# Patent

## Title
Bicyclic heterocyclic compound

## Abstract

To provide a compound useful as an active ingredient of a pharmaceutical composition for treating 11β-hydroxysteroid dehydrogenase type 1-related diseases such as dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance and the like.
[Means for Solution] A bicyclic heterocyclic compound (the bicyclic heterocycle is formed when a cyclohexane ring is fused with a 5- to 6-membered monocyclic heterocycle that has only a nitrogen atom as a hetero atom) substituted with an acylamino group such as a (hetero)aroylamino group or the like or a pharmaceutically acceptable salt thereof was found to have an excellent selective inhibitory action against 11β-HSD1. Accordingly, the bicyclic heterocyclic compound of the present invention can be used for treating dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance, and the like.

## Background
CROSS REFERENCES TO RELATED APPLICATIONS
This application is a 371 of International Patent Application No. PCT/JP2012/076771, filed on Oct. 17, 2012, and claims priority to Japanese Patent Application No. 2011-228822, filed on Oct. 18, 2011.
TECHNICAL FIELD
The present invention relates to a bicyclic heterocyclic compound or a pharmaceutically acceptable salt thereof that is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-related diseases such as dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance.
BACKGROUND ART
Glucocorticoid is produced from the adrenal gland. In addition, glucocorticoid is converted into an active form from an inactive form at tissue level and acts via its receptor thereof.
11β-hydroxysteroid dehydrogenase (11β-HSD) is an enzyme that catalyzes this conversion, and it is known that there are two subtypes of the enzyme. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that converts the inactive form into the active form and is highly expressed in the liver, and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is an enzyme that converts the active form into the inactive form and is highly expressed in the kidneys.
11β-HSD1 is also known to be highly expressed in the brain, but the 11β-HSD2 is practically not expressed in the brain (Thekkepat C. Sandeep et al., Proceedings of the National Academy of Science, 2004, Vol. 101, p. 6734-6739).
As the relationship between glucocorticoid and patients with dementia, the increase in the level of active glucocorticoid (cortisol) in the saliva or blood in patients with Alzheimer's disease (Giubilei F. et al., Journal of neuroscience research, 2001, Vol. 66, p. 262-265, Zeynel A Erkut et al., Neuropsychopharmacology, 2004, Vol. 29, p. 152-157), correlation between HPA axis disorder (John G Csernansky et al., The American journal of Psychiatry, 2006, Vol. 163, p. 2164-2169) as well as cortisol level and the value of bran atrophy index, and the like have been confirmed (Giubilei F. et al., Journal of neuroscience research, 2001, Vol. 66, p. 262-265). In addition, it has been confirmed that the administration of a cortisol or glucocorticoid preparation to a healthy individual or a patient with Alzheimer's disease induces language disorder or memory disorder (A. H. Young et al., Psychopharmacology, 1999, Vol. 145, p. 260-266, P. S. Aisen et al., Neurology, 2000, Vol. 54, p. 588-593). Moreover, as the relationship between 11β-HSD1 and cognition, they reported an action of improving verbal memory by the administration of non-selective 11β-HSD inhibitor to a patient with type II diabetes mellitus (Thekkepat C. Sandeep et al., Proceeding of National Academy of Science, 2004, Vol. 101, p. 6734-6739), as well as an action of ameliorating cognitive disorder in an aged 11β-HSD1 knockout mouse (Joyce L., W. Yau et al., Proceeding of the National Academy of Science, 2001, Vol. 98, p. 4716-4721), and the like.
In this respect, the 11β-HSD1 inhibitor is expected to suppress the action of glucocorticoid in the brain by inhibiting the conversion of glucocorticoid to the active type, and accordingly remedy cognitive disorder induced by glucocorticoid.
In addition to dementia, the 11β-HSD1 inhibitor is also expected to ameliorate central disorders such as schizophrenia (X. Y. Zhang et al., Neuropsychopharmacology, 2005, Vol. 30, p. 1532-1538), depression (Bernard J. Carroll et al., Archives of General Psychiatry, 1981, Vol. 38, p. 15-22), anxiety (Veen G. et al., Metabolism, 2009, Vol. 58, p. 821-827), Post-Traumatic Stress Disorder (PTSD) (Charney D. S. et al., Archives of General Psychiatry, 1993, Vol. 50, p. 295-305), Attention Deficit/Hyperactivity Disorder (AD/HD) (Hong H. J. et al., Yonsei Medical Journal, 2003, Vol. 44, p. 608-614), panic disorder (Angelika E. et al., Neuropsychopharmacology, 2006, Vol. 31, p. 2515-2522), sleep disorder (Andersen M. L. et al., Journal of sleep research, 2005, Vol. 14, p. 83-90), which are closely related to stress and show HPA axis disorder or the increase in plasma cortisol level.
In addition, as the relationship between 11β-HSD1 and metabolic diseases, increased activity of 11β-HSD1 in the adipose tissue of an obese individual is known (Rask E. et al., The Journal of Clinical Endocrinology & Metabolism, 2001, Vol. 86, p. 1418-1421), and it is reported that the activity of 11β-HSD1 is closely correlated with BMI as the index of obesity, HOMA-IR as the index of insulin resistance, and the fasting blood glucose level (Lindsay R. S. et al., The Journal of Clinical Endocrinology & Metabolism, 2003, Vol. 88, p. 2738-2744). It is also reported that a transgenic mouse over-expressing 11β-HSD1 in an adipose tissue-selective manner shows increase in the level of glucocorticoid in the adipose tissue and insulin resistance, visceral fat obesity, hyperlipidemia, and hypertension (Masuzaki H. et al., Science, 2001, Vol. 294, p. 2166-2170, Masuzaki H. et al., The Journal of Clinical Investigation, 2003, Vol. 112, p. 83-90), and that a 11β-HSD1 knockout mouse shows improvement in glucose tolerance, decrease in blood triglyceride levels, and increase in HDL-cholesterol levels (Morton N. M. et al., The Journal of Biological Chemistry, 2001, Vol. 276, p. 41293-41300).
In this respect, a selective inhibitor of 11β-HSD1 is expected to suppress the action of glucocorticoid in a tissue by inhibiting the conversion of glucocorticoid to the active type, and consequently remedy metabolic abnormality such as hyperglycemia, insulin resistance, obesity, hyperlipidemia, and hypertension induced by glucocorticoid.
It is also reported that a non-selective 11β-HSD inhibitor, carbenoxolone, ameliorates deficient secretion of insulin caused by the addition of inactive glucocorticoid in rat pancreatic β-cells (Davani B. et al., The Journal of Biological Chemistry, 2000, Vol. 275, p. 34841-34844), so the 11β-HSD1 inhibitor has a possibility of ameliorating not only insulin resistance but also hyperglycemia by promoting insulin secretion.
In addition, it is reported that a triazole compound having the 11β-HSD1 inhibitory action is effective in a spinal nerve ligation model as an animal model of neuropathic pain and an animal model of fibromyalgia caused by repeated reserpine administration (Patent Document 1), so the 11β-HSD1 inhibitor is expected to be effective for treating pain, particularly neuropathic pain and fibromyalgia.
Examples of other 11β-HSD1-related diseases include osteoporosis (Cooper M. S. et al., Bone, 2000, Vol. 27, p. 375-381) and glaucoma (Rauz S. et al., Investigative Opthalmology & Visual Science, 2001, Vol. 42, p. 2037-2042), and the 110-HSD1 inhibitor is expected to be effective for ameliorating these diseases.
Patent Document 2 discloses that a compound represented by the following the formula (A) has the 11β-HSD1 inhibitory action and is useful for treating diseases such as diabetic diseases and metabolic syndrome. However, in the compound, the moiety corresponding to amide of the present application is cyclic amide.




(see the corresponding gazette for symbols in the formula)

Patent Document 3 discloses that a compound represented by the following formula (B) has the action of regulating hydroxysteroid dehydrogenases such as 11β-HSD1 and is useful for treating a large number of diseases including diabetes, metabolic syndrome, and dementia. However, this compound does not include a ring corresponding to the ringA of the present application.




(see the corresponding gazette for symbols in the formula)

Patent Document 4 discloses that a compound represented by the following the formula (C) has an inhibitory action against 11β-HSD1, 11β-HSD2, 17β-HSD3, and the like and is useful for treating a large number of diseases including diabetes, metabolic syndrome, and dementia. However, this compound does not include a ring corresponding to the ring A of the present application.




(see the corresponding gazette for symbols in the formula)

Patent Document 5 discloses that a compound represented by the following formula (D) has the action of regulating a TRPV 1 receptor and is useful for treating pain. However, this document does not disclose the 11β-HSD1 inhibitory action and the usefulness of the compound with respect to dementia.




(see the corresponding gazette for symbols in the formula)

Patent Document 6 discloses that a compound represented by the following formula (E) has the action of regulating a histamine H3 receptor and is useful for treating a large number of diseases including obesity, diabetes, and Alzheimer's disease.




(see the corresponding gazette for symbols in the formula)

Patent Document 7 discloses that a compound represented by the following formula (F) has the action of regulating stearoyl-CoA desaturase and is useful for treating hyperlipidemia, circulatory diseases, diabetes, obesity, metabolic syndrome and the like. However, the document does not make disclosures about the 11β-HSD1 inhibitory action and usefulness of the compound with respect to dementia.




(see corresponding gazette for symbols in the formula)

Patent Document 8 discloses that a compound represented by the following formula (G) has the action of regulating a C5A receptor and is useful for treating various inflammatory diseases and immunological diseases. However, the document does not disclose the 11β-HSD1 inhibitory action.




(see the corresponding gazette for symbols in the formula)

Patent Document 9 discloses that a compound represented by the following formula (H) has an antibacterial activity and is useful for treating infection. However, the document does not disclose the 11β-HSD1 inhibitory action and the usefulness of the compound with respect to dementia.




(see the corresponding gazette for symbols in the formula)

RELATED ART
Patent Document
Patent Document 1: Pamphlet of International Publication WO2012/033070
Patent Document 2: Pamphlet of International Publication WO2007/124254
Patent Document 3: Pamphlet of International Publication WO2007/145834
Patent Document 4: Pamphlet of International Publication WO2008/088540
Patent Document 5: Pamphlet of International Publication WO2007/069773
Patent Document 6: Pamphlet of International Publication WO01/068652
Patent Document 7: Pamphlet of International Publication WO2007/050124
Patent Document 8: Pamphlet of International Publication WO03/082826
Patent Document 9: Pamphlet of International Publication WO2006/105289
DISCLOSURE OF INVENTION
Technical Problem
Problems to Be Solved by the Invention 
The present invention provides a novel compound that is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating 11β-hydroxysteroid dehydrogenase type 1-related diseases such as dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance and the like.
Means for Solving the Problems
The present inventors conducted thorough research regarding a compound having 11β-HSD1 inhibitory action that can be expected to ameliorate dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance. As a result, they found that a bicyclic heterocyclic compound (the bicyclic heterocycle is formed when a cyclohexane ring is fused with a 5- to 6-membered monocyclic heterocycle having only a nitrogen atom as a hetero atom) substituted with an acylamino group such as a (hetero)aroylamino group or a pharmaceutically acceptable salt thereof has an excellent selective inhibitory action against 11β-HSD1, thereby completing the present invention.
That is, the present invention relates to a compound of the formula (I) or a salt thereof and a pharmaceutical composition containing the compound of the formula (I) or a salt thereof and an excipient.




[symbols in the formula represent the following:
ring A: a 5- to 6-membered monocyclic heterocycle which may be substituted and has only the nitrogen atoms as the hetero atom; wherein the atoms in the position where the ring is fused with the adjacent ring are carbon atoms,
R1: lower alkyl, halogeno-lower alkyl, or cycloalkyl which may be substituted,
R2: halogen or lower alkyl,
R3: aryl, heteroaryl, or lower alkylene-heteroaryl; wherein each of the aryl and heteroaryl represented by R3 may be substituted,
n: an integer of 0 to 3, and
a dotted line represents a single bond or a double bond].
In addition, the present invention relates to a pharmaceutical composition which contains the compound of the formula (I) or a salt thereof and is for treating dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance. In addition, the pharmaceutical composition includes an agent which containing the compound of the formula (I) or a salt thereof and for treating dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance.
Moreover, the present invention relates to use of the compound of the formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance; use of the compound of the formula (I) or a salt thereof for treating dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance; the compound of the formula (I) or a salt thereof for treating dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance; and a method of treating dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance, which includes administering the effective amount of the compound of the formula (I) or a salt thereof to a subject. In addition, the “subject” refers to human being or other animals that require the prevention or treatment of the above diseases. As another embodiment, the “subject” refers to a human being who requires the prevention or treatment of the above diseases.
That is, the present invention relates to

    (1) A pharmaceutical composition including the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
    (2) The pharmaceutical composition according to (1), which is an inhibitor of 11β-hydroxysteroid dehydrogenase type 1;
    (3) The pharmaceutical composition according to (1), which is an agent for preventing or treating dementia, schizophrenia, depression, or pain;
    (4) The pharmaceutical composition according to (1), which is an agent for preventing or treating dementia;
    (5) The pharmaceutical composition according to (1), which is an agent for preventing or treating pain;
    (6) Use of the compound of the formula (I) or a pharmaceutically acceptable thereof for the manufacture of an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 or an agent for preventing or treating dementia, schizophrenia, depression, or pain;
    (7) Use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating dementia, schizophrenia, depression, or pain;
    (8) The compound of the formula (I) or a pharmaceutically acceptable salt thereof for preventing or treating dementia, schizophrenia, depression, or pain;
    (9) A method of preventing or treating dementia, schizophrenia, depression, or pain, including administering an effective amount of the compound of the formula (I) or a salt thereof to a patient.


Effects of the Invention
The compound of the formula (I) or a salt thereof has a 11β-HSD1 inhibitory action and can be used as an agent for preventing and/or treating dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance, and the like.


