JP2002255971A - Fused heterocyclic derivative, method for manufacturing the same and usage of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new fused thiophene derivative as a prophylactic treating agent or the like for diseases of bone or joint, an industrially advantageous method for manufacturing the same at a low cost and a new production interme diate for the same. SOLUTION: A compound expressed by general formula (I) [wherein, R<1> is a (substituted) hydrocarbon residue, heterocycle, sulfinyl, sulfonyl, hydroxy, thiol or amino; R<2> is cyano, formyl, thioformyl or the like; the ring A is an aromatic 5-membered heterocyclic ring expressed by general formula (II), (III) or (IV) (wherein, R<3> is H or a (substituted) hydrocarbon residue, heterocyclic, hydroxy, amino, sulfonyl or acryl; R<14> is H, a halogen or the like), and the ring B is a (substituted) 5- to 7-membered hydrocarbon ring] or a salt of the compound. A production intermediate for the compound a method for manufacturing the compound, a pharmaceutical composition containing a compound expressed by general formula (I) as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention has an activity of inducing the differentiation of undifferentiated cells such as progenitor osteoblasts, progenitor chondrocytes, and the like. Furthermore, the present invention relates to a condensed thiophene derivative or a salt thereof used as a preventive or therapeutic agent for a disease based on neurodegeneration, a method for producing the same, and a use thereof. The present invention also relates to a novel intermediate which is useful for producing the fused thiophene derivative of the present invention.

[0002]

2. Description of the Related Art Bone diseases include non-metabolic bone diseases such as bone fractures, bone deformity / osteomyelosis, osteosarcoma, myeloma, osteogenesis imperfecta, scoliosis, and osteoporosis, osteomalacia, rickets, fibrosis. There are metabolic bone diseases such as osteomyelitis, renal osteodystrophy and osteochet's disease, but metabolic bone diseases have recently become a problem. For example, osteoporosis, a metabolic bone disease, is a systemic disease characterized by low bone mass and increased bone fragility and osteofractures caused by changes in the microstructure of bone tissue, and its main clinical Symptoms are kyphosis, lumbar spine and fractures of the vertebral body, femoral neck, lower radius, ribs, upper humerus, and the like.
In bone tissue, bone formation and bone destruction due to bone resorption are constantly repeated while maintaining balance. When the balance between bone formation and bone destruction due to bone resorption is lost, the amount of bone is reduced. Conventionally, bone resorption inhibiting substances such as estrogen, calcitonin, bisphosphonate and the like have been mainly used as prophylactic / therapeutic agents for osteoporosis.

[0003] A joint disease is a disease in which degeneration of articular cartilage is the main lesion (for example, rheumatoid arthritis or osteoarthritis). Cartilage is a tissue composed of collagen and proteoglycans.
Proteoglycan release from the cartilage tissue is promoted, and the ability of the tissue to synthesize proteoglycan begins to decrease. At the same time, the release and activation of matrix metalloproteases such as collagenase-3 are enhanced, and collagen of cartilage tissue is degraded. A series of these reactions promotes hardening and destruction of cartilage tissue, and then progression of the lesion causes synovial hyperplasia, destruction of subchondral bone, cartilage hypertrophy or osteogenesis at the margins of the joint, and deformation of the joint. In severe cases, it can lead to dysfunction. Joint disease is most common in knee joints, but also in elbows, hips, feet, and finger joints. Among the joint diseases, osteoarthritis is the disease with the largest number of patients, but aging is considered as one of the causes of this disease. You. As a treatment method, an analgesic antiphlogistic or a hyaluronic acid preparation has been used for the purpose of removing pain associated with cartilage degeneration / subchondral bone sclerosis and destruction. However, all of them are only used as symptomatic treatments and have not been sufficiently effective. Promoting chondrogenesis, suppressing cartilage destruction, and promoting differentiation induction of chondrocytes including precursor chondrocytes are considered to be effective for prevention and treatment of cartilage diseases.

As a fused thiophene derivative, Maybridge (Trevillett, Tintagel, North)
Cornwall, PL34 0HW, UK) 's product catalog (Vol. 241, published October 1991) contains 4,5-
Dihydro-8- (methylthio) isoxazolo [5,4-d] benzo [c] thiophene-6-carboxamide [4,5-dihydro-8-
(methylthio) isoxazolo [5,4-d] benzo [c] thienophene-6-
carboxamide] is described. JP-A-8-2453
No. 86 discloses 4,5-dihydro-8- (methylthio) isoxazolo [5,4-d] benzo [c] thiophene-6-carboxamide [4,5-dihydro-8- (methylthio) isoxazolo [5, 4-d]
A benzo [c] thienophene-6-carboxamide] is described. JP-A-10-130271 (WO98 / 0)
No. 9958) has a cell differentiation inducing factor action enhancing action and an anti-matrix metalloprotease action,
A condensed thiophene compound useful for the prevention and treatment of bone diseases such as osteoporosis, fracture, osteoarthritis and rheumatoid arthritis, arteriosclerosis, cancer metastasis and neurodegenerative diseases, and a method for producing the same are described. In addition, GB 23365
Publication No. 89, Liebigs Analen
n.) pp. 239-245 (1996) and WO 98/09958, condensed thiophene derivatives and methods for their preparation
Heterocycles 43 367
(1996) also describes thiophene derivatives.

In the fused thiophene compound, a compound represented by the general formula (I):

Embedded image [In the formula, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z
² (wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or Represents an amino group), and ring A is

Embedded image (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or an individually substituted A hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B may have a substituent. Shows good 5- to 7-membered hydrocarbon rings. A compound represented by the general formula (I-11):

Embedded image [In the formula, R ^{1 ′} represents a hydrocarbon residue which may be substituted, a heterocyclic group, a sulfinyl group, a sulfonyl group,
Of the hydroxyl group, thiol group or amino group, the formula: -X '
-W '(wherein, X' represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally oxidized sulfur atom, and W 'is a substituted An optionally substituted cyclic group or a carbon atom or a nitrogen atom having two or more substituents).
R ² is a cyano group, a formyl group, a thioformyl group or a formula: —Z ¹ —Z ² (wherein Z ¹ is —CO—, —CS
—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. ) Represents a group represented by
^{3 ″} is an optionally substituted hydrocarbon residue,
A heterocyclic group, a sulfonyl group or an acyl group;
Represents a 5- to 7-membered hydrocarbon ring which may have a substituent. When producing a compound or a salt thereof, for example, when producing a compound 20 shown below,
D. Prim et al. (Synth. Commun., 25, 2449, 1995)
) And a paper by A. Nangia et al. (Indian J. Chem., 35B, 49
Page, 1996), and can be synthesized as in the following formula.

Embedded image

[0006]

In the clinical practice of bone or joint diseases (eg, cartilage diseases), drugs that are excellent in preventing and treating bone or joint diseases are still desired. In particular, a drug excellent in prevention and treatment of joint diseases represented by cartilage diseases is desired. Further, when the synthesis of Compound 20 is actually performed by the above-described synthesis route, the pyrazole ring-closing reaction of Intermediate 4 is inefficient without regioselectivity, and the desired Intermediate 5 can be obtained by column chromatography or the like. A complicated purification operation is required. In a general production facility, there is a problem that a boron trifluoride ether complex, which may be difficult to perform due to a corrosive problem, is used in the process of obtaining the intermediates 3 to 4. The point was highlighted, and it was necessary to develop an industrially advantageous manufacturing method that overcame these problems. In particular, no example has been found in which the problem of ring closure position selectivity has been positively solved.

[0007]

Means for Solving the Problems The inventors of the present invention have made various studies in view of the above circumstances, and have found that a novel fused thiophene derivative represented by the following formula (I) or a salt thereof having the characteristic of ring A is shown below. Has a strong differentiation-inducing activity for undifferentiated cells such as precursor osteoblasts and chondrocytes, and has been found to be useful as a preventive or therapeutic agent for bone or joint diseases. Further, the present inventors have found a novel synthetic intermediate useful for producing a novel fused thiophene derivative represented by the following formula (I) or a salt thereof having the characteristic of ring A.

Further, in the above synthetic route, the intermediate 7 easily obtained by the reaction of the intermediate 1 with trisdimethylaminomethane becomes a good pyrazole ring-closing precursor, and is reacted with the hydrazine derivative MeNHNH _2. Intermediate 8 was provided, and it was found that compound 20 can be produced from the obtained 8 in good yield.

Embedded image Furthermore, when a bulky substituent (here, an aryloxy group) is provided at the 3-position as in the intermediate 9 shown below, it is difficult to regioselectively close the ring. When the reaction was carried out, it was found that regioselectivity was improved and 5 was obtained in good yield.

Embedded image Further studies based on these findings led to the completion of the present invention.

That is, the present invention provides [1] a general formula (I):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. Represents a group.), Wherein ring A is

Embedded image (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or each substituted. Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. A compound represented by the formula:

Embedded image Excluding the compound represented by Also, ring A is In the above, the case where Z ¹ is —CO— and Z ² is an optionally substituted amino group is excluded. ) Or a salt thereof, [2]
The compound of the above-mentioned [1], wherein ring B is a 5- to 7-membered hydrocarbon ring _optionally having 1 to 3 C _1-8 alkyl groups, and [3] ring B has a substituent. The compound of the above-mentioned [1], which is a 5- to 7-membered hydrocarbon ring,
[4] the compound of the above-mentioned [1], wherein ring B is a 6-membered hydrocarbon ring having no substituent, [5] ring A is

Embedded image (Wherein R ¹⁴ has the same meaning as in the above [1]), wherein [6] ring A is

Embedded image Wherein the symbols in the formula are the same as those in the above [1], wherein [7] ring A is

Embedded image(The symbols in the formula have the same meanings as in the above [1].)
The compound of the above [1], [8] R³But (1) hydrogen source
Child, (2) C_1-6Alkoxy, carboxyl, C
_1-6Alkoxy-carbonyl, halogen and hydroxyl groups
May have 1 to 3 substituents selected from
C_1-8Alkyl group, (3) C_7-14Aralkyl groups,
(4) C_2-8Alkanoyl group, (5) C_1-6Arco
Xy-carbonyl group, (6) C_1-6Substituted with alkyl
An optionally substituted carbamoyl group, (7) C_1-8Archi
Rusulfinyl or (8) C_1-8Alkylsulfoni
R ¹⁴Is (1) a hydrogen atom, (2) a halogen,
(3) C_1-8Alkyl or (4) C_1-6Archi
Le, C_1-6Haloalkyl, C_1-6Alkoxy, C
_1-6Haloalkoxy, C_1-6Alkoxy-carboni
Le, amino and C_1-61 selected from alkylthio
I) each having from 3 to 3 substituents;
C _6-10Aryl, ii) one sulfur atom, one nitrogen
A 5-7 membered heterocyclic group containing an atom or one oxygen atom,
iii) a 5-6 membered heterocyclic group containing 2-4 nitrogen atoms, i
v) one or two nitrogen atoms and one sulfur or oxygen
A 5-6 membered heterocyclic group containing atoms, or v) no more than 2
A 5- to 6-membered ring containing a nitrogen atom, a benzene ring or one
Heterocyclic groups ii) to iv) fused with a 5-membered ring containing a sulfur atom
The compound according to the above [1], which is

[9] R³Is C_1-8
In the alkyl group, R¹⁴Is a hydrogen atom.
A compound of [10] R¹Is an optionally substituted carbonized
The compound of the above-mentioned [1], which is a hydrogen residue, [11] R¹
Is an optionally substituted heterocyclic group, [1]
Compound [12] R¹Are each replaced
Sulfinyl group, sulfonyl group or thiol group
A compound of the above-mentioned [1], wherein [13] R¹Is replaced
The compound according to the above [1], which is a hydroxyl group which may be
Object, [14] R¹Is an amino group which may be substituted
Certain compounds described in the above [1], [15] R¹But (1)
Each C_1-8Alkyl or C_7-14Aralkyl
A sulfinyl group or a sulfonyl group which may be substituted with
Or a thiol group, (2) C_1-8Alkyl, C
_6-14Aryl, C_7-14Aralkyl, hydroxyl, C
_1-6Alkoxy, C_1-6Alkylenedioxy, C
_6-14Aryloxy, C_1-6Alkylthio, mole
Holinosulfonyl, formyl, C_1-6Alkyl-cal
Bonyl, carboxyl group, C_1-6Alkoxy-carbo
Nil, C_{6-1 4}Aryloxy-carbonyl, C
_7-14Aralkyloxy-carbonyl, amino, mono
-Or di-C_1-6Alkylamino, mono- or di
-C_1-6Alkyl-carbonylamino, toluenesulfur
Honylamino, C_1-6Alkylaminothiocarbonyl
Amino, nitro, halogen, C_1-6Haloalkyl, C
_1-6Haloalkoxy, C_1-6Alkoxy-C
_6-14Aryl, 2-amino-3- (4-morpholini
Ru) -3-oxo-C_1-6Alkyl, di (C_1-6A
Lucoxy) C having 1 or 2 phosphoryls_1-6A
Selected from alkyl, nitrogen, oxygen and sulfur
5- or 6-membered aromatic having 1-4 heteroatoms
Selected from a ring group, a nitrogen atom, an oxygen atom and a sulfur atom
5- or 6-membered aromatic having 1-4 heteroatoms
Elementary ring-oxy, and nitrogen atom, oxygen atom and sulfur atom
5-membered aromatic having 1-3 heteroatoms selected from the group consisting of
Or 6-membered heterocyclic ring and benzene ring or nitrogen atom, acid
1 to 3 heteroatoms selected from elementary atoms and sulfur atoms
Formed by the condensation of aromatic 5- or 6-membered heterocycles
Or 2 selected from fused bicyclic heterocycle-oxy
I) C_6-10An aryloxy group, ii) a group selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Aromatic 5- or 6-membered heterocyclic ring having 1 to 4 terror atoms
-Oxy or iii) selected from nitrogen, oxygen and sulfur
5- or 6-membered aromatic compound having 1 to 3 hetero atoms
Elementary and benzene rings or nitrogen, oxygen and sulfur
Aromatic having 1 to 3 heteroatoms selected from yellow atoms
A condensed bicyclic ring formed by condensing a 5- or 6-membered heterocyclic ring
Heterocyclic-oxy group, (3) C_1-8Alkyloxy group, C_3-7Cycloal
Killoxy group, C_{7-1 4}An aralkyloxy group or
Dihydrobenzofuranyloxy group, (4) C_1-8Al
Kill, C_6-10Aryl, C_7-14Aralkyl, Ha
B _6-10Aryl, C_1-6Alkyl-carboni
Le, C_6-10Aryl-carbonyl and C_7-14
1 or 2 selected from aralkyl-oxycarbonyl
Amino group which may be substituted with
(5) C_1-8Alkyl group or C_7-14Aralki
A compound according to the above [1], wherein¹But,
(1) C_1-8Sulfi substituted with alkyl
A nyl group, a sulfonyl group or a thiol group, (2) (a)
C_1-6Alkylenedioxy, (b) di (C_1-6Al
Coxy) phosphoryl-C_1-6Alkyl, (c) C
_1-6Haloalkyl, (d) C_7-14Aralkyl
(E) selected from a nitrogen atom, an oxygen atom and a sulfur atom
5- or 6-membered aromatic having 1-4 heteroatoms
Heterocyclic-oxy or (f) a nitrogen atom, an oxygen atom and
Having 1 to 3 heteroatoms selected from sulfur and sulfur
Aromatic 5- or 6-membered heterocyclic ring and benzene ring or nitrogen
Hetero atoms selected from atoms, oxygen atoms and sulfur atoms
Aromatic 5- or 6-membered heterocyclic ring having 1 to 3
Substituted with a fused bicyclic heterocycle-oxy
May be C_6-10Aryloxy group, (3) nitrogen source
Heteroatom selected from oxygen, oxygen and sulfur
5- to 6-membered aromatic heterocyclic-oxy having 1 to 4 aromatic rings
Group or (4) nitrogen atom, oxygen atom and sulfur atom
An aromatic 5-membered member having 1-3 heteroatoms selected from
Or 6-membered heterocyclic ring and benzene ring or nitrogen atom, oxygen atom
1 to 3 heteroatoms selected from
Formed by condensing aromatic 5- or 6-membered heterocyclic ring
The compound of the above-mentioned [1], which is a condensed bicyclic heterocyclic-oxy group.
Compound, [17] R^TwoIs -CO-Z^{2 '} (Where Z^{2 '}Is a hydrogen atom, each of which may be substituted
Represents a hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group.
You. The compound according to the above [1], wherein [18] Z
^{2 '}But C_1-8Alkyl, C_6-14Aryl, C
_7-14Aralkyl, hydroxyl, C_1-6Alkoxy, a
Mino, mono or di C_1-6Alkylamino, C_1-6
Alkoxy-carbonylamino, nitrogen atom, oxygen atom,
And has 1 to 4 heteroatoms selected from sulfur atoms
Aromatic 5- or 6-membered heterocyclic group, C_1-6Haloalk
Le, carboxy C_1-6Alkyl, C_1-6Alkoxy
-Carbonyl-C_1-6Alkyl, carbamoyl C
_1-6Alkyl, nitrogen, oxygen and sulfur
5-membered aromatic having 1-4 heteroatoms selected from
Is a 6-membered heterocyclic -C_1-6Alkyl, nitrogen atom, oxygen atom
And 1 to 4 heteroatoms selected from sulfur atoms
Aromatic 5- or 6-membered heterocyclic -C_1-6Alkyl-C
_6-14Aryl and mono or di C_1-6Alkyl
Amino C_1-61 or 2 positions selected from alkyl
Amino group or morpholino which may be substituted with a substituent
A compound according to the above [17], which is a group; [19] Z^{2 '}But,
One or two C_1-6May be substituted with alkyl
A compound according to the above [17], which is an amino group, [20]
R¹⁴Is a hydrogen atom, the compound of the above-mentioned [1], [2]
1] R¹But (1) each C_1-8Alkyl or C
_7-14Sulfini optionally substituted with aralkyl
Group, sulfonyl group or thiol group, (2) C_1-8
Alkyl, C_6-14Aryl, C_7-14Aralki
, Hydroxyl group, C_1-6Alkoxy, C_1-6Alkylene
Dioxy, C_6-14Aryloxy, C_1-6Archi
Lucio, morpholinosulfonyl, formyl, C_1-6A
Alkyl-carbonyl, carboxyl group, C_1-6Arco
Xy-carbonyl, C_{6-1 4}Aryloxy-carbo
Nil, C_7-14Aralkyloxy-carbonyl, ami
No, mono- or di-C_1-6Alkylamino, mono-
Or di-C_1-6Alkyl-carbonylamino, tol
Ensulfonylamino, C_1-6Alkylaminothioca
Rubonylamino, nitro, halogen, C_1-6Haloal
Kill, C_1-6Haloalkoxy, C_1-6Alkoxy-
C_6-14Aryl, 2-amino-3- (4-morpholy
Nil) -3-oxo-C_1-6Alkyl, di (C_1-6
C having one or two alkoxyl phosphoryls_1-6
Selected from alkyl, nitrogen, oxygen and sulfur
5- or 6-membered aromatic having 1-4 heteroatoms
Selected from heterocyclic group, nitrogen atom, oxygen atom and sulfur atom
5- or 6-membered aromatic having 1-4 heteroatoms
Heterocycle-oxy, and nitrogen, oxygen and sulfur
Aromatic 5 having 1 to 3 hetero atoms selected from atoms
Membered or 6-membered heterocyclic ring and benzene ring or nitrogen atom,
1 to a hetero atom selected from an oxygen atom and a sulfur atom
3 aromatic 5- or 6-membered heterocyclic ring condensed to form
1 or selected from the condensed bicyclic heterocycle-oxy
Each of which may be substituted with two substituents, i) C_6-10An aryloxy group, ii) a group selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Aromatic 5- or 6-membered heterocyclic ring having 1 to 4 terror atoms
-Oxy or iii) selected from nitrogen, oxygen and sulfur
5- or 6-membered aromatic compound having 1 to 3 hetero atoms
Elementary and benzene rings or nitrogen, oxygen and sulfur
Aromatic having 1 to 3 heteroatoms selected from yellow atoms
A condensed bicyclic ring formed by condensing a 5- or 6-membered heterocyclic ring
Heterocyclic-oxy group, (3) C_1-8Alkyloxy group, C_3-7Cycloal
Killoxy group, C_{6-1 4}Aryloxy group, C
_7-14Aralkyloxy group or dihydrobenzof
Ranyloxy group, (4) C_1-8Alkyl, C_6-10
Aryl, C_7-14Aralkyl, Halo C _6-10Ants
, C_1-6Alkyl-carbonyl, C_6-10Ants
Carbonyl and C_7-14Aralkyl-oxy
Substituted with one or two substituents selected from carbonyl
An optionally substituted amino group, or (5) C_1-8Archi
Group or C_7-14An aralkyl group, R^TwoIs -C
O-Z^{2 '}And Z^{2 '}But C_1-8Alkyl, C_6-14A
Reel, C_7-14Aralkyl, hydroxyl, C_1-6Al
Coxy, amino, mono or di C _1-6Alkylam
No, C_1-6Alkoxy-carbonylamino, nitrogen source
Heteroatom selected from oxygen, oxygen and sulfur
An aromatic 5- or 6-membered heterocyclic group having 1 to 4 carbon atoms, C
_1-6Haloalkyl, carboxy C_1-6Alkyl, C
_{1- 6}Alkoxy-carbonyl-C_1-6Alkyl, mosquito
Lubamoyl C_1-6Alkyl, nitrogen, oxygen and
Having 1 to 4 heteroatoms selected from sulfur and sulfur atoms
Aromatic 5- or 6-membered heterocycle-C_1-6Alkyl, nitrogen source
Heteroatom selected from oxygen, oxygen and sulfur
Aromatic 5- or 6-membered heterocycle having 1 to 4 -C_1-6
Alkyl-C_6-14Aryl and mono or di C
_1-6Alkylamino C_1-61 selected from alkyl
Or an amino group which may be substituted with two substituents.
Or a morpholino group, R³Is (1) hydrogen atom, (2)
C_1-6Alkoxy, carboxyl, C_{1- 6}Alkoki
1 selected from c-carbonyl, halogen and hydroxyl
C to C 3 optionally having 3 substituents_1-8Archi
Group, (3) C_7-14Aralkyl group, (4) C_2-8
Alkanoyl group, (5) C_1-6Alkoxy-carboni
Group, (6) C_1-6Optionally substituted with alkyl
Carbamoyl group, (7) C_{1- 8}Alkylsulfinyl
Or (8) C_1-8Alkylsulfonyl, R
¹⁴Are (1) hydrogen atom, (2) halogen, (3) C
_1-8Alkyl or (4) C_{1 -6}Alkyl, C
_1-6Haloalkyl, C_1-6Alkoxy, C_1-6C
Lower alkoxy, C_1-6Alkoxy-carbonyl, amine
No and C_1-61 to 3 selected from alkylthio
I) C_6-1
0Aryl, ii) one sulfur atom, one nitrogen atom
Or a 5- to 7-membered heterocyclic group containing one oxygen atom, iii) 2
A 5-6 membered heterocyclic group containing ４4 nitrogen atoms, iv) 1-2
Contains one nitrogen atom and one sulfur or oxygen atom
A 5-6 membered heterocyclic group, or v) no more than 2 nitrogen atoms
Including a 5- to 6-membered ring, a benzene ring or one sulfur atom
A heterocyclic group condensed with a 5-membered ring containing
But one to three C_1-8Even if it has an alkyl group
The compound according to the above [1], which is a good 5- to 7-membered hydrocarbon ring.
Compound or salt thereof, [22] R¹But (a) C_1-6A
Lucylenedioxy, (b) di (C_1-6Alkoxy) ho
Suphoryl-C_1-6Alkyl, (c) C_1-6Haloal
Kill, (d) C_7-14Aralkyloxy, (e) nitrogen
Hetero atoms selected from atoms, oxygen atoms and sulfur atoms
5- or 6-membered heterocycle-oxy having 1 to 4
Or (f) from nitrogen, oxygen and sulfur atoms
5-membered aromatic or aromatic member having 1-3 selected heteroatoms
Is a 6-membered heterocyclic ring and a benzene ring or a nitrogen or oxygen atom
And 1 to 3 heteroatoms selected from sulfur and sulfur
Formed by the condensation of aromatic 5- or 6-membered heterocycles
Unsubstituted bicyclic heterocyclic-oxy optionally substituted C
_6-10In the aryloxy group, R^TwoIs -CO-Z^{2 '}so,
Z^{2 '}Is one or two C_1-6Substituted with alkyl
An optionally substituted amino group,³Is C_1-8In the alkyl group, R
¹⁴Is a hydrogen atom, and ring B is a cyclohexane ring
[1] The compound according to the present invention, [23] a compound represented by the formula (I)
From the product, 9-methylthio-4,5-dihydro-6H-1-O
Kisa-8-thia-2-aza-cyclopenta [e] azulene-7-ka
Luboxamide, 4,5-dihydro-8-methylthio-4-phenyl
Isoxazolo [4,5-e] benzo [c] thiophene-6-cal
Boxamide, 4,5-dihydro-4-methyl-8- (methylthio) i
Soxazolo [4,5-e] benzo [c] thiophene-6-carbo
Oxamide and 4,5-dihydro-4,4-dimethyl-8- (methyl
Ruthio) isoxazolo [4,5-e] benzo [c] thiophene-
The compound of the above-mentioned [1] except 6-carboxamide, [2]
4] The compound represented by the formula (I) further has a lower ring B
6-membered hydrocarbon substituted with a lower alkyl group or a phenyl group
When it is a ring, R¹Is a lower alkylthio group,
And ring B is an unsubstituted 7-membered hydrocarbon ring,¹Is a lower class
A compound according to the above [1] except for a case where the compound is a alkylthio group
Compound and [25] a compound represented by the formula (I)
Dihydro-1-methyl-8-propylthio-1H-thieno [3,4-g]
Indazole-6-carboxamide; 4,5-dihydro-1-methy
-8-propylsulfinyl-1H-thieno [3,4-g] indazo
Ole-6-carboxamide; 4,5-dihydro-1-methyl-8-propyl
Ropyrsulfonyl-1H-thieno [3,4-g] indazole-6-ca
Luboxamide; 4,5-dihydro-8- (3,4-methylenedioxy
Phenoxy) -1-methyl-1H-thieno [3,4-g] indazole-
6-carboxamide; 4,5-dihydro-8-phenoxy-1-methy
Ru-1H-thieno [3,4-g] indazole-6-carboxamide;
4,5-dihydro-8- (3,4-methylenedioxyphenoxy) thio
Eno [3,4-g] -1,2-benzisoxazole-6-carbox
Mido; 8- [4-[(diethoxyphosphoryl) methyl] phenoki
[S] -4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazo
6-carboxamide; 8- [4-[(diethoxyphosphoryl)
Ru) methyl] phenoxy] -4,5-dihydro-1-methyl-1H-thio
Eno [3,4-g] indazole-6-carboxamide; N-ethyl
-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1
-Methyl-1H-thieno [3,4-g] indazole-6-carboxa
Amide; 4,5-dihydro-1-methyl-8- (4-trifluoromethyl
Rufenoxy) -1H-thieno [3,4-g] indazole-6-cal
Boxamide; 4,5-dihydro-1-methyl-8- (6-quinolinyl
Oxy) -1H-thieno [3,4-g] indazole-6-carboxa
Mido; 4,5-dihydro-1-methyl-8-[(3-pyridinyl) oxy
[S] -1H-thieno [3,4-g] indazole-6-carboxami
8-[(4-benzyloxy) phenoxy] -4,5-dihydro-
1-methyl-1H-thieno [3,4-g] indazole-6-carboxa
Amide; or 4,5-dihydro-1-methyl-8- [4- (2-quinolini
Lemethoxy) phenoxy] -1H-thieno [3,4-g] indazo
To provide the compound of the above-mentioned [1],
You.

[0010] The present invention also relates to [26] a prodrug of the compound of the above-mentioned [1] or a salt thereof, [27] a general formula (I):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. Represents a group), and ring A is

Embedded image (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or each substituted. Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. (Wherein ring A is In the above, the case where Z ¹ is —CO— and Z ² is an optionally substituted amino group is excluded. ) Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the prodrug thereof; [28] a compound represented by the formula (I) further comprising 9-methylthio-4,5-dihydro-6H -1-oxa-8-thia
2-aza-cyclopenta [e] azulene-7-carboxamide, 4,5-dihydro-8-methylthio-4-phenylisoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide, 4, 5-dihydro-4-methyl-8- (methylthio) isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide and 4,5-dihydro-4,4-dimethyl-8- (methylthio)
The composition according to the above [27], except for isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide, [29]
When the ring B is a 6-membered hydrocarbon ring substituted with a lower alkyl group or a phenyl group, R ¹ is a lower alkylthio group, and the ring B is unsubstituted from the compound represented by the formula (I). A 7-membered hydrocarbon ring, wherein R ¹ is a lower alkylthio group;
[30] General formula (I):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO—, or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, or an amino group. Represents a group), and ring A is

Embedded image (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or each substituted. Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. A compound represented by the formula:

Embedded image Excluding the compound represented by ) Or a pharmaceutically acceptable salt thereof or a cell differentiation inducer comprising the prodrug thereof; [31] a compound represented by the formula (I), further comprising 9-methylthio-4,5-dihydro- 6H-1-oxa-8-thia
2-aza-cyclopenta [e] azulene-7-carboxamide, 4,5-dihydro-8-methylthio-4-phenylisoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide, 4,5-dihydro-4-methyl-8- (methylthio) isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide and 4,5-dihydro-4,4-dimethyl-8- (methylthio )
The cell differentiation inducer according to the above [30], except for isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide,
[32] From the compound represented by the formula (I), a ring B
Is a 6-membered hydrocarbon ring substituted with a lower alkyl group or a phenyl group; R ¹ is a lower alkylthio group; and when Ring B is an unsubstituted 7-membered hydrocarbon ring, R ¹ is a lower alkylthio group. Except for certain cases, the cell differentiation inducer according to the above [30], [33] a general formula (I):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. Represents a group), and ring A is

Embedded image (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or each substituted. Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. A compound represented by the formula:

Embedded image Excluding the compound represented by ) Or a pharmaceutically acceptable salt thereof or a prodrug thereof, for preventing or treating a bone or joint disease, and [34] wherein the bone or joint disease is osteoporosis, fracture, osteoarthritis or chronic joint It is intended to provide the prophylactic / therapeutic agent according to the above [33], which is rheumatism.

Further, the present invention provides a compound represented by the following general formula (35):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ⁴ represents a substituted hydroxyl group, and ring C represents a 5- to 7-membered hydrocarbon ring which may have a substituent.] Or a salt thereof, [36] Formula (IX):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ¹³ represents an optionally substituted amino group or a hydroxyl group, and ring D ′ is a 5- to 7-membered hydrocarbon ring optionally having a substituent. Is shown. A compound represented by the general formula (IV):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. And ring D represents a 5- to 7-membered hydrocarbon ring which may have a substituent. And an amide acetal.
1):

Embedded image [Wherein, R ¹¹ represents an amino group which may be substituted,
Ring D′-1 represents an optionally substituted 5- to 7-membered hydrocarbon ring, and the other symbols have the same meanings as described above. [38] A method for producing a compound represented by the general formula (II):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ⁴ represents a hydroxyl group which may be substituted, and ring C represents a 5- to 7-membered hydrocarbon ring which may have a substituent. ] To a dealcoholation reaction, wherein the general formula (IX-2):

Embedded image [In the formula, ring D′-2 may have a substituent.
A member hydrocarbon ring, and other symbols have the same meanings as described above. A method for producing a compound represented by the formula
9] General formula (IX):

Embedded image [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ¹³ represents an optionally substituted amino group or a hydroxyl group, and ring D ′ is a 5- to 7-membered hydrocarbon ring optionally having a substituent. Is shown. Or a salt thereof, hydroxylamine or a salt thereof, or a compound represented by the formula: R ^{3 ′} NHNH ₂ wherein R ^{3 ′} is a hydrogen atom, a hydrocarbon residue which may be substituted, a heterocyclic ring Group, sulfonyl group or acyl group. A compound represented by the general formula (I): wherein the compound or a salt thereof is subjected to a ring-closure reaction to convert the compound into an optionally substituted hydroxyl group or amino group.

Embedded image [Wherein ring A is

Embedded image (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or an respectively substituted group. A hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And the other symbols are as defined above. Having. And a process for producing a compound represented by the general formula (IX-3):

Embedded image [In the formula, R ^{1 ′} is a hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, each of which may be substituted;
W '(wherein X' represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally oxidized sulfur atom, and W 'is an optionally substituted An optionally substituted cyclic group or a carbon atom or a nitrogen atom having two or more substituents).
² is a cyano group, formyl group, thioformyl group or a formula:
-Z ¹ -Z ² (where Z ¹ is -CO-, -CS-, -S
O— or —SO ₂ — is represented, and Z ² represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group which may be substituted. ), R ^{13 ′} represents an optionally substituted amino group or a hydroxyl group,
Ring D′-3 represents a 5- to 7-membered hydrocarbon ring which may have a substituent. And a salt thereof, in the presence of an acid and under substantially anhydrous conditions, with the formula: R ^{3 ″} NHNH ₂
[In the formula, R ^{3 ′ ″} represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group. A compound represented by the general formula (I-11):

Embedded image [In the formula, ring B-1 represents a 5- to 7-membered hydrocarbon ring which may have a substituent, and other symbols have the same meanings as described above. And a process for producing the compound or a salt thereof.

[0012]

DESCRIPTION OF THE PREFERRED EMBODIMENTS A description of the above general formulas and definitions included within the scope of the present invention, and preferred examples thereof will be given below.

R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group.

Examples of the hydrocarbon residue in the optionally substituted hydrocarbon residue in R ¹ include an optionally substituted aliphatic hydrocarbon residue, an alicyclic hydrocarbon residue and an aliphatic hydrocarbon residue. A cyclic-aliphatic hydrocarbon residue, an aromatic hydrocarbon residue, or an aromatic-aliphatic hydrocarbon residue (aralkyl group);

Examples of the aliphatic hydrocarbon residue include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, C 1-8 saturated aliphatic hydrocarbon residues such as octyl (eg, alkyl groups), for example, vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-
Butenyl, 3-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4
-Pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-hexadienyl, 1-
Heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
-Butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadynyl, 1-heptynyl, 1 −
Examples thereof include an unsaturated aliphatic hydrocarbon residue having 2 to 8 carbon atoms such as octynyl (eg, an alkenyl group, an alkynyl group, an alkadienyl group, and an alkadiynyl group).

The alicyclic hydrocarbon residue is, for example, a saturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl (eg, cycloalkyl group). , 1-
Cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl,
2-cycloheptenyl, 3-cycloheptenyl, 2,4
-An unsaturated alicyclic hydrocarbon residue having 3 to 7 carbon atoms such as cycloheptadienyl (e.g., cycloalkenyl group, cycloalkadienyl group, etc.), 1-indenyl, 2-indenyl, 1-indanyl, -Indanyl, 1,2,3,4-
Tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,
4-dihydro-1-naphthyl, 3,4-dihydro-2-
Partially saturated condensed bicyclic hydrocarbon residue such as naphthyl [preferably C _9-10 partially saturated condensed bicyclic hydrocarbon residue or the like (a benzene ring is bonded to a 5- to 6-membered non-aromatic cyclic hydrocarbon group) And the like))].

The alicyclic-aliphatic hydrocarbon residue includes:
Those in which the alicyclic hydrocarbon residue and the aliphatic hydrocarbon residue are bonded, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3
-Cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3
-Cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2-
(3,4-dihydro-2-naphthyl) ethyl, 2- (1,
2,3,4-tetrahydro-2-naphthyl) ethyl, 2-
Those having 4 to 14 carbon atoms such as (3,4-dihydro-2-naphthyl) ethenyl (eg, C _3-7 cycloalkyl-C _1-4)
Alkyl group, C _3-7 cycloalkenyl-C _1-4 alkyl group, C _3-7 cycloalkyl-C _2-4 alkenyl group, C _3-7
Cycloalkenyl-C _2-4 alkenyl group, C _9-10 partially saturated condensed bicyclic hydrocarbon-C _1-4 alkyl group, C _9-10 partially saturated condensed bicyclic hydrocarbon-C _2-4 alkenyl group, etc. ).

Examples of the aromatic hydrocarbon residue include phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro- 1-naphthyl, 5,
6,7,8-tetrahydro-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4- And aryl groups having 6 to 10 carbon atoms (including those in which a 5- to 6-membered non-aromatic hydrocarbon ring is fused to a phenyl group) such as naphthyl.

The aromatic-aliphatic hydrocarbon residue includes:
For example, benzyl, phenethyl, 1-phenylethyl, 1
-Phenylpropyl, 2-phenylpropyl, 3-phenyl
Phenyl-C such as nilpropyl_1-4Alkyl group, for example
Α-naphthylmethyl, α-naphthylethyl, β-naphthyl
Naphthyl-C such as tylmethyl and β-naphthylethyl
_1-4C 7-14 aralkyl groups such as alkyl groups
(C_6-10Aryl-C_1-4Alkyl group), for example, still
Phenyl-C such as cinnamyl_2-4Alkenyl group
Which C_6-10Aryl-C_2-4Alkenyl groups, etc.
It is.

The heterocyclic group of the optionally substituted heterocyclic group in R ¹ includes, for example, (i) a heterocyclic group containing one sulfur atom, one nitrogen atom or one oxygen atom;
A 7-membered heterocyclic group, (ii) a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms, or (iii) a 1 to 2 nitrogen atom and 1
And (iv) a 5- to 6-membered ring containing not more than 2 nitrogen atoms, a benzene ring or one sulfur-containing 5 to 6-membered heterocyclic group containing 2 or less nitrogen atoms. It may be condensed with a 5-membered ring containing an atom. The heterocyclic groups exemplified in (i) to (iv) may each be a saturated or unsaturated heterocyclic group, and the unsaturated heterocyclic group may be any of aromatic and non-aromatic. Is also good.

Examples of the heterocyclic group in the optionally substituted heterocyclic group for R ¹ include an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group and a non-aromatic heterocyclic group. Specific examples of the heterocyclic group in the optionally substituted heterocyclic group for R ¹ include (i) an aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.), (ii) aromatic Group fused heterocyclic groups (eg, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl , Thianthrenyl, phenanthrinyl, phenanthrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl,
Pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4- Triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,
3-b] pyridazinyl) and (iii) a non-aromatic heterocyclic group (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
Thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like).

R¹In the above, an optionally substituted sulf
The sulfinyl group in the finyl group is as described above.
R¹Hydrocarbons each of which may be substituted
A "hydrocarbon residue" in the "residue or heterocyclic group" or
Those in which a "heterocyclic group" and -SO- are bonded;
You. Preferably, methyl, ethyl, propyl, isopro
Pill, butyl, isobutyl, sec-butyl, tert
-Butyl, pentyl, isopentyl, neopentyl, t
ert-pentyl, hexyl, isohexyl, hepti
C, such as le and octyl _1-8Alkyl and sulfinyl groups
C is_1-8Alkylsulfinyl; phenyl,
α-naphthyl, β-naphthyl, 4-indenyl, 5-a
Ndenyl, 4-indanyl, 5-indanyl, 5,6,
7,8-tetrahydro-1-naphthyl, 5,6,7,8-te
Trahydro-2-naphthyl, 5,6-dihydro-1-na
Futyl, 5,6-dihydro-2-naphthyl, 5,6-dihi
Dro-3-naphthyl, 5,6-dihydro-4-naphthyl
Such as C_6-10Aryl and sulfinyl groups are linked
C_6-10Arylsulfinyl; aromatic monocyclic compound
Elementary ring groups (eg, furyl, thienyl, pyrrolyl, oxazoly
, Isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazoli
1,2,4-oxadiazolyl, 1,3,4-oxadi
Azolyl, flazanil, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazol
1,2,3-triazolyl, 1,2,4-triazolyl
, Tetrazolyl, pyridyl, pyrimidinyl, pyridazi
Nil, pyrazinyl, triazinyl, etc.) and sulfinyl
A group to which a group is bonded; an aromatic fused heterocyclic group (eg,
Ranyl, isobenzofuranyl, benzo [b] thienyl,
Drill, isoindolyl, 1H-indazolyl, ben
Zoimidazolyl, benzoxazolyl, 1,2-benzo
Isothiazolyl, 1H-benzotriazolyl, quinori
, Isoquinolyl, cinnolinyl, quinazolinyl, quino
Xalinyl, phthalazinyl, naphthyridinyl, purini
, Pteridinyl, carbazolyl, α-carbolinyl,
β-carbolinyl, γ-carbolinyl, acridinyl,
Phenoxazinyl, phenothiazinyl, phenazinyl,
Phenoxathiinyl, thianthrenyl, phenanthredge
Nil, phenanthrolinyl, indolizinyl, pyrrolo
[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridi
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyridyl, imidazo [1,5-a] pyridyl, i
Midazo [1,2-b] pyridazinyl, imidazo [1,2-a] pi
Limidinyl, 1,2,4-triazolo [4,3-a] pyridi
1,2,4-triazolo [4,3-b] pyridazinyl, etc.)
And a group in which a sulfinyl group is bonded. More preferred
Or methyl, ethyl, propyl, isopropyl,
Chill, isobutyl, sec-butyl, tert-butyl
, Pentyl, isopentyl, neopentyl, tert
-Pentyl, hexyl, isohexyl, heptyl, octyl
C such as chill_1-8Alkyl and sulfinyl groups are linked
C_1-8Alkylsulfinyl.

R¹In the above, an optionally substituted sulf
As the sulfonyl group in the honyl group, the above-mentioned R¹
As the "optionally substituted hydrocarbon residue"
Or heterocyclic group "," hydrocarbon residue "or" heterocycle "
Group ”and -SO₂And-are bonded. Like
Or methyl, ethyl, propyl, isopropyl,
Chill, isobutyl, sec-butyl, tert-butyl
, Pentyl, isopentyl, neopentyl, tert
-Pentyl, hexyl, isohexyl, heptyl, octyl
C such as chill _1-8Alkyl and sulfonyl groups bonded
C_1-8Alkylsulfonyl; phenyl, α-naphthy
, Β-naphthyl, 4-indenyl, 5-indenyl,
4-indanyl, 5-indanyl, 5,6,7,8-tetra
Lahydro-1-naphthyl, 5,6,7,8-tetrahydro
-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,
6-dihydro-2-naphthyl, 5,6-dihydro-3-
C such as naphthyl, 5,6-dihydro-4-naphthyl
_6-10C having an aryl group and a sulfonyl group bonded_6-1
0Arylsulfonyl; aromatic monocyclic heterocyclic group (eg,
Furyl, thienyl, pyrrolyl, oxazolyl, isooxo
Sazolyl, thiazolyl, isothiazolyl, imidazoly
, Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thio
Asiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
Triazolyl, 1,2,4-triazolyl, tetrazolyl
, Pyridyl, pyrimidinyl, pyridazinyl, pyrazini
, Triazinyl, etc.) and a sulfonyl group;
 Aromatic fused heterocyclic group (eg, benzofuranyl, isoben
Zofuranyl, benzo [b] thienyl, indolyl, isoi
Ondolyl, 1H-indazolyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzoisothiazolyl,
1H-benzotriazolyl, quinolyl, isoquinolyl,
Cinnolinyl, quinazolinyl, quinoxalinyl, phthala
Zinyl, naphthyridinyl, prenyl, pteridinyl, ka
Rubazolyl, α-carbolinyl, β-carbolinyl, γ
-Carbolinyl, acridinyl, phenoxazinyl,
Enothiazinyl, phenazinyl, phenoxathiinyl,
Thiantrenyl, phenanthrinyl, phenanthroli
Nil, indolizinyl, pyrrolo [1,2-b] pyridazini
, Pyrazolo [1,5-a] pyridyl, imidazo [1,2-a]
Pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,
2-b] pyridazinyl, imidazo [1,2-a] pyridyl, i
Midazo [1,5-a] pyridyl, imidazo [1,2-b] pyrida
Dinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-
Triazolo [4,3-a] pyridyl, 1,2,4-triazolo
[4,3-b] pyridazinyl) and sulfonyl group
Groups. More preferably, methyl, ethyl,
Ropyl, isopropyl, butyl, isobutyl, sec-
Butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, tert-pentyl, hexyl, isohe
C for xyl, heptyl, octyl, etc._1-8With alkyl
C to which a sulfonyl group is bonded_1-8Alkylsulfonyl
No.

R¹Optionally substituted hydroxyl
As the group, a hydroxyl group and a suitable substituent for this hydroxyl group,
For example, R¹"They may be substituted
Hydroxyl group substituted with a `` hydrocarbon residue or heterocyclic group ''
No. Preferably, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopen
Chill, tert-pentyl, hexyl, isohexyl,
C such as heptyl and octyl _1-8Substituted with alkyl
C_1-8Alkyloxy; phenyl, α-naphthy
, Β-naphthyl, 4-indenyl, 5-indenyl,
4-indanyl, 5-indanyl, 5,6,7,8-tetra
Lahydro-1-naphthyl, 5,6,7,8-tetrahydro
-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,
6-dihydro-2-naphthyl, 5,6-dihydro-3-
C such as naphthyl, 5,6-dihydro-4-naphthyl
_6-10C substituted with an aryl group_6-10Arlio
Xy; aromatic monocyclic heterocyclic group (eg, furyl, thienyl
, Pyrrolyl, oxazolyl, isoxazolyl, thia
Zolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazo
Ryl, 1,3,4-oxadiazolyl, furanil, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, pi
Limidinyl, pyridazinyl, pyrazinyl, triazinyl
A) substituted aromatic group; fused aromatic heterocyclic group
(Eg, benzofuranyl, isobenzofuranyl, benzo
[b] thienyl, indolyl, isoindolyl, 1H-a
Ndazolyl, benzimidazolyl, benzoxazoly
1,2-benzoisothiazolyl, 1H-benzotri
Azolyl, quinolyl, isoquinolyl, cinnolinyl,
Nazolinyl, quinoxalinyl, phthalazinyl, naphthyl
Dinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenanthrinil, phenanthrolinyl, indolizy
Nil, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5]
-A] pyridyl, imidazo [1,2-a] pyridyl, imidazo
[1,5-a] pyridyl, imidazo [1,2-b] pyridazini
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyrida
And a hydroxyl group substituted with dilinyl or the like. More preferred
Or C_6-10Aryloxy (particularly preferably
Enyloxy) or an aromatic monocyclic heterocyclic group (particularly preferred).
Preferably pyridyl) or an aromatic fused heterocyclic group (especially
Preferably a hydroxyl group substituted with quinolyl).
You. As a substituent of the substituted hydroxyl group exemplified here
The “hydrocarbon residue” or “heterocyclic group” is a group represented by R¹
As the "optionally substituted hydrocarbon residue"
Or heterocyclic group ''
May have the same substituents as the “ring group”.

