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  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to an embodiment of a heterocyclic compound or the like that has antagonist activity against the melanocortin 2 receptor (MC2R) and is useful in the treatment or prevention of conditions, diseases, and disorders that respond to MC2R antagonism, such as endocrine 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), eye diseases (e.g., cataracts, glaucoma), and infectious diseases, and is useful in the field of medicine.
• endocrine diseases e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyper
• hypothalamic-pituitary-adrenal (HPA) system is responsible for the biological response to stress, and is an essential neuroendocrine mechanism for protecting the organism from stress and maintaining homeostasis.
• CRF corticotropin-releasing factor
• CRF acts on adrenocorticotropic hormone-producing cells in the anterior pituitary via the pituitary portal vein, promoting the synthesis and secretion of adrenocorticotropic hormone (ACTH), which consists of 39 amino acids.
• ACTH secreted from the anterior pituitary acts on the adrenal cortex via the bloodstream, promoting the secretion of adrenal cortical hormones such as glucocorticoids, and inducing a biological response to stress by regulating the metabolism and immune response of the entire body.
• adrenal cortical hormones such as glucocorticoids
• glucocorticoids also play a role in terminating the activation of the HPA axis through a negative feedback mechanism that acts on the hypothalamus and anterior pituitary gland to suppress the secretion of ACTH.
• the HPA axis is an important physiological response for the body to adapt to external environmental stimuli, on the other hand, the breakdown of its function, such as an excessive activation state of the HPA axis, is thought to be deeply involved in the manifestation of various systemic pathologies.
• ACTH secreted from the anterior pituitary gland exerts its physiological action by selectively binding to the ACTH receptor.
• the ACTH receptor is composed of MC2R, a seven-transmembrane G protein-coupled receptor, and melanocortin-2 receptor accessory protein-1 (MRAP), an accessory protein.
• MRAP melanocortin-2 receptor accessory protein-1
• a selective antagonist of this receptor can selectively block the ACTH signal in the adrenal gland, and is expected to be effective in treating or preventing conditions, diseases, and disorders caused by excessive ACTH signaling.
• attempts have been made in this field to develop MC2R antagonists (Patent Document 1; Non-Patent Document 1).
• the efficacy and safety of these antagonists are still insufficient, and the development of more useful MC2R antagonists has been awaited.
• the present invention aims to solve the above problems by providing, as an embodiment thereof, a novel heterocyclic compound having MC2R antagonist activity.
• the present inventors discovered that the heterocyclic compound represented by the following formula (I) or a salt thereof has MC2R antagonist activity, and as a result of further research, they have completed the present invention.
• Specific embodiments of the present invention are as follows. However, the present invention is not limited to these.
• R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group
• R 2 represents a hydrogen atom or an optionally substituted C 1-6 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
• Z represents a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (In the formula, R3 represents an optionally substituted C1-6 alkyl group or an optionally substituted saturated ring group.)
• compound (I) represents a salt thereof.
• X is an optionally substituted aryl group, an optionally substituted nitrogen-containing aromatic heterocyclic group, or an optionally substituted saturated hydrocarbon ring group
• Y is an optionally substituted nitrogen-containing aromatic heterocyclic group or an optionally substituted aryl group; The compound or a salt thereof according to the above-mentioned [1].
• X is an optionally substituted C 6-14 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
• 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 aryl group; The compound or a salt thereof according to the above-mentioned [1] or [2].
• 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; The compound or salt thereof according to any one of the above [1] to [3].
• 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; The compound or salt thereof according to any one of the above [1] to [4].
• the "optionally substituted saturated hydrocarbon ring group" in X is an "optionally substituted C 3-10 cycloalkyl group", The compound or a salt thereof according to any one of the above [3] to [5].
• X is an optionally substituted phenyl group or an optionally substituted C 3-10 cycloalkyl group. The compound or salt thereof according to any one of the above [1] to [6].
• Z is a hydrogen atom, a hydroxyl group, NH2 , or NHR3 (In the formula, R 3 represents an optionally substituted C 1-6 alkyl group or an optionally substituted 3- to 8-membered saturated ring group.) That is, The compound or salt thereof according to any one of the above [1] to [7].
• R 1 is a hydrogen atom or a C 1-6 alkyl group
• R 2 is a hydrogen atom or a C 1-6 alkyl group
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group, or a C 3-10 cycloalkyl group optionally substituted by 1 to 3 C 1-6 alkyl groups optionally substituted by 1 to 3 halogen atoms
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups, or a phenyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups
• Z is a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (Wherein, R3 is (i) a hydroxy group, a C alkoxy group, (mon
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups; The compound or salt thereof according to any one of the above [1] to [9].
• R 1 is a C 1-6 alkyl group, and R2 is a hydrogen atom; The compound or salt thereof according to any one of the above [1] to [10].