EMBODIMENTS FOR CARRYING OUT THE INVENTION
Hereafter, the present invention will be described in detail.
In the present specification, “lower alkyl” refers to linear or branched alkyl having 1 to 6 carbon atoms (hereinafter, abbreviated to C1-6), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or the like. As another embodiment, the lower alkyl is C1-4 alkyl, and as still another embodiment, the lower alkyl is methyl, ethyl, n-propyl, or isopropyl.
“Lower alkylene” refers to linear or branched C1-6 alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methyl methylene, ethyl ethylene, 1,2-dimethyl ethylene, 1,1,2,2-tetramethyl ethylene or the like. As another embodiment, the lower alkylene is C1-4 alkylene, and as still another embodiment, the lower alkylene is methylene, ethylene, or trimethylene.
“Halogen” refers to F, Cl, Br, or I.
“Halogeno-lower alkyl” refers to lower alkyl substituted with one or more halogen atoms. As another embodiment, the halogeno-lower alkyl is lower alkyl substituted with 1 to 5 halogen atoms, and as still another embodiment, the halogeno-lower alkyl is fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, or the like.
“Cycloalkyl” refers to a saturated C3-10 hydrocarbon ring group which may have a bridge. The cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl or the like. As another embodiment, the cycloalkyl is C3-8 cycloalkyl, and as still another embodiment, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
“Aryl” refers to a mono- to tri-cyclic C6-14 aromatic hydrocarbon ring group, for example, phenyl, naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl or the like. As another embodiment, the aryl is phenyl or naphthyl, and as still another embodiment, the aryl is phenyl.
A “heterocycle” refers to a 3- to 15-membered, or, as another embodiment, 5- to 10-membered mono- to tri-cyclic heterocyclic group containing 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen. The heterocycle includes a saturated ring, an aromatic ring, and cyclic groups formed when these rings are partially hydrogenated. Sulfur or nitrogen as a ring atom may be oxidized to form oxide or dioxide. The heterocycle is specifically pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthylidyl, cinnolinyl, phthalazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, carbazolyl, dibenzo[b,d]furanyl, dibenzo[b,d]thienyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, dioxanyl, tetrahydrothiopyranyl, indolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzimidazolyl, tetrahydrobenzimidazolyl, tetrahydroindazolyl, tetrahydroquinoxalinyl, tetrahydrocinnolinyl, dihydroquinoxalinyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, dihydrobenzofuryl, 1,3-benzodioxolyl, chromanyl, chromenyl, methylenedioxyphenyl, ethylenedioxyphenyl, quinuclidinyl or the like. As another embodiment, the heterocycle is 5- to 10-membered mono- to bicyclic heterocyclic group, and as still another embodiment, the heterocycle is pyridyl, thiazolyl, thienyl, furyl, indolyl, benzothienyl, indazolyl, pyrrolidinyl, morpholinyl, oxetanyl, or tetrahydropyranyl.
“Heteroaryl” refers to, among the above “heterocycles”, a 5- to 15 membered, or, as another embodiment, 5- to 10-membered mono- to tri-cyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen. Sulfur or nitrogen as a ring atom may be oxidized to form oxide or dioxide. The heteroaryl is specifically pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, naphthylidyl, cinnolinyl, phthalazinyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, carbazolyl, benzo[b,d]furanyl, benzo[b,d]thienyl, or the like.
As another embodiment, the heteroaryl is 5- to 10-membered mono- to bicyclic heteroaryl, and as still another embodiment, the heteroaryl is 5- to 6-membered monocyclic heteroaryl. As another embodiment, the heteroaryl is pyridyl, thiazolyl, thienyl, furyl, indolyl, benzothienyl, or indazolyl.
The “5- to 6-membered monocyclic heterocycle having only a nitrogen atom as a hetero atom” refers to, among the above “heterocycles”, a 5- to 6-membered monocyclic heterocyclic group having only 1 to 3 nitrogen atoms as hetero atoms, and includes a saturated ring, an aromatic ring, and cyclic groups formed when these rings are partially hydrogenated. Nitrogen as a ring atom may be oxidized to form oxide. The monocyclic heterocycle is specifically pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. As another embodiment, the monocyclic heterocycle is pyrazolyl, pyridazinyl, or pyrimidinyl.
In the present specification, the words “may be substituted” mean that a group is unsubstituted or has 1 to 5 substituents. In addition, the word “substituted” means that a group has 1 to 5 substituents. When a group has a plurality of substituents, these substituents may be the same as or different from each other.
“(R2)n—” on a cyclohexane ring or a cyclohexene ring as a bicyclic ring that is formed when the ring A is fused with an adjacent cyclohexane ring or cyclohexene ring means that the ring is substituted with n groups represented by R2 in the portion of a cyclohexane ring or a cyclohexene ring as a bicyclic ring that is formed when the ring A is fused with an adjacent cyclohexane ring or cyclohexene ring (wherein the ring is not substituted when n represents 0). When n represents a plural number, the respective substituents represented by R2 may be the same as or different from each other.
Examples of the substituent in the “5- to 6-membered monocyclic heterocycle having only a nitrogen atom as a hetero atom” that may be substituted in the ring A include a group selected from halogen, lower alkyl, halogeno-lower alkyl, —OR0, —O-halogeno-lower alkyl, and oxo (wherein R0 represents —H or lower alkyl, the same shall apply hereinafter).
Examples of the substituent in the “aryl” or “heteroaryl” that may be respectively substituted in R3 include a group selected from the following Group G Group G: halogen, cyano, lower alkyl, halogeno-lower alkyl, —N(R0)2, —OR0—, —O-halogeno-lower alkyl, —O-(lower alkyl substituted with cycloalkyl), -(lower alkylene that may be substituted with halogen)-OR0, lower alkylene-O-cycloalkyl, lower alkylene-O-aryl, lower alkylene-O-heterocyclic group, lower)alkylene-N(R0)2, lower alkylene-CO2R0, lower) alkylene-C(O)N(R0)2, —S-lower alkyl, —S(O)-lower alkyl, —S(O)2-lower alkyl, lower alkylene-S-lower alkyl, lower alkylene-S(O)-lower alkyl, lower alkylene-S(O)2-lower alkyl, —CO2R0, —C(O)N(R0)2, cycloalkyl, aryl, a heterocyclic group, lower alkylene-cycloalkyl, lower alkylene-aryl, lower alkylene-heterocyclic group, —O-cycloalkyl, —O-aryl, —O-heterocyclic group, —O-lower alkylene-aryl, and —O-lower alkylene-heterocyclic group.
Here, the aryl and heterocyclic group in Group G may be respectively substituted with halogen, cyano, nitro, lower alkyl, halogeno-lower alkyl, —OR0, —O-halogeno-lower alkyl, lower alkylene-OR0, —S(O)2-lower alkyl, cycloalkyl, —CO2R0, —C(O)N(R0)2, or oxo, and the cycloalkyl in Group G may be substituted with halogen or lower alkyl.
Alternatively, two groups in Group G may form lower alkylene, —N(R0)-lower alkylene, or lower)alkylene-N(R0)— in combination.
Examples of another embodiment of the substituent in the “aryl” or “heteroaryl” that may be respectively substituted in R3 include a group selected from the following Group Q.
Group Q: halogen, lower alkyl, halogeno-lower alkyl, —OR0, lower alkylene-OR0, —S-lower alkyl, aryl, a heterocyclic group, and lower alkylene-heterocyclic group.
Here, the aryl and heterocyclic group in Group Q may be substituted with halogen, cyano, lower alkyl, —OR0, or oxo.
Examples of still another embodiment of the substituent in the “aryl” or “heteroaryl” that may be respectively substituted in R3 include a group selected from (i) phenyl or pyridyl that may be respectively substituted with halogen or cyano, (ii) halogen, (iii) lower alkyl, and (iv) —O-lower alkyl.
Examples of the substituent in “cycloalkyl” that may be substituted in an R1 ring include halogen, lower alkyl, and the like.
Embodiments of the compound of the present invention represented by the formula (I) will be shown below.
(1) A compound in which R1 represents methyl, ethyl, n-propyl, isopropyl or cyclopropyl, as another embodiment, a compound in which R1 represents cyclopropyl
(2) A compound in which the bicyclic ring formed when the ring A is fused with an adjacent ring is 4,5,6,7-tetrahydroindazol-5-yl which may be substituted with halogen, lower alkyl, halogeno-lower alkyl, —OR0, or —O-halogeno-lower alkyl, as another embodiment, a compound in which the bicyclic ring formed when the ring A is fused with an adjacent ring is 4,5,6,7-tetrahydroindazol-5-yl
(3) A compound in which n represents 0
(4) A compound in which R3 represents aryl or heteroaryl which may be respectively substituted with a group selected from Group Q,
as another embodiment, a compound in which R3 represents phenyl, indolyl, or indazolyl which may be respectively substituted with a group selected from Group Q,
as another embodiment, a compound in which R3 represents phenyl that may be substituted with a group selected from (i) phenyl or pyridyl which may be respectively substituted with halogen or cyano, (ii) halogen, (iii) lower alkyl, and (iv) —O-lower alkyl; as still another embodiment, a compound in which R3 represents phenyl which may be substituted with phenyl substituted with halogen or cyano and may be further substituted with halogen; as another embodiment, a compound in which R3 represents phenyl which may be substituted with phenyl substituted with halogen or cyano at a 4-position and may be further substituted with halogen; and as another embodiment, a compound in which R3 represents phenyl that may be substituted with 2-cyanophenyl which may be substituted with halogen at a 4-position and may be further substituted with halogen,
as another embodiment, a compound in which R3 represents phenyl substituted with lower alkyl or —O-lower alkyl; and as another embodiment, a compound in which R3 represents phenyl substituted with —O-lower alkyl,
as another embodiment, a compound in which R3 represents indolyl which may be substituted with lower alkyl or —O-lower alkyl, and as another embodiment, a compound in which R3 represents indol-4-yl which may be substituted with lower alkyl or —O-lower alkyl
(6) A compound which is a combination of two or more groups according to the above embodiments (1) to (5)
As specific embodiments of the combination of two or more groups according to the above embodiments (1) to (5) of embodiment (6), the following (a) to (f) are exemplified.
(a) The compound represented by the formula (I) in which n represents 0
(b) The compound according to (a), in which R1 represents cyclopropyl
(c) The compound according to (b), in which the bicyclic group formed when the ring A is fused with an adjacent ring is 4,5,6,7-tetrahydroindazol-5-yl
(d) The compound according to (c), in which R3 represents phenyl, indolyl, or indazolyl which may be respectively substituted with a group selected from the Group Q
(e) The compound according to (d), in which R3 represents phenyl which may be substituted with a group selected from a group consisting of (i) phenyl or pyridyl that which be respectively substituted with halogen or cyano, (ii) halogen, (iii) lower alkyl, and
(iv) —O-lower alkyl
(f) The compound according to (d), in which R3 represents indolyl which may be substituted with lower alkyl or —O-lower alkyl Examples of specific compounds included in the present invention include the following compounds:
A compound selected from a group consisting of (−)-N-cyclopropyl-4-isopropoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide,

    (−)-2′-cyano-N-cyclopropyl-6′-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide,
    N-cyclopropyl-1-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide,
    N-cyclopropyl-7-methoxy-1-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide,
    2′-cyano-N-cyclopropyl-4′-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide,
    2′-cyano-N-cyclopropyl-3-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide,
    N-cyclopropyl-2′,6′-difluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide,
    N-cyclopropyl-4-(3,5-difluoropyridin-4-yl)-N-(4,5,6,7-tetrahydro-2H-indazol-5-yl)benzamide, and
    N-cyclopropyl-4-isopropoxy-2-methoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide


The compound of the formula (I) may have tautomers or geometric isomers depending on the type of substituents. In the present specification, the compound of the formula (I) is described only in one form of isomer in some cases. However, the present invention includes other isomers, separated isomers, or a mixture of these. For example, 4,5,6,7-tetrahydroindazol-5-yl is described as a tautomer of one of the following (A) and (B) in the present specification, but tautomers of both the (A) and (B) are also included in the present invention.




In addition, the compound of the formula (I) has asymmetric carbon atoms or axis chirality in some cases, and there may be optical isomers based on this case. The present invention includes separated optical isomers of the compound of the formula (I) or a mixture of these.
The present invention also includes pharmaceutically acceptable prodrugs of the compound represented by the formula (I). The pharmaceutically acceptable prodrugs refer to compounds having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form the prodrugs include the groups disclosed in Prog. Med., 5, 2157-2161 (1985) or in “Pharmaceutical Research and Development”, (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design 163-198.
The salt of the compound of the formula (I) refers to a pharmaceutically acceptable salt of the compound of the formula (I), and forms an acid addition salt or a salt with a base depending on the type of substituents. Specific examples of the salt include acid addition salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, or phosphoric acid or with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartrate, ditoluoyl tartrate, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, or glutamic acid, salts with an inorganic base such as sodium, potassium, magnesium, calcium, or aluminum, or with an organic base such as methylamine, ethylamine, ethanolamine, lysine, or ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine, ammonium salts, and the like.
(Preparation Process)
The compound of the formula (I) or a salt thereof can be prepared by applying various known synthesis processes, by using characteristics based on the basic structure thereof or the type of substituents. At this time, depending on the type of functional groups, it is in some cases effective to substitute the functional group in advance with an appropriate protective group (group that can be easily converted into the functional group) during the period from the stage of a starting material to the stage of an intermediate. Examples of the protective group include the protective groups disclosed in Wuts (P. G M. Wuts) and Greene (T. W. Greene), “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)”, and the like. The protective group may be used by being appropriately selected according to the reaction conditions thereof. In this method, the protective group is introduced to cause a reaction, and then the protective group is optionally removed, whereby a desired compound can be obtained.
In addition, a prodrug of the compound of the formula (I) can be prepared by introducing a specific group during the period from the stage of a starting material to the stage of an intermediate just like the above protective group, or by further causing a reaction by using the obtained compound of the formula (I). The reaction can be performed by applying methods known to a person skilled in the art, such as general esterification, amidation, and dehydration.
Hereinafter, a typical preparation process of the compound of the formula (I) will be described. Each preparation process can be performed with reference to the reference document included in the corresponding description. Moreover, the preparation process of the present invention is not limited to the following examples.
(Preparation Process 1)




A compound (1) of the present invention can be obtained from an amidation reaction between a compound (1) and a compound (2).
In this reaction, the compounds (1) and (2) are used in an equal amount, or one of the compounds used in an excess amount than the other. A mixture of these is generally stirred for 0.1 hours to 5 days under cooling to heating preferably at −20° C. to 60° C. in a solvent inactive to the reaction in the presence of a condensing agent. Though not particularly limited, examples of the solvent used herein include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, ethers such as diethylether, tetrahydrofuran (THF), dioxane, and dimethoxyethane, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), ethyl acetate, acetonitrile, water, and a mixture of these. Examples of the condensing agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodimide, dicyclohexylcarbodimide, 1,1′-carbonyldiimidazole, diphenyl phosphate azide, and phosphorus oxychloride, and N-[(dimethylamino)(3H-[1,2,3]triazo[4,5,-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU), but the present invention is not limited thereto. It is preferable to use an additive (for example, 1-hydroxybenzotriazole) in some cases for the reaction. It is advantageous to perform the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, in terms of causing the reaction to proceed smoothly.
In addition, it is also possible to use a method of converting carboxylic acid (1) into a reactive derivative and then reacting this with amine (2). Examples of the reactive derivative of carboxylic acid include acid halides obtained when the carboxylic acid reacts with a halogenating agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydrides obtained when the carboxylic acid reacts with isobutyl chloroformate or the like, and active esters obtained when the carboxylic acid is condensed with 1-hydroxybenzotriazole or the like. The reaction between these reactive derivatives and the compound (2) can be performed in a solvent inactive to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling to heating preferably at −20° C. to 60° C.
Moreover, if the ring A is pyrazole, it is in some cases effective to perform a reaction by using the compound (2) protected with a protective group such as ethoxycarbonyloxy, tert-butoxycarbonyl, benzyloxycarbonyl, or benzyloxymethyl and then performing deprotection, for obtaining the compound (1) of the present invention. As the deprotection reaction, for example, the method disclosed in Wuts (P. G M. Wuts) and Greene (T. W. Greene), “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” can be used.
(Preparation Process 2)




A compound (I-a) of the present invention can be obtained by reacting a compound (3) with a compound (4) and then causing a cyclization reaction between the product and hydrazine.
The reaction between the compound (3) and compound (4) can be performed in the presence of a base such as triethylamine, by using the compound (3) and the compound (4) in an equal amount, or using one of the compounds in an excess amount than the other, without using a solvent or in a solvent inactive to the reaction, under heating. The solvent is not particularly limited as long as it is a solvent inactive to the reaction, but for example, ethers, aromatic hydrocarbons, and the like can be used.
The cyclization reaction between the product obtained from the reaction between the compound (3) and compound (4) and hydrazine can be performed without using a solvent or in a solvent inactive to the reaction, under heating. The solvent is not particularly limited as long as it is a solvent inactive to the reaction, but for example, ethers, aromatic hydrocarbons, alcohols such as methanol and ethanol, water, and the like can be used.
In addition, some of the compounds represented by the formula (I) can also be prepared from the compound of the present invention obtained in the above manner, by arbitrarily combining steps that a person skilled in the art can employ, such as acylation, a substitution reaction, oxidation, reduction, hydrolysis, and amidation.
Starting materials used for preparing the compound of the present invention can be prepared by, for example, the following method, the method described in the preparation example described later, known methods, or methods clearly known to a person skilled in the art, or by applying modified methods of these.
(Starting Material Synthesis 1)




The compound (2) can be obtained from a reductive amination reaction between a compound (5) and a compound (6).
In this reaction, the compound (5) and the compound (6) are used in an equal amount, or one of these compounds is used in an excess amount than the other. A mixture of these is generally stirred for 0.1 hours to 5 days at −45° C. to heating under reflux preferably at 0° C. to room temperature in a solvent inactive to the reaction, in the presence of a reductant. Though not particularly limited, examples of the solvent used herein include alcohols such as methanol and ethanol, ethers such as diethylether, tetrahydrofuran, dioxane, and dimethoxyethane, and a mixture of these. Examples of the reductant include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and the like. It is preferable to perform the reaction in the presence of a dehydrating agent such as molecular sieves or an acid such as acetic acid, hydrochloric acid, or a titanium(IV) isopropoxide complex in some cases. Depending on the reaction, an imine is generated by the condensation of the compounds (5) and (6) and can be isolated as a stable intermediate in some cases. In this case, the compound (2) can be obtained by a reduction reaction of the imine intermediate. In addition, instead of treating the compounds with the reductant, it is possible to perform the reaction in a solvent such as methanol, ethanol, or ethyl acetate in the presence or absence of an acid such as acetic acid or hydrochloric acid by using a reduction catalyst (for example, palladium carbon or Raney nickel). In this case, it is preferable to perform the reaction in a hydrogen atmosphere under normal pressure to 50 atm, under cooling to heating.
(Starting Material Synthesis 2)




A compound (3) can be obtained by preparing a compound (8) by causing amidation between the compound (1) and the compound (7) and then deprotecting ketal of the compound (8).
The amidation reaction can be performed in the same manner as in Preparation process 1.
For the deprotection of ketal, the method disclosed in Wuts (P. G M. Wuts) and Greene (T. W. Greene), “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)” can be used.
The compound of the formula (I) is isolated as a free compound, a salt thereof, hydrate, solvate, or polymorphic substance and purified. The salt of the compound of the formula (I) can be prepared by a salt preparation reaction using a common method.
Isolation and purification are performed by applying general chemical operations such as extraction, fractionated crystallization, and various types of fractionation chromatography.
Various isomers can be prepared by selecting appropriate starting compounds, or can be separated using difference in physicochemical characteristics between isomers. For example, an optical isomer is obtained by general optical resolution (for example, fractionated crystallization for obtaining a diastereomeric salt with an optically active base or acid or chromatography using a chiral column) of a racemic mixture, or can be prepared from an appropriate starting compound that is optically active.
The pharmacological activity of the compound of the formula (I) was confirmed by the following test.
Test Method 1: Test for Measuring Human 11β-HSD1/11β-HSD2 Inhibitory Activity
11β-HSD1 inhibitory activity was measured in the following order. In addition, an enzymatic reaction and assay was performed using a 384-well plate. The enzyme was prepared according to a document (Walker E. A. et al., Journal of Biological Chemistry, 2001, Vol. 276, p. 21343-21350). The reaction was performed in a manner in which various concentrations of test compounds were added to a reaction liquid including a 10 mM a phosphoric acid buffer (pH 6.6), 200 nM cortisone, 40 μM reduced nicotinamide adenine dinucleotide phosphate (NADPH), and recombinant human 11β-HSD1, followed by incubation for an hour at room temperature (10 μl/well). The test compound was dissolved in dimethylsulfoxide (DMSO), and the DMSO concentration was adjusted so as to be 1% in the reaction liquid. After the enzymatic reaction, cortisol was detected using Homogenous Time-Resolved Fluorescence (HTRF) to measure enzyme inhibitory activity. XL-665-labeled cortisol including 400 μM carbenoxolone and a cryptate-labeled cortisol antibody (CIS bio international) were added respectively to the plate at 5 μl/well, followed by incubation for 2 hours at room temperature, and then fluorescence intensity was measured using a fluorospectrometer (trade name: Discovery, manufactured by PerkinElmer Inc.), thereby calculating enzyme inhibitory activity from the ratio of fluorescence intensity between two wavelengths (665 nm/620 nm).
11β-HSD2 inhibitory activity was measured in the same manner as in the measurement of the 11β-HSD1 inhibitory activity, except for the conditions of the enzymatic reaction. The enzymatic reaction was performed in the manner in which various concentrations of test substances were added to a reaction liquid including 40 mM tris-hydrochloric acid buffer (Tris-HCl) (pH 8.0), 200 nM cortisol, 200 μM nicotinamide adenine dinucleotide (NAD), and recombinant human 11β-HSD2, followed by incubation for 2 hours at 37° C. (10 μl/well).
The results of measurement were calculated by obtaining the average of the values of three wells under the same condition. The ratio obtained when DMSO was added instead of the test compound was regarded as 0%, and the ratio obtained when 11β-HSD1 or 11β-HSD2 was not added was regarded as 100%, whereby a concentration at which the test compound suppresses the enzyme activity by 50% was calculated as IC50 of the inhibitory activity of the compound.
The IC50 values of typical compounds of the present invention are shown in the following Table 1. In addition, Ex represents example number.









TABLE 1






Human 11β-
Human 11β-



HSD1
HSD2


Ex
(IC50/μM)
(IC50/μM)

















1
0.048
>30


5
0.056


7-1
0.018
>3


8-1
0.026
>30


27
0.062
>3


30
0.028
>3


81
0.024
>30


132
0.038
>30


159
0.040
>30


176
0.088


190
0.025


216
0.043


228
0.053


237
0.040









From the above results, it was confirmed that some of the compounds of the present invention exhibit potent inhibitory activity against 11β-HSD1, and the 11β-HSD1 inhibitory activity is selective compared to 11β-HSD2.
Test Method 2: Test for Spontaneous Alternation Behavior Disorder Induced by Scopolamine
Test drugs were orally administered to 5- to 7-week old male ddY mice. 10 minutes later, scopolamine was intraperitoneally administered to the animals at 0.5 mg/kg. 20 minutes later, the animal was put in Y-maze having arms with the same length and extending in three directions and allowed to freely explore for 8 minutes. During the exploration, spontaneous arm-alternating behavior (entering different arms 3 times consecutively) was counted to calculate the rate of spontaneous alternation (spontaneous alternation behavior/(number of times of entering−2)×100), thereby judging drug efficacy.
Results of typical compounds of the present invention are shown in Table 2.










