Melanocortin 2-type receptor antagonist

Abstract

According to the present application, a heterocyclic compound (I) represented by formula (I) (where each symbol is as disclosed in the description) or a salt thereof is disclosed as one embodiment of the present invention, the heterocyclic compound (I) having antagonist activity against a melanocortin 2-type receptor and being useful for the treatment or prevention of endocrine system diseases and the like.

Description

Melanocortin type 2 receptor antagonist

[0001] The present invention relates to an embodiment thereof, which relates to a heterocyclic compound, etc. that has antagonist activity against the melanocortin 2 receptor (MC2R) and is useful for the treatment or prevention of conditions, diseases, and disorders responsive to MC2R antagonism, such as endocrine system diseases (e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome), metabolic diseases (e.g., obesity, type 2 diabetes, dyslipidemia, osteoporosis, or sarcopenia), cardiovascular system diseases (e.g., hypertension, arteriosclerosis), central nervous system diseases (e.g., depression, dementia, insomnia), ophthalmological diseases (e.g., cataract, glaucoma), and infectious diseases. The present invention is useful in the field of medicine.

[0002] The hypothalamic-pituitary-adrenal (HPA) axis is responsible for the biological response to stress and is an essential neuroendocrine mechanism for protecting the body from stress and maintaining homeostasis. In response to stressful stimuli, corticotropin-releasing factor (CRF)-producing neurons in the paraventricular nucleus of the hypothalamus secrete CRF. This CRF then travels through the pituitary portal vein and acts on adrenocorticotropic hormone-producing cells in the anterior pituitary gland, promoting the synthesis and secretion of adrenocorticotropic hormone (ACTH), a 39-amino acid hormone. ACTH secreted from the anterior pituitary gland then acts on the adrenal cortex via the bloodstream, promoting the secretion of glucocorticoids and other adrenocorticoid hormones, thereby regulating the body's overall metabolic and immune responses, thereby inducing a biological response to stress. Furthermore, glucocorticoids act on the hypothalamus and anterior pituitary gland to suppress ACTH secretion through a negative feedback mechanism, thereby terminating activation of the HPA axis. While the HPA axis is an important physiological response for the body's adaptation to external environmental stimuli, its dysfunction, such as excessive activation, is thought to be deeply involved in the development of a variety of systemic pathologies. ACTH secreted from the anterior pituitary gland exerts its physiological effects by selectively binding to the ACTH receptor. The ACTH receptor is composed of the seven-transmembrane G protein-coupled receptor MC2R and the accessory protein melanocortin-2 receptor accessory protein-1 (MRAP). When ACTH binds to the receptor, adenylate cyclase is activated via Gas, which increases intracellular cyclic AMP and transmits downstream signals into the cell. Since MC2R expression is limited to the adrenal gland and ACTH is the only endogenous ligand for MC2R, ACTH-MC2R / MRAP signaling is thought to be a specific and essential pathway for steroidogenesis in the adrenal gland. Therefore, selective antagonists of this receptor can selectively block ACTH signaling in the adrenal gland and are expected to be effective in treating or preventing conditions, diseases, and disorders caused by excessive ACTH signaling.Under these circumstances, attempts have been made in the field to develop MC2R antagonists (Patent Document 1; Non-Patent Document 1). However, their efficacy and safety have not yet been sufficient, and the development of more useful MC2R antagonists has been eagerly awaited.

[0003] International Publication No. 2019 / 236699

[0004] Front Endocrinol (Lausanne). 2016 Aug 5;7:101. doi: 10.3389 / fendo.2016.00101. PMID: 27547198; PMCID: PMC4974254.

[0005] In order to solve the above problems, an object of the present invention is to provide, as an embodiment thereof, a novel heterocyclic compound having MC2R antagonist activity.

[0006] The present inventors have found that a heterocyclic compound represented by the following formula (I) or a salt thereof has MC2R antagonist activity, and as a result of further research, have completed the present invention. Specific embodiments of the present invention are as follows, but the present invention is not limited thereto.

[0007] [1] Formula (I):

[0008]

[0009] [In the formula, R １ represents a hydrogen atom or an optionally substituted C １－６ represents an alkyl group, R ２ represents a hydrogen atom or an optionally substituted C １－６ represents an alkyl group, X represents an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group, Y represents an optionally substituted aromatic heterocyclic group, or an optionally substituted aryl group, and Z represents a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ is an optionally substituted C １－６[2] A compound represented by the formula (I) (hereinafter also referred to as "compound (I)") or a salt thereof. [2] The compound according to the above [1], wherein X is an optionally substituted aryl group, an optionally substituted nitrogen-containing aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group, and Y is an optionally substituted nitrogen-containing aromatic heterocyclic group, or an optionally substituted aryl group. [3] A compound represented by the formula (I) (hereinafter also referred to as "compound (I)") (hereinafter also referred to as "compound (I)") or a salt thereof. [3] A compound according to the above [1], wherein X is an optionally substituted C ６－１４ an aryl group, an optionally substituted 5- to 14-membered (preferably 5- to 6-membered) nitrogen-containing aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group; and Y is an optionally substituted 5- to 14-membered (preferably 5- to 6-membered) nitrogen-containing aromatic heterocyclic group, or an optionally substituted C ６－１４ [4] The compound or salt thereof according to any one of the above [1] to [3], wherein X is an optionally substituted phenyl group, an optionally substituted pyridyl group, or an optionally substituted saturated hydrocarbon ring group, and Y is an optionally substituted pyridyl group or an optionally substituted phenyl group. [5] The compound or salt thereof according to any one of the above [1] to [4], wherein X is an optionally substituted phenyl group or an optionally substituted saturated hydrocarbon ring group, and Y is an optionally substituted pyridyl group or an optionally substituted phenyl group. [6] The compound or salt thereof according to any one of the above [1] to [4], wherein X is an optionally substituted phenyl group or an optionally substituted saturated hydrocarbon ring group, and Y is an optionally substituted pyridyl group or an optionally substituted phenyl group. [7] The compound or salt thereof according to any one of the above [1] to [4], wherein X is an optionally substituted saturated hydrocarbon ring group, or an optionally substituted pyridyl group or an optionally substituted phenyl group. ３－１０ [7] The compound or salt thereof according to any one of the above [3] to [5], wherein X is an optionally substituted phenyl group, or an optionally substituted C ３－１０ [8] The compound or salt thereof according to any one of the above [1] to [6], wherein Z is a cycloalkyl group, a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ is an optionally substituted C １－６[9] The compound or salt thereof according to any one of the above [1] to [7], wherein R represents an alkyl group or an optionally substituted 3- to 8-membered saturated cyclic group. １ is a hydrogen atom or C １－６ is an alkyl group, R ２ is a hydrogen atom or C １－６ an alkyl group, wherein X is 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms, １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; or 2) a C 1-C 2-C 3-C 4-C 5-C 6-C 7-C 8-C 9-C 10-C 11-C 12-C 13-C 14-C 15-C 16-C 17-C 18-C 19-C １－６ C optionally substituted with 1 to 3 alkyl groups ３－１０ is a cycloalkyl group, and Y is 1 to 3 C １－６ a pyridyl group optionally substituted by an alkoxy group, or 1 to 3 C １－６ a phenyl group optionally substituted with an alkoxy group, and Z is a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or (ii) C １－６ alkyl group, C １－６

[10] The compound or salt thereof according to any one of the above [1] to [8], wherein X is 1) a halogen atom, 2) a C optionally substituted with 1 to 3 halogen atoms, 3) a C optionally substituted with 1 to 3 halogen atoms, 4) a C optionally substituted with 1 to 3 halogen atoms, 5) a C optionally substituted with 1 to 3 halogen atoms, 6) a C optionally substituted with 1 to 3 halogen atoms, 7) a C optionally substituted with 1 to 3 halogen atoms, 8) a C optionally substituted with 1 to 3 halogen atoms, 9) a C optionally substituted with 1 to 3 halogen atoms, 10) a C optionally substituted with 1 to 3 halogen atoms, 11) a C optionally substituted with 1 to 3 halogen atoms, 12) a C optionally substituted with 1 to 3 halogen atoms, 13) a C optionally substituted with 1 to 3 halogen atoms, 14) a C optionally substituted with 1 to 3 halogen atoms, 15) a C optionally substituted with 1 to 3 halogen atoms, 16) a C optionally substituted with 1 to 3 halogen atoms, 17) a C optionally substituted with 1 to 3 halogen atoms, 18) a C optionally substituted with 1 to 3 halogen atoms, 19) a C optionally substituted with 1 to 3 halogen atoms, 19) a C optionally substituted with 1 to 3 halogen atoms, 10 ...2) a C optionally substituted with 1 to 3 halogen atoms, 13) a C optionally substituted with 1 to 3 halogen atoms, 14) a C optionally substituted with 1 to 3 halogen atoms, 15) a C optionally substituted with 1 to 3 halogen atoms, 16) a C optionally substituted with 1 to 3 halogen atoms １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, and 2) a cyano group; and １－６

[11] The compound or salt thereof according to any one of the above [1] to [9], wherein R is a pyridyl group optionally substituted with an alkoxy group. １ But C １－６ is an alkyl group, and R ２

[12] The compound or salt thereof according to any one of the above [1] to

[10] , wherein Z is a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group, a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ (ii) (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) C １－６ alkyl group, C １－６

[13] The compound or salt thereof according to any one of the above [1] to

[11] , wherein Z is a hydroxyl group, or NHR ３ (In the formula, R ３ is (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) C １－６ alkyl group, C １－６

[14] The compound or salt thereof according to any one of the above [1] to

[12] , wherein R is a 3- to 8-membered nitrogen-containing saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from an alkoxy-carbonyl group, and an oxo group. １ But C １－６ is an alkyl group, R ２ is a hydrogen atom, and X is 1) a halogen atom, 2) a C optionally substituted with 1 to 3 halogen atoms. １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; and Y is 1 to 3 C １－６ a pyridyl group optionally substituted with an alkoxy group, and Z is a hydroxyl group or NHR ３ (In the formula, R ３ is C １－６

[15] The compound or a salt thereof according to any one of the above [1] to

[13] , wherein compound (I) is a compound represented by the following formula (Ia):

[0010]

[0011]

[16] 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 49), 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 52), 3-[(6R,8aS)-2-(4-chloro-2-cyanophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 54), 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 61), 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 64), or a salt of each of the above compounds,

[0012]

[17] A pharmaceutical comprising, as an active ingredient, the compound according to any one of [1] to

[16] above or a salt thereof.

[18] The pharmaceutical according to

[17] above, which is an MC2R antagonist.

[19] The pharmaceutical according to

[17] or

[18] above, which is a preventive or therapeutic agent for endocrine system diseases, metabolic diseases, cardiovascular diseases, central nervous system diseases, eye diseases, and / or infectious diseases.

[20] The pharmaceutical according to any one of

[17] to

[19] above, which is a preventive or therapeutic agent for Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome, obesity, type 2 diabetes, dyslipidemia, osteoporosis, sarcopenia, hypertension, arteriosclerosis, depression, dementia, insomnia, cataracts, glaucoma, and / or infectious diseases.

[21] A method for preventing and / or treating endocrine system diseases, metabolic diseases, cardiovascular diseases, central nervous system diseases, eye diseases, and / or infectious diseases, comprising administering an effective amount of the compound according to any one of the above-mentioned [1] to

[16] or a salt thereof to a mammal in need thereof.

[22] The compound according to any one of the above-mentioned [1] to

[16] or a salt thereof used for the prevention and / or treatment of endocrine system diseases, metabolic diseases, cardiovascular diseases, central nervous system diseases, eye diseases, and / or infectious diseases.

[23] Use of the compound according to any one of the above-mentioned [1] to

[16] or a salt thereof for the manufacture of a medicament for the prevention and / or treatment of endocrine system diseases, metabolic diseases, cardiovascular diseases, central nervous system diseases, eye diseases, and / or infectious diseases.

[0013] The present invention provides, as one embodiment, a heterocyclic compound or a salt thereof which has antagonist activity against MC2R and is useful for the prevention or treatment of conditions, diseases, or disorders responsive to MC2R antagonism, such as endocrine system diseases (e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome), metabolic diseases (e.g., obesity, type 2 diabetes, dyslipidemia, osteoporosis, or sarcopenia), cardiovascular diseases (e.g., hypertension, arteriosclerosis), central nervous system diseases (e.g., depression, dementia, insomnia), ophthalmological diseases (e.g., cataract, glaucoma), and infectious diseases.

[0014] The present invention is now described in detail; unless otherwise defined in the context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications and patents mentioned herein are incorporated by reference for the purpose of describing and disclosing, for example, the constructs and methodologies described in the publications that may be used in connection with the described invention.

[0015] [Regarding Compound (I)] According to one embodiment of the present invention, there is provided a compound represented by the following formula (I):

[0016]

[0017] [In the formula, R １ represents a hydrogen atom or an optionally substituted C １－６ represents an alkyl group, R ２ represents a hydrogen atom or an optionally substituted C １－６ represents an alkyl group, X represents an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group, Y represents an optionally substituted aromatic heterocyclic group, or an optionally substituted aryl group, and Z represents a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ is an optionally substituted C １－６ represents an alkyl group, or an optionally substituted saturated cyclic group. ) represents a compound represented by the formula (I) or a salt thereof.

[0018] Each group of the compound (I) will be described below. １－６ However, when the group constitutes a part of another group (for example, "C １ -C ６Unless otherwise specified, in the case of "alkyl-carbonyloxy group"), for the corresponding parts, reference can be made to the explanation for each group.

[0019] In this specification, "C ａ－ｂ ” (e.g., C １－６ ) or "C ａ -C ｂ ” (e.g., C １ -C ６ ) indicates that the group has a to b carbon atoms (for example, 1 to 6).

[0020] In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0021] In this specification, "C １－６ Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0022] In this specification, "C １－６ Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0023] As used herein, an "aryl group" refers to a monocyclic or polycyclic unsaturated hydrocarbon group, such as, for example, C ６－１４ Specific examples thereof include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. ６－１０ Aryl groups are preferred.

[0024] In the present specification, examples of the "saturated hydrocarbon ring group" include monocyclic or bicyclic C ３－１０Specific examples thereof include cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, and decahydronaphthyl. ３－８ Cycloalkyl groups are preferred, and C ３－６ Cycloalkyl groups are more preferred.

[0025] In the present specification, examples of the "heterocyclic group" include (i) an aromatic heterocyclic group and (ii) a non-aromatic heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0026] In the present specification, examples of the "aromatic heterocyclic group" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc. Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0027] In the present specification, examples of the "non-aromatic heterocyclic group" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazol ... thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydroisothiazolyl, tetrahydro 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as dihydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, and the like; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl and 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups such as tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0028] In the present specification, examples of the "saturated heterocyclic group" include saturated heterocyclic groups containing no unsaturated bond among the above-mentioned "heterocyclic groups".

[0029] When the above-mentioned "heterocyclic group" or "saturated heterocyclic group" is specified as "nitrogen-containing" or "oxygen-containing," this means that the "heterocyclic group" or "saturated heterocyclic group" contains at least one nitrogen atom or at least one oxygen atom as a ring-constituting atom other than carbon atoms.

[0030] In the present specification, examples of the "saturated cyclic group" include those described above as "saturated hydrocarbon cyclic groups" and "saturated heterocyclic groups." In the above, 3- to 8-membered monocyclic groups are preferred, and "C ３－８ "Cycloalkyl group" and "3- to 8-membered monocyclic saturated heterocyclic group" are more preferred, and among them, "C ３－６ "Cycloalkyl group" and "3- to 8-membered monocyclic saturated heterocyclic group containing nitrogen or oxygen as a ring-constituting atom" are more preferred.

[0031] In the present specification, "optionally substituted C １－６ Examples of the "substituent" in the "optionally substituted group or ring" in the definition of compound (I), such as "alkyl group," include substituents selected from the following [Substituent Group A]. One to five (preferably one to three) of the "substituents" may be present at substitutable positions, and when the number of substituents is two or more, the respective substituents may be the same or different. When a special explanation is given for the "substituent" in each group or ring, etc., that explanation shall be followed.

[0032] [Substituent Group A] (1) halogen atom, (2) nitro group, (3) cyano group, (4) oxo group, (5) hydroxy group, (6) optionally halogenated C １ -C ６ Alkoxy groups (e.g., methoxy, chloromethoxy, trifluoroethoxy), (7) C ６ -C １４ Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C ７ -C １６ aralkyloxy group (e.g., benzyloxy), (9) C １ -C ６Alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), (10) C ６ -C １４ Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (11) C １ -C ６ alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (12) 5- to 14-membered aromatic heterocyclic groups (e.g., thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl), wherein a 5- to 6-membered monocyclic aromatic heterocyclic group is preferred, and a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group is more preferred, (13) 3- to 14-membered non-aromatic heterocyclic groups (e.g., aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyri (13) a 3- to 8-membered monocyclic non-aromatic heterocyclic group is preferred, and a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group or a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group is more preferred; (14) a formyl group; (15) a carboxy group; (16) an optionally halogenated C １ -C ６ Alkyl-carbonyl group (e.g., acetyl, chloroacetyl, trifluoroacetyl), (17) C ６ -C １４Aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl), (18) C １ -C ６ (19) an alkoxycarbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl), (20) a carbamoyl group, (21) a mono- or di-C １ -C ６ alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (22) mono- or di-C ６ -C １４ (23) an arylamino group (e.g., phenylamino), (24) C １ -C ６ Alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (25) C １ -C ６ an alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (26) an optionally halogenated C １ -C ６ Alkyl groups (e.g., methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl), (27) C ２ -C ６ Alkenyl groups (e.g., ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl), (28) C ２ -C ６ Alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl), (29) C ３ -C １０ Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl), (30) C３ -C １０ Cycloalkenyl groups (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), (31) C ６ -C １４ Aryl groups (e.g., phenyl, naphthyl), (32) (mono- or di-C １ -C ６ alkylamino)carbonyl group (e.g., methylamino-carbonyl group), and (33) C １ -C ６ Alkyl-sulfonyl groups (eg, methylsulfonyl groups).

[0033] Preferred embodiments of the groups represented by each symbol in compound (I) are described below.

[0034] R １ is present at a substitutable position on the ring to which it is attached and is as defined above, but is not a hydrogen atom, or C １－６ Preferably, it is an alkyl group, and C １－６ It is more preferable that it is an alkyl group.

[0035] R ２ is as defined above, but is a hydrogen atom or C １－６ An alkyl group is preferred, and a hydrogen atom is more preferred.

[0036] X is as defined above, but is preferably (1) an optionally substituted (preferably 1) halogen atom, or 2) a C group optionally substituted with 1 to 3 halogen atoms. １－６ an aryl group optionally substituted with 1 to 3 substituents selected from 1) an alkyl group, and 2) a cyano group; an optionally substituted (preferably, 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms; １－６ a nitrogen-containing aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from 3) an alkyl group, and 4) a cyano group, or a C １－６(2) a saturated hydrocarbon ring group which is optionally substituted (preferably 1) a halogen atom, 2) a C group which is optionally substituted with 1 to 3 halogen atoms; １－６ 1) optionally substituted with 1 to 3 substituents selected from an alkyl group, and 2) a cyano group. ６－１４ an aryl group, optionally substituted (preferably 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms; １－６ a 5- to 14-membered (preferably 5- or 6-membered) nitrogen-containing aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from 3) an alkyl group, and 4) a cyano group; or a C １－６ and a saturated hydrocarbon ring group (which may be substituted with 1 to 3 alkyl groups) (here, the saturated hydrocarbon ring group is a C ３－１０ (3) optionally substituted (preferably 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms, １－６ a phenyl group which may be substituted with 1 to 3 substituents selected from 1) an alkyl group, and 2) a cyano group; an optionally substituted (preferably, 1) a halogen atom, 2) a C group which may be substituted with 1 to 3 halogen atoms; １－６ a pyridyl group which may be substituted with 1 to 3 substituents selected from 3) an alkyl group, and 4) a cyano group, or a C １－６ and a saturated hydrocarbon ring group (which may be substituted with 1 to 3 alkyl groups) (here, the saturated hydrocarbon ring group is a C ３－１０ (4) optionally substituted (preferably 1) a halogen atom, 2) a C alkyl group optionally substituted with 1 to 3 halogen atoms, １－６a phenyl group which may be substituted with 1 to 3 substituents selected from 3) an alkyl group, and 4) a cyano group; or a C １－６ and a saturated hydrocarbon ring group (which may be substituted with 1 to 3 alkyl groups) (here, the saturated hydrocarbon ring group is a C ３－１０ (5) optionally substituted (preferably 1) a halogen atom, 2) a C alkyl group optionally substituted with 1 to 3 halogen atoms, １－６ a phenyl group which may be substituted with 1 to 3 substituents selected from 3) an alkyl group, and 4) a cyano group; or a C １－６ C may be substituted with 1 to 3 alkyl groups ３－１０ (6) 1) a halogen atom, 2) a C alkyl group optionally substituted with 1 to 3 halogen atoms, １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; or 2) a C １－６ C optionally substituted with 1 to 3 alkyl groups ３－１０ (7) 1) a halogen atom, 2) a C alkyl group optionally substituted with 1 to 3 halogen atoms, １－６ and 3) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group and a cyano group.

