Title of Invention	CALCIUM RECEPTOR MODULATING COMPOUND AND USE THEREOF
Abstract	There is provided a calcium receptor modulator comprising a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7- membered ring; ring B is an optionally substituted 5- to 7- membered heterocyclic ring; X1 is CR1, CR1R2, N or NR13; X2 is N or NR3; Y is C, CR4 or N, Z is CR5, CR5R6, N or NR7; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and is a single bond or a double bond; R1, R2, R3, R4, R5, R6, R7 and R13 are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): wherein ring A is an optionally substituted 5- to 7- membered ring; Q is C, CR5 or N; R8, R9, R10, R11 and R12 are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also specify X1, R3, R1, Y and X3 in formula (II) and (III) as before.

Title of Invention

CALCIUM RECEPTOR MODULATING COMPOUND AND USE THEREOF

Abstract

There is provided a calcium receptor modulator comprising a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7- membered ring; ring B is an optionally substituted 5- to 7- membered heterocyclic ring; X1 is CR1, CR1R2, N or NR13; X2 is N or NR3; Y is C, CR4 or N, Z is CR5, CR5R6, N or NR7; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and is a single bond or a double bond; R1, R2, R3, R4, R5, R6, R7 and R13 are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): wherein ring A is an optionally substituted 5- to 7- membered ring; Q is C, CR5 or N; R8, R9, R10, R11 and R12 are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also specify X1, R3, R1, Y and X3 in formula (II) and (III) as before.