TABLE 2








Dose improving minimum




spontaneous alternation rate



Ex
(mg/kg)









7-1
1.0



8-1
0.3










From the above results, it was confirmed that some of the compounds of the present invention are effective for treating dementia.
Test Method 3: Test for Spinal Nerve Ligation Model
This test was performed according to Pain, 1992, Vol. 50, p 355-363. The skin and muscle in the lumbar region of rats (SD, male, 5- to 6-week old) were excised under pentobarbital anesthesia, and a lumbar L6 transverse process was removed to expose lumbar nerves. L5 and L6 spinal nerves were ligated with a silk thread, and then the wound was sutured. The procedure was performed in the left side. In addition, in the case of pseudo-operation, the wound was sutured without performing nerve ligation.
The drug efficacy was evaluated on the postoperative days 7 to 12 by von Frey hair test. The threshold of retraction response was calculated according to Journal of Neuroscience Methods, 1994, Vol. 53, p 55-63. By using 8 types of von Frey filaments (0.41 g to 15.14 g), the sole of the rat's hindlimb was stimulated, and the threshold of 50% retraction response was determined by an up-and-down method. The test started from 2.04 g of a filament, and when the limb retraction response was confirmed, this was regarded as “response”.
The day before the drug efficacy evaluation, animals showing reduction in the threshold through the von Frey hair test were selected in advance, and the animals were grouped such that the difference in the average of the threshold between the respective groups was reduced.
The test substance was suspended in a 0.5% methyl cellulose solution and orally administered 1 hour before the drug efficacy evaluation. The test substance was evaluated by calculating the improvement rate of the test substance-administered group, under the condition that the threshold of the procedure-performed limb of the pseudo-operation animal group was regarded as 100% and the threshold of the procedure-performed limb of the solvent-administered animal group having undergone operation was regarded as 0%.
The results of typical compounds of the present invention are shown in Table 3.










TABLE 3








Improvement rate % (applied



Ex
dose)









7-1
52 (1 mg/kg)



8-1
73 (1 mg/kg)










From the above results, it was confirmed that some of the compounds of the present invention are useful for treating neuropathic pain.
Test Method 4: Test for Model with Fibromyalgia Caused by Repeated Reserpine Administration
This test was performed according to Pain, 2009, Vol. 146, p 26-33., by using rats (SD, male, 7-week old).
The threshold of muscle tenderness was measured according to the method of Schafers et al. (Pain, 2003, Vol. 104, p 579-588). A pressure stimulus slowly increasing up to 250 g was applied to the gastrocnemius muscle of the right lower leg of the rat. The magnitude of the minimum pressure stimulus at which the rat exhibited retraction response to the pressure stimulus in the right lower leg was measured as a muscle tenderness threshold (g). The measurement was performed 3 times for each point in time, and the average thereof was taken as a measured value.
A solvent (0.5% aqueous acetic acid) or reserpine (1 mg/kg) was subcutaneously administered to the back of the rat once a day for three days. The dose of both the solvent and reserpine administered was 1 mL per 1 kg of the body weight of the animal. 6 days after the beginning of the administration of the solvent or reserpine, the muscle tenderness threshold of each rat was measured, and the rats were grouped such that the difference in the average of threshold between the respective groups was reduced. The drug efficacy evaluation was performed on the next day. The test substance was suspended in a 0.5% methyl cellulose solution and orally administered. 30, 60, and 120 minutes after the administration, the muscle tenderness threshold was measured. For healthy rats, the drug was not administered, and only the muscle tenderness threshold was measured. The drug efficacy was measured by an experimenter who did not know how the drug was administered to the animals. The test substance was evaluated by calculating improvement rate of the test substance-administered group, under the condition that a muscle tenderness threshold of a healthy rat measured in any point in time 30, 60, and 120 minutes after the administration was regarded as 100%, and a muscle tenderness threshold of a reserpine-administered rat administered with the solvent was regarded as 0%.
The results of typical compounds of the present invention are shown in Table 4.









TABLE 4






Maximum improvement
Calculated point


Ex
rate % (applied dose)
in time (min)







