Title of Invention

HETEROCYCLIC COMPOUNDS HAVING TYPE I 11B HYDROXYSTEROID DEHYDROGENASE INHIBITORY ACTIVITY

Abstract

Disclosed is a compound useful as a type I llBhydroxysteroid dehydrogenase inhibitor. A compound represented by the formula: a pharmaceutically acceptable salt or solvate thereof, wherein R<sup>1</sup> is optionally substituted alkyl or the like, one of R<sup>2</sup> and R<sup>4</sup> is a group of formula: -Y-R5, wherein Y is -0- or the like, R<sup>5</sup> is substituted alkyl (the substituent is optionally substituted cycloalkyl or the like), optionally substituted branched alkyl or the like, the other of R<sup>2</sup>and R<sup>4</sup> is hydrogen or optionally substituted alkyl, R<sup>3</sup> is a group of formula: -C(=0)-Z-R<sup>6</sup> wherein Z is -NR<sup71</sup>- or -NR<sup71</sup>-W-, R<sup>6</sup> is optionally substituted cycloalkyl or the like, R<sup>7</sup> is hydrogen or optionally substituted alkyl, W is optionally substituted alkylene, X is =N- or the like, with the proviso that compounds wherein R<sup>2</sup> is 2-(morphorino)ethoxy, R<sup>3</sup> is N-(l-adamantyl)carbamoyl and R<sup>1</sup> is benzyl are excluded.

Full Text

Description Heterocyclic compounds having type I 116 hydroxysteroid dehydrogenase inhibitory activity Field of the invention [0001] This invention relates to a pharmaceutically usuful compound with an inhibitory activity to βhydroxysteroid dehydrogenase type 1, hereinafter referred to as 11β-HSD-l Background Art [0002] 116-HSD-l is an enzyme that converts inactive steroids, ll6-dehydrosteroid into its active steroids and is considered to be important in the basal metabolic rate in the living body (Non-patent Document 1). Moreover, 116-HSD-l knockout mice have the resistance to hyperglycemia induced by obesity or stress (Non-patent Document 2). In addition, a similar phenomenon was observed in human on administration of 116-HSD-l inhibitor, carbenoxolone (Non-patent Document 3). These facts suggest that the 116-HSD-l inhibitors could be useful as drugs for the treatment of insulin independent diabetes or obesity (Non-patent Document 4). [0003] Patent document 1 describes that pyrazole derivatives are useful as herbicide. Patent document 2 describes that pyrazole derivatives are useful as pesticide. Patent document 3 describes that pyrazole derivatives are useful as herbicide. Patent document 4 describes that pyrazole derivatives are useful as insecticide. Patent document 5 describes that pyrazole derivatives are useful as insecticide. Patent document 6 describes that pyrazole derivatives are useful as pesticide. Patent document 7 describes that pyrazole derivatives are useful as herbicide. The compounds disclosed in these patents have the carbamoyl group that is substituted with a substituent selected from a group consisting of substituted aryl, substituted arylalkyl, substituted heteroaryl and alkyl at 4-position of the pyrazole ring, and they are different from the compounds in the present invention. Furthermore the compounds having straight alkyloxy at 5-position on the pyrazole ring are disclosed in patent document 8 and useful for the treatment of schizophrenia, and they are different from the present invention. Moreover patent document 9 describes that the pyrazole derivatives shown below are useful as a cannabinoid receptor agonist, but does not describe the inhibitory activity to llβ-HSD-1. [0004] [Non-patent Document 1] Clin.Endocrinol, 1996, 44, 493 [Non-patent Document 2] Proc.Nat.Acad.Sci.USA, 1997, 94, 14924 [Non-patent Document 3] J.Clin.Endocrinol.Metab. 1995, 80, 3155 [Non-patent Document 4] Lancet, 1997, 349, 1210 [Patent Document 1] WO05/070889 [Patent Document 2] WO02/096882 [Patent Documents] W093/25535 [Patent Document 4] JP06-025199 [Patent Document 5] JP03-223256 [Patent Document 6] JPO1-207289 [Patent Document 7] JP60-214785 [Patent Document 8] US4226877 [Patent Document 9] W098/41519 Disclosure of Invention Problems to be solved by the Invention [0005] The present invention provides usuful compounds having an inhibitory activity to llβhydroxysteroid dehydrogenase type 1. Means for Solving the Problem [0006] The present invention provides; (1) A compound represented by formula (I): a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, one of R2 and R4 is a group of formula: -Y-R5, wherein Y is -0-or -S -, and R5 is substituted straight alkyl wherin the substituent of said straight alkyl is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, optionally substituted branched alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, the other of R2 and R4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, R3 is a group of formula: -C(=0)-Z-R6, wherein Z is -NR'7- or -NR7W-, and R6 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or optionally substituted heterocycle, R7 is hydrogen or optionally substituted alkyl, or R6 and R7 taken together may form optionally substituted ring, W is optionally substituted alkylene, Xis =N- or =CR8-, and R8 is hydrogen or optionally substituted alkyl, with the proviso that compounds wherein R2is 2-(morphorino)ethoxy, R3is N-(l-adamantyl)carbamoyl and R1 is benzyl are excluded. (2) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is substituted alkyl wherein the substituent of said substituted alkyl is optionally substituted amino or optionally substituted heterocycle, (3) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is substituted ethyl wherin the substituent of said substituted ethyl is optionally substituted amino or optionally substituted heterocycle, (4) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is unsubstituted alkyl, (5) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is a group of formula: -Y-R5, wherein Y and R^ have the same meaning as defined in the above (1), (6) The compound according to the above (5), a pharmaceutically acceptable salt or a solvate thereof, wherein Y is -0-, (7) The compound according to the above (5) or (6), a pharmaceutically acceptable salt or a solvate thereof, wherein Rs is substituted straight alkyl wherein the substituent of said substituted straight alkyl is optionally substituted cycloalkyl, (8) The compound according to the above (7), a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is substituted otraight methyl wherien the substituent of said substituted straight methyl is optionally substituted cycloalkyl, (9) The compound according to the above (7) or (8), a pharmaceutically acceptable salt or a solvate thereof, wherein said optionally substituted cycloalkyl is optionally substituted cyclohexyl, (10) The compound according to the above (5) or (6), a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is branched alkyl, (11) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein Z is -NR7-, and R7 has the same meaning as defined in the above (1), (12) The compound according to the above (11), a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is hydrogen, (13) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is optionally substituted cycloalkyl, (14) The compound according to the above (13), a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is adamantyl, (15) The compound according to the above (13), a pharmaceutically acceptable salt or a solvate thereof, wherein R3is a group of formula ( II ): [Formula 3] (16) The compound according to any one of the above (1) to (15), a pharmaceutically acceptable salt or a solvate thereof, wherein X is =N-, (17) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is a group of formula: -CH=CH-C(R9R10)-R11-R12, wherein R9 and R10 are each independently hydrogen, optionally substituted alkyl or halogen, or R9 and R10 taken together with the carbon atom to which they are attached may form an optionally substituted ring, R11 is -(CH2)n-, wherein n is an integer of 0 to 3, and R12 is hydrogen, hydroxy, carboxy, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkyloxycarbonyl, optionally substituted arylalkylcarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted sulfamoyl, optionally substituted'amino, optionally substituted carbamoyloxy, optionally substituted alkyloxy or optionally substituted alkylthio, a group of formula: -C(=0)-NR13R14, wherein R13 and R14 are each independently hydrogen, optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl or optionally substituted heterocyclesulfonyl, or R13and R14 taken together with the nitrogen atom to which they are attached may form an optionally substituted ring or, a group of formula: -NR15sR16 wherein R15 and R16 are each independently hydrogen, carboxy, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted alkyloxycarbonyl or optionally substituted sulfamoyl, or R15 and R16 taken together with the nitrogen atom to which they are attached may form optionally substituted ring, (18) The compound according to the above (1), a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is a group of formula: -CH2-CH2-C(R9R10).R11-.R12 wherein R9, R10, R11 and R12 have the same meaning as defined in the above (17), (19) The compound according to the above (17) or (18), a pharmaceutically acceptable salt or a solvate thereof, wherein R9and R10 are each independently optionally substituted alkyl, or R9 and R10 taken together with the carbon atom to which they are attached may form optionally substituted ring, (20) The compound according to any one of the above (17) to (19), a pharmaceutically acceptable salt or a solvate thereof, wherein R11 is -(CH2)n-, wherein n is an integer of 0 to 1, (21) The compound according to any one of the above (17) to (20), a pharmaceutically acceptable salt or a solvate thereof, wherein R12 is carboxy, cyano or heterocycle, (22) The compound according to any one of the above (17) to (20), a pharmaceutically acceptable salt or a solvate thereof, wherein R12 is a group of formula: -C(=0)-NR13R14 wherein R13and R14 are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optional!