New regulations for seven-membered ring condensation compounds

Abstract

Compounds of formula (I): JPEG2025512138000045.jpg5595 Each symbol is as defined in the specification. Or a pharma- ceutical acceptable salt thereof has an excellent Notch signaling inhibitory effect, and is useful for the prevention or treatment of various diseases associated with Notch signaling.

Description

[Technical field]

[0001] The present invention relates to a novel seven-membered ring fused compound. More specifically, the present invention relates to a novel seven-membered ring fused compound having an inhibitory effect on Notch signaling. [Background technology]

[0002] Notch signaling is an evolutionarily conserved pathway that plays an essential role in mammalian development and tissue homeostasis. Notch receptors and ligands have a single transmembrane domain and are expressed on the cell surface, making Notch signaling particularly important in mediating communication between neighboring cells expressing the receptor and ligand. Four Notch receptors are known in rodents and humans, designated Notch1 to Notch4. Notch receptors are heterodimeric proteins consisting of an extracellular domain and an intracellular domain, and are initially synthesized as a single polypeptide. Receptor-ligand interaction triggers a series of proteolytic degradation of the Notch receptor polypeptide, involving gamma-secretase activity. The gamma-secretase activity cleaves the intracellular domain of Notch from the inside of the cell membrane and translocates to the nucleus to form a transcription factor complex. The Notch intracellular domain (Notch intracellular domain (NICD)) is the active form of the protein. There are various Notch signaling functions, including proliferation, differentiation, apoptosis, angiogenesis, migration, and self-renewal (Non-Patent Documents 1 to 3).

[0003] NICD also translocates into the nucleus and forms a stable complex with the DNA-binding proteins RBP-J and MAML, thereby activating the transcription of the target genes Hes1 and Hes5.

[0004] Therefore, compounds capable of inhibiting various Notch signaling functions may be useful pharmaceutical agents for various diseases in which those functions are involved. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Bray, Nature Reviews Molecular Cell Biology, 7:678-689 (2006). [Non-Patent Document 2] Fortini, Developmental Cell 16:633-647 (2009). [Non-Patent Document 3] Ables, JL et al., Neurosci., 12: 269-283 (2011). Summary of the Invention

[0006] Problem to be solved by the invention An object of the present invention is to provide a compound having an inhibitory effect on Notch signaling and a drug containing said compound that is useful for treating various diseases.

[0007] That is, the present invention relates to the following. [1] A compound represented by the following formula (I):

[0008] [ka]

[0009] [In the formula, R1 is represented by any one of the following formulas (I-1) to (I-2):

[0010] [ka]

[0011] * is the bonding site with N (nitrogen atom); R 1ais hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 1b is hydrogen, optionally substituted alkyl, or -W 11 -W 12 -R 13 (In the formula, W 11 is -(CO)- or -(SO2)-, W 12 is a single bond, -O- or -N(R 14 )-and R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 14 is hydrogen or optionally substituted alkyl; R 13 and R 14 may be bonded to form a saturated or unsaturated 4- to 7-membered ring which may contain a carbon atom, a nitrogen atom, or an oxygen atom, and an aryl ring or a heteroaryl ring may be condensed therein, substituent -X 15 -R 15 may be substituted on the formed saturated or unsaturated 4- to 7-membered ring, or on a fused aryl ring or heteroaryl ring, X15 is -O-, -NH-, or a single bond, R 15 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 1c is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; m is 1 or 0; L is -CH(R 9a )-, and when m is 0, -CH(R 9a )-CH(R 9b )-(wherein, R 9a and R 9b is independently hydrogen or optionally substituted alkyl; R3 is -W 31 -W 32 -R 33 (In the formula, W 31 is -(CO)-, -(SO2)-, or -CH2-, W 32 is -O-, -NH-, or a single bond, and R 33 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

[0012] [ka]

[0013] is represented by any one of the following formulas (I-3) to (I-4):

[0014] [ka]

[0015] R 4a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4b is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4a and R 4b may form a spiro ring together with the carbon to which they are attached and may have an oxygen atom or a nitrogen atom in the ring; A is -CH(R5)-, -N(R5)-, -O- or a single bond; R5 is hydrogen or optionally substituted alkyl; and Ring B is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted heterocycloalkyl ring. or a pharma- ceutically acceptable salt thereof.

[0016] [2] A is -CH2- or -O-; and Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; [1] The compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

[0017] [3] m is 1; L is -CH(R 9a )--and R 9a is hydrogen or methyl; The compound according to [1] or [2], or a pharma- ceutically acceptable salt thereof.

[0018] [4] m is 0; L is -CH(R 9a )-CH(R 9b )--and R 9a and R 9b are independently hydrogen or methyl; The compound according to [1] or [2], or a pharma- ceutically acceptable salt thereof.

[0019] [5] R 1a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 1b is hydrogen; R 1c is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and R2 is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; The compound according to any one of [1] to [4], or a pharma- ceutically acceptable salt thereof.

[0020] [6]R 4a is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4b is hydrogen or optionally substituted alkyl; and R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring; The compound according to any one of [1] to [5] or a pharma- ceutically acceptable salt thereof.

[0021] [7] A is -CH2- or -O-; Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; m is 1; L is -CH(R 9a )-and; R 9a is hydrogen or methyl; R 1a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 1b is hydrogen; R 1c is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R2 is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 4a is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R4b is hydrogen or optionally substituted alkyl; and R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring; The compound according to any one of [1] to [3], [5] and [6], or a pharma- ceutically acceptable salt thereof.

[0022] [8] A is -CH2- or -O-; Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; m is 0; L is -CH(R 9a )-CH(R 9b )-and; R 9a and R 9b are independently hydrogen or methyl; R 1a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 1b is hydrogen; R 1c is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R2 is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 4a is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4b is hydrogen or optionally substituted alkyl; and R4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring; The compound according to any one of [1], [2] and [4] to [6], or a pharma- ceutically acceptable salt thereof.

[0023] [9] A pharmaceutical composition comprising the compound according to any one of [1] to [8] or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutical acceptable carrier or diluent.

[0024]

[10] The pharmaceutical composition described in [9], wherein the composition contains an effective amount of the compound.

[0025]

[11] A method for treating or preventing a disease associated with Notch signaling, comprising administering to a subject in need thereof a compound of [1] to [8] or a pharma- ceutical acceptable salt thereof, or a composition according to [9] or

[10] , in an amount effective for treating or preventing the disease.

[0026]

[12] An agent for treating or preventing a disease associated with Notch signaling, comprising the compound according to any one of [1] to [8] or a pharma- ceutically acceptable salt thereof.

[0027]

[13] A compound according to any one of [1] to [8] or a pharma- ceutical acceptable salt thereof, or a composition according to [9] or

[10] , for use as a pharmaceutical for treating or preventing a disease associated with Notch signaling. Effect of the Invention

[0028] The compounds of formula (I) in the present invention inhibit Notch signaling and therefore can be used for the treatment of various diseases in which Notch signaling is associated. [Brief description of the drawings]

[0029] [Figure 1]FIG. 1 shows the 1H NMR (400 MHz, CDCl3) data of D-8. [Diagram 2] FIG. 2 shows the 1H NMR (400 MHz, CDCl3) data of D-10. [Diagram 3] FIG. 3 shows the 1H NMR (400 MHz, CDCl3) data of ID-39. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] [Description of the embodiment] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings for purposes of this application.

[0031] "Lower" means, unless otherwise indicated, that the specified radical comprises between 1 and 6 carbon atoms.

[0032] "Optionally substituted" means that, unless otherwise indicated, a given group may consist solely of hydrogen substituents according to available valences, or may further include one or more non-hydrogen substituents according to available valences. In general, a non-hydrogen substituent may be any substituent that may be attached to an atom of a given group that is specified to be substituted. Examples of substituents include -R6, -OR6, -COR6, -COOR6, -OCOR6, -CONR6R7, -NR6R7, -NR7COR6, -NR7COOR6, -SR6, -S2R6, -SON2NR6R7, -S2OR6, -OSO2R6, -NHC(NHR6)NR7, -NHC(NH2)NH, -CN, -NO2, halogen, and methylenedioxy (where R 6 and R 7 are independently selected from hydrogen, straight or branched chain, cyclic or acyclic, substituted or unsubstituted alkyl chains, aryl, heteroaryl, arylalkyl, and heteroarylalkyl moieties.

[0033] "Halogen" means fluorine, chlorine, bromine or iodine. "Halo" means fluoro, chloro, bromo or iodo.

[0034] "Alkyl" means a group having a straight or branched, saturated aliphatic, chain of carbon atoms. C X-Y Alkyl is typically used. The number of carbon atoms in the chain is preferably 1 to 10, more preferably 1 to 6 (C 1-6 ), more preferably 1 to 4 (C 1-4 ) Non-exclusive examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and isohexyl.

[0035] "Alkenyl" means a carbon chain that may be straight or branched and contains at least one carbon-carbon double bond. C X-Y Alkenyl is typically used. The number of carbon atoms in the chain is preferably 2 to 10 (C 2-10 ), more preferably 2 to 6 (C 2-6 Non-exclusive examples of alkenyl include ethenyl (vinyl), allyl, isopropenyl, 2-methylallyl, 1-pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl.

[0036] "Alkynyl" means a carbon chain that is straight or branched and contains at least one carbon-carbon triple bond. C X-Y Alkynyl is typically used. The number of carbon atoms in the chain is preferably 2 to 10 (C 2-10 ), more preferably 2 to 6 (C 2-6 ) Non-exclusive examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl, and the like.

[0037] "Alkylene" means, unless otherwise indicated, a straight or branched, saturated, aliphatic, polyvalent carbon chain. C X-Y Alkylene is typically used. The number of carbon atoms in the chain is preferably 1 to 10 (C 1-10 ), more preferably 1 to 6 (C 1-6 Non-exclusive examples of alkylene include methylene (-CH-), ethylene (-CHCH-), methylmethylene (-CH(CH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,2-butylene (-CHCH(CHCH)-), 1,3-butylene (-CHCHCH(CH)-), 1,4-butylene (-CHCHCHCHCH-), 2-methyltetramethylene (-CHCH(CH)CHCH-), pentamethylene (-CHCHCHCHCHCH-), 1,2,3-propanetriyl, and 1,3,3-propanetriyl.

[0038] "Heteroatom" refers to an atom that is not a carbon or hydrogen atom. Specific examples of heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur.

[0039] "Aryl" means a monocyclic or polycyclic group in which each ring is aromatic or, when fused to one or more rings, forms an aromatic ring. C X-Y Aryl is typically used. The number of carbon atoms in the ring is preferably 6 to 14 (C 6-14 ), more preferably 6 to 10 (C 6-10 ). Non-exclusive examples of aryl include phenyl, naphthyl, indenyl, azulenyl, biphenyl, fluorenyl, anthracenyl, phenalenyl, and the like. An "aryl" may be partially hydrogenated. Non-exclusive examples of partially hydrogenated aryl include tetrahydronaphthyl, indanyl, and the like.

