RU2383539C2 - Heterocyclic compounds - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R², R³, R⁴ and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

Description

Field of Invention

The present invention relates to heterocyclic compounds, in particular to heterocyclic compounds useful as HSD1 inhibitors.

State of the art

As is usually noted with Cushing's syndrome, an excess systemic effect of glucocorticoids causes metabolic abnormalities, such as accumulation of visceral fat, characteristic changes in the distribution of adipose tissue in the body, insulin resistance, diabetes, hyperlipidemia, increased blood pressure, etc.

For more than half a century, it has been known that glucocorticoids play a key role in diabetes and, for example, removal of the pituitary or adrenal glands in an animal with diabetes leads to a weakening of the most severe manifestations of diabetes, as well as a decrease in blood glucose concentration (see Long, C.D. and FDW Leukins (1936), J. Exp. Med. 63: 465-490 and Houssay, BA (1942), Endocrinology, 30: 884-892).

It is known that glucocorticoids (1) are necessary for adipocyte differentiation and inhibition, as a characteristic insulin antagonist hormone due to insulin metabolism of glucose and fats at different stages, (2) lead to an increase in blood pressure through the induction of synthesis of angiotensinogen, which is a substrate of renin , enhancing the expression of angiotensin II receptors, etc., (3) cause hyperorexia and obesity, being a powerful antagonist of leptins and the like. (see Rinshoi , vol. 30 no 9, 2004; 1782-1787).

In addition, it is noted that the action of pathologically activated glucocorticoids on adipose tissue is involved in the pathogenesis of metabolic syndrome, which combines many metabolic diseases, such as diabetic hyperlipidemia, hypertension, fatty liver, etc. in one individual (see Moller DE. New drug targets for 2 diabetes and the metabolic syndrome, Nature 2001; 414: 821-7).

These facts suggest that reducing the effects of glucocorticoids is useful for the treatment or prevention of metabolic diseases such as diabetes, insulin resistance, diabetes complications, obesity, hyperlipidemia, hypertension, fatty liver, and the like. and metabolic syndrome, combining metabolic diseases in one individual, and moreover, fatal vascular events, which are myocardial infarction and brain apoplexy associated with these diseases.

An active glucocorticoid (cortisol in humans and corticosterone in rodents) exhibiting a glucocorticoid effect is synthesized from cortisone or 11-dehydrocorticosterone, each of which is an inactive 11-ketometabolite, by the action of a converting enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1 only) but also in various tissues and cells (see Agurwal et al., J. Biol. Chem 264, 18939-46, 1989). Since 11βHSD1 knockout mice cannot convert the introduced inactive glucocorticoid to the active form, this enzyme has been shown to be the only active enzyme that converts glucocorticoids in vivo (see Kotelevtsev, Y et al .: Proc. Natl. Acad. Sci. USA, USA. 94: 14924, 1997). There is a reported case of pituitary Cushing's disease with hyperglucocorticoidemia in which manifestations of Cushing's syndrome were not observed due to a significantly reduced coincidence of 11βHSD1 activity (see Tomlinson, JW et al .: J. Clin. Endocrinol. Metab., 87: 57, 2002 )

These results demonstrate that regulation of 11βHSD1 activity is essential for the action of glucocorticoids. In other words, the regulation of 11βHSD1 activity is useful for the treatment and prevention of metabolic diseases such as diabetes, insulin resistance, diabetes complications, obesity, hyperlipidemia, hypertension, fatty liver, etc. and metabolic syndrome, including a combination of metabolic diseases in one individual, and moreover, fatal vascular events, which are myocardial infarction and brain apoplexy associated with these diseases.

It was found that transgenic mice with overexpression of 11βHSD1 have the same level as in obese subjects only in adipose tissue and have significant manifestations of the metabolic syndrome, such as visceral type obesity, insulin-resistant diabetes, hyperlipidemia, hypertension, fatty liver, etc. (see Masuzaki, H et al .: Science 2001; 294: 2166-70 and Masuzaki H et al .: J. Clin. Invest 2003; 112: 83-90). In addition, transgenic mice that exhibit liver-specific overexpression of 11βHSD1 do not exhibit the visceral type of obesity, but exhibit insulin resistance and impairment in the form of hypertension, fatty liver, etc. (see Janice M. Paterson et al .: PNAS 2004; 101: 7088-7093). Conversely, 11βHSD1 knockout mice show resistance to induction of hepatic gluconeogenesis enzymes (PEPCK, G6-phosphatase, etc.) due to stress or a high-fat diet, and show a distinct resistance to diabetes (see Kotelevtsev, Y et al .: Proc. Natl. Acad. Sci. USA, 94: 14924, 1997).

Moreover, 11βHSD1 knockout mice showed reduced blood triglycerides and increased blood levels of HDL cholesterol, while the expression of molecular groups associated with fat catabolism and their coordinating transcription factor PPARα were significantly increased. 11βHSD1 knockout mice have been shown to show a distinct attenuation of visceral adipose tissue accumulation and the development of metabolic abnormalities caused by a high-fat diet (see Morton NM et al. J. Biol. Chem. 2001; 44: 41293-301).

In fact, since insulin sensitivity increases with 11βHSD1 deficiency, it is expected that the inhibition of this enzyme will be useful in the treatment or prevention of non-insulin-dependent diabetes and obesity (see Seckl, JR et al. Eur. J. Biochem. 249: 361, 1997 and Morton NM et al. Diabetes 2004; 53: 931-938).

These findings indicate that a decrease in the action of 11βHSD1 is useful for the treatment and prevention of metabolic diseases such as diabetes, insulin resistance, diabetes complications, obesity, hyperlipidemia, hypertension, fatty liver, etc. and metabolic syndrome, including a combination of metabolic diseases in one individual, and moreover, fatal vascular events, which are myocardial infarction and brain apoplexy associated with these diseases.

Removing the adrenal glands weakens the effects of hunger, which increases food intake and expression of the hypothalamic neuropeptide Y. This confirms the role of glucocorticoids in increasing food intake and suggests that inhibition of 11βHSD1 in the brain will increase saturation and thereby reduce food intake (see Woods, S.C. . et al. (1998) Science, 280: 1378-1383). This means that a decrease in the action of 11βHSD1 is believed to be useful for the treatment or prevention of hyperorexia.

Stress and glucocorticoids impair cognitive function (see de Quervain, D.J.-F., B. Roozendaal, and J.L. McGaugh (1998), Nature, 394: 787-790). In fact, 11βHSD1 knockout mice show a significant improvement in cognitive dysfunction caused by aging (see Yau JL et al. PNAS 2001; 98: 4716-4721), and a recent report indicates that the non-specific 11βHSD1 inhibitor carbenoxolone is effective in cognitive dysfunction in the elderly people (see Sandeep T et al. PNAS 2004; 101: 6734-6739). In addition, 11βHSD1 regulates the level of action of glucocorticoids in the brain, thereby promoting neurotoxicity (see Rajan, V., C. RW Edwards, and JR Seckl, J. (1996), Neuroscience, 16: 65-70 and Seckl, JR, Front. (2000), Neuroendocrinol, 18: 49-99). Moreover, inhibition of 11βHSD1 in the brain leads to a decrease in anxiety, which is based on the above known action of glucocorticoids in the brain (see Tronche, F. et al. (1999), Nature Genetics, 23: 99-103). Thus, these facts taken together suggest that a decrease in the action of 11βHSD1 in the human brain prevents the reactivation of cortisone into cortisol, and is useful in the treatment or prevention of cognitive impairment, neurodegenerative diseases associated with loss of nerve cells, emotional disorders, such as anxiety, depression, mania, etc., schizophrenia, disorders of nerve functions, including stimulation of appetite, etc.

It is well known that glucocorticoids suppress the immune system. Therefore, a decrease in the effect of 11βHSD1 is believed to be useful in the treatment or prophylaxis of diseases exhibiting immunosuppression, such as immunodeficiency and the like. or for the treatment or prevention of diseases requiring activation of the immune system.

Recent evidence suggests that levels of glucocorticoid target receptors and 11βHSD1 enzyme determine predisposition to glaucoma. (Stokes, J. Et al. (2000), Invest. Ophthalmol. 41: 1629-1638). Therefore, the proposed reduction in the effect of 11βHSD1 provides an excellent effect for the treatment or prevention of glaucoma.

Although glucocorticoids play an integral role in skeletal growth and function, excess glucocorticoids are harmful. Glucocorticoid-induced bone loss is at least partially induced through inhibition of bone formation, including inhibition of osteoblast growth and collagen synthesis (see Kim, C. H., SL Cheng, and GS Kim (1999), J. Endocrinol, 162: 371-379).

A negative effect on the formation of osteons can be blocked by a non-specific inhibitor of 11βHSD1 carbenoxolone, which suggests an important role of 11βHSD1 in the action of glucocorticoids (see Bellows, C.G., A. Ciaccia, and JNM Heersche, (1998), Bone, 23: 119 -125). Therefore, a decrease in the action of 11βHSD1 is believed to be useful in the treatment or prevention of osteoporosis.

Accordingly, it can be said that a substance having the ability to reduce the action of 11βHSD1 is applicable as a medicine for the treatment or prevention of pathologies associated with glucocorticoids, such as

1) metabolic diseases, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension and fatty liver,

2) metabolic syndrome,

3) fatal vascular events, which are myocardial infarction and brain apoplexy associated with such diseases,

4) hyperorexia,

5) diseases, including cognitive impairment, neurodegenerative diseases accompanied by loss of nerve cells, emotional disorders such as anxiety, depression, mania, etc., schizophrenia and disorders of the nervous functions, including stimulation of appetite,

6) diseases requiring treatment or prevention of weakening of the immune system or strengthening the immune system, such as immunodeficiency and the like,

7) glaucoma,

8) osteoporosis

and the like.

As heterocyclic compounds, for example, the following are known. For example, WO99 / 43663 discloses the following heterocyclic compound as a compound having NHE1 inhibitory activity.

As known, for example, the following 11βHSD1 inhibitors may be mentioned. WO2004 / 089470 discloses the following compounds as compounds having an inhibitory effect on 11βHSD1:

Disclosure of invention

There is a great need to develop a compound suitable as an agent for the prophylaxis or treatment of metabolic diseases such as diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension, fatty liver, etc. and the like, which have more preferred properties than existing drugs, in terms of efficacy, duration of action, specificity, low toxicity, oral absorption, pharmacokinetics, etc.

Thus, an object of the present invention is a compound having an inhibitory effect against HSD1 and the like. and useful as an agent for the prevention or treatment of metabolic diseases such as diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension, fatty liver, etc. and the like, which has a different chemical structure than the known compounds, including the aforementioned compounds and their use.

It was first discovered according to the present invention that the heterocyclic compound mentioned below has a potent inhibitory effect against HSD1, and is suitable as an agent for the prevention and treatment of metabolic diseases such as diabetes, insulin resistance, diabetes complications, obesity, hyperlipidemia, hypertension, fatty liver, etc. etc. Studies have been conducted based on these findings, and based on them, the present invention has been completed. Accordingly, the present invention specifically relates to the following.

1. The compound represented by the following formula [1 ']:

Where

ring A represents

(1) containing nitrogen, a saturated, monocyclic, heterocyclic group, or

(2) a cycloalkyl group,

said ring A is optionally substituted with one or more, same or different substituents R ¹ ,

the specified Deputy R ¹ represents

1) a hydrogen atom,

2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _1-6 alkoxygroup)), and

e) C _1-6 alkoxy groups,

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group, and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom, and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups, and

(iv) C _1-6 alkoxy groups),

e) C _1-6 alkoxy groups, and

f) carboxyl group),

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom, and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group,

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) -CO-C _1-6 alkyl groups, and

c) oxo groups),

(g) C _1-6 alkoxy groups, or

(h) a nitrogen-containing unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different halogen atoms),

or

(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen, saturated, monocyclic, heterocyclic group, or a heterocyclic group, which is a fused ring of said heterocycle and carbon ring (both of which heterocyclic groups are optionally substituted with one or more, same or different substituents selected from the following a) to i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _1-6 alkoxygroup),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy)

3) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to d):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

c) C _1-6 alkoxy groups, and

d) an aryl group), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) -CO-C _1-6 alkyl groups, and

c) oxo groups),

4) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to h):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

e) C _1-6 alkoxy groups,

f) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

g) a carboxyl group and

h) aryloxy groups),

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(d) an aryl group (said aryl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms), and (3) a C _1-6 alkoxy group), or

(e) a carboxyl group,

5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group),

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(d) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),

6) a cycloalkyl group,

7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or an aryl group ( said aryl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),

8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group,

10) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):

(a) a carboxyl group,

(b) a halogen atom,

(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),

(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO — C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or R ⁴⁰ and R ⁴¹ optionally form, together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, or —S (═O) ₂ —R ⁴² , where R ⁴² represents a C _1-6 alkyl group, or R ³⁸ and R ³⁹ optionally form together e to the nitrogen atom with which they are bonded, containing nitrogen, a saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),

(e) —CO — NR ⁴³ R ⁴⁴ , where R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴³ and R ⁴⁴ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(f) —COO — C _1-6 alkyl group) or

11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (a) to (h):

(a) a carboxyl group,

(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy)

(c) a cycloalkyl group,

(d) a halogen atom,

(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴⁵ and R ⁴⁶ optionally form together with the nitrogen atom with which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

(f) -COO-C _1-6 alkyl groups,

(g) cyano groups and

(h) C _1-6 alkoxy);

-X- represents

(1) -N (R ¹ ) -, where R ¹ is as defined above or

(2) —C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are the same or different and each represents

1) a hydrogen atom,

2) —NR ¹⁶ R ¹⁷ , where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or —CO-NR ³⁶ R ³⁷ , where R ³⁶ and R ³⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁶ and R ³⁷ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen containing, saturated, monocyclic, heterocyclic group, or R ¹⁶ and R ¹⁷ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, saturated, monocyclic, heterocyclic th group,

3) —CONR ¹⁸ R ¹⁹ where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more carboxyl groups) or an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one silt and a large number of identical or different halogen atoms), or R ¹⁸ and R ¹⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group, or

5) a carboxyl group;

R ² represents

(1) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different substituents selected from the following group: 1) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or various substituents selected from the following group: (a) a hydroxyl group and (b) a C _1-6 alkoxy group), and 2) a _1-6 alkoxy group); and

R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom, 2) a hydroxyl group, 3) C _1-6 alkoxy groups and 4) -OCO-C _1-6 alkyl groups),

(3) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following 1) to 6):

1) a halogen atom,

2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom, (b) a hydroxyl group, and (c) C _{1 -6} alkoxy groups),

3) a C _1-6 alkoxy group (said C _1-6 alkoxy group is optionally substituted with one or more, same or different halogen atoms),

4) a carboxyl group,

5) -COO-C _1-6 alkyl groups and

6) cyano groups),

(4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom and 2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

(5) a hydroxyl group or

(6) C _1-6 alkoxy],

or its salt.

2. The compound represented by the following formula [1]:

Where

-X- represents

(1) -N (R ¹ ) -, where R ¹ represents

1) a hydrogen atom,

2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy groups),

e) C _1-6 alkoxy groups and

f) carboxyl group),

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group,

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(g) C _1-6 alkoxy; or

(h) a nitrogen-containing unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms),

or

(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen, saturated, monocyclic, heterocyclic group, or a heterocyclic group, which is a fused ring of said heterocycle and carbon ring (both of which heterocyclic groups are optionally substituted with one or more, same or different substituents selected from the following a) to i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy)

3) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to d):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

c) C _1-6 alkoxy; and

d) an aryl group), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

4) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to h):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

e) C _1-6 alkoxy groups,

f) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

g) a carboxyl group and

h) aryloxy groups),

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(d) an aryl group (said aryl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms), and (3) a C _1-6 alkoxy group), or

(e) a carboxyl group,

5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group),

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(d) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),

6) a cycloalkyl group,

7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or an aryl group ( said aryl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),

8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group,

10) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):

(a) a carboxyl group,

(b) a halogen atom,

(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),

(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO — C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or R ⁴⁰ and R ⁴¹ optionally form, together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, or —S (═O) ₂ —R ⁴² , where R ⁴² represents a C _1-6 alkyl group, or R ³⁸ and R ³⁹ optionally form together e to the nitrogen atom with which they are bonded, containing nitrogen, a saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),

(e) —CO — NR ⁴³ R ⁴⁴ , where R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴³ and R ⁴⁴ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(f) —COO — C _1-6 alkyl group) or

11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (a) to (h):

(a) a carboxyl group,

(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy)

(c) a cycloalkyl group,

(d) a halogen atom,

(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴⁵ and R ⁴⁶ optionally form together with the nitrogen atom with which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

(f) -COO-C _1-6 alkyl groups,

(g) cyano groups and

(h) C _1-6 alkoxy), or

(2) —C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are the same or different and each represents

1) a hydrogen atom,

2) —NR ¹⁶ R ¹⁷ , where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or —CO-NR ³⁶ R ³⁷ , where R ³⁶ and R ³⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁶ and R ³⁷ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen containing, saturated, monocyclic, heterocyclic group, or R ¹⁶ and R ¹⁷ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, saturated, monocyclic, heterocyclic th group,

3) —CONR ¹⁸ R ¹⁹ where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more carboxyl groups) or an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one silt and a large number of identical or different halogen atoms)), or R ¹⁸ and R ¹⁹ optionally form, together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group, or

5) a carboxyl group;

R ² represents

(1) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different substituents selected from the following group: 1) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or various substituents selected from the following group: (a) a hydroxyl group and (b) a C _1-6 alkoxy group), and 2) a _1-6 alkoxy group); and

R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom, 2) a hydroxyl group, 3) C _1-6 alkoxy groups and 4) -OCO-C _1-6 alkyl groups),

(3) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following 1) to 6):

1) a halogen atom,

2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom, (b) a hydroxyl group, and (c) C _{1 -6} alkoxy groups),

3) a C _1-6 alkoxy group (said C _1-6 alkoxy group is optionally substituted with one or more, same or different halogen atoms),

4) a carboxyl group,

5) -COO-C _1-6 alkyl groups and

6) cyano groups),

(4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom and 2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

(5) a hydroxyl group or

(6) C _1-6 alkoxy],

or its salt.

3. The compound according to any one of the above paragraphs 1 and 2, where -X- represents -C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are the same as in the above paragraph 1 or its salt.

4. The compound according to any one of the above items 1 to 3, where R ⁸ represents

1) —NR ¹⁶ R ¹⁷ where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁶ and R ¹⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

2) —CONR ¹⁸ R ¹⁹ where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁸ and R ¹⁹ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, or

3) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group,

or its salt.

5. The compound according to any one of the above paragraphs 1 or 2, where -X- represents -N (R ¹ ) -, where R ¹ is the same as in the above paragraph 1 or its salt.

6. The compound according to any one of the above items 1, 2 and 5, where R ¹ represents

1) a hydrogen atom,

2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy groups),

e) C _1-6 alkoxy groups and

f) carboxyl group),

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups), or

(g) a nitrogen-containing unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms),

or

(h) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not simultaneously hydrogen atoms),

3) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to d):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

c) C _1-6 alkoxy; and

d) an aryl group), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

4) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to h):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

e) C _1-6 alkoxy groups,

f) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

g) a carboxyl group and

h) aryloxy groups),

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(d) an aryl group (said aryl group is substituted with one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said C _{A 1-6} alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or

(e) a carboxyl group,

5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group),

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(d) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),

6) a cycloalkyl group,

7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or an aryl group ( said aryl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),

8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group,

10) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):

(a) a carboxyl group,

(b) a halogen atom,

(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),

(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO — C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or R ⁴⁰ and R ⁴¹ optionally form, together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, or —S (═O) ₂ —R ⁴² where R ⁴² represents a C _1-6 alkyl group) or R ³⁸ and R ³⁹ optionally form together e to the nitrogen atom with which they are bonded, containing nitrogen, a saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),

(e) —CO — NR ⁴³ R ⁴⁴ , where R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴³ and R ⁴⁴ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(f) —COO — C _1-6 alkyl group) or

11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (a) to (h):

(a) a carboxyl group,

(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy)

(c) a cycloalkyl group and

(d) a halogen atom,

(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴⁵ and R ⁴⁶ optionally form together with the nitrogen atom with which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

(f) -COO-C _1-6 alkyl groups,

(g) cyano groups and

(h) C _1-6 alkoxy groups),

or its salt.

7. The compound according to any one of the above paragraphs 1, 2 and 5, where R ¹ represents

1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy groups),

e) C _1-6 alkoxy groups and

f) carboxyl group),

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(g) C _1-6 alkoxy; or

(h) a nitrogen-containing unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms)

or

(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) a C _1-6 alkoxy group) (provided that R ⁵ and R ⁶ are not any combination of substituents selected from the following group: (i) a hydrogen atom and (ii) an unsubstituted C _1-6 alkyl group),

2) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

c) C _1-6 alkoxy; and

d) an aryl group), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

3) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

e) C _1-6 alkoxy groups,

f) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

g) a carboxyl group and

h) aryloxy groups),

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(d) an aryl group (said aryl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms), and (3) a C _1-6 alkoxy group), or

(e) a carboxyl group,

4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (d):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group),

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(d) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),

5) a cycloalkyl group,

6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or an aryl group (indicated an aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom, and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different gal atoms ogen)),

7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

8) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group, or

9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is substituted by one or more identical or different substituents selected from the following (a) to (g):

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy)

(b) a cycloalkyl group,

(c) a halogen atom,

(d) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴⁵ and R ⁴⁶ optionally form together with the nitrogen atom with which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

(e) -COO-C _1-6 alkyl groups,

(f) cyano groups and

(g) C _1-6 alkoxy)

or its salt.

8. The compound according to any one of the above paragraphs 1, 2 and 5, where R ¹ represents

1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy groups),

e) C _1-6 alkoxy groups and

f) carboxyl group),

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups and

b) —CO — C _1-6 alkyl groups; and

c) oxo groups), or

(g) a nitrogen-containing unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms)

or

(h) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not simultaneously hydrogen atoms),

2) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

c) C _1-6 alkoxy; and

d) an aryl group), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

3) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

e) C _1-6 alkoxy groups,

f) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

g) a carboxyl group and

h) aryloxy groups),

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(d) an aryl group (said aryl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms), and (3) a C _1-6 alkoxy group), or

(e) a carboxyl group,

4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (d):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group),

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(d) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),

5) a cycloalkyl group,

6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or an aryl group (indicated an aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom, and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different gal atoms ogen)),

7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

8) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group, or

9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is substituted by one or more identical or different substituents selected from the following (a) to (g):

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy)

(b) a cycloalkyl group,

(c) a halogen atom,

(d) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴⁵ and R ⁴⁶ optionally form together with the nitrogen atom with which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

(e) -COO-C _1-6 alkyl groups,

(f) cyano groups and

(g) C _1-6 alkoxy)

or its salt.

9. The compound according to any one of the above 1 to 8, wherein R ² is a cyclopropyl group or a 1-methylcyclopropyl group or a salt thereof.

10. The compound according to any one of the above items 1 to 9, where R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom and 2) —OCO-C _1-6 alkyl group) ,

(3) an aryl group (said aryl group is substituted with one or more, same or different substituents selected from the following 1) to 5):

1) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a hydroxyl group),

2) a C _1-6 alkoxy group (said C _1-6 alkoxy group is substituted with one or more identical or different halogen atoms),

3) a carboxyl group,

4) -COO-C _1-6 alkyl groups and

5) cyano groups) or

(4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is substituted by one or more, same or different substituents selected from the following group: 1) a halogen atom and 2) a C _1-6 alkyl group ( said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

(provided that R ³ and R ⁴ are not simultaneously hydrogen atoms),

or its salt .

11. The compound according to the above item 1, where R ¹ represents

1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy groups),

e) C _1-6 alkoxy groups and

f) carboxyl group),

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(g) C _1-6 alkoxy; or

(h) a nitrogen-containing unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms), or

(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not simultaneously hydrogen atoms),

2) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

c) C _1-6 alkoxy; and

d) an aryl group), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups)),

3) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

e) C _1-6 alkoxy groups,

f) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

g) a carboxyl group and

h) aryloxy groups),

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

(d) an aryl group (said aryl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms), and (3) a C _1-6 alkoxy group), or

(e) a carboxyl group,

4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (d):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group),

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(d) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),

5) a cycloalkyl group,

6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or an aryl group (indicated an aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom, and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different gal atoms ogen)),

7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

8) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group,

9) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):

(a) a carboxyl group,

(b) a halogen atom,

(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),

(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO — C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or R ⁴⁰ and R ⁴¹ optionally form, together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, or —S (═O) ₂ —R ⁴² where R ⁴² represents a C _1-6 alkyl group) or R ³⁸ and R ³⁹ optionally form together e to the nitrogen atom with which they are bonded, containing nitrogen, a saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),

(e) —CO — NR ⁴³ R ⁴⁴ , where R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴³ and R ⁴⁴ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(f) —COO — C _1-6 alkyl group) or

10) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is substituted with one or more identical or different substituents selected from the following (a) to (h):

(a) a carboxyl group,

(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy)

(c) a cycloalkyl group,

(d) a halogen atom,

(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴⁵ and R ⁴⁶ optionally form together with the nitrogen atom with which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

(f) -COO-C _1-6 alkyl groups,

(g) cyano groups and

(h) C _1-6 alkoxy groups),

or its salt.

12. The compound of paragraph 1 above, or a salt thereof, selected from the following:

(1) 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine,

(2) 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(3) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(4) 1- [1- (1-carbamoylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(5) 1- {1- [1- (2-carboxyphenylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(6) 1- {5-cyclopropyl-1- [1- (2-hydroxymethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(7) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(8) 1- {5-cyclopropyl-1- [1- (2-hydroxyethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(9) 1- {5-cyclopropyl-1- [1- (2-hydroxy-1,1-dimethylethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(10) 1- {1- [1- (2-Acetylaminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(11) 1- {1- [1- (2-aminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(12) 1- {5-cyclopropyl-1- [1- (1,1-dioxothiomorpholine-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(13) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(14) 1- {5-cyclopropyl-1- [1- (4-hydroxypiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(15) 1- {1- [1- (azetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,

(16) 1- {5-cyclopropyl-1- [1- (3-hydroxypyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(17) 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(18) 1- {5-cyclopropyl-1- [1- (4,4-difluoropiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(19) 1- {5-cyclopropyl-1- [1- (3,3-difluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(20) 1- {5-cyclopropyl-1- [1- (3-hydroxyazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(21) 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(22) 1- (5-cyclopropyl-1- {1 - [(S) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(23) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-methylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(24) 1- {5-cyclopropyl-1- [1- (4-hydroxymethylpiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(25) 1- {1- [1- (4-carboxypiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(26) 1- {5-cyclopropyl-1- [1- (3-oxopiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(27) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxymethylpyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(28) 1- {5-cyclopropyl-1- [1- (3-hydroxymethylazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(29) 1- {5-cyclopropyl-1- [1- (4-methylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(30) 1- {5-cyclopropyl-1- [1- (4-isopropylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(31) 1- {1- [1- (4-acetylpiperazin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(32) 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypiperidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(33) 1- {1- [1- (4-carbamoylpiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(34) 1- {1- [1- (3-carbamoylazetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(35) 1- {1- [1- (4-aminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(36) 1- {1- [1- (3-aminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(37) 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(38) 1- {5-cyclopropyl-1- [1- (4-dimethylaminopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(39) 1- {1- [1- (4-acetylaminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(40) 1- {1- [1- (3-acetylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(41) 1- {5-cyclopropyl-1- [1- (3-dimethylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(42) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(43) 1- {1- [1- (1-acetylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(44) 1- {5-cyclopropyl-1- [1- (4-oxopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(45) 1- {1- [1- (3-acetylaminoazetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(46) 1- {5-cyclopropyl-1- [1- (3-oxopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(47) 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(48) 1- {5-cyclopropyl-1- [1- (3,3,4,4-tetrafluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(49) 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-2-methylpropylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(50) 1- (1- {1 - [(S) -1-benzyl-2-hydroxyethylcarbamoyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(51) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-phenylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(52) 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-3-methylbutylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(53) 1- {5-cyclopropyl-1- [1- (2-hydroxyphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(54) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopentylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(55) 1- [1- (1-Benzenesulfonylaminocarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(56) 1- [5-cyclopropyl-1- (1-methanesulfonylaminocarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(57) 1- [5-cyclopropyl-1- (1-methoxycarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(58) 1- {5-cyclopropyl-1- [1- (2-hydroxyethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(59) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(60) 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(61) 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(62) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(63) 1- {1- [1- (1-acetylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(64) 1- [1- (1-cyclopropanecarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(65) 1- {5-cyclopropyl-1- [1- (2-hydroxyacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(66) 1- (5-cyclopropyl-1- {1- [1- (4-fluorophenyl) cyclopropanecarbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(67) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(68) 1- {1- [1- (2-acetylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(69) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(70) 1- {1- [1- (2-Acetylamino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(71) 1- (1- {1 - [(S) -2-acetylaminopropionyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(72) 1- (1- {1 - [(S) -2-acetylamino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(73) 1- {5-cyclopropyl-1- [1- (3,3,3-trifluoropropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(74) 1- (5-cyclopropyl-1- {1 - [(S) -5-oxopyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(75) 1- {1- [1- (3-acetylaminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(76) 1- {5-cyclopropyl-1- [1- (3-hydroxy-2,2-dimethylpropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(77) 1- {1- [1- (2-aminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(78) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(79) 1- {1- [1- (2-amino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(80) 1- {5-cyclopropyl-1- [1- (4-hydroxybutyryl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(81) 1- (5-Cyclopropyl-1- {1 - [(S) -pyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) hydrochloride) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(82) 1- (5-Cyclopropyl-1- {1 - [(S) -1-methylpyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl hydrochloride) - [(S) - 3- (2-trifluoromethylphenyl)] pyrrolidine,

(83) 1- {1- [1- (3-aminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(84) 1- (1- {1 - [(S) -2-amino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) hydrochloride) - [(S) - 3- (2-trifluoromethylphenyl)] pyrrolidine,

(85) 1- {5-cyclopropyl-1- [1- (2-methylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(86) 1- {5-cyclopropyl-1- [1- (piperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine,

(87) 1- {5-cyclopropyl-1- [1- (2-isobutyrylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(88) 1- {1- [1- (2-Cyclopropanecarbonylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(89) 1- (1- {1 - [(S) -1-acetylpyrrolidin-2-carbonyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(90) 1- {5-cyclopropyl-1- [1- (2-methanesulfonylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(91) 1- {1- [1- (1-acetylpiperidin-4-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(92) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(93) 1- {1- [1- (3-carbamoylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(94) 1- [1- (1-carbamoylmethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(95) 1- [5-cyclopropyl-1- (1-methylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(96) 1- {1- [1- (1-carbamoyl-1-methylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(97) 1- {1- [1- (2-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(98) 1- [5-cyclopropyl-1- (1-cyclopropylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(99) 1- [5-cyclopropyl-1- (1-cyclopropylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(100) 1- [5-cyclopropyl-1- (1-dimethylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(101) 1- [1- (1-carboxymethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(102) 1- [1- (1-carboxyethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(103) 1- {1- [1- (1-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(104) 1- {1- [1- (2-carboxy-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(105) 1- {1- [1- (2-carbamoyl-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(106) 1- {1- [1- (1-carbamoylcyclopropylmethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(107) 1- (5-Cyclopropyl-1- {1- [1- (2-hydroxyethylcarbamoyl) cyclopropylmethyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(108) 1- [5-cyclopropyl-1- (1-trifluoromethanesulfonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(109) 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethanesulfonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(110) 1- {1- [1- (1-cyanoiminoethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(111) 1- (1- {1- [cyanoimino (methylamino) methyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,

(112) 1- {1- [1- (N-cyanocarbamimidoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(113) 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,

(114) 3- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,

(115) 5- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiophene-2-carboxylic acid,

(116) 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiazole-4-carboxylic acid,

(117) 1- {5-cyclopropyl-1- [1- (5-methyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(118) 1- {5-cyclopropyl-1- [1- (5-cyclopropyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(119) 1- {5-cyclopropyl-1- [1- (5-hydroxymethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(120) 1- {5-cyclopropyl-1- [1- (5-trifluoromethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(121) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(122) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(123) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(124) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(125) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(126) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(127) (-) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl} pyrrolidine,

(128) (+) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl} pyrrolidine,

(129) 1- [5-cyclopropyl-1- (1-pyrazin-2-ylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride ,

(130) 1- [1- (trans-4-carbamoylcyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(131) 1- [5-cyclopropyl-1- (trans-4-ureidocyclohexyl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(132) 1- {5-cyclopropyl-1- [trans-4- (1H-tetrazol-5-yl) cyclohexyl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,

(133) 1- {5- (1-methylcyclopropyl) -1- [1- (4-trifluoromethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine ,

(134) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-methoxycyclopropyl) -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(135) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3-phenyl-3-trifluoromethylpyrrolidine,

(136) 3- (2-chlorophenyl) -1- {5-cyclopropyl-1- [1- (2,4-difluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine,

(137) 3- (2-chloropyridin-3-yl) -1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine,

(138) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (2,2,3,3-tetramethylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (pyridine -3-yl) pyrrolidine,

(139) 1- {5-cyclohexyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(140) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethoxyphenyl) pyrrolidine,

(141) 1- {5-cyclopropyl-1- [1- (4-trifluoromethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(142) 1- (5-cyclopropyl-1- {1 - [((S) -1-carboxy-2-methylpropyl) methylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- ( 2-trifluoromethylphenyl) pyrrolidine,

(143) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3-methoxy-3- (2-trifluoromethylphenyl) pyrrolidine,

(144) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-hydroxymethylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(145) 1- {5-cyclopropyl-1- [1- (thiazol-2-ylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(146) 1- {1- [1- (isopropoxycarbamoyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(147) 1- {5-cyclopropyl-1- [1- (4-fluorobenzylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(148) 1- {1- [1- (2,3-dihydroindol-1-carbonyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (pyridine -3-yl) pyrrolidine,

(149) 1- {1- [1- (2,3-dihydro [1,4] oxazin-4-carbonyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl } -3- (pyridin-3-yl) pyrrolidine,

(150) 1- {5-cyclopropyl-1- [1- (2,6-dichloropyridin-3-ylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine ,

(151) 1- {5- (1-methylcyclopropyl) -1- [1- (2,3,4,5-tetrahydrobenzo [b] azepin-1-carbonyl) piperidin-4-yl] -1H-pyrazol-4 -carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(152) ethyl 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoate,

(153) 1- [1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine,

(154) 1- {1- [1- (3-carboxy-3-methylbutyryl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(155) 1- {5-cyclopropyl-1- [1- (2-phenoxyacetyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(156) 1- {1- [1- (3-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(157) 1- {1- [1- (2-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(158) 1- [5-cyclopropyl-1- (1-oxalylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine,

(159) 1- {1- [1- (4-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(160) 1- (5-cyclopropyl-1- {1- [2- (4-fluorophenyl) acetyl] piperidin-4-yl} -1H-pyrazol-4-carbonyl) -3- (pyridin-3-yl) pyrrolidine

(161) 1- {5-cyclopropyl-1- [1- (3-trifluoromethylbenzoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(162) 1- {5-cyclopropyl-1- [1- (3-methoxybenzoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(163) 1- {1- [1- (4-fluorobenzyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine hydrochloride,

(164) 1- [1- (1-benzenesulfonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine,

(165) 1- {1- [1- (4-carbamoylphenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(166) 1- {5-cyclopropyl-1- [1- (4-hydroxymethylphenyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(167) 1- {1- [1- (5-carbamoylpyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(168) 1- {1- [1- (4-aminophenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(169) 1- (5-cyclopropyl-1- {1- [4- (2-oxooxazolidin-3-yl) phenyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- (2- trifluoromethylphenyl) pyrrolidine,

(170) 1- (5-cyclopropyl-1- {1- [4- (3-methoxyureido) phenyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- (2-trifluoromethylphenyl) pyrrolidine,

(171) 1- {5-cyclopropyl-1- [1- (4-methanesulfonylaminophenyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(172) 1- [1- (1-ethoxycarbamoylpiperidin-4-yl) -5- (1-methylcyclopropyl) -1H-pyrazol-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine,

(173) 1- [1- (5-chloropyridin-2-yl) azetidin-3-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine,

(174) 1- {1- [1- (5-chloropyridin-2-yl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3-methoxymethyl-3- phenylpyrrolidine,

(175) 1- {1- [1- (5-cyanopyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(176) 3- (2-acetoxyethyl) -3- (4-fluorophenyl) -1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl} pyrrolidine,

(177) {(3S *, 4R *) - 3-methyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazole hydrochloride -4-carbonyl} -4-phenylpyrrolidine,

(178) methyl 6- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) nicotinate,

(179) methyl-2- {1- [5- (1-methylcyclopropyl) -1- (1-pyrimidin-2-ylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] pyrrolidin-3-yl} benzoate ,

(180) 3- (2-hydroxymethylphenyl) -1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} pyrrolidine

(181) 1- [5-cyclopropyl-1- (1-pyridin-2-ylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] -3-hydroxy-3- (pyridin-3-yl) pyrrolidine,

(182) 1- {1- [1- (4-acetylaminophenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,

(183) 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) -3-fluorobenzoate,

(184) 3- (2-cyanophenyl) -1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine,

(185) 3-hydroxymethyl-1- {1- [1- (4-methoxypyrimidin-2-yl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3 hydrochloride α-phenylpyrrolidine,

(186) 3- (3,5-difluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H- hydrochloride pyrazole-4-carbonyl} pyrrolidine,

(187) 1- {1- [1- (3-chloropyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine ,

(188) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (thiazol-2-yl) pyrrolidine,

(189) (S) -2 - [(trans-4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} cyclohexanecarbonyl) methylamino] -3- methylbutyric acid

(190) 1- {5- (1-methylcyclopropyl) -1- [trans-4- (2-fluorophenylcarbamoyl) cyclohexyl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine and

(191) cis-4- {5- (1-methylcyclopropyl) -4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl) cyclohexanecarboxylic acid.

13. A pharmaceutical composition comprising a compound according to any one of the above 1 to 12, or a salt thereof.

14. An 11βHSD1 inhibitor comprising a compound according to any one of the above 1 to 12, or a salt thereof.

15. An agent for the treatment or prophylaxis of a pathology associated with a glucocorticoid, containing any compound according to items 1 to 12 above or a salt thereof.

16. The agent according to the above paragraph 15, for which the pathology associated with the glucocorticoid is:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy,

(4) hyperorexia,

(5) a disease with impaired nervous function, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia, or stimulation of appetite,

(6) a disease associated with decreased immune function,

(7) glaucoma or

(8) osteoporosis.

17. A method of inhibiting 11βHSD1, which comprises administering a pharmaceutically effective amount of a compound according to any one of the above 1-12 or a salt thereof.

18. A method of treating or preventing a pathology associated with a glucocorticoid, which comprises administering a pharmaceutically effective amount of a compound according to any one of the above 1-12 or a salt thereof.

19. The method according to paragraph 18, wherein the pathology associated with the glucocorticoid is one of the following:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy,

(4) hyperorexia,

(5) a disease with impaired neural functions, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,

(6) a disease associated with decreased immune function,

(7) glaucoma or

(8) osteoporosis.

20. The use of any of the compounds according to the above items 1 to 12 or a salt thereof for the production of an 11βHSD1 inhibitor.

21. The use of any of the compounds according to the above items 1 to 12, or a salt thereof, for the preparation of an agent for the treatment or prophylaxis of a pathology associated with a glucocorticoid.

22. The use according to paragraph 21, in which the pathology associated with the glucocorticoid is one of the following:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy,

(4) hyperorexia,

(5) a disease with impaired neural functions, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,

(6) a disease associated with decreased immune function,

(7) glaucoma or

(8) osteoporosis.

23. Commercial packaging, including written instructions stating that the pharmaceutical composition according to paragraph 13 may or should be used to treat or prevent a disease selected from the following:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy,

(4) hyperorexia,

(5) a disease with impaired neural functions, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,

(6) a disease associated with decreased immune function,

(7) glaucoma or

(8) osteoporosis.

24. The pharmaceutical composition according to paragraph 13 for use in combination with from 1 to 3 agents selected from agents in the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

25. The 11βHSD1 inhibitor according to paragraph 14 for use in combination with from 1 to 3 agents selected from agents in the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

26. The agent according to the above paragraphs 15 or 16 for use in combination with from 1 to 3 agents selected from agents in the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

27. The method according to paragraph 17, characterized in that it further includes the introduction of from 1 to 3 agents selected from agents in the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

28. A pharmaceutical agent comprising from 1 to 3 agents selected from agents according to the following items (1) to (5) and a compound according to any one of items 1 to 12 or a salt thereof:

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

29. A method for the treatment or prophylaxis of a pathology associated with a glucocorticoid, according to the above paragraphs 18 or 19, characterized in that it further includes the introduction of from 1 to 3 agents selected from agents in the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

30. The application of paragraph 20, which is combined with the use of 1 to 3 agents selected from the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

31. The use according to the above paragraphs 21 or 22, which is combined with the use of 1 to 3 agents selected from the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

32. The pharmaceutical composition according to paragraph 13, characterized in that it is used to suppress an increase in the level of glucocorticoids in the blood by use in combination with a pharmaceutical agent that increases the level of glucocorticoids in the blood.

33. The 11βHSD1 inhibitor according to paragraph 14, which is used to suppress an increase in blood glucocorticoids by use in combination with a pharmaceutical agent that increases blood glucocorticoids.

34. The method according to paragraph 17, characterized in that it further includes the introduction of a pharmaceutical agent that increases the level of glucocorticoids in the blood.

35. The use of paragraph 21 to suppress an increase in blood glucocorticoids in combination with a pharmaceutical agent that increases blood glucocorticoids.

36. A method of suppressing blood glucocorticoids by increasing, which comprises administering a pharmaceutical agent that increases blood glucocorticoids and an 11βHSD1 inhibitor according to paragraph 14.

37. Dimethyl-2 - [(S) -2-nitro-1- (2-trifluoromethylphenyl) ethyl] malonate.

38. Methyl- (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidine-3-carboxylate.

39. (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one.

40. (S) -3- (2-trifluoromethylphenyl) pyrrolidine or a salt thereof.

41. A method for producing dimethyl-2 - [(S) -2-nitro-1- (2-trifluoromethylphenyl) ethyl] malonate, which comprises the step of reacting 1 - ((E) -2-nitrovinyl) -2-trifluoromethylbenzene with dimethyl malonate the presence of 1- (3,5-bis-trifluoromethylphenyl) -3 - ((1S, 2S) -2-dimethylaminocyclohexyl) thiourea.

42. A method for producing methyl- (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidine-3-carboxylate, which comprises the step of reducing and ring-closing dimethyl-2 - [(S) -2-nitro-1- ( 2-trifluoromethylphenyl) ethyl] malonate.

43. A process for producing (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one, which comprises the step of hydrolyzing and decarboxylating methyl (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidin-3-carboxylate.

44. A process for preparing a salt of (S) -3- (2-trifluoromethylphenyl) pyrrolidine, which comprises the step of reducing (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one and the step of treating the resulting compound with an acid to form a salt.

The present invention also encompasses the following.