R¹In the above, an optionally substituted thio
Thiol groups and suitable thiol groups
A suitable substituent such as R¹`` Each replaced
An optionally substituted hydrocarbon residue or heterocyclic group ''
Thiol groups. Preferably, methyl, d
Chill, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isope
Pentyl, neopentyl, tert-pentyl, hexyl
C such as octyl, isohexyl, heptyl and octyl _1-8
C substituted with alkyl_1-8Alkylthio; phenyl
, Α-naphthyl, β-naphthyl, 4-indenyl, 5
-Indenyl, 4-indanyl, 5-indanyl, 5,
6,7,8-tetrahydro-1-naphthyl, 5,6,7,8
-Tetrahydro-2-naphthyl, 5,6-dihydro-1
-Naphthyl, 5,6-dihydro-2-naphthyl, 5,6-
Dihydro-3-naphthyl, 5,6-dihydro-4-naph
C such as chill_6-10C substituted with an aryl group
_6-10Arylthio; aromatic monocyclic heterocyclic group (eg,
Furyl, thienyl, pyrrolyl, oxazolyl, isooxo
Sazolyl, thiazolyl, isothiazolyl, imidazoly
, Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Frazanil, 1,2,3-thiadiazolyl, 1,2,4-thio
Asiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
Triazolyl, 1,2,4-triazolyl, tetrazolyl
, Pyridyl, pyrimidinyl, pyridazinyl, pyrazini
Thiol groups substituted with thiol, triazinyl, etc .;
Aromatic fused heterocyclic group (eg, benzofuranyl, isobenzofuran)
Ranyl, benzo [b] thienyl, indolyl, isoindo
Ryl, 1H-indazolyl, benzimidazolyl, ben
Zoxazolyl, 1,2-benzisothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, syn
Nolinyl, quinazolinyl, quinoxalinyl, phthalazini
, Naphthyridinyl, prenyl, pteridinyl, carb
Zolyl, α-carbolinyl, β-carbolinyl, γ-ca
Ruborinyl, acridinyl, phenoxazinyl, pheno
Thiazinyl, phenazinyl, phenoxathiinyl, thia
Entrenyl, phenanthrinil, phenanthrolini
, Indolizinyl, pyrrolo [1,2-b] pyridazinyl,
Pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl
Jill, imidazo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyridyl, imida
Zo [1,5-a] pyridyl, imidazo [1,2-b] pyridazini
, Imidazo [1,2-a] pyrimidinyl, 1,2,4-tri
Azolo [4,3-a] pyridyl, 1,2,4-triazolo [4,
3-b] pyridazinyl and the like)
Can be Substituents of the substituted thiol groups exemplified here
As the "hydrocarbon residue" or "heterocyclic group"
R¹As the carbonized carbon which may be substituted
Hydrocarbon residue or heterocyclic group ''
Or "heterocyclic group", each having the same substituent as
Is also good. More preferably, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopen
Chill, tert-pentyl, hexyl, isohexyl,
C such as heptyl and octyl_1-8Substituted with alkyl
C_1-8And alkylthio.

The amino group which may be substituted in R ¹ includes an amino group, an N-monosubstituted amino group and an N, N-disubstituted amino group. Examples of the substituted amino group include, for example, an optionally substituted hydrocarbon residue (for example, the same as the optionally substituted hydrocarbon residue represented by R ¹ , more specifically, C _{1 -8} alkyl group, C _3-7 cycloalkyl group, C _2-8 alkenyl group, C
_2-8 alkynyl group, C _3-7 cycloalkenyl group, C _6-10 aryl group which may have a C _1-4 alkyl group, etc.),
An optionally substituted heterocyclic group (for example, the same as the optionally substituted heterocyclic group represented by R ¹ ), or a compound of the formula: —COR ′ (where R ′ is a hydrogen atom or And a hydrocarbon residue or a heterocyclic group which may be substituted, wherein the “hydrocarbon residue or heterocyclic group which may be substituted” as R ′ is the above “each of R ′” substituted "hydrocarbon residue in even optionally substituted hydrocarbon group or heterocyclic group" optionally "or" heterocyclic group "similar to substituents which may have, respectively.), preferably C _1-10 An amino group having one or two acyl groups (eg, C _2-7 alkanoyl, benzoyl, nicotinoyl, etc.) as a substituent (eg, methylamino, dimethylamino, ethylamino, diethylamino,
Dipropylamino, dibutylamino, diallylamino,
Cyclohexylamino, phenylamino, N-methyl-
N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.). Further, two groups in the substituted amino group may be bonded to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, piperazino, morpholino, thiomorpholino, and the like).

The "hydrocarbon residue", "heterocyclic group", "heterocyclic group", "hydrocarbon residue, heterocyclic group, sulfinyl group, and sulfonyl group" each represented by R ¹
The “sulfinyl group” and the “sulfonyl group” may each be substituted with 1 to 3 substituents, for example, a lower (C _1-6 ) alkyl group (eg, methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, hexyl, etc.), lower (C _2-6 ) alkenyl groups [eg, vinyl, allyl (ally
l), 1-propenyl, 2-methyl-1-propenyl, 1
-Butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3
-Pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.], lower ( _C2-6 ) alkynyl group (eg, ethynyl) , 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.), C _3-7 cycloalkyl group (e.g. , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl, etc.), C _6-10 aryl group (eg, phenyl, α-naphthyl, β-naphthyl, etc.), aromatic heterocyclic group [eg, furyl, thienyl, pyrrolyl, oxazolyl,
Isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,
4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothininyl, phenazidinyl Nil, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a]
Pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl, 1, (I) an aromatic 5- or 6-membered heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, such as 2,4-triazolo [4,3-b] pyridazinyl; ii) an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and a benzene ring or 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; A condensed bicyclic heterocyclic group formed by condensing an aromatic 5- or 6-membered heterocyclic ring having three, (iii) an aromatic having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom 5- or 6-membered heterocycle, Benzene ring and a nitrogen atom, an oxygen atom, a hetero atom selected from sulfur atom 1
Condensed tricyclic heterocyclic group formed by condensing three aromatic 5- or 6-membered heterocyclic rings or benzene rings], and each of the above heterocyclic groups (i), (ii) and (iii) and an oxy group Are bonded to form a heterocyclic-oxy group, a non-aromatic heterocyclic group (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,
A nitrogen atom such as thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, an oxygen atom, a 4- to 7-membered non-aromatic heterocyclic group having 1 to 3 heteroatoms selected from sulfur atoms), C
_7-14 aralkyl groups (eg, benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, α-naphthylmethyl,
C _6-10 aryl-C _1-4 alkyl groups such as α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl, etc.), amino group, N-monosubstituted amino group [eg, methylamino, ethylamino, allyl (Allyl) N- (C _1-6 alkyl) amino group such as amino, cyclohexylamino, phenylamino, N- (C _2-6 alkenyl) amino group, N- (C _3-7 cycloalkyl) amino group, N − (C
_6-10 aryl) amino group, etc.], N, N- disubstituted amino group [e.g., dimethylamino, diethylamino, dibutylamino, diallyl (allyl) amino, such as N- methyl -N- phenylamino, C _1-6 An amino group substituted with two substituents selected from an alkyl group, a C _2-6 alkenyl group, a C _3-7 cycloalkyl group and a C _6-10 aryl group], an amidino group, an acyl group (eg, formyl Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonoyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl and the like
_2-8 alkanoyl group, C _3-8 alkenoyl group, C _3-7 cycloalkyl-carbonyl group, C _3-7 cycloalkenyl-
Carbonyl group, C _{6-1 0} aryl - carbonyl group, a nitrogen atom, an oxygen atom, a hetero atom selected from sulfur atom 1
A 5- or 6-membered aromatic or non-aromatic heterocyclic ring having 3 carbon atoms and a carbonyl group to form a heterocyclic-carbonyl group, etc.), a carbamoyl group, an N-monosubstituted carbamoyl group [eg, methylcarbamoyl, ethyl N- (C _1-6 alkyl) carbamoyl groups such as carbamoyl, cyclohexylcarbamoyl and phenylcarbamoyl;
N- (C _2-6 alkenyl) carbamoyl group, N- (C _3-7
Cycloalkyl) carbamoyl group, N- (C _6-10 aryl) carbamoyl group, etc., N, N-disubstituted carbamoyl group [eg, dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, diallyl (carbyl) carbamoyl, N-methyl- A carbamoyl group substituted with two substituents selected from a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _3-7 cycloalkyl group and a C _6-10 aryl group, such as N-phenylcarbamoyl; ], A sulfamoyl group, an N-monosubstituted sulfamoyl group [eg, N- such as methylsulfamoyl, ethylsulfamoyl, cyclohexylsulfamoyl, phenylsulfamoyl, etc.]
(C _1-6 alkyl) sulfamoyl group, N- (C _2-6 alkenyl) sulfamoyl group, N- (C _3-7 cycloalkyl) sulfamoyl group, N- (C _6-10 aryl) sulfamoyl group, etc. , N-disubstituted sulfamoyl groups [eg, C _1-6 alkyl groups such as dimethylsulfamoyl, diethylsulfamoyl, dibutylsulfamoyl, diallyl (sulfamoyl), N-methyl-N-phenylsulfamoyl and the like] , A C _2-6 alkenyl group, a C _3-7
A sulfamoyl group substituted with two substituents selected from a cycloalkyl group and a C _6-10 aryl group], a carboxyl group, a lower (C _1-6 ) alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), hydroxyl group, lower (C _1-6 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, pentyloxy, hexyloxy), lower (C _2-6) alkenyloxy group [e.g., allyl (allyl) oxy, 2-butenyloxy, - pentenyl oxy, 3
-Hexenyloxy and the like], C _3-7 cycloalkyloxy groups (eg, cyclopropyloxy, cyclobutyloxy,
Cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), C _6-10 aryloxy group (eg,
C _6-10 aryl-C such as phenoxy, naphthyloxy, C _7-14 aralkyloxy group (eg, phenyl-C _1-4 alkyloxy, naphthyl-C _1-4 alkyloxy)
_1-4 alkyloxy group, etc.), mercapto group, lower (C
_1-6 ) alkylthio group (eg, methylthio, ethylthio,
Propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, etc.), a C _7-14 aralkylthio group (eg, phenyl-C _1-4 alkylthio, Naphthyl-C _1-4
C _6-10 aryl-C _1-4 alkylthio groups such as alkylthio, etc., C _6-10 arylthio groups (eg, phenylthio, naphthylthio, etc.), lower (C _1-6 ) alkylsulfinyl groups (eg, methylsulfinyl, ethyl Sulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, s
ec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, hexylsulfinyl, etc., a C _7-14 aralkylsulfinyl group (eg, phenyl-C _1-4 alkylsulfinyl, naphthyl-C _{1-) 4,} such as C _6-10 aryl -C _1-4 alkylsulfinyl group such as alkylsulfinyl), C _6-10 arylsulfinyl group (e.g., phenylsulfinyl, etc. naphthylsulfinyl), lower (C _1-6) alkylsulfonyl group ( For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, ter
t-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl, etc.), a C _7-14 aralkylsulfonyl group (eg,
Phenyl-C _1-4 alkylsulfonyl, naphthyl-C _1-4
Alkyl such as sulfo C _{6- 10} aryl -C _1-4 alkyl sulfonyl group such as sulfonyl), C _6-10 arylsulfonyl group (e.g., phenylsulfonyl, naphthyl, etc. naphthyl sulfonyl), a sulfo group, a cyano group, azido group, a halogen atom ( E.g., fluorine, chlorine, bromine, iodine), nitro group,
A nitroso group, an optionally esterified phosphono group [eg, a (C _1-6) group such as a phosphono group, ethoxyphosphoryl, etc.
An alkoxy) phosphoryl group, a di (C _1-6 alkoxy) phosphoryl group such as diethoxyphosphoryl, etc.], a lower (C
_1-6 ) alkyl group (eg, phosphono-C _1-6 alkyl group, C
_1-6 alkoxycarbonyl phosphoryl -C _1-6 alkyl group, such as di (C _1-6 alkoxy) phosphoryl -C _1-6 alkyl group such as diethoxyphosphorylmethyl), C _{1 -6} haloalkyl group (e.g., trifluoromethyl A C _1-6 alkyl group substituted with 1 to 4 halogens such as a C _1-6 haloalkoxy group (eg, a C _1-6 alkoxy group substituted with 1 to 4 halogens such as trifluoromethoxy and the like) ). Among the above substituents, when hydroxyl group and lower the (C _1-6) alkoxy groups are adjacent as substituents form a C _{1 -6} alkylenedioxy such as methylenedioxy and ethylenedioxy Is also good.

The above C _6-10 aryl group, aromatic heterocyclic group,
A C _6-10 aryl group as a substituent of an N-monosubstituted amino group, a C _6-10 aryl group as a substituent of an N, N-disubstituted amino group, and a C _6-10 aryl group as a substituent of an N-monosubstituted carbamoyl group _6-10 aryl group, N, N- C _6-10 aryl group as a substituent of di-substituted carbamoyl group, C _6-10 aryl as a substituent of the N- mono-substituted sulfamoyl group, N, N-
A C _6-10 aryl group as a substituent of a disubstituted sulfamoyl group, a C _6-10 aryl group in a C _6-10 aryloxy group,
A C _6-10 aryl group in a C _7-14 aralkyloxy group,
_7-14 aralkylthio C _6-10 aryl group in the group, C _6-10 aryl groups in C _6-10 arylthio group, C _{7- 14} aralkyl sulfinyl C _6-10 aryl group in the Le group, C _6-10 C _6-10 aryl groups in the aryl sulfinyl group, C _6-10 aryl groups C _6-10 aryl groups, and C _6-10 during arylsulfonyl groups in C _7-14 aralkylsulfonyl groups, further 1
May be substituted with up to 3 substituents, such as a lower (C _1-6 ) alkyl group, an amino group,
N- (C _1-6 alkyl) amino group, N, N-di (C _1-6 alkyl) amino group, amidino group, carbamoyl group, N-
(C _1-6 alkyl) carbamoyl group, N, N-di (C _1-6
Alkyl) carbamoyl group, sulfamoyl group, N-
(C _1-6 alkyl) sulfamoyl group, N, N-di (C
_1-6 alkyl) sulfamoyl group, carboxyl group, lower (C _2-7 ) alkoxycarbonyl group, hydroxyl group, lower (C _1-6 ) alkoxy group, mercapto group, lower (C _1-6 )
Alkylthio group, sulfo group, cyano group, azido group, halogen atom, nitro group, nitroso group, phosphono group which may be esterified [eg, phosphono group, C _1-6 alkoxyphosphoryl group, di (C _1-6 Alkoxy) phosphoryl group, etc., and a lower (C _1-6 ) alkyl group substituted with an optionally esterified phosphono group [eg, phosphono-C _1-6
Alkyl group, C _1-6 alkoxyphosphoryl-C _1-6 alkyl group, di (C _1-6 alkoxy) phosphoryl-C _1-6 alkyl group such as diethoxyphosphorylmethyl, etc.]. Among the above substituents, when hydroxyl group and lower the (C _1-6) alkoxy groups are adjacent as substituents form a C _1-6 alkylenedioxy, such as methylenedioxy and ethylenedioxy Is also good.

R ¹ is preferably an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group. That is, R ¹ has the formula: -S
A group represented by R, —SOR, —SO ₂ R, or —OR (wherein, R represents an optionally substituted hydrocarbon residue or a heterocyclic group) is preferable. Here, as the “optionally substituted hydrocarbon residue” represented by R, those similar to the “optionally substituted hydrocarbon residue or heterocyclic group” represented by R ¹ can be mentioned. However, R is preferably a group having 2 or more carbon atoms, more preferably an optionally substituted cyclic group, and particularly preferably an optionally substituted aromatic group (more preferably, A nitrogen-containing heterocyclic ring which may be substituted) is preferable.

R ^{1 ′} is an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group;
X'-W '(wherein, X' represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally oxidized sulfur atom, and W 'is And a carbon group or a nitrogen atom having two or more substituents which may be substituted). In R ^{1 ′} , an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group, or an amino group may be an optionally substituted hydrocarbon residue as R ^1. And a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group. In R ^{1 ′} ,
Formula: -X'-W '(wherein X' represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally oxidized sulfur atom, W '
Represents a cyclic group which may be substituted or a carbon atom or a nitrogen atom having two or more substituents. In the group represented by the formula (1), the "optionally substituted carbon atom" represented by X 'represents two hydrogen atoms, one hydrogen atom and one substituent or two substituents at a carbon atom. The term "optionally substituted nitrogen atom" represented by X 'represents a divalent group having one hydrogen atom or a substituent at the nitrogen atom. As the substituent, the substituent which the "hydrocarbon residue" or "heterocyclic group" in the above-mentioned "hydrocarbon residue or heterocyclic group which may be substituted" as R ¹ may have And the same groups as the "optionally substituted hydrocarbon residue or heterocyclic group" as R ¹ . The "optionally oxidized sulfur atom" for X 'is -S-, SO- or-
It represents a divalent sulfur atom represented by SO ₂ —. As the "cyclic group" in the "carbon atom or a nitrogen atom having an optionally substituted cyclic group or 2 or more substituents" represented as W ', even if "substituted respectively as R ¹ described above A cyclic group in the `` good hydrocarbon residue or heterocyclic group '', for example, an optionally substituted alicyclic hydrocarbon residue, an optionally substituted aromatic hydrocarbon residue, an optionally substituted heterocyclic group; And a cyclic group (aromatic monocyclic heterocyclic group, aromatic condensed heterocyclic group, and non-aromatic heterocyclic group). As a substituent that the “cyclic group” may have, R ¹ And the same substituents as the "hydrocarbon residue" or "heterocyclic group" in "the hydrocarbon residue or heterocyclic group which may be substituted". The “carbon atom having two or more substituents” in the “optionally substituted cyclic group or carbon atom having two or more substituents” shown as W ′ is, for example, t-butyl, i And the same or different 2 to 3 substituents are bonded to the carbon atom like -propyl (in other words, those having 0 to 1 hydrogen atom on the atom are mentioned. as "hydrocarbon residue" or "heterocyclic group" may have substituents and R ¹ in "each optionally substituted hydrocarbon residue or heterocyclic group" as R ¹ described above And the same groups as the “optionally substituted hydrocarbon residue or heterocyclic group”.
The nitrogen atom having two or more substituents is an N, N-disubstituted amino group. Examples of the substituent in the “N, N-disubstituted amino group” include the same substituents as the “amino group” in the “optionally substituted amino group” for R ¹ described above. R ^{1 ′} is an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group,
Of the sulfonyl group, hydroxyl group, thiol group or amino group, a compound represented by the formula: -X'-W '(wherein X' represents an oxygen atom or a sulfur atom which may be oxidized, and W ' A good cyclic group) is preferred.

R ² is a cyano group, a formyl group, a thioformyl group or a formula: -Z ¹ -Z ² (wherein Z ¹ is -CO
—, —CS—, —SO— or —SO ₂ —, and Z ²
Represents a hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group which may be substituted. ). R
Z ^{1 in 2} is preferably -CO- or -CS-, and more preferably -CO-. As R ² , -CO-
A group represented by Z ^{2 ′} (wherein, Z ^{2 ′} represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group) is preferable. Examples of the optionally substituted hydrocarbon residue for Z ² include, for example, R
^{And the same as the} optionally substituted hydrocarbon residue in 1. As the optionally substituted hydrocarbon residue in Z ² , preferably, the aliphatic hydrocarbon residue is more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Examples thereof include a saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, alkyl) such as butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, and octyl. Examples of the optionally substituted heterocyclic group for Z ² include the same as the optionally substituted heterocyclic group for R ¹ .

Examples of the optionally substituted amino group for Z ² include, for example, the same as the optionally substituted amino group for R ¹ , as well as —NHOR, —NHNH
R or —NHNRR ′ (wherein, R is as defined above,
R ′ represents an optionally substituted hydrocarbon residue or a heterocyclic group. ). R '
Examples of the “optionally substituted hydrocarbon residue or heterocyclic group” represented by are the same as those represented by R. The amino group which may be substituted in Z ^2, preferably an amino group (e.g. having an amino group, and a C _1-8 alkyl group as a one or two substituents, methylamino, dimethylamino, ethylamino, Diethylamino, dibutylamino, etc.). Examples of the optionally substituted hydroxyl group for Z ² include the same as the optionally substituted hydroxyl group for R ¹ . The optionally substituted hydroxyl group for Z ² is preferably a hydroxyl group, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, _{C 1-8} alkyloxy substituted with _{C 1-8} alkyl such as octyl. In R ² Z ² a hydroxyl group which may be the amino group or substituted or optionally substituted it is preferable. In R ² Z ² is amino group which may be substituted more preferred. Especially, Z ² in R ² is an amino group or an amino group having a C _1-8 alkyl group as a one or two substituents, (e.g., methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, etc.) is preferred .

R ^{3 ′} represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group. Examples of the hydrogen atom of R ^{3 ′,} an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group, and an acyl group include a hydrogen atom of R ³ , an optionally substituted hydrocarbon residue, The same as the ring group, the sulfonyl group or the acyl group can be mentioned. R
^{3 ″} represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group. R
^{3 ″} each optionally substituted hydrocarbon residue,
As the heterocyclic group, sulfonyl group or acyl group, R ³
And the same as the optionally substituted hydrocarbon residue, heterocyclic group, sulfonyl group and acyl group.

R ⁴ Represents a substituted hydroxyl group. R ⁴ To
The substituted hydroxyl group in R ¹ Replacement indicated by
In the optionally substituted hydroxyl group
Hydroxyl group, for example, a suitable substituent for the hydroxyl group, for example,
If R ¹ `` The carbons that may be substituted
A hydroxyl group substituted with a `` hydrogen residue or a heterocyclic group ''
Can be Preferably, methyl, ethyl, propyl, iso
Propyl, butyl, isobutyl, sec-butyl, te
rt-butyl, pentyl, isopentyl, neopentier
Tert-pentyl, hexyl, isohexyl, f
C for petil, octyl, etc. _1-8 Substituted with alkyl
C _1-8 Alkyloxy; phenyl, α-naphthyl,
β-naphthyl, 4-indenyl, 5-indenyl, 4-
Indanyl, 5-indanyl, 5,6,7,8-tetrahi
Dro-1-naphthyl, 5,6,7,8-tetrahydro-2
-Naphthyl, 5,6-dihydro-1-naphthyl, 5,6-
Dihydro-2-naphthyl, 5,6-dihydro-3-naph
C, such as tyl, 5,6-dihydro-4-naphthyl
_6-10 C substituted with an aryl group _6-10 Arlio
Xy; aromatic monocyclic heterocyclic group (eg, furyl, thienyl
, Pyrrolyl, oxazolyl, isoxazolyl, thia
Zolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazo
Ryl, 1,3,4-oxadiazolyl, furanil, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, tetrazolyl, pyridyl, pi
Limidinyl, pyridazinyl, pyrazinyl, triazinyl
A) substituted aromatic group; fused aromatic heterocyclic group
(Eg, benzofuranyl, isobenzofuranyl, benzo
[b] thienyl, indolyl, isoindolyl, 1H-a
Ndazolyl, benzimidazolyl, benzoxazoly
1,2-benzoisothiazolyl, 1H-benzotri
Azolyl, quinolyl, isoquinolyl, cinnolinyl,
Nazolinyl, quinoxalinyl, phthalazinyl, naphthyl
Dinyl, purinyl, pteridinyl, carbazolyl, α-
Carbolinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathiinyl, thianthrenyl,
Phenanthrinil, phenanthrolinyl, indolizy
Nil, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5
-A] pyridyl, imidazo [1,2-a] pyridyl, imidazo
[1,5-a] pyridyl, imidazo [1,2-b] pyridazini
Le, imidazo [1,2-a] pyridyl, imidazo [1,5-a]
Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo
[1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3
-A] pyridyl, 1,2,4-triazolo [4,3-b] pyrida
And a hydroxyl group substituted with dilinyl or the like. More preferred
Or methyl, ethyl, propyl, isopropyl,
Chill, isobutyl, sec-butyl, tert-butyl
, Pentyl, isopentyl, neopentyl, tert
-Pentyl, hexyl, isohexyl, heptyl, octyl
C such as chill _1-8 C substituted with alkyl _1-8 Al
Kiloxy; more preferably methyl, ethyl, pro
Pill, C substituted with isopropyl _1-3 Alkyloxy
Shi. Placement of the substituted hydroxyl group exemplified here
A “hydrocarbon residue” or “heterocyclic group” as a substituent is
R mentioned above ¹ As "each may be substituted
"Hydrocarbon residue or heterocyclic group"
Group or a substituent which the "heterocyclic group" may have
May have such substituents.

R ⁵ represents the optionally substituted sulfinyl or sulfonyl group in R ¹ .
R ⁶ has the same meaning as the optionally substituted thiol group in R ¹ . R ⁷ has the same meaning as the substituent of the optionally substituted amino group in R ¹ . R ⁸ is
And R ² have the same meanings. R ⁹ has the same meaning as Z ² described above. R ¹⁰ represents a carboxyl-protecting group. R ¹⁰
Examples of the carboxyl protecting group represented by include the same groups as the optionally substituted hydrocarbon residue represented by R ¹ . R ¹¹ represents an amino group which may be substituted. Examples of the optionally substituted amino group for R ¹¹ include the same as the optionally substituted amino group for R ¹ , for example, an amino group, an N-monosubstituted amino group and an N, N-disubstituted amino group. Groups. Examples of the substituted amino group include, for example, an optionally substituted hydrocarbon residue (for example, the same as the optionally substituted hydrocarbon residue represented by R ¹ , more specifically,
C which may have a _1-8 alkyl group, a C _3-7 cycloalkyl group, a C _2-8 alkenyl group, a C _2-8 alkynyl group, a C _3-7 cycloalkenyl group, a C _1-4 alkyl group _6-10 aryl group and the like, an _optionally substituted heterocyclic group (for example,
Or the same as the optionally substituted heterocyclic group represented by R ¹ , or a group represented by the formula: —COR ′ (wherein, R ′ is a hydrogen atom or an optionally substituted hydrocarbon residue or heterocyclic group, respectively) In addition, it shows a cyclic group, wherein "a hydrocarbon residue or a heterocyclic group which may be respectively substituted" as R '.
May have the same substituent as the above-mentioned `` hydrocarbon residue '' or `` heterocyclic group '' in the `` hydrocarbon residue or heterocyclic group which may be substituted '' as R ′ Good. ), Preferably an amino group having one or two C _1-10 acyl groups (eg, C _2-7 alkanoyl, benzoyl, nicotinoyl, etc.) as substituents
(E.g., methylamino, dimethylamino, ethylamino,
Diethylamino, propylamino, dipropylamino,
Dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, etc.). More preferably, an N, N-disubstituted amino group (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, N-methyl-N-phenylamino, etc.), still more preferably, N, N-diamino A _C1-3 alkylamino group (eg, dimethylamino, diethylamino, dipropylamino, etc.) is exemplified. Further, two groups in the substituted amino group may be bonded to form a nitrogen-containing 5- to 7-membered ring (for example, piperidino, morpholino, thiomorpholino, etc.).

R¹³May be respectively substituted
Indicates an amino group or a hydroxyl group. R^{1 3}As the R
⁴Or the R¹¹And the same groups as mentioned above. R^{13 '}
Represents an optionally substituted amino group or hydroxyl
Represents a group. R ^{13 '}Is a hydroxyl group, R⁴Or
The R¹¹And the same groups as mentioned above. X is fluorine, salt
Z which represents a halogen atom such as iodine, bromine and iodine⁵Is -CO
Indicates-. Z⁶Is Z^TwoMay be substituted
It has the same meaning as the amino group.

[0037] ^{Z 7} shows a -CO-. Z ⁸ has the same meaning as the optionally substituted hydrocarbon residue or heterocyclic group in Z ² .

Ring A is

Embedded image (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or an respectively substituted group. A 5-membered heterocyclic ring represented by a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group. Ring A is

Embedded image (Wherein, R ³ and R ¹⁴ have the same meanings as described above.)
The aromatic 5-membered heterocyclic ring represented by

R³Is a hydrogen atom, each of which is
Hydrocarbon residues, heterocyclic groups, hydroxyl groups, amino groups,
It represents a sulfonyl group or an acyl group. R³Replacement in
Examples of the optionally substituted hydrocarbon residue include, for example, R¹
And the same as the optionally substituted hydrocarbon residue in
Is included. R³Optionally substituted charcoal in
As the hydride residue, preferably an aliphatic hydrocarbon residue
But more preferably, for example, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopen
Chill, tert-pentyl, hexyl, isohexyl,
C1-C8 saturated aliphatic carbon such as heptyl and octyl
And a hydride residue (eg, an alkyl group). R³In
Examples of the optionally substituted heterocyclic group include, for example,
R¹And the same as the optionally substituted heterocyclic group in
Is included. R³Optionally substituted water in
Examples of the acid group include R¹Even if
The same thing as a good hydroxyl group is mentioned. R³Place in
Examples of the optionally substituted amino group include, for example, R¹To
The same as the optionally substituted amino group in
I can do it. R³Optionally substituted sulfoni
As the group, for example, R¹Even if
Examples include the same as a good sulfonyl group. R³In
Examples of the optionally substituted acyl group include, for example,
R¹Represented by the "hydrocarbon optionally substituted"
An aryl or heterocyclic group "and a carbonyl group
And preferably R¹Hydrocarbon residue represented by, complex
Ring, sulfinyl, and sulfonyl substituents
The same as the acyl group are exemplified. R¹⁴Is the water
An elemental atom, halogen or each may be substituted
Hydrocarbon residue, heterocyclic group, hydroxyl group, amino group, sulfonyl group
Represents an acyl group or an acyl group. R ¹⁴Halogen in
Examples include fluorine, chlorine, bromine, iodine, etc.
You. R¹⁴Each of which may be optionally substituted
Hydrogen residue, heterocyclic group, hydroxyl group, amino group, sulfonyl group
Or, as the acyl group, R³Similar to those shown in
Are included. R¹⁴Is preferably a hydrogen atom.

Ring B, B-1, C, D, D-2, D-3, D-4, D ', D'
-1, D'-2, D'-3 each may have a substituent 5 to
Shows a 7-membered hydrocarbon ring. 5 which may have the substituent
As a 5- to 7-membered hydrocarbon ring of a to 7-membered hydrocarbon ring
Is a 5- to 7-membered alicyclic or aromatic hydrocarbon
It may be a ring. The alicyclic 5- to 7-membered hydrocarbon ring;
Then, C_5-7Saturated alicyclic hydrocarbon ring (for example, cyclo
C such as pentane, cyclohexane and cycloheptane
_5-7Cycloalkane) and C_5-7Unsaturated alicyclic hydrocarbon
Elementary rings (for example, 1-cyclopentene, 2-cyclopente
3-cyclopentene, 1-cyclohexene, 2-si
Clohexene, 3-cyclohexene, 1-cyclohepte
2-cycloheptene, 3-cycloheptene, 2,4
C such as cycloheptadiene, etc._5-7Cycloalkene,
C _5-7Cycloalkadiene) and the like. The fragrance
Examples of the aromatic hydrocarbon residue include a benzene ring.
It is. Preferably, C_5-7Saturated alicyclic hydrocarbon ring, and more
Preferably C₆Saturated alicyclic hydrocarbon ring (cyclohexa
N).

Rings B, B-1, C, D, D-2, D-3, D-4,
D ', D'-1, D' -2, as the substituents to 7-membered hydrocarbon ring 5 which may have a substituent in D'-3, for example, "substituted for R ¹ And the like as the substituents of the "good hydrocarbon residue". The number of substituents is preferably one to three. The substituent of the 5- to 7-membered hydrocarbon ring which may have a substituent is preferably an aliphatic hydrocarbon residue, more preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -Butyl, tert-butyl, pentyl,
C1-8 saturated aliphatic hydrocarbon residues such as isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl and octyl (eg alkyl groups)
Is mentioned. Ring B, B-1, C, D, D-2, D-3, D-
4, D ', D'-1, D'-2, and D'-3 each represent a 5- to 7-membered hydrocarbon ring which may have a substituent, and preferably has no substituent. And a 7-membered hydrocarbon ring. More preferably, 5 to 7 not having a substituent
Membered saturated hydrocarbon rings. More preferably, a 6-membered saturated hydrocarbon ring having no substituent is used.

In the above formula (I), R ¹ is an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group; R ² is —Z ¹ -Z ² (wherein Z ¹
Is, -CO- or -CS- indicates, ^{Z 2} represent, respectively, optionally substituted hydroxyl group or an amino group. );
Ring A is

[Of 60] [Wherein, R ³ has the same meaning as described above. A compound wherein Ring B is a 5- to 7-membered hydrocarbon ring which may have a substituent, or a salt thereof is preferred.

In the above formula (I), R ¹ is
A sulfinyl group or a sulfonyl group bonded by _1-8 alkyl, a thiol group optionally substituted by C _1-8 alkyl, or a C _6-10 aryl each optionally substituted by 1 to 3 substituents ( particularly preferably phenyl), an aromatic monocyclic Hajime Tamaki (particularly preferably pyridyl) or an aromatic fused Hajime Tamaki (particularly preferably hydroxy group which may be substituted by quinolyl); is R ^2, -Z ¹
-Z ² (wherein, Z ¹ represents -CO-, and Z ² represents an optionally substituted hydroxyl group or an amino group, respectively);

Embedded image [Wherein, R ³ has the same meaning as described above. R ³
Is a saturated aliphatic hydrocarbon residue having 1 to 8 carbon atoms (eg, an alkyl group); a compound wherein Ring B is a C _5-7 saturated alicyclic hydrocarbon ring or a salt thereof is more preferred.

As the compound represented by the formula (I), 4,5-dihydro-1-methyl-8-propylsulfanyl-1H-thieno
[3,4-g] indazole-6-carboxamide; 4,5-dihydro
-1-methyl-8-propylsulfinyl-1H-thieno [3,4-g]
Indazole-6-carboxamide; 4,5-dihydro-1-methyl-8-propylsulfonyl-1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-8- (3,4- Methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-8-phenoxy-1-methyl-1H-thieno [3,4-g] Indazole-6-carboxamide; 4,5-dihydro-8- (3,4-methylenedioxyphenoxy) thieno [3,4-g] -1,2-benzisoxazole-6-carboxamide; 8- [4 -[(Diethoxyphosphoryl) methyl]
Phenoxy] -4,5-dihydro-2-methyl-2H-thieno [3,4-g]
Indazole-6-carboxamide; 8- [4-[(diethoxyphosphoryl) methyl] phenoxy] -4,5-dihydro-1-methyl-
1H-thieno [3,4-g] indazole-6-carboxamide; N-
Ethyl-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl -8- (4-trifluoromethylphenoxy) -1H-thieno [3,4-g] indazole-6
-Carboxamide; 4,5-dihydro-1-methyl-8- (6-quinolinyloxy) -1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl-8- [ (3-pyridinyl)
Oxy] -1H-thieno [3,4-g] indazole-6-carboxamide; 8-[(4-benzyloxy) phenoxy] -4,5-dihydro-1-methyl-1H-thieno [3,4-g ] Indazole-6-carboxamide; or 4,5-dihydro-1-methyl-8- [4- (2-quinolinylmethoxy) phenoxy] -1H-thieno [3,4-g] indazole-6-carboxamide preferable.

In the above formula (II), R ¹ is an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group; R ² is -Z ¹ -Z ² (wherein Z ¹
Is, -CO- or -CS- indicates, ^{Z 2} represent, respectively, optionally substituted hydroxyl group or an amino group. );
A compound or a salt thereof, wherein R ⁴ is C _1-8 alkyloxy; and ring C is a 5- to 7-membered hydrocarbon ring which may have a substituent. In the above formula (II), R ¹ is, sulfinyl group or sulfonyl group attached at C _1-8 alkyl, respectively, thiol group that may be substituted with C _1-8 alkyl or 1-3 respectively substituted, Substituted with a C _6-10 aryl (particularly preferably phenyl), an aromatic monocyclic heterocyclic group (particularly preferably pyridyl) or a fused aromatic heterocyclic group (particularly preferably quinolyl) which may be substituted with a group. An optionally substituted hydroxyl group; R ² is
-Z ¹ -Z ² (wherein, ^{Z 1} represents a -CO-, ^{Z 2} represent, respectively, optionally substituted hydroxyl group or an amino group.); ^{R 4} is, C _1-3 alkyloxy; Ring C is
Compounds that are compounds that are C _5-7 saturated alicyclic hydrocarbon rings or salts thereof are more preferred.

The compound of the present invention represented by the formula (I) [referred to as compound (I). Or a salt of a raw material compound for producing the salt thereof, is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a base And salts with acidic or acidic amino acids. Preferred examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
Salts with ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like are included. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
Salts with citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, etc., and preferred examples of the salt with an acidic amino acid include
For example, salts with aspartic acid, glutamic acid and the like can be mentioned.

Compound (I) or a salt thereof is prepared by
It may be a rag. Compound (I) or a salt thereof
Lodrugs are enzymes and stomach acids under physiological conditions in vivo.
To a compound (I) or a salt thereof by a reaction such as
Compounds, i.e. enzymatic oxidation, reduction, hydrolysis
Which changes into compound (I) or a salt thereof
Compounds caused by hydrolysis by substances, gastric acid, etc.
It refers to a compound that changes to (I) or a salt thereof. Compound
As a prodrug of (I) or a salt thereof, a compound
The hydroxyl group of (I) or a salt thereof is acylated, alkyl,
Or phosphorylated or borated compounds or their salts (eg
For example, when the hydroxyl group of compound (I) or a salt thereof is acetyl
, Palmitoylation, propanoylation, pivaloylation,
Succinylation, fumarylation, alanylation, dimethylamino
No methylcarbonyl compound or its salt
And the carboxyl group of compound (I) or a salt thereof is
Esterified or amidated compounds (for example, compounds
The carboxyl group of (I) or a salt thereof is an ethyl ester
, Phenylesterification, carboxyoxymethyles
Telluration, dimethylaminomethylesterification, pivaloyl
Oxymethyl esterification, ethoxycarbonyloxy
Tyl esterification, phthalidyl esterification, (5-methyl
-2-oxo-1,3-dioxolen-4-yl) methyl
Esterification, cyclohexyloxycarbonylethyl
Esterified or methylamidated compound or salt thereof
Etc.) are used. These prodrugs are themselves
Manufacture according to a known method or a method equivalent thereto
be able to. Further, the compound (I) or a salt thereof
Drugs, Hirokawa Shoten 1990, “Development of Pharmaceuticals”
As described in Volume 7, Molecular Design, pages 163-198
Compound that changes to compound (I) or a salt thereof under physiological conditions
It may be.

The compounds of the present invention (I) or a salt thereof isotope ^{(eg, 2 H, 3 H, 14} C, 3 5 S, etc. ¹²⁵ I) may be labeled with a.

In the above formula (IX), R ¹ is an optionally substituted sulfinyl group, sulfonyl group, hydroxyl group or thiol group; R ² is —Z ¹ -Z ² (wherein Z ¹
Is, -CO- or -CS- indicates, ^{Z 2} represent, respectively, optionally substituted hydroxyl group or an amino group. );
R ¹³ is a C _1-8 alkyloxy or N, N-disubstituted amino group; a compound wherein Ring D is an optionally substituted 5- to 7-membered hydrocarbon ring or a salt thereof is preferable. In the above formula (IX), R ¹ is a sulfinyl group or a sulfonyl group each bonded by C _1-8 alkyl,
_A thiol group optionally substituted with _1-8 alkyl, or a C _6-10 aryl (particularly preferably phenyl), each optionally substituted with 1 to 3 substituents, an aromatic monocyclic heterocyclic group (Particularly preferably pyridyl) or a hydroxyl group which may be substituted by an aromatic condensed heterocyclic group (particularly preferably quinolyl); R ² represents -Z ¹ -Z ² (wherein
Z ¹ represents —CO—, and Z ² represents an optionally substituted hydroxyl group or amino group. ); R ¹³ is
N, N-di C _1-3 alkylamino group or C _1-3 alkyloxy; a compound wherein Ring D is a C _5-7 saturated alicyclic hydrocarbon ring or a salt thereof is more preferred.

As the compound represented by the formula (IX), 3- (3,4
-Dimethoxyphenoxy) -5-ethoxymethylidene-4,5,6,
7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester; 3- (3,4-dimethoxyphenoxy)
-5-dimethylaminomethylidene-4,5,6,7-tetrahydro-4
-Oxobenzo [c] thiophen-1-carboxylic acid ethyl ester; or 5-dimethylaminomethylidene-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester Is preferred.

The compound of the present invention represented by the formula (IX) [referred to as compound (IX). Or a salt thereof represented by the present invention represented by the salt or a salt of a raw material compound for producing the salt thereof, is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, an inorganic salt, Examples thereof include salts with acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.
Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Suitable examples of salts with inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid,
Salts with sulfuric acid, phosphoric acid and the like can be mentioned. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of salts with basic amino acids include:
For example, salts with arginine, lysine, ornithine and the like are mentioned, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid. Compound (IX) or a salt thereof isotopes present invention ^{(Example, 2 H, 3 H, 14} C, 3 5 S, etc. ¹²⁵ I) may be labeled with a. When the compound or a salt thereof obtained in the present invention has a double bond in the molecule,
When the Z or E configuration is present, either each or a mixture thereof is included in the present invention. When the compound obtained in the present invention or a salt thereof has a stereoisomer such as having an asymmetric carbon in the molecule, each of them or a mixture thereof is also included in the present invention.

The method for producing the compound of the present invention will be described below. Compound (I) or a salt thereof can be produced, for example, by the following Method A to Method F or a method analogous thereto. [Method A]

Embedded image [Wherein, compound (III) represents hydroxylamine or monosubstituted hydrazine (R ^{3 ′} NHNH ₂ ) or a salt thereof, and the other symbols have the same meanings as described above. ]

In this reaction, compound (II) and compound (II)
Compound (I) is produced by reaction with I). This reaction is carried out according to a conventional method, in a neutral or in the presence of an acid or a base, in a solvent that does not adversely influence the reaction. As the acid,
For example, mineral acids such as hydrochloric acid and sulfuric acid; methanesulfonic acid, p-
Organic acids such as toluenesulfonic acid, benzoic acid, acetic acid, and trifluoroacetic acid are included. Examples of the base include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydride and the like, potassium t-butoxide, sodium acetate, triethylamine, pyridine, 1,8-diazabicyclo
Organic bases such as [5.4.0] -7-undecene, sodium methoxide and the like can be mentioned. Acids and compounds (III)
Is preferably about 1 to about compound (II).
About 5 molar equivalents. Solvents which do not adversely affect the reaction include, for example, alcohols such as water, methanol, ethanol and propanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; benzene, toluene and xylene Aromatic hydrocarbons such as;
Examples include amides such as N, N-dimethylformamide and 1-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -50
To about 150 ° C, preferably from about 0 to about 100 ° C. The reaction time is generally about 0.5 to about 20 hours. R ^{3 ′} on Ring A generated by this reaction can be converted to an optionally substituted hydroxyl group or amino group described as R ³ using a method known per se. The compound (I) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (II) used as a starting compound in the above-mentioned Method A is a novel compound and the compound (I)
V):

Embedded image Wherein each symbol has the same meaning as described above. And orthoformic acid ester. That is, Compound (IV) can be prepared by a known method, for example, Indian Journal of Chemistry Section B (Indian.
J. Chem. Sec. B) 35: 49-51 (1996)
Year) or a method analogous thereto. That is, this reaction is usually performed in the presence of an acid and a base in a solvent that does not adversely influence the reaction. The amount of the orthoformate to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV). Examples of the acid include a boron trifluoride-ether complex. The amount of the acid to be used is preferably about 1 to about 1 relative to compound (IV).
0 molar equivalent. As the base, triethylamine,
Diisobutylethylamine, 1,8-diazabicyclo
[5.4.0] -7-undecene and the like. The amount of the base to be used is preferably about 1 to about 10 molar equivalents relative to compound (IV). Examples of the solvent that does not adversely affect the reaction include halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, toluene, and xylene. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
Usually, about -100 to about 150C, preferably about -70 to
About 0 ° C. The reaction time is generally about 0.5 to about 20 hours. Compound (II) thus obtained is
Isolation and purification can be performed by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

Among the compounds (IV) used as starting compounds, for example, compound (IV-1):

Embedded image Is a known compound and is a known compound.
igs Ann.) 1996, pp. 239-245, or Synthetic Communications (Synth. Commu.
n.) 1995, pp. 2449-2455.

In the above-mentioned Method A, the R of compound (I)
Compound (IV-2,3) used as a starting compound of a compound represented by the amino group wherein ¹ may be substituted
Is produced by the following synthesis method. (Step 1)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (V) is produced by reacting 1,3-cycloalkanedione with an alkyl isothiocyanate or an aryl isothiocyanate in the presence of a base. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline, 1,8-
Amines such as diazabicyclo [5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. Can be The amount of the reaction reagent used is preferably about 1 to about 10 molar equivalents based on 1,3-cycloalkanedione. The amount of the base to be used is preferably about 1 to about 10 molar equivalents relative to 1,3-cycloalkanedione. The reaction temperature is generally about -50 to about 150C, preferably about 0 to about 100C. The reaction time is generally about 0.5 to about 20 hours. The compound (V) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 2)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (VI) is produced by reacting compound (V) with compound (VII). This method is carried out according to a conventional method in the presence of a base in a solvent that does not adversely influence the reaction. As the compound (VII), for example, haloacetic acid ester, halomethylnitrile or halomethylketone, specifically, ethyl chloroacetate, ethyl bromoacetate,
Examples include t-butyl bromoacetate, chloroacetone, chloroacetylbenzene, chloroacetonitrile and the like. The amount of compound (VII) to be used is preferably about 1 to about 10 molar equivalents relative to compound (V). Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate and the like; pyridine,
Triethylamine, N, N-dimethylaniline, 1,8
Amines such as diazabicyclo [5.4.0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t.-butoxide Is mentioned. The amount of the base to be used is preferably about 1 to about 5 molar equivalents relative to compound (V). Solvents that do not adversely affect the reaction include, for example, aromatic hydrocarbons such as benzene, toluene and xylene;
Ethers such as tetrahydrofuran, dioxane, and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N, N-dimethylformamide; and sulfoxides such as dimethylsulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -50
To about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours.
The compound (VI) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 3)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (IV-2) is produced from compound (VI). This method is carried out according to a conventional method in the presence of a base in a solvent that does not adversely influence the reaction. As the base,
Alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, potassium carbonate; pyridine, triethylamine, N, N-dimethylaniline,
1,8-diazabicyclo [5.4.0] undec-7-
Amines such as ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. The amount of these bases used is
The amount is preferably about 1 to about 5 molar equivalents relative to compound (VI). Examples of the solvent that does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about-
50 to about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours. Compound (IV-2) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction,
It can be isolated and purified by crystallization, recrystallization, phase transfer, chromatography and the like.

(Step 4)

Embedded image Wherein each symbol has the same meaning as described above. In this reaction, compound (IV-2) is acylated to produce compound (IV-3). The present method relates to the compound (IV-2)
And an acylating agent are appropriately reacted. Here, examples of the acylating agent include acid anhydrides, acid halides (acid chloride, acid bromide), imidazolide, and mixed acid anhydrides (eg, anhydrides with methyl carbonate, ethyl carbonate, isobutyl carbonate, and the like). Can be The amount of these acylating agents to be used depends on the amount of the compound (IV-
It is preferably about 1 to about 5 molar equivalents relative to 2). Examples of the solvent that does not adversely affect the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran, dioxane, and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide; These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -50 to about 150C, preferably about -10 to about 100C. The reaction time is generally about 0.5 to about 20 hours. The compound (IV-3) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[Method B]

Embedded image Wherein ring A ′ is

Embedded image And each symbol has the same meaning as described above. ]

In this method, compound (I-1) is produced by reacting compound (I-2) with a nucleophilic reagent. The reaction is
It is carried out by a method known per se, for example, the method described in WO98 / 18792 or a method analogous thereto. Examples of the nucleophilic reagent include metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents,
Aryl metal reagents, thioalcoholates, amines and the like. The amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-2). Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is
Usually, it is about -50 to about 150C, preferably about -10 to about 100C. The reaction time is usually about 0.5 to about 20.
Time. Compound (I-1) thus obtained
Can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The compound (I-2) used as a starting compound in the above-mentioned Method B can be produced by the following method.

