HK1125110B - Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof - Google Patents

Description

Fused heterocyclic derivative, pharmaceutical composition containing same, and pharmaceutical use thereof

Technical Field

The present invention relates to fused heterocyclic derivatives.

More particularly, the present invention relates to fused heterocyclic derivatives which have an antagonistic activity against gonadotropin-releasing hormone and are useful for the prevention or treatment of sex hormone dependent diseases, such as benign prostatic hypertrophy, uterine myoma, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea and the like, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutical composition containing the same, and the like.

Background

Gonadotropin-releasing hormone (GnRH, GnRH is also called luteinizing hormone-releasing hormone: LHRH, hereinafter referred to as "GnRH") is a peptide consisting of 10 amino acids: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) It is secreted from the hypothalamus. GnRH secreted into the portal pituitary vein promotes the production and secretion of anterior pituitary hormone gonadotropins, luteinizing hormone: LH and follicle stimulating hormone: FSH. These gonadotropins affect the gonads, ovaries and testes, promote follicular growth, ovulation and luteinization, and spermatogenesis, and also promote the production and secretion of sex hormones such as estrogen, progesterone and androgen (see non-patent reference 1). Therefore, antagonists specifically and selectively acting on GnRH receptors should control the activity of GnRH and control the production and secretion of gonadotropins and sex hormones, and thus are expected to be useful as agents for the prevention or treatment of sex hormone-dependent diseases.

As agents for inhibiting GnRH receptors, GnRH receptor functions, superagonists have been used as agents for treating sex hormone-dependent diseases such as prostate cancer, breast cancer, endometriosis and the like. GnRH receptor superagonists bind to GnRH receptors and exert an initial transient gonadotropin secretion-stimulating effect, the so-called "flare-up" phenomenon, and then inhibit function by causing gonadotropin depletion and down-regulation of GnRH receptors. Therefore, GnRH receptor superagonists have a problem in that the disease can be transiently exacerbated by initially promoting the secretion of gonadotropins. On the other hand, since the mechanism of inhibition of a GnRH receptor antagonist (hereinafter referred to as "GnRH antagonist") is inhibition of binding to a GnRH receptor, it is expected that the inhibitory effect will be exerted rapidly without secretion of gonadotropins. Over the years, peptide GnRH antagonists such as abarelix and cetrorelix have been developed as GnRH antagonists and used for the treatment of prostate cancer, infertility, and the like. However, due to poor oral absorption of these peptide GnRH antagonists, they are administered subcutaneously or intramuscularly. Thus, there is a need to develop a non-peptide GnRH antagonist that can be orally administered, in which local reactivity at the injection site can be reduced and the dose can be flexibly adjusted (see non-patent reference 2).

As a fused pyrimidine derivative having a non-peptide GnRH antagonistic activity, compounds described in patent references 1 and 2 are known. However, any of the compounds described in patent reference 1 has a 5-membered heterocyclic ring fused with a pyrimidine ring and an aryl substituent on the 5-membered heterocyclic ring. Further, the compounds described in patent reference 2 are pyrimidine derivatives fused with an aromatic 6-membered ring, and do not always have sufficiently high oral absorbability. In recently published patent reference 3, a pyrimidine derivative fused with a 5-membered heterocyclic ring having a non-peptide GnRH antagonistic activity is described. However, there is no specific description about the compound other than that the compound has a sulfonamide or amide group, and there is no specific description about hemodynamics of oral administration.

Further, as a compound having a pyrimidine ring fused with a 5-membered heterocyclic ring, various compounds are exemplified as a serine protease inhibitor in patent reference 4, a coagulation factor Xa inhibitor in patent reference 5, a herbicide in patent reference 6, and the like. However, these references do not describe or suggest that the compounds of the present invention having a pyrimidine ring fused with a 5-membered heterocyclic ring have GnRH antagonistic activity.

Non-patent reference 1: hyojun Seirigaku (Standard Physiology), 5 th edition, Igakusyon, page 882-.

Non-patent reference 2: sanka to Fujinka (Obstetrics and Gynecology), 2004, Vol.71, No.3, 280-.

Patent reference 1: international publication No. WO96/24577 text.

Patent reference 2: international publication No. wo2005/019188 text.

Patent reference 3: international publication No. wo2006/083005 text.

Patent reference 4: U.S. patent publication No.2003/0004167 specification.

Patent reference 5: international publication No. wo00/39131 text.

Patent reference 6: japanese patent publication (Tokuhyo) No. H6-510992 publication.

Disclosure of Invention

Object of the Invention

The object of the present invention is to provide a compound having GnRH antagonistic activity.

Means of the invention

The present inventors have earnestly studied in order to solve the above problems. As a result, it has been newly found that a pyrimidine derivative fused with a 5-membered heterocyclic ring, represented by the following general formula (I), has excellent GnRH antagonistic activity and exerts more excellent oral hemodynamics than a pyrimidine derivative fused with an aromatic 6-membered ring, thereby forming the basis of the present invention.

Namely, the present invention relates to:

a fused heterocyclic derivative represented by the general formula (I), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

[ chemical formula 1]

Wherein ring A represents a 5-membered cyclic unsaturated hydrocarbon or a 5-membered heteroaryl;

R^Arepresents a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted lower alkynyl groupOptionally substituted (lower alkyl) sulfonyl, optionally substituted (lower alkyl) sulfinyl, tetrazolyl, OW¹，SW¹，COW¹，COOW¹，NHCOW¹，NHCONW²W³，NW²W³，CONW²W³Or SO₂NW²W³Wherein W is¹To W³Independently represents a hydrogen atom or an optionally substituted lower alkyl group, or W²And W³May be taken together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group;

m represents an integer of 0 to 3;

ring B represents aryl or heteroaryl;

R^Brepresents a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW⁴，COW⁴，COOW⁴Or CONW⁵W⁶Wherein W is⁴To W⁶May be taken together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group;

n represents an integer of 0 to 2;

E¹represents an oxygen atom, a sulfur atom or N-CN;

E²represents an oxygen atom or NH;

u represents a single bond or an optionally substituted lower alkylene group;

x represents a group represented by: y, -CO-Y, -SO₂-Y，-S-L-Y，-O-L-Y，-CO-L-Y，-COO-L-Y，-SO-L-Y，-SO₂-L-Y, -S-Z, -O-Z or-COO-Z, wherein L represents optionally substituted lower alkylene;

y represents a group consisting of Z or-NW⁷W⁸A group represented by wherein W⁷And W⁸Independently represents a hydrogen atom, optionally substituted lower alkyl or Z, with the proviso that W⁷And W⁸Not both are hydrogen atoms; or W⁷And W⁸May be combined with adjacent nitrogen atoms to form optionally substitutedA cyclic amino group;

z represents optionally fused and optionally substituted cycloalkyl, optionally fused and optionally substituted heterocycloalkyl, optionally fused and optionally substituted aryl or optionally fused and optionally substituted heteroaryl;

a fused heterocyclic derivative as described in the above [1], wherein ring a represents a 5-membered heteroaryl ring, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;

a fused heterocyclic derivative as described in the above [2], wherein the 5-membered heteroaryl ring of Ring A is any one of thiophene rings represented by the following formula:

[ chemical formula 2]

A fused heterocyclic derivative as described in the above [3], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the 5-membered heteroaryl ring of the A ring is a thiophene ring represented by the following formula:

[ chemical formula 3]

As described above [1]To [ 4]]The fused heterocyclic derivative of any one of (1), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein R is^ARepresents a halogen atom, an optionally substituted lower alkyl group, COOW¹Or CONW²W³Wherein W is¹To W³Independently represents a hydrogen atom or an optionally substituted lower alkyl group, or W²And W³May be combined with adjacent nitrogen atoms to formTo an optionally substituted cyclic amino group;

as described above [5]The fused heterocyclic derivative, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein R is^ARepresents a lower alkyl group substituted with any group selected from a hydroxyl group, a carboxyl group and a carbamoyl group; a carboxyl group; or a carbamoyl group;

a fused heterocyclic derivative as described in any one of the above [1] to [6], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein m represents 0 or 1;

as described above [7]The fused heterocyclic derivative, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein m represents 1, and ring A is wherein R^AA thiophene ring bonded to the position of ring A represented by the following general formula:

[ chemical formula 4]

As described above [1]To [ 8]]The fused heterocyclic derivative of any one of (1), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein E¹Represents an oxygen atom;

as described above [1]To [ 9]]The fused heterocyclic derivative of any one of (1), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein E²Represents an oxygen atom;

a fused heterocyclic derivative as described in any one of the above [1] to [10], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein ring B represents a benzene ring, a thiophene ring or a pyridine ring;

a fused heterocyclic derivative as described in the above [11], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the B ring is any ring represented by the formula:

[ chemical formula 5]

As described above [12]The fused heterocyclic derivative, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein n is 1 or 2, and ring B is wherein R is^BAny ring bound to the position of the B ring represented by the formula:

[ chemical formula 6]

In the formula, R^BHave the same meaning as above, and when two R's are present^BWhen they are the same as or different from each other;

the fused heterocyclic derivative as described in the above [12] or [13], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein the B ring is any ring represented by the formula:

[ chemical formula 7]

As described above [1]To [14 ]]The fused heterocyclic derivative of any one of (1), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein R is^BRepresents a halogen atom; optionally substituted lower alkyl; OW⁴Wherein W⁴Represents a hydrogen atom or an optionally substituted lower alkyl group; or a cyano group;

as described above [15]The fused heterocyclic derivative, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein R is^BRepresents a halogen atom, or a lower alkyl group which may be substituted by a halogen atom, or OW⁴Wherein W⁴Represents a hydrogen atom or an optionally substituted lower alkyl group;

as described above [16]The fused heterocyclic derivative, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein R is^BRepresents a fluorine atom, a chlorine atom, or OW⁴Wherein W⁴Represents a lower alkyl group;

a fused heterocyclic derivative as described in any one of the above [1] to [17], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein U represents a single bond, a methylene group or an ethylene group;

as described above [1]To [18 ]]The fused heterocyclic derivative of any one of (1), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein X represents a group represented by: y, -S-L-Y, -O-L-Y, -CO-L-Y, -SO₂-L-Y, -S-Z or-O-Z, wherein L, Y and Z have the same meaning as above;

as described above [19]]The fused heterocyclic derivative, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein U represents a single bond, and X represents a group represented by: -S-L-Y, -O-L-Y, -CO-L-Y or-SO₂-L-Y, wherein L and Y have the same meaning as above;

as described above [19]]The fused heterocyclic derivative, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein U represents a methylene group, X represents a group represented by Y, -S-Z or-O-Z, wherein Y represents-NW⁷W⁸Wherein W is⁷And W⁸Independently represents a hydrogen atom, an optionally substituted lower alkyl group or Z, with the proviso that W⁷And W⁸Not both are hydrogen atoms; orW is⁷And W⁸May be taken together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group, wherein Z has the same meaning as described above;

a fused heterocyclic derivative as described in the above [19], wherein U represents an ethylene group, X represents Y, provided that Y represents Z and Z has the same meaning as described above, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;

as described above [1]To [20 ]]The fused heterocyclic derivative of any one of (1), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein L represents C_1-3An alkylene group;

a fused heterocyclic derivative as described in any one of the above [1] to [23], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein Z represents an optionally fused and optionally substituted aryl group;

a pharmaceutical composition comprising, as an active ingredient, a fused heterocyclic derivative as described in any one of the above [1] to [24], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof;

the pharmaceutical composition as described in the above [25], which is a gonadotropin-releasing hormone antagonist;

the pharmaceutical composition according to the above [25], which is an agent for preventing or treating a sex hormone-dependent disease, a reproduction regulator, a contraceptive, an ovulation inducer or an agent for preventing postoperative recurrence of sex hormone-dependent cancer;

the pharmaceutical composition as described in the above [27], wherein the sex hormone dependent disease is selected from the group consisting of benign prostatic hypertrophy, hysteromyoma, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, short stature, sleep disorders, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumors;

the pharmaceutical composition according to the above [25], wherein the composition is an oral preparation; and a method for preventing or treating a sex hormone dependent disease, a method for reproductive regulation, contraception, ovulation induction or prevention of postoperative recurrence of sex hormone dependent cancer, which comprises administering an effective amount of the heterocyclic derivative; the use of said heterocyclic derivatives for the preparation of a pharmaceutical composition; a pharmaceutical composition comprising in combination with at least one drug selected from the group consisting of: gonadotropin-releasing hormone agonists, chemotherapeutic agents, peptide gonadotropin-releasing hormone antagonists, 5 alpha-reductase inhibitors, alpha-adrenoreceptor inhibitors, aromatase inhibitors, adrenoandrogen production inhibitors and hormone therapeutic agents; and so on.

Effects of the invention

Since the fused heterocyclic derivative (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof has an excellent GnRH antagonistic activity, it can control the action of gonadotropin-releasing hormone and control the production and secretion of gonadotropin and sex hormone, and thus, it can be used as an agent for the prophylaxis or treatment of sex hormone-dependent diseases.

Best mode for carrying out the invention

The meanings of the terms used in the present specification are as follows.

The term "5-membered cyclic unsaturated hydrocarbon" refers to a 5-membered hydrocarbon ring having one or two double bonds.

The term "heteroaryl" refers to a monocyclic heteroaryl group having 1 or more heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, such as thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, furazan, and the like.

The term "optionally substituted" means that there may be substituents.

The term "5-membered heteroaryl" refers to a 5-membered monocyclic heteroaryl group as described above, which may be exemplified by thiazole, oxazole, isothiazole, isoxazole, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, and furazan rings, and the like.

The term "aryl" refers to phenyl.

The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

The term "lower alkyl" refers to an optionally branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and the like.

The term "lower alkenyl" refers to an optionally branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-methylallyl, and the like.