[0040] "Heteroaryl" refers to a monocyclic or polycyclic aromatic ring group in which at least one ring atom is a heteroatom and the remaining ring atoms are carbon. "X-Y membered heteroaryl" is typically used, where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly. The number of carbon atoms and heteroatoms in the ring is preferably 5-14, more preferably 5-10. Monocyclic heteroaryl groups include, but are not limited to, cyclic aromatic ring groups having 5 or 6 ring atoms in which at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The nitrogen atom may be optionally quaternized and the sulfur atom may be optionally oxidized. Non-exclusive examples of monocyclic heteroaryl rings of the present invention include, but are not limited to, furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, triazole, and tetrazole. "Heteroaryl" also includes, but is not limited to, bicyclic or tricyclic rings, where the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring. Non-exclusive examples of bicyclic or tricyclic heteroaryl rings include benzofuran (e.g., benzo[b]furan), benzothiophene (e.g., benzo[b]thiophene), benzimidazole, benzotriazine (e.g., benzo[e][1,2,4]triazine, benzo[d][1,2,3]triazine), pyridopyrimidine (e.g., pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[2,3 -d]pyrimidine), pyridopyrazines (e.g., pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine), pyridopyridazines (e.g., pyrido[2,3-c]pyridazine, pyrido[3,4-c]pyridazine, pyrido[4,3-c]pyridazine, pyrido[3,2-c]pyridazine), pyridotriazines (e.g., pyrido[2,3-d][1,2,3]triazine, pyrido[3,4-d][1,2,3]triazine, pyrido[4,3-d][1,2,3]triazine, pyrido[3,2-d][1,2,3]triazine, pyrido[3,4-e][1,2,4]triazine, pyrido[3,2-e][1,2,4]triazine), benzothiadiazoles (e.g., benzo[c][1,2,5]thiadiazole), furopyridines (e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-c]pyridine, furo[2,3-b]pyridine), oxazolopyridines (e.g., oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, ]pyridine, oxazolo[5,4-b]pyridine), thiazolopyridines (e.g., thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-c]pyridine, thiazolo[5,4-b]pyridine), imidazopyridines (e.g., imidazo[1,2-a]pyridine, imidazo[4,5-c]pyridine, imidazo[1,5-a]pyridine), quinazolines, thienopyridines (e.g., thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine), indolizines, quinolines, isoxazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-c]pyridine, thiazolo[5,4-b]pyridine), Indoles, phthalazines, quinoxalins, cinnolines, naphthyridines, quinolizines, indoles, isoindoles, indazoles, indolines, benzoxazoles, benzopyrazoles, benzothiazoles, pyrazolopyridines (e.g., pyrazolo[1,5-a]pyridine), imidazopyrimidines (e.g., imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine, imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine), pyrrolopyridines (e.g., pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridines), pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine), pyrrolopyrimidines (e.g., pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine), pyrrolopyrazines (e.g., pyrrolo[2,3-b]pyrazine, pyrrolo[1,2-a]pyrazine), pyrrolopyridazines (e.g., pyrrolo[1,2-b]pyridazine), triazopyridines (e.g., triazo[1,5-a]pyridine), pteridines, purines, carbazoles, acridines, permidines, 1,Examples include, but are not limited to, 10-phenanthroline, phenoxathiin, phenoxazine, phenothiazine, phenazine, etc. The bicyclic or tricyclic heteroaryl ring can be attached to the parent molecule either through the heteroaryl group itself or through an aryl, cycloalkyl, or heterocycloalkyl group to which it is fused.

[0041] "Cycloalkyl" means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring radical. X and Y indicate the number of carbon atoms in the ring assembly. X-Y Cycloalkyl is typically used. The number of carbon atoms in the ring is preferably 3 to 10 (C 3-10 ), more preferably 3 to 8 (C 3-8 Non-exclusive examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, and bicyclo[2.2.1]hept-1-yl.

[0042] "Heterocycloalkyl" means cycloalkyl, as defined herein, provided that one or more of the atoms forming the ring is a heteroatom independently selected from N, O, and S. An "X-Y membered heterocycloalkyl" is typically used, where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly. The number of carbon atoms and heteroatoms in the ring is preferably 3-10, more preferably 3-8. Non-exclusive examples of heterocycloalkyl include piperidyl, 4-morpholinyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, and the like.

[0043] Moreover, the above definitions may also apply to the groups to which the above substituents are attached. For example, "arylalkyl" refers to a straight or branched chain alkyl group substituted with one or more aryl groups, such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. "Heteroarylalkyl" refers to a straight or branched chain alkyl group substituted with one or more "heteroaryl" groups.

[0044] "Cycloalkylalkyl" means a straight-chain or branched alkyl group substituted with one or more cycloalkyl groups, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, bicyclo[2.2.1]hept-1-yl.

[0045] "Heterocycloalkylalkyl" means a straight-chain or branched alkyl group that is substituted with one or more heterocycloalkyl groups.

[0046] As used herein, "monocyclic ring" refers to a monocyclic saturated or unsaturated carbocyclic ring or a monocyclic saturated or unsaturated heterocyclic ring. Typically, "X-membered monocyclic ring" is used, where X represents the number of carbon atoms and heteroatoms in the ring assembly. The number of carbon atoms and heteroatoms in the ring is preferably 4 to 7, more preferably 5 or 6. "Monocyclic heterocyclic ring" means a monocyclic aromatic or non-aromatic ring, in which at least one ring atom is a heteroatom (preferably S, N or O) and the remaining ring atoms are carbon. The nitrogen atom may be optionally quaternized and the sulfur atom may be optionally oxidized.

[0047] Non-exclusive examples of monocyclic saturated carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.

[0048] Non-exclusive examples of monocyclic unsaturated carbocycles include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, benzene, and the like.

[0049] Non-exclusive examples of monocyclic saturated heterocycles include pyrrolidine, piperidine, morpholine, piperazine, 1,3-dioxane, 1,4-dioxane, and the like.

[0050] Non-exclusive examples of monocyclic unsaturated heterocycles include pyrazole, dihydro-pyrrole, pyrrole, dihydro-pyrazole, imidazole, thiophene, thiazole, isothiazole, thiadiazole, furan, oxazole, isoxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, and the like.

[0051] "Spirocycle," as used herein, refers to a saturated or unsaturated cycloalkane or a saturated or unsaturated heterocycloalkane.

[0052] "Cycloalkane" means a non-aromatic, saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring. X and Y indicate the number of carbon atoms in the ring assembly. X-Y Cycloalkanes are typically used. The number of carbon atoms in the ring is preferably 3 to 10 (C 3-10 ), more preferably 3 to 8 (C 3-8 Non-exclusive examples of cycloalkanes include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0053] "Heterocycloalkane" means a cycloalkane, as defined herein, provided that one or more of the atoms forming the ring is a heteroatom independently selected from N, O, and S. An "X-Y membered heterocycloalkane" is typically used, where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly. The number of carbon atoms and heteroatoms in the ring is preferably 3-10, more preferably 3-8. Non-exclusive examples of heterocycloalkanes include piperidine, morpholine, piperazine, pyrrolidine, perhydropyrrolidine, tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, and the like.

[0054] The term "saturated or unsaturated 4- to 7-membered ring" refers to the above monocyclic ring having 4 to 7 members.

[0055] "Protected derivatives" refers to derivatives of compounds in which a reactive site is blocked with a protecting group. A comprehensive list of suitable protecting groups can be found in TW Greene, Protecting Groups in Organic Synthesis, 5th edition, John Wiley & Sons, Inc. 2014.

[0056] "Isomers" means any compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and stereoisomers that are non-superimposable mirror images are called "enantiomers" or sometimes "optical isomers". A carbon atom bonded to four different substituents is called a "chiral center". A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of two enantiomeric forms is called a "racemic mixture". A compound with more than one chiral center has two n-1The compound has enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers (called "diastereomeric mixture"). When one chiral center is present, a stereoisomer can be characterized by the absolute configuration of the chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and are described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Rules for stereochemical nomenclature, methods for determining stereochemistry and methods for separating stereoisomers are well known in the art (see, for example, "Advanced Organic Chemistry", 4th edition, March, Jerry, John Wiley & Sons, New York, 1992). The compounds of the present invention may include these isomers.

[0057] "Animal" includes humans, non-human mammals (e.g., mice, rats, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, and deer, etc.) and non-mammals (e.g., birds, etc.).

[0058] "Disease" specifically includes any unhealthy condition of an animal or part thereof, including an unhealthy condition that may be caused by or that may accompany a medical or veterinary therapy administered to the animal (i.e., a "side effect" of such therapy).

[0059] "Pharmaceutically acceptable" means generally safe, non-toxic, and useful in the preparation of pharmaceutical compositions which are not biologically or otherwise undesirable, and includes acceptable for veterinary use as well as human pharmaceutical use.

[0060] "Pharmaceutically acceptable salt" or "salt" refers to a salt of the compound of the present invention, as defined above, which is pharma- ceutically acceptable and has the desired pharmacological activity. Such salts include, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts of acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, benzoic ... and acid addition salts formed with organic acids such as benzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, trifluoroacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0061] Pharmaceutically acceptable salts also include base addition salts that can be formed when the acidic protons present can react with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

[0062] "Amount effective for treating a disease" means the amount that, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

[0063] A "prophylactically effective amount" means the amount that, when administered to an animal for preventing a disease, is sufficient to effect such prevention for the disease.

[0064] An "effective amount" is equivalent to a "treatingly effective amount" and a "prophylactically effective amount."

[0065] "Treatment" or "treating" means any administration of a compound of the invention, including: (1) preventing the development of disease in animals that may be susceptible to the disease but have not yet experienced or exhibited the pathology or symptomology of the disease; (2) inhibiting the disease (i.e., halting further progression of the pathology and / or symptomology) in an animal experiencing or exhibiting the pathology or symptomology of the disease; or (3) Amelioration of the disease (i.e., reversal of pathology and / or symptomology) in an animal experiencing or exhibiting the pathology or symptomology of the disease.

[0066] It should be noted that with respect to all definitions provided herein, the definition should be construed as open-ended in the sense that additional substituents beyond those specified may be included.