7-1
 82 (10 mg/kg)
60


8-1
104 (10 mg/kg)
60









From the above results, it was confirmed that some of the compounds of the present invention are useful for treating fibromyalgia.
Test Method 5: Pharmacokinetic Test
A 0.5% methyl cellulose suspension including the test substance was orally administered to 5-week old male mice, and the blood and brain were collected after a certain time passed from the administration. The collected blood sample was treated with sodium heparin, and then the plasma was separated, thereby preparing a plasma sample. In addition, a phosphoric acid buffer (pH 7.0) was added to the collected brain sample, in an amount that was 4 times the weight of the brain, thereby preparing 20% brain homogenate. The concentration of the respective test substances in the plasma and brain was measured using LC-MS/MS. An hour after Example 8-1 was administered at 1 mg/kg, the concentration of the substance in the plasma was 153 ng/ml, and the concentration in the brain was 58 ng/ml.
Test Method 6: Pharmacokinetic Test Under Cortisone Load
A 0.5% methyl cellulose solution or a 0.5% methyl cellulose suspension including the test substance was orally administered to 5-week old male ddY mice. After 30 minutes, cortisone was intraperitoneally administered at 1 mg/kg, and 20 minutes later, the brain was collected. A phosphoric acid buffer (pH 7.0) was added to the collected brain sample, in an amount that was 9 times the weight of the brain, thereby preparing 10% brain homogenate. The quantity of cortisol in the brain homogenate was determined by ELISA, and the inhibition rate resulting from the test substance was calculated, under the condition that the amount of cortisol produced from the mouse orally administered with 0.5% methyl cellulose was regarded as 100%. When Example 8-1 was orally administered at 1 mg/kg, an inhibition rate of 43% was obtained.
As a result of the respective tests described above, it was confirmed that the compound of the present invention has a 11β-HSD1 inhibitory action. This result clearly shows that the compound of the present invention is useful as an active ingredient of a pharmaceutical composition for preventing or treating diseases such as dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance, obesity, hyperlipidemia, hypertension, osteoporosis, and glaucoma, particularly for treating dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance. In addition, as another embodiment, the compound of the present invention is useful as an active ingredient of a pharmaceutical composition for preventing and/or treating dementia (particularly, Alzheimer's type dementia), schizophrenia, and depression. As still another embodiment, the compound of the present invention is useful as an active ingredient of a pharmaceutical composition preventing and/or treating dementia (particularly, Alzheimer's type dementia). As still another embodiment, the compound of the present invention is useful as an active ingredient of a pharmaceutical composition preventing and/or treating pain (particularly, neuropathic pain or fibromyalgia).
The pharmaceutical composition containing one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared using excipients generally used in the related art, that is, using excipients or carriers for medications, by methods generally used.
The composition can be administered in any forms such as oral administration by using a tablet, a pill, a capsule, granules, powder, or liquid, and parenteral administration by using a preparation for injection such as intra-articular injection, intravenous injection, and intramuscular injection, a suppository, an eye drop, an eye ointment, a transdermal liquid, an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, or an inhalation.
As a solid composition for oral administration, a tablet, powder, granules, and the like are used. In such a solid composition, one or two or more kinds of active ingredients are mixed with at least one kind of inactive excipient. The composition may contain inactive additives, for example, a lubricant, a disintegrating agent, a stabilizer, and a dissolution adjuvant according to common methods. The tablet or pill may optionally be coated with sugar or with film of a gastric or enteric material.
A liquid composition for oral administration includes a pharmaceutically acceptable opalizer, solution, suspension, syrup, elixir, or the like, and contains a generally used inactive diluent, for example, purified water or ethanol. The liquid composition may contain an auxiliary agent such as a solubilizer, a moisturizer, or a suspension, a sweetener, a flavor, an aromatic, and a preservative, in addition to the inactive diluent.
The injection preparation for parenteral administration contains a sterile aqueous or non-aqueous solution, a suspension, or an opalizer. Examples of the aqueous solution include distilled water for injection and physiological saline. Examples of the non-aqueous solution include alcohols such as ethanol. These compositions may further contain a tonicity agent, a preservative, a moisturizer, an emulsifier, a dispersant, a stabilizer, or a solubilizer. These are sterilized by, for example, filtering in which they are filtered through a bacteria retentive filter, by being mixed with a germicide, or by irradiation. Moreover, these can be used by being prepared as a sterile solid composition and dissolved or suspended in sterile water or a sterile solvent for injection before use.
Examples of agents for external use include an ointment, a plaster, a cream, a jelly, a cataplasm, a spray, a lotion, eye drops, an eye ointment, and the like. The agent for external use contains generally used substrates of ointments and lotions, an aqueous or non-aqueous liquid formulation, a suspension, an emulsion, and the like.
Transmucosal agents such as an inhalation and a transnasal agent are used in the form of a solid, a liquid or a semisolid, and can be prepared according to methods known in the related art. For example, a known excipient, a pH adjustor, a preservative, a surfactant, a lubricant, a stabilizer, a thickener or the like may be appropriately added thereto. For administration, appropriate devices for inhalation or insufflation can be used. For example, by using a known device such as a metered dose inhaler or an atomizer, the compound can be administered alone or administered as powder of a formulated mixture or as a solution or suspension which is a combination of the compound with a pharmaceutically acceptable carrier. A dry powder inhaler and the like may be for single administration or multiple administration, and dry powder or powder-containing capsules can be used. Alternatively, the compound may be administered in the form of a pressurized aerosol spray using an appropriate ejection agent, for example, a suitable gas such as a chlorofluoroalkane, or carbon dioxide.
Generally, in the case of oral administration, an appropriate daily dose is about 0.001 mg/kg to 100 mg/kg in terms of body weight, preferably 0.1 mg/kg to 30 mg/kg, and more preferably 0.1 mg/kg to 10 mg/kg, which is administered once or two to four times in separate doses. In the case of intravenous administration, an appropriate daily dose is about 0.0001 mg/kg to 10 mg/kg in terms of body weight, which is administered once or plural times in separate doses. In addition, the transmucosal agent is administered once a day or plural times a day in separate doses, in a dose of about 0.001 mg/kg to 100 mg/kg in terms of body weight. The dose is appropriately determined case by case in consideration of the symptoms, age, gender, and the like.
The pharmaceutical composition of the present invention contains one or more kinds of the compound of the formula (I) and a salt thereof as an active ingredient, in an amount of 0.01% by weight to 100% by weight, and 0.01% by weight to 50% by weight as an embodiment, even though the amount varies with the route of administration, dosage forms, site of administration, and the type of excipient or additive.
The compound of the formula (I) can be used concurrently with an agent for treating or preventing various diseases considered to be diseases for which the compound of the formula (I) is effective. In concurrent use, the compound and the agent may be administered simultaneously, administered sequentially one by one, or administered at a desired time interval. The preparation for simultaneous administration may be a combination drug or individual preparations.
EXAMPLES
Hereinafter, the preparation process of the compound of the formula (I) will be described in more detail based on examples, but the present invention is not limited to the compound described in the following examples. In addition, the preparation process of starting compounds will be shown in preparation examples. The preparation process of the compound of the formula (I) is not limited to the preparation processes of the specific examples shown below. The compound of the formula (I) can also be prepared by combining those preparation processes, or by a method that is clearly known to a person skilled in the art.
In addition, in examples, preparation examples, and tables described later, the following abbreviations will be used in some cases.
PEx: preparation example number, Ex: example number, Structure: structural formula (when there is a plurality of structure formulae, this means that a compound is a mixture of those compounds), Data: physical data (EI: EI-MS; ESP+: ESI-MS (Pos); ESN-; ESI-MS (Neg); CI+: CI-MS (Pos); APCI/ESP+: meaning simultaneous measurement of APCI (Pos) and ESI (Pos); NMR-DMSO-d6: δ (ppm) of a characteristic peak in 1H-NMR in DMSO-d6, NMR-CDCl3: δ(ppm) of a characteristic peak in 1H-NMR in CDCl3, [α]D: specific optical rotation in sodium D-line), Note: notes (Sal: salt (HCl: hydrochloride, if this abbreviation is not indicated for a compound, this means that the compound does not contain HCl, and the number placed before the salt indicates a compositional ratio; for example, if a compound is described 2HCl, this means that the compound is dihydrochloride, Chiral: this means that though the compound described as a planar structure since the steric structure thereof is unclear, the compound is chiral), Syn: preparation method (the number shows that the compound was prepared using the corresponding starting material just like the example compound having the number as the example compound number; when there is P before the number, this means that the compound was prepared using the corresponding starting material in the same manner as the compound of the preparation example having the same number as the preparation example number; when there is a plurality of numbers, this shows that the compound was prepared by performing the preparation methods in order from the preparation method corresponding to the previous number), PSyn: preparation method (this means that the compound was prepared using the corresponding starting material just like the compound of the preparation example having the same number as the preparation example number; when there is a plurality of numbers, this means that the compound was prepared by performing the preparation methods in order from the preparation method corresponding to the previous number.))
Preparation Example 1
N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyri din-3-yloxy)methylidene]-N-methyl methanaminium hexafluorophosphate (HATU) (235 mg) and diisopropylethylamine (184 mg) were added to a DMF (2 mL) solution of 4-isopropoxy-2-methoxybenzoic acid (100 mg) and benzyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate hydrochloride (165 mg), followed by stirring overnight at 60° C. Thereafter, water was added to the reaction mixture, extraction was performed using ethyl acetate, followed by washing with water and saturated brine in this order and drying over anhydrous magnesium sulfate, thereby obtaining a crude product. The crude product obtained was purified by silica gel column chromatography (30% to 100%, ethyl acetate/hexane), thereby obtaining benzyl 5-[cyclopropyl(4-isopropoxy-2-methoxybenzoyl)amino]-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (140 mg).
Preparation Example 2
Oxalyl chloride (0.167 ml) and one drop of DMF were added to a dichloromethane (9 ml) suspension of 2′-cyano-6′-fluorobiphenyl-4-carboxylic acid (470 mg) at 0° C., followed by stirring for 3 hours at room temperature. Thereafter, the reaction liquid was cooled again to 0° C., diisopropylethylamine (0.61 ml) was added thereto, and then a dichloromethane (4.5 ml) solution of tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (450 mg) was added dropwise thereto, followed by stirring for 2 hours at room temperature. Water was added to the reaction liquid, extraction was performed using ethyl acetate, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order and drying over anhydrous magnesium sulfate, thereby obtaining a crude product. The crude product was purified by silica gel column chromatography (30% to 100%, ethyl acetate/hexane), thereby obtaining tert-butyl 5-{[(2′-cyano-6′-fluorobiphenyl-4-yl)carbonyl] (cyclopropyl)amino}-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (700 mg).
Preparation Example 3
Thionyl chloride (890 mg) was added to a dichloromethane (2 ml) solution of 1-(2-methoxyethyl)-1H-indole-4-carboxylic acid (125 mg) and 1H-1,2,3-benzotriazole (900 mg) at room temperature. After stirring for 2 hours at room temperature, the insoluble material was removed by filtration, followed by washing with a small amount of toluene. Anhydrous magnesium sulfate was added to the filtrate, followed by stirring, and then the solid was removed by filtration, and the filtrate was concentrated. The residue obtained was dissolved in dichloromethane (3 ml) and added to a dichloromethane (2 ml) solution of tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (150 mg) and isopropylethylamine (150 mg), followed by stirring for 16 hours at room temperature. The reaction liquid was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 4:6), thereby obtaining tert-butyl 5-(cyclopropyl {[1-(2-methoxyethyl)-1H-indol-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (34 mg) as a colorless oil-like substance.
Preparation Example 4
An aqueous solution (3 ml) of tetrakis triphenylphosphine palladium (115 mg) and sodium carbonate (530 mg) was added to a dioxane (20 ml) solution of 2-bromo-3-fluorobenzonitrile (667 mg) and 4-(methoxycarbonyl)phenyl boronic acid (600 mg), followed by stirring overnight at 100° C. in an argon atmosphere, thereafter, cooling to room temperature, diluting with ethyl acetate, washing with saturated brine, and drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The solid of the crude product obtained was washed with diisopropylether and dried under reduced pressure, thereby obtaining methyl 2′-cyano-6′-fluorobiphenyl-4-carboxylate (740 mg).
Preparation Example 5
Under an argon gas atmosphere, tris(dibenzylideneacetone)dipalladium (14 mg) and tri-tert-butylphosphonium tetrafuloroborate (11 mg) were added to a mixture of 2-bromo-3-fluorobenzonitrile (150 mg), 4-methoxycarbonyl-2-methylphenylboronic acid pinacol ester (259 mg), potassium fluoride (144 mg), THF (1.8 mL), and water (0.23 mL), followed by stirring for 14 hours at room temperature. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 2′-cyano-6′-fluoro-2-methylbiphenyl-4-carboxylate (70 mg).
Preparation Example 6
A mixture of 4-bromo-3,5-dichloropyridine (357 mg), 4-methoxycarbonylphenyl boronic acid (236 mg), a 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (107 mg), cesium fluoride (398 mg), and 1,2-dimethoxyethane (3.5 mL) was stirred under heating for an hour at an oil temperature of 80° C. under an argon gas atmosphere, followed by cooling to room temperature. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 4-(3,5-dichloropyridin-4-yl)benzoate (298 mg).
Preparation Example 7
Tris(dibenzylideneacetone)dipalladium (24 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (43 mg) were added to a mixture of methyl 3,5-dimethyl-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (409 mg), 2-cyanophenyl boronic acid (385 mg), tripotassium phosphate (835 mg), and toluene (2.6 mL) under an argon gas atmosphere, followed by stirring under heating for 3 hours at an oil temperature of 110° C., and cooling to room temperature. Water was added to the reaction liquid, followed by diluting with ethyl acetate, washing with saturated brine, drying, and then concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 2′-cyano-2,6-dimethylbiphenyl-4-carboxylate (347 mg).
Preparation Example 8
Lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene solution, 5.57 mL) was added to a THF (7.5 mL) solution of 3,5-difluoropyridine (1.26 g) under an argon gas atmosphere at −78° C. with dry ice/acetone, followed by stirring for 0.5 hours, and then zinc chloride (1.55 g) was added thereto, followed by stirring again for 0.5 hours at the same temperature. After the temperature was elevated to room temperature, a N-methylpyrrolidin-2-one (NMP) (7.5 mL) solution of ethyl 4-bromobenzoate (0.50 g) and tetrakis(triphenylphosphine)palladium (0.50 g) were added thereto, followed by stirring under heating for 8 hours at an oil temperature of 100° C., and cooling to room temperature. 1 M hydrochloric acid was added to the reaction liquid, and then the generated solid was collected by filtration, thereby obtaining 4-(3,5-difluoropyridin-4-yl)benzoic acid (Preparation Example 8-1, 80 mg). The filtrate was diluted with ethyl acetate and then washed with saturated brine, followed by drying and then concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining ethyl 4-(3,5-difluoropyridin-4-yl)benzoate (Preparation Example 8-2, 83 mg).
Preparation Example 9
Under an argon gas atmosphere, n-butyllithium (1.63 M n-hexane solution, 2.41 mL) was added to a THF (3.0 mL) solution of 3-chloro-5-fluoropyridine (517 mg) under cooling at −78° in a dry ice/acetone bath, followed by stirring for 0.5 hours, and then zinc chloride (0.5 M THF solution, 7.86 mL) was added thereto, followed by stirring again for 0.5 hours at the same temperature. After the temperature was elevated to room temperature, a THF (3.0 mL) solution of ethyl 4-bromobenzoate (300 mg) and tetrakis(triphenylphosphine)palladium (303 mg) were added thereto, followed by stirring under heating for 16 hours at an oil temperature of 60° C., and cooling to room temperature. 1 M hydrochloric acid was added to the reaction liquid, followed by diluting with ethyl acetate, washing with saturated brine, drying, and then concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining ethyl 4-(3-chloro-5-fluoropyridin-4-yl)benzoate (194 mg).
Preparation Example 10
(Tributylphosphoranylidene)acetonitrile (1.38 g) was added to a mixture of methyl 1H-indole-4-carboxylate (500 mg), (3-methyloxetan-3-yl)methanol (583 mg), and toluene (15 mL) under an argon gas atmosphere, followed by reflux overnight, and then cooling to room temperature. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 1-[(3-methyloxetan-3-yl)]-1H-indole-4-carboxylate (700 mg).
Preparation Example 11
60% sodium hydride (134 mg) was slowly added to a DMF (5 mL) solution of methyl 1H-indole-4-carboxylate (507 mg) in an ice bath under cooling, followed by stirring for 30 minutes. 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (660 mg) was added thereto, and the temperature was slowly elevated to room temperature, followed by stirring for 5 hours. Thereafter, the reaction liquid was poured into water, followed by extracting with ethyl acetate, washing with saturated brine, drying over anhydrous magnesium sulfate, and concentrating under reduced pressure. The residue was purified by a silica gel column, thereby obtaining methyl 1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1H-indole-4-carboxylate (260 mg).
Preparation Example 12
Potassium carbonate (196 mg) and 1-iodopropane (482 mg) were added to a DMF (2.5 mL) solution of methyl 1H-indazole-4-carboxylate (250 mg), followed by stirring overnight at room temperature. Thereafter, water was added to the reaction liquid, followed by extracting with ethyl acetate, and washing with saturated brine, thereby obtaining a crude product. The crude product obtained was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 1-propyl-1H-indazole-4-carboxylate (130 mg).
Preparation Example 13
2,2′-dimethyloxirane (412 mg) and cesium carbonate (1.4 g) were added to a DMF (10 ml) solution of methyl 1H-indole-4-carboxylate (500 mg), followed by stirring for an hour at 100° C. Thereafter, 2,2′-dimethyloxirane (411 mg) was further added thereto, followed by stirring for an hour, followed by cooling to room temperature. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 1-(2-hydroxy-2-methylpropyl)-1H-indole-4-carboxylate (560 mg).
Preparation Example 14
Potassium tert-butoxide (241 mg) was added to a DMF (2.2 mL) solution of methyl 7-methoxy-1H-indole-4-carboxylate (220 mg) under ice cooling, followed by stirring for 30 minutes. Thereafter, iodomethane (183 mg) was added thereto, followed by stirring for 3 hours at room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, thereby obtaining a crude product. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 7-methoxy-1-methyl-1H-indole-4-carboxylate (200 mg).
Preparation Example 15
Potassium carbonate (55 mg) was added to an acetone (3 mL) solution of tert-butyl 5-{cyclopropyl[(6-hydroxy-1-benzothiophen-3-yl)carbonyl]amino}-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (120 mg) at room temperature, followed by stirring for 30 minutes. Iodomethane (25 μL) was added thereto under ice cooling, followed by stirring for 14 hours at room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solid was filtered, the solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography, thereby obtaining tert-butyl 5-{cyclopropyl[(6-methoxy-1-benzothiophen-3-yl)carbonyl]amino}-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (35 mg).
Preparation Example 16
A THF solution (3.45 mL) of 1 M tetrabutylammonium fluoride was added to a mixture of methyl 5-methoxy-1-(triisopropylsilyl)-1H-indole-4-carboxylate (1.04 g) and THF (10 mL) under ice cooling under an argon gas atmosphere, followed by stirring for an hour at the same temperature. Iodomethane (0.897 mL) was added thereto, followed by stirring for an hour at the same temperature and then for 12 hours at room temperature. The reaction liquid was diluted with ethyl acetate and was washed with water and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 5-methoxy-1-methyl-1H-indole-4-carboxylate (205 mg).
Preparation Example 17
2,6-difluorobenzylamine (0.710 mL) and p-toluenesulfonic acid hydrate (70 mg) were added to a toluene (20 mL) solution of ethyl 2-acetyl-4-oxopentanoate (1.00 g), followed by stirring for 14 hours at 110° C. The reaction mixture was returned to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue obtained was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 85/15), thereby obtaining ethyl 1-(2,6-difluorobenzyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (1.073 g) as a pale yellow solid.
Preparation Example 18
2,4-dichloroaniline (1.37 g) was added to an acetic acid (10 mL) solution of ethyl 2-acetyl-4-oxopentanoate (1.50 g), followed by stirring for 14 hours at 100° C. The reaction mixture was concentrated, and then a saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue obtained was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 90/10), thereby obtaining ethyl 1-(2,4-dichlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (1.469 g) as a yellow oil-like substance.
Preparation Example 19
A 4 M aqueous lithium hydroxide solution (5 mL) was added to an ethanol (10 mL) solution of ethyl 2-methyl-1-(2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate (840 mg), followed by stirring for 2.5 days at 80° C. 1 M hydrochloric acid (20 ml) was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue obtained was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 80/20 or 60/40), thereby obtaining 2-methyl-1-(2-methylphenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-3-carboxylate (225 mg) as a pale yellow solid.
Preparation Example 20 
A 5M aqueous sodium hydroxide solution (5.7 ml) was added to an ethanol (11 ml) suspension of methyl 2′-cyano-6′-fluorobiphenyl-4-carboxylate (730 mg) at room temperature, followed by stirring for 30 minutes at 70° C., followed by cooling. The reaction liquid was acidified using 1M hydrochloric acid. The precipitate was collected by filtration, washed with water, and concentrated under reduced pressure, thereby obtaining 2′-cyano-6′-fluorobiphenyl-4-carboxylic acid (560 mg).
Preparation Example 21
A 1M THF solution (1.12 mL) of N,N,N-tributylbutan-1-ammonium fluoride (TBAF) was added dropwise to a THF (2.6 mL) solution of methyl 1-(2-oxopropyl)-1H-indole-4-carboxylate (260 mg) and trimethyl(trifluoro)silane (240 mg) under ice cooling, followed by stirring overnight at room temperature. Thereafter, 1 M hydrochloric acid was added to the reaction liquid, followed by stirring for 30 minutes, and extracting with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure, thereby obtaining a crude product. The crude product obtained was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 1-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-1H-indole-4-carboxylate (230 mg).
Preparation Example 22
n-Butyllithium (1.65 M THF solution) (4.1 mL) was added dropwise to a diethylether (20 mL) solution of 3-bromo-4-fluoro-1-benzothiophene (1.4 g) at −70° C. under a nitrogen flow, followed by stirring for 30 minutes at −70° C. Thereafter, the reaction liquid was added to dry ice. After the reaction liquid was returned to room temperature, the solvent was concentrated under reduced pressure. Water was added to the residue, followed by washing with hexane. 1M hydrochloric acid was added to the aqueous layer for neutralization, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solid was removed by filtration, followed by concentration under reduced pressure. Diethylether was added thereto, followed by stirring, and the solid was collected by filtration and dried under reduced pressure at 40° C., thereby obtaining 4-fluoro-1-benzothiophene-3-carboxylic acid (0.57 g).
Preparation Example 23
Borane tribromide (3.76 mL, 1 M solution) was added to a dichloromethane (1.3 mL) solution of N-cyclopropyl-1-(3-methoxypropyl)-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide (130 mg) under ice cooling in an argon atmosphere, followed by stirring for 60 hours at room temperature. Thereafter, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solid was removed by filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0 to 9:1), thereby obtaining 1-(3-bromopropyl)-N-cyclopropyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide (68 mg).
Preparation Example 24
A mixture of benzyl cyclopropyl(4-oxocyclohexyl)carbamate (18.4 g), 1,1-dimethoxy-N,N-dimethylmethanamine (40 mL), and triethylamine (40 mL) was stirred under heating for 30 minutes at an oil temperature of 140° C., and a volatile substance was evaporated.
Thereafter, 1,1-dimethoxy-N,N-dimethylmethanamine (40 mL) and triethylamine (40 mL) were added thereto, followed by stirring under heating for 30 minutes at 140° C. By using the respective reagents in an amount of 200 mL in total, the above operation was repeated 5 times. The reaction liquid was concentrated under reduced pressure, and ethanol (100 mL) and a hydrazine hydrate (10.1 mL) were added to the residue, followed by stirring for 60 hours at room temperature. After the reaction liquid was diluted with ethyl acetate, followed by washing with water 3 times and then with saturated brine, drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining benzyl cyclopropyl(4,5,6,7-tetrahydro-1H-indazol-5-yl)carbamate (15.0 g).
Preparation Example 25
Tris(dibenzylideneacetone)dipalladium (18 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (33 mg) were added to a mixture of 2-bromo-3,5-difluoropyridine (250 mg), [4-(methoxycarbonyl)phenyl]boronate (180 mg), tripotassium phosphate (637 mg), and toluene (1.8 mL) under an argon gas atmosphere, followed by stirring under heating for 4 hours at an oil temperature of 110° C., and then the reaction liquid was cooled to room temperature. Water was added to the reaction liquid, followed by diluting with ethyl acetate, washing with saturated brine, drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 4-(3,5-difluoropyridin-2-yl)benzoate (249 mg).
Preparation Example 26
Sodium triacetoxy borohydride (5.41 g) and acetic acid (2.19 mL) were added to a mixture of a mixture (3.45 g) of benzyl 5-oxo-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate and a regioisomer thereof, cyclopropylamine (0.878 mL), and 1,2-dichloroethane (70 mL) under an argon gas atmosphere, followed by stirring for 18 hours at room temperature. Water was added to the reaction liquid, followed by stirring for 2 hours at room temperature, and then pH thereof was adjusted to 8 by using saturated aqueous bicarbonate, followed by liquid separation. The organic layer was dried and then concentrated under reduced pressure. A dioxane solution (4.15 mL) of 4 M hydrogen chloride was added to a mixture of the residue and ethyl acetate (100 mL), followed by stirring for an hour at room temperature. The precipitate was collected by filtration and washed with ethyl acetate, thereby obtaining a mixture (3.26 g) of benzyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate monohydrochloride and a regioisomer thereof.
Preparation Example 27
1 M hydrochloric acid (100 mL) was added to a mixture of benzyl cyclopropyl(1,4-dioxaspiro[4.5]dec-8-yl)carbamate (23.1 g) and THF (200 mL) under ice cooling, followed by stirring for 48 hours at room temperature. Thereafter, 1 M hydrochloric acid (100 mL) was added thereto, followed by stirring again for 10 hours at room temperature. The reaction liquid was diluted with ethyl acetate, followed by liquid separation. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine and dried, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining benzyl cyclopropyl(4-oxocyclohexyl)carbamate (18.4 g).
Preparation Example 28
Diisopropylethylamine (9.59 mL) and benzyloxycarbonyl chloride (6.40 mL) were added to a mixture of 1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] (6.73 g) and THF (70 mL) under ice cooling under an argon gas atmosphere, followed by stirring for 3 hours under ice cooling. The reaction liquid was diluted with ethyl acetate and then washed with water and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining benzyl 6′,7′-dihydrospiro[1,3-dioxolane-2,5′-indazole]-2′(4′H)-carboxylate (11.1 g).
Preparation Example 29
Triethylamine (35.3 mL), benzyl chlorocarbonate (29.0 mL), and 4-dimethylaminopyridine in a catalytic amount were added to a mixture of N-cyclopropyl-1,4-dioxaspiro[4.5]decan-8-amine (20 g) and dichloromethane (200 mL) under ice cooling under an argon gas atmosphere, followed by stirring for an hour under ice cooling and then for 12 hours at room temperature. The reaction liquid was diluted with chloroform, and then the resultant was washed with 1 M hydrochloric acid, water, and saturated aqueous sodium bicarbonate in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining benzyl cyclopropyl(1,4-dioxaspiro[4.5]dec-8-yl)carbamate (23.9 g).
Preparation Example 30
A mixture of a mixture (17.1 g) of tert-butyl 5-{[(benzyloxy)carbonyl](cyclopropylamino}-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate and a regioisomer thereof, 10% palladium supported on activated charcoal (1.7 g), and ethanol (200 mL) was stirred for 2 hours at room temperature under a hydrogen atmosphere at 1 atm. The 10% palladium supported on activated charcoal was removed from the reaction liquid by filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining a mixture (10.5 g) of tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate monohydrochloride and a regioisomer thereof.
Preparation Example 31
A mixture of tert-butyl dicarbonate (13.7 g) and dichloromethane (100 mL) was added to a mixture of benzyl cyclopropyl(4,5,6,7-tetrahydro-1H-indazol-5-yl)carbamate (18.0 g) and dichloromethane (200 mL) under an argon gas atmosphere, followed by stirring for 12 hours at room temperature. Thereafter, a mixture of tert-butyl dicarbonate (5.3 g) and dichloromethane (10 mL) was added thereto, followed by stirring again for 24 hours at room temperature. The reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining a mixture (17.1 g) of tert-butyl 5-{[(benzyloxy)carbonyl] (cyclopropylamino}-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate and a regioisomer thereof.
Preparation Example 32
Triethylamine (635 μL) and di-tert-butyl dicarbonate (597 mg) were added to a THF (3.7 mL) solution of 4′-[cyclopropyl(4,5,6,7-tetrahydro-1H-indazol-5-yl)carbamoyl]biphenyl-2-carboxylic acid (366 mg), followed by stirring for 16 hours at room temperature. Water was added to the reaction liquid, followed by diluting with ethyl acetate, washing with saturated brine, drying, and then concentrating under reduced pressure, thereby obtaining 4′-{[2-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl](cyclopropyl)carbamoyl}biphenyl-2-carboxylic acid (300 mg). N—[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (57 mg), diisopropylethylamine (19 mg), and 4-dimethylaminopyridine in a catalytic amount were added to a DMF (1.2 mL) solution of 4′-{[2-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-2H-indazol-5-yl](cyclopropyl)carbamoyl}biphenyl-2-carboxylic acid (50 mg), followed by stirring overnight at 60° C. Thereafter, water was added to the reaction liquid, followed by extracting with ethyl acetate, washing with water and saturated brine in this order, and drying over anhydrous magnesium sulfate, thereby obtaining a crude product. The obtained crude product was purified by silica gel column chromatography (30% to 100%, ethyl acetate/hexane), thereby obtaining tert-butyl 5-(cyclopropyl){[2′-(dimethylcarbamoyl)biphenyl-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (30 mg).
Preparation Example 33
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane ditetrafluoroborate (2.36 g) was added to a mixture of methyl 2-methyl-1H-indole-4-carboxylate (1.17 g) and acetonitrile (20 mL) under ice cooling, followed by stirring for 3 hours at room temperature. The reaction liquid was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate and then hexane/chloroform), thereby obtaining methyl 3-fluoro-2-methyl-1H-indole-4-carboxylate (102 mg).
Preparation Example 34