Full Text	DESCRIPTION CALCIUM RECEPTOR MODULATING COMPOUND AND USE THEREOF BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to heterocyclic compounds having calcium-sensing receptor (CaSR, hereinafter simply referred to as Ca receptor) modulating (agonistic or antagonistic) activity, pharmaceutical compositions containing them and intermediate compounds useful for synthesizing them. Background Art Calcium ion (hereinafter simply referred to as Ca) plays an essential role to maintain and modulate functions of various cells such as endocrine and exocrine cells, etc., in addition to nerve and muscle. For this reason, the blood Ca level is strictly maintained in a narrow range. Parathyroid hormone (PTH) plays a central role in maintaining this blood Ca level. Therefore, secretion of PTH from parathyroid gland responds sharply to change in the blood Ca level and is must be modulated according to this. In fact, when the blood Ca level is changed, the blood PTH level is rapidly changed in response to this. The possibility of a mechanism by which the extracellular Ca concentration is sensed by parathyroid gland cells and the information transmitted into cells has been pointed out early by Brown et al. In 1993, they succeeded in the cloning and characterization of a Ca-sensing receptor (CaSR; hereinafter, simply referred to as Ca receptor) from bovine parathyroid (Nature, 366, 575-580(1993)). The Ca receptor is composed of a large terminal extracellular region spanning 600 amino acids at the N- terminal, having seven transmembrane spanning domains like other G protein coupled receptors, and an intracellular region consisting of 200 or less amino acids at the caboxyl C-terminal. It is considered that, when the extracellular Ca concentration is increased, phospholipase (PL)-C is activated, leading to increase in the intracellular Ca concentration and inhibition of PTH secretion due to increase in inositol triphosphate (IP3) . Since when a high value of the extracellular Ca concentration is maintained, the intracellular Ca concentration is thereafter increased continuously, it is considered that influx of Ca from the outside of a cell is also promoted. PL-A2 and D are activated due to increase in extracellular Ca, but there is a possibility that these are via protein kinase (PK)-C and the like which are activated at the same time via Ca receptor. The Ca receptor also inhibits adenylyl cyclase via Gi protein or via arachidonic acid production due to activation of PL-A2 and decreases intracellular cyclic AMP (Bone, 20, 303-309 (1997)). Ca receptor mRNA is expressed in many tissues, and the expression amount is high, in parathyroid gland, thyroid gland C cell, medulla and cortex thick ascending limb (MTAL and CTAL) of kidney uriniferous tubule, intramedullary collecting tubule (IMCD) and encephalic subfornical organ (SFO) and hippocampus (Bone, 20, 303-309 (1997)). In addition, expression is recognized in many tissues such as encephalic hypothalamus, cerebellum and olfactory nucleus, regions other than TAL of renal uriniferous tubule, lung, stomach, pancreas, intestine and skin. Since the Ca receptor is present in various tissues, its physiological function has yet to be fully understood. However, it is expected that the Ca receptor modulating (agonistic or antagonistic) drug would provide for a novel treatment of various disease states which include the following: 1. Drugs for Treating Bone Diseases Since the anabolic activity is manifested by intermittent administration of PTH, Ca receptor modulating drugs which are considered to be able to regulate secretion of PTH are promising as a drug for treating osteoporosis. In addition, Ca receptor modulating drugs which are selectable for thyroid gland C cell may be also effective for treating osteoporosis by stimulation of calcitonin secretion. Whether the same Ca receptor as that of parathyroid gland is present in osteoblast, osteoclast and bone cell or not is disputable. However, some Ca-sensing mechanism is assuredly present therein and, therefore, drugs which directly act on them can be expected as a drug for treating bone diseases. 2. Kidney-Acting Drugs Handling of water and mineral in kidney is not only based on the results of function as a target organ for hormones, such as PTH, vitamin D etc., but also the Ca receptor in kidney is presumed to function in a response to the Ca concentration and the magnesium ion concentration in the extracellular fluid (Kidney Int, 50, 2129-2139 (1996)). Further, it is also considered that Ca receptor modulating drugs may modulate the blood amount in kidney, the amount of glomerulus filtration, renin secretion and activation of vitamin D in addition to control of influx and efflux of water and mineral. 3. Central Nervous System and Endocrine-Acting Drugs Ca receptor is present in almost all areas in the central nervous system, and is remarkably expressed, in particular, in the hippocampus, cerebellum and subfornical organ (Brain Res, 744. 47-56 (1997)). Although the details of the function are still unclear, the term of Ca receptor expression after birth in the hippocampus is consistent with the term of acquisition of LTP (Long Tightening Phenomenon) (Develop Brain Res, 100, 13-21 (1997)) and, therefore, the relationship with memory and learning can be presumed. Therefore, Ca receptor modulating drugs which are high in brain-blood barrier permeability and selective for the central nerve system may be utilized for treating Alzheimer's disease. In addition, since dry mouth occurs in hypercalcemic patient, Ca receptor modulating drugs may control them. The presence of Ca receptor in mouse pituitary gland cells which secreteACTH has been reported (Mol Endocrinol, 10, 555-565 (1996)). It is also considered that Ca receptor modulating drugs can be applied to Sheehann's syndrome and hypopituitarism or hyperpituitarism. 4. Digestive System-Acting Drugs It is considered that a Ca receptor is present in the Auerbach nerve plexus of the digestive tract and controls intestinal tract motion. Constipation is known in hypercalcemic patients and stimulation of digestive tract motion is known in hypocalcemic patients in clinical tests. The existence of a Ca receptor in the gastrin secreting cell (G cell) of the stomach has been reported (J. Clin Invest, 99, 2328-2333 (1997)), and intestinal tract absorption, constipation, diarrhea, defecation and secretion of acid in the stomach may be controlled by drugs which act on a Ca receptor in the digestive tract. Further, it has been found that a Ca receptor is present in human colon cancer cell strains and it controls c-myc expression and proliferation (Biochem Biophys Res Commum, 232, 80-83 (1997)), this is better consistent with the fact that the Ca uptake and sideration of colon and rectum cancers exhibit the negative correlation and, therefore, Ca receptor regulating drugs can be expected also as a drug for preventing and treating such cancers. Various heterocyclic compounds have been disclosed in the prior art. For example, WO 01/53266 discloses a compound of the formula: where in R, R1 and R2 are independently H, hydroxyl, etc. This compound has a phosphoinositide 3-kinase inhibitory activity and is useful for treating coronary obstruction, etc. Indian J. Chem., Sect. B (1993), 32B(5), 586-9 discloses the synthesis of a compound of the formula: wherein R is hydrogen, chlorine, methyl or methoxy. However, no utility is disclosed. U.S. Patent 4,746,656 (JP 63-33380 A) discloses a compound of the formula: wherein R1 is aryl or heterocyclic group, R2 is aryl, etc., R3 and R4 are independently H, alkyl, etc. This compound is a Ca channel blocker. EP 217142 discloses a compound of the formula: wherein R is hydrogen, alkyl, etc., R1 is hydrogen, nitro, cyano, etc., R2 is phenyl, cycloalkyl, etc., R3 is hydrogen, acyl etc., and R8is carboxyl, carbamoyl, etc. This compound is also a Ca channel blocker. However, a heterocyclic compound having Ca receptor modulating activity is not found in the prior art. OBJECTS OF THE INVENTION One object of the present invention is to provide compounds having Ca receptor modulating activity including novel compounds. Another object of the present invention is to provide pharmaceutical compositions containing the compounds of the present invention. These objects as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following description. SUMMARY OF THE INVENTION The present inventors have intensively investigated compounds having Ca receptor modulating activity. As a result, it has been found that compounds represented by formula (I) as shown hereinafter have Ca receptor modulating activity useful for medicine and, among them, compounds represented by the formulas (II), (III) and (IIIa) as shown hereinafter are novel compounds. According to the present invention, there is provided: 1. A compound of the formula (II): wherein ring A is an optionally substituted 5- to 7- membered ring; Q is C, CR5 (wherein R5 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or - SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group)), or N; X1 is CR1 (wherein R1 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) ) , CR1R2 (wherein R1 is as defined above, and R2 is H, or an optionally substituted hydrocarbon group), N, or NR13 (wherein R13 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)); R3 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above); Y is C, CR4 (wherein R4 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)), or N; Ar is an optionally substituted cyclic group; R9 and R10 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) ; and R11 and R12 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as defined above); or R9 and R10, or R11 and R12 may be combined to form an oxo group, methylene group or a ring; or R10 and R11 may be combined to form a ring; and - - - is a single bond or a double bond; provided that (1) when ring A is a 6-membered ring and Q is C or CR5, X1 is C-Z1-Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and both R9 and R10 are not H, or R9 and R10 are not combined to form an oxo group, or R10 and R11 are not combined to form a 5-membered ring, (2) when ring A is a 6-membered ring and Q is N, X1 is C- Z1-Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and R9 and R10 are not combined to form an oxo group, (3) when ring A is a 5-membered ring and Q is C or CR5, X1 is C-Z1-Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and Z2 is an optionally substituted amino group, and (4) when ring A is a 5-membered ring and Q is N, at least one of R9 and R10 is CHR15R16 (wherein at least one of R15 and R16 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula:-Z1-Z2 (wherein -Z1- and Z2 are as defined above)) and the other is other than an optionally substituted phenyl group; or a salt thereof; 2. A compound of the formula (III): wherein R1 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or - SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group); R3 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above); Y is C, CR4 (wherein R4 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)) or N; R8 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) ; Ar is an optionally substituted cyclic group; R9 and R10 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) , or R9 and R10 may be combined to form an oxo group, methylene group or a ring; X3 is a bond, oxygen atom, an optionally oxidized sulfur atom, N, NR7' (wherein R7' is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula - Z1'-Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as defined above)), or an optionally substituted bivalent C1-2 hydrocarbon group; and is a single bond or a double bond; provided that at least one of R9 and R10 is CHR15R16 (wherein R15 and R16 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula:-Z1-Z2 (wherein -Z1- and Z2 are as defined above)) and the other is other than an optionally substituted phenyl group; or a salt thereof; 3. The compound according to the above 1 or 2, wherein R1 is (1) an optionally substituted heterocyclic group, or (2) a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group); 4. The compound according to the above 3, wherein Z1 is -CO- and Z2 is an optionally substituted hydroxyl group or an optionally substituted amino group; 5. The compound according to the above 2, wherein R3 is H, a C1-6 alkyl group or a C7-14 aralkyl group; 6. The compound according to the above 2, wherein R8 is H, a C1-6 alkyl group, a C1-6 alkylthio group or a C1-6 alkoxy group which may be substituted with hydroxyl group; 7. The compound according to the above 1 or 2, wherein R9 and R10 are the same or different and are a C1-6 alkyl group or R9 and R10 are combined each other to form a ring; 8. The compound according to the above 2, wherein R1 is a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, - CS-, -SO- or -SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group) ; R3 is H; Ar is an optionally substituted aromatic ring group; X3 is CR11R12 (wherein R11 and R12 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) , or R11 and R12 may be combined to form an oxo group, methylene group or a ring) ; and R9 and R10 are the same or different and a C1-6 alkyl group, or R9 and R10 may be combined to form a ring; 9. The compound according to the above 8, wherein R1 is an optionally substituted carbamoyl group; 10. The compound according to the above 9, wherein R1 is a group of the formula: -CONR20 (CR21R22R23) (wherein R20 is H or an optionally substituted hydrocarbon group, and R21, R22, and R23 are the same or different and are an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R20 and R21 may be combined to form a ring); 11. A compound of the formula (IIIa): wherein R1a is (1) an optionally substituted heterocyclic group, or (2) a group of the formula: -Z1a-Z2a (wherein -Z1a- is -CO-, -CS-, -SO- or -SO2-, and Z2a is (i) an optionally substituted heterocyclic group, (ii) -NR20a (CR21aR22aR23a) (wherein (a) R20a is H or an optionally substituted hydrocarbon group; and R21a is an optionally substituted heterocyclic group which may be fused with an optionally substituted benzene ring, or an optionally substituted phenyl group which may be fused with an optionally substituted aromatic heterocyclic ring and R22a and R23a are the same or different and are an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group or R22a and R23a may be combined to form a ring, or (b) R20a is H or an optionally substituted hydrocarbon group; and R21a, R22a and R23a are the same or different and are an optionally substituted C1-8 aliphatic hydrocarbon group, provided that the sum total of the number of carbon atoms is 7 or more) , (iii) -NR20aR25a (wherein R20a is as defined above and R25a is an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10 aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7- 14 aralkylamino-C2-4 alkyl, heterocyclic ring-C2-4 alkyl or heterocyclic group), (iv) a substituted 5- to 7-membered cyclic amino group, or (v) -OR24a (wherein R24a is (a) an optionally substituted C7-14 aralkyl group, (b) an optionally substituted C3-7 alicyclic hydrocarbon group, (c) an optionally substituted C7-24 aliphatic hydrocarbon group, or (d) an optionally substituted heterocyclic group); R3 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group); Y is C, CR4 (wherein R4 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1--Z2 (wherein -Z1- and Z2 are as defined above)) or N; R8 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above); Ar is an optionally substituted cyclic group; R9 and R10 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) , or R9 and R10 may be combined to form an oxo group, methylene group or a ring; X3 is a bond, oxygen atom, an optionally oxidized sulfur atom, N, NR7' (wherein R7' is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula - Z1--Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as defined above)), or an optionally substituted bivalent C1-2 hydrocarbon group; and is a single bond or a double bond; provided that at least one of R9 and R10 is CHR15R16 (wherein R15 and R16 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula:-Z1-Z2 (wherein -Z1- and Z2 are as defined above)) and the other is other than an optionally substituted phenyl group; or a salt thereof; 12. The compound according to the above 11, wherein R1a is a group of the formula: -CONR20a (CR21bR22bR23b) (wherein R20a is as defined above and at least one of R21b, R22b, and R23b is an optionally substituted heterocyclic group which may be fused with an optionally substituted benzene ring, or an optionally substituted phenyl group which may be fused with an optionally substituted aromatic heterocyclic ring); 13. The compound according to the above 11, wherein R1a is (1) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or (2) a group of the formula: -CO-Z2c (wherein Z2c is (i) an optionally substituted 5- to 7- membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (ii) -NR20c (CR21cR22cR23c) (wherein (a) R20c is H or an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic- C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-Ci-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group; and R21c is 1) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be fused with an optionally substituted benzene ring, or 2) an optionally substituted C6-10 aryl group which may be fused with an optionally substituted 5- to 7-membered aromatic heterocyclic ring having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; and R22c and R23c are the same or different and are an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-Ci-g saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group or an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or R22c and R23c may be combined to form a C3-7 carbon ring, or (b) R20c is H or an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3_7 saturated or unsaturated alicyclic- C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group; and R21c, R22c and R23c are the same or different and are an optionally substituted C1-8 aliphatic hydrocarbon group, provided that the sum total of the number of carbon atoms is 7 or more), (iii) -NR20cR25c (wherein R20c is as defined above and R25c is an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10 aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7-14 aralkylamino-C2-4 alkyl, 5- to 7-membered heterocyclic ring (having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom) -C2-4 alkyl or 5- to 7-membered heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), (iv) a substituted 5- to 7-membered cyclic amino group, or (v) -OR24c (wherein R24c is (a) an optionally substituted C7- 14 aralkyl group, (b) an optionally substituted C3-7 alicyclic hydrocarbon group, (c) an optionally substituted C7-24 aliphatic hydrocarbon group, or (d) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; wherein said substituents for R1a, Z2c, R20c, R21c, R22c, R23c, R24c and R25c are 1 to 3 substituents selected from the group consisting of 1) C1-6 alkyl, 2) C2-6 alkenyl, 3) C2-6 alkynyl, 4) C3-7 cycloalkyl, 5) C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl, amino, N-(C1-6 alkyl) amino, N, N-di-(C1-6 alkyl) amino, amidino, carbamoyl, N-(C1-6 alkyl) carbamoyl, N,N-di-(C1-6 alkyl) carbamoyl, sulfamoyl, N- (C1-6 alkyl) sulfamoyl, N,N- di-(C1-6 alkyl) sulfamoyl, carboxyl, C2-7 alkoxycarbonyl, hydroxyl, C1-6 alkoxy, mercapto, C1-6 alkylthio, sulfo, cyano, azido, halogen, nitro, nitroso, phosphono, C1-6 alkoxyphosphoryl, di- (C1-6 alkoxy) phosphoryl and C1-6 alkyl substituted with phosphono, C1-6 alkoxyphosphoryl and di- (C1-6 alkoxy)phosphoryl (hereinafter the group of 5) is referred to as group "C"), 6) aromatic heterocyclic group selected from (a) aromatic 5- or 6-membered heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (b) fused bicyclic heterocyclic group formed by condensation of an aromatic 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom with benzene ring or an aromatic 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom and (c) fused tricyclic heterocyclic group formed by condensation of [1] an aromatic 5- or 6- membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, [2] benzene ring, and [3] an aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom or benzene ring, 7) heterocyclic-oxy group formed by combining each of the above aromatic heterocyclic groups (a) , (b) and (c) with oxy group, 8) non-aromatic 4- or 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, 9) C7-14 aralkyl which may be substituted with 1 to 3 substituents selected from the group "C", 10) amino group, 11) N-mono-substituted amino selected from N-(C1-6 alkyl) amino, N- (C2-6 alkenyl) amino, N-(C3-7 cycloalkyl) amino group and N- (C6-10 aryl) amino which may be substituted with 1 to 3 substituents selected from the group "C", 12) amino substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkenyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 13) amidino, 14) acyl selected from C2-8 alkanoyl, C3-8 alkenoyl, C3-7 cycloalkyl-carbonyl, C3-7 cycloalkenyl-carbonyl, C6-10 aryl-carbonyl which may be substituted with 1 to 3 substituents selected from the group "C", and heterocyclic-carbonyl formed by binding of an aromatic or non-aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom with carbonyl, 15) carbamoyl, 16) mono-substituted carbamoyl group selected from N-(C1-6 alkyl) carbamoyl, N- (C2-6 alkenyl) carbamoyl, N- (C3-7 cycloalkyl) carbamoyl and N- (C6-10 aryl) carbamoyl which may be substituted with 1 to 3 substituents selected from the group "C", 17) carbamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 18) sulfamoyl, 19) N-mono-substituted sulfamoyl selected from N-(C1-6 alkyl) sulfamoyl, N- (C2-6 alkenyl) sulfamoyl, N- (C3-7 cycloalkyl) sulfamoyl and N-(C6-10 aryl) sulfamoyl which may be substituted with 1 to 3 substituents selected from the group "C", 20) sulfamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 21) carboxyl, 22) C1-6 alkoxy-carbonyl, 23) hydroxy1, 24) C1-6 alkoxy, 25) C2-10 alkenyloxy, 26) C3-7 cycloalkyloxy, 27) C6-10 aryloxy which may be substituted with 1 to 3 substituents selected from the group "C", 28) C7-14 aralkyloxy which may be substituted with 1 to 3 substituents selected from the group "C", 29) mercapto, 30) C1-6 alkylthio, 31) C7-14 aralkylthio which may be substituted with 1 to 3 substituents selected from the group "C", 32) C6-10 arylthio which may be substituted with 1 to 3 substituents selected from the group "C", 33) C1-6 alkylsulfinyl, 34) C7-14 aralkylsulfinyl which may be substituted with 1 to 3 substituents selected from the group "C", 35) C6-10 arylsulfinyl which may be substituted with 1 to 3 substituents selected from the group "C", 36) C1-6 alkylsulfonyl, 38) C7-14 aralkylsulfonyl which may be substituted with 1 to 3 substituents selected from the group "C", 39) C6-10 arylsulfonyl which may be substituted with 1 to 3 substituents selected from the group "C", 40) sulfo, 41) cyano, 42) azido, 43) halogen, 44) nitro, 45) nitroso, 46) phosphono, 47) C1-6 alkoxy-phosphoryl 48) di-C1-6 alkoxy-phosphoryl, 49) C1-6 alkyl substituted with phosphono, C1-6 alkoxyphosphoryl or di-(C1-6 alkoxy) phosphoryl 50) C1-6 alkyl substituted with 1 to 4 halogen atoms 51) C1-6 alkoxy substituted with 1 to 4 halogen atoms and 52) C1-6 alkylenedioxy (hereinafter the group of above 1) to 52) is referred to as group "B"); R3 is H, a C1-6 alkyl group or a C7-14 aralkyl group; Y is CH; R8 is H, a C1-6 alkyl group, a C1-6 alkylthio group or a C1-6 alkoxy group which may be substituted with hydroxyl group; Ar is (1) a C6-10 aryl group, (2) a 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or (3) a C3-7 saturated or unsaturated alicyclic hydrocarbon group, each of which may be substituted with 1 to 3 substituents selected from the group "B"; one of R9 and R10 is a hydrogen atom or C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group "B" and the other is (1) a hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic- C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group, each of which may be substituted with 1 to 3 substituents selected from the group "B" or (2) a 5- to 7- membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be substituted with 1 to 3 substituents selected from the group "B", or R9 and R10 may be combined to form a C5-7 carbon ring; and X3 is CH2; 14. The compound according to the above 8, wherein R1 is a group of the formula: -CONR20 (CR21R22R23) (wherein R20 is H, and R21, R22, and R23 are the same or different and are an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group); R3 is H; Ar is an optionally substituted aromatic ring group; X3 is CH2; Y is CH; R8 is H or an optionally substituted hydrocarbon group, an optionally substituted alkoxy group, an optionally substituted sulfanyl group, an optionally substituted sulfinyl group, or an optionally substituted sulfonyl group, C1-6 alkoxy-carbonyl; and R9 and R10 are the same or different and are an optionally substituted hydrocarbon group; 15. The compound according to the above 14, wherein at least one of R21, R22, and R23 is an optionally substituted heterocyclic group or an optionally substituted phenyl group; 16. The compound according to the above 14, wherein R20 and R21 are combined to form an optionally substituted 5- to 7-membered ring, and R22 and R23 are the same or different and are an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted phenyl group; 17. The compound according to the above 14, wherein R21 and R22 are the same or different and are a C1-8 hydrocarbon group, and R23 is an optionally substituted 5- membered heterocyclic group which may be fused with an optionally substituted benzene ring, or an optionally substituted phenyl group; 18. The compound according to the above 16, wherein R20 and R21 are combined to form a 5- or 6-membered ring which may be fused with benzene ring and/or substituted with 1 to 3 substituents selected from the group consisting of (1) halogen, (2) hydrogen, (3) a phenoxy which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl- sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N- di-C1-6 alkyl-carbamoyl, (4) C1-6 alkoxy which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, halogeno C1-6 alkyl, amino, mono-C1-6 alkyl-amino, di- C1-6 alkyl-amino, C1-6 alkyl-sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N-di-C1-6 alkyl-carbamoyl, and (5) a C1-8 hydrocarbon group which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl, N,N-di-C1-6 alkyl- carbamoyl and phenyl which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, halogeno C1-6 alkyl, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl- sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N- di-C1-6 alkyl-carbamoyl, and R22 and R23 are the same or different and C1-8 hydrocarbon group which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, halogeno C1-6 alkyl, amino, mono-C1-6 alkyl-amino, di- C1-6 alkyl-amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N-di-C1-6 alkyl-carbamoyl; 19. N-(1-ethyl-1-(4-methylphenyl)propyl)-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide or a salt thereof, N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)- 7,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxamide or a salt thereof, N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-5- phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxamide or a salt thereof, N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5- phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxamide or a salt thereof, N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide or a salt thereof, N-(1-ethyl-1-(4-ethylphenyl)propyl)-5-(2-fluorophenyl)- 2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide or a salt thereof, 5-(2-chlorophenyl)-N-(1-ethyl-1-(4-methylphenyl)propyl)- 2,7, 7-trimethyl-4,5,6,7-tetrahydropyrazolo [1,5- a]pyrimidine-3-carboxamide or a salt thereof, N-(1-(4-(dimethylamino)phenyl)-1-ethylpropyl)-5-(2- fluorophenyl)-2,7,7-trimethyl-4, 5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(1,1-diethylbutyl)-5-(2-fluorophenyl)-2,7,7-trimethyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(1-ethyl-1-phenylpropyl)-5-(2-fluorophenyl)-2,7,7- trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxamide or a salt thereof, 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3, 4-oxadiazol-2- yl)-2,7,7-trimethyl-5-phenyl-4 ,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof, 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3,4-thiadiazol-2- yl) -2, 7, 7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof, 3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidinyl)carbonyl)-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine or a salt thereof, 3-((2,2-diethyl-4-methoxy-1-pyrrolidinyl)carbonyl)-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine or a salt thereof, or 3-((2,2-diethyl-4-fluoro-1-pyrrolidinyl)carbonyl)-7,7- dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine or a salt thereof; 20. The compound according to the above 19, which is an optically active compound; 21. A prodrug of the compound according to the above 1, 2 or 13; 22. A pharmaceutical composition which comprises the compound according to the above 1, 2 or 13 or a prodrug thereof; 23. A composition for modulating calcium receptor which comprises a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7- membered ring; ring B is an optionally substituted 5- to 7-membered heterocyclic ring; X1 is CR1 (wherein R1 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or - SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group) ) , CR1R2 (wherein R1 is as defined above, R2 is H or an optionally substituted hydrocarbon group), N or NR13 (wherein R13 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)); X2 is N or NR3 (wherein R3 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above); Y is C, CR4 (wherein R4 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)) or N; Z is CR5 (wherein R5 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) ) , CR5R6 (wherein R5 and R6 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)) , N or NR7 (wherein R7 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)); Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, an optionally substituted sulfonyl group or an optionally substituted sulfinyl group, or R and Z may be combined to form a ring B; and is a single bond or a double bond; or a salt thereof or a prodrug thereof; 24. The composition according to the above 23, which is a calcium receptor antagonist; 25. The composition according to the above 23, which is an agent for preventing or treating diseases caused by abnormality of calcium concentration in a living body or a calcium receptor; 26. The composition according to the above 23, which is an agent for preventing or treating bone diseases; 27. The composition according to the above 23, which is an agent for preventing or treating osteoporosis or fracture; 28. A method for modulating a calcium receptor which comprises administering to a mammal an effective amount of a compound of the formula (I) or a salt thereof or a prodrug thereof according to the above 23; 29. A method for preventing or treating bone diseases, which comprises administering to a mammal an effective amount of a compound of the formula (I) or a salt thereof or a prodrug thereof according to the above 23; 30. Use of the compound of the formula (I) or a salt thereof or a prodrug thereof according to the above 23 for producing a calcium receptor modulator; and 31. Use of the compound of the formula (I) or a salt thereof or a prodrug thereof according to the above 23 for producing a composition for preventing or treating bone diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The above formula (I) includes a monocyclic heterocyclic compound containing ring A and a condensed heterocyclic compound containing rings A and B. In the above formulas, ring A of the formulas (I) and (II) is an optionally substituted 5- to 7-membered ring. Examples of the "5- to 7-membered ring" of "an optionally substituted 5- to 7-membered ring" includes an aromatic or non-aromatic 5- to 7-membered hydrocarbon ring or 5- to 7-membered heterocyclic ring which may contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms as the ring constituting atoms in addition to carbon atoms. Specific examples thereof include a hydrocarbon ring such as benzene, tropilidene, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene, 2,4- cycloheptadiene, etc.; a heterocyclic ring such as pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene, dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine, hexamethylenimine, heptamethylenimine, tetrahydrofuran, piperazine, homopiperazine, tetrahydrooxazepine, morpholine, thiomorpholine, pyrrole, pyrazole, 1,2,3-triazole, oxazole, oxazolidine, thiazole, thiazolidine, isoxazole, imidazoline, triazole, thiadiazole, oxadiazole, oxathiadiazole, triazine, etc.; and the like. Examples of the substituent(s) of "an optionally substituted 5- to 7-membered ring group" include halogen, nitro, cyano, oxo, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted sulfinyl group, an optionally substituted sulfonyl group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, an optionally substituted phosphoryl group, or the like. Examples of halogen include fluorine, chlorine, bromine, iodine, and the like, preferably, fluorine and chlorine. Examples of the hydrocarbon group in an optionally substituted hydrocarbon group as the substituent of the 5- to 7-membered ring group include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted alicyclic-aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic-aliphatic hydrocarbon group (an aralkyl group), and the like. Examples of said aliphatic hydrocarbon group include a saturated aliphatic hydrocarbon group having 1-8 carbon atoms (e.g., alkyl group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; and an unsaturated aliphatic hydrocarbon group having 2-8 carbon atoms (e.g., alkenyl group, alkynyl group, alkadienyl group, alkadiynyl group, etc.) such as vinyl, allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4- hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl, 1-heptynyl, 1-octynyl, etc. Examples of said alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkyl group, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienyl group, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3- cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3- cycloheptenyl, 2,4-cycloheptadienyl, etc.; a partly saturated and fused bicyclic hydrocarbon group [preferably, C6-10 partly saturated and fused bicyclic hydrocarbon group, etc. (including those where the benzene ring is combined to 5- or 6-membered non-aromatic cyclic hydrocarbon group)] such as 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2- naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4- dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl, etc.; and the like. Said alicyclic hydrocarbon group may be cross-linked. Examples of said alicyclic-aliphatic hydrocarbon group include those where the above-mentioned alicyclic hydrocarbon group and the above-mentioned aliphatic hydrocarbon group are combined, for example, those having 4-14 carbon atoms such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3- cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2-(3,4-dihydro-2- naphtyl)ethyl, 2-(1,2,3,4-tetrahydro-2-naphtyl)ethyl, 2- (3,4-dihydro-2-naphtyl)ethenyl, etc. (e.g., C3-7 cycloalkyl- C1-4 alkyl group, C3-7 cycloalkenyl-C1-4 alkyl group, C3-7 cycloalkyl-C2-4 alkenyl group, C3-7 cycloalkenyl-C2-4 alkenyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl groups, etc.). Examples of said aromatic hydrocarbon group include an aryl group having 6-10 carbon atoms (including that where a 5- to 6-membered non-aromatic hydrocarbon ring is fused with phenyl group) such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8- tetrahydro-1-naphthyl, 5, 6,7,8-tetrahydro-2-naphthyl, 5,6- dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3- naphthyl, 5,6-dihydro-4-naphthyl, etc.; and the like. Examples of said aromatic-aliphatic hydrocarbon group include an aralkyl group having 7-14 carbon atoms (C6-10 aryl-C1-4 alkyl group) such as phenyl-C1-4 alkyl group, e.g., benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2- phenylpropyl, 3-phenylpropyl, etc.; naphthyl-C1-4 alkyl group such as α-naphthylmethyl, α-naphthylethyl, β- naphthylmethyl, β-naphthylethyl, etc.; C6-10 aryl-C2-4 alkenyl group such as phenyl-C2-4 alkenyl group, e.g., styryl, cinnamyl, etc.; and the like. Examples of the heterocyclic group in an optionally substituted heterocyclic group as the substituent of the 5- to 7-membered ring include (i) a 5- to 7-membered heterocyclic group containing one sulfur atom, one nitrogen atom, or one oxygen atom, (ii) a 5- to 6-membered heterocyclic group containing 2-4 nitrogen atoms, (iii) a 5- to 6-membered heterocyclic group containing 1-2 nitrogen atoms and one sulfur or oxygen atom, or the like; and (iv) these heterocyclic groups may be fused with a 5- to 6- membered ring containing 2 or less nitrogen atoms, benzene ring, or a 5-membered ring containing one sulfur atom. In addition, each of the heterocyclic groups exemplified in (i) to (iv) may be a saturated or unsaturated heterocyclic group and the unsaturated heterocyclic group may be either aromatic or non-aromatic. Examples of the heterocyclic group in an optionally substituted heterocyclic group as the substituent of the 5- to 7-membered ring include an aromatic monocyclic heterocyclic group, an aromatic fused heterocyclic group, and a non-aromatic heterocyclic group. Specific examples of the heterocyclic group in an optionally substituted heterocyclic group as the substituent of the 5- to 7-membered ring include (i) an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.); (ii) an aromatic fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H- indazolyl, benzimidazolyl, benzoxazolyl, 1,2- benzisothiazolyl, lH-benztriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, a- carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo[l,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[l,2- b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl, l,2,4-triazolo[4,3- b]pyridazinyl, etc.); and (iii) a non-aromatic, heterocyclic group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.). Examples of sulfinyl group in an optionally substituted sulfinyl group as the substituent of the 5- to 7-membered ring include that where -SO- is combined with "the hydrocarbon group" or "the heterocyclic group" in "an optionally substituted hydrocarbon group" or "an optionally substituted heterocyclic group" of the substituent of the 5- to 7-membered ring. Preferred examples include a C1-8 alkylsulf inyl group where sulfinyl group is combined with a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert- pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C6-10 arylsulfinyl group where sulfinyl group is combined with a C6-10 aryl group such as phenyl, a-naphthyl, p-naphthyl, 4- indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8- tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6- dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3- naphthyl, 5,6-dihydro-4-naphthyl, etc.; a group where sulfinyl group is combined with an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.); and a group where sulfinyl group is combined with an aromatic fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H-benztriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ- carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[l,5- a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.). More preferred examples include a C1-8 alkylsulf inyl group where sulfinyl group is combined with a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc. Examples of sulfonyl group in an optionally substituted sulfonyl group as the substituent of the 5- to 7-membered ring include a group where -SO2- is combined with "the hydrocarbon group" or "the heterocyclic group" in "an optionally substituted hydrocarbon group" or "an optionally substituted heterocyclic group" of the substituent of the 5- to 7-membered ring. Preferred examples include a C1-8 alkylsulfonyl group where sulfonyl group is combined with a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert- pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C6-10 arylsulfonyl group where sulfonyl group is combined with a C6-10 aryl group such as phenyl, a-naphthyl, (3-naphthyl, 4- indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8- tetrahydro-1-naphthyl, 5, 6,7,8-tetrahydro-2-naphthyl, 5,6- dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3- naphthyl, 5,6-dihydro-4-naphthyl, etc.; a group where sulfonyl group is combined with an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, or the like); and a group where the sulfonyl group is combined with an aromatic, fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H- benztriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5- a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.). More preferred examples include a C1-8 alkylsulf onyl group where sulfonyl group is combined with a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc. Examples of an optionally substituted hydroxyl group as the substituent of the 5- to 7-membered ring include hydroxyl group and that having an appropriate substituent, for example, "an optionally substituted hydrocarbon group" or "an optionally substituted heterocyclic group" of the above substituent of the 5- to 7-membered ring. Preferred examples include a C1-8 alkyloxy group whose substituent is a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C6-10 aryloxy group whose substituent is a C6-10 aryl group such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8- tetrahydro-1-naphthyl, 5, 6, 7 , 8-tetrahydro-2-naphthyl, 5,6- dihydro-1-naphthyl, 5, 6-dihydro-2-naphthyl, 5, 6-dihydro-3- naphthyl, 5,6-dihydro-4-naphthyl, etc.; a hydroxyl group substituted with an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3- oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.); a hydroxyl group substituted with an aromatic fused heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H- benztriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5- a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.). More preferred examples include a C6-10 aryloxy group (in particular, phenyloxy) or a hydroxyl group substituted with an aromatic monocyclic heterocyclic group (in particular, pyridyl) or an aromatic fused heterocyclic group (in particular, quinolyl). "The hydrocarbon group" or "the heterocyclic group" as the substituent of the substituted hydroxyl group exemplified above may have the same substituent as that of "the hydrocarbon group" or "the heterocyclic group" in "an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group" of the substituent of the 5- to 7-membered ring. Examples of an optionally substituted thiol group as the substituent of the 5- to 7-membered ring include thiol group and that substituted with an appropriate group such as "an optionally substituted hydrocarbon group" or "an optionally substituted heterocyclic group" of the substituent of the 5- to 7-membered ring. Preferred examples include a C1-8 alkylthio group, whose substituent is a C1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C5-10 arylthio group, whose substituent is a C6-10 aryl group such as phenyl, a-naphthyl, P-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2- naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.; a thiol group substituted with an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3,4- oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.); and a thiol group substituted with an aromatic fused heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[l,5- a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.). "The hydrocarbon group" or "the heterocyclic group" as the substituent of the substituted thiol group exemplified above may have the same substituent as that of "the hydrocarbon group" or "the heterocyclic group" in "an optionally substituted hydrocarbon group" or "an optionally substituted heterocyclic group" of the substituent of the 5- to 7-membered ring. More preferred examples include a C1-8 alkylthio group substituted with a C1-8 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, or the like. Examples of an optionally substituted amino group as the substituent of the 5- to 7-membered ring include amino group, an N-mono-substituted amino group, and an N,N-di- substituted amino group. Examples of said substituted amino groups include that having one or two substituents of an optionally substituted hydrocarbon group (e.g., the same group as an optionally substituted hydrocarbon group of the substituent of the 5- to 7-membered ring, more specifically, a C1-8 alkyl group, a C3-7 cycloalkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C3-7 cycloalkenyl group, a C6- 10 aryl group that may have a C1-4 alkyl group, etc.), an optionally substituted heterocyclic group (e.g., the same group as an optionally substituted heterocyclic group of the substituent of the 5- to 7-membered ring) , or the formula: -COR' (wherein R' represents hydrogen atom or an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. As for "the hydrocarbon group" or "the heterocyclic group" in "an optionally substituted hydrocarbon group" or "an optionally substituted heterocyclic group" of R' may have the same substituent as that of "the hydrocarbon group" or "the heterocyclic group" in "an optionally substituted hydrocarbon group" or "an optionally substituted heterocyclic group" of the substituent of the 5- to 7- membered ring), preferably a C1-10 acyl group (e.g., a C2-7 alkanoyl, benzoyl, nicotinoyl, etc.). Specific examples thereof include methylamino, dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, and the like. In addition, the two groups in said substituted amino groups may be combined to form a nitrogen-containing 5- to 7-membered ring (e.g., piperidino, piperadino, morpholino, thiomorpholino, etc.). Examples of the optionally substituted acyl group as the substituent of the 5- to 7-membered ring include (i) formyl or (ii) a group where the carbonyl group is combined with a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-7 cycloalkyl group, a C5-7 cycloalkenyl group, or an aromatic group (e.g., phenyl group, pyridyl group, etc.) (e.g., acetyl, propionyl, butyryl, isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2- cyclohexenecarbonyl, benzoyl, etc.) and the like. Examples of the optionally esterified carboxyl group as the substituent of the 5- to 7-membered ring include, in addition to carboxyl group, an alkyloxycarbonyl group, an alkenyloxycarbonyl, an alkynyloxycarbonyl, an aralkyloxycarbonyl group, an acyoxycarbonyl group, an aryloxycarbonyl group, and the like. Examples of the alkyl group in said alkyloxycarbonyl group include a C1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.). Examples of the alkenyl group in said alkenyloxycarbonyl group include a C2-6 alkenyl group (e.g., vinyl, allyl, isopropenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-methylallyl, etc.). Examples of the alkynyl group in said alkynyloxycarbonyl group include a C2-6 alkynyl group (e.g., ethynyl, 2-propynyl, etc.). The aralkyl group in said aralkyloxycarbonyl group means an aryl-alkyl group (e.g., C6-10 aryl-C1-6 alkyl, etc.). The aryl group in said aryl-alkyl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group, and preferred examples include phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, and the like. They may have a substituent such as a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C4-8 cycloalkadienyl group, an aryl group (e.g., C6-14 aryl, etc.), an aromatic heterocyclic group (e.g., the same aromatic heterocyclic group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group of the above substituent of the 5- to 7-membered ring, etc.), a non-aromatic heterocyclic group (e.g., the same non-aromatic heterocyclic group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group of the above substituent of the 5- to 7-membered ring, etc.), an aralkyl group (e.g., a C6-14 aryl-C1-6 alkyl group, etc.), amino group, an N-mono-substituted amino group (e.g., the same N-mono-substituted amino group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group of the above substituent of the 5- to 7-membered ring, preferably a N-mono-C1-4 alkylamino group, etc.), a N,N- disubstituted amino group (e.g., the same N,N-disubstituted amino group as that of the substituent in the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group of the above substituent of the 5- to 7-membered ring, preferably a N,N-di-C1-4 alkylamino group, etc.), amidino group, an acyl group (e.g., the same acyl group as that of the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group of the above substituent of the 5- to 7-membered ring, etc.), carbamoyl group, a N-mono-substituted carbamoyl group (e.g., a N- mono-C1-4 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.; phenylcarbamoyl; etc.), a N,N- disubstituted carbamoyl group (a N,N-di-C1-4 alkyl-carbamoyl group such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, etc.; piperidinocarbamoyl; morpholinocarbamoyl; etc.), sulfamoyl group, a N-mono-substituted sulfamoyl group (e.g., a N-mono-C1-4 alkylsulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, etc.; phenylsulfamoyl; p-toluenesulfamoyl; etc.), a N,N-disubstituted sulfamoyl group (e.g., a N,N- disubstituted C1-4 alkylsulf amoyl group such as N,N- dimethylsulfamoyl, etc.; a N-C1-4 alkyl-N-phenylsulfamoyl group such as N-methyl-N-phenylsulfamoyl, etc.; piperidinosulfamoyl; morpholinosulfamoyl; etc.), carboxyl group, a C1-10 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxyl group, a C1-10 alkoxy group, a C2-10 alkenyloxy group, a C3-7 cycloalkyloxy group, an aralkyloxy group (e.g., C6-14 aryl- C1-6 alkyloxy, etc.), an aryloxy group (e.g., C6-14 aryloxy, etc.), mercapto group, a C1-10 alkylthio group, an aralkylthio group (e.g., C6-14 aryl-C1-6 alkylthio, etc.), an arylthio group (e.g., C6-14 arythio, etc.), sulfo group, cyano group, azido group, nitro group, nitroso group, a halogen atom, or the like. As for an alkyl group in said aryl-alkyl group, a C1-6 alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.) is preferred. Preferred examples of said aralkyl group, i.e., an aryl-alkyl group include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl)methyl, (2- naphthyl)methyl, and the like. Among them, benzyl, phenethyl, and the like are preferred. As the acyl group in said acyloxycarbonyl group, for example, there are formyl, a C2-4 alkanoyl group, a C3-4 alkenoyl group, a C3-4 alkynoyl group, and the like. As the aryl group in said aryloxycarbonyl group, for example, there are phenyl, naphthyl, and the like. Examples of the amidated carboxyl group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, the sulfinyl group and the heterocyclic group of the substituent of the 5- to 7-membered ring include the carboxyl group amidated with an optionally substituted amino group as the substituent of the hydrocarbon group, the acyl group, the sulfonyl group, and the heterocyclic group of the above substituent of the 5- to 7-membered ring, each of which may be substituted. Example of an optionally substituted phosphoryl group of the substituent of the 5- to 7-membered ring include phosphoryl group, a (C1-6 alkoxy) phosphoryl group such as ethoxyphosphoryl, a di-(C1-6 alkoxy)phosphoryl group such as diethoxyphosphoryl, etc.; a lower (C1-6) alkyl group substituted with an optionally esterified phosphono group such as a phosphono-C1-6 alkyl group, a C1-6 alkoxyphosphoryl-C1-6 alkyl group, a di- (C1-6 alkoxy) phosphoryl-C1-6 alkyl group such as diethoxyphosphorylmethyl, etc.; and the like. "The hydrocarbon group", "the heterocyclic group", "the sulfinyl group", or "the sulfonyl group" in "an optionally substituted hydrocarbon group", "an optionally substituted heterocyclic group", "an optionally substituted sulfinyl group", or "an optionally substituted sulfonyl group" of the substituent of the 5- to 7-membered ring may be further substituted with 1 to 3 substituents. Examples of said substituents include a lower (C1-6) alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.); a lower (C2-6) alkenyl group (e.g., vinyl, allyl, 1- propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3- butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexenyl, etc.); a lower (C2-6) alkynyl group (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl, etc.); a C3-7 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); a C6-10 aryl group (e.g., phenyl, α-naphthyl, β-naphthyl, etc.); an aromatic heterocyclic group [e.g., (i) an aromatic 5- or 6-membered heterocyclic group having 1-4 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom; (ii) a fused bicyclic heterocyclic group formed by condensation of an aromatic 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom with benzene ring or an aromatic 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom; (iii) a fused tricyclic heterocyclic group formed by condensation of [1] an aromatic, 5- or 6-membered heterocyclic group having 1-3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, [2] benzene ring, and [3] an aromatic 5- or 6- membered heterocyclic group having 1-3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom or benzene ring, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H-benztriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5- a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl, 1, 2, 4-triazolo[4,3-b]pyridazinyl, etc.]; a heterocyclic-oxy group formed by combining each of the above heterocyclic groups (i), (ii) and (iii) with oxy group; a non-aromatic heterocyclic group (e.g., a non-aromatic, 4- or 7-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.); a C7-14 aralkyl group (e.g., a C6-10 aryl-C1-4 alkyl group such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2- phenylpropyl, 3-phenylpropyl, α-naphthylmethyl, α- naphthylethyl, β-naphthylmethyl, β-naphthylethyl, etc.); amino group; a N-mono-substituted amino group [e.g., a N- (C1-6 alkyl)amino group such as methylamino, ethylamino, allylamino, cyclohexylamino, phenylamino, a N- (C2-6 alkenyl) amino group, a N-(C3-7 cycloalkyl) amino group, a N- (C6-10 aryl) amino group, etc.]; a N, N-disubstituted amino group [e.g., an amino group substituted with two substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-7 cycloalkenyl group, and a C6-10 aryl group, such as dimethylamino, diethylamino, dibutylamino, diallylamino, N-methyl-N-phenylamino, etc.]; amidino group; an acyl group (e.g., formyl, a C2-8 alkanoyl group such as acetyl, propionyl, butyryl, isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, crotonyl, 2- cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.; a C3-8 alkenoyl group; a C3-7 cycloalkyl-carbonyl group; a C3-7 cycloalkenyl-carbonyl group; a C6-10 aryl-carbonyl group; a heterocyclic-carbonyl group formed by binding of an aromatic or non-aromatic 5- or 6-membered heterocyclic group having 1-3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom with carbonyl group, etc.); carbamoyl group; a mono-substituted carbamoyl group [e.g., a N-(C1-6 alkyl)carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, etc.]; a N-(C2-6 alkenyl) carbamoyl group; a N-(C3-7 cycloalkyl) carbamoyl group; a N-(C6-10 aryl) carbamoyl group; etc.]; a N,N-disubstituted carbamoyl group [e.g., a carbamoyl group substituted with two substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-7 cycloalkyl group, and a C6-10 aryl group, such as dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, diallylcarbamoyl, N-methyl-N-phenylcarbamoyl, etc.]; sulfamoyl group, a N-mono-substituted sulfamoyl group [e.g., a N-(C1-6 alkyl)sulfamoyl group such as methylsulfamoyl, ethylsulfamoyl, cyclohexylsulfamoyl, phenylsulfamoyl, etc.; a N-(C2-6 alkenyl) sulfamoyl group; a N-(C3-7 cycloalkyl) sulfamoyl group; a N-(C6-10 aryl) sulfamoyl group; etc.], a N,N-disubstituted sulfamoyl group [e.g., sulfamoyl group substituted with two substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-7 cycloalkyl group, and a C6-10 aryl group, such as dimethylsulf amoyl, diethylsulfamoyl, dibutylsulfamoyl, diallylsulfamoyl, N- methyl-N-phenylsulfamoyl, etc.]; carboxyl group; a lower (C1-6) alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.); hydroxyl group; a lower (C1-6) alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.); a lower (C2-10) alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy, etc.); a C3-7 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.); a C6-10 aryloxy group (e.g., phenoxy, naphthyloxy, etc.); a C7-14 aralkyloxy group (e.g., a C6-10 aryl-C1-4 alkyloxy group such as phenyl-C1-4 alkyloxy, naphthyl-C1-4 alkyloxy, etc.); mercapto group; a lower (C1-6)alkylthio group (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec- butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, etc.), a C7-14 aralkylthio group (e.g., a C6-10 aryl-C1-4 alkylthio group such as phenyl-C1-4 alkylthio, naphthyl-C1-4 alkylthio, etc.); a C6-10 arylthio group (e.g., phenylthio, naphtylthio, etc.), a lower (C1-6) alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, hexylsulfinyl, etc.); a C7-14 aralkylsulfinyl group (e.g., a C6-10 aryl-C1-4 alkylsulf inyl group such as phenyl-C1-4 alkylsulf inyl, naphthyl-C1-4 alkylsulf inyl, etc.); a C6-10 arylsulfinyl group (e.g., phenylsulfinyl, naphtylsulfinyl, etc.); a lower (C1-6) alkylsulf onyl group (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec- butylsulf onyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl, etc.), a C7-14 aralkylsulf onyl group (e.g., a C6-10 aryl-C1-4 alkylsulfonyl group such as phenyl-C1-4 alkylsulfonyl, naphthyl-C1-4 alkylsulf onyl, etc.), a C6-10 arylsulfonyl group (e.g., phenylsulfonyl, naphtylsulfonyl, etc.); sulfo group; cyano group; azido group; a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.); nitro group; nitroso group; an optionally esterified phosphono group [e.g., phosphono group, a (C1-6 alkoxy)phosphoryl group such as ethoxyphosphoryl, a di-(C1-6 alkoxy)phosphoryl group such as diethoxyphosphoryl, etc.]; a lower (C1-6) alkyl group substituted with an optionally esterified phosphono group (e.g., a phosphono-C1-6 alkyl group, a C1-6 alkoxyphosphoryl- C1-6 alkyl group, a di-(C1-6 alkoxy) phosphoryl-C1-6 alkyl group such as diethoxyphosphorylmethyl, etc.); a C1-6 haloalkyl group (e.g., a C1-6 alkyl group substituted with 1 to 4 halogen such as trifluoromethyl, etc.); a C1-6 haloalkoxy group (e.g., a C1-6 alkoxy group substituted with 1 to 4 halogen such as trif luoromethoxy, etc.); and the like. Among the above substituents, when hydroxyl group is located adjacent to a lower (C1-6) alkoxy group, they may form C1-6 alkylenedioxy groups such as methylenedioxy, ethylenedioxy, or the like. The above C6-10 aryl group, the C6-10 aryl group as a substituent of the aromatic heterocyclic group and the N- mono-substituted amino group, the C6-10 aryl group as a substituent of the N, N-di-substituted amino group, the C6-10 aryl group as a substituent of the N-mono-substituted carbamoyl group, the C6-10 aryl group as a substituent of the N, N-di-substituted carbamoyl group, the C6-10 aryl as a substituent of the N-mono-substituted sulfamoyl group, the C6-10 aryl group as a substituent of the N, N-disubstituted sulfamoyl group, the C6-10 aryl group as a substituent of the C6-10 aryloxy group, the C6-10 aryl group of the C7-14 aralkyloxy group, the C6-10 aryl group of the C7-14 aralkylthio groups, the C6-10 aryl group of the C6-10 arylthio groups, the C6-10 aryl group of the C7-14 aralkylsulf inyl groups, the C6-10 aryl group of the C6-10 arylsulfinyl group, the C6-10 aryl group of the C7-3.4 aralkylsulfonyl groups, and the C6-10 aryl group in the C6-10 arylsulfonyl group may be substituted further with 1 to 3 substituents. Examples of said substituent include a lower (C1-6) alkyl group, amino group, a N-(C1-6 alkyl) amino group, a N,N-di-(C1-6 alkyl)amino group, amidino group, carbamoyl group, a N- (C1-6 alkyl) carbamoyl group, a N,N-di-(C1-6 alkyl)carbamoyl group, sulfamoyl group, a N-(C1-6 alkyl)sulfamoyl group, a N,N-di-(C1-6 alkyl)sulfamoyl group, carboxyl group, a lower (C2-7) alkoxycarbonyl group, hydroxyl group, a lower (C1-6) alkoxy group, mercapto group, a lower (C1-6) alkylthio group, sulfo group, cyano group, azido group, a halogen atom, nitro group, nitroso group, an optionally substituted phosphono group [e.g., phosphono group, a C1-6 alkoxyphosphoryl group, a di- (C1-6 alkoxy) phosphoryl group, etc.], a lower (C1-6) alkyl group substituted with an optionally esterified phosphono group [e.g., a phosphono-C1-6 alkyl group, a C1-6 alkoxyphosphoryl- C1-6 alkyl group, a di- (C1-6 alkoxy) phosphoryl-C1-6 alkyl group such as diethoxyphosphorylmethyl, etc.], and the like Among the above substituent, when hydroxyl group is located adjacent to a lower (C1-6) alkoxyl group, they may form a C1-6 alkylenedioxy group such as methylenedioxy, ethylenedioxy, or the like. The number of the substituents of the 5- to 7-membered ring is 1 to 3, preferably 1 to 2 and the substituents may be the same or different and present at any possible positions of the ring. Q of the formula (II) is C, CR5, or N. R5 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group). Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group and an optionally substituted heterocyclic group of R5 or Z2 include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. Examples of halogen and an optionally substituted thiol group of R5 include the same groups as those exemplified with respect to the above substituent of the 5- to 7-membered ring of ring A. X1 in the formulas (I) and (II) is CR1, CR1R2, N or NR13. R1 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) . Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, halogen and an optionally substituted heterocyclic group of R1 include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. R2 is H, or an optionally substituted hydrocarbon group, and examples of an optionally substituted hydrocarbon group of R2 include the same group as that exemplified with respect to the substituent of the 5- to 7- membered ring of ring A. R13 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) . Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group and an optionally substituted heterocyclic group of R13 include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. R1 of the formula (III) is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, - SO- or -SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group). In R1 of the formula (III), preferred example of the group of the formula: -Z1-Z2 is a group of the formula: - CONR20(CR21R22R23) , wherein R20 is H or an optionally substituted hydrocarbon group, and R21, R22, and R23 are the same or different and are an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or R20 and R21 may be combined to form a ring. Examples of an optionally substituted hydrocarbon group of R1, R20, R21, R22 and R23, an optionally substituted heterocyclic group of R1, R21, R22 and R23, and an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group and halogen of R1 include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A of the formulas (I) and (II) . Preferably, at least one of R21, R22 and R23 is an optionally substituted heterocyclic group which may be fused with an optionally substituted benzene ring, or an optionally substituted phenyl group which may be fused with an optionally substituted aromatic heterocyclic ring. Examples of the "fused heterocyclic group" of the "optionally substituted heterocyclic group which may be fused with an optionally substituted benzene ring" and the "fused phenyl group" of the " optionally substituted phenyl group which may be fused with an optionally substituted aromatic heterocyclic ring" of R21, R22 and R23 include the same groups as those exemplified with respect to the aromatic fused heterocyclic group as the substituents of the 5- to 7-membered ring of ring A. Examples of these substituents include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A of the formulas (I) and (II). The ring formed in combination with R20 and R21 is preferably an optionally substituted 5- to 7-membered ring, more preferably an optionally substituted 5- or 6-membered ring, and may be fused with an optionally substituted benzene ring. Such rings include the same rings as those exemplified with respect to the "5- to 7-membered ring" of "an optionally substituted 5- to 7-membered ring" in the ring A of the formulas (I) and (II). These rings may have 1 to 3 substituents selected from the group consisting of (1) halogen, (2) hydrogen, (3) a phenoxy which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl (e.g., formyl, C2-6 alkanoyl, etc.), cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl- sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N- di-C1-6 alkyl-carbamoyl, (4) C1-6 alkoxy which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, halogeno C1-6 alkyl (e.g., trifluoromethyl, etc.), amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl- sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N- di-C1-6 alkyl-carbamoyl, and (5) a C1-8 hydrocarbon group (e.g., C1-8 alkyl, C3-7 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkenyl, etc.) which may be substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl- amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl, C1-6 alkyl- sulfonyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl- carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl which may be substituted with 1 to 3 sunstitutents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, halogeno C1-6 alkyl (e.g., trifluoromethyl, etc.), amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl- sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N- di-C1-6 alkyl-carbamoyl. Specific examples of these substituents include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A of the formulas (I) and (II) . R1a of the formula (IIIa) is (1) an optionally substituted heterocyclic group or (2) a group of the formula: -Z1a-Z2a (wherein -Z1a- is -CO-, -CS-, -SO- or -SO2-, and Z2a is (i) an optionally substituted heterocyclic group, (ii) -NR20a(CR21aR22aR23a) (wherein (a) R20a is H or an optionally substituted hydrocarbon group; and R21a is an optionally substituted heterocyclic group which may be fused with an optionally substituted benzene ring, or an optionally substituted C6-10 aryl group which may be fused with an optionally substituted aromatic heterocyclic ring and R22a and R23a are the same or different and are an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group or R22a and R23a may be combined to form a ring, or (b) R20a is H or an optionally substituted hydrocarbon group; and R21a, R22a and R23a are the same or different and are an optionally substituted C1-8 aliphatic hydrocarbon group, provided that the sum total of the number of carbon atoms is 7 or more), (iii) -NR20aR25a (wherein R20a is as defined above and R25a is an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10 aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7-14 aralkylamino-C2-4 alkyl, heterocyclic ring-C2-4 alkyl or heterocyclic group), (iv) a substituted 5- to 7-membered cyclic amino group, or (v) -OR24a (wherein R24a is (a) an optionally substituted C7-14 aralkyl group, (b) an optionally substituted C3-7 alicyclic hydrocarbon group, (c) an optionally substituted C7-24 aliphatic hydrocarbon group, or (d) an optionally substituted heterocyclic group)). Examples of an optionally substituted hydrocarbon group of R20a, R22a and R23a and an optionally substituted heterocyclic group of Rla, Z2a, R21a, R22a and R23a include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A of the formulas (I) and (II) . Examples of the "fused heterocyclic group" of the "optionally substituted heterocyclic group which may be fused with an optionally substituted benzene ring" and the "fused phenyl group" of "an optionally substituted phenyl group which may be fused with an optionally substituted aromatic heterocyclic ring" of R21a, R22a and R23a include the same groups as those exemplified with respect to the aromatic fused heterocyclic group as the substituents of the 5- to 7-membered ring of ring A. Examples of the ring formed in combination with R20a and R21a and the substituents thereof include the same rings and substituents as those exemplified with respect to the ring formed in combination with R20 and R21 and the substituents thereof. Examples of the "optionally substituted C1-8 aliphatic hydrocarbon group" of R20a include the same groups as those exemplified with respect to the aliphatic hydrocarbon group as the substituents of the 5- to 7-membered ring of ring A. Examples of the "optionally substituted C7-14 aralkyl group", the "optionally substituted C3-7 alicyclic hydrocarbon group" and the "optionally substituted heterocyclic group" of R24a include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A respectively. Examples of the "C7-24 aliphatic hydrocarbon group" of the "optionally substituted C7-24 aliphatic hydrocarbon group" in R24a include, for example, C7-24 alkyl, C7-24 alkenyl, C7-24 alkynyl, C7-24 alkadienyl, C7-24 alkadiynyl such as heptyl, octyl, 1-heptenyl, 1-octenyl, 1-heptynyl, 1- octynyl, etc. Examples of the substituents of the "optionally substituted C7-24 aliphatic hydrocarbon group" in R24a include the same substituents as those exemplified with respect to the substituents of the hydrocarbon group as the substituents of 5- to 7-membered ring of ring A. In the formula (IIIa), Rla is preferably (1) an optionally substituted 5- to 7-membered aromatic or non- aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or (2) a group of the formula: -CO-Z2c (wherein Z2c is (i) an optionally substituted 5- to 7-membered aromatic or non- aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (ii) -NR20c(CR21cR22cR23c) (wherein (a) R20c is H or an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group; and R21c is 1) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be fused with an optionally substituted benzene ring, or 2) an optionally substituted C6-10 aryl group (e.g., phenyl group, etc.) which may be fused with an optionally substituted 5- to 7-membered aromatic heterocyclic ring having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; and R22c and R23c are the same or different and are an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group, or an optionally substituted 5- to 7-membered aromatic or non- aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom or R22c and R23c may be combined to form a C3-7 carbon ring, or (b) R20c is H or an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic- C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group; and R21c, R22c and R23c are the same or different and are an optionally substituted C1-8 aliphatic hydrocarbon group, provided that the sum total of the number of carbon atoms is 7 or more), (iii) -NR20cR25c (wherein R20c is as defined above and R25c is an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10 aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7-14 aralkylamino-C2-4 alkyl, 5- to 7-membered heterocyclic ring (having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom)-C2-4 alkyl or 5- to 7-membered heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), (iv) a substituted 5- to 7-membered cyclic amino group (e.g., piperidino, piperadino, morpholino, thiomorpholino, etc.), or (v) -OR24c (wherein R24c is (a) an optionally substituted C7- 14 aralkyl group, (b) an optionally substituted C3-7 alicyclic hydrocarbon group, (c) an optionally substituted C7-24 aliphatic hydrocarbon group, or (d) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; wherein said substituents for R1a, Z2c, R20c, R21c, R22c, R23c, R24c and R25c are 1 to 3 substituents selected from the group consisting of 1) C1-6 alkyl, 2) C2-6 alkenyl, 3) C2-6 alkynyl, 4) C3-7 cycloalkyl, 5) C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl, amino, N-(C1-6 alkyl) amino, N,N-di-(C1-6 alkyl) amino, amidino, carbamoyl, N-(C1-6 alkyl) carbamoyl, N,N-di-(C1-6 alkyl)carbamoyl, sulfamoyl, N-(C1-6 alkyl)sulfamoyl, N,N- di-(C1-6 alkyl) sulfamoyl, carboxyl, C2-7 alkoxycarbonyl, hydroxyl, C1-6 alkoxy, mercapto, C1-6 alkylthio, sulfo, cyano, azido, halogen, nitro, nitroso, phosphono, C1-6 alkoxyphosphoryl, di-(C1-6 alkoxy) phosphoryl and C1-6 alkyl substituted with phosphono, C1-6 alkoxyphosphoryl and di- (C1-6 alkoxy)phosphoryl (hereinafter the group of 5) is referred to as group "C") , 6) aromatic heterocyclic group selected from (a) aromatic 5- or 6-membered heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (b) fused bicyclic heterocyclic group formed by condensation of an aromatic 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom with benzene ring or an aromatic 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom and (c) fused tricyclic heterocyclic group formed by condensation of [1] an aromatic 5- or 6- membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, [2] benzene ring, and [3] an aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom or benzene ring, 7) heterocyclic-oxy group formed by combining each of the above aromatic heterocyclic groups (a) , (b) and (c) with oxy group, 8) non-aromatic 4- or 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, 9) C7-14 aralkyl which may be substituted with 1 to 3 substituents selected from the group "C", 10) amino group, 11) N-mono-substituted amino selected from N-(C1-6 alkyl) amino, N-(C2-6 alkenyl) amino, N- (C3-7 cycloalkyl) amino group and N- (C6-10 aryl) amino which may be substituted with 1 to 3 substituents selected from the group "C", 12) amino substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkenyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 13) amidino, 14) acyl selected from C2-8 alkanoyl, C3-8 alkenoyl, C3-7 cycloalkyl-carbonyl, C3-7 cycloalkenyl-carbonyl, C6-10 aryl-carbonyl which may be substituted with 1 to 3 substituents selected from the group "C", and heterocyclic-carbonyl formed by binding of an aromatic or non-aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom with carbonyl, 15) carbamoyl, 16) mono-substituted carbamoyl group selected from N-(C1-6 alkyl) carbamoyl, N- (C2-6 alkenyl) carbamoyl, N-(C3-7 cycloalkyl) carbamoyl and N-(C6-10 aryl) carbamoyl which may be substituted with 1 to 3 substituents selected from the group "C", 17) carbamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C5-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 18) sulfamoyl, 19) N-mono-substituted sulfamoyl selected from N-(C1-6 alkyl) sulfamoyl, N- (C2-6 alkenyl) sulfamoyl, N-(C3-7 cycloalkyl) sulfamoyl and N-(C6-10 aryl) sulfamoyl which may be substituted with 1 to 3 substituents selected from the group "C", 20) sulfamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 21) carboxyl, 22) C1-6 alkoxy-carbonyl, 23) hydroxyl, 24) C1-6 alkoxy, 25) C2-10 alkenyloxy, 26) C3-7 cycloalkyloxy, 27) C6-10 aryloxy which may be substituted with 1 to 3 substituents selected from the group "C", 28) C7-14 aralkyloxy which may be substituted with 1 to 3 substituents selected from the group "C", 29) mercapto, 30) C1-6 alkylthio, 31) C7-14 aralkylthio which may be substituted with 1 to 3 substituents selected from the group "C", 32) C6-10 arylthio which may be substituted with 1 to 3 substituents selected from the group "C", 33) C1-6 alkylsulfinyl, 34) C7-14 aralkylsulfinyl which may be substituted with 1 to 3 substituents selected from the group "C", 35) C6-10 arylsulfinyl which may be substituted with 1 to 3 substituents selected from the group "C", 36) C1-6 alkylsulfonyl, 38) C7-14 aralkylsulf onyl which may be substituted with 1 to 3 substituents selected from the group "C", 39) C6-10 arylsulfonyl which may be substituted with 1 to 3 substituents selected from the group "C", 40) sulfo, 41) cyano, 42) azido, 43) halogen, 44) nitro, 45) nitroso, 46) phosphono, 47) C1-6 alkoxy-phosphoryl 48) di-C1-6 alkoxy-phosphoryl, 49) C1-6 alkyl substituted with phosphono, C1-6 alkoxyphosphoryl or di-(C1-6 alkoxy) phosphoryl 50) C1-6 alkyl substituted with 1 to 4 halogen atoms 51) C1-6 alkoxy substituted with 1 to 4 halogen atoms and 52) C1-6 alkylenedioxy (hereinafter the group of above 1) to 52) is referred to as group "B"). Specific examples of these substituents include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. As R1a of the formula (IIIa), more preferred is the group represented by the formula: CONR20c(CR21cR22cR23c) (wherein R20c, R21c, R22c and R23c are as defined above). Further more preferably, R1a is (1) a 5- to 7-membered aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom (e.g., 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, etc.) which is substituted with C1-4 alkyl-C7-14 aralkyl (e.g., 1-ethyl- 1-(4-methylphenyl)propyl, etc.), or (2) a group represented by the formula: -CO-Z2c' (wherein Z2c' is (i) -NR20c' (CR21c'R22c'R23c') (wherein (a) R20c' is H or C1-6 alkyl; R21c' is a C6-10 aryl group or a 5- to 7-membered aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, each of which may be substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6 alkyl, C2-6 alkenyl, halogeno C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, carboxyl, C1-6 alkoxy-carbonyl, C1-6 alkyl- carbonyloxy, C1-6 alkyl-carbonyloxy-C1-6 alkyl, carboxy-C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkyl, C1-6 alkoxy-carbonyl- C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy-C1-6 alkyl, carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di- C1-6 alkylamino, phenyl (said phenyl may be substituted with 1 to 3 substituents selected from halogen, C1-6 alkyl and halogeno C1-6 alkyl) and a 5- to 7-membered aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; R22c' and R23c' are the same or different and are C1-6 alkyl group, C5-7 cycloalkyl group, phenyl group (said phenyl group may be substituted with 1 to 3 substituents selected from C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy) , C1-6 alkoxy- carbonyl-C1-6 alkyl group or C1-6 alkyl-carbonyl-C2-6 alkenyl group, or R22c' and R23c' may be combined each other to form a C3-7 carbon ring; or (b) R20c' and R21c' are combined each other to form a 5- to 7-membered ring and said ring may be substituted with C1-6 alkoxy or C7-14 aralkyl, and R22c' and R23c' are C1-6 alkyl group) , (ii) -NR20C'R25C' (wherein R20c' is H or C1-6 alkyl group; R25c' is C6-10 aryl-C2-4 alkyl group, C6-10 aryloxy-C2-4 alkyl group, C6-10 arylamino-C2-4 alkyl group, C7-14 aralkylamino-C2-4 alkyl group, 5- to 7-membered heterocyclic ring-C2-4 alkyl group or 5- to 7-membered heterocyclic group, each of which may be substituted with 1 or 2 substituents selected from the group consisting of halogen, C1-6 alkyl, C6-10 aryl, C1-6 alkoxy, amino, mono- or di- C1-6 alkylamino, 5- to 7- membered cyclic amino, hydroxy, oxo, C1-6 alkoxy-carbonyl and cyano), or (iii) a 5- to 7-membered cyclic amino group which is substituted with 1 to 3 substituents selected from the group consisting of halogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy-C1-6 alkyl, C5-7 cycloalkyl, C6-10 aryl (said aryl may have 1 or 2 substituents selected from halogen, C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy) , C7-14 aralkyl (said aralkyl may have 1 or 2 substituents selected from halogen, C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy) , hydroxy, hydroxy-C1-6 alkyl, C6-10 aryloxy (said aryloxy may have 1 or 2 substituents selected from halogen, C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy) , C7-14 aralkyloxy, C6-10 aryl- carbonyl, carboxyl, C1-6 alkoxy-carbonyl, carbamoyl, C6-10 aryl-carbamoyl, amino, C6-10 aryl-carbonylamino, C1-6 alkyl- carbonylamino, C1-6 alkoxy-carbonylamino, C6-10 arylthio, C6- 10 arylsulfonyl, cyano, oxo and 5- to 7-membered heterocyclic group.). R3 of the formulas (II), (III) and (IIIa) is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above). Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group and an optionally substituted heterocyclic group of R3 include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. R3 is preferably H, a C1-6 alkyl group or a C7-14 aralkyl group, and more preferably R3 is H. Y in the formulas (I), (II), (III) and (IIIa) is C, CR4, or N. R4 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) . Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group and halogen of R4 include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. Y is preferably CH. R8 of the formulas (III) and (IIIa) is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above). Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, halogen atom and an optionally substituted heterocyclic group of R include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. R8 is preferably H, a C1-6 alkyl group, a C1-6 alkylthio group or a C1-6 alkoxy group which may be substituted with hydroxyl group, and more preferably R8 is H or a C1-6 alkyl group. Ar in the formulas (I), (II), (III) and (IIIa) is an optionally substituted cyclic group. Examples of the optionally substituted cyclic group of Ar include an optionally substituted aromatic or non- aromatic hydrocarbon ring group or an optionally substituted aromatic or non-aromatic heterocyclic group, and the like. Examples of the aromatic hydrocarbon ring group and the heterocyclic group of Ar include the same aromatic hydrocarbon group and heterocyclic group as exemplified with respect to the above substituents of the 5- to 7- membered ring of ring A. Examples of the non-aromatic hydrocarbon ring group include a saturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkyl group, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienyl group, etc.) such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4- cycloheptadienyl, etc.; a partly saturated and fused bicyclic hydrocarbon group [preferably, C9-10 partly saturated and fused bicyclic hydrocarbon group, etc. (including those where the benzene ring is combined to 5- or 6-membered non-aromatic cyclic hydrocarbon group)] such as 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl, 1,2,3,4- tetrahydro-1-naphthyl, 1, 2, 3, 4-tetrahydro-2-naphthyl, 1,2- dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1- naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl, etc.; and the like. Examples of the substituent of an optionally substituted aromatic ring group and an optionally substituted heterocyclic group of Ar include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. Ar is preferably (1) a C6-10 aryl group, (2) a 5- to 7- membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or (3) a C3-7 saturated or unsaturated alicyclic hydrocarbon group, each of which may be substituted with 1 to 3 substituents selected from the group "B". More preferably, Ar is a C6-10 aryl group which may be substituted with 1 to 3 substituents selected from the group "B", a 5- to 7-membered aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom which may be substituted with 1 to 3 substituents selected from the group "B", or a C3-7 saturated or unsaturated alicyclic hydrocarbon group. Further more preferably, Ar is (1) a C6-10 aryl group (e.g., phenyl, naphthyl, etc.) which may be substituted with 1 or 2 substituents selected from the group consisting of halogen atom, C1-6 alkyl, C1-6 alkoxy, hydroxy, C7-14 aralkyloxy and mono- or di-C1-4 alkylamino, (2) a 5- to 7- membered aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom (e.g., pyridyl, furyl, thiazolyl, thienyl, etc.) which may be substituted with C1-4 alkyl or (3) a C5-7 cycloalkyl group (e.g., cyclohexyl etc.), and most preferably, Ar is an optionally halogenated phenyl group. R9 and R10 of the formulas (II), (III) and (IIIa) are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above), or R9 and R10 may be combined to form an oxo group, methylene group or a ring. Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom and an optionally substituted heterocyclic group of R9 and R10 include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. One of R9 and R10 is preferably a hydrogen atom or C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group "B" and the other is (1) a hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group, each of which may be substituted with 1 to 3 substituents selected from the group "B" or (2) a 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be substituted with 1 to 3 substituents selected from the group "B", or R9 and R10 may be combined to form a C5-7 carbon ring. More preferably, one of R9 and R10 is preferably a hydrogen atom or C1-6 alkyl group and the other is an optionally halogenated C1-6 alkyl group, C6-10 aryl group, C7- 10 aralkyl group or a 5- to 7-membered aromatic heterocyclic group, or R9 and R10 are a C5-7 carbon ring formed by combining together. Examples of R11 and R12 of the forumula (II) are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1'-Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as defined above). Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom and an optionally substituted heterocyclic group of R11 and R12 include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. R9 and R10, or R11 and R12 may be combined to form an oxo group, methylene group or a ring such as a C3-6 saturated or unsaturated carbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentenyl, 2- cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl, etc.); or R10 and R11 may be combined to form a ring such as a C3-6 saturated or unsaturated carbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, etc.). is a single bond or a double bond. Z in the formula (I) is CR5, CR5R6, N or NR7, and CR5 is as defined above. R6 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)). Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, and an optionally substituted heterocyclic group of R6 include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. R7 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above)). Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, a halogen atom and an optionally substituted heterocyclic group of R7 include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. R5, R6 and R7 may be the same or different. R5 is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, an optionally substituted sulfonyl group or an optionally substituted sulfinyl group. Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, an optionally substituted sulfonyl group and an optionally substituted sulfinyl group of R include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. R and Z may be combined to form a ring B Ring B in the formula (I) is an optionally substituted 5- to 7-membered heterocyclic ring and examples thereof include the same group as that exemplified with respect to the 5- to 7-membered ring of ring A. X2 of the formula (I) is N or NR3 and R3 are as defined above. X3 of the formula (III) and (IIIa) is a bond, oxygen atom, an optionally oxidized sulfur atom, N, NR7', or an optionally substituted bivalent C1-2 hydrocarbon group. R7' is H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted heterocyclic group, or a group of the formula -Z1'-Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as defined above)). Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, and an optionally substituted heterocyclic group of R7' include the same groups as those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. Examples of an optionally substituted bivalent Ci_2 hydrocarbon group include -CH2-, -(CH2)2-, -CH=CH- and the like which may be substituted with one or two substituents selected from those exemplified with respect to the substituents of the 5- to 7-membered ring of ring A. In the formula (IIIa), X3 is preferably CH2. Prefered compounds of the formula (I) include not only the compounds of the formula (IIIa) but also the other compounds wherein -Z1- is -CO- and Z2 is an optionally substituted hydroxyl group (e.g., hydroxy, C1-6 alkoxy, etc.) or amino group which is substituted with an optionally substituted phenyl group or an optionally substituted condensed phenyl group (e.g., phenylamino, 3,5- dimethoxyphenylamino, 3-biphenylylamino, 2,3-dihydro-1H- inden-5-yl-amino, quinolin-6-yl-amino, etc.). In the formula (II), (1) when ring A is a 6-membered ring and Q is C or CR5, X1 is C-Z1-Z2, C(-Z1-Z2)R2 or N-Z1Z2, and both R9 and R10 are not H, or R9 and R10 are not combined to form an oxo group, or R10 and R11 are not combined to form a 5-membered ring; (2) when ring A is a 6-membered ring and Q is N, X1 is C- Z1-Z2, C(-Z1-Z2)R2 or N-Z1Z2, and R9 and R10 are not combined to form an oxo group; (3) when ring A is a 5-membered ring and Q is C or CR5, X1 is C-Z1Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and Z2 is an optionally substituted amino group; and (4) when ring A is a 5-membered ring and Q is N, at least one of R9 and R10 is CHR15R16 (wherein R15 and R16 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula:- Z1-Z2 (wherein -Z1- and Z2 are as defined above) . Examples of an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom and an optionally substituted heterocyclic group include the same groups as those exemplified with respect to the above substituents of the 5- to 7-membered ring of ring A. In the formulas (II) and (III) , preferably, R1 is a group of the formula: -Z1-Z2; Z1 is -CO- and Z2 is an optionally substituted hydroxyl group or an optionally substituted amino group; Ar is an optionally substituted aromatic ring group; and both R9 and R10 are the same or different and are C1-6 alkyl groups or R9 and R10 are combined to form a ring such as a saturated or unsaturated C3-6 ring as described above. In the formula (III), preferably, R3 is H. More preferably, in the formula (III), R1 is a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -SO2-, and Z2 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxyl group, or an optionally substituted amino group) ; R3 is H; Ar is an optionally substituted aromatic ring group; X3 is CR11R12 (wherein R11 and R12 are the same or different and are H, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, cyano group, a halogen atom, an optionally substituted heterocyclic group, or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined above) , or R11 and R12 may be combined to form an oxo group, methylene group or a ring such as a saturated or unsaturated C3-6 ring as described above) ; and R9 and R10 are the same or different and are a C1-6 alkyl group, or R9 and R10 may be combined to form a ring such as a saturated or unsaturated C3-6 ring as described above. As for a salt of the compound of formula (I), (II), (III) or (IIIa) (hereinafter sometimes referred to as Compound (1), (II), (III) or (IIIa)), a pharmaceutically acceptable salt is preferred. Examples thereof include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like. Preferred examples of a salt with an inorganic base include an alkali metal salt such as sodium salt, potassium salt, or the like; an alkaline earth metal salt such as calcium salt, magnesium salt, or the like; and aluminum salt; ammonium salt; or the like. Preferred examples of a salt with an organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, or the like. Preferred examples of a salt with an inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or the like. Preferred examples of a salt with an organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like. Preferred examples of a salt with a basic amino acid include a salt with arginine, lysine, ornithine or the like. Preferred examples of a salt with an acidic amino acid include a salt with aspartic acid, glutamic acid, or the like. Compound (I), (II), (III) or (IIIa) may be in the form of a prodrug thereof. The prodrug of Compound (I), (II), (III) or (IIIa) refers to a compound that is converted into Compound (I), (II), (III) or (IIIa) by a reaction with an enzyme, gastric acid, or the like under a physiological condition in the living body, namely, (i) a compound that is converted into Compound (I), (II), (III) or (IIIa) by an enzymatic oxidation, reduction, hydrolysis, or the like, and (ii) a compound that is converted into Compound (I), (II), (III) or (IIIa) by hydrolysis with gastric acid or the like. Examples of a prodrug of Compound (I), (II), (III) or (IIIa) to be used include a compound or its salt wherein hydroxyl group in Compound (I), (II), (III) or (IIIa) is acylated, alkylated, phosphorylated, or converted into borate (e.g., a compound or its salt wherein hydroxyl group in Compound (I), (II), (III) or (IIIa) is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, dimethylaminomethylcarbonyloxy, etc.), a compound or its salt wherein carboxyl group in Compound (I), (II), (III) or (IIIa) is esterified or amidated (e.g., a compound or its salt wherein carboxyl group in Compound (I), (II), (III) or (IIIa) is subjected to ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-l,3-dioxolan-4- yl)methyl esterification, cyclohexyloxycarbonyl esterification, or conversion into the methyl amide, etc.), or the like. These prodrugs can be produced according to a per se known method or its modified method. Further, a prodrug of Compound (I), (II), (III) or (IIIa) may be a compound or its salt that is converted into Compound (I), (II), (III) or (IIIa) under physiological conditions as described in "Development of Drugs", Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages 163-198. Compound (I), (II), (III) or (IIIa) may be labeled with an isotope (for example, 2H, 3H, 14C, 35S, 125I, or the like) or the like. When the compound obtained by the present invention or a salt thereof has a double bond in its molecule and a steric configuration of Z or E exsits, each of the stereoisomers and a mixture thereof are included in the present invention. When a steric configuration exsits due to an asymmetric carbon in the molecule of the compound obtained by the present invention or a salt thereof, each of them and a mixture thereof are included in the present invention. Hereinafter, production of the compound of the present invention will be illustrated. A process for preparing Compound (II), Compound (III) and Compound (IIIa) of the present invention will be shown in the following schemes 1 to 13. A compound wherein Q is N, and Y is C or CR4 in Compound (II) can be prepared according to the schemes 1 to 3. A compound wherein Q is C, and Y is C or CR4 in Compound (II) can be prepared according to the scheme 4. A compound wherein Q is N, and Y is N in Compound (II) can be prepared according to the scheme 5. A compound wherein Y is C or CR4 in Compound (III) and Compound (IIIa) can be prepared by the scheme 6. A compound wherein Y is N in Compound (III) and Compound (IIIa) can be prepared by the scheme 7. A compound wherein Q is C, and Y is N in Compound (II) can be prepared by the scheme 13. wherein A-1 is the same as A, and the other symbols are as defined above. In step A, Compound (II-1) is prepared by cyclization reaction of Compound (IV-1) and Compound (X) with an acid or a base. Examples of the acid used in this reaction include: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p- toluenesulfonic acid; and Lewis acids such as zinc (II) chloride, tin (IV) chloride, aluminium chloride and the like. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8- diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. An amount of these acids or bases to be used is preferably about 0.1 to about 5 mole equivalent relative to Compound (IV-1). Examples of a solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dimethoxyethane, dioxane and diethyl ether; amides such as N,N-dimethylformamide; alcohol such as ethanol, propanol, tert-butanol and methoxyethanol; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about -50°C to about 200°C, preferably about -10°C to about 150°C. A reaction time is usually about 0.5 to about 60 hours. The thus obtained compound (II-l) can be isolated and purified by the known separating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Compound (IV-1) used herein can be prepared, for example, according to the method described in Bilestein, vol.25, p.2033. In addition, Compound (X) can be prepared, for example, according to Organometallics, vol.11, p.954. In step B, Compound (II-2) is prepared by a reduction reaction for Compound (II-l). In the present reaction, a catalytic hydrogenation method using palladium carbon, palladium hydroxide or the like, or reduction using a reducing agent is performed. As the reducing agent, sodium borohydride, aluminium lithium hydride and lithium borohydride are used. In the present reaction, if needed, any solvents can be used as long as they do not inhibit the reaction. Inter alia, alcohols (e.g. C1-3 alcohol such as methanol, ethanol, propanol and the like) or ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane etc.) are preferable. A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound (II-2) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein A-1 is the same as A, and the other symbols are as defined above. In step C, Compound (V) is prepared by a reaction for cyclizing Compound (IV-1) and Compound (XI). The present reaction is carried out in the presence of an acid in a solvent having no adverse effect on the reaction or without a solvent according to the conventional method. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; Lewis acids such as zinc (II) chloride, tin (IV) chloride, aluminium chloride and the like. An amount of these acids is preferably about 0.1 to about 5 mole equivalent relative to Compound (IV-1). Examples of the solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N- dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about -50°C to 150°C, preferably about -10°C to about 120°C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound ( V ) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step B, Compound (II-3) can be prepared according to step B in the scheme 1. wherein Y' is C or CR4, and L and L' is a leaving group, and L is more reactive than L' , and the other symbols are as defined above. In step D, Compound (VI-1) is prepared from Compound (IV-1). The present method is carried out in the presence of a base in a solvent having no adverse effect on the reaction according to the conventional method. Specific examples of leaving groups L and L' include halogen atom, sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, and acyloxy group such as acetyloxy group and benzoyloxy group. Example of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8- diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. An amount of these bases to be used is preferably about 1 to about 5 mole equivalent relative to Compound (IV) . Examples of the solvent having no adverse effect on the reaction include: aromatic hydrocarbon such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; amides such as N,N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about -50 to about 150°C, preferably about -10°C to about 120°C. A reaction time is usually about 0.5 about 20 hours. The thus obtained Compound (VI-1) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step E, Compound (II-4) is prepared by an intramolecular cyclization reaction of Compound (VI-1). The present method is carried out in the presence of an acid or a base in a solvent having no adverse effect on the reaction according to the conventional method. Specific example of a leaving group L' include halogen atom, p- toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group. Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; and Lewis acids such as zinc (II) chloride, tin (IV) chloride, aluminium chloride and the like. Examples of the base include: alkali metal salts such as potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8- diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and t- butoxide. An amount of these acids or bases to be used is preferably about 1 to about 5 mole equivalent relative to Compound (IV-1). Examples of the solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; haloganated hydrocarbons such as chloroform and dichloromethane; amides such as N,N- dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about -50°C to about 150°C, preferably about -10°C to about 120°C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound (II-4) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein A-2 is the same as A, and the other symbols are as defined above. In step F, Compound (VI-2) is prepared from Compound (IV-2) and Compound (XII). The present method is carried out in the presence of a base in a solvent having no adverse effect on the reaction according to the conventional method. Examples of the base include: alkali metal salts such as potassium carbonate, sodium carbonate and cesium carbonate; amines such as pyridine, triethylamine, N,N- dimethylaniline and 1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. An amount of these bases to be used is preferably about 1 to about 5 mole equivalent relative to Compound (IV-2). Examples of the solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran; dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N- dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about -50°C to about 200°C, preferably about -10°C to about 150°C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound (VI-2) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step G, Compound (II-5) is prepared by a reaction for reducing Compound (VI-2). In the present reaction, a catalytic hydrogenation method using palladium carbon, palladium hydroxide or Raney nickel, or reduction using a reducing agent is carried out. As the reducing agent, sodium borohydride, aluminium lithium hydride and lithium borohydride are used. In the present reaction, if needed, any solvents can be used as long as they do not inhibit the reaction. Inter alia, alcohols (e.g. C1-3 alcohol such as methanol, ethanol, propanol and the like) or ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane etc.) are preferable. A reaction time is usually about 0.5 to 20 hours. The thus obtained Compound (II-5) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. hydrocarbon ring or an optionally substituent non-aromatic heterocyclic ring, Ar2 is an optionally substituted aromatic hydrocarbon ring or an optionally substituted aromatic heterocyclic ring, and A-3 is the same as A, and the other symbols are as defined above. In step H, an amino group of Compound (IV-3) is converted into a diazonium salt, and ylide is reacted thereon to prepare Compound (VIII-1). Diazotization in the present method is carried out in the presence of an acid in a solvent having no adverse effect on the reaction according to the conventional method. As the acid, for example, acetic acid and hydrochloric acid are used. As a diazotizing agent, sodium nitrite, alkyl nitrite or sulfated nitrosyl is used. As the solvent, water, dioxane, tetrahydrofuran and the like are used. A reaction temperature is usually about -50°C to about 150°C, preferably about -10°C to about 100°C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained diazonium salt of Compound (IV-3) is reacted with ylide produced from Compound (XIII-1) to prepare Compound (VIII-1). The present step is carried out in the presence of a base in a solvent having no adverse effect on the reaction. Examples of the base include: alkali metal salts such as potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8- diazabicyclo[5,4,0] undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. An amount of these bases to be used is preferably about 1 to about 3 mole equivalent relative to Compound (XIII-1) . Examples of the solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahyrdorufan, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N- dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. Since the thus obtained Compound (VIII-1) is unstable depending on a kind of the compound, it is used in the next step without isolation and purification. In step I, a reduction reaction of Compound (VIII-1) is carried out to prepare Compound (IX-1). In the present reaction, a catalytic hydrogenation method using platinum oxide, Raney nickel, palladium carbon or palladium hydroxide, or reduction using a reducing agent is used. As the reducing agent, sodium borohydride, aluminium lithium hydride and lithium borohydride are used. In the present reaction, if needed, any solvents can be used as long as they do not inhibit the reaction. Inter alia, alcohols (e.g. C1-3 alcohol such as methanol, ethanol, propanol etc.) or ethers (diethyl ether, diisopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane etc.) are preferable. A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound (IX-1) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step J, Compound (II-7) is prepared by a reductive amination reaction between Compound (IX-1) and ketone (XV). The present method is carried out in the presence of a reducing agent in a solvent having no adverse effect on the reaction. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium borohydride. Although alcohol solvents such as ethanol and methanol, dichloromethane, chloroform and carbon tetrachloride are used as a solvent, any solvents can be used as long as they do not inhibit the reaction. The thus obtained Compound (II-7) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In step K, a bismuth regent is acted on Compound (IX- 1) to prepare Compound (II-8). The present method is carried out in the presence of a metal catalyst in a solvent having no adverse effect on the reaction. As the metal catalyst, for example, copper catalysts such as copper (II) acetate and copper (II) pivalate are used. Although dichloromethane, chloroform and carbon tetrachloride are used as a solvent, any solvents can be used as long as they do not inhibit the reaction. A reaction temperature is usually about -80°C to about 150°C, preferably about -80°C to about 100°C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound (II-8) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein X4 is the same as X3, and the other symbols are as defined above. Step D and step E can be carried out according to step D and step E of the scheme 3, respectively, to prepare Compound (III-l). wherein Ar3 is an optionally substituted hydrocarbon ring, an optionally substituted non-aromatic heterocyclic ring, an aromatic hydrocarbon ring or an aromatic heterocyclic ring, X5 is the same as X3, and other respective symbols have the same meanings as described above.) Step H, step I, step J and step K can be carried out according to step H, step I, step J, and step K of the scheme 5, respectively, to prepare Compound (III-2) . In Compound (II), when X1 is C-COOR16, it can be converted as follows: wherein A-4 denote the same meaning as that of A, R16 denotes an optionally substituted carbon atom, and the other symbols are as defined above. In step L, Compound (11-10) is prepared by a reaction for leaving a carboxyl-protecting group. All conventional methods used in a reaction for leaving a carboxyl-protecting group, for example, hydrolysis, reduction and elimination using a Lewis acid can be applied to the present reaction. It is preferable that hydrolysis is carried out in the presence of a base or an acid. Examples of the suitable base include inorganic bases such as alkali metal hydroxide (e.g. sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxide (e.g. magnesium hydroxide and potassium hydroxide), alkali metal carbonate (e.g. sodium carbonate and potassium carbonate), alkaline earth metal carbonate (e.g. magnesium carbonate and calcium carbonate) , alkali metal bicarbonate (e.g. sodium bicarbonate and potassium bicarbonate), alkali metal acetate (e.g. sodium acetate and potassium acetate), alkaline earth metal phosphate (e.g. magnesium phosphate and calcium phosphate) and alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate and dipotassium hydrogen phosphate), and organic bases such as trialkylamine (e.g. trimethylamine and triethylamine), picoline, N- methylpyrrolidine, N-methylmorpholine, 1,5- diazabicyclo[4.3.2]non-5-ene, 1,4-diazabicyclo[2.2.2]non-5- ene and 1,8-diazabicyclo[4.3.0]-7-undecene. Hydrolysis using a base is carried out in water or a hydrophilic organic solvent or a mixed solvent in many cases. Examples of the suitable acid include formic acid, hydrobromic acid and sulfuric acid. The present hydrolysis reaction is usually carried out in an organic solvent, water or a mixed solvent thereof. A reaction temperature is not particularly limited, but is appropriately selected depending on a kind of a carboxyl- protecting group and an elimination method. Elimination using a Lewis acid is carried out by reacting Compound (II- 9) or a salt thereof with a Lewis acid, for example, trihalogenated boron (e.g. boron trichloride and boron trifluoride), tetrahalogenated titanium (e.g. titanium tetrachloride and titanium tetrabromide), and halogenated aluminium (e.g. aluminium chloride and aluminium bromide), or an organic acid (e.g. trichloroacetic acid and trifluoroacetic acid). This elimination reaction is preferably carried out in the presence of a cation scavenger (e.g. anisole and phenol) and is usually carried out in a solvent such as nitroalkane (e.g. nitromethane and nitroethane), alkylene halide (e.g., methylene chloride and ethylene chloride), diethyl ether, carbon disulfide, and a solvent having no adverse effect on the reaction. These solvents may be used as a mixture thereof. It is preferable that elimination by reduction is applied to elimination of a protecting group such as halogenated alkyl (e.g. 2-iodoethyl and 2,2,2- trichloroethyl) ester, and aralkyl (e.g. benzyl) ester. Examples of a reduction method using in the present elimination reaction include the conventional catalytic reduction in the presence of a combination of a metal (e.g. zinc and zinc amalgam) or a salt of a chromium compound (e.g. chromate chloride and chromate acetate) and an organic or inorganic acid (e.g. acetic acid, propionic acid and hydrochloric acid); or the conventional metal catalyst (e.g. palladium carbon and Raney nickel). A reaction temperature is not particularly limited, but a reaction is carried out under cooling, at room temperature of under warming. The thus obtained Compound (11-10) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein R17 and R18 are optionally substituted alkyl group, allyl group or hydroxy group; or R17 and R18 may be combined each other to form a ring, Y" is the same as Y, and the other symbols are as defined above. In the present method, Compound (11-12) is prepared by reacting Compound (11-11) or a reactive derivative at a carboxyl group thereof and a salt thereof with the above Compound (XVI) or a reactive derivative at an amino group thereof or a salt thereof. Examples of the suitable reactive derivative at an amino group of Compound (XVI) include: Schiff base type imino produced by a reaction of Compound (XVI) with a carbonyl compound such as aldehyde, ketone and the like; silyl derivative produced by a reaction of Compound (XVI) and a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl) acetamide, bis(trimethylsilyl)urea and the like; derivative produced by a reaction of Compound (XVI) with phosphorus trichloride or phosgene. Specific examples of the suitable reactive derivative at a carboxyl group of Compound (II-11) include acid halide, acid anhydride, activated amide, activated ester and the like. Examples of the suitable reactive derivative include: acid chloride; acid azide; mixed acid anhydride with an acid such as substituted phosphoric acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid and the like, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid such as methanesulfonic acid and the like, aliphatic carboxylic acid such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid and the like or aromatic carboxylic acid such as benzoic acid and the like; symmetric acid anhydride; activated amide with imidazole; 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; activated ester such as cyanomethylester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p- nitrophenyl ester, p-cresyl thioester, carboxylmethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester and the like, or esters with N-hydroxy compound such as N,N-dimethylhydroxyamine, l-hydroxy-2- (1H)-pyridone, N-hydroxysuccineimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and the like. These reactive derivatives can be arbitrarily selected depending on a kind of Compound (II-11) to be used. Examples of the suitable reactive derivative of Compound (II-12) include alkali metal salts such as sodium salt, potassium salt and the like, alkaline earth metal salts such as calcium salt, magnesium salt and the like, and basic salts such as organic base salts such as ammonium salt, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt and the like. Although the reaction is usually carried out in the conventional solvent such as water, alcohols such as methanol, ethanol and the like, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N- dimethylformamide and pyridine, the reaction may be carried out in any other organic solvents as long as they have no adverse effect on the reaction. These conventional solvents may be used as a mixture with water. When Compound (II-11) is used as the form of a free acid or a salt thereof in this reaction, it is desirable that the reaction is carried out in the presence of the normally used condensing agent such as so-called Vilsmeier regent and the like prepared by a reaction of N,N'- dicyclohexylcarbodiimide; N-cyclohexyl-N'- morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4- diethylaminocyclohexyl)carbodiimide; N,N'- diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl- N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis(2- methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1- alkoxy-1-chloroethylene; trialkyl phosphite; polyethyl phosphate; polyisopropyl phosphate; phosphorus oxychloride; diphenylphosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate such as ethyl chloroformate; isopropyl chloroformate and the like; triphenylphosphine; 2-ethyl-7-hydroxybenzisooxazolium salt, 2-ethyl-5-(m- sulfopheny)isooxazoliumhydroxide internal salt; N- hydroxybenzotriazole; 1-(p-chlorobenzenesulfonyloxy)-6- chloro-1H-benzotriazole; N-N'-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or the like. Alternatively, the reaction may be carried out in the presence of an inorganic base or an organic base such as alkali metal bicarbonate salt, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine and the like. A reaction temperature is not particularly limited, but the reaction is carried out under cooling or under warming. An amount of Compound (XVI) to be used is 1 to 10 mole equivalent, preferably 1 to 3 equivalent relative to Compound (II-11) . A reaction temperature is usually -30°C to 100°C. A reaction time is usually 0.5 to 20 hours. In addition, when a mixed acid anhydride is used, Compound (II-11) and chlorocarbonic ester (e.g. methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate etc.) are reacted in the presence of a base (e.g. triethylamine, N-methylmorpholine, N,N- dimethylaniline, sodium bicarbonate, sodium carbonate, potassium carbonate etc.) and is further reacted with Compound (XVI). An amount of Compound (XVI) to be used is usually 1 to 10 mole equivalent, preferably 1 to 3 mole equivalent relative to Compound (11-11). A reaction temperature is usually -30°C to 100°C. A reaction time is usually 0.5 to 20 hours. The thus obtained Compound (II-12) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. When X1 is C-COOR16 in Compound (III), the conversion can be carried out as follows: wherein the symbols are as defined above. Step L and step M can be carried out according to step L in the scheme 8 and step M in the scheme 9, respectively, to prepare Compound (III-4) and Compound (III-5). wherein R19 is an optionally substituted alkyl group, allyl group, hydroxy group, amino group or sulfanyl group, and the other symbols are as defined above. In the present method, Compound (11-13) is prepared by a reaction between Compound (V) and a nucleophilic regent. Examples of the nucleophilic regent include metal phenolate, metal alcoholate, Grignard regent, alkyl metal regent, aryl metal regent and thioalcoholate. An amount of the nucleophilic regent to be used is preferably about 1 to about 5 mole equivalent relative to Compound (V). Examples of a solvent having no adverse effect on the reaction include: ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N,N- dimethylformamide and 1-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about -50°C to about 150°C, preferably about -10 to about 100°C. A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound (II-13) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. wherein the symbols are as defined above. Step N can be carried out according to step N in the scheme 11 to prepare Compound (III-4). wherein A-6 is the same as A, and the other symbols are as defined above. In step H, an amino group of Compound (IV-5) is converted into a diazonium salt, and ylide is reacted thereon to prepare Compound (VIII-3). Diazotization in this method is carried out in the presence of an acid in a solvent having no adverse effect on the reaction according to the conventional method. As the acid, for example, acetic acid and hydrochloric acid are used. As the diazotizing agent, sodium nitrite, alkyl nitrite or sulfated nitrosyl is used. As the solvent, water, dioxane, tetrahydrofuran and the like are used. A reaction temperature is usually about -50°C to about 150°C, preferably about -10°C to about 100°C. A reaction time is about 0.5 to about 20 hours. The thus obtained diazonium salt of Compound (IV-5) is reacted with ylide produced from Compound (XVII) to prepare Compound (VIII-3). The present step is carried out in the presence of a base in a solvent having no adverse effect on the reaction. Examples of the base include: alkali metal salts such as potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8- diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. An amount of these bases to be used is preferably about 1 to about 3 mole equivalent relative to Compound (XVII). Examples of the solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N- dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. Since the thus obtained Compound (VIII-3) is unstable depending on a kind of the compound, it is used in the next step without isolation and purification. Step I, step J and step K can be carried out according to step I, step J and step K, respectively, to prepare Compound (11-14) and Compound (11-15). When R3 is a hydrogen atom in Compound (II) the following conversion is possible. wherein the symbols are as above. In step 0, Compound (II-4) is subjected to alkylation, acylation, carbamoylation, oxycarbonization or thiocarbamoylation to prepare Compound (II-6). The reaction is carried out according to the conventional method. In alkylation, alkyl halide is reacted, in acylation, acid halide or acid anhydride is reacted, in carbamoylation, isocyanate or carbonylimidazole is reacted and, thereafter, amine is reacted, in oxycarbonization, oxycarbonyl halide or oxycarboic acid anhydride is reacted and, in thiocarbamoylation, thioisocyanate is reacted, respectively, to prepare the compound. The present reaction is generally carried out in the presence of a base in a solvent having no adverse effect on the reaction. Examples of the base include alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate; amines such as pyridine, triethyamine, N,N-dimethylaniline and 1,8-diazabicyclo[5,4,0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide. An amount of these bases to be used is preferably about 1 to about 5 mole equivalent relative to Compound (H-4) . Examples of the solvent having no adverse effect on the reaction include: aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether: halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N- dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used by mixing at an appropriate ratio. A reaction temperature is usually about -50°C to about 150°C, preferably about -10°C to about 120°C A reaction time is usually about 0.5 to about 20 hours. The thus obtained Compound (II-6) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under the reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. When R3 is a hydrogen atom in Compound (III), the following conversion is possible. wherein the symbols are as above. Step 0 step J and step K can be carried out according to step 0 in the scheme 14, respectively, to prepare Compound (III). All the compounds used or obtained in the present invention include corresponding salts, even if specifically stated, and they can be exchanged to one another by a per se known method or modified methods thereof. When the compounds or salts thereof obtained by the present invention are asymmetric molecules, they can be separated into d-form isomer and 1-form isomer according to conventional optical resolution methods. The compound or its salt obtained by the present invention may be used in a next step as its reaction mixture without sufficient purification. Compound (I), (II), (III) or (IIIa) of the present invention has an excellent Ca receptor modulating activity and enhances the secretion of PTH, and therefore useful as drugs for treating bone diseases, kidney-acting drugs, central nervous system and endocrine-acting drugs, digestive system-acting drugs, and the like. Further, the toxicity is low. Therefore, Compound (I), (II), (III) or (IIIa) may be safely administered to mammalian animals (for example, human, rat, mouse, dog, rabbit, cat, cow, horse, pig, and the like). Thus, a pharmaceutical composition containing compound (I), (II), (III) or (IIIa) of the present invention is expected to be useful in the treatment and prevention of diseases, in which Ca receptor modulating activity is required, such as Ca receptor modulating drugs: primary or secondary hyper parathyroidism; hypoparathyroidism; hyperthyroidism; hypothyroidism; Graves' disease; Hashimoto's toxicosis; Paget's disease; hypercalcemia associated with malignant tumor; hypercalcemia; hypocalcemia; postmenopausal osteoporosis; senile osteoporosis; secondary osteoporosis; osteomalacia; renal osteodystrophy; fracture; osteoarthritis; rheumatoid arthritis; osteosarcoma; myeloma; hypertension; diabetes; myocardial infarction; Hachington's diseases; Parkinson's diseases; Alzheimer's disease; dementia; cerebral apoplexy; brain tumor; spinal injury; diabetic renal disease; renal insufficiency; gastric ulcer; duodenal ulcer; Basedow's disease; parathyroid gland tumor; thyride gland tumor; arteriosclerosis; and the like; Ca receptor antagonistic drugs: hyperthyroidism; hypocalcemia; postmenopausal osteoporosis; senile osteoporosis; secondary osteoporosis; osteomalacia; renal osteodystrophy; fracture; osteoarthritis; rheumatoid arthritis; osteosarcoma; myeloma; central nervous system diseases; and the like, in particular osteoporosis. The dosage of Compound (I), (II), (III) or (IIIa) can be selected in various ways depending on the administration route and the symptom of a patient to be treated. The dosage as Compound (I), (II), (III) or (IIIa) per an adult (a body weight of 50 kg) can be usually selected in a range of about 0.1 mg to about 500 mg, preferably about 1 mg to about 100 mg in the case of oral administration and in a range of about 0.01 mg to about 100 mg, further preferably about 0.1 mg to about 10 mg in the case of parenteral administration. The dosage can be administered with being divided in 1-3 times daily. Compound (I), (II), (III) or (IIIa) of the present invention can be formulated with a pharmaceutically acceptable carrier and can be orally or parenterally administered as solid formulations such as tablets, capsules, granules, powders, or the like; or liquid formulations such as syrups, injections, or the like. Also, there can be prepared formulations for transdermal administration such as patchings, cataplasms, ointments (including creams), plasters, tapes, lotions, liquids and solutions, suspensions, emulsions, sprays, and the like. As for a pharmaceutically acceptable carrier, a variety of organic or inorganic carrier substances, which have been conventionally employed as formulation materials, is used and compounded as a bulking agent, a lubricant, a binding agent, and a disintegrator in solid formulations; a vehicle, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, and an analgesic in liquid formulations. If necessary, formulation excipients such as a preservative, an antioxidant, a stabilizer, a coloring agent, a sweetening agent, and the like can be used. Preferred examples of the bulking agent include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include magnesium stearate, potassium stearate, talc, colloidal silica, and the like. Preferred examples of the binding agent include crystalline cellulose, α-starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like. Preferred examples of the disintegrator include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and the like. Preferred examples of the vehicle include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like. If necessary, for the purpose of taste masking, enteric coating, or prolonged action, oral formulations can be prepared by coating by a per se known method. Examples of this coating agent include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate phthalate, Eudragit (manufactured by Rohm Company, methacrylic acid- acrylic acid copolymer), and the like. Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisamiomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Preferred examples of the suspending agent include surface active agents such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and the like; hydrophilic, high molecular substances such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like; and so on. Preferred examples of the isotonicity agent include sodium chloride, glycerin, D- mannitol, and the like. Preferred examples of the buffering agent include buffer solutions of a phosphate, an acetate, a carbonate, a citrate, or the like. Preferable examples of the analgesic include benzyl alcohol and the like. Preferred examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferred examples of the antioxidant include sulfites, ascorbic acid, and the like. The following examples, preparations and experiments describe the manner and process of making and using the present invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the present invention as defined by the claims appended hereto. Abbreviations employed herein are defined below. DCM = dichloromethane DCE = dichloroethane DMAP = dimethylaminopyridine DMF = dimethylformamide WSC = 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride M+H = monoisotopic mass plus one proton Me = methyl Et = ethyl Ph = phenyl h = hours min = minutes HPLC = high performance liquid chromatography HOBt = hydroxybenzotriazole LC/MS = liquid chromatography/mass spectrometry MS = mass spectrometry Rt = retention time TEA = triethylamine TFA = trifluoroacetic acid IPE = diisopropylether TLC = thin layer chromatography THF = tetrahydrofuran TMSCN = trimethylsilyl cyanide HATU = 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl- uronium hexafulorophosphate DIPEA = diisopropylethylamine Example 1 Ethyl 5-phenyl- 7-(trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate Step A: A mixture of 4,4,4-trifluoro-1-phenyl-1,3- butanedione 1 (6.97 g, 32.24 mmol) and ethyl 3- aminopyrazole-4-carboxylate 2 (5.0 g, 32.22 mmol) in AcOH 3 (100 mL) was refluxed for 4 h. The mixture was cooled to room temperature and concentrated and precipitated crystals were collected by filtration to give 8.63 g (79%) of the title compound as yellow crystals. 1H NMR (CDC13, 200 MHz): 1.47 (3H, t, J=7.0 Hz), 4.47 (2H, q, J=7.0 Hz), 7.54-7.61 (3H, m), 7.80 (1H, s), 8.23-8.28 (2H, m), 8.68 (1H, s). Step B: To a solution of 3 (3.51 g, 10.3 mmol) in MeOH was added NaBH4 (1.4 g, 3.7 mmol) at room temperature. The whole was stirred at the same temperature for 5 h, quenched with saturated citric acid solution, concentrated in vacuo, and extracted with AcOEt. The extract was successively washed with aq. NaHCO3, water and brine, dried over MgSO4 and then concentrated to give 1.73 g (49%) of compound 4 as colorless oil. 1H HMR (CDC13, 200 MHz): 1.32 (3H, t, J=6.8 Hz), 2.28-2.46 (1H, m) , 2.50-2.61 (1H, m) , 4.25 (2H, q, J=6.8 Hz), 4.58 (1H, dd, J=11.4, 3.4 Hz), 4.85 (1H, ddd, J=3.4, 3.0, 2.6 Hz), 6.15 (1H, s)7.34-7.48 (5H, m) , 7.74 (1H, s) . Compounds of Examples 2-14, shown in the Table 1, were prepared in a manner similar to that described in Example 1. Example 15 Ethyl 7,7-dimethyl-5-(2-pyridyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate Step A: To a stirred solution of compound 1 (7.0 g, 4 4.3 mmol) in THF (100 mL) was added n-BuLi (1.6 M hexane solution, 28 mL, 44.8 mmol) at -78 °C. After the mixture was stirred for 30 min, compound 2(6.34 g, 44.3 mmol) was added thereto. The resulting mixture was stirred at -78-- 50°C for 2h, quenched with saturated citric acid solution and extracted with AcOEt. The extract was successively washed with water and brine, dried over MgSO4 and then concentrated in vacuo. The residue was chromatographed on silica gel with AcOEt/hexane (1:9) as an eluent to give 3.16 g (44% yield) of compound 3 as colorless liquid. Step B: To a solution of compound 3 and compound 4 in methoxyethanol (60 mL) was added TFA (4.47 g, 39.2 mmol) with ice-water cooling. The mixture was refluxed for 12 h, diluted with AcOEt, and the mixture was washed with saturated NaHCO3 solution, water and brine, dried over MgSO4, and then concentrated in vacuo. The residue was chromatographed on silica gel with AcOEt/hexane (1:4) as an eluent to give 2.03 g (36% yield) of compound 5 as colorless prisms. Step C: A mixture of 5 (1.98 g, 6.96 mmol) and 10 % Pd-C (1.0 g) in EtOH (100 mL) was stirred for 2h under the H2 atmosphere (balloon pressure). After the insoluble materials were filtered off, the residue was concentrated in vacuo to give the residue. Crystallization from hexane/IPE gave the title compound 6 (1.00g, 48%) as colorless solid. 1H NMR (CDC13, 200 MHz): 1.34 (3H, t, J=7.0 Hz), 4.26 (2H, q, J=7.0 Hz), 4.80 (1H, dd, J=11.4, 2.6 Hz), 6.39 (1H, s) , 7.24-7.31 (1H, m) , 7.51 (1H, d, J=7.6 Hz), 7.76 (1H, td, J=7.6, 1.8 Hz), 8.60-8.63 (1H, m). Compounds of Examples 16-29, 439-447 and 924-938 shown in the Table 2, were prepared in a manner similar to that described in Example 15. A mixture or 1, 1.5 N KOH solution (14 mL) and EtOH (20 mL) was stirred at 60 °C for 12h, acidified with saturated citric acid solution, and the precipitated solid was collected by filtration, which was washed with water and IPE to give 1.59 g (76% yield) of the title compound as colorless prisms, mp 184.8-185.0 °C, 1H NMR (CDC13, 300 MHz): 2.31-2.44 (1H, m), 2.50-2.59 (1H, m), 4.59 (1H, dd, J=11.4, 3.0 Hz), 4.79 (1H, m), 6.10 (1H, s), 7.20-7.26 (5H, m) , 7.78 (lH,s) . Compounds of Examples 22-39, 448-458 and 939-953 shown in the Table 3, were prepared in a manner similar to that described in Example 21. Example 4 0 N-Cyclooctyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Cyclooctylamine (24 mg, 0. 19 mmol) was added to a suspension of compound 1 (0.05 g, 0. 16 mmol), WSC (37 mg, 0. 19 mmol), HOBt (29 mg, 0.19 mmol) and DMAP (23 mg, 0. 19 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 14 h, diluted with DCM (0.5mL) and saturated NaHCO3 solution (0.5 mL) , and then separated using PHASE-SEP filtration syringe. The organic layer was concentrated and loaded onto preparative HPLC (Gilson 215 system). The purest fractions were combined to give 64.6 mg (96% yield) of the title compound as a white solid. Reverse Phase LC/MS: CAPCELLPAKCC18UG120, S-3 µ m, 2.0 x 50 mm, UV detection at 220, 8 min. gradient 10-100% Solvent B/A (Solvent A: CH3CN with 0.1% TFA, Solvent B: H2O with 0.1% TFA), 0.5 mL/min. Rt=1.90 min, (96% pure). MS (M+H: 421). Example 41 N-(1-ethyl-1-(4-(trifluoromethyl)phenyl)propyl)-7,7- dimethyl-5-phenyl-4, 5, 6, 7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide To a solution of 3 (0.5g, 1.84mmol) and HATU (0.84g, 2.21mmol) in DMF (3mL) was added DIPEA (0.67mL, 3.68mmol) at room temperature. After 30 min, compound 2 (0.59g, 2.21mmol) was added thereto. The resulting mixture was stirred at 80 °C for 18 h, concentrated in vacuo, and the residue was chromatographed on silica gel with AcOEt/hexane (1/1) as an eluent to give 0.28 g (31% yield) of compound 4 as colorless prisms, mp 193-194 °C. Compounds of Examples 42 - 434, 459-867 and 954-1008 shown in the table 4, were prepared in a manner similar to that described in Example 40 or 41. Example 1009 Ethyl 7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate Racemic compound obtained in Example 16 (80 g) was subjected to preparative high performance liquid chromatography (HPLC) to afford optically pure materials (38 g, 99.8% ee (shorter retention time) and 39 g, 99.4% ee (longer retention time)). [column: CHIRALCEL OD 50 mmol x 500 mm (manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature: 30°C, mobile phase: hexane/Ethanol = 95/5, flow rate: 60 ml/minute, detection wavelength: 254 ran, and 1 shot: about 800 mg]. Compounds of Examples 1010 - 1017 shown in the Table 8~11, were prepared in a manner similar to that described in Example 1009. The determination of the optical purity was carried out by HPLC using a chiral column (column: CHIRALCEL OD 4.6 mmΦ x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30°C, mobile phase: hexane/ethanol = 96/4, flow rate: 0.5 ml/minute, and detection wavelength: 254 nm). The determination of the optical purity was carried out by HPLC using a chiral column (column: CHIRALPAK AD 4.6 mmΦ x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30°C, mobile phase: hexane/IPA = 95/5, flow rate: 0.5 ml/minute, and detection wavelength: 254 nm). The determination of the optical purity was carried out by HPLC using a chiral column (column: CHIRALPAK AD 4.6 mmΦ x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30°C, mobile phase: hexane/ethanol = 995/5, flow rate: 0.5 ml/minute, and detection wavelength: 220 nm). Table 11 The determination of the optical purity was carried out by HPLC using a chiral column (column: CHIRALCEL OD 4.6 mmΦ x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki Kaisha), temperature: about 30°C, mobile phase: hexane/ethanol = 95/5, flow rate: 0.5 ml/minute, and detection wavelength: 258 nm). Example 1018 (-)-7,7-Dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of 1(0.73 g) obtained in Example 1009, KOH (0.41 g) , H2O(20 ml) and EtOH (20 mL) was stirred at 90 °C for 12h, acidified with 1N HCl, and extracted with AcOEt. Compounds of Examples 1019-1027 shown in the Table 12, were prepared in a manner similar to that described in Example 1018. (S)-N-(1-(4-Chlorophenyl)-1-ethylpropyl)-7,7-dimethyl- 5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3- carboxamide hydrochloride Step A: To a solution of 1 (0.4g, 1.47mmol) and HATU (0.67g, 1.77mmol) in DMF (5mL) was added DIPEA (0.57g, 4.41mmol) at room temperature. After 1 h, compound 2 (0.41g, 1.77mmol) was added thereto. The resulting mixture was stirred at 80 °C for 12 h, and concentrated in vacuo. The residue was diluted with AcOEt, washed with sat.NaHCO3aq and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel with AcOEt/hexane (1/1) to give 0.41 g (62% yield) of compound 4 as colorless prisms, mp 105-106 °C. [α]D20°c = -17.68 in CHC13, C = 0.30. Step B: To a stirred solution of compound 3 (90 mg, 0.2 mmol) in Et2O (3 mL) was added 4M HCl-AcOEt (0.1 mL, 0.4 mmol) at room temperature. The precipitate was collected by filtration to give 60mg (62% yield) of compound 4 as prisms. mp 130-132 °C. [α]D20°c = 24.3 in CHC13 C = 0.48. Compounds of Examples 102 9 - 1122 shown in the Table 13, were prepared in a manner similar to that described in Example 1028. Example 435 N-(1-adamantyl)-7-ethyl-5-phenyl-7-(trifluoromethyl)- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Step A: To a stirred solution of compound 1 (2.00 g, 6.00 mmol) in DCM (50 mL) was added triethylaluminium (2.0 M hexane solution, 18 mL, 36 mmol) at room temperature. After the mixture was stirred for 2 h, it was quenched with water, and extracted with AcOEt. The extract was successively washed with water and brine, dried over MgSO4 and then concentrated in vacuo to give compound 2 (2.20 g, 100% yield) as yellow syrup. MS (ESI,m/z) 366 (M + H)+ . Step B: A mixture of compound 2 (2.20 g, 6.00 mmol), LiOH (0.51 g, 12.15 mmol), EtOH (50 mL) and H2O (30 mL) was stirred at 70 °C for 12 h, concentrated in vacuo, diluted with aq.citric acid solution and extracted with AcOEt. The extract was successively washed with water, saturated NaHCO3 solution and brine, dried over MgSO4 and then concentrated to give compound 3 (2.00 g, 100%) as colorless crystals. MS (ESI,m/z) 352 (M + H)+ . Step C: 1-Adamantylamine (0.72 g, 4.7 6 mmol) was added to a suspension of compound 3 (1.60 g, 4.74 mmol), WSC (0.91 g, 4.74 mmol), HOBt (0.64 g, 4.74 mmol) and DMAP (0.58 g, 4.75 mmol) in DMF (20 mL) . The reaction mixture was stirred at 70 °C for 13 h and then concentrated in vacuo. The residue was chromatographed on silica gel with AcOEt/hexane (1/6) as an eluent to give compound 4 (0.71 g, 32 %) as colorless crystals. MS(ESI,m/z) 472 (M+H)+. Step D: To a solution of 4 (0.58 g, 1.23 mmol) in EtOH was added NaBH4 (0.2 g, 5.29 mmol) at room temperature. The whole was stirred at 60 °C for 3 h, concentrated in vacuo, diluted with water and extracted with AcOEt. The extract was successively washed with aq. NaHCO3, water and brine, dried over MgSO4 and then concentrated to give 0.43 g (74%) of compound 5 as colorless crystals. MS(ESI,m/z) 474 (M+H)+. Compounds of Examples 436, shown in the Table 5, were prepared in a manner similar to that described in Example 435. Example 4 37 2-cyclohexyl-4-methyl-N-(1-methyl-1-phenylethyl) - 1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine-8- carboxamide Step A: To a 250 mL round bottom flask equipped with magnetic stir bar and 2 addition funnels was added 1.0 g (6.44 mmol) of compound 1 by 3.5 ml of cone, hydrochloric acid and 7.0 ml of water. The solution was cooled to 0 °C and a solution containing 0.50 g (7.25 mmol) of sodium nitrite in 2 ml of water dropwise. After complete addition, the reaction was allowed to stir for 30 min. at 0 °C, followed by the addition of 65 ml of dichloromethane and 35 ml of a saturated sodium bicarbonate solution while maintaining the reaction temperature below 10 °C. A solution containing 2.05 g (6.44 mmol) of 1- triphenylphosphoroanylidene-2-propanone in 30 ml of dichloromethane was then added dropwise. After complete addition, the reaction was allowed to stir for 5 min., diluted with 50 ml of dichloromethane and washed with water. The organic phase was separate and the solvent removed under reduced pressure to afford 3.50 g (100%) of crude compound 2 which is taken on without further purification. MS Calcd.: 206; Found 207 (M+H). Step B: To a solution containing the crude product from above in 30 ml of ethanol and 30 ml of THF under a nitrogen atmosphere was added 1.20 g (3.72 mmol) of sodium borohydride. The reaction was allowed to stir at room temperature for 30 min. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over MgSO4. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 70% AcOEt/hexanes gave 0.7 9 g (58.9%) of compound 3 as a pale yellow solid. MS Calcd.: 208; Found 209 (M+H) Step C: A solution containing 0.54 g (2.59 mmol) of compound 3 and 0.18 g of LiOH (7.52 mmol) in 15 ml of ethanol and 10 ml of water was heated to 70 °C. After 1.5h, HPLC of reaction mixture indicated no starting material remaining. The ethanol was removed under reduced pressure and the residue acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent gave 0.48 g (92.2%) of compound 4. MS Calcd.: 180; Found 181 (M+H). Step D: To a solution containing 2.80 g (15.54 mmol) of compound 4 in 150 ml of DMF under a nitrogen atmosphere was added 6.50 g (17.10 mmol) of HATU, 2.31 g (17.10 mmol) of cumyl amine and 2.98 ml (17.10 mmol) of diisopropylethylamine. The reaction was heated to 50 °C overnight, diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 60% AcOEt/ hexanes gave 3.0 9 g (66.9%) of compound 5. MS Calcd.: 297; Found 298 (M+H). Step E: To a Parr flask was added 1.11 g (3.90 mmol) of compound 5 and 75 ml of EtOH. The flask was purged with nitrogen and 0.30 g of platinum oxide added. The flask was evacuated and pressurized to 20 psig hydrogen (3x) then pressurized to 50 psig hydrogen and shaken for 1h. After completion as determined by HPLC, the reaction was filtered through GF/F filter paper and the filtrate concentrated under reduced pressure to afford 1.1 g (100%) of compound 6. MS Calcd.: 299; Found 300 (M+H) Step F: To a solution containing 0.43 g (1.44 mmol) of compound 6 in 4 0 ml of DCE under a nitrogen atmosphere was added 0.30 ml (2.89 mmol) of cyclohexanone followed by 0.90 g (4.25 mmol) of sodium triacetoxy borohydride. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over MgSO4. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 75% AcOEt/hexanes gave 0.35 g (63.7%) of compound 7. MS Calcd.: 381; Found 382 (M+H) Example 438 4-Methyl-N-(1-methyl-1-phenylethyl)-2-phenyl-l,2,3,4- tetrahydropyrazolo[5,1-c][1,2,4]triazine-8-carboxamide To a solution containing 0.20 g (0.71 mmol) of compound 1 in 25 ml of DCM under a nitrogen atmosphere at - 78 °C was added 0.36 g (0.64 mmol) of triphenylbismuth diacetate followed by 0.02 g (0.075 mmole) of copper (II) dipivalate. The reaction was allowed to warm to 0 °C over 1.5 h. The reaction was diluted with dichloromethane and washed with saturate sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 70% AcOEt/ hexanes gave 0.025 g (9.4%) of compound 2. MS Calcd.: 375; Found 376 (M+H) Example 1123 1-(7,7-Dimethyl-5-phenyl-4, 5, 6, 7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2-(4- methylphenyl)-1-propanone Step A 4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2) : To a 100 mL round bottom flask equipped with a magnetic stir bar was added 1.80 g (6.01 mmol) of 7,7-dimethyl-5- phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine-3- carboxylic acid ethyl ester, 30 mL of DMF and 0.786 mL (6.61 mmol) of benzyl bromide, followed by 0.265 g (6.6 mmol) of sodium hydride (60% dispersion in mineral oil) which was added in several portions. After 2 h, the reaction was quenched with water and the product was extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude N-benzylated ester as a golden colored oil. The crude ester was dissolved in 15 mL of ethanol and 2.5 mL of 6 N potassium hydroxide was added. The solution was then heated to 70 °C for 18 h at which time no starting material could be detected by HPLC analysis. The crude reaction mixture was concentrated in vacuo and diluted with water. The aqueous solution was acidified with 6 N HC1 and the resulting cream-colored precipitate was collected by filtration. The crude acid thus isolated was dissolved in AcOEt, dried over sodium sulfate, filtered and concentrated to a cream colored powder. The resulting acid was washed with several portions of hexanes and dried in vacuo to give 1.95 g (90%) of the title compound as an off white powder. 1H NMR (DMSO-d6) δ 1.10 (s, 3H) , 1.40 (s, 3H) , 1.98-2.16 (m, 2H) , 3.71 (d, J = 15.4 Hz, 1H), 4.36 (dd, J = 4.5, 11.5 Hz, 1H), 5.81 (d, J = 15.6 Hz), 6.97 (dd, J = 1.4, 7.2 Hz, 2H) , 7.26-7.45 (m, 7H), 7.67 (s, 1H), 11.81 (s, 1H). MS Calcd.: 361; Found: 344 (M-OH). Step B 4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6, 7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid methoxy-methyl-amide (3) : To a 5 mL NMP solution containing 0.72 g (1.99 mmol) of 2 was added 0.91 g (2.39 mmol) of O-7-azabenzotriazolo-1-yl) -N,N,N' ,N'- tetramethyluroniumhexafluorophosphate (HATU) and 0.416 mL (2.39 mmol) of diisopropylethylamine. After stirring for 30 min, 0.233 g (2.39 mmol) of O,N-dimethyl-hydroxylamine hydrochloride was added and the reaction heated to 50 °C. After 1 h, the reaction mixture was poured into water and extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude oil. Purification of this oil by flash chromatography eluting with a 60 to 50% hexanes/AcOEt gradient gave 0.65 g (81%) of the title (M+H). Step C l-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(4- methylphenyl) ethanone (4) : To 0.65 g (1.61 mmol) of 3 dissolved in 20 mL of THF was added 6.4 mL (3.2 mmol) of a 0.5 M solution of 4-methylbenzylmagnesium chloride in THF via syringe over 10 min. After stirring at room temperature for 1 h, the reaction was quenched by addition of approximately 2 mL of saturated aqueous ammonium chloride. The reaction was then diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product as an oil. Purification of this oil by flash chromatography eluting with 75% hexanes/ AcOEt gave 0.64 g (89%) of the title compound as a white foam. MS Calcd.: 449; Found: 450 (M+H). Step D 1-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(4- methylphenyl)-1-propanone (5) : To 0.64 g (1.42 mmol) of 4 dissolved in 10 mL of THF was added 0.177 mL (2.85 mmol) of iodomethane followed by 0.11 g (2.8 mmol) of sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 2 h, the reaction was quenched by addition of approximately 2 mL of saturated aqueous ammonium chloride. The reaction was then diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product. Purification by flash chromatography eluting with 90% hexanes/ethyl acetate gave 0.42 g (64%) of the title compound as a cream colored powder. MS Calcd.: 463; Found: 464 (M+H). Step E 1-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2-(4- methylphenyl)-1-propanone (6) : To 0.110 mL (0.785 mmol) of diisopropyl amine dissolved in 5 mL of THF at -78 °C was added 0.314 mL (0.785 mmol) of a 2.5 M solution of n- butyllithium in hexanes. After stirring for 30 min, 0.28 g (0.604 mmol) of 5 was added as a solution in 1 mL of THF. The reaction was stirred at room temperature for 1 h before 0.04 9 mL (0.79 mmol) of iodomethane was added as a solution in 1 mL of THF. After 1h the reaction was quenched by addition of approximately 0.5 mL of saturated aqueous ammonium chloride, diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product. Purification by flash chromatography eluting with 90% hexanes/ AcOEt gave 0.067 g (23%) of the title compound as an off white solid. MS Calcd.: 477; Found: 478 (M+H). Step F 1-(7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-3-yl)-2-methyl-2-(4-methylphenyl)-1-propanone (7) : To 0.060 g (0.126 mmol) of 6 dissolved in 4 mL of 1:1 THF:ethanol was added 0.080 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 1 h, the catalyst was removed via filtration and the filtrate concentrated to a cream colored solid. Purification by flash chromatography eluting with 90% hexanes/ethyl acetate gave 0.041 g (84%) of the title compound as a white solid. 1H NMR (CDC13) δ 1.49 (s, 3H) , 1.54 (s, 9H), 2.04-2.11 (m, 2H), 2.32 (s, 3H), 4.63 (dd, J = 4.1, 10.7 Hz, 1H), 6.66 (s, 1H), 7.12-7.26 (m, 5H), 7.31-7.44 (m, 5H). MS Calcd.: 387; Found: 388 (M+H). Compounds of Examples 1124-1131 shown in the Table 14, were prepared in a manner similar to that described in Example 1123. Table 14 Example 1132 7,7-Dimethyl-3-((1-methyl-1-(4- methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine Step A p-Tolylmethanesulfonylacetonitrile (2): To a 10 mL ethanol solution containing 4.1 g (30 mmol) of p-tolylmethanethiol at 0 °C was added 4.1 mL (30 mmol) of triethylamine and 4.4 g (30 mmol) of sodium iodide. After allowing the reaction to stir at room temperature for approximately 30 min, the reaction cooled to 0 °C and 1.9 mL (30 mmol) of chloroacetonitrile was added dropwise as a solution in 10 mL of ethanol. The reaction was allowed to reach room temperature overnight and was subsequently filtered and concentrated. The concentrate was partitioned between water and ether and separated. The ether layer was washed successively with 2 N sodium carbonate and brine and was then concentrated to an oil that solidified. The crude solid was then dissolved in 90 mL of glacial acetic acid, treated with 12.1 mL (107 mmol) of 30% hydrogen peroxide and heated to 100 °C. The reaction was cooled to room temperature after 3 h at which time a white solid precipitated. The precipitate was collected via filtration, washed with glacial acetic acid and dried in vacuo to give 6.4 g (69%) of the title compound as a white solid. 1H NMR (CDC13) δ 2.39 (s, 3H), 3.70 (s, 2H) , 4.48 (s, 2H) , 7.32 (dd, J = 7.3, 40.2 Hz, 4H). Step B 3-Ethoxy-2-p-tolylmethanesulfonylacrylonitrile (3) : To a solution of 4.4 g (21 mmol) of 2 in 17.5 mL (105 mmol) of triethylorthoformate was added 9.9 mL (105 mmol) of acetic anhydride. The resulting solution was heated to reflux for 18 h before being concentrated to a solid. Recrystallization from AcOEt-hexanes gave 5.0 g (90%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.29 (t, J = 7.0 Hz, 3H) , 2.36 (s, 3H) , 4.19 (q, J = 7.0 Hz, 2H), 4.35 (s, 2H), 7..23 (dd, J = 8.0, 19.9 Hz) 7.37 (s, 1H). Step C 7,7-Dimethyl-3-(4-methylbenzyl)sulfonyl)-5-phenyl-4,7- dihydropyrazolo[l,5-a]pyrimidine (4) : A slurry of 1.9 g (7.2 mmol) of 3 in 25 mL of ethanol was treated with 0.38 mL (7.9 mmol) of hydrazine monohydrate and heated to reflux for 3 h. The reaction was concentrated in vacuo to give crude 4-p-tolylmethanesulfonyl-2H-pyrazol-3-ylamine as a tan solid. The crude pyrazole, 1.3 g (7.9 mmol) of 3- methyl-1-phenyl-but-2-en-1-one and 2.8 mL (36 mmol) of trif luoroacetic acid was dissolved in 25 mL of 2- methoxyethanol and heated to reflux for 3 days. The reaction was then cooled to room temperature, concentrated in vacuo and dissolved in AcOEt. This solution was washed successively with saturated sodium bicarbonate, water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude material was purified by flash chromatography eluting with a 75 to 33% hexanes/ AcOEt gradient to give 1.25 g (44%) of the title compound as a powder. 1H NMR (CDC13) δ 1.67 (s, 6H) , 2.13 (s, 3H) , 4.26 (s, 2H) , 4.81 (d, J = 2.0 Hz, 1H) , 6.39 (s, 1H) , 7.05 (dd, J = 8.0, 18.5 Hz, 4H) , 7.20 (dd, J = 3.7, 7.4 Hz, 2H), 7.36-7.39 (m, 3H), 7.52 (s, 1H). MS Calcd.: 393; Found: 394 (M+H). Step D 7,7-Dimethyl-3-((4-methylbenzyl)sulfonyl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine (5) : To 0.500 g (1.27 mmol) of 4 dissolved in 8 mL of 1:1 THF:ethanol was added 0.50 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 2 days at room temperature, the catalyst was removed via filtration and the filtrate concentrated to a solid. Purification by flash chromatography eluting with a 75 to 33% hexanes/AcOEt gradient gave 0.385 g (77%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.59 (s, 3H), 1.83-1.97 (m, 2H), 2.37 (s, 3H) , 4.09-4.24 (m, 3H) , 5.03 (s, 1H) , 7.06-7.13 (m, 6H) , 7.30- 7.39 (m, 3H) , 7.45 (s, 1H) . MS Calcd. : 395; Found: 396 (M+H). Step E 4-Benzyl-7,7-dimethyl-3-((4-methylbenzyl)sulfonyl)-5- phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (6) : To a solution of 0.34 g (0.86 mmol) of 5 in 10 mL of THF at 0 °C was added 0.128 mL (1.07 mmol) of benzyl bromide followed by 0.034 g (0.86 mmol) of sodium hydride (60% dispersion in mineral oil) . The reaction was allowed to warm to room temperature after 30 min and stirred for an additional 30 min before being quenched with water. The quenched reaction was diluted with five volumes of water and extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 70% hexanes/AcOEt to give 0.39 g (93%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.27 (s, 3H) , 1.52 (s, 3H) , 1.93-2.05 (m, 2H), 2.27 (s, 3H), 3.83 (d, J = 15.8 Hz, 1H) , 4.18-4.30 (m, 3H), 5.51 (d, J = 15.8 Hz, 1H), 6.98-7.00 (m, 2H), 7.09 (dd, J = 8.2, 12.1 Hz, 4H), 7.17 (d, J = 6.8 Hz, 2H), 7.26-7.30 (m, 3H), 7.32-7.40 (m, 3H), 7.47 (s, 1H). Step F 4-Benzyl-7,7-dimethyl-3-((1-(4- methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine (7) : A solution of 0.23 g (0.47 mmol) of 6 in 4 mL of THF was cooled to 0 °C and treated with 0.24 mL (0.59 mmol) of n-butyllithium (2.5 M solution in hexanes) and allowed to reach room temperature for 20 min. After cooling the reaction to 0 °C, 0.103 mL (1.66 mmol) of iodomethane was added as a solution in 2 mL of THF. The reaction was allowed to warm to room temperature for 30 min at which time the reaction was quenched with a few drops of saturated ammonium chloride. The reaction was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 80% hexanes/AcOEt to give 0.14 g (60%) of the title compound as a white solid. MS Calcd.: 499; Found: 500 (M+H). Step G 4-Benzyl-7,7-dimethyl-3-((1-methyl-1-(4- methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine (8) : Using the method described for the synthesis of 7, the title compound was prepared in 51% isolated yield. MS Calcd.: 513; Found: 514 (M+H). Step H 7,7-Dimethyl-3-((1-methyl-1-(4- methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine (9) : To 0.075 g (0.146 mmol) of 8 dissolved in 6 mL of 1:1 THF:ethanol was added 0.10 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 2 h at room temperature, the catalyst was removed via filtration and the filtrate concentrated to give 0.056 g (91%) of the title compound as a white solid. MS Calcd.: 423; Found: 424 (M+H). Compounds of Examples 1133-1134, shown in the Table 15, were prepared in a manner similar to that described in Example 1132. Example 1135 3-(3-Benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5- phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine Step A (3-Benzylpyrrolidine-1-sulfonyl)acetonitrile (2) : To a 20 mL ether solution containing 1.34 g (8.31 mmol) of 3- benzylpyrrolidine cooled to -45 °C was added 0.61 g (4.4 mmol) of 2-cyanoethanesulfonyl chloride as a solution in 10 mL of ether. The reaction was allowed to warm to room temperature and was stirred for 24 h over which time an oil formed on the flask wall. The ether solution was poured away from the oil and filtered through a short plug of silica gel. The filtrate thus obtained was concentrated in vacuo to give a solid that was purified by flash chromatography eluting with 75% hexanes/AcOEt to give 1.25 g (44%) of the title compound as a wax. 1H NMR (CDC13) δ 1.73-1.83 (m, 1H) , 2.08-2.15 (m, 1H) , 2.57-2.67 (m, 1H) , 2.71-2.79 (m, 2H) , 3.21 (dd, J = 8.2, 9.7, Hz, 1H), 3.49-3.55 (m, 1H), 3.63 (dd, J = 7.0, 9.4 Hz, 1H), 3.69-3.74 (m, 1H), 3.95 (s, 2H), 7.16 (d, J = 7.4 Hz, 2H), 7.21-7.33 (m, 3H). Step B 2-(3-Benzylpyrrolidine-1-sulfonyl)-3-ethoxyacrylonitrile (3) : To a solution of 0.14 g (0.53 mmol) of 2 in 0.43 mL (2.6 mmol) of triethylorthoformate was added 0.25 mL (2.6 mmol) of acetic anhydride. The resulting solution was heated to reflux for 4 h before being concentrated to an oil. The crude oil thus obtained was purified by flash chromatography eluting with 75% hexanes/AcOEt to give 0.079 g (46%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H) , 1.67-1.77 (m, 1H) , 2.01-2.09 (m, 1H) , 2.53-2.62 (m, 1H) , 2.71 (d, J = 7.4 Hz, 2H) , 3.05 (dd, J = 8.4, 9.8 Hz, 1H) , 3.35-3.41 (m, 1H) , 3.48 (dd, J = 7.0, 9.5 Hz, 1H), 3.53-3.59 (m, 1H), 4.31 (q, J = 7.2 Hz, 2H) , 7.15-7.17 (m, 2H) , 7.19-7.23 (m, 1H) , 7.26-7.31 (m, 2H) , 7.76 (s, 1H). Step C 3-(3-Benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (4): A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 was treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated to reflux for 5 h. The reaction was concentrated in vacuo to give crude 4-(3-benzylpyrrolidine- 1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanol containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2- en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture was refluxed for three days then concentrated and purified by flash chromatography eluting with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1- sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5- a] pyrimidine that was found to be only 90% pure by HPLC analysis. This material was then dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 90 min at room temperature, the catalyst was removed via filtration and the filtrate concentrated to an oil. Purification by flash chromatography eluting with 75% hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a light yellow oil. 1H NMR (CDC13) δ 1.55-1.66 (m, 7H) , 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H) , 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H) , 2.90-2.97 (m, 1H) , 3.18-3.27 (m, 1H) , 3.31-3.42 (m, 2H) , 4.53-4.60 (m, 1H) , 5.71(s, 1H) , 7.11-7.14 (m, 2H) , 7.19-7.23 (m, 1H) , 7.26-7.40 (m, 7H) , 7.53 (s, 1H) . MS Calcd.: 450; Found: 451 (M+H). Example 1136 4,4-Dimethyl-8-[5-(1-methyl-1-phenyl-ethyl)- [l,3,4]oxadiazol-2-yl]-2-phenyl-l,2,3,4- tetrahydropyrrolo[1,2-a]pyrimidine Step A 2-Amino-1H-pyrrole-3-carboxylic acid ethyl ester (1) : Carbamimidoyl-acetic acid ethyl ester (3.357g, 25.8 mmol) was dissolved in AcOEt (20 mL) . Chloroacetaldehyde (50% solution in water, 1.8 mL, 28.7 mmol) was added rapidly at room temperature. The solution stirred for 2 minutes until a precipitant formed. The solution was then brought to 65 °C for 0.5 h. The reaction mixture was then cooled and flash chromatographed with AcOEt. Product containing fractions were concentrated to give the desired material as a green solid. 0.68 g obtained, 31% yield. 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J= 7.2 Hz, 3H), 4.24 (q, J= 7.0 Hz, 2H), 5.08 (brs, 2H) , 6.10 - 6.13 (m, 1H) , 6.25 (t, J = 3.12, 1 Hz), 8.60 (brs, 1H); MS Calcd.: 154; Found 155 (M+H). Step B 4,4-Dimethyl-2-phenyl-l,2,3,4-tetrahydro-pyrrolo[1,2- a]pyrimidine-8-carboxylic acid ethyl ester (2) : Compound 1 (0.68g, 4.41 mmol) was dissolved in DMF (5 mL) . NaH (60% in mineral oil, 0.19g, 4.7 mmol) was added at room temperature affording rapid gas evolution. The reaction stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1- one (0.50g, 3.15 mmol) was added. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH4 (1.19g) were added. The solution was brought to 60 °C for 0.5 h. and then cooled to room temperature. The solution was quenched with water, extracted with Et20 (3 times) , dried (Na2SO4) and concentrated. Flash chromatography (10% AcOEt) to give the desired product as a tan solid (0.60g, 63% yield). MS Calcd.: 298; Found 299 (M+H). Step C 4,4-Dimethyl-2-phenyl-l,2,3,4-tetrahydro-pyrrolo[1,2,- a]pyrimidine-8-carboxylic acid hydrazide (3) : Compound 2 (0.210g, was diluted with anhydrous hydrazine (5 mL) and heated to 100 °C for 3 days. The reaction was then cooled and diluted with water. The solution was extracted with AcOEt (3 times), dried (Na2SO4) and concentrated. The residue was flash chromatographed (10% MeOH/AcOEt) to give the desired material. 0.12g, 60% yield). 1H NMR(400 MHz, CDC13) δ 1.54 (s, 6H) , 1.99 - 2.13 (m, 2H), 3.89 (brs, 2H), 4.64 (dd, J= 3.5, 11.7 Hz, 1H), 6.02 (d, J= 3.9 Hz), 6.22 (d, J = 3.9 Hz, 1H), 6.55 (brs, 1H), 6.74 (brs, 1H), 7.31 - 7.46 (m, 5H). MS Calcd.: 284; Found 285 (M+H). Step D 4,4-Dimethyl-2-phenyl-l,2,3,4-tetrahydro-pyrrolo[1,2,- a]pyrimidine-8-carboxylic acid N-(2-methyl-2-phenyl- propionyl)-hydrazide (4) : Compound 3 (0.085g, 0.30 mmol) was dissolved in THF (2 mL). HBTU (0.136g, 0.36 mmol), α,α-dimethyl-phenylacetic acid (0.059g, 0.36 mmol), and DIEA (0.10 mL, 0.60 mmol) were added. The reaction stirred for 2 h. and was concentrated. Flash chromatography (50% AcOEt/hexanes) gave the desired product. 0.123g obtained (96% yield). 1H NMR (400 MHz, CDC13) δ 1.49 (s, 3H), 1.50 (s, 3H), 1.60 (s, 3H) , 1.61 (s, 3H) , 1.95 - 2.10 (m, 2H), 4.56 (dd, J = 3.1, 11.3 Hz, 1H), 6.13 (d, J= 3.5 Hz, 1H), 6.17 (d, 3.5 Hz, 1H), 6.65 (brs, 1H) , 7.22 - 7.43 (m, 10H), 7.81 (brs, 1H), 7.92 (brs, 1H) . MS Calcd.: 430; Found 431 (M+H). Step E 4,4-Dimethyl-8-[5-(1-methyl-1-phenyl-ethyl)- [1,3,4]oxadiazol-2-yl]-2-phenyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrimidine (5) : Compound 4 (0.060g, 0.14 mmol) was diluted in POC13 (3 mL) . The solution was heated to 75 °C for 3 h. The solution was cooled and carefully quenched with water. The solution was diluted with AcOEt and the mixture carefully neutralized with sat. NaHCO3. The organic layer was separated and the aqueous layer was extracted twice more with AcOEt portions. The combined organic layers were dried (Na2SO4) , concentrated, and flash chromatographed to give the desired product as a white solid. 0.016g obtained (28% yield). 1H NMR(400 MHz, CDCl3) δ 1.55 (s, 6H) , 1.80 (s, 6H) , 2.02 - 2.16 (m, 2H) , 4.68 (dd, J = 3.2, 11.6 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H), 6.30 (d, J= 3.2 Hz, 1H), 7.20 - 7.46 (m, 10H). MS Calcd.; 412; Found 413 (M+H). Example 1137 3-Methyl-2-phenyl-2,3-dihydro-1H-imidazo[1,2- b]pyrazole-7-carboxylic acid [1-ethyl-1-(4-trifluoromethyl- phenyl)-propyl]-amide Step A 5-Amino-1-(l-methyl-2-oxo-2-phenyl-ethyl)-1H-pyrazole-4- carboxylic acid ethyl ester (1) : 5-Amino-1H-pyrazole-4- carboxylic acid ethyl ester (7.35g, 47.3 mmol) was dissolved in 160 mL of DMF. Na2CO3 (5.02g, 47.3 mmol) was added followed by 2-bromopropiophenone (7.2 mL, 47.3 mmol). The reaction stirred at room temperature for 2 days. The solution was diluted with AcOEt and the organic layer was washed with sat. NaHCO3, brine, dried (MgSO4) , and concentrated. Flash chromatography (20-45% AcOEt/hexane) gave the desired product (1.58g, 12% yield). 1H NMR(400 MHz, CDC13) δ 1.3 (t, J = 7.0 Hz, 3H) , 1.7 (d, J = 7.4 Hz, 3H) , 4.2 (q, J == 7.0 Hz, 2H) , 5.4 (bs, 2H) , 5.9 (q, J = 7.0 Hz, 1H), 7.41 - 7.59 (m, 3H), 7.60 (s, 1H), 8.0 (d, J = 8.0 Hz, 2H) . Step B 5-Amino-1- (2-hydroxy-1-methyl-2-phenyl-ethyl) -1H-pyrazole- 4-carboxylic acid ethyl ester (2) :Compound 1 (0.7g, 2.43 mmol) was dissolved in 34 mL EtOH. NaBH4 (0.18g, 4.87 mmol) was added in one shot. The reaction stirred at room temperature for 0.5 h. The solution was quenched with sat. NH4Cl and extracted with CH2C12 (3 times) . The organic layer was washed with brine, dried (MgSO4) , concentrated to give a fluffy white solid 2 (0.69g, 98% yield). MS: Calcd.: 289; Found: 290 (M+H). Step C 3-Methyl-2--phenyl-2, 3-dihydro-1H-imidazo [1, 2-b] pyrazole-7- carobxylic acid ethyl ester (3) : Compound 2 (0.80g, 2.8 mmol) was dissolved in CH2C12. SOC12 (0.61 mL, 8.3 mmol) was added dropwise. After 90 minutes, the solution was concentrated to give a yellow solid. After pumping on high vacuum for 5 minutes, the solid was dissolved in CHC13. Et3N (2.7 mL, 19.5 mmol) was added dropwise and the reaction mixture stirred for 1 hour. The reaction was quenched with water and diluted with AcOEt. The solution was washed with sat. NH4Cl, sat. NaHCO3, brine, and then dried (MgSO4) . Flash chromatography (20% AcOEt/hexane) gave both the syn (0.10g, 14%) and anti (0.62g, 82%) isomers 3. Anti isomer 1H NMR(400 MHz, CDC13) δ 1.23 (t, J = 7.0 Hz, 3H), 1.80 (d, J = 6.6 Hz, 3H) , 4.10 - 4.20 (m, 2H), 4.25 - 4.35 (m, 1H), 4.38 (brs, 1H) , 5.10 (d, J = 9.8 Hz, 1H), 7.17 - 7.25 (m, 5H) , 7.59 (s, 1H) . Syn isomer 1H NMR(400 MHz, CDC13) δ 1.28 (d, J= 7.0 Hz, 3H), 7.38 (t, J = 7.4 Hz, 3H) , 4.25 - 4.35 (m, 2H) , 7.43 - 7.52 (m, 1H) , 5.17 (brs, 1H) , 5.23 (d, J= 9.8 Hz, 1H) , 7.37 - 7.45 (m, 5H) . Step D and E 3-Methyl-2-phenyl-2, 3-dihydro-1H-imidazo [1, 2-b] pyrazole-7- carboxylic acid [1-ethyl-1-(4-trifluoromethyl-phenyl)- propyl]-amide (5) : Compound 3 (0.085g, 0.3 mmol) was dissolved in EtOH (3 mL). KOH (6M in water, 0.9 mL, 1.78 mmol) was added. The reaction stirred at 60 °C for 3 h. The solution was cooled, diluted with AcOEt (10 mL) and water (10 mL) and shaken vigorously. The Aqueous layer was separated and acidified to pH = 3. This acidic layer was then extracted with AcOEt (3 times). The combined AcOEt layers were washed with brine, dried (Na2SO4) and concentrated. The residue was then dissolved in NMP (1 mL) and 1-ethyl-1-(4- trifluoromethyl-phenyl)-propylamine (0.087g, 0.37 mmol), HATU (0.14g, 0.37 mmol), and DIEA (0.14 mL, 0.78 mmol) were added. The reaction was heated to 80 °C for 2 days. The solution Was then cooled, washed with water, dried (MgSO4) , and concentrated. Flash chromatography (20% AcOEt/hexanes) gave 0.017g (12% yield) of amide 5. 1H NMR (400 MHz, CDC13) δ 0.79 - 0.83 (m, 6H) , 1.26 (d, J = 7.0 Hz, 3 H), 1.99 - 2.05 (m, 2H) , 2.23 - 2.31 (m, 2H) , 4.44 - 4.48 (m, 1H) , 5.19 (brs, 1H) , 5.24 (d, J = 10 Hz, 1H), 5.66 (brs, 1H) , 7.37 - 7.63 (m, 9H) . MS Calcd.: 456; Found: 457 (M+H). Example 1138 8-Methyl-5-phenyl-5, 6, 7, 8-tetrahydro-4H- pyrazolo[l,5,a][1,3]diazepine-3-carboxylic acid (1-methyl- 1-phenyl-ethyl)-amide Step A 5-Amino-1-[4-tert-butyl-dimethyl-silanyloxy]-1-methyl-4- phenyl-butyl]-1H-pyrazole-4-carboxylic acid ethyl ester (1) : 5-Amino-lH-pyrazole-4-carboxylic acid ethyl ester (1.60g, 10.3 mmol) was dissolved in 10 mL of DMF. The solution was cooled to 0 °C and NaH (60% in mineral oil, 0.82g, 20.6 mmol) was added in one portion. The reaction warmed to room temperature after H2 evolution ceased. The reaction stirred for 0.5 h till a bright orange color persisted. The reaction was again brought to 0 °C and methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-4-phenyl- butyl ester (3.49g, 9.38 mmol) was then added as a solution in 6 mL DMF. The reaction warmed to room temperature and stirred for 2.5 days. The solution was quenched with water and diluted with AcOEt. The organic layer was separated and the aqueous layer was extracted twice more with AcOEt. The combined organic layers were dried (MgSO4) , concentrated and flash chromatographed (15% AcOEt/hexanes) to give 0.530g (13% yield) of the desired product as an oil. 1H NMR (400 MHz, CDC13) δ 0.16 (s, 3H) , 0.17 (s, 3H) , 1.04 (d, J = 10 Hz, 9H), 1.48 - 1.52 (m, 3H) , 1.55 (d, J = 6.4 Hz, 3H) , 1.60 (d, J = 6.8 Hz, 3H - other diastereomer) , 1.62 - 1.75 (m, 2H) , 1.97 - 2.07 (m, 2H) , 2.10 - 2.20 (m, 2H - other diastereomer), 4.02 - 4.07 (m, 1H), 4.21 - 4.29 (m, 1H - other diastereomer), 4.40 - 4.43 (m, 2H) , 4.79 - 4.86 (m, 1H), 5.04 (brs, 1H), 5.25 (brs, 1H - other diastereomer), 7.36 - 7.47 (m, 5H) , 7.79 (s, 1H) ; MS Calcd.: 431; Found 432 (M+H). Step B and C 8-Methyl-5-phenyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5,a][1,3]diazepine-3-carboxylic acid ethyl ester (3) : Compound 1 (2.0g, 4.6 mmol) was dissolved in 9 mL THF. TBAF (1M in THF, 13.9 mL, 13.9 mmol) was added at room temperature. The reaction stirred for 0.5 h. The reaction was diluted with ether and washed with brine and water. The ether layer was dried (MgSO4) and concentrated to give the crude alcohol product 2. MS Cald.: 317; Found 318 (M+H). Alcohol 2 was taken up in CH2C12 (80 mL) . SOC12 (1.7 mL, 23.4 mmol) was added. After 1 h, the solution was concentrated and re-dissolved in 80 mL DMF. CsCO3 (12.6g, 39 mmol) was added. After 3 h, additional CsCO3 (12.6g, 39 mmol) was added. The reaction ran 1.5 days. The reaction was quenched with water and diluted with AcOEt. After separation of the organic layer, the aqueous layer was washed twice with AcOEt. The combined organic layers were dried (MgSO4) , concentrated, and flash chromatographed to give 0.35g (26% yield) of a mixture of cis and trans isomers which were readily separated. Anti isomer - 1H NMR(400 MHz, CDC13) δ 1.24 (t, J = 7.0 Hz, 3H), 1.40 (d, J= 7.0 Hz, 3H), 1.93 - 2.34 (m, 4H), 4.05 (d, 1H) , 4.09 - 4.23 (m, 2H) , 4.79 - 4.85 (m, 1H) , 6.40 (bs, 1H) , 7.27 - 7.44 (m, 5H) , 7.64 (s, 1H) . MS Calcd. : 299; Found 300 (M+H). Syn isomer - 1H NMR(400 MHz, CDC13) δ 1.24 (t, J= 7.0 Hz, 3H), 1.68 (d, J = 7.0 Hz, 3H), 1.70 - 1.80 (m, 1H) , 2.00 - 2.23 (m, 3H) , 4.17 - 4.30 (m, 4H) , 6.43 (brs, 1H) , 7.22 - 7.40 (m, 5H) , 7.63 (s, 1H) . MS Calcd.: 299; Found 300 (M+H). Step D 8-Methyl-5-phenyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5,a] [1,3]diazepine-3-carboxylic acid (1-methyl- 1-phenyl-ethyl)-amide (4) : Compound 3 (0.074g, 0.25 mmol) was diluted with EtOH (0.8 mL). KOH (6M in water, 0.23 mL) was added and the reaction stirred at 60 °C for 3.5 h. The solution was cooled and diluted with AcOEt and water. After vigorous shaking, the aqueous layer was removed and acidified to pH = 3. The aqueous layer was then extracted with AcOEt(3 times). The organic layers were combined, dried (MgSO4) , and concentrated to give 0.070g of desired carboxylic acid. MS Calcd.: 271; Found 272 (M+H). This acid residue (0.070g, 0.26 mmol) was dissolved in NMP (2 mL). HATU (0.12g, 0.31 mmol) and cumylamine (0.042g, 0.31 mmol) were added followed by DIEA (0.090 mL, 0.52 mmol) . The reaction stirred at 90 °C for 2 h. The solution was cooled to room temperature and diluted with water. The solution was extracted from AcOEt (3 times), dried (MgSO4) , and concentrated. Flash chromatography (30% AcOEt/hexanes) gave the desired product. 0.065g obtained (65% yield). 1H NMR (400 MHz, CDC13) 8 1.65 (d, J = 6.6 Hz, 3H), 1.71 (s, 3H), 1.75 (s, 3H), 2.00 - 2.21 (m, 4H), 4.21 - 4.29 (m, 2H), 5.80 (brs, 1H), 7.02 (brs, 1H) , 7.18 - 7.47 (m, 10H), 7.49 (s, 1H); MS Calcd.: 388; Found 389 (M+H). Example 1142 (1R,4S)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl-5-(2- fluorophenyl)-2,7,7-trimethyl-4,5,6,7- 1) To a solution of 1 (0.4g, 1.32 mmol) and DMF (1 drop) in toluene (4 mL) was added SOCl2 (0.31, 2.64 mmol) at room temperature. After stirring at 60°C 1 h, the solvent was concentrated in vacuo. The residue was diluted with toluene, and borneol (0.3g, 1.98 mmol) and Et3N (0.3g, 2.90 mmol) was added there to. After stirring at 60 ° C 1 h, the reaction mixture was washed with 1N HCl and brine, dried over MgSO4, and concentrated in vacuo. Flash chromatography to give the desired product as oil. To a stirred solution of the oil obtained (90 mg, 0.2 mmol) in AcOEt (2 mL) was added 4M HCl-AcOEt (0.5 mL, 2.0 mmol) at room temperature. The precipitate was collected by filtration to give 2 as HC1 salt. MS Calcd.: 440; Found 441 (M+H). Compounds of Examples 1139-1141 shown in the Table 16, were prepared in a manner similar to that described in Example 1142. Table 16 Compounds of Examples 868 - 923 and 1143-1146 shown in the table 6, were prepared from compound of Examples 35 in a manner similar to that described in followed reference 1~6. 1) Poulan R F., Tartar A L., Deprez B p., Tetrahedron Lett. 2001, 42, 1495. 2) Rigo B., Cauliesz P., Fasseur D., Couturier D.,Synthetic Communications 1986, 16, 1665. 3) Carlsen H J., Jorgensen K B., J. Heterocyclic Chem., 1994, 3.1, 805. 4) Kiryanov A A., Sampson P., Seed J., J. Org. Chem., 2001, 66, 7925. 5) Kelly T R., Lang F R., Tetrahedron Lett., 1995, 36, 5319. 6) Walia J S., Walia A S., Lankin D C., Petterson R C, Singh J., J. Heterocyclic Chem., 1985, 22, 1117. Strategy for cloning of the cDNAs encoding the human CaR Strategy for cloning of the cDNAs encoding the human CaR is shown below. To amplify the cDNA encoding the N- terminal moiety of the human CaR, the synthetic DNA primers, Cal-U : 5'-AGAGTCGACGCCACCATGGCATTTTATAGCTGCTGCTGG-3' and Cal-L : 5'-AAATGAGCTCTCGGTTGGTGGCCTTGAC-3' , were constructed. In this case, SalI site was added at the 5' end of amplified cDNA. To amplify the cDNA encoding the C-terminal moiety of the human CaR, the synthetic DNA primers, Ca2-U : 5'-AAACGAGCTCTCCTACCTCCTCCTCTTC-3' and Ca2-L : 5'- TCTGCGGCCGCTCCCTAGCCCAGTCTTCTCCTTCC-3', were constructed. In this case, NotI site was added at the 3' end of amplified cDNA. PCR was carried out by Hot Start method. The reaction solution of the upper phase was added of 1 pg of the human kidney-derived cDNA (TOYOBO), 0.3 mM dNTPs and 2.5 unit LA Taq DNA polymerase (Takara shuzo co.) and filled up to 30 µl with water and buffer attached to the enzyme. To the reaction solution of the lower phase was added 12.5 uM each of the synthetic primers and 0.5 mM dNTPs and filled up to 20 µl with water and buffer attached to the enzyme. The reaction solution of the upper phase was added on the lower phase covered with an AmpliWax PCR Gem100 (Takara Shuzo Co.). The samples were subject to PCR amplification using a Thermal Cycler (Perkin-Elmer Co.). The amplified cDNAs were confirmed by agarose gel electrophoresis. Experiment 2 Preparation of CaR-expression CHO cells The PCR products obtained in Experiment 1 were separated by agarose gel electrophoresis. The PCR products were excised and purified from the gel and subcloned into pT7Blue-T vector (Takara Shuzo Co.). The cDNA fragment encoding the N-terminal moiety of the human CaR was released from the subcloned pT7Blue-T vector treated with SalI and SacI. The cDNA fragment encoding the C-terminal moiety of the human CaR was released from the subcloned pT7Blue-T vector treated with SacI and NotI. Using DNA Ligation kit (Takara Shuzo Co.), these fragments were inserted between the site of SalI- and NotI- in the digested pMSRαneo vector. Thus, the pMSRαneo-CaR for animal cell expression was constructed. Ten ug of the pMSRαneo-CaR was added to the solution containing 8xl06 CH0-K1 cells, and transfection was carried out using Gene Pulser (0.4cm cuvette, 0.25kV, 960mF) (Bio- Rad Laboratories). The cells were cultured in HamF12 containing 10% fetal calf serum for one day. After passage, the cells were cultured in HamF12 containing 10% fetal and 500ug/ml Genetisine. The cells were seeded on 96-well plate in 1x103 cells/well and transformants, CaR-expressing CHO cells, were selected in the selection medium. Experiment 3 Selection of the CaR-expressing CHO cell line by- calcium mobilization assay A method for calcium mobilization assay is shown below. The CaR-expressing CHO cells were seeded on a 96-well white plate in 2xl04 cells/well, followed by cultivation for 48 hours. After washing the cells with Phosphate-Buffered Saline, 100 µl of buffer solution (120 mM NaCl, 22 mM NaHCO3, 6 mM KCl, 0.2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, 5 mM HEPES (pH 7.4)) containing 5 uM FuraPE3AM (Texas Fluorescence Laboratories) was added to the wells and kept at 37 °C for 1 hour. The cells were washed twice with Phosphate-Buffered Saline. After adding 180 ul of the reaction buffer solution (130 mM NaCl, 5.4 mM KCl, 0.2 mM CaCl2, 0.9 mM MgCl2, 10 mM glucose, 20 mM HEPES (pH 7.4)) to the wells, 20 ul of 60 mM CaCl2 was added and intracellular calcium concentration were measured with a fluorometric imaging plate reader (FDSS 2000, Hamamatsu photonics). One clone increasing intracellular calcium concentration was selected and used for the following experiment. Experiment 4 GTPγS binding assay Preparation of membrane fraction is described bellow. The human CaR-expressing CHO cells were inoculated to a F500 flask in 1.8xl05 cells/flask followed by cultivation for 2 days. The cells were scraped with 10ml of Phosphate- Buffered Saline containing 0.02% EDTA. After centrifugation (2000 rpm, 10 min) of the cells, the cell pellet was resuspended into 12 ml of homogenate buffer solution (10 mM NaHCO3, 1 mM EDTA, lx Protease inhibitor cocktail (pH 7.4)) and homogenized by Polytron™ (20000 rpm, 1 min) . The cell debris was removed by centrifugation (2000 rpm, 10 min), and then the CaR-expressing cell membrane fraction was collected by ultracentrifugation (Beckman 70 Ti type rotor, 30000 rpm, 1 hour). The GTPyS binding activity was measured as follows. Twenty ug of the CaR-expressing cell membrane was incubated with test compounds for 10min. The assays were carried out at room temperature for an hour in a reaction solution mixture containing 20 mM HEPES (pH.7.4), 100 mM NaCl, 1 mM MgCl2, 167 µg/ml DTT, 5 µM guanosine 5'-diphosphate, 0.4 nM [35S]-guanosine 5'-(γ-thio) triphosphate ( [35S]-GTPγS) and 6 mM CaCl2. The mixture was filtered through a GF/C filter. After washing fourth with 300 µl of Phosphate-Buffered Saline, the amount of [35S]-GTPYS bound to the filter was measured using a Top-count scintillation counter. Effects of test compounds on [35S]-GTPYS binding were expressed in percentage terms. This was calculated from the equation [100x(t'-b)]/(t-b) where t', t and b are values of [35S]-GTPYS binding (dpm) , t' in the presence of 6mM calcium and the test compound, t in the presence of 6mM calcium only and b in the absence of both 6mM calcium and the test compound. The antagonist dose-dependently decreased [35S]-GTPYS binding in membrane preparation. The agonist dose- dependently increased [35S]-GTPΓS binding in membrane preparation. The results are shown in Table 7. INDUSTRIAL APPLICABILITY Compound (I), (II), (III) or (IIIa) of the present invention has an excellent Ca receptor modulating activity and enhances the secretion of PTH, and therefore, useful as drugs for treating bone diseases, kidney-acting drugs, central nervous system and endocrine-acting drugs, digestive system-acting drugs, and the like. WE CLAIM: 1. A compound of the formula (IIIa): wherein R1a is (1) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or (2) a group of the formula: -CO-Z2c (wherein Z2c is (i) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (ii) -NR20c(CR21cR22cR23c) (wherein (a) R20c is H or an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group; and R21c is 1) an optionally substituted 5- to 7-membered aromatic or non- aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be fused with an optionally substituted benzene ring, or 2) an optionally substituted C6-10 aryl group which may be fused with an optionally substituted 5- to 7-membered aromatic heterocyclic ring having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; and R22c and R are the same or different and are an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group or an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or R22c and R23cmay be combined to form a C3-7 carbon ring, or (b) R20c is H or an optionally substituted hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group; and R21c, R22c and R23c are the same or different and are an optionally substituted C1-8 aliphatic hydrocarbon group, provided that the sum total of the number of carbon atoms is 7 or more), (iii) -NR20cR25c (wherein R20cis as defined above and R25cis an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10 aryloxy-C2-4 alkyl, C6-10 atylamino-C2-4 alkyl, C7-14 aralkylamino- C2-4 alkyl, 5- to 7-membered heterocyclic ring (having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom)-C2-4 alkyl or 5- to 7-membered heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), (iv) a substituted 5- to 7-membered cyclic amino group, or (v) -OR24c (wherein R24c is (a) an optionally substituted C7-14 aralkyl group, (b) an optionally substituted C3-7 alicyclic hydrocarbon group, (c) an optionally substituted C7-24 aliphatic hydrocarbon group, or (d) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; wherein said substituents for R1a, Z2c, R20c, R21c, R22c, R23c, R24c and R25c are 1 to 3 substituents selected from the group consisting of 1) C1-6 alkyl, 2) C2-6 alkenyl, 3) C2-6 alkynyl, 4) C3-7 cycloalkyl, 5) C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl, amino, N-(C1-6 alkyl)amino, N,N-di-(C1-6 alkyl)amino, amidino, carbamoyl, N-(C1-6 alkyl)carbamoyl, N,N-di-(C1-6 alkyl)carbamoyl, sulfamoyl, N-(C1-6 alkyl)sulfamoyl, N,N-di-(C1-6 alkyl)sulfamoyl, carboxyl, C2-7 alkoxycarbonyl, hydroxyl, C1-6 alkoxy, mercapto, C1-6 alkylthio, sulfo, cyano, azido, halogen, nitro, nitroso, phosphono, C1-6 alkoxyphosphoryl, di-(C1-6 alkoxy)phosphoryl and C1-6 alkyl substituted with phosphono, C1-6 alkoxyphosphoryl and di-(C1-6 alkoxy)phosphoryl (hereinafter the group of 5) is referred to as group "C"), 6) aromatic heterocyclic group selected from (a) aromatic 5- or 6-membered heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (b) fused bicyclic heterocyclic group formed by condensation of an aromatic 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom with benzene ring or an aromatic 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom and (c) fused tricyclic heterocyclic group formed by condensation of [1] an aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, [2] benzene ring, and [3] an aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom or benzene ring, 7) heterocyclic-oxy group formed by combining each of the above aromatic heterocyclic groups (a), (b) and (c) with oxy group, 8) non-aromatic 4- or 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, 9) C7-14 aralkyl which may be substituted with 1 to 3 substituents selected from the group "C", 10) amino group, 11) N-mono-substituted amino selected from N-(C1-6 alkyl)amino, N-(C2-6 alkenyl)amino, N-(C3-7 cycloalkyl)amino group and N-(C6-10 aryl)amino which may be substituted with 1 to 3 substituents selected from the group "C", 12) amino substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkenyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 13) amidino, 14) acyl selected from C2-8 alkanoyl, C3-8 alkenoyl, C3-7 cycloalkyl-carbonyl, C3-7 cycloalkenyl-carbonyl, C6-10 aryl-carbonyl which may be substituted with 1 to 3 substituents selected from the group "C", and heterocyclic-carbonyl formed by binding of an aromatic or non-aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom with carbonyl, 15) carbamoyl, 16) mono-substituted carbamoyl group selected from N-(C1-6 alkyl)carbamoyl, N-(C2-6 alkenyl)carbamoyl, N-(C3-7 cycloalkyl)carbamoyl and N-(C6-10 aryl)carbamoyl which may be substituted with 1 to 3 substituents selected from the group "C", 17) carbamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3- 7 cycloalkyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 18) sulfamoyl, 19) N-mono-substituted sulfamoyl selected from N-(C1-6 alkyl)sulfamoyl, N-(C2-6 alkenyl)sulfamoyl, N-(C3-7 cycloalkyl)sulfamoyl and N-(C6-10 aryl)sulfamoyl which may be substituted with 1 to 3 substituents selected from the group "C", 20) sulfamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3- 7 cycloalkyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group "C", 21) carboxyl, 22) C1-6 alkoxy-carbonyl, 23) hydroxyl, 24) C1-6 alkoxy, 25) C2-10 alkenyloxy, 26) C3-7 cycloalkyloxy, 27) C6-10 aryloxy which may be substituted with 1 to 3 substituents selected from the group "C", 28) C7-14 aralkyloxy which may be substituted with 1 to 3 substituents selected from the group "C", 29) mercapto, 30)C1-6alkylthio, 31) C7-14 aralkylthio which may be substituted with 1 to 3 substituents selected from the group "C", 32) C6-10 arylthio which may be substituted with 1 to 3 substituents selected from the group "C", 33) C1-6 alkylsulfinyl, 34) C7-14 aralkylsulfinyl which may be substituted with 1 to 3 substituents selected from the group "C", 35) C6-10 arylsulfinyl which may be substituted with 1 to 3 substituents selected from the group "C", 36) C1-6 alkylsulfonyl, 38) C7-14 aralkylsulfonyl which may be substituted with 1 to 3 substituents selected from the group "C", 39) C6-10 arylsulfonyl which may be substituted with 1 to 3 substituents selected from the group "C", 40) sulfo, 41) cyano, 42) azido, 43) halogen, 44) nitro, 45) nitroso, 46) phosphono, 47) C1-6 alkoxy-phosphoryl 48) di-C1-6 alkoxy-phosphoryl, 49) C1-6 alkyl substituted with phosphono, C1-6 alkoxyphosphoryl or di-(C1-6 alkoxy)phosphoryl 50) C1-6 alkyl substituted with 1 to 4 halogen atoms 51) C1-6 alkoxy substituted with 1 to 4 halogen atoms and 52) C1-6 alkylenedioxy (hereinafter the group of above 1) to 52) is referred to as group "B"); R3 is H, a C1-6 alkyl group or a C7-14 aralkyl group; R6 is H, a C1-6 alkyl group, a C1-6 alkylthio group or a C1-6 alkoxy group which may be substituted with hydroxyl group; Ar is (1) a C6-10 aryl group, (2) a 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, or (3) a C3-7 saturated or unsaturated alicyclic hydrocarbon group, each of which may be substituted with 1 to 3 substituents selected from the group "B"; one of R9 and R10 is a hydrogen atom or C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group "B" and the other is (1) a hydrocarbon group selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group, each of which may be substituted with 1 to 3 substituents selected from the group "B" or (2) a 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be substituted with 1 to 3 substituents selected from the group "B", or R9 and R10 may be combined to form a C5.7 carbon ring, provided that at least one of R9and R10 is C1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the group "B" and the other is other than a phenyl group which may be substituted with 1 to 3 substituents selected from the group "B"; or a salt thereof. 2. The compound as claimed in claim 1 comprises N-(l-ethyl-1-(4-methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-7,7-dimethyl-4,5,6,7- tefrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(l-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(l-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(1-ethyl-1-(4-ethylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyra2olo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, 5-(2-chlorophenyl)-N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(1-(4-(dimethylamino)phenyl)-1-ethylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl- 4,5,6,74etrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof, N-(1,1-diethylbutyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidine-3-carboxamide or a salt thereof, N-(1-ethyl-1-phenylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof, 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3,4-oxadiazol-2-yl)-2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof, 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-l,3,4-thiadiazol-2-yl)-2,7,7-trimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrirnidine or a salt thereof, 3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidmyl)carbonyl)-7,7-dirnethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof, 3-((2,2-diethyl-4-methoxy-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof, or 3-((2,2-diethyl-4-fluoro-1-pyirolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof. 3. N-(1-ethyl-1-(4-methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 4. N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-7,7-dimethyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 5. N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 6. N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 7. N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 8. N-(1-ethyl-1-(4-ethylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 9. 5-(2-chlorophenyl)-N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrirnidine-3-carboxamide or a salt thereof. 10. N-(1-(4-(dimethylamino)phenyl)-1-ethylpropyl)-5-(2-fluorophenyl)-2,7,7- trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 11. N-(1, 1-diethylbutyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof. 12. N-(1-ethyl-1-phenylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxarnide or a salt thereof. 13. 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-l,3,4-oxadiazol-2-yl)-2,7,7- trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof. 14. 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-l,3,4-thiadiazol-2-yl)-2,7,7- trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof. 15. 3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5- phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof. 16. 3-((2,2-diethyl-4-methoxy-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof. 17. 3-((2,2-diethyl-4-fluoro-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof. 18. The compound according to claim 2, which is an optically active compound. 19. A pharmaceutical composition which comprises the compound according to claim 1. 20. A composition for modulating calcium receptor which comprises a compound of claim 1. 21. The composition according to claim 20, which is a calcium receptor antagonist. 22. The composition according to claim 20, which is an agent for preventing or treating diseases caused by abnormality of calcium concentration in a living body or a calcium receptor. 23. The composition according to claim 20, which is an agent for preventing or treating bone diseases. 24. The composition according to claim 20, which is an agent for preventing or treating osteoporosis or fracture. There is provided a calcium receptor modulator comprising a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7- membered ring; ring B is an optionally substituted 5- to 7- membered heterocyclic ring; X1 is CR1, CR1R2, N or NR13; X2 is N or NR3; Y is C, CR4 or N, Z is CR5, CR5R6, N or NR7; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and is a single bond or a double bond; R1, R2, R3, R4, R5, R6, R7 and R13 are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): wherein ring A is an optionally substituted 5- to 7- membered ring; Q is C, CR5 or N; R8, R9, R10, R11 and R12 are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also specify X1, R3, R1, Y and X3 in formula (II) and (III) as before.

