) can be obtained by converting the hydroxyl moiety of compound (28) into an amino group, followed by treatment with a base. As a method of converting the hydroxyl group of the compound (28) into an amino group, it can be carried out, for example, according to the above-mentioned Production Method 8. Alternatively, the compound (31) can also be prepared by treating the alcohol (28) with an oxidizing agent and then reductively aminating the resulting aldehyde. Specific examples of the oxidizing agent used in the above reaction are preferably pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), pyridinium sulfur trioxide, and the like. The amine may, for example, be ammonia water, primary alkylamines such as methylamine or ethylamine, or primary aralkylamines such as benzylamine, p-methoxybenzylamine or 2,4-dimethoxybenzylamine. The reduction method includes the method of hydrogenation using a palladium catalyst, Raney nickel catalyst or platinum catalyst, the reaction of reducing agents such as sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride, etc., which can be determined according to the compound. Properties and other trade-offs to select reagents and conditions. In addition, the base used in the above step can be appropriately selected from the bases described in Production Method 7 for use. Adopt above-mentioned compound (30) and amine, utilize the method described in literature (Tetrahedron, Lett., volume 41, page 1141, 2000; Heterocycles, volume 53, page 173, 2000) or apply this method, can prepare compound ( 31). The amine used may, for example, be primary alkylamines such as ammonia, methylamine or ethylamine; primary aralkylamines such as benzylamine or p-methoxybenzylamine; aniline or the like.

Compound (32) can be prepared by treating the above compound (31) with a reducing agent in a solvent under cooling to heating. The reducing agent may, for example, be borane-tetrahydrofuran complex, borane-methyl sulfide complex, or lithium aluminum hydride. Reagents and reaction conditions may be selected according to the properties of the compound. As the solvent, organic solvents that do not react with substrates, products, reagents, etc. can be used, and tetrahydrofuran, 1,4-dioxane, etc. are particularly preferred.

Using the compounds (30), (31) and (32) obtained by the above method, the optically active substance (1c) of the compound of the present invention can be obtained according to the above Production Method 8.

The above-mentioned preparation steps are examples of one type of optically active substance, and optically active substances having different stereoconfigurations can be produced by the same procedure as long as starting materials having different stereoconfigurations are used.

[Preparation method 11]

The compound (1) in which T ¹ is a -CO-CO-N(R')- group (R' in the group is as described above) can be prepared according to the following steps.

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CO-CO-N(R')-group (R in the group ' as previously stated)]

That is, the carboxylic acid (33) is derivatized into acid halides or active esters, etc., and reacted with diamine (2) to obtain compound (4), and under the same conditions, the obtained compound (4) is mixed with carboxylic acid ( 5) Reaction, the compound (1) of this invention can be obtained. In the reactions of the above-mentioned steps, the reaction reagents and conditions generally used for peptide synthesis may be used. The above acid halides can be prepared by treating carboxylic acid (33) with acid halides such as thionyl chloride and oxalyl chloride. Various esters can be used as active esters, such as N, N'-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·hydrochloride etc. The mixture can be obtained by reacting phenols such as p-nitrophenol, N-hydroxybenzotriazole or N-hydroxysuccinimide with carboxylic acid (33). In addition, by reaction of carboxylic acid (33) with pentafluorophenyl trifluoroacetate, etc., reaction of carboxylic acid (33) with 1-benzotriazolyl-tripyrrolidinylphosphonium hexafluorophosphate, carboxylic acid (33 ) and the reaction of diethyl cyanophosphonate (salt into method), the reaction of carboxylic acid (33) with triphenylphosphine and 2,2'-dipyridyl disulfide (Xiangshan method), etc., can also produce active ester. In the presence of a suitable base, in an inert solvent, react the mixed anhydride, acid halide or active ester of the carboxylic acid (33) obtained above with diamine (2) at -78°C to 150°C to obtain the compound (4). The compound (1) of the present invention can be obtained by reacting the obtained compound (4) with the mixed anhydride, acid halide or active ester of the carboxylic acid (5) under the same conditions. The reagents and reaction conditions in the reaction of compound (4) and carboxylic acid (5) are the same as those in the reaction of diamine (2) and carboxylic acid (3osmium). The base and solvent used in each of the above steps can be appropriately selected from those described in Production Method 1.

In addition, in preparation ^Q3 is the following group,

[In the group, R ³ , R ⁴ and Q ⁵ are as described above, and the numbers of 1 and 2 indicate the position] When the relationship between the 1-position and the 2-position is trans and cis compound (1), the preparation method 5 can be used The described diamine (2a) or (2b).

In addition, when preparing compounds (1) containing heteroatoms such as nitrogen atoms, oxygen atoms or sulfur atoms in ^Q5 , in the reaction of compound (2c) and carboxylic acid (3) described in Preparation Method 7, carboxylic acid ( 33) Substitution of carboxylic acid (3). That is, the heteroatom-containing compound (1) in Q ⁵ , that is, compound (1c), can be prepared by the following procedure.

[wherein, Q ¹ , Q ² , Q ⁴ , R ² , R ⁴ , R', A, m and n are as described above, and T ¹ is -CO-CO-N(R')-group (group R' in is as previously described)]

[Preparation method 12]

The compound (1) in which T ¹ is a -CO-CO-N(R')- group (R' in the group is as described above) can also be prepared by the following steps.

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CO-CO-N(R')-group (R in the group ' as previously stated)]

In the reaction of amine (9) and carboxylic acid (33), the same reagents and reaction conditions as described in Production Method 1 can be used.

The amine (9) used here can be produced, for example, by the procedure described in the production method 2, which is the production procedure of the following amine (41).

[wherein, R ³ , R ⁴ , Q ¹ , Q ² and Q ⁵ are as described above, and R ⁵² represents a protecting group for amino]

In a solvent such as dichloromethane, the compound (34) in the above preparation step can be obtained by treating cycloalkene with perbenzoic acid or its derivatives and the like for epoxidation. As the reaction conditions, conventional conditions for epoxidizing alkenes can be used. In addition, compound (34) can also be produced by the method described in J.Org.Chem., Vol. 61, 8687-8691 (1996) or a method based thereon.

Compound (36) can be prepared by catalytically reducing the azide (35) obtained by treating compound (34) with sodium azide or the like according to a conventional method, and then protecting the amino group. In this case, the protecting group for the amino group may, for example, be the protecting group described in Production Method 2. Compound (39) can be obtained by performing the same procedure as described in Production Method 5 to form azide (38) from compound (36), and then remove the protecting group of the amino group. Compound (41) can be obtained by reacting compound (39) and carboxylic acid (5) to form compound (40) by catalytic reduction.

[Preparation method 13]

Change the reaction of compound (9) and carboxylic acid (3) in the step recorded in Preparation Method 2 into the reaction of compound (9) and carboxylic acid (33), and T can ^also be obtained as -CO-CO-N( R')-group (R' in the group is as described above) compound (1).

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CO-CO-N(R')-group (R in the group ' as previously stated)]

The reaction conditions can adopt the conditions described in Preparation Method 2.

In addition, in preparation ^Q3 is the following group,

[In the group, R ³ , R ⁴ and Q ⁵ are as described above, and the numbers of 1 and 2 indicate positions]

When compound (1) containing heteroatoms such as nitrogen atom, oxygen atom or sulfur atom in ^Q5 , in the reaction of compound (21) and carboxylic acid (3) described in Preparation Method 8, carboxylic acid (33) can be used instead of carboxylic acid acid (3). That is, the heteroatom-containing compound (1) in Q ⁵ , that is, compound (1c), can be prepared by the following procedure.

[wherein, Q ¹ , Q ² , Q ⁴ , R ³ , R ⁴ , R', A, m and n are as described above, and T ¹ is -CO-CO-N(R')-group (group In R 'as previously described), R ⁵¹ represents the protecting group of amino]

[Preparation method 14]

^{T _} _{_} ¹ is -CO-A ¹ -N(R")-group (in the formula, R" represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, and A ¹ represents a substituent with 1 to 5 carbon atoms that may have substituents. Alkyl) compound (1). As a condensing agent, N, N'-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide can be exemplified Hydrochloride, etc. As the inert solvent, haloalkyl-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, ether-based solvents such as tetrahydrofuran, 1,2-dimethoxyethane, and dioxane, Aromatic solvents such as benzene and toluene, amide solvents such as N,N-dimethylformamide, etc.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R" are as described above, T ¹ is -CO-A ¹ -N(R")-group (in the formula, R "Represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group, and ^A1 represents an alkylene group of carbon atoms with 1 to 5 substituents)]

For example, in a solvent such as acetonitrile or N,N-dimethylformamide, in the presence of a base such as potassium carbonate, after reacting an aromatic amine such as 4-chloroaniline with an ester of bromoalkanic acid at 40 to 120 ° C, use hydrogen The compound (42) described in the above preparation method can be obtained by hydrolyzing the ester with bases such as lithium oxide, potassium hydroxide, and sodium hydroxide. Potassium salt of compound 42, etc. can be directly used in the reaction.

[Preparation method 15]

In an inert solvent, react the compound (9) described in Production Method 2 with isocyanate (Q ⁴ -N=C=O) or isothiocyanate (Q ⁴ -N=C=S) at -20 to 50°C , Compound (1) in which T ¹ is -C(=O)-NH-group or -C(=S)-NH-group can be prepared. As an inert solvent, the solvent described in Production method 14 can be mentioned as a representative example. When the isocyanate or isothiocyanate to be used is not available commercially, it can be prepared by a usual method as a production method of isocyanate or isothiocyanate.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are as described above, T ¹ is -C(=O)-NH-group or -C(=S)-NH-group ]

[Preparation method 16]

In an inert solvent, react the compound (9) described in Production Method 2 with Q ⁴ -NH-NH-CO ₂ Ph(43) at room temperature to 150°C in the presence of a base as needed to obtain T ¹ as - CO-NH-NH-based compound (1). As an inert solvent, in addition to acetonitrile or N,N-dimethylformamide, the solvent described in the production method 14 can be mentioned as a representative example. As the base, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazepam Heterobicyclo[5.4.0]undecene-7 (DBU).

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are as described above, T ¹ is -CO-NH-NH-, Ph is phenyl]

For example, in solvents such as acetonitrile, N,N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, benzene, toluene, etc., at room temperature to 120°C The compound (43) described in the above production method can be prepared by reacting an arylhydrazine such as 4-chlorophenylhydrazine with diphenyl carbonate.

[Preparation method 17]

In an inert solvent, using a condensing agent, react the compound (9) described in Preparation Method 2 with Q ⁴ -CO-A ² -CO ₂ H (44) at -50 to 50°C to obtain T ¹ as -CO -A ² -CO- group (wherein A ² is a single bond or an alkylene group having 1 to 5 carbon atoms) compound (1). The condensing agent may, for example, be N,N'-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·hydrochloride. The solvent may, for example, be the solvent described in Production Method 16, or the like.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are as described above, T ¹ is -CO-A ² -CO- group (in the formula, A ² is a single bond or a carbon atom Alkylene groups with numbers 1 to 5)]

When ^A2 is a single bond, for example, bases such as lithium hydroxide, potassium hydroxide, and sodium hydroxide can be used to pass through aromatic heterocycles such as chlorobenzene or thiophene and ethyl chlorooxyacetate (for example, The compound (44) described in the above-mentioned production method can be produced by hydrolyzing the compound (for example, Q ⁴ CO-CO ₂ Et) produced by the Friedel-Crafts reaction of ClCO-CO ₂ Et).

In addition, when ^A2 is a methylene group, for example, in the presence of magnesium chloride and triethylamine, aryl formyl chlorides such as 4-chlorobenzoyl chloride and heteroaryl formyl chlorides such as thiophenoyl chloride are mixed with malonate monoester A ketone ester derivative (for example, Q ⁴ -CO-CH ₂ -CO ₂ Et) is obtained by reacting a potassium salt of a carboxylic acid, and then the derivative is hydrolyzed with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, Compound (44) can be obtained. The carboxylic acid obtained by the hydrolysis of the carbonyl group of the above-mentioned ketoester derivatives after ketalization with ethylene glycol can also be used for the reaction with compound (9). In addition, when ^A2 is an alkylene group having 2 or more carbon atoms, for example, bases such as lithium hydroxide, potassium hydroxide, and sodium hydroxide are used to pass aromatic hydrocarbons such as benzene or aromatic heterocycles such as thiophene and alkylenes. Compound (44) can be prepared by hydrolyzing the ketoester derivative (for example, Q ⁴ -CO-A ² -CO ₂ Et) prepared by Friedel-Crafts reaction of dicarboxylic acid monoester-acyl chloride.

[Preparation method 18]

In an inert solvent, using a condensing agent, react the compound (9) described in Preparation Method 2 with Q ⁴ -NH-CO-A ³ -CO ₂ H (45) at -50 to 50°C to obtain T ¹ as Compound (1) having a -CO-A ³ -CO-NH- group (wherein A ³ is an alkylene group having 1 to 5 carbon atoms). The condensing agent may, for example, be N,N'-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·hydrochloride. Examples of inert solvents include halogenated alkyl solvents such as dichloromethane, chloroform, and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, and dioxane, and aromatic solvents such as benzene and toluene. solvents, amide solvents such as N,N-dimethylformamide, etc.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ and R ² are as described above, and T ¹ is -CO-A ³ -CO- group (in the formula, A ³ is the number of carbon atoms from 1 to 5 alkylene)]

In an inert solvent, using a condensing agent, make an aromatic amine such as 4-chloroaniline equivalent to Q ⁴ -NH ₂ or a heteroaryl amine such as aminopyridine and an alkylene dicarboxylic acid monoester monocarboxylic acid at -50 to 50°C Potassium salt reaction to obtain compound (for example, Q ⁴ -NH-CO-A ³ -CO ₂ Et), and then hydrolyze the compound with alkali such as lithium hydroxide, potassium hydroxide, sodium hydroxide, etc. to obtain compound (45).

[Preparation method 19]

The compound (1) in which T ¹ is -CS-CO-N(R')- (in the group, R' is as described above) can be prepared according to the following steps.

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CS-CO-N(R')-group (in the group, R' as previously stated)]

That is, the compound (1) of the present invention can be produced by dissolving or suspending sodium thiosulfate (46) and compound (9) in a solvent and heating. The reaction temperature is preferably from 80 to 200°C, particularly preferably around 150°C. The solvent used for this reaction may, for example, be water, alcohols such as methanol and ethanol, basic solvents such as pyridine and N-methylmorpholine, halogenated alkyl solvents such as dichloromethane and chloroform, tetrahydrofuran, 1,2-dimethyl Ether-based solvents such as oxyethane and dioxane, amide-based solvents such as N,N-dimethylformamide, and the like. These solvents can be used in combination as appropriate, and examples of the mixed solvent include a mixed solvent of methanol and dichloromethane, and the like. In addition, in this reaction, it is not necessary to reflux the solvent. For example, when using a mixed solvent of methanol and dichloromethane, the reaction solution (or reaction mixture) is heated to an external temperature of 150° C., and the solvent is distilled off. temperature to continue heating the residue.

[Preparation method 20]

The compound (1) in which T ¹ is a -CO-CS-N(R')- group (in the group, R' is as described above) can be prepared according to the following steps.

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CO-CS-N(R')-group (in the group, R' as previously stated)]

That is, in the presence of a base, compound (9) is reacted with chloroacetyl chloride to obtain compound (47), and compound (47) and sodium thiosulfate are heated in a solvent to obtain a sodium thiosulfate derivative (48). Compound (1) of the present invention can be obtained by heating (48) obtained above and an amine, ie, NH(R')-Q ⁴ .

The reaction conditions and solvents used to prepare compound (47) from compound (9) can be the reaction conditions and solvents commonly used in the reaction of amines and acid chlorides. To prepare compound (48) from compound (47), it can be heated to reflux with sodium thiosulfate in a solvent such as ethanol for about 1 hour. When compound (47) is a salt such as hydrochloric acid, the reaction can be carried out in the presence of a base such as sodium bicarbonate. The preparation conditions of compound (48) are not limited to those described here, and the temperature, the type of solvent, and the type of base can be appropriately changed. The reaction conditions of compound (48) and NH(R')-Q ⁴ are the same as those described in Preparation 19.

[Preparation method 21]

Compound (1) in which T ⁰ is a thiocarbonyl group (-CS-group) can be produced by the following procedure.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ and R ² are as described above, and T ¹ is -SO ₂ -, -CO-, -CO-NH-, -CS-NH- , -CO-NH-NH-group, -CO-CO-N(R')-group (in the group, R' is as described above), -CO-CS-N(R')-group (in the group, R' as previously described), -CS-CO-N(R')-group (in the group, R' as previously described), -CS-CS-N(R')-group (in the group, R' As mentioned above), -CO-A ¹ -N(R")-group (in the group, A ¹ and R" are as described above), -CO-A ² -CO-group (in the group, A ² is as As mentioned above), -CO-A ³ -CO-NH- group (in the group, A ³ is as described above), -CO-A ³ -CO- group (in the group, A ³ is as described above)]

That is, in the presence of an acid catalyst such as p-toluenesulfonic acid, compound (49) and amine (50) are subjected to a dehydration reaction to obtain compound (51), which is mixed with The compound (1) of the present invention can be obtained by heating sulfur powder together. The conditions for preparing compound (51) from compound (49) and amine (50) can be those commonly used for the preparation of Schiff bases. Specifically, the compound can be heated to reflux in benzene or toluene in the presence of an acid catalyst using a Dean-Stark apparatus or the like under conditions such that water is removed from the reaction system. In addition, molecular sieves can also be used in the case of removing water from the reaction system.

[Preparation method 22]

The compound (1) in which T ¹ is -CS-CO-N(R')- (in the group, R' is as described above) can be prepared according to the following steps.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CS-CO-N(R')-group (in the group, R' as previously stated)]

In an inert solvent such as N,N-dimethylformamide or a basic solvent such as pyridine, at -78°C to 150°C, make an aromatic amine such as 4-chloroaniline or aminopyridine equivalent to HN(R')Q ⁴ Compound (52) can be prepared by reacting heteroarylamine with dichloroacetyl chloride. In addition, compound (52) can also be prepared by reacting dichloroacetic acid with an amine corresponding to HN(R')Q ⁴ under the reagents and conditions described in Production Method 1.

Suspend compound (52) and sulfur powder in a solvent, add a base such as diisopropylethylamine or triethylamine and diamine (9), and react them at a reaction temperature of 0°C to 200°C to obtain more Compound (1) is efficiently produced. The amount of sulfur powder used for the reaction is preferably 1N. The reaction temperature is preferably from 60°C to 160°C, particularly preferably from 90°C to 140°C. The solvent used for this reaction may, for example, be an amide solvent such as N,N-dimethylformamide, an alkaline solvent such as N-methylmorpholine or pyridine, an alcohol such as ethanol or butanol, or an ether solvent such as dioxane. Solvents, acetonitrile, water, etc.

[Preparation method 23]

The compound (1) in which T ¹ is -CS-CO-N(R')- (in the group, R' is as described above) can be prepared according to the following steps.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CS-CO-N(R')-group (in the group, R' as previously stated)]

In an inert solvent such as N,N-dimethylformamide or a basic solvent such as pyridine, at -78°C to 150°C, make an aromatic amine such as 4-chloroaniline or aminopyridine equivalent to HN(R')Q ⁴ Compound (53) can be prepared by reacting heteroarylamine with chloroacetyl chloride. In addition, compound (53) can also be prepared by reacting monochloroacetic acid with an amine corresponding to HN(R')Q ⁴ under the reagents and conditions described in Production Method 1.

Suspend compound (53) and sulfur powder in a solvent, add a base such as diisopropylethylamine or triethylamine, stir for 5 minutes to 8 hours, then add diamine (9) and a condensation agent to allow the reaction to proceed. Compound (1) was obtained. The amount of sulfur powder used for the reaction is preferably at least 2N. The reaction temperature is preferably from 0°C to 80°C. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·hydrochloride or N,N'-dicyclohexylcarbodiimide. The solvent used for this reaction may, for example, be an amide solvent such as N,N-dimethylformamide, an alkaline solvent such as N-methylmorpholine or pyridine, a halogenated alkyl solvent such as methylene chloride or chloroform, or dioxane Ether solvents, acetonitrile, etc. In addition, this reaction can also be carried out without a condensing agent to obtain compound (1). At this time, alcohols such as methanol and ethanol, water, and the like can be used in addition to the aforementioned solvents.

[Preparation method 24]

Compound (1) in which T ¹ is -CS-CO-N(R')-group (in the group, R' is as described above) can also be obtained by T ¹ being -CS-CO-N(R')-group (In the group, R' is as described above), the compound (4) is prepared by the following steps.

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CS-CO-N(R')-group (in the group, R' as previously stated)]

That is, in a solvent, in the presence of a base, react dichloroacetamide (52) or chloroacetamide (53), sulfur powder and amine (7), remove the protecting group, and obtain compound (4) , Compound (1) of the present invention can be obtained by condensing the obtained compound (4) with carboxylic acid (5). Suspend compound (52) and sulfur powder in a solvent, add a base such as diisopropylethylamine or triethylamine and amine (7), and carry out the reaction at a reaction temperature of 0 to 200°C to more effectively prepare Compound (54). The amount of sulfur powder used for the reaction is preferably 1N. The reaction temperature is preferably from 60°C to 160°C, particularly preferably from 90°C to 140°C. The solvent used for this reaction may, for example, be an amide solvent such as N,N-dimethylformamide, an alkaline solvent such as N-methylmorpholine or pyridine, an alcohol such as ethanol or butanol, or an ether solvent such as dioxane. Solvents, acetonitrile and water etc. In addition, suspend compound (53) and sulfur powder in a solvent, add a base such as diisopropylethylamine or triethylamine, stir for 5 minutes to 5 hours, add amine (7) and a condensing agent to react, and it can also be prepared Compound (54) was obtained. The amount of sulfur powder used for the reaction is preferably at least 2N. The reaction temperature is preferably from 0°C to 80°C. The condensing agent may, for example, be 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·hydrochloride or N,N'-dicyclohexylcarbodiimide. The solvent used for this reaction may, for example, be an amide solvent such as N,N-dimethylformamide, an alkaline solvent such as N-methylmorpholine or pyridine, a halogenated alkyl solvent such as methylene chloride or chloroform, or dioxane Ether solvents, acetonitrile, etc. In addition, this reaction can also be carried out without a condensing agent to obtain compound (54). At this time, alcohols such as methanol and ethanol, water, and the like can be used in addition to the aforementioned solvents. Alternatively, compound (54) can also be prepared by reacting sodium thiosulfate (46) with amine (7) under the reaction conditions described in Preparation Method 19. Compound (4) can be obtained by treating compound (54) with trifluoroacetic acid or the like at -20°C to 70°C.

Adopt the method described in preparation method 1, make the compound (4) and carboxylic acid (5) of compound (4) of -CS-CO-N(R')-base (in the group, R' as previously described) that T is prepared ^above . ) reaction, compound (1) of the present invention can be prepared.

The tert-butoxycarbonyl group of compound (7) can be replaced by other amino-protecting groups described in Production Method 2. The type of protecting group can be selected according to the nature of the compound, etc., and when the protecting group is cut off, the reagent and reaction conditions can also be selected according to the protecting group.

[Preparation method 25]

The compound (1) in which T ¹ is -CO-N(R')-CO- group (in the group, R' is as described above) can be prepared according to the following steps.

[In the formula, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -CO-N(R')-CO-group (in the group, R' as previously stated)]

That is, reacting an arylamide such as 4-chlorobenzamide or a heteroarylamide such as picolinamide corresponding to NH(R')COQ ⁴ (55) with an amine (7) via an acyl isocyanate intermediate to obtain Compound (54), and compound (1) of the present invention can be obtained by deprotecting compound (54) and condensing compound (4) obtained with carboxylic acid (5).

For example, in an inert solvent, at a reaction temperature of 20°C to 100°C, the amide (55) is reacted with oxalyl chloride to prepare an acyl isocyanate derivative, and at a reaction temperature of 0°C to 100°C, the derivative Compound (54) can be obtained by reaction with amine (7). The inert solvent that is used for this reaction can exemplify halogenated alkyl solvents such as dichloromethane, chloroform, dichloroethane, ether solvents such as tetrahydrofuran, dioxane, aromatic solvents such as benzene, toluene, N, N-di Amide solvents such as methylformamide and N,N-dimethylacetamide, acetonitrile, etc.

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

Using the method described in Preparation Method 1, the compound (4) and carboxylic acid (5) that make the above-prepared ^T1 be -CO-N(R')-CO-base (in the group, R' is as described above) reaction, the compound (1) of the present invention can be prepared.

The tert-butoxycarbonyl group of compound (7) can be replaced by other amino-protecting groups described in Production Method 2. The type of protecting group can be selected according to the nature of the compound, etc., and when the protecting group is cut off, the reagent and reaction conditions can also be selected according to the protecting group.

[Preparation method 26]

The compound (1) in which T ¹ is -SO ² -N(R')- (in the group, R' is as described above) can be prepared according to the following steps.

[wherein, Q ¹ , Q ² , Q ³ , Q ⁴ , R ¹ , R ² and R' are as described above, and T ¹ is -SO ₂ -N(R')-group (in the group, R' is as previously mentioned)]

In an inert solvent, at a reaction temperature of -78°C to 30°C, react amines such as 4-chloroaniline equivalent to HN(R')Q ⁴ with chlorosulfonic acid to prepare sulfamic acid derivatives. Compound (1) can be obtained by activating the derivative with a reagent such as phosphorus pentachloride and reacting it with amine (9). As a reagent for activating the sulfamic acid derivative, in addition to halogenating reagents such as phosphorus pentachloride and phosphorus oxychloride, for example, condensing agents such as 1,1-carbonyldiimidazole can also be used. In this reaction, when halogenating reagents such as phosphorus pentachloride and phosphorus oxychloride are used for activation, it is best to heat at 50°C to 120°C. The inert solvent that is used for this reaction can exemplify halogenated alkyl solvents such as dichloromethane, chloroform, dichloroethane, ether solvents such as tetrahydrofuran, dioxane, aromatic solvents such as benzene, toluene, N, N-di Amide solvents such as methylformamide and N,N-dimethylacetamide, acetonitrile, etc.

Hereinafter, important intermediates described in Production Methods 1 to 21 of Compound (1) of the present invention will be described.

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

HN(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (4)

[wherein, R ¹ , R ² , Q ³ and Q ⁴ are as described above, T ¹ is carbonyl, sulfonyl or -CO-CO-N(R')-yl (in the group, R' is as described above )]

Among the above-mentioned intermediates, ^T is preferably -C(=O)-C(=O)-N(R')-(in the group, R' is a hydrogen atom, hydroxyl, alkyl or alkoxy) ^T1 in the compound and the above formula is a carbonyl group, and ^Q3 is the following group

(In the group, R ³ and R ⁴ are as described above, and Q ⁵ represents the group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(In the group, m and n are independently, representing 0, an integer of 1 to 3, A represents oxygen atom, nitrogen atom, sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-).

2) 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.

Q ¹ -Q ² -C(=O)-N(R ¹ )-Q ³ -NHR ² (9)

[wherein, R ¹ , R ² , Q ¹ , Q ² and Q ³ are as described above]

Among the above-mentioned intermediates, preferably ^Q3 is the following group

(In the group, R ³ and R ⁴ are as described above, and Q ⁵ represents the group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(In the group, m and n are independently, representing 0, an integer of 1 to 3, A represents oxygen atom, nitrogen atom, sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -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.

[wherein, Q ⁴ , R ³ , R ⁴ , A, m and n are as described above, T ¹ is carbonyl, sulfonyl or -CO-CO-N(R')-yl (in the group, R' is as previously mentioned)]

Among the above-mentioned intermediates, it is preferred that ^T in the above formula is a compound of -CO-CO-N(R')-group (in the group, R' is as described above), and ^T is a carbonyl group, and A is an oxygen group. atom, nitrogen atom, sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH -compound of.

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

[wherein, Q ⁴ , R ³ , R ⁴ , A, m and n are as described above, T ¹ is carbonyl, sulfonyl or -CO-CO-N(R')-yl (in the group, R' is as As mentioned above), R ⁵¹ is the protecting group of amino]

Among the above-mentioned intermediates, it is preferred that ^T in the above formula is a compound of -CO-CO-N(R')-group (in the group, R' is as described above), and ^T is a carbonyl group, and A is an oxygen group. atom, nitrogen atom, sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH -compound of.

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

[wherein, Q ⁵ , R ¹ , R ² , R ³ and R ⁴ are as described above, and R ⁵⁰ is a protecting group for amino]

Among the above-mentioned intermediates, it is preferred that Q ⁵ in the above-mentioned formula represents a group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -(in which m and n are independently represented by 0, An integer of 1 to 3, A represents oxygen atom, nitrogen atom, sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, -NH-NH-, -S-NH-, -SO -NH- or -SO ₂ -NH-) compounds.

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

[wherein, R ³ , R ⁴ , A, m and n are as described above, and R ⁵¹ is a protecting group for amino]

Among the above intermediates, preferably A in the above formula is oxygen atom, nitrogen atom, sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH-, -NH-NH-, -S A compound of -NH-, -SO-NH- or -SO ₂ -NH-.

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

That is, the following trans compounds (30), (31) and (32) having optical activity,

[wherein, R ³ , m and n are as described above, and R ⁵¹ and R ⁶¹ are protecting groups for amino groups]

Enantiomers (30a), (31a) and (32a) of the above compound obtained in the same way,

[wherein, R ³ , m and n are as described above, and R ⁵¹ and R ⁶¹ are protecting groups for amino groups]

cis compounds (30b), (31b), (32b),

[wherein, R ³ , m and n are as described above, and R ⁵¹ and R ⁶¹ are protecting groups for amino groups]

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

[wherein, R ³ , m and n are as described above, and R ⁵¹ and R ⁶¹ are protecting groups for amino groups] It is very important as an intermediate for the preparation of compound (1) of the present invention.

Since the diamine derivatives of the present invention exhibit a powerful inhibitory effect on activated coagulation factor ten, they are used as pharmaceuticals for mammals including humans, especially activated coagulation factor ten inhibitors, coagulation inhibitors, Prophylactic and/or therapeutic agents for thrombosis or embolism, prophylactic and/or therapeutic agents for thrombotic diseases, cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, thromboangiitis obliterans, deep vein thrombosis , disseminated intravascular coagulation syndrome, thrombosis after prosthetic valve/joint replacement, thrombosis and reocclusion after revascularization, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), in vitro It is useful as a prophylactic and/or therapeutic agent for thrombosis during circulation or blood coagulation during blood collection.

When the compound of the present invention is used as a medicine for human body, the dosage for an adult is 1 mg to 1 g per day, preferably 10 mg to 300 mg. The dosage for animals varies according to the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and degree of pathogenic bacteria infected, and the dosage for 1 day generally corresponds to 1 kg of animal body weight. 0.1 mg to 200 mg, preferably 0.5 mg to 100 mg. The daily dose can be administered once a day or divided into 2 to 4 times. In addition, the dose per day may exceed the above-mentioned amount as needed.

The pharmaceutical composition containing the compound of the present invention can be prepared by selecting an appropriate formulation according to the method of administration, and can be prepared by various commonly used formulation methods. The dosage form of the pharmaceutical composition containing the compound of the present invention as a main agent may, for example, be oral preparations such as tablets, powders, granules, capsules and solutions, syrups, elixirs, and oily to aqueous suspensions.

As injections, stabilizers, preservatives, and solubilizers can be used in the preparation, and the solution containing these adjuvants is filled in a container, and then freeze-dried to form a preparation that is further prepared when used as a solid preparation. In addition, the dose for one administration may be contained in one container, or the dose for multiple doses may be contained in one container.

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

In addition to the compound of the present invention, the solid preparation can also contain pharmaceutically acceptable additives, such as fillers, bulking agents, binders, disintegrants, solubilizers, wetting agents, etc. Agents, lubricants, etc., and then formulated.

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

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

(A) General formula (1)

Q ¹ -C(=O)-N(R ¹ )-Q ² -N(R ² )-T ¹ -Q ³ (1)

The indicated compounds, their salts, their solvates or their N-oxides;

In the formula, R ¹ and R ² are each independently representing a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q ¹ represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5-6 membered heterocyclic group that may have a substituent, a saturated or unsaturated 2-membered hydrocarbon group that may have a substituent A cyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have substituents;

^Q represents the following groups,

Q ⁴ in this group is an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or a group -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -( m and n in the group are independent, representing an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH -, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-, 1 and 2 represent positions);

R ³ and R ⁴ are substituted on the carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁴ , and each independently represents a hydrogen atom, hydroxyl, alkyl, alkenyl, alkynyl, halogen atom, haloalkyl, Cyano, cyanoalkyl, amino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, optionally substituted acylamino, alkoxy Imino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl Amino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and which may have a substituent on the alkyl group N, N-dialkylcarbamoyl, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoyl Base-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 substituents , carbamoylalkyl, N-alkylcarbamoylalkyl that may have substituents on the alkyl, N, N-dialkylcarbamoylalkyl that may have substituents on the alkyl, carbamoyloxy Alkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, 3-6 membered heterocyclic carbonylalkyl which may have substituents, may have substituents 3-6 membered heterocyclic carbonyloxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, Arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, Aralkoxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkane Oxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3-6 membered heterocyclic sulfonyl groups with substituents, N-alkylaminoacyl groups, N,N-dialkylaminoacyl groups, N,N-dialkylcarbamoylacyl groups that may have substituents on the alkyl group, N, N-dialkylcarbamoylalkylsulfonyl, alkylsulfonylacyl, etc. that may have substituents on the alkyl group or ^R3 and ^R4 together represent an alkylene group with 1 to 5 carbon atoms, carbon atoms Alkenylene with 2 to 5 carbon atoms, alkylenedioxy or carbonyldioxy with 1 to 5 carbon atoms;

^Q represents an aryl group that may have a substituent, an aryl alkenyl group that may have a substituent, a heteroaryl group that may have a substituent, a heteroaryl alkenyl group that may have a substituent, a saturated or alkenyl group that may have a substituent Unsaturated bicyclic or tricyclic fused hydrocarbon group, optionally substituted saturated or unsaturated bicyclic or tricyclic fused heterocyclic group; ^T1 represents carbonyl or sulfonyl.

(B) General formula (1)

Q ¹ -Q ² -C(=O)-N(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (1)

The indicated compounds, their salts, their solvates or their N-oxides;

In the formula, R ¹ and R ² are each independently representing a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q ¹ represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5-6 membered heterocyclic group that may have a substituent, a saturated or unsaturated 2-membered hydrocarbon group that may have a substituent A cyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have substituents;

^Q2 represents a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a divalent saturated or unsaturated 5-6 ring heterocyclic group that may have a substituent, or a substituent A divalent saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have substituents;

^Q represents the following groups,

Q ⁵ in this group is an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -( m and n in the group are independent, representing an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH -, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-);

R ³ and R ⁴ are substituted on the carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁵ , each independently representing a hydrogen atom, hydroxyl, alkyl, alkenyl, alkynyl, halogen atom, haloalkyl, Cyano, cyanoalkyl, amino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, optionally substituted acylamino, alkoxy Imino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl Amino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and which may have a substituent on the alkyl group N, N-dialkylcarbamoyl, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoyl Base-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 substituents , carbamoylalkyl, N-alkylcarbamoylalkyl that may have substituents on the alkyl, N, N-dialkylcarbamoylalkyl that may have substituents on the alkyl, carbamoyloxy Alkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, 3-6 membered heterocyclic carbonylalkyl which may have substituents, may have substituents 3-6 membered heterocyclic carbonyloxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, Arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, Aralkoxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkane Oxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3-6 membered heterocyclic sulfonyl groups with substituents, N-alkylaminoacyl groups, N,N-dialkylaminoacyl groups, N,N-dialkylcarbamoylacyl groups that may have substituents on the alkyl group, N, N-dialkylcarbamoylalkylsulfonyl, alkylsulfonylacyl, etc. that may have substituents on the alkyl group or ^R3 and ^R4 together represent an alkylene group with 1 to 5 carbon atoms, carbon atoms Alkenylene with 2 to 5 carbon atoms, alkylenedioxy or carbonyldioxy with 1 to 5 carbon atoms;

^Q represents an aryl group that may have a substituent, an aryl alkenyl group that may have a substituent, a heteroaryl group that may have a substituent, a heteroaryl alkenyl group that may have a substituent, a saturated or alkenyl group that may have a substituent An unsaturated bicyclic or tricyclic fused hydrocarbon group, a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have substituents;

T ¹ represents a carbonyl group, a sulfonyl group or a group -C(=O)-C-(=O)-N(R')- (R' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group).

(C) General formula (1)

Compounds represented by Q ¹ -Q ² -C(=O)-N(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (1), their salts, their solvates or their N-oxide;

In the formula, R ¹ and R ² are each independently representing a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q ¹ represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5-7 membered heterocyclic group that may have a substituent, a saturated or unsaturated 2-membered hydrocarbon group that may have a substituent A cyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have substituents;

^Q2 represents a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a divalent saturated or unsaturated 5-7 ring heterocyclic group that may have a substituent, or a substituent A divalent saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have substituents;

^Q represents the following groups,

Q ⁵ in this group is an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -( m and n in the group are independent, representing an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH -, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-);

R ³ and R ⁴ are substituted on the carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁵ , each independently representing a hydrogen atom, hydroxyl, alkyl, alkenyl, alkynyl, halogen atom, haloalkyl, Cyano, cyanoalkyl, amino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, optionally substituted acylamino, alkoxy Imino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl Amino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and which may have a substituent on the alkyl group N, N-dialkylcarbamoyl, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoyl Base-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 substituents , carbamoylalkyl, N-alkylcarbamoylalkyl that may have substituents on the alkyl, N, N-dialkylcarbamoylalkyl that may have substituents on the alkyl, carbamoyloxy Alkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, 3-6 membered heterocyclic carbonylalkyl which may have substituents, may have substituents 3-6 membered heterocyclic carbonyloxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, Arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, Aralkoxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkane Oxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3-6 membered heterocyclic sulfonyl groups with substituents, N-alkylaminoacyl groups, N,N-dialkylaminoacyl groups, N,N-dialkylcarbamoylacyl groups that may have substituents on the alkyl group, The N, N-dialkylcarbamoylalkylsulfonyl or alkylsulfonylacyl groups that may have substituents on the alkyl group, etc. or ^R3 and ^R4 together represent an alkylene group with 1 to 5 carbon atoms, carbon atoms Alkenylene with 2 to 5 carbon atoms, alkylenedioxy or carbonyldioxy with 1 to 5 carbon atoms;

^Q represents an optionally substituted aryl group, an optionally substituted arylalkenyl group, an optionally substituted arylalkynyl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl chain Alkenyl, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group that may have a substituent, a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have a substituent;

^T represents a carbonyl group, a sulfonyl group, a group -C(=O)-C-(=O)-N(R')-(R' in the group represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), Group -C(=O)-A ¹ -N(R")-(A ¹ in the group represents an alkylene group having 1 to 5 carbon atoms which may have a substituent, and R" represents a hydrogen atom, a hydroxyl group, an alkane group or alkoxy group), group-C(=O)-NH-, group-C(=S)-NH-, group-C(=O)-NH-NH-, group-C(=O)- A ² -C(=O)-(A ² in the group represents a single bond or an alkylene group with 1 to 5 carbon atoms), group -C(=O)-A ³ -C(=O)-NH -(A ³ in the group represents an alkylene group having 1 to 5 carbon atoms) or a thiocarbonyl group.

(D) general formula

Compounds represented by Q ¹ -Q ² -T ⁰ -N(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (1), their salts, their solvates or their N-oxidation thing;

In the formula, R ¹ and R ² are each independently representing a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q ¹ represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5-7 membered heterocyclic group that may have a substituent, a saturated or unsaturated 2-membered hydrocarbon group that may have a substituent A cyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have substituents;

^Q2 represents a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a divalent saturated or unsaturated 5-7 ring heterocyclic group that may have a substituent, or a substituent A divalent saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have substituents;

^Q represents the following groups,

Q ⁵ in this group is an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -( m and n in the group are independent, representing an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH -, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-);

R ³ and R ⁴ are substituted on the carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁵ , each independently representing a hydrogen atom, hydroxyl, alkyl, alkenyl, alkynyl, halogen atom, haloalkyl, Cyano, cyanoalkyl, amino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, optionally substituted acylamino, alkoxy Imino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl Amino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and which may have a substituent on the alkyl group N, N-dialkylcarbamoyl, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoyl Base-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 substituents , carbamoylalkyl, N-alkylcarbamoylalkyl that may have substituents on the alkyl, N, N-dialkylcarbamoylalkyl that may have substituents on the alkyl, carbamoyloxy Alkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, 3-6 membered heterocyclic carbonylalkyl which may have substituents, may have substituents 3-6 membered heterocyclic carbonyloxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, Arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, Aralkoxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkane Oxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3-6 membered heterocyclic sulfonyl groups with substituents, N-alkylaminoacyl groups, N,N-dialkylaminoacyl groups, N,N-dialkylcarbamoylacyl groups that may have substituents on the alkyl group, The N, N-dialkylcarbamoylalkylsulfonyl or alkylsulfonylacyl groups that may have substituents on the alkyl group, etc. or ^R3 and ^R4 together represent an alkylene group with 1 to 5 carbon atoms, carbon atoms Alkenylene with 2 to 5 carbon atoms, alkylenedioxy or carbonyldioxy with 1 to 5 carbon atoms;

^Q represents an optionally substituted aryl group, an optionally substituted arylalkenyl group, an optionally substituted arylalkynyl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl chain Alkenyl, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group that may have a substituent, a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have a substituent;

T ⁰ represents carbonyl or thiocarbonyl;

T ¹ represents carbonyl, sulfonyl, group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C-(=O)-N(R') -, group-C(=O)-C-(=S)-N(R')-, group-C(=S)-C-(=S)-N(R')-(in the group R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group -C(=O)-A ¹ -N(R")-(A ¹ in the group represents the number of carbon atoms that may have substituents 1 ~5 alkylene groups, R" represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group -C(=O)-NH-, a group -C(=S)-NH-, a group -C(= O)-NH-NH-, group-C(=O) ^-A2 -C(=O)-( ^A2 in the group represents a single bond or an alkylene group with 1 to 5 carbon atoms), group- C(=O)-A ³ -(=O)-NH-(A ³ in the group represents an alkylene group with 1 to 5 carbon atoms), group-C(=O)-C(=NOR ^a ) -N(R ^b )-, group-C(=S)-C(=NOR ^a )-N(R ^b )-(R ^a in the group represents hydrogen atom, alkyl or alkanoyl, R ^b represents hydrogen atom, hydroxy, alkyl or alkoxy), group -C(=O)-N=N-, group -C(=S)-N=N- or thiocarbonyl.

(E) General formula (1)

Compounds represented by Q ¹ -Q ² -T ⁰ -N(R ¹ )-Q ³ -N(R ² )-T ¹ -Q ⁴ (1), their salts, their solvates or their N-oxidation thing;

In the formula, R ¹ and R ² are each independently representing a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group;

Q ¹ represents a saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a saturated or unsaturated 5-7 membered heterocyclic group that may have a substituent, a saturated or unsaturated 2-membered hydrocarbon group that may have a substituent A cyclic or tricyclic fused hydrocarbon group or a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group which may have substituents;

^Q2 represents a single bond, a divalent saturated or unsaturated 5-6 membered cyclic hydrocarbon group that may have a substituent, a divalent saturated or unsaturated 5-7 ring heterocyclic group that may have a substituent, or a substituent A divalent saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group or a divalent saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have substituents;

^Q represents the following groups,

Q ⁵ in this group is an alkylene group with 1 to 8 carbon atoms, an alkenylene group with 2 to 8 carbon atoms, or -(CH ₂ ) _m -CH ₂ -A-CH ₂ -(CH ₂ ) _n -( m and n in the group are independent, representing an integer of 0, 1 to 3, A represents an oxygen atom, a nitrogen atom, a sulfur atom, -SO-, -SO ₂ -, -NH-, -O-NH -, -NH-NH-, -S-NH-, -SO-NH- or -SO ₂ -NH-);

R ³ and R ⁴ are substituted on the carbon atom, nitrogen atom or sulfur atom on the ring containing Q ⁵ , each independently representing a hydrogen atom, hydroxyl, alkyl, alkenyl, alkynyl, halogen atom, haloalkyl, Cyano, cyanoalkyl, amino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, acyl, acylalkyl, optionally substituted acylamino, alkoxy Imino, hydroxyimino, acylaminoalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl Amino group, carboxyalkylamino group, alkoxycarbonylamino group, alkoxycarbonylaminoalkyl group, carbamoyl group, N-alkylcarbamoyl group which may have a substituent on the alkyl group, and which may have a substituent on the alkyl group N, N-dialkylcarbamoyl, N-alkenylcarbamoyl, N-alkenylcarbamoylalkyl, N-alkenyl-N-alkylcarbamoyl, N-alkenylcarbamoyl Base-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 substituents , carbamoylalkyl, N-alkylcarbamoylalkyl that may have substituents on the alkyl, N, N-dialkylcarbamoylalkyl that may have substituents on the alkyl, carbamoyloxy Alkyl, N-alkylcarbamoyloxyalkyl, N,N-dialkylcarbamoyloxyalkyl, 3-6 membered heterocyclic carbonylalkyl which may have substituents, may have substituents 3-6 membered heterocyclic carbonyloxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylaminoalkyl, Arylsulfonylaminoalkyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl, alkylsulfonylaminocarbonylalkyl, arylsulfonylaminocarbonylalkyl, oxo, carbamoyloxy, Aralkoxy, carboxyalkoxy, acyloxy, acyloxyalkyl, arylsulfonyl, alkoxycarbonylalkylsulfonyl, carboxyalkylsulfonyl, alkoxycarbonylacyl, alkoxyalkane Oxycarbonyl, hydroxyacyl, alkoxyacyl, haloacyl, carboxyacyl, aminoacyl, acyloxyacyl, acyloxyalkylsulfonyl, hydroxyalkylsulfonyl, alkoxyalkylsulfonyl, 3-6 membered heterocyclic sulfonyl groups with substituents, N-alkylaminoacyl groups, N,N-dialkylaminoacyl groups, N,N-dialkylcarbamoylacyl groups that may have substituents on the alkyl group, The N, N-dialkylcarbamoylalkylsulfonyl or alkylsulfonylacyl groups that may have substituents on the alkyl group, etc. or ^R3 and ^R4 together represent an alkylene group with 1 to 5 carbon atoms, carbon atoms Alkenylene with 2 to 5 carbon atoms, alkylenedioxy or carbonyldioxy with 1 to 5 carbon atoms;

^Q represents an optionally substituted aryl group, an optionally substituted arylalkenyl group, an optionally substituted arylalkynyl group, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl chain Alkenyl, a saturated or unsaturated bicyclic or tricyclic fused hydrocarbon group that may have a substituent, a saturated or unsaturated bicyclic or tricyclic fused heterocyclic group that may have a substituent;

T ⁰ represents carbonyl or thiocarbonyl;

T ¹ represents carbonyl, sulfonyl, group-C(=O)-C-(=O)-N(R')-, group-C(=S)-C-(=O)-N(R') -, group-C(=O)-C-(=S)-N(R')-, group-C(=S)-C-(=S)-N(R')-(in the group R' represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), the group -C(=O)-A ¹ -N(R")-(A ¹ in the group represents the number of carbon atoms that may have substituents 1 ~5 alkylene groups, R" represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group -C(=O)-NH-, a group -C(=S)-NH-, a group -C(= O)-NH-NH-, group-C(=O) ^-A2 -C(=O)-( ^A2 in the group represents a single bond or an alkylene group with 1 to 5 carbon atoms), group- C(=O)-A ³ -C(=O)-NH-(A ³ in the group represents an alkylene group with 1 to 5 carbon atoms), group-C(=O)-C(=NOR ^a )-N(R ^b )-, group-C(=S)-C(=NOR ^a )-N(R ^b )-(R ^a in the group represents a hydrogen atom, an alkyl group or an alkanoyl group, and R ^b represents a hydrogen atom, a hydroxyl group, an alkyl group or an alkoxy group), a group -C(=O)-N=N-, a group -C(=S)-N=N- or a thiocarbonyl group.

Example

Hereinafter, the present invention will be described by citing examples

[Reference Example 1] tert-butyl pyridin-4-ylcarbamate

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

¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 6.86 (1H, br.s), 7.30 (2H, dd, J=1.5, 4.9Hz), 8.44 (2H, dd, J=1.5, 4.9Hz).

MS (FAB) m/z: 195 (M+H) ⁺ .

[Reference Example 2] tert-butyl 3-mercaptopyridin-4-ylcarbamate

The compound (61.6 g) obtained in Reference Example 1 was dissolved in tetrahydrofuran (2000 ml), and stirred at -78°C for 10 minutes. n-Butyllithium (1.59N hexane solution, 500 ml) was added dropwise to the reaction solution, stirred for 10 minutes, and then stirred for 2 hours under ice cooling. After the reaction solution was cooled to -78°C, sulfur powder (12.2 g) was added, and the mixture was heated to room temperature and then stirred for 1 hour. Water (1000 ml) was added to the reaction solution for liquid separation. After adding 3N hydrochloric acid to the aqueous layer to adjust the pH to 3-4, dichloromethane was added to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain the title compound (33.2 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.52 (9H, s), 7.89 (1H, d, J=6.4Hz), 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 obtained in Reference Example 2 (33.2 g) was dissolved in formic acid (250 ml), and heated to reflux for 3 days. The reaction solution was concentrated under reduced pressure, and 5N aqueous potassium hydroxide solution (100 ml) and diethyl ether were added to the residue for liquid separation. After 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 (dichloromethane:methanol=25:1) to obtain the title compound (9.03 g).

¹ H-NMR (CDCl ₃ ) 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 obtained in Reference Example 3 (1.61 g) was dissolved in N,N-dimethylformamide (50 ml), and methyl iodide (1.50 ml) was added thereto, followed by heating and stirring at 80° C. for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (100 ml), sodium borohydride (1.53 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated potassium carbonate aqueous solution and diethyl ether were added to the residue for liquid separation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain the title compound (1.28 g).

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

MS (FAB) m/z: 155 (M+H) ⁺ .

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

The compound obtained in Reference Example 4 (6.43 g) was dissolved in anhydrous tetrahydrofuran (200 ml), and n-butyllithium (1.47N hexane solution, 34.0 ml) was added dropwise at -78°C and stirred for 40 minutes. After introducing carbon dioxide gas into the reaction solution at -78°C, the temperature was raised to room temperature, and the reaction solution was concentrated under reduced pressure to obtain the title compound (9.42 g).

¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.64-2.77 (4H, m), 3.54 (2H, s).

MS (FAB) m/z: 199 (M+H) ⁺ .

[Reference Example 6] tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5[4H]-carboxylate

Dissolve 1-tert-butoxycarbonyl-4-piperidone (40.0g) in cyclohexane (80ml), add p-toluenesulfonic acid monohydrate (191mg) and pyrrolidine (17.6ml), and use Dean - Heat to reflux for 2 hours while dehydrating in a Starkey apparatus. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (60 ml), and sulfur powder (6.42 g) was added thereto. A methanol solution (10 ml) of cyanamide (8.44 g) was slowly added dropwise under ice cooling, and stirred at room temperature for 5 hours. The precipitated solid was collected by filtration to obtain the title compound (31.0 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (9H, s), 2.44 (2H, t, J=5.6Hz), 3.57 (2H, t, J=5.6Hz), 4.29 (2H, s), 6.79(2H,s).

MS (EI) m/z: 255 (M ⁺ ).

[Reference Example 7] tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5[4H]-carboxylate

Copper bromide (1.05g) was suspended in N, N-dimethylformamide (20ml), after adding tert-butyl nitrite (0.696ml) and the compound (1.00g) obtained in Reference Example 6 under ice cooling, in The reaction solution was heated and stirred at 40°C for 30 minutes. The reaction solution 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).

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.85 (2H, br.s), 3.72 (2H, br.s), 4.56 (2H, br.s).

MS (FAB) m/z: 319 (M+H) ⁺ .

[Reference Example 8] 2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine trifluoroacetate

The compound obtained in Reference Example 7 (890 mg) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (15 ml) was added and stirred at room temperature for 30 seconds. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (867 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 2.98 (2H, t, J = 6.1 Hz), 3.45 (2H, t, J = 6.1 Hz), 4.35 (2H, s), 9.53 (2H, br.s ).

MS (FAB) m/z: 219 (M+H) ⁺ .

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

The compound (422mg) obtained in Reference Example 8 was suspended in dichloromethane (10ml), and triethylamine (0.356ml) was added to dissolve it, followed by adding acetic acid (0.216ml), aqueous formaldehyde (35% solution, 0.202ml), three Sodium acetoxyborohydride (428mg), stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution (100 ml), dichloromethane (100 ml) and 3N aqueous sodium hydroxide solution (3 ml) were added to the reaction solution for liquid separation. After 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 (dichloromethane:methanol=100:3) to obtain the title compound (286 mg).

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

MS (FAB) m/z: 233 (M+H) ⁺ .

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

The compound obtained in Reference Example 9 (531 mg) was dissolved in anhydrous diethyl ether (20 ml), and n-butyllithium (1.54N hexane solution, 1.63 ml) was added dropwise at -78°C, and stirred under ice cooling for 30 minutes. After introducing carbon dioxide gas into the reaction liquid at -78°C for 10 minutes, the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound (523 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 2.64-2.85 (4H, m), 3.54 (2H, s).

[Reference Example 11] Ethyl 2-[(E)-2-phenylvinyl]oxazole-4-carboxylate

Synthesized according to the report of Panek et al. (J.Org.Chem., 1996, vol. 61, p. 6496). Sodium bicarbonate (22.8 g) and ethyl bromopyruvate (10.5 ml) were added to a solution of cinnamamide (10.0 g) in tetrahydrofuran (250 ml) at room temperature, and the mixture was heated to reflux 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 (30 ml) was added to a solution of the residue in tetrahydrofuran (30 ml) at 0°C, and the temperature was gradually raised to room temperature. After stirring for 63 hours, saturated aqueous sodium bicarbonate solution (500 ml) and ethyl acetate (150 ml) were added to the reaction mixture for liquid separation, 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).

¹ H-NMR (CDCl ₃ ) 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

To a solution of the compound obtained in Reference Example 11 (8.57 g) in dichloromethane (80 ml) was added dropwise diisobutylaluminum hydride (1.0 N hexane solution, 66 ml) at -78°C. After stirring for 15 minutes, methanol (11 ml) was added dropwise, and the temperature was raised to room temperature over 1 hour. After 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 (2×100ml) after separation. The organic layers were combined, washed with saturated aqueous sodium bicarbonate (100 ml) and saturated brine (100 ml), and the combined filtrate was filtered through celite, dried over anhydrous sodium sulfate, and the solvent was evaporated 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).

¹ H-NMR (CDCl ₃ ) 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

To a solution of (methyl)triphenylphosphonium bromide (8.16g) in tetrahydrofuran (80ml) was added dropwise at 0°C n-butyllithium (1.54N hexane solution, 14.2ml), and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C again, a tetrahydrofuran (20 ml) solution of the compound (3.64 g) obtained in Reference Example 12 was added, and the temperature was raised to room temperature. After stirring for 2 hours, water (200 ml) and ethyl acetate (100 ml) were added to separate the layers, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:1) to obtain the title compound (2.84 g).

¹ H-NMR (CDCl ₃ ) δ: 5.33 (1H, dd, J=1.5, 10.7Hz), 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

To a tetrahydrofuran (500 ml) solution of the compound obtained in Reference Example 13 (13.0 g) was added 9-borabicyclo[3.3.1]nonane (0.5N tetrahydrofuran solution, 158 ml) at 0°C, and stirred at room temperature for 15 hours. Water (10 ml), 3N aqueous sodium hydroxide solution (80 ml) and aqueous hydrogen peroxide solution (80 ml) were successively added dropwise to the reaction mixture at 0° C., followed by stirring at room temperature for 6 hours. Water (600 ml) and ethyl acetate (200 ml) were added to the reaction mixture for liquid separation, and the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers were washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→ethyl acetate only) to obtain the title compound (14.1 g).

¹ H-NMR (CDCl ₃ ) δ: 2.69 (1H, br.s), 2.80 (2H, t, J=5.6Hz), 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)-di ketone

At room temperature, phthalimide (200 mg), triphenylphosphine (357 mg) and diethyl azodicarboxylate (0.214 ml) were added to a solution of the compound (292 mg) obtained in Reference Example 14 in tetrahydrofuran (15 ml). ), stirred for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (447 mg).

¹ H-NMR (CDCl ₃ ) δ: 2.98 (2H, t, J = 7.2Hz), 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

At room temperature, hydrazine monohydrate (1.50ml) was added to the ethanol (150ml) solution of the compound (6.40g) obtained in Reference Example 15, and after stirring for 1 hour, hydrazine monohydrate (0.500ml) was added again at room temperature, and stirred 2 hours. Then, dichloromethane (150 ml), saturated aqueous sodium bicarbonate solution (150 ml) and di-tert-butyl dicarbonate (13.4 g) 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 (50ml). After the combined organic layers were dried over anhydrous sodium sulfate, 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 (5.06 g).

¹ H-NMR (CDCl ₃ ) 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-phenylethenyl]-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)carboxylate

To a solution of the compound obtained in Reference Example 16 (190 mg) in toluene (15 ml) were added paraformaldehyde (54.5 mg) and p-toluenesulfonic acid (7.2 mg) at room temperature. After heating to reflux for 1 hour and cooling naturally, ethyl acetate (15 ml) and saturated aqueous sodium bicarbonate solution (15 ml) were added to the reaction mixture for liquid separation. After the aqueous layer was extracted with ethyl acetate (10 ml), 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).

¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.67 (2H, br.s), 3.73 (2H, br.s), 4.55 (2H, s), 6.90 (1H, d, J= 16.1Hz), 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] tert-butyl 2-formyl-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-carboxylate

At room temperature, acetone (8.0ml), water (4.0ml), N-oxide-N-methylmorpholine (577mg) and 0.039 moles of tetrahydrofuran (16ml) were added to a solution of the compound (803mg) obtained in Reference Example 17. An aqueous solution of hydrogen peroxide (3.20ml) was stirred overnight. Ethyl acetate (50 ml) and 10% aqueous sodium thiosulfate solution (50 ml) were added to the reaction mixture for liquid separation, and the aqueous layer was extracted with ethyl acetate (30 ml). After the combined organic layers were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. To a solution of the residue in tetrahydrofuran (16 ml) were added methanol (8.0 ml), water (8.0 ml) and sodium metaperiodate (790 mg) at room temperature. After stirring for 3 hours, ethyl acetate (30 ml) and water (50 ml) were added to the reaction mixture for liquid separation, and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml), 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). This aldehyde is unstable, so it is used immediately in the subsequent reaction.

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.77 (2H, br.s), 3.77 (2H, br.s), 4.62 (2H, s), 9.70 (1H, s).

[Reference Example 19] 5-(tert-butyl) 2-methyl 6,7-dihydrooxazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate

At room temperature, sodium cyanide (220 mg) and manganese dioxide (780 mg) were added to a methanol (9.0 ml) solution of the compound (225 mg) obtained in Reference Example 18, and after stirring for 30 minutes, the filter. The filtrate was washed with water (50 ml) and saturated brine (50 ml), 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=3:2→1:1) to obtain the title compound (120 mg).

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

MS (FAB) m/z: 283 (M+H) ⁺ .

[Reference Example 20] Methyl 5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine-2-carboxylate

To a dichloromethane (15 ml) solution of the compound (500 mg) obtained in Reference Example 19 was added trifluoroacetic acid (15 ml) at room temperature, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure, dichloromethane (20ml), triethylamine (0.495ml), acetic acid (205ml), formalin (0.230ml) and triacetoxy borohydrogenation were added to the resulting residue at room temperature Sodium (570mg). After stirring for 15 minutes, dichloromethane (20ml) and saturated aqueous sodium bicarbonate solution (50ml) were added to the reaction mixture for liquid separation, and the aqueous layer was extracted with dichloromethane (3×20ml). After the combined organic layers were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1→10:1) to obtain the title compound (257 mg).

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

MS(FAB) m/z: 197(M+H) ⁺ , 165(M-OCH ₃ ) ⁺ .

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

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

¹ H-NMR (DMSO-d ₆ ) 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] Methyl 5-chloro-6-fluoroindole-2-carboxylate

Under reflux, a mixture of methyl 3-chloro-4-fluoro-α-azidocinnamate (Japanese Patent Laid-Open No. 7-149723) (1.85 g) and xylene (140 ml) was heated for 1 hour, and then distilled off. solvent. The residue was purified by silica gel column chromatography (dichloromethane) to obtain the title compound (491 mg).

¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 7.13-7.15 (1H, m), 7.20 (1H, dd, J=9.3, 0.49Hz), 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 obtained in Reference Example 22 (461 mg) was dissolved in a mixed solvent of tetrahydrofuran (15 ml), methanol (10 ml) and water (10 ml), and lithium hydroxide (283 mg) was added at room temperature and stirred for 4 hours. The solvent was distilled off under reduced pressure, and 1N hydrochloric acid was added to the residue to make it weakly acidic. The resulting powder was collected by filtration and dried to obtain the title compound (422 mg).

¹ H-NMR (CDCl ₃ ) 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) Suspend phosphorus pentasulfide (500 g) in formamide (3000 ml) under ice cooling, and stir overnight. Water and ether were added to the reaction solution for liquid separation. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oily substance. It was dissolved in n-butanol (350ml), and 3-chloro-4-oxo-1-piperidinecarboxylic acid ethyl ester (150g ), stirred at 100°C for 2.5 hours. The reaction solution was filtered through celite, and the filtrate was washed with saturated aqueous sodium bicarbonate solution and saturated brine, respectively, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane～ethyl acetate:hexane=1:2) to obtain 6,7-dihydrothiazolo[5,4-c]pyridine-5(4H) - Ethyl carboxylate (79.0 g).

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

MS (FAB) m/z: 213 (M+H) ⁺ .

2) Add 3.5N aqueous sodium hydroxide solution (250ml) to the above product (33.5g), and heat to reflux overnight. After cooling the reaction solution to room temperature, di-tert-butyl dicarbonate (103 g) was added under ice-cooling, followed by stirring overnight at room temperature. 3N hydrochloric acid was added to the reaction solution to adjust the pH to 1-2, and then dichloromethane was added to carry out a liquid separation operation. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)- tert-Butyl carboxylate (21.1 g).

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.94 (2H, br.s), 3.76 (2H, br.s), 4.68 (2H, s), 8.67 (1H, s).

MS (FAB) m/z: 241 (M+H) ⁺ .

3) To a solution of the compound (5.00 g) obtained in the above 2) in dichloromethane (25 ml) was added trifluoroacetic acid (25 ml) at room temperature. After stirring for 10 minutes, the reaction solution was concentrated under reduced pressure. 4-Bromopyridine (5.20 g), N,N-dimethylformamide (30 ml) and triethylamine (15.5 ml) were added to the residue at room temperature, stirred at 150° C. for 2 days, and then naturally cooled to room temperature. The resulting colorless precipitate was filtered off, and the filtrate was concentrated under reduced pressure, dichloromethane (50 ml) and saturated aqueous sodium bicarbonate solution (100 ml) were added, and the aqueous layer was saturated with salt. After separation, the aqueous layer was extracted with dichloromethane (5×30ml). 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 (dichloromethane:methanol=20:1→8:1) to obtain the title compound (2.97 g).

¹ H-NMR (CDCl ₃ ) δ: 3.07 (2H, t, J=5.9Hz), 3.81 (2H, t, J=5.9Hz), 4.61 (2H, s), 6.74 (2H, t, J=6.5 Hz), 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) Dissolve tetrahydro-4H-pyran-4-one (5.0g) in cyclohexane (20ml), add pyrrolidine (4.35ml), p-toluenesulfonic acid monohydrate (48mg), and use Dean- The Stark apparatus was heated to reflux for 70 minutes while removing the water. After the reaction solution was cooled to room temperature, the supernatant was collected and concentrated under reduced pressure. The residue was dissolved in methanol (15ml), sulfur powder (1.60g) was added under water cooling, and after 15 minutes, a methanol solution (10ml) of cyanamide (2.10g) was added dropwise over 20 minutes, and stirred for 3 days. The solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane:methanol=20:1→10:1→4:1) to obtain 6,7-dihydro-4H-pyrano[4 , 3-d] Thiazol-2-ylamine (3.97 g).

¹ H-NMR (CDCl ₃ ) 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) Dissolve copper chloride (4.10g) in acetonitrile (50ml), and add tert-butyl nitrite (3.93g) in one batch under water cooling. After 10 minutes, the compound (3.97 g) obtained by the above reaction was added over about 1 hour, followed by stirring at room temperature for 1 hour. Then, the reaction solution was heated to 65° C., and stirring was continued for 2 hours. After adding silica gel (20 g) to the reaction solution, 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).

¹ H-NMR (CDCl ₃ ) 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 salt of 6,7-dihydro-4H-pyrano[4,3-d]thiazole-2-carboxylate

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

¹ H-NMR (CDCl ₃ ) 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 above product (1.14 g) was dissolved in diethyl ether (30 ml), cooled to -78°C, and then 1.6N butyllithium (6.6 ml) was added and stirred. After 20 minutes, carbon dioxide gas was introduced for 15 minutes. After the temperature of the reaction liquid returned to room temperature, it was concentrated under reduced pressure to obtain the title compound (1.65 g).

¹ H-NMR (DMSO-d ₆ ) 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 (JP-A-4-321691) (9.20 g) was dissolved in formic acid (60 ml), and heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and 5N aqueous potassium hydroxide solution (100 ml) and diethyl ether were added to the residue for liquid separation. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off 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).

¹ H-NMR (CDCl ₃ ) 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 Reference Example 27 in the same manner as in Reference Example 4.

¹ H-NMR (CDCl ₃ ) 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 salt of 5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine-2-carboxylate

The title compound was obtained from the compound obtained in Reference Example 28 in the same manner as in Reference Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (3H, s), 2.64 (2H, br.s), 2.80 (2H, br.s), 3.44 (2H, br.s).

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

In methanol (100ml), ammonium acetate (8.2g) and sodium cyanoborohydride (4.0g) were added, and heated to reflux 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 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 (50 ml), and aqueous formaldehyde (4.29 g) and sodium cyanoborohydride (3.49 g) were added at room temperature, followed by stirring for 12 hours. The solvent was distilled off under reduced pressure, dichloromethane was added, washed with saturated sodium bicarbonate solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the title compound (740 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.71-1.78 (1H, m), 2.10-2.19 (1H, m), 2.35 (6H, s), 2.66-2.94 (5H, m).

MS (FAB) m/z: 217 (M+H) ⁺ .

[Reference Example 31] Lithium salt of 6-(dimethylamino)-4,5,6,7-tetrahydrobenzothiazole-2-carboxylate

The compound obtained in Reference Example 30 (750 mg) was dissolved in diethyl ether (15 ml), cooled to -78°C, 1.5N tert-butyllithium (3.5 ml) was added thereto, stirred for 20 minutes, and carbon dioxide gas was introduced for about 15 minutes. After the temperature of the reaction solution returned to room temperature, it was concentrated under reduced pressure to obtain the title compound.

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

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

Dissolve 1-tert-butoxycarbonyl-3-pyrrolidone (1.58g) in cyclohexane (10ml), add p-toluenesulfonic acid monohydrate (8.12mg) and pyrrolidine (607mg), and use Dean-Star Heat to reflux for 1.5 hours while dehydrating the device. The supernatant was collected and concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), sulfur powder (274 mg) was added, and the mixture was stirred for 15 minutes under ice cooling. A methanol solution (2 ml) of cyanamide (377 mg) was slowly added dropwise to the reaction solution, followed by stirring overnight at room temperature. Then, it was heated to reflux for 2 hours, and after concentrating the reaction solution, dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:39) to obtain the title compound (248 mg).

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

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

MS (FAB) m/z: 305 (M+H) ⁺ .

[Reference Example 34] Lithium salt of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 7 in the same manner as in Reference Example 10.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (9H, s), 2.69-2.77 (2H, m), 3.60-3.68 (2H, m), 4.51-4.58 (2H, m).

[Reference Example 35] Methyl 2-bromo-4-(2-methoxy-2-oxoethyl)thiazole-5-carboxylate

Under ice cooling, copper bromide (26.8 g) was added in one portion to a solution of t-butyl nitrite (15.5 g) in acetonitrile (500 ml). Acetonitrile solution (500 ml) of 2-amino-5-methoxycarbonyl-4-thiazole-acetic acid methyl ester (Pharmaceutical Journal, 1966, volume 86, page 300) (23.0 g) was added dropwise to the reaction solution over 45 minutes. , stirred under ice-cooling for 1 hour, and then stirred at room temperature for 30 minutes. The reaction solution was concentrated, 10% hydrochloric acid and diethyl ether were added to the residue, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (25.9 g).

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

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

Under ice-cooling, a tetrahydrofuran (500 ml) solution of the compound (23.4 g) obtained in Reference Example 35 was added dropwise to a suspension of lithium aluminum hydride (9.03 g) in tetrahydrofuran (500 ml) over 1 hour. After stirring for 1 hour under ice-cooling, water (9 ml), 35% aqueous sodium hydroxide solution (9 ml) and water (27 ml) were added successively, followed by stirring at room temperature for 1 hour. After adding anhydrous magnesium sulfate to the reaction solution and stirring, the 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).

¹ H-NMR (CDCl ₃ ) 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] 2-(5-{[(methylsulfonyl)oxy]methyl}thiazol-4-yl)ethyl methanesulfonate

The compound obtained in Reference Example 36 (8.64 g) and triethylamine (45.4 ml) were dissolved in dichloromethane (500 ml), and methanesulfonyl chloride (12.6 ml) was added dropwise to this solution at -78° C. over 20 minutes. dichloromethane solution. After stirring at -78°C for 15 minutes and at 0°C for 1 hour, water was added, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (13.4 g).

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

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

Under ice-cooling, 1-methylcyclopropylamine hydrochloride (J.Org.Chem., 1989, vol. 54, p. 1815) was added to dichloromethane (20 ml) containing the compound (4.46 g) obtained in Reference Example 37. (1.89 g), stirred overnight at room temperature. Then, 1-methylcyclopropylamine hydrochloride (1.89 g) was added, stirred at room temperature for 20 hours, and then heated and refluxed and stirred for 5 hours. Dichloromethane and water were added to the reaction solution, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:49) to obtain the title compound (944 mg).

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

MS (ESI) m/z: 195 (M+H) ⁺ .

[Reference Example 39] Lithium salt of 5-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 38 in the same manner as in Reference Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 0.39 (2H, br.s), 0.56 (2H, br.s), 1.10 (3H, br.s), 2.66 (2H, br.s), 2.89 ( 2H, br.s), 3.75 (2H, br.s).

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

The title compound was obtained from the compound obtained in Reference Example 37 and 2-amino-2-methyl-1-propanol in the same manner as in Reference Example 38.

¹ H-NMR (CDCl ₃ ) δ: 1.15 (6H, s), 2.91 (4H, s), 3.45 (2H, s), 3.87 (2H, s), 8.63 (1H, s).

[Reference Example 41] 5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazole And[5,4-c]pyridine

At room temperature, tert-butylchlorodiphenylsilane (1.93 g) and imidazole (994 mg) were added to a solution of the compound (1.24 g) obtained in Reference Example 40 in N,N-dimethylformamide (5 ml), and stirred overnight . Water and ether were added to the reaction solution, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain the title compound (2.46 g).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.15 (6H, s), 2.83-2.90 (2H, m), 2.93-3.00 (2H, m), 3.63 (2H, s), 3.97 (2H, s), 7.35-7.48 (6H, m), 7.63-7.70 (4H, m), 8.58 (1H, s).

MS (ESI) m/z: 451 (M+H) ⁺ .

[Reference Example 42] 5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazole Lithium salt of [5,4-c]pyridine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 41 in the same manner as in Reference Example 5.

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

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

1) At room temperature, dissolve 4,5-dimethylthiazole (5.00g), N-bromosuccinimide (15.7g) and α,α'-azobisisobutyronitrile (362mg) in dichloroethyl Alkane (500ml), heated to reflux for 1 hour. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane:diethyl ether=1:4) to obtain 4,5-bis(bromomethyl)thiazole (5.24 g).

¹ H-NMR (CDCl ₃ ) δ: 4.64 (2H, s), 4.74 (2H, s), 8.75 (1H, s).

2) Under ice-cooling, suspend 4,5-bis(bromomethyl)thiazole (1.37g) and 1,2-trimethylenehydrazine hydrochloride (WO9532965) (732mg) in ethanol (15ml), drop in 5 minutes Add triethylamine (2.82ml). After stirring at room temperature for 2 hours, the solvent was evaporated, dichloromethane (50 ml) and 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 distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=3:47) to obtain the title compound (358 mg).

¹ H-NMR (CDCl ₃ ) δ: 2.10-2.25 (2H, m), 3.01 (4H, br.s), 3.95 (2H, s), 3.99 (2H, br.s), 8.64 (1H, s) .MS(FAB)m/z: 182(M+H) ⁺ .

[Reference Example 44] Lithium salt of 4,7,8,10-tetrahydro-6H-pyrazolo[1,2-a]thiazolo[4,5-d]pyridazine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 43 in the same manner as in Reference Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 1.90-2.10 (2H, m), 2.60-3.10 (4H, br.s), 3.65-4.00 (4H, m).

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

Using the same method as in Reference Example 43, 4,5-bis(bromomethyl)thiazole (2.20 g) obtained in 1) of Reference Example 43 and 1,2-tetramethylenehydrazine hydrochloride (US5726126) were obtained. title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (4H, br.s), 2.20-3.50 (4H, br.s), 3.92 (4H, br.s), 8.65 (1H, s).

MS (FAB) m/z: 196 (M+H) ⁺ .

[Reference Example 46] Lithium salt of 4,6,7,8,9,11-hexahydropyridazino[1,2-a]thiazolo[4,5-d]pyridazine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 45 in the same manner as in Reference Example 5.

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

At room temperature, 1-(tert-butoxycarbonyl)-3-pyrrolidone (4.57 g) and N,N-dimethylformamide dimethyl acetal (30 ml) were added, and the mixture was heated at 140° C. for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. Add hexane to the residue, collect the precipitated yellow powder by filtration, dissolve it in ethanol (100ml), add methylisothiourea sulfate (9.24g) and sodium ethylate (4.52g) to the solution at room temperature, and heat to reflux 24 hours. Saturated saline and diethyl ether were added to the reaction solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:99) to obtain the title compound (1.10 g).

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

MS (FAB) m/z: 268 (M+H) ⁺ .

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

Under ice-cooling, m-chloroperbenzoic acid (1.99 g) was added to a dichloromethane solution (20 ml) of the compound obtained in Reference Example 47 (1.08 g), followed by stirring for 5 hours. After adding saturated aqueous sodium sulfite solution, saturated aqueous sodium bicarbonate solution and dichloromethane to the reaction solution for liquid separation, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, and the precipitated powder was collected by filtration to obtain the title compound (1.09 g).

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

MS (FAB) m/z: 300 (M+H) ⁺ .

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

To a solution of the compound obtained in Reference Example 48 (1.05 g) in dichloromethane (30 ml) was added tetrabutylammonium cyanide (1.04 g) at room temperature, followed by stirring at room temperature for 1 hour. 1N sodium hydroxide was added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:acetone=20:1) to obtain the title compound (776 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 4.70-4.85 (4H, m), 8.68-8.77 (1H, m).

MS (FAB) m/z: 247 (M+H) ⁺ .

[Reference Example 50] 6-(t-butyl) 2-methyl 5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-2,6-dicarboxylate

Concentrated hydrochloric acid (5 ml) was added to a methanol (10 ml) solution of the compound (776 mg) obtained in Reference Example 49 at room temperature, followed by stirring at 100°C for 1 hour. After natural cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml), triethylamine (2.20 ml) and di-tert-butyl dicarbonate (1.37 g) were added at room temperature, and stirred for 1 hour. After concentration under reduced pressure, dichloromethane and saturated brine were added 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 (methanol:dichloromethane=3:97) to obtain the title compound (317 mg).

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

MS (FAB) m/z: 280 (M+H) ⁺ .

[Reference Example 51] Lithium salt of 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine-2-carboxylate

1) Dissolve 4,5-bis(bromomethyl)thiazole (600 mg) obtained in 1) of Reference Example 43 in ethanol (20 ml), and add 1,2-dimethylhydrazine hydrochloride (294 mg) under ice-cooling , triethylamine (1.23ml) was added in one portion, stirred at room temperature for 30 minutes and then at 50°C for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d ] Pyridazine (90 mg).

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

2) The title compound was obtained from 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo[4,5-d]pyridazine in the same manner as in Reference Example 5.

₁ H-NMR (DMSO-d ₆ ) δ: 2.28 (3H, s), 2.39 (3H, s), 3.66 (2H, br.s), 3.88 (2H, br.s).

[Reference Example 52] 4-nitrophenyl 5-chloroindole-2-carboxylate

Suspend 5-chloroindole-2-carboxylic acid (20g) in dichloromethane (1500ml), add N,N-dimethylformamide (2ml), and add thionyl chloride (11ml) dropwise at room temperature . After heating the reaction solution under reflux overnight, it was concentrated under reduced pressure. The residue was dissolved in dichloromethane (1000ml), triethylamine (8.47ml) was added under ice-cooling, p-nitrophenol (14.2g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate and 0.2N hydrochloric acid were added to the residue to carry out a liquid separation operation. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (29.9 g).

¹ H-NMR (CDCl ₃ ) δ: 7.35 (1H, dd, J=9.0, 1.7Hz), 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 (2.50 g) was dissolved in dichloromethane (25 ml), m-chloroperbenzoic acid (3.71 g) was added under ice-cooling, and stirred at room temperature for 1 hour. After diluting with dichloromethane, it was washed with aqueous sodium thiosulfate and aqueous sodium hydroxide, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (40ml), then trimethylsilyl cyanide (2.0ml) and N,N-dimethylcarbamoyl chloride (1.50ml) were added, and heated to reflux for 9 Hour. Then, trimethylsilyl cyanide (1.0ml) and N,N-dimethylcarbamoyl chloride (0.80ml) were added, heated to reflux for 16 hours, diluted with dichloromethane, and 10% potassium carbonate aqueous solution (40ml ), stirred for 30 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Dichloromethane 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).

¹ H-NMR (DMSO-d ₆ ) 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 (1.73 g) obtained in Reference Example 53 was dissolved in concentrated hydrochloric acid (40 ml), and heated under reflux for 19 hours. After the temperature was lowered to room temperature, the precipitate was collected by filtration and washed with water to obtain the title compound (1.81 g).

¹ H-NMR (DMSO-d ₆ ) 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

Dissolve (±)-(4-chlorophenyl)alanine methyl ester hydrochloride (2.00g) in dichloromethane (20ml), add 1-(3-dimethylaminopropyl)-3-ethane Carbodiimide hydrochloride (1.60g), 1-hydroxybenzotriazole monohydrate (1.23g), N-methylmorpholine (1.90ml) and formic acid (0.30ml), stirred for 15 minutes, then , added formic acid (0.30ml) and stirred for 15 minutes. This operation was repeated 3 times, and the reaction solution was diluted with dichloromethane. 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).

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

MS (FAB) m/z: 242 (M+H) ⁺ .

[Reference Example 56] Methyl 7-chloro-3-isoquinolinecarboxylate

The compound (1.45 g) obtained in Reference Example 55 was dissolved in dichloromethane (40 ml), and oxalyl chloride (0.57 ml) was added dropwise. After stirring at room temperature for 30 minutes, ferric chloride (1.17 g) was added at an external temperature of about -10°C, and stirred at room temperature for 4 days. 1N hydrochloric acid was added, diluted with dichloromethane, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in methanol (38 ml), concentrated sulfuric acid (2 ml) was added, and the mixture was heated under reflux for 20 hours. Aqueous sodium bicarbonate solution was added, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→ethyl acetate) to obtain the title compound (0.25 g).

¹ H-NMR (CDCl ₃ ) δ: 4.07 (3H, s), 7.74 (1H, dd, J=8.8, 2.0Hz), 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-isoquinolinecarboxylic acid hydrochloride

The compound (0.23 g) obtained in Reference Example 56 was dissolved in concentrated hydrochloric acid (10 ml), and heated under reflux for 18 hours. After the temperature of the reaction solution was lowered to room temperature, the precipitate was collected by filtration and washed with water to obtain the title compound (0.21 g).

¹ H-NMR (DMSO-d ₆ ) 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

Dissolve (3R)-1-benzyl-3-hydroxypyrrolidine (500μl) and imidazole (466mg) in N,N-dimethylformamide (15ml), and add tert-butyldiphenylsilyl under ice cooling Chlorine (1.57ml), stirred at room temperature for 9 days. The solvent was evaporated under reduced pressure, dichloromethane and water were added to the residue for 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 flash column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (1.27 g).

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

MS (ESI) m/z: 416 (M+H) ⁺ .

[Reference Example 59] N-[(1R ^* ,2S ^* )-2-aminocyclopropyl]-5-chloroindole-2-carboxamide

At room temperature, in cis-1,2-cyclopropanediamine hydrochloride (J.Med.Chem., 1998, volume 41, pages 4723-4732) (405 mg) and 5-chloroindole-2-carboxylic acid (546mg) in N,N-dimethylformamide (10ml) was added 1-hydroxybenzotriazole monohydrate (377mg), 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (642mg) and isopropylethylamine (1.95ml) were stirred for 50 hours. After the reaction mixture was concentrated under reduced pressure, dichloromethane (50 ml) and saturated aqueous sodium bicarbonate (200 ml) were added, and the precipitated colorless solid was filtered off. 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 distilled off under reduced pressure to obtain a residue. The resulting residue was purified by silica gel flash column chromatography (dichloromethane:methanol=100:7→10:1) to obtain the title compound (110 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 0.44 (1H, dd, J=10.7, 4.4Hz), 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

In the same manner as in Reference Example 59, the title compound was obtained from cis-1,2-cyclobutylene diamine hydrochloride (J, Am. Chem. Soc., 1942, Vol. 64, pp. 2696-2700).

¹ H-NMR (DMSO-d ₆ ) δ: 1.55-2.20 (4H, m), 3.52-3.62 (1H, m), 4.35-4.50 (1H, m), 7.16 (1H, dd, J = 8.7, 2.1 Hz), 7.19(1H, s), 7.42(1H, d, J=8.7Hz), 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 ^* )-tert-butyl 2-aminocyclopentylcarbamate

Dissolve (±)-trans-1,2-cyclopentanediamine (WO 98/30574) (692 mg) in dichloromethane (10 ml), add triethylamine (1.1 ml), 2-(tert Butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg), stirred at 0°C for 1 hour. Then, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (493 mg) was added thereto, followed by stirring at room temperature for 7 hours. A water solution was added to the reaction solution, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel flash column chromatography (dichloromethane:methanol=9:1) to obtain the title compound (395 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.25-1.40 (2H, m), 1.49 (9H, s), 1.59-1.77 (2H, m), 1.92-2.08 (1H, m), 2.10-2.17 (1H, m), 2.98(1H, q, J=7.2Hz), 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]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine- 2-Formamide hydrochloride

The compound (175 mg) obtained in Reference Example 61 was dissolved in N,N-dimethylformamide (3 ml), and 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c] Lithium pyridine-2-carboxylate (purity 90%, 258mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (252mg), 1-hydroxybenzotri Azole monohydrate (60mg), stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure with a pump, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue for liquid separation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (dichloromethane:methanol=47:3). The obtained pale yellow oil was dissolved in hydrochloric acid ethanol (5 ml), stirred 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).

¹ H-NMR (DMSO-d ₆ ) δ: 1.63-1.73 (4H, m), 1.99-2.06 (2H, m), 2.91 (3H, s), 3.09-3.14 (1H, m), 3.25-3.70 ( 4H, m), 4.27-4.32 (1H, m), 4.42-4.46 (1H, m), 4.68-4.71 (1H, m), 8.20-8.23 (3H, m), 9.09 (1H, d, J = 8.3 Hz), 11.82-12.01(1H, m).

MS (ESI) m/z: 281 (M+H) ⁺ .

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

The compound (1.40 g) obtained in Reference Example 61 was dissolved in N,N-dimethylformamide (15 ml), and 5-chloroindole-2-carboxylic acid (1.64 g), 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g) and 1-hydroxybenzotriazole monohydrate (473 mg) were stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue, and the precipitate was collected by filtration. The precipitate was washed with ethyl acetate, dichloromethane and methanol. On the other hand, the filtrate was liquid-separated, and the organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (dichloromethane:methanol=19:1) to obtain a pale yellow solid. The pale yellow solid and the precipitate obtained by filtration were combined, dissolved in dichloromethane (10 ml), trifluoroacetic acid (10 ml) was added, and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, dichloromethane and 1N aqueous sodium hydroxide solution were added to the residue, and the precipitate was collected by filtration. The organic layer of the filtrate was separated and dried over anhydrous sodium sulfate. The precipitate collected by filtration was added to this solution, and 4N hydrochloric acid dioxane solution (20 ml) was added thereto, and the solvent was distilled off under reduced pressure. Dichloromethane (10 ml) and 4N hydrochloric acid dioxane solution (10 ml) were added to the residue, and the solvent was distilled off again under reduced pressure. Ethyl acetate was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (1.83 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.75 (4H, m), 2.05-2.10 (2H, m), 3.49 (1H, q, J=7.6Hz), 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 ^* )-tert-butyl 2-aminocyclohexylcarbamate

In the same manner as in Reference Example 61, the title compound was obtained from (±)-trans-1,2-cyclohexanediamine.

Melting point: 79～81℃

¹ H-NMR (CDCl ₃ ) δ: 1.05-1.34 (4H, m), 1.45 (9H, s), 1.68-1.75 (2H, m), 1.92-2.02 (2H, m), 2.32 (1H, dt, J=10.3, 3.9Hz), 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 - Formamide trifluoroacetate (and hydrochloride)

The title compound was obtained from the compound obtained in Reference Example 64 in the same manner as in Reference Example 62.

¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.80 (7H, m), 1.95-2.05 (1H, m), 2.97 (3H, s), 3.00-3.20 (3H, m), 3.63 (2H, br.s), 3.72-3.88(1H, m), 4.61(2H, br.s), 7.98(3H, s), 8.89(1H, d, J=9.2Hz).

MS (FAB) m/z: 295 (M+H) ⁺ .

The hydrochloride is likewise obtained.

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

In the same manner as in Reference Example 61, the title compound was obtained from cis-1,2-cyclohexanediamine.

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.70 (17H, m), 2.98-3.05 (1H, m), 3.60 (1H, br.s), 4.98 (1H, br.s).

MS (FAB) m/z: 215 (M+H) ⁺ .

[Reference Example 67] N-[(1R ^* ,2S ^* )-2-aminocyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2 -Formamide hydrochloride (and trifluoroacetate)

The title compound was prepared from the compound obtained in Reference Example 66 in the same manner as in Reference Example 62.

¹ H-NMR (DMSO-d ₆ ) 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 ^* )-tert-butyl 2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate

At room temperature, 5-chloroindole-2-carboxylic acid (2.88 g), 1-hydroxybenzo Triazole monohydrate (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.95 g). After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, dichloromethane (30ml), saturated aqueous sodium bicarbonate solution (150ml) and water (150ml) were added to the resulting residue, and the resulting colorless precipitate was collected by filtration and dried to obtain The title compound (5.21 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.45 (4H, m), 1.21 (9H, s), 1.68 (2H, d, J = 8.1 Hz), 1.86 (2H, t, J = 16.2 Hz ), 3.22-3.42 (1H, m), 3.69 (1H, br.s), 6.66 (1H, d, J=8.5Hz), 7.02 (1H, s), 7.15 (1H, dd, J=8.5, 2.0 Hz), 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 solution of the compound obtained in Reference Example 68 (5.18 g) in dichloromethane (100 ml) was added hydrochloric acid ethanol solution (100 ml) at room temperature. After stirring for 2 days, the reaction mixture was concentrated under reduced pressure, diethyl ether (300 ml) was added to the resulting residue, and the resulting colorless precipitate was collected by filtration and dried to obtain the title compound (4.30 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.36 (2H, m), 1.36-1.50 (2H, m), 1.60 (2H, br.s), 1.90 (1H, d, J=13.0Hz) , 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 ^* )-tert-butyl 2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate

The title compound was prepared from the compound obtained in Reference Example 66 in the same manner as in Reference Example 68.

¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.45 (11H, m), 1.45-1.70 (4H, m), 1.70-1.85 (2H, m), 3.76 (1H, br.s), 4.08 ( 1H, br.s), 6.64 (1H, d, J=7.6Hz), 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 prepared from the compound obtained in Reference Example 70 in the same manner as in Reference Example 69.

¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.50 (2H, m), 1.55-1.95 (6H, m), 3.41 (1H, br.s), 4.32 (1H, br.s), 7.19 ( 1H, dd, J=8.7, 2.0Hz), 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 (3.85 g) was added a little at a time to 30% hydrogen peroxide aqueous solution (45 ml) and 88% formic acid (180 ml), stirred at 40-50°C for 1 hour, and then stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and a 35% aqueous sodium hydroxide solution was added to the residue to make it basic. After the reaction liquid was stirred at 40-50° C. for 10 minutes, ethyl acetate was added for liquid separation, and ethyl acetate was used to perform four extraction operations from the water layer. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (4.56 g).

¹ H-NMR (CDCl ₃ ) 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 obtained in Reference Example 72 (4.56 g) was dissolved in dichloromethane (35 ml), triethylamine (29 ml) was added, and cooled to -78°C. Methanesulfonyl chloride (8.13 ml) was added dropwise thereto. Dichloromethane (10 ml) was added and stirred at the same temperature for 20 minutes, then at 0°C for 1.5 hours. Water was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance. This oil was dissolved in N,N-dimethylformamide (90 ml), sodium azide (13.65 g) was added, and stirred at 65°C for 18 hours. Diethyl ether and water were added to the reaction solution for liquid separation, and the ether layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance.

The oil was dissolved in ethanol (70 ml), 10% palladium carbon (containing 50% water, 4 g) was added, and stirred in an atmosphere of hydrogen (3.5 atm) for 4 days. 10% palladium carbon was filtered, 1N hydrochloric acid ethanol solution (70 ml) was added to the filtrate, and the solvent was distilled off under reduced pressure. This was dissolved in methanol, ethyl acetate was added, and the solvent was again distilled off under reduced pressure. The resulting precipitate was collected by filtration to obtain the title compound (3.57 g).

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

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

The title compound was prepared from the compound obtained in Reference Example 73 in the same manner as in Reference Example 59.

¹ H-NMR (DMSO-d ₆ ) δ: 1.49-1.52 (4H, m), 1.72-1.91 (6H, m), 4.04-4.10 (1H, m), 7.17-7.23 (2H, m), 7.44 ( 1H, d, J = 8.8Hz), 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

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

¹ H-NMR (CDCl ₃ ) δ: 1.48-1.58 (6H, m), 1.64-1.75 (4H, m), 1.86-1.96 (2H, m), 2.28 (2H, d, J=2.9Hz), 3.90 (2H, d, J=8.3Hz).

MS (FAB) m/z: 145 (M+H) ⁺ .

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

Dissolve cis-1,2-cyclooctanediol (4.82g) in dichloromethane (60ml), add triethylamine (27.7ml), replace the gas in the container with argon, and cool to -78°C. Methanesulfonyl chloride (7.7ml, 100mmol) was added dropwise. After stirring at the same temperature for a total of 1 hour, stir at 0°C for 1 hour, add water to the reaction solution, wash the organic layer with water, 0.5N aqueous hydrochloric acid, water, and saturated aqueous sodium bicarbonate, and dry over anhydrous sodium sulfate. . The solvent was distilled off under reduced pressure, the residue was dissolved in N,N-dimethylformamide (80 ml), sodium azide (13.0 g) was added, and the mixture was stirred at 65°C for 19 hours. Diethyl ether and water were added to the reaction solution for liquid separation, and the ether layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane:ethyl acetate=6:1) to obtain the title compound (4.85 g).

¹ H-NMR (CDCl ₃ ) δ: 1.49-1.64 (6H, m), 1.67-1.78 (2H, m), 1.81-1.97 (4H, m), 3.74-3.76 (2H, m).

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

The compound obtained in Reference Example 76 (4.85 g) was dissolved in ethanol (55 ml), 10% palladium carbon (containing 50% water, 3.0 g) was added, and stirred in an atmosphere of hydrogen (4.5 atm) for 21 hours. The catalyst was filtered off, 1N hydrochloric acid ethanol solution (50 ml) 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).

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

MS (ESI) m/z: 143 (M+H) ⁺ .

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

The title compound was prepared from the compound obtained in Reference Example 77 in the same manner as in Reference Example 59.

MS (ESI) m/z: 320 (M+H) ⁺ .

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

3-Cyclopenten-1-ol (1.68g) and methyl iodide (1.25ml) were dissolved in tetrahydrofuran (20ml), and under ice-cooling, 60% sodium hydride (800mg) was added to the solution in small amounts each time. Stir overnight. Water and ether were added to the reaction solution for liquid separation, 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 (90 ml) and 30% hydrogen peroxide (3.17 ml) were added to the obtained 4-methoxy-1-cyclopentene at room temperature, followed by stirring overnight at room temperature. The reaction solution was concentrated under reduced pressure, 35% aqueous sodium hydroxide solution was added to the residue to make the reaction solution alkaline, and the mixture was stirred at 50°C for 10 minutes. After cooling to room temperature, it was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain the title compound (1.21 g).

¹ H-NMR (CDCl ₃ ) 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 at position 4)

The compound obtained in Reference Example 79 (1.21 g) and triethylamine (7.66 ml) were dissolved in dichloromethane (20 ml), and methanesulfonyl chloride (2.13 ml) was added dropwise at -78°C over 20 minutes. After the dropwise addition, the temperature was raised to 0°C and stirred for 80 minutes to obtain crude (1R ^* ,2R ^* )-1,2-bis(methylsulfonyloxy)-4-methoxycyclopentane. This was dissolved in N,N-dimethylformamide (20ml), sodium azide (3.57g) was added, and heated and stirred at 65°C for 22 hours. Then, sodium azide (3.57 g) was added, and it stirred at 70 degreeC for 2 days. The reaction liquid was naturally cooled, and after separation with water and ether, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (584 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.65-1.80 (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-cyclopentadiamine hydrochloride (mixture of stereoisomers at position 4)

The compound obtained in Reference Example 80 (584 mg) was dissolved in ethanol, 10% palladium on carbon (321 mg) was added, and hydrogenation was carried out at normal temperature and pressure for 2 days. After removing the catalyst by filtration and concentration, 1N ethanol hydrochloric acid solution and ethyl acetate were added to the residue, followed by concentration to obtain the title compound (488 mg).

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

MS (ESI) m/z: 261 (2M+H) ⁺ .

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

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

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

By the same method as in Reference Example 79, after benzylation of 4-hydroxymethyl-1-cyclopentene (J.Heterocycl.Chem., 1989, vol. 26, p. 451) with benzyl bromide, using formic acid- Hydrogen peroxide afforded the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.44-1.52 (1H, m), 1.77-1.85 (1H, m), 1.89-1.97 (1H, m), 2.25-2.35 (1H, m), 2.46-2.58 ( 1H, m), 3.40-3.50 (2H, m), 3.89 (1H, br.s), 4.08 (1H, br.s), 4.54 (2H, s), 7.27-7.39 (5H, m).

MS (FAB) m/z: 223 (M+H) ⁺ .

[Reference Example 84] (1R ^* , 2R ^* )-4-[(benzyloxy)methyl]-1,2-cyclopentanediamine (mixture of stereoisomers at position 4)

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

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

The title compound was prepared from the compound of Reference Example 84 in the same manner as in Reference Example 59.

¹ H-NMR (DMSO-d ₆ ) 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

(1R ^* , 4R ^* , 5R ^* )-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (J.Org.Chem., 1996, volume 61, page 8687) (14.3g) was dissolved in ethanol (130ml), and 2N aqueous sodium hydroxide solution (34.5ml) was added under ice-cooling, followed by stirring at room temperature for 7 hours. After distilling off the solvent under reduced pressure, the residue was extracted with dichloromethane by adding water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=83:17) to obtain the title compound (6.54 g).

¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J=7.1Hz), 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 Reference Example 86 was dissolved in N,N-dimethylformamide (100ml), and ammonium chloride (6.45g) and sodium azide (7.8g) were added successively at room temperature. °C and stirred for 12 hours. After the solvent was concentrated to about 1/3, it was diluted with water and ethyl acetate, and stirred for 3 minutes. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (15.8 g).

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

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

The compound obtained in Reference Example 87 (100 mg) and di-tert-butyl dicarbonate (133 mg) were dissolved in ethyl acetate (12 ml), a catalytic amount of 10% palladium on carbon was added, and the mixture was stirred at room temperature under hydrogen flow for 12 hours. After filtering off insoluble matter, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (145 mg).

¹ H-NMR (CDCl ₃ ) 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] Ethyl (1R ^* , 3S ^* , 4R ^* )-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate and (1R ^* , 3S ^* , 4S ^* )-4-Azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester

The compound obtained in Reference Example 88 (16 g) and triethylamine (38 ml) were dissolved in dichloromethane (150 ml), and after cooling to -78°C, methanesulfonyl chloride (13 ml) was added dropwise at the same temperature. Then, the mixture was stirred at the same temperature for 15 minutes, heated up to 0° C., stirred for 30 minutes, and then stirred at room temperature for 2 hours. After adding 0.1N hydrochloric acid and diluting with dichloromethane, the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]cyclohexane ethyl carboxylate

The above product was dissolved in N,N-dimethylformamide (100ml), sodium azide (18g) was added at room temperature, the temperature was raised to 75°C, and the mixture was stirred for 12 hours. The solvent was concentrated to about 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 distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound [(1R ^* , 3S ^* , 4R ^* ), 6.74g] and [(1R ^* , 3S ^* , 4S ^* ) body, 1.32 g].

(1R ^* , 3S ^* , 4R ^* ) bodies:

¹ H-NMR (CDCl ₃ ) 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 ^* ) bodies:

¹ H-NMR (CDCl ₃ ) 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, qJ=7.1Hz), 4.67 (1H, br.s).

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

Ethyl (1R ^* , 3S ^* , 4R ^* )-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate (5.4 g) obtained in Reference Example 89 was dissolved in ethanol ( 10 ml) and ethyl acetate (10 ml), a catalytic amount of 10% palladium on carbon was added, and stirred at room temperature for 20 hours under hydrogen flow. After filtering the insoluble matter, 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]-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl Ethyl alkane carboxylate

The compound (4.62 g) obtained in Reference Example 90 was dissolved in dichloromethane (50 ml), and 5-chloroindole-2-carboxylic acid (3.63 g), 1-hydroxybenzotriazole monohydrate ( 2.43 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45 g), stirred for 12 hours. A 0.1N aqueous hydrochloric acid solution was added to the reaction solution, followed by extraction with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain the title compound (5.3 g).

¹ H-NMR (CDCl ₃ ) 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, volume 61, page 8687) (89.3g ) was suspended in ethanol (810ml), and after adding 2N aqueous sodium hydroxide solution (213ml), the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=17:3) to obtain the title compound (41.3 g).

[α] _D ²⁵ = -58° (c = 1.0, chloroform).

[Reference Example 93] Ethyl (1S,3R,4R)-3-azido-4-hydroxycyclohexanecarboxylate

The compound (41g) obtained in Reference Example 92 was dissolved in N,N dimethylformamide (300ml), and ammonium chloride (19.3g) and sodium azide (23.5g) were added successively at room temperature, and stirred at 76°C 13 hours. The reaction solution was filtered, and the filtrate was concentrated. The previous filtrate was added to the residue, and water was added to dissolve it. It 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 ²⁵ = +8° (c = 1.0, chloroform)

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

The compound (51.2g) obtained in Reference Example 93 and di-tert-butyl dicarbonate (68.1g) were dissolved in ethyl acetate (1000ml), 5% palladium carbon (5.0g) was added, and ^the Stir overnight under hydrogen pressure. After filtering the insoluble matter, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:1) and solidified by adding hexane to obtain the title compound (46.9 g).

[α] _D ²⁵ = +25° (c = 1.0, chloroform).

[Reference Example 95] Ethyl (1S, 3R, 4S)-4-azido-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate and (1S, 3R, 4R)-4-azido Nitro-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester

The compound obtained in Reference Example 94 (53.5 g) and triethylamine (130 ml) were dissolved in dichloromethane (500 ml), and methanesulfonyl chloride (42 ml) was added dropwise over 20 minutes under cooling at -10 to -15°C. After stirring at the same temperature for 20 minutes, the temperature was raised to room temperature over 2 hours. The reaction solution was cooled to 0°C, 0.5N hydrochloric acid (800ml) was added dropwise, and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain crude (1S, 3R, 4R)-3-[(tert-butoxycarbonyl) Ethyl amino]-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate.

The above crude compound was dissolved in N,N-dimethylformamide (335ml), sodium azide (60.5g) was added, and stirred at 67-75°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and 250 ml of solvent was distilled off. The residue and 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 distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:4) to obtain the (1S, 3R, 4S) body (18.4 g) of the title compound and the (1S, 3R, 4R) body of the title compound (3.3g). (1S, 3R, 4S) body: [α] _D ²⁵ = +62° (c = 1.0, chloroform), (1S, 3R, 4R) body: [α] _D ²⁵ = -19° (c = 1.0, chloroform) ).

[Reference Example 96] (1S,3R,4S)-4-Amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester

The compound obtained in Reference Example 95 (4.0 g) was dissolved in a mixed solvent of ethanol (150 m) and ethyl acetate (150 ml), 5% palladium carbon ( ^0.5 g) was added, and the Stir at room temperature for 17 hours. After filtering off the insoluble matter, 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 (4.2 g) obtained in Reference Example 96 was dissolved in dichloromethane (50 ml), and 5-chloroindole-2-carboxylic acid (3.33 g), 1-hydroxybenzotriazole monohydrate (2.52 g) were added at room temperature g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.15 g), stirred for 12 hours. 0.1N hydrochloric acid aqueous solution was added to the reaction 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, and the solvent was distilled off under reduced pressure, and the residue was washed with silica gel column After purification by chromatography (ethyl acetate:hexane=1:1), the title compound (4.36 g) was obtained.

[α] _D = -27° (c = 1.0, chloroform).

[Reference Example 98] (1R ^* , 3S ^* , 4R ^* )-3-[(tert-butoxycarbonyl)amino]-4-{[(5-methyl-4,5,6,7-tetrahydrothiazole Ethyl [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

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

[Reference Example 99] Benzyl 3-cyclohexene-1-carboxylate

Dissolve (±)-3-cyclohexene-1-carboxylic acid (50g) in N,N-dimethylformamide (550ml), add triethylamine (170ml) and benzyl bromide (61ml) under ice-cooling, Stir at room temperature for 12 hours. Water was added, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (70.8 g).

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

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

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

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

MS (FAB) m/z: 233 (M+H) ⁺ .

[Reference Example 101] (1R ^* , 3S ^* , 4S ^* )-4-azido-3-hydroxycyclohexanecarboxylic acid benzyl ester

The compound obtained in Reference Example 100 (52.3g) was dissolved in N,N-dimethylformamide (1000ml), ammonium chloride (21.9g) and sodium azide (18.1g) were added, heated at 70°C, and stirred 24 hours. The solvent was distilled off under reduced pressure, water was added to the residue and extracted with ethyl acetate, 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).

¹ H-NMR (CDCl ₃ ) δ: 1.51-1.66 (2H, m), 1.91-1.98 (1H, m), 2.07-2.10 (1H, m), 2.27-2.32 (1H, m), 2.51-2.52 ( 1H, m), 2.81-2.86 (1H, m), 3.30-3.36 (1H, m), 3.70-3.75 (1H, m), 5.13 (2H, s), 7.30-7.39 (5H, m).

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

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

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.59-1.66 (2H, m), 1.88-2.00 (2H, m), 2.29-2.32 (1H, m), 2.80-2.85 (1H, m), 3.02(1H, br.s), 3.42(1H, br.s), 3.59-3.65(1H, m), 4.56(1H, br.s), 5.12(2H, q, J=12.5Hz) , 7.30-7.38 (5H, m).

MS (FAB) m/z: 350 (M+H) ⁺ .

[Reference Example 103] Methyl (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl)amino]-3-hydroxycyclohexanecarboxylate

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

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.36-2.32 (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] Methyl (1R ^* , 3R ^* , 4S ^* )-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate and (1R ^* , 3S ^* , 4S ^* )-Methyl 3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound (1.81 g) obtained in Reference Example 103 was dissolved in dichloromethane (36 ml), and triethylamine (4.6 ml) and methanesulfonyl chloride (1.63 ml) were added at -78 ° C, and the temperature was raised to 0 ° C after 30 minutes, and then Stir for 30 minutes. 1N hydrochloric acid was added, extracted with dichloromethane, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1R ^* , 3S ^* , 4S ^* )-4-[(tert-butoxycarbonyl)amino]-3-[(methylsulfonyl)oxy]cyclohexane Methyl carboxylate. The above crude compound was dissolved in N,N-dimethylformamide (23ml), sodium azide (1.29g) was added, heated at 70°C, and stirred for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:17) to obtain (1R ^* , 3S ^* , 4S ^* )-3-azido-4-[(tert Methyl butoxycarbonyl)amino]cyclohexanecarboxylate (85 mg) and (1R ^* , 3R ^* , 4S ^* )-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexane Methyl carboxylate (590 mg).

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

MS (FAB) m/z: 299 (M+H) ⁺ .

[Reference Example 105] Methyl (1R ^* , 3R ^* , 4S ^* )-3-amino-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The (1R ^* , 3R ^* , 4S ^* ) compound (230 mg) obtained in Reference Example 104 was dissolved in ethyl acetate (8 ml), a catalytic amount of 10% palladium on carbon was added, and stirred under hydrogen flow for 20 hours. Insoluble materials were 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]-3-{[(5-methyl-4,5,6,7-tetrahydrothiazole Methyl [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was prepared from the compound obtained in Reference Example 105 and the compound obtained in Reference Example 10 in the same manner as in Reference Example 91.

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

MS (FAB) m/z: 453 (M+H) ⁺ .

[Reference Example 107] (1R ^* , 3R ^* , 4S ^* )-4-[(tert-butoxycarbonyl)amino]-3-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl methyl alkane carboxylate

The title compound was prepared from the compound obtained in Reference Example 105 in the same manner as in Reference Example 91.

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

[Reference Example 108] (1S,3R,6R)-7-Oxabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester

1) Obtain (1R)-3 from (1R)-3-cyclohexene-1-carboxylic acid (J.Am.Chem.Soc, 1978, volume 100, page 5199) in the same manner as in Reference Example 99. -Benzyl cyclohexene-1-carboxylate.

2) By the same method as in Reference Example 100, the title compound was obtained from the above product.

MS (FAB) m/z: 233 (M+H) ⁺ .

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

1) In the same manner as in Reference Example 101, benzyl (1R,3S,4S)-4-azido-3-hydroxycyclohexanecarboxylate was prepared from the compound obtained in Reference Example 108.

2) Using the same method as in Reference Example 102, the title compound was prepared from the above product.

MS (FAB) m/z: 350 (M+H) ⁺ .

[Reference Example 110] Benzyl (1R,3R,4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The title compound was prepared from the compound obtained in Reference Example 109 in the same manner as in Reference Example 104.

¹ H-NMR (CDCl ₃ ) 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] Methyl (1R,3R,4S)-3-azido-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound obtained in Reference Example 110 (3.5 g) was dissolved in tetrahydrofuran (130 ml) and water (16 ml), lithium hydroxide (291 mg) was added under ice-cooling, the temperature was returned to room temperature after 10 minutes, and stirred for 20 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:20) to obtain (1R,3R,4S)-3-azido-4 - [(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid (3.34 g). Dissolve it in methanol (18ml) and toluene (64ml), add 2 moles of trimethylsilyl diazomethane hexane solution (6.1ml) under ice cooling, return the temperature to room temperature after 10 minutes, and stir for 2 hours . After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (3.35 g).

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

MS (FAB) m/z: 299 (M+H) ⁺ .

[Reference Example 112] (1R,3R,4S)-4-[(tert-butoxycarbonyl)amino]-3-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5 , Methyl 4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

1) Prepare (1R,3R,4S)-3-amino-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid methyl ester from the compound obtained in Reference Example 111 by the same method as in Reference Example 105 .

2) The title compound was prepared from the above product and the compound obtained in Reference Example 10 in the same manner as in Reference Example 106.

MS (FAB) m/z: 453 (M+H) ⁺ .

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

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

MS (ESI) m/z: 435 (M+H) ⁺ .

[Reference Example 114] Benzyl (1R,6S)-6-{[(benzyloxy)carbonyl]amino}-3-cyclohexen-1-ylcarbamate

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

¹ H-NMR (CDCl ₃ ) δ: 2.03 (2H, m), 2.53 (2H, d, J = 17.1 Hz), 3.77 (2H, m), 5.03 (2H, q, J = 12.3 Hz), 5.09 ( 2H, q, J=12.3Hz), 5.59(2H, s), 7.32(10H, m).

MS (ESI) m/z: 381 (M+H) ⁺ .

[Reference Example 115] Benzyl (1R ^* , 2S ^* )-2-{[(benzyloxy)carbonyl]amino}-5-hydroxycyclohexylcarbamate

The compound obtained in Reference Example 114 (10 g) was dissolved in anhydrous tetrahydrofuran (70 ml), borane dimethyl sulfide complex (7.4 ml) was added at 0° C., and the mixture was slowly warmed to room temperature and stirred for 14 hours. Ice was added to the reaction solution to decompose the excess borane, then 1N aqueous sodium hydroxide solution (80ml) and 30% hydrogen peroxide solution (80ml) were added, and the mixture was directly stirred for 1 hour. It was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain the title compound (9.2 g).

¹ H-NMR (CDCl ₃ ) δ: 1.98 (1H, m), 2.08 (1H, m), 2.30 (1H, m), 3.43 (2H, m), 3.73 (1H, m), 5.06 (6H, m ), 7.32(10H, s).

MS (ESI) m/z: 399 (M+H) ⁺ .

[Reference Example 116] Benzyl (1R ^* , 2S ^* )-2-{[(benzyloxy)carbonyl]amino}-5-oxocyclohexylcarbamate

Under cooling and stirring at -60°C, dimethyl sulfoxide (8.2 ml) was added to a solution of oxalyl chloride (9.9 ml) in dichloromethane (90 ml), and then the compound (9.2 g) obtained in Reference Example 115 was added in one portion. solution in tetrahydrofuran (90ml). After 1 hour, the temperature was raised to -40°C, and triethylamine (26ml) was added in one portion. After directly warming to room temperature, the mixture was stirred for 3 hours. The reaction solution 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 distilled off 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).

¹ H-NMR (CDCl ₃ ) δ: 2.27-2.43 (4H, m), 2.78 (1H, dd, J = 14.4, 3.9 Hz), 3.86 (2H, m), 5.08 (4H, m), 5.22 (2H , m), 7.32(10H, m).

MS (ESI) m/z: 397 (M+H) ⁺ .

[Reference Example 117] Benzyl (1R ^* , 2S ^* )-2-{[(benzyloxy)carbonyl]amino}-5,5-dimethoxycyclohexylcarbamate

The compound (3.89 g) obtained in Reference Example 116 was dissolved in a mixed solvent of methanol (15 ml) and tetrahydrofuran (15 ml), 2,2-dimethoxypropane (10.7 ml) and p-toluenesulfonic acid (187 mg) were added, Stir at room temperature for 3 hours. The solution was concentrated, saturated aqueous sodium bicarbonate was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off 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).

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.41 (4H, m), 1.93 (1H, m), 2.38 (1H, m), 3.19 (6H, s), 3.46 (1H, m), 3.59 (1H , m), 5.03(2H, q, J=12.5Hz), 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 (1.45 g) obtained in Reference Example 117 was dissolved in methanol (12 ml), 10% palladium on carbon (290 mg) was added, and stirred at room temperature for 20 hours in a hydrogen atmosphere. Further 10% palladium carbon (290 mg) and methanol (10 ml) were added thereto, followed by stirring for 8 hours. Filter the reaction solution with celite, concentrate the mother liquor, dissolve the residue in N,N-dimethylformamide (10ml), add 5-chloroindole-2-carboxylic acid (320mg), 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (377mg), 1-hydroxybenzotriazole monohydrate (301mg) and N-methylmorpholine (360ml), stirred at room temperature for 14 Hour. The reaction solution was poured into an 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 distilled off under reduced pressure, separated and purified by preparative silica gel thin layer chromatography (dichloromethane:methanol=93:7) to obtain N-[(1R ^* ,2S ^* )-2-amino-4,4-dimethyl Oxycyclohexyl]-5-chloroindole-2-carboxamide (or N-[(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:

¹ H-NMR (CDCl ₃ ) 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:

¹ H-NMR (CDCl ₃ ) 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]dec-8-ylcarbamate benzyl ester

The compound obtained in Reference Example 116 (4.0 g) was dissolved in anhydrous tetrahydrofuran (30 ml), ethylene glycol (5.6 ml) and p-toluenesulfonic acid (192 mg) were added, and stirred at room temperature for 17 hours. The reaction solution was poured into 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 distilled off 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).

¹ H-NMR (CDCl ₃ ) δ: 1.65-1.71 (4H, m), 2.00 (1H, m), 2.11 (1H, m), 3.49 (1H, m), 3.73 (1H, m), 3.93 (4H , s), 5.03(2H, q, J=12.2Hz), 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]dec-8-yl]-5-chloroindole-2-carboxamide and N -[(7R ^* ,8S ^* )-8-Amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-carboxamide

Using the same method as in Reference Example 118, from the compound obtained in Reference Example 119, N-[(7R ^* , 8S ^* )-7-amino-1,4-dioxaspiro[4.5]dec-8-yl] was obtained -5-chloroindole-2-carboxamide or (N-[(7R ^* ,8S ^* )-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole Indole-2-carboxamide) and N-[(7R ^* , 8S ^* )-8-amino-1,4-dioxaspiro[4.5]dec-7-yl]-5-chloroindole-2-methan Amide (or N-[(7R ^* ,8S ^* )-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide).

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

¹ H-NMR (CDCl ₃ ) δ: 1.68-1.81 (4H, m), 2.11 (2H, m), 2.87 (1H, td, J=3.9, 11.2Hz), 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]dec-7-yl]-5-chloroindole-2-carboxamide (or N-[(7R ^* ,8S ^* )-7-amino-1,4-dioxaspiro[4.5]dec-8-yl]-5-chloroindole-2-carboxamide):

¹ H-NMR (CDCl ₃ ) δ: 1.65 (2H, m), 1.88 (1H, m), 1.96 (1H, m), 2.31 (1H, dd, J=12.9, 3.2Hz), 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, 2.0 Hz), 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)-tert-butyl 6-[(tert-butoxycarbonyl)amino]-3-cyclohexen-1-ylcarbamate

Dissolve cis-4-cyclohexene-1,2-diamine hydrochloride (4.0g) in water (40ml) and acetonitrile (40ml), add di-tert-butoxycarbonate (11.8g) and triethyl Amine (12ml), stirred at room temperature for 4.5 hours. The reaction solution was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (6.12 g).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (18H, s), 1.98 (2H, dd, J=9.3, 15.9Hz), 2.48 (2H, br.d, J=15.9Hz), 3.66 (2H, br .s), 4.88(2H, br.s), 5.58(2H, d, J=2.7Hz).

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

The compound (6.1g) obtained in Reference Example 121 was dissolved in anhydrous tetrahydrofuran (40ml), and borane-dimethylsulfide complex (2.22ml) was added under ice-cooling, and the temperature was directly raised to room temperature while stirring for 16 Hour. Ice was added to the reaction solution, 1N aqueous sodium hydroxide solution and 30% hydrogen peroxide aqueous solution (50 ml) were added, and the mixture was stirred at room temperature for 2 hours. It was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2→2:1) to obtain the title compound (6.1 g).

¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.43 (9H, s), 1.83-1.67 (5H, m), 2.15 (1H, m), 2.22 (1H, s), 3.34 (1H , m), 3.78(1H, m), 4.15(1H, s), 4.98(1H, q, J=9.0Hz), 5.02(1H, q, J=9.0Hz).

MS (ESI) m/z: 331 (M+H) ⁺ .

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

Oxalyl chloride (8.2ml) and dimethylsulfoxide (6.8ml) were dissolved in dichloromethane (100ml), cooled to -60°C, and the compound obtained in Reference Example 122 (mixture of stereoisomers) (6.32g ) in tetrahydrofuran (80ml), stirred for 1 hour. The temperature was raised to -40°C, triethylamine (21 ml) was added, the temperature was raised to room temperature, and poured into water after 3 hours. It was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (3.8 g).

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

MS (ESI) m/z: 329 (M+H) ⁺ .

[Reference Example 124] (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl)amino]-5-(methoxyimino)cyclohexylcarbamate tert-butyl ester

The compound obtained in Reference Example 123 (1.5 g) was dissolved in methanol (30 ml), O-methylhydroxylamine hydrochloride (572 mg) and pyridine (737 ml) were added, and stirred at room temperature for 17 hours. After concentrating the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (1.52 g).

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

MS (ESI) m/z: 358 (M+H) ⁺ .

[Reference Example 125] (1R ^* , 2S ^* )-2-[(tert-butoxycarbonyl)amino]-5-{[tert-butyl(diphenyl)silyl]oxy}cyclohexylcarbamate tert Butyl ester (stereoisomer A)

In the same manner as in Reference Example 58, the title compound was obtained from the compound (mixture of stereoisomers) obtained in Reference Example 122. Furthermore, tert-butyl (1R ^* ,2S ^* )-2-[(tert-butoxycarbonyl)amino]-5-hydroxycyclohexylcarbamate (stereoisomer B) was recovered.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.39 (9H, s), 1.40 (9H, s), 1.72 (1H, m), 1.86 (1H, m), 2.13 (1H, m ), 3.24(2H, m), 3.65(1H, m), 4.83(1H, m), 7.37(10H, m).

[Reference Example 126] (1R ^* , 2S ^* )-2-{[(benzyloxy)carbonyl]amino}-5-hydroxy-5-methylcyclohexylcarbamate benzyl ester

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

Stereoisomer A:

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

MS (FAB) m/z: 413 (M+H) ⁺ .

Stereoisomer B:

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

MS (FAB) m/z: 413 (M+H) ⁺ .

[Reference Example 127] (3R ^* , 4S ^* )-3,4-diamino-1-methylcyclohexanol (Stereoisomer A)

10% palladium on carbon (350 mg) was suspended in a methanol solution (100 ml) of the compound (stereoisomer A) (780 mg) obtained in Reference Example 126, and stirred under a hydrogen stream for 5 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain the title compound (Stereoisomer A) (190 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 1.25-2.4g (11H, m), 2.62 (1H, br.s), 2.7g (1H, br.s).

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

In the same manner as in Reference Example 59, the title compound was obtained from the compound (stereoisomer A) obtained in Reference Example 127 and 5-chloroindole-2-carboxylic acid.

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

[Reference Example 129] (1R ^* , 2R ^* , 5S ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)cyclohexylcarbamate tert-butyl ester

1) From the (1R ^* , 3S ^* , 4S ^* ) body obtained in Reference Example 89, the (1R ^* , 3S ^* , 4S ^* )-3-[( tert-butoxycarbonyl)amino]-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylic acid ethyl ester.

¹ H-NMR (CDCl ₃ ) δ: 1.22-1.72 (6H, m), 2.15-2.28 (2H, m), 2.41-2.49 (1H, m), 2.85 (1H, brs), 3.62-3.75 (1H, m), 3.78-3.92(1H, m), 4.12-4.28(2H, m), 4.56-4.63(1H, m), 6.88(1H, brs), 7.20(1H, dd, J=8.8and 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 above product (735mg) was dissolved in dichloromethane (10ml), and a 1N hexane solution (5ml) of diisobutylaluminum hydride was added at -78°C, stirred for 3 hours, and then stirred at 0°C for 30 minutes . Add saturated aqueous ammonium chloride solution at -78°C, extract with dichloromethane, wash the organic layer with saturated aqueous sodium bicarbonate solution and saturated brine, and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=19:1) to obtain the title compound (480 mg).

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

MS (ESI) m/z: 422 (M+H) ⁺ .

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

1) Dissolve (1R ^* , 4R ^* , 5R ^* )-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (2.8g) in tetrahydrofuran (27ml) and water (3ml) Concentrated hydrochloric acid (0.1 ml) was added to the mixed solvent, and heated to reflux for 1 hour. The solvent was distilled off under reduced pressure to obtain (IR ^* , 3R ^* , 4R ^* )-3-hydroxy-4-iodocyclohexanecarboxylic acid (3.23 g) as a colorless solid.

2) The product obtained by the above reaction (3.22g) was dissolved in tetrahydrofuran (50ml), and borane-dimethylsulfide complex (2 molar solution in tetrahydrofuran, 47ml) was added under ice cooling, and stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in isopropanol (10 ml), 1N aqueous sodium hydroxide solution (12 ml) was added at room temperature, and the mixture was stirred for 12 hours. After the solvent was concentrated to about 1/5, it was diluted with water and dichloromethane, and stirred for 10 minutes. The organic layer was separated, washed successively with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain (1R ^* , 3R ^* , 6S ^* )-7-oxabis as a colorless oil Cyclo[4.1.0]hept-3-ylmethanol (1.25 g).

3) The product (4.63 g) obtained by the above reaction 2) was dissolved in tetrahydrofuran (50 ml), and potassium bis(trimethylsilyl)amide (0.5 N toluene solution, 80 ml) was added at -78°C, After stirring at the same temperature for 10 minutes, methyl iodide (2.93 ml) was added. After heating up to 0°C, stir for 1 hour, add saturated aqueous ammonium chloride solution, and dilute with diethyl ether. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (3.7 g).

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

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

The title compound was prepared from the compound obtained in Reference Example 130 in the same manner as in Reference Example 87.

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

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

The title compound was prepared from the compound obtained in Reference Example 131 in the same manner as in Reference Example 88.

¹ H-NMR (CDCl ₃ ) 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 ^* )-tert-butyl 2-azido-5-(methoxymethyl)cyclohexylcarbamate

In the same manner as in Reference Example 89, the title compound was obtained from the compound obtained in Reference Example 132 via its mesylate.

¹ H-NMR (CDCl ₃ ) 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)cyclohexylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 133 in the same manner as in Reference Example 90.

[Reference Example 135] (1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(methoxymethyl)cyclohexylcarbamate tertiary Butyl ester

In the same manner as in Reference Example 91, the title compound was obtained from the compound obtained in Reference Example 134 and 5-chloroindole-2-carboxylic acid.

¹ H-NMR (CDCl ₃ ) δ: 1.12-2.31 (16H, m), 3.14-3.30 (2H, m), 3.34 (3H, s), 3.92 (1H, br.s), 4.13 (1H, br. s), 4.88(1H, br.s), 6.82(1H, s), 7.21(1H, br.d, J=8.8Hz), 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)cyclohexylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 91 in the same manner as in Reference Example 129.

¹ H-NMR (CDCl ₃ ) δ: 0.78-2.30 (16H, m), 3.41-3.59 (3H, m), 3.86-3.95 (1H, m), 4.12-4.20 (1H, m), 4.82-4.91 ( 1H, m), 6.81 (1H, s), 7.17-7.40 (2H, m), 7.60 (1H, s), 8.03 (1H, br.s), 9.18 (1H, br.s).

MS (ESI) m/z: 422 (M+H) ⁺ .

[Reference Example 137] (1R ^* , 2S ^* , 5S ^* )-5-(azidomethyl)-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexylcarbamate tertiary Butyl ester

The title compound was prepared from the compound obtained in Reference Example 136 in the same manner as in Reference 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, stirred at room temperature for 1 hour, It was then stirred at 90°C for 2 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) and then by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the title compound (24.9 g).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.45-1.60 (1H, m), 1.80-1.90 (2H, m), 2.05-2.20 (2H, m), 2.35-2.45 (1H, m), 3.78(1H,br), 4.56(1H,br), 5.55-5.65(1H,m), 5.65-5.75(1H,m).

[Reference Example 139] (3R ^* ,4S ^* )-3,4-dihydroxycyclohexylcarbamate tert-butyl ester

The compound (1.24 g) obtained in Reference Example 138 was dissolved in a mixed solvent of acetonitrile (15 ml) and water (5 ml), and N-oxide-N-methylmorpholine (0.90 g) and microencapsulated 10% Osmium oxide (1 g), stirred at about 80°C for 1 day. After filtering off insoluble matter, 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).

¹ H-NMR (CDCl ₃ ) δ: 1.15-1.30 (1/2H, m), 1.35-2.00 (15H, m), 2.15-2.30 (3/2H, m), 2.40-2.60 (1H, m), 3.64(1H, br), 3.75-3.90(3/2H, m), 4.00(1/2H, br).

MS (FAB) m/z: 232 (M+H) ⁺ .

[Reference Example 140] (3R ^* , 4S ^* )-tert-butyl 3,4-diazidocyclohexylcarbamate (Stereoisomer A and Stereoisomer B)

Using the same method as in Reference Example 80, the title compound (stereoisomer A and stereoisomer B) was prepared from the compound obtained in Reference Example 139.

Stereoisomer A:

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.40-1.55 (1H, m), 1.55-1.80 (3H, m), 1.95-2.15 (2H, m), 3.53 (1H, m) , 3.59(1H, br), 3.80(1H, m), 4.70(1H, br).

Stereoisomer B:

¹ H-NMR (CDCl ₃ ) δ: 1.27 (1H, m), 1.44 (9H, s), 1.40-1.55 (1H, m), 1.80-2.00 (2H, m), 2.00-2.15 (1H, m) , 2.21(1H, m), 3.48(1H, m), 3.77(1H, br), 3.89(1H, br), 4.34(1H, br).

[Reference Example 141] (1R, 3R, 4S)-4-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester

The compound (3.10 g) obtained in Reference Example 96 was dissolved in tetrahydrofuran (50 ml), and saturated aqueous sodium bicarbonate solution (50 ml) was added. Benzyloxycarbonyl chloride (1.71 ml) was added dropwise to the reaction solution under ice-cooling, followed by stirring at room temperature for 4 days. Ethyl acetate (200 ml) and water (200 ml) were added to the reaction liquid to conduct a liquid separation operation. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration to obtain the title compound (3.24 g).

¹ H-NMR (CDCl ₃ ) 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 obtained in Reference Example 141 (620 mg) was dissolved in tetrahydrofuran (20 ml), and an aqueous solution (10 ml) of lithium hydroxide monohydrate (93 mg) was added, followed by stirring at room temperature for 16 hours. Lithium hydroxide monohydrate (217 mg) was added to the reaction liquid, and after stirring at room temperature for 2 hours, 1N hydrochloric acid aqueous solution was added to neutralize, and it 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).

¹ H-NMR (CDCl ₃ ) δ: 1.22-2.20 (6H, m), 1.44 (9H, s), 2.45 (1H, br.s), 3.60-3.80 (1H, br), 4.09 (1H, br. s), 4.66(1H, br.s), 5.00-5.20(2H, m), 5.26(1H, br.s), 7.20-7.40(5H, m).

MS (ESI) m/z: 393 (M+H) ⁺ .

[Reference Example 143] Benzyl (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexylcarbamate

After suspending the compound (600 mg) obtained in Reference Example 142 and dimethylamine hydrochloride (240 mg) in dichloromethane (50 ml), an appropriate amount of tetrahydrofuran was added to form a solution. To this solution were added triethylamine (0.41 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (422 mg) and 1-hydroxybenzotriazole 1 hydrate (338 mg) was stirred at room temperature for 1 hour. Dimethylamine hydrochloride (480 mg) and triethylamine (0.82 ml) were additionally added to the reaction solution, followed by further stirring at room temperature for 18 hours. The reaction solution 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 distilled off 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).

¹ H-NMR (CDCl ₃ ) δ: 1.20-1.50 (2H, m), 1.44 (9H, s), 1.50-2.10 (4H, m), 2.60 (1H, br.t, J=11.6Hz), 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]cyclohexylcarbamate tert-butyl ester

10% palladium carbon (57 g) was added to a solution of the compound (190 g) obtained in Reference Example 143 in methanol (8000 ml), and the mixture was stirred under 7 atmospheres of hydrogen for 3 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. After adding toluene to the residue and concentrating under reduced pressure, the residue was solidified by adding hexane (2500 ml), collected by filtration, and dried to obtain the title compound (121 g).

¹ H-NMR (CDCl ₃ ) δ: 1.20-1.77 (6H, m), 1.45 (9H, s), 2.20-2.35 (1H, br), 2.63-2.74 (1H, m), 2.92 (3H, s) , 3.02(3H, s), 3.02-3.11(2H, m), 3.74-3.82(1H, m), 4.88-5.00(1H, br) MS(ESI) m/z: 286(M+H) ⁺ .

[Reference Example 145] (1R, 2S, 5S)-tert-butyl 2-{[(6-chloroquinolin-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 54 in the same manner as in Reference Example 91.

¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, br), 1.50-1.70 (1H, m), 1.75-1.95 (2H, m), 1.95-2.25 (3H, m), 2.65-2.80 (1H, m), 2.96(3H, s), 3.07(3H, s), 4.15-4.30(1H, m), 4.30-4.40(1H, m), 4.95(1H, br), 7.66(1H, d, J= 8.8Hz), 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)-tert-butyl 2-{[(7-chloroquinolin-3-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 57 in the same manner as in Reference Example 91.

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.65 (10H, br), 1.75-1.90 (2H, m), 1.90-2.25 (3H, m), 2.65-2.90 (1H, br), 2.96 (3H, s), 3.08(3H, s), 4.20-4.30(1H, m), 4.30-4.40(1H, m), 4.93(1H, br), 7.68(1H, m), 7.90(1H, br), 7.99 (1H, s), 8.35-8.70 (2H, m), 9.01 (1H, br).

MS (FAB) m/z: 475 (M+H) ⁺ .

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

The title compound was prepared from the compound obtained in Reference Example 8 in the same manner as in Reference Example 9.

¹ H-NMR (CDCl ₃ ) 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 salt of 5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 147 in the same manner as in Reference Example 10.

¹ H-NMR (DMSO-d ₆ ) 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] 4-nitrophenyl 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate

In the same manner as in Reference Example 52, the title compound was prepared from the compound obtained in Reference Example 10 and p-nitrophenol.

¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H, s), 2.88 (2H, t, J=5.7Hz), 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

Add triethylamine (2.0 ml) and benzyl to a solution of 3-oxocyclobutanecarboxylic acid (J.Org.Chem., volume 53, pages 3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml) Bromide (1.2ml), stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain the title compound (886 mg).

¹ H-NMR (CDCl ₃ ) δ: 3.22-3.33 (3H, m), 3.37-3.48 (2H, m), 5.19 (2H, s), 7.31-7.42 (5H, m).MS (FAB) m/ z: 205(M+H ⁺ ).

[Reference Example 151] Benzyl 3-hydroxycyclobutanecarboxylate

Sodium borohydride (76 mg) was added to a mixed solution of the compound obtained in Reference Example 150 (781 mg) in tetrahydrofuran (10 ml) and methanol (0.5 ml) at 0°C, followed by stirring at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain the title compound (770 mg).

¹ H-NMR (CDCl ₃ ) δ: 2.13-2.27 (3H, m), 2.55-2.71 (3H, m), 4.14-4.23 (1H, m), 5.12 (2H, s), 7.28-7.39 (5H, m).

MS (FAB) m/z: 207 (M+H ⁺ ).

[Reference Example 152] 3-Hydroxycyclobutanecarboxylic acid

10% palladium on carbon (108 mg) was added to a solution of the compound (706 mg) obtained in Reference Example 151 in ethanol (10 ml), followed by stirring at room temperature in a hydrogen atmosphere for 2 hours. After filtering the catalyst through celite, the filtrate was concentrated under reduced pressure to obtain the title compound (399 mg).

¹ H-NMR (CD ₃ OD) δ: 2.00-2.21 (2H, m), 2.41-2.61 (3H, m), 4.01-4.13 (1H, m).

[Reference Example 153] Benzyl 3-methoxycyclobutanecarboxylate

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

¹ H-NMR (CDCl ₃ ) δ: 2.14-2.24 (2H, m), 2.44-2.54 (2H, m), 2.59-2.72 (1H, m), 3.21 (3H, s), 3.73-3.81 (1H, m), 5.11(2H, s), 7.22-7.39(5H, m).

MS (ESI) m/z: 221 (M+H ⁺ ).

[Reference Example 154] 3-Methoxycyclobutanecarboxylic acid

The title compound was prepared from the compound obtained in Reference Example 153 in the same manner as in Reference Example 152.

¹ H-NMR (CDCl ₃ ) δ: 2.17-2.27 (2H, m), 2.48-2.58 (2H, m), 2.62-2.73 (1H, m), 3.25 (3H, s), 3.76-3.86 (1H, m), 8.60-9.30 (1H, br).

[Reference Example 155] Methyl 3-methoxy-2-(methoxymethyl)propionate

Sodium methoxide (1.21 g) was added to a solution of methyl 2-(bromomethyl)acrylate (1.0 ml) in methanol (10 ml), followed by heating under reflux for 26 hours. After the reaction solution was cooled, it was diluted with ether, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (726 mg).

₁ H-NMR (CDCl ₃ ) δ: 2.90-2.96 (1H, m), 3.34 (6H, s), 3.57 (2H, dd, J=9.3, 5.9Hz), 3.64 (2H, dd, J=9.3, 6.6Hz), 3.73(3H, s).

¹³ C-NMR (CDCl ₃ ) δ: 172.71, 70.31, 59.91, 46.49.

MS (ESI) m/z: 163 (M+H ⁺ ).

[reference example 1561 tetrahydro-2H-pyran-4-carboxylic acid

20% hydrochloric acid (20 ml) was added to dimethyl tetrahydro-4H-pyran-4,4-dicarboxylate (4.04 g), and the mixture was heated under reflux for 19 hours. Water was added to the reaction solution and extracted with ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After the obtained residue was solidified with hexane, the obtained solid was collected by filtration and washed to obtain the title compound (2.63 g).

¹ H-NMR (CDCl ₃ ) δ: 1.75-1.95 (4H, m), 2.55-2.65 (1H, m), 3.40-3.52 (2H, m), 3.93-4.05 (2H, m).

[Reference Example 157] Methyl 3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethylpropionate

In the same manner as in Reference Example 41, the title compound was obtained from methyl 2,2-dimethyl-3-hydroxypropionate.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (9H, s), 1.20 (6H, s), 3.64-3.68 (5H, m), 7.38-7.44 (6H, m), 7.63-7.65 (4H, m) .

[Reference Example 158] 3-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethylpropanoic acid

Under ice-cooling, water (0.24 ml) was added to a suspension of potassium tert-butoxide (5.32 g) and diethyl ether (100 ml), and the mixture was stirred for 5 minutes. The compound (2.22 g) obtained in Reference Example 157 was added thereto, and stirred overnight at room temperature. Water was added to the reaction solution, the solution was made acidic with 1N aqueous hydrochloric acid, and extracted three times with ether. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6) to obtain the title compound (735 mg).

¹ H-NMR (CDCl ₃ ) 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

Under ice cooling, 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (25.0 g) in tetrahydrofuran was added dropwise to a suspension formed by 60% sodium hydride (8.32 g) and tetrahydrofuran (100 ml) suspended in oil (300ml) solution and stirred at 60°C for 1 hour. Methyl iodide (53.7 g) was added to the reaction liquid, followed by further stirring at room temperature for 2 hours. Water was carefully added, extracted twice with dichloromethane, 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: 140～142°C (atmospheric pressure)

¹ H-NMR (CDCl ₃ ) 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 compound obtained in Reference Example 159 was treated in the same manner as in Reference Example 158 to obtain the title compound.

¹ H-NMR (CDC ₁ 3) 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 (25 g) was dissolved in methanol (250 ml), and cooled with ice. Then, 1N aqueous sodium hydroxide solution (158 ml) was added dropwise, the temperature was returned to room temperature, and the mixture was stirred overnight. After evaporating methanol, wash with chloroform, cool the aqueous layer with ice, adjust the pH to 2 with concentrated hydrochloric acid aqueous solution, extract with ethyl acetate, then dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain the title compound (16.8g).

¹ H-NMR (CDCl ₃ ) δ: 1.76-1.80 (2H, m), 1.82-1.88 (2H, m), 3.79 (3H, s), 12.73 (1H, br).

[Reference Example 162] Methyl 1-(hydroxymethyl)cyclopropanecarboxylate

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

¹ H-NMR (CDCl ₃ ) δ: 0.87-0.93 (2H, m), 1.28-1.30 (2H, m), 3.63 (2H, s), 3.70 (3H, s).

[Reference Example 163] Methyl 1-(bromomethyl)cyclopropanecarboxylate

In a nitrogen atmosphere, at room temperature, triphenylphosphine (10 g) and carbon tetrabromide (16 g) were added to a dichloromethane solution (168 ml) of the compound (4.20 g) obtained in Reference Example 162, and after 2 minutes, saturated Aqueous sodium bicarbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain the title compound (2.15 g).

¹ H-NMR (CDC] ₃ ) δ: 1.00-1.05 (2H, m), 1.52-1.59 (2H, m), 3.61 (2H, s), 3.73 (3H, s).

[Reference Example 164] (4S)-4-[(E)-3-Ethoxy-3-oxo-1-propenyl]-2,2-Dimethyl-1,3-oxazolidine-3 - tert-butyl carboxylate

(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylic acid tert-butyl ester (11.7g), (ethoxycarbonylmethylene)tri A mixed solution of phenylphosphorane (20.7 g) and toluene (100 ml) was heated and stirred for 18 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (17 g).

¹ H-NMR (CDCl ₃ ) 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), 4.30-4.6l (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- tert-Butyl 3-carboxylate

A mixed solution of the compound obtained in Reference Example 164 (22.2 g), benzylamine (16 g) and ethanol (100 ml) was heated under reflux for 2 days. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (26 g).

¹ H-NMR (CDCl ₃ ) 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 carbon (10 g) was added to a solution of the compound obtained in Reference Example 165 (13.6 g) in ethanol (200 ml), and stirred under a hydrogen atmosphere for 2 days. It was filtered through a pad of celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure to obtain the title compound (10.5 g).

¹ H-NMR (DMSO-d ₆ ) 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, tert-butyl 3-oxazolidine-3-carboxylate

The compound (3.0 g) obtained in Reference Example 166 was suspended in 9% aqueous sodium bicarbonate (56 ml), and N-(benzyloxycarbonyloxy)succinimide (2.3 g) in dioxane ( 12 ml) solution, and stirred for 3 hours while slowly returning the temperature to room temperature. The reaction solution 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 resulting residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (3.8 g).

¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J=6.6Hz), 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-hydroxyvaleric acid ethyl ester (low polar compound ) and ethyl (3R,4S)-3-{[(benzyloxy)carbonyl]amino}-4-[(tert-butoxycarbonyl)amino]-5-hydroxyvalerate (highly polar compound)

High Polarity Compounds Low Polarity Compounds High Polarity Compounds

Under ice-cooling, trifluoroacetic acid (100 ml) was added dropwise to a dichloromethane (100 ml) solution of the compound (30 g) obtained in Reference Example 167, and stirred for 3 hours while gradually returning to room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (100 ml). Under ice-cooling, a solution of triethylamine (20 ml) and di-tert-butyl dicarbonate (19 g) in dichloromethane (100 ml) was added dropwise to the solution, 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 (7.6 g) and the title high polar compound (10 g).

Low polar compounds:

¹ H-NMR (CDCl ₃ ) 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:

¹ H-NMR (CDCl ₃ ) 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] (3R,4S)-4-[(methylsulfonyl)oxy]tetrahydro-3-furyl methanesulfonate

Under ice cooling, triethylamine (12.0 ml) and methanesulfonyl chloride (3.6 ml) were successively added dropwise to a solution of 1,4-anhydroerythritol (5.0 g) in dichloromethane (50 ml), and stirred for 10 minutes under ice cooling. The reaction solution was diluted with dichloromethane, washed with 10% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate 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 (9.2 g).

¹ H-NMR (CDCl ₃ ) 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 obtained in Reference Example 169 (9.2 g) was dissolved in N,N-dimethylformamide (50 ml), sodium azide (18 g) was added, and the mixture was heated and stirred at 100° C. for 18 hours. The reaction solution 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).

¹ H-NMR (CDCl ₃ ) 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 obtained in Reference Example 170 (3.8 g) was dissolved in ethanol (50 ml), 10% palladium on carbon (1.0 g) was added, and stirred under a hydrogen atmosphere for 18 hours. The insoluble matter was filtered off through a pad of celite, and the filtrate was concentrated under reduced pressure. 1N hydrochloric acid ethanol solution was added to the obtained residue to form hydrochloride, and then recrystallized from a mixed solvent of ethanol and diethyl ether to obtain the title compound (2.0 g).

¹ H-NMR (CDCl ₃ ) δ: 3.90 (2H, dd, J=9.0, 3.7Hz), 4.01-4.13 (4H, m), 8.84 (6H, s).

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

At room temperature, 5-chloroindole-2-carboxylic acid (0.29 g), 1-hydroxybenzene Triazole (0.2g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6g) were heated and stirred at 50°C for 1 day. The reaction solution was concentrated, and the resulting residue was diluted with a mixed solvent of chloroform:methanol (9:1), and washed with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound (0.2 g).

¹ H-NMR (CDCl ₃ ) δ: 1.80-1.92 (1H, m), 3.62 (1H, dd, J = 9.3, 4.2 Hz), 3.68-3.80 (2H, m), 4.06 (1H, dd, J = 9.3, 5.6Hz), 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 - tert-butyl carboxylate

The title compound was obtained from (4S)-tert-butyl 4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate in the same manner as in Reference Example 164.

¹ H-NMR (CDCl ₃ ) 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- tert-Butyl 3-carboxylate

The title compound was prepared from the compound obtained in Reference Example 173 in the same manner as in Reference Example 165.

¹ H-NMR (CDCl ₃ ) 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 catalytic reduction of the compound obtained in Reference Example 174 in the same manner as in Reference Example 166 to remove the benzyl group, and condensation with 5-chloroindole-2-carboxylic acid in the same manner as in Reference Example 172.

¹ H-NMR (CDCl ₃ ) 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-ylcarbamate tert-butyl Esters (low polar compounds) and (3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-6-oxotetrahydro-2H-pyran-3-ylamino tert-butyl formate (highly polar compound)

High Polarity Compounds Low Polarity Compounds High Polarity Compounds

To a solution of the compound (1.0 g) obtained in Reference Example 175 in ethanol (20 ml) was added 1N aqueous sodium hydroxide solution (4.0 ml), followed by stirring 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 distilled off under reduced pressure. The resulting residue was dissolved in methanol (50 ml), tosylate monohydrate (0.1 g) was added and stirred for 18 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain the title low polar compound (0.3 g) and high polar compound (0.3g).

Low polar compounds:

¹ H-NMR (CDCl ₃ ) 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:

¹ H-NMR (CDCl ₃ ) 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 solution of N-tert-butoxycarbonyl-L-methionine sulfomethyl ester (60.2g) in tetrahydrofuran (900ml) was cooled to -78°C, and 0.5M bis(trimethylsilyl)amine was added dropwise Potassium (toluene solution, 900ml), stirred at -78°C for 2 hours, and at room temperature for 4 and a half hours. 1M aqueous ammonium chloride solution was added and stirred. After the reaction liquid 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 previously separated aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Then, the aqueous layers used for washing were combined, extracted again with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The ethyl acetate extracts were combined, dried and concentrated under reduced pressure to obtain the title compound (27.7 g) (total amount of the title compound: 40.1 g).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.85-1.96 (1H, m), 2.76-2.78 (1H, m), 3.34-3.46 (2H, m), 4.05 (1H, dd, J=13.5, 3.7Hz), 4.14(1H, d, J=13.5Hz), 4.38-4.44(1H, m), 5.46(1H, br).

MS(ESI)m/z: 262(MH) ^- .

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

Sodium borohydride (2.17 g) was added to a suspension of the compound (10.1 g) obtained in Reference Example 177 in methanol (200 ml), followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the residue, and after separation, the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (9.96 g).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.21-2.36 (2H, m), 3.03-3.17 (2H, m), 3.26-3.28 (2H, m), 3.77-3.80 (2H, m), 4.26-4.28 (1H, m), 5.05-5.07 (1H, m)

MS(ESI)m/z: 264[(MH) ^- ].

[Reference Example 179] (3R ^* , 4R ^* )-3-amino-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate tert-butyl ester (low polar compound) and (3R ^* ,4S ^* )-tert-butyl 3-amino-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate (highly polar compound)

High Polarity Compounds Low Polarity Compounds High Polarity Compounds

(racemate) (racemate)

Diethyl azodicarboxylate (6.96 g) was added to a solution of the compound obtained in Reference Example 178 (9.66 g) and triphenylphosphine (10.5 g) in tetrahydrofuran (150 ml), followed by stirring at room temperature for 4.5 hours. After the reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the resulting solid was collected by filtration. The filtered solid was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain 1,1-dioxo-1,2,3,4-tetrahydrothiopyran containing A mixture of tert-butyl-4-ylcarbamate (7.25 g). Then, the mother liquor was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain 1,1-dioxo-1,2,3, A mixture of tert-butyl 4-tetrahydrothiopyran-4-ylcarbamate (9.18 g) (total amount: 16.4 g). The resulting mixture was dissolved in dioxane (60ml), added with 28% ammonia water (60ml), and stirred at 60°C for 4.5 hours in a sealed tube. After natural cooling, the reaction solution was concentrated under reduced pressure. After evaporating dioxane, it was extracted 5 times with dichloromethane. The organic layers were combined and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (dichloromethane:methanol=96:4) to obtain the title low polar compound (2.31 g) and high polar compound (4.31 g).

Low polar compounds:

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.14-2.28 (2H, m), 3.01-3.08 (3H, m), 3.23 (1H, dd, J=13.8, 3.9Hz), 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:

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.94-2.01 (1H, m), 2.37-2.44 (1H, m), 2.91 (1H, dd, J=11.2, 14.1Hz), 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(methoxymethoxy)-1,4-butanediol

Under ice-cooling, in the mixed solution that L-diethyl tartrate (8.6g) and diisopropylethylamine (40ml) and methylene chloride (40ml) forms dropwise into chloromethyl methyl ether (4.8ml), slowly Stir for 18 hours while warming to room temperature. The reaction solution was concentrated, and the resulting residue was diluted with ethyl acetate, and washed with 10% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in tetrahydrofuran. Under ice-cooling, the above solution was added dropwise to a suspension of lithium aluminum hydride (2.2 g) in tetrahydrofuran, and the mixture was stirred under ice-cooling for 2 hours. Under ice-cooling, 10% aqueous sodium bisulfate solution was carefully added, stirred for 1 hour, diluted with saturated brine, and ethyl acetate was extracted. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (3.0 g).

¹ H-NMR (CDCl ₃ ) δ: 1.55-1.64 (2H, m), 3.44 (6H, s), 3.70-3.81 (6H, m), 4.70 (2H, d, J=6.9Hz), 4.76 (2H , d, J=6.9Hz).

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

Diethyl azodicarboxylate (2.64ml) was added dropwise to a mixed solution formed of the compound (3.0g) obtained in Reference Example 180, triphenylphosphine (4.5g), tetrahydrofuran (10ml) and toluene (40ml), and Stirred for 4 days. The reaction solution was concentrated, and a mixed solvent (160 ml) of hexane:ether (1:1) was added to the obtained residue, and the precipitated insoluble matter was filtered off after stirring for 3 hours. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (1.95 g).

¹ H-NMR (CDCl ₃ ) δ: 3.38 (6H, s), 3.80 (2H, dd, J=9.2, 1.7Hz), 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 (2.1 ml) was added to a methanol (6.0 ml) solution of the compound (1.95 g) obtained in Reference Example 181, followed by stirring for 18 hours. The reaction solution was concentrated, and the resulting residue was diluted with chloroform, dried over potassium carbonate, and the solvent was distilled off under reduced pressure to obtain the title compound (0.52 g).

¹ H-NMR (CDCl ₃ ) 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

From the compound obtained in Reference Example 182, the title compound was obtained by the same method as described in Reference Examples 169 to 171.

¹ H-NMR (CDCl ₃ ) δ: 1.35-1.46 (4H, m), 3.19 (2H, dd, J = 5.6, 4.1 Hz), 3.50 (2H, dd, J = 9.0, 4.1 Hz), 4.09 (2H , dd, J=9.0, 5.6Hz).

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

In the same manner as in Reference Example 180, the title compound was obtained from D-diethyltartrate.

¹ H-NMR: Consistent with Reference Example 180 as the enantiomer.

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

The title compound was obtained from the compound obtained in Reference Example 184 in the same manner as in Reference Example 181.

¹ H-NMR: Consistent with Reference Example 181 as the enantiomer.

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

The title compound was prepared from the compound obtained in Reference Example 185 in the same manner as in Reference Example 182.

¹ H-NMR: Consistent with Reference Example 182 as the enantiomer.

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

The title compound was obtained from the compound obtained in Reference Example 186 in the same manner as in Reference Example 183.

¹ H-NMR: Consistent with Reference Example 183 as the enantiomer.

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

Add L-tartaric acid (30 g) and benzylamine (22 ml) into xylene (150 ml), and heat to reflux at 150° C. for 3 hours with a Dean-Stark dehydrator. After the reaction solution was naturally cooled overnight, the crystals were collected by filtration and washed with acetone. The resulting crude was recrystallized from ethanol to obtain the title compound (23.2 g).

¹ H-NMR (DMSO-d ₆ ) δ: 4.36-4.40 (2H, m), 4.55 (each 1H, AB type d, J=15Hz), 6.26-6.30 (2H, m), 7.25-7.35 (5H , m).

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

Under ice-cooling, the compound obtained in Reference Example 188 (11 g) was dissolved in tetrahydrofuran (110 ml), and lithium aluminum hydride (5.69 g) was added a little at a time. After raising the temperature to room temperature, it was heated to reflux for 1 hour, and then continued to be heated to reflux overnight. After natural cooling, it was cooled with ice, and water (5.7ml), 15% aqueous sodium hydroxide solution (5.7ml) and water (17.1ml) were added in sequence, and the temperature was returned to room temperature and stirred for 1 hour. The precipitate was filtered through celite, and the mother liquor was concentrated, followed by recrystallization from ethyl acetate to obtain the title compound (6.35 g).

¹ H-NMR (CDCl ₃ ) δ: 2.40-2.44 (2H, m), 2.88-2.92 (2H, m), 3.58 (each 1H, AB type d, J=7.8Hz), 4.04 (2H, t, J=4.2Hz), 7.25-7.34(5H, m).

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

The title compound was prepared from the compound obtained in Reference Example 189 in the same manner as in Reference Example 169.

¹ H-NMR (CDCl ₃ ) 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 obtained in Reference Example 190 (1.57 g) was dissolved in 1,2-dichloroethane (16 ml), 1-chloroethyl chloroformate (0.73 ml) was added at room temperature, and the mixture was heated under reflux for 4 hours. After distilling off the solvent under reduced pressure, methanol (16 ml) was added to the obtained residue, heated to reflux for 1 hour, cooled naturally, concentrated, and the crystals were collected by filtration with ethyl acetate to obtain (3S, 4S)-3 as colorless crystals. 4-Bis[(methylsulfonyl)oxy]pyrrolidine hydrochloride (1.30 g). Di-tert-butyl dicarbonate (1.15 ml) was added to a solution of the obtained hydrochloride and triethylamine (1.40 ml) in dichloromethane (26 ml), followed by stirring at room temperature overnight. After concentration, it was diluted with ethyl acetate, 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 silica gel column chromatography (ethyl acetate:hexane=1:9 to 1:1) to obtain the title compound (1.40 g).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.12 (6H, s), 3.70-3.73 (2H, m), 3.79 (1H, d, J=4.5Hz), 3.82 (1H, d , J=4.5Hz), 5.19(2H,br).

[Reference Example 192] (3R,4R)-3,4-diazido-1-pyrrolidinecarboxylate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 191 in the same manner as in Reference Example 170.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 3.37-3.46 (2H, m), 3.64-3.71 (2H, m), 3.96 (2H, t, J=3.2Hz).

[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 prepared from the compound obtained in Reference Example 192 by the same method as described in Reference Examples 171 and 172.

¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 2.95-3.00 (1H, m), 3.09-3.13 (1H, m), 3.52 (1H, dd, J=10, 6.5Hz) , 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)-tert-butyl 5-oxotetrahydro-3-furylcarbamate

To (3S)-(-)-tetrahydro-5-oxo-3-furylcarbamate benzyl ester (3.3g) in tetrahydrofuran (20ml) was added di-tert-butyl dicarbonate (4.1g) and 10% Palladium carbon (0.4 g), stirred in a hydrogen atmosphere for 1 day. The insoluble matter was filtered off through a Celite pad, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (1.5 g).

¹ H-NMR (CDCl ₃ ) 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)-tert-butyl 4-azido-5-oxotetrahydro-3-furylcarbamate

To a tetrahydrofuran (20 ml) solution of the compound (0.87 g) obtained in Reference Example 194 was added dropwise at -78°C 1M potassium bis(trimethylsilyl)amide (tetrahydrofuran solution, 8.65 ml), and stirred for 30 minutes. Then, a tetrahydrofuran (10 ml) solution of p-toluenesulfonyl azide (1.02 g) was added, and after stirring for 5 minutes, trimethylchlorosilane (1.7 ml) was added, and the mixture was stirred for 2 hours while gradually returning the temperature to room temperature. The reaction solution was diluted with ether, washed with 10% aqueous hydrochloric acid, 5% saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (0.62 g).

¹ H-NMR (CDCl ₃ ) 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)-tert-butyl 4-{[(5-chloroindol-2-yl)carbonyl]amino}-5-oxotetrahydro-3-furylcarbamate

The title compound was prepared from the compound of Reference Example 195 by the same method as described in Reference Examples 90 and 91.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 4.01-4.13 (1H, m), 4.20-4.36 (1H, m), 4.78-4.93 (2H, m), 6.15 (1H, s) , 6.93(1H, s), 7.03-7.11(1H, m), 7.20-7.28(1H, m), 7.30(1H, d, J=8.8Hz), 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-furylcarbamate tert-butyl ester

Similar to Reference Example 90, after preparing (3S,4S)-4-amino-5-oxotetrahydro-3-furylcarbamate tert-butyl ester from the compound obtained in Reference Example 195, according to the reaction conditions of Reference Example 91, The title compound was prepared by reacting the compound obtained in Reference Example 10.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.52 (3H, s), 2.83 (2H, t, J=5.9Hz), 2.79-3.02 (2H, m), 3.74 (2H, s ), 4.03-4.12(1H, m), 4.21-4.36(1H, m), 4.80-4.95(2H, m), 6.14-6.24(1H, m), 7.76-7.85(1H, m).

[Reference Example 198] 2-[((3S)-3-[(tert-butoxycarbonyl)amino]-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-hydroxybutyl Acyl) amino] ethyl acetate

The compound obtained in Reference Example 196 (0.4 g), glycine ethyl ester hydrochloride (1.0 g) and triethylamine (1.0 ml) were added to ethanol (20 ml), and heated under reflux at 60°C for 18 hours. The reaction solution was diluted with chloroform, washed with 10% citric acid aqueous solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to obtain the title compound (0.31 g).

¹ H-NMR (DMSO-d ₆ ) 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(0.4 H, 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

Using the reaction conditions described in Reference Example 181, the compound obtained in Reference Example 198 was converted into a pyrrolidone derivative, followed by removal of the t-butoxycarbonyl group in the same manner as in Reference Example 69 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (2H, t, J = 7.0Hz), 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)-tert-butyl 4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-5-oxopyrrolidin-3-ylcarbamate ester

The compound obtained by reacting the compound obtained in Reference Example 196 with methylamine (40% methanol solution) was treated under the same conditions as in Reference Example 181 as in Reference Example 198 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.90 (3H, s), 4.26 (1H, br.s), 4.36 (2H, m), 4.51-4.52 (1H, m), 5.35 (1H, br.s), 6.95-6.99 (2H, m), 7.22-7.32 (3H, m), 7.63 (1H, s), 8.95 (1H, br.s)

[Reference Example 201] N-[(3S,4R)-4-amino-1-methyl-2-oxopyrrolidin-3-yl]-5-chloroindole-2-carboxamide

The compound obtained in Reference Example 200 was treated in the same manner as in Reference Example 69 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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

Di-tert-butyl dicarbonate (6.55 g) was added to a mixture of 1,2,3,6-tetrahydropyridine (2.50 g) and 10% aqueous sodium carbonate solution (3.0 ml), followed by stirring at room temperature for 20 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed successively with 0.5N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (5.08 g).

¹ H-NMR (CDCl ₃ ) 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-piperidinecarboxylate tert-butyl ester

The compound (18.45g) obtained in Reference Example 202 was dissolved in acetonitrile (200ml), water (38ml), 0.039 mole osmium tetroxide aqueous solution (82ml), N-oxide-N-methylmorpholine (23.13g) were added, and room temperature Stirring was continued for 17 hours. Excess oxidant was treated with saturated aqueous sodium sulfite and extracted with ethyl acetate. The organic layer was washed successively with water, 0.5N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain the title compound (15.0 g).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.60-1.73 (1H, m), 1.77-1.90 (1H, m), 2.68 (1H, br.s), 2.80-3.20 (1H, br), 3.22-3.32(1H, m), 3.42(1H, dd, J=14.3, 3.4Hz), 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-piperidinecarboxylate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 203 in the same manner as Reference 169.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.85-1.97 (1H, m), 2.08-2.20 (1H, m), 3.00-4.20 (4H, m), 3.12 (6H, s) , 4.85(1H, br.s), 4.94(1H, br.s).

[Reference Example 205] (3R ^* ,4S ^* )-3,4-diazido-1-piperidinecarboxylate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 204 in the same manner as in Reference Example 170.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.70-1.80 (1H, m), 1.90-2.00 (1H, m), 3.05-4.00 (6H, m).

[Reference Example 206] (3R ^* ,4S ^* )-3,4-diamino-1-piperidinecarboxylate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 205 in the same manner as in Reference Example 171.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.48-1.60 (2H, m), 1.80-2.10 (4H, br), 2.85-2.91 (2H, m), 2.97 (1H, br. s), 3.09 (1H, dd, J=13.6, 2.7Hz), 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 Reference Example 206 was dissolved in N,N-dimethylformamide (100ml), triethylamine (2.08ml) and the compound (3.80g) obtained in Reference Example 52 were added, and stirred at room temperature for 3 sky. The reaction solution was concentrated under reduced pressure, water was added to the residue and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 10:1) to obtain the title compound (2.70 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.58 (3H, m), 1.41 (9H, s), 1.75-1.90 (1H, m), 2.95 (1H, br.s), 2.98-3.05 ( 1H, m), 3.19-3.28 (1H, m), 3.74 (1H, dd, J=19.5, 15.4Hz), 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]pyridine-2- Base)carbonyl]amino}-1-piperidinecarboxylate tert-butyl

The compound (3.23 g) obtained in Reference Example 206 was dissolved in N,N-dimethylformamide (100 ml), and triethylamine (2.08 ml) was added. Then, the compound (3.83 g) obtained in Reference Example 149 was added, followed by stirring at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water was added to the residue and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol=10:1 to 5:1) to obtain the title compound (2.27 g).

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.62 (3H, m), 1.47 (9H, s), 1.78-1.88 (1H, m), 2.51 (3H, s), 2.81 (2H, t, J= 5.9Hz), 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 prepared from the compound obtained in Reference Example 206 and 5-fluoroindole-2-carboxylic acid in the same manner as in Reference Example 172.

¹ H-NMR (CDCl ₃ ) δ: 1.40-1.70 (3H, m), 1.48 (9H, s), 2.79-2.92 (1H, m), 2.99-3.14 (1H, m), 4.00-4.23 (3H, m), 6.85(1H, s), 7.04(1H, td, J=9.0, 2.4Hz), 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

Under ice-cooling, triethylamine (4.80 ml) and methanesulfonyl chloride ( 1.55mml), stirred under ice cooling for 30 minutes. The reaction solution was diluted with chloroform, washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain methanesulfonyl (9.20 g). A mixed solution of the obtained methanesulfonyl product, sodium azide (5.64 g) and N,N-dimethylformamide (100 ml) was stirred at 80°C for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine. After 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 (chloroform) to obtain the title compound (5.42 g).

¹ H-NMR (CDCl ₃ ) 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] Benzyl (4S,5R)-5-[(tert-butoxycarbonyl)amino]-2-oxopiperidin-4-ylcarbamate

Add Lindella catalyst (2.71g) to the ethanol (150ml) of the compound (5.42g) that reference example 210 obtains, tetrahydrofuran (10.0ml) mixed solution, after stirring 3 hours in hydrogen atmosphere, stir 14 hours under nitrogen condition. Hour. Insoluble matter was filtered off through a celite pad, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (30 ml), triethylamine (3.0 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=25:1) to obtain the title compound (2.50 g).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 2.30-2.50 (1H, br), 2.65-2.90 (1H, br), 3.15-3.30 (1H, br), 3.35-3.65 (1H, br), 4.00-4.25 (2H, br), 5.11 (2H, s), 5.55-5.60 (1H, br), 5.65-5.90 (1H, br), 6.25-6.55 (1H, br), 7.28-7.40 ( 5H, m).

MS (ESI) m/z: 364 (M+H) ⁺ .

[Reference Example 212] Benzyl (3R,4S)-3-[(tert-butoxycarbonyl)amino]piperidin-4-ylcarbamate

Under ice-cooling, 1 mole of borane-tetrahydrofuran complex (tetrahydrofuran solution, 34.0 ml) was added dropwise to a solution of the compound (2.49 g) obtained in Reference Example 211 in tetrahydrofuran (70 ml), and stirred for 20 hours while slowly warming up to room temperature . Methanol (100 ml) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Ethanol (45 ml), water (5 ml) and triethylamine (10 ml) were added to the obtained residue, and the mixture was heated under reflux for 24 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:water=7:3:1, lower layer) to obtain the title compound (1.61 g).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.65-1.72 (2H, m), 2.67 (1H, t, J=12.0Hz), 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-ylcarbamate tert-butyl ester

In dichloromethane, the compound obtained in Reference Example 212 was reacted with acetyl chloride in the presence of triethylamine to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.85-2.15 (2H, m), 2.07 (1.5H, s), 2.14 (1.5H, s), 2.75-2.90 (1H, m) , 3.10-3.20 (0.5H, m), 3.25-3.35 (0.5H, br.d, J=14.2Hz), 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)-tert-butyl-1-acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-ylcarbamate

10% palladium carbon (532 mg) was added to a solution of the compound obtained in Reference Example 213 (745 mg) in ethanol (50 ml), followed by stirring at room temperature for 16 hours in a hydrogen atmosphere. After removing insoluble matter by filtration through celite, the filtrate was concentrated under reduced pressure. The obtained residue was treated with 5-chloroindole-2-carboxylic acid (467 mg) in the same manner as in Reference Example 68 to obtain the title compound (650 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.60-1.80 (2H, m), 2.12 (1H, s), 2.16 (2H, s), 2.30-2.45 (0.5H, 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 prepared from the (3R,4S)-compound (highly polar compound) obtained in Reference Example 168 in the same manner as in Reference Example 210.

¹ H-NMR (CDCl ₃ ) 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] Benzyl (4R,5R)-5-[(tert-butoxycarbonyl)amino]-2-oxopiperidin-4-ylcarbamate

The compound obtained in Reference Example 215 was treated in the same manner as in Reference Example 211 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.35 (9H, s), 2.19 (1H, dd, J = 17.4, 9.1 Hz), 2.41-2.51 (1H, m), 2.97 (1H, t, J = 9.1Hz), 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] Benzyl (3R,4R)-3-[(tert-butoxycarbonyl)amino]piperidin-4-ylcarbamate

The compound obtained in Reference Example 216 was treated in the same manner as in Reference Example 212 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.39 (9H, s), 2.05 (2H, d, J=12.9Hz), 2.40 (1H, t, J=11.0Hz), 2.63 (1H, t, J=12.0 Hz), 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-ylcarbamate tert-butyl ester

The compound obtained in Reference Example 217 was treated in the same manner as in Reference Example 213 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.53-1.67 (1H, m), 1.89-2.00 (1H, m), 2.09 (1.5H, s), 2.15 (1.5H, s) , 2.57(1H, t, J=12.0Hz), 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-ylcarbamate tert-butyl ester

The compound obtained in Reference Example 218 was treated in the same manner as in Reference Example 214 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.42-1.56 (2H, m), 2.00-2.10 (1H, m), 2.12 (1.5H, s), 2.17 (1.5H, s) , 2.31-2.43(1H, m), 2.67-3.00(1H, m), 3.55-3.63(1H, m), 3.78-4.00(1H, m), 4.03-4.21(1H, m), 4.78-5.24( 2H, m), 6.91(0.5H, s), 6.92(0.5H, s), 7.22-7.32(1H, m), 7.33(1H, d, J=8.8Hz), 7.58(1H, s), 9.45 (0.5H, s), 9.51 (0.5H, s).

[Reference Example 220] Benzyl (3R,4S)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylcarbamate

The title compound was obtained from the compound obtained in Reference Example 212 and methoxyacetyl chloride in the same manner as in Reference Example 213.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.70-2.15 (2H, m), 2.70-2.85 (1H, m), 2.90-3.30 (1H.m), 3.35-3.70 (1H, m), 3.43(3H, s), 3.75-3.90(2H, m), 3.90-4.25(3H, m), 4.40-4.80(1H, m), 5.05-5.09(1H, m), 5.10(2H, br.s), 7.30-7.40 (5H, m).

MS (ESI) m/z: 322 (M+H ⁺ ).

[Reference Example 221] (3R,4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-ylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 220 in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.60-1.80 (1H, m), 2.20-2.40 (1H, m), 2.70-2.80 (0.6H, m), 2.90-3.00 (0.4 H, m), 3.15-3.30 (0.4H, m), 3.32-3.40 (0.6H, m), 3.46, 3.49 (all 3H, each s), 3.85-4.30 (5H, m), 4.55-4.80 ( 1H, m), 5.11 (0.4H, br.s), 6.05 (0.6H, br.s), 6.86 (1H, s), 7.20 (1H, dd, J=8.7, 2.0Hz), 7.33 (1H, d, J=8.7Hz), 7.61(1H, s), 8.40-8.60(1H, m), 9.41(1H, br.s).

MS (FAB) m/z: 465 (M+H ⁺ ).

[Reference Example 222] Benzyl (3R,4R)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylcarbamate

The title compound was prepared from the compound obtained in Reference Example 217 and methoxyacetyl chloride in the same manner as in Reference Example 213.

¹ H-NMR (CDCl ₃ ) 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-ylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 222 and 5-chloroindole-2-carboxylic acid in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.41-1.56 (2H, m), 2.11-2.23 (0.5H, m), 2.34-2.50 (0.5H, m), 2.78-2.89 ( 0.5H, m), 3.01-3.12 (0.5H, m), 3.42 (5H, s), 3.45-3.56 (1H, m), 3.78-3.89 (1H, m), 4.00-4.21 (2H, m), 4.78-5.21(2H, m), 6.91(0.5H, 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) Ethyl silyl]oxy}valerate

Under ice-cooling, triethylamine (0.47ml) was successively added to a solution of (3R,4S)-compound (highly polar compound) (0.74g) obtained in Reference Example 168 in N,N-dimethylformamide (30ml) , imidazole (0.19g) and tert-butylchlorodiphenylsilane (0.7ml), and stirred for 4 days while slowly returning to room temperature. The reaction solution was diluted with ethyl acetate, washed with 10% citric acid aqueous solution and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound (0.85 g)

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.19 (3H, t, J=7.4Hz), 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=7.4 Hz), 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 -Chlorindol-2-yl)carbonyl]amino}pentanoic acid ethyl ester

In the same manner as in Reference Example 214, the benzyloxycarbonyl group of the compound obtained in Reference Example 224 was removed and condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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] tert-butyl amino}-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate

The title compound was prepared from the (3R ^* , 4R ^* )-compound (low polarity compound) obtained in Reference Example 179 and the compound obtained in Reference Example 10 in the same manner as in Reference Example 68.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.30-2.37 (2H, m), 2.51 (3H, s), 2.82-2.85 (2H, m), 2.92-2.95 (2H, m) , 3.17-3.20(4H, m), 3.40-3.43(1H, m), 3.69-3.77(2H, m), 3.97-3.98(1H, m), 4.98(1H, br), 5.25(1H, br) .

[Reference Example 227] N-(3R ^* , 4R ^* )-4-amino-1,1-dioxohexahydro-1-thiopyran-3-yl]-5-methyl-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 226 was treated in the same manner as in Reference Example 69 to prepare the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.29-2.33 (2H, m), 2.93 (3H, s), 3.16 (2H, br), 3.40 (2H, br), 3.52 (2H, br), 3.69 -3.76(3H,m), 4.48(1H,br), 4.71-4.82(2H,m), 8.34(2H,br), 8.82(1H,br).

MS (ESI) m/z: 345 (M+H) ⁺ .

[Reference Example 228] (3R ^* , 4R ^* )-3-{[(5-chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran-4- tert-butyl carbamate

In the same manner as in Reference Example 68, the title compound was prepared from the (3R ^* , 4R ^* )-compound (low polarity compound) obtained in Reference Example 179 and 5-chloroindole-2-carboxylic acid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.34 (9H, s), 2.09 (2H, br), 3.07 (1H, d, J=12.6Hz), 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 compound obtained in Reference Example 228 was treated in the same manner as in Reference Example 69 to prepare the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.24-2.33 (2H, m), 3.43-3.55 (3H, m), 3.60-3.66 (1H, m), 3.77 (1H, br), 4.75-4.79 ( 1H, m), 7.18-7.21 (2H, m), 7.46 (1H, d, J=8.8Hz), 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] tert-butyl amino}-1,1-dioxohexahydro-1-thiopyran-4-ylcarbamate

The title compound was prepared from the (3R ^* , 4S ^* )-compound (highly polar compound) obtained in Reference Example 179 and the compound obtained in Reference Example 10 in the same manner as in Reference Example 98.

¹ H-NMR (CDCl ₃ ) δ: 1.32 (9H, s), 2.14-2.24 (1H, m), 2.33-2.38 (1H, m), 2.50 (3H, s), 2.78-2.83 (2H, m) , 2.86-2.95(2H, m), 3.08-3.14(3H, m), 3.55(1H, d, J=13.4Hz), 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 compound obtained in Reference Example 230 was treated in the same manner as in Reference Example 69 to prepare the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.03-2.12 (1H, m), 2.51 (1H, br), 2.93 (3H, s), 3.14 (2H, d, J=12.2Hz), 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- tert-butyl carbamate

In the same manner as in Reference Example 68, the title compound was prepared from the (3R ^* , 4R ^* )-compound (low polarity compound) obtained in Reference Example 179 and 5-fluoroindole-2-carboxylic acid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.37 (9H, s), 2.10-2.13 (2H, m), 3.06 (1H, br), 3.37-3.49 (3H, m), 4.13 (1H, br) , 4.57 (1H, br), 6.95-7.01 (2H, m), 7.14 (1H, br), 7.30 (1H, d, J=8.5Hz), 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 compound obtained in Reference Example 232 was treated in the same manner as in Reference Example 69 to prepare the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.25-2.31 (1H, m), 2.47 (1H, br), 3.30 (1H, br), 3.49-3.53 (2H, m), 3.60-3.66 (1H, m), 3.78(1H, br), 4.79(1H, br), 7.01-7.05(1H, m), 7.21(1H, s), 7.38(1H, d, J=9.0Hz), 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

At room temperature, in a mixed solvent formed of (3R, 4S)-compound (highly polar compound) (0.5 g), dimethyl sulfoxide (6.8 ml) and triethylamine (2.6 ml) obtained in Reference Example 168, slowly Add sulfur trioxide pyridinium complex salt (1.5 g), and stir for 20 minutes. The reaction solution was poured into water, extracted with ethyl acetate, and the obtained organic layer was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (0.51 g).

¹ H-NMR (CDCl ₃ ) 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] Benzyl (4R)-5-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxopiperidin-4-ylcarbamate

Under ice-cooling, acetic acid (0.27 ml) and 2M methylamine (tetrahydrofuran solution, 1.0 ml) were successively added to the ethanol (10 ml) solution of the compound (0.51 g) obtained in Reference Example 234, and stirred while slowly returning to room temperature. hours, sodium cyanoborohydride (0.15 g) was added and stirred for 18 hours. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in toluene (20 ml). Triethylamine (2 ml) was added to the solution, heated to reflux for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to obtain the title compound (0.28 g).

¹ H-NMR (DMSO-d ₆ ) 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 (1.2Hs ), 2.80(1.8Hs), 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(1.2Hs), 5.01(0.8H, s), 6.89-7.02(0.5H, m), 7.23-7.44( 5.5H, m).

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

The title compound was prepared from the compound obtained in Reference Example 235 and 5-chloroindole-2-carboxylic acid in the same manner as in Reference Example 214.

¹ H-NMR (DMSO-d ₆ ) 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), heated to reflux at 120°C for 19 hours. After cooling to room temperature, ethyl acetate was added, extracted with water, and concentrated hydrochloric acid was added to the aqueous layer to make it acidic. After the aqueous layer was washed with ethyl acetate, the aqueous layer was concentrated, and the precipitated solid was collected by filtration to prepare the title compound (8.37 g).

¹ H-NMR (DMSO-d ₆ ) 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 obtained in Reference Example 237 (12.4 g) was dissolved in methanol (200 ml), concentrated sulfuric acid (5 ml) was added at room temperature, and the mixture was heated under reflux for 3 hours. After the reaction was complete, the solvent was distilled off, and saturated aqueous sodium bicarbonate solution was added to the residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was solidified by adding hexane to obtain the title compound (9.86 g).

¹ H-NMR (CDCl ₃ ) 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 obtained in Reference Example 238 (1.49 g) was dissolved in dichloromethane (30 ml), 70% m-chloroperbenzoic acid (3.46 g) was added, and stirred at room temperature for 1 hour. An aqueous sodium sulfite solution was added for liquid separation, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.33 g).

¹ H-NMR (DMSO) δ: 3.88 (3H, s), 7.86 (2H, d, J = 7.2Hz), 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 obtained in Reference Example 239 (802 mg) was dissolved in dioxane (20 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, refluxed for 1 hour, and stirred at room temperature for 2 hours. 1N aqueous hydrochloric acid solution (5 ml) was added for neutralization, water (5 ml) was added, and the resulting precipitate was collected by filtration to obtain the title compound (627 mg).

¹ H-NMR (DMSO) δ: 7.85 (2H, d, J = 7.2 Hz), 7.91 (2H, d, J = 8.3 Hz), 8.03 (2H, d, J = 8.3 Hz), 8.30 (2H, d , J=7.2Hz).

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

From 2-bromopyridine, the title compound was obtained in the same manner as in Reference Examples 237, 238, 239 and 240.

¹ H-NMR (DMSO-d ₆ ) δ: 7.41-7.45 (2H, m), 7.65-7.69 (1H, m), 7.94 (2H, d, J = 8.3 Hz), 8.02 (2H, d, J = 8.3Hz), 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

Under ice-cooling, to a solution of 4-chloroaniline (1.16g) and dichloromethane (26ml) were successively added triethylamine (1.52ml) and ethyl chlorooxyacetate (1.11ml), and stirred at room temperature for 14 hours. After adding saturated aqueous sodium bicarbonate solution to the reaction solution for liquid separation, the organic layer was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, hexane was added to the residue to precipitate crystals, which were collected by filtration and dried to obtain the title compound (1.89 g).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J=7.1Hz), 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 dichloromethane (26ml), under ice-cooling, ethyl chlorooxyacetate (1.10ml) was added, and stirred at room temperature for 14 hours . After adding saturated aqueous sodium bicarbonate solution to the reaction solution 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 (hexane:ethyl acetate=3:1). The obtained pale yellow solid was dissolved in methanol (20 ml), and stirred at 50°C for 11 hours. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and dried to obtain the title compound (0.43 g).