45. The compound represented by the following formula [2]:

Where

-X- represents

(1) -N (R ¹ ) -, where R ¹ represents

1) a hydrogen atom,

2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy groups),

e) C _1-6 alkoxy groups and

f) carboxyl group),

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups), or

(g) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, heterocyclic group or heterocyclic group, which is a fused ring of said heterocycle and carbon ring (both of these heterocyclic groups are optional substituted by one or more, same or different substituents selected from the following a) to i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy)

3) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

c) C _1-6 alkoxy), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

4) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to g):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

e) C _1-6 alkoxy groups,

f) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

g) a carboxyl group),

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group),

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(d) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),

6) a cycloalkyl group,

7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or an aryl group ( said aryl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),

8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group,

10) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):

(a) a carboxyl group,

(b) a halogen atom,

(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),

(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO — C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or R ⁴⁰ and R ⁴¹ optionally form, together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, or —S (═O) ₂ —R ⁴² where R ⁴² represents a C _1-6 alkyl group) or R ³⁸ and R ³⁹ optionally form together e to the nitrogen atom with which they are bonded, containing nitrogen, a saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),

(e) —CO — NR ⁴³ R ⁴⁴ , where R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴³ and R ⁴⁴ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

(f) —COO — C _1-6 alkyl group) or

11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (a) to (g):

(a) a carboxyl group,

(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy)

(c) a cycloalkyl group,

(d) a halogen atom,

(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ⁴⁵ and R ⁴⁶ optionally form together with the nitrogen atom with which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group,

(f) -COO-C _1-6 alkyl groups; and

(g) cyano groups) or

(2) —C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are the same or different and each represents

1) a hydrogen atom,

2) —NR ¹⁶ R ¹⁷ , where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or —CO-NR ³⁶ R ³⁷ , where R ³⁶ and R ³⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁶ and R ³⁷ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen containing, saturated, monocyclic, heterocyclic group, or R ¹⁶ and R ¹⁷ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, saturated, monocyclic, heterocyclic th group,

3) —CONR ¹⁸ R ¹⁹ where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more carboxyl groups) or an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one silt and a large number of identical or different halogen atoms), or R ¹⁸ and R ¹⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group, or

5) a carboxyl group;

R ² represents

(1) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (a) a hydroxyl group; and (b) a C _1-6 alkoxy group)); and

R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom, 2) a hydroxyl group, and 3) C _1-6 alkoxy groups),

(3) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following 1) to 6):

1) a halogen atom,

2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom, (b) a hydroxyl group, and (c) C _{1 -6} alkoxy groups),

3) a C _1-6 alkoxy group (said C _1-6 alkoxy group is optionally substituted with one or more, same or different halogen atoms),

4) a carboxyl group,

5) -COO-C _1-6 alkyl groups and

6) cyano groups), or

(4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom and 2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),

or its salt.

46. The compound according to the above paragraph 45, which is represented by the following formula [2]:

Where

-X- represents

(1) -N (R ¹ ) -, where R ¹ represents

1) a hydrogen atom,

2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy) and

e) C _1-6 alkoxy)

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups), or

(g) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy)

3) -COOR ¹⁰ , where R ¹⁰ represents,

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

c) C _1-6 alkoxy), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

4) -COR ¹¹ , where R ¹¹ represents,

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to e):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

e) C _1-6 alkoxy)

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (c):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group) and

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are connected, containing nitrogen, saturated, monocyclic, heterocyclic group),

6) a cycloalkyl group,

7) —S (= O) ₂ —R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms),

8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group,

10) an aryl group (said aryl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said C _{A 1-6} alkyl group is optionally substituted with one or more identical or different halogen atoms) and (3) a carboxy group) or

11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (a) to (c):

(a) a carboxyl group,

(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy), and

(c) a cycloalkyl group), or

(2) —C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are the same or different and each represents

1) a hydrogen atom,

2) —NR ¹⁶ R ¹⁷ , where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or —CO-NR ³⁶ R ³⁷ , where R ³⁶ and R ³⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁶ and R ³⁷ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen containing, saturated, monocyclic, heterocyclic group, or R ¹⁶ and R ¹⁷ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, saturated, monocyclic, heterocyclic th group,

3) —CONR ¹⁸ R ¹⁹ where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁸ and R ¹⁹ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, or

4) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group;

R ² represents

(1) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different C _1-6 alkyl groups); and

R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

(3) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following 1) and 2):

1) a halogen atom and

2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)), or

(4) a 5 membered or 6 membered unsaturated, monocyclic, heterocyclic group,

or its salt.

47. The compound of paragraphs 45 or 46 above, wherein —X— is —C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are as in the above 46, or a salt thereof.

48. The compound according to any one of the above items 45 to 47, where R ⁸ represents

1) —NR ¹⁶ R ¹⁷ where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁶ and R ¹⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

2) —CONR ¹⁸ R ¹⁹ where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁸ and R ¹⁹ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, or

3) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group),

or its salt.

49. The compound of paragraphs 45 or 46 above, wherein —X— is —N (R ¹ ) -, where R ¹ is as in paragraph 46 above), or a salt thereof.

50. The compound according to any one of the above paragraphs 45, 46 and 49, where R ¹ represents

1) a hydrogen atom,

2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy), and

e) C _1-6 alkoxy)

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups), or

(g) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not simultaneously hydrogen atoms),

3) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

c) C _1-6 alkoxy), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

4) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to e):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

e) C _1-6 alkoxy)

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (c):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group) and

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are connected, containing nitrogen, saturated, monocyclic, heterocyclic group),

6) a cycloalkyl group,

7) —S (= O) ₂ —R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms),

8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group,

10) an aryl group (said aryl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said C _{A 1-6} alkyl group is optionally substituted with one or more identical or different halogen atoms) and (3) a carboxy group) or

11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (a) to (c):

(a) a carboxyl group,

(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy), and

(c) a cycloalkyl group),

or its salt.

51. The compound according to any one of the above paragraphs 45, 46 and 49, where R ¹ represents

1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy), and

e) C _1-6 alkoxy)

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups), or

(g) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not both hydrogen atoms and unsubstituted C _1-6 alkyl groups),

2) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

c) C _1-6 alkoxy), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

3) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to e):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

e) C _1-6 alkoxy)

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (c):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group) and

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are connected, containing nitrogen, saturated, monocyclic, heterocyclic group),

5) a cycloalkyl group,

6) -S (= O) ₂ -R ¹² where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more identical or different halogen atoms),

7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

8) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group, or

9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is substituted by one or more, same or different substituents selected from the following (a) and (b):

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy) and

(b) a cycloalkyl group),

or its salt.

52. The compound according to any one of the above items 45, 46 and 49, where R ¹ represents

1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents

(a) a hydrogen atom,

(b) an aryl group (said aryl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) a carboxyl group,

d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and

e) C _1-6 alkoxy)

(c) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),

(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:

a) a hydroxyl group,

b) a halogen atom,

c) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),

d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following (i) to (iv):

(i) a halogen atom,

(ii) a hydroxyl group,

(iii) oxo groups and

(iv) C _1-6 alkoxy), and

e) C _1-6 alkoxy)

(e) -S (= O) ₂ -R ⁹ where R ⁹ represents an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or

(f) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups), or

(g) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a ) by i):

a) a halogen atom,

b) a hydroxyl group,

c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

d) a carboxyl group,

e) -CO-C _1-6 alkyl groups,

f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²² and R ²³ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,

g) oxo groups,

h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, or R ²⁴ and R ²⁵ optionally form together with the nitrogen atom to which they are bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not both hydrogen atoms and unsubstituted C _1-6 alkyl groups),

2) -COOR ¹⁰ , where R ¹⁰ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):

a) a hydroxyl group,

b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

c) C _1-6 alkoxy), or

(b) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

3) -COR ¹¹ , where R ¹¹ represents

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to e):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group, or R ²⁸ and R ²⁹ optionally form, together with the nitrogen atom to which they are attached, containing nitrogen, a saturated, monocyclic, heterocyclic group,

d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, a saturated, monocyclic, heterocyclic group, and

e) C _1-6 alkoxy)

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and

b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or

(c) a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups),

4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (c):

(a) a carboxyl group,

(b) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group), or R ³² and R ³³ optionally form together with a nitrogen atom with which they are associated, containing nitrogen, saturated, monocyclic, heterocyclic group) and

(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are connected, containing nitrogen, saturated, monocyclic, heterocyclic group),

5) a cycloalkyl group,

6) -S (= O) ₂ -R ¹² where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more identical or different halogen atoms),

7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,

8) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ¹⁴ and R ¹⁵ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group, or

9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is substituted by one or more, same or different substituents selected from the following (a) and (b):

(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):

a) a halogen atom,

b) a hydroxyl group and

c) C _1-6 alkoxy) and

(b) a cycloalkyl group),

or its salt.

53. The compound according to any one of the above items 45 to 52, wherein R ² is a cyclopropyl group, or a 1-methylcyclopropyl group, or a salt thereof.

54. The compound according to any one of the above items 45 to 53, where R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),

(3) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following 1) and 2):

1) a halogen atom and

2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)), or

(4) a 5 membered or 6 membered unsaturated, monocyclic, heterocyclic group,

or its salt.

55. The compound according to the above item 45 or a salt thereof, which is selected from the following compounds:

(1) 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine,

(2) 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(3) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,

(4) 1- [1- (1-carbamoylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(5) 1- {1- [1- (2-carboxyphenylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(6) 1- {5-cyclopropyl-1- [1- (2-hydroxymethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(7) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(8) 1- {5-cyclopropyl-1- [1- (2-hydroxyethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(9) 1- {5-cyclopropyl-1- [1- (2-hydroxy-1,1-dimethylethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(10) 1- {1- [1- (2-Acetylaminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(11) 1- {1- [1- (2-aminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(12) 1- {5-cyclopropyl-1- [1- (1,1-dioxothiomorpholine-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(13) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(14) 1- {5-cyclopropyl-1- [1- (4-hydroxypiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(15) 1- {1- [1- (azetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,

(16) 1- {5-cyclopropyl-1- [1- (3-hydroxypyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(17) 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(18) 1- {5-cyclopropyl-1- [1- (4,4-difluoropiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(19) 1- {5-cyclopropyl-1- [1- (3,3-difluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(20) 1- {5-cyclopropyl-1- [1- (3-hydroxyazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(21) 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(22) 1- (5-cyclopropyl-1- {1 - [(S) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(23) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-methylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(24) 1- {5-cyclopropyl-1- [1- (4-hydroxymethylpiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(25) 1- {1- [1- (4-carboxypiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(26) 1- {5-cyclopropyl-1- [1- (3-oxopiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(27) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxymethylpyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(28) 1- {5-cyclopropyl-1- [1- (3-hydroxymethylazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(29) 1- {5-cyclopropyl-1- [1- (4-methylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(30) 1- {5-cyclopropyl-1- [1- (4-isopropylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(31) 1- {1- [1- (4-acetylpiperazin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(32) 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypiperidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(33) 1- {1- [1- (4-carbamoylpiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(34) 1- {1- [1- (3-carbamoylazetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine, (35) 1- {1- [1- (4-aminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(36) 1- {1- [1- (3-aminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(37) 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(38) 1- {5-cyclopropyl-1- [1- (4-dimethylaminopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(39) 1- {1- [1- (4-acetylaminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(40) 1- {1- [1- (3-acetylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(41) 1- {5-cyclopropyl-1- [1- (3-dimethylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(42) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(43) 1- {1- [1- (1-acetylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(44) 1- {5-cyclopropyl-1- [1- (4-oxopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(45) 1- {1- [1- (3-acetylaminoazetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(46) 1- {5-cyclopropyl-1- [1- (3-oxopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(47) 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(48) 1- {5-cyclopropyl-1- [1- (3,3,4,4-tetrafluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(49) 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-2-methylpropylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(50) 1- (1- {1 - [(S) -1-benzyl-2-hydroxyethylcarbamoyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(51) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-phenylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(52) 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-3-methylbutylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(53) 1- {5-cyclopropyl-1- [1- (2-hydroxyphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(54) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopentylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(55) 1- [1- (1-Benzenesulfonylaminocarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(56) 1- [5-cyclopropyl-1- (1-methanesulfonylaminocarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(57) 1- [5-cyclopropyl-1- (1-methoxycarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(58) 1- {5-cyclopropyl-1- [1- (2-hydroxyethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(59) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(60) 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(61) 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(62) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(63) 1- {1- [1- (1-acetylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(64) 1- [1- (1-cyclopropanecarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(65) 1- {5-cyclopropyl-1- [1- (2-hydroxyacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(66) 1- (5-cyclopropyl-1- {1- [1- (4-fluorophenyl) cyclopropanecarbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(67) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(68) 1- {1- [1- (2-acetylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(69) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(70) 1- {1- [1- (2-Acetylamino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(71) 1- (1- {1 - [(S) -2-acetylaminopropionyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(72) 1- (1- {1 - [(S) -2-acetylamino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(73) 1- {5-cyclopropyl-1- [1- (3,3,3-trifluoropropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(74) 1- (5-cyclopropyl-1- {1 - [(S) -5-oxopyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(75) 1- {1- [1- (3-acetylaminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(76) 1- {5-cyclopropyl-1- [1- (3-hydroxy-2,2-dimethylpropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(77) 1- {1- [1- (2-aminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(78) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(79) 1- {1- [1- (2-amino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(80) 1- {5-cyclopropyl-1- [1- (4-hydroxybutyryl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(81) 1- (5-Cyclopropyl-1- {1 - [(S) -pyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) hydrochloride) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(82) 1- (5-Cyclopropyl-1- {1 - [(S) -1-methylpyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl hydrochloride) - [(S) - 3- (2-trifluoromethylphenyl)] pyrrolidine,

(83) 1- {1- [1- (3-aminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(84) 1- (1- {1 - [(S) -2-amino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) hydrochloride) - [(S) - 3- (2-trifluoromethylphenyl)] pyrrolidine,

(85) 1- {5-cyclopropyl-1- [1- (2-methylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(86) 1- {5-cyclopropyl-1- [1- (piperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine,

(87) 1- {5-cyclopropyl-1- [1- (2-isobutyrylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(88) 1- {1- [1- (2-Cyclopropanecarbonylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(89) 1- (1- {1 - [(S) -1-acetylpyrrolidin-2-carbonyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,

(90) 1- {5-cyclopropyl-1- [1- (2-methanesulfonylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(91) 1- {1- [1- (1-acetylpiperidin-4-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(92) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(93) 1- {1- [1- (3-carbamoylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(94) 1- [1- (1-carbamoylmethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(95) 1- [5-cyclopropyl-1- (1-methylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(96) 1- {1- [1- (1-carbamoyl-1-methylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(97) 1- {1- [1- (2-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(98) 1- [5-cyclopropyl-1- (1-cyclopropylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(99) 1- [5-cyclopropyl-1- (1-cyclopropylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(100) 1- [5-cyclopropyl-1- (1-dimethylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(101) 1- [1- (1-carboxymethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(102) 1- [1- (1-carboxyethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,

(103) 1- {1- [1- (1-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(104) 1- {1- [1- (2-carboxy-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(105) 1- {1- [1- (2-carbamoyl-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,

(106) 1- {1- [1- (1-carbamoylcyclopropylmethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

(107) 1- (5-Cyclopropyl-1- {1- [1- (2-hydroxyethylcarbamoyl) cyclopropylmethyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,

(108) 1- [5-cyclopropyl-1- (1-trifluoromethanesulfonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(109) 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethanesulfonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,

(110) 1- {1- [1- (1-cyanoiminoethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(111) 1- (1- {1- [cyanoimino (methylamino) methyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,

(112) 1- {1- [1- (N-cyanocarbamimidoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(113) 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,

(114) 3- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,

(115) 5- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiophene-2-carboxylic acid,

(116) 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiazole-4-carboxylic acid,

(117) 1- {5-cyclopropyl-1- [1- (5-methyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(118) 1- {5-cyclopropyl-1- [1- (5-cyclopropyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(119) 1- {5-cyclopropyl-1- [1- (5-hydroxymethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(120) 1- {5-cyclopropyl-1- [1- (5-trifluoromethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(121) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(122) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(123) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(124) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(125) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(126) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,

(127) (-) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl} pyrrolidine,

(128) (+) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl} pyrrolidine,

(129) 1- [5-cyclopropyl-1- (1-pyrazin-2-ylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride ,

(130) 1- [1- (trans-4-carbamoylcyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,

(131) 1- [5-cyclopropyl-1- (trans-4-ureidocyclohexyl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine and

(132) 1- {5-cyclopropyl-1- [trans-4- (1H-tetrazol-5-yl) cyclohexyl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine.

56. A pharmaceutical composition comprising a compound according to any one of the above items 45 to 55 or a salt thereof.

57. The 11βHSD1 inhibitor, comprising the compound according to any one of paragraphs 45 to 55 or its salt.

58. An agent for the treatment or prevention of a pathology associated with a glucocorticoid, which comprises a compound according to any one of paragraphs 45 to 55 or a salt thereof.

59. The agent according to paragraph 58, for which the pathology associated with the glucocorticoid is:

(1) a metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy associated with these diseases,

(4) hyperorexia,

(5) a disease with impaired nerve function, including cognitive impairment, neurodegenerative diseases accompanied by loss of nerve cells, emotional disorders, including anxiety, depression or mania, schizophrenia or stimulation of appetite,

(6) a disease requiring treatment or prevention of weakened immunity or increased immunity, including immunodeficiency,

(7) glaucoma, or

(8) osteoporosis.

60. A method of inhibiting 11βHSD1, which comprises administering a pharmaceutically effective amount of a compound according to any one of paragraphs 45 to 55 or a salt thereof.

61. A method of treating or preventing a pathology associated with a glucocorticoid, which comprises administering a pharmaceutically effective amount of a compound according to any one of paragraphs 45-55 or a salt thereof.

62. The method according to paragraph 61, wherein the pathology associated with a glucocorticoid is:

(1) a metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy associated with these diseases,

(4) hyperorexia,

(5) a disease with impaired nerve function, including cognitive impairment, neurodegenerative diseases accompanied by loss of nerve cells, emotional disorders, including anxiety, depression or mania, schizophrenia or stimulation of appetite,

(6) a disease requiring treatment or prevention of weakened immunity or increased immunity, including immunodeficiency,

(7) glaucoma or

(8) osteoporosis.

63. The use of the compound according to the above items 45 to 55, or a salt thereof, for the preparation of an 11βHSD1 inhibitor.

64. The use of the compound according to any one of the above items 45 to 55, or a salt thereof, for the preparation of an agent for the treatment or prophylaxis of a pathology associated with a glucocorticoid.

65. The use according to the above paragraph 64, in which the pathology associated with the glucocorticoid is:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy associated with these diseases,

(4) hyperorexia,

(5) a disease with impaired nervous function, including cognitive impairment, neurodegenerative diseases accompanied by loss of nerve cells, emotional disorders, including anxiety, depression or mania, schizophrenia, or stimulation of appetite,

(6) a disease requiring treatment or prevention of weakened immunity or increased immunity, including immunodeficiency,

(7) glaucoma or

(8) osteoporosis.

66. Commercial packaging, including written instructions stating that the pharmaceutical composition of paragraph 56 may or should be used to treat or prevent a disease selected from the following:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy associated with these diseases,

(4) hyperorexia,

(5) a disease with impaired nervous function, including cognitive impairment, neurodegenerative diseases accompanied by loss of nerve cells, emotional disorders, including anxiety, depression or mania, schizophrenia, or stimulation of appetite,

(6) a disease requiring treatment or prevention of weakened immunity or increased immunity, including immunodeficiency,

(7) glaucoma or

(8) osteoporosis.

67. The pharmaceutical composition according to the above paragraph 56, characterized in that it is used in combination with from 1 to 3 agents selected from the following agents in paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

68. The 11βHSD1 inhibitor according to the above paragraph 57, characterized in that it is used in combination with from 1 to 3 agents selected from the following agents according to paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

69. The agent according to the above paragraphs 58 or 59, which is used in combination with from 1 to 3 agents selected from the following paragraphs (1) through (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

70. The method according to the above paragraph 60, characterized in that it further includes the introduction of from 1 to 3 agents selected from agents in the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

71. A pharmaceutical agent containing from 1 to 3 agents selected from the following agents according to items (1) to (5), and a compound according to any one of the above items 45 to 55, or a salt thereof in combination:

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

72. A method for the treatment or prophylaxis of a pathology associated with a glucocorticoid according to the above paragraphs 61 or 62, characterized in that it further includes the introduction of from 1 to 3 agents selected from agents in the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

73. The use according to the above paragraph 63, which is combined using from 1 to 3 agents selected from the following agents according to paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

74. The use according to the above paragraphs 64 or 65, which is combined using 1 to 3 agents selected from the following agents according to paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

75. The pharmaceutical composition according to paragraph 56 above, characterized in that it is used to suppress an increase in blood glucocorticoids by use in combination with a pharmaceutical agent that increases blood glucocorticoids.

76. The 11βHSD1 inhibitor according to paragraph 57 above, characterized in that it is used to suppress an increase in blood glucocorticoids by use in combination with a pharmaceutical agent that increases blood glucocorticoids.

77. The method according to the above paragraph 60, characterized in that it further includes the introduction of a pharmaceutical agent that increases the level of glucocorticoids in the blood.

78. The use of paragraph 64 above to suppress an increase in blood glucocorticoids by use in combination with a pharmaceutical agent that increases blood glucocorticoids.

79. A method of suppressing an increase in blood glucocorticoids, which comprises administering a pharmaceutical agent that increases blood glucocorticoids and an 11βHSD1 inhibitor according to paragraph 57 above.

The present invention also includes the following.

80. The compound represented by the following formula [3]:

Where

R ¹ represents

(1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each is

1) a hydrogen atom,

2) a C _1-6 alkyl group,

3) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different C _1-6 alkyl groups) or

4) an aryl group (said aryl group is optionally substituted with one or more, same or different halogen atoms),

(2) an aryl group (said aryl group is optionally substituted with one or more carboxyl groups) or

(3) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more carboxyl groups);

R ² represents

(1) a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different C _1-6 alkyl groups); and

R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more hydroxyl groups),

(3) an aryl group (said aryl group is optionally substituted with one or more identical or different substituents selected from a halogen atom and a C _1-6 alkyl group optionally substituted with one or more halogen atoms) or

(4) a 5 membered or 6 membered unsaturated, monocyclic, heterocyclic group,

or a pharmaceutically acceptable salt thereof.

81. The compound of paragraph 80 above, wherein R ¹ is

(1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each is

1) a hydrogen atom,

2) a C _1-6 alkyl group,

3) a cyclopropyl group (said cyclopropyl group is optionally substituted with one or more, same or different C _1-6 alkyl groups) or

4) a phenyl group (said phenyl group is optionally substituted with one or more identical or different halogen atoms),

(2) a phenyl group (said phenyl group is optionally substituted with one or more carboxyl groups) or

(3) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more carboxyl groups) or a pharmaceutically acceptable salt thereof.

82. The compound of paragraph 80 above, wherein R ² is a cyclopropyl group or a methylcyclopropyl group or a pharmaceutically acceptable salt thereof.

83. The compound according to the above paragraph 80, in which R ³ and R ⁴ are the same or different and each represents

(1) a hydrogen atom,

(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more hydroxyl groups),

(3) a phenyl group (said phenyl group is optionally substituted with one or more identical or different substituents selected from a halogen atom and a C _1-6 alkyl group optionally substituted with one or more halogen atoms) or

(4) A 5 membered or 6 membered unsaturated, monocyclic, heterocyclic group or a pharmaceutically acceptable salt thereof.

84. The compound of paragraph 80 above or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

(1) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - (3-pyridin-3-yl) pyrrolidine,

(2) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {(R) -3- (2-trifluoromethylphenyl)} pyrrolidine ,

(3) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {(R) -3- (2-trifluoromethylphenyl)} pyrrolidine ,

(4) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {(R) -3- (2-trifluoromethylphenyl)} pyrrolidine ,

(5) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {(S) -3- (2-trifluoromethylphenyl)} pyrrolidine ,

(6) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {(S) -3- (2-trifluoromethylphenyl)} pyrrolidine ,

(7) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {(S) -3- (2-trifluoromethylphenyl)} pyrrolidine ,

(8) (-) 1- {5- (1-methylcyclopropyl) -1 - [(1-pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (4) hydrochloride -fluorophenyl) -3-hydroxymethylpyrrolidine,

(9) (+) 1- {5- (1-methylcyclopropyl) -1 - [(1-pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (4) hydrochloride -fluorophenyl) -3-hydroxymethylpyrrolidine,

(10) 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,

(11) 3- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,

(12) 5- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiophene-2-carboxylic acid and

(13) 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiazole-4-carboxylic acid.

85. A pharmaceutical composition comprising a compound according to any one of the above 80 to 84, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

86. An 11βHSD1 inhibitor containing the compound of any one of the above 80 to 84, or a pharmaceutically acceptable salt thereof, as an active ingredient.

87. An agent for the treatment or prevention of a pathology associated with a glucocorticoid, which comprises a compound according to any one of the above items 80-84 or a pharmaceutically acceptable salt thereof as an active ingredient.

88. The agent according to the above paragraph 87, for which the pathology associated with glucocorticoids is:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy associated with these diseases,

(4) hyperorexia,

(5) a disease with impaired nervous function, including cognitive impairment, neurodegenerative diseases accompanied by loss of nerve cells, emotional disorders, including anxiety, depression or mania, schizophrenia, or stimulation of appetite,

(6) a disease requiring treatment or prevention of weakened immunity or increased immunity, including immunodeficiency,

(7) glaucoma or

(8) osteoporosis.

89. The pharmaceutical composition according to the above paragraph 85, characterized in that it is used in combination with from 1 to 3 agents selected from the following agents according to paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

90. The 11βHSD1 inhibitor according to the above paragraph 86, characterized in that it is used in combination with from 1 to 3 agents selected from the following paragraphs (1) to (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

91. The agent according to the above paragraphs 87 or 88, which is used in combination with 1-3 agents selected from the following paragraphs (1) through (5):

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes,

(5) an agent for treating or preventing hypertension.

92. The pharmaceutical composition according to paragraph 85 above, characterized in that it is used to suppress an increase in blood glucocorticoids in combination with a pharmaceutical agent that increases blood glucocorticoids.

93. The 11βHSD1 inhibitor according to paragraph 86 above, characterized in that it is used to suppress an increase in blood glucocorticoids by use in combination with a pharmaceutical agent that increases blood glucocorticoids.

The best way to implement the invention

The present invention is described in detail as follows.

The following definitions of substituents are used in the present invention.

The term “C _1-6 alkyl group” is a straight or branched chain alkyl group having from 1 to 6 carbon atoms and, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group can be mentioned a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1,2-dimethylpropyl group, a hexyl group, a 1,3-dimethylbutyl group and the like, with preferred formation in line a straight or branched chain alkyl group having from 1 to 4 carbon atoms.

For R ^{1, a} preferred “C _1-6 alkyl group” is a methyl group, an ethyl group, an isopropyl group or an isobutyl group.

For R ³ or R ^{4, a} preferred “C _1-6 alkyl group” is a methyl group.

For R ⁵ or R ^{6, a} preferred “C _1-6 alkyl group” is an ethyl group, an isopropyl group, a tert-butyl group, a 1,2-dimethylpropyl group or a 1,3-dimethylbutyl group.

For R ^{9, a} preferred “C _1-6 alkyl group” is a methyl group.

For R ^{10, a} preferred “C _1-6 alkyl group” is a methyl group or an ethyl group.

For R ^{11, a} preferred “C _1-6 alkyl group” is a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group or a tert-butyl group.

For R ^{12, a} preferred “C _1-6 alkyl group” is a methyl group or an ethyl group.

For R ^{13, a} preferred “C _1-6 alkyl group” is a methyl group.

For R ¹⁴ or R ^{15, a} preferred “C _1-6 alkyl group” is a methyl group.

The term “C _2-6 alkenyl group” is a straight or branched chain alkenyl group having from 2 to 6 carbon atoms and, for example, a vinyl group, an n-propenyl group, an isopropenyl group, an n-butenyl group, an isobutenyl group can be mentioned group, sec-butenyl group, tert-butenyl group, n-pentenyl group, isopentenyl group, neopentenyl group, 1-methylpropenyl group, n-hexenyl group, isohexenyl group, 1,1-dimethylbutenyl group, 2,2-dimethylbutenyl group, 3.3- imetilbutenilnaya group, a 3,3-dimetilpropenilnaya group, 2-etilbutenilnaya group and the like.

The term “C _1-6 alkoxy group” is an alkoxy group, where the alkyl residue is a “C _1-6 alkyl group” as defined above and, for example, methoxy group, ethoxy group, propoxy group, isopropyloxy group, butoxy group, isobutyloxy group, tert-butyloxy group, pentyloxy, hexyloxy and the like.

The term “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. A fluorine atom or a chlorine atom is preferred, and a fluorine atom is more preferred.

The term “aryl group” is an aromatic hydrocarbon group having from 6 to 14 carbon atoms and, for example, phenyl group, naphthyl group, antryl group, azulenyl group, phenanthryl group and the like can be mentioned. A phenyl group is preferred.

The term “aryloxy group” is an aryloxy group, wherein the aryl residue is an “aryl group” as defined above and, for example, phenoxy group, naphthyloxy group and the like can be mentioned.

The term “cycloalkyl group” is a cycloalkyl group having from 3 to 8 carbon atoms and, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like can be mentioned. A cycloalkyl group having 3 to 6 carbon atoms is preferred, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. Particularly preferred are a cyclopropyl group and a cyclopentyl group.

The term “5-membered or 6-membered unsaturated, monocyclic, heterocyclic group” is a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group, in addition having at least one carbon atom, preferably from 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Unsaturation includes partial unsaturation and complete unsaturation. For example, a 5-membered, monocyclic aromatic, heterocyclic group such as a furyl group, thienyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group, oxadiazolyl group, a tetrazolyl group, a thiadiazolyl group and the like, and a 6-membered, monocyclic aromatic, heterocyclic group such as a pyridyl group, pyridazinyl group, pyri idinilnaya group, pyrazinyl group, triazinyl group, thiazinyl group oksadiazinilnaya group, pyranyl group, thiopyranyl group and the like. As a 5 membered, monocyclic aromatic, heterocyclic group, a thienyl group or a thiazolyl group is preferred. As a 6 membered, monocyclic aromatic, heterocyclic group, a pyridyl group or a pyrimidinyl group is preferred.

For R ^{1, the} preferred “5-membered or 6-membered unsaturated, monocyclic, heterocyclic group” is a pyridyl group, a thienyl group, a thiazolyl group, a triazolyl group (a 1,2,4-triazolyl group is particularly preferred), a tetrazolyl group, a pyrimidinyl group or a pyrazinyl group.

For R ³ or R ^{4, the} preferred “5 membered or 6 membered unsaturated, monocyclic, heterocyclic group” is a pyridyl group or a thiazolyl group. More preferred is a pyridyl group.

The term “nitrogen-containing, saturated, monocyclic, heterocyclic group” is, for example, a 4- to 6-membered saturated, monocyclic heterocycle having at least one nitrogen atom, such as an azetidinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group group, oxazolidinyl group, 2-oxopyrrolidinyl group, thiazolidinyl group, isothiazolidinyl group, piperidyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, 2- ksopiperidinilnaya group, 4-oksopiperidinilnaya group, a 2,6-dioksopiperidinilnaya group and the like. A preferred “nitrogen-containing, saturated, monocyclic, heterocyclic group” is an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group or a thiomorpholinyl group.

For -NR ⁵ R ^{6, the} preferred “nitrogen containing, saturated, monocyclic, heterocyclic group” is the azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group or thiomorpholinyl group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following group: a halogen atom,

hydroxyl group

With a _1-6 alkyl group optionally substituted with one or more hydroxyl groups,

carboxyl group,

acetyl group

carbamoyl group,

an amino group optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and an acetyl group and an oxo group).

For -NR ²⁰ R ^{21, the} preferred “nitrogen containing, saturated, monocyclic, heterocyclic group” is an azetidinyl group, a pyrrolidinyl group or a piperidyl group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from a halogen atom and a hydroxyl group )

For —NR ²⁶ R ^{27, a} preferred “nitrogen containing, saturated, monocyclic, heterocyclic group” is a piperidyl group or a pyrrolidinyl group, more preferably a piperidyl group.

For R ¹⁰ , a piperidyl group is the preferred “nitrogen-containing, saturated, monocyclic, heterocyclic group”.

For R ^{11, a} preferred “nitrogen-containing, saturated, monocyclic, heterocyclic group” is a pyrrolidinyl group or a piperidyl group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from a C _1-6 alkyl group, —CO — C _1-6 alkyl groups and oxo groups).

The presence of the term “optionally substituted with one or more substituents” means the presence of unsubstituted or optionally substituted with at least one to an acceptable maximum number of substituents. For example, in the case of a methyl group, this means the presence of optionally substituted from 1 to 3 substituents, and in the case of an ethyl group, this means the presence of optionally substituted from 1 to 5 substituents. Substituents in the case of substitution from two or more substituents, may be the same or different and the position of the substituents is not specifically limited and may be any.

The term “C _1-6 alkyl group optionally substituted with one or more identical or different substituents” is preferably a C _1-6 alkyl group optionally substituted with the same or different from 1 to 3 substituents. Particularly, a “C _1-6 alkyl group optionally substituted with one or more identical or different halogen atoms” is preferably a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, more preferably a C _1-6 alkyl group is optionally substituted with three halogen atoms and more preferably a trifluoromethyl group or a 2,2,2-trifluoroethyl group.

Preferred groups of each group are as follows.

[Preferred ring A]

Ring A represents

(1) a nitrogen containing, saturated, monocyclic, heterocyclic group (i.e., —X— is —N (R ¹ ) -) or

(2) a cycloalkyl group (i.e., —X— represents —C (R ⁷ R ⁸ ) -) and preferably

(1) an azetidinyl group or a piperidyl group, or

(2) a cyclohexyl group.

[Preferred R ² ]

R ^{2 is} preferably a cyclopropyl group or a cyclohexyl group optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group (said C _1-6 alkyl group is an optionally substituted hydroxyl group) and a C _1-6 alkoxy group . More preferably, it is a cyclopropyl group or a cyclohexyl group optionally substituted with one or more methyl groups (said methyl group is an optionally substituted hydroxyl group) or methoxy groups. Particularly preferably, it represents a cyclopropyl group, a methylcyclopropyl group, a methoxycyclopropyl group, a tetramethylcyclopropyl group, a hydroxymethylcyclopropyl group or a cyclohexyl group.

[Preferred R ³ and R ⁴ ]

R ³ and R ^{4 are} preferably not simultaneously hydrogen atoms.

More preferably, one of R ³ and R ⁴ represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from a halogen atom, a hydroxyl group , methoxy groups and acetyloxy groups) or a C _1-6 alkoxy group and the other is not a hydrogen atom.

In addition, preferably one of R ³ and R ⁴ represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from a halogen atom, hydroxyl group, methoxy group and acetyloxy group) or a C _1-6 alkoxy group and the other is a substituent selected from the following group, which is optionally substituted with one or more identical or different substituents iterators selected from a halogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms or a hydroxyl group), C _1-6 alkoxy group (said C _1-6 alkoxy group is optionally substituted by one or more identical or different halogen atoms), a C _1-6 alkoxycarbonyl group and a cyano group:

• phenyl group,

• pyridyl group and

• thiazolyl group.

It is particularly preferred that one of R ³ and R ⁴ represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from a halogen atom, a hydroxyl groups, methoxy groups and acetyloxy groups) or a methoxy group and the other is a substituent selected from the following group, which is optionally substituted with one or more, same or different substituents, selected from a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a methoxycarbonyl group, a hydroxymethyl group, and a cyano group:

• phenyl group,

• pyridyl group and

• thiazolyl group.

[Preferred R ⁵ and R ⁶ ]

R ⁵ and R ⁶ are preferably the same or different and each represents

• hydrogen atom,

• a phenyl group optionally substituted with one or more identical or different substituents selected from a hydroxyl group, a halogen atom, a carboxyl group and a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more hydroxyl groups or halogen atoms)

• a cycloalkyl group having from 3 to 6 carbon atoms (said cycloalkyl group is optionally substituted with a C _1-6 alkyl group, optionally substituted with one or more hydroxyl groups),

• A C _1-6 alkyl group optionally substituted with one or more, same or different substituents selected from a hydroxyl group, a halogen atom, a phenyl group (said phenyl group is optionally substituted with a halogen atom), a carboxyl group and —NR ²⁰ R ²¹ (where R ²⁰ and R ²¹ are as defined for formula [1]),

• -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group or a C _1-6 alkyl group,

• optionally saturated C _1-6 alkoxy group,

• a pyridinyl group optionally substituted with a halogen atom at the 2-position and 6-position,

• optionally substituted, nitrogen-containing unsaturated, heterocyclic group or

• containing nitrogen, a saturated, monocyclic, heterocyclic group, optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and a -CO-C _1-6 alkyl group, or

• R ⁵ and R ⁶ can form, together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, heterocyclic group selected from an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group and a thiomorpholinyl group, or a heterocyclic group selected from dihydroindolyl group, dihydro [1,4] oxazinyl group and tetrahydrobenzo [b] azepinyl group, which is a fused ring of said heterocycle and carbon ring (both of these hetero the cyclic groups being optionally substituted by one or more identical or different substituents selected from the following group:

halogen atom

hydroxyl group

With a _1-6 alkyl group optionally substituted with one or more hydroxyl groups,

carboxyl group,

acetyl group

carbamoyl group,

an amino group optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and an acetyl group, and

oxo groups).

More preferably, when R ⁵ and R ⁶ are the same or different and each represents

• hydrogen atom,

• a phenyl group optionally substituted at the ortho position and / or para position with substituents selected from a hydroxyl group, a halogen atom, a carboxyl group and a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more hydroxyl groups or halogen atoms),

• a cyclopropyl group or a cyclopentyl group optionally substituted with a C _1-6 alkyl group, optionally substituted with one or more hydroxyl groups,

• With a _1-6 alkyl group substituted by one or more, same or different substituents selected from a hydroxyl group, a halogen atom, a phenyl group (said phenyl group is optionally substituted by a halogen atom), a carboxyl group and —NR ²⁰ R ²¹ (where R ²⁰ and R ²¹ are as defined for formula [1]),

• -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group or a methyl group,

• With _1-6 alkoxygroup,

• a pyridinyl group substituted by a halogen atom at the 2-position and 6-position,

• optionally saturated thiazolyl group or

• a piperidin-4-yl group optionally substituted at the 1-position with one substituent selected from a C _1-6 alkyl group and a -CO-C _1-6 alkyl group or

• R ⁵ and R ⁶ can form, together with the nitrogen atom to which they are attached, a nitrogen-containing, saturated, monocyclic, heterocyclic group selected from an azetidin-1-yl group, a pyrrolidin-1-yl group, a piperidin-1-yl group a piperazin-1-yl group and a thiomorpholin-4-yl group or a heterocyclic group selected from a dihydroindol-1-yl group, a dihydro [1,4] oxazin-1-yl group and tetrahydrobenzo [b] azepin-1-yl group , which is a condensed ring of the indicated heterocycle and carbon ring (both the indicated heterocyclic groups are optionally substituted with one or more, same or different substituents selected from the following group:

halogen atom

hydroxyl group

With a _1-6 alkyl group optionally substituted with one or more hydroxyl groups,

carboxyl group,

acetyl group

carbamoyl group,

an amino group optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and an acetyl group; and

oxo groups).

Moreover, preferably, when R ⁵ and R ⁶ are the same or different and each represents

• hydrogen atom,

• a phenyl group substituted at the ortho position and / or para position with substituents selected from a hydroxyl group, a halogen atom, a carboxyl group and a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more hydroxyl halogen groups or atoms),

• a cyclopropyl group or a cyclopentyl group substituted with a C _1-6 alkyl group substituted with one or more hydroxyl groups,

• With a _1-6 alkyl group substituted with one substituent selected from a hydroxyl group, a halogen atom, a phenyl group (said phenyl group is optionally substituted with a halogen atom), a carboxyl group and —NR ²⁰ R ²¹ (where R ²⁰ and R ²¹ are those as defined for formula [1]),

• -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group or a methyl group,

• With _1-6 alkoxygroup,

• a pyridin-3-yl group substituted by a halogen atom at the 2-position and 6-position,

• thiazolyl group or

• a piperidin-4-yl group optionally substituted at the 1-position with -CO-C _1-6 alkyl group or

• R ⁵ and R ⁶ can form, together with the nitrogen atom to which they are attached, a nitrogen-containing, saturated, monocyclic, heterocyclic group selected from an azetidin-1-yl group, a pyrrolidin-1-yl group, a piperidin-1-yl group a piperazin-1-yl group and a thiomorpholin-4-yl group or a heterocyclic group selected from a dihydroindol-1-yl group, a dihydro [1,4] oxazin-1-yl group and tetrahydrobenzo [b] azepin-1-yl group , which is a condensed ring of the indicated heterocycle and carbon ring (both the indicated heterocyclic groups are optionally substituted with one or more, same or different substituents selected from the following group:

halogen atom

hydroxyl group

With a _1-6 alkyl group optionally substituted with one or more hydroxyl groups,

carboxyl group,

acetyl group

carbamoyl group,

an amino group optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and an acetyl group, and

oxo groups).

Particularly preferably, when R ⁵ and R ⁶ are the same or different and each represents

• hydrogen atom,

• 2-fluorophenyl group,

• 2-carboxyphenyl group,

• 2-hydroxymethylphenyl group,

• 1-hydroxymethylcyclopropyl group,

• 2-hydroxyethyl group,

• 2-hydroxy-1,1-dimethylethyl group,

• 2-acetylaminoethyl group,

• 2-aminoethyl group,

• 2-dimethylaminoethyl group,

• 2-piperidin-1-yl-ethyl group,

• 2-hydroxy-1-methylethyl group,

• piperidin-4-ilen group,

• 1-methylpiperidin-4-ilen group,

• 1-acetylpiperidin-4-ilen group,

• 2,2,2-trifluoroethyl group,

• 1-hydroxymethyl-2-methylpropyl group,

• 1-hydroxymethyl-2-phenylethyl group,

• 2-hydroxy-1-phenylethyl group,

• 1-hydroxymethyl-3-methylbutyl group,

• 2-hydroxyphenyl group,

• 1-hydroxymethylcyclopentyl group,

• benzenesulfonyl group,

• 4-trifluoromethylphenyl group,

• 2,4-difluorophenyl group,

• 1-carboxy-2-methylpropyl group,

• thiazol-2-yl group,

• isopropoxy group,

• 4-fluorobenzyl group,

• 2,6-dichloropyridin-3-ilen group,

• ethoxy group or

• mesyl group or

• R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen, saturated, monocyclic, heterocyclic group, or a heterocyclic group, which is a fused ring of said heterocycle and a carbon ring that is selected from the following group:

azetidin-1-yl group,

3-hydroxyazetidin-1-yl group,

3-hydroxymethylazetidin-1-yl group,

3-acetylazetidin-1-ilen group,

3-acetylaminoazetidin-1-ilen group,

3-hydroxypyrrolidin-1-yl group,

3,3-difluoropyrrolidin-1-yl group,

3,3,4,4-tetrafluoropyrrolidin-1-yl group,

2-hydroxymethylpyrrolidin-1-yl group,

2-aminopyrrolidin-1-ilen group,

2-acetylaminopyrrolidin-1-yl group,

2-dimethylaminopyrrolidin-1-yl group,

3-oxopyrrolidin-1-yl group,

4-hydroxypiperidin-1-yl group,

4,4-difluoropiperidin-1-yl group,

4-hydroxymethylpiperidin-1-yl group,

4-carboxypiperidin-1-yl group,

3-hydroxypiperidin-1-yl group,

4-carbamoylpiperidin-1-yl group,

4-aminopiperidin-1-yl group,

4-dimethylaminopiperidin-1-yl group,

4-acetylaminopiperidin-1-yl group,

4-methylpiperazin-1-yl group,

4-isopropylpiperazin-1-yl group,

4-acetylpiperazin-1-yl group,

1,1-dioxothiomorpholin-4-yl group,

3-oxopiperidin-1-yl group,

4-oxopiperidin-1-yl group,

2,3-dihydroindol-1-yl group,

2,3-dihydro [1,4] oxazin-1-yl group and

2,3,4,5-tetrahydrobenzo [b] azepin-1-yl group.