• Z is a hydrogen atom, a hydroxyl group, NH2 , or NHR3 (Wherein, R3 is (i) a hydroxy group, a C alkoxy group, (mono- or di-C 1-6 alkyl)amino group, C 3-10 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, a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted by a C 1-6 alkoxy-carbonyl group, A C alkyl -carbonylamino group, a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a (mono- or di-C 1-6 alkylamino)carbonyl group and a C 1-6 alkyl-sulfonyl group, or (ii) (a) a)
• Z is a hydroxyl group or NHR 3 (Wherein, R3 is (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) a C 1-6 alkyl group, C 1-6 alkoxy-carbonyl group, and oxo group, which may be substituted by 1 to 3 substituents selected from a 3- to 8-membered nitrogen-containing saturated heterocyclic group. That is, The compound or a salt thereof according to any one of the above [1] to [12].
• R 1 is a C 1-6 alkyl group
• R2 is a hydrogen atom
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups
• Z is a hydroxyl group or NHR 3
• R3 represents a pyrrolidinyl group optionally substituted with 1 to 3 substituents selected from a C1-6 alkyl group and an oxo group.
• [17] A medicine comprising the compound or a salt thereof according to any one of the above [1] to [16] as an active ingredient.
• a method for preventing and/or treating an endocrine disease, a metabolic disease, a cardiovascular disease, a central nervous system disease, an eye disease, and/or an infectious disease 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.
• the compound or salt thereof according to any one of the above-mentioned [1] to [16] which is used for the prevention and/or treatment of an endocrine disease, a metabolic disease, a cardiovascular disease, a central nervous system disease, an eye disease, and/or an infectious disease.
• the present invention provides, as one embodiment thereof, a heterocyclic compound or a salt thereof that has antagonist activity against MC2R and is useful for the prevention or treatment of conditions, diseases, or disorders that respond to MC2R antagonism, such as endocrine 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), eye diseases (e.g., cataracts, glaucoma), and infectious diseases.
• endocrine diseases e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome
• R 1 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group
• R 2 represents a hydrogen atom or an optionally substituted C 1-6 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
• Z represents a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (In the formula, R3 represents an optionally substituted C1-6 alkyl group or an optionally substituted saturated ring group.)
• a salt thereof is provided.
• each group of the above compound (I) will be described below. Note that, although each group (e.g., “C 1-6 alkyl group”) will be described below, even if the group constitutes a part of another group (e.g., "C 1-6 alkyl -carbonyloxy group”), the description of each group can be referred to for the corresponding part unless otherwise specified.
• C ab e.g., C 1-6
• C a -C b e.g., C 1 -C 6
• halogen atoms include fluorine, chlorine, bromine, and iodine.
• examples of the "C 1-6 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.
• examples of the "C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
• an "aryl group” refers to a monocyclic or polycyclic unsaturated hydrocarbon group, and examples thereof include C 6-14 aryl groups. Specific examples thereof include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. Of these, C 6-10 aryl groups are preferred.
• examples of the "saturated hydrocarbon ring group” include a monocyclic or bicyclic C 3-10 cycloalkyl group. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, decahydronaphthyl and the like. Of these, a C 3-8 cycloalkyl group is preferable, and a C 3-6 cycloalkyl group is more preferable.
• heterocyclic group examples include (i) aromatic heterocyclic groups and (ii) non-aromatic heterocyclic groups, each of which contains, in addition to carbon atoms, one to four heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms.
• aromatic heterocyclic group examples 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.
• aromatic heterocyclic group examples 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, thieno
• non-aromatic heterocyclic group examples 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.
• non-aromatic heterocyclic group examples include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydroiso
• 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]thieny
• saturated heterocyclic group refers to the above-mentioned “heterocyclic groups” that do not contain unsaturated bonds.
• heterocyclic group or “saturated heterocyclic group” is specified as “nitrogen-containing” or “oxygen-containing”, it 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.
• examples of the "saturated ring group” include those described above as the “saturated hydrocarbon ring group” and the “saturated heterocyclic group”.
• a 3- to 8-membered monocyclic group is preferable, and a "C 3-8 cycloalkyl group” and a “3- to 8-membered monocyclic saturated heterocyclic group” are more preferable, and among them, a "C 3-6 cycloalkyl group” and a "3- to 8-membered monocyclic saturated heterocyclic group containing nitrogen or oxygen as a ring-constituting atom" are even more preferable.
• examples of the "substituent” in the “optionally substituted group or ring” in the definition of compound (I) such as the “optionally substituted C 1-6 alkyl group” include substituents selected from the following [Substituent group A].
• the "substituent” may be present in 1 to 5 (preferably 1 to 3) substitutable positions, and when the number of substituents is 2 or more, the respective substituents may be the same or different.
• the explanation should be followed.
• [Substituent Group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1 -C 6 alkoxy group (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 6 alkyl-carbonyloxy groups (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
• 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 14 aryl-carbonyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl), (18) C 1 -C 6 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), (19) a carbamoyl group, (20) an amino group, (21) mono- or di-C 1 -C 6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino,
• R 1 is present at a substitutable position in the ring to which it is attached and is as defined above, but is preferably a hydrogen atom or a C 1-6 alkyl group, more preferably a C 1-6 alkyl group.