The term "lower alkynyl" refers to an optionally branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 2-propynyl, and the like.

The term "(lower alkyl) sulfonyl" refers to a sulfonyl group substituted with a lower alkyl group as described above.

The term "(lower alkyl) sulfinyl" refers to a sulfinyl group substituted with the above-mentioned lower alkyl.

The term "lower alkylene" refers to optionally branched alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, methyl methylene, trimethylene, dimethyl methylene, ethyl methylene, methyl ethylene, propyl methylene, isopropyl methylene, dimethyl ethylene, butyl methylene, ethyl methyl methylene, pentamethylene, diethyl methylene, dimethyl trimethylene, hexamethylene, diethyl ethylene and the like.

The term "C_1-3The alkylene group "means the above-mentioned lower alkylene group having 1 to 3 carbon atoms.

The term "lower alkoxy" refers to an optionally branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy and the like.

The term "(lower alkoxy) carbonyl" refers to an optionally branched alkoxycarbonyl group having 2 to 7 carbon atoms.

The term "(lower alkyl) thio" refers to an optionally branched alkylthio group having 1 to 6 carbon atoms.

The term "cycloalkyl" refers to a monocyclic cycloalkyl group having 3 to 8 carbon atoms, and can be exemplified by monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The term "heterocycloalkyl" refers to a3 to 8 membered heterocycloalkyl having 1 or more heteroatoms selected from nitrogen, oxygen and sulfur atoms and optionally having 1 or 2 oxo groups, for example pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azokanyl, tetrahydrofuranyl, tetrahydropyranyl and the like. In the case of having a sulfur atom in the ring, the sulfur atom may be oxidized.

The term "optionally fused" means that a ring selected from the group consisting of the above-mentioned cycloalkyl group, the above-mentioned heterocycloalkyl group, the above-mentioned aryl group and the above-mentioned heteroaryl group can be fused. Examples of the "fused cycloalkyl group," fused heterocycloalkyl group, "fused aryl group" and "fused heteroaryl group" include indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolizinyl, naphthyridinyl, pteridinyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, indolinyl, isoindolinyl, 2, 3, 4, 5-tetrahydrobenzo [ b ] oxepine, 6, 7, 8, 9-tetrahydro-5H-benzocycloheptenyl, chromanyl and the like, and the free valence thereof may be in any ring.

The term "cyclic amino" refers to a group having at least one nitrogen atom with a binding site in the ring among the above optionally fused heterocycloalkyl groups. Examples thereof include 1-pyrrolidinyl group, 1-piperidinyl group, 1-piperazinyl group, 4-morpholinyl group, 4-thiomorpholinyl group, 2, 3, 4, 5, 6, 7-hexahydro-1H-azepin-1-yl group, 1-indolinyl group, 2-isoindolinyl group, 3, 4-dihydro-1, 5-naphthyridin-1 (2H) -yl group, 1, 2, 3, 4-tetrahydroquinolin-1-yl group, 3, 4-dihydroquinolin-1 (2H) -yl group, 3, 4-dihydroisoquinolin-2 (1H) -yl group, octahydroquinolin-1 (2H) -yl group, octahydroisoquinolin-2 (1H) -yl group, perhydroquinolin-1-yl group, 2, 3-dihydro-4H-1, 4-benzoxazin-4-yl, 2, 3-dihydro-4H-1, 4-benzothiazin-4-yl, 3, 4-dihydroquinoxalin-1 (2H) -yl, 2, 3-dihydro-4H-pyrido [3, 2-b ] [1, 4] oxazin-4-yl, 2, 3, 4, 5-tetrahydro-1H-1-benzazepin-1-yl, 1, 3, 4, 5-tetrahydro-2H-2-benzazepin-2-yl, 3, 4-dihydro-1, 5-benzoxepin-5 (2H) -yl, 2, 3-dihydro-4, 1-benzothiazepin-1 (5H) -yl, 3, 4-dihydro-1, 5-benzothiazepin-5 (2H) -yl, 2, 3-dihydro-4, 1-benzoxazepin-1 (5H) -yl, 2, 3, 4, 5-tetrahydro-1H-1, 5-benzodiazepin-1-yl, 2, 3, 4, 5-tetrahydro-1H-1, 4-benzodiazepin-1-yl, 5, 6, 7, 8-tetrahydro-4H-thieno [3, 2-b ] azepin-4-yl, 3, 4, 5, 6-tetrahydro-1-benzazocin-1 (2H) -yl, and the like.

The term "(di) (lower alkyl) amino" refers to an amino group which is mono-or di-substituted with a lower alkyl group as described above. In the di-substituted amino group, the two lower alkyl groups may be different, and the two lower alkyl groups may be bonded together with the adjacent nitrogen atom to form a cyclic amino group.

The term "(di) (lower alkyl) carbamoyl" refers to a carbamoyl group mono-or di-substituted with the above lower alkyl. In the di-substituted amino group, the two lower alkyl groups may be different, and the two lower alkyl groups may be bonded together with the adjacent nitrogen atom to form a cyclic amino group.

The term "acyl" refers to an optionally branched aliphatic carboxylic acid group having 2 to 7 carbon atoms, a cycloalkyl carboxylic acid group, a heterocycloalkyl carboxylic acid group, an aryl carboxylic acid group, or a heteroaryl carboxylic acid group.

The term "acylamino" refers to an amino group substituted with the acyl group described above.

In the general formula (I), for ring A, 5-membered heteroaryl is preferable, thiophene ring is more preferable, and thiophene ring represented by the following formula is particularly preferable:

[ chemical formula 8]

For R^APreferably a halogen atom, optionally substituted lower alkyl, COOW¹、CONW²W³Wherein W is¹To W³Independently represents a hydrogen atom or an optionally substituted lower alkyl group, or W²And W³May be bonded together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group or the like, more preferably a lower alkyl group substituted with a group selected from a hydroxyl group, a carboxyl group and a carbamoyl group, and a carboxyl group or a carbamoyl group, with a carboxyl group being most preferred. If m is 2 or more, R^AMay be the same or different. For m, 0 or 1 is preferred, and when m is 1, for R on the ring^AThe thiophene ring represented by the following formula is particularly preferable:

[ chemical formula 9]

In this case, for R^AOptionally substituted lower alkyl, COOW¹Or CONW²W³Is more preferred, wherein W¹To W³Independently represents a hydrogen atom or an optionally substituted lower alkyl group, or W²And W³May be combined with an adjacent nitrogen atom to form an optionally substituted cyclic amino group.

In the general formula (I), for E¹Oxygen atoms are preferred. For E²Preferably an oxygen atom.

In the general formula (I), as for ring B, a benzene ring, a thiophene ring or a pyridine ring is preferable, and a benzene ring or a thiophene ring is more preferable. In this case, the binding site of ring B is preferably represented by the following formula:

[ chemical formula 10]

And more preferably represented by the following formula:

[ chemical formula 11]

Wherein the left bond represents a bond to a nitrogen atom of the fused pyrimidine ring and the right bond represents a bond to U.

If n is 1 or 2, for having R on the ring^BRing B of (a), a benzene ring, a thiophene ring or a pyridine ring represented by the following formula:

[ chemical formula 12]

Wherein is different from R^BThe left bond of the bond represents a bond to a nitrogen atom of the fused pyrimidine ring and the right bond represents a bond to U. For R^BHalogen atom, optionally substituted lower alkyl, OW⁴(wherein W⁴Represents a hydrogen atom or an optionally substituted lower alkyl group), cyano group and the like are preferable, and a halogen atom, a lower alkyl group (which may be substituted with a halogen atom) or OW⁴More preferably, fluorine atom, chlorine atom or OW⁴(wherein W⁴Is lower alkyl) is particularly preferred. If n is 2, the two RBs may be the same or different. Furthermore, if R is present on the ring^BRing B of (a) is a benzene ring, a thiophene ring or a pyridine ring represented by the following formula:

[ chemical formula 13]

Wherein is different from R^B1And R^B2The left bond of any one of the bonds represents a bond to a nitrogen atom of the fused pyrimidine ring, the right bond represents a bond to U, and for R^B1Fluorine or chlorine atoms are preferred for R^B2Fluorine atom, methoxy group or ethoxy group is preferable, and methoxy group is more preferable.

In the general formula (I), preferably U is a single bond, a methylene group or an ethylene group.

In particular, (i) when U is a single bond, it is preferably represented by-S-L-Y, -O-L-Y, -CO-L-Y or-SO₂-L-Y, wherein L represents optionally substituted lower alkylene; y represents Z or-NW⁷W⁸Wherein W is⁷And W⁸Independently represents a hydrogen atom, an optionally substituted lower alkyl group or Z, provided that both are not simultaneously a hydrogen atom, or W⁷And W⁸Can be adjacent toThe adjacent nitrogen atoms are combined together to form an optionally substituted cyclic amino group; z represents optionally fused and optionally substituted cycloalkyl, optionally fused and optionally substituted heterocycloalkyl, optionally fused and optionally substituted aryl or optionally fused and optionally substituted heteroaryl, (ii) when U is methylene, for X, a group represented by Y is preferred, with the proviso that Y represents-NW⁷W⁸Wherein W is⁷And W⁸Independently represents a hydrogen atom, an optionally substituted lower alkyl group or Z, provided that both are not simultaneously a hydrogen atom, and preferably W⁷Is Z, or W⁷And W⁸(ii) may be taken together with the adjacent nitrogen atom to form an optionally substituted cyclic amino group, -S-Z or-O-Z, (iii) when U is ethylene, for X, preferably Y, provided that Y is Z and Z has the same meaning as defined above, since they give good haemodynamics.

For L, C_1-3Lower alkylene is preferred.

For Z, an optionally fused and optionally substituted heteroaryl group or an optionally fused and optionally substituted aryl group is preferable, and an optionally fused and optionally substituted aryl group is more preferable. In Z, as for a substituent which the optionally substituted heteroaryl group or the optionally substituted aryl group may have, a halogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group is preferable, and a halogen atom, a lower alkyl group which may be substituted by a halogen atom, a lower alkoxy group or a hydroxy group, or a lower alkoxy group which may be substituted by a halogen atom, a lower alkoxy group or a hydroxy group is more preferable.

As the substituent which the optionally substituted cyclic amino group, the optionally substituted cycloalkyl group or the optionally substituted heterocycloalkyl group may have, there may be exemplified, for example, an oxo group, a halogen atom, a cyano group, a hydroxyl group, an optionally substituted lower alkyl group, a cycloalkyl group, an optionally substituted lower alkoxy group, an optionally substituted (lower alkyl) thio group, a carboxyl group, an optionally substituted (lower alkoxy) carbonyl group, a carbamoyl group, a (di) (lower alkyl) carbamoyl group, an optionally substituted aryl group, an aryloxy group, a heteroaryl group, a heteroaryloxy group, an acylamino group and the like, and there may be mentionedIn the case of two or more groups selected from these groups, which may be the same or different, with the proviso that for R^AOptionally substituted cyclic amino NW in (1)²W³Forms may have substituents excluding aryl-containing groups from the above.

As the substituent which the optionally substituted aryl group or the optionally substituted heteroaryl group may have, for example, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an optionally substituted lower alkyl group, a cycloalkyl group, an optionally substituted lower alkoxy group, an optionally substituted (lower alkyl) thio group, a carboxyl group, an optionally substituted (lower alkoxy) carbonyl group, a carbamoyl group, a (di) (lower alkyl) carbamoyl group, an aryl group, an aryloxy group, a heteroaryl group, a heteroaryloxy group, an amido group and the like, and two or more groups selected from these groups, which may be the same or different, may be present.

In the optionally fused and optionally substituted cycloalkyl group, the optionally fused and optionally substituted heterocycloalkyl group, the optionally fused and optionally substituted aryl group, and the optionally fused and optionally substituted heteroaryl group, the above substituents may be present in the same or different rings in the fused ring.

If Z is optionally fused and optionally substituted cycloalkyl or optionally fused and optionally substituted heterocycloalkyl, it is preferred for the substituents which this group may have, optionally substituted aryl or heteroaryl.

As the substituent which the optionally substituted lower alkyl, optionally substituted lower alkylene, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted (lower alkyl) sulfonyl, optionally substituted (lower alkyl) sulfinyl, optionally substituted lower alkoxy, optionally substituted (lower alkyl) thio or optionally substituted (lower alkoxy) carbonyl may have, there may be exemplified halogen atom, cyano, hydroxy, lower alkoxy, (lower alkyl) thio, amino, (di) (lower alkyl) amino, carboxy, (lower alkoxy) carbonyl, carbamoyl, (di) (lower alkyl) carbamoyl, aryl, heteroaryl and the like, and two or more selected from these which may be the same or different, may be presentA group of radicals, with the proviso that in R^AIn (b), aryl or heteroaryl-containing groups are excluded from the above.

Examples of the method for producing the fused heterocyclic derivative represented by the general formula (I) of the present invention are shown below.

[ method 1]

In the fused heterocyclic derivative represented by the general formula (I) of the present invention, a compound wherein E is¹A compound which is an oxygen atom, for example, by the method 1.

[ chemical formula 14]

In the formula, R¹Represents a nitrile group or a (lower alkoxy) carbonyl group, ring A, ring B, R^A、R^B、m、n、E²U and X have the same meaning as defined above.

Step 1-1

The amine compound (1) can be converted into the isocyanato compound (2) by treating it in an inert solvent (e.g., tetrahydrofuran, dichloromethane, a mixed solvent thereof, etc.) for 30 minutes to 1 day in the presence of a base (e.g., triethylamine, N-diisopropylethylamine, pyridine, etc.) usually under ice cooling to reflux temperature using a reagent such as phosgene, diphosgene, triphosgene, etc.

