Heterocyclic compounds as inhibitors of casein kinase 1δ and / or activin receptor-like kinase 5

Abstract

The object of the present invention is to provide a compound having CK1δ inhibitory activity and / or ALK5 inhibitory activity, etc. The above object can be solved by a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (wherein, 2-[4-(2,3-dihydro-5-benzofuranyl)-2-(1,1-dimethylethyl)-1H-imidazol-5-yl]-6-methylpyridine is excluded), [In the formula, R 1 ~R 10 each independently represents hydrogen, alkyl, cycloalkyl or halogen, wherein R 2 and R 3 , or R 4 and R 5 together with the two carbon atoms to which they are bonded form a 5-membered ring which may be substituted with alkyl and contains one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom].

Description

Technical Field

[0001] The present invention relates to a compound, an inhibitor of casein kinase 1δ and / or activin receptor-like kinase 5, a therapeutic agent for circadian rhythm sleep disorder, a therapeutic agent for Alzheimer's disease dementia, a therapeutic agent for corneal dystrophy, a therapeutic agent for cancer, and a therapeutic agent for male pattern hair loss. Background Art

[0002] The rhythm of sleep and wakefulness is regulated by the biological clock to a rhythm of about 1 day, and such a rhythm is called a circadian rhythm. The period of the human biological clock is about 25 hours, while the period of the earth for 1 day is 24 hours, with a deviation of about 1 hour. Usually, this 1-hour deviation is corrected by various stimuli (e.g., light, exercise, diet). However, if the state where this deviation cannot be corrected continues for a long time, it becomes impossible to sleep and wake up at the appropriate time. In addition, if the deviation is forcibly corrected, physical discomfort such as fatigue, loss of appetite, and headache may sometimes occur. The sleep disorder related to such a circadian rhythm is called circadian rhythm sleep disorder.

[0003] It is known that familial advanced sleep phase syndrome, which is a type of circadian rhythm sleep disorder, is a disease caused by a point mutation in the human casein kinase 1δ (CK1δ) gene (Non-Patent Document 1), suggesting that the human circadian rhythm changes under the regulation of CK1δ. In addition, it has been reported that the control of the circadian rhythm in rodents such as mice and non-rodents such as monkeys is also related to CK1δ (Non-Patent Document 2).

[0004] In addition, it has been reported many times in non-clinical studies that CK1δ inhibitors change the circadian rhythm in vitro and in vivo, and CK1δ inhibitors are highly expected as therapeutic agents for circadian rhythm sleep disorder.

[0005] In addition, the relationship between CK1δ and Alzheimer's disease dementia has also been reported (Patent Document 1). Specifically, it is considered that the cause of Alzheimer's disease dementia is the intracellular aggregation of hyperphosphorylated Tau protein (neurofibrillary tangles), suggesting that the phosphorylation of Tau protein is caused by CK1δ. Therefore, it is expected to treat Alzheimer's disease dementia by inhibiting CK1δ.

[0006] In addition, the relationships between corneal dystrophy (Patent Document 2), cancer (Non-Patent Document 3) and activin receptor-like kinase 5 (ALK5) have also been reported. It should be noted that ALK5 is sometimes also abbreviated as activin-like kinase, and its official name is activin receptor-like kinase. It has been reported that corneal dystrophy occurs due to cell death of corneal endothelial cells induced by endoplasmic reticulum stress mediated by degenerated proteins excessively accumulated in corneal tissues, and activation of ALK5 (TGF-β type I receptor) signaling causes endoplasmic reticulum stress. In addition, TGF-β is known to have a cell proliferation inhibitory effect, but it has been reported that in the late stage of carcinogenesis, TGF-β promotes the proliferation and metastasis of cancer cells. Therefore, it is expected to treat corneal dystrophy and cancer by inhibiting ALK5. It should be noted that as ALK5 inhibitors, compounds described in Patent Documents 3 and 4, etc. have been reported.

[0007] Prior Art Documents

[0008] Patent Documents

[0009] Patent Document 1: Japanese Patent Application Laid-Open No. 2014-503527

[0010] Patent Document 2: WO 2015 / 064768

[0011] Patent Document 3: Japanese Patent Application Laid-Open No. 2004-517068

[0012] Patent Document 4: WO 2001 / 062756

[0013] Non-Patent Document 1: Nature 2005, 434, 640-644

[0014] Non-Patent Document 2: Proc. Natl. Acad. Sci. USA, 2010, 107, 15240-15245

[0015] Non-Patent Document 3: Anticancer Res. 2007, 27, 4149-4158 Summary of the Invention

[0016] Problems to be Solved by the Invention

[0017] An object of the present invention is to provide a compound having CK1δ inhibitory activity and / or ALK5 inhibitory activity, and an inhibitor of CK1δ and / or ALK5, a therapeutic agent for circadian rhythm sleep disorder, a therapeutic agent for Alzheimer's type dementia, a therapeutic agent for corneal dystrophy, a therapeutic agent for cancer, and a therapeutic agent for male pattern hair loss, which contain the aforementioned compound.

[0018] Means for Solving the Problems

[0019] The inventors of the present application and others have conducted in-depth research and found that compounds with a specific structure have CK1δ inhibitory activity and / or ALK5 inhibitory activity, thus completing the present invention.

[0020] The present invention includes the following embodiments. [1]

[0022] A compound or a pharmaceutically acceptable salt thereof (excluding 2-[4-(2,3-dihydro-5-benzofuranyl)-2-(1,1-dimethylethyl)-1H-imidazol-5-yl]-6-methylpyridine), which is represented by the following formula (1):

[0023] [Chemical formula 1]

[0024]

[0025] In the formula,

[0026] R 1 ~R 10 each independently represents hydrogen, alkyl, cycloalkyl or halogen,

[0027] wherein, R 2 and R 3 , or R 4 and R 5 together with the two carbon atoms to which they are bonded form a 5-membered ring which may be substituted by alkyl and contains one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. [2]

[0029] The compound or a pharmaceutically acceptable salt thereof according to [1], wherein R 1 ~R 10 each independently represents hydrogen, alkyl, or halogen,

[0030] wherein, R 2 and R 3 , or R 4 and R 5 together with the two carbon atoms to which they are bonded form a 5-membered ring which may be substituted by alkyl and contains one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.

[0031] [2-1]

[0032] The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein, except for R 2 and R 3 that form the 5-membered ring, or R 4 and R 5 outside, R 1 ~R 5 is hydrogen.