[0037] Y is present at a substitutable position in the ring to which it is attached and is as defined above, but (1) may be substituted (preferably, 1 to 3 C １－６ a nitrogen-containing aromatic heterocyclic group optionally substituted with an alkoxy group, or １－６ (2) an aryl group which may be substituted (preferably with 1 to 3 C alkoxy groups);１－６ a 5- to 14-membered (preferably 5- or 6-membered) nitrogen-containing aromatic heterocyclic group optionally substituted (preferably substituted by an alkoxy group) or １－６ C, which may be substituted with an alkoxy group ６－１４ (3) an optionally substituted (preferably, 1 to 3 C) aryl group; １－６ a pyridyl group optionally substituted with an alkoxy group, or a pyridyl group optionally substituted with an alkoxy group, １－６ (4) a phenyl group optionally substituted with an alkoxy group; １－６ a pyridyl group optionally substituted by an alkoxy group, or 1 to 3 C １－６ (5) a phenyl group optionally substituted with an alkoxy group; １－６ Particularly preferred is a pyridyl group which may be substituted with an alkoxy group.

[0038] Z is as defined above, but (1) Z is a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ is an optionally substituted C １－６ (2) a hydrogen atom, a hydroxyl group, an NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or (ii) C １－６ alkyl group, C １－６ (3) a hydrogen atom, a hydroxyl group, an NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or (ii) C １－６ alkyl group, C １－６ (4) a hydrogen atom, a hydroxyl group, an NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group, a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ (ii) (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) C １－６ alkyl group, C １－６ (5) a hydroxyl group, or an NHR ３ (In the formula, R ３ is (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) C １－６ alkyl group, C １－６ alkoxy-carbonyl group, and oxo group), is particularly preferred.

[0039] Specific preferred examples of compound (I) or a salt thereof include the following.

[0040] [Compound A-1] R １ is a hydrogen atom, or C １－６ is an alkyl group, R ２ is a hydrogen atom, or C １－６ an alkyl group, wherein X is 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms, １－６ 1) a phenyl group optionally substituted by 1 to 3 substituents selected from an alkyl group, and 2) a cyano group; 3) a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C group optionally substituted by 1 to 3 halogen atoms. １－６ a pyridyl group optionally substituted by 1 to 3 substituents selected from 3) an alkyl group, and 4) a cyano group, or a C １－６ C optionally substituted with 1 to 3 alkyl groups ３－１０ is a cycloalkyl group, and Y is 1 to 3 C １－６a pyridyl group optionally substituted by an alkoxy group, or 1 to 3 C １－６ a phenyl group optionally substituted with an alkoxy group, Z being a hydrogen atom, a hydroxyl group, or NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or (ii) C １－６ alkyl group, C １－６ alkoxy-carbonyl group, and oxo group (preferably the optionally substituted 3- to 8-membered monocyclic saturated heterocyclic group)).

[0041] [Compound A-2] X is 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; or 2) a C 1-C 2-C 3-C 4-C 5-C 6-C 7-C 8-C 9-C 10-C 11-C 12-C 13-C 14-C 15-C 16-C 17-C 18-C 19-C １－６ C optionally substituted with 1 to 3 alkyl groups ３－１０ The above-mentioned [Compound A-1] and salts thereof, wherein the compound A-1 is a cycloalkyl group.

[0042] [Compound A-3] R １ is a hydrogen atom, or C １－６ is an alkyl group, R ２ is a hydrogen atom, or C １－６an alkyl group, wherein X is 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms, １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, and 2) a cyano group; and Y is 1 to 3 C １－６ and Z is a pyridyl group optionally substituted with an alkoxy group, and Z is a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or (ii) C １－６ alkyl group, C １－６ an alkoxy-carbonyl group, and an oxo group (preferably an optionally substituted 3- to 8-membered monocyclic saturated heterocyclic group),

[0043] [Compound A-4] R １ is a hydrogen atom, or C １－６ is an alkyl group, R ２ is a hydrogen atom, or C １－６ alkyl group, wherein preferably R １ But C １－６ is an alkyl group, R ２ is a hydrogen atom), and X is 1) a halogen atom, 2) a C optionally substituted with 1 to 3 halogen atoms. １－６1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; and １－６ Z is a pyridyl group optionally substituted with an alkoxy group, Z is a hydrogen atom, a hydroxyl group, NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group (e.g., a pyrazolyl group, a pyridyl group), a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group (e.g., an oxetanyl group, a morpholinyl group), C １－６ a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group (e.g., azetinidyl group, piperidinyl group) optionally substituted by an alkoxy-carbonyl group; １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ (ii) (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group (e.g., a tetrahydrofuranyl group), or (b) C １－６ alkyl group, C １－６ the above-mentioned [Compound A-1] or a salt thereof, wherein R represents a 3- to 8-membered monocyclic nitrogen-containing saturated heterocyclic group (e.g., a pyrrolidinyl group) optionally substituted by 1 to 3 substituents selected from an alkoxy-carbonyl group, and an oxo group.

[0044] [Compound A-5] Z is a hydroxyl group or NHR ３ (In the formula, R ３ is (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) C １－６ alkyl group, C １－６the above-mentioned [Compounds A-1] to [Compounds A-4], or salts thereof, wherein:

[0045] [Compound A-6] R １ But C １－６ is an alkyl group, R ２ is a hydrogen atom, and X is 1) a halogen atom, 2) a C optionally substituted with 1 to 3 halogen atoms. １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; and Y is 1 to 3 C １－６ a pyridyl group optionally substituted with an alkoxy group, and Z is a hydroxyl group or NHR ３ (In the formula, R ３ is C １－６ The compound A-1, or a salt thereof, is represented by the formula:

[0046] In the above [Compound A-1] to [Compound A-6], compound (I) is a compound represented by the following formula (Ia):

[0047]

[0048] It is more preferable that the compound has a structure represented by the following formula:

[0049] [Compound A-7] 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 49), 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 52), 3-[(6R,8aS)-2-(4-chloro-2-cyanophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 54), 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 61), 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide (compound of Example 64), or a salt of the above-mentioned compound [Compound A-6] or a salt thereof.

[0050] Other preferred specific examples of compound (I) include the following.

[0051] [Compound B-1] R １is a hydrogen atom, or C １－６ is an alkyl group, R ２ is a hydrogen atom, or C １－６ an alkyl group, and X is a halogen atom or a C group optionally substituted with 1 to 3 halogen atoms; １－６ a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group and a cyano group, or a C １－６ C optionally substituted with 1 to 3 alkyl groups ３－１０ is a cycloalkyl group, and Y is 1 to 3 C １－６ a pyridyl group optionally substituted by an alkoxy group, or 1 to 3 C １－６ a phenyl group optionally substituted with an alkoxy group, Z being a hydrogen atom, a hydroxyl group, or NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or (ii) C １－６ alkyl group, C １－６ alkoxy-carbonyl group, and oxo group), or a salt thereof.

[0052] [Compound B-2] R １ But C １－６ is an alkyl group, R ２ is a hydrogen atom, and X is a halogen atom, C optionally substituted with 1 to 3 halogen atoms.１－６ a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group and a cyano group, １－６ a pyridyl group optionally substituted with an alkoxy group, wherein Z is a hydrogen atom, a hydroxyl group, or an NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or (ii) C １－６ alkyl group, C １－６ alkoxy-carbonyl group, and oxo group), or a salt thereof.

[0053] [Compound B-3] Z is a hydrogen atom, a hydroxyl group, or NH ２ , or NHR ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups (mono- or di-C １－６ alkyl)amino group, C ３－１０ a cycloalkyl group, a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group, a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C１－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ (ii) (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) C １－６ alkyl group, C １－６ alkoxy-carbonyl group, and oxo group), or a salt thereof.

[0054] [Compound B-4] Z is NHR ３ (In the formula, R ３ is C １－６ alkyl group, C １－６ alkoxy-carbonyl group, and oxo group), or a salt thereof.

[0055] [Compound B-5] R １ But C １－６ is an alkyl group, R ２ is a hydrogen atom, and X is a halogen atom, C optionally substituted with 1 to 3 halogen atoms. １－６ a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group and a cyano group, １－６ a pyridyl group optionally substituted with an alkoxy group, and Z is NHR ３ (In the formula, R ３ is C １－６ The compound B-4 is a pyrrolidinyl group optionally substituted with 1 to 3 substituents selected from an alkyl group and an oxo group, or a salt thereof.

[0056] Compound (I) can be used in either free form or in the form of its salt (preferably, its pharmaceutically acceptable salt).Those skilled in the art can carry out the present invention by appropriately selecting from both forms, taking into account the properties of each compound (I) used.Examples of pharmaceutically acceptable salts include salts with acids such as salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts with organic acids such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, maleate, etc.; salts with bases such as alkali metal salts such as sodium salt, potassium salt, alkaline earth metal salts such as calcium salt; salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, aspartate, etc.

[0057] [Regarding the Production Method of Compound (I) or a Salt Thereof] The production method of compound (I) or a salt thereof (hereinafter sometimes collectively referred to as the present compound) is explained below.

[0058] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compounds of the present invention described above.

[0059] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into the free form or another desired type of salt by a method known per se.

[0060] The compounds obtained in each step can be used in the next reaction either as a reaction solution or as a crude product. Alternatively, the compounds obtained in each step can be isolated and / or purified from the reaction mixture by conventional separation techniques such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, and chromatography. Racemic compounds can be separated and purified into chiral compounds using a chiral column. Diastereomeric mixtures can be separated by silica gel column chromatography or recrystallization.

[0061] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0062] In the reactions of each step, the reaction time may vary depending on the reagents and solvent used; however, unless otherwise specified, it is usually 1 minute to 4 days, preferably 10 minutes to 8 hours. In the reactions of each step, the reaction temperature may vary depending on the reagents and solvent used; however, unless otherwise specified, it is usually -78°C to 300°C, preferably -78°C to 150°C. In the reactions of each step, the pressure may vary depending on the reagents and solvent used; however, unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm. In the reactions of each step, for example, a Microwave synthesis apparatus such as the Initiator manufactured by Biotage may be used. The reaction temperature may vary depending on the reagents and solvent used; however, unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvent used; however, unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0063] In the reactions of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When a reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When a reagent also serves as a reaction solvent, the reagent is used in the amount of the solvent.

[0064] Unless otherwise specified, the reactions in each step are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, heptane, etc.; Amides: N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, dichloroethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water. Two or more of the above solvents may be mixed in an appropriate ratio.

[0065] When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the Examples can be used: inorganic bases: sodium hydroxide, potassium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, sodium hydrogencarbonate, etc.; organic bases: triethylamine, N,N-diisopropylethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; metal alkoxides: sodium ethoxide, potassium tert-butoxide, N-methylimidazole, etc.; alkali metal hydrides: sodium hydride, etc.; metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; organic lithiums: n-butyllithium, etc.

[0066] When an acid or an acidic catalyst is used in the reaction of each step, for example, the following acids or acidic catalysts or acids or acidic catalysts described in the Examples can be used: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0067] Unless otherwise specified, the reactions in each step are carried out according to a method known per se, for example, those described in "Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); "New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); "Fine Organic Chemistry, Revised 2nd Edition" (L.F. Tietz, Th. Eicher, Nankodo); "Revised Organic Named Reactions: Their Mechanisms and Key Points" (by Hideo Togo, Kodansha); "ORGANIC SYNTHESES Collective, Volumes I-VII" (John Wiley & Sons Inc.); "Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental" (John Wiley & Sons Inc.); The synthesis is carried out in accordance with the methods described in "Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14" (Elsevier Japan Co., Ltd.); "Strategies for Organic Synthesis Learned from Named Reactions" (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); "Comprehensive Organic Transformations" (VCH Publishers Inc.) 1989, or the methods described in the Examples.

[0068] When a Curtius rearrangement reaction is carried out in each step, examples of the reagent used include diphenylphosphoryl azide and an organic base. In addition, ethyl chloroformate, a base, sodium azide, etc. can also be used as a reagent.

[0069] When a reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a method using a catalyst such as palladium-carbon or Lindlar's catalyst may be used.

[0070] When Mitsunobu reaction is carried out in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) etc.), triphenylphosphine or tributylphosphine are used as reagents.

[0071] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups 3rd Ed." (P. J. Kocienski), published by Thieme in 2004, or the method described in the Examples. Examples of protecting groups for hydroxyl groups of alcohols and phenolic hydroxyl groups include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate ester; sulfonic acid ester-type protecting groups such as methanesulfonate ester; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of protecting groups for carbonyl groups of aldehydes include acetal-type protecting groups such as dimethyl acetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for carbonyl groups of ketones include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of protecting groups for carboxyl groups include ester-type protecting groups such as methyl ester and benzyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the protecting group for thiol include ether-type protecting groups such as benzylthioether, and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of the protecting group for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate and tert-butylcarbamate, amide-type protecting groups such as acetamide, alkylamine-type protecting groups such as benzylamine, p-methoxybenzylamino, and N-triphenylmethylamine, and sulfonamide-type protecting groups such as methanesulfonamide.The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), a reduction method (e.g., palladium / carbon under a hydrogen atmosphere), or an oxidation method (e.g., ammonium cerium(IV) nitrate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone). The conversion of an alkyl ester compound to a carboxylic acid compound can be carried out using a strong base (sodium hydroxide or potassium trimethylsilanolate), a hydrogen-palladium catalyst, or a zero-valent palladium catalyst.

[0072] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (e.g., amines, imidazole) and a base (e.g., organic bases, inorganic bases) are used as reagents.

[0073] When a coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride, and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as chloro(1,5-cyclooctadiene)rhodium(I) (dimer) and tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; platinum compounds, etc. Furthermore, a base may be added to the reaction, and examples of such bases include organic bases and inorganic bases.

[0074] When an oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and the like. Alternatively, the oxidation reaction can be carried out in an alcohol solvent in the presence of potassium hydroxide and iodine, or by Pinnic oxidation using sodium chlorite and sodium dihydrogen phosphate in the presence of 2-methyl-2-butene.

[0075] In the case where an esterification reaction, an amidation reaction, or a urea reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides and acid bromides; acid anhydrides; activated carboxylic acids such as activated esters; and the like. Examples of activators for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoric acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Examples of suitable condensing agents include hexafluorophosphate (HATU); sulfuric acid; triphosgene; 2-bromo-1-ethylpyridinium tetrafluoroborate; chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH); and combinations thereof. When using a carbodiimide condensing agent, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be added to the reaction. Furthermore, when an amino group and an ester group or a carboxyl group are present in the same molecule, intramolecular amidation can also be performed under heating conditions. Furthermore, when performing a urea reaction, reagents include triphosgene, 1,1-carbonyldiimidazole (CDI), and 2,2,2-trichloroethyl chloroformate, and two different amines may also be used. The urea reaction can be performed using isocyanates and amines.

[0076] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid, triethylsilane, or the like may be added to reductively trap the by-product tert-butyl cation.

[0077] When an alkylation reaction is carried out in each step, a nucleophile (e.g., amines, alcohols, active methylene compounds adjacent to an electron-withdrawing group, etc.), an electrophile (e.g., alkyl halides, sulfonate esters), and a base (e.g., organic bases, alkali metal hydrides, metal alkoxides, inorganic bases, etc.) are used. Alternatively, the alkylation reaction in each step may be carried out by converting an alcohol into a sulfonate ester compound with a substituted sulfonyl chloride (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.) and a base (e.g., organic bases, alkali metal hydrides, metal alkoxides, inorganic bases, etc.), followed by reacting with amines or amides in the molecule.

[0078] In each step, when a Michael reaction is carried out, an acrylic acid ester or an acrylic acid (e.g., itaconic acid) and an amine are used. Reaction conditions include a condition in an acid solvent such as acetic acid, a condition in which a base (e.g., an organic base, a metal alkoxide, an inorganic base) is added, or a condition in which only a solvent (e.g., N-methyl-2-pyrrolidone) is used.

[0079] Specific examples of the method for producing compound (I) are as follows, but the method is not limited to these.

[0080] Production Method 1 Compound (I) can be produced by the following method.

[0081]

[0082] [In the formula, A represents a halogen atom (e.g., chlorine, iodine, bromine), and the other symbols are as defined above.]

[0083] Production Method 2 Compound (I) can be produced by the following method.

[0084]

[0085] [In the formula, A represents a halogen atom (e.g., chlorine, iodine, bromine), and the other symbols are as defined above.]

[0086] Production Method 3 Among the compounds (I), compounds (13), (14), (15) and (16) in the formula can be produced by the following method.

[0087]

[0088] [The symbols in the formula have the same meanings as defined above.]

[0089] Production Method 4 Among compounds (I), compounds (5), (6), (7) and (8) in the formula can be produced by the following method.

[0090]

[0091] [In the formula, A represents a halogen atom (e.g., chlorine, iodine, bromine), and the other symbols are as defined above.]

[0092] In addition, in the process of producing compound (I) from a raw material compound and / or a production intermediate of compound (I), depending on various substituents that compound (I) can have, compound (I) can be synthesized by carrying out a Curtius reaction, a reduction reaction, a protection reaction, a urea reaction, a deprotection reaction, an aromatic nucleophilic substitution reaction, a coupling reaction, an oxidation reaction, a hydrolysis reaction, an alkylation reaction, an amidation reaction, or a Mitsunobu reaction, either alone or in combination of two or more thereof, as desired.

[0093] The starting compounds and / or intermediates for compound (I) may form salts, and are not particularly limited as long as the reaction is achieved. For example, salts similar to those that may be formed by compound (I) may be used. The starting compounds and / or intermediates for compound (I) may produce configurational isomers (E,Z isomers). Once the configurational isomers (E,Z isomers) are produced, they can be isolated and purified by conventional separation means such as extraction, recrystallization, distillation, and chromatography, thereby producing a pure compound. Furthermore, double bond isomerization can be carried out using heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation, a strong base catalyst, or the like, according to the methods described in New Experimental Chemistry Lectures 14 (edited by the Chemical Society of Japan), pp. 251-253, and Fourth Edition Experimental Chemistry Lectures 19 (edited by the Chemical Society of Japan), pp. 273-274, or methods equivalent thereto, to obtain the corresponding pure isomers. If the target product is obtained in a free state by the above reaction, it may be converted into a salt by a conventional method. Alternatively, if the target product is obtained as a salt, it may be converted into the free form or another salt by a conventional method. Compound (I) thus obtained can be isolated and purified from the reaction solution by known means, such as solvent transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc. Compound (I), other reaction intermediates, and starting compounds thus obtained can be isolated and purified from the reaction mixture by known methods, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, preparative high-performance liquid chromatography (preparative HPLC), and medium-pressure preparative liquid chromatography (medium-pressure preparative LC). Compound (I) may form a salt, which can be produced by known means, for example, by adding an inorganic or organic acid when compound (I) is a basic compound, or by adding an organic or inorganic base when compound (I) is an acidic compound. When compound (I) is a solvate (e.g., hydrate), the starting compound is reacted in an appropriate solvent, and then the solvate of the target compound can be isolated from the reaction mixture by various methods such as distillation, crystallization, etc.A solvate-free product can be produced by desolvating the solvate by heating, drying, or the like. When compound (I) may have optical isomers, both these individual optical isomers and mixtures thereof are naturally encompassed within the scope of the present invention. If desired, these isomers can be optically resolved or individually produced by known methods. When compound (I) exists as configurational isomers (configurational isomers), diastereomers, conformers, or the like, they can be isolated, if desired, by the separation and purification methods described above. Furthermore, when compound (I) is a racemate, it can be separated into the S- and R-isomers by conventional optical resolution methods. When compound (I) has stereoisomers, both the isomers alone and mixtures thereof are encompassed within the scope of the present invention.

[0094] [Use of Compound (I) or a Salt Thereof] Compound (I) or a salt thereof has an excellent MC2R antagonist activity, and therefore may be effective in the prevention or treatment of diseases caused by abnormal ACTH signaling, such as endocrine system diseases (e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome), metabolic diseases (e.g., obesity, type 2 diabetes, dyslipidemia, osteoporosis, sarcopenia), cardiovascular system diseases (e.g., hypertension, arteriosclerosis), central nervous system diseases (e.g., depression, dementia, insomnia), eye diseases (e.g., cataract, glaucoma), and infectious diseases. In particular, compound (I) or a salt thereof may be useful as a prophylactic or therapeutic agent for endocrine system diseases (e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome), metabolic diseases (e.g., obesity, type 2 diabetes, dyslipidemia, osteoporosis, sarcopenia), cardiovascular system diseases (e.g., hypertension, arteriosclerosis), central nervous system diseases (e.g., depression, dementia, insomnia), eye diseases (e.g., cataract, glaucoma), infectious diseases, etc., based on its MC2R antagonist activity.