N-ethyl-N-isopropylpropan-2-amine (4.08 mL) and benzyl chloromethyl ether (0.792 mL) were added to a mixture of 3′-methyl-1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] (925 mg) and dichloromethane (20 mL) under ice cooling under an argon gas atmosphere, followed by stirring for 4.5 hours at room temperature. The reaction liquid was diluted with ethyl acetate and then washed with water, saturated aqueous sodium bicarbonate, and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining a mixture (1.11 g) of l′-[(benzyloxy)methyl]-3′-methyl-1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] and a regioisomer thereof.
Preparation Example 35
A hydrazine hydrate (0.756 mL) was added to a mixture of 1-(8-hydroxy-1,4-dioxaspiro[4.5]dec-7-en-7-yl)ethanone (1.03 g) and ethanol (10 mL), followed by stirring for 12 hours at room temperature. The reaction liquid was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and saturated brine in this order, followed by drying, and concentrating under reduced pressure, thereby obtaining 3′-methyl-1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] (948 mg).
Preparation Example 36
A mixture of benzyl cyclopropyl(3-oxo-2,3,5,6,7,8-hexahydrocinnolin-6-yl)carbamate (172 mg) and phosphoric trichloride (0.50 mL) was stirred under heating for 3.5 hours at an oil temperature of 100° C. under an argon gas atmosphere and then cooled to room temperature. The reaction liquid was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining benzyl (3-chloro-5,6,7,8-tetrahydrocinnolin-6-yl)cyclopropyl carbamate (74 mg).
Preparation Example 37
A mixture of benzyl 5-[cyclopropyl(4-hydroxybenzoyl)amino]-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (80 mg), (R)-(−)-2-butanol (19 μL), triphenylphosphine (63 mg), and THF (1.0 mL) was cooled with ice water under an argon gas atmosphere, and diisopropyl azodicarboxylate (40% toluene solution, 127 μL) was added thereto, and the temperature was elevated to room temperature, followed by stirring for 6 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining benzyl 5-[{4-[(2S)-butan-2-yloxy]benzoyl}(cyclopropyl)amino]-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (18 mg).
Preparation Example 38
Tetrabutylammonium fluoride (1 M THF solution, 742 μL) was added to a THF (6.0 mL) solution of benzyl 5-(cyclopropyl{4-[(triethylsilypoxy]benzoyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (270 mg), followed by stirring for 3 days at room temperature. The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining benzyl 5-[cyclopropyl(4-hydroxybenzoyl)amino]-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (129 mg).
Preparation Example 39
A mixture of methyl 1H-indazole-4-carboxylate (505 mg), iodobenzene (1.17 g), copper(I) iodide (107 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (161 mg), tripotassium phosphate (1.22 g), and dioxane (5 mL) was stirred under heating for 8 hours at an oil temperature of 95° C. The reaction liquid was cooled to room temperature, followed by diluting with ethyl acetate, and washing with water and saturated brine. The organic layer was dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 1-phenyl-1H-indazole-4-carboxylate (345 mg).
Preparation Example 40
A dichloromethane (0.8 mL) solution of trifluoroacetic acid (111 mg) was added dropwise to diethyl zinc (1 M dichloromethane solution, 0.97 mL) under ice cooling, followed by stirring for 20 minutes. Thereafter, a dichloromethane (0.8 mL) solution of diiodomethane (274 mg) was added dropwise to the reaction liquid, and then the temperature was elevated to room temperature, followed by stirring for 20 minutes. Thereafter, a dichloromethane (0.8 mL) solution of methyl 1-[2-(vinyloxy)ethyl]-1H-indazole-4-carboxylate (120 mg) was added dropwise thereto under ice cooling, and the temperature was slowly elevated to room temperature, followed by stirring overnight. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous hydrogen carbonate solution and saturated brine in this order and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure and purification by silica gel column chromatography, thereby obtaining methyl 1-[2-(cyclopropyloxy)ethyl]-1H-indazole-4-carboxylate (30 mg).
Preparation Example 41
N-bromosuccinimide (1.125 g) was added to a chloroform (20 mL) solution of (1-benzothiophen-6-yloxy)(tert-butyl)diphenylsilane (2.34 g) at room temperature, followed by stirring for 60 hours. Thereafter, water was added thereto, followed by extraction with chloroform, and the organic layer was concentrated. Subsequently, the residue was purified by silica gel column chromatography (hexane), thereby obtaining [(3-bromo-1-benzothiophen-6-yl)oxy](tert-butyl)diphenylsilane (1.16 g) as a colorless oil-like substance.
Preparation Example 42
tert-Butyl(chloro)diphenylsilane (4.9 mL) was added dropwise to a dichloromethane (20 ml) solution of 1-benzothiophen-6-ol (2.5 g) and diisopropylethylamine under ice cooling, followed by stirring for 16 hours at room temperature. A saturated aqueous ammonium chloride solution was added thereto, followed by extracting with chloroform, drying over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10:0 to 95:5), thereby obtaining (1-benzothiophen-6-yloxy)(tert-butyl)diphenylsilane (5.37 g) as a colorless oil-like substance.
Preparation Example 43
A 4 M aqueous sodium hydroxide solution (2 mL) was added to a mixture of methanol (2 mL) and THF (2 mL) of tert-butyl 5-(cyclopropyl{[2′-(methoxycarbonyl)biphenyl-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (470 mg) at room temperature, followed by stirring overnight. Thereafter, 1 M hydrochloric acid was added to the reaction liquid for neutralization, and the solvent was evaporated under reduced pressure, thereby obtaining 4′-[cyclopropyl(4,5,6,7-tetrahydro-1H-indazol-5-yl)carbamoyl]biphenyl-2-carboxylic acid (366 mg).
Preparation Example 44
Acetyl chloride (0.140 mL) was added to a mixture of N-cyclopropyl-4-isopropyl-N-[4-(pyrrolidin-1-yl)cyclohex-3-en-1-yl benzamide (630 mg), diisopropylethylamine (0.367 mL), and chloroform (17 mL) under an argon gas atmosphere, followed by stirring for 26 hours at room temperature. 1 M hydrochloric acid was added to the reaction liquid, followed by stirring for an hour at room temperature, and ethyl acetate was added thereto to perform liquid separation. The organic layer was washed with water and saturated brine in this order and dried, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining N-(3-acetyl)-4-hydroxycyclohex-3-en-1-yl)-N-cyclopropyl-4-isopropyl benzamide (203 mg).
Preparation Example 45
Pyrrolidine (0.846 mL) was added to a mixture of N-cyclopropyl-4-isopropyl-N-(4-oxocyclohexyl benzamide (500 mg), anhydrous magnesium sulfate (1.5 g), and toluene (5 mL) under an argon gas atmosphere, followed by stirring for 24 hours at room temperature. Magnesium sulfate was removed from the reaction liquid by filtration, followed by concentrating under reduced pressure and drying, thereby obtaining N-cyclopropyl-4-isopropyl-N-[4-(pyrrolidin-1-yl)cyclohex-3-en-1-yl]benzamide (640 mg).
Preparation Example 46
A mixture of ethyl 2-acetamide-3-oxobutanoate (400 mg), benzylamine (0.700 mL), and acetic acid (4 mL) was heated under reflux for 28 hours. Acetic acid was evaporated from the reaction liquid under reduced pressure, followed by dilution with chloroform, and washing with water. The organic layer was dried and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining ethyl 1-benzyl-2,5-dimethyl-1H-imidazole-4-carboxylate (384 mg).
Preparation Example 47
Optical resolution was performed on racemic tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (228 mg) by supercritical fluid chromatography (column: Chiralpak AYH 10×250 mm manufactured by DAICEL CORPORATION, mobile phase: liquefied carbon dioxide gas/0.1% diethylamine-containing methanol). As a result, optically active tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (Preparation Example 47-1, 80.8 mg) having a retention time of 6.49 min and optically active tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (Preparation Example 47-2, 88.8 mg) having a retention time of 9.32 min were obtained.
Preparation Example 48
A mixture of N-cyclopropyl-4-isopropyl-N-(4-oxocyclohexyl)benzamide (1 g), 1,1-dimethoxy-N,N-dimethylmethanamine (2 mL), and triethylamine (2 mL) was stirred under heating for 30 minutes at an oil temperature of 140° C., and a volatile substance was evaporated. Thereafter, 1,1-dimethoxy-N,N-dimethylmethanamine (2 mL) and triethylamine (2 mL) were added thereto, followed by stirring under heating for 30 minutes at an oil temperature of 140° C. By using the respective reagents in an amount of 10 mL in total, the above operation was repeated 5 times. The reaction liquid was concentrated under reduced pressure. Ethanol (10 mL) and O-methylisourea hydrochloride (769 mg) were added to the residue, followed by stirring for an hour at room temperature, heating for 21 hours at an oil temperature of 60° C. and, stirring under heating for 12 hours at an oil temperature of 80° C., and cooling to room temperature. The reaction liquid was diluted with ethyl acetate and then washed with water and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining benzyl cyclopropyl(2-methoxy-5,6,7,8-tetrahydroquinazolin-6-yl)carbamate (204 mg).
Preparation Example 49
A hexane solution (6.96 mL) of 1.65 M n-butyllithium was added to a mixture of N-isopropylpropan-2-amine (1.62 mL) and THF (30 mL) while being cooled in an acetone/dry ice bath under an argon gas atmosphere, followed by stirring for 30 minutes at the same temperature. A mixture of benzyl cyclopropyl(4-oxocyclohexyl)carbamate (3 g) and THF (26 mL) was added thereto, and the temperature was slowly elevated to the temperature of ice cooling over 3 hours, followed by stirring for 10 minutes at the same temperature. Hexamethylphosphate triamide (HMPA) (1.83 mL) and ethyl cyanoformate (1.13 mL) were further added thereto while being cooled in an acetone/dry ice bath, followed by stirring for an hour at the same temperature. The reaction liquid was diluted with ethyl acetate and then washed with water and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining ethyl 5-{[(benzyloxy)carbonyl] (cyclopropyl)amino}-2-hydroxycyclohexa-1-ene-1-carboxylate (692 mg).
Preparation Example 50
A mixture of benzyl cyclopropyl(4-oxocyclohexyl)carbamate (500 mg) and a glyoxylic acid hydrate (160 mg) was stirred under heating for 23 hours at 50° C. under an argon gas atmosphere. Thereafter, acetic acid (0.5 mL) was added thereto, followed by stirring under heating for 21 hours at an oil temperature 50° C. and then for 7 hours at an oil temperature of 100° C. Subsequently, acetic acid (1 mL) and a hydrazine hydrate (0.127 mL) were added thereto, followed by stirring under heating for 18 hours at an oil temperature of 100° C., and then the reaction liquid was cooled to room temperature. The reaction liquid was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining benzyl cyclopropyl(3-oxo-2,3,5,6,7,8-hexahydrocinnolin-6-yl)carbamate (343 mg).
Preparation Example 51
Pyridine (0.030 mL) and ethyl chloroformate (0.036 mL) were added to a mixture of a mixture (117 mg) of benzyl cyclopropyl(2-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-5-yl)carbamate and a regioisomer thereof and dichloromethane (2 mL) under ice cooling under an argon gas atmosphere, followed by stirring for 2 hours at the same temperature. The reaction liquid was diluted with ethyl acetate and then washed with a saturated aqueous ammonium chloride solution and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining ethyl 5-{[(benzyloxycarbonyl](cyclopropyl)amino}-2-methyl-3-oxo-2,3,4,5,6,7-tetrahydro-1H-indazole-1-carboxylate (117 mg).
Preparation Example 52
A mixture of ethyl 5-{[(benzyloxy)carbonyl] (cyclopropylamino}-2-hydroxycyclohex-1-ene-1-carboxylate (210 mg), methyl hydrazine (0.062 mL), and ethanol (4 mL) was stirred under heating for 3 hours and then cooled to room temperature. The reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining a mixture (129 mg) of benzyl cyclopropyl(2-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-5-yl)carbamate and a regioisomer thereof.
Preparation Example 53
Potassium tert-butoxide (0.596 g) was added to a mixture of 4-bromo-5-methoxy-1H-indole (1.0 g) and DMF (10 mL) under ice cooling under an argon gas atmosphere, followed by stirring for an hour at room temperature. After ice cooling, chloro(triisopropyl)silane (1.13 mL) was added thereto, followed by stirring for 2 hours at the same temperature. The reaction liquid was diluted with ethyl acetate and then washed with water (3 times) and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining 4-bromo-5-methoxy-1-(triisopropylsilyl)-1H-indole (1.72 g).
Preparation Example 54
A hexane solution (2.85 mL) of 1.62 M n-butyllithium was added to a mixture of 4-bromo-5-methoxy-1-(triisopropylsilyl)-1H-indole (1.47 g) and THF (30 mL) while being cooled in a dry ice/acetone bath under an argon gas atmosphere, followed by stirring for 50 minutes at the same temperature. Dimethyl carbonate (0.647 mL) was added thereto, and the temperature was elevated to the temperature of ice cooling over 8 hours. The reaction liquid was diluted with ethyl acetate and then washed with water and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 5-methoxy-1-(triisopropylsilyl)-1H-indole-4-carboxylate (1.00 g).
Preparation Example 55
A hydrazine hydrate (133 mg) was added to an ethanol (10 mL) solution of ethyl 5-{[(benzyloxy)carbonyl](cyclopropyl)amino}-2-hydroxycyclohexa-1-ene-1-carboxylate (478 mg), followed by heating under reflux for 3 hours. Thereafter, the reaction liquid was poured into water, extraction was performed 3 times by using chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol/chloroform), thereby obtaining benzyl cyclopropyl(3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-5-yl)carbamate (308 mg).
Preparation Example 56
Potassium tert-butoxide (705 mg) was added to a DMF (5 mL) solution of 3-methyl-1H-indole-4-carboxylate (500 mg) under ice cooling, followed by stirring for 40 minutes. Thereafter, iodomethane (1.2 g) was added thereto, followed by stirring overnight at room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, thereby obtaining a crude product. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 3-dimethyl-1H-indole-4-carboxylate (480 mg).
Preparation Example 57
Water (1.5 mL), 2-cyanophenyl boronic acid (231 mg), triphenylphosphine (45 mg), and sodium carbonate (416 mg) were added in this order to a 1,4-dioxane (10 mL) solution of 4-bromo-3-chlorobenzoic acid (308 mg), followed by stirring under heating for 3 hours at 100° C. in an argon atmosphere. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, thereby obtaining a crude product. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining 2-chloro-2′-cyanobiphenyl-4-carboxylic acid (363 mg).
Compounds of Preparation Examples 58 to 432 shown in the table described later were prepared in the same manner as in Preparation Examples 1 to 57. The structures of compounds of the preparation examples are shown in Tables 5 to 81, and physicochemical data and preparation process of the compounds are shown in Tables 82 to 92 respectively.
Example 1
Trifluoroacetic acid (260 mg) was added to a dichloromethane (1.1 mL) solution of tert-butyl 5-{[(2′-cyanobiphenyl-4-yl)carbonyl](cyclopropyl)amino}-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (110 mg), followed by stirring for 2 hours at room temperature. Thereafter, the solvent was evaporated under reduced pressure, followed by diluting with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (methanol/chloroform), thereby obtaining 2′-cyano-N-cyclopropyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide (66 mg).
Example 2 
A 4 M hydrogen chloride/ethyl acetate solution (2 mL) was added to a mixture of ethyl acetate (1.9 mL) and ethanol (0.48 mL) of tert-butyl 5-(cyclopropyl {[1-(2-fluoroethyl)-1H-indol-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (95 mg) at room temperature, followed by stirring for 2 hours. Thereafter, the reaction liquid was concentrated under reduced pressure and alkalified using a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by a silica gel column (0% to 10% methanol/chloroform), and then a 4 M hydrogen chloride/ethyl acetate solution was added thereto, followed by evaporation of the solvent under reduced pressure, thereby obtaining N-cyclopropyl-1-(2-fluoroethyl)-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide hydrochloride (44 mg).
Example 3
A mixture of tert-butyl 5-(cyclopropyl {[1-(1-phenyl ethyl)-1H-indazol-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (184 mg), trifluoroacetic acid (0.25 mL), and dichloromethane (5 mL) was stirred overnight at room temperature. The reaction liquid was poured into saturated aqueous sodium bicarbonate, and extraction was performed using chloroform. The organic layer was dried and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol), followed by dissolving into ethyl acetate. A 4 M hydrogen chloride/ethyl acetate solution was added thereto, and the generated solid was collected by filtration, thereby obtaining N-cyclopropyl-1-(1-phenylethyl)-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indazole-4-carboxamide hydrochloride (60 mg).
Example 4
Oxalyl chloride (100 μl) and DMF (20 μl) were added to a mixture of 1-benzyl-1H-indole-2-carboxylic acid (140 mg) and dichloromethane (5 mL), followed by stirring for an hour at room temperature, and then the solvent was evaporated under reduced pressure. Dichloromethane (5 ml) was added to the residue that was obtained by azeotropy and drying using toluene, and tert-butyl-5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate monohydrochloride (150 mg) and triethylamine (200 μl) were further added thereto at 0° C., followed by stirring for 20 hours at room temperature. The reaction liquid was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and saturated brine in this order, followed by drying, and concentrating under reduced pressure. A 4 M hydrogen chloride/ethyl acetate solution (5 ml) was added to the residue, followed by stirring for 24 hours at room temperature. The solvent was evaporated from the reaction liquid under reduced pressure, and ethyl acetate was added to the obtained residue, followed by washing with saturated aqueous sodium bicarbonate and saturated brine in this order, drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining 1-benzyl-N-cyclopropyl-N-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-1H-indole-2-carboxamide (217 mg).
Example 5
A 5 M aqueous sodium hydroxide solution was added to a tetrahydrofuran (1.4 mL) solution of benzyl 5-[cyclopropyl(4-isopropoxy-2-methoxybenzoyl)amino]-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (140 mg), followed by stirring for 2 hours at room temperature. Thereafter, the reaction liquid was neutralized by 1 M hydrochloric acid, followed by extraction with chloroform, concentration under reduced pressure, and purification by silica gel column chromatography, thereby obtaining N-cyclopropyl-4-isopropoxy-2-methoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide (40 mg).
Example 6
Boron tribromide (1 M THF solution, 5.3 mL) was added dropwise to a dichloromethane (3 mL) solution of benzyl 5-{[(2′-cyano-6′-fluoro-3-methoxybiphenyl-4-yl)carbonyl](cyclopropyl)amino}-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (300 mg) under ice cooling, followed by stirring for 3 days at room temperature. Thereafter, the reaction liquid was poured into water and weakly alkalified using a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and concentration under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform), thereby obtaining 2′-cyano-N-cyclopropyl-6′-fluoro-3-hydroxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide (180 mg).
Example 7
Optical resolution was performed on racemic 2′-cyano-N-cyclopropyl-6′-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide (500 mg) by supercritical fluid chromatography (column: AS-H, eluting solvent: liquefied carbon dioxide gas/ethanol=80/20, flow rate: 12 mL/min). As a result, (−)-2′-cyano-N-cyclopropyl-6′-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide (210 mg) (Example 7-1) and (+)-2′-cyano-N-cyclopropyl-6′-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide (190 mg) (Example 7-2) were obtained.
Example 8 
Optical resolution was performed on racemic N-cyclopropyl-4-isopropoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide (450 mg) by supercritical fluid chromatography (column: AY-H, eluting solvent: liquefied carbon dioxide/ethanol=7/3, flow rate: 10 mL/min). As a result, (−)-N-cyclopropyl-4-isopropoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide (190 mg) (Example 8-1) and (+)—N-cyclopropyl-4-isopropoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide (187 mg) (Example 8-2) were obtained.
Example 9
Silver trifluoroacetate (45 mg) was added to a 1,4-dioxane (1 mL)/water (0.25 mL) solution of 1-(3-bromopropyl)-N-cyclopropyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide (65 mg) at room temperature, followed by stirring for 40 hours at room temperature. Ethanol was added thereto, and the insoluble material was removed by filtration by using celite. The solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10:0 to 9:1), thereby obtaining N-cyclopropyl-1-(3-hydroxypropyl)-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide (18 mg).
Example 10
A mixture of N-cyclopropyl-4-isopropyl-N-(4-oxocyclohexyl)benzamide (500 mg), 1,1-dimethoxy-N,N-dimethylmethanamine (1 mL), and triethylamine (1 mL) was stirred under heating for 30 minutes at an oil temperature of 140° C., and a volatile substance was evaporated. Thereafter, 1,1-dimethoxy-N,N-dimethylmethanamine (1 mL) and triethylamine (1 mL) were added thereto, followed by stirring under heating for 30 minutes at an oil temperature of 140° C. By using the respective reagents in an amount of 5 mL in total, and the above operation was repeated 5 times. The reaction liquid was concentrated under reduced pressure. Ethanol (2.5 mL) and a hydrazine hydrate (0.243 mL) were added to the residue, followed by stirring for 12 hours at room temperature. The reaction liquid was diluted with ethyl acetate and then washed with water (3 times) and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining N-cyclopropyl-4-isopropyl-N-(4,5,6,7-tetrahydro-2H-indazol-5-yl)benzamide (380 mg).
Example 11
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (113 mg), diisopropylethylamine (0.127 mL), and 4-dimethylaminopyridine in a catalytic amount were added to a mixture of N-cyclopropyl-5,6,7,8-tetrahydrocinnolin-6-amine monohydrochloride (56 mg), 1-methyl-1H-indole-4-carboxylic acid (52 mg), and DMF (2 mL) under an argon gas atmosphere, followed by stirring under heating for 60 hours at an oil temperature of 60° C., and then the resultant was cooled to room temperature. The reaction liquid was diluted with ethyl acetate and then washed with water (3 times) and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining N-cyclopropyl-1-methyl-N-(5,6,7,8-tetrahydrocinnolin-6-yl)-1H-indole-4-carboxamide (9.3 mg).
Example 12
A 1 M aqueous sodium hydroxide solution (3 ml) and 30% aqueous hydrogen peroxide (600 μl) were added to a mixture of 4-cyano-N-cyclopropyl-N-(4,5,6,7-tetrahydro-2H-indazol-5-yl)benzamide (130 mg) and ethanol (5 mL), followed by stirring for 2.5 hours at room temperature. The reaction liquid was diluted with chloroform and washed with water and saturated brine, followed by drying, and concentrating under reduced pressure. A 4 M hydrogen chloride/ethyl acetate solution (5 ml) was added to the residue, followed by stirring for 24 hours at room temperature. Ethyl acetate was added to the residue that was obtained by evaporating the solvent from the reaction liquid under reduced pressure, followed by washing with saturated aqueous sodium bicarbonate and saturated brine in this order, drying, and concentrating under reduced pressure. The residue was purified by NH-silica gel column chromatography (chloroform/methanol), thereby obtaining N-cyclopropyl-N-(4,5,6,7-tetrahydro-2H-indazol-5-yl)terephthalamide (85 mg).
Example 13
A hydrazine hydrate (0.0840 mL) was added to a mixture of N-(3-acetyl)-4-hydroxycyclohex-3-en-1-yl)-N-cyclopropyl-4-isopropyl benzamide (197 mg) and ethanol (2 mL), followed by stirring for 72 hours at room temperature. The reaction liquid was diluted with ethyl acetate and then washed with water and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate methanol) and made into hydrochloride by using a 4 M hydrogen chloride/ethyl acetate solution, thereby obtaining N-cyclopropyl-4-isopropyl-N-(3-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide monohydrochloride (130 mg).
Example 14
A 5 M aqueous sodium hydroxide solution (0.059 mL) was added to a mixture of ethyl 5-{cyclopropyl[(1-methyl-1H-indol-4-yl)carbonyl]amino}-2-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazole-1-carboxylate (64 mg), methanol (1 mL), and THF (1 mL), followed by stirring for an hour at room temperature. 1 M hydrochloric acid was added to the reaction liquid for neutralization, followed by concentration under reduced pressure. The residue was diluted with chloroform and washed with water, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol), thereby obtaining N-cyclopropyl-1-methyl-N-(2-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide (28 mg).
Example 15
10% palladium supported on activated charcoal (20 mg) was added to a mixture of ethanol (4 mL) of N-{1-[(benzyloxy)methyl]-3-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl]-N-cyclopropyl-5-[2-(trifluoromethyl)phenyl]-2-furamide (199 mg) and 6 M hydrochloric acid (1 mL), followed by stirring for 3.5 hours in a nitrogen atmosphere at 1 atm. The 10% palladium supported on activated charcoal was removed from the reaction liquid by filtration, followed by concentration under reduced pressure. The residue was alkalified using saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) and made into hydrochloride by using a 4 M hydrogen chloride/ethyl acetate solution, thereby obtaining N-cyclopropyl-N-(3-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)-5-[2-(trifluoromethyl)phenyl]-2-furamide monohydrochloride (147 mg).
Example 16
A mixture of 4-(dimethylamino)benzoic acid (6.5 mg), oxalyl chloride (3.0 μL), dichloromethane (0.5 mL), and DMF (catalytic amount) was stirred for 2 hours at 50° C. and cooled to room temperature. Thereafter, a dichloromethane solution (0.5 mL) of tert-butyl 5-(ethylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate hydrochloride (9.1 mg) and diisopropylethylamine (16 μL) were added thereto, followed by stirring overnight at room temperature. PS-trisamine (manufactured by Biotage, 3.90 mmol/g, 60 mg) and chloroform (1 mL) were added thereto, followed by stirring for 4 hours at room temperature. After the reaction liquid was filtered, the solvent was evaporated under reduced pressure, followed by dissolving in ethyl acetate (1 mL). A 4 M hydrogen chloride/ethyl acetate solution (0.5 mL) was added thereto, followed by stirring overnight at room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC (0.1% aqueous formic acid solution/methanol), thereby obtaining 4-(diethylamino)-N-ethyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide (6.4 mg).
Example 17
A mixture of 2,5-dimethyl-1-(2-thienylmethyl)-1H-pyrrole-3-carboxylic acid (7.8 mg), oxalyl chloride (3.0 μL), dichloromethane (0.5 mL), and DMF (catalytic amount) was stirred for 2 hours at 50° C. After the resultant was cooled to room temperature, a dichloromethane solution (0.5 mL) of tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate hydrochloride (9.4 mg) and isopropylethylamine (16 μL) were added thereto, followed by stirring overnight at room temperature. PS-trisamine
(manufactured by Biotage, 3.90 mmol/g, 60 mg) and chloroform (1 mL) were added thereto, followed by stirring for 6 hours at room temperature. After the reaction liquid was filtered, the solvent was evaporated under reduced pressure, followed by dissolving in ethanol (1 mL). A 4 M hydrogen chloride/ethyl acetate solution (0.5 mL) was added thereto, followed by stirring overnight at room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC (0.1% aqueous formic acid solution/methanol), thereby obtaining N-cyclopropyl-2,5-dimethyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1-(2-thienylmethyl)-1H-pyrrole-3-carboxamide (1.9 mg).
Example 18
A mixture of 2′-(trifluoromethyl)biphenyl-4-carboxylate (8.8 mg), 1-chloro-N,N,2-trimethylpropenylamine (4.0 μl), and dichloromethane (0.8 mL) was stirred for an hour at room temperature. A dichloromethane solution (0.7 mL) of tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate hydrochloride (9.4 mg) and pyridine (7.3 μl) were added thereto, followed by stirring overnight at room temperature. Water (1.5 mL) was added to the reaction liquid, and extraction was performed using chloroform (2 mL). The solvent was evaporated under reduced pressure, followed by dissolving in ethanol (1 mL). A 4 M hydrogen chloride/ethyl acetate solution (0.5 mL) was added thereto, followed by stirring overnight at room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC (0.1% aqueous formic acid solution/methanol), thereby obtaining N-cyclopropyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-2′-(trifluorophenyl)biphenyl-4-carboxamide (1.1 mg).
Example 19
A mixture of 4-(1,3-benzodioxol-5-yl)benzoic acid (8.0 mg), tert-butyl 5-(cyclopropylamino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate hydrochloride (9.4 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (11.4 mg), diisopropylethylamine (16 and DMF (1 mL) was stirred overnight at 80° C. After cooling to room temperature, water (1.5 mL) was added to the reaction liquid, followed by extraction with chloroform (2 mL). The solvent was evaporated under reduced pressure, and the resultant was dissolved in ethanol (1 mL). A 4 M hydrogen chloride/ethyl acetate solution (0.5 mL) was added thereto, followed by stirring overnight at room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was purified by HPLC (0.1% aqueous formic acid solution/methanol), thereby obtaining 4-(1,3-benzodioxol-5-yl)-N-cyclopropyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide (3.8 mg).
Example 20
Boron tribromide (1 M THF solution, 5.3 mL) was added dropwise to a dichloromethane (3 mL) solution of N-cyclopropyl-1-(2-methoxyethyl)-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide (300 mg) under ice cooling, followed by stirring for 3 days at room temperature. Thereafter, the reaction liquid was poured into water and weakly alkalified using a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and concentration under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform), thereby obtaining N-cyclopropyl-1-(2-hydroxyethyl)-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide (69 mg).
Example 21
Boron tribromide (1 M THF solution, 1.5 mL) was added dropwise to a dichloromethane (2 mL) solution of N-cyclopropyl-4′-methoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide monohydrochloride (100 mg) under ice cooling, followed by stirring for 3 hours at room temperature. Thereafter, the reaction liquid was poured into water and weakly alkalified using a saturated aqueous sodium hydrogen carbonate, followed by extraction with chloroform, and concentration under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform), thereby obtaining N-cyclopropyl-4′-hydroxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide (88 mg).
Example 22
Boron tribromide (1 M THF solution, 0.63 mL) was added dropwise to a dichloromethane (5 mL) solution of N-cyclopropyl-N-(2-methoxy-5,6,7,8-tetrahydroquinazolin-6-yl)-1-methyl-1H-indole-4-carboxamide (79 mg) under ice cooling, followed by stirring overnight at room temperature. Thereafter, the reaction liquid was poured into water and weakly alkalified using a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and concentration under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform), thereby obtaining N-cyclopropyl-1-methyl-N-(2-oxo-1,2,5,6,7,8-hexahydroquinazolin-6-yl)-1H-indole-4-carboxamide (23 mg).
Example 23
p-Tosyl acid monohydrate (434 mg) and water (33 mL) were added to an acetone (33 mL) solution of N-cyclopropyl-N-(1,4-dioxaspiro[4.5]dec-8-yl)-4-isopropoxybenzamide (4.1 g), followed by stirring for 2 hours at 70° C., followed by cooling to room temperature, concentrating under reduced pressure, neutralizing with a saturated aqueous sodium hydrogen carbonate solution, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous magnesium sulfate, and concentrating under reduced pressure, thereby obtaining N-cyclopropyl-4-isopropoxy-N-(4-oxocyclohexyl)benzamide (3.5 g). N,N-dimethylformamide dimethylacetal (7.3 mL) and triethylamine (7.3 mL) were added to N-cyclopropyl-4-isopropoxy-N-(4-oxocyclohexyl)benzamide (3.5 g), and a volatile substance was evaporated by distillation at 120° C. This operation was repeated 5 times. Subsequently, ethanol (19 mL) was added to the residue, and hydrazine monohydrate (1.67 g) was added thereto, followed by stirring overnight at room temperature. Thereafter, the reaction liquid was diluted with water, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), thereby obtaining N-cyclopropyl-4-isopropoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide (2 g).
Example 24
A THF (1.5 mL) solution of tert-butyl 5-(cyclopropyl{[2′-(methoxycarbonyl)biphenyl-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (200 mg) was cooled with ice water under an argon gas atmosphere. A THF (1.5 mL) solution of lithium tetrahydroborate (17 mg) was added dropwise thereto, followed by stirring for 4 hours with heating under reflux at an oil temperature of 70° C., cooling to room temperature, diluting with ethyl acetate, washing with saturated brine and dried, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining tert-butyl 5-(cyclopropyl{[2′-(hydroxymethyl)biphenyl-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (189 mg). Trifluoroacetic acid (199 mg) was added to a dichloromethane (2 mL) solution of the obtained tert-butyl 5-(cyclopropyl{[2′-(hydroxymethyl)biphenyl-4-yl]carbonyl}amino)-4,5,6,7-tetrahydro-2H-indazole-2-carboxylate (85 mg), followed by stirring overnight at room temperature, concentrating under reduced pressure, neutralizing with a saturated aqueous sodium hydrogen carbonate solution, extracting with chloroform, and purifying by silica gel column chromatography (0% to 10%, methanol/chloroform), thereby obtaining N-cyclopropyl-2′-(hydroxymethyl)-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide (57 mg).
Compounds of Examples 25 to 315 shown in the table described later were prepared in the same manner as in Examples 1 to 24. The structures of the example compounds are shown in Tables 93 to 152, and the physicochemical data and preparation processes of the compounds are shown in Tables 153 to 161 respectively.