• R 2 is as defined above, but is preferably a hydrogen atom or a C 1-6 alkyl group, and more preferably a hydrogen atom.
• X is as defined above, (1) an optionally substituted (preferably, an aryl group optionally substituted with 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and 3) a cyano group; an optionally substituted nitrogen-containing aromatic heterocyclic group (preferably optionally substituted with 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and 3) a cyano group, or an optionally substituted saturated hydrocarbon ring group (preferably optionally substituted by 1 to 3 C 1-6 alkyl groups optionally substituted by 1 to 3 halogen atoms);
• (2) a C 6-14 aryl group which may be substituted preferably, optionally substituted with 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group which may be substituted with 1 to
• Y is present at a substitutable position on the ring to which it is attached and is as defined above, but (1) a nitrogen-containing aromatic heterocyclic group which may be substituted (preferably, which may be substituted with 1 to 3 C 1-6 alkoxy groups), or an optionally substituted (preferably optionally substituted with 1 to 3 C 1-6 alkoxy groups) aryl group; In this case, (2) an optionally substituted (preferably optionally substituted by 1 to 3 C 1-6 alkoxy groups) 5- to 14-membered (preferably 5- to 6-membered) nitrogen-containing aromatic heterocyclic group, or an optionally substituted C 6-14 aryl group (preferably optionally substituted by 1 to 3 C 1-6 alkoxy groups); It is more preferable if (3) a pyridyl group which may be substituted (preferably, which may be substituted with 1 to 3 C alkoxy groups), or a phenyl group which may be substituted (preferably, a phenyl group which may be substituted by 1 to 3 C 1-6 alkoxy groups
• Z is as defined above, (1) Z is a hydrogen atom, a hydroxyl group, NH2 , or NHR3 (wherein R 3 represents an optionally substituted C 1-6 alkyl group or an optionally substituted 3- to 8-membered saturated ring group).
• R3 is (i) a hydroxy group, a C alkoxy group, (mono- or di-C 1-6 alkyl)amino group, C 3-10 cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by a C 1-6 alkoxy-carbonyl group, A C alkyl -carbonylamino group, a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a (mono- or di-C 1-6 alkylamino)carbonyl group, and a C 1-6 alkyl-sulfonyl group, or (ii) a C 1-6 alkyl group; a 3- to 8-membered saturated ring group optionally substituted by 1 to 3 substituents selected
• R3 is (i) a hydroxy group, a C alkoxy group, (mono- or di-C 1-6 alkyl)amino group, C 3-10 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, a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted by a C 1-6 alkoxy-carbonyl group, A C alkyl -carbonylamino group, a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a (mono- or di-C 1-6 alkylamino)carbonyl group, and a C 1-6 alkyl - sulfonyl group, or (ii) (a
• R3 is (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) a C 1-6 alkyl group, C 1-6 alkoxy-carbonyl group, and oxo group, which may be substituted by 1 to 3 substituents selected from a 3- to 8-membered nitrogen-containing saturated heterocyclic group. It is particularly preferred if
• Suitable compounds (I) or salts thereof include the following:
• R 1 is a hydrogen atom or a C 1-6 alkyl group
• R 2 is a hydrogen atom or a C 1-6 alkyl group
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group
• a pyridyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group, or a C 3-10 cycloalkyl group optionally substituted by 1 to 3 C 1-6 alkyl groups optionally substituted by 1 to 3 halogen atoms
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups, or a phenyl group
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group, or a C 3-10 cycloalkyl group optionally substituted by 1 to 3 C 1-6 alkyl groups optionally substituted by 1 to 3 halogen atoms;
• substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group, or a C 3-10 cycloalkyl group optionally substituted by 1 to 3 C 1-6 alkyl groups optionally substituted by 1 to 3 halogen atoms;
• R 1 is a hydrogen atom or a C 1-6 alkyl group
• R 2 is a hydrogen atom or a C 1-6 alkyl group
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups
• Z is a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (Wherein, R3 is (i) a hydroxy group, a C alkoxy group, (mono- or di-C 1-6 alkyl)amino group, C 3-10 cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, a 3- to 8-membered monocyclic non-aromatic heterocycl
• R 1 is a hydrogen atom or a C 1-6 alkyl group
• R 2 is a hydrogen atom or a C 1-6 alkyl group
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups
• Z is a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (Wherein, R3 is (i) a hydroxy group, a C alkoxy group, (mono- or di-C 1-6 alkyl)amino group, C 3-10 cycloalkyl group, 5- to 6-membered monocycl
• [Compound A-5] Z is a hydroxyl group or NHR 3 (Wherein, R3 is (a) a 3- to 8-membered monocyclic oxygen-containing saturated heterocyclic group, or (b) a C 1-6 alkyl group, C 1-6 alkoxy-carbonyl group, and oxo group, which may be substituted by 1 to 3 substituents selected from a 3- to 8-membered nitrogen-containing saturated heterocyclic group. That is, The above-mentioned [Compound A-1] to [Compound A-4] or a salt thereof.