[0095] As used herein, "prevention" includes preventing the onset of a disease (all pathologies or one or more pathologies) and delaying the onset of the disease. A "prophylactically effective amount" refers to a dose of compound (I) sufficient to achieve such a purpose. As used herein, "treatment" includes curing a disease (all pathologies or one or more pathologies), ameliorating the disease, and suppressing the progression of the severity of the disease. A "therapeutically effective amount" refers to a dose of compound (I) sufficient to achieve such a purpose.

[0096] Compound (I) or a salt thereof (the present compound) can be used in either a single form or in the form of a pharmaceutical composition containing the present compound as an active ingredient together with a pharmaceutically acceptable carrier.

[0097] Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosal patch films), injections (e.g., subcutaneous injections, intravenous injections (e.g., bolus), intramuscular injections, intraperitoneal injections), drip infusions, transdermal preparations, ointments, lotions, patches, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops.

[0098] As used herein, the term "pharmaceutically acceptable carrier" refers to any of a variety of carriers commonly used in the field of pharmaceutical formulation technology.

[0099] Specific examples of "pharmaceutically acceptable carriers" that can be used in solid preparations include excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., magnesium stearate, talc, colloidal silica, etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), and disintegrants (e.g., starch, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylstarch, L-hydroxypropylcellulose, etc.).

[0100] Liquid preparations may contain solvents (e.g., water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizing agents (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffers (e.g., buffer solutions such as phosphates and citrates, etc.), and soothing agents (e.g., benzyl alcohol, etc.).

[0101] If necessary, formulation additives such as preservatives (e.g., paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, α-tocopherol, etc.), colorants, sweeteners, etc. may be further added.

[0102] The above pharmaceutical compositions may be prepared by adding the compound of the present invention in an amount of usually 0.01 to 99% (w / w), preferably 0.1 to 85% (w / w), based on the total amount of the formulation, although this may vary depending on the dosage form, administration method, carrier, etc. The pharmaceutical compositions may be prepared by conventional methods in the field of formulation technology depending on the form. The pharmaceutical compositions may also be formed into sustained-release preparations containing the active ingredient.

[0103] (Regarding the Subject of Administration) The present compound is expected to have low toxicity and few side effects, and also has excellent properties as a pharmaceutical. Therefore, the compound of the present invention can be safely administered to mammals (e.g., humans, dogs, or cats, particularly humans). (Regarding the Administration Route) The present compound, either alone or as a pharmaceutical composition, can be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intraorgan, intranasally, intradermally, by ophthalmic administration, intracerebrally, rectally, intravaginally, intraperitoneally, and administration into a lesion). (Regarding the Dosage) The dosage of the present compound varies depending on the subject of administration, the administration route, and the age and symptoms of the subject, but is not particularly limited. For example, the dosage of the present compound per administration is 1 to 250 mg when administered orally, and 0.1 to 1000 mg when administered parenterally.

[0104] (Use as a Prodrug) Compound (I) can also be used in the form of a prodrug, and such prodrugs are encompassed by compound (I). A prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in the body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis, or the like, with gastric acid, or the like. Examples of prodrugs of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated [e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated, etc.]; compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or phosphorylated Examples of such compounds include oxidized compounds (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated); and compounds in which the carboxyl group of compound (I) is esterified or amidated [e.g., compounds in which the carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified, cyclohexyloxycarbonylethyl-esterified, or methylamidized]. These compounds can be produced from compound (I) by methods known per se. Furthermore, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, Hirokawa Publishing, 1990.

[0105] Compound (I) may be any of a hydrate, a non-hydrate, a solvate, and a non-solvate. Compound (I) may also be an isotope (e.g., ２ H. ３ H.１１ C. １４ C. １８ F. ３５ S. １２５ The compound may be a compound labeled or substituted with an isotope, such as I, and a compound labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and can be useful in fields such as medical diagnosis. １ H ２ Compound (I) also encompasses deuterium conversion products converted to H(D). Tautomers are also encompassed by compound (I). Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt refers to a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). A co-crystal or a co-crystal salt can be produced by a co-crystallization method known per se.

[0106] (Regarding Combination with Other Drugs) The present compound may be used in combination with other active ingredients (hereinafter abbreviated as "concomitant drugs"). The concomitant drugs may be appropriately formulated with compounds or salts thereof that have preventive and / or therapeutic effects depending on the disease to be prevented or treated. Examples of such concomitant drugs include adrenal steroid synthesis enzyme inhibitors such as osilodrostat and metyrapone, glucocorticoid receptor antagonists such as mifepristone, somatostatin analogs such as pasireotide, CRF1 receptor antagonists such as clineservant and tildaservant, glucocorticoids such as hydrocortisone, prednisolone, and dexamethasone, and mineralocorticoids such as fludrocortisone. By combining the present compound with a concomitant drug, the following excellent effects can be obtained: (1) the dosage can be reduced compared to when the present compound or the concomitant drug is administered alone; (2) the drug to be used in combination with the present compound can be selected depending on the patient's symptoms (mild, severe, etc.); (3) the therapeutic effect can be sustained by selecting a concomitant drug with a different mechanism of action from the present compound; and (4) a synergistic effect can be obtained by using the present compound in combination with a concomitant drug.

[0107] Hereinafter, the use of the present compound in combination with a concomitant drug will be referred to as a "combination drug of the present compound." When using a combination drug of the present compound, the administration timing of the present compound and the concomitant drug is not limited, and the present compound or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof may be administered to the subject simultaneously or at staggered times. The dosage of the concomitant drug may be similar to the dosage used clinically and may be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present compound is not particularly limited, as long as the present compound and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the present compound and the concomitant drug, (2) simultaneous administration of two preparations obtained by separately formulating the present compound and the concomitant drug via the same administration route, (3) administration of two preparations obtained by separately formulating the present compound and the concomitant drug via the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the present compound and the concomitant drug via different administration routes, (5) administration of two preparations obtained by separately formulating the present compound and the concomitant drug via different administration routes with a time lag (e.g., administration in the order of the present compound and the concomitant drug, or administration in the reverse order), etc. The compounding ratio of the present compound to the concomitant drug in the concomitant preparation of the present compound can be appropriately selected depending on the subject of administration, the administration route, the disease, etc. For example, the content of the present compound in a combination drug of the present compound varies depending on the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total formulation. The content of the concomitant drug in a combination drug of the present compound varies depending on the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight, based on the total formulation. The content of additives such as carriers in a combination drug of the present compound varies depending on the formulation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total formulation. Furthermore, similar contents may be used when the present compound and the concomitant drug are formulated separately.

[0108] The present invention will be further described in detail by the following examples, test examples, and formulation examples. However, these do not limit the present invention and may be changed within the scope of the present invention. In the following examples, "room temperature" generally refers to about 10°C to about 35°C. The ratios shown in mixed solvents indicate volume ratios unless otherwise specified. % indicates weight % unless otherwise specified. Elution in column chromatography in the examples was performed under observation by TLC (thin layer chromatography) unless otherwise specified. For TLC observation, Merck 60F254 was used as the TLC plate, and the solvent used as the elution solvent in column chromatography was used as the developing solvent. A UV detector was used for detection. In silica gel column chromatography, when NH is used, aminopropylsilane-bonded silica gel was used.

[0109] In the following examples, the following abbreviations are used: MS: Mass spectrum M: Molar concentration N: Normality CDCl ３ : deuterated chloroform DMSO-d ６ : deuterated dimethyl sulfoxide １ HNMR: proton nuclear magnetic resonance LC / MS: liquid chromatography mass spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization DMSO: dimethyl sulfoxide HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HPLC: high performance liquid chromatogram Boc: tert-butoxycarbonyl t-Bu: tert-butyl DPPA: diphenylphosphoryl azide dppf: 1,1'-bis(diphenylphosphino)ferrocene DtBPF: 1,1'-bis(di-tert-butylphosphino)ferrocene TCFH: chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

[0110] １ ​H NMR was measured by Fourier transform NMR. ACD / SpecManager (trade name) or the like was used for analysis. Peaks with very gentle protons such as hydroxyl groups and amino groups are not recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data are recorded as actual measurements (found). Usually, the molecular ion peak ([M+H] ＋ , [M-H] － For example, in the case of a compound having a tert-butoxycarbonyl group, a peak resulting from the elimination of the tert-butoxycarbonyl group or the tert-butyl group is observed as a fragment ion, and in the case of a compound having a hydroxyl group, a peak resulting from the elimination of the tert-butoxycarbonyl group or the tert-butyl group is observed as a fragment ion. ２ A peak resulting from the elimination of O may also be observed. In the case of salts, a molecular ion peak or fragment ion peak of the free form is usually observed.

[0111] Example 1 3-[2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde

[0112] A) tert-Butyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate. To a mixture of tetrahydrofuran (50 mL) and 4-chloro-2-(trifluoromethyl)benzoic acid (3.0 g, 13.39 mmol), triethylamine (5.7 mL, 40.18 mmol) and diphenylphosphoryl azide (5.75 mL, 26.78 mmol) were added at 0°C. The reaction mixture was stirred at the same temperature for 1 hour. Then, 1-(tert-butyl)3-methylpiperazine-1,3-dicarboxylate (3.92 g, 16.07 mmol) was added at room temperature, and the reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was diluted with aqueous sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (3 g). 1 H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 2.75-2.88 (2H, m), 3.01-3.19 (1H, m), 4.11-4.24 (3H, m), 4.54-4.65 (1H, m), 7.27-7.28 (1H, m), 7.67 (1H, d, J = 8.25 Hz), 7.79 (1H, s). MS: 334.2.

[0113] B) tert-Butyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate To a mixture of tert-butyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-1,3-dioxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate (1.5 g, 3.46 mmol) in tetrahydrofuran (30 mL) was added borane-tetrahydrofuran complex (17.32 ml, 17.32 mmol, 1.0 M tetrahydrofuran solution) at 0°C and stirred at 70°C for 16 hours. After completion of the reaction, methanol and saturated aqueous sodium hydroxide were added to the reaction mixture, which was stirred for 1 hour and then extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (1.2 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.43 (9H, s), 2.67-2.79 (2H, m), 2.88 (2H, td, J = 12.65, 3.55 Hz), 3.63-3. 69 (1H, m), 3.70-3.78 (2H, m), 3.88-3.95 (1H, m), 4.00-4.12 (1H, m), 7.58 (1H, d, J = 8.0 Hz), 7.83-7.87 (2H, m). MS: 420.38.

[0114] C) 2-(4-Chloro-2-(trifluoromethyl)phenyl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one hydrochloride. To a mixture of tert-butyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate (1.2 g, 2.86 mmol) and 1,4-dioxane (20 mL) was added 4N hydrogen chloride (5 mL, 1,4-dioxane solution) at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was washed with diethyl ether and n-pentane to obtain the title compound (1.1 g). 1 H NMR (400 MHz, DMSO-d6) δ 2.78-2.92 (2H, m), 3.21-3.31 (2H, m), 3.39-3.45 (2H, m), 3.79-3.87 (2H, m), 4.07-4.18 (1H, m), 7.64 (1H, d, J = 9.29 Hz), 7.85-7.93 (2H, m), 9.46-9.54 (2H, m). MS: 320.26.

[0115] D) 6-Bromo-3-(2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)picolinaldehyde. To a mixture of 2-(4-chloro-2-(trifluoromethyl)phenyl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one hydrochloride (0.938 g, 2.94 mmol) in toluene (10 mL) was added potassium carbonate (1.01 g, 7.35 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, and then 6-bromo-3-fluoropicolinaldehyde (0.5 g, 2.45 mmol) was added at room temperature, and the reaction mixture was stirred at 120° C. for 16 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (0.35 g).1 H NMR (400 MHz, DMSO-d6) δ 2.83-2.93 (2H, m), 3.24 (1H, td, J = 12.47, 3.42 Hz), 3.34-3.37 (2H, m), 3.48 (1H, d, J = 10.27 Hz), 3.77 (1H, dd, J = 13.08, 2.08 Hz), 3.84 (1H, t, J = 8.6 Hz), 4.06-4.11 (1H, m), 7.61 (1H, d, J = 8.31 Hz), 7.67 (1H, d, J = 8.80 Hz), 7.79 (1H, d, J = 8.80 Hz), 7.84-7.91 (2H, m), 9.90 (1H, s). MS: 502.9.

[0116] E) 5-(2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carbaldehyde 6-bromo-3-(2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)picolinaldehyde (0.350 g, 0.69 mmol), (2-ethoxypyridin-3-yl)boronic acid (0.174 g, 1.04 mmol), potassium phosphate (0.442 g, 2.09 mmol, 3.0 eq.) and A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.056 g, 0.07 mmol) in 1,4-dioxane-water (10 mL, 4:1) was stirred at room temperature, degassed, and then stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (0.18 g). 1H NMR (400 MHz, CDCl3) δ 1.45 (3H, t, J = 7.09 Hz), 2.91-3.07 (2H, m), 3.30-3.49 (4H, m), 3.84 (1H, t, J = 8.68 Hz), 4.10 (1H, dd, J = 13.20, 2.20 Hz), 4.30-4.39 (1H, m), 4.52 (2H, q, J = 7.09 Hz), 7.05 (1H, dd, J = 7.46, 5.01 Hz), 7.34 (1H, d, J = 8.56 Hz), 7.48 (1H, d, J = 8.80 Hz), 7.60 (1H, dd, J = 8.44, 2.32 Hz), 7.71 (1H, d, J = 2.20 Hz), 8.21 (1H, dd, J = 4.89, 1.96 Hz), 8.26 (1H, d, J = 8.80 Hz), 8.40 (1H, dd, J = 7.34, 1.96 Hz), 10.20 (1H, brs). MS: 546.0.

[0117] Example 2 3-[2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide

[0118] A) 5-(2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid To a mixture of 5-(2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazine-7(1H)-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carbaldehyde (0.150 g, 0.27 mmol) and methanol (3 mL) was added a mixture of potassium hydroxide (0.046 g, 0.82 mmol) and methanol (2 mL) at 0°C, and the mixture was stirred at the same temperature for 3 minutes. Then, iodine (0.027 mmol) was added and the mixture was stirred at the same temperature for 16 minutes. The mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water and extracted with ethyl acetate. The aqueous layer was acidified with 1N HCl and extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.1 g). 1 H NMR (500 MHz, DMSO-d6) δ 1.37 (3H, t, J = 7.0 Hz), 1.80-1.88 (2H, m), 3.08-3.12 (2H, m), 3.36-3.38 (1H, m), 3.44-3.47 (1H, m), 3.77-3.86 (2H, m), 3.94-3.98 (1H, m), 4.44 (2H, q, J = 7.0 Hz), 7.11-7.14 (1H, m), 7.61 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 9.0 Hz), 7.86-7.88 (2H, m), 8.12 (1H, d, J = 9.0 Hz), 8.20-8.26 (2H, m), 12.01 (1H, brs). MS: 562.4.

[0119] B) 3-[2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide. To a stirred mixture of 5-(2-(4-chloro-2-(trifluoromethyl)phenyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)-2'-ethoxy-[2,3'-bipyridine]-6-carboxylic acid (0.060 g, 0.11 mmol) and N,N-dimethylformamide / tetrahydrofuran (4 mL, 1:1) was added N,N-diisopropylethylamine (0.093 ml, 0.53 mmol) and HATU (0.081 g, The reaction mixture was stirred at room temperature for 1 hour, and then ammonium chloride (0.028 g, 0.53 mmol) was added at room temperature, and the reaction mixture was stirred at the same temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue. This residue was purified by preparative HPLC to give the title compound (35 mg). Preparative HPLC column: Inertsil ODS (250*20) mm, 5 μm. Mobile phase: A - 0.1% trifluoroacetic acid aqueous solution; B - acetonitrile. 1H NMR (500 MHz, CDCl3) δ 1.46 (3H, t, J = 7.02 Hz), 2.78-3.02 (2H, m), 3.33-3.48 (3H, m), 3.58 (1H, d, J = 10.38 Hz), 3.81 (1H, t, J = 8.54 Hz), 4.08 (1H, d, J = 11.60 Hz), 4.27-4.33 (1H, m), 4.54 (2H, q, J = 7.0 Hz), 5.47 (1H, brs), 7.00-7.08 (1H, m), 7.33 (1H, d, J = 8.54 Hz), 7.49-7.63 (2H, m), 7.70 (1H, d, J = 2.14 Hz), 7.98 (1H, brs), 8.17-8.21 (3H, m). MS: 561.3.

[0120] Example 3 6-(2-Ethoxypyridin-3-yl)-3-[3-oxo-2-[1-(trifluoromethyl)cyclopentyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]pyridine-2-carboxamide. Synthesized according to the methods described in Examples 1 and 2 or methods analogous thereto. MS: 519.0.

[0121] Example 4 3-[2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 1 and 2 or methods analogous thereto. MS: 632.3.

[0122] Example 5 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde

[0123] A) tert-Butyl (3S)-4-[[4-chloro-2-(trifluoromethyl)phenyl]carbamoyl]-3-(hydroxymethyl)piperazine-1-carboxylate. To a mixture of toluene (100 mL), 4-chloro-2-(trifluoromethyl)benzoic acid (2.08 g, 9.25 mmol), and triethylamine (1.93 mL, 13.9 mmol) was added DPPA (2.39 mL, 11.1 mmol). After stirring at room temperature for 1 hour, tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.0 g, 9.25 mmol) was added and the mixture was stirred at 100 °C for 5 hours. After concentration of the solvent, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.6 g). MS: 382.2.

[0124] B) tert-Butyl (8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate. To a mixture of tetrahydrofuran (50 mL), tert-butyl (3S)-4-[[4-chloro-2-(trifluoromethyl)phenyl]carbamoyl]-3-(hydroxymethyl)piperazine-1-carboxylate (1.6 g, 3.65 mmol), and triphenylphosphine (1.441 g, 5.48 mmol), diisopropyl azodicarboxylate (1.18 mL, 5.48 mmol) was added and stirred overnight at room temperature. After concentration of the solvent, the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.88 g, 2.10 mmol). MS: 364.2.

[0125] C) (8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one. A mixture of tetrahydrofuran (10 mL), tert-butyl (8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (0.88 g, 2.10 mmol), and 6M hydrochloric acid (5.0 mL) was stirred at room temperature overnight. The mixture was made basic with aqueous sodium hydroxide and aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give the title compound (0.64 g). MS: 320.2.

[0126] D) 6-(2-Ethoxy-3-pyridyl)-3-fluoropyridine-2-carbaldehyde. A mixture of 6-chloro-3-fluoro-pyridine-2-carbaldehyde (2.00 g, 12.5 mmol), (2-ethoxy-3-pyridyl)boronic acid (2.09 g), tetrakis(triphenylphosphine)palladium(0) (0.724 g, 0.627 mmol), 2M aqueous sodium carbonate (2.00 mol / L, 31.3 mL, 63.7 mmol), and 1,2-dimethoxyethane (50 mL) was degassed under a stream of nitrogen and heated to 80 °C. After stirring at 80 °C for 2 hours, water and ethyl acetate were added to the mixture. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a colorless oil. The resulting oil was solidified from hexane, and the solid formed was filtered and washed with hexane to give the title compound (2.67 g). 1H NMR (300 MHz, DMSO-d6) δ 1.36 (3H, t, J = 7.0 Hz), 4.46 (2H, q, J = 7.0 Hz), 7.16-7.22 (1H, m), 8.03 (1H, dd, J = 10.1, 9.2 Hz), 8.28 (1H, s), 8.30 (1H, q, J = 2.0 Hz), 8.37 (1H, dd, J = 8.9, 3.9 Hz), 10.10 (1H, s). MS: 247.1.

[0127] E) 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde (8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one (130.0 mg, 0.407 mmol), 6-(2-ethoxy-3-pyridyl)-3-fluoropyridine-2-carbaldehyde (100 mg, 0.407 mmol), and potassium carbonate (281 mg, 2.03 mmol) were heated in toluene (5 mL) at 110°C. The mixture was stirred overnight at rt. After completion of the reaction, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (100 mg). MS: 546.4.

[0128] Example 6 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde (100 mg, 0.183 mmol), NaH2PO4 (44.0 mg, 0.366 mmol) and 2-Methyl-2-butene (389 μL, 3.66 mmol) was mixed in tert-butanol (3 mL) and water (3 mL), and NaClO (51.8 mg, 0.458 mmol) was added. The mixture was stirred at room temperature for 2 hours. Aqueous NaSO was added to the mixture, which was then concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give a residue. The residue was used in the next step without further purification. To a solution of the resulting residue and N',N'-dimethylethane-1,2-diamine (16.1 mg, 0.183 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (63.8 μL, 0.366 mmol) and HATU (90.5 mg, 0.238 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was purified by silica gel column chromatography (NH, hexane / ethyl acetate) to obtain the title compound (61.0 mg). 1H NMR (300 MHz, DMSO-d6) δ1.37 (3H, t, J = 7.06 Hz), 2.19 (6H, s), 2.42 (2H, s), 2.67-2.89 (2H, m), 3.07-3.24 (1H, m), 3.34-3.43 (4H, m), 3.46-3.56 (1H, m), 3.70-3.79 (1H, m), 3.80-3.90 (1H, m), 3.93-4.03 (1H, m), 4.44 (2H, d, J = 6.97 Hz), 7.13 (1H, dd, J = 7.47, 4.91 Hz), 7.62 (2H, dd, J = 8.34, 4.49 Hz), 7.82-7.93(2H, m), 8.10 (1H, d, J = 8.62 Hz), 8.20 (1H, dd, J = 4.86, 1.93 Hz), 8.32 (1H,dd, J = 7.52, 1.93 Hz), 8.47-8.57 (1H, m). MS: 632.5.