Embedded image Wherein each symbol has the same meaning as described above. In this method, compound (I-2) is produced from compound (I-3) using an oxidizing agent. This reaction is carried out by a method known per se, for example, as an oxidizing agent, manganese dioxide, permanganate,
Chromic acid, lead tetraacetate, halogen, ozone, hydrogen peroxide,
Organic peroxides, organic peroxy acids, hydrogen peroxide-sodium tungstate, oxygen, N-halocarboxylic amides, hypohalous esters, iodosyl compounds, nitric acid, nitrous oxide, dimethyl sulfoxide, ethyl azodicarboxylate, chloro It is performed by a method using gold (III) acid or the like, or by anodic oxidation or a method analogous thereto. That is, this reaction is usually performed in the presence of an oxidizing agent in a solvent that does not adversely affect the reaction. As the oxidizing agent, for example, m-chloroperbenzoic acid, peracetic acid and the like are preferable. Examples of the solvent that does not adversely affect the reaction include ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene, and xylene; Amides such as dimethylformamide and 1-methylpyrrolidone are exemplified. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -50 to about 150C, preferably about-
10 to about 100 ° C. The reaction time is usually about 0.5
~ 20 hours. The compound (I-2) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

[Method C]

Embedded image Wherein each symbol has the same meaning as described above. ]

In this method, compound (I-5) is produced by an elimination reaction of a carboxyl protecting group. This reaction includes all the conventional methods used for the elimination reaction of a carboxyl protecting group. For example, hydrolysis, reduction, elimination using a Lewis acid, and the like can be applied. When the carboxyl protecting group is an ester, it can be eliminated by hydrolysis or elimination with a Lewis acid. Hydrolysis can be eliminated by elimination with a base or Lewis acid. The hydrolysis is
It is preferable to carry out the reaction in the presence of a base or an acid. Suitable bases include, for example, alkali metal hydroxides (e.g., sodium hydroxide, calcium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (e.g., carbonate Sodium, potassium carbonate, etc.), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetates (e.g., sodium acetate, potassium acetate Inorganic bases such as alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphates (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), and trialkylamines (e.g., For example, trimethylamine, triethylamine, etc.), picoline, N-methyl Roridins, N- methylmorpholine, 1,5-diazabicyclo [4.3.2] non -
5-ene, 1,4-diazabicyclo [2.2.2] non-
5-ene, 1,8-diazabicyclo [4.3.0] -7-
Organic bases such as undecene. The hydrolysis using a base is often performed in water, a hydrophilic organic solvent or a mixed solvent. Suitable acids include organic acids
(For example, formic acid, hydrobromic acid, sulfuric acid, etc.). This hydrolysis reaction is usually performed in an organic solvent, water or a mixed solvent composed of these. The reaction temperature is not particularly limited, and is appropriately selected depending on the type of the carboxyl protecting group and the elimination method. Elimination using a Lewis acid can be carried out by subjecting compound (I-4) or a salt thereof to a Lewis acid such as boron trihalide (eg, boron trichloride, boron trifluoride, etc.), titanium tetrahalide (eg, titanium tetrachloride, Titanium tetrabromide, etc.), aluminum halide
(For example, aluminum chloride, aluminum bromide, etc.) and trihaloacetic acid (for example, trichloroacetic acid, trifluoroacetic acid, etc.). This elimination reaction is preferably performed in the presence of a cation scavenger (e.g., anisole, phenol, etc.), and is usually nitroalkane (e.g., nitromethane, nitroethane, etc.), alkylene halide (e.g., methylene chloride, ethylene chloride, etc.), The reaction is performed in a solvent such as diethyl ether, carbon disulfide, or a solvent that does not adversely affect the reaction. These solvents may be used as a mixture thereof. The elimination by reduction is preferably applied to the elimination of protecting groups such as alkyl halide (eg, 2-iodoethyl, 2,2,2-trichloroethyl and the like) esters and aralkyl (eg benzyl and the like) esters. As the reduction method used in the present elimination reaction, for example, a metal (e.g., zinc, zinc amalgam, etc.) or a salt of a chromium compound (e.g., chromic chloride, chromium acetate, etc.) and an organic or inorganic salt (e.g., acetic acid, propionic acid, etc.) , Hydrochloric acid, etc.); conventional catalytic reduction in the presence of a conventional metal catalyst (eg, palladium carbon, Raney nickel, etc.). The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, or under heating. The compound (I-5) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

In the general formula (I), R ² is a group represented by the formula: -Z ⁵ -Z ⁶
(Wherein, Z ⁵ represents —CO— and an amino group which may be substituted with Z ⁶ ). (I-6) is produced, for example, by the following Method D. [Method D]

Embedded image [In the formula, compound (VIII) represents Z ⁶ H, and the other symbols have the same meanings as described above. In this method, compound (I-6) is reacted with a reactive derivative at the carboxyl group or a salt thereof with compound (VIII) or a reactive derivative at the amino group or a salt thereof to obtain compound (I-6). )
To manufacture. Suitable reactive derivatives at the amino group of compound (VIII) include Schiff base imino or its enamine tautomer, which is formed by the reaction of compound (VIII) with a carbonyl compound such as an aldehyde or ketone; VIII) a silyl derivative produced by the reaction of a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea; etc .; produced by the reaction of compound (VIII) with phosphorus trichloride or phosgene Derivatives.

Examples of suitable reactive derivatives at the carboxyl group of compound (I-5) include acid halides, acid anhydrides, activated amides, activated esters and the like. Preferred examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, and dialkyl phosphite. ,
Sulfurous acid, thiosulfuric acid, sulfuric acid, for example, sulfonic acid such as methanesulfonic acid, for example, carboxylic acid such as acetic acid, propionic acid, butyric acid, pivalic acid isobutyrate, pentanoic acid, isopentanoic acid, and trichloroacetic acid, or aromatic compound such as benzoic acid Mixed anhydrides with acids such as aromatic carboxylic acids; symmetric anhydrides; activated amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or, for example, cyano Methyl ester, methoxy methyl ester, dimethyl imino methyl ester,
Vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-
Activated esters such as nitrophenyl ester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or, for example, N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) -pyridone,
Examples include esters with N-hydroxy compounds such as N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-1H-benzotriazole. These reactive derivatives can be arbitrarily selected depending on the type of the compound (I-5) to be used. Suitable salts of the reactive derivative of the compound (I-5) include, for example, alkali metal salts such as sodium salt and potassium salt, for example, alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salts such as trimethylamine salt. Triethylamine salt,
Pyridine salt, picoline salt, dicyclohexylamine salt,
And base salts such as organic base salts such as N, N-dibenzylethylenediamine salt. The reaction is generally carried out with water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, and the like.
The reaction is carried out in a conventional solvent such as N, N-dimethylformamide or pyridine, but the reaction can be carried out in any other organic solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water.

In the reaction, when the compound (I-5) is used in the form of a free acid or a salt thereof, N, N'-
Dicyclohexylcarbodiimide; N-cyclohexyl-
N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylamino Propyl) carbodiimide; N, N'-carbonylbis (2-
Methyl imidazole); Pentamethyleneketene-N-cyclohexylimine; Diphenylketene-N-cyclohexylimine; Ethoxyacetylene; 1-alkoxy-1-chloroethylene; Trialkyl phosphite; Ethyl polyphosphate; Phosphoryl chloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; for example, ethyl chloroformate;
2-ethyl-7-hydroxybenzisoxazolium salt, 2
-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazo-
1- (p-chlorobenzenesulfonyloxy) -6-chloro
-1H-benzotriazole; in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of N, N'-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is desirable to carry out the reaction. The reaction also involves alkali metal bicarbonate tri (lower) alkylamine, pyridine, N-
It may be carried out in the presence of an inorganic or organic base such as (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. The reaction temperature is not particularly limited,
Usually, the reaction is carried out under cooling or heating. The amount of compound (VIII) to be used is 1 to 5 based on compound (I-5).
It is 10 molar equivalents, preferably 1-3 molar equivalents. The reaction temperature is usually -30C to 100C. The reaction time is usually 0.5 to 20 hours.

When a mixed acid anhydride is used, the compound (I-5) and a chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) are used as bases (eg, triethylamine, N-methylmorpholine). ,
(N, N-dimethylaniline, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, etc.) and further react with compound (VIII). Compound (VII
The amount of I) to be used is generally 1-based on compound (I-5).
It is 10 molar equivalents, preferably 1-3 molar equivalents. The reaction temperature is usually -30C to 100C. The reaction time is usually 0.5 to 20 hours. The compound (I-6) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound (I-5) used as a starting compound in the above method D is produced by the above method C.

[Method E]

Embedded image Wherein each symbol has the same meaning as described above. In this method, compound (I-8) is produced from compound (I-7) in the presence of a dehydrating agent. This reaction is carried out with compound (I-7))
And a dehydrating agent are appropriately reacted.
Here, examples of the dehydrating agent include acetic anhydride, trifluoroacetic anhydride, phosphorus pentoxide, thionyl chloride and the like. The amount of the dehydrating agent to be used is 0.1 to 100 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (I-7). The reaction temperature is usually -30C to 100C. The reaction time is usually 0.5 to 20 hours. The compound (I-8) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. . The compound (I-7) used as a starting compound in the above method E is produced by the above method D or B.

For example, when an acid halide is used, the reaction is carried out in the presence of a base in a solvent that does not adversely influence the reaction. Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio.

In the formula (I), R ² is a group represented by the formula: -Z ⁷ -Z ⁸ (wherein Z ⁷ is -CO-, and Z ⁸ is a hydrocarbon residue or heterocyclic group which may be substituted, respectively) Or a hydroxyl group) is represented by the following formula (I-10):
It is manufactured by the method. [Method F]

[Of 75] [Wherein, R ¹ has the same meaning as described above. In this method, compound (I-10) is produced by reacting nucleophilic reagent with compound (I-9). As the nucleophilic reagent,
For example, metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents, aryl metal reagents, thioalcoholates and the like are used. The amount of the nucleophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-9). This reaction is generally performed in a solvent that does not adversely influence the reaction. Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; Examples include amides such as dimethylformamide and 1-methylpyrrolidone; and sulfoxides such as dimethyl sulfoxide. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is generally about -70 to about 150
° C, preferably from about -70 to about 0 ° C. The reaction time is
Usually, about 0.5 to about 20 hours. Compound (I-10) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer,
It can be isolated and purified by chromatography and the like. Compound (I-9) used as a starting compound in the above-mentioned Method F can be produced by Method D. Compound (I) can also be obtained by the following production method other than the above production method.

[Method G]

Embedded image Wherein each symbol has the same meaning as described above. (IX-1) is produced by reacting the compound (IV) with an amide acetal. Examples of the amide acetal include, for example, an active acetal form of N, N-dialkylformamide,
Preferably N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide diethyl acetal,
Methoxybis (dimethylamino) methane, ethoxybis (dimethylamino) methane, t-butoxybis (dimethylamino) methane, tris (dimethyl) aminomethane,
N, N-dimethylformamide dipropyl acetal, N, N-
Dimethylformamide bis (2-trimethylsilylethyl) acetal, N, N-dimethylformamidedibenzylacetal, N, N-dimethylformamidedi-t-butylacetal, N, N-dimethylformamidedineopentylacetal, N, N-dimethyl Active acetal forms of dimethylformamide such as formamide dicyclohexyl acetal and N, N-dimethylformamide diisopropyl acetal are used, and more preferably N, N-dimethylformamide dimethyl acetal, N, N-dimethylformamide diethyl acetal, methoxybis (dimethylamino)
Methane, ethoxybis (dimethylamino) methane, t-
Butoxybis (dimethylamino) methane, tris (dimethylamino) methane, N, N-dimethylformamide dipropyl acetal, N, N-dimethylformamide diisopropyl acetal and the like are used. The amount of the amide acetal to be used is 1 mol to 50 mol, preferably 1 mol to 30 mol, per 1 mol of compound (IV). As a solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, and examples thereof include hydrocarbons (eg,
n-hexane, n-heptane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, etc.), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), amides ( For example, N, N-
N, N-diC _1-3 alkylformamide such as dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc., esters (eg, ethyl acetate, methyl acetate, etc.), nitriles (eg, acetonitrile, etc.) ), Sulfoxides (eg, dimethyl sulfoxide, etc.), or a mixture of two or more. The reaction is carried out at a reaction temperature of 0 to 150 ° C., preferably 50 to 120 ° C. for about 30 minutes.
The reaction is carried out for minutes to 24 hours, preferably for 1 to 6 hours.

The amide acetals described here are known per se and can be easily obtained as commercial products. Compound (IV) can be prepared by a known method, for example, the article of D. Prim et al.
nth.Commun., 25, 2449, 1995),
Alternatively, it is manufactured by a method equivalent thereto.

[Method H]

Embedded image Wherein each symbol has the same meaning as described above. Compound (IX-2) is produced by a dealcoholation reaction of compound (II). This reaction is performed using an acid or a base. As the acid, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid,
Organic acids such as benzenesulfonic acid and p-toluenesulfonic acid, and the like.Examples of the base include alkali metal or alkaline earth metal hydrides such as sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, and sodium. Amides of alkali metals or alkaline earth metals such as hexamethyldisilazide, lower alkoxides of alkali metals or alkaline earth metals such as sodium methoxide, sodium ethoxide and potassium t-butoxide, potassium hydroxide, hydroxide Alkali metal or alkaline earth metal hydroxides such as sodium, potassium carbonate, sodium carbonate, cesium carbonate and other such carbonates, potassium hydrogen carbonate, sodium hydrogen carbonate and other such alkali metal or alkaline earth metal bicarbonate, Triethylua Min, diisopropylamine, pyridine, dimethylaminopyridine, 1,8-diazabicyclo
Organic bases such as [5,4,0] -7-undecene.
Of these, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid are preferable, and 1 mole of compound (II) 0.1 mol to 100
Mol, preferably 1 mol to 30 mol. In this reaction, if necessary, any solvent can be used as long as it does not inhibit the reaction. Among them, alcohols (eg, _C1-3 alcohols such as methanol, ethanol, and propanol) are preferable. Further, the above-mentioned acid or base may be used also as a solvent. The reaction is carried out at a reaction temperature of 0 to 50 ° C, preferably 0 to 30 ° C.
The reaction is carried out for about 10 minutes to 6 hours, preferably 30 minutes to 3 hours. Compound (II) is compound (I)
V), such as the article by A. Nangia et al. (Indian
J. Chem., 35B, 49, 1996) or a method analogous thereto.

[Method I]

Embedded image Wherein each symbol has the same meaning as described above. The compound represented by the general formula (I) is obtained by converting the compound (VII) to hydroxylamine or a salt thereof, or R ^{3 ′} NHNH ₂ (R
^{3 '} has the same meaning as described above. )) Or a salt thereof. In this reaction, hydroxylamine or hydrazines are used in an amount of 1 mol to 10 mol, preferably 1 mol to 5 mol, per 1 mol of compound (IX). As a solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction.
Preferably, alcohols (eg, _C1-3 alcohols such as methanol, ethanol, propanol, etc.) and a mixed system of alcohols and another suitable solvent or water are used. In the present reaction, an acid may be present in order to adjust the reaction rate, regioselectivity, solubility and the like. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. It is used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol. Further, it may be used also as a solvent. In this reaction, the reaction temperature is 0 to 120 ° C,
The reaction is carried out preferably at 50 to 100 ° C. for about 10 minutes to 6 hours, preferably 1 hour to 3 hours. Note that R ^{3 ′} on ring A generated by this reaction is R ³
Can be converted into an optionally substituted hydroxyl group or amino group described in the formula (1) using a method known per se.

[J method]

Embedded image Wherein each symbol has the same meaning as described above. In the reaction for cyclizing compound (IX-3) with a hydrazine represented by R ^{3 ″} NHNH ₂ in the presence of an acid to produce compound (I-11), compound (VII-2) 1 1 mol to 10 mol, preferably 1 mol to 5 mol of hydrazines, per mol.
Used in moles. As a solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, but alcohols (eg, _C1-3 alcohols such as methanol, ethanol, and propanol) are preferably used. The anhydrous condition in this reaction means a substantially anhydrous condition, specifically, a solvent in which water is not actively added, for example, a solvent having a water content of about 5% or less, preferably a water content of about 3% or less. This means that the reaction is carried out using a solvent, more preferably a solvent having a water content of 1% or less. Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Particularly, methanesulfonic acid is preferable, and is used in an amount of 0.1 mol to 100 mol, preferably 1 mol to 30 mol, per 1 mol of compound (IX-3). Further, it may be used also as a solvent. This reaction is carried out at a reaction temperature of 0 to 120 ° C, preferably 40 to 70 ° C, for about 10 minutes to 6 hours, preferably 1 hour to 3 hours.

In the formula (IX-3), a compound having a hydroxyl group in which R ^{13 ′} is substituted with a cyclic group can be obtained from a compound (IV) by a known method, for example, a dissertation by D. Prim et al. (Synth. , 244
9 (1995) or a method analogous thereto. Compound (IX) is subjected to a general acid hydrolysis reaction (for example, a mixed system of alcohols or amides and water as a solvent). And the reaction is carried out at a reaction temperature of 0 to 120 ° C. for 10 minutes to 6 hours using the same acid as described above in an amount of 0.1 mol to 10 mol per 1 mol of compound (IX). In addition, R in the general formula (IX-3)
By using an "amino group which may be substituted" as ^{13 '} , the compound (IX-3) can be prepared without using a compound such as a boron trifluoride ether complex, which has a problem of corrosivity in the production of the compound (IX-3). The compounds can be produced industrially advantageously.

[K method]

Embedded image The compound (I-12) in which R ¹ is a thiol which may be substituted in the general formula (I) is led to the compound (I-13) as follows. First, compound (I-12) is subjected to an oxidation reaction to give compound (I-13). As the oxidizing agent, a peracid such as metachloroperbenzoic acid, peracetic acid, formic acid, and trifluoroperacetic acid, a peroxide such as dioxirane, hydrogen peroxide in the presence of a metal catalyst, and oxone (trade name) are used. Can be used in an amount of 2 to 10 mol per 1 mol of compound (I-12). When oxidizing with peracetic acid or the like, an acid such as hydrochloric acid or sulfuric acid is added in an amount of 1 to 10 mol, preferably 2 to 5 mol, per 1 mol of compound (I-12) to promote the reaction. . The solvent used in this reaction may be any solvent as long as it does not inhibit the reaction, and examples thereof include hydrocarbons (eg, n-hexane, n-heptane, benzene, toluene, xylene, etc.), halogenated hydrocarbons ( eg dichloromethane), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), alcohols (e.g., methanol, ethanol, C _1-3 alcohols propanol), amides (e.g., N N, N-diC _1-3 alkylformamide such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.),
Nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ketones (acetone, 2-butanone, 4-methyl-2-pentanone, cyclohexone, etc.), carboxylic acids (eg, formic acid, acetic acid, Trifluoroacetic acid, etc.) or a mixture of two or more. The temperature and time in this reaction vary depending on the oxidizing agent used.For example, when the reaction is performed with peracetic acid, the reaction temperature is 0 to 100 ° C, preferably 30 to 60 ° C
For 1 to 24 hours, preferably 2 to 5 hours. The compound (I-13) obtained as described above is subjected to a substitution reaction to produce a compound (I-14). In this reaction, R ″ -OH was used per 1 mol of compound (I-13).
Is used in an amount of 1 to 2 mol, preferably 1 to 1.5 mol. The R ″ —O portion of R ″ —OH corresponds to the optionally substituted hydroxyl group of R ¹ . Examples of the base used in this reaction include the bases described in [Method H]. Among them, sodium methoxide, sodium ethoxide, potassium t-
Butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like are preferable, and 1 to 3 mol per 1 mol of compound (I-13),
Preferably 1 to 2 moles are used. As the solvent used in this reaction, any solvent may be used as long as it does not inhibit the reaction, and examples thereof include hydrocarbons (eg, n-hexane, n-heptane, benzene, toluene, xylene, etc.), halogenated hydrocarbons ( Examples: dichloromethane, etc.), ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.) , Esters (eg, ethyl acetate, methyl acetate, etc.),
Nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), ketones (acetone, 2-butanone, 4-methyl-2-pentanone, cyclohexone, etc.), and hydrocarbons (among others) For example, n-hexane, N-heptane, benzene, toluene,
Xylene, etc.), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.),
Ketones (acetone, 2-butanone, 4-methyl-2-
Preferred are pentanone, cyclohexone, etc.) and ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.). These solvents are used alone or as a mixture of two or more. This reaction is carried out at a reaction temperature of 20
To 120 ° C, preferably 70 to 100 ° C, 1 to 24
The reaction is carried out for a time, preferably 2 to 6 hours.

[L method]

Embedded image Compound (I-4) wherein R ¹⁰ represents a carboxyl-protecting group
Can be converted to compound (I-7) in one step by reacting with formamide in the presence of a base. Formamide is usually used also as a solvent, and 1 to 30 ml, preferably 2 to 10 ml per gram of compound (I-4)
Use milliliters. As the base used in this reaction, [H
Method], sodium methoxide, sodium ethoxide, potassium t-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like are preferable,
It is used in an amount of 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (I-4). When a solvent is used in this reaction, any solvent may be used as long as it does not inhibit the reaction.
Alcohols (eg, _C1-3 alcohols such as methanol, ethanol, and propanol), amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, formamide, etc.) are preferred. This reaction is carried out at a reaction temperature of 20 to 120 ° C., preferably 70 to 1
The reaction is carried out at 00 ° C. for 1 to 12 hours, preferably 1 to 3 hours.

[Method M]

Embedded image [In the formula, R ″ ′ represents an optionally substituted hydrocarbon group or a heterocyclic group, Rp represents a hydroxyl-protecting group, and other symbols have the same meanings as described above.] In general formula (I) Compounds wherein Rp is a protecting group for a hydroxyl group (I-1
5) leads to a compound (I-16) by a deprotection reaction, and is subjected to a subsequent substitution reaction to produce a compound (I-17). As Rp of compound (I-15) used in the first reaction, for example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, C _7-10 Aralkyl (eg, benzyl, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), benzoyl, C _7-10 aralkyl-carbonyl (eg, benzyl carbonyl, etc.),
2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C
_2-6 alkenyl (eg, 1-allyl and the like) and the like. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, propyl, etc.),
_It may be substituted by _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) or nitro. The removal of these protecting groups used in this reaction can be performed by a method known per se, for example, Protective Groups in Organic Synthesis.
and the method described in John Wiley and Sons (1980). For example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide and the like) and the like. , A reduction method and the like are used. The “optionally substituted hydrocarbon residue or heterocyclic group” represented by R ″ ′ is the same as the optionally substituted hydrocarbon residue or heterocyclic group represented by R ^1. Is mentioned. The compound (I-16) obtained as described above is subjected to a substitution reaction to give the compound (I-
17) Manufacturing. In this reaction, 1 to 2 mol, preferably 1 to 1.5 mol of R ′ ″-X is used per 1 mol of compound (I-16). Examples of the base used in this reaction include the bases described in [Method H], among which sodium fluoride, potassium fluoride, cesium fluoride and the like are preferable, and 1 to 3 based on 1 mol of compound (I-16) Mol, preferably 1 to 2 mol. As a solvent used in this reaction,
Any one may be used as long as it does not inhibit the reaction. Examples thereof include hydrocarbons (eg, n-hexane, n-heptane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, etc.), ethers (Diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.), amides (eg, N, N-dimethylformamide, N, N-
Dimethylacetamide, N-methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethylsulfoxide, etc.), ketones (acetone, 2-butanone) , 4-methyl-2-pentanone, cyclohexone and the like, among which hydrocarbons (eg, n-hexane, N-heptane, benzene, toluene, xylene and the like),
Amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), ketones (acetone, 2-butanone, 4- Preferred are methyl-2-pentanone, cyclohexone, etc.) and ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, etc.). These solvents are used alone or as a mixture of two or more. This reaction is carried out at a reaction temperature of 20 to 120 ° C.
The reaction is carried out preferably at 70 to 90 ° C. for 1 to 24 hours, preferably 2 to 6 hours.

[N method]

Embedded image [Wherein, Rr represents a hydrocarbon residue which may be substituted. In this method, the compound (I-19) obtained by brominating the compound (I-18) represented by the general formula is reacted with a nucleophilic reagent, and the compound (I-19) is treated with a metal reagent. After that, the compound (I-20) is produced by a reaction with an electrophilic reagent or a coupling reaction with, for example, a boronic acid reagent in the presence of a metal catalyst and a base. As the nucleophilic reagent, for example,
Metal phenolates, metal alcoholates, Grignard reagents, alkyl metal reagents, aryl metal reagents, thioalcolates and the like are used. As the electrophilic reagent, alkyl halides, aralkyl alides, aldehydes, ketones and the like are used. On the other hand, as the metal catalyst, bis (triphenylphosphine) palladium chloride or the like is used, and as the base, sodium carbonate, sodium hydrogen carbonate, cesium fluoride or the like is used. The amount of the nucleophilic reagent and the electrophilic reagent to be used is preferably about 1 to about 5 molar equivalents relative to compound (I-19). The amount of the metal catalyst used is determined by the amount of the compound (I-
It is preferably about 0.01 to about 0.1 molar equivalent with respect to 19), and the used amount of the base is preferably about 1 to about 5 molar equivalent with respect to compound (I-19). This reaction is generally performed in a solvent that does not adversely influence the reaction. Solvents that do not adversely affect the reaction include, for example, ethers such as diethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene, and xylene;
Examples include amides such as N, N-dimethylformamide and 1-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually about -70
To about 150C, preferably about -70 to about 100C. The reaction time is generally about 0.5 to about 20 hours.
Compound (I-20) thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, phase transfer, chromatography and the like. The “optionally substituted hydrocarbon residue” represented by Rr includes the same as the optionally substituted hydrocarbon residue represented by R ¹ . Compound (I-9) used as a starting compound in the above Method F
Can be produced by Method D.

All compounds used or obtained in the present invention include the corresponding salts, unless otherwise specified, and can be converted into each other by a method known per se or a method analogous thereto. When the compound or a salt thereof obtained in the present invention is an asymmetric molecule, it can be separated into d-form and l-form by ordinary optical resolution means. The compound obtained in the present invention or a salt thereof,
For example, solvent extraction, vacuum concentration, crystallization, recrystallization, distillation,
Isolation and purification can be performed by means such as chromatography.

The compound or a salt thereof obtained in the present invention can be used as it is in the reaction solution or without purification.
It may be used for the next step.

The compound (I) of the present invention or a salt thereof has an excellent alkaline phosphatase-inducing activity, a chondromodulin production promoting effect and / or an expression enhancing effect. Osteoblast differentiation induction and differentiation induction promoting action including blast cells, chondrogenesis promotion action, chondrocyte differentiation induction and differentiation induction promotion action including precursor chondrocytes, and BMP
An effect enhancing effect is expected. Such a differentiation-inducing and differentiation-inducing action acts not only on osteoblast and chondrocyte differentiation, but also on differentiation induction of various cells. Further, the compound (I) of the present invention or a salt thereof is expected to have an activity enhancing activity of a neurotrophic factor. Furthermore, the compound (I) of the present invention or a salt thereof is expected to have anti-matrix metalloprotease (anti-MMP) activity. In addition, stability,
It is excellent in clinically useful properties such as absorbability (particularly, oral absorbability) and bioavailability. Moreover, its toxicity is low. Therefore, the compound (I) or a salt thereof of the present invention can be safely administered to mammals (eg, human, rat, mouse, dog, rabbit, cat, cow, horse, pig, etc.).

The compound (I) of the present invention or a salt thereof has a potent osteogenesis-promoting action, an osteoblast differentiation induction and differentiation-inducing promotion action including progenitor osteoblasts, a chondrogenesis promotion action, and a progenitor chondrocyte. Since a chondrocyte differentiation-inducing and differentiation-inducing action and a BMP action-enhancing action are expected, an agent for preventing or treating a bone or joint disease containing the compound (I) of the present invention or a salt thereof may be used, for example, in promoting bone formation. Agents, bone disease prevention and treatment agents, bone fracture prevention and treatment agents, cartilage formation promoting agents and cartilage disease prevention and treatment agents, specifically, fractures, re-fractures, bone deformity / osteomyelosis, osteosarcoma,
Non-metabolic bone diseases such as myeloma, osteogenesis imperfecta, and scoliosis; bone defects, osteoporosis, osteomalacia, rickets, fibrous osteomyelitis, renal osteodystrophy, bone Petchet disease, ankylosing myelitis, etc. As a preventive or remedy for metabolic bone disease; or as a joint disease represented by cartilage disease such as osteoarthritis or rheumatoid arthritis; as a bone tissue repair agent after surgery for multiple myeloma, lung cancer, breast cancer, etc. , Can be used. In the dental field, it can be expected to be applied to treatment of periodontal disease, repair of periodontal tissue defect in periodontal disease, stabilization of artificial roots, repair of ridges and cleft palate. Further, the compound (I) of the present invention
Or salts thereof are expected to have neurotrophic factor action-enhancing activity, so that Alzheimer's dementia and general senile dementia, motor neuron disorders (such as amyotrophic lateral sclerosis), and diabetic The treatment and prevention of various neurodegenerative diseases such as peripheral neuropathy can be expected.
Furthermore, since the pharmaceutical composition containing the compound (I) of the present invention or a salt thereof is expected to have anti-MMP activity, it is involved in MMP such as osteoarthritis, rheumatoid arthritis, arteriosclerosis, and cancer metastasis. The treatment and prevention of the disease can be expected.

The dose of the compound (I) of the present invention or a salt thereof can be variously selected depending on the administration route and the condition of the patient to be treated. For oral administration per person, for example, about 0.1 mg to about 500 mg, preferably about 1 mg to
About 100 mg, for parenteral administration, about 0.01 mg to about 100 mg, more preferably about 0.1 mg to about 10 m
g can be selected from the range of 1 to 3 times a day.

The objective compound (I) of the present invention or a salt thereof is mixed with a pharmaceutically acceptable carrier to prepare a solid preparation such as tablets, capsules, granules and powders; or a syrup,
It can be administered orally or parenterally as a liquid preparation such as an injection. Transdermal preparations such as patches, cataplasms, ointments (including creams), plasters, tapes, lotions, solutions, suspensions, emulsions and sprays can also be made. As a pharmaceutically acceptable carrier,
Various conventional organic or inorganic carrier substances are used as the drug substance, and excipients, lubricants, binders, and
Disintegrant: incorporated as a solvent, a dissolution aid, a suspending agent, a tonicity agent, a buffer, a soothing agent and the like in a liquid preparation. Also, if necessary, preservatives, antioxidants, stabilizers,
Pharmaceutical additives such as coloring agents and sweetening agents can also be used.

Preferred examples of the excipient include lactose,
Sucrose, D-mannitol, starch, crystalline cellulose,
And light anhydrous silicic acid. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, pregelatinized starch, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferred examples of disintegrants include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium,
Sodium carboxymethyl starch; low-substituted hydroxypropylcellulose; Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

If necessary, oral preparations can be prepared by coating with a method known per se for the purpose of taste masking, enteric coating or sustainability.
Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bruronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (ROHM) And methacrylic acid / acrylic acid copolymer).

Preferred examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include, for example, stearyltriethanolamine,
Surfactants such as sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate;
For example, polyvinyl alcohol, polyvinyl pyrrolidone,
Examples include hydrophilic polymer substances such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

Further, the compound (I) or a salt thereof may be, for example, a cyclooxygenase inhibitor (Cox-I, C
ox-II inhibitors), disease-modifying antirheumatic drugs and immunosuppressants, biologics, analgesics and anti-inflammatory drugs or other prophylactic / therapeutic drugs for bone or joint diseases, etc., as a single preparation or simultaneously or simultaneously It can be administered at intervals. Cyclooxygenase inhibitors (Cox-I, Cox-
Examples of the (II inhibitor) include salicylic acid derivatives such as celecoxib, rofecoxib, and aspirin, diclofenac, indomethacin, loxoprofen and the like. The dosage of these oral preparations is, for example, about 100 to 200 mg / day for celecoxib, about 10 to 30 mg / day for rofecoxib, about 1000 to 4500 mg / day for salicylic acid derivatives such as aspirin, and about 25 to 75 mg / day for diclofenac. Sun, indomethacin is about 50 ~
150mg / day, loxoprofen about 60-180m
g / day. As disease-modifying antirheumatic drugs and immunosuppressants,
Examples include methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, and oral gold preparations. The dosage of these oral preparations is, for example, about 2.5 to 7.5 mg / week for methotrexate, about 20 to 100 mg / day for leflunomide, about 1 to 5 mg / day for prograf, and about 500 to 200 mg for sulfasalazine.
0 mg / day, D-penicillamine is about 100-600 mg / day
The daily oral dose is about 3-6 mg / day. Examples of the biological agent include monoclonal antibodies (eg, anti-TNF-α antibody, anti-IL-12 antibody, anti-IL-
6 antibodies, anti-ICAM-I antibodies, anti-CD4 antibodies, etc.), soluble receptors (eg, soluble TNF-α receptors, etc.),
And proteinaceous ligands (such as IL-I receptor antagonists). The dose of these oral preparations is, for example, about 0.1 to 50 mg / kg / day, preferably 0.5 to 20 mg / kg / day. Examples of analgesics and anti-inflammatory agents include central analgesics (eg, morphine, codeine, pentadisine, etc.), steroids (eg, prednisolone, dexamethasone, betamethasone, etc.), anti-inflammatory enzyme agents (eg, bromercin, lysozyme, proctase, etc.) ). The dosage of these oral preparations is, for example, about 1 to 10 for central analgesics.
00 mg / day, preferably about 5-300 mg / day, for steroids about 0.1-400 mg / day, preferably about 0.
5-100 mg / day, about 1-100 mg /
Days, preferably about 5 to 40 mg / day. Destruction of joint tissue in other bone or joint diseases [eg, fracture, refracture, bone defect, osteoporosis, osteomalacia, bone Pechet disease, ankylosing myelitis, rheumatoid arthritis, osteoarthritis and similar diseases] For bone tissue repair after surgery for multiple myeloma, lung cancer, breast cancer, etc.], for example, calcium preparations (eg, calcium carbonate), calcitonin preparations (eg, eel calcitonin, salmon) calcitonin, porcine calcitonin, Abikatonin etc.), vitamin _{D 3} compounds (e.g., 1.alpha.-hydroxy vitamin _D 3, l [alpha], 25-dihydroxyvitamin _D 3,
Flocalcitriol, Secarciferol, etc.), sex hormone-related compounds (eg, tibolone, estrogen, estradiol, osaterone, raloxifene, droloxifene, olmeloxifen, tamoxifen, mifebristone, etc.), prostaglandin A ₁ , bisphosphonic acids ( Examples: etidronate, simidronate, alendronate, tiludronate, risedronate, clodronate, etc.), ipriflavones, fluorine compounds (eg, sodium fluoride, etc.), vitamin K ₂ , osteogenic protein (BMP), fibroblast growth factor (FGF) ), Platelet-derived growth factor (PDGF), transforming growth factor (TGF-β), insulin-like growth factors-1 and 2 (IGF-1,2), parathyroid hormone (PT
H) (eg, PTH (1-34), PTH (1-8
4), PTH (1-36), etc.).

[0092]

The present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples, but the present invention is not limited thereto. In the following, Me is methyl, Et is ethyl, n-Pr is n-propyl, i
Pr and i-Pr are isopropyl, tBu and t-
Bu is tertiary butyl, Ph is phenyl, Cbz
Represents benzyloxycarbonyl, and Ac represents acetyl. AcOEt is ethyl acetate, HOBt is 1-hydroxybenzotriazole, hexane is n-hexane,
THF represents tetrahydrofuran, ether represents diethyl ether, WSC represents 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, DMF represents N, N-dimethylformamide, and Pd-C represents palladium carbon. . Reference Example 1

Embedded image 2- [benzylamino (sulfanyl) methylene] -1,3-cyclohexanedione: 1,3-cyclohexanedione (19.5 g)
And benzyl isothiocyanate (26.0 g) were dissolved in acetonitrile (200 ml). Triethylamine (24.3 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour and further at 80 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the residual oil was subjected to silica gel column chromatography. Ethyl acetate-
From the portion eluted with hexane (1: 3), the title compound (15.0 g,
33%) as pale yellow needles. Melting point: 47-48 ° C.

Reference Example 2

Embedded image 2-[[benzylamino (2,6-dioxocyclohexylidene)
Methyl] sulfanyl] acetic acid t-butyl ester: 2- [benzylamino (sulfanyl) methylene] -1,3-cyclohexanedione (8.0 g), bromoacetic acid t-butyl ester (5.7
ml) and potassium carbonate (5.4 g) in N, N-dimethylformamide (DMF) (40 ml) were stirred under ice cooling for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. After washing the organic layer with water, the solvent was distilled off under reduced pressure. The obtained crystals are ethyl acetate
Recrystallization from -hexane gave the title compound (8.15 g, 71%) as colorless needles. Melting point: 142-143 ° C.

Reference Example 3

Embedded image 3-benzylamino-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t-butyl ester: 2-
[[Benzylamino (2,6-dioxocyclohexylidene) methyl] sulfanyl] acetic acid t-butyl ester (10.0 g) and potassium t-butoxide (4.5 g) in 2-propanol
(110 ml) The solution was stirred at 50 ° C. for 70 minutes. The reaction solution was concentrated under reduced pressure, the residual oil was poured into water, and extracted with ethyl acetate. After the organic layer was dried (MgSO ₄ ), the solvent was distilled off under reduced pressure.
The obtained oil was subjected to silica gel column chromatography. The title compound (3.5 g, 37%) was obtained from the fraction eluted with ethyl acetate-hexane (1: 4). Recrystallization from ethyl acetate-hexane gave colorless needles. Melting point: 125-126
° C.

In the same manner as in Reference Examples 1 to 3, the compounds of Reference Examples 4 to 10 were obtained.

[Table 1]

Reference Example 11

Embedded image 3-[(N-benzoyl-N-benzyl) amino] -4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid t
-Butyl ester: 3-benzylamino-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t-
To a solution of butyl ester (3.0 g) in DMF (40 ml) was added 60% sodium hydride (0.47 g) under ice cooling, followed by stirring for 15 minutes. Benzoyl chloride (1.2 ml) was added to the solution, and the mixture was stirred for 1 hour under ice cooling and further for 2 hours at room temperature. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 4), the title compound (2.83 g, 73%) was obtained as a colorless amorphous solid. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.52 (9
H, s), 1.7-1.9 (2H, m), 2.23 (2H, t, J = 6.4Hz), 2.99 (2H, m
t, J = 6.4 Hz), 5.11 (2H, brs), 7.1-7.5 (10H, m).

In the same manner as in Reference Example 11, Reference Examples 12 to 15
Was synthesized. Reference Example 12

Embedded image 3- [N-benzoyl-N- (4-chlorophenyl) amino] -4,5,
6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t-butyl ester: pale yellow prism crystals (yield: 79%), melting point: 220-221 ° C
(Recrystallization solvent: ether-hexane).

Reference Example 13

Embedded image 3-[(N-benzoyl-N-methyl) amino] -4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t-
Butyl ester: colorless prism crystals (yield: 77%), melting point: 135-136 ° C (recrystallization solvent: AcOEt-hexane).

Reference Example 14

Embedded image 3-[(N-benzoyl-N-phenyl) amino] -4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid
-Butyl ester: pale yellow needles (yield: 80%), melting point: 192-193 ° C (recrystallization solvent: AcOEt-hexane).

Reference Example 15

Embedded image 3-[(N-benzoyl-N-phenyl) amino] -4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carbonitrile: colorless prism crystals (yield: 82%), melting point : 137-138 ° C (recrystallization solvent: AcOEt-hexane).

Reference Example 16

Embedded image 3-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1
-Carboxylic acid t-butyl ester: 3-phenylamino-4,
5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-
To a solution of carboxylic acid t-butyl ester (6.0 g) in DMF (40 ml) was added 60% sodium hydride (1.0 g) under ice cooling, followed by stirring for 20 minutes. Benzyl chloroformate (3.5 ml) was added to the solution, and the mixture was stirred under ice cooling for 3 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1: 3), the title compound (9.2 g, 95%) was obtained as a pale yellow oil.
¹ H-NMR (δ ppm in CDCl ₃ ): 1.53 (9H, s), 1.9-2.0 (2H,
m), 2.46 (2H, t, J = 6.4Hz), 3.18 (2H, t, J = 6.4Hz), 5.19 (2H, t, J = 6.4Hz)
H, s), 7.2-7.5 (10H, m).

In the same manner as in Reference Example 16, Reference Examples 17 to 18
Was synthesized.

Reference Example 17

Embedded image 3-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1
-Carboxylic acid ethyl ester: pale yellow oil (yield: 90%), ¹ H-NMR (δ ppm in CDCl ₃ ):
1.32 (3H, t, J = 7.2Hz), 1.9-2.1 (2H, m), 2.47 (2H, t, J = 6.4
Hz), 3.21 (2H, t, J = 6.4Hz), 4.29 (2H, q, J = 7.2Hz), 5.20
(2H, s), 7.2-7.4 (10H, m).

Reference Example 18

Embedded image 3-[(N-benzyloxycarbonyl-N-propyl) amino]-
4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1
-Carboxylic acid ethyl ester: pale yellow oil (yield: 100%), ¹ H-NMR (δ ppm in CDC
l ₃ ): 0.89 (3H, t, J = 7.2Hz), 1.36 (3H, t, J = 7.2Hz), 1.5-
1.8 (2H, m), 1.9-2.1 (2H, m), 2.42 (2H, t, J = 6.2Hz), 3.20
(2H, t, J = 6.2Hz), 3.68 (2H, t, J = 7.4Hz), 4.33 (2H, q, J = 7.
2Hz), 5.12 (1H, s), 7.1-7.4 (5H, m).

Reference Example 19

Embedded image 3-[(N-benzoyl-N-benzyl) amino] -5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t-butyl ester: Boron ether complex (3.2 ml) in dichloromethane (15 ml)-
It was added dropwise to triethyl orthoformate (3.4 g) cooled to 40 ° C. The solution was stirred under ice cooling for 15 minutes and then cooled to -70 ° C. 3-[(N-benzoyl-N-benzyl) amino]-
4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1
-Carboxylic acid t-butyl ester (2.6 g) in dichloromethane (25 ml), then diisopropylethylamine (4.9
ml) was added dropwise. After stirring at -70 ° C for 1 hour, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed successively with water, diluted hydrochloric acid and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 5), the title compound (2.9
g, 91%) as a pale yellow oil. ¹ H-NMR (δ ppm in
CDCl ₃ ): 1.11 (3H, t, J = 7.0Hz), 1.51 (9H, s), 1.8-2.2 (2
H, m), 2.3-2.5 (1H, m), 2.6-2.9 (1H, m), 3.2-3.9 (5H, m),
4.99 (1H, d, J = 3.2Hz), 5.0-5.2 (2H, m), 7.1-7.5 (10H,
m).

In the same manner as in Reference Example 19, Reference Examples 20 to 25
Was obtained. Reference Example 20

Embedded image 3-[(N-benzoyl-N-4-chlorophenyl) amino] -5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo
[c] thiophene-1-carboxylic acid t-butyl ester: pale yellow amorphous solid (yield: 73%), elemental analysis: calculated values [C, 63, 74; H, 5.87; N, 2.40 (C ₃₁ H ₃₄₎ NO ₆ SCl)],
Analytical values [C, 63.65; H, 5.59; N, 2.40].

Reference Example 21

Embedded image 3-[(N-benzoyl-N-methyl) amino] -5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid t-butyl ester: pale yellow Oil (yield: 100%), ¹ H-NMR (δ ppm in CDC
l ₃ ): 1.13 (3H, t, J = 7.0Hz), 1.23 (3H, t, J = 7.0Hz), 1.54
(9H, s), 1.9-2.2 (2H, m), 2.4-2.6 (1H, m), 2.79 (1H, ddd,
J = 5.2, 10.4, 18.0Hz), 3.41 (3H, s), 3.4-3.8 (5H, m),
5.02 (1H, d, J = 3.4Hz), 7.2-7.5 (5H, m).

Reference Example 22

Embedded image 3-[(N-benzoyl-N-phenyl) amino] -5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid t-butyl ester: pale yellow Oil (yield: 93%), ¹ H-NMR (δ ppm in CDCl ₃ ):
1.11 (3H, t, J = 7.2Hz), 1.21 (3H, t, J = 7.2Hz), 1.53 (9H,
s), 2.0-2.3 (2H, m), 2.5-2.7 (1H, m), 2.90 (1H, ddd, J = 5.
8, 10.0, 18.0Hz), 3.4-3.8 (5H, m), 5.04 (1H, d, J = 3.4H
z), 7.1-7.7 (10H, m).

Reference Example 23

Embedded image 3-[(N-benzyloxycarbonyl-N-phenyl) amino]-
5-Diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t-butyl ester: pale yellow oil (yield: 92%), ¹ H-NMR ( δ ppm in CDCl ₃ ):
1.07 (3H, t, J = 7.2Hz), 1.21 (3H, t, J = 7.2Hz), 1.53 (9H,
s), 2.1-2.4 (2H, m), 2.5-2.7 (1H, m), 2.8-3.0 (1H, m),
3.4-3.8 (5H, m), 5.06 (1H, d, J = 3.4Hz), 5.13 (1H, d, J = 12.
4Hz), 5.26 (1H, d, J = 12.4Hz), 7.2-7.4 (10H, m).

Reference Example 24

Embedded image 3-[(N-benzyloxycarbonyl-N-phenyl) amino]-
5-Diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: pale yellow oil (yield: 86%), ¹ H-NMR (δ ppm in CDCl ₃ ):
1.07 (3H, t, J = 7.2Hz), 1.23 (3H, t, J = 7.2Hz), 1.32 (3H, t, J
J = 7.2Hz), 2.0-2.4 (2H, m), 2.5-2.7 (1H, m), 2.92 (1H, dd
d, J = 5.4, 10.2, 18.0Hz), 3.4-3.8 (5H, m), 5.05 (1H, d, J
= 3.4Hz), 5.13 (1H, d, J = 12.4Hz), 5.26 (1H, d, J = 12.4Hz),
7.2-7.5 (10H, m).

Reference Example 25

Embedded image 3-[(N-benzyloxycarbonyl-N-propyl) amino]-
5-Diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: pale yellow oil (yield: 94%), ¹ H-NMR (δ ppm in CDCl ₃ ):
0.89 (3H, t, J = 7.4Hz), 1.07 (3H, t, J = 7.2Hz), 1.23 (3H, t, J
J = 7.2Hz), 1.36 (3H, t, J = 7.2Hz), 1.5-1.7 (2H, m), 2.0-
2.3 (2H, m), 2.5-2.7 (1H, m), 2.90 (1H, ddd, J = 5.4, 10.6,
18.0Hz), 3.4-3.8 (7H, m), 4.33 (2H, q, J = 7.2Hz), 5.04
(1H, d, J = 3.2Hz), 5.06 (1H, d, J = 12.4Hz), 5.17 (1H, d, J = 1
2.4Hz), 7.1-7.4 (5H, m).

Reference Example 26

Embedded image 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: 4,
5,6,7-tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester (5.0
To a dichloromethane solution (150 ml) of g), m-chloroperbenzoic acid (16.0 g) was added under ice-cooling, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate.
The precipitated crystals were collected by filtration, washed with an aqueous sodium hydrogen carbonate solution and water, and further washed with ethyl acetate-hexane,
The title compound (5.5 g, 98%) was obtained as pale yellow crystals. Recrystallization from ethyl acetate-THF gave pale yellow prism crystals. Melting point: 199-200 ° C.

Reference Example 27

Embedded image 4,5,6,7-tetrahydro-3-methyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo [c] Thiophene-1-carboxylic acid ethyl ester (27.4 g) anhydrous TH
A 3M methylmagnesium bromide ether solution (31 ml) was added dropwise to the F solution (500 ml). After stirring the mixture at room temperature for 3 hours, an aqueous citric acid solution was added to the reaction solution. The THF was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. The title compound (5.9 g, 27%) was obtained as pale yellow crystals from a portion eluted with ethyl acetate-hexane (1: 3).
Recrystallization from ethyl acetate-hexane gave colorless crystals.
Melting point: 76-77 ° C.