[0033] [2-2]

[0034] The compound according to any one of [1] to [2-1], or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, alkyl or cycloalkyl.

[0035] [2-3]

[0036] The compound according to any one of [1] to [2-2], or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen or alkyl.

[0037] [2-4]

[0038] The compound according to any one of [1] to [2-3], or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

[0039] [2-5]

[0040] The compound according to any one of [1] to [2-4], or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen or alkyl.

[0041] [2-6]

[0042] The compound according to any one of [1] to [2-5], or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.

[0043] [2-7]

[0044] The compound according to any one of [1] to [2-6], or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or halogen.

[0045] [2-8]

[0046] The compound according to any one of [1] to [2-7], or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.

[0047] [2-9]

[0048] The compound according to any one of [1] to [2-8], or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.

[0049] [2-10]

[0050] The compound according to any one of [1] to [2-9], or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen. [3]

[0052] The compound according to any one of [1] to [2-10] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , or R 4 and R 5 together with the two carbon atoms to which they are attached form a tetrahydrofuran ring which may be substituted by alkyl.

[0053] [3-1]

[0054] The compound according to [3] or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the two carbon atoms to which they are attached form a tetrahydrofuran ring which may be substituted by alkyl. [4]

[0056] The compound according to [3] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the two carbon atoms to which they are attached form a tetrahydrofuran ring which may be substituted by alkyl. [5]

[0058] The compound according to [4] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the two carbon atoms to which they are attached form an unsubstituted tetrahydrofuran ring.

[0059] [5-1]

[0060] The compound according to any one of [3] to [5] or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , or R 4 and R 5 form a tetrahydrofuran ring having the following structure:

[0061] [Chemical formula 2]

[0062]

[0063] The carbon atom marked with an asterisk (*) represents the carbon atom of the benzene ring to which R 2 and R 3 , or R 4 and R 5 are attached. [6]

[0065] The compound according to [1] or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds.

[0066] [Chemical formula 3]

[0067] [7]

[0069] Casein kinase 1δ inhibitor, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof. [8]

[0071] Therapeutic agent for circadian rhythm sleep disorder, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof. [9]

[0073] The therapeutic agent according to [8], wherein the circadian rhythm sleep disorder is irregular sleep-wake rhythm disorder or sundown syndrome associated with Alzheimer's type dementia.

[10]

[0075] Therapeutic agent for Alzheimer's type dementia, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[11]

[0077] Activin receptor-like kinase 5 inhibitor, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[12]

[0079] Therapeutic agent for cancer, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[13]

[0081] The therapeutic agent according to

[12] , wherein the cancer is brain tumor, liver cancer, bladder cancer, myelodysplastic syndrome, colorectal cancer, or pancreatic cancer.

[14]

[0083] The therapeutic agent according to

[12] or

[13] , which is used in combination with a cancer therapeutic agent different from the therapeutic agent according to

[12] or

[13] and / or radiotherapy.

[15]

[0085] Therapeutic agent for corneal dystrophy, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[16]

[0087] Therapeutic agent for male pattern hair loss, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[17]

[0089] Inhibitor of casein kinase 1δ and activin receptor-like kinase 5, comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[0090] In addition, the present invention also includes the following embodiments.

[0091] [A1]

[0092] A method for inhibiting casein kinase 1δ and / or activin receptor-like kinase 5, the method comprising administering to a patient in need thereof an effective amount of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[0093] [A2]

[0094] A method for treating circadian rhythm sleep disorder, the method comprising administering to a patient in need thereof an effective amount of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[0095] [A3]

[0096] A method for treating Alzheimer's type dementia, the method comprising administering to a patient in need thereof an effective amount of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[0097] [A4]

[0098] A method for treating corneal dystrophy, the method comprising administering to a patient in need thereof an effective amount of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[0099] [A5]

[0100] A method for treating cancer, the method comprising administering to a patient in need thereof an effective amount of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[0101] [A6]

[0102] A method for treating male pattern hair loss, the method comprising administering to a patient in need thereof an effective amount of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.

[0103] [B1]

[0104] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for use in inhibiting casein kinase 1δ and / or activin receptor-like kinase 5.

[0105] [B2]

[0106] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for use in treating circadian rhythm sleep disorder.

[0107] [B3]

[0108] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, for the treatment of Alzheimer's dementia.

[0109] [B4]

[0110] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, for the treatment of corneal dystrophy.

[0111] [B5]

[0112] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, for the treatment of cancer.

[0113] [B6]

[0114] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, for the treatment of male pattern hair loss.

[0115] [C1]

[0116] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for inhibiting casein kinase 1δ and / or activin receptor-like kinase 5.

[0117] [C2]

[0118] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for the treatment of circadian rhythm sleep disorder.

[0119] [C3]

[0120] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for the treatment of Alzheimer's dementia.

[0121] [C4]

[0122] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for the treatment of corneal dystrophy.

[0123] [C5]

[0124] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for the treatment of cancer.

[0125] [C6]

[0126] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for the treatment of male pattern hair loss.

[0127] [D1]

[0128] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a casein kinase 1δ inhibitor and / or an activin receptor-like kinase 5 inhibitor.

[0129] [D2]

[0130] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for circadian rhythm sleep disorder.

[0131] [D3]

[0132] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for Alzheimer's type dementia.

[0133] [D4]

[0134] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for corneal dystrophy.

[0135] [D5]

[0136] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for cancer.

[0137] [D6]

[0138] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for male pattern hair loss.

[0139] Effects of the Invention

[0140] According to the present invention, it is possible to provide a compound having CK1δ inhibitory activity and / or ALK5 inhibitory activity, and an inhibitor of CK1δ and / or ALK5, a therapeutic agent for circadian rhythm sleep disorder, a therapeutic agent for Alzheimer's type dementia, a therapeutic agent for corneal dystrophy, a therapeutic agent for cancer, and a therapeutic agent for male pattern hair loss, which contain the aforementioned compound. Detailed Description of the Invention

[0141] Hereinafter, embodiments of the present invention will be specifically described, but the present invention is not limited thereto, and various modifications can be made without departing from the gist thereof.