[0129] Example 7 3-[(8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde Synthesized according to the method described in Example 5 or a method analogous thereto. MS: 546.3.

[0130] Example 8 3-[(8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide Synthesized according to the method described in Example 6 or a method analogous thereto. MS: 632.5.

[0131] Example 9 3-[2-[4-chloro-2-(trifluoromethyl)phenyl]-8a-methyl-3-oxo-1,5,6,8-tetrahydroimidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde Synthesized according to the methods described in Examples 1 and 5 or methods analogous thereto. MS: 560.3.

[0132] Example 10 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde

[0133] A) Methyl (2R)-2-[[(2R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoyl]amino]butanoate HATU (66.8 g, 176 mmol) was added to a mixture of (2R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid (28.0 g, 117 mmol), methyl (2R)-2-aminobutanoate hydrochloride (21.6 g, 140 mmol), and N,N-diisopropylethylamine (45.4 g, 351 mmol) in acetonitrile (280 mL) at room temperature. The mixture was stirred at the same temperature over the weekend. Saturated aqueous sodium bicarbonate was added to the mixture. The mixture was extracted with ethyl acetate (x3). The organic layer was washed with 1M hydrochloric acid, then water and saturated brine, dried over magnesium sulfate, and concentrated to give residue A. The aqueous layer of 1N hydrochloric acid was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to give residue B. Residues A and B were purified by silica gel column chromatography (ethyl acetate / hexane) to give a colorless solid. This solid was washed with toluene / ethyl acetate (2:1) to give colorless solid A (17.76 g). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (NH, hexane / ethyl acetate) to give colorless solid B (16.31 g). Solids A and B were combined to give the title compound (34.0 g).1 H NMR (300 MHz, DMSO-d6) δ 0.86 (3H, t, J = 7.4 Hz), 1.54-1.80 (2H, m), 3.43-3.68 (5H, m), 4.07-4.28 (2H, m), 4.82 (1H, br s), 5.03 (2H, MS), 7.22 (1H, br d, J= 8.3 Hz), 7.28-7.46 (5H, m), 8.17 (1H, br d, J = 7.5 Hz).

[0134] B) (3R,6R)-3-Ethyl-6-(hydroxymethyl)piperazine-2,5-dione. A mixture of methyl (2R)-2-[[(2R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoyl]amino]butanoate (34 g, 100 mmol) and 10% Pd / C (1.7 g, ca. 55% water content) in methanol (340 mL) was stirred under a hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was used in the next reaction without further purification. A mixture of the obtained residue and methanol (200 mL) was stirred at 80°C for 24 hours and then concentrated. The residue was washed with ethyl acetate to obtain the title compound (12.1 g). 1 H NMR (300 MHz, DMSO-d6) δ 0.87 (3H, t, J = 7.4 Hz), 1.61-1.89 (2H, m), 3.52 (1H, ddd, J = 10.7, 5.2, 3.0 Hz), 3.61-3.82 (3H, m), 5.01 (1H, t, J = 5.5 Hz), 7.88 (1H, br s), 8.15 (1H, br s). MS: 173.2.

[0135] C) tert-Butyl (2R,5S)-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate To a mixture of (3R,6R)-3-ethyl-6-(hydroxymethyl)piperazine-2,5-dione (2.85 g, 16.6 mmol) and tetrahydrofuran (20 mL) was added borane-tetrahydrofuran complex (1 M tetrahydrofuran solution, 122 mL, 122 mmol) at room temperature. The mixture was stirred at 70°C for 16 hours. After cooling to 0°C, methanol (40 mL) was added to the reaction mixture. Then, 6 M hydrochloric acid (20 mL) was added to the reaction mixture. The mixture was stirred at 70°C for 2 hours. The mixture was concentrated, and toluene was added to the residue. The mixture was concentrated. Toluene was further added to the residue, and the mixture was concentrated. The resulting residue was used in the next reaction without further purification. To a mixture of the resulting residue in methanol (60 mL) and triethylamine (16.8 g, 166 mmol) was added di-tert-butyl dicarbonate (14.5 g, 66.3 mmol) at 0°C. The mixture was stirred at 70°C for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated. A solution of water (30 mL) and sodium hydroxide (1.79 g, 44.8 mmol) in water was added to a mixture of ethanol (60 mL) and the residue at room temperature. The mixture was refluxed for 16 hours. After cooling to room temperature, a solution of water (15 mL) and sodium hydroxide (895 mg, 22.4 mmol) in water was added to the mixture. The mixture was refluxed for 4 hours. After cooling to room temperature, the mixture was concentrated in vacuo to remove ethanol. The residue was adjusted to pH 8-9 with 1M HCl and diluted with ethyl acetate and tetrahydrofuran. Then, sodium chloride was added to the mixture. This mixture was extracted with ethyl acetate and tetrahydrofuran. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (2.78 g). 1H NMR (300 MHz, DMSO-d6) δ 0.78 (3H, br t, J = 7.3 Hz), 1.39 (9H, s), 1.5-1.8 (2H, m), 2.1-2.5 (4H, m), 2.5-2.7 (1H, m), 2.79 (1H, br d, J = 11.6 Hz), 3.79 (2H, br d, J = 12.5 Hz), 4.62 (1H, br s).

[0136] D) tert-Butyl (2R,5S)-4-[[4-chloro-2-(trifluoromethyl)phenyl]carbamoyl]-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate To a mixture of tetrahydrofuran (100 mL), 4-chloro-2-(trifluoromethyl)aniline (2.61 g, 13.4 mmol), and triethylamine (3.38 g, 33.4 mmol), triphosgene (1.65 g, 5.57 mmol) was added at 0° C. After stirring at room temperature for 16 hours, a mixture of tetrahydrofuran (20 mL), tert-butyl (2R,5S)-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate (2.72 g, 11.1 mmol), and triethylamine (3.38 g, 33.4 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, and then water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.12 g). 1 H NMR (300 MHz, DMSO-d6) δ 0.85 (3H, t, J = 7.5Hz), 1.3-1.6 (11H, m), 2.7-2.9 (2H, m), 3.4-3.6 (2H, m), 3.8-4.1 (4H, m), 5.68 (1H, br s), 7.6-7.7 (3H, m), 8.70 (1H, br s). MS: 488.3.

[0137] E) tert-Butyl (6R,8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate Methanesulfonyl chloride (2.31 g, 20.2 mmol) was added dropwise to a mixture of tert-butyl (2R,5S)-4-[[4-chloro-2-(trifluoromethyl)phenyl]carbamoyl]-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate (3.12 g, 6.70 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (8.16 g, 53.6 mmol) in tetrahydrofuran (50 mL) at 0°C. The mixture was stirred at room temperature for 16 hours, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.34 g). 1 H NMR (300 MHz, DMSO-d6) δ 0.8-0.9 (3H, m), 1.4-1.7 (11H, m), 2.7-3.0 (1H, m), 3.03 (1H, td, J = 4.8, 13.6 Hz), 3.3-3.4 (1H, m), 3.58 (1H, br dd, J = 6.7, 13.3 Hz), 3.7-3.8 (2H, m), 3.9-4.1 (2H, m), 7.60 (1H, d, J = 8.1 Hz), 7.8-7.9 (2H, m). MS: 448.3.

[0138] F) (6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one. A mixture of tert-butyl (6R,8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (2.33 g, 5.20 mmol) and trifluoroacetic acid (20 mL) was stirred at room temperature for 2 hours, and the mixture was concentrated. Toluene was added to the residue. The mixture was concentrated. The residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, and sodium chloride was added to the aqueous layer. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give the title compound (1.81 g). 1 H NMR (300 MHz, DMSO-d6) δ 0.85 (3H, t, J = 7.4 Hz), 1.4-1.6 (2H, m), 2.6-2.8 (3H, m), 3.02 (1H, dd, J = 4.1, 12.9 Hz), 3.20 (1H, dd, J = MS: 348.2.

[0139] G) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde 6-Bromo-3-fluoro-pyridine-2-carbaldehyde (733 mg, 3.59 mmol) and potassium carbonate (993 mg, 7.19 mmol) were added to a mixture of (6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one (833 mg, 2.40 mmol) in toluene (3 mL) at room temperature. The mixture was stirred at 110°C for 48 hours. After cooling to room temperature, water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (661 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.72 (3H, t, J = 7.3 Hz), 1.4-1.7 (2H, m) , 3.2-3.3 (1H, m), 3.3-3.5 (3H, m), 3.5-3.6 (1H, m), 3.70 (1H, d, J = MS: 531.2.

[0140] H) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbaldehyde PdCl2(dppf)-CHCl 2 (99.9 mg, 0.122 mmol) was added to a mixture of 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (651 mg, 1.22 mmol), (2-ethoxy-3-pyridyl)boronic acid (225 mg, 1.35 mmol), and 2 M aqueous sodium carbonate (1.84 mL, 3.67 mmol) in toluene (8 mL) at room temperature. The mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The mixture was filtered through Celite with ethyl acetate. The filtrate was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (390 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.76 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.1 Hz), 1.5-1.7 (2H, m), 3.2-3.3 (1H, m), 3.3-3.5 (3H, m), 3.5-3.7 (1H, m), 3.74 (1H, d, J = 13.1 Hz), 3.8-3.9 (1H, m), 3.9-4.0 (1H, m), 4.46 (2H, q, J = 7.1 Hz), 7.15 (1H, dd, J = 4.9, 7.5 Hz), 7.64 (1H, d, J = 8.1 Hz), 7.73 (1H, 7.8-7.9 (2H, m), 8.2-8.3 (2H, m), 8.33 (1H, dd, J = 2.0, 7.5 Hz), 10.02 (1H, s).

[0141] Example 11 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(oxan-4-ylmethyl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 659.3.

[0142] Example 12 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(2-methoxyethyl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 619.3.

[0143] Example 13 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(oxan-4-yl)ethyl]pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 673.3.

[0144] Example 14 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(3-pyridin-2-ylpropyl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 680.3.

[0145] Example 15 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3-hydroxyoxetan-3-yl)methyl]pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 647.2.

[0146] Example 16 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 631.3.

[0147] Example 17 tert-Butyl 3-[[3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbonyl]amino]pyrrolidine-1-carboxylate. Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 730.4.

[0148] Example 18 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(2-methylsulfonylethyl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 667.2.

[0149] Example 19 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(2-pyridin-2-ylethyl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 666.3.

[0150] Example 20 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(oxolan-3-yl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 631.3.

[0151] Example 21 tert-Butyl 4-[2-[[3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbonyl]amino]ethyl]piperidine-1-carboxylate. Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 772.4.

[0152] Example 22 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(3-pyrazol-1-ylpropyl)pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 669.3.

[0153] Example 23 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Examples 5 and 6 or methods analogous thereto. MS: 644.3.

[0154] Example 24 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-pyrrolidin-3-ylpyridine-2-carboxamide dihydrochloride

[0111] This was synthesized by treating tert-butyl 3-[[3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbonyl]amino]pyrrolidine-1-carboxylate with hydrochloric acid and concentrating. MS: 630.3.

[0155] Example 25 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(2-piperidin-4-ylethyl)pyridine-2-carboxamide dihydrochloride tert-butyl 4-[2-[[3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbonyl]amino]ethyl]piperidine-1-carboxylate was treated with hydrochloric acid and concentrated to prepare the desired compound. MS: 672.3.

[0156] Example 26 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. 1 H NMR (300 MHz, CHLOROFORM-d) δ 0.81-0.93 (3H, m), 1.39-1.51 (4H, m), 1.73 (1H, br dd, J = 6.83, 3.26 Hz), 2.32 (6H, s), 2.57 (2H, t, J = 6.10 Hz), 3.14 (1H, br dd, J = 11.65, 4.31 Hz), 3.41-3.62 (6H, m), 3.79 (1H, t, J = 8.62 Hz), 3.98 (1H, d, J = 12.38 Hz), 4.12 (1H, br dd, J = 10.22, 4.45 Hz), 4.46-4.55 (2H, m), 7.01 (1H, dd, J = 7.52, 4.86 Hz), 7.36 (2H, t, J = 7.84 Hz), 7.59 (1H, dd, J = 8.48, 2.34 Hz), 7.71 (1H, d, J = 2.38 Hz), 8.15-8.17 (1H, m), 8.18 (1H, s), 8.30-8.40 (2H, m).

[0157] Example 27 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 589.2.

[0158] Example 28 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-pyrrolidin-3-ylpyridine-2-carboxamide 3-[(8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (150 mg, 0.267 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (59.7 mg, 0.320 mmol). To a mixture of N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (93.0 μL, 0.534 mmol) and HATU (132 mg, 0.347 mmol) were added. The mixture was stirred at room temperature overnight. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the crude product. The crude product was used in the next step without further purification. 6M hydrochloric acid was added to the crude product and tetrahydrofuran (2.0 mL), and the mixture was stirred at room temperature for 5 hours. The mixture was made basic with aqueous sodium hydroxide and aqueous potassium carbonate solutions, and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was dissolved in acetonitrile and water, and lyophilized to obtain the title compound. MS: 630.4.

[0159] Example 29 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(5-oxopyrrolidin-3-yl)pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 672.3.

[0160] Example 30 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3-hydroxyoxetan-3-yl)methyl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 675.3.

[0161] Example 31 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10, Example 28, and Example 38, or methods analogous thereto. MS 658.3.

[0162] Example 32 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 659.3.

[0163] Example 33 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(2R)-2-hydroxypropyl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 647.3.

[0164] Example 34 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 647.3.

[0165] Example 35 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 661.3.

[0166] Example 36 N-(2-acetamidoethyl)-3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide. Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 674.3.

[0167] Example 37 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)-2-oxoethyl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 660.3.

[0168] Example 38 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Example 38a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid

[0169] A) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid. NaClO2 (507 mg, 5.60 mmol) was dissolved in 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carbaldehyde (1.61 g, 2.80 mmol), NaH2PO4 (1.34 g, 11.2 mmol), and HCl. To a mixture of 2-methyl-2-butene (1.38 g, 19.6 mmol) and 2-methyl-2-butene (1.38 g, 19.6 mmol) in tert-butanol (10 mL), tetrahydrofuran (5 mL), and water (5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of ammonium chloride were added to the reaction mixture. The mixture was diluted with ethyl acetate, and the organic layer was separated. NaCl was added to the aqueous layer. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated to give the title compound (1.65 g). 1H NMR (300 MHz, DMSO-d6) δ 0.79 (3H, t, J = 7.3 Hz) , 1.38 (3H, t, J = 7.1 Hz), 1.5-1.7 (2H, m), 3.2-3.3 (4H, m), 3.5-3.6 (1H, m), 3.73 (1H, d, J = 13.1 Hz), 3.8-4.0 (2H, m), 4.44 (2H, q, J = 7.1 Hz), 7.11 (1H, dd, J = 4.9, 7.5 Hz), 7.62 (2H, dd, J = 2.9, 8.5 Hz), 7.8-8.0 (2H, m), 8.10 (1H, d, J = 8.8 Hz), 8.19 (1H, dd, J = 1.9, 4.9 Hz), 8.27 (1H, dd, J = 1.9, 7.5 Hz), 12.5-13.8 (1H , m). MS: 590.3.

[0170] B) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide. To a mixture of tert-butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate (255 mg, 1.27 mmol) in ethyl acetate-ethanol (2 mL) was added 4N hydrogen chloride in cyclopentyl methyl ether (12 mL) at room temperature. After stirring at room temperature for 3 hours, the mixture was concentrated. The resulting residue was dissolved in N,N-dimethylformamide (10 mL), and 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (600 mg, 1.02 mmol) and N,N-diisopropylethylamine (0.522 mL, 3.05 mmol) were added. After stirring at room temperature for 10 minutes, HATU (464 mg, 1.22 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and extracted twice with ethyl acetate / diethyl ether (2:1). The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate and ethyl acetate / methanol) to obtain the title compound (580 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.77 (3H, t, J = 7.2 Hz), 1.37 (4H, t, J = 7.0 Hz), 1.48-1.73 (1H, m), 2.28 (1H, dd, J = 16.8, 5.6 Hz), 2.53-2.63 (1H, m), 3.11-3.27 (4H, m), 3.34-3.38 (1H, m), 3.41-3.53 (1H, m), 3.60 (1H, dd, J = 9.5, 7.3 Hz), 3.72 (1H, d, J = 13.0 Hz), 3.80-3.98 (2H, m), 4.44 (2H, q, J = 7.0 Hz), 4.50-4.70 (1H, m), 7.13 (1H, dd, J = 7.4, 4.9 Hz), 7.55 (1H, d, J = 8.8 Hz), 7.61-7.71 (2H, m), 7.82-7.93 (2H, m), 8.07 (1H, d, J = 8.8 Hz), 8.18 (1H, dd, J = 4.9, 2.0Hz), 8.32 (1H, dd, J = 7.5, 2.0 Hz), 8.86 (1H, d, J = 6.4 Hz). MS: 674.4.

[0171] Example 39 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3S)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide To a mixture of tert-butyl N-[(3S)-5-oxopyrrolidin-3-yl]carbamate (27 mg, 0.135 mmol) in ethyl acetate-ethanol (0.5 mL) was added 4N hydrogen chloride / cyclopentyl methyl ether solution (0.500 mL, 2.00 mmol) at room temperature. After stirring at room temperature for 3 hours, the mixture was concentrated. The resulting residue was dissolved in N,N-dimethylformamide (1 mL) and 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (25.0 mg, 0.0424 mmol) and N,N-diisopropylethylamine (0.0580 mL, 0.339 mmol) were added. After stirring at room temperature for 10 minutes, HATU (0.0322 g, 0.0847 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and extracted twice with ethyl acetate / diethyl ether (2:1). The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate and ethyl acetate / methanol) to obtain the title compound (0.0180 g). 1H NMR (300 MHz, DMSO-d6) δ 0.77 (3H, t, J = 7.3 Hz), 1.32-1.50 (4H, m), 1.52-1.70 (1H, m), 2.24 (1H, dd, J = 16.7, 5.6 Hz), 2.52-2.60 (1H, m), 3.11-3.41 (5H, m), 3.42-3.53 (1H, m), 3.61 (1H, dd, J = 9.9, 7.4 Hz), 3.71 (1H, d, J = 12.9 Hz), 3.80-3.98 (2H, m), 4.44 (2H, q, J = 7.0 Hz), 4.51-4.65 (1H, m), 7.12 (1H, dd, J = 7.5, 4.9 Hz), 7.55 (1H, d, J = 8.8 Hz), 7.60-7.71 (2H, m), 7.84-7.92 (2H, m), 8.07 (1H, d, J = 8.7 Hz), 8.18 (1H, MS: 672.3.

[0172] Example 40 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(2R)-1-(methylamino)-1-oxopropan-2-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 674.3.

[0173] Example 41 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(2S)-1-(methylamino)-1-oxopropan-2-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 674.3.

[0174] Example 42 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-(1-methyl-5-oxopyrrolidin-3-yl)pyridine-2-carboxamide 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (20.0 mg, 0.0339 To a solution of N,N-dimethylformamide (0.5 mL) containing N,N-diisopropylethylamine (0.0464 mL, 0.271 mmol), 4-amino-1-methyl-pyrrolidin-2-one hydrochloride (15.3 mg, 0.102 mmol), and N,N-diisopropylethylamine (0.0464 mL, 0.271 mmol) was added HATU (0.0258 g, 0.0678 mmol) at room temperature. After stirring at room temperature for 18 hours, the mixture was diluted with water and extracted twice with ethyl acetate-diethyl ether (2:1). The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate and methanol / ethyl acetate) to give the title compound (0.0150 g). 1H NMR (300 MHz, DMSO-d6) δ 0.77 (3H, t, J = 7.3 Hz), 1.30-1.48 (4H, m), 1.52-1.69 (1H, m), 2.28-2.43 (1H, m), 2.73 (3H, d, J = 3.6 Hz), 3.10-3.40 (6H, m), 3.41-3.53 (1H, m), 3.66-3.79 (2H, m), 3.81-3.98 (2H, m), 4.37-4.60 (3H, m), 7.13 (1H, dd, J = 7.5, 4.9 Hz), 7.55 (1H, dd, J = 8.8, 1.5 Hz), 7.63 (1H, d, J = 8.1 Hz), 7.84-7.91 (2H, m), 8.07 (1H, d, J = 8.8 Hz), 8.18 (1H, dd, J = 4.9, 1.9 Hz), 8.31 (1H, dd, J = 7.5, 2.0 Hz), 8.86 (1H, dd, J = 6.6, 2.6 Hz). MS: 686.3.