¹ H-NMR (CDCl ₃ ) 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

The (R)-(+)-α-methylbenzylamine salt of (1S)-3-cyclohexene-1-carboxylic acid (J.Am.Chem.Soc., 1978, volume 100, 5199-5203 Page) (95.0g) was dissolved in ethyl acetate (1.61) and 2N hydrochloric acid (1.61), after the organic layer was separated, the aqueous layer was extracted with ethyl acetate (500ml×2 times), the organic layers were combined, and washed with saturated brine Wash (300ml×2 times) and separate the organic layer. The aqueous layer was extracted with ethyl acetate (200ml), the organic layer was washed with saturated brine (100ml), all organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (48.3g).

[α] ²⁵ _D = -104° (c = 1, chloroform).

¹ H-NMR (CDCl ₃ ) δ: 1.66-1.77 (1H, m), 2.00-2.20 (3H, m), 2.20-2.38 (2H, m), 2.57-2.65 (1H, m), 5.65-5.75 ( 2H, m).

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

At an internal temperature of 5°C, iodine (125.4 g) was added to a mixture of the compound obtained in Reference Example 244 (48.0 g), dichloromethane (580 ml), potassium iodide (82.1 g), sodium bicarbonate (42.0 g) and water (530 ml). g), stirring at room temperature for 3 hours. After adding 1N aqueous sodium thiosulfate solution (800ml) to the reaction solution, it was extracted with dichloromethane (1L, 500ml), and the organic layer was washed with aqueous sodium bicarbonate solution (300ml), water (500ml) and saturated brine (300ml). After washing, drying over anhydrous magnesium sulfate, and concentration. The precipitated crystals were collected by filtration, washed with hexane and dried to obtain the title compound (89.5 g).

Melting point: 130～131℃

[α] ²⁵ _D = -41° (c = 1, chloroform)

¹ H-NMR (CDCl ₃ ) δ: 1.78-1.96 (2H, m), 2.12 (1H, dd, J=16.5Hz, 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

2N aqueous sodium hydroxide solution (213 ml) was added to a suspension of the compound (89.3 g) obtained in Reference Example 245 in ethanol (810 ml) while being stirred at room temperature, and the mixture was stirred for 3 hours. After the reaction solution was concentrated under reduced pressure at a bath temperature of 35°C, water (500 ml) was added to the obtained oily substance, followed by extraction with dichloromethane (500 ml and 300 ml). The organic layer was washed with water (300 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate=85:15) to obtain the title compound (41.3 g).

[α] ²⁵ _D = -58° (c = 1, chloroform).

¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J=7.2Hz), 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] Ethyl (1S,3R,4R)-3-azido-4-hydroxycyclohexanecarboxylate

A mixture of the compound (41.0 g) obtained in Reference Example 246, N,N-dimethylformamide (300 ml), ammonium chloride (19.3 g) and sodium azide (23.5 g) was subjected to 13 hours at 76° C. Stir. After collecting the insoluble matter by filtration, the filtrate was concentrated under reduced pressure while the filtrate was not dry, and the previous filtrate was added to the residue, which was dissolved in water (500 ml). Extracted with ethyl acetate (500 ml, 300 ml), washed with water, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the title compound (51.5 g).

[α] ²⁵ _D = +8° (c = 1, chloroform)

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J=7.1Hz), 1.37-1.64 (3H, m), 1.86-1.95 (1H, m), 2.04-2.16 (1H, m), 2.32 -2.41(1H, m), 2.44(1H, br.s), 2.68-2.78(1H, m), 3.45-3.60(2H, m), 4.17(2H, q, J=7.1Hz).

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

Under hydrogen pressure (7kg/em ² ), stir the compound obtained in Reference Example 247 (51.2g), di-tert-butyl dicarbonate (68.1g), 5% palladium on carbon (5.0g) and ethyl acetate (1000ml) at room temperature overnight )mixture. The reaction solution was filtered and concentrated, and the obtained 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). Furthermore, the mother liquor was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain the title compound (6.74 g).

[α] ²⁵ _D = +25° (c = 1, chloroform).

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J=7.1Hz), 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 (42 ml) was added dropwise to a solution of the compound obtained in Reference Example 248 (53.5 g), dichloromethane (500 ml) and triethylamine (130 ml) at -10°C to -15°C over 20 minutes. The temperature was raised to room temperature over 2 hours and stirred for 2 hours. At 0°C, 0.5N hydrochloric acid (800ml) was added dropwise into the reaction solution to make the solution acidic, and extracted with dichloromethane (500ml, 300ml). The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystals were dissolved in N,N-dimethylformamide (335ml), sodium azide (60.5g) was added, and stirred at 67-75°C for 16 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to remove 250 ml of solvent. The residue and previous filtration were combined, dissolved in water (500ml) and extracted with ethyl acetate (11 and 300ml). The organic layer was washed with saturated brine (400ml, 200ml), dried over anhydrous magnesium sulfate, and concentrated. The resulting crystals were purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (18.4g) .

[α] ²⁵ _D = +62° (c = 1, chloroform).

¹ H-NMR (CDCl ₃ ) 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 (102 mg) and water (5 ml) were added to a tetrahydrofuran (25 ml) solution of the compound (1.0 g) obtained in Reference Example 249, stirred for 17 hours, and then lithium hydroxide (50 mg) was added and stirred for 4 hours. 1N aqueous hydrochloric acid solution (6.3 ml) was added to the reaction solution, followed by extraction with ethyl acetate. After the organic layer was dried, the solvent was distilled off under reduced pressure to obtain the title compound (980 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.30-2.20 (6H, m), 1.45 (9H, s), 2.70-2.80 (1H, m), 3.94 (2H, br.s), 4.73 (1H, br. s).

[Reference Example 251] (1R,2S,5S)-2-Azido-5-[(dimethylamino)carbonyl]cyclohexylcarbamate tert-butyl ester

The compound (4.77g) obtained in Reference Example 250 was dissolved in dichloromethane (150ml), and dimethylamine hydrochloride (3.26g), 1-ethyl-3-(3-dimethylaminopropyl) carbonization Diimine hydrochloride (4.60 g), 1-hydroxybenzotriazole monohydrate (3.24 g) and N-methylmorpholine (8.09 g) were stirred at room temperature for 18 hours. After adding saturated aqueous sodium bicarbonate solution to the reaction solution for liquid separation, the organic layer was dried, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol:dichloromethane=1:50) to obtain the title compound (4.90 g).

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.90 (4H, m), 1.45 (9H, s), 1.97-2.18 (2H, m), 2.75-2.85 (1H, m), 2.92 (3H, s) , 3.02(3H, s), 3.68-3.80(1H, m), 4.05-4.20(1H, m), 4.55-4.75(1H, m).

[Reference Example 252] N-{(1R,2S,5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7- Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound obtained in Reference Example 251 (9.13 g) was dissolved in dichloromethane (100 ml), hydrochloric acid ethanol solution (100 ml) was added, and stirred at room temperature for 1 minute. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in N,N-dimethylformamide (200ml), and the compound obtained in Reference Example 10 (7.75g), 1-hydroxybenzotriazole monohydrate (4.47g ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.2g) and triethylamine (2.02ml), stirred overnight at room temperature. Next, the compound (2.38 g) obtained in Reference Example 10 and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) were added, and stirred for 3 days. The reaction solution was concentrated under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue for liquid separation, and the obtained organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=47:3) to obtain the title compound (7.38 g).

¹ H-NMR (CDCl ₃ ) δ: 1.72-1.97 (4H, m), 2.10-2.27 (2H, m), 2.51 (3H, s), 2.77-3.05 (11H, m), 3.68 (1H, d, J=15.4Hz), 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-tetrahydrothiazole And[5,4-c]pyridine-2-carboxamide

To a solution of the compound (9.0 g) obtained in Reference Example 252 in methanol (300 ml) was added 10% palladium on carbon (6.0 g), and vigorously stirred at room temperature for 11 hours under 4 atmospheres of hydrogen. The catalyst was filtered off, and the filtrate was concentrated to obtain the title compound (7.67 g).

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.54 (1H, m), 1.66-1.89 (5H, m), 2.30-2.40 (1H, m), 2.51 (3H, s), 2.68-3.05 (6H, m), 2.92(3H, s), 3.00(3H, s), 3.10-3.18(1H, m), 3.65-3.77(2H, m), 4.21-4.28(1H, m), 7.52(1H, d, J=6.1Hz).

[Reference Example 254] Methyl 2-(4-fluoroanilino)-2-oxoacetate

By the same method as described in Reference Example 242, the title compound was obtained from 4-fluoroaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 7.00-7.14 (2H, m), 7.55-7.68 (2H, m), 8.85 (1H, br.s).

MS (ESI) m/z: 198 (M+H) ⁺ .

[Reference Example 255] Methyl 2-(4-bromoanilino)-2-oxoacetate

By the same method as described in Reference Example 242, the title compound was obtained from 4-bromoaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

By the same method as described in Reference Example 242, the title compound was obtained from 4-chloro-2-methylaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 3.99 (3H, s), 7.15-7.30 (2H, m), 7.98 (1H, d, J=8.8Hz), 8.77 (1H, br ).

MS (FAB) m/z: 228 (M+H) ⁺ .

[Reference Example 257] Methyl 2-[(4-chloro-3-methylanilino)-2-oxoacetate

By the same method as described in Reference Example 242, the title compound was obtained from 4-chloro-3-methylaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

By the same method as described in Reference Example 242, the title compound was obtained from 4-chloro-2-fluoroaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

By the same method as described in Reference Example 242, the title compound was obtained from 2,4-difluoroaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 6.87-7.00 (2H, m), 8.29-8.38 (1H, m), 8.99 (1H, br.s).

MS (ESI) m/z: 215M ⁺ .

[Reference Example 260] Methyl 2-(3,4-difluoroanilino)-2-oxoacetate

By the same method as described in Reference Example 242, the title compound was obtained from 3,4-difluoroaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 7.10-7.28 (2H, m), 7.67-7.78 (1H, m), 8.83 (1H, br.s).

MS (ESI) m/z: 215M ⁺ .

[Reference Example 261] Methyl 2-oxo-2-(pyridin-4-ylamino)acetate

By the same method as described in Reference Example 242, the title compound was obtained from 4-aminopyridine and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

By the same method as described in Reference Example 242, the title compound was obtained from 2-amino-5-bromopyridine and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

Dissolve 5-amino-2-chloropyridine (386mg) in N,N-dimethylformamide (8ml), then add 2-ethoxy-2-oxoacetic acid potassium salt (469mg), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (863 mg) and 1-hydroxybenzotriazole monohydrate (203 mg) were stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate solution were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and purified by silica gel flash column chromatography (hexane:ethyl acetate=2:1) to obtain a residue (200 mg) containing the title compound.

¹ H-NMR (CDCl ₃ ) 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 (516 mg) was dissolved in pyridine (26 ml), triethylamine (665 μl) and methyl chlorooxyacetate (441 μl) were added successively under ice cooling, and stirred at room temperature for 14 hours. After adding water to the reaction liquid, the liquid 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).

¹ H-NMR (CDCl ₃ ) 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

By the same method as described in Reference Example 242, the title compound was obtained from 2-amino-5-chlorothiazole and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 4.02 (3H, s), 7.48 (1H, s), 11.03 (1H, br.s).

MS (ESI) m/z: 221 (M+H) ⁺ .

[Reference Example 266] Lithium salt of 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate

To a tetrahydrofuran solution (20 ml) of the compound (1.12 g) obtained in Reference Example 243 were added water (5.0 ml) and lithium hydroxide (128 mg) at room temperature, followed by stirring for 5 hours. The solvent was distilled off under reduced pressure, hexane (30 ml) was added to the resulting white solid and stirred for 30 minutes, the solid was collected by filtration and dried to obtain the title compound (1.02 g).

¹ H-NMR (DMSO-d ₆ ) δ: 7.90 (1H, dd, J=8.9, 2.6Hz), 8.12 (1H, d, J=8.9Hz), 8.34 (1H, d, J=2.6Hz), 10.18(1H, s).

[Reference Example 267] 2-(4-Chloroanilino) ethyl acetate

4-Chloroaniline (2.0 g) was dissolved in acetonitrile (20 ml), ethyl bromoacetate (2.1 g) and lithium carbonate (2.2 g) were added, and stirred at 60° C. for 2 days. The reaction solution was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:chloroform=2:1) to obtain the title compound (2.3 g).

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J=7.3Hz), 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

By the same method as described in Reference Example 267, the title compound was obtained from 4-chloro-2-fluoroaniline and ethyl bromoacetate.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J=7.3Hz), 3.91 (2H, s), 4.22 (2H, q, J=7.3Hz), 4.42-4.51 (1H, m), 6.49(1H, t, J=8.8Hz), 6.98(1H, dt, J=8.8, 2.5Hz), 7.01(1H, dd, J=11.3, 2.5Hz).

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

The compound (1.5 g) obtained in Reference Example 253 was dissolved in N,N-dimethylformamide (15 ml), and 2-ethoxy-2-oxoacetic acid potassium salt (962 mg), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.18 g) and 1-hydroxybenzotriazole monohydrate (277 mg) were stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure, and an aqueous sodium bicarbonate solution and dichloromethane were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (dichloromethane:methanol=47:3) to obtain the title compound (1.13 g).

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J=7.1Hz), 1.55-2.15 (6H, m), 2.52 (3H, s), 2.77-2.89 (3H, m), 2.94 (5H , br.s), 3.06(3H, s), 3.71(1H, d, J=15.5Hz), 3.73(1H, d, J=15.5Hz), 4.06-4.13(1H, m), 4.32(2H, q, J=7.1Hz), 4.60-4.63(1H, m), 7.39(1H, d, J=8.3Hz), 7.83(1H, d, J=7.6Hz).

MS (ESI) m/z: 466 (M+H) ⁺ .

[Reference Example 270] 2-[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole Lithium salt of [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]-2-oxoacetate

The compound obtained in Reference Example 269 (1.13 g) was dissolved in tetrahydrofuran (20 ml), methanol (10 ml) and water (10 ml), lithium hydroxide (58 mg) was added, and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (1.10 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.41-1.73 (4H, m), 2.00-2.07 (2H, m), 2.39 (3H, s), 2.74-2.99 (11H, m), 3.67 (2H, s), 3.82-3.88(1H, m), 4.28-4.30(1H, m), 8.66-8.70(2H, m).

[Reference Example 271] N-{(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 prepared from the compound obtained in Reference Example 293 and the compound obtained in Reference Example 251 by the same method as described in Reference Example 252.

¹ H-NMR (CDCl ₃ ) δ: 1.73-1.87 (4H, m), 2.11-2.20 (2H, m), 2.67 (3H, s), 2.85-2.90 (1H, m), 2.93 (3H, s) , 3.00(3H, s), 3.90-4.10(5H, m), 4.57-4.62(1H, m), 7.20-7.22(1H, m).

MS (FAB) m/z: 378 (M+H) ⁺ .

[Reference Example 272] N-{(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-5,6-dihydro-4H-pyrrole And[3,4-d]thiazole-2-carboxamide

The title compound was prepared from the compound obtained in Reference Example 271 by the same method as described in Reference Example 253.

¹ H-NMR (CDCl ₃ ) δ: 1.67-1.97 (6H, m), 2.36-2.40 (1H, m), 2.67 (3H, s), 2.92 (3H, s), 3.00 (3H, s), 3.07 -3.18(1H, m), 3.92-3.95(2H, m), 4.02-4.06(2H, m), 4.23-4.26(1H, m), 7.50-7.52(1H, m).

[Reference Example 273] Methyl 5-chloro-4-fluoroindole-2-carboxylate

In an argon atmosphere, ethanol (100 ml) was added to sodium hydride (60%, 4.7 g) at 0°C and stirred for 10 minutes. 2-Nitropropane (11 ml) was added to the reaction mixture and stirred for 10 minutes, then 1-(bromomethyl)-3-chloro-2-fluorobenzene (10 g) was added, followed by stirring 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 diethyl ether and water, and the organic layer was washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7) to obtain crude 3-chloro-2-fluorobenzaldehyde (5.5 g) as a light yellow oily compound. Under an argon atmosphere, methanol (20 ml) was added to sodium hydride (60% content, 1.6 g) at 0°C and stirred for 10 minutes. The reaction solution was cooled to -20°C, and a solution of crude 3-chloro-2-fluorobenzaldehyde (5.5 g) and methyl 2-azidoacetate (5.0 g) in methanol (10 ml) was added within 20 minutes. The reaction solution was warmed up to 0°C, stirred for 2.5 hours, and then water (40ml) was added. The reaction solution 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 evaporated, 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 (2.6g). It was dissolved in xylene (50ml) and stirred at 130-140°C for 3 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane), and then recrystallized from ether-hexane to obtain the title compound (440 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 4.08 (3H, s), 7.20 (1H, s), 7.31-7.38 (2H, m).

MS (FAB) m/z: 228 (M+H) ⁺ .

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

The compound (440 mg) obtained in Reference Example 273 was dissolved in tetrahydrofuran (10 ml), and an aqueous solution (5 ml) of lithium hydroxide (160 mg) was added, followed by stirring at room temperature for 3 hours. An aqueous solution (5 ml) of lithium hydroxide (240 mg) was added to the reaction liquid, and after stirring at room temperature for 1 hour, the reaction liquid was concentrated under reduced pressure. The residue was neutralized with 1N aqueous hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (390 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 6.79 (1H, s), 7.16-7.26 (2H, m)

MS (FAB) m/z: 214 (M+H) ⁺ .

[Reference Example 275] Ethyl 1-benzyl-5-chloroindole-2-carboxylate

Dissolve ethyl 5-chloroindole-2-carboxylate (1.4g) in N,N-dimethylformamide (30ml), then add potassium carbonate (2.9g) and benzyl chloride (2.4ml), in It was heated and stirred at a bath temperature of 100° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, 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).

¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, t, J = 7.1 Hz), 4.33 (2H, q, J = 7.1 Hz), 5.83 (2H, s), 7.00-7.02 (2H, d), 7.20-7.38(6H, m), 7.67(1H, d, J=1.7Hz).

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

1-Fluoro-2,6-dichloropyridinium triflate (4.4 g) was added to a dichloromethane solution (30 ml) of the compound (2.2 g) obtained in Reference Example 275, and heated under reflux 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 successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:24) to obtain a crude title compound (2.8 g). A portion of this was purified by preparative silica gel thin layer chromatography to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.25 (3H, t, J = 7.1 Hz), 4.29 (2H, q, J = 7.1 Hz), 5.77 (2H, s), 6.97-6.99 (2H, m ), 7.18-7.28 (3H, m), 7.39 (1H, dd, J=9.0, 2.1Hz), 7.69 (1H, dd, J=9.0, 2.1Hz), 7.78 (1H, d, J=2.1Hz)

[Reference Example 277] Ethyl 5-chloro-3-fluoroindole-2-carboxylate

The crude compound (1.4 g) obtained in Reference Example 276 was dissolved in anisole (30 ml), and aluminum chloride (2.9 g) was added a little at a time under ice cooling. The reaction solution was stirred at room temperature for 30 minutes, and then aluminum chloride (2.9 g) was added and stirred for 18 hours. Aluminum chloride (8.0 g) was added to the reaction liquid, and after stirring for 5 hours, water was added. The reaction solution was extracted with ethyl acetate, and the combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane) to obtain the title compound (470 mg).

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 277 in the same manner as in Reference Example 274.

¹ H-NMR (DMSO-d ₆ ) δ: 7.31 (1H, dd, J=8.8, 1.9Hz), 7.42 (1H, dd, J=8.8, 1.9Hz), 7.70 (1H, d, J=1.9Hz ), 11.78(1H,s)

MS (FAB) m/z: 214 (M+H) ⁺ .

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

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 278 in the same manner as in Reference Example 97.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.73-2.11 (6H, m), 2.65 (1H, br.s), 2.96 (3H, s), 3.07 (3H, s), 4.20 (1H, br.s), 4.28(1H, br.s), 4.78(1H, br), 7.23-7.30(3H, m), 7.58(1H, s), 9.03(1H, s).

MS (FAB) m/z: 481 (M+H) ⁺ .

[Reference Example 280] Ethyl 3-bromo-5-chloroindole-2-carboxylate

To a solution of ethyl 5-chloroindole-2-carboxylate (500 mg) in N,N-dimethylformamide (10 ml) was added N-bromosuccinimide (440 mg) under ice-cooling. After stirring the reaction solution at room temperature for 18 hours, the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9), and the obtained white powder was washed with hexane to obtain the title compound (680 mg)

¹ H-NMR (CDCl ₃ ) δ: 1.42-1.48 (3H, m), 4.43-4.49 (2H, m), 7.30-7.32 (2H, m), 7.65 (1H, d, J=0.74Hz), 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 prepared from the compound obtained in Reference Example 280 in the same manner as in Reference Example 274.

¹ H-NMR (DMSO-d ₆ ) 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]cyclohexyl tert-butyl carbamate

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 281 in the same manner as in Reference Example 97.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.58-2.17 (6H, m), 2.70 (1H, br.s), 2.96 (3H, s), 3.07 (3H, s), 4.23 -4.28(2H, m), 4.83(1H, br), 7.34-7.41(3H, m), 7.52(1H, s), 9.76(1H, s).

MS (FAB) m/z: 542 (M+H) ⁺ .

[Reference Example 283] Ethyl 3-chloro-5-fluoroindole-2-carboxylate

Dissolve ethyl 5-fluoroindole-2-carboxylate (2.0g) in N,N-dimethylformamide (20ml), under ice-cooling, drop N-chlorosuccinimide (1.4g) into N , N-dimethylformamide (10ml) solution, stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (1.9 g).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J=7.4Hz), 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 prepared from the compound obtained in Reference Example 283 in the same manner as in Reference Example 274.

¹ H-NMR (DMSO-d ₆ ) 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] Ethyl 5-chloro-3-formylindole-2-carboxylate

Phosphorus oxychloride (2.0ml) was added to N-methyl-N-formanilide (2.9g), and after stirring for 15 minutes, 1,2-dichloroethane (50ml) and 5-chloroindole-2- Ethyl carboxylate (4.0 g) was heated to reflux for 1 hour. Under ice-cooling, the reaction solution was poured into an aqueous solution (28 ml) of sodium acetate (14 g), stirred for 18 hours, and the insoluble matter was collected by filtration. After it was washed with water and diethyl ether successively, the title compound (3.56 g) was obtained.

¹ H-NMR (DMSO-d ₆ ) 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 obtained in Reference Example 285 (1.0 g) was dissolved in ethanol (10 ml), and 1N aqueous sodium hydroxide solution (10 ml) was added dropwise, followed by heating and stirring at 50°C for 2 hours. 1N aqueous hydrochloric acid solution (11 ml) was added to the reaction solution, and after stirring, the precipitated insoluble matter was collected by filtration to obtain the title compound (0.86 g).

¹ H-NMR (DMSO-d ₆ ) 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 obtained in Reference Example 286 (1.5g) and sulfamic acid (1.7g) were dissolved in tert-butanol (30ml)-water (30ml), sodium chlorite (1.6g) was added and stirred for 8 hours. The reaction solution was diluted with water, extracted with ethyl acetate, washed successively with 1N aqueous hydrochloric acid and saturated brine, 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).

¹ H-NMR (DMSO-d ₆ ) 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] Ethyl 5-chloro-3-[(dimethylamino)carbonyl]indole-2-carboxylate

The compound (0.7 g) obtained in Reference Example 287 was dissolved in N,N-dimethylformamide (10 ml), and dimethylamine hydrochloride (0.26 g), 1-hydroxybenzotriazole monohydrate ( 0.43g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0g), stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of isopropyl ether-hexane to obtain the title compound (0.6 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.29 (3H, t, J = 7.1 Hz), 2.78 (3H, s), 3.04 (3H, s), 4.30 (2H, q, J = 7.1 Hz), 7.31(1H, dd, J=8.0, 1.4Hz), 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 prepared from the compound obtained in Reference 288 in the same manner as in Reference Example 286.

¹ H-NMR (DMSO-d ₆ ) 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

Under ice cooling, benzenesulfonamide (638mg) and 4,5-bis(bromomethyl)thiazole (M.Al.Hariri, O.Galley, F.Pautet, H.Fillion, Eur.J.Org.Chem.1998 , 593-594) (1.10 g) was dissolved in N, N-dimethylformamide (10 ml), sodium hydride (60% oily, 357 mg) was added all at once, and stirred at room temperature for 3 hours. Water and dichloromethane were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and purified by silica gel column chromatography (dichloromethane:ethyl acetate=9:1) to obtain the title compound (137 mg).

¹ H-NMR (CDCl ₃ ) δ: 4.60-4.63 (2H, m), 4.70-4.73 (2H, m), 7.52-7.64 (3H, m), 7.88-7.92 (2H, m), 8.71 (1H, s).

MS (FAB) m/z: 267 (M+H) ⁺ .

[Reference Example 291] 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazole 2 hydrobromide

A mixture of the compound obtained in Reference Example 290 (800 mg), phenol (800 µl) and 47% aqueous hydrobromic acid (5.00 ml) was heated under reflux for 2 hours. After cooling to room temperature, ethyl acetate and water were added for liquid separation, and the solvent was evaporated from the aqueous layer under reduced pressure. Ethyl acetate was added to the residue to collect the precipitate by filtration, and the title compound (521 mg) was obtained after drying.

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Reference Example 291 in the same manner as described in Reference Example 9.

¹ H-NMR (CDCl ₃ ) δ: 2.67 (3H, s), 3.95-3.99 (2H, m), 4.01-4.05 (2H, m), 8.69 (1H, s).

MS (ESI) m/z: 141 (M+H) ⁺ .

[Reference Example 293] Lithium salt of 5-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 292 in the same manner as described in Reference Example 5.

¹ H-NMR (DMSO-d ₆ ) 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]cyclohexylcarbamate tert-butyl

Using the same method as in Reference Example 97, from the compound obtained in Reference Example 144 and 6-chloronaphthalene-2-carboxylic acid (Eur.J.Chem-Chim.Ther., 1984, Vol. 19, pp. 205-214) obtained title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.30-2.00 (15H, m), 2.60-2.80 (1H, m), 2.96 (3H, s), 3.09 (3H, s), 4.00-4.20 (1H, m) , 4.20-4.30(1H, m), 4.75-4.95(1H, m), 7.44(1H, d, J=9.0Hz), 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), and morpholine (1.70ml) was added dropwise under ice-cooling. After stirring at room temperature for 1 hour, it was concentrated under reduced pressure and analyzed by silica gel column chromatography (dichloro methane:methanol=20:1) to obtain the title compound (3.72 g).

¹ H-NMR (CDCl ₃ ) 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-Chlorodiazobenzenetetrafluoroborate

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 under ice cooling and stirred for 10 minutes. Then, concentrated hydrochloric acid (5.3ml) and sodium tetrafluoroborate (6.90g) were added, and after stirring for 30 minutes under ice cooling, the precipitate was collected by filtration, washed with water, methanol, and ether to obtain the title compound (2.63g). It was used directly in subsequent reactions.

[Reference Example 297] Ethyl 7-chlorocinnoline-3-carboxylate

The compound obtained in Reference Example 295 (1.45 g) was dissolved in acetonitrile (100 ml), and the compound obtained in Reference Example 296 (1.73 g) was added, stirred at room temperature for 1 hour, and then heated to reflux for 7 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane→dichloromethane:ethyl acetate 10:1, then hexane:ethyl acetate=4:1→1:1) to obtain the title compound ( 0.25g).

¹ H-NMR (CDCl ₃ ) δ: 1.53 (3H, t, J = 7.1 Hz), 4.62 (2H, q, J = 7.1 Hz), 7.80 (1H, dd, J = 8.8, 2.0 Hz), 7.95 ( 1H, d, J=8.8Hz), 8.64(1H, s), 8.68(1H, d, J=2.0Hz).

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

The title compound was prepared from the compound obtained in Reference Example 297 in the same manner as in Reference Example 286.

¹ H-NMR (DMSO-d ₆ ) 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-chlorocinnolin-3-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 298 in the same manner as in Reference Example 97.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (9H, s), 1.80-2.20 (5H, m), 2.72 (1H, m), 2.96 (3H, s), 3.07 (3H, s), 3.49 (1H , d, J = 3.7Hz), 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]cyclohexyl tert-butyl carbamate

To a tetrahydrofuran (5.0 ml) solution of the compound (235 mg) obtained in Reference Example 143 was added 10% palladium on carbon (50 mg), followed by stirring at room temperature overnight in a hydrogen atmosphere. After the reaction mixture was filtered and the filtrate was concentrated, the resulting product and 5-chlorobenzimidazole-2-carboxylic acid (Bull. Chem. Soc. Jpn., 1989, Vol. 62, p. 2668) (165 mg) were mixed at room temperature 1-Hydroxybenzotriazole monohydrate (100 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodisulfide were added to a solution of N,N-dimethylformamide (5.0ml) Imine hydrochloride (171 mg), stirred for 4 days. After concentrating the reaction mixture, dichloromethane, aqueous sodium bicarbonate solution and water were added for liquid separation, and the aqueous layer was extracted with dichloromethane. 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 flash column chromatography (dichloromethane:methanol=10:1) to obtain the title compound (250 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.01-2.00 (6H, m), 1.34 (9H, s), 2.79 (3H, s), 2.80-2.95 (1H, m), 2.98 (3H, s) , 3.89-4.06 (2H, m), 7.08 (1H, d, J = 6.6Hz), 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

Dissolve methyl 2-amino-3-(4-fluorophenyl)propanoate (2.01g), p-toluenesulfonyl chloride (2.25g), 4-dimethylaminopyridine (309mg) in chloroform (30ml), add Pyridine (3.0ml) was heated to reflux for 4.5 hours. Add p-toluenesulfonyl chloride (92.20 g) and heat to reflux for 3.5 hours. The reaction solution was poured into ice and 1N hydrochloric acid (17 ml) for liquid separation, and the organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) to obtain the title compound (2.89 g).

¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.90-3.10 (2H, m), 3.51 (3H, s), 4.10-4.20 (1H, m), 5.04 (1H, d, J= 9.0Hz), 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 (1.50 g) obtained in Reference Example 301 and paraformaldehyde (207 mg) were dissolved in chloroform (40 ml), and replaced with argon. Then, trifluoroborane-diethyl ether complex (1.20 ml) was added, followed by stirring at room temperature for 7.5 hours. The reaction solution was poured into ice and saturated aqueous sodium bicarbonate solution for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (1.45 g).

¹ H-NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.15 (2H, d, J = 3.9 Hz), 3.46 (3H, s), 4.45 (1H, d, J = 15.9 Hz), 4.69 ( 1H, d, J=15.9Hz), 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] Methyl 7-fluoroisoquinoline-3-carboxylate

The compound obtained in Reference Example 302 (1.45 g) was dissolved in N,N-dimethylformamide (40 ml). Oxygen was introduced into this reaction liquid, and it stirred at 100 degreeC for 3.5 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate and dichloromethane were added to the residue for liquid separation. The organic layer was washed successively with 10% aqueous citric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (0.59 g).

¹ H-NMR (CDCl ₃ ) δ: 4.07 (3H, s), 7.55-7.65 (1H, m), 7.65-7.75 (1H, m), 8.00-8.05 (1H, m), 8.61 (1H, s) , 9.30(1H, s).

MS (ESI) m/z: 206 (M+H) ⁺ .

[Reference Example 304] 7-Fluoroisoquinoline-3-carboxylate hydrochloride

The compound (1.45 g) obtained in Reference Example 303 was dissolved in concentrated hydrochloric acid (18 ml), and heated under reflux for 2.5 hours. After cooling the reaction liquid, the precipitated crystals were collected by filtration, washed with water and dried to obtain the title compound (0.46 g).

¹ H-NMR (DMSO-d ₆ ) δ: 7.90-8.00 (1H, m), 8.15-8.25 (1H, m), 8.40-8.50 (1H, m), 8.82 (1H, s), 9.55 (1H, s).

MS (FAB) m/z: 192 (M+H) ⁺ .

[Reference Example 305] Ethyl 7-chloro-2H-chromene-3-carboxylate

4-Chloro-2-hydroxybenzaldehyde (Acta.Chem.Scand., 1999, volume 53, page 258) (510 mg) was dissolved in tetrahydrofuran (40 ml), and sodium hydride (60% oily, 157 mg) was added at room temperature Stir for 2 hours. Then, a tetrahydrofuran solution (10 ml) of 2-diethylphosphonoethyl acrylate (J.Org.Chem. 1978, volume 43, page 1256) (769 mg) was added to the reaction solution, stirred at room temperature for 2 hours and then heated Reflux overnight. After cooling the reaction solution to room temperature, water and ether were added for liquid separation. After 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).

¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (3H, t, J = 7.1 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.99 (2H, d, J = 1.2 Hz), 6.85 ( 1H, d, J=1.2Hz), 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 prepared from the compound obtained in Reference Example 305 in the same manner as in Reference Example 274.

¹ H-NMR (DMSO-d ₆ ) 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] tert-butyl cyclohexylcarbamate

The title compound was prepared from the compound obtained in Reference Example 144 and 4-chlorocinnamic acid in the same manner as in Reference Example 97.

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.55 (3H, m), 1.48 (9H, s), 1.60-2.30 (4H, m), 2.57-2.70 (1H, m), 2.95 (3H, s) , 3.06(3H, s), 4.01(1H, br s), 4.10-4.20(1H, m), 4.78(1H, br.s), 6.30(1H, d, J=15.6Hz), 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] Methyl 6-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate

Dimethyl acetylene dicarboxylate (13.5 ml) was added to a solution of 4-chloroaniline (12.76 g) in methanol (150 ml) and heated to reflux for 8 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in diphenyl ether (70 ml), and heated and stirred at 240° C. for 4 hours. After cooling the reaction liquid, a mixed solvent of hexane and ether was added, and the precipitated crystals were collected by filtration and washed to obtain the title compound (11.09 g).

¹ H-NMR (DMSO-d ₆ ) δ: 3.97 (3H, s), 7.76 (1H, dd, J=9.0, 2.5Hz), 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 prepared from the compound obtained in Reference Example 308 in the same manner as in Reference Example 286.

¹ H-NMR (DMSO-d ₆ ) δ: 6.90-7.05 (1H, m), 7.90-8.05 (2H, m), 10.10-10.30 (1H, m), 12.13 (1H, br.s).

MS (ESI) m/z: 224 (M+H) ⁺ .

[Reference Example 310] (1R, 2S, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate tert-butyl ester

Water (10 ml) and lithium hydroxide (263 mg) were added to a tetrahydrofuran (40 ml) solution of the compound (5.00 g) obtained in Reference Example 97, followed by stirring overnight at room temperature. After filtering the reaction mixture, the filtrate was concentrated, and 1-hydroxybenzotriazole monohydrate was added to a solution of the resulting residue and dimethylamine hydrochloride (1.85 g) in N,N-dimethylformamide (100 ml) at room temperature (1.75g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.32g) and diisopropylethylamine (11.3ml), stirred for 2 days. After concentrating the reaction mixture, dichloromethane, aqueous sodium bicarbonate solution and water were added for liquid separation, and the aqueous layer was extracted with dichloromethane. 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 (dichloromethane:acetone=2:1→1:1) to obtain the title compound (4.59 g).

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.76 (2H, m), 1.73 (9H, s), 1.76-1.87 (1H, m), 1.93 (1H, br.s), 2.14 (1H, br. s), 2.28(1H, br.s), 2.65(1H, br.s), 2.95(3H, s), 3.05(3H, s), 4.01(1H, br.s), 4.21(1H, br.s) 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]cyclohexylcarbamate tert-butyl ester

1) In the same manner as in Reference Example 91, (1R, 3R, 4S)-3-[(tert-butoxycarbonyl)amino]-4- was obtained from the compound obtained in Reference Example 96 and 5-fluoroindole-2-carboxylic acid. Ethyl {[(5-fluoroindol-2-yl)carbonyl]amino}cyclohexylcarboxylate

¹ H-NMR (CDCl ₃ ) 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 prepared from the above compound in the same manner as in Reference Example 310.

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.57-1.79 (2H, m), 1.79-2.00 (2H, m), 2.14 (1H, br.s), 2.31 (1H, br. s), 2.65(1H, br.s), 2.95(3H, s), 3.07(3H, s), 4.02(1H, br.s), 4.17-4.25(1H, m), 4.80(1H, br. s), 6.82 (1H, br.s), 7.02 (1H, dt, J=2.3, 9.0Hz), 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

Under argon flow, copper (I) cyanide (918 mg) was dissolved in tetrahydrofuran (50 ml), cooled to -20 ° C and dropped into n-butyllithium (1.56N hexane solution, 6.41 ml) in 5 minutes, Stir at -20°C for 30 minutes. After cooling the reaction solution to -50°C, diisobutylaluminum hydride (1.00 mol hexane solution) was added dropwise over 20 minutes, followed by stirring at -50°C for 1 hour. Add 2,2-dimethyl-5-oxo-5,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester (Helv.Chim.Acta, 1998) to the reaction solution dropwise in 5 minutes , vol. 81, p. 303) (986 mg) in tetrahydrofuran (5 ml) and stirred at -50°C for 2 hours. After the temperature was raised to -20°C, bromine (4.90 ml) was added dropwise at one time, and stirred at -20°C for 30 minutes. Water and ethyl acetate were added to the reaction solution for liquid separation, and the organic layer was washed with saturated aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was dissolved in N,N-dimethylformamide (10 ml), thiourea (760 mg) was added and stirred overnight at 50°C. After the solvent was evaporated, dichloromethane and saturated aqueous sodium bicarbonate solution were added for liquid separation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1) to obtain the title compound (412 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J=7.1Hz), 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 (431 mg) was suspended in acetonitrile (8 ml), and tert-butyl nitrite (249 mg) was added dropwise at room temperature. Under ice-cooling, an acetonitrile solution (8 ml) of the compound (412 mg) obtained in Reference Example 312 was added to the reaction solution, and the temperature was raised to 50° C., followed by stirring for 15 minutes. The solvent was distilled off, diethyl ether and 10% hydrochloric acid were added to the residue for liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to obtain the title compound (151 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J=7.1Hz), 1.55 (6H, s), 2.79-2.81 (2H, m), 4.10 (2H, q, J=7.1Hz), 4.65-4.67(2H, m).

MS (ESI) m/z: 319 (M+H) ⁺ .

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

To a diethyl ether solution (5 ml) of the compound (432 mg) obtained in Reference Example 313 was added n-butyllithium (1.56N hexane solution, 1.04 ml) at -78°C, and stirred at -78°C for 30 minutes. Water and diethyl ether were added to the reaction solution for liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (307 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.55 (6H, s), 2.90 (2H, s), 4.12 (2H, q, J = 7.1 Hz), 4.75 ( 2H, m), 8.63 (1H, s).

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

The compound (307 mg) obtained in Reference Example 314 was dissolved in a mixed solvent of water (5 ml), ethanol (5 ml) and dioxane (5 ml), and lithium hydroxide (598 mg) was added to the reaction solution and heated under reflux for 7 days. After standing to room temperature, water and dichloromethane were added for liquid separation, and the aqueous layer was extracted 6 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain the title compound (207 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, s), 2.71-2.73 (2H, m), 4.09-4.11 (2H, m), 8.61 (1H, s).

MS (ESI) m/z: 168 (M ⁺ ).

[Reference Example 316] tert-butyl 6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylate

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

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.52 (6H, s), 2.87 (2H, s), 4.69 (2H, s), 8.62 (1H, s).

MS (ESI) m/z: 269 (M+H) ⁺ .

[Reference Example 317] Lithium salt of 4-chloro-5-(1,3-dioxolan-2-yl)thiazole-2-carboxylate

2,4-dichlorothiazole-5-formaldehyde ethylene acetal (J.Chem.Soc.Perkin Trans.1, 1992, page 973) (2.26g) was dissolved in tetrahydrofuran (15ml), cooled with dry ice-acetone After adding n-butyllithium (1.5N hexane solution, 6.8 ml) and stirring for 20 minutes, carbon dioxide was introduced at the same temperature. From this state, the temperature was slowly raised to room temperature over 1.5 hours, concentrated under reduced pressure, powdered by adding hexane, suspended in ethyl acetate after filtration, and the powder was collected by filtration again to obtain the title compound (1.65 g).

[Reference Example 318] Ethyl 4-chloro-5-(1,3-dioxolan-2-yl)thiazole-2-carboxylate

The compound (242 mg) obtained in Reference Example 317 and ethanol (0.2 ml) were dissolved in N,N-dimethylformamide (2 ml), and 1-hydroxybenzotriazole monohydrate (136 mg) and 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg), stirred overnight at room temperature. The solvent was concentrated under reduced pressure, ether and dilute hydrochloric acid were added to separate the organic layer. The organic layer was washed with water and saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (170 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.3Hz), 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] Ethyl 4-chloro-5-formylthiazole-2-carboxylate

The compound (132 mg) obtained in Reference Example 318 was dissolved in diethyl ether (5 ml), added with 20% aqueous hydrochloric acid (0.3 ml) and stirred at room temperature for 7 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction 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).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, t, J=7.1Hz), 4.52 (2H, q, J=7.1Hz), 10.12 (1H, s).

[Reference Example 320] Ethyl 4-azido-5-formylthiazole-2-carboxylate

The compound obtained in Reference Example 319 (5.15 g) was dissolved in dimethyl sulfoxide (30 ml), sodium azide (1.52 g) was added and stirred at room temperature for 2.5 hours. Ice water was added to the reaction solution, extracted with ether, washed twice with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=24:1) to obtain the title compound (1.78 g).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J=7.1Hz), 4.50 (2H, q, J=7.1Hz), 9.95 (1H, s).

[Reference Example 321] Ethyl 6-methyl-6,7-dihydrothiazolo[4,5-d]pyridine-2-carboxylate

The compound obtained in Reference Example 320 (1.56 g) was dissolved in dichloromethane (20 ml), acetic acid (2 ml), methylamine (2N tetrahydrofuran solution, 21 ml) and sodium triacetoxyborohydride (2.98 g) were added and stirred . After 1 hour, additional sodium triacetoxyborohydride (2.98 g) was added, and stirring was continued for 4.5 hours. A 0.5 N aqueous sodium hydroxide solution (100 ml) was added to the reaction solution to make it alkaline, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a brown oil (1.43 g). The oil was dissolved in ethanol (50ml), 10% palladium carbon (2.0g) was added, and hydrogenation was carried out at normal temperature and pressure. After 2.5 hours, filter off the catalyst, concentrate the filtrate, dissolve the residue in dichloromethane (30ml), add trimethyl orthoformate (0.7ml) and boron trifluoride-ether complex (0.3ml), and stir at room temperature 15 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane, and 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=97:3) to obtain the title compound (100 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.1 Hz), 2.95 (3H, s), 4.44 (2H, q, J = 7.1 Hz), 4.87 (2H, s), 7.06 ( 1H, s).

MS (ESI) m/z: 226 (M+H) ⁺ .

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

The compound obtained in Reference Example 321 (463 mg) was dissolved in tetrahydrofuran (20 ml), lithium hydroxide (54.1 mg) and water (4 ml) were added and stirred at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure and dried with a vacuum pump to obtain the title compound (460 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (3H, s), 4.71 (2H, s), 7.03 (1H, s).

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

Condensation of the compound obtained in Reference Example 250 and ethylmethylamine was carried out to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.08, 1.18 (3H, each t, J=7.1 Hz), 1.46 (9H, s), 1.52-1.80 (4H, m), 2.04-2.08 (2H, m) , 2.71-2.77 (1H, m), 2.89, 2.98 (3H, each s), 3.32, 3.39 (2H, each q, J=7.1Hz), 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}cyclohexyl tert-butyl carbamate

The compound (1.44 g) obtained in Reference Example 323 was dissolved in methanol (20 ml), and 10% palladium on carbon (150 mg) was added thereto, followed by stirring under a hydrogen stream. After 24 hours, the catalyst was filtered off, and the solvent was concentrated under reduced pressure to obtain a colorless oil, which was directly used in the following reaction.

This oil was dissolved in dichloromethane (30 ml), and the compound (850 mg) obtained in Reference Example 57, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.27 g), 1-hydroxybenzotriazole monohydrate) (900 mg), N-methylmorpholine (1.34 g), and stirred at room temperature. After 17 hours, dichloromethane and saturated aqueous sodium bicarbonate were added to the reaction solution for liquid separation, the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol:dichloro methane=1:50) to obtain the title compound (1.61 g).

¹ H-NMR (CDCl ₃ ) δ: 1.10, 1.22 (3H, each t, J = 7.1 Hz), 1.43 (9H, s), 1.84-2.17 (6H, m), 2.66 (1H, br.s) , 2.92, 3.03 (3H, each s), 3.35-3.44 (2H, m), 4.20-4.30 (2H, m), 5.30 (1H, br.s), 7.70 (1H, d, J=8.6Hz) , 7.92(1H, d, J=8.6Hz), 8.00(1H, s), 8.40(1H, br.s), 8.56(1H, s), 9.03(1H, s).

MS (FAB) m/z: 489 (M+H) ⁺ .

[Reference Example 325] N-((1S,2R,4S)-2-amino-4-[(7-chloroisoquinolin-3-yl)carbonyl]-4-{[ethyl(methyl)amino] Carbonyl}cyclohexyl)-7-chloroisoquinoline-3-carboxamide

The compound (1.60 g) obtained in Reference Example 324 was dissolved in hydrochloric acid ethanol solution (25 ml), and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was separated by adding dichloromethane and 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with dichloromethane, the combined organic layers were dried over potassium carbonate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue to collect the precipitate by filtration to obtain the title compound (1.22 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.10, 1.23 (3H, each t, J = 7.1 Hz), 1.26 (2H, br.s), 1.69-2.11 (6H, m), 2.89 (1H, br.s), 2.93, 3.05 (3H, each s), 3.38-3.45 (2H, m), 3.52 (1H, s), 4.18 (1H, br.s), 7.70 (1H, dd, J=8.8 , 2.0Hz), 7.94(1H, d, J=8.8Hz), 8.02(1H, d, J=2.0Hz), 8.50(1H, br.s), 8.59(1H, s), 9.11(1H, s ).

MS (FAB) m/z: 389 (M+H) ⁺ .

[Reference Example 326] (1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl Ethyl alkane carboxylate

The compound obtained in Reference Example 88 (28.0 g) was dissolved in N,N-dimethylformamide (500 ml), and tert-butyldiphenylsilyl chloride (63.5 ml) and imidazole (19.9 g) were added. After stirring at room temperature for 10 hours, ethyl acetate and water were added to the reaction liquid for liquid separation. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed twice with water. After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→47:3) to obtain N,N-dimethyl The title compound (52.5 g) as methyl formamide.

¹ H-NMR (CDCl ₃ ) 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)cyclohexanecarbamate tert-butyl ester

Under argon replacement, lithium aluminum hydride (7.11 g) was suspended in dry ether (100 ml) at 0°C, and an ether solution (500 ml) of the compound (52.5 g) obtained in Reference Example 326 was added dropwise over 30 minutes. After stirring at 0°C for 30 minutes, methanol (100 ml) was added dropwise to the reaction solution. 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).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.32-1.74 (16H, m), 1.87 (1H, t, J=10.4Hz), 3.35-3.55 (2H, m), 3.71 (1H , br.s), 3.79 (1H, br.s), 4.36 (1H, br.s), 7.34-7.44 (6H, m), 7.65-7.72 (4H, m).

[Reference Example 328] Methanesulfonic acid ((1R ^* , 3S ^* , 4S ^* )-3-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(diphenyl)silyl]oxy Cyl}cyclohexyl) methyl ester

The compound obtained in Reference Example 327 (29.5 g) was dissolved in dichloromethane (200 ml) and pyridine (20 ml), methanesulfonyl chloride (9.5 ml) was added, and stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed twice with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (29.8 g).

¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 1.38 (9H, s), 1.43-1.61 (5H, m), 1.86-1.89 (2H, m), 3.02 (3H, s), 3.77 (1H, br.s), 3.81 (1H, br.s), 4.10 (2H, d, J=5.4Hz), 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)cyclohexanecarbamate tert Butyl ester

The compound obtained in Reference Example 328 (29.8 g) was dissolved in N,N-dimethylformamide (400 ml), sodium cyanide (3.64 g) was added, and stirred at 80° C. for 11 hours. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction solution for liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (20.6 g).

¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 1.38 (9H, s), 1.43-1.68 (5H, m), 1.79-1.85 (1H, m), 1.88-1.95 (1H, m) , 2.32(2H, d, J=7.1Hz), 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)cyclohexaneamino tert-butyl formate

The compound (2.00 g) obtained in Reference Example 329 was dissolved in anhydrous dichloromethane (20 ml), replaced with argon, and then cooled to -78°C. Diisobutylaluminum hydride (0.95 M hexane solution, 8.55 ml) was added dropwise thereto, and then the mixture was warmed up to room temperature and stirred for 3 hours. After cooling the reaction solution to 0°C, methanol (10 ml) 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).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.38 (9H, s), 1.43-1.54 (5H, m), 1.82-1.88 (1H, m), 2.06 (1H, br.s) , 2.42-2.43(2H, m), 3.72(1H, br.s), 3.77(1H, br.s), 4.38(1H, br.s), 7.34-7.44(6H, m), 7.65-7.68( 4H, m), 9.77 (1H, t, J=1.7Hz).

MS (FAB) m/z: 496 (M+H) ⁺ .

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

The compound (8.40g) obtained in Reference Example 330 was dissolved in a mixed solvent of water (33ml) and tert-butanol (120ml), and then 2-methyl-2-butene (8.08ml), sodium dihydrogen phosphate di Hydrate (2.64g) and sodium chlorite (3.45g), stirred at room temperature for 1.5 hours. Dichloromethane and water were added to the reaction solution for dilution, and the pH of the aqueous layer was adjusted to about 4 with 1N hydrochloric acid aqueous solution. After separation, the aqueous layer was extracted twice 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).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.22-1.63 (15H, m), 1.82 (1H, br.s), 2.17 (1H, br.s), 2.27-2.33 (1H, m), 3.69(1H, br.s), 3.84(1H, br.s), 7.00(1H, br.s), 7.33-7.42(6H, m), 7.63-7.65(4H, m).MS( ESI) m/z: 512(M+H) ⁺ .

[Reference Example 332] (1R ^* , 2R ^* , 5S ^* )-2-{[tert-butyl(diphenyl)silyl]oxy}-5-[2-(dimethylamino)-2- tert-Butyl Oxoethyl]cyclohexanecarbamate

The compound (7.62g) obtained in Reference Example 331 was dissolved in N,N-dimethylformamide (150ml), and dimethylamine hydrochloride (6.07g), 1-(3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (8.56g), 1-hydroxybenzotriazole monohydrate (1.01g) and triethylamine (10.3ml), stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue for 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).

¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 1.38 (9H, br.s), 1.43-1.55 (5H, m), 1.79-1.86 (1H, m), 2.03 (1H, br. s), 2.21-2.32(2H, s), 2.94(3H, s), 3.03(3H, s), 3.74(1H, br.s), 3.80(1H, br.s), 4.49(1H, br.s) 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-hydroxycyclohexanecarbamate tert-butyl ester

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

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.46-1.60 (4H, m), 1.79-1.84 (2H, m), 2.28-2.35 (3H, s), 2.82 (1H, br. s), 2.95(3H, s), 3.01(3H, s), 3.56(2H, br.s), 4.67(1H, br.s).

MS (ESI) m/z: 301 (M+H) ⁺ .

[Reference Example 334] Methanesulfonic acid (1R ^* , 2R ^* , 4S ^* )-2-[(tert-butoxycarbonyl)amino]-4-[2-(dimethylamino)-2-oxoethyl ] cyclohexyl ester

The compound obtained in Reference Example 333 (8.05 mg) was dissolved in dichloromethane (50 ml), cooled to -78°C under an argon atmosphere, and methanesulfonyl chloride (2.70 ml) was added dropwise. After raising the temperature to 0°C and stirring for 30 minutes, the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution for liquid separation, 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 distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane:ethyl acetate=1:1→0:1) to obtain the title compound (3.63 g).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.59-1.74 (4H, m), 1.85-2.30 (5H, m), 2.95 (3H, s), 3.00 (3H, s), 3.10 (3H, s), 3.79-3.83 (1H, m), 4.72 (1H, br.s), 4.91 (1H, br.s).

MS (ESI) m/z: 379 (M+H) ⁺ .

[Reference Example 335] (1R ^* , 2S ^* , 5S ^* )-2-azido-5-[2-(dimethylamino)-2-oxoethyl]cyclohexanecarbamate tert-butyl ester

The compound obtained in Reference Example 334 (3.62 g) was dissolved in N,N-dimethylformamide (20 ml), sodium azide (3.11 g) was added, and stirred at 75° C. for 17 hours. The reaction solution was poured into a mixed solution of water and ethyl acetate for liquid separation. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with water, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (ethyl acetate) to obtain the title compound (1.30 g).

¹ H-NMR (CDCl ₃ ) 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-chloroind Indole-2-carboxamide hydrochloride

In the same manner as in Reference Example 324, the compound obtained in Reference Example 335 was catalytically reduced, and the product obtained by condensation with 5-chloroindole-2-carboxylic acid was treated in the same manner as in Reference Example 69 to obtain the title compound .

¹ H-NMR (DMSO-d ₆ ) 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)-tert-butyl 2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(hydroxymethyl)cyclohexanecarbamate

Using the same method as in 2) of Reference Example 129, the title compound was prepared from the compound obtained in Reference Example 97

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

The compound obtained in Reference Example 337 (500 mg) and triethylamine (329 ml) were dissolved in tetrahydrofuran (8 ml)-dichloromethane (8 ml), and cooled at -78°C. Methanesulfonyl chloride (138 ml) was added dropwise to this solution, and the liquid temperature was gradually raised to -5°C, followed by stirring at the same temperature for 15 hours. After concentrating the reaction solution, water was added to the residue, followed by extraction with dichloromethane three 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).

¹ H-NMR (CDCl ₃ ) 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]cyclohexanecarbamate Butyl ester

The compound obtained in Reference Example 338 (654 mg) was dissolved in N,N-dimethylformamide (8 ml), 15% aqueous sodium thiomethoxide (1.8 ml) was added, and stirred at room temperature for 4 hours. The reaction solution was poured into water, and extracted three times with ethyl acetate. The organic layer was washed with 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).

¹ H-NMR (CDCl ₃ ) δ: 1.52 (9H, s), 1.87-3.04 (13H, m), 3.91-3.94 (1H, m), 4.12-4.15 (1H, m), 4.95 (1H, br. s), 6.81(1H, s), 7.19(1H, dd, J=8.8, 1.2Hz), 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]cyclohexanecarbamate tert-butyl ester

The compound obtained in Reference Example 339 (300 mg) was dissolved in dichloromethane (10 ml), and m-chloroperbenzoic acid (70%, 400 mg) was added with stirring at 0°C. 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), separated with saturated aqueous sodium bicarbonate and ethyl acetate, and the organic layer was concentrated to obtain the title compound (254 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.44-2.19 (13H, m), 2.22-2.30 (2H, m), 2.89-3.25 (7H, m), 3.93-4.15 (2H, m), 4.98 (1H, br.s), 6.82(1H, s), 7.21(1H, dd, J=8.8, 2.0Hz), 7.34(1H, d, J=8.8Hz), 7.60(1H, br.s), 9.54(1H , br.s).

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

5-Chlorothiophene-3-carboxylic acid (Monatsh.Chem., 1989, volume 120, page 53) (6.93g) was dissolved in tetrahydrofuran (750ml), triethylamine (27.3ml), ethyl chloroformate ( 18.7ml), stirred at room temperature for 2.5 hours. Then, an aqueous solution (41 ml) of sodium borohydride (19.3 g) was added dropwise over 10 minutes, followed by stirring at room temperature for 18.5 hours. After adding acetic acid to the reaction solution to make it acidic, the solvent was distilled off under reduced pressure. Water and dichloromethane were added to the residue to separate, and the organic layer was washed with water and saturated aqueous sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (ethyl acetate:hexane=1:4) to obtain the title compound (5.17 g).

¹ H-NMR (CDCl ₃ ) 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 (5.17 g) obtained in Reference Example 341 was dissolved in dichloromethane (400 ml), and manganese dioxide (51.3 g) was added thereto, followed by stirring at room temperature for 15 hours. After the reaction liquid was filtered, the solvent was distilled off under reduced pressure to obtain the title compound (2.84 g).

¹ H-NMR (CDCl ₃ ) δ: 7.35 (1H, d, J=1.7Hz), 7.88 (1H, d, J=1.7Hz), 9.75 (1H, s).

[Reference Example 343] Ethyl 2-azido-3-(5-chlorothien-3-yl)acrylate

Add ethanol (15 ml) to 20% ethanol solution of sodium ethoxide (10.7 ml), and after cooling at 0° C., drop the compound (1.01 g) obtained in Reference Example 342 and ethyl azidoacetate (3.55 ml) in 30 minutes. g) was stirred at 0°C for 3 hours. Added cold ammonium chloride aqueous solution to the reaction liquid, extracted 3 times with ether. The organic layers were combined, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate:hexane=1:49) to obtain the title compound (1.04 g).

¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J=7.1Hz), 4.34 (2H, q, J=7.1Hz), 6.75 (1H, s), 7.39 (1H, d, J=1.7 Hz), 7.54 (1H, d, J=1.7Hz).

[Reference Example 344] Ethyl 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate

The compound (0.97 g) obtained in Reference Example 343 was dissolved in xylene (20 ml), and heated under reflux for 30 minutes. After cooling, the solvent was distilled off under reduced pressure. Hexane was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (0.608 g).

¹ H-NMR (CDCl ₃ ) δ: 1.38 (3H, t, J=7.0Hz), 4.35 (2H, q, J=7.0Hz), 6.90 (1H, s), 7.00 (1H, d, J=1.9 Hz), 9.32 (1H, br).

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

The title compound was prepared from the compound obtained in Reference Example 344 in the same manner as in Reference Example 274.

¹ H-NMR (CD ₃ OD) δ: 3.35 (1H, s), 6.94 (1H, s), 6.96 (1H, s).

MS(ESI)m/z: 200(MH) ^- .

[Reference Example 346] 1-chloro-4-(2,2-dibromovinyl)benzene

4-Chlorobenzaldehyde (2.81g) was dissolved in dichloromethane (300ml), carbon tetrabromide (13.3g) and triphenylphosphine (21.0g) were added, and stirred at room temperature for 90 minutes. After the precipitated insoluble matter was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the title compound (5.54 g).

¹ H-NMR (CDCl ₃ ) δ: 7.33 (2H, d, J=8.5Hz), 7.43 (1H, s), 7.47 (2H, d, J=8.5Hz).

MS (EI) m/z: 296 (M ⁺ ).

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

The compound obtained in Reference Example 346 (1.0 g) was dissolved in tetrahydrofuran (30 ml), and n-butyllithium (1.59N hexane solution, 4.46 ml) was added dropwise at -78°C under argon flow. The reaction solution was warmed up to room temperature and then stirred for 1 hour. The reaction solution was cooled to -78°C again, stirred for 2 minutes under a stream of carbon dioxide, and then warmed up to room temperature. After the reaction solution was concentrated under reduced pressure, saturated brine and ethyl acetate were added to the residue for liquid separation. 3N hydrochloric acid was added to the aqueous layer to make it acidic, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (453 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 7.55 (2H, d, J=8.5Hz), 7.66 (2H, d, J=8.5Hz), 13.90 (1H, br.s).

MS (EI) m/z: 180 (M ⁺ ).

[Reference Example 348] Ethyl 6-chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylate

Ethyl chlorooxyacetate (2.0 ml) was added to a solution of 2-amino-5-chlorobenzamide (2.50 g) in pyridine (15 ml), followed by stirring at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in acetic acid (50 ml), acetic anhydride (5.0 ml) was added and the mixture was heated under reflux for 16 hours. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and the precipitated crystals were collected by filtration and washed to obtain the title compound (2.71 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.35 (3H, t, J = 7.1 Hz), 4.38 (2H, q, J = 7.1 Hz), 7.85 (1H, d, J = 8.6 Hz), 7.91 ( 1H, dd, J=8.6, 2.3Hz), 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

Lithium hydroxide (263 mg) was added to a mixed solution of the compound (1.26 g) obtained in Reference Example 348 in water (5 ml)-tetrahydrofuran (15 ml), followed by stirring at room temperature for 18 hours. Under ice-cooling, the reaction solution was neutralized with 1N hydrochloric acid (11 ml), and stirred for 1 hour. The precipitated crystals were collected by filtration and washed with water to obtain the title compound (0.96 g).

¹ H-NMR (DMSO-d ₆ ) δ: 7.50-8.20 (3H, m), 12.44 (1H, br.s).

MS (ESI) m/z: 265 (M+H+CH ₃ CN) ⁺ .

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

p-Chloroaniline (3.82g) was dissolved in ethyl acetate (30ml), and chloroacetyl chloride (2.39ml) was added at room temperature, followed by stirring for 1 hour. After heating and stirring the reaction solution at 60°C for 3.5 hours, 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).

¹ H-NMR (CDCl ₃ ) 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] Sodium S-[2-(4-chloroanilino)-2-oxoethyl]thiosulfate

The compound (5.79g) obtained in Reference 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°C, and heated to reflux for 1.5 hours. After the reaction solution was concentrated to about 1/10, the precipitated powder was collected by filtration to obtain the title compound (8.20 g).

¹ H-NMR (DMSO-d ₆ ) 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 (3.85 g) was dissolved in ethyl acetate (60 ml), and chloroacetyl chloride (2.39 ml) was added at room temperature and stirred for 1 hour. After heating and stirring the reaction solution at 60°C for 30 minutes, chloroacetyl chloride (0.5 ml) was added and stirred at 60°C for 1 hour. The precipitated powder was collected by filtration to obtain the title compound (6.18 g).

¹ H-NMR (DMSO-d ₆ ) δ: 4.36 (2H, s), 7.94 (1H, dd, J=8.8, 2.7Hz), 8.09 (1H, d, J=8.8Hz), 8.40 (1H, d , J=2.7Hz), 11.03(1H, s).

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

Under stirring at 80° C., in a solution obtained by dissolving the compound (6.18 g) obtained in Reference Example 352 in ethanol (130 ml), dissolved sodium thiosulfate 5 hydrate (6.35 g) and sodium bicarbonate (2.15 ml) were added in one portion. g) in an aqueous solution (130ml), heated to reflux at an external temperature of 110°C for 2 hours. Concentrate to dryness under reduced pressure, add ethanol (500ml) to the residue, heat and extract twice. The extract was concentrated to about 1/20, diethyl ether was added, and the precipitated insoluble matter was collected by filtration to obtain the title compound (6.65 g).

¹ H-NMR (DMSO-d ₆ ) δ: 3.77 (2H, s), 7.89 (1H, dd, J=9.0, 2.7Hz), 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 obtained in Reference Example 253 (100 mg) was dissolved in ethyl acetate (10 ml), chloroacetyl chloride (21.6 µl) was added, and the mixture was heated and stirred at 60°C for 30 minutes. After standing to cool, the insoluble matter was collected by filtration, dissolved in dichloromethane-methanol, and the solvent was distilled off under reduced pressure to obtain the crude title compound (112 mg).

¹ H-NMR (DMSO-d ₆ ) 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}thiosulfate sodium salt

The compound (106 mg) obtained in Reference Example 354 was dissolved in ethanol (1.5 ml), and an aqueous solution (1.5 ml) in which sodium thiosulfate 5 hydrate (55 mg) and sodium bicarbonate (18.6 mg) were dissolved was added in one portion with stirring at 90°C. ), heated to reflux for 1 hour. Concentrate to dryness under reduced pressure, add ethanol (10 ml) to the residue, and extract while heating. The extract was concentrated to about 1/2, isopropyl ether (10 ml) was added, and the precipitated insoluble matter was collected by filtration to obtain the title compound (72 mg).

¹ H-NMR (DMSO-d ₆ ) 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 (1.25 ml) and diphenylphosphoryl azide (1.55 ml) were added to a suspension of 5-chlorothiophene-2-carboxylic acid (0.99 g) in toluene (20 ml), and stirred at 80°C for 1 hour. After the reaction solution was cooled to room temperature, tert-butanol (2 ml) was added, and the mixture was heated to reflux for 19 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (200 ml) was added to the obtained residue, washed with distilled water, 10% aqueous citric acid solution, distilled water, saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain tert-butyl 5-chloro-2-thienylcarbamate (1.05 g).

¹ H-NMR (CDCl ₃ ) 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 above product (1.87 g) was added to 4N hydrochloric acid dioxane solution (40 ml), stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. The residue was suspended in tetrahydrofuran (50 ml), sodium bicarbonate (2.02 g) and methyl chlorooxyacetate (0.883 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, water and methylene chloride were added to the residue for liquid separation, 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 distilled off to obtain the title compound (1.44 g).

¹ H-NMR (CDCl ₃ ) δ: 3.98 (3H, s), 6.61 (1H, d, J=4.2Hz), 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

By the same method as described in Reference Example 242, the title compound was obtained from 2-amino-5-fluoropyridine and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

By the same method as described in Reference Example 242, the title compound was obtained from 4-chloro-2-trifluoroaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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 (28 mg) was added to a mixed solution of the compound (297 mg) obtained in Reference Example 358 in tetrahydrofuran (7 ml)-water (3 ml), followed by stirring at room temperature for 2 hours. 1N hydrochloric acid (8 ml) and dichloromethane (20 ml) were added to the reaction solvent, and a liquid separation operation was performed. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated and dried under reduced pressure to obtain the title compound (291 mg).

¹ H-NMR (CDCl ₃ ) 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, anion) m/z: 267 (MH) ^- .

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

In the same manner as in Reference Example 143, condensation of 5-chloro-2-nitrobenzoic acid and dimethylamine was carried out to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 2.86 (3H, s), 3.16 (3H, s), 7.38 (1H, d, J=2.2Hz), 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

Add iron trichloride hexahydrate (9.93g) and zinc powder (8.01g ), heated to reflux for 20 minutes. The reaction solution was filtered through Celite 545, and ethyl acetate (200 ml) was added to the filtrate for liquid separation. The aqueous layer was washed with ethyl acetate (100ml×2), and the combined organic layers were washed with distilled water (100ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting 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) .

¹ H-NMR (CDCl ₃ ) 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

In the same manner as in Reference Example 242, the title compound was obtained from the compound obtained in Reference Example 361 and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

In the same manner as in Reference Example 361, the title compound was obtained from 5-chloro-2-nitroanisole.

¹ H-NMR (CDCl ₃ ) 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

In the same manner as in Reference Example 242, the title compound was obtained from the compound obtained in Reference Example 363 and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

Using the same method as the method described in the literature (Cilchrist, T.L.; Peek, M.E.; Rees, C.W.; J.Chem.Soc.Chem.Commun., 1975, 913.), from 4-chloroaniline (3.03g) and 2 -Ethyl chloro-2-hydroxyiminoacetate to prepare the title compound.

¹ H-NMR (CDCl ₃ ) 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 (ESI) m/z: 243 (M+H) ⁺ .

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

To a solution of the compound obtained in Reference Example 365 (350 mg) in ethanol (5.0 ml) was added the compound obtained in Reference Example 144 (597 mg), followed by stirring at 70°C for 3 days. The reaction solution 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).

¹ H-NMR (CD ₃ OD) δ: 1.46 (9H, s), 1.47-1.84 (6H, m), 1.88-1.95 (1H, m), 2.90 (3H, s), 3.08 (3H, s), 3.90-3.97(1H, m), 4.11-4.17(1H, m), 6.84(2H, d, J=8.8Hz), 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)piperidine-3 - tert-butyl carbamate

From the compound obtained in Reference Example 374 and the compound obtained in Reference Example 220, the title compound was prepared in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.55-1.75 (1H, br), 1.94-2.07 (1H, br), 2.70-3.00 (1H, m), 3.10-3.37 (1H, m), 3.44(3H, s), 3.88-4.22(4H, m), 4.55-4.69(1H, br), 4.80-4.90(0.5H, br), 5.36-5.48(0.5H, br), 7.20- 7.30(1H, br), 7.32(2H, d, J=8.8Hz), 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 Base) tert-butyl piperidin-3-ylcarbamate

The title compound was prepared from the compound obtained in Reference Example 266 and the compound obtained in Reference Example 220 in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ )6: 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, brd, 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 Base) tert-butyl piperidin-3-ylcarbamate

The title compound was prepared from the compound obtained in Reference Example 375 and the compound obtained in Reference Example 220 in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.75 (1H, m), 1.95-2.13 (1H, br), 2.70-2.98 (1H, m), 3.05-3.36 (1H, m), 3.45(3H, s), 3.80-4.24(4H, m), 4.57-4.73(1H, br), 4.85-4.95(0.25H, br), 5.10-5.15(0.25H, br), 5.45- 5.58 (0.5H, br), 7.30-7.38 (1H, m), 7.84 (1H, dd, J=8.8, 2.2Hz), 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-oxopropionate

At room temperature, add ethyl malonate potassium salt (3.2 g), 1-hydroxybenzotriazole (2.1 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 g), stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and 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).

¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.3Hz), 3.47 (2H, s), 4.26 (2H, q, J = 7.3Hz), 7.29 (2H, d, J = 8.8 Hz), 7.51 (2H, d, J=8.8Hz), 9.32 (1H, br.s).

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

To a solution of the compound (1.0 g) obtained in Reference Example 370 in ethanol (10 ml) was added dropwise 1N aqueous sodium hydroxide solution (10 ml) at room temperature and stirred for 2 hours. 1N aqueous hydrochloric acid solution (10 ml) was added to the reaction solution, and after stirring, the precipitated insoluble matter was collected by filtration to obtain the title compound (0.5 g).

¹ H-NMR (DMSO-d ₆ ) 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-oxopropionate

In the same manner as in Reference Example 370, the title compound was obtained by condensation of 3-chloroaniline and ethyl malonate potassium salt.

¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.3Hz), 3.47 (2H, s), 4.26 (2H, q, J = 7.3Hz), 7.09 (1H, d, J = 8.8 Hz), 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-oxopropionic acid

The title compound was prepared from the compound obtained in Reference 372 in the same manner as in Reference Example 371.

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Reference Example 242 in the same manner as in Reference Example 359.

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Reference Example 262 in the same manner as in Reference Example 359.

¹ H-NMR (DMSO-d ₆ ) 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

Under ice-cooling, sodium chlorite (17g) was added in small amounts each time in a mixed solution formed by 4-chloro-3-fluorobenzaldehyde (10g), sulfamic acid (18g), tert-butanol (50ml) and water (50ml). ), stirring for 4 days while slowly warming up to room temperature. The reaction solution was diluted with ethyl acetate, washed with water, 1N aqueous hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and after distilling off the solvent under reduced pressure, the resulting residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g).

¹ H-NMR (DMSO-d ₆ ) δ: 7.72 (1H, dt, J=8.3, 1.5Hz), 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

In the same manner as in Reference Example 356, the compound obtained in Reference Example 376 was subjected to Curtis rearrangement reaction, and then condensed with methyl chlorooxyacetate to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 7.25-7.27 (1H, m), 7.39 (1H, t, J=8.5Hz), 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 prepared from the compound obtained in Reference Example 377 in the same manner as in Reference Example 359.

¹ H-NMR (DMSO-d ₆ ) 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-oxopropionate

Under ice-cooling, triethylamine (17 ml) and magnesium chloride (5.5 g) were added to a suspension of ethyl malonate potassium salt (8.2 g) in ethyl acetate (100 ml), and the mixture was stirred for 18 hours while gradually raising the temperature to room temperature. In addition, after heating a suspension formed of 4-chlorobenzoic acid (5.0 g), thionyl chloride (12 ml), N,N-dimethylformamide (1 drop) and toluene (100 ml) under reflux for 1 hour, The reaction solution was concentrated. The resulting residue was dissolved in ethyl acetate, added dropwise to the above reaction solution under ice cooling, and stirred for 18 hours while gradually raising the temperature to room temperature. Add 10% citric acid aqueous solution to the reaction solution, stir for 30 minutes, and separate the organic layer. The obtained organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (6.4 g).

¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.3Hz), 3.96 (2H, s), 4.21 (2H, q, J = 7.3Hz), 7.46 (2H, d, J = 8.8 Hz), 7.89 (2H, d, J=8.8Hz).

[Reference Example 380] Ethyl 3-(4-chlorophenyl)-3-hydroxypropionate

Under ice-cooling, sodium borohydride (0.2 g) was added a little at a time to a tetrahydrofuran (10 ml) solution of the compound (1.0 g) obtained in Reference Example 379, and the mixture was stirred for 2 hours while gradually raising the temperature to room temperature. A 10% aqueous citric acid solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (chloroform) to obtain the title compound (0.56 g).

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 380 in the same manner as in Reference Example 359.

¹ H-NMR (DMSO-d ₆ ) δ: 3.25-3.32 (1H, m), 4.89-4.95 (1H, m), 5.45-5.53 (1H, m), 7.35-7.36 (5H, m), 12.11- 12.18(1H, m).

MS (ESI, anion) m/z: 198 (MH) ^- .

[Reference Example 382] (1R, 2S, 5S)-2-{[3-(4-chlorophenyl)-3-hydroxypropionyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylamino tert-butyl formate

The title compound was obtained by condensation of the compound obtained in Reference Example 144 and the compound obtained in Reference Example 381 in the same manner as in Reference Example 91.

¹ H-NMR (CDCl ₃ ) δ: 1.21-1.44 (2H, m), 1.46 (9H, s), 1.76-1.92 (2H, m), 1.95-2.10 (2H, m), 2.40-2.55 (2H, m), 2.55-2.68(1H, m), 2.94(3H, s), 3.05(3H, s), 3.82-3.96(1H, m), 4.02-4.17(1H, m), 4.65-4.80(2H, m), 5.03-5.13 (1H, m), 7.28-7.33 (5H, m).

MS (ESI) m/z: 468 (M+H) ⁺ .

[Reference Example 383] (1R, 2S, 5S)-2-{[3-(4-chlorophenyl)-3-oxopropionyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl tert-butyl carbamate

To a solution of the compound obtained in Reference Example 382 (0.5 g) in 1,4-dioxane (20 ml) was added manganese dioxide (0.47 g) at room temperature, followed by stirring for 4 days. The insoluble matter was filtered off through a pad of celite, and the resulting filtrate was concentrated under reduced pressure to obtain the title compound (0.46 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.28-1.39 (1H, m), 1.40 (9H, s), 1.41-1.63 (3H, m), 2.25-2.42 (2H, m), 2.76 (3H, s), 2.90-2.97(1H, m), 2.98(3H, s), 3.56(2H, s), 3.89-3.97(1H, m), 4.88-4.98(1H, m), 6.65-6.70(1H, m), 7.30-7.35 (4H, m), 7.33 (1H, dd, J=2.9, 1.7Hz).

MS (ESI, anion) m/z: 464 (MH) ^- .

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

The title compound was prepared from the compound obtained in Reference Example 248 in the same manner as in Reference Example 249.

[α] ²⁵ _D +62° (c=1, chloroform)

¹ H-NMR (CDCl ₃ ) 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]cyclohexanecarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 384 in the same manner as in Reference Example 250 and Reference Example 251.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.40-2.20 (6H, m), 2.70-2.80 (1H, m), 2.93 (3H, s), 3.03 (3H, s), 3.60 -3.78(1H, m), 3.83-3.95(1H, m), 4.65(1H, d, J=7.2Hz).

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

The title compound was prepared by converting the azido group of the compound obtained in Reference Example 385 into an amino group in the same manner as in Reference Example 90, and then condensing with the compound obtained in Reference Example 266 in the same manner as in Reference Example 91.

¹ H-NMR (CDCl ₃ ) δ: 1.13-2.25 (16H, m), 2.94 (3H, s), 3.03 (3H, s), 3.60-3.78 (1H, m), 4.13-4.31 (1H, m) , 4.45-4.65 (1H, m), 7.80 (1H, dd, J=8.8, 2.4Hz), 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 prepared from the compound obtained in Reference Example 385 and the compound obtained in Reference Example 10 in the same manner as in Reference Example 252.

¹ H-NMR (CDCl ₃ ) δ: 1.75-2.08 (6H, m), 2.20-2.32 (1H, m), 2.51 (3H, s), 2.75-2.97 (4H, m), 2.95 (3H, s) , 3.04(3H, s), 3.65-3.80(3H, m), 4.27-4.39(1H, m), 7.17-7.28(1H, m).

MS (ESI) m/z: 392 (M+H) ⁺ .

[Reference Example 388] tert-butyl 4-[(2-methoxy-2-oxoacetyl)amino]piperidine-1-carboxylate

In the same manner as in Reference Example 242, the title compound was obtained from (4-amino-N-tert-butoxycarbonyl)piperidine and methyl chlorooxyacetate.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (9H, s), 1.34-1.51 (2H, m), 1.89-1.98 (2H, m), 2.82-2.96 (2H, m), 3.91 (3H, s), 3.88-4.14(3H, m), 6.96-7.07(1H, m).

MS (FAB) m/z: 287 (M+H) ⁺ .

[Reference Example 389] 4-{[2-({(1R, 2S, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino) Carbonyl]cyclohexyl}amino)-2-oxoacetyl]amino}piperidine-1-carboxylate tert-butyl

The title compound was prepared from the compound obtained in Reference Example 310 and the compound obtained in Reference Example 388 in the same manner as in Reference Example 191.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (9H, s), 1.35-2.28 (11H, m), 2.70-3.18 (9H, m), 3.80-4.57 (4H, m), 6.78 (1H, s), 7.15-8.12 (6H, m), 9.45 (1H, s).

MS (FAB) m/z: 617 (M+H) ⁺ .

[Reference Example 390] Methyl 2-[(5-chloropyridin-2-yl)(methyl)amino]-2-oxoacetate

In the same manner as in Reference Example 242, the title compound was prepared from 5-chloro-N-methyl-2-pyridinamine and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 3.43 (3H, s), 3.81 (3H, s), 7.08 (1H, br.s), 7.68-7.78 (1H, m), 8.27 (1H, br.s) .

MS (ESI) m/z: 229 (M+H) ⁺ .

[Reference Example 391] Methyl 2-[(5-chloro-pyrimidin-2-yl)amino]-2-oxoacetate

In the same manner as in Reference Example 242, the title compound was prepared from 2-amino-5-chloropyrimidine and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 8.63 (2H, s), 9.58 (1H, br.s).

MS (ESI) m/z: 215 (M+H) ⁺ .

[Reference Example 392] N-((1R,2S,5S)-2-azido-5-{[ethyl(methyl)amino]carbonyl}cyclohexyl)-5-methyl-5,6-di Hydrogen-4H-pyrrolo[3,4-d]thiazole-2-carboxamide

The title compound was prepared from the compound obtained in Reference Example 323 and the compound obtained in Reference Example 293 in the same manner as in Reference Example 252.

¹ H-NMR (CDCl ₃ ) δ: 1.08, 1.15 (3H, each t, J = 7.1 Hz), 1.74-1.88 (4H, m), 2.12-2.22 (2H, m), 2.67 (3H, s) , 2.81-2.86(1H, m), 2.89, 2.96(3H, each s), 3.28-3.43(2H, m), 3.91-4.10(5H, m), 4.60-4.62(1H, m), 7.21( 1H, d, J=7.6Hz).

MS (ESI) m/z: 392 (M+H) ⁺ .

[Reference Example 393] Methyl 2-(4-chloro-3-methoxyanilino)-2-oxoacetate

The amino compound was obtained by reducing 2-chloro-5-nitroanisole in the same manner as in Reference Example 361, and then condensed with methyl chlorooxyacetate in the same manner as in Reference Example 242 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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 Reference Example 393 in the same manner as in Reference Example 359.

¹ H-NMR (DMSO-d ₆ ) δ: 3.81 (3H, s), 7.36 (1H, d, J = 8.7Hz), 7.43 (1H, d, J = 8.7Hz), 7.65 (1H, d, J =2.2Hz), 10.79(1H,s).

MS (ESI, anion) m/z: 288 (MH) ^- .

[Reference Example 395] N ¹ -{(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N ² -(4-chloro-3-methoxybenzene base) oxalamide

The compound obtained in Reference Example 144 and the compound obtained in Reference Example 394 were condensed in the same manner as in Reference Example 97, treated with hydrochloric acid in the same manner as in Reference Example 69, and neutralized with 1N aqueous sodium hydroxide solution. , to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.48-2.00 (8H, m), 2.84-2.93 (1H, m), 2.95 (3H, s), 3.08 (3H, s), 3.33-3.35 (1H, m) , 3.89-3.94 (4H, m), 7.06 (1H, dd, J = 8.5, 2.2Hz), 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

In the same manner as in Reference Example 242, the title compound was obtained from 4-ethynylaniline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) 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

In the same manner as in Reference Example 266, the compound obtained in Reference Example 396 was hydrolyzed with sodium hydroxide to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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

Using the same method as Reference Example 242, 2-amino-5-chloropyrazine and chlorooxo Methyl acetate to prepare the title compound.

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 398 in the same manner as in Reference Example 359.

¹ H-NMR (DMSO-d ₆ ) 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

In the same manner as in Reference Example 242, 4-chloro-3-nitroaniline and methyl chlorooxyacetate were condensed, followed by hydrolysis in the same manner as in Reference Example 359 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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). The proton of the carboxylic acid was not seen.

MS(EI) m/z: 244M ⁺ .

[Reference Example 401] 2-(4-Chloro-2-nitroanilino)-2-oxoacetic acid sodium salt

Using the same method as in Reference Example 242, after condensing 4-chloro-2-nitroaniline and methyl chlorooxyacetate, hydrolyze according to the method described in Reference Example 266, dissolve the resulting residue in methanol, and add 1N Sodium hydroxide aqueous solution, and the resulting precipitate was collected by filtration to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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-pyridinamine

2-Chloro-4-methyl-5-nitropyridine (173 mg) was dissolved in ethanol (5 ml), a catalytic amount of Raney nickel was added, and the mixture was stirred at room temperature for 9 hours under a hydrogen atmosphere. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the title compound (113 mg).

¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 3.85 (2H, br.s), 6.96 (1H, s), 7.74 (1H, s).

MS(EI) m/z: 142M ⁺ .

[Reference Example 403] N ¹ -(2-aminophenyl)-N ² -(4-chlorophenyl)oxalamide

The title compound was prepared by condensation of 1,2-phenylenediamine and the compound obtained in Reference Example 374 in the same manner as in Reference Example 59.

¹ H-NMR (DMSO-d ₆ ) δ: 5.00 (2H, s), 6.59-6.63 (1H, m), 6.78 (1H, dd, J=8.1, 1.2Hz), 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

In the same manner as in Reference Example 252, the compound obtained in Reference Example 323 was treated with hydrochloric acid, deprotected, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (1/2of 3H, t, J=7.2Hz), 1.14 (1/2of 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 saturated aqueous sodium bicarbonate, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain as (4-Chlorophenyl)hydrazine as a brown solid. This was dissolved in benzene (15 ml) and heated to reflux, and a solution of diphenyl carbonate (5.22 g) in benzene (8.0 ml) was added dropwise over 30 minutes. After reflux for 19 hours, cool to room temperature naturally, add benzene (15ml) after concentration, suspend it by ultrasonic wave, add hexane (50ml), stir for 30 minutes, filter the insoluble matter, and obtain the title compound (1.05g) after drying.

¹ H-NMR (CDCl ₃ ) δ: 5.86 (1H, br.s), 6.83-6.92 (3H, m), 7.17 (1H, br.s), 7.20-7.32 (4H, m), 7.37 (2H, t, J=7.7Hz).

MS (ESI) m/z: 263 (M+H) ⁺ .

[Reference Example 406] Lithium salt of 5-tert-butoxycarbonyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 33 in the same manner as in Reference Example 10.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (9H, s), 4.30-4.70 (4H, m).

[Reference Example 407] Benzyl 1-hydroxycyclopropanecarboxylate

Triethylamine (1.0 ml) and benzyl bromide (650 µl) were added to a solution of 1-hydroxycyclopropanecarboxylic acid (409 mg) in tetrahydrofuran (3.0 ml), followed by stirring at room temperature for 23 hours. Dichloromethane and 1N hydrochloric acid aqueous solution were added to the reaction solution, and the mixture was separated into two layers. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (607 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.16 (2H, dd, J=7.9, 4.9Hz), 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 (5.0 ml) solution of the compound (600 mg) obtained in Reference Example 407 were added 60% oily sodium hydride (345 mg) and methyl iodide (900 µl), and refluxed for 28 hours. Ethyl acetate and saturated ammonium chloride aqueous solution were added to the reaction liquid, and the mixture was separated into two layers. The organic layer was washed with brine and dried over sodium sulfate. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain the title compound (340 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.16 (2H, dd, J = 7.9, 4.8 Hz), 1.31 (2H, dd, J = 7.9, 4.8 Hz), 3.42 (3H, s), 5.18 (2H, s ), 7.30-7.39 (5H, m).

MS (FAB) m/z: 207 (M+H) ⁺ .

[Reference Example 409] 1-methoxycyclopropanecarboxylic acid

The title compound was prepared from the compound obtained in Reference Example 408 in the same manner as in Reference Example 152.

¹ H-NMR (CDCl ₃ ) δ: 1.23 (2H, dd, J = 8.0, 4.9 Hz), 1.38 (2H, dd, J = 8.0, 4.9 Hz), 3.45 (3H, s), 8.80-9.00 (1H ,br).

[Reference Example 410] (3R, 4S)-4-{[(7-chloroisoquinolin-3-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-ylamino tert-butyl formate

The title compound was prepared from the compound obtained in Reference Example 220 and the compound obtained in Reference Example 57 in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) 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) tert-butyl piperidin-3-ylcarbamate

The title compound was prepared by condensation of the compound obtained in Reference Example 220 and the compound obtained in Reference Example 377 in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.60-1.75 (1H, m), 1.92-2.08 (1H, m), 2.68-2.80 (0.5H, m), 2.88-3.03 (0.5 H, 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 Base) tert-butyl piperidin-3-ylcarbamate

The title compound was obtained by hydrolyzing the lithium salt of carboxylic acid obtained from the compound obtained in Reference Example 220 and the compound obtained in Reference Example 356 in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) 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 (0.3 H, 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] Ethyl 5-methyl-5H-pyrrolo[3,4-d]thiazolo-2-carboxylate

1) Add ethyl 2-thioacetate (26.75 g) to a solution of 3-bromo-2-butanone (26.36 g) in ethanol (250 ml), and reflux for 14 hours. After the reaction solution was cooled, it was concentrated under reduced pressure, ethyl acetate and saturated brine were added to the residue, and the mixture was separated into two layers. The organic layer was washed with saturated aqueous sodium bicarbonate 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 obtain ethyl 4,5-dimethylthiazole-2-carboxylate (19.53 g).

¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J=7.1Hz), 2.42 (3H, s), 2.44 (3H, s), 4.45 (2H, q, J=7.1Hz).

2) Add N-bromosuccinimide (62.42g) and 2,2'-azobisisobutyronitrile (227mg ), reflux for 42 hours. After cooling the reaction liquid, water and dichloromethane were added, and the layers were separated into two layers. The organic layer was washed with saturated brine, and then concentrated under reduced pressure to obtain a crude product (40.54 g) as a dark brown oil. Triethylamine (8.0 ml) and 2 molar methylamine tetrahydrofuran solution (11.0 ml) were added to an acetonitrile solution (400 ml) of the obtained crude product (8.41 g) at 0°C, followed by stirring at room temperature for 3 days. After the reaction solution was concentrated under reduced pressure, dichloromethane and saturated brine were added to the residue, and the mixture was separated into two layers. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (270 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J=7.1Hz), 3.91 (3H, s), 4.48 (2H, q, J=7.1Hz), 6.73 (1H, d, J=1.7 Hz), 7.30 (1H, d, J=1.7Hz).

MS (ESI) m/z: 211 (M+H) ⁺ .