[0067] In the present invention, a compound represented by the following formula (I):

[0068] [ka]

[0069] [In the formula, R1 is represented by any one of the following formulas (I-1) to (I-2):

[0070] [ka]

[0071] * is the bonding site with N (nitrogen atom); R 1ais hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 1b is hydrogen, optionally substituted alkyl, or -W 11 -W 12 -R 13 (In the formula, W 11 is -(CO)- or -(SO2)-, W 12 is a single bond, -O- or -N(R 14 )-and R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 14 is hydrogen or optionally substituted alkyl; R 13 and R 14 may be bonded to form a saturated or unsaturated 4- to 7-membered ring which may contain a carbon atom, a nitrogen atom, or an oxygen atom, and an aryl ring or a heteroaryl ring may be condensed therein, substituent -X 15 -R 15 may be substituted on the formed saturated or unsaturated 4- to 7-membered ring, or on a fused aryl ring or heteroaryl ring, X15 is -O-, -NH-, or a single bond, R 15 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 1c is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; R2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; m is 1 or 0; L is -CH(R 9a )-, and when m is 0, -CH(R 9a )-CH(R 9b )-(wherein, R 9a and R 9b is independently hydrogen or optionally substituted alkyl; R3 is -W 31 -W 32 -R 33 (In the formula, W 31 is -(CO)-, -(SO2)-, or -CH2-, W 32 is -O-, -NH-, or a single bond, and R 33 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl;

[0072] [ka]

[0073] is represented by any one of the following formulas (I-3) to (I-4):

[0074] [ka]

[0075] R 4a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4b is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4a and R 4b may form a spiro ring together with the carbon to which they are attached and may have an oxygen atom or a nitrogen atom in the ring; A is -CH(R5)-, -N(R5)-, -O- or a single bond; R5 is hydrogen or optionally substituted alkyl; and Ring B is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted heterocycloalkyl ring. or a pharma- ceutically acceptable salt thereof is disclosed.

[0076] In one embodiment of Formula (I), R1a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0077] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl, and the like.

[0078] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0079] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0080] Examples of optionally substituted aryl and optionally substituted heteroaryl include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0081] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0082] Examples of optionally substituted heterocycloalkyls include piperidyl, 4-morpholinyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, acetylpiperidinyl, and the like.

[0083] Examples of the arylalkyl group which may be substituted as required include unsubstituted arylalkyl or arylalkyl having an alkyl group, such as benzyl, α-methylbenzyl, phenethyl, α-methylphenethyl, α,α-dimethylbenzyl, α,α-dimethylphenethyl, 4-methylphenethyl, 4-methylbenzyl, and 4-isopropylbenzyl; arylalkyl having an aryl group or arylalkyl group, such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, 4-n-hexyloxybenzyl, and 4-n-hexyloxybenzyl; Examples of aryl alkyl having a substituted oxy group include butadecyloxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, and 4-phenethyloxybenzyl; aryl alkyl having a hydroxyl group such as 4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl; aryl alkyl having a halogen atom such as 4-fluorobenzyl, 3-chlorobenzyl, and 3,4-dichlorobenzyl; diphenylmethyl, diphenylpropyl, 1-naphthylmethyl, and 2-naphthylmethyl.

[0084] Examples of optionally substituted heteroarylalkyl groups include 2-furfuryl, 2-benzodioxolylmethyl, 3-benzodioxolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidinylmethyl, 5-pyrimidinylmethyl, 3-pyridazinylmethyl, 2-indolylmethyl, 5-indolylmethyl, 2-benzofuranylmethyl, 5-indolylmethyl, 2-benzothienylmethyl, 5-benzothienylmethyl, 6-fluoro-2-benzofuranylmethyl, 6-chloro-2-benzofuranylmethyl, 6-methoxy-2-benzofuranylmethyl, 6-fluoro-2-benzothienylmethyl, 6-chloro-2-benzothienylmethyl, 6-methoxy-2-benzothienylmethyl, and 6-phenyl-3-pyridazinylmethyl.

[0085] Examples of optionally substituted cycloalkylalkyl groups include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl, bromocyclopropylmethyl, iodocyclopropylmethyl, methylcyclopropylmethyl, 1,1-dimethylcyclopropylmethyl, 1,2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl, methoxycyclopropylmethyl, ethoxycyclopropylmethyl, methoxycarbonylcyclopropylmethyl, methylcarbamoylcyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclopropylhexyl, and the like.

[0086] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0087] In another embodiment of formula (I), R 1a is hydrogen, optionally substituted alkyl (e.g., isobutyl, propyl, aminopropyl), optionally substituted aryl (e.g., naphthyl, phenyl), optionally substituted heteroaryl (e.g., quinolinyl, pyridyl), optionally substituted cycloalkyl (e.g., cyclohexyl), optionally substituted arylalkyl (e.g., benzyl), optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl.

[0088] In yet another embodiment of formula (I), R 1a is hydrogen, optionally substituted alkyl (e.g., isobutyl, propyl, aminopropyl), optionally substituted aryl (e.g., naphthyl, phenyl), optionally substituted heteroaryl (e.g., quinolinyl, pyridyl), optionally substituted cycloalkyl (e.g., cyclohexyl), optionally substituted arylalkyl (e.g., benzyl).

[0089] In one embodiment of Formula (I), R 1bis hydrogen, optionally substituted alkyl, or -W 11 -W 12 -R 13 (In the formula, W 11 is -(CO)- or -(SO2)-, W 12 is a single bond, -O- or -N(R 14 )-and R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 14 is hydrogen or optionally substituted alkyl; R 13 and R 14 may be bonded to form a saturated or unsaturated 4- to 7-membered ring which may contain a carbon atom, a nitrogen atom, or an oxygen atom, and an aryl ring or a heteroaryl ring may be condensed therein, substituent -X 15 -R 15 may be substituted on the formed saturated or unsaturated 4- to 7-membered ring, or on a fused aryl ring or heteroaryl ring, X 15 is -O-, -NH-, or a single bond, R 15 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0090] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl, and the like.

[0091] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0092] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0093] Examples of optionally substituted aryl groups and optionally substituted heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0094] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0095] Examples of optionally substituted heterocycloalkyls include piperidyl, 4-morpholinyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, and the like.

[0096] Examples of the arylalkyl group which may be substituted as required include unsubstituted arylalkyl or arylalkyl having an alkyl group, such as benzyl, α-methylbenzyl, phenethyl, α-methylphenethyl, α,α-dimethylbenzyl, α,α-dimethylphenethyl, 4-methylphenethyl, 4-methylbenzyl, and 4-isopropylbenzyl; arylalkyl having an aryl group or arylalkyl group, such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, 4-n-hexyloxybenzyl, and 4-n-hexyloxybenzyl; Examples of aryl alkyl having a substituted oxy group include butadecyloxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, and 4-phenethyloxybenzyl; aryl alkyl having a hydroxyl group such as 4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl; aryl alkyl having a halogen atom such as 4-fluorobenzyl, 3-chlorobenzyl, and 3,4-dichlorobenzyl; diphenylmethyl, diphenylpropyl, 1-naphthylmethyl, and 2-naphthylmethyl.

[0097] Examples of optionally substituted heteroarylalkyl groups include 2-furfuryl, 2-benzodioxolylmethyl, 3-benzodioxolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidinylmethyl, 5-pyrimidinylmethyl, 3-pyridazinylmethyl, 2-indolylmethyl, 5-indolylmethyl, 2-benzofuranylmethyl, 5-indolylmethyl, 2-benzothienylmethyl, 5-benzothienylmethyl, 6-fluoro-2-benzofuranylmethyl, 6-chloro-2-benzofuranylmethyl, 6-methoxy-2-benzofuranylmethyl, 6-fluoro-2-benzothienylmethyl, 6-chloro-2-benzothienylmethyl, 6-methoxy-2-benzothienylmethyl, 6-phenyl-3-pyridazinylmethyl, and the like.

[0098] Examples of optionally substituted cycloalkylalkyl groups include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl, bromocyclopropylmethyl, iodocyclopropylmethyl, methylcyclopropylmethyl, 1,1-dimethylcyclopropylmethyl, 1,2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl, methoxycyclopropylmethyl, ethoxycyclopropylmethyl, methoxycarbonylcyclopropylmethyl, methylcarbamoylcyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclopropylhexyl, and the like.

[0099] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0100] Examples of saturated or unsaturated 4- to 7-membered rings which may contain carbon atoms, nitrogen atoms, or oxygen atoms include hydrocarbon rings such as benzene, tropilidene, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentene, 2-cyclopentene, 3-cyclopentene, 1-cyclohexene, 2-cyclohexene, 3-cyclohexene, 1-cycloheptene, 2-cycloheptene, 3-cycloheptene, and 2,4-cycloheptadiene; pyridine, pyrazine, pyrimidine, imidazole, furan, and the like. Examples of such an alkyl group include thiophene, dihydropyridine, diazepine, oxazepine, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, piperazine, homopiperazine, tetrahydroxazepine, morpholine, thiomorpholine, pyrrole, pyrazole, 1,2,3-triazole, oxazole, oxazolidine, thiazole, thiazolidine, isoxazole, imidazoline, triazole, thiadiazole, oxathiadiazole, and triazine.

[0101] The aryl ring or heteroaryl ring may be condensed with a saturated or unsaturated 4- to 7-membered ring.

[0102] Examples of aryl rings include benzene, naphthalene, etc. Examples of heteroaryl rings include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine, etc. Also, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyridine Examples of aromatic heterocycles include 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as quinidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathine, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0103] In another embodiment of Formula (I), R 1b is hydrogen.

[0104] In one embodiment of Formula (I), R 1c is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0105] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0106] Examples of optionally substituted heterocycloalkyls include piperidyl, 4-morpholinyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, and the like.

[0107] Examples of optionally substituted aryl and optionally substituted heteroaryl include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0108] In another embodiment of formula (I), R 1c is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl (eg, acetylpiperidinyl).

[0109] In yet another embodiment of formula (I), R 1c is an optionally substituted heterocycloalkyl (eg, acetylpiperidinyl).

[0110] In one embodiment of Formula (I), R2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0111] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl, and the like.

[0112] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0113] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0114] Examples of the arylalkyl group which may be substituted as required include unsubstituted arylalkyl or arylalkyl having an alkyl group such as benzyl, α-methylbenzyl, phenethyl, α-methylphenethyl, α,α-dimethylbenzyl, α,α-dimethylphenethyl, 4-methylphenethyl, 4-methylbenzyl, and 4-isopropylbenzyl; arylalkyl having an aryl group or arylalkyl group such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, 4-n-heptadecylobenzyl, and the like. arylalkyl having a substituted oxy group, such as 4-hydroxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, 4-phenethyloxybenzyl, etc.; arylalkyl having a hydroxy group, such as 4-hydroxyphenethyl, 4-hydroxybenzyl, 4-hydroxy-3-methoxybenzyl, etc.; arylalkyl having a halogen atom, such as 4-fluorobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, etc.; diphenylmethyl, diphenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, etc.