TABLE 5





PEx
Structure
Note







1







 


2







 


3







 


4







 


5





















TABLE 6







6






 


7






 


8






 


9






 


10






 


11





















TABLE 7







12






 


13






 


14






 


15






 


16






 


17





















TABLE 8







18






 


19






 


20






 


21






 


22






 


23






















TABLE 9







24







 


25







 


26




Sal: HCl


 


27







 


28







 


29






















TABLE 10







30




Sal: HCl


 


31







 


32







 


33







 


34







 


35





















TABLE 11







36






 


37






 


38






 


39






 


40






 


41























TABLE 12









42







 



43







 



44







 



45







 



46























TABLE 13







47-1




Chiral


 


47-2




Chiral


 


48  







 


49  







 


50  







 


51  























TABLE 14









52







 



53







 



54







 



55







 



56























TABLE 15







57







 


58







 


59







 


60




Sal: HCl


 


61







 


62























TABLE 16









63







 



64







 



65







 



66







 



67







 



68






















TABLE 17







69






 


70






 


71






 


72






 


73






 


74























TABLE 18









75







 



76







 



77







 



78







 



79







 



80
























TABLE 19









81







 



82







 



83







 



84







 



85







 



86
























TABLE 20









87







 



88







 



89







 



90







 



91







 



92






















TABLE 21







93






 


94






 


95






 


96






 


97





















TABLE 22







98






 


99






 


100






 


101






 


102























TABLE 23









103







 



104







 



105







 



106







 



107







 



108






















TABLE 24







109






 


110






 


111






 


112





















TABLE 25







113






 


114






 


115






 


116






 


117






















TABLE 26







118







 


119







 


120







 


121







 


122







 


123







 


124






















TABLE 27







125






 


126






 


127






 


128






 


129





















TABLE 28







130






 


131






 


132






 


133






 


134





















TABLE 29







135






 


136






 


137






 


138





















TABLE 30







139






 


140






 


141






 


142






 


143





















TABLE 31







144






 


145






 


146






 


147






 


148





















TABLE 32







149






 


150






 


151






 


152






 


153





















TABLE 33







154






 


155






 


156






 


157






 


158





















TABLE 34







159






 


160






 


161






 


162






 


163





















TABLE 35







164






 


165






 


166






 


167






 


168





















TABLE 36







169






 


170






 


171






 


172






 


173






 


174





















TABLE 37







175






 


176






 


177






 


178






 


179






 


180





















TABLE 38







181






 


182






 


183






 


184






 


185






 


186






















TABLE 39







187




Chiral


 


188




Chiral


 


189







 


190







 


191






















TABLE 40







192







 


193







 


194







 


195







 


196







 


197






















TABLE 41







198







 


199







 


200







 


201







 


202







 


203






















TABLE 42







204







 


205







 


206







 


207







 


208







 


209






















TABLE 43







210







 


211







 


212







 


213







 


214







 


215






















TABLE 44







216







 


217







 


218







 


219







 


220







 


221






















TABLE 45







222







 


223




Sal: HCl


 


224







 


225







 


226







 


227






















TABLE 46







228







 


229







 


230







 


231







 


232







 


233






















TABLE 47







234







 


235







 


236







 


237







 


238







 


239






















TABLE 48







240







 


241







 


242







 


243







 


244







 


245






















TABLE 49







246







 


247







 


248







 


249







 


250







 


251






















TABLE 50







252







 


253







 


254







 


255







 


256






















TABLE 51







257







 


258







 


259







 


260







 


261







 


262






















TABLE 52







263







 


264







 


265







 


266







 


267







 


268






















TABLE 53







269







 


270







 


271







 


272







 


273







 


274







 


275





















TABLE 54







276






 


277






 


278






 


279






 


280






 


281






 


282






 


283






 


284






 


285





















TABLE 55







286






 


287






 


288






 


289






 


290





















TABLE 56







291






 


292






 


293






 


294






 


295






 


296





















TABLE 57







297






 


298






 


299






 


300






 


301





















TABLE 58







302






 


303






 


304






 


305






 


306






 


307





















TABLE 60







308






 


309






 


310






 


311






 


312






 


313





















TABLE 61







314






 


315






 


316






 


317






 


318






 


319





















TABLE 62







320






 


321






 


322






 


323






 


324






 


325





















TABLE 63







326






 


327






 


328






 


329






 


330






















TABLE 64







331







 


332







 


333







 


334







 


335




Sal: HCl


 


336




Sal: HCl


















TABLE 65







337




Sal: HCl


 


338







 


339







 


340







 


341







 


342





















TABLE 66







343






 


344






 


345






 


346






 


347






 


348






 


349






















TABLE 67







350







 


351







 


352







 


353




Sal: HCl


 


354







 


355





















TABLE 68







356






 


357






 


358






 


359






 


360






 


361





















TABLE 69







362






 


363






 


364






 


365






 


366






 


367





















TABLE 70







368






 


369






 


370






 


371






 


372






 


373





















TABLE 71







374






 


375






 


376






 


377






 


378






 


379





















TABLE 72







380






 


381






 


382






 


383






 


384





















TABLE 73







385






 


386






 


387






 


388






 


389





















TABLE 74







390






 


391






 


392






 


393






 


394






 


395





















TABLE 75







396






 


397






 


398






 


399






 


400






 


401





















TABLE 76







402






 


403






 


404






 


405






 


406






 


407





















TABLE 77







408






 


409






 


410






 


411






 


412






 


413





















TABLE 78







414






 


415






 


416






 


417






 


418





















TABLE 79







419






 


420






 


421






 


422






 


423






 


424





















TABLE 80







425






 


426






 


427






 


428






 


429





















TABLE 81







430






 


431






 


432






















TABLE 82





PEx
PSyn
Data

















1
1
ESI+: 504


2
2
ESI+: 501.4


3
3
ESI+: 479


4
4
ESI+: 256.2


5
5
ESI+: 270


6
6
ESI+: 282, 284, 286


7
7
ESI+: 266


8
8
ESI+: 264


9
9
ESI+: 280, 282


10
10
ESI+: 260.1


11
11
ESI+: 287.2


12
12
ESI+: 219.2


13
13
ESI+: 248.1


14
14
NMR-CDCl3: 3.94 (s, 3H), 3.98 (s, 3H), 4.06 (s, 3H),




6.61 (d, J = 8 Hz, 1H), 7.04 (m, 2H), 7.84 (d,




J = 8 Hz, 1H).