[Reference Example 414] Ethyl 6-chloro-4-oxo-4H-chromene-2-carboxylate

Under argon substitution, oily about 60% sodium hydride (1.68 g) was added to ethanol (10 ml), and the mixture was stirred at room temperature for 10 minutes. After adding diethyl oxalate (3.36ml), add dropwise the ethanol solution (20ml) of 5'-chloro-2'-hydroxyacetophenone (2.82g), add ethanol (40ml), and reflux for 1.5 hours. Stir at 50°C for 14 hours. Concentrated sulfuric acid (1.5 ml) and ethanol (10 ml) were added to the mixture, and the mixture was refluxed for 4 hours. After cooling, the solvent was reduced to half by concentration under reduced pressure, and toluene and 1N aqueous sodium hydroxide solution (15 ml) were added to the concentrate. It 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, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1), and the obtained solid was washed with hexane to obtain the title compound (1.20 g).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.1Hz), 4.47 (2H, q, J = 7.1Hz), 7.12 (1H, s), 7.58 (1H, d, J = 9.0 Hz), 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 prepared from the compound obtained in Reference Example 414 in the same manner as in Reference Example 359.

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 249 in the same manner as in Reference Example 90.

¹ H-NMR (CDCl ₃ ) 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]cyclohexylcarbamate tert-butyl ester

N,N-Dimethylformamide (0.02 ml) was added to a solution of the compound (213 mg) obtained in Reference Example 415 in thionyl chloride (2.0 ml), and the mixture was refluxed for 15 minutes. The reaction solution was concentrated under reduced pressure, the residue was prepared as a solution in tetrahydrofuran (4.0 ml), triethylamine (500 µl) and the compound obtained in Reference Example 144 (294 mg) were added thereto, and the mixture was stirred at room temperature for 15 minutes. Ethyl acetate and 10% citric acid aqueous solution were added to the reaction liquid, and it separated into 2 layers. The organic layer was washed with saturated aqueous sodium bicarbonate 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).

¹ H-NMR (CDCl ₃ ) δ: 1.33-1.77 (3H, m), 1.50 (9H, s), 1.81-2.34 (3H, m), 2.63-2.80 (1H, m), 2.95 (3H, s) , 3.10(3H, s), 3.90-4.04(1H, br), 4.18-4.31(1H, br), 4.93-5.12(1H, br), 7.13(1H, s), 7.55(1H, d, J= 8.8Hz), 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-ylcarbamate tert-butyl ester

The title compound was obtained from the compound obtained in Reference Example 220 and the lithium salt of carboxylic acid obtained by hydrolysis of the ester described in Reference Example 297 in the same manner as in Reference Example 214.

¹ H-NMR (CDCl ₃ ) δ: 1.38 (9H, s), 1.65-1.90 (1H, m), 1.90-2.15 (1H, m), 2.80-3.00 (0.6H, m), 3.00-3.15 (0.4 H, 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-[(dimethyl Amino)carbonyl]cyclohexylcarbamate tert-butyl ester

The title compound was prepared by condensing the compound obtained in Reference Example 144 and the compound obtained in Reference Example 266 in the same manner as in Reference Example 68.

¹ H-NMR (CDCl ₃ ) 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(0.3 H, br), 7.68 (1H, dd, J=8.9, 2.6Hz), 7.83 (1H, br

s), 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] N ¹ -{(1S, 2R, 4S) ^-2 -amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N ² -(5-chloropyridin-2-yl)ethyl Diamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 419 in the same manner as in Reference Example 69.

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.51 (1H, m), 1.65-1.85 (3H, m), 1.96-2.10 (2H, m), 2.81 (3H, s), 3.07 (3H, s), 3.23-3.33(1H, m), 3.74(1H, br s), 3.84-3.92(1H, m), 8.02(1H, dd, J=9.0, 2.5Hz), 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 compound obtained in Reference Example 420 and 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[3,2-c]pyridine-2-carboxylic acid (WO 94/21599) were carried out Condensation affords the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.73-1.95 (3H, m), 1.95-2.06 (1H, m), 2.08-2.20 (2H, m), 2.82 (3H, br s ), 2.94(3H, s), 3.03(3H, s), 3.60-3.80(2H, m), 3.96-4.08(1H, m), 4.44(2H, br s), 4.66(1H, br s), 6.74 (1H, br s), 7.20-7.32 (1H, m), 7.66 (1H, dd, J=9.0, 2.4Hz), 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 in the same manner as in Reference Example 350.

¹ H-NMR (CDCl ₃ ) 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] Sodium S-[2-(4-fluoroanilino)-2-oxoethyl]thiosulfate

The title compound was prepared from the compound obtained in Reference Example 422 in the same manner as in Reference Example 351.

¹ H-NMR (DMSO-d ₆ ) 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} tert-butyl cyclohexylcarbamate

The compound (1.1 g) obtained in Reference Example 144 and the compound (1.24 g) obtained in Reference Example 423 were dissolved in N-methylmorpholine (20 ml), and the bath temperature was raised from room temperature to 140° C. over 15 minutes. Heat and stir at room temperature for 15 minutes. After natural cooling, ice water was added to the reaction solution, and the insoluble matter was collected by filtration. The resulting insoluble matter was purified by silica gel column chromatography (dichloromethane:methanol=200:1→197:3) to obtain the title compound (1.43 g).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.70-2.10 (5H, m), 2.10-2.30 (1H, m), 2.60-2.80 (1H, m), 2.96 (3H, s) , 3.07(3H, s), 4.30-4.50(2H, m), 4.65-4.85(1H, m), 7.06(2H, t, J=8.5Hz), 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

In the same manner as in Reference Example 352, the title compound was prepared from 2-amino-5-fluoropyridine.

¹ H-NMR (DMSO-d ₆ ) δ: 4.35 (2H, s), 7.74-7.82 (1H, m), 8.10 (1H, dd, J=9.0, 4.2Hz), 8.36 (1H, d, J= 2.9Hz), (1H, br s).

MS (ESI) m/z: 188 (M+H) ⁺ .

[Reference Example 426] Sodium S-{2-[(5-fluoropyridin-2-yl)amino]-2-oxoacetyl}thiosulfate

The title compound was prepared from the compound obtained in Reference Example 425 in the same manner as in Reference Example 353.

¹ H-NMR (DMSO-d ₆ ) δ: 3.75 (2H, s), 7.67-7.77 (1H, m), 8.07 (1H, dd, J=9.2, 4.2Hz), 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-oxothio Acetyl}amino)cyclohexylcarbamate tert-butyl

Heat a solution of the compound (1.20 g) obtained in Reference Example 144 in pyridine (70 ml) at 120° C., add the compound (2.42 g) obtained in Reference Example 426, stir for 30 minutes, then cool naturally to room temperature, and evaporate the solvent under reduced pressure . Dichloromethane (100 ml), saturated aqueous sodium bicarbonate solution (100 ml) and water (50 ml) were added to the obtained residue for 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. The resulting residue was purified by silica gel column chromatography (hexane:tetrahydrofuran=1:1), and the obtained solid was treated with isopropyl ether (40ml) for 1 hour. After forming a slurry, it was collected by filtration and dried to obtain the title compound (920 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.70-2.10 (5H, m), 2.27 (1H, br s), 2.70 (1H, br s), 2.96 (3H, s), 3.08 (3H, s), 4.34-4.44 (2H, m), 4.77 (1H, br s), 7.44-7.51 (1H, m), 8.18-8.27 (2H, m), 9.90 (1H, br s), 10.57 (1H, s).

MS (ESI) m/z: 468 (M+H) ⁺ .

[Reference Example 428] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxothioacetyl}amino)-5-[(two Methylamino)carbonyl]cyclohexylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 353 in the same manner as in Reference Example 427.

¹ H-NMR (CDCl ₃ ) 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

Methanol (4.53 g) in 2-chloro-5-oxo-4,5,6,7-tetrahydrobenzo[d]thiazole (Helv. 200ml) solution was added ammonium acetate (18.58g) and sodium cyanoborohydride (10.68g), heated to reflux. After 19 hours, hydrochloric acid was added to decompose the excess reagent, and the reaction solution was concentrated under reduced pressure. After making the reaction solution alkaline with 1N aqueous sodium hydroxide solution, dichloromethane was added to separate the liquid. 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 oil was dissolved in dichloromethane (100ml), and formic acid (530μl), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.68g), 1 -Hydroxybenzotriazole (2.60g) and N-methylmorpholine (3.88g), stirred at room temperature. After 20 hours, dichloromethane and saturated aqueous sodium bicarbonate solution were added to the reaction solution for liquid separation. 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) to obtain the title compound (2.21 g).

¹ H-NMR (CDCl ₃ ) δ: 1.93-2.11 (2H, m), 2.63-2.69 (1H, m), 2.83-2.89 (2H, m), 3.

13(1H, dd, J=16.2, 4.4Hz), 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 (50 ml) solution of the compound (2.11 g) obtained in Reference Example 429 was added a 1 M borane-tetrahydrofuran complex tetrahydrofuran solution (14.6 ml), followed by heating to reflux. After 15 hours, 1 M borane-tetrahydrofuran complex tetrahydrofuran solution (6.0 ml) was added, and the mixture was heated to reflux. After 4 hours, ethanol (10ml) and 1N hydrochloric acid (15ml) were added and heated to reflux. After 3 hours, the reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution and dichloromethane were added, and after separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane (50 ml), triethylamine (1.28 g) and di-tert-butyl dicarbonate (2.21 g) were added thereto, followed by stirring at room temperature. After 30 minutes, dichloromethane and 1N hydrochloric acid were added to separate the layers, 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 (hexane:ethyl acetate=2:1) to obtain the title compound (2.26 g).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.96-1.98 (2H, m), 2.80-2.96 (7H, m), 4.40-4.50 (1H, m).

MS (FAB) m/z: 303 (M+H) ⁺ .

[Reference Example 431] N-(2-[({(1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino) -5-[(Dimethylamino)carbonyl]cyclohexyl}amino)carbonyl]-4,5,6,7-tetrahydrobenzothiazol-6-yl)-N-methylcarbamate tert-butyl

To the ether (10ml)-tetrahydrofuran (5ml) solution of the compound (1.0g) obtained in Reference Example 430, add 1.6N tert-butyllithium pentane solution (3.1ml) cooled to -78°C, and stir for 20 minutes , and introduce carbon dioxide gas for 20 minutes. After the temperature of the reaction solution returned to room temperature, it was concentrated under reduced pressure to obtain lithium 6-[(tert-butoxycarbonyl)(methyl)amino]-4,5,6,7-tetrahydrobenzothiazole-2-carboxylate Salt.

Add lithium carboxylate salt (350.2 mg) and 1-(3-dimethylaminopropyl Base)-3-ethylcarbodiimide hydrochloride (287.6mg), 1-hydroxybenzotriazole (202.7mg) and N-methylmorpholine (0.319ml), stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, water and dichloromethane were added to the residue for liquid separation, and the organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol=40:1→20:1) to obtain the title compound (323.9 mg).

¹ H-NMR (CDCl ₃ ) 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

In the same manner as in Reference Example 69, the compound obtained in Reference Example 310 was deprotected to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 salt of 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate

At 0°C, add methyl chlorooxyacetate (78.7ml) dropwise to a suspension of 2-amino-5-chloropyridine (100g) and sodium bicarbonate (78.4g) in tetrahydrofuran (2000ml), and stir at room temperature for 2 hours . The reaction solution was added to a mixture of diethyl ether (2000ml), ammonium chloride (62.4g) and water (1000ml) with stirring, and the layers were 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, followed by drying to obtain methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (162 g). Water (450 ml) and lithium hydroxide (18.2 g) were added to tetrahydrofuran (1800 ml) of this ester (160 g). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and hexane (3000 ml) was added to the resulting residue and stirred for 3 hours. The solid was collected by filtration, dried, and acetonitrile (1000ml) was added to the obtained solid (190g). After stirring for 1 hour, the resulting solid was collected by filtration, washed with ether (500ml) and dried to obtain the title compound (158g).

¹ H-NMR (DMSO-d ₆ ) 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-[(dimethyl Amino)carbonyl]cyclohexylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 433 in the same manner as in Reference Example 91.

¹ H-NMR (CDCl ₃ ) δ: 1.25-1.55 (1H, m), 1.45 (9H, s), 1.60-2.15 (5H, m), 2.56-2.74 (1H, br), 2.95 (3H, s) , 3.06(3H, s), 3.90-4.01(1H, m), 4.18-4.27(1H, m), 4.70-4.85(0.7H, 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] N ¹ -{(1S,2R,4S)-2-amino-4-[(dimethylamino)carbonyl]cyclohexyl}-N ² -(5-chloropyridin-2-yl)ethyl Diamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 434 in the same manner as in Reference Example 69.

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.51 (1H, m), 1.65-1.85 (3H, m), 1.92-2.09 (2H, m), 2.80 (3H, s), 3.06 (3H, s), 3.20-3.32 (1H, m), 3.55-4.40 (2H, br), 8.02 (1H, dd, J=9.1, 2.5Hz), 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]cyclohexylcarbamate benzyl ester

The title compound was prepared from the compound obtained in Reference Example 142 and methylamine hydrochloride in the same manner as in Reference Example 143.

¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 1.40-1.61 (4H, m), 1.63-1.73 (1H, m), 1.75-1.85 (1H, m), 2.23-2.48 ( 1H, m), 2.53(3H, d, J=4.6Hz), 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]cyclohexylcarbamate tert-butyl ester

The compound obtained in Reference Example 436 was deprotected by the same method as in Reference Example 144, and the obtained amine was condensed with the compound obtained in Reference Example 433 by the same method as in Reference Example 91 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.35-1.75 (3H, m), 1.39 (9H, s), 1.75-1.86 (2H, m), 1.87-1.95 (1H, m), 2.30-2.40 ( 1H, m), 2.55 (3H, d, J=4.6Hz), 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 [(MH) ^- , Cl ³⁵ ], 454 [(MH) ^- , Cl ³⁷ ]

[Reference Example 438] 2-Chloro-N-(5-methylpyridin-2-yl)acetamide hydrochloride

In the same manner as in Reference Example 425, the title compound was obtained from 2-amino-5-picoline.

¹ H-NMR (DMSO-d ₆ ) 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] Sodium S-{2-[(5-methylpyridin-2-yl)amino]-2-oxoethyl}thiosulfate

The title compound was prepared from the compound obtained in Reference Example 438 in the same manner as in Reference Example 353.

¹ H-NMR (DMSO-d ₆ ) 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-oxo tert-butyl thioacetyl}amino)cyclohexylcarbamate

The title compound was prepared from the compound obtained in Reference Example 144 and the compound obtained in Reference Example 439 in the same manner as in Reference Example 427.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.60-2.10 (5H, m), 2.15-2.35 (1H, m), 2.31 (3H, s), 2.60-2.80 (1H, m) , 2.95(3H, s), 3.07(3H, s), 4.30-4.45(2H, m), 4.65-4.85(1H, m), 7.54(1H, dd, J=8.5, 2.0Hz), 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)piper tert-butyl pyridin-3-ylcarbamate

The title compound was prepared by deprotecting the compound obtained in Reference Example 220 by catalytic reduction in the same manner as in Reference Example 214, and then condensing the obtained amine with the compound obtained in Reference Example 351 in the same manner as in Reference Example 427.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.59-1.84 (1H, m), 2.10-2.33 (1H, m), 2.68-2.81 (0.7H, m), 2.94-2.04 (0.3 H, 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) ⁺ , Cl ³⁵ ], 487[(M+H) ⁺ , Cl ³⁷ ].

[Reference Example 442] (1R, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexylcarbamate 9H-fluoren-9-ylmethyl ester

The compound obtained in Reference Example 144 (856 mg) was dissolved in acetone (10 ml), 9-fluorenylmethyl pentafluorophenylcarbamate (1.34 g) and sodium bicarbonate (302 mg) were added, and stirred at room temperature for 2.5 hours. Then, 9-fluorenylmethyl pentafluorophenylcarbamate (609 mg) and sodium bicarbonate (151 mg) were added thereto, followed by heating under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (SI-40B, dichloromethane:methanol=93:7) on silica gel to obtain the title compound (1.47 g).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.30-2.05 (6H, m), 2.63 (1H, br.s), 2.94 (3H, s), 3.04 (3H, s), 3.69 (1H, br.s), 4.15(1H, br.s), 4.21(1H, br.s), 4.37(2H, br.s), 4.73(1H, br.s), 5.41(1H, br.s). s), 7.29 (2H, t, J = 7.3Hz), 7.39 (2H, t, J = 7.3Hz), 7.57 (2H, d, J = 7.3Hz), 7.75 (2H, d, J = 7.3Hz) .

MS (ESI) m/z: 508 (M+H) ⁺ .

[Reference Example 443] (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)thioformyl]cyclohexylcarbamate 9H-fluorene-9- methyl ester

The compound obtained in Reference Example 442 (1.26 g) was dissolved in toluene (50 ml), Ro-Son's reagent (1.00 g) was added, and stirred at 60° C. for 1 hour. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (50 ml), and di-tert-butyl dicarbonate (541 mg) and sodium bicarbonate (208 mg) were added. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1→dichloromethane:methanol=9:1). The title compound (609 mg) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.43-2.10 (6H, m), 2.92 (1H, br.s), 3.31 (3H, s), 3.47 (3H, s), 3.74 (1H, br.s), 4.09-4.19 (2H, m), 4.38 (2H, br.s), 4.75 (1H, br), 5.29 (1H, br.s), 7.29 (2H, t, J= 7.3Hz), 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-[(dimethyl Amino)thioformyl]cyclohexylcarbamate tert-butyl ester

The compound obtained in Reference Example 443 (1.11 g) was dissolved in N,N-dimethylformamide (30 ml), piperazine (3.0 ml) was added, and stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added to the residue for liquid separation. The aqueous layer was extracted twice with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. This residue was condensed with the compound obtained in Reference Example 433 in the same manner as in Reference Example 91 to obtain the title compound (629 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.48-2.23 (6H, m), 2.98 (1H, br.s), 3.36 (3H, s), 3.49 (3H, s), 3.98 -4.04(1H, m), 4.22-4.25(1H, m), 4.75(1H, br.s), 7.70(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) ⁺ , Cl ³⁵ ], 486[(M+H) ⁺ , Cl ³⁷ ].

[Reference Example 445] N ¹ -{(1S, 2R, 4S)-2-amino-4-[(dimethylamino)thioformyl]cyclohexyl}-N ² -(5-chloropyridine-2- base) oxalamide dihydrochloride

The title compound was prepared from the compound obtained in Reference Example 444 in the same manner as in Reference Example 69.

¹ H-NMR (DMSO-d ₆ ) δ: 1.66-2.11 (6H, m), 3.38 (3H, s), 3.42 (3H, s), 3.52 (1H, br.s), 3.75 (1H, br. s), 3.88(1H, br.s), 8.03-8.09(2H, m), 8.21(3H, br.s), 8.48(1H, d, J=2.2Hz), 9.06(1H, d, J= 6.8Hz), 10.34(1H, s).

MS(FAB) m/z: 384[(M+H) ⁺ , Cl ³⁵ ], 386[(M+H) ⁺ , Cl ³⁷ ].

[Reference Example 446] (3R,4S)-3-[(tert-butoxycarbonyl)amino]-1-(2-methoxyacetyl)piperidin-4-ylcarbamate 9H-fluoren-9-yl methyl ester

The compound obtained in Reference Example 220 was deprotected by catalytic reduction in the same manner as in Reference Example 214, and the resulting amine was treated in the same manner as in Reference Example 442 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.55-1.80 (1H, m), 1.92-2.20 (1H, m), 2.70-3.35 (2H, m), 3.44 (3H, s) , 3.77-4.90 (10H, m), 5.29-5.45 (0.6H, br), 5.75-5.90 (0.4H, br), 7.26-7.34 (2H, m), 7.39 (2H, t, J=7.6Hz) , 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-ylcarbamate 9H-fluorene-9 -Methyl ester

The title compound was prepared from the compound obtained in Reference Example 446 in the same manner as in Reference Example 443.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.50-1.80 (1H, m), 2.07-2.23 (1H, m), 3.04-3.18 (0.5H, m), 3.25-3.37 (0.5 H, 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-methoxysulfur Acetyl)piperidin-3-ylcarbamate tert-butyl ester

In the same manner as in Reference Example 444, the compound obtained in Reference Example 447 was deprotected by treatment with diethylamine, and then condensed with the compound obtained in Reference Example 433 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.73-1.88 (1H, m), 2.07-2.22 (1H, m), 3.05-3.15 (1H, m), 3.27-3.42 (1H, m), 3.45(1H, s), 3.48(2H, s), 4.10-4.54(5H, m), 5.12-5.21(0.3H, br), 5.48-5.56(0.7H, br), 5.61-5.74( 1H, br), 7.70 (1H, dd, J=8.5, 2.0Hz), 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) ⁺ , Cl ³⁵ ], 488 [(M+H) ⁺ , Cl ³⁷ ].

[Reference Example 449] (1S, 3R, 4S)-4-{[(allyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid ethyl ester

To a mixed solution of the compound (10.0 g) obtained in Reference Example 141 in tetrahydrofuran (40 ml) and ethanol (40 ml) was added 10% palladium carbon catalyst (10.2 g), and stirred at room temperature for 63 hours in 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), and after adding pyridine (2.3ml) at room temperature, allyl chloroformate (2.70ml) was added dropwise at 0°C and stirred for 20 minutes. Ice and ethyl acetate were added to the reaction solution, and after stirring for 5 minutes, 10% citric acid aqueous solution was added to make it acidic. The organic layer was washed with saturated aqueous sodium bicarbonate solution and 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).

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 449 in the same manner as in Reference Example 142.

¹ H-NMR (CDCl ₃ ) δ: 1.35-2.15 (6H, br), 1.45 (9H, s), 2.35-2.65 (1H, br), 3.65-3.75 (1H, m), 4.00-4.15 (1H, br), 4.48-4.63(2H, m), 4.63-4.80(1H, br), 5.03-5.33(1H, br), 5.21(1H, d, J=10.3Hz), 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

Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to a solution of the compound (5.93g) obtained in Reference Example 450 in N,N-dimethylformamide (40ml) Salt (4.99g), 1-hydroxybenzotriazole (2.81g), 2,2,2-trichloroethanol (4.15ml) and 4-dimethylaminopyridine (4.15g), stirred at room temperature for 1.5 hours. After the reaction solution 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 layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain the title compound (8.88 g).

¹ H-NMR (CDCl ₃ ) 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×Cl ³⁵ ], 475 [(M+H) ⁺ , 2×Cl ³⁵ , Cl ³⁷ ], 477 [(M+H) ⁺ , Cl ³⁵ , 2×Cl ³⁷ ]

[Reference Example 452] (1S,3R,4S)-4-Amino-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid 2,2,2-trichloroethyl ester

Diethylamine (20 ml) and tetrakis(triphenylphosphine)palladium (719 mg) were added to a tetrahydrofuran (35 ml) solution of the compound (8.83 g) obtained in Reference Example 451, followed by stirring at room temperature under argon for 2.5 hours. 10% citric acid aqueous solution (250ml) was added to the reaction solution to make it acidic, and diethyl ether was added. After the aqueous layer was washed with ether, sodium carbonate was added to make it basic, and extracted with dichloromethane. The dichloromethane layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (4.35 g).

¹ H-NMR (CDCl ₃ ) δ: 1.20-1.50 (3H, m), 1.46 (9H, s), 1.58-1.69 (1H, m), 1.70-1.81 (2H, m), 1.98-2.07 (1H, m), 2.22-2.31(1H, m), 2.55-2.66(1H, m), 2.97-3.04(1H, m), 3.79-3.93(1H, br), 4.70(1H, d, J=12.0Hz) , 4.75-4.85 (1H, br), 4.78 (1H, d, J=12.0Hz).

MS (ESI) m/z: 389 [(M+H) ⁺ , 3×Cl ³⁵ ], 391 [(M+H) ⁺ , 2×Cl ³⁵ , Cl ³⁷ ], 393 [(M+H) ⁺ , Cl ³⁵ , 2×Cl ³⁷ ].

[Reference Example 453] (1S, 3R, 4S)-3-[(tert-butoxycarbonyl)amino]-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxo Acetyl}amino)cyclohexanecarboxylic acid 2,2,2-trichloroethyl ester

The title compound was prepared by condensation of the compound obtained in Reference Example 452 and the compound obtained in Reference Example 433 in the same manner as in Reference Example 91.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.50-1.63 (1H, m), 1.65-1.79 (2H, m), 1.87-2.08 (2H, m), 2.10-2.22 (2H, m), 2.50-2.70(1H, br), 3.94-4.02(1H, m), 4.17-4.30(1H, br), 4.73(1H, d, J=12.0Hz), 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×Cl ³⁵ ], 573 [(M+H) ⁺ , 2×Cl ³⁵ , Cl3 ⁷ ], 575 [(M+H) ⁺ , Cl ³⁵ , 2×Cl ³⁷ ].

[Reference Example 454] 2-[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]-2-(methoxyimino)acetic acid methyl ester

The compound (435 mg) obtained in Reference Example 144 and methyl 2-(methoxyimino)-2-(methylsulfonyl)acetate (WO 99/67209) (233 mg) were dissolved in tetrahydrofuran (5 ml). Triethylamine (332 μl) was added to the solution, and stirred overnight at 70°C. The reaction solution was concentrated under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate were added for liquid separation, and the oil layer was dried over anhydrous sodium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=91;9) to obtain the title compound (111 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.42-2.10 (6H, m), 2.52 (3H, s), 2.70-3.10 (11H, m), 3.71 (2H, br.s), 3.83 (3H, s) , 3.84(3H, s), 4.22-4.35(1H, m), 4.55-4.65(1H, m), 5.16(1H, d, J=8.8Hz), 7.25-7.30(1H, m).

MS (ESI) m/z: 481 (M+H) ⁺ .

[Reference Example 455] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole And[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -{5-[2-(trimethylsilyl)ethynyl]pyridin-2-yl}ethanedi Amide

The compound (658 mg) obtained in Example 204 was dissolved in tetrahydrofuran (10 ml), N,N-dimethylformamide (10 ml) and triethylamine (20 ml), and triphenylphosphine (87 mg), trimethylform Silylacetylene (471 µl) and palladium acetate (50 mg) were stirred at 80°C for 14 hours in an argon atmosphere. The reaction solution was filtered through celite and washed well with dichloromethane. Water was added to the filtrate for liquid separation, and the organic layer was decolorized with activated carbon (about 3 g), and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=93:7) to obtain the title compound (360 mg).

¹ H-NMR (CDCl ₃ ) δ: 0.25 (9H, s), 1.66-2.13 (6H, m), 2.52 (3H, s), 2.78-2.96 (8H, m), 3.05 (3H, s), 3.70 (1H, d, J = 15.4Hz), 3.73 (1H, d, J = 15.4Hz), 4.08-4.15 (1H, m), 4.66-4.69 (1H, m), 7.42 (1H, d, J = 8.4 Hz), 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=2.1 Hz), 9.74(1H, s).

MS (ESI) m/z: 610 (M+H) ⁺ .

[Reference Example 456] Methyl 5-methyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate

Methyl 4,5-bis(chloromethyl)-2-thiophenecarboxylate (D.J.Zwanenburg and Hans wynberg, J.Org.Chem., 34, 333-340, (1969)) (520 mg) was dissolved in acetonitrile ( 600ml), methylamine (40% methanol solution, 722μl) was added, and stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=1:0→19:1) to obtain the title compound (176 mg).

¹ H-NMR (CDCl ₃ ) δ: 2.63 (3H, s), 3.82-3.83 (2H, m), 3.86 (3H, s), 3.97-3.99 (2H, m), 7.51 (1H, s).

MS (ESI) m/z: 198 (M+H) ⁺ .

[Reference Example 457] 2-Chloro-N-(6-chloropyridazin-3-yl)acetamide

3-Amino-6-chloropyridazine (10.4g) 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 distilled off under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the residue. The precipitated solid was collected by filtration and washed with ethyl acetate and water to obtain the title compound (9.39 g).

¹ H-NMR (CDCl ₃ ) 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] Sodium S-{2-[(6-chloropyridazin-3-yl)amino]-2-oxoethyl}thiosulfate

The title compound was prepared from the compound obtained in Reference Example 457 in the same manner as in Reference Example 353.

¹ H-NMR (DMSO-d ₆ ) 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-[( tert-Butyl Dimethylamino)carbonyl]cyclohexylcarbamate

The title compound was prepared from the compound obtained in Reference Example 458 and the compound obtained in Reference Example 144 in the same manner as in Reference Example 427.

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 459 in the same manner as in Reference Example 69.

¹ H-NMR (DMSO-d ₆ ) 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) ⁺ , Cl ³⁵ ], 387[(M+H) ⁺ , Cl ³⁷ ].

[Reference Example 461] 2-Chloro-N-(6-chloropyridin-3-yl)acetamide

In the same manner as in Reference Example 457, the title compound was prepared from 5-amino-2-chloropyridine.

¹ H-NMR (CDCl ₃ ) 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] Sodium S-{2-[(6-chloropyridin-3-yl)amino]-2-oxoethyl}thiosulfate

The title compound was prepared from the compound obtained in Reference Example 461 in the same manner as in Reference Example 353.

¹ H-NMR (DMSO-d ₆ ) 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-[(two Methylamino)carbonyl]cyclohexylcarbamate tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 462 and the compound obtained in Reference Example 144 in the same manner as in Reference Example 427.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, br.s), 1.60-2.23 (6H, m), 2.68 (1H, br.s), 2.96 (3H, s), 3.08 (3H, s) , 4.34-4.38(2H, m), 4.78(1H, m), 7.33(1H, d, J=8.5Hz), 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) ⁺ , Cl ³⁵ ], 508 [(M+Na) ⁺ , Cl ³⁷ ].

[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 prepared from the compound obtained in Reference Example 463 in the same manner as in Reference Example 69.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46-1.49 (1H, m), 1.79-1.81 (3H, m), 1.99-2.03 (1H, m), 2.14-2.16 (1H, m), 2.82 ( 3H, s), 3.06 (3H, s), 3.25-3.28 (1H, m), 3.99 (1H, br.s), 4.30-4.60 (1H, br), 7.55 (1H, d, J=8.7Hz) , 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) ⁺ , Cl ³⁵ ], 386[(M+H) ⁺ , Cl ³⁷ ].

[Reference Example 465] 2'-Aminosulfonyl-1,1'-biphenyl-4-carboxylic acid

2-Bromobenzenesulfonamide (800 mg) and 4-carboxyphenylboronic acid (563 mg) were suspended in a mixed solvent of toluene (5 ml)-water (5 ml). Tetrakis(triphenylphosphine)palladium (392 mg) and anhydrous sodium carbonate (1.08 g) were successively added to the reaction liquid, and heated to reflux overnight. After cooling to room temperature, ether and water were added for liquid separation, and the organic layer was extracted twice with water. All the obtained aqueous layers were combined, and 12N aqueous hydrochloric acid was added to the solution to make the solution acidic. It was concentrated to about 20 ml under reduced pressure, and the precipitated colorless powder was collected by filtration and dried under reduced pressure to obtain the title compound (539 mg).

MS(EI) m/z: 277M ⁺ .

[Reference Example 466] Methyl 2-[(5-methylpyridin-2-yl)amino]-2-oxoacetate

In the same manner as in Reference Example 242, the title compound was prepared from 2-amino-5-picoline and methyl chlorooxyacetate.

¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s), 3.98 (3H, s), 7.57 (1H, dd, J=8.4, 2.0Hz), 8.14 (1H, d, J=8.4Hz), 8.17(1H, d, J=2.0Hz).

MS (ESI) m/z: 195 (M+H) ⁺ .

[Reference Example 467] Lithium salt of 2-[(5-methylpyridin-2-yl)amino]-2-oxoacetate

The title compound was prepared from the compound obtained in Reference Example 466 in the same manner as in Reference Example 266.

¹ H-NMR (DMSO-d ₆ ) 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

In the same manner as in Reference Example 242, the title compound was prepared from p-toluidine and methyl chlorooxyacetate.

MS (ESI) m/z: 194 (M+H) ⁺ .

[Reference Example 469] (1R, 2S, 5S)-5-[(dimethylamino)carbonyl]-2-{[2-oxo-2(4-methylanilino)acetyl]amino}cyclohexylamino tert-butyl formate

The title compound was prepared by condensing the lithium salt of 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] Methyl 4-bromomethyl-3-chlorothiophene-2-carboxylate

In 3-chloro-4-methyl-2-thiophenecarboxylic acid methyl ester (3.81g) in carbon tetrachloride (40ml) solution, add N-bromosuccinimide (3.56g) and Azodiisobutyronitrile (200 mg) was heated to reflux for 2.5 hours. After filtering off insoluble matter, 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 (2.92 g) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 3.91 (3H, s), 4.46 (2H, s), 7.59 (1H, s).

MS (ESI) m/z: 269 (M+H) ⁺ .

[Reference Example 471] 4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-chloro-2-thiophenecarboxylic acid

To a tetrahydrofuran (30 ml) solution of methylamine (2 mol/L, tetrahydrofuran solution, 27 ml), a tetrahydrofuran (50 ml) solution of the compound (2.92 g) obtained in Reference Example 470 was added dropwise over 30 minutes. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to about half of the reaction liquid, di-tert-butyl dicarbonate (3.0 g) was added, and the mixture was stirred at room temperature for 75 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue and left overnight. Water was added to separate the organic layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1→19:1) to obtain a colorless oil (4.0 g). Water (5 ml) and sodium hydroxide (1.2 g) were added to a solution of this oil (4.0 g) in methanol (35 ml), followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, ice water was added to the residue, acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, crystallized by adding hexane to obtain the title compound (2.67 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.74 (3H, br.s), 4.14 (2H, br.s), 7.40 (0.5H, br.s), 7.48 (0.5H, br.s).

[Reference Example 472] (1R,2S)-tert-butyl 2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)cyclohexylcarbamate

The title compound was obtained by condensation of the compound obtained in Reference Example 266 with (1R,2S)-tert-butyl 2-aminocyclohexylcarbamate (WO01/74774) in the same manner as in Reference Example 68.

¹ H-NMR (CDCl ₃ ) δ: 1.35-1.90 (8H, m), 1.46 (9H, s), 3.97 (1H, br.s), 4.00-4.12 (1H, m), 4.73-4.82 (1H, m), 7.69 (1H, dd, J=8.8, 2.5Hz), 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]-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-ylamine

In 3-bromo-1-[(4-methylphenyl)sulfonyl]-4-azepanone (J.Chem.Soc.Perkin Trans., 1995, volume 1, page 2355) (6.54g ) in N,N-dimethylformamide (100ml) solution was added thiourea (1.44g), heated and stirred overnight at 60°C. After distilling off the solvent under reduced pressure, dichloromethane (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml) were added to the residue for liquid separation. The aqueous layer was extracted with dichloromethane (100 ml), combined with the previously obtained organic layer, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate (100 ml) was added to the resulting residue, and the precipitated pale yellow powder was collected by filtration to obtain 5-[(4-methylphenyl)sulfonyl]-5 as a crude product. 6,7,8-Tetrahydro-4H-thiazolo[5,4-c]azepin-2-ylcarboxamide (1.86 g). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain 5-[(4-methylphenyl)sulfonyl]-5,6,7,8- Mixture of tetrahydro-4H-thiazolo[5,4-c]azepin-2-ylcarboxamide and the title compound (4.01 g). The mixture and the aforementioned crude product were combined, suspended in dioxane (50 ml), added with 3N hydrochloric acid (50 ml), and heated to reflux for 1 hour. The solvent was evaporated under reduced pressure, dichloromethane (250ml) and saturated aqueous sodium carbonate solution (200ml) were added for liquid separation, and the oil layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. Diisopropyl ether (100 ml) was added to the residue, and the precipitated pale yellow powder was collected by filtration to obtain the title compound (4.47 g).

¹ H-NMR (CDCl ₃ ) δ: 1.75-1.87 (2H, m), 2.40 (3H, s), 2.62 (2H, t, J=5.7Hz), 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]azepin-2-ylamine hydrobromide

The compound obtained in Reference Example 473 was treated in the same manner as in Reference Example 291 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.95 (2H, br.s), 2.70-2.90 (2H, m), 3.38 (2H, br.s), 4.56 (2H, br.s), 9.07 ( 3H, br.s).

MS (ESI) m/z: 170 (M+H) ⁺ .

[Reference Example 475] 5-Methyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-ylamine

The compound (2.73 g) obtained in Reference Example 474 was suspended in methanol, and triethylamine (2.30 ml), acetic acid (453 μl), 37% aqueous formaldehyde (668 μl) and sodium cyanoborohydride ( 544mg). After stirring at room temperature overnight, saturated aqueous sodium bicarbonate solution (20 ml) was added, and the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (methanol:dichloromethane=3:17). Methanol (100 ml) and anhydrous sodium carbonate (20 g) were added to the obtained crude product, and the mixture was stirred at room temperature for 30 minutes, and then the insoluble matter was filtered off. After the filtrate was concentrated under reduced pressure, dichloromethane (250 ml) and methanol (50 ml) 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 (100 ml) to obtain the title compound (1.23 g).

¹ H-NMR (CDCl ₃ ) δ: 1.70-1.85 (2H, s), 2.38 (3H, s), 2.77 (2H, t, J=5.6Hz), 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]azepine-

The compound obtained in Reference Example 475 (1.13 g) was suspended in water (10 ml), 48% aqueous hydrobromic acid (7.0 ml) was added, and stirred under ice-cooling. An aqueous solution (3.0 ml) containing sodium nitrite (639 mg) was carefully added dropwise to the reaction solution. After the addition was complete, the suspension was stirred overnight at room temperature. Under ice-cooling, dichloromethane (100 ml) was added to the reaction liquid, and while stirring, a saturated aqueous sodium carbonate solution was added for neutralization. After separation, the aqueous layer was extracted with dichloromethane (100ml), and the organic layers were combined and dried over anhydrous sodium sulfate. Then, it was purified by silica gel column chromatography (methanol:dichloromethane=3:47) to obtain the title compound (582 mg) as a pale orange oil.

¹ H-NMR (CDCl ₃ ) δ: 1.70-1.85 (2H, s), 2.38 (3H, s), 2.95-3.05 (4H, m), 3.79 (2H, s).

MS (ESI) m/z: 247 (M+H) ⁺ .

[Reference Example 477] Lithium salt of 5-methyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 476 in the same manner as in Reference Example 10.

¹ H-NMR (DMSO-d ₆ ) δ: 1.65 (2H, br.s), 2.23 (3H, s), 2.80-2.97 (4H, m), 3.75 (2H, s).

[Reference Example 478] 4,4,5-Trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-ylamine

Add pyrrolidine (1.31ml) and p-toluenesulfonic acid 1 hydrate (7.48mg) successively to a solution of 1,2,2-trimethylpyrrolidin-3-one (1.00g) in cyclohexane (5ml), Heat to reflux for 3 days. After standing to 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). Formamidine disulfide hydrochloride (1.20 g) was added to a solution of this compound in dimethylformamide (10 ml), followed by stirring at room temperature for 4 days. After concentration under reduced pressure, methanol (50 ml) and anhydrous sodium carbonate (20 g) were added to the residue, stirred at room temperature for 1 hour, 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).

¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, s), 2.48 (3H, s), 3.83 (2H, s), 4.83 (2H, br.s).

MS (ESI) m/z: 184 (M+H) ⁺ .

[Reference Example 479] 2-bromo-4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole

The title compound was prepared from the compound obtained in Reference Example 478 in the same manner as in Reference Example 476.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, s), 2.49 (3H, s), 3.91 (2H, s).

MS (ESI) m/z: 247 (M+H) ⁺ .

[Reference Example 480] 2,3-Dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylic acid

p-2-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylic acid ethyl ester (Chem.Commun., 2001 , page 1102) was treated in the same manner as in Reference Example 291 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 4.60-4.75 (4H, m), 8.17 (1H, s), 8.78 (1H, s), 9.69 (2H, br.s).

MS (ESI) m/z: 165 (M+H) ⁺ .

[Reference Example 481] 2-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate lithium salt

Thionyl chloride (3.0 ml) was added to a methanol (100 ml) solution of the compound (1.66 g) obtained in Reference Example 480, followed by heating under reflux overnight. After standing to room temperature, the solvent was distilled off under reduced pressure, and dichloromethane (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml) were added to the residue for liquid separation. Dichloromethane (100 ml) and di-tert-butyl dicarbonate (1.40 g) were added to the aqueous layer and stirred at room temperature for 2 hours. After liquid separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane (50ml) was added to the residue, and the precipitated pale yellow powder was collected by filtration to obtain crude 2-(tert-butoxycarbonyl)-1,3-dihydro-2H-pyrrolo[3,4-c] Methyl pyridine-6-carboxylate (602 mg). To a solution of the crude product (564 mg) in methanol (10 ml) was added 1N lithium hydroxide aqueous solution (2.20 ml), followed by stirring overnight at room temperature. It was concentrated to dryness under reduced pressure to obtain the title compound (591 mg) as a light brown solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46 (9H, br.s), 4.63 (2H, br.s), 4.65 (2H, br.s), 7.93 (0.5H, br.s), 7.96 (0.5H, br.s), 8.40(1H, br.s).

MS(ESI)m/z: 265(M-Li+2H) ⁺ .

[Reference Example 482] Methyl 5-(pyridin-4-yl)pyrimidine-2-carboxylate

By the method described in Reference Example 237, the compound formed by pyridin-4-ylboronic acid and 5-bromopyrimidine-2-carboxylic acid was esterified with methanol and thionyl chloride to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 4.12 (3H, s), 7.57 (2H, d, J = 6.1 Hz), 8.83 (2H, d, J = 6.1 Hz), 9.18 (2H, s).

MS (ESI) m/z: 216 (M+H) ⁺ .

[Reference Example 483] Lithium salt of 5-(pyridin-4-yl)pyrimidine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 482 in the same manner as in Reference Example 322.

¹ H-NMR (DMSO-d ₆ ) δ: 7.85 (2H, d, J=6.0Hz), 8.692 (H, 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

In the same manner as in Reference Example 237, the title compound was prepared from 2-bromotoluene and 4-formylphenylboronic acid.

¹ H-NMR (CDCl ₃ ) 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 (1.51 g) obtained in Reference Example 484 was suspended in water (100 ml), and tert-butanol (10 ml), 2-methyl-2-butene (20 ml), and sodium chlorite were successively added to the suspension (3.67g) and sodium dihydrogen phosphate dihydrate (3.62g), stirred overnight at room temperature. Diisopropyl ether (200 ml) was added to the reaction solution for liquid separation, and the organic layer was washed with 3N hydrochloric acid (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with hexane to obtain the title compound (1.43 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, s), 7.20-7.35 (4H, m), 7.65 (2H, d, J=8.1Hz), 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 (1.42 g) obtained in Reference Example 485 was suspended in methanol, and thionyl chloride (1 ml) was added to the suspension and heated under reflux for 2 hours. After standing to room temperature, saturated aqueous sodium bicarbonate solution (100 ml) and dichloromethane (100 ml) were added to the reaction solution for liquid separation. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (1.51 g) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.26 (3H, s), 3.94 (3H, s), 7.20-7.35 (4H, m), 7.40 (2H, d, J=7.8Hz), 8.08 (2H, d , J=7.8Hz).

MS (ESI) m/z: 227 (M+H) ⁺ .

[Reference Example 487] Methyl 2'-[(dimethylamino)methyl]-[1,1'-biphenyl]-4-carboxylate

The compound (663 mg) obtained in Reference Example 486 was dissolved in 1,2-dichloroethane (30 ml), and to the solution were added N-bromosuccinimide (521 mg) and 2,2'-azobisisobutyl Nitrile (48.1 mg) was heated at reflux for 1 hour. After the reaction, the mixture was cooled to 0° C., dimethylamine (40% aqueous solution, 0.99 ml) was added, and stirred at room temperature for 3 days. Water (100 ml) and dichloromethane (100 ml) were added to the mixture for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane=1:25) to obtain the title compound (607 mg) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 2.13 (6H, s), 3.31 (2H, s), 3.95 (3H, s), 7.23 (1H, dd, J=7.4, 1.5Hz), 7.31 (1H, dt , J=1.5, 7.4Hz), 7.37 (1H, dt, J=1.5, 7.4Hz), 7.46 (2H, d, J=8.2Hz), 7.52 (1H, dd, J=7.4, 1.5Hz), 8.07 (2H, d, J=8.2Hz).

MS (ESI) m/z: 270 (M+H) ⁺ .

[Reference Example 488] Lithium salt of 2'-[(dimethylamino)methyl]-[1,1'-biphenyl]-4-carboxylate

The title compound was prepared from the compound obtained in Reference Example 487 in the same manner as in Reference Example 322.

¹ H-NMR (DMSO-d ₆ ) δ: 2.06 (6H, s), 3.29 (2H, s), 7.20-7.38 (5H, m), 7.49 (1H, d, J=7.3Hz), 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 Reference Example 239.

¹ H-NMR (CDCl ₃ ) δ: 2.60 (3H, s), 3.96 (3H, s), 7.42 (1H, dd, J=6.8, 2.7Hz), 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 (980 mg) obtained in Reference Example 489 in acetic anhydride (25 ml) was stirred at 130°C for 30 minutes. After cooling to 90°C, methanol (50 ml) was added and stirred for 1 hour. After adding dichloromethane (50ml) and saturated aqueous sodium bicarbonate (150ml) to the reaction solution, solid sodium bicarbonate was added until the reaction solution was alkaline. After stirring for 3 hours, the layers were separated and the aqueous layer was extracted with dichloromethane (2 x 50ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After purification by silica gel column chromatography (dichloromethane:methanol=40:1→10:1), the obtained residue was purified with silica gel as a carrier Purification by column chromatography (hexane:ethyl acetate=2:1→1:1) gave the title compound (749 mg) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.96 (3H, s), 5.29 (2H, s), 7.47 (1H, dd, J=5.1, 1.7Hz), 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] 4-(2-{[(tert-butoxycarbonyl)amino]methyl)pyridin-4-yl)methyl benzoate

To a solution of the compound obtained in Reference Example 490 (532 mg) in tetrahydrofuran (4.0 ml) were added water (1.0 ml) and lithium hydroxide (137 mg) at room temperature. After stirring for 24 hours, tetrahydrofuran was distilled off under reduced pressure, and water (4.0 ml) and 1N hydrochloric acid (5.65 ml) were added. The resulting solid was collected by filtration, washed with water, and dried to obtain a white solid (400 mg). Part of this solid (272 mg) was suspended in tetrahydrofuran (10 ml), and methanol (2.0 ml) and trimethylsilyldiazomethane (2.0 M hexane solution, 890 µl) were added at room temperature. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Ethyl acetate (5.0 ml), trimethylamine hydrochloride (12 mg), methanesulfonyl chloride (140 µl) and triethylamine (252 µl) were added to a solution of the obtained solid in dichloromethane (10 ml) at room temperature. After stirring for 3 hours, saturated aqueous sodium bicarbonate solution (20ml) and dichloromethane (20ml) were added for liquid separation, and the aqueous layer was extracted with dichloromethane (2×15ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Sodium azide (155 mg) was added to a solution of the obtained red-purple oil in N,N-dimethylformamide (5.0 ml) at room temperature. After stirring for 1 hour, water (100ml) and dichloromethane (30ml) were added for liquid separation, and the aqueous layer was extracted with dichloromethane (3×20ml). The organic layers were combined, dried over anhydrous sodium sulfate, dioxane (5.0 ml) was added, and the mixture was concentrated to about 5 ml under reduced pressure. Tetrahydrofuran (5.0 ml), di-tert-butyl dicarbonate (400 mg) and 10% palladium on carbon (100 mg) were added to the obtained brown solution, followed by stirring at room temperature for 14 hours under a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:acetone=20:1) to obtain the title compound (270 mg) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) 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=8.3 Hz), 8.61 (1H, d, J=5.1Hz).

MS (ESI) m/z: 343 (M+H) ⁺ .

[Reference Example 492] Ethyl 1-(phenylsulfonyl)piperidine-4-carboxylate

To a solution of ethyl hexahydroisonicotinate (1.08ml) in tetrahydrofuran (10ml) was added triethylamine (1.40ml), then benzenesulfonyl chloride (1.02ml) was added at 0°C, and stirred at room temperature for 21 hours. Then, the mixture was stirred with ice for 10 minutes, and then ethyl acetate and 0.5N hydrochloric acid were added to separate the reaction liquid into two layers. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to obtain the title compound (1.66 g) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J=7.1Hz), 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 prepared from the compound obtained in Reference Example 492 in the same manner as in Reference Example 274.

¹ H-NMR (CDCl ₃ ) δ: 1.74-1.90 (2H, m), 1.90-2.04 (2H, m), 2.23-2.33 (1H, m), 2.39-2.54 (2H, m), 3.58-3.72 ( 2H, m), 7.48-7.64 (3H, m), 7.67-7.80 (2H, m).

MS (ESI) m/z: 270 (M+H) ⁺ .

[Reference Example 494] 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.

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 494 in the same manner as in Reference Example 274.

¹ H-NMR (CDCl ₃ ) δ: 1.60-2.20 (4H, br), 2.57-2.68 (1H, m), 2.98-3.20 (2H, m), 3.55-4.00 (1H, br), 4.25-4.65 ( 1H, br), 7.09 (2H, t, J=8.5Hz), 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

In the same manner as in Reference Example 492, the title compound was obtained from pyrrolidine and monomethyl terephthalic acid chloride.

¹ H-NMR (CDCl ₃ ) δ: 1.85-1.93 (2H, m), 1.94-2.01 (2H, m), 3.38 (2H, t, J=6.6Hz), 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 prepared from the compound obtained in Reference Example 496 in the same manner as in Reference Example 274.

¹ H-NMR (CDCl ₃ ) 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 compound obtained in Reference Example 496 was treated in the same manner as in Reference Example 212 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.75-1.84 (4H, m), 2.47-2.56 (4H, m), 3.37 (2H, s), 3.90 (3H, s), 7.41 (2H, d, J= 8.3Hz), 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]cyclohexylcarbamate 9H-fluoren-9-ylmethyl ester

To a methanol (20 ml) solution of the compound (823 mg) obtained in Reference Example 436 was added 10% palladium carbon catalyst (117 mg), and 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 (622 mg) in 1,2-dimethoxyethane (15 ml) was added saturated aqueous sodium bicarbonate (5 ml), water (2 ml), succinimidyl carboxyl Acid fluoren-9-ylmethyl ester (867mg), stirred at room temperature for 13 hours. The reaction solution was diluted with ethyl acetate, and water was added to divide into two layers. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue to wash the slurry, and a white powder was collected by filtration. In addition, after concentrating the mother liquor under reduced pressure, the slurry was washed with ether, and the white powder was collected by filtration. The filtered powder was dissolved in ethyl acetate, mixed, and the solvent was evaporated under reduced pressure, followed by drying with a vacuum pump to obtain the title compound (939 mg) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, br.s), 1.60-1.74 (1H, m), 1.78-1.92 (2H, m), 1.92-2.07 (2H, m), 2.10-2.26 ( 1H, m), 2.81 (3H, d, J=4.9Hz), 3.62-3.77 (1H, br), 3.85-4.63 (5H, m), 5.30-5.67 (2H, br), 7.24-7.33 (2H, m), 7.39 (2H, t, J=7.6Hz), 7.58 (2H, br.d, J=7.1Hz), 7.76 (2H, d, J=7.6Hz).

MS (ESI) m/z: 394 (M-COOtBu) ⁺ .

[Reference Example 500] (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-[(methylamino)thioformyl]cyclohexylcarbamate 9H-fluoren-9-yl methyl ester

The title compound was prepared from the compound obtained in Reference Example 499 in the same manner as in Reference Example 443.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, br.s), 1.55-2.10 (6H, m), 2.45-2.72 (1H, br), 3.17 (3H, d, J=4.4Hz), 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 ) thioformyl] tert-butyl cyclohexyl carbamate

The title compound was prepared from the compound obtained in Reference Example 500 in the same manner as in Reference Example 444.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-1.70 (1H, m), 1.80-2.16 (5H, m), 2.60-2.75 (1H, br), 3.19 (3H, d, J=4.9Hz), 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

Add dichloroacetyl chloride (1.44ml) and sodium bicarbonate (1.26g) to a solution of 2-amino-5-chloropyrimidine (1.30g) in N,N-dimethylformamide (30ml), and stir at room temperature for 1 Hour. The solvent was distilled off under reduced pressure, and dichloromethane and water were added to the residue for 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 distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1). The resulting white solid was washed with a mixed solvent of hexane-diethyl ether (4:1) and filtered to obtain the title compound (1.24 g) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 6.43 (1H, br.s), 8.65 (2H, s), 9.07 (1H, br.s).

MS (ESI) m/z: 240 (M+H) ⁺ .

[Reference Example 503] (1R, 2S, 5S)-2-({2-[(5-chloropyrimidin-2-yl)amino]-2-oxothioacetyl}amino)-5-[(two Methylamino)carbonyl]cyclohexylcarbamate tert-butyl ester

Add the compound (8.03g) obtained in Reference Example 144, the compound (6.76g) obtained in Reference Example 502, and sulfur (947mg) to N,N-dimethylformamide (90ml), and heat at 120°C. Diisopropylethylamine (9.57 ml) was added, followed by stirring at the same temperature for 10 minutes. The solvent was distilled off under reduced pressure, dichloromethane was added to the residue, and the insoluble matter was filtered through celite. Water was added to the filtrate, and the organic layer was washed with water. Purified by flash column chromatography (dichloromethane:methanol=19:1) using silica gel as a carrier, the obtained crude product was dissolved in dichloromethane, and the solid was collected by adding hexane to obtain the title compound as a pale yellow solid ( 940mg). Furthermore, the filtrate was purified by silica gel column chromatography to obtain the title compound (940 mg) containing N,N-dimethylformamide as a light brown solid.

¹ H-NMR (DMSO) δ: 1.28-2.22 (15H, m), 2.71 (1H, br.s), 2.96 (3H, s), 3.07 (3H, s), 4.25-4.42 (2H, m), 8.62(2H, s), 9.88(1H, br.s), 10.89(1H, s).

[Reference Example 504] 2-chloro-N-(4-chloro-3-nitrophenyl)acetamide

By the same method as in Reference Example 502, the title compound was prepared from 4-chloro-3-nitroaniline and chloroacetyl chloride.

¹ H-NMR (CDCl ₃ ) δ: 4.23 (2H, s), 7.54 (1H, d, J = 8.8Hz), 7.74 (1H, dd, J = 8.8, 2.4Hz), 8.22 (1H, d, J =2.4Hz), 8.39(1H, br.s).

[Reference example 505] (1R, 2S, 5S)-2-{[2-(4-chloro-3-nitroanilino)-2-oxothioacetyl]amino}-5-[(dimethyl tert-Butylamino)carbonyl]cyclohexylcarbamate

Sulfur (128 mg) and triethylamine (833 µl) were added to a solution of the compound (498 mg) obtained in Reference Example 504 in N,N-dimethylformamide (4 ml), followed by stirring at room temperature for 1 hour. The compound obtained in Reference Example 144 (571 mg) and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (767 mg) were added to the reaction solution, followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure, dichloromethane and a water solution were added to the residue, and the water layer was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by flash column chromatography (ethyl acetate) on silica gel gave the title compound (688 mg) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, m), 1.48-1.59 (1H, m), 1.72-1.81 (1H, m), 1.86-1.95 (2H, m), 2.04 (1H, br. s), 2.23 (1H, br.s), 2.69 (1H, br.s), 2.96 (3H, s), 3.09 (3H, s), 4.34-4.39 (2H, m), 4.78 (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-chlorocinnoline-3-yl)carbonyl]amino}cyclohexanecarboxylic acid ethyl ester

The title compound was prepared by condensing the compound obtained in Reference Example 96 and the compound obtained in Reference Example 298 in the same manner as in Reference Example 97.

¹ H-NMR (CDCl ₃ ) 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=8.8 Hz), 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)thioformyl]amino}cyclohexyl Ethyl alkane carboxylate

The title compound was prepared from the compound obtained in Reference Example 506 in the same manner as in Reference Example 443.

¹ H-NMR (CDCl ₃ ) 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)thioformyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylamino tert-butyl formate

In the same manner as in Reference Example 251, the compound obtained in Reference Example 507 was hydrolyzed, and the resulting carboxylic acid was condensed with dimethylamine hydrochloride to prepare the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, br.s), 1.66 (1H, br.s), 1.82-2.05 (4H, m), 2.29-2.32 (1H, m), 2.76 (1H, br.s), 2.97(3H, s), 3.09(3H, s), 4.56-4.59(1H, m), 4.90(2H, br.s), 7.75(1H, dd, J=8.7, 2.0Hz) , 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-dimethylcyclohexane Formamide

The title compound was prepared from the compound obtained in Reference Example 508 in the same manner as in Reference Example 325.

MS (ESI) m/z: 392 (M+H) ⁺ .

[Reference Example 510] (1R, 2S, 5S)-2-({[(4-chlorobenzoyl)amino]carbonyl}amino)-5-[(dimethylamino)carbonyl]cyclohexylcarbamate tert-butyl ester

Oxalyl chloride (435 µl) was added to a solution of p-chlorobenzamide (311 mg) in dichloroethane (20 ml), and heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and an acetonitrile (10 ml) solution of the residue was added dropwise to an acetonitrile (20 ml) solution of the compound (571 mg) obtained in Reference Example 144, followed by stirring at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue and the solid was collected by filtration to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H, s), 1.52-2.01 (6H, m), 2.68 (1H, br.s), 2.95 (3H, s), 3.08 (3H, s), 3.95 (1H, br.s), 4.29 (1H, br.s), 4.84 (1H, br.s), 7.41 (2H, d, J=8.3Hz), 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 prepared from the compound obtained in Reference Example 510 in the same manner as in Reference Example 325.

¹ H-NMR (CDCl ₃ ) δ: 1.51 (2H, br.s), 1.67-1.96 (6H, m), 2.90 (1H, br.s), 2.95 (3H, s), 3.08 (3H, s) , 3.44(1H, br.s), 3.93(1H, br.s), 7.47(2H, d, J=8.5Hz), 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 solution of sodium hydride (60% oil, 580mg) suspended in tetrahydrofuran (30ml) was added dropwise a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.35ml) in tetrahydrofuran (30ml) at -30°C. After stirring at the same temperature for 30 minutes, a solution of tetrahydrofuran (10 ml) and 5-chloropyridine-2-carbaldehyde (J. Med. Chem. 1970, vol. 13, p. 1124) (1.96 g) in tetrahydrofuran (15 ml) was added. After slowly raising the temperature to room temperature over 1 hour, water (100 ml) and diethyl ether (50 ml) were added for liquid separation, and the aqueous layer was extracted with diethyl ether (50 ml). The organic layers were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane (30 ml) was added to the resulting white solid and stirred for 30 minutes, followed by filtration to obtain the title compound (1.89 g) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.82 (3H, s), 6.91 (1H, dd, J=15.7, 0.9Hz), 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] tert-butyl cyclohexylcarbamate

In the same manner as in Reference Example 97, the obtained compound was hydrolyzed with the compound obtained in Reference Example 512, and the lithium salt of the obtained carboxylic acid was condensed with the compound obtained in Reference Example 144 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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) 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, 2.4 Hz), 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

Zinc powder (1.96 g) was added to a solution of 4-chlorobenzaldehyde (141 mg) in benzene (20 ml), and a catalytic amount of iodine was added while heating to reflux. A benzene solution (2.5 ml) of ethyl bromofluoroacetate (185 mg) was added dropwise thereto, followed by stirring for 2.5 hours. The reaction solution was ice-cooled, 1N hydrochloric acid (12.5 ml) was added, and stirred at room temperature for 1.5 hours. Water 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 distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (117 mg) as a colorless oily mixture of diastereomers.

¹ H-NMR (CDCl ₃ ) δ: 1.16-1.24 (3H, m), 3.35 (1H, br.d, J=51.9Hz), 4.15-4.25 (2H, m), 4.89-5.11 (2H, m) , 7.31-7.33 (4H, m).

MS (EI) m/z: 246 (M ⁺ ).

[Reference Example 515] (Z)-3-(4-Chlorophenyl)-2-fluoroethyl acrylate

Pyridine (100 µl) was added to a dichloromethane (1.0 ml) solution of the compound (51 mg) obtained in Reference Example 514, cooled at 0°C, thionyl chloride (20 µl) was added, and stirred at 0°C for 20 minutes. 1N hydrochloric acid aqueous solution 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 distilled off under reduced pressure. The residue was dissolved in dichloromethane (2 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (34 μl) was added, and stirred at room temperature for 3.5 hours. 1N hydrochloric acid and dichloromethane were added to separate the layers, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (22 mg) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) 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 prepared from the compound obtained in Reference Example 515 in the same manner as in Reference Example 274.

¹ H-NMR (DMSO-d ₆ ) 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 (MH) ^- .

[Reference Example 517] (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexylcarbamate 2,2,2-trichloroethane ester

2,2,2-Trichloroethyl chloroformate (10.6 ml) was added dropwise to a solution of the compound (10.0 g) obtained in Reference Example 144 in pyridine (175 ml), and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, dichloromethane and 0.5N aqueous hydrochloric acid were added to separate the layers, and the obtained organic layer was washed twice with 0.5N aqueous hydrochloric acid and then once with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of dichloromethane, hexane was added and the solid was collected by filtration. This was slurry washed with diethyl ether to give the title compound (13.6 g) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.62-1.97 (6H, m), 2.67 (1H, br.s), 2.94 (3H, s), 3.05 (3H, s), 3.71 -3.76(1H, m), 4.16(1H, br.s), 4.64-4.86(3H, m), 5.62(1H, d, J=7.3Hz).

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}cyclohexylcarbamate 2,2,2-trichloroethyl ester

In the same manner as in Reference Example 252, the compound obtained in Reference Example 517 was treated with hydrochloric acid, deprotected, and then condensed with the obtained compound in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.53-2.17 (6H, m), 2.52 (3H, s), 2.74-2.93 (8H, m), 3.03 (3H, s), 3.72 (2H, br.s) , 3.83-3.90 (1H, m), 4.62-4.79 (3H, m), 5.65 (1H, br.d, J=6.8Hz), 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}cyclohexylcarbamate tert-butyl ester

The compound obtained in Reference Example 518 (5.01 g) was dissolved in a mixed solvent of ethanol (100 ml) and water (5 ml), and zinc (6.06 g) and ammonium chloride (2.48 g) were added thereto, and stirred at 40° C. for 4.5 hours. Zinc was filtered off with celite, sodium bicarbonate (7.78 g) and di-tert-butyl dicarbonate (6.08 g) were added to the filtrate, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, dichloromethane and water solution were added to the residue, and the water layer was extracted twice with dichloromethane. 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 (ethyl acetate: methanol = 7: 3) using silica gel as a carrier, and then purified by preparative cycle HPLC (Japan Analytical Industry Co., Ltd. LC908-C60, column: JAIGEL 1H-40 and 2H-40, solvent: chloroform) was purified to obtain the title compound (2.30 g) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 1.48-2.07 (6H, m), 2.52 (3H, s), 2.70-2.96 (8H, m), 3.00 (3H, s), 3.68 -3.77(3H, m), 4.57-4.60(1H, m), 4.94(1H, br.s), 7.33(1H, br.s).

MS (ESI) m/z: 466 (M+H) ⁺ .

[Reference Example 520] 2,2-Dichloro-N-(5-chloropyridin-2-yl)acetamide

In the same manner as in Reference Example 457, the title compound was prepared from 2-amino-5-chloropyridine.

¹ H-NMR (CDCl ₃ ) 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-[(form tert-Butylamino)carbonyl]cyclohexylcarbamate

To a solution of the compound (1.01 g) obtained in Reference Example 436 in methanol (50 ml) was added 10% palladium carbon catalyst (0.35 g), followed by stirring at room temperature for 16 hours in 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 obtained in Reference Example 520 (600mg), diisopropylethylamine (5.0ml) and sulfur (80.3g) were added, and stirred at 120°C 2 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue, which was extracted twice with dichloromethane (200 ml). The organic layer was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=50:1→30:1) to obtain the title compound (812 mg) as a yellow glassy solid.

¹ H-NMR (CDCl ₃ ) δ: 1.25-2.50 (7H, m), 1.46 (9H, s), 2.82 (3H, d, J=4.9Hz), 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 prepared from the compound obtained in Reference Example 427 in the same manner as in Reference Example 69.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.55 (1H, m), 1.72-1.90 (3H, m), 2.00-2.09 (1H, m), 2.11-2.28 (1H, m), 2.82 ( 3H, s), 3.08 (3H, s), 3.27-3.40 (1H, m), 4.03 (1H, br.s), 4.35-4.45 (1H, m), 7.89 (1H, dt, J = 2.9, 9.0 Hz), 8.14 (1H, dd, J=9.0, 4.2Hz), 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

Under ice-cold stirring, hydrogen chloride gas was introduced into a solution of 3-cyanobenzoic acid (5 g) in ethanol (100 ml) to make the solution saturated. Ethanol (400 ml) was added to the obtained suspension to dissolve it, and the temperature was raised to room temperature, and then sealed and left for 18 hours. Concentrate to dryness under reduced pressure, add ethanol (100 ml) to the resulting residue to dissolve it, and introduce ammonia gas under ice-cold stirring to make the solution saturated. After warming up to room temperature, it was sealed for 18 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified with synthetic adsorbent HP-20 (water→acetonitrile:water=1:4). The resulting crude product was dissolved in methanol/dichloromethane=1/4, the insoluble matter was filtered off, and purified by silica gel column chromatography (methanol:dichloromethane=1:4) to obtain the title compound (5.53 g).

¹ H-NMR (DMSO-d ₆ ) 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 (5.0 ml) solution of the compound (250 mg) obtained in Reference Example 523 were added diisopropylethylamine (952 µl) and di-tert-butoxycarbonate (480 mg). After stirring for 3 days, the solvent was distilled off under reduced pressure, and the resulting residue was purified by medium-pressure column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain the title compound (285 mg) as a white foamy solid. .

¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J=7.2Hz), 1.56 (9H, s), 4.41 (2H, q, J=7.2Hz), 7.52 (1H, t, J=7.8 Hz), 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]cyclohexylcarbamate tert-butyl ester

To a solution of the compound obtained in Reference Example 144 (800 mg) and 3-cyanobenzoyl chloride (560 mg) in dichloromethane (30 ml) was added diisopropylethylamine (730 µl) at room temperature. After stirring for 4 hours, water and a saturated aqueous ammonium chloride solution were added for liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, 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 as a white foamy solid (1.15g).

¹ H-NMR (CDCl ₃ ) δ: 1.40-1.78 (2H, m), 1.47 (9H, s), 1.78-1.94 (2H, m), 2.08-2.40 (2H, m), 2.60-2.70 (1H, m), 2.96(3H, s), 3.09(3H, s), 3.94-4.08(1H, m), 4.16-4.34(1H, m), 4.79-4.88(1H, m), 7.55(1H, t, J=7.9Hz), 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 (250 mg) obtained in Reference Example 523 were added dichloromethane (10 ml), diisopropylethylamine (952 µl) and ethyl chloroformate (160 µl). After stirring for 8 hours, saturated aqueous sodium bicarbonate and dichloromethane were added for liquid separation, and the aqueous layer was extracted with dichloromethane. After the combined organic layers were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by medium-pressure column chromatography (dichloromethane:methanol=25:1) using silica gel as a carrier to obtain the title compound as a white solid. Compound (270 mg).

¹ H-NMR (CDCl ₃ ) 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

To a solution of 2-amino-5-fluoropyridine (250 mg) in ethyl acetate (10 ml) was added dichloroacetyl chloride (279 µl) at room temperature, followed by stirring at 60-70°C for 2.5 hours. After cooling the reaction solution, saturated aqueous sodium bicarbonate solution was added, 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).

¹ H-NMR (CDCl ₃ ) δ: 6.05 (1H, s), 7.45-7.55 (1H, m), 8.15-8.25 (2H, m), 8.72 (1H, s).

MS (ESI) m/z: 223 (M+H) ⁺ .

[Reference Example 528] (1R, 2S, 5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)amino]-2-oxothio Acetyl}amino)cyclohexylcarbamate tert-butyl

Add N,N-dimethylformamide (1.0ml) and diisopropylethylamine (1.0ml ), and the mixture was stirred at 130° C. for 20 minutes. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with dichloromethane. 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). The NMR data was completely consistent with the compound of Reference Example 424.

[Reference Example 529] Methyl 4-morpholinobenzoate

Thionyl chloride (436 µl) was added dropwise to methanol (10 ml) under ice-cooling. 4-Morpholinylbenzoic acid (207 mg) was added to this solution, and after heating to reflux for 1.5 hours, the solvent was distilled off under reduced pressure. Dichloromethane and a water 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.

¹ H-NMR (CDCl ₃ ) 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 (10 ml) solution of the compound (207 mg) obtained in Reference Example 529 were added benzyltriethylammonium chloride (639 mg) and potassium permanganate (222 mg), followed by stirring at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogensulfite was added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:2) to obtain the title compound (41 mg).

¹ H-NMR (CDCl ₃ ) δ: 3.80-3.83 (2H, m), 3.92 (3H, s), 4.03-4.07 (2H, m), 4.36 (2H, s), 7.47 (2H, dt, J= 9.0, 2.2Hz), 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 prepared from the compound obtained in Reference Example 530 in the same manner as in Reference Example 274.

¹ H-NMR (DMSO-d ₆ ) δ: 3.78-3.82 (2H, m), 3.97-4.01 (2H, m), 4.23 (2H, s), 7.57 (2H, dt, J=9.1, 2.2Hz) , 7.96 (2H, dt, J=9.1, 2.2Hz), 12.97 (1H, br.s).

[Reference Example 532] Ethyl 3-(5-chlorothien-2-yl)-2-fluoro-3-hydroxypropionate

Add zinc powder (19.6g) to a solution of 5-chlorothiophene-2-carbaldehyde (1.07ml) in benzene (200ml) and heat to reflux. A catalytic amount of iodine was added thereto, followed by a solution of ethyl bromofluoroacetate (3.70 g) in benzene (25 ml) dropwise. After heating to reflux for 1.5 hours, a catalytic amount of iodine was added, followed by heating to reflux for 3.5 hours. After cooling the reaction liquid naturally, 1N hydrochloric acid aqueous solution (125 ml) was added 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 distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane→hexane:ethyl acetate=4:1) to obtain the title compound (2.53 g).

¹ H-NMR (CDCl ₃ ) δ: 1.24-1.31 (3H, m), 3.09-3.21 (1H, m), 4.21-4.31 (2H, m), 4.97-5.12 (1H, m), 5.21-5.28 ( 1H, m), 6.79-6.86 (2H, m).

MS (EI) m/z: 252 (M ⁺ ).

[Reference Example 533] (Z)-3-(5-Chlorothiophen-2-yl)-2-fluoroethyl acrylate

Under ice cooling, pyridine (4.70 ml) and thionyl chloride (849 μl) were added to a solution of the compound (2.46 g) obtained in Reference Example 532 in dichloromethane (50 ml), stirred at 0° C. for 30 minutes, and stirred at room temperature for 1 Hour. A 1N aqueous hydrochloric acid solution was added to the reaction solution for liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with 1N aqueous hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (150 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.60 ml) was added, and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and purified by flash column chromatography (hexane:ethyl acetate=7:1) on silica gel to obtain the title compound (1.05 g).

¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 4.34 (2H, q, J = 7.1 Hz), 6.90 (1H, dd, J = 3.9, 2.0 Hz), 7.06 ( 1H, d, J=33.7Hz), 7.08-7.10 (1H, m).

MS (FAB) m/z: 235 (M+H) ⁺

[Reference Example 534] (Z)-3-(5-Chlorothiophen-2-yl)-2-fluoroacrylic acid

The title compound was prepared from the compound obtained in Reference Example 533 in the same manner as in Reference Example 274.

¹ H-NMR (DMSO-d ₆ ) 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 (MH) ^- .

[Reference Example 535] 6-Methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine

Same as the method described in Reference Example 475, from 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine (Japanese Patent Laid-Open No. 2-45489 Gazette) to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.66-2.69 (2H, m), 2.71 (4H, s), 2.80-2.83 (2H, m), 4.66 (2H, s).

MS (ESI) m/z: 184 (M+H) ⁺ .

[Reference Example 536] 2-bromo-6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-

The title compound was prepared from the compound obtained in Reference Example 535 in the same manner as in Reference Example 476.

¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 2.66-2.72 (4H, m), 2.85-2.88 (2H, m), 3.03-3.06 (2H, m).

MS (ESI) m/z: 247 (M+H) ⁺ .

[Reference Example 537] Lithium salt of 6-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine-2-carboxylate

The title compound was prepared from the compound obtained in Reference Example 536 in the same manner as in Reference Example 10.

¹ H-NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 2.56-2.63 (4H, m), 2.77-2.93 (4H, m).

MS (ESI) m/z: 213 (M+H) ⁺ .

[Reference Example 538] 5,6,7,8-tetrahydro[1,6]naphthyridine-2-carbonitrile hydrochloride

In 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) 4N hydrochloric acid-dioxane solution (14 ml) was added, stirred at room temperature for 65 minutes, and at 40°C for 40 minutes. A 4N hydrochloric acid-dioxane solution (8 ml) was added to the reaction solution, followed by further stirring at 45°C for 75 minutes. Ethyl acetate was added to the reaction solution, and the precipitated powder was collected by filtration to obtain the title compound (3.20 g) as a colorless powder.

¹ H-NMR (DMSO-d ₆ ) 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 compound obtained in Reference Example 538 was reacted in the same manner as in Reference Example 9 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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 (12 ml) was added to the compound (2.46 g) obtained in Reference Example 539, followed by heating at 100-110°C for 5.5 hours. Water was added to the reaction solution, concentrated under reduced pressure, water was added, and it was made alkaline with 1N aqueous sodium hydroxide solution. The solution was concentrated to about half, neutralized with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. Add ethanol to the residue, heat at 40-50°C, and filter the insoluble matter through diatomaceous earth. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethanol, 1N hydrochloric acid-ethanol (18 ml) was added, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, and the insoluble matter was collected by filtration to obtain the crude title compound (2.33 g).

¹ H-NMR (DMSO-d ₆ ) 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)-tert-butyl 4-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

The compound (7.15 g) obtained in Reference Example 142 was dissolved in dichloromethane (100 ml), and 2-methyl-2-propanol (4.88 ml), 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (4.89g) and 4-dimethylaminopyridine (2.08g) were stirred at room temperature for 19 hours. The reaction solution was diluted with dichloromethane (200 ml), washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and 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).

¹ H-NMR (CDCl ₃ ) δ: 1.20-2.09 (6H, m), 1.43 (9H, s), 1.44 (9H, s), 2.26 (1H, br.s), 3.62-3.72 (1H, m) , 4.10 (1H, br.s), 4.52-5.40 (4H, m), 7.27-7.38 (5H, m).

MS (FAB) m/z: 449 (M+H) ⁺ .

[Reference Example 542] (1S, 3R, 4S)-3-[(tert-butoxycarbonyl)amino]-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxo Thioacetyl}amino)cyclohexanecarboxylate tert-butyl

To a methanol (7.0ml)-tetrahydrofuran (7.0ml) solution of the compound (700mg) obtained in Reference Example 541 was added 10% palladium on carbon catalyst (wet, 350mg), and stirred at room temperature under a hydrogen atmosphere for 16 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (10 ml), sulfur (65 mg), the compound obtained in Reference Example 520 (374 mg) and diisopropylethylamine (0.816 ml) were added thereto, and stirred at 120°C for 8 hours. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=100:1→50:1) to obtain the title compound (373 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.48 (9H, s), 1.49-1.70 (2H, m), 1.80-2.40 (5H, m), 4.26-4.39 (2H, m) , 4.79 (1H, br.s), 7.70 (1H, dd, J=9.0, 2.4Hz), 8.19 (1H, d, J=9.0Hz), 8.32 (1H, d, J=2.4Hz), 10.01 ( 1H, br.s), 10.58(1H, s).

MS (ESI) m/z: 513 (M+H) ⁺ .

[Reference Example 543] (1S, 3R, 4S)-3-amino-4-({2-[(5-chloropyridin-2-yl)amino]-2-oxothioacetyl}amino)cyclohexyl tert-butyl alkanecarboxylate hydrochloride

1N hydrochloric acid-ethyl acetate solution (1.30 ml) was added to a solution of the compound (530 mg) obtained in Reference Example 542 in ethyl acetate (3.90 ml), followed by stirring at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (284 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (9H, s), 1.49-1.61 (1H, m), 1.71-1.88 (2H, m), 1.88-2.03 (1H, m), 2.04-2.26 ( 2H, m), 2.71-2.85 (1H, m), 3.84-4.12 (1H, m), 4.44 (1H, br.s), 8.00-8.29 (5H, m), 8.44-8.51 (1H, m), 10.67(1H, s), 10.91(1H, d, J=6.8Hz).

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-oxo tert-butyl acetyl}amino)cyclohexanecarboxylate

To a methanol (20ml)-tetrahydrofuran (20ml) solution of the compound (1.00g) obtained in Reference Example 541 was added 10% palladium carbon catalyst (wet, 500mg), and stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (10 ml), and the compound obtained in Reference Example 266 (231 mg), 1-hydroxybenzo Triazole (139 mg) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg) were stirred overnight at room temperature. After concentrating the reaction solution under reduced pressure, ethyl acetate and 10% aqueous citric acid solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium bicarbonate and saturated brine. After the oil layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (364 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.46 (9H, s), 1.54-2.09 (6H, m), 2.20-2.38 (1H, m), 3.83-3.98 (1H, m) , 4.08-4.29 (1H, m), 4.71 (1H, br.s), 7.69 (1H, dd, J=8.9, 2.6Hz), 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

Under ice cooling, dichloromethane ( 6ml) was added trifluoroacetic acid (3ml) to the solution and stirred for 30 minutes. The concentrated reaction solution was diluted with chloroform, neutralized with 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 obtain 1,2,3,4-tetrahydroisoquinone Phenyl-6-carboxylic acid methyl ester (154 mg). This compound was dissolved in dichloromethane (5 ml), and formalin (90.6 µl) was added at room temperature. After stirring for 10 minutes, acetic acid (46 µl) and sodium triacetoxyborohydride (269 mg) were added under ice-cooling. After stirring at room temperature for 105 minutes, the mixture was neutralized with saturated aqueous sodium 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).

¹ H-NMR (CDCl ₃ ) δ: 2.47 (3H, s), 2.70 (2H, dd, J = 6.0 Hz), 2.96 (2H, dd, J = 6.0 Hz), 3.62 (2H, s), 3.90 ( 3H, s), 7.08(1H, d, J=7.6Hz), 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]cyclohexylcarbamate fluoren-9-ylmethyl ester

Under ice-cooling, the compound (1.92 g) obtained in Reference Example 142 was dissolved in N,N-dimethylformamide (30 ml), and ammonium chloride (523 mg), 1-hydroxybenzotriazole ( 661mg), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.41g) and diisopropylethylamine (1.70ml), placed until the temperature returned to room temperature, stirred 3 days. The reaction solution was concentrated under reduced pressure, and ethyl acetate and 10% citric acid aqueous solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, hexane was added to the resulting residue for solidification, and crude (1R,2S,5S)-5-(aminocarbonyl)-2-{[(benzyloxy tert-butyl)carbonyl]amino}cyclohexylcarbamate (1.66g). A mixture of the crude product (1.65 g), 10% palladium on carbon catalyst (400 mg) and methanol (150 ml) 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 succinimidylcarboxylate (2.13g), 1,2-dimethoxyethane (130ml) and saturated Sodium bicarbonate aqueous solution (130ml), stirred at room temperature overnight. Ethyl acetate, saturated brine and water were added to the reaction solution for 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).

¹ H-NMR (CDCl ₃ ) 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-(carbamoyl)-2-[(tert-butoxycarbonyl)amino]cyclohexylcarbamate fluoren-9-ylmethyl ester

The compound obtained in Reference Example 546 (1.98 g) was dissolved in tetrahydrofuran (200 ml), and Ro-Son's reagent (1.22 g) was added to the solution, followed by stirring at room temperature for 4 days. Then, Ro-Son's reagent (0.50 g) was added to the reaction solution and stirred overnight. Silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1). Diethyl ether was added to the obtained oil, followed by stirring, and the precipitated powder was collected by filtration to obtain the title compound (1.25 g).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, br.s), 1.57-2.10 (6H, m), 2.69 (1H, br.s), 3.71 (1H, br.s), 4.06-4.27 ( 2H, m), 4.36 (2H, br.s), 4.89 (1H, br.s), 5.46 (1H, br.s), 7.11 (1H, br.s), 7.26-7.34 (2H, m), 7.39(2H, t, J=7.3Hz), 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-(aminothioformyl)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl} Amino) tert-butyl cyclohexylcarbamate and (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5- tert-butyl cyanocyclohexylcarbamate

The compound obtained in Reference Example 547 (4.64 g) was dissolved in N,N-dimethylformamide (50 ml), piperidine (2.78 ml) was added to the solution, and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, purified by silica gel column chromatography (methanol:dichloromethane=3:47→3:17) to obtain crude (1R,2S,5S)-2-amino-5-(aminosulfur Formyl)cyclohexylcarbamate tert-butyl ester (2.17g). This compound was dissolved in N,N-dimethylformamide (100ml), and the compound obtained in Reference Example 266 (1.78g), 1-hydroxybenzotriazole (1.07g) and 1-( Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.28 g), stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, dichloromethane and 10% citric acid aqueous solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain the title compound (427 mg) having a cyano group at the 5-position and The title compound having a thiocarbamoyl group (718 mg).

5-cyano form: ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.56-1.66 (1H, m), 1.74-1.87 (1H, m), 1.90-2.23 (4H, m), 2.72 (1H, br.s), 4.02-4.23 (2H, m), 4.71 (1H, br.s), 7.71 (1H, dd, J=8.8, 2.4Hz), 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-(aminothioformyl) body: ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.74-2.17 (6H, m), 2.70 (1H, s), 3.94-4.04 (1H, m), 4.23 (1H, br.s), 4.86 (1H, br.s), 6.97 (1H, br.s), 7.50 (1H, br.s), 7.70 (1H, dd, J = 8.8, 2.4 Hz), 7.98(1H, br.s), 8.18(1H, d, J=8.8Hz), 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-(thiazole-2- base) tert-butyl cyclohexylcarbamate

The compound (72 mg) having a thiocarbamoyl group at the 5th position obtained in Reference Example 548 and bromoacetaldehyde dimethyl acetal (20.4 μl) were dissolved in N,N-dimethylformamide (5 ml), and heated at 50° C. Stir for 8 hours. Then, bromoacetaldehyde dimethyl acetal (80 µl) was added, stirred for 13 hours, and allowed to stand at room temperature. Di-tert-butyl dicarbonate (34.5 mg) and anhydrous sodium bicarbonate (200 mg) were added to the reaction solution, and after stirring at room temperature for 1 hour, triethylamine (97 μl) was added and stirred for 2 hours. Ethyl acetate and 10% citric acid aqueous solution were added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, saturated aqueous sodium bicarbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1) to obtain the title compound (37.5 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.40-1.51 (9H, m), 1.75-2.16 (5H, m), 2.19-2.39 (1H, m), 3.10-3.38 (1H, m), 3.91-4.08 ( 1H, m), 4.21-4.40 (1H, m), 4.80-4.94 (0.5H, m), 5.61-5.90 (0.5H, m), 7.24-7.26 (1H, m), 7.66-7.74 (2H, m ), 7.80-7.90(0.5H, m), 8.02-8.11(0.5H, m), 8.16-8.22(1H, m), 8.27-8.33(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) tert-butyl cyclohexylcarbamate

Suspend the compound (427 mg) having a cyano group at the 5-position obtained in Reference Example 548 and anhydrous sodium bicarbonate (84.9 mg) in ethanol, add hydroxylamine sulfate (82.9 mg) to the suspension, heat at 60°C, and stir 6 days. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane=1:9) to obtain crude (1R,2S,5S)-5-[amino(hydroxyimino) tert-butyl methyl]-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)cyclohexylcarbamate (183 mg). At room temperature, methyl orthoformate (5 ml) and boron trifluoride etherate (1 drop) were added to this compound, heated at 55° C., and stirred for 20 minutes. After allowing to stand to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol:dichloromethane=1:9) to obtain the title compound (57.6 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.53-1.70 (1H, m), 1.73-1.94 (1H, m), 1.95-2.30 (4H, m), 3.03 (1H, br. s), 4.00-4.11(1H, m), 4.27(1H, br.s), 4.87(1H, br.s), 7.70(1H, dd, J=8.9, 2.4Hz), 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(MH) ^- .

[Reference Example 551] (1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(5-methyl-1,2,4-oxadiazol-2-yl)cyclohexyl Benzyl carbamate

The compound (4.0 g) obtained in Reference Example 142 was dissolved in N,N-dimethylformamide (100 ml), and hydrazine monohydrate (765 mg) and 1-hydroxybenzotriazole (1.38 g) were added to the solution. and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g), and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and dichloromethane and sodium bicarbonate aqueous solution were added to the residue for liquid separation. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate, silica gel (25 g) and methanol (15 ml) were added and stirred to the obtained filtrate, 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). Methyl orthoacetate (10 ml) and boron trifluoride etherate (2 drops) were added to the obtained crude product (1.73 g), heated at 70°C and stirred overnight. After standing to room temperature, the solvent was distilled off under reduced pressure, and dichloromethane and aqueous sodium bicarbonate solution were added to the obtained residue for liquid separation. 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).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.68-2.27 (6H, m), 2.50 (3H, s), 2.95-3.09 (1H, m), 3.66-3.86 (1H, m) , 4.08-4.24(1H, m), 4.76(1H, br.s), 5.04-5.16(2H, m), 5.27-5.36(1H, m), 7.29-7.39(5H, m).

MS (ESI) m/z: 431 (M+H) ⁺ .

[Reference Example 552] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(5-methyl -1,3,4-oxadiazol-2-yl) tert-butyl cyclohexylcarbamate

In a hydrogen atmosphere, a mixture of the compound obtained in Reference Example 551 (1.10 g), 10% palladium on carbon catalyst (300 mg) and methanol (50 ml) was stirred at room temperature for 1 hour. After the catalyst was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in N,N-dimethylformamide (50 ml). To this solution were sequentially added the compound (632 mg) obtained in Reference Example 266, 1-hydroxybenzotriazole (381 mg) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 810mg), stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and ethyl acetate and 10% citric acid aqueous solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (944 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.58-1.88 (2H, m), 1.92-2.31 (4H, m), 2.52 (3H, s), 3.04 (1H, br.s) , 3.98-4.09 (1H, m), 4.27 (1H, br.s), 4.83 (1H, br.s), 7.71 (1H, dd, J=8.8, 2.4Hz), 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)cyclohexylcarbamate benzyl ester

In the same manner as in Reference Example 551, the compound obtained in Reference Example 142 was condensed with hydrazine, followed by cyclization with methyl orthoformate to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.71-2.30 (6H, m), 3.04-3.15 (1H, m), 3.80 (1H, br.s), 4.17 (1H, br. s), 4.75(1H, br.s), 5.05-5.15(2H, m), 5.25(1H, s), 7.30-7.38(5H, m), 8.35(1H, s).

MS (ESI) m/z: 417 (M+H) ⁺ .

[Reference Example 554] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,3, 4-oxadiazol-2-yl) tert-butyl cyclohexylcarbamate

In the same manner as in Reference Example 552, the compound obtained in Reference Example 553 was deprotected, and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.59-1.92 (2H, m), 2.00-2.33 (4H, m), 3.02-3.22 (1H, m), 3.94-4.10 (1H, m), 4.27 (1H, br.s), 4.83 (1H, br.s), 7.71 (1H, dd, J=8.9, 2.6Hz), 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}cyclohexylcarbamate benzyl ester

In the same manner as in Reference Example 143, the compound obtained in Reference Example 142 was condensed with 2-aminoethanol to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.50-2.07 (6H, m), 2.28-2.39 (1H, m), 3.26-3.49 (1H, m), 3.45-3.63 (1H, m), 3.65-3.84(3H, m), 3.90-4.07(1H, m), 5.02-5.28(4H, m), 6.21-6.35(1H, m), 7.28-7.39(5H, m).

MS (ESI) m/z: 436 (M+H) ⁺ .