Moreover, it is preferable when R ⁵ and R ⁶ are not simultaneously hydrogen atoms. More preferably, one of R ⁵ and R ⁶ is a hydrogen atom and the other is not a hydrogen atom.

[Preferred R ¹⁰ ]

R ^{10 is} preferably

• a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more, same or different substituents selected from a hydroxyl group, a phenyl group and —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or each and each is a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form a piperidyl group together with the nitrogen atom to which they are attached) or

• a piperidyl group (said piperidyl group is optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and a -CO-C _1-6 alkyl group).

R ¹⁰ is more preferably

• a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more, same or different substituents selected from a hydroxyl group, a phenyl group and —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or each and each is a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form a piperidyl group together with the nitrogen atom to which they are attached) or

• a piperidin-4-yl group (said piperidin-4-yl group is optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and a -CO-C _1-6 alkyl group).

R ^{10 is} further preferably

• a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from a hydroxyl group, a phenyl group and —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form a piperidyl group together with the nitrogen atom to which they are attached) or

• a piperidin-4-yl group (said piperidin-4-yl group is optionally substituted with one or more, same or different substituents selected from a C _1-6 alkyl group and a -CO-C _1-6 alkyl group).

R ¹⁰ is particularly preferably

• methyl group,

• 2-hydroxyethyl group,

• 2-dimethylaminoethyl group,

• 2-piperidin-1-yl-ethyl group,

• piperidin-4-ilen group,

• 1-methylpiperidin-4-ilen group,

• benzyl group or

• 1-acetylpiperidin-4-ilen group.

[Preferred R ¹¹ ]

R ^{11 is} preferably

• a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to g):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,

d) a carbamoyl group,

e) a carboxyl group,

f) phenoxy groups and

g) fluorophenyl group),

• a cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group optionally substituted with one or more identical or different halogen atoms and

b) a C _1-6 alkyl group optionally substituted with one or more hydroxyl groups),

• an aryl group (said aryl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) one or more identical or different halogen atoms,

b) a C _1-6 alkyl group optionally substituted with one or more, same or different halogen atoms, and

c) C _1-6 alkoxy)

• carboxyl group or

• containing nitrogen, a saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups).

R ^{11 is} more preferably

• a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to g):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,

d) a carbamoyl group,

e) a carboxyl group,

f) phenoxy groups and

g) fluorophenyl group),

• a cyclopropyl group (said cyclopropyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group optionally substituted with one or more identical or different halogen atoms and

b) a C _1-6 alkyl group optionally substituted with one or more hydroxyl groups),

• a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):

a) one or more identical or different halogen atoms,

b) a C _1-6 alkyl group optionally substituted with one or more, same or different halogen atoms, and

c) C _1-6 alkoxy)

• carboxyl group or

• containing nitrogen, a saturated, monocyclic, heterocyclic group selected from a pyrrolidinyl group and a piperidyl group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following a) to c):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups).

R ^{11 is} further preferably

• a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to g):

a) a halogen atom,

b) a hydroxyl group,

c) —NR ²⁸ R ²⁹ , where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,

d) a carbamoyl group,

e) a carboxyl group,

f) phenoxy groups and

g) fluorophenyl group),

• a cyclopropyl group (said cyclopropyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):

a) an aryl group optionally substituted with one or more identical or different halogen atoms and

b) a C _1-6 alkyl group optionally substituted with one or more hydroxyl groups),

• a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following a) to c):

a) one or more identical or different halogen atoms,

b) a C _1-6 alkyl group optionally substituted with one or more, same or different halogen atoms, and

c) C _1-6 alkoxy)

• carboxyl group or

• containing nitrogen, a saturated, monocyclic, heterocyclic group selected from a pyrrolidin-2-yl group and a piperidin-4-yl group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following a) to c ):

a) C _1-6 alkyl groups,

b) —CO — C _1-6 alkyl groups; and

c) oxo groups).

R ¹¹ is particularly preferably

• 2,2,2-trifluoroethyl group,

• hydroxymethyl group,

• 3-hydroxypropyl group,

• 2-hydroxy-1,1-dimethylethyl group,

• aminomethyl group,

• 2-aminoethyl group,

• 1-amino-1-methylethyl group,

• 1-amino-2-methylpropyl group,

• methylaminomethyl group,

• dimethylaminomethyl group,

• acetylaminomethyl group,

• 1-acetylaminoethyl group,

• 2-acetylaminoethyl group,

• 1-acetylamino-1-methylethyl group,

• 1-acetylamino-2-methylpropyl group,

• isobutyrylaminomethyl group,

• cyclopropanecarbonylaminomethyl group,

• methanesulfonylaminomethyl group,

• 2-carbamoylethyl group,

• cyclopropyl group,

• 1- (4-fluorophenyl) cyclopropyl group,

• 1-methylcyclopropyl group,

• 1-hydroxymethylcyclopropyl group,

• pyrrolidin-1-ilen group,

• pyrrolidin-2-ilen group,

• piperidin-4-ilen group,

• 1-methylpyrrolidin-2-ilen group,

• 1-methylpiperidin-4-ilen group,

• 1-acetylpyrrolidin-2-ilen group,

• 1-acetylpiperidin-4-ilen group,

• 2-carboxy-2-methylpropyl group,

• phenoxymethyl group,

• 2-chlorophenyl group,

• 3-chlorophenyl group,

• 4-chlorophenyl group,

• carboxyl group,

• 4-fluorobenzyl group,

• 3-trifluoromethylphenyl group,

• 3-methoxyphenyl group or

• 5-oxopyrrolidin-2-ilen group.

The salt of the compound of the present invention is preferably a pharmaceutically acceptable salt. The salt of the compounds of the present invention represented by the formula [1 '] can be obtained in the usual way. A salt of a compound of the present invention represented by the formula [1 '] can be obtained by reacting a compound of the formula [1'] (hereinafter, the compound [1 '] and its salts also all by definition refer to the compound of the present invention) with, for example inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like; organic acids such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide and the like; organic bases such as methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline, cichonin and the like; amino acids such as lysine, arginine, alanine and the like. The present invention also includes aqueous products, hydrates and solvates of the compounds of the present invention.

In addition, the compound of the present invention has various isomers. For example, the E form and the Z form can be represented as geometric isomers when an asymmetric carbon atom is present, the enantiomer and diastereomer are represented as stereoisomers of the compound, and tautomers can also be present. Therefore, the present invention encompasses said isomers and mixtures thereof. Moreover, in addition to the compounds of the present invention, the present invention encompasses prodrugs of the compounds and metabolites of the compounds as equivalent compounds.

As used herein, the term “prodrug” means a derivative that has a chemically or metabolically cleavable group and exhibits pharmaceutical activity after decomposition by hydrolysis or solvolysis, or under physiological conditions. A prodrug is used, for example, to improve absorption when administered orally or to target a target in an object. Since such a chemically or metabolically cleavable group is used, and how it is incorporated into a compound, has been well studied in the field of pharmaceutical agents, similar known techniques may be used in this invention. As a functional group that can be modified to obtain a prodrug of a compound of the invention, highly reactive functional groups such as a hydroxyl group, a carboxyl group, an amino group, a thiol group and the like, which may be indicated for the compound according to the present invention.

For example, a derivative may be mentioned where a substituent, such as —CO — C _1-6 alkyl group, —CO ₂ —C _1-6 alkyl group, —CONH-C _1-6 alkyl group, —CO-C _2-6 alkenyl group, —CO ₂ —C _2-6 alkenyl group, —CONH-C _2-6 alkenyl group, —CO-aryl group, —CO ₂ aryl group, —CONH aryl group, —CO-heterocyclic group, - CO ₂ heterocyclic group, —CONH heterocyclic group (C _1-6 alkyl group, C _2-6 alkenyl group, aryl group and heterocyclic group, optionally substituted with a halogen atom, C _1-6 alkyl group, hydroxyl group, C _1-6 alkoxy group, carboxyl group, amino group, amino acid residue, -PO ₃ H ₂ , -SO ₃ H, -CO-polyethylene glycol residue, -CO ₂ -polyethylene glycol residue, monoalkyl ether -CO-polyethylene glycol residue, monoalkyl residue ether -CO ₂ -polyethylene glycol and the like) and the like are included in the hydroxyl group.

In addition, a derivative may be mentioned where a substituent, such as a —CO — C _1-6 alkyl group, —CO ₂ —C _1-6 alkyl group, —CO — C _2-6 alkenyl group, —CO ₂ —C _{2 -6} alkenyl group, -CO-aryl group, -CO ₂ -aryl group, -CO-heterocyclic group, -CO ₂ -heterocyclic group (C _1-6 alkyl group, C _2-6 alkenyl group, aryl group and heterocyclic group optionally substituted with a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkoxy group, a carboxyl group, an amino group, an amino acid residue, —PO ₃ H ₂ , —SO ₃ H, a residue of -CO-polyethylene glycol, a residue of -CO ₂ -polyethylene glycol, a residue of a monoalkyl ether of -CO-polyethylene glycol, a residue of a monoalkyl ether of -CO ₂ -polyethylene glycol, -PO ₃ H ₂ and the like) and the like) are included in the amino group.

Moreover, a derivative may be mentioned where a substituent such as a C _1-6 alkoxy group, an aryloxy group (C _1-6 alkoxy group and aryloxy group are optionally substituted with a halogen atom, a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkoxy group, carboxyl group, amino group, amino acid residue, —PO ₃ H ₂ , —SO ₃ H, polyethylene glycol residue, monoalkyl ether of polyethylene glycol and the like) and the like) are included in the carboxyl group.

As indicated above, the term “heterocyclic group” is a 5-membered or 6-membered saturated or unsaturated (including partial unsaturation and complete unsaturation), monocyclic, heterocyclic group having in addition to the carbon atom at least one, preferably from 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom or a fused ring group of a heterocycle or a fused ring group of a heterocycle and a carbon ring selected from benzene, cyclopentane and cyclohexane .

As the “5-membered or 6-membered saturated, monocyclic, heterocyclic group”, for example, mention may be made of a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, an imidazolidinyl group, a pyrazolidinyl group, a 1,3-dioxolanyl group, 1,3-oxathioranyl group, oxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl a n-group, a 2-oxo-pyrrolidinyl group, a 2-oxo-piperidinyl group, a 4-oxo-piperidinyl group, a 2,6-dioxopiperidinyl group and the like.

As the “5-membered or 6-membered unsaturated, monocyclic, heterocyclic group”, for example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, 1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group, diazolyl can be mentioned group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, triazolyl group (1,2,4-triazolyl group, 1,2,3-triazolyl group), tetrazolyl group, 1,3,4-oxadiazolyl group, 1, 2,4-oxadiazolyl group, 1,3,4-thia diazolyl group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group, pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, pyrazinyl group, 1,3,5-triazinyl group, imidazolinyl group, pyrazolinyl group, oxazolinyl group (2-oxazolinyl group, 3-oxazolinyl group, 4-oxazolinyl group), isoxazolinyl group, thiazolinyl group, isothiazolinyl group, pyranyl group, 2-oxopyranyl group, 2-oxo-2,5-dihydrofuranyl group 1,1-d ioxo-1H-isothiazolyl group.

As the “heterocyclic group which is a fused ring”, for example, an indolyl group (eg, a 4-indolyl group, a 7-indolyl group and so on), an isoindolyl group, 1,3-dihydro-1,3- can be mentioned dioxoisoisoindolyl group, benzofuranyl group (e.g. 4-benzofuranyl group, 7-benzofuranyl group and so on), indazolyl group, isobenzofuranyl group, benzothiophenyl group (e.g. 4-benzothiophenyl group, 7-benzothiophenyl group and so on), benzooxazole an alkyl group (e.g., a 4-benzooxazolyl group, a 7-benzooxazolyl group and so on), a benzimidazolyl group (e.g. a 4-benzimidazolyl group, a 7-benzimidazolyl group and so on), a benzothiazolyl group (e.g. a 4-benzothiazolyl group, 7- benzothiazolyl group and so on), indolysinyl group, quinolyl group, isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, quinolysinyl group, puryl group ppa, pteridinyl group, indolinyl group, isoindolinyl group, 5,6,7,8-tetrahydroquinolyl group, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo [ 1,3] dioxolyl group, 3,4-methylenedioxypyridyl group, 4,5-ethylenedioxypyrimidinyl group, chromenyl group, chromanyl group, isochromanyl group and the like.

The term "pharmaceutical composition" includes, in addition to the definition of "composition", containing the active ingredient as a pharmaceutical agent and a combination drug and the like, a combination of the agent with another drug and the like. Needless to say, the pharmaceutical composition of the present invention can be simultaneously used with any other drug within the limits of acceptability in a clinical situation. Thus, the present pharmaceutical composition can also be considered as a pharmaceutical composition for combination with another drug.

Moreover, the pharmaceutical composition of the present invention can be introduced not only to humans, but also to other mammals (mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, etc.). Therefore, the pharmaceutical composition of the present invention is also applicable as a pharmaceutical product for animals, not to mention humans.

The compound of the present invention and its salt can be mixed with a pharmaceutically acceptable carrier and administered orally or parenterally in the form of tablets, pills, powders, granules, suppositories, injections, eye drops, solution, capsules, troches, aerosol, elixir, suspension, emulsion, syrup and the like

As a "pharmaceutically acceptable carrier", various organic or inorganic carrier materials are used, usually used as the main substance of the drug, which is added as a neutral filler, lubricant, binder, disintegrant, solvent, auxiliary solvent, suspending agent, isotonicizing agent buffer, softening agent, etc. If necessary, auxiliary substances, such as preservatives, antioxidants, colorants, sweeteners, etc. can also be used. As examples of the aforementioned excipients, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silicic anhydride and the like can be cited. As the aforementioned lubricants, for example, magnesium stearate, calcium stearate, talc, colloidal silicon and the like can be cited. Polymeric compounds such as crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and the like can be exemplified by the aforementioned binders. As examples of the aforementioned disintegrants, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch and the like can be mentioned. Examples of the aforementioned solvents may be water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, propylene glycol esters of fatty acids, and the like. As examples of the aforementioned dissolution promoting substances, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, thietanolamine, sodium carbonate, sodium citrate and the like can be cited. Surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopripionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glyceryl monostearate and the like can be exemplified as the aforementioned suspending agents; polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose and the like. As examples of the aforementioned isotonic agents, sodium chloride, glycerin, D-mannitol and the like can be mentioned. As examples of the aforementioned buffering agents, buffers such as phosphate, acetate, carbonate, citrate and the like can be given. As examples of the aforementioned emollients, benzyl alcohol and the like can be given. As examples of the aforementioned preservatives, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenyl alcohol, dehydroacetic acid, sorbic acid, and the like can be cited. As examples of the aforementioned antioxidants, sulfite, ascorbic acid and the like can be mentioned. As examples of the aforementioned sweeteners, aspartame, sodium saccharin, stevia and the like can be mentioned. As examples of the aforementioned colorants, food colorings such as Food Color Yellow No. may be mentioned. 5, Food Color Red No. 2 and Food Color Blue No. 2, etc., food lake colors, iron oxide, etc.

The term “11βHSD1 inhibitor” means the disappearance or attenuation of the activity of 11βHSD1 by specifically inhibiting its function as an enzyme and, for example, means specifically inhibiting the function of 11βHSD1 in the conditions of the following experimental example 1, and preferably means that its concentration is necessary to achieve 50% inhibition of 11βHSD1 under the conditions of the following experimental example 1 is less than 10 μm, preferably less than 1 μm, more preferably less than 100 nm and even more preferably its 10 nM.

The term “glucocorticoid-related pathology” means, for example,

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy,

(4) hyperorexia,

(5) a disease with impaired neural function, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,

(6) a disease associated with a decrease in immune function,

(7) glaucoma or

(8) osteoporosis

etc.

If a compound of the present invention is used as a medicament for the treatment or prophylaxis of a pathology demonstrating glucocorticoid involvement, it can be administered systemically, topically, orally or parenterally. Since the dose varies depending on age, body weight, condition, effect of treatment, etc., for example, the drug can be administered in the range from 0.1 to 1 g per adult for one to several times a day. The compound of the present invention can also be used as a drug for the treatment or prevention of the aforementioned diseases in humans, other than human animals, especially mammals. The same applies to the use of a compound of the present invention as a medicament for the treatment or prophylaxis of the following diseases:

(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,

(2) metabolic syndrome,

(3) a fatal vascular event, including myocardial infarction or brain apoplexy,

(4) hyperorexia,

(5) a disease with impaired neural function, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,

(6) a disease associated with a decrease in immune function,

(7) glaucoma, or

(8) osteoporosis

Etc.

To obtain a preparation of a compound of the present invention, such as a solid composition or a liquid composition for oral administration, or injections for parenteral administration and the like, this compound can be mixed with excipients, such as a suitable diluent, dispersing agent, adsorbent, solubilizing means, etc. In addition, the pharmaceutical composition of the present invention may take a known form, such as tablets, pills, powder, granules, suppositories, injections, eye drops, solution, capsules, plates, aerosol, elixir, suspension, emulsion, syrup and the like.

In cases where the pharmaceutical composition of the present invention is, for example, a solid preparation, such as a tablet, pill, powder, granules and the like, excipients include, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone , magnesium aluminum metasilicate, silicon anhydride powder, and the like. In the manufacture of tablets or pills, a shell may be used if necessary from a substance that is soluble in the stomach or intestines, such as sucrose, gelatin, hydroxypropyl cellulose or hydroxymethyl cellulose phthalate, etc. or a multilayer tablet having two or more layers may be produced.

A compound, pharmaceutical composition or preparation of the present invention can be used in combination with (hereinafter, the term “combined use”) another pharmaceutical composition or preparation (hereinafter, the term “combined preparation” is used).

The duration of administration of the pharmaceutical composition or preparation of the present invention and the combination preparation is not limited, and they can be administered to the subject in the form of a combination preparation, administered simultaneously or in stages. Moreover, a pharmaceutical agent, which is a kit containing the pharmaceutical composition or preparation of the present invention and a combination preparation, can be administered. The dose of the combination drug which can be appropriately determined may be clinically applied depending on the subject receiving the therapy, his age and body weight, general condition, time of administration, dosage form, route of administration, combination, and the like. The route of administration of the combination drug is not particularly limited, and may be any if the pharmaceutical composition and the combination drug are combined.

A pharmaceutical agent consisting of 1-3 agents selected from the following (1) to (5), and a compound of the present invention or a salt thereof in combination:

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes, (4) an agent for treating or preventing diabetes complications,

(5) agent for treating or preventing hypertension

means pharmaceutical agents, such as the case where the “pharmaceutical agent” is a combination preparation, the case where the “pharmaceutical agent” is a kit containing a preparation containing said “1-3 agents selected from items (1) through (5)” and a preparation containing a compound of the present invention, a case where a “pharmaceutical agent” and a preparation containing a compound of the present invention are administered simultaneously or at certain intervals, and the like. This pharmaceutical agent is preferably an agent for the treatment or prophylaxis of a pathology associated with glucocorticoids.

As a combination drug may be mentioned

(1) an agent for treating or preventing hyperlipidemia,

(2) an agent for treating or preventing obesity,

(3) an agent for treating or preventing diabetes,

(4) an agent for treating or preventing complications of diabetes, and

(5) an agent for treating or preventing hypertension,

and 1-3 agents based on them and the compound of the present invention can be used in combination.

As an “agent for the treatment or prophylaxis of hyperlipidemia", for example,

(1) fibrates (PPARα receptor agonists),

(2) PPAR-δ receptor agonists,

(3) inhibitors of the microsomal triglyceride carrier protein,

(4) cholesterol ester carrier protein inhibitors,

(5) statins (HMG-CoA reductase inhibitors),

(6) anion exchange resins,

(7) probucol,

(8) nicotinic acid preparations,

(9) phytosterol,

(10) apolipoprotein-A1 inducers (Apo-A1),

(11) lipoprotein lipase activators (LPL),

(12) endothelial lipase inhibitors,

(13) ezetimibe,

(14) IBAT inhibitors,

(15) squalene synthase inhibitors,

(16) ACAT inhibitors,

(17) LXR receptor agonists,

(18) FXR receptor agonists,

(19) FXR receptor antagonists, and

(20) adenosine A1 agonists

and, in particular, clofibrate, bezafibrate, fenofibrate, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, cerivastatin, cholestyramine, colestimide, tocopherol nicotinate nicolol .

As an “agent for the treatment or prevention of obesity”, for example,

(1) leptins,

(2) pancreatic lipase inhibitors,

(3) norepinephrine and serotonin reuptake inhibitors,

(4) cannabinoid receptor antagonists,

(5) monoamine reuptake inhibitors,

(6) diacylglycerol acyltransferase (DGAT) inhibitors,

(7) glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists,

(8) leptin receptor agonists,

(9) subtype 3 bombesin receptor agonists (BRS-3),

(10) perilipin inhibitors,

(11) acetyl CoA carboxylase 1 (ACC1) inhibitors,

(12) acetyl CoA carboxylase 2 (ACC2) inhibitors,

(13) fatty acid synthase inhibitors,

(14) sn-1-acyl-glycerol-3-phosphate acyltransferase (AGPAT) inhibitors,

(15) pancreatic phospholipase A2 inhibitors (pPLA2), (16) melanocortin (MC) receptor agonists, (17) neuropeptide Y5 receptor antagonists (NPY5),

(18) an inducer or activators of uncoupling protein (UCP),

(19) carnitine O-palmitoyltransferase 1 (CPT-1) activators,

(20) agonists CCK1 (CCKA),

(21) ciliary neurotrophic factor (CNTF),

(22) CRF agonists 2,

(23) Y2 neuropeptide receptor antagonists (NPY2),

(24) antagonists of the neuropeptide receptor Y4 (NPY4),

(25) thyroid hormone beta receptor agonists,

(26) growth hormones,

(27) ATP inhibitors of citrate lyase,

(28) 5-HT6 antagonists, and

(29) 5-HT2C agonists

and in particular, leptin, orlistat, sibutramine, rimonabant and mazindole and the like may be mentioned.

As an “agent for the treatment or prevention of diabetes”, for example,

(1) insulin preparations (injections),

(2) oral preparations of low molecular weight insulin,

(3) sulfonylurea receptor agonists (SU agents),

(4) non-sulfonylurea agents that increase insulin secretion (SU agents),

(5) potassium dependent ATP channel opening agents (KATP),

(6) α-glucosidase inhibitors,

(7) α-amylase inhibitors,

(8) insulin sensitivity enhancers,

(9) low molecular weight tGLP-1 receptor agonists,

(10) peptide analogues of tGLP-1,

(11) dipeptidyl peptidase IV (DPP-IV) inhibitors,

(12) glucagon receptor antagonists,

(13) glucorticosteroid receptor antagonists,

(14) biguanides,

(15) SGLUT inhibitors,

(16) fructose 1,6-bisphosphatase inhibitors (FBPase),

(17) glycogen synthase kinase 3 inhibitors (GSK-3),

(18) phosphoenolpyruvate carboxykinase inhibitors (PEPCK),

(19) protein tyrosine phosphatase 1B inhibitors (PTPase 1B),

(20) SH2 inhibitors of domain-containing inositol phosphatase (SHIP2),

(21) glycogen phosphorylase (GP) inhibitors,

(22) glucokinase activators,

(23) GPR40 receptor agonists,

(24) pyruvate dehydrogenase kinase inhibitors (PDHK),

(25) glutamine-fructose-6-phosphataminotransferase (GFAT) inhibitors,

(26) antioxidants; nitric oxide acceptors,

(27) carnitine-O-palmitoyltransferase 1 (CPT-1) inhibitors,

(28) growth hormone releasing factors (GHRF),

(29) inhibitors of triacylglycerol lipase (hormone-sensitive lipase),

(30) PPAR γ receptor agonists,

(31) PPARγ receptor antagonists,

(32) PPAR α / γ receptor agonists,

(33) activators of an AMP-activated protein kinase,

(34) adiponectin receptor agonists, and

(35) β3-adrenergic agonists,

and, in particular, insulin, tolbutamide, glycopyramide, acetohexamide, chloropropamide, glibuzol, glibenclamide, glyclazide, glimepiride, mitiglinide, repaglinide, acarbose, miglitol, roslichloridoformone, roslichloridylamine, rosglichloridylonchloride, rosiglichloridone, may be mentioned etc.

As an “agent for the treatment or prevention of diabetes complications”, for example,

(1) a protein kinase inhibitor C β (PKCβ),

(2) an angiotensin II receptor antagonist,

(3) an aldose reductase inhibitor,

(4) an angiotensin converting enzyme (ACE) inhibitor,

(5) glycation end product production inhibitors (AGE),

(6) therapeutic agents for the treatment of neuropathy, and

(7) therapeutic agents for the treatment of diabetic nephropathy

and in particular, epalrestat (kinedak), mexiletine hydrochloride, imidapril hydrochloride, and the like may be mentioned.

As an “agent for the treatment or prophylaxis of hypertension”, for example,

(1) thiazide diuretics,

(2) thiazide-like diuretics,

(3) loop diuretics,

(4) potassium-sparing diuretics,

(5) β-blockers,

(6) α, β-blockers,

(7) α-blockers,

(8) central sympathetic neurosuppressors,

(9) peripheral sympathetic neurosuppressors (rauwolfia preparations),

(10) Ca antagonists (benzothiazepine),

(11) Ca antagonists (dihydropyridine),

(12) vasodilators,

(13) angiotensin converting enzyme (ACE) inhibitors,

(14) angiotensin II receptor antagonists,

(15) nitrates,

(16) ETA endothelin receptor antagonists,

(17) endothelin-converting enzyme inhibitors; neprilysin inhibitors

(18) prostaglandin; prostanoid agonists FP,

(19) renin inhibitors,

(20) means for improving the expression of NOS3; prostacyclin analogues

(21) phosphodiesterase V inhibitors (PDE5A),

(22) prostacyclin analogues, and

(23) aldosterone antagonists

and, in particular, hydrochlorothiazide, trichloromethiazide, benzylhydrochlorothiazide, methicran, indapamide, tripamide, chlortalidone, mefruside, furosemide, spironolactone, triamteren, atenolol hydrochloride hydrochloride, celolitholol hydrochloride, celolithol hydrochloride, celolithol hydrochloride nipradilol, tilisolol hydrochloride, nadolol, propranolol hydrochloride, indenalol hydrochloride, carteolol hydrochloride, pindolol, sustained-release pindolol preparation, bunitrolol hydrochlor d, penbutolol sulfate, bopindolol malonate, amosulalol hydrochloride, arotinolol hydrochloride, carvedilol, labetalol hydrochloride, urapidil, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, prazosin hydrochloride, phentolamine mesylate, clonidine hydrochloride, guanfacine hydrochloride, guanabentsa acetate, methyldopa, reserpine, rescinnamine , amlodipine besilate, aranidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nizoldipine, nitrendipine, nifedipine, sustained release nifedipine preparation, nil adipic, barnidipine hydrochloride, felodipine, benidipine hydrochloride, manidipine hydrochloride, azelnidipine, diltiazem hydrochloride, hydrazine hydrochloride, todoralazina hydrochloride, budralazine, cadralazine, captopril, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride quinapril hydrochloride, trandolapril, perindopril erbumin, candesartancylexetil, valsartan, thermisartan, olmesartan medoxomil, sodium nitroprusside, nitroglycerin, etc. .

As a combination drug, a drug may be mentioned that increases the level of glucocorticodes in the blood, such as an adrenal corticosteroid and the like. Blood glucocorticoids mean not only endogenous glucocorticoids, such as corticosterone, cortisol, etc., but also exogenous glucocorticoids due to the administration of an adrenal corticosteroid. Thus, from 1 to 3 agents and the compound of the present invention can be used in combination.

Some of the following examples of methods for preparing the compounds of the present invention are provided. However, methods for preparing the compounds of the present invention are not limited to these examples. Even in the absence of a description of the preparation method, if necessary, an effective preparation can be presented by introducing a protective group into a functional group followed by deprotection in the next step by replacing the order of the respective steps. As a protective group, for example, a carboxy protecting group (in the present description, a carboxy protecting group means one which is usually used in the field of synthetic organic chemistry, such as a methyl group, an ethyl group, a propyl group, a tert-butyl group, a benzyl group, can be mentioned). a group, a p-methoxybenzyl group and the like, which are in the form of esters capable of easily leading to carboxylic acid by hydrolysis, catalytic hydrogenation and the like), an amino protecting group (present scripture, an amino protecting group means one that is typically used in the field of synthetic organic chemistry, such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group and the like, which can easily be converted to an amino group by hydrolysis, catalytic hydrogenation, and the like), hydroxyl-protecting group (in the present description, hydroxyl-protecting group means one that is usually used in the field of synthetic organic chemistry, such as tetrahydropyranyl group, m ethoxymethyl group, methoxyethoxymethyl group, benzyloxymethyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, trimethylsilyl group, tert-butyldimethylsilyl group, acetyl group, benzoyl group, allyl group, tert-butyl group and the like, which can easily turn into a hydroxyl group by hydrolysis, catalytic hydrogenation and the like) and the like. The post-reaction treatment at each stage can be carried out in a conventional manner, in which, if necessary, isolation and purification are performed by selecting or combining conventional methods, such as crystallization, recrystallization, silica gel chromatography, preparative HPLC and the like.

Production Method 1

In the compound of formula [1 ′] of the present invention, a compound where —X— is —NH— can be obtained by performing the following steps.

where R 'represents a carboxy-protecting group (in the present description, a carboxy-protecting group means that which is usually used in the field of synthetic organic chemistry, such as a methyl group, an ethyl group, a propyl group, a tert-butyl group, a benzyl group, p-methoxybenzyl group and the like) which, in the form of esters, can easily lead to carboxylic acid by hydrolysis, catalytic hydrogenation and the like, R "represents an amino protecting group (in the present description, an amino protecting I group means one that is usually used in the field of synthetic organic chemistry, such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group and the like), which can be easily removed by hydrolysis, catalytic hydrogenation and the like and other values radicals are as defined above.

Stage 1

A compound of formula (3) can be prepared by reacting a β-ketoester (1) synthesized by a known method with dimethylformamide dimethylacetal (2), in a solvent or in the absence of a solvent. As the solvent, methanol, ethanol, benzene, toluene, xylene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 250 ° C. The reaction time is usually from an hour to 24 hours. The amount of dimethylformamide dimethylacetal (2) to be used is usually from about 1.5 to about 3 mol per 1 mol of β-ketoester (1). The amount of solvent to be used is not particularly limited and can be appropriately determined depending on the type and amount of the reaction substrate used (β-keto ester (1) and dimethylformamide dimethylacetal (2)), reaction temperature, reaction time and the like (similar explanations regarding the amount of solvent used in each step are given below).

Stage 2 : Stage closure of the pyrazole ring

A compound of formula (5) is prepared by reacting hydrazine (4) synthesized by a known method with a compound of formula (3) in a solvent. As the solvent, methanol, ethanol, n-propanol, n-butanol, isopropanol, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture can be mentioned. specified solvents and the like. The temperature of the reaction mixture is usually in the range from 20 ° C to 250 ° C. The reaction time is usually from an hour to 24 hours. The amount of hydrazine (4) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (3). When hydrazine (4) is used in the form of a salt, the reaction is carried out in the presence of a base (the amount of base for administration is usually from about 1 and up to about 2 mol per 1 mol of compound (3)), such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N-diisopropylethylamine, pyridine and the like.

Stage 3 : Stage deprotection of the carboxyl group

The compound of formula (6) is obtained by eliminating the carboxyl protecting group R ′ of compound (5) using a known method.

Stage 4 : Amidation Stage

A compound of formula (8) is prepared by reacting a compound (6) with an amine (7) in a solvent in the presence of a condensing agent and an additive. As the condensing agent, there may be mentioned dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenylphosphorylazide (like DPPA and . As an additive, 1-hydroxybenzotriazole (HOBT), N-hydrosuccin imide (HOSu), 4-dimethylaminopyridine (DMAP) and the like can be mentioned. As the solvent, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of amine (7) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (6). In addition, the amount of condensing agent and additive that is used is usually from about 1 and about 1.5 mol, and from about 1 and about 1.5 mol, respectively, per 1 mol of compound (6). When the amine (7) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N- diisopropylethylamine, pyridine and the like. Alternatively, carboxylic acid (6) can be converted to acid halide or mixed acid anhydride and reacted with amine (7) in the presence of a base. The amount of base to be used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (6).

Stage 5 : Stage deprotection of the amino group

The compound of formula (9) is obtained by eliminating the amino protecting group R ″ of compound (8) using a known technique. If necessary, it can be converted into salt using a known technique.

The method of obtaining 2

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is —CONR ⁵ R ⁶ , where R ⁵ is a hydrogen atom, can be obtained by performing the following stages.

where each radical has a meaning, as defined above.

Stage 1 : Stage urea derivative

1) When R ^{6 is} not hydrogen

The compound of formula (11) is obtained by reacting compound (9) with isocyanate (10) in a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of isocyanate (10) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like (the amount of base used is usually from about 1 and up to about 2 mol per 1 mol of compound (9)). Alternatively, the compound of formula (9) can react with 1,1'-carbonyldiimidazole (CDI) (The amount of CDI that is used is usually from about 1 and up to about 3 mol per 1 mol of compound (9)) and then reacts with the corresponding amine .

When R ⁶ is an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group and so on having a functional group, it can be adequately protected by a protective group, and after receiving the urea derivative, the protection is removed. When the alkyl group, cycloalkyl group, aryl group, heterocyclic group and the like have substituents, they can be converted, after obtaining the urea derivative, into other functional groups using known methods. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

2) When R ⁶ is hydrogen

The compound of formula (11) is obtained by reacting compound (9) with cyanate in a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, water, acetic acid and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of cyanate that is used is usually from about 1 and up to about 10 mol per 1 mol of compound (9). When amine (9) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N- diisopropylethylamine, pyridine and the like (the amount of base used is usually from about 1 and up to about 2 mol per 1 mol of compound (9)).

The method of obtaining 3

The compound of the present invention [1 '], where —X— is —N (R ¹ ) - and R ¹ is —CONR ⁵ R ⁶ , can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage phenylcarbamate

The compound of formula (13) is obtained by reacting compound (9) with 4-nitrophenylchloroformate (12) in a solvent in the presence of a base. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. As the base, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of 4-nitrophenyl chloroformate (12) to be used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out with a base in an amount of from about 2 and up to about 4 mol per 1 mol of compound (9).

Stage 2 : Stage of obtaining a derivative of urea

A compound of formula (11) is prepared by reacting an intermediate phenyl carbamate (13) with an amine (14) in a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 150 ° C. The reaction time is usually from an hour to 24 hours. The amount of amine (14) that is used is usually from about 1 and up to about 3 mol per 1 mol of compound (9). When amine (14) is a salt, the reaction is carried out in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like (the amount of base that is used is usually from about 1 and up to about 3 mol per 1 mol of compound (13)).

As another method, as shown in formula 2), a compound of formula (15) is obtained in Step 1 by reacting an amine (14) with 4-nitrophenyl chloroformate (12) in a solvent, and a compound of formula (15) is reacted with an amine (9) in Step 2 to give a compound of formula (11).

Moreover, another chloroformate or 1,1'-carbonyldiimidazole (CDI) can be used instead of 4-nitrophenyl chloroformate (12).

When R ⁵ and / or R ⁶ is / represents an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group and so on, which have a functional group, they are adequately protected with a protecting group and, after obtaining the urea derivative, the protection is removed. When the alkyl group, cycloalkyl group, aryl group, heterocyclic group and the like have substituent (s), they can be converted to other functional groups after obtaining the urea derivative using a known technique. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 4

In the compound of formula [1 ′] of the present invention, a compound wherein —X— is —N (R ¹ ) -, R ¹ is —CONR ⁵ R ⁶ , where R ⁵ is a hydrogen atom and R ⁶ = —S ( = O) ₂ R ⁹ ) can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage sulfonylurea

A compound of formula (17) is prepared by reacting a compound (9) with a sulfonyl isocyanate (16) in a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of sulfonyl isocyanate (16) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like (the amount of base used is usually from about 1 and up to about 2 mol per 1 mol of compound (9)).

The method of obtaining 5

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is —COOR ¹⁰ can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage carbamate

The compound of formula (20) is obtained by reacting compound (9) with chlorocarbonate (18) or carbonate (19) in the presence of a base, in a solvent or without a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. As the base, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 150 ° C. The reaction time is usually from an hour to 24 hours. The amount of chlorocarbonate (18) or carbonate (19) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out with a base in an amount of from about 2 and up to about 4 mol per 1 mol of compound (9).

When R ¹⁰ represents an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group and so on having a functional group, they are appropriately protected by a protective group, and after receiving carbamate, the protection is removed. When the alkyl group, cycloalkyl group, aryl group, heterocyclic group and the like have substituent (s), they can be converted to other functional groups after receiving carbamate using a known technique. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

As another method, as shown in Formula 2), the phenyl carbamate intermediate (13) obtained in Production Method 3, Step 1 is reacted with alcohol (21) in a solvent in the presence of a base to produce a Compound of formula (20). As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. As the base, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 150 ° C. The reaction time is usually from an hour to 24 hours. The amount of alcohol (21) that is used is usually from about 1 and up to about 3 mol per 1 mol of phenyl carbamate intermediate (13). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of phenyl carbamate intermediate (13).

When R ¹⁰ represents an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group, and so on having a functional group, they are adequately protected with a protective group, and after receiving carbamate, the protection is removed. When the alkyl group, cycloalkyl group, aryl group, heterocyclic group and the like have substituent (s), they can be converted to other functional groups after the carbamate production using known methods. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 6

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is —COR ¹¹ can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Amidation Stage

A compound of formula (23) is obtained by reacting a compound (9) with a carboxylic acid (22) in a solvent in the presence of a condensing agent and an additive. As the condensing agent, there may be mentioned dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenylphosphorylazide (like DPPA and . As an additive, 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine (DMAP) and the like can be mentioned. As the solvent, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of carboxylic acid (22) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (9). In addition, the amount of condensing agent and additive that is used is usually from about 1 and about 1.5 mol, and from about 1 and about 1.5 mol, respectively, per 1 mol of compound (9). When the compound of formula (9) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N -diisopropylethylamine, pyridine and the like. Moreover, carboxylic acid (22) can be converted to acid halide or mixed acid anhydride and reacted with a compound of formula (9) in the presence of a base. The amount of base to be used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (9).

When R ¹¹ represents an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group and so on having a functional group, they are adequately protected by the protective group and, after amidation, the protection is removed. When the alkyl group, cycloalkyl group, aryl group, heterocyclic group and the like have substituent (s), they can be converted to other functional groups after amidation using a known technique.

For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 7

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is a C _1-6 alkyl group or cycloalkyl group can be obtained by performing the following steps.

where X 'represents a halogen atom and other radicals are those as defined above.

Stage 1 : Stage N-alkylation

A compound of formula (25) is prepared by reacting a compound (9) with an alkyl halide (24) in a solvent in the presence of a base. As the base, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. like that. As the solvent, acetonitrile, acetone, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from 30 minutes to 24 hours. The amount of alkyl halide (24) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out with a base in an amount of from about 2 and up to about 4 mol per 1 mol of compound (9). This is possible to perform reductive amination of compound (9) with the corresponding aldehyde, ketone or their equivalent.

When R ¹ is an alkyl group having a functional group, it is appropriately protected by a protecting group and, after N-alkylation, the protection is removed. When the alkyl group has substituent (s), it can be converted to another functional group after N-alkylation using a known technique. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 8

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is —S (= O) ₂ R ¹² can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage sulfonylation

The compound of formula (27) can be obtained by reacting compound (9) with sulfonyl chloride (26) in a solvent in the presence of a base. As the base, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. like that. As the solvent, acetonitrile, acetone, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from 30 minutes to 24 hours. The amount of sulfonyl chloride (26) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out with a base in an amount of from about 2 and up to about 4 mol per 1 mol of compound (9). In addition, the compound of formula (9) may be reacted with the corresponding sulfonic acid anhydride.

When R ¹² is an alkyl group having a functional group, it is appropriately protected by a protecting group and, after sulfonylation, the protection is removed. When the alkyl group has substituent (s), it can be converted to another functional group after sulfonylation using a known technique. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 9

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is —C (= NCN) R ¹³ can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage receiving N-cyanoamidine

A compound of formula (29) is prepared by reacting compound (9) with N-cyanoimidoacetate (28) in a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of N-cyanoimidoacetate (28) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like (the amount of base used is usually from about 1 and up to about 2 mol per 1 mol of compound (9)).

The method of obtaining 10

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is —C (= NCN) NR ¹⁴ R ¹⁵ can be obtained by performing the following steps.

where Ph represents a phenyl group and other radicals are those as defined above.

Stage 1

A compound of formula (31) is prepared by reacting a compound (9) with diphenyl-N-cyanocarbonimidate (30) in a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of diphenyl-N-cyanocarbonimidate (30) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). When the amine (9) is a salt, the reaction is carried out in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like (the amount of base used is usually from about 1 and up to about 2 mol per 1 mol of compound (9)).

Stage 2 : Stage receiving N-cyanoguanidine

A compound of formula (33) is prepared by reacting compound (31) with an amine (32) in a solvent. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 150 ° C. The reaction time is usually from an hour to 24 hours. The amount of amine (32) that is used is usually from about 1 and up to about 5 mol per 1 mol of compound (31). When amine (32) is a salt, the reaction is carried out in the presence of a base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like (the amount of base used is usually from about 1 and up to about 20 mol per 1 mol of compound (31)).

The method of obtaining 11

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is an aryl group or a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage closure of the pyrazole ring of hydrazine (34) and the compounds of formula (3)

The compound of formula (35) is obtained by reacting hydrazine (34) synthesized by a known method with the compound of formula (3) obtained in Method 1, Step 1, in a solvent. As the solvent, methanol, ethanol, n-propanol, n-butanol, isopropanol, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture can be mentioned. specified solvents and the like. The temperature of the reaction mixture is usually in the range from 20 ° C to 250 ° C. The reaction time is usually from an hour to 24 hours. The amount of hydrazine (34) that is used is usually from about 1.5 and up to about 3 mol per 1 mol of compound (3). When hydrazine (34) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N- diisopropylethylamine, pyridine and the like (the amount of base used is usually from about 1.5 and up to about 3 mol per 1 mol of compound (3)).

Stage 2 : Stage deprotection of the carboxyl group R '

The compound of formula (36) is obtained by eliminating the carboxyl protecting group R ′ using a known technique.

Stage 3 : Amidation Stage

A compound of formula (37) is prepared by reacting compound (36) with an amine (7) in a solvent in the presence of a condensing agent and an additive. As the condensing agent, there may be mentioned dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenylphosphorylazide (like DPPA and . As an additive, 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine and the like can be mentioned. As the solvent, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of amine (7) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (36). In addition, the amount of condensing agent and additive that is used is usually from about 1 and about 1.5 mol and from about 1 and about 1.5 mol, respectively, per 1 mol of compound (36). When the amine (7) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N- diisopropylethylamine, pyridine and the like. In addition, carboxylic acid (36) can be converted to acid halide and then reacted with amine (7) in the presence of a base. The amount of base to be used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (36).

When R ¹ represents an aryl group or a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group having a functional group, it is appropriately protected by a protective group and then the protection is removed. When an aryl group or a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group has a substituent (s), it can be converted to another functional group using a known technique after this step. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 12

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is an aryl group or a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Buchwald / Hartwig type amination step catalyzed by palladium

The compound of formula (39) is obtained by reacting the compound (9) obtained in Method 1 and aromatic halogen (38) in a solvent in the presence of a palladium catalyst and a base. As the palladium catalyst, a mixture of palladium acetate and 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, bis (diphenylphosphino) ferrocene palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium and the like can be mentioned. As the base, tripotassium phosphate (K ₃ PO ₄ ), sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium tert-butoxide and the like can be mentioned. As the solvent, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, tert-butanol and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 250 ° C. The reaction time is usually from an hour to 24 hours. The amount of aromatic halogen (38) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (9). The amount of palladium catalyst and base to be used is usually from about 0.01 and about 0.1 mol and from about 1 and about 2 mol, respectively, per 1 mol of compound (9).