Full Text

DESCRIPTION
CALCIUM RECEPTOR MODULATING COMPOUND AND USE THEREOF
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to heterocyclic
compounds having calcium-sensing receptor (CaSR,
hereinafter simply referred to as Ca receptor) modulating
(agonistic or antagonistic) activity, pharmaceutical
compositions containing them and intermediate compounds
useful for synthesizing them.
Background Art
Calcium ion (hereinafter simply referred to as Ca)
plays an essential role to maintain and modulate functions
of various cells such as endocrine and exocrine cells, etc.,
in addition to nerve and muscle. For this reason, the
blood Ca level is strictly maintained in a narrow range.
Parathyroid hormone (PTH) plays a central role in
maintaining this blood Ca level. Therefore, secretion of
PTH from parathyroid gland responds sharply to change in
the blood Ca level and is must be modulated according to
this. In fact, when the blood Ca level is changed, the
blood PTH level is rapidly changed in response to this.

The possibility of a mechanism by which the extracellular
Ca concentration is sensed by parathyroid gland cells and
the information transmitted into cells has been pointed out
early by Brown et al. In 1993, they succeeded in the
cloning and characterization of a Ca-sensing receptor
(CaSR; hereinafter, simply referred to as Ca receptor) from
bovine parathyroid (Nature, 366, 575-580(1993)).
The Ca receptor is composed of a large terminal
extracellular region spanning 600 amino acids at the N-
terminal, having seven transmembrane spanning domains like
other G protein coupled receptors, and an intracellular
region consisting of 200 or less amino acids at the caboxyl
C-terminal.
It is considered that, when the extracellular Ca
concentration is increased, phospholipase (PL)-C is
activated, leading to increase in the intracellular Ca
concentration and inhibition of PTH secretion due to
increase in inositol triphosphate (IP3) . Since when a high
value of the extracellular Ca concentration is maintained,
the intracellular Ca concentration is thereafter increased
continuously, it is considered that influx of Ca from the
outside of a cell is also promoted. PL-A2 and D are
activated due to increase in extracellular Ca, but there is
a possibility that these are via protein kinase (PK)-C and
the like which are activated at the same time via Ca

receptor. The Ca receptor also inhibits adenylyl cyclase
via Gi protein or via arachidonic acid production due to
activation of PL-A2 and decreases intracellular cyclic AMP
(Bone, 20, 303-309 (1997)).
Ca receptor mRNA is expressed in many tissues, and the
expression amount is high, in parathyroid gland, thyroid
gland C cell, medulla and cortex thick ascending limb (MTAL
and CTAL) of kidney uriniferous tubule, intramedullary
collecting tubule (IMCD) and encephalic subfornical organ
(SFO) and hippocampus (Bone, 20, 303-309 (1997)). In
addition, expression is recognized in many tissues such as
encephalic hypothalamus, cerebellum and olfactory nucleus,
regions other than TAL of renal uriniferous tubule, lung,
stomach, pancreas, intestine and skin. Since the Ca
receptor is present in various tissues, its physiological
function has yet to be fully understood. However, it is
expected that the Ca receptor modulating (agonistic or
antagonistic) drug would provide for a novel treatment of
various disease states which include the following:
1. Drugs for Treating Bone Diseases
Since the anabolic activity is manifested by
intermittent administration of PTH, Ca receptor modulating
drugs which are considered to be able to regulate secretion
of PTH are promising as a drug for treating osteoporosis.
In addition, Ca receptor modulating drugs which are

selectable for thyroid gland C cell may be also effective
for treating osteoporosis by stimulation of calcitonin
secretion. Whether the same Ca receptor as that of
parathyroid gland is present in osteoblast, osteoclast and
bone cell or not is disputable. However, some Ca-sensing
mechanism is assuredly present therein and, therefore,
drugs which directly act on them can be expected as a drug
for treating bone diseases.
2. Kidney-Acting Drugs
Handling of water and mineral in kidney is not only
based on the results of function as a target organ for
hormones, such as PTH, vitamin D etc., but also the Ca
receptor in kidney is presumed to function in a response to
the Ca concentration and the magnesium ion concentration in
the extracellular fluid (Kidney Int, 50, 2129-2139 (1996)).
Further, it is also considered that Ca receptor modulating
drugs may modulate the blood amount in kidney, the amount
of glomerulus filtration, renin secretion and activation of
vitamin D in addition to control of influx and efflux of
water and mineral.
3. Central Nervous System and Endocrine-Acting Drugs
Ca receptor is present in almost all areas in the
central nervous system, and is remarkably expressed, in
particular, in the hippocampus, cerebellum and subfornical
organ (Brain Res, 744. 47-56 (1997)). Although the details

of the function are still unclear, the term of Ca receptor
expression after birth in the hippocampus is consistent
with the term of acquisition of LTP (Long Tightening
Phenomenon) (Develop Brain Res, 100, 13-21 (1997)) and,
therefore, the relationship with memory and learning can be
presumed. Therefore, Ca receptor modulating drugs which
are high in brain-blood barrier permeability and selective
for the central nerve system may be utilized for treating
Alzheimer's disease. In addition, since dry mouth occurs
in hypercalcemic patient, Ca receptor modulating drugs may
control them. The presence of Ca receptor in mouse
pituitary gland cells which secreteACTH has been reported
(Mol Endocrinol, 10, 555-565 (1996)). It is also
considered that Ca receptor modulating drugs can be applied
to Sheehann's syndrome and hypopituitarism or
hyperpituitarism.
4. Digestive System-Acting Drugs
It is considered that a Ca receptor is present in the
Auerbach nerve plexus of the digestive tract and controls
intestinal tract motion. Constipation is known in
hypercalcemic patients and stimulation of digestive tract
motion is known in hypocalcemic patients in clinical tests.
The existence of a Ca receptor in the gastrin secreting
cell (G cell) of the stomach has been reported (J. Clin
Invest, 99, 2328-2333 (1997)), and intestinal tract

absorption, constipation, diarrhea, defecation and
secretion of acid in the stomach may be controlled by drugs
which act on a Ca receptor in the digestive tract. Further,
it has been found that a Ca receptor is present in human
colon cancer cell strains and it controls c-myc expression
and proliferation (Biochem Biophys Res Commum, 232, 80-83
(1997)), this is better consistent with the fact that the
Ca uptake and sideration of colon and rectum cancers
exhibit the negative correlation and, therefore, Ca
receptor regulating drugs can be expected also as a drug
for preventing and treating such cancers.
Various heterocyclic compounds have been disclosed in
the prior art. For example, WO 01/53266 discloses a
compound of the formula:

where in R, R1 and R2 are independently H, hydroxyl, etc.
This compound has a phosphoinositide 3-kinase inhibitory
activity and is useful for treating coronary obstruction,
etc. Indian J. Chem., Sect. B (1993), 32B(5), 586-9
discloses the synthesis of a compound of the formula:

wherein R is hydrogen, chlorine, methyl or methoxy.
However, no utility is disclosed. U.S. Patent 4,746,656
(JP 63-33380 A) discloses a compound of the formula:

wherein R1 is aryl or heterocyclic group, R2 is aryl, etc.,
R3 and R4 are independently H, alkyl, etc. This compound
is a Ca channel blocker.
EP 217142 discloses a compound of the formula:

wherein R is hydrogen, alkyl, etc., R1 is hydrogen, nitro,
cyano, etc., R2 is phenyl, cycloalkyl, etc., R3 is hydrogen,

acyl etc., and R8is carboxyl, carbamoyl, etc. This
compound is also a Ca channel blocker.
However, a heterocyclic compound having Ca receptor
modulating activity is not found in the prior art.
OBJECTS OF THE INVENTION
One object of the present invention is to provide
compounds having Ca receptor modulating activity including
novel compounds.
Another object of the present invention is to provide
pharmaceutical compositions containing the compounds of the
present invention.
These objects as well as other objects and advantages
of the present invention will become apparent to those
skilled in the art from the following description.
SUMMARY OF THE INVENTION
The present inventors have intensively investigated
compounds having Ca receptor modulating activity. As a
result, it has been found that compounds represented by
formula (I) as shown hereinafter have Ca receptor
modulating activity useful for medicine and, among them,
compounds represented by the formulas (II), (III) and
(IIIa) as shown hereinafter are novel compounds.
According to the present invention, there is provided:

1. A compound of the formula (II):

wherein ring A is an optionally substituted 5- to 7-
membered ring;
Q is C, CR5 (wherein R5 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -
SO2-, and Z2 is an optionally substituted hydrocarbon group,
an optionally substituted heterocyclic group, an optionally
substituted hydroxyl group, or an optionally substituted
amino group)), or N;
X1 is CR1 (wherein R1 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above) ) , CR1R2 (wherein R1 is as defined above, and R2 is H,
or an optionally substituted hydrocarbon group), N, or NR13

(wherein R13 is H, an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- and Z2 are as defined above));
R3 is H, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted
heterocyclic group, or a group of the formula: -Z1-Z2
(wherein -Z1- and Z2 are as defined above);
Y is C, CR4 (wherein R4 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above)), or N;
Ar is an optionally substituted cyclic group;
R9 and R10 are the same or different and are H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group, cyano group,
a halogen atom, an optionally substituted heterocyclic
group, or a group of the formula: -Z1-Z2 (wherein -Z1- and
Z2 are as defined above) ; and R11 and R12 are the same or

different and are H, an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-,
and Z2 is as defined above); or R9 and R10, or R11 and R12
may be combined to form an oxo group, methylene group or a
ring; or R10 and R11 may be combined to form a ring; and
- - - is a single bond or a double bond;
provided that
(1) when ring A is a 6-membered ring and Q is C or CR5, X1
is C-Z1-Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and both R9 and R10 are
not H, or R9 and R10 are not combined to form an oxo group,
or R10 and R11 are not combined to form a 5-membered ring,
(2) when ring A is a 6-membered ring and Q is N, X1 is C-
Z1-Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and R9 and R10 are not combined
to form an oxo group,
(3) when ring A is a 5-membered ring and Q is C or CR5, X1
is C-Z1-Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and Z2 is an optionally
substituted amino group, and
(4) when ring A is a 5-membered ring and Q is N, at least
one of R9 and R10 is CHR15R16 (wherein at least one of R15 and
R16 are the same or different and are H, an optionally
substituted hydrocarbon group, an optionally substituted

hydroxyl group, an optionally substituted amino group, an
optionally substituted thiol group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula:-Z1-Z2 (wherein -Z1- and Z2 are as defined
above)) and the other is other than an optionally
substituted phenyl group; or a salt thereof;
2. A compound of the formula (III):

wherein R1 is H, an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted thiol group, an optionally
substituted amino group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -
SO2-, and Z2 is an optionally substituted hydrocarbon group,
an optionally substituted heterocyclic group, an optionally
substituted hydroxyl group, or an optionally substituted
amino group);
R3 is H, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted
heterocyclic group, or a group of the formula: -Z1-Z2

(wherein -Z1- and Z2 are as defined above);
Y is C, CR4 (wherein R4 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above)) or N;
R8 is H, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, cyano group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- and Z2 are as defined above) ;
Ar is an optionally substituted cyclic group;
R9 and R10 are the same or different and are H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group, cyano group,
a halogen atom, an optionally substituted heterocyclic
group, or a group of the formula: -Z1-Z2 (wherein -Z1- and
Z2 are as defined above) , or R9 and R10 may be combined to
form an oxo group, methylene group or a ring;
X3 is a bond, oxygen atom, an optionally oxidized sulfur
atom, N, NR7' (wherein R7' is H, an optionally substituted

hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted heterocyclic group, or a group of the formula -
Z1'-Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as
defined above)), or an optionally substituted bivalent C1-2
hydrocarbon group; and
is a single bond or a double bond;
provided that at least one of R9 and R10 is CHR15R16 (wherein
R15 and R16 are the same or different and are H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group, a halogen
atom, an optionally substituted heterocyclic group, or a
group of the formula:-Z1-Z2 (wherein -Z1- and Z2 are as
defined above)) and the other is other than an optionally
substituted phenyl group; or a salt thereof;
3. The compound according to the above 1 or 2,
wherein R1 is (1) an optionally substituted heterocyclic
group, or (2) a group of the formula: -Z1-Z2 (wherein -Z1-
is -CO-, -CS-, -SO- or -SO2-, and Z2 is an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an optionally substituted hydroxyl
group, or an optionally substituted amino group);
4. The compound according to the above 3, wherein Z1
is -CO- and Z2 is an optionally substituted hydroxyl group

or an optionally substituted amino group;
5. The compound according to the above 2, wherein R3
is H, a C1-6 alkyl group or a C7-14 aralkyl group;
6. The compound according to the above 2, wherein R8
is H, a C1-6 alkyl group, a C1-6 alkylthio group or a C1-6
alkoxy group which may be substituted with hydroxyl group;
7. The compound according to the above 1 or 2,
wherein R9 and R10 are the same or different and are a C1-6
alkyl group or R9 and R10 are combined each other to form a
ring;
8. The compound according to the above 2, wherein R1
is a group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -
CS-, -SO- or -SO2-, and Z2 is an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic
group, an optionally substituted hydroxyl group, or an
optionally substituted amino group) ; R3 is H; Ar is an
optionally substituted aromatic ring group; X3 is CR11R12
(wherein R11 and R12 are the same or different and are H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group, cyano group,
a halogen atom, an optionally substituted heterocyclic
group, or a group of the formula: -Z1-Z2 (wherein -Z1- and
Z2 are as defined above) , or R11 and R12 may be combined to
form an oxo group, methylene group or a ring) ; and R9 and

R10 are the same or different and a C1-6 alkyl group, or R9
and R10 may be combined to form a ring;
9. The compound according to the above 8, wherein R1
is an optionally substituted carbamoyl group;
10. The compound according to the above 9, wherein R1
is a group of the formula: -CONR20 (CR21R22R23) (wherein R20 is
H or an optionally substituted hydrocarbon group, and R21,
R22, and R23 are the same or different and are an optionally
substituted hydrocarbon group or an optionally substituted
heterocyclic group, or R20 and R21 may be combined to form a
ring);
11. A compound of the formula (IIIa):

wherein R1a is (1) an optionally substituted heterocyclic
group, or (2) a group of the formula: -Z1a-Z2a (wherein -Z1a-
is -CO-, -CS-, -SO- or -SO2-, and Z2a is (i) an optionally
substituted heterocyclic group, (ii) -NR20a (CR21aR22aR23a)
(wherein (a) R20a is H or an optionally substituted
hydrocarbon group; and R21a is an optionally substituted
heterocyclic group which may be fused with an optionally
substituted benzene ring, or an optionally substituted
phenyl group which may be fused with an optionally

substituted aromatic heterocyclic ring and R22a and R23a are
the same or different and are an optionally substituted
hydrocarbon group or an optionally substituted heterocyclic
group or R22a and R23a may be combined to form a ring, or (b)
R20a is H or an optionally substituted hydrocarbon group;
and R21a, R22a and R23a are the same or different and are an
optionally substituted C1-8 aliphatic hydrocarbon group,
provided that the sum total of the number of carbon atoms
is 7 or more) , (iii) -NR20aR25a (wherein R20a is as defined
above and R25a is an optionally substituted C6-10 aryl-C2-4
alkyl, C6-10 aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7-
14 aralkylamino-C2-4 alkyl, heterocyclic ring-C2-4 alkyl or
heterocyclic group), (iv) a substituted 5- to 7-membered
cyclic amino group, or (v) -OR24a (wherein R24a is (a) an
optionally substituted C7-14 aralkyl group, (b) an
optionally substituted C3-7 alicyclic hydrocarbon group, (c)
an optionally substituted C7-24 aliphatic hydrocarbon group,
or (d) an optionally substituted heterocyclic group);
R3 is H, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted
heterocyclic group, or a group of the formula: -Z1-Z2
(wherein -Z1- is -CO-, -CS-, -SO- or -SO2-, and Z2 is an
optionally substituted hydrocarbon group, an optionally
substituted heterocyclic group, an optionally substituted

hydroxyl group, or an optionally substituted amino group);
Y is C, CR4 (wherein R4 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1--Z2 (wherein -Z1- and Z2 are as defined
above)) or N;
R8 is H, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, cyano group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- and Z2 are as defined above);
Ar is an optionally substituted cyclic group;
R9 and R10 are the same or different and are H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group, cyano group,
a halogen atom, an optionally substituted heterocyclic
group, or a group of the formula: -Z1-Z2 (wherein -Z1- and
Z2 are as defined above) , or R9 and R10 may be combined to
form an oxo group, methylene group or a ring;
X3 is a bond, oxygen atom, an optionally oxidized sulfur
atom, N, NR7' (wherein R7' is H, an optionally substituted

hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted heterocyclic group, or a group of the formula -
Z1--Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as
defined above)), or an optionally substituted bivalent C1-2
hydrocarbon group; and
is a single bond or a double bond;
provided that at least one of R9 and R10 is CHR15R16 (wherein
R15 and R16 are the same or different and are H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group, a halogen
atom, an optionally substituted heterocyclic group, or a
group of the formula:-Z1-Z2 (wherein -Z1- and Z2 are as
defined above)) and the other is other than an optionally
substituted phenyl group; or a salt thereof;
12. The compound according to the above 11, wherein
R1a is a group of the formula: -CONR20a (CR21bR22bR23b) (wherein
R20a is as defined above and at least one of R21b, R22b, and
R23b is an optionally substituted heterocyclic group which
may be fused with an optionally substituted benzene ring,
or an optionally substituted phenyl group which may be
fused with an optionally substituted aromatic heterocyclic
ring);
13. The compound according to the above 11, wherein

R1a is (1) an optionally substituted 5- to 7-membered
aromatic or non-aromatic heterocyclic group having 1-4
hetero atoms selected from nitrogen atom, oxygen atom and
sulfur atom, or (2) a group of the formula: -CO-Z2c
(wherein Z2c is (i) an optionally substituted 5- to 7-
membered aromatic or non-aromatic heterocyclic group having
1-4 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom, (ii) -NR20c (CR21cR22cR23c) (wherein (a) R20c is
H or an optionally substituted hydrocarbon group selected
from C1-8 saturated aliphatic hydrocarbon group, C2-8
unsaturated aliphatic hydrocarbon group, C3-7 saturated
alicyclic hydrocarbon group, C3-7 unsaturated alicyclic
hydrocarbon group, C9-10 partly saturated and fused bicyclic
hydrocarbon group, C3-7 saturated or unsaturated alicyclic-
C1-8 saturated or unsaturated aliphatic hydrocarbon group,
C9-10 partly saturated and fused bicyclic hydrocarbon-Ci-4
alkyl group, C9-10 partly saturated and fused bicyclic
hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14
aralkyl group; and R21c is 1) an optionally substituted 5-
to 7-membered aromatic or non-aromatic heterocyclic group
having 1-4 hetero atoms selected from nitrogen atom, oxygen
atom and sulfur atom, which may be fused with an optionally
substituted benzene ring, or 2) an optionally substituted
C6-10 aryl group which may be fused with an optionally
substituted 5- to 7-membered aromatic heterocyclic ring

having 1-4 hetero atoms selected from nitrogen atom, oxygen
atom and sulfur atom; and R22c and R23c are the same or
different and are an optionally substituted hydrocarbon
group selected from C1-8 saturated aliphatic hydrocarbon
group, C2-8 unsaturated aliphatic hydrocarbon group, C3-7
saturated alicyclic hydrocarbon group, C3-7 unsaturated
alicyclic hydrocarbon group, C9-10 partly saturated and
fused bicyclic hydrocarbon group, C3-7 saturated or
unsaturated alicyclic-Ci-g saturated or unsaturated
aliphatic hydrocarbon group, C9-10 partly saturated and
fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly
saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group,
C6-10 aryl group and C7-14 aralkyl group or an optionally
substituted 5- to 7-membered aromatic or non-aromatic
heterocyclic group having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom, or R22c and R23c
may be combined to form a C3-7 carbon ring, or
(b) R20c is H or an optionally substituted hydrocarbon group
selected from C1-8 saturated aliphatic hydrocarbon group,
C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated
alicyclic hydrocarbon group, C3-7 unsaturated alicyclic
hydrocarbon group, C9-10 partly saturated and fused bicyclic
hydrocarbon group, C3_7 saturated or unsaturated alicyclic-
C1-8 saturated or unsaturated aliphatic hydrocarbon group,
C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4

alkyl group, C9-10 partly saturated and fused bicyclic
hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14
aralkyl group; and R21c, R22c and R23c are the same or
different and are an optionally substituted C1-8 aliphatic
hydrocarbon group, provided that the sum total of the
number of carbon atoms is 7 or more),
(iii) -NR20cR25c (wherein R20c is as defined above and R25c is
an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10
aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7-14
aralkylamino-C2-4 alkyl, 5- to 7-membered heterocyclic ring
(having 1-4 hetero atoms selected from nitrogen atom,
oxygen atom and sulfur atom) -C2-4 alkyl or 5- to 7-membered
heterocyclic group having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom),
(iv) a substituted 5- to 7-membered cyclic amino group, or
(v) -OR24c (wherein R24c is (a) an optionally substituted C7-
14 aralkyl group, (b) an optionally substituted C3-7
alicyclic hydrocarbon group, (c) an optionally substituted
C7-24 aliphatic hydrocarbon group, or (d) an optionally
substituted 5- to 7-membered aromatic or non-aromatic
heterocyclic group having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom;
wherein said substituents for R1a, Z2c, R20c, R21c, R22c, R23c,
R24c and R25c are 1 to 3 substituents selected from the group
consisting of

1) C1-6 alkyl,
2) C2-6 alkenyl,
3) C2-6 alkynyl,
4) C3-7 cycloalkyl,
5) C6-10 aryl which may be substituted with 1 to 3
substituents selected from the group consisting of C1-6
alkyl, amino, N-(C1-6 alkyl) amino, N, N-di-(C1-6 alkyl) amino,
amidino, carbamoyl, N-(C1-6 alkyl) carbamoyl, N,N-di-(C1-6
alkyl) carbamoyl, sulfamoyl, N- (C1-6 alkyl) sulfamoyl, N,N-
di-(C1-6 alkyl) sulfamoyl, carboxyl, C2-7 alkoxycarbonyl,
hydroxyl, C1-6 alkoxy, mercapto, C1-6 alkylthio, sulfo,
cyano, azido, halogen, nitro, nitroso, phosphono, C1-6
alkoxyphosphoryl, di- (C1-6 alkoxy) phosphoryl and C1-6 alkyl
substituted with phosphono, C1-6 alkoxyphosphoryl and di-
(C1-6 alkoxy)phosphoryl (hereinafter the group of 5) is
referred to as group "C"),
6) aromatic heterocyclic group selected from (a) aromatic
5- or 6-membered heterocyclic group having 1-4 hetero
atoms selected from nitrogen atom, oxygen atom and sulfur
atom, (b) fused bicyclic heterocyclic group formed by
condensation of an aromatic 5- or 6-membered heterocyclic
group having 1 to 3 hetero atoms selected from nitrogen
atom, oxygen atom and sulfur atom with benzene ring or an
aromatic 5- or 6-membered heterocyclic group having 1 to
3 hetero atoms selected from nitrogen atom, oxygen atom

and sulfur atom and (c) fused tricyclic heterocyclic
group formed by condensation of [1] an aromatic 5- or 6-
membered heterocyclic group having 1-3 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom,
[2] benzene ring, and [3] an aromatic 5- or 6-membered
heterocyclic group having 1-3 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom or benzene
ring,
7) heterocyclic-oxy group formed by combining each of the
above aromatic heterocyclic groups (a) , (b) and (c) with
oxy group,
8) non-aromatic 4- or 7-membered heterocyclic group
having 1 to 3 hetero atoms selected from nitrogen atom,
oxygen atom and sulfur atom,
9) C7-14 aralkyl which may be substituted with 1 to 3
substituents selected from the group "C",
10) amino group,
11) N-mono-substituted amino selected from N-(C1-6
alkyl) amino, N- (C2-6 alkenyl) amino, N-(C3-7
cycloalkyl) amino group and N- (C6-10 aryl) amino which may
be substituted with 1 to 3 substituents selected from the
group "C",
12) amino substituted with two substituents selected from
C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkenyl and C6-10 aryl
which may be substituted with 1 to 3 substituents

selected from the group "C",
13) amidino,
14) acyl selected from C2-8 alkanoyl, C3-8 alkenoyl, C3-7
cycloalkyl-carbonyl, C3-7 cycloalkenyl-carbonyl, C6-10
aryl-carbonyl which may be substituted with 1 to 3
substituents selected from the group "C", and
heterocyclic-carbonyl formed by binding of an aromatic or
non-aromatic 5- or 6-membered heterocyclic group having
1-3 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom with carbonyl,
15) carbamoyl,
16) mono-substituted carbamoyl group selected from N-(C1-6
alkyl) carbamoyl, N- (C2-6 alkenyl) carbamoyl, N- (C3-7
cycloalkyl) carbamoyl and N- (C6-10 aryl) carbamoyl which may
be substituted with 1 to 3 substituents selected from the
group "C",
17) carbamoyl substituted with two substituents selected
from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C6-10 aryl
which may be substituted with 1 to 3 substituents
selected from the group "C",
18) sulfamoyl,
19) N-mono-substituted sulfamoyl selected from N-(C1-6
alkyl) sulfamoyl, N- (C2-6 alkenyl) sulfamoyl, N- (C3-7
cycloalkyl) sulfamoyl and N-(C6-10 aryl) sulfamoyl which may
be substituted with 1 to 3 substituents selected from the

group "C",
20) sulfamoyl substituted with two substituents selected
from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C6-10
aryl which may be substituted with 1 to 3 substituents
selected from the group "C",
21) carboxyl,
22) C1-6 alkoxy-carbonyl,
23) hydroxy1,
24) C1-6 alkoxy,
25) C2-10 alkenyloxy,
26) C3-7 cycloalkyloxy,

27) C6-10 aryloxy which may be substituted with 1 to 3
substituents selected from the group "C",
28) C7-14 aralkyloxy which may be substituted with 1 to 3
substituents selected from the group "C",
29) mercapto,
30) C1-6 alkylthio,
31) C7-14 aralkylthio which may be substituted with 1 to 3
substituents selected from the group "C",

32) C6-10 arylthio which may be substituted with 1 to 3
substituents selected from the group "C",
33) C1-6 alkylsulfinyl,
34) C7-14 aralkylsulfinyl which may be substituted with 1
to 3 substituents selected from the group "C",
35) C6-10 arylsulfinyl which may be substituted with 1 to