}' substituted heteroarylsulfonyl, optionally substituted heterocyclesulfonyl or optionally substituted heterocycle, or R^^ and Ri"* taken together with the nitrogen atom to which they are attached may form an optionally substituted ring, (23) The compound according to any one of the above (17) to (20), a pharmaceutically acceptable salt or a solvate thereof, wherein R12 is a group of formula: -NR15R16 wherein R15and R16 have the same meaning as defined in the above ( 17, (24) The compound according to the above ( 23, a pharmaceutically acceptable salt or a solvate thereof, wherein R15 is a group of formula: -C(=0)R', wherein R' is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted amino or optionally substituted alkyloxy, (25) A pharmaceutical composition which comprises the compound according to any one of the above (1) to (24), a pharmaceutically acceptable salt or a solvate thereof as an active ingredient, (26) The pharmaceutical composition according to the above (25) for treating and/or preventing diabetes. The present invention is characterized in the followings. 1) Possess a 5-membered N-containing heteroring, 2) Possess a substituent of formula: -Y-R5 on the above 5-membered heteroring, 3) R5 is substituted alkyl wherein the substituent of said substituted alkyl is substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, optionally substituted branched alkyl, optionally substituted alkenyl. optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, 4) Possess a substituent of formula: -C(=0)-Z-R6 on the above 5-membered heteroring, 5) R6 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or optionally substituted heterocycle, or R6 and R'7 taken together may form an optionally substituted ring, 6) Possess optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle on a nitrogen atom of the above 5-membered heteroring, Effect of the Invention [0007] The compounds of the present invention possess an inhibitory activity to llβ hydroxysteroid dehydrogenase type 1 and the pharmaceutical compositions comprising them are very useful for a medicament, especially a medicament for treating and/or preventing hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X. Moreover, the compounds of the present invention selectively inhibit llβhydroxysteroid dehydrogenase type 1. The preferable compounds in the present compounds have a high metabolic stability, a weak drug metabolizing enzyme induction, a weak drug metabolizing enzyme inhibition or a high oral absorption, and they are especially useful for a medicament. In addition, the present invention includes compounds having a low clearance and a long half-life period for exhibiting the drug activity. Best Mode for Carrying Out the Invention [0008] Terms used in the present specification are explained below. Each term has the following meanings alone or together with other terms. "Alkyl" means a CI to CIO straight or branched alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or the like. Preferred is a Cl to C6 alkyl or a Cl to C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl. "Straight alkyl" means a Cl to CIO straight alkyl group, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or the like. Preferred is a Cl to C6 or a Cl to C4 straight alkyl. "Branched alkyl" means a C3 to CIO branched alkyl group, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl or the like. Preferred is a C3 to C6 branched alkyl. "Alkylene" means a di-valent group derived from the above "alkyl", which includes a Cl to CIO straight or branched alkylene. Preferred is methylene, ethylene, propylene, trimethylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene or the like. "Alkenyl" means a C2 to C8 straight or branched alkenyl group, which includes a group having one or more double bond(s), for example 1 to 3 double bond(s) in the above "alkyl". Exemplified is vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl -2-butenyl or the like. "Alkynyl" means a C2 to C8 straight or branched alkynyl group, which includes a group having one or more triple bond(s), for example 1 to 3 triple bond(s) in the above "alkyl". Exemplified is ethynyl or the like. Moreover, "alkynyl" can possess 1 to 3 double bond(s). "Cycloalkyl" means a C3 to Cl5 saturated cyclic hydrocarbon group. Bridged cyclic hydrocarbon group is also included. Exemplified is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or bridged cyclic hydrocarbon, exemplified as follows. "Cycloalkenyl" means a C3 to C7 unsaturated aliphatic hydrocarbon group, including bridged cyclic hydrocarbon group. Exemplified is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. Preferred is cyclopropenyl. cyclobutenyl, cyclopentenyl or cyclohexenyl. Furthermore, cycloalkenyl means a group that has unsaturated bond in the above exemplified bridged cyclic hydrocarbon group. "Aryl" means a monocyclic aromatic hydrocarbon group (e.g., phenyl) or a fuzed aromatic hydrocarbon group (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl, "Heteroaryl" means a monocyclic aromatic heterocyclic group or fused aromatic heterocyclic group. The monocyclic aromatic heterocyclic group means a group derived from 5 to 8-membered aromatic heterocycle which may contain 1 to 4 oxygen, sulfur and/or nitrogen atom(s) in the ring. The binding bond can be at any substitutable position. The fused aromatic heterocyclic group means a group derived from 5 to 8-membered aromatic heterocycle which may contain 1 to 4 oxygen, sulfur and/or nitrogen atom(s) in the ring fused with one to four of 5 to 8-membered aromatic carbocycle(s) or other 5 to 8-membered aromatic heterocycle(s). The binding bond can be at any substitutable position. For example, it is furyl (e.g., furan-2-yl or furan-3-yl), thienyl (e.g., thiophene-2-yl or thiophene-3-yl), pyrrolyl (e.g., pyrrole-1-yl, pyrrole-2-yl or pyrrole-3-yl), imidazolyl (e.g., imidazole-1-yl, imidazole-2-yl or imidazole-4-yl), pyrazolyl (e.g., pyrazole-1-yl, pyrazole-3-yl or pyrazole-4-yl), triazolyl (e.g., 1,2,4-triazole-l-yl, l,2,4-triazole-3-yl or l,2,4-triazole-4-yl), tetrazolyl (e.g., tetrazole-1-yl, tetrazole-2-yl or tetrazole-5-yl), oxazolyl (e.g., oxazole-2-yl, oxazole-4-yl or oxazole-5-yl), isoxazolyl (e.g., isoxazole-3-yl, isoxazole-4-yl or isoxazole-5-yl), thiazolyl (e.g., thiazole-2-yl, thiazole-4-yl or thiazole-5-yl), thiadiazolyl, isothiazolyl (e.g., isothiazole-3-yl, isothiazole-4-yl or isothiazole-5-yl), pyridyl (e.g., pyridine-2-yl, pyridine-3-yl or pyridine-4-yl), pyridazinyl (e.g., pyridazine-3-yl or pyridazine-4-yl), pyrimidinyl (e.g., pyrimidine-2-yl, pyrimidine-4-yl or pyrimidine-5-yl), furazanyl (e.g., furazan-3-yl), pyrazinyl (e.g., pyrazine-2-yl), oxadiazolyl (e.g.. l,3,4-oxadiazole-2-yl), benzofuryl (e.g., benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl or benzo[b]furan-7-yl), benzothienyl (e.g., benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl or benzo[b]thiophene-7-yl), benzimidazolyl (e.g., benzimidazole-1-yl, benzimidazole-2-yl, benzimidazole-4-yl or benzimidazole-5-yl), dibenzofuryl, benzoxazolyl, . quinoxalyl (e.g., quinoxaline-2-yl, quinoxaline-5-yl or quinoxaline-6-yl), cinnolyl (e.g., cinnoline-3-yl, cinnoline-4-yl, cinnoline-5-yl, cinnoline-6-yl, cinnoline-7-yl' or cinnoline-8-yl), quinazolyl (e.g., quinazoline-2-yl, quinazoline-4-yl, quinazoline-5-yl, quinazoline-6-yl, quinazoline-7-yl or quinazoline-8-yl), quinolyl (e.g., quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl or quinoline-8-yl), phthalazinyl (e.g., phthalazine-1-yl, phthalazine-5-yl or phthalazine-6-yl), isoquinolyl (e.g., isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl or isoquinoline-8-yl), puryl, pteridinyl (e.g., pteridine-2-yl, pteridine-4-yl, pteridine-6-yl or pteridine-7-yl), carbazolyl, phenanthridinyl, acridinyl (e.g., acridine-1-yl, acridine-2-yl, acridine-3-yl, acridine-4-yl or acridine-9-yl) , indolyl (e.g., indole-1-yl, indole-2-yl, indole-3-yl, indole-4-yl, indole-5-yl, indole-6-yl or indole-7-yl), isoindolyl, phenazinyl (e.g., phenazine-1-yl or phenazine-2-yl), phenothiazinyl (e.g., phenothiazine-1-yl, phenothiazine-2-yl, phenothiazine-3-yl or phenothiazine-4-yl) or the like. "Heterocycle" means a 5 to 8-membered nonaromatic heterocycle group which may contain 1 to 4 oxygen, sulfur and/or nitrogen atom(s) in the ring. The binding bond can be at any substitutable position. Moreover, the nonaromatic heterocycle group can be substituted with a Cl to C5 alkylene chain or a C2 to C5 alkenylene chain to form fused ring(including bicyclic ring) or spiro ring, or can be fused with cycloalkane(preferred is 5 to 6-membered ring) or benzene ring. Heterocycle can be saturated or unsaturated, as long as it is