When R ¹ represents an aryl group or a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group having a functional group, it is appropriately protected by a protective group and then the protection is removed. When an aryl group or a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group has a substituent (s), it can be converted to another functional group after this step using a known technique.

For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 13

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is an aryl group or a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group can be obtained by performing the following steps.

where R ″ is a substituent (for example, an ethoxycarbonyl group, a benzoyl group, a 9-fluorenylmethoxycarbonyl group and the like) on a nitrogen atom, and other radicals are as defined above.

Stage 1 : Stage tiourenirovaniya

The compound of formula (41) is obtained by reacting the compound (9) obtained in Production Method 1 with isothiocyanate (40) in a solvent and cleaving the substituent (R ″) on a nitrogen atom using a known technique. As isothiocyanate (40), ethoxycarbonyl isothiocyanate, benzoyl isothiocyanate, 9-fluorenylmethoxycarbonyl isothiocyanate and the like can be mentioned. As the solvent, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of isothiocyanate (40) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (9). It is possible to react the compound of formula (9) with thiophosgene (the amount of thiophosgene used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (9)), followed by treatment with ammonia.

Stage 2 : Stage of closure of the thiazole ring

The compound of formula (43) is obtained by reacting compound (41) with halogenmethyl ketone (42) in a solvent. As the solvent, methanol, ethanol, n-propanol, n-butanol, isopropanol, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture can be mentioned. specified solvents and the like. The temperature of the reaction mixture is usually in the range from 20 ° C to 250 ° C. The reaction time is usually from an hour to 24 hours. The amount of halogen methyl ketone (42) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (41).

A thiazolyl group having a functional group can be appropriately protected by a protective group, and then the protection is removed. When the thiazolyl group has substituent (s), it can be converted to another functional group after the indicated step using a known technique. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 14

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - and R ¹ is a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group can be obtained by performing the following stages.

where X ′ represents a halogen atom, alkyl represents a C _1-6 alkyl group, R ″ ″ represents a carboxyl group, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or various substituents selected from a halogen atom and a hydroxyl group) or a cycloalkyl group and other radicals are as defined above.

Stage 1

Isothiourea hydrohalide (45) is obtained by reacting the compound (41) obtained in Production Method 13, Step 1, with an alkyl halide (44) in a solvent. As the solvent, acetonitrile, acetone, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from 30 minutes to 24 hours. The amount of alkyl halide (44) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (41).

Stage 2 : Stage of creating a triazole ring from isothiourea and hydrazide

The compound of formula (47) can be obtained by reacting isothiourea hydrohalide (45) with hydrazide (46) synthesized by a known technique in a solvent in the presence of a base. As the solvent, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane, 1,2-dichloroethane, chloroform can be mentioned. , benzene, chlorobenzene, O-dichlorobenzene, toluene, xylene, pyridine, 2,6-lutadine, 2,4,6-collidine, acetic acid, water and a mixture of these solvents and the like. As the base, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydride, potassium hydride, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. like that. The temperature of the reaction mixture is usually in the range from 20 ° C to 250 ° C. The reaction time is usually from 30 minutes to 24 hours. The amount of hydrazide (46) that is used is usually from about 1 and up to about 2 mol per 1 mol of isothiourea with a hydrogen halide (45). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of isothiourea hydrohalogen (45). When hydrazide (46) is a salt, the reaction is carried out with a base in an amount of from about 2 to about 4 mol per 1 mol of isothiourea hydrohalide (45).

A triazolyl group having a functional group can be appropriately protected by a protective group, and then the protection is removed. When the triazolyl group has a substituent (s), the substituent (s) can be converted by a known technique into another functional group after the indicated step. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 15

In the compound of formula [1 ′] of the present invention, a compound where —X— is —N (R ¹ ) - can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage deprotection of the amino group

The compound of formula (48) is obtained by eliminating the amino protecting group R ″ of compound (5) obtained in Production Method 1, Step 2.

Stage 2 : Introduction R ¹

The compound of formula (49) is obtained by introducing R ¹ into the compound of formula (48) in accordance with a procedure similar to that described in Production Methods 2 to 10 and Production Methods 12 to 14.

Stage 3 : Stage deprotection of the carboxyl group

A compound of formula (50) is obtained by eliminating the carboxy protecting group R ′ of compound (49) using a known technique.

Stage 4 : Amidation Stage

A compound of formula (51) is obtained by reacting compound (50) with an amine (7) in a solvent in the presence of a condensing agent and an additive. As the condensing agent, there may be mentioned dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenylphosphorylazide (like DPPA and . As an additive, 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine (DMAP) and the like can be mentioned. As the solvent, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, 1,4-dioxane, N, N-dimethylformamide and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of amine (7) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (50). In addition, the amount of condensing agent and additive that is used is usually from about 1 and about 1.5 mol and from about 1 and about 1.5 mol, respectively, per 1 mol of compound (50). When the amine (7) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N- diisopropylethylamine, pyridine and the like (the amount of base to be used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (50)).

R ¹ having a functional group is appropriately protected by a protective group and then the protection is removed. When R ¹ has a substituent (s), it can be converted to another functional group after the indicated step using a known technique. For example, there may be mentioned transformations from a hydroxyl group to an alkoxy group or a ketone, from an amino group to an alkylamino group, an alkylcarbonylamino group or an alkylsulfonylamino group, from an alkoxycarbonyl group to a carboxyl group, an aminocarbonyl group, an alkylaminocarbonyl group or a hydroxymethyl sulfonyl group and hydroxymethyl sulfonyl group and

The method of obtaining 16

In the compound of formula [1 ′] of the present invention, a compound where —X— is —C (R ⁷ R ⁸ ) - can be obtained by performing the following steps.

where each radical has the meaning as defined above, where R "" represents a carboxy-protecting group (in the present description, a carboxy-protecting group means one that is usually used in the field of synthetic organic chemistry, such as a methyl group, an ethyl group, a propyl group, a tert-butyl group, a benzyl group, a p-methoxybenzyl group and the like, which is present in the form of esters, which can easily be converted into a carboxylic acid by hydrolysis, catalytic hydrogenation and the like approved)

Stage 1 : reductive alkylation

A compound of formula (54) is prepared by reacting a ketone (52) with tert-butylcarbazate (53) in a solvent in the presence of a reducing agent. As the reducing agent, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane complex and the like can be mentioned. As a solvent, methanol, ethanol, n-propanol, n-butanol, isopropanol, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, benzene, toluene, xylene, acetic acid and a mixture of these solvents and the like. The temperature of the reaction mixture is usually in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of reduction agent that is used is usually from about 2 to about 5 mol per 1 mol of compound (52).

Stage 2 : removal of the group-BOC (tert-butoxycarbonyl group)

The compound of formula (54) interacts with 4 N. a solution of hydrochloric acid in ethyl acetate or 4 N. a solution of hydrochloric acid in 1,4-dioxane to obtain hydrazine hydrochloride (55). In addition, after removal of the BOC group by exposure to trifluoroacetic acid in a solvent, it can be converted to hydrochloride. As the solvent, dichloromethane, chloroform and the like can be mentioned.

Stage 3 : Stage of creating a pyrazole ring from hydrazine hydrochloride (55) and the compounds of formula (3)

A compound of formula (56) is prepared by reacting hydrazine hydrochloride (55) with a compound of formula (3) in a solvent in the presence of a base. As the solvent, methanol, ethanol, n-propanol, n-butanol, isopropanol, acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, xylene and a mixture can be mentioned. specified solvents and the like. As the base, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 250 ° C. The reaction time is usually from an hour to 24 hours. The amount of hydrazine hydrochloride (55) that is used is usually from about 1 and up to about 2 mol per 1 mol of compound (3). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of compound (3).

Stage 4 : Stage deprotection of the carboxyl group

A compound of formula (57) is prepared by eliminating the carboxy protecting group R ′ of compound (56) using a known technique.

Stage 5 : Amidation Stage

A compound of formula (58) is obtained by reacting compound (57) with an amine (7) in a solvent in the presence of a condensing agent and an additive. As the condensing agent, there may be mentioned dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), diphenylphosphorylazide (like DPPA and . As an additive, 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine (DMAP) and the like can be mentioned. As the solvent, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of amine (7) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (57). In addition, the amount of condensing agent and additive that is used is usually from about 1 and about 1.5 mol, and from about 1 and about 1.5 mol, respectively, per 1 mol of compound (57). When the amine (7) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N- diisopropylethylamine, pyridine and the like. In addition, carboxylic acid (57) can be introduced into the acid halide or mixed acid anhydride and reacted with the amine (7) in the presence of a base. The amount of base to be used is usually from about 1 and up to about 1.5 mol per 1 mol of compound (57).

Stage 6 : Stage deprotection of the carboxyl group

Carboxylic acid (59) is obtained by eliminating the carboxy protecting group R ″ ”of compound (58) using a known technique.

Stage 7 : Amidation Stage

A compound of formula (61) is prepared by reacting a carboxylic acid (59) with an amine (60) in a solvent in the presence of a condensing agent and an additive. As the condensing agent, there may be mentioned dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), diisopropylcarbodiimide, 1,1'-carbonyldiimidazole (CDI) or, diphenylphosphorylazide and impera (DPPA) like that. As an additive, 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine (DMAP) and the like can be mentioned. As the solvent, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of amine (60) that is used is usually from about 1 and up to about 1.5 mol per 1 mol of carboxylic acid (59). In addition, the amount of condensing agent and additive that is used is usually from about 1 and up to about 1.5 mol and from about 1 and up to about 1.5 mol, respectively, per 1 mol of compound (59). When amine (60) is a salt, the reaction is carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N, N- diisopropylethylamine, pyridine and the like. Moreover, carboxylic acid (59) can be introduced into acid halide or mixed acid anhydride and reacted with amine (60) in the presence of a base. The amount of base to be used is usually from about 1 and up to about 1.5 mol per 1 mol of carboxylic acid (59).

The method of obtaining 17

In the compound of formula [1 ′] of the present invention, a compound where —X— is —C (R ⁷ R ⁸ ) - can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Stage urea derivative

Carboxylic acid (59) reacts with diphenylphosphoryl azide (DPPA) in a solvent in the presence of a base for conversion to isocyanate, which reacts with an amine (62) to produce urea (63). As the solvent, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, benzene, toluene, xylene and the like can be mentioned. As the base, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. The temperature of the reaction mixture for the stage that gives the isocyanate is usually in the range from 20 ° C to 150 ° C and the stage that gives the urea is, as a rule, in the range from 0 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours for both stages. The amount of DPPA that is used is usually from about 1 to about 2 mol per 1 mol of carboxylic acid (59). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of carboxylic acid (59). The amount of amine (62) that is used is usually from about 1 and up to about 5 mol per 1 mol of carboxylic acid (59).

The method of obtaining 18

In the compound of formula [1 ′] of the present invention, a compound where —X— is —C (R ⁷ R ⁸ ) - can be obtained by performing the following steps.

where each radical has a meaning, as defined above.

Stage 1 : Cyanide Stage

Nitrile (64) is obtained by reacting amide (61) with a dehydration agent in a solvent in the presence of a base. As the dehydration agent, trifluoromethanesulfonic acid anhydride, p-toluenesulfonyl chloride, trichloroacetyl chloride, trifluoroacetic acid anhydride, phosphorus oxychloride, thionyl chloride and the like can be mentioned. As the base, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be mentioned. As the solvent, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, pyridine and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 100 ° C. The reaction time is usually from an hour to 24 hours. The amount of dehydration agent that is used is usually from about 1 and up to about 2 mol per 1 mol of amide (61). The amount of base to be used is usually from about 1 and up to about 2 mol per 1 mol of amide (61).

Stage 2 : Stage closure tetrazole ring

Nitrile (64) reacts in a solvent in the presence of an azidation reagent to give tetrazole (65). As the azidation reagent, sodium azide, azidetrimethyltin, azidetributyltin, azidetrimethylsilane and the like can be mentioned. As the solvent, dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N, N-dimethylformamide, benzene, toluene, xylene and a mixture of these solvents and the like can be mentioned. The temperature of the reaction mixture is usually in the range from 20 ° C to 150 ° C. The reaction time is usually from an hour to 24 hours. The amount of azidation reagent that is used is usually from about 1 and up to about 2 mol per 1 mol of nitrile (64).

The production methods described herein are examples of methods for preparing the compounds of the present invention, and compounds other than those described above can be obtained by combining known conventional techniques in the field of synthetic organic chemistry.

EXAMPLES

Heterocyclic compounds and methods for their preparation according to the present invention are described in detail below, referring to examples, which should not be construed as limiting.

Example 1

Preparation of 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine

Stage 1

Preparation of methyl 2-cyclopropylcarbonyl-3-dimethylaminoacrylate

Methyl 3-cyclopropyl-3-oxopropionate (2.0 g) was dissolved in toluene (20 ml). Dimethylformamide dimethylacetal (3.0 ml) was added to the resulting solution, and the resulting mixture was heated at the boil under reflux for 3 hours. The reaction mixture was allowed to cool, concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane: acetone = 2: 1) to obtain the title compound as a yellow oil (2.61 g).

Stage 2

Preparation of methyl 1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carboxylate

Methyl 2-cyclopropylcarbonyl-3-dimethylaminoacrylate (1.0 g), obtained as indicated in the previous step, and benzyl 4-hydrazinopiperidine-1-carboxylate hydrochloride (1.49 g) synthesized by a known method are suspended in ethanol. Triethylamine (0.78 ml) was added to the suspension, and the resulting mixture was heated at the boil under reflux for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The diethyl ether layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2.5: 1) to obtain the title compound as a yellow oil (1.58 g).

Stage 3

Preparation of 1- (1-Benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carboxylic acid

Methyl 1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carboxylate (1.58 g), obtained as indicated in the previous step, is dissolved in tetrahydrofuran (5 ml), methanol (5 ml) and water (10 ml), lithium hydroxide monohydrate (834 mg) was added and the resulting mixture was stirred at 50 ° C for 6 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and acidified with 2N. hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain the title compound as a white amorphous solid (1.27 g).

Stage 4

Preparation of 1- [1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine

1- (1-Benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carboxylic acid (800 mg) obtained as indicated in the previous step, 1-hydroxybenzotriazole (332 mg) and 1-ethyl-3 hydrochloride - (3-Dimethylaminopropyl) carbodiimide (498 mg) was dissolved in N, N-dimethylformamide (10 ml) and the resulting mixture was stirred for 15 minutes. To the resulting solution were added 3- (pyridin-3-yl) pyrrolidine (330 mg) and 4-dimethylaminopyridine (catalytic amount) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 11: 1) to obtain the title compound as a white amorphous solid (1.06 g).

Stage 5

Preparation of 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine

1- [1- (1-Benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine (970 mg), obtained as indicated in the previous step, dissolved in methanol (12 ml), add 10% palladium on charcoal (50% water content) (200 mg) and the resulting mixture was stirred in a hydrogen atmosphere for 2.5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (neutral alumina) (chloroform: methanol = 7: 1) to obtain the title compound as a white amorphous solid (718 mg).

Example 2

Preparation of 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

Stage 1

Preparation of (S) -3-acetyl-4-isopropyl-5,5-diphenyloxazolidin-2-one

In an argon atmosphere, (S) -4-isopropyl-5,5-diphenyloxazolidin-2-one (1.56 g) is suspended in tetrahydrofuran (22 ml) and a 1.6 M solution of n-butyllithium / n-hexane is added (3, 64 ml) under ice cooling. After 10 minutes, acetyl chloride (0.47 ml) was added and the resulting mixture was stirred overnight, during which time the temperature of the mixture was allowed to gradually drop to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the resulting mixture was concentrated under reduced pressure. Water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1 N. hydrochloric acid solution, water, a saturated aqueous solution of sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound as white crystals (1.69 g).

Stage 2

Preparation of (S) -4-isopropyl-3 - [(S) -4-nitro-3- (2-trifluoromethylphenyl) butyryl] -5,5-diphenyloxazolidin-2-one

(S) -3-Acetyl-4-isopropyl-5,5-diphenyloxazolidin-2-one (4.74 g), obtained as indicated in the previous step, is dissolved in dichloromethane (73 ml) under argon atmosphere and titanium tetrachloride ( 3.17 ml) and N, N-diisopropylethylamine (3.06 ml) at a temperature of -78 ° C. The mixture was gradually heated to 0 ° C for 30 minutes, cooled again to -78 ° C and a solution of 1 - [(E) -2-nitrovinyl] -2-trifluoromethylbenzene (3.50 g) in dichloromethane (27 ml) was added. ) Titanium tetrachloride (3.17 ml) was added and after 2 hours a saturated aqueous solution of ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with 1N. hydrochloric acid solution, water, a saturated aqueous solution of sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1) and crystallized from diethyl ether: n-pentane to give the title compound as white crystals (2, 62 g).

Stage 3

Preparation of (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one

K (S) -4-isopropyl-3 - [(S) -4-nitro-3- (2-trifluoromethylphenyl) butyryl] -5,5-diphenyloxazolidin-2-one (2.51 g), prepared as indicated of the previous step, ethanol (35 ml), ethyl acetate (35 ml) were added, and then Raney nickel (50% in water) (2.8 g) was added. After stirring overnight in a hydrogen atmosphere, the insoluble matter was filtered through celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain the title compound as white crystals (850 mg).

Stage 4

Preparation of (S) -3- (2-trifluoromethylphenyl) pyrrolidine

To (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one (803 mg) obtained as indicated in the previous step, tetrahydrofuran (7 ml) was added and then lithium aluminum hydride (200 mg) was added. After heating at the boil under reflux for 1.5 hours, add water (0.2 ml), 4 N. an aqueous solution of sodium hydroxide (0.2 ml) and water (0.4 ml) under ice cooling. Anhydrous magnesium sulfate was added, the insoluble product was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow oil (722 mg).

[α] ²⁵ D = +23.9 (c = 0.504, EtOH)

Stage 5

Preparation of 1- [1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- (1-Benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carboxylic acid (235 mg) obtained in Example 1, Step 3, 1-hydroxybenzotriazole (127 mg) and 1-ethyl- hydrochloride 3- (3-Dimethylaminopropyl) carbodiimide (159 mg) was dissolved in N, N-dimethylformamide (6 ml) and the mixture was stirred for 15 minutes. To the resulting solution were added (S) -3- (2-trifluoromethylphenyl) pyrrolidine (151 mg), obtained as indicated in the previous step, and 4-dimethylaminopyridine (78 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, 1 N. aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate: methanol = 40: 1) to obtain the title compound as a white amorphous solid (287 mg).

Stage 6

Preparation of 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

1- [1- (1-Benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (2.0 g) obtained as indicated in the previous step, dissolved in methanol (14 ml), palladium hydroxide on carbon (0.2 g) was added and the resulting mixture was stirred in a hydrogen atmosphere for 15 hours. The catalyst was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (6.4 ml) and 4N was added. a solution of hydrochloric acid in ethyl acetate (1.32 ml). The mixture was concentrated under reduced pressure and crystallized from ethyl acetate + diisopropyl ether to give the title compound as white crystals (1.45 g).

Stage 7

(S) -3- (2-Trifluoromethylphenyl) pyrrolidine obtained in the above Step 4 and its hydrochloride can also be obtained in accordance with the following Step.

Stage 7-1

Preparation of dimethyl-2 - [(S) -2-nitro-1- (2-trifluoromethylphenyl) ethyl] malonate

Toluene (40 ml) is added to 1 - ((E) -2-nitrovinyl) -2-trifluoromethylbenzene (4.34 g) and then dimethyl malonate (3.4 ml) and 1- (3,5-bis-trifluoromethylphenyl) are added -3 - ((1S, 2S) -2-dimethylaminocyclohexyl) thiourea (413 mg), disclosed in WO2005 / 000803 and J. Am. Chem. Soc., 2005, 127, 119-125 under ice cooling. The mixture was stirred under ice cooling for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from 2-propanol to give the title compound (5.31 g) as white crystals.

Said reaction can also be carried out using the catalysts disclosed in J. Am. Chem. Soc., 1999, 121, 10215-10216, J. Am. Chem. Soc., 2005, 127, 9958-9959, J. Am. Chem. Soc., 2006, 128, 1454-1455 and the like, instead of 1- (3,5-bis-trifluoromethylphenyl) -3 - ((1S, 2S) -2-dimethylaminocyclohexyl) thiourea.

Stage 7-2

Preparation of methyl- (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidine-3-carboxylate

Dimethyl-2 - [(S) -2-nitro-1- (2-trifluoromethylphenyl) ethyl] malonate (4.0 g), obtained as indicated in the previous step, is added to a suspension of Raney nickel (2.0 g) in a mixture tetrahydrofuran (10 ml) / methanol (10 ml) and the resulting mixture was stirred in a hydrogen atmosphere at a pressure of 3.5 atmospheres at room temperature for 24 hours. Insoluble products are filtered through celite. The filtrate and washing are combined and concentrated under reduced pressure. Toluene was added to the residue, and the resulting mixture was washed with a 10% aqueous potassium carbonate solution and water, and the organic layer was concentrated under reduced pressure. The residue was crystallized from toluene + n-hexane to give the title compound (2.38 g) as white crystals.

This reaction can also be carried out using palladium on charcoal instead of Raney nickel in the presence of an acid such as acetic acid, toluenesulfonic acid, methanesulfonic acid and the like.

Stage 7-3

Preparation of (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one

Methanol (3.8 ml) was added to methyl- (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidine-3-carboxylate (1.0 g) obtained as indicated in the previous step, then 1N was added. an aqueous solution of sodium hydroxide (3.8 ml) and the resulting mixture was stirred at a temperature of 65 ° C for one hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was acidified with 1N. hydrochloric acid solution under ice cooling and extracted twice with butyl acetate. The organic layers are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Butyl acetate (10 ml) was added again to the residue, and the resulting mixture was stirred overnight at 100 ° C. The reaction mixture was concentrated under reduced pressure and the residue was crystallized from n-hexane to give the title compound (667 mg) as white crystals.

Stage 7-4

Preparation of (S) -3- (2-trifluoromethylphenyl) pyrrolidine hydrochloride

To a solution of (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one (22.9 g) obtained as indicated in the previous step in THF (100 μl) was added dropwise a 1M solution of lithium aluminum hydride in THF (100 μl) in an argon atmosphere at a temperature of 85 ° C for an hour and then the resulting mixture was stirred at the indicated temperature for an hour. After the mixture was allowed to cool, a 50% aqueous solution of Rochelle salt was added under ice-cooling, and the resulting mixture was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (60 ml) was added to the residue, then 4N was added. a solution of hydrochloric acid in ethyl acetate (37.5 ml) under ice-cooling, and the resulting mixture was stirred at room temperature. The precipitated crystals were collected by filtration to obtain the title compound (20.6 g) as white crystals.

[α] ²⁵ D = +10.3 (c = 0.55, MeOH)

Example 3

Preparation of 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

1- [5-Cyclopropyl-1- (piperidin-4-yl) -1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine (100 mg) obtained in Example 1, Step 5, is dissolved in chloroform (2 ml), triethylamine (38 μl) and 2-fluorophenyl isocyanate (34 μl) were added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 11: 1) to obtain the title compound as a white amorphous solid (111 mg).

Example 4

Preparation of 1- [1- (1-carbamoylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- [5-Cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (1.0 g) obtained in accordance with with a procedure analogous to the preparation of the compound described in Example 1, Step 5, was dissolved in acetic acid (3 ml) and water (6 ml), and then an aqueous solution (6 ml) of sodium cyanide (300 mg) was added dropwise at room temperature. The mixture was stirred at room temperature for 6 hours, during which an additional amount of sodium cyanide was added (750 mg total amount). The mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with 1N. hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and brine and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (chloroform: methanol = 10: 1). Diethyl ether (10 ml) was added and the resulting mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and dried to obtain the title compound as white crystals (581 mg).

Example 5

Preparation of 1- {1- [1- (2-carboxyphenylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

The 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride (703 mg) from Example 2 was suspended in chloroform (7 ml) and triethylamine (0.23 ml) was added. Under ice cooling, 2-methoxycarbonylphenyl isocyanate (292 mg) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 30: 1) to obtain 1- {5-cyclopropyl-1- [1- (2-methoxycarbonylphenylcarbamoyl) piperidin-4-yl] - 1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (992 mg) as a white amorphous solid.

The resulting 1- {5-cyclopropyl-1- [1- (2-methoxycarbonylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (244 mg) was dissolved in tetrahydrofuran (0.4 ml) and methanol (0.2 ml), 4N were added. an aqueous solution of sodium hydroxide (0.4 ml) and the resulting mixture was stirred at a temperature of 60 ° C for 4 hours. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in water. Under ice cooling, the mixture is acidified with 2 N. hydrochloric acid solution and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. N-hexane is added to the residue, which leads to the precipitation of a crystal. The resulting crystal was washed with n-hexane and dried under reduced pressure to obtain the title compound as a white amorphous solid (181 mg).

Example 6

Preparation of 1- {5-cyclopropyl-1- [1- (2-hydroxymethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- {5-Cyclopropyl-1- [1- (2-methoxycarbonylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (213 mg ) obtained in Example 5 is dissolved in tetrahydrofuran (2 ml) and ethanol (2 ml) and lithium chloride (30 mg) and sodium borohydride (26 mg) are added under ice-cooling. The mixture was stirred overnight at room temperature. The insoluble product precipitated is collected by filtration and washed with chloroform. The filtrate and washing were combined and the resulting mixture was washed with water, a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 30: 1) to obtain the title compound as a white amorphous solid (109 mg).

Example 7

Preparation of 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 5, the title compound was obtained as a white amorphous solid (530 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (1.07 g) according to Example 2.

Example 8

Preparation of 1- {5-cyclopropyl-1- [1- (2-hydroxyethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 5, the title compound was obtained as a white amorphous solid (202 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (206 mg) according to Example 2.

Example 9

Preparation of 1- {5-cyclopropyl-1- [1- (2-hydroxy-1,1-dimethylethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 5, the title compound was obtained as a white amorphous solid (341 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (350 mg) according to Example 2.

Example 10

Preparation of 1- {1- [1- (2-Acetylaminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Preparation of 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

To 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride (5.04 g) from Example 2, chloroform (50 μl), N, N-diisopropylethylamine (4.68 ml) was added, and then 4-nitrophenyl chloroformate (2.39 g) was added under ice-cooling, and the resulting mixture was stirred at room temperature for one hour. The mixture is concentrated under reduced pressure, acidified with 1 N. hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain the title compound in pale yellow amorphous form (5.41 g).

Stage 2

Preparation of 1- {1- [1- (2-Acetylaminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- {5-Cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg ), obtained as indicated in the previous step, was dissolved in N-methylpyrrolidone (1 ml) and N- (2-aminoethyl) acetamide (96 μl) was added. The mixture is stirred overnight at a temperature of 80 ° C. After the mixture was allowed to cool, a 10% aqueous potassium carbonate solution was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, 1 N. hydrochloric acid solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 15: 1) to obtain the title compound in white amorphous form (65 mg).

Example 11

Preparation of 1- {1- [1- (2-aminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

1- {5-Cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg ) obtained in Example 10, Step 1, and tert-butyl- (2-aminoethyl) carbamate (160 mg) were dissolved in acetonitrile (1 ml) and the resulting mixture was heated at reflux overnight. The mixture was diluted with chloroform, the resulting mixture was washed with water, a saturated aqueous solution of potassium hydrogen carbonate, water and brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (chloroform: methanol = 10: 1). The resulting amorphous solid was dissolved in ethyl acetate (1 ml) and 4N was added. a solution of hydrochloric acid in ethyl acetate (4 ml). The precipitated solid was collected by filtration and dried to obtain the title compound as a white amorphous solid (111 mg).

Example 12

Preparation of 1- {5-cyclopropyl-1- [1- (1,1-dioxothiomorpholin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

1- {5-Cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (250 mg ) obtained in Example 10, Step 1 and thiomorpholine (0.13 ml) were dissolved in N-methylpyrrolidone (1 ml) and the resulting mixture was stirred overnight at a temperature of 100 ° C. After the mixture was allowed to cool, the mixture was diluted with diethyl ether, washed with water, 5% aqueous potassium carbonate and brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate: methanol = 30: 1) to obtain 1- {5-cyclopropyl-1- [1- (thiomorpholine-4-carbonyl) piperidin-4-yl ] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine as a white amorphous solid (224 mg). The resulting product was dissolved in chloroform (4 ml) and m-chloroperbenzoic acid (319 mg) was added under ice-cooling. The mixture is stirred for 3 hours, during which the temperature of the mixture is allowed to gradually drop to room temperature. A saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added, and the resulting mixture was extracted with chloroform. The chloroform layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (ethyl acetate: methanol = 30: 1) to obtain the title compound as a white amorphous solid (198 mg).

Example 13

Preparation of 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a yellow amorphous solid (130 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 14

Preparation of 1- {5-cyclopropyl-1- [1- (4-hydroxypiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (176 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 15

Preparation of 1- {1- [1- (azetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (150 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 16

Preparation of 1- {5-cyclopropyl-1- [1- (3-hydroxypyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (175 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 17

Preparation of 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a pale yellow amorphous solid (170 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl ) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 18

Preparation of 1- {5-cyclopropyl-1- [1- (4,4-difluoropiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a pale yellow amorphous solid (132 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) ) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 19

Preparation of 1- {5-cyclopropyl-1- [1- (3,3-difluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a pale yellow amorphous solid (152 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) ) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 20

Preparation of 1- {5-cyclopropyl-1- [1- (3-hydroxyazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (158 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 21

Preparation of 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (171 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 22

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (172 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 23

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-methylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a yellow amorphous solid (60 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 24

Preparation of 1- {5-cyclopropyl-1- [1- (4-hydroxymethylpiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (94 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg).

Example 25

Preparation of 1- {1- [1- (4-carboxypiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (65 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (172 mg).

Example 26

Preparation of 1- {5-cyclopropyl-1- [1- (3-oxopiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (143 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 27

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxymethylpyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a yellow amorphous solid (150 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 28

Preparation of 1- {5-cyclopropyl-1- [1- (3-hydroxymethylazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a yellow amorphous solid (178 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 29

Preparation of 1- {5-cyclopropyl-1- [1- (4-methylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (66 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg).

Example 30

Preparation of 1- {5-cyclopropyl-1- [1- (4-isopropylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (50 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg).

Example 31

Preparation of 1- {1- [1- (4-Acetylpiperazin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (56 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg).

Example 32

Preparation of 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypiperidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a yellow amorphous solid (170 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg).

Example 33

Preparation of 1- {1- [1- (4-carbamoylpiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (108 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg).

Example 34

Preparation of 1- {1- [1- (3-carbamoylazetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (93 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (171 mg).

Example 35

Preparation of 1- {1- [1- (4-aminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 11, the title compound was obtained as a white amorphous solid (302 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (478 mg).

Example 36

Obtaining hydrochloride 1- {1- [1- (3-aminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 11, the title compound was obtained as a pale brown yellow amorphous solid (635 mg) from 1- {5-cyclopropyl-1- [1- (4 -nitrophenoxycarbonyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (478 mg).

Example 37

Preparation of 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl hydrochloride )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 11, the title compound was obtained as a white amorphous solid (59 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (478 mg).

Example 38

Preparation of 1- {5-cyclopropyl-1- [1- (4-dimethylaminopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (74 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (478 mg).

Example 39

Preparation of 1- {1- [1- (4-acetylaminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (100 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (478 mg).

Example 40

Preparation of 1- {1- [1- (3-Acetylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (127 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (478 mg).

Example 41

Preparation of 1- {5-cyclopropyl-1- [1- (3-dimethylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a pale brown yellow amorphous solid (141 mg) from 1- {5-cyclopropyl-1- [1- (4 -nitrophenoxycarbonyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (478 mg).

Example 42

Preparation of 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (116 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (181 mg).

Example 43

Preparation of 1- {1- [1- (1-acetylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (41 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (181 mg).

Example 44

Preparation of 1- {5-cyclopropyl-1- [1- (4-oxopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (155 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (540 mg).

Example 45

Preparation of 1- {1- [1- (3-Acetylamino-azetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (68 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (90 mg).

Example 46

Preparation of 1- {5-cyclopropyl-1- [1- (3-oxopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (155 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (300 mg).

Example 47

Preparation of 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

Stage 1

Preparation of 4-nitrophenyl- (2,2,2-trifluoroethyl) carbamate

2,2,2-Trifluoroethylamine (392 mg) was dissolved in chloroform (4 ml) and pyridine (0.35 ml) and 4-nitrophenyl chloroformate (2.39 g) were added under ice cooling. The mixture was stirred at room temperature for one hour. It was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1 N. hydrochloric acid solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain the title compound as a white solid (501 mg).

Stage 2

Preparation of 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

4-Nitrophenyl- (2,2,2-trifluoroethyl) carbamate (113 mg), obtained as indicated in the previous step, and 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazol-4 hydrochloride -carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) from Example 2 was dissolved in pyridine (1 ml) and the resulting mixture was stirred at 80 ° C. for 2 hours. After the mixture was allowed to cool, toluene was added and the resulting mixture was concentrated under reduced pressure. A 10% aqueous potassium carbonate solution was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a 10% aqueous solution of potassium carbonate, water, 1 N. hydrochloric acid solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 15: 1) to give the title compound in pale yellow amorphous form (162 mg).

Example 48

Preparation of 1- {5-cyclopropyl-1- [1- (3,3,4,4-tetrafluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 47, the title compound was obtained as a pale yellow amorphous solid (138 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (468 mg) according to Example 2.

Example 49

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-2-methylpropylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 47, the title compound was obtained as a white amorphous solid (166 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-Pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (250 mg) according to Example 2.

Example 50

Preparation of 1- (1- {1 - [(S) -1-benzyl-2-hydroxyethylcarbamoyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 47, the title compound was obtained as a white amorphous solid (140 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-Pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (300 mg) according to Example 2.

Example 51

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-phenylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 47, the title compound was obtained as a white amorphous solid (170 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-Pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (300 mg) according to Example 2.

Example 52

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-3-methylbutylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 47, the title compound was obtained as a yellow amorphous solid (256 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-Pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (250 mg) according to Example 2.

Example 53

Preparation of 1- {5-cyclopropyl-1- [1- (2-hydroxyphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 47, the title compound was obtained as a white amorphous solid (125 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 54

Preparation of 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopentylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 47, the title compound was obtained as a white amorphous solid (92 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 55

Preparation of 1- [1- (1-benzenesulfonylaminocarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Chloroform (3 ml) was added to 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride (250 mg) from Example 2, then triethylamine (81 μl) and toluenesulfonyl isocyanate (78 μl) were added and the resulting mixture was stirred for 2 hours. It was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The chloroform layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 10: 1). The resulting solid was recrystallized from ethyl acetate to give the title compound as a pale yellow solid (40 mg).

Example 56

Preparation of 1- [5-cyclopropyl-1- (1-methanesulfonylaminocarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 55, the title compound was obtained as a pale yellow amorphous solid (200 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (500 mg) according to Example 2.

Example 57

Preparation of 1- [5-cyclopropyl-1- (1-methoxycarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

The 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride (200 mg) from Example 2 is suspended in chloroform (2.0 ml) and potassium carbonate (177 mg) was added under ice-cooling. Methyl chloroformate (49.4 μl) was added and the temperature of the resulting mixture was allowed to return to room temperature and stirred for 1.5 hours. Methyl chloroformate (49.4 μl) was then added and the resulting mixture was stirred at room temperature for 15.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 30: 1) to obtain the title compound as a white amorphous solid (210 mg).

Example 58

Preparation of 1- {5-cyclopropyl-1- [1- (2-hydroxyethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 57, the title compound was obtained as a white amorphous solid (214 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) 3- (2-trifluoromethylphenyl)] pyrrolidine (300 mg) according to Example 2.

Example 59

Preparation of 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (166 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (300 mg).

Example 60

Preparation of 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 10, the title compound was obtained as a white amorphous solid (219 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (300 mg).

Example 61

Preparation of 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl hydrochloride )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 11, the title compound was obtained as a pale yellow amorphous solid (53 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl ) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (102 mg).

Example 62

Preparation of 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (64 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidine -4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (124 mg).

Example 63

Preparation of 1- {1- [1- (1-Acetylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 12, the title compound was obtained as a white amorphous solid (65 mg) from 1- {5-cyclopropyl-1- [1- (4-nitrophenoxycarbonyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (122 mg).

Example 64

Preparation of 1- [1- (1-cyclopropanecarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Chloroform (5 ml) and triethylamine (0.13 ml) are added to the hydrochloride 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine (200 mg) from Example 2 and then cyclopropanecarboxylic acid chloride (0.047 ml) is added under ice-cooling. After stirring overnight at room temperature, the solvent was removed under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate: methanol = 10: 1) to obtain the title compound as a white amorphous solid (170 mg).

Example 65

Preparation of 1- {5-cyclopropyl-1- [1- (2-hydroxyacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Chloroform (5 ml) and triethylamine (0.16 ml) are added to 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine (250 mg) from Example 2 and acetoxyacetyl chloride (0.069 ml) were added under ice-cooling. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate: methanol = 10: 1). The resulting amorphous solid was dissolved in tetrahydrofuran (2 ml), methanol (2 ml) and water (4 ml) and lithium hydroxide monohydrate (103 mg) was added. The mixture was stirred at 60 ° C for 4 hours. The mixture was concentrated under reduced pressure, a 5% aqueous solution of potassium hydrogen sulfate was added to the resulting residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel chromatography (ethyl acetate: methanol = 20: 1) to obtain the title compound as a white amorphous solid (30 mg).

Example 66

Preparation of 1- (5-cyclopropyl-1- {1- [1- (4-fluorophenyl) cyclopropanecarbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale yellow amorphous solid (193 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 67

Preparation of 1- {5-cyclopropyl-1- [1- (2-dimethylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale yellow amorphous solid (217 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 68

Preparation of 1- {1- [1- (2-Acetylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale brown-yellow amorphous solid (119 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 69

Preparation of 1- {5-cyclopropyl-1- [1- (1-methylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale yellow amorphous solid (178 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 70

Preparation of 1- {1- [1- (2-Acetylamino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale brown yellow amorphous solid (94 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 71

Preparation of 1- (1- {1 - [(S) -2-acetylaminopropionyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 64, the title compound was obtained as a white amorphous solid (183 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 72

Preparation of 1- (1- {1 - [(S) -2-acetylamino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale yellow amorphous solid (212 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 73

Preparation of 1- {5-cyclopropyl-1- [1- (3,3,3-trifluoropropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale yellow amorphous solid (151 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg) according to Example 2.

Example 74

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -5-oxopyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a white amorphous solid (127 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 75

Preparation of 1- {1- [1- (3-acetylaminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 64, the title compound was obtained as a pale yellow amorphous solid (263 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (355 mg) according to Example 2.

Example 76

Preparation of 1- {5-cyclopropyl-1- [1- (3-hydroxy-2,2-dimethylpropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a white amorphous solid (238 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-Pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (250 mg) according to Example 2.

Example 77

Preparation of 1- {1- [1- (2-aminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (219 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 78

1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as white crystals (168 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H- hydrochloride pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (250 mg) according to Example 2.

Example 79

Preparation of 1- {1- [1- (2-amino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 65, the title compound was obtained as a pale brown yellow amorphous solid (154 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 80

Preparation of 1- {5-cyclopropyl-1- [1- (4-hydroxybutyryl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a white amorphous solid (166 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 81

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -pyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- (2) hydrochloride trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (569 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (450 mg).

Example 82

Preparation of 1- (5-cyclopropyl-1- {1 - [(S) -1-methylpyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- hydrochloride (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (192 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (450 mg).

Example 83

Preparation of 1- {1- [1- (3-aminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (414 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (355 mg) according to Example 2.

Example 84

Preparation of 1- (1- {1 - [(S) -2-amino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- hydrochloride (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale brown-yellow amorphous solid (182 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg) according to Example 2.

Example 85

Preparation of 1- {5-cyclopropyl-1- [1- (2-methylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale brown-yellow amorphous solid (183 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg) according to Example 2.

Example 86

Preparation of 1- {5-cyclopropyl-1- [1- (piperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (478 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (404 mg) according to Example 2.

Example 87

Preparation of 1- {5-cyclopropyl-1- [1- (2-isobutyrylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale brown yellow amorphous solid (214 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 88

Preparation of 1- {1- [1- (2-cyclopropanecarbonylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (190 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 89

Preparation of 1- (1- {1 - [(S) -1-acetylpyrrolidin-2-carbonyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (189 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (450 mg).

Example 90

Preparation of 1- {5-cyclopropyl-1- [1- (2-methanesulfonylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 65, the title compound was obtained as a white amorphous solid (134 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (152 mg).

Example 91

Preparation of 1- {1- [1- (1-Acetylpiperidin-4-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale yellow amorphous solid (145 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (404 mg) according to Example 2.

Example 92

Preparation of 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a pale brown yellow amorphous solid (151 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (404 mg) according to Example 2.

Example 93

Preparation of 1- {1- [1- (3-carbamoylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 65, the title compound was obtained as a white amorphous solid (61 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 94

Preparation of 1- [1- (1-carbamoylmethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

The 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride (200 mg) from Example 2 was dissolved in N, N-dimethylformamide (2.5 ml) and potassium carbonate (93 mg) and 2-bromoacetamide (50.7 mg) were added. The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain 1- [1- (1-carbamoylmethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [( S) -3- (2-trifluoromethylphenyl)] pyrrolidine (167 mg) as a white amorphous solid.

1- [1- (1-Carbamoylmethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (154 mg), obtained as indicated in the previous step, dissolved in ethyl acetate (2 ml) and 4N were added. a solution of hydrochloric acid in ethyl acetate (159 μl). The mixture is stirred for 10 minutes. The precipitated crystals were collected by filtration and dried to obtain the title compound as a white amorphous solid (109 mg).

Example 95

Preparation of 1- [5-cyclopropyl-1- (1-methylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

1- [5-Cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride (2.5 g) from Example 2 dissolved in N, N-dimethylformamide (20 ml) and potassium carbonate (1.62 g) and ethyl bromoacetate (0.98 g) were added. The mixture was stirred at room temperature for one hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 25: 1) to obtain 1- {5-cyclopropyl-1- [1- (ethoxycarbonylmethyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (2.79 g) as a white amorphous solid.

1- {5-Cyclopropyl-1- [1- (ethoxycarbonylmethyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (1.4 g ), obtained as indicated in the previous step, is dissolved in tetrahydrofuran (5.5 ml) and methanol (2.7 ml) and 4N are added. aqueous sodium hydroxide solution (1.4 ml). The mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water. The aqueous layer was washed twice with diethyl ether, the pH was adjusted to 5-6 with 2 N. hydrochloric acid solution under ice cooling and extracted three times with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and n-hexane was added to the resulting residue. The precipitated solid was collected by filtration and dried to obtain 1- [1- (1-carboxymethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine (1.17 g) as a white solid.

N, N-Dimethylformamide (3.0 ml) was added to 1- [1- (1-carboxymethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine (150 mg) obtained as indicated in the previous step, 1-hydroxybenzotriazole (61 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (76 mg) were added and the resulting mixture was stirred at room temperature In one hour. A 40% aqueous solution of methylamine (106 μl) was added and the resulting mixture was stirred for 5 hours, then a 40% aqueous solution of methylamine (318 μl) was added and the resulting mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1). The obtained amorphous solid was dissolved in ethyl acetate (2.0 ml), 4N was added. a solution of hydrochloric acid in ethyl acetate (100 μl) and the resulting mixture was stirred for 10 minutes. The precipitated crystals were collected by filtration and dried to obtain the title compound as a white amorphous solid (16.9 mg).