Step 1-2

The urea compound (4) or the fused heterocyclic derivative (Ia) of the present invention can be prepared as follows: the isocyanato compound (2) is reacted with the amine compound (3) in an inert solvent (e.g., tetrahydrofuran, dichloromethane, etc.) in the presence or absence of a base (e.g., triethylamine, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc.), usually under ice cooling to reflux temperature, for 1 hour to 3 days.

Steps 1 to 3

The fused heterocyclic derivative (Ia) of the present invention can be prepared as follows: the urea compound (4) is allowed to stand in an inert solvent (e.g., tetrahydrofuran, dichloromethane, methanol, ethanol, N-dimethylformamide, water, etc.) in the presence or absence of a base (e.g., triethylamine, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium hydride, sodium hydroxide, etc.) for 5 minutes to 3 days, usually under ice-cooling to reflux temperature.

[ method 2]

In the fused heterocyclic derivative represented by the general formula (I) of the present invention, a compound wherein E is²A compound having an oxygen atom, for example, according to method 2.

[ chemical formula 15]

In the formula, ring A, ring B, R^A、R^BM, n, U and X have the same meaning as defined above.

Step 2-1

The amide compound (6) can be produced by condensing the carboxylic acid compound (5) and the amine compound (3) by a commonly used acid chloride method or a condensing agent. The acid chloride process may be carried out as follows: for example, the carboxylic acid compound (5) is treated with a reagent such as sulfinyl chloride, oxalyl chloride or the like for 30 minutes to 1 day to be converted into an acid chloride in an inert solvent (dichloromethane, 1, 2-dichloroethane or toluene) in the presence or absence of an additive (e.g., N-dimethylformamide or the like), usually under ice-cooling to reflux temperature, and the acid chloride is reacted with the amine compound (3) in an inert solvent (pyridine, dichloromethane, tetrahydrofuran, water or the like) in the presence or absence of a base (triethylamine, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium bicarbonate or the like), usually under ice-cooling to reflux temperature, for 1 hour to 3 days. The condensing agent method may be carried out as follows: for example, the carboxylic acid compound (5) is reacted with the amine compound (3) in an inert solvent (N, N-dimethylformamide, dichloromethane or tetrahydrofuran), in the presence of an additive (1-hydroxybenzotriazole or the like), in the presence or absence of a base (triethylamine, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine or the like), usually at room temperature to reflux temperature, using a condensing agent (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide or the like), for 1 hour to 3 days.

Step 2-2

The amine compound (7) can be prepared as follows: the nitro group of the amide compound (6) is reduced by a commonly used catalytic reduction method, a metal hydrogen complex reduction method or the like. The catalytic reduction process may be carried out as follows: for example, the amide compound (6) is treated in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.) for 1 hour to 3 days using a catalyst (palladium-carbon powder, etc.), usually at room temperature to reflux temperature. The metal hydrogen complex reduction method may be carried out as follows: for example, the amide compound (6) is treated in an inert solvent (methanol, ethanol, tetrahydrofuran, etc.) with a reducing agent (sodium borohydride, etc.) in the presence of an additive (nickel (II) bromide, etc.), usually under ice cooling to room temperature, for 30 minutes to 1 day.

Step 2 to 3

The fused heterocyclic derivative (Ib) of the present invention can be prepared as follows: the amine compound (7) is treated in an inert solvent (tetrahydrofuran, dichloromethane, N-dimethylformamide and the like) with a reagent such as phosgene, diphosgene, triphosgene, 1' -carbonyldi-1H-imidazole and the like in the presence or absence of a base (triethylamine, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride and the like), usually under ice-cooling to reflux temperature for 30 minutes to 1 day.

Step 2 to step 4

The fused heterocyclic derivative (Ic) of the present invention can be prepared as follows: the amine compound (7) is treated in an inert solvent (tetrahydrofuran, N-dimethylformamide, methanol or ethanol) with a reagent such as carbon disulfide or the like in the presence of a base (triethylamine, N-diisopropylethylamine, sodium hydride, sodium hydroxide, potassium hydroxide or the like), usually under ice cooling to reflux temperature for 1 hour to 3 days.

Step 2 to step 5

The fused heterocyclic derivative (Id) of the present invention can be prepared as follows: the amine compound (7) is treated in an inert solvent (tetrahydrofuran, N-dimethylformamide, methanol or ethanol, etc.) with a reagent such as diphenylcyanocarboximidoate, etc. in the presence of a base (triethylamine, N-diisopropylethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, etc.), usually under ice cooling to reflux temperature, for 1 hour to 3 days.

[ method 3]

In the above method 1 or 2, the amine compound (3) used as a starting material can also be obtained as follows: the nitro compound (8) which is commercially available or synthesized by a method described in the literature or a combination of conventional synthetic methods or the like is reduced by a conventional reduction method or the like. For example, it can be prepared by the following method 3.

[ chemical formula 16]

In the formula, ring B, R^BN, U and X have the same meaning as defined above.

Step 3

The amine compound (3) can be prepared as follows: the nitro compound (8) is reduced by a commonly used catalytic reduction method, a metal hydrogen complex reduction method or the like. The catalytic reduction process may be carried out as follows: for example, the nitro compound (8) is treated in an inert solvent (methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, etc.) using a catalyst (palladium-carbon powder, rhodium-carbon powder, platinum-carbon powder, etc.), usually at room temperature to reflux temperature, for 1 hour to 3 days. The metal hydrogen complex reduction method may be carried out as follows: for example, the nitro compound (8) is treated in an inert solvent (methanol, ethanol, tetrahydrofuran, etc.) with a reducing agent (sodium borohydride, etc.) in the presence of an additive (nickel (II) bromide, etc.), usually under ice cooling to room temperature, for 30 minutes to 1 day.

Further, when the compound used or prepared in the above-mentioned method has a functional group which changes or inhibits the progress of the reaction under the reaction conditions, it is needless to say that the group may be protected with a suitable protecting group which is generally used by those skilled in the art, and the protecting group may be removed in a suitable step.

The fused heterocyclic derivative represented by the general formula (I) of the present invention can be converted into a prodrug by reacting it with a reagent for preparing a prodrug, in which its carboxyl group, hydroxyl group and/or amino group is converted. Further, the prodrug of the fused heterocyclic derivative represented by the general formula (I) of the present invention may be a compound converted into the compound (I) of the present invention under physiological conditions described in the following documents: "Iyakuhin no Kaihatsu" (Development of medicine), Vol.7, Molecular design, pp.163-198, published by Hirokawassyote (Hirokawa Book store).

The fused heterocyclic derivative represented by the general formula (I) or a prodrug thereof can be converted into a pharmaceutically acceptable salt thereof by a conventional method. As such a salt, for example: salts with inorganic acids such as hydrochloric acid, nitric acid, and the like; salts with organic acids such as acetic acid, methanesulfonic acid, and the like; and sodium and potassium salts; addition salts with organic bases such as N, N' -dibenzylethylenediamine, 2-aminoethanol, and the like.

In some cases, a hydrate or solvate of the fused heterocyclic derivative represented by the general formula (I) or a prodrug thereof may be obtained in the form during purification or preparation of a salt thereof. For the pharmaceutical composition of the present invention, a fused heterocyclic derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof may be used.

In addition, the fused heterocyclic derivative represented by the general formula (I) or a prodrug thereof sometimes has tautomers, geometrical isomers and/or optical isomers. For the pharmaceutical composition of the present invention, any isomer and mixture thereof may be used.

The fused heterocyclic derivative (I) of the present invention has excellent GnRH antagonistic activity, and can control the action of gonadotropin releasing technology and control the production and secretion of gonadotropin and sex hormone. Thus, the fused heterocyclic derivative (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is useful as an agent for preventing or treating sex hormone-dependent diseases such as benign prostatic hypertrophy, hysteromyoma, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, short stature, sleep disorders, acne, alopecia, alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumor; useful as a reproduction regulator, a contraceptive and an ovulation inducer or an agent for preventing postoperative recurrence of sex hormone-dependent cancer, etc.

The fused heterocyclic derivative (I) of the present invention, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof can be mixed with a conventional pharmaceutical carrier to prepare a pharmaceutical composition.

Pharmaceutical carriers may optionally be used in combination in the dosage forms described below. As the pharmaceutical carrier, there can be exemplified, for example, excipients such as lactose and the like; lubricants such as magnesium stearate and the like; disintegrants such as carboxymethylcellulose and the like; binders such as hydroxypropyl methylcellulose, and the like; surface active substances such as polyethylene glycol and the like; foaming agents such as sodium bicarbonate and the like; dissolution aids such as cyclodextrins and the like; acidic agents such as citric acid and the like; stabilizers such as sodium edetate and the like; pH adjusting agents such as phosphates and the like.

As the dosage form of the pharmaceutical composition of the present invention, there can be exemplified, for example, oral administration preparations such as powder, granules, fine granules, dry syrup, tablets, capsules and the like; parenteral administration preparations such as injections, creams, suppositories, and the like, and oral administration preparations are preferable.

Preferably, the above-mentioned preparation is prepared in such a manner that an appropriate dose of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof of the present invention in the preparation is in the range of 0.1 to 1,000 mg per day in the case of oral administration to each adult, and in the range of about 0.01 to 100 mg per day in the case of parenteral injection to each adult.

In addition, the pharmaceutical compositions of the present invention may include other drugs. Examples of the other drugs may be exemplified by, including GnRH agonists (e.g., leuprolide acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin, lecirelin, etc.), chemotherapeutic agents (e.g., ifosfamide, doxorubicin, puromycin, cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, mitoxantrone, taxol, polyenoic taxol (dotaxel), etc.), peptide GnRH antagonists (e.g., cetrorelix, ganirelix, abarelix, ozarelix, itorelix, degarelix, teverrelix, etc.), 5 α -reductase inhibitors (e.g., finasteride, dutasteride, etc.),

alpha-adrenoceptor inhibitors (e.g., tamsulosin, cilostaxin, urapidil, etc.), aromatase inhibitors (e.g., fadrozole, letrozole, anastrozole, formestane, etc.), adrenoandrogen production inhibitors (e.g., liazole, etc.), hormone therapy agents (e.g., antiestrogens such as tamoxifen, fulvestrant, etc., progestational agents such as medroxyprogesterone, etc., androgenic agents, estrogenic agents and antiandrogenic agents such as oxandrolone, flutamide, nilutamide, bicalutamide, etc.), and the like.

Examples

The present invention is further illustrated in more detail by the following examples and test examples. However, the present invention is not limited thereto.

Reference example 1

2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline

To a suspension of 1, 2, 3, 4-tetrahydroquinoline (3.12 g) and sodium bicarbonate (2.66 g) in tetrahydrofuran (60 ml) were added water (6 ml) and a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (5.4 g) in tetrahydrofuran (30 ml) in this order, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water, 1mol/L hydrochloric acid, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1- [ (4-chloro-3-nitrophenyl) sulfonyl ] -1, 2, 3, 4-tetrahydroquinoline (5.0 g). This material was dissolved in tetrahydrofuran (45 ml). To the solution were added methanol (45 ml), nickel (II) bromide (0.15 g) and sodium borohydride (1.61 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 3/1) to give the title compound (4.33 g).

Reference examples 2 to 11

The compounds of reference examples 2 to 11 described in tables 1 to 2 were obtained in a similar manner to that described in reference example 1 using the corresponding starting materials.

Reference example 12

2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylmethyl) aniline

To a solution of 4-chloro-3-nitrobenzyl alcohol (1 g) in dichloromethane (10 ml) were added triethylamine (1.12 ml) and methanesulfonyl chloride (0.5 ml) under ice-cooling, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give (4-chloro-3-nitrobenzyl) methanesulfonate (1.08 g). This material was dissolved in acetonitrile (4 ml) -ethanol (4 ml). To this solution was added 1, 2, 3, 4-tetrahydroquinoline (1.62 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60 ℃ overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate-3/1) to give 1- (4-chloro-3-nitrobenzyl) -1, 2, 3, 4-tetrahydroquinoline (1.22 g). This material was dissolved in tetrahydrofuran (12 ml). To the solution were added methanol (12 ml), nickel (II) bromide (44 mg) and sodium borohydride (0.46 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 3/1) to give the title compound (0.79 g).

Reference example 13

3-benzyloxy-6-chloroaniline

4-chloro-3-nitrophenol (0.13 g) was dissolved in N, N-dimethylformamide (3 ml). To the solution were added potassium carbonate (0.31 g) and benzyl bromide (0.14 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethyl ether, and the resulting mixture was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (3 ml). To the solution were added methanol (3 ml), nickel (II) bromide (8 mg) and sodium borohydride (85 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.15 g).

Reference examples 14 to 17

The compounds of reference examples 14 to 17 described in table 2 were obtained in a similar manner to that described in reference example 13 using the corresponding starting materials.

Reference example 18

3- (2-phenylethyl) aniline

A mixture of 3-bromonitrobenzene (1 g), styrene (1.7 ml), palladium (II) acetate (95 mg), tris (2-methylphenyl) phosphine (0.3 g) and N, N-diisopropylamine (5 ml) was heated at reflux for 24 hours. The reaction mixture was diluted with ether, and the resulting mixture was washed with 1mol/L hydrochloric acid, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate ═ 10/1) to give 3- ((E) -2-phenylvinyl) nitrobenzene (0.76 g). To a solution of the obtained 3- ((E) -2-phenylvinyl) nitrobenzene (0.26 g) in methanol (10 ml) was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.22 g).

Reference example 19

Diethyl 2-aminothiophene-3, 4-dicarboxylate

To a mixture of sulfur (6.9 g), ethyl pyruvate (25 g) and ethyl cyanoacetate (24.4 g) in N, N-dimethylformamide (130 ml) was added triethylamine (21.8 g) over 30 minutes at room temperature, and the reaction mixture was stirred at 50 ℃ for 2 hours. Water (1 l) and brine (50 ml) were added to the reaction mixture, and the resulting mixture was extracted three times with diethyl ether (250 ml). The extract was dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (eluent: ether) to obtain the title compound (28.2 g).

