New regulations for bicyclic compounds

Abstract

Compounds of formula (I): JPEG2023545331000111.jpg3772 Each symbol is as defined in the specification. or a pharmaceutically acceptable salt thereof has an excellent inhibitory effect on Notch signaling 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 through 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 1-3).

[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 a compound having Notch inhibitory activity and a drug containing said compound that is 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] [In the formula, Q is represented by any one of the following formulas (I-1) to (I-2):

[0011] [ka]

[0012] * is the bonding site with N (nitrogen atom); R 1a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 1b is hydrogen, optionally substituted alkyl, or -W 11 -W 12 -R 13 (In the formula, W 11 is —(CO)— or —(SO2)—, W 12 is a bond, -O- or -N(R 14 )- and R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 14 is hydrogen or optionally substituted alkyl; R 13 and R 14 may be bonded to form a saturated or unsaturated 4- to 7-membered ring which may contain a carbon atom, a nitrogen atom or an oxygen atom, and which may be fused with an aryl ring or a heteroaryl ring, substituent -X 15 -R 15may be substituted on the formed saturated or unsaturated 4- to 7-membered ring, or on a fused aryl ring or heteroaryl ring, X 15 is —O—, —NH—, or a single bond, R 15 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 1c is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; U is —(CO)— or CH—; R2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R3 is -W 31 -W 32 -R 33 (In the formula, W 31 is —(CO)—, —(SO2)—, or —CH2—, W 32 is —O—, —NH—, or a single bond, and R 33 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl); R 4ais optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4b is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring; R5 is hydrogen or optionally substituted alkyl. or a pharmaceutically acceptable salt thereof; However, (3R,6S)isopropyl-3-ethyl-8-isopentyl-6-(2-(methylthio)ethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxylate is excluded.

[0013] [2]R 1a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R 1b is hydrogen, optionally substituted alkyl, or -W 11’ -W 12’ -R 13’ (In the formula, W 11’ is -(CO)-, W 12’ is -NH-, and R 13’is optionally substituted alkyl or optionally substituted arylalkyl; R2 is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R3 is -W 31’ -W 32’ -R 33’ (In the formula, W 31’ is —(CO)—, —(SO2)—, or —CH2—, W 32’ is —O—, —NH—, or a bond, and R 33’ is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl); R 4a is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4b is hydrogen or optionally substituted alkyl; R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring; R5 is hydrogen or optionally substituted alkyl; [1] The compound according to [1] or a pharmaceutically acceptable salt thereof.

[0014] [3] The compound according to [1], represented by the following formula (Ia):

[0015] [ka]

[0016] [In the formula, R 1aa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 1ba is hydrogen, optionally substituted alkyl, or -W 11a -W 12a -R 13a (In the formula, W 11a is —(CO)— or —(SO2)—, W 12a is a bond, —O— or —NH—, and R 13a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 2a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 3a Ha-W 31a -W 32a -R 33a (In the formula, W 31a is —(CO)— or —(SO2)—, W 32a is —O— or —NH—, and R 33a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl); R 4aa is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4ba is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4aa and R 4ba may be taken together with the carbons to which they are attached to form a spiro ring; R 5a is hydrogen or optionally substituted alkyl] or a pharmaceutically acceptable salt thereof; However, (3R,6S)isopropyl-3-ethyl-8-isopentyl-6-(2-(methylthio)ethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxylate is excluded.

[0017] [4]R 1aa is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R 1ba is hydrogen, optionally substituted alkyl, or -W 11a’ -W 12a’ -R 13a’ (In the formula, W 11a’ is -(CO)-, W 12a’ is -NH-, and R 13a’ is optionally substituted alkyl or optionally substituted arylalkyl; R 2a is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 3a But -W 31a’ -W 32a’ -R 33a’ (In the formula, W 31a’ is -(CO)-, W 32a’ is —O— or —NH—, and R 33a’ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl); R 4aa is optionally substituted alkyl, optionally substituted arylalkyl, or cycloalkylalkyl; R 4ba is hydrogen; R 5a is hydrogen, [3] The compound according to [3] or a pharmaceutically acceptable salt thereof.

[0018] [5]R 1a is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R 1b is hydrogen, optionally substituted alkyl, or -W 11’ -W 12’ -R 13’ (In the formula, W 11’ is -(CO)-, W 12’ is -NH-, and R 13’ is optionally substituted alkyl or optionally substituted arylalkyl; [1] The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof.

[0019] [6]R 1aa is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R 1ba is hydrogen, optionally substituted alkyl, or -W 11a’ -W 12a’ -R 13a’ (In the formula, W 11a’ is -(CO)-, W 12a’ is -NH-, and R 13a’ is optionally substituted alkyl or optionally substituted arylalkyl; The compound according to [3] or [4] or a pharmaceutically acceptable salt thereof.

[0020] [7]R 1c is an optionally substituted heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0021] [8] The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein U is -(CO)-.

[0022] [9] The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl.

[0023]

[10] R 2a is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl, or a pharmaceutically acceptable salt thereof.

[0024]

[11] R3 is -W 31’ -W 32’ -R 33’ (In the formula, W 31’ is —(CO)— or —CH—, W 32’ is —O—, —NH—, or a bond, and R 33’ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl), or a pharmaceutically acceptable salt thereof.

[0025]

[12] R 4a is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4b is hydrogen The compound according to [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.

[0026]

[13] R 4aais optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4ba is hydrogen, R 5a is hydrogen, The compound according to [3] or [4] or a pharmaceutically acceptable salt thereof.

[0027]

[14] A pharmaceutical composition comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0028]

[15] The pharmaceutical composition according to

[14] , wherein the composition comprises an effective amount of the compound.

[0029]

[16] A method for treating or preventing a disease associated with Notch signaling, comprising administering to a subject in need thereof a compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof, or a composition according to

[14] or

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

[0030]

[17] An agent for treating or preventing a disease associated with Notch signaling, comprising the compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof.

[0031]

[18] A compound according to any one of [1] to

[13] or a pharmaceutically acceptable salt thereof, or a composition according to

[14] or

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

[0032] 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]

[0033] [Figure 1] FIG. 1 shows the 1H NMR (400 MHz, CDCl3) data of D-10. [Figure 2] FIG. 2 shows the 1H NMR (400 MHz, CDCl3) data of D-13-Int1. [Figure 3] FIG. 3 shows the 1H NMR (400 MHz, CDCl3) data of D-13. [Figure 4] FIG. 4 shows the 1H NMR (400 MHz, CDCl3) data of D-8. [Figure 5] FIG. 5 shows the 1H NMR (400 MHz, CDCl3) data of D-12. [Figure 6] FIG. 6 shows the 1H NMR (400 MHz, CDCl3) data of D-82. [Figure 7] FIG. 7 shows the 1H NMR (400 MHz, CDCl3) data of B-128-Int1. [Figure 8] FIG. 8 shows the 1H NMR (400 MHz, CDCl3) data of B-128. [Figure 9] FIG. 9 shows the 1H NMR (400 MHz, CDCl3) data of B-72. [Figure 10] FIG. 10 shows the 1H NMR (400 MHz, CDCl3) data of A-22-Int2. [Figure 11] FIG. 11 shows the 1H NMR (400 MHz, CDCl3) data of A-22-Int3. [Figure 12] FIG. 12 shows the 1H NMR (400 MHz, CDCl3) data of A-22-Int4. [Figure 13] FIG. 13 shows the 1H NMR (400 MHz, CDCl3) data of A-22-Int5. [Figure 14] FIG. 14 shows the 1H NMR (400 MHz, CDCl3) data of A-22-Int6. [Figure 15] FIG. 15 shows the 1H NMR (400 MHz, CDCl3) data of A-22. [Figure 16] FIG. 16 shows the 1H NMR (400 MHz, CDCl3) data of A-43-Int3. [Figure 17] FIG. 17 shows the 1H NMR (400 MHz, DMSO) data of A-43. [Figure 18] FIG. 18 shows the 1H NMR (400 MHz, CDCl3) data of A-60-Int2. [Figure 19] FIG. 19 shows the 1H NMR (400 MHz, DMSO) data of A-60-Int3. [Figure 20] FIG. 20 shows the 1H NMR (400 MHz, CDCl3) data of A-60. [Figure 21] FIG. 21 shows the 1H NMR (400 MHz, DMSO) data of A-52-Int2. [Figure 22] FIG. 22 shows the 1H NMR (400 MHz, CDCl3) data of A-52-Int3. [Figure 23] FIG. 23 shows the 1H NMR (400 MHz, DMSO) data of A-52-Int4. [Figure 24] Figure 24 shows the 1H NMR (400 MHz, DMSO) data of A-52-Int5. [Figure 25] Figure 25 shows the 1H NMR (400 MHz, DMSO) data of A-52-Int6. [Figure 26] FIG. 26 shows the 1H NMR (400 MHz, CDCl3) data of A-52. [Figure 27] Figure 27 shows the 1H NMR (400 MHz, CDCl3) data of I-128. [Figure 28] Figure 28 shows the 1H NMR (300 MHz, CDCl3) data of I-182. DETAILED DESCRIPTION OF THE INVENTION

[0034] [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.

[0035] "Lower" means that the given radical comprises between 1 and 6 carbon atoms, unless otherwise indicated.

[0036] "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, -R, -NR, -NR, -COR, -NR, -COOR, -SR, -SOR, -SOR, -SOR, -OSOR, -NHC(NHR)NR, -NHC(NH)NH, -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.

[0037] "Halogen" means fluorine, chlorine, bromine or iodine. "Halo" means fluoro, chloro, bromo or iodo.

[0038] "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-YAlkyl is typically used. The number of carbon atoms in the chain is preferably 1 to 10, more preferably 1 to 6, and even more preferably 1 to 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.

[0039] "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, more preferably 2 to 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.

[0040] "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, more preferably 2 to 6. Non-exclusive examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl.

[0041] "Alkylene" means, unless otherwise indicated, a straight or branched, saturated aliphatic, polyvalent carbon chain. C X-YAlkylene is typically used. The number of carbon atoms in the chain is preferably 1 to 10, more preferably 1 to 6. Non-exclusive examples of alkylene include methylene (-CH-), ethylene (-CHCH-), methylmethylene (-CH(CH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,2-butylene (-CHCH(CHCH)-), 1,3-butylene (-CHCHCH(CH)-), 1,4-butylene (-CHCHCHCHCH-), 2-methyltetramethylene (-CHCH(CH)CHCH-), pentamethylene (-CHCHCHCHCHCH-), 1,2,3-propanetriyl, and 1,3,3-propanetriyl.

[0042] "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.

[0043] "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, more preferably 6 to 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.

[0044] "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, lysine, 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), indolizine, quinoline, isoquinoline , phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine), imidazolopyridine (e.g., imidazolo[1,2-a]pyrimidine, imidazolo[1,2-c]pyrimidine, imidazolo[1,5-a]pyrimidine, imidazolo[1,5-c]pyrimidine), pyrrolopyridine (e.g., pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine), pyridine, 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.

[0045] "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, more preferably 3 to 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.

[0046] "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. C, where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly. X-Y Heterocycloalkyl is typically used. 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.

[0047] 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.

[0048] "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).

[0049] 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.

[0050] Non-exclusive examples of monocyclic saturated carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.

[0051] Non-exclusive examples of monocyclic unsaturated carbocycles include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, benzene, and the like.

[0052] Non-exclusive examples of monocyclic saturated heterocycles include pyrrolidine, piperidine, morpholine, piperazine, 1,3-dioxane, 1,4-dioxane, and the like.

[0053] 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.

[0054] "Spirocycle," as used herein, refers to a saturated or unsaturated cycloalkane or a saturated or unsaturated heterocycloalkane.

[0055] "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, more preferably 3 to 8. Non-exclusive examples of cycloalkanes include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0056] "Heterocycloalkane" means a cycloalkane, as defined herein, provided that one or more of the atoms forming the ring is a heteroatom independently selected from N, O, and S. C is a heterocyclic group, where X and Y indicate the number of carbon atoms and heteroatoms in the ring assembly. X-Y Heterocycloalkanes are typically used. 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, and 1,4-dioxane.

[0057] The term "saturated or unsaturated 4- to 7-membered ring" refers to a 4- to 7-membered monocyclic ring among the above monocyclic rings.

[0058] "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.

[0059] "Isomers" means any compounds that have identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images are called "enantiomers," or sometimes "optical isomers." A carbon atom bonded to four different substituents is called a "chiral center." A compound with one chiral center has two enantiomeric forms of opposite chirality. A mixture of two enantiomeric forms is called a "racemic mixture." A compound with more than one chiral center has two n-1The compound has enantiomeric pairs (where n is the number of chiral centers). Compounds with more than one chiral center 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.

[0060] "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.).

[0061] "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).

[0062] "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.

[0063] "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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] An "effective amount" is the same as a "therapeutically effective amount" and a "prophylactically effective amount."

[0068] "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.

[0069] 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.

[0070] In the present invention, a compound represented by the following formula (I):

[0071] [ka]

[0072] [In the formula, Q is represented by any one of the following formulas (I-1) to (I-2):

[0073] [ka]

[0074] * is the bonding site with N (nitrogen atom); R 1ais hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 1b is hydrogen, optionally substituted alkyl, or -W 11 -W 12 -R 13 (In the formula, W 11 is —(CO)— or —(SO2)—, W 12 is a bond, -O- or -N(R 14 )- and R 13 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 14 is hydrogen or optionally substituted alkyl; R 13 and R 14 may be bonded to form a saturated or unsaturated 4- to 7-membered ring which may contain a carbon atom, a nitrogen atom or an oxygen atom, and which may be fused with an aryl ring or a heteroaryl ring, substituent -X 15 -R 15 may be substituted on the formed saturated or unsaturated 4- to 7-membered ring, or on a fused aryl ring or heteroaryl ring, X 15 is —O—, —NH—, or a single bond, R 15 is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R 1c is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; U is —(CO)— or CH—; R2 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R3 is -W 31 -W 32 -R 33 (In the formula, W 31 is —(CO)—, —(SO2)—, or —CH2—, W 32 is —O—, —NH—, or a single bond, and R 33 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl); R 4a is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4bis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4a and R 4b may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring; R5 is hydrogen or optionally substituted alkyl. or a pharmaceutically acceptable salt thereof.

[0075] In another embodiment of the present invention, there is provided a compound represented by formula (Ia):

[0076] [ka]

[0077] [In the formula, R 1aa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 1ba is hydrogen, optionally substituted alkyl, or -W 11a -W 12a -R 13a (In the formula, W 11a is —(CO)— or —(SO2)—, W 12a is a bond, —O— or —NH—, and R 13ais hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 2a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 3a Ha-W 31a -W 32a -R 33a (In the formula, W 31a is —(CO)— or —(SO2)—, W 32a is —O— or —NH—, and R 33a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl); R 4aa is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4bais hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R 4aa and R 4ba may be taken together with the carbons to which they are attached to form a spiro ring; R 5a is hydrogen or optionally substituted alkyl] or a pharmaceutically acceptable salt thereof.

[0078] In formula (I) or formula (Ia), R 1a (In the case of formula (Ia), R 1aa ) is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0079] 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.

[0080] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0081] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0082] 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.

[0083] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0088] In another embodiment of Formula (I) or Formula (Ia), R 1a (In the case of formula (Ia), R 1aa) is hydrogen, optionally substituted alkyl (e.g., butyl, propyl, methyl, CH2CONH2, CH2OH, 2,2-diphenylethyl, naphthylmethyl, CH2COOH, phenylethyl), optionally substituted aryl (e.g., naphthyl, phenyl), optionally substituted heteroaryl (e.g., pyridyl), optionally substituted cycloalkyl (e.g., cyclohexyl), optionally substituted arylalkyl (e.g., benzyl, hydroxybenzyl), optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl.

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

[0090] In one embodiment of Formula (Ia), R 1ba is hydrogen, optionally substituted alkyl, or -W 11a -W 12a -R 13a (In the formula, W 11a is —(CO)— or —(SO2)—, W 12a is a bond, —O— or —NH—, and R 13a is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl).

[0091] 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.

[0092] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0093] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0094] 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.

[0095] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0096] 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.

[0097] 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.

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

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

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

[0101] In another embodiment of formula (I), R 1b is hydrogen, optionally substituted alkyl, or -W11’ -W 12’ -R 13’ (In the formula, W 11’ is -(CO)-, W 12’ is -NH-, and R 13’ is optionally substituted alkyl (e.g., —(CH)OH, —(CH)OH, pentyl, hexyl, —(CH)CONH, —(CH)CONH), optionally substituted cycloalkyl, optionally substituted arylalkyl (e.g., —(CH)Ph, —(CH)Ph, —(CH)Ph(OH)), optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl). In another embodiment of Formula (Ia), R 1ba is hydrogen, optionally substituted alkyl, or -W 11a’ -W 12a’ -R 13a’ (In the formula, W 11a’ is -(CO)-, W 12a’ is -NH-, and R 13a’ is optionally substituted alkyl (e.g., —(CH)OH, —(CH)OH, pentyl, hexyl, —(CH)CONH, —(CH)CONH), optionally substituted cycloalkyl, optionally substituted arylalkyl (e.g., —(CH)Ph, —(CH)Ph, —(CH)Ph(OH)), optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl). In another embodiment of Formula (I) or Formula (Ia), R (in the case of Formula (Ia), R 2a) is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0102] 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.

[0103] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0104] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0105] 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.

[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) or Formula (Ia), R2 (in the case of Formula (Ia) is R 2a ) is hydrogen, optionally substituted alkyl (e.g., methyl, propyl, butyl, -(CH)NH, -CHOH, -CHCONH, -CHCHCONH, -CHCOOH, guanidinopropyl), optionally substituted arylalkyl (e.g., benzyl, hydroxybenzyl), optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl (e.g., cyclohexylmethyl).

[0110] In another embodiment of Formula (I), R3 is -W 31 -W 32 -R 33 (In the formula, W 31 is —(CO)—, —(SO2)—, or —CH2—, W 32 is —O—, —NH—, or a single bond, and R 33is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl); R 4a is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0111] In another embodiment of Formula (Ia), R 3a Ha-W 31a -W 32a -R 33a (In the formula, W 31a is —(CO)— or —(SO2)—, W 32a is —O— or —NH—, and R 33a is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0112] 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.

[0113] 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.

[0114] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0115] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, and the like.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0120] In another embodiment of Formula (I), R3 is -W 31’ -W 32’ -R 33’ (In the formula, W 31’ is —(CO)—, —(SO2)—, or —CH2—, W 32’ is —O—, —NH—, or a bond, and R 33’ is optionally substituted alkyl, 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.

[0121] In another embodiment of Formula (Ia), R 3a -W 31a’ -W 32a’ -R 33a’ (In the formula, W 31a’ is -(CO)-, W 32a’ is —O— or —NH—, and R 33a’ is optionally substituted alkyl (e.g., methyl, propyl, butyl, pentyl, hexyl, diphenylpropyl), optionally substituted arylalkyl (e.g., benzyl, naphthylmethyl, hydroxyphenylethyl, phenylethyl), optionally substituted heteroarylalkyl (e.g., pyridinylmethyl), or optionally substituted cycloalkylalkyl (e.g., cyclohexylmethyl) or optionally substituted heterocycloalkylalkyl.

[0122] In one embodiment of Formula (I) or Formula (Ia), R 4a (In the case of formula (Ia), R 4aa ) is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0123] 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.

[0124] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0125] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0130] In another embodiment of Formula (I) or Formula (Ia), R 4a (In the case of formula (Ia), R 4a ) is optionally substituted alkyl (e.g., methyl, ethyl, propyl, butyl, guanidinopropyl, -CHOH, -CHCONH, -CHCHCONH), optionally substituted arylalkyl (e.g., benzyl, hydroxybenzyl), optionally substituted cycloalkylalkyl (e.g., cyclohexylmethyl).

[0131] In another embodiment of Formula (I) or Formula (Ia), R 4b (In the case of formula (Ia), R 4ba ) is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0132] 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.

[0133] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0134] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0139] In another embodiment of formula (I), R 4b is hydrogen or optionally substituted alkyl (e.g., methyl).

[0140] In another embodiment of Formula (Ia), R 4ba is hydrogen.

[0141] In another embodiment of formula (I), R 4a and R 4b may form a spiro ring together with the carbon to which they are attached. 4a and R 4b However, the spiro rings that may be formed together with the carbon to which they are attached include, for example, cyclopropane.

[0142] The spiro ring may have an oxygen atom or a nitrogen atom in the ring.

[0143] In one embodiment of Formula (I) or Formula (Ia), R5 (in the case of Formula (Ia) is R 5a ) is hydrogen or optionally substituted alkyl.

[0144] 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.

[0145] In another embodiment of Formula (I) or Formula (Ia), R5 (in the case of Formula (Ia), R 5a ) is hydrogen.

[0146] A preferred embodiment of formula (I) is a compound having the following formula (II): or a pharmaceutically acceptable salt thereof:

[0147] [ka]

[0148] [In the formula, R 1a’ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R 1b’ is hydrogen, optionally substituted alkyl or -W 11a’ -W 12a’ -R 13a’ (In the formula, W 11a’is -(CO)-, W 12a’ is -NH-, and R 13a’ is optionally substituted alkyl, or optionally substituted arylalkyl); R 2’ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 3’ Ha-W 31a’ -W 32a’ -R 33a’ (In the formula, W 31a’ is -(CO)-, W 32a’ is —O— or —NH—, and R 33a’ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl); R 4a’ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R 4b’ is hydrogen; R 5’ is hydrogen].

[0149] Hereinafter, the compounds having formula (I), (Ia) or (II) will also be referred to as "compounds of the present invention".

[0150] 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 BOC: tert-butoxycarbonyl t-BuOH: tert-butanol (Boc)2O: di-tert-butyl dicarbonate Cbz: benzyloxycarbonyl CDCl3: deuterated chloroform CIP: 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethane DCM: dichloromethane DIAD: Diisopropyl azodicarboxylate DIBAL: Diisobutylaluminum DIC: N,N'-methanediylidenebis[1-methylethanamine] DIEA: N,N-diisopropylethylamine DIPEA: N-ethyl-N-isopropyl-propan-2-amine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EtO(OEt): Ethoxy EtOH: ethanol Fmoc: 9-fluorenylmethyloxycarbonyl HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate MeCN: acetonitrile MeO(OMe): methoxy MeOH: Methanol NHPI: N-hydroxyphthalimide NMM: N-methylmorpholine OAc(AcO): Acetoxy Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl PE:EA:Petroleum ether:Ethyl acetate PG: amino protecting group Ph: Phenyl PhthN: N-phthalimidyl PPh3: Triphenylphosphine rt: room temperature TBS: tert-butyldimethylsilyl TBSCl: tert-butyl(chloro)dimethylsilane tBu: tert-butyl THF: tetrahydrofuran TLC: Thin Layer Chromatography Trt: Trityl

[0151] Manufacturing method 1) Manufacturing method 1 When U is -(CO)-;

[0152] [ka]

[0153] [Step 1] Synthesis of intermediate D Intermediate D (wherein Q and R are defined as above) can be synthesized according to known methods, such as reductive alkylation using a compound represented by formula Ia (wherein R is defined as above) and an aldehyde compound represented by formula Ib (wherein Q is defined as above), or substitution reaction using a compound represented by formula Ic having Q and a leaving group X (wherein Q is defined as above). The term "leaving group" refers to an atom or atomic group that is released from an organic compound undergoing an elimination or substitution reaction. Examples of leaving groups include, but are not limited to, a halogen group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and a toluenesulfonyloxy group.

[0154] Intermediate D can also be synthesized by known methods such as reductive alkylation or substitution reaction using a leaving group X shown below.

[0155] [ka]

[0156] In the compounds represented by formulae Id, Ie and If, Q and R5 are as defined above, and X is a leaving group.

[0157] [Step 2] Synthesis of intermediate B Intermediate B can be synthesized by an amidation condensation reaction between intermediate D and a carboxylic acid derivative of intermediate E (wherein R2 has the same meaning as above and PG is a protecting group for the amino group), followed by a deprotection reaction. Generally known amidation reagents and conditions can be used in the amidation condensation reaction. HATU or DMT-MM is preferred as the condensation agent, and DMF, MeOH, THF, etc. is preferred as the solvent. The reaction temperature is preferably from 0°C to the boiling point of the solvent. Examples of amino-protecting groups include benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, benzyl chloroformate (Cl-Z), benzyl bromoformate (Br-Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, 9-fluorenylmethyloxycarbonyl (Fmoc), and trityl (Trt). Generally known deprotection reactions can be used. When PG in the formula is an Fmoc group, the deprotection reaction is preferably carried out using ethyl acetate, THF, MeOH, or dichloromethane as the solvent and piperidine or DBU as the deprotecting agent. When PG is a Cbz group, the deprotection reaction is preferably carried out using methanol, ethanol, or THF as a solvent under a H atmosphere with a palladium catalyst such as Pd(OH) or Pd / C. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0158] [Step 3] Synthesis of Compound (I) Intermediate B and Intermediate A (R3, R 4a and R 4bCompound (I) (the symbols in the formula are as defined above) can be synthesized by an amidation condensation reaction of 2-(2-(2-methyl-2-propanol)-2-methyl-1-propanol) (the symbols in the formula are as defined above), followed by a ring-closure reaction in the presence of an acid. In the amidation condensation reaction, commonly known amidation reagents and conditions can be used. HATU or DMT-MM is preferred as the condensation agent, DMF, MeOH, THF, etc. is preferred as the solvent, and the reaction temperature is preferably from 0°C to the boiling point of the solvent. Furthermore, formic acid is preferred as the acid used in the ring-closure reaction, and formic acid can also be used as the solvent. Furthermore, the reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0159] Intermediate A can be prepared by the following method.

[0160] [ka]

[0161] Amino acid derivative Ig(R 4a and R 4b The amino group of the resulting intermediate Ih (R is as defined above) can be converted to a hydroxy group under NaNO3 / H2SO4 conditions. 4a and R 4b The carboxylic acid group of intermediate Ii (PG2 is a protecting group for carboxylic acid, and other symbols in the formula are as defined above) can be converted to intermediate Ii (PG2 is a protecting group for carboxylic acid, and other symbols in the formula are as defined above) by commonly known methods, such as the method described in "Greene's Protective Groups in Organic Synthesis, 5th Edition" by John Wiley & Sons, Inc. Examples of protecting groups for carboxylic acid include methyl, ethyl, t-butyl, benzyl, methoxymethyl, triphenylmethyl, etc. The hydroxy group of Ii can be converted to an N-hydroxyphthalimide group under Mitsunobu reaction conditions. Intermediate Ik (symbols in the formula are as defined above) can be obtained by deprotecting the phthalimide group of intermediate Ij (symbols in the formula are as defined above) using hydrazine. Intermediate Im (symbols in the formula are as defined above) can be obtained by the reaction of Ik and R with triphosgene. 33 -X(R 33is as defined above, and X is an amino group or an alcohol group). Intermediate A can be obtained by deprotecting the protecting group PG2.

[0162] 2) Manufacturing method 2

[0163] [ka]

[0164] Q is -CH(-R 1a )(-R 1b ), R 1b -(CO)-NH-R 13 Compound (I), in which the other symbols are as defined above, is a compound in which Q is —CH(—R 1a )(-COOtBu), where the other symbols are as defined above, can be synthesized according to the following scheme using intermediate B. In the ring-closing reaction, the t-butyl ester group is deprotected in the presence of HCOOH and converted into a carboxylic acid group. Io (where the symbols are as defined above) and intermediate C (R 13 In the amidation condensation reaction of (wherein ) is as defined above, commonly known amidation reagents and conditions can be applied. The condensation agent is preferably HATU, CIP, or DMT-MM, the solvent is preferably DMF, MeOH, THF, or the like, and the reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0165] 3) Manufacturing method 3

[0166] [ka]

[0167] R3 is -(CO)-NH-R 33 Compound (I) can be prepared by deprotecting intermediate AB-1 (PG is an amino-protecting group, and the other symbols in the formula are as defined above) and then converting the amine derivative R 33AB-1 can be synthesized by a condensation reaction with -NH2. AB-1 can be produced by a commonly known method or by the above-mentioned steps 1, 2 and 3.

[0168] Representative examples of the amino-protecting group PG include benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc). Generally known reactions can be applied to the deprotection reaction. When PG in the formula is an Fmoc group, the deprotection reaction is preferably carried out using ethyl acetate or dichloromethane as a solvent and piperidine or DBU as a deprotecting agent. When PG is a Cbz group, the deprotection reaction is preferably carried out under an H atmosphere using methanol, ethanol, or THF as a solvent and a palladium catalyst such as Pd(OH) or Pd / C. The reaction temperature is preferably from 0°C to the boiling point of the solvent used. In the condensation reaction, DCM, DCE, THF, or the like is preferred as the solvent, and the reaction temperature is preferably from 0°C to the boiling point of the solvent used.

[0169] 4) Manufacturing method 4

[0170] [ka]

[0171] R3 is -(CO)-OR 33 Compound (I) can be prepared by reacting intermediate Ip, alcohol derivative R 33 It can be synthesized by a reaction using -OH and triphosgene. DCM, DCE, THF, etc. are preferred solvents, and the reaction temperature is preferably from 0°C to the boiling point of the solvent used.

[0172] 5) Manufacturing method 5

[0173] [ka]

[0174] R3 is -(CO)-R 33 Compound (I) can be prepared by reacting intermediate Ip with R33 -COOH (or R 33 The compound can be synthesized by an amidation condensation reaction using R. —COCl. DMF, DCM, DCE, THF, MeOH, etc. are preferred solvents, and the reaction temperature is preferably from 0°C to the boiling point of the solvent. 33 When -COOH is used, a commonly known amidation reagent such as HATU, CIP, or DMT-MM is used as the condensing agent.

[0175] 6) Manufacturing method 6

[0176] [ka]

[0177] R3 is -(SO2)-R 33 Compound (I) can be prepared by reacting intermediate Ip with R 33 It can be synthesized by n reaction using -SO2Cl. DCM, DCE, THF, etc. are preferred solvents. The reaction temperature is preferably from 0°C to the boiling point of the solvent used.

[0178] 7) Manufacturing method 7

[0179] [ka]

[0180] R3 is -(CH2)-R 33 Compound (I), 33The compound can be synthesized by carrying out a reaction using -CHO in the presence of a reducing agent. Preferred reducing agents include commonly known reducing agents such as sodium triacetoxyhydride, sodium cyanohydride, sodium tetrahydroborate, lithium tetrahydroborate, THF-borane complex, pyridine-borane complex, picoline-borane complex, diisobutylaluminum hydride (DIBAL), and lithium aluminum hydride. Preferred solvents include MeOH, THF, chloroform, DCM, DCE, diethyl ether, and diisopropyl ether. The reaction temperature is preferably from -78°C to the boiling point of the solvent.

[0181] 8) Manufacturing method 8

[0182] [ka]

[0183] Compound (I) in which U is —(CH)— can be synthesized using intermediate AB-2 and a reducing agent according to the following scheme. AB-2 can be produced by a commonly known method or by the above-mentioned steps 1, 2, and 3. Preferred reducing agents include commonly known reducing agents such as sodium triacetoxyhydride, sodium cyanohydride, sodium tetrahydroborate, lithium tetrahydroborate, THF-borane complex, pyridine-borane complex, picoline-borane complex, diisobutylaluminum hydride (DIBAL), and lithium aluminum hydride. Preferred solvents include MeOH, THF, chloroform, DCM, DCE, diethyl ether, and diisopropyl ether. The reaction temperature is preferably from −78° C. to the boiling point of the solvent.

[0184] The protecting groups used in each step are not limited to those specifically shown in the scheme (e.g., diethylacetal group), and commonly known protecting groups such as dimethylacetal group may also be used. The deprotection in step 2 or step 3 can be carried out by a general method corresponding to the protecting group. R 1a , R 1b , R13 , R2, R3, R 4a , R 4b When R5 or R5 has a protected functional group, deprotection can be carried out at any step. In some cases, the compound synthesized in each step of the reaction is used directly in the next reaction without isolation. In addition, under the conditions of step 3, the ring-closing reaction and the deprotection reaction may proceed simultaneously.

[0185] The compound obtained in the cyclization reaction can be isolated and purified by conventional methods such as extraction, washing with water, washing with an acid, washing with an alkali, crystallization, recrystallization, silica gel column chromatography, and the like.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.).

[0190] 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 / aqueous phase, etc.), ionization constant tests, and crystallization tests.

[0191] 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 regulated by the Notch signaling pathway.

[0192] 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).

[0193] 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.

[0194] The compounds of the present invention can inhibit Notch signaling by interacting with the Notch intracellular domain.

[0195] 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).

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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).

[0209] 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.

[0210] 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.

[0211] 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 tissues affected by trauma or neurodegenerative diseases.

[0212] The following non-limiting examples illustrate the compounds, compositions, and methods of use of the present invention.

[0213] 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. In the examples, the Bruker AVANCE III 400, the Bruker AVANCE III 400HD300, and the Bruker AVANCE NEO40 or the Bruker AVANCE III 300 were used. 1 H NMR was measured.

[0214] Preparative HPLC (prep-HPLC) was performed using a GILSON-GX-28 or Waters FractionLynx system under the following preparative conditions:

[0215] Typical prep-HPLC conditions (AcOH): Column: C30-UG 25mm ID*150mm L, 5μm Mobile phase A: 0.10% v / v acetic acid in water Mobile phase B: acetonitrile UV detection wavelength: 220 nm Flow rate: 25ml / min Temperature: room temperature Gradient timetable: 0 minutes B=x%,A=100-x% 0.01-10.99 min linear gradient 11.00 min B=y%,A=100-y% 11.01-11.20 min B=y%, A=100-y% 11.21-13.00 minutes B=100% 13:01-15:00 min B=z%, A=100-z% The x, y and z values ​​depend on the type of compound.

[0216] Typical prep-HPLC conditions (TFA): Column: L-Column2 ODS 20mmID*150mmL, 5μm Mobile phase A: acetonitrile containing 0.10% v / v TFA Mobile phase B: Acetonitrile containing 0.10% v / v acetonitrile UV detection wavelength: 220 nm Flow rate: 20ml / min Temperature: room temperature Gradient timetable: 0 minutes B=x%,A=100-x% 0.01-6.99 min linear gradient 7.00 min B=y%,A=100-y% 7.01-10.99 minutes B=100% 11:00-12:00 min B=z%, A=100-z% The x, y and z values ​​depend on the type of compound.

[0217] LCMS analysis was carried out by the following methods A to D. (Method A) LCMS was measured using an Agilent 1100 LC & Agilent G1956A (ELSD: 1260 Infinity). Analysis was performed under the conditions shown in Table 1 or Table 2.

[0218] [Table 1]

[0219] [Table 2]

[0220] (Method B) System: Shimadzu UFLC / MS System (Shimadzu-2020 mass spectrometer) Column: ODS column for chromatography Eluent: A (0.04% TFA in water) and B (0.04% TFA in acetonitrile)

[0221] (Method C) System: Shimadzu UFLC / MS System (Shimadzu-2020 mass spectrometer) Column: ODS column for chromatography Eluents: A (5 mM AcONH4 in water) and B (5 mM AcONH4 in acetonitrile)

[0222] (Method D) System: Water 2795 System Column: Develosil C30-UG-5, 50x4.6mm, Nomura Chemical Co., Ltd. Eluent: A (water containing 0.1% HCOOH) and B (acetonitrile containing 0.1% HCOOH) Flow rate: 1.0 mL / min

[0223] Production Example 1: Synthesis of Intermediate D-10

[0224] [ka]

[0225] To a solution of 2,2-diethoxyethan-1-amine (75 g, 0.67 mol) in MeOH (1.0 L) was added cyclohexanecarbaldehyde (89 g, 0.67 mol). After stirring overnight, sodium borohydride (38.2 g, 1.0 mol) was added to the mixture at 0 °C and stirred at room temperature for 1.5 h. The mixture was concentrated, and the residue was dissolved in ethyl acetate (1.0 L), washed with water (1.0 L) and brine (1.0 L), dried over sodium sulfate, filtered, and evaporated. Distillation under reduced pressure (140 °C, 5-10 mmHg) afforded the desired product D-10 (130 g, colorless oil, 85% yield). D-10 Compound 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 1. Intermediates D-1, D-2, D-3, D-55, D-67, D-135, D-137, D-157, D-158, D-178, D-179 and D-182 were synthesized according to the same method as above or known methods.

[0226] Preparation Example 2: Synthesis of Intermediate D-13

[0227] [ka]

[0228] 2-1) Synthesis of D-13-Int1 To a solution of N-benzyl-2,2-diethoxyethan-1-amine (200 g, 0.90 mol) and acrylamide (77 g, 1.08 mol) in THF (4.0 L) was added SiO (40 g) at room temperature. After refluxing for 7 days, the mixture was filtered and evaporated. Flash chromatography afforded the desired product D-13-Int1 (194 g, yellow liquid, 82% yield). The obtained compound 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 2.

[0229] 2-2) Synthesis of D-13 A mixture of D-13-Int1 (90 g, 0.3 mol) and Pd(OH) / C (9 g) in MeOH was stirred under H (50 psi) at room temperature for 3 h. TLC showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated to give crude product D-13 as a yellow oil, which was used directly. D-13 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 3. Intermediate D-58 was synthesized according to the same method as above or known methods.

[0230] Production Example 3: Synthesis of Intermediate D-8

[0231] [ka]

[0232] To a solution of 2-bromo-1,1-diethoxyethane (50 g, 0.69 mol) in MeCN (0.7 L) was added potassium carbonate (94.5 g, 0.69 mol) and n-butylamine (50 g, 0.69 mol). After refluxing overnight, the mixture was filtered and evaporated. The residue was dissolved in ethyl acetate (1.0 L), washed with water (0.5 L) and brine (0.5 L), dried over sodium sulfate, filtered, and evaporated. Distillation under reduced pressure (70 °C, 5-10 mmHg) afforded the desired product D-8 (71 g, colorless oil, 55% yield). D-8 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 4. Intermediates D-32, D-50, D-53, D-73, D-128 and D-161 were synthesized according to the same method as above or known methods.

[0233] Production Example 4: Synthesis of D-12

[0234] [ka]

[0235] A solution of 2-bromopropane (300 g, 2.44 mol), 2,2-diethoxyethanamine (341 g, 2.56 mol), and potassium carbonate (674 g, 4.88 mol) in MeCN (3.0 L) was stirred at 80 °C for 16 h. The solution was filtered, and the filtrate was concentrated. The crude product was dissolved in ethyl acetate (2.0 L) and washed with water (1.0 L) and brine (1.0 L); it was dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product D-12 (300 g, 1.71 mol, 70% yield) as a yellow oil, which was used in the next step without purification. D-12 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 5. Intermediates D-28, D-30, D-31, D-33 and D-70 were synthesized according to the same method as above or known methods.

[0236] Preparation Example 5: Synthesis of Intermediate D-82

[0237] [ka]

[0238] To a solution of tert-butyl (2S)-2-aminohexanoate (310 g, 1.66 mol) in methanol (2.50 L) was added 2,2-dimethoxyacetaldehyde (315.92 g, 1.82 mol, 274.72 mL, 60% purity), followed by CHCOOH (2.10 g, 34.97 mmol, 2 mL), and the mixture was stirred for 16 h. Next, NaBHCN (124.82 g, 1.99 mol) was added at 0 °C, and the mixture was warmed to 20 °C and stirred for 2 h. TLC (petroleum ether:ethyl acetate = 2:1) showed that most of the starting material (tert-butyl (2S)-2-aminohexanoate) was consumed. The reaction mixture was concentrated in vacuo to give a yellow oil. This yellow oil was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 20:1 to 5:1) to give D-82 (530 g, 1.92 mol, 58% yield) as a pale yellow oil. D-82 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 6. Intermediates D-80, D-91, D-94, D-180 and D-183 were synthesized according to the same method as above or known methods.

[0239] A list of intermediates D is shown in Table 3 (Table 3-1 and Table 3-2).

[0240] [Table 3-1]

[0241] [Table 3-2]

[0242] Intermediate E listed in Table 4 (Table 4-1 and Table 4-2) is a known compound or was synthesized by a known method or the following method.

[0243] [Table 4-1]

[0244] [Table 4-2]

[0245] Preparation Example 6: Synthesis of Intermediate B-128

[0246] [ka]

[0247] 6-1) Synthesis of B-128-Int1 To a stirred mixture of 2,2-diethoxy-N-ethyl-ethanamine (D-128, 11.0 g, 68.2 mmol), (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propanoic acid (E-15, 21.2 g, 68.2 mmol), and N,N-diisopropylethylamine (17.6 g, 136 mmol, 24.0 mL) in DCM (200 mL) was added HATU (25.9 g, 68.2 mmol) in an ice bath in portions. After stirring at 0 °C for 30 min, the reaction mixture was stirred at 10 °C for 16 h. TLC (petroleum ether / ethyl acetate = 3:1) showed the reaction was complete. The reaction mixture was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10:1 to 2:1) to give the product B-128-Int1 (23.0 g, 50.6 mmol, 74% yield). B-128-Int1 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 7.

[0248] 6-2) Synthesis of intermediate B-128 A mixture of B-128-Int1 (23.0 g, 50.6 mmol) and Pd / C (5.00 g, 10% w / w) in EtOAc (200 mL, containing 1% v / v piperidine) was stirred under H 50 psi for 48 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (SiO , CHCl :MeOH = 1:0 to 20:1) to give B-128 (10.5 g, 45.3 mmol, 89% yield). B-128 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 8.

[0249] Production Example 7: Synthesis of Intermediate B-72

[0250] [ka]

[0251] B-72-Int1 was synthesized using D-128 and E-69 in the same manner as in Production Example 6:6-1). To a solution of B-72-Int1 (56.0 g, 79.6 mmol) in EtOH (300 mL) under nitrogen, Pd / C (6 g, 10% purity) was added. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 72 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give B-72 (35.0 g, 45.3 mmol, 57% yield). B-72 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 9.

[0252] Intermediate B is listed in Table 5 (Table 5-1 to Table 5-15). Intermediate B was synthesized using the corresponding intermediate D and intermediate E according to Production Example 6, Production Example 7, or a known method.

[0253] [Table 5-1]

[0254] Table 5-2

[0255] Table 5-3

[0256] Table 5-4

[0257] Table 5-5

[0258] Table 5-6

[0259] Table 5-7

[0260] Table 5-8

[0261] Table 5-9

[0262] Table 5-10

[0263] Table 5-11

[0264] [Table 5-12]

[0265] [Table 5-13]

[0266] [Table 5-14]

[0267] [Table 5-15]

[0268] Production Example 8: Synthesis of Intermediate A-22

[0269] [ka]

[0270] 8-1) Synthesis of A-22-Int2 A-22-Int1 (400 g, 3.42 mol) was placed in a 10 L three-neck flask and 0.5 M H2SO4 (5.2 L) was added. The reaction was cooled to 0 °C, and then 2 mol / L NaNO2 (2.6 L) was added dropwise. After the addition was complete, the reaction was stirred overnight at room temperature. After this time, the reaction mixture was extracted with ethyl acetate (EA) (3 x 3 L). The combined EA extracts were dried over Na2SO4, filtered, and concentrated. The resulting crude solid was recrystallized from petroleum ether to give compound A-22-Int2 (230 g). A-22-Int2 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 10.

[0271] 8-2) Synthesis of A-22-Int3 A solution of DIC (533 g, 4.23 mol) and CuCl (8 g, 0.08 mol) in t-BuOH (325.6 g, 4.4 mol) was stirred at room temperature under nitrogen for 5 days. The reaction was diluted with DCM (1 L). A-22-Int2 (200 g, 1.69 mol) was added portionwise to the solution at 0 °C. The reaction was stirred at room temperature for 5 h and then filtered through a pad of Celite. The filtrate was washed with saturated aqueous Na2CO3 and brine, dried over Na2SO4, concentrated, and the residue was purified by distillation to give A-22-Int3 (200 g). A-22-Int3 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 11.

[0272] 8-3) Synthesis of A-22-Int4 To a stirred solution of A-22-Int3 (100 g, 0.57 mol), PPh3 (194.1 g, 0.74 mol), and compound N-hydroxyphthalimide (110.8 g, 0.68 mol) in DCM (1 L) was added DIAD (157.6 g, 0.74 mol) at −20 to −40 °C. After 40 min at the same temperature, the reaction mixture was concentrated and directly purified by flash chromatography (PE:EA = 100:1 to 10:1) to give A-22-Int4 (73.8 g). A-22-Int4 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 12.

[0273] 8-4) Synthesis of A-22-Int5 To a stirred solution of A-22-Int4 (100 g, 0.31 mol) in DCM (500 mL) and MeCN (100 mL) was added NHNH·HO (39.2 g, 0.78 mol) at 0 °C. After the addition, the mixture was warmed to room temperature and stirred at the same temperature for 3 h, then filtered. The filtrate was washed with saturated aqueous NaCO and brine, dried over NaSO, filtered, and concentrated to give A-22-Int5 (54 g). The crude product was used as is. A-22-Int5 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 13.

[0274] 8-5) Synthesis of A-22-Int6 A 1000 mL three-neck flask was charged with 1-naphthalenemethanol (31.6 g, 200 mmol) dissolved in DCM (200 mL) at -10 °C. DIEA (35 mL) was then slowly added dropwise, turning the solution pale red. After stirring for 5 min, triphosgene (solid, 29.6 g, 0.1 mol) was added slowly in portions to maintain the temperature below 0 °C. After the addition, the mixture was stirred at that temperature for 20 min, and TLC was used to monitor the reaction, indicating that the starting material had been consumed. A-22-Int5 (32 g, 0.17 mol) in DCM (100 mL) was added dropwise slowly to maintain the temperature below 0 °C, and the mixture was stirred at that temperature for 20 min. DIEA was added until no more smoke was generated. The mixture was then stirred at room temperature for 30 min. TLC confirmed the reaction was complete. The mixture was then diluted with 300 mL of DCM, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a residue that was purified by flash chromatography (PE:EA 100:1 to 10:1) to give A-22-Int6 (36 g). A-22-Int6 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 14.

[0275] 8-6) Synthesis of intermediate A-22 A-22-Int6 (25 g, 67 mmol) was dissolved in formic acid (250 mL). After stirring at room temperature for 6 hours, the mixture was concentrated. The residue was purified by pre-HPLC to give A-22 (13 g). A-22 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 15.

[0276] Production Example 9: Synthesis of Intermediate A-43

[0277] [ka]

[0278] A-43-Int2 was synthesized in the same manner as in Production Example 8: 8-1) to 8-3). To a solution of A-43-Int2 (10.0 g, 21.1 mmol) in CHCl3 (100 mL) and ethyl alcohol (100 mL) was added Pd / C (1.20 g, 10% purity) under nitrogen protection at 25 °C. The suspension was degassed under vacuum, purged with H2 three times, and stirred under hydrogen at 15 psi for 8 h. The mixture was filtered, and the filtrate was concentrated to give A-43-Int3 (43.0 g, 96.5 mmol, 91% yield) as a yellow oil. A-43-Int3 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 16. Using A-43-Int3, A-43 was synthesized in the same manner as in Production Example 8: 8-4) to 8-6). A-43 1 The 1 H NMR (400 MHz, DMSO) data is shown in FIG.

[0279] Production Example 10: Synthesis of Intermediate A-60

[0280] [ka]

[0281] A-60-Int2 was synthesized in the same manner as in Preparation Example 9, where A-43-Int2 was synthesized from A-43-Int1. A-60-Int2 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 18. To a solution of A-60-Int2 (500 mg, 1.63 mmol) and imidazole (222 mg, 3.26 mmol) in dichloromethane (5 mL) was added TBSCl (369 mg, 2.49 mmol) at 0 °C, and the mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with water (10 mL × 2), and the organic phase was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 20 / 1) to give the product A-60-Int3 (500 mg, 1.19 mmol, 73%) as a colorless oil. A-60-Int3 1 The 1 H NMR (400 MHz, DMSO) data is shown in FIG. A-60 was synthesized using A-60-Int3 in the same manner as in Production Example 8: 8-4) to 8-6). A-60 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 20.

[0282] Production Example 11: Synthesis of Intermediate A-52

[0283] [ka]

[0284] 11-1) Synthesis of A-52-Int2 (for 2 batches) To a solution of A-52-Int1 (665 g, 2.18 mol), 2-hydroxyisoindoline-1,3-dione (391 g, 2.4 mol), and triphenylphosphane (745 g, 2.84 mol) in THF (7.0 L) under nitrogen at −20° C., diisopropyl azodicarboxylate (574 g, 2.84 mol, 552 mL) was added. The mixture was then warmed to 20° C. and stirred for 16 h. TLC (petroleum ether:ethyl acetate=5:1) showed that the starting material (A-52-Int1) was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue, which was then poured into a mixture of ethyl acetate (1.0 L) and petroleum ether (10.0 L). The resulting white solid was separated and filtered. The organic layer was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, petroleum ether: ethyl acetate = 50:1 to 15:1) to give A-52-Int2 (1.80 kg, yield 83%) as a white solid. A-52-Int2 1 The 1 H NMR (400 MHz, DMSO) data is shown in FIG.

[0285] 11-2) Synthesis of A-52-Int3 (for 14 batches) To a solution of A-52-Int2 (120 g, 267 mmol) in MeCN (720 mL) was added a solution of hydrofluoric acid (33.4 g, 801 mmol, 30.3 mL, 48% purity) in HO at 0 °C. The mixture was then stirred at 20 °C for 15 min. TLC (petroleum ether:ethyl acetate = 5:1) showed that the starting material (A-52-Int2) was completely consumed. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (1.0 L) and then extracted with ethyl acetate (1.0 L). The combined organic layers were washed with brine (750 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give A-52-Int3 (1.20 kg, 3.58 mol, 96% yield) as a yellow oil. A-52-Int3 1 H NMR (400 MHz, CDCl3) data is shown in Figure 22.

[0286] 11-3) Synthesis of A-52-Int4 (for 2 batches) To a solution of A-52-Int3 (600 g, 1.79 mol), 4-4-3b (586 g, 1.79 mol), and PPh3 (563 g, 2.15 mol) in DCM (8.0 L) was slowly added diisopropyl azodicarboxylate (434 g, 2.15 mol, 417 mL) over 2 h at -20 °C. The mixture was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1) indicated that the major spot was the target compound. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (4.0 L) and ethyl acetate (4.0 L). A large amount of white solid separated. It was filtered, and the organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 50:1 to 5:1) to obtain a crude product. The crude product was then dissolved in EtOH (8.0 L) and stirred for approximately 2 hours to precipitate a large amount of white solid. The precipitate was filtered to obtain A-52-Int4 (2.0 kg, 3.10 mol, 87% yield) as a white solid. A-52-Int4 1 The 1 H NMR (400 MHz, DMSO) data is shown in Figure 23.

[0287] 11-4) Synthesis of A-52-Int5 (for 3 batches) To a solution of A-52-Int4 (100 g, 155 mmol) in EtOH (400 mL) and CHCl3 (400 mL) under nitrogen, Pd / C (5.0 g, 155 mmol, 10% purity) was added at 20 °C. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (45 psi) at 40 °C for 48 h. TLC (petroleum ether:ethyl acetate = 2:1) showed complete consumption of the starting material (A-52-Int4). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in THF (1.0 L) and concentrated under reduced pressure to give A-52-Int5 (110 g, 292 mmol, 63% yield) as a white solid. A-52-Int5 1 The 1 H NMR (400 MHz, DMSO) data is shown in FIG.

[0288] 11-5) Synthesis of A-52-Int6 and A-52 (for 5 batches) To a solution of A-52-Int5 (136 g, 292 mmol) in THF (1.8 L) was added cesium carbonate (353 g, 1.08 mol) and 2,2,4,6,7-pentamethyl-3H-benzofuran-5-sulfonyl chloride (209 g, 723 mmol). The mixture was stirred at 45 °C for 16 h. A new major spot was detected by TLC (petroleum ether:ethyl acetate = 1:1). The reaction mixture was quenched at 23 °C by adding water (2.0 L) and then extracted with ethyl acetate (2.0 L × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 1:1) to give A-52-Int6 (400 g, 636 mmol, 44% yield) as a white solid. A-52-Int6 1 The 1 H NMR (400 MHz, DMSO) data is shown in Figure 25. A-52 was synthesized in the same manner as in Production Example 8 using A-52-Int6. A-52 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 26.

[0289] Intermediate A shown in Table 6 (Table 6-1 to Table 6-7) was synthesized using the corresponding starting material according to the above-described method or a known method.

[0290] [Table 6-1]

[0291] [Table 6-2]

[0292] [Table 6-3]

[0293] [Table 6-4]

[0294] [Table 6-5]

[0295] [Table 6-6]

[0296] [Table 6-7]

[0297] Intermediate C shown in Table 7 is either commercially available or synthesized according to known methods.

[0298] [Table 7]

[0299] Example 1: Synthesis of I-128

[0300] [ka]

[0301] To a solution of A-36 (123 mg, 0.50 mmol, 0.50 mmol / mL in MeOH) and B-128 (0.40 mmol, 0.40 mmol / mL in MeOH, 1.0 eq.) in methanol (2 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmolinium chloride n-hydrate (DMT-MM) (0.45 mmol, 0.45 mmol / mL in MeOH, 1.1 eq.). The mixture was allowed to stand at 10 °C for 2 h and then concentrated under reduced pressure. The residue was diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in formic acid (3 mL) and allowed to stand at 10 °C for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC (FA) to give the product I-128. I-128 1 The H NMR (400 MHz, CDCl3) data is shown in Figure 27.

[0302] Reference example 1

[0303] [ka]

[0304] Compound ref1-1 (4.05 g, 6.5 mmol) was dissolved in formic acid (30 mL), and the mixture was stirred for 1 day at 25° C. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give compound ref1-2.

[0305] Example 2: Synthesis of I-129

[0306] [ka]

[0307] I-129-Int1 was synthesized in the same manner as in Example 1 and Reference Example 1 using A-129 and B-129. To a solution of I-129-Int1 (0.09 mmol, 0.045 mmol / mL in N,N-DMF, 1.0 eq.) and C-82 (0.18 mmol, 0.09 mmol / mL in DMF, 2.0 eq.) in DMF (2.0 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.14 mmol, 0.28 mmol / mL in DMF, 1.5 eq.) in DMF (0.5 mL) and N-ethyl-N-isopropyl-propan-2-amine (DIPEA) (0.28 mmol, 0.56 mmol / mL in DMF, 3.0 eq.) in DMF (0.5 mL) at 25 ° C. The mixture was stirred at 25 ° C. for 2 h. The reaction mixture was filtered to obtain a filtrate, which was purified by prep-HPLC (FA conditions) to obtain the target compound I-129.

[0308] Using the intermediates shown in Table 8 (Tables 8-1 to 8-3), compounds I-1 to I-140, I-153 to I-157, I-161 to I-165, and I-176 to I-180 were synthesized according to the above-described method or known methods.

[0309] [Table 8-1]

[0310] [Table 8-2]

[0311] [Table 8-3]

[0312] Example 3: Synthesis of I-141

[0313] [ka]

[0314] Example 3-1) Synthesis of I-141-Int1 A stirred mixture of AB-141 (86 mg) and Pd / C (5 wt%, 33 mg) in THF (3 mL) was exposed to H (balloon pressure) at room temperature. The reaction mixture was stirred for 2 h, after which the H was removed. Filtration over a Celite pad and evaporation of the filtrate afforded I-141-Int1 (70 mg) as a dark brown solid. This crude solid was used in the next reaction without further purification. LCMS (Method B): m / z=421.4[M+H] + .

[0315] Example 3-2) Synthesis of I-141 To a solution of I-141-Int1 (70 mg), AcOH (60 μL), and 3-phenylpropanal (I-141-Int2, 88 μL) in DCE (4 mL) was added NaBH(OAc)3 (140 mg) at room temperature. After stirring for 1 day, 1 mol / L aqueous sodium hydroxide solution (30 mL) was added. The organic layer was separated, washed with water (10 mL), dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC (column: C30-UG-5, 0.1% MeCN / AcOH solution = 20 / 80-70 / 30) to give I-141 (21 mg) as a white solid. LCMS (Method B): m / z=539.6[M+H] + .

[0316] Example 4: Synthesis of I-145

[0317] [ka]

[0318] To a solution of AB-145 (25 mg), AcOH (10 μL), and quinoline-2-carbaldehyde (7.8 mg) in DCE (1 mL) was added NaBH(OAc) (71 mg) at room temperature. After stirring for 1 day, 1 mol / L aqueous sodium hydroxide solution (1.0 mL) was added. The organic layer was separated, dried over NaSO, concentrated in vacuo, and purified by preparative HPLC (column: C30-UG-5, 0.1% MeCN / AcOH solution = 10 / 90-60 / 40) to give I-145 (5.6 mg) as a pale yellow solid. LCMS (Method B): m / z=671.4[M+H] + .

[0319] Example 5: Synthesis of I-147

[0320] [ka]

[0321] Example 5-1) Synthesis of I-147-Int1 To a stirred biphasic mixture of AB-5 (0.26 g) in THF (5 mL) and NaCO (0.11 g) in water (5 mL) was added BocO (0.13 g) at room temperature. After stirring for 1 h, the mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO (20 mL). The organic layer was separated, dried over NaSO, concentrated in vacuo, and purified by chromatography (SiO, n-hexane:AcOEt = 90:10 to 20:80, gradient) to give I-147-Int1 (0.32 g) as a white amorphous solid. LCMS (Method B): m / z=545.3[M-tBu+H] + ,623.3[M+Na] + .

[0322] Example 5-2) Synthesis of I-147-Int2 A stirred mixture of I-147-Int1 (0.32 g) and Pd / C (5 wt%, 57 mg) in THF (5 mL) was exposed to H2 (balloon pressure) at room temperature. The reaction mixture was stirred for 1 h, after which the H2 was removed. Filtration over a pad of Celite and evaporation of the filtrate afforded I-147-Int2 (0.22 g) as a white solid. This crude solid was used in the next reaction without further purification. LCMS (Method B): m / z=367.2[M-Boc+H] + ,411.2[M-tBu+H] + .

[0323] Example 5-3) Synthesis of I-147-Int3 To a solution of I-147-Int2 (80 mg), AcOH (10 μL), and 3-phenylpropanal (I-141-Int2, 53 μL) in DCE (2 mL) was added NaBH(OAc)3 (0.17 g) at room temperature. After stirring for 1 day, 2 mol / L aqueous sodium hydroxide solution (10 mL) was added. The organic layer was separated, washed with water (10 mL), dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC (column: C30-UG-5, 0.1% MeCN / AcOH solution = 50 / 50-100 / 0) to give I-147-Int3 (42 mg). LCMS (Method D): m / z=529.1[M-tBu+H] + ,607.2[M+Na] + .

[0324] Example 5-4) Synthesis of I-147 To a flask containing I-147-Int3 (20 mg), formic acid (1 mL) was added, and the mixture was allowed to stand at room temperature. After 4 days, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: C30-UG-5, 0.1% MeCN / AcOH solution = 30 / 70-80 / 20) to give I-147 (13 mg) as a white solid. LCMS (Method D): m / z=485.1[M+H] + .

[0325] Example 6: Synthesis of I-148

[0326] [ka]

[0327] Example 6-1) Synthesis of I-148-Int1 A mixture of AB-148 (0.99 g) and palladium on carbon (10 wt%) (0.31 g) in THF (20 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The mixture was filtered through Celite. The filtrate was concentrated in vacuo to give I-148-Int1 (0.74 g) as a dark brown solid. LCMS (Method B): m / z=381.4[M+H] +

[0328] Example 6-2) Synthesis of I-148-Int3 To a solution of I-148-IntI (0.15 g), I-148-Int2 (0.22 g), and acetic acid (99 μL) in 1,2-dichloroethane (7 mL) was added sodium triacetoxyborohydride (0.25 g). The mixture was stirred at room temperature for 16 hours. To this mixture was added 1 mol / L aqueous NaOH (20 mL) and chloroform (40 mL). The organic layer was separated and then washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, AcOEt:MeOH = 80:20 to 20:80, gradient) to give I-148-Int3 (0.16 g) as a colorless oil. LCMS (Method B): m / z=604.6[M+H] +

[0329] Example 6-3) Synthesis of I-148-Int4 A mixture of I-148-Int4 (0.16 g) and palladium on carbon (10 wt%) (56 mg) in THF (3 mL) was stirred under a hydrogen atmosphere at room temperature for 1 hour. The mixture was filtered through Celite. The filtrate was concentrated in vacuo to give I-148-Int4 (0.16 g) as a dark brown oil. LCMS (Method B): m / z=606.6[M+H] +

[0330] Example 6-4) Synthesis of I-148-Int5 A mixture of I-148-Int4 (0.14 g) and formic acid (2.0 mL) was allowed to stand at room temperature for 1 hour. The mixture was concentrated in vacuo. To the residue was added chloroform (30 mL) and Na2CO3 (3.0 g). The mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and the filtrate was concentrated in vacuo to give I-148-Int5 (0.17 g) as a pale yellow oil. LCMS (Method B): m / z=506.5[M+H] +

[0331] Example 6-5) Synthesis of I-148 To a mixture of I-148-Int5 (22 mg), I-148-Int6 (11 mg), and N-ethyl-N-isopropylpropan-2-amine (11 μL) in 1,2-dichloroethane (2 mL) was added HATU (25 mg). After stirring at room temperature for 2.5 h, I-148-Int6 (11 mg), N-ethyl-N-isopropylpropan-2-amine (11 μL), and HATU (25 mg) were added to the mixture. After stirring at room temperature for 1 h, 1 mol / L aqueous HCl (10 mL) was added, and the mixture was extracted with chloroform (20 mL). The organic layer was washed with aqueous NaHCO3 (10 mL) and then with water (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (column: C30-UG-5, 0.1% solution of MeCN / AcOH=20 / 80-70 / 30) to give I-148 (0.6 mg) as a white solid. LCMS (Method B): m / z=714.6[M+H] +

[0332] Example 7: Synthesis of I-149

[0333] [ka]

[0334] To a solution of I-148-Int5 (31 mg) in 1,2-dichloroethane (2 mL) was added p-toluenesulfonyl chloride (12 mg) and pyridine (49 mg) at room temperature. After stirring at the same temperature for 17 hours, chloroform (10 mL) and water (20 mL) were added. The organic layer was separated, washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-HPLC (Conditions (AcOH): B = 20-70%). The collected fractions were combined and concentrated in vacuo. The aqueous solution was lyophilized to give I-149 (0.5 mg) as a white solid. LCMS (Method B): m / z=660.5[M+H] + .

[0335] Example 8: Synthesis of I-159 and I-160

[0336] [ka]

[0337] To a solution of AB-159 (0.96 g) in THF (20 mL) cooled in an ice / water bath, BH3·THF (0.9 mol / L in THF, 7.5 mL) was added. After stirring at 0 °C for 1 h and at room temperature for 2 h, MeOH (4 mL) was added dropwise. The mixture was concentrated in vacuo and purified by column chromatography (NH SiO2, n-hexane:AcOEt = 80:20 to 0:100, gradient) to give I-159 (0.17 g) and I-160 (0.27 g) as colorless oils. LCMS (I-159, Method D): m / z=489.1[M+H] + LCMS (I-160, Method D): m / z=475.2[M+H] +

[0338] Example 9: Synthesis of I-173

[0339] [ka]

[0340] To a solution of I-148-Int1 (20 mg) in 1,2-dichloroethane (4 mL) was added 3-benzoylbenzoic acid (21 mg), pyridine (67 mg), and 2-chloro-1,3-dimethyl-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate (CIP, 100 mg) at room temperature. After stirring at the same temperature for 4 h, saturated aqueous sodium bicarbonate (50 mL) and chloroform (20 mL) were added. The organic layer was separated and washed with 1 mol / L hydrochloric acid (15 mL), saturated aqueous sodium bicarbonate (20 mL), and brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by prep-HPLC (conditions (AcOH): B = 10-60%). The collected fractions were combined and concentrated in vacuo. The aqueous solution was lyophilized to give I-173 (10 mg) as a white solid. LCMS (Method B): m / z=589.4[M+H] + .

[0341] Example 10: Synthesis of I-182

[0342] [ka]

[0343] Example 10-1) Synthesis of I-182-Int1 A mixture of AB-182 (2.0 g) and palladium on carbon (10 wt%) (0.51 g) in THF (20 mL) was stirred under a hydrogen atmosphere at room temperature for 100 minutes. The mixture was filtered through Celite. The filtrate was concentrated in vacuo to give I-182-Int1 (1.5 g) as a pale yellow-green solid. LCMS (Method B): m / z=368.2[M+H] +

[0344] Example 10-2) Synthesis of I-182 To a mixture of I-182-Int1 (0.10 g) and pyridine (88 μL) in 1,2-dichloroethane (3 mL) was added I-148-Int2 (0.16 g). After stirring at room temperature for 2 h and at 60 °C for 3 days, the mixture was poured into saturated aqueous sodium bicarbonate and then extracted with chloroform. The organic layer was washed with aqueous NaHCO3 (10 mL) and then water (10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give the crude product (0.12 g), which was purified by preparative HPLC to give I-182 (20 mg) as a white solid. LCMS (Method B): m / z=522.2[M+H] + I-182 1 H NMR (300 MHz, CDCl3) data is shown in Figure 28. Compounds I-141 to I-143 were synthesized using intermediates AB and reagents shown in Table 9 according to the same method as in Example 3 (Production Method 7) or known methods.

[0345] Compounds I-144 to I-146 were synthesized using intermediates AB and reagents shown in Table 9 according to the same method as in Example 4 or known methods. Compounds I-149 to I-152 were synthesized using intermediates AB and reagents shown in Table 9 according to the same method as in Example 7 or known methods. Compounds I-158 to I-160 were synthesized using intermediates AB shown in Table 9 according to the same method as in Example 8 (Production Method 8) or known methods. Compounds I-166 to I-175 were synthesized using intermediates AB and reagents shown in Table 9 according to the same method as in Example 9 (Production Method 5) or known methods. Compounds I-181 to I-182 were synthesized using intermediates AB and reagents shown in Table 9 according to the same method as in Example 10 (Production Method 6) or known methods.

[0346] [Table 9]

[0347] The chemical structures of intermediates AB are shown in Table 10 (Tables 10-1 to 10-2). Intermediate AB was synthesized using the corresponding intermediates A and B shown in Table 10 according to the method of Example 1 or known methods.

[0348] [Table 10-1]

[0349] [Table 10-2]

[0350] The chemical structures of Intermediate A and Intermediate B are shown in Tables 6 and 5, respectively. The chemical structures of the reagents shown in Table 9 are shown in Table 11.

[0351] [Table 11]

[0352] The compound names and molecular weight measurement results of Compounds I-1 to I-183 are shown in Table 12 (Table 12-1 to Table 12-28).

[0353] [Table 12-1]

[0354] [Table 12-2]

[0355] [Table 12-3]

[0356] [Table 12-4]

[0357] Table 12-5

[0358] Table 12-6

[0359] Table 12-7

[0360] Table 12-8

[0361] Table 12-9

[0362] Table 12-10

[0363] Table 12-11

[0364] Table 12-12

[0365] Table 12-13

[0366] Table 12-14

[0367] Table 12-15

[0368] Table 12-16

[0369] Table 12-17

[0370] Table 12-18

[0371] Table 12-19

[0372] Table 12-20

[0373] Table 12-21

[0374] Table 12-22

[0375] Table 12-23

[0376] Table 12-24

[0377] Table 12-25

[0378] [Table 12-26]

[0379] [Table 12-27]

[0380] [Table 12-28]

[0381] Experimental example: Notch assay CellSensor T-REx was engineered by lentiviral transfection of HeLa cells with a Notch response element (CSL-bla) driving β-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, which subsequently allowed the expression of β-lactamase. Specifically, the following protocol was used:

[0382] Notch Assay Protocol (Method 2) 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:

[0383] [ka]

[0384] 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.

[0385] Instead of steps 1 to 3, the following steps a to d can also be performed. Step 4 (Method 1) The rest of the process is the same as in Method 2. a. Cell: HeLa / T-REx TM NICD CSL-bla cells (10 3cells / well), 32 μl / well in complete medium, placed in a 384-well plate. b. Prepare 10x compound in assay medium. c. Add 4 μL compound or 1% DMSO in assay medium to the cells. d. Add 4 μl of 10× doxycycline in assay medium to treated wells and 4 μl of assay medium to untreated or cell-free control wells. The results are shown in Table 13 (Table 13-1 to Table 13-2).

[0386] [Table 13-1]

[0387] [Table 13-2] [Industrial Applicability]

[0388] 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 / 090,185 filed in the United States (filing date: October 10, 2020), the contents of which are incorporated in their entirety herein.

Claims

1. A compound represented by the following formula (I): 【Chemistry 1】 [In the formula, Q is represented by any one of the following formulas (I-1) to (I-2): 【Chemistry 2】 * is the bonding site with N (nitrogen atom); R １ａ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R １ｂ is hydrogen, optionally substituted alkyl, or -W 11 ' -W 12 ' -R 13 ' (In the formula, W 11′ is —(CO)—; W 12′ is —NH—, and R 13′ is optionally substituted alkyl or optionally substituted arylalkyl; R 1c is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; U is -(CO)- or CH ２ - and; R ２ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R ３ But -W 31' -W 32' -R 33' (In the formula, W 31′ is —(CO)—, —(SO ２ ) - or -CH ２ - and W 32′ is —O—, —NH—, or a bond; and R 33′ is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; R ４ａ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R ４ｂ is hydrogen or optionally substituted alkyl; R ４ａ and R ４ｂ may form a spiro ring together with the carbon to which they are attached, and may have an oxygen atom or a nitrogen atom in the ring; R ５ is hydrogen or optionally substituted alkyl. or a pharmaceutically acceptable salt thereof; However, (3R,6S)isopropyl-3-ethyl-8-isopentyl-6-(2-(methylthio)ethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxylate is excluded.

2. The compound according to claim 1, represented by the following formula (Ia): 【Transformation 3】 [In the formula, R １ａａ is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R １ｂａ is hydrogen, optionally substituted alkyl, or —W 11a′ —W 12a′ —R 13a′ (In the formula, W 11a′ is —(CO)—; W 12a′ is —NH—, and R 13a′ is optionally substituted alkyl or optionally substituted arylalkyl; R ２ａ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R ３ａ が、-W 31a' -W 32a' -R 33a' (In the formula, W 31a′ is —(CO)—; W 32a' is -O- or -NH-, and R 33a′ is optionally substituted alkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; R ４ａａ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R ４ｂａ is hydrogen; R 5a is hydrogen. or a pharmaceutically acceptable salt thereof; However, (3R,6S)isopropyl-3-ethyl-8-isopentyl-6-(2-(methylthio)ethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxylate is excluded.

3. R １ａ is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R １ｂ is hydrogen, optionally substituted alkyl, or -W １１’ -W １２’ -R １３’ (In the formula, W １１’ is —(CO)—, W １２’ is —NH—, and R １３’ is optionally substituted alkyl or optionally substituted arylalkyl; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ａａ is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted arylalkyl; R １ｂａ is hydrogen, optionally substituted alkyl, or -W １１ａ’ -W １２ａ’ -R １３ａ’ (In the formula, W １１ａ’ is —(CO)—, W １２ａ’ is —NH—, and R １３ａ’ is optionally substituted alkyl or optionally substituted arylalkyl; 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof.

5. R １ｃ 2. The compound of claim 1, wherein is optionally substituted heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

6. 2. The compound of claim 1, wherein U is --(CO)--, or a pharmaceutically acceptable salt thereof.

7. R ２ 2. The compound of claim 1, wherein is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl, or a pharmaceutically acceptable salt thereof.

8. R ３ But, -W ３１’ -W ３２’ -R ３３’ (In the formula, W ３１’ is —(CO)— or —CH ２ - and W ３２’ is —O—, —NH—, or a bond, and R ３３’ or a pharmaceutically acceptable salt thereof.

9. R ４ａ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted cycloalkylalkyl; R ４ｂ is hydrogen R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

11. 11. The pharmaceutical composition of claim 10, wherein the composition comprises an effective amount of the compound.

12. An agent for treating or preventing a disease associated with Notch signaling, comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

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