[0115] Examples of optionally substituted heteroarylalkyl groups include 2-furfuryl, 2-benzodioxolylmethyl, 3-benzodioxolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidinylmethyl, 5-pyrimidinylmethyl, 3-pyridazinylmethyl, 2-indolylmethyl, 5-indolylmethyl, 2-benzofuranylmethyl, 5-indolylmethyl, 2-benzothienylmethyl, 5-benzothienylmethyl, 6-fluoro-2-benzofuranylmethyl, 6-chloro-2-benzofuranylmethyl, 6-methoxy-2-benzofuranylmethyl, 6-fluoro-2-benzothienylmethyl, 6-chloro-2-benzothienylmethyl, 6-methoxy-2-benzothienylmethyl, and 6-phenyl-3-pyridazinylmethyl.

[0116] Examples of optionally substituted cycloalkylalkyl groups include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl, bromocyclopropylmethyl, iodocyclopropylmethyl, methylcyclopropylmethyl, 1,1-dimethylcyclopropylmethyl, 1,2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl, methoxycyclopropylmethyl, ethoxycyclopropylmethyl, methoxycarbonylcyclopropylmethyl, methylcarbamoylcyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclopropylhexyl, and the like.

[0117] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0118] In another embodiment of formula (I), R2 is hydrogen, optionally substituted alkyl (e.g., methyl, isopropyl, isobutyl, -CH2CH2COOH), optionally substituted arylalkyl (e.g., benzyl, hydroxybenzyl), optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl.

[0119] In yet another embodiment of formula (I), R2 is hydrogen, optionally substituted alkyl (e.g., methyl, isopropyl, isobutyl, -CH2CH2COOH), optionally substituted arylalkyl (e.g., benzyl, hydroxybenzyl).

[0120] In one embodiment of Formula (I), m is 1 or 0.

[0121] In another embodiment of Formula (I), m is 1.

[0122] In one embodiment of Formula (I), L is -CH(R 9a )-, and when m is 0, -CH(R 9a )-CH(R 9b)-.

[0123] R 9a and R 9b are independently hydrogen or optionally substituted alkyl (e.g., methyl), preferably both are hydrogen atoms.

[0124] In one embodiment of Formula (I), R3 is -W 31 -W 32 -R 33 (In the formula, W 31 is -(CO)-, -(SO2)-, or -CH2-, W 32 is -O-, -NH-, or a single bond, and R 33 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0125] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl, and the like.

[0126] Examples of optionally substituted aryl and optionally substituted heteroaryl include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0127] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0128] Examples of optionally substituted heterocycloalkyls include piperidyl, 4-morpholinyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, and the like.

[0129] Examples of the arylalkyl group which may be substituted as required include unsubstituted arylalkyl or arylalkyl having an alkyl group such as benzyl, α-methylbenzyl, phenethyl, α-methylphenethyl, α,α-dimethylbenzyl, α,α-dimethylphenethyl, 4-methylphenethyl, 4-methylbenzyl, and 4-isopropylbenzyl; arylalkyl having an aryl group or arylalkyl group such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, 4-n-heptadecylobenzyl, and the like. arylalkyl having a substituted oxy group, such as 4-hydroxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, 4-phenethyloxybenzyl, etc.; arylalkyl having a hydroxy group, such as 4-hydroxyphenethyl, 4-hydroxybenzyl, 4-hydroxy-3-methoxybenzyl, etc.; arylalkyl having a halogen atom, such as 4-fluorobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, etc.; diphenylmethyl, diphenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, etc.

[0130] Examples of optionally substituted heteroarylalkyl groups include 2-furfuryl, 2-benzodioxolylmethyl, 3-benzodioxolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidinylmethyl, 5-pyrimidinylmethyl, 3-pyridazinylmethyl, 2-indolylmethyl, 5-indolylmethyl, 2-benzofuranylmethyl, 5-indolylmethyl, 2-benzothienylmethyl, 5-benzothienylmethyl, 6-fluoro-2-benzofuranylmethyl, 6-chloro-2-benzofuranylmethyl, 6-methoxy-2-benzofuranylmethyl, 6-fluoro-2-benzothienylmethyl, 6-chloro-2-benzothienylmethyl, 6-methoxy-2-benzothienylmethyl, and 6-phenyl-3-pyridazinylmethyl.

[0131] Examples of optionally substituted cycloalkylalkyl groups include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl, bromocyclopropylmethyl, iodocyclopropylmethyl, methylcyclopropylmethyl, 1,1-dimethylcyclopropylmethyl, 1,2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl, methoxycyclopropylmethyl, ethoxycyclopropylmethyl, methoxycarbonylcyclopropylmethyl, methylcarbamoylcyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclopropylhexyl, and the like.

[0132] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0133] In another embodiment of formula (I), R3 is -W 31’ -W 32’ -R 33’ (In the formula, W 31’ is -(CO)-, -(SO2)-, or -CH2-, W 32’is -O-, -NH-, or a bond, and R 33’ is optionally substituted alkyl (e.g., isobutyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl (e.g., benzyl, naphthylmethyl, diphenylpropyl, methylbenzyl, hydroxyphenethyl), optionally substituted heteroarylalkyl (e.g., pyridylmethyl, thienylmethyl, benzodioxolylmethyl), optionally substituted cycloalkylalkyl (e.g., cyclohexylmethyl) or optionally substituted heterocycloalkylalkyl.

[0134] In yet another embodiment of formula (I), R3 is -W 31’’ -W 32’’ -R 33’’ (In the formula, W 31’’ is -(CO)- or -(SO2)-, W 32’ is -O-, -NH- or a single bond, and R 33’ is optionally substituted alkyl (e.g., isobutyl), optionally substituted arylalkyl (e.g., benzyl, naphthylmethyl, diphenylpropyl, methylbenzyl, hydroxyphenethyl), optionally substituted heteroarylalkyl (e.g., pyridylmethyl, thienylmethyl, benzodioxolylmethyl), or optionally substituted cycloalkylalkyl (e.g., cyclohexylmethyl).

[0135] In one embodiment of Formula (I),

[0136] [ka]

[0137] is represented by any one of the following formulas (I-3) to (I-4):

[0138] [ka]

[0139] In another embodiment of formula (I), R 4a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0140] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl, and the like.

[0141] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0142] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0143] Examples of the arylalkyl group which may be substituted as required include unsubstituted arylalkyl or arylalkyl having an alkyl group such as benzyl, α-methylbenzyl, phenethyl, α-methylphenethyl, α,α-dimethylbenzyl, α,α-dimethylphenethyl, 4-methylphenethyl, 4-methylbenzyl, and 4-isopropylbenzyl; arylalkyl having an aryl group or arylalkyl group such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, 4-n-heptadecylobenzyl, and the like. arylalkyl having a substituted oxy group, such as 4-hydroxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, 4-phenethyloxybenzyl, etc.; arylalkyl having a hydroxy group, such as 4-hydroxyphenethyl, 4-hydroxybenzyl, 4-hydroxy-3-methoxybenzyl, etc.; arylalkyl having a halogen atom, such as 4-fluorobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, etc.; diphenylmethyl, diphenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, etc.

[0144] Examples of optionally substituted heteroarylalkyl groups include 2-furfuryl, 2-benzodioxolylmethyl, 3-benzodioxolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidinylmethyl, 5-pyrimidinylmethyl, 3-pyridazinylmethyl, 2-indolylmethyl, 5-indolylmethyl, 2-benzofuranylmethyl, 5-indolylmethyl, 2-benzothienylmethyl, 5-benzothienylmethyl, 6-fluoro-2-benzofuranylmethyl, 6-chloro-2-benzofuranylmethyl, 6-methoxy-2-benzofuranylmethyl, 6-fluoro-2-benzothienylmethyl, 6-chloro-2-benzothienylmethyl, 6-methoxy-2-benzothienylmethyl, and 6-phenyl-3-pyridazinylmethyl.

[0145] Examples of optionally substituted cycloalkylalkyl groups include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl, bromocyclopropylmethyl, iodocyclopropylmethyl, methylcyclopropylmethyl, 1,1-dimethylcyclopropylmethyl, 1,2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl, methoxycyclopropylmethyl, ethoxycyclopropylmethyl, methoxycarbonylcyclopropylmethyl, methylcarbamoylcyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclopropylhexyl, and the like.

[0146] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0147] In another embodiment of formula (I), R 4a is hydrogen, optionally substituted alkyl (e.g., methyl, -CH2CH2CONH2), optionally substituted arylalkyl (e.g., benzyl), or optionally substituted cycloalkylalkyl.

[0148] In yet another embodiment of formula (I), R 4a is hydrogen, optionally substituted alkyl (e.g., methyl, -CH2CH2CONH2), or optionally substituted arylalkyl (e.g., benzyl).

[0149] In one embodiment of Formula (I), R 4b is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0150] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl, and the like.

[0151] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0152] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0153] Examples of the arylalkyl group which may be substituted as required include unsubstituted arylalkyl or arylalkyl having an alkyl group such as benzyl, α-methylbenzyl, phenethyl, α-methylphenethyl, α,α-dimethylbenzyl, α,α-dimethylphenethyl, 4-methylphenethyl, 4-methylbenzyl, and 4-isopropylbenzyl; arylalkyl having an aryl group or arylalkyl group such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, 4-n-heptadecylobenzyl, and the like. arylalkyl having a substituted oxy group, such as 4-hydroxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, 4-phenethyloxybenzyl, etc.; arylalkyl having a hydroxy group, such as 4-hydroxyphenethyl, 4-hydroxybenzyl, 4-hydroxy-3-methoxybenzyl, etc.; arylalkyl having a halogen atom, such as 4-fluorobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl, etc.; diphenylmethyl, diphenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, etc.

[0154] Examples of optionally substituted heteroarylalkyl groups include 2-furfuryl, 2-benzodioxolylmethyl, 3-benzodioxolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidinylmethyl, 5-pyrimidinylmethyl, 3-pyridazinylmethyl, 2-indolylmethyl, 5-indolylmethyl, 2-benzofuranylmethyl, 5-indolylmethyl, 2-benzothienylmethyl, 5-benzothienylmethyl, 6-fluoro-2-benzofuranylmethyl, 6-chloro-2-benzofuranylmethyl, 6-methoxy-2-benzofuranylmethyl, 6-fluoro-2-benzothienylmethyl, 6-chloro-2-benzothienylmethyl, 6-methoxy-2-benzothienylmethyl, and 6-phenyl-3-pyridazinylmethyl.

[0155] Examples of optionally substituted cycloalkylalkyl groups include cyclopropylmethyl, fluorocyclopropylmethyl, chlorocyclopropylmethyl, bromocyclopropylmethyl, iodocyclopropylmethyl, methylcyclopropylmethyl, 1,1-dimethylcyclopropylmethyl, 1,2-dimethylcyclopropylmethyl, hydroxycyclopropylmethyl, methoxycyclopropylmethyl, ethoxycyclopropylmethyl, methoxycarbonylcyclopropylmethyl, methylcarbamoylcyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl, cyclopropylhexyl, and the like.