• R 1 is a C 1-6 alkyl group
• R2 is a hydrogen atom
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from 1) a halogen atom, 2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and 3) a cyano group
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups
• Z is a hydroxyl group or NHR 3
• R3 represents a pyrrolidinyl group optionally substituted with 1 to 3 substituents selected from a C1-6 alkyl group and an oxo group.
• R 1 is a hydrogen atom or a C 1-6 alkyl group
• R 2 is a hydrogen atom or a C 1-6 alkyl group
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and a cyano group, or a C 3-10 cycloalkyl group optionally substituted by 1 to 3 of a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups, or a phenyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups
• Z is a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (Wherein, R3 is (i) a hydroxy group, a C alkoxy group, (mono
• R 1 is a C 1-6 alkyl group
• R2 is a hydrogen atom
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and a cyano group
• Y is a pyridyl group optionally substituted by 1 to 3 C alkoxy groups
• Z is a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (Wherein, R3 is (i) a hydroxy group, a C alkoxy group, (mono- or di-C 1-6 alkyl)amino group, C 3-10 cycloalkyl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by a C 1-6 alkoxy-carbonyl group, A C al
• Z is a hydrogen atom, a hydroxyl group, NH 2 , or NHR 3 (Wherein, R3 is (i) a hydroxy group, a C alkoxy group, (mono- or di-C 1-6 alkyl)amino group, C 3-10 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, a 3- to 8-membered monocyclic nitrogen-containing non-aromatic heterocyclic group optionally substituted by a C 1-6 alkoxy-carbonyl group, A C alkyl -carbonylamino group, a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a (mono- or di-C 1-6 alkylamino)carbonyl group, and a C 1-6 alkyl - sulfonyl group, or (ii)
• [Compound B-4] Z is NHR 3 (Wherein, R3 is C 1-6 alkyl group, C 1-6 alkoxy-carbonyl group, and oxo group, which may be substituted by 1 to 3 substituents selected from a 3- to 8-membered monocyclic nitrogen-containing saturated heterocyclic group. That is, The above-mentioned [Compound B-3] or a salt thereof.
• R 1 is a C 1-6 alkyl group
• R2 is a hydrogen atom
• X is a phenyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and a cyano group
• Y is a pyridyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups
• Z is NHR 3 (wherein R 3 represents a pyrrolidinyl group optionally substituted by 1 to 3 substituents selected from a C 1-6 alkyl group and an oxo group).
• Compound (I) can be used in either the free form or the form of its salt (preferably, its medicamentously acceptable salt).
• a person skilled in the art can carry out the present invention by appropriately selecting either form based on the characteristics of each compound (I) used.
• pharma- ceutically acceptable salts include 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, etc., and 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.
• the raw materials and reagents used in each step of the manufacturing method described below, 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.
• 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, if the compound obtained in each step is a salt, it can be converted into a free form or another type of desired salt by a method known per se.
• the compounds obtained in each step can be used in the next reaction either as the reaction solution or as a crude product, or can be isolated and/or purified from the reaction mixture by conventional separation methods 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.
• the raw materials and reagent compounds for each process are commercially available, the commercially available products can be used as is.
• the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 4 days, preferably 10 minutes to 8 hours.
• the reaction temperature may vary depending on the reagents and solvents used, but is usually ⁇ 78° C. to 300° C., preferably ⁇ 78° C. to 150° C., unless otherwise specified.
• the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.
• a Microwave synthesis apparatus such as Initiator manufactured by Biotage may be used.
• the reaction temperature may vary depending on the reagents and solvent used, but 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, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.
• reagent In the reactions of each step, unless otherwise specified, 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents of reagent are used relative to the substrate. When a reagent is used as a catalyst, 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents of reagent are used relative to the substrate. When a reagent also serves as a reaction solvent, the reagent is used in the amount of the solvent.
• the reactions in each step are carried out without a solvent or by dissolving or suspending the components in a suitable solvent.
• 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, and the like
• Aromatic hydrocarbons chlorobenzene, toluene, xylene, etc.
• Saturated hydrocarbons cyclohexane, hexane, heptane, etc.
• Amides N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and the like
• Halogenated hydrocarbons dichloromethane, dichloroethane, carbon tetrachloride, etc.
• Nitriles Nitriles:
• Inorganic bases sodium hydroxide, potassium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate, 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, and the like;
• Metal alkoxides sodium ethoxide, potassium tert-butoxide, N-methylimidazole, and the like;
• Alkali metal hydrides sodium hydride, etc.
• Metal amides sodium amide, lithium diisopropylamide, lithium
• 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 ferric chloride, and the like.
• the reagents used include diphenylphosphoryl azide and organic bases. Ethyl chloroformate, bases, sodium azide, etc. can also be used as reagents.