Example 96

Preparation of 1- {1- [1- (1-carbamoyl-1-methylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

Cumylamine (1.1 g) and triethylamine (1.2 ml) were dissolved in chloroform (10 ml) and a solution of 2-bromisobutyryl bromide (1.0 ml) in chloroform (2 ml) was added under ice-cooling for 5 minutes. The mixture was stirred at room temperature for 15 minutes. It was then concentrated under reduced pressure, ethyl acetate was added to the resulting residue, and the resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting white solid was washed with diisopropyl ether and dried to give 2-bromo-2-methyl-N- (1-methyl-1-phenylethyl) propylamide as a white solid (1.73 g).

The 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride from Example 2 is dissolved in tetrahydrofuran (5, 5 ml) and 60% sodium hydride solution (104 mg) is added. The mixture was stirred at 60 ° C. for one hour and at room temperature for 5 minutes. 2-Bromo-2-methyl-N- (1-methyl-1-phenylethyl) propylamide (329 mg) obtained as indicated in the previous step was added, and the resulting mixture was stirred at 60 ° C for 22 hours. After the mixture was allowed to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain 1- (5-cyclopropyl-1- {1- [1-methyl-1- (1-methyl-1-phenylethylcarbamoyl) ethyl] piperidin-4-yl} -1H-pyrazol-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine in pale yellow amorphous form (78 mg).

1- (5-Cyclopropyl-1- {1- [1-methyl-1- (1-methyl-1-phenylethylcarbamoyl) ethyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) The -3- (2-trifluoromethylphenyl)] pyrrolidine obtained as indicated in the previous step was dissolved in trifluoroacetic acid (2 ml) and the resulting mixture was stirred at 80 ° C for 8 hours. Then trifluoroacetic acid (1 ml) was added and then the resulting mixture was stirred at a temperature of 80 ° C for 8 hours. After the mixture was allowed to cool, the resulting mixture was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: acetone = 4: 5 → chloroform: methanol = 10: 1). The resulting residue was dissolved in ethyl acetate (1 ml) and 4N was added. a solution of hydrochloric acid in ethyl acetate (1 ml) and diethyl ether (1.5 ml). The resulting solid was collected by filtration and dried to give the title compound as a pale yellow solid (36 mg).

Example 97

Preparation of 1- {1- [1- (2-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 94, the title compound was obtained as a white amorphous solid (149 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 98

Preparation of 1- [5-cyclopropyl-1- (1-cyclopropylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 94, the title compound was obtained as white crystals (133 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H- hydrochloride pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (150 mg) according to Example 2.

Example 99

Preparation of 1- [5-cyclopropyl-1- (1-cyclopropylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 94, the title compound was obtained as a pale brown-yellow amorphous solid (144 mg) from 1- [5-cyclopropyl-1- (piperidin-4) hydrochloride -yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 100

Preparation of 1- [5-cyclopropyl-1- (1-dimethylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

In accordance with a procedure similar to the preparation of the compound described in Example 95, the title compound was obtained as a white amorphous solid (20 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (2.5 g) according to Example 2.

Example 101

Preparation of 1- [1- (1-carboxymethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

The title compound was obtained as a white amorphous solid (24 mg) from 1- [1- (1-carboxymethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) - 3- (2-trifluoromethylphenyl)] pyrrolidine (112 mg) obtained in Example 95.

Example 102

Preparation of 1- [1- (1-carboxyethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 95, the title compound was obtained as a pale yellow amorphous solid (295 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (350 mg).

Example 103

Preparation of 1- {1- [1- (1-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 95, the title compound was obtained as a pale yellow amorphous solid (146 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (350 mg).

Example 104

Preparation of 1- {1- [1- (2-carboxy-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 95, the title compound was obtained as a pale yellow amorphous solid (71 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (400 mg).

Example 105

Preparation of 1- {1- [1- (2-carbamoyl-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 95, the title compound was obtained as a white amorphous solid (52 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (400 mg).

Example 106

Preparation of 1- {1- [1- (1-carbamoylcyclopropylmethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

According to a similar procedure to the preparation of the compound described in Example 95, the title compound was obtained as a white amorphous solid (82 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (400 mg).

Example 107

Preparation of 1- (5-cyclopropyl-1- {1- [1- (2-hydroxyethylcarbamoyl) cyclopropylmethyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 95, the title compound was obtained as a white amorphous solid (84 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (400 mg).

Example 108

Preparation of 1- [5-cyclopropyl-1- (1-trifluoromethanesulfonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

The 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride (200 mg) from Example 2 was dissolved in methylene chloride (2.0 ml) and in an argon atmosphere, the solution was cooled to -78 ° C, triethylamine (178 μl) and trifluoromethanesulfonic acid anhydride (78.8 μl) were added, after which the resulting mixture was stirred for 2.5 hours. Trifluoromethanesulfonic anhydride (78.8 μl) was then added and the resulting mixture was stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture at −78 ° C., and the resulting mixture was extracted with chloroform. The organic layer is washed with 1 N. hydrochloric acid solution, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain the title compound as a yellow amorphous form (192 mg).

Example 109

Preparation of 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethanesulfonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 108, the title compound was obtained as a yellow amorphous solid (29 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) - hydrochloride 1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (200 mg) according to Example 2.

Example 110

Preparation of 1- {1- [1- (1-cyanoiminoethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

The 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride from Example 2 (300 mg) was dissolved in chloroform (5 ml) and then triethylamine (97 μl) and methyl N-cyanoacetoimidate (66 μl) are added. Then, after stirring at room temperature for 30 minutes and at a temperature of 45 ° C for 1.5 hours, triethylamine (97 μl) and methyl N-cyanoacetoimidate (66 μl) were added and the resulting mixture was stirred at 45 ° C for 2 hours. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 15: 1) to obtain the title compound in pale yellow amorphous form (214 mg).

Example 111

Preparation of 1- (1- {1- [cyanoimino (methylamino) methyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Preparation of 1- (1- {1- [cyanoimino (phenoxy) methyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Chloroform (5 ml) was added to the 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride from Example 2 (500 mg) and then triethylamine (0.162 ml) and diphenyl-N-cyanocarbonimidate (284 mg) are added. The mixture was stirred for 1.5 hours. It was then concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (chloroform: acetone = 1: 1 → 2: 3 → 1: 2) to give the title compound in pale yellow amorphous form (575 mg) .

Stage 2

Preparation of 1- (1- {1- [cyanoimino (methylamino) methyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- (1- {1- [Cyanoimino (phenoxy) methyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ( 575 mg), obtained as indicated in the previous step, was dissolved in chloroform (10 ml), methylamine hydrochloride (81 mg) and triethylamine (0.31 ml) were added, and the resulting mixture was stirred at room temperature for 30 minutes and at a temperature of 55 ° C for 5 hours. Methylamine hydrochloride (81 mg) and triethylamine (2 ml) are then added and the resulting mixture is stirred at 55 ° C for one hour and at 60 ° C for 30 minutes. Methylamine hydrochloride (162 mg) was then added again and the resulting mixture was stirred at 60 ° C. for 2.5 hours. After the mixture was allowed to cool, the mixture was concentrated under reduced pressure and the resulting residue was dissolved in chloroform, and the resulting mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 10: 1) to obtain the title compound as a white amorphous solid (242 mg).

Example 112

Preparation of 1- {1- [1- (N-cyanocarbamimidoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 111, the title compound was obtained as a pale yellow amorphous solid (249 mg) from 1- [5-cyclopropyl-1- (piperidin-4-yl) hydrochloride ) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine from Example 2 (302 mg).

Example 113

Preparation of 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid

Stage 1

Preparation of tert-butyl-1- [1- (4-ethoxycarbonylphenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carboxylate

tert-Butyl-2-cyclopropylcarbonyl-3-dimethylaminoacrylate (1.12 g), obtained in accordance with a procedure similar to the preparation of the compound described in Example 1, Stage 1 and ethyl-4- (4-hydrazinopiperidin-1-yl hydrochloride) ) benzoate (692 mg) obtained using a known method, suspended in ethanol (15 ml). Triethylamine (0.81 ml) was added to the resulting suspension, and the resulting mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the title compound as a yellow oil (673 mg).

Stage 2

Preparation of 1- [1- (4-ethoxycarbonylphenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carboxylic acid

tert-Butyl-1- [1- (4-ethoxycarbonylphenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carboxylate (673 mg), obtained as indicated in the previous step, is dissolved in chloroform (4 ml ), trifluoroacetic acid (4 ml) was added under ice-cooling, and the resulting mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether and n-hexane were added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain the title compound as a white solid (556 mg).

Stage 3

Preparation of 5-cyclopropyl-1- {1- [1- (4-ethoxycarbonylphenyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {3- (2-trifluoromethylphenyl)} pyrrolidine

5-Cyclopropyl-1- [1- (4-ethoxycarbonylphenyl) piperidin-4-yl] -1H-pyrazole-4-carboxylic acid (550 mg) obtained as indicated in the previous step, 1-hydroxybenzotriazole (285 mg) and hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (357 mg) was dissolved in N, N-dimethylformamide (8 ml). To the resulting solution was added 3- (2-trifluoromethylphenyl) pyrrolidine (308 mg) and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound as a white amorphous solid (757 mg).

Stage 4

Preparation of 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid

1- {1- [1- (4-Ethoxycarbonylphenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - {3- (2-trifluoromethylphenyl)} pyrrolidine (720 mg), obtained as indicated in the previous step, dissolved in tetrahydrofuran (3 ml) and methanol (1.5 ml) and add 4 N. aqueous sodium hydroxide solution (1.2 ml). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water. The aqueous layer was washed with diethyl ether, acidified with 2 N. hydrochloric acid solution under ice cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether: n-hexane (1: 1) was added to the resulting residue, and the precipitated solid was collected by filtration and dried to obtain the title compound as a white solid (600 mg).

Example 114

Preparation of 3- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid

1- [5-Cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine (195 mg), obtained in accordance with the procedure similar to the method for obtaining the compound, described in Example 1 and ethyl 3-iodobenzoate (142 mg) was dissolved in 1,4-dioxane (1 ml) and tert-butanol (1 ml) and then tris (dibenzylideneacetone) dipalladium (14.2 mg) was added, 2- dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl (24.3 mg) and cesium carbonate (235 mg). The mixture was heated at reflux overnight. After the mixture was allowed to cool, the insoluble product was filtered through celite and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: acetone = 1: 1) to obtain ethyl 3- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidine-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoate as an amorphous white solid (179 mg).

Ethyl 3- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoate (179 mg), prepared as indicated the previous stage, dissolved in tetrahydrofuran (1 ml) and ethanol (1 ml) and add 4 N. aqueous sodium hydroxide solution (1 ml). The mixture was heated at the boil under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water and acidified with 2N hydrochloric acid solution under ice cooling. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound as a white solid (165 mg).

Example 115

Preparation of 5- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiophen-2-carboxylic acid

1- [5-Cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine (220 mg), obtained in accordance with the procedure similar to the method for obtaining the compound, described in Example 1 and ethyl 5-bromothiophene-2-carboxylate (137 mg) was dissolved in toluene (4 ml) and palladium acetate (13 mg), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl was added (36 mg) and cesium carbonate (265 mg). The mixture is heated at the boil under reflux for 6 hours. After the mixture was allowed to cool, the insoluble product was filtered through celite and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: acetone = 1: 1) to obtain ethyl 5- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidine-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiophene-2-carboxylate (162 mg) as a white amorphous solid.

Ethyl 5- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiophene-2-carboxylate (162 mg), obtained as indicated in the previous step, dissolved in tetrahydrofuran (1 ml) and ethanol (1 ml) and add 4 N. aqueous sodium hydroxide solution (1 ml). The mixture was heated at the boil under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water and acidified with 2N hydrochloric acid solution under ice cooling. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure. The resulting solid was purified by silica gel chromatography (chloroform: acetone = 6: 1) and recrystallized from ethyl acetate to give the title compound as a pale green solid (28 mg).

Example 116

Preparation of 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiazole-4-carboxylic acid

Stage 1

Preparation of 4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-thiocarboxamide

1- [5-Cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine (420 mg) obtained in accordance with a procedure analogous to the procedure for obtaining the compound, described in Example 1 was dissolved in chloroform (10 ml) and triethylamine (0.139 ml) and 9-fluorenylmethoxycarbonylisothiocyanate (285 mg) were added at room temperature. The mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform: methanol = 50: 1). The resulting purified product was dissolved in N, N-dimethylformamide (7 ml) and piperidine (0.7 ml) was added at room temperature. The mixture was stirred for one hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting mixture was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound as a white solid (287 mg).

Stage 2

Preparation of 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiazole-4-carboxylic acid

4- {5-Cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-thiocarboxamide (280 mg), obtained as indicated in the previous step, is suspended in ethanol ( 5 ml) and ethyl bromopyruvate (0.09 ml) was added to the resulting suspension. The mixture was heated at the boil under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain ethyl 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidine-1-carbonyl] pyrazole- 1-yl} piperidin-1-yl) thiazole-4-carboxylate (361 mg) as a white amorphous solid.

Ethyl 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiazole-4-carboxylate (355 mg), obtained as indicated in the previous step, dissolved in tetrahydrofuran (0.6 ml) and methanol (0.3 ml), and 4 N. an aqueous solution of sodium hydroxide (0.57 ml) at room temperature. The mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and 1N was added to the resulting residue. an aqueous solution of sodium hydroxide and the resulting mixture was washed with diethyl ether. A layer of aqueous solution is acidified with 2 N. hydrochloric acid solution and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound as a white solid (272 mg).

Example 117

Preparation of 1- {5-cyclopropyl-1- [1- (5-methyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Preparation of methyl 4- {5-cyclopropyl-4 - [(S) -3- (2-trifluoromethylphenyl) pyrrolidine-1-carbonyl] pyrazol-1-yl} piperidin-1-imidothiocarboxylate hydroiodide

4- {5-Cyclopropyl-4 - [(S) -3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-thiocarboxamide (500 mg) obtained in accordance with a similar procedure the preparation of the compound described in Example 116, Step 1, was dissolved in chloroform (5 ml) and methyl iodide (0.1 ml) was added. The mixture was stirred overnight at room temperature. It was concentrated under reduced pressure, diethyl ether was added to the resulting residue, the precipitated solid was collected by filtration and dried to obtain the title compound as a pale yellow solid (654 mg).

Stage 2

Preparation of 1- {5-cyclopropyl-1- [1- (5-methyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Hydroiodide methyl 4- {5-cyclopropyl-4 - [(S) -3- (2-trifluoromethylphenyl) pyrrolidine-1-carbonyl] pyrazol-1-yl} piperidin-1-imidothiocarboxylate (317 mg), prepared as indicated of the previous step, acetic acid hydrazide (50 mg) and sodium acetate (43 mg) were suspended in dioxane (2 ml) and water (0.4 ml), and the resulting mixture was heated at reflux overnight. The solvent was removed under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (chloroform: methanol = 10: 1). The resulting amorphous solid was dissolved in ethyl acetate (1 ml) and 4N was added. a solution of hydrochloric acid in ethyl acetate (0.4 ml). The precipitated solid was collected by filtration and dried to obtain the title compound as white crystals (72 mg).

Example 118

Preparation of 1- {5-cyclopropyl-1- [1- (5-cyclopropyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 117, the title compound was obtained as white crystals (253 mg) from methyl 4- {5-cyclopropyl-4 - [(S) -3- ( 2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-imidothiocarboxylate (475 mg).

Example 119

Preparation of 1- {5-cyclopropyl-1- [1- (5-hydroxymethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 117, the title compound was obtained as white crystals (25 mg) from methyl 4- {5-cyclopropyl-4 - [(S) -3- ( 2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-imidothiocarboxylate (317 mg).

Example 120

Preparation of 1- {5-cyclopropyl-1- [1- (5-trifluoromethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

In accordance with a procedure similar to the preparation of the compound described in Example 117, the title compound was obtained as white crystals (130 mg) from methyl 4- {5-cyclopropyl-4 - [(S) -3- ( 2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-imidothiocarboxylate (317 mg).

Example 121

Preparation of 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Preparation of methyl 5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carboxylate

Methyl 1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carboxylate (15.9 g) obtained in Example 1, Step 2, was dissolved in methanol (12 ml) and palladium was added on coal (1.5 g). The mixture was stirred overnight in a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. N-hexane was added to the resulting residue, and after filtration, the title compound was obtained as a white amorphous solid (9.66 g).

Stage 2

Preparation of methyl 5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylate

Methyl 5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carboxylate (2.82 g), obtained as indicated in the previous step, was dissolved in chloroform (28 ml) and triethylamine (1, 58 ml).

To the resulting mixture was added 2-fluorophenyl isocyanate (1.4 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 3) to obtain the title compound as a white amorphous solid (4.23 g).

Stage 3

Preparation of 5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylic acid

Methyl 5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylate (4.23 g), obtained as indicated in the previous step, was dissolved in tetrahydrofuran (11 ml ) and methanol (5 ml) and add 4 N. aqueous sodium hydroxide solution (11 ml). The mixture was stirred at 60 ° C for 6 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The resulting residue was dissolved in water. The aqueous layer was washed with diethyl ether and acidified with concentrated hydrochloric acid while cooling with ice. The precipitated solid was collected by filtration, washed with water and n-hexane and dried under reduced pressure to obtain the title compound as a white solid (3.89 g).

Stage 4

Preparation of 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - {(R) -3- (2-trifluoromethylphenyl)} pyrrolidine

5-Cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylic acid (101 mg) obtained as indicated in the previous step, 1-hydroxybenzotriazole (46 mg) and hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (57 mg) was dissolved in N, N-dimethylformamide (15 ml). (R) -3- (2-Trifluoromethylphenyl) pyrrolidine (65 mg) * and 4-dimethylaminopyridine (37 mg) were added to the resulting solution, and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain the title compound as a white amorphous solid (136 mg).

[α] ²⁵ D = +10.9 (c = 0.495, EtOH)

* (R) -3- (2-Trifluoromethylphenyl) pyrrolidine is prepared according to a procedure analogous to the preparation of the compound described in Example 2, Steps 1 to 4, and using (R) -4-isopropyl-5,5-diphenyloxazolidine -2-he.

[α] ²⁵ D = -21.0 (c = 0.500, EtOH)

Example 122

Preparation of 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Preparation of methyl 5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylate

1-Methylcyclopropane-1-carboxylic acid (1.81 g), diphenylphosphoryl azide (4.67 ml) and triethylamine (2.77 ml) were dissolved in toluene (30 ml) and the resulting mixture was heated under reflux for one hour until receiving isocyanate.

Methyl 5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carboxylate (1.50 g) obtained in Example 121, Step 1, and triethylamine (0.84 ml) were dissolved in tetrahydrofuran ( 15 ml) and add the isocyanate toluene solution obtained in advance until the starting product (methyl 1- (piperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carboxylate) disappears. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 15: 1) to obtain the title compound as a white amorphous solid (1.92 g).

Stage 2

Preparation of 5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylic acid

Methyl 5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylate (1.92 g), obtained as indicated in the previous step, is dissolved in tetrahydrofuran (20 ml ) and methanol (10 ml) and add 4 N. aqueous sodium hydroxide solution (15 ml). The mixture was stirred at 60 ° C for 6 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The resulting residue was dissolved in water and the aqueous layer was washed with diethyl ether. Under ice cooling, the resulting mixture was acidified with concentrated hydrochloric acid and extracted with chloroform. The chloroform layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain the title compound as a white solid (1.68 g).

Stage 3

Preparation of 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine

5-Cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylic acid (91 mg) obtained as indicated in the previous step, 1-hydroxybenzotriazole (46 mg) and hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (57 mg) was dissolved in N, N-dimethylformamide (1.5 ml). To the resulting solution were added (R) -3- (2-trifluoromethylphenyl) pyrrolidine (65 mg) and 4-dimethylaminopyridine (37 mg) and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 15: 1) to obtain the title compound as a white amorphous solid (123 mg).

[α] ²⁵ D = +13.1 (c = 0.495, EtOH)

Example 123

Preparation of 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Preparation of methyl 5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylate

Methyl 5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carboxylate (1.87 g) obtained in Example 121, Step 1, was dissolved in chloroform (20 ml) and triethylamine (1 05 ml). Isopropylisocyanate (0.7 ml) was added to the resulting mixture under ice-cooling, and then it was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform: methanol = 15: 1) to obtain the title compound as a white amorphous solid (2.00 g).

Stage 2

Preparation of 5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylic acid

Methyl 5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylate (2.00 g), obtained as indicated in the previous step, is dissolved in tetrahydrofuran (6 ml ) and methanol (3 ml), and 4 N was added. aqueous sodium hydroxide solution (6 ml). The mixture is stirred at a temperature of 60 ° C for 4.5 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The resulting residue was dissolved in water and the aqueous layer was washed with diethyl ether and acidified with concentrated hydrochloric acid under ice cooling. The mixture was extracted with chloroform. The chloroform layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting residue was added n-hexane, the precipitated solid was collected by filtration and dried to obtain the title compound as a white solid (1.58 g).

Stage 3

Preparation of 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine

5-Cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carboxylic acid (88 mg) obtained as indicated in the previous step, 1-hydroxybenzotriazole (46 mg) and hydrochloride 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (57 mg) was dissolved in N, N-dimethylformamide (1.5 ml). To the resulting solution were added (R) -3- (2-trifluoromethylphenyl) pyrrolidine (65 mg) and 4-dimethylaminopyridine (37 mg) and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and then it was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 15: 1) to obtain the title compound as a white amorphous solid (120 mg).

[α] ²⁵ D = +14.2 (c = 0.500, EtOH)

Example 124

Preparation of 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 121, Step 4, the title compound was obtained as a white amorphous solid (127 mg) from 5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidine -4-yl] -1H-pyrazol-4-carboxylic acid (123 mg), (S) -3- (2-trifluoromethylphenyl) pyrrolidine (78 mg).

[α] ²⁵ D = -10.8 (c = 0.510, EtOH)

Example 125

Preparation of 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 123, Step 3, the title compound was obtained as a white amorphous solid (123 mg) from 5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidine -4-yl] -1H-pyrazol-4-carboxylic acid (107 mg), (S) -3- (2-trifluoromethylphenyl) pyrrolidine (79 mg).

[α] ²⁵ D = -13.2 (c = 0.515, EtOH)

Example 126

Preparation of 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 122, Step 3, the title compound was obtained as a white amorphous solid (149 mg) from 5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidine -4-yl] -1H-pyrazol-4-carboxylic acid (107 mg), (S) -3- (2-trifluoromethylphenyl) pyrrolidine (76 mg).

[α] ²⁵ D = -13.6 (c = 0.500, EtOH)

Example 127

Preparation of (-) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H- hydrochloride pyrazole-4-carbonyl} pyrrolidine

Stage 1

Obtaining ethylcyano- (4-fluorophenyl) acetate

Toluene (40 ml) was added to 4-fluorophenylacetonitrile (15.0 g) and diethyl carbonate (66.9 ml), then sodium ethylate (8.30 g) was added. The mixture is stirred for 2 hours as the solvent is evaporated at a temperature in the range from 110 ° C to 130 ° C. After the mixture was allowed to cool, the reaction mixture was poured into water and acetic acid (13 ml) was added. The mixture was stirred for 5 minutes and then it was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a pale yellow oil (25.0 g).

Stage 2

Obtaining diethyl-2-cyano-2- (4-fluorophenyl) succinate

Tetrahydrofuran (40 ml) was added to 60% sodium hydride (2.12 g) and a solution of ethyl cyano (4-fluorophenyl) acetate (10.0 g) was added dropwise, obtained as indicated in the previous step in tetrahydrofuran (40 ml) under cooling ice. The mixture was stirred for 40 minutes and ethyl bromoacetate (6.4 ml) was added under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the title compound as a pale yellow oil (14.7 g).

Stage 3

Obtaining ethyl 3- (4-fluorophenyl) -5-oxopyrrolidine-3-carboxylate

A solution of diethyl 2-cyano-2- (4-fluorophenyl) succinate (7.0 g), obtained as indicated in the previous step, in ethanol (50 ml) was added to Raney nickel (7.0 g) and the resulting mixture was stirred in overnight in a hydrogen atmosphere. The reaction mixture was filtered through celite, the filtrate and washing were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 25: 1), and a mixed solvent of diethyl ether and n-hexane was added to the obtained solid residue. The mixture was filtered and dried to give the title compound as white crystals (3.96 g).

Stage 4

Preparation of ethyl 1-benzyl-3- (4-fluorophenyl) -5-oxopyrrolidine-3-carboxylate

Tetrahydrofuran (25 ml) was added to 60% sodium hydride (1.63 g) and a solution of ethyl 3- (4-fluorophenyl) -5-oxopyrrolidine-3-carboxylate (10.3 g), prepared as indicated in the previous step in a mixture of tetrahydrofuran (30 ml) / N, N-dimethylformamide (10 ml) under ice cooling. The mixture is stirred for 10 minutes. Under ice cooling, benzyl bromide (4.86 ml) was added. The mixture was stirred at the same temperature for 30 minutes and at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound as a pale yellow oil (12.1 g).

Stage 5

Preparation of 1-benzyl-3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine

Tetrahydrofuran (20 ml) was added to lithium aluminum hydride (1.16 g) and a solution of ethyl 1-benzyl-3- (4-fluorophenyl) -5-oxopyrrolidine-3-carboxylate (4.16 g) was obtained dropwise, prepared as indicated in the previous step in tetrahydrofuran (20 ml) under ice cooling. The mixture was stirred at the boil under reflux for 3.5 hours. After the mixture was allowed to cool, water (0.9 ml), 4N, was added sequentially. an aqueous solution of sodium hydroxide (0.9 ml) and water (2.7 ml) under ice-cooling, and then diethyl ether and magnesium sulfate were added. The mixture was stirred for 20 minutes and filtered through celite. The filtrate and washing were combined and concentrated under reduced pressure to obtain the title compound as a pale yellow oil (3.18 g).

Stage 6

Preparation of 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine

To a solution of 1-benzyl-3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine (3.18 g), obtained as indicated in the previous step, in methanol (30 ml) was added palladium hydroxide (300 mg) and the resulting mixture was stirred for nights in a hydrogen atmosphere (3 atmospheres). The reaction mixture was filtered through celite, the filtrate and washing were combined and concentrated under reduced pressure to obtain the title compound as a pale yellow oil (2.30 g).

Stage 7

Obtaining tert-butyl-3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine-1-carboxylate

To 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine (2.30 g) obtained as indicated in the previous step, tetrahydrofuran (40 ml) and triethylamine (5.7 ml) are added, and then di-tert-butyl dicarbonate ( 4.60 g) under ice cooling. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added. The mixture was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound as a colorless oil (2.70 g).

Stage 8

Preparation of (-) - 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine

To tert-butyl 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine-1-carboxylate (1.02 g), obtained as indicated in the previous step, chloroform (10 ml), triethylamine (962 μl) and 4-dimethylaminopyridine are added (421 mg) and then (S) - (+) - 3,3,3-trifluoro-2-methoxy-2-phenylpropionyl chloride (969 μl) was added under ice cooling. The mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogen sulfate, water, an aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: diethyl ether = 5: 3) to give a less polar diastereomer as a colorless oil (871 mg). In addition, the more polar diastereomer was obtained as a colorless oil (781 mg).

A colorless oil (871 mg) of less polar diastereomer was dissolved in tetrahydrofuran (4 ml) and methanol (2 ml), and then 4N was added. aqueous sodium hydroxide solution (2.6 ml). The mixture is stirred at a temperature of 60 ° C for 40 minutes. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted three times with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a colorless oil (481 mg).

Methanol (3 ml) and 4N were added to the resulting colorless oil (481 mg). a solution of hydrochloric acid in ethyl acetate (3.3 ml) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was washed with diethyl ether and the aqueous layer was made alkaline with 2 N aqueous solution of sodium hydroxide. The mixture was extracted 5 times with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the title compound as a colorless oil (312 mg).

[α] ²⁵ D = -9.70 (c = 0.598, EtOH)

Preparation of (+) - 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine

By using a similar procedure to the preparation of (-) - 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine and using colorless oil (781 mg) of the more polar diastereomer, the title compound was obtained as a colorless oil (251 mg).

[α] ²⁵ D = +10.37 (c = 0.588, EtOH)

Stage 9

Preparation of tert-butyl 5- (1-methylcyclopropyl) -1- (1-pyrimidin-2-ylpiperidin-4-yl) -1H-pyrazole-4-carboxylate

tert-Butyl-5- (1-methylcyclopropyl) -1- (piperidin-4-yl) -1H-pyrazole-4-carboxylate (1.15 g) obtained in accordance with a procedure analogous to the procedure for obtaining the compounds described in Example 121, Step 1, and 2-chloropyrimidine (700 mg) was dissolved in 1,4-dioxane (12 ml) and palladium acetate (85 mg), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl ( 352 mg) and cesium carbonate (1.84 g). The mixture was heated at the boil under reflux for 3 hours. After the mixture was allowed to cool, the insoluble product was filtered through celite and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the title compound as a white amorphous solid (922 mg).

Stage 10

Preparation of 5- (1-methylcyclopropyl) -1- (1-pyrimidin-2-yl-piperidin-4-yl) -1H-pyrazole-4-carboxylic acid hydrochloride

tert-Butyl-5- (1-methylcyclopropyl) -1- (1-pyrimidin-2-yl-piperidin-4-yl) -1H-pyrazole-4-carboxylate (922 mg), obtained as indicated in the previous step, is dissolved in chloroform (2 ml) and trifluoroacetic acid (4 ml) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting crystal was dissolved in tetrahydrofuran. Add 4 n. a solution of hydrochloric acid in ethyl acetate (2 ml) and the resulting mixture was concentrated under reduced pressure. The resulting crystalline residue was washed as a suspension with ethyl acetate (10 ml) for one hour to give the title compound as a white solid (800 mg).

Stage 11

Preparation of (-) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H- hydrochloride pyrazole-4-carbonyl} pyrrolidine

5- (1-Methylcyclopropyl) -1- (1-pyrimidin-2-yl-piperidin-4-yl) -1H-pyrazole-4-carboxylic acid hydrochloride (150 mg) obtained as indicated in the previous step, 1-hydroxybenzotriazole (81 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (102 mg) were dissolved in N, N-dimethylformamide (3 ml). (-) - 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine (88 mg) obtained in Step 8, triethylamine (0.057 ml) and 4-dimethylaminopyridine (50 mg) were added to the resulting solution, and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and then it was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) and the resulting free base was dissolved in methanol (3 ml). Add 4 n. a solution of hydrochloric acid in 1,4-dioxane (0.2 ml) and the resulting mixture was concentrated under reduced pressure. The resulting crystalline residue was washed in suspension with ethyl acetate (3 ml) for 15 minutes to obtain the title compound as white crystals (203 mg).

[α] ²⁵ D = -21.3 (c = 0.506, MeOH)

Example 128

Preparation of (+) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H- hydrochloride pyrazole-4-carbonyl} pyrrolidine

According to a similar procedure to the preparation of the compound described in Example 127, Step 11, the title compound was obtained as white crystals (198 mg) from 5- (1-methylcyclopropyl) -1- (1-pyrimidin-2 hydrochloride) -yl-piperidin-4-yl) -1H-pyrazole-4-carboxylic acid (150 mg), (+) - 3- (4-fluorophenyl) -3-hydroxymethylpyrrolidine (88 mg) obtained in Example 127, Step 8 .

[α] ²⁵ D = +26.0 (c = 0.508, MeOH)

Example 129

Preparation of 1- [5-cyclopropyl-1- (1-pyrazin-2-yl-piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride

The title compound was obtained as a yellow amorphous solid (165 mg) from 1- [5-cyclopropyl-1- (1-pyrazin-2-yl-piperidin-4-yl) -1H-pyrazole-4-carboxylic hydrochloride acid (281 mg) obtained in accordance with a procedure analogous to the procedure for obtaining the compounds described in Example 127.

Example 130

Preparation of 1- [1- (trans-4-carbamoylcyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Obtaining ethyl trans-4- (2-tert-butoxycarbonylhydrazino) cyclohexanecarboxylate

Ethyl 4-cyclohexanone carboxylate (8.0 g) and tert-butyl carbazate (6.2 g) were dissolved in chloroform (150 ml) and acetic acid (5.4 ml) and then sodium triacetoxyborohydride (30 g) was added under ice cooling. The temperature of the mixture is allowed to gradually return to room temperature and then it is stirred for 7 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound as a white solid (4.63 g).

Stage 2

Obtaining ethyl trans-4-hydrazinocyclohexanecarboxylate hydrochloride

Ethyl trans-4- (2-tert-butoxycarbonylhydrazino) cyclohexanecarboxylate (4.63 g), obtained as indicated in the previous step, was dissolved in ethanol (30 ml) and 4N were added. a solution of hydrochloric acid in ethyl acetate (82 ml). The mixture was stirred for 5.5 hours. It is concentrated under reduced pressure and diethyl ether is added to the resulting residue. The mixture was filtered and dried to give the title compound as a white powder (3.86 g).

Stage 3

Preparation of tert-butyl-1- (trans-4-ethoxycarbonylcyclohexane) -5-cyclopropyl-1H-pyrazole-4-carboxylate

Ethyl trans-4-hydrazinocyclohexanecarboxylate hydrochloride (3.80 g), prepared as indicated in the previous step, and tert - butyl-2-cyclopropylcarbonyl-3-dimethylaminoacrylate (3.71 g), synthesized in accordance with a procedure analogous to the preparation procedure the compounds described in Example 1, Step 1, are dissolved in ethanol (50 ml) and triethylamine (4.32 ml) is added. The mixture was stirred at reflux for one hour. After the mixture was allowed to cool, the mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the title compound as a yellow liquid (4.80 g).

Stage 4

Preparation of 1- (trans-4-ethoxycarbonylcyclohexane) -5-cyclopropyl-1H-pyrazole-4-carboxylic acid

To a solution of tert-butyl-1- (trans-4-ethoxycarbonylcyclohexane) -5-cyclopropyl-1H-pyrazole-4-carboxylate (4.80 g), obtained as indicated in the previous step, in chloroform (14 ml) was added trifluoroacetic acid (14 ml) and the resulting mixture was heated to a temperature of 40 ° C and stirred for 1.5 hours. After the mixture was allowed to cool, the mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluene. Ethyl acetate was added to the residue, which allowed crystals to precipitate. The mixture was concentrated once under reduced pressure, n-hexane was added to the residue, the crystals were collected by filtration and dried to obtain the title compound as a white powder (3.09 g).

Stage 5

Preparation of 1- {5-cyclopropyl-1- (trans-4-ethoxycarbonylcyclohexyl) -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- (Trans-4-ethoxycarbonylcyclohexane) -5-cyclopropyl-1H-pyrazole-4-carboxylic acid (1.50 g) obtained as indicated in the previous step, and (S) -3- (2-trifluoromethylphenyl) pyrrolidine ( 1.16 g) was dissolved in N, N-dimethylformamide (15 ml) and 1-hydroxybenzotriazole (825 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.03 g) and 4-dimethylaminopyridine ( 658 mg). The mixture was stirred at room temperature for 14 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed twice with water. The organic layer is washed with 1 N. hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 20: 1) to obtain the title compound as a brown amorphous (2.34 g).

Stage 6

Preparation of 1- [1- (trans-4-carboxycyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- {5-Cyclopropyl-1- (trans-4-ethoxycarbonylcyclohexyl) -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (2.34 g), obtained as indicated in the previous step, dissolved in tetrahydrofuran (12 ml) and methanol (6 ml) and then a solution of lithium hydroxide monohydrate (973 mg) in water (12 ml) was added. The mixture was stirred at 45 ° C for one hour. It is concentrated under reduced pressure and water is added to the resulting residue. The mixture was washed twice with diethyl ether and the aqueous solution was acidified with 2N hydrochloric acid solution and extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain the title compound as a milky white solid (2.13 g).

Stage 7

Preparation of 1- [1- (trans-4-carbamoylcyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- [1- (Trans-4-carboxycyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (300 mg) obtained as indicated above stages, dissolved in N, N-dimethylformamide (3.5 ml) and 1-hydroxybenzotriazole (106 mg), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (133 mg), ammonium chloride (80 mg) are added and triethylamine (0.105 ml). The mixture was stirred at room temperature for 15 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was washed successively with water, 1N. hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. diethyl ether was added to the obtained solid residue, and the resulting mixture was stirred for 10 minutes. The solid was collected by filtration and dried to give the title compound as a white amorphous solid (171 mg).

Example 131

Preparation of 1- [5-cyclopropyl-1- (trans-4-ureidocyclohexyl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Toluene (3.0 ml) was added to 1- [1- (trans-4-carboxycyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ( 200 mg) obtained in Example 130, Step 6, and then triethylamine (76 μl) and diphenylphosphonic azide (118 μl) were added under argon. The mixture was heated at the boil under reflux for 2 hours. After the mixture was allowed to cool, a toluene solution was added dropwise to a 28% aqueous solution of ammonia (10 ml) and ethyl acetate (4 ml) under ice cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted three times with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform: methanol = 10: 1). Diethyl ether was added to the obtained solid residue, and the resulting mixture was stirred for 10 minutes. The solid was collected by filtration and dried to give the title compound as a white amorphous solid (135 mg).

Example 132

Preparation of 1- {5-cyclopropyl-1- [trans-4- (1H-tetrazol-5-yl) cyclohexyl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

Stage 1

Preparation of 1- [1- (trans-4-cyanocyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- [1- (Trans-4-carbamoylcyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (514 mg) obtained in Example 130, Step 7, dissolved in tetrahydrofuran (6 ml) and pyridine (180 μl) and trifluoromethanesulfonic anhydride (220 μl) are added. The mixture was stirred at room temperature for one hour. Pyridine (180 μl) and trifluoromethanesulfonic anhydride (220 μl) were then added and the resulting mixture was stirred at room temperature for one hour. The mixture was concentrated under reduced pressure and 1N was added. aqueous solution of potassium hydrosulfate. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography (chloroform: methanol = 15: 1) to give the title compound in pale yellow amorphous form (207 mg).

Stage 2

Preparation of 1- {5-cyclopropyl-1- [trans-4- (1H-tetrazol-5-yl) cyclohexyl] -1H-pyrazol-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine

1- [1- (Trans-4-cyanocyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine (207 mg) obtained as indicated in the previous stages, dissolved in 1,4-dioxane (2.5 ml) and aztributyltin (188 mg) was added. The mixture was heated at reflux overnight. Then, azide tributyltin (94 mg) was added and the resulting mixture was heated at the boil under reflux for 4 hours. The mixture was concentrated under reduced pressure, 1N was added. hydrochloric acid solution and the resulting mixture was extracted twice with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography (chloroform: methanol = 25: 2) and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried to obtain the title compound as a white amorphous solid (122 mg).

Example 133

Preparation of 1- {5- (1-methylcyclopropyl) -1- [1- (4-trifluoromethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 134

Preparation of 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-methoxycyclopropyl) -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 135

Preparation of 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazol-4-carbonyl} -3-phenyl-3-trifluoromethylpyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 136

Preparation of 3- (2-chlorophenyl) -1- {5-cyclopropyl-1- [1- (2,4-difluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 137

Preparation of 3- (2-chloropyridin-3-yl) -1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 138

Preparation of 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (2,2,3,3-tetramethylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (pyridin-3 -yl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 139

Preparation of 1- {5-cyclohexyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 140

Preparation of 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethoxyphenyl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 141

Preparation of 1- {5-cyclopropyl-1- [1- (4-trifluoromethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 142

Preparation of 1- (5-cyclopropyl-1- {1 - [((S) -1-carboxy-2-methylpropyl) methylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- (2- trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 12, the title compound was obtained from the corresponding starting compound.

Example 143

Preparation of 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3-methoxy-3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 144

Preparation of 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-hydroxymethylcyclopropyl) -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a procedure similar to that described in Example 3, the title compound was obtained from the corresponding starting compound.

Example 145

Preparation of 1- {5-cyclopropyl-1- [1- (thiazol-2-ylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 146

Preparation of 1- {1- [1- (isopropoxycarbamoyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 147

Preparation of 1- {5-cyclopropyl-1- [1- (4-fluorobenzylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 148

Preparation of 1- {1- [1- (2,3-dihydroindol-1-carbonyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (pyridin-3 -yl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 149

Preparation of 1- {1- [1- (2,3-dihydro [1,4] oxazin-4-carbonyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} - 3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 150

Preparation of 1- {5-cyclopropyl-1- [1- (2,6-dichloropyridin-3-ylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 151

Preparation of 1- {5- (1-methylcyclopropyl) -1- [1- (2,3,4,5-tetrahydrobenzo [b] azepin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl } -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 152

Preparation of Ethyl 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoate

In accordance with a similar procedure to that described in Example 114, the title compound was obtained from the corresponding starting compound.

Example 153

Preparation of 1- [1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine

In accordance with a procedure similar to that described in Example 1, Step 4, the title compound is obtained.

Example 154

Preparation of 1- {1- [1- (3-carboxy-3-methylbutyryl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 65, the title compound was obtained from the corresponding starting compound.

Example 155

Preparation of 1- {5-cyclopropyl-1- [1- (2-phenoxyacetyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 64, the title compound was obtained from the corresponding starting compound.

Example 156

Preparation of 1- {1- [1- (3-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 64, the title compound was obtained from the corresponding starting compound.

Example 157

Preparation of 1- {1- [1- (2-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 64, the title compound was obtained from the corresponding starting compound.

Example 158

Preparation of 1- [5-cyclopropyl-1- (1-oxalylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 65, the title compound was obtained from the corresponding starting compound.

Example 159

Preparation of 1- {1- [1- (4-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 64, the title compound was obtained from the corresponding starting compound.

Example 160

Preparation of 1- (5-cyclopropyl-1- {1- [2- (4-fluorophenyl) acetyl] piperidin-4-yl} -1H-pyrazol-4-carbonyl) -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 64, the title compound was obtained from the corresponding starting compound.

Example 161

Preparation of 1- {5-cyclopropyl-1- [1- (3-trifluoromethylbenzoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 64, the title compound was obtained from the corresponding starting compound.

Example 162

Preparation of 1- {5-cyclopropyl-1- [1- (3-methoxybenzoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 64, the title compound was obtained from the corresponding starting compound.

Example 163

Preparation of 1- {1- [1- (4-fluorobenzyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine hydrochloride

In accordance with a procedure similar to that described in Example 94, the title compound was obtained from the corresponding starting compound.

Example 164

Preparation of 1- [1- (1-benzenesulfonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 108, the title compound was obtained from the corresponding starting compound.

Example 165

Preparation of 1- {1- [1- (4-carbamoylphenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 166

Preparation of 1- {5-cyclopropyl-1- [1- (4-hydroxymethylphenyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 167

Preparation of 1- {1- [1- (5-carbamoylpyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 168

Preparation of 1- {1- [1- (4-aminophenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 169

Preparation of 1- (5-cyclopropyl-1- {1- [4- (2-oxooxazolidin-3-yl) phenyl] piperidin-4-yl} -1H-pyrazol-4-carbonyl) -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 170

Preparation of 1- (5-cyclopropyl-1- {1- [4- (3-methoxyureido) phenyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 171

Preparation of 1- {5-cyclopropyl-1- [1- (4-methanesulfonylaminophenyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 172

Preparation of 1- [1- (1-ethoxycarbamoylpiperidin-4-yl) -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 10, the title compound was obtained from the corresponding starting compound.