In the same manner as in Reference Example 27, Reference Examples 28 to 30
Was obtained. Reference Example 28

Embedded image 3-n-butyl-4,5,6,7-tetrahydro-4-oxobenzo [c]
Thiophene-1-carboxylic acid ethyl ester: colorless needles (yield: 30%), melting point: 48-49 ° C (recrystallization solvent: AcOEt-hexane).

Reference Example 29

Embedded image 3-benzyl-4,5,6,7-tetrahydro-4-oxobenzo [c]
Thiophene-1-carboxylic acid ethyl ester: pale yellow needles (yield: 21%), melting point: 96-97 ° C (recrystallization solvent: AcOEt-hexane).

Reference Example 30

Embedded image 3-n-hexyl-4,5,6,7-tetrahydro-4-oxobenzo
[c] Thiophene-1-carboxylic acid ethyl ester: pale yellow oil (yield: 47%), ¹ H-NMR (δ ppm in CDC
l ₃ ): 0.89 (3H, t, J = 6.4Hz), 1.2-1.8 (8H, m), 1.38 (3H, t,
J = 7.2Hz), 2.0-2.2 (2H, m), 2.54 (2H, t, J = 6.4Hz), 3.21
(2H, t, J = 6.4Hz), 3.25 (2H, t, J = 6.8Hz), 4.34 (2H, q, J = 7.
2Hz).

In the same manner as in Reference Example 19, Reference Examples 31 to 36
Was obtained. Reference Example 31

Embedded image 5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxo-3
-n-propylsulfanylbenzo [c] thiophen-1-carboxylic acid ethyl ester: pale yellow oil (yield: 97%), ¹ H-NMR (δ ppm in CDC
l ₃ ): 1.11 (3H, t, J = 7.2Hz), 1.14 (3H, t, J = 7.2Hz), 1.25
(3H, t, J = 7.2Hz), 1.37 (3H, t, J = 7.2Hz), 1.7-2.0 (2H, m),
2.1-2.4 (2H, m), 2.71 (1H, ddd, J = 3.2, 5.0, 10.6Hz),
2.88 (1H, ddd, J = 5.7,10.6,18.0Hz), 3.03 (2H, t, J = 7.2H
z), 3.5-3.9 (5H, m), 4.33 (2H, q, J = 7.2Hz), 5.15 (1H, d, J =
3.2Hz).

Reference Example 32

Embedded image 5-Diethoxymethyl-4,5,6,7-tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: pale yellow oil (yield: 93%), ¹ H -NMR (δ ppm in CDC
l ₃ ): 1.14 (3H, t, J = 7.0Hz), 1.25 (3H, t, J = 7.0Hz), 1.38
(3H, t, J = 7.0Hz), 2.0-2.4 (2H, m), 2.61 (3H, s), 2.72 (1H,
ddd, J = 3.0, 5.0, 10.4Hz), 2.90 (1H, ddd, J = 5.0, 10.4,
18.0Hz), 3.5-3.9 (5H, m), 4.34 (2H, q, J = 7.0Hz), 5.15 (1
H, d, J = 3.0Hz).

Reference Example 33

Embedded image 5-diethoxymethyl-4,5,6,7-tetrahydro-3-methyl-4
-Oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: pale yellow oil (yield: 99%), ¹ H-NMR (δ ppm in CDC
l ₃ ): 1.15 (3H, t, J = 7.0Hz), 1.24 (3H, t, J = 7.0Hz), 1.37
(3H, t, J = 7.0Hz), 2.0-2.4 (2H, m), 2.70 (1H, ddd, J = 3.6,
4.8, 10.6Hz), 2.79 (3H, s), 2.90 (1H, ddd, J = 4.8, 10.6,
17.8Hz), 3.5-3.9 (5H, m), 4.33 (2H, q, J = 7.0Hz), 5.09
(1H, d, J = 3.6Hz).

Reference Example 34

Embedded image 3-n-butyl-5-diethoxymethyl-4,5,6,7-tetrahydro
-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: pale yellow oil (yield: 100%), ¹ H-NMR (δ ppm in CD
Cl ₃ ): 0.95 (3H, t, J = 7.2Hz), 1.15 (3H, t, J = 7.2Hz), 1.37
(3H, t, J = 7.2Hz), 1.3-1.8 (4H, m), 2.0-2.4 (2H, m), 2.70
(1H, ddd, J = 4.0, 4.8, 10.4Hz), 2.91 (1H, ddd, J = 4.8, 1
0.4, 18.0Hz), 3.24 (2H, dd, J = 7.0, 8.2Hz), 3.5-3.9 (5
H, m), 4.33 (2H, q, J = 7.2Hz), 5.10 (1H, d, J = 3.6Hz).

Reference Example 35

Embedded image 3-benzyl-5-diethoxymethyl-4,5,6,7-tetrahydro
-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: pale yellow oil (yield: 100%), ¹ H-NMR (δ ppm in CD
Cl ₃ ): 1.14 (3H, t, J = 7.4Hz), 1.25 (3H, t, J = 7.4Hz), 1.28
(3H, t, J = 7.4Hz), 2.0-2.4 (2H, m), 2.74 (1H, dt, J = 4.4,
9.8Hz), 2.92 (1H, ddd, J = 5.6, 10.4, 18.0Hz), 3.5-3.9
(5H, m), 4.28 (2H, q, J = 7.4Hz), 4.59 (2H, s), 5.11 (1H, d,
J = 3.6Hz), 7.2-7.4 (5H, m).

Reference Example 36

Embedded image 5-Diethoxymethyl-3-n-hexyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: pale yellow oil (yield: 91%), ¹ H-NMR (δ ppm in CDC
l ₃ ): 0.88 (3H, t, J = 6.6Hz), 1.14 (3H, t, J = 6.4Hz), 1.24
(3H, t, J = 7.2Hz), 1.37 (3H, t, J = 7.2Hz), 1.3-1.8 (6H, m),
2.0-2.3 (2H, m), 2.6-2.7 (1H, m), 2.90 (1H, ddd, J = 5.6,
10.4, 18.0Hz), 3.23 (2H, t, J = 7.6Hz), 3.5-3.9 (6H, m),
4.1-4.3 (1H, m), 4.33 (2H, q, J = 7.2Hz), 5.10 (1H, d, J = 3.2
Hz).

Reference Example 37

Embedded image 4,5,6,7-tetrahydro-4-oxo-3-phenoxybenzo
[c] thiophene-1-carboxylic acid ethyl ester: 4,5,6,
7-tetrahydro-3-methylsulfonyl-4-oxobenzo
[c] Sodium hydride (1.0 g) was added to a solution of thiophene-1-carboxylic acid ethyl ester (6.0 g) and phenol (2.2 g) in tetrahydrofuran (50 ml), and the mixture was stirred at room temperature for 14 hours.
An aqueous citric acid solution was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residual oil was poured into water and extracted with ethyl acetate. After the organic layer was dried (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain a crude crystal. Recrystallization from ethyl acetate-diisopropyl ether gave the title compound (5.0 g, 80%) as colorless prisms. Melting point:
125-127 ° C.

In the same manner as in Reference Example 37, Reference Examples 38 to
56 compounds were synthesized.

[Table 2]

[Table 3] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.28 (3H, t, J = 7.0 H
z), 2.00−2.20 (2H, m), 2.57 (2H, t, J = 6.4 Hz), 3.22
(2H, t, J = 6.4 Hz), 3.88 (3H, s), 3.91 (3H, s), 4,24
(2H, q, J = 7.0 Hz), 6.80-7.20 (3H, m) .2) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.32 (3H, t, J = 7.0 Hz),
2.00−2.20 (2H, m), 2.57 (2H, t, J = 6.2 Hz), 3.23 (2
H, t, J = 6.2 Hz), 4.28 (2H, q, J = 7.0 Hz), 6.82 (2H,
d, J = 9.0 Hz), 7.09 (2H, d, J = 9.0 Hz).

Reference Example 57 Diethoxymethyl-4,5,6,7-tetrahydro-4-oxo-3-phenoxybenzo [c] thiophen-1-carboxylic acid ethyl ester Reference Example 37 was prepared in the same manner as in Reference Example 19. The title compound was obtained as colorless prism crystals from the compound obtained in (1). Melting point: 73-74
゜ C (recrystallization solvent: AcOEt-hexane).

The compounds of Reference Examples 58 to 76 were synthesized in the same manner as in Reference Example 57.

[Table 4]

[Table 5] 3) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.26 (3H, t, J = 7.0 H
z), 1.29 (6H, t, J = 7.0 Hz), 2.18−2.34 (2H, m), 2.66
−2.80 (1H, m), 2.80−2.99 (1H, m), 3.51−3.88 (5H,
m), 3.83 (3H, s), 4.25 (2H, q, J = 7.0 Hz), 5.15 (1H,
d, J = 3.2 Hz), 6.91−6.96 (2H, m), 7.17−7.22 (2H,
m). 4) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.23 (3H, t, J = 7.0 H
z), 1.25 (3H, t, J = 7.0 Hz), 1.26 (3H, t, J = 7.0 Hz),
2.15−2.39 (2H, m), 2.65 (1H, m), 2.81−2,99 (1H, m),
3.53−3.78 (4H, m), 4.27 (2H, q, J = 7.0 Hz), 5.12 (1
H, d, J = 3.4 Hz), 7.12 (2H, dt, J = 9.2, 2.2 Hz), 7.55
(2H, dt, J = 9.2, 2.2 Hz) .5) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.17 (3H, t, J = 7.0 H)
z), 2.08-2.30 (2H, m), 2.66-2.96 (2H, m), 3.54-3.8
4 (5H, m), 4.25 (2H, q, J = 7.0 Hz), 4.27 (4H, t, J = 4.8
Hz), 5.16 (1H, d, J = 3.2 Hz), 6.81−6.88 (3H, m) .6) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.31 (3H, t, J = 7.0 H)
z), 1.25 (6H, t, J = 7.0 Hz), 2.16−2.33 (2H, m), 2.66
−2.33 (1H, m), 2.75−2.98 (1H, m), 3.54−3.83 (5H, m
m), 4.27 (2H, q, J = 7.0 Hz), 5.14 (1H, d, J = 3.4 Hz),
6.01 (2H, s), 6.76−7.25 (3H, m) .7) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.22 (3H, t, J = 7.0 H
z), 1.26 (3H, t, J = 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz),
2.00−2.40 (2H, m), 2.60−3.00 (2H, m), 3.40−3.90 (5
H, m), 3.87 (3H, s), 3.90 (3H, s), 4.23 (2H, q, J = 7.0
Hz), 5.16 (1H, d, J = 3.6 Hz), 6.80−7.20 (3H, m) .8) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.67 (3H, t, J = 7.2 H)
z), 1.26 (3H, t, J = 7.2 Hz), 1.30 (3H, t, J = 7.2 Hz),
2.00−2.40 (2H, m), 2.71 (1H, ddd, J = 10.6, 4.8,3.4 H
z), 2.90 (1H, ddd, J = 18.0, 10.6, 5.2 Hz), 3.50-3.9
0 (5H, m), 3.81 (3H, s), 4.26 (2H, q, J = 7.2 Hz), 5.14
(1H, d, J = 3.4 Hz), 6.70−6.90 (3H, m), 7.33 (1H, t, J
9) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.16 (3H, t, J = 7.2 H)
z), 1.25 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz),
2.10−2.40 (2H, m), 2.60−2.80 (1H, m), 2.90 (1H, dd
d, J = 17.4, 10.0, 5.6 Hz), 3.50−3.90 (5H, m), 4.27
(2H, q, J = 7.2 Hz), 5.13 (1H, d, J = 3.2 Hz), 6.90−7.1
0 (2H, m), 7.20−7.40 (1H, m) .10) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.17 (3H, t, J = 7.0 H
z), 1.26 (3H, t, J = 7.0Hz), 1.32 (3H, t, J = 7.0Hz),
2.00−2.40 (2H, m), 2.60−2.80 (1H, m), 2.90 (1H, dd
d, J = 18.2, 10.8, 5.2 Hz), 3.50−3.90 (5H, m), 4.27
(2H, q, J = 7.0 Hz), 5.15 (1H, d, J = 3.4 Hz), 7.00−7.5
0 (9H, m). 11) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.17 (3H, t, J = 7.0
Hz), 1.25 (6H, t, J = 7.0Hz), 1.26 (6H, t, J = 7.0Hz),
2.00−2.40 (2H, m), 3.50−4.10 (9H, m), 4.25 (2H, q,
J = 7.0 Hz), 5.14 (1H, d, J = 3.4 Hz), 7.21 (2H, d, J = 8.
4 Hz), 7.39 (2H, dd, J = 8.4, 2.4 Hz).

Reference Example 77

Embedded image 4,5-dihydro-1-methyl-8-methylsulfanyl-
1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 5-diethoxymethyl-3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydrobenzo [c] thiophene-1 -Carboxylic acid ethyl ester (21.57 g), methylhydrazine monohydrate (6.87
g), a solution of 2N hydrochloric acid (100 ml) and ethanol (200 ml) was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the residual oil was poured into water, and extracted with ethyl acetate. Dry the organic layer (M
After gSO ₄ ), the solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 4), the title compound (1
5.25 g, 89%) were obtained as yellow needles. Melting point: 113-114
° C.

Reference Example 78

Embedded image 4,5-dihydro-1-methyl-8-methylsulfonyl-1
H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-1-methyl-8-methylsulfanyl-1H-thieno [3,4-g] indazole- A dichloromethane solution (120 ml) of 6-carboxylic acid ethyl ester (5.4 g) and m-chloroperbenzoic acid (15 g) was stirred at room temperature for 2 days. The reaction solution was distilled off under reduced pressure, and the precipitated crystals were collected by filtration.
%) As yellow needles. Melting point: 140-141 ° C.

Reference Example 79

Embedded image T-butyl 5-[(E) -ethoxymethylidene] -4,5,6,7-tetrahydro-8- (3,4-methylenedioxyphenoxy) -4-oxobenzo [c] thiophene-1-carboxylate Ester: 5-diethoxymethyl-4,
5,6,7-tetrahydro-3-methylsulfonyl-4
To a solution of -oxobenzo [c] thiophene-1-carboxylic acid t-butyl ester (5.55 g) in THF (100 ml) was added potassium t-butoxide (1.58 g), and the mixture was stirred at room temperature for 1 hour. Poured into water and extracted with ethyl acetate.
The extract was washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure.
Next, the obtained crystals (2.40 g) were treated with sesamol (0.95 g) and potassium t-butoxide (0.77 g) in a THF solution (100 m
After stirring at room temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.36 (3H, t, J = 7.0Hz),
1.52 (9H, s), 2.67 (2H, t, J = 7.0Hz), 3.17 (2H, t, J = 7.0H
z), 4.13 (2H, q, J = 7.0Hz), 6.03 (2H, s), 6.70-6.83 (3H,
m), 7.51 (1H, s).

Reference Example 80

Embedded image 3- [4- (acetylamino) phenoxy] -5-[(E)-
Ethoxymethylidene] -6,7-dihydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: N-acetyl-4-hydroxyaniline (1.57
g) and potassium t-butoxide (1.17 g) in THF
After stirring the solution (100 ml) at room temperature for 1 hour, it was added to 5-[(E) -ethoxymethylidene] -4,5,6,7-tetrahydro-8-methanesulfonyl-4-oxobenzoate.
[c] Thiophene-1-carboxylic acid ethyl ester (4.0
4g) was added. The reaction solution was stirred at room temperature for 15 hours, poured into water, and extracted with a mixed solution of THF and ethyl acetate. The organic layer was washed with water, sodium hydrogen carbonate, and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The precipitated crystals were washed with ethanol to give the title compound (2.48 g, 58%) as colorless prisms. Melting point: 230 ° C (decomposition).

In the same manner as in Reference Example 80, Reference Examples 81 and 82
Was obtained. Reference Example 81

Embedded image 3- (2,3-dihydrobenzofuran-6-yloxy)
-5-[(E) -ethoxymethylidene] -6,7-dihydro-4-oxobenzo [c] thiophene-1-carboxylic acid
Ethyl ester: yellow prism crystals (78% yield), melting point: 166-167 ° C (recrystallization solvent: ethanol)

Reference Example 82

Embedded image 5-[(E) -ethoxymethylidene] -4,5,6,7-tetrahydro-4-oxo-3- [4- (1H-pyrrol-1-yl) phenoxy] benzo [c] thiophene- 1-carboxylic acid ethyl ester: yellow prism crystals (yield 85%), melting point: 192-193 ° C (recrystallization solvent: ethanol)

In the same manner as in Reference Example 80, Reference Examples 83 and 84
Was synthesized. Reference Example 83

Embedded image 5-[(E) -ethoxymethylidene] -3- (4-fluorophenoxy) -4,5,6,7-tetrahydro-4-oxobenzo
[c] Thiophene-1-carboxylic acid ethyl ester: yellow prism crystals (65% yield), melting point: 144-146 ° C (recrystallization solvent: AcOEt-hexane)

Reference Example 84

Embedded image 5-[(E) -ethoxymethylidene] -3- (4-methylphenoxy) -4,5,6,7-tetrahydro-4-oxobenzo [c]
Thiophene-1-carboxylic acid ethyl ester: yellow prism crystals (yield 72%), melting point: 190-191 ° C (recrystallization solvent: AcOEt-hexane)

Reference Example 85

Embedded image 6,6-dimethyl-4,5,6,7-tetrahydro-5-[(E) -hydroxymethylidene] -3- (methylsulfanyl) -4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: Ethyl formate (1.24 g) was added to a THF suspension (30 ml) of sodium hydride (0.27 g) under ice-cooling, and the mixture was stirred for 10 minutes, and then 4,5,6,7-tetrahydro-6,6-dimethyl-3. -Methylsulfanyl-4-
A solution of oxobenzo [c] thiophene (1.0 g) in THF (10 ml) was added to 10
The mixture was added dropwise over a minute, returned to room temperature, and further stirred for 18 hours. The reaction solution was poured into citric acid aqueous solution and extracted with ethyl acetate.
The organic layer was washed with water and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.65 g, 60%). ¹ H-NMR
(δ ppm in CDCl ₃ ): 1.20 (6H, s), 1.39 (3H, t, J = 7.0Hz),
2.66 (3H, s), 3.10 (2H, s), 4.34 (2H, q, J = 7.0Hz), 7.56 (1
(H, d, J = 10.6Hz).

Reference Example 86

Embedded image 4,5-dihydro- (3-methylsulfonyl) -1,4,4-trimethyl-8-1H-thieno [3,4-g] indazole-6
-Carboxylic acid ethyl ester and 4,5-dihydro-
(3-Methylsulfonyl) -2,4,4-trimethyl-8-2H
-Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 6,6-dimethyl-4,5,6,7-tetrahydro-5-
[(E) -hydroxymethylidene] -3- (methylsulfanyl)-
4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester (7.50 g), methylhydrazine sulfate (4.97)
g), ethanol (100 ml) and water (20 ml).
The mixture was stirred at 70 ° C for 2 hours. After the reaction solution was concentrated, it was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off to give 4,5-dihydro- (3-methylsulfanyl) -1,4,4-trimethyl-8.
-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester and 4,5-dihydro- (3-methylsulfanyl) -2,4,4-trimethyl-8-2H-thieno [3,4
[G] Indazole-6-carboxylic acid ethyl ester (7.25 g, 94%) was obtained. This mixture (7.13 g) was added to THF
(200 ml), m-chloroperbenzoic acid (12 g) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated and poured into an aqueous sodium hydrogen carbonate solution. After extraction with ethyl acetate, the organic layer was washed with brine, dried (MgSO ₄ ), the solvent was distilled off, and the remaining crude crystals were subjected to silica gel column chromatography. The title compound was obtained from the portion eluted with ethyl acetate-hexane (AcOEt-hexane = 1: 2). 4,5-dihydro- (3-methylsulfonyl) -1,4,4-trimethyl-8-1H-thieno [3,4-g] indazole-6
-Carboxylic acid ethyl ester: colorless prism crystals (5.77
g, 74%), melting point: 129-131 ° C 4,5-dihydro- (3-methylsulfonyl) -2,4,4-trimethyl-8-2H-thieno [3,4-g] indazole-6
-Carboxylic acid ethyl ester: pale yellow needles (1.82
g, 23%), melting point: 208-210 ° C (recrystallization solvent: AcOEt)

The compounds of Reference Examples 87 to 88 were synthesized in the same manner as in Reference Example 37.

[Table 6] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.2-1.4 (27H, m), 2.0-
2.2 (2H, m), 2.4-2.7 (3H, m), 3.1-3.4 (4H, m), 4.25 (2H, m
q, J = 7.0Hz), 4.7-4.9 (4H, m), 7.17 (2H, d, J = 8.8Hz), 7.3
7 (2H, d, J = 8.8Hz).

The compounds of Reference Examples 89 to 90 were synthesized in the same manner as in Reference Example 19.

[Table 7] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.22 (6H, d, J = 6.0 Hz), 1.
25 (6H, d, J = 6.0Hz), 1.37 (6H, d, J = 6.0Hz), 1.40 (6H, d, J =
6.0Hz), 1.2-1.4 (9H, m), 2.0-2.4 (2H, m), 2.6-3.0 (2H,
m), 3.5-3.9 (5H, m), 4.26 (2H, q, J = 7.0Hz), 4.6-4.9 (4H,
m), 5.11 (1H, d, J = 3.8Hz), 7.23 (2H, d, J = 8.0Hz), 7.95 (2H
H, d, J = 8.0Hz), 8.25 (1H, dd, J = 10.0,47.2Hz). 2) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.2-1.5 (33H, m), 2.1-
3.9 (12H, m), 4.24 (2H, q, J = 7.0Hz), 4.6-4.9 (4H, m), 5.1
5 (1H, d, J = 3.4Hz), 7.16 (2H, d, J = 8.4Hz), 7.36 (2H, d, J =
8.4Hz).

The compounds of Reference Examples 91 to 92 were synthesized in the same manner as in Reference Example 79.

[Table 8]

Reference Example 93

Embedded image 2- (4-fluorophenoxy) -3-pyridinol 2- (4-fluorophenoxy) -3-aminopyridine (20 g) in 6N
To a solution dissolved in hydrochloric acid (80 ml), sodium nitrate (7.59 g)
Was dissolved in water (28 ml) under ice cooling. After stirring for 30 minutes, 60% hexafluorophosphine (16 ml) was added dropwise, and the mixture was further stirred for 15 minutes. Water (15 ml) was added, and the precipitated crystals were collected by filtration. The crystals were added little by little to acetic anhydride (100 ml) at 100 ° C., and the mixture was stirred for 1 hour. Then, the reaction solution was concentrated under reduced pressure. The residue was neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried (MgS
O ₄ ) and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and 17.4 g of 3-acetoxy-2- (4-fluorophenoxy) aminopyridine was obtained as a colorless oil from a portion eluted with ethyl acetate: hexane (1: 5).
A 1N aqueous solution of sodium hydroxide (100 ml) was added dropwise to a solution of this in methanol (100 ml), and the mixture was stirred at room temperature for 30 minutes.
The reaction solution was concentrated under reduced pressure. After neutralization with 6N hydrochloric acid, the organic layer extracted with ethyl acetate was washed with saturated saline, dried (MgSO ₄ ), and the solvent was distilled off to obtain 15.4 g (75%) of the title compound as colorless crystals. ¹ H-NMR (CDCl ₃ ) d: 5.62 (1H, s), 6.95 (1H, dd, J = 7.
8,5.0Hz), 7.04-7.18 (4H, m), 7.28 (1H, dd, J = 7.8,1.4H
z). The following title compound was obtained in the same manner as in Reference Example 93.

Reference Example 94

Embedded image 2- (4-fluorophenoxy) -5-pyridinol ¹ H-NMR (CDCl ₃ ) d: 6.34 (1 H, brs), 6.80 (1 H, d, J = 8.6 Hz),
7.02-7.06 (4H, m), 7.25 (1H, dd, J = 8.8,3.0Hz), 7.78 (1H,
d, J = 2.8Hz).

Reference Example 95

Embedded image 6- (2-methoxyethoxy) -3-pyridinol ¹ H-NMR (CDCl ₃ ) d: 3.45 (3H, s), 3.72-3.77 (2H, m), 4.36-
4.41 (2H, m), 6.68 (1H, d, J = 8.8Hz), 7.16 (1H, dd, J = 8.8,
3.0Hz), 7.72 (1H, d, J = 2.8Hz).

Reference Example 96

Embedded image 6- (cyclohexyl) -3-pyridinol ¹ H-NMR (CDCl ₃ ) d: 1.20-2.15 (10H, m), 4.75-4.85 (1H, m),
6.62 (1H, d, J = 8.8Hz), 7.18 (1H, dd, J = 8.8,3.2Hz), 7.76
(1H, d, J = 3.0Hz).

Reference Example 97

Embedded image 2-Diethylamino-5-hydroxypyridine ¹ H-NMR (CDCl ₃ ) d: 1.16 (6H, t, J = 7.2 Hz), 3.46 (2H, q, J = 7.
2Hz), 6.45 (1H, d, J = 9.2Hz), 7.15 (1H, dd, J = 3.0Hz), 7.8
5 (1H, d, J = 2.8Hz).

Reference Example 98

Embedded image 3-hydroxy-2- (2,2,2-trifluoroethyl) pyridine 3-benzyloxy-2-chloropyridine (4.55 g) and 2,2,
Sodium hydride (0.99 g) was added to a DMF solution (30 ml) of 2-trifluoroethanol (2.69 g) under ice cooling, followed by stirring at 90 ° C. for 14 hours. After the reaction solution was concentrated, it was poured into water and extracted with ethyl acetate.
The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried (MgSO ₄ ) and evaporated to give 3-benzyloxy-2- (2,2,2-trifluoroethyl) pyridine. Dissolve this in ethanol (200 ml) and add 10% palladium carbon
(0.2 g) was added and the mixture was stirred under a hydrogen atmosphere for 2 hours. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.57 g, 64%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) d: 4.83 (2H, q, J = 8.4H
z), 5.60 (1H, brs), 6.92 (1H, dd, J = 7.2,4.8Hz), 7.21 (1
H, dd, J = 7.2,1.6 Hz), 7.69 (1H, dd, J = 4.8,1.6 Hz). The following title compound was obtained in the same manner as in Reference Example 98.

Reference Example 99

Embedded image 2- {2- [methyl (phenyl) amino] ethoxy} pyridine-3-
All ¹ H-NMR (CDCl ₃ ) d: 2.99 (3H, s), 3.77 (2H, t, J = 5.6 Hz), 4.
56 (2H, t, J = 5.6Hz), 6.17-6.89 (4H, m), 7.08 (1H, dd, J = 7.
8,1.4Hz), 7.21-7.30 (2H, m), 7.65 (1H, dd, J = 4.8,1.4H
z).

Reference Example 100

Embedded image 1- {2-[(3-hydroxypyridin-2-yl) oxy] ethyl}
Pyrrolidin-2-one ¹ H-NMR (CDCl ₃ ) d: 2.05 (2H, tt, J = 8.0, 7.0 Hz), 2.41 (2H,
t, J = 8.0Hz), 3.50 (2H, t, J = 7.0Hz), 3.71 (2H, t, J = 5.2H
z), 4.51 (2H, t, J = 5.2Hz), 6.82 (1H, dd, J = 7.8,5.2Hz),
7.14 (1H, dd, J = 7.8,1.4Hz), 7.65 (1H, dd, J = 5.2,1.4Hz).

Example 1

Embedded image 8-[(N-benzoyl-N-benzyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid
t-butyl ester: 3-[(N-benzoyl-N-benzyl) amino] -5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t- A solution of butyl ester (2.8 g), hydroxylamine hydrochloride (1.8 g) and sodium acetate (2.1 g) in ethanol (60 ml) was added at 80 ° C. for 15 minutes.
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. Wash the organic layer with saturated saline and dry
(MgSO ₄ ) and concentrated under reduced pressure. The obtained residual oil was dissolved in tetrahydrofuran (50 ml), and 4N hydrochloric acid-ethyl acetate (5 m
l) was added. After stirring at 80 ° C. for 2 hours, the reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. The title compound (0.60 g, 25%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1: 2). ^{1 H-NMR (δ ppm in} CDCl 3): 1.54 (9H, s), 2.4-
2.6 (2H, m), 3.0-3.2 (2H, m), 5.1-5.3 (2H, m), 7.1-7.5 (1
0H, m), 8.05 (1H, s).

In the same manner as in Example 1, Examples 2 to 4
Was obtained. Example 2

Embedded image 8-[(N-benzoyl-N-methyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid t
-Butyl ester: pale yellow oil (yield: 57%), ¹ H-NMR (δ ppm in CDCl ₃ ):
1.56 (9H, s), 2.64 (2H, t, J = 7.6Hz), 3.24 (2H, t, J = 7.6H
z), 3.53 (3H, s), 7.1-7.5 (5H, m), 8.15 (1H, s).

Embodiment 3

Embedded image 8- (4-chlorophenylamino) -4,5-dihydrothieno [3,4-
g] -1,2-Benzisoxazole-6-carboxylic acid t-butyl ester: pale brown crystal (yield: 65%), melting point: 197-198 ° C. (recrystallization solvent: AcOEt-hexane).

Embodiment 4

Embedded image 4,5-dihydro-8-phenylaminothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid t-butyl ester: colorless needles (yield: 62%), melting point : 148-149 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 5

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-1H-thieno [3,4-g] indazole-6-carboxylic acid t-butyl ester: 3-[(N-benzyloxycarbonyl-N-phenyl) amino] -5-diethoxymethyl- 4,5,6,7
-Tetrahydro-4-oxobenzo [c] thiophene-1-carboxylic acid t-butyl ester (3.0 g), hydrazine monohydrate
(1.5 ml) and 1N hydrochloric acid (8.0 ml) were dissolved in ethanol (50 ml), and the mixture was refluxed for 15 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline,
Dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained yellow oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 2), the title compound (2.5 g, 97%) was obtained as pale yellow crystals. ether
Recrystallization from -hexane gave colorless prism crystals. Melting point: 183-184 ° C.

Embodiment 6

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Reference Example 24 in the same manner as in Example 5.
The title compound was obtained from the compound obtained in the above. Light pink prism crystal (yield: 92%), melting point: 181-182 ° C (recrystallization solvent: Ac
OEt-hexane).

Embodiment 7

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole
-6-Carboxylic acid ethyl ester: 8-[(N-benzyloxycarbonyl-N-phenyl) amino] -4,5-dihydro-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester
To a solution of (1.2 g) in N, N-dimethylformamide (DMF) (15 ml) was added 60% sodium hydride (0.12 g) under ice-cooling, followed by stirring for 20 minutes. To this solution was added methyl iodide (0.20 ml), and the mixture was stirred for 2 hours under ice cooling. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained yellow oil was subjected to silica gel column chromatography. The title compound (1.0 g, 81%) was obtained as a pale yellow oil from a portion eluted with ethyl acetate-hexane (1: 2).
¹ H-NMR (δ ppm in CDCl ₃ ): 1.33 (3H, t, J = 7.2Hz), 2.75
(2H, t, J = 7.2Hz), 3.32 (2H, t, J = 7.2Hz), 3.77 (3H, s), 4.
29 (2H, q, J = 7.2Hz), 5.15 (2H, s), 7.0-7.6 (11H, m).

Embodiment 8

Embedded image 4,5-dihydro-1-methyl-8-phenylamino-1H-thieno
[3,4-g] indazole-6-carboxylic acid ethyl ester: 3
-[(N-benzyloxycarbonyl-N-phenyl) amino] -5
-Diethoxymethyl-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester (5.5
g), methylhydrazine (1.0 g) and 1N hydrochloric acid (10 ml) in ethanol (50 ml) were heated under reflux for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was poured into an aqueous citric acid solution, and extracted with ethyl acetate. The extract is washed with water and saturated saline, then dried
(MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained yellow oil and 5% Pd-C (2.2 g) were added to ethanol (50 ml) -tetrahydrofuran (THF) (25 ml), followed by a catalytic reduction reaction at room temperature and normal pressure for 2 hours. Attached to The catalyst was filtered, and the filtrate was distilled off under reduced pressure. The obtained crystals were recrystallized from THF-ethyl acetate to give the title compound.
(2.8 g, 80%) was obtained as pale yellow needles. Melting point: 202-203
° C.

Embodiment 9

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole
-6-Carboxylic acid ethyl ester: 4,5-dihydro-1-methyl-8-phenylamino-1H-thieno [3,4-g] indazole-6
To a DMF solution (8 ml) of -carboxylic acid ethyl ester (150 mg) was added 60% sodium hydride (20 mg) under ice-cooling, followed by stirring for 10 minutes. To this solution was added benzyl chloroformate (73 μl), and the mixture was stirred under ice cooling for 4 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried (MgSO ₄ ). The solvent is distilled off under reduced pressure,
The obtained yellow oil was subjected to silica gel column chromatography. The title compound (130 mg, 63%) was obtained as a colorless oil from a portion eluted with ethyl acetate-hexane (1: 2). ¹ H-NMR (δ ppm in CDCl ₃ ): 1.33 (3H, t, J = 7.2Hz),
2.5-2.7 (2H, m), 3.0-3.5 (2H, m), 3.81 (3H, s), 4.30 (2H, m
q, J = 7.2Hz), 5.14 (2H, s), 7.0-7.4 (10H, m).

Embodiment 10

Embedded image 8-[(N-benzoyl-N-benzyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid: 8-[(N-benzoyl- N-benzyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid t-butyl ester (0.58 g), anisole (1 drop) and trifluoro The mixture of acetic acid (10 ml) was stirred for 3 hours under ice cooling. The reaction solution was concentrated under reduced pressure, and the residue was washed with isopropyl ether to give the title compound (0.35 g, 68%) as pale-yellow crystals. Melting point: 217-218 ° C (decomposition).

The compounds of Examples 11 to 14 were obtained in the same manner as in Example 10. Example 11

Embedded image 8-[(N-benzoyl-N-methyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid: pale brown crystal (yield: 90 %), Melting point: 232-233 ° C (decomposition).

Embodiment 12

Embedded image 8- (4-chlorophenylamino) -4,5-dihydrothieno [3,4-
g] -1,2-Benzisoxazole-6-carboxylic acid: pale brown crystal (yield: 75%), melting point: 235 ° C. (decomposition) (recrystallization solvent: THF-AcOEt).

Embodiment 13

Embedded image 4,5-dihydro-8-phenylaminothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid: pale brown crystal (yield: 78%), melting point: 211-212 ° C. (Disassembly).

Embodiment 14

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-1H-thieno [3,4-g] indazole-6-carboxylic acid: pale pink crystal (yield: 86%), melting point: 278-279 ° C.

Embodiment 15

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole
-6-carboxylic acid: 8-[(N-benzyloxycarbonyl-N-phenyl) amino] -4,5-dihydro-2-methyl-2H-thieno [3,4
-g] Indazole-6-carboxylic acid ethyl ester (1.0 g)
Was dissolved in a mixed solvent of THF (10 ml) -methanol (10 ml) and cooled with ice. To this solution, 85% potassium hydroxide (0.30 g) was added to water (5
ml) was added. After stirring at room temperature for 15 hours,
The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried (MgSO ₄ ).
The solvent was distilled off under reduced pressure, and the obtained yellow oil was purified with ethyl acetate.
Crystallization from -hexane gave the title compound (720 mg, 76%) as colorless prisms. Melting point: 200-201 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 16

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole
-6-carboxamide: 8-[(N-benzyloxycarbonyl-
N-phenyl) amino] -4,5-dihydro-1-methyl-1H-thieno
[3,4-g] indazole-6-carboxylic acid ethyl ester (0.
85g) was dissolved in a mixed solvent of THF (15ml) -methanol (15ml) and cooled with ice. To this solution, 85% potassium hydroxide (0.30 g)
Was dissolved in water (5 ml). After stirring at room temperature for 7 hours, the reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated saline and dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained yellow oil was purified with DMF (15
ml) and cooled on ice. To this solution was added 1-hydroxybenzotriazole-ammonia complex (HOBt-NH ₃ ) (0.35 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (0.44 g), and the mixture was added to ice. The mixture was stirred under cooling for 15 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (MgSO ₄ ). The solvent is distilled off under reduced pressure,
The resulting brown oil was subjected to silica gel column chromatography. The title compound (210 mg, 26%) was obtained as a pale brown oil from the fraction eluted with chloroform-methanol (50: 1). ¹ H-NMR (δ ppm in CDCl ₃ ): 2.5-2.7 (2H,
m), 3.0-3.3 (2H, m), 3.81 (3H, s), 5.15 (2H, s), 5.68 (2
H, brs), 7.1-7.4 (10H, m).

Embodiment 17

Embedded image 8-[(N-benzoyl-N-benzyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxamide: 8-[(N-benzoyl-N -Benzyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid (0.25 g) was dissolved in DMF (10 ml) and cooled with ice. To this solution, HOBt-NH ₃ (0.14 g) and WSC (0.17 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure.
Crystallization from -hexane gave the title compound (214 mg, 86%) as pale-brown prism crystals. Melting point: 235-236 ° C (recrystallization solvent: AcOEt-hexane).

Examples 18 to 22 were carried out in the same manner as in Example 17.
Was obtained. Example 18

Embedded image 8-[(N-benzoyl-N-methyl) amino] -4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxamide: pale yellow prism crystals (yield: 60 %), Melting point: 197-198 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 19

Embedded image 8- (4-chlorophenylamino) -4,5-dihydrothieno [3,4-
g] -1,2-Benzisoxazole-6-carboxamide: light brown prism crystals (yield: 63%), melting point: 224-225 ° C. (recrystallization solvent: THF).

Embodiment 20

Embedded image 4,5-dihydro-8-phenylaminothieno [3,4-g] -1,2-benzisoxazole-6-carboxamide: pale yellow crystal (yield: 40%), melting point: 235-236 ° C. Disassembly).

Embodiment 21

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-1H-thieno [3,4-g] indazole-6-carboxamide: colorless prism crystals (yield: 77%), melting point: 240-241 ° C. (recrystallization solvent: THF-AcOEt).

Embodiment 22

Embedded image 8-[(N-benzyloxycarbonyl-N-phenyl) amino]-
4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole
-6-carboxamide: pale pink prism crystals (yield: 94%), melting point: 220-221 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 23

Embedded image 4,5-dihydro-1-methyl-8-n-propylamino-1H-thieno
[3,4-g] indazole-6-carboxylic acid ethyl ester:
The title compound was obtained from the compound obtained in Reference Example 25 in the same manner as in Example 8. Colorless needles (yield: 73%), melting point: 161-162 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 24

Embedded image 8-[(N-benzyloxycarbonyl-Nn-propyl) amino] -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Example 9 Similarly, the title compound was obtained from the compound obtained in Example 23. Pale yellow oil (yield: 92%), ¹ H-NMR (δ ppm in CDCl ₃ ):
0.86 (3H, t, J = 7.4Hz), 1.58 (3H, t, J = 7.2Hz), 1.5-1.8 (2
H, m), 2.4-3.1 (4H, m), 3.69 (3H, s), 3.5-4.0 (2H, m), 4.
35 (2H, q, J = 7.2Hz), 5.18 (2H, s), 7.2-7.4 (5H, m), 7.35
(1H, s).

Embodiment 25

Embedded image 8-[(N-benzyloxycarbonyl-Nn-propyl) amino] -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: as in Example 15 Example 24
The title compound was obtained from the compound obtained in the above. Colorless prism crystals (yield: 73%), melting point: 231-232 ° C (recrystallization solvent: THF-AcOEt).

Embodiment 26

Embedded image 8-[(N-benzyloxycarbonyl-Nn-propyl) amino] -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: As in Example 17 From the compound obtained in Example 25, the title compound was obtained. Colorless oil (yield: 89%), ¹ H-NMR (δ ppm in CDCl ₃ ): 0.
86 (3H, t, J = 7.4Hz), 1.5-1.8 (2H, m), 2.5-3.2 (4H, m), 3.
4-3.6 (1H, m), 3.69 (3H, s), 3.8-4.0 (1H, m), 5.18 (2H,
s), 5.65 (2H, br s), 7.2-7.4 (5H, m), 7.35 (1H, s).

Embodiment 27

Embedded image 4,5-dihydro-1-methyl-8-n-propylamino-1H-thieno
[3,4-g] indazole-6-carboxamide: 8-[(N-benzyloxycarbonyl-Nn-propyl) amino] -4,5-dihydro-1-methyl-1H-thieno [3,4-g] Indazole-6-carboxamide (0.55 g) and 5% Pd-C (0.25 g) in methanol (15 ml)
In addition to tetrahydrofuran (THF) (15 ml), room temperature for 80 minutes,
It was subjected to a catalytic reduction reaction at normal pressure. The catalyst was filtered, and the filtrate was distilled off under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate to give the title compound (295 mg, 78%) as colorless prisms. 207-208 ° C.

In the same manner as in Example 27, Examples 28 to 30
Was obtained. Example 28

Embedded image 4,5-dihydro-1-methyl-8-phenylamino-1H-thieno
[3,4-g] indazole-6-carboxamide: pale yellow prism crystals (yield: 57%), melting point: 140-141 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 29

Embedded image 4,5-dihydro-8-phenylamino-1H-thieno [3,4-g] indazole-6-carboxamide: pale yellow needles (yield: 57%), melting point: 233-234 ° C (recrystallization solvent : AcOEt-MeOH).

Embodiment 30

Embedded image 4,5-dihydro-2-methyl-8-phenylamino-2H-thieno
[3,4-g] indazole-6-carboxamide: colorless prism crystals (yield: 65%), melting point: 245-246 ° C. (recrystallization solvent: THF-AcOEt).

Embodiment 31

Embedded image N ', N'-Dimethyl-4,5-dihydro-8-phenylaminothieno [3,4-g] -1,2-benzisoxazole-6-carboxyhydrazide: 4,5-dihydro-8-phenyl Aminothieno [3,4-
g] -1,2-Benzisoxazole-6-carboxylic acid (0.30 g) and 1,1-dimethylhydrazine (88 ml) were dissolved in DMF (10 ml) and cooled with ice. To this solution, 1-hydroxybenzotriazole (HOBt) (0.18 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (0.22 g) were added, and the mixture was stirred for 7 hours under ice cooling. . The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained brown crystals were subjected to silica gel column chromatography. From the part eluted with ethyl acetate-methanol (20: 1), the title compound (230 m
g, 68%) as pale yellow crystals. Melting point: 179-180 ° C.

Embodiment 32

Embedded image 4,5-dihydro-6-morpholinocarbonyl-8- (phenylamino) thieno [3,4-g] -1,2-benzisoxazole: 4,5-
Dihydro-8- (phenylamino) thieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid (0.20 g) in anhydrous THF (10 m
l) Add oxalyl chloride (84 ml) and DMF under ice-cooling to the solution.
(1 drop) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was ice-cooled, and morpholine (0.20 ml) was added. After stirring for 1 hour under ice cooling, the reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried (MgS
O ₄ ). The solvent was distilled off under reduced pressure, and the obtained yellow prism crystals were washed with ethyl acetate-hexane to give the title compound (167 mg,
68%) as pale yellow prism crystals. Melting point: 177-178
° C.

In the same manner as in Example 32, the compound of Example 33 was obtained. Example 33

Embedded image N-methyl-4,5-dihydro-8- (phenylamino) thieno [3,4
-g] -1,2-benzisoxazole-6-carboxamide: pale yellow prism crystals (yield: 58%), melting point: 193-194 ° C.

Embodiment 34

Embedded image N- (2-pyridyl) -4,5-dihydro-8- (phenylamino) thieno [3,4-g] -1,2-benzisoxazole-6-carboxamide 4,5-dihydro-8- ( Phenylamino) thieno [3,4-g] -1,2-
Benzisoxazole-6-carboxylic acid (0.20 g) in anhydrous THF
(10 ml) solution, oxalyl chloride (84 ml) and ice-cooled
DMF (1 drop) was added and stirred at room temperature for 2 hours. The reaction solution was cooled on ice, and 2-aminopyridine (72 mg) and triethylamine
(0.17 ml) was added. After stirring for 2 hours under ice cooling, the reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The title compound (90 mg, 36%) was obtained as pale-yellow prism crystals from a portion eluted with ethyl acetate-hexane (2: 1). Melting point: 196-197 ° C (recrystallization solvent: THF-Ac
OEt).

Embodiment 35

Embedded image N- [4- (2,4-dioxothiazolidine-5-ylmethyl) phenyl] -4,5-dihydro-8-phenylaminothieno [3,4-g] -1,2
-Benzisoxazole-6-carboxamide: anhydrous 4,5-dihydro-8- (phenylamino) thieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid (0.30 g) In a THF (20 ml) solution, oxalyl chloride (0.13 ml) and DMF (1 drop) under ice-cooling
Was added and stirred at room temperature for 2 hours. The reaction solution is cooled on ice and
(2,4-dioxothiazolidine-5-ylmethyl) aniline (0.
26 g) and 4- (N, N-dimethylamino) pyridine (0.39 g) were added. After stirring under ice cooling for 3 hours, the reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The title compound (80 mg, 16%) was obtained as pale yellow prism crystals from the portion eluted with ethyl acetate-hexane (2: 1). Melting point: 151-152 ° C.

Embodiment 36

Embedded image N- (1,3,4-thiadiazol-2-yl) -4,5-dihydro-8- (phenylamino) thieno [3,4-g] -1,2-benzisoxazole-6-carboxamide: In the same manner as in Example 35, the title compound (yield: 29%) was obtained as pale yellow crystals. Melting point: 227-2
29 ° C (recrystallization solvent: AcOEt-MeOH).

Embodiment 37

Embedded image N- (4,5-dihydro-8-phenylaminothieno [3,4-g] -1,2-
Benzisoxazol-6-ylcarbonyl) glycine t-
Butyl ester: title compound in the same manner as in Example 31
(Yield: 69%) was obtained as pale yellow crystals. Melting point: 115-116 ° C
(Recrystallization solvent: ether-i-Pr ₂ O).

Embodiment 38

Embedded image N- (4,5-dihydro-8- (phenylamino) thieno [3,4-g] -1,
2-benzisoxazol-6-ylcarbonyl) glycine:
In the same manner as in Example 10, the title compound (yield: 98%) was obtained as pale yellow crystals from the compound obtained in Example 37. Melting point: 193-194 ° C.

Embodiment 39

Embedded image N-carbamoylmethyl-4,5-dihydro-8- (phenylamino) thieno [3,4-g] -1,2-benzisoxazole-6-carboxamide: Example 38 in the same manner as in Example 17. The title compound (yield: 71%) was obtained as pale yellow prism crystals from the compound obtained in (1). Melting point: 213-214 ° C (recrystallization solvent: AcOEt).

Embodiment 40

Embedded image 3- (4,5-dihydro-8- (phenylamino) thieno [3,4-g] -1,
2-Benzisoxazol-6-ylcarbonyl) carbazic acid ethyl ester: The title compound (yield: 71%) was obtained as pale yellow crystals in the same manner as in Example 31. Melting point: 216-2
17 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 41

Embedded image 3-acetyl-4,5-dihydro-8-[(N-acetyl-N-phenyl)
Amino] thieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid t-butyl ester: 4,5-dihydro-8- (phenylamino) thieno [3,4-g]- 1,2-benzisoxazole-6-
A mixture of carboxylic acid t-butyl ester (2.5 g), 4-dimethylaminopyridine (0.25 g), and acetic anhydride (80 ml) was added to 7
Stirred at 0 ° C. for 20 hours. The reaction solution was concentrated under reduced pressure, the residue was poured into an aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed successively with an aqueous solution of sodium hydrogen carbonate, water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1: 3), the title compound (1.2 g, 43%) was obtained as a pale yellow oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.52 (9H, s), 2.10 (3H,
s), 2.20 (3H, s), 2.72 (2H, t, J = 7.4Hz), 3.2-3.5 (2H, m),
7.2-7.5 (5H, m).