[0142] <Compound>

[0143] One embodiment of the present invention relates to a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (wherein, 2-[4-(2,3-dihydro-5-benzofuranyl)-2-(1,1-dimethylethyl)-1H-imidazol-5-yl]-6-methylpyridine is excluded),

[0144] [Chemical Formula 4]

[0145]

[0146] [In the formula,

[0147] R 1 ~R 10 each independently represents hydrogen, an alkyl group, a cycloalkyl group or a halogen,

[0148] wherein, R 2 and R 3 , or R 4 and R 5 together with the two carbon atoms to which they are bonded form a 5-membered ring which may be substituted by an alkyl group and contains one heteroatom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. It should be noted that the tautomer formed by the movement of the proton and the double bond in the imidazole group of formula (1) is also included in formula (1).

[0149] In formula (1), R 2 and R 3 , or R 4 and R 5 preferably together with the two carbon atoms to which they are bonded form a 5-membered ring which may be substituted by an alkyl group and contains one oxygen atom (tetrahydrofuran ring).

[0150] In formula (1), R 2 and R 3 more preferably together with the two carbon atoms to which they are bonded form a tetrahydrofuran ring which may be substituted by an alkyl group.

[0151] In formula (1), R 4 and R 5 may together with the two carbon atoms to which they are bonded form a tetrahydrofuran ring which may be substituted by an alkyl group.

[0152] In formula (1), R 2 and R 3 are further preferably together with the two carbon atoms to which they are bonded form an unsubstituted tetrahydrofuran ring.

[0153] In formula (1), R 2 and R 3 , or R 4 and R 5 the formed tetrahydrofuran ring preferably has the following structure,

[0154] [Chemical Formula 5]

[0155]

[0156] [The carbon atom marked with an asterisk (*) represents R2 and R 3 , or R 4 and R 5 the carbon atoms of the benzene ring to which it is bonded].

[0157] In formula (1), except for R 2 and R 3 , or R 4 and R 5 outside, R 1 ~R 5 is preferably hydrogen.

[0158] In formula (1), R 6 is preferably hydrogen, alkyl or cycloalkyl, more preferably hydrogen or alkyl, and further preferably hydrogen.

[0159] In formula (1), R 7 is preferably hydrogen or alkyl, more preferably hydrogen.

[0160] In formula (1), R 8 is preferably hydrogen or halogen, more preferably hydrogen.

[0161] In formula (1), R 9 and R 10 are preferably hydrogen.

[0162] In this specification, the alkyl is preferably an alkyl having 1 to 6 carbon atoms, more preferably an alkyl having 1 to 3 carbon atoms, and further preferably methyl. The alkyl includes linear alkyls and branched alkyls.

[0163] In this specification, the cycloalkyl is preferably a cycloalkyl having 3 to 6 carbon atoms, more preferably a cycloalkyl having 3 to 5 carbon atoms.

[0164] In this specification, the halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine.

[0165] The compound represented by formula (1) is not particularly limited, and preferably the following compounds.

[0166] [Chemical formula 6]

[0167]

[0168] The pharmaceutically acceptable salts of the compound represented by formula (1) are not particularly limited as long as they can be used as pharmaceuticals. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide, etc.; and organic acid salts such as fumarate, maleate, malate, tartrate, succinate, citrate, mesylate, p-toluenesulfonate, acetate, lactate, palmitate, etc. can be cited.

[0169] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof may form a solvate such as a hydrate. In the present specification, the solvate is included in the compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0170] <Kinase inhibitor>

[0171] One embodiment of the present invention relates to an inhibitor of CK1δ and / or ALK5, which comprises the above compound or a pharmaceutically acceptable salt thereof.

[0172] (Casein kinase 1δ inhibitor)

[0173] One embodiment of the present invention relates to a CK1δ inhibitor. For the existing PF-670462 as a CK1δ inhibitor, the concentration for inhibiting CK1δ is close to the concentration for inhibiting p38α, so side effects may occur. For the CK1δ inhibitor of this embodiment, the CK1δ inhibition concentration is sufficiently different from the p38α inhibition concentration, and it can selectively inhibit CK1δ.

[0174] Specifically, the p38α inhibition concentration (IC 50 ) / CK1δ inhibition concentration (IC 50 ) is preferably 10 or more, more preferably 20 or more, further preferably 40 or more, still more preferably 80 or more, and particularly preferably 150 or more. The upper limit of the p38α inhibition concentration (IC 50 ) / CK1δ inhibition concentration (IC 50 ) is not particularly limited, and for example, it can be set to 10,000, 1,000, 500, etc. The p38α inhibition concentration and the CK1δ inhibition concentration can be measured by the method described in Test Example 1 below.

[0175] The CK1δ inhibition concentration (IC 50 ) of the CK1δ inhibitor of this embodiment is preferably 200 nM or less, more preferably 160 nM or less, further preferably 120 nM or less, still more preferably 80 nM or less, and particularly preferably 60 nM or less. The lower limit of the CK1δ inhibition concentration (IC 50 ) is not particularly limited, and for example, it can be set to 0.1 nM, 1 nM, 10 nM, etc.

[0176] By using the CK1δ inhibitor of this embodiment, diseases related to CK1δ can be treated.

[0177] (Activin receptor-like kinase 5 inhibitor)

[0178] One embodiment of the present invention relates to an ALK5 inhibitor. The ALK5 inhibition concentration (IC 50)Preferably, it is 400 nM or lower, more preferably 300 nM or lower, still more preferably 200 nM or lower, even more preferably 100 nM or lower, and particularly preferably 50 nM or lower. The ALK5 inhibitory concentration (IC 50 ) has no particular limitation on the lower limit, and can be set to, for example, 0.1 nM, 1 nM, 10 nM, etc. The ALK5 inhibitory concentration can be measured by the method described in Test Example 3 below.

[0179] By using the ALK5 inhibitor of the present embodiment, ALK5-related diseases can be treated.

[0180] <Therapeutic agent>

[0181] One embodiment of the present invention relates to a therapeutic agent for circadian rhythm sleep disorder, Alzheimer's type dementia, corneal dystrophy, cancer and / or male pattern hair loss, which contains the above compound or a pharmaceutically acceptable salt thereof.

[0182] As the circadian rhythm sleep disorder, for example, there can be mentioned sleep disorders caused by a deviation of the biological clock within a short period due to artificial or social reasons, and endogenous sleep disorders caused by a malfunction of the function of synchronizing the biological clock with the external cycle. More specifically, for example, there can be mentioned jet lag syndrome, shift work sleep disorder, advanced sleep phase syndrome, delayed sleep phase syndrome, non-24-hour sleep-wake syndrome, irregular sleep-wake rhythm disorder, circadian rhythm disorder associated with Alzheimer's type dementia (for example, sundown syndrome associated with Alzheimer's type dementia), and circadian rhythm disorder associated with Parkinson's disease. Although there is no particular limitation, it is preferably used for the treatment of irregular sleep-wake rhythm disorder or sundown syndrome associated with Alzheimer's type dementia.