nonaromatic. Preferred is 5 to 8-membered ring. Exemplified is 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyI, morpholino, tetrahydropyranyl, or the following groups. Each ring can be optionally substituted at any substitutable position. [0009] "A ring formed by taking together R6 and R7' means 5 to 8-membered ring including the nitrogen atom attached to R7 in the ring. The above ring is attached to the carbon atom of the carbonyl group through the binding bond from the nitrogen atom attached to R7. The ring is composed of carbon, oxygen, sulfer atom(s) or the like, besides the above nitrogen atom. The ring can contain 1 to 4 oxygen, sulfer and/or nitrogen atom(s) in the ring. Moreover, the ring can be substituted with Cl to C5 alkylene chain or C2 to C5 alkenylene chain to form fused ring(including bicycle ring), spiro ring or can be fused with cycloalkane(preferred is 5 to 6-membered ring) or benzene ring. The ring can be saturated or unsaturated. Preffered is 5 to 8-membered ring, for example, 1-pyrrolinyl, 1-pyrrolidinyl, 1-imidazolinyl, 1-imidazolidinyl, 1-pyrazolinyl, 1-pyrazolidinyl, piperidino, 1-piperadinyl, morpholino, or the following groups. Each ring can be optionally substituted. [0010] "A ring formed by taking together R9 and R10 with the carbon atom to which they are attached" means 3 to 15-membered saturated or unsaturated hydrocarbon ring or 3 to l5-membered saturated or unsaturated hetero ring containing 1 to 4 oxygen, sulfer, and/or nitrogen atom(s) in said hydrocarbon ring. Preffered is nonaromatic ring, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopropane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, or the like. Exemplified is saturated or unsaturated hetero ring containing 1 to 4 oxygen, sulfer, and/or nitrogen atom(s) in the hydrocarbon ring. For example, a group of formula: -C(R9R10)-, wherein R9 and R10 taken together with the carbon atom to which they are attached may form an optionally substituted ring, is exemplified as follows. Each ring can be optionally substituted. "A ring formed by taking together R13 and Ri14 with the nitrogen atom to which they are attached" and "a ring formed by taking together R15 and R16 with the nitrogen atom to which they are attached" mean 3 to 15-membered nonaromatic hetero ring which may contain 1 to 4 oxygen, sulfer, and/or nitrogen atom(s) besides the above nitrogen atom in the ring. The nonaromatic hetero ring can be bridged with C1 to C4 alkyl chain and be fused with cycloalkane (preffered is 5 to 6-membered ring) or benzene ring. The ring can be saturated or unsaturated, as long as it is nonaromatic. Preffered is 5 to 8-membered ring. For example, a group of formula:-NR13R14 wherein R13 and R14 taken together with the nitrogen atom to which they are attached may form an optionally substituted ring and a group of formula:-NR15R16 wherein R15\ and R16 taken together with the nitrogen atom to which they are attached may form an optionally substituted alkyl", "optionally substituted alkylene", "optionally substituted alkenyl", "optionally substituted alkynyl", "substituted straight alkyl", "optionally substituted branched alkyl", "a ring formed by taking together R6 and R7", "optionally substituted imino", "a ring formed by taking together R9 and R10 with the carbon atom to which they are attached", "a ring formed by taking together R13 and R14 with the nitrogen atom to which they are attached", "a ring formed by taking together R15 and R16 with the nitrogen atom to which they are attached" and "optionally substituted methylene" may be substituted with 1 to 4 substituent(s) selected from a group consisting of, for example, hydroxy, carboxy, halogen (e.g.: F, C1, Br, I), optionally substituted alkyl (e.g.: methyl, ethyl, isopropyl, tert-butyl, halogenated alkyl (e.g.: -CF3, -CH2CF3, -CH2CC13), optionally substituted alkylthio (e.g.: methylthio), optionally substituted alkylsulfonyl (e.g.: methansulfonyl, ethansulfonyl), optionally substituted carbamoyl (e.g.: optionally substituted alkylcarbamoyl (e.g.: methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl), optionally substituted alkylsulfonylcarbamoyl), optionally substituted alkenyl (e.g.: vinyl), optionally substituted alkenyloxy (e.g.: vinyloxy, allyloxy), alkynyl (e.g.: ethynyl), optionally substituted cycloalkyl (e.g.: cyclopropyl), optionally substituted cycloalkenyl (e.g.: cyclopropenyl), optionally substituted alkyloxy (e.g.: methoxy, ethoxy, propoxy, butoxy, carboxymethyloxy), optionally substituted alkyloxycarbonyl (e.g.: methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), nitro, nitroso, optionally substituted amino (e.g.: alkylamino (e.g.: methylamino, ethylamino, diethylamino), acylamino (e.g.: optionally substituted alkylcarbonylamino, optionally substituted arylcarbonylamino, optionally substituted heteroarylcarbonylamino, optionally substituted heterocyclecarbonylamino). optionally substituted arylalkylamino (e.g.: benzylamino, tritylamino), hydroxyamino, optionally substituted alkyloxycarbonylamino, optionally substituted alkylsulfonylamino, optionally substituted carbamoylamino, optionally substituted arylsulfonylamino, optionally substituted arylamino), azide, optionally substituted aryl (e.g.: phenyl), optionally substituted arylalkyl (e.g.: benzyl), optionally substituted heteroaryl, optionally' substituted heterocycle, cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto, optionally substituted sulfamoyl, acyl (e.g.: formyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heterocyclecarbonyl), formyloxy, haloformyl, oxalo, thioformyl, thiocarboxy, dithiocarboxy, optionally substituted thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazine, azide, ureido, amidino, guanidino, phthalimide, oxo, alkylene, alkylenedioxy (-O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, or the like), optionally substituted heterocyclecarbonyl, phosphoester (e.g., -P(=0)(0Et)2), optionally substituted cycloalkylthio, optionally substituted arylthio, optionally substituted heteroarylthio, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted heterocycleoxy, optionally substituted imino. optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted alkylsulfinyl, optionally substituted arylsulfinyl, optionally substituted alkylcarbonyloxy, optionally substituted arylcarbonyloxy, optionally substituted heteroarylcarbonyloxy, optionally substituted heterocyclcarbonyloxy, optionally substituted alkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted heteroaryloxycarbonyl, optionally substituted heterocycleoxycarbonyl, optionally substituted methylene. The alkyl part of "optionally substituted alkylsulfonyl", "optionally substituted alkylsulfinyl". "optionally substituted alkyloxy", "optionally substituted alkylsulfonylamino", "optionally substituted alkylcarbonyloxy", "optionally substituted alkylcarbonyl", "optionally substituted alkyloxycarbonyl", "optionally substituted alkyloxycarbonylamino", "optionally substituted alkylthio", "optionally substituted alkylcarbamoyl" and "optionally substituted alkylsulfonylcarbamoyl" is the same as the above "alkyl". The alkyl part can be optionally substituted with the same substituent as the above "optionally substituted alkyl". The alkenyl part of "optionally substituted alkenylcarbonyl", "optionally substituted alkenyloxy" is the same as the above "alkenyl". The alkenyl part can be optionally substituted with the same substituent as the above "optionally substituted alkenyl. The cycloalkyl part of "optionally substituted cycloalkylthio" is the same as the above "cycloalkyl". The cycloalkyl part can be optionally substituted with the same substituent as the above "optionallj' substituted cycloalkyl". The aryl part of "optionally substituted arylsulfonyl", "optionally substituted arylsulfinyl", "optionally substituted arylsulfonylamino", "optionally substituted arylcarbonyloxy", ' "optionally substituted aryloxycarbonyl", "optionally substituted arylcarbonyl", "optionally substituted arylamino", "optionally substituted arylthio", "optionally substituted aryloxy" is the same as the above "aryl". The aryl part can be optionally substituted with the same substituent as the above "optionally substituted aryl". The heteroaryl part of "optionally substituted heteroarylcarbonyloxy", "optionally substituted heteroarylcarbonyl", "optionally substituted heteroaryloxycarbonyl", "optionally substituted heteroarylthio" and "optionally substituted heteroaryloxy" is the same as the above "heteroaryl". The heteroaryl part can be optionally substituted with the same substituent as the above "optionally substituted heteroaryl". The heterocycle part of "optionally substituted heterocyclecarbonyloxy", "optionally substituted heterocycleoxycarbonyl", "optionally substituted heterocyclecarbonyl" and "optionally substituted heterocycleoxy" is the same as the above "heterocycle". The heterocycle part can be optionally substituted with the same substituent as the above "optionally substituted heterocycle". The aryl part of "optionally substituted arylalkylamino" is the same as the above "aryl" and the alkyl part is the same as the above "alkyl". The aryl part can be optionally substituted with the same substituent as the above "optionally substituted aryl" and the alkyl part can be optionally