3 substituents selected from the group "C",
36) C1-6 alkylsulfonyl,
38) C7-14 aralkylsulfonyl which may be substituted with 1
to 3 substituents selected from the group "C",
39) C6-10 arylsulfonyl which may be substituted with 1 to
3 substituents selected from the group "C",
40) sulfo,
41) cyano,
42) azido,
43) halogen,
44) nitro,
45) nitroso,
46) phosphono,
47) C1-6 alkoxy-phosphoryl
48) di-C1-6 alkoxy-phosphoryl,
49) C1-6 alkyl substituted with phosphono, C1-6
alkoxyphosphoryl or di-(C1-6 alkoxy) phosphoryl
50) C1-6 alkyl substituted with 1 to 4 halogen atoms
51) C1-6 alkoxy substituted with 1 to 4 halogen atoms and
52) C1-6 alkylenedioxy
(hereinafter the group of above 1) to 52) is referred to
as group "B");
R3 is H, a C1-6 alkyl group or a C7-14 aralkyl group;
Y is CH;
R8 is H, a C1-6 alkyl group, a C1-6 alkylthio group or a C1-6

alkoxy group which may be substituted with hydroxyl group;
Ar is (1) a C6-10 aryl group, (2) a 5- to 7-membered
aromatic or non-aromatic heterocyclic group having 1-4
hetero atoms selected from nitrogen atom, oxygen atom and
sulfur atom, or (3) a C3-7 saturated or unsaturated
alicyclic hydrocarbon group, each of which may be
substituted with 1 to 3 substituents selected from the
group "B";
one of R9 and R10 is a hydrogen atom or C1-6 alkyl group
which may be substituted with 1 to 3 substituents selected
from the group "B" and the other is (1) a hydrocarbon group
selected from C1-8 saturated aliphatic hydrocarbon group,
C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated
alicyclic hydrocarbon group, C3-7 unsaturated alicyclic
hydrocarbon group, C9-10 partly saturated and fused bicyclic
hydrocarbon group, C3-7 saturated or unsaturated alicyclic-
C1-8 saturated or unsaturated aliphatic hydrocarbon group,
C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4
alkyl group, C9-10 partly saturated and fused bicyclic
hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14
aralkyl group, each of which may be substituted with 1 to 3
substituents selected from the group "B" or (2) a 5- to 7-
membered aromatic or non-aromatic heterocyclic group having
1-4 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom, which may be substituted with 1 to 3

substituents selected from the group "B", or
R9 and R10 may be combined to form a C5-7 carbon ring; and
X3 is CH2;
14. The compound according to the above 8, wherein R1
is a group of the formula: -CONR20 (CR21R22R23) (wherein R20 is
H, and R21, R22, and R23 are the same or different and are an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group); R3 is H; Ar is an
optionally substituted aromatic ring group; X3 is CH2; Y is
CH; R8 is H or an optionally substituted hydrocarbon group,
an optionally substituted alkoxy group, an optionally
substituted sulfanyl group, an optionally substituted
sulfinyl group, or an optionally substituted sulfonyl group,
C1-6 alkoxy-carbonyl; and R9 and R10 are the same or
different and are an optionally substituted hydrocarbon
group;
15. The compound according to the above 14, wherein
at least one of R21, R22, and R23 is an optionally
substituted heterocyclic group or an optionally substituted
phenyl group;
16. The compound according to the above 14, wherein
R20 and R21 are combined to form an optionally substituted
5- to 7-membered ring, and R22 and R23 are the same or
different and are an optionally substituted hydrocarbon
group, an optionally substituted heterocyclic group, or an

optionally substituted phenyl group;
17. The compound according to the above 14, wherein
R21 and R22 are the same or different and are a C1-8
hydrocarbon group, and R23 is an optionally substituted 5-
membered heterocyclic group which may be fused with an
optionally substituted benzene ring, or an optionally
substituted phenyl group;
18. The compound according to the above 16, wherein
R20 and R21 are combined to form a 5- or 6-membered ring
which may be fused with benzene ring and/or substituted
with 1 to 3 substituents selected from the group consisting
of (1) halogen, (2) hydrogen, (3) a phenoxy which may be
substituted with 1 to 3 substituents selected from halogen,
hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino,
mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-
sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6
alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N-
di-C1-6 alkyl-carbamoyl,
(4) C1-6 alkoxy which may be substituted with 1 to 3
substituents selected from halogen, hydroxyl, C1-6 alkyl,
C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino,
di-C1-6 alkyl-amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl,
C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6
alkyl-carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl
which may be substituted with 1 to 3 substituents selected

from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl,
cyano, halogeno C1-6 alkyl, amino, mono-C1-6 alkyl-amino, di-
C1-6 alkyl-amino, C1-6 alkyl-sulfanyl, C1-6 alkyl-sulf inyl,
C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6
alkyl-carbamoyl and N,N-di-C1-6 alkyl-carbamoyl,
and (5) a C1-8 hydrocarbon group which may be substituted
with 1 to 3 substituents selected from halogen, hydroxyl,
C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6
alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-sulfanyl, C1-6
alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl,
carbamoyl, N-C1-6 alkyl-carbamoyl, N,N-di-C1-6 alkyl-
carbamoyl and phenyl which may be substituted with 1 to 3
substituents selected from halogen, hydroxyl, C1-6 alkyl,
C1-6 alkoxy, C1-6 acyl, cyano, halogeno C1-6 alkyl, amino,
mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-
sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6
alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N-
di-C1-6 alkyl-carbamoyl,
and R22 and R23 are the same or different and C1-8
hydrocarbon group which may be substituted with 1 to 3
substituents selected from halogen, hydroxyl, C1-6 alkyl,
C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino,
di-C1-6 alkyl-amino, C1-6 alkyl-sulfanyl, C1-6 alkyl-sulf inyl,
C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6
alkyl-carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl

which may be substituted with 1 to 3 substituents selected
from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl,
cyano, halogeno C1-6 alkyl, amino, mono-C1-6 alkyl-amino, di-
C1-6 alkyl-amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl,
C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6
alkyl-carbamoyl and N,N-di-C1-6 alkyl-carbamoyl;
19. N-(1-ethyl-1-(4-methylphenyl)propyl)-7,7-
dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-
7,7-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide or a salt thereof,
N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-5-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide or a salt thereof,
N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide or a salt thereof,
N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-
2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-ethyl-1-(4-ethylphenyl)propyl)-5-(2-fluorophenyl)-
2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide or a salt thereof,
5-(2-chlorophenyl)-N-(1-ethyl-1-(4-methylphenyl)propyl)-

2,7, 7-trimethyl-4,5,6,7-tetrahydropyrazolo [1,5-
a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-(4-(dimethylamino)phenyl)-1-ethylpropyl)-5-(2-
fluorophenyl)-2,7,7-trimethyl-4, 5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt
thereof,
N-(1,1-diethylbutyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
or a salt thereof,
N-(1-ethyl-1-phenylpropyl)-5-(2-fluorophenyl)-2,7,7-
trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide or a salt thereof,
3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3, 4-oxadiazol-2-
yl)-2,7,7-trimethyl-5-phenyl-4 ,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof,
3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3,4-thiadiazol-2-
yl) -2, 7, 7-trimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof,
3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidinyl)carbonyl)-7,7-
dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine or a salt thereof,
3-((2,2-diethyl-4-methoxy-1-pyrrolidinyl)carbonyl)-7,7-
dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine or a salt thereof, or
3-((2,2-diethyl-4-fluoro-1-pyrrolidinyl)carbonyl)-7,7-

dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine or a salt thereof;
20. The compound according to the above 19, which is
an optically active compound;
21. A prodrug of the compound according to the above
1, 2 or 13;
22. A pharmaceutical composition which comprises the
compound according to the above 1, 2 or 13 or a prodrug
thereof;
23. A composition for modulating calcium receptor
which comprises a compound of the formula (I):

wherein ring A is an optionally substituted 5- to 7-
membered ring;
ring B is an optionally substituted 5- to 7-membered
heterocyclic ring;
X1 is CR1 (wherein R1 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -
SO2-, and Z2 is an optionally substituted hydrocarbon group,

an optionally substituted heterocyclic group, an optionally
substituted hydroxyl group, or an optionally substituted
amino group) ) , CR1R2 (wherein R1 is as defined above, R2 is H
or an optionally substituted hydrocarbon group), N or NR13
(wherein R13 is H, an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, cyano group, a halogen
atom, an optionally substituted heterocyclic group, or a
group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as
defined above));
X2 is N or NR3 (wherein R3 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, cyano group, a
halogen atom, an optionally substituted heterocyclic group,
or a group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are
as defined above);
Y is C, CR4 (wherein R4 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above)) or N;
Z is CR5 (wherein R5 is H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,

an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above) ) , CR5R6 (wherein R5 and R6 are the same or different
and are H, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, cyano group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- and Z2 are as defined above)) , N or NR7
(wherein R7 is H, an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, cyano group, a halogen
atom, an optionally substituted heterocyclic group, or a
group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as
defined above));
Ar is an optionally substituted cyclic group;
R is H, an optionally substituted hydrocarbon group, an
optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, an optionally substituted sulfonyl group or an
optionally substituted sulfinyl group, or R and Z may be
combined to form a ring B; and
is a single bond or a double bond;

or a salt thereof or a prodrug thereof;
24. The composition according to the above 23, which
is a calcium receptor antagonist;
25. The composition according to the above 23, which
is an agent for preventing or treating diseases caused by
abnormality of calcium concentration in a living body or a
calcium receptor;
26. The composition according to the above 23, which
is an agent for preventing or treating bone diseases;
27. The composition according to the above 23, which
is an agent for preventing or treating osteoporosis or
fracture;
28. A method for modulating a calcium receptor which
comprises administering to a mammal an effective amount of
a compound of the formula (I) or a salt thereof or a
prodrug thereof according to the above 23;
29. A method for preventing or treating bone diseases,
which comprises administering to a mammal an effective
amount of a compound of the formula (I) or a salt thereof
or a prodrug thereof according to the above 23;
30. Use of the compound of the formula (I) or a salt
thereof or a prodrug thereof according to the above 23 for
producing a calcium receptor modulator; and
31. Use of the compound of the formula (I) or a salt
thereof or a prodrug thereof according to the above 23 for

producing a composition for preventing or treating bone
diseases.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The above formula (I) includes a monocyclic
heterocyclic compound containing ring A and a condensed
heterocyclic compound containing rings A and B.
In the above formulas, ring A of the formulas (I) and
(II) is an optionally substituted 5- to 7-membered ring.
Examples of the "5- to 7-membered ring" of "an
optionally substituted 5- to 7-membered ring" includes an
aromatic or non-aromatic 5- to 7-membered hydrocarbon ring
or 5- to 7-membered heterocyclic ring which may contain 1
to 3 heteroatoms selected from nitrogen, oxygen and sulfur
atoms as the ring constituting atoms in addition to carbon
atoms. Specific examples thereof include a hydrocarbon
ring such as benzene, tropilidene, cyclopentane,
cyclohexane, cycloheptane, 1-cyclopentene, 2-cyclopentene,
3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene,
1-cycloheptene, 2-cycloheptene, 3-cycloheptene, 2,4-
cycloheptadiene, etc.; a heterocyclic ring such as pyridine,
pyrazine, pyrimidine, imidazole, furan, thiophene,
dihydropyridine, diazepine, oxazepine, pyrrolidine,
piperidine, hexamethylenimine, heptamethylenimine,
tetrahydrofuran, piperazine, homopiperazine,

tetrahydrooxazepine, morpholine, thiomorpholine, pyrrole,
pyrazole, 1,2,3-triazole, oxazole, oxazolidine, thiazole,
thiazolidine, isoxazole, imidazoline, triazole, thiadiazole,
oxadiazole, oxathiadiazole, triazine, etc.; and the like.
Examples of the substituent(s) of "an optionally
substituted 5- to 7-membered ring group" include halogen,
nitro, cyano, oxo, an optionally substituted hydrocarbon
group, an optionally substituted heterocyclic group, an
optionally substituted sulfinyl group, an optionally
substituted sulfonyl group, an optionally substituted
hydroxyl group, an optionally substituted thiol group, an
optionally substituted amino group, an optionally
substituted acyl group, an optionally esterified or
amidated carboxyl group, an optionally substituted
phosphoryl group, or the like.
Examples of halogen include fluorine, chlorine,
bromine, iodine, and the like, preferably, fluorine and
chlorine.
Examples of the hydrocarbon group in an optionally
substituted hydrocarbon group as the substituent of the 5-
to 7-membered ring group include an optionally substituted
aliphatic hydrocarbon group, an optionally substituted
alicyclic hydrocarbon group, an optionally substituted
alicyclic-aliphatic hydrocarbon group, an optionally
substituted aromatic hydrocarbon group, an optionally

substituted aromatic-aliphatic hydrocarbon group (an
aralkyl group), and the like.
Examples of said aliphatic hydrocarbon group include a
saturated aliphatic hydrocarbon group having 1-8 carbon
atoms (e.g., alkyl group) such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl,
octyl, etc.; and an unsaturated aliphatic hydrocarbon group
having 2-8 carbon atoms (e.g., alkenyl group, alkynyl group,
alkadienyl group, alkadiynyl group, etc.) such as vinyl,
allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-
butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-
pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-
hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4-
hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-
propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-
pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-
hexynyl, 4-hexynyl, 5-hexynyl, 2,4-hexadiynyl, 1-heptynyl,
1-octynyl, etc.
Examples of said alicyclic hydrocarbon group include a
saturated alicyclic hydrocarbon group having 3-7 carbon
atoms (e.g., cycloalkyl group, etc.) such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the
like; an unsaturated alicyclic hydrocarbon group having 3-7
carbon atoms (e.g., cycloalkenyl group, cycloalkadienyl

group, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3-
cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-
cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-
cycloheptenyl, 2,4-cycloheptadienyl, etc.; a partly
saturated and fused bicyclic hydrocarbon group [preferably,
C6-10 partly saturated and fused bicyclic hydrocarbon group,
etc. (including those where the benzene ring is combined to
5- or 6-membered non-aromatic cyclic hydrocarbon group)]
such as 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl,
1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-
naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl,
1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4-
dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl, etc.; and the
like. Said alicyclic hydrocarbon group may be cross-linked.
Examples of said alicyclic-aliphatic hydrocarbon group
include those where the above-mentioned alicyclic
hydrocarbon group and the above-mentioned aliphatic
hydrocarbon group are combined, for example, those having
4-14 carbon atoms such as cyclopropylmethyl,
cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl,
cyclopentylmethyl, 2-cyclopentenylmethyl, 3-
cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2-
cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl,
cycloheptylmethyl, cycloheptylethyl, 2-(3,4-dihydro-2-
naphtyl)ethyl, 2-(1,2,3,4-tetrahydro-2-naphtyl)ethyl, 2-

(3,4-dihydro-2-naphtyl)ethenyl, etc. (e.g., C3-7 cycloalkyl-
C1-4 alkyl group, C3-7 cycloalkenyl-C1-4 alkyl group, C3-7
cycloalkyl-C2-4 alkenyl group, C3-7 cycloalkenyl-C2-4 alkenyl
group, C9-10 partly saturated and fused bicyclic
hydrocarbon-C1-4 alkyl group, C9-10 partly saturated and
fused bicyclic hydrocarbon-C2-4 alkenyl groups, etc.).
Examples of said aromatic hydrocarbon group include an
aryl group having 6-10 carbon atoms (including that where a
5- to 6-membered non-aromatic hydrocarbon ring is fused
with phenyl group) such as phenyl, α-naphthyl, β-naphthyl,
4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-
tetrahydro-1-naphthyl, 5, 6,7,8-tetrahydro-2-naphthyl, 5,6-
dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-
naphthyl, 5,6-dihydro-4-naphthyl, etc.; and the like.
Examples of said aromatic-aliphatic hydrocarbon group
include an aralkyl group having 7-14 carbon atoms (C6-10
aryl-C1-4 alkyl group) such as phenyl-C1-4 alkyl group, e.g.,
benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-
phenylpropyl, 3-phenylpropyl, etc.; naphthyl-C1-4 alkyl
group such as α-naphthylmethyl, α-naphthylethyl, β-
naphthylmethyl, β-naphthylethyl, etc.; C6-10 aryl-C2-4
alkenyl group such as phenyl-C2-4 alkenyl group, e.g.,
styryl, cinnamyl, etc.; and the like.
Examples of the heterocyclic group in an optionally
substituted heterocyclic group as the substituent of the 5-

to 7-membered ring include (i) a 5- to 7-membered
heterocyclic group containing one sulfur atom, one nitrogen
atom, or one oxygen atom, (ii) a 5- to 6-membered
heterocyclic group containing 2-4 nitrogen atoms, (iii) a
5- to 6-membered heterocyclic group containing 1-2 nitrogen
atoms and one sulfur or oxygen atom, or the like; and (iv)
these heterocyclic groups may be fused with a 5- to 6-
membered ring containing 2 or less nitrogen atoms, benzene
ring, or a 5-membered ring containing one sulfur atom. In
addition, each of the heterocyclic groups exemplified in
(i) to (iv) may be a saturated or unsaturated heterocyclic
group and the unsaturated heterocyclic group may be either
aromatic or non-aromatic.
Examples of the heterocyclic group in an optionally
substituted heterocyclic group as the substituent of the 5-
to 7-membered ring include an aromatic monocyclic
heterocyclic group, an aromatic fused heterocyclic group,
and a non-aromatic heterocyclic group.
Specific examples of the heterocyclic group in an
optionally substituted heterocyclic group as the
substituent of the 5- to 7-membered ring include (i) an
aromatic monocyclic heterocyclic group (e.g., furyl,
thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-

thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl,
pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.); (ii)
an aromatic fused heterocyclic group (e.g., benzofuranyl,
isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-
indazolyl, benzimidazolyl, benzoxazolyl, 1,2-
benzisothiazolyl, lH-benztriazolyl, quinolyl, isoquinolyl,
cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
naphthyridinyl, purinyl, pteridinyl, carbazolyl, a-
carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,
phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl,
thianthrenyl, phenanthredinyl, phenanthrolinyl, indolizinyl,
pyrrolo[l,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,
imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[l,2-
b]pyridazinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,
imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,
l,2,4-triazolo[4,3-a]pyridyl, l,2,4-triazolo[4,3-
b]pyridazinyl, etc.); and (iii) a non-aromatic,
heterocyclic group (e.g., oxiranyl, azetidinyl, oxetanyl,
thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,
piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,
piperazinyl, etc.).
Examples of sulfinyl group in an optionally
substituted sulfinyl group as the substituent of the 5- to
7-membered ring include that where -SO- is combined with

"the hydrocarbon group" or "the heterocyclic group" in "an
optionally substituted hydrocarbon group" or "an optionally
substituted heterocyclic group" of the substituent of the
5- to 7-membered ring.
Preferred examples include a C1-8 alkylsulf inyl group
where sulfinyl group is combined with a C1-8 alkyl group
such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-
pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C6-10
arylsulfinyl group where sulfinyl group is combined with a
C6-10 aryl group such as phenyl, a-naphthyl, p-naphthyl, 4-
indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-
tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 5,6-
dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-
naphthyl, 5,6-dihydro-4-naphthyl, etc.; a group where
sulfinyl group is combined with an aromatic monocyclic
heterocyclic group (e.g., furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl,
pyrazinyl, triazinyl, etc.); and a group where sulfinyl
group is combined with an aromatic fused heterocyclic group
(e.g., benzofuranyl, isobenzofuranyl, benzo[b]thienyl,

indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,
benzoxazolyl, 1,2-benzisothiazolyl, 1H-benztriazolyl,
quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,
quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl,
pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-
carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,
phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl,
phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,
pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[l,5-
a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl,
imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl,
1,2,4-triazolo[4,3-b]pyridazinyl, etc.).
More preferred examples include a C1-8 alkylsulf inyl
group where sulfinyl group is combined with a C1-8 alkyl
group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.
Examples of sulfonyl group in an optionally
substituted sulfonyl group as the substituent of the 5- to
7-membered ring include a group where -SO2- is combined
with "the hydrocarbon group" or "the heterocyclic group" in
"an optionally substituted hydrocarbon group" or "an
optionally substituted heterocyclic group" of the
substituent of the 5- to 7-membered ring.

Preferred examples include a C1-8 alkylsulfonyl group
where sulfonyl group is combined with a C1-8 alkyl group
such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-
pentyl, hexyl, isohexyl, heptyl, octyl, etc.; a C6-10
arylsulfonyl group where sulfonyl group is combined with a
C6-10 aryl group such as phenyl, a-naphthyl, (3-naphthyl, 4-
indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-
tetrahydro-1-naphthyl, 5, 6,7,8-tetrahydro-2-naphthyl, 5,6-
dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-
naphthyl, 5,6-dihydro-4-naphthyl, etc.; a group where
sulfonyl group is combined with an aromatic monocyclic
heterocyclic group (e.g., furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-
oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl,
pyrazinyl, triazinyl, or the like); and a group where the
sulfonyl group is combined with an aromatic, fused
heterocyclic group (e.g., benzofuranyl, isobenzofuranyl,
benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl,
benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H-
benztriazolyl, quinolyl, isoquinolyl, cinnolinyl,
quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,

purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,
γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,
phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl,
phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,
pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-
a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl,
imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl,
1,2,4-triazolo[4,3-b]pyridazinyl, etc.).
More preferred examples include a C1-8 alkylsulf onyl
group where sulfonyl group is combined with a C1-8 alkyl
group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,
neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.
Examples of an optionally substituted hydroxyl group
as the substituent of the 5- to 7-membered ring include
hydroxyl group and that having an appropriate substituent,
for example, "an optionally substituted hydrocarbon group"
or "an optionally substituted heterocyclic group" of the
above substituent of the 5- to 7-membered ring.
Preferred examples include a C1-8 alkyloxy group whose
substituent is a C1-8 alkyl group such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl,
heptyl, octyl, etc.; a C6-10 aryloxy group whose substituent

is a C6-10 aryl group such as phenyl, α-naphthyl, β-naphthyl,
4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8-
tetrahydro-1-naphthyl, 5, 6, 7 , 8-tetrahydro-2-naphthyl, 5,6-
dihydro-1-naphthyl, 5, 6-dihydro-2-naphthyl, 5, 6-dihydro-3-
naphthyl, 5,6-dihydro-4-naphthyl, etc.; a hydroxyl group
substituted with an aromatic monocyclic heterocyclic group
(e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-
oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl,
furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
etc.); a hydroxyl group substituted with an aromatic fused
heterocyclic group (e.g., benzofuranyl, isobenzofuranyl,
benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl,
benzimidazolyl, benzoxazolyl, 1,2-benzisothiazolyl, 1H-
benztriazolyl, quinolyl, isoquinolyl, cinnolinyl,
quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,
purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,
γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,
phenazinyl, phenoxatinyl, thianthrenyl, phenanthredinyl,
phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,
pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-
a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl,
imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,

imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl,
1,2,4-triazolo[4,3-b]pyridazinyl, etc.).
More preferred examples include a C6-10 aryloxy group
(in particular, phenyloxy) or a hydroxyl group substituted
with an aromatic monocyclic heterocyclic group (in
particular, pyridyl) or an aromatic fused heterocyclic
group (in particular, quinolyl).
"The hydrocarbon group" or "the heterocyclic group" as
the substituent of the substituted hydroxyl group
exemplified above may have the same substituent as that of
"the hydrocarbon group" or "the heterocyclic group" in "an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group" of the substituent of the
5- to 7-membered ring.
Examples of an optionally substituted thiol group as
the substituent of the 5- to 7-membered ring include thiol
group and that substituted with an appropriate group such
as "an optionally substituted hydrocarbon group" or "an
optionally substituted heterocyclic group" of the
substituent of the 5- to 7-membered ring.
Preferred examples include a C1-8 alkylthio group,
whose substituent is a C1-8 alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,
isohexyl, heptyl, octyl, etc.; a C5-10 arylthio group, whose

substituent is a C6-10 aryl group such as phenyl, a-naphthyl,
P-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl,
5,6,7,8-tetrahydro-1-naphthyl, 5,6,7,8-tetrahydro-2-
naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl,
5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl, etc.; a
thiol group substituted with an aromatic monocyclic
heterocyclic group (e.g., furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
pyrazolyl, 1,2,3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3,4-
oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl,
pyrazinyl, triazinyl, etc.); and a thiol group substituted
with an aromatic fused heterocyclic groups (e.g.,
benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl,
isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,
1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl,
isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,
phthalazinyl, naphthyridinyl, purinyl, pteridinyl,
carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl,
acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,
phenoxatinyl, thianthrenyl, phenanthredinyl,
phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,
pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[l,5-
a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl,

imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl,
1,2,4-triazolo[4,3-b]pyridazinyl, etc.).
"The hydrocarbon group" or "the heterocyclic group" as
the substituent of the substituted thiol group exemplified
above may have the same substituent as that of "the
hydrocarbon group" or "the heterocyclic group" in "an
optionally substituted hydrocarbon group" or "an optionally
substituted heterocyclic group" of the substituent of the
5- to 7-membered ring.
More preferred examples include a C1-8 alkylthio group
substituted with a C1-8 alkyl such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl,
octyl, or the like.
Examples of an optionally substituted amino group as
the substituent of the 5- to 7-membered ring include amino
group, an N-mono-substituted amino group, and an N,N-di-
substituted amino group. Examples of said substituted
amino groups include that having one or two substituents of
an optionally substituted hydrocarbon group (e.g., the same
group as an optionally substituted hydrocarbon group of the
substituent of the 5- to 7-membered ring, more specifically,
a C1-8 alkyl group, a C3-7 cycloalkyl group, a C2-8 alkenyl
group, a C2-8 alkynyl group, a C3-7 cycloalkenyl group, a C6-

10 aryl group that may have a C1-4 alkyl group, etc.), an
optionally substituted heterocyclic group (e.g., the same
group as an optionally substituted heterocyclic group of
the substituent of the 5- to 7-membered ring) , or the
formula: -COR' (wherein R' represents hydrogen atom or an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group. As for "the hydrocarbon
group" or "the heterocyclic group" in "an optionally
substituted hydrocarbon group" or "an optionally
substituted heterocyclic group" of R' may have the same
substituent as that of "the hydrocarbon group" or "the
heterocyclic group" in "an optionally substituted
hydrocarbon group" or "an optionally substituted
heterocyclic group" of the substituent of the 5- to 7-
membered ring), preferably a C1-10 acyl group (e.g., a C2-7
alkanoyl, benzoyl, nicotinoyl, etc.). Specific examples
thereof include methylamino, dimethylamino, ethylamino,
diethylamino, dipropylamino, dibutylamino, diallylamino,
cyclohexylamino, phenylamino, N-methyl-N-phenylamino,
acetylamino, propionylamino, benzoylamino, nicotinoylamino,
and the like.
In addition, the two groups in said substituted amino
groups may be combined to form a nitrogen-containing 5- to
7-membered ring (e.g., piperidino, piperadino, morpholino,
thiomorpholino, etc.).

Examples of the optionally substituted acyl group as
the substituent of the 5- to 7-membered ring include (i)
formyl or (ii) a group where the carbonyl group is combined
with a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10
alkynyl group, a C3-7 cycloalkyl group, a C5-7 cycloalkenyl
group, or an aromatic group (e.g., phenyl group, pyridyl
group, etc.) (e.g., acetyl, propionyl, butyryl, isobytyryl,
valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,
octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,
cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-
cyclohexenecarbonyl, benzoyl, etc.) and the like.
Examples of the optionally esterified carboxyl group
as the substituent of the 5- to 7-membered ring include, in
addition to carboxyl group, an alkyloxycarbonyl group, an
alkenyloxycarbonyl, an alkynyloxycarbonyl, an
aralkyloxycarbonyl group, an acyoxycarbonyl group, an
aryloxycarbonyl group, and the like.
Examples of the alkyl group in said alkyloxycarbonyl
group include a C1-6 alkyl group (e.g., methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
etc.).
Examples of the alkenyl group in said
alkenyloxycarbonyl group include a C2-6 alkenyl group (e.g.,
vinyl, allyl, isopropenyl, 1-propenyl, 1-butenyl, 2-butenyl,
3-methylallyl, etc.).

Examples of the alkynyl group in said
alkynyloxycarbonyl group include a C2-6 alkynyl group (e.g.,
ethynyl, 2-propynyl, etc.).
The aralkyl group in said aralkyloxycarbonyl group
means an aryl-alkyl group (e.g., C6-10 aryl-C1-6 alkyl, etc.).
The aryl group in said aryl-alkyl group means a monocyclic
or condensed polycyclic aromatic hydrocarbon group, and
preferred examples include phenyl, naphthyl, anthryl,
phenanthryl, acenaphthenyl, and the like. They may have a
substituent such as a C1-10 alkyl group, a C2-10 alkenyl
group, a C2-10 alkynyl group, a C3-8 cycloalkyl group, a C3-8
cycloalkenyl group, a C4-8 cycloalkadienyl group, an aryl
group (e.g., C6-14 aryl, etc.), an aromatic heterocyclic
group (e.g., the same aromatic heterocyclic group as that
of the substituent of the hydrocarbon group, the acyl group,
the sulfonyl group, the sulfinyl group and the heterocyclic
group of the above substituent of the 5- to 7-membered ring,
etc.), a non-aromatic heterocyclic group (e.g., the same
non-aromatic heterocyclic group as that of the substituent
of the hydrocarbon group, the acyl group, the sulfonyl
group, the sulfinyl group and the heterocyclic group of the
above substituent of the 5- to 7-membered ring, etc.), an
aralkyl group (e.g., a C6-14 aryl-C1-6 alkyl group, etc.),
amino group, an N-mono-substituted amino group (e.g., the
same N-mono-substituted amino group as that of the

substituent of the hydrocarbon group, the acyl group, the
sulfonyl group, the sulfinyl group and the heterocyclic
group of the above substituent of the 5- to 7-membered ring,
preferably a N-mono-C1-4 alkylamino group, etc.), a N,N-
disubstituted amino group (e.g., the same N,N-disubstituted
amino group as that of the substituent in the hydrocarbon
group, the acyl group, the sulfonyl group, the sulfinyl
group and the heterocyclic group of the above substituent
of the 5- to 7-membered ring, preferably a N,N-di-C1-4
alkylamino group, etc.), amidino group, an acyl group (e.g.,
the same acyl group as that of the substituent of the
hydrocarbon group, the acyl group, the sulfonyl group, the
sulfinyl group and the heterocyclic group of the above
substituent of the 5- to 7-membered ring, etc.), carbamoyl
group, a N-mono-substituted carbamoyl group (e.g., a N-
mono-C1-4 alkyl-carbamoyl group such as methylcarbamoyl,
ethylcarbamoyl, etc.; phenylcarbamoyl; etc.), a N,N-
disubstituted carbamoyl group (a N,N-di-C1-4 alkyl-carbamoyl
group such as N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,
etc.; piperidinocarbamoyl; morpholinocarbamoyl; etc.),
sulfamoyl group, a N-mono-substituted sulfamoyl group (e.g.,
a N-mono-C1-4 alkylsulfamoyl group such as methylsulfamoyl,
ethylsulfamoyl, etc.; phenylsulfamoyl; p-toluenesulfamoyl;
etc.), a N,N-disubstituted sulfamoyl group (e.g., a N,N-
disubstituted C1-4 alkylsulf amoyl group such as N,N-

dimethylsulfamoyl, etc.; a N-C1-4 alkyl-N-phenylsulfamoyl
group such as N-methyl-N-phenylsulfamoyl, etc.;
piperidinosulfamoyl; morpholinosulfamoyl; etc.), carboxyl
group, a C1-10 alkoxy-carbonyl group (e.g., methoxycarbonyl,
ethoxycarbonyl, isopropoxycarbonyl, sec-butoxycarbonyl,
isobutoxycarbonyl, tert-butoxycarbonyl, etc.), hydroxyl
group, a C1-10 alkoxy group, a C2-10 alkenyloxy group, a C3-7
cycloalkyloxy group, an aralkyloxy group (e.g., C6-14 aryl-
C1-6 alkyloxy, etc.), an aryloxy group (e.g., C6-14 aryloxy,
etc.), mercapto group, a C1-10 alkylthio group, an
aralkylthio group (e.g., C6-14 aryl-C1-6 alkylthio, etc.), an
arylthio group (e.g., C6-14 arythio, etc.), sulfo group,
cyano group, azido group, nitro group, nitroso group, a
halogen atom, or the like. As for an alkyl group in said
aryl-alkyl group, a C1-6 alkyl group (e.g., methyl, ethyl,
propyl, butyl, etc.) is preferred. Preferred examples of
said aralkyl group, i.e., an aryl-alkyl group include
benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl)methyl, (2-
naphthyl)methyl, and the like. Among them, benzyl,
phenethyl, and the like are preferred.
As the acyl group in said acyloxycarbonyl group, for
example, there are formyl, a C2-4 alkanoyl group, a C3-4
alkenoyl group, a C3-4 alkynoyl group, and the like.
As the aryl group in said aryloxycarbonyl group, for
example, there are phenyl, naphthyl, and the like.

Examples of the amidated carboxyl group as the
substituent of the hydrocarbon group, the acyl group, the
sulfonyl group, the sulfinyl group and the heterocyclic
group of the substituent of the 5- to 7-membered ring
include the carboxyl group amidated with an optionally
substituted amino group as the substituent of the
hydrocarbon group, the acyl group, the sulfonyl group, and
the heterocyclic group of the above substituent of the 5-
to 7-membered ring, each of which may be substituted.
Example of an optionally substituted phosphoryl group
of the substituent of the 5- to 7-membered ring include
phosphoryl group, a (C1-6 alkoxy) phosphoryl group such as
ethoxyphosphoryl, a di-(C1-6 alkoxy)phosphoryl group such as
diethoxyphosphoryl, etc.; a lower (C1-6) alkyl group
substituted with an optionally esterified phosphono group
such as a phosphono-C1-6 alkyl group, a C1-6
alkoxyphosphoryl-C1-6 alkyl group, a di- (C1-6
alkoxy) phosphoryl-C1-6 alkyl group such as
diethoxyphosphorylmethyl, etc.; and the like.
"The hydrocarbon group", "the heterocyclic group",
"the sulfinyl group", or "the sulfonyl group" in "an
optionally substituted hydrocarbon group", "an optionally
substituted heterocyclic group", "an optionally substituted
sulfinyl group", or "an optionally substituted sulfonyl
group" of the substituent of the 5- to 7-membered ring may

be further substituted with 1 to 3 substituents. Examples
of said substituents include a lower (C1-6) alkyl group
(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,
etc.); a lower (C2-6) alkenyl group (e.g., vinyl, allyl, 1-
propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-
butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-
pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-
hexenyl, 4-hexenyl, 5-hexenyl, etc.); a lower (C2-6) alkynyl
group (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-
butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-
pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-
hexynyl, etc.); a C3-7 cycloalkyl group (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); a
C6-10 aryl group (e.g., phenyl, α-naphthyl, β-naphthyl,
etc.); an aromatic heterocyclic group [e.g., (i) an
aromatic 5- or 6-membered heterocyclic group having 1-4
heteroatoms selected from nitrogen atom, oxygen atom, and
sulfur atom; (ii) a fused bicyclic heterocyclic group
formed by condensation of an aromatic 5- or 6-membered
heterocyclic group having 1 to 3 heteroatoms selected from
nitrogen atom, oxygen atom, and sulfur atom with benzene
ring or an aromatic 5- or 6-membered heterocyclic group
having 1 to 3 heteroatoms selected from nitrogen atom,
oxygen atom, and sulfur atom; (iii) a fused tricyclic

heterocyclic group formed by condensation of [1] an
aromatic, 5- or 6-membered heterocyclic group having 1-3
heteroatoms selected from nitrogen atom, oxygen atom and
sulfur atom, [2] benzene ring, and [3] an aromatic 5- or 6-
membered heterocyclic group having 1-3 heteroatoms selected
from nitrogen atom, oxygen atom and sulfur atom or benzene
ring, such as furyl, thienyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-
thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,
pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl,
isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,
1,2-benzisothiazolyl, 1H-benztriazolyl, quinolyl,
isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,
phthalazinyl, naphthyridinyl, purinyl, pteridinyl,
carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl,
acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,
phenoxatinyl, thianthrenyl, phenanthredinyl,
phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,
pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-
a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyridyl,
imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,
imidazo[1,2-a]pyrimidinyl, l,2,4-triazolo[4,3-a]pyridyl,

1, 2, 4-triazolo[4,3-b]pyridazinyl, etc.]; a heterocyclic-oxy
group formed by combining each of the above heterocyclic
groups (i), (ii) and (iii) with oxy group; a non-aromatic
heterocyclic group (e.g., a non-aromatic, 4- or 7-membered
heterocyclic group having 1 to 3 heteroatoms selected from
nitrogen atom, oxygen atom and sulfur atom, such as
oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,
tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl,
morpholinyl, thiomorpholinyl, piperazinyl, etc.); a C7-14
aralkyl group (e.g., a C6-10 aryl-C1-4 alkyl group such as
benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-
phenylpropyl, 3-phenylpropyl, α-naphthylmethyl, α-
naphthylethyl, β-naphthylmethyl, β-naphthylethyl, etc.);
amino group; a N-mono-substituted amino group [e.g., a N-
(C1-6 alkyl)amino group such as methylamino, ethylamino,
allylamino, cyclohexylamino, phenylamino, a N- (C2-6
alkenyl) amino group, a N-(C3-7 cycloalkyl) amino group, a N-
(C6-10 aryl) amino group, etc.]; a N, N-disubstituted amino
group [e.g., an amino group substituted with two
substituents selected from a C1-6 alkyl group, a C2-6 alkenyl
group, a C3-7 cycloalkenyl group, and a C6-10 aryl group,
such as dimethylamino, diethylamino, dibutylamino,
diallylamino, N-methyl-N-phenylamino, etc.]; amidino group;
an acyl group (e.g., formyl, a C2-8 alkanoyl group such as
acetyl, propionyl, butyryl, isobytyryl, valeryl, isovaleryl,

pivaloyl, hexanoyl, heptanoyl, octanoyl,
cyclopropanecarbonyl, cyclobutanecarbonyl,
cyclopentanecarbonyl, cyclohexanecarbonyl, crotonyl, 2-
cyclohexenecarbonyl, benzoyl, nicotinoyl, etc.; a C3-8
alkenoyl group; a C3-7 cycloalkyl-carbonyl group; a C3-7
cycloalkenyl-carbonyl group; a C6-10 aryl-carbonyl group; a
heterocyclic-carbonyl group formed by binding of an
aromatic or non-aromatic 5- or 6-membered heterocyclic
group having 1-3 heteroatoms selected from nitrogen atom,
oxygen atom and sulfur atom with carbonyl group, etc.);
carbamoyl group; a mono-substituted carbamoyl group [e.g.,
a N-(C1-6 alkyl)carbamoyl group such as methylcarbamoyl,
ethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl,
etc.]; a N-(C2-6 alkenyl) carbamoyl group; a N-(C3-7
cycloalkyl) carbamoyl group; a N-(C6-10 aryl) carbamoyl group;
etc.]; a N,N-disubstituted carbamoyl group [e.g., a
carbamoyl group substituted with two substituents selected
from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-7
cycloalkyl group, and a C6-10 aryl group, such as
dimethylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl,
diallylcarbamoyl, N-methyl-N-phenylcarbamoyl, etc.];
sulfamoyl group, a N-mono-substituted sulfamoyl group [e.g.,
a N-(C1-6 alkyl)sulfamoyl group such as methylsulfamoyl,
ethylsulfamoyl, cyclohexylsulfamoyl, phenylsulfamoyl, etc.;
a N-(C2-6 alkenyl) sulfamoyl group; a N-(C3-7

cycloalkyl) sulfamoyl group; a N-(C6-10 aryl) sulfamoyl group;
etc.], a N,N-disubstituted sulfamoyl group [e.g., sulfamoyl
group substituted with two substituents selected from a C1-6
alkyl group, a C2-6 alkenyl group, a C3-7 cycloalkyl group,
and a C6-10 aryl group, such as dimethylsulf amoyl,
diethylsulfamoyl, dibutylsulfamoyl, diallylsulfamoyl, N-
methyl-N-phenylsulfamoyl, etc.]; carboxyl group; a lower
(C1-6) alkoxy-carbonyl group (e.g., methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,
tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,
etc.); hydroxyl group; a lower (C1-6) alkoxy group (e.g.,
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.); a
lower (C2-10) alkenyloxy group (e.g., allyloxy, 2-butenyloxy,
2-pentenyloxy, 3-hexenyloxy, etc.); a C3-7 cycloalkyloxy
group (e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy, cycloheptyloxy, etc.); a C6-10 aryloxy group
(e.g., phenoxy, naphthyloxy, etc.); a C7-14 aralkyloxy group
(e.g., a C6-10 aryl-C1-4 alkyloxy group such as phenyl-C1-4
alkyloxy, naphthyl-C1-4 alkyloxy, etc.); mercapto group; a
lower (C1-6)alkylthio group (e.g., methylthio, ethylthio,
propylthio, isopropylthio, butylthio, isobutylthio, sec-
butylthio, tert-butylthio, pentylthio, isopentylthio,
neopentylthio, hexylthio, etc.), a C7-14 aralkylthio group

(e.g., a C6-10 aryl-C1-4 alkylthio group such as phenyl-C1-4
alkylthio, naphthyl-C1-4 alkylthio, etc.); a C6-10 arylthio
group (e.g., phenylthio, naphtylthio, etc.), a lower (C1-6)
alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl,
propylsulfinyl, isopropylsulfinyl, butylsulfinyl,
isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl,
pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl,
hexylsulfinyl, etc.); a C7-14 aralkylsulfinyl group (e.g., a
C6-10 aryl-C1-4 alkylsulf inyl group such as phenyl-C1-4
alkylsulf inyl, naphthyl-C1-4 alkylsulf inyl, etc.); a C6-10
arylsulfinyl group (e.g., phenylsulfinyl, naphtylsulfinyl,
etc.); a lower (C1-6) alkylsulf onyl group (e.g.,
methylsulfonyl, ethylsulfonyl, propylsulfonyl,
isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-
butylsulf onyl, tert-butylsulfonyl, pentylsulfonyl,
isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl, etc.),
a C7-14 aralkylsulf onyl group (e.g., a C6-10 aryl-C1-4
alkylsulfonyl group such as phenyl-C1-4 alkylsulfonyl,
naphthyl-C1-4 alkylsulf onyl, etc.), a C6-10 arylsulfonyl
group (e.g., phenylsulfonyl, naphtylsulfonyl, etc.); sulfo
group; cyano group; azido group; a halogen atom (e.g.,
fluorine, chlorine, bromine, iodine, etc.); nitro group;
nitroso group; an optionally esterified phosphono group
[e.g., phosphono group, a (C1-6 alkoxy)phosphoryl group such
as ethoxyphosphoryl, a di-(C1-6 alkoxy)phosphoryl group such

as diethoxyphosphoryl, etc.]; a lower (C1-6) alkyl group
substituted with an optionally esterified phosphono group
(e.g., a phosphono-C1-6 alkyl group, a C1-6 alkoxyphosphoryl-
C1-6 alkyl group, a di-(C1-6 alkoxy) phosphoryl-C1-6 alkyl
group such as diethoxyphosphorylmethyl, etc.); a C1-6
haloalkyl group (e.g., a C1-6 alkyl group substituted with 1
to 4 halogen such as trifluoromethyl, etc.); a C1-6
haloalkoxy group (e.g., a C1-6 alkoxy group substituted with
1 to 4 halogen such as trif luoromethoxy, etc.); and the
like.
Among the above substituents, when hydroxyl group is
located adjacent to a lower (C1-6) alkoxy group, they may
form C1-6 alkylenedioxy groups such as methylenedioxy,
ethylenedioxy, or the like.
The above C6-10 aryl group, the C6-10 aryl group as a
substituent of the aromatic heterocyclic group and the N-
mono-substituted amino group, the C6-10 aryl group as a
substituent of the N, N-di-substituted amino group, the C6-10
aryl group as a substituent of the N-mono-substituted
carbamoyl group, the C6-10 aryl group as a substituent of
the N, N-di-substituted carbamoyl group, the C6-10 aryl as a
substituent of the N-mono-substituted sulfamoyl group, the
C6-10 aryl group as a substituent of the N, N-disubstituted
sulfamoyl group, the C6-10 aryl group as a substituent of
the C6-10 aryloxy group, the C6-10 aryl group of the C7-14

aralkyloxy group, the C6-10 aryl group of the C7-14
aralkylthio groups, the C6-10 aryl group of the C6-10
arylthio groups, the C6-10 aryl group of the C7-14
aralkylsulf inyl groups, the C6-10 aryl group of the C6-10
arylsulfinyl group, the C6-10 aryl group of the C7-3.4
aralkylsulfonyl groups, and the C6-10 aryl group in the C6-10
arylsulfonyl group may be substituted further with 1 to 3
substituents. Examples of said substituent include a lower
(C1-6) alkyl group, amino group, a N-(C1-6 alkyl) amino group,
a N,N-di-(C1-6 alkyl)amino group, amidino group, carbamoyl
group, a N- (C1-6 alkyl) carbamoyl group, a N,N-di-(C1-6
alkyl)carbamoyl group, sulfamoyl group, a N-(C1-6
alkyl)sulfamoyl group, a N,N-di-(C1-6 alkyl)sulfamoyl group,
carboxyl group, a lower (C2-7) alkoxycarbonyl group,
hydroxyl group, a lower (C1-6) alkoxy group, mercapto group,
a lower (C1-6) alkylthio group, sulfo group, cyano group,
azido group, a halogen atom, nitro group, nitroso group, an
optionally substituted phosphono group [e.g., phosphono
group, a C1-6 alkoxyphosphoryl group, a di- (C1-6
alkoxy) phosphoryl group, etc.], a lower (C1-6) alkyl group
substituted with an optionally esterified phosphono group
[e.g., a phosphono-C1-6 alkyl group, a C1-6 alkoxyphosphoryl-
C1-6 alkyl group, a di- (C1-6 alkoxy) phosphoryl-C1-6 alkyl
group such as diethoxyphosphorylmethyl, etc.], and the like
Among the above substituent, when hydroxyl group is

located adjacent to a lower (C1-6) alkoxyl group, they may
form a C1-6 alkylenedioxy group such as methylenedioxy,
ethylenedioxy, or the like.
The number of the substituents of the 5- to 7-membered
ring is 1 to 3, preferably 1 to 2 and the substituents may
be the same or different and present at any possible
positions of the ring.
Q of the formula (II) is C, CR5, or N.
R5 is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, cyano group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -SO2-, and Z2 is
an optionally substituted hydrocarbon group, an optionally
substituted heterocyclic group, an optionally substituted
hydroxyl group, or an optionally substituted amino group).
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group and an optionally
substituted heterocyclic group of R5 or Z2 include the same
groups as those exemplified with respect to the above
substituents of the 5- to 7-membered ring of ring A.
Examples of halogen and an optionally substituted
thiol group of R5 include the same groups as those

exemplified with respect to the above substituent of the 5-
to 7-membered ring of ring A.
X1 in the formulas (I) and (II) is CR1, CR1R2, N or NR13.
R1 is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, cyano group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- and Z2 are as defined above) .
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, halogen and an optionally
substituted heterocyclic group of R1 include the same
groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A.
R2 is H, or an optionally substituted hydrocarbon
group, and examples of an optionally substituted
hydrocarbon group of R2 include the same group as that
exemplified with respect to the substituent of the 5- to 7-
membered ring of ring A.
R13 is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted
heterocyclic group, or a group of the formula: -Z1-Z2

(wherein -Z1- and Z2 are as defined above) .
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group and an optionally
substituted heterocyclic group of R13 include the same
groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A.
R1 of the formula (III) is H, an optionally
substituted hydrocarbon group, an optionally substituted
hydroxyl group, an optionally substituted thiol group, an
optionally substituted amino group, cyano group, a halogen
atom, an optionally substituted heterocyclic group, or a
group of the formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -
SO- or -SO2-, and Z2 is an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic
group, an optionally substituted hydroxyl group, or an
optionally substituted amino group).
In R1 of the formula (III), preferred example of the
group of the formula: -Z1-Z2 is a group of the formula: -
CONR20(CR21R22R23) , wherein R20 is H or an optionally
substituted hydrocarbon group, and R21, R22, and R23 are the
same or different and are an optionally substituted
hydrocarbon group, an optionally substituted heterocyclic
group, or R20 and R21 may be combined to form a ring.
Examples of an optionally substituted hydrocarbon

group of R1, R20, R21, R22 and R23, an optionally substituted
heterocyclic group of R1, R21, R22 and R23, and an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group and halogen of
R1 include the same groups as those exemplified with
respect to the substituents of the 5- to 7-membered ring of
ring A of the formulas (I) and (II) .
Preferably, at least one of R21, R22 and R23 is an
optionally substituted heterocyclic group which may be
fused with an optionally substituted benzene ring, or an
optionally substituted phenyl group which may be fused with
an optionally substituted aromatic heterocyclic ring.
Examples of the "fused heterocyclic group" of the
"optionally substituted heterocyclic group which may be
fused with an optionally substituted benzene ring" and the
"fused phenyl group" of the " optionally substituted phenyl
group which may be fused with an optionally substituted
aromatic heterocyclic ring" of R21, R22 and R23 include the
same groups as those exemplified with respect to the
aromatic fused heterocyclic group as the substituents of
the 5- to 7-membered ring of ring A.
Examples of these substituents include the same groups
as those exemplified with respect to the substituents of
the 5- to 7-membered ring of ring A of the formulas (I) and
(II).