[0183] As the Alzheimer's type dementia, for example, there can be mentioned Alzheimer's type dementia accompanied by the accumulation of β-amyloid in the brain, and Alzheimer's type dementia accompanied by the accumulation of Tau.

[0184] As the corneal dystrophy, for example, there can be mentioned epithelial, stromal and endothelial corneal dystrophies. Although there is no particular limitation, it is preferably used for the treatment of endothelial Fuchs corneal dystrophy.

[0185] As the cancer, for example, there can be mentioned brain tumors (for example, glioma and glioblastoma multiforme), liver cancer (for example, hepatocellular carcinoma), bladder cancer, myelodysplastic syndrome, colorectal cancer, and pancreatic cancer. Although there is no particular limitation, it is preferably used for the treatment of brain tumors or liver cancer.

[0186] In the case of treating cancer, a further anti-cancer drug (hereinafter referred to as "the second anti-cancer drug") and / or radiotherapy can be used in combination. As the second anti-cancer drug, existing anti-cancer drugs can be used. There is no particular limitation on the second anti-cancer drug, and examples thereof include immune checkpoint inhibitors, cancer vaccine therapies, cancer antibody drugs, gene therapy drugs, and other anti-tumor drugs (for example, temozolomide, Gemcitabine, pomalidomide, and paclitaxel). The second anti-cancer drug can be one kind or two or more kinds. The anti-cancer drug of the present embodiment and the second anti-cancer drug can be provided as a compound preparation or separately.

[0187] The therapeutic agent of the present embodiment can be administered orally or parenterally. As dosage forms for oral administration, for example, tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions can be mentioned. As dosage forms for parenteral administration, for example, injections, infusions, drip infusions, eye drops, and suppositories can be mentioned.

[0188] If necessary, the therapeutic agent of the present embodiment can contain excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, fragrances, flavoring agents, stabilizers, thickeners, etc.

[0189] The dosage of the therapeutic agent of the present embodiment varies depending on the patient's condition, body weight, type of compound, type of disease, administration route, etc., and an appropriate amount can be determined by a doctor. As an example, in the case of treating circadian rhythm sleep disorder, for an adult (body weight of about 60 kg), 0.1 to 3000 mg can be administered orally, and 0.01 to 1000 mg can be administered parenterally. In the case of treating Alzheimer's disease dementia, for an adult (body weight of about 60 kg), 0.1 to 3000 mg can be administered orally, and 0.01 to 1000 mg can be administered parenterally. In the case of treating corneal endothelial dystrophy, for an adult (body weight of about 60 kg), 0.1 to 3000 mg can be administered orally, and 0.001 to 1000 mg can be administered parenterally. In the case of treating cancer, for an adult (body weight of about 60 kg), 0.1 to 3000 mg can be administered orally, and 0.01 to 1000 mg can be administered parenterally.

[0190] <Method for manufacturing the compound>

[0191] The above-mentioned compound or its pharmaceutically acceptable salt can be appropriately synthesized by known methods. As an example of the synthesis method, the following Route A can be mentioned.

[0192] [Chemical Formula 7]

[0193]

[0194] [R 1 ~R 10 Same as above.]

[0195] (Step A1)

[0196] In Step A1, in the presence of a condensing agent, compound (A1) is reacted with N,O-dimethylhydroxylamine to obtain compound (A2). Compound (A1) can be a commercially available product or can be produced according to known methods.

[0197] The condensing agent used in Step A1 is not particularly limited. For example, 1,1'-carbonyldiimidazole (CDI), water-soluble carbodiimide (WSC), 1-hydroxybenzotriazole (HOBT), 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), 2-chloro-1-methylpyridinium iodide, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc. can be mentioned.

[0198] (Step A2)

[0199] In Step A2, compound (A3) is reacted with an organolithium compound and then with compound (A2) to obtain compound (A4). Compound (A3) can be a commercially available product or can be produced according to known methods.

[0200] The organolithium compound used in Step A2 is not particularly limited. For example, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, etc. can be mentioned.

[0201] (Step A3)

[0202] In Step A3, in the presence of acetic acid, compound (A4) is reacted with sodium nitrite to obtain compound (A5).

[0203] (Step A4)

[0204] In Step A4, in the presence of ammonium acetate and acetic acid, compound (A5) is reacted with compound (A6) to obtain compound (A7).

[0205] (Step A5)

[0206] In step A5, compound (A7) is reacted with triethyl phosphite to obtain compound (A8).

[0207] As another synthesis method of the above compound or its pharmaceutically acceptable salt, the following Route B can also be cited.

[0208] [Chemical Formula 8]

[0209]

[0210] [R 1 ~R 10 Same as above.]

[0211] (Step B1)

[0212] In step B1, compound (B1) is reacted with 4-methylbenzenesulfinic acid and formamide to obtain compound (B2). Compound (B1) can be a commercially available product or can be prepared according to a known method.

[0213] (Step B2)

[0214] In step B2, compound (B2) is reacted with phosphorus oxychloride to obtain compound (B3).

[0215] (Step B3)

[0216] In step B3, compound (B4) is reacted with ammonia and then with compound (B3) to obtain compound (B5). Compound (B4) can be a commercially available product or can be prepared according to a known method.

[0217] The synthesis method is not limited to the above Routes A and B. For example, it can be synthesized through other synthetic routes with reference to the following Preparation Examples.

[0218] Examples

[0219] Hereinafter, the present invention will be described in more detail using Examples, but the technical scope of the present invention is not limited thereto.

[0220] [Preparation Example 1-1]

[0221] N-Methoxy-N-methyl-1,3-dihydroisobenzofuran-5-carboxamide

[0222] [Chemical Formula 9]

[0223]

[0224] To a mixture of 1,1'-carbonyldiimidazole (16 g, 98 mmol) and N,N-dimethylformamide (DMF) (160 ml) at 0 °C was added 1,3-dihydroisobenzofuran-5-carboxylic acid (12 g, 76 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C, and at the same temperature, N,O-dimethylhydroxylamine hydrochloride (9.6 g, 98 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate-tetrahydrofuran (2:1) (400 ml × 3 times). The organic layer was washed successively with water (50 ml × 2 times) and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane = 1:1) to obtain the title compound (11 g).