substituted with the same substituent as the above "optionally substituted alkyl". A substituent of "optionally substituted amino", "optionally substituted carbamoylamino", "optionally substituted carbamoyl", "optionally substituted thiocarbamoyl", "optionally substituted sulfamoyl", "optionally substituted imino" includes optionally substituted alkyl, optionally substituted alkenyl. optionally substituted aryl, optionally substituted heteroaryl, acyl, hydroxy, optionally substituted alkylsulfonyl, optionally substituted alkylsulfinyl, optionally substituted arylsulfonyl, optionally substituted arylsulfinyl, optionally substituted amino or the like. A substituent of "optionally substituted alkylsulfonyl", "optionally substituted alkylsulfinyl", "optionally substituted arylsulfonyl," "optionally substituted arylsulfinyl" includes the same substituent as optionally substituted alkyl or optionally substituted aryl. "Acyl" means formyl, optionally substituted alkylcarbonyl, optionally substituted alkenylcarbonyl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl or optionally substituted heterocyclecarbonyl. A substituent of "optionally substituted alkylcarbonyl", "optionally substituted alkenylcarbonyl", "optionally substituted arylcarbonyl", "optionally substituted heteroarylcarbonyl", "optionally substituted heterocyclecarbonyl" includes the same substituent as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle. "Arylalkyl" means the above alkyl which is substituted with 1 to 3 of the above aryl. [0013] R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl. optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle Preferably R1 is substituted alkyl wherein the substituent of said substutited alkyl is optionally substituted amino or optionally substituted heterocycle, unsubstituted alkyl, a group of formula: -CH=CH-C(R9R10)-R11-R12 or a group of formula: -CH2-CH2-C(R9R10).R11.R12 wherein R9 and Rio ■ are each independently hydrogen, optionally substituted alkyl or halogen, or R9 and R10 taken together with the carbon atom to which they are attached'may form an optionally substituted ring, .'* ' R11 is -(CH2)n- wherein n is an integer of 0 to 3, R12 is hydrogen, hydroxy, carboxy, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkyloxycarbonyl, optionally substituted arylalkylcarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted carbamoyloxy, optionally substituted alkyloxy or optionally substituted alkylthio, a group of formula: -C(=0)-NR13R14 wherein R13and R14 are each independently hydrogen, optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl. optionally substituted heterocyclesulfonyl, or R13 and R14 taken together with the nitrogen atom to which they are attached may form an optionally substituted ring or, a group of formula: -NR15R16 wherein R15and R16 are each independently hydrogen, carboxy, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted alkyloxycarbonyl, optionally substituted sulfamoyl, or R15 and R16 taken together with the nitrogen atom to which they are attached may form optionally substituted ring. One of R2and R4 is a group of formula: -Y-R 5wherein Y is -0-or -S-, and R5 is substituted straight alkyl wherein the substituent of substituted straight alkyl is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, optionally substituted branched alkyl, optionally substituted alkenyl or optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, the other of R2 and R4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl. optionally substituted heteroaryl or optionally substituted heterocycle. Preferably R2 is a group of formula: -Y-Rs wherein R5 has the same meaning as defined in the above (1). More Preferable as R2 is a a group of formula: -Y-R5 wherein Y is -0-, and R5 is substituted straight alkyl wherein the substituent of said substituted straight alkyl is optionally substituted cycloalkyl. As to said alkyl, methyl, ethyl, propyl(especially, methyl) are preferred. As to said cycloalkyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl(especially, cyclohexyl) are preferred. R3 is a group of formula: -C(=O)-Z-R6, wherein Z is -NR7- or -NR7-W-, and R6 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or optionally substituted heterocycle, R'7 is hydrogen or optionally substituted alkyl, or R6 and R7taken together may form optionally substituted ring, W is optionally substituted alkylene. Preferable as Z is -NR'7- wherein R7 has the same meaning as defined in the above (1). More preferable as Z is -NH-. Moreover, as to R6 optionally substituted cycloalkyl is preferable. Adamantyl(especially, 2-adamantyl) is more preferable as R6. X is =N- or =CR8- wherein R8 is hydrogen or optionally substituted alkyl. Preferable is =N-. [0014] As to R1, for example, the following groups are preferable. [Formula 9] wherein R is optionally substituted alkyl or optionally substituted aryl. [0015] As to a group of formula: -V-R5, for example, the following groups are preferable. As to the substituent of substituted alkyl of R5, the followings are preferable: A) optionally substituted cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), B) optionally substituted cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), C) optionally substituted aryl (phenyl, naphthyl). D) heteroaryl (e.g., pyridyl, imidazolyl), E) optionally substituted heterocycle(e.g., 4-piperidinyl, 2-pyrrolidinyl, morpholino, 2-morpholinyl, piperidino, 3,5-dimethylmorpholino, piperazinyl, N-tert-butoxycarbonyl-3-piperidinyl, 1-pyrrolidinyl, tetrahydropyranyl). [0017] As to optionally substituted cycloalkyl of R6, for example, the following groups are preferable. [Formula 13] [0018] Pharmaceutically acceptable salts of the compounds of the present invention are exemplified as follows. Basic salts, for example, are salts of alkali metal such as sodium, potassium or the like; salts of alkaline-earth metal such as calcium, magnesium or the like; salts of ammonium; salts of aliphatic amine such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumine, diethanol amine, ethylenediamine or the like; salts of arylalkyl amine such as N,N-dibenzylethylenediamine, benetamine or the like; salts of hetero aromatic amine such as pyridine, picoline, quinoline, isoquinoline or the like; salts of quaternary ammonium such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium, methyltrioctylammonium, tetrabutylammonium or the like; salts of basic amino acid such as arginine, lysine or the like. Acidic salts, for example, are salts of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrogencarbonic acid, perchloric acid or the like; salts of organic acid such as acetic acid, propionic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, malic acid, citric acid or ascorbic acid; salts of sulfonic acid such as methansulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like; salts of acidic amino acid such as aspartic acid, glutamic acid or the like. [0019] Solvate means a solvate of a compound of the present invention or a pharmaceutically acceptable salt thereof, for example, alcohol(e.g., ethanol) solvate, hydrate or the like. As to hydrate, monohydrate, dihydrate or the like are exemplified. [0020] A general method for producing a compound of the present invention is explained below. Each symbol is the same as the above (1). In addition, the treatment of the conventional organic synthesis such as extraction, purification and the like can be used for the synthesis of a compound of the present invention. [0021] [Formula 15] wherein R1, R5 and R6 are the same as the above, R10 is a protecting group(e.g., alkyl or the like), R11is a protecting grouop(e.g.,benzyl or the like), and X is a leaving group (e.g.,halogen or the like). [0022] l=st step st step is a process for manufacturing a compound of formula (II-2) which comprises reacting a compound of formula (II-l) with R1NH2NH2. R10QH can be used as a reaction solvent. This reaction can be performed at room temperature or under refluxing temperature. [0023] 2nd step 2nd step is a process of manufacturing a compound of formula (II-3) which comprises reacting a compound of formula (II-2) with R11X. Benzylhalide can be as R11X. This reaction is preferably performed in the presence of a base and can be carried out at room temperature or under refluxing temperature. Acetone, dimethylformamide or the like can be used as a reaction solvent. [0024] 3rd step 3rd step is a process of manufacturing a compound of formula (II-4) which comprises hydrolyzing a compound of formula (II-3). This reaction can be performed in a hydrous solvent and in the presense of a base. A hydrous solvent includes hydrous alcohol, hydrous tetrahydrofuran or the like. The mixed solvent of the above can be used. Sodium hydroxide, lithium hydroxide or the like can be used as a base. This reaction can be carried out at room temperature or under refluxing temperature. The preferable reaction temperature is room temperature. [0025] 4thstep 4th step is a process of manufacturing a compound of formula (II-5) which comprises reacting a compound of formula (II-4) with R6NHR7 This reaction can be performed with the reaction condition known as the conditon used for the condensation reaction of carboxylic acid and amine. For