Example 173

Preparation of 1- [1- (5-chloropyridin-2-yl) azetidin-3-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 174

Preparation of 1- {1- [1- (5-chloropyridin-2-yl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazol-4-carbonyl} -3-methoxymethyl-3-phenylpyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 175

Preparation of 1- {1- [1- (5-cyanopyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 176

Preparation of 3- (2-acetoxyethyl) -3- (4-fluorophenyl) -1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H- hydrochloride pyrazole-4-carbonyl} pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 177

Preparation of {(3S *, 4R *) - 3-methyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazol-4 hydrochloride -carbonyl} -4-phenylpyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 178

Preparation of methyl 6- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) nicotinate

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 179

Preparation of methyl 2- {1- [5- (1-methylcyclopropyl) -1- (1-pyrimidin-2-ylpiperidin-4-yl) -1H-pyrazol-4-carbonyl] pyrrolidin-3-yl} benzoate

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 180

Preparation of 3- (2-hydroxymethylphenyl) -1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine hydrochloride

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 181

Preparation of 1- [5-cyclopropyl-1- (1-pyridin-2-ylpiperidin-4-yl) -1H-pyrazol-4-carbonyl] -3-hydroxy-3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 182

Preparation of 1- {1- [1- (4-acetylaminophenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 114, the title compound was obtained from the corresponding starting compound.

Example 183

Preparation of 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) -3-fluorobenzoate sodium

In accordance with a similar procedure to that described in Example 114, the title compound was obtained from the corresponding starting compound.

Example 184

Preparation of 3- (2-cyanophenyl) -1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine

In accordance with a similar procedure to that described in Example 121, the title compound was obtained from the corresponding starting compound.

Example 185

Preparation of 3-hydroxymethyl-1- {1- [1- (4-methoxypyrimidin-2-yl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3-phenylpyrrolidine hydrochloride

In accordance with a procedure similar to that described in Example 127, the title compound was obtained from the corresponding starting compound.

Example 186

Preparation of 3- (3,5-difluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazol- hydrochloride 4-carbonyl} pyrrolidine

In accordance with a procedure similar to that described in Example 127, the title compound was obtained from the corresponding starting compound.

Example 187

Preparation of 1- {1- [1- (3-chloropyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 113, the title compound was obtained from the corresponding starting compound.

Example 188

Preparation of 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (thiazol-2-yl) pyrrolidine

In accordance with a similar procedure to that described in Example 121, the title compound was obtained from the corresponding starting compound.

Example 189

Preparation of (S) -2 - [(trans-4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} cyclohexanecarbonyl) methylamino] -3-methylbutyric acid

In accordance with a similar procedure to that described in Example 130, the title compound was obtained from the corresponding starting compound.

Example 190

Preparation of 1- {5- (1-methylcyclopropyl) -1- [trans-4- (2-fluorophenylcarbamoyl) cyclohexyl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine

In accordance with a similar procedure to that described in Example 130, the title compound was obtained from the corresponding starting compound.

Example 191

Preparation of cis-4- {5- (1-methylcyclopropyl) -4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} cyclohexanecarboxylic acid

In accordance with a similar procedure to that described in Example 130, the title compound was obtained from the corresponding starting compound.

The structural formula and quantitative characteristics of the compounds for each Example are shown in the tables (Tables 1-1 to Table 1-45) below.

Table 1-1 Etc. No. Structural formula NMR one

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.63-0.77 (2H, m), 0.97-1.11 (2H, m), 1.70-1.82 (1H, m ), 1.96-2.67 (8H, m), 2.83-2.97 (2H, m), 3.33-3.53 (3H, m), 3.55-4.17 (3H , m), 4.50-4.64 (1H, m), 7.23-7.32 (1H, m), 7.48-7.64 (2H, m), 8.46-8.61 (2H, m) 2

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.75 (2H, m), 0.94-1.07 (2H, m), 1.86-2.36 (8H , m), 3.00-3.21 (2H, m), 3.30-3.93 (6H, m), 4.69-4.88 (1H, m), 7.44-7.64 (2H, m), 7.66-7.78 (3H, m), 8.83 (1H, broad s), 9.22 (1H, broad s) 3

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.83 (2H, m), 0.99-1.15 (2H, m), 1.73-1.84 (1H, m ), 1.90-2.50 (6H, m), 3.02-3.20 (2H, m), 3.36-3.55 (1.5H, m), 3.56-3.80 (2H, m), 3.83-3.99 (1H, m), 4.06-4.17 (0.5H, m), 4.18-4.36 (2H, m), 4.54 -4.71 (1H, m), 6.71 (1H, br s), 6.93-7.00 (1H, m), 7.02-7.14 (2H, m), 7.24 -7.32 (1H, m), 7.50-7.62 (2H, m), 8.02-8.09 (1H, m), 8.47-8.59 (2H, m) four

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.84 (2H, m), 1.03-1.14 (2H, m), 1.54-2.47 (7H, m ), 2.94-3.14 (2H, m), 3.40-4.20 (7H, m), 4.47-4.67 (2H, m), 7.32-7.72 (6H , m)

Table 1-2 Etc. No. Structural formula NMR 5

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.75 (2H, m), 0.92-1.07 (2H, m), 1.81-2.36 (6H , m), 3.04-3.23 (2H, m), 3.44-3.93 (6H, m), 4.10-4.27 (2H, m), 4.65-4.83 (1H, m), 6.98-7.07 (1H, m), 7.39-7.61 (3H, m), 7.63-7.79 (3H, m), 7.92-8 02 (1H, m), 8.37-8.40 (1H, m), 11.0-11.2 (1H, m), 13.6 (1H, broad s) 6

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.85 (2H, m), 1.01-1.14 (2H, m), 1.70-2.44 (7H, m ), 2.72-2.86 (1H, m), 2.97-3.13 (2H, m), 3.41-4.09 (5H, m), 4.20-4.35 (2H , m), 4.51-4.75 (3H, m), 6.97-7.04 (1H, m), 7.11-7.19 (1H, m), 7.28-7.60 (5H, m), 7.64-7.72 (1H, m), 7.92-7.98 (1H, m), 8.13-8.23 (1H, m) 7

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.61-0.94 (6H, m), 0.98-1.17 (2H, m), 1.64-1.86 (3H, m ), 1.93-2.23 (3H, m), 2.24-2.48 (1H, m), 2.79-2.99 (2H, m), 3.32-4.22 (9H , m), 4.38-4.63 (1H, m), 5.64-5.87 (1H, m), 7.29-7.60 (4H, m), 7.60-7.71 (1H, m) 8

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.66-0.82 (2H, m), 0.99-1.12 (2H, m), 1.20-1.34 (1H, m ), 1.67-1.88 (4H, m), 1.95-2.21 (3H, m), 2.23-2.46 (1H, m), 2.82-3.02 (2H , m), 3.28-3.48 (3H, m), 3.52-3.99 (5H, m), 3.99-4.22 (2H, m), 4.41-4.63 (1H, m), 5.16-5.33 (1H, m), 7.28-7.71 (5H, m)

Table 1-3 Etc. No. Structural formula NMR 9

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.87 (2H, m), 0.98-1.17 (2H, m), 1.31 (3H, s), 1, 32 (3H, s), 1.66-2.25 (6H, m), 2.26-2.47 (1H, m), 2.83-3.02 (2H, m), 3.39- 4.20 (9H, m), 4.43-4.64 (1H, m), 4.67-4.84 (1H, m), 5.00-5.46 (1H, br s), 7.32-7.40 (1H, m), 7.41-7.60 (3H, m), 7.61-7.72 (1H, m) 10

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.82 (2H, m), 1.00-1.11 (2H, m), 1.70-1.83 (1H, m ), 1.83-1.95 (3H, m), 1.99 (3H, br s), 2.04-2.22 (3H, m), 2.27-2.43 (1H, m) ), 2.86-3.01 (2H, m), 3.33-3.43 (4H, m), 3.54-4.18 (6H, m), 4.44-4.63 (1H , m), 5.42-5.53 (1H, m), 6.33-6.41 (1H, m), 7.32-7.71 (5H, m) eleven

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.58-0.74 (2H, m), 0.91-1.05 (2H, m), 1.78-2.34 (7H, m), 2.78-2.99 (5H, m), 3.22-3.94 (6H, m), 4.06-4.21 (2H, m), 4.54-4.72 ( 1H, m), 6.46-6.95 (1H, m), 7.42-7.77 (5H, m), 7.88-8.03 (3H, m) 12

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.86 (2H, m), 1.01-1.16 (2H, m), 1.71-1.86 (1H, m ), 1.89-2.46 (6H, m), 2.91-3.15 (6H, m), 3.40-4.14 (11H, m), 4.47-4.67 (1H m) 7.32-7.73 (5H, m)

Table 1-4 Etc. No. Structural formula NMR 13

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.68-0.86 (2H, m), 1.00-1.15 (2H, m), 1.58-2.49 (15H, m), 2.84-3.03 (2H, m), 3.20-3.39 (2H, m), 3.41-4.25 (7H, m), 4.44-4.65 ( 1H, m), 5.13-5.29 (1H, m), 7.31-7.73 (5H, m) fourteen

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.82 (2H, m), 1.03-1.12 (2H, m), 1.46-1.60 (3H, m ), 1.72-1.97 (5H, m), 2.00-2.44 (4H, m), 2.80-3.07 (4H, m), 3.42-4.10 (10H , m), 4.43-4.61 (1H, m), 7.32-7.71 (5H, m) fifteen

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.83 (2H, m), 1.02-1.14 (2H, m), 1.71-2.45 (9H, m ), 2.81-2.96 (2H, m), 3.42-4.22 (11H, m), 4.45-4.63 (1H, m), 7.32-7.72 (5H , m) 16

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.66-0.85 (2H, m), 0.99-1.17 (2H, m), 1.71-2.45 (10H, m ), 2.79-3.00 (2H, m), 3.27-4.11 (11H, m), 4.39-4.63 (2H, m), 7.32-7.73 (5H , m)

Table 1-5 Etc. No. Structural formula NMR 17

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.75 (2H, m), 0.92-1.06 (2H, m), 1.32-1.47 (1H , m), 1.63-1.98 (6H, m), 2.02-2.39 (2H, m), 2.78-3.00 (4H, m), 3.02-3.16 (2H, m), 3.38-3.54 (4H, m), 3.54-3.78 (3H, m), 3.80-4.55 (8H, m), 4.55-4 72 (1H, m), 7.01-7.20 (1H, br s), 7.41-7.60 (2H, m), 7.65-7.78 (3H, m), 9 99-10.16 (1H, broad s) eighteen

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.86 (2H, m), 1.01-1.15 (2H, m), 1.71-2.45 (11H, m ), 2.83-3.01 (2H, m), 3.33-3.51 (4H, m), 3.57-4.11 (7H, m), 4.45-4.62 (1H , m), 7.31-7.73 (5H, m) 19

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.86 (2H, m), 1.02-1.15 (2H, m), 1.70-2.46 (9H, m ), 2.83-3.01 (2H, m), 3.41-4.12 (11H, m), 4.46-4.65 (1H, m), 7.31-7.73 (5H , m) twenty

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.84 (2H, m), 1.00-1.16 (2H, m), 1.71-2.26 (6H, m ), 2.27-2.45 (1H, m), 2.50-2.59 (1H, m), 2.81-3.00 (2H, m), 3.42-4.12 (9H , m), 4.46-4.68 (2H, m), 7.31-7.72 (5H, m)

Table 1-6 Etc. No. Structural formula NMR 21

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.84 (2H, m), 0.99-1.15 (2H, m), 1.71-2.44 (10H, m ), 2.78-2.99 (2H, m), 3.26-4.12 (11H, m), 4.42-4.62 (2H, m), 7.31-7.72 (5H , m) 22

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.85 (2H, m), 0.99-1.16 (2H, m), 1.68-2.47 (10H, m ), 2.76-2.99 (2H, m), 3.27-4.11 (11H, m), 4.41-4.62 (2H, m), 7.32-7.73 (5H , m) 23

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.81 (2H, m), 1.05-1.15 (2H, m), 1.71-2.45 (7H, m ), 1.94-2.44 (6H, m), 2.85-3.05 (2H, m), 3.35-4.20 (9H, m), 4.45-4.65 (1H , m), 4.65-4.75 (1H, m), 7.30-8.30 (5H, m) 24

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.83 (2H, m), 1.02-1.13 (2H, m), 1.15-1.32 (3H, m ), 1.35-1.46 (1H, m), 1.63-2.45 (9H, m), 2.73-2.98 (4H, m), 3.40-4.12 (11H , m), 4.42-4.63 (1H, m), 7.29-7.74 (5H, m)

Table 1-7 Etc. No. Structural formula NMR 25

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.59-0.74 (2H, m), 0.91-1.06 (2H, m), 1.42-1.63 (2H, m), 1.72-2.46 (10H, m), 2.75-3.03 (4H, m), 3.43-3.96 (9H, m), 4.48-4.72 ( 1H, m), 7.38-7.83 (5H, m), 12.1-12.4 (1H, m) 26

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.66-0.85 (2H, m), 0.97-1.17 (2H, m), 1.68-2.46 (7H, m ), 2.84-3.08 (2H, m), 3.36-4.13 (13H, m), 4.44-4.67 (1H, m), 6.54-6.71 (1H , m), 7.30-7.73 (5H, m) 27

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.84 (2H, m), 1.00-1.15 (2H, m), 1.43-1.59 (1H, m ), 1.61-2.45 (10H, m), 2.78-3.01 (2H, m), 3.32-4.10 (11H, m), 4.18-4.31 (1H , m), 4.45-4.63 (1H, m), 7.31-7.72 (5H, m) 28

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.83 (2H, m), 0.96-1.16 (2H, m), 1.70-2.29 (6H, m ), 2.29-2.39 (1H, m), 2.67-2.69 (1H, m), 2.82-2.97 (2H, m), 3.38-4.18 (13H , m), 4.41-4.65 (1H, m), 7.30-7.74 (5H, m)

Table 1-8 Etc. No. Structural formula NMR 29th

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.59-0.73 (2H, m), 0.94-1.06 (2H, m), 1.79-2.34 (7H, m), 2.74-2.82 (3H, m), 2.89-3.93 (17H, m), 4.55-4.74 (1H, m), 7.42-7.80 ( 5H, m), 10.4-10.6 (1H, m) thirty

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.59-0.75 (2H, m), 0.92-1.06 (2H, m), 1.22-1.35 (6H, m), 1.77-2.46 (7H, m), 2.85-3.11 (5H, m), 3.21-3.96 (13H, m), 4.52-4.74 ( 1H, m), 7.42-7.82 (5H, m), 10.3-10.5 (1H, m) 31

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.85 (2H, m), 1.02-1.16 (2H, m), 1.71-2.47 (10H, m ), 2.87-3.03 (2H, m), 3.20-4.15 (15H, m), 4.45-4.66 (1H, m), 7.31-7.73 (5H , m) 32

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.62-0.84 (2H, m), 0.97-1.15 (2H, m), 1.37-1.55 (1H, m ), 1.55-1.96 (6H, m), 1.99-2.46 (5H, m), 2.77-3.03 (1H, m), 3.15-4.12 (12H , m), 4.38-4.65 (1H, m), 7.30-7.74 (5H, m)

Table 1-9 Etc. No. Structural formula NMR 33

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.85 (2H, m), 1.01-1.14 (2H, m), 1.62-1.99 (7H, m ), 1.99-2.47 (5H, m), 2.74-3.00 (4H, m), 3.41-3.53 (0.6H, m), 3.56-4.11 (8.4H, m), 4.43-4.61 (1H, m), 5.44 (1H, broad s), 5.56 (1H, broad s), 7.32-7.38 (1H, m), 7.39-7.60 (3H, m), 7.62-7.71 (1H, m) 34

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.83 (2H, m), 0.99-1.15 (2H, m), 1.67-1.96 (3H, m ), 1.98-2.24 (3H, m), 2.25-2.44 (1H, m), 2.78-3.00 (2H, m), 3.20-3.39 (1H , m), 3.40-3.53 (0.5H, m), 3.53-4.09 (6.5H, m), 4.10-4.25 (4H, m), 4.40 -4.66 (1H, broad s), 5.59 (1H, broad s), 5.77 (1H, broad s), 7.31-7.39 (1H, m), 7.40-7 60 (3H, m), 7.62-7.71 (1H, m) 35

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.72 (2H, m), 0.94-1.06 (2H, m), 1.39-1.56 (2H , m), 1.78-2.01 (6H, m), 2.05-2.34 (2H, m), 2.72-3.01 (4H, m), 3.24-3.27 (1H, m), 3.43-4.01 (9H, m), 4.53-4.70 (1H, m), 7.43-7.60 (2H, m), 7.66-7 77 (3H, m), 8.33 (3H, broad s) 36

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.55-0.73 (2H, m), 0.89-1.08 (2H, m), 1.69-2.38 (10H , m), 2.77-3.02 (2H, m), 3.12-4.15 (11H, m), 4.52-4.73 (1H, m), 7.41-7.77 (3H, m), 8.18-8.40 (3H, m), 8.42-8.61 (1H, m), 9.36-9.63 (1H, m)

Table 1-10 Etc. No. Structural formula NMR 37

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.73 (2H, m), 0.92-1.04 (2H, m), 1.55-1.70 (2H , m), 1.74-1.98 (7H, m), 2.02-2.36 (2H, m), 2.73-3.02 (4H, m), 3.19-3.33 (2H, m), 3.45-4.32 (8H, m), 4.53-4.72 (1H, m), 6.44-6.62 (1H, m), 7.42-7 79 (5H, m), 8.62 (1H, broad s), 8.72 (1H, broad s) 38

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.74 (2H, m), 0.92-1.06 (2H, m), 1.47-1.68 (2H , m), 1.78-2.56 (8H, m), 2.62-3.03 (4H, m), 2.77 (6H, s), 3.24-3.94 (10H, m ), 4.54-4.70 (1H, m), 7.42-7.62 (2H, m), 7.63-7.79 (3H, m), 10.2-10.4 (1H , m) 39

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.84 (2H, m), 1.02-1.14 (2H, m), 1.31-1.46 (2H, m ), 1.71-2.45 (9H, m), 1.97 (3H, s), 2.81-3.00 (4H, m), 3.42-4.10 (10H, m), 4.44-4.61 (1H, m), 5.29-5.43 (1H, m), 7.33-7.72 (5H, m) 40

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.83 (2H, m), 1.00-1.13 (2H, m), 1.68-2.46 (13H, m ), 2.81-3.00 (2H, m), 3.28-4.10 (10H, m), 4.36-4.63 (2H, m), 5.61-5.72 (1H , m), 7.31-7.70 (5H, m)

Table 1-11 Etc. No. Structural formula NMR 41

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.71 (2H, m), 0.92-1.03 (2H, m), 1.76-2.36 (8H , m), 2.70-2.80 (6H, broad s), 2.81-3.03 (2H, m), 3.24-3.92 (13H, m), 4.52-4 , 71 (1H, m), 7.41-7.77 (5H, m), 10.76-10.91 (1H, broad s) 42

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.74 (2H, m), 0.92-1.05 (2H, m), 1.60-2.00 (9H , m), 2.03-2.38 (2H, m), 2.65-3.93 (15H, m), 4.04-4.24 (2H, m), 4.51-4.73 (1H, m), 6.28-6.65 (1H, m), 7.41-7.81 (5H, m), 9.88 (1H, br s) 43

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.83 (2H, m), 1.02-1.15 (2H, m), 1.22-1.38 (2H, m ), 1.70-2.26 (11H, m), 2.28-2.46 (1H, m), 2.67-2.79 (1H, m), 2.86-3.04 (2H , m), 3.10-3.24 (1H, m), 3.40-4.21 (9H, m), 4.32-4.45 (1H, m), 4.47-4.64 (2H, m), 7.32-7.72 (5H, m) 44

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.85 (2H, m), 1.02-1.18 (2H, m), 1.70-2.57 (11H, m ), 2.91-3.08 (2H, m), 3.38-4.13 (11H, m), 4.74-4.66 (1H, m), 7.32-7.76 (5H , m)

Table 1-12 Etc. No. Structural formula NMR 45

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.85 (2H, m), 0.96-1.17 (2H, m), 1.65-1.95 (3H, m ), 1.96-2.22 (3H, m), 1.99 (3H, s), 2.25-2.48 (1H, m), 2.81-3.02 (2H, m), 3.38-3.5 (0.6H, m), 3.54-4.14 (8.4H, m), 4.19-4.37 (2H, m), 4.43-4.72 (2H, m), 6.24-6.40 (1H, m), 7.32-7.40 (1H, m), 7.41-7.61 (3H, m), 7.62-7 , 70 (1H, m) 46

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.88 (2H, m), 1.02-1.17 (2H, m), 1.71-1.87 (1H, m ), 1.88-2.45 (6H, m), 2.48-2.60 (2H, m), 2.90-3.06 (2H, m), 3.43-4.11 (11H , m), 4.49-4.66 (1H, m), 7.33-7.72 (5H, m) 47

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.81 (2H, m), 1.01-1.12 (2H, m), 1.71-1.82 (1H, m ), 1.83-1.96 (3H, m), 1.99-2.25 (3H, m), 2.26-2.43 (1H, m), 2.93-3.08 (2H , m), 3.41-4.00 (6H, m), 4.00-4.20 (2H, m), 4.49-4.64 (1H, m), 4.85-4.97 (1H, m), 7.30-7.70 (5H, m) 48

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.86 (2H, m), 1.01-1.17 (2H, m), 1.71-2.45 (7H, m ), 2.86-3.06 (2H, m), 3.42-4.12 (11H, m), 4.49-4.67 (1H, m), 7.31-7.73 (5H , m)

Table 1-13 Etc. No. Structural formula NMR 49

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.83 (2H, m), 0.92-1.02 (6H, m), 1.02-1.13 (2H, m ), 1.22-1.33 (2H, m), 1.71-1.98 (4H, m), 1.99-2.45 (4H, m), 2.88-3.08 (2H , m), 3.14-3.28 (1H, br s), 3.38-4.24 (8H, m), 4.47-4.73 (2H, m), 7.32-7 , 72 (5H, m) fifty

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.63-0.81 (2H, m), 0.96-1.13 (2H, m), 1.60-1.81 (3H, m ), 1.90-2.21 (3H, m), 2.26-2.46 (1H, m), 2.72-2.98 (4H, m), 3.38-4.13 (9H , m), 4.37-4.59 (1H, m), 4.94-5.04 (1H, m), 7.16-7.73 (10H, m) 51

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.82 (2H, m), 1.00-1.12 (2H, m), 1.69-1.85 (3H, m ), 1.96-2.22 (3H, m), 2.25-2.45 (1H, m), 2.84-3.01 (2H, m), 3.39-3.50 (2H , m), 3.54-4.27 (7H, m), 4.41-4.61 (1H, m), 4.93-5.04 (1H, m), 5.38-5.55 (1H, m), 7.23-7.73 (10H, m) 52

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.79 (2H, m), 0.89-0.99 (6H, m), 1.02-1.12 (2H, m ), 1.31-1.43 (2H, m), 1.60-1.85 (4H, m), 2.00-2.20 (3H, m), 2.25-2.45 (1H , m), 2.81-3.00 (2H, m), 3.39-4.21 (10H, m), 4.42-4.60 (1H, m), 4.79-4.92 (1H, m), 7.30-7.73 (5H, m)

Table 1-14 Etc. No. Structural formula NMR 53

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.66-0.83 (2H, m), 1.00-1.14 (2H, m), 1.67-1.90 (3H, m ), 1.98-2.27 (3H, m), 2.27-2.24 (1H, m), 2.98-3.14 (2H, m), 3.42-4.11 (5H , m), 4.22-4.40 (2H, m), 4.50-4.66 (1H, m), 6.78-6.88 (1H, m), 6.98-7.13 (3H, m), 7.14-7.21 (1H, m), 7.34-7.61 (4H, m), 7.64-7.73 (1H, m), 9.24-9 , 36 (1H, m) 54

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.85 (2H, m), 0.97-1.16 (2H, m), 1.51-2.46 (15H, m ), 2.84-3.07 (2H, m), 3.42-4.19 (9H, m), 4.47-4.64 (1H, m), 4.65-4.75 (1H , m), 5.14-5.24 (1H, m), 7.31-7.73 (5H, m) 55

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.61-0.85 (2H, m), 0.95-1.18 (2H, m), 1.36-2.25 (7H, m ), 2.25-2.44 (1H, m), 2.76-3.05 (2H, m), 3.38-3.47 (0.5H, m), 3.52-3.91 (3.5H, m), 3.95-4.31 (3H, m), 4.34-4.60 (1H, m), 7.29-7.73 (8H, m), 8.00 -8.13 (2H, m) 56

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.63-0.83 (2H, m), 0.98-1.16 (2H, m), 1.65-1.91 (3H, m ), 1.92-2.23 (3H, m), 2.24-2.50 (1H, m), 2.80-3.05 (2H, m), 3.16-3.34 (3H , m), 3.39-3.51 (0.6H, m), 3.52-4.13 (5.4H, m), 4.19-4.43 (2H, m), 4.44 -4.64 (1H, m), 7.30-7.39 (1H, m), 7.41-7.60 (3H, m), 7.61-7.70 (1H, m)

Table 1-15 Etc. No. Structural formula NMR 57

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.83 (2H, m), 0.98-1.15 (2H, m), 1.65-1.94 (3H, m ), 1.94-2.25 (3H, m), 2.25-2.45 (1H, m), 2.77-3.05 (2H, m), 3.43-4.07 (8H , m), 4.11-4.45 (2H, m), 4.45-4.65 (1H, m), 7.30-7.72 (5H, m) 58

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.67-0.84 (2H, m), 1.03-1.15 (2H, m), 1.69-2.59 (8H, m), 2.86-3.11 (2H, m), 3.38-4.13 (7H, m), 4.19-4.44 (4H, m), 4.48-4.66 ( 1H, m), 7.30-7.74 (5H, m) 59

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.87 (2H, m), 0.99-1.18 (2H, m), 1.72-1.86 (1H, m ), 1.87-1.99 (2H, m), 2.06-2.47 (4H, m), 2.63-3.23 (10H, m), 3.26-3.42 (2H , m), 3.43-4.13 (3H, m), 4.20-4.75 (5H, m), 7.33-7.39 (1H, m), 7.40-7.63 (3H, m), 7.64-7.69 (1H, m), 12.69 (1H, br s) 60

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.72-0.83 (2H, m), 1.07-1.23 (2H, m), 1.35-1.56 (1H, m ), 1.79-2.00 (4H, m), 2.06-2.45 (6H, m), 2.68-3.20 (4H, m), 3.27-3.41 (2H , m), 3.43-4.08 (9H, m), 4.22-4.48 (2H, m), 4.58-4.82 (3H, m), 7.34-7.40 (1H, m), 7.44-7.50 (1H, m), 7.53-7.60 (1H, m), 7.65-7.72 (2H, m), 12.22 (1H , broad.s)

Table 1-16 Etc. No. Structural formula NMR 61

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.88 (2H, m), 1.03-1.21 (2H, m), 1.79-2.01 (3H, m ), 2.01-2.32 (7H, m), 2.33-2.45 (1H, m), 2.81-3.12 (2H, m), 3.11-4.14 (9H , m), 4.15-4.49 (2H, m), 4.54-4.75 (1H, m), 4.92-5.09 (1H, m), 7.33-7.41 (1H, m), 7.44-7.61 (2H, m), 7.63-7.75 (2H, m), 9.45-9.81 (2H, m) 62

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.87 (2H, m), 1.04-1.21 (2H, m), 1.78-2.01 (3H, m ), 2.03-2.49 (7H, m), 2.50-2.68 (1H, m), 2.72-3.14 (7H, m), 3.23-4.07 (7H , m), 4.17-4.44 (2H, m), 4.57-4.75 (1H, m), 4.76-4.89 (0.5H, m), 5.01-5 09 (0.5H, m), 7.33-7.41 (1H, m), 7.43-7.52 (1H, m), 7.52-7.61 (1H, m), 7 , 62-7.73 (2H, m), 12.38-12.70 (1H, m) 63

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.66-0.85 (2H, m), 0.99-1.16 (2H, m), 1.57-2.25 (13H, m ), 2.26-2.46 (1H, m), 2.79-3.11 (2H, m), 3.27-3.54 (2.6H, m), 3.55-4.12 (6.4H, m), 4.14-4.66 (3H, m), 4.85-5.00 (1H, m), 7.31-7.40 (1H, m), 7.41 -7.61 (3H, m), 7.62-7.71 (1H, m) 64

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.87 (4H, m), 0.91-1.18 (4H, m), 1.70-1.86 (2H, m ), 1.88-2.48 (6H, m), 2.65-2.89 (1H, m), 3.13-3.39 (1H, m), 3.41-4.13 (5H , m), 4.27-4.89 (3H, m), 7.31-7.76 (5H, m)

Table 1-17 Etc. No. Structural formula NMR 65

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.87 (2H, m), 1.01-1.16 (2H, m), 1.69-1.86 (1H, m ), 1.90-2.49 (6H, m), 2.85-3.02 (1H, m), 3.07-3.26 (1H, m), 3.40-4.12 (7H , m), 4.16-4.29 (2H, m), 4.54-4.82 (2H, m), 7.31-7.77 (5H, m) 66

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.63-0.83 (2H, m), 0.98-1.10 (2H, m), 1.12-1.23 (2H, m ), 1.38-1.51 (2H, m), 1.66-2.22 (6H, m), 2.27-2.45 (1H, m), 2.73-3.03 (2H , m), 3.37-4.11 (5H, m), 4.15-4.95 (3H, m), 6.94-7.73 (9H, m) 67

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.74 (2H, m), 0.92-1.06 (2H, m), 1.15-1.20 (1H , m), 1.75-2.36 (4H, m), 2.78-2.87 (6H, br s), 3.14-3.36 (1H, m), 3.40-3 92 (9H, m), 4.22-4.56 (3H, m), 4.64-4.86 (1H, m), 7.40-7.62 (2H, m), 7.64 -7.77 (3H, m), 9.61-9.74 (1H, broad s) 68

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.72-0.84 (2H, m), 1.04-1.16 (2H, m), 1.72-1.86 (1H, m ), 1.90-2.28 (8H, m), 2.28-2.45 (1H, m), 2.81-2.96 (1H, m), 3.15-3.29 (1H , m), 3.42-3.51 (0.5H, m), 3.58-4.21 (7.5H, m), 4.58-4.79 (2H, m), 6.58 -6.67 (1H, br s), 7.33-7.42 (1H, m), 7.42-7.62 (3H, m), 7.63-7.72 (1H, m)

Table 1-18 Etc. No. Structural formula NMR 69

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.54-0.67 (2H, m), 0.71-0.86 (2H, m), 0.92-1.02 (2H, m ), 1.04-1.14 (2H, m), 1.28-1.40 (3H, m), 1.72-1.86 (1H, m), 1.89-2.24 (5H , m), 2.27-2.46 (1H, m), 2.86-3.13 (2H, m), 3.41-4.12 (5H, m), 4.51-4.71 (3H, m), 7.32-7.75 (5H, m) 70

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.82 (2H, m), 1.01-1.12 (2H, m), 1.60-1.71 (7H, m ), 1.71-2.45 (10H, m), 2.93-3.12 (1H, m), 3.37-4.10 (6H, m), 4.47-4.70 (2H , m), 6.70-6.79 (1H, broad s), 7.28-7.71 (5H, m) 71

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.84 (2H, m), 1.02-1.13 (2H, m), 1.29-1.41 (4H, m ), 1.71-1.84 (1H, m), 1.89-2.45 (7H, m), 2.76-2.96 (2H, m), 3.16-3.34 (2H , m), 3.39-4.15 (5H, m), 4.56-4.79 (2H, m), 4.85-4.99 (1H, m), 6.55-6.67 (1H, m), 7.31-7.70 (5H, m) 72

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.83 (2H, m), 0.84-1.03 (6H, m), 1.03-1.14 (2H, m ), 1.22-1.34 (2H, m), 1.71-2.44 (9H, m), 2.76-2.92 (1H, m), 3.17-4.79 (9H , m), 4.84-4.95 (1H, m), 6.19-6.30 (1H, m), 7.31-7.71 (5H, m)

Table 1-19 Etc. No. Structural formula NMR 73

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.66-0.86 (2H, m), 0.99-1.18 (2H, m), 1.69-1.85 (1H, m ), 1.89-2.45 (6H, m), 2.78-2.94 (1H, m), 3.19-3.39 (3H, m), 3.41-3.50 (0 , 6H, m), 3.56-4.10 (5.4H, m), 4.56-4.83 (2H, m), 7.32-7.40 (1H, m), 7.41 -7.61 (3H, m), 7.62-7.71 (1H, m) 74

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.85 (2H, m), 1.03-1.15 (2H, m), 1.69-1.86 (1H, m ), 1.91-2.61 (9H, m), 2.76-2.95 (1H, m), 3.18-4.11 (8H, m), 4.44-4.83 (3H , m), 5.76-5.93 (1H, m), 7.32-7.75 (5H, m) 75

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.82 (2H, m), 1.02-1.13 (2H, m), 1.69-1.84 (1H, m ), 1.85-2.01 (6H, m), 2.02-2.23 (2H, m), 2.26-2.46 (1H, m), 2.47-2.60 (2H , m), 2.71-2.84 (1H, m), 3.11-3.26 (1H, m), 3.41-4.10 (8H, m), 4.54-4.68 (1H, m), 4.69-4.82 (1H, m), 6.32-6.40 (1H, br s), 7.31-7.70 (5H, m) 76

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.87 (2H, m), 1.02-1.18 (2H, m), 1.31 (3H, s), 1, 33 (3H, s), 1.72-1.88 (1H, m), 1.90-2.48 (6H, m), 2.88-3.10 (2H, m), 3.42- 4.15 (8H, m), 4.47-4.75 (3H, m), 7.32-7.74 (5H, m)

Table 1-20 Etc. No. Structural formula NMR 77

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.74 (2H, m), 0.93-1.05 (2H, m), 1.21-1.32 (1H , m), 1.72-2.34 (5H, m), 2.79-2.98 (1H, m), 3.13-3.34 (1H, m), 3.39-4.36 (9H, m), 4.38-4.55 (1H, m), 4.63-4.84 (1H, m), 7.40-7.60 (2H, m), 7.63-7 74 (3H, m), 8.80-8.18 (3H, broad s) 78

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.89 (4H, m), 0.97-1.16 (4H, m), 1.71-1.86 (1H, m ), 1.88-2.24 (6H, m), 2.27-2.46 (1H, m), 2.90-3.11 (2H, m), 3.41-4.11 (7H , m), 4.54-4.74 (3H, m), 7.33-7.74 (5H, m) 79

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.74 (2H, m), 0.94-1.03 (2H, m), 1.50-1.65 (7H , m), 1.74-2.38 (5H, m), 2.99-3.28 (2H, m), 3.37-3.90 (5H, m), 3.94-4.65 (3H, m), 4.67-4.89 (1H, m), 7.40-7.78 (5H, m), 8.12-8.32 (3H, br.s) 80

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.83 (2H, m), 1.02-1.14 (2H, m), 1.70-1.85 (1H, m ), 1.85-2.46 (8H, m), 2.49-2.60 (2H, m), 2.69-2.85 (2H, m), 3.13-3.29 (1H , m), 3.41-3.50 (0.5H, m), 3.55-4.14 (7.5H, m), 4.53-4.70 (1H, m), 4.71 -4.85 (1H, m), 7.31-7.40 (1H, m), 7.40-7.61 (3H, m), 7.62-7.73 (1H, m)

Table 1-21 Etc. No. Structural formula NMR 81

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.74 (2H, m), 0.93-1.10 (2H, m), 1.70-2.48 (12H , m), 2.83-3.03 (1H, m), 3.11-4.08 (9H, m), 4.41-4.85 (2H, m), 7.42-7.53 (2H, m), 7.65-7.78 (3H, m), 9.91-10.05 (1H, broad s), 10.12-10.24 (1H, broad s) 82

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.75 (2H, m), 0.92-1.03 (2H, m), 1.74-2.17 (11H , m), 2.18-2.35 (1H, m), 2.73-2.87 (3H, m), 2.88-3.90 (10H, m), 4.43-4.56 (1H, m), 4.60-4.85 (1H, m), 7.41-7.76 (5H, m), 9.53-9.70 (1H, broad s) 83

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.72 (2H, m), 0.93-1.04 (2H, m), 1.69-2.02 (5H , m), 2.03-2.16 (1H, m), 2.17-2.34 (1H, m), 2.64-2.87 (3H, m), 2.91-3.07 (2H, m), 3.16-3.32 (1H, m), 3.42-3.78 (6H, m), 3.80-3.99 (1H, m), 4.44-4 58 (1H, m), 7.42-7.94 (8H, m) 84

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.73 (2H, m), 0.87-1.10 (8H, m), 1.73-2.17 (8H , m), 2.18-2.34 (1H, m), 2.81-2.98 (1H, m), 3.21-3.37 (1H, m), 3.40-3.92 (4H, m), 4.04-4.19 (1H, m), 4.23-4.41 (1H, m), 4.46-4.61 (1H, m), 4.66-4 85 (1H, m), 7.43-7.61 (2H, m), 7.64-7.77 (3H, m), 8.07-8.24 (3H, m)

Table 1-22 Etc. No. Structural formula NMR 85

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.74 (2H, m), 0.92-1.06 (2H, m), 1.72-2.35 (8H , m), 2.53-2.62 (3H, m), 2.80-2.98 (1H, m), 3.18-3.34 (1H, m), 3.42-3.90 (5H, m), 3.98-4.23 (2H, m), 4.40-4.54 (1H, m), 4.66-4.82 (1H, m), 7.42-7 78 (5H, m), 8.77-9.02 (2H, m) 86

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.72 (2H, m), 0.93-1.02 (2H, m), 1.67-1.84 (6H , m), 1.85-2.00 (4H, m), 2.03-2.17 (1H, m), 2.18-2.33 (1H, m), 2.65-2.81 (1H, m), 2.84-3.08 (3H, m), 3.16-3.32 (4H, m), 3.52-3.90 (3H, m), 4.05-4 , 19 (1H, m), 4.44-4.57 (1H, m), 4.63-4.79 (1H, m), 7.40-7.75 (5H, m), 8.62 -8.78 (1H, m), 9.04-9.16 (1H, m) 87

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.84 (2H, m), 1.03-1.12 (2H, m), 1.14-1.22 (7H, m ), 1.66-2.24 (6H, m), 2.27-2.54 (2H, m), 2.79-2.96 (1H, m), 3.13-3.27 (1H , m), 3.39-3.50 (1H, m), 3.55-4.18 (6H, m), 4.53-4.79 (2H, m), 6.58-6.61 (1H, m), 7.31-7.71 (5H, m) 88

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.83 (4H, m), 0.92-1.01 (2H, m), 1.01-1.13 (2H, m ), 1.45-1.54 (1H, m), 1.68-2.44 (8H, m), 2.80-2.95 (1H, m), 3.12-3.29 (1H , m), 3.41-3.50 (1H, m), 3.57-4.22 (6H, m), 4.56-4.79 (2H, m), 6.68-6.76 (1H, m), 7.31-7.70 (5H, m)

Table 1-23 Etc. No. Structural formula NMR 89

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.82 (2H, m), 1.03-1.14 (2H, m), 1.70-1.84 (1H, m ), 1.85-2.25 (12H, m), 2.25-2.42 (1H, m), 2.75-2.95 (1H, m), 3.18-4.21 (9H , m), 4.54-4.78 (2H, m), 4.87-4.97 (1H, m), 7.32-7.71 (5H, m) 90

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.85 (2H, m), 1.02-1.16 (2H, m), 1.70-1.86 (1H, m ), 1.89-2.45 (6H, m), 2.83-2.96 (1H, m), 2.96-3.03 (3H, m), 3.16-3.31 (1H , m), 3.41-3.50 (0.6H, m), 3.56-4.12 (7.4H, m), 4.57-4.77 (2H, m), 5.35 -5.44 (1H, m), 7.32-7.40 (1H, m), 7.41-7.61 (3H, m), 7.62-7.71 (1H, m) 91

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.81 (2H, m), 1.04-1.12 (2H, m), 1.62-2.44 (11H, m ), 2.09 (3H, br s), 2.66-2.82 (3H, m), 3.05-3.17 (1H, m), 3.18-3.31 (1H, m ), 3.39-3.50 (1H, m), 3.55-3.99 (5H, m), 4.00-4.15 (1H, m), 4.51-4.70 (2H , m), 4.71-4.84 (1H, m), 7.31-7.70 (5H, m) 92

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.72 (2H, m), 0.93-1.05 (2H, m), 1.67-2.02 (11H , m), 2.04-2.16 (1H, m), 2.18-2.34 (1H, m), 2.66-2.75 (3H, broad s), 2.86-3 01 (2H, m), 3.09-3.32 (1H, m), 3.36-3.91 (6H, m), 3.99-4.16 (1H, m), 4.44 -4.58 (2H, m), 4.63-4.80 (1H, m), 7.43-7.76 (5H, m), 10.21-10.33 (1H, m)

Table 1-24 Etc. No. Structural formula NMR 93

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.84 (2H, m), 1.03-1.12 (2H, m), 1.14-1.22 (7H, m ), 1.66-2.24 (6H, m), 2.27-2.54 (2H, m), 2.79-2.96 (1H, m), 3.13-3.27 (1H , m), 3.39-3.50 (1H, m), 3.55-4.18 (6H, m), 4.53-4.79 (2H, m), 6.58-6.61 (1H, m), 7.31-7.71 (5H, m) 94

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.57-0.73 (2H, m), 0.90-1.05 (2H, m), 1.82-2.53 (8H , m), 3.23-3.79 (6H, m), 3.81-4.24 (4H, m), 4.63-4.97 (1H, m), 7.39-7.77 (6H, m), 7.98-8.17 (1H, m), 9.99-10.27 (1H, m) 95

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.75 (2H, m), 0.91-1.07 (2H, m), 1.82-2.46 (8H , m), 2.64-2.76 (3H, m), 3.21-3.99 (10H, m), 4.61-4.82 (1H, m), 7.41-7.79 (5H, m), 8.48-8.69 (1H, m), 9.99-10.24 (1H, m) 96

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.61-0.82 (2H, m), 1.02-1.18 (2H, m), 1.69 (6H, s), 1, 70-1.84 (1H, m), 2.05-2.23 (3H, m), 2.29-2.46 (1H, m), 3.03-4.07 (11H, m), 5.02 (1H, broad s), 5.74 (1H, broad s), 7.34-7.41 (1H, m), 7.44-7.50 (1H, m), 7, 51-7.60 (2H, m), 7.65-7.70 (1H, m), 9.13 (1H, broad s), 11.80 (1H, broad s)

Table 1-25 Etc. No. Structural formula NMR 97

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.58-0.77 (2H, m), 0.90-1.06 (2H, m), 1.83-1.98 (1H , m), 2.04-2.74 (6H, m), 3.07-3.96 (13H, m), 4.64-4.97 (1H, m), 7.20-7.85 (7H, m), 10.09-10.49 (1H, m) 98

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.30-0.49 (2H, m), 0.56-0.76 (4H, m), 0.88-1.05 (2H , m), 1.07-1.22 (1H, m), 1.81-1.98 (1H, m), 1.99-2.38 (6H, m), 2.88-3.04 (2H, m), 3.09-3.26 (2H, m), 3.41-3.95 (7H, m), 4.58-4.86 (1H, m), 7.34-7 85 (5H, m), 10.17-10.53 (1H, m) 99

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.74 (2H, m), 0.75-0.85 (2H, m), 0.93-1.04 (2H , m), 1.12-1.23 (2H, m), 1.86-2.54 (7H, m), 2.71-2.82 (1H, m), 3.28-3.92 (9H, m), 4.66-4.83 (1H, m), 7.42-7.77 (5H, m), 10.60-10.79 (1H, m) one hundred

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.57-0.75 (2H, m), 0.91-1.05 (2H, m), 1.82-2.53 (7H , m), 2.85-3.01 (6H, m), 3.18-4.44 (11H, m), 4.62-4.83 (1H, m), 7.41-7.78 (5H, m), 9.66-9.97 (1H, broad)

Table 1-26 Etc. No. Structural formula NMR 101

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.75 (2H, m), 0.91-1.06 (2H, m), 1.84-2.00 (1H , m), 2.03-2.45 (6H, m), 3.15-3.95 (9H, m), 4.06-4.23 (2H, m), 4.63-4.83 (1H, m), 7.41-7.80 (5H, m) 102