Reference example 20

1- (2-fluoro-6-methoxyphenyl) ethanol

To a solution of 2-fluoro-6-methoxybenzaldehyde (0.5 g) in tetrahydrofuran (10 ml) was added methyllithium (1.15 mol/l in diethyl ether, 3.4 ml) at-78 ℃, and the mixture was stirred at the same temperature for 1 hour. The mixture was then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.45 g).

Reference example 21

2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] aniline

To a solution of 4-fluoro-3-nitrophenol (which was synthesized according to the procedure described in international publication WO 97/39064) (0.2 g), 1- (2-fluoro-6-methoxyphenyl) ethanol (0.22 g), and triphenylphosphine (0.4 g) in tetrahydrofuran (1.5 ml) was added diisopropyl azodicarboxylate (40% toluene solution, 0.84 ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 8/1) to give 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] -1-nitrobenzene (0.15 g). This material was dissolved in tetrahydrofuran (3 ml). To the solution were added methanol (3 ml), nickel (II) bromide (5 mg) and sodium borohydride (55 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 3/1) to give the title compound (0.11 g).

Reference examples 22 to 29

The compounds of reference examples 22 to 29 described in tables 3 to 4 were obtained in a similar manner to that described in reference example 13 or reference example 21 using the corresponding starting materials.

Reference example 30

1- [ 4-fluoro-3- (tert-butoxycarbonylamino) phenyl ] -2-methyl-1-propanone

To concentrated sulfuric acid (10 ml) was added 1- (4-fluorophenyl) -2-methyl-1-propanone (2.92 g) at-20 ℃, and the mixture was stirred at the same temperature for 15 minutes. A mixture of fuming nitric acid (1.4 ml) and concentrated sulfuric acid (4.2 ml) was added to the mixture at-20 ℃, and the mixture was stirred at the same temperature for 20 minutes. Ice (100 g) was added to the reaction mixture, and the mixture was warmed to room temperature with stirring. The mixture was extracted with ethyl acetate, and the extract was washed successively with water (three times), saturated aqueous sodium bicarbonate solution (two times), brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 95/5-85/15) to give 1- (4-fluoro-3-nitrophenyl) -2-methyl-1-propanone (1.8 g). This material was dissolved in ethanol (5 ml). To the solution was added 10% palladium-carbon powder (0.36 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 90/10-83/17) to give 1- (3-amino-4-fluorophenyl) -2-methyl-1-propanone (1.45 g). This material was dissolved in tetrahydrofuran (33 ml). To the solution were added 4-dimethylaminopyridine (0.29 g) and di (tert-butyl) dicarbonate (3.49 g), and the mixture was heated under reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: N-hexane-N-hexane/ethyl acetate-95/5) to give 1- { 4-fluoro-3- [ N, N-di (tert-butoxycarbonyl) amino ] phenyl } -2-methyl-1-propanone (1.8 g). This material was dissolved in methanol (15 ml). To the solution was added potassium carbonate (1.96 g), and the mixture was stirred at 60 ℃ for 30 minutes. The reaction mixture was cooled to room temperature. Water and brine were added to the mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 5/1) to give the title compound (1.14 g).

Reference example 31

1- (3-amino-4-fluorophenyl) -2- (5-fluoro-2-methoxyphenyl) -2-methyl-1-propanone

A mixture of 1- [ 4-fluoro-3- (tert-butoxycarbonylamino) phenyl ] -2-methyl-1-propanone (0.11 g), 2-bromo-4-fluoroanisole (0.057 ml), palladium (II) acetate (4.5 mg), tris (tert-butyl) phosphonium tetrafluoroborate (5.8 mg) and sodium tert-butoxide (96 mg) in tetrahydrofuran (1 ml) was stirred at 70 ℃ under an argon atmosphere for 3 days. Water was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was poured into 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate ═ 10/1) to give 1- [ 4-fluoro-3- (tert-butoxycarbonylamino) phenyl ] -2- (5-fluoro-2-methoxyphenyl) -2-methyl-1-propanone (45 mg). This material was dissolved in hydrochloric acid (4 mol/l ethyl acetate solution, 3 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by aminopropyl silica gel column chromatography (eluent: n-hexane/ethyl acetate 4/1-3/1) to give the title compound (25 mg).

Reference examples 32 to 35

The compounds of reference examples 32 to 35 described in tables 4 to 5 were obtained in a similar manner to that described in reference example 31 using the corresponding starting materials.

Reference example 36

3- (1-Phenylethylthio) anilines

To a mixture of 3-mercaptoaniline (1 g) and potassium carbonate (1.21 g) in N, N-dimethylformamide (20 ml) was added 1-phenethyl bromide (1.2 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 1/1) to give the title compound (1.78 g).

Reference example 37

The compound of referential example 37 described in table 5 was obtained in a similar manner to that described in referential example 36 using the corresponding starting materials.

Reference example 38

3- (1-methyl-1-phenylethylthio) aniline

To a mixed solution of water (1.6 ml) -concentrated sulfuric acid (1.6 ml) was added 3-nitrothiophenol (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the mixture was added a solution of α -methylstyrene (0.38 g) in tetrahydrofuran (1.6 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate solution and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 3/2) to give 3- (1-methyl-1-phenylethynylthio) nitrobenzene (0.88 g). This material was dissolved in tetrahydrofuran (10 ml). To the solution were added methanol (10 ml), nickel (II) bromide (35 mg) and sodium borohydride (0.37 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 3/2) to give the title compound (0.69 g).

Reference example 39

3-amino-4-fluoro-N-methyl-N-phenylbenzamides

To a solution of 4-fluoro-3-nitrobenzoic acid (2 g) in dichloromethane (50 ml) were added N, N-dimethylformamide (0.01 ml) and oxalyl chloride (6.86 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (10 ml) was added to a mixture of N-methylaniline (1.22 g) and sodium bicarbonate (2.72 g) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1mol/l hydrochloric acid, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-fluoro-3-nitro-N-methyl-N-phenylbenzamide (2.95 g). This material was dissolved in tetrahydrofuran (50 ml). To the solution were added methanol (50 ml), nickel (II) bromide (0.12 g) and sodium borohydride (1.26 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 1/1) to give the title compound (2.33 g).

Reference example 40

The compound of referential example 40 described in table 5 was obtained in a similar manner to that described in referential example 39 using the corresponding starting materials.

Reference examples 41 to 42

The compounds of referential examples 41 to 42 described in table 5 were obtained in a similar manner to that described in referential example 21 using the corresponding starting materials.

Reference example 43

4-fluoro-2-methoxy-5-nitrobenzenesulfonyl chloride

A mixture of 3-fluoro-4-nitrophenol (2.56 g), potassium carbonate (4.5 g) and methyl iodide (4.63 g) in N, N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was washed with diethyl ether. The extract was washed twice with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-fluoro-4-nitroanisole (2.56 g). This material was dissolved in 1, 2-dichloroethane (13 ml). Chlorosulfonic acid (1.3 ml) was added to the solution, and the mixture was heated at reflux for 4 hours. The reaction mixture was diluted with dichloromethane, and the resulting mixture was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 2/1) to give the title compound (0.51 g).

Reference examples 44 to 69

The compounds of reference examples 44 to 69 described in tables 6 to 9 were obtained in a similar manner to that described in reference example 1 using the corresponding starting materials.

Reference example 70

4-amino-5-methylthiophene-2, 3-dicarboxylic acid dimethyl ester hydrochloride

To methanol (15 ml), sodium (0.38 g) was added under ice-cooling, and the mixture was stirred at the same temperature until the sodium was dissolved. To the reaction mixture were added ethyl 2-mercaptopropionate (1.81 g) and dimethyl fumarate (2.17 g), and the mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature. To the mixture was added water (100 ml), and the resulting mixture was washed with diethyl ether. The aqueous layer was cooled in ice, acidified by adding 2 mol/L hydrochloric acid, and the resulting mixture was extracted twice with ethyl acetate. The extracts were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 4/1-3/1) to give 5-methyl-4-oxo-2, 3-dimethoxycarbonyltetrahydrothiophene (2.68 g). This material was dissolved in methanol (8 ml). Hydroxylamine hydrochloride (0.92 g) was added to the solution, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (24 ml) was added to the mixture, and the resulting mixture was stirred for 10 minutes. The precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give the title compound (0.77 g).

Reference examples 71 to 72

The compounds of reference examples 71 to 72 described in table 9 were obtained in a similar manner to that described in reference example 30 using the corresponding starting materials.

Reference examples 73 to 77

The compounds of referential examples 73 to 77 described in tables 9 to 10 were obtained in a similar manner to that described in referential example 31 using the corresponding starting materials.

Reference example 78

4-bromo-2- (tert-butoxycarbonylamino) -1-fluorobenzene

To a mixture of 1-bromo-4-fluoro-3-nitrobenzene (1.56 g), nickel (II) bromide (78 mg), methanol (28 ml) and tetrahydrofuran (28 ml) was added sodium borohydride (805 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 30 minutes, and the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5-bromo-2-fluoroaniline (1.3 g). This material was dissolved in tetrahydrofuran (30 ml). To the solution were added 4-dimethylaminopyridine (0.26 g) and di (tert-butyl) dicarbonate (3.1 g), and the mixture was heated under reflux for 1.5 hours. The reaction mixture was poured into 0.5 mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Methanol (21 ml) and potassium carbonate (2.94 g) were added to the residue, and the mixture was heated under reflux for 2 hours. Water was added to the reaction mixture, and the mixture was poured into brine. The resulting mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 95/5) to give the title compound (1.72 g).

Reference example 79

2- (3-amino-4-fluorophenyl) -1- (2-methoxyphenyl) -2-methyl-1-propanone

A mixture of 1- (2-methoxyphenyl) -2-methyl-1-propanone (0.58 g), 4-bromo-2- (tert-butoxycarbonylamino) -1-fluorobenzene (0.94 g), palladium (II) acetate (37 mg), tris (tert-butyl) phosphonium tetrafluoroborate (47 mg) and sodium tert-butoxide (0.78 g) in tetrahydrofuran (10 ml) was stirred at 60 ℃ overnight under an argon atmosphere. Water was added to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was poured into 1mol/l hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 95/5-85/15) to give 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl ] -1- (2-methoxyphenyl) -2-methyl-1-propanone (0.91 g). To the obtained 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl ] -1- (2-methoxyphenyl) -2-methyl-1-propanone (0.34 g) was added hydrochloric acid (4 mol/l ethyl acetate solution, 3 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.22 g).

Reference examples 80 to 81

The compounds of referential examples 80 to 81 described in Table 10 were obtained in a similar manner to that described in referential example 79 using the corresponding starting materials.

Reference example 82

In a similar manner to that described in reference example 21, using phenol and 4-chloro-3-nitrobenzyl alcohol in place of 4-fluoro-3-nitrophenol and 1- (2-fluoro-6-methoxyphenyl) ethanol, respectively, the compounds described in reference example 82 in Table 11 were obtained.

Reference example 83

2-chloro-5- (2-phenylethyl) aniline

To a suspension of 4-chloro-3-nitrobenzaldehyde (1 g) and benzyltriphenylphosphonium bromide (2.34 g) in toluene (35 ml) was added sodium hydride (55%, 0.28 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 10/1) to give 2-chloro-5- ((Z) -2-phenylvinyl) -1-nitrobenzene (0.79 g). The obtained 2-chloro-5- ((Z) -2-phenylvinyl) -1-nitrobenzene (0.16 g) was dissolved in ethanol (6 ml) -methanol (2 ml). To the solution were added 5% rhodium-carbon powder (20 mg) and morpholine (5 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 5/1) to give the title compound (87 mg).

Reference example 84

1- (tert-Butoxycarbonylamino) -5-ethynyl-2-fluorobenzene

A mixture of 4-bromo-2- (tert-butoxycarbonylamino) -1-fluorobenzene (0.57 g), trimethylsilylacetylene (0.55 ml), tetrakis (triphenylphosphine) palladium (0) (23 mg) and copper (I) iodide (7 mg) in N, N-diisopropylamine (5.7 ml) was stirred at 80 ℃ overnight. The reaction mixture was cooled to room temperature and the mixture was diluted with ether. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 15/1) to give 1- (tert-butoxycarbonylamino) -2-fluoro-5-trimethylsilylethynyl benzene (0.6 g). This material was dissolved in tetrahydrofuran (10 ml). To the solution was added tetra (n-butyl) ammonium fluoride (1 mol/l tetrahydrofuran solution, 2.4 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 20/1-10/1) to give the title compound (0.34 g).

Reference example 85

2-bromo-3, 4-difluoroanisole

To a solution of 3, 4-difluoroanisole (2 ml) in tetrahydrofuran (50 ml) was added n-butyllithium (2.67 mol/l n-hexane solution, 6.95 ml) at-78 ℃, and the mixture was stirred at the same temperature for 30 minutes. Bromine (1.04 ml) was added to the reaction mixture, and the mixture was stirred at-78 ℃ for 15 minutes. The mixture was stirred for 1 hour under ice-cooling. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate solution and brine, successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 9/1) to give the title compound (0.91 g).

Reference example 86

2-fluoro-5- (2-phenylethyl) aniline

A mixture of 1- (tert-butoxycarbonylamino) -5-ethynyl-2-fluorobenzene (0.11 g), iodobenzene (0.1 g), tetrakis (triphenylphosphine) palladium (0) (16 mg), and copper (I) iodide (5 mg) in N, N-diisopropylamine (2 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 10/1) to give 1- (tert-butoxycarbonylamino) -2-fluoro-5-phenylethynylbenzene (0.14 g). The material was dissolved in ethyl acetate (30 ml). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give 1- (tert-butoxycarbonylamino) -2-fluoro-5- (2-phenylethyl) benzene (0.11 g). Hydrochloric acid (4 mol/l ethyl acetate solution, 3 ml) was added to the substance, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 8/1-5/1) to give the title compound (53 mg).