[Reference Example 556] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,3- Oxazol-2-yl) tert-butyl cyclohexylcarbamate

Under a nitrogen atmosphere, dimethyl sulfoxide (3.47 ml) was added dropwise to a solution of oxalyl chloride (2.85 ml) in dichloromethane (50 ml) cooled to -60° C., and then the compound obtained in Reference Example 555 was added dropwise over 15 minutes ( 3.55g) in dichloromethane (20ml). After stirring at -60°C for 45 minutes, triethylamine (11.4 ml) was added dropwise, followed by further stirring for 30 minutes. Water was added to the reaction solution at -60°C, extracted with chloroform after the temperature returned to room temperature, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1→10:1) to obtain a yellow solid (2.43 g). In the dichloromethane (25ml) solution of triphenylphosphine (4.41g), add hexachloroethane (3.32g), triethylamine (4.69ml) and the dichloromethane (35ml) of gained yellow solid (2.43g) successively The solution was stirred at room temperature for 20 hours. After adding saturated aqueous sodium bicarbonate solution and stirring for 30 minutes, the reaction mixture was extracted with chloroform, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated residue obtained was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain A mixture of oxazole cyclization and triphenylphosphine oxide. The resulting mixture was dissolved in methanol (30 ml), 10% palladium carbon catalyst (2.08 g) was added, and stirred at room temperature for 14 hours under a hydrogen atmosphere. A 10% palladium-carbon catalyst (1.02 g) was added, and the mixture was stirred under a hydrogen atmosphere for 6 hours, and then the catalyst was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1→10:1), and N,N-dimethylformamide (15 ml) of the obtained compound and the compound (612 mg) obtained in Reference Example 266 at room temperature To the solution were added 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (872 mg) and 1-hydroxybenzotriazole monohydrate (461 mg). After the reaction solution was stirred for 12 hours, chloroform was added to the reaction solution, and the reaction solution was washed with water and a protective aqueous sodium bicarbonate solution successively, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel flash column chromatography (methanol:chloroform=50:1) to obtain the title compound (390 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.54-2.30 (6H, m), 2.90-3.07 (1H, m), 3.97-4.08 (1H, m), 4.15-4.30 (1H, m), 4.91-5.10 (1H, m), 7.03 (1H, s), 7.58 (1H, s), 7.70 (1H, dd, J=8.8, 2.4Hz), 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) ring Hexane carboxylic acid

A mixture of the compound obtained in Reference Example 141 (4.20 g), 10% palladium on carbon catalyst (1.0 g) and ethanol (100 ml) was stirred at room temperature under a hydrogen atmosphere for 5 hours. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. Dioxane (50 ml), water (50 ml) and triethylamine (2.09 ml) were added to the obtained residue, followed by cooling with ice. 1-[2-(Trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (2.85 g) was added to the mixture, followed by stirring at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and ethyl acetate and 10% citric acid aqueous solution were added to the residue for liquid separation. The oil layer was washed successively with saturated brine, aqueous sodium bicarbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a pale yellow oil (4.46 g). Water (10 ml) and lithium hydroxide (479 mg) were added to a solution of this oil in tetrahydrofuran (50 ml), followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure, and ethyl acetate and 10% citric acid aqueous solution were added to the residue for liquid separation. The oil layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting colorless powder was washed with hexane to obtain the title compound (3.51 g).

¹ H-NMR (CDCl ₃ ) 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(MH) ^- ].

[Reference Example 558] N-hydroxyacetamidine

Hydroxylamine (50% aqueous, 661mg) was dissolved in acetonitrile (10ml), and stirred overnight at 60°C. The solvent was distilled off under reduced pressure, and the obtained colorless powder was washed with ether to obtain the title compound (673 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.62 (3H, s), 5.33 (2H, br.s), 8.66 (1H, br.s).

[Reference Example 559] (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexyl 2-(Trimethylsilyl)ethyl carbamate

The compound (201 mg) obtained in Reference Example 557 and the compound (37 mg) obtained in Reference Example 558 were suspended in 1,2-dimethoxyethane (5 ml), and 1-(dimethylaminopropyl (1)-3-ethylcarbodiimide hydrochloride (115 mg), stirred overnight at room temperature. Then, molecular sieves (MS-4A, powder, 1.0 g) were added to this reaction liquid, and it heated and refluxed overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (96.5 mg).

¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.98 (2H, t, J=8.4Hz), 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, 2-(trimethylsilyl)ethyl 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamate

The compound (96.5 mg) obtained in Reference Example 559 was dissolved in ethanol (10 ml), and p-toluenesulfonic acid (45.8 mg) was added to the solution at room temperature. The reaction solution was heated to 60°C and stirred overnight. After standing to room temperature, the solvent was evaporated under reduced pressure to obtain a colorless powder. To this powder were added the compound (67 mg) obtained in Reference Example 10 and N,N-dimethylformamide (5 ml). 1-Hydroxybenzotriazole (44.5 mg) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg) were added to this solution, followed by stirring overnight at room temperature. After distilling off the solvent under reduced pressure, dichloromethane and aqueous sodium bicarbonate solution were added to the residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol:dichloromethane=3:47) to obtain the title compound (110 mg).

¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.97 (2H, dd, J=9.9, 7.0Hz), 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)cyclohexylcarbamate 2-( Trimethylsilyl) ethyl ester

The compound (1.0 g) obtained in Reference Example 557 was dissolved in N,N-dimethylformamide (20 ml), and to this solution were added successively formic hydrazide (149 mg), 1-hydroxybenzotriazole (335 mg) and 1-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (713 mg), stirred overnight at room temperature. After the reaction liquid was concentrated under reduced pressure, ethyl acetate and 10% aqueous citric acid solution were added to the residue to separate the liquid. The oil layer was washed with saturated brine, aqueous sodium bicarbonate and saturated brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a colorless powder (1.12 g). Toluene (50 ml) and Ro-Son's reagent (2.0 g) were added to the powder at room temperature, followed by heating under reflux for 1 hour. After standing to room temperature, silica gel was added to the solution, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to obtain the title compound (511 mg).

¹ H-NMR (CDCl ₃ ) 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)cyclohexylcarbamate 2-(trimethylsilyl)ethyl ester

In the same manner as in Reference Example 560, the compound obtained in Reference Example 561 was treated with p-toluenesulfonic acid, deprotected and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.03 (9H, s), 0.97 (2H, t, J=8.5Hz), 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

4N hydrochloric acid-dioxane solution (350ml) was added dropwise to the dioxane (350ml)-methanol (200ml) suspension of the compound (73.3g) obtained in Reference Example 427 over 5 minutes, and stirred in ice water for 10 minutes. Stir at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, azeotroped with dioxane and tetrahydrofuran, and dried to obtain the title compound (76.4 mg).

¹ H-NMR (DMSO-d ₆ ) 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

1N hydrochloric acid ethanol solution (36 ml) was added to the compound (3.00 g) obtained in Reference Example 10, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered 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).

¹ H-NMR (D ₂ O) 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)cyclohexyl 2-(Trimethylsilyl)ethyl carbamate

Using the same method as in Reference Example 561, the compound obtained in Reference Example 557 was condensed with acetylhydrazide, reacted with Ro-Son's reagent, and heated to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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)cyclohexylcarbamate 2-(trimethylsilyl)ethyl ester

In the same manner as in Reference Example 560, the compound obtained in Reference Example 565 was treated with p-toluenesulfonic acid, deprotected and then condensed with the compound obtained in Reference Example 564 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.97 (2H, 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] Benzyl (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-(1,3-oxazol-5-yl)cyclohexylcarbamate

To a mixture of quinoline (8.00 ml) and p-toluenesulfonyl chloride (4.84 g) was added dropwise N-methylformamide (0.99 ml) at 75°C under reduced pressure. The generated gas was cooled with a Liebig condenser to turn it into a liquid, and recovered in an eggplant-shaped flask cooled to -78°C to obtain formazan (553 mg). To a solution of formazan (349 mg) in tetrahydrofuran (10 ml) was added n-butyllithium (1.57M in hexane, 6.95 ml) at -78°C under a nitrogen atmosphere and stirred for 15 minutes. A tetrahydrofuran (10 ml) solution of the compound (1.02 g) obtained in Reference Example 141 was added dropwise to the reaction solution at -78°C, followed by stirring for 30 minutes. The reaction solution was warmed up to 0°C, stirred for 15 minutes, then cooled to -78°C again, and acetic acid (0.62ml) was added. The reaction solution was stirred at 0°C for another 45 minutes, diluted with ether, washed with water and saturated brine in sequence, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by flash column chromatography on silica gel (methanol:dichloromethane=1:49→3:97) to obtain the title compound (663 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-2.20 (6H, m), 2.75-2.88 (1H, m), 3.69-3.81 (1H, m), 4.19-4.23 (1H, m), 4.65-4.84(1H, m), 5.05-5.18(2H, m), 6.78(1H, s), 7.30-7.45(6H, m), 7.77(1H, s).

MS (ESI) m/z: 416 (M+H) ⁺ .

[Reference Example 568] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,3- Oxazol-5-yl) tert-butyl cyclohexylcarbamate

In the same manner as in Reference Example 552, the compound obtained in Reference Example 567 was deprotected and condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.53-1.68 (1H, m), 1.70-1.92 (2H, m), 1.94-2.24 (3H, m), 2.78-2.95 (1H, m), 3.94-4.05(1H, m), 4.16-4.30(1H, m), 4.88-5.04(1H, m), 6.78(1H, s), 7.69(1H, dd, J=8.8, 2.4Hz) , 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] 2-(trimethylsilyl)ethyl (1S,2R,4S)-4-(aminocarbonyl)-2-[(tert-butoxycarbonyl)amino]cyclohexylcarbamate

In the same manner as in Reference Example 143, the compound obtained in Reference Example 557 was condensed with ammonium chloride to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.97 (2H, t, J=8.3Hz), 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] 2-(trimethylsilyl)ethyl (1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-cyanocyclohexylcarbamate

The compound obtained in Reference Example 569 (1.48g) and triethylamine (1.04ml) were dissolved in dichloromethane (25ml), and trifluoroacetic anhydride (0.790ml) was added to the solution under ice-cooling. After stirring at room temperature for 1 hour, saturated aqueous sodium bicarbonate solution and dichloromethane were added to the solution for liquid separation. 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 for solidification to obtain the title compound (1.18 g).

¹ H-NMR (DMSO-d ₆ ) δ: 0.01 (9H, s), 0.91 (2H, dd, J = 9.0, 7.1 Hz), 1.38 (9H, s), 1.48-1.64 (3H, m), 1.65 -1.77(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)cyclohexyl 2-(Trimethylsilyl)ethyl carbamate

In the same manner as in Reference Example 550, the compound obtained in Reference Example 570 was reacted with hydroxylamine, followed by cyclization with trimethyl orthoacetate to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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, 2-(trimethylsilyl)ethyl 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamate

In the same manner as in Reference Example 560, the compound obtained in Reference Example 571 was treated with p-toluenesulfonic acid, deprotected, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.96 (2H, t, J=8.4Hz), 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) ring Benzyl hexylcarbamate

Triethylamine (1.67 ml) and diphenylphosphoryl azide (2.06 ml) were added to a toluene (60 ml) solution of the compound (3.14 g) obtained in Reference Example 142, followed by stirring at 80°C for 2 hours. After cooling to room temperature, trimethylsilyl ethanol (4.59 ml) was added, and stirred at 90° C. for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and dissolved in ethyl acetate. The solution was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate 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=50:1), hexane was added to the obtained solid, and filtration was performed to obtain the title compound (2.72 g).

¹ H-NMR (CDCl ₃ ) δ: 0.03 (9H, s), 0.91-1.01 (2H, m), 1.23-1.64 (3H, m), 1.44 (9H, s), 1.90-2.08 (3H, m) , 3.51-3.75(2H, m), 4.04-4.18(3H, m), 4.49(1H, br.s), 4.78(1H, br.s), 5.03-5.14(2H, m), 5.36(1H, br.s), 7.28-7.38 (5H, m).

MS (ESI) m/z: 508 (M+H) ⁺ .

[Reference Example 574] Benzyl (1S, 2R, 4S)-4-amino-2-[(tert-butoxycarbonyl)amino]cyclohexylcarbamate

To a tetrahydrofuran (6.0 ml) solution of the compound (1.02 g) obtained in Reference Example 573 was added 1N tetrabutylammonium tetrahydrofuran solution (6.0 ml), followed by stirring at room temperature for 3 days. Ethyl acetate was added to the reaction liquid, followed by washing with saturated aqueous sodium bicarbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol: concentrated ammonia water = 100:10:1) to obtain the title compound (660 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.19-1.63 (3H, m), 1.44 (9H, s), 1.80-2.06 (3H, m), 2.79-2.91 (1H, m), 3.63-3.72 (1H, m), 4.11 (1H, br.s), 4.68 (1H, br.s), 5.03-5.14 (2H, m), 5.27 (1H, br.s), 7.28-7.38 (5H, m).

MS (ESI) m/z: 363 (M+H) ⁺ .

[Reference Example 575] (1S,2R,4S)-2-[(tert-butoxycarbonyl)-4-(4H-1,2,4-triazol-4-yl)amino]cyclohexylcarbamate benzyl ester

To a pyridine (3.0 ml) solution of the compound (182 mg) obtained in Reference Example 574 were added 1,2-dicarboxylhydrazide (154 mg), triethylamine (0.464 ml) and chlorotrimethylsilane (0.952 ml), and Heat and stir at 80°C for 6 hours. After the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate and dichloromethane were added to separate the layers, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol 30:1→10:1) to obtain the title compound (127 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.54-1.91 (3H, m), 1.91-2.15 (2H, m), 2.21 (1H, d, J=12.5Hz), 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) tert-butyl cyclohexylcarbamate

In the same manner as in Reference Example 552, the compound obtained in Reference Example 575 was deprotected and then condensed with the compound obtained in Reference Example 266 to prepare the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.60-1.98 (2H, m), 2.05-2.20 (2H, m), 2.25-2.35 (1H, m), 2.36-2.45 (1H, m), 4.03-4.13 (1H, m), 4.37 (1H, br.s), 4.47 (1H, br.s), 5.42 (1H, br.s), 7.71 (1H, dd, J = 8.8, 2.4 Hz), 8.04(1H, br.s), 8.17(1H, d, J=8.8Hz), 8.31-8.33(3H, m), 9.71(1H, s).

MS (ESI) m/z: 464 (M+H) ⁺ .

[Reference Example 577] (1R,2S,5S)-tert-butyl-2-amino-5-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexylcarbamate

The compound obtained in Reference Example 551 (5.74 g) was dissolved in methanol (110 ml), 10% palladium carbon catalyst (1.22 g) was added, and stirred at room temperature for 17 hours in a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off under reduced pressure to obtain the title compound (3.95 g).

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.65-2.45 (6H, m), 2.51 (3H, s), 3.03-3.60 (3H, m), 4.12-4.35 (1H, m) , 5.45-5.76(1H, m), 6.86-7.17(1H, m).

MS (ESI) m/z: 297 (M+H) ⁺ .

[Reference Example 578] Lithium salt of 2-[(5-bromopyridin-2-yl)amino]-2-oxoacetate

The title compound was prepared from the compound obtained in Reference Example 262 in the same manner as in Reference Example 266.

¹ H-NMR (DMSO-d ₆ ) 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) tert-butyl cyclohexylcarbamate

To a solution of the compound (900 mg) obtained in Reference Example 577 in N,N-dimethylformamide (40 ml) was added the compound (1.24 g) obtained in Reference Example 578, 3-(3-dimethylaminopropyl)- 1-Ethylcarbodiimide hydrochloride (1.17g) and 1-hydroxybenzotriazole (205mg) were stirred at 40°C for 7 hours. Ethyl acetate and aqueous solution were added to the reaction solution, 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 flash column chromatography on silica gel (dichloromethane:methanol=19:1) to obtain the title compound (1.51 g).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.56-2.31 (6H, m), 2.52 (3H, s), 3.01-3.12 (1H, m), 4.00-4.08 (1H, m) , 4.26 (1H, br.s), 4.92 (1H, br.s), 7.84 (1H, dd, J=8.8, 2.5Hz), 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-oxadiazole -2-yl) tert-butyl cyclohexylcarbamate

In the same manner as in Reference Example 579, the compound obtained in Reference Example 297 was hydrolyzed, and the obtained lithium carboxylate salt was condensed with the compound obtained in Reference Example 577 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (9H, s), 1.68-1.82 (1H, m), 1.82-1.99 (1H, m), 2.01-2.37 (4H, m), 2.53 (3H, s) , 3.12 (1H, br.s), 4.40 (2H, br.s), 4.96 (1H, br.s), 7.79 (1H, dd, J=8.8, 1.8Hz), 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-oxadi tert-butyl cyclohexylcarbamate (azol-2-yl)

In the same manner as in Reference Example 579, the compound obtained in Reference Example 577 was condensed with the compound obtained in Reference Example 57 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.57-1.74 (1H, m), 1.79-2.49 (5H, m), 2.53 (3H, s), 3.00-3.16 (1H, m) , 4.24-4.38 (2H, m), 5.00 (1H, br.s), 7.71 (1H, dd, J=8.8, 1.7Hz), 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)cyclohexylcarbamate 2-( Trimethylsilyl) ethyl ester

A mixture of the compound obtained in Reference Example 569 (994 mg) and N,N-dimethylformamide dimethyl acetal (10 ml) was stirred at 120°C for 2 hours. After standing to room temperature, the reaction solution was concentrated under reduced pressure, and hexane was added to the residue to obtain a colorless powder. A 70% aqueous acetic acid solution (10 ml) and hydroxylamine (50% aqueous, 197 mg) were added to the powder, and stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the obtained residue to separate the layers. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (759 mg).

¹ H-NMR (CDCl ₃ ) δ: 0.04 (9H, s), 0.91-1.04 (2H, m), 1.46 (9H, s), 1.61-2.44 (6H, m), 2.98-3.49 (1H, m) , 3.73(1H, br.s), 4.03-4.25(2H, m), 4.85(1H, br.s), 5.30(1H, br.s), 6.70(1H, br.s), 8.34(1H, s).

MS (ESI) m/z: 449 (M+Na) ⁺ , 327 (M-Boc) ⁺ .

[Reference Example 583] (1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl] Amino}-4-(1,2,4-oxadiazol-5-yl)cyclohexylcarbamate 2-(trimethylsilyl)ethyl ester

Using the same method as in Reference Example 560, the compound obtained in Reference Example 583 was deprotected by treatment with p-toluenesulfonic acid, and then condensed with the compound obtained in Reference Example 564 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.02 (9H, s), 0.97 (2H, dd, J=9.9, 7.0Hz), 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} ring Benzyl hexylcarbamate

To a solution of the compound (4.00 g) obtained in Reference Example 142 in N,N-dimethylformamide (100 ml) was added hydrazine monohydrate (765 mg), 1-hydroxybenzotriazole (1.38 g), 1- (Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g), stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and dichloromethane and aqueous sodium bicarbonate solution were added to the residue to separate the layers. The aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. After filtering off anhydrous sodium sulfate, silica gel (25 g) and methanol (15 ml) were added to the obtained filtrate and stirred, and insoluble matter was filtered off. The solvent was evaporated under reduced pressure to obtain crude benzyl (1S,2R,4S)-2-[(tert-butoxycarbonyl)amino]-4-(hydrazinocarbonyl)cyclohexylcarbamate as a colorless oily substance Esters (3.71 g). Dichloromethane (10 ml) and triethylamine (115 µl) were added to the obtained colorless oily substance (306 mg), trifluoroacetic anhydride (116 µl) was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Then, triethylamine (115 µl) and trifluoroacetic anhydride (116 µl) were added thereto, followed by stirring at room temperature for 1 hour. Dichloromethane and aqueous solution were added to the reaction solution, and the aqueous layer was extracted with dichloromethane, and the resulting organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain the title compound (283 mg).

¹ H-NMR (CDCl ₃ ) 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) s), 4.99-5.15(3H, m), 5.34(1H, d, J=7.3Hz), 7.27-7.36(5H, m), 8.92-9.36(1H, m).

MS (ESI) m/z: 525 (M+Na) ⁺ , 403 (M-Boc) ⁺ .

[Reference Example 585] (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-[5-(trifluoromethyl)-1,3,4-oxadiazole-2- Benzyl]cyclohexylcarbamate

Triphenylphosphine (392 mg) was dissolved in dichloromethane (10 ml), and hexachloroethane (296 mg), triethylamine (416 μl) and diethylamine of the compound (250 mg) obtained in Reference Example 584 were successively added to the solution under ice-cooling. Chloromethane (5ml). After stirring overnight at room temperature, dichloromethane and 10% citric acid aqueous solution were added to the reaction solution for liquid separation. The organic layer was washed with saturated brine, aqueous sodium bicarbonate 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).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.51-1.62 (1H, m), 1.71-1.90 (1H, m), 1.92-2.16 (2H, m), 2.16-2.25 (1H, m), 2.28-2.38(1H, m), 3.16(1H, br.s), 3.81(1H, br.s), 4.20(1H, br.s), 4.56-4.84(1H, m), 5.04- 5.16(2H, m), 5.20-5.28(1H, m), 7.29-7.39(5H, m).

MS (ESI) m/z: 429 (M-tBu) ⁺ , 385 (M-Boc) ⁺ .

[Reference Example 586] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-[5-(tri Fluoromethyl)-1,3,4-oxadiazol-2-yl]cyclohexylcarbamate tert-butyl ester

In the same manner as in Reference Example 552, the compound obtained in Reference Example 585 was deprotected, and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.55-1.66 (1H, m), 1.79-1.94 (1H, m), 1.98-2.19 (2H, m), 2.23-2.32 (1H, m), 2.32-2.41(1H, m), 3.18(1H, br.s), 4.00-4.10(1H, m), 4.29(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}cyclohexylcarbamate benzyl ester

To a solution of the compound obtained in Reference Example 574 (872 mg) in dichloromethane (30 ml) were added chloroethyl chloroformate (323 µl) and triethylamine (499 µl) under ice-cooling, and stirred at 0°C for 1 hour. A water solution was added to the reaction solution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=3:2) to obtain the title compound (1.03 g).

¹ H-NMR (CDCl ₃ ) 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)cyclohexylcarbamate Benzyl ester

To a suspension of 60% sodium hydride (87 mg) in N,N-dimethylformamide (5.0 ml) was added a solution of the compound (926 mg) obtained in Reference Example 587 in N,N-dimethylformamide (5.0 ml) , stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution to separate the layers, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (hexane:ethyl acetate=2:3) on silica gel to obtain the title compound (680 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.45-2.08 (6H, m), 3.44-3.54 (2H, m), 3.64 (1H, br.s), 3.77-3.87 (1H, m), 4.20 (1H, br.s), 4.29-4.36 (2H, m), 4.84 (1H, br.s), 5.05-5.13 (2H, m), 5.37 (1H, br.s), 7.27- 7.36(5H, m).

MS (ESI) m/z: 434 (M+H) ⁺ .

[Reference Example 589] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(2-oxo -1,3-oxazolidin-3-yl) tert-butyl cyclohexylcarbamate

In the same manner as in Reference Example 552, the compound obtained in Reference Example 588 was deprotected, and then condensed with the compound obtained in Reference Example 266 to prepare the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.58-1.65 (2H, m), 1.79-2.05 (4H, m), 3.47-3.55 (2H, m), 3.84-3.93 (2H, m), 4.29 (1H, br.s), 4.33-4.39 (2H, m), 5.08 (1H, br.s), 7.70 (1H, dd, J=8.8, 2.5Hz), 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] Benzyl (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-(formylamino)cyclohexylcarbamate

To a solution of the compound (200 mg) obtained in Reference Example 574 in dichloromethane (5 ml) were added formic acid (31.1 μl), 1-hydroxybenzotriazole (108 mg), triethylamine (115 μl) and 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (210 mg), stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off 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).

¹ H-NMR (CDCl ₃ ) δ: 1.27-1.50 (2H, m), 1.44 (9H, s), 1.94-2.07 (4H, m), 3.66-3.74 (1H, m), 3.97-4.07 (1H, m), 4.08-4.15(1H, m), 4.80-4.88(1H, m), 5.05(1H, d, J=12.2Hz), 5.10(1H, d, J=12.0Hz), 5.33-5.41(1H , m), 5.43-5.50 (1H, m), 7.30-7.37 (5H, m), 8.12 (1H, s).

MS (ESI) m/z: 392 (M+H) ⁺ .

[Reference Example 591] (1R, 2S, 5S)-2-[(benzyloxycarbonyl)amino]-5-(tetrazol-1-yl)cyclohexylcarbamate tert-butyl ester

Under ice-cooling, trichloromethyl chloroformate (268 µl) was added dropwise to a dichloromethane (10 ml) solution of the compound obtained in Reference Example 590 (792 mg) and pyridine (1.63 ml), followed by stirring at the same temperature for 10 minutes. After the reaction mixture returned to room temperature, it was stirred for 15 minutes, trimethylsilyl azide (295 μl) was added, and stirring was continued for 22 hours. The solvent was distilled off under reduced pressure, aqueous sodium bicarbonate solution was added to the residue, the insoluble matter was collected by filtration, washed with water, and the obtained solid was purified by silica gel column chromatography (dichloromethane:methanol=199:1→49:1) to obtain the title Compound (60mg).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.55-1.59 (1H, m), 2.02-2.14 (2H, m), 2.21-2.32 (2H, m), 2.41-2.49 (1H, m), 3.84-3.92(1H, m), 4.20-4.25(1H, m), 4.65-4.76(1H, m), 5.07-5.16(3H, m), 5.21-5.28(1H, m), 7.32- 7.38(5H, m), 8.68(1H, s).

MS (ESI) m/z: 417 (M+H) ⁺ .

[Reference Example 592] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(tetrazole-1 -yl) tert-butyl cyclohexylcarbamate

In the same manner as in Reference Example 552, the compound obtained in Reference Example 591 was deprotected, and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.73-1.92 (1H, m), 2.07-2.21 (2H, m), 2.28-2.41 (2H, m), 2.45-2.53 (1H, m), 4.10-4.19 (1H, m), 4.33-4.40 (1H, m), 4.71-4.89 (1H, m), 4.99-5.14 (1H, m), 7.71 (1H, dd, J = 8.8, 2.4 Hz), 7.96-8.04(1H, m), 8.17(1H, d, J=8.8Hz), 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] Benzyl (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-(1H-pyrrol-1-yl)cyclohexylcarbamate

1N hydrochloric acid (550 μl ), stirred at 80°C for 2.5 hours. After standing to room temperature, a saturated aqueous sodium bicarbonate solution and dichloromethane were added to the reaction solution for liquid separation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, followed by purification by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to obtain the title compound (84 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.71-2.20 (5H, m), 2.22-2.31 (1H, m), 3.78 (1H, br.s), 3.99 (1H, br. s), 4.22(1H, br.s), 4.73(1H, br.s), 5.04-5.16(2H, m), 5.29(1H, br.s), 6.15(2H, t, J=2.2Hz) , 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-pyrrole- 1-yl) tert-butyl cyclohexylcarbamate

By the same method as in Reference Example 552, the compound obtained in Reference Example 593 was deprotected, and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.80-2.33 (6H, m), 3.92-4.08 (2H, m), 4.31 (1H, br.s), 4.89 (1H, br. s), 6.17 (2H, t, J=2.0Hz), 6.71 (2H, t, J=2.0Hz), 7.69 (1H, dd, J=8.8, 2.2Hz), 8.02 (1H, br.s), 8.17(1H, d, J=8.8Hz), 8.31(1H, d, J=2.2Hz), 9.72(1H, br.s).

MS (ESI) m/z: 462 (M+H) ⁺ .

[Reference Example 595] (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-({[(dimethylamino)methylene]amino}carbonyl)cyclohexylcarbamate benzyl ester

Ammonium chloride (409 mg), 1-hydroxybenzotriazole (516 mg), 1-(dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (1.03g) and triethylamine (1.06ml), stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and ethyl acetate and 10% citric acid aqueous solution were added to the residue for liquid separation. The organic layer was washed with saturated brine, aqueous sodium bicarbonate 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 (30 ml), and stirred at 120°C for 2 hours. After standing to room temperature, the precipitated colorless powder was collected by filtration and washed with diethyl ether to obtain the title compound (957 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.25-1.40 (1H, m), 1.44 (9H, s), 1.53-1.66 (1H, m), 1.73-2.08 (4H, m), 2.32-2.46 (1H, m), 3.07(3H, s), 3.11(3H, s), 3.63-3.75(1H, m), 4.13(1H, br.s), 4.59-4.75(1H, m), 5.07(1H, d, J=12.2Hz), 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] Benzyl (1S, 2R, 4S)-2-[(tert-butoxycarbonyl)amino]-4-(1,2,4-triazol-5-yl)cyclohexylcarbamate

Hydrazine monohydrate (51.9 µl) was added to a solution of the compound (400 mg) obtained in Reference Example 595 in acetic acid (10 ml), followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and aqueous sodium bicarbonate and ethyl acetate were added to the obtained residue to separate the layers. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (370 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 1.48-1.62 (2H, m), 1.62-1.75 (2H, m), 1.88-2.06 (2H, m), 3.06 (1H, br.s), 3.56(1H, br.s), 3.95(1H, br.s), 4.95-5.10(2H, m), 6.62(1H, br.s), 7.00(1H, br.s), 7.27-7.38(5H, m), 13.59(1H, br.s).

MS (ESI) m/z: 416 (M+H) ⁺ .

[Reference Example 597] (1R, 2S, 5S)-2-({2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-5-(1,2, tert-butyl 4-triazol-5-yl)cyclohexylcarbamate

In the same manner as in Reference Example 552, the compound obtained in Reference Example 596 was deprotected and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.39 (9H, s), 1.50-2.03 (5H, m), 2.05-2.17 (1H, m), 2.94-3.20 (1H, m), 3.85-3.99 ( 2H, m), 7.06 (1H, br.s), 7.80 (0.5H, br.s), 8.03 (1H, dd, J=8.8, 2.2Hz), 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)ring Benzyl hexylcarbamate

To a solution of the compound (400 mg) obtained in Reference Example 595 in acetic acid (10 ml) was added methylhydrazine (56.9 µl), followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and ethyl acetate were added to the obtained residue to separate the layers. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain the title compound (224 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.53-1.80 (2H, m), 1.88-2.18 (4H, m), 2.77-2.89 (1H, m), 3.71-3.83 (1H, m), 3.86(3H, s), 4.17(1H, br.s), 4.74(1H, br.s), 5.08(1H, d, J=12.2Hz), 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)cyclohexylcarbamate tert-butyl ester

In the same manner as in Reference Example 552, the compound obtained in Reference Example 598 was deprotected and condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.50-1.65 (1H, m), 1.72-1.87 (1H, m), 1.95-2.22 (4H, m), 2.81-2.94 (1H, m), 3.87(3H, s), 3.97-4.06(1H, m), 4.25(1H, br.s), 4.91(1H, d, J=8.8Hz), 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-trimethylsilyl ethyl ester

Add 9% sodium bicarbonate aqueous solution (150ml) to the dioxane (50ml) solution of the compound (5.98g) obtained in Reference Example 212, after cooling to 0°C, add 1-[(2-trimethylsilyl ) Ethoxycarbonyloxy]pyrrolidine-2,5-dione (4.83g) in dioxane (20ml) was stirred at room temperature for 20 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was washed with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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-carbamate 2-trimethylsilyl ethyl ester

In the same manner as in Reference Example 552, the compound obtained in Reference Example 600 was deprotected, and then condensed with the compound obtained in Reference Example 266 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.05 (9H, s), 0.84-0.92 (2H, m), 1.47 (9H, s), 1.51-1.70 (1H, m), 1.98 (1H, d, J= 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 (90 ml) solution of the compound (6.92 g) obtained in Reference Example 601 was added a 1.0 mmol/l tetrabutylammonium fluoride tetrahydrofuran solution (40 ml), and stirred at room temperature for 5 days. Ethyl acetate and saturated aqueous sodium chloride solution were added to the reaction solution. The aqueous layer was extracted with ethyl acetate and dichloromethane, and the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1→20:1→10:1) to obtain a crude product (7.96 g). Ethyl acetate was added to the crude product, and the insoluble matter was collected by filtration to obtain the title compound (466 mg). Furthermore, water was added to the filtrate, extracted with ethyl acetate and dichloromethane, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (4.86 g) of the title compound containing about 30% tetrabutylammonium fluoride.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.55-1.72 (2H, m), 1.84-1.99 (1H, m), 2.71 (1H, t, J=10.7Hz), 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] tert-butyl carbamate

2-Bromothiazole (115 μl), sodium tert-butoxide (91 mg), (S)-(-)-2 , 2'-bis(diphenylphosphino)-1,1'-binaphthyl (65mg) and tris(dibenzylideneacetone)dipalladium(O) (28mg), stirred at 80°C under argon atmosphere 3 days. After cooling the reaction solution, ethyl acetate was added, the insoluble matter was filtered off through celite, and saturated aqueous sodium chloride solution was added to the filtrate. After extraction with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride. 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=2:1→1:1) to obtain the title compound (169 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.78-1.93 (1H, m), 2.07-2.18 (1H, m), 3.05-3.19 (1H, m), 3.27 (1H, dd, J=13.2, 1.7Hz), 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 was added to a solution obtained by dissolving the compound (108 mg) obtained in Reference Example 59 and the compound (124 mg) obtained in Reference Example 10 in N,N-dimethylformamide (3 ml) at room temperature Monohydrate (71 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg) were stirred for 8 days. After concentrating the reaction solution under reduced pressure with a vacuum pump, water (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml) were added, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by preparative silica gel thin-layer chromatography (dichloromethane:methanol=10:1). 1N hydrochloric acid ethanol solution, dichloromethane and methanol were added to the resulting amorphous substance, followed by concentration to obtain the title compound (72 mg).

¹ H-NMR (DMSO-d ₆ ) 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 (117 mg) obtained in Reference Example 60 was dissolved in N,N-dimethylformamide (5 ml), and the compound (136 mg) obtained in Reference Example 10, 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride (255 mg) and 1-hydroxybenzotriazole monohydrate (90 mg), stirred overnight at room temperature. The solvent was distilled off under reduced pressure with a vacuum pump, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue to separate the layers. 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 (methanol:dichloromethane=7:93). Ethyl acetate and 1N hydrochloric acid ethanol solution were added to the obtained compound to make the reaction solution acidic, and the solvent was concentrated under reduced pressure. Ethyl acetate was added again, and the resulting precipitate was collected by filtration and dried to obtain the title compound (56 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 2.00-2.35 (4H, m), 2.88 (3H, s), 3.10 (2H, br.s), 3.20-3.75 (3H, m), 4.20-4.85 ( 3H, m), 7.09(1H, s), 7.16(1H, d, J=8.8Hz), 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 (120 mg) obtained in Reference Example 62 was dissolved in N,N-dimethylformamide (5 ml), and 5-chloroindole-2-carboxylic acid (80 mg), 1-(3-dimethylaminopropyl base)-3-ethylcarbodiimide hydrochloride (98 mg), 1-hydroxybenzotriazole monohydrate (23 mg) and triethylamine (141 μl), and stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue to separate the layers. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=93:7). Dichloromethane (5 ml) and 1N hydrochloric acid ethanol solution (282 µl) were added to the obtained pale yellow solid. 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).

¹ H-NMR (DMSO-d ₆ ) δ: 1.64-1.74 (4H, m), 1.98-2.02 (2H, m), 2.89 (3H, s), 3.14 (2H, br.s), 3.47-3.65 ( 2H, m), 4.29-4.63 (4H, m), 7.10 (1H, d, J=1.5Hz), 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 (400 mg) obtained in Reference Example 67 was suspended in dichloromethane (10 ml), and triethylamine (0.514 ml) and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (Japanese Patent Laid-Open 2000-119253) (319 mg), stirred at room temperature for 15 minutes. Water was added to the reaction solution to carry out a liquid separation operation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:3) to obtain a pale yellow foamy substance. This substance was dissolved in tetrahydrofuran (3 ml), methanol (2 ml) and 1N aqueous sodium hydroxide solution (1.5 ml) were added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane and 1N aqueous hydrochloric acid 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). 1N hydrochloric acid (1 ml) was added to the resulting product and concentrated under reduced pressure to obtain the title compound (108 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.78 (8H, m), 2.94 (3H, s), 3.13 (2H, br.s), 3.22-3.40 (1H, m), 3.44-3.70 ( 3H, m), 3.83-3.95 (1H, m), 4.20-4.70 (1H, m), 6.78 (1H, s), 7.18-7.30 (2H, m), 7.44 (1H, s), 7.69 (1H, br.s), 8.09(1H, br.s), 11.92(1H, s).

MS (FAB) m/z: 508 (M+H) ⁺ .

[Example 5] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6, 7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound (300 mg) obtained in Reference Example 65 was dissolved in N,N-dimethylformamide (20 ml), and 5-chloroindole-2-carboxylic acid (109 mg), 1-hydroxybenzotriazole monohydrate were added (9mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (321mg) and triethylamine (0.232ml), stirred overnight at room temperature. Concentrate the reaction solution under reduced pressure with a vacuum pump, add dichloromethane and water to the residue for liquid separation, and then dry the organic layer with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and use silica gel column chromatography (dichloromethane :methanol=25:1) to obtain a colorless foamy substance. 1N hydrochloric acid (1 ml) was added thereto, followed by concentration under reduced pressure to obtain the title compound (203 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.40 (2H, m), 1.46-1.81 (4H, m), 1.88-1.98 (2H, m), 2.89 (3H, s), 3.00-3.76 ( 5H, m), 3.86-3.97 (1H, m), 4.00-4.10 (1H, m), 4.25-4.72 (1H, m), 7.03 (1H, s), 7.12 (1H, dd, J = 8.5, 1.2 Hz), 7.38(1H, d, J=8.5Hz), 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 prepared from the compound obtained in Reference Example 67 and 5-chloroindole-2-carboxylic acid in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 1.35-1.70 (6H, m), 1.80-2.06 (2H, m), 2.89 (3H, s), 3.00-3.27 (2H, m), 3.35-3.51 ( 1H, m), 3.57-3.82 (1H, m), 4.15-4.30 (2H, m), 4.32-4.48 (1H, m), 4.60-4.74 (1H, m), 7.15 (1H, s), 7.17 ( 1H, dd, J=8.8, 2.0Hz), 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-tetra Hydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

Using the same method as in Example 5, the compound (275 mg) obtained in Reference Example 67, 6-chloronaphthalene-2-carboxylic acid (Eur.J.Chem.Chim.Ther., 1984, 19 volumes, 205-214 Page) (148mg), triethylamine (0.298ml) and 1-hydroxybenzotriazole monohydrate (11mg) were dissolved in N,N-dimethylformamide (20ml), and 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (412 mg) were reacted to obtain the title compound (186 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.56 (2H, m), 1.57-1.77 (4H, m), 1.90-2.10 (2H, m), 2.90 (3H, s), 3.13 (2H, br.s), 3.28-3.74(2H, m), 4.26(2H, br.s), 4.30-4.74(2H, m), 7.59(1H, d, J=8.6Hz), 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-benzothiophen-2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4, 5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as in Example 5, the compound (255 mg) obtained in Reference Example 65, 6-chlorobenzo[b]thiophene-2-carboxylic acid (Japanese Patent Laid-Open No. 2000-119253) (141 mg), triethylamine (0.276ml) and 1-hydroxybenzotriazole monohydrate (10mg) were dissolved in N,N-dimethylformamide (20ml), and 1-(3-dimethylaminopropyl)-3-ethane Carbodiimide hydrochloride (382 mg) was reacted to obtain the title compound (239 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.98 (8H, m), 2.88 (3H, s), 3.00-3.72 (4H, m), 3.84-4.09 (2H, m), 4.20-4.75 ( 2H, m), 7.41 (1H, dd, J=8.6, 1.7Hz), 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 prepared from the compound obtained in Reference Example 65 and 5-fluoroindole-2-carboxylic acid in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.38 (2H, m), 1.40-1.57 (1H, m), 1.54-1.68 (1H, m), 1.71 (2H, d, J=7.3Hz) , 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 prepared from the compound obtained in Reference Example 65 and the compound obtained in Reference Example 23 in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.40 (2H, m), 1.40-1.80 (4H, m), 1.80-2.00 (2H, m), 2.87 (3H, s), 3.01 (2H, br.s), 3.30-3.80(2H, m), 3.81-3.97(2H, m), 4.20-4.80(2H, m), 7.06(1H, s), 7.28(1H, d, J=10.0Hz) , 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 prepared from the compound obtained in Reference Example 67 and 5-bromoindole-2-carboxylic acid in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 1.43 (2H, br.s), 1.61 (4H, br.s), 1.80-2.10 (2H, m), 2.88 (3H, s), 3.00-3.26 ( 2H, m), 3.40(1H, br.s), 3.65(1H, br.s), 4.22(1H, br.s), 4.26(1H, br.s), 4.41(1H, br.s), 4.67 (1H, d, J = 15.6Hz), 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

Add triethylamine (6ml), N,N-dimethylformamide (5ml), trimethyl Silylacetylene (0.250ml) and palladium acetate (20mg). After stirring at 90° C. for 2 hours, the reaction solution was naturally cooled to room temperature, and dichloromethane (20 ml) and saturated aqueous sodium bicarbonate solution (30 ml) were added for separation. The aqueous layer was extracted with dichloromethane (3×10ml), 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. This solid was dissolved in methanol (6 ml), potassium carbonate (120 mg) was added and stirred for 1 hour. Dichloromethane (20ml) and water (20ml) were added to the reaction solution to separate the layers, and the aqueous layer was extracted with dichloromethane (2×15ml). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative silica gel thin-layer chromatography (dichloromethane:acetone:methanol=10; 10:1), dissolved in water-methanol-dichloromethane and concentrated to obtain the title compound (72 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.50-2.25 (8H, m), 2.53 (3H, s), 2.85 (2H, br.s), 2.93 (2H, br.s), 3.01 (1H, s) , 3.74(1H, d, J=14.1Hz), 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 prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 51 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) 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-pyran And[4,3-d]thiazole-2-carboxamide

The title compound was prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 26 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.36-1.72 (6H, m), 1.90-2.10 (2H, m), 2.80-2.87 (2H, m), 3.93 (2H, t, J=5.6Hz) , 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 hydrochloride

The title compound was prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 29 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.32-1.74 (6H, m), 1.82-2.10 (2H, m), 2.92 (3H, s), 3.12-3.50 (3H, m), 3.69 (1H, br.s), 4.13-4.39(3H, m), 4.51(1H, br.s), 7.10-7.19(2H, m), 7.41(1H, d, J=8.6Hz), 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 prepared from the compound obtained in Reference Example 69 and the compound obtained in Reference Example 21 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.23-1.39 (2H, m), 1.40-1.81 (4H, m), 1.82-1.98 (2H, m), 2.60-3.00 (5H, m), 3.20- 3.70(2H, m), 3.87-3.96(1H, m), 3.98-4.10(1H, m), 4.12-4.70(2H, m), 7.04(1H, d, J=1.5Hz), 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-tetrahydrothiophene And[3,2-c]pyridine-2-carboxamide hydrochloride

Using the same method as in Example 2, the compound obtained in Reference Example 71 and 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2- Carboxylic acid (WO 94/21599) was condensed, treated with hydrochloric acid for deprotection, and the title compound was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (2H, br.s), 1.56-1.76 (4H, m), 1.98-2.11 (2H, m), 3.04 (2H, br.s), 3.32- 3.45(2H, m), 4.15(3H, br.s), 4.26(1H, br.s), 7.14(1H, dd, J=8.8, 2.0Hz), 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 obtained in Example 17 (171 mg) was suspended in dichloromethane (10 ml), triethylamine (0.104 ml) was added and stirred at room temperature for 10 minutes. After adding acetic acid (0.059 ml) to the reaction solution, 35% formalin (0.070 ml) and sodium triacetoxyborohydride (118 mg) were added, followed by stirring at room temperature for 30 minutes. After adding 1N aqueous sodium hydroxide solution (3 ml) to the reaction solution, water was added to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=50:3) to obtain a colorless foamy substance. 1N hydrochloric acid was added thereto for suspension, and then concentrated under reduced pressure to obtain the title compound (85 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.40 (2H, br.s), 1.50-1.71 (4H, m), 1.97-2.05 (2H, m), 2.87 (3H, s), 2.98-3.20 ( 1H, m), 3.30-3.38 (2H, m), 3.54-3.70 (1H, m), 4.05-4.42 (4H, m), 7.14 (1H, d, J=8.6Hz), 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 prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 31 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (2H, br.s), 1.52-1.68 (4H, m), 1.87-2.08 (3H, m), 2.30-2.40 (1H, m), 2.65- 2.75(1H,m), 2.77(6H,s), 2.95-3.17(2H,m), 3.30-3.70(2H,m), 4.15-4.30(2H,m), 7.10-7.20(2H,m), 7.41 (1H, d, J = 8.6Hz), 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]amino}cyclohexyl)-5-(pyridin-4-yl)-4 , 5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

To a tetrahydrofuran (3 ml) solution of the compound (204 mg) obtained in Reference Example 24 was added dropwise n-butyl lithium (1.60 N hexane solution, 0.704 ml) at -78°C, followed by stirring at 0°C for 30 minutes. After cooling to -78°C again, the temperature was raised to room temperature over 20 minutes while introducing carbon dioxide gas, and the reaction solution was concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (6 ml) were added the compound (400 mg) obtained in Reference Example 71, 1-hydroxybenzotriazole monohydrate (254 mg), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (360mg) and diisopropylamine (0.491ml). After stirring for 3 days, the reaction mixture was concentrated under reduced pressure, dichloromethane (30ml), saturated aqueous sodium bicarbonate solution (100ml) and water (100ml) were added to the residue to separate the liquid, and the aqueous layer was washed with dichloromethane (4×15ml). extraction. 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 (dichloromethane:methanol=20:1→10:1), dissolved in 1N aqueous hydrochloric acid-methanol-dichloromethane and concentrated to obtain the title compound (245 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.42 (2H, br.s), 1.60 (4H, br.s), 1.84-1.94 (1H, m), 1.94-2.08 (1H, m), 2.97 ( 2H, br.s), 3.97-4.13(2H, m), 4.19(1H, br.s), 4.27(1H, br.s), 5.03(2H, s), 7.13(1H, br.s), 7.16 (1H, dd, J = 8.8, 2.0Hz), 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-chloroindol-2-yl)carbonyl]amino}cycloheptyl)-5-methyl-4,5,6 , 7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 74 and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.51-1.55 (4H, m), 1.75-1.80 (6H, m), 2.88 (3H, s), 3.12 (1H, br.s), 3.35-3.63 ( 4H, m), 4.10-4.13 (1H, m), 4.29-4.61 (2H, m), 7.06 (1H, s), 7.14 (1H, dd, J=8.8, 2.0Hz), 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 prepared from the compound obtained in Reference Example 78 and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.61-2.06 (12H, m), 2.90 (3H, s), 3.08-3.17 (2H, m), 3.43-3.45 (1H, m), 3.67 (1H, br.s), 4.43(3H, br.s), 4.67(1H, br.s), 7.16-7.18(2H, m), 7.42(1H, d, J=8.8Hz), 7.70(1H, s) , 8.24 (1H, br.s), 8.58 (1H, d, J=8.3Hz), 11.43, 11.63 (1H, each br.s), 11.80 (1H, s).

MS (ESI) m/z: 500 (M+H) ⁺ .

[Example 23] N-((1R ^* , 2R ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclopentyl)-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the reaction product of the compound obtained in Reference Example 63 and the compound obtained in Reference Example 34 was treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.82 (4H, m), 1.91-2.15 (2H, m), 3.08 (2H, s), 3.37-3.49 (2H, m), 4.28-4.56 ( 4H, m), 7.13(1H, s), 7.15(1H, d, J=8.8Hz), 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 obtained in Example 23 (30 mg) was suspended in dichloromethane (20 ml), triethylamine (260 µl) was added and stirred at room temperature for 15 minutes. Acetic acid (179 μl) and acetone (920 μl) were added to the reaction mixture and stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (796 mg) was added to the reaction solution, followed by stirring at room temperature for 5 hours. A 1N aqueous sodium hydroxide solution (10 ml) was added to the reaction solution to carry out a liquid separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was 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 dichloromethane, and 1N hydrochloric acid ethanol solution (1 ml) was added. The solution was concentrated under reduced pressure to obtain the title compound (205 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.27-1.39 (6H, m), 1.58-1.80 (4H, m), 1.95-2.10 (2H, m), 3.00-3.12 (1H, m), 3.25- 3.45(2H,m), 3.59-3.77(2H,m), 4.25-4.39(1H,m), 4.40-4.55(2H,m), 4.57-4.65(1H,m), 7.10(1H,s), 7.14 (1H, d, J = 8.8Hz), 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 obtained in Example 23 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), triethylamine (576 μl) and ethyl iodide (329 μl) were added thereto, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and water was added to the residue to collect insoluble matter by filtration. 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 (2 ml), and the solution was concentrated under reduced pressure to obtain the title compound (180 mg).

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Reference Example 63 and the compound obtained in Reference Example 39 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 0.81 (2H, br.s), 1.20-1.55 (5H, br), 1.55-1.80 (4H, m), 1.95-2.12 (2H, m), 3.05- 3.40 (2H, br), 3.60-3.80 (2H, br), 4.25-4.80 (4H, m), 7.10 (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)

The compound obtained in Reference Example 82 (a mixture of stereoisomers at the 4-position) (268 mg) was condensed with the compound obtained in Reference Example 10 in the same manner as in Example 2 to synthesize stereoisomers A and A of the title compound. The mixture of B was separated by silica gel column chromatography to form hydrochloride to obtain stereoisomer A (75 mg) and stereoisomer B (70 mg) of the title compound.

Stereoisomer A:

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-2.15 (4H, m), 2.90 (3H, s), 3.00-3.90 (8H, m), 4.10-4.80 (4H, m), 7.08 (1H, s), 7.16 (1H, d, J = 8.8Hz), 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:

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-2.10 (4H, m), 2.89 (3H, s), 3.00-3.70 (7H, m), 3.70-3.90 (1H, m), 4.20-4.80 ( 4H, m), 7.05-7.20 (2H, m), 7.38 (1H, d, J=8.8Hz), 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) Using the same method as in Example 2, the compound obtained in Reference Example 85 and the compound obtained in Reference Example 42 were used to prepare N-((1R ^* , 2R ^* )-4-[(benzyloxy)methyl]- 2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclopentyl)-5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1 - Stereoisomer A and Stereoisomer B of -dimethylethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide.

Stereoisomer A:

¹ H-NMR (CDCl ₃ ) δ: 1.05 (9H, s), 1.168, 1.171 (6H, each s), 1.53-1.61 (1H, m), 1.76-1.88 (1H, m), 2.30-2.37 ( 2H, m), 2.78-2.79 (2H, m), 2.87-2.90 (1H, m), 2.96-3.00 (1H, m), 3.37-3.47 (2H, m), 3.58 (2H, s), 3.96 ( 1H, q, J = 13.1Hz), 4.41-4.45 (1H, m), 4.51-4.57 (2H, m), 6.88 (1H, d, J = 1.5Hz), 7.17 (1H, dd, J = 8.8, 2.0Hz), 7.23-7.43(12H, m), 7.52(1H, d, J=7.6Hz), 9.37(1H, br.s).

Stereoisomer B:

¹ H-NMR (CDCl ₃ ) 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) Suspend the above stereoisomer A (288 mg) in dichloromethane (20 ml), add dimethyl sulfide (1.15 ml), anhydrous aluminum chloride (350 mg), and stir at room temperature for 1 hour. 1N aqueous sodium hydroxide solution (10 ml) was added to the reaction solution, extracted with dichloromethane, 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=9:1) to obtain 5-(2-{[tert-butyl(diphenyl)silyl]oxyl}- 1,1-Dimethylethyl)-N-[(1R ^* ,2R ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-(hydroxymethyl) ring Pentyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Stereoisomer A) (184 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.15 (6H, s), 1.54-1.62 (1H, m), 1.73-1.81 (1H, m), 1.99-2.25 (2H, m) , 2.34-2.38(2H, m), 2.67-2.85(3H, m), 2.92-2.97(1H, m), 3.48-3.62(4H, m), 3.93(1H, q, J=15.6Hz), 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) (180 mg) obtained in the above 2) was dissolved in a 1N solution of tetrabutylammonium fluoride in tetrahydrofuran (2 ml), and stirred overnight at room temperature. Dichloromethane, 1N aqueous sodium hydroxide solution, and sodium chloride were added to the reaction liquid for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=19:1). The obtained powder was dissolved in methanol, 1N hydrochloric acid ethanol solution (229 μl) was added, and ethyl acetate was added under reduced pressure. The solvent was concentrated to obtain the title compound (63 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.33-1.50 (8H, m), 1.70-1.91 (2H, m), 2.07-2.14 (1H, m), 2.23-2.24 (1H, m), 3.04- 3.10(1H, m), 3.27-3.44(4H, m), 3.57-3.70(2H, m), 3.92-3.95(1H, m), 4.29-4.72(4H, m), 5.81(1H, br.s ), 7.11 (1H, s), 7.15 (1H, dd, J=8.6, 2.0Hz), 7.39 (1H, d, J=8.6Hz), 7.68 (1H, d, J=2.0Hz), 8.53-8.56 (1H, m), 8.83 (1H, d, J=8.3Hz), 10.36 (1H, br.s), 11.75, 11.77 (1H, each s).

MS (ESI) m/z: 546 (M+H) ⁺ .

[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 prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 44 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Reference Example 46 and the compound obtained in Reference Example 71 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) 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 ]cyclohexyl}indole-2-carboxamide hydrochloride

Under an argon atmosphere, the compound obtained in Reference Example 33 (171 mg) was dissolved in diethyl ether (5 ml), and n-butyllithium (1.60N hexane solution, 385 µl) was added dropwise at -78°C. After stirring at -78°C for 10 minutes, carbon dioxide gas was introduced over 20 minutes, and then the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in N,N-dimethylformamide (10 ml), and the compound (184 mg) obtained in Reference Example 71, 1-hydroxybenzotriazole monohydrate (76 mg) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215 mg), stirred at room temperature for 3 days. After concentrating the reaction solution, dichloromethane and saturated aqueous sodium bicarbonate solution were added, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=3:97). Hydrochloric acid ethanol solution (5 ml) was added to the resultant, stirred at room temperature for 1 hour, and the reaction solution was concentrated. Ethyl acetate was added to the resulting residue for solidification, and the powder was collected by filtration to obtain the title compound (31 mg).

¹ H-NMR (DMSO-d ₆ ) 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-di tert-Butyl Hydrogen-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate

After hydrolyzing the compound obtained in Reference Example 50 with lithium hydroxide, it was reacted with the compound obtained in Reference Example 71 in the same manner as in Example 2 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.55-2.30 (8H, m), 4.23 (1H, br.s), 4.53 (1H, br.s), 4.74-4.83 (4H, m), 6.99 (1H, d, J = 1.5Hz), 7.19 (1H, dd, J = 8.8, 2.1Hz), 7.34 (1H, d, J = 8.8Hz), 7.62 (1H, d, J = 2.1 Hz), 8.11(1H, br.s), 8.48-8.53(1H, br), 8.70-8.76(1H, br), 9.60-9.70(1H, br).

MS (ESI) m/z: 539 (M+H) ⁺ .

[Example 33] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-6-methyl-6,7-dihydro -5H-pyrrolo[3,4-d]pyrimidine-2-carboxamide hydrochloride

To a solution obtained by dissolving the compound obtained in Example 32 (34.0 mg) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) at room temperature and stirred for 1 hour. Concentrate under reduced pressure, dissolve the residue in dichloromethane (1ml), add triethylamine (17.6μl), acetic acid (7.21μl), 35% formalin (8.13μl) and sodium triacetoxyborohydride at room temperature (20.1 mg), stirred for 1 hour. Dichloromethane (10 ml) and saturated aqueous sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=7:93), solidified by adding 1N hydrochloric acid ethanol solution and ethyl acetate, and filtered to obtain the title compound (8.00 mg) .

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.55 (2H, m), 1.55-1.75 (4H, m), 1.80-2.05 (2H, m), 2.98 (3H, br.s), 4.28 ( 2H, br.s), 4.65 (4H, br.s), 7.14-7.20 (2H, m), 7.41 (1H, d, J=8.8Hz), 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-tetrahydrothiazole And[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as in Example 2, the reaction product of the compound obtained in Reference Example 71 and the compound obtained in Reference Example 34 was treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.39-1.52 (2H, m), 1.62 (4H, br.s), 1.86-2.09 (2H, m), 3.03 (2H, br.s), 3.40- 3.47(2H, m), 4.17-4.32(2H, m), 4.44(2H, s), 7.15(1H, s), 7.17(1H, dd, J=8.6, 2.0Hz), 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 prepared from the compound obtained in Example 34 and 2-methoxyethyl bromide in the same manner as in Example 25.

¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (2H, br.s), 1.62 (4H, br.s), 1.85-2.10 (2H, m), 2.76-3.21 (6H, m), 3.28 ( 3H, s), 3.64 (2H, br.s), 4.00-4.52 (4H, m), 7.14 (1H, s), 7.17 (1H, dd, J=8.8, 2.0Hz), 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

In the same manner as in Example 25, the title compound was obtained from the compound obtained in Example 34 and methyl bromoacetate.

¹ H-NMR (CDCl ₃ ) δ: 1.52-1.98 (7H, m), 2.17 (1H, br.s), 2.87-3.10 (4H, m), 3.49 (2H, s), 3.76 (3H, s) , 3.93 (1H, d, J = 15.4Hz), 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

In the same manner as in Example 24, the title compound was prepared from the compound obtained in Example 34 and acetone.

¹ H-NMR (DMSO-d ₆ ) δ: 1.18-1.73 (8H, m), 1.81-2.10 (2H, m), 2.97-3.16 (1H, m), 3.20-3.41 (2H, m), 3.52- 3.80(2H, m), 4.19-4.31(2H, m), 4.34-4.77(2H, m), 7.17(1H, s), 7.18(1H, dd, J=8.8, 2.0Hz), 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 prepared from the compound obtained in Example 34 and tetrahydro-4H-pyran-4-one in the same manner as in Example 24.

¹ H-NMR (DMSO-d ₆ ) δ: 1.30-3.56 (19H, m), 3.70-4.01 (3H, m), 4.17-4.30 (2H, m), 4.32-4.80 (1H, m), 7.15 ( 1H, s), 7.17 (1H, dd, J=8.6, 2.0Hz), 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, tert-butyl 7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]ethylcarbamate

The title compound was prepared from the compound obtained in Example 34 and N-(tert-butoxycarbonyl)aminoacetaldehyde (J. Org. Chem., 1988, Vol. 53, p. 3457) in the same manner as in Example 24.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.54-1.98 (7H, m), 2.10-2.20 (1H, m), 2.74 (2H, br.s), 2.92 (4H, br. s), 3.34(2H, br.s), 3.84(2H, br.s), 4.21(1H, br.s), 4.45(1H, br.s), 6.86(1H, s), 7.19(1H, dd, J=8.8, 2.0Hz), 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 obtained in Example 39 (450 mg) was dissolved in dichloromethane (5 ml), hydrochloric acid ethanol solution (30 ml) was added and stirred at room temperature for 1 minute. The reaction solution 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).

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.50 (2H, m), 1.61 (4H, br.s), 1.85-2.08 (2H, m), 3.00-4.62 (12H, m), 7.14 ( 1H, s), 7.16 (1H, dd, J=8.8, 2.0Hz), 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 (110 mg) was dissolved in pyridine (3 ml), methanesulfonyl chloride (30 µl) was added, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and a solution of dichloromethane:methanol = 85:15 and water were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 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 (0.3 ml), and the solution was concentrated under reduced pressure to obtain the title compound (63 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.50 (2H, m), 1.55-1.70 (4H, m), 1.86-2.05 (2H, m), 2.97 (3H, s), 3.02-3.25 ( 2H, m), 3.30-3.60 (5H, m), 3.78 (1H, br.s), 4.18-4.30 (2H, m), 4.45-4.86 (2H, m), 7.14 (1H, s), 7.16 ( 1H, dd, J = 8.8, 2.0Hz), 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, Methyl 7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl]ethylcarbamate hydrochloride

The compound obtained in Example 40 (144 mg) was dissolved in pyridine (3 ml), and triethylamine (138 µl) was added thereto, followed by stirring at room temperature for 5 minutes. To this solution was added dropwise a solution prepared by adding triphosgene (49 mg) to tetrahydrofuran (1 ml) containing methanol (20 µl) at room temperature, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane:methanol=9:1, water was added for liquid separation, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:3) to obtain a colorless foamy substance. This was suspended in 1N hydrochloric acid (0.2 ml), and the solution was concentrated under reduced pressure to obtain the title compound (60 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.50 (2H, m), 1.61 (4H, br.s), 1.85-2.04 (2H, m), 2.80-3.49 (8H, m), 3.52 ( 3H, s), 3.62-4.91 (4H, m), 7.14 (1H, s), 7.16 (1H, dd, J=8.8, 2.0Hz), 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} ring Hexyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 40 (90 mg) was dissolved in N,N-dimethylformamide (3 ml), triethylamine (65 µl) and acetic anhydride (22 µl) were added thereto, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, dichloromethane and 0.3N aqueous sodium hydroxide solution were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:3) to obtain a colorless foamy substance. This was suspended in 1N hydrochloric acid (0.3 ml), and the solution was concentrated under reduced pressure to obtain the title compound (73 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.39-1.52 (2H, m), 1.54-1.70 (4H, m), 1.83 (3H, s), 1.84-2.06 (2H, m), 3.02-3.87 ( 8H, m), 4.16-4.32 (2H, m), 4.40-4.52 (1H, m), 4.78-4.88 (1H, m), 7.14 (1H, s), 7.16 (1H, d, J=8.6Hz) , 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-carboxamide

The title compound was prepared from the compound obtained in Example 34 and 2-bromoethanol in the same manner as in Example 25.

¹ H-NMR (DMSO-d ₆ ) δ: 1.37-1.69 (6H, m), 1.86-2.03 (2H, m), 2.54-2.61 (2H, m), 2.75-2.86 (4H, m), 3.52- 3.59(2H, m), 3.75(2H, s), 4.47(1H, t, J=5.4Hz), 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 prepared from the compound obtained in Example 34 and 1-bromobutane in the same manner as in Example 25.

¹ H-NMR (DMSO-d ₆ ) 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-carboxamide

The compound obtained in Example 34 (100 mg) was dissolved in N,N-dimethylformamide (3 ml), triethylamine (84 µl) and acetic anhydride (29 µl) were added thereto, and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dichloromethane and 1N hydrochloric acid were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:3) to obtain the title compound (86 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.52-1.85 (5H, m), 1.91 (2H, br.s), 2.10-2.28 (4H, m), 2.77-3.00 (2H, m), 3.70-4.00 ( 2H, m), 4.19-4.38 (1H, m), 4.45 (1H, br.s), 4.68-4.99 (2H, m), 6.85 (1H, s), 7.17-7.22 (1H, m), 7.30- 7.39 (1H, m), 7.50-7.84 (3H, m), 9.7

2-10.05(1H, m).

MS (FAB) m/z: 500 (M+H) ⁺ .

[Example 47] N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-(methylsulfonyl)-4, 5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound obtained in Example 34 (100 mg) was dissolved in pyridine (3 ml), triethylamine (168 μl) and methanesulfonyl chloride (48 μl) were added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, dichloromethane and 1N hydrochloric acid were added to the residue, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain the title compound (79 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.82 (5H, m), 1.90 (2H, br.s), 2.13 (1H, br.s), 2.89 (3H, s), 2.91-2.98 (2H, m), 3.60-3.70 (2H, m), 4.30 (1H, br.s), 4.44 (1H, br.s), 4.58 (2H, s), 6.87 (1H, s), 7.19 (1H, d, J=8.8Hz), 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 prepared from the compound obtained in Reference Example 67 and 5-methylindole-2-carboxylic acid in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) 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, 1.5 Hz), 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, Ethyl 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound (1.40 g) obtained in Reference Example 91 was suspended in ethanol (8 ml), and hydrochloric acid ethanol solution (10 ml) was added at room temperature and stirred for 12 hours. The solvent was distilled off under reduced pressure to obtain (1R ^* , 3S ^* , 4R ^* )-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylic acid ethyl ester salt salt (1.25g).

The title compound was prepared from the above product and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ ) 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), 3.73and 3.78 (each 1H, each d, J = 14.4Hz), 4.08-4.17 (1H, m), 4.18 (2H, q, J = 7.2Hz), 4.55-4.65 (1H , m), 6.85 (1H, br.s), 7.21 (1H, dd, J=8.8, 2.0Hz), 7.33 (1H, d, J=8.8Hz), 7.48 (1H, d, J=7.6Hz) , 7.63(1H, d, J=2.0Hz), 7.98(1H, d, J=7.6Hz), 9.30(1H, s).

MS (ESI) m/z: 544 (M+H) ⁺ .

[Example 50] (1R, 3R, 4S)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7 -Ethyl tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound (4.2 g) obtained in Reference Example 97 was suspended in ethanol (25 ml), and hydrochloric acid ethanol solution (55 ml) was added 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 product (4.15g) was dissolved in N,N-dimethylformamide (40ml), and the compound obtained in Reference Example 10 (2.86g) and 1-hydroxybenzotriazole monohydrate (1.72g) were added at room temperature . 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.15 g), stirred for 39 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue and extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain the title compound (1.71 g).

[α] _D -94° (c=1.0, chloroform)

[Example 51] (1R ^* , 3R ^* , 4S ^* )-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5, Methyl 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

In the same manner as in Example 49, the compound obtained in Reference Example 107 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.80 (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, Ethyl 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

In the same manner as in Example 49, the compound obtained in Reference Example 98 was treated with ethanol hydrochloric acid solution, and then condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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, Methyl 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate hydrochloride

In the same manner as in Example 49, the compound obtained in Reference Example 106 was treated with 4N hydrochloric acid dioxane solution, and then condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.80 (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 -Methyl tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

In the same manner as in Example 49, the compound obtained in Reference Example 112 was treated with 4N hydrochloric acid in dioxane and condensed with 5-chloroindole-2-carboxylic acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.67-1.76 (3H, m), 1.88-1.91 (1H, m), 2.01 (1H, br.s), 2.13-2.22 (1H, m), 2.52- 2.67(4H, m), 2.86(2H, br.s), 3.04(2H, br.s), 3.33-3.41(1H, m), 3.61(3H, s), 4.22-4.36(3H, m), 7.17-7.22(2H, m), 7.42(1H, d, J=8.8Hz), 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-carboxamide

In the same manner as in Example 49, the compound obtained in Reference Example 113 was treated with 4N hydrochloric acid dioxane solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.78-2.40 (7H, m), 2.53 (3H, s), 2.80-2.89 (1H, m), 2.91-3.00 (1H, m), 3.68-3.76 (2H, m), 4.08-4.19 (1H, m), 4.54-4.65 (1H, m), 6.80 (1H, br.s), 7.21 (1H, dd, J=8.4, 1.6Hz), 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 acid

The compound (916mg) obtained in Example 49 was suspended in a mixed solvent of ethanol (10ml) and tetrahydrofuran (8ml), and 1N aqueous sodium hydroxide solution (3.3ml) was added at room temperature, and stirred at the same temperature for 12 hours. After adding 1N hydrochloric acid ethanol solution (3.3 ml), the solvent was evaporated under reduced pressure, and the residue was washed with water and diethyl ether to obtain the title compound (712 mg).

[Example 57] N-{(1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl] Cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

To the chloroform suspension (10 ml) of the compound (168 mg) obtained in Example 56 were added triethylamine (0.25 ml), dimethylamine hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (53 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg), stirred for 72 hours. The solvent was distilled off under reduced pressure, water was added to the residue and 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 (dichloromethane:methanol=93:7). The obtained colorless solid (135mg) was suspended in ethanol (5ml), and 1N hydrochloric acid ethanol solution (0.5 ml) was stirred for 2 hours. The solvent was distilled off to obtain the title compound (112 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-2.07 (6H, m), 2.73-3.70 (10H, m), 2.88 (3H, s), 2.97 (3H, s), 4.03-4.20 (1H, m), 4.51-4.67 (1H, m), 7.04 (1H, br.s), 7.16 (1H, br, J=8.8Hz), 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 obtained in Example 50 (1.6 g) was suspended in a mixed solvent of ethanol (20 ml) and tetrahydrofuran (15 ml), 1N aqueous sodium hydroxide solution (5.9 ml) was added at room temperature, and stirred at the same temperature for 12 hours. After adding 1N hydrochloric acid (5.9 ml), the solvent was evaporated under reduced pressure, and the residue was washed with water and diethyl ether to obtain the title compound (1.19 g).

Melting point: 234～236℃

[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 prepared from the compound obtained in Example 58 and cyclopropylamine in the same manner as in Example 57.

¹ H-NMR (DMSO-d ₆ ) δ: 0.32-0.40 (2H, m), 0.53-0.63 (2H, m), 1.50-2.10 (6H, m), 2.25-2.40 (1H, m), 2.45- 2.70(2H, m), 2.91(3H, s), 3.05-3.80(3H, m), 4.05-4.17(1H, m), 4.30-4.55(2H, m), 4.55-4.80(1H, m), 7.03 (1H, d, J = 1.5Hz), 7.16 (1H, dd, J = 8.8, 2.0Hz), 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 prepared from the compound obtained in Example 58 and pyrrolidine in the same manner as in Example 57.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-2.10 (10H, m), 2.75-2.90 (2H, m), 2.90 (3H, s), 3.10-3.70 (H, m), 4.05-4.20 ( 1H, m), 4.25-4.80 (3H, m), 7.05 (1H, s), 7.17 (1H, d, J=8.7Hz), 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) ring Hexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Example 56 and morpholine in the same manner as in Example 57.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-2.05 (6H, m), 2.75-3.70 (18H, m), 4.02-4.17 (1H, m), 4.55-4.69 (1H, m), 7.05 ( 1H, br.s), 7.17 (1H, br, J=8.8Hz), 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 obtained in Example 58 (150 mg) was dissolved in N,N-dimethylformamide (3 ml), and N-ethylamine hydrochloride (119 mg), 1-hydroxybenzotriazole monohydrate (79 mg) were added , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112 mg) and triethylamine (326 μl), stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=47:3). The obtained solid was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (171 µl) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (74 mg).

¹ H-NMR (DMSO-d ₆ ) 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 obtained in Example 58 (900 mg) was dissolved in N,N-dimethylformamide (50 ml), and dimethylamine hydrochloride (304 mg), 1-hydroxybenzotriazole monohydrate (262 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (369 mg) and diisopropylethylamine (1.83 ml) were stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the residue, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=47:3). The resulting white solid was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (1.49ml) was added, and The solvent was evaporated down. 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)

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Example 58 in the same manner as in Example 57.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.99 (6H, m), 2.80, 3.01 (3H, each s), 2.91 (3H, s), 3.03 (1H, br.s), 3.16 ( 2H, s), 3.23 (3H, s), 3.35-3.67 (6H, m), 4.09-4.16 (1H, m), 4.43-4.67 (3H, m), 7.04-7.06 (1H, m), 7.16 ( 1H, dd, J=8.8, 2.0Hz), 7.42(1H, d, J=8.8Hz), 7.69(1H, br.s), 8.29-8.41(2H, m), 11.59(1H, br.s) , 11.80 (1H, br.s).

MS (FAB) m/z: 587 (M+H) ⁺ .

[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 prepared from the compound obtained in Example 58 in the same manner as in Example 57.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.55 (1H, m), 1.74-1.84 (3H, m), 1.94-1.97 (2H, m), 2.67, 3.02 (3H, each s), 2.91(3H, s), 3.10-3.68(9H, m), 4.11-4.13(1H, m), 4.43-4.66(4H, m), 7.05(1H, s), 7.16(1H, dd, J=8.7 , 2.0Hz), 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} ring Hexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Example 58 and azetidine hydrochloride in the same manner as in Example 57.

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.55 (1H, m), 1.65-1.82 (3H, m), 1.88-2.01 (2H, m), 2.16 (2H, quint., J=7.6Hz ), 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

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and (S)-3-fluoropyrrolidine (Synlett., 1995, p. 55).

¹ H-NMR (DMSO-d ₆ ) δ: 1.23-3.77 (22H, m), 4.11-4.16 (1H, m), 4.58-4.51 (1H, m), 5.23-5.42 (1H, m), 7.05 ( 1H, s), 7.16 (1H, d, J = 8.3Hz), 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, Lithium salt of 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The compound obtained in Example 51 (1.20 g) was dissolved in tetrahydrofuran (32 ml), lithium hydroxide (60.8 mg) and water (4 ml) were successively added under ice cooling, and stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure to obtain the title compound (1.12 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.70 (2H, m), 1.70-2.05 (4H, m), 2.10-2.20 (1H, m), 2.25-2.40 (4H, m), 2.50- 2.80(4H,m), 3.45-3.65(3H,m), 4.10-4.30(2H,m), 7.00-7.20(2H,m), 7.50-7.65(2H,m).

[Example 69] N-{(1R ^* , 2S ^* , 4S ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}-4-[(dimethylamino)carbonyl] Cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Example 68 and dimethylamine hydrochloride in the same manner as in Example 57.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.60 (2H, m), 1.65-1.80 (2H, m), 1.95-2.10 (2H, m), 2.84 (3H, s), 2.90-3.05 ( 1H, m), 2.92 (3H, s), 3.06 (3H, s), 3.15-3.75 (4H, m), 4.25-4.75 (4H, m), 7.02 (1H, d, J=1.5Hz), 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) Dissolve the compound (1.18 g) obtained in Reference Example 58 in methanol (12 ml), add 1N hydrochloric acid (240 μl) and palladium hydroxide (221 mg), introduce hydrogen, and carry out a catalytic reduction reaction at room temperature for 4.5 hours under normal pressure . The catalyst was filtered off, and the filtrate was concentrated to dryness under reduced pressure to obtain crude (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}pyrrolidine hydrochloride (984 mg).

The resulting product (249 mg), the compound obtained in Example 58 (295 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126 mg) and 1-hydroxybenzene Triazole monohydrate (87mg) was dissolved in N,N-dimethylformamide (10ml). Under ice cooling, diisopropylethylamine (450 μl) was added dropwise, and stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue for 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 (methanol:dichloromethane=3:97) to obtain 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).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (9H, s), 1.50-1.60 (1H, m), 1.75-2.10 (5H, m), 2.20-2.50 (2H, m), 2.54 (3H, d, J=2.8Hz), 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 above product (240mg) was dissolved in pyridine (10ml), and hydrogen fluoride·pyridine (3.0ml) was added dropwise under ice cooling, and stirred at 0°C for 4.5 hours. Under ice cooling, ethyl acetate (80 ml) was added to the reaction solution for dilution, and the diluted reaction solution was poured into ice water. Sodium bicarbonate was added to this solution to make it alkaline, and a liquid separation operation was performed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:19→1:9). The obtained crude product was dissolved in dichloromethane and methanol, 1N hydrochloric acid ethanol solution (225 μl) was added and evaporated to dryness once, and methanol-ether was added to the residue to solidify to obtain the title compound (114 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.60 (1H, m), 1.70-2.10 (6H, m), 2.75-2.85 (1H, m), 2.92 (3H, s), 3.10-3.80 ( 8H, m), 4.10-5.10 (6H, m), 7.05 (1H, d, J = 1.7Hz), 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-carboxamide or N-((1R*,2S*)-2-{[(5-chloroindole -2-yl)carbonyl]amino}-4,4-dimethoxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2- Formamide

The title compound was prepared from the compound obtained in Reference Example 118 and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ ) δ: 2.11-2.15 (1H, m), 2.21-2.25 (1H, m), 2.41-2.43 (1H, m), 2.46 (3H, s), 2.70-2.75 (1H, m), 2.81-2.88(1H, m), 3.21(3H, s), 3.24(3H, s), 3.49(1H, s), 3.58(1H, d, J=15.6Hz), 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-carboxamide or N-((1R ^* , 2S ^* )-2-{[(5-chloroindol-2-yl )carbonyl]amino}-4-oxocyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound obtained in Example 71 (100 mg) was dissolved in chloroform (2 ml), trifluoroacetic acid (0.5 ml) and water (0.5 ml) were added, and stirred at room temperature for 3.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin-layer chromatography (dichloromethane:methanol=19:1). The obtained colorless solid was dissolved in methanol (4 ml), 1N hydrochloric acid ethanol solution (0.38 ml) was added, and the solvent was distilled off under reduced pressure to obtain the title compound (35 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.83-1.90 (1H, m), 2.08-2.10 (1H, m), 2.28-2.32 (1H, m), 2.50-2.59 (1H, m), 2.87 ( 3H, s), 2.96 (1H, t, J=13.0Hz), 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=8.8 Hz), 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-methan Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide or N-[(1R ^* ,2S ^* )-2-{[(5-chloroindole- 2-yl)carbonyl]amino}-4-(hydroxyimino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound obtained in Example 72 (133 mg) was dissolved in a mixed solvent of pyridine (8 ml) and methanol (8 ml), hydroxylamine hydrochloride (30 mg) was added, and stirred at room temperature for 3 days. The reaction solution was concentrated, water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3→17:3) to obtain the title compound (131 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.43-1.86 (3H, m), 1.98-2.03 (1H, m), 2.26-2.30 (1H, m), 2.45 (3H, s), 2.47-2.51 (1H, m), 2.67-2.71(1H, m), 2.78-2.86(3H, m), 3.86-3.43(2H, m), 4.16-4.24(2H, m), 6.85(1H, s), 7.13-7.16( 1H, m), 7.20-7.24 (1H, m), 7.46, 7.50 (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]decane-7 -yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide or N-((7R ^* , 8S ^* )-7-{[ (5-chloroindol-2-yl)carbonyl]amino}-1,4-dioxaspiro[4.5]dec-8-yl)-5-methyl-4,5,6,7-tetrahydrothiazole And[5,4-c]pyridine-2-carboxamide

The title compound was prepared from the compound obtained in Reference Example 120 and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.87 (6H, m), 2.14-2.17 (1H, m), 2.30-2.32 (1H, m), 2.47 (3H, s), 2.70-2.75 (1H, m), 2.81-2.89(2H, m), 3.58(1H, d, J=15.4Hz), 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-carboxamide or N-[(1R ^* ,2S ^* )-2-{[(5-chloroind Indol-2-yl)carbonyl]amino}-4-(methoxyimino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine- 2-formamide

1) The compound obtained in Reference Example 124 (2.21 g) was dissolved in dichloromethane (30 ml), trifluoroacetic acid (6 ml) was added, and stirred at room temperature for 1.5 hours. After the concentrated reaction solution was dried with a vacuum pump, it was dissolved in N,N-dimethylformamide (20ml), and 5-chloroindole-2-carboxylic acid (500mg), 1-(3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (593 mg), 1-hydroxybenzotriazole monohydrate (473 mg) and N-methylmorpholine (2.8 ml), stirred at room temperature for 10 hours. Then, 5-chloroindole-2-carboxylic acid (242 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (237 mg) and 1-hydroxybenzo Triazole monohydrate (189 mg), stirred for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, 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 distilled off 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 (300mg).

2) N-[(1R ^* ,2S ^* )-2-amino-5-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxamide, one of the products obtained by the above reaction Or N-[(1R ^* , 2S ^* )-2-amino-4-(methoxyimino)cyclohexyl]-5-chloroindole-2-carboxamide and the compound obtained in Reference Example 10, by implementing The same method as in Example 2 was used to prepare the title compound (mixture of syn and anti isomers of the methoxyimino moiety).

¹ H-NMR (CDCl ₃ ) 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-carboxamide (stereoisomer A) or N-((1R ^* , 2S ^* )-2-{[(5-chloro Indol-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 method as in 1) of Example 75, after removing the tert-butoxycarbonyl group of the (1R ^* , 2S ^* ) body (stereoisomer A) obtained in Reference Example 125, by mixing with 5-chloroindole -2-Carboxylic acid reaction to obtain N-((1R ^* ,2S ^* )-2-amino-4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)-5-chloroind Indole-2-carboxamide (stereoisomer A) and N-((1R ^* , 2S ^* )-2-amino-5-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl )-5-chloroindole-2-carboxamide (stereoisomer A).

2) From the mixture obtained from the above product and Reference Example 10, the same method as in Example 2 was used to obtain N-((1R ^* , 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-carboxamide (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).

¹ H-NMR (CDCl ₃ ) δ: 1.06 (9H, s), 1.55-1.61 (1H, m), 1.85-1.90 (1H, m), 2.18-2.25 (1H, m), 2.46 (3H, s) , 2.51(2H, d, J=7.6Hz), 2.68-2.76(1H, m), 3.56(1H, s), 3.57(1H, d, J=15.3Hz), 3.72(1H, d, J=15.3 Hz), 3.71-3.81(1H, m), 3.88-3.95(1H, m), 6.78(1H, s), 7.17(1H, dd, J=2.0, 8.8Hz), 7.37-7.44(7H, m) , 7.59(1H, s), 7.65-7.68(6H, m), 9.30(1H, s).

3) For the compound obtained by the above reaction, the title compound was prepared by the same method as in 3) of Example 28.

¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.30 (2H, m), 1.45-1.64 (2H, m), 1.86 (1H, d, J=9.0Hz), 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-hydroxyl-5-methylcyclohexyl)-5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (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-carboxamide (isomer A2)

In the same manner as in Example 2, the compound obtained in Reference Example 128 was reacted with the compound obtained in Reference Example 10 to obtain the title compound.

Isomer A1:

¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (3H, s), 1.33-1.82 (4H, m), 2.34 (3H, s), 2.67-3.64 (8H, m), 4.02-4.10 (2H, m), 4.67(1H, br.s), 7.02(1H, s), 7.13(1H, d, J=8.6Hz), 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 A2:

¹ H-NMR (DMSO-d ₆ ) 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-carboxamide

In the same manner as in Example 49, the compound obtained in Reference Example 129 was treated with ethanol hydrochloric acid, and then condensed with the compound obtained in Reference Example 10 to prepare the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.90 (5H, m), 2.07-2.26 (3H, m), 2.46 (3H, s), 2.67-2.95 (4H, m), 3.55-3.80 ( 4H, m), 3.80-3.95 (1H, m), 4.13-4.25 (1H, m), 6.84 (1H, br.s), 7.17 (1H, dd, J=8.8, 2.0Hz), 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-carboxamide

In the same manner as in Example 49, the compound obtained in Reference Example 135 was treated with ethanol hydrochloric acid, and then condensed with the compound obtained in Reference Example 10 to prepare the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.20-1.38 (1H, m), 1.50-1.67 (2H, m), 1.88-2.03 (2H, m), 2.03-2.14 (1H, m), 2.21-2.32 ( 1H, m), 2.53(3H, s), 2.75-2.95(2H, m), 3.20-3.35(2H, m), 3.37(3H, s), 3.73(1H, d, J=16.0Hz), 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 = 5.6 Hz), 9.49 (1H, br.s).

[Example 80] N-((1R ^* , 2S ^* , 5S ^* )-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-{[(methylsulfonyl)amino ]methyl}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

1) The compound obtained in Reference Example 137 (437 mg) was dissolved in ethanol (5 ml), and 4N hydrochloric acid dioxane solution (5 ml) was added at room temperature, followed by stirring for 13 hours. The solvent was evaporated, and the residue was dissolved in N,N-dimethylformamide (10ml), and triethylamine (0.7ml), the compound obtained in Reference Example 10 (300mg), and 1-hydroxybenzotriazole monohydrate were added (162 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg), stirred for 13 hours. The solvent was distilled off under reduced pressure, water was added and extracted with chloroform, the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (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 (330mg).

¹ H-NMR (DMSO-d ₆ ) 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 obtained by the above reaction (300 mg) was dissolved in ethanol (8 ml), a catalytic amount of 10% palladium on carbon was added, and the mixture was stirred at room temperature for 168 hours under hydrogen flow. The insoluble matter was filtered, the solvent was distilled off, and 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 added under ice-cooling Triethylamine (0.2ml) and methanesulfonyl chloride (0.035ml) were stirred for 13 hours. The solvent was distilled off under reduced pressure, water was added and extracted with chloroform, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=24:1) to obtain the title compound (56 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.18-1.34 (2H, m), 1.50-1.75 (4H, m), 1.90-2.30 (4H, m), 2.53 (3H, s), 2.78-2.90 (2H, m), 2.90-3.05(6H, m), 3.20-3.30(1H, m), 3.68-3.81(2H, m), 3.98-4.08(1H, m), 4.54-4.62(1H, m), 6.10- 6.19(1H, m), 6.86(1H, s), 7.19(1H, dd, J=8.8, 2.0Hz), 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 ]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide trifluoroacetate

The title compound was prepared from the amine obtained in 2) of Example 80 in the same manner as in Example 24.

¹ H-NMR (DMSO-d ₆ ) δ: 1.15-2.22 (7H, m), 2.40-2.65 (2H, m), 2.68-2.85 (6H, m), 2.92-3.08 (5H, m), 3.10- 3.18(2H, m), 4.08-4.20(1H, m), 4.35-4.51(2H, m), 7.04(1H, s), 7.14-7.20(1H, m), 7.41(1H, d, J=8.8 Hz), 7.67(1H, s), 8.25-8.42(2H, m), 9.11(1H, br.s), 9.89(1H, s).

MS (ESI) m/z: 529 (M+H) ⁺ .

[Example 82] (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexylcarbamate tert-butyl ester (isomer B) and (3R ^* , 4S ^* )-3-{[(5 -Chlorindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl ]Amino}cyclohexylcarbamate tert-butyl ester (isomer B)

The compound obtained in Reference Example 140 (Stereoisomer B) (1.79 g) was dissolved in tetrahydrofuran (36 ml), 10% palladium on carbon (0.40 g) was added, and stirred at room temperature for 20 hours under a stream of hydrogen. After filtering off the catalyst, concentrate the filtrate under reduced pressure, dissolve the residue in N, N-dimethylformamide (36ml), add 5-chloroindole-2-carboxylic acid p-nitrophenol ester (2.02g) and stir for 16 hours . Concentrate the reaction solution under reduced pressure, add ethyl acetate and water to filter the insoluble matter, wash with ethyl acetate to obtain crude (3R ^* , 4S ^* )-3-amino-4-{[(5-chloroindole- 2-yl)carbonyl]amino}cyclohexylcarbamate tert-butyl ester (or (3R ^* ,4S ^* )-4-amino-3-{[(5-chloroindol-2-yl)carbonyl]amino}cyclohexyl tert-butyl carbamate) (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-chloro Indol-2-yl)carbonyl]amino}cyclohexylcarbamate tert-butyl ester (or (3R ^* ,4S ^* )-3-amino-4-{[(5-chloroindol-2-yl)carbonyl]amino } tert-Butylcyclohexylcarbamate) (isomer B2) (0.37 g).

One of the title compounds was prepared from the above-mentioned isomer B1 and the compound obtained in Reference Example 10 by the same method as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.50 (1H, m), 1.37 (9H, s), 1.50-1.65 (1H, m), 1.75-2.20 (4H, m), 2.37 (3H, s), 2.70-3.00 (4H, m), 3.60-3.80 (3H, m), 4.13 (1H, br.s), 4.43 (1H, br.s), 6.92 (1H, d, J=7.1Hz) , 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=7.8 Hz), 8.37(1H, d, J=7.1Hz), 11.78(1H, s).

MS (FAB) m/z: 587 (M+H) ⁺ .

Furthermore, another titled compound was obtained from the above-mentioned isomer B2 in the same manner.