15
15
ESI+: 468


16
16
ESI+: 220


17
17
ESI+: 294


18
18
ESI+: 312


19
19
ESI+: 256


20
20
ESI−: 240.1


21
21
ESI+: 302.1


22
22
ESI+: 197


23
23
ESI+: 441, 443


24
24
ESI+: 312


25
25
ESI+: 250


26
26
ESI+: 312


27
27
ESI+: 310 (M + Na)+


28
28
ESI+: 315


29
29
ESI+: 354 (M + Na)+


30
30
ESI+: 278


31
31
ESI+: 412


32
32
APCI/ESI+: 529


33
33
ESI+: 208


34
34
ESI+: 315


35
35
ESI+: 195


36
36
ESI+: 358


37
37
ESI+: 488


38
38
ESI+: 454


39
39
ESI+: 253


40
40
ESI+: 261.1


















TABLE 83







41
41
CI+: 466, 468


42
42
EI: 388


43
43
APCI/ESI+: 402


44
44
ESI+: 342


45
45
NMR-CDCl3: 0.37-0.70 (4H, m), 1.15-1.35 (6H, m),




1.60-3.10 (16H, m), 3.95-4.70 (2H, m), 7.10-7.50 (4H, m)


46
46
ESI+: 259


47-1
47
ESI+: 278


47-2
47
ESI+: 278


48
48
ESI+: 354


49
49
ESI+: 360


50
50
ESI+: 340


51
51
ESI+: 414


52
52
ESI+: 342


53
53
NMR-CDCl3: 1.14 (18H, d, J = 4.0 Hz), 1.60-1.73 (3H, m),




3.93 (3H, s), 6,65 (1H, d, J = 4.0 Hz), 6.85 (1H, d,




J = 8.0 Hz), 7.29 (1H, d, J = 4.0 Hz), 7.38 (1H, d, J = 8.0 Hz)


54
54
ESI+: 362


55
55
ESI+: 328


56
56
ESI+: 204


57
57
ESI−: 256


58
2
ESI+: 344


59
27
ESI+: 300


60
31
ESI+: 266


61
2
ESI+: 412


62
2
ESI+: 426


63
17
ESI+: 284


64
20
ESI−: 264


65
17
ESI+: 294


66
46
ESI+: 245


67
20
ESI+: 266


68
20
ESI+: 284, 286


69
20
ESI+: 231


70
20
ESI+: 217


71
2
ESI+: 490


72
2
ESI+: 476


73
17
ESI+: 258


74
35
ESI+: 209


75
20
ESI+: 230


76
17
ESI+: 272


77
17
ESI+: 250


78
17
ESI+: 264




















TABLE 84









79
20
ESI+: 244



80
17
ESI+: 326



81
17
ESI+: 326



82
17
ESI+: 326



83
17
ESI+: 288



84
17
ESI+: 288



85
17
ESI+: 288



86
20
ESI+: 222



87
20
ESI+: 236



88
20
ESI−: 296



89
20
ESI−: 296



90
34
ESI+: 329



91
17
ESI+: 292, 294



92
17
ESI+: 292



93
17
ESI+: 292, 294



94
2
ESI+: 495



95
2
ESI+: 481



96
20
ESI−: 296



97
20
ESI−: 258



98
20
ESI+: 264, 266



99
20
ESI+: 264, 266



100
2
ESI+: 557



101
2
ESI+: 579 (M + Na)+



102
20
ESI−: 258



103
20
ESI−: 258



104
20
ESI+: 264, 266



105
27
ESI+: 271



106
27
ESI+: 285



107
26
ESI+: 312



108
26
ESI+: 326



109
2
ESI+: 579 (M + Na)+



110
2
ESI+: 519



111
2
ESI+: 519



112
2
ESI+: 519



113
2
ESI+: 523



114
2
ESI+: 550



115
2
ESI+: 564



116
17
ESI+: 252



117
17
ESI+: 266



118
17
ESI+: 259



119
17
ESI+: 259



120
17
ESI+: 264





















TABLE 85









121
17
ESI+: 278



122
20
ESI−: 222



123
20
ESI+: 238



124
20
ESI+: 231



125
20
ESI+: 231



126
20
ESI+: 250



127
20
ESI+: 236



128
2
ESI+: 383 (M − Boc + H)+



129
2
ESI+: 397 (M − Boc + H)+



130
2
ESI+: 390 (M − Boc + H)+



131
2
ESI+: 490



132
2
ESI+: 409 (M − Boc + H)+



133
2
ESI+: 395 (M − Boc + H)+



134
2
ESI+: 525



135
2
ESI+: 512



136
2
ESI+: 512



137
2
ESI+: 516



138
2
ESI+: 516



139
12
ESI+: 267



140
20
ESI+: 253



141
2
ESI+: 512



142
2
ESI+: 512



143
10
ESI+: 260



144
2
ESI+: 512



145
20
ESI+: 246



146
2
ESI+: 462



147
2
ESI+: 488



148
2
ESI+: 472



149
2
ESI+: 490



150
2
ESI+: 512



151
11
ESI+: 274



152
2
ESI+: 492



153
22
ESI−: 195



154
2
ESI+: 456



155
2
ESI+: 534, 536



156
20
ESI+: 260



157
2
ESI+: 505



158
2
ESI+: 456



159
2
ESI+: 452



160
2
ESI+: 449



161
2
ESI+: 456



162
3
ESI+: 483



















TABLE 86







163
22
ESI+: 433


164
20
ESI+: 190


165
1
ESI+: 449


166
1
ESI+: 692


167
1
ESI+: 519


168
14
ESI+: 296


169
10
ESI+: 247


170
10
ESI+: 289


171
1
ESI+: 435


172
1
ESI+: 435


173
1
ESI+: 499


174
20
ESI+: 282


175
20
ESI+: 233


176
20
ESI+: 275


177
1
ESI+: 541


178
1
NMR-CDCl3: 0.42-0.58 (4H, m), 1.64 (s, 9H),




2.19-2.27 (m, 1H), 2.33-2.50 (m, 5H), 2.61-2.67




(m, 1H), 2.72-3.30 (m, 6H), 3.67 (t, 4H), 4.25




(t, 2H), 4.40-4.53 (m, 1H), 6.49-6.51 (m, 1H),




7.13-7.79 (m, 5H)


179
1
ESI+: 492


180
20
ESI+: 190


181
1
ESI+: 450


182
1
ESI+: 449


183
10
ESI+: 248


184
10
ESI+: 262


185
20
ESI+: 234


186
20
ESI+: 248


187
1
ESI+: 435


188
1
ESI+: 435


189
1
ESI+: 507


190
1
ESI+: 493


191
2
ESI+: 436


192
10
ESI+: 246.1


193
10
ESI+: 248.2


194
10
ESI+: 222.1


195
10
ESI+: 236.1


196
23
ESI+: 455, 457


197
20, 1
ESI+: 493.0


198
1
ESI+: 436


199
20, 1
ESI+: 505.0


200
20, 1
ESI+: 491.4


















TABLE 87







201
20, 1
ESI+: 467.3


202
20, 1
ESI+: 481.0


203
20, 1
ESI+: 493.3


204
 1
NMR-CDCl3: 0.40-0.56 (m, 4H), 1.64 (s, 9H),




2.20-3.31 (m, 7H), 4.43-4.54 (m, 1H), 6.55




(m, 1H), 7.14-8.39 (m, 5H), 8.33-8.50 (m, 1H)


205
12
NMR-DMSOd6: 2.17 (s, 3H), 3.90 (s, 3H), 5.26




(s, 2H), 7.00 (m, 1H), 7.22 (t, J = 8 Hz, 1H),




7.43 (m, 1H), 7.66 (d, J = 8 Hz, 1H), 7.76




(d, J = 8 Hz, 1H).


206
10
ESI+: 246.1


207
20, 1
ESI+: 532.4


208
20, 1
ESI+: 547.3


209
 1
ESI+: 506.3


210
30
ESI+: 220


211
14
NMR-CDCl3: 3.99 (s, 3H), 5.15 (s, 2H), 6.79




(m, 1H), 7.19-7.36 (m, 4H), 7.55 (d, J = 8 Hz,




1H), 7.91 (d, J = 8 Hz, 1H), 8.80 (m, 1H).


212
20, 1
ESI+: 518.4


213
12
ESI+: 192


214
20
NMR-DMSOd6: 4.49 (3H, s), 7.49 (1H, t, J =




8.0 Hz), 8.09 (1H, d, J = 8.0 Hz), 8.30 (1H,




d, J = 8.0 Hz), 13.6 (1H, br s)


215
 1
ESI+: 437


216
12
ESI+: 268


217
30
ESI+: 194


218
30
ESI+: 206


219
20
ESI−: 252


220
 1
ESI+: 513


221
10
NMR-CDCl3: 3.99 (s, 3H), 4.45-4.55 (m, 2H),




5.84-6.15 (m, 1H), 7.20-7.33 (m, 3H), 7.56




(d, J = 8 Hz, 1H), 7.92-7.94 (m, 1H).


222
30
ESI+: 280


223
30
ESI+: 190


224
 1
ESI+: 437


225
20, 1
ESI+: 485.2


226
 1
ESI+: 436.2


227
14
ESI+: 235.2


228
14
ESI+: 223.2


229
12
ESI+: 275


230
20, 1
ESI+: 468.3


231
20, 1
ESI+: 480.3


232
14
ESI+: 205.2


233
20, 1
ESI+: 450.4



















TABLE 88








234
14
ESI+: 219.2



235
20, 1
ESI+: 464.4



236
20, 1
ESI+: 464.4



237
14
ESI+: 237.2



238
20
ESI+: 261



239
1
ESI+: 520



240
12
ESI+: 245



241
14
ESI+: 249.2



242
20, 1
ESI+: 494.4



243
14
ESI+: 263.2



244
20, 1
ESI+: 466.3



245
12
ESI+: 247.1



246
12
ESI+: 335



247
39
ESI+: 253



248
20
ESI+: 321



249
1
ESI+: 436



250
20
ESI+: 231



251
12
ESI+: 249.1



252
20, 1
ESI+: 494.3



253
1
ESI+: 580



254
1
ESI+: 490



255
1
ESI+: 424.2



256
1
ESI+: 458.2



257
21
ESI+: 494.3



258
4
ESI+: 238.1



259
20
ESI+: 224



260
1
ESI+: 483.3



261
1
ESI+: 486.4



262
20
ESI+: 239



263
12
ESI+: 283.1



264
4
ESI+: 252.2



265
20, 1
ESI+: 497.4



266
4
ESI+: 291.2



267
20, 1
ESI+: 536.4



268
4
ESI+: 228



269
1
ESI+: 498



270
24
ESI+: 181



271
20, 1
ESI+: 528.4



272
20
ESI+: 214



273
20
ESI+: 206



274
12
ESI+: 249.2



275
12
ESI+: 247.2



















TABLE 89








276
12
ESI+: 321.2



277
12
ESI+: 287.2



278
1
ESI+: 473



279
1
ESI+: 465



280
20, 1
ESI+: 532.3



281
20, 1
ESI+: 494.2



282
20, 1
ESI+: 566.2



283
57
ESI+: 277.2



284
20, 1
ESI+: 522.3



285
1
ESI+: 518.4



286
4
ESI+: 252



287
20, 1
ESI+: 497



288
57
ESI−: 236



289
1
ESI+: 497



290
1
ESI+: 517, 519



291
12
ESI+: 281



292
4
ESI+: 239



293
20, 1
ESI+: 484.2



294
4
ESI+: 271.2



295
20, 1
ESI+: 516.4



296
12
ESI+: 247



297
12
ESI+: 233



298
12
ESI+: 247



299
20
ESI−: 265



300
14
ESI+: 268



301
1
ESI+: 459



302
1
ESI+: 526



303
4
ESI+: 257



304
1
ESI+: 516



305
20
ESI+: 233



306
20
ESI+: 219



307
1
ESI+: 475.3



308
20, 1
ESI+: 506.3



309
14
ESI+: 292



310
20
ESI+: 254



311
20
ESI+: 233



312
12
ESI+: 261



313
1
ESI+: 492



314
1
ESI+: 478



315
1
ESI+: 492



316
27
ESI+: 271



317
4
ESI+: 279.1



















TABLE 90








318
20, 1
ESI+: 524.3



319
4
ESI+: 256.1



320
20, 1
ESI+: 501.4



321
20, 1
ESI+: 511



322
1
ESI+: 513



323
4
ESI+: 239.1



324
14
ESI+: 222



325
20
ESI+: 247



326
20
ESI+: 278



327
12
ESI+: 292



328
1
ESI+: 537



329
20, 1
ESI+: 484.3



330
1
ESI+: 506



331
20
ESI+: 208



332
20
ESI+: 278



333
1
ESI+: 537



334
1
ESI+: 467



335
26
ESI+: 300



336
26
ESI+: 286



337
26
ESI+: 314



338
4
ESI+: 254.1



339
4
ESI+: 215



340
1
ESI+: 536



341
20, 1
ESI+: 498



342
1
ESI+: 513.3



343
4
ESI+: 242.1



344
1
ESI+: 501.2



345
4
ESI+: 215



346
20
ESI+: 201



347
20
ESI−: 201



348
1
ESI+: 483.2



349
4
ESI+: 232.1



350
20, 1
ESI+: 477.3



351
4
ESI+: 228.2



352
20, 1
ESI+: 473.3



353
26
ESI+: 314



354
1
ESI+: 460



355
1
ESI+: 480



356
1
ESI+: 494



357
57
EI: 252



358
4
EI: 270



















TABLE 91








359
4, 20, 1
ESI+: 501.4



360
4, 20, 1
ESI+: 417.3, 417.9



361
1
ESI+: 460



362
4
EI: 243



363
4
ESI+: 232.1



364
20, 1
ESI+: 477.2



365
4
ESI+: 228.2



366
20, 1
ESI+: 473.3



367
2
ESI+: 494



368
20
ESI−: 237



369
20
ESI−: 255



370
57
ESI+: 255



371
20
ESI−: 228



372
1
ESI+: 498



373
20
ESI−: 239



374
1
ESI+: 516



375
1
ESI+: 493



376
4
ESI−: 240



377
1
ESI+: 501



378
5
ESI+: 257



379
4
ESI+: 242



380
1
APCI/ESI+: 401 [M-Boc]



381
4
ESI+: 255



382
1
APCI/ESI+: 500



383
20
ESI+: 243



384
1
ESI+: 502



385
1
ESI+: 523



386
1
ESI+: 494.0



387
20
ESI+: 241



388
20
ESI+: 256



389
1
ESI+: 515



390
1
APCI/ESI+: 400 [M-Boc]



391
1
APCI/ESI+: 438.1



392
1
APCI/ESI+: 466.0



393
1
APCI/ESI+: 492.1



394
1
APCI/ESI+: 476.0



395
1
APCI/ESI+: 326 [M-Boc]



396
1
APCI/ESI+: 486.1



397
1
APCI/ESI+: 484



398
20, 1
ESI+: 529



















TABLE 92








399
4
ESI−: 240



400
1
ESI+: 535



401
4
ESI+: 272.0



402
1
ESI+: 486



403
1
ESI+: 565.3



404
1
ESI+: 516.1



405
1
ESI+: 488



406
20
ESI+: 236



407
1
ESI+: 529



408
20
ESI+: 268, 270



409
1
ESI+: 561, 563



410
1
ESI+: 472



411
1
ESI+: 488



412
1
ESI+: 486



413
1
ESI+: 492.1



414
1
ESI+: 517



415
20
ESI+: 252, 254



416
1
ESI+: 545, 547



417
1
ESI+: 488



418
1
ESI+: 510



419
1
ESI+: 502



420
1
ESI+: 536



421
20, 1
ESI+: 526



422
1
ESI+: 488.4



423
1
ESI+: 508.1



424
1
ESI+: 536



425
1
ESI+: 540



426
1, 38
ESI+: 432



427
1
ESI+: 558.4



428
4, 1
ESI+: 540.1



429
4, 1
ESI+: 522.0



430
37
ESI+: 488



431
1
ESI+: 508



432
2
ESI+: 360.3


















TABLE 93





Ex
Structure
Note







1







 


2




Sal: HCl


 


3




Sal: HCl


 


4







 


5






















TABLE 94







6







 


7-1




Chiral


 


7-2




Chiral


 


8-1




Chiral


 


8-2




Chiral


















TABLE 95







 9







 


10







 


11







 


12







 


13




Sal: HCl


 


14






















TABLE 96







15




Sal: HCl


 


16







 


17







 


18







 


19






















TABLE 97







20




 


 


21







 


22







 


23







 


24






















TABLE 98







25




Sal: HCl


 


26




Sal: HCl


 


27




Sal: HCl


 


28







 


29






















TABLE 99







30







 


31







 


32




Sal: 2HCl


 


33




Sal: 2HCl


 


34






















TABLE 100







35







 


36




Sal: HCl


 


37




Sal: HCl


 


38







 


39






















TABLE 101







40







 


41




Sal: HCl


 


42




Sal: HCl


 


43




Sal: HCl


 


44




Sal: HCl


















TABLE 102







45




Sal: HCl


 


46




Sal: HCl


 


47




Sal: HCl


 


48




Sal: HCl


 


49




Sal: HCl


















TABLE 103







50




Sal: 2HCl


 


51




Sal: 2HCl


 


52




Sal: HCl


 


53




Sal: HCl


 


54




Sal: HCl


















TABLE 104







55




 


 


56







 


57







 


58







 


59







 


60






















TABLE 105







61




 


 


62







 


63







 


64







 


65







 


66






















TABLE 106







67







 


68




Sal: HCl


 


69







 


70




Sal: HCl


 


71




Sal: HCl


















TABLE 107







72







 


73







 


74







 


75




Sal: HCl


 


76




Sal: HCl


















TABLE 108







77







 


78







 


79







 


80







 


81







 


82




Sal: 2HCl


















TABLE 109







83




Sal: 2HCl


 


84




Sal: 2HCl


 


85




Sal: HCl


 


86




Sal: HCl


 


87




Sal: HCl


















TABLE 110







88




Sal: HCl


 


89




Sal: 2HCl


 


90




Sal: HCl


 


91




Sal: HCl


 


92




Sal: HCl


















TABLE 111







93




Sal: HCl


 


94




Sal: HCl


 


95




Sal: HCl


 


96




Sal: HCl


 


97




Sal: HCl


 


98




Sal: HCl


















TABLE 112







 99







 


100




Sal: HCl


 


101




Sal: HCl


 


102




Sal: HCl


 


103




Sal: HCl


 


104




Sal: HCl


















TABLE 113







105




Sal: HCl


 


106




Sal: HCl


 


107







 


108




Sal: 2HCl


 


109






















TABLE 114







110







 


111




Sal: HCl


 


112







 


113







 


114







 


115






















TABLE 115







116







 


117







 


118




Sal:  HCl


 


119







 


120







 


121




Sal: HCl


















TABLE 116







122




Sal: HCl


 


123




Sal: HCl


 


124







 


125







 


126







 


127






















TABLE 117







128




Sal: HCl


 


129







 


130







 


131







 


132







 


133























TABLE 118









134







 



135







 



136







 



137







 



138







 



139






















TABLE 119







140






 


141






 


142






 


143






 


144






 


145





















TABLE 120







146






 


147






 


148






 


149






 


150






 


151





















TABLE 121







152






 


153






 


154






 


155






 


156





















TABLE 122







157






 


158






 


159






 


160






 


161























TABLE 123









162







 



163







 



164







 



165







 



166
























TABLE 124









167







 



168







 



169







 



170







 



171






















TABLE 125







172






 


173






 


174






 


175






 


176





















TABLE 126







177






 


178






 


179






 


180






 


181





















TABLE 127







182






 


183






 


184






 


185






 


186






















TABLE 128







187







 


188




Sal:HCl


 


189







 


190







 


191





















TABLE 129







192






 


193






 


194






 


195






 


196























TABLE 130









197







 



198







 



199







 



200







 



201






















TABLE 131







202






 


203






 


204 






 


205






 


206






















TABLE 132







207







 


208







 


209







 


210




Sal:HCl

















TABLE 133







211






 


212






 


213






 


214























TABLE 134









215







 



216







 



217







 



218







 



219






















TABLE 135







220






 


221






 


222






 


223






 


224





















TABLE 136







225






 


226






 


227






 


228






 


229





















TABLE 137







230






 


231






 


232






 


233






 


234





















TABLE 138







235






 


236






 


237






 


238






 


239






 


240





















TABLE 139







241






 


242






 


243






 


244






 


245





















TABLE 140







246






 


247






 


248






 


249






 


250





















TABLE 141







251






 


252






 


253






 


254






 


255





















TABLE 142







256






 


257






 


258






 


259






 


260






 


261





















TABLE 143







262






 


263






 


264






 


266






 


266






 


267





















TABLE 144







268






 


269






 


270






 


271






 


272






 


273





















TABLE 145







274






 


275






 


276






 


277






 


278





















TABLE 146







279






 


280






 


281






 


282






 


283





















TABLE 147







284






 


285






 


286






 


287






 


288






 


289





















TABLE 148







290






 


291






 


292






 


293






 


294






 


295





















TABLE 149







296






 


297






 


298






 


299






 


300






 


301





















TABLE 150







302






 


303






 


304






 


305






 


306





















TABLE 151







307






 


308






 


309






 


310






 


311





















TABLE 152







312






 


313






 


314






 


315






















TABLE 153





Ex
Syn
Data

















1
1
ESI+: 383.2


2
2
ESI+: 367.2


3
3
ESI+: 426


4
4
ESI+: 411


5
5
ESI+: 370.3, NMR-DMSOd6: 0.21-0.60 (m, 4H), 1.27




(d, J = 8 H, 6H), 1.93-2.34 (m, 2H), 2.57-3.00 (m,




5H), 3.78 (s, 3H), 4.16-4.31 (m, 1H), 4.62-4.71




(m, 1H), 6.50-6.53 (m, 2H), 7.06 (d, J = 8 Hz,




1H), 7.29, 12.3 (two brs, 2H).