The ring formed in combination with R20 and R21 is
preferably an optionally substituted 5- to 7-membered ring,
more preferably an optionally substituted 5- or 6-membered
ring, and may be fused with an optionally substituted
benzene ring. Such rings include the same rings as those
exemplified with respect to the "5- to 7-membered ring" of
"an optionally substituted 5- to 7-membered ring" in the
ring A of the formulas (I) and (II).
These rings may have 1 to 3 substituents selected from
the group consisting of (1) halogen, (2) hydrogen, (3) a
phenoxy which may be substituted with 1 to 3 substituents
selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6
acyl (e.g., formyl, C2-6 alkanoyl, etc.), cyano, amino,
mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-
sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6
alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N-
di-C1-6 alkyl-carbamoyl,
(4) C1-6 alkoxy which may be substituted with 1 to 3
substituents selected from halogen, hydroxyl, C1-6 alkyl,
C1-6 alkoxy, C1-6 acyl, cyano, amino, mono-C1-6 alkyl-amino,
di-C1-6 alkyl-amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl,
C1-6 alkyl-sulf onyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6
alkyl-carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl
which may be substituted with 1 to 3 substituents selected
from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl,

cyano, halogeno C1-6 alkyl (e.g., trifluoromethyl, etc.),
amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-
sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6
alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N-
di-C1-6 alkyl-carbamoyl,
and (5) a C1-8 hydrocarbon group (e.g., C1-8 alkyl, C3-7
cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkenyl,
etc.) which may be substituted with 1 to 3 substituents
selected from halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6
acyl, cyano, amino, mono-C1-6 alkyl-amino, di-C1-6 alkyl-
amino, C1-6 alkyl-sulf anyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-
sulfonyl, C1-6 alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-
carbamoyl, N,N-di-C1-6 alkyl-carbamoyl and phenyl which may
be substituted with 1 to 3 sunstitutents selected from
halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, cyano,
halogeno C1-6 alkyl (e.g., trifluoromethyl, etc.), amino,
mono-C1-6 alkyl-amino, di-C1-6 alkyl-amino, C1-6 alkyl-
sulfanyl, C1-6 alkyl-sulf inyl, C1-6 alkyl-sulf onyl, C1-6
alkoxy-carbonyl, carbamoyl, N-C1-6 alkyl-carbamoyl and N,N-
di-C1-6 alkyl-carbamoyl.
Specific examples of these substituents include the
same groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A of the
formulas (I) and (II) .
R1a of the formula (IIIa) is (1) an optionally

substituted heterocyclic group or (2) a group of the
formula: -Z1a-Z2a (wherein -Z1a- is -CO-, -CS-, -SO- or -SO2-,
and Z2a is (i) an optionally substituted heterocyclic group,
(ii) -NR20a(CR21aR22aR23a) (wherein (a) R20a is H or an
optionally substituted hydrocarbon group; and R21a is an
optionally substituted heterocyclic group which may be
fused with an optionally substituted benzene ring, or an
optionally substituted C6-10 aryl group which may be fused
with an optionally substituted aromatic heterocyclic ring
and R22a and R23a are the same or different and are an
optionally substituted hydrocarbon group or an optionally
substituted heterocyclic group or R22a and R23a may be
combined to form a ring, or (b) R20a is H or an optionally
substituted hydrocarbon group; and R21a, R22a and R23a are the
same or different and are an optionally substituted C1-8
aliphatic hydrocarbon group, provided that the sum total of
the number of carbon atoms is 7 or more),
(iii) -NR20aR25a (wherein R20a is as defined above and R25a is
an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10
aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7-14
aralkylamino-C2-4 alkyl, heterocyclic ring-C2-4 alkyl or
heterocyclic group), (iv) a substituted 5- to 7-membered
cyclic amino group, or (v) -OR24a (wherein R24a is (a) an
optionally substituted C7-14 aralkyl group, (b) an
optionally substituted C3-7 alicyclic hydrocarbon group, (c)

an optionally substituted C7-24 aliphatic hydrocarbon group,
or (d) an optionally substituted heterocyclic group)).
Examples of an optionally substituted hydrocarbon
group of R20a, R22a and R23a and an optionally substituted
heterocyclic group of Rla, Z2a, R21a, R22a and R23a include the
same groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A of the
formulas (I) and (II) .
Examples of the "fused heterocyclic group" of the
"optionally substituted heterocyclic group which may be
fused with an optionally substituted benzene ring" and the
"fused phenyl group" of "an optionally substituted phenyl
group which may be fused with an optionally substituted
aromatic heterocyclic ring" of R21a, R22a and R23a include the
same groups as those exemplified with respect to the
aromatic fused heterocyclic group as the substituents of
the 5- to 7-membered ring of ring A.
Examples of the ring formed in combination with R20a
and R21a and the substituents thereof include the same rings
and substituents as those exemplified with respect to the
ring formed in combination with R20 and R21 and the
substituents thereof.
Examples of the "optionally substituted C1-8 aliphatic
hydrocarbon group" of R20a include the same groups as those
exemplified with respect to the aliphatic hydrocarbon group

as the substituents of the 5- to 7-membered ring of ring A.
Examples of the "optionally substituted C7-14 aralkyl
group", the "optionally substituted C3-7 alicyclic
hydrocarbon group" and the "optionally substituted
heterocyclic group" of R24a include the same groups as those
exemplified with respect to the substituents of the 5- to
7-membered ring of ring A respectively.
Examples of the "C7-24 aliphatic hydrocarbon group" of
the "optionally substituted C7-24 aliphatic hydrocarbon
group" in R24a include, for example, C7-24 alkyl, C7-24
alkenyl, C7-24 alkynyl, C7-24 alkadienyl, C7-24 alkadiynyl such
as heptyl, octyl, 1-heptenyl, 1-octenyl, 1-heptynyl, 1-
octynyl, etc.
Examples of the substituents of the "optionally
substituted C7-24 aliphatic hydrocarbon group" in R24a
include the same substituents as those exemplified with
respect to the substituents of the hydrocarbon group as the
substituents of 5- to 7-membered ring of ring A.
In the formula (IIIa), Rla is preferably (1) an
optionally substituted 5- to 7-membered aromatic or non-
aromatic heterocyclic group having 1-4 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom,
or (2) a group of the formula: -CO-Z2c (wherein Z2c is (i)
an optionally substituted 5- to 7-membered aromatic or non-
aromatic heterocyclic group having 1-4 hetero atoms

selected from nitrogen atom, oxygen atom and sulfur atom,
(ii) -NR20c(CR21cR22cR23c) (wherein (a) R20c is H or an
optionally substituted hydrocarbon group selected from C1-8
saturated aliphatic hydrocarbon group, C2-8 unsaturated
aliphatic hydrocarbon group, C3-7 saturated alicyclic
hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon
group, C9-10 partly saturated and fused bicyclic hydrocarbon
group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated
or unsaturated aliphatic hydrocarbon group, C9-10 partly
saturated and fused bicyclic hydrocarbon-C1-4 alkyl group,
C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4
alkenyl group, C6-10 aryl group and C7-14 aralkyl group; and
R21c is 1) an optionally substituted 5- to 7-membered
aromatic or non-aromatic heterocyclic group having 1-4
hetero atoms selected from nitrogen atom, oxygen atom and
sulfur atom, which may be fused with an optionally
substituted benzene ring, or 2) an optionally substituted
C6-10 aryl group (e.g., phenyl group, etc.) which may be
fused with an optionally substituted 5- to 7-membered
aromatic heterocyclic ring having 1-4 hetero atoms selected
from nitrogen atom, oxygen atom and sulfur atom; and R22c
and R23c are the same or different and are an optionally
substituted hydrocarbon group selected from C1-8 saturated
aliphatic hydrocarbon group, C2-8 unsaturated aliphatic
hydrocarbon group, C3-7 saturated alicyclic hydrocarbon

group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10
partly saturated and fused bicyclic hydrocarbon group, C3-7
saturated or unsaturated alicyclic-C1-8 saturated or
unsaturated aliphatic hydrocarbon group, C9-10 partly
saturated and fused bicyclic hydrocarbon-C1-4 alkyl group,
C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4
alkenyl group, C6-10 aryl group and C7-14 aralkyl group, or an
optionally substituted 5- to 7-membered aromatic or non-
aromatic heterocyclic group having 1-4 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom or
R22c and R23c may be combined to form a C3-7 carbon ring, or
(b) R20c is H or an optionally substituted hydrocarbon group
selected from C1-8 saturated aliphatic hydrocarbon group,
C2-8 unsaturated aliphatic hydrocarbon group, C3-7 saturated
alicyclic hydrocarbon group, C3-7 unsaturated alicyclic
hydrocarbon group, C9-10 partly saturated and fused bicyclic
hydrocarbon group, C3-7 saturated or unsaturated alicyclic-
C1-8 saturated or unsaturated aliphatic hydrocarbon group,
C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4
alkyl group, C9-10 partly saturated and fused bicyclic
hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14
aralkyl group; and R21c, R22c and R23c are the same or
different and are an optionally substituted C1-8 aliphatic
hydrocarbon group, provided that the sum total of the
number of carbon atoms is 7 or more),

(iii) -NR20cR25c (wherein R20c is as defined above and R25c is
an optionally substituted C6-10 aryl-C2-4 alkyl, C6-10
aryloxy-C2-4 alkyl, C6-10 arylamino-C2-4 alkyl, C7-14
aralkylamino-C2-4 alkyl, 5- to 7-membered heterocyclic ring
(having 1-4 hetero atoms selected from nitrogen atom,
oxygen atom and sulfur atom)-C2-4 alkyl or 5- to 7-membered
heterocyclic group having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom),
(iv) a substituted 5- to 7-membered cyclic amino group
(e.g., piperidino, piperadino, morpholino, thiomorpholino,
etc.), or
(v) -OR24c (wherein R24c is (a) an optionally substituted C7-
14 aralkyl group, (b) an optionally substituted C3-7
alicyclic hydrocarbon group, (c) an optionally substituted
C7-24 aliphatic hydrocarbon group, or (d) an optionally
substituted 5- to 7-membered aromatic or non-aromatic
heterocyclic group having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom;
wherein said substituents for R1a, Z2c, R20c, R21c, R22c, R23c,
R24c and R25c are 1 to 3 substituents selected from the group
consisting of
1) C1-6 alkyl,
2) C2-6 alkenyl,
3) C2-6 alkynyl,
4) C3-7 cycloalkyl,

5) C6-10 aryl which may be substituted with 1 to 3
substituents selected from the group consisting of C1-6
alkyl, amino, N-(C1-6 alkyl) amino, N,N-di-(C1-6 alkyl) amino,
amidino, carbamoyl, N-(C1-6 alkyl) carbamoyl, N,N-di-(C1-6
alkyl)carbamoyl, sulfamoyl, N-(C1-6 alkyl)sulfamoyl, N,N-
di-(C1-6 alkyl) sulfamoyl, carboxyl, C2-7 alkoxycarbonyl,
hydroxyl, C1-6 alkoxy, mercapto, C1-6 alkylthio, sulfo,
cyano, azido, halogen, nitro, nitroso, phosphono, C1-6
alkoxyphosphoryl, di-(C1-6 alkoxy) phosphoryl and C1-6 alkyl
substituted with phosphono, C1-6 alkoxyphosphoryl and di-
(C1-6 alkoxy)phosphoryl (hereinafter the group of 5) is
referred to as group "C") ,
6) aromatic heterocyclic group selected from (a) aromatic
5- or 6-membered heterocyclic group having 1-4 hetero
atoms selected from nitrogen atom, oxygen atom and sulfur
atom, (b) fused bicyclic heterocyclic group formed by
condensation of an aromatic 5- or 6-membered heterocyclic
group having 1 to 3 hetero atoms selected from nitrogen
atom, oxygen atom and sulfur atom with benzene ring or an
aromatic 5- or 6-membered heterocyclic group having 1 to
3 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom and (c) fused tricyclic heterocyclic
group formed by condensation of [1] an aromatic 5- or 6-
membered heterocyclic group having 1-3 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom,

[2] benzene ring, and [3] an aromatic 5- or 6-membered
heterocyclic group having 1-3 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom or benzene
ring,
7) heterocyclic-oxy group formed by combining each of the
above aromatic heterocyclic groups (a) , (b) and (c) with
oxy group,
8) non-aromatic 4- or 7-membered heterocyclic group
having 1 to 3 hetero atoms selected from nitrogen atom,
oxygen atom and sulfur atom,
9) C7-14 aralkyl which may be substituted with 1 to 3
substituents selected from the group "C",
10) amino group,
11) N-mono-substituted amino selected from N-(C1-6
alkyl) amino, N-(C2-6 alkenyl) amino, N- (C3-7
cycloalkyl) amino group and N- (C6-10 aryl) amino which may
be substituted with 1 to 3 substituents selected from the
group "C",
12) amino substituted with two substituents selected from
C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkenyl and C6-10 aryl
which may be substituted with 1 to 3 substituents
selected from the group "C",
13) amidino,
14) acyl selected from C2-8 alkanoyl, C3-8 alkenoyl, C3-7
cycloalkyl-carbonyl, C3-7 cycloalkenyl-carbonyl, C6-10

aryl-carbonyl which may be substituted with 1 to 3
substituents selected from the group "C", and
heterocyclic-carbonyl formed by binding of an aromatic or
non-aromatic 5- or 6-membered heterocyclic group having
1-3 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom with carbonyl,
15) carbamoyl,
16) mono-substituted carbamoyl group selected from N-(C1-6
alkyl) carbamoyl, N- (C2-6 alkenyl) carbamoyl, N-(C3-7
cycloalkyl) carbamoyl and N-(C6-10 aryl) carbamoyl which may
be substituted with 1 to 3 substituents selected from the
group "C",
17) carbamoyl substituted with two substituents selected
from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C5-10 aryl
which may be substituted with 1 to 3 substituents
selected from the group "C",
18) sulfamoyl,
19) N-mono-substituted sulfamoyl selected from N-(C1-6
alkyl) sulfamoyl, N- (C2-6 alkenyl) sulfamoyl, N-(C3-7
cycloalkyl) sulfamoyl and N-(C6-10 aryl) sulfamoyl which may
be substituted with 1 to 3 substituents selected from the
group "C",
20) sulfamoyl substituted with two substituents selected
from C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl and C6-10
aryl which may be substituted with 1 to 3 substituents

selected from the group "C",
21) carboxyl,
22) C1-6 alkoxy-carbonyl,
23) hydroxyl,
24) C1-6 alkoxy,
25) C2-10 alkenyloxy,
26) C3-7 cycloalkyloxy,

27) C6-10 aryloxy which may be substituted with 1 to 3
substituents selected from the group "C",
28) C7-14 aralkyloxy which may be substituted with 1 to 3
substituents selected from the group "C",
29) mercapto,
30) C1-6 alkylthio,
31) C7-14 aralkylthio which may be substituted with 1 to 3
substituents selected from the group "C",
32) C6-10 arylthio which may be substituted with 1 to 3
substituents selected from the group "C",
33) C1-6 alkylsulfinyl,
34) C7-14 aralkylsulfinyl which may be substituted with 1
to 3 substituents selected from the group "C",
35) C6-10 arylsulfinyl which may be substituted with 1 to
3 substituents selected from the group "C",
36) C1-6 alkylsulfonyl,
38) C7-14 aralkylsulf onyl which may be substituted with 1
to 3 substituents selected from the group "C",

39) C6-10 arylsulfonyl which may be substituted with 1 to
3 substituents selected from the group "C",
40) sulfo,
41) cyano,
42) azido,
43) halogen,
44) nitro,
45) nitroso,
46) phosphono,
47) C1-6 alkoxy-phosphoryl
48) di-C1-6 alkoxy-phosphoryl,
49) C1-6 alkyl substituted with phosphono, C1-6
alkoxyphosphoryl or di-(C1-6 alkoxy) phosphoryl
50) C1-6 alkyl substituted with 1 to 4 halogen atoms
51) C1-6 alkoxy substituted with 1 to 4 halogen atoms and
52) C1-6 alkylenedioxy
(hereinafter the group of above 1) to 52) is referred to
as group "B").
Specific examples of these substituents include the
same groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A.
As R1a of the formula (IIIa), more preferred is the
group represented by the formula:
CONR20c(CR21cR22cR23c) (wherein R20c, R21c, R22c and R23c are as
defined above).

Further more preferably, R1a is (1) a 5- to 7-membered
aromatic heterocyclic group having 1-4 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom
(e.g., 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, etc.) which
is substituted with C1-4 alkyl-C7-14 aralkyl (e.g., 1-ethyl-
1-(4-methylphenyl)propyl, etc.), or (2) a group represented
by the formula: -CO-Z2c' (wherein Z2c' is
(i) -NR20c' (CR21c'R22c'R23c') (wherein (a) R20c' is H or C1-6
alkyl; R21c' is a C6-10 aryl group or a 5- to 7-membered
aromatic heterocyclic group having 1-4 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom,
each of which may be substituted with 1 to 3 substituents
selected from the group consisting of halogen, C1-6 alkyl,
C2-6 alkenyl, halogeno C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6
alkoxy, carboxyl, C1-6 alkoxy-carbonyl, C1-6 alkyl-
carbonyloxy, C1-6 alkyl-carbonyloxy-C1-6 alkyl, carboxy-C1-6
alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkyl, C1-6 alkoxy-carbonyl-
C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy-C1-6 alkyl,
carbonyl, C1-6 alkyl-carbonyl, amino, mono- or di- C1-6
alkylamino, phenyl (said phenyl may be substituted with 1
to 3 substituents selected from halogen, C1-6 alkyl and
halogeno C1-6 alkyl) and a 5- to 7-membered aromatic
heterocyclic group having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom; R22c' and R23c'
are the same or different and are C1-6 alkyl group, C5-7

cycloalkyl group, phenyl group (said phenyl group may be
substituted with 1 to 3 substituents selected from C1-6
alkyl, halogeno C1-6 alkyl and C1-6 alkoxy) , C1-6 alkoxy-
carbonyl-C1-6 alkyl group or C1-6 alkyl-carbonyl-C2-6 alkenyl
group, or R22c' and R23c' may be combined each other to form a
C3-7 carbon ring; or (b) R20c' and R21c' are combined each
other to form a 5- to 7-membered ring and said ring may be
substituted with C1-6 alkoxy or C7-14 aralkyl, and R22c' and
R23c' are C1-6 alkyl group) ,
(ii) -NR20C'R25C' (wherein R20c' is H or C1-6 alkyl group; R25c'
is C6-10 aryl-C2-4 alkyl group, C6-10 aryloxy-C2-4 alkyl group,
C6-10 arylamino-C2-4 alkyl group, C7-14 aralkylamino-C2-4 alkyl
group, 5- to 7-membered heterocyclic ring-C2-4 alkyl group
or 5- to 7-membered heterocyclic group, each of which may
be substituted with 1 or 2 substituents selected from the
group consisting of halogen, C1-6 alkyl, C6-10 aryl, C1-6
alkoxy, amino, mono- or di- C1-6 alkylamino, 5- to 7-
membered cyclic amino, hydroxy, oxo, C1-6 alkoxy-carbonyl
and cyano), or
(iii) a 5- to 7-membered cyclic amino group which is
substituted with 1 to 3 substituents selected from the
group consisting of halogen, C1-6 alkyl, C2-6 alkenyl, C1-6
alkoxy-C1-6 alkyl, C5-7 cycloalkyl, C6-10 aryl (said aryl may
have 1 or 2 substituents selected from halogen, C1-6 alkyl,
halogeno C1-6 alkyl and C1-6 alkoxy) , C7-14 aralkyl (said

aralkyl may have 1 or 2 substituents selected from halogen,
C1-6 alkyl, halogeno C1-6 alkyl and C1-6 alkoxy) , hydroxy,
hydroxy-C1-6 alkyl, C6-10 aryloxy (said aryloxy may have 1 or
2 substituents selected from halogen, C1-6 alkyl, halogeno
C1-6 alkyl and C1-6 alkoxy) , C7-14 aralkyloxy, C6-10 aryl-
carbonyl, carboxyl, C1-6 alkoxy-carbonyl, carbamoyl, C6-10
aryl-carbamoyl, amino, C6-10 aryl-carbonylamino, C1-6 alkyl-
carbonylamino, C1-6 alkoxy-carbonylamino, C6-10 arylthio, C6-
10 arylsulfonyl, cyano, oxo and 5- to 7-membered
heterocyclic group.).
R3 of the formulas (II), (III) and (IIIa) is H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted heterocyclic group, or a
group of the formula: -Z1-Z2 (wherein -Z1- and Z2 are as
defined above).
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group and an optionally
substituted heterocyclic group of R3 include the same
groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A.
R3 is preferably H, a C1-6 alkyl group or a C7-14 aralkyl
group, and more preferably R3 is H.
Y in the formulas (I), (II), (III) and (IIIa) is C,

CR4, or N.
R4 is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, cyano group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- and Z2 are as defined above) .
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted heterocyclic group and halogen of R4 include
the same groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A.
Y is preferably CH.
R8 of the formulas (III) and (IIIa) is H, an
optionally substituted hydrocarbon group, an optionally
substituted hydroxyl group, an optionally substituted amino
group, an optionally substituted thiol group, cyano group,
a halogen atom, an optionally substituted heterocyclic
group, or a group of the formula: -Z1-Z2 (wherein -Z1- and
Z2 are as defined above).
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, halogen atom and an optionally

substituted heterocyclic group of R include the same
groups as those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A.
R8 is preferably H, a C1-6 alkyl group, a C1-6 alkylthio
group or a C1-6 alkoxy group which may be substituted with
hydroxyl group, and more preferably R8 is H or a C1-6 alkyl
group.
Ar in the formulas (I), (II), (III) and (IIIa) is an
optionally substituted cyclic group.
Examples of the optionally substituted cyclic group of
Ar include an optionally substituted aromatic or non-
aromatic hydrocarbon ring group or an optionally
substituted aromatic or non-aromatic heterocyclic group,
and the like.
Examples of the aromatic hydrocarbon ring group and
the heterocyclic group of Ar include the same aromatic
hydrocarbon group and heterocyclic group as exemplified
with respect to the above substituents of the 5- to 7-
membered ring of ring A.
Examples of the non-aromatic hydrocarbon ring group
include a saturated alicyclic hydrocarbon group having 3-7
carbon atoms (e.g., cycloalkyl group, etc.) such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like; an unsaturated alicyclic
hydrocarbon group having 3-7 carbon atoms (e.g.,

cycloalkenyl group, cycloalkadienyl group, etc.) such as 1-
cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-
cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-
cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-
cycloheptadienyl, etc.; a partly saturated and fused
bicyclic hydrocarbon group [preferably, C9-10 partly
saturated and fused bicyclic hydrocarbon group, etc.
(including those where the benzene ring is combined to 5-
or 6-membered non-aromatic cyclic hydrocarbon group)] such
as 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl, 1,2,3,4-
tetrahydro-1-naphthyl, 1, 2, 3, 4-tetrahydro-2-naphthyl, 1,2-
dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-
naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl,
3,4-dihydro-2-naphthyl, etc.; and the like.
Examples of the substituent of an optionally
substituted aromatic ring group and an optionally
substituted heterocyclic group of Ar include the same
groups as those exemplified with respect to the above
substituents of the 5- to 7-membered ring of ring A.
Ar is preferably (1) a C6-10 aryl group, (2) a 5- to 7-
membered aromatic or non-aromatic heterocyclic group having
1-4 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom, or (3) a C3-7 saturated or unsaturated
alicyclic hydrocarbon group, each of which may be
substituted with 1 to 3 substituents selected from the

group "B".
More preferably, Ar is a C6-10 aryl group which may be
substituted with 1 to 3 substituents selected from the
group "B", a 5- to 7-membered aromatic heterocyclic group
having 1-4 hetero atoms selected from nitrogen atom, oxygen
atom and sulfur atom which may be substituted with 1 to 3
substituents selected from the group "B", or a C3-7
saturated or unsaturated alicyclic hydrocarbon group.
Further more preferably, Ar is (1) a C6-10 aryl group
(e.g., phenyl, naphthyl, etc.) which may be substituted
with 1 or 2 substituents selected from the group consisting
of halogen atom, C1-6 alkyl, C1-6 alkoxy, hydroxy, C7-14
aralkyloxy and mono- or di-C1-4 alkylamino, (2) a 5- to 7-
membered aromatic heterocyclic group having 1-4 hetero
atoms selected from nitrogen atom, oxygen atom and sulfur
atom (e.g., pyridyl, furyl, thiazolyl, thienyl, etc.) which
may be substituted with C1-4 alkyl or (3) a C5-7 cycloalkyl
group (e.g., cyclohexyl etc.), and most preferably, Ar is
an optionally halogenated phenyl group.
R9 and R10 of the formulas (II), (III) and (IIIa) are
the same or different and are H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of

the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above), or R9 and R10 may be combined to form an oxo group,
methylene group or a ring.
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, a halogen atom and an optionally
substituted heterocyclic group of R9 and R10 include the
same groups as those exemplified with respect to the above
substituents of the 5- to 7-membered ring of ring A.
One of R9 and R10 is preferably a hydrogen atom or C1-6
alkyl group which may be substituted with 1 to 3
substituents selected from the group "B" and the other is
(1) a hydrocarbon group selected from C1-8 saturated
aliphatic hydrocarbon group, C2-8 unsaturated aliphatic
hydrocarbon group, C3-7 saturated alicyclic hydrocarbon
group, C3-7 unsaturated alicyclic hydrocarbon group, C9-10
partly saturated and fused bicyclic hydrocarbon group, C3-7
saturated or unsaturated alicyclic-C1-8 saturated or
unsaturated aliphatic hydrocarbon group, C9-10 partly
saturated and fused bicyclic hydrocarbon-C1-4 alkyl group,
C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4
alkenyl group, C6-10 aryl group and C7-14 aralkyl group, each
of which may be substituted with 1 to 3 substituents
selected from the group "B" or (2) a 5- to 7-membered

aromatic or non-aromatic heterocyclic group having 1-4
hetero atoms selected from nitrogen atom, oxygen atom and
sulfur atom, which may be substituted with 1 to 3
substituents selected from the group "B", or
R9 and R10 may be combined to form a C5-7 carbon ring.
More preferably, one of R9 and R10 is preferably a
hydrogen atom or C1-6 alkyl group and the other is an
optionally halogenated C1-6 alkyl group, C6-10 aryl group, C7-
10 aralkyl group or a 5- to 7-membered aromatic
heterocyclic group, or R9 and R10 are a C5-7 carbon ring
formed by combining together.
Examples of R11 and R12 of the forumula (II) are the
same or different and are H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1'-Z2 (wherein -Z1'- is -CS-, -SO- or -SO2-,
and Z2 is as defined above).
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, a halogen atom and an optionally
substituted heterocyclic group of R11 and R12 include the
same groups as those exemplified with respect to the above

substituents of the 5- to 7-membered ring of ring A.
R9 and R10, or R11 and R12 may be combined to form an
oxo group, methylene group or a ring such as a C3-6
saturated or unsaturated carbon ring (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentenyl, 2-
cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-
cyclohexenyl, 3-cyclohexenyl, etc.); or R10 and R11 may be
combined to form a ring such as a C3-6 saturated or
unsaturated carbon ring (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, 1-cyclopentenyl, 2-cyclopentenyl,
3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-
cyclohexenyl, etc.).
is a single bond or a double bond.
Z in the formula (I) is CR5, CR5R6, N or NR7, and CR5
is as defined above.
R6 is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, cyano group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:
-Z1-Z2 (wherein -Z1- and Z2 are as defined above)).
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, and an optionally substituted

heterocyclic group of R6 include the same groups as those
exemplified with respect to the above substituents of the
5- to 7-membered ring of ring A.
R7 is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above)).
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, a halogen atom and an
optionally substituted heterocyclic group of R7 include the
same groups as those exemplified with respect to the above
substituents of the 5- to 7-membered ring of ring A.
R5, R6 and R7 may be the same or different.
R5 is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted thiol
group, an optionally substituted sulfonyl group or an
optionally substituted sulfinyl group.
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, an optionally substituted sulfonyl

group and an optionally substituted sulfinyl group of R
include the same groups as those exemplified with respect
to the above substituents of the 5- to 7-membered ring of
ring A.
R and Z may be combined to form a ring B
Ring B in the formula (I) is an optionally substituted
5- to 7-membered heterocyclic ring and examples thereof
include the same group as that exemplified with respect to
the 5- to 7-membered ring of ring A.
X2 of the formula (I) is N or NR3 and R3 are as defined
above.
X3 of the formula (III) and (IIIa) is a bond, oxygen
atom, an optionally oxidized sulfur atom, N, NR7', or an
optionally substituted bivalent C1-2 hydrocarbon group.
R7' is H, an optionally substituted hydrocarbon group,
an optionally substituted hydroxyl group, an optionally
substituted amino group, an optionally substituted
heterocyclic group, or a group of the formula -Z1'-Z2
(wherein -Z1'- is -CS-, -SO- or -SO2-, and Z2 is as defined
above)).
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, and an optionally
substituted heterocyclic group of R7' include the same
groups as those exemplified with respect to the

substituents of the 5- to 7-membered ring of ring A.
Examples of an optionally substituted bivalent Ci_2
hydrocarbon group include -CH2-, -(CH2)2-, -CH=CH- and the
like which may be substituted with one or two substituents
selected from those exemplified with respect to the
substituents of the 5- to 7-membered ring of ring A.
In the formula (IIIa), X3 is preferably CH2.
Prefered compounds of the formula (I) include not only
the compounds of the formula (IIIa) but also the other
compounds wherein -Z1- is -CO- and Z2 is an optionally
substituted hydroxyl group (e.g., hydroxy, C1-6 alkoxy,
etc.) or amino group which is substituted with an
optionally substituted phenyl group or an optionally
substituted condensed phenyl group (e.g., phenylamino, 3,5-
dimethoxyphenylamino, 3-biphenylylamino, 2,3-dihydro-1H-
inden-5-yl-amino, quinolin-6-yl-amino, etc.).
In the formula (II),
(1) when ring A is a 6-membered ring and Q is C or CR5, X1
is C-Z1-Z2, C(-Z1-Z2)R2 or N-Z1Z2, and both R9 and R10 are
not H, or R9 and R10 are not combined to form an oxo group,
or R10 and R11 are not combined to form a 5-membered ring;
(2) when ring A is a 6-membered ring and Q is N, X1 is C-
Z1-Z2, C(-Z1-Z2)R2 or N-Z1Z2, and R9 and R10 are not combined
to form an oxo group;
(3) when ring A is a 5-membered ring and Q is C or CR5, X1

is C-Z1Z2, C(-Z1-Z2)R2 or N-Z1-Z2, and Z2 is an optionally
substituted amino group; and
(4) when ring A is a 5-membered ring and Q is N, at least
one of R9 and R10 is CHR15R16 (wherein R15 and R16 are the
same or different and are H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, a halogen atom, an optionally
substituted heterocyclic group, or a group of the formula:-
Z1-Z2 (wherein -Z1- and Z2 are as defined above) .
Examples of an optionally substituted hydrocarbon
group, an optionally substituted hydroxyl group, an
optionally substituted amino group, an optionally
substituted thiol group, a halogen atom and an optionally
substituted heterocyclic group include the same groups as
those exemplified with respect to the above substituents of
the 5- to 7-membered ring of ring A.
In the formulas (II) and (III) , preferably, R1 is a
group of the formula: -Z1-Z2; Z1 is -CO- and Z2 is an
optionally substituted hydroxyl group or an optionally
substituted amino group; Ar is an optionally substituted
aromatic ring group; and both R9 and R10 are the same or
different and are C1-6 alkyl groups or R9 and R10 are
combined to form a ring such as a saturated or unsaturated
C3-6 ring as described above.

In the formula (III), preferably, R3 is H. More
preferably, in the formula (III), R1 is a group of the
formula: -Z1-Z2 (wherein -Z1- is -CO-, -CS-, -SO- or -SO2-,
and Z2 is an optionally substituted hydrocarbon group, an
optionally substituted heterocyclic group, an optionally
substituted hydroxyl group, or an optionally substituted
amino group) ; R3 is H; Ar is an optionally substituted
aromatic ring group; X3 is CR11R12 (wherein R11 and R12 are
the same or different and are H, an optionally substituted
hydrocarbon group, an optionally substituted hydroxyl group,
an optionally substituted amino group, an optionally
substituted thiol group, cyano group, a halogen atom, an
optionally substituted heterocyclic group, or a group of
the formula: -Z1-Z2 (wherein -Z1- and Z2 are as defined
above) , or R11 and R12 may be combined to form an oxo group,
methylene group or a ring such as a saturated or
unsaturated C3-6 ring as described above) ; and R9 and R10 are
the same or different and are a C1-6 alkyl group, or R9 and
R10 may be combined to form a ring such as a saturated or
unsaturated C3-6 ring as described above.
As for a salt of the compound of formula (I), (II),
(III) or (IIIa) (hereinafter sometimes referred to as
Compound (1), (II), (III) or (IIIa)), a pharmaceutically
acceptable salt is preferred. Examples thereof include a
salt with an inorganic base, a salt with an organic base, a

salt with an inorganic acid, a salt with an organic acid, a
salt with a basic or acidic amino acid, or the like.
Preferred examples of a salt with an inorganic base include
an alkali metal salt such as sodium salt, potassium salt,
or the like; an alkaline earth metal salt such as calcium
salt, magnesium salt, or the like; and aluminum salt;
ammonium salt; or the like. Preferred examples of a salt
with an organic base include a salt with trimethylamine,
triethylamine, pyridine, picoline, ethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine, N,N'-
dibenzylethylenediamine, or the like. Preferred examples
of a salt with an inorganic acid include a salt with
hydrochloric acid, hydrobromic acid, nitric acid, sulfuric
acid, phosphoric acid, or the like. Preferred examples of a
salt with an organic acid include a salt with formic acid,
acetic acid, trifluoroacetic acid, fumaric acid, oxalic
acid, tartaric acid, maleic acid, citric acid, succinic
acid, malic acid, methanesulfonic acid, benzenesulfonic
acid, p-toluenesulfonic acid, or the like. Preferred
examples of a salt with a basic amino acid include a salt
with arginine, lysine, ornithine or the like. Preferred
examples of a salt with an acidic amino acid include a salt
with aspartic acid, glutamic acid, or the like.
Compound (I), (II), (III) or (IIIa) may be in the form
of a prodrug thereof. The prodrug of Compound (I), (II),

(III) or (IIIa) refers to a compound that is converted into
Compound (I), (II), (III) or (IIIa) by a reaction with an
enzyme, gastric acid, or the like under a physiological
condition in the living body, namely, (i) a compound that
is converted into Compound (I), (II), (III) or (IIIa) by an
enzymatic oxidation, reduction, hydrolysis, or the like,
and (ii) a compound that is converted into Compound (I),
(II), (III) or (IIIa) by hydrolysis with gastric acid or
the like. Examples of a prodrug of Compound (I), (II),
(III) or (IIIa) to be used include a compound or its salt
wherein hydroxyl group in Compound (I), (II), (III) or
(IIIa) is acylated, alkylated, phosphorylated, or converted
into borate (e.g., a compound or its salt wherein hydroxyl
group in Compound (I), (II), (III) or (IIIa) is converted
into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy,
succinyloxy, fumaryloxy, alanyloxy,
dimethylaminomethylcarbonyloxy, etc.), a compound or its
salt wherein carboxyl group in Compound (I), (II), (III) or
(IIIa) is esterified or amidated (e.g., a compound or its
salt wherein carboxyl group in Compound (I), (II), (III) or
(IIIa) is subjected to ethyl esterification, phenyl
esterification, carboxyoxymethyl esterification,
dimethylaminomethyl esterification, pivaloyloxymethyl
esterification, ethoxycarbonyloxyethyl esterification,
phthalidyl esterification, (5-methyl-2-oxo-l,3-dioxolan-4-

yl)methyl esterification, cyclohexyloxycarbonyl
esterification, or conversion into the methyl amide, etc.),
or the like. These prodrugs can be produced according to a
per se known method or its modified method.
Further, a prodrug of Compound (I), (II), (III) or
(IIIa) may be a compound or its salt that is converted into
Compound (I), (II), (III) or (IIIa) under physiological
conditions as described in "Development of Drugs", Volume 7,
Molecular Design, Hirokawa Shoten, 1990; pages 163-198.
Compound (I), (II), (III) or (IIIa) may be labeled
with an isotope (for example, 2H, 3H, 14C, 35S, 125I, or the
like) or the like.
When the compound obtained by the present invention or
a salt thereof has a double bond in its molecule and a
steric configuration of Z or E exsits, each of the
stereoisomers and a mixture thereof are included in the
present invention.
When a steric configuration exsits due to an
asymmetric carbon in the molecule of the compound obtained
by the present invention or a salt thereof, each of them
and a mixture thereof are included in the present invention.
Hereinafter, production of the compound of the present
invention will be illustrated.
A process for preparing Compound (II), Compound (III)
and Compound (IIIa) of the present invention will be shown

in the following schemes 1 to 13.
A compound wherein Q is N, and Y is C or CR4 in
Compound (II) can be prepared according to the schemes 1 to
3.
A compound wherein Q is C, and Y is C or CR4 in
Compound (II) can be prepared according to the scheme 4.
A compound wherein Q is N, and Y is N in Compound (II)
can be prepared according to the scheme 5.
A compound wherein Y is C or CR4 in Compound (III) and
Compound (IIIa) can be prepared by the scheme 6.
A compound wherein Y is N in Compound (III) and
Compound (IIIa) can be prepared by the scheme 7.
A compound wherein Q is C, and Y is N in Compound (II)
can be prepared by the scheme 13.

wherein A-1 is the same as A, and the other symbols are as
defined above.
In step A, Compound (II-1) is prepared by cyclization
reaction of Compound (IV-1) and Compound (X) with an acid
or a base. Examples of the acid used in this reaction

include: inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid and phosphoric acid;
organic acids such as acetic acid, trifluoroacetic acid,
methanesulfonic acid, benzenesulfonic acid and p-
toluenesulfonic acid; and Lewis acids such as zinc (II)
chloride, tin (IV) chloride, aluminium chloride and the
like.
Examples of the base include alkali metal salts such
as potassium hydroxide, sodium hydroxide, sodium
bicarbonate and potassium carbonate; amines such as
pyridine, triethylamine, N,N-dimethylaniline and 1,8-
diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as
potassium hydride and sodium hydride; and alkali metal
alkoxides such as sodium methoxide, sodium ethoxide and
potassium t-butoxide.
An amount of these acids or bases to be used is
preferably about 0.1 to about 5 mole equivalent relative to
Compound (IV-1).
Examples of a solvent having no adverse effect on the
reaction include aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as tetrahydrofuran,
dimethoxyethane, dioxane and diethyl ether; amides such as
N,N-dimethylformamide; alcohol such as ethanol, propanol,
tert-butanol and methoxyethanol; and sulfoxides such as
dimethyl sulfoxide. These solvents may be used by mixing

at an appropriate ratio.
A reaction temperature is usually about -50°C to about
200°C, preferably about -10°C to about 150°C.
A reaction time is usually about 0.5 to about 60 hours.
The thus obtained compound (II-l) can be isolated and
purified by the known separating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
Compound (IV-1) used herein can be prepared, for
example, according to the method described in Bilestein,
vol.25, p.2033. In addition, Compound (X) can be prepared,
for example, according to Organometallics, vol.11, p.954.
In step B, Compound (II-2) is prepared by a reduction
reaction for Compound (II-l).
In the present reaction, a catalytic hydrogenation
method using palladium carbon, palladium hydroxide or the
like, or reduction using a reducing agent is performed. As
the reducing agent, sodium borohydride, aluminium lithium
hydride and lithium borohydride are used. In the present
reaction, if needed, any solvents can be used as long as
they do not inhibit the reaction. Inter alia, alcohols
(e.g. C1-3 alcohol such as methanol, ethanol, propanol and
the like) or ethers (diethyl ether, diisopropyl ether,
ethylene glycol dimethyl ether, tetrahydrofuran, dioxane

etc.) are preferable.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound (II-2) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.

wherein A-1 is the same as A, and the other symbols are as
defined above.
In step C, Compound (V) is prepared by a reaction for
cyclizing Compound (IV-1) and Compound (XI). The present
reaction is carried out in the presence of an acid in a
solvent having no adverse effect on the reaction or without
a solvent according to the conventional method.
Examples of the acid include inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and
phosphoric acid; organic acids such as acetic acid,
trifluoroacetic acid, methanesulfonic acid, benzenesulfonic
acid and p-toluenesulfonic acid; Lewis acids such as zinc

(II) chloride, tin (IV) chloride, aluminium chloride and
the like.
An amount of these acids is preferably about 0.1 to
about 5 mole equivalent relative to Compound (IV-1).
Examples of the solvent having no adverse effect on
the reaction include aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as tetrahydrofuran, dioxane
and diethyl ether; halogenated hydrocarbons such as
chloroform and dichloromethane; amides such as N,N-
dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used by mixing at an
appropriate ratio.
A reaction temperature is usually about -50°C to 150°C,
preferably about -10°C to about 120°C.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound ( V ) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
In step B, Compound (II-3) can be prepared according
to step B in the scheme 1.

wherein Y' is C or CR4, and L and L' is a leaving group,
and L is more reactive than L' , and the other symbols are
as defined above.
In step D, Compound (VI-1) is prepared from Compound
(IV-1). The present method is carried out in the presence
of a base in a solvent having no adverse effect on the
reaction according to the conventional method. Specific
examples of leaving groups L and L' include halogen atom,
sulfonyloxy group such as p-toluenesulfonyloxy group,
methanesulfonyloxy group and trifluoromethanesulfonyloxy
group, and acyloxy group such as acetyloxy group and
benzoyloxy group.
Example of the base include alkali metal salts such as
potassium hydroxide, sodium hydroxide, sodium bicarbonate
and potassium carbonate; amines such as pyridine,
triethylamine, N,N-dimethylaniline and 1,8-
diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as
potassium hydride and sodium hydride; and alkali metal
alkoxides such as sodium methoxide, sodium ethoxide and

potassium t-butoxide.
An amount of these bases to be used is preferably
about 1 to about 5 mole equivalent relative to Compound
(IV) .
Examples of the solvent having no adverse effect on
the reaction include: aromatic hydrocarbon such as benzene,
toluene and xylene; ethers such as tetrahydrofuran, dioxane
and diethyl ether; amides such as N,N-dimethylformamide;
and sulfoxides such as dimethyl sulfoxide. These solvents
may be used by mixing at an appropriate ratio.
A reaction temperature is usually about -50 to about
150°C, preferably about -10°C to about 120°C.
A reaction time is usually about 0.5 about 20 hours.
The thus obtained Compound (VI-1) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
In step E, Compound (II-4) is prepared by an
intramolecular cyclization reaction of Compound (VI-1).
The present method is carried out in the presence of an
acid or a base in a solvent having no adverse effect on the
reaction according to the conventional method. Specific
example of a leaving group L' include halogen atom, p-
toluenesulfonyloxy group, methanesulfonyloxy group and

trifluoromethanesulfonyloxy group.
Examples of the acid include inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid and
phosphoric acid; organic acids such as acetic acid,
trifluoroacetic acid, methanesulfonic acid, benzenesulfonic
acid and p-toluenesulfonic acid; and Lewis acids such as
zinc (II) chloride, tin (IV) chloride, aluminium chloride
and the like. Examples of the base include: alkali metal
salts such as potassium carbonate; amines such as pyridine,
triethylamine, N,N-dimethylaniline and 1,8-
diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as
potassium hydride and sodium hydride; and alkali metal
alkoxides such as sodium methoxide, sodium ethoxide and t-
butoxide.
An amount of these acids or bases to be used is
preferably about 1 to about 5 mole equivalent relative to
Compound (IV-1).
Examples of the solvent having no adverse effect on
the reaction include aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as tetrahydrofuran, dioxane
and diethyl ether; haloganated hydrocarbons such as
chloroform and dichloromethane; amides such as N,N-
dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used by mixing at an
appropriate ratio.

A reaction temperature is usually about -50°C to about
150°C, preferably about -10°C to about 120°C.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound (II-4) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.

wherein A-2 is the same as A, and the other symbols are as
defined above.
In step F, Compound (VI-2) is prepared from Compound
(IV-2) and Compound (XII). The present method is carried
out in the presence of a base in a solvent having no
adverse effect on the reaction according to the
conventional method.
Examples of the base include: alkali metal salts such
as potassium carbonate, sodium carbonate and cesium
carbonate; amines such as pyridine, triethylamine, N,N-
dimethylaniline and 1,8-diazabicyclo[5.4.0]undec-7-ene;
metal hydrides such as potassium hydride and sodium

hydride; and alkali metal alkoxides such as sodium
methoxide, sodium ethoxide and potassium t-butoxide.
An amount of these bases to be used is preferably
about 1 to about 5 mole equivalent relative to Compound
(IV-2).
Examples of the solvent having no adverse effect on
the reaction include aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as tetrahydrofuran; dioxane
and diethyl ether; halogenated hydrocarbons such as
chloroform and dichloromethane; amides such as N,N-
dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used by mixing at an
appropriate ratio.
A reaction temperature is usually about -50°C to about
200°C, preferably about -10°C to about 150°C.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound (VI-2) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
In step G, Compound (II-5) is prepared by a reaction
for reducing Compound (VI-2).
In the present reaction, a catalytic hydrogenation
method using palladium carbon, palladium hydroxide or Raney

nickel, or reduction using a reducing agent is carried out.
As the reducing agent, sodium borohydride, aluminium
lithium hydride and lithium borohydride are used. In the
present reaction, if needed, any solvents can be used as
long as they do not inhibit the reaction. Inter alia,
alcohols (e.g. C1-3 alcohol such as methanol, ethanol,
propanol and the like) or ethers (diethyl ether,
diisopropyl ether, ethylene glycol dimethyl ether,
tetrahydrofuran, dioxane etc.) are preferable.
A reaction time is usually about 0.5 to 20 hours.
The thus obtained Compound (II-5) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.

hydrocarbon ring or an optionally substituent non-aromatic
heterocyclic ring, Ar2 is an optionally substituted
aromatic hydrocarbon ring or an optionally substituted
aromatic heterocyclic ring, and A-3 is the same as A, and
the other symbols are as defined above.
In step H, an amino group of Compound (IV-3) is
converted into a diazonium salt, and ylide is reacted
thereon to prepare Compound (VIII-1). Diazotization in the
present method is carried out in the presence of an acid in
a solvent having no adverse effect on the reaction
according to the conventional method. As the acid, for
example, acetic acid and hydrochloric acid are used. As a
diazotizing agent, sodium nitrite, alkyl nitrite or
sulfated nitrosyl is used.
As the solvent, water, dioxane, tetrahydrofuran and
the like are used.
A reaction temperature is usually about -50°C to about
150°C, preferably about -10°C to about 100°C.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained diazonium salt of Compound (IV-3) is
reacted with ylide produced from Compound (XIII-1) to
prepare Compound (VIII-1). The present step is carried out
in the presence of a base in a solvent having no adverse
effect on the reaction. Examples of the base include:
alkali metal salts such as potassium carbonate; amines such

as pyridine, triethylamine, N,N-dimethylaniline and 1,8-
diazabicyclo[5,4,0] undec-7-ene; metal hydrides such as
potassium hydride and sodium hydride; and alkali metal
alkoxides such as sodium methoxide, sodium ethoxide and
potassium t-butoxide.
An amount of these bases to be used is preferably
about 1 to about 3 mole equivalent relative to Compound
(XIII-1) .
Examples of the solvent having no adverse effect on
the reaction include aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as tetrahyrdorufan, dioxane
and diethyl ether; halogenated hydrocarbons such as
chloroform and dichloromethane; amides such as N,N-
dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used by mixing at an
appropriate ratio.
Since the thus obtained Compound (VIII-1) is unstable
depending on a kind of the compound, it is used in the next
step without isolation and purification.
In step I, a reduction reaction of Compound (VIII-1)
is carried out to prepare Compound (IX-1). In the present
reaction, a catalytic hydrogenation method using platinum
oxide, Raney nickel, palladium carbon or palladium
hydroxide, or reduction using a reducing agent is used. As
the reducing agent, sodium borohydride, aluminium lithium

hydride and lithium borohydride are used. In the present
reaction, if needed, any solvents can be used as long as
they do not inhibit the reaction. Inter alia, alcohols
(e.g. C1-3 alcohol such as methanol, ethanol, propanol etc.)
or ethers (diethyl ether, diisopropyl ether, ethylene
glycol dimethyl ether, tetrahydrofuran, dioxane etc.) are
preferable.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound (IX-1) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
In step J, Compound (II-7) is prepared by a reductive
amination reaction between Compound (IX-1) and ketone (XV).
The present method is carried out in the presence of a
reducing agent in a solvent having no adverse effect on the
reaction. Examples of the reducing agent include sodium
borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride and lithium borohydride. Although
alcohol solvents such as ethanol and methanol,
dichloromethane, chloroform and carbon tetrachloride are
used as a solvent, any solvents can be used as long as they
do not inhibit the reaction.
The thus obtained Compound (II-7) can be isolated and

purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
In step K, a bismuth regent is acted on Compound (IX-
1) to prepare Compound (II-8). The present method is
carried out in the presence of a metal catalyst in a
solvent having no adverse effect on the reaction. As the
metal catalyst, for example, copper catalysts such as
copper (II) acetate and copper (II) pivalate are used.
Although dichloromethane, chloroform and carbon
tetrachloride are used as a solvent, any solvents can be
used as long as they do not inhibit the reaction.
A reaction temperature is usually about -80°C to about
150°C, preferably about -80°C to about 100°C.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound (II-8) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.

wherein X4 is the same as X3, and the other symbols are as
defined above.
Step D and step E can be carried out according to step
D and step E of the scheme 3, respectively, to prepare
Compound (III-l).

wherein Ar3 is an optionally substituted hydrocarbon ring,
an optionally substituted non-aromatic heterocyclic ring,
an aromatic hydrocarbon ring or an aromatic heterocyclic
ring, X5 is the same as X3, and other respective symbols
have the same meanings as described above.)

Step H, step I, step J and step K can be carried out
according to step H, step I, step J, and step K of the
scheme 5, respectively, to prepare Compound (III-2) .
In Compound (II), when X1 is C-COOR16, it can be
converted as follows:

wherein A-4 denote the same meaning as that of A, R16
denotes an optionally substituted carbon atom, and the
other symbols are as defined above.
In step L, Compound (11-10) is prepared by a reaction
for leaving a carboxyl-protecting group.
All conventional methods used in a reaction for
leaving a carboxyl-protecting group, for example,
hydrolysis, reduction and elimination using a Lewis acid
can be applied to the present reaction. It is preferable
that hydrolysis is carried out in the presence of a base or
an acid. Examples of the suitable base include inorganic
bases such as alkali metal hydroxide (e.g. sodium hydroxide
and potassium hydroxide), alkaline earth metal hydroxide
(e.g. magnesium hydroxide and potassium hydroxide), alkali

metal carbonate (e.g. sodium carbonate and potassium
carbonate), alkaline earth metal carbonate (e.g. magnesium
carbonate and calcium carbonate) , alkali metal bicarbonate
(e.g. sodium bicarbonate and potassium bicarbonate), alkali
metal acetate (e.g. sodium acetate and potassium acetate),
alkaline earth metal phosphate (e.g. magnesium phosphate
and calcium phosphate) and alkali metal hydrogen phosphate
(e.g. disodium hydrogen phosphate and dipotassium hydrogen
phosphate), and organic bases such as trialkylamine (e.g.
trimethylamine and triethylamine), picoline, N-
methylpyrrolidine, N-methylmorpholine, 1,5-
diazabicyclo[4.3.2]non-5-ene, 1,4-diazabicyclo[2.2.2]non-5-
ene and 1,8-diazabicyclo[4.3.0]-7-undecene. Hydrolysis
using a base is carried out in water or a hydrophilic
organic solvent or a mixed solvent in many cases. Examples
of the suitable acid include formic acid, hydrobromic acid
and sulfuric acid.
The present hydrolysis reaction is usually carried out
in an organic solvent, water or a mixed solvent thereof. A
reaction temperature is not particularly limited, but is
appropriately selected depending on a kind of a carboxyl-
protecting group and an elimination method. Elimination
using a Lewis acid is carried out by reacting Compound (II-
9) or a salt thereof with a Lewis acid, for example,
trihalogenated boron (e.g. boron trichloride and boron

trifluoride), tetrahalogenated titanium (e.g. titanium
tetrachloride and titanium tetrabromide), and halogenated
aluminium (e.g. aluminium chloride and aluminium bromide),
or an organic acid (e.g. trichloroacetic acid and
trifluoroacetic acid). This elimination reaction is
preferably carried out in the presence of a cation
scavenger (e.g. anisole and phenol) and is usually carried
out in a solvent such as nitroalkane (e.g. nitromethane and
nitroethane), alkylene halide (e.g., methylene chloride and
ethylene chloride), diethyl ether, carbon disulfide, and a
solvent having no adverse effect on the reaction. These
solvents may be used as a mixture thereof.
It is preferable that elimination by reduction is
applied to elimination of a protecting group such as
halogenated alkyl (e.g. 2-iodoethyl and 2,2,2-
trichloroethyl) ester, and aralkyl (e.g. benzyl) ester.
Examples of a reduction method using in the present
elimination reaction include the conventional catalytic
reduction in the presence of a combination of a metal (e.g.
zinc and zinc amalgam) or a salt of a chromium compound
(e.g. chromate chloride and chromate acetate) and an
organic or inorganic acid (e.g. acetic acid, propionic acid
and hydrochloric acid); or the conventional metal catalyst
(e.g. palladium carbon and Raney nickel). A reaction
temperature is not particularly limited, but a reaction is

carried out under cooling, at room temperature of under
warming.
The thus obtained Compound (11-10) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.

wherein R17 and R18 are optionally substituted alkyl group,
allyl group or hydroxy group; or R17 and R18 may be combined
each other to form a ring, Y" is the same as Y, and the
other symbols are as defined above.
In the present method, Compound (11-12) is prepared by
reacting Compound (11-11) or a reactive derivative at a
carboxyl group thereof and a salt thereof with the above
Compound (XVI) or a reactive derivative at an amino group
thereof or a salt thereof. Examples of the suitable
reactive derivative at an amino group of Compound (XVI)
include: Schiff base type imino produced by a reaction of
Compound (XVI) with a carbonyl compound such as aldehyde,

ketone and the like; silyl derivative produced by a
reaction of Compound (XVI) and a silyl compound such as
bis(trimethylsilyl)acetamide, mono(trimethylsilyl)
acetamide, bis(trimethylsilyl)urea and the like; derivative
produced by a reaction of Compound (XVI) with phosphorus
trichloride or phosgene.
Specific examples of the suitable reactive derivative
at a carboxyl group of Compound (II-11) include acid halide,
acid anhydride, activated amide, activated ester and the
like. Examples of the suitable reactive derivative
include: acid chloride; acid azide; mixed acid anhydride
with an acid such as substituted phosphoric acid such as
dialkylphosphoric acid, phenylphosphoric acid,
diphenylphosphoric acid, dibenzylphosphoric acid,
halogenated phosphoric acid and the like,
dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,
sulfuric acid, sulfonic acid such as methanesulfonic acid
and the like, aliphatic carboxylic acid such as acetic acid,
propionic acid, butyric acid, isobutyric acid, pivalic acid,
pentanoic acid, isopentanoic acid, trichloroacetic acid and
the like or aromatic carboxylic acid such as benzoic acid
and the like; symmetric acid anhydride; activated amide
with imidazole; 4-substituted imidazole, dimethylpyrazole,
triazole or tetrazole; activated ester such as
cyanomethylester, methoxymethyl ester, dimethyliminomethyl

ester, vinyl ester, propargyl ester, p-nitrophenyl ester,
trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl
ester, phenylazophenyl ester, phenyl thioester, p-
nitrophenyl ester, p-cresyl thioester, carboxylmethyl
thioester, pyranyl ester, pyridyl ester, piperidyl ester,
8-quinolyl thioester and the like, or esters with N-hydroxy
compound such as N,N-dimethylhydroxyamine, l-hydroxy-2-
(1H)-pyridone, N-hydroxysuccineimide, N-hydroxyphthalimide,
1-hydroxy-1H-benzotriazole and the like. These reactive
derivatives can be arbitrarily selected depending on a kind
of Compound (II-11) to be used. Examples of the suitable
reactive derivative of Compound (II-12) include alkali
metal salts such as sodium salt, potassium salt and the
like, alkaline earth metal salts such as calcium salt,
magnesium salt and the like, and basic salts such as
organic base salts such as ammonium salt, trimethylamine
salt, triethylamine salt, pyridine salt, picoline salt,
dicyclohexylamine salt, N,N-dibenzylethylenediamine salt
and the like. Although the reaction is usually carried out
in the conventional solvent such as water, alcohols such as
methanol, ethanol and the like, acetone, dioxane,
acetonitrile, chloroform, methylene chloride, ethylene
chloride, tetrahydrofuran, ethyl acetate, N,N-
dimethylformamide and pyridine, the reaction may be carried
out in any other organic solvents as long as they have no

adverse effect on the reaction. These conventional
solvents may be used as a mixture with water.
When Compound (II-11) is used as the form of a free
acid or a salt thereof in this reaction, it is desirable
that the reaction is carried out in the presence of the
normally used condensing agent such as so-called Vilsmeier
regent and the like prepared by a reaction of N,N'-
dicyclohexylcarbodiimide; N-cyclohexyl-N'-
morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-
diethylaminocyclohexyl)carbodiimide; N,N'-
diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-
N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonylbis(2-
methylimidazole); pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-
alkoxy-1-chloroethylene; trialkyl phosphite; polyethyl
phosphate; polyisopropyl phosphate; phosphorus oxychloride;
diphenylphosphorylazide; thionyl chloride; oxalyl chloride;
lower alkyl haloformate such as ethyl chloroformate;
isopropyl chloroformate and the like; triphenylphosphine;
2-ethyl-7-hydroxybenzisooxazolium salt, 2-ethyl-5-(m-
sulfopheny)isooxazoliumhydroxide internal salt; N-
hydroxybenzotriazole; 1-(p-chlorobenzenesulfonyloxy)-6-
chloro-1H-benzotriazole; N-N'-dimethylformamide with
thionyl chloride, phosgene, trichloromethyl
chloroformate, phosphorus oxychloride or the like.

Alternatively, the reaction may be carried out in the
presence of an inorganic base or an organic base such as
alkali metal bicarbonate salt, tri(lower)alkylamine,
pyridine, N-(lower)alkylmorpholine, N,N-
di(lower)alkylbenzylamine and the like. A reaction
temperature is not particularly limited, but the reaction
is carried out under cooling or under warming.
An amount of Compound (XVI) to be used is 1 to 10 mole
equivalent, preferably 1 to 3 equivalent relative to
Compound (II-11) .
A reaction temperature is usually -30°C to 100°C.
A reaction time is usually 0.5 to 20 hours.
In addition, when a mixed acid anhydride is used,
Compound (II-11) and chlorocarbonic ester (e.g. methyl
chlorocarbonate, ethyl chlorocarbonate, isobutyl
chlorocarbonate etc.) are reacted in the presence of a base
(e.g. triethylamine, N-methylmorpholine, N,N-
dimethylaniline, sodium bicarbonate, sodium carbonate,
potassium carbonate etc.) and is further reacted with
Compound (XVI).
An amount of Compound (XVI) to be used is usually 1 to
10 mole equivalent, preferably 1 to 3 mole equivalent
relative to Compound (11-11).
A reaction temperature is usually -30°C to 100°C.
A reaction time is usually 0.5 to 20 hours.

The thus obtained Compound (II-12) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
When X1 is C-COOR16 in Compound (III), the conversion
can be carried out as follows:

wherein the symbols are as defined above.
Step L and step M can be carried out according to step
L in the scheme 8 and step M in the scheme 9, respectively,
to prepare Compound (III-4) and Compound (III-5).

wherein R19 is an optionally substituted alkyl group, allyl
group, hydroxy group, amino group or sulfanyl group, and
the other symbols are as defined above.

In the present method, Compound (11-13) is prepared by
a reaction between Compound (V) and a nucleophilic regent.
Examples of the nucleophilic regent include metal
phenolate, metal alcoholate, Grignard regent, alkyl metal
regent, aryl metal regent and thioalcoholate.
An amount of the nucleophilic regent to be used is
preferably about 1 to about 5 mole equivalent relative to
Compound (V).
Examples of a solvent having no adverse effect on the
reaction include: ethers such as diethyl ether,
tetrahydrofuran and dioxane; aromatic hydrocarbons such as
benzene, toluene and xylene; amides such as N,N-
dimethylformamide and 1-methylpyrrolidone; sulfoxides such
as dimethyl sulfoxide. These solvents may be used by
mixing at an appropriate ratio.
A reaction temperature is usually about -50°C to about
150°C, preferably about -10 to about 100°C.
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound (II-13) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.

wherein the symbols are as defined above.
Step N can be carried out according to step N in the
scheme 11 to prepare Compound (III-4).

wherein A-6 is the same as A, and the other symbols are as
defined above.
In step H, an amino group of Compound (IV-5) is
converted into a diazonium salt, and ylide is reacted
thereon to prepare Compound (VIII-3). Diazotization in
this method is carried out in the presence of an acid in a
solvent having no adverse effect on the reaction according
to the conventional method. As the acid, for example,
acetic acid and hydrochloric acid are used. As the

diazotizing agent, sodium nitrite, alkyl nitrite or
sulfated nitrosyl is used.
As the solvent, water, dioxane, tetrahydrofuran and
the like are used.
A reaction temperature is usually about -50°C to about
150°C, preferably about -10°C to about 100°C.
A reaction time is about 0.5 to about 20 hours.
The thus obtained diazonium salt of Compound (IV-5) is
reacted with ylide produced from Compound (XVII) to prepare
Compound (VIII-3). The present step is carried out in the
presence of a base in a solvent having no adverse effect on
the reaction. Examples of the base include: alkali metal
salts such as potassium carbonate; amines such as pyridine,
triethylamine, N,N-dimethylaniline and 1,8-
diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as
potassium hydride and sodium hydride; and alkali metal
alkoxides such as sodium methoxide, sodium ethoxide and
potassium t-butoxide.
An amount of these bases to be used is preferably
about 1 to about 3 mole equivalent relative to Compound
(XVII).
Examples of the solvent having no adverse effect on
the reaction include aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as tetrahydrofuran, dioxane
and diethyl ether; halogenated hydrocarbons such as

chloroform and dichloromethane; amides such as N,N-
dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used by mixing at an
appropriate ratio.
Since the thus obtained Compound (VIII-3) is unstable
depending on a kind of the compound, it is used in the next
step without isolation and purification.
Step I, step J and step K can be carried out according
to step I, step J and step K, respectively, to prepare
Compound (11-14) and Compound (11-15).
When R3 is a hydrogen atom in Compound (II) the
following conversion is possible.

wherein the symbols are as above.
In step 0, Compound (II-4) is subjected to alkylation,
acylation, carbamoylation, oxycarbonization or
thiocarbamoylation to prepare Compound (II-6).
The reaction is carried out according to the
conventional method. In alkylation, alkyl halide is
reacted, in acylation, acid halide or acid anhydride is
reacted, in carbamoylation, isocyanate or carbonylimidazole

is reacted and, thereafter, amine is reacted, in
oxycarbonization, oxycarbonyl halide or oxycarboic acid
anhydride is reacted and, in thiocarbamoylation,
thioisocyanate is reacted, respectively, to prepare the
compound. The present reaction is generally carried out in
the presence of a base in a solvent having no adverse
effect on the reaction. Examples of the base include
alkali metal salts such as potassium hydroxide, sodium
hydroxide, sodium bicarbonate and potassium carbonate;
amines such as pyridine, triethyamine, N,N-dimethylaniline
and 1,8-diazabicyclo[5,4,0]undec-7-ene; metal hydrides such
as potassium hydride and sodium hydride; and alkali metal
alkoxides such as sodium methoxide, sodium ethoxide and
potassium t-butoxide.
An amount of these bases to be used is preferably
about 1 to about 5 mole equivalent relative to Compound
(H-4) .
Examples of the solvent having no adverse effect on
the reaction include: aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as tetrahydrofuran, dioxane
and diethyl ether: halogenated hydrocarbons such as
chloroform and dichloromethane; amides such as N,N-
dimethylformamide; and sulfoxides such as dimethyl
sulfoxide. These solvents may be used by mixing at an
appropriate ratio.

A reaction temperature is usually about -50°C to about
150°C, preferably about -10°C to about 120°C
A reaction time is usually about 0.5 to about 20 hours.
The thus obtained Compound (II-6) can be isolated and
purified by the known isolating and purifying methods, for
example, concentration, concentration under the reduced
pressure, extraction with solvent, crystallization,
recrystallization, transfer dissolution and chromatography.
When R3 is a hydrogen atom in Compound (III), the
following conversion is possible.

wherein the symbols are as above.
Step 0 step J and step K can be carried out according
to step 0 in the scheme 14, respectively, to prepare
Compound (III).
All the compounds used or obtained in the present
invention include corresponding salts, even if specifically
stated, and they can be exchanged to one another by a per
se known method or modified methods thereof.
When the compounds or salts thereof obtained by the

present invention are asymmetric molecules, they can be
separated into d-form isomer and 1-form isomer according to
conventional optical resolution methods.
The compound or its salt obtained by the present
invention may be used in a next step as its reaction
mixture without sufficient purification.
Compound (I), (II), (III) or (IIIa) of the present
invention has an excellent Ca receptor modulating activity
and enhances the secretion of PTH, and therefore useful as
drugs for treating bone diseases, kidney-acting drugs,
central nervous system and endocrine-acting drugs,
digestive system-acting drugs, and the like. Further, the
toxicity is low. Therefore, Compound (I), (II), (III) or
(IIIa) may be safely administered to mammalian animals (for
example, human, rat, mouse, dog, rabbit, cat, cow, horse,
pig, and the like).
Thus, a pharmaceutical composition containing compound
(I), (II), (III) or (IIIa) of the present invention is
expected to be useful in the treatment and prevention of
diseases, in which Ca receptor modulating activity is
required, such as
Ca receptor modulating drugs: primary or secondary hyper
parathyroidism; hypoparathyroidism; hyperthyroidism;
hypothyroidism; Graves' disease; Hashimoto's toxicosis;
Paget's disease; hypercalcemia associated with malignant

tumor; hypercalcemia; hypocalcemia; postmenopausal
osteoporosis; senile osteoporosis; secondary osteoporosis;
osteomalacia; renal osteodystrophy; fracture;
osteoarthritis; rheumatoid arthritis; osteosarcoma;
myeloma; hypertension; diabetes; myocardial infarction;
Hachington's diseases; Parkinson's diseases; Alzheimer's
disease; dementia; cerebral apoplexy; brain tumor; spinal
injury; diabetic renal disease; renal insufficiency;
gastric ulcer; duodenal ulcer; Basedow's disease;
parathyroid gland tumor; thyride gland tumor;
arteriosclerosis; and the like;
Ca receptor antagonistic drugs: hyperthyroidism;
hypocalcemia; postmenopausal osteoporosis; senile
osteoporosis; secondary osteoporosis; osteomalacia; renal
osteodystrophy; fracture; osteoarthritis; rheumatoid
arthritis; osteosarcoma; myeloma; central nervous system
diseases; and the like, in particular osteoporosis.
The dosage of Compound (I), (II), (III) or (IIIa) can
be selected in various ways depending on the administration
route and the symptom of a patient to be treated. The
dosage as Compound (I), (II), (III) or (IIIa) per an adult
(a body weight of 50 kg) can be usually selected in a range
of about 0.1 mg to about 500 mg, preferably about 1 mg to
about 100 mg in the case of oral administration and in a
range of about 0.01 mg to about 100 mg, further preferably

about 0.1 mg to about 10 mg in the case of parenteral
administration. The dosage can be administered with being
divided in 1-3 times daily.
Compound (I), (II), (III) or (IIIa) of the present
invention can be formulated with a pharmaceutically
acceptable carrier and can be orally or parenterally
administered as solid formulations such as tablets,
capsules, granules, powders, or the like; or liquid
formulations such as syrups, injections, or the like. Also,
there can be prepared formulations for transdermal
administration such as patchings, cataplasms, ointments
(including creams), plasters, tapes, lotions, liquids and
solutions, suspensions, emulsions, sprays, and the like.
As for a pharmaceutically acceptable carrier, a
variety of organic or inorganic carrier substances, which
have been conventionally employed as formulation materials,
is used and compounded as a bulking agent, a lubricant, a
binding agent, and a disintegrator in solid formulations; a
vehicle, a solubilizing agent, a suspending agent, an
isotonicity agent, a buffering agent, and an analgesic in
liquid formulations. If necessary, formulation excipients
such as a preservative, an antioxidant, a stabilizer, a
coloring agent, a sweetening agent, and the like can be
used.
Preferred examples of the bulking agent include

lactose, sucrose, D-mannitol, starch, crystalline cellulose,
light anhydrous silicic acid, and the like. Preferred
examples of the lubricant include magnesium stearate,
potassium stearate, talc, colloidal silica, and the like.
Preferred examples of the binding agent include crystalline
cellulose, α-starch, sucrose, D-mannitol, dextrin,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
polyvinyl pyrrolidone, and the like. Preferred examples of
the disintegrator include starch, carboxymethyl cellulose,
calcium carboxymethyl cellulose, croscarmellose sodium,
sodium carboxymethyl starch, low-substituted hydroxypropyl
cellulose, and the like. Preferred examples of the vehicle
include water for injection, alcohol, propylene glycol,
macrogol, sesame oil, corn oil, and the like.
If necessary, for the purpose of taste masking,
enteric coating, or prolonged action, oral formulations can
be prepared by coating by a per se known method. Examples
of this coating agent include hydroxypropylmethyl cellulose,
ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl
cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68
[polyoxyethylene (160) polyoxypropylene (30) glycol],
cellulose acetate phthalate, hydroxypropylmethyl cellulose
phthalate, hydroxymethyl cellulose acetate phthalate,
Eudragit (manufactured by Rohm Company, methacrylic acid-
acrylic acid copolymer), and the like.

Preferred examples of the solubilizing agent include
polyethylene glycol, propylene glycol, benzyl benzoate,
ethanol, trisamiomethane, cholesterol, triethanolamine,
sodium carbonate, sodium citrate, and the like. Preferred
examples of the suspending agent include surface active
agents such as stearyltriethanolamine, sodium lauryl
sulfate, laurylaminopropionic acid, lecithin, benzalkonium
chloride, benzethonium chloride, glycerin monostearate, and
the like; hydrophilic, high molecular substances such as
polyvinyl alcohol, polyvinyl pyrrolidone, sodium
carboxymethyl cellulose, methyl cellulose, hydroxymethyl
cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
and the like; and so on. Preferred examples of the
isotonicity agent include sodium chloride, glycerin, D-
mannitol, and the like. Preferred examples of the
buffering agent include buffer solutions of a phosphate, an
acetate, a carbonate, a citrate, or the like. Preferable
examples of the analgesic include benzyl alcohol and the
like. Preferred examples of the preservative include
paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol,
phenethyl alcohol, dehydroacetic acid, sorbic acid, and the
like. Preferred examples of the antioxidant include
sulfites, ascorbic acid, and the like.
The following examples, preparations and experiments
describe the manner and process of making and using the

present invention and are illustrative rather than limiting.
It is to be understood that there may be other embodiments
which fall within the spirit and scope of the present
invention as defined by the claims appended hereto.
Abbreviations employed herein are defined below.
DCM = dichloromethane
DCE = dichloroethane
DMAP = dimethylaminopyridine
DMF = dimethylformamide
WSC = 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide
hydrochloride
M+H = monoisotopic mass plus one proton
Me = methyl
Et = ethyl
Ph = phenyl
h = hours
min = minutes
HPLC = high performance liquid chromatography
HOBt = hydroxybenzotriazole
LC/MS = liquid chromatography/mass spectrometry
MS = mass spectrometry
Rt = retention time
TEA = triethylamine
TFA = trifluoroacetic acid
IPE = diisopropylether

TLC = thin layer chromatography
THF = tetrahydrofuran
TMSCN = trimethylsilyl cyanide
HATU = 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl-
uronium hexafulorophosphate
DIPEA = diisopropylethylamine
Example 1
Ethyl 5-phenyl- 7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate

Step A: A mixture of 4,4,4-trifluoro-1-phenyl-1,3-
butanedione 1 (6.97 g, 32.24 mmol) and ethyl 3-
aminopyrazole-4-carboxylate 2 (5.0 g, 32.22 mmol) in AcOH
3 (100 mL) was refluxed for 4 h. The mixture was cooled to
room temperature and concentrated and precipitated crystals
were collected by filtration to give 8.63 g (79%) of the
title compound as yellow crystals. 1H NMR (CDC13, 200 MHz):

1.47 (3H, t, J=7.0 Hz), 4.47 (2H, q, J=7.0 Hz), 7.54-7.61
(3H, m), 7.80 (1H, s), 8.23-8.28 (2H, m), 8.68 (1H, s).
Step B: To a solution of 3 (3.51 g, 10.3 mmol) in MeOH
was added NaBH4 (1.4 g, 3.7 mmol) at room temperature. The
whole was stirred at the same temperature for 5 h, quenched
with saturated citric acid solution, concentrated in vacuo,
and extracted with AcOEt. The extract was successively
washed with aq. NaHCO3, water and brine, dried over MgSO4
and then concentrated to give 1.73 g (49%) of compound 4 as
colorless oil. 1H HMR (CDC13, 200 MHz): 1.32 (3H, t, J=6.8
Hz), 2.28-2.46 (1H, m) , 2.50-2.61 (1H, m) , 4.25 (2H, q,
J=6.8 Hz), 4.58 (1H, dd, J=11.4, 3.4 Hz), 4.85 (1H, ddd,
J=3.4, 3.0, 2.6 Hz), 6.15 (1H, s)7.34-7.48 (5H, m) , 7.74
(1H, s) .
Compounds of Examples 2-14, shown in the Table 1, were
prepared in a manner similar to that described in Example 1.

Example 15
Ethyl 7,7-dimethyl-5-(2-pyridyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate

Step A: To a stirred solution of compound 1 (7.0 g,
4 4.3 mmol) in THF (100 mL) was added n-BuLi (1.6 M hexane
solution, 28 mL, 44.8 mmol) at -78 °C. After the mixture
was stirred for 30 min, compound 2(6.34 g, 44.3 mmol) was
added thereto. The resulting mixture was stirred at -78--
50°C for 2h, quenched with saturated citric acid solution
and extracted with AcOEt. The extract was successively
washed with water and brine, dried over MgSO4 and then
concentrated in vacuo. The residue was chromatographed on
silica gel with AcOEt/hexane (1:9) as an eluent to give
3.16 g (44% yield) of compound 3 as colorless liquid.
Step B: To a solution of compound 3 and compound 4 in
methoxyethanol (60 mL) was added TFA (4.47 g, 39.2 mmol)
with ice-water cooling. The mixture was refluxed for 12 h,
diluted with AcOEt, and the mixture was washed with
saturated NaHCO3 solution, water and brine, dried over

MgSO4, and then concentrated in vacuo. The residue was
chromatographed on silica gel with AcOEt/hexane (1:4) as an
eluent to give 2.03 g (36% yield) of compound 5 as
colorless prisms.
Step C: A mixture of 5 (1.98 g, 6.96 mmol) and 10 %
Pd-C (1.0 g) in EtOH (100 mL) was stirred for 2h under the
H2 atmosphere (balloon pressure). After the insoluble
materials were filtered off, the residue was concentrated
in vacuo to give the residue. Crystallization from
hexane/IPE gave the title compound 6 (1.00g, 48%) as
colorless solid. 1H NMR (CDC13, 200 MHz): 1.34 (3H, t,
J=7.0 Hz), 4.26 (2H, q, J=7.0 Hz), 4.80 (1H, dd, J=11.4,
2.6 Hz), 6.39 (1H, s) , 7.24-7.31 (1H, m) , 7.51 (1H, d,
J=7.6 Hz), 7.76 (1H, td, J=7.6, 1.8 Hz), 8.60-8.63 (1H, m).
Compounds of Examples 16-29, 439-447 and 924-938 shown
in the Table 2, were prepared in a manner similar to that
described in Example 15.

A mixture or 1, 1.5 N KOH solution (14 mL) and EtOH
(20 mL) was stirred at 60 °C for 12h, acidified with
saturated citric acid solution, and the precipitated solid
was collected by filtration, which was washed with water
and IPE to give 1.59 g (76% yield) of the title compound as
colorless prisms, mp 184.8-185.0 °C, 1H NMR (CDC13, 300
MHz): 2.31-2.44 (1H, m), 2.50-2.59 (1H, m), 4.59 (1H, dd,
J=11.4, 3.0 Hz), 4.79 (1H, m), 6.10 (1H, s), 7.20-7.26 (5H,
m) , 7.78 (lH,s) .
Compounds of Examples 22-39, 448-458 and 939-953 shown
in the Table 3, were prepared in a manner similar to that
described in Example 21.

Example 4 0
N-Cyclooctyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Cyclooctylamine (24 mg, 0. 19 mmol) was added to a
suspension of compound 1 (0.05 g, 0. 16 mmol), WSC (37 mg,
0. 19 mmol), HOBt (29 mg, 0.19 mmol) and DMAP (23 mg, 0. 19
mmol) in DMF (1.5 mL). The reaction mixture was stirred at
room temperature for 14 h, diluted with DCM (0.5mL) and
saturated NaHCO3 solution (0.5 mL) , and then separated
using PHASE-SEP filtration syringe. The organic layer was
concentrated and loaded onto preparative HPLC (Gilson 215
system). The purest fractions were combined to give 64.6 mg
(96% yield) of the title compound as a white solid. Reverse
Phase LC/MS: CAPCELLPAKCC18UG120, S-3 µ m, 2.0 x 50 mm, UV
detection at 220, 8 min. gradient 10-100% Solvent B/A
(Solvent A: CH3CN with 0.1% TFA, Solvent B: H2O with 0.1%
TFA), 0.5 mL/min. Rt=1.90 min, (96% pure). MS (M+H: 421).
Example 41
N-(1-ethyl-1-(4-(trifluoromethyl)phenyl)propyl)-7,7-
dimethyl-5-phenyl-4, 5, 6, 7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide

To a solution of 3 (0.5g, 1.84mmol) and HATU (0.84g,
2.21mmol) in DMF (3mL) was added DIPEA (0.67mL, 3.68mmol)
at room temperature. After 30 min, compound 2 (0.59g,
2.21mmol) was added thereto. The resulting mixture was
stirred at 80 °C for 18 h, concentrated in vacuo, and the
residue was chromatographed on silica gel with AcOEt/hexane
(1/1) as an eluent to give 0.28 g (31% yield) of compound 4
as colorless prisms, mp 193-194 °C.
Compounds of Examples 42 - 434, 459-867 and 954-1008
shown in the table 4, were prepared in a manner similar to
that described in Example 40 or 41.

Example 1009
Ethyl 7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate
Racemic compound obtained in Example 16 (80 g)
was subjected to preparative high performance liquid
chromatography (HPLC) to afford optically pure materials
(38 g, 99.8% ee (shorter retention time) and 39 g, 99.4% ee
(longer retention time)). [column: CHIRALCEL OD 50 mmol x
500 mm (manufactured by Daicel Kagaku Kogyo Kabushiki
Kaisha), temperature: 30°C, mobile phase: hexane/Ethanol =
95/5, flow rate: 60 ml/minute, detection wavelength: 254 ran,
and 1 shot: about 800 mg].
Compounds of Examples 1010 - 1017 shown in the
Table 8~11, were prepared in a manner similar to that
described in Example 1009.

The determination of the optical purity was carried out
by HPLC using a chiral column (column: CHIRALCEL OD 4.6 mmΦ
x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki
Kaisha), temperature: about 30°C, mobile phase:
hexane/ethanol = 96/4, flow rate: 0.5 ml/minute, and
detection wavelength: 254 nm).

The determination of the optical purity was carried out
by HPLC using a chiral column (column: CHIRALPAK AD 4.6 mmΦ
x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki
Kaisha), temperature: about 30°C, mobile phase: hexane/IPA
= 95/5, flow rate: 0.5 ml/minute, and detection wavelength:
254 nm).

The determination of the optical purity was carried out
by HPLC using a chiral column (column: CHIRALPAK AD 4.6 mmΦ
x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki
Kaisha), temperature: about 30°C, mobile phase:
hexane/ethanol = 995/5, flow rate: 0.5 ml/minute, and
detection wavelength: 220 nm).
Table 11

The determination of the optical purity was carried out
by HPLC using a chiral column (column: CHIRALCEL OD 4.6 mmΦ
x 250 mm (manufactured by Daicel Kagaku Kogyo Kabushiki
Kaisha), temperature: about 30°C, mobile phase:
hexane/ethanol = 95/5, flow rate: 0.5 ml/minute, and
detection wavelength: 258 nm).
Example 1018
(-)-7,7-Dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of 1(0.73 g) obtained in Example 1009, KOH
(0.41 g) , H2O(20 ml) and EtOH (20 mL) was stirred at 90 °C
for 12h, acidified with 1N HCl, and extracted with AcOEt.

Compounds of Examples 1019-1027 shown in the Table 12,
were prepared in a manner similar to that described in
Example 1018.

(S)-N-(1-(4-Chlorophenyl)-1-ethylpropyl)-7,7-dimethyl-
5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-
carboxamide hydrochloride

Step A: To a solution of 1 (0.4g, 1.47mmol) and HATU
(0.67g, 1.77mmol) in DMF (5mL) was added DIPEA (0.57g,
4.41mmol) at room temperature. After 1 h, compound 2 (0.41g,
1.77mmol) was added thereto. The resulting mixture was
stirred at 80 °C for 12 h, and concentrated in vacuo. The
residue was diluted with AcOEt, washed with sat.NaHCO3aq
and brine, dried over MgSO4, and concentrated in vacuo. The
residue was chromatographed on silica gel with AcOEt/hexane

(1/1) to give 0.41 g (62% yield) of compound 4 as colorless
prisms, mp 105-106 °C. [α]D20°c = -17.68 in CHC13, C = 0.30.
Step B: To a stirred solution of compound 3 (90 mg, 0.2
mmol) in Et2O (3 mL) was added 4M HCl-AcOEt (0.1 mL, 0.4
mmol) at room temperature. The precipitate was collected by
filtration to give 60mg (62% yield) of compound 4 as prisms.
mp 130-132 °C. [α]D20°c = 24.3 in CHC13 C = 0.48.
Compounds of Examples 102 9 - 1122 shown in the Table
13, were prepared in a manner similar to that described in
Example 1028.

Example 435
N-(1-adamantyl)-7-ethyl-5-phenyl-7-(trifluoromethyl)-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A: To a stirred solution of compound 1 (2.00 g,
6.00 mmol) in DCM (50 mL) was added triethylaluminium (2.0
M hexane solution, 18 mL, 36 mmol) at room temperature.
After the mixture was stirred for 2 h, it was quenched with
water, and extracted with AcOEt. The extract was
successively washed with water and brine, dried over MgSO4
and then concentrated in vacuo to give compound 2 (2.20 g,
100% yield) as yellow syrup. MS (ESI,m/z) 366 (M + H)+ .
Step B: A mixture of compound 2 (2.20 g, 6.00 mmol),
LiOH (0.51 g, 12.15 mmol), EtOH (50 mL) and H2O (30 mL) was

stirred at 70 °C for 12 h, concentrated in vacuo, diluted
with aq.citric acid solution and extracted with AcOEt. The
extract was successively washed with water, saturated
NaHCO3 solution and brine, dried over MgSO4 and then
concentrated to give compound 3 (2.00 g, 100%) as colorless
crystals. MS (ESI,m/z) 352 (M + H)+ .
Step C: 1-Adamantylamine (0.72 g, 4.7 6 mmol) was added
to a suspension of compound 3 (1.60 g, 4.74 mmol), WSC
(0.91 g, 4.74 mmol), HOBt (0.64 g, 4.74 mmol) and DMAP
(0.58 g, 4.75 mmol) in DMF (20 mL) . The reaction mixture
was stirred at 70 °C for 13 h and then concentrated in
vacuo. The residue was chromatographed on silica gel with
AcOEt/hexane (1/6) as an eluent to give compound 4 (0.71 g,
32 %) as colorless crystals. MS(ESI,m/z) 472 (M+H)+.
Step D: To a solution of 4 (0.58 g, 1.23 mmol) in EtOH
was added NaBH4 (0.2 g, 5.29 mmol) at room temperature. The
whole was stirred at 60 °C for 3 h, concentrated in vacuo,
diluted with water and extracted with AcOEt. The extract
was successively washed with aq. NaHCO3, water and brine,
dried over MgSO4 and then concentrated to give 0.43 g (74%)
of compound 5 as colorless crystals. MS(ESI,m/z) 474 (M+H)+.
Compounds of Examples 436, shown in the Table 5, were
prepared in a manner similar to that described in Example
435.

Example 4 37
2-cyclohexyl-4-methyl-N-(1-methyl-1-phenylethyl) -
1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine-8-
carboxamide

Step A: To a 250 mL round bottom flask equipped with
magnetic stir bar and 2 addition funnels was added 1.0 g
(6.44 mmol) of compound 1 by 3.5 ml of cone, hydrochloric
acid and 7.0 ml of water. The solution was cooled to 0 °C
and a solution containing 0.50 g (7.25 mmol) of sodium
nitrite in 2 ml of water dropwise. After complete addition,
the reaction was allowed to stir for 30 min. at 0 °C,
followed by the addition of 65 ml of dichloromethane and 35
ml of a saturated sodium bicarbonate solution while
maintaining the reaction temperature below 10 °C. A
solution containing 2.05 g (6.44 mmol) of 1-
triphenylphosphoroanylidene-2-propanone in 30 ml of
dichloromethane was then added dropwise. After complete

addition, the reaction was allowed to stir for 5 min.,
diluted with 50 ml of dichloromethane and washed with water.
The organic phase was separate and the solvent removed
under reduced pressure to afford 3.50 g (100%) of crude
compound 2 which is taken on without further purification.
MS Calcd.: 206; Found 207 (M+H).
Step B: To a solution containing the crude product
from above in 30 ml of ethanol and 30 ml of THF under a
nitrogen atmosphere was added 1.20 g (3.72 mmol) of sodium
borohydride. The reaction was allowed to stir at room
temperature for 30 min. The reaction was diluted with ethyl
acetate and washed with water. The organic phase was dried
over MgSO4. Filtration, removal of solvent and purification
of the residue via Biotage chromatography eluting with 70%
AcOEt/hexanes gave 0.7 9 g (58.9%) of compound 3 as a pale
yellow solid. MS Calcd.: 208; Found 209 (M+H)
Step C: A solution containing 0.54 g (2.59 mmol) of
compound 3 and 0.18 g of LiOH (7.52 mmol) in 15 ml of
ethanol and 10 ml of water was heated to 70 °C. After 1.5h,
HPLC of reaction mixture indicated no starting material
remaining. The ethanol was removed under reduced pressure
and the residue acidified with 1N hydrochloric acid and
extracted with ethyl acetate. The organic phase was dried
over magnesium sulfate. Filtration and removal of solvent
gave 0.48 g (92.2%) of compound 4. MS Calcd.: 180; Found

181 (M+H).
Step D: To a solution containing 2.80 g (15.54 mmol)
of compound 4 in 150 ml of DMF under a nitrogen atmosphere
was added 6.50 g (17.10 mmol) of HATU, 2.31 g (17.10 mmol)
of cumyl amine and 2.98 ml (17.10 mmol) of
diisopropylethylamine. The reaction was heated to 50 °C
overnight, diluted with ethyl acetate and washed with water.
The organic phase was dried over magnesium sulfate.
Filtration, removal of solvent and purification of the
residue via Biotage chromatography eluting with 60% AcOEt/
hexanes gave 3.0 9 g (66.9%) of compound 5. MS Calcd.: 297;
Found 298 (M+H).
Step E: To a Parr flask was added 1.11 g (3.90 mmol)
of compound 5 and 75 ml of EtOH. The flask was purged with
nitrogen and 0.30 g of platinum oxide added. The flask was
evacuated and pressurized to 20 psig hydrogen (3x) then
pressurized to 50 psig hydrogen and shaken for 1h. After
completion as determined by HPLC, the reaction was filtered
through GF/F filter paper and the filtrate concentrated
under reduced pressure to afford 1.1 g (100%) of compound 6.
MS Calcd.: 299; Found 300 (M+H)
Step F: To a solution containing 0.43 g (1.44 mmol) of
compound 6 in 4 0 ml of DCE under a nitrogen atmosphere was
added 0.30 ml (2.89 mmol) of cyclohexanone followed by 0.90
g (4.25 mmol) of sodium triacetoxy borohydride. The

reaction was allowed to stir at room temperature overnight.
The reaction was diluted with dichloromethane and washed
with saturated sodium bicarbonate solution. The organic
phase was dried over MgSO4. Filtration, removal of solvent
and purification of the residue via Biotage chromatography
eluting with 75% AcOEt/hexanes gave 0.35 g (63.7%) of
compound 7. MS Calcd.: 381; Found 382 (M+H)
Example 438
4-Methyl-N-(1-methyl-1-phenylethyl)-2-phenyl-l,2,3,4-
tetrahydropyrazolo[5,1-c][1,2,4]triazine-8-carboxamide

To a solution containing 0.20 g (0.71 mmol) of
compound 1 in 25 ml of DCM under a nitrogen atmosphere at -
78 °C was added 0.36 g (0.64 mmol) of triphenylbismuth
diacetate followed by 0.02 g (0.075 mmole) of copper (II)
dipivalate. The reaction was allowed to warm to 0 °C over
1.5 h. The reaction was diluted with dichloromethane and
washed with saturate sodium bicarbonate. The organic phase
was dried over magnesium sulfate. Filtration, removal of
solvent and purification of the residue via Biotage

chromatography eluting with 70% AcOEt/ hexanes gave 0.025 g
(9.4%) of compound 2. MS Calcd.: 375; Found 376 (M+H)
Example 1123
1-(7,7-Dimethyl-5-phenyl-4, 5, 6, 7-
tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2-(4-
methylphenyl)-1-propanone

Step A
4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2) :
To a 100 mL round bottom flask equipped with a magnetic

stir bar was added 1.80 g (6.01 mmol) of 7,7-dimethyl-5-
phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine-3-
carboxylic acid ethyl ester, 30 mL of DMF and 0.786 mL
(6.61 mmol) of benzyl bromide, followed by 0.265 g (6.6
mmol) of sodium hydride (60% dispersion in mineral oil)
which was added in several portions. After 2 h, the
reaction was quenched with water and the product was
extracted with AcOEt. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and
concentrated to give the crude N-benzylated ester as a
golden colored oil. The crude ester was dissolved in 15 mL
of ethanol and 2.5 mL of 6 N potassium hydroxide was added.
The solution was then heated to 70 °C for 18 h at which
time no starting material could be detected by HPLC
analysis. The crude reaction mixture was concentrated in
vacuo and diluted with water. The aqueous solution was
acidified with 6 N HC1 and the resulting cream-colored
precipitate was collected by filtration. The crude acid
thus isolated was dissolved in AcOEt, dried over sodium
sulfate, filtered and concentrated to a cream colored
powder. The resulting acid was washed with several
portions of hexanes and dried in vacuo to give 1.95 g (90%)
of the title compound as an off white powder. 1H NMR
(DMSO-d6) δ 1.10 (s, 3H) , 1.40 (s, 3H) , 1.98-2.16 (m, 2H) ,
3.71 (d, J = 15.4 Hz, 1H), 4.36 (dd, J = 4.5, 11.5 Hz, 1H),

5.81 (d, J = 15.6 Hz), 6.97 (dd, J = 1.4, 7.2 Hz, 2H) ,
7.26-7.45 (m, 7H), 7.67 (s, 1H), 11.81 (s, 1H). MS Calcd.:
361; Found: 344 (M-OH).
Step B
4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6, 7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid
methoxy-methyl-amide (3) : To a 5 mL NMP solution
containing 0.72 g (1.99 mmol) of 2 was added 0.91 g (2.39
mmol) of O-7-azabenzotriazolo-1-yl) -N,N,N' ,N'-
tetramethyluroniumhexafluorophosphate (HATU) and 0.416 mL
(2.39 mmol) of diisopropylethylamine. After stirring for
30 min, 0.233 g (2.39 mmol) of O,N-dimethyl-hydroxylamine
hydrochloride was added and the reaction heated to 50 °C.
After 1 h, the reaction mixture was poured into water and
extracted with AcOEt. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and
concentrated in vacuo to give a crude oil. Purification of
this oil by flash chromatography eluting with a 60 to 50%
hexanes/AcOEt gradient gave 0.65 g (81%) of the title

(M+H).
Step C
l-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(4-
methylphenyl) ethanone (4) : To 0.65 g (1.61 mmol) of 3
dissolved in 20 mL of THF was added 6.4 mL (3.2 mmol) of a
0.5 M solution of 4-methylbenzylmagnesium chloride in THF
via syringe over 10 min. After stirring at room
temperature for 1 h, the reaction was quenched by addition
of approximately 2 mL of saturated aqueous ammonium
chloride. The reaction was then diluted with AcOEt and
dried over sodium sulfate. Filtering the solution through
a short plug of silica gel and concentrating in vacuo
provided the crude product as an oil. Purification of this
oil by flash chromatography eluting with 75% hexanes/ AcOEt
gave 0.64 g (89%) of the title compound as a white foam.
MS Calcd.: 449; Found: 450 (M+H).
Step D
1-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-(4-
methylphenyl)-1-propanone (5) : To 0.64 g (1.42 mmol) of 4
dissolved in 10 mL of THF was added 0.177 mL (2.85 mmol) of
iodomethane followed by 0.11 g (2.8 mmol) of sodium hydride
(60% dispersion in mineral oil). After stirring at room
temperature for 2 h, the reaction was quenched by addition

of approximately 2 mL of saturated aqueous ammonium
chloride. The reaction was then diluted with AcOEt and
dried over sodium sulfate. Filtering the solution through
a short plug of silica gel and concentrating in vacuo
provided the crude product. Purification by flash
chromatography eluting with 90% hexanes/ethyl acetate gave
0.42 g (64%) of the title compound as a cream colored
powder. MS Calcd.: 463; Found: 464 (M+H).
Step E
1-(4-Benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)-2-methyl-2-(4-
methylphenyl)-1-propanone (6) : To 0.110 mL (0.785 mmol) of
diisopropyl amine dissolved in 5 mL of THF at -78 °C was
added 0.314 mL (0.785 mmol) of a 2.5 M solution of n-
butyllithium in hexanes. After stirring for 30 min, 0.28 g
(0.604 mmol) of 5 was added as a solution in 1 mL of THF.
The reaction was stirred at room temperature for 1 h before
0.04 9 mL (0.79 mmol) of iodomethane was added as a solution
in 1 mL of THF. After 1h the reaction was quenched by
addition of approximately 0.5 mL of saturated aqueous
ammonium chloride, diluted with AcOEt and dried over sodium
sulfate. Filtering the solution through a short plug of
silica gel and concentrating in vacuo provided the crude
product. Purification by flash chromatography eluting with
90% hexanes/ AcOEt gave 0.067 g (23%) of the title

compound as an off white solid. MS Calcd.: 477; Found: 478
(M+H).
Step F
1-(7,7-Dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidin-3-yl)-2-methyl-2-(4-methylphenyl)-1-propanone
(7) : To 0.060 g (0.126 mmol) of 6 dissolved in 4 mL of 1:1
THF:ethanol was added 0.080 g of 10% palladium on carbon.
The reaction vessel was capped with a rubber septum and
charged with hydrogen via a balloon. After 1 h, the
catalyst was removed via filtration and the filtrate
concentrated to a cream colored solid. Purification by
flash chromatography eluting with 90% hexanes/ethyl acetate
gave 0.041 g (84%) of the title compound as a white solid.
1H NMR (CDC13) δ 1.49 (s, 3H) , 1.54 (s, 9H), 2.04-2.11 (m,
2H), 2.32 (s, 3H), 4.63 (dd, J = 4.1, 10.7 Hz, 1H), 6.66 (s,
1H), 7.12-7.26 (m, 5H), 7.31-7.44 (m, 5H). MS Calcd.: 387;
Found: 388 (M+H).
Compounds of Examples 1124-1131 shown in the Table 14,
were prepared in a manner similar to that described in
Example 1123.
Table 14

Example 1132
7,7-Dimethyl-3-((1-methyl-1-(4-
methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine

Step A
p-Tolylmethanesulfonylacetonitrile (2): To a 10 mL ethanol
solution containing 4.1 g (30 mmol) of p-tolylmethanethiol
at 0 °C was added 4.1 mL (30 mmol) of triethylamine and 4.4
g (30 mmol) of sodium iodide. After allowing the reaction
to stir at room temperature for approximately 30 min, the
reaction cooled to 0 °C and 1.9 mL (30 mmol) of
chloroacetonitrile was added dropwise as a solution in 10
mL of ethanol. The reaction was allowed to reach room
temperature overnight and was subsequently filtered and
concentrated. The concentrate was partitioned between
water and ether and separated. The ether layer was washed
successively with 2 N sodium carbonate and brine and was

then concentrated to an oil that solidified. The crude
solid was then dissolved in 90 mL of glacial acetic acid,
treated with 12.1 mL (107 mmol) of 30% hydrogen peroxide
and heated to 100 °C. The reaction was cooled to room
temperature after 3 h at which time a white solid
precipitated. The precipitate was collected via filtration,
washed with glacial acetic acid and dried in vacuo to give
6.4 g (69%) of the title compound as a white solid. 1H NMR
(CDC13) δ 2.39 (s, 3H), 3.70 (s, 2H) , 4.48 (s, 2H) , 7.32
(dd, J = 7.3, 40.2 Hz, 4H).
Step B
3-Ethoxy-2-p-tolylmethanesulfonylacrylonitrile (3) : To a
solution of 4.4 g (21 mmol) of 2 in 17.5 mL (105 mmol) of
triethylorthoformate was added 9.9 mL (105 mmol) of acetic
anhydride. The resulting solution was heated to reflux for
18 h before being concentrated to a solid.
Recrystallization from AcOEt-hexanes gave 5.0 g (90%) of
the title compound as a white solid.
1H NMR (CDCl3) δ 1.29 (t, J = 7.0 Hz, 3H) , 2.36 (s, 3H) ,
4.19 (q, J = 7.0 Hz, 2H), 4.35 (s, 2H), 7..23 (dd, J = 8.0,
19.9 Hz) 7.37 (s, 1H).
Step C
7,7-Dimethyl-3-(4-methylbenzyl)sulfonyl)-5-phenyl-4,7-
dihydropyrazolo[l,5-a]pyrimidine (4) : A slurry of 1.9 g
(7.2 mmol) of 3 in 25 mL of ethanol was treated with 0.38

mL (7.9 mmol) of hydrazine monohydrate and heated to reflux
for 3 h. The reaction was concentrated in vacuo to give
crude 4-p-tolylmethanesulfonyl-2H-pyrazol-3-ylamine as a
tan solid. The crude pyrazole, 1.3 g (7.9 mmol) of 3-
methyl-1-phenyl-but-2-en-1-one and 2.8 mL (36 mmol) of
trif luoroacetic acid was dissolved in 25 mL of 2-
methoxyethanol and heated to reflux for 3 days. The
reaction was then cooled to room temperature, concentrated
in vacuo and dissolved in AcOEt. This solution was washed
successively with saturated sodium bicarbonate, water and
brine before being dried over sodium sulfate. The solution
was filtered, concentrated in vacuo and the resulting crude
material was purified by flash chromatography eluting with
a 75 to 33% hexanes/ AcOEt gradient to give 1.25 g (44%)
of the title compound as a powder. 1H NMR (CDC13) δ 1.67
(s, 6H) , 2.13 (s, 3H) , 4.26 (s, 2H) , 4.81 (d, J = 2.0 Hz,
1H) , 6.39 (s, 1H) , 7.05 (dd, J = 8.0, 18.5 Hz, 4H) , 7.20
(dd, J = 3.7, 7.4 Hz, 2H), 7.36-7.39 (m, 3H), 7.52 (s, 1H).
MS Calcd.: 393; Found: 394 (M+H).
Step D
7,7-Dimethyl-3-((4-methylbenzyl)sulfonyl)-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine (5) : To 0.500 g (1.27
mmol) of 4 dissolved in 8 mL of 1:1 THF:ethanol was added
0.50 g of 10% palladium on carbon. The reaction vessel was
capped with a rubber septum and charged with hydrogen via a

balloon. After 2 days at room temperature, the catalyst
was removed via filtration and the filtrate concentrated to
a solid. Purification by flash chromatography eluting
with a 75 to 33% hexanes/AcOEt gradient gave 0.385 g (77%)
of the title compound as a white solid. 1H NMR (CDCl3) δ
1.49 (s, 3H), 1.59 (s, 3H), 1.83-1.97 (m, 2H), 2.37 (s, 3H) ,
4.09-4.24 (m, 3H) , 5.03 (s, 1H) , 7.06-7.13 (m, 6H) , 7.30-
7.39 (m, 3H) , 7.45 (s, 1H) . MS Calcd. : 395; Found: 396
(M+H).
Step E
4-Benzyl-7,7-dimethyl-3-((4-methylbenzyl)sulfonyl)-5-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (6) : To
a solution of 0.34 g (0.86 mmol) of 5 in 10 mL of THF at
0 °C was added 0.128 mL (1.07 mmol) of benzyl bromide
followed by 0.034 g (0.86 mmol) of sodium hydride (60%
dispersion in mineral oil) . The reaction was allowed to
warm to room temperature after 30 min and stirred for an
additional 30 min before being quenched with water. The
quenched reaction was diluted with five volumes of water
and extracted with AcOEt. The combined organic layers were
washed with brine, dried over sodium sulfate, filtered and
concentrated in vacuo. The crude product was purified by
flash chromatography eluting with 70% hexanes/AcOEt to give
0.39 g (93%) of the title compound as a white solid. 1H
NMR (CDCl3) δ 1.27 (s, 3H) , 1.52 (s, 3H) , 1.93-2.05 (m,

2H), 2.27 (s, 3H), 3.83 (d, J = 15.8 Hz, 1H) , 4.18-4.30 (m,
3H), 5.51 (d, J = 15.8 Hz, 1H), 6.98-7.00 (m, 2H), 7.09 (dd,
J = 8.2, 12.1 Hz, 4H), 7.17 (d, J = 6.8 Hz, 2H), 7.26-7.30
(m, 3H), 7.32-7.40 (m, 3H), 7.47 (s, 1H).
Step F
4-Benzyl-7,7-dimethyl-3-((1-(4-
methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine (7) : A solution of
0.23 g (0.47 mmol) of 6 in 4 mL of THF was cooled to 0 °C
and treated with 0.24 mL (0.59 mmol) of n-butyllithium (2.5
M solution in hexanes) and allowed to reach room
temperature for 20 min. After cooling the reaction to 0 °C,
0.103 mL (1.66 mmol) of iodomethane was added as a solution
in 2 mL of THF. The reaction was allowed to warm to room
temperature for 30 min at which time the reaction was
quenched with a few drops of saturated ammonium chloride.
The reaction was dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by flash
chromatography eluting with 80% hexanes/AcOEt to give 0.14
g (60%) of the title compound as a white solid. MS
Calcd.: 499; Found: 500 (M+H).
Step G
4-Benzyl-7,7-dimethyl-3-((1-methyl-1-(4-
methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine (8) : Using the method

described for the synthesis of 7, the title compound was
prepared in 51% isolated yield. MS Calcd.: 513; Found:
514 (M+H).
Step H
7,7-Dimethyl-3-((1-methyl-1-(4-
methylphenyl)ethyl)sulfonyl)-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine (9) : To 0.075 g (0.146
mmol) of 8 dissolved in 6 mL of 1:1 THF:ethanol was added
0.10 g of 10% palladium on carbon. The reaction vessel was
capped with a rubber septum and charged with hydrogen via a
balloon. After 2 h at room temperature, the catalyst was
removed via filtration and the filtrate concentrated to
give 0.056 g (91%) of the title compound as a white solid.
MS Calcd.: 423; Found: 424 (M+H).
Compounds of Examples 1133-1134, shown in the Table 15,
were prepared in a manner similar to that described in
Example 1132.

Example 1135
3-(3-Benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine

Step A
(3-Benzylpyrrolidine-1-sulfonyl)acetonitrile (2) : To a 20
mL ether solution containing 1.34 g (8.31 mmol) of 3-
benzylpyrrolidine cooled to -45 °C was added 0.61 g (4.4
mmol) of 2-cyanoethanesulfonyl chloride as a solution in 10
mL of ether. The reaction was allowed to warm to room

temperature and was stirred for 24 h over which time an oil
formed on the flask wall. The ether solution was poured
away from the oil and filtered through a short plug of
silica gel. The filtrate thus obtained was concentrated in
vacuo to give a solid that was purified by flash
chromatography eluting with 75% hexanes/AcOEt to give 1.25
g (44%) of the title compound as a wax.
1H NMR (CDC13) δ 1.73-1.83 (m, 1H) , 2.08-2.15 (m, 1H) ,
2.57-2.67 (m, 1H) , 2.71-2.79 (m, 2H) , 3.21 (dd, J = 8.2,
9.7, Hz, 1H), 3.49-3.55 (m, 1H), 3.63 (dd, J = 7.0, 9.4 Hz,
1H), 3.69-3.74 (m, 1H), 3.95 (s, 2H), 7.16 (d, J = 7.4 Hz,
2H), 7.21-7.33 (m, 3H).
Step B
2-(3-Benzylpyrrolidine-1-sulfonyl)-3-ethoxyacrylonitrile
(3) : To a solution of 0.14 g (0.53 mmol) of 2 in 0.43 mL
(2.6 mmol) of triethylorthoformate was added 0.25 mL (2.6
mmol) of acetic anhydride. The resulting solution was
heated to reflux for 4 h before being concentrated to an
oil. The crude oil thus obtained was purified by flash
chromatography eluting with 75% hexanes/AcOEt to give 0.079
g (46%) of the title compound as a yellow oil. 1H NMR
(CDCl3) δ 1.42 (t, J = 7.2 Hz, 3H) , 1.67-1.77 (m, 1H) ,
2.01-2.09 (m, 1H) , 2.53-2.62 (m, 1H) , 2.71 (d, J = 7.4 Hz,
2H) , 3.05 (dd, J = 8.4, 9.8 Hz, 1H) , 3.35-3.41 (m, 1H) ,
3.48 (dd, J = 7.0, 9.5 Hz, 1H), 3.53-3.59 (m, 1H), 4.31 (q,

J = 7.2 Hz, 2H) , 7.15-7.17 (m, 2H) , 7.19-7.23 (m, 1H) ,
7.26-7.31 (m, 2H) , 7.76 (s, 1H).
Step C
3-(3-Benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (4): A 2 mL
ethanol solution containing 0.079 g (0.247 mmol) of 3 was
treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate
and heated to reflux for 5 h. The reaction was
concentrated in vacuo to give crude 4-(3-benzylpyrrolidine-
1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus
obtained was dissolved in 2 mL of 2-methoxyethanol
containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-
en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid
was added. The mixture was refluxed for three days then
concentrated and purified by flash chromatography eluting
with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1-
sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-
a] pyrimidine that was found to be only 90% pure by HPLC
analysis. This material was then dissolved in 1 mL of 1:1
THF:ethanol and 0.010 g of 10% palladium on carbon. The
reaction vessel was capped with a rubber septum and charged
with hydrogen via a balloon. After 90 min at room
temperature, the catalyst was removed via filtration and
the filtrate concentrated to an oil. Purification by
flash chromatography eluting with 75% hexanes/AcOEt gave

0.024 g (20% from 3) of the title compound as a light
yellow oil. 1H NMR (CDC13) δ 1.55-1.66 (m, 7H) , 1.94-2.03
(m, 1H), 2.08-2.16 (m, 2H) , 2.37-2.50 (m, 1H), 2.58-2.70 (m,
2H) , 2.90-2.97 (m, 1H) , 3.18-3.27 (m, 1H) , 3.31-3.42 (m,
2H) , 4.53-4.60 (m, 1H) , 5.71(s, 1H) , 7.11-7.14 (m, 2H) ,
7.19-7.23 (m, 1H) , 7.26-7.40 (m, 7H) , 7.53 (s, 1H) . MS
Calcd.: 450; Found: 451 (M+H).
Example 1136
4,4-Dimethyl-8-[5-(1-methyl-1-phenyl-ethyl)-
[l,3,4]oxadiazol-2-yl]-2-phenyl-l,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidine

Step A
2-Amino-1H-pyrrole-3-carboxylic acid ethyl ester (1) :
Carbamimidoyl-acetic acid ethyl ester (3.357g, 25.8 mmol)
was dissolved in AcOEt (20 mL) . Chloroacetaldehyde (50%
solution in water, 1.8 mL, 28.7 mmol) was added rapidly at
room temperature. The solution stirred for 2 minutes until
a precipitant formed. The solution was then brought to
65 °C for 0.5 h. The reaction mixture was then cooled and
flash chromatographed with AcOEt. Product containing
fractions were concentrated to give the desired material as
a green solid. 0.68 g obtained, 31% yield. 1H NMR (400 MHz,
CDCl3) δ 1.32 (t, J= 7.2 Hz, 3H), 4.24 (q, J= 7.0 Hz, 2H),
5.08 (brs, 2H) , 6.10 - 6.13 (m, 1H) , 6.25 (t, J = 3.12, 1
Hz), 8.60 (brs, 1H); MS Calcd.: 154; Found 155 (M+H).
Step B
4,4-Dimethyl-2-phenyl-l,2,3,4-tetrahydro-pyrrolo[1,2-
a]pyrimidine-8-carboxylic acid ethyl ester (2) : Compound 1
(0.68g, 4.41 mmol) was dissolved in DMF (5 mL) . NaH (60%
in mineral oil, 0.19g, 4.7 mmol) was added at room
temperature affording rapid gas evolution. The reaction
stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1-
one (0.50g, 3.15 mmol) was added. The reaction stirred for
0.5 h upon which EtOH (5 mL) and NaBH4 (1.19g) were added.
The solution was brought to 60 °C for 0.5 h. and then

cooled to room temperature. The solution was quenched with
water, extracted with Et20 (3 times) , dried (Na2SO4) and
concentrated. Flash chromatography (10% AcOEt) to give the
desired product as a tan solid (0.60g, 63% yield). MS
Calcd.: 298; Found 299 (M+H).
Step C
4,4-Dimethyl-2-phenyl-l,2,3,4-tetrahydro-pyrrolo[1,2,-
a]pyrimidine-8-carboxylic acid hydrazide (3) : Compound 2
(0.210g, was diluted with anhydrous hydrazine (5 mL) and
heated to 100 °C for 3 days. The reaction was then cooled
and diluted with water. The solution was extracted with
AcOEt (3 times), dried (Na2SO4) and concentrated. The
residue was flash chromatographed (10% MeOH/AcOEt) to give
the desired material. 0.12g, 60% yield). 1H NMR(400 MHz,
CDC13) δ 1.54 (s, 6H) , 1.99 - 2.13 (m, 2H), 3.89 (brs, 2H),
4.64 (dd, J= 3.5, 11.7 Hz, 1H), 6.02 (d, J= 3.9 Hz), 6.22
(d, J = 3.9 Hz, 1H), 6.55 (brs, 1H), 6.74 (brs, 1H), 7.31 -
7.46 (m, 5H). MS Calcd.: 284; Found 285 (M+H).
Step D
4,4-Dimethyl-2-phenyl-l,2,3,4-tetrahydro-pyrrolo[1,2,-
a]pyrimidine-8-carboxylic acid N-(2-methyl-2-phenyl-
propionyl)-hydrazide (4) :
Compound 3 (0.085g, 0.30 mmol) was dissolved in THF (2 mL).
HBTU (0.136g, 0.36 mmol), α,α-dimethyl-phenylacetic acid
(0.059g, 0.36 mmol), and DIEA (0.10 mL, 0.60 mmol) were

added. The reaction stirred for 2 h. and was concentrated.
Flash chromatography (50% AcOEt/hexanes) gave the desired
product. 0.123g obtained (96% yield). 1H NMR (400 MHz,
CDC13) δ 1.49 (s, 3H), 1.50 (s, 3H), 1.60 (s, 3H) , 1.61 (s,
3H) , 1.95 - 2.10 (m, 2H), 4.56 (dd, J = 3.1, 11.3 Hz, 1H),
6.13 (d, J= 3.5 Hz, 1H), 6.17 (d, 3.5 Hz, 1H), 6.65 (brs,
1H) , 7.22 - 7.43 (m, 10H), 7.81 (brs, 1H), 7.92 (brs, 1H) .
MS Calcd.: 430; Found 431 (M+H).
Step E
4,4-Dimethyl-8-[5-(1-methyl-1-phenyl-ethyl)-
[1,3,4]oxadiazol-2-yl]-2-phenyl-1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrimidine (5) : Compound 4 (0.060g,
0.14 mmol) was diluted in POC13 (3 mL) . The solution was
heated to 75 °C for 3 h. The solution was cooled and
carefully quenched with water. The solution was diluted
with AcOEt and the mixture carefully neutralized with sat.
NaHCO3. The organic layer was separated and the aqueous
layer was extracted twice more with AcOEt portions. The
combined organic layers were dried (Na2SO4) , concentrated,
and flash chromatographed to give the desired product as a
white solid. 0.016g obtained (28% yield). 1H NMR(400 MHz,
CDCl3) δ 1.55 (s, 6H) , 1.80 (s, 6H) , 2.02 - 2.16 (m, 2H) ,
4.68 (dd, J = 3.2, 11.6 Hz, 1H), 6.23 (d, J = 3.2 Hz, 1H),
6.30 (d, J= 3.2 Hz, 1H), 7.20 - 7.46 (m, 10H). MS Calcd.;
412; Found 413 (M+H).

Example 1137
3-Methyl-2-phenyl-2,3-dihydro-1H-imidazo[1,2-
b]pyrazole-7-carboxylic acid [1-ethyl-1-(4-trifluoromethyl-
phenyl)-propyl]-amide

Step A
5-Amino-1-(l-methyl-2-oxo-2-phenyl-ethyl)-1H-pyrazole-4-
carboxylic acid ethyl ester (1) : 5-Amino-1H-pyrazole-4-
carboxylic acid ethyl ester (7.35g, 47.3 mmol) was
dissolved in 160 mL of DMF. Na2CO3 (5.02g, 47.3 mmol) was

added followed by 2-bromopropiophenone (7.2 mL, 47.3 mmol).
The reaction stirred at room temperature for 2 days. The
solution was diluted with AcOEt and the organic layer was
washed with sat. NaHCO3, brine, dried (MgSO4) , and
concentrated. Flash chromatography (20-45% AcOEt/hexane)
gave the desired product (1.58g, 12% yield). 1H NMR(400 MHz,
CDC13) δ 1.3 (t, J = 7.0 Hz, 3H) , 1.7 (d, J = 7.4 Hz, 3H) ,
4.2 (q, J == 7.0 Hz, 2H) , 5.4 (bs, 2H) , 5.9 (q, J = 7.0 Hz,
1H), 7.41 - 7.59 (m, 3H), 7.60 (s, 1H), 8.0 (d, J = 8.0 Hz,
2H) .
Step B
5-Amino-1- (2-hydroxy-1-methyl-2-phenyl-ethyl) -1H-pyrazole-
4-carboxylic acid ethyl ester (2) :Compound 1 (0.7g, 2.43
mmol) was dissolved in 34 mL EtOH. NaBH4 (0.18g, 4.87
mmol) was added in one shot. The reaction stirred at room
temperature for 0.5 h. The solution was quenched with sat.
NH4Cl and extracted with CH2C12 (3 times) . The organic
layer was washed with brine, dried (MgSO4) , concentrated to
give a fluffy white solid 2 (0.69g, 98% yield). MS: Calcd.:
289; Found: 290 (M+H).
Step C
3-Methyl-2--phenyl-2, 3-dihydro-1H-imidazo [1, 2-b] pyrazole-7-
carobxylic acid ethyl ester (3) : Compound 2 (0.80g, 2.8
mmol) was dissolved in CH2C12. SOC12 (0.61 mL, 8.3 mmol)
was added dropwise. After 90 minutes, the solution was

concentrated to give a yellow solid. After pumping on high
vacuum for 5 minutes, the solid was dissolved in CHC13.
Et3N (2.7 mL, 19.5 mmol) was added dropwise and the
reaction mixture stirred for 1 hour. The reaction was
quenched with water and diluted with AcOEt. The solution
was washed with sat. NH4Cl, sat. NaHCO3, brine, and then
dried (MgSO4) . Flash chromatography (20% AcOEt/hexane)
gave both the syn (0.10g, 14%) and anti (0.62g, 82%)
isomers 3. Anti isomer 1H NMR(400 MHz, CDC13) δ 1.23 (t, J
= 7.0 Hz, 3H), 1.80 (d, J = 6.6 Hz, 3H) , 4.10 - 4.20 (m,
2H), 4.25 - 4.35 (m, 1H), 4.38 (brs, 1H) , 5.10 (d, J = 9.8
Hz, 1H), 7.17 - 7.25 (m, 5H) , 7.59 (s, 1H) . Syn isomer 1H
NMR(400 MHz, CDC13) δ 1.28 (d, J= 7.0 Hz, 3H), 7.38 (t, J
= 7.4 Hz, 3H) , 4.25 - 4.35 (m, 2H) , 7.43 - 7.52 (m, 1H) ,
5.17 (brs, 1H) , 5.23 (d, J= 9.8 Hz, 1H) , 7.37 - 7.45 (m,
5H) .
Step D and E
3-Methyl-2-phenyl-2, 3-dihydro-1H-imidazo [1, 2-b] pyrazole-7-
carboxylic acid [1-ethyl-1-(4-trifluoromethyl-phenyl)-
propyl]-amide (5) :
Compound 3 (0.085g, 0.3 mmol) was dissolved in EtOH (3 mL).
KOH (6M in water, 0.9 mL, 1.78 mmol) was added. The
reaction stirred at 60 °C for 3 h. The solution was cooled,
diluted with AcOEt (10 mL) and water (10 mL) and shaken
vigorously. The Aqueous layer was separated and acidified

to pH = 3. This acidic layer was then extracted with AcOEt
(3 times). The combined AcOEt layers were washed with
brine, dried (Na2SO4) and concentrated. The residue was
then dissolved in NMP (1 mL) and 1-ethyl-1-(4-
trifluoromethyl-phenyl)-propylamine (0.087g, 0.37 mmol),
HATU (0.14g, 0.37 mmol), and DIEA (0.14 mL, 0.78 mmol) were
added. The reaction was heated to 80 °C for 2 days. The
solution Was then cooled, washed with water, dried (MgSO4) ,
and concentrated. Flash chromatography (20% AcOEt/hexanes)
gave 0.017g (12% yield) of amide 5.
1H NMR (400 MHz, CDC13) δ 0.79 - 0.83 (m, 6H) , 1.26 (d, J =
7.0 Hz, 3 H), 1.99 - 2.05 (m, 2H) , 2.23 - 2.31 (m, 2H) ,
4.44 - 4.48 (m, 1H) , 5.19 (brs, 1H) , 5.24 (d, J = 10 Hz,
1H), 5.66 (brs, 1H) , 7.37 - 7.63 (m, 9H) . MS Calcd.: 456;
Found: 457 (M+H).
Example 1138
8-Methyl-5-phenyl-5, 6, 7, 8-tetrahydro-4H-
pyrazolo[l,5,a][1,3]diazepine-3-carboxylic acid (1-methyl-
1-phenyl-ethyl)-amide

Step A
5-Amino-1-[4-tert-butyl-dimethyl-silanyloxy]-1-methyl-4-
phenyl-butyl]-1H-pyrazole-4-carboxylic acid ethyl ester
(1) :
5-Amino-lH-pyrazole-4-carboxylic acid ethyl ester (1.60g,
10.3 mmol) was dissolved in 10 mL of DMF. The solution was
cooled to 0 °C and NaH (60% in mineral oil, 0.82g, 20.6
mmol) was added in one portion. The reaction warmed to
room temperature after H2 evolution ceased. The reaction
stirred for 0.5 h till a bright orange color persisted.
The reaction was again brought to 0 °C and methanesulfonic
acid 4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-4-phenyl-

butyl ester (3.49g, 9.38 mmol) was then added as a solution
in 6 mL DMF. The reaction warmed to room temperature and
stirred for 2.5 days. The solution was quenched with water
and diluted with AcOEt. The organic layer was separated
and the aqueous layer was extracted twice more with AcOEt.
The combined organic layers were dried (MgSO4) ,
concentrated and flash chromatographed (15% AcOEt/hexanes)
to give 0.530g (13% yield) of the desired product as an oil.
1H NMR (400 MHz, CDC13) δ 0.16 (s, 3H) , 0.17 (s, 3H) , 1.04
(d, J = 10 Hz, 9H), 1.48 - 1.52 (m, 3H) , 1.55 (d, J = 6.4
Hz, 3H) , 1.60 (d, J = 6.8 Hz, 3H - other diastereomer) ,
1.62 - 1.75 (m, 2H) , 1.97 - 2.07 (m, 2H) , 2.10 - 2.20 (m,
2H - other diastereomer), 4.02 - 4.07 (m, 1H), 4.21 - 4.29
(m, 1H - other diastereomer), 4.40 - 4.43 (m, 2H) , 4.79 -
4.86 (m, 1H), 5.04 (brs, 1H), 5.25 (brs, 1H - other
diastereomer), 7.36 - 7.47 (m, 5H) , 7.79 (s, 1H) ; MS
Calcd.: 431; Found 432 (M+H).
Step B and C
8-Methyl-5-phenyl-5,6,7,8-tetrahydro-4H-
pyrazolo[1,5,a][1,3]diazepine-3-carboxylic acid ethyl ester
(3) : Compound 1 (2.0g, 4.6 mmol) was dissolved in 9 mL THF.
TBAF (1M in THF, 13.9 mL, 13.9 mmol) was added at room
temperature. The reaction stirred for 0.5 h. The reaction
was diluted with ether and washed with brine and water.
The ether layer was dried (MgSO4) and concentrated to give

the crude alcohol product 2. MS Cald.: 317; Found 318
(M+H).
Alcohol 2 was taken up in CH2C12 (80 mL) . SOC12 (1.7
mL, 23.4 mmol) was added. After 1 h, the solution was
concentrated and re-dissolved in 80 mL DMF. CsCO3 (12.6g,
39 mmol) was added. After 3 h, additional CsCO3 (12.6g, 39
mmol) was added. The reaction ran 1.5 days. The reaction
was quenched with water and diluted with AcOEt. After
separation of the organic layer, the aqueous layer was
washed twice with AcOEt. The combined organic layers were
dried (MgSO4) , concentrated, and flash chromatographed to
give 0.35g (26% yield) of a mixture of cis and trans
isomers which were readily separated.
Anti isomer - 1H NMR(400 MHz, CDC13) δ 1.24 (t, J = 7.0 Hz,
3H), 1.40 (d, J= 7.0 Hz, 3H), 1.93 - 2.34 (m, 4H), 4.05 (d,
1H) , 4.09 - 4.23 (m, 2H) , 4.79 - 4.85 (m, 1H) , 6.40 (bs,
1H) , 7.27 - 7.44 (m, 5H) , 7.64 (s, 1H) . MS Calcd. : 299;
Found 300 (M+H). Syn isomer - 1H NMR(400 MHz, CDC13) δ
1.24 (t, J= 7.0 Hz, 3H), 1.68 (d, J = 7.0 Hz, 3H), 1.70 -
1.80 (m, 1H) , 2.00 - 2.23 (m, 3H) , 4.17 - 4.30 (m, 4H) ,
6.43 (brs, 1H) , 7.22 - 7.40 (m, 5H) , 7.63 (s, 1H) . MS
Calcd.: 299; Found 300 (M+H).
Step D
8-Methyl-5-phenyl-5,6,7,8-tetrahydro-4H-
pyrazolo[1,5,a] [1,3]diazepine-3-carboxylic acid (1-methyl-

1-phenyl-ethyl)-amide (4) : Compound 3 (0.074g, 0.25 mmol)
was diluted with EtOH (0.8 mL). KOH (6M in water, 0.23 mL)
was added and the reaction stirred at 60 °C for 3.5 h. The
solution was cooled and diluted with AcOEt and water.
After vigorous shaking, the aqueous layer was removed and
acidified to pH = 3. The aqueous layer was then extracted
with AcOEt(3 times). The organic layers were combined,
dried (MgSO4) , and concentrated to give 0.070g of desired
carboxylic acid. MS Calcd.: 271; Found 272 (M+H).
This acid residue (0.070g, 0.26 mmol) was dissolved in
NMP (2 mL). HATU (0.12g, 0.31 mmol) and cumylamine (0.042g,
0.31 mmol) were added followed by DIEA (0.090 mL, 0.52
mmol) . The reaction stirred at 90 °C for 2 h. The
solution was cooled to room temperature and diluted with
water. The solution was extracted from AcOEt (3 times),
dried (MgSO4) , and concentrated. Flash chromatography (30%
AcOEt/hexanes) gave the desired product. 0.065g obtained
(65% yield). 1H NMR (400 MHz, CDC13) 8 1.65 (d, J = 6.6 Hz,
3H), 1.71 (s, 3H), 1.75 (s, 3H), 2.00 - 2.21 (m, 4H), 4.21
- 4.29 (m, 2H), 5.80 (brs, 1H), 7.02 (brs, 1H) , 7.18 - 7.47
(m, 10H), 7.49 (s, 1H); MS Calcd.: 388; Found 389 (M+H).
Example 1142
(1R,4S)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl-5-(2-
fluorophenyl)-2,7,7-trimethyl-4,5,6,7-

1) To a solution of 1 (0.4g, 1.32 mmol) and DMF (1 drop) in
toluene (4 mL) was added SOCl2 (0.31, 2.64 mmol) at room
temperature. After stirring at 60°C 1 h, the solvent was
concentrated in vacuo. The residue was diluted with toluene,
and borneol (0.3g, 1.98 mmol) and Et3N (0.3g, 2.90 mmol)
was added there to. After stirring at 60 ° C 1 h, the
reaction mixture was washed with 1N HCl and brine, dried
over MgSO4, and concentrated in vacuo. Flash chromatography
to give the desired product as oil. To a stirred solution
of the oil obtained (90 mg, 0.2 mmol) in AcOEt (2 mL) was
added 4M HCl-AcOEt (0.5 mL, 2.0 mmol) at room temperature.
The precipitate was collected by filtration to give 2 as
HC1 salt. MS Calcd.: 440; Found 441 (M+H).
Compounds of Examples 1139-1141 shown in the Table 16,
were prepared in a manner similar to that described in
Example 1142.
Table 16

Compounds of Examples 868 - 923 and 1143-1146 shown in
the table 6, were prepared from compound of Examples 35 in
a manner similar to that described in followed reference
1~6.
1) Poulan R F., Tartar A L., Deprez B p., Tetrahedron Lett.
2001, 42, 1495.
2) Rigo B., Cauliesz P., Fasseur D., Couturier D.,Synthetic
Communications 1986, 16, 1665.
3) Carlsen H J., Jorgensen K B., J. Heterocyclic Chem.,

1994, 3.1, 805.
4) Kiryanov A A., Sampson P., Seed J., J. Org. Chem., 2001,
66, 7925.
5) Kelly T R., Lang F R., Tetrahedron Lett., 1995, 36, 5319.
6) Walia J S., Walia A S., Lankin D C., Petterson R C,
Singh J., J. Heterocyclic Chem., 1985, 22, 1117.

Strategy for cloning of the cDNAs encoding the human
CaR
Strategy for cloning of the cDNAs encoding the human
CaR is shown below. To amplify the cDNA encoding the N-
terminal moiety of the human CaR, the synthetic DNA primers,
Cal-U : 5'-AGAGTCGACGCCACCATGGCATTTTATAGCTGCTGCTGG-3' and
Cal-L : 5'-AAATGAGCTCTCGGTTGGTGGCCTTGAC-3' , were constructed.
In this case, SalI site was added at the 5' end of
amplified cDNA. To amplify the cDNA encoding the C-terminal
moiety of the human CaR, the synthetic DNA primers, Ca2-U :
5'-AAACGAGCTCTCCTACCTCCTCCTCTTC-3' and Ca2-L : 5'-
TCTGCGGCCGCTCCCTAGCCCAGTCTTCTCCTTCC-3', were constructed.
In this case, NotI site was added at the 3' end of
amplified cDNA. PCR was carried out by Hot Start method.
The reaction solution of the upper phase was added of 1 pg
of the human kidney-derived cDNA (TOYOBO), 0.3 mM dNTPs and
2.5 unit LA Taq DNA polymerase (Takara shuzo co.) and
filled up to 30 µl with water and buffer attached to the
enzyme. To the reaction solution of the lower phase was
added 12.5 uM each of the synthetic primers and 0.5 mM
dNTPs and filled up to 20 µl with water and buffer attached
to the enzyme. The reaction solution of the upper phase was
added on the lower phase covered with an AmpliWax PCR
Gem100 (Takara Shuzo Co.). The samples were subject to PCR
amplification using a Thermal Cycler (Perkin-Elmer Co.).

The amplified cDNAs were confirmed by agarose gel
electrophoresis.
Experiment 2
Preparation of CaR-expression CHO cells
The PCR products obtained in Experiment 1 were
separated by agarose gel electrophoresis. The PCR products
were excised and purified from the gel and subcloned into
pT7Blue-T vector (Takara Shuzo Co.). The cDNA fragment
encoding the N-terminal moiety of the human CaR was
released from the subcloned pT7Blue-T vector treated with
SalI and SacI. The cDNA fragment encoding the C-terminal
moiety of the human CaR was released from the subcloned
pT7Blue-T vector treated with SacI and NotI. Using DNA
Ligation kit (Takara Shuzo Co.), these fragments were
inserted between the site of SalI- and NotI- in the
digested pMSRαneo vector. Thus, the pMSRαneo-CaR for animal
cell expression was constructed.
Ten ug of the pMSRαneo-CaR was added to the solution
containing 8xl06 CH0-K1 cells, and transfection was carried
out using Gene Pulser (0.4cm cuvette, 0.25kV, 960mF) (Bio-
Rad Laboratories). The cells were cultured in HamF12
containing 10% fetal calf serum for one day. After passage,
the cells were cultured in HamF12 containing 10% fetal and
500ug/ml Genetisine. The cells were seeded on 96-well plate

in 1x103 cells/well and transformants, CaR-expressing CHO
cells, were selected in the selection medium.
Experiment 3
Selection of the CaR-expressing CHO cell line by-
calcium mobilization assay
A method for calcium mobilization assay is shown below.
The CaR-expressing CHO cells were seeded on a 96-well white
plate in 2xl04 cells/well, followed by cultivation for 48
hours. After washing the cells with Phosphate-Buffered
Saline, 100 µl of buffer solution (120 mM NaCl, 22 mM
NaHCO3, 6 mM KCl, 0.2 mM CaCl2, 1 mM MgCl2, 5 mM glucose, 5
mM HEPES (pH 7.4)) containing 5 uM FuraPE3AM (Texas
Fluorescence Laboratories) was added to the wells and kept
at 37 °C for 1 hour. The cells were washed twice with
Phosphate-Buffered Saline. After adding 180 ul of the
reaction buffer solution (130 mM NaCl, 5.4 mM KCl, 0.2 mM
CaCl2, 0.9 mM MgCl2, 10 mM glucose, 20 mM HEPES (pH 7.4))
to the wells, 20 ul of 60 mM CaCl2 was added and
intracellular calcium concentration were measured with a
fluorometric imaging plate reader (FDSS 2000, Hamamatsu
photonics). One clone increasing intracellular calcium
concentration was selected and used for the following
experiment.

Experiment 4
GTPγS binding assay
Preparation of membrane fraction is described bellow.
The human CaR-expressing CHO cells were inoculated to a
F500 flask in 1.8xl05 cells/flask followed by cultivation
for 2 days. The cells were scraped with 10ml of Phosphate-
Buffered Saline containing 0.02% EDTA. After centrifugation
(2000 rpm, 10 min) of the cells, the cell pellet was
resuspended into 12 ml of homogenate buffer solution (10 mM
NaHCO3, 1 mM EDTA, lx Protease inhibitor cocktail (pH 7.4))
and homogenized by Polytron™ (20000 rpm, 1 min) . The cell
debris was removed by centrifugation (2000 rpm, 10 min),
and then the CaR-expressing cell membrane fraction was
collected by ultracentrifugation (Beckman 70 Ti type rotor,
30000 rpm, 1 hour).
The GTPyS binding activity was measured as follows.
Twenty ug of the CaR-expressing cell membrane was incubated
with test compounds for 10min. The assays were carried out
at room temperature for an hour in a reaction solution
mixture containing 20 mM HEPES (pH.7.4), 100 mM NaCl, 1 mM
MgCl2, 167 µg/ml DTT, 5 µM guanosine 5'-diphosphate, 0.4 nM
[35S]-guanosine 5'-(γ-thio) triphosphate ( [35S]-GTPγS) and 6
mM CaCl2. The mixture was filtered through a GF/C filter.
After washing fourth with 300 µl of Phosphate-Buffered
Saline, the amount of [35S]-GTPYS bound to the filter was

measured using a Top-count scintillation counter.
Effects of test compounds on [35S]-GTPYS binding were
expressed in percentage terms. This was calculated from the
equation [100x(t'-b)]/(t-b) where t', t and b are values of
[35S]-GTPYS binding (dpm) , t' in the presence of 6mM
calcium and the test compound, t in the presence of 6mM
calcium only and b in the absence of both 6mM calcium and
the test compound.
The antagonist dose-dependently decreased [35S]-GTPYS
binding in membrane preparation. The agonist dose-
dependently increased [35S]-GTPΓS binding in membrane
preparation.
The results are shown in Table 7.

INDUSTRIAL APPLICABILITY
Compound (I), (II), (III) or (IIIa) of the present
invention has an excellent Ca receptor modulating activity

and enhances the secretion of PTH, and therefore, useful as
drugs for treating bone diseases, kidney-acting drugs,
central nervous system and endocrine-acting drugs,
digestive system-acting drugs, and the like.

WE CLAIM:
1. A compound of the formula (IIIa):

wherein R1a is
(1) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic
group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,
or (2) a group of the formula: -CO-Z2c (wherein Z2c is
(i) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic group
having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,
(ii) -NR20c(CR21cR22cR23c) (wherein
(a) R20c is H or an optionally substituted hydrocarbon group selected from C1-8
saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic hydrocarbon group,
C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic hydrocarbon
group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7 saturated or
unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group, C9-10

partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated
and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl
group; and R21c is 1) an optionally substituted 5- to 7-membered aromatic or non-
aromatic heterocyclic group having 1-4 hetero atoms selected from nitrogen atom,
oxygen atom and sulfur atom, which may be fused with an optionally substituted
benzene ring, or 2) an optionally substituted C6-10 aryl group which may be fused with
an optionally substituted 5- to 7-membered aromatic heterocyclic ring having 1-4
hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom; and R22c and
R are the same or different and are an optionally substituted hydrocarbon group
selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic
hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated
alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon
group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic
hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl
group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10
aryl group and C7-14 aralkyl group or an optionally substituted 5- to 7-membered
aromatic or non-aromatic heterocyclic group having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom, or R22c and R23cmay be combined to form
a C3-7 carbon ring, or (b) R20c is H or an optionally substituted hydrocarbon group

selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic
hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated
alicyclic hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon
group, C3-7 saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic
hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl
group, C9-10 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10
aryl group and C7-14 aralkyl group; and R21c, R22c and R23c are the same or different and
are an optionally substituted C1-8 aliphatic hydrocarbon group, provided that the sum
total of the number of carbon atoms is 7 or more),
(iii) -NR20cR25c (wherein R20cis as defined above and R25cis an optionally substituted C6-10
aryl-C2-4 alkyl, C6-10 aryloxy-C2-4 alkyl, C6-10 atylamino-C2-4 alkyl, C7-14 aralkylamino-
C2-4 alkyl, 5- to 7-membered heterocyclic ring (having 1-4 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom)-C2-4 alkyl or 5- to 7-membered
heterocyclic group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom),
(iv) a substituted 5- to 7-membered cyclic amino group, or
(v) -OR24c (wherein R24c is
(a) an optionally substituted C7-14 aralkyl group,
(b) an optionally substituted C3-7 alicyclic hydrocarbon group,

(c) an optionally substituted C7-24 aliphatic hydrocarbon group, or
(d) an optionally substituted 5- to 7-membered aromatic or non-aromatic heterocyclic
group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom;
wherein said substituents for R1a, Z2c, R20c, R21c, R22c, R23c, R24c and R25c are 1 to 3
substituents selected from the group consisting of

1) C1-6 alkyl,
2) C2-6 alkenyl,
3) C2-6 alkynyl,
4) C3-7 cycloalkyl,
5) C6-10 aryl which may be substituted with 1 to 3 substituents selected from the group
consisting of C1-6 alkyl, amino, N-(C1-6 alkyl)amino, N,N-di-(C1-6 alkyl)amino, amidino,
carbamoyl, N-(C1-6 alkyl)carbamoyl, N,N-di-(C1-6 alkyl)carbamoyl, sulfamoyl, N-(C1-6
alkyl)sulfamoyl, N,N-di-(C1-6 alkyl)sulfamoyl, carboxyl, C2-7 alkoxycarbonyl, hydroxyl,
C1-6 alkoxy, mercapto, C1-6 alkylthio, sulfo, cyano, azido, halogen, nitro, nitroso,
phosphono, C1-6 alkoxyphosphoryl, di-(C1-6 alkoxy)phosphoryl and C1-6 alkyl substituted
with phosphono, C1-6 alkoxyphosphoryl and di-(C1-6 alkoxy)phosphoryl (hereinafter the
group of 5) is referred to as group "C"),
6) aromatic heterocyclic group selected from (a) aromatic 5- or 6-membered heterocyclic
group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur

atom, (b) fused bicyclic heterocyclic group formed by condensation of an aromatic 5- or
6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom,
oxygen atom and sulfur atom with benzene ring or an aromatic 5- or 6-membered
heterocyclic group having 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom
and sulfur atom and (c) fused tricyclic heterocyclic group formed by condensation of [1]
an aromatic 5- or 6-membered heterocyclic group having 1-3 hetero atoms selected from
nitrogen atom, oxygen atom and sulfur atom, [2] benzene ring, and [3] an aromatic 5- or
6-membered heterocyclic group having 1-3 hetero atoms selected from nitrogen atom,
oxygen atom and sulfur atom or benzene ring,
7) heterocyclic-oxy group formed by combining each of the above aromatic heterocyclic
groups (a), (b) and (c) with oxy group,
8) non-aromatic 4- or 7-membered heterocyclic group having 1 to 3 hetero atoms
selected from nitrogen atom, oxygen atom and sulfur atom,
9) C7-14 aralkyl which may be substituted with 1 to 3 substituents selected from the group
"C",

10) amino group,
11) N-mono-substituted amino selected from N-(C1-6 alkyl)amino, N-(C2-6
alkenyl)amino, N-(C3-7 cycloalkyl)amino group and N-(C6-10 aryl)amino which may be
substituted with 1 to 3 substituents selected from the group "C",

12) amino substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-7
cycloalkenyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected
from the group "C",
13) amidino,
14) acyl selected from C2-8 alkanoyl, C3-8 alkenoyl, C3-7 cycloalkyl-carbonyl, C3-7
cycloalkenyl-carbonyl, C6-10 aryl-carbonyl which may be substituted with 1 to 3
substituents selected from the group "C", and heterocyclic-carbonyl formed by binding
of an aromatic or non-aromatic 5- or 6-membered heterocyclic group having 1-3 hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom with carbonyl,
15) carbamoyl,
16) mono-substituted carbamoyl group selected from N-(C1-6 alkyl)carbamoyl, N-(C2-6
alkenyl)carbamoyl, N-(C3-7 cycloalkyl)carbamoyl and N-(C6-10 aryl)carbamoyl which
may be substituted with 1 to 3 substituents selected from the group "C",
17) carbamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-
7 cycloalkyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected
from the group "C",
18) sulfamoyl,
19) N-mono-substituted sulfamoyl selected from N-(C1-6 alkyl)sulfamoyl, N-(C2-6
alkenyl)sulfamoyl, N-(C3-7 cycloalkyl)sulfamoyl and N-(C6-10 aryl)sulfamoyl which may
be substituted with 1 to 3 substituents selected from the group "C",

20) sulfamoyl substituted with two substituents selected from C1-6 alkyl, C2-6 alkenyl, C3-
7 cycloalkyl and C6-10 aryl which may be substituted with 1 to 3 substituents selected
from the group "C",
21) carboxyl,
22) C1-6 alkoxy-carbonyl,
23) hydroxyl,
24) C1-6 alkoxy,
25) C2-10 alkenyloxy,
26) C3-7 cycloalkyloxy,
27) C6-10 aryloxy which may be substituted with 1 to 3 substituents selected from the
group "C",
28) C7-14 aralkyloxy which may be substituted with 1 to 3 substituents selected from the
group "C",
29) mercapto,
30)C1-6alkylthio,

31) C7-14 aralkylthio which may be substituted with 1 to 3 substituents selected from the
group "C",
32) C6-10 arylthio which may be substituted with 1 to 3 substituents selected from the
group "C",

33) C1-6 alkylsulfinyl,
34) C7-14 aralkylsulfinyl which may be substituted with 1 to 3 substituents selected from
the group "C",
35) C6-10 arylsulfinyl which may be substituted with 1 to 3 substituents selected from the
group "C",
36) C1-6 alkylsulfonyl,

38) C7-14 aralkylsulfonyl which may be substituted with 1 to 3 substituents selected from
the group "C",
39) C6-10 arylsulfonyl which may be substituted with 1 to 3 substituents selected from the
group "C",
40) sulfo,
41) cyano,
42) azido,
43) halogen,
44) nitro,
45) nitroso,
46) phosphono,
47) C1-6 alkoxy-phosphoryl
48) di-C1-6 alkoxy-phosphoryl,

49) C1-6 alkyl substituted with phosphono, C1-6 alkoxyphosphoryl or di-(C1-6
alkoxy)phosphoryl
50) C1-6 alkyl substituted with 1 to 4 halogen atoms
51) C1-6 alkoxy substituted with 1 to 4 halogen atoms and
52) C1-6 alkylenedioxy
(hereinafter the group of above 1) to 52) is referred to as group "B");
R3 is H, a C1-6 alkyl group or a C7-14 aralkyl group;
R6 is H, a C1-6 alkyl group, a C1-6 alkylthio group or a C1-6 alkoxy group which may be
substituted with hydroxyl group;
Ar is (1) a C6-10 aryl group, (2) a 5- to 7-membered aromatic or non-aromatic heterocyclic
group having 1-4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,
or (3) a C3-7 saturated or unsaturated alicyclic hydrocarbon group, each of which may be
substituted with 1 to 3 substituents selected from the group "B";
one of R9 and R10 is a hydrogen atom or C1-6 alkyl group which may be substituted with 1
to 3 substituents selected from the group "B" and the other is (1) a hydrocarbon group
selected from C1-8 saturated aliphatic hydrocarbon group, C2-8 unsaturated aliphatic
hydrocarbon group, C3-7 saturated alicyclic hydrocarbon group, C3-7 unsaturated alicyclic
hydrocarbon group, C9-10 partly saturated and fused bicyclic hydrocarbon group, C3-7
saturated or unsaturated alicyclic-C1-8 saturated or unsaturated aliphatic hydrocarbon group,

C9-10 partly saturated and fused bicyclic hydrocarbon-C1-4 alkyl group, C9-10 partly saturated
and fused bicyclic hydrocarbon-C2-4 alkenyl group, C6-10 aryl group and C7-14 aralkyl group,
each of which may be substituted with 1 to 3 substituents selected from the group "B" or
(2) a 5- to 7-membered aromatic or non-aromatic heterocyclic group having 1-4 hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom, which may be
substituted with 1 to 3 substituents selected from the group "B", or
R9 and R10 may be combined to form a C5.7 carbon ring,
provided that at least one of R9and R10 is C1-6 alkyl group which may be substituted with 1
to 3 substituents selected from the group "B" and the other is other than a phenyl group
which may be substituted with 1 to 3 substituents selected from the group "B"; or a salt
thereof.
2. The compound as claimed in claim 1 comprises
N-(l-ethyl-1-(4-methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-7,7-dimethyl-4,5,6,7-
tefrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof,
N-(l-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof,
N-(l-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-

tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-ethyl-1-(4-ethylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-
tetrahydropyra2olo[1,5-a]pyrimidine-3-carboxamide or a salt thereof,
5-(2-chlorophenyl)-N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-(4-(dimethylamino)phenyl)-1-ethylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-
4,5,6,74etrahydropyrazolo[l,5-a]pyrimidine-3-carboxamide or a salt thereof,
N-(1,1-diethylbutyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrimidine-3-carboxamide or a salt thereof,
N-(1-ethyl-1-phenylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof,
3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-1,3,4-oxadiazol-2-yl)-2,7,7-trimethyl-5-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof,
3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-l,3,4-thiadiazol-2-yl)-2,7,7-trimethyl-5-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrirnidine or a salt thereof,
3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidmyl)carbonyl)-7,7-dirnethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof,

3-((2,2-diethyl-4-methoxy-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof, or
3-((2,2-diethyl-4-fluoro-1-pyirolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof.
3. N-(1-ethyl-1-(4-methylphenyl)propyl)-7,7-dimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
4. N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-7,7-dimethyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
5. N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
6. N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
7. N-(1-ethyl-1-(4-methylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
8. N-(1-ethyl-1-(4-ethylphenyl)propyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
9. 5-(2-chlorophenyl)-N-(1-ethyl-1-(4-methylphenyl)propyl)-2,7,7-trimethyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrirnidine-3-carboxamide or a salt thereof.
10. N-(1-(4-(dimethylamino)phenyl)-1-ethylpropyl)-5-(2-fluorophenyl)-2,7,7-
trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.

11. N-(1, 1-diethylbutyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a salt thereof.
12. N-(1-ethyl-1-phenylpropyl)-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxarnide or a salt thereof.
13. 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-l,3,4-oxadiazol-2-yl)-2,7,7-
trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof.
14. 3-(5-(1-ethyl-1-(4-methylphenyl)propyl)-l,3,4-thiadiazol-2-yl)-2,7,7-
trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof.
15. 3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-
phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof.
16. 3-((2,2-diethyl-4-methoxy-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof.
17. 3-((2,2-diethyl-4-fluoro-1-pyrrolidinyl)carbonyl)-7,7-dimethyl-5-phenyl-
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine or a salt thereof.
18. The compound according to claim 2, which is an optically active compound.
19. A pharmaceutical composition which comprises the compound according to
claim 1.
20. A composition for modulating calcium receptor which comprises a
compound of claim 1.

21. The composition according to claim 20, which is a calcium receptor
antagonist.
22. The composition according to claim 20, which is an agent for preventing or
treating diseases caused by abnormality of calcium concentration in a living body or a
calcium receptor.
23. The composition according to claim 20, which is an agent for preventing or
treating bone diseases.
24. The composition according to claim 20, which is an agent for preventing or
treating osteoporosis or fracture.

There is provided a calcium receptor modulator
comprising a compound of the formula (I):

wherein ring A is an optionally substituted 5- to 7-
membered ring; ring B is an optionally substituted 5- to 7-
membered heterocyclic ring; X1 is CR1, CR1R2, N or NR13; X2
is N or NR3; Y is C, CR4 or N, Z is CR5, CR5R6, N or NR7; Ar
is an optionally substituted cyclic group; R is H, an
optionally substituted hydrocarbon group, etc.; and
is a single bond or a double bond; R1, R2, R3, R4, R5, R6, R7
and R13 are independently H, an optionally substituted
hydrocarbon group; or a salt thereof or a prodrug thereof.
Compounds of the formula (II) and (III):

wherein ring A is an optionally substituted 5- to 7-
membered ring; Q is C, CR5 or N; R8, R9, R10, R11 and R12 are
independently, H, an optionally substituted hydrocarbon
group, etc., or a salt thereof are also provided.
Also specify X1, R3, R1, Y and X3 in formula (II) and (III)
as before.

Documents:

00280-kolnp-2005 abstract.pdf

00280-kolnp-2005 claims.pdf

00280-kolnp-2005 correspondence-1.1.pdf

00280-kolnp-2005 correspondence-1.2.pdf

00280-kolnp-2005 correspondence-1.3.pdf

00280-kolnp-2005 correspondence-1.4.pdf

00280-kolnp-2005 correspondence.pdf

00280-kolnp-2005 description(complete).pdf

00280-kolnp-2005 form-1-1.1.pdf

00280-kolnp-2005 form-1.pdf

00280-kolnp-2005 form-18.pdf

00280-kolnp-2005 form-2.pdf

00280-kolnp-2005 form-3.pdf

00280-kolnp-2005 form-5.pdf

00280-kolnp-2005 g.p.a.pdf

00280-kolnp-2005 international publication.pdf

00280-kolnp-2005 international search authority report-1.1.pdf

00280-kolnp-2005 international search authority report.pdf

00280-kolnp-2005 pct others.pdf

00280-kolnp-2005 pct request.pdf

00280-kolnp-2005 priority document.pdf

00280-kolnp-2005 sequence listing form.pdf

280-KOLNP-2005-FORM-27.pdf

280-kolnp-2005-granted-abstract.pdf

280-kolnp-2005-granted-claims.pdf

280-kolnp-2005-granted-correspondence.pdf

280-kolnp-2005-granted-description (complete).pdf

280-kolnp-2005-granted-examination report.pdf

280-kolnp-2005-granted-form 1.pdf

280-kolnp-2005-granted-form 13.pdf

280-kolnp-2005-granted-form 18.pdf

280-kolnp-2005-granted-form 2.pdf

280-kolnp-2005-granted-form 3.pdf

280-kolnp-2005-granted-form 5.pdf

280-kolnp-2005-granted-gpa.pdf

280-kolnp-2005-granted-reply to examination report.pdf

280-kolnp-2005-granted-sequence listing.pdf

280-kolnp-2005-granted-specification.tif

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Patent Number

227614

Indian Patent Application Number

280/KOLNP/2005

PG Journal Number

03/2009

Publication Date

16-Jan-2009

Grant Date

14-Jan-2009

Date of Filing

25-Feb-2005

Name of Patentee

TAKEDA PHARMACEUTICAL COMPANY LIMITED

Applicant Address

1-1, DOSHOMACHI 4-CHOME, CHUO-KU, OSAKA-SHI, OSAKA

Inventors:

#	Inventor's Name	Inventor's Address
1	HIROYUKI KIMURA	2-20-808, OHAMANAKAMACHI 1-CHO, SAKAI-SHI, OSAKA
2	MASATO YOSHIDA	228-2, HIRONO, SANDA-SHI, HYOGO
3	ALBERT CHARLES GYOROKOS	11795 DECATUR DRIVE, WESTMINSTER, CO 80234
4	SCOTT ALAN PRATT	13099 ALCOTT PLACE, BROOMFIELD, CO 80020
5	CHRISTOPHER PETER CORRETTE	13839 W. 66TH ARVADA, CO 80004
6	TSUNEO YASUMA	20-5, TAKADA-CHO, IBARAKI-SHI, OSAKA
7	AKIRA MORI	358, KASHIRA-CHO, NIJO-SAGARU, SHINAINOMACHI, SAKYO-KU, KYOTO-SHI, KYOTO
8	MASAHIRO KAWASE	14-5, WAKABA 2-CHOME, INAGAWA-CHO, KAWABE-GUN, HYOGO

PCT International Classification Number

A61K

PCT International Application Number

PCT/US2003/026317

PCT International Filing date

2003-08-21

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/466,129	2003-04-28	U.S.A.
2	60/406,012	2002-08-26	U.S.A.