¹ H-NMR (DMSO-d ₆ ) δ: 1.15-1.30 (1H, m), 1.35 (9H, s), 1.45-1.60 (1H, m), 1.65-1.75 (1H, m), 1.85-1.95 ( 1H, m), 2.05-2.20 (2H, m), 2.34 (3H, s), 2.65-2.85 (4H, m), 3.55-3.70 (3H, m), 4.05-4.14 (1H, m), 4.40 ( 1H, br.s), 6.80 (1H, d, J = 7.3Hz), 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-chloroindole -2-yl)carbonyl]amino}cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide) hydrochloride (stereoiso Construct B)

The compound synthesized from isomer B1 in Example 82 (stereoisomer B) (1.11 g) was suspended in dichloromethane (20 ml), added with hydrochloric acid ethanol solution (20 ml) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel filtration (Sephadex LH-20, methanol) to obtain the title compound (1.05 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.65 (1H, m), 1.75-1.90 (2H, m), 1.95-2.20 (2H, m), 2.20-2.40 (1H, m), 2.90 ( 3H, s), 3.10-3.20 (1H, m), 3.20-3.50 (3H, m), 3.65-3.75 (1H, m), 4.10-4.20 (1H, m), 4.35-4.50 (1H, m), 4.55-4.65(1H, m), 4.65-4.75(1H, m), 7.07(1H, s), 7.17(1H, dd, J=8.8, 2.0Hz), 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]cyclohexyl} -5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide or N-[(1R ^* , 2S ^* )-2-{[(5- Chlorindol-2-yl)carbonyl]amino}-4-[(methylsulfonyl)amino]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c] pyridine-2-carboxamide (stereoisomer B)

The compound obtained in Example 83 (0.20 g) was suspended in dichloromethane (7 ml), triethylamine (0.16 ml) and methanesulfonyl chloride (28 µl) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with dichloromethane, washed with aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1→15:1) to obtain the title compound (67.9 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.55 (1H, m), 1.65-1.85 (2H, m), 1.90-2.05 (2H, m), 2.15-2.25 (1H, m), 2.41 ( 3H, s), 2.75-2.95 (4H, m), 2.92 (3H, s), 3.55-3.80 (3H, m), 4.10-4.20 (1H, m), 4.45-4.55 (1H, m), 7.08 ( 1H, s), 7.15-7.20 (2H, m), 7.41 (1H, d, J=8.8Hz), 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-chloroindol-2-yl)carbonyl]amino}cyclohexyl)-5-methyl Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide 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-carboxamide (Stereoisomer B)

The compound obtained in Example 83 (Stereoisomer B) (0.20 g) was suspended in dichloromethane (7 ml), and triethylamine (0.16 ml) and acetic anhydride (34 µl) were added at room temperature and stirred at room temperature for 20 hours. Dichloromethane and aqueous sodium hydroxide solution were added to the reaction solution, and the insoluble matter was collected by filtration. The organic layer of the separated filtrate 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=15:1→10:1) to obtain the title compound (0.12 g).

¹ H-NMR (DMSO-d ₆ ) 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 obtained in Example 58 (250mg) was dissolved in N,N-dimethylformamide (5ml), and N,O-dimethylhydroxylamine hydrochloride (142mg), 1-(3-dimethylamino Propyl)-3-ethylcarbodiimide hydrochloride (111 mg), 1-hydroxybenzotriazole monohydrate (89 mg), N-methylmorpholine (213 ml), and stirred at room temperature for 19 hours. After the reaction solution was concentrated, saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, 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=47:3→23:2) to obtain a colorless amorphous solid (179 mg). This solid was dissolved in methanol-tetrahydrofuran, and 1N hydrochloric acid ethanol solution (960 ml) was added to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.57-1.91 (4H, m), 1.96-2.00 (1H, m), 2.10-2.21 (1H, m), 2.92 (3H, s), 2.93-3.03 ( 2H, m), 3.08 (3H, s), 3.10-3.28 (2H, m), 4.16-4.19 (1H, m), 4.50-4.52 (1H, m), 4.69 (1H, br.s), 7.06 ( 1H, s), 7.17 (1H, dd, J=8.8, 1.5Hz), 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

In the same manner as in Example 57, the title compound was obtained from the compound obtained in Example 58 and N,N-dimethylhydrazine.

¹ H-NMR (DMSO-d ₆ ) δ: 1.49-1.54 (1H, m), 1.76-1.81 (2H, m), 1.89-1.93 (2H, m), 2.07-2.17 (1H, m), 2.33- 3.60(14H, m), 4.15-4.19(1H, m), 4.40-4.47(2H, m), 4.70-4.72(1H, m), 7.04(1H, s), 7.17(1H, dd, J=8.5 , 2.0Hz), 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

In the same manner as in Example 49, the compound obtained in Reference Example 145 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to prepare the title compound.

¹ H-NMR (DMSO-d ₆ ) 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=8.3 Hz), 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

Using the same method as in Reference Example 91, the compound obtained in Reference Example 144 and the compound obtained in Reference Example 274 were condensed, and then the compound obtained was treated with 4N hydrochloric acid dioxane solution, and then it was mixed with the compound obtained in Reference Example 10. Condensation affords the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.24-1.98 (6H, m), 2.33-3.33 (6H, m), 2.81 (3H, s), 2.90 (3H, s), 2.99 (3H, s) , 4.12(1H, br.s), 4.30-4.70(1H, m), 4.60(1H, br.s), 7.21(1H, s), 7.27(2H, br.s), 8.37(1H, d, J=8.1Hz), 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

In the same manner as in Example 49, the compound obtained in Reference Example 146 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.65 (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

In the N, N-dimethylformamide (20ml) solution of the compound (0.12g) obtained in Reference Example 172, add the compound (0.1g) obtained in Reference Example 10, 1-hydroxybenzotriazole monohydrate ( 78 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2 g), stirred at room temperature for 1 day. The reaction solution was concentrated, and the resulting residue was diluted with chloroform:methanol (9:1), washed with saturated aqueous sodium bicarbonate and saturated brine, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to obtain the free base of the title compound, which was treated with ethanol hydrochloric acid to obtain the title compound (0.1 g).

¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H, s), 2.70-2.90 (4H, m), 3.67 (1H, s), 3.70 (1H, s), 3.86 (1H, dd, J=9.2, 6.3Hz), 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

From the compound obtained in Reference Example 183, the title compound was obtained according to the methods in Reference Example 172 and Example 91.

¹ H-NMR (CDCl ₃ ) 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

From the compound obtained in Reference Example 187, the title compound was prepared according to the methods of Reference Example 172 and Example 91.

¹ H-NMR and MS (FAB): consistent with Example 92 as the enantiomer.

[Example 94] (3R, 4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester

From the compound obtained in Reference Example 193 and the compound obtained in Reference Example 10, the title compound was prepared according to the method in Example 91.

Melting point: 190～192℃

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.46 (3H, s), 2.74-2.81 (4H, m), 3.24-3.37 (2H, m), 3.54-3.70 (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 obtained in Example 94 (170 mg) was dissolved in dichloromethane (3 ml), and trifluoroacetic acid (2 ml) was added at room temperature and stirred for 1 hour. After concentration, chloroform and saturated aqueous sodium bicarbonate solution were added, the organic layer was 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:water=7:3:1, lower layer), and methanol hydrochloride was added to the target product to form a hydrochloride to obtain the title compound (90 mg) (NMR as free alkali determination).

Melting point: 248～250°C (decomposition)

¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 2.70-2.80 (4H, m), 2.97-3.05 (2H, m), 3.46-3.68 (4H, m), 4.49-4.52 (1H, m), 4.60-4.65(1H, m), 6.86(1H, s), 7.05-7.08(1H, m), 7.20(1H, d, J=8.5Hz), 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-oxotetrahydrofuran-3-yl)-5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as in Reference Example 69, the compound obtained in Reference Example 10 was reacted with the compound obtained in Reference Example 10 in the same manner as in Example 91 after removing the tert-butoxycarbonyl group of the compound obtained in Reference Example 196 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.90 (3H, s), 3.02-3.17 (2H, m), 3.23-3.34 (4H, m), 4.20 (1H, t, J=8.6Hz), 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-oxotetrahydrofuran-3-yl)-5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as in Reference Example 69, the compound obtained in Reference Example 197 was reacted with 5-chloroindole-2-carboxylic acid in the same manner as in Example 91 after removing the tert-butoxycarbonyl group to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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=5.4 Hz), 8.51-8.63(1H, m), 9.22(1H, s).

MS (FAB) m/z: 474 (M+H ⁺ ).

[Example 98] (3S, 4R)-2-(3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6, 7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-2-oxopyrrolidin-1-yl)ethyl acetate hydrochloride

From the compound obtained in Reference Example 199 and the compound obtained in Reference Example 10, the title compound was obtained in the same manner as in Example 91 (measured by NMR as a free base).

¹ H-NMR (DMSO-d ₆ ) 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

From the compound obtained in Reference Example 201 and the compound obtained in Reference Example 10, the title compound was obtained in the same manner as in Example 91.

¹ H-NMR (CDCl ₃ ) δ: 2.49 (3H, s), 2.77-2.82 (2H, m), 2.86-2.91 (5H, m), 3.69 (2H, d, J=1.2Hz), 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] 2-[((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6 , Methyl 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)sulfonyl]acetate

The compound obtained in Example 95 (230 mg) and triethylamine (0.10 ml) were dissolved in dichloromethane (6.9 ml), and cooled with ice. Then, methoxycarbonylmethanesulfonyl chloride (Synthesis, p. 321, 1975) (105 mg) was added, the temperature was returned to room temperature, and the mixture was stirred overnight. After diluting with chloroform, it 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).

¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s), 2.76-2.86 (4H, m), 3.49-3.73 (4H, m), 3.87 (3H, s), 3.94-3.98 (1H, m) , 4.08-4.11(1H, m), 4.13(2H, s), 4.69-4.72(1H, m), 4.88-4.91(1H, m), 6.89(1H, s), 7.12-7.15(1H, m) , 7.27-7.28(1H, m), 7.50(1H, s), 7.81-7.86(2H, m), 9.92(1H, s).

MS (FAB) m/z: 595 (M+H ⁺ ).

[Example 101] 2-[((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6 , 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)sulfonyl]acetic acid

The compound obtained in Example 100 (100 mg) was dissolved in tetrahydrofuran (4 ml)-water (1 ml), and cooled with ice. Then, lithium hydroxide monohydrate (7.8 ml) was added, and the temperature was returned to room temperature, followed by stirring for 4 hours. After neutralizing with 1N aqueous hydrochloric acid solution and concentrating, the precipitate was collected by filtration, washed with water and 50% ethanol, and dried under reduced pressure at 50°C overnight to obtain the title compound (87 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 2.50 (3H, s), 2.92 (4H, s), 3.34-3.43 (4H, m), 3.76-3.85 (2H, m), 4.27 (each 1H, AB type d, J=14.5Hz), 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] 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)methyl acetate

The compound obtained in Example 95 (230 mg) and potassium carbonate (90 mg) were dissolved in N,N-dimethylformamide (4.6 ml), and cooled with ice. Then, methyl bromoacetate (0.062 ml) was added and stirred for 45 minutes. The reaction solution was diluted with ethyl acetate, 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=10:1), and then pulverized with methanol-water to obtain the title compound (190 mg).

¹ H-NMR (CDCl ₃ ) δ: 2.35 (2H, s), 2.48 (3H, s), 2.73-2.95 (4H, m), 3.34-3.42 (2H, m), 3.46 (2H, q, J= 6.5Hz), 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

From the compound obtained in Example 102, the title compound was prepared in the same manner as in Example 101.

¹ H-NMR (DMSO-d ₆ ) δ: 2.42 (3H, s), 2.69-2.87 (6H, m), 3.13 (1H, t, J=9.0Hz), 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] 3-((3R, 4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6, 7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propionic acid methyl ester

From the compound obtained in Example 95 and methyl 3-bromopropionate, the title compound was obtained in the same manner as in Example 102.

¹ H-NMR (CDCl ₃ ) δ: 1.96-2.20 (2H, m), 2.49 (3H, s), 2.61-2.96 (8H, m), 3.17-3.21 (2H, m), 3.62-3.72 (2H, m), 3.69(3H, s), 4.46-4.49(1H, m), 4.56-4.61(1H, m), 6.87(1H, s), 7.05-7.14(1H, m), 7.32(1H, d, J=9.2Hz), 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)propionic acid

From the compound obtained in Example 104, the title compound was obtained in the same manner as in Example 101.

¹ H-NMR (DMSO-d ₆ ) δ: 2.38 (3H, s), 2.39-2.84 (10H, m), 2.93 (1H, t, J=8.8Hz), 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] 3-((3R,4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-methyl-4,5,6, 7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)-3-oxopropionic acid ethyl ester

The title compound was prepared in the same manner as in Example 100 from the compound obtained in Example 95 and ethyl malonyl chloride.

¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (3H, t, J=7.0Hz), 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-oxopropionic acid

From the compound obtained in Example 106, the title compound was prepared in the same manner as in Example 101.

¹ H-NMR (DMSO-d ₆ ) δ: 2.39 (3H, s), 2.77 (2H, s), 2.85 (2H, s), 3.29-3.55 (4H, m), 3.68 (2H, s), 3.82 -4.01(2H, m), 4.62-4.68(1H, m), 4.77-4.86(1H, m), 7.14(1H, s), 7.18(1H, d, J=8.8Hz), 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] 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 compound obtained in Example 95 and methyl 1-(bromomethyl)cyclopropanecarboxylate were carried out in the same manner as in Example 102 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 0.78-0.79 (2H, m), 1.24-1.26 (2H, m), 2.49 (3H, s), 2.62-2.88 (6H, m), 3.20-3.28 (2H, m), 3.66(3H, s), 3.61-3.75(4H, m), 4.45-4.62(2H, m), 6.86(1H, s), 7.12-7.15(1H, m), 7.24-7.28(1H, m), 7.52(1H, d, J=8.5Hz), 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

From the compound obtained in Example 108, the same operation as in Example 101 was performed to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 0.73-0.78 (2H, m), 1.04-1.07 (2H, m), 2.37 (3H, s), 2.65-2.84 (6H, m), 3.11-3.20 ( 4H, m), 3.64(2H, s), 4.59-4.74(2H, m), 7.16(1H, s), 7.17(1H, d, J=8.5Hz), 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-carboxylate tert-butyl

From the compound obtained in Reference Example 193 and the compound obtained in Reference Example 148, the title compound was obtained in the same manner as in Example 91.

¹ H-NMR (CDCl ₃ ) 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 compound obtained in Example 110 was carried out in the same manner as in Example 95 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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] 3-((3R, 4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5,6 , 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propionic acid ethyl ester

The compound obtained in Example 111 and ethyl 3-bromopropionate were carried out in the same manner as in Example 102 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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), 7.30-7.32(2H, m), 7.59(1H, s), 7.62(1H, s), 9.56(1H, s).

MS (FAB) m/z: 587 (M+H ⁺ ).

[Example 113] 3-((3R, 4R)-3-{[(5-chloroindol-2-yl)carbonyl]amino}-4-{[(5-isopropyl-4,5,6 , 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pyrrolidin-1-yl)propionic acid

The compound obtained in Example 112 was carried out in the same manner as in Example 101 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 111 and acetic anhydride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 254～258°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.34-1.37 (6H, m), 1.96 (3H, s), 3.30-3.55 (5H, m), 3.66-3.82 (3H, m), 3.95 (1H, q, J = 8.3Hz), 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 compound obtained in Example 111 and methanesulfonyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 230～235°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.32-1.36 (6H, m), 3.32 (3H, s), 3.43-3.46 (5H, m), 3.68-3.75 (4H, m), 4.48 (1H, m), 4.62-4.72 (2H, m), 4.83 (1H, t, J = 5.5Hz), 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-carboxylate ethyl ester hydrochloride

The compound obtained in Example 111 and ethyl chloroformate were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 225～228℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) 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 compound obtained in Reference Example 207 and the compound obtained in Reference Example 10 were carried out in the same manner as in Example 91 to obtain the title compound.

Melting point: 152～154°C (decomposition)

¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 1.62-1.80 (1H, m), 2.23-2.30 (1H, m), 2.52 (3H, s), 2.75-3.05 (5H, m) , 3.10-3.25(1H, m), 3.68-3.82(2H, m), 4.15-4.45(4H, m), 6.89(1H, s), 7.19(1H, dd, J=8.8, 1.8Hz), 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

From the compound obtained in Example 117, the title compound was prepared in the same manner as in Example 95.

Melting point: 240～258°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.85-2.00 (1H, m), 2.05-2.20 (2H, m), 2.93 (3H, s), 3.05-3.60 (7H, m), 3.65-3.75 ( 1H, m), 4.10-4.52 (2H, m), 4.60-4.75 (2H, m), 7.10-7.21 (2H, m), 7.43 (1H, d, J=8.6Hz), 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, tert-butyl 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylate

The compound obtained in Reference Example 208 and 5-chloroindole-2-carboxylic acid were carried out in the same manner as in Example 91 to obtain the title compound.

Melting point: 187～189℃ (decomposition)

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.72-1.90 (1H, m), 2.00 (1H, br.s), 2.00-2.10 (1H, m), 2.45 (3H, s) , 2.60-2.70 (2H, m), 2.70-2.80 (2H, m), 3.23 (1H, t, J=10.8Hz), 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 compound obtained in Example 119 was carried out in the same manner as in Example 95 to obtain the title compound.

Melting point: 276～278°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.77-1.88 (1H, m), 2.40-2.50 (2H, m), 2.89 (3H, s), 2.90-3.20 (4H, m), 3.30-3.50 ( 2H, m), 3.63 (1H, br.s), 4.33-4.47 (2H, m), 4.62-4.75 (2H, m), 7.18 (1H, dd, J=8.8, 1.9Hz), 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 compound obtained in Reference Example 209 and the compound obtained in Reference Example 10 were carried out in the same manner as in Example 91 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 1.65-1.78 (1H, m), 2.23-2.32 (1H, br), 2.52 (3H, s), 2.78-3.03 (5H, m) , 3.15-3.24 (1H, br), 3.68-3.82 (2H, br), 4.16-4.45 (4H, br), 6.91 (1H, s), 7.02 (1H, td, J=9.0, 2.7Hz), 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 compound obtained in Example 121 was carried out in the same manner as in Example 95 to obtain the title compound.

Melting point: 236～245℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.85-1.98 (1H, br), 2.06-2.18 (1H, br), 2.89 (3H, s), 3.05-3.75 (8H, s), 4.34-4.54 ( 2H, br), 4.60-4.75 (2H, br), 7.04 (1H, td, J=9.3, 2.4Hz), 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 compound obtained in Example 118 and acetic anhydride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 215～225°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.85 (1H, m), 1.88, 2.06 (all 3H, each s), 1.90-2.10 (1H, m), 2.91 (3H, s), 3.00 -3.30(2H, m), 3.30-3.55(2H, m), 3.60-3.90(3H, m), 3.98-4.50(4H, m), 4.65-4.75(1H, m), 7.09(1H, d, J=15.6Hz), 7.17(1H, d, J=8.8Hz), 7.41(1H, d, J=8.8Hz), 7.71(1H, s), 8.23-8.53(2H, m), 11.20-11.55( 1H, m), 11.85 (1H, br.d, J=5.4Hz).

MS (ESI) m/z: 515 (M+H ⁺ ).

[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 compound obtained in Example 120 and acetic anhydride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 225～250℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) 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, J=8.3Hz), 11.20-11.50 (1H, m), 11.89, 11.92 (all 1H, each s).

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 compound obtained in Example 122 and acetic anhydride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 202°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) 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 compound obtained in Example 118 and methanesulfonyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 225～230℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.80-1.90 (1H, m), 2.05-2.15 (1H, m), 2.30-2.80 (5H, m), 2.85-3.80 (9H, m), 4.20- 4.90 (4H, m), 7.08 (1H, d, J = 1.7Hz), 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

The compound obtained in Example 120 and methanesulfonyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 228～245°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.85 (1H, m), 2.25-2.40 (1H, m), 2.40-2.60 (2H, m), 2.76 (3H, br.s), 2.90 ( 3H, s), 2.93-3.05 (3H, m), 3.12 (1H, d, J=10.6Hz), 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 prepared in the same manner as in Example 100 from the compound obtained in Example 122 and methanesulfonyl chloride.

Melting point: 216～250℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.80-1.90 (1H, m), 2.01-2.12 (1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.00-3.80 (8H, m), 4.28-4.53 (3H, m), 4.60-4.80 (1H, br), 7.01-7.12 (2H, m), 7.37-7.44 (2H, m), 8.00-8.18 (1H, br), 8.39- 8.50(1H, br), 11.00-11.60(1H, br), 11.72-11.80(1H, br).

MS (FAB) m/z: 535 (M+H ⁺ ).

[Example 129] (3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl)carbonyl]amino}-3-{[(5-methyl-4,5,6,7 -tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylic acid methyl ester hydrochloride

The title compound was prepared in the same manner as in Example 100 from the compound obtained in Example 118 and methyl chloroformate.

Melting point: 248～253°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.78 (1H, m), 1.88-2.03 (1H, m), 2.90 (3H, s), 3.00-3.80 (9H, m), 3.80-3.90 ( 1H, m), 3.90-4.08 (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 compound obtained in Example 118 and ethyl chloroformate were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 215～225°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 0.85-1.30 (3H, m), 1.65-1.78 (1H, m), 1.90-2.03 (1H, m), 2.90 (3H, s), 3.10-3.40 ( 4H, m), 3.48(1H, br.s), 3.65(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 compound obtained in Example 118 and 2-methoxyethyl chloroformate were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 224～226°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.68-1.78 (1H, m), 1.90-2.03 (1H, m), 2.89 (3H, s), 3.00-3.75 (11H, m), 3.80-3.90 ( 1H, m), 3.95-4.18 (3H, m), 4.20-4.70 (4H, m), 7.10 (1H, s), 7.17 (1H, dd, J=8.8, 2.0Hz), 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-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylic acid ethyl ester hydrochloride

The compound obtained in Example 120 and ethyl chloroformate were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 213～225°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 0.75-1.30 (3H, m), 1.60-1.72 (1H, m), 2.12-2.25 (1H, m), 2.89 (3H, s), 2.95-3.20 ( 4H, m), 3.40-3.88 (4H, m), 3.90-4.10 (2H, m), 4.10-4.30 (2H, m), 4.30-4.40 (1H, m), 4.40-4.80 (1H, m), 7.10 (1H, s), 7.18 (1H, dd, J = 8.8, 2.0Hz), 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 compound obtained in Example 118 and propionyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 214～228°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 0.88-1.10 (3H, m), 1.70-2.05 (2H, m), 2.06-2.60 (2H, m), 2.91 (3H, s), 3.14 (2H, br.s), 3.20-3.90 (5H, m), 3.95-4.80 (5H, m), 7.09 (1H, d, J=11.0Hz), 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 compound obtained in Example 118 and isobutyryl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 266～272°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 0.80-1.15 (6H, m), 1.70-2.05 (2H, m), 2.65-2.80 (1H, m), 2.90 (3H, s), 2.90-4.80 ( 12H, m), 7.09 (1H, d, J = 11.0Hz), 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)piper Pyridin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and trimethylacetyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 250～255℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.20 (9H, s), 1.70-1.81 (1H, m), 1.90-2.00 (1H, m), 2.88 (3H, s), 3.10 (2H, br. s), 3.20-3.70(4H, m), 3.95-4.08(1H, m), 4.10-4.20(1H, m), 4.25-4.35(1H, m), 4.35-4.80(3H, m), 7.10( 1H, s), 7.16 (1H, dd, J=8.8, 1.9Hz), 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)piper Pyridin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and tert-butylacetyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 260～265℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 0.91, 1.04 (all 9H, each s), 1.68-1.82 (1H, m), 1.93-2.40 (3H, m), 2.91 (3H, s), 3.00 -3.20(2H, m), 3.20-4.80(10H, m), 7.08(1H, s), 7.17(1H, dd, J=8.7, 1.2Hz), 7.41(1H, d, J=8.7Hz), 7.69(1H, d, J=7.6Hz), 7.93-8.18(1H, m), 8.38-8.45(1H, m), 10.95-11.30(1H, m), 11.80-11.90(1H, m).

MS (ESI) m/z: 571 (M+H ⁺ ).

[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 compound obtained in Example 118 and trifluoroacetic anhydride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 262～267°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.82-1.98 (1H, m), 2.05-2.21 (1H, m), 2.89 (3H, s), 3.05-3.20 (2H, m), 3.40-3.75 ( 4H, m), 3.85-3.95 (1H, m), 4.00-4.07 (1H, m), 4.20-4.70 (4H, m), 7.10 (1H, s), 7.18 (1H, dd, J = 8.6, 1.9 Hz), 7.41(1H, d, J=8.6Hz), 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 ]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and cyclopropanecarbonyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 280～286°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 0.25-0.80 (4H, m), 1.65-2.15 (4H, m), 2.91 (3H, s), 2.90-3.20 (3H, m), 3.35-3.70 ( 2H, m), 4.00-4.80 (6H, m), 7.06 (1H, s), 7.18 (1H, d, J=8.8Hz), 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 compound obtained in Example 118 and cyclobutanecarbonyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 271～275°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-2.30 (8H, m), 2.89 (3H, s), 3.12 (2H, br.s), 3.20-3.75 (6H, m), 3.75-3.90 ( 1H, m), 4.05-4.80 (4H, m), 7.08 (1H, s), 7.15 (1H, dd, J=9.0, 2.0Hz), 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 compound obtained in Example 118 and cyclopentanecarbonyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 254～260°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.30-2.10 (10H, m), 2.90 (3H, s), 3.00-3.20 (2H, m), 3.20-3.75 (5H, m), 3.80-4.80 ( 6H, m), 7.09(1H, s), 7.17(1H, dd, J=8.7, 2.0Hz), 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 compound obtained in Example 118 and acetoxyacetyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.70-2.00 (1H, m), 2.05-2.48 (3H, m), 2.51 (3H, s), 2.70-3.05 (4H, m), 3.05-4.10 (5H, m), 4.20-4.48(1H, m), 4.50-5.10(4H, m), 6.87(1H, br.s), 7.10-7.82(4H, m), 7.32(1H, d, J=8.8Hz) , 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 obtained in Example 141 (301.8 mg) was dissolved in tetrahydrofuran (10 ml), 1N aqueous sodium hydroxide solution (0.53 ml) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, extracted with dichloromethane, and the organic layer was washed with water and saturated brine in sequence. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1-10:1), and the solvent was evaporated under reduced pressure. The purified product was dissolved in ethanol (3 ml) and dichloromethane (2 ml), and 1N hydrochloric acid ethanol solution (0.40 ml) was added thereto and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was solidified with ether to obtain the title compound (195 mg).

Melting point: 216～230℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.80 (1H, m), 1.88-2.10 (2H, m), 2.68 (3H, s), 3.18 (2H, s), 3.08-3.70 (5H, m), 3.80-3.95(1H, m), 4.00-4.25(3H, m), 4.25-4.50(2H, m), 4.50-4.65(1H, m), 7.09(1H, d, J=11.0Hz) , 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)piperidine- 3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 was carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 214～228°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s), 3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82(7H, m), 3.88-4.80(5H, m), 7.09(1H, d, J=9.0Hz), 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)piperidine- 3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 122 and methoxyacetyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 190～208℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.83 (1H, br), 1.85-2.10 (1H, m), 2.91 (3H, s), 3.00-3.55 (10H, m), 3.62-3.85 ( 1H, m), 3.90-4.50 (6H, m), 4.63-4.78 (1H, br), 7.04 (1H, td, J=9.4, 2.4Hz), 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-carboxamide

To a solution of the compound obtained in Reference Example 158 (261 mg) in chloroform (10 ml) were added thionyl chloride (3.0 ml) and a catalytic amount of dimethylformamide, followed by stirring at 60°C overnight. The reaction solution was concentrated under reduced pressure, and the title compound (241 mg) was obtained in the same manner as in Example 100 from the obtained yellow oil and the compound obtained in Example 118 (200 mg).

Melting point: 153°C

¹ H-NMR (CDCl ₃ ) 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-hydroxyl-2,2-dimethyl Propionyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

Under ice-cooling, tetrabutylammonium fluoride (1 molar solution in tetrahydrofuran, 0.594 ml) was added to a solution of the compound obtained in Example 145 (241 mg) in tetrahydrofuran (30 ml), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in dichloromethane, 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 (dichloromethane:methanol=9:1) to obtain the title compound (116 mg).

Melting point: 220°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) 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-di Methylpropionyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

From the compound obtained in Example 118 and the compound obtained in Reference Example 160, the title compound was obtained in the same manner as in Example 145.

Melting point: 240°C (decomposition)

¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, s), 1.37 (3H, s), 1.65-1.77 (1H, m), 2.33-2.37 (1H, m), 2.53 (3H, s), 2.82 -3.29(6H, m), 3.34(3H, s), 3.41(1H, d, J=9.3Hz), 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 compound obtained in Example 118 and 2-acetoxyisobutyryl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 190°C (decomposition)

¹ H-NMR (CDCl ₃ ) δ: 1.56-1.67 (8H, m), 2.08 (3H, s), 2.35 (1H, d, J=10.5Hz), 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]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

Sodium methoxide (76.8 mg) was added to a methanol (50 ml) solution of the compound (190 mg) obtained in Example 148, followed by stirring overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=9:1) to obtain the title compound (130 mg).

Melting point: 190°C (decomposition)

¹ H-NMR (CDCl ₃ ) δ: 1.53 (3H, s), 1.56-1.78 (5H, m), 2.34 (1H, d, J=10.5Hz), 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]piper Pyridin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

Add the compound (306mg ), N-methylmorpholine (200μl), 1-hydroxybenzotriazole monohydrate (87mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 mg), stirred at room temperature for 3 days. The reaction solution was diluted with dichloromethane, and then saturated aqueous sodium bicarbonate solution was added to divide into two layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain the free base of the title compound (207 mg). Treatment of the free base with 1N ethanolic hydrochloric acid gave the title compound.

Melting point: 200°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.78-2.10 (4H, m), 2.24-2.68 (3H, m), 2.75-5.20 (14H, m), 2.91 (3H, s), 7.08 (0.5H , s), 7.09 (0.5H, s), 7.18 (1H, dd, J=8.8, 2.0Hz), 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]piper Pyridin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and the compound obtained in Reference Example 154 were carried out in the same manner as in Example 150 to obtain the title compound.

Melting point: 191°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.69-2.23 (4H, m), 2.25-2.40 (1H, m), 2.71-2.84 (0.5H, m), 2.89-3.93 (9.5H, m), 2.91(3H, s), 3.01(1H, s), 3.14(2H, s), 4.05-4.80(5H, m), 7.09(1H, s), 7.18(1H, d, J=8.4Hz), 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-(methyl Oxymethyl)propionyl]piperidin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 155 was hydrolyzed, and the resulting carboxylic acid was condensed with the compound obtained in Example 118 in the same manner as in Example 150 to obtain the title compound.

Melting point: 178～184°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) 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.s), 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-yl Carbonyl)piperidin-3-yl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and the compound obtained in Reference Example 156 were carried out in the same manner as in Example 150 to obtain the title compound.

Melting point: 225～248°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.68 (4H, m), 1.70-1.85 (1H, m), 1.85-2.05 (1H, m), 2.60-2.95 (1H, m), 2.89 ( 3H, s), 2.95-3.20 (3H, m), 3.20-4.00 (9H, m), 4.00-4.80 (4H, m), 7.08 (1H, s), 7.17 (1H, dd, J = 8.8, 2.0 Hz), 7.42(1H, d, J=8.8Hz), 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 compound obtained in Example 118 and benzoyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 215～225°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.90 (1H, m), 1.90-2.20 (1H, m), 2.93 (3H, s), 3.10-4.00 (8H, m), 4.05-4.80 ( 4H, m), 7.00-7.60 (5H, m), 7.08 (1H, s), 7.16 (1H, dd, J=8.8, 1.6Hz), 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-carboxylate tert-butyl ester

The compound obtained in Reference Example 207 and the compound obtained in Reference Example 42 were carried out in the same manner as in Example 91 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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]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- Formamide 2 hydrochloride

The compound obtained in Example 155 was treated in the same manner as in Example 95 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.04 (9H, s), 1.43, 1.48 (all 6H, each s), 1.85-2.00 (1H, m), 2.05-2.20 (1H, m), 2.95 -3.20(2H, m), 3.25-3.60(6H, m), 3.80-3.90(1H, m), 3.95-4.05(1H, m), 4.45-4.55(1H, m), 4.60-4.85(3H, m), 7.10-7.20 (2H, m), 7.35-7.55 (7H, m), 7.55-7.75 (5H, m), 8.52 (1H, dd, J=14.4, 7.8Hz), 8.93 (1H, br) , 9.20-9.40 (2H, m), 11.30-11.50 (1H, m), 11.87, 11.92 (all 1H, each s).

MS (ESI) m/z: 769 (M+H ⁺ ).

[Example 157] 5-(2-{[tert-butyl(diphenyl)silyl]oxy}-1,1-dimethylethyl)-N-[(3R ^* , 4S ^* )- 4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidin-3-yl]-4,5,6,7-tetrahydrothiazole And[5,4-c]pyridine-2-carboxamide

The compound obtained in Example 156 and methoxyacetyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.20 (6H, s), 1.60-1.85 (1H, m), 2.25-2.40 (1H, m), 2.36 (2H, s), 2.70 -3.20(4H,m), 3.20-3.55(4H,m), 3.55-3.70(2H,m), 3.95-4.10(3H,m), 4.10-4.90(4H,m), 6.90(1H,d, J=1.5Hz), 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)piperidine- 3-yl]-5-(2-hydroxy-1,1-dimethylethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride Salt

The compound obtained in Example 157 was carried out in the same manner as in Example 146 to obtain the title compound.

Melting point: 221-232°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.32 (3H, s), 1.40 (3H, s), 1.70-1.85 (1H, m), 1.85-2.10 (1H, m), 2.60-3.35 (8H, m), 3.40-3.82(3H, m), 3.85-4.05(3H, m), 4.05-4.35(2H, m), 4.50-4.60(1H, m), 4.55-4.80(2H, m), 5.75- 5.85(1H, m), 7.08(1H, br.s), 7.17(1H, d, J=8.8Hz), 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, tert-butyl 7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidine-1-carboxylate

The compound obtained in Reference Example 209 and the compound obtained in Reference Example 148 were carried out in the same manner as in Example 91 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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 compound obtained in Example 159 was treated in the same manner as in Example 95 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.28-1.40 (6H, m), 1.85-2.00 (1H, m), 2.05-2.20 (1H, m), 2.40-2.60 (1H, m), 2.95- 3.90(8H,m), 4.40-4.55(2H,m), 4.60-4.75(2H,m), 7.00-7.20(2H,m), 7.30-7.50(2H,m), 8.45-8.60(1H,m ), 8.85-9.05(1H, m), 9.05-9.50(2H, m), 11.60-11.90(2H, m).

MS (ESI) m/z: 485 (M+H) ⁺ .

[Example 161] N-[(3R ^* , 4S ^* )-4-{[(5-fluoroindol-2-yl)carbonyl]amino}-1-(2-methoxyacetyl)piperidine- 3-yl]-5-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 160 and methoxyacetyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 214～228°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.40 (6H, m), 1.68-1.82 (1H, m), 1.85-2.10 (1H, m), 2.90-3.60 (8H, m), 3.60- 3.85(2H,m), 3.85-4.40(5H,m), 4.40-4.55(2H,m), 4.60-4.75(1H,m), 7.00-7.15(2H,m), 7.35-7.50(2H,m ), 8.15-8.50 (2H, m), 10.80-11.30 (1H, m), 11.73 (1H, d, J=6.6Hz).

MS (ESI) m/z: 557 (M+H) ⁺ .

[Example 162] N-{(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-[(dimethylamino)carbonyl]piperidine- 3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and N,N-dimethylcarbamoyl chloride were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 267～270℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.78 (1H, m), 1.97-2.10 (1H, m), 2.70 (6H, s), 2.90 (3H, s), 2.95-3.80 (8H, m), 4.25-4.80 (4H, m), 7.08 (1H, s), 7.16 (1H, dd, J = 8.8, 1.8Hz), 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}-14(dimethylamino)carbonyl]piperidine-3- Base)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and ethyl isocyanate were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 221～235°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) 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}piperidine- 3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Example 118 and tert-butyl isocyanate were carried out in the same manner as in Example 100 to obtain the title compound.

Melting point: 236～238°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.21 (9H, s), 1.60-1.70 (1H, m), 1.80-1.90 (1H, m), 2.87 (3H, s), 3.00-3.40 (6H, m), 3.49(1H, br.s), 3.80-3.90(1H, m), 3.90-4.00(1H, m), 4.20-4.35(2H, m), 4.47(1H, br.s), 5.90( 1H, s), 7.06 (1H, s), 7.16 (1H, dd, J=8.8, 1.9Hz), 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)ethyl acetate 2 hydrochloride

The mixture obtained in Example 118 and methyl bromoacetate were carried out in the same manner as in Example 102 to obtain the title compound.

Melting point: 253～255°C (decomposition)

¹ H-NMR (DMSO-d ₆ , 8) 0δ: 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)acetic acid hydrochloride

The compound obtained in Example 165 was treated in the same manner as in Example 101 to obtain the title compound.

Melting point: 234～240℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.95 (1H, m), 2.05-2.20 (1H, m), 2.88 (3H, s), 2.95-3.90 (10H, m), 4.20-4.70 ( 4H, m), 7.11 (1H, s), 7.16 (1H, dd, J=8.8, 2.0Hz), 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)piperidine- 3-yl]-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 was obtained in the same manner as in Example 102 (NMR was determined as a free base).

Melting point: 238～242°C (decomposition)

¹ H-NMR (CDCl ₃ ) δ: 1.75-1.83 (2H, m), 2.27-2.39 (2H, m), 2.52 (3H, s), 2.60-2.66 (1H, m), 2.69-2.75 (1H, m), 2.81-2.90 (2H, m), 2.96-3.07 (2H, m), 3.41 (3H, s), 3.53-3.60 (2H, m), 3.75 (each 1H, AB type d, J=15.5 Hz), 4.02-4.05(1H, m), 4.40(1H, br), 6.88(1H, d, J=1.5Hz), 7.18-7.21(1H, m), 7.31-7.33(1H, m), 7.63 (1H, d, J=1.5Hz), 8.17 (1H, d, J=5.0Hz), 8.26 (1H, d, J=7.0Hz), 9.30 (1H, br.s).

MS (FAB) m/z: 531 (M+H) ⁺ .

[Example 168] N-[(3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-(2-fluoroethyl)piperidine-3- Base]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide 2 hydrochloride

The compound obtained in Example 118 and 2-fluoroethyl bromide were treated in the same manner as in Example 102 to obtain the title compound (measured by NMR as free base).

Melting point: 228～233°C (decomposition)

₁ H-NMR (CDCl ₃ ) 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 Hz), 7.19-7.22(1H, m), 7.32(1H, d, J=8.5Hz), 7.64(1H, d, J=2.0Hz), 8.11(1H, d, J=5.5Hz), 8.20( 1H, d, J=7.3Hz), 9.30(1H, br).

MS (FAB) m/z: 519 (M+H) ⁺ .

[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 (15 ml) of the compound (630 mg) obtained in Reference Example 214 was added 4N hydrochloric acid dioxane solution (7.0 ml), followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the free base of the title compound (330 mg) was obtained in the same manner as in Example 91 using the obtained yellow solid (590 mg) and the compound obtained in Reference Example 10 (379 mg). The free base was treated with ethanolic hydrochloric acid to obtain the title compound (NMR as free base).

Melting point: 202～222°C (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.85 (1H, m), 1.87, 2.06 (all 3H, each s), 1.88-2.10 (1H, m), 2.37 (3H, s), 2.65 -2.77(2H, m), 2.79-2.89(2H, m), 2.99-3.09(0.5H, m), 3.30-3.52(2H, m), 3.64(2H, s), 3.70-3.80(0.5H, m), 3.96-4.21 (2H, m), 4.27 (1H, br.s), 4.35-4.48 (1H, m), 7.07, 7.11 (all 1H, each s), 7.18 (1H, d, J = 8.8Hz), 7.42 (1H, d, J = 8.8Hz), 7.71 (1H, s), 8.16-8.22 (1H, m), 8.37, 8.46 (all 1H, each d, J = 7.8Hz), 11.81 , 11.83 (all 1H, each s).

MS (ESI) m/z: 515 (M+H) ⁺ .

[α] _D ²⁵ = -56.0° (c = 0.50, methanol)

[Example 170] N-((3R,4R)-1-acetyl-4-{[(5-chloroindol-2-yl)carbonyl]amino}piperidin-3-yl)-5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 219 and the compound obtained in Reference Example 10 in the same manner as in Example 169.

Melting point: 221～238℃

¹ H-NMR (DMSO-d ₆ ) 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=8.8 Hz), 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)piperidine-3- Base]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 221 in the same manner as in Example 169.

Melting point: 207～220℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.80 (1H, m), 1.85-2.05 (1H, m), 2.90 (3H, s), 3.00-3.20 (2H, m), 3.16 (3H, s), 3.22-3.82(7H, m), 3.88-4.80(5H, m), 7.09(1H, d, J=9.0Hz), 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)piperidine-3- Base]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 223 in the same manner as in Example 169.

Melting point: 213～230℃

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.56 (0.5H, m), 1.61-1.70 (0.5H, m), 1.89-2.00 (1H, m), 2.05 (3H, s), 2.45- 2.67(1H, m), 2.88(3H, s), 3.00-3.21(4H, m), 3.32-3.56(7H, m), 3.78-3.89(2H, m), 4.00-4.24(2H, m), 4.26-4.43 (2H, m), 7.02 (1H, s), 7.13 (1H, dd, J = 8.8, 2.0Hz), 7.37 (1H, d, J = 8.8Hz), 7.67 (1H, d, J = 2.0Hz), 8.41(1H, d, J=9.8Hz), 8.74(1H, d, J=9.8Hz), 10.80-10.90(1H, m), 11.72(1H, s).

MS (FAB) m/z: 545 (M+H) ⁺ .

[α] _D ²⁵ = -100.3° (c = 0.51, methanol)

[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 low polar compound obtained in Reference Example 176 and the compound obtained in Reference Example 10 were treated in the same manner as in Example 169 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.41-2.56 (2H, m), 2.91 (3H, s), 3.01-3.23 (1H, m), 3.24-3.56 (5H, m), 3.62-3.67 ( 1H, m), 4.21-4.44 (1H, m), 4.56-4.78 (2H, m), 7.11 (1H, s), 7.16 (1H, dd, J=8.8, 2.0Hz), 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 highly polar compound obtained in Reference Example 176 and the compound obtained in Reference Example 10 were treated in the same manner as in Example 169 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 2.41-2.56 (2H, m), 2.91 (3H, s), 3.23-3.41 (2H, m), 3.43-3.50 (2H, m), 3.56-3.67 ( 2H, m), 4.37 (1H, dd, J=13.9, 7.1Hz), 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 compound obtained in Reference Example 225 was treated in the same manner as in Example 169 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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-hydroxyl-4-{[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}pentanoic acid ethyl ester

Under ice-cooling, hydrogen fluoride pyridine (0.4 ml) was added dropwise to a mixed solution of the compound obtained in Reference Example 175 (0.54 g), pyridine (4.0 ml) and tetrahydrofuran (10 ml), and the reaction solution was slowly raised to room temperature. While stirring for 18 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the title compound (0.31 g).

¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J=7.4Hz), 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

4N hydrochloric acid dioxane solution (20 ml) was added to the compound obtained in Example 176 (0.31 g), and the mixture was heated under reflux 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: 221～238°C (decomposition)

¹ H-NMR and MS: consistent 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 compound obtained in Reference Example 227 and 5-chloroindole-2-carboxylic acid were treated in the same manner as in Example 91 to obtain the free base of the title compound. Treatment of the free base with ethanolic hydrochloric acid afforded the title compound.

Melting point: 241～244℃

¹ H-NMR (DMSO-d ₆ ) δ: 2.14 (1H, br), 2.30-2.34 (1H, m), 2.92 (3H, s), 3.10-3.18 (2H, m), 3.41 (4H, br) , 3.68(2H, br), 4.44(1H, br), 4.63-4.78(3H, m), 7.16-7.18(1H, m), 7.21(1H, s), 7.43(1H, d, J=8.5Hz ), 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 compound obtained in Reference Example 227 and 5-fluoroindole-2-carboxylic acid were treated in the same manner as in Example 91 to obtain the free base of the title compound. Treatment of the free base with ethanolic hydrochloric acid afforded the title compound.

Melting point: 243～245℃

¹ H-NMR (DMSO-d ₆ ) δ: 2.14 (1H, br), 2.30-2.33 (1H, m), 2.92 (3H, s), 3.1 ³ (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 compound obtained in Reference Example 229 and the compound obtained in Reference Example 10 were treated in the same manner as in Example 91 to obtain the free base of the title compound. Treatment of the free base with ethanolic hydrochloric acid afforded the title compound.

Melting point: 242～247℃

¹ H-NMR (DMSO-d ₆ ) δ: 2.16 (1H, br), 2.45 (1H, br), 2.93 (3H, s), 3.13 (2H, br), 3.26 (4H, br), 3.69 (2H , br), 4.45(1H, br), 4.65-4.77(3H, m), 7.01(1H, s), 7.17(1H, dd, J=8.7, 1.4Hz), 7.43(1H, d, J=8.5 Hz), 7.69(1H, s), 8.35-8.40(1H, m), 9.04(1H, br), 11.86(1H, s).

MS (ESI) m/z: 522 (M+H ⁺ ).

[Example 181] N-((3R ^* , 4S ^* )-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1,1-dioxohexahydro-1-thiopyran -3-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The compound obtained in Reference Example 231 and 5-chloroindole-2-carboxylic acid were treated in the same manner as in Example 91 to obtain the free base of the title compound. Treatment of the free base with ethanolic hydrochloric acid afforded the title compound.

Melting point: 244～249℃

¹ H-NMR (DMSO-d ₆ ) δ: 2.17-2.27 (2H, m), 2.90 (3H, s), 3.09 (1H, br), 3.18-3.21 (2H, m), 3.31-3.34 (2H, m), 3.60-3.67(3H, m), 4.41-4.49(2H, m), 4.54-4.59(2H, m), 7.04(1H, s), 7.09-7.13(1H, m), 7.39(1H, d, J=8.5Hz), 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 compound obtained in Reference Example 231 and 5-fluoroindole-2-carboxylic acid were treated in the same manner as in Example 91 to obtain the free base of the title compound. Treatment of the free base with ethanolic hydrochloric acid afforded the title compound.

Melting point: 236～241℃

¹ H-NMR (DMSO-d ₆ ) δ: 2.20-2.24 (2H, m), 2.89 (3H, s), 3.07 (1H, br), 3.19-3.22 (2H, m), 3.60-3.66 (4H, m), 4.43-4.58 (5H, m), 6.95-7.00 (1H, m), 7.04 (1H, s), 7.32-7.38 (2H, m), 8.50 (1H, d, J=8.5Hz), 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 compound obtained in Reference Example 233 and the compound obtained in Reference Example 10 were treated in the same manner as in Example 91 to obtain the free base of the title compound. Treatment of the free base with ethanolic hydrochloric acid afforded the title compound.

Melting point: 244～249℃

¹ H-NMR (DMSO-d ₆ ) δ: 2.12-2.18 (1H, m), 2.50 (1H, br), 2.92 (3H, s), ^3.1 7 (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 184] N-((3S,4R)-4-{[(5-chloroindol-2-yl)carbonyl]amino}-1-methyl-6-oxopiperidin-3-yl) -5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (low 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-tetrahydrothiazole A[5,4-c]pyridine-2-carboxamide (highly polar compound)

The compound obtained in Reference Example 236 and the compound obtained in Reference Example 10 were treated in the same manner as in Example 169 to obtain the title compound.

Low polar compounds:

Melting point: 189～203°C (decomposition)

¹ H-NMR (CDCl ₃ ) 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: 183～195℃ (decomposition)

¹ H-NMR (DMSO-d ₆ ) δ: 2.33 (3H, s), 2.41-2.50 (1H, m), 2.62-2.73 (3H, m), 2.75-2.81 (1H, m), 2.82 (3H, s), 3.21-3.32(2H, m), 3.34-3.50(2H, m), 3.55(1H, d, J=15.4Hz), 3.63(1H, d, J=15.4Hz), 4.30-4.40(0.5 H, m), 4.50-4.60 (0.5H, m), 7.04 (1H, s), 7.15 (1H, dd, J=8.8, 2.0Hz), 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 salt salt

The title compound was prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 237 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.52 (2H, m), 1.60-1.80 (4H, m), 1.96-2.10 (2H, m), 4.24-4.39 (2H, m), 7.15 ( 1H, dd, J=8.8, 2.0Hz), 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-oxide

The title compound was prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 240 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.52 (2H, m), 1.60-1.80 (4H, m), 1.88-2.00 (2H, m), 4.21-4.36 (2H, m), 7.12- 7.18(2H, m), 7.41(1H, d, J=8.6Hz), 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 salt salt

In the same manner as in Example 2, the title compound was obtained from the compound obtained in Reference Example 71 and 4-(2-pyridyl)benzoic acid (Japanese Patent Laid-Open No. 2000-119253).

¹ H-NMR (DMSO-d ₆ ) δ: 1.39-1.51 (2H, m), 1.60-1.80 (4H, m), 1.89-2.00 (2H, m), 4.24-4.38 (2H, m), 7.12- 7.16(2H, m), 7.36-7.39(1H, m), 7.42(1H, d, J=8.8Hz), 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-oxide

The title compound was prepared from the compound obtained in Reference Example 71 and the compound obtained in Reference Example 241 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.39-1.51 (2H, m), 1.60-1.79 (4H, m), 1.89-2.00 (2H, m), 4.23-4.37 (2H, m), 7.12- 7.17(2H, m), 7.39-7.43(3H, m), 7.61-7.64(1H, m), 7.67(1H, d, J=2.0Hz), 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]ind Indole-2-carboxamide hydrochloride

In the same manner as in Example 2, the title compound was prepared from the compound obtained in Reference Example 69 and lithium salt of 5-(4-pyridyl)thiazole-2-carboxylate (Japanese Patent Laid-Open No. 2000-143623).

¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (2H, br.s), 1.65 (4H, br.s), 1.85-2.06 (2H, m), 4.23 (1H, br.s), 4.30 ( 1H, br.s), 7.14-7.23 (2H, m), 7.41 (1H, d, J=8.8Hz), 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) (206 mg) was suspended in dichloromethane (50 ml), and thionyl chloride ( 144 μl) was stirred for 30 minutes. After adding triethylamine (969 µl) to the reaction solution, the compound (328 mg) obtained in Reference Example 71 was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the solution was concentrated under reduced pressure, and the precipitated precipitate was collected by filtration to obtain the title compound (310 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.30-2.00 (10H, m), 2.74 (1H, br.s), 3.18 (2H, q, J=12.3Hz), 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] N ¹ -(4-chlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound (288 mg) obtained in Reference Example 242 was dissolved in tetrahydrofuran (8.0 ml), lithium hydroxide (46 mg) and water (1.0 ml) were added successively, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (292 mg) of lithium salt of 2-(4-chloroanilino)-2-oxoacetate as a colorless solid. The crude product and the compound obtained in Reference Example 253 were dissolved in N,N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate (164 mg) and 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (251 mg), stirred at room temperature for 64.5 hours. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and dichloromethane were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=47:3). The obtained pale yellow solid was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (0.52 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (245 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 1.95-2.10 (2H, m), 2.79 (3H, s), 2.80-3.00 ( 1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.40-4.80 ( 3H, m), 7.40 (2H, d, J = 8.8Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound obtained in Reference Example 243 (240 mg) was dissolved in tetrahydrofuran (8.0 ml), lithium hydroxide (41 mg) and water (1.0 ml) were added successively, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain lithium salt of 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (249 mg).

On the other hand, 10% palladium carbon (200 mg) was added to a methanol (10 ml) solution of the compound (293 mg) obtained in Reference Example 252, and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. After the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure to obtain N-{(1R, 2S, 5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5 , a crude product of 6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (259 mg).

The crude product (259 mg) and the above lithium salt (249 mg) were added to N,N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate (166 mg) and 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (235 mg), stirred at room temperature for 63.5 hours. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and dichloromethane were added to the residue to separate the layers, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=93:7). The obtained light yellow solid was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (0.855 ml) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (209 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.57 (1H, m), 1.60-1.80 (3H, m), 1.95-2.13 (2H, m), 2.79 (3H, s), 2.80-3.00 ( 1H, m), 2.92 (3H, s), 2.94 (3H, s), 3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.37-4.80 ( 3H, m), 7.90-8.10(2H, m), 8.45(1H, d, J=2.2Hz), 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] N ¹ -(3-chlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound obtained in Reference Example 270 (222 mg) and 3-chloroaniline (63 μl) were dissolved in N,N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (68 mg) and 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (144 mg), stirred at room temperature for 40 hours. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and dichloromethane were added to the residue to separate the layers, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). The obtained pale yellow solid was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (0.50 ml) was added, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (174 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.62 (1H, m), 1.65-1.90 (3H, m), 1.98-2.20 (2H, m), 2.79 (3H, s), 2.88-3.10 ( 1H, m), 2.93 (3H, s), 2.94 (3H, s), 3.15-3.40 (2H, m), 3.40-3.90 (2H, m), 3.95-4.10 (1H, m), 4.40-4.80 ( 3H, m), 7.19 (1H, dd, J=9.3, 2.0Hz), 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] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(4-fluorophenyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 254 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-2.13 (6H, m), 2.77 (3H, s), 2.93 (3H, s), 2.97 (3H, s), 3.12-3.82 (7H, m) , 3.93-4.04(1H, m), 4.38-4.46(1H, m), 4.35-4.75(1H, m), 7.11-7.21(2H, m), 7.72-7.84(2H, m), 8.73(1H, d, J=7.6Hz), 8.93-9.02(1H, m), 10.70(1H, s).

MS (FAB) m/z: 531 (M+H) ⁺ .

[Example 195] N ¹ -(4-bromophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound obtained in Reference Example 255 (152 mg) was dissolved in tetrahydrofuran (5.0 ml), 1N aqueous sodium hydroxide solution (1.20 ml) and methanol (5.0 ml) were added successively, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (10 ml) and 1N hydrochloric acid (2.0 ml) were added to the residue for liquid separation. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain a crude product of 2-(4-bromoanilino)-2-oxoacetic acid as a colorless solid. The crude product and the compound (280 mg) obtained in Reference Example 253 were dissolved in N,N-dimethylformamide (30 ml), and 1-hydroxybenzotriazole monohydrate (90 mg) and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (226 mg), stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and dichloromethane were added to the residue to separate the layers, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=97:3). The obtained pale yellow solid was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (191 µl) was added, and the solvent was distilled off under reduced pressure. Methanol and diethyl ether were added to the residue, and the resulting precipitate was collected by filtration to obtain the title compound (103 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.57 (1H, m), 1.59-1.80 (3H, m), 1.97-2.10 (2H, m), 2.79 (3H, s), 2.84-2.98 ( 7H, m), 3.18 (2H, br.s), 3.39-3.72 (2H, m), 3.95-4.05 (1H, m), 4.20-4.80 (3H, m), 7.53 (2H, d, J=8.8 Hz), 7.77(2H, d, J=8.8Hz), 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] N ¹ -(4-chloro-2-methylphenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 256 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 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] N ¹ -(4-chloro-3-methylphenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 257 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.53 (1H, m), 1.68-1.80 (3H, m), 1.98-2.09 (2H, m), 2.29 (3H, s), 2.79 (3H, s), 2.80-3.00(1H, m), 2.95(6H, s), 3.17-3.19(3H, m), 3.40-3.80(1H, m), 3.93-4.02(1H, m), 4.44-4.56( 3H, m), 7.38 (1H, d, J = 8.8Hz), 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] N ¹ -(4-chloro-2-fluorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 258 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.55 (1H, m), 1.58-1.80 (3H, m), 1.95-2.12 (2H, m), 2.77 (3H, s), 2.80-3.00 ( 1H, m), 2.91 (3H, s), 2.92 (3H, s), 3.10-3.40 (2H, m), 3.40-3.80 (2H, m), 3.95-4.05 (1H, m), 4.30-4.80 ( 3H, m), 7.29 (1H, d, J = 8.5Hz), 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] N ¹ -(2,4-dichlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound (300 mg) obtained in Reference Example 270 was dissolved in N,N-dimethylformamide (5 ml), and 2,4-dichloroaniline (165 mg), 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (260 mg) and 1-hydroxybenzotriazole monohydrate (91 mg) were stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure, and saturated aqueous sodium bicarbonate solution and dichloromethane were added to the residue to separate the layers. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane methane:methanol=47:3) to obtain the free base of the title compound. This was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (108 µl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, diethyl ether was added dropwise while irradiating with ultrasonic waves, and the resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (60 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.77 (4H, m), 2.03-2.12 (2H, m), 2.79 (3H, s), 2.92-2.96 (7H, m), 3.25 (2H, br.s), 3.49(1H, br.s), 3.69(1H, br.s), 3.98-4.04(1H, m), 4.40-4.43(1H, m), 4.45(1H, br.s), 4.69 (1H, br.s), 7.48 (1H, dd, J=8.5, 2.4Hz), 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] N ¹ -(3,4-dichlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

Dissolve 3,4-dichloroaniline (1.62g) in dichloromethane (20ml), add triethylamine (1.67ml) and methyl chlorooxyacetate (1.01ml) successively under ice cooling, and stir at room temperature for 21 hours . Water and dichloromethane were added to the reaction solution to separate the layers, and 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 obtained residue was dissolved in ethanol (50 ml), water (25 ml) and lithium hydroxide monohydrate (629 mg) were added in that order, and the mixture was stirred at room temperature for 12.5 hours. Then, lithium hydroxide monohydrate (629 mg) was added, followed by stirring 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 layers, hydrochloric acid was added to the aqueous layer to make it acidic. The resulting solid was collected by filtration to obtain a crude product (1.62 g) of 2-(3,4-dichloroanilino)-2-oxoacetic acid as a colorless solid. This crude product (191 mg) and the compound (250 mg) obtained in Reference Example 253 were dissolved in N,N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (110 mg) and 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg), stirred at room temperature for 67 hours. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue to separate the layers, and the aqueous layer was extracted three times with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=95:5) to obtain the title compound (154 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.77-1.88 (1H, m), 1.91-1.95 (1H, m), 2.05-2.10 (3H, m), 2.51 (3H, s), 2.77-2.99 (6H, m), 2.95(3H, s), 3.05(3H, s), 3.68(1H, d, J=15.5Hz), 3.74(1H, d, J=15.5Hz), 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] N ¹ -(2,4-difluorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

In the same manner as in Example 191, the compound obtained in Reference Example 259 was hydrolyzed, and then condensed with the compound obtained in Reference Example 253 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.55-1.62 (1H, m), 1.67-1.98 (2H, m), 2.01-2.18 (4H, m), 2.52 (3H, s), 2.77-3.00 (4H, m), 2.95(3H, s), 2.99(3H, s), 3.65-3.78(2H, m), 4.06-4.15(1H, m), 4.66-4.73(1H, m), 6.85-6.94(2H, m), 7.38(1H, d, J=8.5Hz), 7.96(1H, d, J=7.3Hz), 8.22-8.29(1H, m), 9.36(1H, br).

[Example 202] N ¹ -(3,4-difluorophenyl)-N ² -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

In the same manner as in Example 191, the compound obtained in Reference Example 260 was hydrolyzed, and then condensed with the compound obtained in Reference Example 253 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.56-1.73 (1H, m), 1.77-1.99 (2H, m), 2.00-2.18 (4H, m), 2.52 (3H, s), 2.75-3.00 (4H, m), 2.95(3H, s), 3.06(3H, s), 3.64-3.79(2H, m), 4.05-4.14(1H, m), 4.68-4.75(1H, m), 7.09-7.21(2H, m), 7.38 (1H, d, J=8.8Hz), 7.72 (1H, ddd, J=12.0, 7.1, 2.6Hz), 7.95 (1H, d, J=7.8Hz), 9.22 (1H, br).

[Example 203] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(pyridin-4-yl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 261 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-2.10 (6H, m), 2.77 (3H, s), 2.927 (3H, s), 2.933 (3H, s), 3.05-4.20 (8H, m) , 4.40-4.55(1H, m), 8.27(2H, d, J=6.8Hz), 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] N ¹ -(5-bromopyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

By the same method as in Example 195, the compound obtained in Reference Example 262 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.57 (1H, m), 1.61-1.81 (3H, m), 1.98-2.15 (2H, m), 2.79 (3H, s), 2.86 (3H, s), 2.89-3.01(4H, m), 3.18(2H, br.s), 3.50(2H, br.s), 3.95-4.05(1H, m), 4.35-4.62(3H, m), 7.97( 1H, d, J = 9.0Hz), 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] N ¹ -(6-chloropyridin-3-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound (200 mg) obtained in Reference Example 263 as a crude product was dissolved in methanol (10 ml), heated at 50°C, 1N aqueous sodium hydroxide solution (3 ml) was added and stirred for 5 minutes. 1N hydrochloric acid aqueous solution was added thereto to adjust the pH to slightly acidic, and the solvent was distilled off under reduced pressure to obtain a residue containing 2-[(2-chloropyridin-5-yl)amino]-2-oxoacetic acid. To this residue and the compound (250 mg) obtained in Reference Example 253 were added N,N-dimethylformamide (5 ml), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiethylene Amine hydrochloride (328 mg) and 1-hydroxybenzotriazole monohydrate (46 mg) were stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and dichloromethane were added to the residue for 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=47:3) to obtain the free base of the title compound as a pale yellow solid. This was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (862 µl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, ethyl acetate and 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).

¹ H-NMR (DMSO-d ₆ ) δ: 1.46-1.75 (4H, m), 1.99-2.09 (2H, m), 2.79 (3H, s), 2.92-2.95 (7H, m), 3.12-3.53 ( 3H, m), 3.70 (1H, br.s), 3.99-4.06 (1H, m), 4.44 (2H, br.s), 4.69, 4.73 (1H, each s), 7.53 (1H, d, J =8.5Hz), 8.23-8.25(1H, m), 8.72-8.77(1H, m), 8.85(1H, s), 9.07, 9.16(1H, each d, J=8.1Hz), 11.09(1H, d, J=8.1Hz), 11.78(1H, br.s).

MS (FAB) m/z: 548 (M+H) ⁺ .

[Example 206] N ¹ -(6-chloropyridazin-3-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

Using the same method as in Example 191, the compound obtained in Reference Example 264 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.44-1.57 (1H, m), 1.62-1.80 (3H, m), 2.00-2.10 (2H, m), 2.79 (3H, s), 2.86 (3H, br.s), 2.94(3H, s), 2.95-3.01(1H, m), 3.14-3.23(2H, m), 3.45-3.63(2H, m), 3.96-4.08(1H, m), 4.40- 4.60 (3H, m), 7.97 (1H, d, J = 9.3Hz), 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] N ¹ -(5-chlorothiazol-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

Using the same method as in Example 191, the compound obtained in Reference Example 265 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.35-2.10 (6H, m), 2.77 (3H, s), 2.92 (3H, s), 2.93 (3H, s), 3.05-4.23 (8H, m) , 4.32-4.80(2H, m), 7.59(1H, s), 8.63(1H, d, J=7.6Hz), 9.14(1H, d, J=7.6Hz).

MS (FAB) m/z: 554 (M+H) ⁺ .

[Example 208] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound (210 mg) obtained in Reference Example 266 and the compound (350 mg) obtained in Reference Example 272 were dissolved in N,N-dimethylformamide (15 ml), and 1-hydroxybenzotriazole monohydrate (205 mg) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290 mg), stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and saturated aqueous sodium bicarbonate and dichloromethane were added to the residue for liquid separation. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). The obtained pale yellow solid was dissolved in dichloromethane, and 1N hydrochloric acid was added to Ethanol solution (0.46ml), 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 (248 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.50 (1H, m), 1.69-1.76 (3H, m), 1.98-2.06 (2H, m), 2.79 (3H, s), 2.95 (3H, s), 2.98-3.05(1H, m), 3.10(3H, s), 3.49-4.62(6H, m), 7.98-8.03(2H, m), 8.45(1H, s), 8.73(1H, d, J=7.6Hz), 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 obtained in Reference Example 267 (2.3 g) was dissolved in ethanol (10 ml), 1N aqueous sodium hydroxide solution (20 ml) was added, and stirred at room temperature for 2 hours. 1N hydrochloric acid aqueous solution (20 ml) was added to the reaction solution, diluted with water, and stirred for 30 minutes. The precipitated insoluble matter was collected by filtration. 2-(4-Chloroanilino)acetic acid (1.05 g) was obtained as a colorless solid. The solid and the compound (0.25 g) obtained in Reference Example 253 were dissolved in N,N-dimethylformamide (10 ml), and 1-hydroxybenzotriazole monohydrate (0.11 g) and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g), stirred at room temperature for 4 days. The reaction solution was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and saturated brine, 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 (chloroform:methanol=97:3). The obtained pale yellow solid was dissolved in ethanol, 1N hydrochloric acid ethanol solution 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 (0.15 g).

¹ H-NMR (DMSO-d ₆ ) 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

Using the same method as in Example 209, the compound obtained in Reference Example 268 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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

In the same manner as in Example 2, the compound obtained in Reference Example 432 was condensed with the compound obtained in Reference Example 34, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 obtained in Example 211 (250 mg) was suspended in dichloromethane, added with saturated aqueous sodium bicarbonate solution and stirred well. The organic layer was separated and dried over anhydrous magnesium sulfate, triethylamine (0.5 ml) and ethyl bromoisocyanate (43 µl) were added, and the mixture was stirred at room temperature for 20 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=22:3) to obtain the title compound (227 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.50-2.15 (4H, m), 2.15-2.40 (2H, m), 2.80-3.00 (1H, m), 2.97 (3H, s), 3.11 (3H, s) , 3.70-3.95(4H, m), 4.10-4.30(1H, m), 4.30-4.50(2H, m), 4.60-4.70(1H, m), 4.74(2H, s), 6.85(1H, s) , 7.21 (1H, dd, J=8.8, 2.2Hz), 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 (140 mg) obtained in Reference Example 144 was dissolved in N,N-dimethylformamide (10 ml), and the compound (100 mg) obtained in Reference Example 274, 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride (140 mg) and 1-hydroxybenzotriazole monohydrate (110 mg), stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was partitioned into water-ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain (1R,2S,5S)-2-{[(5-chloro-4-fluoroindole -2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexylcarbamate (260 mg).

The above powder was dissolved in dichloromethane (5 ml), and 4N hydrochloric acid dioxane solution (1.2 ml) was added. After stirring the reaction solution at room temperature for 3.5 hours, the solvent was distilled off under reduced pressure. Dichloromethane (10 ml) was added to the residue to concentrate, and this operation was repeated 3 times, and 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. It was dissolved in N,N-dimethylformamide (50ml), and the compound obtained in Reference Example 10 (150mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt was added Salt (140 mg) and 1-hydroxybenzotriazole monohydrate (110 mg), stirred at room temperature for 18 hours. The solvent was distilled off 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 layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain the free base of the title compound (270 mg). The base was dissolved in dichloromethane (10 ml), 1N hydrochloric acid ethanol solution (0.72 ml) was added, stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration to obtain the title compound (200 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.24-1.98 (6H, m), 2.33-3.33 (6H, m), 2.81 (3H, s), 2.90 (3H, s), 2.99 (3H, s) , 4.12(1H, br.s), 4.30-4.70(1H, m), 4.60(1H, br.s), 7.21(1H, s), 7.27(2H, br.s), 8.37(1H, d, J=8.1Hz), 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 (250 mg) obtained in Reference Example 279 was dissolved in dichloromethane (60 ml), and 4N hydrochloric acid dioxane solution (1.3 ml) was added. After stirring the reaction solution at room temperature for 5.5 hours, 4N hydrochloric acid dioxane solution (0.65 ml) was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, dichloromethane (10 ml) was added to the residue for concentration, and this operation was repeated three times. The residue was dried under reduced pressure, the resulting crude product was dissolved in N,N-dimethylformamide (50 ml), and the compound (160 mg) obtained in Reference Example 10, 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (150 mg) and 1-hydroxybenzotriazole monohydrate (120 mg) were stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, the residue was partitioned into a water-ethyl acetate mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified twice by silica gel column chromatography (methanol:dichloromethane=2:23→1:9) to obtain the free base of the title compound (260 mg). The base was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (0.69 ml) was added, stirred at room temperature for 30 minutes, and the solvent was distilled off. The residue was dissolved in methanol, diethyl ether and hexane were added to crystallize, and the crystals were collected by filtration to obtain the title compound (230 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.56 (1H, m), 1.73-1.78 (3H, m), 1.94-2.02 (2H, m), 2.33-3.55 (6H, m), 2.80 ( 3H, s), 2.92 (3H, s), 2.98 (3H, s), 4.17 (1H, br.s), 4.30-4.80 (1H, br), 4.62 (1H, br.s), 7.25 (1H, d, J = 8.8, 1.7Hz), 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

In the same manner as in Example 214, the compound obtained in Reference Example 282 was treated with 4N hydrochloric acid dioxane solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.51-2.01 (6H, m), 2.33-3.29 (7H, m), 2.81 (3H, s), 2.88 (3H, s), 3.01 (3H, s) , 4.20 (1H, br.s), 4.48 (1H, br), 4.70-4.73 (1H, m), 7.29 (1H, dd, J=8.9, 1.8Hz), 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}-54(dimethylamino)carbonyl]ring Hexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 284 in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) 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 = 2.5 Hz), 12.10(1H, s).

MS (FAB) m/z: 561 (M+H) ⁺ .

[Example 217] N-{(1R, 2S, 5S)-2-{[(5-chloro-3-formyl indol-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 prepared from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 286 in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) 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-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7 -Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ³ ,N ³ -dimethylindole-2,3-dicarboxamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 289 in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) 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 (270 mg) obtained in Reference Example 294 was dissolved in dichloromethane (10 ml), 1N hydrochloric acid ethanol (10 ml) was added, and stirred for 90 minutes. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in N,N-dimethylformamide (7 ml), and the compound (110 mg) obtained in Reference Example 10, 1-(3-dimethylaminopropyl)-3 - Ethylcarbodiimide hydrochloride (100 mg) and 1-hydroxybenzotriazole monohydrate (70 mg), stirred at room temperature for 23 hours. The reaction solution was concentrated under reduced pressure, added with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified twice by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The resulting free base was dissolved in methanol, and 1N hydrochloric acid ethanol solution (0.30ml) was added. . The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to obtain the title compound (130 mg).

¹ H-NMR (DMSO-d ₆ ) 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

In the same manner as in Example 219, the compound obtained in Reference Example 299 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.65 (1H, m), 1.70-1.90 (3H, m), 2.05-2.15 (1H, m), 2.15-2.30 (1H, m), 2.81 (3H, s), 2.85-3.05 (8H, m), 3.15-3.25 (2H, m), 3.40-3.80 (1H, m), 4.25-4.80 (4H, m), 8.02 (1H, dd, J = 8.8, 2.0 Hz), 8.38(1H, d, J=8.8Hz), 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

In the same manner as in Example 219, the compound obtained in Reference Example 300 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.60 (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 prepared from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 304 in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.60 (1H, m), 1.70-1.85 (3H, m), 1.95-2.05 (1H, m), 2.10-2.20 (1H, m), 2.80 ( 3H, s), 2.90-3.90 (5H, m), 2.93 (3H, s), 2.96 (3H, s), 4.10-4.75 (4H, m), 7.75-7.85 (1H, m), 8.00-8.05 ( 1H, m), 8.30-8.35 (1H, m), 8.61 (1H, s), 8.93 (2H, d, J=7.3Hz), 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 (220 mg) obtained in Reference Example 252 was dissolved in methanol (10 ml), 10% palladium on carbon (180 mg) was added, and stirred at room temperature for 4 hours in a hydrogen atmosphere. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (30 ml), and the compound obtained in Reference Example 306 (108 mg), 1-hydroxybenzotriazole monohydrate (78 mg) and 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (196 mg), stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:3) to obtain a pale yellow foamy substance. This foamy substance was dissolved in dichloromethane (2 ml), and 1N hydrochloric acid ethanol solution (363 µl) was added. After the solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitate was collected by filtration to obtain the title compound (175 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.52 (1H, m), 1.55-1.96 (5H, m), 2.78 (3H, s), 2.90 (3H, s), 2.98 (3H, s) , 3.01-3.12(1H, m), 3.13-3.28(2H, m), 3.40-3.85(2H, m), 3.92-4.00(1H, m), 4.35-4.80(3H, m), 4.84(1H, d, J = 14.5Hz), 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

In the same manner as in Example 219, the compound obtained in Reference Example 307 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.35-1.55 (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 prepared from the compound obtained in Reference Example 253 and the compound obtained in Reference Example 309 in the same manner as in Example 5.

¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.60 (1H, m), 1.65-2.10 (3H, m), 2.79 (3H, s), 2.92 (3H, s), 2.99 (3H, s) , 3.05-3.20(2H, m), 3.20-3.80(5H, m), 4.08-4.20(1H, m), 4.35-4.50(1H, m), 4.60-4.70(1H, m), 4.70(1H, d, J = 15.6Hz), 6.77 (1H, br.s), 7.73 (1H, d, J = 8.9Hz), 7.94 (1H, d, J = 8.9Hz), 7.97 (1H, d, J = 2.2 Hz), 8.54(1H, br.s), 8.80-9.00(1H, m), 11.18-11.42(1H, br), 11.70-12.50(1H, br).

MS (ESI) m/z: 571 (M+H) ⁺ .

[Example 226] 2-[({(1R, 2S, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]ring Hexyl}amino)carbonyl]-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylic acid tert-butyl ester

1) The compound obtained in Reference Example 310 (1.46 g) was dissolved in dichloromethane (10 ml), and hydrochloric acid ethanol solution (10 ml) was added at room temperature and stirred for 1 hour. After the reaction, evaporate the solvent, add ethanol to concentrate, add isopropyl ether to the residue, solidify, and filter to obtain N-{(1S, 2R, 4S)-2-amino-4-[(dimethylamino) Carbonyl]cyclohexyl}-5-chloroindole-2-carboxamide hydrochloride.

2) Dissolve the hydrochloride in N,N-dimethylformamide (5ml) at room temperature, add the compound obtained in Reference Example 406 (1.31mg), 1-hydroxybenzotriazole monohydrate (640mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.36 g), and stirred at room temperature for 3 days. The reaction solution was concentrated, and dichloromethane and saturated aqueous sodium bicarbonate solution were added for liquid separation, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:19) to obtain the title compound (1.22 g).

¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 1.70-2.40 (6H, m), 2.80-3.20 (7H, m), 4.15-4.25 (1H, m), 4.55-4.80 (5H, m), 6.83 (1H, d, J = 1.5Hz), 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]-44(dimethylamino)carbonyl]cyclohexyl}indole-2-carboxamide hydrochloride

The compound obtained in Example 226 (1.22 g) was dissolved in dichloromethane (5 ml), and hydrochloric acid ethanol solution (10 ml) was added at room temperature and stirred for 1 hour. After concentrating the reaction solution, saturated aqueous sodium bicarbonate solution and dichloromethane were added to separate the layers, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (methanol:dichloromethane=1:9) to obtain the free base of the title compound (636 mg) as a colorless glassy solid. The free base (200 mg) was dissolved in 1N hydrochloric acid ethanol solution (1 ml), concentrated and solidified by adding ethyl acetate. The obtained colorless powder was collected by filtration and dried to obtain the title compound (195 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.05 (2H, m), 2.80 (3H, s), 2.98 (3H, s), 2.98-3.15(1H, m), 4.05-4.20(1H, m), 4.44(2H, br.s), 4.58(3H, br.s), 7.05(1H, d, J=1.5Hz) , 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 prepared from the compound obtained in Example 227 and formalin in the same manner as in Example 18.

¹ H-NMR (DMSO-d ₆ ) 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] 2-{[((1R, 2S, 5S)-5-[(dimethylamino)carbonyl]-2-{[(5-fluoroindol-2-yl)carbonyl]amino}ring Hexyl)amino]carbonyl}-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole-5-carboxylic acid tert-butyl ester

The title compound was prepared from the compound obtained in Reference Example 311 and the compound obtained in Reference Example 406 in the same manner as in Example 226.

¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 1.60-2.40 (6H, m), 2.80-3.20 (7H, m), 4.15-4.25 (1H, m), 4.55-4.80 (5H, m), 6.84-6.87(1H, m), 7.01(1H, dt, J=2.4, 9.1Hz), 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 prepared from the compound obtained in Example 229 in the same manner as in Example 227.

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Example 230 and formalin in the same manner as in Example 18.

¹ H-NMR (DMSO-d ₆ ) 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 prepared from the compound obtained in Reference Example 294 and the compound obtained in Reference Example 293 in the same manner as in Example 226.

¹ H-NMR (DMSO-d ₆ ) δ: 1.48-1.56 (1H, m), 1.71-1.84 (3H, m), 1.95-2.04 (2H, m), 2.81 (3H, s), 3.00 (3H, s), 3.02(3H, s), 3.06-3.15(2H, m), 4.13-4.14(1H, m), 4.52-4.63(4H, m), 7.60(1H, d, J=8.5Hz), 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- Formamide

4N dioxane hydrochloride solution (3.0 ml) was added to a dioxane (3.0 ml)-dichloromethane (3.0 ml) mixed suspension of the compound (330 mg) obtained in Reference Example 299, and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, the resulting white powder was dissolved in N,N-dimethylformamide (5.0ml), and the compound obtained in Reference Example 293 (172mg), 1-hydroxybenzotriazole monohydrate (130mg ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg), and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1). 1N hydrochloric acid ethanol solution (0.35 ml) was added to an ethanol (4.0 ml) solution of the obtained highly polar main product, and the solvent was distilled off under reduced pressure. Ethanol and ether were added to the residue, and the resulting precipitate was collected by filtration to obtain 7-chloro-N-((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl yl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)cinnoline-3-carboxamide hydrochloride (184 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.65 (1H, m), 1.70-1.90 (3H, m), 2.03-2.12 (1H, m), 2.15-2.30 (1H, m), 2.81 ( 3H, s), 2.90-3.05 (1H, m), 2.96 (3H, s), 3.07 (3H, s), 4.28-4.37 (1H, m), 4.40-4.95 (5H, br), 8.02 (1H, d, J=8.8Hz), 8.38(1H,d,J=8.8Hz), 8.66(1H,s), 8.91(1H,s), 8.97(1H,d,J=7.1Hz), 9.43-9.57( 1H, br), 11.75-11.95 (0.5H, br), 12.35-12.55 (0.5H, br).

MS (FAB) m/z: 542 (M+H) ⁺ .

In addition, 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).

¹ H-NMR (CDCl ₃ ) δ: 1.90-2.25 (6H, m), 2.85-3.00 (1H, m), 2.95 (3H, s), 3.05 (3H, s), 3.91 (3H, s), 4.43 -4.54(1H, m), 4.86-4.95(1H, m), 6.70(1H, d, J=1.5Hz), 7.19(1H, d, J=1.5Hz), 7.59(1H, d, J=8.8 Hz), 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 (500 mg) obtained in Reference Example 146 was dissolved in hydrochloric acid ethanol solution (5 ml), and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, the resulting residue was dissolved in N,N-dimethylformamide (7 ml), and the compound obtained in Reference Example 293 (299 mg), 1-hydroxybenzotriazole monohydrate (71 mg), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (403 mg), stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and dichloromethane were added to the residue for liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=93:7) to obtain the free base of the title compound (260 mg) as a pale yellow solid. This solid was dissolved in dichloromethane, 1N hydrochloric acid ethanol solution (961 µl) was added, and the solvent was distilled off under reduced pressure. A small amount of methanol was added to the residue, and diethyl ether was added dropwise. The resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (260 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.56 (1H, m), 1.71-1.75 (3H, m), 1.95-1.99 (1H, m), 2.12-2.15 (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]ring Hexyl}amino)carbonyl]-6,6-dimethyl-6,7-dihydrothiazolo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester

Under an argon atmosphere, the compound obtained in Reference Example 316 (95.4 mg) was dissolved in diethyl ether (1 ml), and tert-butyllithium (1.60N pentane solution, 244 µl) was added dropwise at -78°C. After stirring at -78°C for 1 hour, carbon dioxide gas was introduced over 10 minutes. After warming up to room temperature, the reaction solution was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylformamide (5ml), and the compound obtained in Reference Example 432 (178mg) and 1-hydroxybenzotriazole monohydrate were added in sequence (48.0 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136 mg), stirred overnight at room temperature. The reaction solution was concentrated, and dichloromethane and saturated aqueous sodium bicarbonate solution were added for liquid separation. After 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 (methanol:dichloromethane=1:19) to obtain the title compound (140 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.52 (3H, s), 1.54 (3H, s), 1.70-2.10 (4H, m), 2.15-2.45 (2H, m), 2.80 -3.20(9H, m), 4.10-4.25(1H, br), 4.60-4.75(3H, m), 6.85(1H, br.s), 7.21(1H, dd, J=8.8, 1.8Hz), 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 prepared from the compound obtained in Example 235 in the same manner as in Example 227.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40 (6H, s), 1.45-1.60 (1H, m), 1.70-2.05 (5H, m), 2.81 (3H, s), 2.95-3.15 (6H, m), 4.05-4.20(1H, br), 4.25-4.45(2H, m), 4.55-4.65(1H, m), 7.06(1H, d, J=1.7Hz), 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]ring Hexyl}amino)carbonyl]-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester

The compound obtained in Reference Example 50 (1.27 g) was dissolved in tetrahydrofuran (48 ml), lithium hydroxide (117 mg) and water (6.0 ml) were added, and stirred at room temperature for 4.5 hours. The reaction solution was evaporated to dryness under reduced pressure to obtain a crude lithium carboxylate salt (1.24 g). The title compound was prepared by condensing with the compound obtained in Reference Example 432 in the same manner as in 2) of Example 226.

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.70 (1H, m), 1.54 (9H, s), 1.80-2.10 (3H, m), 2.25-2.50 (2H, m), 2.85-2.95 (1H, m), 2.99(3H, s), 3.14(3H, s), 4.15-4.25(1H, m), 4.65-4.75(1H, m), 4.80-4.90(4H, m), 6.97(1H, s) , 7.15-7.25(1H, m), 7.30-7.40(1H, m), 7.60-7.65(1H, m), 8.15-8.25(1H, m), 8.40-8.45(1H, m), 8.75-8.85( 1H, m), 9.40-9.45 (1H, m).

MS (ESI) m/z: 611 (M+H) ⁺ .

[Example 238] N-{(1R, 2S, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl} -6-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carboxamide hydrochloride

The compound obtained in Example 237 (367 mg) was dissolved in dichloromethane (10 ml), trifluoroacetic acid (10 ml) was added, and stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the title compound was obtained in the same manner as in Example 18 from the obtained crude product and formalin.

¹ H-NMR (DMSO-d ₆ ) 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 = 8.1 Hz), 9.00(1H, s), 11.80(1H, s), 11.90-12.20(1H, m).

MS (FAB) m/z: 524 (M+H) ⁺ .

[Example 239] 7-chloro-N-((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(6-methyl-6,7-dihydrothiazolo [4,5-d]pyrimidin-2-yl)carbonyl]amino}cyclohexyl)isoquinoline-3-carboxamide hydrochloride

In the same manner as in Example 49, the compound obtained in Reference Example 146 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 322 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.60 (1H, m), 1.70-1.90 (3H, m), 1.90-2.15 (2H, m), 2.81 (3H, s), 2.95 (3H, s), 2.90-3.05(1H, m), 3.26(3H, s), 4.20-4.55(2H, m), 5.00(2H, s), 7.91(1H, d, J=8.8Hz), 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 prepared from the compound obtained in Reference Example 325 and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 0.98, 1.04 (3H, each t, J = 7.1 Hz), 1.52-1.60 (1H, m), 1.74-1.77 (3H, m), 1.96-2.05 ( 1H, m), 2.15-2.18 (1H, m), 2.77-2.93 (8H, m), 3.17-3.32 (3H, m), 3.49 (1H, br.s), 4.22 (1H, br.s), 4.41-4.45(1H, m), 4.51(1H, br.s), 4.69-4.72(1H, m), 7.89(1H, d, J=8.7Hz), 8.26(1H, d, J=8.7Hz) , 8.37(1H, s), 8.60(1H, s), 8.91-8.98(2H, m), 9.32(1H, d, J=6.6Hz), 11.39, 11.53(1H, each m).

MS (FAB) m/z: 569 (M+H) ⁺ .

[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 prepared from the compound obtained in Reference Example 336 and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) 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

Using the same method as in Example 219, the compound obtained in Reference Example 340 was treated with ethanol hydrochloric acid solution, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.35-1.40 (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=8.8 Hz), 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

By the same method as in Example 223, the compound obtained in Reference Example 252 was condensed with the compound obtained in Reference Example 345 after catalytic reduction to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.56-1.66 (1H, m), 1.76-1.93 (2H, m), 2.02-2.06 (1H, m), 2.19-2.26 (1H, m), 2.30-2.34 ( 1H, m), 2.52 (3H, s), 2.79-2.88 (3H, m), 2.91-2.94 (2H, m), 2.96 (3H, s), 3.09 (3H, s), 3.69-3.77 (2H, m), 4.13-4.19(1H, m), 4.58-4.61(1H, m), 6.72(1H, s), 6.84(1H, s), 7.50(1H, d, J=7.3Hz), 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-propioloyl]amino}-5-[(dimethylamino)carbonyl] Cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

By the same method as in Example 223, the compound obtained in Reference Example 252 was condensed with the compound obtained in Reference Example 347 after catalytic reduction to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.50 (1H, m), 1.58-1.92 (4H, m), 2.78 (3H, s), 2.90 (3H, s), 2.97 (3H, s) , 3.01-3.24(3H, m), 3.26-3.80(2H, m), 3.90-3.98(1H, m), 4.30-4.78(3H, m), 7.51(1H, d, J=8.8Hz), 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

Using the same method as in Example 223, the compound obtained in Reference Example 252 was condensed with the compound obtained in Reference Example 349 after catalytic reduction to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 obtained in Reference Example 253 (184 mg) and the compound obtained in Reference Example 351 (150 mg) were dissolved in methanol (1 ml)-dichloromethane (4 ml), heated and stirred at 150° C., and heated for 5 minutes after evaporating the solvent. The resultant after natural cooling was purified by silica gel column chromatography (dichloromethane:methanol=24:1) to obtain the title compound (59 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.65-1.90 (2H, m), 1.90-2.00 (1H, m), 2.00-2.15 (2H, m), 2.20-2.30 (1H, m), 2.52 (3H, s), 2.75-2.95(5H, m), 2.96(3H, s), 3.07(3H, s), 3.68(1H, d, J=15.2Hz), 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 (184 mg) obtained in Reference Example 253 and the compound (150 mg) obtained in Reference Example 353 were dissolved in methanol (0.3 ml)-dichloromethane (0.3 ml), heated and stirred at 150° C., and continued heating for 5 minute. The resultant after natural cooling was purified by silica gel column chromatography (dichloromethane:methanol=24:1) to obtain the title compound (52 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.60-2.00 (3H, m), 2.00-2.20 (2H, m), 2.25-2.40 (1H, m), 2.53 (3H, s), 2.80-2.95 (5H, m), 2.96(3H, s), 3.08(3H, s), 3.70(1H, d, J=15.4Hz), 3.75(1H, d, J=15.4Hz), 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 (72 mg) obtained in Reference Example 355 and 2-amino-5-chloropyridine (100 mg) were dissolved in methanol (0.2 ml)-dichloromethane (0.2 ml), heated and stirred at 150° C., and heated after evaporating the solvent. 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).

¹ H-NMR (CDCl ₃ ) δ: 1.60-2.00 (3H, m), 2.00-2.20 (3H, m), 2.53 (3H, s), 2.75-3.00 (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] N ¹ -(5-chloro-2-thienyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 356 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.55 (1H, m), 1.60-1.85 (3H, m), 1.90-2.15 (2H, m), 2.79 (3H, s), 2.90-3.15 ( 1H, m), 2.92(3H, s), 2.94(3H, s), 3.15-3.30(2H, m), 3.50-3.80(2H, m), 3.95-4.05(1H, m), 4.35-4.90( 3H, m), 6.90 (1H, d, J=4.2Hz), 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 Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

To a dichloromethane (2 ml) solution of the compound (183 mg) obtained in Reference Example 253 was added 4-chlorophenyl isocyanate (76.8 mg), followed by stirring 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 dichloromethane (2ml), 1N hydrochloric acid ethanol solution (0.4ml) was added, and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was solidified with ether to obtain the title compound (160 mg).