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.75 (2H, m), 0.91-1.06 (2H, m), 1.46-1.62 (4H , m), 1.84-2.60 (7H, m), 3.23-3.94 (7H, m), 4.16-4.32 (1H, m), 4.51-5.06 (2H, m), 7.40-7.79 (6H, m), 10.11-10.42 (1H, br s) 103

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.60-0.73 (2H, m), 0.92-1.04 (2H, m), 1.43-1.54 (3H , m), 2.00-2.58 (8H, m), 3.14-4.17 (9H, m), 4.68-4.85 (1H, m), 7.42-7.79 (6H, m), 8.08-8.20 (1H, m), 10.09 (1H, br s) 104

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.61-0.75 (2H, m), 0.94-1.06 (2H, m), 1.22-1.38 (6H , m), 1.82-2.62 (7H, m), 3.13-3.96 (11H, m), 4.69-4.95 (1H, m), 7.38-7.82 (6H, m), 9.23-9.88 (1H, m)

Table 1-27 Etc. No. Structural formula NMR 105

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.59-0.75 (2H, m), 0.93-1.06 (2H, m), 1.22-1.38 (6H , m), 1.83-1.98 (1H, m), 1.99-2.62 (6H, m), 3.14-3.94 (11H, m), 4.69-4.93 (1H, m), 7.27-7.80 (7H, m), 9.05-9.52 (1H, m) 106

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.56-0.77 (2H, m), 0.91-1.07 (2H, m), 1.15-1.39 (4H , m), 1.82-2.62 (7H, m), 3.13-4.03 (11H, m), 4.63-4.97 (1H, m), 7.06-7.32 (2H, m), 7.40-7.81 (5H, m), 9.76-10.08 (1H, m) 107

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.61-0.74 (2H, m), 0.93-1.04 (2H, m), 1.13-1.21 (2H , m), 1.25-1.34 (2H, m), 1.85-1.98 (1H, m), 2.01-2.54 (6H, m), 3.08-3.92 (16H, m), 4.64-4.84 (1H, m), 7.43-7.78 (6H, m), 9.57-9.92 (1H, m) 108

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.82 (2H, m), 1.01-1.14 (2H, m), 1.66-1.83 (1H, m ), 1.94-2.44 (6H, m), 3.18-3.49 (2H, m), 3.54-4.20 (7H, m), 4.53-4.70 (1H , m), 7.28-7.72 (5H, m)

Table 1-28 Etc. No. Structural formula NMR 109

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.83 (2H, m), 0.99-1.11 (2H, m), 1.68-1.83 (1H, m ), 1.91-2.45 (6H, m), 3.04-3.20 (2H, m), 3.38-4.11 (9H, m), 4.47-4.66 (1H m) 7.72-8.35 (5H, m) 110

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.88 (2H, m), 0.98-1.21 (2H, m), 1.66-1.88 (1H, m ), 1.89-2.54 (9H, m), 2.94-3.17 (1H, m), 3.26-3.53 (1.5H, m), 3.54-4.21 (5.5H, m), 4.58-4.93 (2H, m), 7.29-7.75 (5H, m) 111

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.62-0.83 (2H, m), 0.97-1.17 (2H, m), 1.63-1.95 (3H, m ), 1.96-2.24 (3H, m), 2.25-2.47 (1H, m), 2.97-3.19 (5H, m), 3.40-3.49 (0 , 5H, m), 3.55-4.26 (6.5H, m), 4.46-4.69 (1H, m), 5.54-5.76 (1H, m), 7.30 -7.60 (4H, m), 7.61-7.73 (1H, m) 112

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.60-0.81 (2H, m), 0.98-1.16 (2H, m), 1.62-1.82 (3H, m ), 1.93-2.25 (3H, m), 2.26-2.47 (1H, m), 2.90-3.08 (2H, m), 3.35-3.50 (0 , 5H, m), 3.53-4.09 (4.5H, m), 4.17-4.34 (2H, m), 4.45-4.65 (1H, m), 5.94 -6.14 (2H, m), 7.29-7.61 (4H, m), 7.62-7.74 (1H, m)

Table 1-29 Etc. No. Structural formula NMR 113

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.87 (2H, m), 1.03-1.18 (2H, m), 1.71-2.47 (7H, m ), 3.00-3.18 (2H, m), 3.42-4.17 (7H, m), 4.56-4.75 (1H, m), 6.85-6.97 (2H , m), 7.32-7.71 (5H, m), 7.92-8.00 (2H, m) 114

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.87 (2H, m), 1.02-1.19 (2H, m), 1.74-2.50 (7H, m ), 2.81-3.19 (2H, m), 3.44-4.14 (7H, m), 4.48-4.80 (1H, m), 7.07-7.85 (9H , m) 115

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.59-0.77 (2H, m), 0.92-1.08 (2H, m), 1.87-2.36 (7H, m), 3.08-3.94 (9H, m), 4.60-4.81 (1H, m), 6.16-6.29 (1H, m), 7.38-7.80 ( 6H, m), 12.25 (1H, broad singlet) 116

¹ H-NMR (300 MHz, DMSO-D6) δ: 0.62-0.73 (2H, m), 0.96-1.04 (2H, m), 1.87-2.33 (7H, m), 3.18-3.32 (3H, m), 3.44-3.91 (4H, m), 3.97-4.10 (2H, m), 4.66-4.80 ( 1H, m), 7.41-7.60 (2H, m), 7.63-7.78 (4H, m), 12.6 (1H, broad s)

Table 1-30 Etc. No. Structural formula NMR 117

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.59-0.77 (2H, m), 0.93-1.08 (2H, m), 1.88-2.39 (10H, m), 3.21-4.12 (11H, m), 4.64-4.84 (1H, m), 7.41-7.80 (5H, m) 118

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.60-0.75 (2H, m), 0.89-1.09 (6H, m), 1.86-2.36 (8H, m), 3.11-4.11 (11H, m), 4.61-4.82 (1H, m), 7.41-7.80 (5H, m) 119

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.60-0.76 (2H, m), 0.92-1.06 (2H, m), 1.88-2.38 (8H, m), 3.15-4.15 (10H, m), 4.42-4.53 (2H, m), 4.63-4.82 (1H, m), 7.39-7.79 ( 6H, m) 120

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.58-0.77 (2H, m), 0.92-1.06 (2H, m), 1.85-2.41 (7H, m), 3.11-4.10 (9H, m), 4.31-5.07 (2H, m), 7.41-7.79 (5H, m), 13.3-13.5 ( 1H, m)

Table 1-31 Etc. No. Structural formula NMR 121

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.72-0.87 (2H, m), 1.05-1.15 (2H, m), 1.49-2.48 (7H, m ), 3.05-3.22 (2H, m), 3.40-4.14 (5H, m), 4.20-4.36 (2H, m), 4.52-4.73 (1H , m), 6.60-6.71 (1H, m), 6.94-7.16 (3H, m), 7.33-7.72 (5H, m), 8.04-8.14 1H, m) 122

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.57-0.66 (2H, m), 0.66-0.84 (4H, m), 1.01-1.13 (2H, m ), 1.32-1.45 (3H, m), 1.55-2.48 (7H, m), 2.81-3.00 (2H, m), 3.41-4.15 (5H , m), 4.44-4.63 (2H, m), 4.85-4.96 (1H, m), 7.33-7.71 (6H, m) 123

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.82 (2H, m), 1.02-1.13 (2H, m), 1.13-1.22 (6H, m ), 1.55-2.47 (8H, m), 2.84-3.01 (2H, m), 3.41-4.34 (9H, m), 4.45-4.63 (1H m) 7.30-7.71 (6H, m) 124

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.72-0.87 (2H, m), 1.04-1.17 (2H, m), 1.53-2.46 (7H, m ), 3.05-3.21 (2H, m), 3.42-4.11 (5H, m), 4.20-4.35 (2H, m), 4.55-4.71 (1H , m), 6.62-6.70 (1H, m), 6.93-7.16 (3H, m), 7.33-7.72 (5H, m), 8.04-8.14 (1H, m)

Table 1-32 Etc. No. Structural formula NMR 125

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.84 (2H, m), 1.03-1.13 (2H, m), 1.13-1.21 (6H, m ), 1.55-2.47 (8H, m), 2.84-3.01 (2H, m), 3.41-4.31 (9H, m), 4.45-4.63 (1H m) 7.33-7.72 (6H, m) 126

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.58-0.66 (2H, m), 0.66-0.83 (4H, m), 1.02-1.11 (2H, m ), 1.36-1.43 (3H, m), 1.53-2.46 (7H, m), 2.83-2.99 (2H, m), 3.41-4.15 (5H , m), 4.45-4.61 (2H, m), 4.85-4.92 (1H, m), 7.32-7.72 (6H, m) 127

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.56-0.86 (4H, m), 1.32-1.43 (3H, m), 1.85-2.12 (6H, m), 2.28-2.39 (1H, m), 3.09-3.26 (2H, m), 3.31-4.94 (6H, m), 4.74-4.91 ( 3H, m), 6.30 (1H, broad singlet), 6.69-6.75 (1H, m), 7.07-7.37 (4H, m), 7.53-7.62 (1H , m), 8.40-8.50 (2H, m) 128

¹ H-NMR (400 MHz, DMSO-D6) δ: 0.56-0.88 (4H, m), 1.32-1.48 (3H, m), 1.85-2.12 (6H, m), 2.28-2.39 (1H, m), 3.09-3.24 (2H, m), 3.30-4.95 (6H, m), 4.73-4.93 ( 3H, m), 5.81 (1H, broad singlet), 6.64-6.73 (1H, m), 7.06-7.40 (4H, m), 7.50-7.67 (1H m) 8.39-8.49 (2H, m)

Table 1-33 Etc. No. Structural formula NMR 129

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 0.66-0.69 (2H, m), 0.99-1.01 (2H, m), 1.91-2.33 (7H , m), 3.11-3.14 (2H, m), 3.46-3.89 (5H, m), 4.49-4.52 (2H, m), 4.75-4.77 (1H, m), 7.48-7.74 (6H, m), 7.85-7.90 (1H, m), 8.17 (1H, br s), 8.43-8.45 (1H, m) 130

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.79 (2H, m), 0.94-1.10 (2H, m), 1.63-2.44 (12H, m ), 3.38-4.10 (5H, m), 4.32-4.51 (1H, m), 5.33 (1H, broad), 5.51 (1H, broad), 7, 27-7.70 (5H, m) 131

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.62-0.82 (2H, m), 0.95-1.10 (2H, m), 1.23-1.39 (2H, m ), 1.65-2.45 (8H, m), 3.40-4.10 (6H, m), 4.26-4.60 (4H, m), 7.27-7.71 (6H , m) 132

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.79 (2H, m), 0.84-0.92 (2H, m), 1.06-1.15 (2H, m ), 1.22-1.35 (3H, m), 1.73-2.49 (8H, m), 3.05-3.19 (1H, m), 3.39-3.55 (1H , m), 3.61-4.17 (3H, m), 4.46-4.61 (1H, m), 7.33-7.71 (5H, m)

Table 1-34 Etc. No. Structural formula NMR 133

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.95 (4H, m), 1.38-1.47 (3H, m), 1.61-1.88 (2H, m ), 1.99-2.29 (3H, m), 2.34-2.50 (1H, m), 2.94-3.12 (2H, m), 3.36-4.18 (5H , m), 4.25-4.40 (2H, m), 4.54-4.72 (1H, m), 6.99-7.33 (2H, m), 7.44-7.65 (6H, m), 8.44-8.61 (2H, m) 134 ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.89-1.05 (2H, m), 1.22-1.34 (2H, m), 1.94-2.44 (6H, m ), 3.05-3.21 (2H, m), 3.28-3.39 (3H, m), 3.42-4.11 (5H, m), 4.20-4.35 (2H , m), 4.77-4.93 (1H, m), 6.62-6.71 (1H, m), 6.93-7.18 (3H, m), 7.32-7.72 (5H, m), 8.05-8.14 (1H, m) 135

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.57-0.95 (4H, m), 1.34-1.54 (3H, m), 1.83-2.08 (2H, m ), 2.18-2.41 (2H, m), 2.45-2.61 (1H, m), 2.73-2.92 (1H, m), 3.02-3.24 (2H , m), 3.51-4.86 (7H, m), 6.60-6.78 (1H, m), 6.93-7.18 (3H, m), 7.20-7.46 (5H, m), 7.46-7.57 (1H, m), 8.01-8.15 (1H, m) 136

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.81 (2H, m), 1.00-1.14 (2H, m), 1.71-1.85 (1H, m ), 1.93-2.43 (6H, m), 3.05-3.19 (2H, m), 3.40-4.10 (5H, m), 4.20-4.33 (2H , m), 4.55-4.69 (1H, m), 6.48-6.57 (1H, m), 6.81-6.92 (2H, m), 7.17-7.45 (4H, m), 7.50-7.60 (1H, m), 7.94-8.03 (1H, m) 137

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.83 (2H, m), 1.01-1.14 (2H, m), 1.75-1.86 (1H, m ), 1.94-2.36 (6H, m), 2.37-2.49 (1H, m), 3.07-3.20 (2H, m), 3.40-4.14 (4H , m), 4.22-4.34 (2H, m), 4.57-4.71 (1H, m), 6.61-6.70 (1H, m), 6.93-7.03 (1H, m), 7.03-7.17 (3H, m), 7.51-7.70 (2H, m), 8.02-8.15 (1H, m), 8.28-8 , 37 (1H, broad s)

Table 1-35 Etc. No. Structural formula NMR 138

¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, s), 1.33 (6H, s), 2.03-2.11 (4H, m), 2.36-2.39 (2H , m), 3.07-3.09 (2H, m), 3.37-3.76 (4H, m), 3.89-3.96 (1H, m), 4.28-4.32 (4H, m), 6.65 (1H, s), 7.01-7.08 (3H, m), 7.24-7.32 (1H, m), 7.53-7.63 (2H , m), 8.07-8.09 (1H, m), 8.53-8.57 (2H, m) 139

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.25-1.48 (3H, m), 1.69-2.48 (13H, m), 2.85-3.19 (3H, m ), 3.33-4.41 (8H, m), 6.59-6.69 (1H, m), 6.89-7.14 (3H, m), 7.23-7.36 (1H , m), 7.43-7.68 (2H, m), 8.05 (1H, t, J = 8.1 Hz), 8.44-8.59 (2H, m) 140

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.83 (2H, m), 1.01-1.15 (2H, m), 1.72-1.86 (1H, m ), 1.92-2.43 (6H, m), 3.03-3.20 (2H, m), 3.36-4.11 (5H, m), 4.20-4.34 (2H , m), 4.55-4.71 (1H, m), 6.66 (1H, broad s), 6.93-7.16 (3H, m), 7.20-7.42 (4H , m), 7.48-7.63 (1H, m), 8.03-8.14 (1H, m) 141

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.66-0.80 (2H, m), 1.00-1.12 (2H, m), 1.58-1.82 (3H, m ), 1.97-2.23 (3H, m), 2.27-2.47 (1H, m), 2.90-3.06 (2H, m), 3.40-4.11 (5H , m), 4.24-4.41 (2H, m), 4.46-4.62 (1H, m), 7.32-7.73 (10H, m) 142

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.57-0.74 (2H, m), 0.81-1.03 (8H, m), 1.79-2.36 (8H , m), 2.82-2.90 (8H, m), 3.44-3.92 (9H, m), 4.50-4.70 (1H, s), 7.42-7.53 (2H, m), 7.55-7.61 (1H, m), 7.66-7.78 (2H, m)

Table 1-36 Etc. No. Structural formula NMR 143

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.62-0.84 (2H, m), 0.91-1.17 (2H, m), 1.67-1.88 (1H, m ), 1.91-2.08 (2H, m), 2.14-2.42 (2.5H, m), 2.43-2.56 (0.5H, m), 2.57-2 72 (1H, m), 2.88-3.21 (5H, m), 3.45-3.61 (0.6H, m), 3.64-3.91 (2H, m), 3 98-4.13 (1H, m), 4.19-4.36 (2.4H, m), 4.53-4.72 (1H, m), 6.63-6.79 (1H, m), 6.89-7.18 (3H, m), 7.40-7.64 (4H, m), 7.75-7.93 (1H, m), 8.00-8.13 ( 1H, m) 144

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.97 (2H, m), 0.97-1.35 (2H, m), 1.85-2.54 (6H, m ), 2.87-3.21 (2H, m), 3.21-4.14 (7H, m), 4.16-4.46 (2H, m), 4.51-4.79 (1H , m), 5.98-6.35 (1H, m), 6.56-6.78 (1H, m), 6.85-7.20 (3H, m), 7.20-7.79 (5H, m), 7.95-8.16 (1H, m) 145

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.84 (2H, m), 1.01-1.16 (2H, m), 1.68-1.85 (1H, m ), 1.88-2.46 (6H, m), 3.02-3.19 (2H, m), 3.40-4.11 (5H, m), 4.24-4.41 (2H , m), 4.53-4.71 (1H, m), 6.82-6.91 (1H, m), 7.30-7.72 (7H, m) 146

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.99 (4H, m), 1.15-1.31 (6H, m), 1.35-1.52 (3H, m ), 1.73-1.98 (2H, m), 1.98-2.47 (4H, m), 2.86-3.08 (2H, m), 3.42-4.11 (6H , m), 4.12-4.31 (2H, m), 4.53-4.72 (1H, m), 7.08-7.21 (1H, m), 7.30-7.40 (1H, m), 7.41-7.61 (3H, m), 7.61-7.74 (1H, m) 147

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.64-0.81 (2H, m), 0.96-1.13 (2H, m), 1.55-1.93 (3H, m ), 1.95-2.44 (4H, m), 2.84-3.02 (2H, m), 3.36-4.22 (7H, m), 4.30-4.41 (2H , m), 4.43-4.62 (1H, m), 4.83-4.99 (1H, m), 6.91-7.05 (2H, m), 7.17-7.71 (7H, m)

Table 1-37 Etc. No. Structural formula NMR 148

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.73-0.84 (2H, m), 0.85-0.96 (2H, m), 1.45 (3H, s), 1, 84-1.97 (2H, m), 2.01-2.20 (1H, m), 2.26-2.49 (3H, m), 2.97-3.12 (4H, m), 3.37-4.19 (9H, m), 4.61-4.75 (1H, m), 6.86-6.95 (1H, m), 7.08-7.22 (3H, m ), 7.25-7.33 (1H, m), 7.48-7.65 (2H, m), 8.46-8.63 (2H, m) 149

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.82 (2H, m), 0.82-0.96 (2H, m), 1.42 (3H, s), 1, 79-1.97 (2H, m), 1.98-2.19 (4H, m), 2.93-3.08 (2H, m), 3.33-3.82 (5.5H, m ), 3.84-4.01 (1H, m), 4.04-4.23 (2.5H, m), 4.26-4.40 (2H, m), 4.55-4.73 (1H, m), 6.81-6.97 (3H, m), 7.11-7.22 (1H, m), 7.23-7.35 (1H, m), 7.46-7 67 (2H, m), 8.44-8.62 (2H, m) 150

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.85 (2H, m), 1.02-1.18 (2H, m), 1.72-1.87 (1H, m ), 1.94-2.46 (6H, m), 3.08-3.26 (2H, m), 3.41-4.11 (5H, m), 4.18-4.33 (2H , m), 4.57-4.75 (1H, m), 6.97-7.07 (1H, m), 7.23-7.61 (5H, m), 7.64-7.72 (1H, m), 8.53-8.60 (1H, m) 151

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.61-0.89 (4H, m), 1.36 (3H, s), 1.55-1.83 (6H, m), 1, 89-2.17 (3H, m), 2.32-2.47 (1H, m), 2.59-2.82 (4H, m), 3.33-4.18 (9H, m), 4.38-4.52 (1H, m), 7.03-7.14 (2H, m), 7.16-7.32 (3H, m), 7.43-7.64 (2H, m) ), 8.44-8.61 (2H, m) 152

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.85 (2H, m), 1.03-1.16 (2H, m), 1.33-1.42 (3H, m ), 1.73-1.88 (1H, m), 1.93-2.22 (3H, m), 2.25-2.45 (3H, m), 2.96-3.13 (2H , m), 3.41-4.11 (7H, m), 4.28-4.39 (2H, m), 4.52-4.71 (1H, m), 6.85-6.96 (2H, m), 7.32-7.40 (1H, m), 7.41-7.61 (3H, m), 7.63-7.71 (1H, m), 7.89-7 99 (2H, m)

Table 1-38 Etc. No. Structural formula NMR 153

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.79 (2H, m), 1.00-1.09 (2H, m), 1.70-1.97 (3H, m ), 2.00-2.26 (3H, m), 2.31-2.47 (1H, m), 2.86-3.05 (2H, m), 3.35-3.53 (1 , 5H, m), 3.56-3.77 (2H, m), 3.84-3.94 (1H, m), 4.08-4.16 (0.5H, m), 4.25 -4.61 (3H, m), 5.14 (2H, s), 7.23-7.40 (6H, m), 7.49-7.61 (2H, m), 8.47-8 , 57 (2H, m) 154

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.61-0.86 (2H, m), 0.98-1.18 (2H, m), 1.23-1.41 (6H, m ), 1.67-1.86 (1H, m), 1.87-2.47 (6H, m), 2.52-2.88 (3H, m), 3.06-3.32 (1H , m), 3.35-4.15 (6H, m), 4.49-4.85 (2H, m), 7.28-7.73 (5H, m) 155

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.62-0.83 (2H, m), 0.97-1.14 (2H, m), 1.66-2.50 (8H, m ), 2.78-2.95 (1H, m), 3.16-3.34 (1H, m), 3.37-3.54 (1H, m), 3.57-3.79 (2H , m), 3.83-3.97 (1H, m), 4.09-4.29 (1H, m), 4.54-4.80 (4H, m), 6.89-7.04 (3H, m), 7.21-7.38 (3H, m), 7.48-7.68 (2H, m), 8.42-8.70 (2H, m) 156

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.82 (2H, m), 1.00-1.13 (2H, m), 1.67-2.30 (9H, m ), 2.32-2.51 (1H, m), 2.72-3.34 (2H, m), 3.36-4.03 (4H, m), 4.56-4.99 (1H , m), 7.20-7.46 (5H, m), 7.49-7.65 (2H, m), 8.42-8.62 (2H, m) 157

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.85 (2H, m), 0.98-1.13 (2H, m), 1.57-1.92 (3H, m ), 1.96-2.50 (5H, m), 2.90-3.54 (3H, m), 3.56-3.81 (3H, m), 3.83-3.98 (1H , m), 4.53-4.73 (1H, m), 4.85-5.04 (1H, m), 7.21-7.47 (5H, m), 7.49-7.65 (2H, m), 8.45-8.62 (2H, m)

Table 1-39 Etc. No. Structural formula NMR 158

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.62-1.19 (4H, m), 1.62-2.53 (7H, m), 2.70-2.92 (1H, m ), 3.08-3.29 (1H, m), 3.33-4.21 (6H, m), 4.51-4.75 (2H, m), 7.31-7.62 (4H , m), 7.63-7.73 (1H, m) 159

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.82 (2H, m), 0.98-1.12 (2H, m), 1.65-2.32 (9H, m ), 2.34-2.50 (1H, m), 3.08 (2H, broad s), 3.34-4.00 (4H, m), 4.56-4.95 (1H, m) ), 7.23-7.32 (1H, m), 7.35-7.44 (4H, m), 7.48-7.65 (2H, m), 8.45-8.61 (2H , m) 160

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.59-0.83 (2H, m), 0.95-1.14 (2H, m), 1.62-2.20 (6H, m ), 2.30-2.50 (1H, m), 2.69-2.91 (1H, m), 3.06-3.27 (1H, m), 3.33-4.20 (6H , m), 3.73 (2H, s), 4.50-4.66 (1H, m), 4.71-4.85 (1H, m), 6.93-7.10 (2H, m ), 7.15-7.34 (3H, m), 7.45-7.64 (2H, m), 8.41-8.62 (2H, m) 161

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.65-0.81 (2H, m), 0.99-1.13 (2H, m), 1.72-2.50 (9H, m ), 2.85-3.33 (2H, m), 3.35-3.78 (3H, m), 3.81-4.96 (3H, m), 7.22-7.33 (1H , m), 7.47-7.77 (6H, m), 8.44-8.63 (2H, m) 162

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.64-0.82 (2H, m), 1.00-1.12 (2H, m), 1.71-2.32 (8H, m ), 2.33-2.51 (1H, m), 2.85-3.28 (2H, m), 3.32-4.05 (5H, m), 3.83 (3H, s), 4.57-4.99 (1H, m), 6.90-7.04 (3H, m), 7.24-7.38 (2H, m), 7.50-7.69 (2H, m) ), 8.53 (2H, broad s)

Table 1-40 Etc. No. Structural formula NMR 163

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.68-0.86 (4H, m), 1.29-1.38 (3H, m), 1.99-2.17 (2H , m), 2.18-2.66 (5H, m), 3.14-3.32 (2H, m), 3.39-4.50 (8H, m), 4.68-4.83 (1H, m), 7.30-7.40 (2H, m), 7.43-7.53 (1H, m), 7.60-7.82 (6H, m), 10.55-10 , 76 (1H, m) 164

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.59-0.74 (2H, m), 0.93-1.04 (2H, m), 1.61-1.73 (1H, m ), 1.88-2.16 (3H, m), 2.25-2.59 (5H, m), 3.34-3.76 (3.5H, m), 3.83-4.01 (3H, m), 4.08-4.15 (0.5H, m), 4.27-4.39 (1H, m), 7.23-7.31 (1H, m), 7.49 -7.67 (5H, m), 7.79-7.84 (2H, m), 8.46-8.58 (2H, m) 165

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.86 (2H, m), 1.00-1.19 (2H, m), 1.73-1.88 (1H, m ), 1.92-2.21 (3H, m), 2.24-2.47 (3H, m), 2.92-3.12 (2H, m), 3.40-4.12 (7H , m), 4.51-4.69 (1H, m), 5.74 (2H, broad s), 6.87-6.99 (2H, m), 7.31-7.40 (1H , m), 7.41-7.61 (3H, m), 7.63-7.78 (3H, m) 166

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.85 (2H, m), 1.01-1.16 (2H, m), 1.51-1.67 (1H, m ), 1.75-1.89 (1H, m), 1.91-2.23 (3H, m), 2.26-2.49 (3H, m), 2.83-3.00 (2H , m), 3.40-4.12 (7H, m), 4.44-4.68 (3H, m), 6.88-7.04 (2H, m), 7.23-7.31 (2H, m), 7.32-7.40 (1H, m), 7.41-7.62 (3H, m), 7.63-7.72 (1H, m) 167

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.73-0.86 (2H, m), 1.06-1.12 (2H, m), 1.76-1.88 (1H, m ), 1.94-2.08 (2H, m), 2.11-2.44 (5H, m), 3.05-3.19 (2H, m), 3.42-3.51 (0 , 5H, m), 3.59-4.10 (3.5H, m), 4.56-4.78 (3H, m), 5.40-5.94 (2H, br s), 6 , 67-6.74 (1H, m), 7.12-7.22 (1H, m), 7.31-7.40 (1H, m), 7.41-7.60 (2H, m) 7.64-7.73 (1H, m), 7.91-7.99 (1H, m), 8.56-8.63 (1H, m)

Table 1-41 Etc. No. Structural formula NMR 168

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.85 (2H, m), 1.02-1.14 (2H, m), 1.73-1.88 (1H, m ), 1.90-2.22 (3H, m), 2.27-2.51 (3H, m), 2.71-2.88 (2H, m), 3.35-4.11 (9H , m), 4.38-4.56 (1H, m), 6.60-6.71 (2H, m), 6.78-6.91 (2H, m), 7.31-7.40 (1H, m), 7.41-7.62 (3H, m), 7.63-7.71 (1H, m) 169

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.71-0.88 (2H, m), 1.02-1.16 (2H, m), 1.73-1.88 (1H, m ), 1.91-2.19 (3H, m), 2.27-2.50 (3H, m), 2.81-3.00 (2H, m), 3.40-4.17 (9H , m), 4.39-4.63 (3H, m), 6.92-7.04 (2H, m), 7.31-7.72 (7H, m) 170

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.86 (2H, m), 1.01-1.16 (2H, m), 1.72-1.88 (1H, m ), 1.91-2.23 (3H, m), 2.26-2.51 (3H, m), 2.76-2.98 (2H, m), 3.42-4.11 (10H , m), 4.42-4.62 (1H, m), 6.89-7.00 (2H, m), 7.16 (1H, s), 7.31-7.73 (8H, m ) 171

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.86 (2H, m), 1.00-1.16 (2H, m), 1.72-1.88 (1H, m ), 1.92-2.23 (3H, m), 2.26-2.48 (3H, m), 2.84-3.02 (5H, m), 3.38-4.12 (7H , m), 4.45-4.65 (1H, m), 6.25-6.38 (1H, m), 6.88-6.99 (2H, m), 7.11-7.22 (2H, m), 7.32-7.40 (1H, m), 7.41-7.62 (3H, m), 7.63-7.71 (1H, m) 172

¹ H-NMR (400 MHz, CDCl ₃₎ δ: 0,69-1,01 (4H, m), 1,16-1,35 (3H, m), 1,35-1,53 (3H, m ), 1.71-1.97 (2H, m), 1.97-2.49 (4H, m), 2.86-3.09 (2H, m), 3.41-4.31 (9H , m), 4.53-4.75 (1H, m), 7.17-7.30 (1H, m), 7.30-7.40 (1H, m), 7.41-7.60 (3H, m), 7.61-7.74 (1H, m)

Table 1-42 Etc. No. Structural formula NMR 173

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.61-0.87 (2H, m), 1.00-1.19 (2H, m), 1.57-1.87 (1H, m ), 1.93-2.25 (1H, m), 2.25-2.48 (1H, m), 3.31-4.15 (5H, m), 4.35-4.59 (4H , m), 5.44-5.66 (1H, m), 6.26-6.40 (1H, m), 7.30-7.76 (6H, m), 8.02-8.17 (1H, m) 174

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.69-0.93 (4H, m), 1.41-1.52 (3H, m), 1.83-2.01 (2H, m ), 2.13-2.51 (4H, m), 2.97-3.11 (2H, m), 3.16-4.12 (9H, m), 4.41-4.54 (2H , m), 4.65-4.78 (1H, m), 6.62-6.71 (1H, m), 7.12-7.55 (7H, m), 8.10-8.16 (1H, m) 175

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.72-0.85 (2H, m), 1.04-1.16 (2H, m), 1.73-1.88 (1H, m ), 1.94-2.09 (2H, m), 2.10-2.45 (5H, m), 3.07-3.22 (2H, m), 3.42-3.51 (0 , 5H, m), 3.57-4.10 (3.5H, m), 4.52-4.80 (3H, m), 6.62-6.71 (1H, m), 7.32 -7.41 (1H, m), 7.41-7.72 (5H, m), 8.38-8.45 (1H, m) 176

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.46-0.86 (4H, m), 1.07-1.24 (2H, m), 1.27-1.41 (3H , m), 1.73-2.07 (7H, m), 2.15-2.30 (2H, m), 3.06-4.08 (8H, m), 4.72-4.88 (3H, m), 6.66-6.74 (1H, m), 7.08-7.61 (5H, m), 8.38-8.48 (2H, m) 177

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.70-0.97 (7H, m), 1.35-1.42 (3H, m), 1.86-2.03 (4H , m), 2.25-2.46 (1H, m), 2.84-2.95 (1H, m), 3.07-3.24 (3H, m), 3.39-3.57 (1H, m), 3.67-3.77 (1H, m), 3.81-3.94 (1H, m), 4.75-4.88 (3H, m), 6.64-6 72 (1H, m), 7.20-7.41 (5H, m), 7.53-7.61 (1H, m), 8.39-8.44 (2H, m)

Table 1-43 Etc. No. Structural formula NMR 178

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.74-0.86 (2H, m), 1.05-1.15 (2H, m), 1.76-1.88 (1H, m ), 1.93-2.09 (3H, m), 2.11-2.46 (4H, m), 3.04-3.19 (2H, m), 3.43-3.51 (0 , 5H, m), 3.59-4.09 (3.5H, m), 3.84-3.91 (3H, s), 4.58-4.78 (3H, m), 6.61 -6.71 (1H, m), 7.32-7.61 (3.5H, m), 7.63-7.71 (1H, m), 7.98-8.08 (1.5H, m), 8.77-8.83 (1H, m) 179

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.77-0.98 (4H, m), 1.44-1.53 (3H, m), 1.86-2.46 (6H, m ), 2.99-3.15 (2H, m), 3.45-4.06 (7H, m), 4.18-4.41 (1H, m), 4.68-4.85 (1H , m), 4.94-5.09 (2H, m), 6.48-6.55 (1H, m), 7.26-7.56 (4H, m), 7.82-7.92 (1H, m), 8.31-8.37 (2H, m) 180

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.67-0.91 (4H, m), 1.29-1.44 (3H, m), 1.74-2.34 (7H , m), 3.02-4.18 (7H, m), 4.47-4.69 (2H, m), 4.77-4.91 (3H, m), 6.60-6.71 (1H, m), 7.14-7.69 (5H, m), 8.34-8.46 (2H, m) 181

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.77 (2H, m), 0.99-1.15 (2H, m), 1.75-1.89 (1H, m ), 1.92-2.05 (2H, m), 2.18-2.53 (4H, m), 2.96-3.09 (2H, m), 3.68-3.85 (2H , m), 3.87-4.04 (2H, m), 4.44-4.56 (2H, m), 4.58-4.72 (1H, m), 6.58-6.67 (1H, m), 6.68-6.76 (1H, m), 7.29-7.39 (1H, m), 7.45-7.53 (2H, m), 7.75-7 88 (1H, m), 8.17-8.23 (1H, m), 8.54-8.62 (1H, m), 8.69-8.83 (1H, m) 182

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.83 (2H, m), 1.01-1.15 (2H, m), 1.69-1.88 (1H, m ), 1.90-2.21 (6H, m), 2.26-2.50 (3H, m), 2.77-3.00 (2H, m), 3.41-4.11 (7H , m), 4.40-4.62 (1H, m), 6.85-6.97 (2H, m), 7.31-7.71 (7H, m)

Table 1-44 Etc. No. Structural formula NMR 183

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.60-0.75 (2H, m), 0.94-1.06 (2H, m), 1.88-2.34 (7H , m), 2.79-2.98 (2H, m), 3.44-3.93 (7H, m), 4.50-4.68 (1H, m), 6.89-7.03 (1H, m), 7.43-7.80 (7H, m) 184

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.70-0.86 (2H, m), 1.05-1.16 (2H, m), 1.77-1.88 (1H, m ), 1.94-2.53 (6H, m), 3.06-3.22 (2H, m), 3.45-4.16 (5H, m), 4.21-4.35 (2H , m), 4.57-4.73 (1H, m), 6.67 (1H, s), 6.95-7.17 (3H, m), 7.35-7.73 (5H, m ), 8.05-8.13 (1H, m) 185

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.58-0.88 (4H, m), 1.29-1.44 (3H, m), 1.94-2.21 (5H , m), 2.28-2.41 (1H, m), 3.27-3.93 (8H, m), 3.95-4.05 (3H, m), 4.58-4.97 (3H, m), 5.42-6.26 (1H, m), 6.37-6.50 (1H, m), 7.14-7.41 (5H, m), 7.53-7 68 (1H, m), 8.11-8.23 (1H, m) 186

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.55-0.85 (4H, m), 1.32-1.41 (3H, m), 1.84-2.40 (7H , m), 3.06-3.23 (2H, m), 3.29-3.90 (5H, m), 4.72-4.88 (3H, m), 4.89-5.35 (2H, m), 6.66-6.72 (1H, m), 6.91-7.64 (4H, m), 8.39-8.44 (2H, m) 187

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.68-0.85 (2H, m), 1.01-1.13 (2H, m), 1.57-1.88 (2H, m ), 1.93-2.20 (1H, m), 2.33-2.56 (3H, m), 2.94-3.07 (2H, m), 3.35-3.82 (4H , m), 3.86-4.21 (4H, m), 4.52-4.66 (1H, m), 6.82-6.88 (1H, m), 7.24-32 (3H , m), 7.55-7.64 (3H, m), 8.15-8.22 (1H, m), 8.47-8.61 (1H, m)

Table 1-45 Etc. No. Structural formula NMR 188

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.67-0.78 (2H, m), 0.96-1.11 (2H, m), 1.71-1.85 (1H, m ), 1.92-2.09 (3H, m), 2.16-2.57 (4H, m), 3.04-3.21 (2H, m), 3.55-4.00 (4H , m), 4.19-4.34 (2H, m), 4.54-4.68 (1H, m), 6.61-6.70 (1H, m), 6.91-7.15 (3H, m), 7.23-7.31 (1H, m), 7.51-7.58 (1H, m), 7.67-7.76 (1H, m), 8.03-8 , 12 (1H, m) 189

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 0.53-0.69 (2H, m), 0.71-0.88 (2H, m), 0.91-1.11 (6H , m), 1.43-2.39 (10H, m), 2.62-2.82 (2H, m), 2.92-3.06 (3H, m), 3.42-3.92 (6H, m), 4.10-4.74 (2H, m), 7.39-7.59 (2H, m), 7.63-7.81 (2H, m) 190

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.73-0.97 (4H, m), 1.36-1.51 (3H, m), 1.77-1.95 (2H, m ), 1.97-2.26 (7H, m), 2.29-2.49 (2H, m), 3.47-4.11 (5H, m), 4.46-4.64 (1H , m), 7.00-7.20 (3H, m), 7.32-7.72 (6H, m), 8.29-8.42 (1H, m) 191

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.73-0.97 (4H, m), 1.38-1.49 (3H, m), 1.60-1.76 (1H, m ), 1.77-1.90 (2H, m), 1.93-2.18 (2H, m), 2.19-2.56 (5H, m), 2.70-2.81 (1H , m), 3.47-4.09 (5H, m), 4.42-4.61 (1H, m), 7.31-7.72 (5H, m)

The present invention is further specifically disclosed in the examples of the compositions below, which do not serve to limit it.

The composition according to example 1 (receiving capsules) 1) The compound of example 1 30 mg 2) crystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg

Components 1), 2), 3) and 4) are mixed and placed in gelatin capsules.

The composition according to example 2 (receiving tablets) 1) The compound of example 1 30 mg 2) lactose 50 g 3) corn starch 15 g 4) calcium carboxymethyl cellulose 44 g 5) magnesium stearate 1 mg

The entire amount of components 1), 2), 3) and 30 g of component 4) are mixed with water, dried under reduced pressure and ground. The ground powder is mixed with 14 g of component 4) and 1 g of component 5) and tabletted using a tabletting device. Thus, 1000 tablets are obtained containing 30 mg of the compound of Example 1 per tablet.

In the same manner as in the above example preparation 1 or preparation example 2, the compounds of examples 2-191 can also be issued in the form of capsules or tablets.

Experimental example 1 : the in vitro inhibitory activity against HSD-1 (hydroxysteroid dehydrogenase 1) The manifestation of inhibitory activity against HSD-1 is determined by quantifying the inhibition of the conversion of cortisone to cortisol using the SPA system (proximal scintillation analysis) and using as a source the human HSD-1 enzyme (hereinafter recombinant HSD-1) expressed using a baculovirus system. Reagents (100 μl) are added to a 96-well plate (96 well Opti-plates ^TM -96 (Packard)) to the final concentration shown below, and the reaction is carried out at room temperature for 90-120 minutes. As a reaction mixture, 5-100 ng / well of recombinant HSD-1, 500 μM NADPH and 10 nM ³ H-cortisone (American Radiolabeled Chemicals Inc., 50 Ci / mmol) was dissolved in PBS containing 0.1% BSA (Sigma) , and the test substance is 2 μl of a solution of the compound (dissolved in DMSO). Once the reaction has begun, 50 μl of PBS (containing 0.1% BSA (Sigma)) containing 0.2 μg of anti-mouse cortisol monoclonal antibodies (East Coast Biologics), 500 μg of anti-mouse antibodies associated with PVT SPA granules (Amersham Biosciences ), and 133 μM carbenoxolone (Sigma) is added to the reaction mixture to stop the reaction. After completion of the reaction, the mixture is incubated at room temperature for at least 2 hours and the radioactivity is measured using a Topcount counter (Packard). As a control, use the value in the well to which 2 μl DMSO is added instead of the test substance (0% inhibition) and as a positive control use the value in the well to which carbenoxolone (final concentration of 100 μM) is added instead of the test substance (100% inhibition). Inhibition (in%) of the test compound is calculated according to the following formula: ((control value is the value of the test substance) / (control value is the value of the positive control)) x 100 (%). The IC ₅₀ level is calculated by the inhibition values of two points after 50% inhibition. The results are shown in the following tables - from Table 2-1 to Table 2-3.

Table 2-1 Etc. No. hHSD1 (IC ₅₀ (nM)) Etc. No. hHSD1 (IC ₅₀ (nM)) 2 ++ 41 ++ 3 ++ 42 ++ four ++ 43 ++ 6 ++ 44 ++ 7 ++ 45 ++ 8 ++ 47 ++ 9 ++ 48 ++ 10 ++ 49 ++ eleven ++ fifty ++ 12 ++ 51 ++ 13 ++ 52 ++ fourteen ++ 53 ++ fifteen ++ 54 ++ 16 ++ 55 ++ 17 ++ 56 ++ eighteen ++ 57 ++ 19 ++ 58 ++ twenty ++ 59 ++ 21 ++ 60 ++ 22 ++ 61 ++ 23 ++ 63 ++ 24 ++ 64 ++ 25 ++ 65 ++ 26 ++ 66 ++ 27 ++ 67 ++ 28 ++ 68 ++ 29th ++ 69 ++ thirty ++ 71 ++ 31 ++ 72 ++ 32 ++ 73 ++ 33 ++ 74 ++ 34 ++ 75 ++ 35 ++ 76 ++ 36 ++ 77 ++ 37 ++ 78 ++ 39 ++ 79 ++ 40 ++ 80 ++

Table 2-2 Etc. No. hHSD1 (IC ₅₀ (nM)) Etc. No. hHSD1 (IC ₅₀ (nM)) 83 ++ 130 ++ 84 ++ 131 ++ 85 ++ 132 ++ 87 ++ 133 ++ 88 ++ 134 ++ 89 ++ 135 ++ 90 ++ 136 ++ 91 ++ 137 ++ 93 ++ 138 ++ 94 ++ 139 ++ 95 ++ 140 ++ 96 ++ 141 ++ 97 ++ 142 ++ 99 ++ 145 ++ one hundred ++ 146 ++ 103 ++ 147 ++ 105 ++ 148 ++ 106 ++ 149 ++ 107 ++ 150 ++ 108 ++ 151 ++ 109 ++ 154 ++ 110 ++ 155 ++ 111 ++ 156 ++ 112 ++ 157 ++ 113 ++ 158 ++ 114 ++ 165 ++ 115 ++ 166 ++ 116 ++ 167 ++ 117 ++ 168 ++ 118 ++ 169 ++ 119 ++ 170 ++ 120 ++ 171 ++ 124 ++ 172 ++ 125 ++ 173 ++ 126 ++ 174 ++ 128 ++ 175 ++ 129 ++ 176 ++

Table 2-3 Etc. No. hHSD1 (IC ₅₀ (nM)) Etc. No. hHSD1 (IC ₅₀ (nM)) 177 ++ 185 ++ 178 ++ 186 ++ 179 ++ 187 ++ 180 ++ 189 ++ 182 ++ 190 ++ 183 ++ 191 ++ 184 ++

In the above tables, ++ means that the IC ₅₀ value is not more than 30 nM.

Industrial applicability

The heterocyclic compound of the present invention has excellent inhibitory activity against HSD1 and is suitable as an agent for the prevention and treatment of metabolic diseases such as diabetes, insulin resistance, diabetes complications, obesity, hyperlipidemia, hypertension, fatty liver, etc. etc.