[0225] 1 1H-NMR spectrum (CDCl3) δ (ppm): 3.37 (s, 3H), 3.56 (s, 3H), 5.14 (s, 4H), 7.25 - 7.29 (m, 1H), 7.56 (d, J = 1.10 Hz, 1H), 7.60 (dd, J = 7.68, 1.46 Hz, 1H)

[0226] [Production Example 1-2]

[0227] 1-(1,3-Dihydroisobenzofuran-5-yl)-2-(hydroxyimino)-2-(pyridin-2-yl)ethanone

[0228] [Chemical Formula 10]

[0229]

[0230] To a mixture of diisopropylamine (1.9 ml, 14 mmol) and tetrahydrofuran (THF) (50 ml) at -78 °C was added dropwise n-butyllithium (5.0 ml, 13 mmol). After stirring for 30 minutes at the same temperature, 2-picoline (1.5 ml, 15 mmol) was added dropwise at the same temperature. After the reaction mixture was stirred at 0 °C for 30 minutes, the reaction mixture was cooled to -78 °C, and a mixture of N-methoxy-N-methyl-1,3-dihydroisobenzofuran-5-carboxamide (2.5 g, 12 mmol) obtained in Production Example 1-1 and THF (10 ml) was added dropwise at the same temperature. The reaction mixture was gradually warmed to room temperature and stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction was carried out with ethyl acetate. After the organic layer was washed with saturated brine, it was dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. After the residue was purified by NH-silica column chromatography (gradient of ethyl acetate: heptane = 0:1 to 2:3), it was purified again under the same conditions to obtain crude 1-(1,3-dihydroisobenzofuran-5-yl)-2-(pyridin-2-yl)ethanone (600 mg).

[0231] To a mixture of crude 1-(1,3-dihydroisobenzofuran-5-yl)-2-(pyridin-2-yl)ethanone (1.5 g), THF (10 ml) and acetic acid (15 ml) at 0 °C was added dropwise a mixture of sodium nitrite (0.52 g, 7.6 mmol) and water (4 ml), and then, the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica column chromatography (gradient of heptane: ethyl acetate: methanol = 1:1:0 to 0:1:0, then 0:1:0 to 0:9:1) to obtain the labeled compound (1.3 g) in the form of a mixture of E-form and Z-form. The NMR data shown below are the data of the mixture of E-form and Z-form.

[0232] 1 1H-NMR spectrum (CDCl3) δ (ppm): 5.14 (s, 4H), 5.16 (s, 4H), 7.28 - 7.30 (m, 1H), 7.36 (d, J = 7.68 Hz, 1H), 7.36 (d, J = 7.68 Hz, 1H), 7.52 - 7.55 (m, 1H), 7.33 - 7.91 (m, 5H), 7.33 - 7.91 (m, 4H), 7.94 - 8.02 (m, 1H), 8.48 - 8.56 (m, 1H), 8.58 - 8.64 (m, 1H)

[0233] [Example 1]

[0234] 2-(4-(1,3-Dihydroisobenzofuran-5-yl)-1H-imidazol-5-yl)pyridine

[0235] [Chemical Formula 11]

[0236]

[0237] At room temperature, paraformaldehyde (50 mg, 0.56 mmol) was added to a mixture of 1-(1,3-dihydroisobenzofuran-5-yl)-2-(hydroxyimino)-2-(pyridin-2-yl)ethanone (300 mg, 1.1 mmol), ammonium acetate (520 mg, 6.7 mmol), and acetic acid (6 mL) obtained in Production Example 1-2. After stirring at the same temperature for 1 hour, the mixture was stirred at 100 °C for 15 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. At room temperature, triethyl phosphite (0.38 mL, 2.2 mmol) was added to a mixture of the residue (310 mg) and N-methylpyrrolidone (NMP) (7 mL), and the mixture was stirred at 120 °C for 3 hours. The reaction mixture was brought to room temperature, water and ethyl acetate were added, and then a saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate-tetrahydrofuran (2:1). The two organic layers were combined, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica column chromatography (ethyl acetate:methanol = 20:1) to obtain the title compound (44 mg).

[0238] 1 1H-NMR spectrum (CDCl3) δ (ppm): 5.15 (s, 2H), 5.18 (d, J = 1.46 Hz, 2H), 7.12 (ddd, J = 6.59, 4.76, 2.20 Hz, 1H), 7.29 (d, J = 8.05 Hz, 1H), 7.48 - 7.57 (m, 4H), 7.75 (s, 1H), 8.55 (d, J = 4.76 Hz, 1H), 10.39 (br.s., 1H)

[0239] [Example 2]

[0240] 2-(4-(1,3-Dihydroisobenzofuran-5-yl)-2-methyl-1H-imidazol-5-yl)pyridine

[0241] [Chemical Formula 12]

[0242]

[0243] At room temperature, acetaldehyde (13 mg, 0.27 mmol) was added to a mixture of 1-(1,3-dihydroisobenzofuran-5-yl)-2-(hydroxyimino)-2-(pyridin-2-yl)ethanone (61 mg, 0.22 mmol), ammonium acetate (110 mg, 1.4 mmol), and acetic acid (1.5 mL) obtained in Production Example 1-2. After stirring at the same temperature for 15 minutes, the mixture was stirred at 115 °C for 15 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Triethyl phosphite (0.38 mL, 2.2 mmol) was added to a mixture of the residue (67 mg) and NMP (1.5 mL) at room temperature, and the mixture was stirred at 120 °C for 6 hours. The reaction mixture was brought to room temperature, water and ethyl acetate were added, and then a saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate-tetrahydrofuran (2:1). The two organic layers were combined, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate:methanol = 40:1) to obtain the title compound (44 mg).