example, a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCCD), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSCI) or the like can be used. 1-Hydroxybenzotriazole (HOBt), 3,4-Dihydro-hydroxy-4-oxo-l,2,3-benzotriazine(HOOBt) or the like can be used as an additive. Dimethylformamide can be used as a solvent. This reaction can be performed at room temperature. Additionally, after the amidation reaction with R6NH2, R7 group can be introduced by reacting the obtained compound with R7X in the presence of a base. Moreover, R6WNHR^7can be used, instead of R6NHR7. [0026] 5'th step 5th step is a process of manufacturing a compound of formula (II-6) which comprises deprotecting a protective group of a compound of formula (II-5). When R11 is benzyl group, the deprotection reaction can be performed by catalytic reduction. Alcohol can be used as a solvent. This reaction can be carried out by using palladium-carbon(5~10%) as a catalyst under hydrogen atmosphere. [0027] 6th step 6th step is a process of manufacturing a compound of formula (I-l) which comprises reacting a compound of formula (II-6) with R5X. This reaction can be performed in the presence of a base. Potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide or the like can be used as a base. This reaction can be carried out at room temperature or under refluxing temperature. Dimethylformamide can be used as a solvent. [0028] A compound of the present invention wherein X is =CR8- can be synthesized by using a compound having a pyrrole ring instead of a pyrazole ring described in the above formula (II-2) in accordance with the above explained scheme. [0029] Various substituent of a compound of the present invention can be introduced referring to (1) Alan R. Katriszly et al.. Comprehensive Heterocyclic Chemistry, (2) Alan R. Katriszly at al., Comprehensive Heterocyclic Chemistry II, (3) ROOD'S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYCLIC COMPOUNDS, or the like. [0030] A compound of the present invention has a high inhibitory activity to 11β hydroxysteroid dehydrogenase type 1. Therefore, a compound of the present invention can be used for treating and/or preventing a disease concerning 11β hydroxysteroid dehydrogenase type 1, especially, hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X. Especially, a compound of the present invention is useful for treating and/or preventing diabetes. [0031] A compound of the present invention can be administrated via oral or parenteral. When the present compound is administrated via oral, the present compound can be used for in any form of the conventional pharmaceutical formulations, for example, solid formulations such as tablets, powders, granules, capsules or the like; aqueous formulations; oleaginous suspensions; or solution formulations such as syrup or elixir. When the present compound is administrated via parenteral, the present compound can be used as an aqueous or oleaginous suspensions injection or nose droops. In the preparation of such formulations, the conventional pharmaceutical excipients, binding agents, lubricants, aqueous solvents, oleaginous solvents, emulsifying agents, suspending agents, preservatives, stabilizers, and the like can be optionally used. Especially, a compound of the present invention is preferably used as oral agents. A formulation according to the present invention can be manufactured by combining (e.g., admixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation can be manufactured by using of well-known and easily available ingredients in accordance with a known method. A dosage of a compound of the present invention depends on the administration route, age, body weight, conditions of the patient, and kind of disease, but in case of oral administration, the daily dosage for an adult can be between approximately 0.05mg~3000mg, preferably approximately 0.1 mg~1000mg. The daily dosage can be administered in divisions. When a compound of the present invention is administrated via parenteral, the daily dosage for an adult can be between approximately O.Olmg-lOOOmg, preferably approximately 0.05mg~500mg. Moreover, a compound of the present invention can be administrated with other curative agents. Examples are show below for further detail explanation of the present invention, but are not intended to limit the scope of the present invention. To a solution of Compound 1(50.0g) in ethanol was added methylhydrazine(13.5ml) dropwisely under ice-cooloing, then the reaction solution was stirred at room temperature for one hour and refluxed for 4 hours. The solvent was removed under reduced pressure to give a solid. The solid was washed with hexane to give Compound 2(34.2g). To a solution of Compound 2(20.0g) in dimethyl formamide(200ml) were added potassium carbonate(48.7g) and benzylbromide(15.4ml), then the resulting mixture was stirred at room temperature for 4hrs. The insoluble was removed by filtration and the filtrate was poured into a solution of ethyl acetate and O.lN HCl aquesous soln. and extracted with ethyl acetate. The extraction was washed with O.lN HCl aqueous soln., H2O and brine, successively, then dried with sodium sulfate and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give Compound 3(24.0g). To a solution of Compound 3(24.0g) in methanol(150ml)-tetrahydrofuran(30ml)-H2O(130ml) was added 4N lithium hydroxide aqueous soln.(100ml) under ice-cooling. The resulting solution was stirred at room temperature for 30 min. and at 60 °C for 3hrs. The solution was neutralized with 2N HCl aqueous soln. under ice-cooling and extracted with ethyl acetate. The extraction was washed with H2O, brine and dried with magnesium sulfate, and concentrated in vacuo to give Compound 4(18.9g) as a crystal. [Formula17] To a solution of Compound 4(2.32g), 2-aminoadamantane hydrochloride(2.25g) and l-hydroxybenztriazole(405mg) in dimethyl formamide(25ml) were added triethylamine(3.35ml) and 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride(2.30g) successively, then the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a solution of 0.lN HCl aqueous soln. and ethyl acetate and extracted with ethyl acetate. The extraction was washed with H2O, brine and dried with magnesium sulfate and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give Compound A-4(3.12g). To a solution of Compound A-4(1.00g) in ethanol(lOml) was added 5%Pd-C(174mg), then the resulting mixture was stirred under H2 atomosphere(latm) for four hours. The insoluble was removed by filtration using Celite, then the filtrate was concentrated in vacuo to give Compound 5(711mg) as a solid. To a solution of Compound 5(110mg) in dimethyl formamide(1.5ml) were added potassium carbonate(165mg) and bromocyclohexane(59µl), then the resulting solution was stirred at 150 °C for l.5hrs by using microwave. The reaction solution was poured into a solution of 0.lN HCl aquesous soln. and ethyl acetate and extracted with ethyl acetate. The extraction was washed with H2O, brine and dried with magnesium sulfate and concentrated in vacuo. The residue was purified by silicagel columnchromatography to give Compound A-6(16mg). The reaction of Compound 2 with phosphorus oxychloride gave Compound 6. The reaction of Compound 6 with thiophenol in the presence of cesium carbonate gave Compound A-2. A-6 A reaction of catalytic reduction of Compound A-4 gave Compound 5. The obtained compound was reacted with cyclohexylbromide in the presence of potassium carbonate to afford Compound A-6. Compound 5 obtained in Example 6 was reacted with phenethylbromide to give Compound A-7. Additionally, a compound of the present invention can be obtained by using various halides as well as the halides shown in Examples 6 and 7. Compounds C-36~38, 41 were synthesized in accordance with the method shown in the above Examples. Compounds 8 and 8' were synthesized by using Compound 1 as a starting material and HOCH2 CH2 NHNH2 instead of MeNHNH2 in Example 1. The obtained 8 was reacted with 2-adamantanamine to give Compound A-8. Example 9 [0040] [Formula26] According to the above scheme, Compound A-33 was prepared. Additionally, Compound C-70 was synthesized by using hydroxy adamantanamine instead of adamantanamine. triethylamine to give Compound B-1. Compound B-1 was reacted with various amines to afford Compounds A-40, A-41, A-42, A-44, A-45 and A-46. Moreover, Compounds C-1, 2, 12 to 28, 51 to 53, 84, 101, 102, 108 to 110 were synthesized from Compound A-33. Moreover, Compounds C-3 to 6. 