This application is based on Nos patent applications. 2005-168901, 2006-027097 and 2006-138252, registered in Japan and Nos applications. 60/692039 and 60/772734, registered in the United States, the contents of which are incorporated in their entirety by reference.

Claims (40)

1. The compound of the formula [1 ']

where ring A represents
(1) a nitrogen containing, monocyclic, saturated, 4-6 membered heterocyclic group, or
(2) a 3-6 membered cycloalkyl group, said ring A is optionally substituted with one or more, same or different substituents R ¹ ,
the specified Deputy R ¹ represents
1) a hydrogen atom,
2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:
(i) a halogen atom, (ii) a hydroxyl group, and (iii) a C _1-6 alkoxy group) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group,
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(e) a C _1-6 alkoxy group or
(h) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms)
or
(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a 4-6 membered, containing nitrogen and optionally sulfur atom, a saturated, monocyclic, heterocyclic group, or containing nitrogen and optionally an oxygen atom 5-7 a membered heterocyclic group fused to a benzene ring (both of these heterocyclic groups are optionally substituted with one or more, same or different substituents selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups),
d) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
i) C _1-6 alkoxy groups),
3) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy; and
d) a phenyl group), or
(b) a piperidyl group substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
4) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) to (3):
(1) a halogen atom, (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
6) a 3-6 membered cycloalkyl group,
7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or a phenyl group ( said phenyl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),
8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
10) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):
(a) a carboxyl group,
(b) a halogen atom,
(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),
(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO-C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or —S (= O) ₂ —R ⁴² , where R ⁴² represents C _{1 A -6} alkyl group, or R ³⁸ and R ³⁹ optionally form, together with the nitrogen atom to which they are attached, a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),
(e) —CO — NR ⁴³ R ⁴⁴ , where R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(f) —COO-C _1-6 alkyl group) or
11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following from (a) to (h):
(a) a carboxyl group,
(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy)
(c) a cycloalkyl group,
(a) a halogen atom,
(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(f) -COO-C _1-6 alkyl groups,
(g) cyano groups and
(h) C _1-6 alkoxy);
-X- represents
(1) -N (R ¹ ) -, where R ¹ is as defined above or
(2) -CCR ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are the same or different and each represents
1) a hydrogen atom,
2) —NR ¹⁶ R ¹⁷ where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, or —CO — NR ³⁶ R ³⁷ , where R ³⁶ and R ³⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
3) —CONR ¹⁸ R ¹⁹ where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more carboxyl groups) or a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one and whether a large number of identical or different halogen atoms)),
4) a tetrazolyl group, or
5) a carboxyl group;
R ² represents
(1) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following group:
1) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more, same or different substituents selected from the following group: (a) a hydroxyl group and (b) a C _1-6 alkoxy group), and 2) C _1-6 alkoxy); and
R ³ and R ⁴ are the same or different and each represents
(1) a hydrogen atom,
(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom,
2) a hydroxyl group, 3) a C _1-6 alkoxy group, and 4) an -OCO-C _1-6 alkyl group),
(3) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following 1) to 6):
1) a halogen atom,
2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom, (b) a hydroxyl group, and (c) C _{1 -6} alkoxy groups),
3) a C _1-6 alkoxy group (said C _1-6 alkoxy group is optionally substituted with one or more, same or different halogen atoms),
4) carboxyl group
5) -COO-C _1-6 alkyl groups and
6) cyano groups),
(4) a pyridyl or thiazolyl group (said heterocyclic group is optionally substituted with a halogen atom),
(5) a hydroxyl group or
(6) a C _1-6 alkoxy group,
or a pharmaceutically acceptable salt thereof. 2. The compound of the formula [1]

where -X- represents
(1) -N (R ¹ ) -, where R ¹ represents
1) a hydrogen atom,
2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2); (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group,
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(g) C _1-6 alkoxy; or
(h) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms),
or
(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a 4-6 membered, saturated, monocyclic, heterocyclic group containing a nitrogen atom and optionally a sulfur atom, or a 5-7 membered heterocyclic group, containing a nitrogen atom and optionally an oxygen atom fused to a benzene ring (both of these heterocyclic groups are optionally substituted with one or more, same or different substituents selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups),
d) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
i) C _1-6 alkoxy groups),
3) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy groups and
d) a phenyl group), or
(b) a piperidyl group substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
4) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following (1) to (3) :( 1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
6) a 3-6 membered cycloalkyl group,
7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or a phenyl group ( said phenyl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),
8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
9) -C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different, and each represents a hydrogen atom or a C _1-6 alkyl group,
10) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):
(a) a carboxyl group,
(b) a halogen atom,
(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),
(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO-C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, -S (= O) ₂ -R ⁴² , where R ⁴² represents C _{1- 6} an alkyl group, or R ³⁸ and R ³⁹ optionally form, together with the nitrogen atom to which they are bonded, a nitrogen containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is not optionally substituted with one or more oxo groups),
(e) —CO — NR ⁴³ R ⁴⁴ , wherein R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(f) —COO-C _1-6 alkyl group) or
11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following from (a) to (h):
(a) a carboxyl group,
(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy groups),
(c) a cycloalkyl group,
(d) a halogen atom,
(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(f) -COO-C _1-6 alkyl groups,
(g) cyano groups and (h) C _1-6 alkoxy groups)), or
(2) - (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are the same or different and each represents
1) a hydrogen atom,
2) —NR ¹⁶ R ¹⁷ where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or —CO-NR ³⁶ R ³⁷ , where R ³⁶ and R ³⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
3) —CONR ¹⁸ R ¹⁹ , where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more carboxyl groups) or phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one silt and a large number of identical or different halogen atoms)),
4) a tetrazolyl group or
5) a carboxyl group;
R ² represents
(1) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following group:
1) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a hydroxyl group and (b) a C _1-6 alkoxy group), and 2) C _1-6 alkoxy); and
R ³ and R ⁴ are the same or different and each represents
(1) a hydrogen atom,
(2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom, 2) a hydroxyl group, 3) C _1-6 alkoxy groups and 4) -OCO-C _1-6 alkyl groups),
(3) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following 1) to 6):
1) a halogen atom,
2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom, (b) a hydroxyl group, and (c) C _{1 -6} alkoxy groups),
3) a C _1-6 alkoxy group (said C _1-6 alkoxy group is optionally substituted with one or more, same or different halogen atoms),
4) carboxyl group
5) -COO-C _1-6 alkyl groups and
6) cyano groups),
(4) a pyridyl or thiazole group (said heterocyclic group is optionally substituted with a halogen atom),
(5) a hydroxyl group or
(6) With _1-6 alkoxygroup,
or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, where —X— is —C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are as defined in claim 1, or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 2, where —X— is —C (R ⁷ R ⁸ ) -, where R ⁷ and R ⁸ are as defined in claim 1 or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 3, where R ⁸ represents
1) —NR ¹⁶ R ¹⁷ where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
2) —CONR ¹⁸ R ¹⁹ , where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or
3) a tetrazolyl group,
or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 4, where R ⁸ represents
1) —NR ¹⁶ R ¹⁷ where R ¹⁶ and R ¹⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
2) —CONR ¹⁸ R ¹⁹ , where R ¹⁸ and R ¹⁹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or
3) a tetrazolyl group,
or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, where —X— is —N (R ¹ ) -, where R ¹ is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 2, where —X— is —N (R ¹ ) -, where R ¹ is as defined in claim 1, or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 7, where R ¹ represents
1) a hydrogen atom,
2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group:
(i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups), or
(g) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms),
or
(h) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group containing a nitrogen atom and optionally a sulfur atom (said heterocyclic group is optionally substituted with one or a large number of identical or different substituents selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
a) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not
simultaneously by hydrogen atoms),
3) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy; and
d) a phenyl group), or
(b) a piperidyl group optionally substituted with a substituent,
selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
4) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more identical or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following (1) to (3) :( 1) a halogen atom, (2) a C _1-6 alkyl group (said C _{A 1-6} alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different, and each represents a hydrogen atom, A C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
6) a 3-6 membered cycloalkyl group,
7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or a phenyl group ( said phenyl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),
8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
9) —C (= NCN) —NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
10) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):
(a) a carboxyl group,
(b) a halogen atom,
(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),
(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO-C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or —S (= O) ₂ —R ⁴² , where R ⁴² represents C _{1 A -6} alkyl group, or R ³⁸ and R ³⁹ optionally form, together with the nitrogen atom to which they are attached, a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),
(e) —CO — NR ⁴³ R ⁴⁴ , wherein R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(f) —COO-C _1-6 alkyl group) or
11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following from (a) to (h):
(a) a carboxyl group,
(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy groups),
(c) a cycloalkyl group and
(d) a halogen atom,
(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(f) -COO-C _1-6 alkyl groups,
(g) cyano groups and
(h) C _1-6 alkoxy groups),
or a pharmaceutically acceptable salt thereof. 10. The compound according to 8, where R ¹ represents
1) a hydrogen atom,
2) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents (a) a hydrogen atom,
(b) a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups), or
(g) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms),
or
(h) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents, selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
d) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
i) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not
simultaneously by hydrogen atoms),
3) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy; and
d) a phenyl group), or
(b) a piperidyl group optionally substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
4) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following (1) to (3) :( 1) a halogen atom, (2) a C _1-6 alkyl group (said C _{A 1-6} alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
5) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
6) a 3-6 membered cycloalkyl group,
7) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), or a phenyl group ( said phenyl group is optionally substituted by one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted by one or more identical or spill GOVERNMENTAL halogen atoms)),
8) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
9) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
10) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):
(a) a carboxyl group,
(b) a halogen atom,
(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),
(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO-C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, or —S (= O) ₂ —R ⁴² , where R ⁴² represents C _{1 A -6} alkyl group, or R ³⁸ and R ³⁹ optionally form, together with the nitrogen atom to which they are attached, a nitrogen-containing, saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),
(e) —CO — NR ⁴³ R ⁴⁴ , wherein R ⁴³ and R ⁴⁴ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(f) —COO-C _1-6 alkyl group) or
11) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (a) by (h):
(a) a carboxyl group,
(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy groups),
(c) a cycloalkyl group and
(d) a halogen atom,
(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(f) -COO-C _1-6 alkyl groups,
(g) cyano groups and
(h) C _1-6 alkoxy groups),
or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 7, where R 'is 1) -CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group;
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2): (1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(g) a C _1-6 alkoxy group or
(h) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms)
or
(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, 4-7 membered monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents, selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
d) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ , where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO — C _1-6 alkyl group, and
1) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not any combination of substituents selected from the following group: (i) a hydrogen atom and (ii) an unsubstituted C _1-6 alkyl group),
2) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy; and
d) a phenyl group), or
(b) a piperidyl group substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
3) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
5) a 3-6 membered cycloalkyl group,
6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or a phenyl group (indicated a phenyl group is optionally substituted with one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different gal atoms ogen)),
7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
8) -C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is substituted with one or more identical or different substituents selected from the following (a) by (g):
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy groups),
(b) a cycloalkyl group,
(c) a halogen atom,
(d) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(e) -COO-C _1-6 alkyl groups,
(f) cyano groups and
(g) C _1-6 alkoxy groups),
or a pharmaceutically acceptable salt thereof. 12. The compound of claim 8, where R ¹ represents
1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy)
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(g) a C _1-6 alkoxy group, or
(h) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms)
or
(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents, selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
a) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
1) C _1-6 alkoxy groups) (provided that R ⁵ and R ⁶ are not any combination of substituents selected from the following group: (i) a hydrogen atom and (ii) an unsubstituted C _1-6 alkyl group),
2) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ , where R ²⁶ and R ²⁷ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy groups and
d) a phenyl group), or
(b) a piperidyl group substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
3) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
5) a 3-6 membered cycloalkyl group,
6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or a phenyl group (indicated a phenyl group is optionally substituted with one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different gal atoms ogen)),
7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
8) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or
9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is substituted with one or more identical or different substituents selected from the following (a) by (g):
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy groups),
(b) a cycloalkyl group,
(c) a halogen atom,
(d) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(e) -COO-C _1-6 alkyl groups,
(f) cyano groups and
(g) C _1-6 alkoxy groups),
or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 7, where R ¹ represents
1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group and
b) -CO-C _1-6 alkyl groups and
c) oxo groups), or
(g) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms), or
(h) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents, selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
d) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
1) C _1-6 alkoxygroup) (provided that R ⁵ and R ⁶ are not simultaneously hydrogen atoms),
2) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ where R ²⁶ and R ²⁷ are the same or different and
each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form, together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy groups and
d) a phenyl group), or
(b) a piperidyl group substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
3) -COR ¹¹ , where R ¹¹ represents (a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (1) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁴ and R ³⁵ optionally form together with the nitrogen atom with which they are linked, containing nitrogen, a saturated, monocyclic, heterocyclic group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
5) a 3-6 membered cycloalkyl group,
6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or a phenyl group (indicated a phenyl group is optionally substituted with one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different gal atoms ogen)),
7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
8) —C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or
9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is substituted with one or more identical or different substituents selected from the following (a) by (g):
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy)
(b) a cycloalkyl group,
(c) a halogen atom,
(d) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(e) -COO-C _1-6 alkyl groups,
(f) cyano groups and
(g) C _1-6 alkoxy groups),
or a pharmaceutically acceptable salt thereof. 14. The compound of claim 8, where R ¹ represents 1) -CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group; and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group and
b) -CO-C _1-6 alkyl groups and
c) oxo groups), or
(g) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms), or
(h) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents, selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
d) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
1) C _1-6 alkoxygroup) (provided that R ⁵ and R ⁶ are not simultaneously hydrogen atoms),
2) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ where R ²⁶ and R ²⁷ are the same or different and
each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form, together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy; and
d) a phenyl group), or
(b) a piperidyl group substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
3) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (d):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
5) a 3-6 membered cycloalkyl group,
6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or a phenyl group (indicated a phenyl group is optionally substituted with one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different gal atoms ogen)),
7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
8) -C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different, and each represents a hydrogen atom or a C _1-6 alkyl group,
9) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is substituted with one or more identical or different substituents selected from the following (a) by (g):
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy groups),
(b) a cycloalkyl group,
(c) a halogen atom,
(d) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(e) -COO-C _1-6 alkyl groups,
(f) cyano groups and
(g) C _1-6 alkoxy)
or a pharmaceutically acceptable salt thereof. 15. The compound according to claim 1, where R ² represents a cyclopropyl group or a 1-methylcyclopropyl group, or a pharmaceutically acceptable salt thereof. 16. The compound according to claim 2, where R ² represents a cyclopropyl group or a 1-methylcyclopropyl group, or a pharmaceutically acceptable salt thereof. 17. The compound according to claim 1, where R ³ and R ⁴ are the same or different and each represents
(1) a hydrogen atom,
(2) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom and 2) -CO-C _1-6 alkyl group) ,
(3) a phenyl group (said phenyl group is substituted with one or more, same or different substituents selected from the following 1) to 5):
1) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a hydroxyl group),
2) a C _1-6 alkoxy group (said C _1-6 alkoxy group is substituted with one or more identical or different halogen atoms),
3) a carboxyl group,
4) -COO-C _1-6 alkyl groups and
5) cyano groups) or
(4) a pyridyl or thiazolyl group (said heterocyclic group is substituted by a halogen atom),
(provided that R ³ and R ⁴ are not simultaneously hydrogen atoms),
or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 2, where R ³ and R ⁴ are the same or different and each represents
(1) a hydrogen atom,
(2) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group: 1) a halogen atom and 2) -CO-C _1-6 alkyl group) ,
(3) a phenyl group (said phenyl group is substituted with one or more, same or different substituents selected from the following 1) to 5):
1) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more, same or different substituents selected from the following group: (a) a halogen atom and (b) a hydroxyl group),
2) a C _1-6 alkoxy group (said C _1-6 alkoxy group is substituted with one or more identical or different halogen atoms),
3) a carboxyl group,
4) -COO-C _1-6 alkyl groups and
5) cyano groups) or
(4) a pyridyl or thiazolyl group (said heterocyclic
the group is substituted by a halogen atom),
(provided that R ³ and R ⁴ are not simultaneously hydrogen atoms),
or a pharmaceutically acceptable salt thereof. 19. The compound according to claim 1, where R ¹ represents
1) —CONR ⁵ R ⁶ where R ⁵ and R ⁶ are the same or different and each represents
(a) a hydrogen atom,
(b) a phenyl group (said phenyl group is substituted by one or more, same or different substituents selected from the following group:
a) a hydroxyl group,
b) a halogen atom,
c) a carboxyl group,
d) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups) and
e) C _1-6 alkoxy groups),
(c) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more identical or different substituents, selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)),
(d) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following group;
a) a hydroxyl group,
b) a halogen atom,
c) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 -6} alkyl group is optionally substituted with one or more identical or different halogen atoms)),
d) —NR ²⁰ R ²¹ where R ²⁰ and R ²¹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, or R ²⁰ and R ²¹ optionally form together with the nitrogen atom to which they are bonded, containing a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more identical or different substituents selected from the following (i) no (iv ):
(i) a halogen atom,
(ii) a hydroxyl group,
(iii) oxo groups and
(iv) C _1-6 alkoxy groups),
(e) -S (= O) ₂ -R ⁹ where R ⁹ represents a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1 ) a halogen atom and (2) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms)), or a C _1-6 alkyl group or
(f) a nitrogen containing, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(g) a C _1-6 alkoxy group or
(h) a thiazolyl or pyridyl group (said heterocyclic group is optionally substituted with one or more, same or different halogen atoms), or
(i) R ⁵ and R ⁶ optionally form, together with the nitrogen atom to which they are attached, a nitrogen, saturated, monocyclic, 4-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents, selected from the following a) to i):
a) a halogen atom,
b) a hydroxyl group,
c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, and (iii) C _{1 -6} alkoxy groups),
d) a carboxyl group,
e) -CO-C _1-6 alkyl groups,
f) —CO — NR ²² R ²³ , where R ²² and R ²³ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
g) oxo groups,
h) —NR ²⁴ R ²⁵ where R ²⁴ and R ²⁵ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group or a —CO-C _1-6 alkyl group, and
1) C _1-6 alkoxygroup) (provided that R ⁵ and R ⁶ are not simultaneously hydrogen atoms),
2) -COOR ¹⁰ , where R ¹⁰ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to d):
a) a hydroxyl group,
b) —NR ²⁶ R ²⁷ where R ²⁶ and R ²⁷ are the same or different and
each represents a hydrogen atom or a C _1-6 alkyl group, or R ²⁶ and R ²⁷ optionally form, together with the nitrogen atom to which they are attached, a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group,
c) C _1-6 alkoxy; and
d) a phenyl group), or
(b) a piperidyl group substituted with a substituent selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
3) -COR ¹¹ , where R ¹¹ represents
(a) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following a) to h):
a) a halogen atom,
b) a hydroxyl group,
c) —NR ²⁸ R ²⁹ where R ²⁸ and R ²⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, a —CO — C _1-6 alkyl group, a —CO-cycloalkyl group, or —S (= O) ₂ -C _1-6 alkyl group,
d) —CO — NR ³⁰ R ³¹ , where R ³⁰ and R ³¹ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, or R ³⁰ and R ³¹ optionally form together with the nitrogen atom with which they bound, containing nitrogen, saturated, monocyclic, heterocyclic group,
e) C _1-6 alkoxy groups,
f) a phenyl group (said phenyl group is optionally substituted by one or more, same or different substituents selected from the following group: (i) a halogen atom, (ii) a hydroxyl group, (iii) a C _1-6 alkoxy group, and (iv) C _1-6 alkyl groups (said C _1-6 alkyl group is optionally substituted with one or more, same or different halogen atoms)),
g) a carboxyl group and
h) phenyloxy groups),
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more, same or different substituents selected from the following a) and b):
a) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) and (2) :( 1) a halogen atom and (2) a C _1-6 alkyl group (said C _{1 The -6} alkyl group is optionally substituted with one or more, same or different halogen atoms)), and
b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group)), or
(c) a nitrogen containing, saturated, monocyclic, 5-6 membered heterocyclic group (said heterocyclic group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a C _1-6 alkyl group,
b) -CO-C _1-6 alkyl groups and
c) oxo groups),
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (1) to (3): (1) a halogen atom, (2) a C _1-6 alkyl group (said A C _1-6 alkyl group is optionally substituted with one or more identical or different halogen atoms), and (3) a C _1-6 alkoxy group), or
(e) a carboxyl group,
4) a C _1-6 alkyl group (said C _1-6 alkyl group is substituted with one or more, same or different substituents selected from the following (a) to (a):
(a) a carboxyl group,
(b) a 3-6 membered cycloalkyl group (said cycloalkyl group is optionally substituted with one or more identical or different —CO — NR ³² R ³³ , where R ³² and R ³³ are the same or different and each represents a hydrogen atom, C _{A 1-6} alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: (i) a hydroxyl group and (ii) a C _1-6 alkoxy group),
(c) —CO — NR ³⁴ R ³⁵ , where R ³⁴ and R ³⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and
(d) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted one or more identical or different halogen atoms))),
5) a 3-6 membered cycloalkyl group,
6) -S (= O) ₂ -R ¹² , where R ¹² represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more identical or different halogen atoms), or a phenyl group (indicated a phenyl group is optionally substituted with one or more identical or different substituents selected from the following group: a) a halogen atom and b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more identical or different gal atoms ogen)),
7) -C (= NCN) -R ¹³ where R ¹³ represents a C _1-6 alkyl group,
8) -C (= NCN) NR ¹⁴ R ¹⁵ , where R ¹⁴ and R ¹⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
9) a phenyl group (said phenyl group is optionally substituted with one or more, same or different substituents selected from the following (a) to (f):
(a) a carboxyl group,
(b) a halogen atom,
(c) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following group: a) a hydroxyl group, b) a halogen atom, and c) C _1-6 alkoxy groups),
(d) —NR ³⁸ R ³⁹ , where R ³⁸ and R ³⁹ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group, —CO-C _1-6 alkyl group, —CO-NR ⁴⁰ R ⁴¹ where R ⁴⁰ and R ⁴¹ are the same or different and each represents a hydrogen atom,
A C _1-6 alkyl group or a C _1-6 alkoxy group, or —S (= O) ₂ —R ⁴² , where R ⁴² represents a C _1-6 alkyl group) or R ³⁸ and R ³⁹ optionally form together with a nitrogen atom, to which they are associated, containing nitrogen, a saturated, monocyclic, heterocyclic group (said heterocyclic group is optionally substituted with one or more oxo groups),
(e) —CO — NR ⁴³ R ⁴⁴ , wherein R ⁴³ and R ⁴⁴ are the same or different, and each represents a hydrogen atom or a C _1-6 alkyl group, and
(f) —COO-C _1-6 alkyl group) or
10) a 5-membered or 6-membered unsaturated, monocyclic, heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen, oxygen and sulfur atom (said heterocyclic group is substituted by one or more identical or different substituents selected from the following (a) by (h):
(a) a carboxyl group,
(b) a C _1-6 alkyl group (said C _1-6 alkyl group is optionally substituted with one or more, same or different substituents selected from the following a) to c):
a) a halogen atom,
b) a hydroxyl group and
c) C _1-6 alkoxy groups),
(c) a cycloalkyl group,
(d) a halogen atom,
(e) —CO — NR ⁴⁵ R ⁴⁶ , wherein R ⁴⁵ and R ⁴⁶ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
(f) -COO-C _1-6 alkyl groups,
(g) cyano groups and
(h) C _1-6 alkoxy groups),
or a pharmaceutically acceptable salt thereof. 20. The compound according to claim 1 or its pharmaceutically acceptable salt, which is selected from the following compounds:
(1) 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine,
(2) 1- [5-cyclopropyl-1- (piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(3) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(4) 1- [1- (1-carbamoylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(5) 1- {1- [1- (2-carboxyphenylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(6) 1- {5-cyclopropyl-1- [1- (2-hydroxymethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(7) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(8) 1- {5-cyclopropyl-1- [1- (2-hydroxyethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(9) 1- {5-cyclopropyl-1- [1- (2-hydroxy-1,1-dimethylethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(10) 1- {1- [1- (2-Acetylaminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(11) 1- {1- [1- (2-aminoethylcarbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(12) 1- {5-cyclopropyl-1- [1- (1,1-dioxothiomorpholine-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(13) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(14) 1- {5-cyclopropyl-1- [1- (4-hydroxypiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(15) 1- {1- [1- (azetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,
(16) 1- {5-cyclopropyl-1- [1- (3-hydroxypyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(17) 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(18) 1- {5-cyclopropyl-1- [1- (4,4-difluoropiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(19) 1- {5-cyclopropyl-1- [1- (3,3-difluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(20) 1- {5-cyclopropyl-1- [1- (3-hydroxyazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(21) 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(22) 1- (5-cyclopropyl-1- {1 - [(S) -3-hydroxypyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(23) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-methylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(24) 1- {5-cyclopropyl-1- [1- (4-hydroxymethylpiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(25) 1- {1- [1- (4-carboxypiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(26) 1- {5-cyclopropyl-1- [1- (3-oxopiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(27) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxymethylpyrrolidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(28) 1- {5-cyclopropyl-1- [1- (3-hydroxymethylazetidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(29) 1- {5-cyclopropyl-1- [1- (4-methylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(30) 1- {5-cyclopropyl-1- [1- (4-isopropylpiperazin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(31) 1- {1- [1- (4-acetylpiperazin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(32) 1- (5-cyclopropyl-1- {1 - [(R) -3-hydroxypiperidin-1-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(33) 1- {1- [1- (4-carbamoylpiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(34) 1- {1- [1- (3-carbamoylazetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(35) 1- {1- [1- (4-aminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(36) 1- {1- [1- (3-aminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(37) 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(38) 1- {5-cyclopropyl-1- [1- (4-dimethylaminopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(39) 1- {1- [1- (4-acetylaminopiperidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(40) 1- {1- [1- (3-acetylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(41) 1- {5-cyclopropyl-1- [1- (3-dimethylaminopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(42) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(43) 1- {1- [1- (1-acetylpiperidin-4-yl-carbamoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(44) 1- {5-cyclopropyl-1- [1- (4-oxopiperidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(45) 1- {1- [1- (3-acetylamino-azetidin-1-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(46) 1- {5-cyclopropyl-1- [1- (3-oxopyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(47) 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(48) 1- {5-cyclopropyl-1- [1- (3,3,4,4-tetrafluoropyrrolidin-1-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(49) 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-2-methylpropylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(50) 1- (1- {1 - [(S) -1-benzyl-2-hydroxyethylcarbamoyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(51) 1- (5-cyclopropyl-1- {1 - [(S) -2-hydroxy-1-phenylethylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(52) 1- (5-cyclopropyl-1- {1 - [(S) -1-hydroxymethyl-3-methylbutylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(53) 1- {5-cyclopropyl-1- [1- (2-hydroxyphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(54) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopentylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(55) 1- [1- (1-Benzenesulfonylaminocarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(56) 1- [5-cyclopropyl-1- (1-methanesulfonylaminocarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(57) 1- [5-cyclopropyl-1- (1-methoxycarbonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(58) 1- {5-cyclopropyl-1- [1- (2-hydroxyethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(59) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(60) 1- {5-cyclopropyl-1- [1- (2-piperidin-1-yl-ethoxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(61) 1- {5-cyclopropyl-1- [1- (piperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(62) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(63) 1- {1- [1- (1-acetylpiperidin-4-yl-hydroxycarbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(64) 1- [1- (1-cyclopropanecarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(65) 1- {5-cyclopropyl-1- [1- (2-hydroxyacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(66) 1- (5-cyclopropyl-1- {1- [1- (4-fluorophenyl) cyclopropanecarbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(67) 1- {5-cyclopropyl-1- [1- (2-dimethylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(68) 1- {1- [1- (2-acetylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(69) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(70) 1- {1- [1- (2-acetylamino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(71) 1- (1- {1 - [(S) -2-acetylaminopropionyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(72) 1- (1- {1 - [(S) -2-acetylamino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(73) 1- {5-cyclopropyl-1- [1- (3,3,3-trifluoropropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(74) 1- (5-cyclopropyl-1- {1 - [(S) -5-oxopyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(75) 1- {1- [1- (3-acetylaminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(76) 1- {5-cyclopropyl-1- [1- (3-hydroxy-2,2-dimethylpropionyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(77) 1- {1- [1- (2-aminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(78) 1- {5-cyclopropyl-1- [1- (1-hydroxymethylcyclopropanecarbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(79) 1- {1- [1- (2-amino-2-methylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(80) 1- {5-cyclopropyl-1- [1- (4-hydroxybutyryl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(81) 1- (5-Cyclopropyl-1- {1 - [(S) -pyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl hydrochloride) - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(82) 1- (5-Cyclopropyl-1- {1 - [(S) -1-methylpyrrolidin-2-carbonyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl hydrochloride) - [(S) - 3- (2-trifluoromethylphenyl)] pyrrolidine,
(83) 1- {1- [1- (3-aminopropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(84) 1- (1- {1 - [(S) -2-amino-3-methylbutyryl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) hydrochloride) - [(S) - 3- (2-trifluoromethylphenyl)] pyrrolidine,
(85) 1- {5-cyclopropyl-1- [1- (2-methylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(86) 1- {5-cyclopropyl-1- [1- (piperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl )] pyrrolidine,
(87) 1- {5-cyclopropyl-1- [1- (2-isobutyrylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(88) 1- {1- [1- (2-Cyclopropanecarbonylaminoacetyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(89) 1- (1- {1 - [(S) -1-acetylpyrrolidin-2-carbonyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3 - (2-trifluoromethylphenyl)] pyrrolidine,
(90) 1- {5-cyclopropyl-1- [1- (2-methanesulfonylaminoacetyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(91) 1- {1- [1- (1-acetylpiperidin-4-carbonyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(92) 1- {5-cyclopropyl-1- [1- (1-methylpiperidin-4-carbonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(93) 1- {1- [1- (3-carbamoylpropionyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(94) 1- [1- (1-carbamoylmethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(95) 1- [5-cyclopropyl-1- (1-methylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(96) 1- {1- [1- (1-carbamoyl-1-methylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(97) 1- {1- [1- (2-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl)] hydrochloride]] pyrrolidine
(98) 1- [5-cyclopropyl-1- (1-cyclopropylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(99) 1- [5-cyclopropyl-1- (1-cyclopropylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(100) 1- [5-cyclopropyl-1- (1-dimethylcarbamoylmethylpiperidin-4-yl) -1H-pyrazole-4-carbonyl - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(101) 1- [1- (1-carboxymethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(102) 1- [1- (1-carboxyethylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride,
(103) 1- {1- [1- (1-carbamoylethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(104) 1- {1- [1- (2-carboxy-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(105) 1- {1- [1- (2-carbamoyl-2-methylpropyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2 trifluoromethylphenyl)] pyrrolidine,
(106) 1- {1- [1- (1-carbamoylcyclopropylmethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} hydrochloride} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine
(107) 1- (5-Cyclopropyl-1- {1- [1- (2-hydroxyethylcarbamoyl) cyclopropylmethyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) - [(S) -3- ( 2-trifluoromethylphenyl)] pyrrolidine,
(108) 1- [5-cyclopropyl-1- (1-trifluoromethanesulfonylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(109) 1- {5-cyclopropyl-1- [1- (2,2,2-trifluoroethanesulfonyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2- trifluoromethylphenyl)] pyrrolidine,
(110) 1- {1- [1- (1-cyanoiminoethyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(111) 1- (1- {1- [cyanoimino (methylamino) methyl] piperidin-4-yl} -5-cyclopropyl-1H-pyrazole-4-carbonyl) - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,
(112) 1- {1- [1- (N-cyanocarbamimidoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(113) 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,
(114) 3- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoic acid,
(115) 5- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiophene-2-carboxylic acid,
(116) 2- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) thiazole-4-carboxylic acid,
(117) 1- {5-cyclopropyl-1- [1- (5-methyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(118) 1- {5-cyclopropyl-1- [1- (5-cyclopropyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(119) 1- {5-cyclopropyl-1- [1- (5-hydroxymethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(120) 1- {5-cyclopropyl-1- [1- (5-trifluoromethyl-4H- [1,2,4] triazol-3-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl hydrochloride } - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(121) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(122) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(123) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(R) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(124) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(125) 1- {5-cyclopropyl-1- [1- (1-isopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(126) 1- {5-cyclopropyl-1- [1- (1-methylcyclopropylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine ,
(127) (-) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl} pyrrolidine,
(128) (+) - 3- (4-fluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl) pyrrolidine,
(129) 1- [5-cyclopropyl-1- (1-pyrazin-2-yl-piperidin-4-yl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine hydrochloride ,
(130) 1- [1- (trans-4-carbamoylcyclohexyl) -5-cyclopropyl-1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(131) 1- [5-cyclopropyl-1- (trans-4-ureidocyclohexyl) -1H-pyrazole-4-carbonyl] - [(S) -3- (2-trifluoromethylphenyl)] pyrrolidine,
(132) 1- {5-cyclopropyl-1- [trans-4- (1H-tetrazol-5-yl) cyclohexyl] -1H-pyrazole-4-carbonyl} - [(S) -3- (2-trifluoromethylphenyl) ] pyrrolidine,
(133) 1- {5- (1-methylcyclopropyl) -1- [1- (4-trifluoromethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine ,
(134) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-methoxycyclopropyl) -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(135) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3-phenyl-3-trifluoromethylpyrrolidine,
(136) 3- (2-chlorophenyl) -1- {5-cyclopropyl-1- [1- (2,4-difluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine,
(137) 3- (2-chloropyridin-3-yl) -1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine,
(138) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (2,2,3,3-tetramethylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (pyridine -3-yl) pyrrolidine,
(139) 1- {5-cyclohexyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(140) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethoxyphenyl) pyrrolidine,
(141) 1- {5-cyclopropyl-1- [1- (4-trifluoromethylphenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(142) 1- (5-cyclopropyl-1- {1 - [((S) -1-carboxy-2-methylpropyl) methylcarbamoyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- ( 2-trifluoromethylphenyl) pyrrolidine,
(143) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3-methoxy-3- (2-trifluoromethylphenyl) pyrrolidine,
(144) 1- {1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -5- (1-hydroxymethylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(145) 1- {5-cyclopropyl-1- [1- (thiazol-2-ylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(146) 1- {1- [1- (isopropoxycarbamoyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(147) 1- {5-cyclopropyl-1- [1- (4-fluorobenzylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(148) 1- {1- [1- (2,3-dihydroindol-1-carbonyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (pyridine -3-yl) pyrrolidine,
(149) 1- {1- [1- (2,3-dihydro [1,4] oxazin-4-carbonyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl } -3- (pyridin-3-yl) pyrrolidine,
(150) 1- {5-cyclopropyl-1- [1- (2,6-dichloropyridin-3-ylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine ,
(151) 1- {5- (1-methylcyclopropyl) -1- [1- (2,3,4,5-tetrahydrobenzo [b] azepin-1-carbonyl) piperidin-4-yl] -1H-pyrazol-4 -carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(152) ethyl 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) benzoate,
(153) 1- [1- (1-benzyloxycarbonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine,
(154) 1- {1- [1- (3-carboxy-3-methylbutyryl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(155) 1- {5-cyclopropyl-1- [1- (2-phenoxyacetyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(156) 1- {1- [1- (3-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(157) 1- {1- [1- (2-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(158) 1- [5-cyclopropyl-1- (1-oxalylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine,
(159) 1- {1- [1- (4-chlorobenzoyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(160) 1- (5-cyclopropyl-1- {1- [2- (4-fluorophenyl) acetyl] piperidin-4-yl} -1H-pyrazol-4-carbonyl) -3- (pyridin-3-yl) pyrrolidine
(161) 1- {5-cyclopropyl-1- [1- (3-trifluoromethylbenzoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(162) 1- {5-cyclopropyl-1- [1- (3-methoxybenzoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine,
(163) 1- {1- [1- (4-fluorobenzyl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine hydrochloride,
(164) 1- [1- (1-benzenesulfonylpiperidin-4-yl) -5-cyclopropyl-1H-pyrazol-4-carbonyl] -3- (pyridin-3-yl) pyrrolidine,
(165) 1- {1- [1- (4-carbamoylphenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(166) 1- {5-cyclopropyl-1- [1- (4-hydroxymethylphenyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(167) 1- {1- [1- (5-carbamoylpyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(168) 1- {1- [1- (4-aminophenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(169) 1- (5-cyclopropyl-1- {1- [4- (2-oxooxazolidin-3-yl) phenyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- (2- trifluoromethylphenyl) pyrrolidine,
(170) 1- (5-cyclopropyl-1- {1- [4- (3-methoxyureido) phenyl] piperidin-4-yl} -1H-pyrazole-4-carbonyl) -3- (2-trifluoromethylphenyl) pyrrolidine,
(171) 1- {5-cyclopropyl-1- [1- (4-methanesulfonylaminophenyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(172) 1- [1- (1-ethoxycarbamoylpiperidin-4-yl) -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine,
(173) 1- [1- (5-chloropyridin-2-yl) azetidin-3-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl] -3- (2-trifluoromethylphenyl) pyrrolidine,
(174) 1- {1- [1- (5-chloropyridin-2-yl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3-methoxymethyl-3- phenylpyrrolidine,
(175) 1- {1- [1- (5-cyanopyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(176) 3- (2-acetoxyethyl) -3- (4-fluorophenyl) -1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] - hydrochloride 1H-pyrazole-4-carbonyl} pyrrolidine,
(177) {(3S *, 4R *) hydrochloride - 3-methyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazole -4-carbonyl} -4-phenylpyrrolidine,
(178) methyl 6- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) nicotinate,
(179) methyl-2- {1- [5- (1-methylcyclopropyl) -1- (1-pyrimidin-2-ylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] pyrrolidin-3-yl} benzoate ,
(180) 3- (2-hydroxymethylphenyl) -1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} hydrochloride} pyrrolidine
(181) 1- [5-cyclopropyl-1- (1-pyridin-2-ylpiperidin-4-yl) -1H-pyrazole-4-carbonyl] -3-hydroxy-3- (pyridin-3-yl) pyrrolidine,
(182) 1- {1- [1- (4-acetylaminophenyl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine,
(183) 4- (4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} piperidin-1-yl) -3-fluorobenzoate,
(184) 3- (2-cyanophenyl) -1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazole-4-carbonyl} pyrrolidine,
(185) 3-hydroxymethyl-1- {1- [1- (4-methoxypyrimidin-2-yl) piperidin-4-yl] -5- (1-methylcyclopropyl) -1H-pyrazole-4-carbonyl} -3 hydrochloride α-phenylpyrrolidine,
(186) 3- (3,5-difluorophenyl) -3-hydroxymethyl-1- {5- (1-methylcyclopropyl) -1- [1- (pyrimidin-2-yl) piperidin-4-yl] -1H- hydrochloride pyrazole-4-carbonyl} pyrrolidine,
(187) 1- {1- [1- (3-chloropyridin-2-yl) piperidin-4-yl] -5-cyclopropyl-1H-pyrazol-4-carbonyl} -3- (pyridin-3-yl) pyrrolidine ,
(188) 1- {5-cyclopropyl-1- [1- (2-fluorophenylcarbamoyl) piperidin-4-yl] -1H-pyrazol-4-carbonyl} -3- (thiazol-2-yl) pyrrolidine,
(189) (S) -2 - [(trans-4- {5-cyclopropyl-4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl} -cyclohexanecarbonyl) methylamine] -3- methylbutyric acid
(190) 1- {5- (1-methylcyclopropyl) -1- [trans-4- (2-fluorophenylcarbamoyl) cyclohexyl] -1H-pyrazole-4-carbonyl} -3- (2-trifluoromethylphenyl) pyrrolidine and
(191) cis-4- {5- (1-methylcyclopropyl) -4- [3- (2-trifluoromethylphenyl) pyrrolidin-1-carbonyl] pyrazol-1-yl) cyclohexanecarboxylic acid. 21. A pharmaceutical composition having an inhibitory effect on 11βHSD1, containing a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof. 22. An 11βHSD1 inhibitor comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof. 23. An agent for the treatment or prevention of pathology associated with a glucocorticoid, containing the compound according to any one of claims 1 to 20 or its pharmaceutically acceptable salt. 24. The agent according to item 23, where the pathology associated with glucocorticoids is:
(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,
(2) metabolic syndrome,
(3) a fatal vascular event, including myocardial infarction or brain apoplexy,
(4) hyperorexia,
(5) a disease with impaired neural functions, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,
(6) a disease associated with decreased immune function,
(7) glaucoma, or
(8) osteoporosis. 25. A method of inhibiting 11βHSD1, comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof. 26. A method of treating or preventing a pathology associated with glucocorticoids, comprising administering a pharmaceutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof. 27. The method according to p, where the pathology associated with glucocorticoids is one of the following:
(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,
(2) metabolic syndrome,
(3) a fatal vascular event, including myocardial infarction or brain apoplexy,
(4) hyperorexia,
(5) a disease with impaired neural functions, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,
(6) a disease associated with decreased immune function,
(7) glaucoma, or
(8) osteoporosis. 28. The use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for the preparation of an 11βHSD1 inhibitor. 29. The use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for the preparation of an agent for the treatment or prophylaxis of pathology related to glucocorticoids. 30. The application of clause 29, where the pathology associated with a glucocorticoid is one of the following:
(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,
(2) metabolic syndrome,
(3) a fatal vascular event, including myocardial infarction or brain apoplexy,
(4) hyperorexia,
(5) a disease with impaired neural functions, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,
(6) a disease associated with decreased immune function,
(7) glaucoma, or
(8) osteoporosis. 31. Commercial packaging, including written instructions stating that the pharmaceutical composition according to item 21 can or should be used to treat or prevent a disease selected from the following:
(1) metabolic disease, including diabetes, insulin resistance, complications of diabetes, obesity, hyperlipidemia, hypertension or fatty liver,
(2) metabolic syndrome,
(3) a fatal vascular event, including myocardial infarction or brain apoplexy,
(4) hyperorexia,
(5) a disease with impaired neural functions, including cognitive impairment, neurodegenerative diseases, emotional disorders, schizophrenia or stimulation of appetite,
(6) a disease associated with decreased immune function,
(7) glaucoma, or
(8) osteoporosis. 32. The use of clause 29 to suppress an increase in blood glucocorticoids by use in combination with a pharmaceutical agent that increases blood glucocorticoids. 33. Dimethyl-2 - [(S) -2-nitro-1- (2-trifluoromethylphenyl) ethyl] malonate. 34. Methyl- (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidine-3-carboxylate. 35. (S) -4- (2-Trifluoromethylphenyl) pyrrolidin-2-one. 36. (S) -3- (2-Trifluoromethylphenyl) pyrrolidine or a salt thereof. 37. A method of producing dimethyl-2 - [(S) -2-nitro-1- (2-trifluoromethylphenyl) ethyl] malonate, comprising reacting 1 - ((E) -2-nitrovinyl) -2-trifluoromethylbenzene with dimethyl malonate in the presence of 1 - (3,5-bis-trifluoromethylphenyl) -3 - ((1S, 2S) -2-ymethylaminocyclohexyl) thiourea. 38. The method of obtaining methyl- (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidine-3-carboxylate, including the restoration and closure of the ring of dimethyl-2 - [(S) -2-nitro-1- (2- trifluoromethylphenyl) ethyl] malonate. 39. A method of producing (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one, comprising the hydrolysis and decarboxylation of methyl (S) -2-oxo-4- (2-trifluoromethylphenyl) pyrrolidine-3-carboxylate. 40. A method of producing a salt of (3) -3- (2-trifluoromethylphenyl) pyrrolidine, comprising reducing (S) -4- (2-trifluoromethylphenyl) pyrrolidin-2-one and treating the resulting compound with an acid to form a salt.