[0175] Example 43 tert-Butyl (2R)-2-[[[3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbonyl]amino]methyl]azetidine-1-carboxylate To a stirred solution of tert-butyl (2R)-2-(azidomethyl)azetidine-1-carboxylate (32.4 mg, 0.153 mmol) in tetrahydrofuran-water (1.00 mL, 10:1) was added triphenylphosphine (44.0 mg, 0.168 mmol) at room temperature. After stirring at 60 °C for 2 h, the mixture was concentrated and azeotroped twice with toluene. The resulting residue was dissolved in N,N-dimethylformamide (1 mL), followed by the addition of 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (30 mg, 0.0508 mmol) and N,N-diisopropylethylamine (0.0435 mL, 0.254 mmol). HATU (0.0387 g, 0.102 mmol) was added to the mixture at room temperature. After stirring at room temperature for 18 hours, the mixture was diluted with water and extracted twice with ethyl acetate-diethyl ether (2:1). The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, hexane / ethyl acetate) to obtain the title compound (0.0250 g). 1H NMR (300 MHz, CDCl3) δ 0.87 (3H, t, J = 7.3 Hz), 1.51 (13H, s), 1.65-1.82 (1H, m), 1.96-2.13 (1H, m), 2.20-2.36 (1H, m), 3.13 (1H, dd, J = 11.4, 4.3 Hz), 3.34-3.67 (5H, m), 3.71-4.05 (5H, m), 4.07-4.21 (1H, m), 4.39-4.57 (3H, m), 7.02 (1H, dd, J = 7.4, 4.9 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.38 (1H, MS: 758.4.

[0176] Example 44 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-N-[[(2R)-azetidin-2-yl]methyl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide tert-Butyl (2R)-2-[[[3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbonyl]amino]methyl]azetidine-1-carboxylate (22 mg, 0.0290 mmol) and formic acid (2 mL) were stirred at 50° C. for 15 minutes. The mixture was concentrated, and the resulting residue was purified by column chromatography (NH silica gel, ethyl acetate / methanol) to afford the title compound (0.0150 g). 1H NMR (300 MHz, CDCl3) δ 0.77 (3H, t, J = 7.3 Hz), 1.32-1.49 (4H, m), 1.51-1.70 (1H, m), 1.99-2.10 (1H, m), 2.13-2.25 (1H, m), 2.42-2.49 (1H, m), 3.09-3.57 (9H, m), 3.69 (1H, d, J = 12.7 Hz), 3.78-4.00 (3H, m), 4.44 (2H, q, J = 7.0 Hz), 7.12 (1H, dd, J = 7.5, 4.9 Hz), 7.54 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.1 Hz), 7.81-7.92 (2H, m), 8.08 (1H, d, J = 8.7 Hz), 8.18 (1H, dd, J = 4.9, 1.9 Hz), 8.35 (1H, dd, J = 7.5, 1.9 Hz), 8.56 (1H, t, J = 5.9 Hz). MS: 658.3.

[0177] Example 45 tert-Butyl (2S)-2-[[[3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carbonyl]amino]methyl]azetidine-1-carboxylate. Synthesized according to the method described in Example 43 or a method analogous thereto. MS: 758.4.

[0178] Example 46 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-N-[[(2S)-azetidin-2-yl]methyl]-6-(2-ethoxypyridin-3-yl)pyridine-2-carboxamide Synthesized according to the method described in Example 44 or a method analogous thereto. MS: 658.3.

[0179] Example 47 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-2-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 672.3.

[0180] Example 48 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3S)-2-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 672.3.

[0181] Example 49 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide

[0182] A) 1-[(1R)-1-(4-Methoxyphenyl)ethyl]-5-oxo-pyrrolidine-3-carboxylic acid A mixture of (1R)-1-(4-methoxyphenyl)ethanamine (18.0 g, 119 mmol) and itaconic acid (15.5 g, 119 mmol) in N-methyl-2-pyrrolidone (10 mL) was stirred at 130°C for 4 hours. Water (200 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. The precipitate was filtered through filter paper, washed with water, and dried under vacuum at 65°C to obtain the title compound (28.8 g). 1H NMR (DMSO-d6, 300 MHz) δ 1.4-1.5 (3H, m), 2.4-2.5 (1H, m), 2.5-2.6 (1H, m), 3.0-3.2 (2H, m), 3.4-3.6 (1H, m), 3.74 (3H, s), 5.19 (1H, q, J = 7.1 Hz), 6.8-7.0 (2H, m), 7.20 (2H, t, J = 8.1 Hz), 12.60 (1H, br s).

[0183] B) Benzyl (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidine-3-carboxylate To a mixture of N-methyl-2-pyrrolidone (70 mL), 1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidine-3-carboxylic acid (12.2 g, 46.2 mmol), and cesium carbonate (18.1 g, 55.5 mmol) was added benzyl bromide (9.49 g, 55.5 mmol) at room temperature. The mixture was stirred at the same temperature for 14 hours, and water was added to the reaction mixture. The mixture was diluted with ethyl acetate and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (7.06 g). 1 H NMR (CHLOROFORM-d, 300 MHz) δ 1.47 (3H, d, J = 7.2 Hz), 2.6-2.8 (2H, m), 3.0-3.2 (2H, m), 3.52 (1H, dd, J = 5.5, 9.1 Hz), 3.79 (3H, s), 5.14 (2H, s), 5.44 (1H, q, J = 7.2 Hz), 6.86 (2H, d, J = 8.7 Hz), 7.21 (2H, d, J=8.5 Hz), 7.3-7.4 (5H, m). MS: 354.3.

[0184] C) (3R)-1-[(1R)-1-(4-Methoxyphenyl)ethyl]-5-oxo-pyrrolidine-3-carboxylic acid To a solution of benzyl (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidine-3-carboxylate (29.3 g, 83.0 mmol) in ethyl acetate (300 mL) and ethanol (180 mL) was added 10% Pd / C (4.00 g, ca. 55% water content) at room temperature. The mixture was stirred under a hydrogen atmosphere at the same temperature for 6 hours. The insoluble matter was filtered through Celite and washed with ethyl acetate and ethanol, and the filtrate was concentrated. Toluene was added to the residue and concentrated. Toluene was further added to the residue and concentrated to give the title compound (20.7 g). 1 H NMR (CHLOROFORM-d, 300 MHz) δ 1.51 (3H, d, J = 7.2 Hz), 2.7-2.9 (2H, m), 3.0-3.3 (2H, m), 3.58 (1H, dd, J = 5.7, 9.7 Hz), 3.80 (3H, s), 5.45 (1H, q, J = 7.1Hz), 6.87 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.6 Hz). MS: 264.2.

[0185] D) tert-Butyl N-[(3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]carbamate To a mixture of (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidine-3-carboxylic acid (20.7 g, 78.5 mmol) and triethylamine (15.9 g, 157 mmol) in tert-butanol (90 mL) and toluene (180 mL) was added DPPA (32.4 g, 118 mmol) at room temperature. The mixture was stirred at 80°C for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was crystallized from ethyl acetate / diisopropyl ether / hexane to obtain the title compound (18.7 g).1 H NMR (DMSO-d6, 300 MHz) δ 1.3-1.5 (12H, m), 2.23 (1H, dd, J = 6.1, 16.7 Hz), 2.5-2.6 (1H, m), 3.0-3.2 (2H, m), 3.74 (3H, s), 3.9-4.1 (1H, m), 5.20 (1H, q, J = 7.2 Hz), 6.9-7.0 (2H, m), 7.1-7.2 (2H, m), 7.2-7.3 (1H, m). MS: 335.2.

[0186] E) tert-Butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate. A solution of ammonium cerium(IV) nitrate (50.6 g, 92.3 mmol) in acetonitrile (30 mL) and water (30 mL) was added to a mixture of acetonitrile (100 mL), water (100 mL), and tert-butyl N-[(3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]carbamate (12.9 g, 38.5 mmol) under ice-cooling. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate was added to the reaction mixture at 0°C to adjust the pH to 6. The mixture was diluted with ethyl acetate and tetrahydrofuran, and sodium chloride was added. The mixture was extracted with ethyl acetate / tetrahydrofuran. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was washed with diisopropyl ether to obtain the title compound (6.9 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.38 (9H, s), 2.04 (1H, dd, J = 16.6, 6.1 Hz), 2.36 (1H, dd, J = 16.6, 8.3 Hz), 2.99 (1H, dd, J = 9.6, 4.9 Hz), 3.43 (1H, dd, J = 9.8, 7.2 Hz), 3.99-4.25 (1H, m), 7.14-7.38 (1H, m), 7.54 (1H, br s). MS: 145.2.

[0187] F) tert-Butyl N-[(3R)-1-methyl-5-oxo-pyrrolidin-3-yl]carbamate. To a mixture of tert-butyl N-[(3R)-5-oxopyrrolidin-3-yl]carbamate (131 mg, 0.655 mmol) and potassium tert-butoxide (80.9 mg, 0.721 mmol) in tetrahydrofuran (5 mL) at 0°C, iodomethane (102 mg, 0.721 mmol) was added dropwise. This mixture was stirred at room temperature for 16 hours, and then water was added to the reaction mixture. The mixture was diluted with ethyl acetate. Sodium chloride was added to the mixture. The mixture was extracted with ethyl acetate / tetrahydrofuran. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (134 mg). 1 H NMR (DMSO-d6, 300 MHz) δ 1.38 (9H, s), 2.13 (1H, dd, J = 5.3, 16.8 Hz), 2.4-2.5 (1H, m), 2.68 (3H, s), 3.10 (1H, dd, J = 4.4, 10.0 Hz), 3.55 (1H, dd, J = 7.3, 10.0 Hz), 3.9-4.1 (1H, m), 7.26 (1H, br d, J = 5.4 Hz). MS: 159.2.

[0188] G) (4R)-4-Amino-1-methyl-pyrrolidin-2-one 4-methylbenzenesulfonate p-Toluenesulfonic acid monohydrate (3.24 g, 17.0 mmol) was added to a mixture of tert-butyl N-[(3R)-1-methyl-5-oxo-pyrrolidin-3-yl]carbamate (2.43 g, 11.4 mmol) in acetonitrile (40 mL) at room temperature. The mixture was stirred at 60°C for 4 hours. After cooling to room temperature, the mixture was concentrated. The residue was crystallized from ethanol / ethyl acetate / acetonitrile to give the title compound (2.71 g). 1H NMR (DMSO-d6, 300 MHz) δ 2.2-2.3 (4H, m), 2.6-2.8 (4H, m), 3.25 (1H, dd, J =2.9, 11.1 Hz), 3.67 (1H, dd, J = 7.2, 11.1 Hz), 3.8-4.0 (1H, m), 7.12 (2H, d, J= 7.8 Hz), 7.4-7.6 (2H, m), 8.04 (3H, br s). MS: 115.3.

[0189] H) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide HATU (1.70 g, 4.48 mmol) was reacted with 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid To a mixture of (4R)-4-amino-1-methyl-pyrrolidin-2-one 4-methylbenzenesulfonate (1.04 g, 3.64 mmol), (4R)-4-amino-1-methyl-pyrrolidin-2-one 4-methylbenzenesulfonate (1.65 g, 2.80 mmol), (4R)-4-amino-1-methyl-pyrrolidin-2-one 4-methylbenzenesulfonate (1.04 g, 3.64 mmol), and triethylamine (1.13 g, 11.2 mmol) in acetonitrile (15 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, and then saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / methanol) to give a solid. This solid was crystallized from ethanol-water to give the title compound (1.44 g). 1H NMR (DMSO-d6, 300 MHz) δ 0.77 (3H, t, J = 7.3 Hz), 1.3-1.5 (4H, m), 1.5-1.7 (1H, m), 2.37 (1H, dd, J = 5.3, 16.7 Hz), 2.6-2.8 (4H, m), 3.1-3.3 (4H, m), 3.37 (1H, s), 3.4-3.5 (1H, m), 3.7-3.8 (2H, m), 3.8-4.0 (2H, m), 4.44 (2H, q, J = 7.0 Hz), 4.5-4.6 (1H, m), 7.13 (1H, dd, J = 4.9, 7.5 Hz), 7.55 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.8-8.0 (2H, m), 8.07 (1H, d, J = 8.8 Hz), 8.18 (1H,dd, J = 2.0, 4.8 Hz), 8.32 (1H, dd, J = 1.9, 7.4 Hz), 8.86 (1H, d, J = 6.6 Hz). MS: 686.4.

[0190] Example 50 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3S)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide HATU (23 mg, 0.061 mmol) was reacted with 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (30 mg, 0.508 mmol), (4S)-4-amino-1-methyl-pyrrolidin-2-one (7.27 mg, 0.0637 mmol), and N,N-diisopropylethylamine (13.1 mg) in N,N-dimethylformamide (1 mL) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / methanol) to obtain the title compound (19 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.76 (3H, t, J = 7.2 Hz), 1.31-1.47 (4H, m), 1.52-1.74 (1H, m), 2.25-2.39 (1H, m), 2.66 (1H, dd, J = 16.4, 8.3 Hz), 2.74 (3H, s), 3.06-3.29 (3H, m), 3.40-3.54 (2H, m), 3.69-3.79 (2H, m), 3.80-3.95 (2H, m), 4.03 (1H, q, J = 7.1 Hz), 4.36-4.59 (3H, m), 7.13 (1H, dd, J = 7.5, 4.8 Hz), 7.50-7.71 (2H, m), 7.84-7.94 (2H, m), 8.07 (1H, d, J = 8.8 Hz), 8.18 (1H, dd, J = 4.9, 1.9 Hz), 8.31 (1H, dd, J = 7.5, 2.0 Hz), 8.86 (1H, d, J = 6.6 Hz). MS: 686.4.

[0191] Example 51 3-[(6R,8aS)-6-Ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Example 51a 3-[(6R,8aS)-6-Ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid

[0192] A) tert-Butyl (2R,5S)-2-ethyl-4-[[4-fluoro-2-(trifluoromethyl)phenyl]carbamoyl]-5-(hydroxymethyl)piperazine-1-carboxylate To a mixture of dichloromethane (100 mL) and 4-fluoro-2-(trifluoromethyl)aniline (2.2 g, 12.29 mmol) was added triethylamine (4.17 mL, 30.72 mmol) and then triphosgene (1.519 g, 5.12 mmol) under an argon atmosphere at 0°C, and the reaction mixture was stirred at 25°C for 20 hours. To the reaction mixture, a solution of tert-butyl (2R,5S)-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate (2.5 g, 10.24 mmol) and triethylamine (4.17 mL, 30.723 mmol) in dichloromethane (100 mL) was added at 0°C, and the reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the mixture was poured into ice-cold water (300 mL). The aqueous layer was extracted with dichloromethane (300 mL x 3). The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (3 g). 1 H NMR (300 MHz, DMSO-d6) δ0.75-0.97 (3H, m), 1.35-1.42 (9H, m), 1.40-1.53 ​​(2H, m), 2.72-2.92 (2H, m), 3.41-3.59 (2H, m), 3.73-4.10 (4H, m), 5.46-5.70 (1H, m), 7.29-7.70 (3H, m), 8.43-8.70 (1H, m). MS: 450.2.

[0193] B) tert-Butyl (6R,8aR)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate To a mixture of tert-butyl (2R,5S)-2-ethyl-4-[[4-fluoro-2-(trifluoromethyl)phenyl]carbamoyl]-5-(hydroxymethyl)piperazine-1-carboxylate (2.3 g, 5.12 mmol) in dichloromethane (30 mL) was added 1,8-diazabicyclo[5.4.0]-7-undecene (6.11 mL, 40.94 mmol) at 25°C under an argon atmosphere, followed by methanesulfonyl chloride (0.99 mL, 12.79 mmol) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, ice-cold water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.9 g). 1 H NMR (400 MHz, DMSO-d6) δ0.80 (4H, q, J = 7.2 Hz), 1.10-1.35 (1H, m), 1.42 (9H, s), 1.46-1.74 (1H, m), 2.71-3.13 (2H, m), 3.47-4.15 (5H, m), 7.57-7.74 (3H, m). MS: 432.1.

[0194] C) (6R,8aS)-6-Ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one. To a stirred mixture of tert-butyl (6R,8aR)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (2.4 g, 5.563 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (4.3 mL, 55.62 mmol) at 0° C., and the reaction mixture was stirred at 25° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to 0° C. and poured into an aqueous sodium bicarbonate solution under ice-cooling. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.7 g). The residue was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 0.84 (3H, t, J = 7.3 Hz), 1.38-1.61 (2H, m), 2.58-2.71 (2H, m), 2.78 (1H, t, J = 10.3 Hz), 3.02 (1H, dd, J = 4.2, MS: 331.9.

[0195] D) 3-[(6R,8aS)-6-Ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde To a mixture of (6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one (1.7g, 5.136 mmol) in toluene (50 mL) was added 6-bromo-3-fluoro-pyridine-2-carbaldehyde (1.56 g, 7.70 mmol), followed by potassium carbonate (2.126 g, 15.4 mmol) at room temperature. The reaction mixture was heated to reflux for 3 days. The reaction mixture was cooled to 25°C, ice-cold water (200 mL) was added, and the aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.4 g). 1 H NMR (400 MHz, DMSO-d6) δ 0.72 (3H, t, J = 7.3 Hz), 1.46-1.66 (2H, m), 3.20 (1H, dd, J = 12.7, 4.3 Hz), 3.25-3.56 (4H, m), 3.70 (1H, d, J = MS: 515.3.

[0196] E) 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carbaldehyde 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (2.3 g, 4.46 mmol) was dissolved in a mixture of dioxane (27 mL) and water (3 mL), and the solution was degassed and heated at 25°C. (2-Ethoxypyridin-3-yl)boronic acid (1.118 g, 6.695 mmol) and potassium carbonate (1.848 g, 13.39 mmol) were added, and the reaction mixture was again degassed with argon gas for 10 minutes. To this mixture, Pd(DtBPF)Cl2 (145.0 mg, 0.223 mmol) was added, and the reaction mixture was heated at 100 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled to 25 °C, and water (100 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound (2.3 g). 1H NMR (400 MHz, DMSO-d6) δ 0.76 (3H, t, J = 7.2 Hz), 1.38 (3H, t, J = 7.0 Hz), 1.45-1.73 (2H, m), 3.18-3.39 (2H, m), 3.37-3.63 (3H, m), 3.74 (1H, d, J = 13.0 Hz), 3.82 (1H, t, J = 8.4 Hz), 3.94 (1H, s), 4.46 (2H, q, J = 6.9 Hz), 7.15 (1H,dd, J = 4.8, 7.5 Hz), 7.64-7.68 (2H, m), 7.73 (2H, d, J = 9.0 Hz), 8.16-8.25 (2H, m), 8.33 (1H, dd, J = 2.0, 7.5 Hz), 10.01 (1H, s). MS: 557.7.

[0197] F) 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carbaldehyde (2.0 g, 3.591 mmol) in tert-butanol (20 mL), tetrahydrofuran (20 mL), and water (20 mL). To a mixture of 2-methyl-2-butene (3.80 mL, 35.907 mmol), NaClO2 (812.0 mg, 8.977 mmol) was added at 0 °C. A solution of NaH2PO4 (977 mg, 7.181 mmol) and water (20 mL) was added to this mixture at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After completion of the reaction, saturated aqueous sodium thiosulfate and saturated aqueous ammonium chloride were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and a pentane-ether mixture (50 mL, 4:1) was added and stirred for 15 minutes. The precipitated solid was filtered and washed twice with pentane to obtain the title compound (1.75 g). 1H NMR (400 MHz, DMSO-d6) δ 0.83 (3H, t, J = 7.4 Hz), 1.40 (3H, t, J = 7.1 Hz), 1.49-1.82 (2H, m), 3.23-3.34 (2H, m), 3.36-3.48 (2H, m), 3.52-3.63 (1H, m), 3.76 (1H, d, J = 13.1 Hz), 3.85 (1H, t, J = 8.8 Hz), 3.90-4.01 (1H, m), 4.45-4.54 (2H, m), 7.09 (1H, t, J = 6.2 Hz), 7.61 (4H, t, J = 8.9 Hz), 8.10 (1H, d, J = 8.8 Hz), 8.18 (1H, s), 8.28 (1H, d, J = 6.8 Hz), 12.66 (1H, brs). MS: 574.38.