[0156] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0157] In another embodiment of formula (I), R 4b is hydrogen or optionally substituted alkyl (e.g., methyl).

[0158] In another embodiment of formula (I), R 4a and R 4b may form a spiro ring together with the carbon to which they are attached. 4a and R 4b However, the spiro rings which may be formed together with the carbon to which they are attached are, for example, cyclopropane, cyclobutane, and the like.

[0159] The spiro ring may contain an oxygen atom or a nitrogen atom in the ring.

[0160] In one embodiment of Formula (I), A is -CH(R5)-, -N(R5)-, -O-, or a single bond.

[0161] In one embodiment of Formula (I), R5 is hydrogen or optionally substituted alkyl.

[0162] Examples of optionally substituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, guanidinomethyl, guanidinoethyl, guanidinopropyl, and the like.

[0163] In another embodiment of formula (I), R5 is hydrogen.

[0164] In another embodiment of formula (I), A is -CH2- or -O-.

[0165] In one embodiment of formula (I), ring B is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted heterocycloalkyl ring.

[0166] Examples of aryl rings include benzene, naphthalene, etc. Examples of heteroaryl rings include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine, etc. Also, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyridine Examples of aromatic heterocycles include 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as quinidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathine, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0167] Examples of cycloalkyl rings include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.

[0168] Examples of heterocycloalkyl rings include pyrrolidine, piperidine, morpholine, piperazine, 1,3-dioxane, 1,4-dioxane, and the like.

[0169] In another embodiment of formula (I), ring B is an optionally substituted heteroaryl ring (eg, thiophene).

[0170] In one embodiment of the compound of Formula (I), A is -CH2- or -O-; Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; m is 1; L is -CH(R 9a )- and; R 9a is hydrogen or methyl; R 1a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 1b is hydrogen; R 1c is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R2 is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 4a is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4b is hydrogen or optionally substituted alkyl; and R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring.

[0171] In another embodiment of the compound of formula (I), A is -CH2- or -O-; Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; m is 0; L is -CH(R 9a )-CH(R 9b )- and; R 9a and R 9b is independently hydrogen or methyl; R 1a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 1b is hydrogen; R 1c is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R2 is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 4a is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4b is hydrogen or optionally substituted alkyl; and R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring.

[0172] In a further embodiment of the compound of formula (I), A is -CH2- or -O-; Ring B is an optionally substituted heteroaryl ring; m is 1; L is -CH(R 9a )- and; R 9a is hydrogen; R 1a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl; R 1b is hydrogen; R 1c is optionally substituted heterocycloalkyl; R2 is hydrogen, optionally substituted alkyl or optionally substituted arylalkyl; R3 is -W 31’’ -W 32’’ -R 33’’ (In the formula, W 31’’ is -(CO)- or -(SO2)-, W 32’ is -O-, -NH- or a single bond, and R 33’ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R 4a is hydrogen, optionally substituted alkyl, or optionally substituted arylalkyl; R 4a is hydrogen, optionally substituted alkyl; and R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring.

[0173] Hereinafter, the compounds having formula (I) are also referred to as "compounds of the present invention".

[0174] The general synthesis of the compounds of the present invention is described below in the "Processes." The abbreviations used in the processes and examples are as follows: AcOH: acetic acid AcONH4: Ammonium acetate BOC: tert-butoxycarbonyl t-BuOH: tert-butanol Cbz: benzyloxycarbonyl CDCl3: deuterated chloroform CIP: 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DCM: dichloromethane DIAD: Diisopropyl azodicarboxylate DIBAL: Diisobutylaluminum DIC: N,N'-methanediylidenebis[1-methylethanamine] DIEA: N,N-diisopropylethylamine DIPEA: N-ethyl-N-isopropyl-propan-2-amine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EtO(OEt): Ethoxy EtOAc (AcOEt): Ethyl acetate EtOH: Ethanol Fmoc: 9-fluorenylmethyloxycarbonyl HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate MeCN: Acetonitrile MeO(OMe):Methoxy MeOH: Methanol NHPI: N-hydroxyphthalimide NMM: N-methylmorpholine NEt3: Triethylamine OAc(AcO): Acetoxy Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl PE:EA:Petroleum ether:Ethyl acetate PG: amino protecting group Ph: Phenyl PhthN: N-phthalimidyl PPh3: Triphenylphosphine rt: room temperature TBS: tert-butyldimethylsilyl TBSCl: tert-butyl(chloro)dimethylsilane TBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide tetrafluoroborate tBu: tert-butyl TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography Trt: Trityl TsCl: Tosyl chloride

[0175] Manufacturing method 1) Manufacturing method 1

[0176] [ka]

[0177] [Step 1] Synthesis of intermediate A A compound represented by the formula [Int-a] (wherein L is as defined above) and an aldehyde compound represented by the formula [Int-b] (wherein R 1a and R 1b[Intermediate A] (wherein L and R1 are as defined above) can be synthesized according to known methods such as reductive alkylation using a compound represented by formula [Int-c] (wherein X is a leaving group and R1 is as defined above) or substitution reaction using a compound represented by formula [Int-c] (wherein X is a leaving group and R1 is as defined above). The term "leaving group" refers to an atom or group of atoms that is released from an organic compound undergoing a reaction in an elimination or substitution reaction. Examples of leaving groups include, but are not limited to, a halogen group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and a toluenesulfonyloxy group.

[0178] In addition, [Intermediate A] can also be synthesized by known methods such as reductive alkylation or substitution reaction using a leaving group X as shown below.

[0179] [ka]

[0180] In each of the compounds represented by the formulas [Int-d1], [Int-d2], [Int-e] and [Int-f], X is a leaving group, R1, R 9a , R 9b and L has the same meaning as above.

[0181] [Step 2] Synthesis of intermediate C Intermediate C can be synthesized by an amidation condensation reaction between [Intermediate A] and a carboxylic acid derivative of [Intermediate B] (wherein R2 and m are as defined above, and PG1 is a protecting group for an amino group), followed by a deprotection reaction. In the amidation condensation reaction, generally known amidation reagents and conditions can be used. As the condensation agent, HATU, HBTU, or DMT-MM is preferred, as the solvent, DMF, MeOH, THF, or the like is preferred, and the reaction temperature is preferably from 0°C to the boiling point of the solvent. Examples of the amino group protecting group, PG1, include benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, benzyl chloroformate (Cl-Z), benzyl bromoformate (Br-Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trityl (Trt), etc. In the deprotection reaction, a generally known reaction can be applied. When PG1 in the formula is an Fmoc group, the deprotection reaction is preferably performed using ethyl acetate, THF, MeOH, or dichloromethane as a solvent and piperidine or DBU as a deprotecting agent. When PG1 is a Cbz group, the deprotection reaction is preferably carried out using methanol, ethanol, or THF as a solvent under an H2 atmosphere and a palladium catalyst such as Pd(OH)2 or Pd / C. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0182] [Step 3] Synthesis of compound (I) Compound (I) (symbols in the formula are as defined above) can be synthesized by an amidation condensation reaction between [intermediate C] and [intermediate D] (R3 and W are as defined above), followed by a ring-closing reaction in the presence of an acid. In the amidation condensation reaction, generally known amidation reagents and conditions can be applied. As the condensation agent, HATU, HBTU, or DMT-MM is preferred, as the solvent, DMF, MeOH, THF, etc. are preferred, and the reaction temperature is preferably from 0°C to the boiling point of the solvent. In addition, as the acid used in the ring-closing reaction, formic acid is preferred, and formic acid can also be used as the solvent.

[0183] 2) Manufacturing method 2

[0184] [ka]

[0185] [Int-g] (symbols in the formula are as defined above) can be synthesized by an amidation condensation reaction between [Intermediate C] and [Intermediate D] (symbols in the formula are as defined above), followed by a ring-closing reaction in the presence of an acid as described in step 3 of Production Method 1. In the amidation condensation reaction, generally known amidation reagents and conditions can be applied. Deprotection of the tert-butyl ester also proceeds in the presence of an acid. In the ring-closing reaction, the t-butyl ester group is deprotected in the presence of an acid and converted to a carboxylic acid group.

[0186] [Int-g] and [Int-h] (R 13 Compound (I) (symbols in the formula are as defined above) can be synthesized by an amidation condensation reaction of 1,2-dichlorophenyl ether (III) (symbols in the formula are as defined above). In the amidation condensation reaction, a generally known amidation reagent and conditions can be applied. As the condensation agent, HATU, HBTU or DMT-MM is preferred, as the solvent, DMF, MeOH, THF or the like is preferred, and the reaction temperature is preferably from 0°C to the boiling point of the solvent. As the reaction temperature, a temperature from 0°C to the boiling point of the solvent is preferred.

[0187] 3) Manufacturing method 3

[0188] [ka]

[0189] R3 is -(CO)-NH-R 33 Compound (I) can be prepared by deprotecting intermediate [Int-i] (PG2 is an amino-protecting group, and the other symbols in the formula are as defined above) and then reacting it with triphosgene to give amine derivative R 33[Int-i] can be synthesized by a condensation reaction with --NH2. [Int-i] can be produced by a generally known method or by steps 1, 2 and 3 described in Production Method 1.

[0190] Representative examples of the amino-protecting group PG2 include benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). In the deprotection reaction, a generally known reaction can be applied. When PG2 in the formula is an Fmoc group, the deprotection reaction is preferably carried out using ethyl acetate or dichloromethane as a solvent and piperidine or DBU as a deprotecting agent. When PG2 is a Cbz group, the deprotection reaction is preferably carried out using a palladium catalyst such as Pd(OH)2 or Pd / C under an H2 atmosphere and methanol, ethanol or THF as a solvent. The reaction temperature is preferably from 0°C to the boiling point of the solvent used. In the condensation reaction, DCM, DCE, THF, etc. are preferred solvents, and the reaction temperature is preferably from 0°C to the boiling point of the solvent used.

[0191] 4) Manufacturing method 4

[0192] [ka]

[0193] R3 is -(CO)-OR 33 Compound (I) can be prepared by reacting an intermediate [Int-j] with an alcohol derivative R 33 It can be synthesized by a reaction using --OH and triphosgene. DCM, DCE, THF, etc. are preferred solvents, and the reaction temperature is preferably from 0°C to the boiling point of the solvent used.

[0194] 5) Manufacturing method 5

[0195] [ka]

[0196] R3 is -(CO)-R 33Compound (I) can be prepared by reacting intermediate [Int-j] with R 33 -COOH (or R 33 The preferred solvents are DMF, DCM, DCE, THF, MeOH, etc., and the reaction temperature is preferably from 0°C to the boiling point of the solvent. 33 When -COOH is used, a commonly known amidation reagent such as HATU, CIP, or DMT-MM is used as a condensation agent.

