New regulations for bicyclic compounds

Abstract

Compounds of formula (I): JPEG2024504521000049.jpg50106 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 novel bicyclic compounds. More specifically, the present invention relates to novel bicyclic compounds having Notch inhibitory activity. [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. Therefore, Notch signaling is particularly important in mediating communication between neighboring cells expressing the receptor and ligand. Four Notch receptors, designated Notch1 to Notch4, are known in rodents and humans. 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 cleavages of the Notch receptor polypeptide, involving γ-secretase activity. γ-secretase activity cleaves the intracellular domain of Notch from the inner plasma membrane, translocates it to the nucleus, and forms a transcription factor complex. The Notch intracellular domain (NICD) is the active form of the protein. Notch signaling functions include proliferation, differentiation, apoptosis, angiogenesis, migration, and self-renewal (Non-Patent Documents 1 to 3).

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

[0004] Therefore, compounds that can inhibit various Notch signaling functions may be useful pharmaceuticals for various diseases associated with those functions. [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 [Problem to be solved by the invention]

[0006] An object of the present invention is to provide compounds having Notch inhibitory activity and pharmaceutical agents containing said compounds that are useful for treating various diseases. [Means for solving the problem]

[0007] As a result of extensive research to solve the above-mentioned problems, the present inventors discovered that compounds having a specific structure exhibit excellent Notch signaling inhibitory activity (hereinafter also referred to as Notch inhibitors), and thus completed the present invention.

[0008] That is, the present invention relates to the following. [1] A compound represented by the following formula (I):

[0009] [ka]

[0010] wherein R1 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; R2 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; R3 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; Q is -CH2- or -CH2CH2-; V is a bond, —CO—, —SO—, —NHCO—, or —OCO—; and R4 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. or a pharmaceutically acceptable salt thereof.

[0011] [2] A compound of [1] represented by the following formula (II):

[0012] [ka]

[0013] wherein R 1′ is hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl; R2' is optionally substituted alkyl or optionally substituted arylalkyl; R3' is hydrogen, optionally substituted alkyl, or optionally substituted arylalkyl; Q' is -CH2-, or -CH2CH2-; V' is a bond or -CO-; and R4' is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl] or a pharmaceutically acceptable salt thereof.

[0014] [3] A pharmaceutical composition comprising a compound of [1] or [2] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0015] [4] The pharmaceutical composition of [3], wherein the composition comprises an effective amount of the compound.

[0016] [5] A method for treating or preventing a disease associated with Notch signaling, comprising administering to a subject in need thereof a compound of [1] or [2] or a pharmaceutically acceptable salt thereof, or a composition of [3] or [4], in an amount effective to treat or prevent the disease.

[0017] [6] An agent for treating or preventing a disease associated with Notch signaling, comprising the compound of [1] or [2] or a pharmaceutically acceptable salt thereof.

[0018] [7] A compound of [1] or [2] or a pharmaceutically acceptable salt thereof, or a composition of [3] or [4] for use as a pharmaceutical for treating or preventing a disease associated with Notch signaling. [Effects of the Invention]

[0019] The compounds of formula (I) in the present invention inhibit Notch signaling and can therefore be used for the treatment of various diseases associated with Notch signaling. [Brief explanation of the drawings]

[0020] [Figure 1] Figure 1 shows the 1H NMR (400 MHz, CDCl3) data of 2_X01'a. [Figure 2] Figure 2 shows the 1H NMR (400 MHz, CDCl3) data of 7_X01Y01a. [Figure 3] Figure 3 shows the 1H NMR (400 MHz, CDCl3) data of 6_X01''Y04'a. DETAILED DESCRIPTION OF THE INVENTION

[0021] [Description of Implementation] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings for purposes of this application.

[0022] "Lower" means that the given radical comprises between 1 and 6 carbon atoms, unless otherwise indicated.

[0023] "Optionally substituted" means, unless otherwise indicated, that 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, the non-hydrogen substituents may be any substituent that may be attached to an atom of the given group that is specified to be substituted. Examples of substituents include -R, -OR, -COR, -COOR, -OCOR, -CONR, -NR, -NR, -COR, -NRCOOR, -SR, -SOR, -SONR, -SO, -OSOR, -NHC(NHR)NR, -NHC(NH)NH, -OPO(OH), -OPO(ONa), -CN, -NO, 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.

[0024] "Halogen" means fluorine, chlorine, bromine or iodine. "Halo" means fluoro, chloro, bromo or iodo.

[0025] "Alkyl" means a group having a straight or branched, saturated aliphatic chain of carbon atoms. X and Y indicate the number of carbon atoms in the chain. X-Y Alkyl 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 ), 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.

[0026] "Alkenyl" means a carbon chain that is 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.

[0027] "Alkynyl" means a carbon chain, straight or branched, containing at least one carbon-carbon triple bond. X and Y indicate the number of carbon atoms in the chain. 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, 2-heptynyl, and the like.

[0028] "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 1-6Non-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, and the like.

[0029] "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.

[0030] "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.

[0031] "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- to 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 to 14, more preferably 5 to 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 can be optionally quaternized, and the sulfur atom can 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 (wherein 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), quinazoline, thienopyridines (e.g., thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine), indolizines, quinolines, isoxazolo[5,4-b]pyridine, thiazolopyridines (e.g., thiazolo[4,5-b]pyridine, thiazolo[4,5-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, permidine, 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.

[0032] "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, C 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.

[0033] "Heterocycloalkyl" means cycloalkyl, as defined in this Application, provided that one or more of the atoms forming the ring is a heteroatom independently selected from N, O, and S. An "X- to 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 to 10, more preferably 3 to 8. Non-exclusive examples of heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, and the like.

[0034] Furthermore, the above definitions may also apply to the groups to which the above substituents are attached. For example, "arylalkyl" refers to a straight-chain or branched 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-chain or branched alkyl group substituted with one or more "heteroaryl" groups.

[0035] "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).

[0036] "Heterocycloalkylalkyl" means a straight-chain or branched-chain alkyl group substituted with one or more heterocycloalkyl groups.

[0037] As used herein, "monocyclic ring" refers to a monocyclic saturated or unsaturated carbocyclic ring or a monocyclic saturated or unsaturated heterocyclic ring. Typically, an "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 heterocycle" refers to 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. Nitrogen atoms may optionally be quaternized, and sulfur atoms may optionally be oxidized.

[0038] Non-exclusive examples of monocyclic saturated carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.