Embodiment 42

Embedded image 3-acetyl-8-[(N-acetyl-N-phenyl) amino] -4,5-
Dihydrothieno [3,4-g] -1,2-benzisoxazole-6-
Carboxylic acid: In the same manner as in Example 10, the title compound (yield: 100%) was obtained as a pale yellow oil from the compound obtained in Example 41. ¹ H-NMR (δ ppm in CDCl ₃ ): 2.16 (3H, s), 2.
23 (3H, s), 2.74 (2H, t, J = 7.6Hz), 3.2-3.5 (2H, m), 7.2-
7.6 (5H, m).

Embodiment 43

Embedded image 3-acetyl-8-[(N-acetyl-N-phenyl) amino] -4,5-
Dihydro-4,5-dihydrothieno [3,4-g] -1,2-benzisoxazole-6-carboxamide: The title compound (yield) from the compound obtained in Example 42 in the same manner as in Example 17. :Five
1%) as pale yellow crystals. Melting point: 236-237 ° C.

Embodiment 44

Embedded image 4,5-dihydro-8-n-propylsulfanyl-1H-thieno [3,
4-g] Indazole-6-carboxylic acid ethyl ester: The title compound (yield: 68%) was obtained as pale pink prism crystals from the compound obtained in Reference Example 31 in the same manner as in Example 5. Melting point: 161-162 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 45

Embedded image 4,5-dihydro-8-n-propylsulfanyl-1H-thieno [3,
4-g] indazole-6-carboxylic acid: In the same manner as in Example 15, the title compound (yield: 9) was obtained from the compound obtained in Example 44.
8%) as pale yellow crystals. Melting point: 240-241 ° C (decomposition).

Embodiment 46

Embedded image 4,5-dihydro-8-n-propylsulfanyl-1H-thieno [3,
4-g] indazole-6-carboxamide: In the same manner as in Example 17, the title compound (yield: 87%) was obtained as pale yellow prism crystals from the compound obtained in Example 45. Melting point: 163-16
4 ° C (recrystallization solvent: THF-AcOEt).

Embodiment 47

Embedded image 4,5-dihydro-2-methyl-8-n-propylsulfanyl-2H-
Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: The title compound (yield: 25%) was obtained as colorless prism crystals from the compound obtained in Example 44 in the same manner as in Example 7. . Melting point: 90-91 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 48

Embedded image 4,5-dihydro-2-methyl-8-propylsulfanyl-2H-thieno [3,4-g] indazole-6-carboxylic acid: Titled from the compound obtained in Example 47 in the same manner as in Example 15. Compound
(Yield: 47%) was obtained as colorless prism crystals. Melting point: 227-2
28 ° C (decomposition) (recrystallization solvent: THF-hexane).

Embodiment 49

Embedded image 4,5-dihydro-2-methyl-8-n-propylsulfanyl-2H-
Thieno [3,4-g] indazole-6-carboxamide: an example
In the same manner as in 17, the title compound (yield: 49%) was obtained as colorless prism crystals from the compound obtained in Example 48. Melting point: 2
08-209 ° C (recrystallization solvent: THF-AcOEt).

Embodiment 50

Embedded image 4,5-dihydro-1-methyl-8-n-propylsulfanyl-1H-
Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 5-diethoxymethyl-4,5,6,7-tetrahydro-4-oxo-3-n-propylsulfanylbenzo [c] thiophene-1
-Ethanol solution (20 ml) of carboxylic acid ethyl ester (1.0 g), methylhydrazine (0.35 ml), 1N hydrochloric acid (8.7 ml)
The mixture was heated under reflux for 0 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and then dried (M
gSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 4), the title compound (0.6
7g, 80%) as a pale yellow oil. ¹ H-NMR (δ ppm in
CDCl ₃ ): 0.98 (3H, t, J = 7.4Hz), 1.39 (3H, t, J = 7.4Hz), 1.
5-1.8 (2H, m), 2.61 (2H, t, J = 6.8Hz), 2.92 (2H, t, J = 7.4H
z), 3.17 (2H, t, J = 6.8Hz), 4.19 (3H, s), 4.35 (2H, q, J = 7.
4Hz), 7.41 (1H, s).

Embodiment 51

Embedded image 4,5-dihydro-1-methyl-8-n-propylsulfanyl-1H-
Thieno [3,4-g] indazole-6-carboxylic acid: The title compound was obtained from the compound obtained in Example 50 in the same manner as in Example 15.
(Yield: 93%) was obtained as colorless prism crystals. Melting point: 216-2
17 ° C (recrystallization solvent: AcOEt).

Embodiment 52

Embedded image 4,5-dihydro-1-methyl-8-n-propylsulfanyl-1H-
Thieno [3,4-g] indazole-6-carboxamide: an example
In the same manner as in 17, the title compound (yield: 79%) was obtained as colorless prism crystals from the compound obtained in Example 51. Melting point: 1
12-113 ° C (recrystallization solvent: MeOH-AcOEt).

Embodiment 53

Embedded image 2-acetyl-4,5-dihydro-8-n-propylsulfanyl-2
H-thieno [3,4-g] indazole-6-carboxamide: 4,5-
Dihydro-8-n-propylsulfanyl-1H-thieno [3,4-g]
To a DMF solution (15 ml) of indazole-6-carboxylic acid (0.70 g) was added 60% sodium hydride (0.21 g) under ice-cooling, followed by stirring for 20 minutes. Acetyl chloride (0.25 ml) was added dropwise to the mixture, and the mixture was stirred under ice cooling for 3 hours. Next, aqueous ammonia was added to the reaction solution, followed by stirring for 30 minutes. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in DMF (20 ml) and cooled with ice. To this solution, HOBt-NH ₃ (0.47 g) and WSC (0.60 g)
Was added and stirred at room temperature for 16 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate-THF. Water the organic layer,
The extract was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The title compound (0.34 g, 43%) was obtained as pale yellow prism crystals from the portion eluted with chloroform-methanol (30: 1). Melting point: 219-220 ° C (recrystallization solvent: THF-AcOEt).

Embodiment 54

Embedded image 4,5-dihydro-2-methylsulfonyl-8-n-propylsulfanyl-2H-thieno [3,4-g] indazole-6-carboxamide: 4,5-dihydro-8-n-propylsulfanyl-1H-thieno DM of [3,4-g] indazole-6-carboxamide (0.30g)
To the F solution (15 ml) was added 60% sodium hydride (50 mg) under ice cooling, and the mixture was stirred for 20 minutes. Methanesulfonyl chloride (95 μl) was added dropwise to this mixture, and the mixture was stirred under ice cooling for 2 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed successively with water, an aqueous solution of sodium hydrogen carbonate, and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The title compound (0.16 g, 41%) was obtained as pale yellow prism crystals from the portion eluted with chloroform-methanol (50: 1). Melting point: 191-192 ° C (recrystallization solvent: AcOET-
MeOH).

The compounds of Examples 55 to 58 were prepared in Examples
In a similar manner to 54, the compound of Example 59 was obtained in the same manner as in Example 10 from the compound obtained in Example 58.

[Table 9]

Example 60 Ethyl 4,5-dihydro-1-methyl-8-methylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxylate:

Embedded image In the same manner as in Example 50, the title compound (yield: 77%) was obtained as pale yellow prism crystals from the compound obtained in Reference Example 32. Melting point: 113-114 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 61

Embedded image 4,5-dihydro-1-methyl-8-methylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: title compound from the compound obtained in Example 60 in the same manner as in Example 51 The compound (yield: 75%) was obtained as pale yellow crystals. Melting point: 281-282 ° C.

Embodiment 62

Embedded image 4,5-dihydro-1-methyl-8-methylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxamide: title compound from the compound obtained in Example 61 in the same manner as in Example 52
(Yield: 77%) was obtained as pale yellow crystals. Melting point: 177-178 ℃
(Recrystallization solvent: AcOEt).

Embodiment 63

Embedded image 4,5-dihydro-8-methylsulfanyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester: Example 44
In the same manner as in the above, the title compound (yield: 96%) was obtained as pale yellow needles from the compound obtained in Reference Example 32. Melting point: 207-2
08 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 64

Embedded image 4,5-dihydro-8-methylsulfanyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid: As in Example 45,
Title compound (yield: 84%) from the compound obtained in Example 63
Was obtained as pale yellow prism crystals. Melting point: 262-263 ° C (decomposition) (recrystallization solvent: AcOEt-THF).

Embodiment 65

Embedded image 4,5-dihydro-8-methylsulfanyl-1H-thieno [3,4-g]
Indazole-6-carboxamide: In the same manner as in Example 46, the title compound (yield: 4) was obtained from the compound obtained in Example 64.
0%) as pale yellow prism crystals. Melting point: 210-211 ° C
(Recrystallization solvent: AcOEt-THF).

Embodiment 66

Embedded image 4,5-dihydro-2-methyl-8-methylsulfanyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Compound obtained in Example 63 in the same manner as in Example 47 The title compound (yield: 78%) was obtained as pale yellow crystals.
Melting point: 193-194 ° C.

Embodiment 67

Embedded image 4,5-Dihydro-2-methyl-8-methylsulfanyl-2H-thieno [3,4-g] indazole-6-carboxylic acid: Titled from the compound obtained in Example 66 in the same manner as in Example 48. The compound (yield: 87%) was obtained as pale yellow prism crystals. Melting point: 290-29
1 ° C (recrystallization solvent: THF-AcOEt).

Embodiment 68

Embedded image 4,5-dihydro-2-methyl-8-methylsulfanyl-2H-thieno [3,4-g] indazole-6-carboxamide: title compound from the compound obtained in Example 67 in the same manner as in Example 49
(Yield: 73%) was obtained as pale yellow crystals. Melting point: 285-286
° C.

Embodiment 69

Embedded image 4,5-dihydro-1-methyl-8-n-propylsulfinyl-1H-
Thieno [3,4-g] indazole-6-carboxamide: 4,5-dihydro-1-methyl-8-n-propylsulfanyl-1H-thieno
M-chloroperbenzoic acid was added to a dichloromethane solution (12 ml) of [3,4-g] indazole-6-carboxamide (0.30 g) under ice-cooling.
(0.25 g) was added. After stirring at room temperature for 2 hours, the reaction solution was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate. The solution was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (MgSO ₄ ). The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (0.14 g, 43%) as pale-yellow prism crystals. Melting point: 194-195 ° C (recrystallization solvent: MeOH-AcOEt).

Embodiment 70

Embedded image 4,5-dihydro-1-methyl-8-n-propylsulfonyl-1H-thieno [3,4-g] indazole-6-carboxamide: 4,5-dihydro-1-methyl-8-n-propylsulfanyl- 1H-thieno
M-chloroperbenzoic acid was added to a dichloromethane solution (20 ml) of [3,4-g] indazole-6-carboxamide (0.69 g) under ice-cooling.
(1.3 g) was added. After stirring at room temperature for 16 hours, the reaction solution was distilled off under reduced pressure, and the obtained residue was diluted with ethyl acetate. The solution was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. The title compound (0.32 g, 42%) was obtained as pale yellow crystals from a portion eluted with chloroform-methanol (30: 1). Melting point: 142-143 ° C (recrystallization solvent: AcOEt-hexa
ne).

Embodiment 71

Embedded image 4,5-dihydro-1-methyl-8-n-propylsulfanyl-1H-
Thieno [3,4-g] indazole-6-carboxamide hydrochloride: 4,5-dihydro-1-methyl-8-n-propylsulfanyl
-1H-thieno [3,4-g] indazole-6-carboxamide (0.3
To a solution of 0 g) in THF (5 ml) was added 4N hydrochloric acid-ethyl acetate (0.5 ml). The solvent was evaporated under reduced pressure, and the obtained crystals were washed with ethyl acetate to give the title compound (0.31 g, 91%) as pale-yellow crystals. Melting point: 142-143 ° C.

Embodiment 72

Embedded image 4,5-dihydro-1-methyl-8-methylsulfonyl-1H-thieno
[3,4-g] indazole-6-carboxylic acid ethyl ester:
In the same manner as in Example 70, the title compound (yield: 22%) was obtained as pale yellow prism crystals from the compound obtained in Example 60. Melting point: 140-141 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 73

Embedded image 4,5-dihydro-1,8-dimethyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester and 4,5-dihydro
-2,8-dimethyl 2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Reference Example 3 in the same manner as in Example 60
From the compound obtained in 3, 4,5-dihydro-1,8-dimethyl 1H-
Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (yield: 68%) was converted into pale yellow prism crystals (melting point: 118-119 ° C,
AcOEt-hexane) and 4,5-dihydro-2,8-dimethyl
2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (yield: 23%) was converted to colorless prism crystals (melting point: 149-150 ° C,
Recrystallization solvent: AcOEt-hexane).

Embodiment 74

Embedded image 4,5-dihydro-1,8-dimethyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 61, 4,5-dihydro-1,8-dimethyl1H- The title compound (yield: 97%) was obtained as colorless crystals from thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 303 ℃ (decomposition)

Embodiment 75

Embedded image 4,5-dihydro-1,8-dimethyl-1H-thieno [3,4-g] indazole-6-carboxamide: title compound (yield) from the compound obtained in Example 74 in the same manner as in Example 62 : 43%) as colorless prisms. Melting point: 184-185 ° C (recrystallization solvent: AcOEt).

Embodiment 76

Embedded image 4,5-dihydro-2,8-dimethyl-2H-thieno [3,4-g] indazole-6-carboxylic acid: 4,5-dihydro-2,8-dimethyl2H- Title compound from thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (Yield: 100%)
Was obtained as colorless crystals. Melting point: 304-305 ° C (decomposition).

Embodiment 77

Embedded image 4,5-dihydro-2,8-dimethyl-2H-thieno [3,4-g] indazole-6-carboxamide: title compound (yield) from the compound obtained in Example 76 in the same manner as in Example 62. : 84%) as colorless needles. Melting point: 276-277 ° C (recrystallization solvent: Ac
OEt-THF).

Embodiment 78

Embedded image 8-n-butyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester and 8-n-
Butyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: From the compound obtained in Reference Example 34 in the same manner as in Example 60, 8- n-butyl-
4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole
-6-carboxylic acid ethyl ester (yield: 78%) as pale yellow needles (melting point: 80-81 ° C, AcOEt-hexane), and 8-n-butyl-4,5-dihydro-2-methyl -2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (yield: 19%) was converted into pale yellow prism crystals (melting point: 69-70 ° C, recrystallization solvent: AcOEt-he
xane).

Embodiment 79

Embedded image 8-n-butyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid: 8 in the same manner as in Example 61.
The title compound (yield: 97%) was obtained as colorless crystals from -n-butyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 286-287
° C.

Embodiment 80

Embedded image 8-n-butyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxamide: In the same manner as in Example 62, the title compound (yield: 8) was obtained from the compound obtained in Example 79.
0%) as colorless prisms. Melting point: 119-120 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 81

Embedded image 8-n-butyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g]
Indazole-6-carboxylic acid: 8 in the same manner as in Example 61.
The title compound (yield: 87%) was obtained as colorless prisms from -n-butyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. . Melting point: 244
-245 ° C.

Embodiment 82

Embedded image 8-n-butyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g]
Indazole-6-carboxamide: In the same manner as in Example 62, the title compound (yield: 9) was obtained from the compound obtained in Example 81.
4%) as colorless needles. Melting point: 227-228 ° C (recrystallization solvent: AcOEt).

Embodiment 83

Embedded image 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester and 8-benzyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: In the same manner as in Example 60, 8-benzyl- from the compound obtained in Reference Example 35.
4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole
-6-carboxylic acid ethyl ester (yield: 79%) as a pale yellow oil, and 8-benzyl-4,5-dihydro-2-methyl-2
H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (yield: 20%) was obtained as a pale yellow oil. 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester: ¹ H-NMR (δ ppm in CDCl ₃ ): 1.33 (3H, t, J = 7.2Hz), 2.64
(2H, t, J = 6.8Hz), 3.20 (2H, t, J = 6.8Hz), 3.97 (3H, s), 4.
30 (2H, q, J = 7.2Hz), 4.38 (2H, s), 7.2-7.4 (5H, m), 7.44
(1H, s). 8-benzyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester: ¹ H-NMR (δ ppm in CDCl ₃ ): 1.32 (3H, t, J = 7.0Hz), 2.75
(2H, t, J = 7.2Hz), 3.30 (2H, t, J = 7.2Hz), 3.92 (3H, s), 4.
27 (2H, q, J = 7.0Hz), 4.62 (2H, s), 7.18 (1H, s), 7.2-7.5
(5H, m).

Embodiment 84

Embedded image 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid: 8 in the same manner as in Example 61.
The title compound (yield: 84%) was obtained as pale yellow crystals from -benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 300 ° C. or higher (recrystallization solvent: THF-MeOH).

Embodiment 85

Embedded image 8-benzyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxamide: In the same manner as in Example 62, the title compound (yield: 9) was obtained from the compound obtained in Example 84.
4%) as pale yellow prism crystals. Melting point: 126-127 ° C
(Recrystallization solvent: AcOEt).

Embodiment 86

Embedded image 8-benzyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g]
Indazole-6-carboxylic acid: 8 in the same manner as in Example 61.
The title compound (yield: 98%) was obtained as colorless prisms from -benzyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 279
-280 ° C (decomposition) (recrystallization solvent: AcOEt).

Embodiment 87

Embedded image 8-benzyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g]
Indazole-6-carboxamide: In the same manner as in Example 62, the title compound (yield: 8) was obtained from the compound obtained in Example 86.
8%) as colorless needles. Melting point: 212-213 ° C (recrystallization solvent: AcOEt).

Embodiment 88

Embedded image 8-n-hexyl-4,5-dihydro-1-methyl-1H-thieno [3,4-
g] Indazole-6-carboxylic acid ethyl ester and 8-
n-hexyl-4,5-dihydro-2-methyl-2H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester: Example 60
In the same manner as described above, 8-n-hexyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (yield from the compound obtained in Reference Example 36) %: 78%) as a pale yellow oil and 8-n-hexyl-4,5-dihydro-2-
Methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid
The ethyl ester (16% yield) was obtained as a pale yellow oil. 8-n-hexyl-4,5-dihydro-1-methyl-1H-thieno [3,4-
g] Indazole-6-carboxylic acid ethyl ester: ¹ H-NMR (δ ppm in CDCl ₃ ): 1.88 (3H, t, J = 7.0 Hz), 1.2-
1.5 (6H, m), 1.39 (3H, t, J = 7.2Hz), 1.6-1.9 (2H, m), 2.60
(2H, t, J = 6.8Hz), 3.01 (2H, t, J = 8.2Hz), 3.16 (2H, t, J = 6.
8Hz), 3.99 (3H, s), 4.35 (2H, q, J = 7.2Hz), 7.42 (1H, s) .8-n-hexyl-4,5-dihydro-2-methyl-2H-thieno [3 ,Four-
g] Indazole-6-carboxylic acid ethyl ester: ¹ H-NMR (δ ppm in CDCl ₃ ): 0.89 (3H, t, J = 7.0 Hz), 1.2-
1.5 (6H, m), 1.37 (3H, t, J = 7.0Hz), 1.6-1.9 (2H, m), 2.72
(2H, t, J = 7.2Hz), 3.25 (2H, t, J = 6.4Hz), 3.28 (2H, t, J = 7.
2Hz), 3.91 (3H, s), 4.32 (2H, q, J = 7.2Hz), 7.15 (1H, s).

Embodiment 89

Embedded image 8-n-hexyl-4,5-dihydro-1-methyl-1H-thieno [3,4-
g] Indazole-6-carboxylic acid: 8-n-hexyl-4,5-dihydro-1-methyl-1H-thieno in the same manner as in Example 61
The title compound (yield: 95%) was obtained as colorless prism crystals from [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 242-243 ° C (recrystallization solvent: THF-AcOEt).

Embodiment 90

Embedded image 8-n-hexyl-4,5-dihydro-1-methyl-1H-thieno [3,4-
g] Indazole-6-carboxamide: In the same manner as in Example 62, the title compound (yield: 81%) was obtained as colorless prisms from the compound obtained in Example 89. Melting point: 100-101
° C (recrystallization solvent: THF-AcOEt).

Embodiment 91

Embedded image 8-n-hexyl-4,5-dihydro-2-methyl-2H-thieno [3,4-
g] Indazole-6-carboxylic acid: 8-n-hexyl-4,5-dihydro-2-methyl-2H-thieno as in Example 61
The title compound (yield: 82%) was obtained as pale yellow prism crystals from [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 201-202 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 92

Embedded image 8-n-hexyl-4,5-dihydro-2-methyl-2H-thieno [3,4-
g] Indazole-6-carboxamide: In the same manner as in Example 62, the title compound (yield: 92%) was obtained as pale yellow prism crystals from the compound obtained in Example 91. Melting point: 194-19
5 ° C (recrystallization solvent: THF-AcOEt).

In the same manner as in Example 32, Examples 93 to 97
Was obtained.

[Table 10] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 0.93 (3H, t, J = 7.4Hz),
1.5-1.7 (2H, m), 2.5-2.8 (4H, m), 2.81 (2H, t, J = 7.2Hz),
3.08 (6H, s), 4.23 (3H, s), 7.40 (1H, s).

In the same manner as in Example 50, the compounds of Examples 98 to 100 were synthesized. Example 98

Embedded image 4,5-dihydro-8-n-propylsulfanyl-1- (2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-
Carboxylic acid ethyl ester: pale yellow oil (yield: 67%), ¹ H-NMR (δ ppm in CDCl ₃ ):
1.04 (3H, t, J = 7.4Hz), 1.39 (3H, t, J = 7.4Hz), 1.6-1.9 (2H,
m), 2.81 (2H, t, J = 7.0Hz), 2.99 (2H, t, J = 7.0Hz), 3.33 (2
H, t, J = 7.0Hz), 4.35 (2H, q, J = 7.4Hz), 4.7-5.2 (2H, m).

Embodiment 99

Embedded image 1-ethyl-4,5-dihydro-8-n-propylsulfanyl-1H-
Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: pale yellow oil (yield: 89%), ¹ H-NMR (δ ppm in CDCl ₃ ):
0.98 (3H, t, J = 7.2Hz), 1.39 (3H, t, J = 7.2Hz), 1.49 (3H, t, J
= 7.2Hz), 2.61 (2H, t, J = 6.8Hz), 2.93 (2H, t, J = 7.2Hz),
3.18 (2H, t, J = 6.8Hz), 4.35 (2H, q, J = 7.2Hz), 4.58 (2H, q,
J = 7.2Hz), 7.46 (1H, s).

Example 100

Embedded image 4,5-dihydro-1- (2-hydroxyethyl) -8-n-propylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: pale yellow oil (yield: 95 %), ¹ H-NMR (δ ppm in CDCl ₃ ):
0.98 (3H, t, J = 7.4Hz), 1.39 (3H, t, J = 7.4Hz), 1.5-1.8 (2H,
m), 2.62 (2H, t, J = 6.8Hz), 2.92 (2H, t, J = 7.2Hz), 3.19 (2H
H, t, J = 6.8Hz), 4.01 (2H, t, J = 4.8Hz), 4.35 (2H, q, J = 7.4H
z), 4.66 (2H, t, J = 4.8Hz), 7.47 (1H, s).

In the same manner as in Example 51, Examples 101 to 1
Compound 03 was synthesized.

[Table 11]

In the same manner as in Example 52, Examples 104 to 1
Compound 06 was synthesized.

[0242]

[Table 12]

Embodiment 107

Embedded image N-methyl-4,5-dihydro-8-n-propylsulfanyl-1-
(2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 33, the title compound (yield (Rate: 91%)
Was obtained as pale yellow needles. Melting point: 75-76 ° C (recrystallization solvent: i-Pr ₂ O-hexane).

Embodiment 108

Embedded image 4,5-dihydro-8-propylsulfinyl-1- (2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxamide: carried out in the same manner as in Example 69 From the compound obtained in Example 104, the title compound (yield: 96%) was obtained as colorless prisms. Melting point: 165-166 ° C (recrystallization solvent: AcOE
t-hexane).

Embodiment 109

Embedded image 4,5-dihydro-8-n-propylsulfonyl-1- (2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxamide: As in Example 70 From the compound obtained in Example 104, the title compound (yield: 83%) was obtained as pale-yellow prism crystals. Melting point: 141-142 ° C (recrystallization solvent: et
her-hexane).

Embodiment 110

Embedded image 1-ethyl-4,5-dihydro-8-n-propylsulfinyl-1H-
Thieno [3,4-g] indazole-6-carboxamide: an example
In the same manner as in 69, the title compound (yield: 89%) was obtained as pale yellow prism crystals from the compound obtained in Example 105.
Melting point: 151-152 ° C (recrystallization solvent: AcOEt-hexane).

Example 111

Embedded image 1-Ethyl-4,5-dihydro-8-n-propylsulfonyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example 70
In the same manner as in the above, the title compound (yield: 31%) was obtained as colorless prism crystals from the compound obtained in Example 105. Melting point: 143-144 ° C (recrystallization solvent: AcOEt-hexane).

The compounds of Examples 112 to 114 were obtained in the same manner as in Reference Example 32 and Example 60. Example 112

Embedded image 8-benzylsulfanyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: pale yellow oil (yield: 67%), ¹ H-NMR (δ ppm in CDCl ₃ ):
1.39 (3H, t, J = 7.2Hz), 2.50 (2H, t, J = 6.8Hz), 3.11 (2H, t, J
= 6.8Hz), 4.01 (2H, s), 4.08 (3H, s), 4.35 (2H, q, J = 7.2H
z), 7.0-7.2 (5H, m), 7.32 (1H, s).

Embodiment 113

Embedded image 8-isopropylsulfanyl-4,5-dihydro-1-methyl-1
H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: pale yellow oil (yield: 84%), ¹ H-NMR (δ ppm in CDCl ₃ ):
1.24 (6H, d, J = 6.8Hz), 1.39 (3H, t, J = 6.8Hz), 2.62 (2H, t, J
= 6.8Hz), 3.19 (2H, t, J = 6.8Hz), 3.2-3.4 (1H, m), 4.19 (3
H, s), 4.35 (2H, q, J = 6.8Hz), 7.41 (1H, s).

Embodiment 114

Embedded image 8-n-butylsulfanyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: pale yellow oil (yield: 97%), ¹ H -NMR (δ ppm in CDCl ₃ ):
0.87 (3H, t, J = 7.2Hz), 1.39 (3H, t, J = 7.2Hz), 1.3-1.7 (4H,
m), 2.61 (2H, t, J = 6.8Hz), 2.94 (2H, t, J = 6.8Hz), 3.17 (2H, t, J = 6.8Hz)
(H, t, J = 6.8Hz), 4.17 (3H, s), 4.35 (2H, q, J = 7.2Hz), 7.40
(1H, s).

In the same manner as in Example 51, Examples 115 to 1
17 compounds were obtained.

[Table 13]

In the same manner as in Example 52, Examples 118 to 1
20 compounds were obtained.

[Table 14]

In the same manner as in Example 69, Examples 121 to 1
23 compounds were obtained.

[Table 15]

In the same manner as in Example 70, Examples 124 to 1
26 compounds were obtained.

[Table 16] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 2.51 (2H, t, J = 6.8Hz),
3.00 (2H, t, J = 6.8Hz), 4.01 (3H, s), 4.39 (2H, s), 5.81 (2
H, brs), 7.0-7.3 (5H, m), 7.43 (1H, s).

Embodiment 127

Embedded image 4,5-dihydro-8-methyl-1- (2,2,2-trifluoroethyl)
-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester and 4,5-dihydro-8-methyl-2- (2,2,2-trifluoroethyl) -2H-thieno [3, 4-g] Indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-8-methyl-1 from the compound obtained in Reference Example 33 in the same manner as in Example 73
-(2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (yield: 69%) was converted into colorless prism crystals (melting point: 120-121 ° C, Recrystallization solvent: AcOEt-he
xane) and 4,5-dihydro-8-methyl-2- (2,2,2-
(Trifluoroethyl) -2H-thieno [3,4-g] indazole-6
-Carboxylic acid ethyl ester (10% yield) as colorless prisms (melting point: 147-148 ° C, recrystallization solvent: i-Pr ₂ O-hexane)
As obtained.

Embodiment 128

Embedded image 1-benzyl-4,5-dihydro-8-methyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester and 2-benzyl-4,5-dihydro-8-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: As in Example 73, From the compound obtained in Reference Example 33, 1-benzyl-
4,5-dihydro-8-methyl-1H-thieno [3,4-g] indazole
-6-Carboxylic acid ethyl ester (yield: 64%) as colorless prism crystals (melting point: 131-132 ° C, recrystallization solvent: AcOEt-hexane) and 2-benzyl-4,5-dihydro-8-methyl -2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester
(Yield: 18%) was obtained as colorless prism crystals (melting point: 102-103 ° C, recrystallization solvent: AcOEt-hexane).

Example 129

Embedded image 4,5-dihydro-8-methyl-1- (2,2,2-trifluoroethyl)
-1H-thieno [3,4-g] indazole-6-carboxylic acid: Examples
In the same manner as 74, the title compound was obtained from 4,5-dihydro-8-methyl- (2,2,2-trifluoroethyl) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (Yield: 96%)
Was obtained as colorless needles. Melting point: 250-251 ° C (recrystallization solvent: AcOEt-hexane).

Embodiment 130

Embedded image 4,5-dihydro-8-methyl-1- (2,2,2-trifluoroethyl)
-1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 75, the title compound (yield: 99%) was obtained as colorless prisms from the compound obtained in Example 129. Was. Melting point: 144-145 ° C (recrystallization solvent: AcOEt-hexane).

Example 131

Embedded image 4,5-dihydro-8-methyl-2- (2,2,2-trifluoroethyl)
-2H-thieno [3,4-g] indazole-6-carboxylic acid: Example
In the same manner as in 76, the title compound was obtained from 4,5-dihydro-8-methyl- (2,2,2-trifluoroethyl) -2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (Yield: 80%)
Was obtained as colorless prism crystals. Melting point: 270 ° C (decomposition)

Embodiment 132

Embedded image 4,5-dihydro-8-methyl-2- (2,2,2-trifluoroethyl)
-2H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 77, the title compound (yield: 96%) was obtained as colorless needles from the compound obtained in Example 131. Obtained.
Melting point: 227-228 ° C.

Embodiment 133

Embedded image 1-benzyl-4,5-dihydro-8-methyl-1H-thieno [3,4-g]
Indazole-6-carboxylic acid: 1 in the same manner as in Example 74.
The title compound (yield: 96%) was obtained as colorless crystals from -benzyl-4,5-dihydro-8-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point: 231-232
° C.

Embodiment 134

Embedded image 1-benzyl-4,5-dihydro-8-methyl-1H-thieno [3,4-g]
Indazole-6-carboxamide: In the same manner as in Example 75, the title compound (yield: 93%) was obtained as colorless needles from the compound obtained in Example 133. Melting point: 205-206 ° C (recrystallization solvent: MeOH-AcOEt).

Embodiment 135

Embedded image 2-benzyl-4,5-dihydro-8-methyl-2H-thieno [3,4-g]
Indazole-6-carboxylic acid: 2 in the same manner as in Example 76
The title compound (yield: 100%) was obtained as colorless prisms from -benzyl-4,5-dihydro-8-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester. Melting point:
231-232 ° C (recrystallization solvent: THF-AcOEt).

Example 136

Embedded image 2-benzyl-4,5-dihydro-8-methyl-2H-thieno [3,4-g]
Indazole-6-carboxamide: In the same manner as in Example 77, the title compound (yield: 89%) was obtained as colorless needles from the compound obtained in Example 135. Melting point: 182-183 ° C (recrystallization solvent: MeOH-AcOEt).

Example 137

Embedded image 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-1-methyl-8-methylsulfonyl-1H
-Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (2.0 g) and thiophenol (0.60 ml) in THF
(70 ml), under ice cooling, 60% sodium hydride (0.26 g) was added,
The mixture was stirred at the same temperature for 30 minutes and further at room temperature for 5 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography. From the part eluted with ethyl acetate-hexane (1: 2), the title compound (0.90 g, 41
%) As a pale yellow oil. ¹ H-NMR (δ ppm in CDC
l ₃ ): 1.35 (3H, t, J = 7.4Hz), 2.65 (2H, t, J = 6.8Hz), 3.26
(2H, t, J = 6.8Hz), 4.16 (3H, s), 4.32 (2H, q, J = 7.4Hz), 7.
1-7.3 (5H, m).

Example 138

Embedded image 8-t-butylsulfanyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro- 1-methyl-8
-Methylsulfonyl-1H-thieno [3,4-g] indazole-6-
From the carboxylic acid ethyl ester, the title compound (yield: 46
%) Was obtained as pale yellow prism crystals. Melting point: 124-125 ° C (recrystallization solvent: ether-hexane).

Example 139

Embedded image 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 61, from the compound obtained in Example 137, The title compound (yield: 92%) was obtained as colorless prism crystals. Melting point: 286
-287 ° C.

Embodiment 140

Embedded image 8-t-butylsulfanyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: the compound obtained in Example 138 in the same manner as in Example 61 Thus, the title compound (yield: 100%) was obtained as colorless crystals. Melting point: 277-278
° C.

Example 141

Embedded image 4,5-dihydro-1-methyl-8-phenylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example 62
In the same manner as in the above, the title compound (yield: 95%) was obtained as colorless prisms from the compound obtained in Example 139. Melting point: 205-206 ° C (recrystallization solvent: AcOEt-hexane).

Example 142

Embedded image 8-t-butylsulfanyl-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example 62
In the same manner as in the above, the title compound (yield: 95%) was obtained as colorless prisms from the compound obtained in Example 140. Melting point: 146-147 ° C (recrystallization solvent: AcOEt-hexane).

Example 143

Embedded image 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno [3,4
-G] indazole-1-carboxylic acid ethyl ester and 4,5-dihydro-2-methyl-8-phenoxy-2H-thieno [3,
4-g] indazole-1-carboxylic acid ethyl ester: 5-
Diethoxymethyl-4,5,6,7-tetrahydro-4-oxo-3-
Phenoxybenzo [c] thiophene-1-carboxylic acid ethyl ester (6.32 g), methylhydrazine monohydrate (0.7 g), 2
A mixed solution of N hydrochloric acid (23 mL) and ethanol (50 mL) was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and saturated saline, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The title compound was obtained as colorless prism crystals from the portion eluted with ethyl acetate-hexane (1: 2). 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno
[3,4-g] indazole-1-carboxylic acid ethyl ester (2.38 g, 44%), melting point: 91-93 ° C (recrystallization solvent: AcOEt-h
exane). 4,5-dihydro-2-methyl-8-phenoxy-2H-thieno [3,4-g] indazole-1-carboxylic acid ethyl ester (0.87 g, 16%), melting point: 89-90 ° C (recrystallization solvent : AcOEt-h
exane).

In the same manner as in Example 143, Example 144-1
66 compounds were synthesized.

[Table 17]

[Table 18]

[Table 19] 16) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.30 (3H, t, J = 7.2Hz),
2.76 (2H, t, J = 7.6Hz), 3.32 (2H, t, J = 7.0Hz), 3.93 (3
H, s), 4.25 (2H, q, J = 7.2Hz), 6.81 (1H, dd, J = 8.4,1.8Hz),
6.90 (1H, dd, J = 8.4,1.8Hz), 7.02 (1H, t, J = 8.4Hz), 7.15
(1Hs) .12) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.34 (3H, t, J = 7.2
Hz), 2.70 (2H, t, J = 6.8Hz), 3.26 (2H, t, J = 6.8Hz),
4.10 (3H, s), 4.30 (2H, q, J = 7.2 Hz), 7.00−7.40 (10
H, m).

Embodiment 167

Embedded image 4,5-dihydro-8- (4-methylsulfonylphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-8- (4- Methylsulfanylphenoxy)-
1-methyl-1H-thieno [3,4-g] indazole-
To a dichloromethane solution (20 ml) of 6-carboxylic acid ethyl ester (1.95 g) was added m-chloroperbenzoic acid (3.0 g), and the mixture was stirred at room temperature for 12 hours.
Washing was performed in the order of a saturated saline solution. After drying the organic layer (MgSO ₄ )
The solvent was distilled off under reduced pressure to obtain a crude crystal. Recrystallization from ethyl acetate-diisopropyl ether gave the title compound (1.85 g, 8
8%) as pale yellow prism crystals. Melting point: 190-191
° C.

Example 168

Embedded image 4,5-dihydro-1-methyl-8- [4- (3-pyridinyl) phenoxy] -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 8- (4-
Bromophenoxy) -4,5-dihydro-1-methyl-
1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (2.00 g), diethyl (3-pyridyl) borane (0.76 g), tetrakistriphenylphosphinepalladium (0.26 g) and a 2N aqueous sodium carbonate solution ( 6.
6 ml) of dimethoxyethane solution (60 ml) under an argon stream 12
Heated to reflux for an hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer is washed with water and saturated saline in this order and dried (MgS
After O ₄ ), the solvent was distilled off under reduced pressure. The residual oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (2: 1), the title compound (1.61 g, 8
1%) as colorless prisms. Melting point: 160-161 ° C.

In the same manner as in Example 168, Example 16
9 to 171 compounds were synthesized.

[Table 20] 13) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.34 (3H, t, J = 7.0
Hz), 2.72 (2H, t, J = 6.6 Hz), 3.28 (2H, t, J = 6.6 Hz),
4.09 (3H, s), 4.31 (2H, q, J = 7.0 Hz), 7.20−7.25 (1H,
m), 7.35−7.33 (4H, m), 7.37 (1H, s), 7.83−7.89 (1
H, m), 8.63 (1H, dd, J = 4.8, 2.0 Hz), 8.83 (1H, dd, J =
14) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.33 (3H, t, J = 7.0
Hz), 2.70 (2H, t, J = 6.6Hz), 3.27 (2H, t, J = 6.6Hz),
3.80 (3H, s), 3.85 (3H, s), 4.10 (3H, s), 4.30 (2H, q,
J = 7.0 Hz), 6.55 (1H, s), 6.57 (1H, dd, J = 7.2, 2.2 H
z), 7.10 (1H, ddd, J = 7.4, 2.6, 1.8 Hz).

Example 172

Embedded image 4,5-dihydro-1-methyl-8-phenoxy-1H
-Thieno [3,4-g] indazole-1-carboxylic acid:
4,5-dihydro-1-methyl-8-phenoxy-1H
-Thieno [3,4-g] indazole-1-carboxylic acid
Ethyl ester (2.03g), ethanol (50mL) and 0.6N
A mixture of aqueous potassium hydroxide (20 mL) was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, made acidic with 2N hydrochloric acid, and extracted with a mixed solution of ethyl acetate-THF. The organic layer was washed sequentially with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained crude crystals were recrystallized from tetrahydrofuran to give the title compound (1.87 g, 100%) as colorless needles. Melting point: 259-261 ° C

Compounds of Examples 173 to 210 were synthesized in the same manner as in Example 172.

[Table 21]

[Table 22]

[Table 23]

[0278]

[Table 24]

Example 211

Embedded image 4,5-dihydro-1-methyl-8-phenoxy-1H
-Thieno [3,4-g] indazole-6-carboxamide: 4,5-dihydro-1-methyl-8-phenoxy-
1H-thieno [3,4-g] indazole-6-carboxylic acid (0.50 g), HOBt-NH ₃ (0.26 g), WSC (0.36 g) and DMF (1
(0 ml) was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, water was poured into the residual oil, and the mixture was extracted with a mixed solution of ethyl acetate-THF. The organic layer is washed successively with water and saturated saline, and then dried.
(MgSO ₄ ) and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (0.49 g, 99%) as colorless prisms. Melting point: 200-202 ° C

Compounds of Examples 212 to 249 were synthesized in the same manner as in Example 211.

[Table 25]

[Table 26]

[Table 27]

[Table 28]

Example 250

Embedded image N-methoxy-N, 1-dimethyl-4,5-dihydro-
8- (3,4-methylenedioxyphenoxy) -1H-thieno
[3,4-g] indazole-1-carboxamide: 4,
5-dihydro-1-methyl-8- (3,4-methylenedioxyphenoxy) -thieno [3,4-g] indazole-1-carboxylic acid (3.50 g), N, O-dimethylhydroxylamine hydrochloride ( A solution of 1.11 g), WSC (2.17 g) and triethylamine (1.6 ml) in DMF (50 ml) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate.
The organic layer was washed successively with water, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound.
(1.59 g, 41%) was obtained as colorless prisms. Melting point: 130-
131 ° C.

Example 251

Embedded image 1- [4,5-dihydro-8- (3,4-methylenedioxy) phenoxy-1-methyl-1H-thieno [3,4-
g] indazol-6-yl] -1-ethanone: N-methoxy-N, 1-dimethyl-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-
g] To a THF solution (25 ml) of indazole-1-carboxamide (0.33 g) was added a 1.5 M methyllithium-ether solution (0.7 ml) under cooling at -50 ° C. After stirring at −40 to −20 ° C. for 3 hours, the reaction solution was poured into an aqueous oxalic acid solution and extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and saturated saline, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate-isopropyl ether to give the title compound (0.24 g, 83%) as colorless needles. Melting point: 102-103 ° C.

Example 252

Embedded image 1- [4,5-dihydro-8- (3,4-methylenedioxy) phenoxy-1-methyl-1H-thieno [3,4-
g] Indazole-6-yl] -1-propanone: Example 251
In the same manner as in the above, the title compound (2.24 g, 81%) was obtained as colorless needles. Melting point: 99-100 ° C (recrystallization solvent: AcOEt
-i-Pr ₂ O).

Example 253

Embedded image 1- [1-methyl-8- (3,4-methylenedioxy) phenoxy-4,5-dihydro-1H-thieno [3,4-
g] Indazol-6-yl] -1-pentanone: Examples
The title compound (yield: 73%) was synthesized in the same manner as in 251. Melting point: 101-102 ° C.

Example 254

Embedded image [4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazol-6-yl] (3-pyridinyl) methanone: 3
-A solution of bromopyridine (0.25 g) in ether (20
Then, a 1.6 M butyllithium-hexane solution (0.8 ml) was added to the mixture under cooling at -70 ° C. After stirring for 30 minutes, N-
Methoxy-N, 1-dimethyl-4,5-dihydro-8-
(3,4-methylenedioxyphenoxy) -1H-thieno
[3,4-g] indazole-1-carboxamide (0.
6 g) of a THF solution (20 ml) was added, and the mixture was gradually heated to 12
After stirring for an hour, the reaction solution was poured into an aqueous oxalic acid solution and extracted with ethyl acetate. The organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution and saturated saline, dried (MgSO ₄ ) and concentrated under reduced pressure, and the residual oil was subjected to column chromatography. From the portion eluted from ethyl acetate-hexane (3: 2), the title compound (0.31 g, 46%) was obtained as yellow prism crystals. Melting point: 180-182 ° C.

Embodiment 255

Embedded image N-ethyl-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,
4-g] indazole-6-carboxamide: 1-methyl-8- (3,4-methylenedioxyphenoxy) -4,
A suspension of 5-dihydro-1H-thieno [3,4-g] indazole-6-carboxylic acid (1.50 g) in THF (50 m
Oxalyl chloride (0.7 ml) and N, N-dimethylformamide (3 drops) were added to 1) under ice-cooling, stirred at room temperature for 30 minutes, and concentrated under reduced pressure. To a solution obtained by adding THF (50 ml) to the residue was added a 70% ethylamine solution (2 ml) under ice cooling, and the mixture was stirred for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off.
The residual oil was subjected to column chromatography. From the portion eluted from ethyl acetate-hexane (3: 2), the title compound (1.36 g, 84%) was obtained as colorless needles. Melting point: 1
38-139 ° C.

Embodiment 256

Embedded image N- (3-chloropropyl) -4,5-dihydro-8-
(3,4-methylenedioxyphenoxy) -1-methyl-
1H-thieno [3,4-g] indazole-6-carboxamide: title compound (yield: 3
7%) was synthesized. Melting point: 145-147C.

Example 257

Embedded image N- (3-Dimethylaminopropyl) -8- (3,4-methylenedioxyphenoxy) -1-methyl-4,5-dihydro-1H-thieno [3,4-g] indazole-6-carboxamide: working The title compound (yield: 89%) was synthesized in the same manner as in Example 255. Melting point: 109-110 ° C.

Example 258

Embedded image N- (2-methylpropyl) -4,5-dihydro-8-
(3,4-methylenedioxyphenoxy) -1-methyl-
1H-thieno [3,4-g] indazole-6-carboxamide: 4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4
-G] indazole-6-carboxylic acid (1.00 g), isobutylamine (0.22 g), WSC (0.57 g), HOBt (0.45 g) and D
A solution of MF (20 ml) was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, water was poured into the residual oil, and the mixture was extracted with a mixed solution of ethyl acetate-THF. After the organic layer was washed with water and saturated saline in this order,
It was dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (1.13 g, 98%) as colorless prisms. Melting point: 155-157 ° C

Example 259

Embedded image N- (1,1-dimethylethyl) -4,5-dihydro-8
-(3,4-Methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: The title compound (yield: 98%) in the same manner as in Example 258. ) Was synthesized. Melting point: 177-179 ° C.

Example 260

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-N- (4-pyridylmethyl) -1
H-thieno [3,4-g] indazole-6-carboxamide: title compound (yield: 90) in the same manner as in Example 258.
%) Was synthesized. Melting point: 202-204 ° C.

Example 261

Embedded image 6-cyano-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno
[3,4-g] indazole: 4,5-dihydro-8-
(3,4-methylenedioxyphenoxy) -1-methyl-
1H-thieno [3,4-g] indazole-6-carboxamide (1.91 g) was dissolved in trifluoroacetic anhydride (60 ml) and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, water was poured, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, an aqueous solution of sodium hydrogen carbonate and saturated saline and dried (MgS
After O ₄ ), the solvent was distilled off. The residual oil was subjected to column chromatography. From the portion eluted with ethyl acetate-hexane (1: 1), the title compound (1.45 g, 80%) was obtained as colorless needles. Melting point: 132-134 ° C.

Example 262

Embedded image 8-ethoxy-4,5-dihydro-1-methyl-1H-
Thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-1-methyl-8-methylsulfonyl-1H-thieno [3,4-g] indazole-6
Carboxylic acid ethyl ester (0.32 g) and ethanol (0.
1g) in THF (6ml) solution under ice-cooling, sodium hydride (0.05g)
Was added and stirred at room temperature for 14 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. The title compound (0.09 g, 30%) was obtained as colorless prism crystals from the portion eluted with ethyl acetate-hexane (2: 1). Melting point: 109-110 ° C

In the same manner as in Example 262, Examples 263 to
269 compounds were obtained.

[Table 29] 15) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.34 (3H, t, J = 7.0
Hz), 2.69 (2H, t, J = 6.6Hz), 3.25 (2H, t, J = 6.6Hz),
4.02 (3H, s), 4.29 (2H, q, J = 7.0 Hz), 5.14 (2H, s),
5.15 (2H, s), 6.70 (1H, dd, J = 8.8, 3.0 Hz), 6.80 (1H,
d, J = 3.0 Hz), 6.92 (1H, d, J = 8.8 Hz), 7.30−7.46 (1
0H, m).

Example 270

Embedded image 8-ethoxy-4,5-dihydro-1-methyl-1H-
Thieno [3,4-g] indazole-6-carboxylic acid: 8
-Ethoxy-4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (0.43 g), 0.4N KOH (20 ml), THF (20 ml) and ethanol ( (20 ml) was heated to reflux for 4 hours. The reaction solution was concentrated under reduced pressure, the residual oil was acidified with 2N hydrochloric acid, and the precipitated crystals were collected by filtration. Recrystallization from THF gave the title compound (0.39 g, 99%). 258-260 ° C

In the same manner as in Example 270, Examples 271 to
277 compounds were obtained.