[0198] G) 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide To a stirred solution of 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (120 mg) in acetonitrile (5 mL) was added TCFH (180 To the mixture was added N-methylimidazole (0.085 mL, 1.046 mmol) under an argon atmosphere at 25°C, and the reaction mixture was stirred at 25°C for 10 minutes. (4R)-4-aminopyrrolidin-2-one (32 mg, 0.314 mmol) was added at 25°C, and the reaction mixture was stirred at 25°C for 16 hours. After the reaction was completed, ice water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by CombiFlash column chromatography (ethyl acetate / hexane) followed by reverse-phase preparative HPLC to obtain the title compound (20 mg). <Preparative HPLC Conditions> Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Actus C18 (250 × 20 mm, 5 μm), ambient temperature: room temperature, flow rate: 16 mL / min, mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 0.78-0.86 (3H, m), 1.39 (3H, t, J = 6.8 Hz), 1.43 - 1.76 (2H, m), 2.31 (1H, dd, J = 5.5, 16.6 Hz), 2.52-2.64 (1H, m), 3.16-3.45 (5H, m), 3.49-3.60 (1H, m), 3.63 (1H, t, J = 9.2 Hz), 3.74 (1H, d, J = 13.2 Hz), 3.85 (1H, t, J = 8.0 Hz), 3.91-3.96 (1H, m), 4.49 (2H, d, J = 6.8 Hz), 4.55-4.71 (1H, m), 7.10 (1H, t, J = 6.4 Hz), 7.26-7.47 (1H, m), 7.55 (1H, d, J = 8.8 Hz), 7.60 (3H, d, J = 6.4 Hz), 8.05 (1H, d, J = 8.4 Hz), 8.12-8.22 (1H, m), 8.31 (1H, d, J = 6.8 Hz), 8.47-8.71 (1H, m). MS: 656.4.

[0199] Example 52 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-6-Ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (1.26 g) was dissolved in N,N-dimethylformamide (20 The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give a solid. This solid was recrystallized using diisopropyl ether / ethyl acetate / heptane. The mixture was cooled to room temperature over the weekend. The mixture was stirred at 0°C for 1 hour. The crystals were filtered to give the title compound (1.28 g). 1H NMR (400 MHz, DMSO-d6) δ 0.77 (3H, t, J = 7.3 Hz), 1.32-1.44 (4H, m), 1.52-1.73 (1H, m), 2.37 (1H, dd, J = 16.7, 5.1 Hz), 2.62-2.75 (4H, m), 3.05-3.30, (4H,m), 3.34-3.39 (1H, m), 3.41-3.52 (1H, m), 3.65-4.03 (4H, m), 4.35-4.62 (3H, m), 7.13 (1H, dd, J = 7.5, 4.9 Hz), 7.51-7.80 (4H, m), 8.07 (1H, d, J = 8.7Hz), 8.18 (1H, dd, J = 4.9, 1.9 Hz), 8.31 (1H, dd, J = 7.5, 2.0 Hz), 8.86 (1H, d, J = 6.6 Hz). MS: 670.2.

[0200] Example 53 3-[(6R,8aS)-2-(4-chloro-2-cyanophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Example 53a 3-[(6R,8aS)-2-(4-chloro-2-cyano-phenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid A) tert-Butyl (2R,5S)-4-[(4-chloro-2-cyano-phenyl)carbamoyl]-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate To a mixture of dichloromethane (50 mL) and 2-amino-5-chlorobenzonitrile (2.3 g, 15.35 mmol), triethylamine (4.3 mL, 30.70 mmol) and triphosgene (1.5 g, 5.12 mmol) were added under an argon atmosphere at 0°C, and the reaction mixture was stirred at 25°C for 20 hours. To the reaction mixture, a solution of tert-butyl (2R,5S)-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate (2.5 g, 10.23 mmol) and triethylamine (4.3 mL, 30.7 mmol) in dichloromethane (50 mL) was added at 0°C, and the reaction mixture was stirred at 25°C for 4 hours. After completion of the reaction, it was poured into ice-cold water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.65 g). 1H NMR (400 MHz, DMSO-d6) δ 0.86 (3H, t, J = 7.4 Hz), 1.37 (9H, s), 1.42-1.58 (2H, m), 2.77-2.98 (2H, m), 3.42-3.63 (2H, m), 3.76-4.22 (4H, m), 5.39-5.72 (1H, m), 7.52-7.75 (2H, m), 7.89 (1H, d, J = 2.4 Hz), 9.16 (1H, d, J = 6.3 Hz). MS: 423.1.

[0201] B) tert-Butyl (6R,8aR)-2-(4-chloro-2-cyano-phenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate To a mixture of tert-butyl (2R,5S)-4-[(4-chloro-2-cyano-phenyl)carbamoyl]-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate (2.65 g, 6.28 mmol) in dichloromethane (40 mL) was added 1,8-diazabicyclo[5.4.0]-7-undecene (7.5 mL, 50.24 mmol) at 25°C under an argon atmosphere, followed by methanesulfonyl chloride (1.2 mL, 15.70 mmol) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, ice-cold water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by CombiFlash silica gel column chromatography (ethyl acetate / hexane) to give the title compound (2.5 g). 1H NMR (400 MHz, DMSO-d6) δ 0.74-0.86 (3H, m), 1.42 (9H, s), 1.46-1.75 (2H, m), 2.75-2.89 (1H, m), 2.98-3.14 (1H, m), 3.57-3.65 (2H, m), 3.69-3.81 (1H, m), 3.85-4.25 (3H, m), 7.58 (1H, d, J = 8.8 Hz), 7.80 (1H, dd, J = 2.6, 8.8 Hz), 8.02 (1H, d, J = 2.5 Hz). MS: 405.1.

[0202] C) 2-[(6R,8aS)-6-ethyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-5-chloro-benzonitrile. To a stirred mixture of tert-butyl (6R,8aR)-2-(4-chloro-2-cyano-phenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (2.5 g, 6.17 mmol) in acetonitrile (25 mL) was added trifluoroacetic acid (2.4 mL, 30.87 mmol) at 0° C., and the reaction mixture was stirred at 25° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to 0° C. and poured into an aqueous sodium bicarbonate solution under ice-cooling. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.5 g). The residue was used in the next step without further purification. MS: 304.9.

[0203] D) 2-[(6R,8aS)-7-(6-Bromo-2-formyl-3-pyridyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-5-chloro-benzonitrile. To a mixture of 2-[(6R,8aS)-6-ethyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-2-yl]-5-chloro-benzonitrile (1.5 g, 4.92 mmol) in toluene (20 mL) was added 6-bromo-3-fluoro-pyridine-2-carbaldehyde (1.5 g, 7.38 mmol), followed by potassium carbonate (2.1 g, 14.8 mmol) at room temperature. The reaction mixture was heated to reflux for 3 days. The reaction mixture was cooled to 25°C, ice-cold water (100 mL) was added, and the aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.3 g). 1 H NMR (400 MHz, DMSO-d6) δ 0.73 (3H, t, J = 7.3 Hz), 1.43-1.83 (2H, m), 3.19-3.32 (1H, m), 3.35-3.58 (3H, m), 3.57-3.66 (1H, m), 3.74 (1H, d, J = 13.4 Hz), 3.86-4.00 (1H, m), 4.10 (1H, t, J = 8.7 Hz), 7.58-7.69 (2H, m), 7.72 (1H, d, J = 8.8 Hz), 7.81 (1H, dd, J = 2.6, 8.8 Hz), 8.03 (1H, d, J = 2.4 Hz), 9.81 (1H, s). MS: 490.2.

[0204] E) 2-[(6R,8aS)-7-[6-(2-ethoxy-3-pyridyl)-2-formyl-3-pyridyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-5-chloro-benzonitrile A mixture of 2-[(6R,8aS)-7-(6-bromo-2-formyl-3-pyridyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-5-chloro-benzonitrile (1 g, 2.05 mmol), dioxane (90 mL), and water (10 mL) was degassed and heated at 25°C to give (2-ethoxypyridin-3-yl)boronic acid (380 mg, To the mixture was added Pd(DtBPF)Cl (70 mg, 0.102 mmol), and the reaction mixture was heated at 60 °C for 0.5 h. After completion of the reaction, the reaction mixture was cooled to 25 °C, and water (100 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound (800 mg). 1H NMR (400 MHz, DMSO) δ 0.77 (3H, t, J = 7.4 Hz), 1.38 (3H, t, J = 7.0 Hz), 1.50-1.61 (1H, m), 1.64-1.76 (1H, m), 3.39-3.54 (2H, m), 3.59-3.68 (2H, m), 3.77 (1H, d, J = 13.0 Hz), 3.90-4.08 (2H, m), 4.12 (1H, t, J = 8.7 Hz), 4.47 (2H, q, J= 7.0 Hz), 7.15 (1H, dd, J = 7.5, 4.9 Hz), 7.63 (1H, d, J = 8.8 Hz), 7.72 (1H, d, J = 8.9 Hz), 7.82 (1H, dd, J = 8.8, 2.6 Hz), 8.04 (1H, d, J = 2.4 Hz), 8.16-8.25 (2H, m), 8.33 (1H, dd, J = 7.5, 2.0 Hz), 10.02 (1H, s). MS: 530.1.

[0205] F) 3-[(6R,8aS)-2-(4-chloro-2-cyano-phenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid 2-[(6R,8aS)-7-[6-(2-ethoxy-3-pyridyl)-2-formyl-3-pyridyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-5-chloro-benzonitrile (800 mg, 1.51 mmol) in tert-butanol (5 mL), tetrahydrofuran (5 mL), water (5 mL) and 2-methyl-2-butene (1.6 mL, To a mixture of 15.1 mmol of methyl methylpropional (100%) and 100% methylpropional (15.1 mmol), NaClO2 (341 mg, 3.766 mmol) was added at 0 °C. To the mixture, an aqueous solution of NaH2PO4 (410 mg, 3.03 mmol) and water (2 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. After completion of the reaction, saturated aqueous sodium thiosulfate and saturated aqueous ammonium chloride were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL), and a pentane-ether mixture (20 mL, 4:1) was added and stirred for 15 minutes. The precipitated solid was filtered to give the title compound (640 mg). 1H NMR (400 MHz, DMSO) δ 0.84 (3H, t, J = 7.4 Hz), 1.39 (3H, t, J = 7.0 Hz), 1.53-1.65 (1H, m), 1.66-1.82 (1H, m), 3.27-3.37 (2H, m), 3.38-3.54 (1H, m), 3.54-3.70 (2H, m), 3.80 (1H, d, J = 12.8 Hz), 3.92-4.04 (1H, m), 4.11 (1H, t, J = 8.8 Hz), 4.50 (2H, q, J = 6.8 Hz), 7.09 (1H, dd, J = 4.8, 7.5 Hz), 7.62 (2H, dd, J = 5.0, 8.8 Hz), 7.76 (1H, dd, J = 2.5, 8.8 Hz), 7.92 (1H, d, J = 2.4 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.18 (1H, dd, J = 1.9, 4.9 Hz), 8.28 (1H, dd, J = 2.0, 7.5 Hz), 12.74 (1H, brs). MS: 547.28.

[0206] G) 3-[(6R,8aS)-2-(4-chloro-2-cyanophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-(4-chloro-2-cyano-phenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (100 mg, 0.628 mmol) in acetonitrile (5 mL) To the stirred solution, TCFH (180 mg, 0.628 mmol) and N-methylimidazole (0.085 mL, 1.046 mmol) were added at 25°C under an argon atmosphere. The reaction mixture was stirred at the same temperature for 10 minutes. (4R)-4-aminopyrrolidin-2-one (30 mg, 0.274 mmol) was added to the reaction mixture at 25°C, and the mixture was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was poured into ice water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by CombiFlash column chromatography (ethyl acetate / hexane) and then by reverse-phase preparative HPLC to obtain the title compound (35 mg). <Preparative HPLC Conditions> Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Actus C18 (250 × 20 mm, 5 μm), ambient temperature: room temperature, flow rate: 16 mL / min, mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 0.83 (3H, t, J = 7.3 Hz), 1.39 (3H, t, J = 7.0 Hz), 1.46-1.60 (1H, m), 1.64-1.81 (1H, m), 2.30-2.37 (1H, m), 2.54-2.62 (1H, m), 3.20-3.34 (3H, m), 3.40 (1H, t, J = 11.2 Hz), 3.55-3.69 (3H, m), 3.78 (1H, d, J = 12.8 Hz), 3.91-4.03 (1H, m), 4.12 (1H, t, J = 8.4 Hz), 4.50 (2H, q, J = 7.2 Hz), 4.56-4.69 (1H, m), 7.10 (1H, t, J = 5.6 Hz), 7.23-7.43 (1H, m), 7.54 (1H, d, J =8.8 Hz), 7.63 (1H, d, J = 8.8 Hz), 7.77 (1H, d, J = 8.8 Hz), 7.92 (1H, s), 8.05 (1H, d, J = 8.8 Hz), 8.14-8.20 (1H, m), 8.31 (1H, d, J = 7.5 Hz), 8.53-8.59 (1H, m). MS: 629.39.

[0207] Example 54 3-[(6R,8aS)-2-(4-chloro-2-cyanophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-(4-chloro-2-cyano-phenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (202 mg, 0.369 mmol) was dissolved in N,N-dimethylformamide. (3 mL), and to this mixture were added HATU (168 mg, 0.443 mmol), N,N-diisopropylethylamine (0.126 mL, 0.739 mmol), and (4R)-4-amino-1-methyl-pyrrolidin-2-one (52.8 mg, 0.462 mmol). After stirring at room temperature for 18 hours, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give a solid. This solid was recrystallized from diisopropyl ether / ethyl acetate at 75°C. The mixture was cooled to room temperature over the weekend. The mixture was stirred at 0°C for 1 hour. The crystals were filtered to give the title compound (190 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.78 (3H, t, J = 7.2 Hz), 1.30-1.49 (4H, m), 1.57-1.80 (1H, m), 2.37 (1H, dd, J = 16.5, 5.3 Hz), 2.60-2.79 (4H, m), 3.14-3.29 (3H, m), 3.35-3.39 (1H, m), 3.42-3.52 (1H, m), 3.61-3.78 (3H, m), 3.84-4.02 (1H, m), 4.08-4.23 (1H, m), 4.35-4.67 (3H, m), 7.13 (1H, dd, J = 7.5, 4.9 Hz), 7.54 (1H, d, J = 8.9 Hz), 7.63 (1H, d, J = 8.9 Hz), 7.82 (1H, dd, J = 8.8, 2.5 Hz), 8.00-8.10 (2H, m), 8.18 (1H, dd, J = 4.9, MS: 643.1.1.9 Hz), 8.31 (1H, dd, 7.5, 2.0 Hz), 8.87 (1H, d, J = 6.6 Hz)

[0208] Example 55 3-[(6R,8aS)-2-(2-cyano-4-fluorophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 613.39.

[0209] Example 56 3-[(6R,8aS)-2-[2-cyano-4-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 663.25.

[0210] Example 57 3-[(6R,8aS)-2-[2-cyano-4-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 677.41.

[0211] Example 58 3-[(6R,8aS)-2-(2-cyano-4-fluorophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 627.42.

[0212] The above-described embodied compounds are shown in the following Tables 1-1 to 1-13. MS in the tables indicates the actually measured value.

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] Example 59 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclopropyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10, Example 38, and Example 60, or methods analogous thereto. MS: 616.4.

[0227] Example 60 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Example 60a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridinyl)pyridine-2-carboxylic acid

[0228] A) Methyl (2R)-2-[[(2R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoyl]amino]propanoate. To a mixture of (2R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoic acid (5 g, 20.9 mmol) and acetonitrile (40 mL), methyl (2R)-2-aminopropanoate hydrochloride (3.5 g, 25.1 mmol), HATU (20 g, 52.3 mmol), and N,N-diisopropylethylamine (11 mL, 62.7 mmol) were added under an argon atmosphere at room temperature. The reaction mixture was stirred at the same temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was diluted with saturated aqueous sodium carbonate and extracted with ethyl acetate. The extract was washed with 1 M hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (6 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.28 (3H, d, J = 7.2 Hz), 3.45-3.55 (1H, m), 3.61 (4H, s), 4.05-4.15 (1H, m), 4.23-4.34 (1H, m), 4.78-4.86 (1H, m), 5.01-5.06 (2H, m), 7.22 (1H, d, J = 8.3 Hz), 7.28-7.39 (5H, m), 8.29 (1H, d, J = 7.1 Hz). MS: 325.3.

[0229] B) (3R,6R)-3-(Hydroxymethyl)-6-methyl-piperazine-2,5-dione. A mixture of methyl (2R)-2-[[(2R)-2-(benzyloxycarbonylamino)-3-hydroxypropanoyl]amino]propanoate (6 g, 18.5 mmol) and 10% Pd / C (1.3 g, ca. 50% aqueous) in methanol (50 mL) was stirred under a hydrogen atmosphere at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was concentrated. The residue was used in the next reaction without further purification. A mixture of the obtained residue and methanol (30 mL) was stirred at 80°C for 16 hours and then concentrated. The residue was washed with ethyl acetate to obtain the title compound (2.1 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.31 (3H, d, J = 6.9 Hz), 3.63-3.83 (4H, m), 5.06-5.13 (1H, m), 7.88 (1H, s), 8.12 (1H, s).

[0230] C) Di tert-butyl (2S,5R)-2-(hydroxymethyl)-5-methyl-piperazine-1,4-dicarboxylate A mixture of (3R,6R)-3-(hydroxymethyl)-6-methyl-piperazine-2,5-dione (2.1 g, 13.3 mmol) and borane-tetrahydrofuran complex (1 M tetrahydrofuran solution, 100 mL, 100 mmol) was stirred at 70°C for 16 hours. After cooling to 0°C, methanol (60 mL) was added to the reaction mixture, and 5 M hydrochloric acid (30 mL) was added to the reaction mixture. The mixture was stirred at 70°C for 2 hours. The mixture was concentrated, and the residue was washed with tetrahydrofuran. The resulting residue was used in the next reaction without further purification. To a mixture of the resulting residue in methanol (30 mL) were added triethylamine (10 mL, 73.7 mmol) and di-tert-butyl dicarbonate (6.7 mL, 29.5 mmol) at 0°C. The mixture was stirred at 70°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.01 (3H, d, J = 5.8 Hz), 1.35-1.42 (18H, m), 2.74-2.85 (1H, m), 2.90-3.07 (1H, m), 3.36-3.46 (2H, m), 3.50-3.63 (1H, m), 3.79-3.84 (3H, m), 4.73-4.83 (1H, m).

[0231] D) tert-Butyl (2R,5S)-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylate. To a mixture of di tert-butyl (2S,5R)-2-(hydroxymethyl)-5-methyl-piperazine-1,4-dicarboxylate (2.5 g, 7.58 mmol) and ethanol (50 mL), water (25 mL) and an aqueous solution of sodium hydroxide (760 mg, 18.9 mmol) were added and heated to reflux for 16 hours. After cooling to 0°C, the mixture was adjusted to pH 9 with 1.5 M hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to give the title compound (1 g). 1 H NMR (400 MHz, CD3OD-d4) 1.20 (3H, dd, J = 15.2, 6.9 Hz), 1.45 (9H, s), 2.62-2.66 (2H, m), 2.79-2.93 (2H, m), 3.47-3.53 (2H, m), 3.85 (1H, d, J = 10.7 Hz), 4.12-4.18 (1H, m).

[0232] E) tert-Butyl (2R,5S)-4-[[4-chloro-2-(trifluoromethyl)phenyl]carbamoyl]-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylate. To a solution of tert-butyl (2R,5S)-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylate (1 g, 4.34 mmol) in tetrahydrofuran (20 mL), 4-chloro-1-isocyanato-2-(trifluoromethyl)benzene (962 mg, 4.34 mmol) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 4 hours, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (1.2 g). 1H NMR (400 MHz, DMSO-d6) δ 1.04 (3H, d, J = 5.5 Hz), 1.38 (9H, s), 2.76-2.93 (2H, m), 3.49 (2H, s), 3.88-3.99 (4H, m), 5.69 (1H, s), 7.68 (3H, d, J = 9.8 Hz), 8.73 (1H, s). MS: 452.1.

[0233] F) tert-Butyl (6R,8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate To a mixture of tert-butyl (2R,5S)-4-[[4-chloro-2-(trifluoromethyl)phenyl]carbamoyl]-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylate (1.2 g, 2.66 mmol) in dichloromethane (30 mL) was added dropwise 1,8-diazabicyclo[5.4.0]-7-undecene (3.2 mL, 21.2 mmol) at room temperature under an argon atmosphere, and then methanesulfonyl chloride (0.5 mL, 6.64 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 16 hours and then poured into ice water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (900 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.03-1.26 (3H, m), 1.42 (9H, s), 2.74-3.10 (2H, m), 3.50 (1H, d, J = 13.3 Hz), 3.60-4.29 (5H, m), 7.61 (1H, d, J = 8.3 Hz), 7.82-7.90 (2H, m). MS: 433.9.