[0244] 1 1H-NMR spectrum (CDCl3) δ (ppm): 2.50 (s, 3H), 5.12 (s, 2H), 5.15 (d, J = 1.36 Hz, 2H), 7.04 - 7.09 (m, 1H), 7.22 - 7.28 (m, 1H), 7.43 - 7.54 (m, 4H), 8.50 (dt, J = 4.98, 1.36 Hz, 1H), 9.97 (brd, J = 3.17 Hz, 1H)

[0245] [Production Example 3-1]

[0246] N-((1,3-Dihydroisobenzofuran-5-yl)(tosyl)methyl)formamide

[0247] [Chemical Formula 13]

[0248]

[0249] To a mixture of 1,3-dihydroisobenzofuran-5-carbaldehyde (3.3 g, 22 mmol), 4-methylbenzenesulfinic acid (5.3 g, 34 mmol), formamide (2.2 ml, 56 mmol), acetonitrile (30 ml), and toluene (30 ml) at 0 °C was added trimethylchlorosilane (3.1 ml, 25 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, it was stirred at 50 °C for 8 hours and 20 minutes, and the reaction mixture was cooled to room temperature. The insoluble matter was removed by filtration, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane = 4:1) to obtain the titled compound (2.9 g).

[0250] 1 1H-NMR spectrum (CDCl3) δ (ppm): 2.38 - 2.43 (m, 3H), 5.01 (t, J = 5.47 Hz, 4H), 6.36 - 6.43 (m, 1H), 7.34 - 7.39 (m, 1H), 7.40 - 7.51 (m, 4H), 7.69 - 7.76 (m, 2H), 7.90 - 7.95 (m, 1H), 9.72 - 9.80 (m, 1H)

[0251] [Example 3]

[0252] 2-(4-(1,3-Dihydroisobenzofuran-5-yl)-1H-imidazol-5-yl)-5-fluoropyridine

[0253] [Chemical Formula 14]

[0254]

[0255] To a mixture of N-((1,3-dihydroisobenzofuran-5-yl)(tosyl)methyl)formamide (210 mg, 0.62 mmol) obtained in Production Example 3-1 and THF (2 ml) at room temperature was added phosphorus oxychloride (0.12 ml, 1.2 mmol), and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was cooled to 0 °C, and triethylamine (0.52 ml, 3.7 mmol) was added at the same temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture at 0 °C, and extraction was carried out with ethyl acetate. After washing the organic layer with saturated brine, the solvent was distilled off under reduced pressure. The residue was filtered through NH-silica gel column chromatography (ethyl acetate). The solvent was distilled off under reduced pressure to obtain crude 5-(isocyano(tosyl)methyl)-1,3-dihydroisobenzofuran (190 mg). 49 mg of the 190 mg was used for the subsequent reaction.

[0256] A mixture of 5-fluoro-2-pyridinecarboxaldehyde (19 mg, 0.16 mmol) and 28% aqueous ammonia solution (0.50 ml) was stirred at 50 °C for 1 hour, and then the solvent was distilled off under reduced pressure. To the residue at room temperature was added a mixture of crude 5-(isocyano(tosyl)methyl)-1,3-dihydroisobenzofuran (49 mg) and DMF (1 ml), and then potassium carbonate (54 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction was carried out with ethyl acetate. After washing the organic layer with saturated brine, the solvent was distilled off under reduced pressure. The residue was purified by LC-MS (a solvent system of acetonitrile-water containing 0.1% trifluoroacetic acid), and then purified by NH-silica column chromatography (ethyl acetate:methanol = 20:1) to obtain the title compound (1.2 mg).

[0257] 1 1H-NMR spectrum (CDCl3) δ (ppm): 5.13 (s, 2H), 5.16 (d, J = 1.36 Hz, 2H), 7.26 (br s, 1H), 7.28 (s, 1H), 7.49 (br s, 1H), 7.51 (br s, 2H), 7.73 (s, 1H), 8.39 (br d, J = 2.27 Hz, 1H), 9.98 - 10.35 (m, 1H)

[0258] [Example 4]

[0259] 2-(4-(1,3-Dihydroisobenzofuran-5-yl)-1H-imidazol-5-yl)-6-methylpyridine

[0260] [Chemical Formula 15]

[0261]

[0262] A mixture of 6-methyl-2-pyridinecarboxaldehyde (19 mg, 0.16 mmol) and 28% aqueous ammonia solution (0.50 ml) was stirred at 50 °C for 1 hour, and then the solvent was distilled off under reduced pressure. To the residue at room temperature was added a mixture of the crude 5-(isocyano(tosyl)methyl)-1,3-dihydroisobenzofuran (49 mg) obtained in Example 3 and DMF (1 ml), and then potassium carbonate (54 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and extraction was carried out with ethyl acetate. After washing the organic layer with saturated brine, the solvent was distilled off under reduced pressure. The residue was purified by LC-MS (a solvent system of acetonitrile-water containing 0.1% trifluoroacetic acid), and then purified by NH-silica column chromatography (ethyl acetate:methanol = 20:1) to obtain the title compound (2.0 mg).

[0263] 1 1H-NMR spectrum (CDCl3) δ (ppm): 2.54 (s, 3H), 5.13 (s, 2H), 5.15 (d, J = 1.36 Hz, 2H), 6.96 (d, J = 7.25 Hz, 1H), 7.26 - 7.33 (m, 2H), 7.37 - 7.43 (m, 1H), 7.51 - 7.55 (m, 2H), 7.72 (s, 1H), 10.22 - 10.57 (m, 1H)

[0264] [Production Example 5-1]

[0265] N-Methoxy-N-methyl-1,3-dihydroisobenzofuran-5-carboxamide

[0266] [Chemical Formula 16]

[0267]

[0268] To a mixture of 1,3-dihydroisobenzofuran-5-carboxylic acid (1.20 g, 7.31 mmol), N,O-dimethylhydroxylamine hydrochloride (1.42 g, 14.6 mmol), and dichloromethane (20 mL) at 0 °C, N,N-diisopropylethylamine (4.05 mL, 21.9 mmol) was slowly added, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, propylphosphonic anhydride (50% ethyl acetate solution, 9.20 mL, 30.6 mmol) was slowly added, and the mixture was stirred at room temperature for 16 hours. Ice water was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.90 g).

[0269] 1 1H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.48 (m, 2H), 7.38 - 7.36 (m, 1H), 5.02 (s, 4H), 3.53 (s, 3H), 3.25 (s, 3H).

[0270] [Production Example 5-2]

[0271] 1-(1,3-Dihydroisobenzofuran-5-yl)-2-(pyridin-2-yl)ethan-1-one

[0272] [Chemical Formula 17]

[0273]

[0274] Under an argon atmosphere, at -78 °C, lithium diisopropylamide (2 M solution in tetrahydrofuran, 2.51 mL, 5.02 mmol) was slowly added to a mixture of 2-methylpyridine (0.757 mL, 7.72 mmol) and tetrahydrofuran (8.0 mL), and the mixture was stirred at the same temperature for 30 minutes. A mixture of N-methoxy-N-methyl-1,3-dihydroisobenzofuran-5-carboxamide (800 mg, 3.86 mmol) and tetrahydrofuran (4 mL) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.60 g).