Reference examples 87 to 99

The compounds of referential examples 87 to 99 described in tables 11 to 13 were obtained in a similar manner to that described in referential example 86 using the corresponding starting materials.

Reference example 100

2-fluoro-4-methoxy-5- (2-phenylethyl) aniline

A mixture of 2-bromo-5-fluoro-4-nitroanisole (0.46 g), phenylacetylene (67 mg), tetrakis (triphenylphosphine) palladium (0) (38 mg) and copper (I) iodide (13 mg) in N, N-diisopropylamine (5 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 10/1-5/1) to give 5-fluoro-4-nitro-2-phenylethynyl anisole (0.18 g). This material was dissolved in ethyl acetate (5 ml). To the solution was added 10% palladium-carbon powder (0.45 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 10/1-4/1) to give the title compound (87 mg).

Reference example 101

2-fluoro-5- [2- (2-methoxyphenyl) -1, 1-dimethylethyl ] aniline

To a mixture of 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl ] -1- (2-methoxyphenyl) -2-methyl-1-propanone (0.59 g) in tetrahydrofuran (7.5 ml) -water (0.75 ml) was added sodium borohydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate ═ 4/1) to give 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl ] -1- (2-methoxyphenyl) -2-methyl-1-propanol (0.54 g). This material was dissolved in ethanol (8 ml) -tetrahydrofuran (3 ml). To the solution were added 2 mol/l hydrochloric acid (0.2 ml) and 10% palladium-carbon powder (0.27 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. Sodium bicarbonate was added to the reaction mixture, and the mixture was stirred for 10 minutes. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 7/1) to give 2- [3- (tert-butoxycarbonylamino) -4-fluorophenyl ] -1- (2-methoxyphenyl) -2-methylpropane (0.15 g). Hydrochloric acid (4 mol/l ethyl acetate solution, 3 ml) was added to the substance, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give the title compound (0.11 g).

Reference example 102

4-chloro-3-nitrothiophenol

To concentrated hydrochloric acid (30 ml) was added 4-chloro-3-nitroaniline (5.18 g) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. To the mixture was added a solution of sodium nitrite (3.1 g) in water (30 ml). The mixture was heated to 50 ℃. To the mixture was added a solution of O-ethyldithiopotassium carbonate (14.4 g) in water (60 ml), and the mixture was stirred at 50 ℃ for 1 hour. The reaction mixture was cooled to room temperature and the mixture was extracted twice with ether. The extracts were combined, washed with a 1mol/l aqueous sodium hydroxide solution, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 7/3) to give O-ethyl S- (4-chloro-3-nitrophenyl) dithiocarbonate (2.96 g). This material was dissolved in tetrahydrofuran (50 ml). The solution was added to a suspension of lithium aluminum hydride (1.62 g) in tetrahydrofuran (50 ml) under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled in ice. To the mixture were added water (1.8 ml), 15% aqueous sodium hydroxide solution (1.8 ml) and water (5.4 ml), and the mixture was stirred at room temperature for 30 minutes. Insoluble material was removed by filtration and diluted with ethyl acetate. The resulting mixture was washed with 1mol/l hydrochloric acid, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 9/1-1/9) to give the title compound (1.28 g).

Reference example 103

5-benzylthio-2-chloroaniline

To a solution of 4-chloro-3-nitrothiophenol (0.4 g) and benzyl bromide (0.3 ml) in N, N-dimethylformamide (6 ml) was added potassium carbonate (0.44 g), and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 9/1) to give 1-benzylthio-4-chloro-3-nitrobenzene (0.54 g). This material was dissolved in methanol (5 ml) -tetrahydrofuran (5 ml). To the solution were added nickel (II) bromide (21 mg) and sodium borohydride (0.22 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1) to give the title compound (0.38 g).

Reference example 104

2-fluoro-5-mercaptoaniline

To a mixture of 5-bromo-2-fluoroaniline (4.15 g), methyl 3-mercaptopropionate (2.62 g), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.63 g) and N, N-diisopropylethylamine (5.64 g) in 1, 4-dioxane (80 ml) was added tris (dibenzylideneacetone) dipalladium (0) (0.3 g), and the mixture was heated at reflux under an argon atmosphere overnight. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 20/1-5/1-2/1) to give 2-fluoro-5- (2-methoxycarbonylethylthio) aniline (4.62 g). This material was dissolved in tetrahydrofuran (120 ml). To the solution was added potassium tert-butoxide (1 mol/l tetrahydrofuran solution, 80.6 ml) at-78 ℃ and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 1mol/l hydrochloric acid (81 ml), and the mixture was warmed to room temperature and stirred for 5 minutes. The mixture was poured into ethyl acetate, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 4/1) to give the title compound (1.85 g).

Reference example 105

2-fluoro-6-methoxybenzyl alcohol

To a solution of 2-fluoro-6-methoxybenzaldehyde (0.63 g) in tetrahydrofuran (5 ml) were added water (0.5 ml) and sodium borohydride (0.17 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and the solvent was removed under reduced pressure to give the title compound (0.58 g).

Reference examples 106 to 107

The compounds of referential examples 106 to 107 described in Table 14 were obtained in a similar manner to referential example 105 using the corresponding starting materials.

Reference example 108

2-fluoro-6-methoxybenzyl bromide

Methanesulfonyl chloride (0.43 ml) was added to a solution of 2-fluoro-6-methoxybenzyl alcohol (0.78 g) and triethylamine (0.91 ml) in ethyl acetate (12 ml) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The insoluble material was removed by filtration and washed with ethyl acetate (4 ml). The filtrate and washings were combined. Lithium bromide monohydrate (2.62 g) was added to the mixture, and the mixture was stirred at 55 ℃ for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 7/3) to give the title compound (0.82 g).

Reference examples 109 to 110

The compounds of reference examples 109 to 110 described in table 14 were obtained in a similar manner to that described in reference example 108 using the corresponding starting materials.

Reference example 111

2- (5-fluoro-2-methoxyphenyl) -2-propanol

To a solution of 5-fluoro-2-methoxybenzaldehyde (1 g) in acetone (4 ml) was added a solution of potassium permanganate (1.54 g) in water (16 ml) and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature. To the mixture was added 2 mol/l aqueous sodium hydroxide solution (5.2 ml), and insoluble matter was removed by filtration. The filtrate was washed with ethyl acetate. The aqueous layer was acidified by adding 2 mol/L hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1-ethyl acetate) to give 5-fluoro-2-methoxybenzoic acid (0.66 g). This material was dissolved in N, N-dimethylformamide (15 ml). To the solution were added potassium carbonate (0.63 g) and methyl iodide (0.26 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give methyl 5-fluoro-2-methoxybenzoate (0.7 g). This material was dissolved in tetrahydrofuran (10 ml). To the solution was added magnesium methyliodide (3.0 mol/l ether solution, 3.82 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 1/1) to give the title compound (0.65 g).

Reference examples 112 to 113

The compounds of reference examples 112 to 113 described in table 14 were obtained in a similar manner to that described in reference example 111 using the corresponding starting materials.

Reference example 114

2-fluoro-5- (2-fluorobenzylthio) aniline

To a solution of 2-fluoro-5-mercaptoaniline (0.13 g) and 2-fluorobenzyl bromide (0.12 ml) in N, N-dimethylformamide (5 ml) was added potassium carbonate (0.25 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ether, and the resulting mixture was washed with water (twice) and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 6/1) to give the title compound (0.17 g).

Reference examples 115 to 126

The compounds of reference examples 115 to 126 described in tables 15 to 16 were obtained in a similar manner to that described in reference example 114 using the corresponding starting materials.

Reference example 127

2-fluoro-5- (1-methyl-1-phenylethylthio) aniline

To a mixture of water (10 ml) and concentrated sulfuric acid (10 ml) were added a solution of 2-fluoro-5-mercaptoaniline (1.85 g) and 2-phenyl-2-propanol (1.76 g) in this order in tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate solution and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 6/1-3/1) to give the title compound (1.55 g).

Reference examples 128 to 141

The compounds of referential examples 128 to 141 described in tables 16 to 18 were obtained in a similar manner to that described in referential example 127 using the corresponding starting materials.

Reference example 142

4-fluoro-2-methoxy-5-nitrophenol

To a solution of 4-fluoro-2-methoxyphenol (1.42 g) and triethylamine (1.67 ml) in dichloromethane (20 ml) was added ethyl chloroformate (1.05 ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 0.5 mol/l hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. Concentrated sulfuric acid (7 ml) was added to the residue under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. A mixture of fuming nitric acid (0.7 ml) and concentrated sulfuric acid (1 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate. The extract was washed with water (twice) and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 90/10-67/33) to give 2-ethoxycarbonyloxy-5-fluoro-4-nitroanisole (0.48 g). To this material were added methanol (8 ml) and sodium bicarbonate (0.31 g), and the mixture was stirred at room temperature for 42 hours. The reaction mixture was poured into 0.5 mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate-4/1), collected by filtration, and dried under reduced pressure to give the title compound (0.25 g).

Reference examples 143 to 147

The compounds of referential examples 143 to 147 described in tables 18 to 19 were obtained in a similar manner to referential example 142 using the corresponding starting materials.

Reference example 148

2-ethoxy-4-fluoro-5-nitrophenol

To a suspension of 4 '-fluoro-2' -hydroxyacetophenone (3.08 g), cesium carbonate (13.0 g) and sodium iodide (0.6 g) in N, N-dimethylformamide (20 ml) was added ethyl bromide (2.24 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue and a solution of 4, 4' -thiobis (6-tert-butyl-o-cresol) (39 mg) in dichloromethane (57.6 ml) was added 3-chloroperbenzoic acid (4.97 g) under ice-cooling, and the mixture was heated at reflux overnight. The reaction mixture was cooled in ice. To the mixture was added a 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 20 minutes. The organic layer was separated, washed with water (three times), a saturated aqueous sodium bicarbonate solution, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 ml) -tetrahydrofuran (20 ml). Sodium methoxide (28% methanol solution, 5 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-ethoxy-4-fluorophenol (3.0 g). The title compound was obtained in a similar manner to that described in reference example 142 using this material in place of 4-fluoro-2-methoxyphenol.

Reference example 149

The compound of referential example 149 described in table 19 was obtained in a similar manner to that described in referential example 20 using the corresponding starting materials.

Reference example 150

2- [2- (tert-butyldimethylsilyloxy) ethoxy ] benzyl alcohol

To a suspension of 2-hydroxybenzyl alcohol (0.4 g) and potassium carbonate (0.67 g) in N, N-dimethylformamide (6 ml) was added 2- (tert-butyldimethylsilyloxy) ethyl bromide (1.05 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether, and the resulting mixture was washed with water, a 1mol/l aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 5/1) to give the title compound (0.32 g).

Reference example 151

The compound of referential example 151 described in table 19 was obtained in a similar manner to that described in referential example 150 using the corresponding starting materials.

Reference example 152

2- (tert-butyldimethylsilyloxymethyl) benzyl alcohol

To a solution of 1, 2-benzenedimethanol (2 g) and imidazole (1.13 g) in N, N-dimethylformamide (30 ml) was added tert-butyldimethylsilyl chloride (2.08 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1mol/L hydrochloric acid, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 3/2) to give the title compound (1.46 g).

Reference examples 153 to 154

The compounds of referential examples 153 to 154 described in table 20 were obtained in a similar manner to that described in referential example 152 using the corresponding starting materials.

Reference example 155

2, 3-difluoro-6- (2-methoxyethoxy) benzyl alcohol

To a suspension of 2, 3-difluoro-6-hydroxybenzaldehyde (0.63 g) and potassium carbonate (0.83 g) in N, N-dimethylformamide (4 ml) was added 2-methoxyethyl bromide (0.45 ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 85/15-60/40) to give 2, 3-difluoro-6- (2-methoxyethoxy) benzaldehyde (0.62 g). This material was dissolved in tetrahydrofuran (6 ml). To the solution were added water (0.6 ml) and sodium borohydride (0.12 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (0.61 g).

Reference examples 156 to 159

The compounds of referential examples 156 to 159 described in table 20 were obtained in a similar manner to referential example 155 using the corresponding starting materials.

Reference example 160

1- (2, 3-difluoro-6-methoxyphenyl) -1-cyclobutanol

To a solution of 3, 4-difluoroanisole (2.47 g) in tetrahydrofuran (50 ml) at-78 ℃ was added n-butyllithium (2.67 mol/l n-hexane solution, 6.5 ml), and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a tetrahydrofuran (20 ml) solution of cyclobutanone (1 g), and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 5/1) to give the title compound (2.69 g).

Reference example 161

2-chloro-5- (1-methyl-1-phenylethoxy) aniline

To a solution of 4-chloro-3-nitrophenol (0.5 g), tri (N-butyl) phosphine (0.72 ml) and 2-phenyl-2-propanol (0.26 g) in tetrahydrofuran (5 ml) was added 1, 1' -azabicyclo (N, N-dimethylformamide) (0.5 g), and the mixture was stirred at 60 ℃ for 20 hours. The reaction mixture was diluted with ether and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 10/1) to give 2-chloro-5- (1-methyl-1-phenylethoxy) -1-nitrobenzene (0.19 g). This material was dissolved in tetrahydrofuran (3.5 ml). To the solution were added methanol (3.5 ml), nickel (II) bromide (11 mg) and sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 3/1) to give the title compound (0.14 g).

Reference examples 162 to 166

The compounds of referential examples 162 to 166 described in table 21 were obtained in a similar manner to that described in referential example 161 using the corresponding starting materials.

Reference examples 167 to 308

The compounds of reference examples 167 to 308 described in tables 22 to 41 were obtained in a similar manner to that described in reference example 13 or reference example 21 using the corresponding starting materials.