[0039] Non-exclusive examples of monocyclic unsaturated carbocycles include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, benzene, and the like.

[0040] Non-exclusive examples of monocyclic saturated heterocycles include pyrrolidine, piperidine, morpholine, piperazine, 1,3-dioxane, 1,4-dioxane, and the like.

[0041] 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.

[0042] "Spirocycle," as used herein, refers to a saturated or unsaturated cycloalkane or a saturated or unsaturated heterocycloalkane.

[0043] "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.

[0044] "Heterocycloalkane" means a cycloalkane, as defined herein, provided that one or more atoms forming the ring are independently a heteroatom selected from N, O, and S. An "X- to 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 to 10, more preferably 3 to 8. Non-exclusive examples of heterocycloalkanes include piperidine, morpholine, piperazine, pyrrolidine, perhydropyrrolidine, tetrahydrofuran, tetrahydropyran, 1,3-dioxane, 1,4-dioxane, and the like.

[0045] "Derivative" means a compound that differs from another compound by structural modification, for example, by replacing one atom or group of atoms or functional group with another atom or group of atoms or functional group.

[0046] "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 T.W. Greene, Protecting Groups in Organic Synthesis, 5th edition, John Wiley & Sons, Inc. 2014.

[0047] The compounds of the present invention may include these derivatives or protected derivatives.

[0048] "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-1 The compound has enantiomeric pairs (where n is the number of chiral centers). Compounds with more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers (called a "diastereomeric mixture"). When one chiral center is present, a stereoisomer can be characterized by the absolute configuration of that 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. Conventions regarding 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 can include these isomers.

[0049] "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.).

[0050] "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).

[0051] "Pharmaceutically acceptable" means useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes being acceptable for veterinary use as well as human pharmaceutical use.

[0052] "Pharmaceutically acceptable salt" or "salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable, as defined above, and has the desired pharmacological activity. Such salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts with acids such as 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-chlorobenzaldehyde, benzoic acid ... 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 sulfonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0053] Pharmaceutically acceptable salts also include base addition salts, which 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.

[0054] A "therapeutically effective amount" means the amount that, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

[0055] 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.

[0056] An "effective amount" is the same as a "therapeutically effective amount" and a "prophylactically effective amount."

[0057] "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., arresting 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 (ie, reversal of the pathology and / or symptomology) in an animal experiencing or exhibiting the pathology or symptomology of the disease.

[0058] It should be noted that with respect to all definitions provided herein, the definitions should be construed as open-ended in the sense that additional substituents beyond those specified may be included.

[0059] In another embodiment of formula (I), the compound has the following formula (II):

[0060] [ka]

[0061] wherein R 1′ is hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl; R2' is optionally substituted alkyl or optionally substituted arylalkyl; R3' is hydrogen, optionally substituted alkyl, or optionally substituted arylalkyl; Q' is -CH2-, or -CH2CH2-; V' is a bond or -CO-; and R4' is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl. or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment of Formula (I), R1 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.

[0063] 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.

[0064] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0065] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0066] 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.

[0067] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0068] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, benzyloxycarbonylpiperidinyl, and the like.

[0069] Examples of the optionally substituted arylalkyl group 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, and 4-n- Examples include aryl alkyls having a substituted oxy group such as heptadecyloxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, and 4-phenethyloxybenzyl; aryl alkyls having a hydroxy group such as 4-hydroxybenzyl and 4-hydroxy-3-methoxybenzyl; aryl alkyls having a halogen atom such as 4-fluorobenzyl, 3-chlorobenzyl, and 3,4-dichlorobenzyl; 2-furfuryl, diphenylmethyl, 1-naphthylmethyl, and 2-naphthylmethyl.

[0070] Examples of optionally substituted heteroarylalkyl groups include 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.

[0071] 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.

[0072] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0073] In another embodiment of formula (I), R1 is hydrogen, optionally substituted alkyl (e.g., isopentyl), optionally substituted heterocycloalkyl (e.g., benzyloxycarbonylpiperidinyl), optionally substituted arylalkyl (e.g., phenethyl, hydroxyphenethyl), or.

[0074] In one embodiment of Formula (I), R2 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.

[0075] 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, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, and the like.

[0076] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0077] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0078] Examples of optionally substituted aryl groups and optionally substituted heteroaryls 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.

[0079] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0080] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, and the like.

[0081] Examples of the optionally substituted arylalkyl group 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, and 4-n-heptadecyloxybenzyl; aryl alkyl having a substituted oxy group such as 4-hydroxybenzyl, 4-hydroxy-3-methoxybenzyl, hydroxyphenethyl, etc.; aryl alkyl having a hydroxy group such as 4-fluorobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl; aryl alkyl having a halogen atom such as 4-fluorobenzyl, 3-chlorobenzyl, 3,4-dichlorobenzyl; 2-furfuryl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, etc.

[0082] Examples of optionally substituted heteroarylalkyl groups include 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.

[0083] 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.

[0084] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0085] In another embodiment of Formula (I), R2 is optionally substituted alkyl (eg, isobutyl, aminocarbonylethyl) or optionally substituted arylalkyl (eg, benzyl, hydroxybenzyl).

[0086] In one embodiment of Formula (I), R3 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.

[0087] 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, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, and the like.

[0088] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0089] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0090] Examples of optionally substituted aryl groups and optionally substituted heteroaryls 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.

[0091] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0092] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, and the like.

[0093] Examples of the optionally substituted arylalkyl group include unsubstituted arylalkyl groups or arylalkyl groups 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 groups having an aryl group or arylalkyl group, such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, and 4-n-heptadecyl Examples of aryl alkyl having a substituted oxy group include oxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, and 4-phenethyloxybenzyl; aryl alkyl having a hydroxy group such as 4-hydroxybenzyl, 4-hydroxy-3-methoxybenzyl, and 4-hydroxyphenethyl; aryl alkyl having a halogen atom such as 4-fluorobenzyl, 3-chlorobenzyl, and 3,4-dichlorobenzyl; and 2-furfuryl, diphenylmethyl, 1-naphthylmethyl, and 2-naphthylmethyl.

[0094] Examples of optionally substituted heteroarylalkyl groups include 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.

[0095] 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.

[0096] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0097] In another embodiment of formula (I), R3 is hydrogen, optionally substituted alkyl (e.g., isobutyl, hydroxymethyl, methylthioethyl, aminocarbonylethyl), optionally substituted arylalkyl (e.g., benzyl, hydroxybenzyl, hydroxyphenethyl).