¹ H-NMR (DMSO-d ₆ ) 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, each s).

MS (ESI) m/z: 519 (M+H) ⁺ .

[Example 251] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(5-fluoropyridin-2-yl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 357 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.53 (1H, m), 1.68-1.75 (3H, m), 1.99-2.10 (2H, m), 2.80 (3H, s), 2.80-3.00 ( 1H, m), 2.95 (6H, s), 3.18-3.21 (2H, m), 3.40-3.80 (2H, m), 3.87-4.82 (4H, m), 7.82-7.85 (1H, m), 8.01- 8.05(1H, m), 8.40(1H, d, J=2.9Hz), 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] N ¹ -(4-chlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 5,6-Dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 242 and the compound obtained in Reference Example 272 in the same manner as in Example 191.

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.51 (1H, m), 1.69-1.75 (3H, m), 1.98-2.05 (2H, m), 2.80 (3H, s), 2.95 (3H, s), 2.98-3.04(1H, m), 3.10(3H, s), 3.40-4.61(6H, m), 7.41(2H, d, J=8.8Hz), 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] N ¹ -[4-chloro-2-(trifluoromethyl)phenyl]-N ² -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2 -{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

Thionyl chloride (1 ml) was added to a chloroform solution (10 ml) of the compound (269 mg) obtained in Reference Example 359, stirred at 75°C for 30 minutes, and the solvent was evaporated under reduced pressure and dried. Under ice-cooling, a dichloromethane solution (7 ml) of the compound (286 mg) obtained in Reference Example 253 and pyridine (3 ml) were added thereto, and the mixture was stirred for 2 hours while warming to room temperature. After adding saturated aqueous sodium bicarbonate solution (10 ml) to the reaction solution for liquid separation, the obtained organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) and LH-20 column chromatography (molecular sieves, methanol) to obtain a light yellow amorphous solid. Free base of the title compound (90 mg). Dichloromethane (5 ml), ethanol (5 ml) and 1N hydrochloric acid ethanol solution (1 ml) were added thereto, and the mixture was evaporated to dryness under reduced pressure to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.41-1.55 (1H, m), 1.59-1.80 (3H, m), 1.98-2.13 (2H, m), 2.77 (3H, s), 2.91 (6H, s), 3.12-3.26(2H, m), 3.30-3.58(2H, m), 3.60-3.78(1H, m), 3.94-4.04(1H, m), 4.35-4.63(2H, m), 4.64- 4.80(1H, m), 7.73-7.82(2H, m), 7.85(1H, s), 8.68-8.73(1H, m), 9.18(1H, br.s), 10.31(1H, s).

MS (ESI) m/z: 615 (M+H) ⁺ .

[Example 254] N ¹ -{4-chloro-2-[(dimethylamino)carbonyl]phenyl}-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl ]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 362 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.56 (1H, m), 1.59-1.82 (3H, m), 1.98-2.14 (2H, m), 2.79 (3H, s), 2.91 (3H, s), 2.93(3H, s), 2.95(3H, s), 2.98(3H, s), 3.10-3.30(4H, m), 3.62-3.79(1H, m), 3.92-4.01(1H, m) , 4.34-4.50(2H, m), 4.66-4.79(1H, m), 7.52(1H, d, J=2.4Hz), 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] N ¹ -[4-Chloro-2-(hydroxymethyl)phenyl]-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2- {[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 199, the compound obtained in Reference Example 270 was condensed with 4-chloro-2-hydroxymethylaniline, and then treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.57 (1H, m), 1.58-1.81 (3H, m), 1.98-2.14 (2H, m), 2.79 (3H, s), 2.93 (6H, s), 3.12-3.58(4H, m), 3.67-3.80(1H, m), 3.94-4.04(1H, m), 4.37-4.50(1.5H, m), 4.55(2H, s), 4.67-4.80 (1H, m), 5.77-5.92 (0.5H, 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] N ¹ -(4-chloro-2-methoxyphenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 364 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.55 (1H, m), 1.58-1.79 (3H, m), 1.94-2.11 (2H, m), 2.77 (3H, s), 2.92 (6H, s), 3.05-3.55(4H, m), 3.65-3.75(1H, br), 3.90(3H, s), 3.91-4.00(1H, m), 4.36-4.47(2H, br), 4.65-4.77( 1H, br), 7.04 (1H, dd, J=8.5, 2.0Hz), 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-[(dimethyl Amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 366 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.41-1.53 (1H, m), 1.57-1.77 (3H, m), 1.88-2.04 (2H, m), 2.77 (3H, s), 2.91 (6H, s), 3.00-3.60(4H, m), 3.65-3.74(1H, br), 3.87-3.96(1H, m), 4.37-4.48(2H, m), 4.66-4.76(1H, m), 6.70( 2H, d, J = 8.8Hz), 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] N ¹ -(4-chlorophenyl)-N ² -((3R, 4S)-1-(2-methoxyacetyl)-3-{[(5-methyl-4, 5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 367 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.72 (1H, m), 1.99-2.22 (1H, m), 2.90 (3H, s), 3.03-4.80 (17H, m), 7.40 (2H, d, J = 8.8Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((3R, 4S)-1-(2-methoxyacetyl)-3-{[(5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 368 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.72 (1H, m), 1.98-2.20 (1H, m), 2.90 (3H, s), 3.00-4.77 (17H, m), 7.20-7.35 ( 0.8H, br), 7.48-7.56 (0.2H, br), 7.94-8.07 (1H, br), 8.40-8.70 (1H, br), 8.48-8.70 (1H, br), 9.23-9.45 (1H, br ), 10.21-10.35 (1H, br), 11.30-11.70 (1H, br).

MS (ESI) m/z: 550 (M+H) ⁺ .

[Example 260] N ¹ -(5-bromopyridin-2-yl)-N ² -((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide hydrochloride

In the same manner as in Example 214, the compound obtained in Reference Example 369 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.73 (1H, m), 1.97-2.20 (1H, m), 2.90 (3H, s), 3.03-3.52 (7H, m), 3.64-4.07 ( 5H, m), 4.10-4.50 (4H, m), 4.65-4.78 (1H, m), 7.28-7.35 (0.2H, 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] N ¹ -(4-chlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)malonamide hydrochloride

In the same manner as in Example 5, the compound obtained in Reference Example 371 was condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.32-1.50 (1H, m), 1.55-1.87 (5H, m), 2.78 (3H, m), 2.92 (3H, s), 2.98 (3H, s) , 2.99-3.00(1H, m), 3.05-3.50(5H, m), 3.65-3.75(1H, m), 3.80-3.92(1H, m), 4.35-4.45(1H, m), 4.45-4.55( 1H, m), 4.65-4.80 (1H, m), 7.34 (2H, d, J=8.8Hz), 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] N ¹ -(3-chlorophenyl)-N ³ -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)malonamide hydrochloride

In the same manner as in Example 5, the compound obtained in Reference Example 373 was condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.32-1.50 (1H, m), 1.55-1.90 (5H, m), 2.77 (3H, s), 2.91 (3H, s), 2.98 (3H, s) , 2.99-3.00(1H, m), 3.05-3.50(5H, m), 3.65-3.80(1H, m), 3.80-3.90(1H, m), 4.35-4.50(1H, m), 4.50-4.60( 1H, m), 4.65-4.80 (1H, m), 7.09 (1H, d, J=8.8Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

10% palladium on carbon (0.3 g) was added to a solution of the compound (0.33 g) obtained in Reference Example 404 in ethanol (20 ml), and stirred under a hydrogen atmosphere for 24 hours. The 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 obtained in Reference Example 266 (0.3g), 1-hydroxybenzotriazole monohydrate (0.2g ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.37 g), stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with a mixed solvent of chloroform-methanol (9:1), and washed with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform:methanol=95:5), and the target fraction was concentrated. 1N hydrochloric acid ethanol solution was added to the obtained residue to form a hydrochloride, and then recrystallized from a mixed solvent of methanol and diethyl ether to obtain the title compound (0.28 g).

¹ H-NMR (DMSO-d ₆ ) δ: 0.95 (1.5H, 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] N ¹ -(4-chlorophenyl)-N ² -((1S, 2R, 4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 263, the compound obtained in Reference Example 404 was converted into an amine, condensed with the compound obtained in Reference Example 374, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (1.5H, 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] N ¹ -(5-bromopyridin-2-yl)-N ² -((1S, 2R, 4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

Using the same method as in Example 263, the compound obtained in Reference Example 404 was converted into an amine, condensed with the compound obtained in Reference Example 375, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(4-chloro-3-fluorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

Using the same method as in Example 263, the compound obtained in Reference Example 252 was converted into an amine, condensed with the compound obtained in Reference Example 378, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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-oxopropionyl]amino}-5-[(dimethylamino)carbonyl ]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

In the same manner as in Example 214, the compound obtained in Reference Example 383 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (CDCl ₃ ) (free base) δ: 1.22-1.32 (1H, m), 1.49-1.92 (3H, m), 1.95-2.10 (2H, m), 2.53 (3H, s), 2.70- 2.79(1H,m), 2.80-2.90(2H,m), 2.93(6H,s), 2.95-3.09(2H,m), 3.72(2H,s), 3.87(2H,s), 4.05-4.19( 1H, m), 4.60-4.70 (1H, m), 7.20-7.40 (2H, m), 7.42 (2H, d, J=8.3Hz), 7.87 (2H, d, J=8.3Hz).

MS (FAB) m/z: 546 (M+H) ⁺ .

[Example 268] N ¹ -(5-chloropyridin-2-yl)-N ² -((1R, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-5H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

In the same manner as in Example 214, the compound obtained in Reference Example 386 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 293 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00-2.35 (7H, m), 2.96 (3H, s), 3.04 (3H, s), 3.85-3.95 (1H, m), 3.88 (3H, s) , 4.60-4.75 (1H, m), 6.68 (1H, d, J=2.0Hz), 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) ⁺ .

(Calc.; C ₂₃ H ₂₇ ClN ₇ O ₄ S: 532.1534)

[Example 269] N ¹ -[(5-chloropyridin-2-yl)amino]-N ² -((1R, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound obtained in Reference Example 387 was reduced in the same manner as in Reference Example 253, condensed with the compound obtained in Reference Example 266 in the same manner as in Example 208, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.98 (6H, m), 2.82 (3H, s), 2.91 (3H, s), 2.95 (3H, s), 2.86-3.92 (7H, m) , 4.30-4.81(2H, m), 7.92-8.09(2H, m), 8.39-8.47(1H, m), 8.56-8.72(2H, m), 10.17(1H, s).

MS (ESI) m/z: 548 (M+H) ⁺ .

[Example 270] N ¹ -(4-chlorophenyl)-N ² -((1R, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl- 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

The compound obtained in Reference Example 387 was reduced in the same manner as described in Reference Example 253, condensed with the lithium salt formed by hydrolysis of the compound obtained in Reference Example 242 in the same manner as described in Example 191, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.97 (6H, m), 2.82 (3H, s), 2.91 (3H, s), 2.98 (3H, s), 2.83-3.88 (7H, m) , 4.30-4.79(2H, m), 7.37(2H, d, J=8.8Hz), 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] N ¹ -{(1R, 2R, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl }-N ² -(pyridin-4-yl)oxalamide hydrochloride

The compound obtained in Reference Example 310 was deprotected by treatment with hydrochloric acid, and the 2-[(pyridin-4-yl)amino]-2-oxo After condensation of the lithium acetate salt, treatment with hydrochloric acid affords the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-2.01 (6H, m), 2.79 (3H, s), 3.01 (3H, s), 3.00-3.18 (1H, m), 4.02-4.19 (1H, m), 4.45-4.55(1H, m), 7.09(1H, s), 7.13-7.22(1H, m), 7.41(1H, d, J=8.4Hz), 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] N ¹ -{(1R, 2R, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl }-N ² -(pyridin-3-yl)oxalamide hydrochloride

In the same manner as described in Reference Example 242, 3-aminopyridine and methyl 2-chloro-2-oxoacetate were condensed to obtain methyl 2-[(pyridin-3-yl)amino]-2-oxoacetate Using the compound obtained in Reference Example 310 as a starting material, the title compound was obtained in the same manner as in Example 271.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-2.05 (6H, m), 2.80 (3H, s), 3.02 (3H, s), 2.92-3.15 (1H, m), 4.02-4.17 (1H, m), 4.42-4.58(1H, m), 7.10(1H, s), 7.12-7.19(1H, m), 7.40(1H, d, J=8.4Hz), 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] N ¹ -{(1R, 2S, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl }-N ² -(piperidin-4-yl)oxalamide hydrochloride

To a solution of the compound (400 mg) obtained in Reference Example 389 in ethanol (5.0 ml) was added 4N hydrochloric acid dioxane solution (8.0 ml) at room temperature, followed by stirring at the same temperature for 5 hours. The solvent was distilled off under reduced pressure, and after washing with dichloromethane, the insoluble matter was filtered and washed to obtain the title compound (320 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.92 (10H, m), 2.77 (3H, s), 2.96 (3H, s), 2.82-3.35 (6H, m), 3.88-4.10 (2H, m), 4.34-4.43(1H, m), 7.05(1H, s), 7.11-7.17(1H, m), 7.38(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] N ¹ -{(1R, 2R, 5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-[(dimethylamino)carbonyl]cyclohexyl }-N ² -(1-methylpiperidin-4-yl)oxalamide hydrochloride

In the same manner as described in Reference Example 9, the compound obtained in Example 273 was treated with hydrochloric acid after methylation to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-2.01 (11H, m), 2.67 (3H, s), 2.79 (3H, s), 2.98 (3H, s), 2.85-4.48 (7H, m) , 7.07(1H, s), 7.16(1H, dd, J=8.8, 2.0Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ¹ -methyloxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 390 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.32-1.97 (6H, m), 2.42-2.51 (1H, m), 2.76 (3H, s), 2.91 (3H, s), 2.93 (3H, s) , 3.27(3H, s), 3.00-4.80(8H, m), 7.45(1H, br.s), 7.88-7.97(1H, m), 8.25-8.41(2H, m), 8.78-8.91(1H, m).

MS (FAB) m/z: 562 (M+H) ⁺ .

[Example 276] N ¹ -(5-chloropyrimidin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 191, the compound obtained in Reference Example 391 was hydrolyzed, condensed with the compound obtained in Reference Example 253, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-2.10 (7H, m), 2.77 (3H, s), 2.90 (3H, s), 2.93 (3H, s), 3.04-4.80 (8H, m) , 8.60-8.70 (2H, m), 8.82 (2H, s), 9.08 (1H, br.s), 10.64 (1H, s), 11.57 (1H, br.s).

MS (FAB) m/z: 549 (M+H) ⁺ .

[Example 277] N ¹ -(4-chlorophenyl)-N ² -((1S, 2R, 4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[(5- Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound obtained in Reference Example 392 was reduced in the same manner as described in Reference Example 253, condensed with the carboxylic acid obtained by hydrolyzing the compound obtained in Reference Example 242 in the same manner as described in Example 195, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 0.96, 1.02 (3H, each t, J=7.0Hz), 1.47-1.58 (1H, m), 1.65-1.77 (3H, m), 1.98-2.08 ( 2H, m), 2.76-2.91 (4H, m), 3.07 (3H, s), 3.19-3.41 (2H, m), 3.98-4.04 (1H, m), 4.42 (1H, br.s), 4.46- 4.94(4H, m), 7.41(2H, d, J=8.8Hz), 7.83(2H, d, J=8.8Hz), 8.74-8.80(1H, m), 9.02(1H, d, J=7.3Hz ), 10.82(1H, s), 12.41(1H, br.s).

MS (FAB) m/z: 547 (M+H) ⁺ .

[Example 278] N ¹ -(5-bromopyridin-2-yl)-N ² -((1S, 2R, 4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[ (5-Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 392 and the compound obtained in Reference Example 262 in the same manner as described in Example 277.

¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.08 (3H, m), 1.40-2.13 (6H, m), 2.70-3.53 (13H, m), 3.92-4.08 (1H, m), 4.35- 4.47(1H, m), 7.95(1H, d, J=8.8Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-{[ethyl(methyl)amino]carbonyl}-2-{[ (5-Methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was prepared from the compound obtained in Reference Example 392 and the compound obtained in Reference Example 243 in the same manner as described in Example 277.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(4-chloro-3-methoxyphenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 395 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46-1.54 (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] N ¹ -(4-chlorophenyl)-N ² -((1R ^* , 2R ^* )-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)oxalamide hydrochloride

In the same manner as in Example 195, the compound obtained in Reference Example 242 was hydrolyzed, condensed with the compound obtained in Reference Example 62, and treated with hydrochloric acid to obtain the title compound.

₁ H-NMR (DMSO-d ₆ ) δ: 1.65-1.73 (4H, m), 1.91-1.96 (2H, m), 2.91 (3H, s), 3.15 (2H, br.s), 3.49 (1H, br.s), 3.66(1H, br.s), 4.32-4.42(3H, m), 4.66(1H, br.s), 7.40(2H, d, J=8.9Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1R ^* , 2R ^* )-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclopentyl)oxalamide hydrochloride

In the same manner as described in Example 208, the compound obtained in Reference Example 62 and the compound obtained in Reference Example 266 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.71 (4H, br.s), 1.96 (2H, br.s), 2.90 (3H, s), 3.14 (1H, br.s), 3.21 (1H, br.s), 3.47(1H, br.s), 3.68(1H, br.s), 4.34-4.45(3H, m), 4.66(1H, br.s), 7.99-8.06(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] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole And[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(4-ethynylphenyl)oxalamide

The title compound was prepared by condensing the compound obtained in Reference Example 252 and the compound obtained in Reference Example 397 in the same manner as in Example 263.

¹ H-NMR (CDCl ₃ ) δ: 1.67-2.16 (6H, m), 2.51 (3H, s), 2.76-2.91 (5H, m), 2.94 (3H, s), 3.04 (3H, s), 3.07 (1H, s), [3.65 (1H, d, J = 15.5Hz), 3.73 (1H, d, J = 15.5Hz) AB type], 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] N ¹ -(5-chloropyrazin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as described in Reference Example 97, the compound obtained in Reference Example 253 was condensed with the compound obtained in Reference Example 399, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMgO-d ₆ ) 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] N ¹ -(4-chloro-3-nitrophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as described in Reference Example 97, the compound obtained in Reference Example 253 and the compound obtained in Reference Example 400 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(4-chloro-2-nitrophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[( 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in Reference Example 253 and the compound obtained in Reference Example 401 in the same manner as described in Example 208, and then treating with hydrochloric acid.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(3-amino-4-chlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound obtained in Example 285 (236 mg) was dissolved in ethanol (25 ml), a catalytic amount of Raney nickel was added, and the mixture was stirred at room temperature for 17 hours in a hydrogen atmosphere. Then, an additional catalytic amount of Raney nickel was added and stirred for another 7 hours. The catalyst was filtered off, and the solvent was distilled off 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 dichloromethane, and 1N hydrochloric acid ethanol solution (360 µl) was added. The solvent was distilled off under reduced pressure, a small amount of methanol was added to the residue, and diethyl ether was added dropwise while irradiating ultrasonic waves. The resulting precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (95 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.53 (1H, m), 1.66-1.73 (3H, m), 1.97-2.10 (2H, m), 2.78 (3H, s), 2.91-2.94 ( 7H, br.s), 3.11-3.19 (1H, m), 3.29 (1H, br.s), 3.48 (1H, br.s), 3.69 (1H, br.s), 3.95-4.02 (1H, m ), 4.44 (2H, br.s), 4.68, 4.72 (1H, each br.s), 4.86 (2.5H, br.s), 6.98 (1H, dd, J=8.5, 1.9Hz), 7.14 ( 1H, d, J = 8.5Hz), 7.35, 7.38 (1H, each br.s), 8.72-8.77 (1H, m), [8.91 (d, J = 7.8Hz), 8.99 (d, J = 8.5 Hz), 1H], 10.45, 10.47 (1H, each br.s), 11.74 (1H, br.s).

MS (FAB) m/z: 562 (M+H) ⁺ .

[Example 288] N ¹ -(2-amino-4-chlorophenyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5 -Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was prepared from the compound obtained in Example 286 in the same manner as described in Example 287.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.77 (4H, m), 2.06-2.09 (2H, m), 2.78 (3H, s), 2.92 (7H, br.s), 3.12-3.19 ( 1H, m), 3.26-3.28 (1H, m), 3.48 (1H, br.s), 3.70 (1H, br.s), 4.00-4.44 (5.7H, m), 4.70, 4.74 (1H, each br.s), 6.63-6.66(1H, m), 6.85(1H, br.s), 7.18-7.21(1H, m), 8.77-8.81(1H, m), [8.97(d, J=7.8Hz ), 9.06(d, J=8.1Hz), 1H], 9.98(1H, s), 11.60(1H, br.s).

MS (FAB) m/z: 562 (M+H) ⁺ .

[Example 289] N ¹ -(6-chloro-4-methylpyridin-3-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2- {[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 199, the compound obtained in Reference Example 270 and the compound obtained in Reference Example 402 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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-[(dimethyl Amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

Add 10% palladium carbon (200 mg) to the tetrahydrofuran (10 ml) solution of the compound (700 mg) obtained in Reference Example 252, stir at room temperature for 2 days in a hydrogen atmosphere of 1 pressure, and then filter. - To a solution of dimethylformamide (5.0 ml) was added the compound (470 mg) obtained in Reference Example 405, and stirred at 95° C. for 18 hours. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution (50ml), water (50ml) and dichloromethane (30ml) were added, and the aqueous layer was extracted with dichloromethane (2×20ml) after separation. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column chromatography (dichloromethane:methanol=12:1), and treated with 1N hydrochloric acid to obtain the title compound (100 mg).

¹ H-NMR (DMSO-d ₆ ) 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]ring Hexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The reaction conditions of the reaction described in Example 290 were changed to 40°C and stirred for 3 days to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.50 (1H, m), 1.50-1.80 (3H, m), 1.80-1.97 (2H, m), 2.76 (3H, s), 2.80-3.05 ( 2H, m), 2.91 (6H, s), 3.05-3.30 (2H, m), 3.47 (2H, br.s), 4.30-4.50 (2H, m), 4.72 (1H, t, J=12.8Hz) , 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(4, 5,6,7-Tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in Reference Example 34 and the compound obtained in Reference Example 420 in the same manner as described in Example 17, and then treating with hydrochloric acid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.55 (1H, m), 1.60-1.80 (3H, m), 1.95-2.10 (2H, m), 2.78 (3H, s), 2.85-3.00 ( 4H, m), 3.11 (2H, br s), 3.40-3.55 (2H, m), 3.95-4.07 (1H, m), 4.37-4.45 (1H, m), 4.48 (2H, br s), 8.00- 8.01(2H, m), 8.10(1H, d, J=7.1Hz), 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]piper Pyridin-3-yl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as in Example 150, the compound obtained in Example 118 was condensed with 1-hydroxy-1-cyclopropanecarboxylic acid, followed by treatment with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 0.60-0.90 (3H, br), 0.92-1.03 (1H, m), 1.71-1.84 (1H, m), 1.85-2.03 (1H, m), 2.91 ( 3H, s), 3.00-3.80 (7H, m), 4.05-4.80 (5H, m), 6.28-6.42 (1H, br), 7.09 (1H, s), 7.18 (1H, dd, J = 8.8, 1.5 Hz), 7.42 (1H, d, J = 8.8Hz), 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

In the same manner as in Example 150, the compound obtained in Example 118 and the compound obtained in Reference Example 409 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 0.65-1.05 (4H, m), 1.74-1.88 (1H, m), 1.92-2.10 (1H, m), 2.91 (3H, s), 3.00-3.80 ( 10H, m), 4.05-4.83 (6H, m), 7.08 (1H, s), 7.18 (1H, dd, J=8.6, 2.0Hz), 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-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)-3-isoquinolinecarboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 410 was treated with 4N hydrochloric acid dioxane solution for deprotection, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.80 (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] N ¹ -(4-chloro-3-fluorophenyl)-N ² -((3R,4S)-1-(2-methoxyacetyl)-3-{[(5-methyl Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide hydrochloride

In the same manner as in Example 219, the compound obtained in Reference Example 411 was treated with 4N hydrochloric acid dioxane solution for deprotection, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.72 (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] N ¹ -(5-chloro-2-ethynyl)-N ² -((3R, 4S)-1-(2-methoxyacetyl)-3-{[(5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 412 was treated with 4N hydrochloric acid dioxane solution for deprotection, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.73 (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

In the same manner as described in Example 223, the compound obtained in Reference Example 252 was reduced, condensed with p-chlorophenoxyacetic acid, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 compound obtained in Reference Example 413 was hydrolyzed, and the obtained lithium salt of carboxylic acid was condensed with the deprotected compound obtained by acid treatment of the compound obtained in Reference Example 146, followed by treatment with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.11 (2H, m), 1.45-1.60 (1H, m), 1.65-1.85 (1H, m), 1.95-2.06 (1H, m), 2.10- 2.24(1H, m), 2.78(3H, s), 2.87-3.02(1H, m), 2.94(3H, s), 3.88(3H, s), 4.16-4.27(1H, m), 4.45-4.56( 1H, m), 7.03(1H, s), 7.55(1H, s), 7.87(1H, 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-chromene-2-yl)carbonyl]amino}-5-[(dimethyl Amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 417 was treated with 4N hydrochloric acid dioxane solution, the obtained compound was condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.53 (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-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)-3-cinnolinecarboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 418 was treated with 4N hydrochloric acid dioxane solution, the obtained compound was condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.80 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The compound obtained in Reference Example 421 was deprotected with hydrochloric acid, methylated in the same manner as described in Example 18, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.58 (1H, m), 1.59-1.80 (3H, m), 1.83-1.95 (1H, m), 1.97-2.10 (1H, m), 2.78 ( 3H, s), 2.89 (3H, s), 2.96 (3H, s), 3.00-3.10 (1H, m), 3.10-3.20 (2H, m), 3.45-3.80 (1H, m), 3.90-4.00 ( 2H, m), 4.00-4.50 (3H, m), 7.77 (1H, s), 7.95-8.05 (3H, m), 8.44 (1H, t, J=1.6Hz), 8.90 (1H, d, J= 8.6Hz), 10.25(1H, s), 11.12(1H, br s).

MS (ESI) m/z: 547 (M+H) ⁺ .

[Example 303] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was obtained by condensing the compound obtained in Reference Example 148 and the compound obtained in Reference Example 420 in the same manner as described in Example 2, and then treating with hydrochloric acid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.40 (6H, m), 1.38-1.58 (1H, m), 1.59-1.82 (3H, m), 1.95-2.13 (2H, m), 2.40- 2.65(1H, m), 2.49(3H, s), 2.87-3.55(4H, m), 2.49(3H, s), 3.60-3.82(2H, m), 3.93-4.04(1H, m), 4.37- 4.55(2H, m), 4.55-4.72(1H, m), 7.94-8.10(2H, m), 8.43(1H, s), 8.64-8.77(1H, m), 9.12(1/2H, d, J =7.8Hz), 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

In the same manner as described in Example 219, the compound obtained in Reference Example 424 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.60 (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 305] 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 hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 427 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.57 (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

In the same manner as described in Example 219, the compound obtained in Reference Example 428 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 293 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.58 (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

In the same manner as described in Example 219, the compound obtained in Reference Example 428 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 293 in an argon atmosphere, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.58 (1H, m), 1.65-1.87 (3H, m), 1.97-2.10 (1H, m), 2.17-2.30 (1H, m), 2.80 ( 3H, s), 2.96(3H, s), 2.98-3.10(1H, m), 3.07(3H, s), 4.30-5.00(6H, m), 8.00-8.10(1H, m), 8.46(1H, d, J=2.4Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-({[6- (Dimethylamino)-4,5,6,7-tetrahydrobenzothiazol-2-yl]carbonyl}amino)cyclohexyl]oxalamide

The compound obtained in Reference Example 431 was deprotected by treatment with hydrochloric acid, methylated in the same manner as described in Example 18, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.58 (1H, m), 1.59-1.80 (3H, m), 1.90-2.12 (3H, m), 2.30-2.45 (1H, m), 2.70- 3.00(11H, m), 2.92(3H, s), 3.00-3.20(2H, m), 3.25-3.45(1H, m), 3.63-3.80(1H, m), 3.88-4.02(1H, m), 4.35-4.47(1H, m), 8.02(1H, s), 8.42-8.55(1H, m), 8.60-8.68(1H, m), 8.93(1H, dd, J=14.5, 8.2Hz), 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 (10 ml) solution of the compound (328.0 mg) obtained in Reference Example 253 was added 4-chlorophenylsulfonyl isocyanate (148 µl), followed by stirring at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin-layer column chromatography (dichloromethane:methanol=9:1). The obtained product was dissolved in ethanol (2 ml) and dichloromethane (2 ml), 1N hydrochloric acid ethanol solution (0.25 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was solidified with ether to obtain the title compound (104.3 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.25-1.45 (1H, m), 1.45-1.80 (5H, m), 2.76 (3H, s), 2.94 (3H, s), 2.97 (3H, s) , 3.00-3.80(6H, m), 4.35-4.85(3H, m), 6.53(1H, brs), 7.66(2H, d, J=8.5Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

The title compound was prepared from the compound obtained in Reference Example 435 and the compound obtained in Reference Example 10 in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H, s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95(3H, s), 3.06(3H, s), 3.69(1H, d, J=15.4Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide p-toluenesulfonate monohydrate

6.2 g of the compound obtained in Example 310 was dissolved in dichloromethane (120 ml), 1 mol/L p-toluenesulfonic acid-ethanol solution (11.28 ml) was added, and the solvent was distilled off. 15% aqueous ethanol (95 ml) was added to the residue, followed by stirring and dissolving at 60°C. Then, it was cooled to room temperature and stirred for 1 day. The precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure at room temperature for 2 hours to obtain the title compound (7.4 g).

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.54 (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: C ₂₄ H ₃₀ ClN ₇ O ₄ S C ₇ H ₈ O ₃ S H ₂ O

Theoretical value: C; 50.43, H; 5.46, N; 13.28, Cl; 4.80, S; 8.69

Found: C; 50.25, H; 5.36, N; 13.32, Cl; 4.93, S; 8.79

mp (decomposition): 245～248℃

[Example 312] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 437 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.48-1.61 (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) ⁺ , Cl ³⁵ ], 535 [(M+H) ⁺ , Cl ³⁷ ].

[Example 313] N ¹ -(5-chloropyridin-2-yl)-N ² -((3R,4S)-1-(2-methoxyacetyl)-3-{[4-(pyridine- 4-yl)benzoyl]amino}piperidin-4-yl)oxalamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 368 was deprotected with 4N hydrochloric acid dioxane solution, condensed with the compound obtained in Reference Example 237, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.62-1.75 (1H, m), 2.00-2.20 (1H, m), 2.80-4.40 (11H, m), 7.90-8.00 (4H, m), 8.05- 8.13(2H, m), 8.14-8.43(3H, m), 8.40-8.45(1H, m), 8.87-9.04(3H, m), 10.20-10.50(2H, br).

MS(FAB) m/z 551[(M+H) ⁺ , Cl ³⁴ ], 553[(M+H) ⁺ , Cl ³⁷ ].

[Example 314] N-{(1R, 2S, 5S)-5-[(dimethylamino)carbonyl]-2-({24(5-methylpyridin-2-yl)amino]-2-oxo Thioacetyl}amino)cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 440 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.60 (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 = 7.3 Hz), 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

In the same manner as described in Example 219, the compound obtained in Reference Example 441 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.71-1.82 (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) ⁺ , Cl ³⁵ ], 567 [(M+H) ⁺ , Cl ³⁷ ].

[Example 316] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)thioformyl]-2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as described in Example 3, the compound obtained in Reference Example 445 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.66-2.15 (6H, m), 2.93 (3H, s), 3.15-3.40 (9H, m), 3.49 (1H, br.s), 3.71 (1H, br.s), 3.97-4.01(1H, m), 4.42(2H, br.s), 4.70(1H, br.s), 8.01(2H, br.s), 8.46(1H, br.s), 8.78(1H, d, J=6.8Hz), 9.24(1H, br.s), 10.28(1H, s), 11.29(1H, br.s).

MS(FAB) m/z: 564[(M+H) ⁺ , Cl ³⁵ ], 566[(M+H) ⁺ , Cl ³⁷ ].

[Example 317] N ¹ -(5-chloropyridin-2-yl)-N ² -((3R, 4S)-1-(2-methoxythioacetyl)-3-{[(5- Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}piperidin-4-yl)oxalamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 448 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.74-1.85 (1H, m), 2.13-2.35 (1H, m), 2.89 (3H, s), 2.95-3.98 (9H, m), 4.05-5.33 ( 8H, m), 7.95-8.06 (2H, m), 8.43 (1H, s), 8.48-8.73 (1H, br), 9.29-9.45 (1H, br), 10.21-10.34 (1H, br), 11.45- 11.90(1H,br).

MS (ESI) m/z: 566 [(M+H) ⁺ , Cl ³⁵ ], 568 [(M+H) ⁺ , Cl ³⁷ ].

[Example 318] (1S, 3R, 4S)-4-({24(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-3-{[(5-methyl -2,2,2-trichloroethyl 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

In the same manner as described in Example 219, the compound obtained in Reference Example 453 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.87 (2H, m), 2.04-2.15 (2H, m), 2.21-2.32 (2H, m), 2.52 (3H, s), 2.73-2.89 (3H, m), 2.92-2.98(2H, m), 3.71(1H, d, J=15.4Hz), 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×Cl ³⁵ ], 653 [(M+H) ⁺ , 2×Cl ³⁵ , Cl ³⁷ ], 655 [(M+H) ⁺ , Cl ³⁵ , 2×Cl ³⁶⁷ ].

[Example 319] (1S, 3R, 4S)-4-({2-(5-chloropyridin-2-yl)amino]-2-oxoacetyl}amino)-3-{[(5-methyl Base-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic acid

The compound obtained in Example 318 (475 mg) was dissolved in tetrahydrofuran (50 ml), and zinc (2.85 g) and acetic acid (5.7 ml) were successively added to the solution, followed by stirring at room temperature for 3 hours. Diatomaceous earth 545 (2.85 g) was added to the reaction solution to filter off the insoluble matter, and after concentrating the filtrate under reduced pressure, dichloromethane was added to the obtained residue, and a 1N aqueous sodium hydroxide solution was added while stirring to adjust the liquidity to pH7. After separating the organic layer, saturated brine (50 ml) was added to the aqueous layer, followed by extraction with dichloromethane (10×50 ml). The obtained organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=95:5→9:1→4:1) to obtain the title compound (140 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.80 (3H, m), 1.84-1.95 (1H, m), 1.95-2.10 (1H, m), 2.15-2.30 (1H, m), 2.38 ( 3H, s), 2.40-2.50 (1H, m), 2.67-2.80 (2H, m), 2.80-2.95 (2H, m), 3.66 (2H, m), 4.03 (1H, br.s), 4.33 ( 1H, br.s), 7.97-8.10(2H, m), 8.45(1H, s), 8.53(1H, d, J=6.8Hz), 9.19(1H, d, J=8.3Hz), 10.27(1H , br.s).

MS(FAB) m/z: 521[(M+H) ⁺ , ³⁵ Cl], 523[(M+H) ⁺ , ³⁷ Cl].

[Example 320] N-{(1R, 2S, 5S)-2-{[2-(4-chloroanilino)-1-methoxyimino-2-oxoethyl]amino}-5- [(Dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

The ester of the compound obtained in Reference Example 454 was hydrolyzed in the same manner as in Reference Example 142, condensed with 4-chloroaniline in the same manner as in Reference Example 143, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.30-1.17 (1H, m), 1.50-1.62 (1H, m), 1.62-1.75 (2H, m), 1.85-2.00 (2H, m), 2.76 ( 3H, s), 2.93 (6H, br.s), 3.00-3.10 (1H, m), 3.18 (1H, br.s), 3.27 (1H, br.s), 3.49 (1H, br.s), 3.71(1H, br.s), 3.76(3H, s), 3.93(1H, br.s), 4.35-4.50(2H, m), 4.66-4.77(1H, m), 6.09(0.5H, d, J=7.8Hz), 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) ⁺ , ³⁵ Cl], 578[(M+H) ⁺ , ³⁷ Cl].

[Example 321] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-({[1- (Pyridin-4-yl)piperidin-4-yl]carbonyl}amino)cyclohexyl]oxalamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 420 was condensed with 1-(pyridin-4-yl)piperidine-4-carboxylic acid (WO 96/10022) and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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) ⁺ , ³⁵ Cl], 558[(M+H) ⁺ , ³⁷ Cl].

[Example 322] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(5-ethynylpyridin-2-yl)oxalamide

The compound obtained in Reference Example 455 (348 mg) was dissolved in tetrahydrofuran (14 ml), tetrabutylammonium fluoride (1N solution in tetrahydrofuran, 628 µl) was added, and stirred at room temperature for 30 minutes. Activated carbon (about 1 g) was added to the reaction solution for decolorization, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=93:7). The residue was dissolved in dichloromethane (about 1 ml), hexane (about 10 ml) was added, and the resulting precipitate was collected by filtration to obtain the title compound (116 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.62-2.14 (8H, m), 2.52 (3H, s), 2.79-2.95 (6H, m), 3.05 (3H, s), 3.19 (1H, s), [ Type AB 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)carbonyl]amino}cyclohexyl)oxalamide

In the same manner as described in Example 191, the compound obtained in Reference Example 456 was hydrolyzed, and then condensed with the compound obtained in Reference Example 420 to prepare the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.80-2.15 (6H, m), 2.64 (3H, s), 2.76-2.79 (1H, m), 2.94 (3H, s), 3.03 (3H, s), 3.84 -3.86(2H, m), 3.94-3.99(3H, m), 4.58-4.59(1H, m), 6.70(1H, d, J=6.3Hz), 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) ⁺ , Cl ³⁵ ], 535[(M+H) ⁺ , Cl ³⁷ ].

[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

In the same manner as described in Example 3, the compound obtained in Reference Example 460 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.48-1.51 (1H, m), 1.71-1.79 (3H, m), 2.00 (1H, br.s), 2.20-2.23 (1H, m), 2.78 ( 3H, s), 2.90 (3H, s), 2.96 (3H, s), 3.05 (1H, br.s), 3.16-3.47 (3H, m), 3.69 (1H, br.s), 4.43 (1H, br.s), 4.53(1H, br.s), 4.69(2H, br.s), 7.97(1H, d, J=9.6Hz), 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) ⁺ , Cl ³⁵ ], 567[(M+H) ⁺ , Cl ³⁷ ].

[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 Reference Example 464 and the compound obtained in Reference Example 10 with hydrochloric acid in the same manner as described in Example 3.

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.55 (1H, m), 1.66-1.78 (3H, m), 2.02-2.05 (1H, m), 2.21-2.33 (1H, m), 2.79 ( 3H, s), 2.91(3H, s), 2.95(3H, s), 2.99-3.04(1H, m), 3.21(2H, br.s), 3.45-3.75(2H, br), 4.40-4.75( 4H, m), 7.53 (1H, d, J = 8.6Hz), 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) ⁺ , Cl ³⁵ ], 566[(M+H) ⁺ , Cl ³⁷ ].

[Example 326] N ¹ -[(3R, 4S)-3-({[2'-(aminosulfonyl)[1,1'-biphenyl]-4-yl]carbonyl}amino) ^-1- ( 2-Methoxyacetyl)piperidin-4-yl]-N ² -(5-chloropyridin-2-yl)oxalamide

Using the same method as in Example 219, the compound obtained in Reference Example 368 was treated with hydrochloric acid for deprotection, and then condensed with the compound obtained in Reference Example 465 to prepare the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.59-1.85 (1H, m), 2.09-2.23 (1H, m), 2.88-3.13 (1H, m), 3.29-3.51 (4H, m), 4.06-4.20 ( 4H, m), 4.51-4.78 (4H, m), 7.09 (0.25H, br.s), 7.30 (1H, d, J=7.1Hz), 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) ⁺ , Cl ³⁵ ], 631 [(M+H) ⁺ , Cl ³⁷ ]

[Example 327] N ¹ -(5-chloropyridin-2-yl)-N ² -{(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-[(thieno[ 3,2-b]pyridin-2-ylcarbonyl)amino]cyclohexyl}oxalamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 420 was condensed with lithium salt of thieno[3,2-b]pyridine-2-carboxylate (Japanese Patent Laid-Open No. 2001-294572), and treated with hydrochloric acid. , to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.44-1.57 (1H, m), 1.62-1.84 (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) ⁺ , Cl ³⁵ ], 531 [(M+H) ⁺ , Cl ³⁷ ].

[Example 328] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(5-methylpyridin-2-yl)oxalamide hydrochloride

In the same manner as described in Example 208, the compound obtained in Reference Example 467 and the compound obtained in Reference Example 253 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.57 (1H, m), 1.60-1.80 (3H, m), 1.95-2.15 (2H, m), 2.28 (3H, s), 2.78 (3H, s), 2.90-3.10(1H, m), 2.92(3H, s), 2.94(3H, s), 3.07-3.38(2H, m), 3.40-3.58(1H, br), 3.60-3.80(1H, m), 3.95-4.05(1H, m), 4.36-4.50(2H, m), 4.66-4.80(1H, m), 7.73(1H, d, J=8.0Hz), 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] N ¹ -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)-N ² -(4-methylphenyl)oxalamide hydrochloride

In the same manner as described in Example 219, the compound obtained in Reference Example 469 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.55 (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)carbamate tert-butyl

In the same manner as in Example 2, the compound obtained in Reference Example 471 and the compound obtained in Reference Example 420 were condensed to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.50-1.70 (1H, m), 1.80-2.00 (2H, m), 2.00-2.12 (2H, m), 2.14-2.22 (1H, m), 2.72-2.83 (1H, m), 2.88, 2.89 (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=7.6Hz), 8.17(1H, d, J=8.8Hz), 8.31(1H, d, J=2.6Hz), 9.70(1H, br.s).

MS (ESI) m/z: 655 (M+H) ⁺ .

[Example 331] N ¹ -{(1S, 2R, 4S)-2-[({3-chloro-4-[(methylamino)methyl]-2-thienyl}carbonyl)amino]-4- [(Dimethylamino)carbonyl]cyclohexyl}-N ² -(5-chloropyridin-2-yl)oxalamide

The title compound was prepared from the compound obtained in Example 330 in the same manner as in Example 227.

¹ H-NMR (CDCl ₃ ) δ: 1.55-1.70 (1H, m), 1.75-1.98 (2H, m), 2.00-2.22 (2H, m), 2.22-2.32 (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] N ¹ -{(1S, 2R, 4S)-2-{[(3-chloro-4-{[4,5-dihydro-1,3-oxazol-2-yl (methyl )amino]methyl}-2-thienyl)carbonyl]amino}-4-[(dimethylamino)carbonyl]cyclohexyl}-N ² -(5-chloropyridin-2-yl)oxalamide hydrochloride Salt

Triethylamine (0.735 ml) and 2-bromoethyl isocyanate (0.106 ml) were added to a dichloromethane (20 ml) suspension of the compound (590 mg) obtained in Example 331, and stirred at room temperature for 18 hours. The reaction solution was diluted with dichloromethane, and washed successively with water, 0.5N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=20:1), and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in dichloromethane (2ml) and ethanol (3ml), 1N hydrochloric acid ethanol solution (0.5ml) was added, stirred at room temperature for 30 minutes, and then concentrated 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 (197 mg) as a colorless powder.

¹ H-NMR (DMSO-d ₆ ) 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(methyl)carbamate tert-butyl

In the same manner as described in Example 214, the compound obtained in Reference Example 472 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 471 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.15-2.00 (6H, m), 1.46 (9H, s), 2.87 (3H, s), 4.15-4.25 (1H, m), 4.30-4.45 (2H, m) , 4.48-4.56(1H, m), 7.20(1H, d, J=8.1Hz), 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] N ¹ -{(1S, 2R)-2-[({3-chloro-4-[(methylamino)methyl]-2-thienyl}carbonyl)amino]cyclohexyl}-N ^2- (5-Chloropyridin-2-yl)oxalamide

The title compound was prepared from the compound obtained in Example 333 in the same manner as in Example 227.

¹ H-NMR (CDCl ₃ ) δ: 1.48-2.02 (8H, m), 2.46 (3H, s), 3.72 (2H, s), 4.15-4.25 (1H, m), 4.45-4.55 (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] N ¹ -((1S, 2R)-2-{[(3-chloro-4-{[4,5-dihydro-1,3-oxazol-2-yl(methyl)amino ]methyl}-2-thienyl}carbonyl]amino}cyclohexyl)-N ² -(5-chloropyridin-2-yl)oxalamide

The title compound was obtained from the compound obtained in Example 334 in the same manner as in Example 332.

¹ H-NMR (CDCl ₃ ) 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1R, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5- Methyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 477 was condensed with the compound obtained in Reference Example 420, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-1.58 (1H, m), 1.60-1.84 (3H, m), 1.85-2.15 (4H, m), 2.79 (6H, br.s), 2.93 ( 4H, br.s), 3.05-3.25(2H, m), 3.49(1H, br.s), 3.63(1H, br.s), 3.95-4.05(1H, m), 4.42(1H, br.s ), 4.64(1H, br.s), 4.78(1H, br.s), 8.01(2H, br.s), 8.46(1H, br.s), 8.65(1H, d, J=7.3Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(4, 4,5-Trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

Using the same method as in Reference Example 10, 4,4,5-trimethyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazole-2-carboxylate was prepared from the compound obtained in Reference Example 479 lithium salt. Then, the lithium salt was condensed with the compound obtained in Reference Example 420 in the same manner as described in Example 2, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 Reference Example 481 and the compound obtained in Reference Example 420 in the same manner as described in Example 2.

¹ H-NMR (CDCl ₃ ) 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] N ¹ -(5-chloro-2-pyridyl)-N ² -{(1S, 2R, 4S)-2-[(2,3-dihydro-1H-pyrrolo[3,4 -c]pyridin-6-ylcarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexyl}oxalamide hydrochloride

The title compound was prepared from the compound obtained in Example 338 in the same manner as in Example 227.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.61 (1H, m), 1.62-1.84 (3H, m), 1.95-2.10 (2H, m), 2.78 (3H, s), 2.79-2.90 ( 1H, m), 2.90 (3H, s), 3.90-4.15 (1H, m), 4.45-4.53 (1H, br), 4.55-4.68 (4H, m), 8.00 (2H, br.s), 8.10 ( 1H, s), 8.45 (1H, d, J = 1.5Hz), 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] N ¹ -(5-chloro-2-pyridyl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(2- Methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was prepared from the compound obtained in Example 339 and formalin in the same manner as in Example 18.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.59 (1H, m), 1.60-1.85 (3H, m), 1.91-2.10 (2H, m), 2.78 (3H, br.s), 2.80- 2.90(1H, m), 2.90(1.5H, s), 2.92(1.5H, s), 3.01(1.5H, s), 3.02(1.5H, s), 3.90-4.05(1H, m), 4.42- 4.60(3H, m), 4.80-5.00(2H, m), 8.00(2H, br.s), 8.11(1H, s), 8.44(1H, d, J=1.5Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -{(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-[(5,6 , 7,8-tetrahydro[1,6]naphthyridin-2-ylcarbonyl)amino]cyclohexyl}oxalamide hydrochloride

Same as Example 2, methyl 6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro[1,6]naphthyridine-2-carboxylate (Japanese Patent Laid-Open No. 2000-119253) Hydrolysis was carried out, the obtained lithium salt of carboxylic acid was condensed with the compound obtained in Reference Example 420, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.62 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(6- Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

The title compound was prepared from the compound obtained in Example 341 and formalin in the same manner as in Example 18.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.62 (1H, m), 1.63-1.80 (3H, m), 1.86-2.06 (2H, m), 2.80 (3H, br.s), 2.81- 2.96(7H, m), 3.14-3.27(1H, m), 3.11-3.63(2H, m), 3.76(1H, br.s), 3.99(1H, br.s), 4.35-4.52(2H, m ), 4.53-4.65 (1H, m), 7.84 (1H, J=8.0Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-({[5- (Pyridin-4-yl)pyrimidin-2-yl]carbonyl}amino)cyclohexyl]oxalamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 420 and the compound obtained in Reference Example 483 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.63 (1H, m), 1.67-1.85 (3H, m), 1.95-2.12 (2H, m), 2.80 (3H, s), 2.86-2.95 ( 1H, m), 2.95(3H, s), 4.00-4.10(1H, m), 4.45-4.55(1H, m), 8.01(2H, br.s), 8.34(2H, d, J=5.6Hz) , 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] N ¹ -(5-chloropyridin-2-yl)-N ² -{(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-[({2'-[(Dimethylamino)methyl][1,1'-biphenyl]-4-yl}carbonyl)amino]cyclohexyl}oxalamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 420 and the compound obtained in Reference Example 488 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.56 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-({4-[ 2-(Hydroxymethyl)pyridin-4-yl]benzoyl}amino)cyclohexyl]oxalamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 490 was hydrolyzed, the obtained lithium salt of carboxylic acid was condensed with the compound obtained in Reference Example 420, and treated with hydrochloric acid to prepare the title compound.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -{(1S, 2R, 4S)-2-({4-[2-(aminomethyl)pyridin-4-yl]benzoyl}amino)-4-[(dimethyl Amino)carbonyl]cyclohexyl}-N ² -(5-chloropyridin-2-yl)oxalamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 491 was hydrolyzed, the resulting lithium salt of carboxylic acid was condensed with the compound obtained in Reference Example 420, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.58 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]- ² -({[ ¹ - (Phenylsulfonyl)piperidin-4-yl]carbonyl}amino)cyclohexyl]oxalamide

The title compound was prepared by condensing the compound obtained in Reference Example 420 and the compound obtained in Reference Example 493 in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ ) 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-({[1- (4-Fluorobenzoyl)piperidin-4-yl]carbonyl}amino)cyclohexyl]oxalamide D22-5792

The title compound was prepared by condensing the compound obtained in Reference Example 420 and the compound obtained in Reference Example 495 in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ ) δ: 1.60-2.16 (10H, m), 2.37-2.48 (1H, m), 2.64-2.78 (1H, m), 2.80-3.13 (2H, m), 2.94 (3H, s), 3.02(3H, s), 3.65-4.18(1H, br), 3.93-4.01(1H, m), 4.43-4.80(2H, br), 6.32(1H, br.d, J=7.1Hz) , 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[4-( Pyrrolidin-1-ylcarbonyl)benzoyl]amino}cyclohexyl)oxalamide

The title compound was prepared by condensing the compound obtained in Reference Example 420 and the compound obtained in Reference Example 497 in the same manner as in Example 2.

¹ H-NMR (CDCl ₃ ) 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[4-( Pyrrolidin-1-ylmethyl)benzoyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 2, the compound described in Reference Example 498 was hydrolyzed, the resulting lithium salt of carboxylic acid was condensed with the compound obtained in Reference Example 420, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.57 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)thioformyl]-2-{[ (5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 501 was deprotected with 4N hydrochloric acid dioxane solution, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-2.18 (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

To a solution of 4-chloroaniline (255mg) in dichloromethane (15ml) was added chlorosulfonic acid (146ul) at 0°C. After stirring at the same temperature for 1 hour, it was stirred at room temperature for 2 hours. Phosphorus pentachloride (458 mg) was added to the reaction solution and heated under reflux for 2 hours. The temperature was returned to room temperature, the compound (731 mg) obtained in Reference Example 253 was added, and triethylamine was added to adjust the pH to neutral. After stirring at room temperature for 17 hours, a water solution was added to the reaction solution. The aqueous layer was extracted with dichloromethane, the combined organic layers were washed twice with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, first using silica gel as a carrier flash column chromatography (dichloromethane: methanol = 93: 7), and then using preparative thin-layer chromatography (dichloromethane: methanol = 9: 1) to refine 2 times, a light yellow solid (46 mg) was obtained. This solid was dissolved in dichloromethane, and 1N hydrochloric acid ethanol solution (83 µl) 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 (34 mg) as a light yellow solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.34-1.69 (5H, m), 1.98 (1H, br.s), 2.75 (3H, s), 2.85-2.94 (8H, m), 3.17 (2H, br.s), 3.50(1H, br.s), 3.69(1H, br.s), 4.39-4.50(2H, m), 4.69(1H, br.s), 7.08-7.15(4H, m), 7.74(1H, br.s), 7.98(1H, br.s), 9.90(1H, s), 11.35(1H, br.s).

MS (FAB) m/z: 555 (M+H) ⁺ .

[Example 353] N-{(1R, 2S, 5S)-2-({2-[(5-chloropyrimidin-2-yl)amino]-2-oxothioacetyl}amino)-5- [(Dimethylamino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

Using the same method as in Example 219, the compound obtained in Reference Example 503 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO) 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

Using the same method as in Example 219, the compound obtained in Reference Example 505 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO) 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

10% palladium carbon (1.00 g) was added to a solution of the compound obtained in Example 354 (458 mg) in ethanol (30 ml), and stirred at room temperature for 3 days. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol=94:6), the obtained yellow solid (137 mg) was dissolved in dichloromethane (5 ml), and 1N hydrochloric acid ethanol (474 μl) was added . Additional diethyl ether (20ml) was added and the solid was collected by filtration and washed with diethyl ether to give the title compound (144mg) as a yellow solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46-1.54 (1H, m), 1.70-1.78 (3H, m), 1.98-2.07 (1H, m), 2.21-2.23 (1H, m), 2.79 ( 3H, s), 2.91 (3H, s), 2.96 (3H, s), 3.03 (1H, br.s), 3.11-3.19 (1H, m), 3.30 (1H, br.s), 3.47 (1H, br.s), 3.69(1H, br.s), 4.10-4.51(4H, m), 4.68(2H, s), 6.95(1H, dd, J=8.6, 2.3Hz), 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

Using the same method as in Example 219, the compound obtained in Reference Example 428 was treated with hydrochloric acid for deprotection, and then condensed with the compound obtained in Reference Example 481 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.53 (9H, s), 1.56-2.42 (6H, m), 2.85-2.94, (1H, m), 2.98 (3H, s), 3.10 (3H, s), 4.45-4.52(1H, m), 4.70-4.85(5H, m), 7.67(1H, dd, J=8.8, 2.4Hz), 8.18(0.5H, br.s), 8.18(1H, d, J= 8.8Hz), 8.23(0.5H, br.s), 8.31(1H, d, J=2.4Hz), 8.40-8.52(2H, m), 10.29(1H, br.s), 10.60(1H, br.s) 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

After deprotecting the compound obtained in Example 356 with hydrochloric acid, it was methylated in the same manner as described in Example 18, and then treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.46-1.61 (1H, m), 1.62-1.95 (3H, m), 1.95-2.10 (1H, m), 2.10-2.30 (1H, m), 2.79 ( 3H, br.s), 2.84-2.94(4H, m), 2.95(3H, s), 4.45-4.60(3H, m), 4.75(1H, br.s), 4.80-5.00(2H, m), 7.97-8.13(2H, m), 8.16(1H, br.s), 8.46(1H, br.s), 8.76(2H, br.s), 10.51(0.5H, s), 10.55(0.5H, s ), 11.09 (1H, br.s), 11.92 (0.5H, 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

Similar to the method described in Example 219, after deprotecting the compound obtained in Reference Example 428 with hydrochloric acid, it was mixed with 1-(pyridin-4-yl)-4-piperidinecarboxylic acid (Tetrahedron, 1998, Volume 44, 7095) condensation followed by treatment with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.38-1.52 (1H, m), 1.52-1.73 (4H, m), 1.73-1.88 (3H, m), 1.88-2.02 (2H, m), 2.80 ( 3H, s), 3.04(3H, s), 3.10-3.40(4H, m), 4.14-4.36(3H, m), 4.48-4.57(1H, m), 7.18(2H, d, J=6.8Hz) , 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-chlorocinnoline-3-yl)thioformyl]amino}-5-[(dimethylamino)carbonyl] Cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

In the same manner as described in Example 2, the compound obtained in Reference Example 509 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.63 (1H, m), 1.72-1.78 (1H, m), 1.86-1.89 (2H, m), 2.10 (1H, br.s), 2.40- 2.46(1H, m), 2.81(3H, s), 2.91(3H, s), 2.97(3H, s), 3.04(1H, br.s), 3.15-3.20(1H, m), 3.27(1H, br.s), 3.49(1H, br.s), 3.69(1H, br.s), 4.43(1H, br.s), 4.67(1H, br.s), 4.81(1H, br.s), 4.95(1H, br.s), 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

In the same manner as described in Example 2, the compound obtained in Reference Example 511 and the compound obtained in Reference Example 10 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.45-1.50 (1H, m), 1.74-1.84 (4H, m), 1.87-1.95 (1H, m), 2.80 (3H, s), 2.92 (3H, s), 3.02(3H, s), 3.13-3.35(3H, m), 3.47(1H, br.s), 3.69(1H, br.s), 3.97(1H, br.s), 4.41-4.44( 1H, m), 4.62-4.72 (2H, m), 7.56 (2H, d, J=8.6Hz), 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

In the same manner as described in Example 219, the compound obtained in Reference Example 513 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.37-1.52 (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-[(dimethyl Amino)carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

Using the same method as in Example 49, the compound obtained in Reference Example 519 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 516, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.47-1.75 (4H, m), 1.97-2.20 (2H, m), 2.79 (3H, s), 2.92-2.96 (7H, m), 3.20 (2H, br.s), 3.50(1H, br.s), 3.67(1H, br.s), 4.03(1H, br.s), 4.47(2H, br.s), 4.66(1H, br.s), 6.88 (1H, d, J = 38.6Hz), 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

Using the same method as in Example 214, the compound obtained in Reference Example 521 was treated with 4N hydrochloric acid dioxane solution for deprotection, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.48-1.61 (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]azepine-2-carboxamide hydrochloride Salt

In the same manner as in Example 2, the compound obtained in Reference Example 522 and the compound obtained in Reference Example 477 were condensed and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.43-1.60 (1H, m), 1.61-1.90 (3H, m), 1.92-2.18 (3H, m), 2.18-2.35 (1H, m), 2.70- 2.88(6H, m), 2.96(3H, br.s), 2.96-3.00(1H, m), 3.05-3.27(2H, m), 3.40-3.52(1H, br), 3.60-3.80(1H, br ), 4.45-4.60 (1H, m), 4.60-4.75 (2H, m), 4.75-4.90 (1H, m), 7.87 (1H, dt, J=2.9, 9.0Hz), 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] (3-{[(1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydro Thiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}phenyl)(imino)methylcarbamate tert-butyl

To a solution of the compound (250 mg) obtained in Reference Example 524 in tetrahydrofuran (3.0 ml) were added water (1.0 ml) and lithium hydroxide (20.5 mg) at room temperature. After stirring for 15 hours, it was concentrated under reduced pressure. 1-Hydroxybenzotriazole (140 mg) and 1-[3-(dimethyl (amino)propyl]-3-ethylcarbodiimide hydrochloride (330mg). After stirring at the same temperature for 21 hours, the solvent was evaporated under reduced pressure, dichloromethane, water and saturated aqueous sodium bicarbonate solution were added to separate the layers, 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 the resulting residue was purified by medium-pressure column chromatography (dichloromethane:methanol=10:1) using silica gel as a carrier to obtain a light brown bubble The title compound (213 mg) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.40-2.32 (6H, m), 1.56 (9H, s), 2.52 (3H, s), 2.77-2.90 (3H, m), 2.90-3.05 (2H, m) , 2.96(3H, s), 3.11(3H, s), 3.70(1H, d, J=15.5Hz), 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]ring Hexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

To a solution of the compound obtained in Example 365 (210 mg) in dichloromethane (4.0 ml) was added 4N hydrochloric acid dioxane solution (4.0 ml) at room temperature. After stirring for 1 hour, saturated ethanolic hydrochloric acid solution (20 ml) was added. After stirring overnight, the solvent was evaporated under reduced pressure. Water (4.0 ml) was added to the obtained residue, and the solvent was evaporated under reduced pressure, followed by drying to obtain the title compound (210 mg) as a light brown solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.20-2.10 (6H, m), 2.78 (3H, s), 2.90-3.20 (1H, m), 2.91 (3H, s), 2.99 (3H, s) , 3.20-3.35(1H, m), 3.35-3.80(3H, m), 4.00-4.13(1H, m), 4.35-4.80(3H, m), 7.60-7.75(1H, m), 7.85-8.10( 2H, m), 8.10-8.25 (1H, m), 8.40-8.53 (1H, m), 8.53-8.70 (1H, m), 9.25-9.80 (4H, m), 11.91 (1H, br.s).

MS (ESI) m/z: 512 (M+H) ⁺ .

[Example 367] N-{(1R, 2S, 5S)-2-[(3-cyanobenzoyl)amino]-5-[(dimethylamino)carbonyl]cyclohexyl}-5-methyl -4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

In the same manner as described in Example 214, the compound obtained in Reference Example 525 was treated with 4N hydrochloric acid dioxane solution for deprotection, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.66 (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

Ethanol (5.0 ml) and tetrahydrofuran (2.0 ml) were added to dissolve the compound (270 mg) obtained in Example 367, and hydroxylamine hydrochloride (114 mg) and triethylamine (230 µl) were added at room temperature. After heating to reflux for 3 hours, saturated aqueous sodium bicarbonate and dichloromethane were added, and the aqueous layer was extracted with dichloromethane after separation. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography (dichloromethane: methanol = 7: 1), cross-linked Sephadex column (methanol) and preparative reversed-phase high-speed liquid chromatography (acetonitrile-water-formic acid system) using silica gel as a carrier. ) was purified, converted into a hydrochloride salt with 1N hydrochloric acid, and purified sequentially with a Sephadex column (methanol) to obtain the title compound (175 mg) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 1.53-1.67 (1H, m), 1.78-1.97 (5H, m), 2.84 (3H, s), 2.96-3.15 (2H, m), 3.00 (3H, s ), 3.03(3H, s), 3.15-3.26(2H, m), 3.64(2H, br.s), 4.09-4.18(1H, m), 4.55(2H, br.s), 7.55(1H, t , J = 7.8Hz), 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] (3-{[((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)amino]carbonyl}phenyl)(imino)methylcarbamate

In the same manner as in Example 365, the compound described in Reference Example 526 was hydrolyzed, and the lithium salt of the obtained carboxylic acid was condensed with the compound obtained in Reference Example 253 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) 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 370] N-[(1R, 2S, 5S)-5-[(dimethylamino)carbonyl]-2-({3-[imino(methylamino)methyl]benzoyl}amino )cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine- ² -carboxamide formate D22-9226

To the compound obtained in Example 367 (400 mg) was added saturated hydrochloric acid ethanol solution (30 ml) at room temperature. After stirring for 2 days, it was concentrated under reduced pressure to obtain a white solid. After dissolving this solid in methanol (10 ml), methylamine (2.0 M solution in tetrahydrofuran) (30 ml) was added at room temperature. After stirring for 2 hours, it was concentrated under reduced pressure, and the residue was sequentially purified by preparative reverse-phase high-speed liquid chromatography (acetonitrile-water-formic acid system) and cross-linked dextran column (methanol) to obtain the title compound (152 mg) as a white solid .

¹ H-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 = 7.6 Hz). MS (ESI) m/z: 526 (M+H) ⁺ .

[Example 371] N-{(1R, 2S, 5S)-2-({3-[amino(methoxyimino)methyl]benzoyl}amino)-5-[(dimethylamino) Carbonyl]cyclohexyl}-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride

To the compound obtained in Example 367 (300 mg) was added saturated hydrochloric acid ethanol solution (30 ml) at room temperature. After stirring for 2 days, it was concentrated under reduced pressure to obtain a pale yellow solid. After dissolving this solid in methanol (10 ml), O-methylhydroxylamine hydrochloride (1.01 g) and triethylamine (1.69 ml) were added at room temperature. After stirring for 2 hours, dichloromethane and saturated aqueous sodium bicarbonate solution were added to separate the layers, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was sequentially subjected to medium-pressure chromatography using silica gel as a carrier (dichloromethane:methanol=20:1→7:1) and the preparation of a reversed-phase high-speed solution. After purification by phase chromatography (acetonitrile-water-formic acid system), treatment with 1N hydrochloric acid gave the title compound (51.8 mg) as a white solid.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[4-( 3-oxomorpholin-4-yl)benzoyl]amino}cyclohexyl)oxalamide

The title compound was obtained by condensing the compound obtained in Reference Example 531 and the compound obtained in Reference Example 420 in the same manner as described in Example 2.

¹ H-NMR (CDCl ₃ ) δ: 1.72-2.16 (6H, m), 2.78-2.88 (1H, m), 2.95 (3H, s), 3.02 (3H, s), 3.76-3.80 (2H, m) , 4.01-4.08(3H, m), 4.32(2H, s), 4.59-4.65(1H, m), 7.07(1H, d, J=6.9Hz), 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-chlorothiophen-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

Using the same method as in Example 49, the compound obtained in Reference Example 519 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 534, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.42-2.01 (6H, m), 2.79 (3H, s), 2.91-3.02 (7H, m), 3.19 (1H, br.s), 3.25 (1H, br.s), 3.49(1H, br.s), 3.70(1H, br.s), 3.98-4.05(1H, m), 4.39-4.50(2H, m), 4.70(1H, br.s), 7.19 (1H, dd, J = 3.9, 1.7Hz), 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]azepine-2-carboxamide hydrochloride Salt

In the same manner as described in Example 219, the compound obtained in Reference Example 428 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 537, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(5-chloropyridin-2-yl)-N ² -{(1S, 2R, 4S)-2-[(6,7-dihydro-4H-pyrano[4, 3-d]thiazol-2-ylcarbonyl)amino]-4-[(dimethylamino)carbonyl]cyclohexyl}oxalamide

The title compound was obtained by condensing the compound obtained in Reference Example 26 and the compound obtained in Reference Example 420 in the same manner as described in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ: 1.39-1.56 (1H, m), 1.58-1.80 (3H, m), 1.97-2.13 (2H, m), 2.77 (3H, s), 2.92 (6H, br.s), 3.90-4.06(3H, m), 4.35-4.45(1H, m), 4.83(2H, s), 7.96-8.06(2H, m), 8.44(1H, br.s), 8.61( 1H, d, J=7.3Hz), 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

In the same manner as described in Example 219, the compound obtained in Reference Example 428 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 540 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.75 (2H, m), 1.80-2.10 (3H, m), 2.10-2.20 (1H, m), 2.30-2.45 (1H, m), 2.52 (3H, s), 2.75-2.85(2H, m), 2.98(3H, s), 2.95-3.10(2H, m), 3.11(3H, s), 3.66(2H, s), 4.45-4.55(1H, m) , 4.65-4.80 (1H, m), 7.52 (1H, d, J = 7.8Hz), 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-{[( tert-butyl 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylate

The title compound was obtained by condensing the compound obtained in Reference Example 543 and the compound obtained in Reference Example 10 in the same manner as described in Example 2.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.58-1.78 (2H, m), 1.95-2.33 (4H, m), 2.49-2.61 (1H, m), 2.52 (3H, s) , 2.80-2.88(2H, m), 2.93-3.00(2H, m), 3.66-3.79(2H, m), 4.40-4.54(1H, m), 4.71-4.84(1H, m), 7.43(1H, d, J = 8.3Hz), 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}cyclohexanecarboxylate hydrochloride

To a solution of the compound obtained in Example 377 (293 mg) in dioxane (8.0 ml) was added 4N hydrochloric acid-dioxane solution (10 ml), followed by stirring at room temperature for 16 hours. After concentrating the reaction solution under reduced pressure, the residue was suspended in diisopropyl ether and filtered off. The resulting powder was dissolved in water and neutralized with 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. 1N hydrochloric acid-ethanol solution (0.50 ml) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was dissolved in water and lyophilized to obtain the title compound (242 mg).

¹ H-NMR (DMSO-d ₆ ) 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

1N hydrochloric acid-ethyl acetate solution (3.09 ml) was added to the compound (307 mg) obtained in Reference Example 544, and the resulting suspension was stirred at room temperature for 7 hours. Then, 2N hydrochloric acid-ethyl acetate solution (40 ml) was added to the suspension, followed by stirring at room temperature for 2 hours. After distilling off the solvent under reduced pressure, diethyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried under reduced pressure. This solid was dissolved in N,N-dimethylformamide (10 ml), and to this solution were added the compound (191 mg) obtained in Reference Example 26, 1-(3-dimethylaminopropyl)-3-ethane Carbodiimide hydrochloride (288mg) and 1-hydroxybenzotriazole (135mg), stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate solution were added to the residue to separate the layers, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol:dichloromethane=1:49) on silica gel to obtain the title compound (124 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.58-1.76 (2H, m), 1.90-2.21 (4H, m), 2.45-2.55 (1H, m), 2.97 (2H, t, J=5.6Hz), 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 prepared from the compound obtained in Example 379 in the same manner as described in Example 378.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-4-[(dimethylamino)carbonyl]-2-{[(2- Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)carbonyl]amino}cyclohexyl)oxalamide hydrochloride

In the same manner as in Example 2, the compound obtained in Reference Example 545 was hydrolyzed, the resulting lithium salt of carboxylic acid was condensed with the compound obtained in Reference Example 420, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.31-1.46 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4R)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(thiazol-2-yl)cyclohexyl]oxalamide hydrochloride and N ¹ -(5-chloropyridine-2 -yl)-N ² -[(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

In the same manner as described in Example 214, the compound obtained in Reference Example 549 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and the resulting two stereoisomers were treated with hydrochloric acid to obtain the title compound.

Low polar compounds: ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.84 (2H, m), 1.86-1.97 (1H, m), 2.00-2.14 (2H, m), 2.21-2.34 (1H, m), 2.89(3H, br.s), 3.01-3.52(4H, m), 3.61-3.74(1H, m), 4.06-4.49(3H, m), 4.63-4.75(1H, m), 7.63( 1H, d, J = 3.2Hz), 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: ¹ H-NMR (DMSO-d ₆ ) δ: 1.67-1.80 (2H, m), 1.89-1.99 (1H, m), 2.10-2.25 (2H, m), 2.30-2.46 (1H, m), 2.90(3H, br.s), 3.08-3.53(4H, m), 3.65-3.76(1H, m), 4.05-4.53(3H, m), 4.64-4.75(1H, m), 7.62( 1H, br.s), 7.73(1H, br.s), 7.97-8.10(2H, m), 8.44(1H, br.s), 8.69-8.81(1H, m), 9.18-9.34(1H, m ), 10.20-10.35(1H, m), 11.48-11.92(1H, m).

MS (FAB) m/z: 560 (M+H) ⁺ .

[Example 383] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,2,4-oxadiazol-3-yl)cyclohexyl]oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 550 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.64-1.79 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]oxalamide salt salt

In the same manner as described in Example 214, the compound obtained in Reference Example 552 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.66-1.80 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,3,4-oxadiazol-2-yl)cyclohexyl]oxalamide

In the same manner as described in Example 214, the compound obtained in Reference Example 554 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.72-2.00 (2H, m), 2.13-2.23 (2H, m), 2.28-2.36 (1H, m), 2.39-2.46 (1H, m), 2.53 (3H, s), 2.80-2.91(2H, m), 2.93-3.00(2H, m), 3.28-3.38(1H, m), 3.69-3.79(2H, m), 4.14-4.24(1H, m), 4.68- 4.77 (1H, m), 7.51 (1H, d, J = 8.3Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,3-oxazol-2-yl)cyclohexyl]oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 556 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.82 (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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazole-2 -yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide salt salt

The compound obtained in Reference Example 560 (110 mg) was dissolved in dichloromethane (5 ml), and 4N hydrochloric acid-dioxane solution (5 ml) 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 (5 ml), and the compound obtained in Reference Example 266 (71.1 mg), 1-hydroxybenzotriazole (42.7mg) and 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80.9mg), stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, dichloromethane and aqueous sodium bicarbonate solution were added to the residue to separate the layers, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (methanol:dichloromethane=1:19). 1N hydrochloric acid ethanol solution was added to the resulting free substance for concentration, then diethyl ether was added, and the precipitated colorless powder was collected by filtration to obtain the title compound (69.8 mg).

¹ H-NMR (DMSO-d ₆ ) 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) .s), 10.90-11.30(1H, m).

MS (FAB) m/z: 559 (M+H) ⁺ .

[Example 388] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,3,4-thiadiazol-2-yl)cyclohexyl]oxalamide hydrochloride

In the same manner as described in Example 387, the compound obtained in Reference Example 562 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 266, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.68-1.86 (2H, m), 1.96-2.08 (1H, m), 2.11-2.28 (2H, m), 2.38-2.47 (1H, m), 2.94 ( 3H, s), 3.10-3.30 (1H, m), 3.37-3.62 (2H, m), 3.63-3.80 (1H, m), 4.11-4.23 (1H, m), 4.38-4.51 (2H, m), 4.65-4.81(1H, m), 7.99-8.08(2H, m), 8.44-8.48(1H, m), 8.76-8.84(1H, m), 9.20-9.34(1H, m), 9.52(1H, s ), 10.29 (1H, br.s), 10.99-11.33 (1H, m).

MS (ESI) m/z: 561 (M+H) ⁺ .

[Example 389] N-[(1R, 2S, 5S)-5-[(dimethylamino)carbonyl]-2-({2-[(5-fluoropyridin-2-yl)amino]-2- Oxothioacetyl}amino)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

The compound (38.4 g) obtained in Reference Example 10 and 1-hydroxybenzotriazole monohydrate ( 28.8 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (37.6 g) and diisopropylethylamine (35 ml), and stirred at room temperature for 63 hours. After the reaction solution was concentrated under reduced pressure, dichloromethane (1.2 L) and aqueous sodium bicarbonate solution (500 ml) were added to the residue. The aqueous layer was extracted with dichloromethane, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, 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 obtained powder (77.2 g) was dissolved in dichloromethane (500 ml), the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Dichloromethane (250ml) was added again, diethyl ether (1L) was added dropwise, stirred at 0°C for 30 minutes and filtered off to obtain the title compound (71.5g).

¹ H-NMR (CDCl ₃ ) δ: 1.61-1.75 (1H, m), 1.78-2.21 (5H, m), 2.19 (3H, s), 2.27-2.37 (1H, m), 2.52 (3H, s) , 2.77-2.95(4H, m), 2.96(3H, s), 3.70(1H, d, J=15.4Hz), 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 390] 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 citrate monohydrate

The compound obtained in Example 389 (6.26 g) was suspended in 100 ml of 20% aqueous ethanol, and 11.4 ml of 1M citric acid aqueous solution was added. While heating and stirring at 60°C, slowly add 20% aqueous ethanol to dissolve. After filtering while hot, it was naturally cooled to room temperature while stirring, and left for 1 day. The precipitated crystals were collected by filtration, dried under reduced pressure at room temperature for 2 hours, and allowed to stand for 1 day to obtain the title compound (6.95 g).

¹ H-NMR (DMSO-d ₆ ) 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: C ₂₄ H ₃₀ FN ₇ O ₃ S ₂ C ₆ H ₈ O ₇ H ₂ O

Theoretical value: C; 47.55, H; 5.32, N; 12.94, F; 2.51, S; 8.46

Measured value: C; 47.48, H; 5.10, N; 13.05, F; 2.55, S; 8.61mp (decomposition): 176～179

[Example 391] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(5-methyl-1,3,4-thiadiazol-2-yl)cyclohexyl]oxalamide salt salt

In the same manner as described in Example 387, the compound obtained in Reference Example 566 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 266, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.67-1.82 (2H, m), 1.92-2.03 (1H, m), 2.06-2.26 (2H, m), 2.35-2.44 (1H, m), 2.68 ( 3H, s), 2.94 (3H, s), 3.13-3.27 (2H, m), 3.40-3.56 (2H, m), 3.66-3.80 (1H, m), 4.09-4.22 (1H, m), 4.37- 4.51(2H, m), 4.64-4.82(1H, m), 7.98-8.07(2H, m), 8.44-8.48(1H, m), 8.79(1H, br.s), 9.16-9.34(1H, m ), 10.29(1H, s).

MS (ESI) m/z: 575 (M+H) ⁺ .

[Example 392] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,3-oxazol-5-yl)cyclohexyl]oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 568 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.50-1.87 (3H, m), 1.97-2.40 (3H, m), 2.93 (3H, s), 2.96-3.83 (5H, m), 4.04-4.16 ( 1H, m), 4.30-4.53 (2H, m), 4.62-4.80 (1H, m), 6.93 (1H, s), 7.96-8.10 (2H, m), 8.22 (1H, s), 8.45 (1H, s), 8.66-8.80(1H, m), 9.17-9.37(1H, m), 10.24-10.37(1H, m), 11.20-11.54(1H, m).

MS (ESI) m/z: 544 (M+H) ⁺ .

[Example 393] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-4-(5-methyl-1,2,4-oxadiazole-3 -yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide salt salt

In the same manner as described in Example 387, the compound obtained in Reference Example 572 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 266, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.63-1.79 (2H, m), 1.80-1.94 (1H, m), 1.98-2.24 (2H, m), 2.27-2.41 (1H, m), 2.56 ( 3H, s), 2.83 (3H, s), 3.04-3.88 (6H, m), 4.06-4.18 (1H, m), 4.29-4.53 (2H, m), 7.98-8.10 (2H, m), 8.46 ( 1H, d, J=2.4Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(4H-1,2,4-triazol-4-yl)cyclohexyl)oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 576 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.69-1.79 (1H, m), 1.87-2.00 (1H, m), 2.04-2.14 (1H, m), 2.17-2.40 (3H, m), 2.92 ( 3H, s), 3.02-3.84 (4H, m), 4.13-4.22 (1H, m), 4.35-4.83 (4H, m), 7.99-8.05 (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] N ¹ -(5-chloropyridine-2-thienyl)-N ² -((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazole- 2-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide Citrate

At 0°C, 1- (Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (308 mg) and 1-hydroxybenzotriazole (159 mg) were stirred at room temperature for 11 hours. The reaction solution was diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, dissolve the obtained solid in dichloromethane (10 ml), add 4N hydrochloric acid-dioxane solution (10 ml), and stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N,N-dimethylformamide (8 ml), and the compound obtained in Reference Example 10 (262 mg), 1-hydroxybenzotriazole (174 mg), 1- (Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (308 mg) and triethylamine (149 µl). The reaction solution was stirred for 19 hours, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the resulting residue was purified by preparative silica gel thin-layer chromatography (dichloromethane:methanol=10:1). The obtained compound was dissolved in ethanol, hexane was added, and the precipitated solid was collected by filtration. Ethanol (15 ml) and citric acid monohydrate (138 mg) were added to the obtained solid (371 mg) to dissolve, concentrated under reduced pressure, added water, azeotroped 3 times, and dried to obtain the title compound (503 mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.69-1.84 (2H, m), 1.87-1.99 (1H, m), 2.05-2.22 (2H, m), 2.35-2.52 (1H, m) 2.48 (3H , s), 2.65 (2H, d, J = 15.4Hz), 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] N ¹ -(5-bromo-2-pyridyl)-N ² -((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazole-2 -yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide salt salt

In the same manner as described in Example 214, the compound obtained in Reference Example 579 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-2.15 (5H, m), 2.32-2.43 (1H, m), 2.45 (3H, s), 2.92 (3H, s), 3.10-3.30 (3H, m), 3.49(1H, br.s), 3.70(1H, br.s), 4.09-4.17(1H, m), 4.38-4.52(2H, m), 4.69(1H, br.s), 7.99( 1H, d, J = 8.8Hz), 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] N ¹ -(4-chlorophenyl)-N ² -((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazol-2-yl) -2-{[(5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide citrate

In the same manner as described in Example 395, the compound obtained in Reference Example 577 and the compound obtained in Reference Example 374 were condensed, treated with hydrochloric acid for deprotection, condensed with the compound obtained in Reference Example 10, and then treated with citric acid. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 1.66-1.82 (2H, m), 1.85-1.97 (1H, m), 2.02-2.23 (2H, m), 2.34-2.48 (1H, m), 2.46 ( 3H, s), 2.63(2H, d, J=15.4Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazole-2 -yl)-2-{[(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide citrate

Similar to the method described in Example 395, after condensing the compound obtained in Reference Example 577 and the compound obtained in Reference Example 266, deprotect it with hydrochloric acid, then condense with the compound obtained in Reference Example 540, and then treat it with citric acid, The title compound was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.87 (2H, m), 1.90-2.21 (3H, m), 2.29-2.40 (1H, m), 2.47 (3H, s), 2.59 (3H, s), 2.62(2H, d, J=15.4Hz), 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

Same as the method described in Example 395, after condensing the compound obtained in Reference Example 577 and 5-chloroindole-2-carboxylic acid, deprotect it with hydrochloric acid, then condense with the compound obtained in Reference Example 10, and then use lemon Acid treatment afforded the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.71-1.85 (2H, m), 1.90-2.21 (3H, m), 2.31-2.43 (1H, m), 2.47 (3H, s), 2.63 (2H, d, J=15.2Hz), 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] N ¹ -(5-chloro-2-thienyl)-N ² -((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazole-2 -yl)-2-{[(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide citrate

Similar to the method described in Example 395, the lithium salt of carboxylic acid obtained by hydrolyzing the compound of Reference Example 356 was condensed with the compound obtained in Reference Example 577, treated with hydrochloric acid for deprotection, and then condensed with the compound obtained in Reference Example 540 , followed by treatment with citric acid to afford the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.86 (2H, m), 1.90-2.21 (3H, m), 2.27-2.39 (1H, m), 2.46 (3H, s), 2.58 (3H, s), 2.61(2H, d, J=15.4Hz), 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] N ¹ -((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)-N ² -{5-[2-(trimethylsilyl) Ethynyl]pyridin-2-yl}oxalamide

The title compound was prepared from the compound obtained in Example 396 in the same manner as described in Reference Example 455.

¹ H-NMR (CDCl ₃ ) δ: 0.26 (9H, s), 1.77-1.92 (2H, m), 2.08-2.43 (4H, m), 2.52 (6H, s), 2.81-2.89 (2H, m) , 2.93-2.98(2H, m), 3.19-3.28(1H, m), 3.68-3.77(2H, m), 4.13-4.22(1H, m), 4.68-4.74(1H, m), 7.48(1H, d, J=8.4Hz), 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] N ¹ -(5-ethynylpyridin-2-yl)-N ² -((1S,2R,4S)-4-(5-methyl-1,3,4-oxadiazole- 2-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide

Potassium fluoride (116 mg) was added to a solution of the compound obtained in Example 401 (617 mg) in methanol (30 ml), followed by stirring at room temperature for 7 hours. The solvent was distilled off under reduced pressure, and dichloromethane and a water solution were added to the residue. 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 obtained solid was dissolved in methanol, water was added and the solvent was distilled off under reduced pressure to obtain the title compound (287 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.81-1.96 (2H, m), 2.07-2.19 (2H, m), 2.27 (1H, br.s), 2.41 (1H, d, J=13.2Hz), 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

Using the same method as in Example 214, the compound obtained in Reference Example 580 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with citric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.75-1.90 (2H, m), 1.91-2.03 (1H, m), 2.10-2.22 (1H, m), 2.25-2.52 (2H, m), 2.47 ( 3H, s), 2.63(2H, d, J=15.4Hz), 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 lemon salt

Using the same method as in Example 395, the compound obtained in Reference Example 577 and the compound obtained in Reference Example 516 were condensed, treated with hydrochloric acid for deprotection, condensed with the compound obtained in Reference Example 10, and then treated with citric acid. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ ) 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

In the same manner as described in Example 214, the compound obtained in Reference Example 581 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with citric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.69-1.86 (2H, m), 1.89-2.03 (1H, m), 2.05-2.19 (1H, m), 2.20-2.34 (1H, m), 2.34- 2.49(1H, m), 2.47(3H, s), 2.63(2H, d, J=15.4Hz), 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- Quinazoline carboxamide citrate

Using the same method as in Example 395, the compound obtained in Reference Example 577 and the compound obtained in Reference Example 349 were condensed, treated with hydrochloric acid for deprotection, condensed with the compound obtained in Reference Example 10, and then treated with citric acid. The title compound was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 1.71-1.88 (2H, m), 1.90-2.02 (1H, m), 2.07-2.26 (2H, m), 2.34-2.44 (1H, m), 2.47 ( 3H, s), 2.63 (2H, d, J=15.4Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,2,4-oxadiazol-5-yl)cyclohexyl]oxalamide hydrochloride

Using the same method as in Example 387, the compound obtained in Reference Example 583 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 266, and then treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(5-chloropyridin-2-yl)-N ² -{(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl} Glyoxamide hydrochloride

Using the same method as in Example 214, the compound obtained in Reference Example 586 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and then treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.88 (2H, m), 1.95-2.06 (1H, m), 2.10-2.23 (2H, m), 2.42-2.49 (1H, m), 2.92 ( 3H, s), 3.09-3.81 (5H, m), 4.15 (1H, br.s), 4.33-4.56 (2H, m), 4.57-4.79 (1H, m), 7.99-8.08 (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] N ¹ -(5-chloro-2-thienyl)-N ² -((1S,2R,4S)-4-(3-methyl-1,2,4-oxadiazole-5 -yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide salt salt

Using the same method as in Example 387, after treating and deprotecting the compound obtained in Reference Example 560 with hydrochloric acid, it condenses with the lithium salt of carboxylic acid obtained by hydrolyzing the compound in Reference Example 356, and then treats it with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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] N ¹ -(6-chloropyridazin-3-yl)-N ² -((1S,2R,4S)-4-(3-methyl-1,2,4-oxadiazole- 5-yl)-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide Hydrochloride

Using the same method as in Example 387, after deprotecting the compound obtained in Reference Example 560 with hydrochloric acid, it was condensed with the lithium salt of carboxylic acid obtained by hydrolysis of the compound in Reference Example 264, and then treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.69-1.82 (2H, m), 1.97-2.03 (1H, m), 2.08-2.20 (2H, m), 2.32 (3H, s), 2.39-2.45 ( 1H, m), 2.81-2.83 (4H, m), 3.10-3.53 (3H, m), 4.10-4.18 (1H, m), 4.36-4.46 (4H, m), 7.98 (1H, d, J=9.2 Hz), 8.29(1H, d, J=9.2Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(2-oxo-1,3-oxan-3-yl)cyclohexyl]oxalamide

To a methanol (70 ml) solution of the compound (696 mg) obtained in Reference Example 589 was added p-toluenesulfonic acid monohydrate (301 mg), followed by heating under reflux overnight. p-Toluenesulfonic acid monohydrate (82 mg) was added to the reaction solution, followed by heating under reflux for 2 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in N,N-dimethylformamide (50 ml), and the compound (338 mg) obtained in Reference Example 564 and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide salt were added Salt (552mg) and 1-hydroxybenzotriazole (97mg), stirred overnight at room temperature. Triethylamine (599 µl) was added to the reaction mixture, followed by stirring overnight at 45°C. Water and ethyl acetate were added to the reaction solution to separate the layers, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash column chromatography (dichloromethane:methanol=93:7) using silica gel as a carrier, concentrated part of the target product, added ether, and filtered The resulting solid gave the title compound (83 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.58-1.65 (2H, m), 1.79-2.05 (4H, m), 3.47-3.55 (2H, m), 3.84-3.93 (2H, m), 4.29 (1H, br.s), 4.33-4.39 (2H, m), 5.08 (1H, br.s), 7.70 (1H, dd, J=8.8, 2.5Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(tetrazol-1-yl)cyclohexyl]oxalamide

In the same manner as described in Example 214, the compound obtained in Reference Example 592 was deprotected by treatment with hydrochloric acid, and then condensed with the compound obtained in Reference Example 10 to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 1.90-2.02 (1H, m), 2.16-2.29 (2H, m), 2.40-2.52 (2H, m), 2.52 (3H, s), 2.59-2.66 (1H, m), 2.80-2.91(2H, m), 2.94-2.98(2H, m), 3.68-3.78(2H, m), 4.23-4.32(1H, m), 4.78-4.92(2H, m), 7.55( 1H, d, J = 8.1Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1H-pyrrol-1-yl)cyclohexyl]oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 594 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.67-1.78 (1H, m), 1.82-1.95 (1H, m), 1.97-2.06 (1H, m), 2.13-2.31 (3H, m), 2.94 ( 3H, s), 3.29-3.39 (2H, m), 3.51 (1H, br.s), 3.73 (1H, br.s), 4.12-4.30 (2H, m), 4.43 (2H, br.s), 4.66-4.80 (1H, m), 5.96 (2H, br.s), 6.85 (2H, br.s), 7.98-8.06 (2H, m), 8.46 (1H, br.s), 8.72 (1H, br.s) .s), 9.36(1H, br.s), 10.28(1H, br.s), 11.20-11.48(1H, m).