[0234] G) (6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one. To a solution of tert-butyl (6R,8aR)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (900 mg, 2.07 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1.6 mL, 20.7 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was cooled to 0°C and added to ice-cold saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane) to give the title compound (650 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.09 (3H, d, J = 6.9 Hz), 2.66-2.75 (1H, m), 2.83-2.97 (1H, m), 3.01-3.13 (2H, m), 3.19-3.27 (1H, m), 3.36-3.44 (1H, m), 3.58-3.78 (2H, m), 3.98-4.08 (1H, m), 7.56 (1H, d, J = 8.3 Hz), 7.79-7.88 (2H, m). MS: 333.7.

[0235] H) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde. 6-Bromo-3-fluoro-pyridine-2-carbaldehyde (600 mg, 2.92 mmol) and potassium carbonate (810 mg, 5.84 mmol) were added to a mixture of (6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one (650 mg, 1.95 mmol) in toluene (10 mL) at room temperature. The mixture was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature, and ice water was added. The mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (635 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.04 (3H, d, J = 6.6 Hz), 3.24-3.16 (1H, m), 3.43-3.33 (2H, m), 3.49-3.40 (1H, m), 3.57 (1H, d, J = 13.1 Hz), 3.77-3.73 (1H, m), 3.86 (1H, t, J = 8.6 Hz), 4.02-3.98 (1H, m), 7.63 (2H, t, J = 7.9 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.91-7.84 (2H, m), 9.86 (1H, s). MS: 517.1.

[0236] I) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carbaldehyde 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (300 mg, 0.58 mmol) in 1,4-dioxane (18 mL) and water (2 mL) To a degassed solution of (2-ethoxy-3-pyridyl)boronic acid (145 mg, 0.87 mmol) and potassium carbonate (240 mg, 1.74 mmol) were added at room temperature. The reaction mixture was degassed again, and then Pd(DtBPF)Cl2 (20 mg, 0.029 mmol) was added under an argon atmosphere and stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (195 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.06 (3H, d, J = 6.7 Hz), 1.38 (3H, t, J = 7.0 Hz), 3.31 (3H, d, J = 9.5 Hz), 3.35-3.52 (2H, m), 3.55-3.63 (1H, m), 3.77-3.92 (2H, m), 4.40-4.50 (2H, m), 7.11-7.19 (1H, m), 7.62-7.75 (2H, m), 7.85-7.93 (2H, m), 8.19-8.25 (2H, m), 8.30-8.37 (1H, m), 10.05 (1H, s). MS: 560.3.

[0237] J) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridinyl)pyridine-2-carboxylic acid 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carbaldehyde (195 mg, 0.349 mmol) in tert-butanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). To a mixture of 2-methyl-2-butene (0.4 mL, 3.45 mmol), NaClO (80 mg, 0.872 mmol) and KHPO (95 mg, 0.698 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of ammonium chloride were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (1 mL) and a 30% ether in pentane solution (10 mL) were added to the resulting residue, and the mixture was stirred. The resulting crystals were filtered and washed with pentane to give the title compound (155 mg). MS: 576.3.

[0238] K) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (150 mg, 0.26 mmol) in N,N-dimethylformamide To a solution of 2-bromo-1-ethylpyridinium tetrafluoroborate (45 mg, 0.391 mmol), N,N-diisopropylethylamine (0.1 mL, 0.521 mmol), and (4R)-4-amino-1-methyl-pyrrolidin-2-one (45 mg, 0.391 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to obtain the title compound (62 mg). <Preparative HPLC Conditions> Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Triart C18 (100 × 30 mm, 5 μm), ambient temperature: room temperature, flow rate: 30 mL / min, mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile. MS: 672.4.

[0239] Example 61 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Example 61a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)pyridine-2-carboxylic acid

[0240] A) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridyl)pyridine-2-carbaldehyde To a degassed solution of 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (300 mg, 0.58 mmol) in 1,4-dioxane (18 mL) and water (2 mL) was added (2-methoxy-3-pyridyl)boronic acid. (135 mg, 0.869 mmol) and potassium carbonate (240 mg, 1.74 mmol) were added at room temperature. The reaction mixture was degassed again, and then Pd(DtBPF)Cl2 (20 mg, 0.029 mmol) was added under an argon atmosphere and stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (200 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.06 (3H, d, J = 6.3 Hz), 3.31 - 3.36 (1H, m), 3.37 - 3.42 (2H, m), 3.44 - 3.52 (1H, m), 3.56 - 3.63 (1H, m), 3.76 - 3.92 (2H, m), 3.95 - 4.00 (3H, m), 4.01 - 4.06 (1H, m), 7.15 - 7.20 (1H, m), 7.63 - 7.73 (2H, m), 7.85 - 7.92 (2H, m), 8.15 (1H, d, J = 8.9 Hz), 8.22 - 8.34 (2H, m),10.05 (1H, s). MS: 546.2.

[0241] B) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)pyridine-2-carboxylic acid 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridyl)pyridine-2-carbaldehyde (200 mg, 0.37 mmol) in tert-butanol (2 mL), tetrahydrofuran (2 mL), water (2 mL) and 2-methyl-2-butene To a mixture of 1,2-dimethyl-2,4-dichloromethane (0.4 mL, 3.66 mmol), NaClO (83 mg, 0.916 mmol) and KH PO (100 mg, 0.733 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of ammonium chloride were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (2 mL) and a 20% ether in pentane solution (20 mL) were added to the resulting residue, and the mixture was stirred. The resulting crystals were filtered and washed with pentane to give the title compound (155 mg). MS: 562.1.

[0242] C) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)pyridine-2-carboxylic acid (150 mg, 0.267 mmol) in N,N-dimethylformamide (5 To a solution of 2-bromo-1-ethylpyridinium tetrafluoroborate (46 mg, 0.4 mmol), N,N-diisopropylethylamine (0.1 mL, 0.534 mmol), and (4R)-4-amino-1-methyl-pyrrolidin-2-one (46 mg, 0.4 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to obtain the title compound (131 mg). <Preparative HPLC Conditions> Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Triart C18 (100 × 30 mm, 5 μm), ambient temperature: room temperature, flow rate: 30 mL / min, mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ1.07 (3H, d, J = 6.6 Hz), 2.39 (1H, dd, J = 16.8, 5.4 Hz), 2.67 (1H, dd, J = 16.6, 8.8 Hz), 2.76 (3H, s), 3.14 (1H, d, J = 3.9 Hz), 3.27-3.44 (4H, m), 3.60 (1H, d, J = 12.8 Hz), 3.74 (1H, dd, J = 9.9, 7.5 Hz), 3.80-3.97 (3H, m), 4.00 (3H, s), 4.56 (1H, d, J = 7.0 Hz), 7.12 (1H, dd, J = 7.4, 4.9 Hz), 7.57 (2H, dd, J = 17.4, 8.8 Hz), 7.82 (2H, d, J = 7.0 Hz), 8.00 (1H, d, J = 8.6 Hz), 8.21 (1H, d, J = 4.8 Hz), 8.28 (1H, d, J = 7.4 Hz), 8.56 (1H, s). MS: 658.4.

[0243] Example 62 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclopropyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Synthesized according to the methods described in Example 10, Example 38, and Example 60, or methods analogous thereto. MS: 615.5.

[0244] Example 63 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide

[0245] Example 63a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid

[0246] A) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carbaldehyde. To a degassed solution of 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (200 mg, 0.483 mmol) in 1,4-dioxane (18 mL) and water (2 mL) was added (2-ethoxyphenyl)boronic acid (71 mg, To the reaction mixture, Pd(DtBPF)Cl (16 mg, 0.019 mmol) was added at room temperature. The mixture was degassed again, and then Pd(DtBPF)Cl (16 mg, 0.019 mmol) was added under an argon atmosphere. The mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (155 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.02-1.10 (3H, m), 1.36 (3H, t, J = 6.9 Hz), 3.22-3.28 (1H, m), 3.36-3.52 (3H, m), 3.56-3.68 (1H, m), 3.78-3.84 (1H, m), 3.88 (1H, t, J = 8.6 Hz), 3.98-4.08 (1H, m), 4.09-4.19 (2H, m), 7.01-7.18 (2H, m), 7.33-7.43 (1H, m), 7.62-7.70 (2H, m), 7.82-7.92 (3H, m), 8.12 (1H, d, J = 8.8 Hz), 10.06 (1H, s). MS: 559.0.

[0247] B) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carbaldehyde (155 mg, 0.277 mmol) in tert-butanol (3 mL), tetrahydrofuran (3 mL), water (3 mL) and 2-methyl-2-butene (0.3 mL, To a mixture of NaClO2 (65 mg, 0.693 mmol) and KH2PO4 (76 mg, 0.555 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium thiosulfate solution and saturated aqueous ammonium chloride solution were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (1 mL) and a 30% ether in pentane solution (10 mL) were added to the resulting residue and stirred. The resulting crystals were filtered and washed with pentane to obtain the title compound (150 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.02 (3H, d, J = 6.7 Hz), 1.12-1.26 (3H, m), 1.36 (3H, t, J = 7.0 Hz), 3.08-3.16 (1H, m), 3.59 (1H, d, J = 12.9 Hz), 3.68-3.99 (3H, m), 4.07-4.17 (2H, m), 7.00-7.08 (1H, m), 7.12 (1H, d, J = 8.3 Hz), 7.32-7.40 (1H, m), 7.57 (1H, d, J = 8.7 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.78 (1H, d, J = 7.5 Hz), 7.88 (2H, d, J = 11.1 Hz), 8.01 (1H, d, J = 8.8 Hz), 12.28-13.57 (1H, m). MS: 575.3.

[0248] C) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid (150 mg, 0.261 mmol) in N,N-dimethylformamide (5 mL) To the solution, 2-bromo-1-ethylpyridinium tetrafluoroborate (45 mg, 0.391 mmol), N,N-diisopropylethylamine (0.1 mL, 0.522 mmol), and (4R)-4-amino-1-methyl-pyrrolidin-2-one (45 mg, 0.39 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to obtain the title compound (45 mg). <Preparative HPLC Conditions> Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Triart C18 (100 × 30 mm, 5 μm), ambient temperature: room temperature, flow rate: 30 mL / min, mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ1.08 (3H, d, J = 6.7 Hz), 1.36 (3H, t, J = 6.9 Hz), 2.39 (1H, dd, J = 16.8, 5.4 Hz), 2.67 (1H, dd, J = 16.6, 8.7 Hz), 2.76 (3H, s), 3.15 (1H, dd, J = 11.9, 4.1 Hz), 3.28 - 3.45 (4H, m), 3.60 (1H, d, J = 12.8 Hz), 3.74 (1H, dd, J = 10.0, 7.4 Hz), 3.84 - 4.01 (3H, m), 4.14 (2H, q, J = 6.9 Hz), 4.54 - 4.59 (1H, m), 7.05 (1H, t, J = 7.5 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.30 - 7.39 (1H, m), 7.52 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 8.7 Hz), 7.78 - 7.85 (3H, m), 7.94 (1H, d, J = 8.6 Hz), 8.48 (1H, d, J = 6.8 Hz). MS: 671.7.

[0249] Example 64 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide Example 64a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)pyridine-2-carboxylic acid

[0250] A) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)pyridine-2-carbaldehyde. To a degassed solution of 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (100 mg, 0.193 mmol) in 1,4-dioxane (9 mL) and water (1 mL) was added (2-methoxyphenyl)boronic acid (32.3 mg, To the reaction mixture, Pd(DtBPF)Cl (8 mg, 0.01 mmol) was added at room temperature. The mixture was degassed again, and then Pd(DtBPF)Cl (8 mg, 0.01 mmol) was added under an argon atmosphere. The mixture was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (200 mg). MS: 545.2.

[0251] B) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)pyridine-2-carboxylic acid 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)pyridine-2-carbaldehyde (75 mg, 0.138 mmol) in tert-butanol (1 mL), tetrahydrofuran (1 mL), water (1 mL) and 2-methyl-2-butene (0.15 mL, 1.38 mmol). To a mixture of 1,2-dimethyl-2,4-dichloromethane (32 mg, 0.344 mmol) and 1,2-dimethyl-2,4-dichloromethane (40 mg, 0.275 mmol) were added NaClO (32 mg, 0.344 mmol) and KH PO (40 mg, 0.275 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium thiosulfate and saturated aqueous ammonium chloride were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (1 mL) and a 30% ether in pentane solution (10 mL) were added to the resulting residue, and the mixture was stirred. The resulting crystals were filtered and washed with pentane to give the title compound (60 mg). MS: 561.2.

[0252] C) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide A solution of 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)pyridine-2-carboxylic acid (60 mg, 0.107 mmol) in N,N-dimethylformamide (5 mL) was diluted with tetrafluoroborate. 2-Bromo-1-ethylpyridinium (20 mg, 0.16 mmol), N,N-diisopropylethylamine (0.05 mL, 0.214 mmol), and (4R)-4-amino-1-methyl-pyrrolidin-2-one (20 mg, 0.16 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to obtain the title compound (1.5 mg). <Preparative HPLC Conditions> Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Triart C18 (100 × 30 mm, 5 μm), ambient temperature: room temperature, flow rate: 30 mL / min, mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile. MS: 657.6.

[0253] Example 65 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide

[0254] A) tert-Butyl (2R,5S)-2-ethyl-5-(hydroxymethyl)-4-[[1-(trifluoromethyl)cyclobutyl]carbamoyl]piperazine-1-carboxylate To a mixture of dichloromethane (25 mL), 1-(trifluoromethyl)cyclobutanamine (770 mg, 5.525 mmol), and tritylamine (1.7 mL, 12.3 mmol) was added triphosgene (606 mg, 2.046 mmol) at 0°C under an argon atmosphere, and the reaction mixture was stirred at 25°C for 16 hours. To the reaction mixture, a solution of tert-butyl (2R,5S)-2-ethyl-5-(hydroxymethyl)piperazine-1-carboxylate (1 g, 4.093 mmol) in dichloromethane (15 mL) was added, followed by triethylamine (1.7 mL, 12.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was washed with dichloromethane. The filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to afford the title compound (1.25 g). 1 H NMR (400 MHz, DMSO-d6) δ 0.83 (3H, t, J = 7.5 Hz), 1.38 (11H, s), 1.71-1.98 (2H, m), 2.31-2.46 (4H, m), 2.65-2.85 (2H, m), 3.41 (2H, t, J = 4.9 Hz), 3.73-3.77 (1H, m), 3.79-4.05 (3H, m), 5.15-5.21 (1H, m), 6.87 (1H, s).

[0255] B) tert-Butyl (6R,8aR)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate To a solution of tert-butyl (2R,5S)-2-ethyl-5-(hydroxymethyl)-4-[[1-(trifluoromethyl)cyclobutyl]carbamoyl]piperazine-1-carboxylate (1.25 g, 3.05 mmol) in dichloromethane (25 mL) was added 1,8-diazabicyclo[5.4.0]undecene (3.65 mL, 24.4 mmol) at room temperature under an argon atmosphere, followed by methanesulfonyl chloride (0.6 mL, 7.632 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into ice-cold water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (635 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.73-0.86 (3H, m), 1.40 (11H, s), 1.84-1.96 (2H, m), 2.28-2.37 (2H, m), 2.56-2.69 (2H, m), 2.81-2.92 (1H, m), 3.01-3.08 (1H, m), 3.42-3.54 (3H, m), 3.78-4.07 (2H, m).

[0256] C) (6R,8aS)-6-Ethyl-2-[1-(trifluoromethyl)cyclobutyl]-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one. To a stirred mixture of tert-butyl (6R,8aR)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (600 mg, 1.533 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (1.45 mL, 18.4 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was cooled to 0 °C and poured into an ice-cold aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to afford the title compound (400 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.83 (3H, t, J = 7.4 Hz), 1.32 - 1.52 (2H, m), 1.83 - 1.96 (2H, m), 2.26 - 2.36 (2H, m), 2.59 (3H, d, J = 6.3 Hz), 2.83 - 2.93 (2H, m), 3.41 - 3.54 (3H, m), 3.73 - 3.97 (1H, m).

[0257] D) 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde To a mixture of (6R,8aS)-6-ethyl-2-[1-(trifluoromethyl)cyclobutyl]-1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyrazin-3-one (400 mg, 1.545 mmol) in toluene (15 mL) was added 6-bromo-3-fluoro-pyridine-2-carbaldehyde (475 mg, 2.317 mmol), followed by potassium carbonate (640 mg, 4.63 mmol) at room temperature. The reaction mixture was heated to reflux for 3 days. The reaction mixture was cooled to room temperature, ice-cold water (50 mL) was added, and the aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (550 mg). MS: 475.2.

[0258] E) 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carbaldehyde 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (200 mg, 0.421 mmol) was dissolved in a mixture of 1,4-dioxane (9 mL) and water (1 mL), and the mixture was degassed and then heated at room temperature. (2-Ethoxypyridin-3-yl)boronic acid (106 mg, 0.631 mmol) and potassium carbonate (175 mg, 1.262 mmol) were added, and the mixture was degassed again. To this mixture, Pd(DtBPF)Cl2 (15 mg, 0.021 mmol) was added under an argon atmosphere, and the reaction mixture was heated at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and water (100 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (200 mg). MS: 518.2.

[0259] F) 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carbaldehyde (200 mg, 0.386 mmol) in tert-butanol (3 mL), tetrahydrofuran (3 mL), water (3 mL) and 2-methyl-2-butene (0.4 mL, To a mixture of NaClO2 (88 mg, 0.966 mmol) and KH2PO4 (106 mg, 0.773 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium thiosulfate and saturated aqueous ammonium chloride were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (1 mL) and a 30% ether in pentane solution (10 mL) were added to the resulting residue and stirred. The resulting crystals were filtered and washed with pentane to give the title compound (150 mg). MS: 534.1.

[0260] G) 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxy-3-pyridyl)pyridine-2-carboxylic acid (150 mg, 0.281 mmol) in N,N-dimethylformamide (5 mL) To the solution, 2-bromo-1-ethylpyridinium tetrafluoroborate (50 mg, 0.422 mmol), N,N-diisopropylethylamine (0.1 mL, 0.562 mmol), and (4R)-4-amino-1-methyl-pyrrolidin-2-one (50 mg) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to obtain the title compound (36 mg). <Preparative HPLC Conditions> Preparative HPLC was performed on a Waters automated purification system. Column name: YMC-Triart C18 (100 × 30 mm, 5 μm), ambient temperature: room temperature, flow rate: 30 mL / min, mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 0.80 (3H, t, J = 7.3 Hz), 1.36-1.41 (3H, m), 1.41-1.51 (1H, m), 1.52-1.66 (1H, m), 1.98 (2H, q, J = 8.8 Hz), 2.33-2.45 (3H, m), 2.66 (2H, dd, J = 17.1, 8.6 Hz), 2.76 (3H, s), 3.05-3.16 (3H, m), 3.17-3.23 (1H, m), 3.32 (1H, dd, J = 10.0, 4.5 Hz), 3.46-3.53 (1H, m), 3.56-3.82 (4H, m), 4.49 (2H, q, J = 7.0 Hz), 4.53-4.58 (1H, m), 7.05-7.13 (1H, m), 7.52 (1H, d, J = 8.9 Hz), 8.03 (1H, dd, J = 8.7, MS: 630.7.

[0261] Example 66 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide

[0262] A) 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carbaldehyde 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (200 mg, 0.421 mmol) was dissolved in a mixture of 1,4-dioxane (9 mL) and water (1 mL). After degassing, the mixture was heated at 25 °C to give (2-ethoxyphenyl)boronic acid. (106 mg, 0.631 mmol) and potassium carbonate (175 mg, 1.262 mmol) were added, and the mixture was degassed again. To this mixture, Pd(DtBPF)Cl2 (15 mg, 0.021 mmol) was added under an argon atmosphere, and the reaction mixture was heated at 100 °C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and water (100 mL) was added. The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (200 mg). MS: 517.1.

[0263] B) 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid 3-[(6R,8aS)-6-Ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carbaldehyde (200 mg, 0.387 mmol) in tert-butanol (2 mL), tetrahydrofuran (2 mL), water (2 mL) and 2-methyl-2-butene (0.3 mL, 2.78 mmol). To the mixture, NaClO2 (88 mg, 0.968 mmol) and KH2PO4 (106 mg, 0.774 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium thiosulfate solution and saturated aqueous ammonium chloride solution were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (1 mL) and a 30% ether in pentane solution (10 mL) were added to the resulting residue, and the mixture was stirred. The resulting crystals were filtered and washed with pentane to give the title compound (150 mg). MS: 533.2.