Reference example 309

4-cyano-2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) aniline

4-bromo-2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -1- (tert-butoxycarbonylamino) benzene was synthesized in a similar manner to that described in reference example 78 using 4-bromo-2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) aniline in place of 5-bromo-2-fluoroaniline. A mixture of this compound (0.24 g) and copper (I) cyanide (90 mg) in N-methyl-2-pyrrolidone (1 ml) was stirred at 220 ℃ (external temperature) for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 2/1-1/1) to give the title compound (54 mg).

Reference example 310

4-fluoro-3- (2, 3-difluoro-6-methoxybenzyloxy) aniline

A suspension of 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2, 3-difluoro-6-methoxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N, N-dimethylformamide (3 ml) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (6 ml). Methanol (3 ml), water (3 ml) and lithium hydroxide monohydrate (0.5 g) were added to the solution, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1mol/l hydrochloric acid (15 ml), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate ═ 4/1), collected by filtration, and dried under reduced pressure to give 4-fluoro-3- (2, 3-difluoro-6-methoxybenzyloxy) benzoic acid (0.31 g). This material was dissolved in 1, 4-dioxane (4 ml). To the solution were added triethylamine (0.41 ml) and diphenylphosphinoyl azide (0.21 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was then heated at reflux for 4 hours. To the reaction mixture was added 1mol/l aqueous sodium hydroxide solution (4 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 2/1-1/1) to give a crude product. Dichloromethane was added to the crude product and the insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure to give the title compound (70 mg).

Reference examples 311 to 321

The compounds of referential examples 311 to 321 described in tables 41 to 43 were obtained in a similar manner to that described in referential example 13 or referential example 21 using the corresponding starting materials.

Reference example 322

The compound of referential example 322 described in table 43 was obtained in a similar manner to the process described in referential example 160 using the corresponding starting materials.

Reference examples 323 to 324

The compounds of referential examples 323 to 324 described in Table 43 were obtained in a similar manner to that described in referential example 161 using the corresponding starting materials.

Reference example 325

2, 3-difluoro-6-methoxyphenol

To a solution of 2, 3-difluoro-6-methoxybenzaldehyde (2.58 g) in dichloromethane (45 ml) was added 3-chloroperbenzoic acid (5.97 g) under ice-cooling, and the mixture was heated at reflux overnight. The reaction mixture was cooled in ice. To the mixture was added a 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 20 minutes. The organic layer was separated, washed with water (twice), a saturated aqueous sodium bicarbonate solution, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (15 ml) -methanol (7.5 ml). Sodium methoxide (28% methanol solution, 3.75 ml) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 2/3) and aminopropyl silica gel column chromatography (eluent: ethyl acetate/methanol 9/1-3/2) in this order to give the title compound (1.7 g).

Reference example 326

The compound of referential example 326 described in table 43 was obtained in a similar manner to that described in referential example 325, using the corresponding starting materials.

Reference example 327

2, 4-difluoro-5-nitrobenzyl alcohol

Concentrated sulfuric acid (6 ml) was added to a dichloromethane (6 ml) solution of 2, 4-difluorobenzaldehyde (2.27 g) under ice-cooling, and the mixture was stirred for 15 minutes. Fuming nitric acid (1 ml) was added to the mixture under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate. Water was added to the mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate (twice), water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 7/3) to give 2, 4-difluoro-5-nitrobenzaldehyde (2.63 g). The obtained 2, 4-difluoro-5-nitrobenzaldehyde (1 g) was dissolved in tetrahydrofuran (15 ml). Sodium borohydride (0.3 g) was added to the solution, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 1/1) to give the title compound (0.76 g).

Reference example 328

The compound of referential example 328 described in table 43 was obtained in a similar manner to the process described in referential example 327 using the corresponding starting materials.

Reference examples 329 to 331

The compounds of reference examples 329 to 331 described in Table 44 were obtained in a similar manner to that described in reference example 21 using 2, 3-difluoro-6-methoxyphenol or 2, 3-difluoro-6- (2-methoxyethoxy) phenol and 4-fluoro-3-nitrobenzyl alcohol or 2, 4-difluoro-5-nitrobenzyl alcohol or 4-fluoro-2-methoxy-5-nitrobenzyl alcohol in place of 4-fluoro-3-nitrophenol and 1- (2-fluoro-6-methoxyphenyl) ethanol, respectively.

Reference example 332

2, 3-difluoro-6- (2-methoxyethoxy) aniline

To a suspension of 3, 4-difluorophenol (1.43 g) and cesium carbonate (4.89 g) in N, N-dimethylformamide (10 ml) was added 2-methoxyethyl bromide (0.94 ml), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with a 1mol/l aqueous sodium hydroxide solution, water and brine in this order and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (39 ml). To the solution was added n-butyllithium (2.64 mol/l n-hexane solution, 3.25 ml) at-78 ℃, and the mixture was stirred at the same temperature for 30 minutes. Dry ice (10 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by adding 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2, 3-difluoro-6- (2-methoxyethoxy) benzoic acid (1.48 g). The obtained 2, 3-difluoro-6- (2-methoxyethoxy) benzoic acid (0.5 g) was dissolved in 1, 4-dioxane (10 ml). To the solution were added triethylamine (0.45 ml) and diphenylphosphonyl azide (0.61 ml), and the mixture was stirred at room temperature overnight. Ethanol (0.99 g) was added to the reaction mixture, and the mixture was heated at reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1mol/L hydrochloric acid, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a suspension of the residue in ethanol (10 ml) was added 5 mol/L aqueous sodium hydroxide (4.3 ml), and the mixture was heated under reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water (twice) and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 3/1) to give the title compound (75 mg).

Reference example 333

The compound of referential example 333 described in table 44 was obtained in a similar manner to that described in referential example 332 using the corresponding starting materials.

Reference example 334

2-fluoro-5- [ N- (2, 6-difluorophenyl) -N-methylamino ] methyl-4-methoxyaniline

To a solution of 4-fluoro-2-methoxy-5-nitrobenzyl alcohol (0.3 g) in dichloromethane (5 ml) was added triethylamine (0.31 ml) and methanesulfonyl chloride (0.14 ml) at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was diluted with dichloromethane, and the resulting mixture was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in acetonitrile (2 ml) -ethanol (2 ml). To the solution was added a catalytic amount of sodium iodide and 2, 6-difluoroaniline (0.45 ml), and the mixture was stirred at 60 ℃ overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: N-hexane-N-hexane/ethyl acetate 2/3) to give 5-fluoro-2- [ N- (2, 6-difluorophenyl) amino ] methyl-4-nitroanisole (0.41 g). This material was dissolved in N, N-dimethylformamide (3 ml). Sodium hydride (55%, 84 mg) was added to the solution under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added methyl iodide (0.096 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: N-hexane-N-hexane/ethyl acetate 1/1) to give 5-fluoro-2- [ N- (2, 6-difluorophenyl) -N-methylamino ] methyl-4-nitroanisole (0.17 g). This material was dissolved in methanol (3 ml) -tetrahydrofuran (3 ml). To the solution were added nickel (II) bromide (5 mg) and sodium borohydride (52 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium bicarbonate solution, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane-n-hexane/ethyl acetate 3/2) to give the title compound (0.12 g).

Reference example 335

The compound of referential example 335 described in Table 44 was obtained in a similar manner to that described in referential example 334 using the corresponding starting materials.

Reference example 336

2-fluoro-5- [ N- (2-fluoro-6-methoxyphenyl) -N-methylamino ] methylaniline

To a solution of 4-fluoro-3-nitrobenzoic acid (1.57 g) in dichloromethane (25 ml) were added N, N-dimethylformamide (0.005 ml) and oxalyl chloride (4.32 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (5 ml) was added to a suspension of 2-fluoro-6-methoxyaniline (1.2 g) and sodium bicarbonate (2.14 g) in tetrahydrofuran (10 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1mol/l hydrochloric acid, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was suspended in dichloromethane, collected by filtration and dried under reduced pressure to give 4-fluoro-3-nitro-N- (2-fluoro-6-methoxyphenyl) benzamide (1.1 g). This material was dissolved in N, N-dimethylformamide (12 ml). To the solution were added sodium hydride (55%, 172 mg) and methyl iodide (0.76 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water (three times) and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-fluoro-3-nitro-N- (2-fluoro-6-methoxyphenyl) -N-methylbenzamide (1.15 g). The obtained 4-fluoro-3-nitro-N- (2-fluoro-6-methoxyphenyl) -N-methylbenzamide (0.3 g) was dissolved in methanol (10 ml) -tetrahydrofuran (10 ml). To the solution were added nickel (II) bromide (10 mg) and sodium borohydride (0.11 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-amino-4-fluoro-N- (2-fluoro-6-methoxyphenyl) -N-methylbenzamide (0.27 g). This material was dissolved in tetrahydrofuran (8 ml). To the solution was added borane-tetrahydrofuran complex (1 mol/l tetrahydrofuran solution, 3.3 ml), and the mixture was heated at reflux for 2 hours. Methanol was added to the reaction mixture under ice-cooling, and the mixture was stirred for 10 minutes. The mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 3/1) to give the title compound (0.11 g).

Reference examples 337 to 340

The compounds described in reference examples 337 to 340 in table 45 were obtained in a similar manner to that described in reference example 336 using the corresponding starting materials.

Reference examples 341 to 342

The compounds of reference examples 341 to 342 described in table 45 were obtained in a similar manner to that described in reference example 325 using the corresponding starting materials.

Reference examples 343 to 344

The compounds of reference examples 343 to 344 described in Table 45 were obtained in a similar manner to that described in reference example 21 using 2, 3-difluoro-6- (2-ethoxyethoxy) phenol or 2, 3-difluoro-6- [2- (tert-butyldimethylsilyloxy) ethoxy ] phenol and 4-fluoro-3-nitrobenzyl alcohol, respectively, in place of 4-fluoro-3-nitrophenol and 1- (2-fluoro-6-methoxyphenyl) ethanol.

Reference example 345

4-fluoro-3-nitro-2-methoxybenzoic acid

Concentrated sulfuric acid (6 ml) was added to 4-fluoro-2-methoxybenzoic acid (0.96 g) under ice-cooling, and the mixture was stirred for 15 minutes. Concentrated nitric acid (0.6 ml) was added to the mixture under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Ice was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The extract was washed with water (twice) and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To the residue was added a mixed solvent (n-hexane/ethyl acetate 2/1), and insoluble matter was collected by filtration and dried under reduced pressure to give the title compound (0.78 g).

Reference example 346

The compound of referential example 346 described in table 46 was obtained in a similar manner to that described in referential example 336 using the corresponding starting materials.

Example 1

5-methoxycarbonyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a suspension of dimethyl 4-aminothiophene-2, 3-dicarboxylate hydrochloride (0.5 g) and triethylamine (0.84 ml) in tetrahydrofuran (10 ml) was added a solution of triphosgene (0.41 g) in tetrahydrofuran (5 ml), and the mixture was stirred at 60 ℃ for 1 hour. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 ml). The solution was added to a solution of 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) aniline (0.64 g) and 4-dimethylaminopyridine (0.49 g) in tetrahydrofuran (8 ml), and the mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1mol/L hydrochloric acid and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in methanol (15 ml). Sodium methoxide (28% methanol solution, 1.15 ml) was added to the solution, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1mol/L hydrochloric acid, water, and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1) to give the title compound (0.65 g).

Examples 2 to 21

The compounds of examples 2 to 21 described in tables 47 to 49 were obtained in a similar manner to that described in example 1 using the corresponding starting materials. However, in the case of example 6, ethanol and sodium ethoxide were used instead of methanol and sodium methoxide, respectively.

Example 22

5-carboxy-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a solution of 5-methoxycarbonyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (0.2 g) in methanol (12 ml) -tetrahydrofuran (4 ml) was added lithium hydroxide-monohydrate (0.16 g), and the mixture was stirred at 60 ℃ overnight. To the reaction mixture was added 1mol/l hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.18 g).

Examples 23 to 29

The compounds of examples 23 to 29 described in tables 50 to 51 were obtained in a similar manner to that described in example 1 and example 22 using the corresponding starting materials.

Example 30

5-carbamoyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a solution of 5-carboxy-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (14 mg) in tetrahydrofuran (1 ml) was added 1, 1' -carbonyldi-1H-imidazole (9 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (0.5 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine, successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol 10/1) to give the title compound (13 mg).

Example 31

5-methylcarbamoyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

The title compound was obtained in a similar manner to that described in example 30 using the corresponding starting materials.

Example 32

5- (1-hydroxy-1-methylethyl) -3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a solution of 5-methoxycarbonyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (0.1 g) in tetrahydrofuran (10 ml) was added magnesium methyliodide (3 mol/l ether solution, 0.19 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1) to give the title compound (85 mg).

Example 33

5-hydroxymethyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a solution of 5-methoxycarbonyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (0.2 g) in tetrahydrofuran (4 ml) was added diisobutylaluminum hydride (1.01 mol/l in toluene, 1.5 ml) under ice-cooling, and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was stirred for 10 minutes. To the mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1) to give the title compound (0.11 g).

Example 34

5-formyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a solution of 5-hydroxymethyl-3- [ 2-chloro-5- (3, 4-dihydroquinolin-1 (2H) -ylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (77 mg) in N, N-dimethylformamide (2.1 ml) was added manganese dioxide (IV) (0.77 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and filtered to remove insoluble material. The filtrate was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1) to give the title compound (32 mg).

Example 35

5-methoxycarbonyl-3- { 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a mixture of dimethyl 4-aminothiophene-2, 3-dicarboxylate hydrochloride (90 mg) and triethylamine (0.15 ml) in tetrahydrofuran (3 ml) was added a solution of triphosgene (74 mg) in tetrahydrofuran (3 ml), and the mixture was stirred at 60 ℃ for 30 minutes. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml). The solution was added to a solution of 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] aniline (0.1 g) and 4-dimethylaminopyridine (88 mg) in tetrahydrofuran (3 ml), and the mixture was stirred at 60 ℃ overnight. To the reaction mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5 ml). Sodium methoxide (28% methanol solution, 0.21 ml) was added to the solution, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/2) to give the title compound (0.14 g).