• reducing agents used in reduction reactions 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; and triethylsilane.
• a catalyst such as palladium-carbon or Lindlar catalyst can be used.
• azodicarboxylates e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.
• DEAD diethyl azodicarboxylate
• DIAD diisopropyl azodicarboxylate
• triphenylphosphine or tributylphosphine are used as reagents.
• the protection or deprotection reaction of the functional group is carried out according to a method known per se, for example, a 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 a method described in the Examples.
• Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate.
• Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane.
• Examples of the protecting group for the carbonyl group of a ketone 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 the carboxyl-protecting group 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 thiol-protecting group 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 an amino group or an aromatic heterocycle such as imidazole, pyrrole, or indole include carbamate-type protecting groups such as benzyl carbamate and tert-butyl carbamate; 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, a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), a reduction method (e.g., under a hydrogen atmosphere, palladium/carbon), an oxidation method (e.g., ammonium cerium(IV) nitrate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone), etc.
• a method known per se for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride
• an alkyl ester compound When an alkyl ester compound is converted to a carboxylic acid compound, it can be carried out using a strong base (sodium hydroxide, potassium trimethylsilanolate), a hydrogen-palladium catalyst, or a zero-valent palladium catalyst.
• a strong base sodium hydroxide, potassium trimethylsilanolate
• a hydrogen-palladium catalyst or a zero-valent palladium catalyst.
• a nucleophile e.g., amines, imidazole
• a base e.g., organic bases, inorganic bases
• examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), 1,1'-bis(diphenylphosphino)ferrocene palladium (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(triphenyl
• oxidizing agents 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
• peracids such as m-ch
• the oxidation reaction can also be carried out in an alcohol solvent in the presence of potassium hydroxide and iodine.
• the oxidation reaction can be carried out by Pinnic oxidation using sodium chlorite and sodium dihydrogen phosphate in the presence of 2-methyl-2-butene.
• examples of the reagents used include acyl halides such as acid chlorides and acid bromides; acid anhydrides; activated carboxylic acids such as activated esters; and the like.
• 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); diphenylphosphoryl 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,
• an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be further added to the reaction.
• HOBt 1-hydroxybenzotriazole
• HOSu N-hydroxysuccinimide
• DMAP dimethylaminopyridine
• examples of 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 carried out using isocyanates and amines.
• an acid or base is used as a reagent.
• formic acid or triethylsilane may be added to reductively trap the by-product tert-butyl cation.
• nucleophiles e.g., amines, alcohols, active methylene compounds adjacent to electron-withdrawing groups, etc.
• electrophiles e.g., alkyl halides, sulfonate esters
• bases e.g., organic bases, alkali metal hydrides, metal alkoxides, inorganic bases, etc.
• alkylation reactions in each step may be carried out by converting alcohols into sulfonate ester compounds using substituted sulfonyl chlorides (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.) and bases (e.g., organic bases, alkali metal hydrides, metal alkoxides, inorganic bases, etc.), followed by reaction with amines or amides in the molecule.
• substituted sulfonyl chlorides e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.
• bases e.g., organic bases, alkali metal hydrides, metal alkoxides, inorganic bases, etc.
• reaction conditions include conditions in an acid solvent such as acetic acid, conditions with the addition of a base (e.g., organic bases, metal alkoxides, inorganic bases), and conditions using only a solvent (N-methyl-2-pyrrolidone, etc.).
• an acid solvent such as acetic acid
• a base e.g., organic bases, metal alkoxides, inorganic bases
• N-methyl-2-pyrrolidone e.g., N-methyl-2-pyrrolidone, etc.
• Manufacturing method 1 Compound (I) can be produced by the following method.
• A represents a halogen atom (e.g., chlorine, iodine, bromine), and the other symbols are as defined above.]
• A represents a halogen atom (e.g., chlorine, iodine, bromine), and the other symbols are as defined above.]
• A represents a halogen atom (e.g., chlorine, iodine, bromine), and the other symbols are as defined above.]
• compound (I) in the process of producing compound (I) from the raw material compounds and/or production intermediates of compound (I), depending on the 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 of them, as desired.
• 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 of them, as desired.
• the raw material compounds and/or intermediates for the production of compound (I) may form salts. There is no particular limitation as long as the reaction is achieved. For example, salts similar to those which compound (I) and the like may form are used.
• the starting compound and/or the intermediate product of the compound (I) may have a configurational isomer (E,Z isomer), and when the configurational isomer (E,Z isomer) is produced, it can be isolated and purified by a conventional separation means such as extraction, recrystallization, distillation, chromatography, etc., to produce a pure compound.
• the corresponding pure isomer can be obtained by isomerizing the double bond with heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation, a strong base catalyst, or the like.
• the target compound When the target compound is obtained in a free state by the above reaction, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it may be converted into a free form or another salt according to a conventional method.
• Compound (I) thus obtained can be isolated and purified from the reaction solution by known means, such as transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.