[0197] 6) Manufacturing method 6

[0198] [ka]

[0199] R3 is -(SO2)-R 33 Compound (I) can be prepared by reacting intermediate [Int-j] with R 33 -SO2Cl can be used for the synthesis by condensation reaction. DCM, DCE, THF, etc. are preferred solvents. The reaction temperature is preferably from 0°C to the boiling point of the solvent used.

[0200] The protecting group in each step is not limited to the protecting group specifically shown in the scheme (e.g., diethylacetal group), and a commonly known protecting group such as a dimethylacetal group may be used. The deprotection in step 2 in Production Method 1 or Production Method 3 can be carried out by a general method corresponding to the protecting group. 1a , R 1b , R 1c , R 13 , R 14 , R 15 , R2, R3, R 33 , R 4a , R5, R 9a , R 9b Or, when B has a protected functional group, deprotection can be carried out at any step. In some cases, the compound synthesized in each step of the reaction is used in the next reaction without being isolated. In addition, under the conditions of step 3 in the production method 1, the ring-closing reaction and the deprotection reaction may proceed simultaneously.

[0201] The compound obtained in the cyclization reaction can be isolated and purified by conventional methods such as extraction, water washing, acid washing, alkali washing, crystallization, recrystallization, silica gel column chromatography, and the like.

[0202] To explain further, the compound of the present invention, its salt and its derivatives are excellent in pharmacological action selectivity, safety (various toxicities and safety pharmacology), pharmacokinetic properties and physicochemical properties, etc., and therefore their usefulness as active ingredients of drugs can be confirmed.

[0203] Examples of tests for pharmacological action selectivity include, but are not limited to, inhibition or activation assays for various pharmacological target receptors, inhibition assays for various pharmacological target enzymes, ion channels or transporters, and cellular assays used to evaluate various pharmacological actions.

[0204] Examples of tests related to safety include, but are not limited to, the following: cytotoxicity tests (e.g., tests using HL60 cells, hepatocytes, etc.), genotoxicity tests (e.g., Ames test, mouse lymphoma TK test, chromosomal aberration test, micronucleus test, etc.), skin sensitization tests (e.g., Buehler method, GPMT method, APT method, LLNA test, etc.), skin photosensitization tests (e.g., Adjuvant-Strip method, etc.), eye irritation tests (e.g., single eye instillation, short-term continuous eye instillation, repeated eye instillation, etc.), safety pharmacology tests on the cardiovascular system (telemetry method, APD method, hERG inhibition assay, etc.), safety pharmacology tests on the central nervous system (e.g., FOB method, modified Irwin method, etc.), safety pharmacology tests on the respiratory system (e.g., measurement methods using respiratory function measuring devices and measurement methods using blood gas measuring devices, etc.), and general toxicity tests.

[0205] Examples of tests related to pharmacokinetic properties include, but are not limited to, the following: cytochrome P450 enzyme inhibition or induction tests, cell permeability tests (e.g., tests using CaCO-2 cells, MDCK cells, etc.), drug transporter ATPase assay, oral absorption tests, blood concentration transition measurement tests, metabolism tests (e.g., stability tests, metabolite molecular species tests, reactivity tests, etc.), and solubility tests (e.g., solubility tests based on the suspension method, etc.).

[0206] Examples of tests relating to physicochemical properties include, but are not limited to, the following: chemical stability tests (e.g., stability tests using HPLC, etc.), partition coefficients (e.g., partition tests using octanol phase / water phase, etc.), ionization constant tests, and crystallization tests.

[0207] In another embodiment, there are methods of treating various diseases by administering the compounds of the present invention. The compounds of the present invention can be used to prevent or treat diseases regulated by the Notch signaling pathway.

[0208] In one embodiment, screening for inhibitory effects on the Notch signaling pathway is carried out using a doxycycline-inducible lentiviral vector (see Examples for specific procedures).

[0209] Here, the test compound is a compound described herein, i.e., a compound of the present invention. Typically, the test compound will be tested at a number of different concentrations, which will be selected in part depending on the assay conditions.

[0210] The compounds of the present invention can inhibit Notch signaling by interacting with the Notch intracellular domain.

[0211] The present invention also relates to prodrugs using libraries that contain one or more compounds of the present invention. Prodrugs are typically designed to release active agents in the body during or after absorption by enzymatic and / or chemical hydrolysis. Prodrug approaches are an effective means of improving the oral bioavailability or intravenous administration of poorly water-soluble drugs by chemical derivatization to more water-soluble compounds. The most commonly used prodrug approach to increase the water solubility of drugs that contain hydroxyl groups is to prepare esters that contain ionizable groups; for example, phosphate groups, carboxylic acid groups, alkylamino groups (Fleisher et al., Advanced Drug Delivery Reviews, 115-130, 1996; Davis et al., Cancer Res., 7247-7253).

[0212] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention. These compositions can be used in various methods of the invention, as described in detail below.

[0213] The pharmaceutical composition of the present invention can be formulated according to the intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions (e.g., injections) used for parenteral (particularly intravenous), intradermal, or subcutaneous administration can include the following components: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and isotonicity agents such as sodium chloride or dextrose. In addition, the pH can be adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide). Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0214] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL, or the like. TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved free from the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents in the composition, for example, sugars, polyalcohols such as mannitol and sorbitol, sodium chloride. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0215] Sterile injection solutions can be prepared by mixing the active compound, which is, for example, a compound having general formula (I), in the required amount in a suitable solvent with one or a combination of the above-mentioned components, as required, and then sterilizing by filtration.Generally, dispersions are prepared by mixing the active compound in a sterile vehicle containing the other necessary components from those mentioned above and a dispersion medium.In the case of sterile powders for preparing sterile injection solutions, the preferred preparation method is vacuum drying and freeze-drying to prepare a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution.

[0216] Oral compositions generally contain an inert diluent or an edible carrier. These may be sealed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of tablets, troches, or capsules.

[0217] Oral compositions can also be prepared with a liquid carrier for use as a mouthwash, where the compound in the liquid carrier is applied orally and slurped, expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, lozenges and the like can contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch, lactose, disintegrants such as alginic acid, Primogel or cornstarch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavoring.

[0218] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant (eg, a gas such as carbon dioxide) or nebulizer.

[0219] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and include, for example, for transmucosal administration, surfactants, bile salts, fusidic acid derivatives.Transmucosal administration can be achieved by using nasal sprays or suppositories.For transdermal administration, active compounds are generally formulated into ointments, salves, gels or creams known in the art.

[0220] The compounds of the invention can also be prepared in the form of suppositories (eg, with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0221] In one embodiment, the active compound can be prepared with carriers that protect the compound against rapid elimination from the body, such as controlled release dosage forms, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such dosage forms are obvious to those skilled in the art. Materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells with monoclonal antibodies against viral antigens, can also be used as pharma-ceutically acceptable carriers. These can be prepared by methods known to those skilled in the art, for example, as disclosed in U.S. Pat. No. 4,522,811.

[0222] For ease of administration and uniformity of dosage, it may be more advantageous to formulate oral or parenteral compositions in dosage unit form.Dosage unit form as used herein means a physically discrete unit suitable for a single dose for a subject to be treated; each unit contains a predetermined amount of active compound of 5, calculated in association with the necessary pharmaceutical carrier to produce a desired therapeutic effect.The specification for the dosage unit form of the present invention is determined by and directly depends on the unique characteristics of the active compound, the particular therapeutic effect to be achieved, and the inherent limitations of the technology of compounding such active compounds for individual treatment.

[0223] For example, in some embodiments, the pharmaceutical composition of the present invention is suitable for oral administration in a unit dose, such as a tablet or capsule containing about 1 mg to about 1 g of the compound of the present invention. In some other embodiments, the pharmaceutical composition of the present invention is suitable for intravenous, subcutaneous, or intramuscular injection. The patient may receive, for example, an intravenous, subcutaneous, or intramuscular dose of the compound of the present invention of about 1 μg / kg to about 1 g / kg. The intravenous, subcutaneous, and intramuscular doses may be given by means of a bolus injection or by continuous infusion over a period of time. Alternatively, the patient may receive a daily oral dose approximately equal to the daily parenteral dose, with the composition being administered 1 to 4 times per day.

[0224] Preferably, the compound of formula (I) of the present invention can be administered to mammals, including humans, by intravenous administration (particularly preferably, by continuous infusion or rapid intravenous administration).

[0225] In this case, the dosage is appropriately selected depending on various factors such as the patient's body weight and / or age, and / or the severity of symptoms and the administration route. For example, the dosage of the compound of formula (I) for intravenous administration is generally 1 to 10,000 mg / day / m2 per human body surface area by continuous drip administration. 2 Preferably, the range is 1 to 5000 mg / day / m per human body surface area. 2and more preferably 10 to 5000 mg / day / m per human body surface area. 2 It is.

[0226] The pharmaceutical composition containing the compound of the present invention can be used for the disease controlled by the Notch signaling pathway.Specifically, the compound that inhibits the Notch signaling suppresses the expression of Hes1 and Hes5, provides a method for promoting the differentiation of neural stem cells, and is expected to be a candidate for a new nerve regeneration drug.

[0227] The present invention also provides a method for promoting neural stem cell differentiation, comprising contacting neural stem cells with a compound of formula (I) in an amount effective to promote neural stem cell differentiation. Such methods are also useful for treating neurodegenerative diseases (e.g., glaucoma, macular degeneration, Parkinson's disease, Alzheimer's disease) and nervous system injuries. A "neural stem cell" is a clonogenic, undifferentiated, pluripotent cell that can differentiate into neurons, astrocytes, and oligodendrocytes under appropriate conditions. A compound promotes neural stem cell differentiation when the neural stem cells exhibit a statistically significantly higher degree of differentiation in the presence of the compound than in the absence of the compound. Such compounds can be identified using assays involving in vitro cultured stem cells and animal models (Albranches et al., Biotechnol. Lett. 25: 725-30, 2003; Deng et al., Exp. Neurol. 182: 373-82, 2003; Munoz-Elias et al., Stem Cells 21: 437-48, 2003; Kudo et al., Biochem. Pharmacol. 66: 289-95, 2003; Wan et al., Chin. Med. J. 116: 428-31, 2003; Kawamorita et al., Hum. Cell 15: 178-82, 2002; Stavridis and Smith, Biochem. Soc. Trans. 31: 45-9, 2003; Pachemik et al., Reprod. Nutr. Dev. 42: 46-51, 2003). 317-26, 2002; Fukunaga et al., supra). The neural stem cells may be cultured stem cells, freshly isolated stem cells from their source tissue, or stem cells within their source organism. Contacting of the neural stem cells with the compounds according to the invention may therefore be carried out either in vitro (in the case of cultured or freshly isolated stem cells) or in vivo (in the case of stem cells within their source organism). The resulting differentiated neural cells, if generated in vitro, can be transplanted into tissues in need thereof (Lacza et al., supra; Chu et al., supra; Fukunaga et al., supra). Such tissues include brain tissue or other neural tissues affected by trauma or neurodegenerative diseases.