[Table 30]

Example 278

Embedded image 8-ethoxy-4,5-dihydro-1-methyl-1H-
Thieno [3,4-g] indazole-6-carboxamide: 8-ethoxy-4,5-dihydro-1-methyl-1
H-thieno [3,4-g] indazole-6-carboxylic acid
(0.30 g), HOBt-NH ₃ (0.18 g), WSC (0.23 g) and DMF (8 m
The solution of l) was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, water was poured into the residual oil, and the mixture was extracted with a mixed solution of ethyl acetate-THF. The organic layer is washed successively with water and saturated saline, and then dried.
(MgSO ₄ ) and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (0.25 g, 83%) as colorless prisms. Melting point: 200-202 ° C.

In the same manner as in Example 278, Examples 279 to
285 was obtained.

[Table 31]

Example 286

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenoxy) thieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid t-butyl ester: 5-
(Ethoxymethylidene) -4,5,6,7-tetrahydro-8- (3,4-methylenedioxyphenoxy) -4
-Oxobenzo [c] thiophene-1-carboxylic acid t-butyl ester (1.95 g) and hydroxyammonium chloride (0.92 g) in ethanol (50 ml) were added.
The mixture was stirred at 0 ° C. for 1.5 hours, concentrated, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and dried (MgSO ₄ )
Thereafter, the mixture was concentrated under reduced pressure, and the residual oil was subjected to column chromatography. From the fraction eluted from ethyl acetate-hexane (1: 4), the title compound (1.18 g, 64%) was obtained as colorless needles. Melting point: 165-166 ° C.

Example 287

Embedded image 4,5-Dihydro-8- (3,4-methylenedioxyphenoxy) thieno [3,4-g] -1,2-benzisoxazole-6-carboxylic acid: The title is obtained in the same manner as in Example 10. The compound was obtained. Melting point: 226-228 ° C (recrystallization solvent: AcOEt)

Example 288

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenoxy) thieno [3,4-g] -1,2-benzisoxazole-6-carboxamide: The title compound in the same manner as in Example 211. I got Melting point: 167-169 ° C (recrystallization solvent: AcOEt-iPr ₂ O)

Example 289

Embedded image 3- [4- (acetylamino) phenoxy] -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 3- [4-
(Acetylamino) phenoxy] -5-[(E) -ethoxymethylidene] -6,7-dihydro-4-oxobenzo
[c] Thiophene-1-carboxylic acid ethyl ester (2.35 g), methylhydrazine sulfate (0.95 g)
(100 ml) was stirred at 60 ° C. for 3 hours, cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried (MgSO ₄ ), concentrated under reduced pressure, and the residual oil was subjected to column chromatography.
From the portion eluted from ethyl acetate-hexane (1: 2), the title compound (1.13 g, 50%) was obtained as colorless needles. 181-182 ° C.

Embodiment 290

Embedded image 4,5-dihydro-8-[(2,3-dihydrobenzofuran-6-yloxy)]-1-methyl-1H-thieno
[3,4-g] indazole-6-carboxylic acid ethyl ester: 6,7-dihydro-3- (2,3-dihydrobenzofuran-6-yloxy) -5-[(E) -ethoxymethylidene] -4 -Oxobenzo [c] thiophene-1-carboxylic acid ethyl ester (3.28 g) and methanesulfonic acid (2.7 ml)
Methylhydrazine monohydrate in ethanol solution (50 ml) of
(0.55 g) and stirred at 60 ° C. for 3 hours. After the reaction solution was concentrated, it was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried (MgSO ₄ ), concentrated under reduced pressure, and the residual oil was subjected to column chromatography. Ethyl acetate: hexane
From the part eluted from (1: 4), the title compound (2.10 g, 67%)
Was obtained as colorless prism crystals. 137-138 ° C. (Recrystallization solvent: AcOEt-i-Pr ₂ O).

Embodiment 291

Embedded image 4,5-dihydro-1-methyl-8- [4- (1H-pyrro-
Ru-1-yl) phenoxy] -1H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester: From the compound obtained in Reference Example 82 in the same manner as in Example 289,
The title compound (yield: 39%) was obtained as colorless needles. Melting point: 139-140 ° C. (Recrystallization solvent: AcOEt).

Embodiment 292

Embedded image 8- (4-fluorophenoxy) -4,5-dihydro-
1-methyl-1H-thieno [3,4-g] indazole-
6-Carboxylic acid ethyl ester: The title compound (yield: 72%) was obtained as colorless needles from the compound obtained in Reference Example 83 in the same manner as in Example 290. Melting point: 94-95 ° C.
(Recrystallization solvent: AcOEt-iPr ₂ O).

Example 293

Embedded image 4,5-dihydro-1-methyl-8- (4-methylphenoxy) -1H-thieno [3,4-g] indazole-6
-Carboxylic acid ethyl ester: In the same manner as in Example 290, the title compound (yield: 60%) was obtained as colorless needles from the compound obtained in Reference Example 84. Melting point: 147-148
° C. (Recrystallization solvent: AcOEt-hexane).

Example 294

Embedded image 4,5-dihydro-1,4,4-trimethyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-
Dihydro-1,4,4-trimethyl-8-methylsulfonyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester (2.22 g), sesamol (0.88 g), potassium t-butoxide (0 .77 g) of 1-methyl-2-pyrrolidone solution (30 ml) was stirred at 90 ° C. for 12.5 hours, poured into water and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium hydrogencarbonate, water and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The crude crystals were recrystallized from ethyl acetate-hexane to give the title compound as colorless needles (1.07 g, 42%).
Melting point: 128-130 ° C. (Recrystallization solvent: AcOEt-hexane)

Embodiment 295

Embedded image 4,5-dihydro-1,4,4-trimethyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid: As in Example 172 hand,
The title compound (yield: 85%) was obtained. Melting point: 291-293 ° C (recrystallization solvent: THF)

Example 296

Embedded image 4,5-Dihydro-1,4,4-trimethyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide: As in Example 211 The title compound (yield: 89%) was obtained. Melting point: 219-220
° C (recrystallization solvent: THF)

Example 297

Embedded image 3-bromo-4,5-dihydro-1-methyl-8-methylsulfonyl-
1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Compound (0.50 g) obtained in Example 12a, bromine (0.7
0 g) and a solution of sodium acetate (0.36 g) in acetic acid (10 ml) were stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The solution was washed with an aqueous sodium hydrogen carbonate solution and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (0.33 g, yield 54%) as pale-yellow prism crystals. Melting point: 195-196 ° C.

Example 298

Embedded image 8- (6-bromo-3,4-methylenedioxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Example 297 Similarly, from the compound obtained in Example 148 (1.7 g), the title compound (1.71 g,
Yield 84%). Melting point: 175-176 ° C.

Example 299

Embedded image 8- (6-Bromo-3,4-methylenedioxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: As in Example 172 The title compound (1.44 g, yield 97%) was obtained as pale yellow crystals from the compound (1.58 g) obtained in Example 298. Melting point: 285-286 ° C.

Example 300

Embedded image 8- (6-Bromo-3,4-methylenedioxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 211 From the compound obtained in Example 299 (1.2 g), the title compound (1.12 g, 94% yield)
Was obtained as pale yellow prism crystals. Melting point: 196-197 ° C.

Example 301

Embedded image 3-bromo-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Example 13a In a similar manner, the title compound (5.78 g, yield 81%) was obtained as pale yellow needles from the compound (6.25 g) obtained in Example 297. Melting point: 1
70-171 ° C.

Example 302

Embedded image 3-bromo-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: As in Example 172 From the compound (5.6 g) obtained in Example 301, the title compound (5.3 g, yield 100%) was obtained as colorless prism crystals. Melting point: 242-243 ° C.

Example 303

Embedded image 3-Bromo-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 211 From the compound (3.5 g) obtained in Example 302, the title compound (3.25 g, yield 93%)
Was obtained as pale yellow prism crystals. Melting point: 196-197 ° C.

In the same manner as in Example 168, compounds of Examples 304 to 313 were synthesized from the compound obtained in Example 303.

[Table 32]

Example 314

Embedded image 3-n-butyl-4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-
Carboxamide: 3-bromo-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-
Carboxamide (0.40 g), tetra-n-butyltin (0.93 m
l), tetrakistriphenylphosphine palladium (31m
g) and a solution of lithium chloride (115 mg) in DMF (5 ml) were stirred at 100 ° C. for 24 hours in a stream of argon. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried (MgS
O ₄ ) and concentrated under reduced pressure. The obtained oil was dissolved in a mixed solvent of tetrahydrofuran (THF) (10 ml) and methanol (10 ml), 10% palladium on carbon (0.10 g) was added, and catalytic reduction was performed under a hydrogen atmosphere at normal temperature and normal pressure. Filter off the catalyst,
The filtrate was concentrated under reduced pressure, and the obtained yellow oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (2: 1), 45 mg of the title compound, yield 12
%) As colorless needles. Melting point: 161-162 ° C.

Example 315

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenylsulfanyl) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: As in Example 137 ,
From the compound (10 g) obtained in Reference Example 78 and 3,4-methylenedioxythiophenol (4.8 g), the title compound (10.6 g, yield 8
8%) as pale yellow prism crystals. Melting point: 101-102 ° C.

Example 316

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenylsulfanyl) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: carried out in the same manner as in Example 15. From the compound (7.0 g) obtained in Example 315, the title compound (6.5 g, yield: 100%) was obtained as colorless crystals. Melting point: 286-288 ° C (decomposition).

Example 317

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenylsulfanyl) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example in the same manner as in Example 211 From the compound (5.5 g) obtained in 315, the title compound (5.2 g, yield: 100
%) As colorless crystals. Melting point: 171-172 ° C.

Example 318

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenylsulfinyl) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example in the same manner as in Example 69 From the compound (1.0 g) obtained in 317, the title compound (0.64 g, yield: 62)
%) Were obtained as pale yellow prism crystals. Melting point: 182-183 ° C.

Example 319

Embedded image 4,5-dihydro-8- (3,4-methylenedioxyphenylsulfonyl) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example in the same manner as in Example 12a From the compound (1.0 g) obtained in 317, the title compound (0.85 g, yield: 78%)
Was obtained as pale yellow prism crystals. Melting point: 234-235 ° C.

Example 320

Embedded image N-methoxy-N-methyl-4,5-dihydro-1-methyl-8-methylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example 61 in the same manner as in Example 250 From the compound (13.4 g) obtained in (1), the title compound (6.0 g, yield: 39%) was obtained as pale yellow needles. Melting point: 87-88 ° C.

Example 321

Embedded image 1- [4,5-dihydro-1-methyl-8-methylsulfanyl-1H-
Thieno [3,4-g] indazol-6-yl] -1-propanone: The compound (5.7 g) obtained in Example 320 is dissolved in anhydrous THF (150 ml) and cooled to -40 ° C. To this solution was added a 1M-ethylmagnesium bromide THF solution (44 ml), and the mixture was stirred at 4 ° C for 3 hours. The obtained reaction solution was poured into an aqueous citric acid solution, and THF was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (5.0 g, yield 97%) as pale-yellow needles. Melting point:
119-120 ° C.

Example 322

Embedded image 1- [4,5-dihydro-1-methyl-8-methylsulfinyl-1H-
Thieno [3,4-g] indazol-6-yl] -1-propanone: Compound obtained in Example 321 in the same manner as in Example 70 (4.2
g) to give the title compound (3.2 g, yield: 69%) as a pale yellow oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.26 (3H, t, J = 7.4
Hz), 2.65 (2H, t, J = 6.6Hz), 2.93 (2H, q, J = 7.4Hz), 3.18
(2H, t, J = 6.6Hz), 3.21 (3H, s), 4.09 (3H, s), 7.48 (1H,
s).

Example 323

Embedded image 1- [4,5-dihydro-1-methyl-8- (4-methylphenoxy) -1H
-Thieno [3,4-g] indazol-6-yl] -1-propanone:
In the same manner as in Reference Example 79, the compound obtained in Example 322 (1.
0g) to give the title compound (0.15 g, yield: 14%) as pale brown needles. Melting point: 118-119 ° C.

Example 324

Embedded image 1- [4,5-dihydro-1-methyl-8- (3-pyridinyloxy) -1H
-Thieno [3,4-g] indazol-6-yl] -1-propanone
Hydrochloride: The title compound (0.15 g, yield: 13%) was obtained as a pale brown amorphous solid from the compound (1.0 g) obtained in Example 322 in the same manner as in Reference Example 79. ¹ H-NMR (δ ppm in D
_{MSO-d 6): 1.05 (} 3H, t, J = 7.2Hz), 2.68 (2H, t, J = 6.8Hz),
2.84 (2H, q, J = 7.2Hz), 3.19 (2H, t, J = 6.8Hz), 3.98 (3H,
s), 7.40 (1H, s), 7.72 (1H, dd, J = 4.6,8.6Hz), 8.07 (1H, d
d, J = 1.8,8.6Hz), 8.63 (1H, d, J = 4.6Hz), 8.85 (1H, d, J = 1.
8Hz).

Example 325

Embedded image N-methoxy-N-methyl-4,5-dihydro-1-methyl-8-n-propylsulfanyl-1H-thieno [3,4-g] indazole-6-carboxamide: carried out in the same manner as in Example 250 From the compound (4.1 g) obtained in Example 45, the title compound (3.7 g, yield: 79%)
Was obtained as a pale yellow oil. ¹ H-NMR (δ ppm in CDC
l ₃ ): 0.96 (3H, t, J = 7.4Hz), 1.5-1.7 (2H, m), 2.60 (2H, t,
J = 6.6Hz), 2.86 (2H, t, J = 7.0Hz), 3.14 (2H, t, J = 6.6Hz),
3.35 (3H, s), 3.74 (3H, s), 4.21 (3H, s), 7.40 (1H, s).

Example 326

Embedded image 1- [4,5-dihydro-1-methyl-8-n-propylsulfanyl-
1H-thieno [3,4-g] indazol-6-yl] -1-ethanone:
In the same manner as in Example 321, the compound obtained in Example 325
(1.0 g) to give the title compound (0.66 g, yield: 76%) as a pale yellow oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.00 (3H,
t, J = 7.4Hz), 1.6-1.8 (2H, m), 2.53 (3H, s), 2.61 (2H, t, J
= 6.8Hz), 2.95 (2H, t, J = 7.2Hz), 3.17 (2H, t, J = 6.8Hz),
4.18 (3H, s), 7.41 (1H, s).

Example 327

Embedded image 3-bromo-4,5-dihydro-1-methyl-8- (3-pyridinyloxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Performed in the same manner as in Example 297. From the compound (0.60 g) obtained in Example 268, the title compound (0.16 g, yield 22%) was obtained as pale yellow needles. Melting point: 130-131 ° C.

Example 328

Embedded image 3-Bromo-4,5-dihydro-1-methyl-8- (3-pyridinyloxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid: Example 327 in the same manner as in Example 15. Compound obtained in (0.13
g) to give the title compound (0.11 g, yield 86%) as colorless needles. Melting point: 275-276 ° C.

Example 329

Embedded image 3-Bromo-4,5-dihydro-1-methyl-8- (3-pyridinyloxy) -1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 211, The title compound (79 mg, yield 95%) was obtained as colorless prisms from the obtained compound (84 mg). Melting point: 233-234 ° C.

Example 330

Embedded image 4,5-dihydro-1-methyl-8- (1-oxo-3-pyridinyloxy) -1H-thieno [3,4-g] indazole-6-carboxamide: the compound obtained in Example 284 (0.17 g) Was dissolved in acetic acid (5 ml), and a 30% aqueous hydrogen peroxide solution (0.17 ml) was added. After stirring this solution at 60 ° C. for 9 hours, the solvent was distilled off under reduced pressure. The obtained oil was subjected to silica gel column chromatography. The title compound (53 mg, yield 30%) was obtained as pale yellow prism crystals from the portion eluted with chloroform-methanol (9: 1). Melting point: 194-195 ° C.

Example 331

Embedded image 4,5-dihydro-8-dimethylamino-1-methyl-1H-thieno
[3,4-g] indazole-6-carboxylic acid ethyl ester: Trisdimethylaminomethane (26 ml) was added to an N, N-dimethylformamide solution (50 ml) of the compound (11.8 g) obtained in Reference Example 39.
Was added and the mixture was stirred at 60-70 ° C. for 5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. After the extract was washed with saline, the solvent was distilled off under reduced pressure. Residue is ethanol (100ml)
Hydrazine monohydrate (3.2 ml) and 5N-hydrochloric acid (2
0 ml) was added. After stirring the mixture at 60-70 ° C for 2 hours, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained oil was subjected to silica gel column chromatography. The title compound (7.2 g, yield 60%) was obtained as pale pink needles from a portion eluted with ethyl acetate-hexane (3: 2). Melting point: 118-119 ° C.

Example 332

Embedded image 4,5-dihydro-8-dimethylamino-1-methyl-1H-thieno
[3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 15, from the compound (6.6 g) obtained in Example 332, dilute the title compound (5.2 g, yield: 87%). Obtained as yellow crystals. Melting point:
208-209 ° C.

Example 333

Embedded image 4,5-dihydro-8-dimethylamino-1-methyl-1H-thieno
[3,4-g] indazole-6-carboxamide: In the same manner as in Example 211, based on the compound (4.0 g) obtained in Example 332,
The title compound (2.5 g, yield: 64%) was obtained as pale yellow prism crystals. Melting point: 161-162 ° C.

Example 334

Embedded image 4,5-dihydro-8- (3,4-methylenedioxy-6-nitro-phenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: obtained in Example 216 A solution of the compound (0.28 g) in nitric acid (1 ml) was stirred for 1 hour under ice cooling. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained yellow oil was crystallized from ethyl acetate to give the title compound (0.28 g,
(Yield: 89%) as pale yellow prism crystals. Melting point: 230-
231 ° C.

Example 335

Embedded image 4,5-dihydro-8- (3,4-methylenedioxy-6-morpholinosulfonyl-phenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Examples 14a
The compound obtained in (1.5 g) was added little by little to chlorosulfonic acid.
(3.0 g) and stirred at room temperature for 30 minutes, then chloroform (15 m
Diluted in l) and ice-cooled. To this solution, add morpholine (8 ml)
Was added and stirred at room temperature for 2 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained oil was subjected to silica gel column chromatography. The title compound (0.35 g, yield: 17%) was obtained as a pale yellow amorphous solid from a portion eluted with ethyl acetate-hexane (3: 2). ¹ H-NMR (δ ppm in CDCl ₃ ): 1.36 (3H, t, J = 7.2
Hz), 2.73 (2H, t, J = 6.8Hz), 3.1-3.3 (4H, m), 3.29 (2H, t,
J = 6.8Hz), 3.6-3.8 (4H, m), 4.07 (3H, s), 4.32 (2H, q, J =
7.2Hz), 6.10 (2H, s), 6.67 (1H, s), 7.36 (1H, s), 7.38 (1H
H, s).

Example 336

Embedded image 4,5-dihydro-8- (3,4-methylenedioxy-6-morpholinosulfonyl-phenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: Example 15 Similarly, from the compound (0.32 g) obtained in Example 337, the title compound (0.3
0g, yield: 100%) as colorless crystals. Melting point:> 300 ° C.

Example 337

Embedded image 4,5-dihydro-8- (3,4-methylenedioxy-6-morpholinosulfonyl-phenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: same as in Example 211 The title compound (0.265 g, yield: 99%) was obtained as colorless prisms from the compound (0.27 g) obtained in Example 336. Melting point:> 300 ° C.

Example 338

Embedded image 4,5-dihydro-3- [1-hydroxy- (4-methoxyphenyl)
Methyl] -8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide:
The compound (0.50 g) obtained in Example 302 was dissolved in THF (50 ml) and cooled to -70 ° C. A 1.6 M butyllithium solution (1.5 ml) was added to this solution, and the mixture was stirred at the same temperature for 30 minutes. Further, p-anisaldehyde (0.20 ml) was added, and the temperature was raised to -30 ° C over 3 hours. Pour the reaction solution into citric acid aqueous solution,
Extracted with ethyl acetate. After washing the extract with saline,
It was dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained colorless crystals are converted to DMF
(15 ml) and cooled on ice. Add HOBt-NH ₃ (0.17
g) and WSC (0.21 g) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. After washing the extract with an aqueous solution of sodium hydrogen carbonate and saline,
It was dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained yellow oil was subjected to silica gel column chromatography. The title compound (69 mg, yield 13%) was obtained as colorless crystals from a portion eluted with ethyl acetate-hexane-methanol (4: 1: 0.2).
Melting point: 187-188 ° C.

Example 339

Embedded image 4,5-dihydro-8- (4-aminophenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: In the same manner as in Reference Example 80, The title compound (2.5 g, yield: 46%) was obtained as pale yellow prism crystals from the obtained compound (5.0 g). Melting point: 203-204 ° C.

Example 340

Embedded image 4,5-dihydro-8- [4- (p-toluenesulfonylamino) phenoxy] -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: obtained in Example 339 Compound (1.0 g), p-toluenesulfonyl chloride (0.62
g) and a solution of potassium carbonate (0.45 g) in DMF (20 ml) were stirred at room temperature for 6 hours. The reaction solution was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed sequentially with citric acid, water and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained yellow oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 1), the title compound (0.65 g, yield 46%) was obtained as pale pink prism crystals. Melting point: 201-202 ° C.

Example 341

Embedded image 4,5-dihydro-8- [4- (p-toluenesulfonylamino) phenoxy] -1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 15, From the compound (0.78 g) obtained in Example 340, the title compound (0.69 g, yield: 93%) was obtained as colorless crystals. Melting point: 279-280 ° C.

Example 342

Embedded image 4,5-dihydro-8- [4- (p-toluenesulfonylamino) phenoxy] -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: carried out in the same manner as in Example 211 From the compound (0.62 g) obtained in Example 341, the title compound (0.586 g, yield: 9)
5%) as colorless prisms. Melting point: 221-222 ° C.

Example 343

Embedded image 8- [4- (t-butoxycarbonylamino) phenoxy] -4,5-
Dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-
Carboxylic acid ethyl ester: the compound obtained in Example 339 (1.34 g) and di-t-butyl dicarbonate (1.2 g)
THF solution (80 ml) was stirred at 60 ° C. for 2 days. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (1.58 g, yield: 93%) as pale-yellow needles. Melting point: 186-187 ° C.

Example 344

Embedded image 8- [4- (t-butoxycarbonylamino) phenoxy] -4,5-
Dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-
Carboxylic acid: From the compound (1.50 g) obtained in Example 343 in the same manner as in Example 15, the title compound (1.38 g, yield: 98%)
Was obtained as pale yellow crystals. Melting point: 260-261 ° C.

Example 345

Embedded image 4,5-dihydro-8- [4- (t-butoxycarbonylamino) phenoxy] -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: carried out in the same manner as in Example 211 From the compound (1.3 g) obtained in Example 344, the title compound (1.2 g, yield: 93%)
Was obtained as pale yellow crystals. Melting point: 242-243 ° C.

Example 346

Embedded image 4,5-Dihydro-8- (4-aminophenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: Example 34
Compound (0.80 g) obtained in 5 THF (20 ml)-methanol (20 m
1) dissolved in a mixed solvent of l), and further added 5N-hydrochloric acid (20 ml),
Stirred at 0 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was poured into aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, dried (MgSO ₄ ), and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-ether to give the title compound (0.58 g,
(Yield: 94%) as pale yellow prism crystals. Melting point: 214-
216 ° C.

Example 347

Embedded image 4,5-dihydro-8- [4- (methylaminothiocarbonylamino) phenoxy] -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: the compound obtained in Example 346 ( 0.2
8g) and methyl isothiocyanate (0.12ml) in THF
(30 ml) was heated to reflux for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-methanol (20: 1), the title compound (0.19 g, yield 56%) was obtained as colorless prism crystals. Melting point: 199-201 ° C.

Example 348

Embedded image 8- (4-acetyl-3-hydroxyphenoxy) -4,5-dihydro
-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-8- (3-methoxyphenoxy) -1-methyl-1H-thieno [3,4 -g] indazole-6-
Carboxylic acid ethyl ester (1.5 g) and acetyl chloride
To a solution of (0.62 ml) in 1,2-dichloroethane (30 ml) was added aluminum chloride (2.2 g) under ice-cooling, followed by stirring at room temperature for 25 hours.
The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained yellow oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 2), the title compound (0.98 g, yield 61%) was obtained as colorless prism crystals. Melting point: 131-132 ° C.

Example 349

Embedded image 8- (4-acetyl-3-hydroxyphenoxy) -4,5-dihydro
1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 15, from the compound (0.85 g) obtained in Example 348, the title compound (0.78 g, (Yield: 98%) as pale yellow crystals. Melting point:> 276 ° C (decomposition).

Example 350

Embedded image 8- (4-acetyl-3-hydroxyphenoxy) -4,5-dihydro
1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 211, the title compound (0.56 g, yield) was calculated from the compound (0.60 g) obtained in Example 349. %: 92%) as colorless crystals. Melting point: 275-276 ° C.

Example 351

Embedded image 8- (4-acetyl-3-methoxyphenoxy) -4,5-dihydro-1
-Methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro-8- (3-methoxyphenoxy) -1-methyl-1H-thieno [3,4-g ] Indazole-6-carboxylic acid ethyl ester (1.5g) and acetyl chloride
To a solution of (0.56 ml) in 1,2-dichloroethane (30 ml) was added tin chloride (1.44 ml) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained yellow oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (2: 3), the title compound (0.42 g, yield 25%) was obtained as colorless prism crystals. Melting point: 132-133 ° C.

Example 352

Embedded image 8- (4-acetyl-3-methoxyphenoxy) -4,5-dihydro-1
-Methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 15, the title compound (0.33 g, yield) was obtained from the compound (0.38 g) obtained in Example 341. : 91%) as colorless crystals. Melting point: 269-270 ° C.

Example 353

Embedded image 8- (4-acetyl-3-methoxyphenoxy) -4,5-dihydro-1
-Methyl-1H-thieno [3,4-g] indazole-6-carboxamide: In the same manner as in Example 211, from the compound (0.29 g) obtained in Example 352, the title compound (0.25 g, yield: (84%) as colorless prisms. Melting point: 181-182 ° C.

Example 354

Embedded image 8- (4-n-hexanoyl-3-methoxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 4,5-dihydro- 8- (3-methoxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole
Aluminum chloride (1.4 g) was added to 1,6-dichloroethane solution (30 ml) of -6-carboxylic acid ethyl ester (1.25 g) and hexanoyl chloride (0.91 ml) under ice-cooling, followed by stirring at room temperature for 7 hours. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained yellow oil was subjected to silica gel column chromatography. Ethyl acetate-hexane (1: 2)
The title compound (0.89 g, yield 57%) was obtained as a pale yellow oil from the portion eluted with. ¹ H-NMR (δ ppm in CDCl ₃ ): 0.9
4 (3H, t, J = 6.6Hz), 1.2-1.4 (4H, m), 1.35 (3H, t, J = 7.0H
z), 1.6-1.8 (2H, m), 2.72 (2H, t, J = 7.0Hz), 2.94 (2H, t, J
= 7.0Hz), 3.28 (2H, t, J = 7.0Hz), 3.88 (3H, s), 4.01 (3H,
s), 4.32 (2H, q, J = 7.0Hz), 6.7-6.8 (2H, m), 7.36 (1H, s),
7.75 (1H, d, J = 6.0Hz).

Example 355

Embedded image 8- (4-n-hexanoyl-3-methoxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 15, From the compound (0.85 g) obtained in Example 354, the title compound (0.68 g, yield: 85%) was obtained as colorless crystals. Melting point: 265-266 ° C.

Example 356

Embedded image 8- (4-n-hexanoyl-3-methoxyphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide: carried out in the same manner as in Example 211 From the compound (0.57 g) obtained in Example 355, the title compound (0.42 g, yield: 73%)
Was obtained as colorless crystals. Melting point: 164-165 ° C.

Example 357

Embedded image 8- (4-benzyloxyphenoxy) -4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxylic acid: In the same manner as in Example 15, 8- (4- (Benzyloxyphenoxy)-
4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole
The title compound (2.9 g, yield: 91%) was obtained as colorless crystals from -6-carboxylic acid ethyl ester (3.4 g). Melting point: 222-
223 ° C.

Example 358

Embedded image 8- (4-benzyloxyphenoxy) -4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxamide:
In the same manner as in Example 211, the compound obtained in Example 357
(1.5 g), the title compound (1.27 g, yield: 85%) was obtained as colorless prisms. Melting point: 216-217 ° C.

Example 359

Embedded image 4,5-dihydro-1-methyl-8- (3-trifluoromethylphenoxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Reference Example as in Reference Example 80 From the compound (3.0 g) obtained in Step 79, the title compound (1.37 g, yield: 3)
7%) as pale yellow prism crystals. Melting point: 138-139 ° C.

Example 360

Embedded image 4,5-dihydro-1-methyl-8- (3-trifluoromethylphenoxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid: As in Example 15, The title compound (1.12 g, yield: 96%) was obtained as colorless crystals from the obtained compound (1.26 g). Melting point: 296-298 ° C.

Example 361

Embedded image 4,5-dihydro-1-methyl-8- (3-trifluoromethylphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide: obtained in Example 360 in the same manner as in Example 211. From the obtained compound (1.0 g), the title compound (0.96 g, yield: 96%) was obtained as colorless prism crystals. Melting point: 178-179 ° C.

The compounds of Examples 362 to 367 were obtained in the same manner as in Example 143.

[Table 33] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.21 (6H, d, J = 6.2 Hz), 1.
24 (6H, d, J = 6.2Hz), 1.33 (3H, t, J = 7.0Hz), 1.37 (6H, d, J =
6.2Hz), 1.42 (6H, d, J = 6.2Hz), 2.77 (2H, t, J = 7.0Hz), 3.
33 (2H, t, J = 7.0Hz), 3.85 (3H, s), 4.29 (2H, q, J = 7.0Hz),
4.6-4.9 (4H, m), 7.15 (1H, s), 7.23 (2H, d, J = 8.8Hz), 7.9
0 (2H, d, J = 8.8Hz), 8.24 (1H, dd, J = 10.4,47.6Hz). 2) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.25 (6H, t, J = 6.8Hz) ), 1.
32 (3H, t, J = 7.0Hz), 2.83 (2H, t, J = 7.2Hz), 3.16 (2H, d, J =
21.6Hz), 3.35 (2H, t, J = 7.2Hz), 3.9-4.1 (4H, m), 4.28 (2H
H, q, J = 7.0Hz), 7.20 (2H, d, J = 8.8Hz), 7.34 (2H, dd, J = 2.
. 4, 8.8Hz), 7.42 ( 1H, s) 3) 1 H-NMR (δ ppm in CDCl 3): 1.26 (6H, t, J = 7.0Hz), 1.
32 (3H, t, J = 7.0Hz), 1.39 (3H, t, J = 7.0Hz), 2.69 (2H, t, J =
6.8Hz), 3.16 (2H, d, J = 21.6Hz), 3.26 (2H, t, J = 6.8Hz),
3.9-4.5 (8H, m), 7.1-7.4 (5H, m) 4) 1 H-NMR (δ ppm in CDCl 3):. 1.25 (6H, t, J = 7.0Hz), 1.
31 (3H, t, J = 7.0Hz), 1.45 (3H, t, J = 7.0Hz), 2.77 (2H, t, J =
6.8Hz), 3.15 (2H, d, J = 21.6Hz), 3.32 (2H, t, J = 6.8Hz),
3.9-4.1 (4H, m), 4.17 (2H, q, J = 7.0Hz), 4.27 (2H, q, J = 7.0
Hz), 7.1-7.4 (5H, m). 5) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.2-1.4 (15H, m), 2.48 (1
H, tt, J = 6.2, 24.0Hz), 2.70 (2H, t, J = 7.0Hz), 3.1-3.4 (4
H, m), 4.05 (3H, s), 4.28 (2H, q, J = 7.0Hz), 4.7-4.9 (4H,
m), 7.10 (2H, d, J = 8.4Hz), 7.29 (2H, d, J = 8.4Hz), 7.35 (1
H, s). 6) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.54 (9H, s), 2.70 (2H, t,
J = 7.0Hz), 3.24 (2H, t, J = 7.0Hz), 3.67 (2H, s), 4.03 (3H,
. s), 5.15 (2H, s), 7.12 (2H, d, J = 8.8Hz), 7.2-7.4 (8H, m) 7) 1 H-NMR (δ ppm in CDCl 3): 1.53 (9H, s ), 2.76 (2H, t,
J = 7.0Hz), 3.30 (2H, t, J = 7.0Hz), 3.67 (2H, s), 3.88 (3H,
s), 5.15 (2H, s), 7.15 (1H, s), 7.2-7.4 (9H, m). 8) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.53 (9H, s), 2.69 (2H , t,
J = 7.0Hz), 2.8-3.7 (10H, m), 3.24 (2H, t, J = 7.0Hz), 4.02
(3H, s), 4.7-4.9 (1H, m), 5.09 (2H, s), 5.65 (1H, d, J = 9.0
Hz), 7.09 (2H, d, J = 8.4Hz), 7.21 (2H, d, J = 8.4Hz), 7.34
(6H, s). 9) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.52 (9H, s), 2.75 (2H, t,
J = 7.0Hz), 2.8-3.7 (10H, m), 3.30 (2H, t, J = 7.0Hz), 3.88
(3H, s), 4.7-4.9 (1H, m), 5.09 (2H, s), 5.67 (1H, d, J = 9.0
Hz), 7.15 (1H, s), 7.19 (4H, s), 7.35 (5H, s).

In the same manner as in Example 15, the compounds of Examples 368 to 369 were obtained.

[Table 34]

The compounds of Examples 370 to 371 were obtained in the same manner as in Example 211.

[Table 35] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.2-1.4 (24H, m), 2.47 (1
H, tt, J = 6.2, 24.0Hz), 2.72 (2H, t, J = 6.8Hz), 3.1-3.4 (4
H, m), 4.03 (3H, s), 4.6-4.9 (4H, m), 5.58 (2H, brs), 7.0
7 (2H, d, J = 8.6Hz), 7.27 (2H, d, J = 8.6Hz), 7.35 (1H, s).

Example 372

Embedded image 8- (4-formylphenoxy) -4,5-dihydro-1-methyl-1H-
Thieno [3,4-g] indazole-6-carboxamide and 8-
{4-((E) -2-diisopropoxyphosphorylvinyl) phenoxy} -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide Obtained in Example 362 The compound of Group A (2.0 g) was dissolved in a mixed solvent of THF (30 ml) and methanol (30 ml). In this solution,
An aqueous solution (10 ml) of potassium hydroxide (0.47 g) was added and
Stir for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was acidified with an aqueous citric acid solution. Extract with ethyl acetate and dry (M
gSO ₄ ) and concentrated under reduced pressure. The obtained pale yellow crystals (1.7 g) and H
OBt-NH ₃ (0.46 g) was dissolved in DMF (50 ml) and cooled on ice. To this solution was added WSC (0.58 g), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and poured into ice water. The mixed solution was extracted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting brown oil was subjected to silica gel column chromatography. From the part eluted with ethyl acetate, 8- (4-formylphenoxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g]
Indazole-6-carboxamide (0.15 g, yield 15%) was obtained as colorless prisms (melting point: 209-210 ° C). Also, from the part eluted with ethyl acetate: methanol (30: 1), 8- {4-
((E) -2-diisopropoxyphosphorylvinyl) phenoxy} -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide (1.15 g, 79% yield) Was obtained as a pale yellow amorphous solid. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.2
-1.5 (12H, m), 2.73 (2H, t, J = 7.0Hz), 3.19 (2H, t, J = 7.0H
z), 4.01 (3H, s), 4.6-4.9 (2H, m), 5.63 (2H, brs), 6.20
(1H, t, J = 17.2Hz), 7.14 (2H, d, J = 8.8Hz), 7.35 (1H, s),
7.2-7.4 (1H, m), 7.51 (2H, d, J = 8.8Hz).

Example 373

Embedded image 8- (4-Diethoxyphosphorylmethylphenoxy) -4,5-dihydro-1-ethyl-1H-thieno [3,4-g] indazole-6-carboxamide The compound of Group A obtained in Example 364 (2.2 g) was dissolved in a mixed solvent of THF (20 ml) and methanol (20 ml). In this solution,
An aqueous solution (15 ml) of potassium hydroxide (0.80 g) was added, and the mixture was added at room temperature for 1 hour.
Stir for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was acidified with an aqueous citric acid solution. Extract with ethyl acetate and dry (M
gSO ₄ ) and concentrated under reduced pressure. Obtained pale yellow oil (2.1 g)
And HOBt-NH ₃ (0.76 g) were dissolved in DMF (40 ml) and cooled with ice. To this solution was added WSC (0.96 g), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and poured into ice water. The mixed solution was extracted with ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting brown oil was subjected to silica gel column chromatography. The title compound (0.90 g, yield 45%) was obtained as colorless prism crystals from a portion eluted with ethyl acetate: THF: methylene chloride (1: 1: 1). Melting point: 152-153 ° C.

In the same manner as in Example 10, the compounds of Examples 374 to 375 were obtained.

[Table 36]

The compounds of Examples 376 to 377 were obtained in the same manner as in Example 211.

[Table 37] ¹ H-NMR (δ ppm in CDCl ₃ ): 2.76 (2H, t, J = 7.0 Hz), 2.7-
3.7 (10H, m), 3.33 (2H, t, J = 7.0Hz), 3.91 (3H, s), 4.8-5.
0 (1H, m), 5.10 (2H, s), 5.61 (2H, brs), 5.70 (1H, d, J = 8.4
Hz), 7.17 (1H, s), 7.23 (4H, s), 7.35 (5H, s).

Example 378

Embedded image 8- (4-hydroxyphenoxy) -4,5-dihydro-1-ethyl-1
H-thieno [3,4-g] indazole-6-carboxamide To a solution of the compound obtained in Example 358 (2.50 g) in acetic acid (50 ml) was added palladium on carbon (0.50 g), and the mixture was stirred at normal pressure in a hydrogen stream. Stir for 4 hours. The insolubles were removed by filtration, and the filtrate was concentrated to obtain crystals. Recrystallization from tetrahydrofuran gave the title compound (1.88 g, yield 95%) as colorless prisms.
Melting point: 137-139 ° C

Example 379

Embedded image 8- {4- (4-chlorobenzyloxy) phenoxy} -4,5-dihydro-1-ethyl-1H-thieno [3,4-g] indazole-6-carboxamide The compound obtained in Example 378 (0.15 g) and a solution of 60% sodium hydride (20 mg) in DMF (10 ml) were stirred at room temperature for 10 minutes. 4-Chlorobenzyl chloride (64 μl) was added to the solution, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with water and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained brown solid was subjected to silica gel column chromatography. From the part eluted with ethyl acetate,
(56 mg, yield 27%) was obtained as pale yellow prism crystals. Melting point:
216-217 ° C.

[0375]

Example 380 8- (4-formylphenoxy) -4,5-dihydro-2-methyl-2H-
Thieno [3,4-g] indazole-6-carboxamide and 8-
{4-((E) -2-diisopropoxyphosphorylvinyl) phenoxy} -4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxamide Obtained in Example 372 Example 37 from the compound of Group B (2.0 g)
The title compound was obtained in the same manner as 3. 8- (4-formylphenoxy) -4,5-dihydro-2-methyl-2H-
Thieno [3,4-g] indazole-6-carboxamide pale yellow prism crystals (melting point: 210-211 ° C). 8- {4-((E) -2-diisopropoxyphosphorylvinyl) phenoxy} -4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxamide Yellow prism crystals ( Melting point: 21
6-217 ° C).

Example 381

Embedded image 8- {4-((E) -2-diisopropoxyphosphorylethyl) phenoxy} -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide Example 372 The resulting 8- {4-((E) -2-diisopropoxyphosphorylvinyl) phenoxy} -4,5-dihydro-1-methyl-1
H-thieno [3,4-g] indazole-6-carboxamide (1.0 g)
Thus, the title compound (0.73 g, yield 68
%) As colorless crystals. Melting point: 76-77 ° C.

Example 382

Embedded image 8- (4-diethoxyphosphorylmethylphenoxy) -4,5-dihydro-2-ethyl-2H-thieno [3,4-g] indazole-6-carboxamide From the compound of Group B obtained in Example 364, The title compound was obtained as colorless prism crystals in the same manner as in Example 372. Melting point: 130-131 ° C.

Example 383

Embedded image 4- (6-carbamoyl-4,5-dihydro-1-methyl-1H-thieno
[3,4-g] indazol-8-yloxy) phenylacetic acid The compound of Group A (1.1 g) and 5% palladium-carbon (0.4 g) obtained in Example 376 were treated with tetrahydrofuran (25 ml) and methanol (25 ml). In a hydrogen stream at normal pressure
Stir for 2 hours. The insolubles were removed by filtration, and the filtrate was concentrated to obtain crystals. Recrystallization from tetrahydrofuran-methanol gave the title compound (0.93 g, yield 100%) as colorless prisms. Melting point: 213-214 ° C.

Example 384

Embedded image 4- (6-carbamoyl-4,5-dihydro-2-methyl-2H-thieno
[3,4-g] indazol-8-yloxy) phenylacetic acid From the compound of Group B obtained in Example 376, the title compound was obtained as pale yellow prism crystals in the same manner as in Example 383. Melting point: 290 DEG C.- (decomposition).

Example 385

Embedded image 8- [4-[(2S) -2-amino-3- (4-morpholinyl) -3-oxopropyl] phenoxy] -4,5-dihydro-1-methyl-1H-thieno
[3,4-g] indazole-6-carboxamide From the compound of Group A obtained in Example 377, the title compound was obtained as a colorless amorphous solid in the same manner as in Example 383. ¹ H-NMR (δ ppm in CDCl ₃ ): 2.69 (2H, t, J = 7.0 Hz),
2.8-3.7 (12H, m), 3.93 (1H, t, J = 7.2Hz), 4.08 (3H, s), 5.
66 (2H, brs), 7.14 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.4H
z), 7.36 (1H, s).

Example 386

Embedded image 8- [4-[(2S) -2-amino-3- (4-morpholinyl) -3-oxopropyl] phenoxy] -4,5-dihydro-2-methyl-2H-thieno
[3,4-g] indazole-6-carboxamide From the compound of Group B obtained in Example 377, the title compound was obtained as a colorless amorphous solid in the same manner as in Example 383. ¹ H-NMR (δ ppm in CDCl ₃ ): 2.76 (2H, t, J = 7.0 Hz),
2.8-3.6 (10H, m), 3.31 (2H, t, J = 7.0Hz), 3.91 (3H, s), 3.
8-4.0 (1H, m), 5.82 (2H, brs), 7.17 (1H, s), 7.21 (4H, s).

Example 387

Embedded image 8- [4-[(2S) -2-acetylamino-3- (4-morpholinyl) -3-
Oxopropyl] phenoxy] -4,5-dihydro-1-methyl-1
H-thieno [3,4-g] indazole-6-carboxamide The compound obtained in Example 385 (0.90 g), acetyl chloride (0.1
6 ml) and a solution of triethylamine (0.32 ml) in anhydrous tetrahydrofuran (40 ml) were stirred under ice-cooling for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. The obtained brown solid was subjected to silica gel column chromatography. The title compound (0.30 g, yield 31%) was obtained as colorless prism crystals from the fraction eluted with ethyl acetate: methanol (9: 1). Melting point: 139-140 ° C.

Example 388

Embedded image 4,5-dihydro-8- (4-hydroxyphenoxy) -1-methyl-
1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester From the compound of Group A obtained in Example 150, the title compound was obtained as colorless needles in the same manner as in Example 383. Melting point: 24
5-246 ° C.

Example 389

Embedded image 4,5-dihydro-1-methyl-8- [4- (2-quinolinylmethoxy)
Phenoxy] -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester The compound obtained in Example 388 (1.5 g), 2-chloromethylquinoline hydrochloride (1.7 g) and potassium carbonate (1.7 g) A solution of g) in DMF (50 ml) was stirred at 70 ° C. for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was acidified with an aqueous citric acid solution. Extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated under reduced pressure. The resulting brown oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate: hexane (2: 1), the title compound (1.9 g, yield 92%) was obtained as colorless prism crystals.
Melting point: 121-122 ° C.

In the same manner as in Example 389, the compounds of Examples 390 to 392 were obtained from the compound of Example 388.

[Table 38] 1) ¹ H-NMR (δ ppm in CDCl ₃ ): 1.32 (3H, t, J = 7.0Hz), 2.
70 (2H, t, J = 7.0Hz), 3.25 (2H, t, J = 7.0Hz), 4.09 (3H, s),
4.28 (2H, q, J = 7.0Hz), 6.98 (2H, d, J = 9.2Hz), 7.16 (2H, d,
J = 9.2Hz), 7.36 (1H, s), 7.37 (2H, d, J = 6.2Hz), 8.64 (2H,
d, J = 6.2Hz).

The compounds of Examples 393 to 396 were obtained in the same manner as in Example 10.

[Table 39]

The compounds of Examples 397 to 400 were obtained in the same manner as in Example 211.

[Table 40]

Example 401

Embedded image Production of 4,5,6,7-tetrahydro-3-methylthio-4-oxocyclohepta [c] thiophen-1-carboxylic acid ethyl ester: In a three-neck flask (2 L), potassium carbonate (anhydrous) (73 g) was added. N,
N-Dimethylformamide (150 ml) and 1,3-cycloheptanedione (12.3 g) were charged and stirred at room temperature for 10 minutes. Carbon disulfide (11.5 ml) was added at once, and the mixture was stirred at room temperature for 20 minutes. A solution of ethyl chloroacetate (19.7 ml) in N, N-dimethylformamide (150 ml) was added dropwise at 35 ° C. or lower over 1 hour.
After the reaction mixture was stirred at room temperature for 1 hour, methyl iodide (11
ml) was added dropwise, and the reaction mixture was heated to 50 ° C. and reacted for 1 hour. The reaction solution was cooled, water (1 L) was added dropwise, and the precipitated crystals were collected by filtration and washed with water to give 16.5 g (33%) of the title compound as pale red needles. ^{1 H NMR (δ ppm in CDCl} 3): 1.38 (3H, t, J = 7.0Hz), 1.81-
1.92 (4H, m), 2.58 (3H, s), 3.39-3.45 (2H, m), 4.33 (2H,
q, J = 7.0Hz).

Example 402

Embedded image Production of 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxocyclohepta [c] thiophen-1-carboxylic acid ethyl ester: The compound (3.33 g) obtained in Example 401 was treated with trifluoroacetic acid. (30 ml) and 30% hydrogen peroxide under ice-cooling
(8 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off.
2 g (95%) were obtained as colorless crystals. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.39 (3H, t, J = 7.0Hz), 1.89
(4H, quint, J = 3.0Hz), 2.74-2.81 (2H, m), 3.30-3.36 (2H,
m), 3.50 (3H, s), 4.38 (2H, q, J = 7.0Hz).

Embodiment 403

Embedded image Preparation of 4,5,6,7-tetrahydro-3- (3,4-methylenedioxyphenoxy) -4-oxocyclohepta [c] thiophen-1-carboxylic acid ethyl ester: Compound obtained in Example 402 To a solution of (3.33 g) and sesamol (1.74 g) in THF (50 ml) was added sodium hydride (0.44 g) under ice cooling, and the mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. did. The extract was washed with water and saturated saline, and then dried (M
gSO ₄ ) and the solvent was distilled off. Residual oil is silica gel ethyl-
From the portion eluted with hexane (1: 4), 1.80 g of the title compound
(48%) as colorless crystals. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.30 (3H, t, J = 7.0Hz), 1.87
(4H, quint, J = 3.0Hz), 2.71 (2H, t, J = 6.2Hz), 3.37 (2H, t,
J = 6.2Hz), 4.23 (2H, q, J = 7.0Hz), 6.03 (2H, s), 6.71 (1H,
dd, J = 8.4,2.6Hz), 6.74 (1H, d, J = 2.6Hz), 6.81 (1H, d, J =
8.4Hz).