• Compound (I), other reaction intermediates and starting compounds thereof thus obtained can be isolated and purified from the reaction mixture by a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), medium pressure preparative liquid chromatography (medium pressure preparative LC) or the like.
• Compound (I) may form a salt, which can be produced by a method known per se, for example, by adding an inorganic acid or an organic acid when compound (I) is a basic compound, or by adding an organic base or an inorganic base when compound (I) is an acidic compound.
• compound (I) is a solvate (e.g., a 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 non-solvate can be produced by desolvating the solvate by heating or drying, etc.
• compound (I) may have optical isomers, all of these individual optical isomers and mixtures thereof are naturally included in the scope of the present invention, and if desired, these isomers can be optically resolved or individually produced according to known means.
• compound (I) exists as configurational isomers, diastereomers, conformers, etc., they can be isolated by the above-mentioned separation and purification means, if desired.
• compound (I) is a racemate, it can be separated into S- and R-isomers by a conventional optical resolution means.
• the present invention includes both the isomers alone and mixtures thereof.
• compound (I) or a salt thereof Since compound (I) or a salt thereof has an excellent MC2R antagonistic action, it may be effective in preventing or treating diseases caused by ACTH signal abnormalities, 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.
• ACTH signal abnormalities such as endocrine system diseases (e.g., Cushing's disease, ectopic ACTH syndrome, ectopic CRH syndrome, congenital adrenal hyperplasia, polycystic ovary syndrome), metabolic diseases (
• compound (I) or a salt thereof may be useful as a prophylactic or therapeutic agent for endocrine 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 diseases (e.g., hypertension, arteriosclerosis), central nervous system diseases (e.g., depression, dementia, insomnia), eye diseases (e.g., cataracts, glaucoma), infectious diseases, and the like, based on the MC2R antagonist activity.
• endocrine 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,
• 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.
• treatment includes curing a disease (all pathological conditions or one or more pathological conditions), improving the disease, and inhibiting 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.
• Compound (I) or a salt thereof (the present compound) can be used in either a single form or a pharmaceutical composition containing the present compound as an active ingredient together with a medicamentously acceptable carrier.
• Such pharmaceutical compositions include, for example, 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), eye drops, etc.
• tablets
• pharmaceutical acceptable carrier refers to any of the various carriers commonly used in the field of pharmaceutical formulation technology.
• pharmaceutical acceptable carriers 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, calcium carboxymethylcellulose, sodium carboxymethylstarch, L-hydroxypropylcellulose, etc.).
• excipients e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.
• 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 stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic 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.
• formulation additives such as preservatives (e.g., paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, ⁇ -tocopherol, etc.), colorants, sweeteners, etc. may be added.
• preservatives e.g., paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.
• antioxidants e.g., sulfites, ascorbic acid, ⁇ -tocopherol, etc.
• colorants e.g., ascorbic acid, ⁇ -tocopherol, etc.
• the above pharmaceutical compositions may be prepared by adding the compound of the present invention to the total formulation in an amount of usually 0.01-99% (w/w), preferably 0.1-85% (w/w), depending on the dosage form, administration method, carrier, etc.
• the pharmaceutical compositions may be prepared by methods commonly used in the field of formulation technology depending on the form.
• the pharmaceutical compositions may be formed into sustained-release preparations containing the active ingredient.
• the compound of the present invention is expected to have low toxicity and few side effects, and 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).
• mammals e.g., humans, dogs, or cats, particularly humans.
• the compounds may be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, ophthalmically, intracerebrally, intrarectally, intravaginally, intraperitoneally, and into a lesion) alone or as a pharmaceutical composition.
• the dosage of the present compound varies depending on the subject, the route of administration, and the age and symptoms of the subject, but is not particularly limited.
• the dosage of the present compound is 1 to 250 mg per dose when administered orally, and 0.1 to 1000 mg per dose when administered parenterally.
• 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 a living 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 the prodrug 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 borated [e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated or succinilated, etc.].
• the amino group of compound (I)
• 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, methylamidized, etc.).
• 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, published by Hirokawa Shoten in 1990.
• Compound (I) may be any of a hydrate, a non-hydrate, a solvate, and a non-solvate.
• Compound (I) may be a compound labeled or substituted with an isotope (e.g., 2H , 3H , 11C , 14C , 18F , 35S , 125I , etc.), and the compound labeled or substituted with an isotope may be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and may be useful in fields such as medical diagnosis.
• PET tracer used in positron emission tomography
• Compound (I) also encompasses deuterium converters in which 1 H is converted to 2 H (D).
• Compound (I) also encompasses tautomers.
• Compound (I) may be a pharma- ceutically acceptable cocrystal or cocrystal salt.
• a cocrystal or cocrystal salt refers to a crystalline substance composed of two or more unique solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability).
• a cocrystal or cocrystal salt can be prepared according to a cocrystallization method known per se.
• the present compound may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
• the concomitant drug may be a compound or a salt thereof that has a preventive and/or therapeutic effect depending on the disease to be prevented or treated.