[0275] ESI-MS: m / z 240.10 [M+1]+

[0276] [Production Example 5-3]

[0277] 1-(1,3-Dihydroisobenzofuran-5-yl)-2-(hydroxyimino)-2-(pyridin-2-yl)ethan-1-one

[0278] [Chemical Formula 18]

[0279]

[0280] At 0 °C, sodium nitrite (260 mg, 3.76 mmol) with a small amount of water added was slowly added to a mixture of 1-(1,3-dihydroisobenzofuran-5-yl)-2-(pyridin-2-yl)ethan-1-one (600 mg, 2.51 mmol), tetrahydrofuran (10 mL), and acetic acid (10 mL), and the mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was distilled off under reduced pressure, saturated sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.50 g).

[0281] ESI-MS: m / z 266.91 [M-1]-

[0282] [Production Example 5-4]

[0283] 2-Cyclopropyl-4-(1,3-dihydroisobenzofuran-5-yl)-5-(pyridin-2-yl)-1H-imidazol-1-ol

[0284] [Chemical Formula 19]

[0285]

[0286] At 0 °C, ammonium acetate (460 mg, 5.96 mmol) and cyclopropanecarbaldehyde (209 mg, 2.98 mmol) were added to a mixture of 1-(1,3-dihydroisobenzofuran-5-yl)-2-(hydroxyimino)-2-(pyridin-2-yl)ethan-1-one (800 mg, 2.98 mmol) and acetonitrile (12 mL), and the mixture was stirred at room temperature for 10 minutes. Trifluoroacetic acid (34.0 mg, 0.298 mmol) was added to the reaction mixture, and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (0.20 g).

[0287] ESI-MS: m / z 319.13 [M+1]+

[0288] [Example 5]

[0289] 2-(2-Cyclopropyl-4-(1,3-dihydroisobenzofuran-5-yl)-1H-imidazol-5-yl)pyridine

[0290] [Chemical Formula 20]

[0291]

[0292] To a mixture of 2-cyclopropyl-4-(1,3-dihydroisobenzofuran-5-yl)-5-(pyridin-2-yl)-1H-imidazol-1-ol (200 mg, 0.626 mmol) and methanol (2 mL) at 0 °C was slowly added a titanium(III) chloride solution (12% hydrochloric acid solution, 2.0 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, saturated sodium hydrogen carbonate was added to the residue, and the mixture was washed and filtered through diatomaceous earth with 20% methanol / dichloromethane. The organic layer separated from the filtrate was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (XBridge Shield (19×250 mm) 10 μm, 5 mM ammonium acetate / water) to obtain the title compound (0.035 g).

[0293] ESI-MS: m / z 304.29 [M+1]+

[0294] 1 H NMR (400 MHz, DMSO-d6) δ 12.39, 12.13 (s, 1H), 8.57, 8.33 (d, 1H, J = 4.0 Hz), 7.76 - 7.15 (m, 6H), 5.01, 4,99 (s, 4H), 2.08 - 1.97 (m, 1H).

[0295] [Test Example 1]

[0296] Evaluation of CK1δ inhibitory effect and p38α inhibitory effect

[0297] 1. Preparation of test substance solution

[0298] Dissolve the test substance in dimethyl sulfoxide (DMSO), and then dilute it with DMSO to prepare a 100-fold concentrated solution of the test concentration. Further dilute this solution 25-fold with the assay buffer to obtain the test substance solution. For the positive control substance, prepare the positive control substance solution in the same manner.

[0299] 2. Preparation of kinase proteins

[0300] CK1δ: Use the substance that is fused with GST (61KDa) at the N-terminus of the enzyme active domain of human CK1δ (amino acid sequence positions 1 - 294 of accession number NP_001884.2), expressed in Escherichia coli, and purified using the glutathione agarose chromatography system.

[0301] p38α: Use the substance that is fused with GST (66KDa) at the N-terminus of the amino acid sequence positions 9 - 352 of accession number NP_620581.1 of human p38α, expressed in Escherichia coli, purified using the glutathione agarose chromatography system, activated with His-tagged MAP2K6, and then purified again using the glutathione agarose chromatography system.

[0302] 3. Reagents and test methods

[0303] Mix 5 μL of a 4-fold concentrated test substance solution prepared with the assay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH 7.5), 5 μL of a 4-fold concentrated substrate / ATP / metal solution, and 10 μL of a 2-fold concentrated kinase solution in the wells of a 384-well polypropylene culture plate, and react at room temperature for 1 hour. Add 70 μL of the termination buffer (QuickScout Screening Assist MSA; Carna Biosciences) to stop the reaction. Separate and quantify the substrate peptide and phosphorylated peptide in the reaction solution using the LabChip system (Perkin Elmer). The kinase reaction is evaluated using the product ratio (P / (P + S)) calculated from the peak height of the matrix peptide (S) and the peak height of the phosphorylated peptide (P).

[0304] 4. Reaction conditions

[0305] [Table 1]

[0306] Table 1

[0307]

[0308] 5. Data analysis

[0309] The average signal of the control wells containing all reaction components was set as 0% inhibition, and the average signal of the background wells (without added enzyme) was set as 100% inhibition. The inhibition rate was calculated from the average signal of each test well of the test substance. The IC 50 value was obtained by approximating the graph plotted from the test substance concentration and the inhibition rate to a four-parameter logistic curve using the non-linear least squares method. The results are shown in Table 2. The compounds of the examples exhibited good CK1δ inhibitory activity. In addition, a significant separation was observed between the CK1δ inhibitory concentration and the p38α inhibitory concentration.

[0310] [Table 2]

[0311] Table 2

[0312] <![CDATA[CK1δ(IC 50 , nM)]]> <![CDATA[p38a(IC 50 , nM)]]> Ratio (p38α / CK1δ) Example 1 21 4000 190 Example 2 68 ＞10000 ＞150 Example 3 48 4400 92 Example 4 110 5200 47

[0313] [Test Example 2]

[0314] Evaluation of ALK5 inhibition

[0315] 1. Preparation of test substance solution

[0316] A stock solution containing 0.1 mg / mL of BSA (bovine serum albumin) in 10% DMSO (compound concentration 10 mM) was prepared as the test substance solution.