[0228] The following non-limiting examples illustrate the compounds, compositions, and methods of use of the present invention.

[0229] Working Example The present invention will be described in more detail below with reference to Production Examples, Examples, Reference Examples and Test Examples, but the scope of the present invention is not limited thereto.

[0230] In the examples, Bruker AVANCE III 400; Bruker AVANCE III 400HD, and Bruker AVANCE NEO40 or Bruker AVANCE III 300 were used. 1 H NMR was measured.

[0231] Preparative HPLC (prep-HPLC) was carried out using a GILSON-GX-28 or Waters FractionLynx system. The preparative conditions used were as follows: Normal prep-HPLC conditions (AcOH): Column: C30-UG 25mmID*150mmL, 5μm Mobile phase A: 0.10% v / v acetic acid in water Mobile phase B: Acetonitrile UV detection wavelength: 220 nm Flow rate: 25ml / min Temperature: room temperature Gradient time table: 0 minutes B=x%,A=100-x% 0.01-10.99 min Linear gradient 11.00 minutes B=y%,A=100-y% 11.01-11.20 minutes B=y%,A=100-y% 11.21-13.00 minutes B=100% 13.01-15.00 min B=z%, A=100-z% The values ​​of x, y and z depend on the type of compound.

[0232] LCMS analysis was carried out by the following method A or B.

[0233] (Method A) System: Shimadzu UFLC / MS System (Shimadzu-2020 mass spectrometer) Column: ODS column for chromatography Eluents: A (5 mM AcONH4 in water) and B (5 mM AcONH4 in acetonitrile)

[0234] (Method B) System: Shimadzu UFLC / MS System (Shimadzu-2020 mass spectrometer) Column: ODS column for chromatography Eluent: A (water containing 0.04% TFA) and B (acetonitrile containing 0.04% TFA)

[0235] Production Example 1: Synthesis of Intermediate A-02

[0236] [ka]

[0237] To a solution of 2-bromo-1,1-diethoxyethane (50 g, 0.69 mol) in MeCN (0.7 L) was added potassium carbonate (94.5 g, 0.69 mol) and n-butylamine (50 g, 0.69 mol). After refluxing overnight, the mixture was filtered and evaporated. The residue was dissolved in ethyl acetate (1.0 L), washed with water (0.5 L) and brine (0.5 L), dried over sodium sulfate, filtered and evaporated. Distillation under reduced pressure (70° C., 5-10 mmHg) gave the target product A-02 (71 g, colorless oil, 55% yield). A-02 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 1.

[0238] Production Example 2: Synthesis of Intermediate A-03

[0239] [ka]

[0240] To a solution of 2,2-diethoxyethan-1-amine (75 g, 0.67 mol) in MeOH (1.0 L) was added cyclohexanecarbaldehyde (89 g, 0.67 mol). After stirring overnight, sodium borohydride (38.2 g, 1.0 mol) was added at 0° C. while stirring the mixture at room temperature for 1.5 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (1.0 L), washed with water (1.0 L) and brine (1.0 L), dried over sodium sulfate, filtered, and evaporated. Distillation under reduced pressure (140° C., 5-10 mmHg) gave the product A-03 (130 g, colorless oil, 85% yield). A-03 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 2.

[0241] Production Example 3: Synthesis of Intermediate A-09

[0242] [ka]

[0243] To a solution of tert-butyl (4-hydroxybutyl)carbamate (0.20 kg) in dichloromethane (1.5 L) was added triethylamine (0.21 kg) at 10° C. Then methanesulfonyl chloride (0.16 kg) was added dropwise. After stirring at 10° C. for 1 h, the mixture was quenched with saturated sodium bicarbonate solution. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 4-((tert-butoxycarbonyl)amino)butyl methanesulfonate (0.25 kg) as a yellow oil. This product was used in the next step without further purification.

[0244] To a solution of 4-((tert-butoxycarbonyl)amino)butyl methanesulfonate (0.25 kg) in acetonitrile (2.0 L) was added 2,2-diethoxyethanamine (0.13 kg) and potassium carbonate (0.26 kg). The mixture was heated to 60° C. and stirred overnight. The mixture was poured into water and extracted with ethyl acetate (1.0 L×3). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the desired product (0.20 kg) as a yellow oil. This product was used in the next step without further purification.

[0245] Intermediates A-01 to A-12 were synthesized according to the same method as above or known methods. A list of intermediates A is shown in Table 1.

[0246] [Table 1]

[0247] Intermediates B-01 to B-06 in Table 2 are commercially available or can be synthesized according to known methods.

[0248] [Table 2]

[0249] Production Example 4: Synthesis of Intermediate C-06

[0250] [ka]

[0251] To a solution of (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpropanoic acid (30 g) in DMF (0.13 L) was added diisopropylethylamine (42 g) and TBTU (59 g). The mixture was stirred at room temperature for 1 h. Then, N-(cyclohexylmethyl)-2,2-diethoxyethanamine (25 g) was added. The mixture was stirred overnight. The mixture was poured into water and extracted with dichloromethane (0.20 L x 3). The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified on a column on silica gel to give C-06-int1 (37 g) as a yellow oil.

[0252] To a solution of C-06-int1 (37 g) in dichloromethane (0.35 L) was added piperidine (30 g). The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane (0.10 L x 2). The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column on silica gel to give the desired product (10 g) as a yellow oil. LCMS (Method A): m / z=315.2[M+H] + .

[0253] Intermediates C-01 to C-27 in Table 3 (Tables 3-1 to 3-4) were synthesized using Intermediate A and Intermediate B according to the same method as above or a known method.

[0254] [Table 3-1]

[0255] [Table 3-2]

[0256] [Table 3-3]

[0257] [Table 3-4]

[0258] Intermediates D-01 to D-27 in Table 4 (Table 4-1 to Table 4-2) were synthesized by known methods, for example, the method described in WO2010 / 128685.

[0259] [Table 4-1]

[0260] [Table 4-2]

[0261] Example 1: Synthesis of ID-39

[0262] [ka]

[0263] To a solution of C-23 (24 mg) and D-20 (25 mg) in methanol (0.6 mL), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) (24 mg) was added. The mixture was allowed to stand at room temperature for 1 hour. The reaction mixture was diluted with AcOEt (5 mL), washed with saturated sodium bicarbonate solution (1 mL) and water (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO2, n-hexane:AcOEt=50:50-0:100, gradient) to obtain ID-39-int1 (43 mg) as a colorless oil. LCMS (Method B): m / z=674.4[M+H] + ,696.4[M+Na] + .

[0264] ID-39-int1 (43 mg) was dissolved in formic acid (1 mL) and stirred at 40° C. for 18 days and at 50° C. for 3 days. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give the product ID-39 (5.1 mg) as a white solid. LCMS (Method B): m / z=526.3[M+H] + . ID-39 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 3.

[0265] Compounds ID-01 to ID-45 in Table 5 (Table 5-1 to Table 5-7) were synthesized using intermediates C and D according to the same method as above or a known method.

[0266] [Table 5-1]

[0267] [Table 5-2]

[0268] [Table 5-3]

[0269] [Table 5-4]

[0270] [Table 5-5]

[0271] [Table 5-6]

[0272] [Table 5-7]

[0273] For compounds ID-01, 04, 06-14, 20, 22, 27, 31-38, 42 and 45, the diastereomeric mixtures are observed separately by LCMS analysis.

[0274] The chemical names of compounds ID-01 to ID-45 are listed below: ID-01 (7R)-N-Benzyl-7-isopropyl-9-(naphthalen-2-ylmethyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-02 (7R)-9-Butyl-7-isobutyl-4,8-dioxo-N-(pyridin-4-ylmethyl)octahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-03 (7R)-9-(cyclohexylmethyl)-7-methyl-N-(naphthalen-1-ylmethyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-04 (7R)-7-Benzyl-9-butyl-N-(3,3-diphenylpropyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-05 (7R)-N-(3,3-diphenylpropyl)-7-(4-hydroxybenzyl)-9-isopentyl-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-06 (7R)-7-Benzyl-N-(3,3-diphenylpropyl)-9-isopentyl-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-07 (7R)-7-Benzyl-9-(cyclohexylmethyl)-N-(3,3-diphenylpropyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-08 (7R)-7,9-Dibenzyl-N-(3,3-diphenylpropyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-09 (7R)-N-(3,3-diphenylpropyl)-7-isopropyl-4,8-dioxo-9-phenethyloctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-10 (7R)-N-(3,3-diphenylpropyl)-7-isobutyl-4,8-dioxo-9-phenethyloctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide

[0275] ID-11 (7R)-N-(3,3-diphenylpropyl)-7-(4-hydroxybenzyl)-4,8-dioxo-9-phenethyloctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-12 (7R)-7-Benzyl-N-(3,3-diphenylpropyl)-4,8-dioxo-9-phenethyloctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-13 (7R)-N-(3,3-diphenylpropyl)-7-(4-hydroxybenzyl)-4,8-dioxo-9-(quinolin-8-ylmethyl)octahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-14 (7R)-N-(3,3-diphenylpropyl)-7-isopropyl-9-(naphthalen-2-ylmethyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-15 (7R)-N-(cyclohexylmethyl)-7-(4-hydroxybenzyl)-9-(naphthalen-1-ylmethyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-16 (7R)-7-Benzyl-N-(cyclohexylmethyl)-9-(naphthalen-1-ylmethyl)-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-17 (7R)-9-(4-aminobutyl)-7-(4-hydroxybenzyl)-N-isobutyl-4,8-dioxooctahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-18 (7R)-7-(4-Hydroxybenzyl)-4,8-dioxo-9-(pyridin-4-ylmethyl)-N-(thiophen-2-ylmethyl)octahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxamide ID-19 (7R)-7-Benzyl-4,8-dioxo-9-(pyridin-4-ylmethyl)octahydropyrimido[1,2-a][1,4]diazepine-1(2H)-carboxylate isobutyl ID-20 (8R)-N-Benzyl-8-isopropyl-6-(naphthalen-2-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide

[0276] ID-21 (8R)-6,8-Dibenzyl-7,11-dioxo-N-(pyridin-4-ylmethyl)-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-22 (8R)-8-(4-Hydroxybenzyl)-6-(naphthalen-1-ylmethyl)-7,11-dioxo-N-phenethyl-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-23 (8R)-8-Benzyl-7,11-dioxo-N-phenethyl-6-(quinolin-8-ylmethyl)-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-24 (8R)-6-Butyl-8-isobutyl-N-(naphthalen-1-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-25 (8R)-8-Isobutyl-6-isopentyl-N-(naphthalen-1-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-26 (8R)-8-(4-Hydroxybenzyl)-6-isopentyl-N-(naphthalen-1-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-27 (8R)-6-(cyclohexylmethyl)-8-(4-hydroxybenzyl)-N-(naphthalen-1-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-28 (8R)-6-(4-aminobutyl)-8-isobutyl-N-(naphthalen-1-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-29 (8R)-N-(3,3-diphenylpropyl)-8-methyl-6-(naphthalen-2-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-30 (8R)-N-(cyclohexylmethyl)-8-(4-hydroxybenzyl)-7,11-dioxo-6-(quinolin-8-ylmethyl)-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide

[0277] ID-31 (8R)-N-isobutyl-8-methyl-7,11-dioxo-6-(pyridin-4-ylmethyl)-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-32 (8R)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-6-butyl-8-(4-hydroxybenzyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-33 (8R)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-8-(4-hydroxybenzyl)-6-isopentyl-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-34 (8R)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-8-benzyl-6-isopentyl-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-35 (8R)-8-Isopropyl-6-(naphthalen-2-ylmethyl)-7,11-dioxo-N-(thiophen-2-ylmethyl)-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-36 (8R)-6-Butyl-8-(4-hydroxybenzyl)-N-(4-methylbenzyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-37 (8R)-8-(4-hydroxybenzyl)-6-isopentyl-N-(4-methylbenzyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxamide ID-38 (8R)-8-(4-Hydroxybenzyl)-6-(naphthalen-1-ylmethyl)-7,11-dioxo-4a,5,6,7,8,9-hexahydrothieno[3',2':4,5]pyrimido[1,2-a][1,4]diazepine-4(11H)-carboxylate isobutyl ID-39 3-((3R,7R)-3-benzyl-1-((4-hydroxyphenethoxy)carbonyl)-9-methyl-4,8-dioxooctahydro-1H-[1,2,4]oxadiazino[4,3-a][1,4]diazepin-7-yl)propanoic acid ID-40 3-((3R,7R)-3-(3-amino-3-oxopropyl)-1-((benzyloxy)carbonyl)-9-methyl-4,8-dioxooctahydro-1H-[1,2,4]oxadiazino[4,3-a][1,4]diazepin-7-yl)propanoic acid

[0278] ID-41 3-((7R)-1-((benzyloxy)carbonyl)-3,3,9-trimethyl-4,8-dioxooctahydro-1H-[1,2,4]oxadiazino[4,3-a][1,4]diazepin-7-yl)propanoic acid ID-42 3-((7'R)-1'-((benzyloxy)carbonyl)-9'-methyl-4',8'-dioxohexahydro-1'H,4'H-spiro[cyclobutane-1,3'-[1,2,4]oxadiazino[4,3-a][1,4]diazepin]-7'-yl)propanoic acid ID-43 3-((7R)-1-(benzylsulfonyl)-9-methyl-4,8-dioxooctahydro-1H-[1,2,4]oxadiazino[4,3-a][1,4]diazepin-7-yl)propanoic acid ID-44 (7R)-9-(1-acetylpiperidin-4-yl)-7-isobutyl-3,3-dimethyl-4,8-dioxooctahydro-1H-[1,2,4]oxadiazino[4,3-a][1,4]diazepine-1-carboxylate benzyl ID-45 (7'R)-9'-(1-acetylpiperidin-4-yl)-7'-isobutyl-4',8'-dioxohexahydro-1'H,4'H-spiro[cyclobutane-1,3'-[1,2,4]oxadiazino[4,3-a][1,4]diazepine]-1'-carboxylate benzyl

[0279] Experimental example: Notch assay CellSensor T-REx was engineered by lentiviral transfection into HeLa cells with a Notch response element (CSL-bla) driving beta-lactamase reporter gene expression along with a DOX-inducible NICD (Notch intracellular domain) construct. TM We used the NICD CSL-bla HeLa cell line, and addition of DOX to these cells down-regulates the expression of the NICD transcription factor and subsequently allows expression of beta-lactamase. Specifically, the following protocol was used: Notch Assay Protocol 1. Seed cells: HeLa / T-REx TM NICD CSL-bla cells (10 3 cells / well), in complete medium, 32 μl / well, seeded into 384-well plates. 2. Prepare 10x compounds in assay medium. 3.4 μL compound or 1% DMSO in assay medium is added to the cells. 4. Add 4 μl of 10× doxycycline in assay medium to treated wells and 4 μl of assay medium to untreated or cell-free control wells. 5. Incubate the assay plate in a humidified 37°C / 5% CO2 incubator for 16-20 hours. 6.6×LiveBLAzer TM -FRET B / G Substrate (CCF4-AM) Mixture should be prepared according to the manual, and cell loading should be in a place without direct strong lighting. 7. Remove the assay plate from the humidified 37°C / 5% CO2 incubator. Add 8 μl of the 6x Substrate Mixture prepared in step 5 to each well. Cover the plate to protect from light and evaporation. Incubate at room temperature for 4 hours. 8. Read the assay plate using the following filter selections:

[0280] [ka]

[0281] 9. Data Analysis: Use the assay plate layout to identify the location of cell-free wells. These control wells will be used for background subtraction. Measure the average emission of cell-free wells at both 460 nm (average of blue background) and 530 nm (average of green background). Subtract the blue background average (data collected at 460 nm) from all blue emission data. Subtract the green background average (data collected at 530 nm) from all green emission data. Calculate the blue / green emission ratio for each well by dividing the background-subtracted blue emission value by the background-subtracted green emission value. The results are shown in Table 6.

[0282] [Table 6] [Industrial Applicability]

[0283] The compounds of the present invention inhibit Notch signaling and can therefore be used in the treatment of diseases associated with Notch signaling. Although only certain exemplary embodiments of the present invention have been described in detail above, those skilled in the art will readily appreciate that many changes may be made in the exemplary embodiments without substantially departing from the novel teachings and advantages of the present invention, and therefore, all such modifications are intended to be included within the scope of the present invention. This application is based on U.S. Provisional Application No. 63 / 329,657 (filing date: April 11, 2022) filed in the United States, the contents of which are incorporated in their entirety herein.

Claims

1. Compounds represented by the following formula (I): 【Chemistry 1】 [In the formula, R １ It can be expressed by one of the following formulas (I-1) to (I-2): 【Chemistry 2】 * indicates a bonding site with N (nitrogen atom); R １ａ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R １ｂ This is hydrogen, optionally substituted alkyl, or -W １１ -W １２ -R １３ (In the formula, W １１ is -(CO)- or -(SO ２ ) - and W １２ is a single bond, -O-, or -N(R １４ ), and R １３ (is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl) R １４ is a hydrogen atom or an optionally substituted alkyl group. R １３ and R １４ These may bond to form saturated or unsaturated 4- to 7-membered rings which may contain carbon atoms, nitrogen atoms, or oxygen atoms, and aryl rings or heteroaryl rings may be fused together. Substituent -X １５ -R １５ However, the substitution may occur on the formed saturated or unsaturated 4- to 7-membered ring, or on a fused aryl ring or heteroaryl ring. X １５ These are -O-, -NH-, or single bonds. R １５ is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R １ｃ This is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl compound as needed; R ２ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; m is either 1 or 0; L is -CH(R) when m is 1 ９ａ ) - and when m is 0 -CH(R ９ａ )-CH(R ９ｂ )-(wherein, R ９ａ and R ９ｂ is independently a hydrogen atom or an optionally substituted alkyl group; R ３ Ha-W ３１ -W ３２ -R ３３ (In the formula, W ３１ is -(CO)-, -(SO ２ ) -, or -CH ２ - and W ３２ is -O-, -NH-, or a single bond, and R ３３ (is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl); 【Transformation 3】 It can be expressed by one of the following formulas (I-3) to (I-4): 【Chemistry 4】 R ４ａ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R ４ｂ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R ４ａ and R ４ｂ These may form a spiro ring together with the carbon atoms to which they are bonded, and may have oxygen or nitrogen atoms in the ring; A is -CH(R ５ )-,-N(R ５ )-, -O-, or single bond; R ５ is a hydrogen atom or an optionally substituted alkyl group; and Ring B is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted cycloalkyl ring, or an optionally substituted heterocycloalkyl ring. Compounds having or pharmaceutically acceptable salts thereof.

2. A is -CH ２ - or -O-; and Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. m is 1; L is -CH(R ９ａ ) - and; and R ９ａ is hydrogen or methyl; The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

4. m is 0; L is -CH(R ９ａ )-CH(R ９ｂ ) - and; and R ９ａ and R ９ｂ is independently hydrogen or methyl; The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

5. R １ａ However, it is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R １ｂ However, it is hydrogen; R １ｃ However, it is a cycloalkyl or heterocycloalkyl which is substituted as needed; and R ２ is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

6. R ４ａ However, these are hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R ４ｂ However, it is a hydrogen atom or an alkyl atom substituted as needed; and R ４ａ and R ４ｂ These may form a spiro ring together with the carbon atoms to which they are bonded, and the ring may contain an oxygen atom or a nitrogen atom; The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

7. A is -CH ２ - or -O-; Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; m is 1; L is -CH(R ９ａ ) - and; R ９ａ is hydrogen or methyl; R １ａ However, it is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R １ｂ However, it is hydrogen; R １ｃ However, it is a cycloalkyl or heterocycloalkyl that is substituted as needed; R ２ is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R ４ａ However, these are hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R ４ｂ However, it is a hydrogen atom or an alkyl atom substituted as needed; and R ４ａ and R ４ｂ These may form a spiro ring together with the carbon atoms to which they are bonded, and the ring may contain an oxygen atom or a nitrogen atom; The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

8. A is -CH ２ - or -O-; Ring B is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; m is 0; L is -CH(R ９ａ )-CH(R ９ｂ ) - and; R ９ａ and R ９ｂ These are independently hydrogen or methyl; R １ａ However, it is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R １ｂ However, it is hydrogen; R １ｃ However, it is a cycloalkyl or heterocycloalkyl that is substituted as needed; R ２ is hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R ４ａ However, these are hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R ４ｂ However, it is a hydrogen atom or an alkyl atom substituted as needed; and R ４ａ and R ４ｂ These may form a spiro ring together with the carbon atoms to which they are bonded, and the ring may contain an oxygen atom or a nitrogen atom; The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

10. The pharmaceutical composition according to claim 9, wherein the composition contains an effective amount of the compound.

11. An agent for the treatment or prevention of a disease related to Notch signaling, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a pharmaceutically acceptable substance for the treatment or prevention of diseases related to Notch signaling.

13. The composition according to claim 9 for use as a pharmaceutical for the treatment or prevention of diseases related to Notch signaling.

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