• concomitant drug examples 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 clinecerfont and tildacerfont, glucocorticoids such as hydrocortisone, prednisolone, and dexamethasone, and mineralocorticoids such as fludrocortisone.
• 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 clinecerfont and tildacerfont
• glucocorticoids such as hydrocortisone, prednisolone, and dexamet
• the drug to be used in combination with the present compound can be selected depending on the patient's symptoms (mild, severe, etc.); (3) By selecting a concomitant drug with a different mechanism of action from that of the present compound, the therapeutic effect can be sustained. (4) By using the present compound in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
• the combined use of the present compound and a concomitant drug will be referred to as a "concomitant drug of the present compound.”
• the administration time of the present compound and the combination drug is not limited, and the present compound or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the subject at the same time or at a time lag.
• the dosage of the combination drug may be in accordance with the dosage used in clinical practice, 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, and it is sufficient that the present compound and the combination drug are combined at the time of administration.
• Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the present compound and the combination drug, (2) administration of two preparations obtained by separately formulating the present compound and the combination drug by the same administration route, (3) administration of two preparations obtained by separately formulating the present compound and the combination drug by the same administration route with a time difference, (4) administration of two preparations obtained by separately formulating the present compound and the combination drug by the different administration route, (5) administration of two preparations obtained by separately formulating the present compound and the combination drug by the different administration route with a time difference (for example, administration of the present compound; administration of the combination drug in the order of administration, or administration in the reverse order) and the like.
• a time difference for example, administration of the present compound; administration of the combination drug in the order of administration, or administration in the reverse order
• the mixing ratio of the present compound to the concomitant drug in the concomitant drug of the present compound can be appropriately selected depending on the subject of administration, the administration route, the disease, and the like.
• the content of the present compound in a combination drug of the present compound varies depending on the form of 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 weight of the formulation.
• the content of the concomitant drug in the concomitant preparation of the present compound varies depending on the form of the preparation, 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 weight of the preparation.
• the content of additives such as carriers in the concomitant preparation of the present compound varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total weight of the preparation.
• the contents may be similar.
• room temperature generally refers to about 10° C. to about 35° C.
• Ratios shown in mixed solvents are by volume unless otherwise specified.
• % refers to weight % unless otherwise specified.
• TLC Thin Layer Chromatography
• Merck 60F254 was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the developing solvent.
• a UV detector was used for detection.
• silica gel column chromatography when NH is written, aminopropylsilane-bonded silica gel was used.
• molecular ion peaks ([M+H] + , [M ⁇ H] ⁇ , etc.) are observed, but for example, in the case of a compound having a tert-butoxycarbonyl group, a peak resulting from the elimination of a tert-butoxycarbonyl group or a 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 H 2 O may be observed as a fragment ion.
• a molecular ion peak or fragment ion peak of the free form is observed.
• 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 was synthesized according to the methods described in Example 1 and Example 2 or methods analogous thereto. MS: 519.0.
• 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 was synthesized according to the method described in Example 5 or a method analogous thereto. MS: 546.3.
• 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 was synthesized according to the method described in Example 6 or a method analogous thereto. MS: 632.5.
• 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 shown in Example 1 and Example 5 or methods similar thereto. MS: 560.3.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 619.3.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 673.3.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 680.3.
• 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 was synthesized according to the methods shown in Example 5 and Example 6 or methods similar thereto. MS: 647.2.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 631.3.
• 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 shown in Example 5 and Example 6 or methods analogous thereto. MS: 730.4.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 667.2.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 666.3.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 631.3.
• 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 shown in Example 5 and Example 6 or methods analogous thereto. MS: 772.4.
• 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 was synthesized according to the methods described in Example 5 and Example 6 or methods analogous thereto. MS: 669.3.
• 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 was synthesized according to the methods shown in Example 5 and Example 6 or methods similar thereto. MS: 644.3.
• 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 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 was treated with hydrochloric acid and concentrated to prepare the compound. MS: 630.3.
• 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 shown in Example 10 and Example 38 or methods analogous thereto.
• 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 was synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 589.2.
• 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) were reacted with 100 ml of tert-butyl 3-amino
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 672.3.
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 659.3.
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 647.3.
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 661.3.
• 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 was synthesized according to the methods described in Example 10 and Example 38 or methods analogous thereto. MS: 674.3.
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 660.3.
• 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
• the reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium thiosulfate solution and saturated aqueous ammonium chloride solution 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).
• HATU 64 mg, 1.22 mmol
• 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).
• 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.
• HATU (0.0322 g, 0.0847 mmol) was added at room temperature and stirred at room temperature for 18 h.
• 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).
• 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.
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 674.3.
• HATU (0.0387 g, 0.102 mmol) was added 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).
• 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.
• 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.
• 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.
• the reaction mixture was stirred at room temperature for 16 hours, and then saturated aqueous sodium bicarbonate 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 obtain a solid.
• the solid was crystallized from ethanol-water to obtain the title compound (1.44 g).