11 were synthesized from Compound A-44. Compound 6 was reacted with various benzylbromides in the presence of cesium carbonate to give Compounds A-26, A-27 and A-28. Compounds A-7, A-13, A-14, A-19, A-20, A-22, A-23, A-24, A-26, A-27, A-28, A-29, A-34, A-35, A-51, A-52 and A-59 to 65 were synthesized from Compound 6 via Mitsunobu reaction or alkylation reaction. I Compound 12 was reacted with various amines in the presence of HOBt and WSC to afford Compound A-36. Compounds A-37, A-38, A-47 to 50, A-53, A-55, A-57, A-58, A-66, A-67, C-7 to 10, 45 and 54 to 58 were synthesized as well as the above Example. According to the above scheme, Compounds C-39, 40, 42, 72, 73, 74, 75 and 76 were synthesized. Compounds C-79, 81, 151 to 153 were synthesized as well as the above Example. To a solution of Compound 17(5.7g) in ethyl acetate(160ml) was added IBX(7.5g), then the resulting mixture was refluxed for 6hrs. After termination of the reaction, the insoluble was removed by filtration and the filtrate was concentrated to give Compound 18(5.6g). The obtained product was used for the next reaction without further purification. To a solution of Compound 18 in tetrahydrofuran(40ml) was added phosphonium salt(13.5g). Triethylamine(3.4g) was added dropwisely to the solution over 20 min, then the whole mixture was stirred at room solution was stirred at room temperature for 24hrs. After termination of the reaction, the solution was diluted with 2N HCl aqueous soln. and extracted with ethyl acetate. The organic layer was washed with sat. sodium hydrogencarbonate soln. and brine successively, and dried with magnesium sulfate. The residue was purified by silicagel columnchromatography to give Compound 22(176mg). To a solution of Compound 22(176mg) . in methylene chloride(3ml) was added 4N HCl/dioxane(2ml), then the resulting solution was stirred at room temperature for 26hrs. After termination of the reaction, the solution was diluted with diisopropylether to give crystal. The obtained crystal was collected by filtration and washed with diisopropylether, then dried to give Compound C-182(120mg). To a solution of Compound C-182(55mg) in dimethyl formamide(lml) was added l,l'-carbonyldiimidazole(30mg), then the resulting solution was stirred at room temperature for 45min. 28% Ammonia aqueous soln.(0.2ml) was added to the solution and the whole solution was stirred for l.Shrs. After termination of the reaction, the solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with O.lN HCl aqueous soln. and brine successively, and dried with magnesium sulfate and concentrated. The obtained crystal was washed with diisopropylether to afford Compound C-144(35mg). To a solution of Compound C-144(118mg) in tetrahydrofuran(4.4ml)-methanol(0.4ml) was added 10% Pd-C(40mg), then the resulting mixture was stirred for 3.5hrs. under H2 atomosphere. After termination of the reaction, Pd-C was removed by filtration and the solvent was removed to give Compound C-181(117mg). Compounds C-147, 160, 163, 187 and 195 were synthesized as well as To a solution of Compound 23 in methylene chloride(lOOml) was added trifluoroacetic acid(50ml), the resulting solution was stirred at room temperature for 3hrs. After termination of the reaction, the solvent was removed and the residue was diluted with H2O(100ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate and concentrated to give Compound 24(16.6g). To a solution of Compound 24(16.6g) in toluene(70ml) were added triethylamine(5.67g), diphenylphosphoryl azide (14.7g), then the resulting solution was stirred at 100 °C for 3hrs. After termination of the reaction, the solution was diluted with toluene(70ml) and the organic layer was washed with sat. sodium hydrogencarbonate soln. and brine successively, and dried with magnesium sulfate and concentrated. The obtained product was used for the next reaction without further purification. According to the above procedure, the obtained 25 was dissolved in toluene(30ml) and 4-methoxybenzylalcohol(10.6g) was added to the solution. The solution was stirred at 50 °C for 24hrs. After termination of the reaction, the solvent was removed and the residue was purified by silicagel columnchromatography to give Compound 26(19.2g). To a solution of Compound 26 in methylene chloride(lOOml) were added anisole(13.6g) and trifluoroacetic acid(20ml), then the resulting solution was stirred at room temperature for 2hrs. After termination of the reaction, the solvent was removed and the residue was diluted with IN HCl aqueous soln. (50ml) and H2O(60ml). The aqueous layer was washed with hexane and alkalified with 2N NaOH aqueous soln.(30ml). The solution was extracted I with ethyl acetate and the organic layer was washed with brine and dried with magnesium sulfate and concentrated to give Compound 27(9.6g). To a solution of Compound 27(9.6g) in methylene chloride(50ml) were added pyridine(3.9g) and acetic anhydride(4.0g), then the resulting solution was stirred at room temperature for 2hrs. After termination of the reaction, ) the solution was diluted with chloroform and the organic layer was washed with 2N HCl aqueous soln., sat. sodium hydrogencarbonate soln. and brine successively. The organic layer was dried with magnesium sulfate and concentrated. The residue was purified by silicagel columnchromatography to give Compound 28(7.1g). To a solution of Compound 28(7.1g) in tetrahydrofuran(20ml)-methanol(20ml) was added 2N LiOH aqueous soln.(21ml), then the resulting solution was stirred at room temperature for 16hrs. After termination of the reaction, the solution was acidified with 2N HCl aqueous soln. and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate and concentrated to give Compound 29(6.3g). To a solution of Compound 29(102mg) in methylene chloride(2ml) were added hydroxy adamantanamine(81mg), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(82mg), l-hydroxybenzotriazole(14mg) and triethylamine(115µl), then the resulting solution was stirred at room temperature for 13hrs. After termination of the reaction, the solution was acidified with 2N HCl aqueous soln. and extracted with methylene chloride. The organic layer was washed with sat. sodium hydrogencarbonate soln. and brine successively, and dried with sodium sulfate. The residue was purified by silicagel columnchromatography to afford Compound C-202(123mg). Compounds C-194 and 204 were synthesized as well as the aboveExample. Example 31 [0062] [Formula 49] To a solution of Compound 30(400mg) in toluene(8ml) were added triethylamine(l80µl) and diphenylphosphoryl azide(279µl), then the resulting solution was stirred at 100 °C for 2hrs. After cooling to 0 °C, 28% ammonia aqueous soln.(2ml) was added to the solution and the whole solution was stirred at room temperature for 80min. After termination of the reaction, H2O was added to the solution and extracted with ethyl acetate. The organic layer was washed with sat. sodium hydrogencarbonate soln. and brine, and dried with sodium sulfate and concentrated. The residue was purified by silicagel columnchromatography to give Compound 31(303mg). To a solution of Compound 31(303mg) in tetrahydrofuran(3ml)-methanol(1.5ml) was added 2N LiOH aqueous soln. (0.68ml), then the resulting solution was stirred at room temperature for 19hrs. After termination of the reaction, the solution was diluted with H2O and the organic layer was washed with diethylether. The mixture was acidified with 2N HCl aqueous soln., and extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with brine and dried with sodium sulfate and concentrated. The obtained crystal was washed with ethyl acetate-hexane to afford Compound 32(193mg). To a solution of Compound 32(193mg) in dimethyl formamide(4ml) were added hydroxy adamantanamine(152mg), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(155mg), l-hydroxybenzotriazole(26mg) and triethylamine(217µl), then the resulting solution was stirred at room temperature for 18hrs. After termination of the reaction, the solution was acidified with 2N HCl aqueous soln. and extracted with methylene chloride. The organic layer was washed with sat. sodium hydrogencarbonate soln. and brine successively, and dried with sodium sulfate. The residue was purified by silicagel columnchromatography to give Compound C-186(36mg). To a solution of Compound C-186(25mg) in tetrahydrofuran(lml)-methanol(0.1ml) was added 10%Pd-C(12mg), then the resulting mixture was stirred for 24hrs under H2 atomosphere. After termination of the reaction, Pd-C was removed by filtration and the solvent was removed to afford Compound C-184(25mg). Compounds C-183, 185, 198 and 199 were synthesized as well as the above Example. Example 32 [0063] [Formula 50] According to Example 29, Compound 33 was synthesized from Compound 24. To a solution of Compound 33(149mg) in methylene chloride(3ml) were added pyridine(74µl) and anhydrous trifluoroacetic acid(98µl), then the resulting solution was stirred at room temperature for 45min. After termination of the reaction, HC1 aqueous soln. was added to the solution. The mixture was extracted with ethyl acetate and the organic layer was washed with sat. sodium hydrogencarbonate soln. and brine successively, and dried with sodium sulfate and concentrated to give Compound 34(141mg). According to the above procedure, Compound C-192 was synthesized. Example 33 [0064] [Formula 51] To a solution of Compound 38 in toluene(2ml) were added 2-chloroethanol(103µl), triethylamine(2 drops), then the resulting solution was stirred at room temperature for 24hrs. After termination of the reaction, the solvent was removed and the residue was purified by silicagel columnchromatography to give Compound 39(215mg). To a solution of Compound 39(211mg) in tetrahydrofuran(4ml)-dimethyl formamide(4ml) was added sodium hydride(32mg, 60% oil suspension), then the resulting solution was stirred at room temperature for 140min. After termination of the reaction, HCl aqueous soln. was added to the solution. The extraction was carried out with ethyl acetate and the organic layer was washed with brine and dried with sodium sulfate and concentrated. The residue was purified by silicagel columnchromatography to give Compound 