[0264] C) 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide A solution of 3-[(6R,8aS)-6-ethyl-3-oxo-2-[1-(trifluoromethyl)cyclobutyl]-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid (150 mg, 0.282 mmol) in N,N-dimethylformamide (5 mL) was diluted with tetrafluoroborate. 2-Bromo-1-ethylpyridinium (50 mg, 0.422 mmol), N,N-diisopropylethylamine (0.1 mL, 0.563 mmol), and (4R)-4-amino-1-methyl-pyrrolidin-2-one (50 mg) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 16 hours, and then saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by preparative HPLC to obtain the title compound (62 mg). <Preparative HPLC Conditions> Preparative HPLC was performed using a Waters automated purification system. Column: YMC-Triart C18 (100 × 30 mm, 5 μm), ambient temperature: room temperature, flow rate: 30 mL / min, mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile. 1H NMR (400 MHz, DMSO-d6) δ 0.80 (3H, t, J = 7.3 Hz), 1.35 (3H, t, J = 6.9 Hz), 1.39-1.50 (1H, m), 1.50-1.64 (1H, m), 1.98 (2H, q, J = 8.7 Hz), 2.32-2.45 (3H, m), 2.60-2.71 (3H, m), 2.75 (3H, s), 3.04-3.16 (3H, m), 3.17-3.27 (1H, m), 3.31 (1H, dd, J = 10.0, 4.5 Hz), 3.44-3.51 (1H, m), 3.56-3.79 (4H, m), 4.13 (2H, q, J = 6.9 Hz), 4.52-4.57 (1H, m), 7.04 (1H, td, J = 7.4, 1.2 Hz), 7.10 (1H, d, J = 8.3 Hz), 7.29-7.37 (1H, m), 7.48 (1H, d, J = 8.7 Hz), 7.82 (1H, dd, J = 7.7, 1.8 Hz), 7.91 (1H, d, J = 8.7 Hz), 8.46 (1H, d, J = 6.4 Hz). MS: 629.7.

[0265] Example 67 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide

[0266] A) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carbaldehyde 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (200 mg, 0.376 mmol), (2-ethoxyphenyl)boronic acid (68.7 mg, 0.414 mmol), 2M aqueous sodium carbonate (0.564 mL), and toluene To a mixture of (8 mL) and 1,000 mg of dppf-CH2Cl2 (30.7 mg, 0.0376 mmol) was added PdCl2(dppf)-CH2Cl2 (30.7 mg, 0.0376 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 24 hours. After completion of the reaction, the reaction mixture was cooled to 25 °C, water and ethyl acetate were added, and the precipitate was filtered. The filtrate was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (80.6 mg). MS: 573.9.

[0267] B) 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carbaldehyde (80.6 mg, 0.141 mmol), sodium phosphate (67.5 mg, To a mixture of 2-methyl-2-butene (0.104 mL, 0.985 mmol), tert-butanol (1 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL), NaClO2 (25 mg, 0.281 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium thiosulfate and saturated aqueous ammonium chloride were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. Salt was added to the aqueous layer, and the mixture was extracted again with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The resulting residue was used in the next reaction without further purification. To a solution of the resulting residue (83.4 mg), N,N-diisopropylethylamine (0.0485 mL, 0.283 mmol), and HATU (64.6 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added (4R)-4-amino-1-methyl-pyrrolidin-2-one (20 mg, 0.177 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) and preparative HPLC to afford the title compound (58.4 mg). 1H NMR (300 MHz, DMSO-d6) δ 0.77 (3H, t, J = 7.3 Hz), 1.30-1.68 (5H, m), 2.36 (1H, dd, J = 16.6, 5.2 Hz), 2.59-2.69 (1H, m), 2.73 (3H, s), 3.02-3.30 (4H, m), 3.35-3.50 (2H, m), 3.66-3.77 (2H, m), 3.79-3.96 (2H, m), 4.06-4.18 (2H, m), 4.36-4.66 (1H, m), 6.97-7.19 (2H, m), 7.28-7.43 (1H, m), 7.50 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.79-7.91 (3H, m), 7.95 (1H, d, J = 8.7 Hz), 8.82 (1H, d, J = 6.6 Hz). MS: 685.1. Preparative HPLC conditions Column : L-Column2 ODS (20 mmI.D.×150 mm, 5 μm) Mobile phase: A) H2O / TFA = 1000 / 1 (v / v): B) MeCN / TFA = 1000 / 1 (v / v) Flow rate: 20 ml / min Temperature: Room temperature

[0268] Example 67a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylic acid Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 589.2.

[0269] Example 68 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (200 mg, 0.376 mmol), (2-methoxyphenyl)boronic acid (62.9 mg, To a mixture of 2M aqueous sodium carbonate (0.564 mL), 2M aqueous sodium carbonate (0.414 mmol), and toluene (8 mL) was added PdCl2(dppf)-CHCl2 (30.7 mg, 0.0376 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 24 hours. After completion of the reaction, the reaction mixture was cooled to 25 °C, water and ethyl acetate were added, and the precipitate was filtered. The filtrate was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane). The resulting residue was used in the next reaction without further purification. To a mixture of the obtained residue (117 mg), sodium phosphate (101 mg, 0.839 mmol), 2-methyl-2-butene (0.156 mL, 1.47 mmol), tert-butanol (1 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL) was added NaClO2 (38 mg, 0.42 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium thiosulfate and saturated aqueous ammonium chloride were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. Salt was added to the aqueous layer, and the mixture was extracted again with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The obtained residue was used in the next reaction without further purification.To a solution of the resulting residue (122 mg), N,N-diisopropylethylamine (0.0728 mL, 0.425 mmol), and HATU (97 mg, 0.255 mmol) in N,N-dimethylformamide (2 mL) was added (4R)-4-amino-1-methyl-pyrrolidin-2-one (30 mg, 0.266 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) and preparative HPLC to afford the title compound (16 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.77 (3H, t, J = 7.1 Hz), 1.32-1.67 (2H, m), 2.23-2.41 (2H, m), 2.59-2.69 (1H, m), 2.72 (3H, s), 3.02-3.25 (3H, m), 3.36-3.51 (2H, m), 3.64-3.78 (2H, m), 3.79-3.94 (5H, m), 4.41-4.75 (1H, m), 7.00-7.21 (2H, m), 7.30-7.42 (1H, m), 7.50 (1H, d, J = 8.9 Hz), 7.63 (1H, d, J = 8.2 Hz), 7.74-7.99 (4H, m), 8.73-8.94 (1H, m). MS: 671.1. Preparative HPLC conditions Column: L-Column2 ODS (20 mmI.D.×150 mm, 5 μm) Mobile phase: A) H2O / TFA = 1000 / 1 (v / v): B) MeCN / TFA = 1000 / 1 (v / v) Flow rate: 20 ml / min Temperature: Room temperature

[0270] Example 68a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)pyridine-2-carboxylic acid Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 575.9.

[0271] Example 69 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-bromo-pyridine-2-carbaldehyde (200 mg, 0.38 mmol), (2-methoxy-3-pyridyl)boronic acid To a mixture of (63.3 mg, 0.414 mmol), 2M aqueous sodium carbonate (0.564 mL), and toluene (8 mL) was added PdCl2(dppf)-CHCl2 (30.7 mg, 0.0376 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 24 hours. After completion of the reaction, the reaction mixture was cooled to 25 °C, water and ethyl acetate were added, and the precipitate was filtered. The filtrate was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane), and the resulting residue was used in the next reaction without further purification. To a mixture of the obtained residue (116 mg), sodium phosphate (99.4 mg, 0.829 mmol), 2-methyl-2-butene (0.154 mL, 1.45 mmol), tert-butanol (1 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL) was added NaClO2 (38 mg, 0.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium thiosulfate and saturated aqueous ammonium chloride were added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was separated. Salt was added to the obtained aqueous layer, and the mixture was extracted again with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The obtained residue was used in the next reaction without further purification.To a solution of the resulting residue (119 mg), N,N-diisopropylethylamine (0.0707 mL, 0.413 mmol), and HATU (94 mg, 0.248 mmol) in N,N-dimethylformamide (2 mL) was added (4R)-4-amino-1-methyl-pyrrolidin-2-one (30 mg, 0.259 mmol). The reaction mixture was stirred at room temperature for 18 hours, and water was added. The mixture was extracted with ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) and preparative HPLC to afford the title compound (56.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.77 (3H, t, J = 7.3 Hz), 1.33-1.76 (2H, m), 2.37 (1H, dd, J = 16.6, 5.0 Hz), 2.67 (1H, dd, J = 17.0, 8.7 Hz), 2.73 (3H, s), 3.12-3.31 (4H, m), 3.36 (1H, br d, J = 6.3 Hz), 3.42-3.52 (1H, m), 3.65-3.94 (4H, m), 3.96 (3H, s), 4.44-4.66 (1H, m), 7.15 (1H, dd, J = 7.5, 4.9 Hz), 7.54 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.84-7.93 (2H, m), 8.00 (1H, d, J = 8.7 Hz), 8.21 (1H, dd, J = 4.9, 2.0 Hz), 8.30 (1H, dd, J = 7.4, 1.9 Hz), 8.86 (1H, d, J = 6.6 Hz). MS: 672.2. Preparative HPLC conditions Column: L-Column2 ODS (20 mmI.D.×150 mm, 5 μm) Mobile phase: A) H2O / TFA = 1000 / 1 (v / v): B) MeCN / TFA = 1000 / 1 (v / v) Flow rate: 20 ml / min Temperature: Room temperature

[0272] Example 69a 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)pyridine-2-carboxylic acid Synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 576.1.

[0273] The above-described embodied compounds are shown in the following Tables 2-1 to 2-4. MS in the tables indicates the actually measured value.

[0274]

[0275]

[0276]

[0277]

[0278] Test Example 1: Measurement of human MC2R inhibitory activity using intracellular cAMP concentration as an index. GeneBLAzer MC2R-CRE-bla CHO-K1 cells (Thermo Fisher Scientific) that had been cryopreserved were thawed and suspended in Dulbecco's Modified Eagle Medium (Thermo Fisher Scientific) containing fetal bovine serum (10% (v / v), HyClone Laboratories), Non-Essential Amino Acids Solution (1 / 100 (w / w), Thermo Fisher Scientific), HEPES (25 mM, Thermo Fisher Scientific), and Penicillin / Streptomycin (1 / 100 (w / w), Fujifilm Wako). The cell suspension was centrifuged, and the supernatant was removed. The cells were then suspended in D-PBS(-) (Fujifilm Wako), centrifuged again, and the supernatant was removed. Cells were resuspended in assay buffer [Hank's Balanced Salt Solution (Thermo Fisher Scientific) containing HEPES pH 7.5 (10 mM, Thermo Fisher Scientific), fatty-acid-free bovine serum albumin (0.01% (w / v), Sigma), and IBMX (500 μM, Fujifilm Wako)] and plated at 1,500 cells / well in a 384-well white plate (Greiner). Test compounds prepared in assay buffer were then added and incubated for 20 minutes. After incubation, ACTH (Human 1-24) (Peptide Institute) in assay buffer was added (final ACTH concentration, 3 pM) and incubated for 30 minutes at room temperature. Intracellular cAMP levels were measured using a cAMP Gs HiRange kit HTRF (PerkinElmer). The compound's MC2R inhibition rate was calculated using the following formula:Inhibition rate (%) = (C-B) / (A-B) × 100 A: cAMP concentration calculated from wells to which 3 pM ACTH (1-24) was added B: cAMP concentration calculated from wells to which 3 pM ACTH (1-24) was not added C: cAMP concentration calculated from wells to which 3 pM ACTH (1-24) and a predetermined concentration of test compound were added The inhibition rates (%) of MC2R at 1 μM of the test compounds are shown in Tables 3-1 to 3-4.

[0279]

[0280]

[0281]

[0282]

[0283] As described above, the present compound was shown to have excellent MC2R inhibitory activity.

[0284] Test Example 2: Inhibitory effect of ACTH-induced corticosterone secretion in mice Nine-week-old male ICR mice (Charles River Japan, Inc.) were used in the test. Mice were assigned to groups of five based on body weight, with each group consisting of five mice. The test compound was suspended in 0.5% (w / v) methylcellulose solution. ACTH (1-24) (A0948, LKT Laboratories, Inc.) was dissolved in saline. The test compound (10 mg / kg) or vehicle was orally administered to the mice, followed one hour later by subcutaneous administration of ACTH solution (100 μg / kg). Blood was collected from the tail vein before and 0.5, 1, and 2 hours after ACTH administration, and plasma corticosterone concentrations were measured using an ELISA kit (EC3001-1, Assaypro). Plasma corticosterone concentrations at each time point were used to calculate the area under the blood concentration-time curve (AUC) up to 2 hours after administration. 0-2h AUC of the vehicle-administered group was calculated. 0-2h AUC of test compound group 0-2h The percentages are shown in Table 4.

[0285]

[0286] As described above, it was demonstrated that the present compound has an excellent inhibitory effect on ACTH-induced enhancement of corticosterone secretion.

[0287] Formulations of this compound will be explained below by showing examples of formulations containing the compound of Example 1. However, the form of formulations of this compound is not limited to these.

[0288] Formulation Example 1 (Production of Capsules) 1) Compound of Example 1 30 mg 2) Finely powdered cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Total 60 mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0289] Formulation Example 2 (Tablet Production) 1) Compound of Example 1 30 g 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets Total 140 g The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water, vacuum dried, and then sized. This sized powder is mixed with 14 g of 4) and 1 g of 5) and tableted using a tablet press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

[0290] In one embodiment, the present invention provides a compound that has an excellent MC2R antagonist activity and is useful in the pharmaceutical field as a preventive or therapeutic agent for diseases associated with abnormal ACTH signaling, particularly endocrine system diseases (e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia or polycystic ovary syndrome), metabolic diseases (e.g., obesity, type 2 diabetes, dyslipidemia, osteoporosis or sarcopenia), cardiovascular diseases (e.g., hypertension, arteriosclerosis), central nervous system diseases (e.g., depression, dementia, insomnia), eye diseases (e.g., cataract, glaucoma), or infectious diseases.

[0291] This application is based on patent application No. 2023-080580 filed in Japan (filing date: May 16, 2023), the contents of which are incorporated in their entirety herein.

Claims

1. A compound of formula (I): [In the formula, R １ is a hydrogen atom or an optionally substituted C １－６ represents an alkyl group, R ２ is a hydrogen atom or an optionally substituted C １－６ represents an alkyl group, X represents an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group, Y represents an optionally substituted aromatic heterocyclic group, or an optionally substituted aryl group, and Z represents a hydrogen atom, a hydroxyl group, NH ２ , or N.H.R. ３ (In the formula, R ３ is an optionally substituted C １－６ represents an alkyl group, or an optionally substituted saturated cyclic group.] ("Compound (I)") or a salt thereof.

2. The compound according to claim 1, or a salt thereof, wherein X is an optionally substituted aryl group, an optionally substituted nitrogen-containing aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group, and Y is an optionally substituted nitrogen-containing aromatic heterocyclic group, or an optionally substituted aryl group.

3. X is optionally substituted C ６－１４ an aryl group, an optionally substituted 5- to 14-membered nitrogen-containing aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group; and Y is an optionally substituted 5- to 14-membered nitrogen-containing aromatic heterocyclic group, or an optionally substituted C ６－１４ The compound or salt thereof according to claim 2, wherein the aryl group is an aryl group.

4. The compound or salt thereof according to claim 3, wherein X is an optionally substituted phenyl group, an optionally substituted pyridyl group, or an optionally substituted saturated hydrocarbon ring group, and Y is an optionally substituted pyridyl group, or an optionally substituted phenyl group.

5. The compound or salt thereof according to claim 4, wherein X is an optionally substituted phenyl group or an optionally substituted saturated hydrocarbon ring group, and Y is an optionally substituted pyridyl group or an optionally substituted phenyl group.

6. The "optionally substituted saturated hydrocarbon ring group" in X is "optionally substituted C ３－１０ 6. The compound or salt thereof according to any one of claims 3 to 5, wherein R is a cycloalkyl group.

7. X is an optionally substituted phenyl group or an optionally substituted C ３－１０ The compound or salt thereof according to claim 5, which is a cycloalkyl group.

8. Z is a hydrogen atom, a hydroxyl group, or NH ２ , or N.H.R. ３ (In the formula, R ３ is an optionally substituted C １－６ 2. The compound according to claim 1 , wherein R is an alkyl group, or an optionally substituted 3- to 8-membered saturated ring group.

9. R １ is a hydrogen atom, or C １－６ is an alkyl group, R ２ is a hydrogen atom, or C １－６ X is 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms, １－６ 1) a phenyl group optionally substituted by 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; or １－６ C optionally substituted with 1 to 3 alkyl groups ３－１０ is a cycloalkyl group, Y is 1 to 3 C １－６ a pyridyl group optionally substituted by an alkoxy group, or 1 to 3 C １－６ A phenyl group which may be substituted with an alkoxy group, and Z is a hydrogen atom, a hydroxyl group, NH ２ , or N.H.R. ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups, (mono- or di-C１－６ C alkyl)amino group; ３－１０ a cycloalkyl group, a 5- to 6-membered monocyclic aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group, １－６ Alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and C １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ an alkyl group, or １－６ Alkyl group, C １－６ 2. The compound according to claim 1 , or a salt thereof, wherein R is an integer from 1 to 3, and R is an integer from 1 to 3.

10. X is 1) a halogen atom, 2) a C group optionally substituted with 1 to 3 halogen atoms １－６ 1) a phenyl group optionally substituted with 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; and １－６ The compound or salt thereof according to claim 9 , which is a pyridyl group optionally substituted with an alkoxy group.

11. R １ But, C １－６ is an alkyl group, and R ２ The compound or salt thereof according to claim 9 , wherein:

12. Z is a hydrogen atom, a hydroxyl group, or NH ２ , or N.H.R. ３ (In the formula, R ３ (i) a hydroxy group, C １－６ Alkoxy groups, (mono- or di-C １－６ C alkyl)amino group; ３－１０ a cycloalkyl group, a 5- to 6-membered monocyclic nitrogen-containing aromatic heterocyclic group, a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group, C １－６ a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted by an alkoxy-carbonyl group; １－６Alkyl-carbonylamino group, (mono- or di-C １－６ alkylamino)carbonyl group, and １－６ C optionally substituted with 1 to 3 substituents selected from alkyl-sulfonyl groups １－６ (ii) (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) C １－６ Alkyl group, C １－６ 10. The compound according to claim 9, or a salt thereof, wherein R represents a 3- to 8-membered monocyclic nitrogen-containing saturated heterocyclic group optionally substituted by 1 to 3 substituents selected from an alkoxy-carbonyl group, and an oxo group.

13. Z is a hydroxyl group or NHR ３ (In the formula, R ３ (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or １－６ Alkyl group, C １－６ 13. The compound according to claim 12, or a salt thereof, wherein R represents a 3- to 8-membered nitrogen-containing saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from an alkoxy-carbonyl group, and an oxo group.

14. R １ But, C １－６ is an alkyl group, R ２ is a hydrogen atom, and X is 1) a halogen atom, 2) a C optionally substituted with 1 to 3 halogen atoms. １－６ 1) a phenyl group optionally substituted by 1 to 3 substituents selected from an alkyl group, an alkyl group, and a cyano group; １－６ A pyridyl group which may be substituted by an alkoxy group, and Z is a hydroxyl group or NHR ３ (In the formula, R ３ is C １－６ The compound according to claim 9, wherein the compound is a pyrrolidinyl group optionally substituted with 1 to 3 substituents selected from an alkyl group and an oxo group, or a salt thereof.

15. Compound (I) has the following formula (Ia): The compound or salt thereof according to any one of claims 1 to 5, or 7 to 14, having a structure represented by:

16. 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide, 3-[(6R,8aS)-6-ethyl-2-[4-fluoro-2-(trifluoromethyl)phenyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide, 3-[(6R,8aS)-2-(4-chloro-2-cyanophenyl)-6-ethyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide, 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxy-3-pyridinyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide, 3-[(6R,8aS)-2-[4-chloro-2-(trifluoromethyl)phenyl]-6-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-7-yl]-6-(2-methoxyphenyl)-N-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]pyridine-2-carboxamide, or a salt thereof according to claim 1 , which is a compound or a salt thereof selected from:

17. A medicine comprising the compound or salt thereof according to claim 1 as an active ingredient.

18. The pharmaceutical agent according to claim 17, which is an MC2R antagonist.

19. The pharmaceutical agent according to claim 17 or 18, which is a preventive or therapeutic agent for endocrine system diseases, metabolic diseases, cardiovascular diseases, central nervous system diseases, eye diseases, and / or infectious diseases.

20. The pharmaceutical agent according to claim 19, which is a preventive or therapeutic agent for Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome, obesity, type 2 diabetes, dyslipidemia, osteoporosis, sarcopenia, hypertension, arteriosclerosis, depression, dementia, insomnia, cataracts, glaucoma and / or infections.

21. A method for preventing and / or treating an endocrine disorder, a metabolic disorder, a cardiovascular disorder, a central nervous system disorder, an eye disorder, and / or an infectious disease, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to a mammal in need thereof.

22. The compound or salt thereof according to claim 1, for use in the prevention and / or treatment of endocrine system disorders, metabolic disorders, cardiovascular diseases, central nervous system disorders, eye diseases, and / or infectious diseases.

23. Use of a compound according to claim 1 or a salt thereof for the manufacture of a medicament for the prevention and / or treatment of endocrine system disorders, metabolic disorders, cardiovascular diseases, central nervous system disorders, eye diseases, and / or infectious diseases.