• 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 saline, 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).
• 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
• 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 layers were 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).
• 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) in N,N-dimethylformamide (20 mL) To the mixture were added HATU (1.00 g
• 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
• 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 saline, 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).
• reaction mixture was stirred at the same temperature for 10 minutes.
• (4R)-4-aminopyrrolidin-2-one (30 mg, 0.274 mmol) was added at 25°C and stirred at 25°C for 16 hours.
• the reaction mixture was added to ice water and the aqueous layer was extracted with ethyl acetate.
• the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
• the obtained residue was purified by CombiFlash column chromatography (ethyl acetate/hexane) and then by reverse phase preparative HPLC to give the title compound (35 mg).
• 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) in N,N-dimethylformamide (3 mL).
• the solid was recrystallized at 75°C from diisopropyl ether/ethyl acetate. 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).
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 663.25.
• 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 shown in Example 10, Example 38, and Example 60 or methods analogous thereto. MS: 616.4.
• 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
• 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 an ice-cold saturated aqueous solution of sodium bicarbonate. The reaction mixture was extracted with dichloromethane, the organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (methanol/dichloromethane) to obtain the title compound (650 mg).
• 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 obtained organic layer was washed with saturated saline, 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).
• 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
• 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 saline, dried over sodium sulfate, and concentrated. Dichloromethane (2 mL) and a 20% ether in pentane solution (20 mL) were added to the obtained residue and stirred. The obtained crystals were filtered and washed with pentane to obtain the title compound (155 mg). MS: 562.1.
• 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 shown in Example 10, Example 38, and Example 60 or methods analogous thereto. MS: 615.5.
• 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 obtained residue, and the mixture was stirred. The obtained crystals were filtered and washed with pentane to obtain the title compound (150 mg).
• 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
• the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was added to 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 residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (635 mg).
• reaction mixture was cooled to 0° C. and poured into an aqueous solution of sodium bicarbonate under ice-cooling.
• aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water and saturated saline, 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 give the title compound (400 mg).
• 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.
• 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 obtained residue, and the mixture was stirred. The obtained crystals were filtered and washed with pentane to obtain the title compound (150 mg). MS: 534.1.
• 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 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.
• 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 shown in Example 10 and Example 38 or methods analogous thereto. MS: 589.2.
• 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, 0.414 mmol), To a mixture of 1.0 mmol
• 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 obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was used in the next reaction without further purification.
• 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.
• 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 obtained organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained residue was used in the next reaction without further purification.
• 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.
• 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 frozen and stored in advance were thawed and suspended in a medium [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).
• a medium [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
• test compound prepared using the assay buffer was added and incubated for 20 minutes, followed by the addition of assay buffer containing ACTH (Human 1-24) (Peptide Institute) (final ACTH concentration, 3 pM) and incubation at room temperature for 30 minutes.
• ACTH Human 1-24
• final ACTH concentration, 3 pM final ACTH concentration, 3 pM
• the intracellular cAMP level was measured using a cAMP Gs HiRange kit HTRF (PerkinElmer).
• the inhibition rate (%) of the test compound against MC2R at 1 ⁇ M is shown in Tables 3-1 to 3-4.
• this compound was shown to have excellent MC2R inhibitory activity.
• Test Example 2 Inhibitory effect of ACTH-induced corticosterone secretion in mice
• ICR mice Charles River Japan, Inc.
• Mice were assigned to groups based on body weight, with 5 mice per group.
• the test compound was suspended in 0.5% (w/v) methylcellulose solution.
• ACTH (1-24) (A0948, LKT Laboratories, Inc.) was dissolved in physiological saline.
• the test compound (10 mg/kg) or vehicle was orally administered to the mice, and 1 hour later, ACTH solution (100 ⁇ g/kg) was subcutaneously administered.
• Plasma corticosterone concentration was measured using an ELISA kit (EC3001-1, Assaypro). Using the plasma corticosterone concentrations at each time point, the area under the blood concentration-time curve up to 2 hours after administration (AUC 0-2h ) was calculated. Table 4 shows the ratio of AUC 0-2h in the test compound group to AUC 0-2h in the vehicle-administered group.
• Example 1 (Capsule Production) 1) Compound of Example 1 30 mg 2) Fine powder 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.
• Formulation Example 2 (Tablet Production) 1) Compound of Example 1 30 g 2) Lactose 50g 3) Corn starch, 15 g 4) Calcium carboxymethylcellulose 44 g 5) Magnesium stearate 1 g 1000 tablets total 140 g The total amount of 1), 2), and 3) and 30 g of 4) are mixed with water, vacuum dried, and granulated. 14 g of 4) and 1 g of 5) are mixed with the granulated powder, and the mixture is compressed into tablets using a tablet press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
• the present invention provides a compound that has excellent MC2R antagonist activity and is useful in the pharmaceutical field as a preventive or therapeutic agent for diseases involving abnormal ACTH signals, 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., cataracts, glaucoma), or infectious diseases.
• 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,

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