Example 404

Embedded image 5-diethoxymethyl-4,5,6,7-tetrahydro-3- (3,4-methylenedioxyphenoxy) -4-oxocyclohepta [c]
Preparation of thiophene-1-carboxylic acid ethyl ester: Boron trifluoride ether complex (1.81 ml) in dichloromethane (3
5ml) solution was cooled to -50 ° C and triethyl orthoformate (2.14
g). After stirring the solution under ice cooling for 20 minutes,
The compound obtained in C (1.8 g) was added and cooled to -70 ° C. Diisopropylethylamine (3.6 ml) was added dropwise to the solution. After stirring for 12 hours while gradually returning to room temperature, the reaction solution was poured into an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water, diluted hydrochloric acid, and saturated saline sequentially, and then dried (MgS
O ₄ ) and concentrated under reduced pressure. The obtained residual oil was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (1: 5), the title compound g (71%) was obtained as a pale yellow oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.17 (3H, t, J = 7.0Hz), 1.20
(3H, t, J = 7.0Hz), 1.30 (3H, t, J = 7.4Hz), 1.72-1.82 (2H,
m), 1.93-2.17 (2H, m), 2.63-2.39 (1H, m), 3.00-3.12 (1
H, m), 3.53-3.78 (4H, m), 3.86-3.99 (1H, m), 4.25 (2H, q,
J = 7.4Hz), 5.00 (1H, d, J = 7.0Hz), 6.02 (2H, s), 6.69 (1H,
dd, J = 8.0,2.4Hz), 6.73 (1H, d, J = 2.4Hz), 6.79 (1H, d, J =
8.0Hz).

Example 405

Embedded image 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -1-methylthieno [3 ', 4': 6,7] cyclohepta [1,2-
c] pyrazole-7-carboxylic acid ethyl ester and 1,4,
5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -2-methylthieno [3 ', 4': 6,7] cyclohepta [1,2-c]
Preparation of ethyl pyrazole-7-carboxylate: To a solution of the compound obtained in Example 404 (1.62 g) in ethanol (10 ml) was added methanesulfonic acid (0.73 ml), and the mixture was stirred at room temperature for 10 minutes. Under ice cooling, methylhydrazine (0.72 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline. The organic layer was concentrated under reduced pressure, and the residual oil was subjected to silica gel column chromatography. Ethyl acetate-hexane (1: 4)
5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -1-methylthieno [3 ', 4': 6,7] cyclohepta [1,2-c]
Pyrazole-7-carboxylic acid ethyl ester 0.43 g (31%) and 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -2-methylthieno [3 ′, 4 ′: 6, 7] Cyclohepta
[1,2-c] pyrazole-7-carboxylic acid ethyl ester 0.48 g
(34%) were each obtained as a colorless oil. 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -1-methylthieno [3 ', 4': 6,7] cyclohepta [1,2-
c] Pyrazole-7-carboxylic acid ethyl ester: ¹ H-NMR (δ
ppm in CDCl ₃ ): 1.33 (3H, T, J = 7.4 Hz), 2.09 (2H, quint, J
= 7.0Hz), 2.51 (2H, t, J = 7.0Hz), 2.99 (2H, brs), 3.94 (3
H, s), 4.29 (2H, q, J = 7.4Hz), 6.01 (2H, s), 6.64 (1H, dd, J
= 8.6,2.4Hz), 6.69 (1H, d, J = 2.4Hz), 6.78 (1H, d, J = 8.6H
z), 7.38 (1H, s). 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -2-methylthieno [3 ', 4': 6,7] cyclohepta [1 , 2-
c] Pyrazole-7-carboxylic acid ethyl ester: ¹ H-NMR (δ
ppm in CDCl ₃ ): 1.32 (3H, t, J = 7.4Hz), 1.97-2.10 (2H,
m), 2.67 (2H, t, J = 7.0Hz), 3.17-3.23 (2H, m), 3.87 (3H,
s), 4.26 (2H, q, J = 8.4Hz), 5.97 (2H, s), 6.70 (1H, dd, J =
8.4,2.2Hz), 6.71 (1H, d, J = 8.4Hz), 6.78 (1H, d, J = 2.2H
z), 7.19 (1H, s).

Example 406

Embedded image 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -1-methylthieno [3 ', 4': 6,7] cyclohepta [1,2-
c] Production of pyrazole-7-carboxylic acid: 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -1-methylthieno [3 ′, 4 ′ obtained in Example 405 : 6,7] cyclohepta [1,
2-c] pyrazole-7-carboxylic acid ethyl ester (0.43 g),
A mixed solution of 0.4 N aqueous potassium hydroxide (10 ml), THF (10 ml) and ethanol (10 ml) was stirred at room temperature for 24 hours. The reaction solution was concentrated, neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration.
The obtained crystals were dissolved in a mixed solution of THF-ethyl acetate, washed with saturated saline, and the solvent was distilled off to obtain 0.33 g (83%) of the title compound as colorless crystals. ¹ H-NMR (δ ppm in CDCl ₃ ): 2.06-2.29 (2H, m), 2.51 (2H,
t, J = 7.4Hz), 2.93-3.06 (2H, brs), 3.96 (3H, s), 6.02 (2
H, s), 6.66 (1H, dd, J = 8.0,2.2Hz), 6.70 (1H, d, J = 2.2Hz),
6.79 (1H, d, J = 8.0Hz), 7.40 (1H, s).

Example 407

Embedded image 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -1-methylthieno [3 ', 4': 6,7] cyclohepta [1,2-
c] Preparation of pyrazole-7-carboxamide: A solution of the compound obtained in Example 406 (0.30 g) in DMF (10 ml) was added to 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (WSC)
(0.18 g) and 1-hydroxybenzotriazole-ammonia complex (HOBt-NH ₃ ) (0.15 g) were added, the mixture was stirred at room temperature for 7 hours, concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and brine, dried (MgSO4), and the solvent was distilled off.
(63%) as colorless crystals. ¹ H-NMR (δ ppm in CDCl ₃ ): 2.05-2.17 (2H, m), 2.54 (2H,
t, J = 7.2Hz), 2.82-2.93 (2H, m), 3.94 (3H, s), 5.57 (2H, b
rs), 6.01 (2H, s), 6.62 (1H, dd, J = 8.4,2.2Hz), 6.67 (1H,
d, J = 2.2Hz), 6.76 (1H, d, J = 8.4Hz), 7.40 (1H, s).

Example 408

Embedded image 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -2-methylthieno [3'4 ': 6,7] cyclohepta [1,2-
c] Production of pyrazole-7-carboxylic acid: 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -2-methylthieno [3 ′, 4 ′ obtained in Example 405 : 6,7] cyclohepta [1,
2-c] pyrazole-7-carboxylic acid ethyl ester (0.48 g),
0.4N potassium hydroxide aqueous solution (10 ml) and ethanol (10 m
The mixed solution of l) was stirred at room temperature for 14 hours. After concentrating the reaction solution
The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried (MgSO ₄ ), and the solvent was distilled off to obtain 0.26 g (58%) of the title compound as a colorless oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 2.00-2.12 (2H, m), 2.70 (2H,
t, J = 7.0Hz), 3.13-3.21 (2H, m), 3.92 (3H, s), 5.99 (2H,
s), 6.74-6.81 (3H, m), 7.21 (1H, s).

Example 409

Embedded image 1,4,5,6-tetrahydro-9- (3,4-methylenedioxyphenoxy) -2-methylthieno [3 ', 4': 6,7] cyclohepta [1,2-
c] Preparation of pyrazole-7-carboxamide: A solution of the compound obtained in Example 408 (0.26 g) in DMF (10 ml) was treated with 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (WSC)
(0.23 g) and 1-hydroxybenzotriazole-ammonia complex (HOBt-NH ₃ ) (0.18 g) were added, and the mixture was stirred at room temperature for 14 hours, concentrated, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried (MgSO4), and the solvent was distilled off. The obtained residual oil was subjected to silica gel column chromatography. From the portion eluted from ethyl acetate-hexane (2: 1), 0.16 g (36%) of the title compound was obtained as colorless crystals. ^{1 H-NMR: 1.98-2.11 (2H} , m), 2.69 (2H, t, J = 7.0), 3.07-3.1
3 (2H, m), 3.87 (3H, s), 5.47 (2H, brs), 5.98 (2H, s), 6.6
8 (1H, dd, J = 6.6,2.2Hz), 6.74 (1H, d, J = 6.6Hz), 6.76 (1H,
d, J = 2.2Hz), 7.19 (1H, s).

The compounds of Examples 410 to 430 were synthesized in the same manner as in Example 13a.

[Table 41]

[0398]

[Table 42]

1) ¹ H NMR (d ppm in CDCl ₃ ): 1.33 (3H,
t, J = 7.2 Hz), 2.67-2.73 (2H, m), 3.21-3.28 (2H, m),
3.46 (3H, s), 3.74-3.78 (2H, m), 4.10 (3H, s), 4.29 (2
H, q, J = 7.2 Hz), 4.46-4.51 (2H, m), 6.86 (1H, d, J =
8.8 Hz), 7.37 (1H, s), 7.48 (1H, dd, J = 3.0 Hz, 8.8 H
z), 8.09 (1H, d, J = 2.8 Hz) .2) ¹ H NMR (d ppm in CDCl ₃ ): 1.34 (3H, t, J = 7.2 Hz),
2.70 (2H, t, J = 7.0 Hz), 3.26 (2H, t, J = 7.0 Hz), 4.0
7 (3H, s), 4.30 (2H, q, J = 7.2 Hz), 6.97 (1H, d, J = 8.4
Hz), 7.10-7.13 (4H, m), 7.36 (1H, s), 7.56 (1H, dd, J
= 3.0 Hz, 9.0 Hz), 8.09 (1H, d, J = 2.8 Hz) .3) ¹ H NMR (d ppm in CDCl ₃ ): 1.32 (3H, t, J = 7.0 Hz),
2.69 (2H, t, J = 7.0 Hz), 3.25 (2H, t, J = 6.9 Hz), 3.5
1 (4H, t, J = 5.0 Hz), 3.84 (4H, t, J = 4.8 Hz), 4.11 (3
H, s), 4.28 (2H, q, J = 7.0 Hz), 6.66 (1H, d, J = 9.2 H
z), 7.36 (1H, s), 7.42 (1H, dd, J = 3.0 Hz, 9.2 Hz),
8.18 (1H, d, J = 2.6 Hz) .4) ¹ H NMR (d ppm in CDCl ₃ ): 1.30 (3H, t, J = 6.9 Hz),
2.57 (2H, t, J = 7.0 Hz), 3.09 (2H, t, J = 7.0 Hz), 3.3
3 (3H, s), 3.98 (3H, s), 4.26 (2H, q, J = 7.0 Hz), 6.81
(1H, dd, J = 7.8, 5.0 Hz), 7.11 (1H, dd, J = 7.7, 1.5 H
z), 7.36 (1H, s), 7.81 (1H, dd, J = 5.1, 1.5 Hz), 9.18
(1H, s) .5) ¹ H NMR (d ppm in CDCl ₃ ): 1.32 (3H, t, J = 7.2 Hz),
2.70 (2H, t, J = 6.6 Hz), 2.85 (3H, s), 3.29 (2H, t, J
= 6.6 Hz), 3.66 (2H, t, J = 6.0 Hz), 4.28 (2H, q, J = 7.2
Hz), 4.55 (2H, t, J = 6.0 Hz), 6.65-6.69 (3H, m), 6.94
(1, dd, J = 7.6,4.8 Hz), 7.11-7.19 (2H, m), 7.37 (1H,
s), 7.46 (1H, dd, J = 7.6, 1.4 Hz), 8.06 (1H, dd, J = 4.
8, 1.4 Hz).

Example 431

Embedded image 4,5-dihydro-8- (5- (4-fluorophenyl) pyridine-3-
(Iloxy) -1-methyl-1H-thieno [3,4-g] indazole-
6-carboxylic acid: 3- (4-fluorophenyl) -5-hydroxypyridine (1.35 g) in N-methylpyrrolidone (12 ml) solution
Potassium t-butoxide (0.80 g) was added, and the mixture was stirred at room temperature for 10 minutes. The compound (2.04 g) obtained in Example 12a was added to the reaction solution, and the mixture was stirred at 100 ° C. for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract is washed with saturated saline and then dried
(MgSO ₄ ) and the solvent were distilled off. The residue was subjected to silica gel column chromatography, and ethyl acetate-n-hexane
From the fraction eluted from (1: 1), 4,5-dihydro-8- (5- (4-
(Fluorophenyl) pyridin-3-yloxy) -1-methyl-1
1.27 g of ethyl H-thieno [3,4-g] indazole-6-carboxylate was obtained. Ethanol (6 ml) and THF (9 m
l), add 2N aqueous potassium hydroxide solution (3 ml) and add
For 1 hour. The reaction solution was cooled, neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration to give the title compound (0.78 g, 31%) as colorless crystals. ^{1 H NMR (d ppm in DMSO} -d 6): 2.66 (2H,
t, J = 6.8 Hz), 3.18 (2H, t, J = 6.8 Hz), 4.01 (3H, s),
7.32-7.40 (3H, m), 7.83-7.90 (2H, m), 8.21-8.23 (1H,
m), 8.67 (1H, d, J = 2.6 Hz), 8.87 (1H, d, J = 2.2 Hz).

The compounds of Examples 432 to 451 were synthesized in the same manner as in Example 172.

[Table 43]

[0402]

[Table 44]

1) ¹ H NMR (d in CDCl ₃ ): 2.63 (2H, t, J =
6.8 Hz), 3.16 (2H, t, J = 6.8 Hz), 4.03 (3H, s), 6.34
(2H, brs), 6.58 (1H, dd, J = 7.9, 4.9 Hz), 7.49 (1H,
d, J = 8.0Hz), 7.88 (1H, dd, J = 4.8, 1.4 Hz).

Embodiment 452

Embedded image 4,5-dihydro-1-methyl-8-((5- (4-morpholinyl) -3-pyridinyl) oxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid hydrochloride: 5- A solution of (4-morpholinyl) -3-hydroxypyridine (0.85 g) in N-methylpyrrolidone (25 ml) was ter
Potassium t-butoxide (0.53 g) was added, and the mixture was stirred at room temperature for 10 minutes. Next, the compound obtained in Reference Example 78 (1.61 g) was added at 90 ° C.
After stirring for 7 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed successively with water, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residual oil was subjected to silica gel column chromatography, and from the portion eluted with ethyl acetate: hexane (1: 3), 4,5-dihydro-1-methyl-8-((5- (4-morpholinyl) -3
-Pyridinyl) oxy) -1H-thieno [3,4-g] indazole-6
-Carboxylic acid ethyl ester was obtained as an oil. This was dissolved in ethanol (20 ml) and 2N aqueous potassium hydroxide solution (2
ml), and the mixture was stirred at room temperature for 12 hours. 2N hydrochloric acid (3m
After l) was added, the mixture was concentrated, and the precipitated crystals were collected by filtration. water,
After washing with ethyl acetate, the title compound (0.67 g, 32%) was obtained as colorless needles. Melting point: 303-305 ℃

Example 453

Embedded image 4,5-dihydro-1-methyl-8-({2- [2- (2-oxo-1-pyrrolidinyl) ethoxy] -3-pyridinyl} oxy) -1H-thieno [3,
4-g] indazole-6-carboxylic acid: 2- [2- (2-oxo-1-pyrrolidinyl) ethoxy] -3-hydroxypyridine (1.98 g)
To a solution of N-methylpyrrolidone (30 ml) was added potassium tert-butoxide (1.07 g), and the mixture was stirred at room temperature for 10 minutes. Next, Reference Example 7
The compound obtained in 8 (2.88 g) was added, and the mixture was stirred at 90 ° C. for 7 hours, and then poured into water and extracted with ethyl acetate. The extract was washed successively with water, an aqueous sodium hydrogen carbonate solution and saturated brine, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residual oil was subjected to silica gel column chromatography. From the portion eluted from ethyl acetate: hexane (1: 3), 4,5-dihydro-1-methyl-8-({2- [2- (2-oxo- 1-Pyrrolidinyl) ethoxy] -3-pyridinyl} oxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester was obtained as an oil. Ethanol (20 ml) and tetrahydrofuran
(20 ml) and 2N aqueous potassium hydroxide solution (6 ml)
Was added and stirred at room temperature for 12 hours. After adding 2N hydrochloric acid (7 ml) to the reaction mixture, the mixture was concentrated and the precipitated crystals were collected by filtration. Washing with water and ethyl acetate gave the title compound (2.13 g, 55%) as colorless needles. Melting point: 202-204 ° C

Compounds of Examples 454 to 473 were synthesized in the same manner as in Example 211.

[Table 45]

[0407]

[Table 46]

[Table 47]

Example 474

Embedded image 4,5-dihydro-8-hydroxy-1-methyl-1H-thieno [3,4-
g] Indazole-6-carboxylic acid ethyl ester: To a solution of 10 g of the compound obtained in Example 265 in ethanol (200 ml) was added palladium carbon (2 g), and the mixture was added under hydrogen pressure (0.5 g).
(Pa) for 4 hours. The insolubles were removed by filtration, and the filtrate was concentrated to obtain crystals. Recrystallization from tetrahydrofuran gave the title compound (6.95 g, 46%) as colorless prisms. Melting point: 203-205 ° C

Example 475

Embedded image 4,5-dihydro-8- (pyrimidin-2-yloxy) -1-methyl-
1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: A solution of the compound obtained in Example 474 (1.82 g) and sodium fluoride (0.75 g) in DMF (30 ml) at 90 ° C. for 30 minutes. After stirring for 2 minutes, 2-chloropyrimidine (0.75 g) was added, and the mixture was added at 90 ° C for 20 minutes.
Stirred for hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water, and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure.
The title compound (0.75 g, 32%) was obtained as yellow needles. Melting point: 200-202 ° C.

Example 476

Embedded image 4,5-dihydro-8- (pyrimidin-2-yloxy) -1-methyl-
1H-thieno [3,4-g] indazole-6-carboxylic acid: Compound (1.00 g) obtained in Example 475, 2N aqueous potassium hydroxide solution (3.2 ml), ethanol (10 ml) and tetrahydrofuran (10 ml). The mixed solution was stirred at 50 ° C. for 12 hours. The reaction solution was acidified by adding 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried (MgSO ₄ ), and the solvent was concentrated under reduced pressure to obtain crystals. Recrystallization from tetrahydrofuran gave the title compound (0.50 g, 54%) as colorless needles. Melting point: 256-258 ° C

Example 477

Embedded image 4,5-dihydro-8- (pyrimidin-2-yloxy) -1-methyl-
1H-thieno [3,4-g] indazole-6-carboxamide:
Compound obtained in Example 476 (0.49 g), HOBt-NH ₃ (0.14 g)
And a solution of WSC (0.17 g) in DMF (15 ml) was stirred at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure to give the title compound (0.12 g, 24%) as colorless prisms. Melting point: 26
5 ° C (decomposition) (recrystallization solvent: ethyl acetate-isopropyl ether)

Example 478

Embedded image 4,5-dihydro-8-{[6- (4-fluorophenyl) -3-pyridinyl] oxy} -1-methyl-1H-thieno [3,4-g] indazole-
6-carboxamide: the compound obtained in Example 461 (1.08
g), 4-fluorophenylboronic acid (0.50 g), tetrakis (triphenylphosphine) palladium (0.17 g), 2
A mixture of N sodium carbonate (3.6 ml), dimethoxyethane (12 ml) and dimethylacetamide (6 ml) was heated under reflux overnight, poured into water and the precipitated crystals were collected by filtration. Recrystallized from chloroform-ethyl acetate, the title compound (0.71 g, 54
%) As colorless crystals. Melting point: 236-237 ° C.

The compounds of Examples 479 to 482 were synthesized in the same manner as in Example 478.

[Table 48]

Example 483

Embedded image 4,5-dihydro-1-methyl-8- (2-pyridinylsulfanyl)
-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: To a solution of 2-pyridinethiol (1.72 g) in N-methylpyrrolidone (35 ml) was added potassium tert-butoxide (1.81 g). Stirred at C for 30 minutes. Next, the compound (5.00 g) obtained in Reference Example 78 was added, and the mixture was stirred at 100 ° C. for 4 hours, and then poured into water and extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residual oil was subjected to silica gel column chromatography, and the title compound (5.08 g, 93%) was obtained as a colorless oil from the fraction eluted with ethyl acetate: hexane (2: 3). ¹ H NMR
(d ppm in CDCl ₃ ): 1.38 (3H, t, J = 7.4 Hz), 2.67 (2H,
t, J = 6.6 Hz), 3.27 (2H, t, J = 6.6 Hz), 4.10 (3H, s),
4.36 (2H, q, J = 7.4 Hz), 6.95 (1H, dt, J = 8.0, 1.0 H
z), 7.02-7.09 (1H, m), 7.52 (1H, td, J = 8.0, 1.8 Hz),
8.42-8.46 (1H, m).

Example 484

Embedded image 4,5-dihydro-1-methyl-8- (2-pyridinylsulfanyl)
-1H-thieno [3,4-g] indazole-6-carboxylic acid: 4,5-dihydro-1-methyl-8- (2-pyridinylsulfanyl) -1H-thieno [3,4-g] indazole -6-Carboxylic acid ethyl ester (5.00 g) was dissolved in a mixture of ethanol (30 ml) and THF (10 ml), and an aqueous potassium hydroxide solution (30 ml) was added at room temperature.
Stir for 14 hours. The reaction solution was acidified with 2N hydrochloric acid and extracted with a mixed solution of ethyl acetate-THF. The organic layer was washed with water and saturated saline, and then dried (MgSO ₄ ) and the solvent was distilled off. The obtained crystals were recrystallized from THF to give the title compound (2.73 g, 59%) as colorless prisms. Melting point: 231-232 ° C

Embodiment 485

Embedded image 4,5-dihydro-1-methyl-8- (2-pyridinylsulfanyl)
-1H-thieno [3,4-g] indazole-6-carboxamide: To a solution of the compound obtained in Example 484 (1.50 g) in THF (50 ml) was added oxalyl chloride (1.2 ml) under ice-cooling. Plus 30
Minutes. The reaction solution was concentrated under reduced pressure, and the residue was washed with THF (30 m
A 25% aqueous ammonia solution (3 ml) was added to the solution dissolved in l), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried (MgS
O ₄ ) The solvent was distilled off. The obtained crystals were recrystallized from THF-IPE to give the title compound (0.71 g) as colorless prisms.
Melting point: 234-236 ° C.

The following compounds were synthesized in the same manner as in Example 485.

[Table 49]

Example 489 1-methyl-8- (propylsulfanyl) -1H-thieno [3,4-g]
Indazole-6-carboxamide: A solution of the compound obtained in Example 52 (0.33 g) and manganese dioxide (1.5 g) in dichloromethane (30 ml) was heated under reflux for 4 days. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. From the part eluted with ethyl acetate, the title compound (39 mg, yield 12%) was obtained as pale brown crystals. Melting point: 165-166 ° C.

Example 490

Embedded image 1-methyl-8-methylsulfonyl-4,5-dihydro-1H-thieno
[3,4-g] indazole and 8- (6-methoxypyridine-2-
(Iloxy) -1-methyl-4,5-dihydro-1H-thieno [3,4-g]
Indazole-6-carboxylic acid ethyl ester 2-hydroxy-3-methoxypyridine (2.76 g) in 1-methyl-2
-Pyrrolidone (50 ml) was dissolved in potassium t-butoxide (2.69 g), and the mixture was stirred at 70 ° C. for 20 minutes.
Was added and the mixture was stirred at 120 ° C. for 8 hours. The reaction solution was poured into water, and the precipitated solid was collected by filtration. This solid was dissolved in ethyl acetate, washed successively with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 1-methyl-8-methylsulfonyl-4,5-dihydro-1H-thieno [3,4-g] indazole was obtained from the portion obtained from ethyl acetate: hexane (1: 4). 1.
60 g and 8- (6-methoxypyridin-2-yloxy) -1-methyl-4,5-dihydro-1H-thieno [3,4-g] indazole-6-
1.79 g (21%) of the carboxylic acid ethyl ester were obtained. 1-methyl-8-methylsulfonyl-4,5-dihydro-1H-thieno
[3,4-g] indazole: melting point: 192-193 ° C. 1H-NMR (d ppm
in CDCl ₃ ): 2.60-2.27 (4H, m), 3.25 (3H, s), 4.13 (3H,
s), 7.45 (1H, d, J = 7.8 Hz). 8- (6-methoxypyridin-2-yloxy) -1-methyl-4,5-
Dihydro-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: mp 163-164 ° C. ¹ H-NMR (d ppmin CD
Cl ₃ ): 1.38 (3H, t, J = 7.2 Hz), 2.68 (2H, t, J = 6.6 Hz), 3.
25 (2H, t, J = 6.6 Hz), 3.97 (3H, s), 4.11 (3H, s), 4.34 (2
H, q, J = 7.2 Hz), 6.57-7.00 (2H, m), 7.37 (1H, s), 7.66 (1
(H, t, J = 8.1 Hz).

Example 491

Embedded image 1-methyl-8-methylsulfonyl-4,5-dihydro-1H-thieno
[3,4-g] indazole-6-sulfonyl chloride The compound (0.50 g) obtained in Example 490 was added little by little to fuming sulfuric acid (2.4 ml) cooled to -10 ° C, and gradually returned to 8 ° C. Stir for 1 hour. Thionyl chloride (9.6 ml) was added to this solution, and the mixture was heated under reflux for 1 hour. Then, thionyl chloride was distilled off under reduced pressure, and the residue was poured into ice water and extracted with dichloromethane. The extract was washed with water and saturated saline, dried (MgSO ₄ ), and the solvent was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 0.46 g (67%) of the title compound as pale yellow needles. Melting point: 81-82 ° C. ¹ H-NMR (d ppm in CDCl ₃ ): 2.78 (2H, dd,
J = 8.4, 6.2 Hz), 3.16 (2H, dd, J = 8.4, 6.2 Hz), 3.32
(3H, s), 4.12 (3H, s), 7.53 (1H, s).

Example 492

Embedded image 1-methyl-8-methylsulfonyl-4,5-dihydro-1H-thieno
[3,4-g] indazole-6-sulfonamide A 25% aqueous ammonia solution (1 ml) was added to a solution of the compound (0.20 g) obtained in Example 491 in THF (10 ml) under ice-cooling, and the mixture was added at room temperature for 30 minutes. Stir for minutes and extract with ethyl acetate. The extract was washed with water and saturated saline, dried (MgSO ₄ ), and concentrated under reduced pressure to obtain 0.17 g (89%) of the title compound. Melting point: 228-229 ° C. ¹ HN
MR (d ppm in CDCl ₃ ): 2.61 (2H, t, J = 7.2 Hz), 2.93 (2H,
t, J = 7.2 Hz), 3.61 (3H, s), 4.00 (3H, s), 7.51 (1H, s),
8.17 (2H, s).

Example 493

Embedded image 8- (4-fluorophenoxy) -1-methyl-4,5-dihydro-1H-
Thieno [3,4-g] indazole-6-carboxylic acid In the same manner as in Example 172, the title compound (yield: 100%) was obtained as colorless prism crystals from the compound obtained in Example 292. Melting point: 266-268 ℃

Example 494

Embedded image 8- (4-fluorophenoxy) -1-methyl-4,5-dihydro-1H-
Thieno [3,4-g] indazole-6-carboxamide In the same manner as in Example 211, the title compound (yield: 95%) was obtained as colorless prisms from the compound obtained in Example 493. Melting point: 188-189 ℃

Example 1a

Embedded image Production of 4,5,6,7-tetrahydro-3-methylsulfanyl-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: Potassium carbonate (anhydrous) (210 g) was placed in a four-neck flask (5 L) under an argon atmosphere. , 1.50 mol), N, N-dimethylformamide (9
0ml), 1,3-cyclohexanedione (12.3g, 0.55mol, 1.1e
q) was charged and stirred at room temperature (29 ° C.) for 12 minutes. Carbon disulfide
(36 ml, 0.60 mol, 1.2 eq) was added all at once, and the mixture was stirred at room temperature for 15 minutes. A solution of ethyl chloroacetate (61.5 g, 0.50 mol) / N, N-dimethylformamide (500 ml) was added dropwise at 35 ° C. or lower over 2 hours and 40 minutes, and washed with N, N-dimethylformamide (25 ml). After stirring the reaction mixture at room temperature for 20 minutes, it was cooled on ice, and methyl iodide (34 ml, 0.55 mol) was added dropwise over 12 minutes (4 ° C. → 9 ° C.).
The reaction mixture was heated to 50 ± 2 ° C and reacted for 4 hours. The reaction solution was cooled, and water (2.5 L) was added dropwise over 30 minutes (6 ° C. → 18 ° C.). Stirred overnight at room temperature. The crystals were collected by filtration and washed with water (1 L × 2). Vacuum-dried at 40 ° C for 16 hours to obtain light brown crude crystals (111.3 g,
Yield 82.3%). The crude crystals (111.3 g) were added to ethyl acetate.
(1.35 L) and washed with water (1.0 L). Activated carbon (13.5 g, white heron A) was added to the ethyl acetate layer, and the mixture was stirred at room temperature for 30 minutes. The activated carbon was removed by filtration and washed with ethyl acetate (750 ml).
The filtrate (red) was combined and concentrated to dryness. Methanol (650m
Heated (60 ° C) in l) to dissolve. Slowly cooled to room temperature (about 4
Crystals precipitated at 7 ° C). The mixture was ice-cooled and stirred at 5 ° C or lower for 1 hour. The crystals were collected by filtration and washed with ice-cooled methanol (200 ml). After vacuum drying at 40 ° C for 18 hours, the title compound (101.7 g, yield 75.2%) was obtained as pale yellow crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 2.05 (2
H, quint, J = 6.7Hz), 2.54 (2H, t, J = 6.7Hz), 2.60 (3H, s),
3.19 (2H, t, J = 6.7Hz), 4.33 (2H, q, J = 7.1Hz)

Example 2a

Embedded image Production of 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: The compound obtained in Example 1a (10.8 g, 39.9 mmol) was treated with dichloromethane ( 300 ml), and 70% metachloroperbenzoic acid (21.7 g) was gradually added under ice-cooling (3 ° C. → 9 ° C.). Stirred overnight at room temperature. The reaction solution was diluted with saturated aqueous sodium bicarbonate (200 ml × 2) and water (2
00 ml). After drying using magnesium sulfate, the magnesium sulfate was removed by filtration and dichloromethane (30 ml)
And washed. The filtrates were combined and concentrated to dryness. Vacuum dried at 40 ° C for 5 hours to give the title compound (1
2.3 g) were obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64 (3H, t, J = 7.1 Hz), 2.39 (2
H, quint, J = 6.5Hz), 2.92 (2H, t, J = 6.5Hz), 3.52 (2H, t, J =
6.5Hz), 3.78 (3H, s), 4.63 (2H, q, J = 7.1Hz)

Example 3a

Embedded image Preparation of 4,5,6,7-tetrahydro-3-methylsulfonyl-4-oxobenzo [c] thiophen-1-carboxylic acid ethyl ester: The compound (10.8 g, 40.0 mmol) obtained in Example 1a was trifluoro Dissolved in acetic acid (92 ml, 1.20 mol, 30 eq). Under ice-cooling, 30% aqueous hydrogen peroxide (14 g, 123 mmol, 3 eq) was added dropwise.
The mixture was stirred at room temperature for 2 hours and 40 minutes. After the reaction, cool and add 8M
An aqueous sodium hydroxide solution (161 ml) was added dropwise to neutralize. water
(150 ml) was added, the crystallized solution was loosened, and the mixture was stirred at room temperature for 1 hour. The crystals were collected by filtration and washed with water (100 ml). After vacuum drying at 40 ° C. for 3 hours, the title compound (8.53 g, yield 70.6%) was obtained as tan crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64 (3H, t, J = 7.1 Hz), 2.39 (2
H, quint, J = 6.5Hz), 2.92 (2H, t, J = 6.5Hz), 3.52 (2H, t, J =
6.5Hz), 3.78 (3H, s), 4.63 (2H, q, J = 7.1Hz)

Example 4a

Embedded image 3- (3,4-dimethoxyphenoxy) -4,5,6,7-tetrahydro-
Production of 4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: 3,4-dimethoxyphenol (10.2 g, 66.2 mmo
1,1.1 eq) was dissolved in tetrahydrofuran (dehydrated) (728 ml), and potassium t-butoxide (7.42 g, 66.2 mmol, 1.1 eq) was added (25 ° C. → 29 ° C.). After stirring at room temperature for 30 minutes, the compound obtained in Reference Example 89 (18.2 g, 60.1 mmol) was slowly added. The reaction was performed at room temperature for 4 hours. The reaction solution was concentrated to give a residue (69.5 g). Tetrahydrofuran (107 ml) was added to the obtained paste-like concentrated residue. Water (292 ml) was added dropwise over 20 minutes. Stirred at room temperature for 1 hour. The crystals were collected by filtration and washed with tetrahydrofuran-water (1: 3) (90 ml) and water (90 ml). 40 ℃
For 9 hours in vacuo to give the title compound (2
0.1 g, yield 88.7%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 2.07 (2
H, quint, J = 6.5Hz), 2.57 (2H, t, J = 6.5Hz), 3.22 (2H, t, J =
6.5Hz), 3.87 (3H, s), 3.91 (3H, s), 4.26 (2H, q, J = 7.1H
z), 6.83-6.91 (3H, m)

Example 5a

Embedded image 5-diethoxymethyl-3- (3,4-dimethoxyphenoxy) -4,
5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-
Preparation of carboxylic acid ethyl ester: under argon atmosphere,
Triethyl orthoformate (9.2 ml, 8.27 g, d 0.896, 2.0 eq) and dichloromethane (31 ml) were charged and cooled to -40 ° C. Boron trifluoride diethyl ether complex (8.7 ml, 9.89 g, d 1.13
7,69.7 mmol, 2.5 eq) was added dropwise. The mixture was heated to 0 ° C and stirred for 15 minutes. After cooling to -75 ° C, the compound obtained in Example 4 (10.5 g, 27.9 m
mol) / dichloromethane (32 ml) solution was added dropwise over 14 minutes (up to -64 ° C at the highest) and washed with dichloromethane (10 ml). Then N-ethyldiisopropylamine (7.6 ml, 10.82
g, d 1.416, 83.7 mmol, 3.0 eq) was added dropwise in 10 minutes (the highest time was raised to -65 ° C). The reaction was performed at -60 to -70 ° C for 3 hours. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate (300 ml), and the mixture was stirred and separated. The organic layer was washed with 1N hydrochloric acid (100 ml) and pure water (300 ml). The organic layer was dried with magnesium sulfate. The magnesium sulfate was removed by filtration and washed with dichloromethane (30 ml). The filtrate was concentrated, and the residue was dissolved by adding tetrahydrofuran (30 ml). Water (150 ml) was added dropwise, and the mixture was stirred overnight at room temperature (after the addition of water, a candy-like substance precipitated and gradually crystallized). Filter the crystals,
Washed with water (40 ml × 2). Vacuum dried at 40 ° C for 13 hours to give the title compound as a slightly yellow-brown crystalline powder (12.72 g, yield 95.3%)
I got ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.18 (3H, t, J = 7.0 Hz), 1.26
(3H, t, J = 7.0Hz), 1.30 (3H, t, J = 7.1Hz), 2.05-2.35 (2H,
m), 2.71 (1H, ddd, J = 3.9,4.1,10.3Hz), 2.90 (1H, ddd, J =
5.0,11.0,18.0Hz), 3.50-4.00 (5H, m), 3.87 (3H, s), 3.9
1 (3H, s), 4.26 (2H, q, J = 7.1Hz), 5.16 (1H, d, J = 3.2Hz),
6.82-6.90 (3H, m)

Example 6a

Embedded image 3- (3,4-dimethoxyphenoxy) -5-ethoxymethylidene-
4,5,6,7-tetrahydro-4-oxobenzo [c] thiophene-1
-Preparation of carboxylic acid ethyl ester: To the compound obtained in Example 5a (437 mg, 0.913 mmol) was added methanesulfonic acid (1.7 ml,
29.5 eq) and stirred at room temperature for 10 minutes. After cooling on ice, ethanol (5.1 ml) was added dropwise (crystal precipitation, pale yellow-brown suspension). The mixture was stirred for 1 hour under ice cooling. The crystals were collected by filtration and washed with ice-cooled ethanol (3 ml). After vacuum drying at 40 ° C. for 7 hours, the title compound (345 mg, yield 87.4%) was obtained as slightly brown crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 1.37 (3
H, t, J = 7.1Hz), 2.68 (2H, t, J = 6.3Hz), 3.21 (2H, t, J = 6.9H
z), 3.86 (3H, s), 3.91 (3H, s), 4.14 (2H, q, J = 7.1Hz), 4.
25 (2H, q, J = 7.1Hz), 6.83-6.88 (3H, m), 7.54 (1H, s)

Example 7a

Embedded image 8- (3,4-dimethoxyphenoxy) -4,5-dihydro-1-methyl
Production of -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Compound obtained in Example 5a (12.7 g, 26.5 m
mol) was added to methanesulfonic acid (31.8 ml), and the mixture was stirred at room temperature for 10 minutes (black-brown solution). Cool on ice and add ethanol (159 ml) in 1
It was added dropwise over 5 minutes (heat generation, crystallization in the middle, pale yellow-brown suspension). Under ice cooling, methylhydrazine (5.6 ml, 106 mmol, 4 eq) /
An ethanol (31.8 ml) solution was added dropwise over 33 minutes (further increase in precipitates). The reaction was heated to 50-60 ° C and stirred for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure. The residue was suspended in ethyl acetate (190 ml) and slowly poured into a suspension of baking soda (45.3 g, 0.539 mol, 1.1 eq based on methanesulfonic acid) / water (254 ml) (vigorous foaming). The organic layer was separated, and saturated saline (254
ml). The organic layer was concentrated under reduced pressure, and acetonitrile (33 ml) was added to the residue (dark brown oil), which was dissolved by heating (reflux). Crystals were precipitated immediately after slow cooling, and the temperature was returned to room temperature. The mixture was stirred for 1 hour under ice cooling. The crystals were collected by filtration and washed with ice-cooled acetonitrile (9 ml). After vacuum drying at 40 ° C. for 9 hours, the title compound (9.24 g, yield 84.0%) was obtained as slightly brown crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3 H, t, J = 7.1 Hz), 2.70 (2
(H, t, J = 7.0Hz), 3.25 (2H, t, J = 7.0Hz), 3.88 (3H, s), 3.90
(3H, s), 4.11 (3H, s), 4.28 (2H, q, J = 7.1Hz), 6.75-6.88
(3H, m), 7.36 (1H, s)

Example 8a

Embedded image Preparation of ethyl 3- (3,4-dimethoxyphenoxy) -5-dimethylaminomethylidene-4,5,6,7-tetrahydro-4-oxobenzo [c] thiophen-1-carboxylate: Example 4a
N, N-dimethylformamide (30 ml) and N, N-dimethylformamide dimethyl acetal (17.8 ml, d 0.89, 15.8 g, 133 mmol, 10 eq) were added to the compound (5.0 g, 13.28 mmol) obtained at It became cloudy (light purple). The reaction was heated to 100 ° C. and stirred for 4 hours. N, N-dimethylformamide dimethyl acetal (3.6 ml, 2 eq) was added, and the mixture was further stirred at 100 ° C. for 2 hours. After cooling, water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 2). The organic layers were combined and washed with a saturated saline solution (100 ml). Activated carbon (1.0 g) was added to the organic layer, followed by filtration. After washing with ethyl acetate (20 ml), the filtrate was concentrated under reduced pressure. Ethyl acetate (20 ml) was added to the residue and suspended under reflux. The mixture was cooled and stirred for 1 hour under ice cooling. Filter the crystals,
It was washed with ice-cooled ethyl acetate (5 ml). Vacuum dried at 40 ° C for 15 hours to give the title compound as yellow crystals (2.58 g, yield 45.0
%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.1 Hz), 2.87 (2
H, t, J = 6.7Hz), 3.13 (6H, s), 3.18 (2H, t, J = 6.7Hz), 3.85
(3H, s), 3.89 (3H, s), 4.25 (2H, q, J = 7.1Hz), 6.75-6.95
(3H, m), 7.63 (1H, s)

Example 9a

Embedded image 8- (3,4-dimethoxyphenoxy) -4,5-dihydro-1-methyl
Production of -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: Compound obtained in Example 8a (0.50 g, 1.16m
mol) were suspended in ethanol (5 ml). Under cooling with ice, methanesulfonic acid (0.25 ml, d 1.48, 370 mg, 3.85 mmol, 3.3 eq) was added. It dissolved and became brown and transparent. Under ice cooling, methylhydrazine (0.06 ml, d 0.87, 53.4 mg, 464 mmol, 4 eq) /
An ethanol (1.25 ml) solution was added dropwise at 10 ° C or lower. White smoke was generated and crystals precipitated. Heated to 50-60 ° C and stirred for 1.5 hours. After cooling, the reaction solution was diluted with 5N aqueous sodium hydroxide.
The pH was adjusted to 8. Ethyl acetate (5 ml) and water (10 ml) were added and stirred. After standing, the organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (5 ml). Combine the organic layers and add saturated saline (10
ml). The organic layer was concentrated under reduced pressure, and acetonitrile (1 ml) was added to the residue (0.54 g) and dissolved by heating (reflux).
The mixture was gradually cooled and stirred for 1 hour under ice cooling. The crystals were collected by filtration and washed with ice-cooled acetonitrile (1 ml). After vacuum drying at 40 ° C. for 8 hours, the title compound (0.365 g, yield 75.9%) was obtained as crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3 H, t, J = 7.1 Hz), 2.70 (2
(H, t, J = 7.0Hz), 3.25 (2H, t, J = 7.0Hz), 3.88 (3H, s), 3.90
(3H, s), 4.11 (3H, s), 4.28 (2H, q, J = 7.1Hz), 6.75-6.88
(3H, m), 7.36 (1H, s)

Example 10a

Embedded image 5-dimethylaminomethylidene-4,5,6,7-tetrahydro-3-
Production of methylthio-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: Compound (8) obtained in Example 1a
2.0 g, 0.303 mol) in N, N-dimethylformamide (328 ml)
And trisdimethylaminomethane (161 ml, d 0.82,
132.0 g, 0.909 mol, 3 eq) was added. When trisdimethylaminomethane was added, the yellow suspension was almost dissolved. The reaction was heated to 70 ± 5 ° C. and stirred for 3 hours.
Ice cooled. At this time, a large amount was precipitated and hardened. At this time, the color was reddish brown. Water (1.15 L) was added dropwise in 50 minutes. The addition of water generated heat and white smoke. The reaction liquid became a suspension. The mixture was stirred for 2 hours under ice cooling. Filter the crystals, and add water (550m
Washed in l). After vacuum drying at 40 ° C. for 9 hours, the title compound (94.1 g, yield 95.3%,) was obtained as brown crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 2.58
(3H, s), 2.87 (2H, t, J = 6.7Hz), 3.11 (6H, S), 3.17 (2H, t,
J = 6.7Hz), 4.32 (2H, q, J = 7.1Hz), 7.58 (1H, s)

Example 11a

Embedded image 4,5-dihydro-1-methyl-8-methylthio-1H-thieno [3,4-
g] Production of indazole-6-carboxylic acid ethyl ester:
Ethanol (740 ml) was added to the compound (74.0 g, 0.227 mmol) obtained in Example 10a, and the mixture was stirred at room temperature. It became a suspension. Methylhydrazine (25.5ml, d 0.87, 21.0g, 0.45
5 mol, 2 eq) was added. Cool on ice and add 4M hydrochloric acid (171ml, 0.682m
ol, 3eq) was added dropwise. It generated heat with the generation of white smoke and rose to 42 ° C. A part thereof dissolved to form a reddish brown suspension.
Heated to 50-60 ° C and stirred for 1 hour. Dissolved and became reddish brown transparent. After cooling, the reaction solution was adjusted to pH 7 with a 5M aqueous sodium hydroxide solution (45 ml). Water (894 ml) is added dropwise, and ice-cooled
Stir for 1.5 hours. The crystals were collected by filtration and ice-cooled ethanol
-Washed with water (1: 2) (200 ml). The crystals were dried under vacuum at 40 ° C. for 9 hours to give the title compound (68.2 g, yield 97.3%) as dark brown crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39 (3H, t, J = 7.1 Hz), 2.59 (3
H, s), 2.61 (2H, t, J = 6.7Hz), 3.17 (2H, t, J = 6.7Hz), 4.16
(3H, s), 4.37 (2H, q, J = 7.1Hz), 7.40 (1H, s)

Example 12a

Embedded image 4,5-dihydro-1-methyl-8-methylsulfonyl-1H-thieno
Production of [3,4-g] indazole-6-carboxylic acid ethyl ester: Concentrated sulfuric acid (6 ml) was added dropwise to acetic acid (24 ml) under ice cooling. The compound obtained in Example 11a (10.0 g, 32.4 mmol) was slowly added. Under ice cooling, 30% aqueous hydrogen peroxide (11.0 g, 97.0 mmol,
3eq) was added dropwise in 30 minutes. The mixture was gradually heated and stirred at 50 to 55 ° C for 3 hours. After the reaction, cool on ice and add ethanol (30 ml) to the reaction solution.
Was added dropwise, and a 5M aqueous sodium hydroxide solution (115 ml) was added dropwise to adjust the pH to 7.
Was prepared. Water (24 ml) was added, the crystallized solution was loosened, and the mixture was stirred at room temperature for 1 hour. The crystals are collected by filtration and ethanol-water (1: 4)
(15 ml) and water (60 ml). After vacuum drying at 40 ° C. for 6 hours, the title compound (10.4 g, yield 94.3%) was obtained as pale yellow crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (3 H, t, J = 7.1 Hz), 2.66 (2
H, t, J = 6.7Hz), 3.18 (2H, t, J = 6.7Hz), 3.26 (3H, s), 4.09
(3H, s), 4.40 (2H, q, J = 7.1Hz), 7.47 (1H, s)

Example 13a

Embedded image 8- (3,4-dimethoxyphenoxy) -4,5-dihydro-1-methyl
Preparation of -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: 3,4-dimethoxyphenol (2.49 g, 16.16
mmol, 1.1 eq) was dissolved in N-methylpyrrolidone (80 ml) and potassium t-butoxide (1.81 g, 16.16 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 30 minutes (from purple transparent to blackish brown), and the compound (5.0 g, 14.69 mmol) obtained in Reference Example 99 was added. The mixture was stirred at room temperature for 30 minutes and at 80 to 85 ° C for 4 hours. After returning to room temperature, water (160 ml) was added dropwise over 20 minutes. When water was added dropwise, crystals precipitated. The mixture was stirred for 1 hour under ice cooling. The crystals were collected by filtration and washed with water (80 ml). The crystals were dried under vacuum at 40 ° C. to give the title compound (4.37 g, yield 71.8%) as slightly brown crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3 H, t, J = 7.1 Hz), 2.70 (2
(H, t, J = 7.0Hz), 3.25 (2H, t, J = 7.0Hz), 3.88 (3H, s), 3.90
(3H, s), 4.11 (3H, s), 4.28 (2H, q, J = 7.1Hz), 6.75-6.88
(3H, m), 7.36 (1H, s)

Example 14a

Embedded image Production of 4,5-dihydro-1-methyl-8- (3,4-methylenedioxyphenoxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester: obtained in Example 12a Compound (2.
0g) and 3,4-methylenedioxyphenol from Example 13a
In a similar manner to the above, the title compound (1.54 g, yield 65.8%) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (3 H, t, J = 7.1 Hz), 2.68 (2
(H, t, J = 7.0Hz), 3.23 (2H, t, J = 7.0Hz), 4.07 (3H, s), 4.27
(2H, q, J = 7.1Hz), 6.00 (2H, s), 6.64-6.79 (3H, m), 7.34 (1
H, s).