Examples 36 to 47

The compounds of examples 36 to 47 described in tables 52 to 53 were obtained in a similar manner to that described in example 35 using the corresponding starting materials.

Example 48

5-carboxy-3- { 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a mixture of 5-methoxycarbonyl-3- { 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (0.12 g) and methanol (3 ml) was added lithium hydroxide monohydrate (99 mg), and the mixture was stirred at 50 ℃ for 1 hour. The reaction mixture was acidified by adding 1mol/l hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.11 g).

Examples 49 to 60

The compounds of examples 49 to 60 described in tables 53 to 55 were obtained in a similar manner to that described in example 48 using the corresponding starting materials.

Examples 61 to 65

The compounds of examples 61 to 65 described in table 55 were obtained in a similar manner to that described in example 35 using the corresponding starting materials.

Examples 66 to 70

The compounds of examples 66 to 70 described in tables 55 to 56 were obtained in a similar manner to that described in example 48 or example 93 using the corresponding starting materials.

Example 71

The compound of example 71 described in table 56 was obtained in a similar manner to that described in example 35 using the corresponding starting materials.

Example 72

5-methoxycarbonyl-3- [3- (1-phenethylsulfinyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a solution of 5-methoxycarbonyl-3- [3- (1-phenethylthio) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (50 mg) in acetone (3 ml) -water (0.6 ml) were added sodium hydrogencarbonate (24 mg) and OXONE (registered trademark) (84 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1mol/L hydrochloric acid, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was suspended in methanol, collected by filtration and dried under reduced pressure to give the title compound (45 mg).

Example 73

5-methoxycarbonyl-3- [3- (1-phenethylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a solution of 5-methoxycarbonyl-3- [3- (1-phenethylthio) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (50 mg) in acetone (3 ml) -water (0.6 ml) were added sodium hydrogencarbonate (77 mg) and OXONE (registered trademark) (0.28 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1mol/L hydrochloric acid, water and brine in this order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was suspended in methanol, collected by filtration and dried under reduced pressure to give the title compound (48 mg).

Examples 74 to 76

The compounds of examples 74 to 76 described in tables 56 to 57 were obtained in a similar manner to that described in example 35 using the corresponding starting materials.

Example 77

The compound of example 77 described in table 57 was obtained in a similar manner to that described in example 73 using the corresponding starting materials.

Example 78

The compound of example 78 described in table 57 was obtained in a similar manner to that described in example 35 using the corresponding starting materials.

Examples 79 to 82

The compounds of examples 79 to 82 described in table 57 were obtained in a similar manner to that described in example 48 using the corresponding starting materials.

Example 83

The compound of example 83 described in table 58 was obtained in a similar manner to that described in example 73 and example 48 using the corresponding starting materials.

Examples 84 to 87

The compounds of examples 84 to 87 described in table 58 were obtained in a similar manner to that described in example 48 using the corresponding starting materials.

Example 88

The compound of example 88 described in table 58 was obtained in a similar manner to that described in example 73 and example 48 using the corresponding starting materials.

Examples 89 to 92

The compounds of examples 89 to 92 described in tables 58 to 59 were obtained in a similar manner to that described in example 35 using the corresponding starting materials.

Example 93

5-carboxy-3- [ 2-fluoro-5- (N-methyl-N-phenylcarbamoyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

A mixture of 5-methoxycarbonyl-3- [ 2-fluoro-5- (N-methyl-N-phenylcarbamoyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (0.18 g) and lithium hydroxide monohydrate (0.17 g) in tetrahydrofuran (6 ml) -methanol (3 ml) -water (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into 1mol/l hydrochloric acid, and the resulting reaction mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol 8/1) to give the title compound (0.12 g).

Example 94

The compound of example 94 described in table 59 was obtained in a similar manner to that described in example 35 and example 93 using the corresponding starting materials.

Examples 95 to 97

The compounds of examples 95 to 97 described in table 59 were obtained in a similar manner to that described in example 93 using the corresponding starting materials.

Examples 98 to 100

The compounds of examples 98 to 100 described in tables 59 to 60 were obtained in a similar manner to that described in example 35 using the corresponding starting materials.

Examples 101 to 103

The compounds of examples 101 to 103 described in table 60 were obtained in a similar manner to that described in example 48 using the corresponding starting materials.

Examples 104 to 108

The compounds of examples 104 to 108 described in table 61 were obtained in a similar manner to that described in example 1 using the corresponding starting materials.

Examples 109 to 201

The compounds of examples 109 to 201 described in tables 61 to 74 were obtained in a similar manner to that described in example 1 and example 48 or example 93 using the corresponding starting materials.

Example 202

5-carboxy-3- [ 2-fluoro-5- (1-methyl-1-phenethylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

5-methoxycarbonyl-3- [ 2-fluoro-5- (1-methyl-1-phenethylthio) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione was obtained in a similar manner to that described in example 35 using 2-fluoro-5- (1-methyl-1-phenylethylthio) aniline instead of 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] aniline. This compound (0.1 g) was dissolved in dichloromethane (2 ml). 3-Chloroperbenzoic acid (92 mg) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water. To the mixture was added a 1mol/L aqueous solution of sodium thiosulfate, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1-1/2) to give 5-methoxycarbonyl-3- [ 2-fluoro-5- (1-methyl-1-phenethylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (0.1 g). The title compound was obtained in a similar manner to that described in example 93 using the obtained 5-methoxycarbonyl-3- [ 2-fluoro-5- (1-methyl-1-phenethylsulfonyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione instead of 5-methoxycarbonyl-3- [ 2-fluoro-5- (N-methyl-N-phenylcarbamoyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione.

Examples 203 to 232

The compounds of examples 203 to 232 described in tables 75 to 79 were obtained in a similar manner to that described in example 202 using the corresponding starting materials.

Example 233

5-carboxy-3- [ 2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a suspension of dimethyl 4-aminothiophene-2, 3-dicarboxylate hydrochloride (0.13 g) and triethylamine (0.21 ml) in tetrahydrofuran (5 ml) was added triphosgene (99 mg) under ice-cooling, and the mixture was stirred at 60 ℃ for 30 minutes. The reaction mixture was diluted with ethyl acetate and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 ml). The solution was added to a solution of 2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyaniline (0.16 g) and 4-dimethylaminopyridine (0.12 g) in tetrahydrofuran (4 ml), and the mixture was stirred at 60 ℃ for 3 days. The reaction mixture was passed through IST ISOLUTE SCX and eluted with ethyl acetate. The eluate was concentrated under reduced pressure, and the residue was dissolved in methanol (5 ml). Sodium methoxide (28% methanol solution, 0.29 ml) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue and a mixture of lithium hydroxide-monohydrate (0.21 g) in tetrahydrofuran (4 ml) -methanol (2 ml) -water (2 ml) were stirred at room temperature for 30 minutes. The reaction mixture was poured into 1mol/l hydrochloric acid, and the resulting reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/2-ethyl acetate) to give the title compound (0.13 g).

Examples 234 to 391

The compounds of examples 234 to 391 described in tables 79 to 102 were obtained in a similar manner to that described in example 233 using the corresponding starting materials.

Example 392

The compound of example 392 described in table 102 was obtained in a similar manner to that described in example 35 and example 33 using the corresponding starting materials.

Examples 393 to 395

The compounds of examples 393 to 395 described in table 102 were obtained in a similar manner to that described in example 30 using the corresponding starting materials.

Example 396

5-carboxy-3- { 2-fluoro-5- [2, 3-difluoro-6- (2-hydroxyethoxy) benzyloxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a suspension of dimethyl 4-aminothiophene-2, 3-dicarboxylate hydrochloride (0.11 g) and triethylamine (0.19 ml) in tetrahydrofuran (5 ml) was added triphosgene (84 mg) under ice-cooling, and the mixture was stirred at 60 ℃ for 30 minutes. The reaction mixture was diluted with ethyl acetate and filtered to remove insoluble material. The filtrate was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 ml). The solution was added to a solution of 2-fluoro-5- {2, 3-difluoro-6- [2- (tert-butyldimethylsilyloxy) ethoxy ] benzyloxy } aniline (0.17 g) and 4-dimethylaminopyridine (99 mg) in tetrahydrofuran (4 ml), and the mixture was stirred at 60 ℃ overnight. The reaction mixture was passed through ISTISOLUTE SCX and eluted with ethyl acetate. The eluate was concentrated under reduced pressure, and the residue was dissolved in methanol (4 ml). Sodium methoxide (28% methanol solution, 0.23 ml) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in tetrahydrofuran (4 ml). To the solution was added tetra (n-butyl) ammonium fluoride (1 mol/l tetrahydrofuran solution, 1.2 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1mol/l hydrochloric acid, and the resulting reaction mixture was extracted with ethyl acetate. The extract was washed with 1mol l hydrochloric acid, water and brine in this order and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue and lithium hydroxide-monohydrate (0.17 g) tetrahydrofuran (5 ml) -methanol (2.5 ml) -water (2.5 ml) mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 1mol/l hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the title compound (0.13 g).

Examples 397 to 410

The compounds of examples 397 to 410 described in tables 102 to 104 were obtained in a similar manner to that described in example 396 using the corresponding starting materials.

Examples 411 to 416

The compounds of examples 411 to 416 described in tables 104 to 105 were obtained in a similar manner to that described in example 233 using the corresponding starting materials.

Example 417

5-ethoxycarbonyl-3- { 2-fluoro-5- [2, 3-difluoro-6- (2-hydroxyethoxy) benzyloxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a suspension of 5-carboxy-3- { 2-fluoro-5- [2, 3-difluoro-6- (2-hydroxyethoxy) benzyloxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (0.65 g) in ethanol (10 ml) -tetrahydrofuran (5 ml) was added p-toluenesulfonic acid-monohydrate (24 mg), and the mixture was stirred at 90 ℃ (external temperature) overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/2-1/4) to give the title compound (0.39 g).

Example 418

5-ethoxycarbonyl-3- (5- {6- [2- (ethoxycarbonyloxy) ethoxy ] -2, 3-difluorobenzyloxy } -2-fluorophenyl) thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione

To a suspension of 5-ethoxycarbonyl-3- { 2-fluoro-5- [2, 3-difluoro-6- (2-hydroxyethoxy) benzyloxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione (80 mg) in ethyl acetate (2 ml) were added pyridine (0.036 ml) and ethyl chloroformate (0.021 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1mol/l hydrochloric acid, and the resulting reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/2) to give the title compound (38 mg).

Example 419

The compound of example 419 described in table 106 was obtained in a similar manner to that described in example 418 using the corresponding starting materials.

Examples 420 to 426

The compounds of examples 420 to 426 described in tables 106 to 107 were obtained in a similar manner to that described in example 233 using the corresponding starting materials.

Example 427

The compound of example 427 described in table 107 was obtained in a similar manner to that described in example 396 using the corresponding starting material.

Example 428

The compound of example 428 described in table 107 was obtained in a similar manner to that described in example 233 using the corresponding starting materials.

Tables 1 to 46 and tables 47 to 107 show the chemical structures and¹H-NMR data.

Abbreviations in these tables: "Ref No.", "Ex No.", "Strc" and "Solv" denote reference example number, chemical structure and¹H-NMR measurement solvent.

[ Table 1]

[ Table 2]

[ Table 3]

[ Table 4]

[ Table 5]

[ Table 6]

[ Table 7]

[ Table 8]

[ Table 9]

[ Table 10]

[ Table 11]

[ Table 12]

[ Table 13]

[ Table 14]

[ Table 15]

[ Table 16]

[ Table 17]

[ Table 18]

[ Table 19]

[ Table 20]

[ Table 21]

[ Table 22]

[ Table 23]

[ Table 24]

[ Table 25]

[ Table 26]

[ Table 27]

[ Table 28]

[ Table 29]

[ Table 30]

[ Table 31]

[ Table 32]

[ Table 33]

[ Table 34]

[ Table 35]

[ Table 36]

[ Table 37]

[ Table 38]

[ Table 39]

[ Table 40]

[ Table 41]

[ Table 42]

[ Table 43]

[ Table 44]

[ Table 45]

[ Table 46]

[ Table 47]

[ Table 48]

[ Table 49]

[ Table 50]

[ Table 51]

[ Table 52]

[ Table 53]

[ Table 54]

[ Table 55]

[ Table 56]

[ Table 57]

[ Table 58]

[ Table 59]

[ Table 60]

[ Table 61]

[ Table 62]

[ Table 63]

[ Table 64]

[ Table 65]

[ Table 66]

[ Table 67]

[ Table 68]

[ Table 69]

[ Table 70]

[ Table 71]

[ Table 72]

[ Table 73]

[ Table 74]

[ Table 75]

[ Table 76]

[ Table 77]

[ Table 78]

[ Table 79]

[ Table 80]

[ Table 81]

[ Table 82]

[ Table 83]

[ Table 84]

[ Table 85]

[ Table 86]

[ Table 87]

[ Table 88]

[ Table 89]

[ Table 90]

[ Table 91]

[ Table 92]

[ Table 93]

[ Table 94]

[ Table 95]

[ Table 96]

[ Table 97]

[ Table 98]

[ Table 99]

[ Table 100]

[ watch 101]

[ Table 102]

[ Table 103]

[ Table 104]

[ Table 105]

[ Table 106]

[ Table 107]

[ test example 1]

1) Cloning and construction of vectors expressing human GnRH receptor 1(GnRHR1)

A DNA fragment of 45 to 1115bp (accession number L03380) encoding human GnRHR1 reported by Kakar et al was amplified by PCR using human pituitary-derived cDNA (BECTON DICKINSON) as a template and inserted into the multiple cloning site of pcDNA3.1(+) (Invitrogen). The inserted DNA sequence perfectly matched the previously reported sequence.