[0098] In one embodiment of Formula (I), R4 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.

[0099] 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, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, and the like.

[0100] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0101] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0102] Examples of optionally substituted aryl groups and optionally substituted heteroaryls 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.

[0103] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0104] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,4-diazaperhydroepynyl, 1,3-dioxanyl, 1,4-dioxanyl, and the like.

[0105] Examples of the optionally substituted arylalkyl group include unsubstituted arylalkyl groups or arylalkyl groups 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 groups having an aryl group or arylalkyl group, such as 4-benzylbenzyl, 4-phenethylbenzyl, and 4-phenylbenzyl; 4-methoxybenzyl, 4-n-tetradecyloxybenzyl, and 4-n-heptadecyl Examples of aryl alkyl having a substituted oxy group include oxybenzyl, 3,4-dimethoxybenzyl, 4-methoxymethylbenzyl, 4-vinyloxymethylbenzyl, 4-benzyloxybenzyl, and 4-phenethyloxybenzyl; aryl alkyl having a hydroxy group such as 4-hydroxybenzyl, 4-hydroxy-3-methoxybenzyl, and 4-hydroxyphenethyl; aryl alkyl having a halogen atom such as 4-fluorobenzyl, 3-chlorobenzyl, and 3,4-dichlorobenzyl; and 2-furfuryl, diphenylmethyl, 1-naphthylmethyl, and 2-naphthylmethyl.

[0106] Examples of optionally substituted heteroarylalkyl groups include 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.

[0107] 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.

[0108] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0109] In another embodiment of Formula (I), R4 is hydrogen, optionally substituted alkyl (e.g., methyl, isopentyl), optionally substituted aryl (e.g., phenyl), or optionally substituted arylalkyl (e.g., phenethyl, hydroxyphenethyl).

[0110] In another embodiment of Formula (I), Q is -CH2-.

[0111] In another embodiment of Formula (I), Q is -CH2CH2-.

[0112] In another embodiment of Formula (I), V is a bond, —CO—, —SO 2 —, —NHCO—, or —OCO—.

[0113] In another embodiment of Formula (I), V is a bond or -CO-.

[0114] A preferred embodiment of formula (I) is a compound having the following formula (II): or a pharmaceutically acceptable salt thereof:

[0115] [ka]

[0116] wherein R 1′ is hydrogen, optionally substituted alkyl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl; R2' is optionally substituted alkyl or optionally substituted arylalkyl; R3' is hydrogen, optionally substituted alkyl, or optionally substituted arylalkyl; Q' is -CH2-, or -CH2CH2-; V' is a bond or -CO-; and R4' is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl.

[0117] Hereinafter, the compounds having formula (I) or formula (II) will also be referred to as "compounds of the present invention."

[0118] The general synthesis of the compounds of the present invention is described below in the "Preparation" section. The abbreviations used in the Preparations and Examples are as follows: AcOH: acetic acid Ac2O: acetic anhydride aq.:Aqueous solution AZADOL: 2-hydroxy-2-azaadamantane Cbz: benzyloxycarbonyl Bn: Benzyl Boc: tert-butoxycarbonyl Boc2O: di-tert-butyl dicarbonate CHCl3: Chloroform DCM: dichloromethane DIEA: N,N-diisopropylethylamine DIPEA: N-ethyl-N-isopropyl-propan-2-amine DMB: 2,4-dimethoxybenzyl DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EtO(OEt): Ethoxy EtOAc: ethyl acetate Fmoc: 9-fluorenylmethyloxycarbonyl HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt: 1-hydroxybenzotriazole hr: time MeCN: acetonitrile MeO(OMe): methoxy MeOH: Methanol MsO: methanesulfonyloxy OAc(AcO): Acetoxy PE / EA: Petroleum ether: Ethyl acetate Ph: Phenyl rt: room temperature sat.: saturated TBAF: Tetramethylammonium fluoride TBS: tert-butyldimethylsilyl TBDPS: tert-butyldiphenylsilyl tBu: tert-butyl TEA: Triethylamine TFA: Trifluoroacetic acid THF: tetrahydrofuran TMSOTf: Trimethylsilyl triflate Trt: Trityl TsO: toluenesulfonyloxy

[0119] Manufacturing method In the formula, R1 to R4, V and Q are as defined above in compound (I).

[0120] wherein U is —COCl, —COH, —CHO, —SOCl, —NCO, or —OCOCl.

[0121] In the formula, a Boc group is shown as the nitrogen atom-protecting group, a TBDMS group as the hydroxyl group-protecting group, and a Cl group and a Br group as the leaving groups; however, these are not limiting, and commonly known nitrogen atom-protecting groups (e.g., a Cbz group, a Bn group, etc.), hydroxyl group-protecting groups (e.g., a Bn group, etc.), and leaving groups (e.g., an MsO group, a TsO group, etc.) may also be used.

[0122] Each compound in the formula may form a salt if necessary.

[0123] Each step will be described below. Note that the reaction conditions in each step are not limited to those described below, and generally known reagents and reaction conditions can be used.

[0124] Preparation of Compound (I)

[0125] [ka]

[0126] The compound number of the derivative of compound (I) is compound 11_XiYjZmWna,b.

[0127] In the formula of compound 11_XiYjZmWna,b, when R4 is hydrogen and V is a bond, compound 11_XiYjZmWna,b is compound 10_XiYjZma,b.

[0128] [Step 1] Reductive alkylation The corresponding compounds 2_Xia and 2_Xib (compounds 2_Xia, b) can be synthesized by reacting known compounds, such as reagent 1a (Dondoni, Alessandro, et al., Organic Syntheses (2000), 77, 64-77), or 1b (Ouathek Ouerfelli, et al., Synlett (1993), 6, 409-410), with reagent Xi and a reducing agent in a solvent. The reducing agent is preferably NaBH(OAc) or NaBHCN, and the solvent is preferably DCM or MeOH. The reaction temperature is preferably 0-20°C, and the reaction time is preferably 16 hours.

[0129] [Step 2] Amidation Compound 3_XiYja,b (compound 3_XiYja (Q = CH2), 3_XiYjb (Q = CH2CH2)) can be synthesized by reacting 2_Xia,b with a condensing agent Yj and a base in a solvent. EDCI-HOBt or HATU is preferred as the condensing agent, and 2,4,6-trimethylpyridine or DIPEA is preferred as the base. DCM is preferred as the solvent. The reaction temperature is preferably 0 to 20°C, and the reaction time is preferably 16 hours.

[0130] [Step 3] Deprotection Compound 4_XiYja,b (compound 4_XiYja (Q = CH2), 4_XiYjb (Q = CH2CH2)) can be synthesized by reacting 3_XiYja,b with a deprotecting agent in a solvent. The deprotecting agent is preferably TFA, TMSOTf-TEA, or H2SO4. The solvent is preferably DCM, water, or a mixture thereof. The reaction temperature is preferably 0 to 25°C, and the reaction time is preferably 1 to 3 hours.

[0131] [Step 4] Ring closure Compound 5_XiYja,b (compound 5_XiYja (Q = CH2), 5_XiYjb (Q = CH2CH2)) can be synthesized by reacting 4_XiYja,b with a base in a solvent. Na2CO3 is preferred as the base, and MeCN, water, or a mixture thereof is preferred as the solvent. The reaction temperature is preferably -30 to 20°C, and the reaction time is preferably 1 to 16 hours.

[0132] [Step 5] Protection Compound 6_XiYja,b (compound 6_XiYja (Q = CH2), 6_XiYjb (Q = CH2CH2)) can be synthesized by reacting 5_XiYja,b with a protecting agent in a solvent. Boc2O is preferred as the protecting agent. A base may be added, and DIPEA is preferred as the base. DCM is preferred as the solvent. The reaction temperature is preferably 20°C, and the reaction time is preferably 24 hours.

[0133] [Step 6] Hydroxyl group oxidation Compound 7_XiYja,b (compound 7_XiYja (Q = CH2), 7_XiYjb (Q = CH2CH2)) can be synthesized by reacting 6_XiYja,b with an oxidizing agent in a solvent. DMSO-(COCl)2 is preferred as the oxidizing agent. A base may be added, and DIPEA is preferred as the base. DCM is preferred as the solvent. The reaction temperature is preferably -78 to 0°C, and the reaction time is preferably 2 hours.

[0134] NaClO can also be used as an oxidizing agent. In this case, AZADOL is added as a catalyst, KBr is added as an additive, and NaHCO3 is added as a base. A mixed solvent of DCM and water is preferred. The reaction temperature is preferably 0°C, and the reaction time is preferably 0.5 hours.

[0135] [Step 7] Reductive alkylation Compound 8_XiYjZma,b (compound 8_XiYjZma (Q=CH2), 8_XiYjZmb (Q=CH2CH2)) can be synthesized by carrying out [Step 1] using 7_XiYja,b and Zm.

[0136] [Step 8] Deprotection By carrying out [Step 3] using 8_XiYjZma,b, compounds 9_XiYjZma,b (compounds 9_XiYjZma (Q = CH2), 9_XiYjZmb (Q = CH2CH2)) can be synthesized.

[0137] [Step 9] Ring closure Compound 10_XiYjZma,b (compound 10_XiYjZma (Q = CH2), 10_XiYjZmb (Q = CH2CH2)) can be synthesized by heating 9_XiYjZma,b together with an additive in a solvent. AcOH is preferred as the additive, and MeCN or toluene is preferred as the solvent. The reaction temperature is preferably 50 to 80°C, and the reaction time is preferably 4 to 12 hours.

[0138] Alternatively, 10_XiYjZma,b can be synthesized by converting the ester group of 9_XiYjZma,b to a carboxylic acid and then carrying out [Step 2]. In the formula, the ester group is a methyl ester group, but is not limited thereto. For example, when the ester group is a t-butyl ester, it can be converted to a carboxylic acid by deprotection with an acid. In this case, the conversion can be carried out simultaneously with the deprotection in [Step 8].

[0139] [Step 10] Acylation / Alkylation Compound 11_XiYjZmWna,b (compound 11_XiYjZmWna (Q=CH2), 11_XiYjZmWnb (Q=CH2CH2)) can be synthesized by reacting 10_XiYjZma,b with various R4-U(Wn) or acid anhydrides ((R4-CO)2O) in a solvent.

[0140] For example, compound 11_XiYjZmWna,b can be synthesized by reacting R4-U (Wn: U=COCl) or (R4-CO)2O with a base in a solvent, or by performing [Step 1] using R4-U (Wn: U=CHO), or by performing [Step 2] using R4-U (Wn: U=CO2H).

[0141] In the case of R4-U (Wn: U=COCl) or (R4-CO)2O, TEA is preferred as the base and DCM is preferred as the solvent. The reaction temperature is preferably 0 to 20°C, and the reaction time is preferably 16 hours.

[0142] Compound 11_XiYjZmWna,b can also be synthesized by carrying out 8_XiYjZma,b in the order of [Step 10], [Step 8] and [Step 9].

[0143] The above-mentioned Xi, Yj, Zm and Wn may be commercially available products or may be synthesized by known synthesis methods.

[0144] By using optically active forms of 1 (1a or 1b), Yj, and Zm, the conformations at positions 3, 6, and 9a of compound 11_XiYjZmWna,b can be controlled.

[0145] In this case, compound (I) having any stereochemical properties can be produced by isolating the diastereomers in any of [Step 1] to [Step 10] of the above production method.

[0146] For example, the diastereomers can be isolated by purifying 6_XiYja,b or by purifying after protecting the hydroxyl groups. Preferred purification methods include silica gel column chromatography and preparative HPLC. An example is shown below.

[0147] [ka]

[0148] [Step 11-1] Protection of hydroxyl groups Compound 6'_XiYja,b can be synthesized by reacting 6_XiYja,b with a silylating agent and a base in a solvent. The silylating agent is preferably TBDPSCl, and the base is preferably imidazole. The solvent is preferably dichloromethane. The reaction temperature is preferably 20°C, and the reaction time is preferably 16 hours. By protecting the hydroxyl groups in this manner, the diastereomers can be isolated by silica gel column chromatography or preparative HPLC.

[0149] [Step 11-2] Protection of hydroxyl groups Compound 6_XiYja,b can be synthesized by reacting the thus obtained 6'_XiYja,b with a deprotecting agent in a solvent. TBAF is preferred as the deprotecting agent, and THF is preferred as the solvent. The reaction temperature is preferably 20°C, and the reaction time is preferably 0.5 hours.

[0150] In the above production method, any of the substituents R1 to R4 can be converted to a different substituent at any position in the formula by a functional group conversion reaction.

[0151] In the formula, when any of R1 to R4 requires a protecting group, the protection and deprotection can be carried out at any position in the formula. An example is shown below.

[0152] [ka]

[0153] [Step 12] Deprotection Deprotection of 6_X01''Y04''a by catalytic hydrogenation can synthesize 6_X01''Y04''a. Pd / C is preferred as the catalyst, and the reaction is preferably carried out under a hydrogen atmosphere as the hydrogen source. MeOH is preferred as the solvent. The reaction temperature is preferably 0-20°C, and the reaction time is preferably 2 hours.

[0154] The obtained 6_X01''Y04''a can be subjected to [Step 2] using 2,4-dimethoxybenzylamine to synthesize compound 6_X01''Y04'a.

[0155] [ka]

[0156] [Step 13] Deprotection of amide group Compound 6_X01Yja can be synthesized by reacting 6_X01'Yja with a deprotecting agent in a solvent. The deprotecting agent is preferably Li-NH3 (liq.). The solvent is preferably THF. The reaction temperature is preferably -78°C, and the reaction time is preferably 2 hours.

[0157] To further explain, the compound of the present invention, its salts and derivatives thereof are excellent in pharmacological selectivity, safety (various toxicities and safety pharmacology), pharmacokinetic properties, physicochemical properties, etc., and therefore their usefulness as active ingredients of drugs can be confirmed.

[0158] 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.

[0159] Examples of safety tests 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.

[0160] 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 or MDCK cells), drug transporter ATPase assays, 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.).

[0161] 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.

[0162] In another embodiment, there is a method for 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, etc., regulated by the Notch signaling pathway.

[0163] 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).

[0164] Here, the test compound is a compound described herein, i.e., a compound of the present invention. Typically, the test compound can be tested at several different concentrations, which are selected in part depending on the assay conditions.

[0165] The compounds of the present invention can inhibit Notch signaling by interacting with the Notch intracellular domain.

[0166] The present invention also relates to prodrugs using libraries containing one or more compounds of the present invention. Prodrugs are typically designed to release the active drug in the body during or after absorption by enzymatic and / or chemical hydrolysis. The prodrug approach is 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 containing hydroxyl groups is to prepare esters containing ionizable groups, such as phosphate groups, carboxylic acid groups, and alkylamino groups (Fleisher et al., Advanced Drug Delivery Reviews, 115-130, 1996; Davis et al., Cancer Res., 7247-7253).

[0167] 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 present invention, as described in detail below.

[0168] The pharmaceutical compositions of the present invention can be formulated to suit the intended route of administration. Examples of administration routes include parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions (e.g., injectable solutions) used for parenteral (particularly intravenous), intradermal, or subcutaneous administration may contain the following components: a sterile diluent such as water for injection, saline, fixed oil, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate; and an isotonic agent such as sodium chloride or dextrose. Furthermore, the pH can be adjusted with acids or bases (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.

[0169] Pharmaceutical compositions suitable for injection 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 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 preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., 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. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like). In many cases, it is preferable to include isotonic agents (e.g., sugars, polyalcohols such as mannitol or sorbitol, sodium chloride) in the composition. 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.

[0170] Sterile injectable solutions can be prepared by incorporating the active compound, 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 ingredients, as needed, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing the required other ingredients from those mentioned above and a dispersion medium. In the case of sterile powders for preparing sterile injectable 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.

[0171] Oral compositions generally contain an inert diluent or an edible carrier. These may be sealed in gelatin capsules or compressed into tablets. For oral therapeutic purposes, the active compound may be incorporated with excipients and used in the form of tablets, troches, or capsules.

[0172] Oral compositions can also be prepared using 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 adjuvants can be included as part of the composition. Tablets, pills, capsules, troches, etc. 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, or disintegrating agents 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.

[0173] 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 (e.g., a gas such as carbon dioxide) or nebulizer.

[0174] Systemic administration can also be via transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant appropriate to 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, and fusidic acid derivatives.Transmucosal administration can be achieved by using nasal sprays or suppositories.For transdermal administration, the active compound is generally formulated into ointments, salves, gels, or creams known in the art.

[0175] The compounds of the invention can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0176] In one embodiment, the active compound can be prepared with a carrier that protects the compound against rapid elimination from the body, such as a controlled-release dosage form, 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 readily apparent to those skilled in the art. Materials are also commercially available 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 pharmaceutically 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.

[0177] For ease of administration and uniformity of dosage, it may be more advantageous to formulate oral or parenteral compositions in the form of dosage units. As used herein, dosage unit form refers to a physically discrete unit suitable for a single dose for the subject to be treated; each unit contains a predetermined amount of active compound calculated in association with the necessary pharmaceutical carrier to produce the desired therapeutic effect. The specifications for the dosage unit form of the present invention are determined by and directly depend on the unique characteristics of the active compound, the particular therapeutic effect to be achieved, and the limitations inherent in the technology of compounding such active compounds for individual treatment.

[0178] For example, in some embodiments, the pharmaceutical compositions of the present invention are suitable for oral administration in a unit dose, e.g., a tablet or capsule containing about 1 mg to about 1 g of a compound of the present invention. In other embodiments, the pharmaceutical compositions of the present invention are suitable for intravenous, subcutaneous, or intramuscular injection. A patient may receive, for example, an intravenous, subcutaneous, or intramuscular dose of a compound of the present invention of about 1 μg / kg to about 1 g / kg. Intravenous, subcutaneous, and intramuscular doses may be given by means of bolus injection. Alternatively, the intravenous dose may be given by continuous infusion over a period of time. Alternatively, a patient may receive a daily oral dose approximately equivalent to the daily parenteral dose, with the composition being administered 1 to 4 times per day.

[0179] 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).

[0180] 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 parenteral administration is generally 1 to 10,000 mg / day / m per human body surface area by continuous infusion. 2 The range is preferably 1 to 5000 mg / day / m per human body surface area. 2 and more preferably 10 to 5000 mg / day / m per human body surface area. 2 is.

[0181] The pharmaceutical composition containing the compound of the present invention can be used for diseases controlled by the Notch signaling pathway. Specifically, compounds that inhibit Notch signaling suppress the expression of Hes1 and Hes5, providing a method for promoting the differentiation of neural stem cells, and are expected to be candidates for new neuroregenerative drugs.

[0182] 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. "Neural stem cells" are clonogenic, undifferentiated, pluripotent cells that can differentiate into neurons, astrocytes, and oligodendrocytes under appropriate conditions. A compound promotes neural stem cell differentiation if 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: 317-26, 2002; Fukunaga et al., supra). Neural stem cells may be cultured stem cells, stem cells freshly isolated from their source tissue, or stem cells within their source organism. Thus, contacting neural stem cells with the compounds of the present invention can be carried out either in vitro (in the case of cultured stem cells or freshly isolated stem cells) or in vivo (in the case of stem cells within their source organism). The resulting differentiated neural cells, when 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 tissue affected by trauma or neurodegenerative disease.

[0183] The following non-limiting examples illustrate the compounds, compositions, and methods of use of the present invention.

[0184] Example The present invention will be explained 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.

[0185] In the examples, Bruker AVANCE III 400, Bruker AVANCE III 400HD, and Bruker AVANCE NEO40 were used. 1 H NMR was measured. LC / MS was performed using an Agilent 1100 LC and Agilent G1956A (ELSD:1260 Infinity) or a Shimadzu UFLC / MS system (Shimazu-2020 mass spectrometer, ODS column chromatography). LC / MS analysis using the Agilent system was performed under the conditions listed in Table 1 or Table 2. LC / MS analysis using the Shimadzu UFLC / MS system was performed under the following conditions: the mobile phase was either water containing 0.04% TFA or acetonitrile containing 0.04% TFA, or 5 mM AcONH4 in water and 5 mM AcONH4 in acetonitrile.

[0186] [Table 1]

[0187] [Table 2]

[0188] General preparative HPLC conditions (FA): Column: Phenomenex Gemini 25x150mm, 5μm Mobile phase A: 0.225% v / v formic acid in water Mobile phase B: acetonitrile UV detection wavelength: 220 nm Flow rate: 25ml / min Gradient Time Table 0 min Start_b%B (the percentage of A is 100-B) 11 minutes End_b%B 11.2 minutes 100%B 13 minutes 100%B 13.2 minutes 5%B The values ​​of A and B vary depending on the type of compound.

[0189] [Example 1] Synthesis of (3S,6S,9aR)-3,6-diisobutyl-2-methylhexahydro-4H-pyrazino[1,2-a]pyrazine-4,7(6H)-dione (11_X01Y01Z01W01a) [Example 1-1]

[0190] [ka]

[0191] A solution of 1a (0.12 kg) and X01' (57 g) in DCM (2.5 L) was stirred at 20 °C for 1 h. NaBH(OAc) (0.16 kg) was added to the mixture at 0-10 °C. The mixture was then stirred at 20 °C for 16 h. The reaction mixture was adjusted to pH 7 with saturated NaCO aqueous solution and extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 50 / 1 to 0 / 1) to give compound 2_X01'a (0.12 kg) as a yellow oil. 2_X01'a 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 1. [Example 1-2]

[0192] [ka]

[0193] To a solution of 2_X01'a (25 g) and Y01 (21 g) in DCM (0.50 L) was added HOBt (11 g), 2,4,6-trimethylpyridine (10 g), and EDCI (16 g) at 0-10 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (0.10 L). The organic layer was washed with 1 N HCl (0.10 L × 2), saturated Na2CO3 aqueous solution (0.10 L × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 20 / 1) to give 3_X01'Y01a (27 g) as a yellow oil. LCMS:m / z=499.0[M+2]+,497.0[M]+ [Examples 1-3]

[0194] [ka]

[0195] To a solution of 3_X01'Y01a (27 g) in DCM (0.13 L) was added HO (4.8 mL), followed by dropwise addition of TFA (48 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with water (0.10 L) and extracted with EtOAc (80 mL × 2). The combined organic layers were washed with 1 N HCl (80 mL × 2), saturated NaCO aqueous solution (80 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 100 / 1 to 0 / 1) to give 4_X01'Y01a (24 g, TFA salt) as a yellow oil. LCMS:m / z=359.1[M+2]+,357.1[M]+ [Examples 1-4]

[0196] [ka]

[0197] To a solution of 4_X01'Y01a (8.0 g, TFA salt) in MeCN (85 mL) was added Na2CO3 (4.9 g) at -30 to -20 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated to give a residue. The residue was diluted with water (80 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were washed with brine (0.10 L × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. This reaction was carried out in three batches. The combined residue was purified by column chromatography (SiO2, PE / EA = 10 to 0 / 1) to give 5_X01'Y01a (13 g) as a yellow oil. LCMS: m / z=277.2[M+1]+ [Examples 1-5]

[0198] [ka]

[0199] To a solution of 5_X01'Y01a (13 g) in DCM (0.30 L) was added BocO (11 g) and DIEA (8.4 g). The mixture was stirred at 25 °C for 24 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (0.20 L) and extracted with EtOAc (0.15 L × 2). The combined organic layers were washed with 1 N HCl (0.15 L × 2), saturated NaCO aqueous solution (0.15 L × 2), brine (0.10 L × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 20 / 1 to 1 / 1) to give 6_X01'Y01a (12 g) as a yellow oil. LCMS: m / z=377.3[M+1]+ [Examples 1-6]

[0200] [ka]

[0201] To a solution of 6_X01'Y01a (12 g) in DCM (0.14 L) was added imidazole (6.3 g) and TBDPSCl (19 g). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated to give a residue. The residue was diluted with water (0.10 L) and extracted with EtOAc (0.10 L × 2). The combined organic layers were washed with 1 N HCl (0.10 L × 2), saturated Na2CO3 aqueous solution (0.10 L × 2), brine (0.10 L × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 20 / 1) to give 6'_X01'Y01a (20 g) as a yellow oil. LCMS: m / z=615.4[M+1]+ [Examples 1-7]

[0202] [ka]

[0203] To a solution of 6'_X01'Y01a (22 g) in THF (0.25 L) was added TBAF (1 M, 72 mL) at 0 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was then diluted with water (0.20 L) and extracted with EtOAc (0.20 L × 2). The combined organic layers were washed with 1 N HCl (0.20 L × 2), saturated Na2CO3 aqueous solution (0.20 L × 2), brine (0.20 L × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 1 / 1) to give 6_X01'Y01a (9.4 g) as a white solid. LCMS: m / z=377.3[M+1]+ [Examples 1-8]

[0204] [ka]

[0205] NH3 (gas) was added to the flask at -60 °C to give a solution of NH3 (50 mL). Li (1.3 g) was then added portionwise to the solution at -78 °C, followed by stirring at -78 °C for 10 min. Next, a solution of 6_X01'Y01a (4.0 g) in THF (32 mL) was added to the mixture at -78 °C and stirred at -78 °C for 2 h. The mixture was poured into saturated NH4Cl aq. (0.50 L) and extracted with EtOAc (0.10 L × 3). The combined organic layers were washed with brine (0.10 L × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) to give 6_X01Y01a (2.1 g) as a white solid. LCMS: m / z=309.1 [M+Na+]+ [Examples 1-9]

[0206] [ka]

[0207] To a solution of DMSO (2.1 g) in DCM (30 mL) was added (COCl) (2.0 g) at -70 °C, and the mixture was stirred at -70 °C for 1 h. Then, a solution of 6_X01Y01a (3.0 g) in DCM (30 mL) was added dropwise at -70 °C. After the addition, DIPEA (6.8 g) was added dropwise at -60 °C. The mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was washed with 1 N HCl (40 mL × 2), followed by saturated aqueous NaHCO (40 mL × 2) and brine (40 mL × 2). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 20 / 1 to 0 / 1) to give 7_X01Y01a (1.8 g) as a yellow oil. 7_X01Y01a 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 2. [Examples 1-10]

[0208] [ka]

[0209] To a solution of Z01 (1.4 g, HCl salt) in MeOH (20 mL) was added NaOAc (1.0 g), and the mixture was stirred at 20 °C for 0.5 h. Then, 7_X01Y01a (1.8 g) was added, and the mixture was stirred at 20 °C for 0.5 h. NaBH3CN (0.80 g) was added to the mixture, and the mixture was stirred at 20 °C for 15 h. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (50 mL), washed with saturated NaHCO3 aq. (30 mL × 2), brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 8_X01Y01Z01a (0.7 g, TFA salt) as a white solid. LCMS: m / z=414.3[M+1]+ [Examples 1-11]

[0210] [ka]

[0211] To a solution of 8_X01Y01Z01a (0.40 g) in DCM (3.0 mL) was added TFA (3.0 mL). The mixture was stirred at 20 °C for 2 hr. The residue was concentrated below 30 °C to give a residue. The reaction mixture was diluted with 20% K2CO3 aq. (20 mL) and extracted with CHCl3 (20 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 9_X01Y01Z01a (0.25 g) as a white solid. LCMS: m / z=314.2[M+1]+ [Examples 1-12]

[0212] [ka]

[0213] To a solution of 9_X01Y01Z01a (0.25 g) in MeCN (2.0 mL) was added AcOH (2.0 mL), and the mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 10_X01Y01Z01a (0.20 g) as a white solid. LCMS: m / z=282.2[M+1]+ [Examples 1-13]

[0214] [ka]

[0215] To a solution of 10_X01Y01Z01a (60 mg) in MeOH (2.0 mL) was added NaOAc (25 mg), and the mixture was stirred at 20 °C for 0.5 h. Next, W01 (8.4 μL) was added, and the mixture was stirred at 20 °C for 0.5 h. To the mixture was added NaBH3CN (29 mg), and the mixture was stirred at 20 °C for 15 h. The mixture was quenched by the addition of water (0.10 mL) and filtered. The filtrate was purified by prep-HPLC to give 11_X01Y01Z01W01a (29 mg) as an off-white solid.

[0216] Example 2: Synthesis of (3S,6S,9aR)-2-acetyl-3,6-diisobutylhexahydro-4H-pyrazino[1,2-a]pyrazine-4,7(6H)-dione (11_X01Y01Z01W02a)

[0217] [ka]

[0218] To a solution of 10_X01Y01Z01a (60 mg) in DCM (1.0 mL) was added TEA (46 mg) and W02 (13 mg) at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 11_X01Y01Z01W02a (31 mg) as a white solid.

[0219] [Example 3] Synthesis of (3S,6S,9aR)-2-(3-(4-hydroxyphenyl)propanoyl)-3,6-diisobutylhexahydro-4H-pyrazino[1,2-a]pyrazine-4,7(6H)-dione (11_X01Y01Z01W08a)

[0220] [ka]

[0221] To a solution of 10_X01Y01Z01a (44 mg) and W08 (31 mg) in DMF (2.0 mL) was added DIPEA (82 μL) and HATU (72 mg) at 0 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered. The filtrate was purified by prep-HPLC to give 11_X01Y01Z01W08a (34 mg) as a white solid.

[0222] [Example 4] Synthesis of 3-((3S,6S,9aR)-6-isobutyl-2-(4-methylpentyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrazin-3-yl)propenamide (11_X01Y01Z06W03a) [Example 4-1]

[0223] [ka]

[0224] A mixture of W03 (90 mg) and 8_X01Y01Z06'a (0.12 g) in MeOH (2.0 mL) was stirred at 20 °C for 0.5 h. Then, NaBH3CN (34 mg) was added to the reaction mixture. The mixture was stirred at 40 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 50 / 1 to 1 / 1) to give 12_X01Y01Z06'W03a (0.15 g) as a yellow oil. LCMS: m / z=756.4[M+1]+ [Example 4-2]

[0225] [ka]

[0226] To a solution of 12_X01Y01Z06'W03a (0.15 g) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give 13_X01Y01Z06W03a (80 mg) as a yellow oil. LCMS: m / z=413.4[M+1]+ [Example 4-3]

[0227] [ka]

[0228] To a solution of 13_X01Y01Z06W03a (80 mg) in MeCN (2.0 mL) was added AcOH (2.0 mL). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give 11_X01Y01Z06W03a (30 mg) as a white solid.

[0229] [Example 39] Synthesis of (6S,10aR)-6-benzyl-8-isopentyl-2-(3-phenylpropanoyl)hexahydropyrazino[1,2-d][1,4]diazepine-4,7(1H,6H)-dione (11_X02Y02Z07W07b)

[0230] [ka]

[0231] To a solution of 12_X02Y02Z07W07b (5.8 mg) in DCM (0.2 mL) was added TFA (0.1 mL) at rt. After stirring at the same temperature for 3 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (0.2 mL), and DIPEA (3.9 μL) and HATU (4.1 mg) were added at rt. After stirring at the same temperature for 5 h, the reaction was quenched with 1 M HCl aq., and the aqueous layer was extracted with two portions of EtOAc. The combined organic layers were washed with saturated NaHCO3 aq. and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative plate (60% EtOAc in hexane) to give 11_X02Y02Z07W07b (3.9 mg) as a colorless oil.

[0232] Reference Example 1 (Example of an alternative method to the reactions in Examples 1 to 3)

[0233] [ka]

[0234] To a solution of 3_X01'Y03'a (80 g) and TEA (0.28 L) in DCM (1.2 L) was added TMSOTf (0.24 L) dropwise at 0-10 °C. The mixture was stirred at 20 °C for 1 h. The mixture was washed with water (1.5 L × 2) and then with Na2 S Drying over O4, filtration and concentration gave 4_X01'Y03'a (80 g) as a yellow oil. LCMS:m / z=505.2[M+2]+,503.2[M]+

[0235] [Reference Example 2] Synthesis of Intermediate 6_X01''Y04'a [Reference example 2-1]

[0236] [ka]

[0237] To a solution of 6_X01''Y04''a (4.0 g) in MeOH (40 mL) was added Pd / C (0.40 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 23 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. This reaction was carried out in two batches to give 6_X01''Y04''a (5.5 g) as a colorless oil. LCMS: m / z=453.0[M+1]+ [Reference example 2-2]

[0238] [ka]

[0239] To a solution of 6_X01''Y04''a (5.0 g) and (2,4-dimethoxyphenyl)methanamine (3.3 g) in DCM (50 mL) was added HOBt (2.7 g), followed by 2,4,6-trimethylpyridine (2.4 g) at 0-10 °C. The mixture was stirred at 0 °C for 0.5 h, and then EDCI (3.8 g) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 15 h. The reaction mixture was diluted with water (0.10 L). The organic layer was washed with 1 N HCl (0.10 L × 2), saturated Na2CO3 aqueous solution (0.10 L × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 5 / 1 to 0 / 1) to give 6_X01''Y04''a (5.0 g) as a colorless oil. 6_X01''Y04'a 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 3.

[0240] Reference Example 3 (Example of an alternative method for the reactions of Examples 1 to 9)

[0241] [ka]

[0242] 6_X05Y01a (0.25 g), AZADOL (0.80 mg), and KBr (5.9 mg) were dissolved in DCM (3.0 mL) and a mixture of saturated aqueous NaHCO3 (1.0 mL). The mixture was stirred and cooled in an ice bath, and 5% aqueous NaClO (0.62 mL) and saturated aqueous NaHCO3 (1.0 mL) were added dropwise. After stirring for 0.5 h, Na2SO3 (0.13 g) in water (1.0 mL) was added. The mixture was transferred to a separatory funnel with DCM (10 mL) and water (5 mL). The mixture was partitioned, and the aqueous layer was extracted with DCM (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane / EtOAc = 95 / 5 to 40 / 60) to give 7_X05Y01a (0.22 g) as a pale yellow oil. LCMS: m / z=524.3 [M+Na+]+

[0243] Examples 5 to 38, 40 to 43 Example compounds 5 to 38 and 40 to 43 shown in Table 6 were synthesized via various intermediates shown in Tables 4 and 5, using reagents shown in Table 3 appropriately selected in each step of the aforementioned Examples 1 to 4, 39 and Reference Examples 1 to 3.

[0244] The structures, names and MS data of the example compounds are shown in Table 7.

[0245] [Table 3]

[0246] [Table 4]

[0247] [Table 5]

[0248] [Table 6]

[0249] [Table 7-1]

[0250] [Table 7-2]

[0251] [Table 7-3]

[0252] [Table 7-4]

[0253] [Table 7-5]

[0254] [Table 7-6]

[0255] Test 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 (doxycycline)-inducible NICD (Notch intracellular domain) construct. TM We used NICD CSL-bla HeLa cells, and the addition of DOX to these cells downregulated the expression of the NICD transcription factor, allowing subsequent expression of beta-lactamase.

[0256] Specifically, the following protocol was used: Notch Assay Protocol 1. Add 40 nL / well of 1000x working concentration of compound to 384 well assay plate using Echo. 2. Cell: HeLa / T-REx TM NICD CSL-bla cells (10 3 cells / well), 35 μl / well in complete medium, placed in a 384-well plate. 3. Add 5 μl of 8X doxycycline in assay medium to treated wells and 5 μl of assay medium to untreated or cell-free control wells. 4. Incubate the assay plate in a humidified 37°C / 5% CO2 incubator for 16-20 hours. 5.6×LiveBLAzer TM The -FRET B / G Substrate (CCF4-AM) Mixture should be prepared according to the manufacturer's instructions, and cell loading should be performed in a location away from strong direct light. 6. 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 it from light and evaporation. Incubate at room temperature for 4 hours. 7. Read the assay plate using the following filter selections:

[0257] [Table 8]

[0258] 8. 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 blue background) and 530 nm (average green background). Subtract the average blue background (data collected at 460 nm) from all blue emission data. Subtract the average green background (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 9.

[0259] [Table 9]

[0260] Activity A: 100~75%, Activity B:74.9~50%, Active C: 49.9~25%. [Industrial Applicability]

[0261] The compounds of the present invention inhibit Notch signaling and can therefore be used to treat diseases associated with Notch signaling. While 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 materially departing from the novel teachings and advantages of the present invention, and 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 / 139,443 filed in the United States (filing date: January 20, 2021), the contents of which are incorporated in their entirety herein.

Claims

1. A compound represented by the following formula (II): 【Chemical 1】 [In the formula, R １ ' is hydrogen, alkyl, optionally substituted heterocycloalkyl, or optionally substituted arylalkyl; R ２ ' is optionally substituted alkyl or optionally substituted arylalkyl; R ３ ' is hydrogen, optionally substituted alkyl, or optionally substituted arylalkyl; Q' is -CH ２ - or -CH ２ CH ２ - and; V' is a bond or -CO-; and R ４ R 3 ' and R 4 ' are hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; or a pharmaceutically acceptable salt thereof, with the proviso that at least one of R 3 ' and R 4 ' is not hydrogen.

2. In formula (II), R 1 ' is hydrogen, isopentyl, benzyloxycarbonylpiperidinyl, phenethyl, or hydroxyphenethyl; R 2 ' is isobutyl, aminocarbonylethyl, benzyl or 4-hydroxybenzyl; R 3 ' is hydrogen, isobutyl, methylthioethyl, hydroxymethyl, aminocarbonylethyl, benzyl, or 4-hydroxybenzyl; Q' is -CH 2 - or -CH 2 CH 2 -; V' is a bond or -CO-; and 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 ' is hydrogen, methyl, isobutyl, isopentyl, isohexyl, phenyl, phenethyl, phenylpropyl, 4-hydroxyphenethyl, or 4-hydroxyphenylpropyl.

3. 10. A pharmaceutical composition comprising a compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

4. 4. The pharmaceutical composition of claim 3, wherein said composition comprises an effective amount of said compound.

5. An agent for treating or preventing a disease associated with Notch signaling, comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

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