Example 15a

Embedded image 4,5-dihydro-1-methyl-8-phenoxy-1H-thieno [3,4-
g] Production of indazole-6-carboxylic acid ethyl ester:
From the compound (250 mg) obtained in Example 12a and phenol,
In the same manner as in Example 13a, the title compound (115 mg, yield 51.4
%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3 H, t, J = 7.1 Hz), 2.71 (2
(H, t, J = 7.0Hz), 3.26 (2H, t, J = 7.0Hz), 4.06 (3H, s), 4.29
(2H, q, J = 7.1Hz), 7.17-7.43 (5H, m), 7.35 (1H, s).

Example 16a

Embedded image 8- (3,4-dimethoxyphenoxy) -4,5-dihydro-1-methyl
Production of -1H-thieno [3,4-g] indazole-6-carboxylic acid amide: Compound obtained in Example 13a (1.0 g, 2.413 mmol)
To formamide (8 ml, 8 v / w), sodium methoxide (52
1 mg, 9.652 mmol, 4.0 eq) and heated at 100 ° C. for 4 hours. The reaction solution turned from yellow-brown to dark brown. Reaction solution at 75 ° C
Then, N-methylpyrrolidone (5 ml), 5 M aqueous sodium hydroxide solution (0.72 ml, 1.5 eq) and water (0.28 ml) were added. 80 ℃
For 1 hour and 30 minutes, and cooled to room temperature. Upon cooling, crystals precipitated. Water (9 ml), methyl ethyl ketone (20 ml) and ethyl acetate (10 ml) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted three times with ethyl acetate (10 ml). Combine organic layers, 0.5M
Aqueous sodium hydroxide solution 10 ml), saturated saline (10 ml), 0.1
Washed sequentially with M hydrochloric acid (10 ml), water (10 ml), and saturated saline (20 ml). Activated carbon (100 mg, white egret P) was added to the organic layer, and the mixture was stirred and removed at room temperature, and washed with ethyl acetate (5 ml). The filtrate was combined, concentrated under reduced pressure to obtain the title compound (0.87 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.70 (2H, t, J = 6.7 Hz), 3.15 (2
H, t, J = 6.7Hz), 3.86 (3H, s), 3.87 (3H, s), 4.08 (3H, s),
5.79 (2H, broad s), 6.65-6.95 (3H, m), 7.34 (1H, s)

Example 17a

Embedded image 8- (3,4-dimethoxyphenoxy) -4,5-dihydro-1-methyl
Preparation of -1H-thieno [3,4-g] indazole-6-carboxylic acid:
Ethanol (17.2 ml) was added to the compound (4.3 g, 10.4 mmol) obtained in Example 7a, followed by stirring at room temperature (suspension). A 5N aqueous sodium hydroxide solution (4.2 ml, 20.7 mmol, 2.0 eq) was added.
The reaction was heated to 60 ° C. and stirred for 30 minutes. Upon heating, it gradually dissolved and turned into a brown solution. After cooling, add 2N hydrochloric acid to the reaction solution.
(13.0 ml, 2.5 eq) was added dropwise. Fine crystals precipitated from the reaction solution, and became a highly viscous slurry (pH 1.4).
The mixture was stirred for 30 minutes under ice cooling. The crystals were collected by filtration and ethanol-water 9: 1
(5 ml). The crystals were dried under vacuum at 40 ° C. to give the title compound (3.89 g, yield 97.0%) as white crystals. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.73 (2H, t, J = 6.7 Hz), 3.25
(2H, t, J = 6.7Hz), 3.88 (3H, s), 3.89 (3H, s), 4.13 (3H,
s), 6.97-7.19 (3H, m), 7.46 (1H, s)

Example 18a

Embedded image 8- (3,4-dimethoxyphenoxy) -4,5-dihydro-1-methyl
Production of -1H-thieno [3,4-g] indazole-6-carboxylic acid amide: The compound obtained in Example 17a (1.0 g, 2.59 mmol) was converted to N,
It was suspended in N-dimethylformamide (8 ml). 1-hydroxybenzotriazole-ammonium salt (0.59 g, 3.88 mmol,
1.5 eq) was added. Almost dissolved, resulting in a yellow solution. Then N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (0.74 g, 3.88 mmol, 1.5 eq) was added. The suspension did not dissolve. The mixture was stirred at room temperature for 3 hours and 15 minutes. Water (5 ml), 5N aqueous sodium hydroxide solution (2 ml, 4 eq)
And extracted with ethyl acetate (8 ml × 6 times). The organic layers were combined and the solvent was distilled off under reduced pressure. The remaining N, N-dimethylformamide was also distilled off and evaporated. Ethanol (20ml),
Water (1 ml) was added, and the mixture was dissolved by heating (reflux). Return to room temperature,
The mixture was stirred for 30 minutes under ice cooling. The crystals were collected by filtration and washed with ice-cooled ethanol (3 ml). The crystals were dried under vacuum at 40 ° C. to give the title compound (0.80 g, yield 79.9%) as white crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.70 (2H, t, J = 6.7 Hz), 3.15 (2
H, t, J = 6.7Hz), 3.86 (3H, s), 3.87 (3H, s), 4.08 (3H, s),
5.79 (2H, broad s), 6.65-6.95 (3H, m), 7.34 (1H, s)

Example 19a

Embedded image 3- (5-chloro-3-pyridyloxy) -4,5,6,7-tetrahydro
Production of 4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester The compound obtained in Example 3a (20.0 g, 66.14 mmol), 3-chloro-5-hydroxypyridine (9.43 g, 72.76 mmol, 1.1e)
q), anhydrous potassium carbonate (45.7 g, 330.7 mmol, 5.0 eq), toluene (240 ml), and ethyl acetate (160 ml) were mixed and stirred under reflux for 3 hours. The reaction solution was returned to room temperature, water (200 ml) and 2-butanone (200 ml) were added, and the mixture was stirred for 30 minutes. Separation after standing,
The organic layer was washed sequentially with water (200 ml) and saturated saline (200 ml). The organic layer was concentrated to dryness under reduced pressure to give the title compound (21.81 g,
Yield 93.7%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33 (3H, t, J = 7.1 Hz), 2.07 (2
H, t, J = 6.3Hz), 2.53 (2H, t, J = 6.3Hz), 3.24 (2H, t, J = 6.3H
z), 4.30 (2H, q, J = 7.1Hz), 7.50-8.46 (4H, m).

Example 20a

Embedded image Preparation of 8- (5-chloro-3-pyridyloxy) -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester Obtained in Example 19a The compound (21.81 g) was dissolved in acetonitrile (80 ml), and a solution of N, N-dimethylformamidediisopropylacetal (23.5 g, 134 mmol, 2.0 eq) in acetonitrile (20 ml) was added dropwise under reflux for 4 minutes. Reflux 2
Stir for 15 minutes. Under ice cooling, methanesulfonic acid (18.9 g, 197 mmol, 3.0 eq) was added dropwise to the reaction solution. Next, methylhydrazine (68.0 mmol, 1.0 eq) was added dropwise. The mixture was stirred at 50 ° C. for 1 hour, returned to room temperature, added with water (200 ml) and ethyl acetate (200 ml), and separated. The organic layer was washed sequentially with water (200 ml) and saturated saline (200 ml). Activated carbon (4.0 g) was added to the organic layer, and the mixture was filtered and washed with ethyl acetate (20 ml). The mixture was concentrated under reduced pressure, ethanol (60 ml) was added to the residue, and the mixture was dissolved by heating. At 50 ° C., a 1 M aqueous sodium hydroxide solution (13.2 ml, 0.20 eq) was added dropwise, and the mixture was stirred for 30 minutes. After returning to room temperature, water (67 ml) was added dropwise. The mixture was stirred for 30 minutes under ice-cooling, the crystals were collected by filtration, and ice-cooled ethanol-water (1: 2) (15 m
l) and washed with water (15 ml). Drying in vacuo at 50 ° C. afforded the title compound (14.97 g, 58.0% yield) as a dark brown solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (3H, t, J = 7.1 Hz), 2.71 (2
(H, t, J = 6.9Hz), 3.26 (2H, t, J = 6.9Hz), 4.00 (3H, s), 4.31
(2H, q, J = 7.1Hz), 7.35 (1H, s), 7.44-8.42 (3H, m).

Example 21a

Embedded image Production of 4,5,6,7-tetrahydro-4-oxo-3- (4-trifluoromethylphenoxy) benzo [c] thiophen-1-carboxylic acid ethyl ester The compound obtained in Example 3a (15.12 g, 0.050 mol), 4-hydroxybenzotrifluoride (8.92 g, 0.055 mol, 1.1
eq), anhydrous potassium carbonate (20.72 g, 0.150 mol, 3.0 eq), and ethyl acetate (378 ml), stirred under reflux for 3 hours and 25 minutes, and added anhydrous potassium carbonate (6.91 g, 1.0 eq), and further 2 hours Stirred. The reaction was brought to room temperature and water (150 ml) was added.
The layers were separated, and the aqueous layer was extracted with ethyl acetate (75 ml). The organic layers were combined and washed with water (100 ml) and saturated saline (100 ml × 2). The organic layer was concentrated under reduced pressure, and ethanol was added to the residue (19.35 g).
(31 ml) was added and dissolved under reflux. Water (15 ml) was added dropwise to cause crystallization. The mixture was stirred for 1 hour under ice cooling. The crystals were collected by filtration and washed with ice-cooled ethanol-water (1: 2) (20 ml) and water (30 ml). 50 ℃
The title compound was obtained as yellow-brown crystals (15.7 g, yield 81.7%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3 H, t, J = 7.1 Hz), 2.09 (2
H, t, J = 6.3Hz), 2.53 (2H, t, J = 6.3Hz), 3.24 (2H, t, J = 6.3H
z), 4.29 (2H, q, J = 7.1Hz), 7.27-7.69 (4H, m).

Example 22a

Embedded image Production of 4,5-dihydro-1-methyl-8- (4-trifluoromethylphenoxy) -1H-thieno [3,4-g] indazole-6-carboxylic acid ethyl ester The compound obtained in Example 21a ( 1.0 g, 2.60 mmol) and toluene (6 ml) were heated to 100 ° C., and a solution of N, N-dimethylformamide diisopropyl acetal (1.37 g, 7.87 mmol, 3 eq) in toluene (6 ml) was added dropwise over 40 minutes. Stirred at 95-100 ° C for 1.5 hours. After cooling, ethanol (4 ml), methanesulfonic acid (1.5 g, 15.6 mmol, 6 eq), methylhydrazine
(0.13 ml, 2.86 mmol, 1.1 eq) were added sequentially. 50 at 50 ° C
For a minute. After cooling, water (10 ml) was added and the layers were separated. The aqueous layer was extracted with toluene (4 ml), and the organic layers were combined, water (10 ml),
Washed with saturated saline (100 ml). After concentration under reduced pressure, diisopropyl ether (2 ml) was added to the residue, and the mixture was stirred at room temperature to precipitate crystals. The mixture was stirred for 1 hour under ice cooling, and the crystals were collected by filtration.
It was washed with ice-cooled diisopropyl ether (2 ml). 40
C. in vacuo to give the title compound as pale yellow crystals (0.47 g,
Yield 43%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.1 Hz), 2.72 (2
(H, t, J = 7.0Hz), 3.29 (2H, t, J = 7.0Hz), 4.00 (3H, s), 4.32
(2H, q, J = 7.1Hz), 7.23-7.67 (4H, m), 7.36 (1H, s)

Example 23a 5-dimethylaminomethylidene-4,5,6,7-tetrahydro-3-
Production of methylthio-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: Compound obtained in Example 1a
(1.0 g, 3.70 mmol), N, N-dimethylformamide (4 ml)
, N, N-dimethylformamide diisopropyl acetal (2.32 ml, d 0.84, 1.95 g, 11.1 mmol, 3 eq). The mixture was heated to 100 ± 5 ° C and stirred for 6 hours. The reaction solution was black. When cooled, crystals precipitated, and when water (8 ml) was added dropwise, heat was generated, and further crystals precipitated. The mixture was stirred at room temperature for 2 hours and under ice cooling for 1 hour. The crystals were collected by filtration and washed with water (3 ml). After vacuum drying at 40 ° C for 5 hours, the title compound (1.114 g, yield 92.5%) was obtained as dark ocher crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 2.58
(3H, s), 2.87 (2H, t, J = 6.7Hz), 3.11 (6H, S), 3.17 (2H, t,
J = 6.7Hz), 4.32 (2H, q, J = 7.1Hz), 7.58 (1H, s)

Example 24a 5-dimethylaminomethylidene-4,5,6,7-tetrahydro-3-
Production of methylthio-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: Compound obtained in Example 1a
(1.0 g, 3.70 mmol), N, N-dimethylformamide (4 ml)
, N, N-dimethylformamide dimethyl acetal (1.5 m
l, d 0.89, 1.32 g, 11.1 mmol, 3 eq). 100 ± 5
C. and stirred for 8 hours. The reaction solution was black.
After cooling and cooling with ice, water (8 ml) was added dropwise. When water was added dropwise, heat generation and crystals precipitated. The mixture was stirred for 1 hour under ice cooling. The crystals were collected by filtration and washed with water (3 ml). Filtration was poor and time was required for filtration. The crystals were dried under vacuum at 50 ° C. for 9 hours to give the title compound (1.105 g, yield 91.8%) as dark brown crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 2.58
(3H, s), 2.87 (2H, t, J = 6.7Hz), 3.11 (6H, S), 3.17 (2H, t,
J = 6.7Hz), 4.32 (2H, q, J = 7.1Hz), 7.58 (1H, s)

Example 25a 5-dimethylaminomethylidene-4,5,6,7-tetrahydro-3-
Production of methylthio-4-oxobenzo [c] thiophene-1-carboxylic acid ethyl ester: Compound obtained in Example 1a
(5.0 g, 18.5 mmol), N, N-dimethylformamide (15 ml)
, N, N-dimethylformamide di-n-propyl acetal
(11.4 ml, d 0.89, 9.72 g, 55.5 mmol, 3 eq).
The mixture was heated to 100 ± 5 ° C. and stirred for 8 hours. The reaction solution was black. After cooling and cooling with ice, water (30 ml) was added dropwise. When water was added dropwise, heat generation and crystals precipitated. Stirred at room temperature for 2 hours.
The crystals were collected by filtration and washed with water (20 ml). Vacuum dried at 40 ° C for 7 hours to give the title compound as a dark brown crystal (5.455 g, yield 90.6
%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 2.58
(3H, s), 2.87 (2H, t, J = 6.7Hz), 3.11 (6H, S), 3.17 (2H, t,
J = 6.7Hz), 4.32 (2H, q, J = 7.1Hz), 7.58 (1H, s)

Example 26a 5-dimethylaminomethylidene-4,5,6,7-tetrahydro-3-
Preparation of methylthio-4-oxobenzo [c] thiophen-1-carboxylate ethyl ester: Compound obtained in Example 1a
(1.0 g, 3.70 mmol), N, N-dimethylformamide (3 ml)
, Methoxybis (dimethylamino) methane (1.70 ml, d 0.
86, 1.47 g, 11.1 mmol, 3 eq). Heated to 70 ± 5 ° C and stirred for 3 hours. The reaction solution was black. Upon cooling, crystals precipitated. Water (12 ml) was added dropwise while maintaining the temperature at 20 ° C. or lower. The mixture was stirred for 30 minutes under ice cooling. Filter the crystals and water
(4 ml). The crystals were dried under vacuum at 50 ° C. for 5 hours to give the title compound (1.128 g, yield 93.7%) as pale yellow-brown crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 2.58
(3H, s), 2.87 (2H, t, J = 6.7Hz), 3.11 (6H, s), 3.17 (2H, t,
J = 6.7Hz), 4.32 (2H, q, J = 7.1Hz), 7.58 (1H, s)

Test Example 1 Method for measuring mRNA amount of chondromodulin-I (ChM-I): Substrain ATDC5 derived from mouse teratocarcinoma cell AT805 was used. In the presence of the test compound, ATDC5 was added to a Dulbecco's modified Eagle medium / Ham F12 medium 1: 1 mixed medium containing 5% heat-inactivated fetal bovine serum and gentamicin 20 μg / ml.
The cells were cultured for 7 days under conditions of 37 ° C, 5% carbon dioxide, and 95% air.
After culturing, use the RNeasy mini kit (Qiagen
RNA) and then use MessageClean kit
Total RNA was prepared by performing DNase treatment with (Genhunter). The amount of ChM-I mRNA in the total RNA was measured by the RT-PCR method. First, use TaKaRa RNA PCR Kit (AM
V) cDNA was synthesized by a reverse transcription reaction using Ver.2.1 and random 9mer (manufactured by Takara Shuzo) according to the instructions of the kit. Then HotStarTaq DNA polymerase (Qiagen)
Was used to specifically amplify the ChM-I gene. ChM-
As a primer for amplifying the I gene, 1: 5′-CTAAAATCCTTGAACTCTGTGGCGACCTG-3 ′ 2: 5′-CTGCGTCGTCCTGAACATTGGGTCTGG-3 ′ was used. The amplification reaction was performed using GeneAmp PCR System 2400 (Perki
n Elmer) at 95 ° C for 15 minutes.
C., 20 seconds, 58.degree. C., 10 seconds, 72.degree. C., 30 seconds were repeated 32 times. The obtained PCR product was separated by ethidium bromide-containing 2% agarose gel electrophoresis, and the fluorescence intensity of the DNA fragment that appeared at the position corresponding to the size expected from the mouse ChM-I nucleotide sequence (212 bp) by ultraviolet irradiation was Was measured. The ChM-I expression enhancing activity of the test compound was shown by the ChM-I band concentration quantified by bioimage [Table 49]. In addition, the cell line “ATD
"C" stands for RIKEN G
ENE BANK) General Catalog No. 3 May, 1997, page 187, Cell No. = RCB0565; Cell name = ATDC5.

[0451]

[Table 50]

Test Example 2 Bone formation promoting action: Alkaline phosphatase activity was measured as an index of bone formation using stromal cells prepared from bone marrow of normal rat femur. That is, the method of Maniatopoulos et al. [Cell Tissue Research
arch), 254, 317 Tribute (1988)], according to a 7-week-old male Sprague-Dawle.
y) To prepare stromal cells from rat femur bone marrow and form dexamethasone (10
^{The cells} were cultured in an α-MEM (minimum essential medium) solution containing ⁻⁷ M) and β-glycerophosphate (10 ⁻² M). One week later, the confluent primary cells were treated with 0.25% trypsin-0.2% EDTA solution,
The cells were collected and subcultured in culture dishes at a cell density of 1.6 × 10 ⁻⁴ cells / cm ² (day 0 of culture). From the second day of the culture, a test compound (10 ⁻⁵ M) was added to the above culture solution, and further 5
Cultured for days. After washing the cells with phosphate buffer, 0.2% N
Add onidet P-40 and homogenize, 3000 rpm
The supernatant obtained after centrifugation at 10 m for 10 minutes was used and the method of Lowry et al. [Journa of Biological Chemistry (Journa
l of Biological Chemistry), Volume 207, 19 Tribute (1
954)], and alkaline phosphatase activity was measured. The measured values are shown in Table 30 as mean ± standard deviation (mean ± SE). Statistical processing is Student's t-
Performed by test.

[0453]

[Table 51] Mean ± SE (n = 4), ** p (0.01 vs control) Student's t
-test

[0454]

Industrial Applicability The compound represented by the general formula (I) or a salt thereof according to the present invention has an activity of inducing differentiation of undifferentiated cells such as osteoblasts and chondrocytes and promoting the induction of differentiation. In addition, since BMP action enhancing action is expected, it is useful as a preventive and therapeutic agent for metabolic bone diseases including osteoporosis. In addition, cell differentiation inducers having such an action include, for example, bone or cartilage formation promoters, bone diseases such as fractures, bone defects and osteoarthritis in the orthopedic field, or joint diseases typified by cartilage diseases. (Eg, osteoarthritis). Further, in the dental field, effects such as repair of periodontal tissue defects due to periodontal disease, stabilization of artificial dental roots, repair of ridge formation, and cleft palate can be expected. Further, since the compound represented by the general formula (I) or a salt thereof of the present invention is expected to have an activity of enhancing the action of a neurotrophic factor, Alzheimer-type dementia, general senile dementia, motor neuron disorders (muscle neurons) It is expected to be useful for the treatment and prevention of various neurodegenerative diseases such as amyotrophic lateral sclerosis) and diabetic peripheral neuropathy. Further, since the compound represented by the general formula (I) or a salt thereof of the present invention is expected to have anti-MMP activity, it is involved in MMP such as osteoarthritis, rheumatoid arthritis, arteriosclerosis, and cancer metastasis. It is expected to be useful for the treatment and prevention of diseases. Also,
According to the production method of the present invention, a condensed heterocyclic derivative having a bone formation promoting action or a synthetic intermediate thereof can be regioselectively synthesized, so that a target compound can be industrially advantageously used without using a complicated purification operation. Can be manufactured. Furthermore, by using an “amino group which may be substituted” as R ¹³ in the general formula (IX), a boron trifluoride ether complex or the like, which has a problem of corrosiveness when producing the compound (I), is used. Can be industrially advantageously produced without using the compound of the formula (1).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4439 A61K 31/4439 31/5377 31/5377 A61P 1/02 A61P 1/02 9/10 101 9 / 10 101 19/00 19/00 19/02 19/02 19/10 19/10 25/02 25/02 25/28 25/28 29/00 101 29/00 101 35/00 35/00 43/00 105 43/00 105 C07D 498/04 101 C07D 498/04 101 (72) Inventor Masayuki Takizawa 1-7-9 Kasuga, Tsukuba City, Ibaraki Prefecture Takeda Kasuga Heights 1003 (72) Inventor Masataka Miki Toyonaka, Osaka, Japan 1-5-181 Tigura Higashi 1-5-21-2 (72) Inventor Mitsuhiro Takeda 2-4-2-4 Tennoji-cho Minami, Abeno-ku, Osaka-shi, Osaka Spring house 4F East F-term (reference) 4C071 AA01 AA08 BB01 BB05 CC02 CC21 EE13 FF04 GG01 GG02 HH05 HH11 HH17 HH28 JJ0 1 JJ05 JJ06 JJ08 LL01 4C072 AA01 AA07 BB02 CC01 CC11 CC16 EE02 FF19 GG01 GG07 GG08 GG09 HH02 HH05 HH07 HH08 4C086 AA01 AA02 AA03 AA04 CB27 CB31 MA01 MA04 NA14 ZA15 ZAB ZA ZA ZA ZA ZA ZA Z

Claims (41)

[Claims] 1. A compound of the general formula (I): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. And a ring A is represented by the following formula: (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or an individually substituted A hydrocarbon group, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. A compound represented by the formula: Excluding the compound represented by In addition, ring A is In the above, the case where Z ¹ is —CO— and Z ² is an optionally substituted amino group is excluded. ) Or a salt thereof. 2. The compound according to claim 1, wherein ring B is a 5- to 7-membered hydrocarbon ring _optionally having 1 to 3 C _1-8 alkyl groups. 3. The ring B has 5 to 5 unsubstituted groups.
The compound according to claim 1, which is a 7-membered hydrocarbon ring. 4. The compound according to claim 1, wherein ring B is a 6-membered hydrocarbon ring having no substituent. (5) ring A is (Wherein R ¹⁴ is as defined in claim 1). A ring A is represented by the following formula: (The symbol in the formula is the same as defined in claim 1). A ring A is represented by the following formula: (The symbol in the formula is the same as defined in claim 1). 8. R ³ is (1) a hydrogen atom, (2) C
_C1-6 alkoxy, _{carboxy, C 1-6} alkoxy - carbonyl, 1 to 3 substituents substituted _{C 1-8} alkyl group selected from halogen and hydroxyl, _{(3) C 7- 14} aralkyl group, _{(4) C 2-8} alkanoyl group, _{(5) C 1-6} alkoxy - carbonyl group, _{(6) C 1-6} alkyl optionally substituted carbamoyl group, _{(7) C 1-8} alkyl Sulfinyl or (8) C _1-8 alkylsulfonyl, wherein R ¹⁴ is
(1) hydrogen atom, (2) halogen, _{(3) C 1-8} alkyl or _{(4) C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6} haloalkoxy,
C _1-6 alkoxy-carbonyl, amino and C ₁
I) C _6-10 aryl, i which may have 1 to 3 substituents selected from _-6 alkylthio,
i) a 5-7 membered heterocyclic group containing one sulfur atom, one nitrogen atom or one oxygen atom, iii) a 5-6 membered heterocyclic group containing 2-4 nitrogen atoms, iv) A 5-6 membered heterocyclic group containing 1-2 nitrogen atoms and one sulfur or oxygen atom, or v) a 5-6 membered ring containing not more than 2 nitrogen atoms, a benzene ring or one sulfur atom The compound according to claim 1, which is a heterocyclic group of ii) to iv) condensed with a 5-membered ring containing 9. The compound according to claim 1, wherein R ³ is a C _1-8 alkyl group and R ¹⁴ is a hydrogen atom. 10. The compound according to claim 1, wherein R ¹ is an optionally substituted hydrocarbon residue. 11. The compound according to claim 1, wherein R ¹ is an optionally substituted heterocyclic group. 12. The compound according to claim 1, wherein R ¹ is an optionally substituted sulfinyl group, sulfonyl group or thiol group. 13. The compound according to claim 1, wherein R ¹ is an optionally substituted hydroxyl group. 14. The compound according to claim 1, wherein R ¹ is an amino group which may be substituted. 15. R¹But (1) each C_1-8Al
Kill or C_{7-1 4}May be replaced by aralkyl
Sulfinyl group, sulfonyl group or thiol group,
(2) C_1-8Alkyl, C_6-14Aryl, C
_7-14Aralkyl, hydroxyl, C_1-6Alkoxy, C
_1-6Alkylenedioxy, C_6-14Aryloxy
Si, C_1-6Alkylthio, morpholinosulfonyl, e
Lumil, C_1-6Alkyl-carbonyl, carboxyl
Group, C_1-6Alkoxy-carbonyl, C_{6-1 4}Ants
Oxy-carbonyl, C_7-14Aralkyloxy
-Carbonyl, amino, mono- or di-C_1-6Al
Killamino, mono- or di-C_1-6Alkyl-cal
Bonylamino, toluenesulfonylamino, C_1-6A
Alkylaminothiocarbonylamino, nitro, halogen
N, C_1-6Haloalkyl, C_1-6Haloalkoxy,
C_1-6Alkoxy-C_6-14Aryl, 2-amino
-3- (4-morpholinyl) -3-oxo-C_1-6A
Lucil, J (C_1-6Alkoxy) phosphoryl
Is a C having two_1-6Alkyl, nitrogen, oxygen
And has 1 to 4 heteroatoms selected from sulfur atoms
Aromatic 5- or 6-membered heterocyclic group, nitrogen atom, oxygen atom,
And has 1 to 4 heteroatoms selected from sulfur atoms
Aromatic 5- or 6-membered heterocycle-oxy, and nitrogen atom
Heteroatom selected from oxygen, oxygen and sulfur
5- or 6-membered aromatic heterocyclic ring having 1 to 3 rings and benze
Ring or selected from nitrogen, oxygen and sulfur atoms
Aromatic 5-membered having 1-3 heteroatoms or
Fused bicyclic heterocycle-oxo formed by condensing a 6-membered heterocycle
Each substituted with one or two substituents selected from
I) C_6-10An aryloxy group, ii) a group selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Aromatic 5- or 6-membered heterocyclic ring having 1 to 4 terror atoms
-Oxy or iii) selected from nitrogen, oxygen and sulfur
5- or 6-membered aromatic compound having 1 to 3 hetero atoms
Elementary and benzene rings or nitrogen, oxygen and sulfur
Aromatic having 1 to 3 heteroatoms selected from yellow atoms
A condensed bicyclic ring formed by condensing a 5- or 6-membered heterocyclic ring
Heterocyclic-oxy group, (3) C_1-8Alkyloxy group, C_3-7Cycloal
Killoxy group, C_{7-1 4}An aralkyloxy group or
Dihydrobenzofuranyloxy group, (4) C_1-8Al
Kill, C_6-10Aryl, C_7-14Aralkyl, Ha
B _6-10Aryl, C_1-6Alkyl-carboni
Le, C_6-10Aryl-carbonyl and C_7-14
1 or 2 selected from aralkyl-oxycarbonyl
Amino group which may be substituted with
(5) C_1-8Alkyl group or C_7-14Aralki
2. The compound according to claim 1, which is a benzyl group. 16. R ¹ is (1) a sulfinyl group, a sulfonyl group or a thiol group each substituted by C _1-8 alkyl, (2) (a) C _1-6 alkylenedioxy, (b) di ( C _1-6 alkoxy) phosphoryl-C
_1-6 alkyl, (c) C _1-6 haloalkyl, (d)
C _7-14 aralkyloxy, (e) an aromatic 5- or 6-membered heterocyclic oxy having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or (f) a nitrogen atom, an oxygen atom and 5- or 6-membered aromatic heterocyclic ring having 1 to 3 hetero atoms selected from sulfur atoms and 5-membered aromatic ring having 1 to 3 hetero atoms selected from benzene ring or nitrogen atom, oxygen atom and sulfur atom or A condensed bicyclic heterocycle formed by condensing a 6-membered heterocyclic ring-C _6-10 aryloxy group which may be substituted with oxy, and (3) a heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. An aromatic 5- or 6-membered heterocyclic-oxy group having 1 to 4 carbon atoms, or (4) a nitrogen atom,
1 to a hetero atom selected from an oxygen atom and a sulfur atom
A 5-membered or 6-membered aromatic ring having 3 aromatic rings and a 5- or 6-membered aromatic ring having 1 to 3 hetero atoms selected from a benzene ring or a nitrogen atom, an oxygen atom and a sulfur atom are formed by condensation. The compound according to claim 1, which is a fused bicyclic heterocyclic-oxy group. 17. R ² is —CO—Z ^{2 ′} (wherein, Z ^{2 ′} represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, an amino group or a hydroxyl group.) The compound according to claim 1, which is represented by the formula: 18. Z^{2 '}But C_1-8Alkyl, C
_6-14Aryl, C_{7- 14}Aralkyl, hydroxyl, C
_1-6Alkoxy, amino, mono or di C_1-6Al
Killamino, C_1-6Alkoxy-carbonylamino,
Hetero selected from nitrogen, oxygen and sulfur
An aromatic 5- or 6-membered heterocyclic group having 1 to 4 atoms,
C_1-6Haloalkyl, carboxy C_1-6Alkyl,
C_1-6Alkoxy-carbonyl-C_1-6Alkyl,
Carbamoyl C_1-6Alkyl, nitrogen, oxygen
And has 1 to 4 heteroatoms selected from sulfur atoms
Aromatic 5- or 6-membered heterocycle-C_1-6Alkyl, nitrogen
Hetero atoms selected from atoms, oxygen atoms and sulfur atoms
5- or 6-membered heterocyclic -C having 1 to 4 carbon atoms_1-
6Alkyl-C_6-14Aryl and mono or di C
_1-6Alkylamino C _1-61 selected from alkyl
Or an amino group which may be substituted with two substituents.
Or a morpholino group. 19. The compound according to claim 17, wherein Z ^{2 ′} is an amino group optionally substituted with one or two C _1-6 alkyl.
A compound as described. 20. The compound according to claim 1, wherein R ¹⁴ is a hydrogen atom. 21. R¹But (1) each C_1-8Al
Kill or C_{7-1 4}May be replaced by aralkyl
Sulfinyl group, sulfonyl group or thiol group,
(2) C_1-8Alkyl, C_6-14Aryl, C
_7-14Aralkyl, hydroxyl, C_1-6Alkoxy, C
_1-6Alkylenedioxy, C_6-14Aryloxy
Si, C_1-6Alkylthio, morpholinosulfonyl, e
Lumil, C_1-6Alkyl-carbonyl, carboxyl
Group, C_1-6Alkoxy-carbonyl, C_{6-1 4}Ants
Oxy-carbonyl, C_7-14Aralkyloxy
-Carbonyl, amino, mono- or di-C_1-6Al
Killamino, mono- or di-C_1-6Alkyl-cal
Bonylamino, toluenesulfonylamino, C_1-6A
Alkylaminothiocarbonylamino, nitro, halogen
N, C_1-6Haloalkyl, C_1-6Haloalkoxy,
C_1-6Alkoxy-C_6-14Aryl, 2-amino
-3- (4-morpholinyl) -3-oxo-C_1-6A
Lucil, J (C_1-6Alkoxy) phosphoryl
Is a C having two_1-6Alkyl, nitrogen, oxygen
And has 1 to 4 heteroatoms selected from sulfur atoms
Aromatic 5- or 6-membered heterocyclic group, nitrogen atom, oxygen atom,
And has 1 to 4 heteroatoms selected from sulfur atoms
Aromatic 5- or 6-membered heterocycle-oxy, and nitrogen atom
Heteroatom selected from oxygen, oxygen and sulfur
5- or 6-membered aromatic heterocyclic ring having 1 to 3 rings and benze
Ring or selected from nitrogen, oxygen and sulfur atoms
Aromatic 5-membered having 1-3 heteroatoms or
Fused bicyclic heterocycle-oxo formed by condensing a 6-membered heterocycle
Each substituted with one or two substituents selected from
I) C_6-10An aryloxy group, ii) a group selected from a nitrogen atom, an oxygen atom and a sulfur atom.
Aromatic 5- or 6-membered heterocyclic ring having 1 to 4 terror atoms
-Oxy or iii) selected from nitrogen, oxygen and sulfur
5- or 6-membered aromatic compound having 1 to 3 hetero atoms
Elementary and benzene rings or nitrogen, oxygen and sulfur
Aromatic having 1 to 3 heteroatoms selected from yellow atoms
A condensed bicyclic ring formed by condensing a 5- or 6-membered heterocyclic ring
Heterocyclic-oxy group, (3) C_1-8Alkyloxy group, C_3-7Cycloal
Killoxy group, C_{6-1 4}Aryloxy group, C
_7-14Aralkyloxy group or dihydrobenzof
Ranyloxy group, (4) C_1-8Alkyl, C_6-10
Aryl, C_7-14Aralkyl, Halo C _6-10Ants
, C_1-6Alkyl-carbonyl, C_6-10Ants
Carbonyl and C_7-14Aralkyl-oxy
Substituted with one or two substituents selected from carbonyl
An optionally substituted amino group, or (5) C_1-8Archi
Group or C_7-14An aralkyl group, R^TwoIs -CO-Z^{2 '}And Z^{2 '}But C_1-8Alkyl,
C_6-14Aryl, C_7-14Aralkyl, hydroxyl,
C_1-6Alkoxy, amino, mono or di C _1-6A
Lucylamino, C_1-6Alkoxy-carbonylamido
, Nitrogen, oxygen, and sulfur
Aromatic 5- or 6-membered heterocyclic ring having 1 to 4 terror atoms
Group, C_1-6Haloalkyl, carboxy C_1-6Archi
Le, C_{1- 6}Alkoxy-carbonyl-C_1-6Archi
Le, carbamoyl C_1-6Alkyl, nitrogen atom, oxygen source
1 to 4 heteroatoms selected from
Aromatic 5- or 6-membered heterocycle -C_1-6Alkyl,
Hetero selected from nitrogen, oxygen and sulfur
Aromatic 5- or 6-membered heterocycle -C having 1-4 atoms
_1-6Alkyl-C_6-14Aryl and mono or
Di C_1-6Alkylamino C_1-6Selected from alkyl
Amino optionally substituted with one or two substituents
Group or morpholino group, R³Is (1) hydrogen atom, (2) C_1-6Alkoxy,
Carboxyl, C_{1- 6}Alkoxy-carbonyl, halo
One to three substituents selected from the group consisting of
C that you may have_1-8Alkyl group, (3) C
_7-14Aralkyl group, (4) C_2-8Alkanoyl
Group, (5) C_1-6Alkoxy-carbonyl group, (6)
C_1-6Carbamoyl optionally substituted with alkyl
Group, (7) C_{1- 8}Alkylsulfinyl or (8)
C_1-8Alkylsulfonyl, R¹⁴But (1) hydrogen
Atom, (2) halogen, (3) C_1-8Alkyl or
(4) C_{1 -6}Alkyl, C_1-6Haloalkyl, C
_1-6Alkoxy, C_1-6Haloalkoxy, C_1-6
Alkoxy-carbonyl, amino and C_1-6Archi
Each having one to three substituents selected from
I) C_{6-1 0}Aryl, ii) one
Containing a sulfur atom, one nitrogen atom or one oxygen atom
A 5- to 7-membered heterocyclic group, iii) containing 2 to 4 nitrogen atoms
5-6 membered heterocyclic group, iv) 1-2 nitrogen atoms and 1
A 5- or 6-membered heterocyclic group containing a sulfur or oxygen atom,
V) 5- to 6-membered ring containing not more than 2 nitrogen atoms, benzase
Condensed with a 5-membered ring containing one sulfur atom or one sulfur atom
i) to iv), wherein ring B is 1 to 3 C_1-8Having an alkyl group
2. A 5- to 7-membered hydrocarbon ring, which may be
Compound or salt thereof. 22. R ¹ is (a) C _1-6 alkylenedioxy, (b) di (C _1-6 alkoxy) phosphoryl-
C _1-6 alkyl, (c) C _1-6 haloalkyl,
(D) C _7-14 aralkyloxy, (e) nitrogen atom,
1 to a hetero atom selected from an oxygen atom and a sulfur atom
An aromatic 5- or 6-membered heterocyclic ring having 4 oxy or (f) an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur and a benzene ring or Optionally substituted by a fused bicyclic heterocycle-oxy formed by condensing an aromatic 5- or 6-membered heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur _{A 6-10} aryloxy group, R ² is —CO—Z ^{2 ′} , Z ^{2 ′} is an amino group optionally substituted by one or two C _1-6 alkyl, and R ³ is C _{1- 8} alkyl group, with R ¹⁴ is a hydrogen atom a compound according to claim 1 wherein ring B is a cyclohexane ring. 23. A compound represented by the formula (I) further comprising 9-methylthio-4,5-dihydro-6H-1-oxa-8-thia-2
-Aza-cyclopenta [e] azulene-7-carboxamide, 4,5-dihydro-8-methylthio-4-phenylisoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide, 4,5- Dihydro-4-methyl-8- (methylthio) isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide and 4,5-dihydro-4,4-dimethyl-8- (methylthio)
2. The compound according to claim 1, except for isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide. 24. When the ring B is a 6-membered hydrocarbon ring substituted with a lower alkyl group or a phenyl group from the compound represented by the formula (I), and R ¹ is a lower alkylthio group; When ring B is an unsubstituted 7-membered hydrocarbon ring,
The compound according to claim 1, except that R ¹ is a lower alkylthio group. 25. A compound represented by the formula (I): 4,5-dihydro-1-methyl-8-propylthio-1H-thieno [3,4-g] indazole-6-carboxamide; Dihydro-1-methyl
-8-propylsulfinyl-1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl-8-propylsulfonyl-1H-thieno [3,4-g] indazole-6 -Carboxamide; 4,5-dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-
Carboxamide; 4,5-dihydro-8-phenoxy-1-methyl
-1H-thieno [3,4-g] indazole-6-carboxamide; 4,
5-dihydro-8- (3,4-methylenedioxyphenoxy) thieno [3,4-g] -1,2-benzisoxazole-6-carboxamide; 8- [4-[(diethoxyphosphoryl) methyl [Phenoxy]
-4,5-dihydro-2-methyl-2H-thieno [3,4-g] indazole-6-carboxamide; 8- [4-[(diethoxyphosphoryl)
Methyl] phenoxy] -4,5-dihydro-1-methyl-1H-thieno
[3,4-g] indazole-6-carboxamide; N-ethyl-4,5
-Dihydro-8- (3,4-methylenedioxyphenoxy) -1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl-8- (4 -Trifluoromethylphenoxy) -1H-thieno [3,4-g] indazole-6-carboxamide; 4,5-dihydro-1-methyl-8- (6-quinolinyloxy) -1H-thieno [3,4-g ] Indazole-6-carboxamide; 4,5-dihydro-1-methyl-8-[(3-pyridinyl) oxy]
-1H-thieno [3,4-g] indazole-6-carboxamide; 8-
[(4-benzyloxy) phenoxy] -4,5-dihydro-1-methyl-1H-thieno [3,4-g] indazole-6-carboxamide;
2. The compound according to claim 1, which is 4,5-dihydro-1-methyl-8- [4- (2-quinolinylmethoxy) phenoxy] -1H-thieno [3,4-g] indazole. 26. A prodrug of the compound of claim 1 or a salt thereof. 27. The general formula (I): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. And a ring A is represented by the following formula: (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or each substituted. Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. (Wherein ring A is In the above, the case where Z ¹ is —CO— and Z ² is an optionally substituted amino group is excluded. Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. 28. A compound represented by the formula (I) further comprising 9-methylthio-4,5-dihydro-6H-1-oxa-8-thia-2
-Aza-cyclopenta [e] azulene-7-carboxamide, 4,5-dihydro-8-methylthio-4-phenylisoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide, 4, 5-dihydro-4-methyl-8- (methylthio) isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide and 4,5-dihydro-4,4-dimethyl-8- (methylthio)
28. The composition of claim 27, excluding isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide. 29. The compound represented by the formula (I), wherein when ring B is a 6-membered hydrocarbon ring substituted with a lower alkyl group or a phenyl group, R ¹ is a lower alkylthio group; When ring B is an unsubstituted 7-membered hydrocarbon ring,
28. Except when R ¹ is a lower alkylthio group.
A composition as described. 30. The general formula (I): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. And a ring A is represented by the following formula: (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or each substituted. Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. (Provided that the compound has the formula: Excluding the compound represented by Or a pharmaceutically acceptable salt thereof or a prodrug thereof. 31. A compound represented by the formula (I) further comprising 9-methylthio-4,5-dihydro-6H-1-oxa-8-thia-2
-Aza-cyclopenta [e] azulene-7-carboxamide, 4,5-dihydro-8-methylthio-4-phenylisoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide, 4,5- Dihydro-4-methyl-8- (methylthio) isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide and 4,5-dihydro-4,4-dimethyl-8- (methylthio)
31. The cell differentiation inducer according to claim 30, except for isoxazolo [4,5-e] benzo [c] thiophene-6-carboxamide. 32. The compound represented by the formula (I), wherein when ring B is a 6-membered hydrocarbon ring substituted with a lower alkyl group or a phenyl group, R ¹ is a lower alkylthio group; When ring B is an unsubstituted 7-membered hydrocarbon ring,
31. Except when R ¹ is a lower alkylthio group.
The cell differentiation inducer according to the above. 33. The general formula (I): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. And a ring A is represented by the following formula: (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or each substituted. Represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And ring B has a substituent. And represents an optionally substituted 5- to 7-membered hydrocarbon ring. (Provided that a compound represented by the formula: Excluding the compound represented by ) Or a pharmaceutically acceptable salt thereof or a prodrug thereof, for preventing or treating bone or joint diseases. 34. The bone or joint disease is osteoporosis, fracture,
34. It is osteoarthritis or rheumatoid arthritis.
The prophylactic / therapeutic agent according to the above. 35. The general formula (II): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ⁴ represents a substituted hydroxyl group, and ring C represents a 5- to 7-membered hydrocarbon ring which may have a substituent.] Or a salt thereof. 36. The general formula (IX): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ¹³ represents an optionally substituted amino group or a hydroxyl group, and ring D ′ is a 5- to 7-membered hydrocarbon ring optionally having a substituent. Is shown. Or a salt thereof. 37. The general formula (IV): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. And ring D represents a 5- to 7-membered hydrocarbon ring which may have a substituent. And an amide acetal.
1): embedded image [Wherein, R ¹¹ represents an amino group which may be substituted,
Ring D′-1 represents an optionally substituted 5- to 7-membered hydrocarbon ring, and the other symbols have the same meanings as described above. ] Or a salt thereof. 38. The general formula (II): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ⁴ represents a hydroxyl group which may be substituted, and ring C represents a 5- to 7-membered hydrocarbon ring which may have a substituent. To a dealcoholation reaction, wherein the compound has the general formula (IX-2): [In the formula, ring D′-2 may have a substituent.
A member hydrocarbon ring, and other symbols have the same meanings as described above. ] Or a salt thereof. 39. The general formula (IX): [Wherein, R ¹ represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, and R ² represents a cyano group, a formyl group, a thioformyl group. Or the formula: -Z ¹ -Z ²
(Wherein, Z ¹ represents —CO—, —CS—, —SO— or —SO ₂ —, and Z ² represents an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group. R ¹³ represents an optionally substituted amino group or a hydroxyl group, and ring D ′ is a 5- to 7-membered hydrocarbon ring optionally having a substituent. Is shown. Or a salt thereof, hydroxylamine or a salt thereof, or a compound represented by the formula: R ^{3 ′} NHNH ₂ wherein R ^{3 ′} is a hydrogen atom, a hydrocarbon residue which may be substituted, a heterocyclic ring Group, sulfonyl group or acyl group. Wherein the compound represented by the general formula (I) or a salt thereof is subjected to a ring-closure reaction to convert the compound into an optionally substituted hydroxyl group or amino group. Wherein ring A is (Wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group, or an acyl group, and R ¹⁴ represents a hydrogen atom, a halogen, or an respectively substituted group. A hydrocarbon residue, a heterocyclic group, a hydroxyl group, an amino group, a sulfonyl group or an acyl group.), And the other symbols are as defined above. Having. ] Or a salt thereof. (40) a compound of the general formula (IX-3): [In the formula, R ^{1 ′} is a hydrocarbon residue, a heterocyclic group, a sulfinyl group, a sulfonyl group, a hydroxyl group, a thiol group or an amino group, each of which may be substituted;
W '(wherein X' represents a bond, an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom or an optionally oxidized sulfur atom, and W 'is an optionally substituted An optionally substituted cyclic group or a carbon atom or a nitrogen atom having two or more substituents).
² is a cyano group, formyl group, thioformyl group or a formula:
-Z ¹ -Z ² (where Z ¹ is -CO-, -CS-, -S
O— or —SO ₂ — is represented, and Z ² represents a hydrocarbon residue, a heterocyclic group, a hydroxyl group or an amino group which may be substituted. ), R ^{13 ′} represents an optionally substituted amino group or a hydroxyl group,
Ring D′-3 represents a 5- to 7-membered hydrocarbon ring which may have a substituent. And a salt thereof, in the presence of an acid and under substantially anhydrous conditions, with the formula: R ^{3 ″} NHNH ₂
[In the formula, R ^{3 ′ ″} represents an optionally substituted hydrocarbon residue, a heterocyclic group, a sulfonyl group or an acyl group. Wherein the compound represented by the general formula (I-11) or a salt thereof is subjected to a ring closure reaction: [In the formula, ring B-1 represents a 5- to 7-membered hydrocarbon ring which may have a substituent, and other symbols have the same meanings as described above. ] Or a salt thereof. 41. When R ^{1 ′} is a group represented by the formula: —X′—W ′ (X ′
Represents an oxygen atom or an optionally oxidized sulfur atom, and W ′ represents an optionally substituted cyclic group. 41. The production method according to claim 40, which is a group represented by the formula: