JP2010248183A - Heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a useful compound for a preventive or treatment agent of such as a bone disease. <P>SOLUTION: The compound shown by formula (Ia) (wherein each symbol represents as specifically defined), or a salt or a prodrug of the same is provided. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a heterocyclic compound having a calcium-sensitive receptor (CaSR; hereinafter, also simply referred to as “calcium (Ca) receptor”) antagonistic action, a pharmaceutical composition containing them, and the like.

(Background of the Invention)
Calcium ions (hereinafter sometimes simply referred to as “calcium”) are essential for maintaining and / or regulating functions of various cells such as endocrine cells and exocrine cells in addition to nerves and muscles. Playing a role. For this reason, the blood calcium concentration is maintained in a strictly narrow range. Parathyroid hormone (PTH) plays a central role in maintaining this blood calcium level. Therefore, the secretion of PTH from the parathyroid gland is sensitive to changes in blood calcium levels and must be regulated accordingly. In fact, when the blood calcium concentration changes, the blood PTH concentration changes rapidly accordingly. The possibility of a mechanism by which extracellular calcium concentration is sensed by parathyroid cells and information is transmitted to the cells was pointed out by Brown et al. In 1993, they succeeded in cloning and characterizing a calcium-sensitive receptor (CaSR; hereinafter simply referred to as calcium receptor) from bovine parathyroid gland (Non-patent Document 1: Nature, 366, 575-580 (1993)). ).

  The calcium receptor has an N-terminal length of 600 amino acids, a large terminal extracellular region having a 7-transmembrane region similar to other G protein-coupled receptors, and an intracellular region consisting of 200 or less amino acids at the C-terminus. Made from.

When the extracellular calcium concentration increases, phospholipase (PL) -C is activated, inositol triphosphate (IP ₃ ) increases, the intracellular calcium concentration increases, and PTH secretion is suppressed. . It is believed that if the extracellular calcium concentration is maintained at a high value, the intracellular calcium concentration then increases continuously, so that calcium influx from the outside of the cell is also promoted. Increases in extracellular calcium activate PL-A ₂ and D, which may be via protein kinase (PK) -C, which is activated simultaneously through the calcium receptor. The calcium receptor also suppresses adenylyl cyclase through Gi protein or arachidonic acid production through activation of PL-A ₂ and decreases intracellular cyclic AMP (Non-Patent Document 2: Bone, 20, 303-309 (1997)).

  Calcium receptor mRNA is expressed in many tissues, and is expressed in the parathyroid gland, thyroid C cells, renal tubules, thick Henle's ascending limb (TAL) inner medullary collecting tubule (IMCD), subfornical organ ( SFO) and hippocampus (Non-Patent Document 2: Bone, 20, 303-309 (1997)). Expression is observed in many tissues such as the hypothalamus, cerebellum and olfactory nucleus, areas other than TAL of renal tubules, lung, stomach, pancreas, intestine and skin. Since calcium receptors are present in various tissues, their physiological functions are not well understood. However, calcium receptor antagonists are expected to provide new therapies for various pathologies, including:

1. Bone disease therapeutic agent Since anabolic activity has been clarified by intermittent administration of PTH, calcium receptor antagonists that are thought to be able to regulate the secretion of PTH are expected as therapeutic agents for osteoporosis. In addition, calcium receptor antagonists that are selective for thyroid C cells are thought to be effective in the treatment of osteoporosis by stimulation of calcitonin secretion. It is debatable whether the same calcium receptors as parathyroid calcium receptors are present in osteoblasts, osteoclasts and bone cells. However, several calcium sensing mechanisms certainly exist, and therefore agents that act directly on them are expected as therapeutic agents for bone diseases.

2. Renal agonists The treatment of water and minerals in the kidney is not only based on the results of the function as a target organ of hormones such as PTH and vitamin D, but also the calcium receptors in the kidney are the calcium and magnesium ion concentrations in the extracellular fluid. (Non-patent Document 3: Kidney Int, 50, 2129-2139 (1996)). In addition, calcium receptor antagonists may regulate kidney blood volume, glomerular filtration rate, renin secretion, and vitamin D activation in addition to regulating water and mineral influx and efflux.

3. Central nervous system and endocrine agonists Calcium receptors are present in almost all areas of the central nervous system, and are particularly prominently expressed in the hippocampus, cerebellum and subfornical organs (Brain Res, 744. 47-56 ( 1997)). Although the details of the function are not yet clear, in the hippocampus, the calcium receptor expression period after birth coincides with the acquisition period of LTP (Long Tightening Phenomenon) (Non-Patent Document 4: Develop Brain Res, 100 , 13-21 (1997)), so the relationship between memory and learning can be considered. Therefore, calcium receptor antagonists that have high blood-brain barrier permeability and are selective for the central nervous system are considered useful in the treatment of Alzheimer's disease. Also, since thirst occurs in hypercalcemic patients, calcium receptor antagonists are thought to be able to regulate them. The presence of calcium receptors in pituitary cells of mice that secrete ACTH has been reported (Non-Patent Document 5: Mol Endocrinol, 10, 555-565 (1996)). Calcium receptor antagonists are also considered to be applicable to Sheehann syndrome, pituitary dysfunction, hyperpituitary function and the like.

4). Gastrointestinal agonists Calcium receptors are found in the Auerbach plexus of the gastrointestinal tract and are thought to regulate intestinal motility. Constipation is found in hypercalcemic patients, and in clinical trials, irritation of gastrointestinal motility is seen in hypocalcemic patients. The presence of calcium receptors in gastrin-secreting cells (G cells) of the stomach has been reported (Non-patent Document 6: J. Clin Invest, 99, 2328-2333 (1997)). Defecation and acid secretion in the stomach can be controlled by drugs acting on calcium receptors in the gastrointestinal tract. Furthermore, calcium receptors are found in human colon cancer cell lines and have been found to regulate c-myc expression and proliferation (Non-patent Document 7: Biochem Biophys Res Commum, 232, 80-83 (1997). )), Which is in good agreement with the fact that calcium uptake and the development of colorectal and rectal cancers have a negative relationship, and therefore calcium receptor antagonists are also used as prophylactic and therapeutic agents for such cancers. Be expected.

Examples of the compound having a structure similar to the compound described in the present specification include the following.
Patent document 1 (International Publication No. 2003/079973 pamphlet) discloses the following compounds as cancer therapeutic agents:

Etc. are described.

  Patent Document 2 (International Publication No. 2005/058838 pamphlet) discloses the following compounds as agricultural chemicals.

Etc. are described.

  Patent Document 3 (International Publication No. 2007/019933) describes the following compounds as anticancer agents.

Etc. are described.

The following compounds are registered in the chemical abstract.
1) 1- [4,5-Dihydro-5-hydroxy-3- (4-methylphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone (CAS Registration number: RN 433255-03-9);
2) 1- [3- (4-Chlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone (CAS registration) Number: RN 442565-44-8);
3) 1- [4,5-Dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone (CAS Registration number: RN 433242-43-4);
4) 1- [4,5-Dihydro-5-hydroxy-3-phenyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone (CAS Registry Number: RN 376616) -49-8);
5) 1- [3- (4-Bromophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone (CAS) Registration number: RN 376385-73-8);
6) 1- [4,5-Dihydro-5-hydroxy-3- (4-pyridyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone (CAS registration) No .: RN 354787-69-2); and 7) (4-amino-1H-imidazol-5-yl) [4,5-dihydro-5-hydroxy-3- (2-naphthyl) -5- (trifluoro) Methyl) -1H-pyrazol-1-yl] methanone (CAS Registry Number: RN 676624-86-5).

International Publication No. 2003/079973 Pamphlet International Publication No. 2005/058838 Pamphlet International Publication No. 2007/019933 Pamphlet

Nature, 366, 575-580 (1993) Bone, 20, 303-309 (1997) Kidney Int, 50, 2129-2139 (1996) Develop Brain Res, 100, 13-21 (1997) Mol Endocrinol, 10, 555-565 (1996) J. Clin Invest, 99, 2328-2333 (1997) Biochem Biophys Res Commum, 232, 80-83 (1997)

  The object of the present invention is to have an excellent calcium receptor antagonistic action, preventive or therapeutic agent for bone diseases (eg, osteoporosis, fractures), renal action drug, central nervous system and endocrine action drug, digestive system action drug It is to provide a compound useful as such.

As a result of intensive studies to solve the above problems, the present inventors have found that the compound represented by the following formula and the following compound (Ia) have an excellent calcium receptor antagonistic action, and complete the present invention. It came to.
That is, the present invention is as follows.
[1] Formula (Ia):

[Where:
Ring A ^a represents an optionally substituted ring;
R ^1a is
(1) Formula: -X ^1a -R ^6a
(In the formula, X ^1a represents a C _1-6 alkylene group, a C _2-6 alkenylene group, or a C _3-6 cycloalkylene group, and R ^6a represents an optionally substituted C _3-6 cycloalkyl group. , An optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, an _optionally substituted C _{A 7-14} aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group).
(2) an optionally substituted C _3-6 cycloalkyl group,
(3) an optionally substituted C _3-6 cycloalkyloxy group,
(4) an optionally substituted C _6-14 aryl group,
(5) an optionally substituted C _6-14 aryloxy group,
(6) an optionally substituted C _7-14 aralkyloxy group,
(7) an optionally substituted heterocyclic group,
(8) an optionally substituted heterocyclic oxy group, or
(9) represents an optionally substituted amino group;
R ^2a represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group;
R ^3a represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ^2a and R ^3a together may form a C _1-3 alkylidene group or an optionally substituted ring; and R ^4a and R ^5a are the same or different and each represents a hydrogen atom , A halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ^4a and R ^5a may together form an oxo group, a C _1-3 alkylidene group, or an optionally substituted ring.
Or a salt thereof (in this specification, sometimes abbreviated as “compound (Ia)”), or a calcium-sensitive receptor antagonist containing a prodrug thereof;
[2] Formula (I):

[Where:
Ring A represents an optionally substituted C _6-14 aromatic hydrocarbon, or an optionally substituted heterocycle;
R ¹ is
(1): ^-X 1 -R ⁶
(In the formula, X ¹ represents a C _3-6 alkylene group, a C _2-6 alkenylene group, or a C _3-6 cycloalkylene group, and R ⁶ represents an optionally substituted C _3-6 cycloalkyl group. , An optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, an _optionally substituted C _A group represented by a _7-14 aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group;
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. A -6} cycloalkyl group, an _optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, a substituted An optionally substituted C _7-14 aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group). Or
(3) An optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
R ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group or an optionally substituted hydroxy group,
R ³ represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ² and R ³ together may form a C _1-3 alkylidene group or an optionally substituted ring; and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom , A halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ⁴ and R ⁵ together may form an oxo group, a C _1-3 alkylidene group, or an optionally substituted ring]
A compound represented by (however,
1- [4,5-dihydro-5-hydroxy-3- (4-methylphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [3- (4-chlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3-phenyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [3- (4-bromophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3- (4-pyridyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone; and (4- Amino-1H-imidazol-5-yl) [except 4,5-dihydro-5-hydroxy-3- (2-naphthyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] methanone) or A salt thereof (in this specification, sometimes abbreviated as “compound (I)”. In addition, the compound (Ia) includes the compound (I));
[3] R ¹ is
(1): ^-X 1 -R ⁶
(Each symbol in the formula is as defined above)
A group represented by:
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. -6} cycloalkyl group, C _6-14 aryl group which may be substituted, or heterocyclic group which may be substituted)
A group represented by:
(3) an optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
A compound (I);
[4] Compound (I), wherein R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted hydroxy group;
[5] Compound (I), wherein R ³ is an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group. ;
[6] R ² and R ³ together form an optionally substituted C _3-8 cycloalkane, an optionally substituted aliphatic heterocyclic ring, or a C _1-3 alkylidene group. Compound (I);
[7] Compound (I), wherein R ⁴ is a hydrogen atom or a C _1-6 alkyl group;
[8] Compound (I), wherein R ⁵ is a hydrogen atom or a C _1-6 alkyl group;
[9] Compound (I), wherein R ⁴ and R ⁵ are combined to form an _optionally substituted C _3-8 cycloalkane;
[10] Prodrug of compound (I);
[11] A medicament comprising compound (I) or a prodrug thereof;
[12] A preventive or therapeutic agent for bone diseases, comprising Compound (Ia) or a prodrug thereof;
[13] The agent according to [12] above, wherein the bone disease is osteoporosis or a fracture;
[14] A method for antagonizing a calcium-sensitive receptor in a mammal, which comprises administering an effective amount of compound (Ia) or a prodrug thereof to the mammal;
[15] A method for preventing or treating a bone disease in a mammal, which comprises administering an effective amount of compound (Ia) or a prodrug thereof to the mammal;
[16] The method according to [15] above, wherein the bone disease is osteoporosis or a fracture;
[17] Use of compound (Ia) or a prodrug thereof for producing a calcium sensitive receptor antagonist;
[18] Use of compound (Ia) or a prodrug thereof for producing a prophylactic or therapeutic agent for bone disease;
[19] The use according to [18] above, wherein the bone disease is osteoporosis or a fracture.

  Since compound (Ia) has an excellent calcium receptor antagonistic action, it is useful as a preventive or therapeutic agent for bone diseases (eg, osteoporosis, fractures).

(Detailed description of the invention)
In the present specification, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
In the present specification, “C _1-6 alkyl (group)” means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl. Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
In the present specification, “C _2-6 alkenyl (group)” means, for example, vinyl, 1-propenyl, 2-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, 5-hexenyl and the like are shown.
In the present specification, “C _2-6 alkynyl (group)” means, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1,1-dimethylprop-2-in-1-yl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like are shown.

In the present specification, “C _1-6 alkoxy (group)” means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy Etc.
In the present specification, “C _1-6 alkoxy-carbonyl (group)” means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like.
In the present specification, “C _1-6 alkyl-carbonyl (group)” indicates, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl and the like.

In the present specification, “mono C _1-6 alkylamino (group)” means, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino and the like.
In the present specification, “diC _1-6 alkylamino (group)” refers to, for example, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, ditert-butylamino and the like.

In the present specification, “C _3-8 cycloalkyl (group)” refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
In the present specification, “C _3-6 cycloalkyl (group)” includes, for example, those having 3 to 6 carbon atoms among the above C _3-8 cycloalkyl (group).
In the present specification, “C _3-6 cycloalkyloxy (group)” means, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

In the present specification, “C _3-8 cycloalkenyl (group)” means, for example, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl), cyclo Pentenyl (eg, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl), cyclohexenyl (eg, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl) and the like are shown.

In the present specification, “C _6-14 aryl (group)” represents, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
In the present specification, “C _6-14 aryloxy (group)” means, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
In the present specification, “C _7-14 aralkyl (group)” means, for example, benzyl, phenethyl and the like.
In the present specification, “C _7-14 aralkyloxy (group)” indicates, for example, benzyloxy, phenethyloxy and the like.

In the present specification, the “heterocyclic group” refers to an aromatic heterocyclic group and an aliphatic heterocyclic group.
In the present specification, the “aromatic heterocyclic group” refers to a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group.
The “monocyclic aromatic heterocyclic group” is selected from, for example, an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom (which may be oxidized) in addition to a carbon atom as a ring constituent atom. 5- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms such as furyl (eg, 2-furyl, 3-furyl), thienyl (Eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazoli) , 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl ( Examples, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (Eg, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (Eg, 1,2,4-triazol-1-yl, 1,2,4 Triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1) -Yl, tetrazol-5-yl), triazinyl (eg, 1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like.

Examples of the “fused aromatic heterocyclic group” include, for example, an 8- to 12-membered condensed aromatic heterocyclic group, specifically, a ring corresponding to the 5- to 7-membered monocyclic aromatic heterocyclic group. A group derived from a ring condensed with a C _6-14 aromatic hydrocarbon; a group derived from a ring in which rings corresponding to the 5- to 7-membered monocyclic aromatic heterocyclic group are condensed, for example, Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl) , 6-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzazol) Xazolyl), benzisoxazolyl (eg, 7-benzisoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazole) -5-yl), benzotriazolyl (eg, 1H-1,2,3-benzotriazol-5-yl), indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl) , Indol-5-yl), indazolyl (eg, 1H-indazol-3-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b ] Pyrazin-6-yl), imidazopyridyl (eg, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [ , 5-c] pyridin-2-yl, 2H-imidazo [1,2-a] pyridin-3-yl), thienopyridyl (eg, thieno [2,3-b] pyridin-3-yl), imidazopyrazini (Eg, 1H-imidazo [4,5-b] pyrazin-2-yl), pyrazolopyridyl (eg, 1H-pyrazolo [4,3-c] pyridin-3-yl), pyrazolothienyl (eg, 2H- Pyrazolo [3,4-b] thiophen-2-yl), pyrazolotriazinyl (eg, pyrazolo [5,1-c] [1,2,4] triazin-3-yl) and the like.

In the present specification, “aliphatic heterocyclic group” refers to a monocyclic aliphatic heterocyclic group and a condensed aliphatic heterocyclic group.
The “monocyclic aliphatic heterocyclic group” is, for example, selected from oxygen atoms, sulfur atoms (which may be oxidized) and nitrogen atoms (which may be oxidized) in addition to carbon atoms as ring constituent atoms. 3 to 8 membered (preferably 5 or 6 membered) monocyclic aliphatic heterocyclic group containing 1 to 4 heteroatoms such as azetidinyl (eg 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (Eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidyl (eg, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), oxazolidinyl (eg, oxazolidin-2-yl), thiazoly Nil (eg, thiazolidin-2-yl), dihydrothiopyranyl (eg, dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imidazolidinyl (eg, imidazolidin-2-yl, imidazolidine-3) -Yl), oxazolinyl (eg, oxazolin-2-yl), thiazolinyl (eg, thiazolin-2-yl), imidazolinyl (eg, imidazolin-2-yl, imidazolin-3-yl), dioxolyl (eg, 1,3 -Dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4-oxadiazol-3-yl) , Pyranyl (eg, 2-pyranyl, 4-pyranyl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydride) Pyranyl, 4-tetrahydropyranyl), thiopyranyl (eg, 4-thiopyranyl), tetrahydrothiopyranyl (eg, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxide Tetrahydrothiopyranyl (eg, 1-oxidetetrahydrothiopyran-4-yl), 1,1-dioxidetetrahydrothiopyranyl (eg, 1,1-dioxidetetrahydrothiopyran-4-yl), tetrahydrofuryl ( Examples, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (eg, pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), tetrahydropyrimidinyl (eg, tetrahydropyrimidine) -1-yl), dihydrotri Azolyl (eg, 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5-tetrahydro-1H-1,2,3- Triazol-1-yl), azepanyl (eg, 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), dihydropyridyl (eg, dihydropyridin-1-yl, dihydropyridin-2-yl, dihydropyridin-3-yl) , Dihydropyridin-4-yl), tetrahydropyridyl (eg, 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl, 1,2,3,4) -Tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl) and the like.

The “condensed aliphatic heterocyclic group” includes, for example, an 8- to 12-membered condensed aliphatic heterocyclic group, specifically, a ring corresponding to the above-described 3- to 8-membered monocyclic aliphatic heterocyclic group, A group derived from a ring condensed with a C _6-14 aromatic hydrocarbon; a group derived from a ring in which rings corresponding to the 3- to 8-membered monocyclic aliphatic heterocyclic group are condensed; A group derived from a ring obtained by condensing a ring group corresponding to a monocyclic aliphatic heterocyclic ring having 8 to 8 members and a ring corresponding to the monocyclic aromatic heterocyclic group having 5 to 7 members; Groups obtained by partial saturation, such as dihydroindolyl (eg 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg 1,3-dihydro-2H-isoindole-2- Yl), dihydrobenzofuranyl (eg, 2,3-dihydro-1-be) Nzofuran-5-yl), tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), dihydrobenzodioxinyl (eg, 2,3-dihydro-1,4) -Benzodioxin-2-yl), dihydrobenzodioxepinyl (eg, 3,4-dihydro-2H-1,5-benzodioxepin-2-yl), chromenyl (eg, 4H-chromen-2-yl) Yl, 2H-chromen-3-yl), dihydrochromenyl (eg, 3,4-dihydro-2H-chromen-2-yl), dihydroquinolinyl (eg, 1,2-dihydroquinolin-4-yl) Tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-4-yl), tetrahydro Quinolinyl (e.g., 1,2,3,4-tetrahydroisoquinoline-4-yl), dihydrophthalazinyl (e.g., 1,4-dihydro-phthalazine-4-yl), and the like.

In the present specification, the “5-membered heterocyclic group” refers to a 5-membered aromatic heterocyclic group and a 5-membered aliphatic heterocyclic group.
In the present specification, examples of the “5-membered aromatic heterocyclic group” include oxygen atoms, sulfur atoms (which may be oxidized) and nitrogen atoms (which may be oxidized) as ring-constituting atoms in addition to carbon atoms. A 5-membered monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from, for example, furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl) , 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl) 5-isothiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg, 1,2,4- Oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-) Triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazole- 4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl) and the like.

  In the present specification, examples of the “5-membered aliphatic heterocyclic group” include oxygen atoms, sulfur atoms (which may be oxidized) and nitrogen atoms (which may be oxidized) as ring-constituting atoms in addition to carbon atoms. A 5-membered monocyclic aliphatic heterocyclic group containing 1 to 4 heteroatoms selected from, for example, pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), oxazolidinyl (eg, oxazolidin-2- Yl), thiazolidinyl (eg, thiazolidin-2-yl), imidazolidinyl (eg, imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (eg, oxazolin-2-yl), thiazolinyl (eg, thiazoline- 2-yl), imidazolinyl (eg, imidazolin-2-yl, imidazolin-3-yl), dioxolyl (eg, 1,3-dioxo) Lu-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4-oxadiazol-3-yl), Tetrahydrofuryl (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (eg, pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), dihydrotriazolyl (Eg, 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5-tetrahydro-1H-1,2,3-triazole -1-yl) and the like.

  In the present specification, examples of the “heterocyclic oxy group” include a group in which —O— is bonded to the above aromatic heterocyclic group or aliphatic heterocyclic group.

In the present specification, the “C _1-6 alkylene group” means, for example, —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH _{2) 5 -, - (CH} 2) 6 -, - CH (CH 3) -, - C (CH 3) 2 -, - CH (C 2 H 5) -, - CH (C 3 H 7) -, _{-CH (CH (CH 3) 2} ) -, - (CH (CH 3)) 2 -, - CH 2 -CH (CH 3) -, - CH (CH 3) -CH 2 -, - CH 2 -CH _{2 -C (CH 3) 2 -} , - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2 It shows the like - -CH ₂ -CH ₂ -CH _2.
In the present specification, examples of the “C _3-6 alkylene group” include those having 3 to 6 carbon atoms among the above C _1-6 alkylene groups.

In the present specification, the “C _2-6 alkenylene group” means, for example, —CH═CH—, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —, —C (CH ₃ ) ₂ —. _{CH = CH -, - CH =} CH-C (CH 3) 2 -, - CH 2 -CH = CH-CH 2 -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH 2 - _{CH 2 -, - CH = CH} -CH = CH -, - CH = CH-CH 2 -CH 2 -CH 2 -, - CH 2 illustrates a _-CH 2 _-CH 2 _-CH = CH- and the like.

In the present specification, the “C _3-6 cycloalkylene group” means, for example, cyclopropylene, cyclobutylene (eg, 1,2-cyclobutylene, 1,3-cyclobutylene), cyclopentylene (eg, 1, 2-cyclopentylene, 1,3-cyclopentylene), cyclohexylene (eg, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene) and the like.

In the present specification, the “C _1-3 alkylidene group” means, for example, ═CH ₂ , ═CH—CH ₃ , ═CH—CH ₂ —CH ₃ , ═C (CH ₃ ) ₂ or the like.

In the present specification, the “ring” refers to, for example, a C _3-12 alicyclic hydrocarbon, a C _6-14 aromatic hydrocarbon, a heterocyclic ring, and the like.

As “C _3-12 alicyclic hydrocarbon”, for example,
(1) C _3-8 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane),
(2) C _3-8 cycloalkene (cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene),
(3) C _4-10 cycloalkadiene (eg, cyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclodecadiene)
In addition, each of these rings may be condensed with a benzene ring. Examples of such condensed rings include indane, indene, dihydronaphthalene, tetrahydronaphthalene, fluorene and the like.

Examples of the “C _6-14 aromatic hydrocarbon” include benzene and naphthalene.

“Heterocycle” refers to an aromatic heterocycle and an aliphatic heterocycle.
“Aromatic heterocycle” refers to a monocyclic aromatic heterocycle and a fused aromatic heterocycle.
As the “monocyclic aromatic heterocycle”, for example, a hetero atom selected from an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom (which may be oxidized) in addition to a carbon atom as a ring constituent atom 5- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocycle containing 1 to 4 atoms such as furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole , Thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine and the like.
Examples of the “fused aromatic heterocycle” include, for example, an 8- to 12-membered fused aromatic heterocycle, specifically, the 5- to 7-membered monocyclic aromatic heterocycle and a C _6-14 aromatic hydrocarbon. A ring fused with the above 5- to 7-membered monocyclic aromatic heterocycle, such as quinoline, isoquinoline, quinazoline, quinoxaline, benzofuran, benzothiazole, benzoxazole, benzisoxazole, benzothiazole, Benzimidazole, benzotriazole, indole, indazole, pyrrolopyrazine (eg, 1H-pyrrolo [2,3-b] pyrazine), imidazopyridine (eg, 1H-imidazo [4,5-b] pyridine), thienopyridine (eg, Thieno [2,3-b] pyridine), imidazopyrazine (eg, 1H-imidazo [4,5-b] pyrazine) , Pyrazolopyridine (eg, 1H-pyrazolo [4,3-c] pyridine), pyrazolothiophene (eg, 2H-pyrazolo [3,4-b] thiophene), pyrazolotriazine (eg, pyrazolo [5,1 -C] [1,2,4] triazine) and the like.

The “aliphatic heterocyclic ring” refers to a monocyclic aliphatic heterocyclic ring and a condensed aliphatic heterocyclic ring.
Examples of the “monocyclic aliphatic heterocyclic ring” include hetero atoms selected from oxygen atoms, sulfur atoms (which may be oxidized) and nitrogen atoms (which may be oxidized) in addition to carbon atoms as ring constituent atoms. 3 to 8 membered (preferably 5 or 6 membered) monocyclic aliphatic heterocycles containing 1 to 4 atoms, such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxazolidine, thiazolidine, Dihydrothiopyran, imidazolidine, oxazoline, thiazoline, imidazoline, dioxole, dioxolane, dihydrooxadiazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, 1-oxidetetrahydrothiopyran, 1,1-dioxidetetrahydrothiopyran, Tetrahydrofuran, pi Zorijin, pyrazoline, tetrahydropyrimidine, dihydro-triazole, tetrahydro triazole, azepane, dihydropyridine, tetrahydropyridine, and the like.
Examples of the “fused aliphatic heterocycle” include, for example, an 8- to 12-membered condensed aliphatic heterocycle, specifically, the above-described 3- to 8-membered monocyclic aliphatic heterocycle and C _6-14 aromatic hydrocarbon. A ring fused with the above 3 to 8 membered monocyclic aliphatic heterocycle; the above 3 to 8 membered monocyclic aliphatic heterocyclic ring and the above 5 to 7 membered monocyclic aromatic Rings condensed with heterocycles; Rings obtained by partial saturation of these rings, such as dihydroindole, dihydroisoindole, dihydrobenzofuran, tetrahydrobenzofuran, dihydrobenzodioxin, dihydrobenzodioxepin, chromene, dihydrochromene, dihydro Examples include quinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, dihydrophthalazine.

  Hereinafter, each substituent of the formula (Ia) will be described.

R ^2a in formula (Ia) represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group. .
R ^3a in formula (Ia) represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group.
Alternatively, R ^2a and R ^3a may be taken together to form a C _1-3 alkylidene group or an optionally substituted ring.
Here, the rings formed by R ^2a and R ^3a form a pyrazoline ring and a spiro ring of the formula (Ia), respectively.

Represented by R ^2a or ^{R 3a} of the "optionally substituted _{C 1-6} alkyl group", _{"C 1-6} alkyl group", to 1 at substitutable positions 5 (preferably 1 to 3 ) May have a substituent. Examples of such a substituent include a substituent selected from the following substituent group A. When a plurality of substituents are present, each substituent may be the same or different.

Substituent group A:
(1) a halogen atom;
(2) a cyano group;
(3) a nitro group;
(4) hydroxy group;
(5) (a) a halogen atom,
(b) a cyano group, and
(c) a C _3-8 cycloalkyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms;
(6) (a) a halogen atom,
(b) a cyano group, and
(c) a C _6-14 aryl group _optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms;
(7) (a) a halogen atom,
(b) a cyano group,
(c) a C _3-8 cycloalkyl group _optionally having 1 to 3 halogen atoms,
(d) a C _3-8 cycloalkenyl group _optionally having 1 to 3 halogen atoms,
(e) a C _6-14 aryl group _optionally having 1 to 3 halogen atoms, and
(f) 5 or 6-membered monocyclic aromatic 1 to 3 substituents optionally substituted by a C _1-6 alkoxy group selected from a heterocyclic group;
(8) a C _2-6 alkenyloxy group (eg, vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy) optionally having 1 to 3 halogen atoms;
(9) a C _2-6 alkynyloxy group which may have 1 to 3 halogen atoms (eg, ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy);
(10) a C _3-8 cycloalkyloxy group _optionally having 1 to 3 halogen atoms (eg, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy);
(11) a C _3-8 cycloalkenyloxy group (eg, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy) optionally having 1 to 3 halogen atoms;
(12) a C _6-14 aryloxy group _optionally having 1 to 3 halogen atoms;
(13) a C _7-14 aralkyloxy group optionally having 1 to 3 halogen atoms;
(14) (a) a C _1-6 alkyl group,
(b) a C _3-6 cycloalkyl group,
_{(c) C 6-14} aryl group,
(d) a C _1-6 alkoxy group,
(e) a 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) an 8- to 12-membered fused aromatic heterocyclic group,
(g) a 3- to 8-membered monocyclic aliphatic heterocyclic group, and
(h) a carbamoyl group which may be mono- or di-substituted with a substituent selected from 8- to 12-membered fused aliphatic heterocyclic groups;
_{(15) (a) C 1-6} alkyl group,
(b) a C _3-6 cycloalkyl group,
(c) a C _6-14 aryl group,
(d) a C _1-6 alkoxy group,
(e) a 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) an 8- to 12-membered fused aromatic heterocyclic group,
(g) a 3- to 8-membered monocyclic aliphatic heterocyclic group, and
(h) a sulfamoyl group optionally mono- or di-substituted with a substituent selected from 8- to 12-membered fused aliphatic heterocyclic groups;
(16) Formyl;
(17) a C _1-6 alkyl-carbonyl group;
(18) C _2-6 alkenyl-carbonyl group (eg, acryloyl, butenoyl, pentenoyl, hexenoyl, heptenoyl);
(19) C _2-6 alkynyl-carbonyl group (eg, propioyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl);
(20) C _3-8 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl);
(21) C _3-8 cycloalkenyl - carbonyl group (eg, cycloalkyl propenylcarbonyl, cyclo butenyl carbonyl, cyclopentenyl carbonyl, cyclohexenyl carbonyl);
(22) C _6-14 aryl-carbonyl group (eg, benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl);
(23) _{C 3-8} cycloalkyl _{-C 1-6} alkyl - carbonyl group (e.g., cyclopropyl acetyl, 3-cyclopropyl-propionyl, cyclobutyl acetyl, cyclopentyl acetyl, cyclohexyl acetyl, cyclohexyl propionyl);
(24) C _3-8 cycloalkenyl-C _1-6 alkyl-carbonyl group (eg, cyclopentenylacetyl, cyclohexenylacetyl, 3-cyclohexenylpropionyl, 3-cyclohexenylpropionyl);
(25) C _7-14 aralkyl-carbonyl group (eg, phenylacetyl, 3-phenylpropionyl);
(26) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group (eg, furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl) , Imidazolylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl);
(27) 8- to 12-membered condensed aromatic heterocyclic carbonyl group (eg, benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl, isoindolylcarbonyl, indazolyl) Carbonyl, benzimidazolylcarbonyl, benzoxazolylcarbonyl);
(28) 3- to 8-membered monocyclic aliphatic heterocyclic carbonyl group (eg, oxiranylcarbonyl, azetidinylcarbonyl, oxetanylcarbonyl, thietanylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl, thiolanylcarbonyl, Piperidylcarbonyl);
(29) 8- to 12-membered fused aliphatic heterocyclic carbonyl group (eg, dihydrobenzofuranyl);
(30) (a) a C _1-6 alkyl group _optionally having 1 to 3 halogen atoms,
(b) a C _1-6 alkyl-carbonyl group _optionally having 1 to 3 halogen atoms,
(c) a C _3-8 cycloalkyl-carbonyl group,
(d) a C _6-14 aryl-carbonyl group _optionally having 1 to 3 halogen atoms,
(e) a 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group,
(f) an 8- to 12-membered fused aromatic heterocyclic carbonyl group,
(g) a 3- to 8-membered monocyclic aliphatic heterocyclic carbonyl group, and
(h) an 8- to 12-membered condensed aliphatic heterocyclic carbonyl group,
An amino group which may be mono- or di-substituted with a substituent selected from:
(31) a sulfanyl group;
(32) C _1-6 alkylsulfanyl group (eg, methylsulfanyl, ethylsulfanyl);
(33) C _2-6 alkenylsulfanyl group (eg, vinylsulfanyl, propenylsulfanyl);
(34) C _2-6 alkynylsulfanyl group (eg, ethynylsulfanyl, propynylsulfanyl);
(35) C _3-8 cycloalkylsulfanyl group (eg, cyclopropylsulfanyl, cyclobutylsulfanyl);
(36) C _3-8 cycloalkenylsulfanyl group (eg, cyclopropenylsulfanyl, cyclobutenylsulfanyl);
(37) C _6-14 arylsulfanyl group (eg, phenylsulfanyl);
(38) C _3-8 cycloalkyl-C _1-6 alkylsulfanyl group (eg, cyclopropylmethylsulfanyl);
(39) C _3-8 cycloalkenyl-C _1-6 alkylsulfanyl group (eg, cyclopentenylmethylsulfanyl);
(40) C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl);
(41) C _2-6 alkenylsulfinyl group (eg, vinylsulfinyl, propenylsulfinyl);
(42) C _2-6 alkynylsulfinyl group (eg, ethynyl sulfinyl, propynyl sulfinyl);
(43) C _3-8 cycloalkylsulfinyl group (eg, cyclopropylsulfinyl, cyclobutylsulfinyl);
(44) C _3-8 cycloalkenylsulfinyl group (eg, cyclopropenylsulfinyl, cyclobutenylsulfinyl);
(45) C _6-14 arylsulfinyl group (eg, phenylsulfinyl);
(46) C _3-8 cycloalkyl-C _1-6 alkylsulfinyl group (eg, cyclopropylmethylsulfinyl);
(47) C _3-8 cycloalkenyl-C _1-6 alkylsulfinyl group (eg, cyclopentenylmethylsulfinyl);
(48) C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl);
(49) C _2-6 alkenylsulfonyl group (eg, vinylsulfonyl, propenylsulfonyl);
(50) C _2-6 alkynylsulfonyl group (eg, ethynylsulfonyl, propynylsulfonyl);
(51) C _3-8 cycloalkylsulfonyl group (eg, cyclopropylsulfonyl, cyclobutylsulfonyl);
(52) C _3-8 cycloalkenylsulfonyl group (eg, cyclopropenylsulfonyl, cyclobutenylsulfonyl);
(53) C _6-14 arylsulfonyl group (eg, phenylsulfonyl);
(54) C _3-8 cycloalkyl-C _1-6 alkylsulfonyl group (eg, cyclopropylmethylsulfonyl);
(55) C _3-8 cycloalkenyl-C _1-6 alkylsulfonyl group (eg, cyclopentenylmethylsulfonyl);
(56) C _6-14 aryl-C _1-6 alkylsulfonyl group (eg, benzylsulfonyl);
(57) 5- or 6-membered monocyclic aromatic heterocyclic sulfonyl group (eg, furylsulfonyl, thienylsulfonyl, pyridylsulfonyl);
(58) 8- to 12-membered fused aromatic heterocyclic sulfonyl group (eg, benzofuranylsulfonyl, isobenzofuranylsulfonyl);
(59) a 3- to 8-membered monocyclic aliphatic heterocyclic sulfonyl group (eg, oxiranylsulfonyl, azetidinylsulfonyl);
(60) 8- to 12-membered fused aliphatic heterocyclic sulfonyl group (eg, dihydrobenzofuranylsulfonyl);
(61) (a) a halogen atom,
(b) a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms, and
(c) a 5- or 6-membered monocyclic aromatic group optionally substituted with 1 to 3 substituents selected from C _1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms A heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl, pyrazolyl, morpholinyl);
(62) (a) a halogen atom,
(b) a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms, and
(c) 8- to 12-membered condensed aromatic heterocycle optionally substituted with 1 to 3 substituents selected from C _1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms A group (eg, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl);
(63) (a) a halogen atom,
(b) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl) optionally substituted with 1 to 3 substituents selected from oxo groups , Thiolanyl, piperidyl, piperazinyl, dihydrooxadiazolyl);
(64) (a) a halogen atom,
(b) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) an 8- to 12-membered fused aliphatic heterocyclic group (eg, dihydrobenzofuranyl) optionally substituted with 1 to 3 substituents selected from oxo groups;
(65) 5- or 6-membered monocyclic aromatic heterocyclic oxy groups (eg furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy, pyridyl) Oxy, pyrazolyloxy);
(66) 8- to 12-membered condensed aromatic heterocyclic oxy groups (eg, benzofuranyloxy, isobenzofuranyloxy, benzothienyloxy, isobenzothienyloxy, indolyloxy, isoindolyloxy, indazolyl) Oxy, benzimidazolyloxy, benzoxazolyloxy);
(67) a 3- to 8-membered monocyclic aliphatic heterocyclic oxy group (eg, oxiranyloxy, azetidinyloxy, oxetanyloxy, thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, thiolanyloxy, piperidyloxy);
(68) 8- to 12-membered fused aliphatic heterocyclic oxy group (eg, dihydrobenzofuranyloxy);
(69) carboxyl group;
(70) C _1-6 alkoxy-carbonyl group;
(71) C _2-6 alkenyloxy-carbonyl group (eg, vinyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl);
(72) C _2-6 alkynyloxy-carbonyl group (eg, ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl);
(73) C _3-8 cycloalkyloxy-carbonyl group (eg, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl);
(74) C _3-8 cycloalkenyloxy-carbonyl group (eg, cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl);
(75) C _6-14 aryloxy-carbonyl group (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl);
(76) C _3-8 cycloalkyl-C _1-6 alkoxy-carbonyl group (eg, cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, cyclohexyl) Ethyloxycarbonyl);
(77) C _3-8 cycloalkenyl-C _1-6 alkoxy-carbonyl group (eg, cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl, cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl);
(78) C _7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl);
(79) Mono-C _1-6 alkylthiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl);
(80) DiC _1-6 alkylthiocarbamoyl group (eg, dimethylthiocarbamoyl, diethylthiocarbamoyl, dipropylthiocarbamoyl);
(81) a C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy);
(82) An imino group optionally substituted with a hydroxy group.

The “C _3-8 cycloalkyl group” of the “optionally substituted C _3-8 cycloalkyl group” represented by R ^2a or R ^3a is 1 to 5 (preferably 1 to 5) at substitutable positions. 3) substituents may be present. Examples of such a substituent include a substituent selected from the following substituent group B. When a plurality of substituents are present, each substituent may be the same or different.

Substituent group B:
(1) the above substituent group A;
(2) (a) a halogen atom,
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom,
(ii) a cyano group, and
(iii) a C _3-8 cycloalkyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms;
(e) (i) a halogen atom,
(ii) a cyano group, and
(iii) a C _6-14 aryl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms,
(f) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(g) an amino group optionally mono- or di-substituted with C _1-6 alkyl,
(h) a 5- or 6-membered monocyclic aromatic heterocyclic group,
(i) an 8- to 12-membered fused aromatic heterocyclic group,
(j) a 3- to 8-membered monocyclic aliphatic heterocyclic group,
(k) an 8- to 12-membered fused aliphatic heterocyclic group,
(l) a carboxyl group, and
(m) 1 to 3 may be substituted by a halogen atom C _1-6 alkoxy - 1 selected from carbonyl groups to three optionally substituted with a substituent C _1-6 alkyl group;
(3) (a) a halogen atom,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group,
(d) an amino group optionally mono- or di-substituted with C _1-6 alkyl,
(e) a carboxyl group, and
(f) a C _2-6 alkenyl group optionally substituted with 1 to 3 substituents selected from a C _1-6 alkoxy-carbonyl group;
(4) (a) a halogen atom,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group, and
(d) a C _7-14 aralkyl group optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms; and
(5) Oxo group.

As the "optionally substituted hydroxy group" is represented by R ^2a or ^{R 3a,} for example, may be each _{substituted, C 1-6} alkyl _{groups, C 2-6} alkenyl _{groups, C 1-6} Alkyl-carbonyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C _6-14 aryl group, C _7-14 aralkyl group, aromatic heterocyclic group (eg, 5- to 7-membered monocyclic ring) Formula aromatic heterocyclic group, 8- to 12-membered condensed aromatic heterocyclic group), aliphatic heterocyclic group (eg, 3- to 8-membered monocyclic aliphatic heterocyclic group, 8- to 12-membered condensed aliphatic group) And a hydroxy group which may be substituted with a substituent selected from a heterocyclic group) and the like.
C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkyl-carbonyl group, C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group, C shown as substituents for the hydroxy group _6-14 aryl group, C _{7 - 14} aralkyl group, aromatic heterocyclic group and aliphatic heterocyclic group has 1 to 5 at substitutable positions, respectively (preferably 1 to 3) have a substituent It may be.
In the case of a C _1-6 alkyl group, a C _2-6 alkenyl group, and a C _1-6 alkyl-carbonyl group, examples of the substituent include the above substituent group A. When a plurality of substituents are present, each substituent may be the same or different.
C _3-8 cycloalkyl group, C _3-8 cycloalkenyl group and an aliphatic Hajime Tamaki (e.g., 3 to 8-membered monocyclic aliphatic heterocyclic group, 8 to 12 membered fused aliphatic heterocyclic group) In this case, examples of such a substituent include the substituent group B. When a plurality of substituents are present, each substituent may be the same or different.
A C _6-14 aryl group, a C _7-14 aralkyl group and an aromatic heterocyclic group (eg, a 5- to 7-membered monocyclic aromatic heterocyclic group, an 8- to 12-membered condensed aromatic heterocyclic group). In this case, examples of the substituent include the above-mentioned substituent group B excluding the oxo group. When a plurality of substituents are present, each substituent may be the same or different.

When R ^2a and R ^3a in formula (Ia) are combined to form an “optionally substituted ring”, the “ring” includes C _3-8 cycloalkane, C _3-8 cyclo Non-aromatic rings such as alkenes, C _4-10 cycloalkadienes and aliphatic heterocycles (eg, 3- to 8-membered monocyclic aliphatic heterocycles, 8- to 12-membered fused aliphatic heterocycles) can be mentioned. The “ring” may have 1 to 5 (preferably 1 to 3) substituents at substitutable positions. Examples of these substituents include the substituent group B. When a plurality of substituents are present, each substituent may be the same or different.

R ^2a is preferably a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted hydroxy group.

R ^2a is more preferably
(1) hydrogen atom;
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from: or
(3) _{(a) C 1-6} alkyl group (e.g., methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from:
It is.

R ^2a is more preferably
(1) hydrogen atom;
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy), and
(d) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from: or
(3) _{(a) C 1-6} alkyl group (e.g., methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from:
It is.

R ^3a is preferably
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from: or
(3) a C _3-6 cycloalkyl group (eg, cyclopropyl);
It is.

In another suitable example, R ^3a is preferably an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group.

R ^3a is more preferably
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy), and
(d) C _1-6 alkyl-carbonyloxy group (eg, acetoxy)
A C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from:
(2) a C _3-6 cycloalkyl group (eg, cyclopropyl);
It is.

In another embodiment, preferably R ^2a and R ^3a together form an optionally substituted C _3-8 cycloalkane, or an optionally substituted aliphatic heterocycle.
More preferably, R ^2a and R ^3a are taken together
(1) C _3-8 cycloalkane (eg, cyclobutane, cyclopentane), or
(2) C _1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl) and C _1-6 alkyl-carbonyl group (eg, acetyl)
5-membered monocyclic aliphatic heterocycle optionally substituted by 1 to 3 substituents selected from (eg, pyrrolidine, azetidine)
Form.

In still another embodiment, preferably R ^2a and R ^3a are taken together to form an optionally substituted C _3-8 cycloalkane, an optionally substituted aliphatic heterocycle, or C _{1- 3} alkylidene groups are formed.

In another preferred example, more preferably, R ^2a and R ^3a are taken together,
(1) C _3-8 cycloalkane (eg, cyclobutane, cyclopentane),
(2) C _1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl) and C _1-6 alkyl-carbonyl group (eg, acetyl)
A 5-membered monocyclic aliphatic heterocyclic ring (eg, pyrrolidine, azetidine, tetrahydrofuran) optionally substituted with 1 to 3 substituents selected from:
(3) C _1-3 alkylidene group (eg, methylidene)
Form.

R ^4a and R ^5a in formula (Ia) are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group. , Or an optionally substituted hydroxy group.
Alternatively, R ^4a and R ^5a may be taken together to form an oxo group, a C _1-3 alkylidene group, or an optionally substituted ring.
Here, the rings formed by R ^4a and R ^5a form a pyrazoline ring and a spiro ring of the formula (Ia), respectively.

Expressed as the "optionally substituted _{C 1-6} alkyl group" in R ^4a or ^{R 5a,} and "optionally substituted _{C 1-6} alkyl group" represented by ^{R 2a} or ^{R 3a} The same thing is mentioned.

Represented by R ^4a or ^{R 5a} as the "which may _{C 3-6} also be cycloalkyl group ^{substituted", R 2a} or "optionally substituted _{C 3-6} cycloalkyl group represented by ^{R 3a} And the like.

^{Examples of the “} optionally substituted hydroxy group” represented by R ^4a or R ^5a include the same as the “optionally substituted hydroxy group” represented by R ^2a or R ^3a .

As the "optionally substituted ring" R ^4a and R ^5a are formed together, those similar to the "optionally substituted ring" R ^2a and R ^3a form together Can be mentioned.

R ^4a is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl), more preferably a hydrogen atom.

R ^5a is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl), more preferably a hydrogen atom.

Alternatively, in another embodiment, preferably R ^4a and R ^5a are taken together to form a C _3-8 cycloalkane (eg, cyclopentane).

R ^1a in formula (Ia) is:
(1) Formula: -X ^1a -R ^6a
(In the formula, X ^1a represents a C _1-6 alkylene group, a C _2-6 alkenylene group, or a C _3-6 cycloalkylene group, and R ^6a represents an optionally substituted C _3-6 cycloalkyl group. , An optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, an _optionally substituted C _{A 7-14} aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group).
(2) an optionally substituted C _3-6 cycloalkyl group,
(3) an optionally substituted C _3-6 cycloalkyloxy group,
(4) an optionally substituted C _6-14 aryl group,
(5) an optionally substituted C _6-14 aryloxy group,
(6) an optionally substituted C _7-14 aralkyloxy group,
(7) an optionally substituted heterocyclic group,
(8) an optionally substituted heterocyclic oxy group, or
(9) An amino group which may be substituted.

The case where R ^1a is a group represented by the formula: -X ^1a -R ^6a (the definitions of X ^1a and R ^6a are as described above) will be described.

"C _3-6 cycloalkyl group" of the "optionally substituted C _3-6 cycloalkyl group" represented by R ^6a, of the "optionally substituted C _3-6 cycloalkyl group", " “C _3-6 cycloalkyloxy group”, “optionally substituted C _6-14 aryl group” “C _6-14 aryl group”, “ _optionally substituted C _6-14 aryloxy group” "C _6-14 aryloxy group", "C _7-14 aralkyloxy group optionally substituted", "C _7-14 aralkyloxy group", "heterocyclic group optionally substituted""Heterocyclic oxy group (aromatic heterocyclic oxy group, aliphatic heterocyclic oxy group)" of "cyclic group (aromatic heterocyclic group, aliphatic heterocyclic group)" and "optionally substituted heterocyclic oxy group" Are not 1 in each substitutable position. 5 may have a substituent (preferably 1 to 3).

C _3-6 cycloalkyl group, C _3-6 cycloalkyloxy group, aliphatic heterocyclic group (eg, 3- to 8-membered monocyclic aliphatic heterocyclic group, 8- to 12-membered condensed aliphatic heterocyclic group ) And an aliphatic heterocyclic oxy group (eg, 3 to 8 membered monocyclic aliphatic heterocyclic oxy group, 8 to 12 membered condensed aliphatic heterocyclic oxy group), And the substituent group B. When a plurality of substituents are present, each substituent may be the same or different.

C _6-14 aryl group, C _6-14 aryloxy group, C _7-14 aralkyloxy group, aromatic heterocyclic group (eg, 5- to 7-membered monocyclic aromatic heterocyclic group, 8- to 12-membered aromatic group) Condensed aromatic heterocyclic groups) and aromatic heterocyclic oxy groups (eg, 5- to 7-membered monocyclic aromatic heterocyclic oxy groups, 8- to 12-membered condensed aromatic heterocyclic oxy groups) Examples of the substituent include the above substituent group B excluding an oxo group. When a plurality of substituents are present, each substituent may be the same or different.

The “amino group” of the “optionally substituted amino group” represented by R ^6a may be substituted with 1 or 2 substituents. Examples of such a substituent include the same substituents as those of the “optionally substituted hydroxy group” represented by R ^2a or R ^3a . When two substituents are present, each substituent may be the same or different.

R ^6a is preferably
(1) a C _3-6 cycloalkyl group (eg, cyclohexyl),
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(3) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryloxy group (eg, phenyloxy) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(4) C _7-14 aralkyloxy group (eg, benzyloxy),
(5) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a nitro group, and
(p) a heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (preferably a 5- to 7-membered monocyclic heterocyclic group (eg, thienyl, dihydropyridyl)) ,
(6) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) an aromatic heterocyclic oxy group (preferably a 5- to 7-membered monocyclic aromatic heterocyclic oxy group (eg, pyridyl) optionally substituted with 1 to 3 substituents selected from nitro groups Oxy)),
(7) (i) C _3-8 cycloalkyl group (eg, cyclopropyl), C _1-6 alkyl group (eg, methyl) and C _1-6 alkoxy group (eg, methoxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(ii) a carboxyl group, and
(iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aliphatic heterocyclic oxy group (preferably 8) which may be substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) optionally substituted with 1 to 3 substituents selected from To a 12-membered fused aliphatic heterocyclic oxy group (eg, dihydrobenzofuranyloxy)), or
(8) (a) a C _1-6 alkyl group (eg, methyl),
(b) (i) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, morpholinyl),
(ii) a sulfamoyl group optionally mono- or di-substituted with a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, thiazolyl),
(iii) halogen atoms (eg, chlorine atoms), and
(iv) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a cyano group,
(c) an 8- to 12-membered condensed aliphatic heterocyclic group (eg, dihydrobenzofuranyl),
(d) a C _7-14 aralkyl group (eg, benzyl), and
(e) C _6-14 aryl-carbonyl group (eg, benzoyl)
An amino group which may be mono- or di-substituted with a substituent selected from:

X ^1a is preferably
(1) C _1-6 alkylene group (eg, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —),
(2) a C _2-6 alkenylene group (eg, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —), or
(3) C _3-6 cycloalkylene group (eg, cyclopropylene)
It is.

As the "optionally substituted C _3-6 cycloalkyl group" represented by R ^1a, those similar to the "optionally substituted C _3-6 cycloalkyl group" represented by R ^6a Can be mentioned.
Represented by R ^1a The "which may C _3-6 cycloalkyloxy group optionally substituted", similar to the "optionally substituted C _3-6 cycloalkyl group" represented by R ^6a Things.
As the "optionally substituted C _6-14 aryl group" for R ^1a, it includes those similar to the "optionally substituted C _6-14 aryl group" represented by R ^6a .
As the "optionally substituted C _6-14 aryloxy group" represented by R ^1a, those similar to the "optionally substituted C _6-14 aryloxy group" represented by R ^6a Can be mentioned.
As the "optionally substituted C _7-14 aralkyloxy group" represented by R ^1a, those similar to the "optionally substituted C _7-14 aralkyloxy group" represented by R ^6a Can be mentioned.
^Examples of the “optionally substituted heterocyclic group” represented by R ^1a include the same as the “optionally substituted heterocyclic group” represented by R ^6a .
^Examples of the “optionally substituted heterocyclic oxy group” represented by R ^1a include the same as the “optionally substituted heterocyclic oxy group” represented by R ^6a .
^Examples of the “optionally substituted amino group” represented by R ^1a include the same as the “optionally substituted amino group” represented by R ^6a .

R ^1a is preferably
(1) Formula: -X ^1a -R ^6a
(Each symbol in the formula is as defined above)
A group represented by:
(2) an optionally substituted heterocyclic group;
It is.

R ^1a is more preferably
(1) Formula: -X ^1a -R ^6a
(Each symbol in the formula is as defined above)
A group represented by:
(2) an optionally substituted 5-membered heterocyclic group (preferably a 5-membered monocyclic aromatic heterocyclic group (eg, furyl, pyrazolyl, triazolyl, imidazolyl)); or
(3) An optionally substituted 5-membered monocyclic aromatic heterocyclic group condensed with a monocycle (preferably a bicyclic fused furyl group, a bicyclic fused imidazolyl group, a bicyclic Condensed triazolyl group);

R ^1a is more preferably
(1) Formula: -X ^1a -R ^6a
(Each symbol in the formula is as defined above)
A group represented by:
(2) Formula:

(In the formula, ring Ba represents ^a 5-membered heterocyclic ring which may be further substituted, X ^2a represents a bond or a C _1-6 alkylene group, and R ^7a represents an optionally substituted C _3-6 cycloalkyl group, an optionally substituted _{C 3-6} cycloalkyl group, an optionally substituted _{C 6-14} aryl group, optionally substituted _{C 6-14} aryloxy group, a substituted A C _7-14 aralkyloxy group which may be substituted, a heterocyclic group which may be substituted, a heterocyclic oxy group which may be substituted, or an amino group which may be substituted)
A group represented by:
(3) an optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
It is.

In the above formulas, represented by ring B ^a the "further substituted heterocycle may also be 5-membered optionally,""5-membered heterocyclic ring (5-membered aromatic heterocyclic 5-membered aliphatic heterocyclic)" May have 1 to 5 (preferably 1 to 3) substituents at substitutable positions in addition to —X ^2a —R ^7a .

  In the case of a 5-membered aliphatic heterocyclic ring, examples of the substituent include the substituent group B. When a plurality of substituents are present, each substituent may be the same or different.

  In the case of a 5-membered aromatic heterocyclic ring, examples of the substituent include the above-mentioned substituent group B excluding the oxo group. When a plurality of substituents are present, each substituent may be the same or different.

In the above formula, expressed as the "optionally substituted C _3-6 cycloalkyl group" in R ^7a, and "optionally substituted C _3-6 cycloalkyl group" represented by R ^6a The same thing is mentioned.
Represented by R ^7a The "which may C _3-6 cycloalkyloxy group optionally substituted", similar to the "optionally substituted C _3-6 cycloalkyl group" represented by R ^6a Things.
As the "optionally substituted C _6-14 aryl group" represented by R ^7a, include those similar to the "optionally substituted C _6-14 aryl group" represented by R ^6a .
As the "optionally substituted C _6-14 aryloxy group" represented by R ^7a, those similar to the "optionally substituted C _6-14 aryloxy group" represented by R ^6a Can be mentioned.
As the "optionally substituted C _7-14 aralkyloxy group" represented by R ^7a, those similar to the "optionally substituted C _7-14 aralkyloxy group" represented by R ^6a Can be mentioned.
^Examples of the “optionally substituted heterocyclic group” represented by R ^7a include the same as the “optionally substituted heterocyclic group” represented by R ^6a .
^Examples of the “optionally substituted heterocyclic oxy group” represented by R ^7a include the same as the “optionally substituted heterocyclic oxy group” represented by R ^6a .
^Examples of the “optionally substituted amino group” represented by R ^1a include the same as the “optionally substituted amino group” represented by R ^6a .

  In the above formula, “bicyclic fused furyl group” of “optionally substituted bicyclic condensed furyl group”, “bicyclic fused imidazolyl group” of “optionally substituted bicyclic fused furyl group” The “bicyclic condensed triazolyl group” of the “fused imidazolyl group” and the “optionally substituted bicyclic fused triazolyl group” is 1 to 5 (preferably 1 to 3) at each substitutable position. May be substituted.

  When these are a condensed group with a non-aromatic ring, the substituent group B is mentioned as those substituents, for example. When a plurality of substituents are present, each substituent may be the same or different.

  When these are condensed groups with an aromatic ring, examples of the substituent include the above-mentioned substituent group B excluding the oxo group. When a plurality of substituents are present, each substituent may be the same or different.

R ^1a is even more preferably
(1) Formula: -X ^1a -R ^6a
(Each symbol in the formula is as defined above)
A group represented by:
(2) Formula:

(In the formula, ring Ba represents ^a 5-membered heterocyclic ring which may be further substituted, X ^2a represents a bond or a C _1-6 alkylene group, and R ^7a represents an optionally substituted C _{A 3-6} cycloalkyl group, an optionally substituted C _6-14 aryl group, or an optionally substituted heterocyclic group)
A group represented by:
(3) an optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
It is.

R ^1a is particularly preferably
(1) Formula: -X ^1a -R ^6a
( ^Where X ^1a is
(1) C _1-6 alkylene group (eg, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —),
(2) a C _2-6 alkenylene group (eg, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —), or
(3) C _3-6 cycloalkylene group (eg, cyclopropylene)
Is;
R ^6a is
(1) a C _3-6 cycloalkyl group (eg, cyclohexyl),
(2) (a) a halogen atom (eg, fluorine atom, bromine atom),
(b) a nitro group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, pyrrolidinyl), and
(e) C _1-6 alkyl group (eg, methyl)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(3) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl) optionally substituted with one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxy group, and
(v) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryloxy group (eg, phenoxy) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(4) C _7-14 aralkyloxy group (eg, benzyloxy),
(5) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) an oxo group,
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A heterocyclic group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic heterocyclic group (eg, thienyl, dihydropyridyl)),
(6) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) C _1-6 alkyl group (eg, methyl) _optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aromatic heterocyclic oxy group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic aromatic heterocyclic oxy group (eg, pyridyloxy)),
(7) (i) C _3-8 cycloalkyl group (eg, cyclopropyl), C _1-6 alkyl group (eg, methyl) and C _1-6 alkoxy group (eg, methoxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(ii) a carboxyl group, and
(iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aliphatic heterocyclic oxy group (preferably 8) which may be substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) optionally substituted with 1 to 3 substituents selected from To a 12-membered fused aliphatic heterocyclic oxy group (eg, dihydrobenzofuranyloxy)), or
(8) (a) a C _1-6 alkyl group (eg, methyl),
(b) (i) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, morpholinyl),
(ii) a sulfamoyl group optionally mono- or di-substituted with a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, thiazolyl),
(iii) halogen atoms (eg, chlorine atoms), and
(iv) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a cyano group,
(c) an 8- to 12-membered condensed aliphatic heterocyclic group (eg, dihydrobenzofuranyl),
(d) a C _7-14 aralkyl group (eg, benzyl), and
(e) C _6-14 aryl-carbonyl group (eg, benzoyl)
An amino group which may be mono- or di-substituted with a substituent selected from
A group represented by:
(2) Formula:

(Wherein ring ^Ba is
(1) a C _1-6 alkyl group (eg, methyl),
(2) an amino group, and
(3) Halogen atoms (eg, chlorine atoms)
A 5-membered heterocyclic ring (preferably a 5-membered monocyclic aromatic heterocyclic ring (eg, furan, pyrazole, triazole, imidazole)) optionally substituted by 1 to 3 substituents selected from ;
X ^2a is
(1) Join or
(2) a C _1-6 alkylene group (eg, —CH ₂ —, — (CH ₂ ) ₂ —, —CH (CH ₃ ) —);
R ^7a is
(1) (i) a halogen atom (eg, fluorine atom, chlorine atom),
(ii) a cyano group,
(iii) a C _1-6 alkoxy group (eg, methoxy),
(iv) a C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and
(v) 5- or 6-membered monocyclic aliphatic heterocyclic oxy group (eg, tetrahydropyranyloxy)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(2) C _3-8 cycloalkyl group (eg, cyclopropyl, cyclopentyl, cyclohexyl),
(3) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl), or
(4) 5- or 6-membered monocyclic aliphatic heterocyclic group (eg, tetrahydropyranyl)
A group represented by:
(3) (a) a halogen atom (eg, chlorine atom, bromine atom),
(b) a C _1-6 alkyl group (eg, methyl),
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) an amino group, and
(e) a bicyclic condensed furyl group (preferably a furyl group condensed with a benzene ring) or a bicyclic condensed imidazolyl optionally substituted with 1 to 3 substituents selected from nitro groups A group (preferably an imidazolyl group fused with a pyridine ring or a pyridazine ring);
It is.

Ring A ^a in the formula (Ia) shows a ring which may be substituted.
The “ring” in the “optionally substituted ring” represented by ring A ^a may have 1 to 5 (preferably 1 to 3) substituents at substitutable positions. The “ring” includes C _3-8 cycloalkane, C _3-8 cycloalkene, C _4-10 cycloalkadiene and an aliphatic heterocycle (eg, 3 to 8 membered monocyclic aliphatic heterocycle, 8 to In the case of a 12-membered condensed aliphatic heterocyclic ring), examples of the substituent include the substituent group B. When a plurality of substituents are present, each substituent may be the same or different.
When the “ring” is a C _6-14 aromatic hydrocarbon and an aromatic heterocycle (eg, a 5- to 7-membered monocyclic aromatic heterocycle, an 8- to 12-membered fused aromatic heterocycle), Examples of the substituent include the above substituent group B excluding oxo. When a plurality of substituents are present, each substituent may be the same or different.

Ring A ^a is preferably an optionally substituted C _6-14 aromatic hydrocarbon or an optionally substituted heterocycle (preferably an aromatic heterocycle).

Ring A ^a is more preferably
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) (i) a halogen atom (eg, fluorine atom),
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from a carboxyl group,
(d) a C _1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom),
(e) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(f) a C _1-6 alkyl-carbonyl group (eg, acetyl),
(g) a cyano group,
(h) a nitro group,
(i) (i) a C _1-6 alkyl-carbonyl group (eg, acetyl), and
(ii) C _1-6 alkylsulfonyl group (eg, methylsulfonyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(j) a carbamoyl group,
(k) a carboxyl group,
(l) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(m) a C _1-3 alkylenedioxy group (eg, methylenedioxy), and
(n) C _6-14 aryl group (eg, phenyl)
A C _6-14 aromatic hydrocarbon (eg, benzene, naphthalene) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl),
(b) a C _1-6 alkoxy group (eg, methoxy), and
(c) C _1-6 alkyl-carbonyl group (eg, acetyl)
A heterocyclic ring optionally substituted with 1 to 3 substituents selected from (for example, pyridine, thiophene, thiazole, furan, pyrazole, indole, benzothiophene, dihydrobenzofuran, isoquinoline);
It is.

  Hereinafter, each substituent of formula (I) will be described.

R ² in formula (I) represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group. .
R ³ in Formula (I) represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group.
Alternatively, R ² and R ³ may be taken together to form a C _1-3 alkylidene group or an optionally substituted ring.
Here, the rings formed by R ² and R ³ form a pyrazoline ring and a spiro ring of the formula (I), respectively.

As the "optionally substituted _{C 1-6} alkyl group" represented by R ² or ^{R 3,} optionally "substituted represented by ^{R 2a} or ^{R 3a} of formula (Ia) _{C 1-} The same thing as " ₆ alkyl group" is mentioned.

Represented by R ² or ^{R 3} as "optionally substituted _{C 3-6} cycloalkyl group" may be "substituted represented by ^{R 2a} or ^{R 3a} of formula (Ia) _{C 3 Examples} thereof include those similar to “ _-6 cycloalkyl group”.

The “optionally substituted hydroxy group” represented by R ² or R ³ is the same as the “optionally substituted hydroxy group” represented by R ^2a or R ^3a in formula (Ia). Is mentioned.

The “optionally substituted ring” formed by R ² and R ³ together is the “optionally substituted ring” formed by R ^2a and R ^3a of the formula (Ia) together. The same thing is mentioned.

R ² is preferably a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted hydroxy group.

R ² is more preferably
(1) hydrogen atom;
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from: or
(3) _{(a) C 1-6} alkyl group (e.g., methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from:
It is.

R ² is more preferably
(1) hydrogen atom;
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy), and
(d) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from: or
(3) _{(a) C 1-6} alkyl group (e.g., methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from:
It is.

R ³ is preferably
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from: or
(3) a C _3-6 cycloalkyl group (eg, cyclopropyl);
It is.

In another suitable example, R ³ is preferably an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group.

R ³ is more preferably
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy), and
(d) C _1-6 alkyl-carbonyloxy group (eg, acetoxy)
A C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from:
(2) a C _3-6 cycloalkyl group (eg, cyclopropyl);
It is.

In another embodiment, preferably R ² and R ³ are taken together to form an optionally substituted C _3-8 cycloalkane, or an optionally substituted aliphatic heterocycle.
More preferably, R ² and R ³ are taken together
(1) C _3-8 cycloalkane (eg, cyclobutane, cyclopentane), or
(2) C _1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl) and C _1-6 alkyl-carbonyl group (eg, acetyl)
5-membered monocyclic aliphatic heterocycle optionally substituted by 1 to 3 substituents selected from (eg, pyrrolidine, azetidine)
Form.

In yet another embodiment, preferably R ² and R ³ are taken together to be an optionally substituted C _3-8 cycloalkane, an optionally substituted aliphatic heterocycle, or C _{1- 3} alkylidene groups are formed.

In another preferred example, more preferably, R ² and R ³ are taken together
(1) C _3-8 cycloalkane (eg, cyclobutane, cyclopentane),
(2) C _1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl) and C _1-6 alkyl-carbonyl group (eg, acetyl)
A 5-membered monocyclic aliphatic heterocyclic ring (eg, pyrrolidine, azetidine, tetrahydrofuran) optionally substituted with 1 to 3 substituents selected from:
(3) C _1-3 alkylidene group (eg, methylidene)
Form.

R ⁴ and R ⁵ in formula (I) are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-6 cycloalkyl group. , Or an optionally substituted hydroxy group.
Alternatively, R ⁴ and R ⁵ may be taken together to form an oxo group, a C _1-3 alkylidene group, or an optionally substituted ring.

As the "optionally substituted _{C 1-6} alkyl group" represented by R ⁴ or ^{R 5} are optionally "substituted represented by ^{R 2a} or ^{R 3a} of formula (Ia) _{C 1-} The same thing as " ₆ alkyl group" is mentioned.

The “optionally substituted C _3-6 cycloalkyl group” represented by R ⁴ or R ⁵ is “optionally substituted C ₃ represented by R ^2a or R ^3a in formula (Ia)”. _Examples thereof include those similar to “ _-6 cycloalkyl group”.

The “optionally substituted hydroxy group” represented by R ⁴ or R ⁵ is the same as the “optionally substituted hydroxy group” represented by R ^2a or R ^3a in formula (Ia). Is mentioned.

As the “optionally substituted ring” formed by R ⁴ and R ⁵ together, the “optionally substituted ring” formed by R ^2a and R ^3a of formula (Ia) together can be used. The same thing is mentioned.

R ⁴ is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl), more preferably a hydrogen atom.

R ⁵ is preferably a hydrogen atom or a C _1-6 alkyl group (eg, methyl), more preferably a hydrogen atom.

Alternatively, in another embodiment, preferably R ⁴ and R ⁵ are taken together to form an _optionally substituted C _3-8 cycloalkane, more preferably C _3-8 cycloalkane ( Example, cyclopentane).

R ¹ in formula (I) is
(1): ^-X 1 -R ⁶
(In the formula, X ¹ represents a C _3-6 alkylene group, a C _2-6 alkenylene group, or a C _3-6 cycloalkylene group, and R ⁶ represents an optionally substituted C _3-6 cycloalkyl group. , An optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, an _optionally substituted C _{7-14 represents an} aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group)
A group represented by
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. -6} cycloalkyl group, optionally substituted C _3-6 cycloalkyloxy group, _optionally substituted C _6-14 aryl group, _optionally substituted C _6-14 aryloxy group, substituted An optionally substituted C _7-14 aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group)
A group represented by
(3) An optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group.

Represented by R ⁶ as the "which may C _3-6 also be cycloalkyl group substituted", "substituted C _3-6 optionally cycloalkyl group" represented by R ^6a of formula (Ia) The same thing is mentioned.
As the "optionally substituted C _3-6 cycloalkyl group" represented by R ^6, "optionally substituted C _3-6 cycloalkyloxy represented by R ^6a of formula (Ia) The same thing as "group" is mentioned.
Similarly as expressed as the "optionally substituted _{C 6-14} aryl group" in R ^6, "optionally substituted _{C 6-14} aryl group" represented by ^{R 6a} of formula (Ia) Can be mentioned.
Represented by R ⁶ as the "which may _{C 6-14} aryloxy group optionally substituted", the expression "optionally substituted _{C 6-14} aryloxy group" represented by ^{R 6a} of (Ia) The same thing is mentioned.
Represented by R ⁶ as the _{"C 7-14} aralkyloxy group which may be substituted", "substituted _{C 7-14} optionally aralkyloxy group" represented by ^{R 6a} of formula (Ia) The same thing is mentioned.
As the "optionally substituted heterocyclic group" represented by R ^6, include the same formula "optionally substituted heterocyclic group" represented by R ^6a of (Ia).
As the "optionally substituted heterocyclic group" represented by R ^6, include the same formula "optionally substituted heterocyclic group" represented by R ^6a of (Ia) It is done.
As the "optionally substituted amino group" represented by R ^6, include the same formula "optionally substituted amino group" represented by R ^6a of (Ia).

R ⁶ is preferably
(1) a C _3-6 cycloalkyl group (eg, cyclohexyl),
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(3) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with hydroxy,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryloxy group (eg, phenoxy) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(4) C _7-14 aralkyloxy group (eg, benzyloxy),
(5) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a nitro group, and
(p) an oxo group,
A heterocyclic group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic heterocyclic group (eg, thienyl, dihydropyridyl)),
(6) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl, pyrrolidinyl) optionally substituted by one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) an aromatic heterocyclic oxy group (preferably a 5- to 7-membered monocyclic aromatic heterocyclic oxy group (eg, pyridyl) optionally substituted with 1 to 3 substituents selected from nitro groups Oxy)),
(7) (i) C _3-8 cycloalkyl group (eg, cyclopropyl), C _1-6 alkyl group (eg, methyl) and C _1-6 alkoxy group (eg, methoxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(ii) a carboxyl group, and
(iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aliphatic heterocyclic oxy group (preferably 8) which may be substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) optionally substituted with 1 to 3 substituents selected from To a 12-membered fused aliphatic heterocyclic oxy group (eg, dihydrobenzofuranyloxy)), or
(8) (a) a C _1-6 alkyl group (eg, methyl),
(b) (i) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, morpholinyl),
(ii) a sulfamoyl group optionally mono- or di-substituted with a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, thiazolyl),
(iii) halogen atoms (eg, chlorine atoms), and
(iv) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a cyano group,
(c) an 8- to 12-membered condensed aliphatic heterocyclic group (eg, dihydrobenzofuranyl),
(d) a C _7-14 aralkyl group (eg, benzyl), and
(e) C _6-14 aryl-carbonyl group (eg, benzoyl)
An amino group which may be mono- or di-substituted with a substituent selected from:

X ^1a is preferably
(1) C _3-6 alkylene group (eg, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —),
(2) a C _2-6 alkenylene group (eg, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —), or
(3) C _3-6 cycloalkylene group (eg, cyclopropylene)
It is.

Represented by ring B "further substituted heterocyclic ring may be 5-membered optionally" means a group of the formula (Ia) "further optionally substituted 5-membered heterocyclic ring" represented by ring B ^a described in The same thing is mentioned.

Represented by R ⁷ The "which may C _3-6 also be cycloalkyl group substituted", "substituted C _3-6 optionally cycloalkyl group" represented by R ^6a of formula (Ia) The same thing is mentioned.
As the "optionally substituted C _3-6 cycloalkyl group" represented by R ^7, "optionally substituted C _3-6 cycloalkyloxy represented by R ^6a of formula (Ia) The same thing as "group" is mentioned.
Similarly as expressed as the "optionally substituted _{C 6-14} aryl group" in R ^7, the "optionally substituted _{C 6-14} aryl group" represented by ^{R 6a} of formula (Ia) Can be mentioned.
Represented by R ⁷ The "which may _{C 6-14} aryloxy group optionally substituted", the expression "optionally substituted _{C 6-14} aryloxy group" represented by ^{R 6a} of (Ia) The same thing is mentioned.
Represented by R ⁷ As the _{"C 7-14} aralkyloxy group which may be substituted", "substituted _{C 7-14} optionally aralkyloxy group" represented by ^{R 6a} of formula (Ia) The same thing is mentioned.
Examples of the “optionally substituted heterocyclic group” represented by R ⁷ include those similar to the “optionally substituted heterocyclic group” represented by R ^6a in formula (Ia).
Examples of the “optionally substituted heterocyclic oxy group” represented by R ⁷ include those similar to the “optionally substituted heterocyclic oxy group” represented by R ^6a of formula (Ia). It is done.
Examples of the “optionally substituted amino group” represented by R ⁷ include those similar to the “optionally substituted amino group” represented by R ^6a of formula (Ia).

R ¹ is, preferably,
(1): ^-X 1 -R ⁶
(Each symbol in the formula is as defined above)
A group represented by:
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. -6} cycloalkyl group, C _6-14 aryl group which may be substituted, or heterocyclic group which may be substituted)
A group represented by:
(3) an optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
It is.

R ¹ is more preferably
(1): ^-X 1 -R ⁶
(Where X ¹ is
(1) C _3-6 alkylene group (eg, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —),
(2) a C _2-6 alkenylene group (eg, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —), or
(3) C _3-6 cycloalkylene group (eg, cyclopropylene)
Is;
R ⁶ is
(1) a C _3-6 cycloalkyl group (eg, cyclohexyl),
(2) (a) a halogen atom (eg, fluorine atom, bromine atom),
(b) a nitro group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, pyrrolidinyl), and
(e) C _1-6 alkyl group (eg, methyl)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(3) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl) optionally substituted with one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryloxy group (eg, phenoxy) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(4) C _7-14 aralkyloxy group (eg, benzyloxy),
(5) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) an oxo group,
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A heterocyclic group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic heterocyclic group (eg, thienyl, dihydropyridyl)),
(6) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) C _1-6 alkyl group (eg, methyl) _optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aromatic heterocyclic oxy group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic aromatic heterocyclic oxy group (eg, pyridyloxy)),
(7) (i) C _3-8 cycloalkyl group (eg, cyclopropyl), C _1-6 alkyl group (eg, methyl) and C _1-6 alkoxy group (eg, methoxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(ii) a carboxyl group, and
(iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aliphatic heterocyclic oxy group (preferably 8) which may be substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) optionally substituted with 1 to 3 substituents selected from To a 12-membered fused aliphatic heterocyclic oxy group (eg, dihydrobenzofuranyloxy)), or
(8) (a) a C _1-6 alkyl group (eg, methyl),
(b) (i) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, morpholinyl),
(ii) a sulfamoyl group optionally mono- or di-substituted with a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, thiazolyl),
(iii) halogen atoms (eg, chlorine atoms), and
(iv) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a cyano group,
(c) an 8- to 12-membered condensed aliphatic heterocyclic group (eg, dihydrobenzofuranyl),
(d) a C _7-14 aralkyl group (eg, benzyl), and
(e) C _6-14 aryl-carbonyl group (eg, benzoyl)
An amino group which may be mono- or di-substituted with a substituent selected from
A group represented by:
(2) Formula:

(Wherein ring B is
(1) a C _1-6 alkyl group (eg, methyl),
(2) an amino group, and
(3) Halogen atoms (eg, chlorine atoms)
A 5-membered heterocyclic ring (preferably a 5-membered monocyclic aromatic heterocyclic ring (eg, furan, pyrazole, triazole, imidazole)) optionally substituted by 1 to 3 substituents selected from ;
X ² is,
(1) Join or
(2) a C _1-6 alkylene group (eg, —CH ₂ —, — (CH ₂ ) ₂ —, —CH (CH ₃ ) —);
R ⁷ is
(1) (i) a halogen atom (eg, fluorine atom, chlorine atom),
(ii) a cyano group,
(iii) a C _1-6 alkoxy group (eg, methoxy),
(iv) a C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and
(v) 5- or 6-membered monocyclic aliphatic heterocyclic oxy group (eg, tetrahydropyranyloxy)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(2) C _3-8 cycloalkyl group (eg, cyclopropyl, cyclopentyl, cyclohexyl),
(3) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl), or
(4) 5- or 6-membered monocyclic aliphatic heterocyclic group (eg, tetrahydropyranyl)
A group represented by:
(3) (a) a halogen atom (eg, chlorine atom, bromine atom),
(b) a C _1-6 alkyl group (eg, methyl),
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) an amino group, and
(e) a bicyclic condensed furyl group (preferably a furyl group condensed with a benzene ring) or a bicyclic condensed imidazolyl optionally substituted with 1 to 3 substituents selected from nitro groups A group (preferably an imidazolyl group fused with a pyridine ring or a pyridazine ring);
It is.

Ring A in formula (I) represents an optionally substituted C _6-14 aromatic hydrocarbon or an optionally substituted heterocycle.
“C _6-14 aromatic hydrocarbon” of “ _optionally substituted C _6-14 aromatic hydrocarbon” represented by ring A and “heterocycle (aromatic) of“ optionally substituted heterocycle ” The aromatic heterocycle and the aliphatic heterocycle ”each may have 1 to 5 (preferably 1 to 3) substituents at substitutable positions.

  In the case of an aliphatic heterocycle (eg, 3 to 8-membered monocyclic aliphatic heterocycle, 8- to 12-membered condensed aliphatic heterocycle), examples of the substituent include the substituent group B described above. . When a plurality of substituents are present, each substituent may be the same or different.

In the case of C _6-14 aromatic hydrocarbon and aromatic heterocycle (eg, 5- to 7-membered monocyclic aromatic heterocycle, 8- to 12-membered condensed aromatic heterocycle), as substituents thereof, For example, the above-mentioned substituent group B excluding the oxo group can be mentioned. When a plurality of substituents are present, each substituent may be the same or different.

Ring A is preferably
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) (i) a halogen atom (eg, fluorine atom),
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from a carboxyl group,
(d) a C _1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom),
(e) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(f) a C _1-6 alkyl-carbonyl group (eg, acetyl),
(g) a cyano group,
(h) a nitro group,
(i) (i) a C _1-6 alkyl-carbonyl group (eg, acetyl), and
(ii) C _1-6 alkylsulfonyl group (eg, methylsulfonyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(j) a carbamoyl group,
(k) a carboxyl group,
(l) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(m) a C _1-3 alkylenedioxy group (eg, methylenedioxy), and
(n) C _6-14 aryl group (eg, phenyl)
A C _6-14 aromatic hydrocarbon (eg, benzene, naphthalene) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl),
(b) a C _1-6 alkoxy group (eg, methoxy), and
(c) C _1-6 alkyl-carbonyl group (eg, acetyl)
A heterocyclic ring optionally substituted with 1 to 3 substituents selected from (for example, pyridine, thiophene, thiazole, furan, pyrazole, indole, benzothiophene, dihydrobenzofuran, isoquinoline);
It is.

Compound (I) is
1- [4,5-dihydro-5-hydroxy-3- (4-methylphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [3- (4-chlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3-phenyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [3- (4-bromophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3- (4-pyridyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone; and (4- Amino-1H-imidazol-5-yl) [4,5-dihydro-5-hydroxy-3- (2-naphthyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] methanone is not included.

  Compound (I) is a novel compound.

A preferred specific example of compound (Ia) is compound (I).
Preferable specific examples of compound (I) include the following:

Compound (A-1):
In formula (I):
Ring A is an optionally substituted C _6-14 aromatic hydrocarbon, or an optionally substituted heterocycle;
R ¹ is
(1): ^-X 1 -R ⁶
(Each symbol in the formula is as defined above)
A group represented by:
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. -6} cycloalkyl group, C _6-14 aryl group which may be substituted, or heterocyclic group which may be substituted)
A group represented by:
(3) an optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
Is;
R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted hydroxy group;
R ³ is an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ² and R ³ together may form an optionally substituted C _3-8 cycloalkane, or an optionally substituted aliphatic heterocycle;
R ⁴ is a hydrogen atom; and R ⁵ is a hydrogen atom;
Compound or salt thereof.

Compound (B-1):
In formula (I):
Ring A is
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) (i) a halogen atom (eg, fluorine atom),
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from a carboxyl group,
(d) a C _1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom),
(e) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(f) a C _1-6 alkyl-carbonyl group (eg, acetyl),
(g) a cyano group,
(h) a nitro group,
(i) (i) a C _1-6 alkyl-carbonyl group (eg, acetyl), and
(ii) C _1-6 alkylsulfonyl group (eg, methylsulfonyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(j) a carbamoyl group,
(k) a carboxyl group,
(l) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(m) a C _1-3 alkylenedioxy group (eg, methylenedioxy), and
(n) C _6-14 aryl group (eg, phenyl)
A C _6-14 aromatic hydrocarbon (eg, benzene, naphthalene) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl),
(b) a C _1-6 alkoxy group (eg, methoxy), and
(c) C _1-6 alkyl-carbonyl group (eg, acetyl)
A heterocyclic ring optionally substituted with 1 to 3 substituents selected from (for example, pyridine, thiophene, thiazole, furan, pyrazole, indole, benzothiophene, dihydrobenzofuran, isoquinoline);
Is;
R ¹ is
(1): ^-X 1 -R ⁶
(Where X ¹ is
(1) C _3-6 alkylene group (eg, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —),
(2) a C _2-6 alkenylene group (eg, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —), or
(3) C _3-6 cycloalkylene group (eg, cyclopropylene)
Is;
R ⁶ is
(1) a C _3-6 cycloalkyl group (eg, cyclohexyl),
(2) (a) a halogen atom (eg, fluorine atom, bromine atom),
(b) a nitro group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, pyrrolidinyl), and
(e) C _1-6 alkyl group (eg, methyl)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(3) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl) optionally substituted with one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryloxy group (eg, phenyloxy) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(4) C _7-14 aralkyloxy group (eg, benzyloxy),
(5) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) an oxo group,
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A heterocyclic group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic heterocyclic group (eg, thienyl, dihydropyridyl)),
(6) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) C _1-6 alkyl group (eg, methyl) _optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aromatic heterocyclic oxy group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic aromatic heterocyclic oxy group (eg, pyridyloxy)),
(7) (i) C _3-8 cycloalkyl group (eg, cyclopropyl), C _1-6 alkyl group (eg, methyl) and C _1-6 alkoxy group (eg, methoxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(ii) a carboxyl group, and
(iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aliphatic heterocyclic oxy group (preferably 8) which may be substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) optionally substituted with 1 to 3 substituents selected from To a 12-membered fused aliphatic heterocyclic oxy group (eg, dihydrobenzofuranyloxy)), or
(8) (a) a C _1-6 alkyl group (eg, methyl),
(b) (i) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, morpholinyl),
(ii) a sulfamoyl group optionally mono- or di-substituted with a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, thiazolyl),
(iii) halogen atoms (eg, chlorine atoms), and
(iv) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a cyano group,
(c) an 8- to 12-membered condensed aliphatic heterocyclic group (eg, dihydrobenzofuranyl),
(d) a C _7-14 aralkyl group (eg, benzyl), and
(e) C _6-14 aryl-carbonyl group (eg, benzoyl)
An amino group which may be mono- or di-substituted with a substituent selected from
A group represented by:
(2) Formula:

(Wherein ring B is
(1) a C _1-6 alkyl group (eg, methyl),
(2) an amino group, and
(3) Halogen atoms (eg, chlorine atoms)
A 5-membered heterocyclic ring (preferably a 5-membered monocyclic aromatic heterocyclic ring (eg, furan, pyrazole, triazole, imidazole)) optionally substituted by 1 to 3 substituents selected from ;
X ² is,
(1) Join or
(2) a C _1-6 alkylene group (eg, —CH ₂ —, — (CH ₂ ) ₂ —, —CH (CH ₃ ) —);
R ⁷ is
(1) (i) a halogen atom (eg, fluorine atom, chlorine atom),
(ii) a cyano group,
(iii) a C _1-6 alkoxy group (eg, methoxy),
(iv) a C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and
(v) 5- or 6-membered monocyclic aliphatic heterocyclic oxy group (eg, tetrahydropyranyloxy)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(2) C _3-8 cycloalkyl group (eg, cyclopropyl, cyclopentyl, cyclohexyl),
(3) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl), or
(4) 5- or 6-membered monocyclic aliphatic heterocyclic group (eg, tetrahydropyranyl)
A group represented by:
(3) (a) a halogen atom (eg, chlorine atom, bromine atom),
(b) a C _1-6 alkyl group (eg, methyl),
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) an amino group, and
(e) a bicyclic condensed furyl group (preferably a furyl group condensed with a benzene ring) or a bicyclic condensed imidazolyl optionally substituted with 1 to 3 substituents selected from nitro groups A group (preferably an imidazolyl group fused with a pyridine ring or a pyridazine ring);
Is;
R ² is
(1) hydrogen atom;
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from: or
(3) _{(a) C 1-6} alkyl group (e.g., methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from:
And
R ³ is
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from: or
(3) a C _3-6 cycloalkyl group (eg, cyclopropyl);
Or
R ² and R ³ together
(1) C _3-8 cycloalkane (eg, cyclobutane, cyclopentane), or
(2) C _1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl) and C _1-6 alkyl-carbonyl group (eg, acetyl)
5-membered monocyclic aliphatic heterocycle optionally substituted by 1 to 3 substituents selected from (eg, pyrrolidine, azetidine)
May form;
R ⁴ is a hydrogen atom; and R ⁵ is a hydrogen atom;
Compound or salt thereof.

Compound (A-2):
In formula (I):
Ring A is an optionally substituted C _6-14 aromatic hydrocarbon, or an optionally substituted heterocycle;
R ¹ is
(1): ^-X 1 -R ⁶
(Each symbol in the formula is as defined above)
A group represented by:
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. -6} cycloalkyl group, C _6-14 aryl group which may be substituted, or heterocyclic group which may be substituted)
A group represented by:
(3) an optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
Is;
R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted hydroxy group;
R ³ is an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ² and R ³ together may form an optionally substituted C _3-8 cycloalkane, an optionally substituted aliphatic heterocycle, or a C _1-3 alkylidene group; And R ⁴ is a hydrogen atom or a C _1-6 alkyl group,
R ⁵ is a hydrogen atom or a C _1-6 alkyl group,
Or
R ⁴ and R ⁵ may be taken together to form an _optionally substituted C _3-8 cycloalkane;
Compound or salt thereof.

Compound (B-2):
In formula (I):
Ring A is
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) (i) a halogen atom (eg, fluorine atom),
(ii) a cyano group,
(iii) a hydroxy group, and
(iv) a C _1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from a carboxyl group,
(d) a C _1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy) optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom),
(e) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(f) a C _1-6 alkyl-carbonyl group (eg, acetyl),
(g) a cyano group,
(h) a nitro group,
(i) (i) a C _1-6 alkyl-carbonyl group (eg, acetyl), and
(ii) C _1-6 alkylsulfonyl group (eg, methylsulfonyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(j) a carbamoyl group,
(k) a carboxyl group,
(l) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(m) a C _1-3 alkylenedioxy group (eg, methylenedioxy), and
(n) C _6-14 aryl group (eg, phenyl)
A C _6-14 aromatic hydrocarbon (eg, benzene, naphthalene) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl),
(b) a C _1-6 alkoxy group (eg, methoxy), and
(c) C _1-6 alkyl-carbonyl group (eg, acetyl)
A heterocyclic ring optionally substituted with 1 to 3 substituents selected from (for example, pyridine, thiophene, thiazole, furan, pyrazole, indole, benzothiophene, dihydrobenzofuran, isoquinoline);
Is;
R ¹ is
(1): ^-X 1 -R ⁶
(Where X ¹ is
(1) C _3-6 alkylene group (eg, — (CH ₂ ) ₃ —, — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —),
(2) a C _2-6 alkenylene group (eg, —CH ₂ —CH═CH—, —CH═CH—CH ₂ —), or
(3) C _3-6 cycloalkylene group (eg, cyclopropylene)
Is;
R ⁶ is
(1) a C _3-6 cycloalkyl group (eg, cyclohexyl),
(2) (a) a halogen atom (eg, fluorine atom, bromine atom),
(b) a nitro group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, pyrrolidinyl), and
(e) C _1-6 alkyl group (eg, methyl)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(3) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(b) a cyano group,
(c) a hydroxy group,
(d) (i) a halogen atom (eg, a fluorine atom), and
(ii) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl)
A C _1-6 alkoxy group (eg, methoxy) optionally substituted with 1 to 3 substituents selected from:
(e) a C _7-14 aralkyloxy group (eg, benzyloxy),
(f) a carbamoyl group optionally mono- or disubstituted with a C _3-6 cycloalkyl group (eg, cyclopropyl),
(g) a C _1-6 alkylsulfanyl group (eg, methylsulfanyl),
(h) a C _1-6 alkylsulfinyl group (eg, methylsulfinyl),
(i) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl),
(j) a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl, thiazolyl) optionally substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl),
(k) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, dihydrooxadiazolyl) optionally substituted with one oxo group or thioxo group,
(l) a carboxyl group,
(m) a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl),
(n) (i) a halogen atom (eg, fluorine atom),
(ii) an amino group,
(iii) an imino group optionally substituted with a hydroxy group,
(iv) a carboxyl group, and
(v) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 substituents selected from:
(o) a C _6-14 aryloxy group (eg, phenyloxy) _optionally substituted with 1 to 3 substituents selected from a nitro group,
(4) C _7-14 aralkyloxy group (eg, benzyloxy),
(5) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) an oxo group,
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
A heterocyclic group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic heterocyclic group (eg, thienyl, dihydropyridyl)),
(6) (a) Halogen atoms (eg, chlorine atoms),
(b) a cyano group,
(c) C _1-6 alkyl group (eg, methyl) _optionally substituted by 1 to 3 halogen atoms (eg, fluorine atom)
(d) a carboxyl group, and
(e) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aromatic heterocyclic oxy group optionally substituted with 1 to 3 substituents selected from (preferably a 5- to 7-membered monocyclic aromatic heterocyclic oxy group (eg, pyridyloxy)),
(7) (i) C _3-8 cycloalkyl group (eg, cyclopropyl), C _1-6 alkyl group (eg, methyl) and C _1-6 alkoxy group (eg, methoxy)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(ii) a carboxyl group, and
(iii) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl)
An aliphatic heterocyclic oxy group (preferably 8) which may be substituted with 1 to 3 C _1-6 alkyl groups (eg, methyl) optionally substituted with 1 to 3 substituents selected from To a 12-membered fused aliphatic heterocyclic oxy group (eg, dihydrobenzofuranyloxy)), or
(8) (a) a C _1-6 alkyl group (eg, methyl),
(b) (i) a 3- to 8-membered monocyclic aliphatic heterocyclic group (eg, morpholinyl),
(ii) a sulfamoyl group optionally mono- or di-substituted with a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, thiazolyl),
(iii) halogen atoms (eg, chlorine atoms), and
(iv) a C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from a cyano group,
(c) an 8- to 12-membered condensed aliphatic heterocyclic group (eg, dihydrobenzofuranyl),
(d) a C _7-14 aralkyl group (eg, benzyl), and
(e) C _6-14 aryl-carbonyl group (eg, benzoyl)
An amino group which may be mono- or di-substituted with a substituent selected from
A group represented by:
(2) Formula:

(Wherein ring B is
(1) a C _1-6 alkyl group (eg, methyl),
(2) an amino group, and
(3) Halogen atoms (eg, chlorine atoms)
A 5-membered heterocyclic ring (preferably a 5-membered monocyclic aromatic heterocyclic ring (eg, furan, pyrazole, triazole, imidazole)) optionally substituted by 1 to 3 substituents selected from ;
X ² is,
(1) Join or
(2) a C _1-6 alkylene group (eg, —CH ₂ —, — (CH ₂ ) ₂ —, —CH (CH ₃ ) —);
R ⁷ is
(1) (i) a halogen atom (eg, fluorine atom, chlorine atom),
(ii) a cyano group,
(iii) a C _1-6 alkoxy group (eg, methoxy),
(iv) a C _1-6 alkyl group (eg, methyl) _optionally substituted with 1 to 3 halogen atoms (eg, fluorine atom), and
(v) 5- or 6-membered monocyclic aliphatic heterocyclic oxy group (eg, tetrahydropyranyloxy)
A C _6-14 aryl group (eg, phenyl) _optionally substituted with 1 to 3 substituents selected from:
(2) C _3-8 cycloalkyl group (eg, cyclopropyl, cyclopentyl, cyclohexyl),
(3) 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl), or
(4) 5- or 6-membered monocyclic aliphatic heterocyclic group (eg, tetrahydropyranyl)
A group represented by:
(3) (a) a halogen atom (eg, chlorine atom, bromine atom),
(b) a C _1-6 alkyl group (eg, methyl),
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) an amino group, and
(e) a bicyclic condensed furyl group (preferably a furyl group condensed with a benzene ring) or a bicyclic condensed imidazolyl optionally substituted with 1 to 3 substituents selected from nitro groups A group (preferably an imidazolyl group fused with a pyridine ring or a pyridazine ring);
Is;
R ² is
(1) hydrogen atom;
(2) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 substituents selected from: or
(3) _{(a) C 1-6} alkyl group (e.g., methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from:
And
R ³ is
(1) (a) a halogen atom (eg, fluorine atom, chlorine atom),
(b) a hydroxy group,
(c) a C _1-6 alkoxy group (eg, methoxy),
(d) a C _7-14 aralkyloxy group (eg, benzyloxy), and
(e) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy)
A C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) optionally substituted with 1 to 3 substituents selected from:
(2) (a) a C _1-6 alkyl group (eg, methyl, ethyl), and
(b) (i) a hydroxy group, and
(ii) C _1-6 alkoxy group (eg, methoxy)
C _1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 substituents selected from
A hydroxy group optionally substituted with a substituent selected from: or
(3) a C _3-6 cycloalkyl group (eg, cyclopropyl);
Or
R ² and R ³ together
(1) C _3-8 cycloalkane (eg, cyclobutane, cyclopentane),
(2) C _1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl) and C _1-6 alkyl-carbonyl group (eg, acetyl)
A 5-membered monocyclic aliphatic heterocyclic ring (eg, pyrrolidine, azetidine, tetrahydrofuran) optionally substituted with 1 to 3 substituents selected from:
(3) C _1-3 alkylidene group (eg, methylidene)
And R ⁴ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl),
R ⁵ is a hydrogen atom or a C _1-6 alkyl group (eg, methyl),
Or
R ⁴ and R ⁵ may together form a C _3-8 cycloalkane (eg, cyclopentane);
Compound or salt thereof.

When compound (Ia) is a salt, examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like. Examples include salts. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. Examples include salts with ethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts In addition, when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, Examples thereof include salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

Next, a method for producing the compound (Ia) of the present invention or a salt thereof will be described.
Compound (Ia) or a salt thereof of the present invention can be produced using the following Method A, Method B, Method G, Method H, Method I, Method J, Method K or Method L. The compound represented by compound (IV) or a salt thereof can be produced by the C method, D method, E method or F method described later.

Among compounds (Ia), compound (Ib) in which R ^2a is a hydroxy group and R ^5a is a hydrogen atom can be produced using Method A.
[Method A]

[Each symbol in the formula is as defined above. ]

(Process 1)
This step is a step of producing compound (III) by acetalizing compound (II) or a salt thereof.
When the starting compound (II) or a salt thereof is commercially available, the commercially available product can be used as it is, according to a method known per se [eg, Tetrahedron Letters, 1981, Vol. 22, p.3815, etc.] Can also be manufactured.
This step can be carried out according to a method known per se [eg, New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds [I], 1977, 622 (Maruzen), etc.]. Methanol, trimethyl orthoacetate or the like can be used in the absence of a solvent or in a solvent that does not affect the reaction.
Methanol may be used as a solvent. The amount of trimethyl orthoacetate to be used varies depending on the reaction conditions, but is usually about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (II).
Examples of the acid used include mineral acids (hydrochloric acid, sulfuric acid, etc.), carboxylic acids (oxalic acid, etc.), sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc.), Lewis acid (phosphoryl chloride). , Boron trifluoride diethyl ether complex, etc.), inorganic salts (calcium chloride, ammonium chloride, etc.) and the like. Among them, methanesulfonic acid, p-toluenesulfonic acid and the like are preferable. The amount of the acid to be used varies depending on the reaction conditions, but is usually about 0.01 to 0.5 mol, preferably about 0.05 to 0.1 mol, per 1 mol of compound (II).
Examples of the solvent to be used include methanol, hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, etc.) or a mixture thereof.
The reaction temperature is usually about 0 to 150 ° C., preferably about 10 to 120 ° C., and the reaction time is usually about 10 minutes to 48 hours, preferably about 15 minutes to 24 hours.

(Process 2)
This step comprises compound (III) and the formula:
R ^3a —CO ₂ H (V)
[The symbols in the formula are as defined above. ]
Or a reactive derivative thereof or a salt thereof, is a step for producing compound (IV).
When compound (V) or a salt thereof is commercially available, a commercially available product can be used as it is. The amount to be used is about 1 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (III).
This step can be performed according to a method known per se [eg, Journal of Fluorine Chemistry, 1999, 99, p.177, etc.]. Examples of the condensation method include a method using a condensing agent and a method using a reactive derivative.
Examples of the condensing agent used in the “method using a condensing agent” include dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide and its hydrochloride, benzotriazol-1-yloxy-tris. (Dimethylamino) phosphonium hexafluorophosphate, diphenylphosphoryl azide and the like can be mentioned. These are used alone or in combination with an additive (eg, N-hydroxysuccinimide, 1-hydroxybenzotriazole or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine). You can also. The amount of the condensing agent to be used is about 1 to 10 mol, preferably about 1 to 2 mol, per 1 mol of compound (V). The amount of the additive to be used is about 1 to 10 mol, preferably about 1 to 2 mol, per 1 mol of compound (V).
In this method, the reaction is usually performed in the absence of a solvent or in a solvent that does not adversely influence the reaction, and a convenient base may be added to promote the reaction.
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1,2-dimethoxy, etc.). Ethane, dioxane, tetrahydrofuran, etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, etc.), amides (N, N-dimethylformamide, etc.), aromatic amines (pyridine, etc.), etc. You may do it.
Examples of the base used include metal hydrides (potassium hydride, sodium hydride, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), bicarbonates (sodium bicarbonate, potassium bicarbonate). Etc.), carbonates (sodium carbonate, potassium carbonate, etc.), acetates (sodium acetate, etc.), tertiary amines (trimethylamine, triethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undeca- 7-ene), aromatic amines (pyridine, picoline, N, N-dimethylaniline, etc.) and the like. The amount of the base to be used is generally about 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound (III).
The reaction temperature is usually about −80 to 150 ° C., preferably about 0 to 50 ° C., and the reaction time is usually about 0.5 to 48 hours, preferably about 0.5 to 24 hours. .
In the “method using a reactive derivative”, examples of the reactive derivative include an acid halide, an acid anhydride, a mixed acid anhydride, and an active ester. The conversion to the reactive derivative can be carried out according to a method known per se. For example, as the conversion to an acid halide, a method using an acid halide (eg, thionyl chloride, oxalyl chloride, etc.), phosphorus and And a method using a halide of phosphoric acid (eg, phosphorus trichloride, phosphorus pentachloride, etc.).
In this method, the reaction varies depending on the type of the reactive derivative or substrate, but it is usually carried out in the absence of a solvent or in a solvent that does not adversely affect the reaction, and a convenient base may be added to promote the reaction. good. The kind of solvent and base used in the reaction, the amount used, the reaction temperature, and the reaction time are the same as those described in the above-mentioned “Method using a condensing agent”.

(Process 3)
In this step, compound (IV) is represented by the formula:

[The symbols in the formula are as defined above. ]
Wherein the compound (Ib) is produced by reacting with a compound represented by the formula:
When compound (VI) or a salt thereof is commercially available, a commercially available product can be used as it is, and it can be produced according to a method known per se [eg, pharmaceutical journal, 1955, 75, 353, etc.] You can also. The amount of use is, for example, about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (IV).
This step can be performed according to a method known per se [eg, Journal of Heterocyclic Chemistry, 2005, 42, p.631, etc.], and can be performed in the absence of a solvent or in a solvent that does not affect the reaction.
Examples of the solvent used include alcohols (methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.) ), Ethers (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, etc.), aromatic amines (pyridine, etc.) or a mixture thereof.
The reaction temperature is usually about 10 to 100 ° C., preferably about 50 to 70 ° C., and the reaction time is usually about 5 to 48 hours, preferably about 12 to 24 hours.

Among compounds (Ia), compound (Ic) in which R ^5a is a hydrogen atom can be produced using Method B.
[Method B]

[Each symbol in the formula is as defined above. ]

(Process 4)
In this step, compound (VII) is reacted with hydrazine monohydrate, and then the formula:
R ^1a —CO ₂ H (VIII)
[The symbols in the formula are as defined above. ]
Or a reactive derivative thereof or a salt thereof, is a step for producing compound (Ic).
This step can be performed according to a method known per se [eg, Tetrahedron Letters, 2004, Vol. 45, p. 1489].
The reaction of compound (VII) and hydrazine monohydrate can be carried out, for example, in the absence of a solvent or in a solvent that does not affect the reaction.
The amount of hydrazine monohydrate to be used is about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (VII).
Examples of the solvent used include alcohols (methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.) ), Ethers (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, etc.), aromatic amines (pyridine, etc.) or a mixture thereof.
The reaction temperature is usually about 50 to 150 ° C., preferably about 50 to 100 ° C., and the reaction time is usually about 5 minutes to 5 hours, preferably about 0.5 to 2 hours.
When the compound (VIII) or a salt thereof is commercially available, the commercially available product can be used as it is, and it is produced according to a method known per se [eg, European Journal of Medicinal Chemistry, 1995, 30, p.377 etc.]. You can also The amount thereof to be used is about 1 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (VII).
The condensation method can be carried out by a method known per se, for example, the method described in “Chemical Chemistry Lecture 22, Organic Synthesis IV” published by the Chemical Society of Japan, 1991, or a method analogous thereto. . Examples of these methods include a method using a condensing agent, a method using a reactive derivative, and the like. The method can be performed by the same method as described in Step 2 of Method A, and the solvent used in the reaction. The same applies to the kind of base, amount used, reaction temperature and reaction time.

Compound (VII) which is a raw material of Method B can be produced using Method C.
[Method C]

[Each symbol in the formula is as defined above. ]

(Process 5)
This step is a step for producing compound (X) by condensing compound (IX) or a salt thereof with N, O-dimethylhydroxylamine hydrochloride.
When the starting compound (IX) or a salt thereof is commercially available, the commercially available product can be used as it is, and a method known per se [eg, Journal of the Chemical Society, 1896, 69, p. 1472, etc.] can be used. It can also be manufactured according to this.
This step can be carried out by the same method as that described in Step 2 of Method A, and the types and amounts of the solvent and base used in the reaction, the reaction temperature, and the reaction time are also the same.

(Step 6)
In this step, compound (X) is represented by the formula:

[Wherein, M represents a metal atom such as magnesium or lithium or a halide thereof, and other symbols are as defined above. ]
In which compound (VII) is produced by reacting with a compound represented by the formula:
When the compound (XI) or a salt thereof is commercially available, a commercially available product can be used as it is, and a method known per se, for example, “Chemical Society of Japan, 1991, 4th edition, Experimental Chemistry Course 24, Organic Synthesis” It can also be produced by a method described in “VI” or the like, or a method analogous thereto. The amount used is, for example, about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (X).
This step is usually performed in the absence of a solvent or in a solvent that does not adversely influence the reaction.
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1,2-dimethoxy, etc.). Ethane, tetrahydrofuran, etc.) or a mixture thereof.
The reaction temperature is usually about −80 to 80 ° C., preferably about −10 to 50 ° C., and the reaction time is usually about 0.5 to 48 hours, preferably about 1 to 24 hours.

Compound (VII) which is a raw material of Method B can also be produced using Method D.
[Method D]

[Each symbol in the formula is as defined above. ]

(Step 7)
In this step, compound (XII) is represented by the formula

[Wherein each symbol is as defined above. ]
In which compound (VII) is produced by reacting with a compound represented by the formula:
When the raw material compound (XII) is commercially available, a commercially available product can be used as it is, and a method known per se, for example, “Chemical Society of Japan, 1991, 4th edition, Experimental Chemistry Course 24, Organic Synthesis” It can also be produced by the method described in “VI” or the like, or a method analogous thereto. The amount thereof to be used is, for example, about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (XIII).
When the compound (XIII) or a salt thereof is commercially available, the commercially available product can be used as it is, and is produced according to a method known per se [eg, Tetrahedron Letters, 1981, Vol. 22, p. 3815, etc.] You can also.
This step can be performed by the same method as that described in Step C of Method C, and the solvent used in the reaction, the reaction temperature, and the reaction time are also the same.

Compound (VII), which is a raw material of Method B, can also be produced using Method E.
[E method]

[Each symbol in the formula is as defined above. ]

(Step 8)
This step comprises reacting compound (II) with the formula:

[Wherein L ¹ represents a leaving group. ]
Wherein the compound (XIV) is produced by reacting with a compound represented by the formula:
Examples of the leaving group represented by L ¹ include a halogen atom (such as a chlorine atom, a bromine atom, and an iodine atom), a substituted sulfonyloxy group (such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and a toluenesulfonyloxy group). Is mentioned.
This step can be performed according to a method known per se [eg, Synthesis, 1983, p.1, etc.], and can be performed, for example, in the presence of a base, in the absence of a solvent, or in a solvent that does not affect the reaction.
The amount of compound (XV) to be used is, for example, about 1 to 5 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (II).
Examples of the base include organic bases (trimethylamine, triethylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, picoline, N, N-dimethylaniline, etc.), inorganic Bases (potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), metal hydrides (potassium hydride, Sodium hydride and the like) and organic metals (n-butyllithium, lithium diisopropylamide and the like). Among them, organic metals such as lithium diisopropylamide are preferable. The amount of the base to be used is, for example, about 1 to 5 mol, preferably about 1 to 1.2 mol, per 1 mol of compound (II).
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1,2-dimethoxy, etc.). Ethane, tetrahydrofuran, etc.) or a mixture thereof.
The reaction temperature is usually about −80 to 80 ° C., preferably about −80 to −20 ° C., and the reaction time is usually about 15 minutes to 12 hours, preferably about 30 minutes to 2 hours.

(Step 9)
In this step, compound (XIV) is represented by the formula:

[Each symbol in the formula is as defined above. ]
The compound (VII) is produced by dehydration after the reaction with the compound represented by the formula:
This step can be carried out according to a method known per se [eg, Journal of the American Chemical Society, 1974, Vol. 96, p. 7503, etc.]. The reaction can be carried out in a solvent or in a solvent that does not affect the reaction.
The amount of compound (XVI) to be used is, for example, about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (XIV).
Examples of the Lewis acid used include titanium (IV) chloride, tin (IV) chloride, and boron trifluoride diethyl ether complex. Examples of the Lewis base used include benzyltrimethylammonium fluoride. The amount of Lewis acid or Lewis base to be used varies depending on the reaction conditions, but is usually about 0.01 to 1.5 mol, preferably about 0.1 to 1.1 mol, relative to 1 mol of compound (XIV). Degree.
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, trifluorobenzene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1 , 2-dimethoxyethane, tetrahydrofuran, etc.) or a mixture thereof.
The reaction temperature is usually about −80 to 0 ° C., preferably about −80 to −10 ° C., and the reaction time is usually about 15 minutes to 12 hours, preferably about 30 minutes to 2 hours.
The dehydration reaction can be carried out according to a method known per se [eg, New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds [I], 1977, Item 128 (Maruzen), etc.], for example, trifluoro When an acid anhydride such as acetic anhydride is used, the amount used is usually about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (XIV). As the solvent used, the above-mentioned solvents can be used as they are. The reaction temperature is usually about 0 to 80 ° C., preferably about 0 to 40 ° C., and the reaction time is usually about 15 minutes to 12 hours, preferably about 30 minutes to 2 hours.

Compound (VII) which is a raw material of Method B can also be produced using Method F.
[F method]

[Each symbol in the formula is as defined above. ]

(Process 10)
This step is a step for producing compound (XVII) by brominating compound (II) or a salt thereof.
This step can be performed according to a method known per se [eg, Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, 1987, 1p. 211].
Examples of the brominating agent include bromine, copper (II) bromide, pyrrolidone hydrotribromide, and the amount used varies depending on the reaction conditions, but is usually about 1 to 5 with respect to 1 mol of compound (II). Mole, preferably about 1 to 2 moles.
This step can be carried out in the absence of a solvent or in a solvent that does not affect the reaction. Examples of the solvent used include halogenated hydrocarbons (carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, etc.), carboxylic acids, and the like. (Such as acetic acid), esters (such as ethyl acetate), amides (such as N, N-dimethylformamide) or a mixture thereof.
The reaction temperature is usually about 10 to 150 ° C., preferably about 20 to 100 ° C., and the reaction time is usually about 1 to 48 hours, preferably about 1 to 24 hours.

(Step 11)
This step is a step for producing compound (XVIII) by reacting compound (XVII) or a salt thereof with triethyl phosphite.
This step can be performed according to a method known per se [eg, Pure and Applied Chemistry, 1964, Vol. 9, p. 307, etc.].
The amount of triethyl phosphite to be used is generally about 0.5-3 mol, preferably about 0.8-1.5 mol, per 1 mol of compound (XVII).
This step can be carried out in the absence of a solvent or in a solvent that does not affect the reaction.
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, trifluorobenzene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1 , 2-dimethoxyethane, tetrahydrofuran, etc.), amides (N, N-dimethylformamide, etc.) or mixtures thereof.
The reaction temperature is usually about 70 to 200 ° C., preferably about 90 to 150 ° C., and the reaction time is usually about 1 to 24 hours, preferably about 1 to 12 hours.

(Step 12)
This step is carried out by reacting compound (XVIII) with the formula:

[Each symbol in the formula is as defined above. ]
Is a step of producing compound (VII) by a carbonyl-olefination reaction with a compound represented by the formula:
This step can be performed according to a method known per se [eg, Chemische Berichte, 1959, Vol. 92, p. 2499, etc.], for example, in the presence of a base, without solvent, or a solvent that does not affect the reaction Can be implemented in.
The amount of compound (XXVI) to be used is, for example, about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (XVIII).
Examples of the base include organic bases (trimethylamine, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, picoline, N, N- Dimethylaniline, etc.), inorganic bases (potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.), metal hydrogen Hydrides (potassium hydride, sodium hydride, etc.). The amount of the base to be used is, for example, about 1 to 5 mol, preferably about 1 to 1.2 mol, per 1 mol of compound (XVIII).
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1,2-dimethoxy, etc.). Ethane, tetrahydrofuran, etc.), nitriles (acetonitrile, etc.) or mixtures thereof.
The reaction temperature is usually about −10 to 80 ° C., preferably about 0 to 40 ° C., and the reaction time is usually about 1 to 48 hours, preferably about 8 to 24 hours.
In this step, additives may be added as necessary. Examples of such additives include inorganic salts (such as lithium chloride). The amount thereof to be used is, for example, about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (XVIII).

Compound (Ic) in which R ^5a is a hydrogen atom can also be produced using Method G.
[G method]

[In the formula, L ² represents a leaving group, and other symbols are as defined above. ]
Examples of the leaving group represented by L ² include a halogen atom (chlorine atom, bromine atom, iodine atom, etc.), acyloxy group (acetoxy group, trifluoroacetoxy group, trichloroacetoxy group, etc.), substituted sulfonyloxy group (methane). A sulfonyloxy group, a trifluoromethanesulfonyloxy group, a toluenesulfonyloxy group, etc.). Among them, a halogen atom such as a chlorine atom and a substituted sulfonyloxy group such as a trifluoromethanesulfonyloxy group are preferable.

(Step 13)
In this step, compound (XIX) is represented by the formula:

[Each symbol in the formula is as defined above. ]
Is a step of producing a compound (XX) by reacting with a compound represented by the formula (I) or a salt thereof, and a carbonyl-olefination reaction. The same applies to the type of solvent and base used, the amount used, the reaction temperature, and the reaction time.
When the compound (XIX) as a raw material is commercially available, a commercially available product can be used as it is, and the compound represented by the formula:

[In the formula, L ³ represents a leaving group, and other symbols are as defined above. ]
Is reacted with triethyl phosphite to produce compound (XIX), which can be carried out in the same manner as described in Method F, Step 11, The same applies to the solvent, reaction temperature and reaction time used in the above.
Examples of the leaving group represented by L ³ include halogen atoms (chlorine atom, bromine atom, iodine atom, etc.), acyloxy groups (acetoxy group, trifluoroacetoxy group, trichloroacetoxy group, etc.), substituted sulfonyloxy groups (methane). Sulfonyloxy groups, trifluoromethanesulfonyloxy groups, toluenesulfonyloxy groups, etc.), heterocycles or oxy groups substituted with aryl groups (succinimide, benzotriazole, 4-nitrophenyl, etc.), heterocycles (imidazole, etc.), etc. Is mentioned.

(Step 14)
This step is a step for producing compound (XXI) by reacting compound (XX) with hydrazine monohydrate.
The reaction of compound (XX) and hydrazine monohydrate can be carried out without solvent or in a solvent that does not affect the reaction.
The amount of hydrazine to be used is about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (XX).
Examples of the solvent used include alcohols (methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.) ), Ethers (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, etc.), aromatic amines (pyridine, etc.) or a mixture thereof.
The reaction temperature is usually about 50 to 150 ° C., preferably about 50 to 100 ° C., and the reaction time is usually about 5 minutes to 5 hours, preferably about 0.5 to 2 hours.

(Step 15)
This step includes compound (XXI) and the formula:
R ^1a —CO ₂ H (VIII)
[The symbols in the formula are as defined above. ]
Is a step of producing compound (XXII) by condensing a compound represented by the formula (1) or a reactive derivative thereof or a salt thereof, and can be carried out by the same method as described in Step 2 of Method A. The same applies to the types of solvents and bases used, the amount used, the reaction temperature and the reaction time.
Depending on the conditions, the 3-position carbonyl group of compound (XXI) may react with compound (VIII) to cause esterification. In such a case, after the above reaction, a solvent that does not adversely affect the reaction without solvent The compound (XXII) can be produced by reacting with a base.
Examples of the base include inorganic bases (potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc.), alkali metal alkoxides (sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc.) and the like. Can be mentioned. The amount of the base to be used is, for example, about 1 to 5 mol, preferably about 1 to 1.5 mol, per 1 mol of compound (XVIII).
Examples of the solvent used include alcohols (methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.) ), Ethers (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, etc.), nitriles (acetonitrile, etc.) or mixtures thereof.
The reaction temperature is usually about −10 to 80 ° C., preferably about 0 to 40 ° C., and the reaction time is usually about 1 to 48 hours, preferably about 8 to 24 hours.

(Step 16)
This step is a step for producing compound (XXIII) by converting compound (XXII) or a salt thereof into a reactive derivative.
Conversion to a reactive derivative can be performed according to a method known per se [eg, Synthetic Communications, 1987, Vol. 17, p. 1253, etc.].
For example, conversion to a halide is a method using phosphorus and a phosphoric acid halide (eg, phosphorus trichloride, phosphoryl chloride, etc.), and conversion to a triflate is a sulfonic anhydride (eg, trifluoromethanesulfonic acid). Anhydrides), sulfonyl halides (eg, trifluoromethanesulfonyl chloride, etc.), sulfonamides (eg, N-phenylbis (trifluoromethanesulfonimide), etc.), sulfonate esters (eg, ethyl trifluoromethanesulfonate) Etc.) and the like. The amount thereof to be used is, for example, about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (XXII).
The above reaction varies depending on the type of reactive derivative or substrate, but is usually carried out in the absence of a solvent or in a solvent that does not adversely influence the reaction. Conversion to a triflate can be carried out in the presence of a base.
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, dichloromethane, 1,2-dichloroethane, etc.), ethers (diethyl ether, 1,2-dimethoxy, etc.). Ethane, tetrahydrofuran, etc.) or a mixture thereof.
The reaction temperature is usually about −10 to 80 ° C., preferably about 0 to 40 ° C., and the reaction time is usually about 1 to 48 hours, preferably about 8 to 24 hours.
Examples of the base used include organic amines (trimethylamine, triethylamine, diisopropylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, N, N-dimethyl. Aniline, etc.), alkali metal salts (sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides (potassium hydride, sodium hydride, etc.), etc. Can be mentioned. The amount of the base to be used is about 0.1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound (XXII).

(Step 17)
In this step, compound (XXIII) or a salt thereof is represented by the formula:

[The symbols in the formula are as defined above. ]
Is a step of producing compound (Ic) by subjecting it to a coupling reaction with a compound represented by the formula:
This step can be performed according to a method known per se [eg, Chemical Reviews, 1995, Vol. 95, p. 2457], for example, in the presence of a transition metal catalyst and a base, in the absence of a solvent, or in the reaction. It can be carried out in a solvent that does not adversely affect.
As the transition metal catalyst to be used, for example, a palladium catalyst (palladium acetate, palladium chloride, tetrakistriphenylphosphine palladium, etc.), a nickel catalyst (nickel chloride, etc.), etc. are used, and a ligand (triphenylphosphine, Tri-t-butylphosphine) or a metal oxide (copper oxide, silver oxide, etc.) may be used as a cocatalyst. The amount of the catalyst used varies depending on the type of the catalyst, but is usually about 0.0001 to 1 mol, preferably about 0.01 to 0.5 mol, based on 1 mol of compound (XXIII). Is usually about 0.0001 to 4 mol, preferably about 0.01 to 2 mol, per 1 mol of compound (XXIII), and the amount of cocatalyst used is 1 mol of compound (XXIII). The amount is about 0.0001 to 4 mol, preferably about 0.01 to 2 mol.
Examples of the base used include organic amines (trimethylamine, triethylamine, diisopropylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, N, N-dimethyl. Aniline, etc.), alkali metal salts (sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrides (potassium hydride) Sodium hydride), alkali metal alkoxide (sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide, etc.), alkali disilazide (lithium disilazide, sodium disilazide, potassium disulfide) Shirazide etc.) Etc., and the like. Among them, alkali metal salts such as potassium carbonate, cesium carbonate, sodium phosphate and potassium phosphate, alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide, organic amines such as triethylamine and diisopropylamine, etc. Is preferred. The amount of the base to be used is about 0.1-10 mol, preferably about 1-5 mol, per 1 mol of compound (XXIII).
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.), nitriles (acetonitrile, etc.), ethers (dimethoxyethane, Tetrahydrofuran), alcohols (methanol, ethanol, etc.), aprotic polar solvents (N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.), water or a mixture thereof.
The reaction temperature is usually about −10 to 200 ° C., preferably about 0 to 150 ° C., and the reaction time is usually about 0.5 to 48 hours, preferably about 0.5 to 16 hours. .

[Method H]

[Each symbol in the formula is as defined above. ]

(Step 18)
In this step, compound (XXVII) is represented by the formula:
R ^2a —CO ₂ H (V)
[Each symbol in the formula is as defined above. ]
Wherein the compound (XXVIII) is produced by condensation with a compound represented by the formula:
This step can be performed according to a method known per se [eg, Bioorganic & Medicinal Chemistry Letters, 2006, Vol. 16, p. 2920, etc.], and can be performed by the same method as described in Method A, Step 2. The kind of the solvent and base used in the reaction, the amount used, the reaction temperature and the reaction time are the same.

(Step 19)
This step is performed by converting the compound (XXVIII) into the formula:
R ^4a -L ⁴ and R ^5a -L ⁴ (XXXI)
[In the formula, L ⁴ represents a leaving group, and other symbols are as defined above. ]
Compound (XXIX) can be produced by reacting the compound represented by: or a salt thereof.
Examples of the leaving group represented by L ⁴ include a halogen atom (chlorine atom, bromine atom, iodine atom, etc.), acyloxy group (acetoxy group, trifluoroacetoxy group, trichloroacetoxy group, etc.), substituted sulfonyloxy group (methane). Sulfonyloxy groups, trifluoromethanesulfonyloxy groups, toluenesulfonyloxy groups, etc.), heterocycles or oxy groups substituted with aryl groups (succinimide, benzotriazole, 4-nitrophenyl, etc.), heterocycles (imidazole, etc.), etc. Is mentioned. Of these, a halogen atom such as a bromine atom is preferred.
This step can be performed according to a method known per se [eg, Synthesis, 1995, p. 1163, etc.], for example, in the presence of a base, in the absence of a solvent, or in a solvent that does not affect the reaction.
The amount of compound (XXXI) to be used is, for example, about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound (XXVIII).
Examples of the base used include alkali metal salts (sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, etc.), metal hydrogen Chloride (potassium hydride, sodium hydride, etc.), alkali metal alkoxide (sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide, etc.), alkali disilazide (lithium disilazide, sodium disulfide) Silazide, potassium disilazide, etc.). Of these, alkali metal salts such as potassium carbonate, cesium carbonate, sodium phosphate and potassium phosphate, and alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide are preferable. The amount of the base to be used is, for example, about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound (XXVIII).
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (chloroform, 1,2-dichloroethane, etc.), ethers (dimethoxyethane, tetrahydrofuran), alcohols (methanol) , Ethanol, etc.), aprotic polar solvents (N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.) or mixtures thereof.
The reaction temperature is usually about −10 to 100 ° C., preferably about 0 to 80 ° C., and the reaction time is usually about 5 to 72 hours, preferably about 12 to 48 hours.

(Step 20)
This step is a step of producing compound (XXX) by reacting compound (XXIX) with hydrazine monohydrate, and can be carried out by the same method as described in Step 14 of Method G. The same applies to the solvent used in the reaction, the reaction temperature, and the reaction time.

(Step 21)
This step includes compound (XXX) and the formula:
R ^1a —CO ₂ H (VIII)
[The symbols in the formula are as defined above. ]
Is a step of producing compound (Ia) by condensing a compound represented by the above or a reactive derivative thereof or a salt thereof, and can be carried out by a method similar to the method described in Step A of Method A. The same applies to the types of solvents and bases used, the amount used, the reaction temperature, and the reaction time.

Among compounds (Ia), compound (Id) in which R ^1a is —X ^1a NR ^8a R ^9a can be produced using Method I.
[Method I]

[Wherein, X ^3a represents a group in which X ^1a becomes X ^3a -CH ₂ , R ^8a and R ^9a are the same or different, each represents a substituent, and other symbols are as defined above. ]

(Step 22)
This step is a step of producing compound (XXXIII) by subjecting compound (XXXII) to an oxidation reaction.
The starting compound (XXXII) or a salt thereof can be produced by using the above-mentioned method A, method B, method G, method H or method I.
This step can be performed according to a method known per se, and examples thereof include a method by PCC oxidation, swan oxidation, MnO ₂ oxidation, and Dess-Martin oxidation.
For example, Dess-Martin oxidation can be performed using a Dess-Martin reagent in the absence of a solvent or in a solvent that does not affect the reaction.
The amount of the Dess-Martin reagent to be used is, for example, about 1 to 10 mol, preferably about 2 to 4 mol, per 1 mol of compound (XXXII).
Examples of the solvent used include hydrocarbons (such as trifluorobenzene), halogenated hydrocarbons (such as chloroform, dichloromethane, 1,2-dichloroethane), nitriles (such as acetonitrile), and aprotic polar solvents (such as Dimethyl sulfoxide) or a mixture thereof.
The reaction temperature is usually about −40 to 40 ° C., preferably about −10 to 0 ° C., and the reaction time is usually about 0.5 to 12 hours, preferably about 1 to 2 hours.

(Step 23)
In this step, compound (XXXIII) is represented by the formula:
^{R 8a -NH-R 9a (XXXIV} )
[Each symbol in the formula is as defined above. ]
The compound (Id) is produced by reacting with a compound represented by the formula (I) or a salt thereof and subjecting the produced imine or iminium ion to a reduction reaction.
The reaction for producing imine or iminium ions is usually carried out in the absence of a solvent or in a solvent that does not adversely influence the reaction.
The amount of compound (XXXIV) to be used is, for example, about 1 to 10 mol, preferably about 1 to 2 mol, per 1 mol of compound (XXXIII).
Examples of the solvent to be used include aromatic hydrocarbons (toluene, xylene, etc.), aliphatic hydrocarbons (heptane, hexane, etc.), halogenated hydrocarbons (chloroform, dichloromethane, etc.), ethers (diethyl ether). , Tetrahydrofuran, dioxane, etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol, etc.), nitriles (acetonitrile, etc.), amides (N, N-dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.) ) Or a mixture thereof.
If necessary, the reaction can be advantageously advanced by adding a catalyst. Examples of such catalysts include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), carboxylic acids (formic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), sulfonic acids (methanesulfonic acid, p-toluenesulfone, etc.). Acid), Lewis acids (aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride, etc.), acetates (sodium acetate, potassium acetate, etc.), molecular sieves (molecular sieves 3A, 4A, 5A, etc.) Is mentioned. The amount of the catalyst to be used is, for example, about 0.01 to 50 mol, preferably about 0.1 to 10 mol, per 1 mol of compound (XXXIII).
The reaction temperature is usually about 0 to 200 ° C., preferably about 20 to 150 ° C., and the reaction time is usually about 0.5 to 48 hours, preferably about 0.5 to 24 hours.
The reduction reaction of imine or iminium ion can be performed by a method known per se, and examples thereof include a method using a reducing agent and a method using a catalytic hydrogenation reaction.
Examples of the reducing agent include metal hydrides (sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, dibutylaluminum hydride, Aluminum hydride, lithium aluminum hydride, etc.) and borane complexes (borane-tetrahydrofuran complex, catecholborane, etc.). Preferred reducing agents are sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The amount of the reducing agent to be used is, for example, about 1 to 50 mol, preferably about 1 to 10 mol, per 1 mol of compound (XXXIII).
Examples of the solvent to be used include aromatic hydrocarbons (toluene, xylene, etc.), aliphatic hydrocarbons (heptane, hexane, etc.), halogenated hydrocarbons (chloroform, dichloromethane, etc.), ethers (diethyl ether). , Tetrahydrofuran, dioxane, etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol, etc.), nitriles (acetonitrile, etc.), amides (N, N-dimethylformamide, etc.), sulfoxides (dimethyl sulfoxide, etc.) ) Or a mixture thereof.
The reaction temperature is usually about −80 to 80 ° C., preferably about −40 to 40 ° C., and the reaction time is usually about 5 minutes to 48 hours, preferably about 1 to 24 hours.
The catalytic hydrogenation reaction can be usually performed in a solvent that does not affect the reaction, in a hydrogen atmosphere, and in the presence of a catalyst. Examples of the catalyst used include palladium (palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (Raney nickel, etc.), platinum (platinum oxide, platinum carbon, etc.), rhodium (rhodium acetate, etc.), etc. The amount of the catalyst used is about 0.001-1, preferably about 0.01-0.5.
Examples of the solvent used include alcohols (methanol, ethanol, propanol, butanol, etc.), hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl) Ether, dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, etc.), amides (N, N-dimethylformamide, etc.), carboxylic acids (acetic acid, etc.), water, or a mixture thereof.
The hydrogen pressure at which the reaction is carried out is usually about 1-50 atm, preferably about 1-10 atm.
The reaction temperature is usually about 0 to 150 ° C., preferably about 20 to 100 ° C., and the reaction time is usually about 5 minutes to 72 hours, preferably about 0.5 to 40 hours.
In this step, the compound (Id) may be obtained directly from the compound (XXXIII) by simultaneously performing the above-described imine or iminium ion formation reaction and reduction reaction without isolating the intermediate imine or iminium ion. I can do it. In this case, the pH of the reaction mixture is preferably about 4-5.

Among compounds (Ia), compound (Id) in which R ^1a is —X ^1a NR ^8a R ^9a can also be produced using Method J.
[J method]

[Wherein L ⁵ represents a leaving group, and other symbols are as defined above. ]
As the leaving group for L ⁵ , for example, a halogen atom (a chlorine atom, a bromine atom, an iodine atom, etc.), a substituted sulfonyloxy group (a C _1-6 alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, etc.); C _6-14 arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy; C _7-16 aralkylsulfonyloxy groups such as benzylsulfonyloxy), acyloxy groups (acetoxy, benzoyloxy, etc.), heterocycles or aryl Examples thereof include a hydroxy group substituted with a group (succinimide, benzotriazolyl, quinolyl, 4-nitrophenyl, etc.), a heterocyclic group (imidazole, etc.) and the like.

(Step 24)
In this step, compound (XXXV) is represented by the formula:
^{R 8a -NH-R 9a (XXXIV} )
[Each symbol in the formula is as defined above. ]
Wherein the compound (Id) is produced by reacting with a compound represented by the formula:
The starting compound (XXXV) or a salt thereof can be produced by using the above-mentioned method A, method B, method G, method H or method I.
The reaction can be usually carried out by reacting compound (XXXV) with compound (XXXIV) in the presence of a base, in the absence of a solvent, or in a solvent that does not affect the reaction.
The amount of compound (XXXIV) to be used is, for example, about 1 to 10 mol, preferably about 1 to 2 mol, per 1 mol of compound (XXXV).
Examples of the solvent used include alcohols (methanol, ethanol, propanol, etc.), ethers (dimethoxyethane, dioxane, tetrahydrofuran, etc.), ketones (acetone, etc.), nitriles (acetonitrile, etc.), amides (N , N-dimethylformamide, etc.), sulfoxides (dimethylsulfoxide, etc.), water, etc., may be used as appropriate.
Examples of the base used include organic bases (trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, etc.), inorganic bases (potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide). Etc.). The amount of the base to be used is, for example, about 1 to about 100 mol, preferably about 1 to about 10 mol, per 1 mol of compound (XXXV).
In this step, if necessary, additives can be added to promote the reaction. Examples of such additives include iodide salts (sodium iodide, potassium iodide, etc.), and the amount used is about 0.1 to 10 mol, preferably about 1 to 10 mol, relative to 1 mol of compound (XXXV). Is about 0.1 to 5 moles.
The reaction temperature is usually about −10 to 200 ° C., preferably about 0 to 110 ° C., and the reaction time is usually about 0.5 to 48 hours, preferably about 0.5 to 16 hours. It is.

Among compounds (Ia), compound (Ie) in which R ^1a is —X ^1a OR ^8a can be produced using the K method.
[K method]

[Each symbol in the formula is as defined above. ]

(Step 25)
In this step, compound (XXXII) is represented by the formula:
R ^8a -OH (XXXVI)
[Each symbol in the formula is as defined above. ]
In which compound (Ie) is produced by condensation with a compound represented by the formula:
This step can be performed according to a method known per se, and examples thereof include a method by Mitsunobu reaction and a dehydration reaction under an acid catalyst.
For example, the Mitsunobu reaction can be usually carried out by reacting compound (XXXII) with compound (XXXVI) in the absence of a solvent or in the presence of an azodicarboxylic acid ester and phosphine in a solvent that does not affect the reaction.
The amount of compound (XXXVI) to be used is, for example, about 1 to 10 mol, preferably about 1 to 2 mol, per 1 mol of compound (XXXII).
Examples of the solvent used include hydrocarbons (benzene, toluene, xylene, etc.), ethers (dimethoxyethane, dioxane, tetrahydrofuran, etc.), nitriles (acetonitrile, etc.), water, etc. May be used.
Examples of the azodicarboxylic acid ester used include dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butyl azodicarboxylate, 1,1 ′-(azodicarbonyl). ) Dipiperidine and the like are included. Examples of phosphine include triphenylphosphine, tricyclohexylphosphine, and tributylphosphine. The amount of the azodicarboxylic acid ester to be used is, for example, about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (XXXII).
The amount of phosphine to be used is, for example, about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound (XXXII).
The reaction temperature is usually about −10 ° C. to 100 ° C., preferably about 0 ° C. to 40 ° C., and the reaction time is usually about 0.5 hour to 48 hours, preferably about 1 hour to 24 hours. It is.

Among compounds (Ia), compound (Ie) in which R ^1a is —X ^1a OR ^8a can also be produced using Method L.
[L method]

[Each symbol in the formula is as defined above. ]

(Step 26)
This step is carried out by reacting compound (XXXV) with the formula R ^8a -OH (XXXVI)
[Each symbol in the formula is as defined above. ]
The compound (Ie) is produced by subjecting it to a substitution reaction with a compound represented by the formula:
The amount of compound (XXXVI) to be used is, for example, about 1 to 10 mol, preferably about 1 to 2 mol, per 1 mol of compound (XXXV). The same applies to the type of solvent and base used in the reaction, the amount used, the reaction temperature, and the reaction time.

  In each reaction of the target compound and raw material synthesis, when the raw material compound has an amino group, a carboxyl group, or a hydroxy group as a substituent, these groups are protected with a protecting group that is generally used in peptide chemistry or the like. It may be. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of such protecting groups, e.g., Wiley-Interscience Co. 1999 annual ^{"ProtectiveGroups in Organic Synthesis, 3 rd Ed} . " (Theodora W. Greene, Peter GM Wuts Author) include those described in.

Examples of amino-protecting groups include formyl group, C _1-6 alkyl-carbonyl group (acetyl, propionyl group, etc.), phenylcarbonyl group, C _1-6 alkyl-oxycarbonyl group (methoxycarbonyl, ethoxycarbonyl group, etc.). ), Aryloxycarbonyl groups (such as phenyloxycarbonyl groups), C _7-10 aralkyl-carbonyl groups (such as benzyloxycarbonyl groups), benzyl groups, benzhydryl groups, trityl groups, phthaloyl groups, etc., and these protecting groups May have a substituent. Examples of these substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms, etc.), C _1-6 alkyl-carbonyl groups (acetyl, propionyl, butylcarbonyl groups, etc.), nitro groups, etc. The number of groups is about 1-3.

Examples of the protecting group for the carboxyl group include a C _1-6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl group, etc.), phenyl group, trityl group, silyl group and the like. These protective groups may have a substituent. Examples of these substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms, etc.), formyl groups, C _1-6 alkyl-carbonyl groups (acetyl, propionyl, butylcarbonyl groups, etc.), nitro groups and the like. The number of substituents is about 1 to 3.

Examples of the protective group for the hydroxy group include a C _1-6 alkyl group (methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl group, etc.), a phenyl group, a C _7-10 aralkyl group (benzyl group). Etc.), formyl group, C _1-6 alkyl-carbonyl group (acetyl, propionyl group etc.), aryloxycarbonyl group (phenyloxycarbonyl group etc.), C _7-10 aralkyl-carbonyl group (benzyloxycarbonyl group etc.), A pyranyl group, a furanyl group, a silyl group, etc. are mentioned, These protecting groups may have a substituent. Examples of these substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms, etc.), C _1-6 alkyl groups, phenyl groups, C _7-10 aralkyl groups, nitro groups, and the like. The number is about 1 to 4.

Removal of the protecting groups, known or Wiley-Interscience, 1999, ^{"Protective Groups in Organic Synthesis, 3 rd} Ed. " (Theodora W. Greene, Peter GM Wuts Author) methods are described in, for example, or by methods analogous thereto It can be carried out. For example, a method of treating with acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like can be used.

  When compound (Ia) is obtained as a free compound in the above method, according to a conventional method, for example, inorganic acid (hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acid (methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid) , Oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium) or organic bases (trimethylamine, triethylamine, pyridine, A salt with picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine etc.) can also be formed, and when compound (Ia) is obtained in the form of a salt, Free according to law It is also possible to convert compound or another salt.

  In each of the reactions described above, when the starting compound can form a salt, the compound may be used as a salt. As such salt, for example, those exemplified as the salt of compound (Ia) are used.

  The compound (Ia) of the present invention produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.

  When compound (Ia) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (Ia), and synthetic methods and separation methods (concentration) known per se. , Solvent extraction, column chromatography, recrystallization, etc.), each can be obtained as a single product. For example, when compound (Ia) has an optical isomer, an optical isomer resolved from the compound is also encompassed in compound (Ia).

  The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.

  As the optical resolution method, a method known per se, for example, fractional recrystallization method, chiral column method, diastereomer method and the like are used.

1) Fractional recrystallization method Racemate and optically active compound (for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, (−)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.) to form a salt, which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step. Method.

2) Chiral column method A method in which a racemate or a salt thereof is separated by applying to a column for optical isomer separation (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), and water, various buffer solutions (phosphate buffer solution, etc.), organic Optical isomers are separated by developing a solvent (ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) as a single or mixed solution. Further, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science).

3) Diastereomer method The racemic mixture is made into a diastereomer mixture by chemical reaction with an optically active reagent, and this is made into a single substance through normal separation means (fractional recrystallization, chromatography method, etc.). Thereafter, an optical isomer is obtained by separating an optically active reagent site by chemical treatment such as hydrolysis. For example, when the compound (Ia) has a hydroxy group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid etc.], (−)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when the compound (Ia) has a carboxylic acid group, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.

Compound (Ia) or a salt thereof may be a crystal.
A crystal of compound (Ia) or a salt thereof (hereinafter sometimes abbreviated as a crystal of the present invention) is produced by crystallization by applying a crystallization method known per se to compound (Ia) or a salt thereof. can do.
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, and a crystallization method from a melt.

  The “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent. In general, there are methods for shifting from a supersaturated state to a supersaturated state. Specific examples include a concentration method, a cooling method, a reaction method (diffusion method, electrolysis method, etc.), a hydrothermal growth method, and a flux method. Examples of the solvent used include aromatic hydrocarbons (benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), saturated hydrocarbons (hexane, heptane, cyclohexane, etc.), ethers, etc. (Diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (acetonitrile, etc.), ketones (acetone, etc.), sulfoxides (dimethyl sulfoxide, etc.), amides (N, N-dimethylformamide, etc.), esters ( Ethyl acetate etc.), alcohols (methanol, ethanol, isopropyl alcohol etc.), water, etc. are used. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)).

Examples of the “crystallization method from vapor” include vaporization methods (sealed tube method, air flow method, etc.), gas phase reaction methods, chemical transport methods, and the like.
Examples of the “crystallization from a melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method, etc.), zone melting method (zone leveling method, float zone method, etc.), special growth method ( VLS method, liquid phase epitaxy method, etc.).
As a preferred example of the crystallization method, compound (Ia) or a salt thereof is dissolved in an appropriate solvent (alcohol such as methanol or ethanol) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved. The method etc. which cool to below the temperature (for example, 0-50 degreeC, Preferably it is 0-20 degreeC) etc. are mentioned.

  The crystals of the present invention thus obtained can be isolated by, for example, filtration.

In the present specification, the melting point means a melting point measured using, for example, a trace melting point measuring device (Yanako, MP-500D type) or a DSC (Differential Scanning Calorimetry) apparatus (SEIKO, EXSTAR6000).
Moreover, in this specification, the peak by powder X-ray diffraction is measured, for example, using a Cu-Kα1 line (tube voltage: 40 KV; tube current: 50 mA) as a radiation source and using a RINT2100 type (Rigaku Denki) or the like. Means a peak.
In general, the melting point and the peak due to powder X-ray diffraction may vary depending on the measuring instrument, measurement conditions, and the like. The crystal in the present specification may be a crystal having a value different from the melting point or the peak by powder X-ray diffraction described in the present specification as long as it is within a normal error range.

  The crystals of the present invention are excellent in physicochemical properties (melting point, solubility, stability, etc.) and biological properties (pharmacokinetics (absorption, distribution, metabolism, excretion), drug efficacy, etc.), and are extremely useful as pharmaceuticals. is there.

  Compound (Ia) may be used as a prodrug. The prodrug of compound (Ia) is a compound that is converted to compound (Ia) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, compound (Ia) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (Ia) upon hydrolysis or the like by gastric acid or the like.

As a prodrug of compound (Ia), for example,
(1) Compound (Ia) in which amino is acylated, alkylated or phosphorylated (for example, compound (Ia) in which amino is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2- Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropylcarbonylated compounds, etc.);
(2) Compound in which hydroxy of compound (Ia) is acylated, alkylated, phosphorylated, borated (eg, hydroxy of compound (Ia) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated , Fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.);
(3) A compound in which carboxy of compound (Ia) is esterified or amidated (for example, carboxy of compound (Ia) is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, Valoyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamide Compound etc.);
Etc. These compounds can be produced from compound (Ia) by a method known per se.

  The prodrug of compound (Ia) is a compound that changes to compound (Ia) under physiological conditions as described in Hirokawa Shoten 1990 "Drug Development", Volume 7, Molecular Design, pages 163 to 198. There may be.

  In the present specification, compound (Ia), compound (I), and prodrugs thereof may be collectively abbreviated as “the compound of the present invention”.

  When compound (Ia) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., any one of the isomers and a mixture are encompassed in compound (Ia). For example, when compound (Ia) has an optical isomer, the optical isomer resolved from the racemate is also encompassed in compound (Ia). Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).

Compound (Ia) may be in the form of a crystal, and is included in compound (Ia) regardless of whether the crystal form is single or a mixture of crystal forms. The crystal can be produced by crystallization by applying a crystallization method known per se.
Compound (Ia) may be any of hydrate, non-hydrate, solvate and solvate.
A compound labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) is also encompassed in compound (Ia).
Furthermore, a deuterium converter obtained by converting ¹ H into ² H (D) is also encompassed in compound (Ia).

  The compound of the present invention has low toxicity and is used as it is or mixed with a pharmacologically acceptable carrier to make a pharmaceutical composition, so that a mammal (eg, human, mouse, rat, rabbit, dog, cat, Cattle, horses, pigs, monkeys) can be used as preventive or therapeutic agents for various diseases described below.

  Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.

  Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Examples thereof include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.

  Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.

  Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.

  Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

  Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

  Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.

  Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.

  Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
A preferred example of the soothing agent is benzyl alcohol.

Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
Preferable examples of the antioxidant include sulfite and ascorbate.

  Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (E.g., the aluminum salt of the water-soluble edible tar dye) and natural dyes (e.g., [beta] -carotene, chlorophyll, bengara).

  Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and lozenges. Oral preparations such as syrup, emulsion, suspension, film (eg, orally disintegrating film); and injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, Intravenous preparations, external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops Oral preparations are mentioned.
These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration).

  These preparations may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations.

  The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.

  The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.

  When producing an oral preparation, it may be coated for the purpose of taste masking, enteric properties or sustainability, if necessary.

  Examples of the coating base used for coating include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained-release film coating base.

  As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

  Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.

  Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ], Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], and natural products such as shellac.

  Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].

  Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.

  The compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats) can be used as preventive or therapeutic agents for various diseases or as diagnostic agents.

  Since the compound of the present invention has an excellent calcium receptor antagonistic action and enhances the secretion of PTH, it is used as a therapeutic agent for bone diseases, a renal action drug, a central nervous system and endocrine action drug, a digestive system action drug, etc. Useful.

Specifically, the compound of the present invention is useful for the prevention or treatment of bone diseases involving hyperactivity of calcium receptors, such as osteoporosis and fractures.
Among them, the compound of the present invention is useful as an agent for preventing / treating osteoporosis or fracture.

The compound of the present invention can be used in the active phase of ADFR (Active-Depress-Free-Repeat) therapy.
Here, ADFR therapy is a rest period in bone remodeling → active period → resorption period → reversal period → formation period, in the short period of rest period,
1) stimulate bone resorption (Active),
2) Depress bone resorption by emerging osteoclasts (Depress)
3) Release bone formation activity by osteoblasts from inhibition and promote bone formation (Free)
4) Repeat this,
It means a therapy that expects an increase in new bone.

  The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom and the like. For example, when administered orally to an adult bone disease patient, the dose is usually about 0.01 to 100 mg / kg. The body weight is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

  The compound of the present invention can be used in combination with another drug (hereinafter abbreviated as “concomitant drug”) for the purpose of enhancing the action of the compound or reducing the dose of the compound. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

Specific examples of concomitant drugs include the following:
(1) Diabetes therapeutic agent Insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli or yeast; insulin zinc; protamine insulin zinc; insulin fragments Or derivative (eg, INS-1), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), TAK-379, rosiglitazone or a salt thereof (preferably maleate) , Tesaglitazar, Ragaglitazar, Muraglitazar, Edaglitazone, Metaglidasen, Naveglitazar, AMG-131, THR-0921, α-glucosidase, α-glucosidase , Acarbose, miglito , Emiglitate), biguanide (eg, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinate)), insulin secretagogue [sulfonylsulfonyl (eg, tolbutamide, glibenclamide, gliclazide, chlor) Propamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybsol), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate, glucose-dependent insulin secretagogue (eg, TAK-875)], dipeptidyl Peptidase IV inhibitor (eg, alogliptin, vildagliptin, sitagliptin, saxagliptin, T-6666, TS-021), β3 agonist (eg, AJ-9677), GPR40 agonist , GLP-1 receptor agonist [eg, GLP-1, GLP-1 MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH _2, CJC-1131], amylin agonists (e.g., pramlintide), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate), gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists Agents), SGLUT (sodium-glucose cotransporter) inhibitors (eg, T-1095), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868) ), Leptin resistance improving drug, somatostatin receptor agonist, glucokinase activator (eg, Ro-28-1675), GIP (Glucose-dependent insulinotropic peptide) and the like.
(2) Treatment for diabetic complications aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minarerestat, fidarestat, CT-112), neurotrophic factors and their increasing drugs (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2 -Methylphenoxy) propyl] oxazole)), TAK-583, nerve regeneration promoter (eg, Y-128), PKC inhibitor (eg, ruboxistaurin mesylate), AGE inhibitor (eg, ALT946) , Pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridoline (Pyridorin), pyridoxamine), active oxygen scavenger (eg, thioctic acid), cerebral vasodilator (Eg, tiapride, mexiletine), somatostatin receptor agonist (eg, BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitor, and the like.
(3) Antihyperlipidemic agent Statin compounds (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, calcium salt)), squalene synthetase inhibitor ( E.g., lapaquistat acetate or salt thereof), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (e.g., Avasimibe, eflucimibe), Anion exchange resins (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol), ethyl icosapentate, plant sterols (eg, soysterol), cancer Oryzanol (γ-oryzanol)) and the like.
(4) Antihypertensive agent Angiotensin converting enzyme inhibitor (eg, captopril, enalapril, delapril), angiotensin II antagonist (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2'- (2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid, TAK-491), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, levcromakalim, L-27152, AL 0671, NIP-121), clonidine and the like.
(5) Anti-obesity drugs Central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex; MCH receptor antagonist ( Example, SB-568849; SNAP-7941; compounds described in WO01 / 82925 and WO01 / 87834); neuropeptide Y antagonist (eg, CP-422935); cannabinoid receptor antagonist (eg, SR-141716, SR- 147778); ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498)), pancreatic lipase inhibitor (eg, orlistat, cetiristat), β3 agonist (eg, AJ-9677, AZ40140), peptide Anorectic agents (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (eg, lynchtripto) FPL-15849), anorexigenic agents (e.g., P-57) or the like.

(6) Diuretics Xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentfurizide, polythiazide, methiclo Thiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, Bumetanide, furosemide, etc.
(7) antithrombotic agents heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drugs (eg, argatroban, dabigatran), Thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride) , Cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, E5555, SHC 530348, prasugrel), FXa inhibitors (eg, TAK-442, rivaroxaban (rive aroxaban), apixaban, DU-176b, YM150) and the like.
(8) Chemotherapeutic agents Alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil derivatives (eg, furtulon, neoflutulon)), anticancer antibiotics (eg, Mitomycin, adriamycin), plant-derived anticancer agents (eg, vincristine, vindesine, taxol), cisplatin, carboplatin, etopoxide and the like.
(9) Immunotherapeutic agents Microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), immunopotentiating polysaccharides (eg, lentinan, schizophyllan, krestin), cytokines obtained by genetic engineering techniques (eg, interferon) Interleukin (IL) (eg, IL-1, IL-2, IL-12)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin) and the like.

(10) Drugs that have been shown to improve cachexia in animal models and clinically Progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225 Page, 1994], metoclopramide drugs, tetrahydrocannabinol drugs (the literature is the same as above), fat metabolism improving agents (eg, eicosapentaenoic acid) [British Journal of Cancer, Vol. 68, pp.314- 318, 1993], antibodies to growth hormone, IGF-1, or cachexia-inducing factors such as TNF-α, LIF, IL-6, and oncostatin M.

(11) Anti-inflammatory agents Steroids (eg, dexamethasone), sodium hyaluronate, cyclooxygenase inhibitors (eg, indomethacin, ketoprofen, loxoprofen, meloxicam, ampiroxicam, celecoxib, rofecoxib) and the like.
(12) Agents for preventing and treating climacteric disorders Estrogen, selective estrogen receptor modulators (SERM) (eg, raloxifene) and the like.
(13) Bone resorption inhibitor Estrogen, Selective Estrogen Receptor Modulators (SERM) (eg, raloxifene), RANKL inhibitor (eg, AMG-162), calcitonin, active vitamin D3, vitamin K2 , Isoflavone preparations (eg, irruriflavone), vitronectin receptor antagonists, VH + -ATPase inhibitors, Src kinase inhibitors, cathepsin K inhibitors (eg, AAE581, 462795), bisphosphonic acid and the like.
(14) Osteogenesis promoter PTH preparation, strontium, etc.
(15) Calcium preparation (16) LH-RH analog Leuplin and the like.

(17) Others Glycation inhibitors (eg, ALT-711), nerve regeneration promoters (eg, Y-128, VX853, prosaptide), central nervous system agonists (eg, desipramine, amitriptyline, imipramine, floxetine, paroxetine, doxepin) , Antidepressants such as duloxetine and venlafaxine), antiepileptic drugs (eg, lamotrigine, carbamazepine, gabapentin), antiarrhythmic drugs (eg, mexiletine), acetylcholine receptor ligands (eg, ABT-594), endothelin receptors Antagonists (eg, ABT-627), monoamine uptake inhibitors (eg, tramadol), indoleamine uptake inhibitors (eg, floxetine, paroxetine), narcotic analgesics (eg, morphine), non-narcotic analgesics (eg, , Buprenorphine, axomadol), GABA receptor agonist, G ABA uptake inhibitors (eg, tiagabine), α ₂ receptor agonists (eg, clonidine), local analgesics (eg, capsaicin), protein kinase C inhibitors (eg, LY-333531), anxiolytics (eg, Benzodiazepines), phosphodiesterase inhibitors (eg, sildenafil), dopamine receptor agonists (eg, apomorphine), dopamine receptor antagonists (eg, haloperidol), serotonin receptor agonists (eg, tandospirone citrate, sumatriptan, Tegaserod), serotonin receptor antagonists (eg, cyproheptadine hydrochloride, ondansetron), serotonin uptake inhibitors (eg, fluvoxamine maleate, floxetine, paroxetine), sleep inducers (eg, triazolam, zolpidem), anticholinergics ( E.g. atropine, scopolamine), α ₁ receptor blockers (eg, tamsulosin, urapidil, naphthopidyl), muscle relaxants (eg, baclofen), potassium channel openers (eg, nicorandil), calcium channel blockers (eg, nifedipine), chloride channel openers ( Eg, rubiprostone), Alzheimer's disease preventive / therapeutic (eg, donepezil, rivastigmine, galantamine), Parkinson's disease (eg, L-dopa), multiple sclerosis preventive / therapeutic (eg, interferon β-1a), Histamine H ₁ receptor inhibitors (eg, promethazine hydrochloride), proton pump inhibitors (eg, lansoprazole, omeprazole), antithrombotic agents (eg, aspirin, cilostazol), NK-2 receptor antagonists (eg, GR159897, GR1499861, SR48968 (saredutant)) NK-3 receptor antagonist (eg, talnetant), treatment for HIV infection (saquinavir, zidovudine, lamivudine, nevirabine), treatment for chronic obstructive pulmonary disease (salmeterol, tiotropium bromide, silomilast), diuretic (eg, furosemide) Antidiuretics (eg, vasopressin V2 receptor agonists), aromatase inhibitors (eg, fadrozole hydrochloride, anastrozole, letrozole, exemestane, borozole, formestane) and the like.

  Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.

  The combination drug of the present invention is preferably a climacteric disorder preventive / therapeutic agent, bone resorption inhibitor, bone resorption promoter, calcium preparation, LH-RH analog, etc., among which bone resorption inhibitors (estrogens, selective estrogen receptors) Regulators (Selective Estrogen Receptor Modulators, SERM) (eg, raloxifene, etc.), RANKL inhibitors (eg, AMG-162, etc.), calcitonin, active vitamin D3, vitamin K2, isoflavone preparations (eg, irigliflavone), vitronectin Receptor antagonists, VH + -ATPase inhibitors, Src kinase inhibitors, cathepsin K inhibitors (eg, AAE581, 462795, etc.)) are preferred.

Hereinafter, the present invention will be described in more detail based on Reference Examples, Examples, Formulation Examples, and Test Examples, but the present invention is not limited to the Examples and is within a range not departing from the scope of the present invention. It may be changed.
Elution in column chromatography of Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, Merck 60F254 was used as a TLC plate, and the solvent used as an elution solvent in column chromatography was used as a developing solvent. A UV detector was used for detection. As silica gel for column chromatography, silica gel 60 (70-230 mesh) manufactured by Merck was used, and Chromatorex NH DM1020 (trade name) manufactured by Fuji Silysia Chemical was used as NH silica gel. Room temperature usually means a temperature of about 10 ° C to 35 ° C. Furthermore, anhydrous sodium sulfate or anhydrous magnesium sulfate was used for drying the extract.

The meanings of the abbreviations in Examples and Reference Examples are as follows.
LC: Liquid chromatography MS: Mass spectrometry spectrum ESI: Electrospray ionization method M: Molecular ion peak NMR: Nuclear magnetic resonance spectrum Hz: Hertz J: Coupling constant m: Multiplet quin: Quintet q: Quartet t: Triplet d: Doublet s: Singlet br: Broad
^t Bu: tert-butyl group, t-butyl group Boc: tert-butoxycarbonyl Rf: retardation factor Rt: retention time N: specified concentration MPa: megapascal wt%: weight percent DMF: N, N-dimethylformamide THF: Tetrahydrofuran DMSO: Dimethyl sulfoxide IPE: Diisopropyl ether HOBt: 1-hydroxybenzotriazole WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Boc ₂ O: Di-tert-butyl dicarbonate

LC-MS in Examples and Reference Examples was measured under the following conditions.
Analysis by LC-MS Measuring instrument: Waters LC-MS system HPLC part: Agilent HP1100
MS Department: Micromass ZMD
HPLC conditions Column: CAPCELL PAK C18UG120, S-3 μm, 1.5 × 35 mm (Shiseido)
Solvent: Solution A; 0.05% trifluoroacetic acid-containing water, Solution B; 0.05% trifluoroacetic acid-containing acetonitrile Gradient cycle: 0.00 minutes (A solution / B solution = 90/10), 2.00 minutes (A liquid / B liquid = 5/95) 2.75 minutes (A liquid / B liquid = 5/95) 2.76 minutes (A liquid / B liquid = 90/10) 3.60 minutes (A Liquid / B liquid = 90/10)
Injection volume: 2 μL, flow rate: 0.5 mL / min, detection method: UV 220 nm
MS conditions Ionization method: ESI
Analysis by LC Measuring instrument: Shimadzu Corporation CLASS-VP system HPLC conditions Column: Inertsil ODS-2, CAPCELL PAK C18UG120, 5 μm, 4.6 × 150 mm (GL Sciences Inc.)
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile Gradient cycle: 0.00 minutes (A solution / B solution = 70/30), 15.00 minutes (A liquid / B liquid = 15/85), 15.01 minutes (A liquid / B liquid = 5/95), 20.00 minutes (A liquid / B liquid = 5/95), 20.01 minutes (A Liquid / B liquid = 70/30), 25.00 minutes (A liquid / B liquid = 70/30)
Injection volume: 10 μL, flow rate: 1.0 mL / min, detection method: UV 220 nm
Purification by preparative HPLC in Examples and Reference Examples was performed under the following conditions.
Equipment: Gilson high-throughput purification system Column: YMC CombiPrep ODS-AS-5 μm, 50 × 20 mm
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile Gradient cycle: 0.00 minutes (A solution / B solution = 95/5), 1.00 minutes (A liquid / B liquid = 95/5), 5.20 minutes (A liquid / B liquid = 5/95), 6.40 minutes (A liquid / B liquid = 5/95), 6.50 minutes (A Liquid / B liquid = 95/5), 6.60 minutes (A liquid / B liquid = 95/5)
Flow rate: 25 mL / min, detection method: UV 220 nm

Reference example 1
1-Benzyl-1H-pyrazole-4-carbohydrazide ethyl 1-Benzyl-1H-pyrazole-4-carboxylate (2.00 g) in methanol (10.0 mL) was added hydrazine monohydrate (479 mg) at room temperature. , And refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure and crystallized from methanol / IPE to give the title compound (1.78 g, 94%) as colorless crystals.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.13 (2H, brs), 5.34 (2H, s), 7.08-7.49 (5H, m), 7.87 (1H, s) , 8.23 (1H, s), 9.35 (1H, brs). MS (ESI +): 217 (M + H)

The compound of Reference Example 2 shown below was obtained in the same manner as described in Reference Example 1.
Reference example 2
4- (4-Cyanophenoxy) butanohydrazide
¹ H-NMR (400 MHz, CDCl ₃ ): δ1.91-2.06 (2H, m), 2.16-2.21 (2H, m), 4.05 (2H, t, J = 6.4 Hz) ), 4.24 (2H, brs), 7.09 (2H, d, J = 8.7 Hz), 7.76 (2H, d, J = 8.7 Hz), 8.99 (1H, s).
MS (ESI +): 220 (M + H)

Reference example 3
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-hydroxy-1-butanone (step 1)
A solution of 3 ′, 5′-dimethylacetophenone (5.00 g), methanesulfonic acid (162 mg) and trimethyl orthoacetate (4.29 g) in methanol (25.0 mL) was stirred at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by NH silica gel chromatography (solvent gradient; 0 → 15% ethyl acetate / hexane) to give 1- (1,1-dimethoxyethyl) -3,5-dimethylbenzene (2. 87 g, 44%) as a yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.52 (3H, s), 2.32 (6H, s), 3.19 (6H, s), 6.91 (1H, s), 7.11 (2H, s).
(Process 2)
A THF (4.00 mL) solution of trifluoroacetic anhydride (4.20 g) at 0 ° C. was added to a THF (8.00 mL) solution of the compound (1.94 g) obtained in Step 1 and pyridine (1.58 g). In addition, the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 30% ethyl acetate / hexane) to give 4- (3,5-dimethylphenyl) -1,1,1-trifluoro-4. A cis and trans mixture of -methoxy-3-buten-2-one (2.43 g, 94%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.34 (6H, s), 3.92 (3H, s), 5.78 (1H, s), 7.01-7.13 (3H, m) .
MS (ESI +): 259 (M + H)
(Process 3)
A solution of the compound obtained in Step 2 (516 mg) and 4-hydroxybutanohydrazide (265 mg) in methanol (6.00 mL) was heated to reflux for 14 hours. After cooling the reaction solution to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was separated and purified by NH silica gel chromatography (solvent gradient; 40 → 90% ethyl acetate / hexane), and recrystallized from IPE to give the title compound (670 mg, 97%) as colorless crystals. .
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.91-2.06 (3H, m), 2.36 (6H, s), 2.80-3.10 (2H, m), 3.43- 3.56 (1H, m), 3.61-3.71 (1H, m), 3.71-3.80 (2H, m), 6.27 (1H, brs), 7.11 (1H, s), 7.30 (2H, s).
MS (ESI +): 345 (M + H)
Melting point: 66-68 ° C
Elemental _{analysis: C 16 H 19 F 3 N} 2 O 3
Calculated values: C, 55.81; H, 5.56; N, 8.14
Found: C, 55.71; H, 5.62; N, 8.12

Reference example 4
4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-oxobutanal In Reference Example 3 A solution of the obtained compound (470 mg) and Dess-Martin reagent (695 mg) in acetonitrile (13.0 mL) was stirred at 0 ° C. for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 60% ethyl acetate / hexane), and recrystallized from IPE to give the title compound (333 mg, 72%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.36 (6H, s), 2.74-2.99 (2H, m), 3.08-3.27 (1H, m), 3.54 ( 1H, d, J = 1.5 Hz), 3.59-3.75 (1H, m), 6.06 (1H, s), 7.12 (1H, s), 7.19-7.44 ( 3H, m), 9.88 (1H, s).
MS (ESI +): 343 (M + H)
Melting point: 127-129 ° C
Elemental _{analysis: C 16 H 17 F 3 N} 2 O 3
Calculated value: C, 56.14; H, 5.01; N, 8.18
Found: C, 56.07; H, 5.03; N, 8.02

Reference Example 5
N-methoxy-N, 3-dimethylbut-2-enamide Sodium carbonate (65.0 g) was dissolved in water (250 mL) and toluene (125 mL) and N, O-dimethylhydroxylamine hydrochloride (30.6 g) were added. added. Further, a toluene (125 mL) solution of 3-methylbut-2-enoyl chloride (25.0 g) was slowly added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours. After raising the temperature to room temperature, water (100 mL) was added to the reaction mixture. The organic layer was separated, washed with saturated brine, dried, and the solvent was evaporated under reduced pressure to give the title compound (25.5 g, 87%) as a yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.91 (3H, s), 2.14 (3H, s), 3.20 (3H, s), 3.68 (3H, s), 6.12 (1H, s).
MS (ESI +): 144 (M + H)

Reference Example 6
1- (3-Methoxyphenyl) -3-methylbut-2-en-1-one The compound (7) obtained in Reference Example 5 in a 1.0 mol / L THF solution (65.2 mL) of 3-methoxyphenylmagnesium bromide .47 g) in THF (26.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 15% ethyl acetate / hexane) to give the title compound (7.43 g, 75%) as a pale-yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.02 (3H, d, J = 1.1 Hz), 2.21 (3H, d, J = 1.1 Hz), 3.86 (3H, s), 6.71-6.75 (1H, m), 7.07 (1H, ddd, J = 8.1, 2.7, 0.9 Hz), 7.35 (1H, t, J = 8.0 Hz) 7.46-7.48 (1 H, m), 7.50 (1 H, dt, J = 7.8, 1.1 Hz).
MS (ESI +): 191 (M + H)

Reference Example 7
3-Methyl-1- (3-methylphenyl) but-2-en-1-one 2.5 mol / Ln-butyl in a solution of 1-bromo-3-methylbenzene (10.2 g) in THF (50.0 mL) Lithium hexane solution (23.4 mL) was added at −40 ° C. under a nitrogen atmosphere, and the mixture was stirred at −40 ° C. for 15 minutes. A THF (25.0 mL) solution of the compound (1.92 g) obtained in Reference Example 5 was added to the reaction mixture at −40 ° C., and the mixture was heated to room temperature over 1 hour with stirring. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 1% ethyl acetate / petroleum ether) to give the title compound (1.79 g, 34%) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.94 (3H, s), 2.13 (3H, d, J = 0.8 Hz), 2.33 (3H, s), 6.65-6. 67 (1H, m), 7.27-7.30 (2H, m), 7.63-7.69 (2H, m).

In the same manner as described in Reference Example 6, the compounds of Reference Examples 8, 10, 13, 14, and 16 to 18 shown below were obtained. In the same manner as described in Reference Example 7, the following reference examples were obtained. 9, 11, 12, and 15 compounds were obtained.
Reference Example 8
3-methyl-1-phenylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.01 (3H, s), 2.21 (3H, s), 6.75 (1H, s), 7.41-7.51 (3H, m) , 7.91-7.94 (2H, m).
Reference Example 9
1- (3-Chlorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.97 (3H, d, J = 0.8 Hz), 2.15 (3H, d, J = 1.2 Hz), 6.62-6.64 (1H M), 7.32 (1H, t, J = 7.8 Hz), 7.41-7.46 (1H, m), 7.71-7.75 (1H, m), 7.81-7 .83 (1H, m).
Reference Example 10
1- (3-Fluorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.88-2.13 (3H, m), 2.17-2.25 (3H, m), 6.70 (1H, s), 7.17- 7.24 (1H, m), 7.38-7.45 (1H, m), 7.56-7.64 (1h, m), 7.78-7.72 (1H, m).
MS (ESI +): 179 (M + H)

Reference Example 11
1- [3- (Benzyloxy) phenyl] -3-methylbut-2-en-1-one
¹ H-NMR (400 MHz, CDCl ₃ ): δ2.00 (3H, d, J = 1.2 Hz)
2.19 (3H, d, J = 1.2 Hz), 5.10 (2H, s), 6.69-6.71 (1 H, m), 7.10-7.15 (1 H, m) 7.30-7.48 (6H, m), 7.48-7.55 (2H, m).
Reference Example 12
1- (2-methoxyphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.94 (3H, d, J = 1.2 Hz), 2.20 (3H, d, J = 1.2 Hz), 3.85 (3H, s), 6.58-6.60 (1H, m), 6.95 (1H, dt, J = 8.2, 1.2 Hz), 6.98 (1H, dd, J = 7.6, 0.8 Hz) 7.38 (1H, dt, J = 7.8, 1.6 Hz), 7.53 (1H, dd, J = 8.0, 1.8 Hz).
Reference Example 13
1- (2-Chlorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.99 (3H, s), 2.23 (3H, s), 6.45 (1H, s), 7.27-7.50 (4H, m) .
MS (ESI +): 195 (M + H)

Reference Example 14
3-Methyl-1- [2- (trifluoromethyl) phenyl] but-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.98 (3H, d, J = 1.1 Hz), 2.20 (3H, d, J = 0.8 Hz), 6.33-6.36 (1H M), 7.44 (1H, d, J = 7.6 Hz), 7.48-7.62 (2H, m), 7.70 (1H, d, J = 7.2 Hz).
MS (ESI +): 229 (M + H)
Reference Example 15
1- (4-Methoxyphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.93 (3H, d, J = 0.8 Hz), 2.11 (3H, d, J = 0.8 Hz), 3.79 (3H, s), 6.63-6.65 (1H, m), 6.83-6.90 (2H, m), 7.84-7.92 (2H, m).
Reference Example 16
3-Methyl-1- (4-methylphenyl) but-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.01 (3H, s), 2.20 (3H, s), 2.39 (3H, s), 6.73 (1H, s), 7.23 -7.25 (2H, m), 7.82-7.85 (2H, m).
MS (ESI +): 175 (M + H)

Reference Example 17
1- (4-tert-butylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ1.33 (9H, s), 2.00 (3H, s), 2.20 (3H, s), 6.74 (1H, s), 7.45 (2H, d, J = 8.3 Hz), 7.88 (2H, d, J = 8.7 Hz).
MS (ESI +): 217 (M + H)
Reference Example 18
1- (4-Fluorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.01 (3H, s), 2.20 (3H, s), 6.70 (1H, s), 7.07-7.13 (2H, m) , 7.92-7.97 (2H, m).
MS (ESI +): 179 (M + H)

Reference Example 19
1- (3,5-Dimethylphenyl) -3-methylbut-2-en-1-one The compound obtained in Reference Example 5 in a 0.5 mol / L THF solution (100 mL) of 3,5-dimethylphenylmagnesium bromide A solution of (5.73 g) in THF (20.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 15% ethyl acetate / hexane) to give the title compound (6.32 g, 84%) as a pale-yellow oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.01 (3H, d, J = 1.5 Hz), 2.19 (3H, d, J = 1.5 Hz), 2.37 (6H, s), 6.69-6.75 (1H, m), 7.16 (1H, s), 7.53 (2H, s).
MS (ESI +): 189 (M + H)

Reference Example 20
1- [4- (trifluoromethyl) benzyl] -1H-pyrazole-4-carboxylic acid (Step 1)
4-Trifluoromethylbenzyl bromide (5.00 g) was added to a solution of ethyl 1H-pyrazole-4-carboxylate (2.00 g) and potassium carbonate (9.71 g) in acetone (20.0 mL) at 60 ° C. Stir for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure and crystallized with hexane to obtain ethyl 1- [4- (trifluoromethyl) benzyl] -1H-pyrazole-4-carboxyl. Lat (4.07 g, 98%) was obtained as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.34 (3H, t, J = 7.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 5.37 (2H, s), 7.34 (2H, d, J = 8.0 Hz), 7.62 (2H, d, J = 8.3 Hz), 7.91 (1H, s), 7.96 (1H, s).
MS (ESI +): 299 (M + H)
Melting point: 103-105 ° C
Elemental _{analysis: C 14 H 13 F 3 N} 2 O 2
Calculated C, 56.38; H, 4.39; N, 9.39
Found C, 56.31; H, 4.41; N, 9.42
(Step 2) To a mixed solution of the compound (2.00 g) obtained in Step 1 above in THF (5.00 mL) and ethanol (5.00 mL) was added 8N sodium hydroxide solution (2.51 mL), and For 16 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was neutralized with 6N hydrochloric acid. The resulting precipitate was collected by filtration and recrystallized from ethyl acetate / IPE to give the title compound (1.47 g, 81%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.39 (2H, s), 7.36 (2H, d, J = 8.0 Hz), 7.64 (2H, d, J = 8.0 Hz), 7.97 (1H, s), 8.02 (1H, s), 11.16 (1H, s).
MS (ESI +): 271 (M + H)
Melting point: 148-150 ° C
Elemental _{analysis: C 12 H 9 F 3 N} 2 O 2
Calculated C, 53.34; H, 3.36; N, 10.37
Found C, 53.19; H, 3.42; N, 10.23

The compounds of Reference Examples 21 to 26 shown below were obtained in the same manner as described in Reference Example 20.
Reference Example 21
1- (4-Cyanobenzyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.39 (2H, s), 7.32 (2H, d, J = 8.3 Hz), 7.67 (2H, d, J = 8.3 Hz), 7.9 (1H, s), 8.02 (1H, s).
MS (ESI +): 228 (M + H)
Melting point: 212-214 ° C
Elemental analysis value: C ₁₂ H ₉ N ₃ O ₂ .0.1C ₄ H ₈ O ₂ .0.2H ₂ O
Calculated C, 62.15; H, 4.25; N, 17.54
Found C, 61.95; H, 4.23; N, 17.45
Reference Example 22
1- (2-Cyanobenzyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.55 (2H, s), 7.33 (1H, d, J = 7.6 Hz), 7.43-7.50 (1H, m), 7. 58-7.66 (1H, m), 7.72 (1H, dd, J = 7.6, 1.1 Hz), 8.02 (1H, s) 8.11 (1H, s), 11.06 (1H, brs).
MS (ESI +): 228 (M + H)
Melting point: 192-194 ° C
Elemental _{analysis: C 12 H 9 N 3 O} 2 · 0.2H 2 O
Calculated C, 62.44; H, 4.10; N, 18.20
Found C, 62.61; H, 4.17; N, 18.09
Reference Example 23
1- (Pyridin-2-ylmethyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.48 (2H, s), 7.19 (1H, d, J = 8.0 Hz), 7.25-7.31 (1H, m), 7. 71 (1H, td, J = 7.8, 1.9 Hz), 8.01 (1H, s), 8.15 (1H, s), 8.63 (1H, dd, J = 4.9, 0 .76 Hz).
Melting point: 162-164 ° C
Elemental analysis value: C ₁₀ H ₉ N ₃ O ₂ .0.1H ₂ O
Calculated value C, 58.59; H, 4.52; N, 20.50
Found C, 58.51; H, 4.48; N, 20.40

Reference Example 24
1- (Cyclohexylmethyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.88-1.09 (2H, m), 1.11-1.40 (4H, m), 1.53-1.82 (6H, m), 1.83 to 2.02 (3H, m), 3.96 (2H, d, J = 7.2 Hz), 7.90 (1H, s), 7.97 (1H, s), 11.34 (1H, brs).
MS (ESI +): 209 (M + H)
Melting point: 123-125 ° C
Elemental analysis value: C ₁₁ H ₁₆ N ₂ O ₂
Calculated C, 63.44; H, 7.74; N, 13.45
Found C, 63.41; H, 7.81; N, 13.36
Reference Example 25
1- (1-phenethyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.92 (3H, d, J = 7.2 Hz), 5.55 (1H, q, J = 6.9 Hz), 7.21-7.29 (2H M), 7.30-7.42 (3H, m), 7.94 (1H, s), 8.00 (1H, s).
MS (ESI +): 217 (M + H)
Melting point: 136-138 ° C
Elemental analysis value: C ₁₂ H ₁₂ N ₂ O ₂
Calculated C, 66.65; H, 5.59; N, 12.96
Found C, 66.59; H, 5.55; N, 12.80
Reference Example 26
1- (2-phenethyl) -1H-pyrazole-4-carboxylic acid
^{1 H-NMR (300MHz, CDCl} 3): δ3.19 (2H, t, J = 7.2Hz), 4.37 (2H, t, J = 7.2Hz), 7.03-7.09 (2H M), 7.19-7.33 (3H, m), 7.69 (1H, s), 7.99 (1H, s), 11.35 (1H, s).
MS (ESI +): 217 (M + H)
Melting point: 122-124 ° C
Elemental analysis value: C ₁₂ H ₁₂ N ₂ O ₂
Calculated C, 66.65; H, 5.59; N, 12.96
Found C, 66.35; H, 5.56; N, 12.94

Reference Example 27
4- [4- (Trifluoromethyl) phenoxy] butanoic acid (Step 1) 4-trifluoromethylphenol (5.00 g), potassium carbonate (4.99 g) and potassium iodide (5.99 g) in acetone (50 To the solution, ethyl 4-bromobutanoate (4.87 mL) was added and heated to reflux for 21.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 25% ethyl acetate / hexane) to give ethyl 4- [4- (trifluoromethyl) phenoxy] butanoate (7.92 g, 96% ) Was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.26 (3H, t, J = 7.2 Hz), 2.08-2.19 (2H, m), 2.52 (2H, t, J = 7) .2 Hz), 4.05 (2H, t, J = 6.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 6.94 (2H, d, J = 8.3 Hz), 7 .53 (2H, d, J = 8.3 Hz).
MS (ESI +): 277 (M + H)
(Step 2) To a mixed solution of the compound (7.31 g) obtained in Step 1 above in THF (20.0 mL) and ethanol (20.0 mL) was added 8N sodium hydroxide solution (9.92 mL), and For 30 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was neutralized with 6N hydrochloric acid. The resulting precipitate was collected by filtration and recrystallized from methanol / ethyl acetate to give the title compound (6.76 g, 95%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.06-2.17 (2H, m), 2.58 (2H, t, J = 7.2 Hz), 3.99 (2H, t, J = 5) .9 Hz), 6.81 (2H, d, J = 9.1 Hz), 7.22 (2H, d, J = 8.7 Hz), 10.81 (1H, s).
MS (ESI +): 231 ( M-H 2 O + H)
Melting point: 122-124 ° C
Elemental _{analysis: C 11 H 11 F 3 O} 3 · 0.3H 2 O
Calculated value C, 52.10; H, 4.61
Found C, 52.14; H, 4.32.

In the same manner as in the method described in Reference Example 27, the compounds of Reference Examples 28 to 35 shown below were obtained.
Reference Example 28
4- [4- (trifluoromethoxy) phenoxy] butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.13 (2H, quin, J = 6.5 Hz), 2.59 (2H, t, J = 7.0 Hz), 4.01 (2H, t, J = 5.9 Hz), 6.87 (2H, d, J = 8.7 Hz), 7.13 (2H, d, J = 8.7 Hz). MS (ESI +): 247 ( M-H 2 O + H)
Melting point: 89-91 ° C
Elemental analysis value: C ₁₁ H ₁₁ F ₃ O ₄
Calculated value C, 50.01; H, 4.20
Found C, 49.82; H, 4.48
Reference Example 29
4- [4- (Benzyloxy) phenoxy] butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.05-2.15 (2H, m), 2.58 (2H, t, J = 7.2 Hz), 3.97 (2H, t, J = 6) .1 Hz), 5.01 (2H, s), 6.78-6.85 (2H, m), 6.86-6.93 (2H, m), 7.28-7.45 (5H, m) ), 10.31 (1H, s).
MS (ESI +): 269 ( M-H 2 O + H)
Melting point: 125-127 ° C
Elemental analysis value: C ₁₇ H ₁₈ O ₄
Calculated value C, 71.31; H, 6.34
Found C, 70.94; H, 6.31
Reference Example 30
4- [3,5-Bis (trifluoromethyl) phenoxy] butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.18 (2H, quin, J = 6.6 Hz), 2.61 (2H, t, J = 7.0 Hz), 4.12 (2H, t, J = 6.1 Hz), 7.29 (2H, s), 7.46 (1H, s).
MS (ESI +): 299 (M-OH + H)
Melting point: 90-92 ° C
Elemental _{analysis: C 12 H 10 F 6 O} 3
Calculated C, 45.58; H, 3.19
Found C, 45.68; H, 3.47

Reference Example 31
4- (Pyridin-2-yloxy) butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.08-2.11 (2H, m), 2.65 (2H, t, J = 7.4 Hz), 4.37 (2H, t, J = 6) .2 Hz), 6.73 (1 H, d, J = 8.5 Hz), 6.87 (1 H, ddd, J = 7.0, 5.1, 0.9 Hz), 7.58 (1 H, ddd, J = 7.0, 6.0, 1.0 Hz), 8.14 (1H, ddd, J = 5.1, 2.1, 0.8 Hz).
Melting point: 81-83 ° C
Elemental analysis value: C ₉ H ₁₁ NO ₃
Calculated C, 59.66; H, 6.12; N, 7.73
Found C, 59.66; H, 6.04; N, 7.73
Reference Example 32
4-[(6-Methylpyridin-2-yl) oxy] butanoic acid
^{1 H-NMR (300MHz, CDCl} 3): δ2.11 (2H, quin, J = 6.7Hz), 2.43 (3H, s), 2.56 (2H, t, J = 7.2Hz), 4.34 (2H, t, J = 6.1 Hz), 6.52 (1H, d, J = 8.3 Hz), 6.71 (1H, d, J = 7.2 Hz), 7.46 (1H) , T, J = 7.8 Hz), 8.35 (1H, brs).
MS (ESI +): 196 (M + H)
Reference Example 33
4-[(4-Chloropyridin-2-yl) oxy] butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.11 (2H, quin, J = 6.7 Hz), 2.55 (2H, t, J = 7.2 Hz), 4.33 (2H, t, J = 6.3 Hz), 6.68 (1H, d, J = 9.5 Hz), 7.52 (1H, dd, J = 8.9, 2.8 Hz), 8.07 (1H, d, J = 2.3 Hz).
MS (ESI +): 216 (M + H)

Reference Example 34
4-{[5- (trifluoromethyl) pyridin-2-yl] oxy} butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.14 (2H, quin, J = 6.8 Hz), 2.56 (2H, t, J = 7.2 Hz), 4.42 (2H, t, J = 6.2 Hz), 6.80 (1H, d, J = 8.7 Hz), 7.77 (1H, dd, J = 8.7, 1.9 Hz), 8.42 (1H, s).
Melting point: 94-96 ° C
Elemental _{analysis: C 10 H 10 F 3 NO} 3
Calculated C, 48.20; H, 4.04; N, 5.62
Found C, 48.18; H, 4.14; N, 5.62
Reference Example 35
4-[(3-Cyano-4,6-dimethylpyridin-2-yl) oxy] butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.15 (2H, quin, J = 6.6 Hz), 2.43 (3H, s), 2.44 (3H, s), 2.58 (2H, t, J = 7.2 Hz), 4.46 (2H, t, J = 6.1 Hz), 6.68 (1H, s).
Melting point: 150-152 ° C
Elemental _{analysis: C 12 H 14 N 2 O} 3
Calculated C, 61.53; H, 6.02; N, 11.96
Found C, 61.38; H, 6.09; N, 11.58

In the same manner as in the method described in Reference Example 6, the compounds of Reference Examples 36 to 52 shown below were obtained. Reference Example 36
1- (3-Chloro-5-methylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.95-2.06 (3H, m), 2.16-2.24 (3H, m), 2.38 (3H, s), 6.67 ( 1H, brs), 7.31 (1H, brs), 7.59 (1H, brs), 7.68 (1H, brs).
MS (ESI +): 209 (M + H)
Reference Example 37
1- (3,5-dichlorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.04 (3H, s), 2.23 (3H, s), 6.54-6.69 (1H, m), 7.48 (1H, t, J = 1.9 Hz), 7.75 (2H, d, J = 1.9 Hz).
MS (ESI +): 229 (M)
Reference Example 38
1- (3-Chloro-5-fluorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.04 (3H, s), 2.23 (3H, s), 6.65 (1H, s), 7.16-7.29 (1H, m) , 7.43-7.55 (1H, m), 7.62-7.71 (1H, m).
MS (ESI +): 213 (M + H)

Reference Example 39
1- (3,5-difluorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.04 (3H, s), 2.23 (3H, s), 6.56-6.68 (1H, m), 6.84-7.05 ( 1H, m), 7.42 (2H, dd, J = 8.0, 2.3 Hz).
MS (ESI +): 197 (M + H)
Reference Example 40
1- [3,5-bis (trifluoromethyl) phenyl] -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.11 (3H, s), 2.28 (3H, s), 6.76 (1H, s), 8.02 (1H, s), 8.35 (2H, s).
MS (ESI +): 297 (M + H)
Reference Example 41
1- (3,5-diethylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.26 (6H, t, J = 7.6 Hz), 2.01 (3H, s), 2.20 (3H, s) 2.68 (4H, q , J = 7.6 Hz), 6.74 (1H, s), 7.20 (1H, s), 7.58 (2H, d, J = 1.5 Hz).
MS (ESI +): 217 (M + H)

Reference Example 42
1- (2-Methoxy-5-methylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.95 (3H, s), 2.21 (3H, s), 2.28 (3H, s), 3.82 (3H, s), 6.55 -6.77 (1H, m), 6.77-6.88 (1H, m), 7.19 (1H, dd, J = 8.3, 1.9Hz), 7.35 (1H, d, J = 2.3 Hz).
MS (ESI +): 205 (M + H)
Reference Example 43
1- (2,5-Dimethoxyphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.97 (3H, d, J = 1.1 Hz), 2.23 (3H, d, J = 1.1 Hz), 3.79 (3H, s), 3.83 (3H, s), 6.63-6.67 (1H, m), 6.88 (1H, d, J = 9.0 Hz), 6.97 (1H, dd, J = 9.0) , 3.3 Hz), 7.12 (1H, d, J = 3.0 Hz). MS (ESI +): 221 (M + H)
Reference Example 44
1- (5-Fluoro-2-methoxyphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.97 (3H, d, J = 1.1 Hz)
, 2.22 (3H, d, J = 1.1 Hz), 3.84 (3H, s), 6.53-6.67 (1H, m), 6.78-7.17 (2H, m) 7.26 (1H, dd, J = 8.7, 3.2 Hz).
MS (ESI +): 209 (M + H)

Reference Example 45
1- (3-Fluoro-4-methylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.02 (3H, d, J = 1.3 Hz)
, 2.21 (3H, d, J = 1.1 Hz), 2.28-2.36 (3H, m), 6.64-6.72 (1H, m), 7.17-7.31 ( 1H, m), 7.48-7.68 (2H, m).
MS (ESI +): 193 (M + H)
Reference Example 46
1- (4-Fluoro-3-methylphenyl) -3-methylbut-2-en-1-one
^{1 H-NMR (300MHz, CDCl} 3): δ2.01 (3H, s), 2.19 (3H, s), 2.31 (3H, s), 6.69 (1H, s), 6.95 -7.10 (1H, m), 7.64-7.86 (2H, m).
MS (ESI +): 193 (M + H)
Reference Example 47
1- (3,4-Difluorophenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.03 (3H, s), 2.21 (3H, s), 6.67 (1H, s), 7.14-7.29 (1H, m) , 7.63-7.85 (2H, m).
MS (ESI +): 197 (M + H)

Reference Example 48
1- (2,3-Dimethylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.96 (3H, d, J = 1.3 Hz), 2.17 (3H, d, J = 1.1 Hz), 2.30 (6H, brs), 6.36-6.42 (1H, m), 7.05-7.16 (1H, m), 7.17-7.28 (2H, m).
MS (ESI +): 189 (M + H)
Reference Example 49
1- (4-Methoxy-3,5-dimethylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.00 (3H, d, J = 1.1 Hz), 2.18 (3H, d, J = 1.1 Hz), 2.32 (6H, s), 3.74 (3H, s), 6.63-6.73 (1H, m), 7.61 (2H, s).
MS (ESI +): 219 (M + H)
Reference Example 50
3-Methyl-1- (3-methylthiophen-2-yl) but-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.98 (3H, d, J = 1.5 Hz), 2.21 (3H, d, J = 1.5 Hz), 2.58 (3H, s), 6.54-6.58 (1H, m), 6.93 (1H, d, J = 4.9 Hz), 7.36 (1H, d, J = 5.3 Hz).
MS (ESI +): 181 (M + H)

Reference Example 51
3-Methyl-1- (naphthalen-2-yl) but-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.08 (3H, s), 2.26 (3H, s), 6.91 (1H, s), 7.51-7.63 (2H, m) 7.85-7.93 (2H, m), 7.97 (1H, d, J = 7.2 Hz), 8.03 (1H, dd, J = 8.7, 1.5 Hz), 8. 44 (1H, s).
MS (ESI +): 211 (M + H)
Melting point: 48-50 ° C
Elemental _{analysis: C} 15 _{H 14} O
Calculated value C, 85.68; H, 6.71
Found C, 85.51; H, 6.75
Reference Example 52
3-Methyl-1- (naphthalen-1-yl) but-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.02 (3H, s), 2.26 (3H, s), 6.60 (1H, s). 7.41-7.61 (3H, m), 7.75 (1H, d, J = 7.2 Hz), 7.86-7.91 (1H, m), 7.94 (1H, d, J = 8.3 Hz), 8.44 (1H, d, J = 8.0 Hz).
MS (ESI +): 211 (M + H)

Reference Example 53
1- (2-methoxy-3,5-dimethylphenyl) -3-methylbut-2-en-1-ol To a solution of 2-methoxy-3,5-dimethylbenzaldehyde (1.00 g) in THF (20.0 mL) Then, a 0.5 mol / L THF solution (50.0 mL) of 2-methyl-1-propenylmagnesium bromide was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to saturated ammonium chloride at 0 ° C. and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 1 → 50% ethyl acetate / hexane) to give the title compound (940 mg, 74%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.75 (3H, d, J = 1.1 Hz)
, 1.81 (3H, d, J = 1.1 Hz), 2.25-2.30 (7H, m) 3.74 (3H, s), 5.39-5.50 (1 H, m), 5.63-5.78 (1H, m), 6.90 (1H, d, J = 2.3 Hz), 7.08 (1H, d, J = 1.9 Hz).
MS (ESI +): 203 ( M-H 2 O + H)

Reference Example 54
1- (2-Methoxy-3,5-dimethylphenyl) -3-methylbut-2-en-1-one To a solution of the compound obtained in Reference Example 53 (560 mg) in ethyl acetate (40.0 mL) was added manganese dioxide. (6.00 g) was added at room temperature, and the mixture was stirred at 60 ° C. for 15 hours. The reaction solution was filtered, and the filtrate was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 1 → 50% ethyl acetate / hexane) to give the title compound (135 mg, 24%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.97 (3H, s), 2.14-2.37 (9H, m) 3.68 (3H, s), 6.65 (1H, s), 7.09 (1H, s), 7.15 (1H, s).
MS (ESI +): 219 (M + H)

Reference Example 55
Methyl 4,6-dimethylpyridine-2-carboxylate To a solution of 4,6-dimethylpyridine-2-carboxylic acid (960 mg) in DMF (30.0 mL), potassium carbonate (2.60 g) and iodomethane (1.00 mL) Was added at room temperature and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 10% ethyl acetate / hexane) to give the title compound (961 mg, 92%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.38 (3H, s), 2.61 (3H, s), 3.99 (3H, s), 7.17 (1H, s), 7.79 (1H, s).
MS (ESI +): 166 (M + H)

Reference Example 56
(4,6-dimethylpyridin-2-yl) methanol To a solution of lithium aluminum hydride (888 mg) in THF (20.0 mL), a solution of the compound (961 mg) obtained in Reference Example 55 in THF (15.0 mL) was added. It added at 0 degreeC and stirred at room temperature for 16 hours. To the reaction mixture were added 8N aqueous sodium hydroxide solution (2.70 mL) and water (1.80 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hr. After the mixed solution was dried, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 15 → 50% ethyl acetate / hexane) to give the title compound (529 mg, 66%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.28 (3H, s), 2.46 (3H, s), 4.67 (2H, s), 5.06 (1H, brs), 6.84 (1H, s), 6.94 (1H, s).
MS (ESI +): 138 (M + H)

Reference Example 57
1- (4,6-Dimethylpyridin-2-yl) -3-methylbut-2-en-1-ol To a solution of the compound (529 mg) obtained in Reference Example 56 in acetonitrile (15.0 mL) was added Dess-Martin. Reagent (2.50 g) was added at 0 ° C., and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried, and then the solvent was distilled off under reduced pressure. To a THF (10.0 mL) solution of the obtained residue, a 0.5 mol / L THF solution (30.0 mL) of 2-methyl-1-propenylmagnesium bromide was added at 0 ° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture was added to saturated ammonium chloride at 0 ° C. and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 50% ethyl acetate / hexane) to give the title compound (294 mg, 40%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.79 (3H, s), 1.88 (3H, s), 2.22-2.35 (3H, m), 2.43-2.55 ( 3H, m), 5.13-5.42 (2H, m), 6.78 (1H, s), 6.86 (1H, s). MS (ESI +): 192 (M + H)

Reference Example 58
1- (4,6-Dimethylpyridin-2-yl) -3-methylbut-2-en-1-one To a solution of the compound obtained in Reference Example 57 (294 mg) in acetonitrile (20.0 mL) was added Dess-Martin. A reagent (1.50 g) was added at 0 ° C. under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 20% ethyl acetate / hexane) to give the title compound (216 mg, 74%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.02 to 2.08 (3H, m), 2.26-2.31 (3H, m), 2.35 (3H, s), 2.57 ( 3H, s) 7.09 (1H, s), 7.49 (1H, s), 7.71 (1H, s).
MS (ESI +): 190 (M + H)

Reference Example 59
(2E) -4,4,4-trifluoro-N-methoxy-N, 3-dimethylbut-2-enamide (2E) -4,4,4-trifluoro-3-methylbut-2-enoic acid (4 .62 g), N, O-dimethylhydroxylamine hydrochloride (3.51 g), WSC (6.90 g), HOBt (5.50 g) and triethylamine (6.07 g) in DMF (40.0 mL) at room temperature. Stir for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 40% ethyl acetate / hexane) to give the title compound (1.93 g, 99%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.13 (3H, s), 3.25 (3H, s), 3.70 (3H, s), 6.76 (1H, s).
MS (ESI +): 198 (M + H)

The compound of Reference Example 60 shown below was obtained in the same manner as in the method described in Reference Example 6 using the compound obtained in Reference Example 59.
Reference Example 60
(2E) -4,4,4-trifluoro-1- (3-methoxyphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.15 (3H, s), 3.87 (3H, s), 7.15-7.21 (2H, m), 7.40-7.51 ( 3H, m).
MS (ESI +): 245 (M + H)

Reference Example 61
1- (3,5-Dimethylphenyl) -3-ethylpent-2-en-1-one
(Step 1) To a solution of diisopropylamine (7.50 g) in THF (70.0 mL), a 1.6 mol / Ln-butyllithium hexane solution (46.0 mL) was added at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 15 minutes. did. 3 ′, 5′-dimethylacetophenone (10.0 g) was added to the reaction mixture at −78 ° C., and the mixture was stirred at −78 ° C. for 1.5 hours. Chlorotrimethylsilane (8.80 g) was added to the reaction mixture at -78 ° C, and the mixture was stirred at -78 ° C for 1 hour. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and the solvent was evaporated under reduced pressure to give {[1- (3,5-dimethylphenyl) ethenyl] oxy} (trimethyl) silane (13.0 g, 85% ) Was obtained as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.48 (9H, s), 2.53 (6H, s), 4.61 (1H, s), 5.09 (1H, s), 7.14 (1H, s), 7.42 (2H, s).
(Step 2) To a solution of 3-pentanone (2.16 g) and titanium tetrachloride (4.75 g) in trifluorobenzene (50.0 mL), trifluorobenzene of the compound (5.51 g) obtained in Step 1 above. (10.0 mL) solution was added at −78 ° C. and stirred at −78 ° C. for 1 hour. After raising the temperature to room temperature, trifluoroacetic anhydride (5.25 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (5.06 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 30% ethyl acetate / hexane), and further purified by preparative HPLC to give the title compound (468 mg, 9%) as a yellow oil Got as.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.14 (6H, dt, J = 14.8, 7.4 Hz), 2.30 (2H, q, J = 7.3 Hz), 2.37 (6H , S), 2.60 (2H, q, J = 7.6 Hz), 6.63 (1H, s), 7.16 (1H, s), 7.53 (2H, s).
MS (ESI +): 217 (M + H)

The compounds of Reference Examples 62 to 63 shown below were obtained in the same manner as described in Reference Example 61.
Reference Example 62
3-Ethyl-1- (3-methoxyphenyl) pent-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.10-1.18 (6H, m), 2.26-2.31 (2H, m), 2.57-2.65 (2H, q, J = 7.5 Hz), 3.85 (3 H, s), 6.65 (1 H, s), 7.01-7.12 (1 H, m), 7.34 (1 H, t, J = 7.9 Hz) ), 7.45-7.56 (2H, m).
MS (ESI +): 219 (M + H)
Reference Example 63
1- (3-methoxyphenyl) -3-methylpent-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.16 (3H, t, J = 7.4 Hz), 2.19 (3H, s), 2.22-2.32 (2H, m), 3. 86 (3H, s), 6.63 (1H, s), 7.01-7.12 (1H, m), 7.34 (1H, t, J = 7.9 Hz), 7.45-7. 56 (2H, m).
MS (ESI +): 205 (M + H)
E / Z ratio = 2.5: 1

Reference Example 64
Diethyl [2- (3,5-dimethylphenyl) -2-oxoethyl] phosphonate (Step 1) To a solution of 3 ′, 5′-dimethylacetophenone (15.5 g) in ethyl acetate (200 mL) was added copper (II) bromide. A solution of (44.7 g) in ethyl acetate (350 mL) was slowly added, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere, and then heated to reflux for 14 hours. After cooling to room temperature, the reaction mixture was filtered, and water was added to the filtrate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 40% ethyl acetate / hexane) to give 2-bromo-1- (3,5-dimethylphenyl) ethanone (24.0 g, 100%) as an oil.
(Step 2) A 1,2-dimethoxyethane (33.0 mL) solution of the compound (13.9 g) obtained in Step 1 above and triethyl phosphite (8.13 g) was heated to reflux for 7 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 80% ethyl acetate / hexane) to give the title compound (10.4 g, 60%) as an oil.
^{1 H-NMR (300MHz, CDCl} 3): δ1.29 (6H, t, J = 7.0Hz), 2.37 (6H, s), 3.61 (2H, d, J = 22.5Hz), 4.14 (4H, quin, J = 7.4 Hz), 7.22 (1H, s), 7.61 (2H, s).
MS (ESI +): 285 (M + H)

The compounds of Reference Examples 65 to 66 shown below were obtained in the same manner as described in Reference Example 64.
Reference Example 65
Diethyl [2- (3-methoxyphenyl) -2-oxoethyl] phosphonate
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.29 (6H, t, J = 7.0 Hz), 3.59-3.66 (2H, m), 3.85 (3H, s), 4. 09-4.19 (4H, m), 7.01-7.21 (1H, m), 7.38 (1H, t, J = 8.0 Hz), 7.54 (1H, d, J = 1) .5 Hz), 7.60 (1H, d, J = 7.6 Hz).
MS (ESI +): 287 (M + H)
Reference Example 66
Diethyl [2- (2,4-dimethyl-1,3-thiazol-5-yl) -2-oxoethyl] phosphonate
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.30-1.35 (6H, m), 2.71 (6H, s), 3.38-3.46 (2H, m), 4.10 − 4.23 (4H, m).
MS (ESI +): 292 (M + H)

Reference Example 67
4- (Benzyloxy) -1- (3,5-dimethylphenyl) -3-methylbut-2-en-1-one THF (54.0 mL) solution of the compound (3.70 g) obtained in Reference Example 64 To the mixture, potassium tert-butoxide (1.89 g) was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Benzyloxyacetone (3.01 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 40% ethyl acetate / hexane) to give the title compound (2.30 g, 60%) as an oil.
MS (ESI +): 295 (M + H)
E / Z mixture

The compounds of Reference Examples 68 to 77 shown below were obtained in the same manner as described in Reference Example 67 using the compounds obtained in Reference Examples 64 to 66.
Reference Example 68
4- (Benzyloxy) -1- (3-methoxyphenyl) -3-methylbut-2-en-1-one MS (ESI +): 297 (M + H)
E / Z ratio = 2: 1
Reference Example 69
4-Methoxy-1- (3-methoxyphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.11 (3H, s), 3.43 (3H, s), 3.58 (2H, s), 3.79-3.90 (3H, m) , 4.00 (1H, s), 7.08 (1H, dd, J = 8.0, 3.4 Hz), 7.36 (1H, t, J = 8.0 Hz), 7.48-7. 56 (2H, m).
MS (ESI +): 221 (M + H)
E / Z ratio = 3: 1
Reference Example 70
2-Cyclobutylidene-1- (3-methoxyphenyl) ethanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.18 (2H, q, J = 7.8 Hz), 2.91-2.97 (2H, m), 3.23-3.28 (2H, m ), 3.85 (3H, s), 6.73 (1H, t, J = 2.2 Hz), 7.07-7.09 (1H, m), 7.35 (1H, t, J = 7) .8 Hz), 7.47-7.56 (2H, m).
MS (ESI +): 203 (M + H)

Reference Example 71
2-Cyclopentylidene-1- (3-methoxyphenyl) ethanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.66-1.96 (4H, m), 2.28-2.35 (2H, m), 2.54-2.58 (2H, m), 3.85 (3H, s), 6.98 (1H, brs), 7.07-7.09 (1H, m), 7.35 (1H, t, J = 7.8 Hz), 7.47- 7.57 (2H, m).
MS (ESI +): 217 (M + H)
Reference Example 72
(2E) -1- (3-methoxyphenyl) -3- (trifluoromethyl) pent-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.4 Hz), 2.56 (2H, q, J = 7.5 Hz), 3.87 (3H, s), 7.07-7.09 (2H, m), 7.35 (1H, t, J = 7.8 Hz), 7.45-7.58 (2H, m).
MS (ESI +): 259 (M + H)
Reference Example 73
(2E) -1- (3-methoxyphenyl) -3- (trifluoromethyl) hex-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.95 (3H, dd, J = 7.4 Hz), 1.60 (2H, dd, J = 15.5, 7.7 Hz), 2.52 (1H , D, J = 16.0 Hz), 2.52 (1H, t, J = 2.5 Hz), 3.86 (3H, s), 7.15 (1H, ddd, J = 8.2, 2.. 6, 0.9 Hz), 7.21 (1 H, d, J = 1.3 Hz), 7.39 (1 H, t, J = 7.8 Hz), 7.44-7.55 (2 H, m). MS (ESI +): 273 (M + H)

Reference Example 74
1- (2,4-Dimethyl-1,3-thiazol-5-yl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.98 (3H, s), 2.21 (3H, s), 2.68 (3H, s), 2.71 (3H, s), 6.40 (1H, s).
Reference Example 75
(2E) -1- (3-methoxyphenyl) but-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.94-2.05 (3H, m), 3.86 (3H, s), 6.83-6.95 (1H, m), 7.00- 7.15 (2H, m), 7.36 (1 H, t, J = 7.8 Hz), 7.43-7.53 (2H, m).
MS (ESI +): 177 (M + H)
Reference Example 76
(2E) -1- (3-methoxyphenyl) pent-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.14 (3H, t, J = 7.3 Hz), 2.35 (2H, q, J = 7.5 Hz), 3.86 (3H, s), 6.88 (1H, m), 7.03-7.17 (2H, m), 7.37 (1H, t, J = 7.9 Hz), 7.44-7.55 (2H, m).
MS (ESI +): 191 (M + H)

Reference Example 77
(2E) -3-cyclopropyl-1- (3,5-dimethylphenyl) prop-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.71-0.75 (2H, m), 0.99-1.03 (2H, m), 1.64-1.76 (1H, m), 2.37 (6H, s), 6.53 (1H, dd, J = 15.1, 10.2 Hz), 7.00 (1H, d, J = 15.1 Hz), 7.17 (1H, s ), 7.54 (2H, s).
MS (ESI +): 201 (M + H)

Reference Example 78
(2E) -1- (3-methoxyphenyl) -4-methylpent-2-en-1-one Toluene (50.0 mL) and THF (10.0 mL) of the compound (4.00 g) obtained in Reference Example 65 ) Was added potassium tert-butoxide (1.65 g) at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. Isobutyraldehyde (1.51 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 40% ethyl acetate / hexane) to give the title compound (2.27 g, 78%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.12 (6H, d, J = 7.0 Hz), 2.47-2.65 (1H, m), 3.84 (3H, s), 6. 80 (1H, d, J = 15.5 Hz), 6.96-7.13 (2H, m), 7.36 (1H, t, J = 8.0 Hz), 7.43-7.55 (2H , M).
MS (ESI +): 205 (M + H)

The compound of Reference Example 79 shown below was obtained in the same manner as described in Reference Example 78.
Reference Example 79
(2E) -3-Cyclopropyl-1- (3-methoxyphenyl) prop-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.64-0.81 (2H, m), 0.94-1.09 (2H, m), 1.58-1.79 (1H, m), 3.85 (3H, s), 6.56 (1H, dd, J = 14.8, 10.2 Hz), 6.97-7.02 (1H, m), 7.08 (1H, dd, J = 8.7, 2.3 Hz), 7.36 (1 H, t, J = 7.8 Hz), 7.44-7.56 (2 H, m).

Reference Example 80
(2E) -1- (3,5-Dimethylphenyl) -4,4-dimethylpent-2-en-1-one The compound obtained in Reference Example 64 in a solution of lithium chloride (636 mg) in acetonitrile (150 mL) (4.26 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (1.95 g) are added, and 2,2-dimethylpropanal (1.10 g) is added last, and nitrogen is added. The mixture was stirred at room temperature for 2 days. After adding water to the reaction mixture, the reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 40% ethyl acetate / hexane) to give the title compound (2.12 g, 78%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.16 (9H, s), 2.38 (6H, s), 6.69-6.82 (1H, m), 7.05 (1H, d, J = 15.4 Hz), 7.18 (1H, s), 7.52 (2H, s).
MS (ESI +): 217 (M + H)

Reference Example 81
(2E) -4- (Benzyloxy) -1- (3,5-dimethylphenyl) but-2-en-1-one Obtained in Reference Example 64 in a solution of lithium chloride (636 mg) in acetonitrile (150 mL). The compound (4.26 g) and N-ethyldiisopropylamine (1.61 g) were added, and benzyloxyacetaldehyde (1.88 g) was finally added, followed by stirring at room temperature for 2 hours under a nitrogen atmosphere. After adding water to the reaction mixture, the reaction mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 15% ethyl acetate / hexane) to give the title compound (2.25 g, 64%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.36 (6H, s), 4.28 (2H, dd, J = 4.0, 1.7 Hz), 4.62 (2H, s), 6. 96-7.15 (1H, m), 7.13-7.44 (7H, m), 7.56 (2H, s).

Reference Example 82
To a solution of 5,5-dimethylpyrazolidin-3-one hydrazine monohydrate (1.82 g) in ethanol (20.0 mL), ethyl 3-methylbut-2-enoate (3.85 g) in ethanol (10. 0 mL) solution was added, stirred at room temperature for 1 hour, and then heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by NH silica gel chromatography (solvent gradient; 50 → 100% ethyl acetate / hexane) to give the title compound (2.51 g, 73%). Obtained as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.30 (6H, s), 2.33 (2H, s), 4.13 (1H, s), 7.39 (1H, s).
MS (ESI +): 115 (M + H)

Reference Example 83
5,5-Dimethyl-1- (4-phenoxybutanoyl) pyrazolidin-3-one 4-phenoxybutanoic acid (12.8 g) in THF (130 mL) was added one drop of thionyl chloride (9.90 g) and DMF. The mixture was further stirred at room temperature for 1.5 hours. The reaction mixture was added to a solution of the compound (3.77 g) obtained in Reference Example 82 and N-ethyldiisopropylamine (12.8 g) in N, N-dimethylacetamide (25.0 mL) at 0 ° C., and then at room temperature for 24 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. A 28% sodium methoxide methanol solution (7.00 g) was added to a methanol (5.00 mL) solution of the obtained residue, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether. The aqueous layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from IPE / hexane to give the title compound (4.72 g, 52%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.63 (6H, s), 2.10-2.27 (2H, m), 2.52-2.59 (2H, m), 2.71 ( 2H, s), 4.03 (2H, t, J = 5.7 Hz), 6.81-7.02 (3H, m), 7.18-7.35 (2H, m), 9.25 ( 1H, brs).
MS (ESI +): 277 (M + H)

Reference Example 84
1- (3-Chloro-4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl) -4-phenoxy-1-butanone The compound obtained in Reference Example 83 (4.15 g) and chloride A mixture of phosphoryl (4.60 g) was stirred at 70 ° C. for 1.5 hours. The reaction mixture was added to a mixed solution of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried, the solvent was filtered through silica gel, and the filtrate was distilled off under reduced pressure. The title compound (3.13 g, 71%) was obtained as an orange oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.62 (6H, s), 2.05-2.16 (2H, m), 2.76 (2H, t, J = 7.4 Hz), 2. 93 (2H, s), 3.99-4.03 (2H, m), 6.83-6.97 (3H, m), 7.21-7.32 (2H, m).

Reference Example 85
Ethyl 3-ethylpent-2-enoate Sodium hydride (4.80 g, 50-72% oily) in THF (80.0 mL) was suspended in ethyl diethylphosphonoacetate (27.0 mL) in THF (20.0 mL). ) The solution was added at 0 ° C. and stirred at 0 ° C. for 1 hour. To the reaction mixture, a solution of 3-pentanone (12.3 mL) in THF (20.0 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 50% ethyl acetate / hexane) to give the title compound (15.0 g, 84%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.07 (6H, t, J = 7.2 Hz), 1.28 (3H, t, J = 7.0 Hz), 2.19 (2H, q, J = 7.3 Hz), 2.62 (2H, q, J = 7.6 Hz), 4.15 (2H, q, J = 7.2 Hz), 5.60 (1H, s).

Using the compound obtained in Reference Example 85, the compound of Reference Example 86 shown below was obtained in the same manner as in the method described in Reference Example 82.
Reference Example 86
5,5-Diethylpyrazolidine-3-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.91 (6H, t, J = 7.6 Hz), 1.24-1.96 (4H, m), 2.30 (2H, s), 3. 97 (1H, s), 7.67 (1H, brs).

Reference Example 87
1-[(1-Benzyl-1H-pyrazol-4-yl) carbonyl] -5,5-diethylpyrazolidine-3-one THF of 1-benzyl-1H-pyrazole-4-carboxylic acid (2.36 g) (30.0 mL) To the solution was added thionyl chloride (0.882 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to a solution of the compound obtained in Reference Example 86 (1.66 g) and N-ethyldiisopropylamine (3.00 mL) in N, N-dimethylacetamide (15.0 mL) at 0 ° C. Stir for hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane). A 28% sodium methoxide methanol solution (10.0 mL) was added to a methanol solution (3.00 mL) of the obtained residue, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. 6N hydrochloric acid and 1N hydrochloric acid were added to the obtained residue, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from IPE to give the title compound (676 mg, 18%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.90 (6H, t, J = 7.4 Hz), 1.61-1.79 (2H, m), 2.20-2.46 (2H, m ), 2.75 (2H, s), 5.26 (2H, s), 7.15-7.43 (5H, m), 7.94 (1H, s), 8.31 (1H, s) , 11.65 (1H, brs).
MS (ESI +): 327 (M + H)
Melting point: 170-177 ° C

The compound of Reference Example 88 shown below was obtained in the same manner as described in Reference Example 83 using the compound obtained in Reference Example 86.
Reference Example 88
1- [4- (Benzyloxy) butanoyl] -5,5-diethylpyrazolidine-3-one ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.93 (6H, brs), 1.43-1. 80 (2H, m), 1.87-2.91 (8H, m), 3.53 (2H, t, J = 5.8 Hz), 4.51 (2H, brs), 7.11-7. 51 (5H, m), 10.05 (1H, brs).
MS (ESI +): 319 (M + H)

Reference Example 89
1- [3- (3,5-Dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] -4-hydroxy-1-butanone Compound obtained in Reference Example 88 A mixture of (670 mg) and phosphoryl chloride (852 mg) was stirred at 70 ° C. for 2.5 hours. The reaction mixture was added to a mixed solution of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution at 0 ° C., the organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 100% ethyl acetate / hexane). To a mixed solution of the obtained residue in acetonitrile (3.00 mL) and water (1.50 mL), potassium carbonate (400 mg), 3,5-dimethylphenylboronic acid (260 mg) and tetrakis (triphenylphosphine) palladium (0 ) (50.0 mg) and microwave irradiation at 150 ° C. for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane) to give the title compound (175 mg, 26%) as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.82 (6H, t, J = 7.5 Hz), 1.65-1.75 (2H, m), 1.85-2.07 (2H, m ), 2.20-2.47 (8H, m), 2.96 (2H, t, J = 6.8 Hz), 3.10 (2H, s), 3.74 (2H, t, J = 5) .8 Hz), 7.06 (1H, s), 7.32 (2H, s). MS (ESI +): 317 (M + H)

Reference Example 90
4-chloro-1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Compound (1) obtained in Reference Example 6 .20 g) and hydrazine monohydrate (0.375 mL) in pyridine (6.00 mL) were stirred at 80 ° C. under an argon atmosphere for 2 hours. After cooling the reaction solution to room temperature, a solution of 4-chlorobutyryl chloride (2.20 mL) in toluene (10.0 mL) was added to the reaction mixture at 0 ° C., and the mixture was stirred at 0 ° C. for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 20% ethyl acetate / hexane) to give the title compound (1.93 g, 99%) as a white powder.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.65 (6H, s), 2.08-2.24 (2H, m), 2.91 (2H, t, J = 7.2 Hz), 3. 09 (2H, s), 3.66 (2H, t, J = 6.4 Hz), 3.85 (3H, s), 6.92-6.99 (1H, m), 7.19-7. 37 (3H, m).
MS (ESI +): 309 (M + H)

The compounds of Reference Examples 91 to 94 shown below were obtained in the same manner as described in Reference Example 90 using the compounds obtained in Reference Examples 19, 36 and 77.
Reference Example 91
5-Chloro-1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-pentanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.65 (6H, s), 1.78-1.95 (4H, m), 2.69-2.84 (2H, m), 3.05 ( 2H, s), 3.51-3.63 (2H, m), 3.86 (3H, s), 6.86-7.05 (1H, m), 7.18-7.41 (3H, m).
MS (ESI +): 323 (M + H)
Reference Example 92
4-Chloro-1- [4,5-dihydro-3- (3,5-dimethylphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.64 (6H, s), 2.03-2.28 (2H, m), 2.35 (6H, s), 2.92 (2H, t, J = 7.3 Hz) 3.10 (2H, s), 3.67 (2H, t, J = 6.5 Hz), 7.05 (1H, s), 7.31 (2H, m).
MS (ESI +): 307 (M + H)
Reference Example 93
4-Chloro-1- [3- (3-chloro-5-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.65 (6H, s), 2.10-2.24 (2H, m), 2.38 (3H, s), 2.91 (2H, t, J = 7.3 Hz) 3.08 (2H, s), 3.67 (2H, t, J = 6.5 Hz), 7.20 (1 H, s), 7.37 (1 H, s), 7. 47 (1H, s).
MS (ESI +): 291 (M-HCl + H)

Reference Example 94
4-Chloro-1- [5-cyclopropyl-3- (3,5-dimethylphenyl) -4,5-dihydro-1H-pyrazol-1-yl] -1-butanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.18-0.29 (1H, m), 0.38-0.76 (4H, m), 1.10 (1H, qt, J = 8.0) , 4.9 Hz), 2.21 (2H, quin, J = 6.9 Hz), 2.36 (6H, s), 2.83-3.06 (2H, m), 3.23-3.38. (1H, m), 3.68 (2H, t, J = 6.6 Hz), 4.20-4.32 (1H, m), 7.06 (1H, s), 7.35 (2H, s ). MS (ESI +): 319 (M + H)

Reference Example 95
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-hydroxy-1-butanone The compound obtained in Example 114 Formic acid (10.2 mL) was added to a suspension of (3.62 g) and 10% palladium carbon (51% water-containing product, 1.27 g) in methanol (127 mL), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, washed with saturated sodium hydrogen carbonate, water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 25% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give the title compound (1.86 g, 67%) as colorless. Obtained as crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.65 (6H, s), 1.97 (2H, quin, J = 6.3 Hz), 2.35 (6H, s), 2.89-2. 96 (3H, m), 3.11 (2H, s), 3.72 (2H, q, J = 5.8 Hz), 7.06 (1H, s), 7.29 (2H, s).
MS (ESI +): 289 (M + H)
Melting point: 76-78 ° C
Elemental analysis value: C ₁₇ H ₂₄ N ₂ O ₂
Calculated value C, 70.80; H, 8.39; N, 9.71
Found C, 70.59; H, 8.46; N, 9.46

Using the compound obtained in Reference Example 82, the compound of Reference Example 96 shown below was obtained in the same manner as in the method described in Reference Example 83.
Reference Example 96
5,5-Dimethyl-1- (4-phenylbutanoyl) pyrazolidine-3-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.54 (6H, s), 1.97-2.07 (2H, m), 2.31 (2H, t, J = 7.6 Hz), 2. 63-2.72 (4H, m),
7.16-7.31 (5H, m), 9.37 (1H, brs).
MS (ESI +): (M + H) 261

Using the compound obtained in Reference Example 96, the compound of Reference Example 97 shown below was obtained in the same manner as in the method described in Reference Example 84.
Reference Example 97
1- (3-Chloro-4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl) -4-phenyl-1-butanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.26 (6H, s), 1.92-1.98 (2H, m), 2.52-2.73 (4H, m), 2.93 ( 2H, s), 7.10-7.30 (5H, m).

The compound of Reference Example 98 shown below was obtained in the same manner as described in Reference Example 6 using the compound obtained in Reference Example 5.
Reference Example 98
1- (3-Methoxy-5-methylphenyl) -3-methylbut-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.01 (3H, d, J = 1.5 Hz), 2.20 (3H, s), 2.37 (3H, s), 3.83 (3H, s), 6.68-6.73 (1H, m), 6.88 (1H, s), 7.27 (1H, s), 7.32 (1H, s).
MS (ESI +): 205 (M + H)

Reference Example 99
1-Benzyl-1H-imidazole-5-carboxylic acid (Step 1)
Methyl 1H-imidazole-4-carboxylate (2.00 g) was added to a solution of sodium hydride (932 mg) in DMF (20.0 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 5 minutes. Benzyl bromide (2.26 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 100% ethyl acetate / hexane) to give methyl 1-benzyl-1H-imidazole-5-carboxylate (575 mg, 17%) colorless. Obtained as crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.82 (3H, s), 5.52 (2H, s), 7.15-7.20 (2H, m), 7.29-7.38 ( 3H, m), 7.62 (1H, s), 7.78 (1H, d, J = 0.8 Hz).
MS (ESI +): 217 (M + H)
Melting point: 64-66 ° C
Elemental analysis value: C ₁₂ H ₁₂ N ₂ O ₂
Calculated C, 66.65; H, 5.59; N, 12.96
Found C, 66.93; H, 5.62; N, 12.73
(Process 2)
To a mixed solution of the compound (540 mg) obtained in (Step 1) above in THF (10.0 mL) and methanol (10.0 mL) was added 2N sodium hydroxide solution (3.74 mL), and the mixture was stirred at room temperature for 6 days. did. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was neutralized with 1N hydrochloric acid. The resulting precipitate was collected by filtration and recrystallized from methanol / ethyl acetate / diethyl ether to give the title compound (423 mg, 84%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.53 (2H, s), 7.12-7.18 (2H, m), 7.23-7.37 (3H, m), 7.63 ( 1H, s), 8.08 (1H, d, J = 0.8 Hz), 12.81 (1H, brs).
MS (ESI +): 203 (M + H)
Melting point: 220-222 ° C
Elemental analysis value: C ₁₁ H ₁₀ N ₂ O ₂
Calculated C, 65.34; H, 4.98; N, 13.85
Found C, 65.31; H, 5.04; N, 13.65

The compound of Reference Example 100 shown below was obtained in the same manner as described in Reference Example 99 using methyl 1H-pyrazole-3-carboxylate.
Reference Example 100
1-Benzyl-1H-pyrazole-3-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.36 (2H, s), 6.60 (1H, d, J = 2.3 Hz), 7.22-7.39 (5H, m), 7. 84 (1H, d, J = 2.3 Hz).
MS (ESI +): 203 (M + H)
Melting point: 155-157 ° C
Elemental analysis value: C ₁₁ H ₁₀ N ₂ O ₂
Calculated C, 65.34; H, 4.98; N, 13.85
Found C, 65.33; H, 5.05; N, 13.73

The compounds of Reference Examples 101 to 108 shown below were obtained in the same manner as described in Reference Example 20 using ethyl 1H-pyrazole-4-carboxylate.
Reference Example 101
1- (2,3-dichlorobenzyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.47 (2H, s), 7.02 (1H, dd, J = 7.6, 1.5 Hz), 7.21 (1H, t, J = 7 .8 Hz), 7.47 (1H, dd, J = 8.0, 1.5 Hz), 8.01 (2H, s).
MS (ESI +): 271 (M + H)
Melting point: 172-174 ° C
Reference Example 102
1- (3-Cyanobenzyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.36 (2H, s), 7.47-7.51 (2H, m), 7.53 (1H, s), 7.63-7.67 ( 1H, m), 7.98 (1H, s), 8.02 (1H, s).
MS (ESI +): 228 (M + H)
Melting point: 212-214 ° C
Elemental _{analysis: C 12 H 9 N 3 O} 2 · 0.2H 2 O
Calculated C, 62.44; H, 4.10; N, 18.20
Found C, 62.54; H, 4.03; N, 17.89
Reference Example 103
1- [4- (Tetrahydro-2H-pyran-4-yloxy) benzyl] -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.72-1.85 (2H, m), 1.96-2.07 (2H, m), 3.58 (2H, ddd, J = 11.6) , 8.2, 3.2 Hz), 3.98 (2H, ddd, J = 11.3, 6.5, 4.2 Hz), 4.49 (1H, tt, J = 7.7, 3.8 Hz). ), 5.24 (2H, s), 6.91 (2H, d, J = 8.7 Hz), 7.21 (2H, d, J = 8.7 Hz), 7.86 (1H, s), 7.98 (1H, s).
Melting point: 136-138 ° C
Reference Example 104
1- (2-Cyano-5-fluorobenzyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.54 (2H, s), 6.99 (1H, dd, J = 8.9, 2.5 Hz), 7.16 (1H, dt, J = 2) .7, 8.1 Hz), 7.73 (1H, dd, J = 8.7, 5.3 Hz), 8.04 (1H, s), 8.12 (1H, s).
MS (ESI +): 246 (M + H)
Melting point: 210-212 ° C
Elemental analysis value: C ₁₂ H ₈ FN ₃ O ₂
Calculated C, 58.78; H, 3.29; N, 17.14
Found C, 58.80; H, 3.29; N, 17.16

Reference Example 105
1- {1- [3- (trifluoromethyl) phenyl] ethyl} -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.95 (3H, d, J = 7.2 Hz) 5.60 (1H, q, J = 7.2 Hz), 7.37-7.43 (1H, m), 7.45-7.52 (2H, m), 7.56-7.62 (1H, m), 8.01 (1H, s), 8.02 (1H, s).
MS (ESI +): 285 (M + H)
Melting point: 130-132 ° C
Elemental _{analysis: C 13 H 11 F 3 N} 2 O 2
Calculated C, 54.93; H, 3.90; N, 9.86
Found C, 54.90; H, 3.91; N, 9.90
Reference Example 106
1- (Cyclopropylmethyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.38-0.45 (2H, m), 0.67-0.75 (2H, m), 1.24-1.39 (1H, m), 4.02 (2H, d, J = 7.2 Hz), 7.98 (1H, s), 8.08 (1H, s).
MS (ESI +): 167 (M + H)
Melting point: 134-136 ° C
Elemental analysis value: C ₈ H ₁₀ N ₂ O ₂
Calculated C, 57.82; H, 6.07; N, 16.86
Found C, 57.64; H, 6.06; N, 16.83
Reference Example 107
1- (Cyclopentylmethyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.17-1.36 (2H, m), 1.50-1.83 (6H, m), 2.38-2.52 (1H, m), 4.07 (2H, d, J = 7.6 Hz), 7.94 (1H, s), 7.96 (1H, s).
MS (ESI +): 195 (M + H)
Melting point: 124-126 ° C
Elemental _{analysis: C 10 H 14 N 2 O} 2
Calculated C, 61.84; H, 7.27; N, 14.42
Found C, 61.74; H, 7.27; N, 14.42
Reference Example 108
1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-pyrazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.28-1.45 (2H, m), 1.45-1.54 (2H, m), 2.14-2.25 (1H, m), 3.37 (2H, dt, J = 2.3, 11.7 Hz), 3.94-4.00 (2H, m), 4.02 (2H, d, J = 7.2 Hz), 7.91 (1H, s), 7.97 (1H, s).
MS (ESI +): 211 (M + H)

Reference Example 109
1- (2,3-Dichlorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid (Step 1)
Methanesulfonyl chloride (2.64 mL) was added to a solution of (2,3-dichlorophenyl) methanol (5.00 g) and triethylamine (4.72 mL) in dichloromethane (57.0 mL) under a nitrogen atmosphere under ice-cooling, and at room temperature. Stir for 1 hour. Water was slowly added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 20% ethyl acetate / hexane) to give 2,3-dichlorobenzyl methanesulfonate (7.00 g, 97%) as a yellow oil. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.06 (3H, s), 5.36 (2H, s), 7.28 (1H, t, J = 8.0 Hz), 7.43 (1H, dd, J = 7.6, 1.6 Hz), 7.52 (1H, dd, J = 8.2, 1.4 Hz).
(Process 2)
Sodium azide (4.46 g) was added to a DMF (55.0 mL) solution of the compound (7.00 g) obtained in the above (Step 1) at room temperature, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 20% ethyl acetate / hexane) to give 1- (azidomethyl) -2,3-dichlorobenzene (5.00 g, 90%). Obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.53 (2H, s), 7.23-7.26 (1H, m), 7.33 (1H, d, J = 7.2 Hz), 7. 46 (1H, d, J = 8.0 Hz).
(Process 3)
To a solution of methyl prop-2-inoate (2.08 mL) in THF (40.0 mL), copper (I) bromide (710 mg), copper acetate (II) (899 mg) and the compound obtained in the above (Step 2) A solution of (5.00 g) in tetrahydrofuran (10.0 mL) was added in order, and the mixture was stirred at 50 ° C. for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (30% ethyl acetate / hexane) to give methyl 1- (2,3-dichlorobenzyl) -1H-1,2,3-triazole-4-carboxylate. (3.50 g, 49%) was obtained as colorless crystals.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.95 (3H, s), 5.75 (2H, s), 7.15 (1H, dd, J = 8.0, 1.2 Hz), 7. 25 (1H, t, J = 8.0 Hz), 7.52 (1H, dd, J = 8.0, 1.6 Hz), 8.10 (1H, s).
(Process 4)
A solution of sodium hydroxide (587 mg) in water (5.00 mL) was added to a solution of the compound (3.50 g) obtained in (Step 3) above in methanol (25.0 mL), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and the mixture was washed with ethyl acetate. The aqueous layer was acidified (pH 2) with 6N hydrochloric acid. The resulting precipitate was collected by filtration and washed with ethyl acetate to give the title compound (2.60 g, 78%) as colorless crystals.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.81 (2H, s), 7.19 (1H, dd, J = 7.8, 1.4 Hz), 7.41 (1H, t, J = 8) .0Hz), 7.68 (1H, dd, J = 8.0, 1.6 Hz), 8.75 (1H, s), 13.20 (1H, brs).
MS (ESI +): 272 (M + H)

In the same manner as in the method described in Reference Example 109, the compounds of Reference Examples 110 to 115 shown below were obtained.
Reference Example 110
1- (2,4-Dichlorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid
^{1 H-NMR (400MHz, CDCl} 3): δ5.75 (2H, s), 7.31 (1H, d, J = 8.4Hz), 7.49 (1H, dd, J = 8.4,2 .0Hz), 7.72 (1H, d, J = 2.0 Hz), 8.74 (1H, s), 13.20 (1H, brs).
MS (ESI +): 272 (M + H)
Reference Example 111
1- (2-Cyanobenzyl) -1H-1,2,3-triazole-4-carboxylic acid
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.87 (2H, s), 7.40 (1H, d, J = 7.6 Hz), 7.58 (1H, dd, J = 7.6, 6 .8 Hz), 7.74 (1H, dt, J = 1.2, 7.6 Hz), 7.93 (1H, dd, J = 7.6, 1.2 Hz), 8.80 (1H, s) , 13.17 (1H, brs).
MS (ESI +): 229 (M + H)
Reference Example 112
1- (Pyridin-2-ylmethyl) -1H-1,2,3-triazole-4-carboxylic acid
¹ H-NMR (400 MHz, CDCl ₃ ): δ 5.80 (2H, s), 7.34-7.38 (2H, m), 7.84 (1H, dt, J = 1.6, 7.8 Hz) ), 8.33-8.55 (1H, m), 8.77 (1H, s), 13.10 (1H, brs).
MS (ESI +): 205 (M + H)
Reference Example 113
1- (1-Phenylethyl) -1H-1,2,3-triazole-4-carboxylic acid
^{1 H-NMR (400MHz, CDCl} 3): δ1.90 (3H, d, J = 7.2Hz), 6.00 (1H, q, J = 7.2Hz), 7.28-7.38 (5H M), 8.84 (1H, s), 13.08 (1H, brs).
MS (ESI +): 218 (M + H)
Reference Example 114
1- (cyclohexylmethyl) -1H-1,2,3-triazole-4-carboxylic acid
¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.90-0.99 (2H, m), 1.13-1.23 (3H, m), 1.48-1.51 (2H, m), 1.59-1.61 (1H, m), 1.65-1.68 (2H, m), 1.80-1.91 (1H, m), 4.26 (2H, d, J = 7) .2 Hz), 8.65 (1 H, s).
MS (ESI +): 210 (M + H)
Reference Example 115
1- (4-Methoxybenzyl) -1H-1,2,3-triazole-4-carboxylic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.82 (3H, s), 5.52 (2H, s), 6.93 (2H, d, J = 8.7 Hz), 7.21-7. 28 (2H, m), 7.9 (1H, s).
MS (ESI +): 234 (M + H)
Melting point: 182-184 ° C
Elemental _{analysis: C 11 H 11 N 3 O} 3
Calculated C, 56.65; H, 4.75; N, 18.02
Found C, 65.36; H, 4.78; N, 17.73

The compounds of Reference Examples 116 and 117 shown below were obtained in the same manner as described in Reference Example 27 using ethyl 4-bromobutanoate.
Reference Example 116
4- (3-Chloro-4-cyanophenoxy) butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.07-2.26 (2H, m), 2.59 (2H, d, J = 7.2 Hz), 4.09 (2H, t, J = 6) .0Hz), 6.85 (1H, dd, J = 8.7, 2.3 Hz), 7.00 (1H, d, J = 2.6 Hz), 7.57 (1H, d, J = 8. 7 Hz), 10.02 (1H, brs).
Reference Example 117
4- (2-Oxopyridin-1 (2H) -yl) butanoic acid
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.07 (2H, q, J = 7.0 Hz), 2.39 (2H, t, J = 6.9 Hz), 4.05 (2H, t, J = 7.0 Hz), 6.25 (1H, dt, J = 1.3, 6.7 Hz), 6.62 (1H, d, J = 8.7 Hz), 7.16 (1H, brs), 7 .31-7.35 (1H, m), 7.35-7.40 (1H, m).
MS (ESI +): 163 ( M-H 2 O)

The compound of Reference Example 118 shown below was obtained in the same manner as described in Reference Example 4 using the compound obtained in Reference Example 95.
Reference Example 118
4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutanal MS (ESI +): 287 (M + H)

The compounds of Reference Examples 119 and 120 shown below were obtained in the same manner as described in Reference Example 85 using ethyl diethylphosphonoacetate.
Reference Example 119
Ethyl 3-[(benzyloxy) methyl] pent-2-enoate
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.97-1.18 (3H, m), 1.18-1.33 (3H, m), 2.18-2.68 (2H, m), 3.78-4.86 (6H, m), 5.64-6.07 (1H, m), 6.98-7.49 (5H, m).
E / Z mixture

Reference Example 120
Mixture of ethyl (2,2-dimethyl-1,3-dioxane-5-ylidene) acetate and ethyl (2,2-dimethyl-4H-1,3-dioxin-5-yl) acetate
¹ H-NMR (300 MHz, CDCl ₃ ): δ1.22-1.32 (3H, m), 1.40 (3H, s), 1.46 (3H, s), 2.89 (1H, s) , 3.78-4.44 (4H, m), 4.86 (1H, s), 5.46-6.44 (1H, m).

The compound of Reference Example 121 shown below was obtained in the same manner as described in Reference Example 82 using the compound obtained in Reference Example 119.
Reference Example 121
5-[(Benzyloxy) methyl] -5-ethylpyrazolidin-3-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.89 (3H, t, J = 7.4 Hz), 1.42-1.76 (2H, m), 2.17 (1H, d, J = 16) .3 Hz), 2.76 (1H, d, J = 16.3 Hz), 3.10-3.61 (2H, m), 4.55 (2H, s), 7.08-7.45 (5H) , M), 7.72 (1H, brs).
MS (ESI +): 235 (M + H)

The compounds of Reference Examples 122 and 123 shown below were obtained in the same manner as described in Reference Example 87 using the compounds obtained in Reference Examples 86 and 121.
Reference Example 122
5,5-Diethyl-1-{[1- (1-phenylethyl) -1H-pyrazol-4-yl] carbonyl} pyrazolidin-3-one MS (ESI +): 341 (M + H)
Reference Example 123
5-[(Benzyloxy) methyl] -1-[(1-benzyl-1H-pyrazol-4-yl) carbonyl] -5-ethylpyrazolidin-3-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.89 (3H, t, J = 7.4 Hz), 1.64 (1H, dd, J = 14.0, 7.2 Hz), 2.35 (1H , Dd, J = 14.0, 7.2 Hz), 2.70 (1H, d, J = 17.4 Hz), 3.15 (1H, d, J = 17.4 Hz), 3.66 (1H, d, J = 9.5 Hz), 4.18 (1H, d, J = 9.5 Hz), 4.32-4.72 (2H, m), 5.21 (2H, s), 6.96- 7.50 (10H, m), 7.93 (1H, s), 8.27 (1H, s), 11.85 (1H, brs).
MS (ESI +): 419 (M + H)

Reference Example 124
8,8-Dimethyl-1- (4-phenoxybutanoyl) -7,9-dioxa-1,2-diazaspiro [4,5] decan-3-one (Step 1)
A solution of hydrazine monohydrate (2.20 mL) was added to a solution of the compound (7.20 g) obtained in Reference Example 120 in ethanol (30.0 mL), and the mixture was heated to reflux for 24 hours. The reaction mixture was concentrated under reduced pressure to give 8,8-dimethyl-7,9-dioxa-1,2-diazaspiro [4,5] decan-3-one (4.20 g, 62%) as a solid. It was.
(Process 2)
To a solution of 4-phenoxybutyric acid (10.2 g) in THF (20.0 mL) was added thionyl chloride (4.10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to a solution of the compound obtained in Step 1 (4.20 g) and N-ethyldiisopropylamine (10.0 mL) in N, N-dimethylacetamide (15.0 mL) at 0 ° C., and then at room temperature for 24 hours. Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane) to give an oil. A 28% sodium methoxide methanol solution (25.0 mL) was added to a methanol (15.0 mL) solution of the obtained oil, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was evaporated under reduced pressure, water was added and neutralized with 6N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 50 → 100% ethyl acetate / hexane), and the obtained residue was recrystallized from IPE to give the title compound (1.14 g, 14%). Was obtained as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.39 (3H, s), 1.56 (3H, s), 2.09-2.21 (2H, m), 2.41-2.79 ( 2H, m), 3.04 (2H, s), 3.57 (2H, d, J = 11.0 Hz), 4.03 (2H, t, J = 5.9 Hz), 4.75 (2H, brs), 6.67-7.03 (3H, m), 7.14-7.36 (2H, m), 10.36 (1H, brs).
MS (ESI +): 349 (M + H)

Using the compound obtained in Reference Example 64, the compound of Reference Example 125 shown below was obtained in the same manner as in the method described in Reference Example 67.
Reference Example 125
3-[(Benzyloxy) methyl] -1- (3,5-dimethylphenyl) pent-2-en-1-one MS (ESI +): 309 (M + H)
E / Z mixture

Using the compound obtained in Reference Example 65, the compounds of Reference Examples 126 and 127 shown below were obtained in the same manner as in the method described in Reference Example 81.
Reference Example 126
(2E) -1- (3-methoxyphenyl) hex-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.98 (3H, t, J = 7.4 Hz), 1.48-1.63 (2H, m), 2.24-2.36 (2H, m ), 3.86 (3H, s), 6.79-6.90 (1H, m), 7.00-7.14 (2H, m), 7.36 (1H, dt, J = 1.3) , 7.9 Hz), 7.44-7.53 (2H, m).
MS (ESI +): 205 (M + H)
Reference Example 127
(2E) -1- (3-methoxyphenyl) -4,4-dimethylpent-2-en-1-one
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.15 (9H, s), 3.86 (3H, s), 6.75 (1H, d, J = 15.5 Hz), 7.01-7. 14 (2H, m), 7.36-7.40 (1H, m), 7.48-7.51 (2H, m).
MS (ESI +): 219 (M + H)

Using the compound obtained in Reference Example 64, the compounds of Reference Examples 128 and 129 shown below were obtained in the same manner as in the method described in Reference Example 80.
Reference Example 128
(2E) -2- (Dihydrofuran-3 (2H) -ylidene) -1- (3,5-dimethylphenyl) ethanone
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.37 (6H, s), 2.56-2.73 (2H, m), 3.70 (2H, s), 4.36 (2H, t, J = 9.6 Hz), 6.25 (1H, s), 7.20 (1H, s), 7.58 (2H, s).
MS (ESI +): 217 (M + H)
E / Z Mixture Reference Example 129
1,1-dimethylethyl (3E) -3- [2- (3,5-dimethylphenyl) -2-oxoethylidene] pyrrolidine-1-carboxylate
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.46 (9H, s), 2.37 (6H, s), 2.64 (2H, m), 3.63-3.87 (3H, m) , 6.33-6.43 (1H, m), 6.44-6.56 (1H, m), 7.13-7.24 (1H, m), 7.57 (2H, s).
MS (ESI +): 316 (M + H)
E / Z mixture

Reference Example 130
3- (3-Methoxyphenyl) -4,4,5-trimethyl-4H-pyrazole (Step 1)
To a suspension of potassium t-butoxide (26.4 g) in THF (80.0 mL), a solution of 3-methoxyacetophenone (10.0 g) in THF (20.0 mL) was added under ice cooling, and the mixture was stirred at 0 ° C. for 15 minutes. Stir. Ethyl acetate (65.7 mL) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, acidified with 6N hydrochloric acid, and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane) to give 1- (3-methoxyphenyl) butane-1,3-dione (12.3 g, 96 %) As an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.20 (3H, s), 3.86 (3H, s), 6.16 (1H, s), 7.06 (1H, ddd, J = 8. 2, 2.6, 1.3 Hz), 7.35 (1 H, t, J = 8.0 Hz), 7.41-7.46 (2 H, m), 16.13 (1 H, s).
MS (ESI +): 193 (M + H)
(Process 2)
To a suspension of the compound obtained in Step 1 (6.00 g) and potassium carbonate (8.13 g) in THF (6.25 mL) and DMSO (12.5 mL) was added iodomethane (10.0 g), and For 24 hours. Water was added to the reaction mixture, acidified with 6N hydrochloric acid, and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane) to give 1- (3-methoxyphenyl) -2,2-dimethylbutane-1,3-dione. (4.65 g, 90%) was obtained as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.48 (6H, s), 2.09 (3H, s), 3.83 (3H, s), 7.04-7.12 (1H, m) 7.30-7.33 (2H, m), 7.38-7.40 (1H, m).
(Process 3)
Hydrazine monohydrate (0.270 mL) was added to an ethanol (5.00 mL) solution of the compound (1.00 g) obtained in Step 2 above, and the mixture was stirred at 90 ° C. for 5 hours. The reaction mixture was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate / IPE to give the title compound (892 mg, 92%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.41 (6H, s), 2.23 (3H, s), 3.87 (3H, s), 7.02 (1H, dd, J = 8. 1, 1.7 Hz), 7.33-7.39 (1 H, m), 7.48 (1 H, d, J = 7.6 Hz), 7.59-7.62 (1 H, m).
MS (ESI +): 217 (M + H)
Melting point: 85-87 ° C
Elemental analysis value: C ₁₃ H ₁₆ N ₂ O
Calculated: C, 72.19; H, 7.46; N, 12.95
Found: C, 72.03; H, 7.32; N, 12.88

In the same manner as in the method described in Reference Example 130, the compound of Reference Example 131 shown below was obtained.
Reference Example 131
1- (3-methoxyphenyl) -4-methyl-2,3-diazaspiro [4.4] nona-1,3-diene
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.84-1.95 (2H, m), 1.99-2.25 (6H, s), 2.26 (3H, s), 3.87 ( 3H, s), 7.01 (1H, ddd, J = 7.8, 2.5, 1.5 Hz), 7.31-7.38 (1H, m), 7.38-7.42 (1H , M), 7.53-7.57 (1H, m).
MS (ESI +): 243 (M + H)
Elemental _{analysis: C 15 H 18 N 2 O} · 0.2H 2 O
Calculated value: C, 73.26; H, 7.54; N, 11.39
Found: C, 73.26; H, 7.35; N, 11.55

Reference Example 132
1-[(1-Benzyl-1H-pyrazol-4-yl) carbonyl] -3- (3,5-dimethylphenyl) -5-ethyl-4,5-dihydro-1H-pyrazole-5-carbaldehyde To a solution of the compound obtained in Example 302 (880 mg) in acetonitrile (80.0 mL) was added Dess-Martin reagent (1.80 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane) to give the title compound (105 mg, 12%) as colorless crystals.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.88 (3H, t, J = 7.6 Hz), 1.86-2.08 (1H, m), 2.36 (6H, s), 2. 39-2.59 (1H, m), 3.07 (1H, d, J = 17.8 Hz), 3.46 (1H, d, J = 18.2 Hz), 5.34 (2H, s), 7.09 (1H, s), 7.22-7.48 (7H, m), 8.19 (1H, s), 8.37 (1H, s), 9.85 (1H, s).
MS (ESI +): 415 (M + H)
Melting point: 136-139 ° C
Elemental _{analysis: C 25 H 26 N 4 O} 2 · 0.1H 2 O
Calculated values: C, 72.13; H, 6.34; N, 13.46
Found: C, 72.02; H, 6.35; N, 13.24

Example 1
1- [4,5-Dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone (Step 1)
A solution of 3′-methoxyacetophenone (15.0 g), methanesulfonic acid (481 mg) and trimethyl orthoacetate (11.7 g) in methanol (50.0 mL) was stirred at room temperature for 20 hours. The reaction mixture was added to a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by NH silica gel chromatography (solvent gradient; 0 → 10% ethyl acetate / hexane) to give 1- (1,1-dimethoxyethyl) -3-methoxybenzene (15.6 g, 79%) was obtained as a yellow oil.
^{1 H-NMR (300MHz, CDCl} 3): δ1.53 (3H, s), 3.20 (6H, s), 3.82 (3H, s), 6.83 (1H, dd, J = 8. 0, 2.5 Hz), 7.02-7.11 (2H, m), 7.24-7.30 (1 H, m).
(Process 2)
To a THF (30.0 mL) solution of the compound obtained in Step 1 above (5.90 g) and pyridine (4.74 g) was added trifluoroacetic anhydride (12.6 g) at 0 ° C., and the mixture was stirred at room temperature for 17 hours. did. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried, and then the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 30% ethyl acetate / hexane) to obtain 1,1,1-trifluoro-4-methoxy-4- (3-methoxyphenyl) A cis and trans mixture of -3-buten-2-one (6.62 g, 85%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.82 (3H, s), 3.96 (3H, s), 5.82 (1H, s), 6.99-7.09 (3H, m) , 7.31-7.40 (1H, m).
MS (ESI +): 261 (M + H)
(Process 3)
4-phenylbutanohydrazide (1.57 g) was added to a methanol (10.0 mL) solution of the compound (2.08 g) obtained in Step 2 above at room temperature, and the mixture was stirred at 60 ° C. for 14 hours. After cooling the reaction solution, the precipitate was collected by filtration and recrystallized from ethanol / IPE to give the title compound (2.40 g, 74%) as colorless crystals.

In the same manner as in the method described in Example 1, the compounds of Examples 2-34 shown below were obtained.
Example 2
1- [4,5-Dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trichloromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 3
1- [4,5-Dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 4
1- [4,5-Dihydro-5-hydroxy-3-phenyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 5
1- [4,5-Dihydro-5-hydroxy-3-phenyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 6
1- [4,5-Dihydro-5-hydroxy-3- (2-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 7
1- [4,5-dihydro-5-hydroxy-3- (2-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone

Example 8
1- [4,5-Dihydro-5-hydroxy-3- (2-methylphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 9
1- [4,5-Dihydro-5-hydroxy-3- (2-methylphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 10
1- [3- (2-Chlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 11
1- [3- (2-Chlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 12
1- [3- (2-Fluorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 13
1- [3- (2-Fluorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone

Example 14
1- {4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -3- [2- (trifluoromethyl) phenyl] -1H-pyrazol-1-yl} -4-phenyl-1-butanone Example 15
1- {4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -3- [2- (trifluoromethyl) phenyl] -1H-pyrazol-1-yl} -5-phenyl-1-pentanone Example 16
1- [4,5-dihydro-5-hydroxy-3- (4-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 17
1- [4,5-Dihydro-5-hydroxy-3- (4-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 18
1- [3- (4-Fluorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 19
1- [3- (4-Fluorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone

Example 20
1- [4,5-Dihydro-5-hydroxy-3- (thiophen-2-yl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 21
1- [4,5-Dihydro-5-hydroxy-3- (thiophen-2-yl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 22
1- [3- (2,4-Dimethyl-1,3-thiazol-5-yl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl]- 4-Phenyl-1-butanone

Example 23
1- [3- (2,4-Dimethyl-1,3-thiazol-5-yl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl]- 5-Phenyl-1-pentanone Example 24
(5-Amino-1-benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazole -1-yl] methanone Example 25
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 26
4- (3,4-Dimethoxyphenyl) -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl 1-butanone Example 27
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4- (4-methoxyphenyl)- 1-butanone Example 28
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone

Example 29
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone 30
1- [3- (3,5-Dichlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 31
1- [3- (3,5-dichlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4- (4-methoxyphenyl) -1 -Butanone

Example 32
1- [3- (3,5-Dichlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4- (3,4-dimethoxyphenyl) -1-butanone Example 33
1- [3- (3,5-Dichlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 34
1- [3- (3,5-dichlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone

  The chemical structural formulas of the compounds obtained in Examples 1 to 34 are shown in Table 1.

Using the compounds obtained in Reference Examples 1 and 2, the compounds of Examples 35 to 37 shown below were obtained in the same manner as in the method described in Example 1.
Example 35
(1-Benzyl-1H-pyrazol-4-yl) [4,5-dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] methanone Example 36
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl ] Methanone Example 37
4- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-oxobutoxy} benzo Nitrile

  The chemical structural formulas of the compounds obtained in Examples 35 to 37 are shown in Table 2.

Example 38
(1-Benzyl-1H-pyrazol-4-yl) [4,5-dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] methanone Hydrochloride salt To a solution of the compound obtained in Example 35 (222 mg) in methanol (5.00 mL) was added 4N hydrogen chloride / ethyl acetate solution (0.15 mL), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol / ethyl acetate / IPE to give the title compound (190 mg, 79%) as colorless crystals.

The compound of Example 39 shown below was obtained in the same manner as in the method described in Example 38, using the compound obtained in Example 36.
Example 39
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl ] Methanone hydrochloride

Example 40
Sodium 3- (3,5-dimethylphenyl) -4,5-dihydro-1- (4-phenylbutanoyl) -5- (trifluoromethyl) -1H-pyrazole-5-olate obtained in Example 25 To a solution of the compound (100 mg) in methanol (2.50 mL) was added 2N sodium hydroxide solution (0.12 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and recrystallized from methanol / IPE to give the title compound (86 mg, 81%) as colorless crystals.

  The chemical structural formulas of the compounds obtained in Examples 38 to 40 are shown in Table 3.

Example 41
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4- (phenylamino) -1- Butanone To a solution of the compound (70.0 mg) obtained in Reference Example 4 and aniline (23.0 mg) in acetonitrile (3.00 mL) was added sodium triacetoxyhydroborate (127 mg), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was added to a saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 40 → 90% ethyl acetate / hexane) and recrystallized from IPE to give the title compound (60.0 mg, 72%) as colorless crystals. It was.

Example 42
4,5-Dihydro-3- (3-methoxyphenyl) -1- (4-phenylbutanoyl) -5- (trifluoromethyl) -1H-pyrazol-5-yl acetate The compound obtained in Example 1 ( To a solution of 250 mg) and acetyl chloride (58.0 mg) in THF (6.00 mL), triethylamine (125 mg) was added at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 40% ethyl acetate / hexane) to give the title compound (248 mg, 89%) as a colorless oil.

The compound of Example 43 shown below was obtained in the same manner as in the method described in Example 42.
Example 43
4,5-Dihydro-3- (3-methoxyphenyl) -1- (4-phenylbutanoyl) -5- (trifluoromethyl) -1H-pyrazol-5-yl methoxyacetate

Example 44
4,5-Dihydro-3- (3-methoxyphenyl) -1- (4-phenylbutanoyl) -5- (trifluoromethyl) -1H-pyrazol-5-yl hydroxyacetate The method described in Example 42 4,5-dihydro-3- (3-methoxyphenyl) -1- (4-phenylbutanoyl) -5- (trifluoromethyl) -1H-pyrazol-5-yl (benzyloxy) acetate Got.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.90-2.11 (2H, m), 2.69 (2H, t, J = 7.6 Hz), 2.83 (2H, td, J = 7) .4, 1.3 Hz), 3.57-3.80 (2H, m), 3.85 (3H, s), 4.23 (2H, d, J = 5.5 Hz), 4.59 (2H) , D, J = 4.5 Hz), 6.89-7.08 (1H, m), 7.10-7.49 (13H, m).
MS (ESI +): 555 (M + H)
Melting point: 89-91 ° C
Colorless crystals A suspension of the compound obtained above (410 mg) and 10% palladium / carbon (51% water-containing product, 40.0 mg) in ethanol (10.0 mL) was stirred at room temperature in a hydrogen atmosphere for 48 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 40% ethyl acetate / hexane) to give the title compound (152 mg, 45%) as a colorless oil.

The compound of Example 45 shown below was obtained in the same manner as in the method described in Example 42 using the compound obtained in Example 22.
Example 45
3- (2,4-Dimethyl-1,3-thiazol-5-yl) -4,5-dihydro-1- (4-phenylbutanoyl) -5- (trifluoromethyl) -1H-pyrazole-5 Il methoxyacetate

Example 46
1- [4,5-dihydro-5-methoxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone in Example 1 A solution of the obtained compound (197 mg), potassium carbonate (100 mg) and iodomethane (273 mg) in acetonitrile (8.00 mL) was stirred at room temperature for 14 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 60% ethyl acetate / hexane) to give the title compound (173 mg, 86%) as a colorless oil.

In the same manner as in Example 46, the compound of Example 47 shown below was obtained.
Example 47
1- [5-Ethoxy-4,5-dihydro-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Using the compounds obtained in Examples 22 and 25, the compounds of Examples 48 to 49 shown below were obtained in the same manner as in the method described in Example 46.
Example 48
1- [3- (2,4-Dimethyl-1,3-thiazol-5-yl) -4,5-dihydro-5-methoxy-5- (trifluoromethyl) -1H-pyrazol-1-yl]- 4-Phenyl-1-butanone Example 49
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5-methoxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

  The chemical structural formulas of the compounds obtained in Examples 41 to 49 are shown in Table 4.

Example 50
(1-benzyl-1H-pyrazol-4-yl) [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] methanone 1-benzyl-1H- Oxalyl dichloride (0.520 mL) and DMF (0.100 mL) were added to a THF (5.00 mL) solution of pyrazole-4-carboxylic acid (1.06 g), and the mixture was stirred at room temperature for 1 hour, and the reaction mixture was reduced under reduced pressure. Concentrated with.
A solution of the compound obtained in Reference Example 6 (500 mg) and hydrazine monohydrate (0.195 mL) in pyridine (2.00 mL) was stirred at 90 ° C. for 1 hour. After the reaction solution was cooled to room temperature, a solution of the residue obtained above in THF (2.00 mL) was added, and the mixture was stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 100% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give the title compound (315 mg, 31%) as colorless crystals. Obtained.

In the same manner as in the method described in Example 50, the following compounds of Examples 51 to 75 were obtained.
Example 51
[4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] (5-phenylfuran-2-yl) methanone Example 52
[4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] (1-phenyl-1H-pyrazol-4-yl) methanone Example 53
(1-Benzofuran-2-yl) [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] methanone

Example 54
[4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] (3-methyl-1-benzofuran-2-yl) methanone Example 55
[4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] (5-methoxy-1-benzofuran-2-yl) methanone Example 56
[4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] (5-nitro-1-benzofuran-2-yl) methanone

Example 57
[4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] [(1R, 2R) -2-phenylcyclopropyl] methanone Example 58
(3E) -1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenylbut-3-en-1-one Example 59
1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 60
4- (3,4-Dimethoxyphenyl) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 61
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- (4-methoxyphenyl) -1-butanone Example 62
1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- (4-methylphenyl) -1-butanone

Example 63
4- (4-Bromophenyl) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 64
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- (4-nitrophenyl) -1-butanone Example 65
1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- (thiophen-2-yl) -1-butanone

Example 66
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 67
4- (4-Bromophenoxy) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 68
4- (2-Bromophenoxy) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone

Example 69
4- (3-Bromophenoxy) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 70
4- (2,4-Dichlorophenoxy) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 71
4- (Benzyloxy) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone

Example 72
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 73
5- (4-Fluorophenyl) -1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-pentanone Example 74
1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -5-phenoxy-1-pentanone

Example 75
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -6-phenoxy-1-hexanone

  The chemical structural formulas of the compounds obtained in Examples 50 to 75 are shown in Table 5.

The compounds of Examples 76 to 83 shown below were obtained in the same manner as described in Example 50 using the compounds obtained in Reference Examples 7 to 10.
Example 76
1- [4,5-Dihydro-5,5-dimethyl-3-phenyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 77
1- [4,5-Dihydro-5,5-dimethyl-3- (3-methylphenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 78
4-cyclohexyl-1- [4,5-dihydro-5,5-dimethyl-3- (3-methylphenyl) -1H-pyrazol-1-yl] -1-butanone

Example 79
1- [4,5-Dihydro-5,5-dimethyl-3- (3-methylphenyl) -1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 80
1- [3- (3-Chlorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 81
1- [3- (3-Chlorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-cyclohexyl-1-butanone

Example 82
1- [3- (3-Chlorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -5-phenyl-1-pentanone Example 83
1- [3- (3-Fluorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

  The chemical structural formulas of the compounds obtained in Examples 76 to 83 are shown in Table 6.

Example 84
1- [4,5-Dihydro-3- (3-hydroxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone The compound obtained in Reference Example 11 was used. 1- {3- [3- (benzyloxy) phenyl] -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl} -4 in a manner similar to that described in Example 50. -Phenyl-1-butanone was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.58 (6H, s), 1.92-2.00 (2H, m), 2.61-2.72 (4H, m), 3.00 ( 2H, s), 5.03 (2H, s), 6.93-6.97 (1H, m), 7.19-7.20 (5H, m), 7.21-7.30 (4H, m), 7.31-7.35 (2H, m), 7.37-7.40 (2H, m).
MS (ESI +): 427 (M + H)
A suspension of the above-obtained compound (825 mg) and 10% palladium carbon (51% water-containing product, 100 mg) in ethanol (10.0 mL) was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 60% ethyl acetate / hexane), and recrystallized from methanol / IPE to give the title compound (612 mg, 94%) as colorless crystals. It was.

Example 85
1- [3- (3-Ethoxyphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone The compound obtained in Example 84 (168 mg ) And potassium carbonate (138 mg) in acetonitrile (7.00 mL) were added iodoethane (117 mg) and stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 60% ethyl acetate / hexane) to give the title compound (161 mg, 88%) as an oil.

Example 86
3- [4,5-Dihydro-5,5-dimethyl-1- (4-phenylbutanoyl) -1H-pyrazol-3-yl] phenyl acetate The compound obtained in Example 84 (168 mg) and pyridine (79 mg) ) In THF (5.00 mL) was added acetyl chloride (59.0 mg), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 50% ethyl acetate / hexane) to give the title compound (162 mg, 86%) as an oil.

  The chemical structural formulas of the compounds obtained in Examples 84 to 86 are shown in Table 7.

The compounds of Examples 87 to 123 shown below were obtained in the same manner as described in Example 50 using the compounds obtained in Reference Examples 12 to 19.
Example 87
1- [4,5-Dihydro-3- (2-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 88
4-cyclohexyl-1- [4,5-dihydro-3- (2-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 89
1- [4,5-Dihydro-3- (2-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -5-phenyl-1-pentanone

Example 90
1- [3- (2-Chlorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 91
1- {4,5-dihydro-5,5-dimethyl-3- [2- (trifluoromethyl) phenyl] -1H-pyrazol-1-yl} -4-phenyl-1-butanone Example 92
1- [4,5-Dihydro-3- (4-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 93
1- [4,5-Dihydro-5,5-dimethyl-3- (4-methylphenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 94
1- [3- (4-tert-butylphenyl) -4,5-dihydro-5,5-dimethyl-
1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 95
1- [3- (4-Fluorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 96
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 97
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (4-methoxybenzyl) -1H-pyrazol-4-yl] Methanone Example 98
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (4-methylbenzyl) -1H-pyrazol-4-yl] Methanon

Example 99
[1- (4-Chlorobenzyl) -1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] Methanone Example 100
[1- (3,4-Dichlorobenzyl) -1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazole-1- Il] methanone Example 101
[1- (2,4-Dichlorobenzyl) -1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazole-1- Il] methanone

Example 102
[1-Benzyl-3-methyl-1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 103
(1-Benzyl-1H-1,2,3-triazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl ] Methanone Example 104
(1-Benzofuran-2-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone

Example 105
(5-Chloro-1-benzofuran-2-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 106
(5-Bromo-1-benzofuran-2-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 107
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 108
4-Cyclohexyl-1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 109
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 110
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- (4-fluorophenoxy) -1-butanone

Example 111
4- (4-Chlorophenoxy) -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 112
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (methylsulfanyl) phenoxy] -1-butanone Example 113
4- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} benzonitrile

Example 114
4- (Benzyloxy) -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 115
2- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} benzonitrile Example 116
4- (3,5-dimethylphenoxy) -1- [3- (3,5-dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone

Example 117
4- (2,3-dichlorophenoxy) -1- [3- (3,5-dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone Example 118
4- (2,4-dichlorophenoxy) -1- [3- (3,5-dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone Example 119
4- (2,4-Difluorophenoxy) -1- [3- (3,5-dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone

Example 120
4- (3,4-difluorophenoxy) -1- [3- (3,5-dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone Example 121
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -5-phenoxy-1-pentanone Example 122
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -5- (4-fluorophenoxy) -1-pentanone

Example 123
4-({5- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -5-oxopentyl} oxy) benzonitrile

  The chemical structural formulas of the compounds obtained in Examples 87 to 123 are shown in Table 8.

The compounds of Examples 124 to 139 shown below were obtained in the same manner as in the method described in Example 50 using the compounds obtained in Reference Example 19 and Reference Examples 20 to 35.
Example 124
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] {1- [4- (trifluoromethyl) benzyl] -1H-pyrazole- 4-Il} methanone Example 125
4-[(4-{[3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] carbonyl} -1H-pyrazol-1-yl) Methyl] benzonitrile Example 126
2-[(4-{[3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] carbonyl} -1H-pyrazol-1-yl) Methyl] benzonitrile

Example 127
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (pyridin-2-ylmethyl) -1H-pyrazol-4-yl Methanone Example 128
[1- (cyclohexylmethyl) -1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 129
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (1-phenethyl) -1H-pyrazol-4-yl] methanone

Example 130
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (2-phenethyl) -1H-pyrazol-4-yl] methanone Example 131
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (trifluoromethyl) phenoxy] -1- Butanone Example 132
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (trifluoromethoxy) phenoxy] -1- Butanone

Example 133
4- [4- (Benzyloxy) phenoxy] -1- [3- (3,5-dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone Example 134
4- [3,5-bis (trifluoromethyl) phenoxy] -1- [3- (3,5-dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone Example 135
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- (pyridin-2-yloxy) -1-butanone

Example 136
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-[(6-methylpyridin-2-yl) oxy] -1-butanone Example 137
4-[(5-chloropyridin-2-yl) oxy] -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone Example 138
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-{[5- (trifluoromethyl) pyridin-2- Yl] oxy} -1-butanone

Example 139
2- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -4,6-dimethylpyridine -3-carbonitrile

  Table 9 shows the chemical structural formulas of the compounds obtained in Examples 124 to 139.

Using the compounds obtained in Reference Examples 36 to 52, 54, 58, 60 to 63 and 67, the compounds of Examples 140 to 169 shown below were obtained in the same manner as in the method described in Example 50.
Example 140
1- [3- (3-Chloro-5-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 141
1- [3- (3-Chloro-5-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 142
1- [3- (3,5-dichlorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 143
1- [3- (3,5-Dichlorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 144
1- [3- (3-Chloro-5-fluorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 145
1- [3- (3,5-Difluorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 146
1- {3- [3,5-Bis (trifluoromethyl) phenyl] -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl} -4-phenyl-1-butanone Example 147
1- [3- (3,5-Diethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 148
1- [4,5-dihydro-3- (2-methoxy-5-methylphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 149
1- [3- (2,5-Dimethoxyphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 150
1- [3- (5-Fluoro-2-methoxyphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 151
1- [3- (3-Fluoro-4-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 152
1- [3- (4-Fluoro-3-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 153
1- [3- (3,4-Difluorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 154
1- [3- (2,3-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 155
1- [4,5-Dihydro-3- (4-methoxy-3,5-dimethylphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 156
1- [4,5-Dihydro-5,5-dimethyl-3- (3-methylthiophen-2-yl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 157
1- [4,5-dihydro-5,5-dimethyl-3- (naphthalen-2-yl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 158
1- [4,5-Dihydro-5,5-dimethyl-3- (naphthalen-1-yl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 159
1- [4,5-Dihydro-3- (2-methoxy-3,5-dimethylphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 160
1- [3- (4,6-Dimethylpyridin-2-yl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 161
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5-methyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 162
1- [3- (3,5-Dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 163
1- [3- (3,5-Dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] -4-phenoxy-1-butanone

Example 164
1- [5,5-Diethyl-4,5-dihydro-3- (3-methoxyphenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 165
1- [5,5-Diethyl-4,5-dihydro-3- (3-methoxyphenyl) -1H-pyrazol-1-yl] -4- (4-methoxyphenyl) -1-butanone Example 166
1- [5-Ethyl-4,5-dihydro-3- (3-methoxyphenyl) -5-methyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 167
1- [5-Ethyl-4,5-dihydro-3- (3-methoxyphenyl) -5-methyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 168
1- {5-[(benzyloxy) methyl] -4,5-dihydro-3- (3,5-dimethylphenyl) -5-methyl-1H-pyrazol-1-yl} -4-phenyl-1-butanone Example 169
1- {5-[(Benzyloxy) methyl] -4,5-dihydro-3- (3,5-dimethylphenyl) -5-methyl-1H-pyrazol-1-yl} -4-phenoxy-1-butanone

  Table 10 shows the chemical structural formulas of the compounds obtained in Examples 140 to 169.

Example 170
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5- (hydroxymethyl) -5-methyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 168 A suspension of the compound obtained in (150 mg) and 10% palladium carbon (51% water-containing product, 25.0 mg) in ethanol (4.00 mL) was stirred at room temperature under a hydrogen atmosphere for 3 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane) to give the title compound (80.0 mg, 67%) as an oil.

The compound of Example 171 shown below was obtained in the same manner as in the method described in Example 170 using the compound obtained in Example 169.
Example 171
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5- (hydroxymethyl) -5-methyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone

Example 172
1- [4,5-dihydro-5- (hydroxymethyl) -3- (3-methoxyphenyl) -5-methyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone obtained in Reference Example 68 1- {5-[(benzyloxy) methyl] -4,5-dihydro-3- (3-methoxyphenyl) -5-methyl- using the resulting compound in a manner similar to that described in Example 50. 1H-pyrazol-1-yl} -4-phenyl-1-butanone was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.59 (3H, s), 2.09-2.26 (2H, m), 2.95 (3H, td, J = 7.5, 1.7 Hz) ), 3.53 (1H, d, J = 17.4 Hz), 3.69 (1H, d, J = 9.1 Hz), 3.84 (3H, s), 3.99-4.15 (3H M), 4.44-4.63 (2H, m), 6.84-7.02 (4H, m), 7.16-7.40 (10 H, m).
MS (ESI +): 457 (M + H)
The title compound was obtained in the same manner as described in Example 170 using the compound obtained above.

Example 173
[4,5-Dihydro-3- (3-methoxyphenyl) -5-methyl-1- (4-phenylbutanoyl) -1H-pyrazol-5-yl] methyl acetate The compound obtained in Example 172 (183 mg ) And pyridine (79.0 mg) in THF (5.00 mL) were added acetyl chloride (59.0 mg), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 50% ethyl acetate / hexane) to give the title compound (145 mg, 71%) as an oil.

  Table 11 shows the chemical structural formulas of the compounds obtained in Examples 170 to 173.

The compounds of Examples 174 to 187 shown below were obtained in the same manner as described in Example 50 using the compounds obtained in Reference Examples 69 to 80.
Example 174
1- [4,5-Dihydro-5- (methoxymethyl) -3- (3-methoxyphenyl) -5-methyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 175
1- [7- (3-Methoxyphenyl) -5,6-diazaspiro [3.4] oct-6-en-5-yl] -4-phenyl-1-butanone Example 176
1- [3- (3-Methoxyphenyl) -1,2-diazaspiro [4.4] non-2-en-1-yl] -4-phenyl-1-butanone

Example 177
1- [5-Ethyl-4,5-dihydro-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 178
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5-propyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 179
1- [3- (2,4-Dimethyl-1,3-thiazol-5-yl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1- Butanone

Example 180
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5-methyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 181
1- [5-Ethyl-4,5-dihydro-3- (3-methoxyphenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 182
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5- (1-methylethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 183
1- [5-Cyclopropyl-4,5-dihydro-3- (3-methoxyphenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 184
(1-Benzyl-1H-pyrazol-4-yl) [5-cyclopropyl-3- (3,5-dimethylphenyl) -4,5-dihydro-1H-pyrazol-1-yl] methanone Example 185
1- [5-Cyclopropyl-4,5-dihydro-3- (3,5-dimethylphenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 186
1- [5-Cyclopropyl-4,5-dihydro-3- (3,5-dimethylphenyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 187
1- [5- (1,1-Dimethylethyl) -3- (3,5-dimethylphenyl) -4,5-dihydro-1H-pyrazol-1-yl] -4-phenoxy-1-butanone

  Table 12 shows the chemical structural formulas of the compounds obtained in Examples 174 to 187.

Example 188
1- [4,5-dihydro-3- (3-methoxyphenyl) -5- (1-methylethyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone obtained in Reference Example 78 A solution of the compound (408 mg) and hydrazine monohydrate (150 mg) in pyridine (4.00 mL) was stirred at 90 ° C. for 1.5 hours under an argon atmosphere. Sodium hydride (106 mg, 50-72% oily) was added to the reaction mixture and stirred at 90 ° C. for 30 minutes. 4-phenoxybutanoyl chloride (596 mg) was added to the reaction mixture, and the mixture was stirred at 90 ° C. for 3 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 0 → 35% ethyl acetate / hexane) and recrystallized from IPE / hexane to give the title compound (488 mg, 64%) as colorless crystals. It was.

The compound of Example 189 shown below was obtained in the same manner as in the method described in Example 188, using the compound obtained in Reference Example 79.
Example 189
1- [5-Cyclopropyl-4,5-dihydro-3- (3-methoxyphenyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone

Example 190
1- {5-[(Benzyloxy) methyl] -3- (3,5-dimethylphenyl) -4,5-dihydro-1H-pyrazol-1-yl} -4-phenoxy-1-butanone In Reference Example 81 A solution of the obtained compound (560 mg) and hydrazine monohydrate (150 mg) in ethanol (25.0 mL) was heated to reflux for 8 hours. After cooling the reaction solution to room temperature, the reaction mixture was concentrated under reduced pressure. 4-phenoxybutanoyl chloride (993 mg) was added to a solution of the obtained residue in 1-methyl-2-pyrrolidone (15.0 mL), and the mixture was stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane), further purified by preparative HPLC, and recrystallized from IPE to give the title compound (520 mg, 57% ) Was obtained as colorless crystals.

Example 191
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5- (hydroxymethyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone obtained in Example 190 Formic acid (1.00 mL) was added to a suspension of the compound (450 mg) and 10% palladium carbon (51% water-containing product, 90 mg) in ethanol (20.0 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, washed with saturated sodium hydrogen carbonate, water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 70% ethyl acetate / hexane) and recrystallized from ethanol / IPE to give the title compound (159 mg, 43%) as colorless crystals. It was.

Example 192
1- [4,5-Dihydro-3- (4-hydroxy-3,5-dimethylphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone in Reference Example 84 The obtained compound (442 mg), 2,6-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (447 mg), tetrakis (triphenylphosphine) ) A mixed solution of palladium (0) (86.7 mg) and sodium carbonate (350 mg) in acetonitrile (3.33 mL) and water (1.67 mL) was subjected to microwave irradiation at 170 ° C. for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 70% ethyl acetate / hexane) and recrystallized from ethanol / IPE to give the title compound (394 mg, 69%) as colorless crystals. It was.

Example 193
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] methanone In Reference Example 87 A mixture of the obtained compound (630 mg) and phosphoryl chloride (3.33 g) was stirred at 70 ° C. for 3 hours. The reaction mixture was added to a mixed solution of ethyl acetate and saturated aqueous sodium hydrogen carbonate solution at 0 ° C., the organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 100% ethyl acetate / hexane). To a mixed solution of the obtained residue in acetonitrile (3.00 mL) and water (1.50 mL), potassium carbonate (370 mg), 3,5-dimethylphenylboronic acid (240 mg) and tetrakis (triphenylphosphine) palladium (0 ) (46.0 mg) and microwave irradiation at 150 ° C. for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 100% ethyl acetate / hexane) to give the title compound (397 mg, 50%) as an oil.

Example 194
1- [3- (3,5-Dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone (Step 1)
A solution of the compound obtained in Reference Example 89 (250 mg) and Dess-Martin reagent (1.04 g) in acetonitrile (12.0 mL) was stirred at 0 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 3 → 50% ethyl acetate / hexane) to give 4- [3- (3,5-dimethylphenyl) -5,5-diethyl-4. , 5-Dihydro-1H-pyrazol-1-yl] -4-oxobutanal (210 mg, 85%) was obtained as an oil.
(Process 2)
To a solution of the compound obtained in Step 1 (210 mg) in acetonitrile (14.0 mL), aniline (0.090 mL) and sodium triacetoxyhydroborate (425 mg) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to a saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 3 → 30% ethyl acetate / hexane), and further purified by preparative HPLC to give the title compound (223 mg, 85%) as an oil. It was.

  Table 13 shows the chemical structural formulas of the compounds obtained in Examples 188 to 194.

Example 195
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] methanone hydrochloride Examples To a solution of the compound obtained in 193 (224 mg) in ethyl acetate (4.00 mL) was added 4N hydrogen chloride / ethyl acetate solution (0.270 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 15 min. After adding methanol to the reaction mixture, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol / IPE to give the title compound (107 mg, 44%) as colorless crystals.

The compound of Example 196 shown below was obtained in the same manner as in the method described in Example 195, using the compound obtained in Example 96.
Example 196
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone hydrochloride

Example 197
1- [3- (3,5-Dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone p-toluenesulfonic acid Salt To a solution of the compound obtained in Example 194 (131 mg) in ethyl acetate (2.00 mL) was added a solution of p-toluenesulfonic acid monohydrate (64.0 mg) in ethyl acetate (2.00 mL) at 0 ° C. And stirred at 0 ° C. for 15 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (160 mg, 85%) as amorphous crystals.

  Table 14 shows the chemical structural formulas of the compounds obtained in Examples 195 to 197.

Example 198
(5-Amino-1-benzofuran-2-yl) [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] methanone obtained in Example 56 A suspension of the compound (603 mg) and 10% palladium carbon (51% water-containing product, 153 mg) in ethanol (20.0 mL) and THF (10.0 mL) was stirred at room temperature for 72 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate / IPE to give the title compound (294 mg, 53%) as colorless crystals.

Example 199
1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (pyrrolidin-1-yl) phenyl] -1- Butanone hydrochloride 4- (4-aminophenyl) -1- [4,5-dihydro-3- (3-methoxy) was prepared in the same manner as described in Example 198 using the compound obtained in Example 64. Phenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone was obtained.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.64 (6H, s), 1.90-2.03 (2H, m), 2.60 (2H, t, J = 7.5 Hz), 2. 74 (2H, t, J = 7.8 Hz), 3.07 (2H, s), 3.53 (2H, s), 3.86 (3H, s), 6.62 (2H, d, J = 8.3 Hz), 6.95 (1 H, ddd, J = 8.1, 2.7, 0.9 Hz), 7.01-7.25 (2 H, m), 7.32 (1 H, t, J = 8.0 Hz).
MS (ESI +): 366 (M + H)
Melting point: 106-108 ° C
Elemental _{analysis: C 22 H 27 N 3 O} 2
Calculated value C, 72.30; H, 7.45; N, 11.50
Found C, 72.27; H, 7.48; N, 11.32
A solution of the compound (204 mg) obtained above and 1,4-dibromobutane (181 mg) in toluene (2.00 mL) was stirred at 110 ° C. for 20 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 100% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give 1- [4,5-dihydro-3- ( 3-Methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (pyrrolidin-1-yl) phenyl] -1-butanone (166 mg, 71%) as a colorless oil Obtained.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.65 (6H, s), 1.90-2.03 (6H, m), 2.61 (2H, t, J = 7.6 Hz), 2. 75 (2H, t, J = 7.4 Hz), 3.07 (2H, s), 3.25 (4H, t, J = 6.4 Hz), 3.85 (3H, s), 6.51 ( 2H, d, J = 8.7 Hz), 6.95 (1H, dd, J = 8.0, 1.5 Hz), 7.08 (2H, d, J = 8.3 Hz), 7.18-7 .27 (2H, m), 7.31 (1H, t, J = 7.5 Hz).
MS (ESI +): 420 (M + H)
To a solution of the compound obtained above (166 mg) in ethyl acetate (1.00 mL) was added a 4N hydrogen chloride / ethyl acetate solution (0.0988 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 40 minutes. The reaction mixture was concentrated under reduced pressure and recrystallized from methanol / diethyl ether to give the title compound (113 mg, 44%) as colorless crystals.

Example 200
1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone obtained in Reference Example 90 Sodium hydrogen carbonate (107 mg), aniline (136 mg) and sodium iodide (190 mg) were added to a solution of the compound (308 mg) in acetonitrile (10.0 mL) at room temperature, and the mixture was stirred at 80 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 30% ethyl acetate / hexane) and recrystallized from ethyl acetate / IPE to give the title compound (170 mg, 48%) as colorless crystals. Obtained.

Example 201
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone hydrochloride Obtained in Example 200 To a solution of the obtained compound (48.4 mg) in ethyl acetate (4.00 mL) was added 4N hydrogen chloride / ethyl acetate solution (0.150 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 min. The reaction mixture was concentrated under reduced pressure and recrystallized from methanol / IPE to give the title compound (44.9 mg, 84%) as colorless crystals.

The compounds of Examples 202 to 213 shown below were obtained in the same manner as described in Example 200 using the compounds obtained in Reference Examples 90 to 94.
Example 202
1- [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4- (N-methyl-N-phenylamino) -1-butanone Example 203
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -5- (phenylamino) -1-pentanone Example 204
1- [4,5-Dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -5- (N-methyl-N-phenylamino) -1-pentanone

Example 205
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone Example 206
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-{[4- (morpholin-4-yl) phenyl] Amino} -1-butanone Example 207
4-({4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} amino) -N- (1 , 3-Thiazol-2-yl) benzenesulfonamide

Example 208
4- (2,3-Dihydro-1-benzofuran-5-ylamino) -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazole-1- Yl] -1-butanone Example 209
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- (N-methyl-N-phenylamino) -1- Butanone Example 210
4- (N, N-dibenzylamino) -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone

Example 211
1- [3- (3-Chloro-5-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone Example 212
1- [5-Cyclopropyl-4,5-dihydro-3- (3,5-dimethylphenyl) -1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone Example 213
1- [5-Cyclopropyl-4,5-dihydro-3- (3,5-dimethylphenyl) -1H-pyrazol-1-yl] -4- (N-methyl-N-phenylamino) -1-butanone

  Table 15 shows the chemical structural formulas of the compounds obtained in Examples 198 to 213.

Example 214
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (methylsulfinyl) phenoxy] -1-butanone Sodium periodate (3.94 g) was added to a mixed solution of the compound obtained in Example 112 (500 mg) in ethanol (24.0 mL) and water (2.00 mL), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 50% ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to give the title compound (369 mg, 71%) as colorless crystals. Obtained.

Example 215
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (methylsulfonyl) phenoxy] -1-butanone To a solution of the compound (500 mg) obtained in Example 112 in ethyl acetate (10.0 mL), m-chloroperbenzoic acid (1.50 g) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 4.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 50% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give the title compound (227 mg, 42%) as colorless crystals. Obtained.

Example 216
4- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} benzamide obtained in Example 113 To a solution of the compound (400 mg) and DMSO (0.089 mL) in methanol (5.00 mL) were added 30% aqueous hydrogen peroxide (0.175 mL) and 0.1 N sodium hydroxide solution (0.205 mL), and 50 Stir at 5 ° C. for 5 hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was collected by filtration and washed with methanol to give the title compound (326 mg, 78%) as colorless crystals.

Example 217
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (4-methyl-1,3-oxazole) 2-yl) phenoxy] -1-butanone Bromoacetone (0.163 mL) was added to a DMF (2.00 mL) solution of the compound (476 mg) obtained in Example 216, and the mixture was stirred at 100 ° C. for 23 hours. After cooling the reaction mixture to room temperature, ethyl acetate was added. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 50% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give the title compound (48.1 mg, 9.2%) Was obtained as colorless crystals.

Example 218
1- [3- (3,5-Dimethylphenyl) -5,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl] -4- (4-hydroxyphenoxy) -1-butanone Example 133 Formic acid (1.59 mL) was added to a suspension of the compound obtained in step (701 mg) and 10% palladium carbon (51% water-containing product, 198 mg) in methanol (19.8 mL) and THF (7.00 mL), Stir at room temperature for 3 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, washed with saturated sodium hydrogen carbonate, water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 25% ethyl acetate / hexane) and recrystallized from ethyl acetate / IPE to give the title compound (557 mg, 98%) as colorless crystals. Obtained.

Example 219
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- (4-methoxyphenoxy) -1-butanone Example 218 Iodomethane (94.2 mg) was added to a DMF (4.00 mL) solution of the compound obtained in (200 mg) and potassium carbonate (87.6 mg), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 25% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give the title compound (157 mg, 78%) as colorless crystals. Obtained.

In the same manner as in the method described in Example 219, the compound of Example 220 shown below was obtained.
Example 220
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (pyridin-2-ylmethoxy) phenoxy]- 1-butanone

Example 221
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (1,3-thiazol-2-yl) ) Phenoxy] -1-butanone To a solution of triphenylphosphine (281 mg) in THF (4.00 mL) was added a 40% toluene solution of diethyl azodicarboxylate (0.473 mL), and the mixture was stirred at room temperature for 30 minutes. The compound (200 mg) obtained in Reference Example 95 and 4- (1,3-thiazol-2-yl) phenol (194 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The reaction mixture is concentrated under reduced pressure, and the resulting residue is separated and purified by silica gel chromatography (solvent gradient; 5 → 50% ethyl acetate / hexane) and recrystallized from ethyl acetate / hexane to give the title compound ( 65.3 mg, 21%) was obtained as colorless crystals.

In the same manner as in the method described in Example 221, the compounds of Examples 222 to 223 shown below were obtained.
Example 222
Ethyl 4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} benzoate Example 223
Ethyl 4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -3-methoxybenzoate

Example 224
Methyl [(3S) -6- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy}- 2,3-Dihydro-1-benzofuran-3-yl] acetate Methyl [(3S) -6-hydroxy-2,3-dihydro-1-benzofuran- synthesized according to the method described in Patent Document (WO2008 / 001931) To a solution of 3-yl] acetate (1.50 g) in DMF (30.0 mL) was added sodium hydride (576 mg, 50-72% oily) at 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes. The compound obtained in Reference Example 92 (1.50 g) and tetrabutylammonium iodide (180 mg) were added to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with toluene, poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 70% ethyl acetate / hexane), and recrystallized from IPE to give the title compound (632 mg, 27%) as colorless crystals.

Example 225
4- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} benzoic acid Obtained in Example 222 To a mixed solution of the obtained compound (110 mg) in THF (2.00 mL) and ethanol (2.00 mL) was added 1N sodium hydroxide solution (0.758 mL), and the mixture was stirred at room temperature for 1 week. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was neutralized with 1N hydrochloric acid. The resulting precipitate was collected by filtration and recrystallized from methanol / diethyl ether to give the title compound (76.4 mg, 74%) as colorless crystals.

Using the compounds obtained in Examples 223 and 224, the compounds of Examples 226 to 227 shown below were obtained in the same manner as in the method described in Example 225.
Example 226
4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -3-methoxybenzoic acid Example 227
[(3S) -6- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -2 , 3-Dihydro-1-benzofuran-3-yl] acetic acid

Example 228
N-cyclopropyl-2-[(3S) -6- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl]- 4-oxobutoxy} -2,3-dihydro-1-benzofuran-3-yl] acetamide To a solution of the compound obtained in Example 227 (201 mg) in DMF (10.0 mL), HOBt (68.0 mg), cyclohexane Propylamine (74.0 mg) and WSC (108 mg) were added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 100% ethyl acetate / hexane) to give the title compound (44.6 mg, 20%) as amorphous crystals.

Example 229
2-[(3S) -6- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -2,3-dihydro-1-benzofuran-3-yl] -N-methoxy-N-methylacetamide To a solution of the compound obtained in Example 227 (386 mg) in DMF (10.0 mL), HOBt (165 mg), Triethylamine (0.232 mL), N, O-dimethylhydroxylamine hydrochloride (125 mg) and WSC (210 mg) were added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 70% ethyl acetate / hexane) to give the title compound (188 mg, 45%) as an oil.

Example 230
4- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -N′-hydroxybenzenecarboxy Midamide To a solution of the compound obtained in Example 113 (320 mg) in DMSO (8.00 mL), sodium hydrogen carbonate (207 mg) and hydroxyammonium chloride (114 mg) were added at 40 ° C., and the mixture was stirred at 75 ° C. for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from toluene / IPE to give the title compound (220 mg, 63%) as colorless crystals.

Example 231
3- (4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} phenyl) -1 , 2,4-oxadiazol-5 (4H) -one To a mixed solution of the compound (269 mg) obtained in Example 230 in THF (30.0 mL) and DMF (5.00 mL), N, N′— Carbonyldiimidazole (160 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.200 mL) were added, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate / IPE to give the title compound (220 mg, 77%) as colorless crystals.

  Table 16 shows the chemical structural formulas of the compounds obtained in Examples 214 to 231.

Using the compounds obtained in Reference Examples 84 and 97, the compounds of Examples 232 to 246 shown below were obtained in the same manner as in the method described in Example 192.
Example 232
1- [3- (2,6-Dimethoxypyridin-3-yl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 233
3- [4,5-Dihydro-5,5-dimethyl-1- (4-phenylbutanoyl) -1H-pyrazol-3-yl] -5-nitrobenzonitrile Example 234
1- [3- (3-Acetylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 235
Methyl 4- [4,5-dihydro-5,5-dimethyl-1- (4-phenylbutanoyl) -1H-pyrazol-3-yl] benzoate Example 236
1- [3- (2,4-Dimethoxyphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone

Example 237
1- {4,5-dihydro-5,5-dimethyl-3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-1-yl} -4-phenyl-1-butanone Example 238
1- [4,5-Dihydro-3- (2-methoxypyridin-3-yl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 239
1- [4,5-Dihydro-5,5-dimethyl-3- (3-nitrophenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 240
{3- [4,5-Dihydro-5,5-dimethyl-1- (4-phenylbutanoyl) -1H-pyrazol-3-yl] phenyl} acetonitrile Example 241
3- [4,5-Dihydro-5,5-dimethyl-1- (4-phenylbutanoyl) -1H-pyrazol-3-yl] benzonitrile

Example 242
Methyl 3- [4,5-dihydro-5,5-dimethyl-1- (4-phenylbutanoyl) -1H-pyrazol-3-yl] benzoate Example 243
1- [3- (2,4-Dimethoxyphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 244
1- {4,5-dihydro-5,5-dimethyl-3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-1-yl} -4-phenoxy-1-butanone Example 245
1- [4,5-dihydro-5,5-dimethyl-3- (3-nitrophenyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone Example 246
{3- [4,5-dihydro-5,5-dimethyl-1- (4-phenoxybutanoyl) -1H-pyrazol-3-yl] phenyl} acetonitrile

  Table 17 shows the chemical structural formulas of the compounds obtained in Examples 232 to 246.

The compounds of Examples 247 to 251 shown below were obtained in the same manner as described in Example 50 using the compounds obtained in Reference Examples 6, 36, 37, 40, and 98.
Example 247
(6-Chloroimidazo [1,2-a] pyridin-2-yl) [4,5-dihydro-3- (3-methoxyphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 248
1- [4,5-Dihydro-3- (3-methoxy-5-methylphenyl) -5,5-dimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 249
(1-Benzyl-1H-pyrazol-4-yl) [3- (3-chloro-5-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Examples 250
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dichlorophenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 251
(1-Benzyl-1H-pyrazol-4-yl) {3- [3,5-bis (trifluoromethyl) phenyl] -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl} Methanon

Using the compounds obtained in Examples 211 and 249, the compounds of Examples 252 and 253 shown below were obtained in the same manner as in the method described in Example 197.
Example 252
1- [3- (3-Chloro-5-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- (phenylamino) -1-butanone p-toluene Sulfonate Example 253
(1-Benzyl-1H-pyrazol-4-yl) [3- (3-chloro-5-methylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone p- Toluene sulfonate

  Table 18 shows the chemical structural formulas of the compounds obtained in Examples 247 to 253.

The compounds of Examples 254 to 276 shown below were obtained in the same manner as in the method described in Example 50 using the compounds obtained in Reference Example 19 and Reference Examples 99 to 117.
Example 254
(6-Chloroimidazo [1,2-b] pyridazin-2-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] Methanone Example 255
(1-Benzyl-5-methyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 256
(1-Benzyl-5-chloro-3-methyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazole-1 -Il] methanone Example 257
(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazole -1-yl] methanone Example 258
(1-Benzyl-1H-imidazol-5-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone

Example 259
(1-Benzyl-1H-pyrazol-3-yl) [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 260
[1- (2,3-dichlorobenzyl) -1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazole-1- Il] methanone Example 261
3-[(4-{[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] carbonyl} -1H-pyrazol-1-yl) Methyl] benzonitrile Example 262
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] {1- [4- (tetrahydro-2H-pyran-4-yloxy) benzyl ] -1H-pyrazol-4-yl} methanone Example 263
2-[(4-{[3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] carbonyl} -1H-pyrazol-1-yl) Methyl] -4-fluorobenzonitrile

Example 264
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] (1- {1- [3- (trifluoromethyl) phenyl] ethyl} -1H-pyrazol-4-yl) methanone Example 265
[1- (Cyclopropylmethyl) -1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 266
[1- (Cyclopentylmethyl) -1H-pyrazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] methanone Example 267
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-pyrazole -4-yl] methanone Example 268
[1- (2,3-dichlorobenzyl) -1H-1,2,3-triazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl- 1H-pyrazol-1-yl] methanone

Example 269
[1- (2,4-Dichlorobenzyl) -1H-1,2,3-triazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl- 1H-pyrazol-1-yl] methanone Example 270
2-[(4-{[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] carbonyl} -1H-1,2,3- Triazol-1-yl) methyl] benzonitrile Example 271
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (pyridin-2-ylmethyl) -1H-1,2,3 -Triazol-4-yl] methanone Example 272
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] [1- (1-phenylethyl) -1H-1,2,3- Triazol-4-yl] methanone Example 273
[1- (cyclohexylmethyl) -1H-1,2,3-triazol-4-yl] [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-pyrazole-1- Il] methanone

Example 274
[3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-pyrazol-1-yl] [1- (4-methoxybenzyl) -1H-1,2,3-triazole- 4-yl] methanone Example 275
2-chloro-4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} benzonitrile Example 276
1- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} -2 (1H) -pyridinone

  The chemical structural formulas of the compounds obtained in Examples 254 to 276 are as shown in Table 19.

The compounds of Examples 277 to 284 shown below were obtained in the same manner as in the method described in Example 221 using the compound obtained in Reference Example 95.
Example 277
Methyl (4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} phenyl) acetate Example 278
Methyl 4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -2-methylbenzoate Example 279
Methyl 6- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} pyridine-3-carboxylate Example 280
6- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} pyridine-3-carbonitrile

Example 281
4-[(3,5-dichloropyridin-2-yl) oxy] -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazole-1- Yl] -1-butanone Example 282
Methyl 1- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} -1,6-dihydro- 6-Oxopyridine-3-carboxylate Example 283
1- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} -1,6-dihydro-6 -Oxopyridine-3-carbonitrile Example 284
3,5-dichloro-1- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} -2 (1H) -pyridinone

Example 285
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-[(2,6-dimethylpyridin-4-yl) Oxy] -1-butanone hydrochloride (Step 1)
To a solution of triphenylphosphine (1.01 g) in THF (18.0 mL) was added a 40% toluene solution of diethyl azodicarboxylate (1.70 mL), and the mixture was stirred at room temperature for 30 minutes. The compound obtained in Reference Example 95 (900 mg) and 2,6-dimethyl-4-pyridinol (306 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 50% ethyl acetate / hexane) to give 1- [3- (3,5-dimethylphenyl). ) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-[(2,6-dimethylpyridin-4-yl) oxy] -1-butanone (107 mg, 9%) Was obtained as an oil.
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.64 (6H, s), 2.17 (2H, quin, J = 6.6 Hz), 2.35 (6H, s), 2.44 (6H, s), 2.93 (2H, t, J = 7.2 Hz), 3.09 (2H, s), 4.09 (2H, t, J = 6.6 Hz), 6.52 (2H, s) 7.05 (1H, s), 7.30 (2H, s).
MS (ESI +): 394 (M + H)
(Process 2)
To a solution of the compound obtained in Step 1 (107 mg) in ethyl acetate (1.00 mL) was added 4N hydrogen chloride / ethyl acetate solution (0.0681 mL) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. After adding methanol to the reaction mixture, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol / diethyl ether to give the title compound (67.1 mg, 57%) as colorless crystals.

  Table 20 shows the chemical structural formulas of the compounds obtained in Examples 277 to 285.

The compounds of Examples 286 to 288 shown below were obtained in the same manner as in the method described in Example 225 using the compounds obtained in Examples 277 to 279.
Example 286
(4- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} phenyl) acetic acid Example 287
4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} -2-methylbenzoic acid Example 288
6- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} pyridine-3-carboxylic acid

Example 289
N-cyclopropyl-4- {4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutoxy} benzamide To a solution of the compound obtained in Example 225 (113 mg), HOBt (42.7 mg), and WSC (64.8 mg) in DMF (5.00 mL) was added cyclopropylamine (0.0303 mL) and triethylamine (0.0577 mL). And stirred at room temperature for 23 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 100% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give the title compound (40.2 mg, 33%) colorless. Obtained as crystals.

Example 290
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4- [4- (4,5-dihydro-5-thioxo -1,2,4-oxadiazol-3-yl) phenoxy] -1-butanone To a mixed solution of the compound obtained in Example 230 (300 mg) in THF (16.0 mL) and DMF (2.00 mL). 1,1′-thiocarbonyldiimidazole (160 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.212 mL) were added, and the mixture was stirred at room temperature for 13 hours. Water and 1N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 100% ethyl acetate / hexane) to give the title compound (162 mg, 49%) as yellow crystals.

The compound of Example 291 shown below was obtained in the same manner as in the method described in Example 200 using the compound obtained in Reference Example 92.
Example 291
4- [Benzyl (methyl) amino] -1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone

Example 292
4-({4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} amino) benzonitrile Reference Example 118 Acetic acid (209 mg) and borane 2-picoline complex (155 mg) were added to a solution of the compound obtained in step (262 mg) and 4-aminobenzonitrile (140 mg) in methanol (50.0 mL), and the mixture was stirred at room temperature for 5 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 50% ethyl acetate / hexane) to give the title compound (309 mg, 87%) as colorless crystals.

Using the compound obtained in Example 292, the compound of Example 293 shown below was obtained in the same manner as described in Example 195.
Example 293
4-({4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} amino) benzonitrile hydrochloride

The compound of Example 294 shown below was obtained using the compound obtained in Reference Example 118 in the same manner as in the method described in Example 292.
Example 294
2-Chloro-4-({4- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} amino) benzo Nitrile

Example 295
4-Amino-1- [3- (3,5-dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -1-butanone The compound obtained in Example 210 A suspension of ethanol (10.0 mL) in (471 mg), formic acid (0.280 mL) and 10% palladium carbon (51% water-containing product, 70.0 mg) was stirred at room temperature under a hydrogen atmosphere for 4 days. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 100% ethyl acetate / hexane) to give the title compound (119 mg, 41%) as colorless crystals.

Example 296
N- {4- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-dimethyl-1H-pyrazol-1-yl] -4-oxobutyl} benzamide obtained in Example 295 Benzoyl chloride (0.0570 mL) was added to a solution of the compound (94.0 mg) in THF (5.00 mL) under ice cooling, and the mixture was stirred at 80 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 5 → 50% ethyl acetate / hexane) to give the title compound (108 mg, 84%) as an oil.

  Table 21 shows the chemical structural formulas of the compounds obtained in Examples 286 to 296.

The compounds of Examples 297 to 300 shown below were obtained in the same manner as described in Example 193 using the compounds obtained in Reference Examples 88 and 122 to 124.
Example 297
4- (Benzyloxy) -1- [3- (3,5-dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] -1-butanone Example 298
[3- (3,5-Dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] [1- (1-phenylethyl) -1H-pyrazol-4-yl] Methanone Example 299
{5-[(Benzyloxy) methyl] -3- (3,5-dimethylphenyl) -5-ethyl-4,5-dihydro-1H-pyrazol-1-yl} (1-benzyl-1H-pyrazole-4 -Il) Methanone Example 300
1- [3- (3,5-Dimethylphenyl) -4,5-dihydro-5,5-bis (hydroxymethyl) -1H-pyrazol-1-yl] -4-phenoxy-1-butanone

Using the compound obtained in Reference Example 125, the compound of Example 301 shown below was obtained in the same manner as in the method described in Example 50.
Example 301
1- {5-[(benzyloxy) methyl] -3- (3,5-dimethylphenyl) -5-ethyl-4,5-dihydro-1H-pyrazol-1-yl} -4-phenoxy-1-butanone

Example 302
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -5-ethyl-4,5-dihydro-5- (hydroxymethyl) -1H-pyrazol-1-yl] Methanone A suspension of the compound (890 mg) obtained in Example 299, formic acid (0.180 mL) and 10% palladium carbon (51% water-containing product, 195 mg) in ethanol (15.0 mL) at 40 ° C. under a hydrogen atmosphere 30 Stir for hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 70% ethyl acetate / hexane) and recrystallized from methanol / ethyl acetate / IPE to give the title compound (179 mg, 24%) as a colorless product. Obtained as crystals.

The compound of Example 303 shown below was obtained in the same manner as in the method described in Example 302, using the compound obtained in Example 301.
Example 303
1- {3- (3,5-dimethylphenyl) -5-ethyl-4,5-dihydro-5- (hydroxymethyl) -1H-pyrazol-1-yl} -4-phenoxy-1-butanone

The compounds of Examples 304 and 305 shown below were obtained using the compounds obtained in Examples 298 and 302 in the same manner as in the methods described in Examples 195 and 197.
Example 304
[3- (3,5-Dimethylphenyl) -5,5-diethyl-4,5-dihydro-1H-pyrazol-1-yl] [1- (1-phenylethyl) -1H-pyrazol-4-yl] Methanone p-toluenesulfonate Example 305
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -5-ethyl-4,5-dihydro-5- (hydroxymethyl) -1H-pyrazol-1-yl] Methanone hydrochloride

Example 307
(1-Benzyl-1H-pyrazol-4-yl) [3- (3,5-dimethylphenyl) -5-ethyl-4,5-dihydro-5- (1-hydroxyethyl) -1H-pyrazol-1- Il] methanone To a solution of the compound (120 mg) obtained in Reference Example 132 in THF (2.00 mL) was added methylmagnesium bromide in 1.0 mol / L THF (1.00 mL), and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. After drying the organic layer, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 20 → 50% ethyl acetate / hexane) to give the title compound (120 mg, 96%) as amorphous crystals.

  Table 22 shows the chemical structural formulas of the compounds obtained in Examples 297 to 305 and 307.

The compounds of Examples 308 to 311 shown below were obtained in the same manner as in the method described in Example 50 using the compounds obtained in Reference Examples 126 to 129.
Example 308
1- [4,5-dihydro-3- (3-methoxyphenyl) -5-propyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 309
1- [5- (1,1-Dimethylethyl) -4,5-dihydro-3- (3-methoxyphenyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone Example 310
1- [3- (3-Dimethylphenyl) -7-oxa-1,2-diazaspiro [4.4] non-2-en-1-yl] -4-phenoxy-1-butanone Example 311
1,1-dimethylethyl 3- (3,5-dimethylphenyl) -1- (4-phenoxybutanoyl) -1,2,7-triazaspiro [4.4] non-2-ene-7-carboxylate

  The chemical structural formulas of the compounds obtained in Examples 308 to 311 are shown in Table 23.

Example 312
1- [4,5-dihydro-3- (3-methoxyphenyl) -4,4-dimethyl-5-methylidene-1H-pyrazol-1-yl] -4-phenyl-1-butanone 4-phenylbutyric acid (912 mg ) In THF (5.00 mL) was added oxalyl dichloride (0.539 mL) and DMF (0.100 mL), stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. To a THF (10.0 mL) solution of the compound (1.00 g) obtained in Reference Example 130, a THF (10.0 mL) solution of the residue obtained above and triethylamine (0.958 mL) were added under ice cooling. And stirred at 0 ° C. for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 100% ethyl acetate / hexane), and recrystallized from ethyl acetate / hexane to give the title compound (274 mg, 17%) as colorless crystals. Obtained.

The compounds of Examples 313 and 314 shown below were obtained in the same manner as in the method described in Example 312 using the compound obtained in Reference Example 131.
Example 313
1- [4- (3-Methoxyphenyl) -1-methylidene-2,3-diazaspiro [4.4] non-3-en-2-yl] -4-phenyl-1-butanone Example 314
1- [1-Hydroxy-4- (3-methoxyphenyl) -1-methyl-2,3-diazaspiro [4.4] non-3-en-2-yl] -4-phenyl-1-butanone

Example 315
1- [4,5-Dihydro-3- (3-methoxyphenyl) -4,4,5-trimethyl-1H-pyrazol-1-yl] -4-phenyl-1-butanone Compound obtained in Example 312 A suspension of (1.10 g) and 10% palladium carbon (51% water-containing product, 200 mg) in ethanol (40.0 mL) was stirred at room temperature under a hydrogen atmosphere for 17 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (solvent gradient; 10 → 50% ethyl acetate / hexane) to give the title compound (774 mg, 70%) as an oil.

  Table 24 shows the chemical structural formulas of the compounds obtained in Examples 312 to 315.

Formulation Example 1 (Manufacture of capsules)
1) 30 mg of the compound of Example 1
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Formulation Example 2 (Manufacture of tablets)
1) Compound of Example 1 30 g
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, and after vacuum drying, the particles are sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

Experimental Example 1: Cloning of cDNA Encoding Human CaR cDNA encoding human CaR was cloned by the following method. To amplify the cDNA encoding the N-terminal part of human CaR, the following synthetic DNA primers:
Ca1-U: 5'-AGAGTCGACGCCACCATGGCATTTTATAGCTGCTGCTGG-3'20 (SEQ ID NO: 1) and Ca1-L: 5'-AAATGAGCTCTCGGTTGGTGGCCTTGAC-3 '(SEQ ID NO: 2)
Was made. In this case, the SalI site was added to the 5 ′ end of the amplified cDNA.
To amplify cDNA encoding the C-terminal part of human CaR, the following synthetic DNA primers:
Ca2-U: 5'-AAACGAGCTCTCCTACCTCCTCCTCTTC-3 '(SEQ ID NO: 3) and Ca2-L: 5'-TCTGCGGCCGCTCCCTAGCCCAGTCTTCTCCTTCC-3' (SEQ ID NO: 4)
Was made. In this case, a NotI site was added to the 3 ′ end of the amplified cDNA.
PCR was performed by the Hot Start method. To the reaction solution in the upper layer, 1 pg of human kidney-derived cDNA (Toyobo), 0.3 mM dNTP, and 2.5 units of LA Tag DNA polymerase (Takara Shuzo) were added, and the volume was adjusted to 30 μL with water and a buffer attached to the enzyme. To the lower layer reaction solution, 12.5 μmol / L of each synthetic primer and 0.5 mM dNTP were added, and the volume was adjusted to 20 μL with water and a buffer attached to the enzyme. The upper layer reaction solution was added on the lower layer covered with AmpliWax PCR Gem100 (Takara Shuzo). The sample was subjected to PCR amplification using Thermal Cycler (Perkin-Elmer). PCR products (amplified cDNA) were separated by agarose gel electrophoresis. It was cut out from the gel, purified, and subcloned into the pT7Blue-T vector (Takara Shuzo).
The cDNA fragment encoding the N-terminal part of human CaR was treated with SalI and SacI and released from the pT7Blue-T vector. The cDNA fragment encoding the C-terminal part of human CaR was treated with SacI and NotI and released from the pT7Blue-T vector. These fragments were inserted into the pMSRαneo vector digested with SalI and NotI using a DNALigation kit (Takara Shuzo). In this way, pMSRαneo-CaR for animal cell expression was prepared.

Experimental Example 2: Preparation of CaR-expressing CHO cells 10 μg of pMSRαneo-CaR was added to a solution containing 8 × 10 ⁶ CHO-K1 cells, and Gene Pulser (0.4 cm cuvette, 0.25 kV, 960 mF) (Bio-Rad) ) Was used for transduction. The cells were cultured for 1 day in Ham F12 medium containing 10% fetal bovine serum. After passage, the cells were cultured in Ham F12 containing 10% fetal calf serum and 500 μg / mL geneticin. Cells were seeded in a 96-well plate at 1 × 10 ³ cells / well, and transformant CaR-expressing CHO cells were selected.

Experimental Example 3: Selection of CaR-expressing CHO cell line A CaR-expressing CHO cell line was selected by a calcium fluctuation assay. CaR-expressing CHO cells were seeded on a 96-well white plate at 2 × 10 ⁴ cells / well and cultured for 48 hours. After washing the cells with phosphate buffer, 100 μL buffer solution (120 mmol / L NaCl, 22 mmol / L NaHCO ₃ , 6 mmol / L KCl, 0.2 mmol / L CaCl ₂ containing 5 μmol / L FuraPE3AM (Texas Fluorescence Laboratories)) , 1 mmol / L MgCl ₂ , 5 mmol / L glucose, 5 mmol / L HEPES (pH 7.4)) was added to each well and kept at 37 ° C. for 1 hour. The cells were washed twice with phosphate buffer. 180 μL of reaction buffer (130 mmol / LNaCl, 5.4 mmol / L KCl, 0.2 mmol / L CaCl ₂ , 0.9 mmol / L MgCl ₂ , 10 mmol / L glucose, 20 mmol / L HEPES (pH 7.4) in each well ) Was added, 20 μL of 60 mmol / L CaCl ₂ was added, and the intracellular calcium concentration was measured with a fluorometric imaging plate reader (FDSS 2000, Hamamatsu photonics). Clones with increased intracellular calcium concentration were selected and used for the next experiment.

Experimental Example 4: GTPγS binding experiment A membrane fraction was prepared by the following method. Human CaR-expressing CHO cells were seeded in F500 flasks at 1.8 × 10 ⁵ cells / flask and cultured for 2 days. Cells were detached with 10 mL of phosphate buffer containing 0.02% EDTA. After the cells were centrifuged (2000 rpm, 10 minutes), the cell pellet was mixed with 12 mL of a homogenate buffer (10 mmol / L NaHCO ₃ , 1 mmol / L EDTA, 1 × Protease inhibitor cocktail (pH 7
. It was resuspended in 4)) and homogenized with Polytron ^™ (2000 rpm, 1 minute). Cell debris was removed by centrifugation (2000 rpm, 10 minutes), and then the CaR-expressing cell membrane fraction was collected by ultracentrifugation (Beckman 70 Ti type rotor, 30000 rpm, 1 hour). GTPγS binding activity was measured as follows. 20 μg of CaR expressing cell membrane was incubated with the test compound for 10 minutes. The test was performed using 20 mmol / L HEPES (pH 7.4), 100 mmol / L NaCl, 1 mmol / L MgCl ₂ , 167 μg / mL DTT, 5 μmol / L guanosine 5′-diphosphate, 0.4 nmol / L [ ³⁵ S] — The reaction was carried out at room temperature for 70 minutes in a reaction mixed solution containing guanosine 5 ′-(γ-thio) triphosphate ([ ³⁵ S] -GTPγS) and 6 mmol / L CaCl ₂ . The reaction mixture was filtered through a GF / C filter. After washing 4 times with 300 μL of phosphate buffered saline, the amount of [ ³⁵ S] -GTPγS bound to the filter was measured with a top count scintillation counter.
The effect of the test compound on [ ³⁵ S] -GTPγS binding was expressed as a percentage. This was calculated from the formula [100 × (t′−b) / (t−b)]. Where t ′, t and b are the values of bound [ ³⁵ S] -GTPγS (dpm), t ′ is in the presence of 6 mmol / L calcium and test compound, t is only 6 mmol / L calcium And b represents the absence of both 6 mmol / L calcium and the test compound. Antagonists reduced [ ³⁵ S] -GTPγS binding in membrane specimens in a dose-dependent manner. Agonists increased [ ³⁵ S] -GTPγS binding in membrane preparations in a dose-dependent manner. The results are shown in Table 25.

  The compounds of the present invention have an excellent calcium receptor antagonistic action, and preventive or therapeutic agents for bone diseases (eg, osteoporosis, fractures), renal agonists, central nervous system and endocrine agonists, digestive system agonists, etc. Useful as.

Claims (13)

Formula (Ia):

[Where:
Ring A ^a represents an optionally substituted ring;
R ^1a is
(1) Formula: -X ^1a -R ^6a
(In the formula, X ^1a represents a C _1-6 alkylene group, a C _2-6 alkenylene group, or a C _3-6 cycloalkylene group, and R ^6a represents an optionally substituted C _3-6 cycloalkyl group. , An optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, an _optionally substituted C _{A 7-14} aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group).
(2) an optionally substituted C _3-6 cycloalkyl group,
(3) an optionally substituted C _3-6 cycloalkyloxy group,
(4) an optionally substituted C _6-14 aryl group,
(5) an optionally substituted C _6-14 aryloxy group,
(6) an optionally substituted C _7-14 aralkyloxy group,
(7) an optionally substituted heterocyclic group,
(8) an optionally substituted heterocyclic oxy group, or
(9) represents an optionally substituted amino group;
R ^2a represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group;
R ^3a represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ^2a and R ^3a together may form a C _1-3 alkylidene group or an optionally substituted ring; and R ^4a and R ^5a are the same or different and each represents a hydrogen atom , A halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ^4a and R ^5a may together form an oxo group, a C _1-3 alkylidene group, or an optionally substituted ring.
Or a salt thereof or a prodrug thereof, a calcium-sensitive receptor antagonist. Formula (I):

[Where:
Ring A represents an optionally substituted C _6-14 aromatic hydrocarbon, or an optionally substituted heterocycle;
R ¹ is
(1): ^-X 1 -R ⁶
(In the formula, X ¹ represents a C _3-6 alkylene group, a C _2-6 alkenylene group, or a C _3-6 cycloalkylene group, and R ⁶ represents an optionally substituted C _3-6 cycloalkyl group. , An optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, an _optionally substituted C _A group represented by a _7-14 aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group;
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. A -6} cycloalkyl group, an _optionally substituted C _3-6 cycloalkyloxy group, an optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryloxy group, a substituted An optionally substituted C _7-14 aralkyloxy group, an optionally substituted heterocyclic group, an optionally substituted heterocyclic oxy group, or an optionally substituted amino group). Or
(3) An optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
R ² represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group or an optionally substituted hydroxy group,
R ³ represents an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ² and R ³ together may form a C _1-3 alkylidene group or an optionally substituted ring; and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom , A halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group, or
R ⁴ and R ⁵ together may form an oxo group, a C _1-3 alkylidene group, or an optionally substituted ring]
A compound represented by (however,
1- [4,5-dihydro-5-hydroxy-3- (4-methylphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [3- (4-chlorophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3- (3-methoxyphenyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3-phenyl-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [3- (4-bromophenyl) -4,5-dihydro-5-hydroxy-5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone;
1- [4,5-dihydro-5-hydroxy-3- (4-pyridyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] -4-phenyl-1-butanone; and (4- Amino-1H-imidazol-5-yl) [except 4,5-dihydro-5-hydroxy-3- (2-naphthyl) -5- (trifluoromethyl) -1H-pyrazol-1-yl] methanone) or Its salt. R ¹ is
(1): ^-X 1 -R ⁶
(Each symbol in the formula is as defined above)
A group represented by:
(2) Formula:

(In the formula, ring B represents a 5-membered heterocyclic ring which may be further substituted, X ² represents a bond or a C _1-6 alkylene group, and R ⁷ represents an optionally substituted C _{3. -6} cycloalkyl group, C _6-14 aryl group which may be substituted, or heterocyclic group which may be substituted)
A group represented by:
(3) an optionally substituted bicyclic fused furyl group, an optionally substituted bicyclic fused imidazolyl group, or an optionally substituted bicyclic fused triazolyl group;
The compound of claim 2, wherein The compound according to claim ² , wherein R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an optionally substituted hydroxy group. The compound according to claim 2, wherein R ³ is an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 cycloalkyl group, or an optionally substituted hydroxy group. R ² and R ³ are taken together to form an optionally substituted C _3-8 cycloalkane, an optionally substituted aliphatic heterocycle, or a C _1-3 alkylidene group. The described compound. The compound according to claim 2, wherein R ⁴ is a hydrogen atom or a C _1-6 alkyl group. The compound according to claim 2, wherein R ⁵ is a hydrogen atom or a C _1-6 alkyl group. R ⁴ and R ^5, taken together, form an optionally C _3-8 cycloalkane optionally substituted compound of claim 2, wherein.   A prodrug of the compound of claim 2.   A pharmaceutical comprising the compound according to claim 2 or a prodrug thereof.   A preventive or therapeutic agent for bone diseases comprising the compound of formula (Ia) according to claim 1 or a salt thereof or a prodrug thereof.   The agent according to claim 12, wherein the bone disease is osteoporosis or a fracture.