40(191mg). According to the above procedure. Compounds C-201 and 203 were synthesized. Example 35 [0066] [Formula 53] According to the above procedure, the reduction of carboxylic acid, Compound C-182 gave Compound C-193. Compound C-162 was synthesized as well as the above Example. According to Example 29, Compound C-164 was synthesized from Compound C-162. Example 38 [0069] [Formula 56] To a solution of diethyl ethoxymethylenemalonate(21.6g) in ethanol(80ml) was added dropwise hydrazine ethanol(8g) in ethanol(20ml) over 30min at -4 °C. The resulting solution was stirred at 40 °C for 1hr and the solvent was removed. The residue was dissolved in chloroform and the organic layer was washed with sat. sodium hydrogencarbonate soln. and dried with magnesium sulfate and concentrated. The residue was dissolved in ethanol(80ml) and the solution was refluxed for 18hrs. After the termination of the reaction, the solvent was removed to give Compound 45(18.5g). To a solution of Compound 45(6.3g) in dimethyl formamide(30ml) were added cesium carbonate(15.4g) and isobutyl bromide(5.6g), then the resulting mixture was stirred at 70 °C for 3hrs. After termination of the reaction, H2O(60ml) was added to the mixture. The extraction was carried out with ethyl acetate and the organic layer was washed with brine and dried with magnesium sulfate and concentrated to give Compound 46(5.7g). To a solution of Compound 46(8.0g) in methanol(70ml) was added 2N NaOH aqueous soln. (60ml), then the resulting solution was stirred at room temperature for 24hrs. After termination of the reaction, the solution was acidified with 2N HC1 aqueous soln.(65ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate and concentrated. The obtained crystal was washed with diisopropylether to afford Compound 47(6.0g). To a solution of Compound 47(5.0g) in dimethyl formamide(50ml) were added 2-adamantanamine hydrochloride(5.35g), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(5.04g), l-hydroxybenzotriazole(3.55g) and triethylamine(7.6ml), then the resulting solution was stirred at room temperature for 24hrs. After termination of the reaction, the solution was diluted with 2N HCl aqueous soln. and extracted with ethyl acetate. The organic layer was washed with sat. sodium hydrogencarbonate soln. and brine, and dried with sodium sulfate and concentrated. The residue was purified by silicagel columnchromatography to give Compound 48(4.0g). To a solution of Compound 48(4.0g) in ethyl acetate(80ml) was added IBX(6.2g), then the resulting mixture was refluxed for 6hrs. After termination of the reaction, the insoluble matter was removed by filtration and the solvent was concentrated to give Compound 49(4.0g). The obtained product was used for the next reaction without further purification. To a solution of Compound 49(4.0g) in tetrahydrofuran(50ml) was added (carbethoxyethylidene)triphenylphosphorane(5.27g), then the resulting solution was stirred at room temperature for 4hrs. After termination of the reaction, the solution was diluted with H2O and extracted with ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate and concentrated. The residue was purified by silicagel columnchromatography to give Compound 50(3.9g). To a solution of diisopropylamine(2.72ml) in tetrahydrofuran(40ml) was added dropwise n-BuLi(12.2ml, 1.59M in hexane) at -78 °C. After stirring at the same temperature for 45min, 50(3.9g) in tetrahydrofuran(40ml) was added to the solution and the whole solution was stirred for Ih. Iodomethane(0.6ml) was added to the solution, then the solution was stirred for l.5hrs. After termination of the reaction, the solution was diluted with 2N HCl aqueous soln. and extracted with ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate and concentrated. The residue was purified by silicagel columnchromatography to afford Compound 51(2.4g). To a solution of Compound 51(280mg) in tetrahydrofuran(2.5ml)-methanol(2.5ml) was added 2N NaOH aqueous soln. (2.5ml), then the resulting solution was stirred at room temperature for Ih. After termination of the reaction, the solution was acidified with 2N HCl aqueous soln. and extracted with ethyl acetate. The organic layer was washed with brine and dried with sodium sulfate. The solvent was removed to give Compound C-137(259mg). To a solution of Compound C-137(141mg) in dimethyl formamide(3ml) were added tert-butyl- 2-aminoethylcarbamate(68mg), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(76mg) and l-hydroxybenzotriazole(53mg), then the resulting solution was stirred at room temperature for 24hrs. After termination of the reaction, the solution was diluted with 2N HCl aqueous soln. and extracted with ethyl acetate. The organic layer was washed with sat. sodium hydrogencarbonate soln. and brine successively, and dried with sodium sulfate. The solvent was removed and the residue was purified by silicagel columnchromatography to give Compound 52(146mg). To a solution of Compound 52(146mg) in dioxane(1.5ml) was added 4N HCl/dioxane(1.5ml), then the resulting solution was stirred at room temperature for 3hrs. After termination of the reaction, the solution was diluted with diisopropylether to give crystal. The crystal was collected by filtration and washed with diisopropylether and dried to afford Compound C-134(94mg). Compounds C-129, D-13 to 35 were synthesized from the same method. Example 45 [0076] [Formula 63] To a solution of Compound C-137(118mg) in ethanol(3ml) was added 10%Pd-C(12mg), then the resulting mixture was stirred for 5hrs under H2 atomosphere. After termination of the reaction, Pd-C was removed by filtration. The filtrate was concentrated to give Compound C-138(116mg). According to the conventional procedure, Compound C-135 was synthesized. Additiionally, Compounds C-139, Dl to 12 were synthesized as well as the above Example. To a solution of Compound C-185(300mg) in methylene chloride(20ml) was added DAST(168µl) at -78 °C, then the resulting solution was at the same temperature for 1h. After termination of the reaction, the solution was poured into sat. sodium hydrogencarbonate soln. ane extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate and concentrated. The redidue was purified by silicagel columnchromatography to give Compound C-220(270mg). Compound C-219 was synthesized from Compound C-144 by the same procedure. 11-dehydrocorticosterone. After incubation for 2 hours at 37 OC, 5 µl of cortistel europium cryptate-labelled anti- corticQstoron'e antibody and 5 µl of XL665-labeled corticosterone were added. After further incubation for 2 hours at room temperature, the HTRF signal was measured. The corticosterone production was quantitated by a standard curve generated with several known concentrations of corticosterone in each assay. The amount of oortiool or corticosterone production without compounds was served as control, and the percent inhibition by compound at each concentration was calculated., The IC50 value of the compound for 116-HSDl was obtained using the inhibition curve generated by plotting the percent inhibition versus the concentration of test compound. [0103] The results of experimental example 1 and 2 are shown in the following table. [Table 65] (1) Animals Male C57BL/6J Jcl mice were purchased from CLEA Japan at the age of 6 weeks. After 1-week preliminary rearing, the mice were used for this study at the age of 7 weeks (2) Rearing conditions The mice were placed at an animal room, where was set at room temperature of 23 ± 2°C and humidity of 55 ± 10%, and lighting cycle time was 12 hours [light (8:00 - 20:00)/dark (20:00 - 8:00)]. The mice were allowed free access to solid laboratory food (CE-2, CLEA Japan) and sterile tap water through the preliminary rearing and experimental periods. (3) Identification of animals and cages The mice were identified by tail marking with an oil marker pen. Labels identifying the study director, purchased date, strain, sex and supplier were placed on each cage. The mice were housed by 20 mice/cage in the preliminary rearing period, and 3 mice/cage in the experimental period. (4) Group composition Oral administration: 20 mg/kg (n=3) Intravenous administration: 5 mg/kg (n=3) (5) Preparation of dosing formulation Dosing suspension for oral administration was prepared using 0.5% methyl cellulose (1500 cP) aqueous solution. Dosing solution for intravenous administration was prepared using N-dimethylacetamide / polyethyleneglycol 400 (1/2). (6) Dosing method As to oral administration, the dosing suspension at 10 mL/kg was administered into the stomach using a feeding tube. As to intravenous administration, the dosing solution at 2.5 mL/kg was administered into the caudal vein using a glass syringe. (7) Evaluation items The blood samples were collected from the heart at each sampling point. The drug concentration in plasma was measured using HPLC or LC/MS/MS. (8) Statistical analysis The area under the plasma concentration-time curve (AUG) was calculated by WinNonlin, and the bioavailability was calculated by the AUG values after oral and intravenous administration. [0105] The following formulation examples 1 to 8 are provided to further illustrate the present invention and are not intended to limit the scope of the present invention. The term of "active ingredient" means a compound of the present invention, a