[0317] 2. Kinase

[0318] ALK5: Human ALK5, GenBank ID = BC071181.

[0319] 3. Reagents, test methods and reaction conditions

[0320] The kinase assay was performed using the ADP-Glo TM assay kit from Promega according to the following assay reaction formula.

[0321] Component 1: 1 μL of diluted active protein kinase

[0322] Component 2: 1 μL of substrate

[0323] Component 3: 1 μL of kinase assay buffer

[0324] Component 4: 1 μL of compound (10 concentrations) or 10% DMSO

[0325] Component 5: 1 μL of ATP stock solution (25 μM final concentration in the well)

[0326] The reaction mixture is started by incubating in a 384-well culture plate at room temperature for 40 minutes. After incubation, 5 μL of ADP-Glo TM reagent is added. The culture plate is shaken and then incubated at room temperature for 40 minutes. Then, 10 μL of kinase detection reagent is added, the culture plate is shaken, and then incubated at room temperature for 30 minutes. The culture plate is measured using the ADP-Glo TM Luminescence Protocol on a GloMax microplate reader. The blank control is performed using all assay components except adding the appropriate substrate (replaced with an equal volume of assay dilution buffer). The corrected activity value is calculated by subtracting the value of the blank control.

[0327] 4. Data analysis

[0328] Relative luminescence units (RLU) are measured at 10 compound concentrations between 0.3 nM and 10,000 nM. The inhibition rate is calculated by the following method.

[0329] {(Control RLU - Test RLU) / (Control RLU - Background RLU)} × 100

[0330] Nonlinear regression analysis is performed using GraphPad Prism version 5.01 to determine the IC 50 value. The results are shown in Table 3. It is clear that the compound of Example 1 exhibits good ALK5 inhibitory activity.

[0331] [Table 3]

[0332] Table 3

[0333] <![CDATA[ALK5(IC 50 , nM)]]> Example 1 31

[0334] [Test Example 3]

[0335] Evaluation of ALK5 inhibitory effect

[0336] Using the GST-tagged human TGFB recombinant protein (Catalog No. T07-11G) from SignalChem, the substrate peptide TGFBR1 peptide (Catalog No. T36-58), and the ADP-Glo assay kit (Promega), according to the instructions of the ADP-Glo assay kit, the measurement was performed in a 384-well culture plate with a 5 μL reaction system (GloMax microplate reader). The reaction conditions used were: enzyme concentration 5 ng / μL, substrate concentration 200 ng / μL, ATP concentration 25 μM, and reaction time 2 hours. Based on the inhibition rate caused by adding the test substance (8 - 10 concentrations obtained by 3-fold dilution from 3000 nM), the IC 50 value was calculated using GraphPad Prism version 5.01.

[0337] [Table 4]

[0338] Table 4

[0339] <![CDATA[IC 50 (nM)]]> Example 4 46 Example 5 330

[0340] [Test Example 4]

[0341] Evaluation of CK1δ inhibitory effect

[0342] Using the GST-tagged human CK1δ recombinant protein (Catalog No. C65-10G) from SignalChem, the substrate peptide dephosphorylated casein (Catalog No. C03-54BN), and the ADP-Glo assay kit (Promega), according to the instructions of the ADP-Glo assay kit, the measurement was performed in a 384-well culture plate with a 5 μL reaction system (GloMax microplate reader). The reaction conditions used were: enzyme concentration 2 ng / μL, substrate concentration 200 ng / μL, ATP concentration 25 μM, and reaction time 40 minutes. Based on the inhibition rate caused by adding the test substance (8 - 10 concentrations obtained by 3-fold dilution from 3000 nM), the IC 50 value was calculated using GraphPad Prism version 5.01.

[0343] [Table 5]

[0344] Table 5

[0345] <![CDATA[IC 50 (nM)]]> Example 5 200

[0346] [Test Example 5]

[0347] Evaluation of p38α inhibitory effect

[0348] Using the GST-tagged human p38 recombinant protein (Catalog No. M39-10BG) from SignalChem, the substrate peptide p38 substrate (Catalog No. P03-58), and the ADP-Glo assay kit (Promega), the assay was performed in a 5 μL reaction system on a 384-well culture plate (GloMax microplate reader) according to the instructions of the ADP-Glo assay kit. The reaction conditions used were: enzyme concentration 2 ng / μL, substrate concentration 100 ng / μL, ATP concentration 25 μM, and reaction time 40 minutes. Based on the inhibition rate caused by the addition of the test substance (8 - 10 concentrations obtained by 3-fold dilution from 3000 nM), the IC 50 value was calculated using GraphPad Prism version 5.01.

[0349] [Table 6]

[0350] Table 6

[0351] <![CDATA[IC 50 (nM)]]> Example 5 ＞3000

Claims

1. A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, [Chemical formula 1] In formula (1), R 1 ~R 10 Each independently represents hydrogen, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a halogen. Among them, R 2 and R 3 together with the two carbon atoms to which they are bonded form a tetrahydrofuran ring having the following structure which may be substituted by an alkyl group having 1 to 6 carbon atoms: [Chemical formula 5] The carbon atoms marked with an asterisk (*) represent R 2 and R 3 and the carbon atoms of the benzene ring to which they are bonded.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 1 to R 10 each independently represents hydrogen, an alkyl group having 1 to 6 carbon atoms, or a halogen.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 3 together with the two carbon atoms to which they are bonded form the unsubstituted tetrahydrofuran ring.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of the following compounds, [Chemical formula 2] 5. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of a casein kinase 1δ inhibitor.

6. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of a therapeutic agent for circadian rhythm sleep disorder.

7. The use according to claim 6, wherein The circadian rhythm sleep disorder is irregular sleep-wake rhythm disorder or sundown syndrome associated with Alzheimer's type dementia.

8. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of a therapeutic agent for Alzheimer's type dementia.

9. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of an activin receptor-like kinase 5 inhibitor.

10. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for cancer, wherein, The cancer is brain tumor, liver cancer, bladder cancer, myelodysplastic syndrome, colorectal cancer or pancreatic cancer.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of a therapeutic agent for corneal dystrophy.

12. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of a therapeutic agent for male pattern hair loss.

13. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of an inhibitor of casein kinase 1δ and activin receptor-like kinase 5.

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