MS (FAB) m/z: 542 (M+H) ⁺ .

[Example 414] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1,2,4-triazol-5-yl)cyclohexyl]oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 597 was deprotected by treatment with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.64-1.79 (2H, m), 1.83-1.95 (1H, m), 1.97-2.08 (1H, m), 2.09-2.21 (1H, m), 2.28- 2.38(1H, m), 2.89(3H, s), 2.97-3.63(5H, m), 4.04-4.16(1H, m), 4.34-4.62(3H, m), 7.81(1H, br.s), 8.01(1H,dd,J=8.9,2.3Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -[(1S, 2R, 4S)-2-{[(5-methyl-4,5,6,7-tetra Hydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}-4-(1-methyl-1H-1,2,4-triazol-5-yl)cyclohexyl]oxalamide Hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 599 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 564, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.76 (2H, m), 1.77-1.88 (1H, m), 1.94-2.04 (1H, m), 2.05-2.18 (1H, m), 2.25- 2.36(1H, m), 2.85-2.98(4H, m), 3.15-3.67(4H, m), 3.78(3H, s), 4.08(1H, br.s), 4.31-4.70(3H, m), 7.97-8.08(2H, m), 8.30(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

In the same manner as described in Example 387, the compound obtained in Reference Example 560 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 298, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.76-1.90 (2H, m), 1.97-2.06 (1H, m), 2.16-2.23 (1H, m), 2.28-2.38 (4H, m), 2.44- 2.52(1H, m), 2.88(3H, s), 3.21(2H, br.s), 3.27-3.42(1H, m), 3.55(2H, br.s), 4.41-4.56(4H, m), 8.01(1H,dd,J=8.8,1.7Hz), 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] N ¹ -(5-chloropyridin-2-yl)-N ² -((3R,4S)-3-{[(5-methyl-4,5,6,7-tetrahydrothiazole [5,4-c]pyridin-2-yl)carbonyl]amino}-1-(thiazol-2-yl)piperidin-4-yl)oxalamide hydrochloride

In the same manner as described in Example 214, the compound obtained in Reference Example 603 was deprotected with hydrochloric acid, condensed with the compound obtained in Reference Example 10, and treated with hydrochloric acid to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 1.73-1.87 (1H, m), 2.21-2.37 (1H, m), 2.91 (3H, s), 3.03-3.29 (2H, m), 3.31-3.52 ( 2H, (2H, m), 3.84-4.53 (5H, m), 4.64-4.76 (1H, m), 6.91 (1H, br.s), 7.23 (1H, br.s), 8.02 (2H, s) , 8.46 (1H, s), 8.70-8.93 (1H, m), 9.28, 9.36 (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] Measurement of Human FXa Inhibitory Action (IC ₅₀ Value)

Add 10 μl of 5% DMSO solution, 40 μl of Tris buffer solution (100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH 7.4) and After 10 μl of 0.0625U/ml human FXa (Enzyme Research Laboratories, Inc., dissolved and diluted with Tris buffer), 40 μl of 750 μM S-2222 aqueous solution (Chromogenix company) was added, and the absorbance at 405 nm was measured for 10 minutes at room temperature to obtain Increase in absorbance (ΔOD/min). In the control group, Tris buffer was used to replace the test product.

Use the following formula to obtain the inhibition rate (%) at each final concentration of the test product as the vertical axis of the logarithmic probability paper, and use the final concentration of the test product as the horizontal axis to draw curves respectively to obtain 50% Inhibitory concentration ( _IC50 value).

Inhibition rate (%)=(1-ΔOD/min of the test product ÷ ΔOD/min of the control group)×100

(Results) Table 1 shows that the compounds of the present invention have potent FXa inhibitory effects.

Table 1 compound Human FXa inhibitory effect (IC ₅₀ value): nM compound Human FXa inhibitory effect (IC ₅₀ value): nM Example 3 86 Example 194 5.0 Example 7 83 Example 204 1.5 Example 11 92 Example 246 3.1 Example 54 4.2 Example 247 1.9 Example 62 3.5 Example 248 5.4 Example 63 2.5 Example 384 1.0 Example 74 1.4 Example 385 1.3 Example 101 26 Example 387 1.2 Example 130 4.5 Example 394 1.1 Example 138 4.4 Example 395 0.72 Example 143 5.8 Example 396 1.1 Example 164 4.8 Example 402 1.1 Example 191 1.2 Example 413 1.0 Example 192 2.0

[Test Example 2] Measurement of anti-FXa activity in rat plasma after oral administration

(A) Drug administration and blood collection

Give rats oral administration (10ml/kg) of the drug solution (1mg/ml) formed by dissolving or suspending 10mg of the test substance in 0.5% methylcellulose (MC). After 0.5, 1, 2, and 4 hours of administration, use a syringe injected with 50 μl of 3.13% (w/v) trisodium citrate dihydrate aqueous solution to collect 0.5 ml of blood from the jugular vein (collected blood volume: 0.45ml). After administering the 0.5% MC solution to rats in the control group, blood was collected in the same manner as above. Each blood sample was centrifuged at 1500×g at 4° C. for 10 minutes to separate the plasma, which was stored at −40° C. until it was used for the following measurement of anti-FXa activity in plasma.

(B) Determination of FXa inhibitory activity in plasma

In the determination of anti-FXa activity in plasma, S-2222 was used as a substrate for determination. Mix 5456 μl of Tris buffer (100 mM Tris, 200 mM potassium chloride, 0.2% BSA, pH 7.4), 44 μl of human FXa (2.5 U/ml) and 550 μl of water. The resulting human FXa solution was used in the following experiments. Add 5 μl of the rat plasma obtained from the above operation (A) to each well of a 96-well microplate, then add 55 μl of the above-mentioned human FXa solution and 40 μl of 750 μM S-2222 aqueous solution in sequence, and then immediately use an absorbance photometer SPECTRA max340 or 190 (Molecular Devices Co., U.S.A.), measure the absorbance at 405 nm at room temperature, and calculate the reaction rate (ΔOD/min).

The anti-FXa activity, that is, the inhibition rate (%) was calculated by the following formula.

Inhibition rate (%)=[1-(the average value of ΔOD/min of sample ÷ ΔOD/min of control group)]×100

(Results) The compounds described in Examples 63, 191, 192, 194, and 204 exhibited strong plasma FXa inhibitory activity of 62% to 96% when administered orally at 10 mg/kg.

Claims (59)

1. general formula (1)

Q ¹-Q ²-T ⁰-N(R ¹)-Q ³-N(R ²)-T ¹-Q ⁴ (1)

Compound, its salt, its solvate or its N-oxide compound of expression;

In the formula, R ¹And R ²Independent separately, expression hydrogen atom, hydroxyl, alkyl or alkoxyl group;

Q ¹The annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property that condenses that expression can have substituent saturated or undersaturated 5～6 yuan of cyclic hydrocarbon group, can have substituent saturated or undersaturated 5～7 yuan of heterocyclic radicals, can have substituent saturated or undersaturated 2 ring property or 3 ring property;

Q ²The expression singly-bound, the alkylidene group of a straight chain shape or a catenate carbonatoms 1～6, the alkenylene of a straight chain shape or a catenate carbonatoms 2～6, the alkynylene of a straight chain shape or a catenate carbonatoms 2～6, can have saturated or undersaturated 5～6 yuan of cyclic hydrocarbon group of substituent divalent, can have saturated or undersaturated 5～7 yuan of heterocyclic radicals of substituent divalent, the annelated heterocycles base that alkyl maybe can have saturated or undersaturated 2 ring property of substituent divalent or 3 ring property that condenses that can have saturated or undersaturated 2 ring property of substituent divalent or 3 ring property;

Q ³The expression following radicals,

Q in this group ⁵Be the alkylidene group of carbonatoms 1～8, the alkenylene or the base-(CH of carbonatoms 2～8 ₂) m-CH ₂-A-CH ₂-(CH ₂) _n-(m in the group and n are independent separately, the integer of expression 0,1～3, A represent Sauerstoffatom, nitrogen-atoms, sulphur atom ,-SO-,-SO ₂-,-NH-,-O-NH-,-NH-NH-,-S-NH-,-SO-NH-or-SO ₂-NH-);

R ³And R ⁴Containing Q ⁵Ring on carbon atom; replace on nitrogen-atoms or the sulphur atom; independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; cyano group; the cyano group alkyl; amino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; Alkoximino; oxyimino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxy carbonyl alkyl amino; carboxyalkyl amino; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; the formamyl alkyl; can have substituent N-alkyl-carbamoyl alkyl on the alkyl; can have substituent N on the alkyl; N-dialkyl amido formyl radical alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; can have substituent 3～6 yuan of heterocycle carbonylic alkyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; aryl; aralkyl; can have substituent 3～6 yuan of heterocyclic radicals; can have substituent 3～6 yuan of Heterocyclylalkyls; alkyl sulfonyl amino; Arenesulfonyl amino; the amino alkyl of alkyl sulfonyl; the Arenesulfonyl amino alkyl; the amino carbonyl of alkyl sulfonyl; the Arenesulfonyl amino carbonyl; the amino carbonylic alkyl of alkyl sulfonyl; the Arenesulfonyl amino carbonylic alkyl; the oxo base; carbamoyloxy; aralkoxy; the carboxyl alkoxyl group; the alkoxy carbonyl alkoxyl group; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the alkoxyl group alkoxy carbonyl; the hydroxyl acyl group; the alkoxyl group acyl group; the halo acyl group; the carboxyl acyl group; aminoacyl; the acyloxy acyl group; the acyloxy alkyl sulphonyl; the hydroxyalkyl alkylsulfonyl; the alkoxyalkyl alkylsulfonyl; can have substituent 3～6 yuan of heterocycle alkylsulfonyls; can have substituent 3～6 yuan of heterocyclic oxy groups; N-alkylamino acyl group; N; N-dialkyl amido acyl group; can have substituent N on the alkyl; N-dialkyl amido formyl radical acyl group; can have substituent N on the alkyl; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; the N-aryl-amino-carbonyl; N-3～6 yuan heterocyclic amino group formyl radical; N-alkyl-N-aryl-amino-carbonyl; N-alkyl-N-3～6 yuan heterocyclic amino group formyl radical; N-aryl-amino-carbonyl alkyl; N-3～6 yuan heterocyclic amino group formyl radical alkyl; N-alkyl-N-aryl-amino-carbonyl alkyl; N-alkyl-N-3～6 yuan heterocyclic amino group formyl radical alkyl; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl; alkoxyalkyl (thiocarbonyl); alkylthio alkyl or N-acyl group-N-alkylamino alkyl or R ³And R ⁴Represent the alkylidene group of carbonatoms 1～5, the alkenylene of carbonatoms 2～5, the alkylene dioxo base or the carbonyldioxy of carbonatoms 1～5 together;

Q ⁴The annelated heterocycles base that condenses alkyl, can have substituent saturated or unsaturated 2 ring property or 3 ring property that expression can have substituent aryl, can have substituent aromatic yl alkenyl, can have substituent aromatic yl polysulfide yl, can have substituent heteroaryl, can have substituent heteroaryl alkenyl, can have substituent saturated or unsaturated 2 ring property or 3 ring property;

T ⁰Expression carbonyl or thiocarbonyl;

T ¹Expression carbonyl, alkylsulfonyl, base-C (=O)-C-(=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-, base-C (=S)-C (=S)-N (R ')-(R ' expression hydrogen atom, hydroxyl, alkyl or alkoxyl group in the group), base-C (=O)-A ¹-N (R ")-(A in the group ¹Expression can have the alkylidene group of substituent carbonatoms 1～5, R " expression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A ²-C (=O)-(A in the group ²The alkylidene group of expression singly-bound or carbonatoms 1～5), base-C (=O)-A ³-C (=O)-NH-(A in the group ³The alkylidene group of expression carbonatoms 1～5), base-C (=O)-C (=NOR ^a)-N (R ^b)-, base-C (=S)-C (=NOR ^a)-N (R ^bR in the)-(group ^aExpression hydrogen atom, alkyl or alkyloyl, R ^bExpression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=O)-N=N-, base-C (=S)-N=N-, base-C (=NOR ^c)-C (=O)-N (R ^dR in the)-(group ^cExpression hydrogen atom, alkyl, alkyloyl, aryl or aralkyl, R ^dExpression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=N-N-(R ^e) (R ^f))-C (=O)-N (R ^gR in the)-(group ^eAnd R ^fIndependent separately, expression hydrogen atom, alkyl, alkyloyl, alkyl (thiocarbonyl), R ^gExpression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=O)-NH-C (=O)-, base-C (=S)-NH-C (=O)-, base-C (=O)-NH-C (=S)-, base-C (=S)-NHC (=S)-, base-C (=O)-NH-SO ₂-, base-SO ₂-NH-, base-C (=NCN)-NH-C (=O)-, base-C (=S)-C (=O)-or thiocarbonyl.

2. compound as claimed in claim 1, its salt, its solvate or its N-oxide compound, its feature also be, in the formula (1), and group Q ⁴Can have substituent phenyl for being selected from, can have substituent naphthyl, can have substituent anthryl, can have substituent phenanthryl, can have substituent styryl, can have substituent phenylacetylene base, can have substituent pyridyl, can have substituent pyridazinyl, can have substituent pyrazinyl, can have substituent furyl, can have substituent thienyl, can have substituent pyrryl, can have substituent thiazolyl, can have substituting group De oxazolyl, can have substituent pyrimidyl, can have substituent tetrazyl, can have substituent thienyl vinyl, can have substituent pyridyl vinyl, can have substituent indenyl, can have substituent indanyl, can have substituent tetralyl, can have substituent benzofuryl, can have substituent isobenzofuran-base, can have substituent benzothienyl, can have substituent indyl, can have substituent indolinyl, can have substituent pseudoindoyl, can have substituent isoindolinyl, can have substituent indazolyl, can have substituent quinolyl, can have substituent dihydroquinoline base, can have substituent 4-oxo-dihydro quinolyl (dihydroquinoline-4-ketone), can have substituent tetrahydric quinoline group, can have substituent isoquinolyl, can have substituent tetrahydro isoquinolyl, can have substituent chromenyl, can have substituent chromanyl, can have substituent isochroman base, can have substituent 4H-4-oxo benzopyranyl, can have substituent 3,4-dihydro-4H-4-oxo benzopyranyl, can have substituent 4H-quinolizinyl, can have substituent quinazolyl, can have substituent dihydroquinazoline base, can have substituent tetrahydro quinazoline base, can have substituent quinoxalinyl, can have substituent tetrahydroquinoxaline base, can have substituent cinnolines base, can have substituent tetrahydrochysene cinnolines base, can have substituent indolizine base, can have substituent tetrahydrochysene indolizine base, can have substituent benzothiazolyl, can have substituent tetrahydro benzothiazol base, can have substituent benzoxazolyl, can have substituent benzisothiazole base, can have substituent benzoisoxazole base, can have substituent benzimidazolyl-, can have substituent naphthyridinyl, can have substituent Tetrahydronaphthyridderivates base, can have substituent thienopyridine base, can have substituent tetramethylene sulfide and pyridyl, can have substituent thiazole and pyridyl, can have substituent thiazolidine and pyridyl, can have substituent thiazole and pyridazinyl, can have substituent thiazolidine and pyridazinyl, can have substituent pyrrolopyridinyl, can have substituent pyrrolin and pyridyl, can have substituent Pyrrolidine and pyridyl, can have substituent pyrrolo-pyrimidine radicals, can have substituent pyrrolin and pyrimidyl, can have substituent pyrido quinazolyl, can have substituent dihydro pyrido quinazolyl, can have substituent Pyridopyrimidine base, can have substituent tetrahydropyridine and pyrimidyl, can have substituent pyrans benzothiazolyl, can have substituent dihydropyrane benzothiazolyl, can have substituent furo pyridyl, can have substituent tetrahydrofuran (THF) and pyridyl, can have substituting group De oxazole and pyridyl, can have substituent Si Qing oxazole and pyridyl, can have substituting group De oxazole and pyridazinyl, can have substituent Si Qing oxazole and pyridazinyl, can have substituent pyrrolo-thiazolyl, can have substituent pyrrolin benzothiazolyl, can have substituent pyrroles Bing oxazolyl, can have substituent pyrrolin Bing oxazolyl, can have substituent Thienopyrroles base, can have substituent thiazole and pyrimidyl, can have substituent 4-oxo-tetrahydrochysene cinnolines base, can have substituent 1,2,4-benzothiadiazine base, can have substituent 1,1-titanium dioxide-2H-1,2,4-benzothiadiazine base, can have substituent 1,2,4-Ben Bing oxadiazine base, can have substituent cyclopenta pyranyl, can have substituent thienofuran base, can have substituent furo pyranyl, can have substituent Bi Ding Bing oxazinyl, can have substituent Bi Zuo Bing oxazolyl, can have substituent Imidazothiazole base, can have substituent imidazopyridyl, can have substituent imidazolidine and pyridyl, can have substituent pyrazine and pyridazinyl, can have substituent benzisoquinoline base, can have substituent furo cinnolines base, can have substituent pyrazolo thiazole and pyridazinyl, can have substituent tetrahydro-pyrazole and thiazole and pyridazinyl, can have substituent six hydrogen thiazoles and pyridazine and pyridazinyl, can have substituent imidazo-triazine base, can have substituting group De oxazole and pyridyl, can have substituent benzo oxa-_ base, can have substituent benzo-aza _ base, can have substituent tetrahydro benzo azepine _ base, can have substituent benzodiazepine _ base, can have substituent benzo three azepines _ base, can have substituent thieno-azepine _ base, can have substituent tetramethylene sulfide and azepine _ base, can have substituent thieno-diaza _ base, can have substituent thieno-three azepines _ base, can have substituent thiazole and azepine _ base, can have substituent thiazolidine and azepine _ base, can have substituent 4,5,6,7-tetrahydrochysene-5,6-tetramethylene thiazole and pyridazinyl, can have substituent 5,6-trimethylene-4,5,6, the group of 7-thiazolidine and pyridazinyl.

3. compound as claimed in claim 1 or 2, its salt, its solvate or its N-oxide compound, its feature also is, group Q ⁴On substituting group for being selected from hydroxyl; halogen atom; haloalkyl; amino; cyano group; aminoalkyl group; nitro; hydroxyalkyl; alkoxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl alkyl; acyl group; amidino groups; the hydroxyl amidino groups; the straight chain shape; prop up the alkyl of chain or cyclic carbonatoms 1～6, the straight chain shape; prop up the alkoxyl group of chain or cyclic carbonatoms 1～6, the straight chain shape; prop up the amidino groups of the alkyl replacement of chain or cyclic carbonatoms 1～6; the straight chain shape; prop up the amidino groups of the alkoxyl group replacement of chain or cyclic carbonatoms 1～6; the straight chain shape; prop up the amidino groups of the alkoxy carbonyl replacement of chain or cyclic carbonatoms 2～7, the straight chain shape; prop up the alkenyl of chain or cyclic carbonatoms 2～6, the alkynyl of a straight chain shape or a catenate carbonatoms 2～6; the straight chain shape; prop up the alkoxy carbonyl of chain or cyclic carbonatoms 2～6; formamyl has the straight chain shape on nitrogen-atoms; prop up the mono-or dialkylcarbamoyl group of the alkyl replacement of chain or cyclic carbonatoms 1～6, by the straight chain shape; 1～3 group of one or dialkyl amido that the alkyl of chain or cyclic carbonatoms 1～6 replaces and 5～6 yuan nitrogen heterocycle.

4. compound as claimed in claim 1, its salt, its solvate or its N-oxide compound, its feature also are, the group Q in the formula (1) ⁴Be arbitrary group shown below,

[in the base, R ⁵And R ⁶Independent separately; expression hydrogen atom, cyano group, halogen atom, alkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, alkoxy carbonyl, alkoxy carbonyl alkyl or the phenyl that can be replaced by cyano group, hydroxyl, halogen atom, alkyl or alkoxyl group, R ⁷And R ⁸Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, R ⁹And R ¹⁰Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, R ¹¹, R ¹²And R ¹³Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, X ¹Expression CH ₂, CH, NH, NOH, N, O or S, R ¹⁴, R ¹⁵And R ¹⁶Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, X ²Expression NH, N, O or S, X ³Expression N, C or CH, X ⁴Expression N, C or CH, R ¹⁷And R ¹⁸Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl, but X ³And X ⁴For the situation of the combination of C and CH and all be except the situation of C or CH],

[in the base, N represents R ¹⁹1 or 2 of the carbon atom of the ring that replaces is replaced R by nitrogen-atoms ¹⁹, R ²⁰And R ²¹Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, X ⁵Expression CH ₂, CH, N or NH, Z ¹Expression N, NH or O, Z ²Expression CH ₂, CH, C or N, Z ³Expression CH ₂, CH, S, SO ₂Or C=O, X ⁵-Z ²Expression X ⁵And Z ²Close R with singly-bound or two bond ²²And R ²³Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl, R ²⁴Expression hydrogen atom or alkyl],

[in the base, X ⁶Expression O or S, R ²⁵And R ²⁶Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, R ²⁷And R ²⁸Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, E ¹And E ²Independent separately, expression N or CH, R ²⁹And R ³⁰Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, Y ¹Expression CH or N, Y ²Expression-N (R ³³In)-(the base, R ³³The alkyl of expression hydrogen atom or carbonatoms 1～6), O or S, R ³¹And R ³²Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl], and

[in the base, 1～8 numeral position, each N represents that any of 1～4 carbon atom and any of 5～8 carbon atom are replaced R respectively by 1 nitrogen-atoms ³⁴, R ³⁵And R ³⁶Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N, N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl].

5. compound as claimed in claim 1, its salt, its solvate or its N-oxide compound, its feature also be, in the formula (1), and group Q ⁴Be arbitrary group shown below,

[in the base, R ⁵And R ⁶Independent separately, expression hydrogen atom or alkyl, R ⁷The expression hydrogen atom, R ⁸Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, R ⁹The expression hydrogen atom, R ¹⁰Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, R ¹¹And R ¹²All represent hydrogen atom, R ¹³Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, X ¹Expression NH, NOH, N, O or S, R ¹⁴Expression hydrogen atom, halogen atom, acyl group, N-alkyl-carbamoyl, N, N-dialkyl amido formyl radical or alkyl, R ¹⁵Expression hydrogen atom or halogen atom, R ¹⁶Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, X ²Expression NH, O or S, X ³Expression N, C or CH, X ⁴Expression N, C or CH, R ¹⁷The expression hydrogen atom, R ¹⁸Expression hydrogen atom, halogen atom, alkyl or alkynyl, but X ³And X ⁴For the situation of the combination of C and CH and all be except the situation of C or CH],

[in the base, N represents R ¹⁹1 or 2 of the carbon atom of the ring that replaces is replaced R by nitrogen-atoms ¹⁹And R ²⁰All represent hydrogen atom, R ²¹Expression hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl],

[in the base, X ⁵Expression CH ₂, CH, N or NH, Z ¹Expression N, NH or O, Z ²Expression CH ₂, CH, C or N, Z ³Expression CH ₂, CH, S, SO ₂Or C=O, X ⁵-Z ²Expression X ⁵And Z ²Close R with singly-bound or two bond ²²The expression hydrogen atom, R ²³Expression hydrogen atom, halogen atom, alkyl or alkynyl, R ²⁴The expression hydrogen atom],

[in the base, X ⁶Expression O, R ²⁵The expression hydrogen atom, R ²⁶Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, R ²⁷Expression hydrogen atom or halogen atom, R ²⁸Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, E ¹And E ²Independent separately, expression N or CH, R ²⁹Expression hydrogen atom or halogen atom, R ³⁰Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, Y ¹Expression CH or N, Y ²Expression-N (R ³³In)-(the base, R ³³The alkyl of expression hydrogen atom or carbonatoms 1～6), O or S, R ³¹Expression hydrogen atom or halogen atom, R ³²Expression hydrogen atom, halogen atom, alkyl or alkynyl], and

[in the base, 1～8 numeral position, each N represents that any of 1～4 carbon atom and any of 5～8 carbon atom are replaced R respectively by 1 nitrogen-atoms ³⁴Expression hydrogen atom or halogen atom, R ³⁵Expression hydrogen atom or halogen atom, R ³⁶Expression hydrogen atom, halogen atom, alkyl or alkynyl].

6. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～3, its feature also is, the group Q in the formula (1) ⁴Be 4-chloro-styrene base; 4-fluorophenethyl thiazolinyl; 4-bromstyrol base; 4-acetylenylbenzene vinyl; 4-chloro-phenyl-ethynyl; 4-fluorophenyl ethynyl; 4-bromophenyl ethynyl; 4-ethynyl phenyl ethynyl; 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; 7-ethynyl-2-naphthyl; 5-chloro-indole-2-base; 5-fluoro indole-2-base; 5-bromo indole-2-base; 5-Ethynylindole-2-base; 5-skatole-2-base; 5-chloro-4-fluoro indole-2-base; 5-chloro-3-fluoro indole-2-base; 3-bromo-5-chloro-indole-2-base; 3-chloro-5-fluoro indole-2-base; 3-bromo-5-fluoro indole-2-base; 5-bromo-3-chloro-indole-2-base; 5-bromo-3-fluoro indole-2-base; 5-chloro-3-formyl indole-2-base; 5-fluoro-3-formyl indole-2-base; 5-bromo-3-formyl indole-2-base; 5-ethynyl-3-formyl indole-2-base; 5-chloro-3-(N; the N-formyl-dimethylamino) indoles-2-base; 5-fluoro-3-(N; the N-formyl-dimethylamino) indoles-2-base; 5-bromo-3-(N; the N-formyl-dimethylamino) indoles-2-base; 5-ethynyl-3-(N; the N-formyl-dimethylamino) indoles-2-base; 6-chloro-indole-2-base; 6-fluoro indole-2-base; 6-bromo indole-2-base; 6-Ethynylindole-2-base; 6-skatole-2-base; 5-chloro thiophene-2-base; 5-fluorobenzene thiophthene-2-base; 5-bromobenzene thiophthene-2-base; 5-acetylenylbenzene thiophthene-2-base; 5-methylbenzene thiophthene-2-base; 5-chloro-4-fluorobenzene thiophthene-2-base; 6-chloro thiophene-2-base; 6-fluorobenzene thiophthene-2-base; 6-bromobenzene thiophthene-2-base; 6-acetylenylbenzene thiophthene-2-base; 6-methylbenzene thiophthene-2-base; 5-chlorobenzene and furans-2-base; 5-fluorobenzene and furans-2-base; 5-bromobenzene and furans-2-base; 5-ethynyl benzo furans-2-base; 5-methyl cumarone-2-base; 5-chloro-4-fluorobenzene and furans-2-base; 6-chlorobenzene and furans-2-base; 6-fluorobenzene and furans-2-base; 6-bromobenzene and furans-2-base; 6-ethynyl benzo furans-2-base; 6-methyl cumarone-2-base; 5-chloro benzimidazole-2-base; 5-fluorobenzene and imidazoles-2-base; 5-bromobenzene and imidazoles-2-base; 5-ethynyl benzo imidazoles-2-base; 6-chloroquinoline-2-base; 6-fluorine quinoline-2-base; 6-bromoquinoline-2-base; 6-ethynyl quinoline-2-base; 7-chloroquinoline-3-base; 7-fluorine quinoline-3-base; 7-bromoquinoline-3-base; 7-ethynyl quinoline-3-base; 7-chlorine isoquinoline 99.9-3-base; 7-fluorine isoquinoline 99.9-3-base; 7-bromo-isoquinoline-3-base; 7-ethynyl isoquinoline 99.9-3-base; 7-chlorine cinnolines-3-base; 7-fluorine cinnolines-3-base; 7-bromine cinnolines-3-base; 7-ethynyl cinnolines-3-base; 7-chloro-2H-chromene-3-base; 7-fluoro-2H-chromene-3-base; 7-bromo-2H-chromene-3-base; 7-ethynyl-2H-chromene-3-base; 6-chloro-4-oxo-1; 4-dihydroquinoline-2-base; 6-fluoro-4-oxo-1; 4-dihydroquinoline-2-base; 6-bromo-4-oxo-1; 4-dihydroquinoline-2-base; 6-ethynyl-4-oxo-1; 4-dihydroquinoline-2-base; 6-chloro-4-oxo-1; 4-dihydroquinazoline-2-base; 6-fluoro-4-oxo-1; 4-dihydroquinazoline-2-base; 6-bromo-4-oxo-1; 4-dihydroquinazoline-2-base; 6-ethynyl-4-oxo-1; 4-dihydroquinazoline-2-base; phenyl; the 4-chloro-phenyl-; the 4-fluorophenyl; the 4-bromophenyl; the 4-ethynyl phenyl; the 3-chloro-phenyl-; the 3-fluorophenyl; the 3-bromophenyl; the 3-ethynyl phenyl; 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; the 4-dichlorophenyl; 2; the 4-difluorophenyl; 2; the 4-dibromo phenyl; 4-chloro-3-aminomethyl phenyl; 4-fluoro-3-aminomethyl phenyl; 4-bromo-3-aminomethyl phenyl; 4-chloro-2-aminomethyl phenyl; 4-fluoro-2-aminomethyl phenyl; 4-bromo-2-aminomethyl phenyl; 3; the 4-dichlorophenyl; 3; the 4-difluorophenyl; 3; the 4-dibromo phenyl; the 2-pyridyl; the 3-pyridyl; the 4-pyridyl; 4-chloro-2-is than pyridine base; 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; 5-chloro-3-pyridyl; 5-fluoro-3-pyridyl; 5-bromo-3-pyridyl; 5-ethynyl-3-pyridyl; 6-chloro-3-pyridazinyl; 6-fluoro-3-pyridazinyl; 6-bromo-3-pyridazinyl; 6-ethynyl-3-pyridazinyl; 5-chloro-2-thiazolyl; 5-fluoro-2-thiazolyl; 5-bromo-2-thiazolyl; 5-ethynyl-2-thiazolyl; 2-chlorothiophene also [2; 3-b] pyrroles-5-base; 2-fluorine thieno-[2; 3-b] pyrroles-5-base; 2-bromothiophene also [2; 3-b] pyrroles-5-base or 2-thiophene acetylene [2,3-b] pyrroles-5-base also.

7. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～6, its feature also is, the group Q in the formula (1) ¹For having the annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property that condenses of substituent saturated or undersaturated 2 ring property or 3 ring property.

8. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～6, its feature also is, the group Q in the formula (1) ¹For having substituent thienopyridine base, can have substituent tetramethylene sulfide and pyridyl, can have substituent thiazole and pyridyl, can have substituent thiazolidine and pyridyl, can have substituent thiazole and pyridazinyl, can have substituent thiazolidine and pyridazinyl, can have substituent pyrans benzothiazolyl, can have substituent dihydropyrane benzothiazolyl, can have substituent furo pyridyl, can have substituent tetrahydrofuran (THF) and pyridyl, can have substituting group De oxazole and pyridyl, can have substituent Si Qing oxazole and pyridyl, can have substituent pyrrolopyridinyl, can have substituent pyrrolin and pyridyl, can have substituent Pyrrolidine and pyridyl, can have substituent pyrrolo-pyrimidine radicals, can have substituent pyrrolin and pyrimidyl, can have substituting group De oxazole and pyridazinyl, can have substituent Si Qing oxazole and pyridazinyl, can have substituent pyrrolo-thiazolyl, can have substituent pyrrolin benzothiazolyl, can have substituent pyrroles Bing oxazolyl, can have substituent pyrrolin Bing oxazolyl, can have substituent benzothiazolyl, can have substituent tetrahydro benzothiazol base, can have substituent thiazole and pyrimidyl, can have substituent thiazoline and pyrimidyl, can have substituent benzo-aza _ base, can have substituent tetrahydro benzo azepine _ base, can have substituent thiazole and azepine _ base, can have substituent thiazolidine and azepine _ base, can have substituent thieno-azepine _ base, can have substituent tetramethylene sulfide and azepine _ base, can have substituent 4,5,6,7-tetrahydrochysene-5,6-tetramethylene thiazole and pyridazinyl maybe can have substituent 5,6-trimethylene-4,5,6,7-thiazolidine and pyridazinyl.

9. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～8, its feature also is, group Q ¹On substituting group for being selected from hydroxyl, halogen atom, haloalkyl, amino, cyano group, amidino groups, hydroxyl amidino groups, C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl C ₁-C ₆Alkyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, carboxyl, C ₂-C ₆Carboxyalkyl, C ₂-C ₆Alkoxy carbonyl C ₁-C ₆Alkyl, C ₂-C ₆Amidino groups, C that alkoxy carbonyl replaces ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkoxy carbonyl, amino C ₁-C ₆Alkyl, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl, two (C ₁-C ₆Alkyl) amino C ₁-C ₆Alkyl, C ₂-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, C ₁-C ₆Alkyloyl, C ₁-C ₆Alkanoylamino C ₁-C ₆Alkyl, C ₁-C ₆Alkyl sulphonyl, C ₁-C ₆Alkyl sulfonyl-amino C ₁-C ₆Alkyl, formamyl, C ₁-C ₆Alkyl-carbamoyl, N, N-two (C ₁-C ₆Alkyl) formamyl, C ₁-C ₆Alkylamino, two (C ₁-C ₆Alkyl) amino, amino-sulfonyl, aryl sulfonyl, aryl carbonyl, the C that can be replaced by halogen atom etc. ₂-C ₆Alkoxy carbonyl (C ₁-C ₆Alkyl) amino C ₁-C ₆Alkyl, C ₁-C ₆Alkyl sulphonyl C ₁-C ₆Alkyl contains 5～6 yuan of heterocyclic radicals of 1 or 2 identical or different nitrogen, oxygen or sulphur atom, 5～6 yuan of heterocyclic radical-C ₁-C ₄Alkyl, 5～6 yuan of heterocyclic radical-carbonyls, 5～6 yuan of heterocyclic radical-amino-C ₁-C ₄Alkyl, 5～6 yuan of heterocyclic radical-amino, 5～6 yuan of heterocyclic radical-oxygen bases, 3～6 yuan of heterocyclic radical-carbonyl-C ₁-C ₄Alkyl and 5～6 yuan of heterocyclic radical (C ₁-C ₆Alkyl) amino-C ₁-C ₄1～3 substituting group of alkyl.

10. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～9, its feature also is, the group T in the formula (1) ¹For carbonyl, base-C (=O)-C-(=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-or base-C (=S)-C (=S)-N (R ')-(R ' expression hydrogen atom, hydroxyl, alkyl or alkoxyl group in the group).

11. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～9, its feature also is, the group T in the formula (1) ¹For base-C (=O)-C-(=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-or base-C (=S)-C (=S)-N (R ')-(R ' expression hydrogen atom, hydroxyl, alkyl or alkoxyl group in the group).

12. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～11, its feature also is, the group Q in the formula (1) ³With following radicals

Expression, the Q in this group ⁵Alkylidene group or base-(CH for carbonatoms 3～6 ₂) _m-CH ₂-A-CH ₂-(CH ₂) _n-(m in the group and n are independent separately, expression 0 or 1, A is as previously mentioned);

R ³And R ⁴Independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; amino; oxyimino; Alkoximino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; can have substituent 3～6 yuan of heterocyclic radicals; the formamyl alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; on alkyl, can have substituent N-alkyl-carbamoyl alkyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical alkyl; alkyl sulfonyl-amino; the amino alkyl of alkyl sulfonyl; the oxo base; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the carboxyl acyl group; the alkoxyl group alkoxy carbonyl; the halo acyl group; N; N-dialkyl amido acyl group; the acyloxy acyl group; the hydroxyl acyl group; the alkoxyl group acyl group; the alkoxyalkyl alkylsulfonyl; N; N-dialkyl amido formyl radical acyl group; N; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl or alkoxyalkyl (thiocarbonyl).

13. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～11, its feature also is, the group Q in the formula (1) ³With following radicals

Expression, the Q in this group ⁵Be base-(CH ₂) _m-CH ₂-A-CH ₂-(CH ₂) _n-(m in the group and n are independent separately, expression 0 or 1, and A is as previously mentioned;

R ³And R ⁴Independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; amino; oxyimino; Alkoximino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; can have substituent 3～6 yuan of heterocyclic radicals; the formamyl alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; on alkyl, can have substituent N-alkyl-carbamoyl alkyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical alkyl; alkyl sulfonyl-amino; the amino alkyl of alkyl sulfonyl; the oxo base; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the carboxyl acyl group; the alkoxyl group alkoxy carbonyl; the halo acyl group; N; N-dialkyl amido acyl group; the acyloxy acyl group; the hydroxyl acyl group; the alkoxyl group acyl group; the alkoxyalkyl alkylsulfonyl; N; N-dialkyl amido formyl radical acyl group; N; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl or alkoxyalkyl (thiocarbonyl).

14. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～11, its feature also is, the group Q in the formula (1) ³With following radicals

Expression, the Q in this group ⁵Alkylidene group for carbonatoms 3～6;

R ³And R ⁴Independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; amino; oxyimino; Alkoximino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; can have substituent 3～6 yuan of heterocyclic radicals; the formamyl alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; on alkyl, can have substituent N-alkyl-carbamoyl alkyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical alkyl; alkyl sulfonyl-amino; the amino alkyl of alkyl sulfonyl; the oxo base; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the carboxyl acyl group; the alkoxyl group alkoxy carbonyl; the halo acyl group; N; N-dialkyl amido acyl group; the acyloxy acyl group; the hydroxyl acyl group; the alkoxyl group acyl group; the alkoxyalkyl alkylsulfonyl; N; N-dialkyl amido formyl radical acyl group; N; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl or alkoxyalkyl (thiocarbonyl).

15. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～11, its feature also is, the group Q in the formula (1) ³With following radicals

Expression, the Q in this group ⁵Alkylidene group for carbonatoms 4;

R ³The expression hydrogen atom, R ⁴Be illustrated on the alkyl and can have substituent N, N-dialkyl amido formyl radical maybe can have substituent 3～6 yuan of heterocyclic radicals.

16. as each described compound, its salt, its solvate or its N-oxide compound in the claim 1～11, its feature also is, the group Q in the formula (1) ³With following radicals

Expression, the Q in this group ⁵Alkylidene group for carbonatoms 4;

R ³The expression hydrogen atom, R ⁴Expression N, N-dialkyl amido formyl radical.

17. compound as claimed in claim 1, its salt, its solvate or its N-oxide compound, its feature also are, with general formula (1)

Q ¹-Q ²-T ⁰-N(R ¹)-Q ³-N(R ²)-T ¹-Q ⁴ (1)

Expression,

In the formula, R ¹And R ²Independent separately, expression hydrogen atom, hydroxyl, alkyl or alkoxyl group;

Q ¹The annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property that condenses that expression can have substituent saturated or undersaturated 5～6 yuan of cyclic hydrocarbon group, can have substituent saturated or undersaturated 5～7 yuan of heterocyclic radicals, can have substituent saturated or undersaturated 2 ring property or 3 ring property;

Q ²The expression singly-bound, the alkylidene group of a straight chain shape or a catenate carbonatoms 1～6, the alkenylene of a straight chain shape or a catenate carbonatoms 2～6, the alkynylene of a straight chain shape or a catenate carbonatoms 2～6, can have saturated or undersaturated 5～6 yuan of cyclic hydrocarbon group of substituent divalent, can have saturated or undersaturated 5～7 yuan of heterocyclic radicals of substituent divalent, the annelated heterocycles base that alkyl maybe can have saturated or undersaturated 2 ring property of substituent divalent or 3 ring property that condenses that can have saturated or undersaturated 2 ring property of substituent divalent or 3 ring property;

Q ³By following radicals

Expression, the Q in this group ⁵Be base-(CH ₂) _m-CH ₂-A-CH ₂-(CH ₂) _n-(m in the group and n are independent separately, the integer of expression 0,1～3, A represent Sauerstoffatom, nitrogen-atoms, sulphur atom ,-SO-,-SO ₂-,-NH-,-O-NH-,-NH-NH-,-S-NH-,-SO-NH-or-SO ₂-NH-);

R ³And R ⁴Containing Q ⁵Ring on carbon atom; replace on nitrogen-atoms or the sulphur atom; independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; cyano group; the cyano group alkyl; amino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; Alkoximino; oxyimino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxy carbonyl alkyl amino; carboxyalkyl amino; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; the formamyl alkyl; can have substituent N-alkyl-carbamoyl alkyl on the alkyl; can have substituent N on the alkyl; N-dialkyl amido formyl radical alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; can have substituent 3～6 yuan of heterocycle carbonylic alkyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; aryl; aralkyl; can have substituent 3～6 yuan of heterocyclic radicals; can have substituent 3～6 yuan of Heterocyclylalkyls; alkyl sulfonyl amino; Arenesulfonyl amino; the amino alkyl of alkyl sulfonyl; the Arenesulfonyl amino alkyl; the amino carbonyl of alkyl sulfonyl; the Arenesulfonyl amino carbonyl; the amino carbonylic alkyl of alkyl sulfonyl; the Arenesulfonyl amino carbonylic alkyl; the oxo base; carbamoyloxy; aralkoxy; the carboxyl alkoxyl group; the alkoxy carbonyl alkoxyl group; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the alkoxyl group alkoxy carbonyl; the hydroxyl acyl group; the alkoxyl group acyl group; the halo acyl group; the carboxyl acyl group; aminoacyl; the acyloxy acyl group; the acyloxy alkyl sulphonyl; the hydroxyalkyl alkylsulfonyl; the alkoxyalkyl alkylsulfonyl; can have substituent 3～6 yuan of heterocycle alkylsulfonyls; can have substituent 3～6 yuan of heterocyclic oxy groups; N-alkylamino acyl group; N; N-dialkyl amido acyl group; can have substituent N on the alkyl; N-dialkyl amido formyl radical acyl group; can have substituent N on the alkyl; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; the N-aryl-amino-carbonyl; N-3～6 yuan heterocyclic amino group formyl radical; N-alkyl-N-aryl-amino-carbonyl; N-alkyl-N-3～6 yuan heterocyclic amino group formyl radical; N-aryl-amino-carbonyl alkyl; N-3～6 yuan heterocyclic amino group formyl radical alkyl; N-alkyl-N-aryl-amino-carbonyl alkyl; N-alkyl-N-3～6 yuan heterocyclic amino group formyl radical alkyl; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl; alkoxyalkyl (thiocarbonyl); alkylthio alkyl or N-acyl group-N-alkylamino alkyl or R ³And R ⁴Represent the alkylidene group of carbonatoms 1～5, the alkenylene of carbonatoms 2～5, the alkylene dioxo base or the carbonyldioxy of carbonatoms 1～5 together;

Q ⁴The annelated heterocycles base that condenses alkyl, can have substituent saturated or unsaturated 2 ring property or 3 ring property that expression can have substituent aryl, can have substituent aromatic yl alkenyl, can have substituent aromatic yl polysulfide yl, can have substituent heteroaryl, can have substituent heteroaryl alkenyl, can have substituent saturated or unsaturated 2 ring property or 3 ring property;

T ⁰Expression carbonyl or thiocarbonyl;

T ¹Expression carbonyl, alkylsulfonyl or thiocarbonyl.

18. compound as claimed in claim 17, its salt, its solvate or its N-oxide compound, its feature also is, Q ¹Condense the annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property, Q for what can have substituent saturated or undersaturated 2 ring property or 3 ring property ²Be singly-bound.

19. as claim 17 or 18 described compounds, its salt, its solvate or its N-oxide compound, its feature also is, Q ¹For having substituent thienopyridine base, can have substituent tetramethylene sulfide and pyridyl, can have substituent thiazole and pyridyl, can have substituent thiazolidine and pyridyl, can have substituent thiazole and pyridazinyl, can have substituent thiazolidine and pyridazinyl, can have substituent pyrans benzothiazolyl, can have substituent dihydropyrane benzothiazolyl, can have substituent furo pyridyl, can have substituent tetrahydrofuran (THF) and pyridyl, can have substituting group De oxazole and pyridyl, can have substituent Si Qing oxazole and pyridyl, can have substituent pyrrolopyridinyl, can have substituent pyrrolin and pyridyl, can have substituent Pyrrolidine and pyridyl, can have substituent pyrrolo-pyrimidine radicals, can have substituent pyrrolin and pyrimidyl, can have substituting group De oxazole and pyridazinyl, can have substituent Si Qing oxazole and pyridazinyl, can have substituent pyrrolo-thiazolyl, can have substituent pyrrolin benzothiazolyl, can have substituent pyrroles Bing oxazolyl, can have substituent pyrrolin Bing oxazolyl, can have substituent benzothiazolyl, can have substituent tetrahydro benzothiazol base, can have substituent thiazole and pyrimidyl, can have substituent thiazoline and pyrimidyl, can have substituent benzo-aza _ base, can have substituent tetrahydro benzo azepine _ base, can have substituent thiazole and azepine _ base, can have substituent thiazolidine and azepine _ base, can have substituent thieno-azepine _ base, can have substituent tetramethylene sulfide and azepine _ base, can have substituent 4,5,6,7-tetrahydrochysene-5,6-tetramethylene thiazole and pyridazinyl maybe can have substituent 5,6-trimethylene-4,5,6,7-thiazolidine and pyridazinyl.

20. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～19, its feature also is, group Q ¹On substituting group for being selected from hydroxyl, halogen atom, haloalkyl, amino, cyano group, amidino groups, hydroxyl amidino groups, C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl C ₁-C ₆Alkyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, carboxyl, C ₂-C ₆Carboxyalkyl, C ₂-C ₆Alkoxy carbonyl C ₁-C ₆Alkyl, C ₂-C ₆Amidino groups, C that alkoxy carbonyl replaces ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkoxy carbonyl, amino C ₁-C ₆Alkyl, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl, two (C ₁-C ₆Alkyl) amino C ₁-C ₆Alkyl, C ₂-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, C ₁-C ₆Alkyloyl, C ₁-C ₆Alkanoylamino C ₁-C ₆Alkyl, C ₁-C ₆Alkyl sulphonyl, C ₁-C ₆Alkyl sulfonyl-amino C ₁-C ₆Alkyl, formamyl, C ₁-C ₆Alkyl-carbamoyl, N, N-two (C ₁-C ₆Alkyl) formamyl, C ₁-C ₆Alkylamino, two (C ₁-C ₆Alkyl) amino, amino-sulfonyl, aryl sulfonyl, aryl carbonyl, the C that can be replaced by halogen atom etc. ₂-C ₆Alkoxy carbonyl (C ₁-C ₆Alkyl) amino C ₁-C ₆Alkyl, C ₁-C ₆Alkyl sulphonyl C ₁-C ₆Alkyl contains 5～6 yuan of heterocyclic radicals of 1 or 2 identical or different nitrogen, oxygen or sulphur atom, 5～6 yuan of heterocyclic radical-C ₁-C ₄Alkyl, 5～6 yuan of heterocyclic radical-carbonyls, 5～6 yuan of heterocyclic radical-amino-C ₁-C ₄Alkyl, 5～6 yuan of heterocyclic radical-amino, 5～6 yuan of heterocyclic radical-oxygen bases, 3～6 yuan of heterocyclic radical-carbonyl-C ₁-C ₄Alkyl and 5～6 yuan of heterocyclic radical (C ₁-C ₆Alkyl) amino-C ₁-C ₄1～3 substituting group of alkyl.

21. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～20, its feature also is, Q ³With following radicals

Expression, the Q in this group ⁵Be base-(CH ₂) _m-CH ₂-A-CH ₂-(CH ₂) _n-(m in the group and n are independent separately, expression 0 or 1, A is as previously mentioned);

R ³And R ⁴Independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; amino; oxyimino; Alkoximino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; can have substituent 3～6 yuan of heterocyclic radicals; the formamyl alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; on alkyl, can have substituent N-alkyl-carbamoyl alkyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical alkyl; alkyl sulfonyl-amino; the amino alkyl of alkyl sulfonyl; the oxo base; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the carboxyl acyl group; the alkoxyl group alkoxy carbonyl; the halo acyl group; N; N-dialkyl amido acyl group; the acyloxy acyl group; the hydroxyl acyl group; the alkoxyl group acyl group; the alkoxyalkyl alkylsulfonyl; N; N-dialkyl amido formyl radical acyl group; N; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl or alkoxyalkyl (thiocarbonyl).

22. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～21, its feature also is, Q ⁴Can have substituent naphthyl for being selected from, can have substituent anthryl, can have substituent phenanthryl, can have substituent styryl, can have substituent phenylacetylene base, can have substituent thienyl vinyl, can have substituent pyridyl vinyl, can have substituent indenyl, can have substituent indanyl, can have substituent tetralyl, can have substituent benzofuryl, can have substituent isobenzofuran-base, can have substituent benzothienyl, can have substituent indyl, can have substituent indolinyl, can have substituent pseudoindoyl, can have substituent isoindolinyl, can have substituent indazolyl, can have substituent quinolyl, can have substituent dihydroquinoline base, can have substituent 4-oxo-dihydro quinolyl (dihydroquinoline-4-ketone), can have substituent tetrahydric quinoline group, can have substituent isoquinolyl, can have substituent tetrahydro isoquinolyl, can have substituent chromenyl, can have substituent chromanyl, can have substituent isochroman base, can have substituent 4H-4-oxo benzopyranyl, can have substituent 3,4-dihydro-4H-4-oxo benzopyranyl, can have substituent 4H-quinolizinyl, can have substituent quinazolyl, can have substituent dihydroquinazoline base, can have substituent tetrahydro quinazoline base, can have substituent quinoxalinyl, can have substituent tetrahydroquinoxaline base, can have substituent cinnolines base, can have substituent tetrahydrochysene cinnolines base, can have substituent indolizine base, can have substituent tetrahydrochysene indolizine base, can have substituent benzothiazolyl, can have substituent tetrahydro benzothiazol base, can have substituent benzoxazolyl, can have substituent benzisothiazole base, can have substituent benzoisoxazole base, can have substituent benzimidazolyl-, can have substituent naphthyridinyl, can have substituent Tetrahydronaphthyridderivates base, can have substituent thienopyridine base, can have substituent tetramethylene sulfide and pyridyl, can have substituent thiazole and pyridyl, can have substituent thiazolidine and pyridyl, can have substituent thiazole and pyridazinyl, can have substituent thiazolidine and pyridazinyl, can have substituent pyrrolopyridinyl, can have substituent pyrrolin and pyridyl, can have substituent Pyrrolidine and pyridyl, can have substituent pyrrolo-pyrimidine radicals, can have substituent pyrrolin and pyrimidyl, can have substituent pyrido quinazolyl, can have substituent dihydro pyrido quinazolyl, can have substituent Pyridopyrimidine base, can have substituent tetrahydropyridine and pyrimidyl, can have substituent pyrans benzothiazolyl, can have substituent dihydropyrane benzothiazolyl, can have substituent furo pyridyl, can have substituent tetrahydrofuran (THF) and pyridyl, can have substituting group De oxazole and pyridyl, can have substituent Si Qing oxazole and pyridyl, can have substituting group De oxazole and pyridazinyl, can have substituent Si Qing oxazole and pyridazinyl, can have substituent pyrrolo-thiazolyl, can have substituent pyrrolin benzothiazolyl, can have substituent pyrroles Bing oxazolyl, can have substituent pyrrolin Bing oxazolyl, can have substituent Thienopyrroles base, can have substituent thiazole and pyrimidyl, can have substituent 4-oxo-tetrahydrochysene cinnolines base, can have substituent 1,2,4-benzothiadiazine base, can have substituent 1,1-titanium dioxide-2H-1,2,4-benzothiadiazine base, can have substituent 1,2,4-Ben Bing oxadiazine base, can have substituent cyclopenta pyranyl, can have substituent thienofuran base, can have substituent furo pyranyl, can have substituent Bi Ding Bing oxazinyl, can have substituent Bi Zuo Bing oxazolyl, can have substituent Imidazothiazole base, can have substituent imidazopyridyl, can have substituent imidazolidine and pyridyl, can have substituent pyrazine and pyridazinyl, can have substituent benzisoquinoline base, can have substituent furo cinnolines base, can have substituent pyrazolo thiazole and pyridazinyl, can have substituent tetrahydro-pyrazole and thiazole and pyridazinyl, can have substituent six hydrogen thiazoles and pyridazine and pyridazinyl, can have substituent imidazo-triazine base, can have substituting group De oxazole and pyridyl, can have substituent benzo oxa-_ base, can have substituent benzo-aza _ base, can have substituent tetrahydro benzo azepine _ base, can have substituent benzodiazepine _ base, can have substituent benzo three azepines _ base, can have substituent thieno-azepine _ base, can have substituent tetramethylene sulfide and azepine _ base, can have substituent thieno-diaza _ base, can have substituent thieno-three azepines _ base, can have substituent thiazole and azepine _ base, can have substituent thiazolidine and azepine _ base, can have substituent 4,5,6,7-tetrahydrochysene-5,6-tetramethylene thiazole and pyridazinyl, can have substituent 5,6-trimethylene-4,5,6, the group of 7-thiazolidine and pyridazinyl.

23. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～21, its feature also is, Q ⁴On substituting group for being selected from hydroxyl; halogen atom; haloalkyl; amino; cyano group; aminoalkyl group; nitro; hydroxyalkyl; alkoxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl alkyl; acyl group; amidino groups; the hydroxyl amidino groups; the straight chain shape; prop up the alkyl of chain or cyclic carbonatoms 1～6, the straight chain shape; prop up the alkoxyl group of chain or cyclic carbonatoms 1～6, the straight chain shape; prop up the amidino groups of the alkyl replacement of chain or cyclic carbonatoms 1～6; the straight chain shape; prop up the amidino groups of the alkoxyl group replacement of chain or cyclic carbonatoms 1～6; the straight chain shape; prop up the amidino groups of the alkoxy carbonyl replacement of chain or cyclic carbonatoms 2～7, the straight chain shape; prop up the alkenyl of chain or cyclic carbonatoms 2～6, the alkynyl of a straight chain shape or a catenate carbonatoms 2～6; the straight chain shape; prop up the alkoxy carbonyl of chain or cyclic carbonatoms 2～6; formamyl has the straight chain shape on nitrogen-atoms; prop up the mono-or dialkylcarbamoyl group of the alkyl replacement of chain or cyclic carbonatoms 1～6, by the straight chain shape; 1～3 group of one or dialkyl amido that the alkyl of chain or cyclic carbonatoms 1～6 replaces and 5～6 yuan nitrogen heterocycle.

24. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～21, its feature also is, Q ⁴For

[in the base, R ⁵And R ⁶Independent separately; expression hydrogen atom, cyano group, halogen atom, alkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, alkoxy carbonyl, alkoxy carbonyl alkyl or the phenyl that can be replaced by cyano group, hydroxyl, halogen atom, alkyl or alkoxyl group, R ⁷And R ⁸Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, R ⁹And R ¹⁰Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, R ¹¹, R ¹²And R ¹³Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, X ¹Expression CH ₂, CH, NH, NOH, N, O or S, R ¹⁴, R ¹⁵And R ¹⁶Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, X ²Expression NH, N, O or S, X ³Expression N, C or CH, X ⁴Expression N, C or CH, R ¹⁷And R ¹⁸Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl, but X ³And X ⁴For the situation of the combination of C and CH and all be except the situation of C or CH],

[in the base, N represents R ¹⁹1 or 2 of the carbon atom of the ring that replaces is replaced R by nitrogen-atoms ¹⁹, R ²⁰And R ²¹Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, X ⁵Expression CH ₂, CH, N or NH, Z ¹Expression N, NH or O, Z ²Expression CH ₂, CH, C or N, Z ³Expression CH ₂, CH, S, SO ₂Or C=O, X ⁵-Z ²Expression X ⁵And Z ²Close R with singly-bound or two bond ²²And R ²³Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl, R ²⁴Expression hydrogen atom or alkyl],

[in the base, X ⁶Expression O or S, R ²⁵And R ²⁶Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl], perhaps

[in the base, 1～8 numeral position, each N represents that any of 1～4 carbon atom and any of 5～8 carbon atom are replaced R respectively by 1 nitrogen-atoms ³⁴, R ³⁵And R ³⁶Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N, N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl].

25. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～21, its feature also is, Q ⁴For

[in the base, R ⁵And R ⁶Independent separately, expression hydrogen atom or alkyl, R ⁷The expression hydrogen atom, R ⁸Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, R ⁹The expression hydrogen atom, R ¹⁰Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, R ¹¹And R ¹²All represent hydrogen atom, R ¹³Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, X ¹Expression NH, NOH, N, O or S, R ¹⁴Expression hydrogen atom, halogen atom, acyl group, N-alkyl-carbamoyl, N, N-dialkyl amido formyl radical or alkyl, R ¹⁵Expression hydrogen atom or halogen atom, R ¹⁶Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, X ²Expression NH, O or S, X ³Expression N, C or CH, X ⁴Expression N, C or CH, R ¹⁷The expression hydrogen atom, R ¹⁸Expression hydrogen atom, halogen atom, alkyl or alkynyl, but X ³And X ⁴For the situation of the combination of C and CH and all be except the situation of C or CH],

[in the base, N represents R ¹⁹1 or 2 of the carbon atom of the ring that replaces is replaced R by nitrogen-atoms ¹⁹And R ²⁰All represent hydrogen atom, R ²¹Expression hydrogen atom, cyano group, halogen atom, alkyl, alkenyl, alkynyl or haloalkyl],

[in the base, X ⁵Expression CH ₂, CH, N or NH, Z ¹Expression N, NH or O, Z ²Expression CH ₂, CH, C or N, Z ³Expression CH ₂, CH, S, SO ₂Or C=O, X ⁵-Z ²Expression X ⁵And Z ²Close R with singly-bound or two bond ²²The expression hydrogen atom, R ²³Expression hydrogen atom, halogen atom, alkyl or alkynyl, R ²⁴The expression hydrogen atom],

[in the base, X ⁶Expression O, R ²⁵The expression hydrogen atom, R ²⁶Expression hydrogen atom, halogen atom, alkyl or alkynyl], perhaps

[in the base, 1～8 numeral position, each N represents that any of 1～4 carbon atom and any of 5～8 carbon atom are replaced R respectively by 1 nitrogen-atoms ³⁴Expression hydrogen atom or halogen atom, R ³⁵Expression hydrogen atom or halogen atom, R ³⁶Expression hydrogen atom, halogen atom, alkyl or alkynyl].

26. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～21, its feature also is, Q ⁴Be 4-chloro-styrene base; 4-fluorophenethyl thiazolinyl; 4-bromstyrol base; 4-acetylenylbenzene vinyl; 4-chloro-phenyl-ethynyl; 4-fluorophenyl ethynyl; 4-bromophenyl ethynyl; 4-ethynyl phenyl ethynyl; 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; 7-ethynyl-2-naphthyl; 5-chloro-indole-2-base; 5-fluoro indole-2-base; 5-bromo indole-2-base; 5-Ethynylindole-2-base; 5-skatole-2-base; 5-chloro-4-fluoro indole-2-base; 5-chloro-3-fluoro indole-2-base; 3-bromo-5-chloro-indole-2-base; 3-chloro-5-fluoro indole-2-base; 3-bromo-5-fluoro indole-2-base; 5-bromo-3-chloro-indole-2-base; 5-bromo-3-fluoro indole-2-base; 5-chloro-3-formyl indole-2-base; 5-fluoro-3-formyl indole-2-base; 5-bromo-3-formyl indole-2-base; 5-ethynyl-3-formyl indole-2-base; 5-chloro-3-(N; the N-formyl-dimethylamino) indoles-2-base; 5-fluoro-3-(N; the N-formyl-dimethylamino) indoles-2-base; 5-bromo-3-(N; the N-formyl-dimethylamino) indoles-2-base; 5-ethynyl-3-(N; the N-formyl-dimethylamino) indoles-2-base; 6-chloro-indole-2-base; 6-fluoro indole-2-base; 6-bromo indole-2-base; 6-Ethynylindole-2-base; 6-skatole-2-base; 5-chloro thiophene-2-base; 5-fluorobenzene thiophthene-2-base; 5-bromobenzene thiophthene-2-base; 5-acetylenylbenzene thiophthene-2-base; 5-methylbenzene thiophthene-2-base; 5-chloro-4-fluorobenzene thiophthene-2-base; 6-chloro thiophene-2-base; 6-fluorobenzene thiophthene-2-base; 6-bromobenzene thiophthene-2-base; 6-acetylenylbenzene thiophthene-2-base; 6-methylbenzene thiophthene-2-base; 5-chlorobenzene and furans-2-base; 5-fluorobenzene and furans-2-base; 5-bromobenzene and furans-2-base; 5-ethynyl benzo furans-2-base; 5-methyl cumarone-2-base; 5-chloro-4-fluorobenzene and furans-2-base; 6-chlorobenzene and furans-2-base; 6-fluorobenzene and furans-2-base; 6-bromobenzene and furans-2-base; 6-ethynyl benzo furans-2-base; 6-methyl cumarone-2-base; 5-chloro benzimidazole-2-base; 5-fluorobenzene and imidazoles-2-base; 5-bromobenzene and imidazoles-2-base; 5-ethynyl benzo imidazoles-2-base; 6-chloroquinoline-2-base; 6-fluorine quinoline-2-base; 6-bromoquinoline-2-base; 6-ethynyl quinoline-2-base; 7-chloroquinoline-3-base; 7-fluorine quinoline-3-base; 7-bromoquinoline-3-base; 7-ethynyl quinoline-3-base; 7-chlorine isoquinoline 99.9-3-base; 7-fluorine isoquinoline 99.9-3-base; 7-bromo-isoquinoline-3-base; 7-ethynyl isoquinoline 99.9-3-base; 7-chlorine cinnolines-3-base; 7-fluorine cinnolines-3-base; 7-bromine cinnolines-3-base; 7-ethynyl cinnolines-3-base; 7-chloro-2H-chromene-3-base; 7-fluoro-2H-chromene-3-base; 7-bromo-2H-chromene-3-base; 7-ethynyl-2H-chromene-3-base; 6-chloro-4-oxo-1; 4-dihydroquinoline-2-base; 6-fluoro-4-oxo-1; 4-dihydroquinoline-2-base; 6-bromo-4-oxo-1; 4-dihydroquinoline-2-base; 6-ethynyl-4-oxo-1; 4-dihydroquinoline-2-base; 6-chloro-4-oxo-1; 4-dihydroquinazoline-2-base; 6-fluoro-4-oxo-1; 4-dihydroquinazoline-2-base; 6-bromo-4-oxo-1; 4-dihydroquinazoline-2-base; 6-ethynyl-4-oxo-1; 4-dihydroquinazoline-2-base; 2-chlorothiophene also [2; 3-b] pyrroles-5-base; 2-fluorine thieno-[2; 3-b] pyrroles-5-base; 2-bromothiophene also [2; 3-b] pyrroles-5-base or 2-thiophene acetylene [2,3-b] pyrroles-5-base also.

27. as each described compound, its salt, its solvate or its N-oxide compound in the claim 17～26, its feature also is, T ¹Be carbonyl.

28. compound as claimed in claim 1, its salt, its solvate or its N-oxide compound, its feature also are, by general formula (1)

Q ¹-Q ²-T ⁰-N(R ¹)-Q ³-N(R ²)-T ¹-Q ⁴ (1)

Expression;

In the formula, R ¹And R ²Independent separately, expression hydrogen atom, hydroxyl, alkyl or alkoxyl group;

Q ¹The annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property that condenses that expression can have substituent saturated or undersaturated 5～6 yuan of cyclic hydrocarbon group, can have substituent saturated or undersaturated 5～7 yuan of heterocyclic radicals, can have substituent saturated or undersaturated 2 ring property or 3 ring property;

Q ²The expression singly-bound, the alkylidene group of a straight chain shape or a catenate carbonatoms 1～6, the alkenylene of a straight chain shape or a catenate carbonatoms 2～6, the alkynylene of a straight chain shape or a catenate carbonatoms 2～6, can have saturated or undersaturated 5～6 yuan of cyclic hydrocarbon group of substituent divalent, can have saturated or undersaturated 5～7 yuan of heterocyclic radicals of substituent divalent, the annelated heterocycles base that alkyl maybe can have saturated or undersaturated 2 ring property of substituent divalent or 3 ring property that condenses that can have saturated or undersaturated 2 ring property of substituent divalent or 3 ring property;

Q ³By following radicals

Expression, the Q in this group ⁵Be the alkylidene group of carbonatoms 1～8, the alkenylene or the base-(CH of carbonatoms 2～8 ₂) m-CH ₂-A-CH ₂-(CH ₂) _n-(m in the group and n are independent separately, the integer of expression 0,1～3, A represent Sauerstoffatom, nitrogen-atoms, sulphur atom ,-SO-,-SO ₂-,-NH-,-O-NH-,-NH-NH-,-S-NH-,-SO-NH-or-SO ₂-NH-);

R ³And R ⁴Containing Q ⁵Ring on carbon atom; replace on nitrogen-atoms or the sulphur atom; independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; cyano group; the cyano group alkyl; amino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; Alkoximino; oxyimino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxy carbonyl alkyl amino; carboxyalkyl amino; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; the formamyl alkyl; can have substituent N-alkyl-carbamoyl alkyl on the alkyl; can have substituent N on the alkyl; N-dialkyl amido formyl radical alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; can have substituent 3～6 yuan of heterocycle carbonylic alkyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; aryl; aralkyl; can have substituent 3～6 yuan of heterocyclic radicals; can have substituent 3～6 yuan of Heterocyclylalkyls; alkyl sulfonyl amino; Arenesulfonyl amino; the amino alkyl of alkyl sulfonyl; the Arenesulfonyl amino alkyl; the amino carbonyl of alkyl sulfonyl; the Arenesulfonyl amino carbonyl; the amino carbonylic alkyl of alkyl sulfonyl; the Arenesulfonyl amino carbonylic alkyl; the oxo base; carbamoyloxy; aralkoxy; the carboxyl alkoxyl group; the alkoxy carbonyl alkoxyl group; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the alkoxyl group alkoxy carbonyl; the hydroxyl acyl group; the alkoxyl group acyl group; the halo acyl group; the carboxyl acyl group; aminoacyl; the acyloxy acyl group; the acyloxy alkyl sulphonyl; the hydroxyalkyl alkylsulfonyl; the alkoxyalkyl alkylsulfonyl; can have substituent 3～6 yuan of heterocycle alkylsulfonyls; can have substituent 3～6 yuan of heterocyclic oxy groups; N-alkylamino acyl group; N; N-dialkyl amido acyl group; can have substituent N on the alkyl; N-dialkyl amido formyl radical acyl group; can have substituent N on the alkyl; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; the N-aryl-amino-carbonyl; N-3～6 yuan heterocyclic amino group formyl radical; N-alkyl-N-aryl-amino-carbonyl; N-alkyl-N-3～6 yuan heterocyclic amino group formyl radical; N-aryl-amino-carbonyl alkyl; N-3～6 yuan heterocyclic amino group formyl radical alkyl; N-alkyl-N-aryl-amino-carbonyl alkyl; N-alkyl-N-3～6 yuan heterocyclic amino group formyl radical alkyl; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl; alkoxyalkyl (thiocarbonyl); alkylthio alkyl or N-acyl group-N-alkylamino alkyl or R ³And R ⁴Represent the alkylidene group of carbonatoms 1～5, the alkenylene of carbonatoms 2～5, the alkylene dioxo base or the carbonyldioxy of carbonatoms 1～5 together;

Q ⁴The annelated heterocycles base that condenses alkyl, can have substituent saturated or unsaturated 2 ring property or 3 ring property that expression can have substituent aryl, can have substituent aromatic yl alkenyl, can have substituent aromatic yl polysulfide yl, can have substituent heteroaryl, can have substituent heteroaryl alkenyl, can have substituent saturated or unsaturated 2 ring property or 3 ring property;

T ⁰Expression carbonyl or thiocarbonyl;

T ¹Expression base-C (=O)-C-(=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-, base-C (=S)-C (=S)-N (R ')-(R ' expression hydrogen atom, hydroxyl, alkyl or alkoxyl group in the group), base-C (=O)-A ¹-N (R ")-(A in the group ¹Expression can have the alkylidene group of substituent carbonatoms 1～5, R " expression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=O)-NH-, base-C (=S)-NH-, base-C (=O)-NH-NH-, base-C (=O)-A ²-C (=O)-(A in the group ²The alkylidene group of expression singly-bound or carbonatoms 1～5), base-C (=O)-A ³-C (=O)-NH-(A in the group ³The alkylidene group of expression carbonatoms 1～5), base-C (=O)-C (=NOR ^a)-N (R ^b)-, base-C (=S)-C (=NOR ^a)-N (R ^bR in the)-(group ^aExpression hydrogen atom, alkyl or alkyloyl, R ^bExpression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=O)-N=N-, base-C (=S)-N=N-, base-C (=NOR ^c)-C (=O)-N (R ^dR in the)-(group ^cExpression hydrogen atom, alkyl, alkyloyl, aryl or aralkyl, R ^dExpression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=N-N-(R ^e) (R ^f))-C (=O)-N (R ^gR in the)-(group ^eAnd R ^fIndependent separately, expression hydrogen atom, alkyl, alkyloyl, alkyl (thiocarbonyl), R ^gExpression hydrogen atom, hydroxyl, alkyl or alkoxyl group), base-C (=O)-NH-C (=O)-, base-C (=S)-NH-C (=O)-, base-C (=O)-NH-C (=S)-, base-C (=S)-NHC (=S)-, base-C (=O)-NH-SO ₂-, base-SO ₂-NH-, base-C (=NCN)-NH-C (=O)-, base-C (=S)-C (=O)-or thiocarbonyl.

29. compound as claimed in claim 28, its salt, its solvate or its N-oxide compound, its feature also is, Q ¹Condense the annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property, Q for what can have substituent saturated or undersaturated 2 ring property or 3 ring property ²Be singly-bound.

30. as claim 28 or 29 described compounds, its salt, its solvate or its N-oxide compound, its feature also is, Q ¹For having substituent thienopyridine base, can have substituent tetramethylene sulfide and pyridyl, can have substituent thiazole and pyridyl, can have substituent thiazolidine and pyridyl, can have substituent thiazole and pyridazinyl, can have substituent thiazolidine and pyridazinyl, can have substituent pyrans benzothiazolyl, can have substituent dihydropyrane benzothiazolyl, can have substituent furo pyridyl, can have substituent tetrahydrofuran (THF) and pyridyl, can have substituting group De oxazole and pyridyl, can have substituent Si Qing oxazole and pyridyl, can have substituent pyrrolopyridinyl, can have substituent pyrrolin and pyridyl, can have substituent Pyrrolidine and pyridyl, can have substituent pyrrolo-pyrimidine radicals, can have substituent pyrrolin and pyrimidyl, can have substituting group De oxazole and pyridazinyl, can have substituent Si Qing oxazole and pyridazinyl, can have substituent pyrrolo-thiazolyl, can have substituent pyrrolin benzothiazolyl, can have substituent pyrroles Bing oxazolyl, can have substituent pyrrolin Bing oxazolyl, can have substituent benzothiazolyl, can have substituent tetrahydro benzothiazol base, can have substituent thiazole and pyrimidyl, can have substituent thiazoline and pyrimidyl, can have substituent benzo-aza _ base, can have substituent tetrahydro benzo azepine _ base, can have substituent thiazole and azepine _ base, can have substituent thiazolidine and azepine _ base, can have substituent thieno-azepine _ base, can have substituent tetramethylene sulfide and azepine _ base, can have substituent 4,5,6,7-tetrahydrochysene-5,6-tetramethylene thiazole and pyridazinyl maybe can have substituent 5,6-trimethylene-4,5,6,7-thiazolidine and pyridazinyl.

31. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～30, its feature also is, group Q ¹On substituting group for being selected from hydroxyl, halogen atom, haloalkyl, amino, cyano group, amidino groups, hydroxyl amidino groups, C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl C ₁-C ₆Alkyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkoxy C ₁-C ₆Alkyl, carboxyl, C ₂-C ₆Carboxyalkyl, C ₂-C ₆Alkoxy carbonyl C ₁-C ₆Alkyl, C ₂-C ₆Amidino groups, C that alkoxy carbonyl replaces ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkoxy carbonyl, amino C ₁-C ₆Alkyl, C ₁-C ₆Alkylamino C ₁-C ₆Alkyl, two (C ₁-C ₆Alkyl) amino C ₁-C ₆Alkyl, C ₂-C ₆Alkoxycarbonyl amino C ₁-C ₆Alkyl, C ₁-C ₆Alkyloyl, C ₁-C ₆Alkanoylamino C ₁-C ₆Alkyl, C ₁-C ₆Alkyl sulphonyl, C ₁-C ₆Alkyl sulfonyl-amino C ₁-C ₆Alkyl, formamyl, C ₁-C ₆Alkyl-carbamoyl, N, N-two (C ₁-C ₆Alkyl) formamyl, C ₁-C ₆Alkylamino, two (C ₁-C ₆Alkyl) amino, amino-sulfonyl, aryl sulfonyl, aryl carbonyl, the C that can be replaced by halogen atom etc. ₂-C ₆Alkoxy carbonyl (C ₁-C ₆Alkyl) amino C ₁-C ₆Alkyl, C ₁-C ₆Alkyl sulphonyl C ₁-C ₆Alkyl contains 5～6 yuan of heterocyclic radicals of 1 or 2 identical or different nitrogen, oxygen or sulphur atom, 5～6 yuan of heterocyclic radical-C ₁-C ₄Alkyl, 5～6 yuan of heterocyclic radical-carbonyls, 5～6 yuan of heterocyclic radical-amino-C ₁-C ₄Alkyl, 5～6 yuan of heterocyclic radical-amino, 5～6 yuan of heterocyclic radical-oxygen bases, 3～6 yuan of heterocyclic radical-carbonyl-C ₁-C ₄Alkyl and 5～6 yuan of heterocyclic radical (C ₁-C ₆Alkyl) amino-C ₁-C ₄1～3 substituting group of alkyl.

32. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～31, its feature also is, Q ³With following radicals

Expression, the Q in this group ⁵Alkylidene group or base-(CH for carbonatoms 3～6 ₂) _m-CH ₂-A-CH ₂-(CH ₂) _n-(m in the group and n are independent separately, expression 0 or 1, A is as previously mentioned);

R ³And R ⁴Independent separately; the expression hydrogen atom; hydroxyl; alkyl; alkenyl; alkynyl; halogen atom; haloalkyl; amino; oxyimino; Alkoximino; aminoalkyl group; N-alkylamino alkyl; N; the N-dialkyl aminoalkyl; acyl group; the acyl group alkyl; can have substituent acyl amino; acylaminoalkyl; alkoxyl group; alkoxyalkyl; hydroxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl; alkoxy carbonyl alkyl; alkoxycarbonyl amino; the alkoxycarbonyl amino alkyl; formamyl; on alkyl, can have substituent N-alkyl-carbamoyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical; N-alkenyl amino formyl radical; N-alkenyl amino formyl radical alkyl; N-alkenyl-N-alkyl-carbamoyl; N-alkenyl-N-alkyl-carbamoyl alkyl; N-alkoxy amino formyl radical; N-alkyl-N-alkoxy amino formyl radical; N-alkoxy amino formyl radical alkyl; N-alkyl-N-alkoxy amino formyl radical alkyl; can be by the carbazyl of 1～3 alkyl replacement; alkyl sulphonyl; the alkyl sulphonyl alkyl; can have substituent 3～6 yuan of heterocycle carbonyls; can have substituent 3～6 yuan of heterocycle ketonic oxygen base alkyl; can have substituent 3～6 yuan of heterocyclic radicals; the formamyl alkyl; the carbamoyloxy alkyl; N-alkyl carbamoyloxy base alkyl; N; N-dialkyl amido methanoyl alkyl; on alkyl, can have substituent N-alkyl-carbamoyl alkyl; on alkyl, can have substituent N; N-dialkyl amido formyl radical alkyl; alkyl sulfonyl-amino; the amino alkyl of alkyl sulfonyl; the oxo base; acyloxy; the acyloxy alkyl; aryl sulfonyl; the alkoxy carbonyl alkyl alkylsulfonyl; the carboxyalkyl alkylsulfonyl; the alkoxy carbonyl acyl group; the carboxyl acyl group; the alkoxyl group alkoxy carbonyl; the halo acyl group; N; N-dialkyl amido acyl group; the acyloxy acyl group; the hydroxyl acyl group; the alkoxyl group acyl group; the alkoxyalkyl alkylsulfonyl; N; N-dialkyl amido formyl radical acyl group; N; N-dialkyl amido formyl radical alkyl sulphonyl; the alkyl sulphonyl acyl group; amino thioformyl; N-alkylamino thioformyl; N, N-dialkyl amido thioformyl or alkoxyalkyl (thiocarbonyl).

33. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～31, its feature also is, Q ³With following radicals

Expression, the Q in this group ⁵Be the alkylidene group of carbonatoms 4, R ³The expression hydrogen atom, R ⁴Be illustrated on the alkyl and can have substituent N, N-dialkyl amido formyl radical maybe can have substituent 3～6 yuan of heterocyclic radicals.

34. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～31, its feature also is, Q ³With following radicals

Expression, the Q in this group ⁵Be the alkylidene group of carbonatoms 4, R ³The expression hydrogen atom, R ⁴Expression N, N-dialkyl amido formyl radical.

35. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～34, its feature also is, Q ⁴Can have substituent phenyl for being selected from, can have substituent pyridyl, can have substituent pyridazinyl, can have substituent pyrazinyl, can have substituent furyl, can have substituent thienyl, can have substituent pyrryl, can have substituent thiazolyl, can have substituting group De oxazolyl, can have substituent pyrimidyl and can have the group of substituent tetrazyl.

36. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～35, its feature also is, Q ⁴On substituting group for being selected from hydroxyl; halogen atom; haloalkyl; amino; cyano group; aminoalkyl group; nitro; hydroxyalkyl; alkoxyalkyl; carboxyl; carboxyalkyl; alkoxy carbonyl alkyl; acyl group; amidino groups; the hydroxyl amidino groups; the straight chain shape; prop up the alkyl of chain or cyclic carbonatoms 1～6, the straight chain shape; prop up the alkoxyl group of chain or cyclic carbonatoms 1～6, the straight chain shape; prop up the amidino groups of the alkyl replacement of chain or cyclic carbonatoms 1～6; the straight chain shape; prop up the amidino groups of the alkoxyl group replacement of chain or cyclic carbonatoms 1～6; the straight chain shape; prop up the amidino groups of the alkoxy carbonyl replacement of chain or cyclic carbonatoms 2～7, the straight chain shape; prop up the alkenyl of chain or cyclic carbonatoms 2～6, the alkynyl of a straight chain shape or a catenate carbonatoms 2～6; the straight chain shape; prop up the alkoxy carbonyl of chain or cyclic carbonatoms 2～6; formamyl has the straight chain shape on nitrogen-atoms; prop up the mono-or dialkylcarbamoyl group of the alkyl replacement of chain or cyclic carbonatoms 1～6, by the straight chain shape; 1～3 group of one or dialkyl amido that the alkyl of chain or cyclic carbonatoms 1～6 replaces and 5～6 yuan nitrogen heterocycle.

37. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～34, its feature also is, Q ⁴For

[in the base, R ²⁷And R ²⁸Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl]

[in the base, E ¹And E ²Independent separately, expression N or CH, R ²⁹And R ³⁰Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N; N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl], perhaps

[in the base, Y ¹Expression CH or N, Y ²Expression-N (R ³³In)-(the base, R ³³The alkyl of expression hydrogen atom or carbonatoms 1～6), O or S, R ³¹And R ³²Independent separately; expression hydrogen atom, hydroxyl, nitro, amino, cyano group, halogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyl group, alkoxyalkyl, carboxyl, carboxyalkyl, acyl group, formamyl, N-alkyl-carbamoyl, N, N-dialkyl amido formyl radical, alkoxy carbonyl, amidino groups or alkoxy carbonyl alkyl].

38. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～34, its feature also is, Q ⁴For

[in the base, R ²⁷Expression hydrogen atom or halogen atom, R ²⁸Expression hydrogen atom, halogen atom, alkyl or alkynyl],

[in the base, E ¹And E ²Independent separately, expression N or CH, R ²⁹Expression hydrogen atom or halogen atom, R ³⁰Expression hydrogen atom, halogen atom, alkyl or alkynyl], perhaps

[in the base, Y ¹Expression CH or N, Y ²Expression-N (R ³³In)-(the base, R ³³The alkyl of expression hydrogen atom or carbonatoms 1～6), O or S, R ³¹Expression hydrogen atom or halogen atom, R ³²Expression hydrogen atom, halogen atom, alkyl or alkynyl].

39. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～34, its feature also is, Q ⁴Be phenyl, the 4-chloro-phenyl-, the 4-fluorophenyl, the 4-bromophenyl, the 4-ethynyl phenyl, the 3-chloro-phenyl-, the 3-fluorophenyl, the 3-bromophenyl, the 3-ethynyl phenyl, 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, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 4-dibromo phenyl, 4-chloro-3-aminomethyl phenyl, 4-fluoro-3-aminomethyl phenyl, 4-bromo-3-aminomethyl phenyl, 4-chloro-2-aminomethyl phenyl, 4-fluoro-2-aminomethyl phenyl, 4-bromo-2-aminomethyl phenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-dibromo phenyl, the 2-pyridyl, the 3-pyridyl, the 4-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, 5-chloro-3-pyridyl, 5-fluoro-3-pyridyl, 5-bromo-3-pyridyl, 5-ethynyl-3-pyridyl, 6-chloro-3-pyridazinyl, 6-fluoro-3-pyridazinyl, 6-bromo-3-pyridazinyl, 6-ethynyl-3-pyridazinyl, 5-chloro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-bromo-2-thiazolyl or 5-ethynyl-2-thiazolyl.

40. as each described compound, its salt, its solvate or its N-oxide compound in the claim 28～39, its feature also is, T ¹For base-C (=O)-C-(=O)-N (R ')-, base-C (=S)-C (=O)-N (R ')-, base-C (=O)-C (=S)-N (R ')-or base-C (=S)-C (=S)-N (R ')-.

41. pharmaceuticals is characterized in that, contain each described compound in the claim 1～40, its salt, its solvate or its N-oxide compound.

42. activated form factor X inhibitor is characterized in that, contains each described compound in the claim 1～40, its salt, its solvate or its N-oxide compound.

43. the blood coagulation inhibitor is characterized in that, contains each described compound in the claim 1～40, its salt, its solvate or its N-oxide compound.

44. the prevention of thrombus or embolism and/or therapeutical agent is characterized in that, contain each described compound in the claim 1～40, its salt, its solvate or its N-oxide compound.

45. cerebral infarction, cerebral embolism, myocardial infarction, stenocardia, the lung infraction, pulmonary infarction, thromboangiitis obliterans, deep vein thrombosis, the disseminated intravascular coagulation syndrome, thrombosis behind artificial valve/joint replacement, thrombosis after blood flow is built again and inaccessible again, systemic inflammatory reaction syndrome (SIRS), multiple organ dysfunction syndrome (MODS), the prevention and/or the therapeutical agent of the blood coagulation when thrombosis during extracorporeal circulation or blood sampling, it is characterized in that, contain each described compound in the claim 1～40, its salt, its solvate or its N-oxide compound.

46. medical composition is characterized in that, contains each described compound in the claim 1～40, its salt, its solvate or its N-oxide compound.

47. each described compound, its salt, its solvate or its application of N-oxide compound in the preparation of pharmaceuticals in the claim 1～40.

48. each described compound, its salt, its solvate or its application of N-oxide compound in the preparation of activated form factor X inhibitor in the claim 1～40.

49. each described compound, its salt, its solvate or its application of N-oxide compound in the preparation of blood coagulation inhibitor in the claim 1～40.

50. each described compound, its salt, its solvate or its N-oxide compound application in the preparation of the prevention of thrombus or embolism and/or therapeutical agent in the claim 1～40.

51. each described compound in the claim 1～40, its salt, its solvate or its N-oxide compound are at cerebral infarction, cerebral embolism, myocardial infarction, stenocardia, the lung infraction, pulmonary infarction, thromboangiitis obliterans, deep vein thrombosis, the disseminated intravascular coagulation syndrome, thrombosis behind artificial valve/joint replacement, thrombosis after blood flow is built again and inaccessible again, systemic inflammatory reaction syndrome (SIRS), multiple organ dysfunction syndrome (MODS), application in the prevention of the blood coagulation when thrombosis during extracorporeal circulation or blood sampling and/or the preparation of therapeutical agent.

52. the methods of treatment of thrombus or embolism is characterized in that, gives each described compound, its salt, its solvate or its N-oxide compound in the claim 1～40 of significant quantity.

53. cerebral infarction, cerebral embolism, myocardial infarction, stenocardia, the lung infraction, pulmonary infarction, thromboangiitis obliterans, deep vein thrombosis, the disseminated intravascular coagulation syndrome, thrombosis behind artificial valve/joint replacement, thrombosis after blood flow is built again and inaccessible again, systemic inflammatory reaction syndrome (SIRS), multiple organ dysfunction syndrome (MODS), the methods of treatment of the blood coagulation when thrombosis during extracorporeal circulation or blood sampling, it is characterized in that, give each described compound in the claim 1～40 of significant quantity, its salt, its solvate or its N-oxide compound.

54. by following general formula (4)

HN(R ¹)-Q ³-N(R ²)-T ¹-Q ⁴ (4)

Compound, its salt, its solvate or its N-oxide compound of expression, in the formula, R ¹, R ²And T ¹According to claim 1, Q ³With following radicals

Expression, the Q in this group ⁵, R ³And R ⁴According to claim 1, Q ⁴The annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property that condenses that expression can have substituent aryl, can have substituent heteroaryl, can have substituent saturated or undersaturated 2 ring property or 3 ring property.

55. by following general formula (9)

Q ¹-Q ²-C(＝O)-N(R ¹)-Q ³-NHR ² (9)

Compound, its salt, its solvate or its N-oxide compound of expression, in the formula, Q ², R ¹And R ²According to claim 1, Q ¹Expression can have the annelated heterocycles base of substituent saturated or undersaturated 2 ring property or 3 ring property, Q ³With following radicals

Expression, the Q in this group ⁵, R ³And R ⁴According to claim 1.

56. by following general formula (4)

HN(R ¹)-Q ³-N(R ²)-T ¹-Q ⁴ (4)

Compound, its salt, its solvate or its N-oxide compound of expression, in the formula, R ¹, R ²And T ¹As described in claim 17, Q ³With following radicals

Expression, the Q in this group ⁵, R ³And R ⁴As described in claim 17, Q ⁴The annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property that condenses that expression can have substituent aryl, can have substituent heteroaryl, can have substituent saturated or undersaturated 2 ring property or 3 ring property.

57. by following general formula (9)

Q ¹-Q ²-C(＝O)-N(R ¹)-Q ³-NHR ² (9)

Compound, its salt, its solvate or its N-oxide compound of expression, in the formula, Q ², R ¹And R ²As described in claim 17, Q ¹Expression can have the annelated heterocycles base of substituent saturated or undersaturated 2 ring property or 3 ring property, Q ³With following radicals

Expression, the Q in this group ⁵, R ³And R ⁴As described in claim 17.

58. by following general formula (4)

HN(R ¹)-Q ³-N(R ²)-T ¹-Q ⁴ (4)

Compound, its salt, its solvate or its N-oxide compound of expression, in the formula, R ¹, R ²And T ¹As described in claim 28, Q ³With following radicals

Expression, the Q in this group ⁵, R ³And R ⁴As described in claim 28, Q ⁴The annelated heterocycles base that alkyl maybe can have substituent saturated or undersaturated 2 ring property or 3 ring property that condenses that expression can have substituent aryl, can have substituent heteroaryl, can have substituent saturated or undersaturated 2 ring property or 3 ring property.

59. by following general formula (9)

Q ¹-Q ²-C(＝O)-N(R ¹)-Q ³-NHR ² (9)

Compound, its salt, its solvate or its N-oxide compound of expression, in the formula, Q ², R ¹And R ²As described in claim 28, Q ¹Expression can have the annelated heterocycles base of substituent saturated or undersaturated 2 ring property or 3 ring property, Q ³With following radicals

Expression, the Q in this group ⁵, R ³And R ⁴As described in claim 28.