6
6
ESI+: 417


7-1
7
ESI+: 401.2, NMR-DMSOd6: 0.40-0.57 (m, 4H),




2.11-2.34 (m, 2H), 2.63-3.03 (m, 5H), 4.20-4.30




(m, 1H), 7.18-7.87 (m, 8H), 12.3 (brs, 1H).




[□]D-22.2 (CHCl3, c 0.515, 23.6° C.)


7-2
7
ESI+: 401.2


8-1
8
ESI+: 340.2 NMR-DMSOd6: 0.35-0.59 (m, 4H), 1.28




(d, J = 8 Hz, 6H), 2.06-2.25 (m, 2H), 2.58-2.99




(m, 5H), 4.11-4.22 (m, 1H), 4.61-4.71 (m, 1H),




6.90 (d, J = 8 Hz, 2H), 7.45 (d, J = 8 Hz, 2H),




7.30, 12.3 (two brs, 2H). [□]D-30.8 (CHCl3,




c 0.5, 22.5° C.)


8-2
8
ESI+: 340.2


9
9
ESI+: 379


10
10
ESI+: 324


11
11
ESI+: 347


12
12
ESI+: 325


13
13
ESI+: 338


14
14
ESI+: 365


15
15
ESI+: 430


16
16
ESI+: 341


17
17
ESI+: 395


18
18
ESI+: 426


19
19
ESI+: 402


20
20
ESI+: 365


21
21
ESI+: 374


22
22
ESI+: 363


23
23
ESI+: 340.2


24
24
ESI+: 388


25
2
ESI+: 312


26
2
ESI+: 326


27
P2, 2
ESI+: 366


28
P2, 2
ESI+: 415


29
P2, 2
ESI+: 425


30
P1, 2
ESI+: 425


31
P2, 2
ESI+: 443, 445


32
2
ESI+: 390



















TABLE 154








33
2
ESI+: 376



34
P2, 2
ESI+: 389



35
P2, 2
ESI+: 403



36
2
ESI+: 395



37
2
ESI+: 381



38
P2, 2
ESI+: 423, 425



39
P2, 2
ESI+: 423, 425



40
P2, 2
ESI+: 423, 425



41
2
ESI+: 457



42
2
ESI+: 457



43
2
ESI+: 457



44
2
ESI+: 419



45
2
ESI+: 419



46
2
ESI+: 419



47
15 
ESI+: 444



48
2
ESI+: 383



49
2
ESI+: 397



50
2
ESI+: 390



51
2
ESI+: 390



52
2
ESI+: 409



53
2
ESI+: 395



54
15 
ESI+: 403



55
4
ESI+: 411



56
4
ESI+: 389



57
4
ESI+: 349



58
4
ESI+: 372



59
4
ESI+: 362



60
P2, 1
ESI+: 307



61
P2, 1
ESI+: 325



62
P2, 1
ESI+: 341, 343



63
P2, 1
ESI+: 365



64
P2, 1
ESI+: 365



65
P2, 1
ESI+: 411



66
P2, 1
ESI+: 411



67
P2, 1
ESI+: 411



68
2
ESI+: 425



69
P2, 1
ESI+: 350



70
2
ESI+: 412



71
2
ESI+: 412



72
12 
ESI+: 343



73
12 
ESI+: 359, 361



74
P2, 1
ESI+: 369, 371



















TABLE 155








75
2
ESI+: 416



76
2
ESI+: 416



77
P2, 1
ESI+: 356



78
P2, 1
ESI+: 356



79
P2, 1
ESI+: 349



80
P2, 1
ESI+: 363



81
P2, 1
ESI+: 335



82
2
ESI+: 412



83
2
ESI+: 412



84
2
ESI+: 412



85
2
ESI+: 362



86
2
ESI+: 388



87
2
ESI+: 372



88
2
ESI+: 390



89
2
ESI+: 412



90
2
ESI+: 405



91
2
ESI+: 392



92
2
ESI+: 434, 436



93
2
ESI+: 356



94
2
ESI+: 356



95
2
ESI+: 352



96
2
ESI+: 356



97
2
ESI+: 349



98
2
ESI+: 379



99
1
ESI+: 419



100
2
ESI+: 354



101
2
ESI+: 368



102
3
ESI+: 349



103
3
ESI+: 335



104
3
ESI+: 335



105
3
ESI+: 399



106
2
ESI+: 383



107
2
ESI+: 441



108
2
ESI+: 434



109
1
ESI+: 392



110
1
ESI+: 350



111
3
ESI+: 349



112
1
ESI+: 407



113
1
ESI+: 335



114
1
ESI+: 335



115
1
ESI+: 393



116
1
ESI+: 391.2


















TABLE 156







117
1
ESI+: 405.3


118
2
ESI+: 393.3


119
1
ESI+: 336


120
1
ESI+: 336


121
1
ESI+: 393.4


122
2
ESI+: 381.3


123
9
ESI+: 393


124
1
ESI+: 321.5


125
P20,
ESI+: 391.3



P1, 1



126
1
ESI+: 432.3


127
1
ESI+: 447.3


128
P1, 2
ESI+: 392.3


129
1
ESI+: 377


130
1
ESI+: 406.4


131
1
ESI+: 418.2


132
P20,
ESI+: 365.3, NMR-DMSOd6: 0.72-0.47 (m, 4H),



P1, 1
2.08-2.30 (m, 2H), 2.53-3.05 (m, 5H), 3.91 (s, 3),




4.00 (s, 3H), 4.14-4.24 (m, 1H), 6.31 (d, J =




2.8 Hz, 1H), 6.65 (d, J = 8 Hz, 1H), 7.00 (d, J =




8 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.31, 12.3




(brs, 2H).


133
1
ESI+: 337


134
11 
ESI+: 351


135
11 
ESI+: 363


136
1
ESI+: 413


137
1
ESI+: 336.2


138
1
ESI+: 385.2


139
P1, 1
ESI+: 353.2


140
1
ESI+: 380.3


141
1
ESI+: 350.2


142
1
ESI+: 364.2


143
1
ESI+: 364.2


144
P20,
ESI+: 382.2



P1, 1



145
1
ESI+: 368.3


146
1
ESI+: 394.2


147
1
ESI+: 366.2


148
P20,
ESI+: 392.3



P1, 1



149
1
ESI+: 420


150
1
ESI+: 336


151
1
ESI+: 480


152
1
ESI+: 390


















TABLE 157







153
1
ESI+: 394.3


154
1
ESI+: 394.2


155
1
ESI+: 386.2


156
1
ESI+: 397.3


157
1
ESI+: 392.3


158
1
ESI+: 358.3


159
1
ESI+: 428.2


160
1
ESI+: 398


161
1
ESI+: 466.1


162
1
ESI+: 432.3


163
1
ESI+: 394.3


164
1
ESI+: 373


165
1
ESI+: 365


166
1
ESI+: 397


167
1
ESI+: 397


168
1
ESI+: 417, 419


169
1
ESI+: 422.3


170
1
ESI+: 418.3


171
1
ESI+: 384.2


172
1
ESI+: 401.2


173
1
ESI+: 416.2


174
1
ESI+: 359


175
1
ESI+: 424.3


176
1
ESI+: 401.3, NMR-DMSOd6: 0.40-0.60 (m, 4H), 2.10-2.34




(m, 2H), 2.57-3.03 (m, 5H), 4.14-4.24 (m, 1H), 7.13-8.01




(m, 8H), 12.3 (brs, 1H).


177
1
ESI+: 411


178
1
ESI+: 392


179
1
ESI+: 378


180
1
ESI+: 406.2


181
1
ESI+: 375.2


182
1
ESI+: 413


183
1
ESI+: 384.3


184
1
ESI+: 437


185
1
ESI+: 392


186
1
ESI+: 406


187
1
ESI+: 437


188
3
ESI+: 367


189
1
ESI+: 436


190
1
ESI+: 401.2, NMR-DMSOd6: 0.46-0.60 (m, 4H), 2.04-2.34




(m, 2H), 2.63-3.05 (m, 5H), 4.24-4.39 (m, 1H), 7.17-8.00




(m, 8H), 12.3 (brs, 1H).


















TABLE 158







191
1
ESI+: 413.2


192
1
ESI+: 398


193
1
ESI+: 383.2


194
1
ESI+: 377.2


195
1
ESI+: 373.2


196
1
ESI+: 360


197
5
ESI+: 346


198
1
ESI+: 417.1


199
1
ESI+: 401.2


200
5
ESI+: 360


201
P1, 5
ESI+: 332


202
1
ESI+: 377.3


203
1
APCI/ESI+: 373.0


204
1
ESI+: 429


205
1
ESI+: 360


206
P1, 1
ESI+: 415


207
P1, 1
ESI+: 401


208
1
APCI/ESI+: 401


209
5
ESI+: 360


210
1
ESI+: 398


211
1
APCI/ESI+: 401


212
1
APCI/ESI+: 402


213
1
ESI+: 416


214
1
APCI/ESI+: 415


215
5
ESI+: 359


216
1
ESI+: 394.3, NMR-DMSO-d6: 0.43-0.58 (m, 4H),




2.11-2.33 (m, 2H), 2.60-3.03 (m, 5H), 4.14-4.28




(m, 1H), 7.17-7.67 (m, 8H), 12.3 (brs, 1H).


217
P4,
ESI+: 389.3



P1, 5



218
P4,
ESI+: 377.3



P1, 5



219
1
APCI/ESI+: 338.1


220
1
APCI/ESI+: 366.0


221
1
APCI/ESI+: 400


222
1
APCI/ESI+: 400


223
5
ESI+: 389


224
5
APCI/ESI+: 342.1


225
1
APCI/ESI+: 326


226
5
APCI/ESI+: 352.1


227
5
APCI/ESI+: 358.1


228
5
ESI+: 395



















TABLE 159








229
5
ESI+: 401



230
5
ESI+: 350



231
5
ESI+: 352



232
5
ESI+: 354



233
5
ESI+: 395



234
5
ESI+: 382.3



235
P1, 5
ESI+: 340



236
5
ESI+: 427, 429, 431



237
5
ESI+: 338



238
5
ESI+: 354



239
5
ESI+: 358.2



240
5
ESI+: 352



241
5
ESI+: 411, 413



242
5
ESI+: 383



243
5
ESI+: 354



244
5
ESI+: 376



245
5
ESI+: 368



246
5
ESI+: 392



247
5
ESI+: 402



248
5
ESI+: 402



249
5
ESI+: 354.2



250
5
ESI+: 374.2



251
6
ESI+: 410.1



252
5
ESI+: 406



253
6
ESI+: 392.3



254
6
ESI+: 374.3



255
5
ESI+: 354



256
5
ESI+: 354



257
5
ESI+: 374



258
16
ESI+: 328



259
16
ESI+: 360



260
16
ESI+: 337



261
16
ESI+: 340



262
17
ESI+: 375



263
17
ESI+: 364



264
17
ESI+: 376



266
17
ESI+: 370



266
17
ESI+: 389



267
17
ESI+: 393



268
17
ESI+: 371



269
17
ESI+: 366



270
17
ESI+: 405



















TABLE 160








271
17
ESI+: 375



272
17
ESI+: 416



273
17
ESI+: 416



274
17
ESI+: 416



275
17
ESI+: 409



276
17
ESI+: 353



277
17
ESI+: 416



278
17
ESI+: 335



279
17
ESI+: 405



280
17
ESI+: 351



281
17
ESI+: 363



282
17
ESI+: 416



283
17
ESI+: 364



284
17
ESI+: 374



285
17
ESI+: 388



286
17
ESI+: 427



287
17
ESI+: 407



288
17
ESI+: 393



289
17
ESI+: 412



290
17
ESI+: 338



291
17
ESI+: 338



292
17
ESI+: 410



293
17
ESI+: 332



294
17
ESI+: 354



295
17
ESI+: 364



296
17
ESI+: 336



297
17
ESI+: 342



298
17
ESI+: 388



299
17
ESI+: 322



300
17
ESI+: 386



301
17
ESI+: 388



302
17
ESI+: 359



303
17
ESI+: 362



304
18
ESI+: 392



305
18
ESI+: 406



306
18
ESI+: 412



307
18
ESI+: 416



308
18
ESI+: 348



309
18
ESI+: 322



310
19
ESI+: 376



311
19
ESI+: 376



312
19
ESI+: 376



















TABLE 161








313
19
ESI+: 360



314
19
ESI+: 377



315
19
ESI+: 368









INDUSTRIAL APPLICABILITY
The compound of the present invention has an excellent 11β-HSD1 inhibitory action. Therefore, the compound is useful as an active ingredient of a pharmaceutical composition for treating 11β-HSD1-related diseases such as dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance, obesity, hyperlipidemia, hypertension, osteoporosis, and glaucoma, particularly, for treating dementia (particularly, Alzheimer's type dementia), schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), and insulin resistance.

## Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:



wherein:
ring A is a 5- to 6-membered monocyclic heterocycle which may be substituted and has only nitrogen atom(s) as the hetero atom; wherein the atoms in the position where the ring is fused with the adjacent ring are carbon atoms;
R1 is lower alkyl, halogeno-lower alkyl, or cycloalkyl which may be substituted;
R2 is halogen or lower alkyl;
R3 is aryl, heteroaryl, or lower alkylene-heteroaryl; wherein each of the aryl and heteroaryl represented by R3 may be substituted;
n is an integer of 0 to 3; and
a dotted line represents a single bond or a double bond.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein n represents 0.

3. The compound or pharmaceutically acceptable salt therof according to claim 2, wherein R1 represents cyclopropyl.

4. The compound or pharmaceutically acceptable salt thereof according to claim 3, wherein the bicyclic ring which is formed by ring A fused with the adjacent ring is 4,5,6,7-tetrahydroindazol-5-yl.

5. The compound or pharmaceutically acceptable salt thereof according to claim 4, wherein
R3 represents phenyl, indolyl, or indazolyl, which may be substituted respectively with a group selected from Group Q,
Group Q is selected from the group consisting of halogen, lower alkyl, halogeno-lower alkyl, —OR0, lower alkylene-OR0, —S-lower alkyl, aryl, a heterocyclic group, and lower alkylene-heterocyclic group, wherein, said aryl and heterocyclic group in Group Q may be substituted with halogen, cyano, lower alkyl, —OR0, or oxo, and
R0 represents —H or lower alkyl.

6. The compound or pharmaceutically acceptable salt thereof according to claim 5, wherein
R3 represent phenyl which may be substituted with a group selected from the group consisting of
(i) phenyl or pyridyl, which may be respectively substituted with halogen or cyano,
(ii) halogen,
(iii) lower alkyl, and
(iv) —O-lower alkyl.

7. The compound or pharmaceutically acceptable salt thereof according to claim 5,
wherein R3 represents indolyl which may be substituted with lower alkyl or —O-lower alkyl.

8. The compound or pharmaceutically acceptable salt thereof according to claim 1 which is a compound selected from the group consisting of
(−)—N-cyclopropyl-4-isopropoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl) benzamide,
(−)-2′-cyano-N-cyclopropyl-6′-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl) biphenyl-4-carboxamide,
N-cyclopropyl-1-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide,
N-cyclopropyl-7-methoxy-1-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)-1H-indole-4-carboxamide,
2′-cyano-N-cyclopropyl-4′-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide,
2′-cyano-N-cyclopropyl-3-fluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide,
N-cyclopropyl-2′,6′-difluoro-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)biphenyl-4-carboxamide,
N-cyclopropyl-4-(3,5-difluoropyridin-4-yl)-N-(4,5,6,7-tetrahydro-2H-indazol-5-yl) benzamide, and
N-cyclopropyl-4-isopropoxy-2-methoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl) benzamide,
or a pharmaceutically acceptable salt of said compound.

9. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is
(−)—N-cyclopropyl-4-isopropoxy-N-(4,5,6,7-tetrahydro-1H-indazol-5-yl)benzamide, or a pharmaceutically acceptable salt of said compound.

10. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is
(−)-2 ′-cyano-N-cyclopropyl-6′-fluoro-N-(4,5 ,6,7-tetrahydro-1H-indazol-5-yl) biphenyl-4-carboxamide, or a pharmaceutically acceptable salt of said compound.

11. A pharmaceutical composition, comprising:
a compound or pharmaceutically acceptable salt thereof according to claim 8; and
at least one pharmaceutically acceptable carrier.

12. A method of treating dementia, schizophrenia, depression, or pain, comprising administering an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 8 to a patient in need thereof.

13. A method of treating dementia, comprising administering an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 8 to a patient in need thereof.

14. The method according to claim 13, wherein said dementia is Alzheimer's type dementia.

15. A method of treating or pain, comprising administering an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 8 to a patient in need thereof.

16. The method according to claim 15, wherein said pain is neuropathic pain or fibromyalgia.