pharmaceutical acceptable salt, or a hydrate thereof. [0106] (Formulation Example 1) Hard gelatin capsules are prepared with the following ingredients: Dose (mg/capsule) Active ingredient 250 Starch (dried) 200 Magnesium stearate _10 Total 460 mg [0107] (Formulation Example 2) Tablets are prepared with the following ingredients: Dose (mg/tablet) Active ingredient 250 Cellulose (microcrystal) 400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg The ingredients are blended and compressed to form tablets each weighing 665 mg. [0108] (Formulation Example 3) Tablets, each containing 60 mg of active ingredient, are made as follows. Active ingredient 60 mg Starch 45 mg Microcrystals cellulose 35 mg Polyvinylpyrrolidone (as 10% solution in 4 mg water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve, and the mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the obtained powder, and then the admixture is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50 °C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through No. 60 mesh U.S. sieve, are added to the granules, mixed, and then compressed on a tablet machine to yield tablets each weighing 150 mg. [0109] (Formulation Example 4) Capsules, each containing 80 mg of active ingredient, are made as follows; Active ingredient 80 mg Starch 59 mg Microcrystals cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities. [0110] (Formulation Example 5) Suppositories, each containing 225 mg of active ingredient, are made as follows: Active ingredient 225 mg Saturated fatty acid glycerides 2000 mg Total 2225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2g capacity and allowed to cool. [0111] (Formulation Example 6) Suspensions, each containing 50 mg of active ingredient, are made as follows: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mL Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified water to total 5 mL The active ingredient is passed through a No. 45 U.S. sieve, and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution and flavor are diluted with a portion of the water, added and stirred. Then sufficient water is added to produce the required volume. [0112] (Formulation Example 7) An intravenous formulation may be prepared as follows: Active ingredient 100 mg Saturated fatty acid glycerides 1000 mL The solution of the above ingredients is generally administered intravenously to a patient at a rate of 1 mL per minute. a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted arl}, optionally substituted heteroaryl or optionally substituted heterocycle, one of R2 and R'4 is a group of formula: -Y-R5, wherein Y is -O-or -S -, and R5 is substituted straight alkyl wherein the substituent of said substituted straight alkyl is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, optionally substituted branched alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, the other of R2 and R4 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl. optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, R3 is a group of formula: -C(=0)-Z-R6, wherein Z is -NR7- or -NR7-W-, and R6 is optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or optionally substituted heterocycle, R'7 is hydrogen or optionally substituted alkyl, or R6 and R'7 taken together may form optionally substituted ring, W is optionally substituted alkylene, X is =N- or =CR8-, and R8 is hydrogen or optionally substituted alkyl, with the proviso that compounds wherein R2 is 2-(morphorino)ethoxy, R3 is N-(l-adamantyl)carbamoyl and R1 is benzyl are excluded. [2 ] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein R1is substituted alkyl wherein the substituent of said substituted alkyl is optionally substituted amino or optionally substituted heterocycle. [3 ] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is substituted ethyl wherein the substituent of said substituted ethyl is optionally substituted amino or optionally substituted heterocycle. [4] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is unsubstituted alkyl. [ 5 ] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein R2 is a group of formula: -Y-R5, wherein Y and R5 have the same meaning as defined in claim 1. [6 ] The compound according to claim 5, a pharmaceutically acceptable salt or a solvate thereof, wherein Y is -0-. [ 7 ] The compound according to claim 5 or 6, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is substituted straight alkyl wherein the substituent of said substituted straight alkyl is optionally substituted cycloalkyl. [ 8 ] The compound according to claim 7, a pharmaceutically acceptable salt or a solvate thereof, wherein R^5 is substituted otraight methyl wherein the substituent of said substituted straight methyl is optionally substituted cycloalkyl. [ 9 ] The compound according to claim 7 or 8, a pharmaceutically acceptable salt or a solvate thereof, wherein said optionally substituted cycloalkyl is optionally substituted cyclohexyl. [10] The compound according to claim 5 or 6, a pharmaceutically acceptable salt or a solvate thereof, wherein R5 is branched alkyl. [11] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein Z is -NR7-, and R'7 has the same meaning as defined in claim 1. [12] The compound according to claim 11, a pharmaceutically acceptable salt or a solvate thereof, wherein R7 is hydrogen. [13] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is optionally substituted cycloalk. [14] The compound according to claim 13, a pharmaceutically acceptable salt or a solvate thereof, wherein R6 is adamantyl. [15] The compound according to claim 13, a pharmaceutically acceptable salt or a solvate thereof, wherein R3 is a group of formula ( II ): [Formula 2] [16] The compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt or a solvate thereof, wherein X is =N-. [17] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is a group of formula: -CH=CH-C(R9R10)-R11-R12, wherein R9 and R10 are each independently hydrogen, optionally substituted alkyl or halogen, or R9 and R10 taken together with the carbon atom to which they are attached may form an optionally substituted ring, R11 is -(CH2)n-, wherein n is an integer of 0 to 3, and R12 is hydrogen, hydroxy, carboxy, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkyloxycarbonyl, optionally substituted arylalkylcarbonyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted sulfamoyl, optionally substituted amino, optionally substituted carbamoyloxy, optionally substituted alkyloxy or optionally substituted alkylthio, a group of formula: -C(=O)-NR13R14 wherein R13 and R14 are each independently hydrogen, optionally substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl or optionally substituted heterocyclesulfonyl, or R13and R14 taken together with the nitrogen atom to which they are attached may form an optionally substituted ring or, a group of formula: -NR15R16 wherein R15 and R16 are each independently hydrogen, carboxy, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbamoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted alkyloxycarbonyl or optionally substituted sulfamoyl, or R15 and R16 taken together with the nitrogen atom to which they are attached may form optionally substituted ring. [18] The compound according to claim 1, a pharmaceutically acceptable salt or a solvate thereof, wherein R1 is a group of formula: -CH2-CH2-C(R9R10)-R11R12 wherein R9, R10, R11 and R12 have the same meaning as defined in claim 17. [19] The compound according to claim 17 or 18, a pharmaceutically acceptable salt or a solvate thereof, wherein R9 and R10 are each independently optionally substituted alkyl or R9 and R10 taken together with the carbon atom to which they are attached may form optionally substituted ring. [20] The compound according to any one of claims 17 to 19, a pharmaceutically acceptable salt or a solvate thereof, wherein R11 is -(CH2)n-, wherein n is an integer of 0 to 1. [21] The compound according to any one of claims 17 to 20, a pharmaceutically acceptable salt or a solvate thereof, wherein R12 is carboxy, cyano or heterocycle. [22] The compound according to any one of claims 17 to 20, a pharmaceutically acceptable salt or a solvate thereof, wherein R12is a group of formula: -C(=0)-NR13R14, wherein R13 and R14are each independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted heterocyclesulfonyl or optionally substituted heterocycle, or R13 and R14 taken together with the nitrogen atom to which they are attached may form an optionally substituted ring. [23] The compound according to any one of claims 17 to 20, a pharmaceutically acceptable salt or a solvate thereof, wherein R12 is a group of formula: -NR15R16, wherein R15and R16 have the same meaning as defined in claim 17. [2 4] The compound according to claim 23, a pharmaceutically acceptable salt or a solvate thereof, wherein R15 is a group of formula: -C(=O)R', wherein R' is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted amino or optionally substituted alkyloxy. [ 2 5 ] A pharmaceutical composition which comprises the compound according to any one of claims 1 to 24, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient. [26] The pharmaceutical composition according to claim 25 for treating and/or preventing diabetes.

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