2) Preparation of HEK293 (human embryonic kidney) cells expressing human GnRH receptor 1

The expression vector introduced with the human GnRHR1 gene was transfected into cultured HEK293 cells using Lipofectamine 2000(Invitrogen) using the lipofection method (medium: MEM, 10% FCS, containing antibiotics, non-essential amino acids and pyruvic acid). After transfection, cells were cultured for 2 days and used for examination.

3) Analysis of GnRH antagonistic Effect

The antagonistic effect of the compounds on human GnRHR1 was evaluated by changes in calcium levels in GnRH-stimulated cells. After removing the medium from the HEK293 cells transiently expressing human GnRHR1, the cells were washed with 200. mu.L of wash buffer (Hank's balanced salt solution, 20mM N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid, 1.3mM calcium chloride, 0.5mM magnesium chloride, 0.4mM magnesium sulfate) per well. Adding 100. mu.L of Ca²⁺A solution of a sensitizing dye (FLIPR calcium assay kit (Molecular Devices)) was added to the wells, and the cells were incubated at 37 ℃ in 5% CO₂The cells were incubated for 1 hour. Then, intracellular calcium levels were measured using FLEX STATION (Molecular Devices) under the following conditions. In a device warmed to 37 ℃, 50 μ L of test compound diluted with assay buffer (wash buffer, containing 0.1% albumin bovine serum) was added to the wells. After 1 minute, 50 μ L of 5nM GnRH was added to the wells. Using a logarithmic graph (logitplot), the drug concentration (IC) at which 50% GnRH-stimulated intracellular calcium flux was inhibited was calculated₅₀Values) (table 108).

[ Table 108]

Example number	IC50(nM)
		2	199
3	80
		17	101
22	2
		25	85
31	272
		48	29
95	19
		146	10
191	17
		202	20
233	15
		367	15
414	42
		420	29
Control Compound 1	61
		Control Compound 2	3

[ test example 2]

Oral absorbability assay

1) Preparation of measurement sample of drug concentration after intravenous injection of tail vein

For the experimental animals, SD rats (Charles River, male, 7 weeks old, 170-. 1 mg of the test compound was dissolved by adding 0.2 ml of N, N-dimethylacetamide, 0.798 ml of physiological saline and 0.002 ml of 2N NaOH, and then a 1.0 mg/ml solution was prepared. The body weight of the rats was measured and the test compound solution was injected intravenously into the tail vein of non-anesthetized rats at a dose of 1 ml/kg (1 mg/kg). Tail vein injection was performed with a 26G needle and a 1 ml syringe. The sampling times for blood collection were 2, 15, 60, 120, 240 and 360 minutes after the tail vein injection. The blood was centrifuged and the plasma was used as a sample for determining the concentration of the drug in the blood.

2) Preparation of samples for determination of drug concentration after oral administration

For the experimental animals, SD rats (Charles River, male, 7 weeks old, 170-. A 0.3 mg/ml solution was prepared by dissolving 3 mg of the test compound by adding 0.2 ml of N, N-dimethylacetamide, 9.794 ml of 0.5% aqueous sodium methylcellulose solution and 0.006 ml of 2N NaOH. The body weight of the rats was measured and the test compound solution was administered orally at a dose of 10 ml/kg (3 mg/kg). Oral administration was performed using a rat gastric tube and a 2.5 ml syringe. The sampling times for blood collection were 15, 30, 60, 120, 240 and 360 minutes after oral administration. The blood was centrifuged and the plasma was used as a sample for determining the concentration of the drug in the blood.

3) Determination of drug concentration

To 0.025 ml of plasma obtained in 1) and 2) above was added 0.1 ml of an appropriate internal standard substance, followed by deproteinization by addition of 0.875 ml of acetonitrile according to a usual method. After centrifugation, 0.005 ml of the supernatant was injected into LC-MS/MS. The drug concentration in plasma was determined using the LC-MS/MS method under the following conditions. An internal standard substance and various test compounds were appropriately added to 0.05 ml of blank plasma according to a usual method, and the operation similar to that described above was performed, and then a standard curve was made.

LC

The instrument comprises the following steps: agilent1100

Column: cadenza C183. mu.M 4.6X 50mm

Mobile phase: the time and ratio of (A)/(B) 10mM ammonium acetate aqueous solution (pH 4.5) (A)/acetonitrile (B) ((A)/(B) are shown in Table 109)

Column temperature: 40 deg.C

Flow rate: 0.5mL/min

MS/MS

The instrument comprises the following steps: API-4000

An ionization method: ESI (turbo Ion spray)

[ Table 109]

Time (minutes)	A(％)	B(％)
			0.0	90	10
3.0	90	10
			4.0	10	90
7.0	10	90
			7.1	90	10
12.0	90	10

The plasma drug concentrations at each time obtained by the above method were estimated by pharsight corporation using WinNonlin Professional as an area under the curve of each plasma drug concentration-time by tail vein injection and oral administration of the test compound, and then bioavailability (%) was calculated based on the following formula.

Bioavailability (%) { [ (area under plasma drug concentration-time curve for oral administration)/3 ]/(area under plasma drug concentration-time curve for tail vein injection) } × 100

Maximum plasma drug concentration (C) in oral administration_max) Bioavailability and plasma drug concentration 360 min after administration (C)₃₆₀) Are shown in tables 110 to 112.

[ Table 110]

Test compounds	Cmax(ng/mL)
		Example 22	342
Example 48	14460
		Example 95	322
Example 146	17917
		Example 191	13504
Example 202	1308
		Example 233	24959
Example 271	17582
		Example 367	14120
Example 414	25560
		Example 420	15169
Control Compound 1	＜10
		Control Compound 2	10

[ Table 111]

Test compounds	Bioavailability (%)
		Example 22	11
Example 48	65
		Control Compound 1	＜1
Control Compound 2	＜1

[ Table 112]

Test compounds	C360
		Example 146	A
Example 202	B
		Example 233	A
Example 271	A
		Example 367	A
Example 414	A
		Example 420	B
Control Compound 1	＜10
		Control Compound 2	＜10

A：＞1000ng/mL

B: 300ng/mL to 1000ng/mL

In tables 110 to 112, control compound 1 was the sulfonamide compound of example 6(4) described in the above-mentioned patent reference 2, and control compound 2 was the sulfonamide compound of example 31 described in the above-mentioned patent reference 2.

As described above, the fused heterocyclic derivative of the present invention is superior to the control compound in terms of hemodynamics, such as oral availability and persistence. For example, the fused heterocyclic derivatives of examples 48, 146, 191, 202, 233, 271, 367, 414 and 420 gave more excellent availability than the compound of example 22 having a sulfonamide group and the compound of example 95 having an amide group, and thus, they were more preferable as pharmaceutical compositions for oral administration. In addition, the fused heterocyclic derivatives of examples 146, 202, 233, 271, 367, 414 and 420, more preferably examples 146, 233, 271, 367 and 414, maintained their blood concentration 6 hours after oral administration and were superior in terms of persistence to the control compounds. Thus, the fused heterocyclic derivatives of the present invention can be used as long acting formulations substantially without sustained release bases such as hydroxyalkyl celluloses, alkyl celluloses, and the like.

Industrial applicability

The fused heterocyclic derivative (I) of the present invention or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof has an excellent GnRH antagonistic activity, and thus can be used as an agent for the prophylaxis or treatment of sex hormone-dependent diseases by controlling the effect of gonadotropin-releasing hormone and controlling the production and secretion of gonadotropins and sex hormones. Accordingly, the present invention can provide an agent for preventing or treating the following diseases: benign prostatic hypertrophy, hysteromyoma, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, short stature, sleep disorders, acne, alopecia, alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer or pituitary tumor, and as a reproduction regulator, contraceptive, ovulation inducer or agent for preventing postoperative recurrence of sex hormone-dependent cancer, and the like.

Claims (19)

1. A fused heterocyclic derivative represented by the general formula (I):

[ chemical formula 1]

Wherein ring a represents any thiophene ring represented by the formula:

[ chemical formula 2]

R^AIs represented by COOW¹Or CONW²W³Wherein W is¹To W³Independently represents a hydrogen atom or a lower alkyl group;

m represents an integer of 0 to 2;

ring B represents phenyl;

R^Brepresents a halogen atom or OW⁴Wherein W is⁴Represents a lower alkyl group;

n represents an integer of 0 to 2;

E¹represents an oxygen atom;

E²represents an oxygen atom;

u represents a single bond or lower alkylene;

x represents a group represented by: y, -CO-Y, -SO₂-Y，-S-L-Y，-O-L-Y，-CO-L-Y，-SO₂-L-Y or-O-Z, wherein L represents lower alkylene;

y represents a group consisting of Z or-NW⁷W⁸A group represented by wherein W⁷And W⁸Independently represents lower alkyl or Z; or W⁷And W⁸May be taken together with the adjacent nitrogen atom to form 3, 4-dihydroquinolin-1 (2H) -yl;

z represents a phenyl group optionally substituted with an optional substituent selected from the substituent group (C),

substituent group (C): halogen atom, lower alkyl group and lower alkoxy group which may be substituted by one substituent selected from the group consisting of lower alkoxy group and hydroxy group;

lower alkyl means optionally branched alkyl having 1 to 6 carbon atoms, lower alkylene means optionally branched alkylene having 1 to 6 carbon atoms, lower alkoxy means optionally branched alkoxy having 1 to 6 carbon atoms.

2. A fused heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring a is a thiophene ring represented by the following formula:

[ chemical formula 3]

3. A fused heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R^ARepresents a carboxyl group or a carbamoyl group.

4. A fused heterocyclic derivative according to claim 1 or 2, wherein m represents 0 or 1, or a pharmaceutically acceptable salt thereof.

5. A fused heterocyclic derivative according to claim 4, wherein m represents 1, ring A is a thiophene ring, wherein R is^AThe position of binding to ring A is represented by the following general formula:

[ chemical formula 4]

6. A fused heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein n is 1 or 2, ring B is wherein R^BAny ring that binds to the ring B position represented by the formula:

[ chemical formula 5]

In the formula, R^BHaving the same meaning as defined above, when two R are^BWhen present, they may be the same as or different from each other.

7. According toA fused heterocyclic derivative as described in claim 1 or 2, wherein R is^BRepresents a fluorine atom, a chlorine atom or OW⁴Wherein W is⁴Represents a lower alkyl group.

8. A fused heterocyclic derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein U represents a single bond or a methylene group.

9. A fused heterocyclic derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein U represents a single bond, X represents a group represented by: -S-L-Y, -O-L-Y, -CO-L-Y or-SO₂-L-Y, wherein L and Y have the same meaning as defined above.

10. A fused heterocyclic derivative according to claim 1 or 2, wherein U represents a methylene group, X represents a group represented by Y or-O-Z, wherein Y represents-NW, or a pharmaceutically acceptable salt thereof⁷W⁸Wherein W is⁷And W⁸Independently represents lower alkyl or Z; or W⁷And W⁸May be taken together with the adjacent nitrogen atom to form 3, 4-dihydroquinolin-1 (2H) -yl, wherein Z has the same meaning as defined above.

11. A fused heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein L represents C_1-3An alkylene group.

12. A fused heterocyclic derivative according to claim 1, wherein said fused heterocyclic derivative is selected from the group consisting of:

5-carboxy-3- { 2-fluoro-5- [1- (2-fluoro-6-methoxyphenyl) ethoxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione,

5-carboxy-3- [ 2-chloro-5- (2-methyl-2-phenylpropionyl) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione,

5-carboxy-3- [ 2-fluoro-5- (2, 3-difluoro-6-methoxybenzyloxy) -4-methoxyphenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione,

5-carboxy-3- { 2-chloro-5- [1- (2, 6-dichlorophenyl) ethoxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione,

5-carboxy-3- [ 2-chloro-5- (1-methyl-1-phenylethoxy) phenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione,

5-carboxy-3- { 2-fluoro-5- [1- (2, 3-difluoro-6-methoxyphenyl) ethoxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione,

5-carboxy-3- { 2-fluoro-5- [2, 3-difluoro-6- (2-methoxyethoxy) benzyloxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione,

5-carboxy-3- { 2-fluoro-5- [2, 3-difluoro-6- (2-hydroxyethoxy) benzyloxy ] phenyl } thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione, and

5-carboxy-3- [ 2-fluoro-5- (2, 3-difluoro-6-methoxyphenoxymethyl) -4-methoxyphenyl ] thieno [3, 4-d ] pyrimidine-2, 4(1H, 3H) -dione.

13. A pharmaceutical composition comprising the fused heterocyclic derivative as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

14. The pharmaceutical composition of claim 13, which is a gonadotropin releasing hormone antagonist.

15. The pharmaceutical composition according to claim 13, which is an agent for preventing or treating a sex hormone dependent disease, a reproduction regulator, a contraceptive, an ovulation inducer or an agent for preventing postoperative recurrence of a sex hormone dependent cancer.

16. The pharmaceutical composition according to claim 15, wherein the sex hormone dependent disorder is selected from the group consisting of benign prostatic hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosus, hirsutism, short stature, sleep disorders, acne, alopecia, alzheimer's disease, infertility, irritable bowel syndrome, prostate cancer, uterine cancer, ovarian cancer, breast cancer and pituitary tumors.

17. The pharmaceutical composition of claim 13, wherein the composition is an oral formulation.

18. Use of a fused heterocyclic derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the prophylaxis or treatment of a sex hormone dependent disease.

19. Use of a fused heterocyclic derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for reproductive regulation, contraception, ovulation induction or prevention of postoperative recurrence of sex hormone dependent cancer.