KR20070030773A - Thienopyridine derivatives - Google Patents

Abstract

The present invention provides compounds that promote bone formation. (1) The compound which has following general formula (I), or its pharmacologically acceptable salt.

[Formula 1]

[R ¹ : H, alkyl, R ² : R ^a S-, R ^a O-, R ^a NH-, R ^a (R ^b ) N- or cyclic amino, R ^a , R ^b : substitutable alkyl, substitutable cycloalkyl, etc. ]

Description

Thienopyridine derivative {THIENOPYRIDINE DERIVATIVES}

The present invention relates to compounds that promote bone formation.

It is known that thienopyridine derivatives have an IκB kinase complex inhibitory action (see Patent Document 1). 3-amino-4- (dimethylamino) thieno [2,3-b] pyridine-2-carboxamide and 3-amino-4-anilinothieno [2,3-b] pyridine-2- Carboxamide is known as a well-known compound (refer nonpatent literature 1). However, the effect of these compounds on bone has not been reported.

Patent Document 1: International Publication No. 03/103661

Non Patent Literature 1: Pharm. Chem. J. (Engl. Transl.), 26, 870-874, (1992)

Disclosure of the Invention

Problems to be Solved by the Invention

The present inventors earnestly studied the compounds promoting bone formation, and found that thienopyridine derivatives have excellent pharmacological effects, thus completing the present invention.

Means to solve the problem

The present invention

(1) the following general formula (I)

[Formula 1]

[In the meal,

R ¹ represents a hydrogen atom, a cyclopropyl group or a C ₁ -C ₆ alkyl group,

R ² is R ^a S-, R ^a O-, R ^a NH-, R ^a (R ^b ) N- or

[Formula 2]

Represents a group having

R ^a and R ^b are the same or different and are a C ₁ -C ₆ alkyl group which may be substituted with a group selected from a substituent group α and a substituent group γ, respectively; A C ₃ -C ₈ cycloalkyl group which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ; Or a 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ,

R ³ and R ⁴ are the same or different and each is a hydrogen atom; One group selected from a substituent group α, a substituent group β, and a substituent group γ; A C ₁ -C ₆ alkyl group substituted with a group selected from the substituent group γ; Or a C ₁ -C ₆ alkoxy group substituted with a group selected from the substituent group γ,

In addition, when R ³ and R ⁴ are bonded to adjacent carbon atoms, R ³ and R ⁴ contain carbon atoms to which they are bonded, and are substituted with a group selected from substituent group α, substituent group β and substituent group γ. C ₃ -C ₈ cycloalkyl group which may be used; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ; Or a 5-7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ,

Z is a single bond; Double bond; Oxygen atom; Sulfur atom; Sulfinyl; sulfonyl; Or a group having the formula R ⁵ N <,

R ⁵ is a hydrogen atom; A C ₁ -C ₆ alkyl group which may be substituted with a group selected from a substituent group α and a substituent group γ; A C ₂ -C ₆ alkenyl group which may be substituted with a group selected from a substituent group α and a substituent group γ; A C ₃ -C ₈ cycloalkyl group which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ; 5-7 membered heteroaryl group containing 1-3 of the sulfur atom, oxygen atom, and / or nitrogen atom which may be substituted by the group chosen from substituent group (alpha), substituent group (beta), and substituent group (gamma); Formyl group; C ₂ -C ₇ alkylcarbonyl group which may be substituted with a group selected from substituent group α and substituent group γ; 5 to 7 membered heterocyclylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; A C ₇ -C ₁₁ arylcarbonyl group which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; 5 to 7 membered heteroarylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; C ₁ -C ₆ alkylsulfonyl group which may be substituted with a group selected from substituent group α and substituent group γ; C ₆ -C ₁₀ arylsulfonyl group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; 5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; A C ₂ -C ₇ alkoxycarbonyl group which may be substituted with a group selected from a substituent group α and a substituent group γ; C ₇ -C ₁₁ which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ. Aryloxycarbonyl group; Or a formula R ^c (R ^d ) N-CO-, wherein R ^c And R ^d are the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be substituted with a group selected from the substituent group α and the substituent group γ).

n represents an integer of 1 to 4,

Substituent group (alpha) is a halogen atom; Nitro group; Cyano group; Hydroxyl group; A group having the formula R ⁶ -CO-, the formula R ^e (R ^f ) N-, the formula R ^e (R ^f ) N-CO- or the formula R ^e (R ^f ) N-SO _2- (wherein R ⁶ Silver hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenated alkyl group, C ₃ -C ₈ cycloalkyl group, hydroxy group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl group or C ₆ -C ₁₀ An aryloxy group, R ^e and R ^f Are the same or different and each is a hydrogen atom; C ₁ -C ₆ Alkyl group; C ₁ -C ₆ Alkoxy group; C ₆ -C ₁₀ Aryl group; 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms; Formyl group; C ₂ -C ₇ alkylcarbonyl group; C ₂ -C ₇ alkoxycarbonyl group; C ₇ -C ₁₁ arylcarbonyl group; 5 to 7 membered heteroarylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms; C ₁ -C ₆ alkylsulfonyl group; C ₆ -C ₁₀ arylsulfonyl group; Or a 5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, an oxygen atom and / or a nitrogen atom, or R ^e and R ^f contain a nitrogen atom to which they are bonded, a sulfur atom, 4 to 7 membered heterocyclyl group containing 1 to 3 oxygen atoms and / or nitrogen atoms (the heterocyclyl group may have 1 or 2 groups selected from hydroxy group and methyl group); Hydroxyimino groups; C ₁ -C ₆ alkoxyimino group; C ₁ -C ₆ alkoxy group; C ₃ -C ₈ cycloalkyloxy group; C ₁ -C ₆ halogenated alkoxy group; C ₁ -C ₆ Alkylthio group; C ₁ -C ₆ Alkyl sulfinyl group; And C ₁ -C ₆ Group consisting of alkylsulfonyl groups,

Substituent Group β is a substituent C ₁ -C ₆ alkyl group optionally substituted by a group selected from the group α; And, Substituent group α and C ₁ -C ₆ alkyl group substituted with a sulfur atom, an oxygen atom and / or nitrogen atoms which may be substituted with a group selected from 5 to 7 atoms heterocyclyl containing 1 to 3 C in ₁ - Group consisting of C ₆ alkyl groups,

Substituent group γ is a C ₁ -C ₆ alkoxy group substituted with a group selected from substituent group α; A C ₁ -C ₆ alkylthio group substituted with a group selected from the substituent group α; A C ₃ -C ₈ cycloalkyl group which may be substituted with a group selected from a substituent group α and a substituent group β; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α and a substituent group β; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from a substituent group α and a substituent group β; 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α and substituent group β; A C ₃ -C ₈ cycloalkyloxy group which may be substituted with a group selected from a substituent group α and a substituent group β; A 5 to 7 membered heterocyclyloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α and a substituent group β; A C ₆ -C ₁₀ aryloxy group which may be substituted with a group selected from a substituent group α and a substituent group β; 5 to 7 membered heteroaryloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α and substituent group β; And an aryl moiety represents a group consisting of a C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkoxy group which may be substituted with a group selected from a substituent group α and a substituent group β.] Or a pharmacologically acceptable salt thereof.

Among the above, preferred compounds are

(2) a compound in which R ¹ is a hydrogen atom, a cyclopropyl group, or a C ₁ -C ₄ alkyl group,

(3) a compound in which R ¹ is a hydrogen atom, methyl, ethyl, propyl or cyclopropyl,

(4) R ¹ A compound which is a hydrogen atom or methyl,

(5) C ₁ -C wherein R ² is a group having R ^a (R ^b ) N—, and R ^a and R ^b are the same or different and may be substituted with a group selected from substituent group α and substituent group γ, respectively. _A compound which is a ₆ alkyl group,

(6) R ^a is a C ₁ -C ₆ alkyl group which may be substituted with one group selected from substituent group α and substituent group γ, R ^b is a C ₁ -C ₆ alkyl group, and substituent group α is C ₁ -C _6, a C ₁ -C ₆ alkoxy group substituted by a group selected from a group consisting of an alkoxy, substituent group γ is substituent group α; A C ₆ -C ₁₀ aryloxy group which may be substituted with a group selected from a substituent group α and a substituent group β; And a military compound comprising a 5 to 7 membered heteroaryloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α and a substituent group β,

(7) R ²

[Formula 3]

To a group having, R ⁴ is a hydrogen atom, a substituent group R ³ with α, Substituent group β and Substituent group γ C ₃ -C ₈ cycloalkyl group which may be substituted selected from; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ; Or a compound which forms a 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ,

(8) R ²

[Formula 4]

To a group having, Z is a single bond, a group having an oxygen atom, a sulfur atom or a group represented by the formula R ⁵ N <a, R ⁵ is C ₆ optionally substituted by a group selected from Substituent group α, Substituent group β and Substituent group γ -C ₁₀ aryl group; 5-7 membered heteroaryl group containing 1-3 of the sulfur atom, oxygen atom, and / or nitrogen atom which may be substituted by the group chosen from substituent group (alpha), substituent group (beta), and substituent group (gamma); Formyl group; C ₂ -C ₇ alkylcarbonyl group which may be substituted with a group selected from substituent group α and substituent group γ; C ₁ -C ₆ alkylsulfonyl group which may be substituted with a group selected from substituent group α and substituent group γ; C ₆ -C ₁₀ arylsulfonyl group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; 5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; C ₂ -C ₇ which may be substituted with a group selected from substituent group α and substituent group γ Alkoxycarbonyl group; Or a group having the formula R ^c (R ^d ) N-CO-, wherein n is an integer from 1 to 3,

(9) R ³ is a C ₁ -C ₆ alkoxy group; A C ₁ -C ₆ alkyl group which may be substituted with a group selected from the substituent group α; A C ₁ -C ₆ alkoxy group substituted with a group selected from the substituent group α; A C ₆ -C ₁₀ aryloxy group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; A C ₁ -C ₆ alkyl group substituted with a group selected from the substituent group γ; Or a C ₁ -C ₆ alkoxy group substituted with a group selected from the substituent group γ: Z is a single bond: n is 2

(10) a compound in which R ³ is a hydrogen atom, Z is a sulfur atom, n is 1, and

(11) R ³ Is hydrogen atom: Z is a group having the formula R ⁵ N <: R ⁵ is a substituent group α, Substituent group β and Substituent group optionally substituted by a group selected from C ₆ -C ₁₀ aryl group γ; Or a 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ: n is 2 compound,

And its pharmacologically acceptable salts,

Particularly preferred compounds are

(12) One compound selected from the following or a pharmacologically acceptable salt thereof:

3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide,

3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -6-methylthieno [2,3-b] pyridine-2-carboxamide,

3-amino-4- {3- [3- (2-hydroxyethoxy) propyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide,

3-amino-4-{(3S)-[(2-methoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide,

3-amino-4-{(3S) -3-[(3-methoxypropoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide,

3-amino-4- (3-{[2- (dimethylamino) -2-oxoethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carbox mid,

3-amino-4- (3- {3- [2- (dimethylamino) -2-oxoethoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide,

4- [4- (4-acetylphenyl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide,

3-amino-4- [4- (4-propionylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide,

3-amino-4- {4- [4- (dimethylamino) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide,

3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carbox mid,

4- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide,

3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepane-1-yl) -6-methylthieno [2,3-b] pyridine- 2-carboxamide,

3-amino-4- {4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide ,

3-amino-4- (4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide,

3-amino-4- (4- {4- [3- (dimethylamino) -3-oxopropyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide,

3-amino-4- {4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,

3-amino-4- {4- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,

3-amino-4- (4- {4- [2- (dimethylamino) ethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-car Replica,

3-amino-4- {4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide ,

3-amino-4- {4- [3- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide ,

3-amino-4- {4- [4- (3-hydroxypropyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide ,

3-amino-4- {4- [4- (1-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide ,

3-amino-4- {4- [4- (2-oxopropyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide,

3-amino-4- {4- [4- (N-hydroxyethaneimideyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,

3-amino-4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepan-1-yl) thieno [2 , 3-b] pyridine-2-carboxamide,

3-amino-4- [4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepan-1-yl] thieno [ 2,3-b] pyridine-2-carboxamide,

3-amino-4- [4- (1,3-benzoxazol-6-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carboxamide ,

3-amino-4- [4- (4-hydroxyimino-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] thieno [2, 3-b] pyridine-2-carboxamide,

4- [4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepan-1-yl] -3-aminothieno [2,3-b] pyridine-2 Carboxamide,

4- [4- (5-acetylthiophen-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide, And

3-amino-4- (4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl} -1,4-diazepan-1-yl) thieno [2, 3-b] pyridine-2-carboxamide.

The invention also

(13) A pharmaceutical agent containing as an active ingredient the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof, in particular, a bone disease [eg, osteoporosis (eg, menopause Post-osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressants), osteopenia associated with rheumatoid arthritis or osteoporosis due to bone fracture, osteopathy disease, fracture, or microcertification], or prevention or treatment of deformable arthrosis Medicament for

(14) Medicines ｛Particularly, bone diseases [eg, osteoporosis (eg postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressants), osteopenia or osteoarthritis associated with joint rheumatism, bone loss The compound according to any one of the above (1) to (12) as an active ingredient for the manufacture of a medicament for preventing or treating osteogenic insufficiency due to jet disease, fracture, or microcertification; The use of pharmacologically acceptable salts, and

(15) An effective amount of a compound according to any one selected from (1) to (12) or a pharmacologically acceptable salt thereof (eg, a human, a horse, a cow or a pig, preferably a human) or a bird (Preferably chicken, more preferably hen). Promotes bone formation, inhibits bone resorption, and / or improves bone density. Preferred bone disease [e.g., osteoporosis ( Postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis due to the use of steroids or immunosuppressants), osteopenia associated with rheumatoid arthritis or osteoporosis due to bone destruction, osteopathy disease, fractures, or microcertification] or deformity To prevent or treat arthrosis.

In the general formula (I),

R ^1, R ^6, R ^e and R ^f defined "C ₁ -C ₆ alkyl group" in the in; C ₁ -C ₆ alkyl group of "C ₁ -C ₆ alkyl group which may be substituted by group selected from substituent group α and substituent group γ" in the definition of R ^a , R ^b , R ⁵ , R ^c and R ^d ; R ³ and R ⁴ defined "substituent substituted by a group selected from the group γ C ₁ -C ₆ alkyl group" C ₁ -C ₆ alkyl group in the; In the definition of R ⁵ "Substituent group α and Substituent group γ C ₂ -C optionally substituted by a group selected from ₇ alkylcarbonyl group" and "optionally substituted by a group selected from Substituent group α and Substituent Group γ is C ₁ -C ₆ alkylsulfonyl group "; Alkyl moieties of "C ₂ -C ₇ alkylcarbonyl group" and "C ₁ -C ₆ alkylsulfonyl group" in the definition of R ^e and R ^f ; Substituent group α defined "C ₁ -C ₆ alkylthio group" in the, "C ₁ -C ₆ alkylsulfinyl group" or the alkyl portion of the "C ₁ -C ₆ alkylsulfonyl group"; C ₁ -C ₆ alkyl group of "C ₁ -C ₆ alkyl group which may be substituted by group selected from substituent group α" in the definition of the substituent group β; 5-7 membered heterocycle containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α and a C ₁ -C ₆ alkyl group in the definition of the substituent group β. C ₁ -C ₆ alkyl moiety of the C ₁ -C ₆ alkyl group "substituted with a reel; And, the alkyl moiety of the substituent group defined "a C ₁ -C ₆ alkylthio group substituted by a group selected from Substituent group α" in the γ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohhexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3, Straight or branched chains such as 3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl groups Alkyl group, preferably a C ₁ -C ₄ straight or branched alkyl group, more preferably a C ₁ -C ₃ straight or branched alkyl group, still more preferably a methyl, ethyl, propyl or isopropyl group to be.

"C ₃ -C ₈ cycloalkyl group" in the definition of R ⁶ ; A C ₃ -C ₈ cycloalkyl group of “C ₃ -C ₈ cycloalkyl group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ in the definition of R ^a , R ^b and R ⁵ ; R ³ and R ⁴ is formed by containing a carbon atom to which they are bonded "Substituent group α, Substituent group β and Substituent group γ which may be optionally substituted by a group selected from C ₃ -C ₈ cycloalkyl group" of the C ₃ -C ₈ cycloalkyl group; A C ₃ -C ₈ cycloalkyl group of “C ₃ -C ₈ cycloalkyl group which may be substituted with a group selected from substituent group α and substituent group β in the definition of substituent group γ; The substituent in the definition of the α group in the "C ₃ -C ₈ cycloalkyloxy groups" C ₃ -C ₈ cycloalkyl moiety; The C ₃ -C ₈ cycloalkyl moiety of “C ₃ -C ₈ cycloalkyloxy group which may be substituted with a group selected from substituent group α and substituent group β in the definition of substituent group γ is cyclopropyl, cyclo It may be a butyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, preferably a C ₃ -C ₇ cycloalkyl group, more preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

The "4 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms" formed by R ^e and R ^f containing the nitrogen atom to which they are bonded is, for example, azeti. Diyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, thiazolidinyl, oxadiazolidinyl, piperidyl, tetrahydropyridyl, Dihydropyridyl, piperazinyl, morpholinyl, thiomorpholinyl or homopiperidyl, preferably a 4-6 membered hetero containing 1 or 2 sulfur atoms, oxygen atoms and / or nitrogen atoms Cyclyl group, particularly preferably azetidinyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl.

Moreover, said "5-7 membered heterocyclyl group containing 1-3 sulfur atoms, an oxygen atom, and / or a nitrogen atom" may be condensed with another cyclic group (for example, a phenyl group), and such a group, For example 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, indolinyl or isoindolinyl.

1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ in the definition of R ^a , R ^b and R ⁵ . 5-7 membered heterocyclyl group "of 5-7 membered heterocyclyl group; 1 to 1 represents a sulfur atom, an oxygen atom and / or a nitrogen atom which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ formed by R ³ and R ⁴ containing the carbon atom to which they are bonded; 5 to 7 membered heterocyclyl group containing 3 to 7 membered heterocyclyl group ”; 5-7 membered heterocycle containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ in the definition of R ⁵ . 5- to 7-membered heterocyclyl moiety of "ylcarbonyl group"; 5-7 membered heterocycle containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α and a C ₁ -C ₆ alkyl group in the definition of the substituent group β. A 5 to 7 membered heterocyclyl moiety of a C ₁ -C ₆ alkyl group substituted with a aryl group; In the definition of the substituent group γ, "a 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from substituent group α and substituent group β ''. 5 to 7 membered heterocyclyl group; And a 5 to 7 membered heterocyclyl jade containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from the substituent group α and the substituent group β in the definition of the substituent group γ. 5 to 7 membered heterocyclyl moiety includes, for example, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, dioxoranyl, Thiazolidinyl, oxadiazolidinyl, piperidyl, tetrahydropyridyl, dihydropyridyl, 2H-pyranyl, 2-oxo-2H-pyranyl, tetrahydropyranyl, tetrahydrofuranyl, piperazinyl , Morpholinyl, dioxanyl, thiomorpholinyl or homopiperidyl, preferably a 5 or 6 membered heterocyclyl group containing 1 or 2 sulfur atoms, oxygen atoms and / or nitrogen atoms, Particularly preferably Dioxora , Blood is pyrrolidinyl, piperidyl, piperazinyl or morpholinyl.

Moreover, said "5-7 membered heterocyclyl group containing 1-3 sulfur atoms, an oxygen atom, and / or a nitrogen atom" may be condensed with another cyclic group (for example, a phenyl group), and such a group, For example 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, chromanyl, indolinyl or isoindolinyl.

"C ₆ -C ₁₀ aryl group" in the definition of R ^6; C ₆ -C ₁₀ aryl group of "C ₆ -C ₁₀ aryl group which may be substituted by group selected from substituent group α, substituent group β and substituent group γ" in the definition of R ^a , R ^b and R ⁵ ; R ³ and R ⁴ is formed by containing a carbon atom to which they are bonded "Substituent group α, Substituent group β and substituent group that may be substituted by a group selected from the group γ C ₆ -C ₁₀ aryl group" of the C ₆ -C ₁₀ aryl group; R ⁵ in the definition of "Substituent group α, Substituent group β, and γ is Substituent group may be substituted by a group selected from C ₇ -C ₁₁ arylcarbonyl group", "selected from the substituent group α, Substituent group β and Substituent group γ An aryl moiety of a C ₆ -C ₁₀ arylsulfonyl group which may be substituted with a group which is substituted, and a C ₇ -C ₁₁ aryloxycarbonyl group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; The aryl part of the "C ₆ -C ₁₀ aryloxy group" in the definition of R ^6; R ^e and R ^f in the definition of "C ₆ -C ₁₀ aryl group"; Aryl moieties of "C ₇ -C ₁₁ arylcarbonyl group" and "C ₆ -C ₁₀ arylsulfonyl group" in the definition of R ^e and R ^f ; C ₆ -C ₁₀ aryl group of "C ₆ -C ₁₀ aryl group which may be substituted with group selected from substituent group α and substituent group β" in the definition of substituent group γ; The aryl part of the substituent group defined "Substituent group α and Substituent Group C ₆ -C ₁₀ aryloxy group which may be substituted by a group selected from the β" in the γ; Then, the aryl part of the substituent group in the definition of γ 'is an aryl portion Substituent Group α and Substituent Group C ₆ -C ₁₀ aryl -C ₁ -C ₆ alkoxy group which is optionally substituted with a selection from the β "is, for For example phenyl or naphthyl, preferably phenyl.

Further, the "group C ₆ -C ₁₀ aryl" wherein the cycloalkyl group is C ₃ -C ₁₀ (preferably C ₅ -C ₆ cycloalkyl), wherein "heterocyclyl" or a "heteroaryl", and the shaft may be bright Such groups include, for example, 5-indanyl, 5-isoindolinyl, 1-oxo-2-methyl-5-isoindolinyl, 1,3-benzooxazol-5-yl, 1,3 -Benzooxazol-6-yl, chroman-7-yl, 1,2-benzoisoxazol-6-yl, 1,3-benzodioxol-5-yl, 2,3-dihydro-1-benzo Furan-5-yl, quinolin-6-yl, isoquinolin-6-yl, 1,3-benzothiazol-6-yl, indol-5-yl and the like.

1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ in the definition of R ^a , R ^b and R ⁵ . 5-7 membered heteroaryl group of "5-7 membered heteroaryl group"; 1 to 1 represents a sulfur atom, an oxygen atom and / or a nitrogen atom which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ formed by R ³ and R ⁴ containing the carbon atom to which they are bonded; 5 to 7 membered heteroaryl group containing 3 to 7 membered heteroaryl group; 5-7 membered heteroaryl containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ in the definition of R ⁵ ; Carbonyl group "and" a 5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ ". 5 to 7 membered heteroaryl moiety; "5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms" in the definition of R ^e and R ^f ; In the definition of R ^e and R ^f , "a 5 to 7 membered heteroarylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms" and "sulfur atom, oxygen atoms and / or nitrogen atoms are 1 5 to 7 membered heteroaryl moiety of "3 to 5 membered 5 to 7 membered heteroarylsulfonyl group"; In the definition of the substituent group γ, "a 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, which may be substituted with a group selected from substituent group α and substituent group β ''. 5 to 7 membered heteroaryl group; And a 5 to 7 membered heteroaryl jade containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α and substituent group β in the definition of substituent group γ. 5 to 7 membered heteroaryl moiety of the term &quot; , Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or azepinyl, preferably furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, iso 5 to 6 membered heteroaryl groups containing 1 or 2 sulfur atoms, oxygen atoms and / or nitrogen atoms such as thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

Further, in the example a 'sulfur atom, an oxygen atom and / or an aryl of 5 to 7-membered heteroaryl which contains one to three nitrogen atoms "is another cyclic group [for example, C ₆ -C ₁₀ aryl group or C ₃ - C ₈ cycloalkyl group (preferably C ₅ -C ₆ cycloalkyl group)], such a group may be, for example, indolyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, quinazolinyl , 5,6,7,8-tetrahydroquinolyl, or 5,6,7,8-tetrahydroisoquinolyl.

Of "C ₁ -C ₆ alkoxy group substituted with group selected from substituent group γ" in the definition of R ³ and R ⁴ C ₁ -C ₆ alkoxy group; An alkoxy moiety of "C ₂ -C ₇ alkoxycarbonyl group which may be substituted with a group selected from substituent group α and substituent group γ" in the definition of R ⁵ ; R ⁶ and in the definition of substituent group α "C ₁ -C ₆ alkoxy group"; In the definition of R ^e and R ^f "C ₁ -C ₆ alkoxy group"; C ₁ -C ₆ alkoxy moiety of “C ₁ -C ₆ alkoxyimino group” in the definition of the substituent group α; And, a substituent "substituted C ₁ -C ₆ alkoxy group by a group selected from Substituent Group α" C ₁ -C ₆ alkoxy groups may be replaced by oxygen atoms are bonded to the aforementioned "C ₁ -C ₆ alkyl group" in the definition of the group group γ Is preferably a C ₁ -C ₆ straight or branched alkoxy group, more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy, even more preferred Preferably methoxy, ethoxy, propoxy, isopropoxy or butoxy, particularly preferably methoxy or ethoxy.

R ⁵ defined "Substituent group α and the substituent group is substituted by a group selected from the group γ, even C ₂ -C ₆ alkenyl group which is" the C ₂ -C ₆ seen in the alkenyl group is vinyl, 2-propenyl, 1-methyl 2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl -2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-phene Tenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2- It can be a straight or branched chain alkenyl group such as methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl group, preferably C ₂ -C ₄ straight or branched chain It is an alkyl group, More preferably, it is vinyl or 2-propenyl, Especially preferably, it is vinyl.

"C ₂ -C ₇ alkylcarbonyl group" in the definition of R ^e and R ^f ; And C ₂ -C ₇ which may be substituted with a group selected from “substituent group α and substituent group γ in the definition of R ⁵ . C ₂ -C ₇ of the alkylcarbonyl group ” Alkylcarbonyl group is the "C ₁ -C ₆ Alkyl group "is a group bonded to carbonyl, preferably C ₂ -C ₅ Linear or branched alkylcarbonyl groups, more preferably acetyl, propionyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl or tert-butylcarbonyl, even more preferably acetyl, propy Onyl, propylcarbonyl, isopropylcarbonyl or butylcarbonyl, particularly preferably acetyl or propionyl.

5-7 membered heterocycle containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ in the definition of R ⁵ . The 5- to 7-membered heterocyclylcarbonyl group of the "aryl carbonyl group" is a group in which carbonyl is bonded to the "5- to 7-membered heterocyclyl group", and preferably contains 1 or 2 sulfur atoms, oxygen atoms and / or nitrogen atoms. Is a 5 or 6 membered heterocyclylcarbonyl group, and particularly preferably piperidylcarbonyl, piperazinylcarbonyl or morpholinylcarbonyl.

"C ₇ -C ₁₁ arylcarbonyl group" in the definition of R ^e and R ^f ; And, R ⁵ in the definition of "Substituent group α, Substituent group β, and C ₇ -C ₁₁ arylcarbonyl group which is optionally substituted by a group selected from Substituent Group γ" C ₇ -C ₁₁ arylcarbonyl group of the aforementioned "C ₆ -C ₁₀ aryl group "is a group which carbonyl couple | bonded, Preferably it is benzoyl.

"5 to 7 membered heteroarylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms" in the definition of R ^e and R ^f ; And 5 to 7 atoms containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ in the definition of R ⁵ . Heteroarylcarbonyl group &quot; of 5 to 7 membered heteroarylcarbonyl group is a group in which carbonyl is bonded to the “5 to 7 membered heteroaryl group”, and preferably contains 1 or 2 sulfur atoms, oxygen atoms and / or nitrogen atoms. To 5 to 6 membered heteroarylcarbonyl.

Substituent Group α, "C ₁ -C ₆ alkylsulfonyl group" in the definition of R ^e and R ^f; And, the "substituent group α, and substituent group C ₁ -C ₆ alkylsulfonyl group which is optionally substituted by a group selected from γ" in the definition of R ⁵ C ₁ -C ₆ alkylsulfonyl group wherein the "C ₁ -C ₆ alkyl group ”is a group to which sulfonyl is bonded, preferably a C ₁ -C ₄ straight or branched chain alkylsulfonyl group, more preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfur Polyvinyl, isobutylsulfonyl or tert-butylsulfonyl, even more preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl or butylsulfonyl, particularly preferably methylsulfonyl or ethyl Sulfonyl.

"C ₆ -C ₁₀ arylsulfonyl group" in the definition of R ^e and R ^f; And the C ₆ -C ₁₀ arylsulfonyl group of the "C ₆ -C ₁₀ arylsulfonyl group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ" in the definition of R ⁵ . C ₆ -C ₁₀ aryl group ”is a group in which sulfonyl is bonded, preferably phenylsulfonyl.

"5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms" in the definition of R ^e and R ^f ; And 5 to 7 atoms containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from "substituent group α, substituent group β and substituent group γ in the definition of R ⁵ . Heteroarylsulfonyl group ”is a group of 5 to 7 membered heteroarylsulfonyl group in which sulfonyl is bonded to the“ 5 to 7 membered heteroaryl group ”, and preferably 1 or 2 sulfur atom, oxygen atom and / or nitrogen atom. And 5 to 6 membered heteroarylsulfonyl.

"C ₂ -C ₇ alkoxycarbonyl group" in the definition of R ^e and R ^f ; And, the "substituent group α and the substituent group that may be substituted by a group selected from the group γ C ₂ -C ₇ alkoxycarbonyl group" in the definition of R ⁵ C ₂ -C ₇ alkoxycarbonyl group wherein the "C ₁ -C ₆ alkoxy Group ”is a group to which carbonyl is bonded, preferably a C ₂ -C ₅ straight or branched alkoxycarbonyl group, more preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , Butoxycarbonyl, isobutoxycarbonyl or tert-butoxycarbonyl, even more preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or tert-butoxycarbon Carbonyl, particularly preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl.

"C ₆ -C ₁₀ aryloxy group" in the definition of R ⁶ ; And, the substituent group defined "Substituent group α and Substituent Group C ₆ -C ₁₀ aryloxy group which may be substituted by a group selected from the β" in the γ C ₆ -C ₁₀ aryloxy group wherein the "C ₆ -C ₁₀ aryl group ", an oxygen atom bonded thereto, preferably phenoxy.

R ⁵ in the definition of "Substituent group α, Substituent group β and Substituent Group C ₇ -C ₁₁ aryloxycarbonyl group which may be substituted by a group selected from γ" C ₇ -C ₁₁ aryloxycarbonyl group is the "C ₆ -C ₁₀ aryloxy group "is a group which carbonyl couple | bonded, Preferably it is phenoxycarbonyl.

The "halogen atom" in the definition of the substituent group α is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

The "C ₁ -C ₆ halogenated alkyl group" in the definition of R ⁶ is a group in which one or two or more hydrogen atoms of the "C ₁ -C ₆ alkyl group" are substituted with the "halogen atom", preferably C _1- C ₄ halogenated alkyl group, more preferably trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2, 2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2,2-dibromoethyl, even more preferably trifluoromethyl, trichloromethyl, Difluoromethyl or fluoromethyl, most preferably trifluoromethyl.

The "C ₁ -C ₆ halogenated alkoxy group" in the definition of the substituent group α is a group in which one or two or more hydrogen atoms of the "C ₁ -C ₆ alkoxy group" are substituted with the "halogen atom". Preferably a C ₁ -C ₄ halogenated alkoxy group, more preferably trifluoromethyloxy, trichloromethyloxy, difluoromethyloxy, dichloromethyloxy, dibromomethyloxy, fluoromethyloxy, 2, 2,2-trichloroethyloxy, 2,2,2-trifluoroethyloxy, 2-bromoethyloxy, 2-chloroethyloxy, 2-fluoroethyloxy or 2,2-dibromoethyloxy And even more preferably trifluoromethyloxy, trichloromethyloxy, difluoromethyloxy or fluoromethyloxy.

Substituent group α in the definition of "C ₁ -C ₆ alkylthio group"; And substituents C ₁ -C ₆ alkyl, "the C ₁ -C ₆ alkylthio group substituted by a group selected from Substituent group α" in the definition of group γ thio group is a sulfur atom is bonded to the aforementioned "C ₁ -C ₆ alkyl group" Group, preferably a C ₁ -C ₄ straight or branched alkylthio group, more preferably methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio or tert-butylthio, Even more preferred are methylthio, ethylthio, propylthio, isopropylthio or butylthio, particularly preferably methylthio or ethylthio.

The "C ₁ -C ₆ alkylsulfinyl group" in the definition of the substituent group α is a group in which sulfinyl is bonded to the "C ₁ -C ₆ alkyl group", and preferably a C ₁ -C ₄ straight or branched chain alkylsulphie. Nyl group, more preferably methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl or tert-butylsulfinyl, still more preferably methylsulfinyl, ethyl Sulfinyl, propylsulfinyl, isopropylsulfinyl or butylsulfinyl, particularly preferably methylsulfinyl or ethylsulfinyl.

Substituent group α in the definition of "C ₃ -C ₈ cycloalkyloxy groups"; And the substituent in the definition of group γ "Substituent group α and Substituent group optionally substituted by a group selected from β is C ₃ -C ₈ cycloalkyloxy groups" of the C ₃ -C ₈ cycloalkyloxy group wherein the "C ₃ - C ₈ cycloalkyl group &quot; to which an oxygen atom is bonded, preferably a C ₃ -C ₇ cycloalkyloxy group, more preferably cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy to be.

"5- to 7-membered heterocyclyloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α and substituent group β" in the definition of substituent group γ The 5 to 7 membered heterocyclyloxy group is a group in which an oxygen atom is bonded to the "5 to 7 membered heterocyclyl group", and preferably 5 or 6 containing 1 or 2 sulfur atoms, oxygen atoms and / or nitrogen atoms. It is an atomic heterocyclyloxy group, Especially preferably, it is piperidyloxy.

"5- to 7-membered heteroaryloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α and substituent group β" in the definition of substituent group γ The 5-7 membered heteroaryloxy group of which is an oxygen atom couple | bonded with said "5-7 membered heteroaryl containing 1-3 sulfur atoms, an oxygen atom, and / or a nitrogen atom", Preferably it is a sulfur atom, an oxygen atom And / or a 5 to 6 membered heteroaryloxy group containing 1 or 2 nitrogen atoms, more preferably furyloxy, thienyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, Isoxazolyloxy, thiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy or pyrazinyloxy.

The substituent group defined in the γ 'the aryl moiety the substituents group α and Substituent Group C ₆ -C ₁₀ aryl -C ₁ -C ₆ alkoxy group which is optionally substituted with a selection from the β "C ₆ -C ₁₀ aryl- C ₁ -C ₆ alkoxy group and the aforementioned "C ₁ -C ₆ alkoxy group" substituted with the "C ₆ -C ₁₀ aryl group", preferably a benzyloxy, phenethyl or 3-phenyl-oxy-propyloxy, and in particular Preferably benzyloxy.

"The pharmacologically acceptable salt" means that the compound (I) of the present invention can be converted into a salt by reacting with an acid when having a basic functional group such as an amino group or by reacting with a base when having a basic functional group such as a carboxyl group. And the salt thereof.

Salts based on basic functional groups include, for example, inorganic salts such as hydrochloride, nitrate, perchlorate, sulfate or phosphate such as hydrochloride, hydrobromide or hydroiodide; Lower alkanesulfonates such as methanesulfonates, trifluoromethanesulfonates or ethanesulfonates, arylsulfonates or acetates such as benzenesulfonates or p-toluenesulfonates, acetates, fumarates, succinates, citrates Organic acid salts such as carboxylate salts such as ascorbate, tartarate, oxalate or maleate; Or an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate or aspartate.

Salts based on acidic functional groups include, for example, alkali metal salts such as sodium salts, potassium salts or lithium salts, alkaline earth metal salts such as calcium salts or magnesium salts, metal salts such as aluminum salts or iron salts; Ammonium salts; t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclo Hexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris (hydroxymethyl Organic amine salts such as aminomethane salts; Or an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate or aspartate.

The compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may be absorbed by water or absorbed by water, or formed into a hydrate by being left in the air or recrystallized. Included in

In the compound which has General formula (I) of this invention, the optical isomer based on the subsidiary center in a molecule may exist. In the compounds of the present invention, all of these isomers and mixtures of these isomers are represented by a single formula, that is, general formula (I). Accordingly, the present invention includes both these isomers and mixtures of any proportion of these isomers.

As a specific example of the compound which has General formula (I) of this invention, the compound of the following Example compound Table 1-Example compound Table 3 is mentioned, for example.

In Exemplary Compound Tables 1 to 3, "Ac" represents acetyl, "Aze" represents azetidino, and "perhydro-1-Azep" represents perhydroazin-1-yl. , "Perhydro-1-Azoc" represents perhydroazocin-1-yl, "Bn" represents benzyl, "Bu" represents butyl, "iBu" represents isobutyl, and "tBu" is tert -Butyl, "BzIox" represents 1,2-benzoisoxazolyl, "BzDioxa" represents 1,4-benzodioxanyl, "BzDioxo" represents 1,3-benzodioxoranyl, "BzFur" represents 1-benzofuranyl, "Bzhy" represents benzhydryl, "BzOxaz" represents 1,3-benzooxazolyl, "BzThaz" represents 1,3-benzothiazolyl, "Chr" represents chromamanyl, "Dioxa" represents 1,3-dioxanyl, "Dioxo" represents 1,3-dioxoranyl, Et "represents ethyl," Fur "represents furanyl," cHep "represents cycloheptyl," cHx "represents cyclohexyl," IIndn "represents isoindolinyl, and" Ind "is indole Reel, "Iqui" represents isoquinolyl, "decahydro-2-Iqui" represents 1,2,3,4,5,6,7,8,9,10-decahydroisoquinolin-2-yl Represents 1,2,3,4-tetrahydro-2-Iqui, 1,2,3,4-tetrahydroisoquinolin-2-yl, "Me" represents methyl, and "Mor" Morpholin-4-yl, "0xaz" represents oxazolyl, "1,4-Oxazep" represents 1,4-oxazin-4-yl, "0xazn" represents oxazolinyl, and Ph ”represents phenyl,“ Phet ”represents phenethyl,“ Pip ”represents piperidin-4-yl, and“ 3,4-dehydro-Pip ”represents 3,4-dehydropiperidine- 4-day represents "Pipo" for piperidino "Pipra" stands for piperazino, "cPn" stands for cyclopentyl, "neoPn" stands for neopentyl, "Pr" stands for propyl, "iPr" stands for isopropyl, and "Py" stands for Represents pyridyl, "Pydz" represents pyridazinyl, "Pym" represents pyrimidyl, "Pyrld" represents pyrrolidin-1-yl, "Qui" represents quinolyl, and "Qunz" Represents quinazolinyl, "Thaz" represents thiazolyl, "Thazn" represents thiazolinyl, "Thi" represents thienyl, and "1,4-Thiazep" is 1,4-thiazepine- 4- days are represented, and "Thmor" represents thiomorpholin-4-yl.

TABLE 1

[Formula 5]

-------------------------------------------------- ---------------

compound

Number R^One R²

-------------------------------------------------- ---------------

1-1 H MeO

1-2 H EtO

1-3 H iPrO

1-4 H BnO

1-5 H (HOOC) -CH ₂ O

1-6 H cPnO

1-7 H cHxO

1-8 H cHepO

1-9 H MeS

1-10 H EtS

1-11 H iPrS

1-12 H BnS

1-13 H cHxS

1-14 H cHepS

1-15 H Pyrld

1-16 H Pip

1-17 H 3-Me-Pip

1-18 H 4-Me-Pip

1-19 H 4-Bn-Pip

1-20 H 3- (HO-CH ₂ ) -Pip

1-21 H 3- (MeO-CH ₂ ) -Pip

1-22 H 3- (EtO-CH ₂ ) -Pip

1-23 H 3- (PrO-CH ₂ ) -Pip

1-24 H 3- (BnO-CH ₂ ) -Pip

1-25 H 3-Ph-Pip

1-26 H 4-Ph-Pip

1-27 H 3-HO-Pip

1-28 H 3-MeO-Pip

1-29 H 3-EtO-Pip

1-30 H 3-PrO-Pip

1-31 H 3-BnO-Pip

1-32 H 4-HO-Pip

1-33 H 3-AcO-Pip

1-34 H 4-AcO-Pip

1-35 H 1,2,3,4-tetrahydro-2-Iqui

1-36 H decahydro-2-Iqui

1-37 H 3,4-dehydro-Pip

1-38 H 4-Ph-3,4-dehydro-1-Pip

1-39 H perhydro-1-Azep

1-40 H perhydro-1-Azoc

1-41 H Mor

1-42 H 2,6-diMe-Mor

1-43 H 1,4-Oxazep

1-44 H Thmor

1-45 H 1-Oxo-Thmor

1-46 H 1,4-Thiazep

1-47 H 1-Oxo-1,4-Thiazep

1-48 Me MeO

1-49 Me EtO

1-50 Me iPrO

1-51 Me BnO

1-52 Me (HOOC) -CH ₂ O

1-53 Me cPnO

1-54 Me cHxO

1-55 Me cHepO

1-56 Me MeS

1-57 Me EtS

1-58 Me iPrS

1-59 Me BnS

1-60 Me cHxS

1-61 Me cHepS

1-62 Me Pyrld

1-63 Me Pip

1-64 Me 3-Me-Pip

1-65 Me 4-Me-Pip

1-66 Me 4-Bn-Pip

1-67 Me 3- (HO-CH ₂ ) -Pip

1-68 Me 3- (MeO-CH ₂ ) -Pip

1-69 Me 3- (EtO-CH ₂ ) -Pip

1-70 Me 3- (PrO-CH ₂ ) -Pip

1-71 Me 3- (BnO-CH ₂ ) -Pip

1-72 Me 3-Ph-Pip

1-73 Me 4-Ph-Pip

1-74 Me 3-HO-Pip

1-75 Me 3-MeO-Pip

1-76 Me 3-EtO-Pip

1-77 Me 3-PrO-Pip

1-78 Me 3-BnO-Pip

1-79 Me 4-HO-Pip

1-80 Me 3-AcO-Pip

1-81 Me 4-AcO-Pip

1-82 Me 1,2,3,4-tetrahydro-2-Iqui

1-83 Me decahydro-2-Iqui

1-84 Me 3,4-dehydro-Pip

1-85 Me 4-Ph-3,4-dehydro-1-Pip

1-86 Me perhydro-1-Azep

1-87 Me perhydro-1-Azoc

1-88 Me Mor

1-89 Me 2,6-diMe-Mor

1-90 Me 1,4-Oxazep

1-91 Me Thmor

1-92 Me 1-Oxo-Thmor

1-93 Me 1,4-Thiazep

1-94 Me 1-Oxo-1,4-Thiazep

1-95 H 3- [HO- (CH ₂ ) ₂ ] -Pip

1-96 H 3- [HO- (CH ₂ ) ₃ ] -Pip

1-97 H 3- [HO- (CH ₂ ) ₄ ] -Pip

1-98 H 3- [HO- (CH ₂ ) ₅ ] -Pip

1-99 H 3- [HO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-100 H 3- [HO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-101 H 3- [HO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-102 H 3- [HO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-103 H 3- [HO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-104 H 3- [HO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-105 H 3- [HO- (CH ₂ ) ₄ -O-CH ₂ ] -Pip

1-106 H 3- [HO- (CH ₂ ) ₄ -O- (CH ₂ ) ₂ ] -Pip

1-107 H 3- [HO- (CH ₂ ) ₄ -O- (CH ₂ ) ₃ ] -Pip

1-108 H 3- [MeO- (CH ₂ ) ₂ ] -Pip

1-109 H 3- [MeO- (CH ₂ ) ₃ ] -Pip

1-110 H 3- [MeO- (CH ₂ ) ₄ ] -Pip

1-111 H 3- [MeO- (CH ₂ ) ₅ ] -Pip

1-112 H 3- [MeO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-113 H 3- [MeO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-114 H 3- [MeO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-115 H 3- [MeO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-116 H 3- [MeO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-117 H 3- [MeO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-118 H 3- [MeO- (CH ₂ ) ₄ -O-CH ₂ ] -Pip

1-119 H 3- [MeO- (CH ₂ ) ₄ -O- (CH ₂ ) ₂ ] -Pip

1-120 H 3- [MeO- (CH ₂ ) ₄ -O- (CH ₂ ) ₃ ] -Pip

1-121 H 3- [EtO- (CH ₂ ) ₂ ] -Pip

1-122 H 3- [EtO- (CH ₂ ) ₃ ] -Pip

1-123 H 3- [EtO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-124 H 3- [EtO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-125 H 3- [EtO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-126 H 3- [PrO- (CH ₂ ) ₂ ] -Pip

1-127 H 3- [PrO- (CH ₂ ) ₃ ] -Pip

1-128 H 3- [BnO- (CH ₂ ) ₂ ] -Pip

1-129 H 3- [BnO- (CH ₂ ) ₃ ] -Pip

1-130 H 3- [PhO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-131 H 3- [PhO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-132 H 3- [PhO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-133 H 3- [H ₂ N- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-134 H 3- [H ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-135 H 3- [H ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-136 H 3- [H ₂ N- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-137 H 3- [H ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-138 H 3- [H ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-139 H 3- [H ₂ N- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-140 H 3- [H ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-141 H 3- [Me ₂ N- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-142 H 3- [Me ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-143 H 3- [Me ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-144 H 3- [Me ₂ N- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-145 H 3- [Me ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-146 H 3- [Me ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-147 H 3- [Me ₂ N- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-148 H 3- [Me ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-149 H 3- (CN-CH ₂ -O-CH ₂ ) -Pip

1-150 H 3- [CN-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-151 H 3- [CN-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-152 H 3- [CN- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-153 H 3- [CN- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-154 H 3- [CN- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-155 H 3- (Me ₂ NCO-CH ₂ -O-CH ₂ ) -Pip

1-156 H 3- [Me ₂ NCO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-157 H 3- [Me ₂ NCO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-158 H 3- [Me ₂ NCO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-159 H 3- [Me ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-160 H 3- [Me ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-161 H 3- [Me ₂ NCO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-162 H 3- [Me ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-163 H 3- [Me ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-164 H 3- (Et ₂ NCO-CH ₂ -O-CH ₂ ) -Pip

1-165 H 3- [Et ₂ NCO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-166 H 3- [Et ₂ NCO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-167 H 3- [Et ₂ NCO— (CH ₂ ) ₂ —O—CH ₂ ] -Pip

1-168 H 3- [Et ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-169 H 3- [Et ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-170 H 3- [Et ₂ NCO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-171 H 3- [Et ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-172 H 3- [Et ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-173 H 3- [AcNH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-174 H 3- [AcNH- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-175 H 3- [AcNH- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-176 H 3- [AcNH- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-177 H 3- [AcNH- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-178 H 3- [AcNH- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-179 H 3- [AcNH- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-180 H 3- [AcNH- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-181 H 3- [Me- (CH ₂ ) ₄ -CONH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-182 H 3- [BocNH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-183 H 3- [NC- (CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-184 H 3- (H ₂ N-CH ₂ ) -Pip

1-185 H 3- [HO- (CH ₂ ) ₂ -NH-CH ₂ ] -Pip

1-186 H 3- (BocNH-CH ₂ ) -Pip

1-187 H 3- (MeNH-CH ₂ ) -Pip

1-188 H 3- [Me- (CH ₂ ) ₃ -NH-CH ₂ ] -Pip

1-189 H 3- (Me ₂ N-CH ₂ ) -Pip

1-190 H 2- (MeO-CH ₂ ) -Mor

1-191 H 3- [Et ₂ N- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-192 H 3- [Et ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-193 H 3- [Et ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-194 H 3- [Et ₂ N- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-195 H 3- [Et ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-196 H 3- [Et ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-197 H 3- [Et ₂ N- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-198 H 3- [Pyrld- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-199 H 3- [Pyrld- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-200 H 3- [Pyrld- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-201 H 3- [Pyrld- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-202 H 3- [Pyrld- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-203 H 3- [Pyrld- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-204 H 3- [Pyrld- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-205 H 3- [Mor- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-206 H 3- [Mor- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-207 H 3- [Mor- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-208 H 3- [Mor- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-209 H 3- [Mor- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-210 H 3- [Mor- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-211 H 3- [Mor- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-212 H 3- [Pipo- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-213 H 3- [Pipo- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-214 H 3- [Pipo- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-215 H 3- [Pipo- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-216 H 3- [Pipo- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-217 H 3- [Pipo- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-218 H 3- [Pipo- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-219 H 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-220 H 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-221 H 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-222 H 3-[(4-Me-Pipra)-(CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-223 H 3-[(4-Me-Pipra)-(CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-224 H 3-[(4-Me-Pipra)-(CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-225 H 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-226 H 3- (Pyrld-CO-CH ₂ -O-CH ₂ ) -Pip

1-227 H 3- [Pyrld-CO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-228 H 3- [Pyrld-CO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-229 H 3- (Mor-CO-CH ₂ -O-CH ₂ ) -Pip

1-230 H 3- [Mor-CO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-231 H 3- [Mor-CO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-232 H 3- (Pipo-CO-CH ₂ -O-CH ₂ ) -Pip

1-233 H 3- [Pipo-CO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-234 H 3- [Pipo-CO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-235 H 3-[(4-Me-Pipra) -CO-CH ₂ -O-CH ₂ ] -Pip

1-236 H 3-[(4-Me-Pipra) -CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-237 H 3-[(4-Me-Pipra) -CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-238 Me 3- [HO- (CH ₂ ) ₂ ] -Pip

1-239 Me 3- [HO- (CH ₂ ) ₃ ] -Pip

1-240 Me 3- [HO- (CH ₂ ) ₄ ] -Pip

1-241 Me 3- [HO- (CH ₂ ) ₅ ] -Pip

1-242 Me 3- [HO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-243 Me 3- [HO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-244 Me 3- [HO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-245 Me 3- [HO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-246 Me 3- [HO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-247 Me 3- [HO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-248 Me 3- [HO- (CH ₂ ) ₄ -O-CH ₂ ] -Pip

1-249 Me 3- [HO- (CH ₂ ) ₄ -O- (CH ₂ ) ₂ ] -Pip

1-250 Me 3- [HO- (CH ₂ ) ₄ -O- (CH ₂ ) ₃ ] -Pip

1-251 Me 3- [MeO- (CH ₂ ) ₂ ] -Pip

1-252 Me 3- [MeO- (CH ₂ ) ₃ ] -Pip

1-253 Me 3- [MeO- (CH ₂ ) ₄ ] -Pip

1-254 Me 3- [MeO- (CH ₂ ) ₅ ] -Pip

1-255 Me 3- [MeO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-256 Me 3- [MeO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-257 Me 3- [MeO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-258 Me 3- [MeO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-259 Me 3- [MeO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-260 Me 3- [MeO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-261 Me 3- [MeO- (CH ₂ ) ₄ -O-CH ₂ ] -Pip

1-262 Me 3- [MeO- (CH ₂ ) ₄ -O- (CH ₂ ) ₂ ] -Pip

1-263 Me 3- [MeO- (CH ₂ ) ₄ -O- (CH ₂ ) ₃ ] -Pip

1-264 Me 3- [EtO- (CH ₂ ) ₂ ] -Pip

1-265 Me 3- [EtO- (CH ₂ ) ₃ ] -Pip

1-266 Me 3- [EtO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-267 Me 3- [EtO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-268 Me 3- [EtO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-269 Me 3- [PrO- (CH ₂ ) ₂ ] -Pip

1-270 Me 3- [PrO- (CH ₂ ) ₃ ] -Pip

1-271 Me 3- [BnO- (CH ₂ ) ₂ ] -Pip

1-272 Me 3- [BnO- (CH ₂ ) ₃ ] -Pip

1-273 Me 3- [PhO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-274 Me 3- [PhO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-275 Me 3- [PhO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-276 Me 3- [H ₂ N- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-277 Me 3- [H ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-278 Me 3- [H ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-279 Me 3- [H ₂ N- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-280 Me 3- [H ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-281 Me 3- [H ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-282 Me 3- [H ₂ N- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-283 Me 3- [H ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-284 Me 3- [Me ₂ N- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-285 Me 3- [Me ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-286 Me 3- [Me ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-287 Me 3- [Me ₂ N- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-288 Me 3- [Me ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-289 Me 3- [Me ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-290 Me 3- [Me ₂ N- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-291 Me 3- [Me ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-292 Me 3- (CN-CH ₂ -O-CH ₂ ) -Pip

1-293 Me 3- [CN-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-294 Me 3- [CN-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-295 Me 3- [CN- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-296 Me 3- [CN- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-297 Me 3- [CN- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-298 Me 3- (Me ₂ NCO-CH ₂ -O-CH ₂ ) -Pip

1-299 Me 3- [Me ₂ NCO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-300 Me 3- [Me ₂ NCO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-301 Me 3- [Me ₂ NCO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-302 Me 3- [Me ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-303 Me 3- [Me ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-304 Me 3- [Me ₂ NCO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-305 Me 3- [Me ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-306 Me 3- [Me ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-307 Me 3- (Et ₂ NCO-CH ₂ -O-CH ₂ ) -Pip

1-308 Me 3- [Et ₂ NCO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-309 Me 3- [Et ₂ NCO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-310 Me 3- [Et ₂ NCO- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-311 Me 3- [Et ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-312 Me 3- [Et ₂ NCO- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-313 Me 3- [Et ₂ NCO- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-314 Me 3- [Et ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-315 Me 3- [Et ₂ NCO- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-316 Me 3- [AcNH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-317 Me 3- [AcNH- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-318 Me 3- [AcNH- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-319 Me 3- [AcNH- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-320 Me 3- [AcNH- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-321 Me 3- [AcNH- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-322 Me 3- [AcNH- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-323 Me 3- [AcNH- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-324 Me 3- [Me- (CH ₂ ) ₄ -CONH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-325 Me 3- [BocNH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-326 Me 3- [NC- (CH ₂ ) ₂ -CONH- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-327 Me 3- (H ₂ N-CH ₂ ) -Pip

1-328 Me 3- [HO- (CH ₂ ) ₂ -NH-CH ₂ ] -Pip

1-329 Me 3- (BocNH-CH ₂ ) -Pip

1-330 Me 3- (MeNH-CH ₂ ) -Pip

1-331 Me 3- [Me- (CH ₂ ) ₃ -NH-CH ₂ ] -Pip

1-332 Me 3- (Me ₂ N-CH ₂ ) -Pip

1-333 Me 2- (MeO-CH ₂ ) -Mor

1-334 Me 3- [Et ₂ N- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-335 Me 3- [Et ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-336 Me 3- [Et ₂ N- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-337 Me 3- [Et ₂ N- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-338 Me 3- [Et ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-339 Me 3- [Et ₂ N- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-340 Me 3- [Et ₂ N- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-341 Me 3- [Pyrld- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-342 Me 3- [Pyrld- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-343 Me 3- [Pyrld- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-344 Me 3- [Pyrld- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-345 Me 3- [Pyrld- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-346 Me 3- [Pyrld- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-347 Me 3- [Pyrld- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-348 Me 3- [Mor- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-349 Me 3- [Mor- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-350 Me 3- [Mor- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-351 Me 3- [Mor- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-352 Me 3- [Mor- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-353 Me 3- [Mor- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-354 Me 3- [Mor- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-355 Me 3- [Pipo- (CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-356 Me 3- [Pipo- (CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-357 Me 3- [Pipo- (CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-358 Me 3- [Pipo- (CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-359 Me 3- [Pipo- (CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-360 Me 3- [Pipo- (CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-361 Me 3- [Pipo- (CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-362 Me 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -O-CH ₂ ] -Pip

1-363 Me 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -O- (CH ₂ ) ₂ ] -Pip

1-364 Me 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -O- (CH ₂ ) ₃ ] -Pip

1-365 Me 3-[(4-Me-Pipra)-(CH ₂ ) ₃ -O-CH ₂ ] -Pip

1-366 Me 3-[(4-Me-Pipra)-(CH ₂ ) ₃ -O- (CH ₂ ) ₂ ] -Pip

1-367 Me 3-[(4-Me-Pipra)-(CH ₂ ) ₃ -O- (CH ₂ ) ₃ ] -Pip

1-368 Me 3-[(4-Me-Pipra)-(CH ₂ ) ₂ -S-CH ₂ ] -Pip

1-369 Me 3- (Pyrld-CO-CH ₂ -O-CH ₂ ) -Pip

1-370 Me 3- [Pyrld-CO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-371 Me 3- [Pyrld-CO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-372 Me 3- (Mor-CO-CH ₂ -O-CH ₂ ) -Pip

1-373 Me 3- [Mor-CO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-374 Me 3- [Mor-CO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-375 Me 3- (Pipo-CO-CH ₂ -O-CH ₂ ) -Pip

1-376 Me 3- [Pipo-CO-CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-377 Me 3- [Pipo-CO-CH ₂ -O- (CH ₂ ) ₃ ] -Pip

1-378 Me 3-[(4-Me-Pipra) -CO-CH ₂ -O-CH ₂ ] -Pip

1-379 Me 3-[(4-Me-Pipra) -CH ₂ -O- (CH ₂ ) ₂ ] -Pip

1-380 Me 3-[(4-Me-Pipra) -CH ₂ -O- (CH ₂ ) ₃ ] -Pip

-------------------------------------------------- ---------------

TABLE 2

[Formula 6]

-------------------------------------------------- ------

compound

Number R ¹ R ^a R ^b

-------------------------------------------------- -------

2-1 H H Me

2-2 H H Et

2-3 H H Pr

2-4 H H iPr

2-5 H H Bu

2-6 H H iBu

2-7 H H neoPn

2-8 H H cPn

2-9 H H cHx

2-10 H H cHep

2-11 H H Bn

2-12 H H Phet

2-13 H H Ph- (CH ₂ ) ₃

2-14 H H cHxCH ₂

2-15 H H MeOCH ₂ CH ₂

2-16 H H EtOCH ₂ CH ₂

2-17 H Me Me

2-18 H Me Et

2-19 H Me Pr

2-20 H Me iPr

2-21 H Me Bu

2-22 H Me iBu

2-23 H Me neoPn

2-24 H Me cPn

2-25 H Me cHx

2-26 H Me cHep

2-27 H Me Bn

2-28 H Me Phet

2-29 H Me Ph- (CH ₂ ) ₃

2-30 H Me cHxCH ₂

2-31 H Me MeOCH ₂ CH ₂

2-32 H Me EtOCH ₂ CH ₂

2-33 H Et Et

2-34 H Et Pr

2-35 H Et iPr

2-36 H Et Bu

2-37 H Et iBu

2-38 H Et neoPn

2-39 H Et cPn

2-40 H Et cHx

2-41 H Et cHep

2-42 H Et Bn

2-43 H Et Phet

2-44 H Et Ph- (CH ₂ ) ₃

2-45 H Et cHxCH ₂

2-46 H Et MeOCH ₂ CH ₂

2-47 H Et EtOCH ₂ CH ₂

2-48 H Pr Pr

2-49 H Pr iPr

2-50 H Pr Bu

2-51 H Pr iBu

2-52 H Pr neoPn

2-53 H Pr cPn

2-54 H Pr cHx

2-55 H Pr cHep

2-56 H Pr Bn

2-57 H Pr Phet

2-58 H Pr Ph- (CH ₂ ) ₃

2-59 H Pr cHxCH ₂

2-60 H Pr MeOCH ₂ CH ₂

2-61 H Pr EtOCH ₂ CH ₂

2-62 H MeOCH ₂ CH ₂ iPr

2-63 H MeOCH ₂ CH ₂ Bu

2-64 H MeOCH ₂ CH ₂ iBu

2-65 H MeOCH ₂ CH ₂ neoPn

2-66 H MeOCH ₂ CH ₂ cPn

2-67 H MeOCH ₂ CH ₂ cHx

2-68 H MeOCH ₂ CH ₂ cHep

2-69 H MeOCH ₂ CH ₂ Bn

2-70 H MeOCH ₂ CH ₂ Phet

2-71 H MeOCH ₂ CH ₂ Ph- (CH ₂ ) ₃

2-72 H MeOCH ₂ CH ₂ cHxCH ₂

2-73 H MeOCH ₂ CH ₂ MeOCH ₂ CH ₂

2-74 H EtOCH ₂ CH ₂ iPr

2-75 H EtOCH ₂ CH ₂ Bu

2-76 H EtOCH ₂ CH ₂ iBu

2-77 H EtOCH ₂ CH ₂ neoPn

2-78 H EtOCH ₂ CH ₂ cPn

2-79 H EtOCH ₂ CH ₂ cHx

2-80 H EtOCH ₂ CH ₂ cHep

2-81 H EtOCH ₂ CH ₂ Bn

2-82 H EtOCH ₂ CH ₂ Phet

2-83 H EtOCH ₂ CH ₂ Ph- (CH ₂ ) ₃

2-84 H EtOCH ₂ CH ₂ cHxCH ₂

2-85 H EtOCH ₂ CH ₂ EtOCH ₂ CH ₂

2-86 Me H Me

2-87 Me H Et

2-88 Me H Pr

2-89 Me H iPr

2-90 Me H Bu

2-91 Me H iBu

2-92 Me H neoPn

2-93 Me H cPn

2-94 Me H cHx

2-95 Me H cHep

2-96 Me H Bn

2-97 Me H Phet

2-98 Me H Ph- (CH ₂ ) ₃

2-99 Me H cHxCH ₂

2-100 Me H MeOCH ₂ CH ₂

2-101 Me H EtOCH ₂ CH ₂

2-102 Me Me Me

2-103 Me Me Et

2-104 Me Me Pr

2-105 Me Me iPr

2-106 Me Me Bu

2-107 Me Me iBu

2-108 Me Me neoPn

2-109 Me Me cPn

2-110 Me Me cHx

2-111 Me Me cHep

2-112 Me Me Bn

2-113 Me Me Phet

2-114 Me Me Ph- (CH ₂ ) ₃

2-115 Me Me cHxCH ₂

2-116 Me Me MeOCH ₂ CH ₂

2-117 Me Me EtOCH ₂ CH ₂

2-118 Me Et Et

2-119 Me Et Pr

2-120 Me Et iPr

2-121 Me Et Bu

2-122 Me Et iBu

2-123 Me Et neoPn

2-124 Me Et cPn

2-125 Me Et cHx

2-126 Me Et cHep

2-127 Me Et Bn

2-128 Me Et Phet

2-129 Me Et Ph- (CH ₂ ) ₃

2-130 Me Et cHxCH ₂

2-131 Me Et MeOCH ₂ CH ₂

2-132 Me Et EtOCH ₂ CH ₂

2-133 Me Pr Pr

2-134 Me Pr iPr

2-135 Me Pr Bu

2-136 Me Pr iBu

2-137 Me Pr neoPn

2-138 Me Pr cPn

2-139 Me Pr cHx

2-140 Me Pr cHep

2-141 Me Pr Bn

2-142 Me Pr Phet

2-143 Me Pr Ph- (CH ₂ ) ₃

2-144 Me Pr cHxCH ₂

2-145 Me Pr MeOCH ₂ CH ₂

2-146 Me Pr EtOCH ₂ CH ₂

2-147 Me MeOCH ₂ CH ₂ iPr

2-148 Me MeOCH ₂ CH ₂ Bu

2-149 Me MeOCH ₂ CH ₂ iBu

2-150 Me MeOCH ₂ CH ₂ neoPn

2-151 Me MeOCH ₂ CH ₂ cPn

2-152 Me MeOCH ₂ CH ₂ cHx

2-153 Me MeOCH ₂ CH ₂ cHep

2-154 Me MeOCH ₂ CH ₂ Bn

2-155 Me MeOCH ₂ CH ₂ Phet

2-156 Me MeOCH ₂ CH ₂ Ph- (CH ₂ ) ₃

2-157 Me MeOCH ₂ CH ₂ cHxCH ₂

2-158 Me MeOCH ₂ CH ₂ MeOCH ₂ CH ₂

2-159 Me EtOCH ₂ CH ₂ iPr

2-160 Me EtOCH ₂ CH ₂ Bu

2-161 Me EtOCH ₂ CH ₂ iBu

2-162 Me EtOCH ₂ CH ₂ neoPn

2-163 Me EtOCH ₂ CH ₂ cPn

2-164 Me EtOCH ₂ CH ₂ cHx

2-165 Me EtOCH ₂ CH ₂ cHep

2-166 Me EtOCH ₂ CH ₂ Bn

2-167 Me EtOCH ₂ CH ₂ Phet

2-168 Me EtOCH ₂ CH ₂ Ph- (CH ₂ ) ₃

2-169 Me EtOCH ₂ CH ₂ cHxCH ₂

2-170 Me EtOCH ₂ CH ₂ EtOCH ₂ CH ₂

-------------------------------------------------- -------

TABLE 3

[Formula 7]

-------------------------------------------------- --------------

compound

Number R ¹ n R ³ R ⁵

-------------------------------------------------- --------------

3-1 H 1 H H

3-2 H 1 H Me

3-3 H 1 H Et

3-4 H 1 H Pr

3-5 H 1 H iPr

3-6 H 1 H Bn

3-7 H 1 H Bzhy

3-8 H 1 H PhCH = CHCH ₂

3-9 H 1 H Ph

3-10 H 1 H 5-BzDioxo

3-11 H 1 H 6-BzDioxa

3-12 H 1 H 4-F-Ph

3-13 H 1 H 3,4-diF-Ph

3-14 H 1 H 3-Cl-4-F-Ph

3-15 H 1 H 2-Cl-Ph

3-16 H 1 H 3-Cl-Ph

3-17 H 1 H 4-Cl-Ph

3-18 H 1 H 4-Br-Ph

3-19 H 1 H 3-NO ₂ -Ph

3-20 H 1 H 4-NO ₂ -Ph

3-21 H 1 H 4-CN-Ph

3-22 H 1 H 4-Ac-Ph

3-23 H 1 H 4-EtCO-Ph

3-24 H 1 H 4- (HOOC) -Ph

3-25 H 1 H 4- (MeOOC) -Ph

3-26 H 1 H 4- (EtOOC) -Ph

3-27 H 1 H 4-Me ₂ N-Ph

3-28 H 1 H 4- (H ₂ NCO) -Ph

3-29 H 1 H 4- (MeNHCO) -Ph

3-30 H 1 H 4- (Me ₂ NCO) -Ph

3-31 H 1 H 4- (Et ₂ NCO) -Ph

3-32 H 1 H 2-Me-Ph

3-33 H 1 H 3-Me-Ph

3-34 H 1 H 4-Me-Ph

3-35 H 1 H 4-Et-Ph

3-36 H 1 H 4-Pr-Ph

3-37 H 1 H 4-iPr-Ph

3-38 H 1 H 4-tBu-Ph

3-39 H 1 H 3,4-diMe-Ph

3-40 H 1 H 3-F-4-Me-Ph

3-41 H 1 H 4-F-3-Me-Ph

3-42 H 1 H 3-NO ₂ -4-Me-Ph

3-43 H 1 H 3-CF ₃ -Ph

3-44 H 1 H 4-CF ₃ -Ph

3-45 H 1 H 2-MeO-Ph

3-46 H 1 H 3-MeO-Ph

3-47 H 1 H 4-MeO-Ph

3-48 H 1 H 3,4-diMeO-Ph

3-49 H 1 H 3,4,5-triMeO-Ph

3-50 H 1 H 4-EtO-Ph

3-51 H 1 H 4-PrO-Ph

3-52 H 1 H 4-iPrO-Ph

3-53 H 1 H 4-CF ₃ O-Ph

3-54 H 1 H 4-MeS-Ph

3-55 H 1 H 4-MeSO-Ph

3-56 H 1 H 4-MeSO ₂ -Ph

3-57 H 1 H 4-BnO-Ph

3-58 H 1 H 2-Oxaz

3-59 H 1 H 2-Thaz

3-60 H 1 H 2-BzOxaz

3-61 H 1 H 2-BzThaz

3-62 H 1 H 2-Py

3-63 H 1 H 3-Py

3-64 H 1 H 4-Py

3-65 H 1 H 5-Ac-2-Py

3-66 H 1 H 5-Me-2-Py

3-67 H 1 H 6-MeO-3-Py

3-68 H 1 H 2,3,5,6-tetraF-4-Py

3-69 H 1 H 2-Pym

3-70 H 1 H 4-Qunz

3-71 H 1 H 6-Cl-3-Pydz

3-72 H 1 H Ac

3-73 H 1 H Ph-CO

3-74 H 1 H MeSO ₂

3-75 H 1 H tBuO-CO

3-76 Me 1 H Ph

3-77 H 1 Me 3-Me-Ph

3-78 H 2 H H

3-79 H 2 H Me

3-80 H 2 H Et

3-81 H 2 H Pr

3-82 H 2 H iPr

3-83 H 2 H Bn

3-84 H 2 H Bzhy

3-85 H 2 H PhCH = CHCH ₂

3-86 H 2 H Ph

3-87 H 2 H 5-BzDioxo

3-88 H 2 H 6-BzDioxa

3-89 H 2 H 4-F-Ph

3-90 H 2 H 3,4-diF-Ph

3-91 H 2 H 3-Cl-4-F-Ph

3-92 H 2 H 2-Cl-Ph

3-93 H 2 H 3-Cl-Ph

3-94 H 2 H 4-Cl-Ph

3-95 H 2 H 4-Br-Ph

3-96 H 2 H 3-NO ₂ -Ph

3-97 H 2 H 4-NO ₂ -Ph

3-98 H 2 H 4-CN-Ph

3-99 H 2 H 4-Ac-Ph

3-100 H 2 H 4-EtCO-Ph

3-101 H 2 H 4- (HOOC) -Ph

3-102 H 2 H 4- (MeOOC) -Ph

3-103 H 2 H 4- (EtOOC) -Ph

3-104 H 2 H 4-Me ₂ N-Ph

3-105 H 2 H 4- (H ₂ NCO) -Ph

3-106 H 2 H 4- (MeNHCO) -Ph

3-107 H 2 H 4- (Me ₂ NCO) -Ph

3-108 H 2 H 4- (Et ₂ NCO) -Ph

3-109 H 2 H 2-Me-Ph

3-110 H 2 H 3-Me-Ph

3-111 H 2 H 4-Me-Ph

3-112 H 2 H 4-Et-Ph

3-113 H 2 H 4-Pr-Ph

3-114 H 2 H 4-iPr-Ph

3-115 H 2 H 4-tBu-Ph

3-116 H 2 H 3,4-diMe-Ph

3-117 H 2 H 3-F-4-Me-Ph

3-118 H 2 H 4-F-3-Me-Ph

3-119 H 2 H 3-NO ₂ -4-Me-Ph

3-120 H 2 H 3-CF ₃ -Ph

3-121 H 2 H 4-CF ₃ -Ph

3-122 H 2 H 2-MeO-Ph

3-123 H 2 H 3-MeO-Ph

3-124 H 2 H 4-MeO-Ph

3-125 H 2 H 3,4-diMeO-Ph

3-126 H 2 H 3,4,5-triMeO-Ph

3-127 H 2 H 4-EtO-Ph

3-128 H 2 H 4-PrO-Ph

3-129 H 2 H 4-iPrO-Ph

3-130 H 2 H 4-CF ₃ O-Ph

3-131 H 2 H 4-MeS-Ph

3-132 H 2 H 4-MeSO-Ph

3-133 H 2 H 4-MeSO ₂ -Ph

3-134 H 2 H 4-BnO-Ph

3-135 H 2 H 2-Oxaz

3-136 H 2 H 2-Thaz

3-137 H 2 H 2-BzOxaz

3-138 H 2 H 2-BzThaz

3-139 H 2 H 2-Py

3-140 H 2 H 3-Py

3-141 H 2 H 4-Py

3-142 H 2 H 5-Ac-2-Py

3-143 H 2 H 5-Me-2-Py

3-144 H 2 H 6-MeO-3-Py

3-145 H 2 H 2,3,5,6-tetraF-4-Py

3-146 H 2 H 2-Pym

3-147 H 2 H 4-Qunz

3-148 H 2 H 6-Cl-3-Pydz

3-149 H 2 H Ac

3-150 H 2 H Ph-CO

3-151 H 2 H MeSO ₂

3-152 H 2 H tBuO-CO

3-153 Me 2 H H

3-154 Me 2 H Me

3-155 Me 2 H Et

3-156 Me 2 H Pr

3-157 Me 2 H iPr

3-158 Me 2 H Bn

3-159 Me 2 H Bzhy

3-160 Me 2 H PhCH = CHCH ₂

3-161 Me 2 H Ph

3-162 Me 2 H 5-BzDioxo

3-163 Me 2 H 6-BzDioxa

3-164 Me 2 H 4-F-Ph

3-165 Me 2 H 3,4-diF-Ph

3-166 Me 2 H 3-Cl-4-F-Ph

3-167 Me 2 H 2-Cl-Ph

3-168 Me 2 H 3-Cl-Ph

3-169 Me 2 H 4-Cl-Ph

3-170 Me 2 H 4-Br-Ph

3-171 Me 2 H 3-NO ₂ -Ph

3-172 Me 2 H 4-NO ₂ -Ph

3-173 Me 2 H 4-CN-Ph

3-174 Me 2 H 4-Ac-Ph

3-175 Me 2 H 4-EtCO-Ph

3-176 Me 2 H 4- (HOOC) -Ph

3-177 Me 2 H 4- (MeOOC) -Ph

3-178 Me 2 H 4- (EtOOC) -Ph

3-179 Me 2 H 4-Me ₂ N-Ph

3-180 Me 2 H 4- (H ₂ NCO) -Ph

3-181 Me 2 H 4- (MeNHCO) -Ph

3-182 Me 2 H 4- (Me ₂ NCO) -Ph

3-183 Me 2 H 4- (Et ₂ NCO) -Ph

3-184 Me 2 H 2-Me-Ph

3-185 Me 2 H 3-Me-Ph

3-186 Me 2 H 4-Me-Ph

3-187 Me 2 H 4-Et-Ph

3-188 Me 2 H 4-Pr-Ph

3-189 Me 2 H 4-iPr-Ph

3-190 Me 2 H 4-tBu-Ph

3-191 Me 2 H 3,4-diMe-Ph

3-192 Me 2 H 3-F-4-Me-Ph

3-193 Me 2 H 4-F-3-Me-Ph

3-194 Me 2 H 3-NO ₂ -4-Me-Ph

3-195 Me 2 H 3-CF ₃ -Ph

3-196 Me 2 H 4-CF ₃ -Ph

3-197 Me 2 H 2-MeO-Ph

3-198 Me 2 H 3-MeO-Ph

3-199 Me 2 H 4-MeO-Ph

3-200 Me 2 H 3,4-diMeO-Ph

3-201 Me 2 H 3,4,5-triMeO-Ph

3-202 Me 2 H 4-EtO-Ph

3-203 Me 2 H 4-PrO-Ph

3-204 Me 2 H 4-iPrO-Ph

3-205 Me 2 H 4-CF ₃ O-Ph

3-206 Me 2 H 4-MeS-Ph

3-207 Me 2 H 4-MeSO-Ph

3-208 Me 2 H 4-MeSO ₂ -Ph

3-209 Me 2 H 4-BnO-Ph

3-210 Me 2 H 2-Oxaz

3-211 Me 2 H 2-Thaz

3-212 Me 2 H 2-BzOxaz

3-213 Me 2 H 2-BzThaz

3-214 Me 2 H 2-Py

3-215 Me 2 H 3-Py

3-216 Me 2 H 4-Py

3-217 Me 2 H 5-Ac-2-Py

3-218 Me 2 H 5-Me-2-Py

3-219 Me 2 H 6-MeO-3-Py

3-220 Me 2 H 2,3,5,6-tetraF-4-Py

3-221 Me 2 H 2-Pym

3-222 Me 2 H 4-Qunz

3-223 Me 2 H 6-Cl-3-Pydz

3-224 Me 2 H Ac

3-225 Me 2 H Ph-CO

3-226 Me 2 H MeSO ₂

3-227 Me 2 H tBuO-CO

3-228 H 2 Me H

3-229 H 2 Me Me

3-230 H 2 Me Et

3-231 H 2 Me Pr

3-232 H 2 Me iPr

3-233 H 2 Me Bn

3-234 H 2 Me Bzhy

3-235 H 2 Me PhCH = CHCH ₂

3-236 H 2 Me Ph

3-237 H 2 Me 5-BzDioxo

3-238 H 2 Me 6-BzDioxa

3-239 H 2 Me 4-F-Ph

3-240 H 2 Me 3,4-diF-Ph

3-241 H 2 Me 3-Cl-4-F-Ph

3-242 H 2 Me 2-Cl-Ph

3-243 H 2 Me 3-Cl-Ph

3-244 H 2 Me 4-Cl-Ph

3-245 H 2 Me 4-Br-Ph

3-246 H 2 Me 3-NO ₂ -Ph

3-247 H 2 Me 4-NO ₂ -Ph

3-248 H 2 Me 4-CN-Ph

3-249 H 2 Me 4-Ac-Ph

3-250 H 2 Me 4-EtCO-Ph

3-251 H 2 Me 4- (HOOC) -Ph

3-252 H 2 Me 4- (MeOOC) -Ph

3-253 H 2 Me 4- (EtOOC) -Ph

3-254 H 2 Me 4-Me ₂ N-Ph

3-255 H 2 Me 4- (H ₂ NCO) -Ph

3-256 H 2 Me 4- (MeNHCO) -Ph

3-257 H 2 Me 4- (Me ₂ NCO) -Ph

3-258 H 2 Me 4- (Et ₂ NCO) -Ph

3-259 H 2 Me 2-Me-Ph

3-260 H 2 Me 3-Me-Ph

3-261 H 2 Me 4-Me-Ph

3-262 H 2 Me 4-Et-Ph

3-263 H 2 Me 4-Pr-Ph

3-264 H 2 Me 4-iPr-Ph

3-265 H 2 Me 4-tBu-Ph

3-266 H 2 Me 3,4-diMe-Ph

3-267 H 2 Me 3-F-4-Me-Ph

3-268 H 2 Me 4-F-3-Me-Ph

3-269 H 2 Me 3-NO ₂ -4-Me-Ph

3-270 H 2 Me 3-CF ₃ -Ph

3-271 H 2 Me 4-CF ₃ -Ph

3-272 H 2 Me 2-MeO-Ph

3-273 H 2 Me 3-MeO-Ph

3-274 H 2 Me 4-MeO-Ph

3-275 H 2 Me 3,4-diMeO-Ph

3-276 H 2 Me 3,4,5-triMeO-Ph

3-277 H 2 Me 4-EtO-Ph

3-278 H 2 Me 4-PrO-Ph

3-279 H 2 Me 4-iPrO-Ph

3-280 H 2 Me 4-CF ₃ O-Ph

3-281 H 2 Me 4-MeS-Ph

3-282 H 2 Me 4-MeSO-Ph

3-283 H 2 Me 4-MeSO ₂ -Ph

3-284 H 2 Me 4-BnO-Ph

3-285 H 2 Me 2-Oxaz

3-286 H 2 Me 2-Thaz

3-287 H 2 Me 2-BzOxaz

3-288 H 2 Me 2-BzThaz

3-289 H 2 Me 2-Py

3-290 H 2 Me 3-Py

3-291 H 2 Me 4-Py

3-292 H 2 Me 5-Ac-2-Py

3-293 H 2 Me 5-Me-2-Py

3-294 H 2 Me 6-MeO-3-Py

3-295 H 2 Me 2,3,5,6-tetraF-4-Py

3-296 H 2 Me 2-Pym

3-297 H 2 Me 4-Qunz

3-298 H 2 Me 6-Cl-3-Pydz

3-299 H 2 Me Ac

3-300 H 2 Me Ph-CO

3-301 H 2 Me MeSO ₂

3-302 H 2 Me tBuO-CO

3-303 Me 2 Me H

3-304 Me 2 Me Me

3-305 Me 2 Me Et

3-306 Me 2 Me Pr

3-307 Me 2 Me iPr

3-308 Me 2 Me Bn

3-309 Me 2 Me Bzhy

3-310 Me 2 Me PhCH = CHCH ₂

3-311 Me 2 Me Ph

3-312 Me 2 Me 5-BzDioxo

3-313 Me 2 Me 6-BzDioxa

3-314 Me 2 Me 4-F-Ph

3-315 Me 2 Me 3,4-diF-Ph

3-316 Me 2 Me 3-Cl-4-F-Ph

3-317 Me 2 Me 2-Cl-Ph

3-318 Me 2 Me 3-Cl-Ph

3-319 Me 2 Me 4-Cl-Ph

3-320 Me 2 Me 4-Br-Ph

3-321 Me 2 Me 3-NO ₂ -Ph

3-322 Me 2 Me 4-NO ₂ -Ph

3-323 Me 2 Me 4-CN-Ph

3-324 Me 2 Me 4-Ac-Ph

3-325 Me 2 Me 4-EtCO-Ph

3-326 Me 2 Me 4- (HOOC) -Ph

3-327 Me 2 Me 4- (MeOOC) -Ph

3-328 Me 2 Me 4- (EtOOC) -Ph

3-329 Me 2 Me 4-Me ₂ N-Ph

3-330 Me 2 Me 4- (H ₂ NCO) -Ph

3-331 Me 2 Me 4- (MeNHCO) -Ph

3-332 Me 2 Me 4- (Me ₂ NCO) -Ph

3-333 Me 2 Me 4- (Et ₂ NCO) -Ph

3-334 Me 2 Me 2-Me-Ph

3-335 Me 2 Me 3-Me-Ph

3-336 Me 2 Me 4-Me-Ph

3-337 Me 2 Me 4-Et-Ph

3-338 Me 2 Me 4-Pr-Ph

3-339 Me 2 Me 4-iPr-Ph

3-340 Me 2 Me 4-tBu-Ph

3-341 Me 2 Me 3,4-diMe-Ph

3-342 Me 2 Me 3-F-4-Me-Ph

3-343 Me 2 Me 4-F-3-Me-Ph

3-344 Me 2 Me 3-NO ₂ -4-Me-Ph

3-345 Me 2 Me 3-CF ₃ -Ph

3-346 Me 2 Me 4-CF ₃ -Ph

3-347 Me 2 Me 2-MeO-Ph

3-348 Me 2 Me 3-MeO-Ph

3-349 Me 2 Me 4-MeO-Ph

3-350 Me 2 Me 3,4-diMeO-Ph

3-351 Me 2 Me 3,4,5-triMeO-Ph

3-352 Me 2 Me 4-EtO-Ph

3-353 Me 2 Me 4-PrO-Ph

3-354 Me 2 Me 4-iPrO-Ph

3-355 Me 2 Me 4-CF ₃ O-Ph

3-356 Me 2 Me 4-MeS-Ph

3-357 Me 2 Me 4-MeSO-Ph

3-358 Me 2 Me 4-MeSO ₂ -Ph

3-359 Me 2 Me 4-BnO-Ph

3-360 Me 2 Me 2-Oxaz

3-361 Me 2 Me 2-Thaz

3-362 Me 2 Me 2-BzOxaz

3-363 Me 2 Me 2-BzThaz

3-364 Me 2 Me 2-Py

3-365 Me 2 Me 3-Py

3-366 Me 2 Me 4-Py

3-367 Me 2 Me 5-Ac-2-Py

3-368 Me 2 Me 5-Me-2-Py

3-369 Me 2 Me 6-MeO-3-Py

3-370 Me 2 Me 2,3,5,6-tetraF-4-Py

3-371 Me 2 Me 2-Pym

3-372 Me 2 Me 4-Qunz

3-373 Me 2 Me 6-Cl-3-Pydz

3-374 Me 2 Me Ac

3-375 Me 2 Me Ph-CO

3-376 Me 2 Me MeSO ₂

3-377 Me 2 Me tBuO-CO

3-378 H 1 H 4- (MeO-CH ₂ ) -Ph

3-379 H 1 H 3- (MeO-CH ₂ ) -Ph

3-380 H 1 H 4- [MeO- (CH ₂ ) ₂ ] -Ph

3-381 H 1 H 3- [MeO- (CH ₂ ) ₂ ] -Ph

3-382 H 1 H 4- [MeO- (CH ₂ ) ₃ ] -Ph

3-383 H 1 H 3- [MeO- (CH ₂ ) ₃ ] -Ph

3-384 H 1 H 4- (EtO-CH ₂ ) -Ph

3-385 H 1 H 3- (EtO-CH ₂ ) -Ph

3-386 H 1 H 4- [EtO- (CH ₂ ) ₂ ] -Ph

3-387 H 1 H 3- [EtO- (CH ₂ ) ₂ ] -Ph

3-388 H 1 H 4- [EtO- (CH ₂ ) ₃ ] -Ph

3-389 H 1 H 3- [EtO- (CH ₂ ) ₃ ] -Ph

3-390 H 1 H 4-cPrO-Ph

3-391 H 1 H 3-cPrO-Ph

3-392 H 1 H 4- (cPrO-CH ₂ ) -Ph

3-393 H 1 H 3- (cPrO-CH ₂ ) -Ph

3-394 H 1 H 4- [cPrO- (CH ₂ ) ₂ ] -Ph

3-395 H 1 H 3- [cPrO- (CH ₂ ) ₂ ] -Ph

3-396 H 1 H 4- [cPrO- (CH ₂ ) ₃ ] -Ph

3-397 H 1 H 3- [cPrO- (CH ₂ ) ₃ ] -Ph

3-398 H 1 H 4-CHF ₂ O-Ph

3-399 H 1 H 3-CHF ₂ O-Ph

3-400 H 1 H 4- (CHF ₂ O-CH ₂ ) -Ph

3-401 H 1 H 3- (CHF ₂ O-CH ₂ ) -Ph

3-402 H 1 H 4- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-403 H 1 H 3- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-404 H 1 H 4- [CHF ₂ O- (CH ₂ ) ₃ ] -Ph

3-405 H 1 H 3- [CHF ₂ O- (CH ₂ ) ₃ ] -Ph

3-406 H 1 H 3- (H ₂ NCO) -Ph

3-407 H 1 H 4- (H ₂ NCO-CH ₂ ) -Ph

3-408 H 1 H 3- (H ₂ NCO-CH ₂ ) -Ph

3-409 H 1 H 4- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-410 H 1 H 3- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-411 H 1 H 3- (MeNHCO) -Ph

3-412 H 1 H 4- (MeNHCO-CH ₂ ) -Ph

3-413 H 1 H 3- (MeNHCO-CH ₂ ) -Ph

3-414H 1 H 4- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-415 H 1 H 3- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-416 H 1 H 4- (iPrNHCO) -Ph

3-417 H 1 H 3- (iPrNHCO) -Ph

3-418 H 1 H 4- (iPrNHCO-CH ₂ ) -Ph

3-419 H 1 H 3- (iPrNHCO-CH ₂ ) -Ph

3-420 H 1 H 4- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-421 H 1 H 3- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-422 H 1 H 4- (EtNMeCO) -Ph

3-423 H 1 H 3- (EtNMeCO) -Ph

3-424 H 1 H 4- (EtNMeCO-CH ₂ ) -Ph

3-425 H 1 H 3- (EtNMeCO-CH ₂ ) -Ph

3-426 H 1 H 4- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-427 H 1 H 3- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-428 H 1 H 3- (Me ₂ NCO) -Ph

3-429 H 1 H 4- (Me ₂ NCO-CH ₂ ) -Ph

3-430 H 1 H 3- (Me ₂ NCO-CH ₂ ) -Ph

3-431 H 1 H 4- [Me ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-432 H 1 H 3- [Me ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-433 H 1 H 3- (Et ₂ NCO) -Ph

3-434 H 1 H 4- (Et ₂ NCO-CH ₂ ) -Ph

3-435 H 1 H 3- (Et ₂ NCO-CH ₂ ) -Ph

3-436 H 1 H 4- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-437 H 1 H 3- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-438 H 1 H 4-[(MeO) NMeCO] -Ph

3-439 H 1 H 3-[(MeO) NMeCO] -Ph

3-440 H 1 H 4-[(MeO) NMeCO-CH ₂ ] -Ph

3-441 H 1 H 3-[(MeO) NMeCO-CH ₂ ] -Ph

3-442 H 1 H 4-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-443 H 1 H 3-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-444 H 1 H 4- (Aze-CO) -Ph

3-445 H 1 H 3- (Aze-CO) -Ph

3-446 H 1 H 4- (Aze-CO-CH ₂ ) -Ph

3-447 H 1 H 3- (Aze-CO-CH ₂ ) -Ph

3-448 H 1 H 4- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-449 H 1 H 3- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-450 H 1 H 4-[(3-HO-1-Aze) -CO] -Ph

3-451 H 1 H 3-[(3-HO-1-Aze) -CO] -Ph

3-452H 1 H 4-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-453 H 1 H 3-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-454 H 1 H 4-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-455 H 1 H 3-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-456 H 1 H 4- (Pyrld-CO) -Ph

3-457 H 1 H 3- (Pyrld-CO) -Ph

3-458 H 1 H 4- (Pyrld-CO-CH ₂ ) -Ph

3-459 H 1 H 3- (Pyrld-CO-CH ₂ ) -Ph

3-460 H 1 H 4- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-461 H 1 H 3- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-462 H 1 H 4- (Pipo-CO) -Ph

3-463 H 1 H 3- (Pipo-CO) -Ph

3-464 H 1 H 4- (Pipo-CO-CH ₂ ) -Ph

3-465 H 1 H 3- (Pipo-CO-CH ₂ ) -Ph

3-466 H 1 H 4- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-467 H 1 H 3- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-468 H 1 H 4-[(4-Me-Pipra) -CO] -Ph

3-469 H 1 H 3-[(4-Me-Pipra) -CO] -Ph

3-470 H 1 H 4-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-471 H 1 H 3-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-472 H 1 H 4-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-473 H 1 H 3-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-474 H 1 H 4- (Mor-CO) -Ph

3-475 H 1 H 3- (Mor-CO) -Ph

3-476 H 1 H 4- (Mor-CO-CH ₂ ) -Ph

3-477 H 1 H 3- (Mor-CO-CH ₂ ) -Ph

3-478 H 1 H 4- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-479 H 1 H 3- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-480 H 1 H 3-Me ₂ N-Ph

3-481 H 1 H 4- (Me ₂ N-CH ₂ ) -Ph

3-482 H 1 H 3- (Me ₂ N-CH ₂ ) -Ph

3-483 H 1 H 4- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-484 H 1 H 3- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-485 H 1 H 4- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-486 H 1 H 3- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-487 H 1 H 4-Mor-Ph

3-488 H 1 H 3-Mor-Ph

3-489 H 1 H 4- (Mor-CH ₂ ) -Ph

3-490 H 1 H 3- (Mor-CH ₂ ) -Ph

3-491 H 1 H 4- [Mor- (CH ₂ ) ₂ ] -Ph

3-492 H 1 H 3- [Mor- (CH ₂ ) ₂ ] -Ph

3-493 H 1 H 4- [Mor- (CH ₂ ) ₃ ] -Ph

3-494 H 1 H 3- [Mor- (CH ₂ ) ₃ ] -Ph

3-495 H 1 H 4-Pipo-Ph

3-496 H 1 H 3-Pipo-Ph

3-497 H 1 H 4- (Pipo-CH ₂ ) -Ph

3-498 H 1 H 3- (Pipo-CH ₂ ) -Ph

3-499 H 1 H 4- [Pipo- (CH ₂ ) ₂ ] -Ph

3-500 H 1 H 3- [Pipo- (CH ₂ ) ₂ ] -Ph

3-501 H 1 H 4- [Pipo- (CH ₂ ) ₃ ] -Ph

3-502 H 1 H 3- [Pipo- (CH ₂ ) ₃ ] -Ph

3-503 H 1 H 4-HO-Ph

3-504 H 1 H 3-HO-Ph

3-505 H 1 H 4- (HO-CH ₂ ) -Ph

3-506 H 1 H 3- (HO-CH ₂ ) -Ph

3-507 H 1 H 4- [HO- (CH ₂ ) ₂ ] -Ph

3-508 H 1 H 3- [HO- (CH ₂ ) ₂ ] -Ph

3-509 H 1 H 4- [HO- (CH ₂ ) ₃ ] -Ph

3-510 H 1 H 3- [HO- (CH ₂ ) ₃ ] -Ph

3-511 H 1 H 4- [MeCH (OH)]-Ph

3-512 H 1 H 3- [MeCH (OH)]-Ph

3-513 H 1 H 4- [MeCH (OH) -CH ₂ ] -Ph

3-514 H 1 H 3- [MeCH (OH) -CH ₂ ] -Ph

3-515 H 1 H 4- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-516 H 1 H 3- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-517 H 1 H 3-CN-Ph

3-518 H 1 H 4- (CN-CH ₂ ) -Ph

3-519 H 1 H 3- (CN-CH ₂ ) -Ph

3-520 H 1 H 4- [CN- (CH ₂ ) ₂ ] -Ph

3-521 H 1 H 3- [CN- (CH ₂ ) ₂ ] -Ph

3-522 H 1 H 3-Ac-Ph

3-523 H 1 H 4- (Ac-CH ₂ ) -Ph

3-524 H 1 H 3- (Ac-CH ₂ ) -Ph

3-525 H 1 H 4- [Ac- (CH ₂ ) ₂ ] -Ph

3-526 H 1 H 3- [Ac- (CH ₂ ) ₂ ] -Ph

3-527 H 1 H 4- (CF ₃ CO) -Ph

3-528 H 1 H 4- (EtCO) -Ph

3-529 H 1 H 3- (EtCO) -Ph

3-530 H 1 H 4- (EtCO-CH ₂ ) -Ph

3-531 H 1 H 3- (EtCO-CH ₂ ) -Ph

3-532 H 1 H 4- [EtCO- (CH ₂ ) ₂ ] -Ph

3-533 H 1 H 3- [EtCO- (CH ₂ ) ₂ ] -Ph

3-534 H 1 H 4- (iPrCO) -Ph

3-535 H 1 H 4- (cBuCO) -Ph

3-536 H 1 H 4- (cPrCO) -Ph

3-537 H 1 H 4- (Ph-CO) -Ph

3-538 H 1 H 4-Ac-3-MeO-Ph

3-539 H 1 H 4-Ac-3-OH-Ph

3-540 H 1 H 4-Ac-3-Cl-Ph

3-541 H 1 H 4- [CH ₃ C (= N-OH)]-Ph

3-542 H 1 H 3- [CH ₃ C (= N-OH)]-Ph

3-543 H 1 H 4- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-544 H 1 H 3- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-545 H 1 H 4- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-546 H 1 H 3- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-547 H 1 H 4- [CH ₃ C (= N-OMe)]-Ph

3-548 H 1 H 3- [CH ₃ C (= N-OMe)]-Ph

3-549 H 1 H 4- [CH ₃ C (= N-OMe) -CH ₂ ] -Ph

3-550 H 1 H 3- [CH ₃ C (= N-OMe) -CH ₂ ] -Ph

3-551 H 1 H 4- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-552 H 1 H 3- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-553 H 1 H 4- (Me ₂ NSO ₂ ) -Ph

3-554 H 1 H 4-[(MeO) ₂ CH] -Ph

3-555 H 1 H 3-[(MeO) ₂ CH] -Ph

3-556 H 1 H 4-[(MeO) ₂ CH-CH ₂ ] -Ph

3-557 H 1 H 3-[(MeO) ₂ CH-CH ₂ ] -Ph

3-558 H 1 H 4-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-559 H 1 H 3-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-560 H 1 H 4- [Me (MeO) ₂ C] -Ph

3-561 H 1 H 3- [Me (MeO) ₂ C] -Ph

3-562 H 1 H 4- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-563 H 1 H 3- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-564 H 1 H 4- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-565 H 1 H 3- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-566 H 1 H 4-[(EtO) ₂ CH] -Ph

3-567 H 1 H 3-[(EtO) ₂ CH] -Ph

3-568 H 1 H 4-[(EtO) ₂ CH-CH ₂ ] -Ph

3-569 H 1 H 3-[(EtO) ₂ CH-CH ₂ ] -Ph

3-570 H 1 H 4-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-571 H 1 H 3-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-572 H 1 H 4- [Me (EtO) ₂ C] -Ph

3-573 H 1 H 3- [Me (EtO) ₂ C] -Ph

3-574 H 1 H 4- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-575 H 1 H 3- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-576 H 1 H 4- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-577 H 1 H 3- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-578 H 1 H 4- (2-Dioxo) -Ph

3-579 H 1 H 3- (2-Dioxo) -Ph

3-580 H 1 H 4-[(2-Dioxo) -CH ₂ ] -Ph

3-581 H 1 H 3-[(2-Dioxo) -CH ₂ ] -Ph

3-582 H 1 H 4-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-583 H 1 H 3-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-584 H 1 H 4- [2-Me- (2-Dioxo)]-Ph

3-585 H 1 H 3- [2-Me- (2-Dioxo)]-Ph

3-586 H 1 H 4- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-587 H 1 H 3- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-588 H 1 H 4- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-589 H 1 H 3- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-590 H 1 H 4- (2-Dioxa) -Ph

3-591 H 1 H 3- (2-Dioxa) -Ph

3-592 H 1 H 4-[(2-Dioxa) -CH ₂ ] -Ph

3-593 H 1 H 3-[(2-Dioxa) -CH ₂ ] -Ph

3-594 H 1 H 4-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-595 H 1 H 3-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-596 H 1 H 4- [2-Me- (2-Dioxa)]-Ph

3-597 H 1 H 3- [2-Me- (2-Dioxa)]-Ph

3-598 H 1 H 4- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-599 H 1 H 3- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-600 H 1 H 4- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-601 H 1 H 3- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-602 H 1 H 2-Me-1-oxo-5-IIndn

3-603 H 1 H 6-BzOxaz

3-604 H 1 H 4- (HO-N =)-7-Chr

3-605 H 1 H 3-Me-6-BzIox

3-606 H 1 H 2-Me-6-BzOxaz

3-607 H 1 H 2-Me-5-BzOxaz

3-608 H 1 H 2,3-dihydro-5-BzFur

3-609 H 1 H 6-Qui

3-610 H 1 H 6-Iqui

3-611 H 1 H 3- (HO-N =)-2,3-dihydro-6-BzFur

3-612 H 1 H 2-Me-6-BzThaz

3-613 H 1 H 5-Ind

3-614 H 1 H 4-Ac-2-Thaz

3-615 H 1 H 5-Ac-2-Thi

3-616 H 1 H 5-Ac-2-Fur

3-617 H 1 H 5-Me ₂ NCO-2-Py

3-618 H 1 H 5- (Me ₂ NCO-CH ₂ ) -2-Py

3-619 H 1 H 5- [Me ₂ NCO- (CH ₂ ) ₂ ] -2-Py

3-620 H 1 H 4-Me ₂ NCO-2-Thaz

3-621 H 1 H 5-Me ₂ NCO-2-Thaz

3-622 H 1 H 4- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-623 H 1 H 5- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-624 H 1 H 2-Thazn

3-625 H 1 H 2-Oxazn

3-626 Me 1 H 4- (MeO-CH ₂ ) -Ph

3-627 Me 1 H 3- (MeO-CH ₂ ) -Ph

3-628 Me 1 H 4- [MeO- (CH ₂ ) ₂ ] -Ph

3-629 Me 1 H 3- [MeO- (CH ₂ ) ₂ ] -Ph

3-630 Me 1 H 4- [MeO- (CH ₂ ) ₃ ] -Ph

3-631 Me 1 H 3- [MeO- (CH ₂ ) ₃ ] -Ph

3-632 Me 1 H 4- (EtO-CH ₂ ) -Ph

3-633 Me 1 H 3- (EtO-CH ₂ ) -Ph

3-634 Me 1 H 4- [EtO- (CH ₂ ) ₂ ] -Ph

3-635 Me 1 H 3- [EtO- (CH ₂ ) ₂ ] -Ph

3-636 Me 1 H 4- [EtO- (CH ₂ ) ₃ ] -Ph

3-637 Me 1 H 3- [EtO- (CH ₂ ) ₃ ] -Ph

3-638 Me 1 H 4-cPrO-Ph

3-639 Me 1 H 3-cPrO-Ph

3-640 Me 1 H 4- (cPrO-CH ₂ ) -Ph

3-641 Me 1 H 3- (cPrO-CH ₂ ) -Ph

3-642 Me 1 H 4- [cPrO- (CH ₂ ) ₂ ] -Ph

3-643 Me 1 H 3- [cPrO- (CH ₂ ) ₂ ] -Ph

3-644 Me 1 H 4- [cPrO- (CH ₂ ) ₃ ] -Ph

3-645 Me 1 H 3- [cPrO- (CH ₂ ) ₃ ] -Ph

3-646 Me 1 H 4-CHF ₂ O-Ph

3-647 Me 1 H 3-CHF ₂ O-Ph

3-648 Me 1 H 4- (CHF ₂ O-CH ₂ ) -Ph

3-649 Me 1 H 3- (CHF ₂ O-CH ₂ ) -Ph

3-650 Me 1 H 4- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-651 Me 1 H 3- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-652 Me 1 H 4- [CHF ₂ O- (CH ₂ ) ₃ ] -Ph

3-653 Me 1 H 3- [CHF ₂ O— (CH ₂ ) ₃ ] -Ph

3-654 Me 1 H 3- (H ₂ NCO) -Ph

3-655 Me 1 H 4- (H ₂ NCO-CH ₂ ) -Ph

3-656 Me 1 H 3- (H ₂ NCO-CH ₂ ) -Ph

3-657 Me 1 H 4- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-658 Me 1 H 3- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-659 Me 1 H 3- (MeNHCO) -Ph

3-660 Me 1 H 4- (MeNHCO-CH ₂ ) -Ph

3-661 Me 1 H 3- (MeNHCO-CH ₂ ) -Ph

3-662 Me 1 H 4- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-663 Me 1 H 3- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-664 Me 1 H 4- (iPrNHCO) -Ph

3-665 Me 1 H 3- (iPrNHCO) -Ph

3-666 Me 1 H 4- (iPrNHCO-CH ₂ ) -Ph

3-667 Me 1 H 3- (iPrNHCO-CH ₂ ) -Ph

3-668 Me 1 H 4- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-669 Me 1 H 3- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-670 Me 1 H 4- (EtNMeCO) -Ph

3-671 Me 1 H 3- (EtNMeCO) -Ph

3-672 Me 1 H 4- (EtNMeCO-CH ₂ ) -Ph

3-673 Me 1 H 3- (EtNMeCO-CH ₂ ) -Ph

3-674 Me 1 H 4- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-675 Me 1 H 3- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-676 Me 1 H 3- (Me ₂ NCO) -Ph

3-677 Me 1 H 4- (Me ₂ NCO-CH ₂ ) -Ph

3-678 Me 1 H 3- (Me ₂ NCO-CH ₂ ) -Ph

3-679 Me 1 H 4- [Me ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-680 Me 1 H 3- [Me ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-681 Me 1 H 3- (Et ₂ NCO) -Ph

3-682 Me 1 H 4- (Et ₂ NCO-CH ₂ ) -Ph

3-683 Me 1 H 3- (Et ₂ NCO-CH ₂ ) -Ph

3-684 Me 1 H 4- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-685 Me 1 H 3- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-686 Me 1 H 4-[(MeO) NMeCO] -Ph

3-687 Me 1 H 3-[(MeO) NMeCO] -Ph

3-688 Me 1 H 4-[(MeO) NMeCO-CH ₂ ] -Ph

3-689 Me 1 H 3-[(MeO) NMeCO-CH ₂ ] -Ph

3-690 Me 1 H 4-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-691 Me 1 H 3-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-692 Me 1 H 4- (Aze-CO) -Ph

3-693 Me 1 H 3- (Aze-CO) -Ph

3-694 Me 1 H 4- (Aze-CO-CH ₂ ) -Ph

3-695 Me 1 H 3- (Aze-CO-CH ₂ ) -Ph

3-696 Me 1 H 4- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-697 Me 1 H 3- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-698 Me 1 H 4-[(3-HO-1-Aze) -CO] -Ph

3-699 Me 1 H 3-[(3-HO-1-Aze) -CO] -Ph

3-700 Me 1 H 4-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-701 Me 1 H 3-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-702 Me 1 H 4-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-703 Me 1 H 3-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-704 Me 1 H 4- (Pyrld-CO) -Ph

3-705 Me 1 H 3- (Pyrld-CO) -Ph

3-706 Me 1 H 4- (Pyrld-CO-CH ₂ ) -Ph

3-707 Me 1 H 3- (Pyrld-CO-CH ₂ ) -Ph

3-708 Me 1 H 4- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-709 Me 1 H 3- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-710 Me 1 H 4- (Pipo-CO) -Ph

3-711 Me 1 H 3- (Pipo-CO) -Ph

3-712 Me 1 H 4- (Pipo-CO-CH ₂ ) -Ph

3-713 Me 1 H 3- (Pipo-CO-CH ₂ ) -Ph

3-714 Me 1 H 4- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-715 Me 1 H 3- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-716 Me 1 H 4-[(4-Me-Pipra) -CO] -Ph

3-717 Me 1 H 3-[(4-Me-Pipra) -CO] -Ph

3-718 Me 1 H 4-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-719 Me 1 H 3-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-720 Me 1 H 4-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-721 Me 1 H 3-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-722 Me 1 H 4- (Mor-CO) -Ph

3-723 Me 1 H 3- (Mor-CO) -Ph

3-724 Me 1 H 4- (Mor-CO-CH ₂ ) -Ph

3-725 Me 1 H 3- (Mor-CO-CH ₂ ) -Ph

3-726 Me 1 H 4- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-727 Me 1 H 3- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-728 Me 1 H 3-Me ₂ N-Ph

3-729 Me 1 H 4- (Me ₂ N-CH ₂ ) -Ph

3-730 Me 1 H 3- (Me ₂ N-CH ₂ ) -Ph

3-731 Me 1 H 4- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-732 Me 1 H 3- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-733 Me 1 H 4- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-734 Me 1 H 3- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-735 Me 1 H 4-Mor-Ph

3-736 Me 1 H 3-Mor-Ph

3-737 Me 1 H 4- (Mor-CH ₂ ) -Ph

3-738 Me 1 H 3- (Mor-CH ₂ ) -Ph

3-739 Me 1 H 4- [Mor- (CH ₂ ) ₂ ] -Ph

3-740 Me 1 H 3- [Mor- (CH ₂ ) ₂ ] -Ph

3-741 Me 1 H 4- [Mor- (CH ₂ ) ₃ ] -Ph

3-742 Me 1 H 3- [Mor- (CH ₂ ) ₃ ] -Ph

3-743 Me 1 H 4-Pipo-Ph

3-744 Me 1 H 3-Pipo-Ph

3-745 Me 1 H 4- (Pipo-CH ₂ ) -Ph

3-746 Me 1 H 3- (Pipo-CH ₂ ) -Ph

3-747 Me 1 H 4- [Pipo- (CH ₂ ) ₂ ] -Ph

3-748 Me 1 H 3- [Pipo- (CH ₂ ) ₂ ] -Ph

3-749 Me 1 H 4- [Pipo- (CH ₂ ) ₃ ] -Ph

3-750 Me 1 H 3- [Pipo- (CH ₂ ) ₃ ] -Ph

3-751 Me 1 H 4-HO-Ph

3-752 Me 1 H 3-HO-Ph

3-753 Me 1 H 4- (HO-CH ₂ ) -Ph

3-754 Me 1 H 3- (HO-CH ₂ ) -Ph

3-755 Me 1 H 4- [HO- (CH ₂ ) ₂ ] -Ph

3-756 Me 1 H 3- [HO- (CH ₂ ) ₂ ] -Ph

3-757 Me 1 H 4- [HO- (CH ₂ ) ₃ ] -Ph

3-758 Me 1 H 3- [HO- (CH ₂ ) ₃ ] -Ph

3-759 Me 1 H 4- [MeCH (OH)]-Ph

3-760 Me 1 H 3- [MeCH (OH)]-Ph

3-761 Me 1 H 4- [MeCH (OH) -CH ₂ ] -Ph

3-762 Me 1 H 3- [MeCH (OH) -CH ₂ ] -Ph

3-763 Me 1 H 4- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-764 Me 1 H 3- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-765 Me 1 H 3-CN-Ph

3-766 Me 1 H 4- (CN-CH ₂ ) -Ph

3-767 Me 1 H 3- (CN-CH ₂ ) -Ph

3-768 Me 1 H 4- [CN- (CH ₂ ) ₂ ] -Ph

3-769 Me 1 H 3- [CN- (CH ₂ ) ₂ ] -Ph

3-770 Me 1 H 3-Ac-Ph

3-771 Me 1 H 4- (Ac-CH ₂ ) -Ph

3-772 Me 1 H 3- (Ac-CH ₂ ) -Ph

3-773 Me 1 H 4- [Ac- (CH ₂ ) ₂ ] -Ph

3-774 Me 1 H 3- [Ac- (CH ₂ ) ₂ ] -Ph

3-775 Me 1 H 4- (CF ₃ CO) -Ph

3-776 Me 1 H 4- (EtCO) -Ph

3-777 Me 1 H 3- (EtCO) -Ph

3-778 Me 1 H 4- (EtCO-CH ₂ ) -Ph

3-779 Me 1 H 3- (EtCO-CH ₂ ) -Ph

3-780 Me 1 H 4- [EtCO- (CH ₂ ) ₂ ] -Ph

3-781 Me 1 H 3- [EtCO- (CH ₂ ) ₂ ] -Ph

3-782 Me 1 H 4- (iPrCO) -Ph

3-783 Me 1 H 4- (cBuCO) -Ph

3-784 Me 1 H 4- (cPrCO) -Ph

3-785 Me 1 H 4- (Ph-CO) -Ph

3-786 Me 1 H 4-Ac-3-MeO-Ph

3-787 Me 1 H 4-Ac-3-OH-Ph

3-788 Me 1 H 4-Ac-3-Cl-Ph

3-789 Me 1 H 4- [CH ₃ C (= N-OH)]-Ph

3-790 Me 1 H 3- [CH ₃ C (= N-OH)]-Ph

3-791 Me 1 H 4- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-792 Me 1 H 3- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-793 Me 1 H 4- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-794 Me 1 H 3- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-795 Me 1 H 4- [CH ₃ C (= N-OMe)]-Ph

3-796 Me 1 H 3- [CH ₃ C (= N-OMe)]-Ph

3-797 Me 1 H 4- [CH ₃ C (= N-OMe) -CH ₂ ] -Ph

3-798 Me 1 H 3- [CH ₃ C (= N-OMe) -CH ₂ ] -Ph

3-799 Me 1 H 4- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-800 Me 1 H 3- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-801 Me 1 H 4- (Me ₂ NSO ₂ ) -Ph

3-802 Me 1 H 4-[(MeO) ₂ CH] -Ph

3-803 Me 1 H 3-[(MeO) ₂ CH] -Ph

3-804 Me 1 H 4-[(MeO) ₂ CH-CH ₂ ] -Ph

3-805 Me 1 H 3-[(MeO) ₂ CH-CH ₂ ] -Ph

3-806 Me 1 H 4-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-807 Me 1 H 3-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-808 Me 1 H 4- [Me (MeO) ₂ C] -Ph

3-809 Me 1 H 3- [Me (MeO) ₂ C] -Ph

3-810 Me 1 H 4- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-811 Me 1 H 3- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-812 Me 1 H 4- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-813 Me 1 H 3- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-814 Me 1 H 4-[(EtO) ₂ CH] -Ph

3-815 Me 1 H 3-[(EtO) ₂ CH] -Ph

3-816 Me 1 H 4-[(EtO) ₂ CH-CH ₂ ] -Ph

3-817 Me 1 H 3-[(EtO) ₂ CH-CH ₂ ] -Ph

3-818 Me 1 H 4-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-819 Me 1 H 3-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-820 Me 1 H 4- [Me (EtO) ₂ C] -Ph

3-821 Me 1 H 3- [Me (EtO) ₂ C] -Ph

3-822 Me 1 H 4- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-823 Me 1 H 3- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-824 Me 1 H 4- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-825 Me 1 H 3- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-826 Me 1 H 4- (2-Dioxo) -Ph

3-827 Me 1 H 3- (2-Dioxo) -Ph

3-828 Me 1 H 4-[(2-Dioxo) -CH ₂ ] -Ph

3-829 Me 1 H 3-[(2-Dioxo) -CH ₂ ] -Ph

3-830 Me 1 H 4-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-831 Me 1 H 3-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-832 Me 1 H 4- [2-Me- (2-Dioxo)] -Ph

3-833 Me 1 H 3- [2-Me- (2-Dioxo)]-Ph

3-834 Me 1 H 4- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-835 Me 1 H 3- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-836 Me 1 H 4- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-837 Me 1 H 3- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-838 Me 1 H 4- (2-Dioxa) -Ph

3-839 Me 1 H 3- (2-Dioxa) -Ph

3-840 Me 1 H 4-[(2-Dioxa) -CH ₂ ] -Ph

3-841 Me 1 H 3-[(2-Dioxa) -CH ₂ ] -Ph

3-842 Me 1 H 4-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-843 Me 1 H 3-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-844 Me 1 H 4- [2-Me- (2-Dioxa)]-Ph

3-845 Me 1 H 3- [2-Me- (2-Dioxa)]-Ph

3-846 Me 1 H 4- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-847 Me 1 H 3- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-848 Me 1 H 4- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-849 Me 1 H 3- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-850 Me 1 H 2-Me-1-oxo-5-IIndn

3-851 Me 1 H 6-BzOxaz

3-852 Me 1 H 4- (HO-N =)-7-Chr

3-853 Me 1 H 3-Me-6-BzIox

3-854 Me 1 H 2-Me-6-BzOxaz

3-855 Me 1 H 2-Me-5-BzOxaz

3-856 Me 1 H 2,3-dihydro-5-BzFur

3-857 Me 1 H 6-Qui

3-858 Me 1 H 6-Iqui

3-859 Me 1 H 3- (HO-N =)-2,3-dihydro-6-BzFur

3-860 Me 1 H 2-Me-6-BzThaz

3-861 Me 1 H 5-Ind

3-862 Me 1 H 4-Ac-2-Thaz

3-863 Me 1 H 5-Ac-2-Thi

3-864 Me 1 H 5-Ac-2-Fur

3-865 Me 1 H 5-Me ₂ NCO-2-Py

3-866 Me 1 H 5- (Me ₂ NCO-CH ₂ ) -2-Py

3-867 Me 1 H 5- [Me ₂ NCO- (CH ₂ ) ₂ ] -2-Py

3-868 Me 1 H 4-Me ₂ NCO-2-Thaz

3-869 Me 1 H 5-Me ₂ NCO-2-Thaz

3-870 Me 1 H 4- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-871 Me 1 H 5- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-872 Me 1 H 2-Thazn

3-873 Me 1 H 2-Oxazn

3-874 H 2 H 4- (MeO-CH ₂ ) -Ph

3-875 H 2 H 3- (MeO-CH ₂ ) -Ph

3-876 H 2 H 4- [MeO- (CH ₂ ) ₂ ] -Ph

3-877 H 2 H 3- [MeO- (CH ₂ ) ₂ ] -Ph

3-878 H 2 H 4- [MeO- (CH ₂ ) ₃ ] -Ph

3-879 H 2 H 3- [MeO- (CH ₂ ) ₃ ] -Ph

3-880 H 2 H 4- (EtO-CH ₂ ) -Ph

3-881 H 2 H 3- (EtO-CH ₂ ) -Ph

3-882 H 2 H 4- [EtO- (CH ₂ ) ₂ ] -Ph

3-883 H 2 H 3- [EtO- (CH ₂ ) ₂ ] -Ph

3-884 H 2 H 4- [EtO- (CH ₂ ) ₃ ] -Ph

3-885 H 2 H 3- [EtO- (CH ₂ ) ₃ ] -Ph

3-886 H 2 H 4-cPrO-Ph

3-887 H 2 H 3-cPrO-Ph

3-888 H 2 H 4- (cPrO-CH ₂ ) -Ph

3-889 H 2 H 3- (cPrO-CH ₂ ) -Ph

3-890 H 2 H 4- [cPrO- (CH ₂ ) ₂ ] -Ph

3-891 H 2 H 3- [cPrO- (CH ₂ ) ₂ ] -Ph

3-892 H 2 H 4- [cPrO- (CH ₂ ) ₃ ] -Ph

3-893 H 2 H 3- [cPrO- (CH ₂ ) ₃ ] -Ph

3-894 H 2 H 4-CHF ₂ O-Ph

3-895 H 2 H 3-CHF ₂ O-Ph

3-896 H 2 H 4- (CHF ₂ O-CH ₂ ) -Ph

3-897 H 2 H 3- (CHF ₂ O-CH ₂ ) -Ph

3-898 H 2 H 4- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-899 H 2 H 3- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-900 H 2 H 4- [CHF ₂ O- (CH ₂ ) ₃ ] -Ph

3-901 H 2 H 3- [CHF ₂ O— (CH ₂ ) ₃ ] -Ph

3-902 H 2 H 3- (H ₂ NCO) -Ph

3-903 H 2 H 4- (H ₂ NCO-CH ₂ ) -Ph

3-904 H 2 H 3- (H ₂ NCO-CH ₂ ) -Ph

3-905 H 2 H 4- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-906 H 2 H 3- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-907 H 2 H 3- (MeNHCO) -Ph

3-908 H 2 H 4- (MeNHCO-CH ₂ ) -Ph

3-909 H 2 H 3- (MeNHCO-CH ₂ ) -Ph

3-910 H 2 H 4- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-911 H 2 H 3- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-912 H 2 H 4- (iPrNHCO) -Ph

3-913 H 2 H 3- (iPrNHCO) -Ph

3-914 H 2 H 4- (iPrNHCO-CH ₂ ) -Ph

3-915 H 2 H 3- (iPrNHCO-CH ₂ ) -Ph

3-916 H 2 H 4- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-917 H 2 H 3- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-918 H 2 H 4- (EtNMeCO) -Ph

3-919 H 2 H 3- (EtNMeCO) -Ph

3-920 H 2 H 4- (EtNMeCO-CH ₂ ) -Ph

3-921 H 2 H 3- (EtNMeCO-CH ₂ ) -Ph

3-922 H 2 H 4- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-923 H 2 H 3- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-924 H 2 H 3- (Me ₂ NCO) -Ph

3-925 H 2 H 4- (Me ₂ NCO-CH ₂ ) -Ph

3-926 H 2 H 3- (Me ₂ NCO-CH ₂ ) -Ph

3-927 H 2 H 4- [Me ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-928 H 2 H 3- [Me ₂ NCO— (CH ₂ ) ₂ ] -Ph

3-929 H 2 H 3- (Et ₂ NCO) -Ph

3-930 H 2 H 4- (Et ₂ NCO-CH ₂ ) -Ph

3-931 H 2 H 3- (Et ₂ NCO-CH ₂ ) -Ph

3-932 H 2 H 4- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-933 H 2 H 3- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-934 H 2 H 4-[(MeO) NMeCO] -Ph

3-935 H 2 H 3-[(MeO) NMeCO] -Ph

3-936 H 2 H 4-[(MeO) NMeCO-CH ₂ ] -Ph

3-937 H 2 H 3-[(MeO) NMeCO-CH ₂ ] -Ph

3-938 H 2 H 4-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-939 H 2 H 3-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-940 H 2 H 4- (Aze-CO) -Ph

3-941 H 2 H 3- (Aze-CO) -Ph

3-942 H 2 H 4- (Aze-CO-CH ₂ ) -Ph

3-943 H 2 H 3- (Aze-CO-CH ₂ ) -Ph

3-944 H 2 H 4- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-945 H 2 H 3- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-946 H 2 H 4-[(3-HO-1-Aze) -CO] -Ph

3-947 H 2 H 3-[(3-HO-1-Aze) -CO] -Ph

3-948 H 2 H 4-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-949 H 2 H 3-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-950 H 2 H 4-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-951 H 2 H 3-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-952 H 2 H 4- (Pyrld-CO) -Ph

3-953 H 2 H 3- (Pyrld-CO) -Ph

3-954 H 2 H 4- (Pyrld-CO-CH ₂ ) -Ph

3-955 H 2 H 3- (Pyrld-CO-CH ₂ ) -Ph

3-956 H 2 H 4- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-957 H 2 H 3- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-958 H 2 H 4- (Pipo-CO) -Ph

3-959 H 2 H 3- (Pipo-CO) -Ph

3-960 H 2 H 4- (Pipo-CO-CH ₂ ) -Ph

3-961 H 2 H 3- (Pipo-CO-CH ₂ ) -Ph

3-962 H 2 H 4- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-963 H 2 H 3- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-964 H 2 H 4-[(4-Me-Pipra) -CO] -Ph

3-965 H 2 H 3-[(4-Me-Pipra) -CO] -Ph

3-966 H 2 H 4-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-967 H 2 H 3-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-968 H 2 H 4-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-969 H 2 H 3-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-970 H 2 H 4- (Mor-CO) -Ph

3-971 H 2 H 3- (Mor-CO) -Ph

3-972 H 2 H 4- (Mor-CO-CH ₂ ) -Ph

3-973 H 2 H 3- (Mor-CO-CH ₂ ) -Ph

3-974 H 2 H 4- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-975 H 2 H 3- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-976 H 2 H 3-Me ₂ N-Ph

3-977 H 2 H 4- (Me ₂ N-CH ₂ ) -Ph

3-978 H 2 H 3- (Me ₂ N-CH ₂ ) -Ph

3-979 H 2 H 4- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-980 H 2 H 3- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-981 H 2 H 4- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-982 H 2 H 3- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-983 H 2 H 4-Mor-Ph

3-984 H 2 H 3-Mor-Ph

3-985 H 2 H 4- (Mor-CH ₂ ) -Ph

3-986 H 2 H 3- (Mor-CH ₂ ) -Ph

3-987 H 2 H 4- [Mor- (CH ₂ ) ₂ ] -Ph

3-988 H 2 H 3- [Mor- (CH ₂ ) ₂ ] -Ph

3-989 H 2 H 4- [Mor- (CH ₂ ) ₃ ] -Ph

3-990 H 2 H 3- [Mor- (CH ₂ ) ₃ ] -Ph

3-991 H 2 H 4-Pipo-Ph

3-992 H 2 H 3-Pipo-Ph

3-993 H 2 H 4- (Pipo-CH ₂ ) -Ph

3-994 H 2 H 3- (Pipo-CH ₂ ) -Ph

3-995 H 2 H 4- [Pipo- (CH ₂ ) ₂ ] -Ph

3-996 H 2 H 3- [Pipo- (CH ₂ ) ₂ ] -Ph

3-997 H 2 H 4- [Pipo- (CH ₂ ) ₃ ] -Ph

3-998 H 2 H 3- [Pipo- (CH ₂ ) ₃ ] -Ph

3-999 H 2 H 4-HO-Ph

3-1000 H 2 H 3-HO-Ph

3-1001 H 2 H 4- (HO-CH ₂ ) -Ph

3-1002 H 2 H 3- (HO-CH ₂ ) -Ph

3-1003 H 2 H 4- [HO- (CH ₂ ) ₂ ] -Ph

3-1004 H 2 H 3- [HO- (CH ₂ ) ₂ ] -Ph

3-1005 H 2 H 4- [HO- (CH ₂ ) ₃ ] -Ph

3-1006 H 2 H 3- [HO- (CH ₂ ) ₃ ] -Ph

3-1007 H 2 H 4- [MeCH (OH)]-Ph

3-1008 H 2 H 3- [MeCH (OH)]-Ph

3-1009 H 2 H 4- [MeCH (OH) -CH ₂ ] -Ph

3-1010 H 2 H 3- [MeCH (OH) -CH ₂ ] -Ph

3-1011 H 2 H 4- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-1012 H 2 H 3- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-1013 H 2 H 3-CN-Ph

3-1014 H 2 H 4- (CN-CH ₂ ) -Ph

3-1015 H 2 H 3- (CN-CH ₂ ) -Ph

3-1016 H 2 H 4- [CN- (CH ₂ ) ₂ ] -Ph

3-1017 H 2 H 3- [CN- (CH ₂ ) ₂ ] -Ph

3-1018 H 2 H 3-Ac-Ph

3-1019 H 2 H 4- (Ac-CH ₂ ) -Ph

3-1020 H 2 H 3- (Ac-CH ₂ ) -Ph

3-1021 H 2 H 4- [Ac- (CH ₂ ) ₂ ] -Ph

3-1022 H 2 H 3- [Ac- (CH ₂ ) ₂ ] -Ph

3-1023 H 2 H 4- (CF ₃ CO) -Ph

3-1024 H 2 H 4- (EtCO) -Ph

3-1025 H 2 H 3- (EtCO) -Ph

3-1026 H 2 H 4- (EtCO-CH ₂ ) -Ph

3-1027 H 2 H 3- (EtCO-CH ₂ ) -Ph

3-1028 H 2 H 4- [EtCO- (CH ₂ ) ₂ ] -Ph

3-1029 H 2 H 3- [EtCO- (CH ₂ ) ₂ ] -Ph

3-1030 H 2 H 4- (iPrCO) -Ph

3-1031 H 2 H 4- (cBuCO) -Ph

3-1032 H 2 H 4- (cPrCO) -Ph

3-1033 H 2 H 4- (Ph-CO) -Ph

3-1034 H 2 H 4-Ac-3-MeO-Ph

3-1035 H 2 H 4-Ac-3-OH-Ph

3-1036 H 2 H 4-Ac-3-Cl-Ph

3-1037 H 2 H 4- [CH ₃ C (= N-OH)]-Ph

3-1038 H 2 H 3- [CH ₃ C (= N-OH)]-Ph

3-1039 H 2 H 4- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-1040 H 2 H 3- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-1041 H 2 H 4- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-1042 H 2 H 3- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-1043 H 2 H 4- [CH ₃ C (= N-OMe)]-Ph

3-1044 H 2 H 3- [CH ₃ C (= N-OMe)]-Ph

3-1045 H 2 H 4- [CH ₃ C (= N-OMe) -CH ₂ ] -Ph

3-1046 H 2 H 3- [CH ₃ C (= N-OMe) -CH ₂ ] -Ph

3-1047 H 2 H 4- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-1048 H 2 H 3- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-1049 H 2 H 4- (Me ₂ NSO ₂ ) -Ph

3-1050 H 2 H 4-[(MeO) ₂ CH] -Ph

3-1051 H 2 H 3-[(MeO) ₂ CH] -Ph

3-1052 H 2 H 4-[(MeO) ₂ CH-CH ₂ ] -Ph

3-1053 H 2 H 3-[(MeO) ₂ CH-CH ₂ ] -Ph

3-1054 H 2 H 4-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1055 H 2 H 3-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1056 H 2 H 4- [Me (MeO) ₂ C] -Ph

3-1057 H 2 H 3- [Me (MeO) ₂ C] -Ph

3-1058 H 2 H 4- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-1059 H 2 H 3- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-1060 H 2 H 4- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1061 H 2 H 3- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1062 H 2 H 4-[(EtO) ₂ CH] -Ph

3-1063 H 2 H 3-[(EtO) ₂ CH] -Ph

3-1064 H 2 H 4-[(EtO) ₂ CH-CH ₂ ] -Ph

3-1065 H 2 H 3-[(EtO) ₂ CH-CH ₂ ] -Ph

3-1066 H 2 H 4-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1067 H 2 H 3-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1068 H 2 H 4- [Me (EtO) ₂ C] -Ph

3-1069 H 2 H 3- [Me (EtO) ₂ C] -Ph

3-1070 H 2 H 4- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-1071 H 2 H 3- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-1072 H 2 H 4- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1073 H 2 H 3- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1074 H 2 H 4- (2-Dioxo) -Ph

3-1075 H 2 H 3- (2-Dioxo) -Ph

3-1076 H 2 H 4-[(2-Dioxo) -CH ₂ ] -Ph

3-1077 H 2 H 3-[(2-Dioxo) -CH ₂ ] -Ph

3-1078 H 2 H 4-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1079 H 2 H 3-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1080 H 2 H 4- [2-Me- (2-Dioxo)]-Ph

3-1081 H 2 H 3- [2-Me- (2-Dioxo)]-Ph

3-1082 H 2 H 4- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-1083 H 2 H 3- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-1084 H 2 H 4- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1085 H 2 H 3- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1086 H 2 H 4- (2-Dioxa) -Ph

3-1087 H 2 H 3- (2-Dioxa) -Ph

3-1088 H 2 H 4-[(2-Dioxa) -CH ₂ ] -Ph

3-1089 H 2 H 3-[(2-Dioxa) -CH ₂ ] -Ph

3-1090 H 2 H 4-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1091 H 2 H 3-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1092 H 2 H 4- [2-Me- (2-Dioxa)]-Ph

3-1093 H 2 H 3- [2-Me- (2-Dioxa)]-Ph

3-1094 H 2 H 4- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-1095 H 2 H 3- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-1096 H 2 H 4- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1097 H 2 H 3- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1098 H 2 H 2-Me-1-oxo-5-IIndn

3-1099 H 2 H 6-BzOxaz

3-1100 H 2 H 4- (HO-N =)-7-Chr

3-1101 H 2 H 3-Me-6-BzIox

3-1102 H 2 H 2-Me-6-BzOxaz

3-1103 H 2 H 2-Me-5-BzOxaz

3-1104 H 2 H 2,3-dihydro-5-BzFur

3-1105 H 2 H 6-Qui

3-1106 H 2 H 6-Iqui

3-1107 H 2 H 3- (HO-N =)-2,3-dihydro-6-BzFur

3-1108 H 2 H 2-Me-6-BzThaz

3-1109 H 2 H 5-Ind

3-1110 H 2 H 4-Ac-2-Thaz

3-1111 H 2 H 5-Ac-2-Thi

3-1112 H 2 H 5-Ac-2-Fur

3-1113 H 2 H 5-Me ₂ NCO-2-Py

3-1114 H 2 H 5- (Me ₂ NCO-CH ₂ ) -2-Py

3-1 115 H 2 H 5- [Me ₂ NCO- (CH ₂ ) ₂ ] -2-Py

3-1 116 H 2 H 4-Me ₂ NCO-2-Thaz

3-1117 H 2 H 5-Me ₂ NCO-2-Thaz

3-1118 H 2 H 4- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-1119 H 2 H 5- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-1 120 H 2 H 2-Thazn

3-1121 H 2 H 2-Oxazn

3-1122 Me 2 H 4- (MeO-CH ₂ ) -Ph

3-1123 Me 2 H 3- (MeO-CH ₂ ) -Ph

3-1124 Me 2 H 4- [MeO- (CH ₂ ) ₂ ] -Ph

3-1125 Me 2 H 3- [MeO- (CH ₂ ) ₂ ] -Ph

3-1126 Me 2 H 4- [MeO- (CH ₂ ) ₃ ] -Ph

3-1127 Me 2 H 3- [MeO- (CH ₂ ) ₃ ] -Ph

3-1 128 Me 2 H 4- (EtO-CH ₂ ) -Ph

3-1129 Me 2 H 3- (EtO-CH ₂ ) -Ph

3-1130 Me 2 H 4- [EtO- (CH ₂ ) ₂ ] -Ph

3-1131 Me 2 H 3- [EtO- (CH ₂ ) ₂ ] -Ph

3-1132 Me 2 H 4- [EtO- (CH ₂ ) ₃ ] -Ph

3-1133 Me 2 H 3- [EtO- (CH ₂ ) ₃ ] -Ph

3-1134 Me 2 H 4-cPrO-Ph

3-1135 Me 2 H 3-cPrO-Ph

3-1136 Me 2 H 4- (cPrO-CH ₂ ) -Ph

3-1137 Me 2 H 3- (cPrO-CH ₂ ) -Ph

3-1138 Me 2 H 4- [cPrO- (CH ₂ ) ₂ ] -Ph

3-1139 Me 2 H 3- [cPrO- (CH ₂ ) ₂ ] -Ph

3-1140 Me 2 H 4- [cPrO- (CH ₂ ) ₃ ] -Ph

3-1141 Me 2 H 3- [cPrO- (CH ₂ ) ₃ ] -Ph

3-1142 Me 2 H 4-CHF ₂ O-Ph

3-1143 Me 2 H 3-CHF ₂ O-Ph

3-1144 Me 2 H 4- (CHF ₂ O-CH ₂ ) -Ph

3-1145 Me 2 H 3- (CHF ₂ O-CH ₂ ) -Ph

3-1146 Me 2 H 4- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-1147 Me 2 H 3- [CHF ₂ O- (CH ₂ ) ₂ ] -Ph

3-1148 Me 2 H 4- [CHF ₂ O- (CH ₂ ) ₃ ] -Ph

3-1149 Me 2 H 3- [CHF ₂ O- (CH ₂ ) ₃ ] -Ph

3-1150 Me 2 H 3- (H ₂ NCO) -Ph

3-1151 Me 2 H 4- (H ₂ NCO-CH ₂ ) -Ph

3-1152 Me 2 H 3- (H ₂ NCO-CH ₂ ) -Ph

3-1153 Me 2 H 4- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-1154 Me 2 H 3- [H ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-1155 Me 2 H 3- (MeNHCO) -Ph

3-1156 Me 2 H 4- (MeNHCO-CH ₂ ) -Ph

3-1157 Me 2 H 3- (MeNHCO-CH ₂ ) -Ph

3-1158 Me 2 H 4- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-1159 Me 2 H 3- [MeNHCO- (CH ₂ ) ₂ ] -Ph

3-1160 Me 2 H 4- (iPrNHCO) -Ph

3-1161 Me 2 H 3- (iPrNHCO) -Ph

3-1162 Me 2 H 4- (iPrNHCO-CH ₂ ) -Ph

3-1163 Me 2 H 3- (iPrNHCO-CH ₂ ) -Ph

3-1164 Me 2 H 4- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-1165 Me 2 H 3- [iPrNHCO- (CH ₂ ) ₂ ] -Ph

3-1166 Me 2 H 4- (EtNMeCO) -Ph

3-1167 Me 2 H 3- (EtNMeCO) -Ph

3-1168 Me 2 H 4- (EtNMeCO-CH ₂ ) -Ph

3-1169 Me 2 H 3- (EtNMeCO-CH ₂ ) -Ph

3-1170 Me 2 H 4- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-1171 Me 2 H 3- [EtNMeCO- (CH ₂ ) ₂ ] -Ph

3-1172 Me 2 H 3- (Me ₂ NCO) -Ph

3-1173 Me 2 H 4- (Me ₂ NCO-CH ₂ ) -Ph

3-1174 Me 2 H 3- (Me ₂ NCO-CH ₂ ) -Ph

3-1175 Me 2 H 4- [Me ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-1176 Me 2 H 3- [Me ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-1177 Me 2 H 3- (Et ₂ NCO) -Ph

3-1178 Me 2 H 4- (Et ₂ NCO-CH ₂ ) -Ph

3-1179 Me 2 H 3- (Et ₂ NCO-CH ₂ ) -Ph

3-1180 Me 2 H 4- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-1181 Me 2 H 3- [Et ₂ NCO- (CH ₂ ) ₂ ] -Ph

3-1182 Me 2 H 4-[(MeO) NMeCO] -Ph

3-1183 Me 2 H 3-[(MeO) NMeCO] -Ph

3-1184 Me 2 H 4-[(MeO) NMeCO-CH ₂ ] -Ph

3-1185 Me 2 H 3-[(MeO) NMeCO-CH ₂ ] -Ph

3-1186 Me 2 H 4-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-1187 Me 2 H 3-[(MeO) NMeCO- (CH ₂ ) ₂ ] -Ph

3-1188 Me 2 H 4- (Aze-CO) -Ph

3-1189 Me 2 H 3- (Aze-CO) -Ph

3-1190 Me 2 H 4- (Aze-CO-CH ₂ ) -Ph

3-1191 Me 2 H 3- (Aze-CO-CH ₂ ) -Ph

3-1192 Me 2 H 4- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-1193 Me 2 H 3- [Aze-CO- (CH ₂ ) ₂ ] -Ph

3-1194 Me 2 H 4-[(3-HO-1-Aze) -CO] -Ph

3-1195 Me 2 H 3-[(3-HO-1-Aze) -CO] -Ph

3-1196 Me 2 H 4-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-1197 Me 2 H 3-[(3-HO-Aze) -CO-CH ₂ ] -Ph

3-1198 Me 2 H 4-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-1199 Me 2 H 3-[(3-HO-Aze) -CO- (CH ₂ ) ₂ ] -Ph

3-1200 Me 2 H 4- (Pyrld-CO) -Ph

3-1201 Me 2 H 3- (Pyrld-CO) -Ph

3-1202 Me 2 H 4- (Pyrld-CO-CH ₂ ) -Ph

3-1203 Me 2 H 3- (Pyrld-CO-CH ₂ ) -Ph

3-1204 Me 2 H 4- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-1205 Me 2 H 3- [Pyrld-CO- (CH ₂ ) ₂ ] -Ph

3-1206 Me 2 H 4- (Pipo-CO) -Ph

3-1207 Me 2 H 3- (Pipo-CO) -Ph

3-1208 Me 2 H 4- (Pipo-CO-CH ₂ ) -Ph

3-1209 Me 2 H 3- (Pipo-CO-CH ₂ ) -Ph

3-1210 Me 2 H 4- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-1211 Me 2 H 3- [Pipo-CO- (CH ₂ ) ₂ ] -Ph

3-1212 Me 2 H 4-[(4-Me-Pipra) -CO] -Ph

3-1213 Me 2 H 3-[(4-Me-Pipra) -CO] -Ph

3-1214 Me 2 H 4-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-1215 Me 2 H 3-[(4-Me-Pipra) -CO-CH ₂ ] -Ph

3-1216 Me 2 H 4-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-1217 Me 2 H 3-[(4-Me-Pipra) -CO- (CH ₂ ) ₂ ] -Ph

3-1218 Me 2 H 4- (Mor-CO) -Ph

3-1219 Me 2 H 3- (Mor-CO) -Ph

3-1220 Me 2 H 4- (Mor-CO-CH ₂ ) -Ph

3-1221 Me 2 H 3- (Mor-CO-CH ₂ ) -Ph

3-1222 Me 2 H 4- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-1223 Me 2 H 3- [Mor-CO- (CH ₂ ) ₂ ] -Ph

3-1224 Me 2 H 3-Me ₂ N-Ph

3-1225 Me 2 H 4- (Me ₂ N-CH ₂ ) -Ph

3-1226 Me 2 H 3- (Me ₂ N-CH ₂ ) -Ph

3-1227 Me 2 H 4- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-1228 Me 2 H 3- [Me ₂ N- (CH ₂ ) ₂ ] -Ph

3-1229 Me 2 H 4- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-1230 Me 2 H 3- [Me ₂ N- (CH ₂ ) ₃ ] -Ph

3-1231 Me 2 H 4-Mor-Ph

3-1232 Me 2 H 3-Mor-Ph

3-1233 Me 2 H 4- (Mor-CH ₂ ) -Ph

3-1234 Me 2 H 3- (Mor-CH ₂ ) -Ph

3-1235 Me 2 H 4- [Mor- (CH ₂ ) ₂ ] -Ph

3-1236 Me 2 H 3- [Mor- (CH ₂ ) ₂ ] -Ph

3-1237 Me 2 H 4- [Mor- (CH ₂ ) ₃ ] -Ph

3-1238 Me 2 H 3- [Mor- (CH ₂ ) ₃ ] -Ph

3-1239 Me 2 H 4-Pipo-Ph

3-1240 Me 2 H 3-Pipo-Ph

3-1241 Me 2 H 4- (Pipo-CH ₂ ) -Ph

3-1242 Me 2 H 3- (Pipo-CH ₂ ) -Ph

3-1243 Me 2 H 4- [Pipo- (CH ₂ ) ₂ ] -Ph

3-1244 Me 2 H 3- [Pipo- (CH ₂ ) ₂ ] -Ph

3-1245 Me 2 H 4- [Pipo- (CH ₂ ) ₃ ] -Ph

3-1246 Me 2 H 3- [Pipo- (CH ₂ ) ₃ ] -Ph

3-1247 Me 2 H 4-HO-Ph

3-1248 Me 2 H 3-HO-Ph

3-1249 Me 2 H 4- (HO-CH ₂ ) -Ph

3-1250 Me 2 H 3- (HO-CH ₂ ) -Ph

3-1251 Me 2 H 4- [HO- (CH ₂ ) ₂ ] -Ph

3-1252 Me 2 H 3- [HO- (CH ₂ ) ₂ ] -Ph

3-1253 Me 2 H 4- [HO- (CH ₂ ) ₃ ] -Ph

3-1254 Me 2 H 3- [HO- (CH ₂ ) ₃ ] -Ph

3-1255 Me 2 H 4- [MeCH (OH)]-Ph

3-1256 Me 2 H 3- [MeCH (OH)]-Ph

3-1257 Me 2 H 4- [MeCH (OH) -CH ₂ ] -Ph

3-1258 Me 2 H 3- [MeCH (OH) -CH ₂ ] -Ph

3-1259 Me 2 H 4- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-1260 Me 2 H 3- [MeCH (OH)-(CH ₂ ) ₂ ] -Ph

3-1261 Me 2 H 3-CN-Ph

3-1262 Me 2 H 4- (CN-CH ₂ ) -Ph

3-1263 Me 2 H 3- (CN-CH ₂ ) -Ph

3-1264 Me 2 H 4- [CN- (CH ₂ ) ₂ ] -Ph

3-1265 Me 2 H 3- [CN- (CH ₂ ) ₂ ] -Ph

3-1266 Me 2 H 3-Ac-Ph

3-1267 Me 2 H 4- (Ac-CH ₂ ) -Ph

3-1268 Me 2 H 3- (Ac-CH ₂ ) -Ph

3-1269 Me 2 H 4- [Ac- (CH ₂ ) ₂ ] -Ph

3-1270 Me 2 H 3- [Ac- (CH ₂ ) ₂ ] -Ph

3-1271 Me 2 H 4- (CF ₃ CO) -Ph

3-1272 Me 2 H 4- (EtCO) -Ph

3-1273 Me 2 H 3- (EtCO) -Ph

3-1274 Me 2 H 4- (EtCO-CH ₂ ) -Ph

3-1275 Me 2 H 3- (EtCO-CH ₂ ) -Ph

3-1276 Me 2 H 4- [EtCO- (CH ₂ ) ₂ ] -Ph

3-1277 Me 2 H 3- [EtCO- (CH ₂ ) ₂ ] -Ph

3-1278 Me 2 H 4- (iPrCO) -Ph

3-1279 Me 2 H 4- (cBuCO) -Ph

3-1280 Me 2 H 4- (cPrCO) -Ph

3-1281 Me 2 H 4- (Ph-CO) -Ph

3-1282 Me 2 H 4-Ac-3-MeO-Ph

3-1283 Me 2 H 4-Ac-3-OH-Ph

3-1284 Me 2 H 4-Ac-3-Cl-Ph

3-1285 Me 2 H 4- [CH ₃ C (= N-OH)]-Ph

3-1286 Me 2 H 3- [CH ₃ C (═N-OH)]-Ph

3-1287 Me 2 H 4- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-1288 Me 2 H 3- [CH ₃ C (= N-OH) -CH ₂ ] -Ph

3-1289 Me 2 H 4- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-1290 Me 2 H 3- [CH ₃ C (= N-OH)-(CH ₂ ) ₂ ] -Ph

3-1291 Me 2 H 4- [CH ₃ C (= N-OMe)]-Ph

3-1292 Me 2 H 3- [CH ₃ C (═N-OMe)]-Ph

3-1293 Me 2 H 4- [CH ₃ C (═N-OMe) -CH ₂ ] -Ph

3-1294 Me 2 H 3- [CH ₃ C (═N-OMe) -CH ₂ ] -Ph

3-1295 Me 2 H 4- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-1296 Me 2 H 3- [CH ₃ C (= N-OMe)-(CH ₂ ) ₂ ] -Ph

3-1297 Me 2 H 4- (Me ₂ NSO ₂ ) -Ph

3-1298 Me 2 H 4-[(MeO) ₂ CH] -Ph

3-1299 Me 2 H 3-[(MeO) ₂ CH] -Ph

3-1300 Me 2 H 4-[(MeO) ₂ CH-CH ₂ ] -Ph

3-1301 Me 2 H 3-[(MeO) ₂ CH-CH ₂ ] -Ph

3-1302 Me 2 H 4-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1303 Me 2 H 3-[(MeO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1304 Me 2 H 4- [Me (MeO) ₂ C] -Ph

3-1305 Me 2 H 3- [Me (MeO) ₂ C] -Ph

3-1306 Me 2 H 4- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-1307 Me 2 H 3- [Me (MeO) ₂ C-CH ₂ ] -Ph

3-1308 Me 2 H 4- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1309 Me 2 H 3- [Me (MeO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1310 Me 2 H 4-[(EtO) ₂ CH] -Ph

3-1311 Me 2 H 3-[(EtO) ₂ CH] -Ph

3-1312 Me 2 H 4-[(EtO) ₂ CH-CH ₂ ] -Ph

3-1313 Me 2 H 3-[(EtO) ₂ CH-CH ₂ ] -Ph

3-1314 Me 2 H 4-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1315 Me 2 H 3-[(EtO) ₂ CH- (CH ₂ ) ₂ ] -Ph

3-1316 Me 2 H 4- [Me (EtO) ₂ C] -Ph

3-1317 Me 2 H 3- [Me (EtO) ₂ C] -Ph

3-1318 Me 2 H 4- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-1319 Me 2 H 3- [Me (EtO) ₂ C-CH ₂ ] -Ph

3-1320 Me 2 H 4- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1321 Me 2 H 3- [Me (EtO) ₂ C- (CH ₂ ) ₂ ] -Ph

3-1322 Me 2 H 4- (2-Dioxo) -Ph

3-1323 Me 2 H 3- (2-Dioxo) -Ph

3-1324 Me 2 H 4-[(2-Dioxo) -CH ₂ ] -Ph

3-1325 Me 2 H 3-[(2-Dioxo) -CH ₂ ] -Ph

3-1326 Me 2 H 4-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1327 Me 2 H 3-[(2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1328 Me 2 H 4- [2-Me- (2-Dioxo)]-Ph

3-1329 Me 2 H 3- [2-Me- (2-Dioxo)] -Ph

3-1330 Me 2 H 4- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-1331 Me 2 H 3- [2-Me- (2-Dioxo) -CH ₂ ] -Ph

3-1332 Me 2 H 4- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1333 Me 2 H 3- [2-Me- (2-Dioxo)-(CH ₂ ) ₂ ] -Ph

3-1334 Me 2 H 4- (2-Dioxa) -Ph

3-1335 Me 2 H 3- (2-Dioxa) -Ph

3-1336 Me 2 H 4-[(2-Dioxa) -CH ₂ ] -Ph

3-1337 Me 2 H 3-[(2-Dioxa) -CH ₂ ] -Ph

3-1338 Me 2 H 4-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1339 Me 2 H 3-[(2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1340 Me 2 H 4- [2-Me- (2-Dioxa)]-Ph

3-1341 Me 2 H 3- [2-Me- (2-Dioxa)]-Ph

3-1342 Me 2 H 4- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-1343 Me 2 H 3- [2-Me- (2-Dioxa) -CH ₂ ] -Ph

3-1344 Me 2 H 4- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1345 Me 2 H 3- [2-Me- (2-Dioxa)-(CH ₂ ) ₂ ] -Ph

3-1346 Me 2 H 2-Me-1-oxo-5-IIndn

3-1347 Me 2 H 6-BzOxaz

3-1348 Me 2 H 4- (HO-N =)-7-Chr

3-1349 Me 2 H 3-Me-6-BzIox

3-1350 Me 2 H 2-Me-6-BzOxaz

3-1351 Me 2 H 2-Me-5-BzOxaz

3-1352 Me 2 H 2,3-dihydro-5-BzFur

3-1353 Me 2 H 6-Qui

3-1354 Me 2 H 6-Iqui

3-1355 Me 2 H 3- (HO-N =)-2,3-dihydro-6-BzFur

3-1356 Me 2 H 2-Me-6-BzThaz

3-1357 Me 2 H 5-Ind

3-1358 Me 2 H 4-Ac-2-Thaz

3-1359 Me 2 H 5-Ac-2-Thi

3-1360 Me 2 H 5-Ac-2-Fur

3-1361 Me 2 H 5-Me ₂ NCO-2-Py

3-1362 Me 2 H 5- (Me ₂ NCO-CH ₂ ) -2-Py

3-1363 Me 2 H 5- [Me ₂ NCO- (CH ₂ ) ₂ ] -2-Py

3-1364 Me 2 H 4-Me ₂ NCO-2-Thaz

3-1365 Me 2 H 5-Me ₂ NCO-2-Thaz

3-1366 Me 2 H 4- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-1367 Me 2 H 5- (Me ₂ NCO-CH ₂ ) -2-Thaz

3-1368 Me 2 H 2-Thazn

3-1369 Me 2 H 2-Oxazn

-------------------------------------------------- ---------------------------

Preferred compounds in Table 1 to Table 3 above are exemplary compound numbers.

1-7, 1-16, 1-17, 1-20, 1-21, 1-22, 1-23, 1-27, 1-28, 1-29, 1-36, 1-39, 1- 40, 1-44, 1-68, 1-95, 1-96, 1-97, 1-99, 1-100, 1-101, 1-102, 1-105, 1-109, 1-112, 1-115, 1-118, 1-123, 1-133, 1-139, 1-140, 1-141, 1-143, 1-144, 1-146, 1-149, 1-152, 1- 155, 1-156, 1-157, 1-164, 1-173, 1-181, 1-182, 1-183, 1-190, 1-229, 2-33, 2-102, 3-22, 3-30, 3-86, 3-87, 3-88, 3-89, 3-97, 3-98, 3-99, 3-100, 3-104, 3-105, 3-106, 3- 107, 3-110, 3-111, 3-112, 3-116, 3-117, 3-123, 3-124, 3-125, 3-127, 3-131, 3-132, 3-136, 3-138, 3-139, 3-140, 3-142, 3-143, 3-161, 3-182, 3-429, 3-430, 3-431, 3-432, 3-876, 3- 886, 3-894, 3-912, 3-918, 3-924, 3-925, 3-927, 3-934, 3-940, 3-946, 3-952, 3-970, 3-979, 3-1003, 3-1004, 3-1005, 3-1007, 3-1018, 3-1019, 3-1023, 3-1030, 3-1031, 3-1032, 3-1034, 3-1035, 3- 1037, 3-1043, 3-1082, 3-1098, 3-1099, 3-1100, 3-1101, 3-1102, 3-1103, 3-1104, 3-1105, 3-1107, 3-1108, 3-1109, 3-1110, 3-1111, 3-1112, 3-1113, 3-1116, 3-1117, 3-1118 and 3-1120,

More preferred compounds are exemplified compound numbers

1-17, 1-21, 1-22, 1-28, 1-29, 1-68, 1-99, 1-101, 1-102, 1-105, 1-109, 1-112, 1- 115, 1-123, 1-143, 1-144, 1-146, 1-152, 1-155, 1-157, 1-164, 1-229, 3-30, 3-86, 3-87, 3-88, 3-99, 3-100, 3-104, 3-106, 3-107, 3-111, 3-116, 3-124, 3-127, 3-136, 3-142, 3- 143, 3-161, 3-182, 3-429, 3-430, 3-876, 3-924, 3-925, 3-927, 3-934, 3-940, 3-952, 3-970, 3-979, 3-1003, 3-1004, 3-1005, 3-1007, 3-1018, 3-1019, 3-1031, 3-1034, 3-1035, 3-1037, 3-1043, 3- 1082, 3-1098, 3-1099, 3-1100, 3-1101, 3-1102, 3-1104, 3-1110, 3-1111, 3-1113, 3-1116 and 3-1117.

Among these, particularly preferred compounds are

3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example compound number 1-21 ),

3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -6-methylthieno [2,3-b] pyridine-2-carboxamide (example compound Number 1-68),

3-amino-4- {3- [3- (2-hydroxyethoxy) propyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide (example compound Number 1-101),

3-amino-4-{(3S)-[(2-methoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide hydrochloride (examples Compound numbers 1-112),

3-amino-4-{(3S) -3-[(3-methoxypropoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound Nos. 1-115),

3-amino-4- (3-{[2- (dimethylamino) -2-oxoethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carbox Mead (example Compound No. 1-155),

3-amino-4- (3- {3- [2- (dimethylamino) -2-oxoethoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide (example Compound No. 1-157),

4- [4- (4-acetylphenyl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide (example compound number 3- 99),

3-amino-4- [4- (4-propionylphenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example compound number 3 -100),

3-amino-4- {4- [4- (dimethylamino) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide (example compound Number 3-104),

3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carbox Mead (Example Compound No. 3-107),

4- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-142),

3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepane-1-yl) -6-methylthieno [2,3-b] pyridine- 2-carboxamide (example compound number 3-182),

3-amino-4- {4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-876),

3-amino-4- (4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide (example compound number 3-925),

3-amino-4- (4- {4- [3- (dimethylamino) -3-oxopropyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide (Example Compound No. 3-927),

3-amino-4- {4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide (example Compound No. 3-940),

3-amino-4- {4- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,

3-amino-4- (4- {4- [2- (dimethylamino) ethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-car Radiamide (example compound number 3-979),

3-amino-4- {4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-1003),

3-amino-4- {4- [3- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-1004),

3-amino-4- {4- [4- (3-hydroxypropyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-1005),

3-amino-4- {4- [4- (1-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-1007),

3-amino-4- {4- [4- (2-oxopropyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-1019),

3-amino-4- (4- {4-[(1E) -N-hydroxyethaneimideyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (example compound number 3-1037),

3-amino-4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepan-1-yl) thieno [2 , 3-b] pyridine-2-carboxamide (example compound number 3-1082),

3-amino-4- [4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepan-1-yl] thieno [ 2,3-b] pyridine-2-carboxamide (example compound number 3-1098),

3-amino-4- [4- (1,3-benzoxazol-6-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-1099),

3-amino-4- {4-[(4E) -4- (hydroxyimino) -3,4-dihydro-2H-chromen-7-yl] -1,4-diazepan-1-yl } Thieno [2,3-b] pyridine-2-carboxamide (example compound number 3-1100),

4- [4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepan-1-yl] -3-aminothieno [2,3-b] pyridine-2 -Carboxamide (example compound number 3-1110),

4- [4- (5-acetylthiophen-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-1111) and

3-amino-4- (4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl} -1,4-diazepan-1-yl) thieno [2, 3-b] pyridine-2-carboxamide (example compound number 3-1116).

[Embodiment of the Invention]

The compound which has general formula (I) of this invention can be manufactured according to the method described below.

<A law>

In the formula (Ⅰ), and R ¹ is a hydrogen atom, R ² is ^{R a NH-, R a (R} b) N- or

[Formula 8]

A compound having a group can be prepared according to the A method.

[Formula 9]

[Wherein, R ^{2 ′} is R ^a NH—, R ^a (R ^b ) N— in the definition of R ² or

[Formula 10]

Represents a group,

R ⁷ represents methyl or ethyl,

R ⁸ and R ⁹ each contain a C ₁ -C ₆ alkyl group (preferably methyl, ethyl or isopropyl, particularly preferably methyl) or a nitrogen atom to which they are attached, so that a sulfur atom, an oxygen atom and / or a nitrogen atom A 4 to 7 membered heterocyclyl group (preferably pyrrolidinyl, piperidyl, morpholinyl) containing 1 to 2,

R ¹⁰ and R ¹¹ each represent a C ₁ -C ₆ alkyl group (preferably methyl, ethyl or isopropyl, particularly preferably methyl),

X represents a halogen atom (preferably a chlorine atom or a bromine atom, particularly preferably a chlorine atom)]

The first step is a step of producing the compound (3) by reacting the compound (1) with the amine compound (2) in an inert solvent, and is carried out according to the methods described in J. Org. Chem, (1962) 27, 2433-2439 can do.

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene, preferably Methanol, ethanol or N, N-dimethylformamide.

The reaction temperature varies depending on the starting compound or the solvent used, and is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably from room temperature to the reflux temperature of the reaction mixture.

The reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, and is usually 30 minutes to 96 hours, preferably 30 minutes to 24 hours.

After completion | finish of reaction, the precipitate obtained by filtering a reaction liquid or the residue obtained by distilling a solvent off can be used for the next process (2nd process), without refine | purifying especially. Moreover, when amides are used as an inert solvent, the reaction solution can be used as it is in the next step.

The second step is a step of reacting compound (3) with N, N-dialkylformamide dialkylacetal (4) in an inert solvent to produce an amidine derivative (5).

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene, preferably ethanol Or N, N-dimethylformamide.

The amount of N, N-dialkylformamide dialkylacetal (4) used in the reaction is preferably 1 to 2 equivalents relative to 1 equivalent of compound (3).

The reaction temperature varies depending on the starting compound or the solvent used, and is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature.

The reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, and is usually 30 minutes to 96 hours, preferably 30 minutes to 24 hours.

After completion | finish of reaction, the precipitate obtained by filtering a reaction liquid or the residue obtained by distilling a solvent off can be used for the next process (3rd process), without refine | purifying especially. Moreover, when amides are used as an inert solvent, the reaction solution can be used as it is in the next step.

The third step is a step of producing the thiopyridone derivative (6) by treating the amidine derivative (5) in an inert solvent.

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene, preferably ethanol Or N, N-dimethylformamide, and particularly preferably N, N-dimethylformamide.

The reaction temperature varies depending on the starting compound or the solvent used, and is usually at room temperature to the reflux temperature of the reaction mixture, preferably 50 ° C to 120 ° C.

The reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, and is usually 10 minutes to 6 hours, preferably 10 minutes to 2 hours.

After the end of the reaction, if desired, the desired compound is taken from the reaction mixture according to conventional methods (extraction, column chromatography, filtration and concentration). In addition, when amides are used as an inert solvent, the reaction solution can be used as it is in the next step (fourth step).

The fourth step is a step of producing thienopyridine derivative (Ia) by reacting thiopyridone derivative (6) and α-haloacetamide (7) in an inert solvent in the presence of a base.

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Or amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide, preferably Is ethanol or N, N-dimethylformamide.

Bases to be used include, for example, organic bases such as triethylamine or 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Or an aqueous solution of alkali metal hydroxide, preferably 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), sodium ethoxide or aqueous sodium hydroxide solution.

The reaction temperature varies depending on the starting compound, the solvent or base used, and is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from room temperature to the reflux temperature of the reaction mixture.

The reaction time varies depending on the raw material compound, the solvent used, the base or the reaction temperature, and is usually 10 minutes to 6 hours, preferably 30 minutes to 2 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the target compound precipitated by adding water to the reaction mixture is filtered; Alternatively, the reaction mixture is appropriately neutralized, and insoluble matters are removed by filtration, and then water is added, followed by extraction with an organic solvent that is not miscible with water such as ethyl acetate or toluene, and with water or the like. After washing | cleaning and drying an extract liquid with anhydrous magnesium sulfate etc., it is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

The fifth step is a step of reacting compound (3) with N, N-dialkylformamide dialkyl acetal (4) in an inert solvent to produce an amidine derivative (8).

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene, preferably aromatic Hydrocarbons, and particularly preferably toluene.

The amount of N, N-dialkylformamide dialkylacetal (4) used in the reaction is preferably 2 to 3 equivalents relative to 1 equivalent of compound (3).

The reaction temperature varies depending on the starting compound or the solvent used, and is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably from room temperature to the reflux temperature of the reaction mixture.

The reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, and is usually 3 minutes to 6 hours, preferably 3 minutes to 2 hours.

After completion | finish of reaction, the residue obtained by distilling a solvent off under reduced pressure can be used in the next process (sixth process), without refine | purifying especially.

The sixth step is a step of producing the thiopyridone derivative (6) by treating the amidine derivative (8) with an alkaline aqueous solution.

The alkaline aqueous solution used may be, for example, an aqueous solution of an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide or lithium hydroxide), preferably an aqueous sodium hydroxide solution.

The reaction temperature varies depending on the starting compound or the solvent used, usually from room temperature to the reflux temperature of the reaction mixture, preferably the reflux temperature of the reaction mixture.

The reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, and is usually 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

After the end of the reaction, if desired, the desired compound is taken from the reaction mixture according to conventional methods (extraction, column chromatography, filtration and concentration).

<B law>

In the formula (Ⅰ), and R ¹ is C ₁ -C ₆ alkyl group, R ² is ^{R a NH-, R a (R} b) N- or

[Formula 11]

Compounds having a group can be prepared according to the B method.

[Formula 12]

^{(Wherein, R 2 ', R 8,} R 9, R 10, R 11 and X have the same meanings as defined above, R ^1' represents a C ₁ -C ₆ alkyl group in the definition of R ^1, Y Represents CONH ₂ or CN)

7th process is a process of making compound (10) by making compound (9) and amine compound (2) react in inert solvent, and is performed by the method similar to the method of 1st process.

The eighth step is a step of reacting a compound (10) wherein Y is CONH ₂ with (N, N-dialkyl) alkylamidedialkylacetal (11) in an inert solvent to produce a pyridone derivative (12), Pharm. It can carry out according to the method of Chem. J. (Engl. Transl.) 25, (1991), 623-628.

Inert solvents to be used include, for example, aromatic hydrocarbons such as benzene, toluene or xylene; Or amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide, preferably Preferably they are amides, Especially preferably, they are N, N- dimethylformamide.

The reaction temperature varies depending on the starting compound or the solvent used, which is usually from room temperature to the reflux temperature of the reaction mixture, preferably from 50 ° C. to the reflux temperature of the reaction mixture.

The reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, and is usually 1 hour to 24 hours, preferably 1 hour to 5 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It wash | cleans with etc., and after drying an extract liquid with anhydrous magnesium sulfate etc., it is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

The ninth step is a step of producing the chloropyridine derivative (13) by halogenating the pyridone derivative (12) using a halogenating agent in the presence of a base.

When the reaction is carried out in an inert solvent, examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; Alternatively, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane are used, and preferably toluene or dioxane is used.

Bases used are, for example, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N , N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [ 5.4.0] -7-undecene (DBU), and particularly preferably N, N-dimethylaniline.

Halogenating agents used include, for example, human chlorides such as phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride; Or thionyl chloride, preferably phosphorus pentachloride, phosphorus oxy chloride or thionyl chloride.

The reaction temperature varies depending on the starting compound, solvent, base or halogenating agent, usually from room temperature to the reflux temperature of the reaction mixture, preferably from 50 ° C. to the reflux temperature of the reaction mixture.

The reaction time varies depending on the starting compound, the solvent, the base, the halogenating agent or the reaction temperature, and is usually 1 hour to 24 hours, preferably 1 hour to 8 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It wash | cleans with etc., and after drying an extract liquid with anhydrous magnesium sulfate etc., it is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

The tenth step is a step of reacting the chloropyridine derivative (13) and the 2-mercaptoacetamide (14) in an inert solvent in the presence of a base to produce a thienopyridine derivative (Ib).

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Or amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide, preferably Preferably they are alcohols or amides, More preferably, they are ethanol or N, N- dimethylformamide.

Bases to be used include, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Or it may be an aqueous solution of alkali metal hydroxides, Preferably it is sodium ethoxide or sodium hydroxide aqueous solution.

The reaction temperature varies depending on the starting compound, the solvent or base used, and is usually from room temperature to the reflux temperature of the reaction mixture.

The reaction time varies depending on the starting compound, the solvent used, the base or the reaction temperature, and is usually 1 hour to 24 hours, preferably 1 hour to 2 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It wash | cleans with etc., and after drying an extract liquid with anhydrous magnesium sulfate etc., it is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

In addition, 2-mercaptoacetamide (14) can also be generated in the reaction system using 2- (acetylthio) acetamide.

The eleventh step is a step of producing an enamine derivative (15) by reacting a compound (10) in which Y is CN with (N, N-dialkyl) alkylamidedialkylacetal (11) in an inert solvent.

Inert solvents to be used include, for example, alcohols such as methanol or ethanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Or amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide, preferably Preferably alcohols or aromatic hydrocarbons, particularly preferably ethanol, toluene or xylene.

The reaction temperature varies depending on the starting compound or the solvent used, which is usually from room temperature to the reflux temperature of the reaction mixture, preferably from 100 ° C. to the reflux temperature of the reaction mixture.

The reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, and is usually 1 hour to 24 hours, preferably 1 hour to 8 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It wash | cleans with etc., and after drying an extract liquid with anhydrous magnesium sulfate etc., it is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

The twelfth step is a step of producing a pyridone derivative (12) by treating the enamine derivative (15) with an acid.

The acid used may be, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid or polyphosphoric acid; Or inorganic acids such as hydrochloric acid, preferably acetic acid or polyphosphoric acid.

When the reaction is carried out in an inert solvent, examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Alcohols such as methanol or ethanol; Or it may be water or a mixed solvent of water and the said solvent, Especially preferably, it is water.

The reaction temperature varies depending on the starting compound or the acid used, usually from room temperature to the reflux temperature of the reaction mixture, preferably from 50 ° C. to the reflux temperature of the reaction mixture.

The reaction time varies depending on the raw material compound, the acid used or the reaction temperature, and is usually 1 hour to 24 hours, preferably 1 hour to 8 hours.

Step 12B is a step of producing a chloropyridine derivative (13) by reacting an enamine derivative (15) with a halogenating agent.

When the reaction is carried out in an inert solvent, examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Or alcohols such as methanol, ethanol, propanol, 2-propanol or butanol are used, preferably methanol or ethanol.

Halogenating agents used include, for example, human chlorides such as phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride; Sulfone chlorides such as thionyl chloride; Chlorosilanes such as trimethyl chloride chloride and t-butyldimethylsilane chloride; Acid chlorides such as oxalyl chloride; Or inorganic acids such as hydrochloric acid or hydrobromic acid, preferably thionyl chloride, trimethylsilane or oxalyl chloride.

However, when hydrobromic acid is used, a bromopyridine derivative is obtained.

The reaction temperature varies depending on the starting compound, the solvent or the halogenating agent, which is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from room temperature to the reflux temperature of the reaction mixture.

The reaction time varies depending on the starting compound, the solvent or the halogenating agent, and is usually 10 minutes to 24 hours, preferably 30 minutes to 2 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It washes with etc., and extracts are dried by anhydrous magnesium sulfate, etc., and is obtained by removing a solvent.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

The thirteenth step is a step of producing a thiopyridone derivative 16 by reacting a chloropyridine derivative 13 with thiourea or sodium sulfide (preferably thiourea) in an inert solvent.

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Or a mixture of the solvents, preferably alcohols, aromatic hydrocarbons or a mixture of alcohols and aromatic hydrocarbons, more preferably ethanol, toluene or a mixture of ethanol and toluene.

The reaction temperature varies depending on the starting compound or the solvent used, which is usually from room temperature to the reflux temperature of the reaction mixture, preferably from 50 ° C. to the reflux temperature of the reaction mixture.

The reaction time varies depending on the starting compound, the solvent used or the reaction temperature, and is usually 1 hour to 48 hours, preferably 1 hour to 24 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It wash | cleans with etc., and after drying an extract liquid with anhydrous magnesium sulfate etc., it is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

Step 14 is a step of reacting thiopyridone derivative (16) with α-haloacetamide (7) in an inert solvent in the presence of a base to produce thienopyridine derivative (Ib), the method described in the fourth step. It is carried out in the same way as.

<C law>

In the formula (Ⅰ), R ² is R ^a O- The compound can be prepared according to the C method.

[Formula 13]

(Wherein R ¹ , R ^a and X represent the same meaning as above)

The fifteenth step is a step of demethylating the methoxypyridine derivative (17) to produce the compound (18), for example, by heating the methoxypyridine derivative (17) and concentrated hydrochloric acid under reflux in an acetic acid solvent. have.

In the sixteenth step, (a) the compound (18) and the halogen compound (19) are reacted in the presence of a base in an inert solvent, or (b) a light lead reaction is carried out using the compound (18) and the alcohol derivative (20). To produce a 4-alkoxypyridine derivative (21).

(a) Method using halogen compound (19) (etherification reaction)

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane; And ethers or amides, particularly preferably tetrahydrofuran or N, N-dimethylacetamide.

Bases to be used include, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; Or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably alkali metal carbonates or alkali metal hydrides, and more preferably potassium carbonate or sodium hydride.

The reaction temperature varies depending on the starting compound, the solvent or base used, and is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from 0 ° C. to room temperature.

The reaction time varies depending on the starting compound, the solvent used, the base or the reaction temperature, and is usually 1 hour to 48 hours, preferably 1 hour to 24 hours.

(b) Method using alcohol derivative (20) (photoreaction)

The reaction is usually carried out in an inert solvent, and inert solvents used include, for example, aromatic hydrocarbons such as benzene, toluene or xylene; Or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, preferably toluene or tetrahydrofuran.

Reagents used in the photoreaction are, for example, di (C ₁ -C ₆ alkyl) azodicarboxylates or 1,1'- such as diethylazodicarboxylate or diisopropylazodicarboxylate. Azo compounds such as azodicarbonyls such as (azodicarbonyl) dipiperidine, and tri (C ₆ -C ₁₀ aryl) phosphines such as triphenylphosphine or tri (C) such as tri n-butylphosphine _It is a combination of phosphines, such as _1- C ₆ alkyl) phosphines, More preferably, it is a combination of di (C ₁ -C ₆ alkyl) azodicarboxylates and a tri (C ₆ -C ₁₀ aryl) phosphines. Most preferably, it is a combination of diethyl azodicarboxylate and triphenylphosphine.

The reaction temperature varies depending on the starting compound, the solvent used or the reagent, and is usually 0 ° C. to the reflux temperature of the solvent, preferably 0 ° C. to room temperature.

The reaction time varies depending on the starting compound, the solvent used, the reagent or the reaction temperature, and is usually 1 hour to 48 hours, preferably 1 hour to 24 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It washes with etc., and extracts are dried by anhydrous magnesium sulfate, etc., and is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

The seventeenth step is a step of reacting the 4-alkoxypyridine derivative (21) with the 2-mercaptoacetamide (14) in an inert solvent in the presence of a base to produce a thienopyridine derivative (Ic). It is carried out in the same manner as the method described in.

<D law>

In the formula (Ⅰ), R ² Compounds with R ^a S- can be prepared according to the D method.

[Formula 14]

(Wherein R ¹ , R ^a and X represent the same meaning as above)

In the eighteenth step, a dialkylpyridine compound (22) and a thiol compound (23) or an alkali metal salt thereof (e.g., sodium salt) are reacted in an inert solvent in the presence or absence of a base to form a 4-alkylthiopyridine derivative ( 24) manufacturing process.

Inert solvents to be used include, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; Aromatic hydrocarbons such as benzene, toluene or xylene; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; Or sulfoxides such as dimethyl sulfoxide or sulfolane; And ethers or amides, particularly preferably tetrahydrofuran or N, N-dimethylacetamide.

Bases to be used include, for example, alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; Or alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydride or sodium hydroxide.

The reaction temperature varies depending on the starting compound, the solvent or base used, and is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from 0 ° C. to room temperature.

The reaction time varies depending on the starting compound, the solvent used, the base or the reaction temperature, and is usually 1 hour to 24 hours, preferably 1 hour to 6 hours.

After completion of the reaction, if desired, the target compound is taken from the reaction mixture according to a conventional method.

For example, the reaction mixture is suitably neutralized and, if insoluble is present, is removed by filtration, then water is added, extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene, and It washes with etc., and extracts are dried by anhydrous magnesium sulfate, etc., and is obtained by distilling a solvent off.

The obtained compound can be separated and purified by conventional methods, for example, silica gel column chromatography, if necessary.

Moreover, in this process, the 4-alkoxypyridine derivative corresponding to the compound (24) can be manufactured by using the alcohol derivative (20) instead of the thiol compound (23).

The nineteenth step is a step of reacting the 4-alkylthiopyridine derivative (24) with the 2-mercaptoacetamide (14) in an inert solvent in the presence of a base to produce a thienopyridine derivative (Id). It is performed by the method similar to the method described in a process.

Since the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has the action of promoting bone formation, inhibiting bone resorption and / or improving bone density, the pharmaceuticals, in particular, bone diseases [Eg, due to osteoporosis (eg postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressants), osteopenia or osteoarthritis associated with joint rheumatism, osteopathy disease, fractures, or microcertification Medicament for the prevention or treatment of osteopenic insufficiency] or deformed arthrosis}, and can be used in mammals (eg, humans, horses, cattle or pigs, preferably humans) or birds (preferably chickens, more preferably) Preferably a hen). The dosage form can be, for example, oral administration with tablets, capsules, granules, powders or syrups or the like, or parenteral administration with injections or suppositories, and the like for the preparations include excipients, glidants, binders, disintegrants, It is manufactured by well-known methods using additives, such as a stabilizer, a copper, and a diluent.

Excipients include, for example, sugar derivatives such as lactose, white sugar, glucose, mannite or sorbitol, corn starch, potato starch, starch derivatives such as α-starch, dextrin or carboxymethyl starch, crystalline cellulose, low-substituted hydroxy Organic excipients such as cellulose derivatives such as propyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or internally cross-linked carboxymethyl cellulose sodium, gum arabic, dextran or pullulan; Or inorganic excipients such as silicate derivatives such as hard silicic anhydride, synthetic aluminum silicate or magnesium metasilicate aluminate, phosphates such as calcium phosphate, carbonates such as calcium carbonate, or sulfates such as calcium sulfate.

The lubricant includes, for example, a stearic acid metal salt such as stearic acid, calcium stearate or magnesium stearate; Talc; Colloidal silica; Waxes such as gums and sperm; Boric acid; Adipic acid; Sulfates such as sodium sulfate; Glycol; Fumaric acid; Sodium benzoate; DL-leucine; Fatty acid sodium salts; Lauryl sulfate, such as sodium lauryl sulfate or magnesium lauryl sulfate; Silicic acids such as silicic anhydride or silicic acid hydrate; Or the starch derivative.

The binder may be, for example, polyvinylpyrrolidone or macrogol, or the same compound as the excipient.

The disintegrant may be, for example, the same compound as the excipient, or chemically modified starch-celluloses such as croscarmellose sodium, carboxymethyl starch sodium or crosslinked polyvinylpyrrolidone.

Stabilizers include, for example, paraoxybenzoic acid esters such as methylparaben or propylparaben; Alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; Benzalkonium chloride; Phenols such as phenol or cresol; Thimerosal; Dehydroacetic acid; Or sorbic acid.

The mating agent may be a sweetener, acidulant, flavoring or the like which is commonly used.

The amount of the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, administration method, and the like. For example, in the case of oral administration, the lower limit is 0.001 mg / kg (per day). Preferably 0.01 mg / kg) and 100 mg / kg (preferably 10 mg / kg) as an upper limit are divided into 1 time or several times, and it is preferable to administer according to a symptom. In the case of intravenous administration, the adult is divided into 0.0001 mg / kg (preferably 0.001 mg / kg) as the lower limit and 1 mg / kg (preferably 0.1 mg / kg) as one time or several times per day. It is preferable to administer according to the symptoms.

Effects of the Invention

Since the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has the action of promoting bone formation, inhibiting bone resorption and / or improving bone density, the pharmaceuticals, in particular, bone diseases [Eg, due to osteoporosis (e.g. postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressants), osteopenia associated with joint rheumatism or bone destruction, osteopathy disease, fractures, or microcertification It is useful as a medicament for the prevention or treatment of bone dysplasia].

Best Mode for Carrying Out the Invention

Although an Example, a formulation example, and a test example are given to the following and this invention is demonstrated to it further more concretely, this invention is not limited to these.

Example 1 3-amino-4- (dimethylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-17)

It was prepared by the following method with reference to the method described in Pharm. Chem. J. (Engl. Transl.), 26, (1992), 870-874.

(1a) (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide

Cyanothioacetamide (1.00 g, 10 mmol) and N, N-dimethylacetamide dimethyl acetal (1.73 g, 13 mmol) were dissolved in acetonitrile (5 mL) and stirred at room temperature for 1 hour. The precipitated crystals were separated by filtration, and the crystals were further washed with acetonitrile to obtain 1.05 g (yield 62%) of the title compound.

Mp 155-158 ° C .;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.27 (3H, s), 3.03 (6H, s), 8.08 (1H, br), 8.83 (1H, br).

(1b) 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide (1.05 g, 6.2 mmol) and N, N-dimethylformamide dimethylacetal (2.22) prepared in Example 1 (1a) g, 18.6 mmol) was dissolved in toluene (10 mL) and stirred under heating to reflux for 2 hours. The mixture was concentrated under reduced pressure, and the obtained residue was suspended in 1N aqueous sodium hydroxide solution (10 mL) and heated to reflux for 30 minutes. After the reaction mixture was cooled to room temperature, 1N hydrochloric acid (15 mL) was added. The precipitated solid was separated by filtration and washed with water and ethanol to obtain 0.87 g (yield 78%) of the title compound.

Mp 246-250 ° C .;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.12 (6H, s), 6.25 (1H, d, J = 7.3 Hz), 7.29-7.33 (1H, m), 12.40 (1H, br).

(1c) 3-amino-4- (dimethylamino) thieno [2,3-b] pyridine-2-carboxamide

To an N, N-dimethylformamide (10 mL) solution of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (0.87 g) prepared in Example 1 (1b) , 8N sodium hydroxide aqueous solution (2 mL) and 2-chloroacetamide (0.54 g, 5.8 mmol) were added, and it stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the precipitated crystals were separated by filtration and washed with water and ethanol to obtain 0.79 g (yield 54%) of the title compound.

Mp 208-211 ° C;

IR (KBr) ν _max 3430, 3296, 3132, 1673, 1582, 1372, 979 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.80 (6H, s), 6.96 (1H, d, J = 5.5 Hz), 6.97 (2H, br), 7.04 (2H, br), 8.36 (1H, d , J = 5.5 Hz);

MS (FAB) m / z: 237 [M + H] ⁺ ;

analysis. Calc. For C ₁₀ H ₁₂ N ₄ SO: C, 50.83; H, 5. 12; N, 23.71; S, 13.57. Found: C, 50.70; H, 4.98; N, 23.53; S, 13.38.

Example 2 3-amino-4- (diethylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-33)

(2a) (2Z) -2-cyano-3- (diethylamino) buta-2-enthioamide

(2Z) -2-cyano-3-ethoxybuta-2-enthioamide (J.Org.Chem., (1962), 27, 2433-2439) (406 mg, 2.38 mmol) and diethylamine ( 0.36 mL, 3.53 mmol) was suspended in ethanol (5 mL) and stirred at room temperature for 2 hours. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 1) to obtain the title compound (237 mg, yield 50%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.32 (6H, t, J = 7.04 Hz), 2.71 (3H, s), 3.65 (4H, q, J = 7.05 Hz), 6.69 (2H, br s).

(2b) 4- (diethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (diethylamino) prepared in Example 2 (2a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide Using buta-2-enthioamide, the reaction was carried out in the same manner as in Example 1 (1b) to obtain the title compound. Yield 54%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.19 (6H, t, J = 6.8 Hz), 3.21 (1H, s), 3.615 (4H, q, J = 6.8 Hz), 6.34 (1H, d, J = 7.8 Hz), 7.36 (1H, t, J = 7.8 Hz).

(2c) 3-amino-4- (diethylamino) thieno [2,3-b] pyridine-2-carboxamide

4- (diethylamino) -2-thioxo-1 prepared in Example 2 (2b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as in the method described in Example 1 (1c) using, 2-dihydropyridine-3-carbonitrile. Yield 65%.

Mp 127-129 ° C .;

IR (KBr) ν _max 3426, 3304, 3143, 2974, 1672, 1647, 1581, 1504, 1376, 1345, 1262, 1158, 1050, 790, 616 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.98 (6H, t, J = 7.0 Hz), 3.17 (4H, q, J = 7.0 Hz), 7.06 (1H, d, J = 5.1 Hz), 7.09 (2H, s), 7.36 (1H, doublet, J = 5.1 Hz);

MS (FAB) m / z: 264.10 [M + H] ⁺ ;

analysis. Calc. For C ₁₂ H ₁₆ N ₄ OS: C, 54.52; H, 6. 10; N, 21.19; S, 12.13. Found: C, 54.18; H, 5. 86; N, 21.34; S, 12.18.

Example 3 3-amino-4- (dimethylamino) -6-methylthieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-102)

(3a) 4- (dimethylamino) -6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

2-chloro-4- (dimethylamino) -6-methylnicotinonitrile (Pharm. Chem. J., (Engl. Transl.), 25, (1991), 623-628.) (1.46 g, 7.5 mmol) And thiourea (0.74 g, 9.7 mmol) were suspended in toluene (25 mL) and stirred under heating to reflux for 4 hours. Ethanol (40 mL) was added to the reaction mixture, and the mixture was further heated to reflux for 30 minutes. The precipitated solid was left at room temperature overnight, and the precipitated solid was separated by filtration and washed sequentially with ethanol, water and ethanol to obtain the crude product (0.64 g) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.20 (3H, s), 3.18 (6H, s), 6.23 (1H, s), 12.41 (1H, br).

(3b) 3-amino-4- (dimethylamino) -6-methylthieno [2,3-b] pyridine-2-carboxamide

4- (dimethylamino) -6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (0.19 g, 1.0 mmol) prepared in Example 3 (3a) was replaced with N, N-dimethyl It was dissolved in formamide (3 mL), and 8N aqueous sodium hydroxide solution (0.5 mL) and 2-chloroacetamide (0.11 g, 1.2 mmol) were added. The mixture was stirred at rt for 1 h, then water (50 mL) was added. The aqueous layer was extracted with ethyl acetate (3 x 50 mL), the extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain 0.16 g of the title compound (yield 62%).

Mp 167-170 ° C .;

IR (KBr) ν _max 3442, 3327, 3170, 1647, 1580, 1368, 992 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.48 (3H, s), 2.78 (6H, s), 6.84 (1H, s), 6.93 (2H, br), 6.95 (2H, br);

MS (EI) m / z: 250 [M ⁺ ], 218, 205, 190;

analysis. Calc. For C ₁₁ H ₁₄ N ₄ SO.0.5H ₂ O: C, 50.95; H, 5.83; N, 21.60; S, 12.36. Found: C, 50.84; H, 5.94; N, 21.51; S, 12.19.

Example 4 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (example compound number 3-3)

(4a) (2Z) -2-cyano-3- (propylamino) buta-2-enthioamide

(2Z) -2-cyano-3-ethoxybuta-2-enthioamide (J.Org.Chem., (1962), 27, 2433-2439) (0.34 g, 2.0 mmol) and propylamine (0.15 g, 2.5 mmol) was suspended in ethanol (5 mL) and stirred at room temperature for 15 hours. The precipitated solid was obtained by filtration, and further washed with ethanol to obtain 0.29 g of the title compound (yield 79%).

Mp 149-151 ° C .;

IR (KBr) ν _max 3400, 3287, 3187, 2190, 1612 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.97 (3H, t, J = 7.4 Hz), 1.55-1.64 (2H, m), 2.30 (3H, s), 3.35-3.40 (2H, m), 7.65 (1 H, br), 8.45 (1 H, br), 12.74 (1 H, br);

MS (FAB) m / z: 184 [M + H] ⁺ ;

analysis. Calc. For C ₈ H ₁₃ N ₃ S: C, 52.43; H, 7. 15; N, 22.93; S, 17.49. Found: C, 52.59; H, 7. 25; N, 22.83; S, 17.51.

(4b) 3-amino-4- (propylamino) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (propylamino) buta-2-enthioamide (0.29g, 1.6mmol) and N, N-dimethylformamidedimethylacetal (0.57) prepared in Example 4 (4a) g, 4.7 mmol) was mixed with toluene (3 mL), and the mixture was stirred under reflux for 2 hours. To the residue obtained by distilling off the solvent under reduced pressure, 1N aqueous sodium hydroxide solution (5 mL) was added, followed by stirring for 30 minutes under reflux. After cooling the reaction mixture to room temperature, ether (20 mL) was added to separate the liquid. In addition, the organic layer was extracted with 1N aqueous sodium hydroxide solution (5 mL). The combined aqueous layers were neutralized with 1N hydrochloric acid, the precipitated solid was obtained by filtration, and the solid further washed with water and a small amount of ethanol to contain 2-thioxo-1,2-dihydropyridine derivative as a main component (0.17 g) was obtained.

The obtained solid was dissolved in N, N-dimethylformamide (3 mL), and 8N sodium hydroxide aqueous solution (0.5 mL) and 2-chloroacetamide (0.10 g, 1.1 mmol) were added. The mixture was stirred at rt for 1 h, then water (3 mL) was added. The precipitated solid was obtained by filtration and washed with water and ethanol to obtain 106 mg of the title compound. 27% yield from (2Z) -2-cyano-3- (propylamino) buta-2-enthioamide.

Mp 214-215 ° C .;

IR (KBr) ν _max 3348, 3319, 3189, 1650, 1592, 1504, 1364 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.95 (3H, t, J = 7.4 Hz), 1.59-1.68 (2H, m), 3.16-3.21 (2H, m), 6.41 (1H, d, J = 5.6 Hz), 6.44 (1H, brt, J = 5.4 Hz), 6.81 (2H, br), 7.02 (2H, br), 8.05 (1H, d, J = 5.6 Hz);

MS (EI) m / z: 250 [M ⁺ ], 204;

analysis. Calc. For C ₁₁ H ₁₄ N ₄ OS.1.1H ₂ O: C, 48.91; H, 6.04; N, 20.74; S, 11.87. Found: C, 49.06; H, 5.92; N, 20.71; S, 11.90.

Example 5 3-Amino-4- (isobutylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-6)

(5a) (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide

(2Z) -2-cyano-3-ethoxybuta-2-enthioamide (J.Org.Chem., (1962), 27, 2433-2439) (340 mg, 2.0 mmol) and isobutylamine ( 183 mg, 2.5 mmol) was suspended in ethanol (3 mL) and stirred at room temperature for 6 hours. The precipitated solid was collected by filtration, washed with ethanol to obtain 378 mg of the title compound (96%).

Mp 165-167 ° C .;

IR (KBr) ν _max 3373, 3291, 3198, 2190, 1608 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.97 (6H, d, J = 6.7 Hz), 1.82-1.92 (1H, m), 2.30 (3H, s), 3.25-3.28 (2H, m), 7.67 (1 H, br), 8.48 (1 H, br), 12.76 (1 H, br);

MS (FAB) m / z: 198 [M + H] ⁺ ;

analysis. Calc. For C ₉ H ₁₅ N ₃ S: C, 54.79; H, 7. 66; N, 21.30; S, 16.25. Found: C, 54.73; H, 7. 84; N, 21.24; S, 16.18.

(5b) 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide (360 mg, 1.8 mmol) and N, N-dimethylformamide dimethyl acetal prepared in Example 5 (5a) 652 mg, 5.5 mmol) was mixed with toluene (5 mL) and stirred under reflux for 2 hours. To the residue obtained by distilling off the solvent under reduced pressure, an aqueous 1N sodium hydroxide solution (5 mL) was added, followed by stirring for 30 minutes under reflux. The reaction mixture was cooled to room temperature and then partitioned between ether (50 mL) and water (20 mL). The obtained aqueous layer was neutralized with 1N hydrochloric acid (5 mL), and the precipitated solid was obtained by filtration, and further washed with water and a small amount of ethanol to obtain 217 mg of a solid containing the title compound as a main component.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.87 (6H, d, J = 6.7 Hz), 1.78-1.88 (1H, m), 3.06-3.12 (2H, m), 6.33 (1H, d, J = 7.4 Hz), 7.41 (1 H, br), 7.50 (1 H, br), 12.35 (1 H, br).

(5c) 3-amino-4- (isobutylamino) thieno [2,3-b] pyridine-2-carboxamide

The crude product (215 mg, 1.0 mmol) of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 5 (5b) was N, N- It was dissolved in dimethylformamide (3 mL), and 8N aqueous sodium hydroxide solution (0.3 mL) and 2-chloroacetamide (126 mg, 1.3 mmol) were added. The mixture was stirred at rt for 1 h, then water (3 mL) was added. The precipitated solid was obtained by filtration and washed with water and ethanol to obtain 109 mg of the title compound. Yield 23% from 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile.

Mp 117-119 ° C .;

IR (KBr) ν _max 3399, 3352, 3250, 3121, 1676, 1595, 860 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.95 (6H, d, J = 6.7 Hz), 1.90-2.01 (1H, m), 3.04-3.08 (2H, m), 6.43 (1H, d, J = 5.5 Hz), 6.52 (1H, br), 6.83 (2H, br), 7.08 (2H, br), 8.07 (1H, d, J = 5.5 Hz);

MS (EI) m / z: 264 [M ⁺ ], 204;

analysis. Calc. For C ₁₂ H ₁₆ N ₄ OS 0.1 H ₂ O: C, 54.15; H, 6. 14; N, 21.05; S, 12.05. Found: C, 54.11; H, 5.94; N, 21.06; S, 12.17.

Example 6 3-amino-4- (neopentylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-7)

(6a) (2Z) -2-cyano-3- (neopentylamino) buta-2-enthioamide

Neopentylamine was used instead of propylamine, and it reacted like the method described in Example 4 (4a), and obtained the title compound. Yield 54%.

Mp 143-144 ° C .;

IR (KBr) ν _max 3376, 3297, 3202, 2188, 1607 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.99 (9H, s), 2.30 (3H, s), 3.23 (2H, d, J = 5.5 Hz), 7.67 (1H, br), 8.49 (1H, br ), 12.78 (1H, broad singlet);

MS (FAB) m / z: 212 [M + H] ⁺ ;

analysis. Calc. For C ₁₀ H ₁₇ N ₃ S: C, 56.84; H, 8.11; N, 19.88; S, 15.17. Found: C, 56.59; H, 8.09; N, 19.76; S, 14.90.

(6b) 3-amino-4- (neopentylamino) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (neopentylamino) prepared in Example 6 (6a) instead of (2Z) -2-cyano-3- (propylamino) buta-2-enthioamide Using buta-2-enthioamide, the reaction was carried out in the same manner as in Example 4 (4b) to obtain the title compound. Yield 16%.

Mp 238-240 ° C .;

IR (KBr) ν _max 3318, 3190, 1653, 1587, 1105 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.97 (9H, s), 3.08 (2H, d, J = 6.1 Hz), 6.46 (1H, brt, J = 6.1 Hz), 6.54 (1H, d, J = 5.7 Hz), 6.63 (2H, br), 7.14 (2H, br), 8.06 (1H, d, J = 5.7 Hz);

MS (FAB) m / z: 279 [M + H] ⁺ ;

analysis. Calc. For C ₁₃ H ₁₈ N ₄ OS. 1.2H ₂ O: C, 52.05; H, 6. 85; N, 18.68; S, 10.69. Found: C, 52.31; H, 6. 69; N, 18.68; S, 10.67.

Example 7 3-amino-4- (benzylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-11)

(7a) (2Z) -3- (benzylamino) -2-cyanobuta-2-enthioamide

Benzylamine was used instead of propylamine, and it reacted like the method described in Example 4 (4a), and obtained the title compound. Yield 97%.

Mp 157-159 ° C .;

IR (KBr) ν _max 3355, 3287, 3193, 2193, 1627, 1608, 853, 739 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.34 (3H, s), 4.69 (2H, d, J = 5.6 Hz), 7.31-7.43 (5H, m), 7.74 (1H, br), 8.55 (1H , br), 13.02 (1 H, br);

MS (FAB) m / z: 232 [M + H] ⁺ ;

analysis. Calc. For C ₁₂ H ₁₃ N ₃ S: C, 62.31; H, 5. 66; N, 18.17; S, 13.86. Found: C, 62.19; H, 5.88; N, 18.27; S, 13.66.

(7b) 4- (benzylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- (benzylamino) -2-cyanobuta-prepared in Example 7 (7a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide Reaction was performed similarly to the method described in Example 1 (1b), using 2-enthioamide (0.41 g) to obtain a crude product (0.38 g) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.54 (2H, d, J = 6.3 Hz), 6.19 (1H, d, J = 7.4 Hz), 7.24-7.44 (5H, m), 8.12 (1H, br ), 12.45 (1 H, br).

(7c) 3-amino-4- (benzylamino) thieno [2,3-b] pyridine-2-carboxamide

4- (benzylamino) -2-thioxo-1 prepared in Example 7 (7b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile, Using the crude product (0.38 g) of 2-dihydropyridine-3-carbonitrile, the reaction was carried out in the same manner as in Example 1 (1c) to obtain 0.39 g of the title compound. 73% yield from (2Z) -3- (benzylamino) -2-cyanobuta-2-enthioamide.

Mp 260-262 ° C .;

IR (KBr) ν _max 3460, 3394, 3351, 3112, 1654, 1627, 1598 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.52 (2H, d, J = 5.8 Hz), 6.28 (1H, d, J = 5.7 Hz), 6.95 (2H, br), 7.07 (2H, br), 7.16 (1H, broad, J = 5.8 Hz), 7.23-7.42 (5H, m), 8.00 (1H, d, J = 5.7 Hz);

MS (FAB) m / z: 299 [M + H] ⁺ ;

analysis. Calc. For C ₁₅ H ₁₄ N ₄ OS: C, 60.38; H, 4.73; N, 18.78; S, 10.75. Found: C, 60.37; H, 4. 85; N, 18.87; S, 10.65.

Example 8 3-amino-4-[(2-phenethyl) amino] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-12)

(8a) (2Z) -2-cyano-3-[(2-phenethyl) amino] buta-2-enthioamide

Using phenethylamine instead of propylamine, it carried out similarly to the method of Example 4 (4a), and obtained the title compound. Yield 75%.

Mp 95-96 ° C .;

IR (KBr) ν _max 3353, 3300, 3203, 2189, 1626, 1595, 749, 699 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.22 (3H, s), 2.89 (2H, t, J = 7.2 Hz), 3.64-3.69 (1H, m), 7.18-7.31 (5H, m), 7.60 (1 H, br), 8.40 (1 H, br), 12.70 (1 H, br);

MS (FAB) m / z: 246 [M + H] ⁺ ;

analysis. Calc. For C ₁₃ H ₁₅ N ₃ S: C, 63.64; H, 6. 16; N, 17.13; S, 13.07. Found: C, 63.73; H, 6. 11; N, 17.20; S, 13.14.

(8b) 3-amino-4-[(2-phenethyl) amino] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3-[(2-pex) prepared in Example 8 (8a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide 0.34 g of 2-thioxo-1,2- was reacted in the same manner as in the method described in Example 1 (1b) using netyl) amino] buta-2-enthioamide (0.37 g, 1.5 mmol). The crude product of the dihydropyridine derivative was obtained.

The reaction was carried out in the same manner as in the method described in Example 1 (1c) using the obtained 2-thioxo-1,2-dihydropyridine derivative to give 0.25 g of the title compound (yield 53%).

Mp 206-208 ° C .;

IR (KBr) ν _max 3449, 3358, 3121, 1656, 1598, 1514, 1103, 753, 703 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.93 (2H, t, J = 7.5 Hz), 3.44-3.49 (2H, m), 6.49 (1H, d, J = 5.7 Hz), 6.50 (1H, br ), 6.76 (2H, br), 7.04 (2H, br), 7.18-7.32 (5H, m), 8.07 (1H, doublet, J = 5.7 Hz);

MS (FAB) m / z: 313 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₁₆ N ₄ OS: C, 61.52; H, 5. 16; N, 17.93; S, 10.26. Found: C, 61.47; H, 5. 25; N, 17.95; S, 10.33.

Example 9 3-amino-4-[(3-phenylpropyl) amino] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-13)

(9a) (2Z) -2-cyano-3-[(3-phenylpropyl) amino] buta-2-enthioamide

3-phenylpropylamine was used instead of propylamine, and reaction was carried out in the same manner as in Example 4 (4a), to obtain the title compound. Yield 94%.

Mp 125-126 ° C .;

IR (KBr) ν _max 3399, 3285, 3173, 2189, 1612, 1603, 754, 531 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.85-1.92 (2H, m), 2.27 (3H, s), 2.70 (2H, t, J = 7.7 Hz), 3.37-3.42 (2H, m), 7.16 -7.29 (5H, m), 7.64 (1 H, br), 8.45 (1 H, br), 12.79 (1 H, br);

MS (FAB) m / z: 260 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₁₇ N ₃ S: C, 64.85; H, 6. 61; N, 16.20; S, 12.36. Found: C, 65.02; H, 6.52; N, 16.28; S, 12.37.

(9b) 3-amino-4-[(3-phenylpropyl) amino] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3-[(3-phenyl) prepared in Example 9 (9a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide Propyl) amino] buta-2-enthioamide (0.49 g, 1.9 mmol), and the reaction was carried out in the same manner as described in Example 1 (1b) to give 2-thioxo-1,2-dihydropyridine. A crude product of the derivative (0.45 g) was obtained.

The reaction was carried out in the same manner as in the method described in Example 1 (1c) using the obtained 2-thioxo-1,2-dihydropyridine derivative to obtain 0.30 g of the title compound (yield 49%).

Mp 232-234 ° C .;

IR (KBr) ν _max 3424, 3326, 3125, 1659, 1603, 1517, 1362 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.97 (2H, m), 2.69 (2H, t, J = 7.6 Hz), 3.21-3.26 (2H, m), 6.37 (1H, d, J = 5.6 Hz), 6.47 (1H, brt, J = 5.3 Hz), 6.81 (2H, br), 7.02 (2H, br), 7.15-7.29 (5H, m), 8.04 (1H, d, J = 5.6 Hz) ;

MS (FAB) m / z: 327 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₁₈ N ₄ OS: C, 62.55; H, 5.56; N, 17.16; S, 9.82. Found: C, 62.33; H, 5. 76; N, 17.32; S, 9.68.

Example 10 3-amino-4- (cyclopentylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-8)

(10a) (2Z) -2-cyano-3- (cyclopentylamino) buta-2-enthioamide

Cyclopentylamine was used instead of isobutylamine, and it reacted like the method of Example 5 (5a), and obtained the title compound. Yield 89%.

Mp 162-163 ° C .;

IR (KBr) ν _max 3368, 3287, 3196, 2192, 1612 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.53-1.74 (6H, m), 1.92-2.00 (2H, m), 2.33 (3H, s), 4.11-4.19 (1H, m), 7.63 (1H, br), 8.44 (1 H, br), 12.94 (1 H, brd, J = 7.5 Hz);

MS (FAB) m / z: 210 [M + H] ⁺ ;

analysis. Calc. For C ₁₀ H ₁₅ N ₃ S: C, 57.38; H, 7.22; N, 20.08; S, 15.32. Found: C, 57.39; H, 7. 21; N, 19.98; S, 15.26.

(10b) 4- (cyclopentylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (cyclopentylamino) prepared in Example 10 (10a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b) using buta-2-enthioamide (358 mg) to obtain a crude product (318 mg) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.51-1.73 (6H, m), 1.90-1.98 (2H, m), 3.94-4.04 (1H, m), 6.37 (1H, d, J = 7.8 Hz) , 7.44-7.49 (1 H, m), 12.42 (1 H, br).

(10c) 3-amino-4- (cyclopentylamino) thieno [2,3-b] pyridine-2-carboxamide

4- (cyclopentylamino) -2-thioxo-1 prepared in Example 10 (10b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Using the crude product (318 mg) of, 2-dihydropyridine-3-carbonitrile, the reaction was carried out in the same manner as in Example 1 (1c) to give 261 mg of the title compound. Yield 55% from (2Z) -3- (cyclopentylamino) -2-cyanobuta-2-enthioamide.

Mp 212-213 ° C .;

IR (KBr) ν _max 3311, 3177, 1649, 1594, 1513, 1497 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.52-1.73 (6H, m), 2.01-2.08 (2H, m), 3.85-3.92 (1H, m), 6.21 (1H, brd, J = 6.4 Hz) , 6.43 (1H, d, J = 5.6 Hz), 6.72 (2H, br), 7.07 (2H, br), 8.06 (1H, d, J = 5.6 Hz);

MS (EI) m / z: 276 [M ⁺ ], 231;

analysis. Calc. For C ₁₃ H ₁₆ N ₄ OS: C, 56.50; H, 5. 84; N, 20.27; S, 11.60. Found: C, 56.31; H, 5.73; N, 20.13; S, 11.33.

Example 11 3-amino-4- (cyclohexylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-9)

(11a) (2Z) -2-cyano-3- (cyclohexylamino) buta-2-enthioamide

Cyclohexylamine was used instead of isobutylamine, and it reacted like the method of Example 5 (5a), and obtained the title compound. Yield 76%.

Mp 142-144 ° C .;

IR (KBr) ν _max 3412, 3297, 3188, 2187, 1613, 1493, 1410 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.33-1.61 (6H, m), 1.81-1.93 (4H, m), 2.37 (3H, s), 3.55-3.64 (1H, m), 6.38 (1H, br), 6.69 (1 H, br), 12.92 (1 H, br);

MS (EI) m / z: 223 [M ⁺ ], 190.

(11b) 3-amino-4- (cyclohexylamino) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (cyclohexylamino) prepared in Example 11 (11a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as described in Example 1 (1b) using buta-2-enthioamide (0.33 g, 1.5 mmol) to obtain a crude product of 2-thioxo-1,2-dihydropyridine derivative. Product (0.11 g) was obtained.

The reaction was carried out in the same manner as in the method described in Example 1 (1c) using the obtained 2-thioxo-1,2-dihydropyridine derivative to obtain 0.06 g of the title compound (yield 14%).

Mp 244-247 ° C .;

IR (KBr) ν _max 3141, 1664, 1598, 1513, 1497, 1108 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.20-1.98 (10H, m), 3.43-3.50 (1H, m), 6.16 (1H, d, J = 7.5 Hz), 6.46 (1H, d, J = 5.7 Hz), 6.71 (2H, br), 7.08 (2H, br), 8.06 (1H, d, J = 5.7 Hz);

MS (FAB) m / z: 291 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₁₈ N ₄ OS.0.3H ₂ O: C, 56.85; H, 6. 34; N, 18.94; S, 10.85. Found: C, 57.00; H, 6. 27; N, 18.95; S, 10.61.

Example 12 3-amino-4- (cycloheptylamino) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 2-10)

(12a) (2Z) -2-cyano-3- (cycloheptylamino) buta-2-enthioamide

Cycloheptylamine was used instead of isobutylamine, and reaction was performed similarly to the method described in Example 5 (5a), to obtain the title compound. Yield 74%.

Mp 132-134 ° C .;

IR (KBr) ν _max 3380, 3295, 3200, 2189, 1609, 853 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.48-1.63 (10H, m), 1.85-1.92 (2H, m), 2.32 (3H, s), 3.90-3.97 (1H, m), 7.62 (1H, br), 8.43 (1H, br), 12.94 (1H, brd, J = 8.9 Hz);

MS (FAB) m / z: 238 [M + H] ⁺ ;

analysis. Calc. For C ₁₂ H ₁₉ N ₃ S: C, 60.72; H, 8.07; N, 17.70; S, 13.51. Found: C, 60.69; H, 8.12; N, 17.68; S, 13.41.

(12b) 4- (cycloheptylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (cycloheptylamino) prepared in Example 12 (12a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b), using buta-2-enthioamide (339 mg) to obtain a crude product (306 mg) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.40-1.72 (10H, m), 1.76-1.85 (2H, m), 3.61-3.73 (1H, m), 6.30 (1H, d, J = 7.4 Hz) , 6.82 (1 H, br), 7.43 (1 H, br), 12.35 (1 H, br).

(12c) 3-amino-4- (cycloheptylamino) thieno [2,3-b] pyridine-2-carboxamide

4- (cycloheptylamino) -2-thioxo- prepared in Example 12 (12b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Using the crude product (306 mg) of 1,2-dihydropyridine-3-carbonitrile, the reaction was carried out in the same manner as in Example 5 (5c) to obtain 201 mg of the title compound. Yield 46% from (2Z) -2-cyano-3- (cycloheptylamino) buta-2-enthioamide.

Mp 206-208 ° C .;

IR (KBr) ν _max 3334, 1652, 1594, 1514, 1498, 1365 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.49-1.71 (10H, m), 1.93-1.98 (2H, m), 3.60-3.63 (1H, m), 6.21 (1H, d, J = 7.5 Hz) , 6.35 (1H, d, J = 5.8 Hz), 6.70 (2H, br), 7.10 (2H, br), 8.08 (1H, d, J = 5.8 Hz);

MS (FAB) m / z: 305 [M + H] ⁺ ;

analysis. Calc. For C ₁₅ H ₂₀ N ₄ OS.0.1H ₂ O: C, 58.84; H, 6.65; N, 18.30; S, 10.47. Found: C, 58.77; H, 6. 48; N, 18.22; S, 10.34.

Example 13 3-Amino-4-pyrrolidin-1-ylthieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-15)

(13a) (2Z) -2-cyano-3-pyrrolidin-1-ylbuta-2-enthioamide

Pyrrolidine was used instead of propylamine, and it reacted like the method described in Example 4 (4a), and obtained the title compound. Yield 86%.

¹ H NMR (CD ₃ OD, 400 MHz) δ 2.00 (4H, s), 2.47 (3H, s), 3.63 (4H, s).

(13b) 4-pyrrolidin-1-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3-pyrrolidine-1 prepared in Example 13 (13a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b) using -buta-2-enthioamide to obtain the title compound. Yield 80%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91 (4H, s), 3.55-3.75 (4H, br s), 6.21 (1H, d, J = 7.3 Hz), 7.365 (1H, dd, J = 5.9, 7.3 Hz).

(13c) 3-amino-4-pyrrolidin-1-ylthieno [2,3-b] pyridine-2-carboxamide

4-Pyrrolidin-1-yl-2-thioxo prepared in Example 13 (13b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as in the method described in Example 1 (1c) using -1,2-dihydropyridine-3-carbonitrile. Yield 85%.

Mp 275-283 ° C .;

IR (KBr) ν _max 3429, 3297, 3138, 2999, 2877, 1673, 1611, 1584, 1503, 1372, 1341, 1273, 1113, 1056, 1002, 618, 486 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91 (4H, s), 3.30 (4H, s), 6.87 (1H, d, J = 5.8 Hz), 6.88 (2H, s), 7.02 (2H, br s), 8.255 (1H, doublet, J = 5.8 Hz);

MS (FAB) m / z: 262.08 [M + H] ⁺ ;

analysis. Calc. For C ₁₂ H ₁₄ N ₄ OS: C, 54.94; H, 5.38; N, 21.36; S, 12.22. Found: C, 54.54; H, 5.15; N, 21.10; S, 12.03.

Example 14 3-Amino-4-piperidin-1-ylthieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-16)

(14a) (2Z) -2-cyano-3-piperidin-1-ylbuta-2-enthioamide

An ethanol (30 mL) solution of (2Z) -2-cyano-3-ethoxybuta-2-enthioamide (1.70 g, 10 mmol) and piperidine (1.02 g, 12 mmol) was stirred under reflux for 2 hours. , Was left overnight at room temperature. The precipitated solid was separated by filtration, washed with ethanol (3 x 3 mL) to obtain 1.36 g of the title compound (yield 65%).

Mp 161-166 ° C .;

IR (KBr) ν _max 3381, 3268, 3170, 2182, 1600, 1534, 873, 838, 636 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.58-1.63 (6H, m), 2.27 (3H, s), 3.31-3.36 (4H, m), 8.15 (1H, br), 8.86 (1H, br) ;

MS (EI) m / z: 209 [M ⁺ ], 150, 44;

analysis. Calc. For C ₁₀ H ₁₅ N ₃ S: C, 57.38; H, 7.22; N, 20.08; S, 15.32. Found: C, 57.27; H, 7. 16; N, 20.03; S, 15.47.

(14b) 4-piperidin-1-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3-piperidin-1-ylbuta-2-enthioamide (0.42 g, 2.0 mmol) and N, N-dimethylformamidedimethyl prepared in Example 14 (14a) Acetal (0.72 g, 6.0 mmol) was mixed with toluene (3 mL) and stirred under reflux for 2 hours. The solvent was distilled off under reduced pressure, and 1N aqueous sodium hydroxide solution (3 mL) was added to the residue, which was stirred for 30 minutes under reflux. After the reaction mixture was cooled to room temperature, 1N hydrochloric acid (4 mL) was added, and the precipitated solid was obtained by filtration, and further washed with water and a small amount of ethanol to obtain 0.30 g of a solid containing the title compound as a main component.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.50-1.55 (6H, m), 3.48-3.52 (4H, m), 6.38 (1H, d, J = 7.3 Hz), 7.35 (1H, d, J = 7.3 Hz).

(14c) 3-amino-4-piperidin-1-ylthieno [2,3-b] pyridine-2-carboxamide

4-piperidin-1-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (0.30 g) prepared in Example 14 (14b) was replaced with N, N-dimethylformamide (3 mL ), 8N aqueous sodium hydroxide solution (0.6 mL) and 2-chloroacetamide (0.15 g, 1.6 mmol) were added. The mixture was stirred at rt for 1 h, then water (5 mL) was added. The precipitated solid was obtained by filtration and washed with water and ethanol to obtain 0.30 g of solid. The obtained solid was purified by silica gel column chromatography (100% ethyl acetate) to obtain 0.21 g of the title compound. Yield 38% from (2Z) -2-cyano-3-piperidin-1-ylbuta-2-enthioamide.

Mp 191-192 ° C .;

IR (KBr) ν _max 3460, 3329, 3176, 1651, 1589, 1501, 1378, 963 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.72-1.79 (6H, m), 2.55-3.40 (4H, m), 6.93 (2H, br), 6.99 (1H, d, J = 5.1 Hz), 7.07 (2H, br), 8.40 (1H, doublet, J = 5.1 Hz);

MS (FAB) m / z: 277 [M + H] ⁺ ;

analysis. Calc. For C ₁₃ H ₁₆ N ₄ SO.0.5H ₂ O: C, 54.72; H, 6.00; N, 19.63; S, 11.24. Found: C, 54.68; H, 6.03; N, 19.67; S, 11.05.

Example 15 3-amino-4- (4-methylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-18)

(15a) (2Z) -2-cyano-3- (4-methylpiperidin-1-yl) buta-2-enthioamide

4-methyl piperidine was used instead of isobutylamine, and reaction was carried out in the same manner as in Example 5 (5a) to obtain the title compound. Yield 87%.

Mp 156-159 ° C .;

IR (KBr) ν _max 3387, 3262, 3162, 2177, 1604, 1540, 868 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.91 (3H, d, J = 6.1 Hz), 1.15-1.25 (2H, m), 1.62-1.73 (3H, m), 2.27 (3H, s), 3.04 -3.10 (2H, m), 3.62 (2H, broad singlet, J = 13.5 Hz), 8.14 (1H, broad), 8.85 (1H, broad);

MS (EI) m / z: 223 [M ⁺ ], 190;

analysis. Calc. For C ₁₁ H ₁₇ N ₃ S.0.1H ₂ O: C, 58.68; H, 7. 70; N, 18.66; S, 14.27. Found: C, 58.92; H, 7.73; N, 18.77; S, 14.06.

(15b) 4- (4-methylpiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (4-methylpi) prepared in Example 15 (15a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as described in Example 1 (1b), using ferridin-1-yl) buta-2-enthioamide (0.39 g). After completion of the reaction, toluene was added and the mixture was separated. The aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated solid was separated by filtration and washed with water and ethanol to obtain a crude product of the title compound (0.24 g).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.93 (3H, d, J = 6.4 Hz), 1.14-1.24 (2H, m), 1.65-1.76 (3H, m), 3.10-3.16 (2H, m) , 4.08 (2H, brd, J = 13.2 Hz), 6.49 (1H, d, J = 7.5 Hz), 7.44 (1H, d, J = 7.5 Hz), 12.60 (1H, br).

(15c) 3-amino-4- (4-methylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-methylpiperidin-1-yl, prepared in Example 15 (15b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was reacted in the same manner as in the method described in Example 5 (5c) using a crude product of 0.2) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (0.24 g). 0.24 g was obtained. 41% yield from (2Z) -2-cyano-3- (4-methylpiperidin-1-yl) buta-2-enthioamide.

Mp 252-254 ° C;

IR (KBr) ν _max 3430, 3311, 3159, 1667, 1611, 1580, 1504, 1367, 1341 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.98 (3H, d, J = 6.0 Hz), 1.40-1.76 (5H, m), 2.66-2.80 (2H, m), 3.27-3.30 (2H, m) , 6.91 (2H, br), 6.99 (1H, d, J = 5.2 Hz), 7.05 (2H, br), 8.39 (1H, d, J = 5.2 Hz);

MS (FAB) m / z: 291 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₁₈ N ₄ SO: C, 57.91; H, 6. 25; N, 19.29; S, 11.04. Found: C, 57.89; H, 6. 31; N, 19.29; S, 11.06.

Example 16 3-Amino-4- (3-methylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-17)

(16a) 4- (3-methylpiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3-ethoxybuta-2-enthioamide (340 mg, 2.0 mmol) and 3-methylpiperidine (248 mg, 2.5 mmol) were mixed in ethanol (2 mL), Stir at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in toluene (6 mL), N, N-dimethylformamide dimethylacetal (714 mg, 6.0 mmol) was added, and the mixture was stirred under heating to reflux for 2 hours. After distilling off the solvent under reduced pressure, 1N aqueous sodium hydroxide solution (4 mL) was added to the residue. The mixture was stirred for 1 hour under heating reflux, and after cooling, 1N hydrochloric acid (5 mL) was added. The precipitated solid was separated by filtration and washed with water and ethanol to obtain a solid containing 211 mg of the title compound as a main component.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.89 (3H, d, J = 6.7 Hz), 1.14-1.25 (1H, m), 1.47-1.83 (4H, m), 2.82 (1H, dd, J = 10.6, 13.3 Hz), 3.08-3.15 (1H, m), 3.96-4.05 (2H, m), 6.50 (1H, d, J = 6.5 Hz), 7.42-7.45 (1H, m), 12.59 (1H, br ).

(16b) 3-amino-4- (3-methylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

Solid based on 4- (3-methylpiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 16 (16a) (211 mg) Was dissolved in N, N-dimethylformamide (2 mL), 8N aqueous sodium hydroxide solution (0.2 mL) and 2-chloroacetamide (122 mg, 1.3 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water (2 mL) was added to the reaction mixture, and the precipitated solid was separated by filtration and washed with water and ethanol to obtain 158 mg of the title compound. 27% yield from (2Z) -2-cyano-3-ethoxybuta-2-enthioamide.

Mp 201-204 ° C;

IR (KBr) ν _max 3422, 3325, 3162, 1657, 1580, 1501, 1371 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.91 (3H, d, J = 6.3 Hz), 1.70-1.95 (4H, m), 2.23-2.70 (2H, m), 3.20-3.30 (2H, m) , 6.90 (2H, br), 6.99 (1H, d, J = 5.1 Hz), 7.08 (2H, br), 8.40 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 291 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₁₈ N ₄ SO.0.1H ₂ O: C, 57.55; H, 6. 28; N, 19.17; S, 10.97. Found: C, 57.45; H, 6. 10; N, 19.35; S, 11.12.

Example 17 3-Amino-4- [3- (hydroxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-20 )

(2Z) -2-cyano-3-ethoxybuta-2-enthioamide (340 mg, 2.0 mmol) and 3- (hydroxymethyl) piperidine (288 mg, 2.5 mmol) were added to ethanol (3 mL). Mixed with and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in N, N-dimethylformamide (3 mL), and N, N-dimethylformamide dimethylacetal (250 mg, 2.1 mmol) was added thereto for 1 hour at room temperature. It stirred at 100 degreeC by 1 hour. The reaction mixture was cooled to room temperature, 8N aqueous sodium hydroxide solution (0.4 mL) and 2-chloroacetamide (281 mg, 3.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture for separation, and the aqueous layer was further extracted with ethyl acetate (30 mL). The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 10: 1) to give 146 mg of the title compound. Yield 24% from (2Z) -2-cyano-3-ethoxybuta-2-enthioamide.

Mp 125-130 ° C .;

IR (KBr) ν _max 3441, 3335, 3183, 1661, 1595, 1583, 1503, 1375, 1037 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.95-1.15 (1H, m), 1.70-1.99 (4H, m), 2.26-2.70 (2H, m), 3.21-3.43 (4H, m), 4.56 ( 1H, t, J = 5.3 Hz), 6.94 (2H, br), 7.02 (1H, d, J = 5.1 Hz), 7.11 (2H, br), 8.44 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 307 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₁₈ N ₄ SO ₂ .1H ₂ O: C, 51.84; H, 6. 21; N, 17.27; S, 9.88. Found: C, 51.72; H, 6. 15; N, 17.37; S, 9.70.

Example 18 3-amino-4- (4-benzylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-19)

(18a) (2Z) -3- (4-benzylpiperidin-1-yl) -2-cyanobuta-2-enthioamide

4-benzylpiperidine was used instead of isobutylamine, and the reaction was carried out in the same manner as in the method described in Example 5 (5a) to obtain the title compound. Yield 88%.

Mp 151-154 ° C .;

IR (KBr) ν _max 3283, 3173, 2187, 1605, 1542, 867, 749, 702 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.26-1.32 (2H, m), 1.63-1.66 (2H, m), 1.80-1.90 (1H, m), 2.53 (2H, d, J = 7.2 Hz) , 3.02-3.08 (2H, m), 3.65 (2H, brd, J = 13.6 Hz), 7.17-7.31 (1H, m), 8.18 (1H, br), 8.88 (1H, br);

MS (EI) m / z: 299 [M ⁺ ], 240, 91;

analysis. Calc. For C ₁₇ H ₂₁ N ₃ S.0.3H ₂ O: C, 66.98; H, 7.14; N, 13.78; S, 10.52. Found: C, 67.03; H, 6.97; N, 13.78; S, 10.36.

(18b) 4- (4-benzylpiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (4-benzylpi prepared in Example 18 (18a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as described in Example 1 (1b), using ferridin-1-yl) buta-2-enthioamide (0.53 g). After completion of the reaction, toluene was added and the mixture was separated, and the aqueous layer was neutralized with 1N hydrochloric acid, and the precipitated solid was separated by filtration and washed with water and ethanol to obtain a crude product (0.23 g) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.20-1.31 (2H, m), 1.69 (2H, brd, J = 10.9 Hz), 1.82-1.88 (1H, m), 2.54 (2H, d, J = 7.1 Hz), 3.05-3.11 (2H, m), 4.07 (2H, brd, J = 13.2 Hz), 6.45 (1H, d, J = 7.5 Hz), 7.40-7.44 (1H, m), 12.57 (1H, br).

(18c) 3-amino-4- (4-benzylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-benzylpiperidin-1-yl, prepared in Example 18 (18b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridin-3-carbonitrile The reaction was carried out in the same manner as described in Example 5 (5c) using a crude product of 0.5-2-thioxo-1,2-dihydropyridine-3-carbonitrile (0.53 g) to obtain the title compound ( 0.20 g) was obtained. 27% yield from (2Z) -2-cyano-3- (4-benzylpiperidin-1-yl) buta-2-enthioamide.

Mp 220-221 ° C .;

IR (KBr) ν _max 3446, 3330, 3156, 1649, 1579, 1502, 1367, 958, 748, 700 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.48-1.72 (5H, m), 2.52-2.73 (2H, m), 2.59 (2H, d, J = 6.4 Hz), 3.30-3.33 (2H, m) , 6.94 (2H, br), 6.99 (1H, d, J = 5.3 Hz), 7.09 (2H, br), 7.18-7.32 (5H, m), 8.41 (1H, d, J = 5.3 Hz);

MS (FAB) m / z: 367 [M + H] ⁺ ;

analysis. Calc. For C ₂₀ H ₂₂ N ₄ SO.0.1H ₂ O: C, 65.23; H, 6.08; N, 15.21; S, 8.71. Found: C, 65.18; H, 6. 15; N, 15.35; S, 8.54.

Example 19 3-Amino-4- (4-hydroxypiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-32)

(19a) (2Z) -2-cyano-3- (4-hydroxypiperidin-1-yl) buta-2-enthioamide

4-hydroxypiperidine was used instead of isobutylamine, and the reaction was carried out in the same manner as in the method described in Example 5 (5a) to obtain the title compound. Yield 93%.

Mp 160-163 ° C .;

IR (KBr) ν _max 3368, 3167, 2180, 1634, 1536, 1415 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.44-1.52 (2H, m), 1.78-1.83 (2H, m), 2.27 (3H, s), 3.15-3.22 (2H, m), 3.50-3.56 ( 2H, m), 3.75-3.79 (1H, m), 4.82 (1H, d, J = 3.8 Hz), 8.18 (1H, br), 8.88 (1H, br);

MS (FAB) m / z: 226 [M + H] ⁺ ;

analysis. Calc. For C ₁₀ H ₁₅ N ₃ SO: C, 53.31; H, 6. 71; N, 18.65; S, 14.23. Found: C, 53.14; H, 6.65; N, 18.54; S, 14.03.

(19b) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- (4-hydroxypiperidin-1-yl) buta-2-enthioamide

(2Z) -2-cyano-3- (4-hydroxypiperidin-1-yl) buta-2-enthioamide (0.22 g, 1.0 mmol) and N prepared in Example 19 (19a); N-dimethylformamide dimethylacetal (0.13 g, 1.1 mmol) was mixed in ethanol (3 mL), and stirred at room temperature for 3 hours. The precipitated solid was obtained by filtration, and further washed with ethanol to obtain 0.27 g of the title compound (yield 96%).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.49-1.57 (2H, m), 1.83-1.90 (2H, m), 2.50 (3H, s), 2.99 (3H, s), 3.15 (3H, s) , 3.32-3.39 (2H, m), 3.63-3.69 (2H, m), 3.80-3.86 (1H, m), 4.88 (1H, d, J = 3.9 Hz), 8.50 (1H, s);

(19c) 3-amino-4- (4-hydroxypiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- (4-hydroxypiperidin-1-yl) buta-2 prepared in Example 19 (19b) -Enthioamide (0.27 g) was dissolved in N, N-dimethylformamide (5 mL) and stirred at 120 ° C for 1 hour. The reaction solution was cooled to room temperature, and 8N aqueous sodium hydroxide solution (0.3 mL) and 2-chloroacetamide (0.11 g, 1.2 mmol) were added. The mixture was stirred at rt for 1 h, then water (5 mL) was added. The precipitated solid was obtained by filtration and washed with water and ethanol to obtain 0.05 g of the title compound (yield 18%).

Mp 239-241 ° C .;

IR (KBr) ν _max 3445, 3425, 3330, 1645, 1592, 1376, 1045 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.63-1.71 (2H, m), 1.90-1.98 (2H, m), 2.70-3.30 (4H, m), 3.50-3.80 (1H, m), 4.77 ( 1H, br), 6.91 (2H, br), 7.00 (1H, d, J = 5.3 Hz), 7.06 (2H, br), 8.39 (1H, d, J = 5.3 Hz);

MS (FAB) m / z: 293 [M + H] ⁺ ;

analysis. Calc. C ₁₃ H ₁₆ N ₄ SO ₂ · 0 _. 1 H ₂ O: C, 53.08; H, 5.55; N, 19.05; S, 10.90. Found: C, 53.09; H, 5. 37; N, 18.77; S, 10.99.

Example 20 3-amino-4- (4-acetoxypiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-34)

3-amino-4- (4-hydroxypiperidin-1-yl) thieno [2,3-b] pyridine-2- as prepared in Example 19 (19c) in tetrahydrofuran (5 mL) solvent. Carboxamide (0.10 g, 0.3 mmol) and acetic anhydride (0.2 mL) were reacted overnight at room temperature in the presence of a catalytic amount of N, N-dimethylaminopyridine. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (50 mL). The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The obtained solid was washed with ethyl acetate to obtain 0.04 g of the title compound (yield 35%).

Mp 231-235 ° C .;

IR (KBr) ν _max 3439, 3422, 3323, 1710, 1645, 1580, 1268, 1035, 963 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.82-2.10 (4H, m), 2.04 (3H, s), 2.70-3.45 (4H, m), 4.65-5.00 (1H, m), 6.91 (2H, br), 7.02 (1H, d, J = 5.3 Hz), 7.09 (2H, br), 8.41 (1H, d, J = 5.3 Hz);

MS (FAB) m / z: 335 [M + H] ⁺ ;

analysis. Calc. For C ₁₅ H ₁₈ N ₄ SO ₃ .0.24H ₂ O: C, 53.19; H, 5.50; N, 16.54; S, 9.47. Found: C, 53.47; H, 5. 27; N, 16.20; S, 9.22.

Example 21 3-Amino-4- (4-phenyl-3,6-dihydropyridin-1 (2H) -yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound Number 1-38)

(21a) (2Z) -2-cyano-3- (4-phenyl-3,6-dihydropyridin-1 (2H) -yl) buta-2-enthioamide

4-phenyl-1,2,3,6-tetrahydropyridine was used instead of isobutylamine, and it reacted like the method described in Example 5 (5a), and obtained the title compound. Yield 99%.

Mp 170-171 ° C .;

IR (KBr) ν _max 3342, 3293, 3189, 2176, 1637, 1555, 1410, 872, 750 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.36 (3H, s), 2.64-2.71 (2H, m), 3.64 (2H, t, J = 5.5 Hz), 3.98-4.04 (2H, m), 6.16 (1 H, brs), 7.24-7.45 (5 H, m), 8.33 (1 H, br), 9.02 (1 H, br);

MS (FAB) m / z: 284 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₁₇ N ₃ S.0.2H ₂ O: C, 66.96; H, 6. 11; N, 14.64; S, 11.17. Found: C, 67.02; H, 6. 12; N, 14.62; S, 10.81.

(21b) 4-phenyl-2'-thioxo-1 ', 2', 3,6-tetrahydro-2H-1,4'-bipyridine-3'-carbonitrile

(2Z) -2-cyano-3- (4-phenyl- produced in Example 21 (21a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using 3,6-dihydropyridin-1 (2H) -yl) buta-2-enthioamide (1.13g) to determine the title compound. The product (0.13 g) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.66-2.72 (2H, m), 3.88-3.91 (2H, m), 4.26-4.30 (2H, m), 6.24 (1H, brs), 6.56 (1H, d, J = 7.8 Hz), 7.27-7.53 (6H, m), 12.70 (1H, br).

(21c) 3-amino-4- (4-phenyl-3,6-dihydropyridin-1 (2H) -yl) thieno [2,3-b] pyridine-2-carboxamide

4-phenyl-2'-thioxo-1 'prepared in Example 21 (21b), instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile, Reaction was carried out in the same manner as described in Example 5 (5c), using a crude product (0.13 g) of 2 ', 3,6-tetrahydro-2H-1,4'-bipyridine-3'-carbonitrile. Was carried out to obtain the title compound (0.06 g). Yield 4% from (2Z) -2-cyano-3- (4-phenyl-3,6-dihydropyridin-1 (2H) -yl) buta-2-enthioamide.

Mp 235 ° C. (decomposition);

IR (KBr) ν _max 3435, 3325, 1646, 1583, 1369, 954, 747 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.62-2.76 (2H, m), 3.30-3.46 (2H, m), 3.77-3.86 (2H, m), 6.35 (1H, brs), 6.90 (2H, br), 7.09 (1H, d, J = 5.3 Hz), 7.10 (2H, br), 7.25-7.51 (5H, m), 8.43 (1H, d, J = 5.3 Hz);

MS (FAB) m / z: 351 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₁₈ N ₄ SO. 0.7H ₂ O: C, 62.86; H, 5.39; N, 15.43; S, 8.87. Found: C, 63.16; H, 5.04; N, 15.23; S, 8.45.

Example 22 3-Amino-4-morpholin-4-ylthieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-41)

(22a) (2Z) -2-cyano-3-morpholin-1-ylbuta-2-enthioamide

Morpholine was used instead of propylamine, and it reacted like the method of Example 4 (4a), and obtained the title compound. Yield 85%.

Mp 156-160 ° C .;

IR (KBr) ν _max 3374, 3255, 3165, 2177, 1605, 1540, 1119, 985, 884 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.26 (3H, s), 3.36-3.39 (4H, m), 3.64-3.67 (4H, m), 8.38 (1H, br), 9.06 (1H, br) ;

MS (FAB) m / z: 212 [M + H] ⁺ ;

analysis. Calc. For C ₉ H ₁₃ N ₃ SO: C, 51.16; H, 6. 20; N, 19.89; S, 15.18. Found: C, 51.15; H, 6. 14; N, 19.73; S, 15.17.

(22b) 4-morpholin-1-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

4- (dimethoxymethyl) morpholine (Nucleosides and Nucleotides, 12, 1033-1046, (1993)) was used instead of N, N-dimethylformamidedimethylacetal, and (2Z) -2-cyano-3- Example 14 (14b) using (2Z) -2-cyano-3-morpholin-1-ylbuta-2-enthioamide in place of piperidin-1-ylbuta-2-enthioamide The reaction was carried out in the same manner as described in the above. Insoluble matters were removed from the reaction mixture by filtration, and the resulting aqueous solution was neutralized with 1N hydrochloric acid. The precipitated solid was obtained by filtration and washed with water and ethanol to obtain the crude product of the title compound. Yield 43%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.62-3.65 (4H, m), 3.69-3.71 (4H, m), 6.51 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz) 12.75 (1H, broad singlet).

(22c) 3-amino-4-morpholin-4-ylthieno [2,3-b] pyridine-2-carboxamide

4-Morpholin-1-yl-2- produced in Example 22 (22b) instead of 4-piperidin-1-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as in the method described in Example 14 (14c) using thioxo-1,2-dihydropyridine-3-carbonitrile to obtain the title compound. Yield 64%.

Mp 232-234 ° C .;

IR (KBr) ν _max 3427, 3377, 3170, 1670, 1579, 1501, 1373, 1112, 969 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.90-3.15 (4H, m), 3.84-3.86 (4H, m), 6.95 (2H, br), 7.05 (1H, d, J = 5.3 Hz), 7.13 (2H, br), 8.46 (1H, doublet, J = 5.3 Hz);

MS (FAB) m / z: 279 [M + H] ⁺ ;

analysis. Calc. For C ₁₂ H ₁₄ N ₄ SO ₂ .0.3H ₂ O: C, 50.80; H, 5. 19; N, 19.75; S, 11.30. Found: C, 50.95; H, 4.86; N, 19.72; S, 11.28.

Example 23 3-amino-4- (cis-2,6-dimethylmorpholin-4-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-42)

(2Z) -2-cyano-3-ethoxybuta-2-enthioamide (340 mg, 2.0 mmol) and cis-2,6-dimethylmorpholine (288 mg, 2.5 mmol) in ethanol (3 mL) It mixed and stirred at room temperature for 4 hours. The residue obtained by distilling a solvent off under reduced pressure was dissolved in N, N-dimethylformamide (3 mL), and N, N-dimethylformamide dimethylacetal (262 mg, 2.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then at 100 ° C for 1 hour. After cooling to room temperature, 8N aqueous sodium hydroxide solution (0.4 mL) and 2-chloroacetamide (243 mg, 2.6 mmol) were added to the reaction mixture. After stirring at room temperature for 1 hour, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / ethanol / triethylamine = 30: 1: 1) to give 100 mg of the title compound (16%).

Mp 242-244 ° C .;

IR (KBr) ν _max 3441, 3326, 3172, 1650, 1584, 1502, 1373, 1082, 1010 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.13 (6H, d, J = 6.3 Hz), 2.40-2.50 (2H, m), 3.24 (2H, brd, J = 11.3 Hz), 3.90-3.98 (2H , m), 6.92 (2H, br), 7.03 (1H, doublet, J = 5.1 Hz), 7.16 (2H, br), 8.45 (1H, d, J = 5.1 Hz);

MS (EI) m / z: 306 [M ⁺ ], 202;

analysis. Calc. For C ₁₄ H ₁₈ N ₄ SO ₂ : C, 54.88; H, 5.92; N, 18.29; S, 10.47. Found: C, 54.88; H, 5.99; N, 18.37; S, 10.43.

Example 24 3-Amino-4-thiomorpholin-4-ylthieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-44)

(24a) (2Z) -2-cyano-3-thiomorpholin-4-ylbuta-2-enthioamide

Thiomorpholine was used instead of isobutylamine, and it reacted like the method of Example 5 (5a), and obtained the title compound. Yield 73%.

Mp 157-160 ° C. (decomposition);

IR (KBr) ν _max 3346, 3285, 3180, 2183, 1534, 953, 865 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.26 (3H, s), 2.72-2.74 (4H, m), 3.58-3.61 (4H, m), 8.43 (1H, br), 9.11 (1H, br) ;

MS (FAB) m / z: 228 [M + H] ⁺ ;

analysis. Calc. For C ₉ H ₁₃ N ₃ S ₂ .0.1H ₂ O: C, 47.17; H, 5.81; N, 18.34; S, 27.98. Found: C, 47.27; H, 5. 82; N, 18.62; S, 27.84.

(24b) 4-thiomorpholin-4-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3-thiomorpholine-4 prepared in Example 24 (24a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b), using -buta-2-enthioamide (250 mg) to obtain a crude product (157 mg) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.74-2.77 (4H, m), 3.84-3.87 (4H, m), 6.49 (1H, d, J = 7.4 Hz), 7.48 (1H, brd, J = 7.4 Hz), 12.73 (1H, broad singlet).

(24c) 3-amino-4-thiomorpholin-4-ylthieno [2,3-b] pyridine-2-carboxamide

The crude product (157 mg) of 4-thiomorpholin-4-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 24 (24b) was N, N-dimethyl It was dissolved in formamide (2 mL), and 8N aqueous sodium hydroxide solution (0.2 mL) and 2-chloroacetamide (74 mg, 0.8 mmol) were added. After stirring for 1 hour at room temperature, the reaction mixture was added with water (2 mL). The precipitated solid was obtained by filtration and washed with water and ethanol. The obtained crystal was further stirred by heating in ethyl acetate. After cooling, the crystals were filtered off to obtain 37 mg of the title compound. Yield 11% from (2Z) -2-cyano-3-thiomorpholin-4-ylbuta-2-enthioamide.

Mp 255-258 ° C .;

IR (KBr) ν _max 3439, 3322, 3166, 1656, 1582, 1502, 1374, 1344, 935 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.50-3.60 (8H, m), 6.93 (2H, br), 7.04 (1H, d, J = 5.3 Hz), 7.10 (2H, br), 8.43 (1H , d, J = 5.3 Hz);

MS (EI) m / z: 294 [M ⁺ ], 202;

analysis. Calc. For C ₁₂ H ₁₄ N ₄ S ₂ O: C, 48.96; H, 4.79; N, 19.03; S, 21.78. Found: C, 48.90; H, 4. 70; N, 19.04; S, 21.73.

Example 25 3-Amino-4-azane-1-ylthieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-39)

(25a) (2Z) -3-Azepan-1-yl-2-cyanobuta-2-enthioamide

Hexamethyleneimine was used instead of isobutylamine, and it reacted like the method described in Example 5 (5a), and obtained the title compound. Yield 94%.

Mp 158-161 ° C .;

IR (KBr) ν _max 3405, 3292, 3184, 2192, 1607, 1517, 1009, 870 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.61-1.70 (4H, m), 1.87-1.95 (4H, m), 2.74 (3H, s), 3.70-3.73 (4H, m), 6.69 (2H, br) ;

MS (EI) m / z: 223 [M ⁺ ], 190;

analysis. Calc. For C ₁₁ H ₁₇ N ₃ S: C, 59.16; H, 7.67; N, 18.81; S, 14.36. Found: C, 59.10; H, 7.72; N, 18.67; S, 14.07.

(25b) 4-Azepan-1-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3-azepane-1-yl-2-cya prepared in Example 25 (25a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b) using nobuta-2-enthioamide (0.42 g), to obtain a crude product (0.38 g) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.49-1.54 (4H, m), 1.73-1.80 (4H, m), 3.75-3.78 (4H, m), 6.39 (1H, d, J = 7.8 Hz) , 7.37 (1H, doublet of doublets, J = 6.0, 7.8 Hz), 12.46 (1H, br).

(25c) 3-amino-4-azane-1-ylthieno [2,3-b] pyridine-2-carboxamide

4-Azepan-1-yl-2-thioxo prepared in Example 25 (25b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The crude product (0.38 g) of -1,2-dihydropyridine-3-carbonitrile was used to carry out the reaction in the same manner as in Example 5 (5c) to obtain 0.39 g of the titled compound. 71% yield from (2Z) -3-azpan-1-yl-2-cyanobuta-2-enthioamide.

Mp 219-221 ° C .;

IR (KBr) ν _max 3436, 3298, 3131, 1673, 1582, 1371, 930 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.65-1.78 (8H, m), 3.25-3.28 (4H, m), 7.04 (4H, br), 7.05 (1H, d, J = 5.4 Hz), 8.38 (1H, doublet, J = 5.4 Hz);

MS (EI) m / z: 290 [M ⁺ ], 202.

Example 26 3-Amino-4-azokane-1-ylthieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-40)

(26a) (2Z) -3-azono-1-yl-2-cyanobuta-2-enthioamide

Heptamethyleneimine was used instead of isobutylamine, and it reacted like the method of Example 5 (5a), and obtained the title compound. Yield 85%.

Mp 149-150 ° C .;

IR (KBr) ν _max 3340, 3276, 3164, 2176, 1631, 1558, 848 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.45-1.52 (6H, m), 1.72-1.75 (4H, m), 2.34 (3H, s), 3.55-3.58 (4H, m), 8.30 (1H, br), 8.92 (1 H, broad singlet);

MS (FAB) m / z: 238 [M + H] ⁺ ;

analysis. Calc. For C ₁₂ H ₁₉ N ₃ S.0.06H ₂ 0: C, 60.45; H, 8.08; N, 17.62; S, 13.45. Found: C, 60.43; H, 7.93; N, 17.67; S, 13.58.

(26b) 4-Azocan-1-yl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3-azono-1-yl-2-cya prepared in Example 26 (26a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b), using nobuta-2-enthioamide (0.39 g) to obtain a crude product (0.35 g) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.44-1.57 (6H, m), 1.71-1.74 (4H, m), 3.80-3.83 (4H, m), 6.38 (1H, d, J = 7.7 Hz) , 7.35-8.38 (1 H, m), 12.48 (1 H, br).

(26c) 3-amino-4-azokane-1-ylthieno [2,3-b] pyridine-2-carboxamide

4-Azocan-1-yl-2-thioxo prepared in Example 26 (26b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Using the crude product (0.35 g) of -1,2-dihydropyridine-3-carbonitrile, the reaction was carried out in the same manner as in Example 5 (5c) to obtain 0.36 g of the title compound. Yield 72% from (2Z) -3-azono-1-yl-2-cyanobuta-2-enthioamide.

Mp 222-224 ° C .;

IR (KBr) ν _max 3440, 3300, 3132, 1667, 1579, 1499, 1372, 990 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.60-1.75 (10H, m), 3.34-3.36 (4H, m), 7.03 (2H, br), 7.04 (2H, br), 7.08 (1H, d, J = 5.4 Hz), 8.35 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 305 [M + H] ⁺ ;

analysis. Calc. For C ₁₅ H ₂₀ N ₄ SO: C, 58.84; H, 6.65; N, 18.30; S, 10.47. Found: C, 58.84; H, 6.53; N, 18.30; S, 10.37.

Example 27 3-Amino-4- (3,4-dihydroisoquinolin-2 (1H) -yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1- 35)

(27a) (2Z) -2-cyano-3- (3,4-dihydroisoquinolin-2 (1H) -yl) buta-2-enthioamide

Instead of isobutylamine, 1,2,3,4-tetrahydroisoquinoline was used, and reaction was carried out in the same manner as in Example 5 (5a) to obtain the title compound. Yield 93%.

IR (KBr) ν _max 3284, 3167, 2186, 1609, 1538, 878, 752 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.38 (3H, s), 2.95 (2H, t, J = 5.8 Hz), 3.62 (2H, t, J = 5.8 Hz), 4.54 (2H, s), 7.10-7.21 (4 H, m), 8.32 (1 H, br) 8.98 (1 H, br);

MS (EI) m / z: 257 [M ⁺ ], 224.

(27b) 4- (3,4-dihydroisoquinolin-2 (1H) -yl) -2-thioxo-1,2-dihydropyridine- 3-carbonitrile

(2Z) -2-cyano-3- (3,4- produced in Example 27 (27a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The crude product of the title compound was reacted in the same manner as described in Example 1 (1b) using dihydroisoquinolin-2 (1H) -yl) buta-2-enthioamide (470 mg). 175 mg).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.00 (2H, t, J = 5.9 Hz), 3.88 (2H, t, J = 5.9 Hz), 4.76 (2H, s), 6.58 (1H, d, J = 7.4 Hz), 7.22-7.25 (4H, m), 7.51-7.54 (1H, m) 12.72 (1H, br).

(27c) 3-amino-4- (3,4-dihydroisoquinolin-2 (1H) -yl) thieno [2,3-b] pyridine-2-carboxamide

4- (3,4-dihydroisoquinoline-2 prepared in Example 27 (27b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as described in Example 5 (5c) using a crude product (175 mg) of (1H) -yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile. It carried out and obtained the title compound (71 mg). Yield 12% from (2Z) -2-cyano-3- (3,4-dihydroisoquinolin-2 (1H) -yl) buta-2-enthioamide.

Mp 244-245 ° C .;

IR (KBr) ν _max 3395, 3325, 3144, 1659, 1585, 1502, 1378, 739 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.94-3.10 (2H, m), 3.33-3.50 (2H, m), 4.28 (2H, brs), 6.85 (2H, br), 7.08 (1H, d, J = 5.5 Hz), 7.09 (2H, br), 7.17-7.19 (4H, m), 8.44 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 325 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₁₆ N ₄ SO: C, 62.94; H, 4.97; N, 17.27; S, 9.88. Found: C, 62.69; H, 5. 24; N, 17.21; S, 9.85.

Example 28 3-Amino-4- (trans-perhydroisoquinolin-2-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-36)

(28a) (2Z) -2-cyano-3- (trans-perhydroisoquinolin-2-yl) buta-2-enthioamide

Using the trans-perhydroisoquinoline instead of isobutylamine, it carried out similarly to the method of Example 5 (5a), and obtained the title compound. Yield 41%.

Mp 142-147 ° C .;

IR (KBr) ν _max 3375, 3277, 3163, 2184, 1606, 1537, 872 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.88-1.72 (12H, m), 2.27 (3H, s), 2.71-2.77 (1H, m), 3.04-3.11 (1H, m), 3.49-3.51 ( 1 H, m), 3.64-3.68 (1 H, m), 8.15 (1 H, br), 8.87 (1 H, br);

MS (FAB) m / z: 264 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₂₁ N ₃ S: C, 63.84; H, 8.04; N, 15.95; S, 12.17. Found: C, 63.92; H, 7.98; N, 15.93; S, 11.91.

(28b) 4- (trans-perhydroisoquinolin-2-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (trans-perhydro) prepared in Example 28 (28a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b) using isoquinolin-2-yl) buta-2-enthioamide (210 mg) to obtain a crude product (153 mg) of the title compound. .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.91-1.74 (12H, m), 2.75-2.81 (1H, m), 3.09-3.15 (1H, m), 3.94-4.00 (1H, m), 4.10- 4.17 (1H, m), 6.48 (1H, d, J = 7.4 Hz), 7.39-7.43 (1H, m), 12.56 (1H, br).

(28c) 3-amino-4- (trans-perhydroisoquinolin-2-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (trans-perhydroisoquinolin-2-yl, prepared in Example 28 (28b), instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as described in Example 5 (5c) using a crude product of -2--2-oxo-1,2-dihydropyridine-3-carbonitrile (153 mg) to obtain the title compound ( 115 mg) was obtained. 44% yield from (2Z) -2-cyano-3- (trans-perhydroisoquinolin-2-yl) buta-2-enthioamide.

Mp 285-288 ° C .;

IR (KBr) ν _max 3406, 3323, 3143, 1656, 1584, 1502, 1377, 951 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.92-1.76 (12H, m), 2.34-2.45 (1H, m), 2.66-2.79 (1H, m), 3.14-3.22 (1H, m), 3.30- 3.38 (1H, m), 6.92 (2H, br), 7.01 (1H, d, J = 5.1 Hz), 7.10 (2H, br), 8.42 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 331 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₂ N ₄ SO: C, 61.79; H, 6. 71; N, 16.95; S, 9.70. Found: C, 61.63; H, 6. 71; N, 16.94; S, 9.74.

Example 29 3-Amino-4- (cis-perhydroisoquinolin-2-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-36)

(29a) (2Z) -2-cyano-3- (cis-perhydroisoquinolin-2-yl) buta-2-enthioamide

Cis-perhydroisoquinoline was used instead of isobutylamine, and it reacted like the method of Example 5 (5a), and obtained the title compound. Yield 95%.

Mp 173-175 ° C .;

IR (KBr) ν _max 3444, 3250, 3160, 2188, 1603, 1542, 867 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.23-1.95 (12H, m), 2.27 (3H, s), 3.12-3.25 (2H, m), 3.41-3.54 (2H, m), 8.12 (1H, br), 8.85 (1H, broad singlet);

MS (FAB) m / z: 264 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₂₁ N ₃ S: C, 63.84; H, 8.04; N, 15.95; S, 12.17. Found: C, 63.53; H, 8. 10; N, 15.67; S, 12.32.

(29b) 4- (cis-perhydroisoquinolin-2-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (cis-perhydro) prepared in Example 29 (29a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in the method described in Example 1 (1b) using isoquinolin-2-yl) buta-2-enthioamide (490 mg) to obtain a crude product of the title compound (370 mg). .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.22-1.95 (12H, m), 3.10-3.43 (2H, m), 3.78-3.94 (2H, m), 6.47 (1H, d, J = 7.4 Hz) , 7.40 (1 H, d, J = 7.4 Hz), 12.40 (1 H, br).

(29c) 3-amino-4- (cis-perhydroisoquinolin-2-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (cis-perhydroisoquinolin-2-yl, prepared in Example 29 (29b), instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as described in Example 5 (5c) using a crude product (370 mg) of) -2-thioxo-1,2-dihydropyridine-3-carbonitrile to give the titled compound ( 200 mg) was obtained. 33% yield from (2Z) -2-cyano-3- (cis-perhydroisoquinolin-2-yl) buta-2-enthioamide.

Mp 224-226 ° C .;

IR (KBr) ν _max 3443, 3323, 3179, 1646, 1582, 1503, 1370, 957 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.20-2.25 (12H, m), 2.92-3.46 (4H, m), 6.93 (2H, br), 7.03 (1H, d, J = 5.1 Hz), 7.08 (2H, br), 8.40 (1H, doublet, J = 5.1 Hz);

MS (EI) m / z: 330 [M ⁺ ], 285;

analysis. Calc. For C ₁₇ H ₂₂ N ₄ SO.0.1H ₂ O: C, 61.46; H, 6.73; N, 16.86; S, 9.65. Found: C, 61.37; H, 6.76; N, 16.80; S, 9.68.

Example 30 3-amino-4- (1,4-oxazepan-4-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-43)

(30a) (2Z) -2-cyano-3- (1,4-oxazepan-4-yl) buta-2-enthioamide

Homomorpholine was used instead of isobutylamine, and reaction was carried out similarly to the method described in Example 5 (5a) to synthesize the title compound.

Pale yellow powder

Mp 151-156 ° C .;

IR (KBr) ν _max 3348, 3285, 3174, 2184, 1632, 1518, 1417, 1127, 1075, 878, 814 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.86-1.92 (2H, m), 2.31 (3H, s), 3.57 (2H, t, J = 5.5 Hz), 3.62 (2H, t, J = 5.5 Hz), 3.66 (2H, t, J = 5.5 Hz), 3.77 (2H, t, J = 5.5 Hz), 8.29 (1H, brs), 8.94 (1H, brs);

HRMS m / z calc'd C ₁₀ H ₁₆ ON ₃ S 226.1014, found 226.1019;

MS (FAB) m / z: 226 [M + H] ⁺ , 209, 192, 165, 65, 51.

(30b) 4- (1,4-oxazepan-4-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (1,4) prepared in Example 30 (30a) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 5 (5b) using -oxazane-4-yl) buta-2-enthioamide to obtain the title compound.

White powder

Mp 228-233 ° C. (decomposition);

IR (KBr) ν _max 3119, 2952, 2210, 1625, 1520, 1252, 1117, 928, 780 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.94 (2H, m), 3.67 (2H, t, J = 5.5 Hz), 3.77-3.79 (2H, m), 3.33-3.37 (4H, m ), 6.44 (1H, d, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 12.59 (1H, brs);

HRMS m / z calc'd C ₁₁ H ₁₃ ON ₃ S 235.0779, found 235.0790;

MS (EI) m / z: 235 [M ⁺ ], 204, 190, 177, 164, 150, 136, 108, 76, 70, 41.

(30c) 3-amino-4- (1,4-oxazepan-4-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (1,4-oxazepan-4-yl, prepared in Example 30 (30b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was obtained in the same manner as described in Example 5 (5c) using 2-2-thioxo-1,2-dihydropyridine-3-carbonitrile.

White powder

Mp 175-176 ° C .;

IR (KBr) ν _max 3445, 3301, 3141, 1671, 1585, 1497, 1370, 1153, 1060, 940 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.99-2.05 (2H, m), 3.30-3.34 (4H, m), 3.78-3.84 (4H, m), 7.05 (2H, brs), 7.08-7.10 (3H, m), 8.41 (1H, d, J = 5.5 Hz);

HRMS m / z calc. For C ₁₃ H ₁₇ O ₂ N ₄ S 293.1073, found 293.1067;

MS (FAB) m / z: 293 [M + H] ⁺ , 276, 237, 183, 165, 120, 65;

analysis. Calc. For C ₁₃ H ₁₆ N ₄ O ₂ S.0.28H ₂ O: C, 52.50; H, 5.61; N, 18.84; S, 10.78. Found: C, 52.32; H, 5.41; N, 19.03, S, 10.77.

Example 31 3-amino-4- (4-phenylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-26)

(31a) (2Z) -2-cyano-3- (4-phenylpiperidin-1-yl) buta-2-enthioamide

4-phenyl piperidine was used instead of isobutylamine, and the reaction was carried out in the same manner as described in Example 5 (5a) to synthesize the title compound.

Pale yellow powder

Mp 171-172 ° C .;

IR (KBr) ν _max 3389, 3263, 3162, 2185, 1599, 1535, 1364, 1232, 980, 855, 764, 701 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.69-1.86 (4H, m), 2.33 (3H, s), 2.83-2.91 (1H, m), 3.22 (2H, t, J = 12.1 Hz), 3.76 (2H, doublet, J = 12.1 Hz), 7.19-7.83 (5H, m), 8.28 (1H, brs), 8.98 (1H, brs);

HRMS m / z calc. C ₁₆ H ₂₀ N ₃ S 286.1378, found 286.1372;

MS (FAB) m / z: 286 [M + H] ⁺ , 252, 227, 186, 80, 56, 41;

analysis. Calc. For C ₁₆ H ₁₉ N ₃ S: C, 67.33; H, 6. 71; N, 14.72; S, 11.23. Found: C, 67.10; H, 6.75; N, 14.65, S, 11.17.

(31b) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- (4-phenylpiperidin-1-yl) buta-2-enthioamide

(2Z) -2-cyano-3- (4-phenylpiperidin-1-yl) buta-2-enthioamide (373 mg, 1.3 mmol) and N, N prepared in Example 31 (31a) -Dimethylformamide dimethylacetal (312 mg, 2.6 mmol) was mixed with ethanol (12 mL) and stirred for 18 hours. The precipitated solid was obtained by filtration to obtain 446 mg (yield 70%) of the title compound.

Yellow powder

Mp 151-152 ° C .;

IR (KBr) ν _max 2920, 2182, 1614, 1520, 1333, 1289, 1191, 975, 767, 704 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.79-1.91 (4H, m), 2.55 (3H, s), 2.94-3.00 (1H, m), 3.02 (3H, s) 3.18 (3H, s) , 3.30-3.36 (2H, m), 3.93 (2H, d, J = 13.7 Hz), 7.20-7.83 (5H, m), 8.55 (1H, s);

HRMS m / z calc. C ₁₉ H ₂₅ N ₄ S 341.1800, found 341.1797;

MS (FAB) m / z: 341 [M + H] ⁺ , 273, 246, 200, 165, 63;

analysis. Calc. For C ₁₉ H ₂₄ N ₄ S.0.26H ₂ O: C, 66.11; H, 7. 16; N, 16.23; S, 9.29. Found: C, 66.15; H, 6.97; N, 16.14, S, 8.99.

(31c) 3-amino-4- (4-phenylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- (4-phenylpiperidin-1-yl) buta-2- made in Example 31 (31b) A solution of N, N-dimethylformamide (1.8 mL) of enthioamide (299 mg, 0.88 mmol) was stirred at 80 ° C. for 15 minutes. After the reaction mixture was cooled to room temperature, 8N aqueous sodium hydroxide solution (0.37 mL) and 2-chloroacetamide (99 mg, 1.1 mmol) were added. The mixture was stirred at room temperature for 1 hour, and then water and ethyl acetate were added. The precipitated solid was obtained by filtration to obtain 310 mg of the title compound (yield 58%).

Pale yellow crystals

Mp 226-233 ° C .;

IR (KBr) ν _max 3445, 3315, 3130, 1647, 1580, 1501, 1371, 1229, 1052, 959, 701 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.90 (2H, d, J = 11.7 Hz), 2.03 (2H, q, J = 11.7 Hz), 2.70 (1H, t, J = 11.7 Hz), 2.82 -2.91 (2H, m), 3.45 (2H, d, J = 11.7 Hz), 7.02 (2H, brs), 7.07 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 7.22 (1H, t, J = 7.3 Hz), 7.33 (2H, t, J = 7.3 Hz), 7.38 (2H, d, J = 7.3 Hz), 8.46 (1H, d, J = 5.4 Hz);

HRMS m / z calc. C ₁₉ H ₂₀ ON ₄ S 352.1358, found 352.1358;

MS (FAB) m / z: 353 [M + H] ⁺ , 273, 246, 200, 165, 63.

Example 32 3-Amino-4- (1-oxothiomorpholin-4-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-45)

3-amino-4- (thiomorpholin-4-yl) thieno [2,3-b] pyridine-2-carboxamide (73 mg, 0.25 mmol) prepared in Example 24 (24c) was added to methanol. It dissolved and added the aqueous solution (1 mL) of sodium periodate (59 mg, 0.28 mmol). After stirring for 1 hour at room temperature, saturated brine was added to the reaction solution, and the aqueous layer was extracted with a methylene chloride / 2-propanol (4: 1) mixed solvent. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was washed with ether to give 78 mg (yield 92%) of the title compound.

Pale yellow powder

Mp 165-172 ° C .;

IR (KBr) ν _max 3431, 3323, 3183, 1649, 1589, 1500, 1375, 1057, 933 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.95-3.04 (2H, m), 3.21-3.32 (4H, m), 3.52-3.57 (2H, m), 6.99 (2H, brs), 7.15 (3H , brs), 8.48 (1H, doublet, J = 5.4 Hz);

HRMS m / z calc. For C ₁₂ H ₁₄ O ₂ N ₄ S ₂ 310.0558, found 310.0555;

MS (EI) m / z: 310 [M ⁺ ], 278, 261, 244, 230, 202, 189, 176, 148, 122, 101, 76.

Example 33 3-amino-4- (1,4-thiazepan-4-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-46)

(33a) (2Z) -2-cyano-3- (1,4-thiazepan-4-yl) buta-2-enthioamide

Instead of isobutylamine, homothiomorpholine (J.Org.Chem., 25, 1953-1956 (1960)) was used, and the reaction was carried out in the same manner as in Example 5 (5a) to synthesize the title compound. It was.

White powder

Mp 138-142 ° C .;

IR (KBr) ν _max 3438, 23284, 3173, 1597, 1533, 1409, 1251, 867, 569 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.95-2.01 (2H, m), 2.33 (3H, s), 2.67 (2H, t, J = 5.9 Hz), 2.94 (2H, t, J = 5.5 Hz), 3.65 (2H, t, J = 5.9 Hz), 3.70 (2H, t, J = 5.5 Hz), 8.46 (1H, brs), 9.07 (1H, brs);

HRMS m / z calc. C ₁₀ H ₁₅ N ₃ S ₂ 241.0707, found 241.0707;

MS (EI) m / z: 241 [M ⁺ ], 208, 182, 142, 135, 121, 96, 68, 59, 43;

analysis. Calc. For C ₁₀ H ₁₅ N ₃ S ₂ : C, 49.76; H, 6. 26; N, 17.41; S, 26.57. Found: C, 49.47; H, 6. 32; N, 17.14, S, 26.48.

(33b) 4- (1,4-thiazepan-4-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (1,4) prepared in Example 33 (33a) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide The title compound was obtained in the same manner as in Example 5 (5b) using -thiazepan-4-yl) buta-2-enthioamide.

Yellow powder

Mp 265-270 ° C .;

IR (KBr) ν _max 3115, 2949, 2207, 1625, 1524, 1256, 1136, 943, 788 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.96 (2H, quint, J = 5.5 Hz), 2.62 (2H, t, J = 5.9 Hz), 2.90 (2H, t, J = 5.9 Hz), 3.97 (2H, t, J = 5.9 Hz), 4.04 (2H, t, J = 5.9 Hz), 6.42 (1H, d, J = 7.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 12.48 (1H , brs);

HRMS m / z calc'd C ₁₁ H ₁₃ N ₃ S ₂ 251.0551, found 251.0553;

MS (EI) m / z: 251 [M ⁺ ], 236, 223, 204, 190, 177, 164, 150, 136, 108, 60;

analysis. Calc. For C ₁₁ H ₁₃ N ₃ S ₂ : C, 52.56; H, 5. 21; N, 16.72; S, 25.51. Found: C, 52.41; H, 5. 37; N, 17.01, S, 25.62.

(33c) 3-amino-4- (1,4-thiazepan-4-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (1,4-thiazepan-4-yl, prepared in Example 33 (33b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as in Example 5 (5c), using -2--2-oxo-1,2-dihydropyridine-3-carbonitrile to obtain the title compound.

Pale yellow powder

Mp 171-174 ° C .;

IR (KBr) ν _max 3416, 3302, 3171, 1645, 1582, 1498, 1367, 1259, 1125, 481 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.94-1.99 (2H, m), 2.76 (2H, t, J = 5.9 Hz), 2.98 (2H, t, J = 5.9 Hz), 3.29-3.32 ( 2H, m), 3.44-3.46 (2H, m), 7.07 (2H, brs), 7.20 (1H, d, J = 5.4 Hz), 7.41 (2H, brs), 8.46 (1H, d, J = 5.4 Hz );

HRMS m / z calc'd C ₁₃ H ₁₆ ON ₄ S ₂ 308.0765, found 308.0767;

MS (EI) m / z: 308 [M ⁺ ], 276, 244, 230, 202, 188, 176, 148, 122, 78, 45;

analysis. Calc. For C ₁₃ H ₁₆ N ₄ OS ₂ .0.66H ₂ O: C, 48.75; H, 5. 45; N, 17.49. Found: C, 48.44; H, 5. 38; N, 17.79.

(Example 34) 3-amino-4- (1-oxo-1,4-thiazepan-4-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-47 )

3-amino-4- (1) prepared in Example 33 (33c) instead of 3-amino-4- (thiomorpholin-4-yl) thieno [2,3-b] pyridine-2-carboxamide Using the 4-4-thiazepan-4-yl) thieno [2,3-b] pyridine-2-carboxamide, the reaction was carried out in the same manner as in Example 32 to obtain the title compound.

Pale yellow powder

Mp 111-119 ° C .;

IR (KBr) ν _max 3432, 3321, 1648, 1590, 1499, 1368, 1035 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 2.03-2.11 (1H, m), 2.59-2.67 (1H, m), 2.98-3.11 (2H, m), 3.19-3.30 (2H, m), 3.36-3.54 (3H, m), 3.91-3.96 (1H, m), 5.30 (2H, brs), 7.00 (1H, d, J = 4.9 Hz), 7.15 (2H, brs), 8.53 (1H, d, J = 4.9 Hz);

HRMS m / z calc'd C ₁₃ H ₁₇ O ₂ N ₄ S ₂ 325.0793, found 325.0774;

MS (FAB) m / z: 325 [M + H] ⁺ , 273, 178, 165, 51;

Example 35 3-amino-4- (3-phenylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-25)

(35a) (2Z) -2-cyano-3- (3-phenylpiperidin-1-yl) buta-2-enthioamide

3-phenylpiperidine was used instead of isobutylamine, and the reaction was carried out in the same manner as described in Example 5 (5a) to synthesize the title compound.

Light brown powder

Mp 159-162 ° C. (decomposition);

IR (KBr) ν _max 3307, 3184, 2190, 1600, 1533, 1412, 1260, 978, 850, 703 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.65-1.94 (4H, m), 2.32 (3H, s), 2.85-2.91 (1H, m), 3.12-3.19 (2H, m), 3.63 (1H , d, J = 11.2 Hz), 3.74 (1H, d, J = 11.2 Hz), 7.22-7.33 (5H, m), 8.30 (1H, brs), 8.99 (1H, brs);

HRMS m / z calc. C ₁₆ H ₁₉ N ₃ S 285.1299, found 285.1286;

MS (EI) m / z: 285 [M ⁺ ], 251, 226, 186, 160, 135, 109, 104, 91, 59;

analysis. Calc. For C ₁₆ H ₁₉ N ₃ S: C, 67.33; H, 6. 71; N, 14.72; S, 11.23. Found: C, 67.25; H, 6.81; N, 14.53, S, 11.04.

(35b) 4- (3-phenylpiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (3-phenyl produced in Example 35 (35a) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide Using the piperidin-1-yl) buta-2-enthioamide, it carried out similarly to the method described in Example 5 (5b), and obtained the title compound.

Light brown powder

Mp 236-238 ° C. (decomposition);

IR (KBr) ν _max 3118, 2939, 2208, 1622, 1515, 1449, 1309, 1251, 1164, 974, 758, 700 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.64-1.98 (4H, m), 2.84-2.90 (1H, m), 3.18-3.22 (2H, m), 4.12-4.15 (2H, m), 6.55 (1H, d, J = 7.3 Hz), 7.22-7.86 (5H, m), 7.46 (1H, d, J = 7.3 Hz), 12.66 (1H, brs);

HRMS m / z calc'd C ₁₇ H ₁₈ N ₃ S 296.1222, found 296.1196;

MS (FAB) m / z: 296 [M + H] ⁺ , 273, 242, 165, 65, 51;

(35c) 3-amino-4- (3-phenylpiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (3-phenylpiperidin-1-yl, prepared in Example 35 (35b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was obtained in the same manner as described in Example 5 (5c) using 2-2-thioxo-1,2-dihydropyridine-3-carbonitrile.

Pale yellow powder

Mp 267-269 ° C .;

IR (KBr) ν _max 3444, 3328, 3173, 2932, 1643, 1578, 1500, 1370, 1247, 1053, 966, 700 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.58-1.73 (1H, m), 1.86-2.02 (3H, m), 2.73-2.80 (2H, m), 3.09-3.16 (1H, m), 3.38 -3.41 (2H, m), 6.99 (2H, brs), 7.06 (1H, d, J = 5.1 Hz), 7.12 (2H, brs), 7.20-7.33 (5H, m), 8.43 (1H, d, J = 5.1 Hz);

HRMS m / z calc. C ₁₉ H ₂₀ ON ₄ S 352.1358, found 352.1360;

MS (EI) m / z: 352 [M ⁺ ], 334, 307, 274, 252, 233, 202, 176, 91, 77, 73;

analysis. Calc. For C ₁₉ H ₂₀ N ₄ OS.0.34H ₂ O: C, 63.64; H, 5.81; N, 15.62; S, 8.94. Found: C, 63.32; H, 5.57; N, 15.87, S, 8.69.

Example 36 3-amino-4- (3-hydroxypiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-27)

(36a) (2Z) -2-cyano-3- (3-hydroxypiperidin-1-yl) buta-2-enthioamide

3-hydroxypiperidine was used instead of isobutylamine, and the reaction was carried out in the same manner as described in Example 5 (5a) to synthesize the title compound.

Pale yellow powder

Mp 159-162 ° C. (decomposition);

IR (KBr) ν _max 3287, 2939, 2184, 1601, 1539, 1407, 1261, 1071, 859 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.42-1.52 (2H, m), 1.74-1.86 (2H, m), 2.27 (3H, s), 3.03 (1H, dd, J = 7.8, 13.3 Hz ), 3.11-3.16 (1H, m), 3.44 (1H, dd, J = 3.4, 13.3 Hz), 3.59-3.64 (1H, m), 5.01 (1H, d, J = 4.7 Hz), 8.14 (1H, brs), 8.91 (1H, broad singlet);

HRMS m / z calc'd C ₁₀ H ₁₆ ON ₃ S 226.1014, found 226.1024;

MS (FAB) m / z: 226 [M + H] ⁺ , 192, 171, 65;

analysis. Calc. For C ₁₀ H ₁₅ N ₃ OS.0.04H ₂ O: C, 53.14; H, 6. 72; N, 18.59; S, 14.19. Found: C, 53.00; H, 6.52; N, 18.47, S, 14.15.

(36b) 4- (3-hydroxypiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (3-hydrate) prepared in Example 36 (36a) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 5 (5b) using oxypiperidin-1-yl) buta-2-enthioamide to obtain the title compound.

Brown powder

Mp 202-206 ° C;

IR (KBr) ν _max 3119, 2945, 2208, 1625, 1522, 1251, 1173, 995, 962, 773 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.46-1.53 (2H, m), 1.79-1.88 (2H, m), 3.29 (1H, dd, J = 7.8, 13.2 Hz), 3.39-3.44 (1H , m), 3.60-3.71 (2H, m), 3.80 (1H, dd, J = 3.4, 13.2 Hz), 6.48 (1H, d, J = 7.8 Hz), 7.44 (1H, d, J = 7.8 Hz) , 12.59 (1H, broad singlet).

(36c) 3-amino-4- (3-hydroxypiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (3-hydroxypiperidine-1-produced in Example 36 (36b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was obtained in the same manner as in the method described in Example 5 (5c) using il) -2-thioxo-1,2-dihydropyridine-3-carbonitrile.

Yellow powder

Mp 208-211 ° C;

IR (KBr) ν _max 3325, 1633, 1594, 1501, 1374, 1243, 959 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.60-2.02 (4H, m), 3.16-3.96 (5H, m), 6.38 (2H, brs), 6.99 (1H, d, J = 5.1 Hz), 7.05 (2H, broad singlet), 8.40 (1H, doublet, J = 5.1 Hz);

HRMS m / z calc'd C ₁₃ H ₁₆ O ₂ N ₄ S 292.0994, found 292.1013;

MS (EI) m / z: 292 [M ⁺ ], 274, 256, 252, 218, 201, 176, 148, 128, 122, 43;

analysis. Calc. For C ₁₃ H ₁₆ N ₄ O ₂ S.0.16H ₂ O: C, 52.89; H, 5.57; N, 18.98; S, 10.86. Found: C, 53.11; H, 5.55; N, 18.61, S, 10.86.

Example 37 tert-butyl4- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperazine-1-carboxylate (Example Compound No. 3 -75)

(37a) tert-butyl4-[(1Z) -3-amino-2-cyano-1-methyl-3-thioxoprop-1-enyl] piperazine-1-carboxylate

Instead of propylamine, tert-butylpiperazine-1-carboxylate was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 40%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.41 (9H, s), 2.27 (3H, s), 3.36-3.46 (8H, m), 8.36 (1H, s), 9.06 (1H, s).

(37b) tert-Butyl 4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperazine-1-carboxylate

Tert-butyl4-[(1Z) -3-amino-2- as prepared in Example 37 (37a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide Using the cyano-1-methyl-3-thioxoprop-1-enyl] piperazine-1-carboxylate, the reaction was carried out in the same manner as in Example 1 (1b) to obtain the title compound. . Yield 69%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.49 (9H, s), 3.44-3.49 (4H, m), 3.61-3.66 (4H, m), 6.45 (1H, d, J = 7.4 Hz), 6.49 (1H, doublet, J = 7.4 Hz).

(37c) tert-butyl4- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperazine-1-carboxylate

Tert-butyl4- (3-cyano-2-thio) prepared in Example 37 (37b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as described in Example 1 (1c) using oxo-1,2-dihydropyridin-4-yl) piperazine-1-carboxylate. Yield 90%.

Mp 198-203 ° C .;

IR (KBr) ν _max 3428, 3323, 3176, 2974, 1693, 1649, 1584, 1501, 1367, 1241, 1169, 1124, 976, 959, 825, 770 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.42 (9H, s), 3.25 (4H, s), 3.29 (4H, s), 6.95 (2H, br s), 7.03 (1H, d, J = 5.4 Hz), 7.12 (2H, broad singlet), 8.45 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 378 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₃ N ₅ O ₃ S.0.3H ₂ O: C, 53.33; H, 6.21; N, 18.29; S, 8.37. Found: C, 53.14; H, 5.86; N, 18.06; S, 8.41.

Example 38 3-Amino-4-piperazin-1-ylthieno [2,3-b] pyridine-2-carboxamide dihydrochloride (Example Compound No. 3-1)

Tert-butyl4- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperazine-1-carboxylate prepared in Example 37 (37c) 326 mg, 0.86 mmol) was suspended in 1,4-dioxane (10 mL), 4N hydrochloric acid-dioxane (4 mL) was added, and the mixture was stirred for 2 hours. After distilling off the solvent, the obtained yellow solid was dried in vacuo to obtain the title compound (316 mg, yield 100%).

Mp 270-280 ° C .;

IR (KBr) ν _max 3320, 3180, 2925, 2770, 2717, 1648, 1604, 1446, 1395, 1259, 1059, 973, 906, 797, 556, 540, 516 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.58-4.28 (8H, br s), 7.125 (1H, d, J = 5.1 Hz), 7.24 (2H, br s), 8.525 (1H, d, J = 5.1 Hz), 9.45 (2H, broad singlet);

MS (FAB) m / z: 278 [M + H] ⁺ ;

analysis. Calc. For C ₁₂ H ₁₅ N ₅ OS.2HCl.H ₂ O: C, 39.14; H, 5.20; N, 19.02. Found: C, 38.99; H, 5.13; N, 18.77.

Example 39 3-amino-4- (4-methylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-2)

(39a) (2Z) -2-cyano-3- (4-methylpiperazin-1-yl) buta-2-enthioamide

Instead of propylamine, 1-methylpiperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 85%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.18 (3H, s), 2.26 (3H, s), 2.38 (4H, m), 3.35 (4H, m), 8.29 (1H, br s), 8.99 (1H, br s).

(39b) 3-amino-4- (4-methylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (4-methylpiperazin-1-yl) buta-2-enthioamide (301 mg, 1.34 mmol) and dimethylformamidedimethyl prepared in Example 39 (39a) Acetal (0.53 mL, 4.01 mmol) was suspended in toluene (5 mL) and stirred for 3 minutes under heating to reflux. After cooling to room temperature, 1N aqueous sodium hydroxide solution (3.50 mL) was added to the residue obtained by distilling off the solvent, and the mixture was heated to reflux for 30 minutes. After cooling to room temperature, 4N hydrochloric acid-dioxane solution (5 mL) was added to adjust the pH value of the solution to about 3. The mixture was concentrated under reduced pressure, and 2-chloroacetamide (126 mg, 1.35 mmol), 8N aqueous sodium hydroxide solution (2.5 mL) and dimethylformamide (5 mL) were added to the residue, which was stirred for 3 hours. Water (10 mL) was added to the reaction mixture and allowed to stand for 1 week. The produced solid was filtered to obtain the title compound (99 mg, yield 26%).

Mp 260-263 ° C .;

IR (KBr) ν _max 3502, 3424, 3322, 3161, 2939, 2801, 1653, 1588, 1502, 1451, 1371, 1344, 1288, 1246, 1199, 973, 819, 737, 683, 625, 476 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.26 (3H, s), 2.40-2.72 (4H, br s), 2.85-3.22 (4H, br s), 6.89 (2H, br s), 7.00 ( 1H, d, J = 5.5 Hz), 7.07 (2H, s), 8.41 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 291 [M + H] ⁺ ;

analysis. Calc. For C ₁₃ H ₁₇ N ₅ OS.0.3H ₂ O: C, 52.61; H, 5.98; N, 23.60; S, 10.80. Found: C, 52.62; H, 5.79; N, 23.63; S, 10.92.

Example 40 3-Amino-4- (4-ethylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-3)

(40a) (2Z) -2-cyano-3- (4-ethylpiperazin-1-yl) buta-2-enthioamide

Instead of propylamine, 1-ethylpiperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 67%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.00 (3H, t, J = 7.0 Hz), 2.25 (3H, s), 2.36 (2H, q, J = 7.0 Hz), 2.49 (4H, m) , 3.36 (4H, m), 8.29 (1H, broad singlet), 8.99 (1H, broad singlet).

(40b) 3-amino-4- (4-ethylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (4-ethylpiperazin-1-yl) buta-2-enthioamide (299 mg, 1.25 mmol) and dimethylformamidedimethyl prepared in Example 40 (40a) Acetal (0.50 mL, 3.77 mmol) was suspended in toluene (5 mL) and stirred under heating to reflux for 3 minutes. After the reaction mixture was cooled to room temperature, 1N aqueous sodium hydroxide solution (3.50 mL) was added to the residue obtained by distilling off the solvent, and the mixture was heated to reflux for 40 minutes. After cooling to room temperature, the pH value of the solution was adjusted to 4 by adding 4N hydrochloric acid-dioxane solution (2 mL). The mixture was concentrated under reduced pressure, and 2-chloroacetamide (118 mg, 1.27 mmol), 8N aqueous sodium hydroxide solution (2.5 mL) and dimethylformamide (5 mL) were added to the resulting residue, and the mixture was stirred for 3 hours. Water (10 mL) was added to the reaction mixture, and after standing for 1 day, the produced solid was filtered to obtain the title compound (123 mg, yield 32%).

Mp 218-219 ° C .;

IR (KBr) ν _max 3425, 3316, 3173, 2968, 2821, 1644, 1581, 1503, 1448, 1375, 1346, 1243, 1136, 975, 826, 770, 735, 542, 478 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.04 (3H, t, J = 7.0 Hz), 2.415 (2H, q, J = 7.0 Hz), 2.46-3.24 (8H, br s), 6.89 (2H , s), 7.015 (1H, d, J = 5.5 Hz), 7.08 (2H, s), 8.415 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 306 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₁₉ N ₅ OS.0.5H ₂ O: C, 53.48; H, 6.41; N, 22.27; S, 10.20. Found: C, 53.54; H, 6.05; N, 22.17; S, 10.27.

Example 41 3-amino-4- (4-isopropylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-5)

(41a) (2Z) -2-cyano-3- (4-isopropylpiperazin-1-yl) buta-2-enthioamide

Instead of propylamine, 1-isopropylpiperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 67%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.955 (6H, d, J = 6.7 Hz), 2.25 (3H, s), 2.36 (2H, q, J = 7.0 Hz), 2.48 (4H, m) , 2.65 (1H, m), 3.34 (4H, m), 8.25 (1H, br s), 8.94 (1H, br s).

(41b) 3-amino-4- (4-isopropylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (4-isopropylpiperazin-1-yl) buta-2-enthioamide (299 mg, 1.18 mmol) and dimethylformamide prepared in Example 41 (41a) Dimethyl acetal (0.47 mL, 3.56 mmol) was suspended in toluene (5 mL) and stirred for 3 minutes under heating to reflux. After cooling to room temperature, 1N sodium hydroxide aqueous solution (3.50 mL) was added to the residue obtained by distilling a solvent off, and it heated and refluxed for 40 minutes. After cooling to room temperature, 1N hydrochloric acid (5 mL) was added to adjust the pH value of the solution to about 4. The resulting solid was removed by filtration, and the filtrate obtained was concentrated under reduced pressure. 2-chloroacetamide (153 mg, 1.64 mmol), 8N aqueous sodium hydroxide solution (5 mL) and dimethylformamide (1.5 mL) were added to the residue, followed by stirring for 3 hours. Water (10 mL) was added to the reaction mixture, and the resulting solid was filtered and washed with diisopropyl ether (4 x 3 mL) to obtain the title compound (137 mg, yield 28%).

Mp 240-243 ° C .;

IR (KBr) ν _max 3413, 3322, 3121, 2964, 2827, 1660, 1584, 1502, 1448, 1376, 1345, 1245, 1176, 1134, 982, 820, 766, 741, 646, 486 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.015 (6H, d, J = 6.3 Hz), 2.40-3.40 (9H, br s), 6.90 (2H, br s), 7.00 (1H, d, J = 5.5 Hz), 7.06 (2H, s), 8.40 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 319 [M + H] ⁺ ;

analysis. Calc. For C ₁₅ H ₂₁ N ₅ OS.0.19 H ₂ O: C, 55.80; H, 6.67; N, 21.69; S, 9.93. Found: C, 55.82; H, 6.53; N, 21.63; S, 10.06.

Example 42 3-amino-4- (4-phenylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-9)

(42a) (2Z) -2-cyano-3- (4-phenylpiperazin-1-yl) buta-2-enthioamide

Instead of propylamine, 1-phenylpiperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 60%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 3.27 (4H, m), 3.51 (4H, m), 6.78 (1H, t, J = 7.1 Hz), 6.92 (2H, d, J = 7.8 Hz), 7.21 (2H, m), 8.36 (1H, s), 9.05 (1H, s).

(42b) 4- (4-phenylpiperazin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (4-phenylpipepe) prepared in Example 42 (42a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using rajin-1-yl) buta-2-enthioamide to obtain the title compound. Yield 77%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.31 (4H, m), 3.80 (4H, m), 6.535 (1H, d, J = 6.6 Hz), 6.79 (1H, t, J = 7.4 Hz) , 6.93 (2H, d, J = 7.8 Hz), 7.14-7.25 (2H, m), 7.50 (2H, dd, J = 6.9, 7.4 Hz).

(42c) 3-amino-4- (4-phenylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-phenylpiperazin-1-yl)-made in Example 42 (42b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as in the method described in Example 1 (1c) using 2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 75%.

Mp 250-252 ° C .;

IR (KBr) ν _max 3438, 3318, 3176, 2832, 1645, 1596, 1579, 1447, 1377, 1343, 1238, 1136, 1135, 978, 914, 831, 762, 733, 693, 626, 484 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.89-3.71 (8H, br s), 6.70 (1H, t, J = 7.1 Hz), 6.93 (2H, s), 6.99 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 5.5 Hz), 7.10 (2H, s), 7.22 (2H, dd, J = 7.4, 8.6 Hz), 8.44 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 353 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₁₉ N ₅ OS.0.26H ₂ O: C, 60.37; H, 5.49; N, 19.56; S, 8.95. Found: C, 60.18; H, 5.33; N, 19.55; S, 9.02.

Example 43 3-amino-4- (4-benzylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-6)

(43a) (2Z) -3- (4-benzylpiperazin-1-yl) -2-cyanobuta-2-enthioamide

1-benzylpiperazine was used instead of propylamine, and it reacted like the method described in Example 4 (4a), and obtained the title compound. Yield 33%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.25 (3H, s), 2.44 (4H, m), 3.37 (4H, m), 3.50 (2H, s), 7.22-7.34 (5H, m), 8.30 (1 H, s), 8.98 (1 H, s).

(43b) 4- (4-benzylpiperazin-4-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- (4-benzylpiperazin-1-yl) prepared in Example 42 (42a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide Reaction was performed similarly to the method described in Example 1 (1b) using 2-cyanobuta-2-enthioamide, to obtain the title compound. Yield 78%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.49 (4H, m), 3.51 (2H, s), 3.61 (4H, m), 6.45 (1H, d, J = 7.8 Hz), 7.20-7.34 ( 5H, m), 7.50 (1H, d, J = 7.4 Hz).

(43c) 3-amino-4- (4-benzylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-benzylpiperazin-4-yl)-made in Example 42 (42b) -instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as in the method described in Example 1 (1c) using 2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 75%.

Mp 241-242 ° C .;

IR (KBr) ν _max 3435, 3398, 3322, 3128, 2828, 1656, 1585, 1503, 1452, 1373, 1348, 1250, 1232, 1132, 1061, 1009, 973, 826, 742, 699, 627, 551, 487 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.42-3.22 (8H, br s), 3.55 (1H, s), 6.89 (2H, s), 7.02 (1H, d, J = 5.5 Hz), 7.07 (2H, s), 7.20-7.34 (5H, s), 8.415 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 367 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ OS: C, 62.10; H, 5.76; N, 19.06; S, 8.73. Found: C, 61.96; H, 5.63; N, 18.76; S, 8.75.

Example 44 3-Amino-4- (4-pyrimidin-2-ylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-69 )

(44a) (2Z) -2-cyano-3- (4-pyrimidin-2-ylpiperazin-1-yl) buta-2-enthioamide

Instead of propylamine, 1-pyrimidin-2-ylpiperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 87%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 3.51 (4H, m), 3.83 (4H, m), 6.66 (1H, t, J = 4.7 Hz), 8.32 (1H, s), 6.92 (2H, doublet, J = 4.7 Hz), 9.03 (1H, s).

(44b) 4- (4-pyrimidin-2-ylpiperazin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (4-pyrimidine) prepared in Example 44 (44a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The title compound was obtained in the same manner as in the method described in Example 1 (1b) using 2-ylpiperazin-1-yl) buta-2-enthioamide. Yield 77%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.785 (4H, m), 3.89 (4H, m), 6.53 (1H, d, J = 7.4 Hz), 6.69 (1H, t, J = 4.3 Hz) , 7.52 (1H, t, J = 7.8 Hz), 7.50 (2H, d, J = 4.7 Hz), 12.74 (1H, br s).

(44c) 3-amino-4- (4-pyrimidin-2-ylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (4- prepared in Example 44 (44b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as described in Example 1 (1c) using pyrimidin-2-ylpiperazin-1-yl) buta-2-enthioamide. Yield 69%.

Mp 280 ° C. (decomposition);

IR (KBr) ν _max 3439, 3317, 3141, 2835, 1648, 1582, 1548, 1500, 1466, 1359, 1241, 1133, 974, 797, 486 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.72-3.65 (8H, br s), 6.66 (1H, t, J = 4.7 Hz), 6.99 (2H, br s), 7.05 (2H, d, J = 5.1 Hz), 7.11 (2H, broad singlet), 8.39 (2H, d, J = 4.7 Hz), 8.43 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 356 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₁₇ N ₇ OS.0.24H ₂ O: C, 54.07; H, 4.82; N, 27.59; S, 9.02. Found: C, 53.59; H, 4.81; N, 27.03; S, 8.99.

Example 45 3-amino-4- (4-pyridin-2-ylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-62)

(45a) (2Z) -2-cyano-3- (4-pyridin-2-ylpiperazin-1-yl) buta-2-enthioamide

Instead of propylamine, 1-pyridin-2-ylpiperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 92%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.32 (3H, s), 3.53 (4H, m), 3.65 (4H, m), 6.67 (1H, t, J = 4.7 Hz), 6.83 (1H, d, J = 8.9 Hz), 7.57 (1H, t, J = 8.9 Hz), 8.14 (1H, d, J = 4.7 Hz), 8.36 (1H, br s), 9.07 (1H, br s).

(45b) 4- (4-pyridin-2-ylpiperazin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (4-pyridine-) prepared in Example 45 (45a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The title compound was obtained in the same manner as in the method described in Example 1 (1b) using 2-ylpiperazin-1-yl) buta-2-enthioamide. Yield 43%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.70 (4H, m), 3.82 (4H, m), 6.53 (1H, d, J = 7.4 Hz), 6.72 (1H, t, J = 5.9 Hz) , 6.90 (1H, d, J = 8.2 Hz), 7.52 (1H, t, J = 6.7 Hz), 7.64 (1H, t, J = 7.4 Hz), 8.13 (1H, d, J = 5.1 Hz), 12.73 (1H, br s).

(45c) 3-amino-4- (4-pyridin-2-ylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-pyridin-2-ylpiperazin-1 prepared in Example 45 (45b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as in Example 1 (1c) using -yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile to synthesize the title compound. Yield 77%.

Mp 266-270 ° C .;

IR (KBr) ν _max 3438, 3317, 3142, 2834, 1674, 1590, 1582, 1501, 1435, 1369, 1345, 1133, 974, 774, 741, 620, 487 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.80-3.60 (8H, br s), 6.67 (1H, dd, J = 5.1, 6.3 Hz), 6.89 (1H, d, J = 8.2 Hz), 6.97 (2H, s), 7.06 (1H, d, J = 5.1 Hz), 7.11 (2H, s), 7.55 (1H, t, J = 5.1 Hz), 8.39 (1H, d, J = 3.5 Hz), 8.44 (1H, doublet, J = 5.1 Hz);

MS (FAB) m / z: 355 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₁₈ N ₆ OS: C, 57.61; H, 5.12; N, 23.71; S, 9.05. Found: C, 57.25; H, 5.01; N, 23.35; S, 9.04.

Example 46 3-amino-4- [4- (4-methylphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-34)

(46a) (2Z) -2-cyano-3- [4- (4-methylphenyl) piperazin-1-yl] buta-2-enthioamide

Instead of propylamine, reaction was carried out in the same manner as in Example 4 (4a), using 1- (4-methylphenyl) piperazine, to obtain the title compound. Yield 70%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.20 (3H, s), 2.30 (3H, s), 3.20 (4H, m), 3.51 (4H, m), 6.83 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.2 Hz), 8.35 (1H, s), 9.04 (1H, s).

(46b) 4- [4- (4-methylphenyl) piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [4- (4 prepared in Example 46 (46a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using -methylphenyl) piperazin-1-yl] buta-2-enthioamide to obtain the title compound. Yield 77%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.21 (3H, s), 3.22 (4H, m), 3.79 (4H, m), 6.45 (1H, d, J = 7.4 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.05 (2H, d, J = 8.2 Hz), 7.52 (1H, t, J = 7.0 Hz), 12.73 (1H, br s).

(46c) 3-amino-4- [4- (4-methylphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-methylphenyl) piperazin-1 prepared in Example 46 (46b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile -Yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used and reaction was carried out similarly to the method described in Example 1 (1c) to synthesize the title compound. Yield 72%.

Mp 270 ° C. (decomposition);

IR (KBr) ν _max 3433, 3310, 3143, 2829, 1667, 1611, 1580, 1513, 1449, 1371, 1345, 1237, 1134, 1124, 974, 956, 812, 617, 482 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.20 (3H, s), 2.91-3.60 (8H, br s), 6.86-7.12 (9H, m), 8.42 (1H, d, J = 5.5 Hz) ;

MS (FAB) m / z: 367 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ OS.0.24H ₂ O: C, 61.38; H, 5.82; N, 18.84; S, 8.62. Found: C, 61.58; H, 5.58; N, 18.84; S, 8.63.

Example 47 3-Amino-4- [4- (4-fluorophenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3- 12)

(47a) (2Z) -2-cyano-3- [4- (4-fluorophenyl) piperazin-1-yl] buta-2-enthioamide

Using 1- (4-fluorophenyl) piperazine in place of propylamine, the reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 73%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 3.21 (4H, m), 3.52 (4H, m), 6.83 (2H, dd, J = 4.7, 9.0 Hz), 7.02 ( 2H, t, J = 8.6 Hz), 8.37 (1H, s), 9.06 (1H, s).

(47b) 4- [4- (4-fluorophenyl) piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [4- (4 prepared in Example 47 (47a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using -fluorophenyl) piperazin-1-yl] buta-2-enthioamide to obtain the title compound. Yield 74%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.24 (4H, m), 3.80 (4H, m), 6.56 (1H, d, J = 7.4 Hz), 6.98 (2H, dd, J = 4.7, 9.4 Hz), 7.08 (2H, t, J = 8.9 Hz), 7.52 (1H, d, J = 7.4 Hz).

(47c) 3-amino-4- [4- (4-fluorophenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-fluorophenyl) piperazine, prepared in Example 47 (47b), instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as described in Example 1 (1c) using-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 62%.

Mp 275 ° C. (decomposition);

IR (KBr) ν _max 3443, 3324, 3180, 2832, 1646, 1583, 1558, 1509, 1450, 1373, 1345, 1234, 1136, 977, 959, 826, 716, 553 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.93-3.75 (8H, br s), 6.96 (2H, s), 7.00-7.19 (7H, m), 8.48 (1H, d, J = 5.1 Hz) ;

MS (FAB) m / z: 371 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₁₈ FN ₅ OS.0.19H ₂ O: C, 57.67; H, 4.94; N, 18.68; S, 8.55. Found: C, 57.72; H, 4.72; N, 18.58; S, 8.53.

Example 48 3-Amino-4- (4-benzhydrylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-7)

(48a) (2Z) -3- (4-benzhydrylpiperazin-1-yl) -2-cyanobuta-2-enthioamide

Instead of propylamine, 1-benzhydrylpiperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 90%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.22 (3H, s), 2.38 (4H, m), 3.41 (4H, m), 4.34 (1H, s), 7.18 (2H, t, J = 7.4 Hz), 7.28 (4H, t, J = 7.8 Hz), 7.42 (4H, d, J = 7.0 Hz), 8.31 (1H, s), 8.98 (1H, s).

(48b) 4- (4-benzhydrylpiperazin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- (4-benzhydrylpiperazine-1 prepared in Example 48 (48a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using -yl) -2-cyanobuta-2-enthioamide to obtain the title compound. Yield 84%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.44 (4H, m), 3.66 (4H, m), 4.38 (1H, s), 6.47 (1H, d, J = 7.0 Hz), 7.23 (1H, d, J = 7.0 Hz), 7.27-7.66 (10H, m).

(48c) 3-amino-4- (4-benzhydrylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-benzhydrylpiperazin-1-yl, prepared in Example 48 (48b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesize | combined by carrying out similarly to the method of Example 1 (1c) using the 2--2-oxo- 1, 2- dihydropyridine-3-carbonitrile. Yield 63%.

Mp 225-233 ° C .;

IR (KBr) ν _max 3450, 3381, 3171, 2827, 1649, 1580, 1501, 1449, 1366, 1242, 1137, 979, 957, 835, 758, 706, 626, 473 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.20-3.40 (8H, br s), 4.38 (1H, s), 6.89 (1H, s), 7.07 (2H, m), 7.20 (2H, t, J = 7.4 Hz), 7.31 (5H, t, J = 7.4 Hz), 7.47 (5H, d, J = 7.4 Hz), 8.44 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 444 [M + H] ⁺ ;

analysis. Calc. For C ₂₅ H ₂₅ N ₅ OS.0.26H ₂ O: C, 66.99; H, 5.74; N, 15.62; S, 7.15. Found: C, 67.07; H, 5.57; N, 15.36; S, 7.09.

Example 49 3-amino-4- [4- (4-methoxyphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3- 47)

(49a) (2Z) -2-cyano-3- [4- (4-methoxyphenyl) piperazin-1-yl] buta-2-enthioamide

Instead of propylamine, reaction was carried out in the same manner as in Example 4 (4a) using 1- (4-methoxyphenyl) piperazine, to obtain the title compound. Yield 73%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 3.13 (4H, m), 3.52 (4H, m), 3.69 (3H, s), 6.84 (2H, d, J = 9.0 Hz), 6.92 (2H, d, J = 9.3 Hz), 8.39 (1H, s), 9.07 (1H, s).

(49b) 4- [4- (4-methoxyphenyl) piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [4- (4 prepared in Example 49 (49a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using -methoxyphenyl) piperazin-1-yl] buta-2-enthioamide to obtain the title compound. Yield 59%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.14 (4H, m), 3.67 (3H, s), 3.77 (4H, m), 6.45 (1H, d, J = 7.1 Hz), 6.86 (2H, d, J = 9.4 Hz), 7.05 (2H, d, J = 9.4 Hz), 7.52 (1H, t, J = 7.4 Hz).

(49c) 3-amino-4- [4- (4-methoxyphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-methoxyphenyl) piperazine, prepared in Example 49 (49b), instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as described in Example 1 (1c) using-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 79%.

Mp 275 ° C. (decomposition);

IR (KBr) ν _max 3435, 3311, 3160, 2957, 2831, 1664, 1609, 1511, 1449, 1373, 1346, 1242, 1182, 1136, 1035, 976, 959, 826, 740, 605, 480 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.95-3.56 (8H, br s), 3.69 (1H, s), 6.3 (1H, d, J = 9.0 Hz), 6.93 (2H, s), 6.95 (1H, d, J = 9.4 Hz), 7.07 (1H, d, J = 5.5 Hz), 7.09 (2H, s), 8.45 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 384 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ O ₂ S.0.28H ₂ O: C, 58.74; H, 5.59; N, 18.03; S, 8.25. Found: C, 58.57; H, 5.42; N, 18.03; S, 8.03.

Example 50 3-amino-4- {4-[(2E) -3-phenylprop-2-enyl] piperazin-1-yl} thieno [2,3-b] pyridine-2-car Copymid (Example Compound No. 3-8)

(50a) (2Z) -2-cyano-3- {4-[(2E) -3-phenylpropane-2-enyl] piperazin-1-yl} buta-2-enthioamide

Instead of propylamine, reaction was carried out in the same manner as in Example 4 (4a), using 1-[(2E) -3-phenylpropane-2-enyl] piperazine, to obtain the title compound. Yield 38%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.27 (3H, s), 2.50 (4H, m), 3.14 (2H, d, J = 5.9 Hz), 3.40 (4H, m), 3.69 (3H, s), 6.30 (1H, dt, J = 6.6, 16.0 Hz), 6.56 (1H, d, J = 16.0 Hz), 7.24 (1H, t, J = 7.4 Hz), 7.32 (2H, t, J = 7.0 Hz), 7.44 (2H, d, J = 7.0 Hz), 8.32 (1H, s), 9.01 (1H, s).

(50b) 4- {4-[(2E) -3-phenylpropane-2-enyl] piperazin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- {4-[() prepared in Example 50 (50a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide. The reaction was carried out in the same manner as in Example 1 (1b) using 2E) -3-phenylpropane-2-enyl] piperazin-1-yl} buta-2-enthioamide to obtain the title compound. . Yield 84%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.85-4.44 (10H, m), 6.28 (1H, dt, J = 7.8, 14.8 Hz), 6.55 (1H, d, J = 7.4 Hz), 6.79 ( 1H, d, J = 14.9 Hz), 7.31 (1H, d, J = 7.4 Hz), 7.37 (2H, t, J = 7.4 Hz), 7.48 (2H, d, J = 7.4 Hz), 7.57 (1H, t, J = 6.7 Hz), 12.91 (1H, s).

(50c) 3-amino-4- {4-[(2E) -3-phenylprop-2-enyl] piperazin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- {4-[(2E) -3-phenylpropane prepared in Example 50 (50b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile 2-enyl] piperazin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used, and the reaction was carried out in the same manner as in Example 1 (1c). The title compound was synthesized. Yield 60%.

Mp 225-227 ° C;

IR (KBr) ν _max 3433, 3319, 3184, 3024, 2832, 2811, 1649, 1578, 1501, 1448, 1369, 1347, 1129, 971, 823, 736, 693, 627, 470 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.42-3.81 (8H, br s), 3.19 (1H, d, J = 6.3 Hz), 6.32 (1H, dt, J = 6.6, 16.0 Hz), 6.55 (1H, d, J = 16.0 Hz), 6.90 (2H, s), 7.02 (1H, d, J = 5.0 Hz), 7.07 (2H, s), 7.21 (1H, t, J = 7.4 Hz), 7.30 (2H, t, J = 7.4 Hz), 7.43 (2H, d, J = 7.0 Hz), 8.41 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 394 [M + H] ⁺ ;

analysis. Calc. For C ₂₁ H ₂₃ N ₅ OS.0.46H ₂ O: C, 62.78; H, 6.00; N, 17.43; S, 7.98. Found: C, 62.45; H, 5. 70; N, 17.32; S, 7.94.

Example 51 3-Amino-4- (4-benzoylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-73)

3-amino-4-piperazin-1-ylthieno [2,3-b] pyridine-2-carboxamide dihydrochloride (99.7 mg, 0.28 mmol) prepared in Example 38 was prepared with 1,4-dioxane. It suspended in (5 mL), benzoyl chloride (37 microliters, 0.31 mmol) and triethylamine (44 microliters, 0.31 mmol) were added, and it stirred for 12 hours. The solvent was distilled off, and the mixture was left to stand for several hours by adding water (15 mL), and the resulting brown solid was filtered and dried in vacuo to obtain the title compound (31.8 mg, yield 29%).

Mp> 300 ° C .;

IR (KBr) ν _max 3437, 3325, 3182, 2923, 2856, 1635, 1598, 1567, 1495, 1411, 1284, 1244, 1013, 974, 720, 675, 482 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.95-3.66 (8H, br s), 6.99 (2H, s), 7.07 (1H, s), 7.15 (2H, s), 7.42-7.57 (3H, m), 7.96 (2H, m), 8.48 (1H, s);

MS (FAB) m / z: 382 [M + H] ⁺ .

Example 52 3-Amino-4- [4- (4-chlorophenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-17 )

(52a) (2Z) -3- [4- (4-chlorophenyl) piperazin-1-yl] -2-cyanobuta-2-enthioamide

Instead of propylamine, reaction was carried out in the same manner as in Example 4 (4a) using 1- (4-chlorophenyl) piperazine, to obtain the title compound. Yield 73%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 3.29 (4H, m), 3.53 (4H, m), 6.95 (2H, d, J = 9.0 Hz), 7.25 (2H, d, J = 9.0 Hz), 8.39 (1H, s), 9.10 (1H, s).

(52b) 4- [4- (4-chlorophenyl) piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- [4- (4-chlorophenyl) pipet prepared in Example 52 (52a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide Reaction was performed similarly to the method described in Example 1 (1b) using rajin-1-yl] -2-cyanobuta-2-enthioamide, to obtain the title compound. Yield 74%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.31 (4H, m), 3.79 (4H, m), 6.52 (1H, d, J = 7.4 Hz), 6.93 (2H, d, J = 9.4 Hz) , 7.23 (2H, doublet, J = 9.0 Hz), 7.50 (1H, m);

(52c) 3-amino-4- [4- (4-chlorophenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-chlorophenyl) piperazine- as prepared in Example 52 (52b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as in the method described in Example 1 (1c) using 1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 50%.

Mp 297 ° C. (decomposition);

IR (KBr) ν _max 3423, 3317, 3164, 2975, 2832, 1669, 1649, 1580, 1496, 1449, 1370, 1343, 1238, 1137, 1106, 976, 962, 819, 609, 487 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.95-3.66 (8H, br s), 6.94 (2H, s), 7.01 (2H, d, J = 9.0 Hz), 7.065 (1H, d, J = 5.1 Hz), 7.11 (2H, s), 7.25 (2H, d, J = 9.0 Hz), 8.445 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 388 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₁₈ ClN ₅ OS: C, 55.74; H, 4.68; N, 18.06; S, 8.27. Found: C, 55.43; H, 4.75; N, 17.98; S, 8.12.

Example 53 3-Amino-4- [4- (2-methoxyphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3- 45)

(53a) (2Z) -2-cyano-3- [4- (2-methoxyphenyl) piperazin-1-yl] buta-2-enthioamide

Instead of propylamine, 1- (2-methoxyphenyl) piperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 68%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 3.05 (4H, m), 3.51 (4H, m), 3.80 (3H, s), 6.85-7.04 (4H, m), 8.39 (1 H, s), 9.08 (1 H, s).

(53b) 4- [4- (2-methoxyphenyl) piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [4- (2 prepared in Example 53 (53a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using -methoxyphenyl) piperazin-1-yl] buta-2-enthioamide to obtain the title compound. Yield 76%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.08 (4H, m), 3.79 (7H, m), 6.44 (1H, d, J = 7.4 Hz), 6.86 (2H, s), 7.05 (2H, s), 7.49 (1H, t, J = 6.6 Hz), 12.96 (1H, s).

(53c) 3-amino-4- [4- (2-methoxyphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (2-methoxyphenyl) piperazine, prepared in Example 53 (53b), instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as described in Example 1 (1c) using-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 71%.

Mp 294 ° C. (decomposition);

IR (KBr) ν _max 3435, 3311, 3160, 2957, 2831, 1664, 1609, 1511, 1449, 1373, 1346, 1242, 1182, 1136, 1035, 976, 959, 826, 740, 605, 480 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.96-3.56 (8H, br s), 3.79 (3H, s), 6.86-7.00 (6H, m), 7.10 (3H, d, J = 5.1 Hz) , 8.445 (1H, doublet, J = 5.1 Hz);

MS (FAB) m / z: 384 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ O ₂ S.0.1H ₂ O: C, 59.23; H, 5.55; N, 18.18; S, 8.32. Found: C, 58.94; H, 5. 25; N, 18.29; S, 8.21.

Example 54 3-amino-4- [4- (2-chlorophenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-15 )

(54a) (2Z) -3- [4- (2-chlorophenyl) piperazin-1-yl] -2-cyanobuta-2-enthioamide

Instead of propylamine, 1- (2-chlorophenyl) piperazine was used, and reaction was carried out in the same manner as in Example 4 (4a) to obtain the title compound. Yield 71%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 3.05 (4H, m), 3.51 (4H, m), 3.80 (3H, s), 6.85-7.04 (4H, m), 8.39 (1 H, s), 9.08 (1 H, s).

(54b) 4- [4- (2-chlorophenyl) piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- [4- (2-chlorophenyl) pipe prepared in Example 54 (54a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide Reaction was performed similarly to the method described in Example 1 (1b) using rajin-1-yl] -2-cyanobuta-2-enthioamide, to obtain the title compound. Yield 37%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.11 (4H, m), 3.79 (4H, m), 6.44 (1H, d, J = 7.4 Hz), 7.06 (1H, t, J = 7.4 Hz) , 7.16 (1H, d, J = 7.8 Hz), 7.30 (1H, t, J = 7.4 Hz), 7.42 (1H, d, J = 7.8 Hz), 7.51 (1H, t, J = 7.0 Hz).

(54c) 3-amino-4- [4- (2-chlorophenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (2-chlorophenyl) piperazine-prepared in Example 54 (54b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as in the method described in Example 1 (1c) using 1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 79%.

Mp 294-298 ° C. (decomposition);

IR (KBr) ν _max 3449, 3327, 3131, 2842, 1665, 1606, 1581, 1501, 1447, 1375, 1284, 1245, 1230, 1182, 1135, 1038, 976, 957, 826, 766, 627, 483 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.95-3.62 (8H, br s), 6.98 (2H, s), 7.03-7.14 (4H, m), 7.25 (1H, d, J = 7.8 Hz) , 7.33 (1H, t, J = 7.0 Hz), 7.42 (1H, d, J = 7.8 Hz), 8.45 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 388 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₁₈ ClN ₅ OS: C, 55.74; H, 4.68; N, 18.06; S, 8.27. Found: C, 55.48; H, 4.75; N, 17.95; S, 8.04.

Example 55 tert-Butyl 4- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] -1,4-diazepane-1-carboxylate (Example Compound No. 3-152)

(55a) tert-butyl4-[(1Z) -3-amino-2-cyano-1-methyl-3-thiooxoprop-1-enyl] -1,4-diazepane-1-carboxylate

N-Boc-homopiperazine was used instead of isobutylamine, and reaction was carried out in the same manner as described in Example 5 (5a) to synthesize the title compound.

Yellow powder

Mp 189-190 ° C .;

IR (KBr) ν _max 3284, 3196, 2188, 1686, 1526, 1415, 1280, 1167, 884 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.38 (9H, s), 1.75-1.82 (2H, m), 2.27 (3H, s), 3.29-3.52 (8H, m), 8.80 (1H, brs ), 9.02 (1H, broad singlet);

HRMS m / z calc. C ₁₅ H ₂₅ 0 ₂ N ₄ S 325.1798, found 325.1715;

MS (FAB) m / z: 325 [M ⁺ ], 269, 252, 235, 201, 191, 65, 57;

analysis. Calc. For C ₁₅ H ₂₄ N ₄ O ₂ S: C, 55.53; H, 7. 46; N, 12.27; S, 9.88. Found: C, 55.40; H, 7. 48; N, 17.15, S, 9.68.

(55b) tert-butyl4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1-carboxylate

Tert-butyl4-[(1Z) -3-amino-2 prepared in Example 55 (55a) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide -Cyano-1-methyl-3-thiooxoprop-1-enyl] -1,4-diazepane-1-carboxylate, and the reaction was carried out in the same manner as in Example 5 (5b). It carried out and obtained the title compound.

White powder

Mp 203-205 ° C;

IR (KBr) ν _max 2974, 2205, 1692, 1625, 1537, 1478, 1246, 1152, 929, 771 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.27 (4.5 H, s), 1.33 (4.5 H, s), 1.71-1.85 (2H, m), 3.31-3.38 (2H, m), 3.50-3.60 (2H, m), 3.74-3.84 (2H, m), 3.87-4.04 (2H, m), 6.42 (1H, t, J = 7.4 Hz), 7.88 (1H, d, J = 7.4 Hz), 12.44 ( 1H, brs);

HRMS m / z calc. C ₁₆ H ₂ O ₂ N ₄ S 335.1542, found 335.1541;

MS (FAB) m / z: 335 [M + H] ⁺ , 289, 279, 233, 200, 176, 165, 93, 83;

analysis. Calc. For C ₁₆ H ₂₂ N ₄ O ₂ S: C, 57.46; H, 6.63; N, 16.75; S, 9.59. Found: C, 57.10; H, 6. 24; N, 16.66, S, 9.82.

(55c) tert-butyl4- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] -1,4-diazepane-1-carboxylate

Tert-butyl4- (3-cyano-2-, prepared in Example 55 (55b) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Reaction was carried out in the same manner as in Example 5 (5c), using thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1-carboxylate to give the titled compound. Got.

Pale yellow powder

Mp 177-178 ° C .;

IR (KBr) ν _max 3431, 3316, 3145, 2973, 1686, 1581, 1502, 1411, 1366, 1170, 929, 769 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.40 (4.5H, s), 1.43 (4.5H, s), 1.93-2.02 (2H, m), 3.17-3.23 (4H, m), 3.47 (2H , t, J = 6.3 Hz), 3.58-3.63 (2H, m), 7.00 (2H, brs), 7.06 (1H, d, J = 5.1 Hz), 7.08 (2H, brs), 8.39 (1H, d, J = 5.1 Hz);

HRMS m / z calc. For C ₁₈ H ₂₆ O ₃ N ₅ S 392.1757, found 392.1761;

MS (FAB) m / z: 391 [M ⁺ ], 336, 319, 289, 230, 218, 202, 190, 176, 93;

analysis. Calc. For C ₁₈ H ₂₅ N ₅ O ₃ S: C, 55.22; H, 6. 44; N, 17.89; S, 8.19. Found: C, 54.90; H, 6. 40; N, 17.85; S, 8.26.

Example 56 3-Amino-4- (4-benzyl-1,4-diazepane-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-83 )

(56a) (2Z) -3- (4-benzyl-1,4-diazepan-1-yl) -2-cyanobuta-2-enthioamide

1-benzyl homopiperazine was used instead of propylamine, and it reacted like the method described in Example 4 (4a), and obtained the title compound. Yield 88%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.86 (2H, m), 2.30 (3H, s), 2.57 (2H, t, J = 5.1 Hz), 2.67-2.73 (2H, m), 3.50- 3.54 (4H, m), 3.57, (2H, s), 7.21-7.32 (5H, m), 8.18 (1H, s), 8.84 (1H, s).

(56b) 4- (4-benzyl-1,4-diazepan-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- (4-benzyl-1,4-diaza prepared in Example 56 (56a) instead of (2Z) -2-cyano-3- (dimethylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 1 (1b) using zepan-1-yl) -2-cyanobuta-2-enthioamide to obtain the title compound. Yield 70%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.80-4.43 (12H, m), 6.38 (1H, d, J = 7.4 Hz), 7.15-7.61 (6H, m).

(56c) 3-amino-4- (4-benzyl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-benzyl-1,4-diazepane- made in Example 56 (56b) instead of 4- (dimethylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as described in Example 1 (1c) using 1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile. Yield 75%.

Mp 194-195 ° C .;

IR (KBr) ν _max 3429, 3306, 3142, 2937, 2828, 1674, 1646, 1583, 1501, 1452, 1368, 1344, 1262, 1157, 1108, 1026, 925, 740, 699, 483 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.86 (2H, m), 2.70 (2H, m), 2.79 (2H, m), 3.29 (2H, m), 3.35 (2H, m), 3.67 ( 2H, s), 7.04 (2H, s), 7.06 (2H, s), 7.15 (2H, s), 7.25 (1H, m), 7.31-7.37 (4H, m), 8.365 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 382 [M + H] ⁺ ;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS: C, 62.97; H, 6.08; N, 18.36; S, 8.41. Found: C, 62.94; H, 5.75; N, 18.33; S, 8.30.

(Example 57) 3-amino-4- (4-phenyl-1,4-diazepane-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-86 )

(57a) tert-butyl4-phenyl-1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2974, 1694, 1599, 1506, 1415, 1237, 1169, 930, 748, 692 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.93-2.00 (2H, m), 3.19 (1H, t, J = 5.9 Hz), 3.80 ( 1H, t, J = 5.9 Hz), 3.51-3.57 (6H, m), 6.63-6.69 (3H, m), 7.19 (2H, t, J = 7.1 Hz);

HRMS m / z calc'd C ₁ H ₂₄ O ₂ N ₂ 276.1835, found 276.1833;

MS (EI) m / z: 276 [M ⁺ ], 220, 205, 175, 146, 132, 120, 94, 57;

analysis. Calc. For C ₁₆ H ₂₄ N ₂ 0 ₂ .0.14H ₂ 0: C, 68.90; H, 8. 77; N, 10.04. Found: C, 68.96; H, 8.75; N, 9.85.

(57b) 1-phenyl-1,4-diazepane

4N hydrochloric acid-dioxane solution (75 mL) in a methanol (20 mL) solution of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate (16.58 g, 60.0 mmol) prepared in Example 57 (57a) ) Was added and stirred at room temperature for 1 hour. The reaction solution was concentrated, and an aqueous sodium hydrogencarbonate solution (100 mL) was added to the obtained residue, followed by extraction with a methylene chloride / 2-propanol (4: 1) mixed solvent (3 x 100 mL), and the extract was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.57 g, yield 100%).

Yellow liquid

IR (film) ν _max 2931, 1598, 1506, 1394, 1245, 1035, 748, 692 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.87-1.92 (2H, m), 2.83 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.9 Hz), 3.54-3.59 (4H, m), 6.65 (1H, t, J = 8.3 Hz), 6.70 (2H, d, J = 8.3 Hz), 7.21 (2H, t, J = 8.3 Hz);

HRMS m / z calc'd C ₁₁ H ₁₆ N ₂ 176.1313, found 176.1318;

MS (EI) m / z: 176 [M ⁺ ], 146, 134, 120, 106, 94, 77, 69, 43.

(57c) (2Z) -2-cyano-3- (4-phenyl-1,4-diazepan-1-yl) buta-2-enthioamide

Instead of isobutylamine, reaction was carried out in the same manner as described in Example 5 (5a) using 1-phenyl-1,4-diazephan prepared in Example 57 (57b) to synthesize the title compound. .

Pale yellow powder

Mp 151-153 ° C .;

IR (KBr) ν _max 3290, 2185, 1599, 1538, 1503, 1397, 1369, 1011, 873, 754 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.91-1.96 (2H, m), 2.23 (3H, s), 3.50-3.55 (4H, m), 3.61-3.63 (2H, m), 3.71-3.73 (2H, m), 6.61 (1H, t, J = 7.3 Hz), 6.76 (2H, d, J = 7.3 Hz), 7.16 (2H, t, J = 7.3 Hz), 8.33 (1H, brs), 9.00 (1H, br s);

HRMS m / z calc. C ₁₆ H ₂₁ N ₄ S 301.1487, found 301.1465;

MS (FAB) m / z: 300 [M ⁺ ], 267, 242, 195, 175;

analysis. Calc. For C ₁₆ H ₂₀ N ₄ S: C, 63.97; H, 6. 71; N, 18.65; S, 10.67. Found: C, 63.76; H, 6. 47; N, 18.75, S, 10.62.

(57d) 4- (4-phenyl-1,4-diazepane-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (4-phenyl prepared in Example 57 (57c) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide The title compound was synthesized in the same manner as in the method described in Example 5 (5b) using -1,4-diazepan-1-yl) buta-2-enthioamide.

Brown powder

Mp 128-132 ° C .;

IR (KBr) ν _max 2954, 2205, 1626, 1504, 1248, 1136, 928, 750, 617 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.90-1.96 (2H, m), 3.51 (2H, t, J = 5.9 Hz), 3.71 (4H, q, J = 5.9 Hz), 3.93 (2H, t, J = 5.9 Hz), 6.40 (1H, d, J = 7.4 Hz), 6.56 (1H, t, J = 7.1 Hz), 6.74 (2H, d, J = 7.1 Hz), 7.12 (2H, t, J = 7.1 Hz), 7.83 (1H, d, J = 7.4 Hz), 12.47 (1H, brs);

HRMS m / z calc'd C ₁₇ H ₁₈ N ₄ S 310.1252, found 310.1224;

MS (EI) m / z: 310 [M ⁺ ], 281, 251, 204, 165, 132;

analysis. Calc. For C ₁₇ H ₁₈ N ₄ S: C, 65.78; H, 5. 84; N, 18.05; S, 10.33. Found: C, 65.58; H, 5.51; N, 18.03, S, 10.24.

(57e) 3-amino-4- (4-phenyl-1,4-diazepane-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-phenyl-1,4-diazepane prepared in Example 57 (57d) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The title compound was synthesized in the same manner as described in Example 5 (5c) using -1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile.

White powder

Mp 215-218 ° C .;

IR (KBr) ν _max 3340, 3316, 3143, 1645, 1598, 1504, 1369, 1233, 939, 752, 694 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.10-2.15 (2H, m), 3.16-3.19 (2H, m), 3.26-3.29 (2H, m), 3.52 (2H, t, J = 6.3 Hz ), 3.75 (2H, t, J = 6.3 Hz), 6.58 (1H, t, J = 8.2 Hz), 6.74 (2H, d, J = 8.2 Hz), 6.95 (2H, brs), 7.05 (1H, d , J = 5.5 Hz), 7.05 (2H, brs), 7.14 (2H, t, J = 8.2 Hz), 8.36 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₁₉ H ₂₁ N ₅ OS 367.1467, found 367.1462;

MS (EI) m / z: 367 [M ⁺ ], 335, 324, 275, 259, 242, 216, 202, 175, 146, 120;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ OS.0.24H ₂ O: C, 61.38; H, 5. 82; N, 18.84; S, 8.62. Found: C, 61.22; H, 5. 64; N, 18.94; S, 8.49.

(Example 58) 3-amino-4- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-124)

(58a) tert-Butyl 4- (4-methoxyphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2974, 1693, 1513, 1415, 1242, 1169, 1041, 930, 815 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.92-1.99 (2H, m), 3.20 (1H, t, J = 5.9 Hz), 3.31 ( 1 H, t, J = 5.9 Hz), 3.47-3.57 (6H, m), 3.74 (3H, s), 6.65 (2H, d, J = 9.3 Hz), 6.81 (2H, d, J = 9.3 Hz);

HRMS m / z calc. For C ₁₇ H ₂₆ O ₃ N ₂ 306.1943, found 306.1935;

MS (EI) m / z: 306 [M ⁺ ], 250, 235, 205, 189, 162, 150, 121, 70, 57;

analysis. Calc. For C ₁₇ H ₂₆ N ₂ O ₃ .0.36 H ₂ O: C, 65.26; H, 8.61; N, 8.95. Found: C, 64.92; H, 8. 29; N, 8.87.

(58b) 1- (4-methoxyphenyl) -1,4-diazepane

tert-butyl4- (4-methoxyphenyl) -1,4-diazepane prepared in Example 58 (58a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Yellow liquid

IR (film) ν _max 2934, 1513, 1241, 1040, 814 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89 (2H, quint, J = 5.1 Hz), 2.89 (2H, t, J = 5.1 Hz), 3.02 (2H, t, J = 5.1 Hz), 3.48-3.54 (4H, m), 3.75 (3H, s), 6.65 (2H, d, J = 9.0 Hz), 6.82 (2H, d, J = 9.0 Hz);

HRMS m / z calc. C ₁₂ H ₁₈ ON ₂ 206.1419. Found 206.1424;

MS (EI) m / z: 206 [M ⁺ ], 176, 164, 150, 136, 121, 109, 92, 77, 70, 43.

(58c) (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

The reaction was carried out in the same manner as in Example 5 (5a), using 1- (4-methoxyphenyl) -1,4-diazepane prepared in Example 58 (58b) instead of isobutylamine. The title compound was synthesized.

Pale yellow powder

Mp 157-158 ° C .;

IR (KBr) ν _max 3284, 3154, 2179, 1512, 1361, 1243, 1037, 821 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.96 (2H, m), 2.24 (3H, s), 3.44 (2H, t, J = 5.9 Hz), 3.49 (2H, t, J = 5.9 Hz), 3.57-3.63 (4H, m), 3.64 (3H, s), 6.70 (2H, d, J = 9.0 Hz), 6.76 (2H, d, J = 9.0 Hz), 8.27 (1H, brs), 8.95 (1 H, broad singlet);

HRMS m / z calc. C ₁₇ H ₂₃ ON ₄ S 331.1593, found 331.1589;

MS (FAB) m / z: 331 [M + H] ⁺ , 246, 228, 182, 63;

analysis. Calc. For C ₁₇ H ₂₂ N ₄ OS: C, 61.79; H, 6. 71; N, 16.95; S, 9.70. Found: C, 61.51; H, 6. 69; N, 16.99, S, 9.71.

(58d) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] Buta-2-enthioamide

(2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide prepared in Example 58 (58c) ( 476 mg, 1.44 mmol) was suspended in ethanol (15 mL), and N, N-dimethylformamide dimethylacetal (382 µL, 2.88 mmol) was added and stirred at room temperature for 1 day. The precipitated solid was collected by filtration and washed with ethanol to obtain the title compound (452 mg, 81% yield).

Yellow powder

Mp 145-146 ° C .;

IR (KBr) ν _max 2926, 2178, 1610, 1512, 1324, 1294, 1187, 1012, 923, 669, 514 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94-2.00 (2H, m), 2.50 (3H, s), 2.93 (3H, s), 3.14 (3H, s), 3.45-3.49 (2H, m ), 3.65 (3H, s), 3.69-3.79 (6H, m), 6.73 (2H, d, J = 7.8 Hz), 6.78 (2H, d, J = 7.8 Hz), 8.46 (1H, s);

HRMS m / z calc. C ₂₀ H ₂₈ ON ₅ S 386.2014, found 386.2007;

MS (FAB) m / z: 386 [M + H] ⁺ , 369, 352, 273, 242, 196, 165, 65, 55;

analysis. Calc. For C ₂₀ H ₂₇ N ₅ OS: C, 62.31; H, 7.06; N, 18.17; S, 8.32. Found: C, 62.03; H, 6.88; N, 18.02; S, 8.50.

(58e) 3-amino-4- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diama prepared in Example 58 (58d) A N, N-dimethylformamide (2.3 mL) solution of Jepan-1-yl] buta-2-enthioamide (443 mg, 1.15 mmol) was stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, 2-chloroacetamide (129 mg, 1.38 mmol) and 8 M aqueous sodium hydroxide solution (0.49 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction solution, and the resulting solid was filtered to obtain the title compound (378 mg, yield 83%).

Pale yellow powder

Mp 206-208 ° C .;

IR (KBr) ν _max 3446, 3328, 3168, 1578, 1511, 1370, 1240, 1037, 937, 816 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.78-1.86 (2H, m), 2.89-2.95 (2H, m), 2.97-3.01 (2H, m), 3.19 (2H, t, J = 5.9 Hz ), 3.37 (3H, s), 3.37-3.42 (2H, m), 6.43 (2H, d, J = 9.4 Hz), 6.51 (2H, d, J = 9.4 Hz), 6.69 (2H, brs), 6.77 -6.79 (2H, m), 8.10 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ O ₂ N ₅ S 398.1651, found 398.1635;

MS (FAB) m / z: 398 [M + H] ⁺ , 273, 257, 242, 226, 200, 165, 63;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ 0 ₂ S.0.52H ₂ 0: C, 59.04; H, 5.96; N, 17.21. Found: C, 58.73; H, 6.09; N, 17.52.

(Example 59) 3-amino-4- [4- (4-nitrophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-97)

(59a) tert-butyl4- (4-nitrophenyl) -1,4-diazepane-1-carboxylate

4-fluoronitrobenzene (282 mg, 2 mmol) and tert-butoxycarbonyl homopiperazine (801 mg, 4 mmol) were dissolved in dimethyl sulfoxide (5 mL) and stirred at 80 ° C. for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution for separation, and the organic layer was washed with water (20 mL x 5) and brine (20 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. It was. Hexane was added to the obtained residue to solidify and then filtered to obtain the title compound (620 mg, yield 96%).

Yellow powder

IR (KBr) ν _max 1683, 1600, 1482, 1422, 1310, 1253, 1114, 983, 824 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.16 (4.5H, s), 1.27 (4.5H, s), 1.71-1.83 (2H, m), 3.22 (1H, t, J = 5.5 Hz), 3.29 (1H, t, J = 7.4 Hz), 3.50 (1H, t, J = 5.9 Hz), 3.56 (1H, t, J = 5.9 Hz), 3.62-3.65 (2H, m), 3.70-3.77 (2H , m), 6.87 (2H, d, J = 9.4 Hz), 8.00-8.04 (2H, m);

HRMS m / z calc'd C ₁₆ H ₂₃ N ₃ O ₄ 321.1689, found 321.1682;

MS (FAB) m / z: 321 [M ⁺ ], 266, 220, 200, 120.

(59b) 1- (4-nitrophenyl) -1,4-diazepane

tert-butyl4- (4-nitrophenyl) -1,4-diazepane- made in Example 59 (59a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Yellow liquid

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.71-1.77 (2H, m), 2.61 (2H, t, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.56 (2H, t, J = 5.9 Hz), 3.63 (2H, t, J = 5.9 Hz), 6.79 (2H, d, J = 9.4 Hz), 7.99 (2H, d, J = 9.4 Hz).

(59c) (2Z) -2-cyano-3- [4- (4-nitrophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, reaction was carried out in the same manner as in Example 5 (5a), using 1- (4-nitrophenyl) -1,4-diazepane prepared in Example 59 (59b) The title compound was synthesized.

Yellow powder

IR (KBr) ν _max 3190, 2183, 1596, 1516, 1315, 1115 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-1.96 (2H, m), 2.22 (3H, s), 3.54-3.57 (2H, m), 3.52-3.65 (2H, m), 3.69-3.72 (2H, m), 3.90-3.92 (2H, m), 6.91 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz), 8.45 (1H, brs), 9.08 (1H, brs);

HRMS m / z calc. For C ₁₆ H ₂₀ O ₂ N ₅ S 346.1337. Found 346.1342;

MS (FAB) m / z: 346 [M + H] &lt; ⁺ &gt;, 329, 273, 200, 165.

(59d) 4- [4- (4-nitrophenyl) -1,4-diazepane-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [4- () prepared in Example 59 (59c) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide. The title compound was obtained in the same manner as in the method described in Example 5 (5b) using 4-nitrophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide.

Brown powder

IR (KBr) ν _max 2204, 1596, 1515, 1312, 1114, 927, 752 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-1.97 (2H, m), 3.65-3.70 (2H, m), 3.75-3.78 (2H, m), 3.88-3.90 (2H, m), 3.97 -3.99 (2H, m), 6.43 (1H, d, J = 7.8 Hz), 6.92 (1H, t, J = 9.4 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.01 (2H, d, J = 9.4 Hz);

HRMS m / z calc'd C ₁₇ H ₁₈ N ₅ 0 ₂ S 356.1182, found 356.1165;

MS (EI) m / z: 356 [M + H] ⁺ , 273, 246, 182, 120.

(59e) 3-amino-4- [4- (4-nitrophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-nitrophenyl) -1 prepared in Example 59 (59d) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile , 4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used, and the reaction was carried out in the same manner as in Example 5 (5c) to obtain the title compound. Got.

Yellow powder

Mp 244-248 ° C;

IR (KBr) ν _max 3439, 1646, 1596, 1509, 1312, 1114, 824, 7534 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.17-2.23 (2H, m), 3.18-3.24 (2H, m), 3.31-3.36 (2H, m), 3.72 (2H, t, J = 5.9 Hz ), 3.91-3.95 (2H, m), 6.93 (2H, d, J = 9.4 Hz), 7.00 (2H, brs), 7.08 (1H, d, J = 5.5 Hz), 7.12 (2H, brs), 8.07 (2H, t, J = 9.4 Hz), 8.41 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₁₉ H ₂₁ N ₆ O ₃ S 413.1396, found 413.1400;

MS (FAB) m / z: 413 [M + H] ⁺ , 338, 246, 182;

analysis. Calc. For C ₁₉ H ₂₀ N ₆ O ₃ S.0.76H ₂ O: C, 53.55; H, 5.09; N, 19.72; S, 7.52. Found: C, 53.85; H, 4.86; N, 19.54, S, 7.14.

(Example 60) 3-amino-4- [4- (4-chlorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-94)

(60a) tert-butyl4- (4-chlorophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.36 (4.5H, s), 1.43 (4.5H, s), 1.91-1.97 (2H, m), 3.19 (1H, t, J = 6.3 Hz), 3.30 (1H, t, J = 6.3 Hz), 3.48-3.56 (6H, m), 6.59 (2H, d, J = 9.0 Hz), 7.121 (2H, d, J = 3.5, 9.0 Hz).

(60b) 1- (4-chlorophenyl) -1,4-diazepane

tert-butyl4- (4-chlorophenyl) -1,4-diazepane prepared in Example 60 (60a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Yellow liquid

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.87 (2H, quint, J = 5.9 Hz), 2.80 (2H, t, J = 5.9 Hz), 3.00 (2H, t, J = 5.9 Hz), 3.49 (2H , t, J = 5.9 Hz), 3.53 (2H, t, J = 5.9 Hz), 6.58 (2H, t, J = 9.4 Hz), 7.11 (2H, d, J = 9.4 Hz).

(60c) (2Z) -3- [4- (4-chlorophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide

Instead of isobutylamine, reaction was carried out in the same manner as in Example 5 (5a), using 1- (4-chlorophenyl) -1,4-diazepane prepared in Example 60 (60b). Representative compounds were synthesized.

Pale yellow powder

Mp 170-172 ° C. (decomposition);

IR (KBr) ν _max 3370, 3268, 3175, 2187, 1536, 1498, 1397, 813, 510 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.94 (2H, m), 2.22 (3H, s), 3.48-3.53 (4H, m), 3.58-3.60 (2H, m), 3.70-3.72 (2H, m), 6.75 (2H, d, J = 9.0 Hz), 7.14 (2H, d, J = 9.0 Hz), 8.34 (1H, brs), 8.98 (1H, brs);

HRMS m / z calc. C ₁₆ H ₂₀ N ₄ ClS 335.1097, found 335.1095;

MS (FAB) m / z: 335 [M + H] ⁺ , 273, 246, 211, 165, 63;

analysis. Calc. For C ₁₆ H ₁₉ ClN ₄ S: C, 57.39; H, 5.47; N, 16.73; Cl, 10.59; S, 9.58. Found: C, 57.23; H, 5.47; N, 17.77; Cl, 10.59; S, 9.54.

(60d) (2Z) -3- [4- (4-chlorophenyl) -1,4-diazepane-1-yl] -2-cyano-N-[(1E)-(dimethylamino) methylene] buta 2-enthioamide

In Example 60 (60c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 (58d) using prepared (2Z) -3- [4- (4-chlorophenyl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enthioamide Reaction was performed similarly to the method described in the above, to obtain the title compound.

Yellow powder

Mp 259-264 ° C .;

IR (KBr) ν _max 2926, 2176, 1610, 1499, 1328, 1291, 1194, 1012, 923, 820 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94-1.97 (2H, m), 2.46 (3H, s), 2.90 (3H, s) 3.13 (3H, s), 3.54 (2H, t, J = 5.9 Hz), 3.69-3.76 (4H, m), 3.79-3.81 (2H, m), 6.75 (2H, d, J = 9.0 Hz), 7.11 (2H, d, J = 9.0 Hz), 8.42 (1H, s);

HRMS m / z calc. C ₁₉ H ₂₅ N ₅ ClS 390.1519, found 390.1524;

MS (FAB) m / z: 390 [M + H] ⁺ , 356, 318, 273, 208, 196, 180, 166, 90;

analysis. Calc. For C ₁₉ H ₂₄ ClN ₅ S: C, 58.42; H, 6. 20; N, 17.96; Cl, 9.09; S, 8.22. Found: C, 58.41; H, 6. 17; N, 17.66, Cl, 8.91; S, 8.12.

(60e) 3-amino-4- [4- (4-chlorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -3- [4- (4-chlorophenyl) -1,4-diazepan-1-yl] -2-cyano-N produced in Example 60 (60d) instead of enthioamide. The title compound was obtained in the same manner as in Example 58 (58e) using-[(1E)-(dimethylamino) methylene] buta-2-enthioamide.

Pale yellow powder

Mp 92-96 ° C .;

IR (KBr) ν _max 3441, 3323, 2948, 1646, 1594, 1499, 1368, 939, 810 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.11-2.16 (2H, m), 3.15-3.20 (2H, m), 3.26-3.28 (2H, m), 3.53 (2H, t, J = 5.9 Hz ), 3.75 (2H, t, J = 4.4 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.99 (2H, brs), 7.07 (1H, d, J = 5.4 Hz), 7.08 (2H, brs ), 7.17 (2H, t, J = 8.8 Hz), 8.40 (1H, d, J = 5.4 Hz);

HRMS m / z calc. C ₁₉ H ₂₁ N ₅ OClS 402.1155, found 402.1158;

MS (FAB) m / z: 402 [M + H] ⁺ , 385, 273, 258, 246, 211, 200, 93;

analysis. Calc. For C ₁₉ H ₂₀ ClN ₅ OS.0.51 H ₂ O: C, 55.51; H, 5. 15; N, 17.04; Cl, 8.62. Found: C, 55.60; H, 5.09; N, 16.84; Cl, 8.76.

Example 61 3-Amino-4- [4- (2-chlorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound number 3-92)

(61a) tert-butyl4- (2-chlorophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2976, 1692, 1482, 1366, 1160, 751 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46 (4.5H, s), 1.47 (4.5H, s), 1.97-2.04 (2H, m), 3.14-3.21 (4H, m), 3.53-3.64 (4H , m), 6.90 (1H, t, J = 7.1 Hz), 7.04 (1H, d, J = 7.1 Hz), 7.14 (1H, t, J = 7.1 Hz), 7.32 (1H, d, J = 7.1 Hz );

HRMS m / z calc'd C ₁₆ H ₂₃ N ₂ O ₂ ³⁵ Cl 310.1448, found 310.1472;

MS (EI) m / z: 310 [M ⁺ ], 282, 253, 237, 209, 193, 180, 166, 154, 138, 125, 111, 70, 57.

(61b) 1- (2-chlorophenyl) -1,4-diazepane

tert-butyl4- (2-chlorophenyl) -1,4-diazepane- made in Example 61 (61a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Yellow liquid

IR (film) ν _max 2941, 2836, 1588, 1481, 1295, 1040, 752 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.93 (2H, quint, J = 5.9 Hz), 2.18 (1H, brs), 3.03-3.08 (4H, m), 3.23-3.29 (4H, m), 6.87 ( 1H, t, J = 5.9 Hz), 7.07 (1H, d, J = 5.9 Hz), 7.14 (1H, t, J = 5.9 Hz), 7.31 (1H, d, J = 5.9 Hz);

HRMS m / z calc'd C ₁₁ H ₁₅ N ₂ Cl 210.0924, found 210.0916;

MS (EI) m / z: 210 [M ⁺ ], 180, 175, 168, 154, 146, 128, 111, 92, 77, 64.

(61c) (2Z) -3- [4- (2-chlorophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as in Example 5 (5a), using 1- (2-chlorophenyl) -1,4-diazepane prepared in Example 61 (61b). The title compound was synthesized.

Pale yellow powder

Mp 123-124 ° C .;

IR (KBr) ν _max 3367, 3265, 3186, 2184, 1611, 1525, 1402, 1289, 1041, 766, 673 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.12-2.17 (2H, m), 2.69 (3H, s), 3.23 (2H, t, J = 5.9 Hz), 3.34-3.37 (2H, m), 3.91 ( 2H, t, J = 5.9 Hz), 3.97-4.00 (2H, m), 6.70 (2H, brs), 6.97 (1H, dt, J = 1.2, 8.2 Hz), 7.05 (1H, dd, J = 1.2, 8.2 Hz), 7.19 (1H, dt, J = 1.2, 8.2 Hz), 7.35 (1H, dd, J = 1.2, 8.2 Hz);

HRMS m / z calc'd C ₁₆ H ₂₀ N ₄ ClS 335.1097, found 335.1098;

MS (FAB) m / z: 335 [M + H] ⁺ , 273, 246, 211;

analysis. Calc. For C ₁₆ H ₁₉ ClN ₄ S.0.64H ₂ O: C, 55.48; H, 5. 90; N, 16.17; Cl, 10.23; S, 9.26. Found: C, 55.69; H, 5.81; N, 16.19; Cl, 9.97; S, 9.35.

(61d) 3-amino-4- [4- (2-chlorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -3- [4- (2-chlorophenyl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enthioamide (64 mg) prepared in Example 61 (61c). , 0.19 mmol) and N, N-dimethylformamide dimethylacetal (54 mg, 0.45 mmol) were dissolved in ethanol (2 mL), and the mixture was stirred at room temperature for 1 hour, after which the solvent was distilled off. The residue was dissolved in N, N-dimethylformamide (0.3 mL) and stirred at 80 ° C. for 15 minutes. The reaction mixture was cooled to room temperature and 8N aqueous sodium hydroxide solution (0.08 mL) and 2-chloroacetamide (21 mg, 0.22 mmol) were added. After stirring at room temperature for 1 hour, the reaction mixture was separated with water and ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. After the residue was solidified with brine ethanol, the solid was filtered off to obtain 76 mg (yield 31%) of the title compound.

Pale yellow powder

Mp 206-210 ° C .;

IR (KBr) ν _max 3435, 3318, 3168, 1645, 1584, 1501, 1369, 1041, 937, 761 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.05-2.11 (2H, m), 3.28-3.31 (2H, m), 3.41- 3.48 (6H, m), 6.97-7.01 (1H, m), 7.07 (2H, brs), 7.11 (2H, brs), 7.11-7.12 (1H, m), 7.25-7.27 (2H, m), 7.40 (1H, d, J = 7.1 Hz), 8.40 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₁₉ H ₂₁ N ₅ OClS 402.1155, found 402.1153;

MS (FAB) m / z: 402 [M + H] ⁺ , 246, 189, 182;

analysis. Calc. For C ₁₉ H ₂₀ ClN ₅ OS.0.22H ₂ O: C, 56.23; H, 5.08; N, 17.25; Cl, 8.73; S, 7.90. Found: C, 56.18; H, 5.11; N, 17.08; Cl, 8.66; S, 7.62.

(Example 62) 3-amino-4- [4- (4-cyanophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-98)

(62a) tert-Butyl 4- (4-cyanophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Example 59 (59a), using 4-cyanofluorobenzene (242 mg, 2 mmol) and tert-butoxycarbonyl homopiperazine (801 mg, 4 mmol). The target compound (364 mg, yield 60%) was obtained.

Brown liquid

IR (film) ν _max 2975, 2214, 1691, 1606, 1521, 1417, 1365, 1240, 1178, 929, 819, 544 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.16 (4.5H, s), 1.28 (4.5H, s), 1.68-1.85 (2H, m), 3.17 (1H, t, J = 5.9 Hz), 3.25 (1H, t, J = 5.5 Hz), 3.44-3.68 (6H, m), 6.81 (2H, d, J = 9.4 Hz), 7.48 (2H, dd, J = 3.5, 9.4 Hz);

HRMS m / z calc'd C ₁₇ H ₂₃ N ₃ O ₂ 301.1790, found 301.1784;

MS (FAB) m / z: 302 [M + H] ⁺ , 301, 246, 228, 200, 120.

(62b) 1- (4-cyanophenyl) -1,4-diazepane

tert-butyl4- (4-cyanophenyl) -1,4-diazepane prepared in Example 62 (62a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Brown liquid

IR (film) ν _max 2935, 2211, 1606, 1521, 1404, 1178, 817, 544 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.87 (2H, quint, J = 5.9 Hz), 2.81 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.9 Hz), 3.55 (2H , t, J = 5.9 Hz), 3.61 (2H, t, J = 5.9 Hz), 6.65 (2H, t, J = 9.0 Hz), 8.43 (2H, d, J = 9.0 Hz);

HRMS m / z calc'd C ₁₂ H ₁₅ N ₃ 201.1266, found 201.1268;

MS (EI) m / z: 20 1 [M ⁺ ], 171, 159, 145, 131, 116, 102.

(62c) (2Z) -2-cyano-3- [4- (4-cyanophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

The reaction was carried out in the same manner as in Example 5 (5a), using 1- (4-cyanophenyl) -1,4-diazepane prepared in Example 62 (62b) instead of isobutylamine. The title compound was synthesized.

Pale yellow powder

Mp 169-171 ° C. (decomposition);

IR (KBr) ν _max 3290, 2214, 217, 1604, 1519, 1408, 1179, 819, 543 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.94 (2H, m), 2.21 (3H, s), 3.52 (2H, t, J = 5.5 Hz), 3.58-3.63 (4H, m), 3.82 (2H, t, J = 5.5 Hz), 6.85 (2H, d, J = 9.0 Hz), 7.51 (2H, d, J = 9.0 Hz), 8.38 (1H, brs), 9.02 (1H, brs);

HRMS m / z calc. C ₁₇ H ₂₀ N ₅ S 326.1440, found 326.1436;

MS (FAB) m / z: 326 [M + H] ⁺ , 202, 171, 120.

(62d) (2Z) -2-cyano-3- [4- (4-cyanophenyl) -1,4-diazepane-1-yl] -N-[(1E)-(dimethylamino) methylene] Buta-2-enthioamide

In Example 62 (62c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 (58d), using the prepared (2Z) -3- [4- (4-cyanophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide The reaction was carried out in the same manner as in the method described above, to obtain the title compound.

Yellow powder

Mp 120-126 ° C .;

IR (KBr) ν _max 2926, 2211, 2180, 1606, 1519, 1178, 821, 546 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94-1.97 (2H, m), 2.44 (3H, s), 2.90 (3H, s) 3.14 (3H, s), 3.64 (2H, t, J = 5.5 Hz), 3.71-3.77 (4H, m), 3.90 (2H, t, J = 5.5 Hz), 6.85 (2H, d, J = 9.0 Hz), 7.48 (2H, d, J = 9.0 Hz), 8.41 (1H, s);

HRMS m / z calc. C ₂₀ H ₂₅ N ₆ S 381.1861, found 381.1856;

MS (FAB) m / z: 381 [M + H] ⁺ , 336, 257, 230, 202, 180, 90, 65;

analysis. Calc. For C ₂₀ H ₂₄ N ₆ S.0.62H ₂ 0: C, 61.33; H, 6. 50; N, 21.46; S, 8.19. Found: C, 61.36; H, 6. 35; N, 21.25, S, 8.11.

(62e) 3-amino-4- [4- (4-cyanophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 (2Z) -2-cyano-3- [4- (4-cyanophenyl) -1,4-diazepan-1-yl] prepared in Example 62 (62d) instead of enthioamide. The reaction was carried out in the same manner as in Example 58 (58e) using N-[(1E)-(dimethylamino) methylene] buta-2-enthioamide to obtain the title compound.

Yellow powder

Mp 151-153 ° C .;

IR (KBr) ν _max 3439, 3327, 2211, 1605, 1519, 1366, 1178, 938, 818, 544 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13-2.18 (2H, m), 3.17-3.19 (2H, m), 3.61 (2H, t, J = 6.3 Hz), 3.84 (2H, t, J = 5.1 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.96 (2H, brs), 7.05 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 7.52 (2H, t, J = 9.0 Hz), 8.37 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₁ N ₆ OS 393.1497, found 393.1501;

MS (FAB) m / z: 393 [M + H] ⁺ , 273, 246;

analysis. Calc. For C ₂₀ H ₂₀ N ₆ OS.0.94H ₂ O: C, 58.67; H, 5.39; N, 20.53. Found: C, 58.99; H, 5.51; N, 20.22.

Example 63 3-amino-4- [4- (4-trifluoromethylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-121)

(63a) tert-butyl4- (4-trifluoromethylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

White powder

IR (KBr) ν _max 2974, 1673, 1422, 1332, 1197, 1100, 987, 829 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.33 (4.5H, s), 1.41 (4.5H, s), 1.93-1.99 (2H, m), 3.20 (1H, t, J = 6.3 Hz), 3.31 ( 1H, t, J = 5.9 Hz), 3.54-3.62 (6H, m), 6.67 (2H, d, J = 9.0 Hz), 7.40 (2H, d, J = 9.0 Hz);

HRMS m / z calc. C ₁₇ H ₂₃ N ₂ O ₂ F ₃ 344.1711, found 344.1718;

MS (FAB) m / z: 345 [M + H] ⁺ , 344, 289, 243, 214, 174, 120, 57;

analysis. Calc. For C ₁₇ H ₂₃ F ₃ N ₂ O ₂ : C, 59.29; H, 6.73; N, 8.13. Found: C, 59.38; H, 6. 45; N, 7.98.

(63b) 1- (4-trifluoromethylphenyl) -1,4-diazepane

tert-butyl4- (4-trifluoromethylphenyl) -1,4-diaza prepared in Example 63 (63a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using Platen-1-carboxylate.

Yellow liquid

IR (film) ν _max 2936, 1616, 1531, 1402, 1330, 1197, 1106, 818 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 6.3 Hz), 2.81 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.1 Hz), 3.54-3.61 (4H, m), 6.67 (2H, t, J = 9.0 Hz), 8.39 (2H, d, J = 9.0 Hz);

HRMS m / z calc'd C ₁₂ H ₁₅ N ₂ F ₃ 244.1187, found 244.1182;

MS (EI) m / z: 244 [M ⁺ ], 225, 214, 202, 188, 174, 159, 145, 69, 43.

(63c) (2Z) -2-cyano-3- [4- (4-trifluoromethylphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as described in Example 5 (5a), using 1- (4-trifluoromethylphenyl) -1,4-diazepane prepared in Example 63 (63b). It carried out and synthesize | combined the title compound.

Pale yellow powder

Mp 266-269 ° C. (decomposition);

IR (KBr) ν _max 3373, 3267, 3171, 2185, 1614, 1527, 1330, 1104, 822 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-1.95 (2H, m), 2.23 (3H, s), 3.51 (2H, t, J = 5.5 Hz), 3.59-3.63 (4H, m), 3.79 (2H, t, J = 5.1 Hz), 6.87 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.6 Hz), 8.37 (1H, brs), 9.01 (1H, brs);

HRMS m / z calc'd C ₁₇ H ₂₀ N ₄ F ₃ S 369.1361, found 369.1359;

MS (FAB) m / z: 369 [M + H] ⁺ , 335, 245, 227, 200, 166, 63;

analysis. Calc. For C ₁₇ H ₁₉ F ₃ N ₄ S0.10H ₂ O: C, 55.15; H, 5. 23; N, 15.13; F, 15.39. Found: C, 54.92; H, 5. 26; N, 15.25, F, 15.59.

(63d) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-trifluoromethylphenyl) -1,4-diazepane-1-yl Buta-2-enthioamide

In Example 63 (63c) instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 ((2Z) -3- [4- (4-trifluoromethylphenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide, The reaction was carried out in the same manner as in the method described in 58d), to obtain the title compound.

Yellow powder

Mp 251-253 ° C .;

IR (KBr) ν _max 2927, 2177, 1614, 1400, 1332, 1201, 1107, 925, 832 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.95-1.99 (2H, m), 2.47 (3H, s), 2.89 (3H, s), 3.12 (3H, s), 3.63 (2H, t, J = 6.3 Hz), 3.70-3.79 (4H, m), 3.89 (2H, t, J = 5.1 Hz), 6.90 (2H, d, J = 9.0 Hz), 7.42 (2H, d, J = 9.0 Hz), 8.44 (1 H, s);

HRMS m / z calc. C ₂₀ H ₂₅ N ₆ F ₃ S 424.1783, found 424.1783;

MS (FAB) m / z: 424 [M + H] ⁺ , 390, 379, 352, 245, 227, 200, 188, 90, 73;

analysis. Calc. For C ₂₀ H ₂₄ F ₃ N ₅ S: C, 56.72; H, 5.71; N, 16.54; F, 13.46; S, 7.57. Found: C, 56.46; H, 5. 60; N, 16.36, F, 13.32; S, 7.49.

(63e) 3-amino-4- [4- (4-trifluoromethylphenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 Instead of enthioamide, (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-trifluoro) prepared in Example 63 (63d) The title compound was obtained in the same manner as in Example 58 (58e) using methylphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide.

Pale yellow powder

Mp 204-208 ° C;

IR (KBr) ν _max 3326, 1614, 1502, 1330, 1199, 1104, 939, 817 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.15-2.19 (2H, m), 3.17-3.22 (2H, m), 3.30-3.32 (2H, m), 3.62 (2H, t, J = 5.5 Hz ), 3.84-3.86 (2H, m), 6.91 (2H, d, J = 9.0 Hz), 7.00 (2H, brs), 7.09 (1H, d, J = 5.5 Hz), 7.11 (2H, brs), 7.47 (2H, t, J = 9.0 Hz), 8.41 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₁ ON ₅ F ₃ S 436.1419, found 436.1418;

MS (FAB) m / z: 436 [M + H] ⁺ , 419, 246, 214;

analysis. Calc. For C ₂₀ H ₂₀ F ₃ N ₅ OS.0.98H ₂ O: C, 53.01; H, 4.88; N, 15.46; F, 12.58; S, 7.08. Found: C, 52.79; H, 4.61; N, 15.21; F, 12.97; S, 7.12.

Example 64 3-amino-4- {4- [4- (methylthio) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carbox Mead (Example Compound No. 3-131)

(64a) tert-butyl4- [4- (methylthio) phenyl] -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2974, 1693, 1595, 1503, 1416, 1365, 1237, 1168, 1125, 930, 810 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.35 (4.5H, s), 1.42 (4.5H, s), 1.91-1.96 (2H, m), 2.39 (3H, s), 3.19 (1H, t, J = 5.9 Hz), 3.30 (1H, t, J = 5.9 Hz), 3.49-3.54 (6H, m), 6.61 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.6 Hz);

HRMS m / z calc'd C ₁₇ H ₂₆ O ₂ N ₂ S 322.1715, found 322.1714;

MS (FAB) m / z: 322 [M ⁺ ], 266, 221, 178, 57;

analysis. Calc. For C ₁₇ H ₂₆ N ₂ O ₂ S.0.28H ₂ O: C, 62.34; H, 8. 17; N, 8.55. Found: C, 62.38; H, 8.41; N, 8.38.

(64b) 1- [4- (methylthio) phenyl] -1,4-diazepane

tert-butyl4- [4- (methylthio) phenyl] -1,4- produced in Example 64 (64a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using diazephan-1-carboxylate.

Yellow liquid

IR (film) ν _max 2919, 1595, 1503, 1395, 1195, 809 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.40 (3H, s), 2.82 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.1 Hz), 3.47-3.57 (4H, m), 6.64 (2H, d, J = 8.6 Hz), 8.25 (2H, d, J = 8.6 Hz);

HRMS m / z calc'd C ₁₂ H ₁₈ N ₂ S 222.1191, found 222.1178;

MS (EI) m / z: 222 [M ⁺ ], 192, 180, 166, 151, 137, 108, 91, 77, 70, 56, 43.

(64c) (2Z) -2-cyano-3- {4- [4- (methylthio) phenyl] -1,4-diazepan-1-yl} buta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as described in Example 5 (5a), using 1- (4-methylsulfanylphenyl) -1,4-diazephan prepared in Example 64 (64b). It carried out and synthesize | combined the title compound.

Pale yellow powder

Mp 159-160 ° C. (decomposition);

IR (KBr) ν _max 3341, 3154, 2178, 1594, 1501, 1392, 1244, 1011, 879, 811 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.90-1.94 (2H, m), 2.23 (3H, s), 2.36 (3H, s), 3.49-3.54 (4H, m), 3.59-3.61 (2H , m), 3.70-3.73 (2H, m), 6.75 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 8.35 (1H, brs), 9.01 (1H, brs) ;

HRMS m / z calc'd C ₁₇ H ₂₂ N ₄ S ₂ 346.1286, found 346.1245;

MS (EI) m / z: 346 [M ⁺ ], 272, 247, 222, 205, 192, 178, 166, 151, 137, 123, 96, 68, 59, 42;

analysis. Calc. For C ₁₇ H ₂₂ N ₄ S ₂ .0.08H ₂ O: C, 56.68; H, 6. 42; N, 16.10; S, 18.43. Found: C, 58.47; H, 6. 32; N, 15.98, S, 18.39.

(64d) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- {4- [4- (methylthio) phenyl] -1,4-diazepane-1- Buta-2-enthioamide

In Example 64 (64c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 using (2Z) -3- {4- [4- (methylthio) phenyl] -1,4-diazepane-1-yl} -2-cyanobuta-2-enthioamide Reaction was performed similarly to the method described in (58d) to obtain the title compound.

Yellow powder

Mp 133-136 ° C .;

IR (KBr) ν _max 2921, 2177, 1610, 1501, 1396, 1325, 1291, 1195, 1011, 923, 815 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.93-1.98 (2H, m), 2.35 (3H, s), 2.49 (3H, s), 2.92 (3H, s), 3.14 (3H, s), 3.53 (2H, t, J = 5.9 Hz), 3.69-3.81 (6H, m), 6.75 (2H, d, J = 9.0 Hz), 7.14 (2H, d, J = 9.0 Hz), 8.46 (1H, s );

HRMS m / z calc. C ₂₀ H ₂₈ N ₅ S ₂ 402.1786, found 402.1770;

MS (FAB) m / z: 402 [M + H] ⁺ , 368, 330, 221, 192, 178, 166;

analysis. Calc. For C ₂₀ H ₂₇ N ₅ S ₂ .0.2H ₂ O: C, 59.28; H, 6. 82; N, 17.28; S, 15.83. Found: C, 59.53; H, 6. 80; N, 17.00; S, 15.96.

(64e) 3-amino-4- {4- [4- (methylthio) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- {4- [4- (methylthio) prepared in Example 64 (64d) instead of enthioamide. The reaction was carried out in the same manner as in Example 58 (58e) using phenyl] -1,4-diazepan-1-yl} buta-2-enthioamide to obtain the title compound.

Pale yellow powder

Mp 186-188 ° C .;

IR (KBr) ν _max 3433, 3326, 3163, 1657, 1592, 1500, 1367, 1232, 940, 811 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.09-2.14 (2H, m), 2.36 (3H, s), 3.16-3.18 (2H, m), 3.25-3.28 (2H, m), 3.52 (2H , t, J = 6.3 Hz), 3.74 (2H, t, J = 4.7 Hz), 6.73 (2H, d, J = 9.0 Hz), 6.94 (2H, brs), 7.05 (1H, d, J = 5.1 Hz ), 7.06 (2H, brs), 7.17 (2H, t, J = 9.0 Hz), 8.37 (1H, d, J = 5.1 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ ON ₅ S ₂ 414.1422, found 414.1414;

MS (FAB) m / z: 414 [M + H] ⁺ , 413, 397, 275, 230, 218, 192, 178, 166;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS ₂ : C, 58.08; H, 5.61; N, 16.93; S, 15.51. Found: C, 57.91; H, 5. 66; N, 16.68; S, 15.42.

Example 65 3-amino-4- [4- (3-toluyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-110)

(65a) tert-Butyl 4- (3-toluyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2974, 1695, 1602, 1498, 1415, 1175, 930, 692 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.44 (4.5H, s), 1.92-1.98 (2H, m), 2.28 (3H, s), 3.19 (1H, t, J = 6.3 Hz), 3.29 (1H, t, J = 6.3 Hz), 3.49-3.54 (6H, m), 6.46-6.48 (3H, m), 7.06 (1H, t, J = 7.1 Hz);

HRMS m / z calc'd C ₁₇ H ₂₆ O ₂ N ₂ 290.1994, found 290.1981;

MS (FAB) m / z: 290 [M ⁺ ], 235, 217, 189, 120, 91, 70, 57;

analysis. Calc. For C ₁₇ H ₂₆ N ₂ O ₂ .0.16 H ₂ O: C, 69.62; H, 9.05; N, 9.55. Found: C, 69.71; H, 9. 36; N, 9.28.

(65b) 1- (3-toluyl) -1,4-diazepane

tert-butyl4- (3-toluyl) -1,4-diazepane-prepared in Example 65 (65a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Yellow liquid

IR (film) ν _max 2928, 1601, 1498, 1363, 1178, 765, 692 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 4.3 Hz), 2.29 (3H, s), 2.82 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.1 Hz), 3.52-3.57 (4H, m), 6.47-6.51 (3H, m), 7.09 (2H, dd, J = 1.9, 9.4 Hz);

HRMS m / z calc. For C ₁₂ H ₁₈ N ₂ 190.1470, found 190.1456;

MS (EI) m / z: 190 [M ⁺ ], 160, 148, 134, 122, 105, 91, 77, 65, 43.

(65c) (2Z) -2-cyano-3- [4- (3-toluyl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, reaction was carried out in the same manner as in Example 5 (5a), using the 1- (3-toluyl) -1,4-diaze plate prepared in Example 65 (65b). The title compound was synthesized.

Pale yellow powder

Mp 144-148 ° C .;

IR (KBr) ν _max 3151, 2188, 1601, 1542, 1345, 1174, 912, 766 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-1.95 (2H, m), 2.22 (3H, s), 2.23 (3H, s), 3.48-3.54 (4H, m), 3.60-3.63 (2H , m), 3.68-3.71 (2H, m), 6.44 (1H, d, J = 7.0 Hz), 6.55-6.57 (2H, m), 7.03 (1H, t, J = 7.0 Hz), 8.34 (1H, brs), 9.01 (1H, broad singlet);

HRMS m / z calc'd C ₁₇ H ₂₃ N ₄ S 315.1644, found 315.1645;

MS (FAB) m / z: 315 [M + H] ⁺ , 281, 256, 246, 173;

analysis. Calc. For C ₁₇ H ₂₂ N ₄ S: C, 64.93; H, 7.05; N, 17.82; S, 10.20. Found: C, 64.65; H, 7.05; N, 17.73, S, 10.13.

(65d) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (3-toluyl) -1,4-diazepan-1-yl] buta 2-enthioamide

In Example 65 (65c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 (58d) using prepared (2Z) -3- [4- (3-toluyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide The reaction was carried out in the same manner as described in the above to obtain the title compound.

Yellow powder

Mp 256-260 ° C. (decomposition);

IR (KBr) ν _max 2178, 1608, 1394, 1292, 1181, 1118, 773, 692 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94-1.99 (2H, m), 2.21 (3H, s), 2.49 (3H, s), 2.92 (3H, s), 3.14 (3H, s), 3.54 (2H, t, J = 5.9 Hz), 3.68-3.77 (6H, m), 6.43 (1H, d, J = 7.8 Hz), 6.55-6.58 (2H, m), 7.02 (1H, t, J = 7.8 Hz), 8.45 (1 H, s);

HRMS m / z calc. C ₂₀ H ₂₈ N ₅ S 370.2065, found 370.2057;

MS (FAB) m / z: 370 [M + H] ⁺ , 354, 336, 325, 298, 281, 235, 208, 196, 180, 173, 160, 134, 115, 90, 58;

analysis. Calc. For C ₂₀ H ₂₇ N ₅ S.0.06H ₂ 0: C, 64.82; H, 7. 38; N, 18.90; S, 8.65. Found: C, 64.85; H, 7.22; N, 18.61; S, 8.95.

(65e) 3-amino-4- [4- (3-toluyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (3-toluyl) prepared in Example 65 (65d) instead of enthioamide The reaction was carried out in the same manner as in Example 58 (58e) using -1,4-diazepan-1-yl] buta-2-enthioamide to obtain the title compound.

Pale yellow powder

Mp 209-212 ° C .;

IR (KBr) ν _max 3327, 3169, 2830, 1637, 1579, 1498, 1373, 1234, 1182, 942, 767 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.10-2.15 (2H, m), 2.22 (3H, s), 3.14-3.18 (2H, m), 3.26-3.28 (2H, m), 3.52 (2H , t, J = 6.3 Hz), 3.73 (2H, t, J = 4.7 Hz), 6.41 (1H, d, J = 7.8 Hz), 6.53-6.56 (2H, m), 6.97 (2H, brs), 7.01 (1H, t, J = 7.8 Hz), 7.05 (1H, d, J = 5.5 Hz), 7.06 (2H, brs), 8.37 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ ON ₅ S 382.1702, found 382.1699;

MS (FAB) m / z: 382 [M + H] ⁺ , 365, 248, 230, 218, 202, 176;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS.0.08H ₂ 0: C, 62.73; H, 6. 10; N, 18.29; S, 8.37. Found: C, 62.56; H, 6.08; N, 18.14; S, 8.32.

Example 66 3-amino-4- {4- [4- (methylsulfinyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-132)

3-amino-4- {4- [4- (methylthio) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine- prepared in Example 64 (64e)- 2-carboxamide (57 mg, 0.14 mmol) was dissolved in methanol (5 mL), an aqueous solution of sodium periodate (33 mg, 0.15 mmol) (1 mL) was added, and the mixture was heated to reflux for 1 hour. Water (10 mL) was added to the reaction solution, followed by stirring for 2 hours. The resulting powder was filtrated to obtain the title compound (53 mg, 89% yield).

White powder

Mp 153-157 ° C .;

IR (KBr) ν _max 3439, 3324, 3182, 1646, 1592, 1505, 1367, 1093, 1037, 939, 814 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13-2.17 (2H, m), 2.67 (3H, s), 3.18-3.22 (2H, m), 3.29-3.31 (2H, m), 3.61 (2H , t, J = 6.3 Hz, 3.84 (2H, t, J = 6.3 Hz), 6.93 (2H, d, J = 9.0 Hz), 6.94 (2H, brs), 7.09 (1H, d, J = 5.1 Hz ), 7.09 (2H, brs), 7.49 (2H, t, J = 9.0 Hz), 8.40 (1H, d, J = 5.1 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ 0 ₂ N ₅ S ₂ 430.1371, found 430.1386;

MS (FAB) m / z: 430 [M + H] ⁺ , 412, 395, 242, 230, 204, 166, 65;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ O ₂ S ₂ .2.1H ₂ O: C, 51.40; H, 5.87; N, 14.98; S, 13.72. Found: C, 51.61; H, 5.87; N, 15.00; S, 13.52.

(Example 67) 3-amino-4- [4- (2-methoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-122)

(67a) tert-butyl4- (2-methoxyphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2975, 1694, 1503, 1415, 1242, 1165, 1029, 745 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.14-1.46 (9H, m), 1.89-2.00 (2H, m), 3.18-3.31 (4H, m), 3.48-3.62 (4H, m), 3.83 (3H , s), 6.81-6.93 (4H, m);

HRMS m / z calc. For C ₁₇ H ₂₆ O ₃ N ₂ 306.1943, found 306.1972;

MS (EI) m / z: 306 [M ⁺ ], 249, 233, 205, 188, 176, 162, 150, 134, 120, 57.

(67b) 1- (2-methoxyphenyl) -1,4-diazepane

tert-butyl4- (2-methoxyphenyl) -1,4-diazepane prepared in Example 67 (67a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Yellow liquid

IR (film) ν _max 2938, 1593, 1502, 1242, 1028, 744 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.96 (2H, quint, J = 5.9 Hz), 3.05 (2H, t, J = 5.5 Hz), 3.11 (2H, t, J = 5.5 Hz), 3.30-3.34 (4H, m), 3.84 (3H, s), 6.83-6.96 (4H, m);

HRMS m / z calc. C ₁₂ H ₁₈ ON ₂ 206.1419. Found 206.1417;

MS (EI) m / z: 206 [M ⁺ ], 176, 164, 150, 136, 120, 109, 91, 77, 43.

(67c) (2Z) -2-cyano-3- [4- (2-methoxyphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

The reaction was carried out in the same manner as in Example 5 (5a), using 1- (2-methoxyphenyl) -1,4-diazepane prepared in Example 67 (67b) instead of isobutylamine. The title compound was synthesized.

Yellow amorphous

IR (KBr) ν _max 3287, 3171, 2918, 2184, 1607, 1533, 1452, 1238, 1024, 751 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.93-1.98 (2H, m), 2.33 (3H, s), 3.14-3.17 (2H, m), 3.25-3.37 (2H, m), 3.60-3.66 (4H, m), 3.75 (3H, s), 6.79-6.90 (4H, m), 8.23 (1H, brs), 8.91 (1H, brs);

HRMS m / z calc. C ₁₇ H ₂₃ ON ₄ S 331.1593, found 331.1587;

MS (FAB) m / z: 331 [M + H] ⁺ , 315, 273, 200, 165, 63.

(67d) 3-amino-4- [4- (2-methoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

Prepared in Example 67 (67c) instead of (2Z) -3- [4- (2-chlorophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide Example 61 (61d) using (2Z) -2-cyano-3- [4- (2-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Reaction was performed similarly to the method described in the above, to obtain the title compound.

Pale yellow powder

Mp 179-184 ° C .;

IR (KBr) ν _max 3440, 3314, 3141, 1581, 1500, 1371, 1235, 937, 751 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.04-2.10 (2H, m), 3.25-3.40 (8H, m), 3.75 (3H, s), 6.80-6.93 (4H, m), 7.05 (2H , brs), 7.08 (2H, brs), 7.11 (1H, d, J = 5.5 Hz), 8.39 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ O ₂ N ₅ S 398.1651, found 398.1653;

MS (FAB) m / z: 398 [M + H] ⁺ , 273, 246, 200, 63;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ 0 ₂ S.0.14H ₂ 0: C, 60.05; H, 5.87; N, 17.51; S, 8.02. Found: C, 59.87; H, 5.87; N, 17.43; S, 7.85.

(Example 68) 3-amino-4- [4- (3-methoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-123)

(68a) tert-butyl4- (3-methoxyphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2973, 1694, 1612, 1500, 1416, 1165, 930, 753 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.93-2.00 (2H, m), 3.19 (1H, t, J = 6.3 Hz), 3.28- 3.30 (1H, m), 3.49-3.55 (6H, m), 3.77 (3H, s), 6.23-6.25 (2H, m), 6.32 (1H, d, J = 7.0 Hz), 7.11 (1H, t, J = 7.0 Hz);

HRMS m / z calc'd C ₁₇ H ₂₆ O ₃ N ₂ 306.1943, found 306.1937;

MS (EI) m / z: 306 [M ⁺ ], 250, 235, 205, 188, 176, 162, 150, 121, 70, 57;

analysis. Calc. For C ₁₇ H ₂₆ N ₂ 0 ₃ .0.38H ₂ 0: C, 65.18; H, 8.61; N, 8.94. Found: C, 65.22; H, 8.59; N, 8.79.

(68b) 1- (3-methoxyphenyl) -1,4-diazepane

tert-butyl4- (3-methoxyphenyl) -1,4-diazepane prepared in Example 68 (68a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Yellow liquid

IR (film) ν _max 2935, 1611, 1500, 1166, 1054, 923, 752, 688 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.82 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.9 Hz), 3.51-3.57 (4H, m), 3.78 (3H, s), 6.21-6.24 (2H, m), 6.32 (1H, dd, J = 1.9, 9.4 Hz), 7.11 (1H, t, J = 9.4 Hz);

HRMS m / z calc. C ₁₂ H ₁₈ ON ₂ 206.1420, found 206.1403;

MS (EI) m / z: 206 [M ⁺ ], 164, 150, 138, 121, 70, 56.

(68c) (2Z) -2-cyano-3- [4- (3-methoxyphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

The reaction was carried out in the same manner as described in Example 5 (5a), using 1- (3-methoxyphenyl) -1,4-diazepane prepared in Example 68 (68b) instead of isobutylamine. The title compound was synthesized.

Pale yellow powder

Mp 129-131 ° C .;

IR (KBr) ν _max 3349, 3154, 2939, 2187, 1611, 1541, 1344, 1167, 1058, 914, 749 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-1.94 (2H, m), 2.23 (3H, s), 3.49-3.54 (4H, m), 3.59-3.62 (2H, m), 3.69 (3H , s), 3.69-3.73 (2H, m), 6.21 (1H, d, J = 9.0 Hz), 6.25 (1H, s), 6.35 (1H, d, J = 9.0 Hz), 7.05 (1H, t, J = 9.0 Hz), 8.35 (1 H, brs), 9.02 (1 H, brs);

HRMS m / z calc. C ₁₇ H ₂₃ ON ₄ S 331.1592, found 331.1575;

MS (FAB) m / z: 331 [M + H] ⁺ , 246, 200, 165, 63;

analysis. Calc. For C ₁₇ H ₂₂ N ₄ OS: C, 61.79; H, 6. 71; N, 16.95; S, 9.70. Found: C, 61.72; H, 6. 66; N, 16.85, S, 9.44.

(68d) 4- [4- (3-methoxyphenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [4- (3-methoxyphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide prepared in Example 68 (68c) ( 476 mg, 1.44 mmol) and N, N-dimethylformamide dimethylacetal (344 mg, 2.88 mmol) were mixed in ethanol (15 mL) and stirred at room temperature for 18 hours. Precipitated crystals were filtered off to obtain 490 mg (yield 27%) of the title compound.

Pale yellow powder

Mp 224-227 ° C. (decomposition);

IR (KBr) ν _max 2955, 2208, 1608, 1499, 1256, 1166, 1052, 929, 756, 687 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.90-1.95 (2H, m), 3.51 (2H, t, J = 5.4 Hz), 3.69 (3H, s), 3.71-3.73 (4H, m), 3.95 (2H, t, J = 5.4 Hz), 6.20 (1H, d, J = 7.8 Hz), 6.26 (1H, s), 6.37 (1H, t, J = 7.8 Hz), 6.43 (1H, d, J = 7.8 Hz), 7.05 (1H, t, J = 7.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 12.51 (1H, brs);

HRMS m / z calc. C ₁₈ H ₂₁ ON ₄ S 341.1436, found 341.1445;

MS (FAB) m / z: 341 [M + H] ⁺ , 273, 246, 200, 165, 63;

analysis. Calc. For C ₁₈ H ₂₀ N ₄ OS.0.12H ₂ O: C, 63.10; H, 5.95; N, 16.35; S, 9.36. Found: C, 62.84; H, 5.97; N, 16.35, S, 9.36.

(68e) 3-amino-4- [4- (3-methoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (3-methoxyphenyl)-prepared in Example 68 (68d) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as described in Example 5 (5c) using 1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile to be described. The compound was obtained.

Pale yellow powder

Mp 193-195 ° C .;

IR (KBr) ν _max 3426, 3319, 3145, 1611, 1499, 1372, 1228, 1167, 1054, 943, 822 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.11-2.16 (2H, m), 3.16-3.21 (2H, m), 3.26-3.30 (2H, m), 3.53 (2H, t, J = 6.7 Hz ), 3.70 (3H, s), 3.75 (2H, t, J = 4.7 Hz), 6.22 (1H, dd, J = 2.4, 8.2 Hz), 6.26 (1H, t, J = 2.4 Hz), 6.37 (1H , dd, J = 2.4, 8.2 Hz), 7.00 (2H, brs), 7.04-7.08 (2H, m), 7.09 (2H, brs), 8.40 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ O ₂ N ₅ S 398.1651, found 398.1639;

MS (FAB) m / z: 398 [M + H] ⁺ , 273, 246, 200, 63;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ 0 ₂ S.0.16H ₂ 0: C, 60.00; H, 5.87; N, 17.49; S, 8.01. Found: C, 59.86; H, 5.67; N, 17.29; S, 7.83.

Example 69 3-amino-4- [4- (4-fluoro-3-methylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-118)

(69a) tert-butyl4- (4-fluoro-3-methylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2975, 1694, 1509, 1416, 1366, 1232, 1170, 931, 762 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.34 (4.5H, s), 1.42 (4.5H, s), 1.91-1.95 (2H, m), 2.20 (3H, s), 3.18 (1H, t, J = 5.9 Hz), 3.29 (1H, t, J = 5.9 Hz), 3.44-3.55 (6H, m), 6.37-6.44 (2H, m), 6.81 (1H, t, J = 8.6 Hz);

HRMS m / z calc'd C ₁₇ H ₂₅ O ₂ N ₂ F 308.1900, found 308.1892;

MS (EI) m / z: 308 [M ⁺ ], 253, 251, 207, 205, 164, 152, 138, 123, 109, 57;

analysis. Calc. For C ₁₇ H ₂₅ FN ₂ O ₂ : C, 66.21; H, 8. 17; N, 9.08; F, 6.16. Found: C, 66.50; H, 7. 29; N, 8.88; F, 6.18.

(69b) 1- (4-fluoro-3-methylphenyl) -1,4-diazepane

tert-butyl4- (4-fluoro-3-methylphenyl) -1,4 prepared in Example 69 (69a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using diazepan-1-carboxylate.

Yellow liquid

IR (film) ν _max 2929, 1615, 1509, 1228, 839, 797, 761 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 6.3 Hz), 2.23 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.48-3.54 (4H, m), 6.42-6.48 (2H, m), 6.85 (1H, t, J = 9.0 Hz);

HRMS m / z calc. C ₁₂ H ₁₇ N ₂ F 208.1575, found 208.1353;

MS (EI) m / z: 208 [M ⁺ ], 178, 166, 152, 138, 123, 109, 43;

(69c) (2Z) -2-cyano-3- [4- (4-fluoro-3-methylphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, 1- (4-fluoro-3-methylphenyl) -1,4-diazephan prepared in Example 69 (69b) was used, and the same method as described in Example 5 (5a) was used. The reaction was carried out to synthesize the title compound.

Pale yellow powder

Mp 146-150 ° C. (decomposition);

IR (KBr) ν _max 3328, 3152, 2189, 1627, 1543, 1508, 1389, 1220, 1056, 917, 868, 801 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.96 (2H, m), 2.18 (3H, s), 2.24 (3H, s), 3.48-3.53 (4H, m), 3.60-3.62 (2H , m), 3.66-3.69 (2H, m), 6.54-6.60 (1H, m), 6.64-6.67 (1H, m), 6.92 (1H, t, J = 9.0 Hz), 8.35 (1H, brs), 9.01 (1 H, broad singlet);

HRMS m / z calc. C ₁₇ H ₂₂ N ₄ FS 333.1536, found 333.1534;

MS (FAB) m / z: 333 [M + H] ⁺ , 299, 274, 207, 191, 178, 164, 123, 65, 51;

analysis. Calc. For C ₁₇ H ₂₁ FN ₄ S: C, 61.42; H, 6. 37; N, 16.85; S, 9.65. Found: C, 61.18; H, 6. 29; N, 16.71, S, 9.74.

(69d) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-fluoro-3-methylphenyl) -1,4-diazepane-1 -Yl] buta-2-enthioamide

In Example 69 (69c) instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example using using (2Z) -3- [4- (4-fluoro-3-methylphenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide The reaction was carried out in the same manner as described in 58 (58d), to obtain the title compound.

Yellow powder

Mp 148-150 ° C .;

IR (KBr) ν _max 2923, 2178, 1609, 1509, 1324, 1292, 1118, 1015, 512 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94-1.99 (2H, m), 2.15 (3H, s), 2.47 (3H, s), 2.92 (3H, s), 3.14 (3H, s), 3.51 (2H, t, J = 5.9 Hz), 3.72 (2H, t, J = 5.4 Hz), 3.73-3.77 (4H, m), 6.55-6.59 (1H, m), 6.64-6.66 (1H, m) , 6.80 (1H, t, J = 9.3 Hz), 8.45 (1H, s);

HRMS m / z calc. C ₂₀ H ₂₇ N ₅ FS 388.1971, found 388.1962;

MS (FAB) m / z: 388 [M + H] ⁺ , 354, 299, 273, 165, 120, 65, 51;

analysis. Calc. For C ₂₀ H ₂₆ FN ₅ S: C, 61.99; H, 6.76; N, 18.07; F, 4.90; S, 8.27. Found: C, 61.75; H, 6.57; N, 17.81; F, 4.77; S, 8.31.

(69e) 3-amino-4- [4- (4-fluoro-3-methylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-fluoro-) prepared in Example 69 (69d) instead of enthioamide. The reaction was carried out in the same manner as in Example 58 (58e) using 3-methylphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide to obtain the title compound.

White powder

Mp 194-197 ° C .;

IR (KBr) ν _max 3414, 3326, 3172, 1637, 1579, 1507, 1374, 1209, 943 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.10-2.18 (2H, m), 2.18 (3H, s), 3.15-3.21 (2H, m), 3.27-3.29 (2H, m), 3.50 (2H , t, J = 6.3 Hz), 3.71 (2H, t, J = 4,7 Hz), 6.52-6.56 (1H, m), 6.62-6.64 (1H, m), 6.91 (1H, t, J = 9.0 Hz), 6.98 (2H, brs), 7.06 (1H, doublet, J = 5.5 Hz), 7.07 (2H, brs), 8.38 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₃ ON ₅ FS 400.1607, found 400.1632;

MS (FAB) m / z: 400 [M + H] ⁺ , 383, 275, 236, 209;

analysis. Calc. For C ₂₀ H ₂₂ FN ₅ OS.0.14H ₂ O: C, 59.75; H, 5.59; N, 17.42; F, 4.73; S, 7.98. Found: C, 59.82; H, 5.58; N, 17.42; F, 4.45; S, 7.71.

Example 70 3-Amino-4- [4- (2-toluyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound number 3-109)

(70a) tert-butyl4- (2-toluyl) -1,4-diazepane-1-carboxylate

The title compound was synthesized in the same manner as described in J. Org. Chem., 68, 452-459 (2003).

Brown liquid

IR (film) ν _max 2975, 1695, 1492, 1413, 1159, 762, 725 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.47-1.48 (9H, m), 1.87-1.97 (2H, m), 2.29 (3H, s), 3.00-3.10 (4H, m), 3.52-3.60 (4H , m), 6.92 (1H, t, J = 7.8 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.08-7.14 (2H, m);

HRMS m / z calc'd C ₁₇ H ₂₆ O ₂ N ₂ 290.1994, found 290.1977;

MS (FAB) m / z: 290 [M ⁺ ], 249, 233, 189, 166, 146, 130, 95, 51.

(70b) 1- (2-toluyl) -1,4-diazepane

tert-butyl4- (2-toluyl) -1,4-diazepane prepared in Example 70 (70a) instead of tert-butyl4-phenyl-1,4-ziasepan-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Yellow liquid

IR (film) ν _max 2938, 2831, 1598, 1492, 1458, 1213, 1163, 1114, 759, 724 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89 (2H, quint, J = 5.9 Hz), 2.32 (3H, s), 3.02 (2H, t, J = 4.3 Hz), 3.07 (2H, t, J = 5.9 Hz), 3.12-3.17 (4H, m), 6.94 (1H, t, J = 7.8 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.12-7.17 (2H, m);

HRMS m / z calc. C ₁₂ H ₁₈ N ₂ 190.1470, found 190.1443;

MS (EI) m / z: 190 [M ⁺ ], 160, 148, 134, 118, 105, 91, 77, 65, 43.

(70c) (2Z) -2-cyano-3- [4- (2-toluyl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, reaction was carried out in the same manner as described in Example 5 (5a), using 1- (2-toluyl) -1,4-diazephan prepared in Example 70 (70b) The title compound was synthesized.

Pale yellow powder

Mp 99-100 ° C .;

IR (KBr) ν _max 3286, 3173, 2184, 1599, 1521, 1410, 1294, 1220, 881, 765 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.00-2.04 (2H, m), 2.24 (3H, s), 2.36 (3H, s), 3.01 (2H, t, J = 5.4 Hz), 3.16- 3.17 (2H, m), 3.66 (2H, t, J = 5.4 Hz), 3.70-3.72 (2H, m), 6.95 (1H, t, J = 6.8 Hz), 7.07 (1H, d, J = 7.3 Hz ), 7.12-7.17 (2H, m), 8.27 (1H, brs), 8.93 (1H, brs);

HRMS m / z calc. C ₁₇ H ₂₃ N ₄ S 315.1644, found 315.1643;

MS (FAB) m / z: 315 [M + H] ⁺ , 281, 256, 189, 173, 65, 39;

analysis. Calc. For C ₁₇ H ₂₂ N ₄ S.0.56H ₂ O: C, 62.92; H, 7. 18; N, 17.26; S, 9.88. Found: C, 62.65; H, 6.88; N, 17.11, S, 9.13.

(70d) 3-amino-4- [4- (2-toluyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

Prepared in Example 70 (70c) instead of (2Z) -3- [4- (2-chlorophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide (2Z) -2-cyano-3- [4- (2-toluyl) -1,4-diazepane-1-yl] buta-2-enthioamide was used in Example 61 (61d). The reaction was carried out in the same manner as described to obtain the title compound.

Pale yellow powder

Mp 206-209 ° C. (decomposition);

IR (KBr) ν _max 3427, 3308, 3142, 1583, 1493, 1374, 1228, 1053, 944, 767 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.97-2.04 (2H, m), 2.23 (3H, s), 3.11 (2H, t, J = 5.9 Hz), 3.22-3.25 (2H, m), 3.38-3.42 (2H, m), 6.84-6.88 (1H, m), 7.00-7.10 (7H, m), 8.34 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ ON ₅ S 382.1702, found 382.1701;

MS (FAB) m / z: 382 [M + H] ⁺ , 246, 185, 107;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS: C, 62.97; H, 6.08; N, 18.36. Found: C, 62.79; H, 6. 27; N, 18.20.

Example 71 3-amino-4- [4- (3-fluoro-4-methylphenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-117)

(71a) tert-butyl4- (3-fluoro-4-methylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2975, 1695, 1634, 1518, 1416, 1366, 1246, 1171, 1124, 930 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.38 (4.5H, s), 1.45 (4.5H, s), 1.93-1.99 (2H, m), 2.14 (3H, s), 3.20 (1H, t, J = 5.9 Hz), 3.30 (1H, t, J = 5.9 Hz), 3.45-3.55 (6H, m), 6.33-6.36 (2H, m), 6.96 (1H, t, J = 8.6 Hz);

HRMS m / z calc. C ₁₇ H ₂₅ 0 ₂ N ₂ F 308.1900, found 308.1877;

MS (EI) m / z: 308 [M ⁺ ], 253, 207, 178, 164, 152, 138, 123, 109, 57.

(71b) 1- (3-fluoro-4-methylphenyl) -1,4-diazepane

tert-butyl4- (3-fluoro-4-methylphenyl) -1,4 prepared in Example 71 (71a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using diazepan-1-carboxylate.

Yellow liquid

IR (film) ν _max 2929, 1634, 1518, 1459, 1119, 927, 822 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.14 (3H, s), 2.82 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.9 Hz), 3.50 (2H, t, J = 5.9 Hz), 5.53 (2H, t, J = 5.9 Hz), 6.34-6.38 (2H, m), 6.97 (1H, t, J = 9.0 Hz);

HRMS m / z calc. C ₁₂ H ₁₇ N ₂ F 208.1576, found 208.1360;

MS (EI) m / z: 208 [M ⁺ ], 178, 166, 152, 138, 123, 109, 44.

(71c) (2Z) -2-cyano-3- [4- (3-fluoro-4-methylphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, 1- (3-fluoro-4-methylphenyl) -1,4-diazephan prepared in Example 71 (71b) was used, and the same method as described in Example 5 (5a) was used. The reaction was carried out to synthesize the title compound.

Yellow powder

Mp 155-157 ° C. (decomposition);

IR (KBr) ν _max 3163, 2184, 1632, 1516, 1350, 1173, 1120, 872 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.90-1.94 (2H, m), 2.08 (3H, s), 2.25 (3H, s), 3.51-3.53 (4H, m), 3.59-3.61 (2H , m), 3.70-3.72 (2H, m), 6.50 (1H, dd, J = 2.4, 8.8 Hz), 6.56 (1H, dd, J = 2.4, 13.8 Hz), 7.02 (1H, t, J = 8.8 Hz), 8.35 (1 H, brs), 9.01 (1 H, brs);

HRMS m / z calc. For C ₁₇ H ₂₁ N ₄ FSNa 355.1369, found 355.1354;

MS (ESI) m / z: 355.14 [M + Na] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₁ FN ₄ S: C, 61.42; H, 6. 37; N, 16.85; F, 5.71. Found: C, 61.07; H, 6. 21; N, 16.66, F, 6.06.

(71d) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (3-fluoro-4-methylphenyl) -1,4-diazepane-1 -Yl] buta-2-enthioamide

In Example 71 (71c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example using the prepared (2Z) -3- [4- (3-fluoro-4-methylphenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide The reaction was carried out in the same manner as described in 58 (58d), to obtain the title compound.

Yellow powder

Mp 254-256 ° C .;

IR (KBr) ν _max 2925, 2177, 1608, 1517, 1397, 1291, 1120, 1013, 906, 512 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.94-1.98 (2H, m), 2.07 (3H, s), 2.49 (3H, s), 2.93 (3H, s), 3.15 (3H, s), 3.53 (2H, t, J = 5.9 Hz), 3.71 (2H, t, J = 5.4 Hz), 3.77-3.81 (4H, m), 6.51 (1H, dd, J = 2.4, 8.3 Hz), 6.56 (1H , dd, J = 2.4, 13.7 Hz), 7.01 (1H, t, J = 8.3 Hz), 8.46 (1H, s);

HRMS m / z calc. C ₂₀ H ₂₇ N ₅ FS 388.1971, found 388.1986;

MS (FAB) m / z: 388 [M + H] ⁺ , 354, 273, 242, 209, 166;

analysis. Calc. For C ₂₀ H ₂₆ FN ₅ S: C, 61.99; H, 6.76; N, 18.07; F, 4.90; S, 8.27. Found: C, 61.73; H, 6.87; N, 18.08; F, 4.92; S, 8.29.

(71e) 3-amino-4- [4- (3-fluoro-4-methylphenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (3-fluoro-) prepared in Example 71 (71d) instead of enthioamide. The title compound was obtained in the same manner as in the method described in Example 58 (58e) using 4-methylphenyl) -1,4-diazepan-1-yl] buta-2-enthioamide.

Pale yellow powder

Mp 79-83 ° C .;

IR (KBr) ν _max 3440, 3323, 3177, 2926, 1633, 1578, 1517, 1368, 1118, 943, 824 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.07-2.15 (2H, m), 2.09 (3H, s), 3.15-3.20 (2H, m), 3.23-3.27 (2H, m), 3.51 (2H , t, J = 6.3 Hz), 3.73 (2H, t, J = 4,7 Hz), 6.47-6.54 (2H, m), 6.97 (2H, brs), 7.02 (1H, t, J = 8.7 Hz) , 7.06 (1H, d, J = 5.5 Hz), 7.08 (2H, brs), 8.38 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₂₀ H ₂₃ ON ₅ FS 400.1608, found 400.1559;

MS (FAB) m / z: 400 [M + H] ⁺ , 278, 246, 185, 83, 57;

analysis. Calc. For C ₂₀ H ₂₂ FN ₅ OS.0.56H ₂ O: C, 58.65; H, 5.69; N, 17.10; F, 4.64. Found: C, 58.93; H, 6.04; N, 17.04; F, 4.89.

Example 72 3-amino-4- [4- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepan-1-yl] thieno [2 , 3-b] pyridine-2-carboxamide (example compound number 3-88)

(72a) tert-Butyl 4- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Brown liquid

IR (film) ν _max 2974, 1692, 1511, 1416, 1284, 1170, 1072, 931 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.39 (4.5H, s), 1.45 (4.5H, s), 1.92-1.99 (2H, m), 3.20 (1H, t, J = 6.3 Hz), 3.30 ( 1H, t, J = 5.9 Hz), 3.43-3.49 (4H, m), 3.53-3.55 (2H, m), 4.17-4.18 (2H, m), 4.22-4.23 (2H, m), 6.18-6.22 ( 2H, m), 6.72 (1H, doublet, J = 9.8 Hz);

HRMS m / z calc'd C ₁₈ H ₂₇ O ₄ N ₂ 335.1971, found 335.1974;

MS (FAB) m / z: 334 [M ⁺ ], 278, 246, 235, 189, 145, 139, 83, 57;

analysis. Calc. For C ₁₈ H ₂₆ N ₃ O ₄ .0.26H ₂ O: C, 63.76; H, 7.88; N, 8.27. Found: C, 63.75; H, 7. 66; N, 8.02.

(72b) 1- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepane

tert-butyl4- (2,3-dihydro-1,4-benzodi, prepared in Example 72 (72a), instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate Using the auxin-6-yl) -1,4-diazepane-1-carboxylate, it carried out similarly to the method of Example 57 (57b), and obtained the title compound.

Yellow liquid

IR (film) ν _max 2929, 1626, 1510, 1284, 1071, 822, 789 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.87 (2H, quint, J = 6.3 Hz), 2.82 (2H, t, J = 5.9 Hz), 3.00 (2H, t, J = 5.5 Hz), 3.45-3.50 (4H, m), 4.17-4.19 (2H, m), 4.22-4.24 (2H, m), 6.19-6.22 (2H, m), 6.72 (1H, d, J = 9.4 Hz);

HRMS m / z calc'd C ₁₃ H ₁₈ O ₂ N ₂ 234.1368, found 234.1373;

MS (EI) m / z: 234 [M ⁺ ], 204, 192, 178, 166, 149, 136, 117, 79, 56, 43.

(72c) (2Z) -2-cyano-3- [4- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepane-1-yl] buta 2-enthioamide

Instead of isobutylamine, 1- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepane prepared in Example 72 (72b) was used, and The reaction was carried out in the same manner as described in 5 (5a), to synthesize the title compound.

Yellow powder

Mp 114-116 ° C .;

IR (KBr) ν _max 3314, 3155, 2185, 1542, 1510, 1286, 1211, 1068, 869 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.84 (2H, m), 2.25 (3H, s), 3.40-3.45 (2H, m), 3.46-3.52 (2H, m), 3.59 (4H , brs), 4.10-4.12 (2H, m), 4.16-4.18 (2H, m), 6.24-6.27 (2H, m), 6.65 (1H, d, J = 9.5 Hz), 8.30 (1H, brs), 8.97 (1 H, broad singlet);

HRMS m / z calc. For C ₁₈ H ₂₃ O ₂ N ₄ S 359.1542, found 359.1540;

MS (FAB) m / z: 359 [M + H] ⁺ , 338, 273, 226, 182, 165, 120, 63;

analysis. Calc. For C ₁₈ H ₂₂ N ₄ O ₂ S: C, 59.30; H, 6. 27; N, 15.37. Found: C, 59.04; H, 6. 18; N, 15.71.

(72d) (2Z) -2-cyano-3- [4- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepane-1-yl]- N-[(1E)-(dimethylamino) methylene] buta-2-enthioamide

In Example 72 (72c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Prepared (2Z) -2-cyano-3- [4- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepan-1-yl] buta- The reaction was carried out in the same manner as in the method described in Example 58 (58d), using 2-enthioamide to obtain the title compound.

Yellow powder

Mp 127-129 ° C .;

IR (KBr) ν _max 3429, 2925, 2179, 1610, 1410, 1293, 1209, 1069, 513 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.92-1.98 (2H, m), 2.50 (3H, s), 2.95 (3H, s), 3.15 (3H, s), 3.45 (2H, t, J = 5.9 Hz), 3.67-3.72 (4H, m), 3.75-3.77 (2H, m), 4.11-4.13 (2H, m), 4.16-4.18 (2H, m), 6.26-6.29 (2H, m), 6.66 (1 H, d, J = 9.4 Hz), 8.48 (1 H, s);

HRMS m / z calc. For C ₂₁ H ₂₈ O ₂ N ₅ S 414.1964, found 414.1974;

MS (FAB) m / z: 413 [M + H] ⁺ , 380, 342, 273, 235, 178, 65, 39;

analysis. Calc. For C ₂₁ H ₂₇ N ₅ O ₂ S: C, 60.99; H, 6. 58; N, 16.94; S, 7.75. Found: C, 60.86; H, 6. 47; N, 16.79; S, 7.62.

(72e) 3-amino-4- [4- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,4-diazepan-1-yl] thieno [2,3 -b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -2-cyano-3- [4- (2,3-dihydro-1,4-benzodioxin-6-yl) prepared in Example 72 (72d) instead of enthioamide Reaction was carried out in the same manner as described in Example 58 (58e), using -1,4-diazepane-1-yl] -N-[(1E)-(dimethylamino) methylene] buta-2-enthioamide Was carried out to obtain the title compound.

Pale yellow powder

Mp 104-107 ° C .;

IR (KBr) ν _max 3440, 3324, 1645, 1580, 1510, 1368, 1069, 625 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.07-2.13 (2H, m), 3.17-3.23 (2H, m), 3.24-3.29 (2H, m), 3.46 (2H, t, J = 5.9 Hz ), 3.67 (2H, t, J = 4.9 Hz), 4.13-4.14 (2H, m), 4.18-4.20 (2H, m), 6.25-6.29 (2H, m), 6.69 (1H, d, J = 8.8 Hz), 6.98 (2H, brs), 7.08 (1H, doublet, J = 5.4 Hz), 7.09 (2H, brs), 8.41 (1H, d, J = 5.4 Hz);

HRMS m / z calc'd C ₂₁ H ₂₄ O ₃ N ₅ S 426.1600, found 426.1619;

MS (FAB) m / z: 426 [M + H] ⁺ , 409, 182, 165, 120, 63;

analysis. Calc. For C ₂₁ H ₂₃ N ₅ O ₃ S.0.50H ₂ O: C, 58.05; H, 5.57; N, 16.12. Found: C, 57.96; H, 5.85; N, 15.92.

Example 73 3-amino-4- {4- [4- (methylsulfonyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-133)

3-amino-4- {4- [4- (methylthio) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine- prepared in Example 64 (64e)- 2-carboxamide (68 mg, 0.16 mmol) was dissolved in methanol (5 mL), an aqueous solution of oxone (216 mg, 0.35 mmol) (5 mL) was added, and the mixture was stirred at room temperature for 18 hours. Water (10 mL) was added to the reaction solution, and the aqueous layer was extracted with methylene chloride / 2-propanol (4: 1) mixed solvent (3 × 10 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (ethyl acetate / methanol = 20: 1) to obtain the title compound (16 mg, yield 22%).

White powder

Mp 89-96 ° C .;

IR (KBr) ν _max 3330, 1694, 1593, 1557, 1293, 1139, 772, 537 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.11-2.17 (2H, m), 3.00 (3H, s), 3.47 (2H, dd, J = 5.9, 7.4 Hz), 3.55-3.61 (4H, m), 3.68 (2H, t, J = 5.9 Hz), 5.83 (1H, brs), 6.69 (2H, d, J = 9.0 Hz), 6.77 (1H, d, J = 5.5 Hz), 6.88 (1H, brs), 7.70 (2H, t, J = 9.0 Hz), 8.42 (1H, d, J = 5.5 Hz);

HRMS m / z calc'd C ₂₀ H ₂₄ 0 ₃ N ₅ S ₂ 446.1321, found 446.1307;

MS (FAB) m / z: 446 [M + H] ⁺ , 415, 273, 242, 165, 65.

Example 74 3-amino-4- {4- [4- (dimethylamino) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carbox Mead (Example Compound No. 3-104)

(74a) tert-Butyl 4- (4-dimethylaminophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in J. Org. Chem., 65, 1158- (2000) to synthesize the title compound.

Light brown liquid

IR (film) ν _max 2973, 1694, 1519, 1415, 1168, 930, 810 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.38 (4.5H, s), 1.44 (4.5H, s), 1.93-1.98 (2H, m), 2.81 (6H, s), 3.20 (1H, t, J = 6.3 Hz), 3.31 (1H, t, J = 6.3 Hz), 3.45-3.57 (6H, m), 6.67 (2H, d, J = 9.0 Hz), 6.76 (2H, d, J = 9.0 Hz);

HRMS m / z calc. For C ₁₈ H ₃₀ O ₂ NS 320.2338, found 320.2338;

MS (FAB) m / z: 320 [M ⁺ ], 263, 182, 165, 120, 63.

(74b) 1- (4-dimethylaminophenyl) -1,4-diazepane

tert-butyl4- (4-dimethylaminophenyl) -1,4-diazepane prepared in Example 74 (74a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Pale yellow powder

Mp 214-217 ° C. (decomposition);

IR (film) ν _max 2934, 1520, 1472, 1323, 1194, 945, 813 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 2.32 (2H, quint, J = 5.4 Hz), 2.84 (6H, s), 3.24 (2H, t, J = 5.9 Hz), 3.33 (2H, t, J = 4.9 Hz), 3.52 (2H, t, J = 6.8 Hz), 3.73 (2H, t, J = 4.9 Hz), 6.68 (2H, d, J = 9.3 Hz), 6.76 (2H, d, J = 9.3 Hz );

HRMS m / z calc'd C ₁₃ H ₂₁ N ₃ 219.1737, found 219.1752;

MS (EI) m / z: 219 [M ⁺ ], 189, 176, 163, 148, 134, 120.

(74c) (2Z) -2-cyano-3- [4- (4-dimethylaminophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

The reaction was carried out in the same manner as in Example 5 (5a), using 1- (4-dimethylaminophenyl) -1,4-diazepane prepared in Example 74 (74b) instead of isobutylamine. The title compound was synthesized.

Pale yellow powder

Mp 161-164 ° C. (decomposition);

IR (KBr) ν _max 3439, 3314, 3154, 2178, 1601, 1518, 1442, 1292, 1218, 1015, 877, 816 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.91-1.95 (2H, m), 2.26 (3H, s), 2.74 (6H, s), 3.41 (2H, t, J = 5.9 Hz), 3.51 ( 2H, t, J = 5.9 Hz, 3.58-3.62 (4H, m), 6.67 (2H, d, J = 9.8 Hz), 6.71 (2H, d, J = 9.8 Hz), 8.28 (1H, brs), 8.96 (1 H, broad singlet);

HRMS m / z calc'd C ₁₈ H ₂₆ N ₅ S 344.1909, found 344.1901;

MS (EI) m / z: 343 [M ⁺ ], 309, 218, 182, 65;

analysis. Calc. For C ₁₈ H ₂₅ N ₅ S: C, 62.94; H, 7. 34; N, 20.39; S, 9.34. Found: C, 62.66; H, 7.06; N, 20.28, S, 9.11.

(74d) 4- {4- [4- (dimethylamino) phenyl] -1,4-diazepane-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [4- () prepared in Example 74 (74c) instead of (2Z) -2-cyano-3- (isobutylamino) buta-2-enthioamide. The reaction was carried out in the same manner as in Example 5 (5b) using 4-dimethylaminophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide to obtain the title compound.

Light brown powder

Mp 186-188 ° C .;

IR (KBr) ν _max 2948, 2204, 1625, 1517, 1243, 1142, 929, 810 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.92-1.95 (2H, m), 2.73 (6H, s), 3.42 (2H, t, J = 5.9 Hz), 3.63 (2H, t, J = 4.9 Hz), 3.71 (2H, t, J = 5.4 Hz), 3.93 (2H, t, J = 5.4 Hz), 6.42 (1H, d, J = 7.8 Hz), 6.66 (2H, d, J = 9.3 Hz) , 6.69 (2H, d, J = 9.3 Hz), 7.35 (1H, d, J = 7.8 Hz), 12.52 (1H, brs);

HRMS m / z calc. C ₁₉ H ₂₄ N ₅ S 354.1753. Found 354.1772;

MS (FAB) m / z: 353 [M ⁺ ], 182, 165, 65.

(74e) 3-amino-4- {4- [4- (dimethylamino) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-dimethylaminophenyl)-produced in Example 74 (74d) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as described in Example 5 (5c) using 1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile to be described. The compound was obtained.

White powder

Mp 174-176 ° C .;

IR (KBr) ν _max 3438, 3324, 2944, 1644, 1579, 1517, 1368, 1230, 940, 811 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.07-2.12 (2H, m), 2.75 (6H, s), 3.20-3.25 (2H, m), 3.26-3.30 (2H, m), 3.47 (2H , t, J = 5.9 Hz), 3.67 (2H, t, J = 4.4 Hz), 6.71 (4H, s), 6.97 (2H, brs), 7.07-7.08 (3H, m), 8.40 (1H, d, J = 5.4 Hz);

HRMS m / z calc. C ₂₁ H ₂₇ ON ₆ S 411.1967, found 411.1945;

MS (FAB) m / z: 411 [M + H] ⁺ , 394, 273, 242, 200, 189, 175, 93;

analysis. Calc. For C ₂₁ H ₂₆ N ₆ OS.0.16 H ₂ O: C, 61.01; H, 6. 42; N, 20.33; S, 7.76. Found: C, 60.75; H, 6. 34; N, 20.20; S, 7.94.

Example 75 3-amino-6-methyl-4- (4-phenylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-76)

(75a) (1-ethoxyethylidene) malononitrile

An acetic acid (1 mL) solution of malononitrile (4.41 g, 66.8 mmol) and ortho acetate triethyl (14.7 mL, 80.2 mmol) was stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, the resulting powder was obtained by filtration to obtain the title compound (7.14 g, 79% yield).

White powder

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.32 (3H, t, J = 7.0 Hz), 2.45 (3H, s), 4.42 (2H, q, J = 7.0 Hz).

(75b) [1- (4-phenylpiperazin-1-yl) ethylidene] malononitrile

To an ethanol (40 mL) suspension of (1-ethoxyethylidene) malononitrile (1.36 g, 10 mmol) prepared in Example 75 (75a) was added 1-phenylpiperazine (1.68 mL, 11 mmol) for 15 hours. Stir at room temperature. The produced powder was obtained by filtration to obtain the title compound (1.74 g, yield 69%).

White powder

Mp 188-190 ° C .;

IR (KBr) ν _max 2199, 1560, 1450, 1236, 998, 763 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.32 (3H, s), 3.32-3.34 (4H, m), 3.88 (4H, brs), 6.78 (1H, t, J = 8.6 Hz), 6.91 ( 2H, d, J = 8.6 Hz), 7.22 (2H, t, J = 8.6 Hz);

HRMS m / z calc. C ₁₅ H ₁₆ N ₄ 252.1375, found 252.1372;

MS (EI) m / z: 252 [M ⁺ ], 210, 160, 146, 132, 126, 119, 105, 91, 77, 65;

analysis. Calc. For C ₁₅ H ₁₆ N ₄ : C, 71.40; H, 6.39; N, 22.21. Found: C, 71.16; H, 6. 41; N, 22.25.

(75c) [(2E) -3- (dimethylamino) -1- (4-phenylpiperazin-1-yl) buta-2-enylidene] malononitrile

In a xylene (10 mL) suspension of [1- (4-phenylpiperazin-1-yl) ethylidene] malononitrile (1.74 g, 6.9 mmol) prepared in Example 75 (75b), dimethylacetamidedimethylacetal ( 5.0 mL, 34.5 mmol) was added and the mixture was heated to reflux for 4 hours. The reaction solution was concentrated, and the resulting residue was purified using silica gel column chromatography (100% ethyl acetate), and the obtained solid was further washed with ether to obtain the title compound (1.23 g, 55% yield).

Yellow powder

Mp 181-184 ° C .;

IR (KBr) ν _max 2193, 1557, 1511, 1440, 1375, 1258, 1023, 765, 551 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.18 (3H, s), 3.04 (6H, s), 3.24 (4H, t, J = 5.1 Hz), 3.68 (4H, t, J = 5.1 Hz) , 4.53 (1H, s), 6.81 (1H, t, J = 7.8 Hz), 6.95 (2H, d, J = 7.8 Hz), 7.24 (2H, t, J = 7.8 Hz);

HRMS m / z calc. For C ₁₉ H ₂₃ N ₅ 321.1953, found 321.1938;

MS (EI) m / z: 321 [M ⁺ ], 277, 256, 189, 160, 132, 72;

analysis. Calc. For C ₁₉ H ₂₃ N ₅ : C, 71.00; H, 7. 21; N, 21.79. Found: C, 71.03; H, 7. 21; N, 21.60.

(75d) 6-methyl-2-oxo-4- (4-phenylpiperazin-1-yl) -1,2-dihydropyridine-3-carbonitrile

[(2E) -3- (dimethylamino) -1- (4-phenylpiperazin-1-yl) buta-2-enylidene] malononitrile (1.22 g, 3.8 prepared in Example 75 (75c) mmol) was dissolved in acetic acid / water (4: 1) mixed solvent (10 mL) and heated to reflux for 1 hour. The reaction solution was cooled to room temperature, water (10 mL) was added, and the resulting powder was obtained by filtration to obtain the title compound (0.87 g, yield 85%).

Yellow powder

Mp> 270 ° C .;

IR (KBr) ν _max 2837, 2202, 1618, 1497, 1447, 1230, 1003, 755 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.14 (3H, s), 3.27 (4H, t, J = 5.1 Hz), 3.76 (4H, t, J = 5.1 Hz), 6.02 (1H, s) , 6.81 (1H, t, J = 7.8 Hz), 6.96 (2H, d, J = 7.8 Hz), 7.24 (2H, t, J = 7.8 Hz), 11.40 (1H, brs);

HRMS m / z calc. C ₁₇ H ₁₈ ON ₄ 294.1481, found 294.1477;

MS (EI) m / z: 294 [M ⁺ ], 276, 252, 189, 162, 132, 105, 91, 77;

analysis. Calc. For C ₁₇ H ₁₈ N ₄ O.0.16H ₂ O: C, 68.69; H, 6. 21; N, 18.85. Found: C, 69.00; H, 6. 16; N, 18.49.

(75e) 2-chloro-6-methyl-4- (4-phenylpiperazin-1-yl) nicotinonitrile

6-methyl-2-oxo-4- (4-phenylpiperazin-1-yl) -1,2-dihydropyridine-3-carbonitrile (223 mg, 0.76 mmol) prepared in Example 75 (75d) N, N-dimethylaniline (75 µL, 0.53 mmol) and phosphorus oxychloride (1.6 mL, 17.4 mmol) were added to a 1,4-dioxane (3 mL) solution of the resulting mixture and heated to reflux for 2 hours. The reaction solution was concentrated, an aqueous sodium hydrogencarbonate solution (10 mL) was added to the obtained residue, the aqueous layer was extracted with ethyl acetate (3 x 10 mL), the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. . The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 2: 1) to obtain the title compound (117 mg, yield 49%).

Yellow powder

Mp 139-140 ° C .;

IR (KBr) ν _max 2830, 2216, 1582, 1502, 1447, 1229, 989, 758, 695 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.49 (3H, s), 3.36 (4H, t, J = 5.1 Hz), 3.68 (4H, t, J = 5.1 Hz), 6.57 (1H, s), 6.89 -6.95 (3H, m), 7.29 (2H, doublet of doublets, J = 7.1, 8.6 Hz);

HRMS m / z calc'd C ₁₇ H ₁₇ N ₄ Cl 312.1142, found 312.1147;

MS (EI) m / z: 312 [M ⁺ ], 294, 270, 206, 194, 179, 152, 132, 105, 91, 77;

analysis. Calc. For C ₁₇ H ₁₇ ClN ₄ : C, 65.28; H, 5. 48; N, 17.91. Found: C, 65.11; H, 5. 14; N, 17.69.

(75f) 3-amino-6-methyl-4- (4-phenylpiperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

N, N-dimethylformamide (0.6) of 2-chloro-6-methyl-4- (4-phenylpiperazin-1-yl) nicotinonitrile (92 mg, 0.29 mmol) prepared in Example 75 (75e) 2-mercaptoacetamide (purity: about 70%) (48 mg, 0.52 mmol) and 8N sodium hydroxide aqueous solution (0.1 mL) were added to the solution), and it stirred at room temperature for 1 hour. Water was added to the reaction solution, and the precipitated crystals were obtained by filtration to obtain 90 mg (yield 84%) of the title compound.

Pale yellow crystals

Mp 247-250 ° C .;

IR (KBr) ν _max 3435, 2828, 1651, 1581, 1494, 1365, 1223, 993, 762, 694 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.50 (3H, s), 2.88-3.70 (8H, m), 6.80 (1H, t, J = 7.4 Hz), 6.90 (2H, brs), 6.95 ( 1H, s), 7.00 (2H, d, J = 7.4 Hz), 7.04 (2H, brs), 7.23 (2H, t, J = 7.4 Hz);

HRMS m / z calc. C ₁₉ H ₂₁ ON ₅ S 367.1467, found 367.1450;

MS (EI) m / z: 367 [M ⁺ ], 262, 244, 230, 218, 190, 175, 132, 120, 104, 91, 77;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ OS: C, 62.10; H, 5. 76; N, 19.06. Found: C, 62.38; H, 5. 84; N, 18.84.

(Example 76) 3-amino-4- [4- (4-fluorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-89)

(76a) tert-butyl4- (4-fluorophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

White powder (yield 45%)

Mp 88-89 ° C .;

IR (KBr) ν _max 2968, 2921,1682, 1515, 1418, 1244, 828 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.43 (4.5H, s), 1.90-2.01 (2H, m), 3.21 (1H, t, J = 5.9 Hz), 3.32 ( 1H, t, J = 5.9 Hz), 3.46-3.63 (6H, m), 6.61 (2H, dd, J = 9.4, 4.3 Hz), 6.92 (2H, t, J = 8.6 Hz);

MS (EI) m / z: 294 [M ⁺ ], 238, 223, 193;

analysis. Calc. For C ₁₆ H ₂₃ FN ₂ O ₂ .0.14H ₂ O: C, 64.73; H, 7.90; N, 9.44; F, 6.40. Found: C, 64.77; H, 7.92; N, 9.36; F, 6.37.

(76b) 1- (4-fluorophenyl) -1,4-diazepane

tert-butyl4- (4-fluorophenyl) -1,4-diazepane prepared in Example 76 (76a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Pale yellow oil (yield 81%)

IR (film) ν _max 3322, 2935, 1611, 1513, 1228, 814 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.89 (2H, quint, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.4 Hz), 3.51 (2H , t, J = 5.4 Hz), 3.54 (2H, t, J = 6.3 Hz), 6.61 (2H, dd, J = 9.3, 4.4 Hz), 6.91 (2H, t, J = 9.3 Hz);

MS (EI) m / z: 194 [M ⁺ ], 164, 152, 138.

(76c) (2Z) -2-cyano-3- [4- (4-fluorophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

The reaction was carried out in the same manner as in Example 5 (5a), using 1- (4-fluorophenyl) -1,4-diazepane prepared in Example 76 (76b) instead of isobutylamine. The title compound was synthesized.

Yellow brown powder (yield 30%)

Mp 150-152 ° C .;

IR (KBr) ν _max 3356, 3269, 3178, 2177, 1615, 1537, 1507 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.98 (2H, m), 2.23 (3H, s), 3.47-3.54 (4H, m), 3.57-3.63 (2H, m), 3.66-3.72 (2H, m), 6.74 (2H, doublet of doublets, J = 9.0, 4.3 Hz), 6.97 (2H, t, J = 9.0 Hz), 8.31 (1H, bs), 8.96 (1H, bs);

MS (FAB) m / z: 319 [M + H] ⁺ , 273, 259, 242;

analysis. Calc. For C ₁₆ H ₁₉ FN ₄ S.0.4H ₂ O: C, 59.02; H, 6. 13; N, 17.21. Found: C, 58.73; H, 5. 84; N, 17.20.

(76d) (2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-fluorophenyl) -1,4-diazepane-1-yl] Buta-2-enthioamide

In Example 76 (76c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 using (2Z) -2-cyano-3- [4- (4-fluorophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide Reaction was performed similarly to the method described in (58d) to obtain the title compound.

Yellow Powder (Yield 73%)

Mp 127-128 ° C. (decomposition);

IR (KBr) ν _max 2924, 2182, 1610, 1510, 1421, 1395, 1324, 1293 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.93-2.02 (2H, m), 2.47 (3H, s), 2.92 (3H, s), 3.14 (3H, s), 3.53 (2H, t, J = 5.9 Hz), 3.73 (2H, t, J = 5.9 Hz), 3.78 (4H, bs), 6.76 (2H, dd, J = 9.0, 4.3 Hz), 6.97 (2H, t, J = 9.0 Hz), 8.45 (2H, s);

MS (FAB) m / z: 374 [M + H] ⁺ , 340, 273, 195;

analysis. Calc. For C ₁₉ H ₂₄ FN ₅ S: C, 61.10; H, 6. 48; N, 18.75; F, 5.09; S, 8.59. Found: C, 61.01; H, 6. 49; N, 18.50; F, 5.17; S, 8.56.

(76e) 3-amino-4- [4- (4-fluorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-fluorophenyl) prepared in Example 76 (76d) instead of enthioamide. The reaction was carried out in the same manner as in Example 58 (58e), using 1,4-diazepan-1-yl] buta-2-enthioamide to obtain the title compound.

Pale yellow powder (yield 64%)

Mp 203-205 ° C;

IR (KBr) ν _max 3453, 3324, 3179, 2948, 2838, 1646, 1579, 1510, 1369 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.10-2.19 (2H, m), 3.16-3.24 (2H, m), 3.30 (2H, s), 3.49-3.56 (2H, m), 3.71-3.78 (2H, m), 6.76 (2H, doublet of doublets, J = 9.0, 4.4 Hz), 6.96-7.05 (4H, m), 7.06-7.12 (3H, m), 8.40 (1H, d, J = 4.9 Hz);

MS (FAB) m / z: 386 [M + H] ⁺ , 369, 273;

analysis. Calc. For C ₁₉ H ₂₀ FN ₅ OS. 1.35H ₂ O: C, 57.95; H, 5.81; N, 17.78; F, 4.82; S, 8.14. Found: C, 57.58; H, 5.41; N, 17.76; F, 4.73; S, 7.99.

(Example 77) 3-amino-4- [4- (4-methylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example compound Number 3-111)

(77a) tert-butyl4- (4-methylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 36%)

IR (film) ν _max 2974, 2929, 1695, 1619, 1521, 1415, 1365, 1237, 1169 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.38 (4.5H, s), 1.44 (4.5H, s), 1.91-2.01 (2H, m), 2.23 (3H, s), 3.18 (1H, t, J = 5.9 Hz), 3.20 (1H, t, J = 5.9 Hz), 3.46-3.59 (6H, m), 6.60 (2H, d, J = 8.2 Hz), 7.00 (2H, d, J = 8.2 Hz);

MS (EI) m / z: 290 [M ⁺ ], 234, 146.

(77b) 1- (4-methylphenyl) -1,4-diazepane

tert-butyl4- (4-methylphenyl) -1,4-diazepane-1 prepared in Example 77 (77a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate Using the carboxylate, the reaction was carried out in the same manner as in Example 57 (57b) to obtain the title compound.

Pale yellow oil (yield 100%)

IR (film) ν _max 3318, 2923, 1618, 1520, 1394, 1363, 1189, 802 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89 (2H, quint, J = 5.9 Hz), 2.23 (3H, s), 2.79-2.85 (2H, m), 2.99-3.05 (2H, m), 3.49- 3.58 (4H, m), 6.60 (2H, doublet, J = 8.2 Hz), 7.00 (2H, d, J = 8.2 Hz);

MS (EI) m / z: 190 [M ⁺ ], 160, 148, 134.

(77c) 4- [4- (4-methylphenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

1- (4-methylphenyl) -1,4-diazepane (463 mg, 2.39 mmol) and (2Z) -2-cyano-3-ethoxybuta-2-entioa prepared in Example 77 (77b) Mead (J.Org.Chem., (1962), 27, 2433-2439) (386 mg, 2.27 mmol) was dissolved in N, N-dimethylformamide (4.78 mL) and stirred at room temperature for 30 minutes. Subsequently, N, N-dimethylformamide dimethylacetal (302 µL, 2.27 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour, followed by stirring at 60 ° C for 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate (10 mL) and water (50 mL) were added and stirred. The precipitated solid was obtained by filtration and washed sequentially with ethyl acetate and water to obtain 125 mg of the title compound. 28% yield from 1- (4-methylphenyl) -1,4-diazepane.

Light brown powder

Mp 220-223 ° C .;

IR (KBr) ν _max 3115, 2940, 2205, 1626, 1518, 1250, 928,798, 775 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 2.11 (2H, quint, J = 5.9 Hz), 2.25 (3H, s), 3.56 (2H, t, J = 5.9 Hz), 3.71-3.76 (2H, m) , 3.76-3.80 (2H, m), 4.10-4.15 (2H, m), 6.19 (1H, d, J = 7.8 Hz), 6.65 (2H, d, J = 8.2 Hz), 7.05 (2H, d, J = 8.2 Hz), 7.20 (1H, d, J = 7.8 Hz), 11.22 (1H, bs);

MS (EI) m / z: 324 [M ⁺ ], 160, 146;

analysis. Calc. For C ₁₈ H ₂₀ N ₄ S.0.1H ₂ O: C, 66.27; H, 6. 24; N, 17.17; S, 9.83. Found: C, 66.07; H, 6. 19; N, 17.10; S, 9.60.

(77d) 3-amino-4- [4- (4-methylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-methylphenyl) -1, prepared in Example 77 (77c), instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile, The reaction was carried out in the same manner as in Example 5 (5c) using 4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile to give the titled compound. Got it.

Light Brown Powder (Yield 28%)

Mp 175-176 ° C .;

IR (KBr) ν _max 3429, 3317, 3170, 3093, 2942, 2833, 1635, 1579, 1520, 1372 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.07-2.16 (2H, m), 2.18 (3H, s), 3.15-3.22 (2H, m), 3.23-3.30 (2H, m), 3.51 (2H , t, J = 6.3 Hz), 3.72 (2H, t, J = 4.7 Hz), 6.66 (2H, d, J = 8.2 Hz), 6.92-6.99 (4H, m), 7.02-7.09 (3H, m) , 8.37 (1H, doublet, J = 5.1 Hz);

MS (FAB) m / z: 382 [M + H] ⁺ , 365, 275;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS: C, 62.97; H, 6.08; N, 18.36; S, 8.41. Found: C, 62.58; H, 6.02; N, 18.23; S, 8.29.

Example 78 3-amino-4- [4- (3-chlorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-93)

(78a) tert-butyl4- (3-chlorophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 30%)

IR (film) ν _max 2975, 1694, 1594, 1493, 1416, 1365, 1237, 1168 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.44 (4.5H, s), 1.95 (2H, quint, J = 6.3 Hz), 3.21 (1H, t, J = 5.9 Hz) , 3.31 (1H, t, J = 5.9 Hz), 3.46-3.60 (6H, m), 6.54 (1H, dd, J = 9.0, 2.0 Hz), 6.58-6.65 (2H, m), 7.08 (1H, t , J = 8.6 Hz);

MS (EI) m / z: 310 [M ⁺ ], 253, 166.

(78b) 1- (3-chlorophenyl) -1,4-diazepane

tert-butyl4- (3-chlorophenyl) -1,4-diazepane- made in Example 78 (78c) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Light brown oil (yield 100%)

IR (film) ν _max 3323, 2933, 1593, 1494, 1362, 1102, 984, 759, 683 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89 (2H, quint, J = 5.9 Hz), 2.79-2.86 (2H, m), 2.98-3.06 (2H, m), 3.52 (2H, t, J = 5.5 Hz), 3.56 (2H, t, J = 6.3 Hz), 6.56 (1H, dd, J = 8.6, 2.7 Hz), 5.59-6.63 (1H, m), 6.67-6.64 (1H, m), 7.10 (1H , t, J = 8.6 Hz);

MS (EI) m / z: 210 [M ⁺ ], 168, 154.

(78c) (2Z) -3- [4- (3-chlorophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide

Instead of isobutylamine, reaction was carried out in the same manner as described in Example 5 (5a), using 1- (3-chlorophenyl) -1,4-diazepane prepared in Example 78 (78b) The title compound was synthesized.

Slightly brown powder (yield 62%)

Mp 133-134 ° C .;

IR (KBr) ν _max 3320, 3152, 2964, 2187, 1593, 1541, 1488, 1390, 1346 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.97 (2H, m), 2.24 (3H, s), 3.48-3.57 (4H, m), 3.58-3.63 (2H, m), 3.70-3.75 (2H, m), 6.60 (1H, dd, J = 8.2, 1.6 Hz), 6.70 (1H, dd, J = 8.2, 2.3 Hz), 6.75-6.78 (1H, m), 7.14 (1H, t, J = 8.2 Hz), 8.36 (1H, bs), 9.01 (1H, s);

MS (FAB) m / z: 335 [M + H] ⁺ , 246, 200.

(78d) (2Z) -3- [4- (3-chlorophenyl) -1,4-diazepane-1-yl] -2-cyano-N-[(1E)-(dimethylamino) methylene] buta 2-enthioamide

In Example 78 (78c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 (58d) using prepared (2Z) -3- [4- (3-chlorophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide Reaction was performed similarly to the method described in the above, to obtain the title compound.

Yellow Powder (Yield 89%)

Mp 129-130 ° C. (decomposition);

IR (KBr) ν _max 2924, 2925, 2177, 1609, 1397, 1325, 1290 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.92-2.01 (2H, m), 2.49 (3H, s), 3.15 (3H, s), 3.32 (3H, s), 3.57 (2H, t, J = 5.5 Hz), 3.72 (2H, t, J = 5.5 Hz), 3.75-3.80 (2H, m), 3.80-3.84 (2H, m), 6.61 (1H, d, J = 8.3 Hz), 6.73 (1H , dd, J = 8.3, 2.0 Hz), 6.79 (1H, s), 7.14 (1H, t, J = 8.3 Hz), 8.45 (1H, s);

MS (FAB) m / z: 390 [M + H] ⁺ , 356, 211, 180;

analysis. Calc. For C ₁₉ H ₂₄ ClN ₅ S: C, 58.52; H, 6. 20; N, 17.96; Cl, 9.09; S, 8.22. Found: C, 58.26; H, 6. 18; N, 17.83; F, 8.95; S, 8.22.

(78e) 3-amino-4- [4- (3-chlorophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -3- [4- (3-chlorophenyl) -1,4-diazepan-1-yl] -2-cyano-N prepared in Example 78 (78d) instead of enthioamide. The title compound was obtained in the same manner as in Example 58 (58e) using-[(1E)-(dimethylamino) methylene] buta-2-enthioamide.

Slightly brown powder (yield 61%)

Mp 213-215 ° C .;

IR (KBr) ν _max 3442, 3324, 3183, 2950, 2836, 1644, 1593, 1494, 1369 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.10-2.20 (2H, m), 3.13-3.24 (2H, m), 3.25-3.31 (2H, m), 3.51-3.58 (2H, m), 3.77 (2H, t, J = 4.4 Hz), 6.62 (1H, dd, J = 8.3, 2.0 Hz), 6.73 (1H, dd, J = 8.3, 2.0 Hz), 7.01 (1H, bs), 7.06-7.12 ( 3H, m), 7.17 (1H, t, J = 8.3 Hz), 8.40 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 402 [M + H] ⁺ , 385, 273;

analysis. Calc. For C ₁₉ H ₂₀ N ₅ ClOS.0.18H ₂ O: C, 56.33; H, 5.07; N, 17.29; Cl, 8.75; S, 7.91. Found: C, 56.33; H, 5.01; N, 17.38; Cl, 8.77; S, 7.68.

Example 79 3-amino-4- {4- [4- (benzyloxy) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carbox Mead (Example Compound No. 3-134)

(79a) tert-butyl4- [4- (benzyloxy) phenyl] -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 15%)

IR (film) ν _max 2974, 1693, 1512, 1416, 1237, 1168 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.90-2.00 (1H, m), 3.17-3.23 (1H, m), 3.27-3.35 (1H , m), 3.41-3.61 (6H, m), 4.97 (2H, s), 6.62 (2H, d, J = 8.8 Hz), 6.86 (2H, d, J = 8.8 Hz), 7.26-7.44 (5H, m);

MS (EI) m / z: 382 [M ⁺ ], 327, 291, 235.

(79b) 1- [4- (benzyloxy) phenyl] -1,4-diazepane

tert-butyl4- [4- (benzyloxy) phenyl] -1,4- made in Example 79 (79a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using diazephan-1-carboxylate.

Light brown oil (yield 100%)

IR (film) ν _max 3329, 3033, 1512, 1455, 1237, 1025, 812 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.82 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.5 Hz), 3.46-3.54 (4H, m), 4.98 (2H, s), 6.62 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 7.25-7.43 (5H, m);

MS (EI) m / z: 282 [M ⁺ ], 191, 148.

(79c) 4- {4- [4- (benzyloxy) phenyl] -1,4-diazepane-1-yl} -2-thieno-1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, 1- [4- (benzyloxy) phenyl] -1,4-diazepane prepared in Example 79 (79b) was used, and The reaction was carried out in the same manner as in 77 (77c), to obtain the title compound.

Light brown powder (yield 30%)

Mp 190-191 ° C .;

IR (KBr) ν _max 3129, 3045, 2953, 2205, 1625, 1511, 1455, 1240 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.87-1.98 (2H, m), 3.45 (2H, t, J = 5.9 Hz), 3.62-3.75 (4H, m), 3.89-3.96 (2H, m ), 4.96 (2H, s), 6.41 (1H, d, J = 7.8 Hz), 6.70 (2H, d, J-9.0 Hz), 6.83 (2H, d, J = 9.0 Hz), 7.26-7.42 (6H m);

MS (FAB) m / z: 417 [M + H] ⁺ , 325, 200;

analysis. Calc. For C ₂₄ H ₂₄ N ₄ OS.0.54H ₂ O: C, 67.62; H, 5.93; N, 13.14; S, 7.52. Found: C, 67.30; H, 5.97; N, 13.50; S, 7.39.

(79d) 3-amino-4- {4- [4- (benzyloxy) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- {4- [4- (benzyloxy) phenyl produced in Example 79 (79c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile ] -1,4-diazepan-1-yl} -2-thieno-1,2-dihydropyridine-3-carbonitrile is used and reaction is carried out similarly to the method described in Example 5 (5c). To obtain the title compound.

Slightly brown powder (yield 89%)

Mp 211-213 ° C .;

IR (KBr) ν _max 3430, 3320, 3167, 2945, 1646, 1579, 1511, 1367, 1230 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.06-2.16 (2H, m), 3.15-3.22 (2H, m), 3.24-3.30 (2H, m), 3.44-3.51 (2H, m), 3.65 -3.72 (2H, m), 4.99 (2H, s), 6.69 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.98 (2H, bs), 7.05 (1H, d, J = 5.1 Hz), 7.07 (2H, bs), 7.26-7.43 (5H, m), 8.37 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 474 [M + H] ⁺ , 242, 200;

analysis. Calc. For C ₂₆ H ₂₇ N ₅ O ₂ S.0.26H ₂ O: C, 65.29; H, 5.80; N, 14.64; S, 6.70. Found: C, 65.46; H, 6.02; N, 14.59; S, 6.51.

Example 80 3-Amino-4- [4- (3-nitrophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound number 3-96)

(80a) tert-butyl4- (3-nitrophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Orange oil (yield 25%)

IR (film) ν _max 2975, 1692, 1528, 1347, 1166, 735 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.33 (4.5H, s), 1.41 (4.5H, s), 1.98 (2H, quint, J = 5.9 Hz), 3.21-3.26 (1H, m), 3.31- 3.37 (1H, m), 3.56-3.66 (6H, m), 6.94 (1H, dd, J = 8.2, 2.0 Hz), 7.30 (1H, t, J = 8.2 Hz), 7.44-7.50;

MS (FAB) m / z: 321 [M ⁺ ], 266, 248, 222.

(80b) 1- (3-nitrophenyl) -1,4-diazepane

tert-butyl4- (3-nitrophenyl) -1,4-diazepane- made in Example 80 (80a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Red orange oil (yield 100%)

IR (film) ν _max 2935, 2855, 1618, 1525, 1347, 735 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93 (2H, quint, J = 5.9 Hz), 2.85 (2H, t, J = 5.9 Hz), 3.06 (2H, t, J = 5.4 Hz, 3.60 (2H, t, J = 5.4 Hz), 3.64 (2H, t, J = 5.9 Hz), 6.95 (1H, dd, J = 8.3, 2.4 Hz), 7.31 (1H, t, J = 8.3 Hz), 7.44-7.51 ( 2H, m);

MS (EI) m / z: 221 [M ⁺ ], 179, 165.

(80c) (2Z) -2-cyano-3- [4- (3-nitrophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as in Example 5 (5a), using 1- (3-nitrophenyl) -1,4-diazepane prepared in Example 80 (80b). The title compound was synthesized.

Orange powder (yield 71%)

Mp 157-158 ° C .;

IR (KBr) ν _max 3443, 3353, 3277, 3176, 2926, 2182, 1617, 1525, 1346 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.92-2.01 (2H, m), 2.24 (3H, s), 3.53-3.58 (2H, m), 3.62-3.69 (4H, m), 3.81-3.88 (2H, m), 7.20-7.26 (1H, m), 7.40-7.50 (3H, m), 8.40 (1H, bs), 9.05 (1H, bs);

MS (FAB) m / z: 346 [M + H] &lt; ⁺ &gt;, 246, 200.

(80d) 3-amino-4- [4- (3-nitrophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- [4- (3 prepared in Example 80 (80c) instead of (2Z) -2-cyano-3- (propylamino) buta-2-enthioamide The reaction was carried out in the same manner as in Example 4 (4b) using -nitrophenyl) -1,4-diazepan-1-yl] buta-2-enthioamide to obtain the title compound.

Pale yellow powder (yield 6%)

Mp 180-185 ° C .;

IR (KBr) ν _max 3450, 3324, 3169, 2953, 2842, 1646, 1579, 1524,1368, 1345 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.16-2.24 (2H, m), 3.15-3.24 (2H, m), 3.29-3.38 (2H, m), 3.64 (2H, t, J = 5.9 Hz ), 3.84-3.89 (2H, m), 7.01 (2H, bs), 7.09 (1H, d, J = 5.4 Hz), 7.10 (2H, bs), 7.21-7.26 (1H.m), 7.44 (2H, d, J = 5.4 Hz), 8.41 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 413 [M + H] ⁺ , 246, 200.

Example 81 3-amino-4- [4- (3-chloro-4-fluorophenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 3-91)

(81a) tert-butyl4- (3-chloro-4-fluorophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 36%)

IR (film) ν _max 2976, 1693, 1508, 1417, 1237, 1168 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.43 (4.5H, s), 1.89-1.98 (2H, m), 3.21 (1H, t, J = 5.9 Hz), 3.32 ( 1H, t, J = 5.9 Hz), 3.41-3.61 (6H, m), 6.48 (1H, dt, J = 9.0, 3.3 Hz), 6.59-6.65 (1H, m), 6.96 (1H, t, J = 9.0 Hz);

MS (FAB) m / z: 328 [M ⁺ ], 273, 229, 189.

(81b) 1- (3-chloro-4-fluorophenyl) -1,4-diazepane

tert-butyl4- (3-chloro-4-fluorophenyl) -1 prepared in Example 81 (81a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate, The title compound was obtained in the same manner as in the method described in Example 57 (57b) using 4-diazepan-1-carboxylate.

Light brown oil (yield 100%)

IR (film) ν _max 2934, 1611, 1508, 1240, 1047, 797 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.5 Hz), 3.48 (2H , t, J = 5.5 Hz), 3.52 (2H, t, J = 5.9 Hz), 6.49 (1H, dt, J = 9.0, 3.1 Hz), 6.64 (1H, q, J = 3.1 Hz), 6.97 (1H , t, J = 9.0 Hz);

MS (EI) m / z: 228 [M ⁺ ], 186, 172.

(81c) (2Z) -3- [4- (3-chloro-4-fluorophenyl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enthioamide

Instead of isobutylamine, the same procedure as described in Example 5 (5a) was used, using 1- (3-chloro-4-fluorophenyl) -1,4-diazepane prepared in Example 81 (81b). The reaction was carried out to synthesize the title compound.

Light yellow powder (yield 63%)

Mp 148-150 ° C .;

IR (KBr) ν _max 3358, 3265, 3170, 2177, 1615, 1526, 1505, 1408 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.89-1.96 (2H, m), 2.25 (3H, s), 3.49-3.56 (4H, m), 3.58-3.64 (2H, m), 3.68-3.75 (2H, m), 6.73 (1H, dt, J = 9.0, 3.1 Hz), 6.90 (1H, q, J = 3.1 Hz), 7.18 (1H, t, J = 9.0 Hz), 8.37 (1H, bs) , 9.02 (1 H, bs);

MS (FAB) m / z: 353 [M + H] ⁺ , 200, 165.

(81d) (2Z) -3- [4- (3-chloro-4-fluorophenyl) -1,4-diazepane-1-yl] -2-cyano-N-[(1E)-(dimethyl Amino) methylene] buta-2-enthioamide

In Example 81 (81c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide The prepared (2Z) -3- [4- (3-chloro-4-fluorophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide was carried out. Reaction was performed in the same manner as the method described in Example 58 (58d) to obtain the title compound.

Pale yellow powder (yield 45%)

Mp 133-135 ° C. (decomposition);

IR (KBr) ν _max 2924, 2177, 1609, 1506, 1398, 1326, 1289 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-2.00 (2H, m), 2.47 (3H, s), 2.91 (3H, s), 3.14 (3H, s) 3.50-3.58 (2H, m) , 3.68-3.87 (6H, m), 6.73 (1H, dt, J = 9.0, 3.1 Hz), 6.90 (1H, q, J = 3.1 Hz), 7.15 (1H, t, J = 9.0 Hz), 8.43 ( 1H, s);

MS (FAB) m / z: 408 [M + H] ⁺ , 374,273.

(81e) 3-amino-4- [4- (3-chloro-4-fluorophenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carbox mid

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 -(2Z) -3- [4- (3-chloro-4-fluorophenyl) -1,4-diazepan-1-yl] -2 prepared in Example 81 (81d) instead of enthioamide. The reaction was carried out in the same manner as in Example 58 (58e) using -cyano-N-[(1E)-(dimethylamino) methylene] buta-2-enthioamide to obtain the title compound.

Light Brown Powder (Yield 54%)

Mp 181-184 ° C .;

IR (KBr) ν _max 3326, 3095, 2834, 1636, 1579, 1506, 1373 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.09-2.19 (2H, d), 3.13-3.22 (2H, m), 3.24-3.32 (2H, m), 3.51 (2H, t, J = 5.9 Hz ), 3.71-3.77 (2H, m), 6.71 (1H, dt, J = 9.0, 3.1 Hz), 6.85 (1H, q, J = 3.1 Hz), 6.99 (2H, bs), 7.06 (1H, d, J = 5.5 Hz), 7.09 (2H, bs), 7.18 (1H, t, J = 9.0 Hz), 8.38 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 420 [M + H] ⁺ , 273, 176;

analysis. Calc. For C ₁₉ H ₁₉ ClFN ₅ OS: C, 54.35; H, 4.65; N, 16.68; C1, 8.44; F, 4.52; S, 7.64. Found: C, 54.04; H, 4. 43; N, 16.30; Cl, 8.33; F, 4.86; S, 8.03.

(Example 82) 3-amino-4- [4- (4-bromophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-95)

(82a) tert-butyl4- (4-bromophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 27%)

IR (film) ν _max 2975, 1693, 1591, 1498, 1416, 1237, 1167 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37 (4.5H, s), 1.43 (4.5H, s), 1.90-1.99 (2H, m), 3.20 (1H, t, J = 5.9 Hz), 3.31 ( 1H, t, J = 5.9 Hz), 3.48-3.58 (6H, m), 6.56 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz);

MS (FAB) m / z: 355 [M + H] &lt; ⁺ &gt;, 255, 189.

(82b) 1- (4-bromophenyl) -1,4-diazepane

tert-butyl4- (4-bromophenyl) -1,4-diazephan prepared in Example 82 (82a) instead of tert-butyl4-phenyl-1,4-diazephan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Light brown oil (Yield 90%)

IR (film) ν _max 2931, 1591, 1498, 1396, 1362, 1190, 806 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.82 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.4 Hz), 3.51, t , J = 5.4 Hz), 3.55 (2H, t, J = 5.9 Hz), 6.56 (2H, d, J = 8.8 Hz), 7.26 82H, d, J = 8.8 Hz);

MS (EI) m / z: 254 [M ⁺ ], 212, 198.

(82c) (2Z) -3- [4- (4-bromophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide

The reaction was carried out in the same manner as in Example 5 (5a), using 1- (4-bromophenyl) -1,4-diazephan prepared in Example 82 (82b) instead of isobutylamine. The title compound was synthesized.

Light Yellow Powder (Yield 72%)

Mp 152-155 ° C;

IR (KBr) ν _max 3371, 3276, 3174, 2957, 2185, 1589, 1536,1496, 1408, 1357 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.87-1.97 (2H, m), 2.24 (3H, s), 3.48-3.57 (4H, m), 3.58-3.64 (2H, m), 3.70-3.77 (2H, m), 6.74 (2H, doublet, J = 8.8 Hz), 7.28 (2H, d, J = 8.8 Hz), 8.38 (1H, bs), 9.03 (1H, bs);

MS (FAB) m / z: 379 [M + H] ⁺ , 273, 182.

(82d) (2Z) -3- [4- (4-bromophenyl) -1,4-diazepane-1-yl] -2-cyano-N-[(1E)-(dimethylamino) methylene] Buta-2-enthioamide

In Example 82 (82c), instead of (2Z) -2-cyano-3- [4- (4-methoxyphenyl) -1,4-diazepane-1-yl] buta-2-enthioamide Example 58 (58d), using the prepared (2Z) -3- [4- (4-bromophenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide The reaction was carried out in the same manner as in the method), to obtain the title compound.

Pale yellow powder (yield 84%)

Mp 143-146 ° C. (decomposition);

IR (KBr) ν _max 2925, 2176, 1611, 1497, 1397, 1328, 1290 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-2.00 (2H, m), 2.47 (3H, s), 2.92 (3H, s), 3.15 (3H, s), 3.55 (2H, t, J = 5.9 Hz), 3.69-3.85 (6H, m), 6.74 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz), 8.46 (1H, s);

MS (FAB) m / z: 434 [M + H] ⁺ , 400, 273.

(82e) 3-amino-4- [4- (4-bromophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-N-[(1E)-(dimethylamino) methylene] -3- [4- (4-methoxyphenyl) -1,4-diazepan-1-yl] buta-2 (2Z) -3- [4- (4-bromophenyl) -1,4-diazepan-1-yl] -2-cyano- made in Example 82 (82d) instead of enthioamide. The reaction was carried out in the same manner as in Example 58 (58e) using N-[(1E)-(dimethylamino) methylene] buta-2-enthioamide to obtain the title compound.

Slightly brown powder (yield 59%)

Mp 170-173 ° C .;

IR (KBr) ν _max 3442, 3322, 3180, 2948, 2838, 1645, 1588, 1498, 1367 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13 (2H, quint, J = 5.5 Hz), 3.13-3.21 (2H, m), 3.23-3.30 (2H, m), 3.52 (2H, t, J = 6.3 H), 3.71-3.77 (2H, m), 6.72 (2H, d, J = 9.0 Hz), 6.98 (2H, bs), 7.05 81H, d, J = 5.5 Hz), 7.08 (2H, bs) , 7.27 (2H, doublet, J = 9.0 Hz), 8.38 (1H, doublet, J = 5.5 Hz);

MS (FAB) m / z: 446 [M + H] ⁺ , 429, 273.

(Example 83) 3-amino-4- [4- (4-ethoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-127)

(83a) tert-Butyl 4- (4-ethoxyphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 27%)

IR (film) ν _max 2976, 1694, 1513, 1416, 1240,1169 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37 (3H, t, J = 6.8 Hz), 1.38 (4.5H, s), 1.44 (4.5H, s), 1.91-2.00 (2H, m), 3.21 ( 1H, t, J = 5.9 Hz, 3.32 (1H, t, J = 5.9 Hz), 3.45-3.60 (6H, m), 3.96 (2H, q, J = 6.8 Hz), 6.64 (2H, d, J = 9.3 Hz), 6.81 (2H, d, J = 9.3 Hz);

MS (FAB) m / z: 320 [M ⁺ ], 264, 219.

(83b) 1- (4-ethoxyphenyl) -1,4-diazepane

tert-butyl4- (4-ethoxyphenyl) -1,4-diazepane prepared in Example 83 (83a) instead of tert-butyl4-phenyl-1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as described in Example 57 (57b) using -1-carboxylate to obtain the title compound.

Brown oil (yield 98%)

IR (film) ν _max 2931, 1513, 1239, 1050, 812 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.37 (3H, t, J = 7.0 Hz), 1.88 (2H, quint, J = 5.9 Hz), 2.82 (2H, t, J = 5.5H), 3.01 (2H , t, J = 5.5 Hz), 3.46-3.55 (4H, m), 3.95 (2H, q, J = 7.0 Hz), 6.62 (2H, d, J = 9.4 Hz), 6.79 (2H, d, J = 9.4 Hz);

MS (EI) m / z: 220 [M ⁺ ], 178, 164.

(83c) 4- [4- (4-ethoxyphenyl) -1,4-diazepane-1-yl] -2-thioxa-1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, the 1- (4-ethoxyphenyl) -1,4-diazepane prepared in Example 83 (83b) was used, and Example 77 ( The reaction was carried out in the same manner as in the method described in 77c), to obtain the title compound.

Slightly brown powder (yield 25%)

Mp 204-208 ° C;

IR (KBr) ν _max 3118, 2970, 2207, 1625, 1511, 1244 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.38 (3H, t, J = 7.0 Hz), 2.11 (2H, quint, J = 5.9 Hz), 3.50 (2H, t, J = 5.9 Hz), 3.69-3.78 (4H, m), 3.96 (2H, q, J = 7.0 Hz), 4.07-4.13 (2H, m), 6.20 (1H, d, J = 7.6 Hz), 6.66 (2H, d, J = 9.2 Hz) , 6.81 (2H, d, J = 9.2 Hz), 7.22 (1H, d, J = 7.6 Hz), 11.97 (1H, bs);

MS (FAB) m / z: 355 [M + H] ⁺ , 273;

analysis. Calc. For C ₁₉ H ₂₂ N ₄ OS.0.16H ₂ O: C, 63.86; H, 6. 38; N, 15.68; S, 8.97. Found: C, 63.86; H, 6. 26; N, 15.66; S, 8.85.

(83d) 3-amino-4- [4- (4-ethoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-ethoxyphenyl)-produced in Example 83 (83c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as described in Example 5 (5c) using 1,4-diazepane-1-yl] -2-thioxa-1,2-dihydropyridine-3-carbonitrile to be described. The compound was obtained.

Slightly brown powder (yield 84%)

Mp 181-183 ° C .;

IR (KBr) ν _max 3423, 3330, 3116, 2973, 1586, 1512, 1369, 1234 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.28 (3H, t, J = 7.0 Hz), 2.08-2.16 (2H, m), 3.18-3.24 (2H, m), 3.26-3.31 (2H, m ), 3.40 82H, t, J = 5.9 Hz), 3.70 82H, t, J = 4.7 hz), 3.92 (2H, q, J = 7.0 Hz), 6.71 (2H, d, J = 8.8 Hz), 6.80 ( 2H, d, J = 8.8 Hz), 6.99 (2H, bs), 7.05-7.12 (3H, m), 8.40 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 412 [M + H] ⁺ , 75;

analysis. Calc. For C ₂₁ H ₂₅ N ₅ 0 ₂ S.0.42H ₂ 0: C, 60.19; H, 6. 21; N, 16.71; S, 7.65. Found: C, 60.49; H, 6. 32; N, 16.93; S, 7.35.

Example 84 3-amino-4- [4- (3,4-dimethylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-116)

(84a) tert-butyl4- (3,4-dimethylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 17%)

IR (film) ν _max 3366, 2972, 2931, 1695, 1616, 1511, 1415,1242, 1169 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.36 (4.5H, s), 1.45 (4.5H, s), 1.93-2.02 (2H, m), 2.15 (3H, s), 2.22 (3H, s), 3.20 (1H, t, J = 5.9 Hz), 3.30 (1H, d, J = 5.9 Hz), 3.47-3.59 (6H, m), 6.46 (1H, d, J = 8.3 Hz), 6.51 (1H, s ), 6.96 (1 H, d);

MS (FAB) m / z: 304 [M ⁺ ], 249, 203.

(84b) 1- (3,4-dimethylphenyl) -1,4-diazepane

tert-butyl4- (3,4-dimethylphenyl) -1,4-diaza prepared in Example 84 (84a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using Platen-1-carboxylate.

Light Brown Prism Crystal (Yield 100%)

IR (KBr) ν _max 2939, 2860, 2384, 1615, 1512, 1459, 1411, 1280 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.15 (3H, s), 2.21 (3H, s), 2.82 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.5 Hz), 3.49-3.56 (4H, m), 6.45 (1H, dd, J = 8.2, 2.7 Hz), 6.50 (1H, d, J = 2.7 Hz), 6.94 (1H, d, J = 8.2 Hz);

MS (EI) m / z: 204 [M ⁺ ], 174, 162, 148.

(84c) 4- [4- (3,4-dimethylphenyl) -1,4-diazepane-1-yl] -2-thioxa-1,2-dihydropyridine-3-carbonitrile

Example 77, using the 1- (3,4-dimethylphenyl) -1,4-diazepane prepared in Example 84 (84b) instead of 1- (4-methylphenyl) -1,4-diazepane Reaction was performed similarly to the method described in (77c) to obtain the title compound.

Light brown powder (yield 31%)

Mp 251-253 ° C .;

IR (KBr) ν _max 3121, 2937, 2205, 1625, 1511, 1459, 1254 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.93 (2H, quint, J = 5.5 Hz), 2.07 (3H, s), 2.14 (3H, s), 3.48 (2H, t, J = 5.9 Hz) , 3.65-3.74 (4H, m), 3.91-3.98 (2H, m), 6.43 (1H, d, J = 7.6 Hz), 6.50 (1H, dd, J = 8.4, 2.7 Hz), 6.60 (1H, d , J = 2.7 Hz), 6.90 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 7.6 Hz), 12.44 (1H, bs);

MS (FAB) m / z: 339 [M + H] ⁺ , 273, 174;

analysis. Calc. For C ₁₉ H ₂₂ N ₄ S.0.24H ₂ O: C, 66.57; H, 6. 61; N, 16.34; S, 9.35. Found: C, 66.47; H, 6. 44; N, 16.34; S, 9.15.

(84d) 3-amino-4- [4- (3,4-dimethylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (3,4-dimethylphenyl) prepared in Example 84 (84c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile -1,4-diazepane-1-yl] -2-thioxa-1,2-dihydropyridine-3-carbonitrile was used, and the reaction was carried out in the same manner as in Example 5 (5c). The title compound was obtained.

Slightly brown powder (yield 82%)

Mp 195-197 ° C .;

IR (KBr) ν _max 3432, 3324, 3174, 2934, 2829, 1642, 1579, 1507, 1369 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.08-2.15 (2H, m), 2.10 (3H, s), 2.16 (3H, s), 3.15-3.22 (2H, m), 3.25-3.31 (2H , m), 3.52 (2H, t, J = 5.9 Hz), 3.69-3.76 (2H, m), 6.50 (1H, dd, J = 8.3, 2.4 Hz), 6.60 (1H, d, J = 2.4 Hz) , 6.92 (1H, d, J = 8.3 Hz), 6.99 (2H, bs), 7.04-7.13 (3H, m), 8.40 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 396 [M + H] ⁺ , 246, 185;

analysis. Calc. For C ₂₁ H ₂₅ N ₅ OS: C, 63.77; H, 6. 37; N, 17.71; S, 8.11. Found: C, 63.45; H, 6. 33; N, 17.54; S, 8.11.

Example 85 3-amino-4- [4- (3,4-difluorophenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-90)

(85a) tert-butyl4- (3,4-difluorophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 29%)

IR (film) ν _max 2976, 1691, 1521, 1417, 1234, 1168, 777 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.43 (4.5H, s), 1.89-1.98 (2H, m), 3.21 (1H, t, J = 5.9 Hz), 3.31 ( 1H, t, J = 5.9 Hz), 3.41-3.58 (6H, m), 6.27-6.33 (1H, m), 6.38-6.47 (1H, m), 6.96 (1H, q, J = 9.0 Hz);

MS (FAB) m / z: 312 [M ⁺ ], 257, 211.

(85b) 1- (3,4-difluorophenyl) -1,4-diazepane

tert-butyl4- (3,4-difluorophenyl) -1,4 prepared in Example 85 (85a) instead of tert-butyl4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using diazepan-1-carboxylate.

Brown oil (yield 98%)

IR (film) ν _max 2935, 2838, 1631, 1597, 1520, 1275, 777 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.88 (2H, m, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.4 Hz), 3.48 (2H , t, J = 5.4 Hz), 3.52 (2H, t, J = 5.9 Hz), 6.28-6.34 (1H, m), 6.44 (1H, ddd, J = 14.2, 6.8, 2.9 Hz), 6.98 (1H, q, J = 9.3 Hz);

MS (EI) m / z: 212 [M ⁺ ], 170, 156.

(85c) 4- [4- (3,4-difluorophenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, 1- (3,4-difluorophenyl) -1,4-diazepane prepared in Example 85 (85b) was used and carried out. Reaction was performed in the same manner as the method described in Example 77 (77c) to obtain the title compound.

Slightly brown powder (yield 27%)

Mp 250-251 ° C .;

IR (KBr) ν _max 3122, 2959, 2206, 1626, 1520, 1247, 777 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.93 (2H, quint, J = 5.9 Hz), 3.51 (2H, m), 3.68-3.76 (4H, m), 3.92-3.98 (2H, m), 6.43 (1H, d, J = 7.8 Hz), 6.52-6.57 (1H, m), 6.83 (1H, ddd, J = 14.7, 6.8, 2.9 Hz), 7.17 (1H, q, J = 9.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 12.15 (1H, bs);

MS (FAB) m / z: 347 [M + H] ⁺ , 273, 242;

analysis. Calc. For C ₁₇ H ₁₆ F ₂ N ₄ S.0.2H ₂ O: C, 58.34; H, 4.72; F, 10.86; N, 16.01; S, 9.16. Found: C, 58.48; H, 4.73; F, 10.59; N, 16.13; S, 9.04.

(85d) 3-amino-4- [4- (3,4-difluorophenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine2-carboxamide

4- [4- (3,4-difluoro) prepared in Example 85 (85c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Phenyl) -1,4-diazepane-1-yl] -2-thioo-1,2-dihydropyridine-3-carbonitrile, and the reaction is carried out in the same manner as in Example 5 (5c). It carried out and obtained the title compound.

Slightly brown powder (yield 83%)

Mp 199-201 ° C .;

IR (KBr) ν _max 3454, 3324, 3171, 2953, 2839, 1650, 1582, 1519, 1369 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.10-2.18 (2H, m), 3.14-3.23 (2H, m), 3.24-3.32 (2H, m), 3.52 (2H, t, J = 6.4 Hz ), 3.75 (2H, t, J = 5.0 Hz), 6.49-6.56 (1H, m), 6.78 (1H, ddd, J = 14.7, 6.8, 2.9 Hz), 7.00 (2H, bs), 7.08 (1H, d, J = 5.2 Hz), 7.10 (2H, bs), 7.20 (1H, q, J = 9.8 Hz), 8.41 (1H, d, J = 5.2 Hz);

MS (FAB) m / z: 404 [M + H] ⁺ , 387, 246, 200;

analysis. Calc. For C ₁₉ H ₁₉ F ₂ N ₅ O ₂ S.0.24H ₂ O: C, 55.96; H, 4. 82; F, 9.32; N, 17.17; S, 7.86. Found: C, 55.97; H, 4.76; F, 9.25; N, 17.24; S, 7.76.

Example 86 3-amino-4- {4- [3- (trifluoromethyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 3-120)

(86a) tert-butyl 4- [3- (trifluoromethyl) phenyl] -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 13%)

IR (film) ν _max 2976, 1695, 1612, 1463, 1417, 1321, 1164, 1124 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.33 (4.5H, s), 1.43 (4.5H, s), 1.93-2.01 (2H, m), 3.23 81H, t, J = 5.9 Hz, 3.34 (1H , t, J = 5.9 Hz), 3.54-3.64 (6H, m), 6.80-6.94 (3H, m), 7.23-7.32 (1H, m);

MS (FAB) m / z: 344 [M ⁺ ], 289, 243.

(86b) 1- [3- (trifluoromethyl) phenyl] -1,4-diazepane

tert-butyl 4- [3- (trifluoromethyl) phenyl] -1 prepared in Example 86 (86a) instead of tert-butyl 4-phenyl-1,4-diazepane-1-carboxylate, The title compound was obtained in the same manner as in the method described in Example 57 (57b) using 4-diazepan-1-carboxylate.

Brown oil (89% yield)

IR (film) ν _max 2938, 1691, 1611, 1506, 1457, 1321, 1162, 1121 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.91 (2H, t, J = 5.9 Hz), 2.84 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.4 Hz), 3.57 (2H , t, J = 5.4 Hz), 3.60 (2H, t, J = 6.4 Hz), 6.80-6.91 (3H, m), 7.25-7.31 (1H, m);

MS (EI) m / z: 244 [M ⁺ ], 202, 188.

(86c) 2-thioxo-4- {4- [3- (trifluoromethyl) phenyl] -1,4-diazepan-1-yl} -1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, 1- [3- (trifluoromethyl) phenyl] -1,4-diazepane prepared in Example 86 (86b) was used, Reaction was performed in the same manner as in Example 77 (77c) to obtain the title compound.

Slightly brown powder (yield 27%)

Mp 247-248 ° C;

IR (KBr) ν _max 2414, 3129, 2964, 2207, 1625, 1523, 1320, 1120 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.92-2.00 (2H, m), 3.60 (2H, t, J = 5.9 Hz), 3.75 (2H, t, J = 5.9 hz), 3.80 (2H, t, J = 5.4 Hz), 3.08 (2H, t, J = 5.4 Hz), 6.45 (1H, d, J = 7.8 Hz), 6.90 (1H, d, J = 7.3 Hz), 6.99 (1H, s) , 7.07 (1H, doublet of doublets, J = 8.3, 2.0 Hz), 7.33-7.40 (2H, m), 11.53 (1H, bs);

MS (FAB) m / z: 379 [M + H] ⁺ , 273, 226;

analysis. Calc. For C ₁₈ H ₁₇ F ₃ N ₄ S.0.2H ₂ O: C, 56.69; H, 4.59; N, 14.67; S, 8.39. Found: C, 56.60; H, 4.58; N, 14.67; S, 8.39.

(86d) 3-amino-4- {4- [3- (trifluoromethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carbox mid

2-Tioxo-4- {4- [3- made in Example 86 (86c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Reaction was carried out similarly to the method described in Example 5 (5c), using (trifluoromethyl) phenyl] -1,4-diazepane-1-yl} -1,2-dihydropyridine-3-carbonitrile. Was carried out to obtain the title compound.

Slightly brown powder (yield 84%)

Mp 195-197 ° C .;

IR (KBr) ν _max 3427, 3326, 3167, 1639, 1580, 1504, 1371, 1121 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.14-2.23 (2H, m), 3.15-3.25 (2H, m), 3.26-3.36 (2H, m), 3.60 (2H, t, J = 5.9 Hz ), 3.84 (2H, t, J = 4.6 Hz), 6.91 (1H, d, J = 7.3 Hz), 6.95-6.99 (1H, m), 7.01 (1H, bs), 7.06 (1H, dd, J = 8.3, 2.0 Hz), 7.09 (1H, d, J = 5.2 Hz), 7.10 (1H, bs), 7.38 81H, t, J = 8.3 Hz), 8.41 (1H, d, J = 5.2 Hz);

MS (FAB) m / z: 436 [M + H] ⁺ , 419, 240.

Example 87 3-amino-4- {4- [4- (trifluoromethoxy) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamides (Example Compound No. 3-130)

(87a) tert-butyl 4- [4- (trifluoromethoxy) phenyl] -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Light brown oil (yield 41%)

IR (film) ν _max 2976, 1692, 1516, 1417, 1268, 1163 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.33 (4.5H, s), 1.42 (4.5H, s), 1.90-1.98 (2H, m), 3.22 (1H, t, J = 5.9 Hz), 3.32 ( 1H, t, J = 5.5 Hz), 3.48-3.60 (6H, m), 6.61 (2H, d, J = 9.2 Hz), 7.04 (2H, d, J = 9.2 Hz);

MS (FAB) m / z: 360 [M ⁺ ], 305, 259.

(87b) 1- [4- (trifluoromethoxy) phenyl] -1,4-diazepane

tert-butyl 4- [4- (trifluoromethoxy) phenyl] -1 prepared in Example 87 (87a), instead of tert-butyl 4-phenyl-1,4-diazepane-1-carboxylate, The title compound was obtained in the same manner as in the method described in Example 57 (57b) using 4-diazepan-1-carboxylate.

Green oil (yield 57%)

IR (film) ν _max 2936, 1610, 1516, 1265, 1231, 1205, 1156, 805 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.89 (2H, quint, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.4 Hz), 3.53 (2H , t, J = 5.4 Hz), 3.56 (2H, t, J = 5.9 Hz), 6.63 (2H, d, J = 9.3 Hz), 7.05 (2H, d, J = 9.3 Hz);

MS (EI) m / z: 260 [M ⁺ ], 218, 204.

(87c) 2-thioxa-4- {4- [4- (trifluoromethoxy) phenyl] -1,4-diazepane-1-yl} -1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, 1- [4- (trifluoromethoxy) phenyl] -1,4-diazepane prepared in Example 87 (87b) was used, Reaction was performed in the same manner as in Example 77 (77c) to obtain the title compound.

Slightly brown powder (yield 19%)

Mp 240-242 ° C .;

IR (KBr) ν _max 3122, 2957, 2210, 1627, 1514, 1245, 1150 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.91-1.98 (2H, m), 3.55 (2H, t, J = 5.9 Hz), 3.70-3.78 (4H, m), 3.97 (2H, t, J = 5.4 Hz), 6.44 (1H, d, J = 7.8 Hz), 6.83 (2H, d, J = 9.3 Hz), 7.13 (2H, d, J = 9.3 Hz), 7.37 (1H, d, J = 7.8 Hz), 12.53 (1H, bs);

MS (FAB) m / z: 395 [M + H] ⁺ , 175;

analysis. Calc. For C ₁₈ H ₁₇ F ₃ N ₄ OS: C, 54.81; H, 4. 34; N, 14.21; S, 8.13. Found: C, 54.74; H, 4.06; N, 14. 12; S, 8.08.

(87d) 3-amino-4- {4- [4- (trifluoromethoxy) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carbox mid

2-thioxa-4- {4- [4- as prepared in Example 87 (87c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Reaction was carried out similarly to the method described in Example 5 (5c), using (trifluoromethoxy) phenyl] -1,4-diazepane-1-yl} -1,2-dihydropyridine-3-carbonitrile. Was carried out to obtain the title compound.

Slightly brown powder (yield 79%)

Mp 163-165 ° C .;

IR (KBr) ν _max 3413, 3325, 3176, 2947, 2836, 1637, 1579, 1515, 1372 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.11-2.19 (2H, m), 3.16-3.24 (2H, m), 3.26-3.33 (2H, m), 3.55 (2H, t, J = 5.9 Hz ), 3.79 (2H, t, J = 4.6 Hz), 6.82 (2H, d, J = 9.3 Hz), 7.00 (2H, bs), 7.08 (1H, d, J = 5.4 Hz), 7.10 (2H, bs ), 7.15 (2H, d, J = 9.3 Hz), 8.40 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 452 [M + H] &lt; ⁺ &gt;, 435, 216;

analysis. Calc. For C ₂₀ H ₂₀ F ₃ N ₅ 0 ₂ S: C, 53.21; H, 4. 47; F, 12.62; N, 15.51; S, 7.10. Found: C, 53.06; H, 4.13; F, 12.53; N, 15.44; S, 6.93.

Example 88 3-amino-4- [4- (2,3,5,6-tetrafluoropyridin-4-yl) -1,4-diazepan-1-yl] thieno [2,3 -b] pyridine-2-carboxamide (example compound number 3-145)

(88a) tert-butyl 4- (2,3,5,6-tetrafluoropyridin-4-yl) -1,4-diazepane-1-carboxylate

Pentafluoropyridine (878 μL, 8 mmol), tert-butyl 1,4-diazepane-1-carboxylate (1577 μL, 8 mmol) and triethylamine (1227 μL, 8.8 mmol) were dissolved in methylene chloride (40 mL) to obtain room temperature. Stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction solution, the aqueous layer was extracted with methylene chloride (2 x 25 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 (eluent: hexane / ethyl acetate = 5/1) to obtain 2.54 g of the titled target compound (91%).

White powder

Mp 55-59 ° C .;

IR (KBr) ν _max 2985, 1690, 1636, 1523, 1476, 1170, 1143 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.44 (4.5H, s), 1.46 (4.5H, s), 1.90-2.03 (1H, m), 3.47 (1H, m, J = 5.9 Hz, 3.53) , t, J = 5.9 Hz), 3.71-3.56 (6H, m);

MS (FAB) m / z: 350 [M + H] ⁺ , 294, 250.

(88b) 1- (2,3,5,6-tetrafluoropyridin-4-yl) -1,4-diazepane

tert-butyl 4- (2,3,5,6-tetrafluoropyridine- as prepared in Example 88 (88a) instead of tert-butyl 4-phenyl-1,4-diazepane-1-carboxylate The reaction was carried out in the same manner as in Example 57 (57b) using 4-yl) -1,4-diazepane-1-carboxylate to obtain the title compound.

White powder (yield 97%)

Mp 58-61 ° C .;

IR (KBr) ν _max 3356, 2932, 2852, 1638, 1534, 1473, 1126, 1068, 932 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.96 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.5 Hz), 3.62-3.71 (6H, m);

MS (EI) m / z: 249 [M ⁺ ], 207, 193.

(88c) 4- [4- (2,3,5,6-tetrafluoropyridin-4-yl) -1,4-diazepan-1-yl] -2-thioxa-1,2-dihydro Pyridine-3-carbonitrile

1- (2,3,5,6-tetrafluoropyridin-4-yl) -1,4 prepared in Example 88 (88b) instead of 1- (4-methylphenyl) -1,4-diazepane The reaction was carried out in the same manner as in Example 77 (77c) using a diazepane to obtain the title compound.

Light brown powder (yield 22%)

Mp 267-269 ° C .;

IR (KBr) ν _max 3121, 2961, 2210, 1628, 1522, 1471, 1250, 1135, 962 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.97-2.08 (2H, m), 3.58-3.66 (2H, m), 3.76-3.85 (2H, m), 3.89-3.96 (2H, m), 3.97 -4.05 (2H, m), 6.50 (1H, d, J = 7.6 Hz), 7.42 (1H, d, J = 7.6 Hz), 12.51 (1H, bs);

MS (FAB) m / z: 384 [M + H] ⁺ , 200;

analysis. Calc. For C ₁₆ H ₁₃ F ₄ N ₅ S: C, 50.13; H, 3. 42; N, 18.27; S, 8.36. Found: C, 50.08; H, 3. 66; N, 18.35; S, 8.37.

(88d) 3-amino-4- [4- (2,3,5,6-tetrafluoropyridin-4-yl) -1,4-diazepan-1-yl] thieno [2,3-b ] Pyridine-2-carboxamide

4- [4- (2,3,5,6) prepared in Example 88 (88c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile -Tetrafluoropyridin-4-yl) -1,4-diazepane-1-yl] -2-thioxa-1,2-dihydropyridine-3-carbonitrile, using Example 5 (5c) Reaction was performed similarly to the method described in the above, to obtain the title compound.

Light yellow powder (yield 85%)

Mp 228-231 ° C .;

IR (KBr) ν _max 3441, 3325, 3175, 2924, 1641, 1583, 1469, 1371, 1121, 962 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.14-2.23 (2H, m), 3.26-3.35 (2H, m), 3.39-3.48 (2H, m), 3.75-3.82 (2H, m), 3.87 -3.94 (2H, m), 7.04 (2H, bs), 7.10 (1H, d, J = 5.4 Hz), 7.11 (2H, bs), 8.44 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 441 [M + H] ⁺ , 329, 273;

analysis. Calc. For C ₁₈ H ₁₆ F ₄ N ₆ OS: C, 49.09; H, 3. 66; F, 17.25; N, 19.08; S, 7.28. Found: C, 49.02; H, 3.72; F, 16.85; N, 19.13; S, 7.21.

(Example 89) 3-amino-4- (4-quinazolin-4-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-147)

(89a) tert-butyl 4-quinazolin-4-yl-1,4-diazepane-1-carboxylate

Instead of pentafluoropyridine, 4-chloroquinazolin (Helv. Chim. Acta, (2001), 84, 1112-1118) was used, and the reaction was carried out in the same manner as described in Example 88 (88a), to obtain the title compound. Got.

Colorless oil (yield 91%)

Mp 55-59 ° C .;

IR (film) ν _max 2975, 2929, 2869, 1693, 1566, 1506, 1346, 1167 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.34 (4.5H, s), 1.42 (4.5H, s), 2.03-2.21 (2H, m), 3.47 (1H, t, J = 5.9 Hz), 3.56 ( 1H, t, J = 5.5 Hz), 3.65-3.77 (2H, m), 3.90-4.10 (4H, m), 7.41 (1H, t, J = 8.2 Hz), 7.71 (1H, t, J = 8.2 Hz ), 7.86 (1H, d, J = 8.2 Hz), 7.95 (1H, d, J = 8.2 Hz), 8.64 (1H, s);

MS (FAB) m / z: 329 [M + H] ⁺ , 273.

(89b) 4- (1,4-diazepane-1-yl) quinazoline

tert-butyl 4-quinazolin-4-yl-1,4-diazepane prepared in Example 89 (89a) instead of tert-butyl 4-phenyl-1,4-diazepane-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Light brown oil (yield 76%)

IR (film) ν _max 3296, 2937, 1684, 1613, 1567, 1505, 1346 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.03 (2H, m), 2.96-3.02 (2H, m), 3.17-3.22 (2H, m), 3.98-4.04 (4H, m), 7.33-7.39 (1H m), 7.64-7.70 (1H, m), 7.80-7.84 (1H, m), 7.92-7.97 (1H, m), 8.60 (1H, s);

MS (EI) m / z: 228 [M ⁺ ], 185, 172, 159.

(89c) 4- (4-quinazolin-4-yl-1,4-diazepan-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, 4- (1,4-diazepan-1-yl) quinazoline prepared in Example 89 (89b) was used, and Example 77 ( The reaction was carried out in the same manner as in the method described in 77c), to obtain the title compound.

Brown Powder (Yield 19%)

Mp 221-223 ° C .;

IR (KBr) ν _max 3431, 3111, 2926, 2204, 1623, 1566, 1504, 1344, 1242 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.14-2.22 (2H, m), 3.93 (2H, t, J = 5.9 Hz), 3.98 (2H, t, J = 5.5 Hz), 4.13 (4H, bs), 6.47 (1H, d, J = 7.4 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.45-7.52 (1H, m), 7.70-7.79 (2H, m), 8.02 (1H, d , J = 8.2 Hz), 8.50 (1H, s), 12.49 (1H, bs);

MS (FAB) m / z: 363 [M + H] ⁺ , 257, 229;

analysis. Calc. For C ₁₉ H ₁₈ N ₆ S: C, 60.09; H, 5. 29; N, 22.13. Found: C, 60.18; H, 5. 38; N, 22.09.

(89d) 3-amino-4- (4-quinazolin-4-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4-quinazolin-4-yl-1 prepared in Example 89 (89c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The reaction was carried out in the same manner as in Example 5 (5c) using, 4-diazepan-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile to give the titled compound. Got.

Light yellow powder (yield 85%)

Mp 228-231 ° C .;

IR (KBr) ν _max 3439, 3321, 3181, 2957, 1648, 1567, 1501, 1344 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.24-2.36 (2H, m), 3.17-3.30 (2H, m), 3.50-3.59 (2H, m), 4.03-4.13 (2H, m), 4.18 -4.29 (2H, m), 7.00 (2H, bs), 7.06 (1H, d, J = 5.1 Hz), 7.10 (2H, bs), 7.46 (1H, ddd, J = 8.6, 6.0, 2,3 Hz ), 7.70-7.78 (2H, m), 8.10 (1H, d, J = 8.2 Hz), 8.39 (1H, d, J = 5.1 Hz), 8.50 (1H, s);

MS (FAB) m / z: 420 [M + H] ⁺ , 273, 246, 200.

Example 90 3-amino-4- [4- (4-methyl-3-nitrophenyl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-119)

(90a) tert-butyl 4- (4-methyl-3-nitrophenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Orange powder (yield 41%)

Mp 103-106 ° C .;

IR (KBr) ν _max 2978, 1685, 1528, 1415, 1334 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.35 (4.5H, s), 1.42 (4.5H, s), 1.93-2.00 (2H, m), 2.45 (3H, s), 3.23 (1H, t, J = 5.9 Hz), 3.33 (1H, t, J = 5.9 Hz), 3.53-3.62 (6H, m), 6.82 (1H, dd, J = 8.8, 2.9 Hz, 7.13 (1H, d, J = 8.8 Hz, 7.26 (1H, doublet, J = 2.9 Hz);

MS (FAB) m / z: 336 [M + H] ⁺ , 280, 234, 189;

analysis. Calc. For C ₁₇ H ₂₅ N ₃ O ₄ .0.3H ₂ O: C, 59.91; H, 7.57; N, 12.33. Found: C, 59.94; H, 7. 29; N, 12.01.

(90b) 1- (4-methyl-3-nitrophenyl) -1,4-diazepane

tert-butyl 4- (4-methyl-3-nitrophenyl) -1,4 prepared in Example 90 (90a) instead of tert-butyl 4-phenyl-1,4-diazepan-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using diazepan-1-carboxylate.

Red oil (100% yield)

IR (liquid) ν _max 2930, 1628, 1527, 1346 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.91 (2H, t, J = 5.9 Hz), 2.45 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.5 Hz), 3.55 (2H, t, J = 5.5 Hz), 3.59 (2H, t, J = 5.9 Hz), 6.81 (1H, dd, J = 8.3, 2.9 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.26 (1H, doublet, J = 2.9 Hz);

MS (EI) m / z: 235 [M ⁺ ], 193, 179.

(90c) 4- [4- (4-methyl-3-nitrophenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, 1- (4-methyl-3-nitrophenyl) -1,4-diazepane prepared in Example 90 (90b) was used and carried out. Reaction was performed in the same manner as the method described in Example 77 (77c) to obtain the title compound.

Brown Powder (Yield 31%)

Mp 277-278 ° C .;

IR (KBr) ν _max 3437, 3124, 2961, 2206, 1625, 1525, 1341, 1252 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94 (2H, m), 2.32 (3H, s), 3.57 (2H, t, J = 5.9 Hz), 3.70-3.81 (4H, m), 3.92- 3.99 (2H, m), 6.42 (1H, d, J = 7.8 Hz), 7.05 (1H, dd, J = 8.6, 2.7 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.24 (1H, d , J = 2.7 Hz), 7.35 (1H, d, J = 7.8 Hz), 12.47 (1H, bs);

MS (FAB) m / z: 370 [M + H] ⁺ , 259, 242;

analysis. Calc. For C ₁₈ H ₁₉ N ₅ O ₂ S.0.26H ₂ O: C, 57.79; H, 5. 26; N, 18.72; S, 8.57. Found: C, 57.78; H, 5. 16; N, 18.73; S, 8.51.

(90d) 3-amino-4- [4- (4-methyl-3-nitrophenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-methyl-3-nitro) prepared in Example 90 (90c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile Phenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile, and the reaction is carried out in the same manner as in Example 5 (5c). It carried out and obtained the title compound.

Orange powder (yield 91%)

Mp 114-117 ° C .;

IR (KBr) ν _max 3439, 3323, 3181, 2927, 2846, 1650, 1579, 1525, 1366 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.13-2.21 (2H, m), 2.36 (3H, s), 3.14-3.23 (2H, m), 3.27-3.34 (2H, m), 3.59 (2H , t, J = 5.9 Hz), 3.81 (2H, t, J = 4.8 Hz), 7.01 (2H, bs), 7.0-7.15 84H, m), 7.24-7.29 (2H, m), 8.41 (1H, d , J = 5.4 Hz);

MS (FAB) m / z: 427 [M + H] ⁺ , 410, 273, 246;

analysis. Calc. For C ₂₀ H ₂₂ N ₆ O ₃ S.0.5H ₂ O: C, 55.16; H, 5. 32; N, 19.30. Found: C, 54.87; H, 5.49; N, 19.58.

Example 91 3-amino-4- [4- (4-isopropoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-129)

(91a) tert-butyl 4- (4-isopropoxyphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 14%)

IR (film) ν _max 2974, 1694, 1511, 1415, 1366, 1237, 1168, 1122 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.28 (6H, d, J = 5.9 Hz), 1.37 (4.5H, s), 1.43 (4.5H, s), 1.90-2.00 (2H, m), 3.20 ( 2H, t, J = 5.9 Hz, 3.31 (2H, t, J = 5.5 Hz), 3.40-3.61 (6H, m), 4.35 (1H, sept, J = 5.9 Hz), 6.61 (2H, d, J = 9.0 Hz), 6.78 (2H, d, J = 9.0 Hz);

MS (EI) m / z: 334 [M ⁺ ], 278, 236.

(91b) 1- (4-isopropoxyphenyl) -1,4-diazepane

Instead of tert-butyl 4-phenyl-1,4-diazepan-1-carboxylate, tert-butyl 4- (4-isopropoxyphenyl) -1,4-diaza prepared in Example 91 (91a) The title compound was obtained in the same manner as in the method described in Example 57 (57b) using Platen-1-carboxylate.

Off White Prism Crystal (Yield 89%)

Mp 62-64 ° C .;

IR (film) ν _max 2974, 2932, 1511, 1237, 1114, 957, 815 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.29 (6H, d, J = 5.9 Hz), 1.88 (2H, quint, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.01 (2H , t, J = 5.5 Hz), 3.49 (2H, t, J = 5.5 Hz), 3.52 (2H, t, J = 5.9 Hz), 4.35 (1H, sept, J = 5.9 Hz), 6.61 (2H, d , J = 9.0 Hz), 6.79 (2H, d, J = 9.0 Hz);

MS (EI) m / z: 234 [M ⁺ ], 191, 178.

(91c) 4- [4- (4-isopropoxyphenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Example 77, using the 1- (4-isopropoxyphenyl) -1,4-diazepane prepared in Example 91 (91b) instead of the 1- (4-methylphenyl) -1,4-diazepane. Reaction was performed similarly to the method described in (77c) to obtain the title compound.

Slightly brown powder (yield 32%)

Mp 216-218 ° C .;

IR (KBr) ν _max 3440, 3128, 3046, 2974, 2205, 1625, 1511, 1511, 1241 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.30 (6H, d, J = 5.9 Hz), 2.11 (2H, quint, J = 5.9 Hz), 3.51 (2H, t, J = 5.9 Hz), 3.73 (2H , t, J = 5.4 Hz), 3.76 (2H, t, J = 5.9 Hz), 4.12 (2H, t, J = 5.4 Hz), 4.39 (1H, sept, J = 5.9 Hz), 6.21 (1H, d , J = 7.8 Hz), 6.67 (2H, d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz), 7.23 (1H, d, J = 7.8 Hz), 1184 (1H, bs);

MS (EI) m / z: 368 [M ⁺ ], 325, 148;

analysis. Calc. For C ₂₀ H ₂₄ N ₄ OS.0.15H ₂ O: C, 64.71; H, 6. 60; N, 15.09; S, 8.64. Found: C, 64.59; H, 6. 46; N, 15.09; S, 8.47.

(91d) 3-amino-4- [4- (4-isopropoxyphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-isopropoxyphenyl) prepared in Example 91 (91c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile -1,4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used, and the reaction was carried out in the same manner as in Example 5 (5c). The title compound was obtained.

Light Yellow Powder 79%

Mp 173-175 ° C .;

IR (KBr) ν _max 3441, 3324, 2973, 1644, 1579, 1510, 1370, 1235 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.21 (6H, d, J = 5.9 Hz), 2.07-2.16 (2H, m), 3.16-3.24 (2H, m), 3.25-3.33 (2H, m ), 3.47 (2H, t, J = 5.9 Hz), 3.69 (2H, t, J = 4.7 Hz), 4.37 (1H, sept, J = 5.9 Hz), 6.68 (2H, d, J = 9.0 Hz), 6.76 (2H, d, J = 9.0 Hz), 6.97 (2H, bs), 7.03-7.11 (3H, m), 8.37 (1H, d, J = 5.5 Hz);

MS (EI) m / z: 425 [M ⁺ ], 382, 275, 183;

analysis. Calc. For C ₂₂ H ₂₇ N ₅ O ₂ S: C, 62.09; H, 6. 40; N, 16.46; S, 7.54. Found: C, 61.83; H, 6. 23; N, 16.32; S, 7.38.

Example 92 3-amino-4- [4- (4-tert-butylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-115)

(92a) tert-butyl 4- (4-tert-butylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

White powder (yield 9%)

Mp 62-64 ° C .;

IR (KBr) ν _max 2962, 1686, 1520, 1420, 1364, 1246, 1170 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.27 (9H, s), 1.35 (4.5H, s), 1.43 (4.5H, s), 1.91-2.00 (1H, m), 3.21 (1H, t, J = 6.3 Hz), 3.32 (1H, t, J = 5.9 Hz), 3.48-3.59 (6H, m), 6.62 (2H, d, J = 8.8 Hz), 7.20 (2H, d, J = 8.8 Hz);

MS (EI) m / z: 332 [M ⁺ ], 276, 261.

(92b) 1- (4-tert-butylphenyl) -1,4-diazepane

tert-Butyl 4- (4-tert-butylphenyl) -1,4-diaza prepared in Example 92 (92a) instead of tert-butyl 4-phenyl-1,4-diazepane-1-carboxylate The title compound was obtained in the same manner as in the method described in Example 57 (57b) using Platen-1-carboxylate.

Light brown oil (yield 97%)

IR (film) ν _max 2959, 1614, 1520, 1363, 1201, 812, 552 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.28 (9H, s), 1.89 (2H, quint, J = 5.9 Hz), 2.84 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.52 (2H, t, J = 5.5 Hz), 3.54 (2H, t, J = 5.9 Hz), 6.63 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz );

MS (EI) m / z: 232 [M ⁺ ], 217, 190, 176.

(92c) 4- [4- (4-tert-butylphenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Example 77, using the 1- (4-tert-butylphenyl) -1,4-diazepane prepared in Example 92 (92b) instead of the 1- (4-methylphenyl) -1,4-diazepane Reaction was performed similarly to the method described in (77c) to obtain the title compound.

Light brown powder (yield 21%)

Mp 257-258 ° C .;

IR (KBr) ν _max 3121, 3041, 2958, 2205, 1625, 1519, 1459, 1247 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.28 (9H, s), 2.12 (2H, quint, J = 5.9 Hz), 3.56 (2H, t, J = 5.9 Hz), 3.71-3.81 (4H, m) , 4.13 (2H, t, J = 5.1 Hz), 6.20 (1H, d, J = 7.6 Hz), 6.66 (2H, d, J = 8.6 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.24 (2H, d, J = 8.6 Hz), 11.94 (1H, bs);

MS (EI) m / z: 366 [M ⁺ ], 351, 188.

(92d) 3-amino-4- [4- (4-tert-butylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-tert-butylphenyl) prepared in Example 92 (92c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile -1,4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used, and the reaction was carried out in the same manner as in Example 5 (5c). The title compound was obtained.

Light Yellow Powder (Yield 72%)

Mp 231-232 ° C .;

IR (KBr) ν _max 3440, 3324, 3182, 2957, 1645, 1579, 1579, 1519, 1364 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.21 (9H, s), 2.06-2.17 (2H, m), 3.22-3.16 (4H, m), 6.69 (2H, d, J = 9.0), 6.89 (2H, bs), 7.03-7.09 (3H, m), 7.17 (2H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.5 Hz);

MS (EI) m / z: 423 [M ⁺ ], 391, 275;

analysis. Calc. For C ₂₃ H ₂₉ N ₅ OS.0.27H ₂ O: C, 64.48; H, 6.95; N, 16.35; S, 7.48. Found: C, 64.17; H, 6. 64; N, 16.31; S, 7.43.

Example 93 3-Amino-4- [4- (4-ethylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound number 3-112)

(93a) tert-butyl 4- (4-ethylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Org. Lett., 4, 581-584 (2002), to synthesize the title compound.

Colorless oil (yield 11%)

IR (film) ν _max 2964, 1695, 1519, 1415, 1236, 1169 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.19 (3H, t, J = 7.6 Hz), 1.37 (4.5H, s), 1.44 (4.5H, s), 1.92-2.01 (2H, m), 2.53 ( 2H, q, J = 7.6 Hz), 3.19 (1H, t, J = 6.3 Hz), 3.30 (1H, t, J = 5.9 Hz), 3.47-3.59 (6H, m), 6.62 (2H, d, J = 8.4 Hz), 7.02 (2H, d, J = 8.4 Hz);

MS (FAB) m / z: 304 [M ⁺ ], 248, 160.

(93b) 1- (4-ethylphenyl) -1,4-diazepane

tert-butyl 4- (4-ethylphenyl) -1,4-diazepane prepared in Example 93 (93a) instead of tert-butyl 4-phenyl-1,4-diazepane-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Light brown oil (yield 100%)

IR (film) ν _max 2929, 1616, 1519, 1189, 813 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.19 (3H, t, J = 7.6 Hz), 1.88 (2H, quint, J = 5.9 Hz), 2.54 (2H, q, J = 7.6 Hz), 2.82 (2H , t, J = 5.9 Hz), 3.01 (2H, t, J-5.5 Hz), 3.49-3.57 (2H, m), 6.62 (2H, d, J = 8.8 Hz), 7.03 (2H, d, J = 8.8 Hz);

MS (EI) m / z: 204 [M ⁺ ], 162, 148.

(93c) 4- [4- (4-ethylphenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, 1- (4-ethylphenyl) -1,4-diazepane prepared in Example 93 (93b) was used, and Example 77 (77c) was used. The reaction was carried out in the same manner as in the method), to obtain the title compound.

Slightly brown powder (yield 22%)

Mp 226-229 ° C .;

IR (KBr) ν _max 3122, 2959, 2205, 1625, 1517, 1457, 1246 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.20 (2H, t, J = 7.6 Hz), 2.11 (2H, quint, J = 5.9 Hz), 2.55 (2H, q, J = 7.6 Hz), 3.55 (2H , t, J = 5.9 Hz), 3.74 (2H, t, J = 5.9 Hz), 3.77 (2H, t, J = 5.1 Hz), 4.12 (2H, t, J = 5.1 Hz), 6.19 (1H, d , J = 7.6 Hz), 6.65 (2H, d, J = 8.6 Hz), 7.06 (2H, d, J = 8.6 Hz), 7.20 (1H, d, J = 7.6 Hz), 11.58 (1H, bs);

MS (EI) m / z: 338 [M ⁺ ], 323, 174, 160.

(93d) 3-amino-4- [4- (4-ethylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-ethylphenyl) -1 prepared in Example 93 (93c) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile , 4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used, and the reaction was carried out in the same manner as in Example 5 (5c) to obtain the title compound. Got.

White powder (yield 82%)

Mp 186-188 ° C .;

IR (KBr) ν _max 3439, 3324, 3178, 2958, 1643, 1579, 1518, 1369 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.14 (3H, t, J = 7.4 Hz), 2.07-2.17 (2H, m), 2.49 (2H, q, J = 7.4 Hz), 3.15-3.35 ( 4H, m), 3.53 (2H, t, J = 5.9 Hz), 3.74 (2H, t, J = 4.7 Hz), 6.70 (2H, d, J = 8.4 Hz), 6.96 (1H, bs), 7.02 ( 2H, d, J = 8.4 Hz), 7.04-7.14 (3H, m), 8.40 (1H, d, J = 5.5 Hz);

MS (EI) m / z: 395 [M ⁺ ], 377, 189;

analysis. Calc. For C ₂₁ H ₂₅ N ₅ OS: C, 63.77; H, 6. 37; N, 17.71; S, 8.11. Found: C, 63.56; H, 6. 25; N, 17.68; S, 8.10.

Example 94 4- [4- (4-acetylphenyl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-99)

(94a) tert-butyl 4- (4-acetylphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as in Example 59 (59a), using 4-fluoroacetophenone instead of 4-fluoronitrobenzene, to obtain the title compound.

Yellow liquid

IR (film) ν _max 2974, 1596, 1523, 1416, 1363, 1284, 1237, 1191, 929, 819, 756 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.42 (4.5H, s), 1.94-2.01 (2H, m), 2.50 (1H, s), 3.21 (1H, t, J = 5.9 Hz), 3.32 (1H, t, J = 5.9 Hz), 3.58-3.64 (6H, m), 6.66 (2H, d, J = 8.6 Hz), 7.83 (2H, t, J = 8.6 Hz);

HRMS m / z calc. For C ₁₈ H ₂₆ O ₃ N ₂ 318.1944, found 318.1934;

MS (EI) m / z: 318 [M ⁺ ], 261, 247, 217, 188, 174, 162, 132, 105, 91, 57, 41.

(94b) 1- [4- (1,4-diazepane-1-yl) phenyl] ethanone

tert-butyl 4- (4-acetylphenyl) -1,4-diazepane prepared in Example 94 (94a) instead of tert-butyl 4-phenyl-1,4-diazepane-1-carboxylate Using the 1-carboxylate, it carried out similarly to the method described in Example 57 (57b), and obtained the title compound.

Brown liquid

IR (KBr) ν _max 2931, 1658, 1597, 1523, 1403, 1360, 1285, 1191, 820 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.91 (2H, quint, J = 5.9 Hz), 2.50 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.4 Hz), 3.61 (2H, t, J = 5.4 Hz), 3.66 (2H, t, J = 6.4 Hz), 6.68 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz );

HRMS m / z calc'd C ₁₃ H ₁₈ ON ₂ 218.1420.1313, found 218.1422;

MS (EI) m / z: 218 [M ⁺ ], 203, 176, 162, 148, 132, 70, 43.

(94c) (2Z) -3- [4- (4-acetylphenyl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide

The same method as described in Example 5 (5a), using 1- [4- (1,4-diazepan-1-yl) phenyl] ethanone prepared in Example 94 (94b) instead of isobutylamine. The reaction was carried out to obtain the title compound.

Yellow powder

Mp 173-177 ° C .;

IR (KBr) ν _max 3310, 3178, 2183, 1593, 1524, 1407, 1354, 1289, 1194, 825, 594 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.96 (2H, m), 2.23 (3H, s), 2.42 (3H, s), 3.49-3.54 (2H, m), 3.60-3.66 (4H , m), 3.83-3.86 (2H, m), 6.81 (2H, d, J = 9.0 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.16 (2H, t, J = 7.3 Hz), 8.39 (1 H, brs), 9.04 (1 H, brs);

HRMS m / z calc. C ₁₈ H ₂₃ ON ₄ S 343.1592, found 343.1595;

MS (FAB) m / z: 343 [M + H] ⁺ , 326, 273, 246, 219, 165, 120, 65;

analysis. Calc. For C ₁₈ H ₂₂ N ₄ OS.0.40H ₂ O: C, 61.83; H, 6.57; N, 16.02; S, 9.17. Found: C, 61.52; H, 6. 35; N, 15.90, S, 9.52.

(94d) 4-[(4-acetylphenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- [4- (4-acetylphenyl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enthioamide (504 mg) prepared in Example 94 (94c). , 1.47 mmol) and N, N-dimethylformamide dimethylacetal (175 mg, 1.47 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at 60 ° C. for 80 minutes. 1N hydrochloric acid was added to make the reaction solution slightly acidic, and then ethyl acetate (10 mL) and water (20 mL) were added. The precipitated solid was obtained by filtration to obtain the title compound (518 mg, 38%).

Light brown powder

Mp 265-270 ° C .;

IR (KBr) ν _max 2940, 2206, 1625, 1593, 1521, 1355, 1288, 1248, 1238, 1192, 1143, 929, 817 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.91-1.97 (2H, m), 2.42 (3H, s), 3.64 (2H, t, J = 5.9 Hz), 3.76 (2H, t, J = 5.9 Hz), 3.86 (2H, t, J = 5.4 Hz), 3.98 (2H, t, J = 5.4 Hz), 6.44 (1H, d, J = 7.8 Hz), 6.85 (1H, d, J = 8.8 Hz) , 7.87 (1H, t, J = 7.8 Hz), 7.77 (2H, t, J = 8.8 Hz), 12.57 (1H, brs);

HRMS m / z calc. C ₁₉ H ₂₁ ON ₄ S 353.1436, found 353.1425;

MS (EI) m / z: 352 [M ⁺ ], 337, 323, 218, 204, 174, 162, 132, 105, 91, 77, 43;

analysis. Calc. For C ₁₉ H ₂₀ N ₄ OS.0.33H ₂ O: C, 63.66; H, 5.81; N, 15.63; S, 8.95. Found: C, 63.58; H, 5.80; N, 15.63, S, 8.74.

(94e) 4- [4- (4-acetylphenyl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide

4-[(4-acetylphenyl) -1,4 prepared in Example 94 (94d) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile -Diazane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used to carry out the reaction in the same manner as in Example 5 (5c) to obtain the title compound. .

Light brown powder

Mp 279-282 ° C. (decomposition);

IR (KBr) ν _max 3439, 3326, 3183, 1653, 1595, 1364, 1279, 1193, 939, 820 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.16-2.18 (2H, m), 2.44 (3H, s), 3.19-3.20 (2H, m), 3.30-3.32 (2H, m), 3.66 (2H , t, J = 6.3 Hz), 3.87 (2H, t, J = 4.9 Hz), 6.84 (2H, d, J = 8.8 Hz), 6.99 (2H, brs), 7.08 (1H, d, J = 5.4 Hz ), 8.10 (2H, br s), 7.80 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);

MS (EI) m / z: 409 [M ⁺ ].

Example 95 3-Amino-4- [3-methyl-4- (3-methylphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-77)

(95a) 4- [3-methyl-4- (3-methylphenyl) piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Instead of 1- (4-methylphenyl) -1,4-diazepane, reaction was carried out in the same manner as in Example 77 (77c), using 2-methyl-1- (3-methylphenyl) piperazine. The title compound was obtained.

Light brown powder (yield 23%)

Mp 250-251 ° C .;

IR (KBr) ν _max 3122, 3039, 2970, 2208, 1621, 1496, 1447, 1248, 1011 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.99 (3H, d, J = 6.3 Hz), 2.25 (3H, s), 3.14-3.23 (1H, m), 3.37-3.52 (2H, m), 3.67 (1H, dd, J = 13.3, 3.5 Hz), 3.91-3.99 (1H, m), 4.01-4.15 82H, m), 6.53 (2H, d, J = 7.6 Hz), 6.58 (1H, d, J = 7.4 Hz), 6.65-6.71 (2H, m), 7.09 (1H, t, J = 7.4 Hz), 7.49 (1H, d, J = 7.6 Hz);

MS (FAB) m / z: 325 [M + H] ⁺ , 200;

analysis. Calc. For C ₁₈ H ₂₀ N ₄ S.0.32H ₂ O: C, 65.47; H, 6. 30; N, 16.97; S, 9.71. Found: C, 65.24; H, 6. 38; N, 17.19; S, 9.78.

(95b) 3-amino-4- [3-methyl-4- (3-methylphenyl) piperazin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [3-methyl-4- (3-methylphenyl) prepared in Example 95 (95a) instead of 4- (isobutylamino) -2-thioxo-1,2-dihydropyridine-3-carbonitrile ) Piperazin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was reacted in the same manner as in Example 5 (5c) to obtain the title compound. .

Slightly brown powder (yield 81%)

Mp 215-217 ° C;

IR (KBr) ν _max 3449, 3325, 3179, 2972, 2836, 1644, 1580, 1501, 1370 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.99-1.14 (3H, m), 2.27 (3H, s), 2.62-3.51 (7H, m), 6.58-6.69 (1H, m), 6.74-6.85 (2H, m), 6.96 (2H, bs), 7.06-7.19 (4H, m), 8.46 (1H, d, J = 5.5 Hz);

MS (EI) m / z: 382 [M + H] ⁺ , 200;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS.0.16: C, 62.50; H, 6. 12; N, 18.22; S, 8.34. Found: C, 62.49; H, 6. 19; N, 18.15; S, 8.16.

(Example 96) 3-amino-4- (4-pyridin-3-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide (example Compound number 3-140)

(96a) (2Z) -2-cyano-3- (4-pyridin-3-yl-1,4-diazepan-1-yl) buta-2-enthioamide

The method described in Example 5 (5a) using 1-pyridin-3-yl-1,4-diazepane (J.Med. Chem., (2000), 43, 2217-2226) instead of isobutylamine. The reaction was carried out in the same manner as to obtain the title compound. Yield 83%.

Mp 162-164 ° C .;

IR (KBr) ν _max 3300, 3164, 2187, 1583, 1530, 796, 707 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.91-1.97 (2H, m), 2.24 (3H, s), 3.51-3.63 (6H, m), 3.76-3.79 (2H, m), 7.11-7.15 ( 2H, m), 7.82-7.84 (1H, m), 8.14 (1H, brs), 8.35 (1H, br), 9.00 (1H, br);

MS (FAB) m / z: 302 [M + H] ⁺ ;

analysis. Calc. For C ₁₅ H ₁₉ N ₅ S.0.1 H ₂ O: C, 59.42; H, 6. 38; N, 23.10; S, 10.57. Found: C, 59.53; H, 6. 48; N, 22.88; S, 10.57.

(96b) 3-amino-4- (4-pyridin-3-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (4-pyridin-3-yl-1,4-diazepan-1-yl) buta-2-enthioamide (485 mg) prepared in Example 96 (96a) , 1.61 mmol) and N, N-dimethylformamide dimethylacetal (211 mg, 1.77 mmol) were dissolved in N, N-dimethylformamide (3 mL) and stirred at room temperature for 1 hour. Moreover, it stirred at 100 degreeC-120 degreeC for 1.5 hours. The reaction solution was cooled to room temperature, and 8N aqueous sodium hydroxide solution (0.3 mL) and 2-chloroacetamide (196 mg, 2.09 mmol) were added. The mixture was stirred at rt for 3 h, then water (3 mL) was added. The precipitated solid was obtained by filtration and washed with water and ethanol to give 239 mg of solid. The obtained solid was recrystallized with ethanol (2 mL), and 195 mg of the title compound (yield 33%) was obtained.

Mp 214-216 ° C .;

IR (KBr) ν _max 3444, 3324, 3166, 1650, 1579, 1495, 1368, 794, 709 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.14-2.19 (2H, m), 3.16-3.22 (2H, m), 3.27-3.81 (2H, m), 3.55-3.58 (2H, m), 3.79- 3.81 (2H, m), 6.97 (2H, brs), 7.07 (1H, d, J = 5.5 Hz), 7.09 (2H, brs), 7.10-7.16 (2H, m), 7.83 (1H, dd, J = 2.0, 4.3 Hz), 8.16 (1H, d, J = 2.0 Hz), 8.35 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 369 [M + H] ⁺ .

Example 97 3-amino-4- [4- (1,3-thiazol-2-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2 -Carboxamide (Example Compound No. 3-136)

(97a) 1- (1,3-thiazol-2-yl) -1,4-diazepane dihydrochloride

2-bromothiazole (8.20 g, 50 mmol) and homopiperazine (10.00 g, 100 mmol) were stirred for 24 hours under reflux in n-butanol (100 mL). The reaction mixture was left at room temperature for 24 hours, and the precipitated solid was separated by filtration. The filtrate was concentrated under reduced pressure, and 1N aqueous sodium hydroxide solution (30 mL) was added to the residue, and the aqueous layer was extracted with methylene chloride (3 x 100 mL). The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (30 mL) and 4N hydrochloric acid-1,4-dioxane solution (30 mL) was added. Precipitated hydrochloride was obtained by filtration and washed with 1,4-dioxane and acetone to obtain 9.43 g (yield 74%) of the title compound.

IR (neat) ν _max 1603, 1581, 743 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.13-2.19 (2H, m), 3.18-3.25 (2H, m), 3.30-3.36 (2H, m), 3.64-3.67 (2H, m), 3.96-3.99 ( 2H, m), 6.98 (1H, d, J = 3.9 Hz), 7.35 (1H, d, J = 3.9 Hz);

MS (EI) m / z: 183 [M ⁺ ], 83;

analysis. Calc. For C ₈ H ₁₃ N ₃ S.2 (HCl) .0.1 (H ₂ O): C, 37.24; H, 5.94; N, 16.29; S, 12.43; Cl, 27.48. Found: C, 37.33; H, 5.88; N, 16.24; S, 12.37; Cl, 27.27.

(97b) 1- (1,3-thiazol-2-yl) -1,4-diazepane

1- (1,3-thiazol-2-yl) -1,4-diazepane dihydrochloride (5.11 g, 19.9 mmol) prepared in Example 97 (97a) was mixed with 1N aqueous sodium hydroxide solution (60 mL). Then, the mixture was extracted with methylene chloride (3 x 50 mL). The extract was dried over sodium sulfate and concentrated under reduced pressure to yield 3.60 g (yield 99%) of the title compound.

IR (neat) ν _max 3304, 1534, 1139, 614 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.90-1.96 (2H, m), 2.89-2.91 (2H, m), 3.04-3.07 (2H, m), 3.66-3.70 (4H, m), 6.44 (1H, d, J = 3.5 Hz), 7.15 (1H, d, J = 3.5 Hz);

MS (EI) m / z: 183 [M ⁺ ], 83;

analysis. Calc. For C ₈ H ₁₃ N ₃ S: C, 52.43; H, 7. 15; N, 22.93; S, 17.50. Found: C, 52.15; H, 7. 46; N, 22.66; S, 10.50.

(97c) (2Z) -2-cyano-3- [4- (1,3-thiazol-2-yl) -1,4-diazepan-1-yl] buta-2-enthioamide

Instead of isobutylamine, Example 5 (5a) was used, using 1- (1,3-thiazol-2-yl) -1,4-diazepane (3.60 g) prepared in Example 97 (97b). The reaction was carried out in the same manner as described in the above to obtain the title compound (4.56 g). Yield 91%.

Mp 149-152 ° C .;

IR (KBr) ν _max 3276, 3130, 2182, 1531, 885, 615 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.95-2.00 (2H, m), 2.27 (3H, s), 3.57-3.69 (6H, m), 3.80-3.84 (2H, m), 6.77 (1H, d, J = 3.5 Hz), 7.12 (1H, d, J = 3.5 Hz), 8.42 (1H, br), 9.06 (1H, br);

MS (FAB) m / z: 308 [M + H] ⁺ ;

analysis. Calc. For C ₁₃ H ₁₇ N ₅ S ₂ : C, 50.79; H, 5.57; N, 22.78; S, 20.86. Found: C, 50.52; H, 5. 64; N, 22.44; S, 21.10.

(97d) 3-amino-4- [4- (1,3-thiazol-2-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-car Copy mid

(2Z) -2-cyano-3- [4- (1,3-thiazol-2-yl) -1,4-diazepan-1-yl] buta-2 prepared in Example 97 (97c) -Enthioamide (394 mg, 1.28 mmol) and N, N-dimethylformamide dimethyl acetal (168 mg, 1.41 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at room temperature for 1 hour. Moreover, it stirred at 100 degreeC for 1 hour. The reaction solution was cooled to room temperature, and 8N aqueous sodium hydroxide solution (0.3 mL) and 2-chloroacetamide (156 mg, 1.66 mmol) were added. The mixture was stirred at rt overnight, then water (2 mL) was added. The precipitated solid was filtered off to obtain 215 mg of solid. The obtained solid was recrystallized from 95% ethanol (15 mL) to obtain 150 mg of the title compound (yield 31%).

Mp 243-245 ° C .;

IR (KBr) ν _max 3432, 3310, 3154, 1648, 1580, 1509, 1375, 933, 614 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.48-2.50 (2H, m), 3.19-3.37 (4H, m), 3.62 (2H, t, J = 5 9 Hz), 3.93-3.95 (2H, m ), 6.73 (1H, d, J = 3.5 Hz), 7.00 (2H, brs), 7.06 (1H, d, J = 5.5 Hz), 7.10 (2H, brs), 7.13 (1H, d, J = 3.5 Hz ), 8.39 (1H, doublet, J = 3.5 Hz);

MS (EI) m / z: 374 [M ⁺ ];

analysis. Calc. For C ₁₆ H ₁₈ N ₆ OS ₂ 1.1H ₂ O: C, 48.74; H, 5. 16; N, 21.31; S, 16.26. Found: C, 48.98; H, 5.03; N, 21.22; S, 15.89.

Example 98 3-amino-4- [4- (6-methoxypyridin-3-yl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 3-144)

(98a) (2Z) -2-cyano-3- [4- (6-methoxypyridin-3-yl) -1,4-diazepan-1-yl] buta-2-enthioamide

Example 5 using 1- (6-methoxypyridin-3-yl) -1,4-diazepane (J.Med. Chem., (2000), 43, 2217-2226) instead of isobutylamine, Example 5 The reaction was carried out in the same manner as described in (5a), to obtain the title compound. Yield 66%.

Mp 159-161 ° C .;

IR (KBr) ν _max 3306, 3186, 2187, 1643, 1530, 1504, 1041 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.90-1.97 (2H, m), 2.25 (3H, s), 3.44-3.45 (4H, m), 3.60-3.68 (4H, m), 3.74 (3H, s), 6.66 (1H, d, J = 9.0 Hz), 7.28 (1H, dd, J = 3.1, 9.0 Hz), 7.67 (1H, d, J = 3.1 Hz), 8.31 (1H, br), 8.97 ( 1H, br);

MS (EI) m / z: 331 [M ⁺ ];

analysis. Calc. For C ₁₆ H ₂₁ N ₅ SO.0.1H ₂ O: C, 57.67; H, 6. 41; N, 21.02; S, 9.62. Found: C, 57.74; H, 6. 50; N, 20.84; S, 9.49.

(98b) 3-amino-4- [4- (6-methoxypyridin-3-yl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carbox mid

(2Z) -2-cyano-3- [4- (6-methoxypyridin-3-yl) -1,4-diazepan-1-yl] buta-2- prepared in Example 98 (98a) Enthioamide (220 mg, 0.66 mmol) and N, N-dimethylformamide dimethyl acetal (83 mg, 0.70 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at room temperature for 2 hours. Moreover, it stirred at 100 degreeC for 1 hour. The reaction solution was cooled to room temperature, and 8N aqueous sodium hydroxide solution (0.2 mL) and 2-chloroacetamide (80 mg, 0.86 mmol) were added. The mixture was stirred at room temperature for 1 hour, and then partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (100% ethyl acetate), and recrystallized from ethanol to give 96 mg of the title compound (yield 36%).

Mp 170-172 ° C .;

IR (KBr) ν _max 3440, 3323, 3183, 1645, 1579, 1499, 1370, 1033, 939, 819 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.10-2.16 (2H, m), 3.17-3.31 (4H, m), 3.49-3.52 (2H, m), 3.70-3.72 (2H, m), 3.75 ( 3H, s), 6.67 (1H, d, J = 9.0 Hz), 6.98 (2H, br), 7.06 (1H, d, J = 5.5 Hz), 7.07 (2H, br), 7.27 (1H, dd, J = 3.1, 9.0 Hz), 7.67 (1H, d, J = 3.1 Hz), 8.38 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 399 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₂ N ₆ SO ₂ .0.4H ₂ O: C, 56.25; H, 5. 66; N, 20.72; S, 7.90. Found: C, 55.97; H, 5. 44; N, 21.11; S, 7.86.

(Example 99) 3-amino-4- (4-pyridin-2-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide (example compound Number 3-139)

(99a) tert-butyl2-pyridin-2-yl-1,4-diazepan-1-carboxylate

It synthesize | combined as follows with reference to the method of J. Org. Chem., (2001), 66, 7729-7737.

Potassium tert-butoxide (1.68 g, 15 mmol), tris (dibenzylideneacetone) dipalladium (0 valent) (92 mg, 0.1 mmol), 1,3-bis (2,6-diisopropylphenyl) imidazole 2-Ilidene) hydrochloride (85 mg, 0.2 mmol) was mixed with 1,4-dioxane (20 mL), 2-bromopyridine (2.37 g, 15 mmol) and N-Boc-homopiperazine (2.00 g) , 10 mmol) was added dropwise with a 1,4-dioxane (10 mL) solution. After stirring at room temperature for 12 hours, water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and the insolubles were removed by Celite. After separating the organic layer and the aqueous layer, the organic layer was washed with saturated brine (50 mL) and dried over sodium sulfate. The residue obtained by distilling a solvent off under reduced pressure was refine | purified by silica gel column chromatography (hexane / ethyl acetate = 4: 1), and 2.27 g (yield 82%) of the title compound were obtained.

IR (neat) ν _max 1694, 1597, 1494, 1240, 1169, 928, 770 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.38, (4.5H, s), 1.43, (4.5H, s), 1.92-1.99 (2H, m), 3.21-3.34 (2H, m), 3.54- 3.78 (6H, m), 6.47-6.52 (2H, m), 7.38-7.42 (1H, m), 8.10-8.12 (1H, m);

MS (FAB) m / z: 278 [M + H] ⁺ .

(99b) 1-pyridin-2-yl-1,4-diazepane

Tert-Butyl 4-pyridin-2-yl-1,4-diazepane-1-carboxylate (2.17 g, 7.8 mmol) prepared in Example 99 (99a) was dissolved in methylene chloride (8 mL), and ice-cold. Trifluoroacetic acid (8 mL) was then added. After stirring for 3 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Aqueous 1N sodium hydroxide solution (30 mL) was added to the residue, and the aqueous layer was extracted with methylene chloride (3 x 40 mL). The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.34 g (yield 97%) of the title compound as an oil.

IR (neat) ν _max 3308, 1597, 1496, 1440, 769 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.86-1.92 (2H, m), 2.83-2.86 (2H, m), 3.01-3.04 (2H, m), 3.69-3.74 (4H, m), 6.46-6.50 ( 2H, m), 7.40 (1H, double doublet of doublets, J = 2.0, 7.1, 8.6 Hz), 8.12 (1H, double doublet, J = 0.8, 2.0, 5.1 Hz);

MS (EI) m / z: 177 [M ⁺ ], 121.

(99c) (2Z) -2-cyano-3- (4-pyridin-2-yl-1,4-diazepan-1-yl) buta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as described in Example 5 (5a), using 1-pyridin-2-yl-1,4-diazepane prepared in Example 99 (99b) and The compound was obtained. Yield 79%.

Mp 155-157 ° C .;

IR (KBr) ν _max 3398, 3288, 3184, 2185, 1598, 1540, 1494, 1439, 773 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.94 (2H, m), 2.24 (3H, s), 3.55-3.70 (6H, m), 3.89-3.92 (2H, m), 6.57 (1H, dd, J = 5.0, 7.0 Hz), 6.72 (1H, d, J = 8.6 Hz), 7.50 (1H, ddd, J = 2.0, 7.0, 8.6 Hz), 8.07 (1H, dd, J = 2.0, 5.0 Hz ), 8.34 (1 H, br), 9.01 (1 H, br);

MS (FAB) m / z: 302 [M + H] ⁺ .

(99d) 4- (4-pyridin-2-yl-1,4-diazepane-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- (4-pyridin-2-yl-1,4-diazepan-1-yl) buta-2-enthioamide (0.90 g) prepared in Example 99 (99c) , 3.0 mmol) and N, N-dimethylformamide dimethylacetal (0.39 g, 3.3 mmol) were dissolved in N, N-dimethylformamide (5 mL) and stirred at room temperature for 1 hour and at 100 ° C for 1 hour. The reaction solution was cooled to room temperature and partitioned between isopropyl ether (20 mL) and 1N aqueous sodium hydroxide solution (10 mL). The aqueous layer was made acidic (pH = 4) with 1N hydrochloric acid, and neutralized again by adding saturated sodium bicarbonate water. Precipitated crystals were obtained by filtration and washed with water and ethanol to obtain a crude product of the title compound (0.37 g).

Mp 220-224 ° C .;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.94 (2H, m), 3.63-3.66 (2H, m), 3.76-3.79 (2H, m), 3.88-3.98 (4H, m), 6.41 ( 1H, d, J = 7.8 Hz), 6.53 (1H, dd, J = 5.0, 7.0 Hz), 6.71 (1H, d, J = 8.6 Hz), 7.81-7.35 (1H, m), 7.46 (1H, ddd , J = 2.0, 7.0, 8.6 Hz), 8.03 (1H, dd, J = 2.0, 5.0 Hz), 12.50 (1H, br).

(99e) 3-amino-4- (4-pyridin-2-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide

Of 4- (4-pyridin-2-yl-1,4-diazepan-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 99 (99d) The crude product (0.37 g) was dissolved in N, N-dimethylformamide (4 mL) and 8N aqueous sodium hydroxide solution (0.4 mL) and 2-chloroacetamide (0.14 g, 1.5 mmol) were added. The mixture was stirred at rt for 1 h, then water (4 mL) was added. The precipitated solid was obtained by filtration and washed with water and ethanol to obtain 0.33 g of solid. The obtained solid was heated and stirred in 80% ethanol (5 mL), cooled, and then the solid was filtered to obtain 0.30 g of the title compound. 27% yield from (2Z) -2-cyano-3- (4-pyridin-2-yl-1,4-diazepan-1-yl) buta-2-enthioamide.

Mp 237-239 ° C .;

IR (KBr) ν _max 3444, 3325, 3167, 1650, 1596, 1496, 1371, 942, 770 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.11-2.17 (2H, m), 3.17-3.32 (4H, m), 3.70 (2H, t, J = 6.3 Hz), 3.96-4.03 (2H, m) , 6.57 (1H, dd, J = 5.1, 7.0 Hz), 6.69 (1H, d, J = 8.6 Hz), 7.01 (2H, brs), 7.07 (1H, d, J = 5.1 Hz), 7.10 (2H, brs), 7.51 (1H, ddd, J = 2.0, 7.0, 8.6 Hz), 8.09 (1H, dd, J = 2.0, 5.1 Hz), 8.39 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 369 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₂₀ N ₆ SO. 0.3H ₂ O: C, 57.83; H, 5.55; N, 22.48; S, 8.58. Found: C, 57.99; H, 5. 35; N, 22.43; S, 8.59.

Example 100 3-Amino-4- (4-pyridin-4-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound Number 3-141)

(100a) tert-butyl 4-pyridin-4-yl-1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Example 99 (99a), using 4-bromopyridine hydrochloride instead of 2-bromopyridine and 2.1 equivalents of potassium tert-butoxide. The residue obtained by working up the reaction was purified by silica gel column chromatography (Chromatorex NH, Fuji Silysia) (100% ethyl acetate) to obtain the title compound. Yield 34%.

Mp 124-129 ° C .;

IR (KBr) ν _max 1674, 1597, 1167, 987 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.42 (4.5H, s), 1.92-1.99 (2H, m), 3.21-3.34 (2H, m), 3.52-3.59 (4H, m), 6.50 (2H, brd, J = 6.5 Hz), 8.18-8.20 (2H, m);

MS (EI) m / z: 277 [M ⁺ ], 220;

analysis. Calc. For C ₁₅ H ₂₃ N ₃ O ₂ : C, 64.95; H, 8. 36; N, 15.15. Found: C, 64.78; H, 8. 46; N, 15.03.

(100b) pyridin-4-yl-1,4-diazepane

Tert-butyl 4-pyridin-4-yl-1,4-diazepane-1-carboxylate (0.42 g, 1.5 mmol) prepared in Example 100 (100a) was dissolved in methanol (3 mL), and 4N hydrochloric acid. -1,4-dioxane solution (3 mL) was added. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. 1N aqueous sodium hydroxide solution (10 mL) was added to the residue, and the aqueous layer was extracted with methylene chloride (3 x 20 mL). The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.26 g (yield 97%) of the title compound as an oil.

IR (neat) ν _max 3270, 1600, 1518, 804 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.86-1.92 (2H, m), 2.83 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.3 Hz), 3.53-3.61 (4H, m ), 6.51 (2H, d, J = 6.6 Hz), 8.20 (2H, d, J = 6.6 Hz);

MS (FAB) m / z: 178 [M + H] ⁺ .

(100c) (2Z) -2-cyano-3- (4-pyridin-4-yl-1,4-diazepan-1-yl) buta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as described in Example 5 (5a), using 1-pyridin-4-yl-1,4-diazepane prepared in Example 100 (100b), and the resultant The compound was obtained. Yield 57%.

Amorphous solids

IR (KBr) ν _max 3172, 2185, 1600, 1538, 1520, 1411 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.94 (2H, m), 2.23 (3H, s), 3.52-3.62 (6H, m), 3.78-3.80 (2H, m), 6.70 (2H, d, J = 6.7 Hz), 8.09 (2H, d, J = 6.7 Hz), 8.41 (1H, br), 9.04 (1H, br);

MS (FAB) m / z: 302 [M + H] ⁺ .

(100d) 3-amino-4- (4-pyridin-4-yl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3- (4-pyridin-4-yl-1,4-diazepan-1-yl) buta-2-enthioamide (200 mg) prepared in Example 100 (100c) , 0.66 mmol) and N, N-dimethylformamide dimethylacetal (87 mg, 0.73 mmol) were dissolved in N, N-dimethylformamide (3 mL), stirred at room temperature for 2 hours, and then further heated at 100 ° C for 1 hour. Stirred. The reaction solution was cooled to room temperature, and 8N aqueous sodium hydroxide solution (0.2 mL) and 2-chloroacetamide (93 mg, 0.99 mmol) were added. The mixture was stirred at rt for 1 h, then water (4 mL) was added. After standing at room temperature for 15 hours, the precipitated solid was obtained by filtration, washed with water and dried again to obtain 55 mg of crude product. The crude product was suspended in 80% aqueous ethanol (3 mL), heated and stirred, cooled, and then filtered and purified to yield 30 mg of the title compound (yield 12%).

Mp 288-291 ° C. (decomposition);

IR (KBr) ν _max 3334, 1650, 1597, 1573, 1510, 1367 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13-2.18 (2H, m), 3.15-3.30 (4H, m), 3.56-3.59 (2H, m), 3.79-3.81 (2H, m), 6.68 ( 2H, d, J = 6.7 Hz), 6.98 (2H, br), 7.06 (1H, d, J = 5.1 Hz), 7.09 (2H, br), 8.09 (2H, d, J = 6.7 Hz), 8.38 ( 1H, d, J = 5.1 Hz);

MS (EI) m / z: 368 [M ⁺ ], 108;

analysis. Calc. For C ₁₈ H ₂₀ N ₆ OS.0.3H ₂ O: C, 57.83; H, 5.55; N, 22.48; S, 8.58. Found: C, 57.76; H, 5. 48; N, 22.46; S, 8.50.

Example 101 3-Amino-4- [3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-21 )

(101a) tert-butyl 3- (methoxymethyl) piperidine-1-carboxylate

Sodium hydride (55% oily, 0.26 g, 6 mmol) was suspended in tetrahydrofuran (5 mL) and under ice cooling, tert-butyl 3- (hydroxymethyl) piperidine-1-carboxylate (Bioorg.Med.Chem Lett., 8, (1998), 1595-1600) (1.08 g, 5 mmol) of N, N-dimethylformamide (3 mL) solution was added, and methyl iodide (0.85 g, 6 mmol) was further added. After stirring for 3 days at room temperature, water (50 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (50 mL). The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10: 1) to obtain 1.03 g (yield 90%) of the title compound.

IR (neat) ν _max 1696, 1422, 1151 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.16-1.51 (2H, m), 1.46 (9H, s), 1.60-1.82 (3H, m), 2.64 (1H, br), 2.82 (1H, brt, J = 13.3 Hz), 3.24 (2H, d, J = 5.9 Hz), 3.32 (3H, s), 3.87 (1H, dt, J = 4.0, 13.3 Hz), 3.94 (1H, m);

MS (EI) m / z: 229 [M ⁺ ], 114;

analysis. Calc. For C ₁₂ H ₂₃ NO ₃ : C, 62.85; H, 10.11; N, 6.11. Found: C, 62.90; H, 9.77; N, 6.04.

(101b) 3- (methoxymethyl) piperidine

Tert-Butyl 3- (methoxymethyl) piperidine-1-carboxylate (1.03 g, 4.5 mmol) prepared in Example 101 (101a) was dissolved in methylene chloride (4 mL), and trifluoride under ice cooling. Roacetic acid (2 mL) was added. After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. 1N aqueous sodium hydroxide solution (20 mL) was added to the residue, and the aqueous layer was extracted with methylene chloride (3 x 30 mL). The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.50 g (yield 86%) of the title compound as an oil.

IR (neat) ν _max 3312, 1467, 1450, 1270, 1128, 1097 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.06-1.16 (1H, m), 1.40-1.51 (1H, m), 1.63-1.80 (3H, m), 2.33 (1H, t, J = 11.7 Hz), 2.55 (1H, dt, J = 2.7, 11.7 Hz), 3.00 (1H, brd, J = 12.1 Hz), 3.11 (1H, brd, J = 12.1 Hz), 3.20 (2H, d, J = 6.3 Hz), 3.31 (3H, s);

MS (EI) m / z: 129 [M ⁺ ], 114.

(101c) (2Z) -2-cyano-3- [3- (methoxymethyl) piperidin-1-yl] buta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as in Example 5 (5a) using 3- (methoxymethyl) piperidine prepared in Example 101 (101b) to obtain the title compound. Yield 81%.

Mp 151-152 ° C .;

IR (KBr) ν _max 3380, 3255, 3157, 2183, 1605, 1531, 1410, 1261 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.25-1.35 (1H, m), 1.48-1.59 (1H, m), 1.66-1.76 (2H, m), 1.85-1.94 (1H, m), 2.26 ( 3H, s), 2.91-2.97 (1H, m), 3.03-3.10 (1H, m), 3.16-3.24 (2H, m), 3.22 (3H, s), 3.50-3.63 (2H, d, J = 6.3 Hz), 8.18 (1 H, br), 8.90 (1 H, br);

MS (EI) m / z: 253 [M ⁺ ], 220;

analysis. Calc. For C ₁₂ H ₁₉ N ₃ OS.0.1H ₂ O: C, 56.49; H, 7. 58; N, 16.47; S, 12.57. Found: C, 56.62; H, 7.41; N, 16.39; S, 12.60.

(101d) 4- [3- (methoxymethyl) piperidin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [3- (methoxymethyl) piperidin-1-yl] buta-2-enthioamide (0.39 g, 1.5 mmol) prepared in Example 101 (101c) And N, N-dimethylformamide dimethylacetal (0.20 g, 1.7 mmol) were dissolved in N, N-dimethylformamide (3 mL) and stirred at room temperature for 1 hour and at 100 ° C for 1 hour. The reaction solution was cooled to room temperature and water (50 mL) was added. The aqueous layer was extracted with ethyl acetate (3 x 50 mL), the extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 20: 1) to give 125 mg (yield 31%) of the title compound.

Mp 154-156 ° C .;

IR (KBr) ν _max 2208, 1622, 1550, 1517, 1249 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.26-1.93 (5H, m), 3.04 (1H, dd, J = 10.2, 13.3 Hz), 3.18-3.27 (3H, m), 3.24 (3H, s) , 3.96-4.02 (2H, m), 6.46 (1H, d, J = 7.8 Hz), 7.46 (1H, d, J = 7.8 Hz);

MS (EI) m / z: 263 [M ⁺ ], 248, 218;

analysis. Calc. For C ₁₃ H ₁₇ N ₃ OS.0.1H ₂ O: C, 58.89; H, 6. 54; N, 15.85; S, 12.09. Found: C, 58.93; H, 6. 60; N, 16.00; S, 12.07.

(101e) 3-amino-4- [3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [3- (methoxymethyl) piperidin-1-yl] -2-thioxo- 1,2-dihydropyridine-3-carbonitrile (120 mg, 0.46 prepared from Example 101 (101d) mmol) was dissolved in N, N-dimethylformamide (1 mL), and 8N aqueous sodium hydroxide solution (0.2 mL) and 2-chloroacetamide (55 mg, 0.59 mmol) were added. The mixture was stirred at room temperature for 1 hour, followed by separating water by adding water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with saturated brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure. Ether was added to the residue to solidify, and the precipitated solid was obtained by filtration and washed with ether again to obtain 138 mg of the title compound (yield 95%).

Mp 229-230 ° C .;

IR (KBr) ν _max 3432, 3320, 3144, 1653, 1577, 1501, 1375, 1097 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.03-1.15 (1H, m), 1.73-1.84 (3H, m), 2.07-2.19 (1H, m), 2.35-3.44 (4H, m), 3.22 ( 3H, s), 6.97 (2H, br), 7.00 (1H, d, J = 5.1 Hz), 7.09 (2H, br), 8.40 (1H, d, J = 5.1 Hz);

MS (EI) m / z: 320 [M ⁺ ];

analysis. Calc. For C ₁₅ H ₂₀ N ₄ O ₂ S: C, 56.23; H, 6. 29; N, 17.49; S, 10.01. Found: C, 56.21; H, 6. 45; N, 17.37; S, 9.80.

Example 102 3-amino-4- (1,4-diazepane-1-yl) thieno [2,3-b] pyridine-2-carboxamide dihydrochloride (Example Compound No. 3-78)

3-amino-4- (4-tert-butoxycarbonyl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2- prepared in Example 55 (55c) Carboxamide (0.77 g, 2.0 mmol) was dissolved in 1,4-dioxane (4 mL), and 4N hydrochloric acid / 1,4-dioxane (4 mL) was added. After stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure to obtain 0.72 g of the title compound.

Mp> 295 ° C .;

IR (KBr) ν _max 3457, 3371, 3291, 1654, 1614, 1579 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.12-2.19 (2H, m), 3.20-3.26 (2H, m), 3.36-3.42 (2H, m), 3.58-3.64 (2H, m), 3.80- 3.87 (2H, m), 7.11 (1H, d, J = 6.5 Hz), 7.27 (2H, br), 8.44 (1H, d, J = 6.5 Hz), 9.46 (2H, br);

MS (FAB) m / z: 292 [M + H] ⁺ ;

analysis. Calc. For C ₁₃ H ₁₇ N ₅ OS. 2 (HCl). 0.3H ₂ O: C, 42.24; H, 5. 34; N, 18.94; S, 8.67; Cl, 19.18. Found: C, 42.39; H, 5. 22; N, 19.01; S, 8.53; Cl, 18.93.

Example 103 4- (4-acetyl-1,4-diazepane-1-yl) -3-aminothieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-149 )

3-amino-4- (1,4-diazepane-1-yl) thieno [2,3-b] pyridine-2-carboxamide dihydrochloride (182 mg, 0.5 mmol) prepared in Example 102 was prepared. It was suspended in tetrahydrofuran (3 mL), triethylamine (0.15 mL) and acetic anhydride (77 mg, 0.75 mmol) were added, and it stirred at room temperature for 2 hours. Saturated sodium bicarbonate (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with methylene chloride (2 x 30 mL). After drying the extract with sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained solid was recrystallized from ethanol (4 mL) to give 55 mg (yield 33%) of the title compound.

Mp 214-215 ° C .;

IR (KBr) ν _max 3425, 3333, 3188, 1632, 1581, 1370, 938 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.97-2.08 (2H, m), 2.02 (1.5H, s), 2.05 (1.5H, s), 3.15-3.24 (4H, m), 3.55-3.62 ( 2H, m), 3.69-3.77 (2H, m), 7.01 (2H, br), 7.04 (0.5H, d, J = 5.5 Hz), 7.07 (0.5H, d, J = 5.5 Hz), 7.09 (2H , br), 8.38 (0.5H, d, J = 5.5 Hz), 8.41 (0.5H, d, J = 5.5 Hz);

MS (FAB) m / z: 334 [M + H] ⁺ ;

analysis. Calc. For C ₁₅ H ₁₉ N ₅ 0 ₂ S.0.1H ₂ 0: C, 53.75; H, 5.77; N, 20.89; S, 9.57. Found: C, 53.89; H, 5.75; N, 20.73; S, 9.42.

Example 104 3-amino-4- [4- (methylsulfonyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example compound Number 3-151)

3-amino-4- (1,4-diazepane-1-yl) thieno [2,3-b] pyridine-2-carboxamide dihydrochloride (182 mg, 0.5 mmol) prepared in Example 102; Potassium carbonate (221 mg, 1.6 mmol) was suspended in tetrahydrofuran (5 mL), methanesulfonic anhydride (105 mg, 0.6 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Water (20 mL) and ethyl acetate (30 mL) were added to the reaction mixture for separation, and the aqueous layer was extracted again with ethyl acetate (30 mL). After drying the combined organic layers with sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methylene chloride / methanol = 15: 1) to give 72 mg (yield 39%). The title compound of was obtained.

Mp 214-217 ° C .;

IR (KBr) ν _max 3424, 3327, 3155, 1650, 1582, 1371, 1323, 1147, 934 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.02-2.07 (2H, m), 2.96 (3H, s), 3.26-3.84 (2H, m), 3.44-3.47 (2H, m), 3.58-3.61 ( 2H, m), 7.04 (2H, br), 7.10 (1H, d, J = 5.5 Hz), 7.01 (2H, br), 8.44 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 370 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₁₉ N ₅ O ₃ S ₂ : C, 45.51; H, 5. 18; N, 18.96; S, 17.36. Found: C, 45.38; H, 5.08; N, 18.64; S, 17.04.

Example 105 3-amino-4- [4- (6-chloropyridazin-3-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 3-148)

(105a) (2Z) -3- [4- (6-chloropyridazin-3-yl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enthioamide

Example 5 using 1- (6-chloropyridazin-3-yl) -1,4-diazepane (J.Med. Chem., (2002), 45, 4011-4017) instead of isobutylamine, Example 5 The reaction was carried out in the same manner as described in (5a), to obtain the title compound. Yield 60%.

Amorphous solids

IR (KBr) ν _max 3289, 3185, 2191, 1587, 1531, 1453, 1429 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.95 (2H, m), 2.25 (3H, s), 3.59-3.66 (4H, m), 3.74-3.77 (2H, m), 3.97-4.00 ( 2H, m), 7.31 (1H, d, J = 9.8 Hz), 7.51 (1H, d, J = 9.8 Hz), 8.40 (1H, br), 9.04 (1H, br);

MS (FAB) m / z: 337 [M + H] ⁺ .

(105b) 3-amino-4- [4- (6-chloropyridazin-3-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carbox mid

(2Z) -3- [4- (6-chloropyridazin-3-yl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enty prepared in Example 105 (105a) Oamide (0.75 g, 2.2 mmol) and N, N-dimethylformamide dimethyl acetal (0.28 g, 2.3 mmol) were dissolved in N, N-dimethylformamide (5 mL), and the mixture was again heated at 100 ° C. for 1 hour at room temperature. Stir for 2 hours. The reaction solution was cooled to room temperature, and 8N aqueous sodium hydroxide solution (0.5 mL) and 2-chloroacetamide (0.27 g, 2.9 mmol) were added. The mixture was stirred at rt for 1 h, then water (30 mL) was added. The aqueous layer was extracted with ethyl acetate (2 x 50 mL), the extract was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride / methanol = 20: 1), and the obtained crystal was washed with ethanol to obtain 0.15 g of the title compound (yield 17%).

Mp 232-234 ° C .;

IR (KBr) ν _max 3320, 1645, 1584, 1501, 1450, 1372, 939 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13-2.19 (2H, m), 3.18-3.23 (2H, m), 3.30-3.35 (2H, m), 3.75-3.78 (2H, m), 4.00- 4.05 (2H, m), 7.00 (2H, br), 7.05 (1H, d, J = 5.1 Hz), 7.09 (2H, br), 7.26 (1H, d, J = 9.6 Hz), 7.50 (1H, d , J = 9.6 Hz), 8.38 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 404 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₁₈ N ₇ OSCl.0.3H ₂ O: C, 49.89; H, 4.58; N, 23.95; S, 7.83; Cl, 8.66. Found: C, 49.93; H, 4.52; N, 23.93; S, 8.09; Cl, 8.39.

Example 106 3-amino-4- [4- (5-methylpyridin-2-yl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-143)

(106a) tert-butyl 4- (5-methylpyridin-2-yl) -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Example 99 (99a), using 2-bromo-5-methylpyridine instead of 2-bromopyridine. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 5: 1) to obtain the title compound in a yield of 81%.

IR (neat) ν _max 1694, 1612, 1503, 1415, 1170, 929 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.39 (4.5H, s), 1.44 (4.5H, s), 1.92-1.98 (2H, m), 2.19 (3H, s), 3.20-3.33 (2H, m) , 3.54-3.76 (6H, m), 6.45 (1H, d, J = 8.6 Hz), 7.26 (1H, dd, J = 2.0, 8.6 Hz), 7.96 (1H, d, J = 2.0 Hz);

MS (EI) m / z: 291 [M ⁺ ], 135;

analysis. Calc. For C ₁₆ H ₂₅ N ₃ 0 ₂ .0.4H ₂ 0: C, 64.36; H, 8.71; N, 14.07. Found: C, 64.35; H, 8.96; N, 13.98.

(106b) 1- (5-methylpyridin-2-yl) -1,4-diazepane

Reaction was performed in the same manner as in Example 100 (100b) to obtain the title compound in a yield of 97%.

IR (neat) ν _max 3307, 1613, 1503, 1409, 804 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.85-1.91 (2H, m), 2.17 (3H, s), 2.82-2.85 (2H, m), 3.01-3.03 (2H, m), 3.68-3.72 (4H, m), 6.43 (1H, d, J = 8.6 Hz), 7.26 (1H, dd, J = 2.0, 8.6 Hz), 7.97 (1H, d, J = 2.0 Hz);

MS (FAB) m / z: 192 [M + H] ⁺ , 135.

(106c) (2Z) -2-cyano-3-[(4- (5-methylpyridin-2-yl) -1,4-diazepan-1-yl) buta-2-enthioamide

Instead of isobutylamine, 1- (5-methylpyridin-2-yl) -1,4-diazephan prepared in Example 106 (106b) was used, and the same method as described in Example 5 (5a) was used. The reaction was carried out to obtain the title compound. Yield 79%.

Mp 140-145 ° C .;

IR (KBr) ν _max 3274, 3131, 2181, 1611, 1528, 1501, 1411, 885 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.87-1.93 (2H, m), 2.12 (3H, s), 2.24 (3H, s), 3.53-3.67 (6H, m), 3.86-3.89 (2H, m), 6.65 (1H, d, J = 8.6 Hz), 7.34 (1H, dd, J = 2.0, 8.6 Hz), 7.91 (1H, d, J = 2.0 Hz), 8.82 (1H, br), 8.99 ( 1H, br);

MS (FAB) m / z: 316 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₂₁ N ₅ S.0.3H ₂ 0: C, 59.90; H, 6.79; N, 21.83; S, 9.95. Found: C, 59.96; H, 6. 62; N, 21.55; S, 10.19.

(106d) 3-amino-4- [4- (5-methylpyridin-2-yl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

(2Z) -2-cyano-3-[(4- (5-methylpyridin-2-yl) -1,4-diazepan-1-yl) buta-2- prepared in Example 106 (106c) Enthioamide (1.26 g, 4.0 mmol) and N, N-dimethylformamide dimethyl acetal (0.52 g, 4.4 mmol) were dissolved in N, N-dimethylformamide (6 mL), and the mixture was further heated at room temperature for 1 hour and then again at 100. It stirred at 1 degreeC. The reaction solution was cooled to room temperature, and 8N aqueous sodium hydroxide solution (1 mL) and 2-chloroacetamide (0.49 g, 5.2 mmol) were added. The mixture was stirred at rt for 2 h, then water (6 mL) was added. The precipitated solid was obtained by filtration and washed with water and ethanol to obtain 0.87 g of crude product. The crude product was suspended in 80% aqueous ethanol (10 mL), stirred by heating, cooled, and then filtered to obtain a solid that was purified to yield 0.66 g of the title compound (yield 43%).

Mp 205-208 ° C;

IR (KBr) ν _max 3440, 3316, 3155, 1649, 1609, 1579, 1499, 1371, 939 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.08-2.15 (2H, m), 2.13 (3H, s), 3.15-3.28 (4H, m), 3.64-3.67 (2H, m), 3.92-3.98 ( 2H, m), 6.60 (1H, d, J = 8.6 Hz), 6.98 (2H, br), 7.04 (1H, d, J = 5.1 Hz), 7.07 (2H, br), 7.34 (1H, dd, J = 2.3, 8.6 Hz), 7.90 (1H, d, J = 2.0 Hz), 8.36 (1H, d, J = 5.1 Hz);

MS (EI) m / z: 382 [M ⁺ ];

analysis. Calc. For C ₁₉ H ₂₂ N ₆ SO: C, 59.66; H, 5.80; N, 21.97; S, 8.38. Found: C, 59.46; H, 5.93; N, 21.78; S, 8.41.

Example 107 3-amino-4-methoxythieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-1)

(107a) 2-chloro-4-methoxynicotinonitrile

Phosphorus oxychloride of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.50 g, 10 mmol) synthesized by the method of Ogawas (Heterocycles, 36, 145-148, 1993) (10 mL) The solution was heated to reflux for 2 hours. The reaction solution was concentrated, an aqueous sodium hydrogencarbonate solution (10 mL) was added to the obtained residue, followed by extraction with ethyl acetate (3 x 10 mL), the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was triturated with ether to obtain the title compound (1.31 g, yield 78%).

Pale yellow powder

¹ H NMR (DMSOd ₆ , 400 MHz) δ 4.05 (3H, s), 7.40 (1H, d, J = 4.3 Hz), 8.55 (1H, d, J = 4.3 Hz).

(107b) 3-amino-4-methoxythieno [2,3-b] pyridine-2-carboxamide

To a N, N-dimethylformamide (2 mL) solution of 2-chloro-4-methoxynicotinonitrile (169 mg, 10 mmol) prepared in Example 107 (107a), 2-mercaptoacetamide (109 mg, 1.2 mmol) and 8 M aqueous sodium hydroxide solution (0.4 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water (5 mL) was added to the reaction solution, and the produced solid was filtered to obtain the target compound (92 mg, yield 41%).

Yellow powder

Mp 238-241 ° C .;

IR (KBr) ν _max 3482, 3325, 3149, 1667, 1613, 1583, 1504, 1375, 1289, 1044 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.01 (3H, s), 6.95 (2H, brs), 6.98 (1H, d, J = 5.9 Hz), 7.05 (2H, brs), 8.46 (1H, d, J = 5.9 Hz);

HRMS m / z calc. C ₉ H ₉ N ₃ 0 ₂ S 223.0415, found 223.0416;

MS (EI) m / z: 223 [M ⁺ ], 205, 178, 150, 137, 122, 104, 77, 66, 45;

analysis. Calc. For C ₉ H ₉ N ₃ O ₂ S: C, 48.42; H, 4.06; N, 18.82; S, 14.36. Found: C, 48.11; H, 4. 32; N, 18.76, S, 14.18.

Example 108 3-amino-4-ethoxythieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-2)

(108a) 2-chloro-4-ethoxynicotinonitrile

4-methoxy-2-oxo-1,2-dihydropyridine-3 synthesized according to the method of Ogawa (Heterocycles, 36, 145-148, 1993) using ortho triethyl instead of ortho trimethyl The reaction was carried out in the same manner as in Example 107 (107a) using -carbonitrile to synthesize the title compound.

Pale yellow powder

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.39 (3H, t, J = 6.8 Hz), 4.36 (2H, q, J = 6.8 Hz), 7.39 (1H, d, J = 6.4 Hz), 8.52 (1H, doublet, J = 6.4 Hz).

(108b) 3-amino-4-ethoxythieno [2,3-b] pyridine-2-carboxamide

Reaction was carried out in the same manner as in Example 107 (107b), using 2-chloro-4-ethoxynicotinonitrile instead of 2-chloro-4-methoxynicotinonitrile to synthesize the title compound.

Pale yellow powder

Mp 241-243 ° C .;

IR (KBr) ν _max 3446, 3331, 1645, 1584, 1506, 1375, 1294, 1046 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.44 (3H, t, J = 7.1 Hz), 4.30 (2H, q, J = 7.1 Hz), 6.84 (2H, brs), 6.95 (1H, d, J = 5.9 Hz), 7.03 (2H, brs), 8.41 (1H, d, J = 5.9 Hz);

HRMS m / z calc. For C ₁₀ H ₁₁ O ₂ N ₃ S 237.0572, found 237.0574;

MS (EI) m / z: 237 [M ⁺ ], 219, 205, 192, 176, 164, 148, 137, 120, 104;

analysis. Calc. For C ₁₀ H ₁₁ N ₃ O ₂ S: C, 50.62; H, 4.67; N, 17.71; S, 13.51. Found: C, 50.62; H, 4.69; N, 17.97, S, 13.52.

Example 109 ｛[3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] oxy} acetic acid (example compound number 1-5)

(109a) 2-chloro-4-oxo-1,4-dihydropyridine-3-carbonitrile

To the acetic acid (5 mL) solution of 2-chloro-4-methoxynicotinonitrile (0.98 g, 5.81 mmol) prepared in Example 107 (107a) was added concentrated hydrochloric acid (5 mL) and heated to reflux for 2 hours. Water (10 mL) was added to the reaction solution, extraction was performed with ethyl acetate (10 mL), and the extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was triturated with ether to obtain the title compound (0.35 g, yield 39%).

White powder

Mp 214-217 ° C .;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 6.96 (1H, d, J = 5.9 Hz), 8.25 (1H, d, J = 5.9 Hz).

(109b) ｛[3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] oxy} acetic acid

Carbonic acid in a N, N-dimethylacetamide (5 mL) solution of 2-chloro-4-oxo-1,4-dihydropyridine-3-carbonitrile (155 mg, 1.0 mmol) prepared in Example 109 (109a) Potassium (152 mg, 1.1 mmol) and bromoacetic acid tert-butyl ester (162 µL, 1.1 mmol) were added and stirred at room temperature for 5 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution for separation. The organic layer was washed with water (5 x 20 mL) and brine (20 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (2 mL), 2-mercaptoacetamide (118 mg, 1.3 mmol) and 8N aqueous sodium hydroxide solution (0.4 mL) were added, and the mixture was stirred at room temperature for 1 hour. It was. 1N hydrochloric acid (4 mL) was added to the reaction solution, and then concentrated under reduced pressure. The obtained residue was purified using reverse phase chromatography (100% water) to obtain the title compound (78 mg, yield 29%).

Yellow powder

Mp 248-249 ° C. (decomposition);

IR (KBr) ν _max 3462, 3340, 3169, 1647, 1591, 1507, 1376, 1084 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.97 (2H, s), 6.93 (1H, d, J = 5.9 Hz), 7.04 (2H, brs), 7.07 (2H, brs), 8.44 (1H, d, J = 5.9 Hz);

HRMS m / z calc'd C ₁₀ H ₉ O ₄ N ₃ S 267.0314, found 267.0325;

MS (FAB) m / z: 267 [M ⁺ ], 251, 205, 187, 69, 55;

analysis. Calc. For C ₁₀ H ₉ N ₃ O ₄ S.96 H ₂ O: C, 39.70; H, 4. 30; N, 13.89; S, 10.60. Found: C, 39.39; H, 3.99; N, 13.89; S, 10.46.

Example 110 3-amino-4- (benzyloxy) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-4)

Benzyl bromide was used instead of the bromoacetic acid tert-butyl ester, and the reaction was carried out in the same manner as described in Example 109 (109b) to synthesize the title compound.

White powder

Mp 216-221 ° C;

IR (KBr) ν _max 3490, 3324, 3151, 1651, 1580, 1502, 1370, 1290, 1039, 741 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 5.44 (2H, s), 6.89 (2H, brs), 7.04 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 7.36-7.55 ( 5H, m), 8.42 (1H, doublet, J = 5.5 Hz);

HRMS m / z calc'd C ₁₅ H ₁₃ 0 ₂ N ₃ S 299.0728, found 299.0730;

MS (FAB) m / z: 299 [M ⁺ ], 283, 273, 257, 200, 193, 165, 91, 65;

analysis. Calc. For C ₁₅ H ₁₃ N ₃ O ₂ S.0.12H ₂ O: C, 59.75; H, 4. 43; N, 13.94; S, 10.63. Found: C, 60.09; H, 4. 36; N, 13.63; S, 10.26.

Example 111 3-Amino-4-isopropoxycyeno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-3)

(111a) 2,4-dichloronicotinonitrile

A 2-chloro-4-oxo-1,4-dihydropyridine-3-carbonitrile (238 mg, 1.54 mmol) solution of phosphorus oxychloride (0.7 mL) prepared in Example 109 (109a) was heated to reflux for 2 hours. It was. The reaction solution was concentrated, an aqueous sodium hydrogencarbonate solution (10 mL) was added to the obtained residue, extracted twice with ethyl acetate (10 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was triturated with hexane to obtain the title compound (167 mg, yield 63%).

White powder

Mp 107-109 ° C .;

IR (KBr) ν _max 3072, 2235, 1559, 1538, 1444, 1406, 1368, 1220, 820 cm ⁻¹ ;

¹ H NMR (DMSOd ₆ , 400 MHz) δ 7.91 (1H, d, J = 5.5 Hz), 8.65 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₆ H ₂ N ₂ Cl ₂ 171.9595, found 171.9598;

MS (EI) m / z: 172 [M ⁺ ], 137, 110, 101, 75, 62, 51.

(111b) 2-chloro-4-isopropoxynicotinonitrile

To a solution of 2-propanol (84 μL, 1.1 mmol) in THF (1 mL) at 0 ° C. sodium hydride (48 mg, 1.1 mmol) and 2,4-dichloronicotinonitrile (173 mg, prepared in Example 111 (111a)) 1.00 mmol) of N, N-dimethylacetamide (1 mL) solution was added and stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the resulting powder was filtrated to obtain the title compound (125 mg, yield 63%).

White powder

IR (KBr) ν _max 3096, 2985, 2235, 1580, 1550, 1469, 1390, 1316, 1262, 1102, 985, 840 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.36 (6H, d, J = 5.9 Hz), 4.99 (1H, quint, J = 5.9 Hz), 7.43 (1H, d, J = 6.4 Hz), 8.49 (1H, doublet, J = 6.4 Hz);

HRMS m / z calc. C ₉ H ₉ ON ₂ Cl 196.0404, found 196.0401;

MS (EI) m / z: 196 [M ⁺ ], 181, 154, 145, 126, 119, 111, 93, 71, 57, 44.

(111c) 3-amino-4-isopropoxycyeno [2,3-b] pyridine-2-carboxamide

Reaction in the same manner as described in Example 107 (107b), using 2-chloro-4-isopropoxynicotinonitrile prepared in Example 111 (111b) instead of 2-chloro-4-methoxynicotinonitrile. Was carried out to obtain the title compound.

White powder

Mp 238-240 ℃ (decomposition)

IR (KBr) ν _max 3485, 3322, 3137, 1672, 1616, 1582, 1506, 1378, 1287, 1107, 995 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.40 (6H, d, J = 6.3 Hz), 4.94 (1H, quint, J = 6.3 Hz), 6.83 (2H, brs), 6.98 (1H, d, J = 5.9 Hz), 7.02 (2H, br s), 8.39 (1H, d, J = 5.9 Hz);

HRMS m / z calc'd C ₁₀ H ₁₃ 0 ₂ N ₃ S 251.0728, found 251.0742;

MS (EI) m / z: 251 [M ⁺ ], 209, 192, 180, 164, 137, 120, 103, 92, 66, 52, 42.

Example 112 3-amino-4- (cycloheptyloxy) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-8)

(112a) 2-chloro-4- (cycloheptyloxy) nicotinonitrile

Cycloheptyl alcohol was used instead of 2-propanol, and reaction was carried out in the same manner as in Example 111 (111b) to synthesize the title compound.

Colorless liquid

IR (film) ν _max 2933, 2233, 1575, 1464, 1307, 998, 821 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.47-2.05 (12H, m), 4.64-4.69 (1H, m), 6.79 (1H, d, J = 6.3 Hz), 8.34 (1H, d, J = 6.3 Hz);

HRMS m / z calc'd C ₁₃ H ₁₅ ON ₂ ³⁵ Cl 250.0873, found 250.0880;

MS (EI) m / z: 250 [M ⁺ ], 215, 172, 155, 137, 119, 97, 81, 55, 42;

analysis. Calc. For C ₁₃ H ₁₅ ClN ₂ O.0.36H ₂ O: C, 60.71; H, 6. 16; N, 10.89. Found: C, 61.03; H, 6.51; N, 10.93.

(112b) 3-amino-4- (cycloheptyloxy) thieno [2,3-b] pyridine-2-carboxamide

The method described in Example 107 (107b), using 2-chloro-4- (cycloheptyloxy) nicotinonitrile prepared in Example 112 (112a) instead of 2-chloro-4-methoxynicotinonitrile. The reaction was carried out in the same manner as to synthesize the title compound.

White powder

Mp 179-180 ° C .;

IR (KBr) ν _max 3491, 3329, 3163, 2927, 1654, 1582, 1504, 1371, 1288, 1012 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.46-1.70 (8H, m), 1.81-1.90 (2H, m), 2.01-2.08 (2H, m), 4.83-4.89 (1H, m), 6.81 (2H, br s), 6.94 (1 H, d, J = 5.5 Hz), 7.03 (2H, br s), 8.38 (1H, d, J = 5.5 Hz);

HRMS m / z calc. C ₁₅ H ₁₉ O ₂ N ₃ S 305.1198, found 305.1197;

MS (EI) m / z: 305 [M ⁺ ], 209, 192, 164, 120, 97, 55, 41;

analysis. Calc. For C ₁₅ H ₁₉ N ₃ O ₂ S: C, 58.99; H, 6. 27; N, 13.76; S, 10.50. Found: C, 58.81; H, 6. 33; N, 13.60; S, 10.30.

Example 113 3-amino-4- (cyclohexyloxy) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-7)

(113a) 2-chloro-4- (cyclohexyloxy) nicotinonitrile

Cyclohexyl alcohol was used instead of 2-propanol, and reaction was carried out similarly to the method described in Example 111 (111b) to synthesize the title compound.

Colorless liquid

IR (film) ν _max 2941, 2862, 2233, 1578, 1465, 1305, 1016, 987, 824 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.42-1.96 (10H, m), 4.50-4.56 (1H, m), 6.84 (1H, d, J = 6.4 Hz), 8.35 (1H, d, J = 6.4 Hz);

HRMS m / z calc'd C ₁₂ H ₁₃ ON ₂ Cl 236.0717, found 236.0721;

MS (EI) m / z: 236 [M ⁺ ], 207, 195, 181, 155, 119, 83, 67, 55, 42;

analysis. Calc. For C ₁₂ H ₁₃ ClN ₂ O. 0.12H ₂ O: C, 60.34; H, 5.59; N, 11.73; Cl, 14.84. Found: C, 60.06; H, 5.85; N, 11.50; Cl, 15.24.

(113b) 3-amino-4- (cyclohexyloxy) thieno [2,3-b] pyridine-2-carboxamide

Instead of 2-chloro-4-methoxynicotinonitrile, 2-chloro-4- (cyclohexyloxy) nicotinonitrile prepared in Example 113 (113a) was used, and it was described in Example 107 (107b). The reaction was carried out in the same manner as the method to synthesize the title compound.

White powder

Mp 206-208 ° C .;

IR (KBr) ν _max 3492, 3330, 3159, 2935, 1654, 1580, 1504, 1368, 1286, 1041, 1020, 992 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.28-1.77 (8H, m), 1.94-2.03 (2H, m), 4.70-4.76 (1H, m), 6.81 (2H, brs), 7.02 (1H , d, J = 5.9 Hz), 7.04 (2H, brs), 8.38 (1H, d, J = 5.9 Hz);

HRMS m / z calc'd C ₁₄ H ₁₇ O ₂ N ₃ S 291.1041, found 291.1040;

MS (EI) m / z: 291 [M ⁺ ], 209, 192, 164, 137, 120, 55, 41;

analysis. Calc. For C ₁₄ H ₁₇ N ₃ O ₂ S.0.36H ₂ O: C, 56.45; H, 6.00; N, 14.11; S, 10.76. Found: C, 56.75; H, 5. 74; N, 14.07; S, 10.46.

Example 114 3-amino-4- (ethylthio) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-10)

(114a) 2-chloro-4- (ethylthio) nicotinonitrile

To a solution of 2,4-dichloronicotinonitrile (173 mg, 1.00 mmol) prepared in Example 111 (111a) in N, N-dimethylacetamide (1 mL) at 0 ° C., sodium thioethoxide (93 mg, 1.1 mmol), N, N-dimethylacetamide (1 mL) solution was added and stirred at room temperature for 1 hour. Water (3 mL) was added to the reaction solution, and the resulting powder was obtained by filtration, and further purified by silica gel column chromatography (hexane / ethyl acetate = 3: 1) to obtain the title compound (44 mg, yield 22%). Got it.

Pale yellow powder

Mp 97-98 ° C .;

IR (KBr) ν _max 2226, 1556, 1518, 1431, 1379, 1199, 819 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.46 (3H, t, J = 7.3 Hz), 3.12 (2H, q, J = 7.3 Hz), 7.11 (1H, d, J = 5.9 Hz), 8.33 (1H , d, J = 5.9 Hz);

HRMS m / z calc. C ₈ H ₇ N ₂ ³⁵ ClS 198.0018, found 198.0011;

MS (EI) m / z: 198 [M ⁺ ], 183, 170, 165, 147, 134, 126, 108, 98, 76, 69, 64, 46.

(114b) 3-amino-4- (ethylthio) thieno [2,3-b] pyridine-2-carboxamide

Instead of 2-chloro-4-methoxynicotinonitrile, the method described in Example 107 (107b) and 2-chloro-4- (ethylthio) nicotinonitrile prepared in Example 114 (114a) were used. The reaction was carried out in the same manner to obtain the title compound.

Pale yellow powder

Mp 230-235 ° C .;

IR (KBr) ν _max 3460, 3297, 2141, 1666, 1589, 1494, 1365, 625 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.35 (3H, t, J = 7.4 Hz), 3.23 (2H, q, J = 7.4 Hz), 6.94 (2H, brs), 7.20 (2H, brs) , 7.29 (1H, d, J = 5.5 Hz), 8.39 (1H, d, J = 5.5 Hz);

HRMS m / z calc'd C ₁₀ H ₁₁ ON ₃ S ₂ 253.0344, found 253.0333;

MS (EI) m / z: 253 [M ⁺ ], 236, 221, 208, 203, 193, 176, 148, 135, 104, 76, 45.

Example 115 3-amino-4- (cyclohexylthio) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-13)

To a N, N-dimethylacetamide (1 mL) solution of 2,4-dichloronicotinonitrile (173 mg, 1.00 mmol) prepared in Example 111 (111a), mercaptocyclohexane (116 mg, 1.00) under ice cooling mmol) and 8N aqueous sodium hydroxide solution (0.19 mL) were added, and the mixture was stirred for 1 hour. The reaction mixture was partitioned between water and methylene chloride, and the organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4: 1) to give 2-chloro-4- (ethylthio) nicotinonitrile and 2,4-di (cyclohexylthio) nicotinonitrile A mixture with (187 mg) was obtained. The obtained mixture (181 mg) and 2-mercaptoacetamide (66 mg) were dissolved in N, N-dimethylformamide (1.4 mL), 8N sodium hydroxide aqueous solution (0.31 mL) was added, and the mixture was stirred at room temperature for 1 hour. It was. Water was added to the reaction mixture, and the precipitated solid was obtained by filtration, and then washed with ether and ethanol to obtain 23 mg (yield 7%) of the title compound.

Yellow powder

Mp 195-197 ° C .;

IR (KBr) ν _max 3450, 3310, 3154, 2929, 1662, 1585, 1495, 1363, 829, 620 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.39-2.04 (10H, m), 3.60-3.71 (1H, m), 7.06 (2H, brs), 7.19 (2H, brs), 7.38 (1H, d , J = 5.5 Hz), 8.41 (1H, d, J = 5.5 Hz);

HRMS m / z calc'd C ₁₄ H ₁₇ ON ₃ S ₂ 307.0813, found 307.0819;

MS (EI) m / z: 307 [M ⁺ ], 289, 262, 225, 208, 180, 136, 104, 83, 55, 41.

Example 116 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} piperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 3-30)

(116a) tert-butyl 4- {4-[(dimethylamino) carbonyl] phenyl} piperazine-1-carboxylate

1,1'-carbonyldiimidazole (0.58 g) in a tetrahydrofuran (10 mL) solution of 4- [4- (tert-butoxycarbonyl) piperazin-1-yl] benzoic acid (1.00 g, 3.3 mmol) , 3.6 mmol) was added, the mixture was stirred at room temperature for 30 minutes, and then a 50% aqueous dimethylamine solution (0.45 mL) was added. The reaction solution was stirred at room temperature for 4 hours, and saturated saline (100 mL) and ethyl acetate (100 mL) were added and separated. The organic layer was washed with saturated aqueous sodium carbonate solution (30 mL), dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain 1.00 g (yield 92%) of the title compound.

Mp 126-128 ° C .;

IR (KBr) ν _max 1689, 1628, 1241, 1165, 835, 769 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.49 (9H, s), 3.06 (6H, brs), 3.20 (4H, t, J = 5.1 Hz), 3.58 (4H, t, J = 5.1 Hz), 6.89 ( 2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6);

MS (FAB) m / z: 333 [M ⁺ ];

analysis. Calc. For C ₁₈ H ₂₇ N ₃ O ₃ : C, 64.84; H, 8. 16; N, 12.60. Found: C, 64.82; H, 8.41; N, 12.59.

(116b) N, N-dimethyl-4-piperazin-1-ylbenzamide

Tert-butyl 4- {4-[(dimethylamino) carbonyl] phenyl} piperazine-1-carboxylate (1.00 g, 3.0 mmol) prepared in Example 116 (116a) was dissolved in methanol (5 mL) , 4N hydrochloric acid-1,4-dioxane solution (5 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. 1N sodium hydroxide aqueous solution (10 mL) was added to the obtained residue, and the aqueous layer was extracted with methylene chloride (3 x 30 mL). After drying the extract with sodium sulfate, the solvent was distilled off under reduced pressure to obtain 0.70 g (yield 100%) of the title compound.

Mp 108-112 ° C .;

IR (KBr) ν _max 3312, 1611, 1388, 1243, 830, 766 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.75 (1H, br), 3.01-3.04 (4H, m), 3.05 (6H, s), 3.16-3.21 (4H, m), 6.87 (2H, d, J = 8.6 Hz), 7.35 (2H, doublet, J = 8.6);

MS (EI) m / z: 233 [M ⁺ ], 191;

analysis. Calc. For C ₁₄ H ₂₁ N ₃ O.0.1H ₂ O: C, 66.41; H, 8.23; N, 17.87. Found: C, 66.39; H, 8. 30; N, 17.74.

(116c) 4- (4-[(1Z) -3-amino-2-cyano-1-methyl-3-thioxopropa-1-enyl] piperazin-1-yl) -N, N- Dimethylbenzamide

The reaction was carried out in the same manner as in Example 5 (5a), using N, N-dimethyl-4-piperazin-1-ylbenzamide prepared in Example 116 (116b) instead of isobutylamine. The title compound was obtained. Yield 65%.

Mp 193-196 ° C;

IR (KBr) ν _max 3280, 3127, 2187, 1606, 1531, 992, 767 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.82 (3H, s), 2.95 (6H, s), 3.38-3.41 (4H, m), 3.54-3.57 (4H, m), 6.93 (2H, d, J = 7.8 Hz), 7.32 (2H, d, J = 7.8), 8.40 (1H, br), 9.12 (1H, br);

MS (FAB) m / z: 358 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₂₃ N ₅ SO.0.2H ₂ O: C, 59.88; H, 6.53; N, 19.40; S, 8.88. Found: C, 60.08; H, 6. 47; N, 19.15; S, 8.72.

(116d) 4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperazin-1-yl] -N, N-dimethylbenzamide

4- (4-[(1Z) -3-amino-2-cyano-1-methyl-3-thioxopropa-1-enyl] piperazin-1-yl) prepared in Example 116 (116c) -N, N-dimethylbenzamide (650 mg, 1.82 mmol) and N, N-dimethylformamide dimethyl acetal (238 mg, 265 μL, 2.00 mmol) were dissolved in N, N-dimethylformamide (10 mL), and The mixture was heated and stirred for 1 hour at 60 ° C for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was left to stand at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with water and ethanol again to obtain 272 mg (yield 41%) of the title compound.

Mp 246-249 ° C .;

IR (KBr) ν _max 2208, 1606, 1495, 1239, 985, 765 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.95 (6H, s), 3.40-3.43 (4H, m), 3.80-3.83 (4H, m), 6.53 (1H, d, J = 7.4 Hz), 6.92 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.50 (1H, d, J = 7.4 Hz), 12.70 (1H, br);

MS (FAB) m / z: 368 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ OS. 1.2H ₂ O: C, 58.65; H, 6.06; N, 18.00; S, 8.24. Found: C, 58.80; H, 6.06; N, 18.08; S, 8.18.

(116e) 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} piperazin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperazin-1-yl] -N, N-dimethyl prepared in Example 116 (116d) The title compound was obtained in the same manner as in the method described in Example 5 (5c) using benzamide. Yield 82%.

Mp> 270 ° C .;

IR (KBr) ν _max 3447, 3327, 3180, 1652, 1625, 1606, 1577, 1238, 837, 767 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.96 (6H, s), 2.80-3.90 (8H, m), 6.97 (2H, br), 7.04 (2H, d, J = 8.2 Hz), 7.10 (1H , d, J = 5.1 Hz), 7.16 (2H, br), 7.34 (2H, d, J = 8.2 Hz), 8.48 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 425 [M + H] ⁺ ;

analysis. Calc. For C ₂₁ H ₂₄ N ₆ O ₂ S.0.4H ₂ O: C, 58.42; H, 5.79; N, 19.47; S, 7.43. Found: C, 58.56; H, 5.73; N, 19.48; S, 7.35.

Example 117 3-Amino-4- (4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Example Compound No. 3-429)

(117a) tert-butyl 4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazine-1-carboxylate

2- (4-bromophenyl) -N, N-dimethylacetamide (J.Med. Chem., 33, (1990), 2899-2905.) (1.23 g, 5.1 mmol), tert under nitrogen atmosphere -Butyl 1-piperazinecarboxylate (1.13 g, 6.1), sodium tert-butoxide (0.69 g, 71 mmol), tris (dibenzylideneacetone) dipalladium (= Pd2 (dba) 3) (23 mg, 0.03 mmol) and 2-dicyclohexylphosphino-2 '-(N, N-dimethylamino) biphenyl (39 mg, 0.10 mmol) mixed with 1,4-dioxane (10 mL) and tert-butanol (5 mL) It mixed with a solvent and stirred for 2 hours under heating reflux. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture, and insoluble materials were removed using celite. The filtrate was separated and the aqueous layer was extracted again with ethyl acetate (50 mL). After the combined organic layers were dried over sodium sulfate, the solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel column chromatography (100% ethyl acetate) to obtain 1.59 g (yield 91%) of the title compound.

Mp 110-112 ° C .;

IR (KBr) ν _max 1689, 1639, 1431, 1169, 1129, 914 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.48 (9H, s), 2.96 (3H, s), 2.99 (3H, s), 3.09-3.11 (4H, m), 3.56-3.58 (4H, m), 3.64 (2H, s), 6.88 (2H, d, J = 8.2 Hz), 7.16 (2H, d, J = 8.2);

MS (FAB) m / z: 347 [M ⁺ ] i;

analysis. Calc. For C ₁₉ H ₂₉ N ₃ O ₃ : C, 65.58; H, 8.41; N, 12.09. Found: C, 65.58; H, 8. 29; N, 11.89.

(117b) N, N-dimethyl-2- (4-piperazin-1-ylphenyl) acetamide

Methanol of tert-butyl 4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazine-1-carboxylate (1.89 g, 5.4 mmol) prepared in Example 117 (117a) 15 mL) was added to a 4N hydrochloric acid-1,4-dioxane solution (15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and 1N aqueous sodium hydroxide solution (20 mL) was added to the residue, followed by extraction with methylene chloride (3 x 50 mL). After drying the extract with sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.30 g (yield 97%) of the title compound.

Mp 90-92 ° C .;

IR (KBr) ν _max 3269, 1637, 1517, 1241, 1128, 896 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.85 (1H, br), 2.94 (3H, s), 2.98 (3H, s), 3.01-3.03 (4H, m), 3.10-3.13 (4H, m), 3.62 (2H, s), 6.86 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8.6);

MS (EI) m / z: 247 [M ⁺ ], 205, 175;

analysis. Calc. For C ₁₄ H ₂₁ N ₃ O.0.1H ₂ O: C, 67.49; H, 8.58; N, 16.87. Found: C, 67.64; H, 8. 24; N, 16.51.

(117c) 2- (4- {4-[(1Z) -3-amino-2-cyano-1-methyl-3-thioxopropa-1-enyl] piperazin-1-yl} phenyl)- N, N-dimethylacetamide

The same method as described in Example 5 (5a), using N, N-dimethyl-2- (4-piperazin-1-ylphenyl) acetamide prepared in Example (117b) instead of isobutylamine. The reaction was carried out to obtain the title compound. Yield 90%.

Mp 174-177 ° C .;

IR (KBr) ν _max 3283, 3141, 2189, 1622, 1537, 1518, 1236, 991 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.31 (3H, s), 2.81 (3H, s), 2.97 (3H, s), 3.23-3.26 (4H, m), 3.51-3.53 (4H, m) , 3.56 (2H, s), 6.88 (2H, d, J = 8.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 8.40 (1H, br), 9.11 (1H, br);

MS (FAB) m / z: 372 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₅ N ₅ OS.0.2H ₂ O: C, 60.84; H, 6.83; N, 18.67; S, 8.55. Found: C, 61.10; H, 6.65; N, 18.55; S, 8.46.

(117d) 2- {4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperazin-1-yl] phenyl} -N, N-dimethyla Cetamide

(2- (4- {4-[(1Z) -3-Amino-2-cyano-1-methyl-3-thioxopropa-1-enyl] piperazin-prepared in Example 117 (117c)- The reaction was carried out in the same manner as described in Example 116 (116d) using 1-yl} phenyl) -N, N-dimethylacetamide After the reaction was completed, the reaction solution was water (100 mL) and ethyl acetate. The resulting solids were collected by filtration and washed with water and ethanol to obtain 0.274 g (yield 19%) of the title compound.

Mp 248-253 ° C .;

1 H NMR (DMSO-d ₆ , 400 MHz) δ 2.81 (3H, s), 2.97 (3H, s), 3.26-3.28 (4H, m), 3.57 (2H, s), 3.79-3.81 (4H, m), 6.56 (1H, d, J = 6.7 Hz), 6.90 (2H, d, J = 8.2 Hz), 7.09 (2H, d, J = 8.2 Hz), 7.53 (1H, d, J = 6.7 Hz), 12.76 ( 1H, br).

(117e) 3-amino-4- (4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide

2- {4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperazin-1-yl] phenyl}-prepared in Example 117 (117d)- Using the N, N-dimethylacetamide, it carried out similarly to the method of Example 5 (5c), and obtained the title compound. Yield 94%.

Mp> 280 ° C .;

IR (KBr) ν _max 3437, 3318, 1629, 1571, 1382, 1244, 978, 962 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.82 (3H, s), 2.98 (3H, s), 2.80-3.80 (8H, m), 3.58 (2H, s), 6.95-6.97 (4H, m) , 7.09-7.11 (4H, m), 7.13 (1H, d, J = 5.1 Hz), 8.47 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 439 [M + H] ⁺ ;

analysis. Calc. For C ₂₂ H ₂₆ N ₆ O ₂ S.0.4H ₂ O: C, 59.28; H, 6.06; N, 18.85; S, 7.19. Found: C, 59.43; H, 6.02; N, 18.98; S, 7.05.

Example 118 3-amino-4- (4- {3- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Example Compound No. 3-430)

(118a) tert-butyl 4- {3- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazine-1-carboxylate

2- (3-Bromophenyl) -N, N-dimethylacetamide (Arch. Pharm. (Weinheim) 321, 315-320 (1988)) using the method described in Example 117 (117a) The reaction was carried out to obtain the title compound as a store oil. Yield 92%.

IR (neat) ν _max 1685, 1635, 1241, 1171, 1124, 998, 772 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.48 (9H, s), 2.96 (3H, s), 2.99 (3H, s), 3.12-3.14 (4H, m), 3.55-3.57 (4H, m), 3.68 (2H, s), 6.76 (1H, brd, J = 8.0 Hz), 6.81 (1H, dd, J = 2.0, 8.0 Hz), 6.86 (1H, brs), 7.21 (1H, t, J = 8.0 Hz) ;

MS (FAB) m / z: 347 [M ⁺ ] i;

analysis. Calc. For C ₁₉ H ₂₉ N ₃ O ₃ .0.2H ₂ O: C, 65.01; H, 8. 44; N, 11.97. Found: C, 65.14; H, 8.08; N, 11.89.

(118b) N, N-dimethyl-2- (3-piperazin-1-ylphenyl) acetamide

The method described in Example 117 (117b) using tert-butyl 4- {3- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazine-1-carboxylate prepared in (118a). According to the present invention, an oily title compound was synthesized. Yield 99%.

IR (neat) ν _max 3456, 3316, 1640, 1244, 995, 772 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.08 (1H, br), 2.96 (3H, s), 2.99 (3H, s), 3.02-3.05 (4H, m), 3.15-3.17 (4H, m), 3.68 (2H, s), 6.74 (1H, brd, J = 7.4 Hz), 6.81 (1H, dd, J = 2.3, 8.2 Hz), 6.85 (1H, brs), 7.20 (1H, dd, J = 7.4, 8.2 Hz);

MS (EI) m / z: 247 [M ⁺ ], 205.

(118c) 2- {3- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperazin-1-yl] phenyl} -N, N-dimethyla Cetamide

N, N-dimethyl-2- (3-piperazin-1-ylphenyl) acetamide (2.68 g, 10.8 mmol) and (2Z) -2-cyano-3- prepared in Example 118 (118b) Ethoxybuta-2-enthioamide (J. Org. Chem., (1962), 27, 2433-2439) (1.54 g, 9.0 mmol) was mixed with ethanol (30 mL) and stirred at room temperature for 15 hours. The residue obtained by distilling a solvent off under reduced pressure was dissolved in N, N-dimethylformamide (30 mL), and N, N-dimethylformamide dimethylacetal (1.29 g, 1.44 mL, 10.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then stirred at 80 ° C for 2 hours. After cooling to room temperature, the reaction mixture was separated with saturated brine (100 mL) and ethyl acetate (100 mL), and the aqueous layer was extracted with methylene chloride (3 x 50 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride / methanol = 20: 1) to obtain 0.329 g (yield 10%) of the title compound.

Mp 250-254 ° C .;

IR (KBr) ν _max 2206, 1602, 1496, 1238, 985, 772 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.81 (3H, s), 2.98 (3H, s), 3.27-3.29 (4H, m), 3.61 (2H, s), 3.78-3.81 (4H, m) , 6.53 (1H, d, J = 7.4 Hz), 6.65 (1H, brd, J = 7.4 Hz), 6.78-6.80 (2H, m), 7.14 (1H, dd, J = 7.4, 9.0 Hz), 7.49- 7.52 (1 H, m), 12.72 (1 H, br);

MS (FAB) m / z: 382 [M + H] ⁺ ;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS.0.4H ₂ O: C, 61.80; H, 6. 17; N, 18.02; S, 8.25. Found: C, 61.77; H, 6.07; N, 18.04; S, 8.18

(118d) 3-amino-4- (4- {3- [2- (dimethylamino) -2-oxoethyl] phenyl} piperazin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide

2- {3- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperazin-1-yl] phenyl}-prepared in Example 118 (118c)- Using the N, N-dimethylacetamide, it carried out similarly to the method of Example 5 (5c), and obtained the title compound. Yield 78%.

Mp 273-275 ° C .;

IR (KBr) ν _max 3439, 3316, 1632, 1579, 1370, 1240, 976, 771 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.83 (3H, s), 3.00 (3H, s), 2.80-3.80 (8H, m), 3.64 (2H, s), 6.59 (1H, d, J = 7.4 Hz), 6.87-6.90 (2H, m), 6.97 (2H, brs), 7.10 (1H, d, J = 5.5 Hz), 7.15 (2H, brs), 7.18 (1H, dd, J = 7.4, 8.6 Hz), 8.48 (1H, doublet, J = 5.5 Hz);

MS (FAB) m / z: 439 [M + H] ⁺ ;

analysis. Calc. For C ₂₂ H ₂₆ N ₆ O ₂ S.0.1H ₂ O: C, 60.01; H, 6.00; N, 19.08; S, 7.28. Found: C, 59.97; H, 5.97; N, 19.09; S, 7.07.

Example 119 3-amino-4- {4- [4- (1-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2 Carboxamide (Example Compound No. 3-1007)

4- [4- (4-acetylphenyl) -1,4-diazepan-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide prepared in Example 94 ( Sodium borohydride (95 mg, 2.5 mmol) was added to a methanol (6 mL) suspension of 103 mg, 0.25 mmol) and heated to reflux for 2 days. Water (30 mL) was added to the reaction solution, and the precipitated solid was obtained by filtration to obtain the title compound (95 mg, yield 92%).

Yellow powder

Mp 244-248 ° C;

IR (KBr) ν _max 3450, 3337, 1646, 1609, 1518, 1368, 1187, 823 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.29 (3H, d, J = 6.4 Hz), 2.12-2.14 (2H, m), 3.20 (2H, brs), 3.29 (2H, brs), 3.54 ( 2H, t, J = 6.3 Hz, 3.76 (2H, t, J = 5.0 Hz), 4.60 (1H, t, J = 4.9 Hz), 4.83 (1H, d, J = 4.4 Hz), 6.72 (2H, d, J = 8.2 Hz), 6.97 (2H, brs), 7.08 (1H, d, J = 5.4 Hz), 7.08 (2H, brs), 7.15 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 5.4 Hz);

HRMS m / z calc. For C ₂₁ H ₂₆ O ₂ N ₅ S 412.1807, found 412.1815;

MS (FAB) m / z: 411 [M ⁺ ], 394, 273, 242, 183, 166, 120, 65, 51, 39, 31;

analysis. Calc. For C ₂₁ H ₂₅ N ₅ 0 ₂ S.0.34H ₂ 0: C, 60.39; H, 6. 20; N, 16.77; S, 7.68. Found: C, 60.32; H, 6.06; N, 16.72; S, 7.61.

Example 120 3-amino-4- {4- [4- (N-hydroxyethaneimideyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] Pyridine-2-carboxamide (Example Compound No. 3-1037)

4- [4- (4-acetylphenyl) -1,4-diazepan-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide prepared in Example 94 ( To a methanol (3 mL) suspension of 56 mg, 0.14 mmol), hydroxylamine hydrochloride (97 mg, 1.4 mmol) and sodium acetate (115 mg, 1.4 mmol) were added and refluxed for 2 days. Water (10 mL) was added to the reaction solution, and the precipitated solid was obtained by filtration to obtain the target compound (33 mg, yield 56%).

Pale yellow powder

Mp 238-241 ° C .;

IR (KBr) ν _max 3431, 3317, 3169, 1643, 1601, 1521, 1370, 1200, 908, 826, 561, 482 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.09 (3H, s), 2.13-2.16 (2H, m), 3.19 (2H, brs), 3.29-3.32 (2H, m), 3.59 (2H, t , J = 6.4 Hz), 3.80 (2H, t, J = 4.9 Hz), 6.78 (2H, d, J = 8.8 Hz), 6.99 (2H, brs), 7.09 (1H, d, J = 5.4 Hz), 7.09 (2H, brs), 7.49 (2H, doublet, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz), 10.71 (1H, s);

HRMS m / z calc. For C ₂₁ H ₂₅ O ₂ N ₆ S 425.1760, found 425.1761;

MS (FAB) m / z: 425 [M ⁺ ], 407, 273, 246, 228, 182, 65;

analysis. Calc. For C ₂₁ H ₂₄ N ₆ O ₂ S.0.5H ₂ O: C, 58.18; H, 5.81; N, 19.39; S, 7.40. Found: C, 58.39; H, 5.80; N, 19.26; S, 7.27.

(Example 121) 3-amino-4- [4- (4-propionylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 3-100)

(121a) tert-butyl 4- (4-propionylphenyl) -1,4-diazepane-1-carboxylate

Instead of 4-fluoronitrobenzene, 4-fluoropropiophenone was used and reacted in the same manner as in Example 59 (59a) to obtain the title compound (yield 45%).

Yellow oil

IR (film) ν _max 2975, 2936, 1693, 1669, 1599, 1523, 1416, 1365 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.20 (3H, t, J = 7.4 Hz), 1.35 (4.5H, s), 1.42 (4.5H, s), 1.92-2.02 (2H, m), 2.89 ( 2H, q, J = 7.4 Hz), 3.18-3.24 (1H, m), 3.29-3.34 (1H, m), 3.54-3.66 (6H, m), 6.66 (2H, d, J = 9.0 Hz), 7.85 (2H, d, J = 9.0 Hz);

MS (FAB) m / z: 332 M ⁺ ., 277, 259, 231.

(121b) 1- [4- (1,4-diazepane-1-yl) phenyl] propan-1-one

Tert-Butyl 4- (4-propionylphenyl) -1,4-diazepane-1-carboxylate prepared in Example 121 (121a) was used in the same manner as in Example 57 (57b). The reaction was carried out to obtain the title compound (yield 95%).

Light Brown Prism Crystal

Mp 97-98 ° C .;

IR (KBr) ν _max 3343, 2935, 2821, 1652, 1597, 1524, 1407 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.20 (3H, t, J = 7.4 Hz), 1.87-1.95 (2H, m), 2.80-2.85 (2H, m), 2.89 (2H, q, J = 7.4 Hz), 3.01-3.07 (2H, m), 3.58-3.67 (4H, m), 6.65 (2H, d, J = 9.0 Hz), 7.85 (2H, d, J = 9.0 Hz);

MS (EI) m / z: 232 M ^+,, 203, 190, 176.

(121c) 4- [4- (4-propionylphenyl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

N, N-dimethylformamide (8.47) of 1- [4- (1,4-diazepane-1-yl) phenyl] propan-1-one (984 mg, 4.24 mmol) prepared in Example 121 (121b) mL) solution, (2Z) -2-cyano-3-ethoxybute-2-enthioamide (J.Org.Chem., (1962), 27, 2433-2439) (721 mg, 4.24 mmol) It was added and stirred for 15 minutes at room temperature. Subsequently, after adding N, N- dimethylformamide dimethyl acetal (619 microliters, 4.66 mmol) and stirring for 1 hour, it stirred by heating at 80 degreeC for 30 minutes. After the reaction solution was allowed to cool to room temperature, ethyl acetate (8.5 mL) and water (21 mL) were added, and the mixture was stirred for 30 minutes. Precipitated crystals were filtered off, washed sequentially with ethyl acetate and water, and dried to obtain 508 mg of the title compound (yield 33%).

Light brown powder

Mp 157-158 ° C .;

IR (KBr) ν _max 3443, 3353, 3277, 3176, 2926, 2182, 1617, 1525, 1346 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.04 (2H, t, J = 7.3 Hz), 1.90-1.99 (2H, m), 2.87 (2H, q, J = 7.3 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.73-3.78 (2H, m), 3.83-3.88 (2H, m), 3.95-4.00 (2H, m), 6.44 (1H, d, J = 7.8 Hz), 6.84 (2H , d, J = 8.8 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.78 (2H, d, J = 8.8 Hz), 12.53 (1H, br.s);

MS (FAB) m / z: 367 [M + H] ⁺ , 273, 246, 228;

analysis. Calc. For C ₂₀ H ₂₂ N ₄ OS.0.4H ₂ O: C, 64.28; H, 6. 15; N, 14.99; S, 8.58. Found: C, 64.15; H, 6. 23; N, 15.26; S, 8.50.

(121d) 3-amino-4- [4- (4-propionylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [4- (4-propionylphenyl) -1,4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbony prepared in Example 121 (121c) The reaction was carried out in the same manner as in the method described in Example 5 (5c), using a tril, to obtain the title compound. Yield 65%.

Pale yellow powder

Mp 231-233 ° C .;

IR (KBr) ν _max 3440, 3326, 3186, 2934, 1648, 1597, 1368 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.06 (3H, t, J = 7.4 Hz), 2.11-2.21 (2H, m), 2.89 (2H, q, J = 7.4 Hz), 3.13-3.24 ( 2H, m), 3.25-3.34 (2H, m), 3.64 (2H, t, J = 5.1 Hz), 3.82-3.90 (2H, m), 6.82 (2H, d, J = 9.0 Hz), 6.97 (2H , br.s), 7.06 (1H, d, J = 5.1 Hz), 7.09 (2H, br.s), 7.79 (2H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.1 Hz) ;

MS (FAB) m / z: 424 [M + H] ⁺ , 423, 407;

analysis. Calc. For C ₂₂ H ₂₅ N ₅ 0 ₂ S.0.4H ₂ 0: C, 61.35; H, 6.04; N, 16.26; S, 7.44. Found: C, 61.43; H, 6. 23; N, 16.10; S, 7.34.

(Example 122) 3-amino-4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepane-1-yl) Thieno [2,3-b] pyridine-2-carboxamide (example compound number 3-1082)

(122a) 2- (4-bromobenzyl) -2-methyl-1,3-dioxolane

Ethylene glycol (1.67 mL, 30.0 mmol) and p-toluenesulfonic acid monohydrate (380 mg, 2.0 mmol) were added to a toluene (100 mL) solution of 1- (4-bromophenyl) acetone (4.26 g, 20.0 mmol). It stirred at 120 degreeC for 9 hours. After adding excess triethylamine to the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 10: 1) to obtain the title compound (4.80 g, 93%).

Pale yellow liquid

IR (film) ν _max 2983, 2882, 1489, 1376, 1128, 1047, 832 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.30 (3H, s), 2.87 (2H, s), 3.67-3.73 (2H, m), 3.84-3.92 (2H, m), 7.13 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J = 8.6 Hz);

MS (EI) m / z: 256 [M ⁺ ], 243, 241, 171, 169, 87, 43.

(122b) benzyl 4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepane-1-carboxylate

Benzyl 1-homopiperazine using the 2- (4-bromobenzyl) -2-methyl-1,3-dioxolane prepared in Example 122 (122a) according to the method described in Example 117 (117a) The reaction was carried out with a carboxylate to obtain the title compound.

Yellow liquid

IR (film) ν _max 2942, 1700, 1614, 1520, 1421, 1222, 1118, 1046, 927 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.29 (3H, s), 1.91-2.07 (2H, m), 2.81 (2H, s), 3.30 (1H, t, J = 5.9 Hz), 3.37 (1H, t, J = 5.9 Hz), 3.49-3.68 (6H, m), 3.76-3.83 (2H, m), 3.88-3.93 (2H, m), 5.09 (1H, s), 5.33 (1H, s), 6.62 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz), 7.26-7.39 (5H, m);

MS (FAB) m / z: 411 [M + H ⁺ ], 323, 275, 87.

(122c) 1-4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepane

Benzyl 4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepane-1-carboxylate prepared in Example 122 (122b) The hydrolysis reaction was carried out in the presence of a palladium-carbon catalyst in ethanol to obtain the title compound.

Pale yellow liquid

IR (film) ν _max 3319, 2935, 1614, 1520, 1375, 1191, 1045, 813 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.30 (3H, s), 1.82-1.93 (2H, m), 2.80 (2H, s), 2.82 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.53 (2H, t, J = 5.5 Hz), 3.56 (2H, t, J = 5.9 Hz), 3.76-3.82 (2H, m), 3.87-3.93 (2H, m), 6.63 (2H, doublet, J = 8.6 Hz), 7.10 (2H, doublet, J = 8.6 Hz);

MS (EI) m / z: 276 [M ⁺ ], 190, 189, 87.

(122d) 4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepan-1-yl) -2-thioxo- 1,2-dihydropyridine-3-carbonitrile

Example 121 was prepared using 1- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepane prepared in Example 122 (122c). The reaction was carried out according to the method described in 121c) to synthesize the title compound.

Brown powder

Mp 204-206 ° C .;

IR (KBr) ν _max 2949, 2206, 1625, 1518, 1353, 1247, 1139, 1043, 930, 781 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.15 (3H, s), 1.90-1.97 (2H, m), 2.67 (2H, s), 3.51 (2H, t, J = 5.9 Hz), 3.57- 3.64 (2H, m), 3.68-3.80 (6H, m), 3.94 (2H, t, J = 5.9 Hz), 6.41 (1H, d, J = 7.8 Hz), 6.67 (2H, d, J = 8.3 Hz ), 7.01 (2H, d, J = 8.3 Hz), 7.34 (1H, d, J = 7.8 Hz), 12.50 (1H, brs);

MS (FAB) m / z: 411 [M + H ⁺ ], 367, 338, 273, 246;

analysis. Calc. For C ₂₂ H ₂₆ N ₄ O ₂ S.0.25H ₂ O: C, 63.67; H, 6. 44; N, 13.50. Found: C, 63.90; H, 6. 18; N, 13.45.

(122e) 3-amino-4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepan-1-yl) prepared in Example 122 (122d) The reaction was carried out according to the method described in Example 5 (5c) using 2-thioxo-1,2-dihydropyridine-3-carbonitrile to synthesize the title compound.

Pale yellow powder

Mp 227-229 ° C .;

IR (KBr) ν _max 3446, 3333, 3143, 2923, 1643, 1575, 1515, 1372, 1212, 1044, 825 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.16 (3H, s), 2.06-2.19 (2H, m), 2.70 (2H, s), 3.13-3.22 (2H, m), 3.23-3.32 (2H , m), 3.51 (2H, t, J = 5.9 Hz), 3.69-3.86 (6H, m), 6.66 (2H, d, J = 8.6 Hz), 6.98 (2H, brs), 7.02 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 8.37 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 468 [M + H ⁺ ], 273, 246, 165, 93, 63;

analysis. Calc. For C ₂₄ H ₂₉ N ₅ O ₃ S.0.20H ₂ O: C, 61.18; H, 6. 29; N, 14.86. Found: C, 61.19; H, 6. 25; N, 14.81.

Example 123 3-amino-4- {4- [4- (2-oxopropyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 3-1019)

3-amino-4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepan-1-yl prepared in Example 122 ) NN hydrochloric acid (2.0 mL) was added to a methanol (2.0 mL) solution of thieno [2,3-b] pyridine-2-carboxamide (200 mg, 428 µmo1), followed by stirring at room temperature for 2 hours. Excess triethylamine was added to the reaction solution, and the solvent was distilled off under reduced pressure. Methylene chloride / 2-propanol (4: 1) (100 mL) was added to the obtained residue, washed with water (50 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained powder was washed with ethanol to obtain the title compound (160 mg, 88%).

Pale yellow powder

Mp 225-230 ° C .;

IR (KBr) ν _max 3440, 3325, 3150, 2946, 1648, 1576, 1517, 1370, 1232, 939, 819 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.08 (3H, s), 2.09-2.18 (2H, m), 3.17-3.23 (2H, m), 3.25-3.33 (2H, m), 3.53 (2H , t, J = 5.4 Hz), 3.57 (2H, s), 3.75 (2H, t, J = 5.4 Hz), 6.73 (2H, d, J = 8.8 Hz), 7.00 (2H, brs), 7.01 (2H , d, J = 8.8 Hz), 7.07 (1H, d, J = 5.4 Hz), 7.09 (2H, brs), 8.40 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 424 [M + H ⁺ ], 407, 380, 273, 258, 220, 165, 63;

analysis. Calc. For C ₂₂ H ₂₅ N ₅ 0 ₂ S.0.32H ₂ 0: C, 61.55; H, 6.02; N, 16.31. Found: C, 61.94; H, 6. 12; N, 15.88.

Example 124 3-amino-4- {4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2 Carboxamide (Example Compound No. 3-1003)

(124a) benzyl 4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-carboxylate

According to the method described in Example 117 (117a), the reaction was carried out using benzyl 1-homopiperazinecarboxylate and 4-bromophenethyl alcohol to obtain the title compound.

Yellow liquid

IR (film) ν _max 3444, 2939, 1696, 1519, 1423, 1230, 1040 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.91-2.05 (2H, m), 2.76 (2H, t, J = 6.8 Hz), 3.31 (1H, t, J = 5.9 Hz), 3.38 (1H, t, J = 5.9 Hz), 3.49-3.68 (6H, m), 3.77-3.85 (2H, m), 5.09 (1H, s), 5.13 (1H, s), 6.62-6.68 (m, 2H), 7.05-7.10 (2H, m), 7.27-7.38 (5H, m);

MS (EI) m / z: 354 [M ⁺ ], 323, 263, 233, 202, 190, 176, 91.

(124b) 2- [4- (1,4-diazepan-1-yl) phenyl] ethanol

Hydrogenation in the presence of a palladium-carbon catalyst in ethanol using benzyl 4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-carboxylate prepared in Example 124 (124a) The decomposition reaction was carried out to obtain the title compound.

Yellow liquid

IR (film) ν _max 3399, 2934, 1615, 1520, 1414, 1190, 1048, 808 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.83-1.94 (2H, m), 2.76 (2H, t, J = 6.6 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.53 (2H, t, J = 5.5 Hz), 3.56 (2H, t, J = 5.9 Hz), 3.80 (2H, t, J = 6.6 Hz), 6.66 (2H, d, J = 9.0 Hz), 7.07 (2H, doublet, J = 9.0 Hz);

MS (EI) m / z: 220 [M ⁺ ], 56.

(124c) 4- {4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Using the 2- [4- (1,4-diazepane-1-yl) phenyl] ethanol prepared in Example 124 (124b), the reaction was carried out according to the method described in Example 121 (121c) to obtain the title compound. Was synthesized.

Brown powder

Mp 180-185 ° C .;

IR (KBr) ν _max 2939, 2206, 1625, 1517, 1354, 1250, 1042, 928, 805 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.97 (2H, m), 2.57 (2H, t, J = 7.4 Hz), 3.44-3.55 (4H, m), 3.66-3.74 (4H, m ), 3.90-3.97 (2H, m), 4.53 (1H, brs), 6.41 (1H, d, J = 7.4 Hz), 6.67 (2H, d, J = 8.6 Hz), 6.98 (2H, d, J = 8.6 Hz), 7.34 (1H, d, J = 7.4 Hz), 12.50 (1H, brs);

MS (FAB) m / z: 355 [M + H ⁺ ], 273, 257, 242, 176, 165, 120, 63;

analysis. Calc. For C ₁₉ H ₂₂ N ₄ OS.0.25H ₂ O: C, 63.57; H, 6. 32; N, 15.61. Found: C, 63.36; H, 6.00; N, 15.61.

(124d) 3-amino-4- {4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-car Copy mid

4- {4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepan-1-yl} -2-thioxo-1,2-dihydro prepared in Example 124 (124c) The reaction was carried out according to the method described in Example 5 (5c) using pyridine-3-carbonitrile to synthesize the title compound.

White powder

Mp 257-262 ° C .;

IR (KBr) ν _max 3445, 3324, 3151, 2939, 1655, 1576, 1516, 1370, 1232, 1045, 938, 807 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.07-2.16 (2H, m), 2.59 (2H, t, J = 7.4 Hz), 3.13-3.23 (2H, m), 3.24-3.30 (2H, m ), 3.47-3.56 (4H, m), 3.67-3.77 (2H, m), 4.54 (1H, t, J = 5.1 Hz), 6.67 (2H, d, J = 8.6 Hz), 6.95 (2H, brs) , 6.99 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 8.37 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 412 [M + H ⁺ ], 242, 165, 120, 63;

analysis. Calc. For C ₂₁ H ₂₅ N ₅ 0 ₂ S.0.30H ₂ 0: C, 60.50; H, 6. 19; N, 16.80. Found: C, 60.43; H, 6.08; N, 16.79.

Example 125 3-amino-4- {4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2 -Carboxamide (Example Compound No. 3-876)

(125a) 1-bromo-4- (2-methoxyethyl) benzene

A solution of 4-bromophenethyl alcohol (2.01 g, 10.0 mmol) in N, N-dimethylformamide (20 mL) was cooled to 0 ° C., and sodium hydride (55% oily, 436 mg, 10.0 mmol) was added to 0 ° C. Stir for 10 minutes at. Methyl iodide (0.75 mL, 12.0 mmol) was added to the reaction mixture, followed by further stirring at room temperature for 3 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined, washed with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (2.15 g, yield 100%).

Yellow liquid

IR (film) ν _max 2925, 1489, 1382, 1191, 1117, 1011, 804 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.83 (2H, t, J = 7.0 Hz), 3.34 (3H, s), 3.58 (2H, t, J = 7.0 Hz), 7.10 (2H, d, J = 8.2 Hz), 7.41 (2H, doublet, J = 8.2 Hz);

MS (EI) m / z: 214 [M ⁺ ], 171, 169, 135, 104, 90, 45.

(125b) benzyl 4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-carboxylate

Benzyl 1-homopiperazinecarboxylate, according to the method described in Example 117 (117a), using 1-bromo-4- (2-methoxyethyl) benzene prepared in Example 125 (125a) The reaction was carried out to obtain the title compound.

Yellow liquid

IR (film) ν _max 2932, 1699, 1615, 1520, 1421, 1228, 928 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88-2.05 (2H, m), 2.78 (2H, t, J = 7.0 Hz), 3.25-3.41 (5H, m), 3.47-3.67 (8H, m), 5.08 (1H, s), 5.13 (1H, s), 6.59-6.67 (2H, m), 7.03-7.10 (2H, m), 7.27-7.38 (5H, m);

MS (EI) m / z: 368 [M ⁺ ], 324, 323, 277, 233, 216, 190, 178, 160, 146, 118, 107, 91, 70, 44.

(125c) 1- [4- (2-methoxyethyl) phenyl] -1,4-diazepane

Benzyl 4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-carboxylate prepared in Example 125 (125b) and hydrogenated in the presence of a palladium-carbon catalyst in ethanol The decomposition reaction was carried out to obtain the title compound.

Yellow liquid

IR (film) ν _max 3327, 2930, 1615, 1520, 1393, 1191, 1113, 807 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.83-1.92 (2H, m), 2.77 (2H, t, J = 7.0 Hz), 2.82 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.9 Hz), 3.35 (3H, s), 3.49-3.57 (6H, m), 6.62 (2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 8.6 Hz);

MS (FAB) m / z: 234 [M ⁺ ], 204, 189, 178, 164, 146, 132, 118, 105, 91, 70.

(125d) 4- {4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Using 1- [4- (2-methoxyethyl) phenyl] -1,4-diazephan prepared in Example 125 (125c), the reaction was carried out according to the method described in Example 121 (121c) to indicate the reaction. Compounds were synthesized.

Brown powder

Mp 182-185 ° C;

IR (KBr) ν _max 2930, 2204, 1625, 1518, 1353, 1241, 1109, 929, 805 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.89-1.98 (2H, m), 2.65 (2H, t, J = 7.3 Hz), 3.22 (3H, s), 3.44 (2H, t, J = 7.3 Hz), 3.50 (2H, t, J = 5.9 Hz), 3.68-3.75 (4H, m), 3.92-3.97 (2H, m), 6.42 (1H, d, J = 7.8 Hz), 6.70 (2H, d , J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 7.8 Hz), 12.50 (1H, brs);

MS (FAB) m / z: 369 [M + H ⁺ ], 336, 323, 273, 246, 165;

analysis. Calc. For C ₂₀ H ₂₄ N ₄ OS.0.25H ₂ O: C, 64.40; H, 6. 62; N, 15.02. Found: C, 64.43; H, 6.52; N, 14.80.

(125e) 3-amino-4- {4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-car Copy mid

4- {4- [4- (2-methoxyethyl) phenyl] -1,4-diazepan-1-yl} -2-thioxo-1,2-dihydro prepared in Example 125 (125d) The reaction was carried out according to the method described in Example 5 (5c) using pyridine-3-carbonitrile to synthesize the title compound.

Pale yellow powder

Mp 230-235 ° C .;

IR (KBr) ν _max 3443, 3169, 2935, 1655, 1573, 1518, 1452, 1369, 1231, 1102, 938, 807 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.09-2.17 (2H, m), 2.68 (2H, t, J = 7.3 Hz), 3.15-3.23 (2H, m), 3.24 (3H, s), 3.26-3.31 (2H, m), 3.46 (2H, t, J = 7.3 Hz), 3.52 (2H, t, J = 5.9 Hz), 3.71-3.78 (2H, m), 6.69 (2H, d, J = 8.8 Hz), 6.98 (2H, brs), 7.03 (2H, d, J = 8.8 Hz), 7.07 (1H, d, J = 5.4 Hz), 7.08 (2H, brs), 8.40 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 426 [M + H ⁺ ], 409, 380, 273, 230;

analysis. Calc. For C ₂₂ H ₂₇ N ₅ O ₂ S.0.25H ₂ O: C, 61.44; H, 6. 45; N, 16.28. Found: C, 61.26; H, 6. 40; N, 16.09.

Example 126 3-amino-4- {4- [3- (2-hydroxyethyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2 Carboxamide (Example Compound No. 3-1004)

(126a) 1- [2- (benzyloxy) ethyl] -3-bromobenzene

A solution of 3-bromophenethyl alcohol (2.04 g, 10.0 mmol) in N, N-dimethylformamide (20 mL) was cooled to 0 ° C., and sodium hydride (55% oily, 436 mg, 10.0 mmol) was added to 0 ° C. Stirred for 15 min. Subsequently, benzyl bromide (1.40 mL, 12.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane / toluene = 3: 1). Purification was carried out to obtain the title compound (2.60 g, 89%).

Colorless liquid

IR (film) ν _max 2858, 1568, 1475, 1361, 1203, 1103, 695 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.88 (2H, t, J = 7.0 Hz), 3.66 (2H, t, J = 7.0 Hz), 4.50 (2H, s), 7.11-7.15 (2H, m) , 7.23-7.38 (7H, m);

MS (EI) m / z: 292, 290 [M ⁺ ], 262, 260, 184, 169, 91.

(126b) benzyl 4- {3- [2- (benzyloxy) ethyl] phenyl} -1,4-diazepane-1-carboxylate

Benzyl 1-homopiperazincar according to the method described in Example 117 (117a), using 1- [2- (benzyloxy) ethyl] -3-bromobenzene prepared in Example 126 (126a) Reaction was performed with a carboxylate to obtain the title compound.

Brown liquid

IR (film) ν _max 2942, 1699, 1602, 1497, 1421, 1236, 1118, 928, 697 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88-2.04 (2H, m), 2.81-2.91 (2H, m), 3.29 (1H, t, J = 6.3 Hz), 3.37 (1H, t, J = 6.3 Hz), 3.48-3.72 (8H, m), 4.52 (2H, brs), 5.09 (1H, s), 5.14 (1H, s), 6.50-6.59 (3H, m), 7.13 (1H, m), 7.22 -7.40 (10 H, m);

MS (FAB) m / z: 444 [M ⁺ ], 386, 354, 266, 246, 165.

(126c) 2- [3- (1,4-diazepane-1-yl) phenyl] ethanol

Methylene chloride of benzyl 4- {3- [2- (benzyloxy) ethyl] phenyl} -1,4-diazepane-1-carboxylate (2.30 g, 5.20 mmol) prepared in Example 126 (126b) 26 mL) was added to trimethyl iodine iodide (4.8 mL, 33.7 mmol) and stirred at room temperature for 23 hours. Water (50 mL) was added to the reaction solution, liquid separation was carried out, and potassium carbonate was added to the obtained aqueous layer to make the liquid basic. The aqueous layer was extracted three times with methylene chloride / 2-propanol (4: 1) (50 mL) and the extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (1.05 g, yield 92%). .

Brown liquid

IR (film) ν _max 3310, 2935, 1601, 1497, 1363, 1176, 1047, 771, 696 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.84-1.94 (2H, m), 2.76-2.89 (4H, m), 3.03 (2H, t, J = 5.5 Hz), 3.51-3.60 (4H, m), 3.85 (2H, t, J = 5.9 Hz), 6.50-6.61 (3H, m), 7.16 (1H, t, J = 8.2 Hz);

MS (EI) m / z: 220 [M ⁺ ], 190, 178, 164, 152, 150, 133, 118, 91, 77, 43.

(126d) 4- {4- [3- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Using the 2- [3- (1,4-diazepane-1-yl) phenyl] ethanol prepared in Example 126 (126c), the reaction was carried out according to the method described in Example 121 (121c) to obtain the title compound. Was synthesized.

Brown powder

Mp 147-155 ° C .;

IR (KBr) ν _max 2946, 2205, 1625, 1524, 1354, 1250, 1177, 1040, 774 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.87-2.00 (2H, m), 2.64 (2H, t, J = 7.0 Hz), 3.48-3.61 (4H, m), 3.67-3.78 (4H, m ), 3.91-4.00 (2H, m), 4.57 (1H, brs), 6.40-6.51 (2H, m), 6.56-6.66 (2H, m), 7.05 (1H, t, J = 7.8 Hz), 7.37 ( 1 H, d, J = 7.8 Hz), 12.54 (1 H, brs);

MS (FAB) m / z: 355 [M + H ⁺ ], 273, 242, 226, 180.

(126e) 3-amino-4- {4- [3- (2-hydroxyethyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-car Copy mid

4- {4- [3- (2-hydroxyethyl) phenyl] -1,4-diazepan-1-yl} -2-thioxo-1,2-dihydro prepared in Example 126 (126d) The reaction was carried out according to the method described in Example 5 (5c) using pyridine-3-carbonitrile to synthesize the title compound.

Pale yellow powder

Mp 120-123 ° C .;

IR (KBr) ν _max 3436, 3325, 3185, 2939, 1649, 1598, 1499, 1450, 1370, 1234, 1047, 941, 771 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.10-2.18 (2H, m), 2.65 (2H, t, J = 7.3 Hz), 3.16-3.24 (2H, m), 3.25-3.32 (2H, m ), 3.50-3.61 (4H, m), 3.73-3.79 (2H, m), 4.57 (1H, brt), 6.47 (1H, d, J = 7.3 Hz), 6.57-6.63 (2H, m), 6.98 ( 2H, br s), 7.03-7.12 (4H, m), 8.40 (1H, doublet, J = 5.4 Hz);

MS (FAB) m / z: 412 [M + H ⁺ ], 395, 353, 273, 242, 165;

analysis. Calc. For C ₂₁ H ₂₅ N ₅ 0 ₂ S.0.67H ₂ 0: C, 59.55; H, 6. 27; N, 16.54. Found: C, 59.42; H, 6. 21; N, 16.66.

Example 127 3-amino-4- {4- [4- (3-hydroxypropyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2 Carboxamide (Example Compound No. 3-1005)

(127a) 3- (4-bromophenyl) propan-1-ol

To a tetrahydrofuran (80 mL) solution of 3- (4-bromophenyl) propanoic acid (5.02 g, 21.9 mmol) and triethylamine (3.4 mL, 24.1 mmol) under nitrogen atmosphere, methyl chlorocarbonate (1.9) at 0 ° C. mL, 24.1 mmol) was added dropwise and stirred at room temperature for 1 hour. Insoluble matter was removed from the reaction solution by filtration, and an aqueous solution of sodium borohydride (1.24 g, 32.9 mmol) was added to the filtrate, followed by stirring at room temperature for 2 hours. Ethyl acetate (200 mL) was added to the reaction solution, the organic layer was washed twice with saturated brine (200 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (4.36 g, yield 93%). .

Colorless liquid

IR (film) ν _max 3353, 2942, 1711, 1489, 1072, 1012, 833, 796 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.83-1.90 (2H, m), 2.67 (2H, t, J = 7.8 Hz), 3.66 (2H, t, J = 6.3 Hz), 7.06 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2 Hz);

MS (EI) m / z: 214 [M ⁺ ], 196, 169, 117, 104, 91, 90, 77, 51, 50, 39.

(127b) 1- [3- (benzyloxy) propyl] -4-bromobenzene

To a N, N-dimethylformamide (20 mL) solution of 3- (4-bromophenyl) propan-1-ol (4.22 g, 19.6 mmol) prepared in Example 127 (127a) under nitrogen atmosphere at 0 ° C Sodium hydride (55% oily, 1.03 g, 23.5 mmol) was added and stirred for 10 minutes. Benzyl bromide (2.3 mL, 23.5 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and water (10 mL) and ether (50 mL) were added to separate the liquid. The organic layer was washed twice with water (50 mL) and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 5: 1) to obtain the title compound (4.78 g, yield 80%).

Colorless liquid

IR (film) ν _max 2941, 2858, 2384, 1488, 1455, 1364, 1102, 1073, 1012, 736, 698 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.87-1.94 (2H, m), 2.67 (2H, t, J = 7.8 Hz), 3.47 (2H, t, J = 6.3 Hz), 4.50 (2H, s) , 7.04 (2H, doublet, J = 8.6 Hz), 7.29-7.39 (7H, m);

MS (EI) m / z: 304 [M ⁺ ], 225, 213, 183, 169, 117, 104, 91, 65.

(127c) benzyl 4- {4- [3- (benzyloxy) propyl] phenyl} -1,4-diazepane-1-carboxylate

Benzyl1-homopiperazinecarboxylic, using 1- [3- (benzyloxy) propyl] -4-bromobenzene prepared in Example 127 (127b), according to the method described in Example 117 (117a) It reacted with the rate and obtained the title compound.

Pale yellow liquid

IR (film) ν _max 2940, 1700, 1616, 1519, 1422, 1228, 1118, 928, 737, 698 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.85-2.02 (4H, m), 2.60 (2H, t, J = 7.8 Hz), 3.30 (1H, t, J = 5.9 Hz), 3.37 (1H, t, J = 6.3 Hz), 3.48 (2H, t, J = 6.6 Hz), 3.50.3.57 (4H, m), 3.61-3.66 (2H, m), 4.49 (2H, s), 5.07 (1H, s), 5.12 (1H, s), 6.60 (2H, d, J = 8.6 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.25-7.33 (5H, m);

MS (FAB) m / z: 459 [M + H] ⁺ , 458, 368, 351, 260, 242, 219, 65.

(127d) 1- {4- [3- (benzyloxy) propyl] phenyl} -1,4-diazepane

Benzyl 4- {4- [3- (benzyloxy) propyl] phenyl} -1,4-diazepane-1-carboxylate (3.62 g, 7.9 mmol) prepared in Example 127 (127c) (70 mL) 5% palladium-carbon (3.36 g, 1.6 mmol) was added to the solution, and the mixture was stirred for 5 hours under a hydrogen atmosphere. The reaction solution was filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (2.42 g, yield 95%) of the crude title compound.

Colorless liquid

IR (film) ν _max 3335, 2936, 2855, 1616, 1519, 1364, 1189, 1102, 737, 698 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.86-1.93 (4H, m), 2.61 (2H, t, J = 7.8 Hz), 2.83 (2H, t, J = 4.7 Hz), 3.03 (2H, t, J = 5.5 Hz), 3.48-3.57 (6H, m), 4.51 (2H, s), 6.63 (2H, d, J = 8.2 Hz), 7.03 (2H, d, J = 8.2 Hz), 7.29-7.36 ( 5H, m);

MS (EI) m / z: 324 [M ⁺ ], 282, 268, 254, 233, 204, 189, 176, 160, 146, 132, 118, 91, 70, 65, 43, 42.

(127e) 3- [4- (1,4-diazepan-1-yl) phenyl] propan-1-ol

Methylene chloride (50 mL) solution of 1- {4- [3- (benzyloxy) propyl] phenyl} -1,4-diazepane (2.16 g, 6.7 mmol) prepared in Example 127 (127d) under a nitrogen atmosphere. Trimethyl iodide (3.8 mL, 26.6 mmol) was added to the mixture, followed by stirring for 10 minutes. Water (100 mL) was added to the reaction solution, and the aqueous layer was washed twice with methylene chloride (100 mL). An aqueous 4M sodium carbonate solution (50 mL) was added to the aqueous layer, and extracted three times with methylene chloride / isopropanol (4: 1) (100 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (1.32 g, yield 73%).

Light brown liquid

IR (film) ν _max 3310, 2934, 1616, 1519, 1365, 1189, 1058, 800 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.83-1.90 (4H, m), 2.59 (2H, t, J = 7.8 Hz), 2.82 (2H, t, J = 5.9 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.50-3.56 (4H, m), 3.67 (2H, t, J = 6.7 Hz), 6.62 (2H, d, J = 8.6 Hz), 7.03 (2H, d, J = 8.6 Hz) ;

MS (EI) m / z: 234 [M ⁺ ], 204, 192, 178, 160, 146, 130, 118, 117, 91, 90, 77, 43, 42.

(127f) 4- {4- [4- (3-hydroxypropyl) phenyl] -1,4-diazepane-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

The reaction was carried out according to the method described in Example 121 (121c) using 3- [4- (1,4-diazepane-1-yl) phenyl] propan-1-ol prepared in Example 127 (127e). It carried out and synthesize | combined the title compound.

Brown powder

Mp 184-186 ° C .;

IR (KBr) ν _max 2935, 2206, 1626, 1518, 1252, 1039, 930 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.64 (2H, quint, J = 7.8 Hz), 1.91-1.96 (2H, m), 2.45 (2H, t, J = 7.8 Hz), 3.36-3.40 ( 2H, m), 3.50 (2H, t, J = 5.9 Hz), 3.69-3.73 (4H, m), 3.94-3.96 (2H, m), 4.39 (1H, t, J = 4.9 Hz), 6.44 (1H , d, J = 7.8 Hz), 6.69 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 7.8 Hz), 12.53 (1H, brs );

MS (FAB) m / z: 369 [M + H] ⁺ , 273, 257, 246, 176, 63.

(127g) 3-amino-4- {4- [4- (3-hydroxypropyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-car Copy mid

4- {4- [4- (3-hydroxypropyl) phenyl] -1,4-diazepan-1-yl} -2-thioxo-1,2-dihydro prepared in Example 127 (127f) The reaction was carried out according to the method described in Example 5 (5c) using pyridine-3-carbonitrile to synthesize the title compound.

Light brown powder

Mp 237-241 ° C .;

IR (KBr) ν _max 3439, 3325, 3174, 2935, 1645, 1577, 1518, 1370, 1057, 938, 900, 826, 805, 479 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.66 (2H, quint, J = 7.3 Hz), 2.11-2.15 (2H, m), 2.47-2.50 (2H, m), 3.21 (2H, brs), 3.29 (2H, brs), 3.41 (2H, q, J = 6.8 Hz), 3.52 (2H, t, J = 5.9 Hz), 3.74 (2H, t, J = 4.4 Hz), 4.40 (1H, t, J = 4.9 Hz), 6.70 (2H, d, J = 8.3 Hz), 6.97 (2H, brs), 7.00 (2H, d, J = 8.3 Hz), 7.08 (1H, d, J = 5.4 Hz), 7.09 ( 2H, br s), 8.40 (1H, d, J = 5.4 Hz);

HRMS m / z calc. C ₂₂ H ₂₈ O ₂ N ₅ S 426.1964, found 426.1994;

MS (ESI) m / z: 426 [M + H] ⁺ , 360;

analysis. Calc. For C ₂₂ H ₂₇ N ₅ O ₂ S.0.3H ₂ O: C, 61.32; H, 6. 46; N, 16.25; S, 7.44. Found: C, 61.07; H, 6. 38; N, 16.49; S, 7.52.

Example 128 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide (Example Compound No. 3-107)

(128a) benzyl 4- [4- (trifluoroacetyl) phenyl] -1,4-diazepane-1-carboxylate

The reaction was carried out in the same manner as described in Example 59 (59a) using benzyl 1-homopiperazinecarboxylate and 2,2,2,4'-tetrafluoroacetophenone to give the title compound (quantitative). Got it.

Off White Oil

IR (film) ν _max 2959, 1697, 1595, 1528, 1423, 1166 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93-2.06 (2H, m), 3.33-3.38 (1H, m), 3.40-3.46 (1H, m), 3.60-3.74 (6H, m), 5.07 (1H , s), 5.13 (1H, s), 6.67-6.74 (2H, m), 7.25-7.37 (5H, m), 7.91-7.98 (2H, m);

MS (FAB) m / z: 407 [M + H] &lt; ⁺ &gt;, 406, 315, 289.

(128b) 4- {4-[(benzyloxy) carbonyl] -1,4-diazepane-1-yl} benzoic acid

Benzyl 4- [4- (trifluoroacetyl) phenyl] -1,4-diazepane-1-carboxylate (7.18 g, 17.7 mmol) prepared in Example 128 (128a) was converted to N, N-dimethylform. It dissolved in amide (35.4 mL), added 8N sodium hydroxide aqueous solution (4.42 mL, 35.3 mmol), and stirred at 80 degreeC for 1 hour. The reaction solution was cooled, diluted with water (70 mL), and washed with ethyl acetate (70 mL). The aqueous layer was made acidic with 1N hydrochloric acid, extracted with ethyl acetate (10 mL × 3), the organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ether (50 mL) was added to the residue, crystallized and obtained by filtration, washed with ether and dried to obtain 5.82 g (yield 69%) of the title compound.

Colorless Prism Crystal

Mp 135-137 ° C .;

IR (KBr) ν _max 3063, 2947, 2667, 2562, 1699, 1667, 1600, 1417 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92-2.07 (2H, m), 3.30-3.36 (1H, m), 3.41 (1H, t, J = 5.9 Hz), 3.58-3.71 (6H, m), 5.08 (1H, s), 5.14 (1H, s), 6.63-6.72 (2H, m), 7.24-7.38 (5H, m), 7.91-7.99 (2H, m);

MS (EI) m / z: 354 M ⁺ ., 263, 202.

(128c) benzyl 4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepanecarboxylate

J. Org. Chem., (1990), 55, 6252-6259, was synthesized by the following method.

Tetrahydrofuran (80 mL) of 4- {4-[(benzyloxy) carbonyl] -1,4-diazepan-1-yl} benzoic acid (7.09 g, 20 mmol) prepared under ice cooling, in Example 128 (128b). 1,1'-carbonyldiimidazole (3.89 g, 24 mmol) was added to the solution, followed by stirring for 30 minutes. The reaction solution was raised to room temperature, a tetrahydrofuran solution of dimethylamine (2.0M, 15 mL, 30 mmol) was added, and the mixture was stirred for 30 minutes. Saturated sodium hydrogencarbonate aqueous solution (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: ethyl acetate) to obtain 7.63 g (quantitative) of the title compound.

Pale yellow oil

IR (film) ν _max 3475, 2939, 1699, 1608, 1493, 1423, 1391 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.90-2.06 (2H, m), 3.07 (6H, s), 3.26-3.33 (1H, m), 3.34-3.41 (1H, m), 3.52-3.70 (6H , m), 5.10 (1H, s), 5.14 (1H, s), 6.59-6.71 (2H, m), 7.22-7.42 (7H, m);

MS (FAB) m / z: 382 {M + H} ⁺ , 337, 246.

(128d) 4- (1,4-diazepane-1-yl) -N, N-dimethylbenzamide

To an ethanol (11 mL) solution of benzyl 4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepanecarboxylate (1.10 g, 2.88 mmol) prepared in Example 128 (128c), 10% palladium-carbon (function 53 wt%, 1.10 g) was added and stirred for 1 hour under a hydrogen atmosphere. The reaction solution was filtered, the catalyst was washed with ethanol, and the solvent was distilled off under reduced pressure from the filtrate obtained to obtain 671 mg (yield 94%) of the title compound.

Colorless oil

IR (film) ν _max 3444, 3321, 2931, 1672, 1608, 1493, 1390 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.85-1.94 (2H, m), 2.79-2.85 (2H, m), 3.00-3.05 (2H, m), 3.07 (6H, m), 3.54-3.64 (4H m), 6.66 (2H, d, J = 8.6 Hz), 7.36 (2H, d, J = 8.6 Hz);

MS (EI) m / z: 247 M ^+,, 203, 191, 160.

(128e) 4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1-yl] -N, N-dimethylbenza mid

The reaction was carried out according to the method described in Example 121 (121c) using 4- (1,4-diazepane-1-yl) -N, N-dimethylbenzamide prepared in Example 128 (128d), The title compound was synthesized. Yield 24%.

Off-white powder

Mp 239-241 ° C .;

IR (KBr) ν _max 3180, 3147, 3045, 2960, 2918, 2208, 1605, 1525, cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.92-2.00 (2H, m), 2.94 (6H, s), 3.54-3.61 (2H, m), 3.71-3.81 (4H, m), 3.95-4.01 (2H, m), 6.44 (1H, d, J = 7.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 7.8 Hz), 12.50 (1H, broad singlet);

MS (FAB) m / z: 382 [M + H] ⁺ , 337, 273;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS.0.6H ₂ O: C, 61.23; H, 6. 22; N, 17.85; S, 8.17. Found: C, 61.32; H, 6. 18; N, 17.95; S, 8.12.

(128f) 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2- Carboxamide

4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1-yl, prepared in Example 128 (128e)- The reaction was carried out according to the method described in Example 5 (5c) using N, N-dimethylbenzamide, to synthesize the title compound. Yield 83%.

Off-white powder

Mp 159-161 ° C .;

IR (KBr) ν _max 3437, 3327, 3187, 2930, 2847, 1606, 1497, 1387 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.11-2.20 (2H, m), 2.97 (6H, s), 3.16-3.34 (2H, m), 3.58 (2H, t, J = 6.3 Hz), 3.78-3.84 (2H, m), 6.76 (2H, d, J = 9.0 Hz), 6.97 (2H, br.s), 7.04-7.12 (3H, m), 7.28 (2H, d, J = 9.0 Hz) , 8.38 (1H, doublet, J = 5.1 Hz);

MS (FAB) m / z: 439 [M + H] ⁺ , 394, 273;

analysis. Calc. For C ₂₂ H ₂₆ N ₆ O ₂ S.1.2H ₂ O: C, 57.42; H, 6. 22; N, 18.26; S, 6.97. Found: C, 57.17; H, 6.03; N, 18.45; S, 6.83.

Example 129 3-amino-4- {4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] Pyridine-2-carboxamide (Example Compound No. 3-940)

(129a) benzyl 4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepane-1-carboxylate

4- {4-[(benzyloxy) carbonyl] -1,4-diazepan-1-yl} benzoic acid and azetidine prepared in Example 128 (128b) were used and described in Example 128 (128c). The reaction was carried out according to the method to obtain the title compound (quantitative).

Light yellow oil

IR (film) ν _max 3459, 2952, 2886, 1698, 1605, 1428, 1234, 1175 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.90-2.06 (2H, m), 2.32 (2H, quint, J = 7.8 Hz), 3.31 (2H, t, J = 6.3 Hz), 3.35-3.41 (2H, m), 3.52-3.69 (6H, m), 4.13-4.42 (4H, m), 5.08 (1H, s), 5.13 (1H, s), 6.60-6.69 (2H, m), 7.24-7.38 (5H, m), 7.52-7.62 (2H, m);

MS (FAB) m / z: 394 [M + H] ⁺ , 337, 258, 246.

(129b) 1- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepane

Example 128 (128d) using benzyl 4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepane-1-carboxylate prepared in Example 129 (129a) Reaction was performed in accordance with the method described in, to obtain the title compound (yield 98%).

Colorless oil

IR (film) ν _max 3416, 3321, 2941, 1606, 1433, 1406, 1177 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89 (2H, quint, J = 5.9 Hz), 2.26-2.37 (2H, m), 2.78-2.86 (2H, m), 2.99-3.07 (2H, m), 3.53-3.66 (4H, m), 4.11-4.45 (4H, m), 6.65 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0 Hz);

MS (EI) m / z: 259 M ⁺ ., 217, 203, 189.

(129c) 4- {4- [4- (azetidin-1-ylcarbonyl) phenyl} -1,4-diazepan-1-yl} -2-thioxo-1,2-dihydropyridine-3 Carbonnitrile

The reaction was carried out according to the method described in Example 121 (121c) using 1- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepane prepared in Example 129 (129b). It carried out and synthesize | combined the title compound. Yield 25%.

White powder

Mp 136-138 ° C .;

IR (KBr) ν _max 3441, 2950, 2882, 2204, 1605, 1522, 1432, 1402 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.90-1.99 (2H, m), 2.23 (2H, quint, J = 7.8 Hz), 3.59 (2H, t, J = 5.9 Hz), 3.72-3.83 ( 4H, m), 3.88-4.41 (6H, m), 6.44 (1H, d, J = 7.8 Hz), 6.79 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.48 (2H, doublet, J = 8.8 Hz), 12.53 (1H, br.s);

MS (FAB) m / z: 394 [M + H] ⁺ , 378, 337, 273;

analysis. Calc. For C ₂₁ H ₂₃ N ₅ OS. 0.84 H ₂ O: C, 61.72; H, 6.09; N, 17.14; S, 7.85. Found: C, 61.88; H, 5. 82; N, 17.10; S, 7.74.

(129d) 3-amino-4- {4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine- 2-carboxamide

4- {4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepan-1-yl] -2-thioxo-1,2 prepared in Example 129 (129c) The reaction was carried out according to the method described in Example 5 (5c) using dihydropyridine-3-carbonitrile to synthesize the title compound. Yield 77%.

Off-white powder

Mp 141-143 ° C .;

IR (KBr) ν _max 3438, 3325, 3189, 2952, 2882, 1648, 1604, 1432, 1399, cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.10-2.30 (4H, m), 3.14-3.25 (2H, m), 3.26-3.38 (2H, m), 3.55-3.65 (2H, m), 3.79 -3.88 (2H, m), 3.92-4.42 (4H, m), 6.79 (2H, d, J = 8.6 Hz), 6.98 (2H, br.s), 7.08 (1H, d, J = 5.5 Hz), 7.11 (2H, broad singlet), 7.50 (2H, doublet, J = 8.6 Hz), 8.40 (1H, doublet, J = 5.5 Hz);

MS (FAB) m / z: 451 [M + H] ⁺ , 434, 394, 273;

analysis. Calc. For C ₂₃ H ₂₆ N ₆ O ₂ S.1.2H ₂ O: C, 58.81; H, 6.06; N, 17.80; S, 6.79. Found: C, 58.61; H, 6.00; N, 17.50; S, 6.64.

Example 130 3-amino-4- {4- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] Pyridine-2-carboxamide (Example Compound No. 3-970)

(130a) benzyl 4- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepane-1-carboxylate

4- {4-[(benzyloxy) carbonyl] -1,4-diazepan-1-yl} benzoic acid and morpholine prepared in Example 128 (128b) were used and described in Example 128 (128c). The reaction was carried out according to the method to obtain the title compound (quantitative).

Light brown oil

IR (film) ν _max 3485, 2957, 2928, 2857, 1698, 1607, 1424 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.91-2.06 (2H, m), 3.31 (1H, t, J = 6.3 Hz), 3.38 (1H, t, J = 6.3 Hz), 3.54-3.74 (14H, m), 5.09 (1H, s), 5.13 (1H, s), 6.63-6.71 (2H, m), 7.28-7.39 (7H, m);

MS (FAB) m / z: 424 [M + H] ⁺ , 337, 273.

(130b) 1- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepane

Example 128 (128d) using benzyl 4- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepane-1-carboxylate prepared in Example 130 (130a) Reaction was performed in accordance with the method described in, to obtain the title compound (quantitative).

Colorless oil

IR (film) ν _max 3417, 3314, 2929, 2855, 1607, 1524, 1457, 1431 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89 (2H, q, J = 5.9 Hz), 2.78-2.86 (2H, m), 2.99-3.07 (2H, m), 3.53-3.77 (12H, m), 6.66 (2H, doublet, J = 9.0 Hz), 7.34 (2H, doublet, J = 9.0 Hz);

MS (EI) m / z: 289 M ⁺ ., 247, 233, 203.

(130c) 4- {4- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepane-1-yl} -2-thioxo-1,2-dihydropyridine-3 Carbonnitrile

The reaction was carried out according to the method described in Example 121 (121c) using 1- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazephan prepared in Example 130 (130b). It carried out and synthesize | combined the title compound. Yield 46%.

Brown Awards (包 狀物)

IR (KBr) ν _max 3434, 3198, 3132, 2958, 2922, 2854, 2204, 1606, 1520 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.07-2.16 (2H, m), 3.54-3.79 (12H, m), 3.82-3.89 (2H, m), 4.11-4.18 (2H, m), 6.20 (1H , d, J = 7.4 Hz), 6.70 (2H, d, J = 8.6 Hz), 7.23 (1H, d, J = 7.4 Hz), 7.36 (2H, d, J = 8.6 Hz), 11.57 (1H, br .s);

MS (FAB) m / z: 424 [M + H] ⁺ , 337, 273.

(130d) 3-amino-4- {4- [4- (morpholin 4-ylcarbonyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2 Carboxamide

4- {4- [4- (morpholin 4-ylcarbonyl) phenyl] -1,4-diazepan-1-yl} -2-thioxo-1,2- prepared in Example 130 (130c) The reaction was carried out according to the method described in Example 5 (5c) using dihydropyridine-3-carbonitrile to synthesize the title compound. Yield 43%.

Off-white powder

Mp 274-275 ° C .;

IR (KBr) ν _max 3437, 3323, 3189, 2957, 2921, 2852, 1606, 1367 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.12-2.20 (2H, m), 3.18-3.25 (2H, m), 3.27-3.35 (2H, m), 3.48-3.55 (4H, m), 3.57 -3.64 (6H, m), 3.80-3.86 (2H, m), 6.80 (2H, d, J = 8.8 Hz), 6.96 (2H, br.s), 7.06-7.13 (3H, s), 7.29 (2H , d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 481 [M + H] ⁺ , 273, 258, 242;

analysis. Calc. For C ₂₄ H ₂₈ N ₆ O ₃ S: C, 59.98; H, 5.87; N, 17.49; S, 6.67. Found: C, 59.89; H, 5.89; N, 17.28; S, 6.70.

Example 131 3-amino-4- (4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3 -b] pyridine-2-carboxamide (example compound number 3-925)

(131a) benzyl 4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} -1,4-diazepane-1-carboxylate

Instead of tert-butyl 1-piperazinecarboxylate, the reaction was carried out according to the method described in Example 117 (117a), using benzyl 1-homopiperazinecarboxylate to obtain the title compound. Yield 80%.

Yellow oil

IR (film) ν _max 3481, 2939, 1699, 1642, 1520, 1423 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.90-2.06 (2H, m), 2.95 (3H, s), 3.00 (3H, s), 3.27-3.33 (1H, m), 3.34-3.40 (1H, m ), 3.50-3.67 (8H, m), 5.08 (1H, s), 5.13 (1H, s), 6.60-6.68 (2H, m), 7.10 (2H, d, J = 8.2 Hz), 7.27-7.40 ( 5H, m);

MS (FAB) m / z: 396 [M + H] ⁺ , 323, 260.

(131b) 2- [4- (1,4-diazepane-1-yl) phenyl] -N, N-dimethylacetamide

Example 128 using benzyl 4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} -1,4-diazepane-1-carboxylate prepared in Example 131 (131a) The reaction was carried out according to the method described in (128d) to obtain the title compound. Yield 94%

Pale yellow oil

IR (film) ν _max 3430, 2934, 1629, 1520, 1398 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.79-2.84 (2H, m), 2.94 (3H, s), 2.97-3.04 (5H, m), 3.47 ( 2H, s), 3.49-3.57 (4H, m), 6.62 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 9.0 Hz);

MS (FAB) m / z: 262 [M + H] ⁺ , 261, 219, 189.

(131c) 2- {4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepan-1-yl] phenyl} -N , N-dimethylacetamide

The method described in Example 121 (121c) using 2- [4- (1,4-diazepan-1-yl) phenyl] -N, N-dimethylacetamide prepared in Example 131 (131b) According to the reaction, a title compound (yield 47%) was synthesized.

Brown amorphous

IR (KBr) ν _max 3124, 3034, 2938, 2203, 1616, 1519 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.04-2.16 (2H, m), 2.96 (3H, s), 3.02 (3H, s), 3.52- 3.63 (4H, m), 3.69-3.82 (4H, m ), 4.08-4.16 (2H, m), 6.19 (1H, d, J = 7.8 Hz), 6.66 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.22 (1H , d, J = 7.8 Hz), 11.94 (1H, broad s);

MS (FAB) m / z: 396 [M + H] ⁺ , 350, 323, 262.

(131d) 3-amino-4- (4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b ] Pyridine-2-carboxamide

2- {4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1- prepared in Example 131 (131c) The reaction was carried out according to the method described in Example 5 (5c) using general compound of [phenyl] -N, N-dimethylacetamide to synthesize the title compound (yield 56%).

Light yellow powder

Mp 133-135 ° C .;

IR (KBr) ν _max 3435, 3326, 3189, 2935, 2839, 1634, 1579, 1519 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.10-2.18 (2H, m), 2.82 (3H, s), 2.98 (3H, s), 3.15-3.23 (2H, m), 3.25-3.33 (2H , m), 3.49-3.56 (4H, m), 3.72-3.78 (2H, m), 6.71 (2H, d, J = 8.8 Hz), 7.00 (2H, br.s), 7.03 (2H, d, J = 8.8 Hz), 7.07 (1H, d, J = 5.4 Hz), 7.09 (2H, br.s), 8.39 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 453 [M + H] ⁺ , 452, 436, 380;

analysis. Calc. For C ₂₃ H ₂₈ N ₆ O ₂ S.16 H ₂ O: C, 58.35. H, 6. 45; N, 17.75. Found: C, 58.10; H, 6. 19; N, 18.03.

Example 132 3-amino-4- (4- {4- [3- (dimethylamino) -3-oxopropyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3 -b] pyridine-2-carboxamide (Example Compound No. 3-927)

(132a) 3- (4-bromophenyl) -N, N-dimethylpropanamide

According to the method described in Example 128 (128c), the title compound (yield 99%) was obtained using 3- (4-bromophenyl) propionic acid.

Colorless oil

IR (neat) ν _max 1648, 1488, 1400, 1012, 816 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.58 (2H, t, J = 7.8 Hz), 2.92 (2H, t, J = 7.8 Hz), 2.93 (6H, s), 7.08 (2H, d, J = 8.5 Hz), 7.38 (2H, doublet, J = 8.5);

MS (EI) m / z: 255 [M ⁺ ], 169;

analysis. Calc. For C ₁₁ H ₁₄ NOBr.0.1H ₂ O: C, 51.22; H, 5.55; N, 5.43; Br, 30.98. Found: C, 51.03; H, 5.67; N, 5.48; Br, 31.18.

(132b) benzyl 4- {4- [3- (dimethylamino) -3-oxopropyl] phenyl} -1,4-diazepane-1-carboxylate

The method described in Example 117 (117a) using 3- (4-bromophenyl) -N, N-dimethylpropanamide and benzyl 1-homopiperazinecarboxylate prepared in Example 132 (132a). Therefore, reaction was performed and the title object compound (yield 77%) was obtained.

Light yellow oil

IR (film) ν _max 3550, 3488, 2939, 1699, 1645, 1519 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.90-2.04 (2H, m), 2.52-2.59 (2H, m), 2.81-2.88 (2H, m), 2.92 (3H, s), 2.93 (3H, s ), 3.30 (1H, t, J = 6.3 Hz), 3.34-3.39 (1H, m), 3.49-3.59 (4H, m), 3.60-3.67 (2H, m), 5.07 (1H, s), 5.12 ( 1H, s), 6.58-6.64 (2H, m), 7.05 (2H, d, J = 8.2 Hz), 7.25-7.35 (5H, m);

MS (FAB) m / z: 410 [M + H] ⁺ , 409, 323, 274.

(132c) 3- [4- (1,4-diazepane-1-yl) phenyl] -N, N-dimethylpropanamide

Example 128 using benzyl 4- {4- [3- (dimethylamino) -3-oxopropyl] phenyl} -1,4-diazepane-1-carboxylate prepared in Example 132 (132b) The title compound (quantitative) was obtained by reacting according to the method described in (128d).

Light yellow oil

IR (film) ν _max 3445, 3319, 2931, 1635, 1520 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.53-2.60 (2H, m), 2.78-2.88 (4H, m), 2.93 (3H, s), 2.94 ( 3H, s), 2.98-3.03 (2H, m), 3.49-3.57 (4H, m), 6.61 (2H, d, J = 8.6 Hz), 7.04 (2H, d, J = 8.6 Hz);

MS (EI) m / z: 275 M ⁺ ., 233, 219.

(132d) 3- {4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepan-1-yl] phenyl} -N , N-dimethylpropanamide

The method described in Example 121 (121c) using 3- [4- (1,4-diazepane-1-yl) phenyl] -N, N-dimethylpropanamide prepared in Example 132 (132c). The reaction was carried out according to the synthesis of the title compound. Yield 49%.

Brown awards

IR (KBr) ν _max 3124, 2932, 2204, 1732, 1615, 1518 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.06-2.14 (2H, m), 2.53-2.60 (2H, m), 2.81-2.88 (2H, m), 2.94 (6H, s), 3.51-3.57 (2H, m), 3.70-3.80 (4H, m), 4.08-4.13 (2H, m), 6.21 (1H, d, J = 7.8 Hz), 6.63 (2H, d, J = 8.6 Hz), 7.07 ( 2H, d, J = 8.6 Hz), 7.26 (1H, d, J = 7.8 Hz), 12.27 (1H, br.s);

MS (FAB) m / z: 410 [M + H] ⁺ , 219, 176.

(132e) 3-amino-4- (4- {4- [3- (dimethylamino) -3-oxopropyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b ] Pyridine-2-carboxamide

3- {4- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1- prepared in Example 132 (132d) The title compound was synthesized by the reaction according to the method described in Example 5 (5c) using yl} phenyl} -N, N-dimethylpropanamide. Yield 62%.

Off-white powder

Mp 241-243 ° C .;

IR (KBr) ν _max 3445, 3328, 3173, 2941, 2840, 1637, 1578, 1518, 1368 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.06-2.16 (2H, m), 2.49-2.56 (2H, m), 2.63-2.70 (2H, m), 2.80 (3H, s), 2.93 (3H , s), 3.14-3.33 (4H, m), 3.48-3.54 (2H, m), 3.70-3.77 (2H, m), 6.67 (2H, d, J = 8.6 Hz), 6.93 (2H, br.s ), 7.02 (2H, d, J = 8.6 Hz), 7.05 (1H, d, J = 5.5 Hz), 7.06 (2H, br.s), 8.37 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 467 [M + H] ⁺ , 466, 394, 380;

analysis. Calc. For C ₂₄ H ₃₀ N ₆ 0 ₂ S.0.3H ₂ 0: C, 61.07; H, 6.53; N, 17.80; S, 6.79. Found: C, 61.02; H, 6. 42; N, 18.03; S, 6.74.

Example 133 3-amino-4- (4- {4- [2- (dimethylamino) ethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine 2-carboxamide (Example Compound No. 3-979)

(133a) N- {2- [4- (1,4-diazepane-1-yl) phenyl] ethyl} -N, N-dimethylamine

2- [4- (1,4-diazepane-1-yl) prepared in Example 131 (131b) to a suspension of tetrahydrofuran (5 mL) of lithium aluminum hydride (576 mg, 15.2 mmol) under ice cooling. A tetrahydrofuran (20 mL) solution of phenyl] -N, N-dimethylacetamide (1.32 g, 5.06 mmol) was slowly added dropwise. After completion of the dropwise addition, the reaction solution was stirred at room temperature for 1 hour, and then tetrahydrofuran (25 mL) was added. The reaction solution was ice-cooled, 1N aqueous sodium hydroxide solution (2880 µL) was carefully added, and stirred at room temperature for 30 minutes. Anhydrous sodium sulfate was then added, and the mixture was stirred for another 30 minutes at room temperature, and then the insolubles were removed by celite filtration. The insolubles were washed with tetrahydrofuran, and the solvent was distilled off under reduced pressure from the collected filtrate. Toluene was added to the residue and azeotropically under reduced pressure to obtain 1.16 g of the title compound (yield 92%).

Yellow oil

IR (film) ν _max 3315, 2938, 2858, 2818, 2778, 1616, 1520, 1461 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88 (2H, quint, J = 5.9 Hz), 2.28 (6H, s), 2.44-2.50 (2H, m), 2.63-2.69 (2H, m), 2.79- 2.84 (2H, m), 2.98-3.03 (2H, m), 3.48-3.57 (4H, m), 6.62 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz);

MS (EI) m / z: 247 M ^+,, 202, 189.

(133b) 3-amino-4- (4- {4- [2- (dimethylamino) ethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2 Carboxamide

N of N- {2- [4- (1,4-diazepane-1-yl) phenyl] ethyl} -N, N-dimethylamine (1.16 g, 4.68 mmol) prepared in Example 133 (133a), (2Z) -2-cyano-3-ethoxybute-2-enthioamide (J. Org. Chem., (1962), 27, 2433-2439) in N-dimethylformamide (9.36 mL) solution (797 mg, 4.68 mmol) was added and the mixture was stirred at room temperature for 15 minutes. Subsequently, N, N-dimethylformamide dimethylacetal (684 µL, 5.15 mmol) was added and stirred for 1 hour, followed by heating and stirring at 80 ° C for 30 minutes. After the reaction solution was allowed to cool to room temperature, 2-chloroacetamide (526 mg, 5.62 mmol) and 8N-sodium hydroxide aqueous solution (1.75 mL, 14.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (9.36 mL) and ethanol (4.68 mL) were added, followed by stirring for 30 minutes. The precipitated crystals were collected by filtration, washed with 50% aqueous ethanol solution and dried to give 297 mg of the title compound (yield 14%). Got it.

Yellow powder

Mp 200-203 ° C .;

IR (KBr) n _max 3442, 3328, 3164, 2939, 2824, 1650, 1578, 1518 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.05-2.23 (2H, m), 2.17 (6H, s), 2.34-2.41 (2H, m), 2.52-2.61 (2H, m), 3.13-3.35 (4H, m), 3.47-3.55 (2H, m), 3.70-3.77 (2H, m), 6.69 (2H, d, J = 8.6 Hz), 6.98 (2H, br.s), 7.02 (2H, d , J = 8.6 Hz), 7.07 (1H, d, J = 5.4 Hz), 7.09 (2H, br.s), 8.40 (2H, d, J = 5.4 Hz);

MS (FAB) m / z: 439 [M + H] ⁺ , 273, 258, 242;

analysis. Calc. For C ₂₃ H ₃₀ N ₆ OS: C, 62.99; H, 6.89; N, 19.16; S, 7.31. Found: C, 62.59; H, 6.91; N, 19.04; S, 7.07.

Example 134 4- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 3-142)

(134a) tert-butyl 4- (5-acetylpyridin2-yl) -1,4-diazepane-1-carboxylate

5-acetyl-2-bromopyridine (Chem. Ber., (1992), 1169-1190) (1.12 g, 5.6 mmol), tert-butyl1-homopiperazinecarboxylate (1.23 g, 6.2) and sodium carbonate (0.77 g, 7.3) of n-butanol (18 mL) suspension was stirred for 11 hours under reflux. The insolubles were removed by filtration, and the residue obtained by distilling off the solvent was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 1) to give 1.57 g (yield 88%) of the title compound.

Mp 120-122 ° C .;

IR (KBr) ν _max 1677, 1666, 1603, 1167 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.39 (4.5H, s), 1.43 (4.5H, s), 1.93-1.99 (2H, m), 2.49 (3H, s), 3.23-3.37 (2H, m) , 3.55-3.59 (2H, m), 3.66-3.74 (2H, m), 3.82-3.87 (2H, m), 6.51 (1H, d, J = 9.0 Hz), 8.00 (1H, dd, J = 2.4, 9.0 Hz), 8.73 (1H, doublet, J = 2.4 Hz);

MS (EI) m / z: 319 [M ⁺ ], 163, 57;

analysis. Calc. For C ₁₇ H ₂₅ N ₃ O ₃ : C, 63.93; H, 7.89; N, 13.16. Found: C, 63.74; H, 7.91; N, 13.08.

(134b) 1- [6- (1,4-diazepane-1-yl) pyridin-3-yl] ethanone

1,4-dioxane of tert-butyl 4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-carboxylate (1.55 g, 4.9) prepared in Example 134 (134a) 4N hydrochloric acid-1,4-dioxane solution (10 mL) was added to (25 mL) solution, and it stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and an aqueous 1N sodium hydroxide solution (20 mL) was added to the residue, and the aqueous layer was extracted with methylene chloride (2 x 50 mL). After drying the extract with sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.05 g (99%) of the title compound.

IR (neat) ν _max 3324, 1663, 1597, 1285, 957, 813 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.63 (1H, br), 1.87-1.93 (2H, m), 2.50 (3H, s), 2.84-2.87 (2H, m), 3.03-3.06 (2H, m) , 3.75-3.84 (4H, m), 6.52 (1H, d, J = 9.0 Hz), 8.01 (1H, dd, J = 2.0, 9.0 Hz), 8.76 (1H, d, J = 2.0 Hz);

MS (EI) m / z: 219 [M ⁺ ], 163, 149;

analysis. Calc. For C ₁₂ H ₁₇ N ₃ O.0.36H ₂ O: C, 63.84; H, 7.91; N, 18.61. Found: C, 64.04; H, 7.93; N, 18.25.

(134c) (2Z) -3- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide

Instead of isobutylamine, 1- [6- (1,4-diazepane-1-yl) pyridin-3-yl] ethanone prepared in Example 134 (134b) was used, and Example 5 (5a) was used. The reaction was carried out in the same manner as described to obtain the title compound. Yield 87%.

Mp 184-187 ° C. (decomposition);

IR (KBr) ν _max 3298, 3178, 2180, 1661, 1655, 1597, 1273 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.89-1.95 (2H, m), 2.24 (3H, s), 2.45 (3H, s), 3.59-4.03 (8H, m), 6.83 (1H, d, J = 9.0 Hz), 7.97 (1H, doublet of doublets, J = 2.0, 9.0 Hz), 8.41 (1H, br), 8.73 (1H, d, J = 2.0 Hz), 9.06 (1H, br);

MS (FAB) m / z: 344 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₁ N ₅ SO.0.16H ₂ O: C, 58.96; H, 6. 20; N, 20.22; S, 9.26. Found: C, 59.28; H, 6. 29; N, 19.89; S, 8.94.

(134d) 4- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- [4- (5-acetylpyridin-2-yl) -1,4-diazepan-1-yl] -2-cyanobuta-2-entioa prepared in Example 134 (134c) Mid (1.00 g, 3.4 mmol) and N, N-dimethylformamide dimethyl acetal (0.49 g, 0.54 mL, 4.1 mmol) were dissolved in N, N-dimethylformamide (10 mL) and stirred at room temperature for 1 hour. After reacting at 100 ° C. for 2 hours, the reaction mixture was concentrated under reduced pressure. 1N aqueous sodium hydroxide solution (10 mL) and ethyl acetate (50 mL) were added to the residue for separation. 1N hydrochloric acid (10 mL) was added to the aqueous layer, and it neutralized, and extracted with ethyl acetate (3 * 50 mL). The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue, and the precipitated solid was obtained by filtration, and the crude product (0.23 g) of the title compound was obtained by washing with ethanol.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.90-1.96 (2H, m), 2.44 (3H, s), 3.74-4.06 (8H, m), 6.45 (1H, d, J = 7.4 Hz), 6.84 (1H, d, J = 9.4 Hz), 7.35-7.38 (1H, m), 7.95 (1H, brd, J = 9.4 Hz), 8.41 (1H, br), 8.71 (1H, brs), 12.59 (1H, br).

(134e) 4- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide

4- [4- (5-acetylthien-2-yl) -1,4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine- prepared in Example 134 (134d)- The title compound was obtained by reacting according to the method described in Example 5 (5c) using a crude product of 3-carbonitrile. Yield 10% from (2Z) -3- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide.

Mp> 250 ° C .;

IR (KBr) ν _max 3442, 3329, 3170, 1647, 1596, 1277 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.12-2.20 (2H, m), 2.46 (3H, s), 3.17-3.35 (4H, m), 3.78-3.84 (2H, m), 4.04-4.13 ( 2H, m), 6.78 (1H, d, J = 9.0 Hz), 6.98 (2H, br), 7.05 (1H, d, J = 5.5 Hz), 7.09 (2H, br), 7.97 (1H, dd, J = 2.4, 9.0 Hz), 8.37 (1H, d, J = 5.5 Hz), 8.72 (1H, d, J = 2.4 Hz);

MS (FAB) m / z: 411 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₁ N ₅ SO.0.16H ₂ O: C, 58.96; H, 6. 20; N, 20.22; S, 9.26. Found: C, 59.28; H, 6. 29; N, 19.89; S, 8.94.

Example 135 4- [4- (5-acetylthiophen-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 3-1111)

(135a) 1- [5- (1,4-diazepane-1-yl) thiophen-2-yl] ethanone

2-acetyl-5-bromothiophene (1.03 g, 5 mmol) and homopiperazine (1.50 g, 15 mmol) were mixed in water (5 mL) and stirred under heating to reflux for 10 hours. 1N sodium hydroxide aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (2 x 30 mL). After drying the extract with sodium sulfate, the crude crystal obtained by distilling off the solvent under reduced pressure was recrystallized from ethyl acetate (30 mL) to obtain 0.80 g (71%) of the title compound.

Mp 130-132 ° C .;

IR (KBr) ν _max 3322, 1599, 1497, 1328, 788 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.77 (1H, br), 1.90-1.96 (2H, m), 2.40 (3H, s), 2.87-2.90 (2H, m), 3.04-3.07 (2H, m) , 3.53-3.62 (4H, m), 5.85 (1H, d, J = 4.3 Hz), 7.44 (1H, d, J = 4.3 Hz);

MS (EI) m / z: 224 [M ⁺ ], 182, 168;

analysis. Calc. For C ₁₁ H ₁₆ N ₂ SO.0.2H ₂ O: C, 57.97; H, 7. 25; N, 12.29; S, 14.07. Found: C, 58.09; H, 7. 31; N, 12.31; S, 13.86.

(135b) (2Z) -3- [4- (5-acetylthiophen-2-yl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enthioamide

Example 5 (5a), using 1- [5- (1,4-diazepane-1-yl) thiophen-2-yl] ethanone prepared in Example 135 (135a) instead of isobutylamine Reaction was performed similarly to the method as described in, to obtain the title compound. Yield 62%.

Mp 183-185 ° C .;

IR (KBr) ν _max 3331, 3288, 3171, 2186, 1601, 1536, 1493, 1440, 1100 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.95-2.02 (2H, m), 2.26 (3H, s), 2.31 (3H, s), 3.55-3.79 (8H, m), 6.13 (1H, d, J = 4.0 Hz), 7.65 (1H, d, J = 4.0 Hz), 8.48 (1H, br), 9.12 (1H, br);

MS (FAB) m / z: 349 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₂₀ N ₄ S ₂ O.0.1H ₂ O: C, 54.86; H, 5.81; N, 15.99; S, 18.31. Found: C, 54.75; H, 6.01; N, 15.76; S, 18.33.

(135c) 4- [4- (5-acetylthiophen-2-yl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- [4- (5-acetylthiophen-2-yl) -1,4-diazepan-1-yl] -2-cyanobuta-2-enty prepared in Example 135 (135b) Oamide (0.65 g, 1.9 mmol) and N, N-dimethylformamide dimethyl acetal (0.24 g, 0.27 mL, 2.1 mmol) were dissolved in N, N-dimethylformamide (6 mL) and stirred at room temperature for 1 hour. . After reacting at 100 ° C for 2 hours, the reaction mixture was cooled to room temperature. Ethyl acetate and water were added to the reaction mixture, and the precipitated solid was filtered out and washed with water and ethanol to obtain a crude product (0.11 g) of the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94-2.00 (2H, m), 2.28 (3H, s), 3.59-3.61 (2H, m), 3.73-3.75 (2H, m), 3.81-3.83 ( 2H, m), 4.01-4.04 (2H, m), 6.11 (1H, d, J = 4.7 Hz), 6.46 (1H, d, J = 7.4 Hz), 7.36-7.39 (1H, m), 7.59 (1H , d, J = 4.7 Hz).

(135d) 4- [4- (5-acetylthiophen-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carbox mid

4- [4- (5-acetylthiophen-2-yl) -1,4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine prepared in Example 135 (135c) Using the crude product of -3-carbonitrile, the reaction was carried out according to the method described in Example 5 (5c) to obtain the title compound. 10% yield from (2Z) -3- [4- (5-acetylthiophen-2-yl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide.

Mp 239-241 ° C .;

IR (KBr) ν _max 3439, 3326, 3188, 1646, 1580, 1486, 1448, 1093 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.17-2.23 (2H, m), 2.30 (3H, s), 3.18-3.24 (2H, m), 3.32-3.36 (2H, m), 3.56-3.60 ( 2H, m), 3.80-3.84 (2H, m), 6.07 (1H, d, J = 4.5 Hz), 6.99 (2H, br), 7.06 (1H, d, J = 5.5 Hz), 7.10 (2H, br ), 7.64 (1H, d, J = 4.5 Hz), 8.40 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 416 [M + H] ⁺ ;

analysis. Calc. For C ₁₉ H ₂₁ N ₅ S ₂ O ₂ .2.3H ₂ O: C, 49.94; H, 5.65; N, 15.33; S, 14.03. Found: C, 50.05; H, 5.40; N, 15.46; S, 13.83.

Example 136 3-amino-4- (4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl} -1,4-diazepan-1-yl) thier No [2,3-b] pyridine-2-carboxamide (example Compound No. 3-1116)

(136a) tert-butyl 4-[(benzoylamino) carbonothioyl] -1,4-diazepane-1-carboxylate

To a tetrahydrofuran (20 mL) solution of tert-butyl 1,4-diazepane-1-carboxylate (1.97 mL, 10 mmol) was added benzoylisothiocyanate (1.6 mL, 12 mmol) and stirred for 10 hours. The reaction solution was concentrated, and the obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 1: 1) to obtain the title compound (3.46 g, yield 95%).

Light red foam

IR (KBr) ν _max 3244, 2974, 1693, 1526, 1416, 1246, 1166, 709 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.48 (9H, s), 2.09-2.17 (2H, m), 3.48-3.63 (4H, m), 3.79-3.88 (2H, m), 4.10-4.17 (2H m), 7.49-7.51 (2H, m), 7.58-7.60 (1H, m), 7.84 (2H, d, J = 7.8 Hz), 8.26-8.29 (1H, m);

HRMS m / z calc. C ₁₈ H ₂₅ 0 ₃ N ₃ SNa 386.1514, found 386.1508;

MS (FAB) m / z: 364 [M + H] ⁺ , 348, 332, 308, 274, 264, 246, 230, 214, 187, 165, 105, 93, 89, 77, 65, 57.

(136b) tert-butyl 4- (aminocarbonothioyl) -1,4-diazepane-1-carboxylate

To a methanol (50 mL) solution of tert-butyl 4-[(benzoylamino) carbonothioyl] -1,4-diazepane-1-carboxylate (3.46 g, 9.5 mmol) prepared in Example (136a) Sodium methylate (4.9 M methanol solution) (2.1 mL, 10.5 mmol) was added and heated to reflux for 2 days. The reaction solution was concentrated, and the obtained residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound (2.52 g, yield 93%).

White foam

IR (KBr) ν _max 3370, 3199, 2976, 1681, 1641, 1492, 1420, 1365, 1168 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.47 (9H, s), 1.96-1.99 (2H, m), 3.38-3.44 (2H, m), 3.57-3.61 (6H, m), 5.71 (2H, brs );

HRMS m / z calc'd C ₁₁ H ₂₁ O ₂ N ₃ SNa 282.1252, found 282.1228;

MS (ESI) m / z: 282 [M + Na] ⁺ , 260;

analysis. Calc. For C ₁₁ H ₂₁ N ₃ O ₂ S: C, 50.94; H, 8. 16; N, 16.20; S, 12.36. Found: C, 51.01; H, 8. 18; N, 16.02, S, 12.21.

(136c) tert-butyl 4- [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] -1,4-diazepane-1-carboxylate

Triethylamine in an ethanol (20 mL) solution of tert-butyl 4- (aminocarbonothioyl) -1,4-diazepane-1-carboxylate (2.04 g, 7.9 mmol) prepared in Example (136b) (2.2 mL, 15.8 mmol) and ethyl bromopyruvate (2.0 mL, 15.8 mmol) were added and refluxed for 30 minutes. The reaction solution was concentrated, and the obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate-2: 1) to obtain the title compound (2.80 g, 99% yield).

Pale yellow liquid

IR (film) ν _max 2978, 1695, 1550, 1416, 1368, 1212, 1168 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.36 (3H, t, J = 7.3 Hz), 1.43 (4.5H, s), 1.44 (4.5H, s), 2.01 (2H, quint, J = 5.9 Hz ), 3.35 (1H, t, J = 5.9 Hz), 3.43 (1H, t, J = 4.4 Hz), 3.61-3.77 (6H, m), 4.34 (2H, q, J = 7.3 Hz), 7.38 (1H) , s);

MS (FAB) m / z: 356 [M + H] ⁺ , 273, 242, 226, 165, 65.

(136d) tert-butyl 4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl] -1,4-diazepane-1-carboxylate

Trimethylaluminum (2.0 M toluene solution, 7.9 mL, 15.8 mmol) was added dropwise to a toluene (16 mL) solution of dimethylamine hydrochloride (1.28 g, 15.8 mmol) under stirring for 2 hours. Tert-butyl 4- [4- (ethoxycarbonyl) -1,3-thiazol-2-yl] -1,4-diazepane-1-carboxylate prepared in Example (136c) (2.80 g , 7.9 mmol) was added dropwise to the toluene (80 mL) solution and heated to reflux for 50 minutes. An ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the mixture was filtered through Celite. The obtained filtrate was extracted twice with ethyl acetate (50 mL) and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 1: 1) to obtain the title compound (1.69 g, yield 60%).

Pale yellow liquid

IR (film) ν _max 3492, 2932, 1693, 1626, 1546, 1414, 1169 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.44 (9H, s), 2.00 (2H, quint, J = 5.9 Hz), 3.06 (3H, brs), 3.24 (3H, brs), 3.33 (1H, t, J = 5.9 Hz), 3.42 (1H, t, J = 5.9 Hz), 3.57-3.68 (6H, m), 7.02 (1H, s);

MS (FAB) m / z: 355 [M + H] &lt; ⁺ &gt;, 255, 242, 210, 57.

(136e) 2- (1,4-diazepane-1-yl) -N, N-dimethyl-1,3-thiazole-4-carboxamide

Tert-butyl 4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl} -1,4-diazepane-1-carboxylate prepared in Example 136 (136d) Using the reaction method, the reaction was carried out according to the method described in Example 57 (57b) to obtain the title compound.

Pale yellow liquid

IR (film) ν _max 3442, 2936, 1618, 1548, 1453, 1398, 1319, 1175, 719 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93 (2H, quint, J = 5.9 Hz), 2.90 (2H, t, J = 5.9 Hz), 3.04-3.06 (5H, m), 3.25 (3H, brs) , 3.65-3.69 (4H, m), 6.99 (1H, s);

MS (EI) m / z: 254 [M ⁺ ], 211, 198, 185, 172, 167, 139, 128, 112, 83, 70, 56, 44.

(136f) 2- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1-yl] -N, N-dimethyl- 1,3-thiazole-4-carboxamide

Example 118 was prepared using 2- (1,4-diazepane-1-yl) -N, N-dimethyl-1,3-thiazole-4-carboxamide prepared in Example 136 (136e). The reaction was carried out according to the method described in 118c) to synthesize the title compound.

Brown foam

IR (KBr) ν _max 2929, 1621, 1543, 1236, 1174, 1141, 922, 777 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.17 (2H, quint, J = 5.4 Hz), 3.07 (3H, brs), 3.21 (3H, brs), 3.67 (2H, t, J = 6.3 Hz) , 3.86 (2H, t, J = 5.9 Hz), 3.96 (2H, t, J = 5.4 Hz), 4.14 (2H, t, J = 4.9 Hz), 6.25 (1H, d, J = 7.8 Hz), 7.05 (1 H, s), 7.33 (1 H, d, J = 7.8 Hz), 12.35 (1 H, brs);

MS (FAB) m / z: 389 [M + H] ⁺ , 273, 242, 226, 1665, 65.

(136g) 3-amino-4- (4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl} -1,4-diazepan-1-yl) thieno [ 2,3-b] pyridine-2-carboxamide

2- [4- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1-yl] prepared in Example 136 (136f)- The reaction was carried out according to the method described in Example 5 (5c) using N, N-dimethyl-1,3-thiazole-4-carboxamide to synthesize the title compound.

White powder

Mp 285-287 ° C. (decomposition);

IR (KBr) ν _max 3441, 3326, 3165, 1669, 1603, 1532, 1370, 1174, 922, 664, 628 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.20-2.22 (2H, m), 2.93 (3H, brs), 3.12 (3H, brs), 3.24 (2H, brs), 3.38 (2H, brs), 3.65 (2H, t, J = 6.3 Hz), 3.94-3.96 (2H, m), 7.03 (2H, brs), 7.08-7.10 (2H, m), 7.12 (2H, brs), 8.42 (1H, d, J = 5.5 Hz);

HRMS m / z calc'd C ₁₉ H ₂₄ O ₂ N ₇ S ₂ 446.1433, found 446.1409;

MS (ESI) m / z: 446 [M + H] ⁺ , 429;

analysis. Calc. For C ₁₉ H ₂₃ N ₇ O ₂ S ₂ .0.6H ₂ O: C, 50.00; H, 5. 34; N, 21.48. Found: C, 50.01; H, 5. 38; N, 21.37.

Example 137 4- [4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepan-1-yl] -3-aminothieno [2,3-b ] Pyridine-2-carboxamide (Example Compound No. 3-1110)

(137a) tert-butyl 4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepane-1-carboxylate

Tert-butyl 4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl} -1,4-diazepane-1-carboxylate prepared in Example 136 (136d) Methylmagnesium chloride (3M tetrahydrofuran solution) (1.2 mL, 3.6 mmol) was dripped at (1.05 g, 3.0 mmol) tetrahydrofuran (25 mL) solution, and it stirred for 3 hours. Aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, followed by extraction twice with ethyl acetate (50 mL), dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 1: 1) to obtain the title compound (0.66 g, yield 69%).

Colorless liquid

IR (film) ν _max 2975, 1687, 1549, 1416, 1167, 927, 606 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.43 (4.5H, s), 1.44 (4.5H, s), 2.01 (2H, quint, J = 6.4 Hz), 2.53 (3H, s), 3.35 (1H, t, J = 5.9 Hz), 3.43 (1H, t, J = 4.9 Hz), 3.63-3.71 (6H, m), 7.35 (1H, s);

MS (FAB) m / z: 326 [M + H] ⁺ , 270, 252, 224, 169, 57.

(137b) 1- [2- (1,4-diazepane-1-yl) -1,3-thiazol-4-yl] ethanone

Example 57 using tert-butyl 4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepane-1-carboxylate prepared in Example 137 (137a) Reaction was performed in accordance with the method described in (57b) to obtain the title compound.

Yellow liquid

IR (film) ν _max 3329, 2938, 1679, 1550, 1355, 1211, 915, 695, 605 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.94 (2H, quint, J = 4.9 Hz), 2.54 (3H, s), 2.92 (2H, t, J = 5.5 Hz), 3.07 (2H, t, J = 5.5 Hz), 3.69-3.73 (4H, m), 7.34 (1H, s);

MS (EI) m / z: 225 [M ⁺ ], 210, 197, 183, 169, 155, 141, 128, 83, 70, 56, 43.

(137c) 4- [4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine- 3-carbonitrile

Example 121 (121c) using 1- [2- (1,4-diazepane-1-yl) -1,3-thiazol-4-yl] ethanone prepared in Example 137 (137b) The reaction was carried out according to the method described in Synthesis of the title compound.

Brown solid

IR (KBr) ν _max 3097, 2959, 2204, 1672, 1623, 1545, 1354, 1242, 1143, 924, 776, 604 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.96-2.01 (2H, m), 2.42 (3H, s), 3.68 (2H, t, J = 5.9 Hz), 3.84-3.88 (4H, m), 4.09 (2H, t, J = 5.4 Hz), 6.47 (1H, d, J = 7.8 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.64 (1H, s), 12.54 (1H, brs);

MS (FAB) m / z: 360 [M + H] ⁺ , 344, 328, 273, 242, 226, 165, 65;

analysis. Calc. For C ₁₆ H ₁₇ N ₅ OS ₂ .0.33H ₂ O: C, 52.58; H, 4.87; N, 19.16; S, 17.55. Found: C, 52.38; H, 4.68; N, 19.37; S, 17.48.

(137d) 4- [4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine 2-carboxamide

4- [4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepan-1-yl] -2-thioxo-1, prepared in Example 137 (137c), The reaction was carried out according to the method described in Example 5 (5c) using 2-dihydropyridine-3-carbonitrile to synthesize the title compound.

Pale yellow powder

Mp 217-219 ° C .;

IR (KBr) ν _max 3427, 3318, 3172, 1673, 1581, 1543, 1365, 1211, 937, 602 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.19-2.24 (2H, m), 2.45 (3H, s), 3.23 (2H, brs), 3.39 (2H, brs), 3.67 (2H, t, J = 5.9 Hz), 3.97 (2H, brs), 7.01 (2H, brs), 7.08 (1H, d, J = 5.5 Hz), 7.11 (2H, brs), 7.66 (1H, s), 8.04 (1H, d , J = 5.5 Hz);

HRMS m / z calc. For C ₁₈ H ₂₁ O ₂ N ₆ S ₂ 417.1167, found 417.1173;

MS (ESI) m / z: 417 [M + H] ⁺ , 400;

analysis. Calc. For C ₁₈ H ₂₀ N ₆ O ₂ S ₂ .0.33H ₂ O: C, 51.17; H, 4.93; N, 19.89; S, 15.18. Found: C, 51.18; H, 4. 85; N, 20.16; S, 14.83.

Example 138 3-amino-4- [4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepan-1-yl ] Thieno [2,3-b] pyridine-2-carboxamide (example compound number 3-1098)

(138a) ethyl 4-bromo-2-methylbenzoate

4N hydrochloric acid-1,4-dioxane solution was added to the ethanol solution of 4-bromo-2-methyl- benzoic acid (4.30g, 20.0mmol), and it stirred at 80 degreeC for 9 hours. The reaction solution was concentrated, methylene chloride (200 mL) was added to the obtained residue, the mixture was washed with 1N aqueous sodium hydroxide solution (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to give the result. The target compound (4.54 g, yield 93%) was obtained.

Yellow liquid

IR (film) ν _max 2981, 1722, 1589, 1445, 1253, 1082, 863, 771 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.38 (3H, t, J = 7.8 Hz), 2.57 (3H, s), 4.34 (2H, q, J = 7.8 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.40 (1 H, s), 7.77 (1 H, d, J = 8.2 Hz);

MS (EI) m / z: 242 [M ⁺ ], 199, 197, 171, 169, 163, 90, 63.

(138b) ethyl 4-bromo-2- (bromomethyl) benzoate

N-bromosuccinimide (3.62 g, 20.0 mmol), 2, in a carbon tetrachloride (90 mL) solution of ethyl 4-bromo-2-methylbenzoate (4.50 g, 18.5 mmol) prepared in Example 138 (138a) , 2'-azobis (isobutyronitrile) (608 mg, 3.70 mmol) was added sequentially, and it stirred at 90 degreeC for 3 hours. The reaction solution was concentrated and hexane was added to the obtained residue and filtered. The filtrate was concentrated to obtain crude title compound (5.90 g, yield 99%).

Yellow liquid

(138c) 5-bromo-2-methylisoindolin-1-one

2M methylaminemethanol solution was added to ethyl 4-bromo-2- (bromomethyl) benzoate (5.62 g, 17.5 mmol) prepared in Example 138 (138b), followed by stirring at 70 ° C. for 23 hours. The reaction solution was concentrated, and the obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 1: 2 to 1: 4) to obtain the title compound (2.70 g, yield 68%).

White powder

Mp 132-134 ° C .;

IR (KBr) ν _max 2914, 1680, 1400, 1275, 1043, 769 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 3.19 (3H, s), 4.36 (2H, s), 7.58-7.63 (2H, m), 7.70 (1H, d, J = 8.6 Hz);

MS (EI) m / z: 225 [M ⁺ ], 199, 198, 197, 196, 171, 169, 146, 112, 98, 89, 75, 59;

analysis. Calc. For C ₉ H ₈ BrNO: C, 47.82; H, 3.57; N, 6.20. Found: C, 47.80; H, 3.59; N, 6.22.

(138d) benzyl 4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepane-1-carboxylate

Reaction was carried out according to the method described in Example 117 (117a) using 5-bromo-2-methylisoindolin-1-one and benzyl1-homopiperazinecarboxylate prepared in Example 138 (138c). It carried out and obtained the title object compound.

Pale yellow liquid

IR (film) ν _max 3451, 2947, 1679, 1479, 1239, 1120, 927, 754 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93-2.05 (2H, m), 3.14 (3H, s), 3.33 (1H, t, J = 5.9 Hz), 3.41 (1H, t, J = 5.9 Hz) , 3.58-3.70 (6H, m), 4.21 (1H, s), 4.26 (1H, m), 5.05 (1H, s), 5.13 (1H, s), 6.64 (1H, m), 6.73 (1H, m ), 7.26-7.86 (5H, m), 7.65 (1H, m);

MS (FAB) m / z: 380 [M + H ⁺ ], 379, 353, 273, 246, 244.

(138e) 5- (1,4-diazepane-1-yl) -2-methylisoindolin-1-one

Benzyl 4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepane-1-carboxylate prepared in Example 138 (138d) The hydrolysis reaction was carried out in accordance with the method described in Example 128 (128d), to obtain the title compound.

Yellow liquid

IR (film) ν _max 3421, 1658, 1480, 1399, 1250, 1111, 768 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.85-1.96 (2H, m), 2.83 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.5 Hz), 3.14 (3H, s) , 3.60 (2H, t, J = 5.5 Hz), 3.64 (2H, t, J = 5.9 Hz), 4.27 (2H, s), 6.65 (1H, s), 6.74 (1H, d, J = 8.6 Hz) , 7.64 (1H, doublet, J = 8.6 Hz);

MS (EI) m / z: 245 [M ⁺ ], 203, 189, 177, 146, 83, 70.

(138f) 4- [4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepan-1-yl] -2-thioxo -1,2-dihydropyridine-3-carbonitrile

Reaction was carried out according to the method described in Example 121 (121c), using 5- (1,4-diazepan-1-yl) -2-methylisoindolin-1-one prepared in Example 138 (138e) Was carried out to synthesize the title compound.

Brown powder

Mp 257-265 ° C .;

IR (KBr) ν _max 2950, 2203, 1660, 1615, 1522, 1246, 926, 767 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.93-2.00 (2H, m), 3.31 (3H, s), 3.62 (2H, t, J = 5.9 Hz), 3.75 (2H, t, J = 5.9 Hz), 3.82 (2H, t, J = 5.4 Hz), 4.00 (2H, t, J = 5.4 Hz), 4.31 (2H, s), 6.44 (1H, d, J = 7.8 Hz), 6.86 (1H, d, J = 8.8 Hz), 6.92 (1H, s), 7.36 (1H, d, J = 7.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 12.55 (1H, brs);

MS (FAB) m / z: 380 [M + H ⁺ ], 273, 257, 238, 165, 85, 63;

analysis. Calc. For C ₂₀ H ₂₁ N ₅ OS. 1.75 H ₂ O: C, 58.45; H, 6.01; N, 17.04. Found: C, 58.21; H, 5. 66; N, 16.82.

(138g) 3-amino-4- [4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepan-1-yl] thier No [2,3-b] pyridine-2-carboxamide

4- [4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepan-1-yl prepared in Example 138 (138f) ] -2-thioxo-1,2-dihydropyridine-3-carbonitrile was used, and reaction was carried out according to the method described in Example 5 (5c) to synthesize the title compound.

Pale yellow powder

Mp 293-295 ° C .;

IR (KBr) ν _max 3442, 3324, 3171, 2918, 1653, 1503, 1366, 1235, 1110, 767 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.13-2.24 (2H, m), 3.00 (3H, s), 3.14-3.24 (2H, m), 3.28-3.33 (2H, m), 3.63 (2H , t, J = 6.4 Hz), 3.85 (2H, t, J = 4.4 Hz), 4.32 (2H, s), 6.86 (1H, d, J = 8.8 Hz), 6.90 (1H, s), 7.01 (2H , brs), 7.07 (1H, d, J = 5.4 Hz), 7.11 (2H, brs), 7.44 (1H, d, J = 8.8 Hz), 8.40 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 437 [M + H ⁺ ], 420, 273, 246, 165, 93, 63;

analysis. Calc. For C ₂₂ H ₂₄ N ₆ O ₂ S.0.67H ₂ O: C, 58.91; H, 5.69; N, 18.74. Found: C, 58.83; H, 5.65; N, 18.74.

Example 139 3-amino-4- [4- (1,3-benzoxazol-6-yl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2 Carboxamide (Example Compound No. 3-1099)

(139a) tert-butyl 4- (3-hydroxy-4-nitrophenyl) -1,4-diazepane-1-carboxylate

Reaction was performed according to the method described in Example 59 (59a) using 5-fluoro-2-nitrophenol and tert-butyl1-homopiperazinecarboxylate, to obtain the title compound.

Yellow powder

Mp 106-109 ° C .;

IR (KBr) ν _max 3431, 2973, 1690, 1625, 1566, 1415, 1325, 1262, 1166, 927, 754 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.39 (4.5H, s), 1.43 (4.5H, s), 1.95-1.99 (2H, m), 3.27 (1H, t, J = 5.9 Hz), 3.37 ( 1H, t, J = 5.9 Hz), 3.57-3.68 (6H, m), 6.18 (1H, brs), 6.31 (1H, brd, J = 9.3 Hz), 7.95 (1H, d, J = 9.3 Hz), 11.31 (1 H, broad singlet);

MS (EI) m / z: 337 [M ⁺ ], 280, 264, 236, 220, 193, 181, 70, 57;

analysis. Calc. For C ₁₆ H ₂₃ N ₃ O ₅ : C, 56.96; H, 6.87; N, 12.46. Found: C, 56.97; H, 6. 85; N, 12.39.

(139b) tert-butyl 4- (1,3-benzoxazol-6-yl) -1,4-diazepane-1-carboxylate

Ethanol (80 mL) of tert-butyl 4- (3-hydroxy-4-nitrophenyl) -1,4-diazepane-1-carboxylate (5.20 g, 15.4 mmol) prepared in Example 139 (139a) Trimethyl ortho formate (80 mL) and 10% palladium-carbon (5.2 g) were sequentially added to the solution, followed by stirring at room temperature under atmospheric pressure hydrogen atmosphere for 5 hours, followed by stirring at 90 ° C for 17 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 2: 1 to 1: 1) to obtain the title compound (611 mg, yield 13%).

Yellow liquid

IR (film) ν _max 2974, 1688, 1630, 1500, 1416, 1246, 1168, 1057, 929 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.32 (4.5H, s), 1.42 (4.5H, s), 1.96-2.04 (2H, m), 3.21 (1H, t, J = 5.9 Hz), 3.33 ( 1H, t, J = 5.9 Hz), 3.57-3.65 (6H, m), 6.77 (1H, dd, J = 2.0, 8.8 Hz), 6.82 (1H, brs), 7.57 (1H, d, J = 8.8 Hz ), 7.87 (1 H, s);

MS (FAB) m / z: 317 [M ⁺ ], 262, 242, 216, 165, 63.

(139c) 6- (1,4-diazepane-1-yl) -1,3-benzoxazole

Methylene chloride of tert-butyl 4- (1,3-benzoxazol 6-yl) -1,4-diazepan-1-carboxylate (534 mg, 1.68 mmol) prepared in Example 139 (139b) 10 mL) solution was cooled to 0 ° C, 2,6-lutidine (0.5 mL, 4.30 mmol) and trimethylsilyl trifluoromethanesulfonic acid (0.5 mL, 2.76 mmol) were added sequentially and stirred at 0 ° C for 1 hour. . The reaction solution was concentrated, and the obtained residue was purified using silica gel column chromatography (methylene chloride / methanol = 1: 0 to 20: 1) to obtain the title compound (267 mg, yield 73%).

Yellow liquid

IR (film) ν _max 3396, 2932, 1624, 1510, 1358, 1176, 925 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.91-1.97 (2H, m), 2.84 (2H, t, J = 5.9 Hz), 3.07 (2H, t, J = 5.4 Hz), 3.60 (2H, t, J = 5.4 Hz), 3.64 (2H, t, J = 6.3 Hz), 6.77 (1H, dd, J = 2.0, 8.6 Hz), 6.82 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.87 (1 H, s);

MS (FAB) m / z: 218 [M + H ⁺ ], 161, 63.

(139d) (2Z) -3- [4- (1,3-benzoxazol-6-yl) -1,4-diazepane-1-yl] -2-cyanobuta-2-enthioamide

Instead of isobutylamine, the method described in Example 5 (5a) was used, using 6- (1,4-diazepan-1-yl) -1,3-benzoxazole manufactured in Example 139 (139c). Thus, the reaction was carried out to obtain the title compound.

Yellow powder

Mp 177-180 ° C .;

IR (KBr) ν _max 3288, 3170, 2182, 1627, 1517, 1442, 1358, 1289, 1208, 1060, 876, 801 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.95-2.01 (2H, m), 2.24 (3H, s), 3.53 (2H, t, J = 5.4 Hz), 3.62 (2H, t, J = 5.9 Hz), 3.66 (2H, t, J = 5.4 Hz), 3.81 (2H, t, J = 5.9 Hz), 6.88 (1H, dd, J = 2.0, 8.8 Hz), 7.11 (1H, d, J = 2.0 Hz), 7.54 (1H, d, J = 8.8 Hz), 8.37 (1H, brs), 8.41 (1H, s), 9.02 (1H, brs);

MS (FAB) m / z: 342 [M + H ⁺ ], 326, 273, 258, 242, 226, 180, 165, 63;

analysis. Calc. For C ₁₇ H ₁₉ N ₅ OS.0.30H ₂ O: C, 58.91; H, 5.69; N, 20.21. Found: C, 59.26; H, 5.56; N, 19.92.

(139e) 4- [4- (1,3-benzoxazol-6-yl) -1,4-diazepane-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -3- [4- (1,3-benzoxazol-6-yl) -1,4-diazepan-1-yl] -2-cyanobuta-2- prepared in Example 139 (139d) Using enthioamide, the reaction was carried out according to the method described in Example 116 (116d) to synthesize the title compound.

Brown powder

Mp 245-250 ° C .;

IR (KBr) ν _max 3119, 2955, 2204, 1625, 1517, 1354, 1252, 1062, 928, 803 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94-2.02 (2H, m), 3.61 (2H, t, J = 5.9 Hz), 3.73 (2H, t, J = 5.5 Hz), 3.81 (2H, m), 4.00 (2H, t, J = 5.5 Hz), 6.44 (1H, d, J = 7.8 Hz), 6.89 (1H, d, J = 8.6 Hz), 7.13 (1H, brs), 7.36 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.6 Hz), 8.41 (1H, s), 12.53 (1H, brs);

MS (FAB) m / z: 352 [M + H ⁺ ], 273, 258, 242, 226, 165, 83, 63;

analysis. Calc. For C ₁₈ H ₁₇ N ₅ OS.0.56H ₂ O: C, 59.82; H, 5.05; N, 19.38. Found: C, 59.49; H, 4.76; N, 19.86.

(139f) 3-amino-4- [4- (1,3-benzoxazol-6-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-car Copy mid

Example 139 (139e) 4- [4- (1,3-benzoxazol-6-yl) -1,4-diazepan-1-yl] -2-thioxo-1,2-dihydropyridine-3 Using the carbonitrile, the reaction was carried out according to the method described in Example 5 (5c) to synthesize the title compound.

Pale yellow powder

Mp 159-162 ° C .;

IR (KBr) ν _max 3441, 3323, 2948, 1643, 1580, 1500, 1455, 1368, 1204, 1058, 942, 803 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.14-2.22 (2H, m), 3.16-3.23 (2H, m), 3.29-3.36 (2H, m), 3.62 (2H, t, J = 5.9 Hz ), 3.84 (2H, t, J = 4.4 Hz), 6.89 (1H, dd, J = 2.4, 8.8 Hz), 7.00 (2H, brs), 7.06-7.09 (4H, m), 7.55 (1H, t, J = 8.8 Hz), 8.40 (1H, d, J = 5.4 Hz), 8.41 (1H, s);

MS (FAB) m / z: 409 [M + H ⁺ ], 273, 258, 242, 226, 213, 180, 165, 63;

analysis. Calc. For C ₂₀ H ₂₀ N ₆ O ₂ S.0.40H ₂ O: C, 57.79; H, 5.04; N, 20.22. Found: C, 57.69; H, 4.79; N, 20.40.

Example 140 3-amino-4- [4- (4-hydroxyimino-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] thier No [2,3-b] pyridine-2-carboxamide (example compound number 3-1100)

(140a) benzyl 4- (4-acetyl-3-hydroxyphenyl) -1,4-diazepane-1-carboxylate

The reaction was carried out according to the method described in Example 59 (59a) using 4'-fluoro-2'-hydroxyacetophenone and benzyl 1-homopiperazinecarboxylate, to obtain the title compound.

Yellow liquid

IR (film) ν _max 2948, 1699, 1631, 1521, 1424, 1370, 1331, 1232, 928, 754 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93-2.02 (2H, m), 2.49 (3H, s), 3.33 (1H, t, J = 6.3 Hz), 3.40 (1H, t, J = 5.9 Hz) , 3.56-3.64 (6H, m), 5.10 (1H, s), 5.14 (1H, s), 6.11-6.12 (1H, m), 6.20-6.23 (1H, m), 7.30-7.36 (5H, m) , 7.52 (0.5H, d, J = 8.8 Hz), 7.54 (0.5H, d, J = 8.8 Hz), 12.85 (0.5H, s), 12.86 (0.5H, s);

MS (FAB) m / z: 369 [M + H] ⁺ , 353, 327, 273, 242, 226, 165, 65.

(140b) benzyl 4- {4-[(2E) -3- (dimethylamino) prope-2-noyl] -3-hydroxyphenyl} -1,4-diazepane-1-carboxylate

N, N-dimethylform of benzyl 4- (4-acetyl-3-hydroxyphenyl) -1,4-diazepane-1-carboxylate (3.64 g, 9.9 mmol) prepared in Example 140 (140a) The amide dimethylacetal (13 mL, 99 mmol) solution was stirred at 100 ° C. for 2 hours. Ethyl acetate (100 mL) was added to the reaction solution, the organic layer was washed twice with water (100 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (100% ethyl acetate) to obtain the title compound (3.67 g, yield 88%).

Yellow foam

IR (KBr) ν _max 2936, 1698, 1622, 1545, 1361, 1241, 1115 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.95-2.03 (2H, m), 2.84-3.12 (6H, m), 3.31 (1H, t, J = 6.4 Hz), 3.38 (1H, t, J = 5.9 Hz), 3.54-3.64 (6H, m), 5.10 (1H, s), 5.14 (1H, s), 5.65 (1H, d, J = 12.2 Hz), 6.14-6.17 (2H, m), 7.30-7.36 (5H, m), 7.53-7.55 (1H, m), 7.79 (1H, d, J = 12.2 Hz);

MS (FAB) m / z: 424 [M + H] ⁺ , 353, 273, 242, 226, 165, 65;

analysis. Calc. For C ₂₄ H ₂₉ N ₃ 0 ₄ .0.5H ₂ 0: C, 66.65; H, 6. 99; N, 9.72. Found: C, 66.52; H, 6. 64; N, 9.46.

(140c) benzyl 4- (4-oxo-4H-chromen-7-yl) -1,4-diazepane-1-carboxylate

Benzyl 4- {4-[(2E) -3- (dimethylamino) prope-2-noyl] -3-hydroxyphenyl} -1,4-diazepane-1-produced in Example 140 (140b) 80% acetic acid aqueous solution (10 mL) of carboxylate (3.67 g, 8.7 mmol) was stirred at 100 ° C for 2 hours. Ethyl acetate (100 mL) was added to the reaction solution, the organic layer was washed with water (100 mL) and aqueous sodium hydrogen carbonate solution (100 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (ethyl acetate / methanol = 20: 1) to obtain the title compound (3.19 g, yield 97%).

Yellow liquid

IR (film) ν _max 2951, 1697, 1626, 1588, 1446, 1411, 1230, 928, 754 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.95-2.04 (2H, m), 3.55 (1H, t, J = 6.3 Hz), 3.43 (1H, t, J = 6.4 Hz), 3.61-3.69 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.20 (1H, d, J = 6.4 Hz), 6.48-6.50 (1H, m), 6.73-6.77 (1H, m), 7.28-7.33 (5H, m), 7.68 (1H, d, J = 6.4 Hz), 8.00-8.03 (1H, m);

MS (FAB) m / z: 379 [M + H] ⁺ , 353, 273, 243, 226, 165, 91, 65;

analysis. Calc. For C ₂₂ H ₂₂ N ₂ O ₄ .0.5H ₂ O: C, 68.20; H, 5.98; N, 7.23. Found: C, 68.41; H, 5.89; N, 7.15.

(140d) 7- (1,4-diazepan-1-yl) -2,3-dihydro-4H-chromen-4-one

Benzyl 4- (4-oxo-4H-chromen-7-yl) -1,4-diazepane-1-carboxylate (1.98 g, 5.2 mmol) prepared in Example 140 (140c) was subjected to atmospheric hydrogen. Under hydrogen, hydrocracking was carried out for 6 hours in ethanol (50 mL) solvent in the presence of a 10% palladium-carbon catalyst (2.23 g, 1.0 mmol). The catalyst was removed from the reaction solution, and the solvent was evaporated under reduced pressure to obtain the title compound (1.07 g, yield 84%).

Orange liquid

IR (film) ν _max 3322, 2934, 1663, 1601, 1406, 1143, 824 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.89 (2H, quint, J = 5.9 Hz), 2.70 (2H, t, J = 6.4 Hz), 2.83 (2H, t, J = 5.4 Hz), 3.02 (2H , t, J = 5.4 Hz), 3.57 (2H, t, J = 5.4 Hz), 3.62 (2H, t, J = 5.9 Hz), 4.47 (2H, t, J = 6.8 Hz), 6.10 (1H, d , J = 2.4 Hz), 6.39 (1H, dd, J = 2.4, 8.8 Hz), 7.77 (1H, d, J = 8.8 Hz);

MS (EI) m / z: 246 [M ⁺ ], 204, 190, 178, 176, 162, 123, 119, 69, 56, 44, 43.

(140e) 4- [4- (4-oxo-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] -2- thixo-1,2 -Dihydropyridine-3-carbonitrile

In Example 121 (121c), 7- (1,4-diazepan-1-yl) -2,3-dihydro-4H-chromen-4-one prepared in Example 140 (140d) was used. The reaction was carried out according to the described method to synthesize the title compound.

Brown solid

Mp 190-201 ° C. (decomposition);

IR (KBr) ν _max 2957, 2207, 1602, 1516, 1405, 1253, 1141, 926 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.88-1.93 (2H, m), 2.59 (2H, t, J = 5.9 Hz), 3.60 (2H, t, J = 5.5 Hz), 3.75 (2H, t, J = 5.9 Hz), 3.81 (2H, t, J = 5.1 Hz), 3.92-3.95 (2H, m), 4.41 (2H, t, J = 5.9 Hz), 6.24 (1H, d, J = 2.4 Hz), 6.43 (1H, d, J = 7.4 Hz), 6.53 (1H, dd, J = 2.0, 9.0 Hz), 7.36 (1H, d, J = 7.4 Hz), 7.53 (1H, d, J = 9.0 Hz), 12.55 (1H, broad singlet);

MS (FAB) m / z: 381 [M + H] ⁺ , 273, 258, 242, 226, 216, 165, 63, 52.

(140f) 4- [4- (4-hydroxyimino-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] -2-thioxo-1 , 2-dihydropyridine-3-carbonitrile

4- [4- (4-oxo-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] -2- prepared in Example 140 (140e) -2- The title compound was obtained in the same manner as the method described in Example 120 using thioxo-1,2-dihydropyridine-3-carbonitrile.

Brown solid

Mp> 290 ° C .;

IR (KBr) ν _max 2948, 2210, 1625, 1552, 1520, 1256, 1144, 1063, 776 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.90-1.93 (2H, m), 2.74 (2H, t, J = 5.9 Hz), 3.53 (2H, t, J = 5.9 Hz), 3.74 (4H, brs), 3.92-3.94 (2H, m), 4.41 (2H, t, J = 5.9 Hz), 6.21 (1H, d, J = 2.4 Hz), 6.44 (1H, d, J = 7.8 Hz), 6.47 ( 1H, dd, J = 2.4, 8.8 Hz), 7.38 (1H, d, J = 7.8 Hz), 7.56 (1H, d, J = 8.8 Hz), 10.68 (1H, s);

MS (FAB) m / z: 396 [M + H] ⁺ , 378, 273, 242, 226, 65.

(140g) 3-amino-4- [4- (4-hydroxyimino-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] thieno [ 2,3-b] pyridine-2-carboxamide

4- [4- (4-hydroxyimino-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] prepared in Example 140 (140f)- The reaction was carried out according to the method described in Example 5 (5c) using 2-thioxo-1,2-dihydropyridine-3-carbonitrile to synthesize the title compound.

White powder

Mp 178-183 ° C. (decomposition);

IR (KBr) ν _max 3441, 3327, 1606, 1513, 1369, 1183, 1061, 919, 828 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.11-2.15 (2H, m), 2.75 (2H, t, J = 6.3 Hz), 3.17 (2H, brs), 3.26 (2H, brs), 3.53- 3.56 (2H, m), 3.75-3.77 (2H, m), 4.11 (2H, t, J = 6.3 Hz), 6.19 (1H, d, J = 2.7 Hz), 6.45 (1H, dd, J = 2.7, 9.0 Hz), 6.97 (2H, brs), 7.07 (1H, d, J = 5.4 Hz), 7.08 (2H, brs), 7.56 (1H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.4 Hz), 10.63 (1 H, s);

HRMS m / z calc. C ₂₂ H ₂₅ O ₃ N ₆ S 453.1709, found 453.1718;

MS (FAB) m / z: 453 [M + H] ⁺ , 452, 435, 418, 273, 242, 176, 65.

Example 141 3-amino-6-methyl-4- (4-phenyl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound Number 3-161)

(141a) [1- (4-phenyl-1,4-diazepan-1-yl) ethylidene] malononitrile

Using 1-phenyl homopiperazine in place of 1-phenylpiperazine, the reaction was carried out according to the method described in Example 75 (75b) to obtain the title compound.

White powder

Mp 113-114 ° C .;

IR (KBr) ν _max 2957, 2204, 1598, 1562, 1504, 1464, 1356, 928, 754 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.94 (2H, brs), 2.22 (3H, brs), 3.57 (2H, t, J = 5.5 Hz), 3.61-4.02 (6H, m), 6.62 ( 1H, t, J = 7.0 Hz), 6.78 (2H, d, J = 8.2 Hz), 7.16 (2H, dd, J = 7.0, 9.0 Hz);

HRMS m / z calc. C ₁₆ H ₁₈ N ₄ 266.1533, found 266.1525;

MS (EI) m / z: 266 [M ⁺ ], 265, 237, 210, 201, 184, 160, 146, 132, 120, 106, 91, 77, 42, 41;

analysis. Calc. For C ₁₆ H ₁₈ N ₄ .0.1H ₂ O: C, 71.67; H, 6. 84; N, 20.89. Found: C, 71.55; H, 6.76; N, 21.00.

(141b) [(2E) -3- (dimethylamino) -1- (4-phenyl-1,4-diazepan-1-yl) buta-2-enylidene] malononitrile

Reaction was carried out according to the method described in Example 75 (75c), using [1- (4-phenyl-1,4-diazepane-1-yl) ethylidene] malononitrile prepared in Example 141 (141a). Was carried out to obtain the title compound.

Light brown powder

Mp 236-238 ° C. (decomposition);

IR (film) ν _max 2933, 2195, 1722, 1645, 1505, 1440, 1026, 752 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.01-2.07 (2H, m), 2.19 (3H, s), 2.97 (6H, s), 3.57 (2H, t, J = 5.9 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.71 (2H, t, J = 5.1 Hz), 3.83 (2H, t, J = 5.9 Hz), 4.30 (1H, s), 6.70-6.73 (3H, m), 7.22 ( 2H, d, J = 8.6 Hz);

HRMS m / z calc. C ₂₀ H ₂₅ N ₅ 335.2109, found 335.2122;

MS (EI) m / z: 335 [M ⁺ ], 320, 292, 291, 229, 203, 168, 159, 120, 91, 85, 72, 56;

analysis. Calc. For C ₂₀ H ₂₅ N ₅ : C, 71.61; H, 7.51; N, 20.88. Found: C, 71.85; H, 7.56; N, 20.57.

(141c) 6-methyl-2-oxo-4- (4-phenyl-1,4-diazepane-1-yl) -1,2-dihydropyridine-3-carbonitrile

[(2E) -3- (dimethylamino) -1- (4-phenyl-1,4-diazepan-1-yl) buta-2-enylidene] malononitrile prepared in Example 141 (141b) Using the reaction method, the reaction was carried out according to the method described in Example 75 (75d) to obtain the title compound.

White powder

Mp 132-133 ° C .;

IR (KBr) ν _max 2957, 2199, 1625, 1503, 1459, 1351, 1216, 931, 751, 692 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.91-1.95 (2H, m), 2.08 (3H, s), 3.51 (2H, t, J = 6.3 Hz), 3.65-3.70 (4H, m), 3.91 (2H, t, J = 5.4 Hz), 5.88 (1H, s), 6.60 (1H, t, J = 7.3 Hz), 6.78 (2H, d, J = 7.3 Hz), 7.16 (2H, t, J = 7.3 Hz), 11.20 (1H, broad singlet);

HRMS m / z calc. C ₁₈ H ₂₁ ON ₄ 309.1715, found 309.1713;

MS (FAB) m / z: 309, 273, 258, 246, 226, 216, 202, 189, 176, 165, 120, 65.

(141d) 2-chloro-6-methyl-4- (4-phenyl-1,4-diazepan-1-yl) nicotinonitrile

Use of 6-methyl-2-oxo-4- (4-phenyl-1,4-diazepan-1-yl) -1,2-dihydropyridine-3-carbonitrile prepared in Example 141 (141c) The reaction was carried out according to the method described in Example 75 (75e) to obtain the title compound.

White powder

Mp 132-133 ° C .;

IR (KBr) ν _max 3438, 2211, 1593, 1504, 1355, 1220, 1040, 929, 750 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.14 (2H, quint, J = 5.9 Hz), 2.41 (3H, s), 3.57 (2H, t, J = 6.3 Hz), 3.71 (2H, t, J = 5.9 Hz), 3.78 (2H, t, J = 4.9 Hz), 3.98 (2H, t, J = 3.9 Hz), 6.42 (1H, s), 6.72-6.75 (3H, m), 7.24 (2H, d, J = 7.3 Hz);

HRMS m / z calc'd C ₁₈ H ₂₀ N ₄ Cl 327.1377, found 327.1371;

MS (FAB) m / z: 327 [M + H] ⁺ , 326, 273, 242, 226, 165, 120, 65.

(141e) 6-methyl-4- (4-phenyl-1,4-diazepane-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

2-Chloro-6-methyl-4- (4-phenyl-1,4-diazepan-1-yl) nicotinonitrile (6.67 g, 20.4 mmol) and thiourea (7.77) prepared in Example 141 (141d) g, 102.1 mmol) of ethanol (200 mL) suspension was heated to reflux for 3 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered to obtain the title compound (5.91 g, yield 89%).

White powder

Mp 250-253 ° C .;

IR (KBr) ν _max 2962, 2204, 1628, 1598, 1547, 1504, 1351, 1207, 926, 750 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.93-1.98 (2H, m), 2.19 (3H, s), 3.53 (2H, t, J = 5.5 Hz), 3.70-3.74 (4H, m), 3.94 (2H, t, J = 5.9 Hz), 6.33 (1H, s), 6.60 (1H, t, J = 8.2 Hz), 6.78 (2H, d, J = 8.2 Hz), 7.16 (2H, t, J = 8.2 Hz), 12.49 (1H, br s);

HRMS m / z calc. C ₁₈ H ₂₂ N ₄ S 325.1487. Found 325.1501;

MS (FAB) m / z: 325 [M + H] ⁺ , 324, 273, 192, 178, 165, 65, 51, 39.

(141f) 3-amino-6-methyl-4- (4-phenyl-1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carboxamide

6-methyl-4- (4-phenyl-1,4-diazepane-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 141 (141e) The reaction was carried out according to the method described in Example 5 (5c) to synthesize the title compound.

Pale yellow powder

Mp 283-286 ° C .;

IR (KBr) ν _max 3441, 3323, 1645, 1596, 1504, 1367, 1203, 749, 692 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.12-2.14 (2H, m), 2.45 (3H, s), 3.17 (2H, brs), 3.27-3.31 (2H, m), 3.55 (2H, t , J = 6.4 Hz), 3.77 (2H, t, J = 4.4 Hz), 6.61 (1H, t, J = 7.3 Hz), 6.77 (2H, d, J = 7.3 Hz), 6.95 (1H, s), 6.96 (2H, brs), 7.00 (2H, brs), 7.17 (2H, t, J = 7.3 Hz);

HRMS m / z calc. C ₂₀ H ₂₄ ON ₅ S 382.1701, found 382.1696;

MS (EI) m / z: 382 [M + H] ⁺ , 365, 363, 325, 323, 244, 232, 218, 158, 146, 120, 106, 77, 75, 57, 45;

analysis. Calc. For C ₂₀ H ₂₃ N ₅ OS.0.5H ₂ O: C, 61.51; H, 6. 19; N, 17.93; S, 8.21. Found: C, 61.35; H, 5.85; N, 17.92; S, 8.14.

Example 142 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepane-1-yl) -6-methylthieno [2,3- b] pyridine-2-carboxamide (example compound number 3-182)

(142a) 4- [4- (2,2-dicyano-1-methylvinyl) -1,4-diazepane-1-yl] -N, N-dimethylbenzamide

4- (1,4-diazepane-1-yl) -N, N-dimethylbenzamide prepared in Example 128 (128d) in place of 1-phenylpiperazine was used, and Example 75 (75b) was used. The reaction was carried out according to the method described to obtain the title compound.

Colorless liquid

IR (film) ν _max 3439, 2935, 2206, 1608, 1562, 1493, 1396, 1190 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.11 (2H, brs), 2.31 (3H, s), 3.07 (6H, s), 3.55-3.97 (8H, m), 6.68 (2H, d, J = 8.6 Hz), 7.38 (2H, doublet, J = 8.6 Hz);

MS (EI) m / z: 337 [M ⁺ ], 293, 266, 265, 203, 174, 160, 146, 132, 118, 104, 77, 72, 40.

(142b) 4- {4-[(2E) -1- (dicyanomethylene) -3- (dimethylamino) buta-2-en-1-yl] -1,4-diazepan-1-yl}- N, N-dimethylbenzamide

Using 4- [4- (2,2-dicyano-1-methylvinyl) -1,4-diazepan-1-yl] -N, N-dimethylbenzamide prepared in Example 142 (142a) The reaction was carried out according to the method described in Example 75 (75c) to obtain the title compound.

Yellow foam

IR (film) ν _max 2926, 2194, 1607, 1561, 1493, 1440, 1390, 1187, 1025, 763, 554 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 2.03-2.06 (2H, m), 2.20 (3H, s), 2.99 (6H, s), 3.07 (6H, s), 3.60-3.63 (4H, m), 3.75-3.78 (2H, m), 3.83-3.84 (2H, m), 4.31 (1H, s), 6.69 (2H, d, J = 8.8 Hz), 7.38 (2H, d, J = 8.8 Hz);

MS (FAB) m / z: 407 [M + H] ⁺ , 406, 362, 273, 242, 203, 165, 39, 31.

(142c) 4- [4- (3-cyano-6-methyl-2-oxo-1,2-dihydropyridin-4-yl) -1,4-diazepan-1-yl] -N, N -Dimethylbenzamide

4- {4-[(2E) -1- (dicyanomethylene) -3- (dimethylamino) buta-2-en-1-yl] -1,4-diazepane prepared in Example 142 (142b) The reaction was carried out according to the method described in Example 75 (75d) using-1-yl} -N, N-dimethylbenzamide, to obtain the title compound.

Brown powder

Mp 220-223 ° C .;

IR (KBr) ν _max 3434, 2939, 2199, 1621, 1526, 1494, 1454, 1391, 1355, 1189 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.90-1.96 (2H, m), 2.08 (3H, s), 2.95 (6H, s), 3.55-3.57 (2H, m), 3.67-3.69 (2H , m), 3.72-3.74 (2H, m), 3.91-3.93 (2H, m), 5.89 (1H, s), 6.68 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 11.20 (1H, broad singlet);

MS (FAB) m / z: 380 [M + H] ⁺ , 349, 335, 273, 258, 242, 93, 65.

(142d) 4- [4- (2-chloro-3-cyano-6-methylpyridin-4-yl) -1,4-diazepan-1-yl] -N, N-dimethylbenzamide

4- [4- (3-cyano-6-methyl-2-oxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1- prepared in Example 142 (142c) The reaction was carried out in accordance with the method described in Example 75 (75e), using general] -N, N-dimethylbenzamide to obtain the title compound.

White powder

Mp 199-201 ° C .;

IR (KBr) ν _max 2946, 2210, 1618, 1590, 1515, 1392, 1219, 1189, 1038, 926, 830, 763 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 2.14 (2H, quint, J = 5.9 Hz), 2.42 (3H, s), 3.07 (6H, s), 3.60 (2H, t, J = 5.9 Hz), 3.69 (2H, t, J = 5.9 Hz), 3.82 (2H, t, J = 4.9 Hz), 3.98 (2H, t, J = 4.9 Hz), 6.43 (1H, s), 6.70 (2H, d, J = 8.8 Hz), 7.38 (2H, doublet, J = 8.8 Hz);

MS (FAB) m / z: 398 [M + H] ⁺ , 397, 353, 246, 242, 182.

(142e) 4- [4- (3-cyano-6-methyl-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepan-1-yl] -N, N-dimethylbenzamide

4- [4- (2-chloro-3-cyano-6-methylpyridin-4-yl) -1,4-diazepan-1-yl] -N, N- as prepared in Example 142 (142d) The reaction was carried out according to the method described in Example 141 (141e) using dimethylbenzamide, to obtain the title compound.

White powder

Mp 175-178 ° C .;

IR (KBr) ν _max 3205, 2969, 2201, 1607, 1551, 1485, 1352, 1185, 929 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.92-1.97 (2H, m), 2.19 (3H, s), 2.95 (6H, s), 3.56-5.58 (2H, m), 3.72-3.77 (4H , m), 3.95-3.96 (2H, m), 6.34 (1H, s), 6.79 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 12.51 (1H, brs) ;

MS (FAB) m / z: 396 [M + H] ⁺ , 367, 351, 335, 273, 246, 242, 165.

(142f) 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepan-1-yl) -6-methylthieno [2,3-b] Pyridine-2-carboxamide

4- [4- (3-cyano-6-methyl-2-thioxo-1,2-dihydropyridin-4-yl) -1,4-diazepane-1 prepared in Example 142 (142e) The reaction was carried out according to the method described in Example 5 (5c) using -yl] -N, N-dimethylbenzamide, to synthesize the title compound.

White powder

Mp 158-162 ° C .;

IR (KBr) ν _max 3436, 3322, 3182, 1607, 1492, 1371, 1189 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.14-2.16 (2H, m), 2.45 (3H, s), 2.97 (6H, s), 3.16 (2H, brs), 3.28 (2H, brs), 3.59 (2H, t, J = 5.9 Hz), 3.82 (2H, t, J = 4.9 Hz), 6.78 (2H, d, J = 8.8 Hz), 6.96 (1H, s), 6.96 (2H, brs), 7.02 (2H, broad singlet), 7.30 (2H, doublet, J = 8.8 Hz);

HRMS m / z calc. C ₂₃ H ₂₉ O ₂ N ₆ S 453.2027. Found 453.2044;

MS (ESI) m / z: 453 [M + H] ⁺ , 440;

analysis. Calc. For C ₂₃ H ₂₈ N ₆ O ₂ S.4.32H ₂ O: C, 52.08; H, 6.96; N, 15.84; S, 6.05. Found: C, 51.75; H, 6. 72; N, 15.84; S, 5.91.

Example 143 3-amino-4- (3-methoxypiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-28)

(143a) 4- (3-methoxypiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Using the 3-methoxypiperidine (J.Med. Chem., 8, 766, (1965)), the same reaction as in Example 118 (118c) was carried out to obtain the title compound.

Brown powder

Mp 148-152 ° C .;

IR (KBr) ν _max 2943, 2207, 1622, 1515, 1303, 1250, 1167, 1097, 985, 778 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.47-1.62 (2H, m), 1.76-1.83 (1H, m), 1.87-1.93 (1H, m), 3.25 (3H, s), 3.35-3.40 (1H, m), 3.44-3.52 (2H, m), 3.58-3.63 (1H, m), 3.86 (2H, dd, J = 2.4, 13.3 Hz), 6.48 (1H, d, J = 7.4 Hz), 7.44 (1H, doublet, J = 7.4 Hz), 12.60 (1H, brs);

HRMS m / z calc. C ₁₂ H ₁₅ ON ₃ S 249.0935, found 249.0919;

MS (FAB) m / z: 250 [M + H] ⁺ , 218, 180, 39.

(143b) 3-amino-4- (3-methoxypiperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

Example 5 (5c) using 4- (3-methoxypiperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 143 (143a) The reaction was carried out in the same manner as in the method described above, to obtain the title compound.

Pale yellow powder

Mp 182-185 ° C;

IR (KBr) ν _max 3412, 3321, 3146, 2936, 1660, 1585, 1502, 1373, 1246, 1099, 977 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.49-2.09 (4H, m), 2.81-3.46 (4H, m), 3.32 (3H, s), 3.54-3.58 (1H, m), 6.99 (2H , brs), 7.05 (1H, d, J = 5.4 Hz), 7.09 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);

HRMS m / z calc'd C ₁₄ H ₁₈ O ₂ N ₄ S 306.1151, found 306.1154;

MS (EI) m / z: 306 [M ⁺ ], 274, 256, 229, 218, 202, 176, 175, 148, 147, 105, 104, 58, 41;

analysis. Calc. For C ₁₄ H ₁₈ N ₄ O ₂ S: C, 54.88; H, 5.92; N, 18.29; S, 10.47. Found: C, 54.81; H, 5.71; N, 18.11, 10.47.

Example 144 3-amino-4- [3- (ethoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-22 )

(144a) tert-butyl 3- (ethoxymethyl) piperidine-1-carboxylate

According to the method of Example 101 (101a), reaction was performed using ethyl iodide instead of methyl iodide, and the title compound was obtained as an oily substance. Yield 82%.

IR (neat) ν _max 1697, 1423, 1152 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.16-1.27 (1H, m), 1.19 (3H, t, J = 7.0 Hz), 1.38-1.50 (1H, m), 1.46 (9H, s), 1.60-1.66 (1H, m), 1.72-1.83 (2H, m), 2.48-2.91 (2H, m), 3.28 (2H, d, J = 6.3 Hz), 3.41-3.51 (2H, m), 3.80-4.15 (2H m);

MS (EI) m / z: 243 [M ⁺ ], 114, 57, 41.

(144b) 3- (ethoxymethyl) piperidine

4N hydrochloric acid-1,4-di in a methanol (4 mL) solution of tert-butyl 3- (ethoxymethyl) piperidine-1-carboxylate (2.00 g, 8.2 mmol) prepared in Example 144 (144a) Oxane solution (8 mL) was added. After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was treated with 1N aqueous sodium hydroxide solution (20 mL), and the aqueous layer was extracted with methylene chloride (3 x 30 mL). The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 1.01 g (yield 86%) of the title compound as an oil.

IR (neat) ν _max 3310, 1625, 1553, 1270, 1113 cm ^-1 ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.04-1.15 (1H, m), 1.18 (3H, t, J = 7.0 Hz), 1.39-1.50 (1H, m), 1.60 (1H, br), 1.59-1.83 (3H, m), 2.32 (1H, dd, J = 10.2, 12.1 Hz), 2.55 (1H, dt, J = 3.1, 11.7 Hz), 2.99 (1H, brd, J = 12.1 Hz), 3.12 (1H, brd, J = 11.7 Hz), 3.23 (2H, d, J = 6.3 Hz), 3.39-3.50 (2H, m);

MS (EI) m / z: 143 [M ⁺ ], 114, 44.

(144c) (2Z) -2-cyano-3- [3- (ethoxymethyl) piperidin-1-yl] buta-2-enthioamide

Instead of isobutylamine, the reaction was carried out in the same manner as in Example 5 (5a) using 3- (ethoxymethyl) piperidine prepared in Example 144 (144b) to obtain the title compound. Yield 86%.

Mp 146-148 ° C .;

IR (KBr) ν _max 3335, 3277, 3142, 2189, 1627, 1542, 1396, 1110 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.10 (3H, t, J = 7.0 Hz), 1.26-1.93 (5H, m), 2.27 (3H, s), 2.93 (1H, dd, J = 10.2, 13.7 Hz), 3.05-3.12 (1H, m), 3.20-3.30 (2H, m), 3.34-3.46 (2H, m), 3.51-3.62 (2H, m), 8.19 (1H, br), 8.93 (1H , br);

MS (EI) m / z: 267 [M ⁺ ], 234, 204;

analysis. Calc. For C ₁₃ H ₂₁ N ₃ SO: C, 58.39; H, 7.92; N, 15.71; S, 11.99. Found: C, 58.40; H, 7.99; N, 15.60; S, 12.06.

(144d) 4- [3- (ethoxymethyl) piperidin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3- [3- (ethoxymethyl) piperidin-1-yl] buta- prepared in Example 144 (144c) according to the method described in Example 5 (5b). The reaction was carried out using 2-enthioamide, to obtain crude crystals of the title compound.

Mp 151-154 ° C .;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.10 (3H, t, J = 7.0 Hz), 1.26-1.90 (5H, m), 3.08 (1H, dd, J = 10.2, 13.3 Hz), 3.19-3.45 (5H, m), 3.91-3.99 (2H, m), 6.45 (1H, d, J = 7.4 Hz), 7.42-7.45 (1H, m), 12.59 (1H, br).

(144e) 3-amino-4- [3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

Crude crystals of 4- [3- (ethoxymethyl) piperidin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 144 (144d) were obtained. The title compound was obtained by using the reaction according to the method described in Example 5 (5c). 34% yield from (2Z) -2-cyano-3- [3- (ethoxymethyl) piperidin-1-yl] buta-2-enthioamide.

Mp 125-126 ° C .;

IR (KBr) ν _max 3439, 3323, 3174, 1650, 1580, 1501, 1372, 1106 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.01-1.17 (1H, m), 1.08 (3H, t, J = 7.0 Hz), 1.73-1.85 (3H, m), 2.05-2.16 (1H, m) , 2.34-2.70 (2H, m), 3.21-3.46 (6H, m), 6.92 (2H, br), 7.00 (1H, d, J = 5.5 Hz), 7.09 (2H, br), 8.41 (1H, d , J = 5.5 Hz);

MS (FAB) m / z: 335 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₂₂ N ₄ SO ₂ .0.6H ₂ O: C, 55.66; H, 6. 77; N, 16.23; S, 9.29. Found: C, 55.44; H, 6.63; N, 16.33; S, 9.41.

(Example 145) 3-amino-4- {3-[(2-methoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 1-112)

(145a) tert-butyl 3-[(2-methoxyethoxy) methyl] piperidine-1-carboxylate

3- (hydroxymethyl) piperidine-1-carboxylate (Bioorg.Med.Chem.Lett., 8, (1998), 1595-1600) (215 mg, 1 mmol) and 1-bromo-2- To a solution of methoxyethane (278 mg, 0.19 mL, 2 mmol) in toluene (2 mL), tetra-n-butylammonium hydrogen sulfate (68 mg, 0.2 mmol) and 50% aqueous sodium hydroxide solution (1 mL) were added at room temperature. Stirred for time. The reaction mixture was separated with water (30 mL) and ethyl acetate (50 mL), the organic layer was washed with saturated brine (30 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate, 2: 1) to give 177 mg (65%) of the title compound as an oil.

IR (neat) ν _max 1695, 1423, 1152 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.14-1.24 (1H, m), 1.38-1.49 (1H, m), 1.45 (9H, s), 1.59-1.66 (1H, m), 1.76-1.85 (2H, m), 2.52-2.85 (2H, m), 3.32 (2H, d, J = 5.9 Hz), 3.38 (3H, s), 3.50-3.58 (4H, m), 3.82-4.04 (2H, m);

MS (EI) m / z: 273 [M ⁺ ], 172, 114, 57;

analysis. Calc. For C ₁₄ H ₂₇ NO ₄ .0.1H ₂ O: C, 61.11; H, 9.96; N, 5.09. Found: C, 61.01; H, 9.57; N, 5.13.

(145b) 3-[(2-methoxyethoxy) methyl] piperidine

4N hydrochloric acid in a methanol (2 mL) solution of tert-butyl 3-[(2-methoxyethoxy) methyl] piperidine-1-carboxylate (0.87 g, 3.2 mmol) prepared in Example 145 (145a) -1,4-dioxane solution (3 mL) was added, and it stirred at room temperature for 2 hours. To the residue obtained by concentrating the reaction mixture under reduced pressure, 1N aqueous sodium hydroxide solution (10 mL) was added, and the aqueous layer was extracted with methylene chloride (3 x 30 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.51 g (92%) of the title compound as an oil.

IR (neat) ν _max 3413, 1626, 1271, 1111 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.15 (1H, m), 1.40-1.51 (1H, m), 1.62-1.86 (3H, m), 1.76 (1H, br), 2.33 (1H, dd, J = 9.8, 12.1 Hz), 2.56 (1H, ddd, J = 2.7, 11.7, 12.1 Hz), 3.00 (1H, brd, J = 12.1 Hz), 3.14 (1H, brd, J = 11.7 Hz), 3.33 ( 2H, d, J = 6.3 Hz), 3.39 (3H, s), 3.48-3.60 (4H, m);

MS (EI) m / z: 173 [M ⁺ ], 114, 44;

analysis. Calc. For C ₉ H ₁₉ NO ₂ .0.2H ₂ O: C, 61.12; H, 11.06; N, 7.92. Found: C, 61.15; H, 10.67; N, 7.86.

(145c) 3-amino-4- {3-[(2-methoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

3-[(2-methoxyethoxy) methyl] piperidine (0.50 g, 2.9 mmol) and (2Z) -2-cyano-3-ethoxybuta-2- prepared in Example 145 (145b) Enthioamide (J. Org. Chem., (1962), 27, 2433-2439) (0.41 g, 2.4 mmol) was mixed with ethanol (3 mL) and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in toluene (8 mL), N, N-dimethylformamide dimethylacetal (0.86 g, 0.96 mL, 7.2 mmol) was added, and the mixture was stirred under heating to reflux for 30 minutes. After distilling off the solvent under reduced pressure, 1N aqueous sodium hydroxide solution (8 mL) was added to the residue, and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was partitioned between water and ether. The obtained aqueous layer was neutralized with 1N hydrochloric acid (8 mL), and extracted with ethyl acetate (2 x 50 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5 mL), 2-chloroacetamide (0.15 g, 1.6 mmol) and 8N aqueous sodium hydroxide solution (0.5 mL) were added, and the mixture was stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2 x 50 mL). The extract was dried over sodium sulfate, and then the residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (100% ethyl acetate) to obtain 0.25 g (yield 28%) of the title compound.

Mp 138-139 ° C .;

IR (KBr) ν _max 3433, 3323, 3178, 1651, 1579, 1501, 1372, 1088 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.00-1.15 (1H, m), 1.73-1.83 (3H, m), 2.07-2.16 (1H, m), 2.31-2.70 (2H, m), 3.21 ( 3H, s), 3.25-3.53 (8H, m), 6.92 (2H, br), 7.00 (1H, d, J = 5.5 Hz), 7.09 (2H, br), 8.41 (1H, d, J = 5.5 Hz );

MS (FAB) m / z: 365 [M + H] ⁺ .

(Example 146) 3-amino-4- {3-[(2-ethoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 1-123)

(146a) tert-butyl 3-[(2-ethoxyethoxy) methyl] piperidine-1-carboxylate

In accordance with the method described in Example 101 (101a), the reaction was carried out using 2-bromo ethyl ethyl ether instead of methyl iodide to obtain the title compound as an oil. Yield 56%.

IR (neat) ν _max 1696, 1423, 1152 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.14-1.25 (1H, m), 1.21 (3H, t, J = 7.0 Hz), 1.37-1.51 (1H, m), 1.45 (9H, s), 1.60-1.67 (1H, m), 1.75-1.86 (2H, m), 2.50-2.86 (2H, m), 3.30-3.37 (2H, m), 3.54 (2H, q, J = 7.0 Hz), 3.50-3.67 (4H m), 3.84-4.08 (2H, m);

MS (FAB) m / z: 288 [M + H] ⁺ .

(146b) 3-[(2-methoxyethoxy) methyl] piperidine

Reaction was carried out according to the method described in Example 144 (144b) using tert-butyl 3-[(2-ethoxyethoxy) methyl] piperidine-1-carboxylate prepared in Example 146 (146a). The title compound was obtained as an oily substance. Yield 92%.

IR (neat) ν _max 3410, 1640, 1273, 1114 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.15 (1H, m), 1.21 (3H, t, J = 7.0 Hz), 1.40-1.51 (1H, m), 1.62-1.85 (3H, m), 1.75 (1H, br), 2.33 (1H, doublet of doublets, J = 10.0, 12.0 Hz), 2.56 (1H, dt, J = 3.0, 12.0 Hz), 3.01 (1H, brd, J = 12.0 Hz), 3.15 (1H, brd, J = 12.0 Hz), 3.27-3.83 (2H, m), 3.54 (2H, q, J = 7.0 Hz), 3.51-3.62 (4H, m);

MS (EI) m / z: 187 [M ⁺ ], 114, 44.

(146c) 4- {3-[(2-ethoxyethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

3-[(2-ethoxyethoxy) methyl] piperidine (0.48g, 2.6mmol) and (2Z) -2-cyano-3-ethoxybuta-2- prepared in Example 146 (146b) Enthioamide (J. Org. Chem., (1962), 27, 2433-2439) (0.40 g, 2.3 mmol) was mixed with ethanol (5 mL) and stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in toluene (5 mL), N, N-dimethylformamide dimethylacetal (0.82 g, 0.92 mL, 6.9 mmol) was added, and the mixture was stirred under heating to reflux for 30 minutes. After distilling off the solvent under reduced pressure, 1N aqueous sodium hydroxide solution (5 mL) was added to the residue, and the mixture was stirred for 1 hour under reflux. After cooling, the reaction mixture was partitioned between water (10 mL) and ether (50 mL). The obtained aqueous layer was neutralized with 1N hydrochloric acid (5 mL), and extracted with ethyl acetate (2 x 50 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride / methanol = 30: 1) to obtain 0.10 g (yield 13%) of the title compound.

Mp 119-123 ° C .;

IR (KBr) ν _max 2213, 1625, 1552, 1525, 1250, 1120, 1111 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.09 (3H, t, J = 7.0 Hz), 1.26-1.94 (5H, m), 3.09 (1H, dd, J = 9.8, 13.3 Hz), 3.20-3.52 (9H, m), 3.92-4.00 (2H, m), 6.47 (1H, d, J = 7.4 Hz), 7.43-7.47 (1H, m), 12.63 (1H, br);

MS (FAB) m / z: 322 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₂₃ N ₃ SO ₂ : C, 59.78; H, 7. 21; N, 13.07; S, 9.98. Found: C, 59.72; H, 7. 10; N, 13.09; S, 9.87.

(146d) 3-amino-4- {3-[(2-ethoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- {3-[(2-ethoxyethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbony prepared in Example 146 (146c) Tril (100 mg, 0.31 mmol) was dissolved in N, N-dimethylformamide (1 mL), 2-chloroacetamide (38 mg, 0.40 mmol) and 8N aqueous sodium hydroxide solution (0.1 mL) were added, and the mixture was stirred at room temperature. Stirred for 1 hour. Water (30 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2 x 50 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol (2 mL) to obtain 62 mg (yield 53%) of the title compound.

Mp 117-118 ° C .;

IR (KBr) ν _max 3434, 3323, 3180, 1650, 1579, 1501, 1371, 1118 cm ^-1 ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.00-1.15 (1H, m), 1.06 (3H, t, J = 7.0 Hz), 1.70-1.87 (3H, m), 2.06-2.19 (1H, m) , 2.30-2.70 (2H, m), 3.41 (2H, q, J = 7.0 Hz), 3.25-3.54 (8H, m), 6.94 (2H, br), 7.02 (1H, d, J = 5.5 Hz), 7.10 (2H, broad singlet), 8.44 (1H, doublet, J = 5.5 Hz);

MS (FAB) m / z: 379 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₂₆ N ₄ SO ₃ .0.3H ₂ O: C, 56.32; H, 6.98; N, 14.59; S, 8.35. Found: C, 56.16; H, 6. 69; N, 14.72; S, 8.36.

Example 147 3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (example compound Number 1-21)

(147a) tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate

To a tetrahydrofuran (100 mL) suspension of (S) -nifecotate ethyl D-tartarate (15.72 g, 51.2 mmol) and triethylamine (17.08 g, 23.5 mL, 168.8 mmol) under ice-cooling, di-tert- A tetrahydrofuran (50 mL) solution of butyl dicarbonate (11.73 g, 53.7 mmol) was added dropwise in 30 minutes. The reaction solution was raised to room temperature and stirred for 15 hours. Insoluble matters were removed by filtration, and the obtained liquid was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed sequentially with water (50 mL), 1N hydrochloric acid (50 mL) and saturated sodium bicarbonate water (50 mL). The organic layer was dried over sodium sulfate, and then the residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran (50 mL). This solution was added dropwise to a tetrahydrofuran (150 mL) suspension of lithium aluminum hydride (1.94 g, 51.2 mmol) under ice cooling for 30 minutes. After completion of the dropwise addition, the reaction solution was heated to room temperature and stirred at room temperature again for 1 hour. The reaction vessel was transferred onto an ice bath, and a small amount of ethyl acetate and a saturated aqueous ammonium chloride solution were added to the reaction solution, which was then stirred at room temperature for 1 hour. Ethyl acetate was added to the mixture to remove insolubles by decantation (3 × 100 mL). The obtained organic layer was concentrated, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (2 x 100 mL). The extract was dried over sodium sulfate, and then the crude crystal (10.77 g) obtained by distilling off the solvent under reduced pressure was recrystallized from a mixed solvent of ethyl acetate and hexane (1: 5) to obtain 9.03 g (yield 82%) of the title compound. Got.

Mp 94-97 ° C .;

IR (KBr) ν _max 3489, 3466, 1674, 1434, 1154 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.20-1.35 (1H, m), 1.35-1.50 (1H, m), 1.46 (9H, s), 1.58-1.83 (3H, m), 2.12 (1H, br) , 2.75-3.24 (2H, m), 3.50 (2H, brs), 3.40-3.90 (2H, m);

MS (EI) m / z: 215 [M ⁺ ], 57.

analysis. Calc. For C ₁₁ H ₂₁ NO ₃ : C, 61.37; H, 9.83; N, 6.51. Found: C, 61.30; H, 9.75; N, 6.48;

[a] ²⁰ _D : + 18.6 ° (C = 1.11, EtOH).

(147b) (3S) -3- (methoxymethyl) piperidine hydrochloride

Sodium hydride (55% oily, 3.89 g, 89 mmol) was washed with hexane (3 × 10 mL), then suspended in N, N-dimethylformamide (80 mL) at 0 ° C. to methyl iodide (14.47 g, 6.35 mL, 102 mmol) was added, followed by tetrahydro of tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate (18.28 g, 85 mmol) prepared in Example 147 (147a). The furan (80 mL) solution was added dropwise over 30 minutes. The reaction mixture was warmed to room temperature and again stirred at room temperature overnight. Water (200 mL) was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate (2 x 150 mL). The extract was washed with saturated brine (50 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (50 mL) and 4N hydrochloric acid-1,4-dioxane solution (50 mL) was added. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the residue and suspended, and the crystals were filtered and washed again with ethyl acetate to obtain 12.45 g (88%) of the title compound.

Mp 197-199 ° C .;

IR (KBr) ν _max 2944, 1591, 1450, 1129, 1097, 964 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.14-1.25 (1H, m), 1.59-1.78 (3H, m), 1.97-2.08 (1H, m), 2.55-2.61 (1H, m), 2.66- 2.76 (1H, m), 3.22 (3H, s), 3.14-3.26 (4H, m), 8.85-9.15 (2H, br);

MS (EI) m / z: 129 [M ⁺ ], 114;

[a] ²⁰ _D : -12.1 ° (C = 1.02, MeOH).

(147c) (2Z) -2-cyano-3-[(3S) -3- (methoxymethyl) piperidin-1-yl] buta-2-enthioamide

To a (3S) -3- (methoxymethyl) piperidine hydrochloride (10.76 g, 65 mmol) prepared in Example 147 (147b) was added 1N aqueous sodium hydroxide solution (150 mL) to form an aqueous layer with methylene chloride (3 x 100 mL). Was extracted. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The crude product (7.56 g) of (3S) -3- (methoxymethyl) piperidine obtained was dissolved in ethanol (120 mL), and (2Z) -2-cyano-3-ethoxybuta-2-ene Oamide (J. Org. Chem., (1962), 27, 2433-2439) (9.47 g, 56 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, and the precipitated crystals were filtered and washed with ethanol to obtain the title compound (yield 84%).

Mp 149-151 ° C.

(147d) 4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(2Z) -2-cyano-3-[(3S) -3- (methoxymethyl) piperidin-1-yl] buta-2-enthioamide (7.83g) prepared in Example 147 (147c) , 31 mmol) and N, N-dimethylformamide dimethylacetal (4.04 g, 4.5 mL, 34 mmol) were dissolved in N, N-dimethylformamide (60 mL) and stirred at room temperature for 3 hours and at 60 ° C for 2 hours. . Saturated brine (150 mL) was added to the reaction solution, and the aqueous layer was extracted with methylene chloride (4 x 100 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (ethyl acetate / methanol = 15: 1) to give 2.42 g (yield 30%) of the title compound.

Mp 176-177 ° C.

(147e) 3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 147 (147d) In accordance with the method described in Example 5 (5c), the title compound was synthesized. Yield 85%.

Mp 194-196 ° C .;

[α] ²⁰ _D : + 61.3 ° (C = 0.90, MeOH).

Example 148 3-amino-4- (3S)-[(2-methoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide Hydrochloride (Example Compound No. 1-112)

The reaction was carried out according to the method described in Example 145, using tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate prepared in Example 147 (147a). 3-amino-4-{(3S)-[(2-methoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide (410 mg) obtained , 1.1 mmol) was dissolved in ethanol (5 mL), and 1N hydrochloric acid (3 mL) was added. The mixture was concentrated under reduced pressure, and the obtained residue was washed with ethanol to give 320 mg (71%) of the title compound as a yellow solid.

Mp 183-188 ° C;

IR (KBr) ν _max 1647, 1608, 1104 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.17-1.28 (1H, m), 1.68-1.83 (3H, m), 2.02-2.12 (1H, m), 2.78-3.05 (2H, m), 3.22 ( 3H, s), 3.27-3.63 (8H, m), 7.11 (1H, d, J = 5.5 Hz), 7.24 (2H, br), 8.45 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 365 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₄ N ₄ SO ₃ .HCl.0.1H ₂ O: C, 50.70; H, 6. 31; N, 13.91; S, 7.96; Cl, 8.80. Found: C, 50.53; H, 6. 16; N, 13.81; S, 8.08; Cl, 8.96;

[a] ²⁰ _D : + 82.3 ° (C = 1.00, MeOH).

Example 149 3-amino-4-{(3S) -3-[(3-methoxypropoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 1-115)

(149a) tert-butyl (3S) -3-[(3-methoxypropoxy) methyl] piperidine-1-carboxylate

1-bromo instead of 1-bromo-2-methoxyethane using tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate prepared in Example 147 (147a) Using the mother-3-methoxypropane, the reaction was carried out according to the method described in Example 145 (145a) to obtain the title compound as an oil. Yield 63%.

IR (neat) ν _max 1696, 1423, 1152, 1119 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.13-1.25 (1H, m), 1.33-1.50 (1H, m), 1.45 (9H, s), 1.59-1.67 (1H, m), 1.72-1.85 (4H, m), 2.54-2.62 (1H, m), 2.75-2.82 (1H, m), 3.22-3.29 (2H, m), 3.32 (3H, s), 3.42-3.50 (2H, m), 3.45 (2H, t, J = 6.3 Hz), 3.86-4.02 (2H, m);

MS (FAB) m / z: 288 [M + H] ⁺ , 232, 188;

analysis. Calc. For C ₁₅ H ₂₉ NO ₄ : C, 62.69; H, 10.17; N, 4.87. Found: C, 62.79; H, 9.89; N, 4.91.

(149b) (3S) -3-[(3-methoxypropoxy) methyl] piperidine

The tert-butyl (3S) -3-[(3-methoxypropoxy) methyl] piperidine-1-carboxylate prepared in Example 149 (149a) was used and described in Example 144 (144b). The reaction was carried out according to the method to obtain the title compound as an oily substance. Yield 92%.

IR (neat) ν _max 3316, 1621, 1555, 1119 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.15 (1H, m), 1.39-1.50 (1H, m), 1.62 (1H, br), 1.62-1.68 (1H, m), 1.70-1.85 (4H, m), 2.33 (1H, dd, J = 9.8, 11.7 Hz), 2.54 (1H, dt, J = 3.1, 11.7 Hz), 2.99 (1H, brd, J = 11.7 Hz), 3.11 (1H, brd, J = 11.7 Hz), 3.19-3.26 (2H, m), 3.32 (3H, s), 3.41-3.50 (4H, m);

MS (EI) m / z: 188 [M + H] ⁺ , 172, 114, 99;

analysis. Calc. For C ₁₀ H ₂₁ NO ₂ .0.1H ₂ O: C, 63.52; H, 11. 30; N, 7.41. Found: C, 63.70; H, 11. 23; N, 7.36.

(149c) 4-{(3S) -3-[(3-methoxypropoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

(3S) -3-[(3-methoxypropoxy) methyl] piperidine (2.05 g, 10.7 mmol) and (2Z) -2-cyano-3-ethoxy prepared in Example 149 (149b) Buta-2-enthioamide (J.Org. Chem., (1962), 27, 2433-2439) (1.77 g, 10.4 mmol) was mixed with ethanol (30 mL) and stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in N, N-dimethylformamide (30 mL), N, N-dimethylformamide dimethylacetal (1.30 g, 1.45 mL, 10.9 mmol) was added, and the mixture was stirred at 1 room temperature. It stirred for further 1 hour at 60 degreeC. After cooling, saturated brine (200 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 15: 1) to obtain 0.54 g (yield 16%) of the title compound.

Mp 137-140 ° C .;

IR (KBr) ν _max 2212, 1623, 1552, 1522, 1250, 1115 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.27-1.37 (1H, m), 1.49-1.60 (1H, m), 1.69-1.93 (5H, m), 3.09 (1H, dd, J = 10.2, 12.5 Hz), 3.22 (3H, s), 3.20-3.45 (7H, m), 3.92-4.02 (2H, m), 6.47 (1H, d, J = 7.5 Hz), 7.46 (1H, d, J = 7.5 Hz ), 12.62 (1 H, br);

MS (EI) m / z: 321 [M ⁺ ], 306, 218;

analysis. Calc. For C ₁₆ H ₂₃ N ₃ O ₂ S: C, 59.78; H, 7. 21; N, 13.07; S, 9.98. Found: C, 59.99; H, 7. 15; N, 13.13; S, 9.96.

(149d) 3-amino-4-{(3S) -3-[(3-methoxypropoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carbox mid

4-{(3S) -3-[(3-methoxypropoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine prepared in Example 149 (149c) Using the 3-carbonitrile, the reaction was carried out according to the method described in Example 5 (5c) to obtain the title compound. Yield 72%.

Mp 123-124 ° C .;

IR (KBr) ν _max 3421, 3324, 3154, 1656, 1580, 1372, 1111 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.01-1.16 (1H, m), 1.66-1.73 (2H, m), 1.74-1.82 (3H, m), 2.07-2.17 (1H, m), 2.35- 2.67 (2H, m), 3.17 (3H, s), 3.23-3.45 (8H, m), 6.92 (2H, br), 7.00 (1H, d, J = 5.5 Hz), 7.08 (2H, br), 8.41 (1H, doublet, J = 5.5 Hz);

MS (FAB) m / z: 379 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₂₆ N ₄ SO ₃ : C, 57.12; H, 6.92; N, 14.80; S, 8.47. Found: C, 56.94; H, 6. 77; N, 14.68; S, 8.42;

[a] ²⁰ _D : + 79.2 ° (C = 1.16, MeOH).

Example 150 3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -6-methylthieno [2,3-b] pyridine-2-carbox Mead (Example Compound No. 1-68)

(150a) '1-[(3S) -3- (methoxymethyl) piperidin-1-yl] ethylidene} malononitrile

To a methanol (5 mL) solution of (1-ethoxyethylidene) malononitrile (136 mg, 1 mmol) prepared in Example 75 (75a) prepared in Example 147 (147b) (3S) -3- ( Methoxymethyl) piperidine hydrochloride (166 mg, 1 mmol) and triethylamine (139 μL, 1 mmol) were added and stirred at room temperature for 15 hours. The reaction solution was concentrated, ethyl acetate (10 mL) was added to the reaction solution, washed twice with water (10 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 1: 1) to obtain the title compound (169 mg, yield 77%).

Pale yellow liquid

IR (KBr) ν _max 2933, 2206, 1563, 1417, 1110, 967, 616 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.39-1.49 (1H, m), 1.62-1.72 (1H, m), 1.83-1.99 (3H, m), 2.29 (3H, s), 3.13 (1H, dd , J = 9.8, 13.3 Hz), 3.23 (1H, dd, J = 7.3, 9.3 Hz), 3.32 (3H, s), 3.31-3.34 (2H, m), 4.01-4.14 (2H, m);

MS (EI) m / z: 219 [M ⁺ ], 204, 186, 174, 172, 147, 135, 134, 122, 119, 78, 67, 45, 41, 39.

(150b) ｛(2E) -3- (dimethylamino) -1-[(3S) -3- (methoxymethyl) piperidin-1-yl] buta-2-enylidene} malononitrile

Xylene (7 mL) of X1-[(3S) -3- (methoxymethyl) piperidin-1-yl] ethylidene} malononitrile (1.13 g, 5.2 mmol) prepared in Example 150 (150a) N, N-dimethylacetamide dimethylacetal (7 mL) was added to the solution, and the mixture was heated to reflux for 3 hours. Ethyl acetate (50 mL) was added to the residue obtained by concentrating the reaction solution, the organic layer was washed twice with water (50 mL), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (100% ethyl acetate) to obtain the title compound (1.37 g, yield 91%).

Yellow paste

IR (film) ν _max 2929, 2195, 1562, 1508, 1441, 1625, 1127, 1026, 758, 550 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.31-1.39 (1H, m), 1.59-1.68 (1H, m), 1.76-1.90 (3H, m), 2.22 (3H, s), 2.92-2.98 (2H , m), 3.01 (6H, s), 3.27 (2H, t, J = 7.0 Hz), 3.31 (3H, s), 3.90-3.96 (2H, m), 4.37 (1H, s);

MS (EI) m / z: 288 [M ⁺ ], 273, 248, 243, 223, 212, 189, 160, 146, 135, 128, 85, 70, 56, 44, 42.

(150c) 2-chloro-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -6-methylnicotinonitrile

VII (2E) -3- (dimethylamino) -1-[(3S) -3- (methoxymethyl) piperidin-1-yl] buta-2-enylidene prepared in Example 150 (150b) } To a methanol (15 mL) solution of malononitrile (1.37 g, 4.8 mmol) was added oxalyl chloride (3.5 mL, 48 mmol) at 0 ° C. and heated to reflux for 10 minutes. An aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue obtained by concentrating the reaction solution, and the aqueous layer was extracted twice with ethyl acetate (20 mL). The extract was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate = 3: 1) to obtain the title compound (1.00 g, yield 75%).

Yellow liquid

IR (film) ν _max 2929, 2857, 2218, 1590, 1511, 1449, 1215, 1126, 966, 855, 593 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.27-1.37 (1H, m), 1.66-1.77 (1H, m), 1.80-1.88 (2H, m), 1.99-2.07 (1H, m), 2.44 (3H , s), 2.90 (1H, dd, J = 9.08, 12.5 Hz), 3.10 (1H, dt, J = 3.1, 11.0 Hz), 3.25-3.35 (2H, m), 3.34 (3H, s), 3.87- 3.94 (2H, m), 6.53 (1H, s);

MS (EI) m / z: 279 [M ⁺ ], 264, 246, 234, 232, 197, 194, 180, 168, 152, 142, 116, 115, 90, 71, 67, 45, 41.

(150d) 4-[(3S)-(methoxymethyl) piperidin-1-yl] -6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile

2-chloro-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -6-methylnicotinonitrile (1.00 g, 3.57 mmol) prepared in Example 150 (150c) and An ethanol (30 mL) solution of thiourea (1.36 g, 17.9 mmol) was heated to reflux for 24 hours. The reaction solution was concentrated, water (20 ml) was added, and the precipitated crystals were filtered to obtain the title compound (0.83 g, yield 83%).

White powder

Mp 137-145 ° C .;

IR (KBr) ν _max 3366, 3267, 3183, 2216, 1618, 1543, 1453, 1310, 1209, 1093, 723, 626 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.26-1.35 (1H, m), 1.52-1.58 (1H, m), 1.73-1.79 (2H, m), 1.83-1.90 (1H, m), 2.22 (3H, s), 2.98 (1H, dd, J = 10.6, 13.7 Hz), 3.10-3.18 (1H, m), 3.21-3.24 (2H, m), 3.23 (3H, s), 3.91-3.97 (2H m), 6.35 (1 H, s), 12.55 (1 H, brs);

MS (EI) m / z: 277 [M ⁺ ], 262, 247, 232, 192, 178, 150, 144, 90, 71, 45.

(150e) 3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -6-methylthieno [2,3-b] pyridine-2-carboxamide

4-[(3S)-(methoxymethyl) piperidin-1-yl] -6-methyl-2-thioxo-1,2-dihydropyridine-3-carbony prepared in Example 150 (150d) The reaction was carried out in the same manner as in the method described in Example 5 (5c), using a tril, to obtain the title compound.

White powder

Mp 124-132 ° C .;

IR (KBr) ν _max 3439, 3324, 3169, 2924, 1652, 1585, 1546, 1489, 1369, 1122, 1087, 476 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.10-1.19 (1H, m), 1.74-1.93 (3H, m), 2.09 (1H, brs), 2.43-2.48 (1H, m), 2.54-2.59 (1H , m), 2.59 (3H, s), 3.27-3.48 (4H, m), 3.34 (3H, s), 5.23 (2H, brs), 6.75 (1H, s), 6.97 (2H, brs);

HRMS m / z calc. C ₁₆ H ₂₃ O ₂ N ₄ S 335.1542, found 335.1538;

MS (ESI) m / z: 335 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₂₂ N ₄ O ₂ S.1.0H ₂ O: C, 54.33; H, 6. 86; N, 15.90; S, 9.10. Found: C, 54.85; H, 6.55; N, 16.25; S, 8.74.

[a] ²⁰ _D : + 46.9 ° (C = 1.00, MeOH).

(Example 151) 3-amino-4- {3-[(4-hydroxybutoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 1-105)

(151a) tert-butyl 3- [4- (benzyloxy) butoxy] methyl} piperidine-1-carboxylate

Sodium hydride (55% oily, 464 mg, 10.6 mmol) was suspended in tetrahydrofuran (15 mL) under nitrogen atmosphere and tert-butyl 3- (hydroxymethyl) piperidine-1-carboxylate (Bioorg.Med N.N-dimethylformamide (6 mL) solution of .Chem. Lett., 8, (1998), 1595-1600) (1.91 g, 8.87 mmol) was added dropwise. After stirring for 1 hour at room temperature, a tetrahydrofuran (9 mL) solution of benzyl 3-bromobutyl ether (2.5 mL, 13.31 mmol) was added dropwise and stirred overnight at room temperature. Saturated ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was obtained by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.60 g, 48%) as a colorless oily substance.

IR (Liquid film) ν _max 2932, 2856, 1694, 1423, 1366, 1266, 1152, 1115 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.14-1.23 (1H, m), 1.45 (9H, s), 1.60-1.71 (5H, m), 1.73-1.81 (2H, m), 2.58 (1H, br ), 2.79 (1H, t, J = 12.2 Hz), 3.25 (2H, dd, J = 1.7, 6.1 Hz), 3.38-3.42 (2H, m), 3.49 (2H, t, J = 6.1 Hz), 3.89 (2H, d, J = 13.2 Hz), 3.98 (1H, dd, J = 5.5, 11.0 Hz), 4.50 (2H, s), 7.26-7.30 (2H, m), 7.32-7.35 (3H, m);

MS (FAB) m / z: 378 [M + H] ⁺ .

(151b) tert-butyl 3-[(4-hydroxybutoxy) methyl] piperidine-1-carboxylate

Tert-butyl 3-{[4- (benzyloxy) butoxy] methyl} piperidine-1-carboxylate (1.71 g, 4.53 mmol) prepared in Example 151 (151a) was dissolved in ethanol (10 mL). Palladium hydroxide (200 mg) was added, and it stirred at room temperature and atmospheric hydrogen atmosphere for 2 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the title compound (1.30 g, yield 100%) as an oily substance.

IR (Liquid film) ν _max 3741, 2976, 2935, 2859, 1745, 1694, 1426, 1268, 1242, 1154 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.16-1.25 (1H, m), 1.45 (9H, s), 1.40-1.50 (2H, m), 1.60-1.69 (5H, m), 1.75-1.82 (2H , m), 2.78-2.84 (1H, m), 3.29 (2H, d, J = 6.3 Hz), 3.41-3.47 (2H, m), 3.64 (2H, t, J = 5.7 Hz), 3.81-3.91 ( 2H, br), 3.97 (1H, doublet of doublets, J = 5.5, 11.0 Hz);

MS (FAB) m / z: 288 [M + H] ⁺ .

(151c) 4- (piperidin-3-ylmethoxy) butyl acetate

4N hydrochloric acid-ethyl acetate solution (5 mL) was added to tert-butyl 3-[(4-hydroxybutoxy) methyl] pyridine-1-carboxylate (775 mg, 2.70 mmol) prepared in Example (151b). The mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, methylene chloride and 1N aqueous sodium hydroxide solution were added to the residue obtained by distilling off the solvent, and the mixture was separated. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (516 mg, 83%) as an oily substance.

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.06-1.15 (1H, m), 1.41-1.51 (1H, m), 1.59-1.85 (8H, m), 2.05 (3H, s), 2.33 (1H, dd , J = 10.0, 12.2 Hz), 2.55 (1H, dt, J = 2.9, 12.2 Hz), 3.00 (1H, d, J = 11.7 Hz), 3.12 (1H, d, J = 10.7 Hz), 3.22-3.24 (2H, m), 3.38-3.43 (2H, m), 4.08 (2H, t, J = 6.6 Hz);

MS (FAB) m / z: 230 [M + H] ⁺ .

(151d) 4-([1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy) butylacetate

4- (piperidin-3-ylmethoxy) butyl acetate (504 mg, 2.20 mmol) prepared in Example 151 (151c) was dissolved in N, N-dimethylformamide (2 mL), and (2Z) -2 -Cyano-3-ethoxybuta-2-enthioamide (J. Org. Chem., (1962), 27, 2433-2439) (299 mg, 1.76 mmol) was added and stirred at room temperature for 30 minutes. N, N-dimethylformamide dimethylacetal (294 µL, 2.20 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight, and then stirred at 80 ° C for 1 hour. After the reaction was completed, water was added to the reaction solution, the mixture was diluted and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (methylene chloride / methanol = 40: 1 to 20: 1) to obtain an oily substance (135 mg) containing the title compound as a main component.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.36-1.44 (1H, m), 1.57-1.74 (6H, m), 1.83-1.91 (2H, m), 2.05 (3H, s), 3.09 (1H, dd , J = 10.0, 13.1 Hz), 3.25-3.45 (7H, m), 4.08 (2H, t, J = 6.6 Hz), 6.29 (1H, d, J = 7.4 Hz), 7.27 (1H, d, J = 7.4 Hz), 11.9 (1 H, broad singlet).

(151e) 3-amino-4- {3-[(4-hydroxybutoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4-([1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy) butyl prepared in Example 151 (151d) Acetate (134 mg) was dissolved in N, N-dimethylformamide (1.5 mL), 2-chloroacetamide (44.8 mg, 0.479 mmol) and 8N aqueous sodium hydroxide solution (0.3 mL) were added, and the mixture was stirred overnight at room temperature. It was. After the reaction was completed, water was added, the reaction solution was diluted and extracted with ethyl acetate. The obtained 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 using thin layer chromatography (methylene chloride / methanol = 10: 1) to give the title compound (42.2 mg, yield 30% from 4- (piperidin-3-yl methoxy) butyl acetate). Obtained as a pale yellow solid.

Mp 140-141 ° C .;

IR (KBr) ν _max 3436, 3325, 3183, 2933, 2859, 1651, 1581, 1501, 1373, 1347 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.09-1.18 (1H, m), 1.64-1.69 (4H, m), 1.76-1.84 (1H, m), 1.86-1.94 (2H, br), 2.08-2.17 (1H, m), 2.35 (1H, br s), 2.41 (1H, t, J = 11.2 Hz), 2.64 (1H, t, J = 10.5 Hz), 3.28-3.34 (1H, m), 3.36-3.51 (4H, m), 3.52-3.58 (1H, m), 3.64 (2H, d, J = 2.4 Hz), 5.32 (2H, br s), 6.89 (1H, d, J = 5.4 Hz), 6.98 (2H , br s), 8.46 (1H, doublet, J = 5.4 Hz);

MS (FAB) m / z: 379 [M + H] ⁺ ;

analysis. Calc. For C ₁₈ H ₂₆ N ₄ O ₃ S. 3 / 10H ₂ O: C, 56.32; H, 6.98; N, 14.59; S, 8.35. Found C, 56.33; H, 6.71; N, 14.60, S, 8.31.

Example 152 3-amino-4- {3-[(3-hydroxypropoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 1-102)

(152a) benzyl 3-{[3- (benzyloxy) propoxy] methyl} piperidine-1-carboxylate

According to the method described in Example 151 (151a), benzyl 3- (hydroxymethyl) piperidine-1-carboxylate instead of tert-butyl 3- (hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm. (Weinheim Ger.), 323, 1990, 9-12) (2.03 g, 8.14 mmol) was reacted with benzyl 4-bromopropyl ether instead of benzyl 3-bromobutyl ether. The title compound (538 mg, yield 17%) was obtained as an oily substance.

IR (Liquid film) ν _max 3462, 2932, 2859, 1699, 1433, 1262, 1237, 1113 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.14-1.24 (1H, m), 1.45 (1H, br s), 1.60-1.68 (1H, m), 1.71-1.80 (2H, m), 1.85 (2H, qu, J = 6.3 Hz), 2.64 (1H, br d), 2.81-2.88 (1H, m), 3.25 (2H, d, J = 5.5 Hz), 3.43-3.49 (2H, m), 3.51-3.57 ( 2H, m), 3.98 (1H, dt, J = 3.9, 12.9 Hz), 4.06 (1H, br s), 4.47 (2H, s), 5.10 (2H, d, J = 3.9 Hz), 7.23-7.35 ( 10H, m);

MS (FAB) m / z: 398 [M + H] ⁺ .

(152b) benzyl 3-{[3- (benzyloxy) propoxy] methyl} piperidine-1-carboxylate

Benzyl 3-{[3- (benzyloxy) propoxy] methyl} piperidine-1-carboxylate (1.90 g, 4.78 mmol) prepared in Example 152 (152a) was dissolved in ethanol (3 mL), 10% palladium-carbon (180 mg) was added, and it stirred for 1.5 hours under room temperature and atmospheric hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue (1.24 g) was dissolved in methylene chloride (7 mL), di-tert-butyl dicarbonate (1.28 mL, 5.57 mmol) was added, and the mixture was stirred at room temperature and nitrogen atmosphere for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (1.62 g, yield 95%) as an oily substance.

IR (Liquid film) ν _max 2975, 2931, 2858, 1694, 1424, 1366, 1267, 1242, 1179, 1118 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.12-1.26 (1H, m), 1.45 (9H, s), 1.60-1.66 (1H, m), 1.71-1.80 (2H, m), 1.84-1.90 (2H , qu, J = 6.3 Hz), 2.57 (1H, br), 2.77 (1H, t, J = 11.4 Hz), 3.25 (2H, m), 3.45-3.51 (2H, m), 3.55 (2H, t, J = 6.3 Hz), 3.88 (2H, dt, J = 3.7, 12.5 Hz), 3.97 (1H, br), 4.49 (2H, s), 7.24-7.28 (2H, m), 7.30-7.32 (3H, m );

MS (FAB) m / z: 364 [M + H] ⁺ .

(152c) tert-butyl 3-[(3-hydroxypropoxy) methyl] piperidine-1-carboxylate

Example 151 (151b) using benzyl 3-{[3- (benzyloxy) propoxy] methyl} piperidine-1-carboxylate (1.61 g, 4.43 mmol) prepared in Example 152 (152b) The reaction was carried out according to the method described in the above) to obtain the title compound (1.17 g, yield 96%) as a colorless solid.

Mp 78 ° C .;

IR (KBr) ν _max 3466, 2974, 2938, 2861, 1679, 1473, 1438, 1272, 1156, 1121 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.18-1.27 (1H, m), 1.45 (9H, s), 1.56-1.66 (1H, m), 1.67-1.83 (5H, m), 2.36 (1H, br ), 2.78 (2H, br), 2.92 (1H, br), 3.26-3.33 (2H, m), 3.54-3.63 (2H, m), 3.77 (2H, br), 3.86 (1H, d, J = 12.1 Hz);

MS (FAB) m / z: 274 [M + H] ⁺ ;

analysis. Calc. For C ₁₄ H ₂₇ NO ₄ .1 / 10H ₂ O: C, 61.11; H, 9.96; N, 5.09. Found C, 61.05; H, 10.03; N, 4.99.

(152d) 3- (piperidin-3-ylmethoxy) propyl acetate

Example 151 (151c) using tert-butyl 3-[(3-hydroxypropoxy) methyl] piperidine-1-carboxylate (932 mg, 3.41 mmol) prepared in Example 152 (152c). The reaction was carried out according to the method described in the above), to obtain the title compound (655 mg, yield 89%) as an oily substance.

IR (Liquid film) ν _max 3315, 2930, 2856, 1739, 1368, 1244, 1125, 1052 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.06-1.15 (1H, m), 1.41-1.51 (1H, m), 1.62-1.69 (1H, m), 1.72-1.85 (3H, m), 1.86-1.91 (2H, m), 2.05 (3H, s), 2.33 (1H, t, J = 11.3 Hz), 2.55 (1H, t, J = 12.1 Hz), 3.00 (1H, d, J = 12.1 Hz), 3.11 (1H, d, J = 11.3 Hz), 3.24 (2H, d, J = 5.9 Hz), 3.44-3.48 (2H, m), 4.15 (2H, t, J = 6.4 Hz);

MS (EI) m / z: 215 M ⁺ .

(152e) 4-([1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy) propylacetate

The reaction was carried out according to the method described in Example 151 (151d) using 3- (piperidin-3-ylmethoxy) propyl acetate (640 mg, 2.97 mmol) prepared in Example 152 (152d). The oily substance (234 mg) which has the title compound as a main component was obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.35-1.46 (1H, m), 1.57-1.74 (4H, m), 1.83-1.92 (2H, m), 2.05 (3H, s), 3.09 (1H, dd , J = 9.8, 13.2 Hz), 3.26-3.50 (7H, m), 4.14 (2H, t, J = 6.7 Hz), 6.29 (1H, d, J = 7.8 Hz), 7.27 (1H, d, J = 7.8 Hz), 11.9 (1 H, br).

(152f) 3-amino-4- {3-[(3-hydroxypropoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4-([1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy) propyl prepared in Example 152 (152d) The reaction was carried out according to the method described in Example 151 (151e) using acetate to give the title compound (109 mg, yield 10.0% from 3- (piperidin-3-ylmethoxy) propyl acetate) as a light brown solid. Obtained as.

Mp 166-168 ° C .;

IR (KBr) ν _max 3436, 3325, 3180, 2931, 2859, 1652, 1581, 1501, 1373, 1347 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.09-1.18 (1H, m), 1.76-1.86 (3H, m), 1.86-1.94 (2H, br), 2.08-2.17 (1H, m), 2.31-2.36 (1H, m), 2.42 (1H, t, J = 11.5 Hz), 2.62 (1H, t, J = 11.5 Hz), 3.31-3.45 (3H, m), 3.48-3.54 (1H, m), 3.55- 3.66 (2H, m), 3.75 (2H, q, J = 5.5 Hz), 5.33 (2H, br s), 6.86 (1H, d, J = 5.5 Hz), 6.93 (2H, br s), 8.44 (1H , d, J = 5.5 Hz);

MS (FAB) m / z: 365 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₄ N ₄ O ₃ S. 4 / 5H ₂ O: C, 53.89; H, 6.81; N, 14.79; S, 8.46. Found C, 53.93; H, 6.51; N, 14.76, S, 8.22.

Example 153 3-amino-4- [3- (3-hydroxypropyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1 -96)

(153a) 3-piperidin-3-ylpropyl acetate

Tert-butyl 3- (3-hydroxypropyl) piperidine-1-carboxylate (626 mg, 2.57 synthesized with reference to the method described in J. Med. Chem., (1996), 41, 2709-2719) mmol), and the reaction was carried out according to the method described in Example 151 (151c) to obtain the title compound (400 mg, yield 84%) as an oily substance.

IR (Liquid film) ν _max 3321, 2930, 2852, 1738, 1547, 1451, 1367, 1244, 1051, 1037 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.96-1.06 (1H, m), 1.15-1.28 (2H, m), 1.35-1.49 (2H, m), 1.53-1.70 (4H, m), 1.78-1.86 (1H, m), 2.04 (3H, s), 2.23 (1H, t, J = 11.0 Hz), 2.52 (1H, dt, J = 2.7, 12.0 Hz), 2.97-3.04 (2H, m), 4.03 ( 2H, t, J = 6.9 Hz);

MS (FAB) m / z: 186 [M + H] ⁺ .

(153b) 3- [1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] propyl acetate

Using the 3-piperidin-3-ylpropyl acetate (400 mg, 2.16 mmol) prepared in Example 153 (153a), the reaction was carried out according to the method described in Example 151 (151d) to obtain the title compound as a main component. An oily substance (80 mg) was obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.19-1.42 (3H, m), 1.63-1.77 (4H, m), 1.84-1.92 (1H, m), 2, 1.94-2.01 (1H, m), 2.05 (3H, s), 2.85 (1H, dd, J = 10.6, 13.2 Hz), 3.12-3.19 (1H, m), 4.05 (2H, dt, J = 2.0, 6.5 Hz), 4.12 (2H, t, J = 12.5 Hz), 6.25 (1H, d, J = 7.4 Hz), 7.29 (1H, d, J = 7.4 Hz), 12.2 (1H, br).

(153c) 3-amino-4- [3- (3-hydroxypropyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

Using 3- [1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] propylacetate prepared in Example 153 (153b) The reaction was carried out according to the method described in Example 151 (151e) to obtain the title compound (68.0 mg, yield 9.4% from 3-piperidin-3-ylpropyl acetate) as a yellow amorphous.

IR (KBr) ν _max 3440, 3326, 3189, 2931, 2852, 1648, 1581, 1502, 1373, 1346 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.98-1.08 (1H, m), 1.30-1.36 (2H, m), 1.54-1.82 (4H, m), 1.84-2.03 (3H, m), 2.28 (1H , t, J = 11.2 Hz), 2.62 (1H, t, J = 11.2 Hz), 3.38 (2H, t, J = 9.6 Hz), 3.65 (2H, t, J = 6.3 Hz), 5.52 (2H, br s), 6.84 (1H, d, J = 5.1 Hz), 6.97 (2H, br s), 8.41 (1H, d, J = 5.1 Hz);

MS (FAB) m / z: 335 [M + H] ⁺ .

Example 154 3-amino-4- [3- (3-methoxypropyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1 -109)

(154a) tert-butyl 3- (3-methoxypropyl) piperidine-1-carboxylate

tert-butyl 3- (3-hydroxypropyl) piperidine-1-carboxylate (J.Med. Chem., (1996), 41, 2709-2719) (617 mg, 2.54 mmol) It dissolved in furan (10 mL), sodium hydride (55% oily, 230 mg, 5.27 mmol) was added, and it stirred for 30 minutes at room temperature under nitrogen atmosphere. Methyl iodide (0.60 mL, 9.64 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Further, sodium hydride (200 mg, 4.58 mmol) and methyl iodide (1.2 mL, 19.2 mmol) were added to the reaction solution, stirred at room temperature for 1 hour, and then saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain the title compound (618 mg, yield 95%) as an oily substance.

IR (Liquid film) ν _max 2976, 2933, 2856, 1696, 1423, 1366, 1267, 1241, 1177, 1150 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.02-1.11 (1H, m), 1.18-1.32 (2H, m), 1.36-1.49 (2H, m), 1.45 (9H, s), 1.57-1.66 (3H , m), 1.77-1.86 (1H, m), 2.30-2.60 (1H, br), 2.74 (1H, t, J = 11.7 Hz), 3.33 (3H, s), 3.36 (2H, t, J = 6.6 Hz), 3.92 (1H, doublet, J = 12.7 Hz), 3.80-4.10 (1H, br);

MS (EI) m / z: 257 M ⁺ .

(154b) 3- (3-methoxypropyl) piperidine

The method described in Example 151 (151c) using tert-butyl 3- (3-methoxypropyl) piperidine-1-carboxylate (607 mg, 2.36 mmol) prepared in Example 154 (154a). The reaction was carried out according to the following procedure to obtain the title compound (362 mg, yield 98%) as an oily substance.

IR (Liquid film) ν _max 3401, 3311, 2929, 2852, 2737, 1645, 1543, 1451, 1274, 1118 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.96-1.06 (1H, m), 1.13-1.28 (2H, m), 1.35-1.49 (2H, m), 1.53-1.67 (3H, m), 1.79-1.86 (2H, m), 2.22 (1H, t, J = 11.0 Hz), 2.51 (1H, dt, J = 2.5, 11.8 Hz), 2.96-3.06 (2H, m), 3.32 (3H, s), 3.34 ( 2H, t, J = 6.7 Hz);

MS (FAB) m / z: 158 [M + H] ⁺ .

(154c) 4- [3- (3-methoxypropyl) piperidin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

3- (3-methoxypropyl) piperidine (355 mg, 2.26 mmol) prepared in Example 154 (154b) was dissolved in N, N-dimethylformamide (2 mL), and (2Z) -2-sia No-3-ethoxybuta-2-enthioamide (J. Org. Chem., (1962), 27, 2433-2439) (312 mg, 1.83 mmol) was added, and it stirred at room temperature for 1 hour. N, N-dimethylformamide dimethylacetal (266 µL, 1.99 mmol) was added to the reaction solution, the mixture was stirred overnight at room temperature, then water was added and diluted, and the aqueous layer was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography (methylene chloride: methanol = 30: 1 to 20: 1) and thin layer chromatography (100% ethyl acetate) to give the title compound (59.6 mg, 9.0% yield) as yellow. Obtained as an amorphous material.

IR (KBr) ν _max 3115, 2935, 2854, 2209, 1624, 1552, 1519, 1310, 1250, 1116 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.18-1.28 (1H, m), 1.29-1.40 (2H, m), 1.55-1.75 (4H, m), 1.83-1.90 (1H, m), 1.94-2.02 (1H, m), 2.85 (1H, dd, J = 10.8, 13.1 Hz), 3.14-3.21 (1H, m), 3.33 (3H, s), 3.36-3.41 (2H, m), 4.08-4.18 (2H m), 6.27 (1H, d, J = 7.4 Hz), 7.30 (1H, d, J = 7.4 Hz), 12.23 (1H, br);

MS (FAB) m / z: 292 [M + H] ⁺ .

(154d) 3-amino-4- [3- (3-methoxypropyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

4- [3- (3-methoxypropyl) piperidin-1-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile (58.6 mg) prepared in Example 154 (154c). , 0.201 mmol) was dissolved in N, N-dimethylformamide (1 mL), 2-chloroacetamide (32.8 mg, 0.350 mmol) and 8N aqueous sodium hydroxide solution (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added to the reaction solution, the mixture was diluted and extracted with ethyl acetate. The obtained 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 using thin layer chromatography (100% ethyl acetate) to obtain the title compound (65.5 mg, yield 93%) as a yellow amorphous.

IR (KBr) ν _max 3438, 3323, 3178, 2932, 2852, 1651, 1580, 1556, 1501, 1371 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.98-1.08 (1H, m), 1.29-1.35 (2H, m), 1.56-1.68 (2H, m), 1.69-1.82 (2H, m), 1.84-1.92 (1H, m), 1.93-2.01 (1H, m), 2.31 (1H, t, J = 11.0 Hz), 2.62 (1H, t, J = 11.7 Hz), 3.32 (3H, s), 3.35-3.42 ( 2H, m), 3.37 (2H, t, J = 6.5 Hz), 5.29 (2H, br s), 6.85 (1H, d, J = 5.5 Hz), 6.99 (2H, br s), 8.43 (1H, d , J = 5.5 Hz);

MS (FAB) m / z: 349 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₄ N ₄ O ₂ S. 1 / 5H ₂ O: C, 58.00; H, 6.99; N, 15.91; S, 9.11. Found C, 58.06; H, 6.98; N, 15.70; S, 8.85.

Example 155 3-Amino-4- [3- (4-hydroxybutyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1 -97)

(155a) tert-butyl 3- (3-oxopropyl) piperidine-1-carboxylate

tert-butyl 3- (3-hydroxypropyl) piperidine-1-carboxylate (J.Med. Chem., (1996), 41, 2709-2719) (1.08 g, 4.44 mmol) was added to methylene chloride ( 10 mL), Dess-Martin periodinane (2.3 g, 5.42 mmol) was added, and it stirred at room temperature for 2 hours in nitrogen atmosphere. Ether was added to the reaction solution, the organic layer was washed sequentially with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.00 g, yield 93%).

IR (Liquid film) ν _max 2976, 2932, 2857, 1726, 1692, 1425, 1366, 1268, 1174, 1150 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.05-1.14 (1H, m), 1.37-1.60 (4H, m), 1.45 (9H, s), 1.60-1.67 (1H, m), 1.78-1.85 (1H , m), 2.40-2.60 (1H, br), 2.49 (2H, t, J = 7.3 Hz), 2.80 (1H, t, J = 11.2 Hz), 3.88 (1H, dt, J = 3.5, 13.1 Hz) , 3.98 (1 H, br), 9.79 (1 H, s);

MS (FAB) m / z: 242 [M + H] ⁺ .

(155b) tert-butyl 3-[(3) -4-methoxybute-3-enyl] piperidine-1-carboxylate

(Methoxymethyl) triphenylphosphonium chloride (1.76 g, 5.13 mmol) was dissolved in tetrahydrofuran (5 mL), and hexane solution of n-butyllithium (1.50 M, 3.0 mL, 4.5 mmol) was added under ice cooling. The mixture was stirred at 0 ° C. for 30 minutes in a nitrogen atmosphere. To the reaction mixture, a tetrahydrofuran (5 mL) solution of tert-butyl 3- (3-oxopropyl) piperidine-1-carboxylate (675 mg, 2.80 mmol) prepared in Example 155 (155a) was added dropwise. It stirred at 0 degreeC for 1 hour and room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The obtained 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 (hexane: ethyl acetate = 8: 1) to obtain the title compound (475 mg, yield 63%) as an oily substance.

IR (Liquid film) ν _max : 2976, 2932, 2853, 1695, 1656, 1423, 1366, 1267, 1176, 1109 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.98-1.12 (1H, br), 1.15-1.33 (2H, m), 1.37-1.56 (2H, m), 1.45 (9H, s), 1.58-1.66 (1H , m), 1.76-1.87 (1H, m), 1.95 (1H, q, J = 7.0 Hz), 2.08 (1H, dq, J = 1.3, 7.5 Hz), 2.26-2.63 (1H, br), 2.75 ( 1H, t, J = 10.8 Hz), 3.49 (3 / 2H, s), 3.56 (3 / 2H, s), 3.74-4.07 (1H, br), 3.85-3.92 (1H, m), 4.30 (1 / 2H, q, J = 7.0 Hz), 4.68 (1 / 2H, dt, J = 7.5, 12.5 Hz), 5.85 (1 / 2H, d, J = 6.3 Hz), 6.27 (1 / 2H, d, J = 12.5 Hz);

MS (EI) m / z: 269 M ⁺ .

(155c) tert-Butyl 3- (4-hydroxybutyl) piperidine-1-carboxylate

Tert-butyl 3-[(3) -4-methoxybute-3-enyl] piperidine-1-carboxylate (465 mg, 1.73 mmol) prepared in Example 155 (155b) was added to methanol (2 mL). ) And water (2 mL), concentrated sulfuric acid (0.2 mL) was added, and the mixture was stirred at room temperature for 7 hours under a nitrogen atmosphere. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting residue was dissolved in acetone (4 mL), amberlite (IR-120PLUS, 1 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, the filtrate was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude aldehyde compound (237 mg). The obtained compound was dissolved in methanol (5 mL), an excess of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. Water, then saturated aqueous ammonium chloride solution, was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (197 mg, yield 44%) as an oily substance.

IR (Liquid film) ν _max 3443, 2976, 2932, 2859, 1694, 1672, 1428, 1367, 1269, 1152 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.03-1.11 (1H, m), 1.14-1.33 (3H, m), 1.35-1.47 (4H, m), 1.45 (9H, s), 1.52-1.65 (3H , m), 1.78-1.84 (1H, m), 2.48 (1H, br), 2.77-2.82 (1H, m), 3.64 (2H, q, J = 5.4 Hz), 3.71-4.04 (2H, br);

MS (EI) m / z: 257 M ⁺ .

(155d) 4-piperidin-3-ylbutyl acetate

The method described in Example 151 (151c) using tert-butyl 3- (4-hydroxybutyl) piperidine-1-carboxylate (301 mg, 1.17 mmol) prepared in Example 155 (155c). The reaction was carried out according to the above procedure to obtain the title compound (195 mg, yield 84%) as an oily substance.

IR (Liquid film) ν _max 3323, 2930, 2851, 1739, 1645, 1459, 1445, 1367, 1243, 1038 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 0.95-1.05 (1H, m), 1.12-1.25 (2H, m), 1.31-1.49 (4H, m), 1.57-1.66 (3H, m), 1.69-1.85 (2H, m), 2.04 (3H, s), 2.21 (1H, dd, J = 10.5, 12.0 Hz), 2.52 (1H, dt, J = 2.7, 12.0 Hz), 2.96-3.05 (2H, m), 4.04 (2H, t, J = 6.7 Hz);

MS (EI) m / z: 198 (M-H) ⁺ .

(155e) 4- [1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] butyl acetate

Using the 4-piperidin-3-ylbutyl acetate (185 mg, 0.928 mmol) prepared in Example 155 (155d), the reaction was carried out according to the method described in Example 151 (151d) to obtain the title compound as a main component. An oily substance (36 mg) was obtained.

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.16-1.50 (5H, m), 1.59-1.78 (4H, m), 1.84-2.00 (2H, m), 2.06 (3H, s), 3.13-3.19 (1H , m), 3.49-3.55 (1H, m), 4.07 (2H, t, J = 6.4 Hz), 4.09-4.15 (2H, m), 6.25 (1H, d, J = 7.8 Hz), 7.31 (1H, d, J = 7.8 Hz), 12.1 (1H, br).

(155f) 3-amino-4- [3- (4-hydroxybutyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide

Using 4- [1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] butyl acetate prepared in Example 155 (155e), The reaction was carried out according to the method described in Example 151 (151e) to obtain the title compound (15.5 mg, yield 4.8% from 4-pyridin-3-ylbutyl acetate) as a yellow amorphous material.

IR (KBr) ν _max 3441, 3326, 3187, 2931, 2855, 1649, 1581, 1502, 1374, 1247 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 0.99-1.07 (1H, m), 1.25-1.33 (2H, m), 1.36-1.50 (3H, m), 1.54-1.69 (2H, m), 1.70-1.81 (2H, m), 1.85-1.91 (1H, m), 1.96 (1H, d, J = 11.7 Hz), 2.29 (1H, t, J = 11.0 Hz), 2.64 (1H, t, J = 11.7 Hz) , 3.40 (2H, t, J = 11.0 Hz), 3.65 (2H, t, J = 6.6 Hz), 5.34 (2H, br s), 6.87 (1H, d, J = 5.1 Hz), 7.01 (2H, br s), 8.45 (1H, doublet, J = 5.1 Hz);

MS (FAB) m / z: 349 [M + H] ⁺ .

(Example 156) 3-amino-4- {3-[(2-cyanoethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 1-152)

(156a) benzyl 3-[(2-cyanoethoxy) methyl] piperidine-1-carboxylate

Benzyl 3- (hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm (Weinheim Ger.), 323, 1990, 9-12) (6.30 g, 25.3 mmol) in tetrahydrofuran (50 mL) It melt | dissolved, and acrylonitrile (3.31 mL, 50.5 mmol) and sodium hydroxide (160 mg, 2.85 mmol) were added, and it stirred at room temperature for 9 hours in nitrogen atmosphere. In addition, sodium hydroxide (160 mg, 2.85 mmol) was added to the reaction solution, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 2: 1) to obtain the title compound (6.91 g, yield 90%).

IR (Liquid film) ν _max 2937, 2863, 2251, 1698, 1471, 1433, 1262, 1236, 1155, 1117 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.22-1.33 (1H, m), 1.40-1.53 (1H, m), 1.62-1.70 (1H, m), 1.76-1.87 (2H, br), 2.55 (2H , br s), 2.66-2.87 (1H, br), 2.93 (1H, t, J = 11.0 Hz), 3.35 (2H, d, J = 5.1 Hz), 3.59 (2H, br s), 3.92 (1H, dt, J = 4.2, 13.3 Hz), 4.01 (1H, broad singlet), 5.08-5.17 (2H, m), 7.27-7.35 (5H, m);

MS (EI) m / z: 303 [M + H] ⁺ .

(156b) 3- (piperidin-3-ylmethoxy) propanenitrile

Benzyl 3-[(2-cyanoethoxy) methyl] piperidine-1-carboxylate (1.03 g, 3.40 mmol) prepared in Example 156 (156a), using palladium-carbon catalyst in ethanol Hydrocracking reaction was carried out to obtain the title compound (564 mg, 99% yield) as an oily substance.

IR (Liquid film) ν _max 3389, 3326, 2932, 2860, 2251, 1640, 1545, 1418, 1273, 1113 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.08-1.18 (1H, m), 1.40-1.51 (1H, m), 1.62-1.69 (2H, m), 1.75-1.83 (2H, m), 2.36 (1H , dd, J = 10.0, 11.7 Hz), 2.55 (1H, dd, J = 2.7, 11.7 Hz), 2.59 (2H, t, J = 6.4 Hz), 2.99 (1H, dt, J = 3.3, 12.1 Hz) , 3.12 (1H, d, J = 12.1 Hz), 3.32 (2H, d, J = 6.3 Hz), 3.58-3.67 (2H, m);

MS (FAB) m / z: 169 [M + H] ⁺ .

(156c) 4- (3-[(2-cyanoethoxy) methyl] piperazin-1-yl) -2-thioxo-1, dihydropyridine-3-carbonitrile

The reaction was carried out according to the method described in Example 151 (151d) using 3- (piperidin-3-ylmethoxy) propanenitrile (550 mg, 3.27 mmol) prepared in Example 156 (156b), and the reaction was performed. An oily substance (178 mg) containing the compound as a main component was obtained.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.38-1.48 (1H, m), 1.67-1.91 (3H, m), 2.03-2.11 (1H, m), 2.61-2.64 (2H, m), 3.15 (1H , dd, J = 9.8, 13.3 Hz), 3.33-3.41 (2H, m), 3.47 (1H, dd, J = 4.7, 9.8 Hz), 3.60-3.66 (2H, m), 4.08 (2H, t, J = 14.5 Hz), 6.33 (1H, d, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz), 12.2 (1H, br).

(156d) 3-amino-4- {3-[(2-cyanoethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- (3-[(2-cyanoethoxy) methyl] piperazin-1-yl)-2-thioxo-1, dihydropyridine-3-carbonitrile prepared in Example 156 (156c) was used The reaction was carried out according to the method described in Example 151 (151e) to obtain the title compound (42.8 mg, yield 3.6% from 3- (piperidin-3-ylmethoxy) propanenitrile) as a yellow solid. .

Mp 155-156 ° C .;

IR (KBr) ν _max 3439, 3330, 3169, 2932, 2250, 1649, 1580, 1501, 1371, 1346 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.11-1.26 (1H, m), 1.72-1.97 (3H, m), 2.12 (1H, br s), 2.48 (1H, t, J = 11.2 Hz), 2.54 -2.64 (1H, m), 2.59 (2H, t, J = 6.1 Hz), 3.34-3.50 (4H, m), 3.60-3.69 (2H, m), 5.46 (2H, br s), 6.87 (1H, d, J = 4.9 Hz), 6.96 (2H, br s), 8.44 (1H, d, J = 4.9 Hz);

MS (FAB) m / z: 360 [M + H] ⁺ ;

analysis. Calc. For C ₁₇ H ₂₁ N ₅ O ₂ S.½H ₂ O: C, 55.42; H, 6.02; N, 19.01; S, 8.70. Found C, 55.44; H, 6.00; N, 18.88, S, 8.48.

Example 157 3-amino-4- (3-{[3- (dimethylamino) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carbox Mead (Example Compound No. 1-144)

(157a) benzyl 3-[(3-aminopropoxy) methyl] piperidine-1-carboxylate

Benzyl 3-[(2-cyanoethoxy) methyl] piperidine-1-carboxylate (2.06 g, 6.81 mmol) prepared in Example 156 (156a) was dissolved in methanol (30 mL) and cobalt ( II) Chloride (excess amount) and sodium borohydride (excess amount) were added several times, and it stirred for 3.5 hours at 0 degreeC in nitrogen atmosphere. Water and methylene chloride were added to the reaction mixture for separation. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 0: 1) to obtain the title compound (1.31 g, yield 63%) as an oily substance.

IR (Liquid film) ν _max 2935, 2858, 1699, 1470, 1432, 1261, 1236, 1154, 1116, 699 cm ⁻¹ ;

¹ H NMR (CD ₃ OD, 400 MHz): δ 1.20-1.32 (1H, m), 1.38-1.51 (1H, m), 1.62-1.81 (5H, m), 2.55-2.83 (3H, m), 2.92 ( 1H, br s), 3.20-3.33 (2H, m), 3.38-3.51 (2H, m), 3.91 (1H, d, J = 13.3 Hz), 4.04 (1H, d, J = 12.5 Hz), 5.09 ( 2H, s), 7.26-7.33 (5H, m);

MS (FAB) m / z: 307 [M + H] ⁺ .

(157b) benzyl 3-{[3- (dimethylamino) propoxy] methyl} piperidine-1-carboxylate

Benzyl 3-[(3-aminopropoxy) methyl] piperidine-1-carboxylate (890 mg, 2.90 mmol) prepared in Example 157 (157a) was diluted with formic acid (5 mL) and formaldehyde (5 mL). It mixed with and stirred at 100 degreeC for 2 hours in nitrogen atmosphere. The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (933 mg, 96%) as an oily substance.

IR (Liquid film) ν _max 2939, 2858, 1700, 1469, 1432, 1366, 1261, 1236, 1154, 1117 cm ⁻¹ ;

¹ H NMR (CD ₃ OD, 400 MHz): δ 1.19-1.30 (1H, m), 1.38-1.50 (1H, m), 1.62-1.81 (5H, m), 2.15-2.27 (6H, br), 2.31- 2.45 (2H, m), 2.60-2.84 (2H, br), 2.91 (1H, t, J = 12.3 Hz), 3.20-3.28 (1H, m), 3.34-3.46 (2H, m), 3.93 (1H, br s), 4.03-4.09 (1H, m), 5.09 (2H, s), 7.25-7.34 (5H, m);

MS (FAB) m / z: 335 [M + H] ⁺ .

(157c) N, N-dimethyl-N- [3- (piperidin-3-ylmethoxy) propyl] amine

Palladium-carbon in ethanol using benzyl 3-{[3- (dimethylamino) propoxy] methyl} piperidine-1-carboxylate (926 mg, 2.79 mmol) prepared in Example 157 (157b) The hydrocracking reaction was carried out in the presence of a catalyst to obtain the title compound (535 mg, 96% yield) as an oily substance.

IR (Liquid film) ν _max 3400, 2936, 2858, 2796, 1655, 1544, 1468, 1273, 1164, 1115 cm ⁻¹ ;

¹ H NMR (CD ₃ OD, 400 MHz): δ 1.10-1.21 (1H, m), 1.6-1.58 (1H, m), 1.66-1.83 (5H, m), 2.24 (6H, s), 2.33 (1H, dd, J = 10.6, 12.1 Hz), 2.35-2.42 (2H, m), 2.53 (1H, dt, J = 3.1, 12.1 Hz), 2.98 (1H, d, J = 13.3 Hz), 3.09 (1H, d , J = 12.1 Hz), 3.20-3.30 (2H, m), 3.39-3.47 (2H, m);

MS (EI) m / z: 200 [M ⁺ ].

(157d) 4- (3-([3- (dimethylamino) propoxy] methyl) piperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Example 151 (151d) using N, N-dimethyl-N- [3- (piperidin-3-ylmethoxy) propyl] amine (520 mg, 2.60 mmol) prepared in Example 157 (157c) Reaction was performed in accordance with the method described in, to obtain an oily substance (78.7 mg) containing the title compound as a main component.

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.34-1.42 (1H, m), 1.70-1.90 (6H, m), 2.23 (3H, s), 2.25 (3H, s), 2.38 (2H, t, J = 7.4), 3.08 (1H, dd, J = 9.8, 13.1 Hz), 3.23-3.48 (5H, m), 4.02-4.14 (2H, m), 6.30 (1H, d, J = 7.4 Hz), 7.34 ( 1H, d, J = 7.4 Hz), 7.86 (1H, br).

(157e) 3-amino-4- (3-{[3- (dimethylamino) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

4- (3-([3- (dimethylamino) propoxy] methyl) piperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3 prepared in Example 157 (157d) The reaction was carried out according to the method described in Example 151 (151e) using -carbonitrile to give the titled compound (44.1 mg, N, N-dimethyl-N- [3- (piperidin-3-ylmethoxy). Yield 4.3%) from propyl] amine was obtained as a yellow solid.

Mp 174 ° C .;

IR (KBr) ν _max 3450, 3311, 3167, 2936, 2858, 1649, 1579, 1504, 1368, 1345 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.08-1.20 (1H, m), 1.70-1.86 (3H, m), 1.86-1.95 (2H, m), 2.10 (1H, br s), 2.21 (6H, s), 2.32 (2H, t, J = 7.3 Hz), 2.46 (1H, t, J = 10.7 Hz), 2.59 (1H, t, J = 11.2 Hz), 3.27-3.39 (2H, m), 3.41- 3.50 (4H, m), 5.30 (2H, broad singlet), 6.90 (1H, doublet, J = 5.4 Hz), 7.01 (2H, broad singlet), 8.46 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 392 [M + H] ⁺ .

Example 158 3-amino-4- {3-[(cyanomethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide (example compound number 1-149)

(158) benzyl 3-[(cyanomethoxy) methyl] piperidine-1-carboxylate

Benzyl 3- (hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm (Weinheim Ger.), 323, 1990, 9-12) (1.01 g, 4.05 mmol) in tetrahydrofuran (10 mL) It melt | dissolved and added sodium hydride (55% oily, 216 mg, 4.95 mmol) under ice-cooling, and stirred for 30 minutes at room temperature under nitrogen atmosphere. A tetrahydrofuran (7 mL) solution of acetonitrile bromide (0.38 mL, 5.67 mmol) was added dropwise to the reaction solution over 2 hours. After stirring at room temperature for 2 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1-4: 1) to obtain the title compound (655 mg, yield 56%) as an oily substance.

IR (Liquid film) ν _max 3469, 2939, 2862, 1698, 1471, 1434, 1263, 1236, 1155, 1110 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.23-1.33 (1H, m), 1.41-1.54 (1H, m), 1.62-1.71 (1H, m), 1.75-1.90 (2H, m), 2.90-2.97 (1H, m), 2.69-2.87 (1H, br), 3.38-3.50 (2H, m), 3.94-4.10 (1H, br), 3.93 (1H, dt, J = 4.0, 13.4 Hz), 4.18 (2H , br s), 5.07-5.18 (2H, m), 7.27-7.37 (5H, m);

MS (EI) m / z: 289 [M + H] ⁺ .

(158b) (piperidin-3-ylmethoxy) acetonitrile

Benzyl 3-[(cyanomethoxy) methyl] piperidine-1-carboxylate (732 mg, 2.54 mmol) prepared in Example 158 (158a) was dissolved in ethanol (4 mL), and ammonium acetate (106 mg). , 1.38 mmol) and 10% palladium-carbon (90 mg) were added, and the mixture was stirred for 1.5 hours under a room temperature and atmospheric hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, washed with 1N aqueous sodium hydroxide solution, followed by saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (294 mg, yield 75%) as an oily substance. Got it.

IR (Liquid film) ν _max 3323, 2929, 2856, 2810, 2742, 1470, 1443, 1357, 1271, 1106 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.10-1.20 (1H, m), 1.41-1.52 (1H, m), 1.62-1.72 (2H, m), 1.74-1.85 (2H, m), 2.36 (1H , dd, J = 9.8, 11.7 Hz), 2.55 (1H, dt, J = 3.1, 11.7 Hz), 2.99 (1H, dt, J = 3.5, 12.0 Hz), 3.08-3.12 (1H, m), 3.38- 3.45 (2H, m), 4.22 (2H, s);

MS (FAB) m / z: 155 [M + H] ⁺ .

(158c) 4- {3-[(cyanomethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Using the (piperidin-3-ylmethoxy) acetonitrile (292 mg, 1.89 mmol) prepared in Example 158 (158b), the reaction was carried out according to the method described in Example 151 (151d) to obtain the title compound. An oily substance (111 mg) as a main component was obtained.

¹ H NMR (CDCl ₃ , 500 MHz): δ 1.32-1.42 (1H, m), 1.70-1.93 (4H, m), 3.42-3.59 (4H, m), 4.08-4.15 (2H, m), 4.29 (2H , s), 6.29 (1H, d, J = 7.5 Hz), 7.36 (1H, d, J = 7.5 Hz), 12.2 (1H, br).

(158d) 3-amino-4- {3-[(cyanomethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- {3-[(cyanomethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 158 (158c) was used In accordance with the method described in Example 151 (151e), the title compound (11.4 mg, yield 1.7% from (piperidin-3-ylmethoxy) acetonitrile) was obtained as a yellow solid.

Mp 217-218 ° C .;

IR (KBr) ν _max 3426, 3328, 3156, 2932, 1649, 1581, 1504, 1371, 1346, 1111 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz): δ 1.13-1.25 (1H, m), 1.75-1.87 (1H, m), 1.88-1.96 (2H, m), 2.11-2.22 (1H, br), 2.47 (1H , t, J = 11.0 Hz), 2.61 (1H, t, J = 11.0 Hz), 3.40-3.58 (4H, m), 4.24 (2H, s), 5.28 (2H, br s), 6.88 (1H, d , J = 5.5 Hz), 6.96 (2H, broad singlet), 8.45 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 346 [M + H] ⁺ ;

analysis. Calc. For C ₁₆ H ₁₉ N ₅ O ₂ S. 7 / 10H ₂ O: C, 53.68; H, 5.74; N, 19.56; S, 8.96. Found C, 53.67; H, 5.56; N, 19.34, S, 8.96.

Example 159 3-Amino-4- {3-[(2-hydroxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 1-99)

(159a) benzyl 3-[(2-tert-butoxy-2-oxoethoxy) hydroxymethyl] piperidine-1-carboxylate

Benzyl 3- (hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm (Weinheim Ger.), 323, 1990, 9-12) (11.97 g, 48.01 mmol), bromoacetic acid tert-butyl ( To a benzene (18 mL) suspension of 16.3 mL, 110 mmol) and tetra-n-butylammonium hydrogen sulfate (3.8 g, 11 mmol), 50% aqueous sodium hydroxide solution (18 mL) was added several times under ice cooling. It stirred at 0 degreeC for 15 minutes, and after stirring at room temperature overnight, ethyl acetate (30 mL) was added to the reaction mixture and liquid-separated. The organic layer was washed with saturated brine (3 x 60 mL), dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-4: 1) to obtain the title compound (16.88 g, yield 96%).

Colorless liquid

IR (film) ν _max 3033, 2935, 2858, 1747, 1701, 1431, 1368, 1260, 1232, 1138, 979, 850, 734, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.28 (1H, br s), 1.47 (10H, s), 1.67 (1H, br s), 1.84 (2H, br s), 2.76 (1H, br s), 2.88 (1H, t, J = 10.3 Hz), 3.30-3.44 (2H, br m), 3.92 (2H, s), 3.98 (1H, br s), 4.10 (1H, br s), 5.13 (2H, s ), 7.27-7.39 (5H, m);

HRMS m / z: Found [M + H] ⁺ 364.2111, calcd C ₂₀ H ₃₀ NO ₅ [M + H] ⁺ 364.2124.

(159b) (X1-[(benzyloxy) carbonyl] piperidin-3-yl} methoxy) acetic acid

Methylene chloride of benzyl 3-[(2-tert-butoxy-2-oxoethoxy) hydroxymethyl] piperidine-1-carboxylate (5.04 g, 13.9 mmol) prepared in Example 159 (159a) The solution (30 mL) was ice-cooled and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at 0 ° C. for 15 minutes, again at room temperature overnight and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 4-1: 5) to obtain the title compound (3.86 g, yield 91%).

Colorless liquid

IR (film) ν _max 3065, 2937, 1698, 1441, 1263, 1139, 977, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.24-1.40 (1H, m), 1.41-1.56 (1H, m), 1.57-1.72 (1H, m), 1.73-2.00 (2H, m), 2.78-3.30 (2H, m), 3.31-3.48 (2H, m), 3.57-4.15 (4H, m), 5.13 (2H, br s), 7.27-7.40 (5H, m);

MS (FAB) m / z: 308 [M + H] &lt; ⁺ &gt;, 264, 246, 176.

(159c) benzyl 3-[(2-hydroxymethoxy) methyl] piperidine-1-carboxylate

Under nitrogen atmosphere, boron trifluoride complex (3.5 mL, 27.7 mmol) was slowly added dropwise under ice cooling to a tetrahydrofuran (20 mL) suspension of sodium borohydride (0.785 g, 20.8 mmol), followed by stirring for 30 minutes. To the reaction mixture, tetrahydrofuran (22 mL) of (X1-[(benzyloxy) carbonyl] piperidin-3-yl} methoxy) acetic acid (5.317 g, 17.3 mmol) prepared in Example 159 (159b) ) Solution was added dropwise and stirred at 0 ° C. for 3 hours, and then methanol (5 mL) was added. The insolubles were filtered through celite and washed with ethyl acetate (100 mL). The crude product obtained by concentrating the filtrate was purified using silica gel column chromatography (hexane: ethyl acetate = 6: 4 to 100% ethyl acetate) to obtain the title compound (4.546 g, yield 90%).

Colorless liquid

IR (film) ν _max 3446, 2933, 1698, 1435, 1261, 1154, 1072, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.20-1.34 (1H, m), 1.40-1.55 (1H, m), 1.57-1.72 (1H, m), 1.74-1.94 (2H, m), 2.75-3.15 (2H, m), 3.29-3.37 (2H, m), 3.42-3.60 (2H, m), 3.64-4.03 (4H, m), 5.12 (2H, br s), 7.25-7.37 (5H, m);

MS (FAB) m / z: 294 [M + H] ⁺ , 250, 246, 226, 165.

(159d) 2- (piperidin-3-ylmethoxy) ethanol

To a ethanol (7 mL) solution of benzyl 3-[(2-hydroxymethoxy) methyl] piperidine-1-carboxylate (1.767 g, 6.02 mmol) prepared in Example 159 (159c) under a nitrogen atmosphere. , 10% palladium-carbon catalyst (150 mg) was added, and the mixture was stirred for 4 hours under atmospheric hydrogen atmosphere. After completion of the reaction, the catalyst was removed by celite filtration, and the crude product obtained after distilling off the solvent was subjected to silica gel column chromatography (Chromatorex, (NH), Fuji Silysia Chemical LTD.) (100% ethyl acetate). Purification was carried out to obtain the title compound (836 mg, yield 87%).

Colorless liquid

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.05-1.19 (1H, m), 1.39-1.51 (1H, m), 1.61-1.70 (1H, m), 1.73-1.86 (2H, m), 2.11 (2H , br s), 2.37 (2H, t, J = 10.2 Hz), 2.57 (2H, t, J = 11.7 Hz), 2.99 (2H, d, J = 12.1 Hz), 3.12 (2H, d, J = 12.1 Hz), 3.325 (2H, d, J = 6.3 Hz), 3.46-3.58 (2H, m), 3.69-3.77 (2H, m).

(159e) 4- {3-[(2-hydroxyethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

2- (piperidin-3-ylmethoxy) ethanol (749 mg, 4.70 mmol) and (2Z) -2-cyano-3-ethoxybuta-2-enthioamide prepared in Example 159 (159d) (J.Org.Chem., (1962), 27, 2433-2439) (780 mg, 4.58 mmol) was dissolved in N, N-dimethylformamide (8 mL) and stirred at room temperature for 2 hours. Furthermore, N, N-dimethylformamide dimethylacetal (0.73 mL, 5.50 mmol) was added to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 98: 2 to 85:15) and thin layer column chromatography (methylene chloride: methanol = 98: 2) to give the titled compound. (283 mg) was obtained. Yield 21%.

Amorphous

IR (film) ν _max 3193, 3148, 3043, 2932, 2859, 2207, 1621, 1571, 1448, 1361, 1249, 1167, 1121, 1059, 781, 599 cm ⁻¹ ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.27-1.41 (1H, m), 1.62-1.76 (1H, m), 1.86 (2H, br d, J = 9 Hz), 2.08 (1H, br s), 2.70-2.98 (1H, br s), 3.065 (1H, dd, J = 9.8, 13.3 Hz), 3.24-3.38 (2H, m), 3.445 (1H, dd, J = 4.7, 9.8 Hz), 3.48-3.60 (3H, m), 3.74 (2H, t, J = 4.7 Hz), 4.03 (2H, br d, J = 13.7 Hz), 4.325 (2H, br d, J = 13.7 Hz), 6.36 (1H, d, J = 7.4 Hz), 7.395 (1H, d, J = 7.4 Hz);

HRMS m / z: found [M + H] ⁺ 294.1254, calculated C ₁₄ H ₂₀ N ₃ 0 ₂ S [M + H] ⁺ 294.1276.

(159f) 3-amino-4- {3-[(2-hydroxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- {3-[(2-hydroxyethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbony prepared in Example 159 (159e) It synthesize | combined according to the method described in Example 5 (5c) using a tril. Yield 55%.

Amorphous

IR (KBr) ν _max 3438, 3326, 3191, 3148, 2931, 2856, 1648, 1581, 1502, 1448, 1372, 1247, 1123, 1059, 960, 825, 737, 605 cm ⁻¹ ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.07-1.22 (1H, m), 1.72-2.03 (4H, m), 2.15 (1H, br s), 2.46 (1H, br t, J = 10.2 Hz), 2.61 (1H, brt, J = 10.2 Hz), 3.31-3.59 (6H, m), 3.72 (2H, br s), 5.30 (2H, br s), 6.875 (1H, d, J = 5.4 Hz), 6.97 (2H, broad singlet), 7.835 (1H, doublet, J = 5.4 Hz);

HRMS m / z: found [M + H] ⁺ 351.1496, calculated C ₁₆ H ₂₃ N ₄ O ₃ S [M + H] ⁺ 351.1490.

Example 160 tert-Butyl2-(# 1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} meth Methoxy) ethylcarbamate (Example Compound No. 1-182)

(160a) benzyl 3- (X2- (methylsulfonyl) oxy] ethoxy} methyl) piperidine-1-carboxylate

Triethylamine (1.70 mL, 12.1 mmol), methanesulfonylchloride (0.87 mL, 11.2 mmol) under nitrogen atmosphere, and benzyl 3-[(2-hydroxymethoxy) methyl] prepared in Example 159 (159c). A solution of methylene chloride (50 mL) of piperidine-1-carboxylate (2.74 g, 9.34 mmol) was stirred overnight. After adding saturated brine (15 mL) to the reaction solution, an extraction operation was performed. The extract was dried over sodium sulfate, filtered and the crude product obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-2: 1) to give the title compound (3.25 g, yield). 94%) was obtained.

Pale yellow liquid

IR (film) ν _max 2937, 1697, 1433, 1354, 1236, 1175, 1019, 922, 807 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.16-1.28 (1H, m), 1.41-1.55 (1H, m), 1.62-1.73 (1H, m), 1.74-1.87 (2H, m), 2.62-2.82 (1H, m), 2.83-3.13 (4H, m), 3.27-3.41 (2H, m), 3.64 (2H, br s), 3.93-4.17 (2H, m), 4.31 (2H, br s), 5.07 -5.18 (2H, m), 7.28-7.41 (5H, m);

HRMS m / z: Found [M + H] ⁺ 372.1448, calculated C ₁₇ H ₂₆ N ₁ 0 ₆ S [M + H] ⁺ 372.1480.

(160b) benzyl 3-[(2-azideethoxy) methyl] piperidine-1-carboxylate

Sodium azide (723 mg, 11.12 mmol) and benzyl 3- (VII2-[(methylsulfonyl) oxy] ethoxy} methyl) piperidine-1-carboxylate prepared in Example 160 (160a) 3.178 g, 8.56 mmol) of a N, N-dimethylformamide (10 mL) solution was heated and stirred at 80 ° C. for 6 hours. Ethyl acetate (50 mL) and water (20 mL) were added to the reaction mixture for separation. The organic layer was washed with saturated brine (2 x 15 mL), dried over sodium sulfate, filtered and the crude product obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3). The title compound (2.721 g, yield 100%) was obtained.

Pale yellow liquid

IR (film) ν _max 2934, 2103, 1699, 1432, 1235, 1153, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.22-1.34 (1H, m), 1.40-1.54 (1H, m), 1.62-1.72 (1H, m), 1.74-1.89 (2H, m), 2.64-2.95 (2H, m), 3.26-3.41 (4H, m), 3.53-3.63 (2H, m), 3.94-4.15 (2H, m), 5.07-5.19 (2H, m), 7.28-7.39 (5H, m) ;

MS (FAB) m / z: 319 [M + H] ⁺ , 275, 242, 211, 183, 91, 63.

(160c) benzyl 3- (VII2-[(tert-butoxycarbonyl) amino] ethoxy} methyl) piperidine-1-carboxylate

Triphenylhosine (2.280g, 8.69mmol) benzyl 3-[(2-azideethoxy) methyl] piperidine-1-carboxylate (2.635g, 8.28mmol) prepared in Example 160 (160b) Was added to a tetrahydrofuran (8 mL) solution and stirred at room temperature for 20 hours. Water (0.3 mL) was added to the reaction solution, and the resultant was stirred for 20 hours. Then, di-tert-butyl dicarbonate (1.987 g, 9.10 mmol) was added, followed by stirring for 40 hours. The crude product obtained by concentrating the reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain the title compound (3.218 g, yield 99%).

Colorless oil

IR (film) ν _max 3355, 2933, 2861, 1701, 1520, 1433, 1260, 1237, 1155, 1121, 985, 867, 764, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.17-1.30 (1H, m), 1.44 (10H, s), 1.58-1.70 (1H, m), 1.72-1.83 (1H, m), 2.75 (1H, br s), 2.92 (1H, t, J = 10.9 Hz), 3.28 (4H, d, J = 5.9 Hz), 3.37-3.48 (2H, m), 3.87-4.06 (2H, m), 4.68-5.05 (1H) , m), 5.12 (2H, m), 7.25-7.37 (5H, m);

HRMS m / z: Found [M + H] ⁺ 393.2429, calculated C ₂₁ H ₂₉ N ₁₀ O ₂ [M + H] ⁺ 393.2389.

(160d) tert-butyl2- (piperidin-3-ylmethoxy) ethylcarbamate

Benzyl 3- (VII2-[(tert-butoxycarbonyl) amino] ethoxy} methyl) piperidine-1-carboxylate prepared in Example 160 (160c) under nitrogen atmosphere (3.158 g, 8.04) 10% palladium-carbon catalyst (257 mg) was added to the ethanol (14 mL) solution of mmol), and the mixture was stirred overnight under an atmospheric hydrogen atmosphere. The catalyst was removed by celite filtration and washed with ethanol. After the filtrate was concentrated, the crude product obtained was purified by silica gel column chromatography (Chromatorex, (NH), Fuji Silysia Chemical LTD.) (100% ethyl acetate) to obtain the title compound (2.018 g, yield 97%). Got it.

White solid

IR (film) ν _max 3303, 3205, 2978, 2939, 2857, 2804, 1690, 1560, 1367, 1275, 1170, 1126, 979, 949, 869, 777, 608 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.03-1.16 (1H, m), 1.44 (9H, s), 1.56-1.69 (2H, br s), 1.70-1.81 (2H, br s), 2.32 (1H , t, J = 10.9 Hz), 2.54 (1H, t, J = 10.9 Hz), 2.99 (1H, d, J = 12.2 Hz), 3.10 (1H, d, J = 12.2 Hz), 3.20-3.32 (4H , m), 3.43 (2H, broad singlet), 4.86 (1H, broad singlet);

HRMS m / z: found [M + H] ⁺ 259.1998, calculated C ₁₃ H ₂₇ N ₂ O ₃ [M + H] ⁺ 259.2021.

(160e) tert-butyl2- (piperidin-3-ylmethoxy) ethylcarbamate

The reaction was carried out according to the method described in Example 146 (146c) using tert-butyl2- (piperidin-3-ylmethoxy) ethylcarbamate prepared in Example 160 (160d) to give the title compound. Got. Yield 44%.

Pale yellow amorphous

IR (KBr) ν _max 3344, 3190, 3130, 2974, 2933, 2861, 2208, 1703,1620, 1515, 1450, 1365, 1302, 1249, 1170, 1167, 1120, 999, 964, 856, 781 cm ^-1 ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.30-1.40 (1H, m), 1.44 (9H, s), 1.63-1.74 (1H, br s), 1.80-1.91 (2H, br d), 2.02 (1H , br s), 3.00-3.10 (1H, m), 3.22-3.33 (4H, m), 3.38-3.50 (3H, m), 4.03-4.17 (2H, m), 4.89 (1H, br s), 6.28 (1H, d, J = 7.0 Hz), 7.28 (1H, d, J = 7.0 Hz);

HRMS m / z: Found [M + H] ⁺ 393.1998, calcd C ₁₉ H ₂₉ N ₄ O ₃ S [M + H] ⁺ 393.1960.

(160f) tert-butyl2- (VII1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} methoxy) Ethylcarbamate

It synthesize | combined according to the method described in Example 5 (5c) using tert- butyl 2- (piperidin-3-ylmethoxy) ethylcarbamate manufactured in Example 160 (160e). Yield 79%.

Pale yellow amorphous

IR (KBr) ν _max 3440, 3326, 3186, 2973, 2931, 2859, 1706, 1648, 1581, 1502, 1451, 1367, 1248, 1169, 1122, 1056, 995, 961, 865, 736, 557 cm ^-1 ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.05-1.22 (1H, m), 1.42 (9H, s), 1.71-1.95 (3H, m), 2.10 (1H, br s), 2.46 (1H, br t , J = 10.2 Hz), 2.59 (1H, brt, J = 10.2 Hz), 3.21-3.55 (8H, m), 4.82 (1H, br s), 5.33 (2H, br s), 6.90 (1H, d , J = 5.5 Hz), 6.99 (2H, br s), 8.46 (1H, d, J = 5.5 Hz);

HRMS m / z: found [M + H] ⁺ 450.2160, calcd C ₂₁ H ₃₂ N ₅ O ₄ S [M + H] ⁺ 450.2175.

Example 161 3-amino-4- {3-[(2-aminoethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide dihydrochloride (Example Compound No. 1-133)

Tert-butyl2- (VII1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} prepared in Example 160 Methoxy) ethylcarbamate (259 mg, 0.58 mmol) was suspended in 1,4-dioxane (4 mL), and 4N ethyl hydrochloride (3 mL) was added and stirred overnight. After distilling off the solvent, the obtained yellow individual was dried under reduced pressure to obtain the title compound.

IR (KBr) ν _max 3309, 3169, 2967, 2932, 2859, 1649, 1513, 1482, 1385, 1257, 1107, 1044, 963, 803, 729, 555, 476 cm ⁻¹ ;

¹ H NMR (CD ₃ OD, 400 MHz) δ 1.31-1.46 (1H, m), 1.75-1.95 (3H, m), 2.20 (1H, br s), 3.02-3.18 (3H, m), 3.20-3.31 (1H, m), 3.38-3.50 (2H, m), 3.57-3.70 (2H, m), 3.92 (1H, br d, J = 12.5 Hz), 4.04 (1H, br d, J = 12.5 Hz), 7.23 (1H, d, J = 7.0 Hz), 8.35 (1H, d, J = 7.0 Hz);

HRMS m / z: Found 350.1657 [M-2HCl + H] ⁺ , calc. C ₁₆ H ₂₄ N ₅ O ₂ S [M-2HCl + H] ⁺ 350.1650.

Example 162 3-amino-4- (3-{[2- (dimethylamino) -2-oxoethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Example Compound No. 1-155)

(162a) benzyl 3- {2-[(dimethylamino) -2-oxoethoxy] methyl} piperidine-1-carboxylate

Ice-cold in a methylene chloride (25 mL) solution of (# 1-[(benzyloxy) carbonyl] piperidin-3-yl} methoxy) acetic acid (1.062 g, 3.45 mmol) prepared in Example 159 (159b). Triethylamine (0.53 mL, 3.8 mmol) and ethyl chlorocarbonate (0.36 mL, 3.8 mmol) were added and stirred for 1 hour. Furthermore, triethylamine (0.6 mL, 4.32 mmol) and dimethylamine hydrochloride (352 mg, 3.8 mmol) were added to the reaction solution, and the mixture was stirred for 1 hour, followed by stirring at room temperature overnight. Saturated brine (15 mL) was added to the reaction mixture, and the extraction operation was carried out. The extracted organic layer was dried over sodium sulfate, filtered and concentrated to obtain crude product obtained by silica gel column chromatography (hexane: ethyl acetate = 1: 1). ) To obtain the title compound (961 mg, yield 83%).

Pale yellow liquid

IR (film) ν _max 3567, 3495, 2934, 2858, 1698, 1664, 1498, 1432, 1260, 1235, 1152, 1113, 980, 764, 700 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.17-1.32 (1H, m), 1.46 (1H, br s), 1.60-1.72 (1H, m), 1.75-1.91 (2H, m), 2.72 (1H, br s), 2.81-3.09 (7H, m), 3.27-3.44 (2H, m), 3.86-4.13 (4H, m), 4.68-5.05 (2H, m), 5.04-5.16 (2H, m), 7.25 -7.37 (5H, m);

HRMS m / z: found [M + H] ⁺ 335.1964, calculated C ₁₇ H ₂₈ N ₂ O ₄ [M + H] ⁺ 335.1970.

(162b) N, N-dimethyl-2- (piperidin-3-ylmethoxy) acetamide

Ethanol (7 mL) of benzyl 3- {2-[(dimethylamino) -2-oxoethoxy] methyl} piperidine-1-carboxylate (936 mg, 2.80 mmol) prepared in Example 162 (162a) 10% palladium-carbon (102.2 mg) was added to the solution, and the mixture was stirred overnight under an atmospheric hydrogen atmosphere. Palladium was removed by celite filtration and washed with ethanol. After concentration of the filtrate, the crude product obtained was purified by silica gel column chromatography (Chromatorex, (NH), Fuji Silysia Chemical LTD.) (100% ethyl acetate) to give the title compound (506 mg, 90% yield). Got.

Pale yellow liquid

IR (film) ν _max 3460, 3309, 2930, 2854, 1651, 1505, 1447, 1404, 1346, 1265, 1109, 1023, 886, 859, 806, 709, 574 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.07-1.17 (1H, m), 1.38-1.51 (1H, m), 1.61-1.80 (1H, m), 1.70-1.86 (2H, m), 2.36 (1H , dd, J = 9.8, 11.7 Hz), 2.54 (1H, dt, J = 2.7, 11.7 Hz), 2.94 (3H, s), 2.97 (1H, br s), 3.01 (3H, s), 3.14 (1H , br d, J = 12.1 Hz), 3.29-3.36 (2H, m), 4.10 (2H, s);

HRMS m / z: found [M + H] ⁺ 201.1611, calcd C ₁₀ H ₂₁ N ₂ O ₂ [M + H] ⁺ 201.2890.

(162c) 2-{[1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy} -N, N-dimethylacet amides

N, N-dimethyl-2- (piperidin-3-ylmethoxy) acetamide (5.695 g, 28.44 mmol) and (2Z) -2-cyano-3-ethoxy prepared in Example 162 (162b) Buta-2-enthioamide (J. Org. Chem., (1962), 27, 2433-2439) (4.825 g, 28.34 mmol) was suspended in ethanol (100 mL) and stirred at room temperature for 13 hours. After distilling off the solvent, N, N-dimethylformamide (60 mL) and N, N-dimethylformamide dimethylacetal (4.16 mL, 31.27 mmol) were added and stirred at room temperature overnight. The reaction mixture was concentrated, and the crude product obtained was purified using silica gel column chromatography (methylene chloride = 98: 2 to 85:15) to obtain the title compound (2.455 g). Yield 26%.

Light green white amorphous

IR (KBr) ν _max 3138, 3036, 2933, 2858, 2206, 1649, 1618, 1511, 1446, 1300, 1244, 1170, 1164, 1113, 1004, 964, 855, 782 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.29-1.43 (1H, m), 1.59-1.81 (3H, m), 1.99-2.12 (2H, m), 2.95 (3H, s), 2.97 (3H, s ), 3.07-3.11 (1H, m), 3.21-3.31 (1H, m), 3.36-3.53 (2H, m), 4.05-4.18 (4H, m), 6.32 (1H, d, J = 7.4 Hz), 7.31 (1H, doublet, J = 7.4 Hz);

HRMS m / z: found [M + H] ⁺ 335.1545, calculated C ₁₆ H ₂₃ N ₄ O ₂ S [M + H] ⁺ 335.1541.

(162d) 3-amino-4- (3-{[2- (dimethylamino) -2-oxoethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide

2-{[1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy}-prepared in Example 162 (162c)- It synthesize | combined according to the method described in Example 5 (5c) using N, N- dimethylacetamide. Yield 79%.

Light brown solid

IR (KBr) ν _max 3436, 3324, 3187, 2930, 2855, 1646, 1579, 1501, 1466, 1371, 1354, 1248, 1118, 1058, 961, 825, 737, 475 cm ⁻¹ ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.07-1.24 (1H, m), 1.68-1.95 (3H, m), 2.15 (1H, br s), 2.42-2.64 (2H, m), 2.93 (3H, s), 2.98 (3H, s), 3.32-3.57 (4H, m), 4.12 (2H, s), 5.27 (2H, br s), 6.90 (1H, d, J = 5.5 Hz), 6.87 (2H, br s), 8.43 (1H, d, J = 5.5 Hz);

HRMS m / z: found [M + H] ⁺ 392.1754, calculated C ₁₈ H ₂₆ N ₅ 0 ₃ S [M + H] ⁺ 392.1756;

analysis. Calc. For C ₁₈ H ₂₅ N ₅ O ₃ S.H ₂ O: C, 52.79; H, 6.65; N, 17.10. Found: C, 53.12; H, 6.25; N, 17.27.

Example 163 3-amino-4- (3-{[2- (diethylamino) -2-oxoethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine 2-carboxamide (Example Compound No. 1-164)

(163a) benzyl 3- {2-[(diethylamino) -2-oxoethoxy] methyl} piperidine-1-carboxylate

Ice-cold to a methylene chloride (30 mL) solution of (X1-[(benzyloxy) carbonyl] piperidin-3-yl} methoxy) acetic acid (920 mg, 2.99 mmol) prepared in Example 159 (159b). Triethylamine (0.44 mL, 3.14 mmol) and ethyl chlorocarbonate (0.3 mL, 3.14 mmol) were added thereto. After stirring the reaction solution for 1 hour, diethylamine (0.61 mL, 5.98 mmol) was added and stirred for 30 minutes, followed by stirring at room temperature overnight. Saturated brine (15 mL) was added to the reaction solution, and the extraction operation was performed. The extracted organic layer was dried over sodium sulfate, filtered and concentrated to obtain the crude product obtained by silica gel column chromatography (hexane: ethyl acetate = 1: 1). Purification was carried out to obtain the title compound (958 mg, yield 88%).

Colorless liquid

IR (film) ν _max 3553, 3496, 2935, 2858, 1698, 1664, 1468, 1433, 1261, 1235, 1153, 1115, 983, 765, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.04-1.32 (7H, m), 1.46 (1H, br s), 1.58-1.74 (1H, m), 1.82 (2H, br s), 2.71 (1H, br s), 2.86 (1H, brt, J = 10.9 Hz), 3.16-3.46 (6H, m), 3.96 (1H, br s), 4.06 (3H, br s), 5.02-5.18 (2H, m), 7.22-7.37 (5H, m);

HRMS m / z: Found [M + H] ⁺ 363.2290, calcd C ₂₀ H ₃₁ N ₂ O ₄ [M + H] ⁺ 363.2283.

(163b) N, N-diethyl-2- (piperidin-3-ylmethoxy) acetamide

Benzyl 3- {2-[(diethylamino) -2-oxoethoxy] methyl} piperidine-1-carboxylate (946 mg, 2.61 mmol) prepared in Example 163 (163a) under a nitrogen atmosphere. 10% palladium-carbon (110 mg) was added to an ethanol (7 mL) solution, and the mixture was stirred overnight under an atmospheric hydrogen atmosphere. Palladium was removed by celite filtration and washed with ethanol. After the filtrate was concentrated, the obtained crude product was purified by silica gel column chromatography (Chromatorex (NH), Fuji Silysia Chemical LTD.) (100% ethyl acetate) to obtain the title compound (549 mg, yield 92%). .

Colorless liquid

IR (film) ν _max 3464, 3310, 2932, 2853, 1643, 1464, 1440, 1380, 1268, 1221, 1123, 1109, 1035, 858, 796, 590 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.08-1.22 (7H, m), 1.38-1.51 (1H, m), 1.57-1.71 (2H, m), 1.75-1.88 (2H, m), 2.36 (1H , t, J = 11.7 Hz), 2.54 (1H, t, J = 11.7 Hz), 2.99 (1H, d, J = 11.7 Hz), 3.14 (1H, d, J = 11.7 Hz), 3.28-3.43 (6H m), 4.10 (2H, s);

MS (EI) m / z: found [M + H] ⁺ 229.19, calculated C ₁₂ H ₂₅ N ₂ 0 ₂ [M + H] ⁺ 229.34.

(163c) 2-{[1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy} -N, N-diethyl Acetamide

To N, N-diethyl-2- (piperidin-3-ylmethoxy) acetamide (524 mg, 2.3 mmol) and (2Z) -2-cyano-3- prepared in Example 163 (163b) Toxybuta-2-enthioamide (J.Org.Chem., (1962), 27, 2433-2439) (389 mg, 2.3 mmol) was dissolved in N, N-dimethylformamide (100 mL) and at room temperature Stir for 2.5 hours. N, N-dimethylformamide dimethylacetal (0.365 mL, 2.8 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the crude product obtained was purified by silica gel column chromatography (methylene chloride: methanol = 98: 2 to 85:15) and thin layer chromatography (methylene chloride: methanol = 95: 5) to give the titled compound. The mixture (84 mg) containing this as a main component was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.15 (3H, t, J = 7.0 Hz), 1.21 (3H, t, J = 7.0 Hz), 1.26-1.54 (1H, m), 1.64-2.03 (3H, m), 2.03-2.06 (2H, m), 3.05-3.14 (1H, m), 3.23-3.58 (6H, m), 4.03-4.22 (4H, m), 6.38 (1H, d, J = 7.4 Hz) , 7.38 (1H, doublet, J = 7.4 Hz).

(163d) 3-amino-4- (3-{[2- (diethylamino) -2-oxoethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2 Carboxamide

2-{[1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] methoxy}-prepared in Example 163 (163c)- A mixture containing N, N-diethylacetamide (84 mg) was prepared with 2-chloroacetamide (22 mg, 0.23 mmol), 8N aqueous sodium hydroxide solution (1 mL) and N, N-dimethylformamide (1 mL). It mixed and stirred for 3 hours. Ethyl acetate (25 mL) and saturated brine (10 mL) were added to the reaction mixture for separation. The aqueous layer was further extracted with ethyl acetate (15 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified by thin layer chromatography (ethyl acetate: methanol = 95: 5) to obtain the title compound (55 mg). Yield 5% from (2Z) -2-cyano-3-ethoxybuta-2-enthioamide.

IR (KBr) ν _max 3425, 3327, 3178, 2967, 2933, 2857, 1644, 1579, 1501, 1458, 1371, 1354, 1247, 1122, 1108, 1059, 962, 823, 770, 596, 477 cm ^-1 ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.05-1.21 (7H, m), 1.70-1.96 (3H, m), 2.14 (1H, br s), 2.43-2.64 (2H, m), 3.20-3.59 ( 8H, m), 4.10 (2H, s), 5.25 (2H, br s), 6.87 (1H, d, J = 5.1 Hz), 6.97 (2H, br s), 8.43 (1H, d, J = 5.1 Hz );

HRMS m / z: found [M + H] ⁺ 420.2075, calculated C ₁₈ H ₂₆ N ₅ 0 ₃ S [M + H] ⁺ 420.2069.

Example 164 4- (3- [2- (acetylamino) ethoxy] methyl} piperidin-1-yl) -3-aminothieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-173)

3-amino-4- {3-[(2-aminoethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide dichloride prepared in Example 161 Triethylamine (46 μL, 0.331 mmol) and acetyl chloride (8 μL, 0.114 mmol) were added to a methylene chloride (2 mL) solution of an acid salt (38 mg, 0.089 mmol) and stirred overnight. Methylene chloride (10 mL) and saturated brine (10 mL) were added to the reaction solution for separation. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain the crude product obtained by thin layer chromatography (methylene chloride: methanol = 96: 4) to obtain the title compound (29.3 mg, yield 84%).

Amorphous

IR (KBr) ν _max 3437, 3319, 3194, 2930, 2855, 1648, 1555, 1501, 1439, 1372, 1246, 1122, 1056, 996, 960, 824, 736, 475 cm ⁻¹ ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 1.06-1.19 (1H, m), 1.64-2.01 (6H, m), 2.13 (1H, br s), 2.40 (1H, br t, J = 10.7 Hz), 2.64 (1H, brt, J = 10.7 Hz), 3.24-3.61 (8H, m), 5.43 (2H, br s), 5.90 (1H, br s), 6.90 (1H, d, J = 5.4 Hz), 6.99 (2H, broad singlet), 8.47 (1H, doublet, J = 5.4 Hz);

HRMS m / z: found [M + H] ⁺ 392.1769, calculated C ₁₈ H ₂₆ N ₅ 0 ₃ S [M + H] ⁺ 392.1756.

Example 165 3-amino-4- (3-{[2- (hexanoylamino) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-car Copy mid (Example Compound No. 1-181)

Hexane Acid (1.03 mL, 8.27 mmol), N-hydroxysuccinimide (1.0 g, 8.69 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (1.66 g, 8.68 mmol) Solution of methylene chloride (30 mL) was stirred overnight at room temperature. Saturated brine (30 mL) was added to the reaction mixture, and an extraction operation was performed. The extract was dried over sodium sulfate and then filtered and concentrated to give the crude product of the active ester.

Crude active ester (16.6 mg, 0.078 mmol) and 3-amino-4- {3-[(2-aminoethoxy) methyl] piperidin-1-yl} thieno [2, 3-b] triethylamine (38 µL, 0.273 mmol) was added to a methylene chloride (2 mL) solution of pyridine-2-carboxamide dihydrochloride (32.9 mg, 0.078 mmol) and stirred overnight. Methylene chloride (15 mL) and saturated brine (5 mL) were added to the reaction mixture for separation. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain the crude product obtained by thin layer chromatography (ethyl acetate: methanol = 95: 5) to obtain the title compound (23.3 mg, yield 67%).

Amorphous

IR (KBr) ν _max 3440, 3321, 3191, 2929, 2858, 1645, 1579, 1502, 1457, 1373, 1346, 1247, 1122, 1057, 960, 824, 736, 557 cm ⁻¹ ;

¹ H NMR (CDCl ₆ , 400 MHz) δ 0.86 (3H, t, J = 7.0 Hz), 1.06-1.18 (1H, m), 1.20-1.33 (4H, m), 1.53-1.64 (2H, m), 1.72-1.96 (3H, m), 2.06-2.18 (3H, m), 2.41 (1H, brt, J = 10.7 Hz), 2.62 (1H, brt, J = 10.7 Hz), 3.25-3.56 (8H, m), 5.43 (2H, br s), 5.84 (1H, br s), 6.87 (1H, d, J = 5.1 Hz), 6.97 (2H, br s), 8.44 (1H, d, J = 5.1 Hz) ;

HRMS m / z: found [M + H] ⁺ 448.2383, calculated C ₂₂ H ₃₄ N ₅ O ₃ S [M + H] ⁺ 448.2382.

Example 166 3-amino-4- {3- [3- (2-hydroxyethoxy) propyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carbox Mead (Example Compound No. 1-101)

(166a) 3-piperidin-3-yl synthesized with reference to benzyl 3- (3-hydroxypropyl) piperidine-1-carboxylate J.Org.Chem., 1964, 29, 1736-1738 Propan-1-ol (9.86 g, 68.8 mmol) and triethylamine (11.5 mL, 82.6 mmol) were dissolved in methylene chloride (69 mL), and methylene chloride of benzyl chlorocarbonate (10.8 mL, 75.7 mmol) under ice cooling ( 35 mL) was added dropwise. After dripping, it stirred at room temperature for 2 hours, added water (70 mL) to the reaction liquid, and liquid-separated. The aqueous layer was extracted again with methylene chloride (50 mL × 2), and the combined extracts were dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 1 to 1/1) to give 10.13 g (yield 53%) of the title compound.

Light yellow oil

IR (film) ν _max 3445, 2935, 2857, 1699, 1435, 1261, 1238 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.01-1.72 (8H, m), 1.75-1.90 (1H, m), 2.41-2.66 (1H, m), 2.76-2.91 (1H, m), 3.54-3.69 (2H, m), 3.87-4.12 (2H, m), 5.12 (2H, br.s), 7.26-7.42 (5H, m);

MS (FAB) m / z: 278 [M + H] ⁺ , 258, 242, 234.

(166b) benzyl 3- [3- (2-tert-butoxy2-oxoethoxy) propyl] piperidine-1-carboxylate

Instead of benzyl 3- (3-hydroxymethyl) piperidine-1-carboxylate, benzyl 3- (3-hydroxypropyl) piperidine-1-carboxylate prepared in Example 166 (166a) Using the reaction method, the reaction was carried out according to the method described in Example 159 (159a) to obtain the title compound.

Colorless liquid

IR (film) ν _max 2936, 1749, 1701, 1431, 1237, 1136 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.08-1.86 (9H, m), 1.47 (9H, s), 2.80 (1H, t, J = 11.7 Hz), 3.46-3.49 (2H, m), 3.92 ( 2H, s), 3.98-4.11 (3H, m), 5.10 (2H, brs), 7.26-7.33 (5H, m);

MS (FAB) m / z: 392 [M + H] ⁺ , 390, 336, 258, 256, 91.

(166c) (3- {1-[(benzyloxy) carbonyl] piperidin-3-yl} propoxy) acetic acid

Methanol / water of benzyl 3- [3- (2-tert-butoxy2-oxoethoxy) propyl] piperidine-1-carboxylate (1.80 g, 4.60 mmol) prepared in Example 166 (166b). (2: 1) (15 mL) To the suspension, lithium hydroxide was added and stirred at room temperature for 17 hours. The reaction solution was concentrated, and water (100 mL) and methylene chloride (50 mL) were added to the residue for separation. 1N hydrochloric acid (30 mL) was added to the obtained aqueous layer, and extracted three times with methylene chloride (100 mL). The organic layers were combined, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (1.54 g) of the title compound.

Yellow liquid

IR (film) ν _max 3065, 2937, 1760, 1698, 1440, 1263, 1137, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.03-1.17 (1H, m), 1.18-1.54 (4H, m), 1.56-1.74 (3H, m), 1.76-1.89 (1H, m), 2.47-2.65 (1H, m), 2.78-2.95 (1H, m), 3.44-3.61 (2H, m), 3.90-4.11 (2H, m), 4.08 (2H, s), 5.12 (2H, s), 7.27-7.40 (5H, m);

MS (FAB) m / z: 336 [M + H ⁺ ], 273, 242, 226, 180.

(166d) benzyl 3- [3- (2-hydroxyethoxy) propyl] piperidine-1-carboxylate

Using (3- {1-[(benzyloxy) carbonyl] piperidin-3-yl} propoxy) acetic acid prepared in Example 166 (166c), according to the method described in Example 159 (159c) The reaction was carried out to obtain the title compound.

Colorless liquid

IR (film) ν _max 3457, 2935, 1698, 1434, 1362, 1237, 1119, 764, 699 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.02-1.16 (1H, m), 1.18-1.36 (2H, m), 1.37-1.53 (2H, m), 1.54-1.72 (3H, m), 1.80-1.90 (1H, m), 2.40-2.65 (1H, m), 2.74-2.88 (1H, m), 3.34-3.56 (4H, m), 3.68-3.76 (2H, m), 3.89-4.18 (2H, m) , 5.12 (2H, s), 7.27-7.43 (5H, m);

MS (FAB) m / z: 322 [M + H ⁺ ], 278, 242, 226, 186.

(166e) 2- (3-piperidin-3-ylpropoxy) ethanol

Reaction according to the method described in Example 159 (159d) using benzyl 3- [3- (2-hydroxyethoxy) propyl] piperidine-1-carboxylate prepared in Example 166 (166d) Was carried out to obtain the title compound.

Yellow liquid

IR (film) ν _max 3296, 2930, 1450, 1112, 893 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 0.96-1.08 (1H, m), 1.16-1.29 (2H, m), 1.39-1.50 (2H, m), 1.53-1.68 (3H, m), 1.73-1.87 (1H, m), 2.23 (1H, t, J = 10.3 Hz), 2.53 (1H, dt, J = 2.9, 12.2 Hz), 3.00 (1H, d, J = 12.2 Hz), 3.06 (1H, d, J = 11.7 Hz), 3.43-3.50 (2H, m), 3.51-3.55 (2H, m), 3.73 (2H, t, J = 4.9 Hz);

MS (FAB) m / z: 188 [M + H] ⁺ , 126, 96, 44.

(166f) 4- {3- [3- (2-hydroxyethoxy) propyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Using the 2- (3-piperidin-3-ylpropoxy) ethanol prepared in Example 166 (166e), the reaction was carried out according to the method described in Example 121 (121c) to obtain the title compound.

Brown powder

Mp 112-116 ° C .;

IR (KBr) ν _max 3526, 3117, 2940, 2210, 1625, 1547, 1461, 1313, 1249, 1128, 953, 800 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.17-1.46 (3H, m), 1.56-1.77 (4H, m), 1.83-1.90 (1H, m), 1.94-2.02 (1H, m), 2.15 (1H , brs), 2.85 (1H, dd, J = 10.5, 13.2 Hz), 3.16 (1H, dt, J = 2.9, 13.2 Hz), 3.40 (2H, t, J = 6.4 Hz), 3.55 (2H, t, J = 4.4 Hz), 3.74 (2H, t, J = 4.4 Hz), 4.07-4.18 (2H, m), 6.27 (1H, d, J = 7.3 Hz), 7.33 (1H, d, J = 7.3 Hz) , 12.15 (1H, broad singlet);

MS (FAB) m / z: 322 [M + H] ⁺ , 273, 242, 226, 180.

(166g) 3-amino-4- {3- [3- (2-hydroxyethoxy) propyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide

4- {3- [3- (2-hydroxyethoxy) propyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3 prepared in Example 166 (166f) Using the carbonitrile, the reaction was carried out according to the method described in Example 5 (5c) to obtain the title compound.

Pale yellow foam

IR (KBr) ν _max 3326, 2933, 1649, 1580, 1502, 1448, 1373, 1248, 1114, 1057, 960 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.96-1.14 (1H, m), 1.27-1.41 (2H, m), 1.57-1.83 (4H, m), 1.84-2.03 (3H, m), 2.24-2.36 (1H, m), 2.58-2.71 (1H, m), 3.34-3.45 (2H, m), 3.48 (2H, t, J = 6.7 Hz), 3.51-3.55 (2H, m), 3.70-3.75 (2H , m), 5.27 (2H, brs), 6.86 (1H, doublet, J = 5.5 Hz), 6.98 (2H, brs), 8.44 (1H, d, J = 5.5 Hz);

MS (FAB) m / z: 379 [M + H ⁺ ], 362, 258, 242, 226, 165;

analysis. Calc. For C ₁₈ H ₂₆ N ₄ O ₃ S.0.50H ₂ O: C, 55.79; H, 7.02; N, 14.46; S, 8.27. Found: C, 55.56; H, 6.87; N, 14.31, S, 8.24.

Example 167 3-amino-4- (3- {3- [2- (dimethylamino) -2-oxoethoxy] propyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Example Compound No. 1-157)

(167a) benzyl 3- {3- [2- (dimethylamino) -2-oxoethoxy] propyl} piperidine-1-carboxylate

Using (3- {1-[(benzyloxy) carbonyl] piperidin-3-yl} propoxy) acetic acid prepared in Example 166 (166c), according to the method described in Example 116 (116a) The reaction was carried out to obtain the title compound.

Colorless liquid

IR (film) ν _max 2935, 1699, 1433, 1261, 1112 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.06-1.86 (9H, m), 2.81 (1H, dt, J = 3.0, 11.7 Hz), 2.95-3.00 (1H, m), 2.95 (3H, s), 3.00 (3H, s), 3.48 (2H, t, J = 6.3 Hz), 3.99-4.15 (2H, m), 4.12 (2H, s), 5.12 (2H, brs), 7.35-7.36 (5H, m) ;

MS (FAB) m / z: 363 [M + H] ⁺ , 319, 273, 255, 227, 165, 91, 63.

(167b) N, N-dimethyl-2- (3-piperidin-3-ylpropoxy) acetamide

Example 162 (162b) using benzyl 3- {3- [2- (dimethylamino) -2-oxoethoxy] propyl} piperidine-1-carboxylate prepared in Example 167 (167a) Reaction was performed in accordance with the method described in the above, to obtain the title compound.

Pale yellow liquid

IR (film) ν _max 3432, 2932, 1650, 1415, 1271, 1114 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 0.99-1.84 (9H, m), 2.25 (1H, t, J = 11.7 Hz), 2.54 (1H, dt, J = 2.9, 11.7 Hz), 2.96-3.07 ( 2H, m), 2.96 (3H, s), 3.01 (3H, s), 3.48 (2H, t, J = 6.4 Hz), 4.12 (2H, s);

MS (FAB) m / z: 229 [M + H] ⁺ , 165, 63.

(167c) 2- {3- [1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] propoxy} -N, N- Dimethylacetamide

The reaction was carried out according to the method described in Example 121 (121c) using N, N-dimethyl-2- (3-piperidin-3-ylpropoxy) acetamide prepared in Example 167 (167b). To obtain the title compound.

Yellow powder

Mp 186-187 ° C .;

IR (KBr) ν _max 2935, 2205, 1619, 1514, 1302, 1244, 1114, 781 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.19-1.99 (9H, m), 2.84 (1H, dd, J = 10.7, 13.2 Hz), 2.96 (3H, s), 3.00 (3H, s), 3.17 ( 1H, dt, J = 2.9, 13.2 Hz), 3.52 (2H, t, J = 6.4 Hz), 4.10-4.16 (2H, m), 4.14 (2H, s), 6.28 (1H, d, J = 7.3 Hz ), 7.28 (1H, doublet, J = 7.3 Hz), 11.45 (1H, brs);

MS (FAB) m / z: 363 [M + H] ⁺ , 347, 273, 246, 219, 165;

analysis. Calc. For C ₁₈ H ₂₆ N ₄ O ₂ S.0.04H ₂ O: C, 59.52; H, 7.24; N, 15.43; S, 8.83. Found: C, 59.28; H, 7.09; N, 15.42; S, 8.76.

(167d) 3-amino-4- (3- {3- [2- (dimethylamino) -2-oxoethoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide

2- {3- [1- (3-cyano-2-thioxo-1,2-dihydropyridin-4-yl) piperidin-3-yl] propoxy prepared in Example 167 (167c) } -N, N-dimethylacetamide was used, and reaction was carried out in the same manner as in Example 5 (5c) to obtain the title compound.

White foam

IR (KBr) ν _max 3437, 3324, 2933, 1646, 1579, 1500, 1371, 1112, 960 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 0.99-1.07 (1H, m), 1.83-1.87 (2H, m), 1.63-1.81 (4H, m), 1.85-1.90 (1H, m), 1.95-2.00 (1H, m), 2.27-2.83 (1H, m), 2.62 (1H, t, J = 10.7 Hz), 2.95 (3H, s), 3.01 (3H, s), 3.39 (2H, brd, J = 9.8 Hz), 3.51 (2H, t, J = 6.4 Hz), 4.13 (2H, s), 5.27 (2H, brs), 6.88 (1H, d, J = 5.4 Hz), 7.01 (1H, brs), 8.46 ( 1H, d, J = 5.4 Hz);

HRMS m / z calc. C ₂₀ H ₃₀ O ₃ N ₅ S 420.2069, found 420.2058;

MS (ESI) m / z: 420 [M + H] ⁺ , 403;

analysis. Calc. For C ₂₀ H ₂₉ N ₅ 0 ₃ S.0.86H ₂ 0: C, 55.22; H, 7. 12; N, 16.10; S, 7.37. Found: C, 55.21; H, 6.93; N, 16.11; S, 7.10.

Example 168 3-amino-4 (3- {3- [2- (dimethylamino) ethoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-car Copyamide hydrochloride (Example Compound No. 1-143)

(168a) N, N-dimethyl-2- (3-piperidin-3-ylpropoxy) ethanamine

N, N-dimethyl-2- (3-piperidine-3-, prepared in Example 167 (167b), at a suspension of tetrahydrofuran (5 mL) of lithium aluminum hydride (490 mg, 12.9 mmol) at 0 ° C. A tetrahydrofuran (20 mL) solution of ylpropoxy) acetamide (974 mg, 4.3 mmol) was added dropwise and stirred at room temperature for 1 hour. Tetrahydrofuran (25 m1) and 1N sodium hydroxide (2.5 mL) were added to the reaction solution at 0 ° C, stirred for 30 minutes, and then dried over sodium sulfate. Insoluble matter was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (900 mg, yield 98%) as a crude title compound.

Colorless liquid

IR (film) ν _max 2934, 2854, 1466, 1271, 1118, 666 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.97-1.85 (9H, m), 2.26 (6H, s), 2.19-2.26 (1H, m), 2.49 (2H, t, J = 5.9 Hz), 2.47- 2.54 (1H, m), 3.00 (2H, t, J = 13.7 Hz), 3.40 (2H, t, J = 7.0 Hz), 3.50 (2H, t, J = 5.9 Hz);

MS (EI) m / z: 213 [M−H] ⁺ , 205, 182, 170, 144, 142, 126, 124, 96, 84, 71, 58, 41, 40.

(168b) 3-amino-4 (3- {3- [2- (dimethylamino) ethoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide Hydrochloride

The reaction was carried out according to the method described in Example 133 (133b) using N, N-dimethyl-2- (3-piperidin-3-ylpropoxy) ethane amine prepared in Example 168 (168a). To obtain 3-amino-4 (3- {3- [2- (dimethylamino) ethoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide Then, it mixed with 4N ethyl acetate hydrochloride solution and concentrated the mixture to obtain the title compound.

Yellow foam

IR (KBr) ν _max 3319, 3166, 2942, 1650, 1609, 1480, 1387, 1259, 1115, 753 cm ⁻¹ ;

¹ H NMR (CD ₃ OD, 500 MHz) δ 1.31-1.97 (9H, m), 2.91 (6H, s), 2.86-2.94 (1H, s), 3.31-3.36 (3H, m), 3.53-3.55 ( 2H, m), 3.74-3.76 (2H, m), 3.93-3.96 (2H, m), 7.25 (1H, d, J = 6.8 Hz), 7.37 (1H, d, J = 6.8 Hz);

HRMS m / z calc. C ₂₀ H ₃₂ O ₂ N ₅ S 406.2277. Found 406.2280;

MS (ESI) m / z: 406 [M + H] ⁺ , 363;

analysis. Calc. For C ₂₀ H ₃₁ N ₅ O ₂ S.2.6HCl.2H ₂ O: C, 44.58; H, 7.05; N, 13.00; Cl, 17.55. Found: C, 44.22; H, 7.94; N, 12.52; Cl, 17.68.

Example 169 3-amino-4- (3- {3- [3- (dimethylamino) propoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide (Example Compound No. 1-146)

(169a) benzyl 3- [3- (2-cyanoethoxy) propyl] piperidine-1-carboxylate

Using the benzyl 3- (3-hydroxypropyl) piperidine-1-carboxylate prepared in Example 166 (166a), the reaction was carried out according to the method described in Example 156 (156a) to obtain the title compound. Synthesized. Yield 73%.

Colorless oil

IR (film) ν _max 2937, 2860, 2251, 1699, 1432, 1261, 1237 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.03-1.14 (1H, m), 1.18-1.34 (2H, m), 1.37-1.51 (2H, m), 1.56-1.70 (3H, m), 1.80-1.88 (1H, m), 2.42-2.62 (3H, m), 2.78-2.87 (1H, m), 3.40-3.51 (2H, m), 3.57-3.67 (2H, m), 3.91-4.15 (2H, m) , 5.12 (2H, broad singlet), 7.29-7.38 (5H wide, m);

MS (FAB) m / z: 331 [M + H] ⁺ , 223, 195.

(169b) benzyl 3- [3- (3-aminopropyl) propyl] piperidine-1-carboxylate

Reaction according to the method described in Example 157 (157a) using benzyl 3- [3- (2-cyanoethoxy) propyl] piperidine-1-carboxylate prepared in Example 169 (169a) Was carried out to obtain the title compound (quantitative).

Light brown oil

IR (film) ν _max 3376, 2936, 2858, 1699, 1432 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.96-1.72 (8H, m), 1.77-1.98 (3H, m), 2.38-2.56 (1H, m), 2.72-2.88 (1H, m), 2.94-3.12 (1H, m), 3.28-3.60 (5H, m), 3.86-4.12 (2H, m), 5.10 (2H, br.s), 7.20-7.38 (5H, m);

MS (FAB) m / z: 335 [M + H] ⁺ , 316, 273.

(169c) benzyl 3- {3- [3- (dimethylamino) propoxy] propyl} piperidine-1-carboxylate

The reaction was carried out according to the method described in Example 157 (157b) using benzyl 3- [3- (3-aminopropyl) propyl] piperidine-1-carboxylate prepared in Example 169 (169b). To obtain the title compound. Yield 94%.

Colorless oil

IR (film) ν _max 3287, 2935, 2854, 2764, 1620, 1558, 1464 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.99-1.90 (11H, m), 2.22 (6H, s), 2.33 (2H, t, J = 7.4 Hz), 2.38-2.61 (1H, m), 2.74- 2.86 (1H, m), 3.31-3.48 (4H, m), 3.92-4.17 (2H, m), 5.12 (2H, br.s), 7.25-7.41 (5H, m);

MS (FAB) m / z: 363 [M + H] ⁺ , 349, 273, 227.

(169d) N, N-dimethyl-3- (3-piperidin-3-ylpropoxy) propan-1-amine

In the method described in Example 128 (128d) using benzyl 3- {3- [3- (dimethylamino) propoxy] propyl} piperidine-1-carboxylate prepared in Example 169 (169c) Thus, the reaction was carried out to obtain the title compound. Yield 94%.

Colorless oil

IR (film) ν _max 3287, 2935, 2854, 2764, 1620, 1558, 1464 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.95-1.07 (1H, m), 1.12-1.28 (2H, m), 1.33-1.50 (2H, m), 1.51-1.67 (2H, m), 1.68-1.87 (4H, m), 2.15-2.26 (1H, m), 2.23 (6H, s), 2.29-2.37 (2H, m), 2.52 (1H, dt, J = 11.7, 2.7 Hz), 2.95-3.08 (2H , m), 3.39 (2H, t, J = 6.6 Hz), 3.44 (2H, t, J = 6.6 Hz);

MS (EI) m / z: 228 M ⁺ ., 219, 184.

(169e) 3-amino-4- (3- {3- [3- (dimethylamino) propoxy] propyl} pyridin-1-yl) thieno [2,3-b] pyridine-2-carboxamide

According to the method described in Example 133 (133b), using N, N-dimethyl-3- (3-piperidin-3-ylpropoxy) propan-1-amine prepared in Example 169 (169d) The reaction was carried out to obtain the title compound. Yield 15%.

Brown amorphous

IR (film) ν _max 3439, 3321, 3172, 2936, 2855, 2816, 1652, 1580, 1500 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 0.97-1.11 (1H, m), 1.27-1.38 (2H, m), 1.54-1.68 (1H, m), 1.69-1.83 (4H, m), 1.84-1.92 (1H, m), 1.93-2.02 (1H, m), 2.22 (6H, s), 2.26-2.37 (3H, m), 2.57-2.67 (1H, m), 3.35-3.47 (6H, m), 5.33 (2H, br.s), 6.87 (1H, d, J = 5.4 Hz), 7.02 (2H, br.s), 8.46 (1H, d, J = 5.4 Hz);

MS (FAB) m / z: 420 [M + H] ⁺ , 377, 335, 273;

analysis. Calc. For C ₂₁ H ₃₃ N ₅ 0 ₂ S.0.5H ₂ 0: C, 58.85; H, 8.00; N, 16.34, S, 7.48. Found: C, 59.17; H, 7. 64; N, 16.12, S, 7.12.

Example 170 3-amino-4- [2- (methoxymethyl) morpholin-4-yl] thieno [2,3-b] pyridine-2-carboxamide (Example Compound No. 1-190)

(170a) 4- [2- (methoxymethyl) morpholin-4-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile

Example 121 (121c) using 2- (methoxymethyl) morpholine obtained by base treatment of 2- (methoxymethyl) morpholine hydrochloride (J.Med.Chem., 37, 2791, (1994)) The reaction was carried out in the same manner as to obtain the title compound.

Pale yellow powder

Mp 200-202 ° C .;

IR (KBr) ν _max 3122, 2895, 2208, 1621, 1545, 1514, 1445, 1303, 1251, 1099, 1011, 783, 424 cm ⁻¹ ;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.08 (1H, dd, J = 2.7, 13.7 Hz), 3.23-3.28 (1H, m), 3.27 (3H, s), 3.37 (1H, dd, J = 4.3, 10.2 Hz), 3.42 (1H, dd, J = 5.1, 10.2 Hz), 3.56 (1H, dt, J = 2.0, 11.4 Hz), 3.64-3.68 (1H, m), 3.90-4.01 (3H, m), 6.49 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.8 Hz), 12.73 (1H, brs);

MS (FAB) m / z: 266 [M + H] ⁺ , 265, 232, 220, 214, 180, 65, 63, 51, 39, 31, 23.

(170b) 3-amino-4- [2- (methoxymethyl) morpholin-4-yl] thieno [2,3-b] pyridine-2-carboxamide

Example 4- (2- (methoxymethyl) morpholin-4-yl] -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in Example 170 (170a) was used The reaction was carried out in the same manner as in the method described in 5 (5c), to obtain the title compound.

White powder

Mp 109-112 ° C .;

IR (KBr) ν _max 3420, 3319, 3171, 2885, 1651, 1580, 1500, 1371, 1245, 1099, 1003, 825, 743 cm ⁻¹ ;

¹ H NMR ((DMSO-d ₆ , 400 MHz) δ 2.56-2.65 (1H, m), 2.80-2.88 (1H, m), 3.20 (1H, d, J = 12.5 Hz), 3.26 (3H, s) , 3.29-3.31 (1H, m), 3.35 (1H, dd, J = 5.5, 10.2 Hz), 3.41 (1H, dd, J = 5.5, 10.6 Hz), 3.83-4.00 (3H, m), 6.92 (2H , brs), 7.02 (1H, d, J = 5.5 Hz), 7.12 (2H, brs), 8.43 (1H, d, J = 5.5 Hz);

HRMS m / z calc'd C ₁₄ H ₁₉ O ₃ N ₄ S 323.1178, found 323.1178;

MS (ESI) m / z: 323 [M + H] ⁺ , 306;

analysis. Calc. For C ₁₄ H ₁₈ N ₄ O ₃ S.0.44H ₂ O: C, 50.91; H, 5. 76; N, 16.96; S, 9.71. Found: C, 51.03; H, 5.53; N, 17.35; S, 9.32.

Example 171 3-amino-4- {3-[(2-morpholin-4-yl-2-oxoethoxy) methyl] piperidin-1-yl} thieno [2,3-b] Pyridine-2-carboxamide (Example Compound No. 1-229)

(171a) benzyl 3-[(2-morpholin-4-yl-2-oxoethoxy) methyl] pyridine-1-carboxylate

Morpholine was used instead of diethylamine, and reaction was performed according to the method of Example 163 (163a), and the title compound was obtained.

Colorless liquid

IR (film) ν _max 3507, 1698, 1434, 1360, 1236, 1115 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.18-1.30 (1H, m), 1.41-1.57 (1H, m), 1.62-1.72 (1H, m), 1.75-1.90 (2H, m), 2.66-2.79 (1H, m), 2.84-2.96 (1H, m), 3.30-3.74 (10H, m), 3.91-4.16 (4H, m), 5.12 (2H, s), 7.27-7.40 (5H, m);

MS (FAB) m / z: 377 [M + H ⁺ ], 333, 269, 241, 230, 186.

(171b) 4-[(piperidin-3-ylmethoxy) acetyl] morpholine

Example 163 (163b) using benzyl 3-[(2-morpholin-4-yl-2-oxoethoxy) methyl] piperidine-1-carboxylate prepared in Example 171 (171a) Reaction was performed in accordance with the method described in the above, to obtain the title compound.

Pale yellow liquid

IR (film) ν _max 3320, 2924, 1650, 1441, 1274, 1115 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.23 (1H, m), 1.39-1.55 (1H, m), 1.60-1.86 (3H, m), 2.37 (1H, dd, J = 10.1, 11.7 Hz ), 2.55 (1H, dt, J = 2.7, 11.7 Hz), 3.00 (1H, brd, J = 12.1 Hz), 3.12 (1H, brd, J = 12.1 Hz), 3.30-3.35 (2H, m), 3.50 -3.56 (2H, m), 3.57-3.63 (2H, m), 3.64-3.71 (4H, m), 4.11 (2H, s);

MS (FAB) m / z: 243 [M + H] ⁺ , 165, 96.

(171c) 4- {3-[(2-morpholin-4-yl-2-oxoethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3 Carbonnitrile

The title compound was obtained in the same manner as described in Example 163 (163c) using 4-[(piperidin-3-ylmethoxy) acetyl] morpholine prepared in Example 171 (171b). .

Yellow powder

Mp 172-177 ° C .;

IR (KBr) ν _max 3195, 2926, 2205, 1619, 1516, 1446, 1301, 1241, 115, 781 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.33-1.44 (1H, m), 1.65-1.77 (1H, m), 1.84-1.93 (2H, m), 2.03-2.14 (1H, m), 3.10 (1H , dd, J = 10.3, 13.2 Hz), 3.27 (1H, brt, J = 11.2 Hz), 3.41 (1H, t, J = 8.8 Hz), 3.45-3.53 (3H, m), 3.58-3.65 (2H, m), 3.66-3.73 (4H, m), 4.09 (1H, d, J = 13.2 Hz), 4.14-4.22 (3H, m), 6.32 (1H, d, J = 7.3 Hz), 7.29 (1H, d , J = 7.3 Hz), 11.74 (1H, br s);

MS (FAB) m / z: 377 [M + H] &lt; ⁺ &gt;, 345, 262, 232, 230;

analysis. Calc. For C ₁₈ H ₂₄ N ₄ O ₃ S: C, 57.43; H, 6. 43; N, 14.88; S, 8.52. Found: C, 57.18; H, 6. 47; N, 14.84, S, 8.44.

(171d) 3-amino-4- {3-[(2-morpholin-4-yl-2-oxoethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine- 4- {3-[(2-morpholin-4-yl-2-oxoethoxy) methyl] piperidin-1-yl} -2-ti prepared from 2-carboxamide Example 171 (171c) The reaction was carried out in the same manner as in Example 5 (5c), using oxo-1,2-dihydropyridine-3-carbonitrile to obtain the title compound.

Pale yellow powder

Mp 163-165 ° C .;

IR (KBr) ν _max 3451, 3156, 2931, 1649, 1579, 1501, 1366, 1116 cm ⁻¹ ;

¹ H NMR (CDCl ₃ , 500 MHz) δ 1.09-1.23 (1H, m), 1.73-1.97 (3H, m), 2.10-2.20 (1H, m), 2.40-2.52 (1H, m), 2.57-2.68 (1H, m), 3.33-3.74 (12H, m), 4.14 (2H, d, J = 3.9 Hz), 5.29 (2H, brs), 6.89 (1H, d, J = 5.4 Hz), 6.99 (2H, brs), 8.47 (1H, doublet, J = 5.4 Hz);

MS (FAB) m / z: 434 [M + H ⁺ ], 417, 391, 320, 272, 244, 202, 165;

analysis. Calc. For C ₂₀ H ₂₇ N ₅ O ₄ S: C, 55.41; H, 6. 28; N, 16.15; S, 7.40. Found: C, 55.07; H, 6. 30; N, 16.10, S, 7.37.

(Example)

Preparation Example 1 Powder

A powder can be obtained by mixing 5 g of the compound of Example 94, 895 g of lactose and 100 g of corn starch with a blender.

Preparation Example 2 Granules

After mixing 5 g of the compound of Example 74, 865 g of lactose, and 100 g of low-substituted hydroxypropyl cellulose, 300 g of an aqueous 10% hydroxypropyl cellulose solution was added and stirred. This is granulated using an extrusion granulator and dried to obtain granules.

Preparation Example 3 Tablet

Tablets can be obtained by mixing 5 g of the compound of Example 66, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender, followed by tableting with a refiner.

(Test example)

Test Example 1 Osteoblast Differentiation Test

ST2 cells (obtained from Rikagaku Research Institute), which are stromal cells derived from mouse bone marrow, were used. In this test, 10% (v / v) of immobilized fetal bovine serum (available from Hyclone, FBS), Penicillin-Streptomycin, Liquid (obtained from GIBCO BRL Cat.No. 15140-122) was 1 (alpha) -MEM medium (to obtain: GIBCO BRL Cat. No. 10370-021) (Hereinafter, it is called 10% -FBS- (alpha) MEM) was used so that it might become% (v / v). All cultures in this study were conducted in a CO incubator (37 ° C., 95% humidity, 5% CO).

The cells were detached by 2 mL of 0.25% trypsin solution (GlBCO BRL Cat. No. 15050-065), dispersed by adding 10 mL of 10% -FBS-αMEM, and then centrifuged (25 ° C). , 800 rpm, 5 minutes) cells were harvested. The recovered cells were prepared with a cell suspension of 40000 cells / mL using 10% -FBS-αMEM. Cell suspensions were dispensed into each well at 100 μL to 4,000 / well in 96 well microplates (Falcon) and incubated for 24 hours. In the wells except the control group, the compounds were aliquoted to a final concentration of 0.01, 0.03, 0.1, 0.3 μg / ml. Wells of the control group were dispensed with DMSO at a final concentration of 0.1% (v / v). After incubation for 4 days, alkaline phosphatase (ALP) activity was measured for each group.

The measurement of ALP activity was performed as follows. That is, after removing all the medium of each well of the culture plate, each well was washed twice by dispensing with 100 µL of Dulbecco's phosphate buffer (GIBCO BRL Cat. No. 14190-144). A cell lysate containing 10 mM MgCl ₂ , 2% (v / v) TritonX-100 (Sigma) was prepared, and the cell lysate was dispensed at 50 µL / well and stirred at room temperature for 5 minutes. ALP substrate solution containing 50 mM diethanolamine (Wakkoyaku Cat.No. 099-03112), 20mM p-nitrophenylphosphite (Wakkoyaku Cat. No.147-02343) was prepared, and the ALP substrate solution was prepared. 50 µL / well was dispensed and left for 10 minutes at room temperature, and then the absorbance was measured using a microplate reader (Bio-rad). The increase rate (%) of alkali phosphatase activity of the test compound addition group when the measured value of the control group of each plate was made into 100% was computed and evaluated as the degree of differentiation of osteoblasts.

In this test, Examples 14, 16, 17, 24, 29, 57, 58, 59, 64, 65, 66, 68, 72, 74, 76, 77, 83, 84, 93, 94, 96, 97 , 98, 99, 101 and 106 exhibited an increase in alkali phosphatase activity of at least 150% at 0.03 μg / mL.

Test Example 2 Osteoblast Formation Inhibition Test

18-day-old ICR mice were purchased from Nippon SLC and provided for the following experiments. The mouse was cervical dislocated and the left and right femurs and tibias were removed. The tissues around the extracted femur and tibia were removed and then chopped with scissors. 10 mL of 15% -FBS-αMEM was added to the finely divided femur and tibia and stirred for 1 minute, and then the supernatant was collected and filtered with a cell strainer (Becton Dickinson). 50% cells / mL of the cell suspension was prepared using 15% -FBS-αMEM. Cell suspensions were dispensed into each well at 100 μL to 50,000 cells / well in 96 well microplates (Falcon) and incubated for 24 hours. Each well was dispensed with a final concentration of 20 nM of active vitamin D3 (Sigma, Cat. No. D1530). In the wells except the control group, the compounds were aliquoted to a final concentration of 0.01, 0.03, 0.1, 0.3 μg / ml. Wells of the control group were dispensed with DMSO at a final concentration of 0.1% (v / v). After incubation for 5 days, tartaric acid resistant acid phosphatase (TRAP) activity was measured for each group.

The measurement of TRAP activity was performed as follows. That is, after completely removing the medium of each well of the culture plate, each well was washed twice by dispensing with 100 µL of Dulbecco's phosphate buffer (GIBCO BRL Cat. No. 14190-144). After correction for 1 minute with acetone-ethanol mixture (1: 1), the correction solution was removed and stained at 37 ° C for 30 minutes using a Lewkocyte acid phosphatase kit (Cig. No. 387-A, Sigma). . After removing the dyeing solution, 100 μL of 10% sodium dodecylsulfate (Wakkoyakku Cat. No.191-07145) was dispensed and stirred for 5 minutes, and then absorbance was measured using a microplate reader (Bio-rad). When the measured value of the control group of each plate was 100%, the TRAP activity lowering rate (%) of the test compound addition group was calculated and evaluated as osteoclast formation inhibitory activity.

In this test, the compounds of Examples 57, 65, 66, 72, 83, 94, 97, 99, 101, and 106 showed excellent osteoclast formation inhibitory activity.

Test Example 3 Effect on Bone Mineral Density

Eight week old female F344 rats were purchased from Charles River and used for the following experiments. The ketamine (12.5 mg / ml) and xylazine (2.5 mg / ml) mixed solution was intraperitoneally administered at a dose of 0.25 ml / 100 g, followed by an ovarian extraction or a control operation. The test compound suspended in 0.5% carboxymethyl cellulose sodium salt solution (Wakkoyakku Cat. No. 039-01335) from the day after surgery was administered orally once a day, 6 days a week. Six weeks after administration, whole blood was collected from the lower abdominal aorta with ketamine-xylazine, and euthanized, and the left and right femurs were removed.

After removing the soft tissue, the extracted femur was measured for bone density using a DXA apparatus DCS-600R (Aroka Co., Ltd.). Bone mineral density was evaluated by dividing the entire femur and the whole into three proximal, skeletal and distal ends.

In this test, the compound of Example 57 significantly increased bone density at 10 mg / kg.

Test Example 4 Effect on Fracture Healing

Twelve week old magnetic F344 rats were purchased from Charles River and used for the following experiments. Under ketamine-xylazine anesthesia, fracture was performed according to Li's method (J. Bone Miner. Res 1999, 14: 969-979). The test compound suspended in 0.5% carboxymethyl cellulose sodium salt solution (Wakkoyakku Cat. No. 039-01335) from the day after surgery was administered orally once a day, 6 days a week. 39 days after administration, the whole blood was euthanized from the lower abdominal aorta with ketamine-xylazine, and the femur was removed.

After removing the soft tissue, the extracted femur was measured using a bone strength measuring device MZ-500D (Maruto Co., Ltd.). A three point bending test was conducted to evaluate the maximum load.

In this test, the compound of Example 57 significantly improved fracture healing.

Since the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has the action of promoting bone formation, inhibiting bone resorption and / or improving bone density, medicines, in particular, bone Diseases [e.g., osteoporosis (e.g. postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressants), osteopenia or osteoarthritis associated with joint rheumatism, osteopathy disease, fractures, or microcertification Resulting from bone dysfunction] or as a medicament for the prevention or treatment of deformed arthrosis.

Claims (26)

General formula (I) [Formula 1]

[In the meal, R ¹ represents a hydrogen atom, a cyclopropyl group or a C ₁ -C ₆ alkyl group, R ² is R ^a S-, R ^a O-, R ^a NH-, R ^a (R ^b ) N- or [Formula 2]

Represents a group having R ^a And R ^b Is the same or different and is a C ₁ -C ₆ alkyl group which may be substituted with a group selected from a substituent group α and a substituent group γ, respectively; A C ₃ -C ₈ cycloalkyl group which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ; Or a 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ, R ³ And R ⁴ are the same or different and each is a hydrogen atom; One group selected from a substituent group α, a substituent group β, and a substituent group γ; A C ₁ -C ₆ alkyl group substituted with a group selected from the substituent group γ; Or a C ₁ -C ₆ alkoxy group substituted with a group selected from the substituent group γ, In addition, R ³ and R ⁴ Is a C ₃ -C which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ, including the carbon atoms to which they are bonded when R ³ and R ⁴ are bonded to a neighboring carbon atom ₈ cycloalkyl group; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ; Or a 5-7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ, Z is a single bond; Double bond; Oxygen atom; Sulfur atom; Sulfinyl; sulfonyl; Or a group having the formula R ⁵ N <, R ⁵ is a hydrogen atom; A C ₁ -C ₆ alkyl group which may be substituted with a group selected from a substituent group α and a substituent group γ; A C ₂ -C ₆ alkenyl group which may be substituted with a group selected from a substituent group α and a substituent group γ; A C ₃ -C ₈ cycloalkyl group which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; A C ₆ -C ₁₀ aryl group which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ; 5-7 membered heteroaryl group containing 1-3 of the sulfur atom, oxygen atom, and / or nitrogen atom which may be substituted by the group chosen from substituent group (alpha), substituent group (beta), and substituent group (gamma); Formyl group; C ₂ -C ₇ alkylcarbonyl group which may be substituted with a group selected from substituent group α and substituent group γ; 5 to 7 membered heterocyclylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; A C ₇ -C ₁₁ arylcarbonyl group which may be substituted with a group selected from a substituent group α, a substituent group β and a substituent group γ; 5 to 7 membered heteroarylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; C ₁ -C ₆ alkylsulfonyl group which may be substituted with a group selected from substituent group α and substituent group γ; C ₆ -C ₁₀ which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ. Arylsulfonyl group; 5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; C ₂ -C ₇ which may be substituted with a group selected from substituent group α and substituent group γ Alkoxycarbonyl group; C ₇ -C ₁₁ which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ. Aryloxycarbonyl group; Or a group represented by the formula ^{R c (R d) N-} CO- ( wherein, R ^c and R ^d is optionally substituted by the same or different and each is a hydrogen atom, or a substituent group α, and substituent group selected from the group C γ ₁ - A C ₆ alkyl group), n represents an integer of 1 to 4, Substituent group (alpha) is a halogen atom; Nitro group; Cyano group; Hydroxyl group; A group having the formula R ⁶ -CO-, the formula R ^e (R ^f ) N-CO- or R ^e (R ^f ) N-SO _2- (wherein R ⁶ Silver hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ halogenated alkyl group, C ₃ -C ₈ Cycloalkyl group, hydroxy group, C ₁ -C ₆ Alkoxy group, C ₆ -C ₁₀ aryl group or C ₆ -C ₁₀ An aryloxy group, R ^e and R ^f Are the same or different and each is a hydrogen atom; C ₁ -C ₆ Alkyl group; C ₁ -C ₆ Alkoxy group; C ₆ -C ₁₀ Aryl group; 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms; Formyl group; C ₂ -C ₇ Alkylcarbonyl group; C ₂ -C ₇ Alkoxycarbonyl group; C ₇ -C ₁₁ Arylcarbonyl group; 5 to 7 membered heteroarylcarbonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms; C ₁ -C ₆ Alkylsulfonyl group; C ₆ -C ₁₀ arylsulfonyl group; Or a 5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, or R ^e and R ^f Is a 4 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms, including the nitrogen atom to which they are bonded (wherein the heterocyclyl group is selected from hydroxy and methyl groups) May have two groups); Hydroxyimino groups; C ₁ -C ₆ Alkoxy imino group; C ₁ -C ₆ Alkoxy group; C ₃ -C ₈ Cycloalkyloxy group; C ₁ -C ₆ Halogenated alkoxy groups; C ₁ -C ₆ Alkylthio group; C ₁ -C ₆ Alkyl sulfinyl group; C ₁ -C ₆ Group consisting of alkylsulfonyl groups, Substituent Group β is a substituent C ₁ -C ₆ alkyl group optionally substituted by a group selected from the group α; And substituent group α and C ₁ -C ₆ C ₁ -C ₆ substituted with a 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from an alkyl group Group consisting of an alkyl group, Substituent group γ is C ₁ -C ₆ substituted with a group selected from the substituent group α. Alkoxy group; C ₁ -C ₆ substituted with a group selected from the substituent group α Alkylthio group; C ₃ -C ₈ which may be substituted with a group selected from substituent group α and substituent group β. Cycloalkyl group; A 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α and a substituent group β; C ₆ -C ₁₀ which may be substituted with a group selected from substituent group α and substituent group β. Aryl group; 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α and substituent group β; C ₃ -C ₈ which may be substituted with a group selected from substituent group α and substituent group β. Cycloalkyloxy group; A 5 to 7 membered heterocyclyloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from a substituent group α and a substituent group β; A C ₆ -C ₁₀ aryloxy group which may be substituted with a group selected from a substituent group α and a substituent group β; 5 to 7 membered heteroaryloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α and substituent group β; And C ₆ -C _{10 in} which the aryl moiety may be substituted with a group selected from substituent group α and substituent group β. Aryl-C ₁ -C ₆ Group which consists of an alkoxy group] And a pharmacologically acceptable salt thereof. The method of claim 1, R ¹ It is a hydrogen atom, a cyclopropyl group or a C ₁ -C ₄ alkyl group, the compound or its pharmacologically acceptable salts. The method of claim 1, Or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom, methyl, ethyl, propyl or cyclopropyl. The method of claim 1, R ¹ The compound or its pharmacologically acceptable salt which is this hydrogen atom or methyl. The method according to any one of claims 1 to 4, R ² An R ^a (R ^b) a group having a N-, R ^a and R ^b is C ₁ -C ₆ optionally substituted by the same or different and each is a substituent group α, and substituent group selected from the group γ A compound or a pharmacologically acceptable salt thereof that is an alkyl group. The method of claim 5, R^a C may be substituted with one group selected from substituent group α and substituent group γ_One-C₆ Alkyl group, R^b C_One-C₆ Alkyl group, substituent group α is C_One-C₆ C, which is a group consisting of an alkoxy group, and substituent group γ is substituted with a group selected from substituent group α_One-C₆Alkoxy group; C which may be substituted with a group selected from substituent group α and substituent group β₆-C₁₀ Aryloxy group; And a 5-7 membered heteroaryloxy group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from the substituent group α and the substituent group β, or a pharmacologically acceptable thereof. Salt. The method according to any one of claims 1 to 4, R ² [Formula 3]

C ₃ -C ₈ which is a group having R ³ and R ⁴ is a hydrogen atom or may be substituted with a group selected from substituent group α, substituent group β and substituent group γ together with R ^3. Cycloalkyl group; 5 to 7 membered heterocyclyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; C ₆ -C ₁₀ which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ. Aryl group; Or a compound which forms a 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ, or Pharmacologically acceptable salts. The method of claim 7, wherein R ² [Formula 4]

A group having a, wherein Z is a group having a single bond, an oxygen atom, a sulfur atom or a group represented by the formula R ⁵ N <, R ⁵ is a substituent group α, Substituent group β and Substituent group optionally substituted by a group selected from γ C ₆ that -C ₁₀ Aryl group; 5-7 membered heteroaryl group containing 1-3 of the sulfur atom, oxygen atom, and / or nitrogen atom which may be substituted by the group chosen from substituent group (alpha), substituent group (beta), and substituent group (gamma); Formyl group; C ₂ -C ₇ which may be substituted with a group selected from substituent group α and substituent group γ Alkylcarbonyl group; C ₁ -C ₆ which may be substituted with a group selected from the substituent group α and the substituent group γ. Alkylsulfonyl group; C ₆ -C ₁₀ which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ. Arylsulfonyl group; 5 to 7 membered heteroarylsulfonyl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; C ₂ -C ₇ which may be substituted with a group selected from substituent group α and substituent group γ Alkoxycarbonyl group; Or a group having the formula R ^c (R ^d ) N-CO-, wherein n is an integer from 1 to 3; or a pharmacologically acceptable salt thereof. The method of claim 8, R ³ 2 C ₁ -C ₆ Alkoxy group; C ₁ -C ₆ which may be substituted with a group selected from the substituent group α Alkyl group; C ₁ -C ₆ substituted with a group selected from the substituent group α Alkoxy group; A C ₆ -C ₁₀ aryloxy group which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ; C ₁ -C ₆ substituted with a group selected from the substituent group γ Alkyl group; Or C ₁ -C ₆ substituted with a group selected from the substituent group γ An alkoxy group: Z is a single bond: n is 2, or a pharmacologically acceptable salt thereof. The method of claim 8, R ³ Or a pharmacologically acceptable salt thereof, wherein the compound is a hydrogen atom, Z is a sulfur atom, and n is 1; The method of claim 8, R ³ Is a hydrogen atom: Z is a group having the formula R ⁵ N <: R ⁵ is C ₆ -C ₁₀ which may be substituted with a group selected from substituent group α, substituent group β, and substituent group γ. Aryl group; Or a 5 to 7 membered heteroaryl group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms which may be substituted with a group selected from substituent group α, substituent group β and substituent group γ: n is 2 , Compounds or pharmacologically acceptable salts thereof. A compound according to claim 11 or a pharmacologically acceptable salt thereof, selected from: 3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide, 3-amino-4-[(3S) -3- (methoxymethyl) piperidin-1-yl] -6-methylthieno [2,3-b] pyridine-2-carboxamide, 3-amino-4- {3- [3- (2-hydroxyethoxy) propyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide, 3-amino-4-{(3S)-[(2-methoxyethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide, 3-amino-4-{(3S) -3-[(3-methoxypropoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide, 3-amino-4- (3-{[2- (dimethylamino) -2-oxoethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carbox mid, 3-amino-4- (3- {3- [2- (dimethylamino) -2-oxoethoxy] propyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide, 4- [4- (4-acetylphenyl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide, 3-amino-4- [4- (4-propionylphenyl) -1,4-diazepane-1-yl] thieno [2,3-b] pyridine-2-carboxamide, 3-amino-4- {4- [4- (dimethylamino) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide, 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-carbox mid, 4- [4- (5-acetylpyridin-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide, 3-amino-4- (4- {4-[(dimethylamino) carbonyl] phenyl} -1,4-diazepane-1-yl) -6-methylthieno [2,3-b] pyridine- 2-carboxamide, 3-amino-4- {4- [4- (2-methoxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide , 3-amino-4- (4- {4- [2- (dimethylamino) -2-oxoethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide, 3-amino-4- (4- {4- [3- (dimethylamino) -3-oxopropyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide, 3-amino-4- {4- [4- (azetidin-1-ylcarbonyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide, 3-amino-4- {4- [4- (morpholin-4-ylcarbonyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide, 3-amino-4- (4- {4- [2- (dimethylamino) ethyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine-2-car Replica, 3-amino-4- {4- [4- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide , 3-amino-4- {4- [3- (2-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide , 3-amino-4- {4- [4- (3-hydroxypropyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide , 3-amino-4- {4- [4- (1-hydroxyethyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide , 3-amino-4- {4- [4- (2-oxopropyl) phenyl] -1,4-diazepane-1-yl} thieno [2,3-b] pyridine-2-carboxamide, 3-amino-4- {4- [4- (N-hydroxyethaneimideyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide, 3-amino-4- (4- {4-[(2-methyl-1,3-dioxolan-2-yl) methyl] phenyl} -1,4-diazepan-1-yl) thieno [2 , 3-b] pyridine-2-carboxamide, 3-amino-4- [4- (2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl) -1,4-diazepan-1-yl] thieno [ 2,3-b] pyridine-2-carboxamide, 3-amino-4- [4- (1,3-benzoxazol-6-yl) -1,4-diazepan-1-yl] thieno [2,3-b] pyridine-2-carboxamide , 3-amino-4- [4- (4-hydroxyimino-3,4-dihydro-2H-chromen-7-yl) -1,4-diazepan-1-yl] thieno [2, 3-b] pyridine-2-carboxamide, 4- [4- (4-acetyl-1,3-thiazol-2-yl) -1,4-diazepan-1-yl] -3-aminothieno [2,3-b] pyridine-2 Carboxamide, 4- [4- (5-acetylthiophen-2-yl) -1,4-diazepane-1-yl] -3-aminothieno [2,3-b] pyridine-2-carboxamide, And 3-amino-4- (4- {4-[(dimethylamino) carbonyl] -1,3-thiazol-2-yl} -1,4-diazepan-1-yl) thieno [2, 3-b] pyridine-2-carboxamide. A pharmaceutical comprising the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient. The method of claim 13, Medications for the prevention or treatment of bone disease or osteoarthritis. The method of claim 14, A medicament in which a bone disease is osteopenia, osteopenia associated with joint rheumatism or bone dysfunction resulting from bone destruction, osteopathy disease, fracture, or microcertification. The method of claim 15, A medicament in which osteoporosis is postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressants. Use of a compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient for the manufacture of a medicament. The method of claim 17, Use of the medicament for the prevention or treatment of bone disease or deformed arthrosis. The method of claim 18, Use of a bone disease is osteopenia, osteopenia associated with joint rheumatism or osteopenia due to bone destruction, osteopathy disease, fracture, or microcertification. The method of claim 19, Osteoporosis is postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressants. Promoting bone formation, inhibiting bone resorption, and / or comprising administering to a mammal or avian an effective amount of a compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof. How to improve bone density. The method of claim 21, A method for preventing or treating bone disease or deformed arthrosis. The method of claim 22, A bone disease is osteoporosis, osteopenia associated with joint rheumatism or bone dysfunction due to bone destruction, osteopathy disease, fracture, or microcertification. The method of claim 23, Osteoporosis is postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis by the use of steroids or immunosuppressive agents. The method according to any one of claims 21 to 24, The mammal is a human, a horse, a cow or a pig and the bird is a chicken. The method according to any one of claims 21 to 24, A method comprising administering to a human an effective amount a compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof.