Novel Heterocyclic Compound

Abstract

Compounds of formula (I): TIFF2023535847000155.tif75170 where each symbol is as defined in the specification. or a pharmaceutically acceptable salt thereof has excellent cancer cell proliferation inhibitory activity.

Description

[Technical Field]

[0001] The present invention relates to novel heterocyclic compounds. More specifically, the present invention relates to novel heterocyclic compounds having an inhibitory effect on cancer cell proliferation. [Background technology]

[0002] Cancer is a major cause of death in both animals and humans. Many chemotherapeutic agents have been developed that are effective against cancer and tumor cells, but they are not necessarily effective against all types of cancer and tumors, and some have the side effect of destroying normal cells. There is still a need for the development of drugs that are effective specifically against cancer cells with fewer side effects. Summary of the Invention [Problem to be solved by the invention]

[0003] An object of the present invention is to provide a compound that has an inhibitory effect on cancer cell proliferation. [Means for solving the problem]

[0004] As a result of extensive research aimed at solving the above problems, the present inventors discovered that compounds having a specific structure exhibit excellent inhibitory effects on the proliferation of cancer cells, leading to the completion of the present invention.

[0005] That is, the present invention relates to the following. [1] A compound represented by the following formula (I):

[0006] [ka]

[0007] [In the formula, Q is a hydrogen atom or any of the following formulae (II-1) to (II-8):

[0008] [ka]

[0009] R1 is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, or -(CO)-R 1a and; R 1a is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted heteroaryl; R 1b are a hydrogen atom or 1 to 3 of the same or different alkyl; Q 1a is a single bond or an optionally substituted alkylene; Q 1b is a hydrogen atom, hydroxy, halogen, cyano, -Q 1c , -COQ 1c , -CONQ 1c Q 1d , CONQ 1c -OQ 1d , -NQ 1c Q 1d , or -OQ 1c and; Q 1c is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Q 1d is a hydrogen atom or an optionally substituted alkyl; Q 2a is an optionally substituted cycloalkylene; Q 2b and Q 2care the same or different and each is a hydrogen atom or an optionally substituted alkyl; U is -CO- or -CH2-; R2 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or -XN(R 2a )(R 2b ) and; X is an alkylene group; R 2a and R 2b are the same or different and each is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; V is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted partially saturated heteroaryl ring, or an optionally substituted heterocycloalkyl ring; R3 is a hydrogen atom, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C≡CR 3a , or -COOR 3b and; R 3a is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; R 3b is a hydrogen atom or an optionally substituted alkyl;

[0010] [ka]

[0011] represents any one of the following formulas (III-1) to (III-4):

[0012] [ka]

[0013] R4 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; Ar2 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; and R5 is a hydrogen atom or an optionally substituted alkyl; and R6 and R7 are the same or different and each represents a hydrogen atom or a halogen atom. or a pharmaceutically acceptable salt thereof.

[0014] [2] The compound according to [1], which is a compound represented by the following formula (Ia):

[0015] [ka]

[0016] [In the formula, R1 is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, or -(CO)-R 1a and; R 1a is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;

[0017] [ka]

[0018] represents any one of the following formulas (II-1-a) to (II-6-a):

[0019] [ka]

[0020] R 1b are a hydrogen atom or 1 to 3 of the same or different alkyl; R2 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or -XN(R 2a )(R 2b ) and; X is an alkylene group; R 2a and R 2bare the same or different and each is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; Ar1 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; R3 is a hydrogen atom, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C≡CR 3a , or -COOR 3b and; R 3a is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; R 3b is a hydrogen atom or an optionally substituted alkyl;

[0021] [ka]

[0022] represents any one of the following formulas (III-1) to (III-3):

[0023] [ka]

[0024] R4 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; Ar2 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; and R5 is a hydrogen atom or an optionally substituted alkyl. or a pharmaceutically acceptable salt thereof.

[0025] [3] The compound according to [1], which is a compound represented by the following formula (IV):

[0026] [ka]

[0027] (wherein each symbol is as defined in [1]) or a pharmaceutically acceptable salt thereof.

[0028] [4] The compound according to any one of [1] to [3], which is a compound represented by the following formula (IV-a):

[0029] [ka]

[0030] (wherein each symbol is as defined in [2]) or a pharmaceutically acceptable salt thereof.

[0031] [5] The compound according to [1] or [3], wherein Q is represented by any one of the following formulae (VI-1) to (VI-3):

[0032] [ka]

[0033] (wherein each symbol is as defined in [1]) or a pharmaceutically acceptable salt thereof.

[0034] [6] The compound according to any one of [1], [3] and [5], wherein Q is represented by the following formula (II-7):

[0035] [ka]

[0036] Q 1a is alkylene, Q 1b Ha-CONH-Q 1c , -Q 1d , -CO-Q 1d、 -N(Q 1c )-Q 1d (In the formula, Q 1c is a hydrogen atom or alkyl, and Q 1d is a hydrogen atom or heterocycloalkyl optionally substituted with alkyl; or a pharmaceutically acceptable salt thereof.

[0037] [7]

[0038] [ka]

[0039] The compound according to [2] or [4], wherein the compound is represented by any one of the following formulae (VI-1-a) to (VI-3-a):

[0040] [ka]

[0041] or a pharmaceutically acceptable salt thereof.

[0042] [8] The compound according to any one of [2], [4] and [7], or a pharmaceutically acceptable salt thereof, wherein Ar1 is an optionally substituted pyridine ring, an optionally substituted thiazole ring, an optionally substituted benzothiazole ring, or an optionally substituted quinoxaline ring. [9]

[0043] [ka]

[0044] The compound according to [8], wherein the compound is represented by the following formula (VII-1-a), (VII-2-a), or (VII-3-a):

[0045] [ka]

[0046] or a pharmaceutically acceptable salt thereof.

[0047]

[10] R1 is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or -(CO)-R 1a and; R 1a is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted heteroaryl; R 1b is a hydrogen atom; R2 is optionally substituted alkyl, optionally substituted arylalkyl; R 3a is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; R4 is optionally substituted alkyl; Ar2 is an optionally substituted aryl ring; and R5 is a hydrogen atom; The compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof.

[11]

[0048] [ka]

[0049] is represented by the following formula (V), the compound according to any one of [1] to

[10] :

[0050] [ka]

[0051] R4' is optionally substituted alkyl or optionally substituted cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0052]

[12] The compound according to

[11] , or a pharmaceutically acceptable salt thereof, wherein R4' is an alkyl group.

[13] The compound according to

[11] or

[12] , or a pharmaceutically acceptable salt thereof, wherein R4' is an isobutyl group.

[14] The compound according to any one of [1] to

[13] , or a pharmaceutically acceptable salt thereof, wherein R2 is alkyl, optionally substituted with alkylthio or alkylsulfonyl, or arylalkyl.

[15] The compound according to

[14] , or a pharmaceutically acceptable salt thereof, wherein R2 is isobutyl, neopentyl, sec-butyl, or benzyl.

[16] The compound according to any one of [1] to

[15] , or a pharmaceutically acceptable salt thereof, wherein R1 is alkyl or alkyl substituted with one or two hydroxyl groups.

[17] R3 is a hydrogen atom, hydroxy, or -C≡CR 3aand;R 3a

[0023]

[0024] The compound according to any one of [1] to

[16] , wherein is alkyl substituted with hydroxy, or a pharmaceutically acceptable salt thereof.

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

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

[19] The pharmaceutical composition according to

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

[20] A method for treating or preventing cancer, comprising administering to a subject in need thereof a compound according to any one of [1] to

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

[18] or

[19] , in an amount effective for treating or preventing cancer.

[21] An agent for treating or preventing cancer, comprising the compound according to any one of [1] to

[17] or a pharmaceutically acceptable salt thereof.

[22] The compound according to any one of [1] to

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

[18] or

[19] , for use as a pharmaceutical for treating or preventing cancer. [Effects of the Invention]

[0053] The compounds of formula (I) of the present invention inhibit the proliferation of cancer cells and can therefore be used for the treatment of various cancers and tumors. [Brief explanation of the drawings]

[0054] [Figure 1] FIG. 1 shows the 1H NMR (300 MHz, CDCl3) data of A9-4. [Figure 2] FIG. 2 shows the 1H NMR (300 MHz, CDCl3) data of ID-1. [Figure 3] FIG. 3 shows the 1H NMR (300 MHz, CDCl3) data of ID-6. [Figure 4] FIG. 4 shows the 1H NMR (300 MHz, CDCl3) data of ID-11. [Figure 5]FIG. 5 shows the 1H NMR (300 MHz, CDCl3) data of B-4-6-Int2. [Figure 6] FIG. 6 shows the 1H NMR (300 MHz, CDCl3) data of A9-43. DETAILED DESCRIPTION OF THE INVENTION

[0055] [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.

[0056] "Lower" means that the given radical comprises between 1 and 6 carbon atoms, unless otherwise indicated.

[0057] "Optionally substituted" means, unless otherwise indicated, that a given group may consist solely of hydrogen substituents according to available valences, or may further include one or more non-hydrogen substituents according to available valences. In general, the non-hydrogen substituents may be any substituent that may be attached to an atom of the given group that is specified to be substituted. Examples of substituents include -R, -OR, -COR, -COOR, -OCOR, -CONR, -NR, -NR, -COR, -NRCOOR, -SR, -SOR, -SONR, -SOR, -OSOR, -NHC(NHR)NR, -NHC(NH)NH, -CN, -NO, halogen, ethynyl, and methylenedioxy (where R 6 and R 7 are independently selected from hydrogen, straight or branched chain, cyclic or acyclic, substituted or unsubstituted alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl moieties.

[0058] "Halogen" means fluorine, chlorine, bromine or iodine. "Halo" means fluoro, chloro, bromo or iodo.

[0059] "Alkyl" means a group having a straight or branched, saturated aliphatic chain of carbon atoms. X and Y indicate the number of carbon atoms in the chain. X-Y Alkyl is typically used. The number of carbon atoms in the chain is preferably 1 to 10, 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.

[0060] "Alkoxy" means an oxygen moiety further having an alkyl substituent. C X-Y Alkoxy 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 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexyloxy, and isohexyloxy.

[0061] "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.

[0062] "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.

[0063] "Alkylene" means, unless otherwise indicated, a straight or branched, saturated aliphatic, polyvalent carbon chain. C X-Y Alkylene is typically used. The number of carbon atoms in the chain is preferably 1 to 10, 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.

[0064] "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.

[0065] "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-YAryl 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 and indanyl, and the like.

[0066] An "aryl ring" is a monocyclic or polycyclic ring in which each ring is aromatic or, when fused to one or more rings, forms an aromatic ring. C X-Y An aryl ring 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 rings include benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene, and the like.

[0067] "Partially saturated heteroaryl ring" means a heteroaryl ring in which one or more double bonds are replaced with a single bond.

[0068] A "heteroaryl ring" refers to a monocyclic or polycyclic aromatic ring in which at least one ring atom is a heteroatom and the remaining ring atoms are carbon. An "X- to Y-membered heteroaryl ring" 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 rings include, but are not limited to, cyclic aromatic rings having 5 or 6 ring atoms in which at least one ring atom is a heteroatom and the remaining ring atoms are carbon. The nitrogen atom may be optionally quaternized, and the sulfur atom may be optionally oxidized. Non-exclusive examples of monocyclic heteroaryl rings of the present invention include, but are not limited to, furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, triazole, and tetrazole. "Heteroaryl ring" also includes, but is not limited to, bicyclic or tricyclic rings (wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, and another monocyclic heteroaryl or heterocycloalkyl ring). Non-exclusive examples of bicyclic or tricyclic heteroaryl rings include benzofuran (e.g., benzo[b]furan), benzothiophene (e.g., benzo[b]thiophene), benzimidazole, benzotriazine (e.g., benzo[e][1,2,4]triazine, benzo[d][1,2,3]triazine), pyridopyrimidine (e.g., pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrido[2,3 -d]pyrimidine), pyridopyrazines (e.g., pyrido[3,4-b]pyrazine, pyrido[2,3-b]pyrazine), pyridopyridazines (e.g., pyrido[2,3-c]pyridazine, pyrido[3,4-c]pyridazine, pyrido[4,3-c]pyridazine, pyrido[3,2-c]pyridazine), pyridotriazines (e.g., pyrido[2,3-d][1,2,3]triazine, pyrido[3,4-d][1,2,3]triazine, pyrido[4,3-d][1,2,3]triazine, pyrido[3,2-d][1,2,3]triazine, pyrido[3,4-e][1,2,4]triazine, pyrido[3,2-e][1,2,4]triazine), benzothiadiazoles (e.g., benzo[c][1,2,5]thiadiazole), furopyridines (e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-c]pyridine, furo[2,3-b]pyridine), oxazolopyridines (e.g., oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-c]pyridine, pyridine, oxazolo[5,4-b]pyridine), thiazolopyridines (e.g., thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-c]pyridine, thiazolo[5,4-b]pyridine), imidazopyridines (e.g., imidazo[1,2a]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, isoquinone phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine), imidazopyrimidine (e.g., imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine, imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine), pyrrolopyridine (e.g., pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]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), triazolopyridines (e.g., triazolo[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.

[0069] "Heteroaryl" means a group derived from a heteroaryl ring as defined above.

[0070] "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.

[0071] "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.

[0072] 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.

[0073] "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).

[0074] "Heterocycloalkylalkyl" means a straight-chain or branched-chain alkyl group substituted with one or more heterocycloalkyl groups.

[0075] "Alkylthio" means a thio group (-S) substituted with a straight or branched chain alkyl group. Non-exclusive examples of alkylthio include methylthio, ethylthio, propylthio, and the like.

[0076] "Alkylsulfonyl" means a sulfonyl group (-SO2-) substituted with a straight or branched chain alkyl group. Non-exclusive examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, and the like.

[0077] 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" (where X represents the number of carbon atoms and heteroatoms in the ring) is used. 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 (at least one ring atom is a heteroatom (preferably S, N, or O) and the remaining ring atoms are carbon). The nitrogen atom may be optionally quaternized, and the sulfur atom may be optionally oxidized.

[0078] Non-exclusive examples of monocyclic saturated carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.

[0079] Non-exclusive examples of monocyclic unsaturated carbocycles include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, benzene, and the like.

[0080] Non-exclusive examples of monocyclic saturated heterocycles include pyrrolidine, piperidine, morpholine, piperazine, 1,3-dioxane, 1,4-dioxane, and the like.

[0081] 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.

[0082] "Protected derivatives" refers to derivatives of compounds in which reactive sites are protected with protecting groups. 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.

[0083] The term "leaving group" refers to an atom or group of atoms that are released from a reaction substrate in a substitution reaction, elimination reaction, etc. Examples of leaving groups include halogen atoms (e.g., chlorine atom, bromine atom, iodine atom, etc.), C 1-6 Alkyl sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), C 6-10 Arylsulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), C 1-6 Alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, etc.) and the like are exemplified.

[0084] "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.

[0085] "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.).

[0086] "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).

[0087] "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.

[0088] "Pharmaceutically acceptable salt" or "salt" refers to a salt of a compound of the present invention, as defined above, which is pharmaceutically acceptable 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, 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-chlorobenzenesulfonic acid, etc. and acid addition salts formed with organic acids such as benzophenonesulfonic 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] An "effective amount" is the same as a "therapeutically effective amount" and a "prophylactically effective amount."

[0093] "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.

[0094] 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.

[0095] In one embodiment of the present invention, a compound represented by formula (I):

[0096] [ka]

[0097] [In the formula, Q is a hydrogen atom or any of the following formulae (II-1) to (II-8):

[0098] [ka]

[0099] R1 is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, or -(CO)-R 1a and; R 1a is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted heteroaryl; R 1b are a hydrogen atom or 1 to 3 of the same or different alkyl; Q 1a is a single bond or an optionally substituted alkylene; Q 1b is a hydrogen atom, hydroxy, halogen, cyano, -Q 1c , -COQ 1c , -CONQ 1c Q 1d , CONQ 1c -OQ 1d , -NQ 1c Q 1d , or -OQ 1c and; Q 1c is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Q 1d is a hydrogen atom or an optionally substituted alkyl; Q 2a is optionally substituted cycloalkyl; Q 2b and Q 2c are the same or different and each is a hydrogen atom or an optionally substituted alkyl; U is -CO- or -CH2-; R2 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or -XN(R 2a )(R 2b ) and; X is an alkylene group; R 2a and R 2b are the same or different and each is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; V is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted partially saturated heteroaryl ring, or an optionally substituted heterocycloalkyl ring; R3 is a hydrogen atom, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C≡CR 3a , or -COOR 3b and; R 3a is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; R 3b is a hydrogen atom or an optionally substituted alkyl;

[0100] [ka]

[0101] represents any one of the following formulas (III-1) to (III-4):

[0102] [ka]

[0103] R4 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; Ar2 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; and R5 is a hydrogen atom or an optionally substituted alkyl; and R6 and R7 are the same or different and each represents a hydrogen atom or a halogen atom. or a pharmaceutically acceptable salt thereof.

[0104] In one embodiment of the present invention, among the compounds represented by formula (I), a compound represented by the following formula (Ia):

[0105] [ka]

[0106] [In the formula, R1 is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, or -(CO)-R 1a and; R1a is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted heteroaryl;

[0107] [ka]

[0108] represents any one of the following formulas (II-1-a) to (II-6-a):

[0109] [ka]

[0110] R 1b are a hydrogen atom or 1 to 3 of the same or different alkyl; R2 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or -XN(R 2a )(R 2b ) and; X is an alkylene group; R 2a and R 2b are the same or different and each is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; Ar1 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; R3 is a hydrogen atom, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C≡CR 3a , or -COOR 3b and; R 3a is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; R 3b is a hydrogen atom or an optionally substituted alkyl;

[0111] [ka]

[0112] represents any one of the following formulas (III-1) to (III-3):

[0113] [ka]

[0114] R4 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; Ar2 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; and R5 is a hydrogen atom or an optionally substituted alkyl. or a pharmaceutically acceptable salt thereof.

[0115] In one embodiment of formulas (II-1) to (II-6) of Q in formula (I) or formula (Ia), R1 is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl.

[0116] 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, 4-hydroxy-3-(hydroxymethyl)butyl, hydroxyethoxyethyl, pyrimidinylmethyl, and the like.

[0117] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0118] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, isopropylpiperidinyl, acetylpiperidinyl, tetrahydropyranylpiperidinyl, tetrahydropyranyl, cyclohexylpiperidinyl, and the like.

[0119] Examples of optionally substituted aryl groups and optionally substituted heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0124] In one embodiment of formulas (II-1) to (II-6) of Q in formula (I) or formula (Ia), R1 is -(CO)-R 1a where R 1a is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted heteroaryl.

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

[0126] Examples of optionally substituted alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexyloxy, isohexyloxy, and the like.

[0127] Examples of optionally substituted aryl groups and optionally substituted heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, fluoropyrimidinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0128] In another embodiment of formulas (II-1) to (II-6) of Q in formula (I) or formula (Ia), R1 is a hydrogen atom, optionally substituted alkyl (e.g., methyl, isopropyl, hydroxypropyl, hydroxybutyl, 4-hydroxy-3-(hydroxymethyl)butyl, hydroxyethoxyethyl, aminopropyl, carboxypropyl, pyrimidinylmethyl), optionally substituted cycloalkyl (e.g., cyclopropyl, cyclohexyl), optionally substituted heterocycloalkyl (e.g., isopropylpiperidinyl, acetylpiperidinyl, tetrahydropyranylpiperidinyl, tetrahydropyranyl, cyclohexylpiperidinyl), optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl.

[0129] In another embodiment of Formula (I) or Formula (Ia), R1 is -(CO)-R 1a where R 1a is optionally substituted alkyl (e.g., methyl), optionally substituted alkoxy (e.g., tert-butoxy), optionally substituted aryl (e.g., phenyl), or optionally substituted heteroaryl (e.g., fluoropyrimidinyl).

[0130] In one embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 1a is a single bond or an optionally substituted alkylene.

[0131] Examples of optionally substituted alkylene groups include methylene, ethylene, propylene, butylene, pentylene, aminomethylene, aminoethylene, aminopropylene, aminobutylene, carboxymethylene, carboxyethylene, carboxypropylene, carboxybutylene, carbamoylmethylene, carbamoylethylene, carbamoylpropylene, carbamoylbutylene, methoxymethylene, methoxyethylene, methoxypropylene, methoxybutylene, methylthiomethylene, methylthioethylene, methylthiopropylene, methylthiobutylene, hydroxymethylene, hydroxyethylene, hydroxypropylene, hydroxybutylene, ethoxycarbonylmethylene, ethoxycarbonylethylene, benzyloxymethylene, benzyloxyethylene, benzyloxypropylene, benzyloxybutylene, guanidinomethylene, guanidinoethylene, guanidinopropylene, and the like.

[0132] In another embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 1a is a single bond or an optionally substituted alkylene (eg, methylene, ethylene, propylene).

[0133] In one embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 1b is a hydrogen atom, hydroxy, halogen, cyano, -Q 1c , -COQ 1c , -CONQ 1c Q 1d , CONQ 1c -OQ 1d , -NQ 1c Q 1d , or -OQ 1c is;

[0134] Q 1c is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

[0135] Q 1d is a hydrogen atom or an optionally substituted alkyl.

[0136] 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.

[0137] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0138] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, isopropylpiperidinyl, acetylpiperidinyl, tetrahydropyranylpiperidinyl, tetrahydropyranyl, cyclohexylpiperidinyl, and the like.

[0139] Examples of optionally substituted aryl groups and optionally substituted heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0140] In another embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 1b is -CONH2, -CONHCH3, -NHOCH3, methylamino, dimethylamino, piperazinylcarbonyl, thiazolylcarbamoyl, methyl(1-methylpiperidin-4-yl)amino, piperidinyl, or tetrahydropyranyl.

[0141] In one embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 2a is an optionally substituted cycloalkylene.

[0142] Examples of optionally substituted cycloalkylenes include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, adamantylene, and the like.

[0143] In another embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 2a is an optionally substituted cycloalkylene (eg, cyclohexylene).

[0144] In one embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 2b and Q 2c are the same or different and each is a hydrogen atom or an optionally substituted alkyl.

[0145] 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.

[0146] In another embodiment of formulas (II-7) and (II-8) of Q in formula (I), Q 2b and Q 2c are the same or different and each is a hydrogen atom or an optionally substituted alkyl (eg, methyl).

[0147] In one embodiment of Formula (Ia),

[0148] [ka]

[0149] represents any one of the following formulas (II-1-a) to (II-6-a):

[0150] [ka]

[0151] R 1b are a hydrogen atom or 1 to 3 of the same or different alkyl groups (wherein * indicates the binding site).

[0152] In another embodiment of the formulas (II-1) to (II-6) of Q in formula (I) or formula (Ia), R 1b is a hydrogen atom.

[0153] In one embodiment of Formula (I) or Formula (Ia), R2 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl.

[0154] 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.

[0155] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0156] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] In one embodiment of Formula (I) or Formula (Ia), R2 is —XN(R 2a )(R 2b ) where X is an alkylene group and R 2a and R 2b are the same or different and each is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl).

[0161] 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.

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

[0163] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0164] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, and the like.

[0165] Examples of optionally substituted aryl groups and optionally substituted heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] In another embodiment of Formula (I) or Formula (Ia), R2 is optionally substituted alkyl (eg, isobutyl, neopentyl) or optionally substituted arylalkyl.

[0170] In another embodiment of Formula (I) or Formula (Ia), R2 is -XN(R 2a )(R 2b ) where X is an alkylene group and R 2a and R 2b are the same or different and each is a hydrogen atom, an optionally substituted alkyl, an optionally substituted heterocycloalkyl, or an optionally substituted arylalkyl).

[0171] In one embodiment of Formula (I), V is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted partially saturated heteroaryl ring, or an optionally substituted heterocycloalkyl ring.

[0172] Examples of optionally substituted aryl rings include benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene, and the like.

[0173] Examples of optionally substituted heteroaryl rings include furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, triazole, tetrazole, benzofuran, benzothiophene, benzimidazole, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, benzothiadiazole, furopyridine, oxazolopyridine, thiazolopyridine, imidazopyridine, and quinazoline. , thienopyridine, indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrrolopyridazine, triazolopyridine, pteridine, purine, carbazole, acridine, permidine, 1,10-phenanthroline (phenenthroline), phenoxathiin, phenoxazine, phenothiazine, phenazine, and the like.

[0174] Examples of optionally substituted partially saturated heteroaryl rings include heteroaryl rings in which one or more double bonds are replaced with a single bond.

[0175] Examples of optionally substituted heterocycloalkyl rings include pyrrolidine, piperidine, morpholine, piperazine, 1,3-dioxane, 1,4-dioxane, and the like.

[0176] In another embodiment of Formula (I), V is an optionally substituted aryl ring (e.g., benzene, naphthalene), an optionally substituted heteroaryl ring (e.g., pyridine, benzothiazole, thiazole, quinoline, indazole, quinoxaline, thiadiazole, naphthyridine, thiazolopyridine, pyrazole, benzoxazole, pyrimidine, piperidine), an optionally substituted partially saturated heteroaryl ring (e.g., tetrahydrobenzothiazole, dihydropyrazolooxazine) or an optionally substituted heterocycloalkyl ring (e.g., pyrrolidine).

[0177] In one embodiment of Formula (Ia), Ar1 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring.

[0178] Examples of optionally substituted aryl rings include benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene, and the like.

[0179] Examples of optionally substituted heteroaryl rings include furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, triazole, tetrazole, benzofuran, benzothiophene, benzimidazole, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, benzothiadiazole, furopyridine, oxazolopyridine, thiazolopyridine, imidazopyridine, and quinazoline. , thienopyridine, indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrrolopyridazine, triazolopyridine, pteridine, purine, carbazole, acridine, permidine, 1,10-phenanthroline (phenenthroline), phenoxathiin, phenoxazine, phenothiazine, phenazine, and the like.

[0180] In another embodiment of Formula (Ia), Ar1 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring (eg, pyridine, benzothiazole, thiazole, quinoxaline).

[0181] In one embodiment of Formula (I) or Formula (Ia), R3 is a hydrogen atom, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0182] Examples of halogens include fluorine, chlorine, bromine and iodine.

[0183] 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.

[0184] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0185] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, and the like.

[0186] Examples of optionally substituted aryl groups and optionally substituted heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, cinnolinyl, naphthyridinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, furopyridinyl, thienopyridinyl, pyrropyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, and the like.

[0187] In one embodiment of Formula (I) or Formula (Ia), R3 is -C≡CR 3a (In the formula, R 3a is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), or -COOR 3b (In the formula, R 3b is a hydrogen atom or an optionally substituted alkyl).

[0188] 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.

[0189] Examples of optionally substituted cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0190] Examples of optionally substituted heterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolidinyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrazolyl, and the like.

[0191] Examples of optionally substituted heteroaryl groups include 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.

[0192] In another embodiment of Formula (I) or Formula (Ia), R3 is a hydrogen atom, hydroxy, halogen, cyano, oxo, alkylthio, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0193] In another embodiment of Formula (I) or Formula (Ia), R3 is -COOR 3b (In the formula, R 3b is a hydrogen atom or optionally substituted alkyl (e.g., ethyl).

[0194] In another embodiment of Formula (I), R3 is -C≡CR 3a (In the formula, R 3a is a hydrogen atom, optionally substituted alkyl (e.g., hydroxyethyl, hydroxybutyl, hydroxypropyl, hydroxypentyl, hydroxyethoxymethyl, dimethylamino, methylaminocarbonylethyl), optionally substituted cycloalkyl (e.g., aminocyclopropyl), optionally substituted heterocycloalkyl (e.g., tetrahydropyranyl), or optionally substituted heteroaryl.

[0195] In one embodiment of Formula (I),

[0196] [ka]

[0197] represents any one of the following formulas (III-1) to (III-4):

[0198] [ka]

[0199] R4 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; Ar2 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring.

[0200] In one embodiment of the present invention, when the compound of formula (I) is a compound of formula (Ia), In one embodiment of Formula (Ia),

[0201] [ka]

[0202] represents any one of the following formulas (III-1) to (III-3):

[0203] [ka]

[0204] R4 is a hydrogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl; Ar2 is an optionally substituted aryl ring or an optionally substituted heteroaryl ring (where * indicates the point of attachment).

[0205] 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.

[0206] Examples of optionally substituted alkenyl groups include ethenyl, allyl, 1-propenyl, 2-methylallyl, and the like.

[0207] Examples of optionally substituted alkynyl groups include ethynyl, 1-propynyl, and the like.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] Examples of optionally substituted heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl, and the like.

[0212] Examples of optionally substituted aryl rings include benzene, naphthalene, anthracene, phenanthrene, acenaphthylene, indene, and the like.

[0213] Examples of optionally substituted heteroaryl rings include furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, 1,3,4-thiadiazole, triazole, tetrazole, benzofuran, benzothiophene, benzimidazole, benzotriazine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine, benzothiadiazole, furopyridine, oxazolopyridine, thiazolopyridine, imidazopyridine, and quinazoline. , thienopyridine, indolizine, quinoline, isoquinoline, phthalazine, quinoxaline, cinnoline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, pyrazolopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrrolopyridazine, triazolopyridine, pteridine, purine, carbazole, acridine, permidine, 1,10-phenanthroline (phenenthroline), phenoxathiin, phenoxazine, phenothiazine, phenazine, and the like.

[0214] In another embodiment of Formula (I),

[0215] [ka]

[0216] represents any one of the following formulas (III-1) to (III-4):

[0217] [ka]

[0218] R4 is optionally substituted alkyl (e.g., isobutyl), optionally substituted cycloalkylalkyl (e.g., cyclopropylmethyl); Ar2 is an optionally substituted aryl ring (eg, benzene, fluorobenzene). In another embodiment of Formula (Ia),

[0219] [ka]

[0220] represents any one of the following formulas (III-1) to (III-3):

[0221] [ka]

[0222] R4 is optionally substituted alkyl (e.g., isobutyl); Ar2 is an optionally substituted aryl ring.

[0223] In one embodiment of Formula (I) or Formula (Ia), R5 is a hydrogen atom or an optionally substituted alkyl.

[0224] 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.

[0225] In another embodiment of Formula (I) or Formula (Ia), R5 is a hydrogen atom.

[0226] A preferred embodiment of formula (I) is the compound of formula (IV):

[0227] [ka]

[0228] (wherein each symbol is as defined above).

[0229] A preferred embodiment of formula (Ia) is the following formula (IV-a):

[0230] [ka]

[0231] (wherein each symbol is as defined above)

[0232] In a preferred embodiment of formula (I) or formula (IV), Q is represented by any one of the following formulas (VI-1) to (VI-3).

[0233] [ka]

[0234] (wherein the formula, each symbol is defined as above)

[0235] In a preferred embodiment of formula (I) or formula (IV), Q is represented by the following formula (II-7):

[0236] [ka]

[0237] Q 1a is alkylene and Q 1b Ha-CONH-Q 1c , -Q 1d , -CO-Q 1d , -N(Q 1c )-Q 1d (where Q 1c is a hydrogen atom or alkyl, and Q 1d is a hydrogen atom or heterocycloalkyl optionally substituted with alkyl).

[0238] In a preferred embodiment of formula (Ia) or formula (IV-a), R1 is a hydrogen atom, optionally substituted alkyl (e.g., methyl, isopropyl, hydroxybutyl, pyridylmethyl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or -(CO)-R 1a and; R 1a is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, or optionally substituted heteroaryl; R 1b is a hydrogen atom; R2 is optionally substituted alkyl (e.g., isobutyl, neopentyl) or optionally substituted arylalkyl; R 3a is a hydrogen atom, optionally substituted alkyl (e.g., hydroxybutyl, hydroxypropyl, hydroxypentyl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; R4 is optionally substituted alkyl (e.g., isobutyl, 2-ethylbutyl) or optionally substituted cycloalkyl (e.g., cyclohexyl), and Ar2 is an optionally substituted aryl ring.

[0239] In a preferred embodiment of formula (Ia) or formula (IV-a),

[0240] [ka]

[0241] represents any one of the following formulas (VI-1-a) to (VI-3-a).

[0242] [ka]

[0243] In a preferred embodiment of formula (Ia) or formula (IV-a), Ar1 is an optionally substituted pyridine ring, an optionally substituted thiazole ring, an optionally substituted benzothiazole ring, or an optionally substituted quinoxaline ring.

[0244] In a preferred embodiment of formula (Ia) or formula (IV-a),

[0245] [ka]

[0246] represents the following formula (VII-1-a), (VII-2-a) or (VII-3-a):

[0247] [ka]

[0248] In a preferred embodiment of formula (I), formula (Ia), formula (IV) or formula (IV-a),

[0249] [ka]

[0250] is represented by the following formula (V).

[0251] [ka]

[0252] R4' is optionally substituted alkyl or optionally substituted cycloalkyl. Preferred examples of the alkyl group of R4' include isobutyl and 2-ethylbutyl. Preferred examples of the cycloalkyl group of R4' include cyclohexyl.

[0253] In a preferred embodiment of Formula (I) or Formula (IV), or Formula (Ia) or Formula (IV-a), R2 is alkyl optionally substituted with alkylthio or alkylsulfonyl, or arylalkyl.

[0254] In another preferred embodiment of Formula (I) or Formula (IV), or Formula (Ia) or Formula (IV-a), R2 is isobutyl, neopentyl, sec-butyl, or benzyl.

[0255] In a preferred embodiment of formula (Ia) or formula (IV-a), R1 is alkyl (eg, methyl), or alkyl substituted with one or two hydroxy groups.

[0256] In a preferred embodiment of formula (Ia) or formula (IV-a), R3 is a hydrogen atom, hydroxy, or -C≡CR 3a where R 3a is alkyl substituted with hydroxy (e.g., hydroxybutyl, hydroxypropyl, hydroxypentyl).

[0257] Hereinafter, compounds having formula (I), including compounds having formula (IV), or compounds having formula (Ia), including compounds having formula (IV-a), will also be referred to as "compounds of the present invention."

[0258] 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: AcOEt (EtOAc): ethyl acetate AcOH: acetic acid AcONH4: Ammonium acetate t-BuOH: tert-butanol (Boc)2O: di-tert-butyl dicarbonate Cbz: benzyloxycarbonyl CIP: 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: dichloroethane DCM: dichloromethane DIAD: Diisopropyl azodicarboxylate DIC: N,N'-methanediylidenebis[1-methylethanamine] DIEA (DIPEA): N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EtOH: ethanol EtO: Ethoxy Fmoc: 9-fluorenylmethyloxycarbonyl HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HMPA: hexamethylphosphoric triamide LDA: lithium diisopropylamide MeCN: acetonitrile MeOH: Methanol Ms: methanesulfonyl n-BuLi: n-butyllithium NaBH(OAc)3: Sodium triacetoxyborohydride OAc(AcO): Acetoxy OEt (EtO): Ethoxy OMe(MeO): methoxy OTHP(THPO):(tetrahydro-2H-pyran-2-yl)oxy p-TsOH: p-toluenesulfonic acid Pd / C: Palladium on carbon PG: amino protecting group Ph: Phenyl PPh3: Triphenylphosphine rt: room temperature TBS: tert-butyldimethylsilyl tBu: tert-butyl TFA: Trifluoroacetic acid THF: tetrahydrofuran Trt: Trityl

[0259] Manufacturing method The synthesis method will be explained using one of the compounds of formula (I), formula (Ia), as an example, and other compounds can be synthesized in a similar manner.

[0260] [ka]

[0261] [Step 1] Synthesis of intermediate [A3] Compound [A1](R A1 , R1 and R5 are as defined above) and compound [A2] (PG is an amino-protecting group, and R2 is as defined above), followed by an appropriate deprotection reaction of PG to give intermediate [A3] (R A1(R is an alkyl group such as methyl or ethyl, and R, R, and R are as defined above) can be synthesized. In the amidation condensation reaction, commonly known reagents and reaction conditions can be used. The preferred condensation agents are HATU or DMT-MM, and the preferred solvents are DMF, MeOH, THF, etc. The reaction temperature is preferably between 0°C and 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). In the deprotection reaction, commonly known reactions can be used depending on the type of PG. In the formula, when PG is an Fmoc group, the deprotection reaction is preferably carried out using piperidine or DBU as a deprotecting agent in AcOEt, THF, or DCM as a solvent. Furthermore, when PG is a Cbz group, the deprotection reaction is preferably carried out using a palladium catalyst such as Pd(OH) or Pd / C in a H atmosphere in methanol, ethanol, or THF as a solvent. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0262] [Step 2] Synthesis of intermediate [A5] Intermediate [A5] (PG, W, R1, R2, and R5 are as defined above) can be synthesized by an amidation condensation reaction using intermediate [A3] and intermediate [A4] (PG and W are as defined above), followed by a ring-closure reaction in the presence of an acid. Generally known reagents and reaction conditions can be used in the amidation condensation reaction. DMT-MM or HATU is preferred as the condensing agent, and DMF, MeOH, THF, or the like is preferred as the solvent. The reaction temperature is preferably from 0°C to the boiling point of the solvent. Formic acid is preferred as the acid used in the ring-closure reaction, and formic acid can also be used as the solvent. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0263] [Step 3] Synthesis of intermediate [A6] Intermediate [A6] (W, R1, R2, and R5 are as defined above) can be synthesized by an appropriate deprotection reaction depending on the type of PG. When PG is a Cbz group, the deprotection reaction is preferably carried out using a palladium catalyst such as Pd(OH)2 or Pd / C in a solvent of methanol, ethanol, or THF under an H2 atmosphere. When PG is an Fmoc group, the deprotection reaction is preferably carried out using piperidine or DBU as a deprotecting agent in a solvent of AcOEt, THF, or dichloromethane. Either group can be deprotected by a hydrolysis reaction depending on the type of W. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0264] [Step 4] Synthesis of intermediate [A8] Intermediate [A6] and compound [A7] (R A7 is as defined above), to give intermediate [A8] (R A7 (W is an alkyl group such as methyl or ethyl, and W, R1, R2, and R5 are as defined above) can be synthesized. In the amidation condensation reaction, commonly known reagents and reaction conditions can be applied. HATU and CIP are preferred as condensation agents, and DMF, DCM, DCE, THF, etc. are preferred as solvents. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0265] [Step 5] Synthesis of compound (Ia) Compound (Ia) (the formula is the same as above) can be synthesized by the Wadsworth-Emmons (HWE) reaction using intermediate [A8] and compound [A9] in the presence of a basic reagent, with or without a lithium salt such as lithium bromide or lithium chloride. Commonly known bases and reaction conditions can be used in this reaction. Preferred bases include triethylamine, Hunig's base, DBU, potassium carbonate, sodium methoxide, sodium hydride, and LDA. Preferred solvents are THF, chloroform, DCM, DCE, 1,2-dimethoxyethane, methanol, ethanol, and DMSO. The reaction temperature is preferably between -78°C and the boiling point of the solvent.

[0266] [ka]

[0267] [Step 6] Synthesis of compound (Ia) Compound (I) can be synthesized by an amidation condensation reaction of intermediate [A6] and intermediate [A10] (R3 and Ar1 are as defined above). Generally known amidation reagents and conditions can be used in the amidation condensation reaction. HATU and CIP are preferred as condensation agents, and DMF, THF, DCM, DCE, etc. are preferred as solvents. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0268] When R1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or optionally substituted cycloalkylalkyl, the intermediate [A5] can be synthesized according to the following scheme.

[0269] [ka]

[0270] [Step 7] Synthesis of intermediate [B3] Compound [B1](R B1 and R5 are as defined above) and compound [B2] (PG is an amino-protecting group and R2 are as defined above), followed by an appropriate deprotection reaction of PG depending on the type of PG to give intermediate [B3] (R B1 is an alkyl group such as methyl or ethyl, and R2 and R5 are as defined above. In the amidation condensation reaction and deprotection reaction, the same reagents and reaction conditions as in Step 1 can be applied.

[0271] [Step 8] Synthesis of intermediate [B5] Intermediate [B5] (PG, W, R1, R2, and R5 are as defined above) can be synthesized by amidation condensation using intermediate [B3] and intermediate [B4] (PG and W are as defined above), followed by a ring-closure reaction in the presence of an acid. The Boc group is deprotected during the ring-closure reaction. The same reagents and reaction conditions as in Step 2 can be used in the amidation condensation reaction and ring-closure reaction.

[0272] [Step 9] Synthesis of intermediate [A5] In the presence of a base, intermediate [B5] and compound [B6] (R B6 Intermediate [A5] can be synthesized by alkylation using (R is a leaving group, and R is an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl). Preferred bases include triethylamine, Hunig's base, pyridine, DBU, sodium carbonate, potassium carbonate, sodium methoxide, and potassium tert-butoxide. Preferred solvents are THF, MeCN, chloroform, DCM, DCE, DMF, and DMSO. The reaction temperature is preferably between 0°C and the boiling point of the solvent.

[0273] Instead of intermediate [A5], intermediates [B8] and [B10] can also be synthesized according to the following scheme.

[0274] [ka]

[0275] [Step 10] Synthesis of intermediate [B8] Intermediate [B5] and compound [B7] (R B7 and R B7’ is as defined above), to give intermediate [B8] (R B7 and R B7’are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, or optionally substituted cycloalkylalkyl; and W, PG, R2, and R5 are as defined above. Generally known reducing agents and conditions can be used in the reductive amination reaction. Preferred reducing agents include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium tetrahydroborate, lithium tetrahydroborate, THF-borane complex, pyridine-borane complex, and picoline-borane complex. Preferred solvents include MeOH, THF, chloroform, DCM, and DCE. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0276] [Step 11] Synthesis of intermediate [B10] Compound [B5] and compound [B9] (R 1a are as defined above), to give intermediate [B10] (W, PG, R 1a , R2 and R5 are as defined above) can be synthesized. In the amidation condensation reaction, commonly known amination reagents and conditions can be used. Preferred condensation agents are HATU, WSC hydrogen chloride, T3P, and DMT-MM, preferred solvents are DMF, MeOH, THF, etc., and the reaction temperature is preferably from 0°C to the boiling point of the solvent. Compound (I) can be synthesized from intermediates [B8] and [B10] in the same manner as in steps 3, 4, 5 and 6.

[0277] Intermediates [A1] and [B1] can be synthesized according to the following scheme: C1’ corresponds to the intermediate [A1] of R1, and R C1’ corresponds to the Boc-group intermediate [B1].

[0278] [ka]

[0279] [Step 12-1] Synthesis of intermediate [C1] Intermediate [C2](R C1 and R5 are as defined above) and compound [C3] (R C1’ is as defined above) to give intermediate [C1] (R C1 is an alkyl group such as methyl or ethyl, R C1’ is R1 or a Boc group, and R5 is as defined above. In the reductive amination reaction, commonly known reducing agents and conditions can be used, such as those in Step 10.

[0280] [Step 12-2] Synthesis of intermediate [C1] Intermediate [C1] can also be converted to intermediate [C4] (R C1 and R5 are as defined above) and compound [C3]. In the reductive amination reaction, commonly known reducing agents and conditions can be used, such as those in Step 9.

[0281] [Step 12-3] Synthesis of intermediate [C1] Intermediate [C1] can also be converted to intermediate [C5] (R C1 and R5 are as defined above) and compound [C6] (R C1’ is as defined above). In the reductive amination reaction, commonly known reducing agents and conditions can be used, such as those in Step 10.

[0282] [Step 12-4] Synthesis of intermediate [C1] Intermediate [C5] and compound [C7] (R C7 is a leaving group, R C1’ The intermediate [C1] can be synthesized by alkylation using the same as above. In the reductive amination reaction, commonly known reducing agents and conditions as in Step 9 can be used.

[0283] Intermediate [A4] can be synthesized as intermediate [D6] according to the following scheme.

[0284] [ka]

[0285] [Step 13] Synthesis of intermediate [D2] Intermediate [D2] (R4 is as defined above) can be synthesized from compound [D1] (R4 is as defined above) by an esterification reaction. In this reaction, commonly known condensing agents and conditions can be used. DIC is preferred as the condensing agent, tert-butanol is preferred as the solvent, and the reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0286] [Step 14] Synthesis of intermediate [D3] Intermediate [D3] (R4 is as defined above) can be synthesized from intermediate [D2] by Mitsunobu reaction using N-hydroxyphthalimide, triphenylphosphine, and DIAD. In the Mitsunobu amination reaction, commonly known reagents and conditions other than triphenylphosphine and DIAD can be used. The reaction temperature is preferably between 0°C and the boiling point of the solvent.

[0287] [Step 15] Synthesis of intermediate [D4] Using hydrazine, intermediate [D4] (R4 is as defined above) can be synthesized. Generally known conditions can be applied, and the reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0288] [Step 16] Synthesis of intermediate [D5] Depending on the type of PG, intermediate [D5] (PG and R4 are as defined above) can be synthesized using commonly known reagents and conditions. Preferred amino-protecting groups for PG are Cbz and Fmoc groups. Other protecting groups that cannot be deprotected under acidic conditions can also be used. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0289] [Step 17] Synthesis of intermediate [D6] Under acidic conditions, intermediate [D6] (PG and R4 are as defined above) can be synthesized. Commonly known acidic reagents and conditions can be used for the deprotection condensation reaction. Formic acid is preferred as the condensation agent, and is also preferred as the solvent. The reaction temperature is preferably from 0°C to the boiling point of the solvent.

[0290] The protecting groups in each step are not limited to protecting groups. When R1, R2, R3, Ar1, or R5 has a protected functional group, deprotection can be performed in 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 steps 2 and 8, the ring-closing reaction and deprotection reaction may proceed simultaneously.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.).

[0296] 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.

[0297] In another embodiment, there is a method of treating cancer by administering a compound of the present invention. The compound of the present invention has the effect of inhibiting the growth of cancer cells and can be used to treat cancer.

[0298] 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.

[0299] The compounds of the present invention can be used to inhibit cancer cells and are therefore useful in regulating cell proliferation. The compounds of the present invention can also be advantageously used to induce apoptosis in cells.

[0300] In another aspect, the present invention provides pharmaceutical compositions containing the compounds of the present invention, which can be used in various methods of the present invention (e.g., treating cancer), as described in more detail below.

[0301] The pharmaceutical compositions of the present invention can be formulated to suit the intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral (particularly intravenous), intradermal, or subcutaneous administration may contain the following components: a sterile diluent (e.g., water for injection, saline, fixed oil, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents), an antibacterial agent (e.g., benzyl alcohol or methylparaben), an antioxidant (e.g., ascorbic acid or sodium bisulfite), a chelating agent (e.g., ethylenediaminetetraacetic acid), a buffer (e.g., acetate, citrate, or phosphate), and an isotonic agent (e.g., sodium chloride or dextrose). Furthermore, the pH can be adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide). Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0302] 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 ELTM (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 (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like). In many cases, it will be preferable to include isotonic agents (for example, 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.

[0303] Sterile injectable solutions can be prepared by incorporating the active compound, for example, the compound of the present invention, in the required amount in a suitable solvent with the above-mentioned components alone or in combination, as needed, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing the necessary 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.

[0304] 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.

[0305] 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 (e.g., microcrystalline cellulose, tragacanth, or gelatin), excipients (e.g., starch, lactose), disintegrants (e.g., alginic acid, Primogel, or corn starch), lubricants (e.g., magnesium stearate or sterotates), glidants (e.g., colloidal silicon dioxide), sweeteners (e.g., sucrose, saccharin), or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring).

[0306] 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.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] For ease of administration and uniformity of dosage, it may be more advantageous to formulate oral or parenteral compositions in dosage unit form. As used herein, dosage unit form refers to a physically discrete unit suitable for a single dose for a subject to be treated, each unit containing 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.

[0311] For example, in certain embodiments, a suitable pharmaceutical composition of the present invention is one 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, a pharmaceutical composition of the present invention is one 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.

[0312] Preferably, the compounds of the present invention can be administered to mammals, including humans, parenterally, particularly preferably by continuous infusion or rapid intravenous administration.

[0313] 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.

[0314] Pharmaceutical compositions containing the compounds of the present invention can be used to treat diseases, particularly cancer.

[0315] In one embodiment, the present invention provides a method for inhibiting tumor growth. Such a method comprises administering to a subject (e.g., a mammalian subject) having a tumor a compound of the present invention in an amount effective to inhibit tumor growth. The compound or composition inhibits tumor growth if tumor size is statistically significantly smaller in subjects treated with the compound or composition than in those not treated.

[0316] The inhibitory effect of certain compounds or compositions of the present invention on tumor growth may be characterized by inhibition of binding between eIF4E (eukaryotic translation initiation factor 4E) and eIF4G (eukaryotic translation initiation factor 4G) by m7GTP pull-down assay and proximity ligation assay. Blocking the binding of eIF4E to eIF4G inhibits transcription. The binding of certain compounds to eIF4E has also been observed by NMR measurements.

[0317] The inhibitory effect of a particular compound or composition of the present invention on tumor growth may be characterized by any suitable method known in the art. For example, the effect of the compound or composition on survivin expression may be measured. Compounds or compositions that regulate survivin expression are likely to exhibit an inhibitory effect on tumor growth. Furthermore, as described in detail in the Examples, assays using tumor cell lines (e.g., soft agar assays using SW480 cells) and animal models of tumor growth (e.g., nude mice implanted with tumor cells and Min mouse models) may also be used to evaluate the inhibitory effect of a given compound or composition on tumor growth.Other exemplary animal models or xenografts for tumor growth include breast cancer (Guo et al., Cancer Res. 62:4678-84, 2002; Lu et al., Breast Cancer Res. Treat. 57:183-92, 1999), pancreatic cancer (Bouvet et al., Cancer Res. 62:1534-40, 2002), ovarian tumors (Nilsson et al., Cancer Chemother. Pharmacol. 49:93-100, 2002; Bao et al., Gynecol. Oncol. 78:373-9, 2000), melanoma (Demidem et al., Cancer Res. 61:2294-300, 2001), and colorectal cancer (Brown et al., Dig. Dis. Sci. 45:1578-84, 2000; Tsunoda et al. al., Anticancer Res. 19:1149-52, 1999; Cao et al., CHn. Cancer Res. 5:267-74, 1999; Shawler et al., J. Immunother. Emphasis Tumor Immunol. 17:201-8, 1995; McGregor et al., Dis. Colon. Rectum. 36:834-9, 1993; Verstijnen et al., Anticancer Res. 8:1193-200, 1988), hepatocellular carcinoma (Labonte et al., Hepatol. Res. 18:72-85, 2000), and gastric cancer (Takahashi et al., Int. J. Cancer 85:243-7, 2000).

[0318] The compound or composition that inhibits tumor growth can be administered to a tumor-bearing subject via an appropriate route, for example, depending on the tissue in which the tumor remains.Appropriate dosage can be determined using the knowledge and techniques known in the art, as described above.The therapeutic effect of the compound or composition on tumor growth can also be monitored using methods known in the art.Various methods include, for example, colonoscopy, sigmoidoscopy, biopsy, computed tomography, ultrasound, magnetic resonance imaging, and positron emission tomography, and can be used to monitor the progression and / or growth of colorectal cancer.The method for monitoring the progression and / or growth of ovarian cancer includes, for example, ultrasound, computed tomography, magnetic resonance imaging, chest X-ray, laparoscopy, and tissue sampling.

[0319] In a related aspect, the present invention provides methods for treating or preventing cancer. Such methods include administering to a subject in need thereof a compound or composition of the present invention in an amount effective to treat or prevent cancer in the subject. Treating cancer is understood to include reducing or eliminating cancer progression (e.g., cancer growth and metastasis). Preventing cancer is understood to include preventing or delaying the onset of cancer. Various types of cancer can be treated or prevented by the present invention, including, but not limited to, lung cancer, breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, liver cancer, uterine cancer, ovarian cancer, glioma, melanoma, lymphoma, and leukemia. The subject in need of treatment may be a human or non-human primate or other animal suffering from various types of cancer.

[0320] The subject in need of prevention may be a human or non-human primate or other animal at risk of developing cancer. Methods for diagnosing cancer and screening individuals at high risk of cancer are known in the art and can be used in the present invention. For example, colorectal cancer can be diagnosed by fecal occult blood testing, sigmoidoscopy, colonoscopy, air enema, and virtual colonoscopy. Individuals at high risk of colorectal cancer may have one or more risk factors for colorectal cancer, such as a strong family history of colorectal cancer or polyps, a known family history of hereditary colorectal cancer syndromes, a personal history of adenomatous polyps, and a personal history of chronic inflammatory bowel disease.

[0321] The compounds of the present invention useful for treating or preventing cancer can be identified by suitable methods known in the art. As described above, methods that can be used to select compounds for their inhibitory effect on tumor (or cancer cell) growth (or proliferation) can also be used. The route of administration, the dosage of a given compound, and the effect of treatment can be determined using knowledge and techniques known in the art. Factors that can be taken into account in such a determination include, for example, the type and stage of the cancer to be treated.

[0322] The compounds of the present invention that are useful in the treatment and prevention of cancer can be administered in combination with other anti-tumor agents.Anti-tumor agents refer to compounds that inhibit tumor growth.

[0323] Specific examples of other antineoplastic agents include alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs). cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethrin, thamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 11 and calicheamicin omega 11 (see, e.g., Agnew Chem Intl. Ed. Engl. 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates such as clodronate, esperamicin; and neocarzinostatin chromophores and related chromoproteins, enediyne antibiotic chromophores), aclacinomycins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorbicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as florinic acid acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; epothilone; etogluside cid); gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizophyllan; spirogermanium;tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridine A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE™ Cremophor-free albumin-modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois, and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantron e); teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0324] Other examples of anti-neoplastic agents include antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), which act to regulate or inhibit hormone action in tumors (e.g., tamoxifen (including NOLVADEX (RTM) tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON toremifene); and agents that inhibit the enzyme aromatase, which controls the production of estrogen in the adrenal glands. aromatase inhibitors (e.g., 4(5)-imidazole, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestane, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (1,3-dioxolane nucleoside cytosine analogs; antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways associated with abnormal cell proliferation (e.g., PKC-alpha, Ralf, and H-Ras); ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME® and HER2 expression inhibitors); vaccines such as gene therapy vaccines (e.g., ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine); PROLEUKIN® rIL-2; LURTOTECAN® topoisomerase 1 inhibitors; ABARELIX® rmRH; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0325] Further examples of other antineoplastic agents include "growth inhibitory agents," which refer to compounds or compositions that inhibit cell proliferation in vitro and / or in vivo. Thus, growth inhibitory agents can significantly reduce the proportion of cells in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (at a point other than S phase), such as agents that induce G1 or M-phase arrest. Classical M-phase blockers include vincas (vincristine and vinblastine), Taxol®, and topo II inhibitors, such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Agents that arrest G1 also affect S-phase arrest, such as DNA alkylating agents, such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.

[0326] Further examples of other anti-neoplastic agents include "molecularly targeted drugs" that block the growth and metastasis of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancerous cells), tumor growth, or tumor spread. Specific examples of "molecularly targeted drugs" include kinase inhibitors that inhibit tumor kinase activity, such as imatinib, erlotinib, gefitinib, sunitinib, sorafenib, dasatinib, and nilotinib; antibodies that bind to cell surface molecules or growth factors on tumor cells, such as ibritumomab, cetuximab, trastuzumab, panitumumab, bevacizumab, and rituximab; and proteasome inhibitors that inhibit proteasomes, such as bortezomib, which regulate protein expression and function by degrading ubiquitinated proteins; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0327] Further information can be found in Chapter 1, especially page 13, of The Molecular Basis of Cancer, edited by Mendelsohn, Israel, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs," by Murakami et al. (WB Saunders: Philadelphia, 1995).

[0328] A compound of the present invention administered in combination with an anti-neoplastic agent does not necessarily require that the compound and the anti-neoplastic agent be administered at the same time, and the compound and the agent may be administered separately, so long as they both have an effect on the same cancer cells at a given time.

[0329] For example, the administration mode can be exemplified by: (1) administration of a single preparation obtained by simultaneously compounding the compound of the present invention and the other antineoplastic agent; (2) simultaneous administration of two preparations obtained by separately compounding the compound of the present invention and the other antineoplastic agent via the same administration route; (3) administration of two preparations obtained by separately compounding the compound of the present invention and the other antineoplastic agent via the same administration route at intervals; (4) simultaneous administration of two preparations obtained by separately compounding the compound of the present invention and the other antineoplastic agent via different administration routes; (5) administration of two preparations obtained by separately compounding the compound of the present invention and the other antineoplastic agent via different administration routes at intervals (e.g., administration of the compound of the present invention followed by the other antineoplastic agent, or administration in the reverse order). The amount of the other antineoplastic agent to be administered can be appropriately selected based on the dosage used in clinical practice. The mixing ratio of the compound of the present invention and the other antineoplastic agent can be appropriately selected depending on the subject, administration route, disease to be treated, symptoms, combination, etc.

[0330] In a further related aspect, the present invention provides methods for promoting apoptosis in cancer cells. Such methods comprise contacting cancer cells with a compound of the present invention in an amount effective to promote apoptosis in those cells. A compound promotes apoptosis if the number of cancer cells undergoing apoptosis is statistically significantly greater in the presence of the compound than in the absence of the compound. Such compounds can be identified by methods known in the art (e.g., measuring caspase activity and / or cell death) using cultured cancer cell lines, xenografts, or animal cancer models. Preferably, the compound is more active in promoting apoptosis in cancer cells than in normal cells. Cancer cells of various tissue origins are treatable by the present invention.

[0331] The following non-limiting examples illustrate the compounds, compositions, and methods of use of the present invention.

[0332] 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 this example, a Bruker AVANCE III 300 was used. 1 H NMR was measured using a Topspin (Bruker, trade name) for analysis. Mass spectrometry was performed using methods A, B, C or D below: (Method A) System: Shimadzu UFLC / MS system (Shimazu-2020 mass spectrometer) Column: ODS column for chromatography Eluent: A (0.04% TFA in water) and B (0.04% TFA in acetonitrile) (Method B) System: Shimadzu UFLC / MS system (Shimazu-2020 mass spectrometer) Column: ODS column for chromatography Eluents: A (5 mM AcONH4 in water) and B (5 mM AcONH4 in acetonitrile) (Method C) System: Water2795 system Column: Develosil C30-UG-5, 50x4.6mm, Nomura Chemical Co., Ltd. Eluent: A (0.1% HCOOH in water) and B (0.1% HCOOH in acetonitrile) Flow rate: 1.0mL / min (Method D) System: Shimadzu Column: SunFire C18 50x4.6mm 5um Eluents: A (water containing 0.1% trifluoroacetic acid and 10% acetonitrile) and B (acetonitrile containing 0.1% trifluoroacetic acid and 10% water) Flow rate: 2.0mL / min

[0333] A Biotage Initiator was used for microwave organic synthesis.

[0334] Column chromatography was performed using a SHOKO Scientific Purif-espoir 2 and Biotage Isolera One flash purification system with a gradient of n-hexane-AcOEt and / or AcOEt-MeOH as eluents. Depending on the sample amount and purity, one or several of the following prepacked cartridge columns were used for purification: SiO2: CHROMATOREX Q-PACK SI30 (SIZE 10, SIZE 20, SIZE 60, and SIZE 200), Biotage SNAP KP-Sil (10g, 25g, and 50g), Biotage Rening Cartridges (5g, 10g, 30g, 45g, and 80g) NHSiO2: CHROMATOREX Q-PACK NH60 (SIZE 10, SIZE 20, SIZE 60, and SIZE 200), CHROMATOREX Q-PACK DNH600 (SIZE 20, SIZE 60, and SIZE 200)

[0335] Preparative HPLC (prep-HPLC) was performed using a Waters FractionLynx system.

[0336] Typical prep-HPLC conditions (AcOH): Column: C30-UG 25mmID*150mmL, 5um 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.

[0337] Typical prep-HPLC conditions (TFA): Column: L-Column2 ODS 20mmID*150mmL, 5um Mobile phase A: water containing 0.10%v / v TFA Mobile phase B: 0.10% v / v TFA in 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.

[0338] Intermediate B1 listed in Table 1 is a known compound or was synthesized by known methods or the following methods. List of intermediate B1

[0339] [Table 1]

[0340] Preparation Example 1: Synthesis of Intermediate B1-3

[0341] [ka]

[0342] To a solution of tert-butyl (S)-3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (26 g) in MeCN (0.25 L) was added 2,2-diethoxyethan-1-amine (66 g). After stirring at 60 °C for 3 days, the reaction mixture was cooled to room temperature and the precipitated solid was filtered. The filtrate was concentrated in vacuo and purified by column chromatography (SiO, n-hexane:AcOEt = 75:25 to 0:100 and AcOEt:MeOH = 100:0 to 80:20, gradient) to give B1-3 (18 g) as a pale yellow syrup. LCMS (Method A): m / z=303.1[M+H] + .

[0343] Preparation Example 2: Synthesis of Intermediate B1-11

[0344] [ka]

[0345] To a solution of 1-methylpiperidin-4-one (10 g) and 2,2-diethoxyethan-1-amine (12 g) in THF (100 mL) was added 5% Wt palladium-carbon (1.0 g, 5% Wt). The mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to give B1-11 (19 g) as a gray oil. LCMS (Method A): m / z=231.4[M+H] + .

[0346] Intermediate B2 listed in Table 2 is either a known compound or was synthesized by known methods. List of intermediate B2

[0347] [Table 2]

[0348] Intermediate B4 listed in Table 3 is a known compound or was synthesized by known methods or the following methods.

[0349] [Table 3]

[0350] Preparation Example 3: Synthesis of Intermediate B4-6

[0351] [ka]

[0352] 3-1) Synthesis of intermediate B4-6-Int2 To a stirred solution of (S)-3-cyclopropyl-2-hydroxypropanoic acid (B4-6-Int1, CAS No. 300853-97-8, 1.6 g) in dichloromethane (15 mL) was added tert-butyl (Z)-N,N'-diisopropylcarbamimidate (7.4 g) at room temperature. After stirring at room temperature for 2 h, the urea solid was filtered off through a Celite pad. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 70:30, gradient) to give B4-6-Int2 (1.4 g) as a colorless oil. B4-6-Int2 1 The H NMR (300 MHz, CDCl) data is shown in Figure 5.

[0353] 3-2) Synthesis of intermediate B4-6-Int3 To a stirred mixture of B4-6-Int2 (1.4 g), 2-hydroxyisoindoline-1,3-dione (1.4 g), and triphenylphosphane (3.9 g) in dichloromethane (20 mL) was added DIAD (4.5 g) at -20 °C. After stirring at the same temperature for 1 h, the reaction mixture was gradually warmed to room temperature for 1 h. The resulting mixture was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give B4-6-Int3 (2.3 g) as a pale yellow syrup. LCMS (Method A): m / z=332.1[M+H] + .

[0354] 3-3) Synthesis of intermediate B4-6-Int4 To a stirred solution of B4-6-Int3 (2.3 g) in EtOH (5 mL) was added hydrazine monohydrate (0.27 g) at room temperature. After stirring at room temperature for 2 hours, the white precipitate was filtered off through a Celite pad. The filtrate was concentrated under reduced pressure and dissolved in THF (20 mL). Sodium bicarbonate (1.0 g), Cbz-Cl (1.2 g), and water (20 mL) were added. The reaction mixture was stirred at room temperature for 16 hours. After stirring, the mixture was added to 20 mL of brine and 30 mL of AcOEt. The organic layer was separated, washed with 20 mL of brine, dried over Na2SO4, and concentrated in vacuo. The crude mixture was purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 70:30, gradient) to give B4-6-Int4 (1.9 g) as a colorless amorphous solid. LCMS (Method B): m / z=358.1[M+Na] + .

[0355] 3-4) Synthesis of intermediate B4-6 A solution of tert-butyl B4-6-Int4 (1.9 g) in formic acid (39 g) was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, n-hexane:AcOEt = 100:0 to 0:100, gradient) to give B4-6 (1.4 g) as a colorless oil. LCMS (Method B): m / z=302.0[M+Na] + .

[0356] Preparation Example 4: Synthesis of Intermediate B4-8

[0357] [ka]

[0358] 4-1) Synthesis of intermediate B4-8-Int2 To a stirred solution of ethyl 1,3-dithiane-2-carboxylate (1.7 g) and HMPA (1.6 g) in THF (15 mL) was added n-butyllithium (2.6 mol / L) in hexane (3.3 mL) under a nitrogen atmosphere at -70 °C. After stirring for 5 min, a solution of B4-8-Int1 (CAS no. 215385-97-0, 2.1 g) in THF (3 mL) was added. The reaction mixture was gradually warmed to room temperature over 2 h. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution and extracted twice with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give B4-8-Int2 (2.3 g) as a colorless oil. LCMS (Method A): m / z=351.1[M+H] + .

[0359] 4-2) Synthesis of intermediate B4-8-Int3 To a stirred mixture of ethyl B4-8-Int2 (2.3 g) in acetone (97 mL) and water (3 mL) was added sodium bicarbonate (1.7 g) and NBS (7.0 g). After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo. The resulting residue was diluted with AcOEt (20 mL) and washed with water (20 mL) followed by brine. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give B4-8-Int3 (1.3 g) as a colorless oil. LCMS (Method A): m / z=261.1[M+H] + .

[0360] 4-3) Synthesis of intermediate B4-8-Int4 To a mixture of B4-8-Int4 (1.3 g) and formic acid (0.7 mL) was added triethylamine (1.8 mL) and chloro[(1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenyl-1,2-ethanediamine](p-cymene)ruthenium(II) (32 mg). The mixture was stirred for 14 h at room temperature. The reaction mixture was diluted with AcOEt and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give ethyl B4-8-Int4 (1.1 g) as a colorless oil. LCMS (Method A): m / z=263.2[M+H] + .

[0361] 4-4) Synthesis of intermediate B4-8-Int5 To a mixture of B4-8-Int4 (1.0 g), 2-hydroxyisoindoline-1,3-dione (0.75 g), and triphenylphosphine (2.0 g) in CHCl (20 mL) was added DIAD (2.3 g) at −20 °C. After stirring at the same temperature for 1 h, the reaction mixture was gradually warmed to room temperature over 1 h. The resulting mixture was concentrated in vacuo and purified by column chromatography (SiO, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give ethyl B4-8-Int5 (1.5 g) as a pale yellow syrup. LCMS (Method A): m / z=408.2[M+H] + .

[0362] 4-5) Synthesis of B4-8-Int6 To a stirred solution of B4-8-Int5 (1.5 g) in EtOH (5 mL) was added hydrazine monohydrate (0.19 g) at room temperature. After stirring at room temperature for 2 h, the white precipitate was filtered off through a Celite pad. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO, n-hexane:AcOEt = 100:0 to 70:30, gradient) to give B4-8-Int6 (1.1 g) as a colorless oil. LCMS (Method A): m / z=278.2[M+H] + .

[0363] 4-6) Synthesis of intermediate B4-8-Int7 To a stirred solution of B4-8-Int6 (1.0 g) in THF (20 mL) was added sodium bicarbonate (1.1 g), Cbz-Cl (0.77 g), and water (20 mL). The reaction mixture was stirred at room temperature for 16 h. After stirring, the mixture was added to 20 mL of brine and 30 mL of AcOEt. The organic layer was separated, washed with 20 mL of brine, dried over Na2SO4, and concentrated in vacuo. The crude mixture was purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 70:30, gradient) to give B4-8-Int7 (1.5 g) as a colorless oil. LCMS (Method A): m / z=412.2[M+H] + .

[0364] 4-7) Synthesis of intermediate B4-8 To a stirred solution of B4-8-Int7 (1.5 g) in MeOH (10 mL) and water (0.5 mL) was added lithium hydroxide hydrate (0.93 g). After stirring at room temperature for 3 h, the reaction mixture was concentrated in vacuo. To the resulting residue were added water (30 mL), NaCl (4.0 g), and potassium hydrogen sulfate (3.5 g). The solution was extracted with AcOEt (30 mL × 2) and washed with water (20 mL) and then brine. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (SiO2, n-hexane:AcOEt = 80:20 to 0:100, gradient) to give B4-8 (0.54 g) as a colorless oil. LCMS (Method A): m / z=384.2[M+H] + ,406.1[M+Na] + .

[0365] Preparation Example 5: Synthesis of Intermediate B4-12

[0366] [ka]

[0367] 5-1) Synthesis of intermediate B4-12-Int2 B4-12-Int1 (CAS No. 107492-32-0, 33 g), PPh3 (38 g), and 2-hydroxyisoindoline-1,3-dione (27 g) were dissolved in DCM (400 mL), and DIAD (29.5 g, 145 mmol) was added at -20 to -40 °C. The mixture was stirred at room temperature for 16 h. The resulting solid was filtered. The organic layer was washed with brine (100 mL x 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified on a silica column (petroleum ether:ethyl acetate = 1:1) to give B4-12-Int2 (45 g) as a yellow oil. LCMS (Method D): m / z=441.1[M+H] + .

[0368] 5-2) Synthesis of intermediate B4-12-Int3 To a solution of B4-12-Int2 (45 g) in EtOH (400 mL) at room temperature was added hydrazine monohydrate (10 g). The reaction was stirred at room temperature for 16 hours. The mixture was filtered and washed with ethyl acetate. The filtrate was concentrated. The residue was purified on a silica column (petroleum ether:ethyl acetate=1:1) to give B4-12-Int3 (23 g) as a yellow oil. LCMS (Method D): m / z=311.2[M+H] + .

[0369] 5-3) Synthesis of intermediate B4-12 B4-12-Int3 (10 g) was dissolved in water (150 mL) and 1,4-dioxane (150 mL). NaOH (2.5 g) was dissolved in water (50 mL) and then slowly added to the stirred solution over 2 h. The pH was adjusted to approximately 10.5 by adding 2 mol / L aqueous Na2CO3. Benzyl chloroformate (7.0 g) was added simultaneously, while maintaining the pH at approximately 10-11 by adding 2 mol / L aqueous Na2CO3. After the addition was complete, the reaction mixture was stirred at 20 °C for 1 h. AcOEt (150 mL) was then added, and the pH of the resulting mixture was adjusted to 2-3 with concentrated hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with AcOEt (200 mL × 3). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The mixture was filtered and concentrated under reduced pressure. The residue was purified on a silica column (petroleum ether:ethyl acetate=1:1) to give B4-12 (10 g) as a white solid. LCMS (Method D): m / z=431.1[M+H] + .

[0370] Intermediate B5 listed in Table 4 was synthesized by the following method or a known method using intermediates B1, B2 and B4 as synthetic materials.

[0371] List of intermediate B5 and its synthetic materials B1, B2 and B4.

[0372] [Table 4-1]

[0373] [Table 4-2]

[0374] [Table 4-3]

[0375] [Table 4-4]

[0376] [Table 4-5]

[0377] Preparation Example 6: Synthesis of Intermediate B5-4

[0378] [ka]

[0379] 6-1) Synthesis of intermediate B5-4-Int1 A mixed suspension of B1-3 (14 g), B2-2 (18 g), HATU (22 g), and DIEA (11 mL) in THF (0.20 L) was stirred at room temperature for 2 h. After the addition of B2-2 (1.5 g), HATU (1.7 g), and DIEA (1 mL), the reaction mixture was stirred for an additional 1 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted twice with AcOEt. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 95:5 to 50:50, gradient). The resulting material was further purified by column chromatography (NHSiO2, n-hexane:AcOEt = 50:50) to give B5-4-Int1 (21 g) as a colorless gum. LCMS (Method A): m / z=674.4[M+Na] + .

[0380] 6-2) Synthesis of intermediate B5-4-Int2 To a solution of B5-4-Int1 (20 g) in MeOH (0.25 L) was added piperidine (25 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated to approximately half its volume, and the resulting precipitate was filtered off. The filtrate was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 50:50 to 0:100 and AcOEt:MeOH = 100:0 to 80:20, gradient) to give B5-4-Int2 (8.2 g) as a slightly yellow oil. LCMS (Method A): m / z=430.3[M+H] + ,384.3[M-EtOH+H] + .

[0381] 6-3) Synthesis of intermediate B5-4-Int3 A mixture of B5-4-Int2 (9.5 g), B4-1 (7.4 g), and DMT-MM (7.3 g) in MeOH (0.10 L) was stirred at room temperature for 1 h. After adding DMT-MM (1.5 g), the reaction mixture was stirred for another 1 h. After concentrating to approximately one-third of its volume, the mixture was poured into saturated sodium bicarbonate and extracted twice with AcOEt. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 94:6 to 50:50, gradient) to give B5-4-Int3 (15 g) as a colorless syrup. LCMS (Method A): m / z=715.5[M+Na] + ,647.4[M-EtOH+H] +

[0382] 6-4) Synthesis of intermediate B5-4 A solution of B5-4-Int3 (15 g) in formic acid (0.10 L) was stirred at 60 °C for 22 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was dissolved in AcOEt and washed with a mixture of aqueous sodium bicarbonate and aqueous sodium carbonate. The organic layer was concentrated in vacuo and purified by column chromatography (NHSiO, n-hexane:AcOEt = 50:50 to 0:100 and AcOEt:MeOH = 100:0 to 40:60, gradient) to give B5-4 (8.8 g) as a pale yellow amorphous solid. LCMS (Method A): m / z=501.3[M+H] + .

[0383] Intermediate A6 listed in Table 5 was synthesized by the following method or a known method using intermediate B5 as a synthetic material.

[0384] List of intermediate A6 and its synthetic material B5.

[0385] [Table 5]

[0386] Preparation Example 7: Synthesis of Intermediate A6-1

[0387] [ka]

[0388] 7-1) Synthesis of intermediate A6-1-Int1 To a solution of B5-1 (0.33 g) in DCE (10 mL) was added benzoic anhydride (0.23 g) and aqueous sodium bicarbonate (10 mL). After stirring at room temperature overnight, 25% aqueous ammonia was added. The mixture was extracted with chloroform. The organic layer was dried over Na2SO4 and concentrated in vacuo to give A6-1-Int1 (0.31 g) as a white solid, which was used in the next reaction without any purification. LCMS (Method C): m / z=605.1[M+H] + .

[0389] 7-2) Synthesis of intermediate A6-1 A mixture of A6-1-Int1 (0.27 g) and 10% Pd / C (0.10 g) in THF (15 mL) was stirred at room temperature for 2 h under an H atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to give A6-1 (0.26 g) as a gray amorphous solid, which was used in the next reaction without any purification. LCMS (Method C): m / z=471.1[M+H] + .

[0390] Preparation Example 8: Synthesis of Intermediate A6-2

[0391] [ka]

[0392] 8-1) Synthesis of intermediate A6-2-Int1 To a solution of B5-1 (2.9 g) in DCE (30 mL) was added 37% formaldehyde solution (1.4 g) and acetic acid (0.14 g). After stirring for a while, sodium triacetoxyborohydride (1.9 g) was slowly added to the mixture. After stirring for another hour, 1N NaOH solution (40 mL) and chloroform (50 mL) were added. The organic layer was separated, washed with 40 mL of water, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, AcOEt:MeOH = 80:20 to 50:50, gradient) to give A6-2-Int1 (1.1 g) as a colorless oil. LCMS (Method A): m / z=515.5[M+H] + .

[0393] 8-2) Synthesis of intermediate A6-2 To a solution of A6-2-Int1 (1.1 g) in THF (20 mL) was added 10% Pd / C (0.22 g) and stirred at room temperature for 3.5 h under an H atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to give crude A6-2 (0.70 g) as a dark brown solid. LCMS (Method A): m / z=381.4[M+H] + .

[0394] Intermediate A8 listed in Table 6 was synthesized by the following method or a known method using intermediate B5 as a synthetic material.

[0395] List of intermediate A8 and its synthetic materials B5.

[0396] [Table 6-1]

[0397] [Table 6-2]

[0398] [Table 6-3]

[0399] [Table 6-4]

[0400] [Table 6-5]

[0401] [Table 6-6]

[0402] Preparation Example 9: Synthesis of Intermediate A8-2

[0403] [ka]

[0404] 9-1) Synthesis of intermediate A8-2-Int1 To a stirred solution of B5-2 (0.56 g) in DCE (15 mL) was added sodium triacetoxyborohydride (0.35 g), acetone (0.25 g), and AcOH (65 mg) at room temperature. After stirring at 60 °C for 1 h, the mixture was added to 20 mL of saturated aqueous sodium bicarbonate solution and 30 mL of DCM. The organic layer was separated, washed with 30 mL of brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, AcOEt:MeOH = 100:0 to 80:20, gradient) to give A8-2-Int1 (0.35 g) as a colorless solid. LCMS (Method A): m / z=557.4[M+H] + .

[0405] 9-2) Synthesis of intermediate A8-2-Int2 To a stirred solution of A8-2-Int1 (1.7 g) in THF (15 mL) was added 10% palladium-carbon (0.85 g). The resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (balloon pressure). After completion of the reaction, the palladium-carbon was filtered off through a Celite pad. The filtrate was concentrated under reduced pressure to give A8-2-Int2 (1.3 g) as a white solid, which was used in the next reaction without any purification. LCMS (Method A): m / z=423.3[M+H] + .

[0406] 9-3) Synthesis of intermediate A8-2 To a stirred solution of A8-2-Int2 (1.3 g) in DCE (15 mL) was added 2-(diethoxyphosphoryl)acetic acid (0.89 g), DIEA (1.3 mL), and HATU (1.8 g). The reaction mixture was stirred at room temperature for 16 h. After stirring, 30 mL of saturated aqueous sodium bicarbonate solution and 30 mL of DCM were added to the mixture. The organic layer was separated, washed with 30 mL of brine, dried over Na2SO4, and concentrated in vacuo. The crude mixture was purified by column chromatography (NHSiO2, AcOEt:MeOH = 100:0 to 40:60, gradient) to give A8-2 (1.5 g) as a colorless amorphous solid. LCMS (Method B): m / z=601.5[M+H] + .

[0407] A8-1, A8-20, and A8-34 can be synthesized in the same manner as in Production Example 9.

[0408] Preparation Example 10: Synthesis of Intermediate A8-5

[0409] [ka]

[0410] 10-1) Synthesis of intermediate A8-5-Int1 A mixed suspension of B5-4 (7.4 g), 2-(4-bromobutoxy)tetrahydro-2H-pyran (3.9 g), sodium carbonate (4.7 g), and sodium iodide (2.2 g) in DMSO (0.10 L) was stirred at 70 °C for 1 h. After adding 2-(4-bromobutoxy)tetrahydro-2H-pyran (0.36 g), the reaction mixture was stirred for an additional 30 min. After cooling to room temperature, the mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with AcOEt. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, AcOEt:MeOH = 100:0 to 70:30, gradient) and then further purified by column chromatography (SiO2, AcOEt:MeOH = 100:0 to 85:15, gradient) to give A8-5-Int1 (6.2 g) as a pale yellow syrup. LCMS (Method A): m / z=657.5[M+H] + .

[0411] 10-2) Synthesis of intermediate A8-5-Int2 To a solution of A8-5-Int1 (1.6 g) in THF (20 mL) was added 10% palladium-carbon (0.50 g). The resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (balloon pressure). After completion of the reaction, the palladium-carbon was filtered off through a Celite pad. The filtrate was concentrated in vacuo to give A8-5-Int2 (1.3 g) as a colorless syrup, which was used in the next reaction without any purification. LCMS (Method A): m / z=523.4[M+H] + .

[0412] 10-3) Synthesis of intermediate A8-5 To a solution of A8-5-Int2 (1.3 g) in DCE (20 mL) was added 2-(diethoxyphosphoryl)acetic acid (0.63 g), HATU (1.5 g), and DIEA (0.86 mL). After stirring at room temperature for 4 h, the mixture was concentrated in vacuo and purified by column chromatography (NHSiO, n-hexane:AcOEt = 75:25 to 0:100, gradient). The resulting material was dissolved in chloroform and washed with aqueous sodium carbonate. The organic layer was concentrated in vacuo to give A8-5 (1.5 g) as a pale yellow syrup. LCMS (Method A): m / z=701.5[M+H] + .

[0413] A8-3, A8-4, A8-6, A8-19, A8-22, A8-23, A8-27, and A8-33 can be synthesized in the same manner as in Production Example 10.

[0414] Preparation Example 11: Synthesis of Intermediate A8-28

[0415] [ka]

[0416] 11-1) Synthesis of intermediate A8-28-Int1 To a solution of B5-23 (0.50 g) in DCE (50 mL) was added benzaldehyde (0.10 g) and acetic acid (17 mg). After stirring for a while, sodium triacetoxyborohydride (0.24 g) was slowly added to the mixture. After stirring for an additional 40 min, 1 mol / L NaOH solution (20 mL) and chloroform (30 mL) were added. The organic layer was separated, washed with 20 mL of water, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, AcOEt:MeOH = 100:0 to 20:80, gradient) to give A8-28-Int1 (0.28 g) as a white amorphous solid. LCMS (Method B): m / z=620.4[M+H] + .

[0417] 11-2) Synthesis of intermediate A8-28-Int2 To a solution of A8-28-Int1 (0.14 g) in 5 mL of THF was added sodium carbonate (47 mg) and di-tert-butyl dicarbonate (53 mg) in water (5 mL). After stirring overnight, the reaction mixture was diluted with 50 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate solution. The extracted organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The resulting crude product was purified by column chromatography (SiO2, AcOEt:MeOH = 80:20 to 20:80, gradient) to give A8-28-Int2 (77 mg) as a colorless oil. LCMS (Method A): m / z=720.5[M+H] + .

[0418] 11-3) Synthesis of intermediate A8-28 A8-28 was synthesized from A8-28-Int2 in the same manner as in reaction procedures 10-2) and 10-3). LCMS (Method A): m / z=678.4[M+H] + .

[0419] Preparation Example 12: Synthesis of Intermediate A8-29

[0420] [ka]

[0421] 12-1) Synthesis of intermediate A8-29-Int1 0.31 g of A8-29-Int1 (colorless oil) was synthesized from 0.54 g of B5-24 in the same manner as in reaction procedure 10-1). LCMS (Method A): m / z=721.4[M+H] + .

[0422] 12-2) Synthesis of A8-29-Int2 From 0.31 g of A8-29-Int1, 0.33 g of crude A8-29-Int2 (colorless oil) was synthesized in the same manner as in Reaction Procedure 10-1). LCMS (Method A): m / z=735.5[M+H] + .

[0423] 12-3) Synthesis of intermediate A8-29 Crude A8-28 (brown oil) was synthesized from A8-28-Int2 in the same manner as in reaction procedures 10-2) and 10-3). LCMS (Method A): m / z=779.5[M+H] + .

[0424] Preparation Example 13: Synthesis of Intermediate A8-30

[0425] [ka]

[0426] 13-1) Synthesis of intermediate A8-30-Int1 To a solution of B5-25 (52 mg) in CHCl (2 mL) was added methylamine (2 mol / L in THF, 95 μL), DIEA (65 μL), and HATU (72 mg) at room temperature. After stirring at room temperature for 1 h, the mixture was diluted with CHCl (30 mL) and then washed with 1 mol / L aqueous HCl (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL). The organic layer was dried over NaSO, concentrated in vacuo, and purified by column chromatography (SiO, CHCl:MeOH = 100:0 to 90:10, gradient) to give A8-30-Int1 (48 mg) as a white amorphous solid. LCMS (Method C): m / z=503.0[M+H] + .

[0427] 13-2) Synthesis of intermediate A8-30-Int2a and Int2b To a solution of A8-30-Int1 (0.96 g) in THF (20 mL) cooled in an ice / water bath was added BH 3·THF (0.9 M 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 (NHSiO, n-hexane:AcOEt = 80:20 to 0:100, gradient) to give A8-30-Int2a (0.17 g) and A8-30-Int2b (0.27 g) as colorless oils. LCMS (A8-30-Int2a, Method C): m / z=489.1[M+H] + LCMS (A8-30-Int2b, Method C): m / z=475.2[M+H] +

[0428] 13-3) Synthesis of intermediate A8-30-Int3 To a solution of A8-30-Int2b (0.27 g) in DCE (6 mL) was added triethylamine (0.16 mL) and (Boc)2O (0.25 g). After stirring at room temperature for 1 h, the mixture was concentrated in vacuo and purified by column chromatography (NHSiO2, n-hexane:AcOEt = 100:0 to 50:50, gradient) to give A8-30-Int3 (0.30 g) as a colorless oil. LCMS (Method C): m / z=575.2[M+H] + .

[0429] 13-4) Synthesis of intermediate A8-30 A8-30 (brown oil) was synthesized from A8-30-Int3 in the same manner as in reaction procedures 9-2) and 9-3). LCMS (Method C): m / z=619.2[M+H] + .

[0430] Preparation Example 14: Synthesis of Intermediate A8-32

[0431] [ka]

[0432] 14-1) Synthesis of intermediate A8-32-Int1 A mixture of B5-27 (0.34 g), triethylamine (0.34 mL), and di-tert-butyl dicarbonate (0.26 g) in THF (5 mL) was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, n-hexane:AcOEt = 100:0 to 0:100, gradient) to give A8-32-Int1 (0.38 g) as a yellow oil. LCMS (Method A): m / z=569.4[M-Boc+H] + .

[0433] 14-2) Synthesis of intermediate A8-32 A8-32 was synthesized from A8-32-Int1 in the same manner as in reaction procedures 10-2) and 10-3). LCMS (Method A): m / z=613.4[M-Boc+H] + . A8-16 can be synthesized by the same method as in Production Example 14.

[0434] Intermediate A9 listed in Table 7 is a known compound or was synthesized by known methods or the following methods.

[0435] List of intermediate A9

[0436] [Table 7-1]

[0437] [Table 7-2]

[0438] [Table 7-3]

[0439] Preparation Example 15: Synthesis of Intermediate A9-4

[0440] [ka]

[0441] 15-1) Synthesis of intermediate A9-4-Int1 To a suspension of benzo[d]thiazol-5-ol (0.50 g) in DCM (20 mL) and THF (5 mL) was added 3,4-dihydro-2H-pyran (0.80 mL) and p-TsOH monohydrate (30 mg). After stirring at room temperature for 5 h, the mixture was poured into saturated aqueous sodium bicarbonate and extracted twice with chloroform. The organic layer was concentrated in vacuo and purified by column chromatography (SiO, n-hexane:AcOEt = 75:25 to 30:70, gradient) to give A9-4-Int1 (0.73 g) as a colorless syrup. LCMS (Method B): m / z=236.1[M+H] + .

[0442] 15-2) Synthesis of intermediate A9-4 To a solution of A9-4-Int1 (0.73 g) in THF (15 mL) was added n-BuLi (2.8 mol / L) in hexane (1.2 mL) at -70 °C under a nitrogen atmosphere. After stirring for 30 min, a solution of DMF (0.27 g) in THF (1 mL) was added. After stirring at the same temperature for another 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride, warmed to room temperature, and extracted twice with AcOEt. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 94:6 to 50:50, gradient) to give A9-4 (0.64 g) as a yellow solid. A9-4 1 The H NMR (300 MHz, CDCl3) data is shown in Figure 1.

[0443] Preparation Example 16: Synthesis of Intermediate A9-5

[0444] [ka]

[0445] To a stirred solution of 4-bromothiazole-2-carbaldehyde (96 mg) in MeCN (4 mL) was added hex-5-yn-1-ol (98 mg), copper(I) iodide (9.5 mg), triethylamine (0.51 g), and tetrakis(triphenylphosphine)palladium(0) (58 mg). After stirring at 60 °C for 2 h under microwave irradiation, the reaction mixture was cooled to room temperature. The precipitated solid was removed by filtration, and the resulting filtrate was concentrated in vacuo and purified by column chromatography (SiO, n-hexane:AcOEt = 100:0 to 50:50, gradient) to give A9-5 (46 mg) as a pale yellow syrup. LCMS (Method A): m / z=210.0[M+H] + . A9-6, A9-7, A9-36, A9-37, A9-39, A9-40, and A9-41 can be synthesized in the same manner as in Production Example 16.

[0446] Preparation Example 17: Synthesis of Intermediate A9-32

[0447] [ka]

[0448] 17-1) Synthesis of intermediate A9-32 A mixture of (3-hydroxyphenyl)boronic acid (0.13 g), 5-bromopicolinaldehyde (0.15 g), potassium carbonate (0.33 g), and tetrakis(triphenylphosphine)palladium(0) (0.19 g) in toluene (3 mL) and water (1.5 mL) was stirred at 140 °C for 20 min under microwave irradiation. The toluene layer of the mixture was purified by column chromatography (SiO, n-hexane:AcOEt = 100:0 to 0:100, gradient) to give A9-32 (35 mg) as a white powder. LCMS (Method B): m / z=200.1[M+H] + .

[0449] Preparation Example 18: Synthesis of Intermediate A9-35

[0450] [ka]

[0451] 18-1) Synthesis of intermediate A9-35-Int1 To a solution of benzo[d]thiazo-4-ol (0.20 g) in THF (3 mL) cooled in an ice / water bath, imidazole (0.14 g) and TBS-Cl (0.24 g) were added. The cooling bath was removed immediately after the addition of the reagents. After stirring at room temperature for 2 h, saturated aqueous ammonium chloride (5 mL) and water (2.5 mL) were added. The mixture was extracted with AcOEt (10 mL, twice). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give A9-35-Int1 (0.33 g) as a pale yellow syrup. LCMS (Method A): m / z=266.1[M+H] + .

[0452] 18-2) Synthesis of intermediate A9-35 To a solution of A9-35-Int1 (60 mg) in dry THF (0.50 mL) cooled by a CO2 / acetone bath, n-BuLi (2.6 M in n-hexane, 130 μL) was added. After stirring for 30 min, dry DMF (35 μL) in dry THF (0.50 mL) was added dropwise. After stirring for 2 h, saturated aqueous ammonium chloride (2 mL) and water (1 mL) were added. The mixture was extracted twice with AcOEt (8 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 90:10, gradient) to give a mixture of A9-35-Int1 and A9-35 (ca. 2:1, 34 mg) as a yellow syrup, which was used in the next step without further purification. LCMS (Method A): m / z=294.1[M+H] + .

[0453] Preparation Example 19: Synthesis of Intermediate A9-42

[0454] [ka]

[0455] 19-1) Synthesis of intermediate A9-42-Int1 To a stirred mixture of 4-bromo-2-(diethoxymethyl)thiazole (2.7 g) in MeCN (15 mL) was added tert-butyldimethyl(pent-4-yn-1-yloxy)silane (2.4 g), copper(I) iodide (0.19 g), triethylamine (10 g), and Pd(Ph3)4 (1.2 g). After stirring at 60 °C for 2 h under microwave irradiation, the reaction mixture was cooled to room temperature. The precipitated solid was removed by filtration, and the resulting filtrate was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give A9-42-Int1 (2.4 g) as a pale yellow syrup. LCMS (Method A): m / z=384.2[M+H] +

[0456] 19-2) Synthesis of intermediate A9-42-Int2 To a solution of A9-42-Int1 (0.59 g) in THF (10 mL) was added LDA (1.08 mol / L) in hexane (3.7 mL) at -70 °C under a nitrogen atmosphere. After stirring for 10 min, a solution of iodine (1.2 g) in THF (3 mL) was added. After stirring at the same temperature for an additional 5 min, the reaction mixture was gradually warmed to room temperature for 1 h. The reaction mixture was quenched with 10% aqueous sodium thiosulfate solution (20 mL) and extracted twice with AcOEt. The organic layer was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give A9-42-Int2 (0.59 g) as a brown oil. LCMS (Method A): m / z=510.1[M+H] +

[0457] 19-3) Synthesis of intermediate A9-42-Int3 To a stirred mixture of A9-42-Int2 (0.59 g) in MeCN (20 mL) was added ethynyltrimethylsilane (0.23 g), copper(I) iodide (22 mg), triethylamine (1.2 g), and Pd(Ph3)4 (0.13 g). After stirring at 60 °C for 2 h under microwave irradiation, the reaction mixture was cooled to room temperature. The precipitated solid was removed by filtration, and the resulting filtrate was concentrated in vacuo and purified by column chromatography (SiO2, n-hexane:AcOEt = 100:0 to 80:20, gradient) to give 4 A9-42-Int3 (0.49 g) as a pale yellow syrup. LCMS (Method A): m / z=480.2[M+H] +

[0458] 19-4) Synthesis of intermediate A9-42-Int4 To a stirred mixture of A9-42-Int3 (0.24 g) in acetone (9 mL) and water (1 mL) was added p-TsOH monohydrate (0.29 g). After stirring at 80 °C for 3 hours under microwave irradiation, the reaction mixture was cooled to room temperature. The solution was concentrated in vacuo, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted twice with chloroform. The organic layer was concentrated in vacuo to give A9-42-Int4 (0.15 g) as a brown syrup, which was used in the next step without further purification. LCMS (Method A): m / z=292.2[M+H] +

[0459] 19-5) Synthesis of intermediate A9-42 To a stirred mixture of A9-42-Int4 (0.11 g) in THF (10 mL) was added triethylamine trihydrofluoride (0.18 g). After stirring at 60 °C for 1.5 h under microwave irradiation, the reaction mixture was cooled to room temperature. The solution was concentrated in vacuo, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted twice with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give A9-42 (71 mg) as a brown syrup, which was used in the next step without further purification. LCMS (Method B): m / z=220.0[M+H] +

[0460] Preparation Example 20: Synthesis of intermediate A9-43

[0461] [ka]

[0462] 20-1) Synthesis of intermediate A9-43-Int1 A suspension of benzothiazol-5-ol hydrochloride (0.40 g), 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.95 g), and potassium carbonate (0.88 g) in DMF (5 mL) was stirred at room temperature for 2 hours and at 60 °C for 3 hours. After cooling to room temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with AcOEt. The organic layer was washed with brine, concentrated in vacuo, and purified by column chromatography (SiO, n-hexane:AcOEt = 94:6 to 30:70, gradient) to give A9-43-Int1 (0.34 g) as a colorless syrup. LCMS (Method A): m / z=210.1[M-THP+H] + .

[0463] 20-2) Synthesis of intermediate A9-43 In the same manner as in reaction procedure 15-2), 0.25 g of A8-32 (yellow syrup) was synthesized from 0.34 g of A8-43-Int1. A9-43 1 The H NMR (300 MHz, CDCl3) data is shown in Figure 6.

[0464] Intermediate A10 listed in Table 8 is either a known compound or was synthesized by known methods.

[0465] List of intermediate A10

[0466] [Table 8]

[0467] The compounds listed in Table 9 were synthesized using intermediates A8 and A9 shown in Table 9 according to the following method or known methods.

[0468] [Table 9-1]

[0469] [Table 9-2]

[0470] [Table 9-3]

[0471] Example 1: Synthesis of ID-1

[0472] [ka]

[0473] To a mixture of A8-1 (1.6 g), A9-1 (1.2 g), and lithium bromide (0.75 g) in THF (50 mL) was slowly added triethylamine (1.2 g). After stirring at room temperature for 2 h, the mixture was added to 10 mL of water and 0.15 L of ethyl acetate. The organic layer was separated, washed with 30 mL of brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (NHSiO2, n-hexane:AcOEt = 80:20 to 20:80, gradient) to give ID-1 (1.3 g) as a white solid. ID-1 1 The 1 H NMR (300 MHz, CDCl3) data is shown in Figure 2.

[0474] Example 2: Synthesis of ID-6

[0475] [ka]

[0476] Ex2-1) Synthesis of ID-6-Int1 To a mixture of A8-5 (0.50 g), A9-2 (0.14 g), and lithium bromide (0.12 g) in THF (7.0 mL) was added triethylamine (0.14 g). The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with AcOEt and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (NHSiO2, n-hexane:AcOEt = 50:50 to 0:100, gradient) to give ID-6-Int1 (0.28 g) as a yellow amorphous solid. LCMS (Method A): m / z=710.4[M+H] + .

[0477] Ex2-2) Synthesis of ID-6 A mixture of ID-6-Int1 (0.28 g) and p-TsOH monohydrate (0.15 g) in MeOH (7 mL) was stirred at room temperature for 45 min. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with AcOEt and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by prep-HPLC (conditions (AcOH): B = 30-80%). The collected fractions were concentrated in vacuo to give ID-6 (0.19 g) as a pale yellow amorphous powder. ID-6 1 The 1 H NMR (300 MHz, CDCl3) data is shown in Figure 3.

[0478] Example 3: Synthesis of ID-11

[0479] [ka]

[0480] Ex3-1) Synthesis of ID-11-Int1 To A8-5 (73 mg), A9-5 (40 mg), and lithium bromide (18 mg) in THF (2 mL) was added triethylamine (21 mg). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with AcOEt and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (NHSiO2, n-hexane:AcOEt = 50:50 to 0:100, gradient) to give ID-11-Int1 (55 mg) as a yellow amorphous solid. LCMS (Method A): m / z=756.4[M+H] + .

[0481] Ex3-2) Synthesis of ID-11 A mixture of ID-11-Int1 (55 mg) and p-TsOH monohydrate (28 mg) in MeOH (2 mL) was stirred at room temperature for 45 min. The reaction mixture was concentrated in vacuo, diluted with AcOEt, and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC (Condition (AcOH): B = 30-80%). The collected fractions were combined and concentrated in vacuo. The aqueous solution was lyophilized to give ID-11 (30 mg) as a white powder. ID-11 1 The H NMR (300 MHz, CDCl3) data is shown in Figure 4.

[0482] Example 4: Synthesis of ID-42

[0483] [ka]

[0484] Ex4-1) Synthesis of ID-42-Int1 To a solution of A8-7 (80 mg), LiBr (13 mg), and A9-45 (56 μL) in THF (1.5 mL) was added EtN (42 μL). After stirring for 18 h, brine (1.5 mL) and water (3 mL) were added. The mixture was extracted three times with AcOEt (5 mL). The combined organic layer was washed with brine (3 mL), dried over NaSO, concentrated in vacuo, and purified by column chromatography (SiO, AcOEt:MeOH = 100:0 to 90:10, gradient) to give ID-42-Int1 (38 mg) as a pale yellow syrup. LCMS (Method A): m / z=478.4[M-Boc+H] + .

[0485] Ex4-2) Synthesis of ID-42-Int2 To a flask containing ID-42-Int1 (38 mg), formic acid (2.0 mL) was added and the mixture was allowed to stand. After 3 h, the mixture was concentrated in vacuo to give ID-42-Int2 as a pale yellow syrup, which was used in the next step without further purification. LCMS (Method A): m / z=478.4[M+H] + .

[0486] Ex4-3) Synthesis of ID-42 To a solution of ID-42-Int2 (15 mg), AcOH (20 μL), and aqueous HCHO (37%, 7.4 μL) in DCE (2.0 mL) was added NaBH(OAc) (11 mg). After stirring for 2 h, 1 mol / L aqueous sodium hydroxide (1.0 mL) was added. The mixture was extracted three times with CHCl (2 mL). The combined organic layers were washed with brine (1 mL), 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 ID-42 (5.0 mg) as a white solid. LCMS (Method A): m / z=492.4[M+H] + .

[0487] Compound ID-43 was synthesized by the same synthetic method as ID-42.

[0488] The compounds listed in Table 10 were synthesized using intermediates A6 and A10 shown in Table 10 according to the following method or known methods.

[0489] [Table 10]

[0490] Example 5: Synthesis of ID-38

[0491] [ka]

[0492] Ex5-1) Synthesis of ID-38 To a solution of A6-2 (12 mg), A10-2 (6.8 mg), and pyridine (12 μL) in DCE (1.0 mL) was added CIP (26 mg). After stirring for 2 days, saturated aqueous sodium bicarbonate (3 mL) was added. The mixture was extracted three times with CHCl (10 mL). The combined organic layer was washed with brine (2 mL), dried over NaSO, concentrated in vacuo, and purified by preparative HPLC (column: C30-UG-5, 0.1% MeCN / AcOH solution = 20 / 80-70 / 30) to give ID-38 (9.8 mg) as a white solid. LCMS (Method A): m / z=511.4[M+H] + . Compound ID-16 was synthesized according to the following method.

[0493] Example 6: Synthesis of ID-16

[0494] [ka]

[0495] Synthesis of Ex6-1)ID-16-Int1 A mixture of B5-1 (0.34 g), TEA (0.18 mL), and (Boc)2O (0.28 g) in DCE (10 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, n-hexane:AcOEt = 90:10 to 40:60, gradient) to give ID-16-Int1 (0.29 g) as a colorless oil.

[0496] Synthesis of Ex6-2) ID-16-Int2 A mixture of ID-16-Int1 (0.29 g) and 10% Pd / C (0.10 g) in THF (10 mL) was stirred at room temperature for 1 h under an H atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to give ID-16-Int2 (0.22 g) as a white solid. LCMS (Method C): m / z=467.1[M+H] + .

[0497] Synthesis of Ex6-3) ID-16-Int3 A mixture of ID-16-Int2 (0.10 g), (2E)-3-(2-pyridinyl)-2-propenoic acid (75 mg), DIEA (0.24 mL), and HATU (0.27 g) in DCE (6.0 mL) was stirred at room temperature for 41 hours. The mixture was added to DIEA (0.24 mL) and HATU (0.27 g). After stirring for 24 hours, the mixture was added to DIEA (0.12 mL) and HATU (0.13 g). After stirring for 3 days, the mixture was added to 25% aqueous ammonia (0.20 mL) and water (10 mL). The mixture was extracted with CHCl3 (30 mL). The organic layer was washed with aqueous sodium bicarbonate (10 mL) and then with brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (column: C30-UG-5, MeCN-HO with 0.1% AcOH = 50-100%). The collected fractions were combined and concentrated in vacuo. The aqueous solution was lyophilized to give ID-16-Int3 (82 mg).

[0498] Ex6-4) Synthesis of ID-16 A mixture of ID-16-Int3 (25 mg) and formic acid (2.0 mL) was allowed to stand at room temperature for 3 hours. The mixture was azeotroped with CHCl three times. The residue was purified by preparative HPLC (column: C30-UG-5, MeCN-H0 containing 0.1% AcOH = 20-70%). The collected fractions were combined and concentrated in vacuo. The aqueous solution was lyophilized to give ID-16 (15 mg) as a white solid. LCMS (Method C): m / z=498.1[M+H] + . Compound ID-18 was synthesized according to the following method.

[0499] Example 7: Synthesis of ID-18

[0500] [ka]

[0501] Synthesis of Ex7-1)ID-18-Int1 To a solution of B5-25 (16 g) in tert-butanol (160 mL) was added 1,4-dioxane (24 mL), TEA (48 mL), and a catalytic amount of 4-pyrrolidinopyridine (PPY), and the reaction was stirred and cooled to -20 °C. 48 mL of molten (Boc)2O was then added to the mixture. After 10 min, the mixture was warmed to room temperature and stirred overnight. The organic layer was washed with 2 mol / L aqueous HCl and brine. The organic layer was dried over Na2SO4, then filtered, concentrated in vacuo, and further purified by silica gel chromatography to give ID-18-Int1 (15 g) as a colorless oil.

[0502] Ex7-2) Synthesis of ID-18-Int2 To a stirred solution of ID-18-Int1 (13 g) in MeOH (300 mL) was added 20% Pd / C (2.5 g) under an H atmosphere at room temperature. The mixture was stirred overnight at room temperature, filtered, and washed with methanol. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography to give ID-18-Int2 (8.5 g) as a white solid. LCMS (Method A): m / z=356.3[M-tBu+H] + .

[0503] Synthesis of Ex7-3) ID-18-Int3 To a solution of ID-18-Int2 (0.25 g), diethylphosphonoacetate, methyl acetate (0.16 mL), and DIEA (0.63 mL) in DCE (10 mL) was added HATU (0.69 g). After stirring for 1 h, aqueous ammonia (25%, 1.0 mL) and water (20 mL) were added. The mixture was diluted with CHCl3 (30 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (SiO2, AcOEt:MeOH = 100:0 to 90:10, gradient) to give ID-18-Int3 (357 mg) as a colorless syrup. LCMS (Method C): m / z=590.1[M+H] + .

[0504] Synthesis of Ex7-4) ID-18-Int4 To a solution of ID-18-Int3 (96 mg), LiBr (14 mg), and 2-pyridinecarboxaldehyde (17 μL) in THF (3 mL) was added triethylamine (27 μL). After stirring for 1 h, water (10 mL) was added. The mixture was extracted three times with AcOEt (10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over NaSO, concentrated in vacuo, and purified by column chromatography (SiO, n-hexane:AcOEt = 90:10 to 40:60, gradient) to give ID-18-Int4 (60 mg) as a pale yellow syrup.

[0505] Synthesis of Ex7-5)ID-18-Int5 To a flask containing ID-18-Int4 (60 mg), formic acid (3 mL) was added and the mixture was allowed to stand. After 6 h, the mixture was concentrated in vacuo to give ID-18-Int5 as a pale yellow syrup, which was used in the next reaction without any purification. LCMS (Method C): m / z=487.0[M+H] + .

[0506] Ex7-6) Synthesis of ID-18 To a solution of ID-18-Int5 (35 mg), methylamine (2 mol / L in THF, 64 μL), and DIEA (44 μL) in CHCl (2 mL) was added HATU (48 mg). After stirring for 1 h, the mixture was diluted with CHCl (30 mL), washed with 1 mol / L aqueous HCl (10 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10 mL), dried over NaSO, concentrated in vacuo, and purified by preparative HPLC (column: C30-UG-5, MeCN / 0.1% AcOH solution = 30 / 70-80 / 20) to give ID-18 (21.0 mg) as a white solid. LCMS (Method C): m / z=500.1[M+H] + .

[0507] Compounds ID-21, 27, and 28 were synthesized using the amine reagents listed in Table 11 in reaction step Ex7-6).

[0508] [Table 11]

[0509] Compound ID-35 was synthesized according to the following method.

[0510] Example 8: Synthesis of ID-35

[0511] [ka]

[0512] Ex8-1) Synthesis of ID-35 To a solution of ID-19 (27 mg), 1-methyl-4-piperidone (26 μL), and AcOH (9.4 μL) in DCE (2 mL) was added NaBH(OAc) (47 mg). After stirring for 2 h, saturated aqueous sodium bicarbonate (3 mL) was added. The mixture was extracted twice with CHCl (3 mL). The combined organic layers were washed with brine (3 mL), dried over NaSO, concentrated in vacuo, and purified by preparative HPLC (column: C30-UG-5, MeCN / 0.1% AcOH solution = 0 / 100-50 / 50) to give ID-35 (17 mg) as a white solid. LCMS (Method C): m / z=569.1[M+H] + .

[0513] Compound ID-69 was synthesized according to the following method.

[0514] Example 9: Synthesis of ID-69

[0515] [ka]

[0516] Ex9-1) Synthesis of ID-69 To a solution of ID-68 (59 mg) in DMF (4 mL) was added formaldehyde (37%) (34 μL) and sodium triacetoxyborohydride (61 mg). After stirring at room temperature for 1 h, 1 mol / L aqueous sodium hydroxide (10 mL) and brine (5 mL) were added, and the mixture was extracted with AcOEt (30 mL). The organic layer was washed twice with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC (column: C30-UG-5, MeCN-H2O containing 0.1% AcOH = 20-70%). The collected fractions were combined and concentrated in vacuo. The aqueous solution was lyophilized to give ID-69 (32 mg) as a white powder. LCMS (Method A): m / z=540.4[M+H] + .

[0517] Compound ID-36 was synthesized according to the following method.

[0518] Example 10: Synthesis of ID-36

[0519] [ka]

[0520] Ex10-1) Synthesis of ID-36 To a stirred solution of ID-16 (35 mg) in DCE (2 mL) was added sodium triacetoxyborohydride (30 mg), 2-pyrimidinecarboxaldehyde (38 mg), and AcOH (20 μL) at room temperature. After stirring overnight at room temperature, 2 mol / L NaOH solution (10 mL) and chloroform (20 mL) were added. The organic layer was separated, then washed with 10 mL of water, dried over NaSO, and concentrated in vacuo. The crude product was purified by prep-HPLC to give ID-36 (19 mg) as a white solid. LCMS (Method A): m / z=590.4[M+H] + .

[0521] Compounds ID-40, 41, 62 and 63 were synthesized using the reagents listed in Table 12 in reaction step Ex10-1).

[0522] [Table 12]

[0523] Compounds ID-45 and 50 were synthesized according to the following method.

[0524] Example 11: Synthesis of ID-45

[0525] [ka]

[0526] Ex11-1) Synthesis of ID-45-Int1 From 0.88 g of ID-16-Int2, 0.13 g of ID-45-Int1 (yellow oil) was synthesized in the same manner as in reaction procedures 9-2) and Ex2-1). LCMS (Method A): m / z=554.4[M-Boc+H] + ,676.4[M+Na] + .

[0527] Ex11-2) Synthesis of ID-45-Int2 A mixture of ID-43-Int1 (0.13 g) and formic acid (2 mL) was left at room temperature overnight. The mixture was azeotroped with CHCl3 three times to give crude ID-45-Int2 (0.13 g) as a yellow oil, which was used in the next reaction without any purification. LCMS (Method A): m / z=554.4[M+H] + .

[0528] Ex11-3) Synthesis of ID-45 A mixture of ID-45-Int2 (30 mg) and acetic anhydride (10 μL) in sodium carbonate solution (4 mL) and DCE (2 mL) was stirred at room temperature for 2 h. After adding 25% aqueous ammonia (5 mL) and chloroform (20 mL), the organic layer was extracted, dried over NaSO, and concentrated in vacuo. The resulting residue was purified by prep-HPLC to give ID-45 (22 mg) as a white solid. LCMS (Method A): m / z=596.4[M+H] + .

[0529] Example 12: Synthesis of ID-50

[0530] [ka]

[0531] Ex12-4) Synthesis of ID-50 To a solution of 5-fluoropyrimidine-2-carboxylic acid (29 mg) in DCE (1 mL) was added HATU (93 mg) and DIEA (32 mg). After stirring at room temperature for 2 h, ID-45-Int3 (45 mg) in DCE (3 mL) was added, and the mixture was stirred for an additional 95 min. To the mixture, 10 mL of 1 mol / L aqueous HCl and 20 mL of chloroform were added. The organic layer was separated, washed with 10 mL of sodium bicarbonate solution, dried over Na2SO4, and concentrated in vacuo. The resulting crude product was purified by prep-HPLC to give ID-50 (7.8 mg) as a white solid. LCMS (Method A): m / z=678.3[M+H] + .

[0532] The chemical structures of compounds ID-1 to ID-107, the LCMS measurement methods, and the results are shown in Table 13 (Table 13-1 to Table 13-19).

[0533] [Table 13-1]

[0534] [Table 13-2]

[0535] [Table 13-3]

[0536] [Table 13-4]

[0537] [Table 13-5]

[0538] [Table 13-6]

[0539]

Table 13-7

[0540]

Table 13-8

[0541]

Table 13-9

[0542]

Table 13-10

[0543]

Table 13-11

[0544]

Table 13-12

[0545]

Table 13-13

[0546]

Table 13-14

[0547]

Table 13-15

[0548]

Table 13-16

[0549] [Table 13-17]

[0550] [Table 13-18]

[0551] [Table 13-19]

[0552] The chemical names of compounds ID-1 to ID-107 are listed below: ID-1 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-2 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-3 2-((E)-3-((3R,6S,9aS)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-yl)-3-oxoprop-1-en-1-yl)thiazole-4-carbonitrile ID-4 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-(1-(4-hydroxybutyl)piperidin-4-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-5 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-6 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-7 (3R,6S,9aS)-1-((E)-3-(5-hydroxybenzo[d]thiazol-2-yl)acryloyl)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-8 (3R,6S,9aS)-1-((E)-3-(5-hydroxybenzo[d]thiazol-2-yl)acryloyl)-8-(1-(4-hydroxybutyl)azetidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-9 (3R,6S,9aS)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-1-((E)-3-(4-(6-hydroxyhex-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-10 (3R,6S,9aS)-1-((E)-3-(4-(5-hydroxypent-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-isopropylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0553] ID-11 (3R,6S,9aS)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-1-((E)-3-(4-(6-hydroxyhex-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-12 (3R,6S,9aS)-1-((E)-3-(5-hydroxybenzo[d]thiazol-2-yl)acryloyl)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-13 (3R,6S,9aS)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-1-((E)-3-(4-(7-hydroxyhept-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-14 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(pyridin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-15 (3R,6S,9aS)-8-(1-benzoylpiperidin-4-yl)-3,6-diisobutyl-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-16 (3R,6S,9aS)-3,6-Diisobutyl-8-(piperidin-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-17 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(thiazol-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-18 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(pyridin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)-N-methylpropanamide ID-19 (3R,6S,9aS)-3,6-Diisobutyl-8-(3-(methylamino)propyl)-1-((E)-3-(pyridin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-4(3H)-one ID-20 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(quinolin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide

[0554] ID-21 (3R,6S,9aS)-3,6-Diisobutyl-8-(3-oxo-3-(piperazin-1-yl)propyl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-22 3-((3R,6S,9aS)-3,6-diisobutyl-1-((E)-3-(1-methyl-1H-indazol-3-yl)acryloyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-23 3-((3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3,6-diisobutyl-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-24 3-((3R,6S,9aS)-3,6-diisobutyl-1-((E)-3-(naphthalen-2-yl)acryloyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-25 (3R,6S,9aS)-3,8-bis(cyclohexylmethyl)-6-neopentyl-1-((E)-3-(quinoxalin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-26 (3R,6S,9aS)-3-(Cyclohexylmethyl)-6-neopentyl-8-(piperidin-4-ylmethyl)-1-((E)-3-(quinoxalin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-27 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(pyridin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazine-8(1H)-yl)-N-(thiazol-2-yl)propanamide ID-28 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(pyridin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)-N-methoxypropanamide ID-29 3-((3R,6S,9aS)-1-((E)-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)acryloyl)-3,6-diisobutyl-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-30 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(quinoxalin-5-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide

[0555] ID-31 3-((3R,6S,9aS)-1-((E)-3-(1,8-naphthyridin-2-yl)acryloyl)-3,6-diisobutyl-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-32 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(thiazolo[5,4-b]pyridin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-33 Ethyl 2-((E)-3-((3R,6S,9aS)-8-(3-amino-3-oxopropyl)-3,6-diisobutyl-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-yl)-3-oxoprop-1-en-1-yl)thiazole-5-carboxylate ID-34 3-((3R,6S,9aS)-1-((E)-3-(4,5-dimethylthiazol-2-yl)acryloyl)-3,6-diisobutyl-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-35 (3R,6S,9aS)-3,6-Diisobutyl-8-(3-(methyl(1-methylpiperidin-4-yl)amino)propyl)-1-((E)-3-(pyridin-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-4(3H)-one ID-36 (3R,6S,9aS)-3,6-Diisobutyl-1-((E)-3-(pyridin-2-yl)acryloyl)-8-(1-(pyrimidin-2-ylmethyl)piperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-37 3-((3R,6S,9aS)-3,6-diisobutyl-4,7-dioxo-1-((E)-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)acryloyl)hexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-38 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-4-yl)-1-((Z)-3-phenylacryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-39 (3R,6S,9aS)-1-Cinnamoyl-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-40 (3R,6S,9aS)-3,6-Diisobutyl-8-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0556] ID-41 (3R,6S,9aS)-8-(1'-acetyl-[1,4'-bipiperidin]-4-yl)-3,6-diisobutyl-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-42 3-((3R,6S,9aS)-3,6-diisobutyl-1-((E)-3-((S)-1-methylpyrrolidin-2-yl)acryloyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-43 3-((3R,6S,9aS)-3,6-diisobutyl-1-((E)-3-((R)-1-methylpyrrolidin-2-yl)acryloyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-8(1H)-yl)propanamide ID-44 (3R,6S,9aS)-3,6-Diisobutyl-1-((E)-3-(1-methyl-1H-pyrazol-5-yl)acryloyl)-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-45 (3R,6S,9aS)-8-(1-acetylpiperidin-4-yl)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3,6-diisobutyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-46 (3R,6S,9aS)-1-((E)-3-(benzo[d]oxazol-2-yl)acryloyl)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-47 (3R,6S,9aS)-1-((Z)-2-chloro-3-(pyridin-2-yl)acryloyl)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-48 2-((E)-3-((3R,6S,9aS)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-yl)-3-oxoprop-1-en-1-yl)isonicotinonitrile ID-49 (3R,6S,9aS)-1-((E)-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)acryloyl)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-50 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-(1-(5-fluoropyrimidine-2-carbonyl)piperidin-4-yl)-3,6-diisobutyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0557] ID-51 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(6-oxo-1,6-dihydropyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-52 (3R,6S,9aS)-1-((E)-3-(5-fluorobenzo[d]thiazol-2-yl)acryloyl)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-53 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(oxazol-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-54 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(thiazol-4-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-55 (3R,6S,9aS)-1-((E)-3-(5-chloropyrimidin-2-yl)acryloyl)-3,6-diisobutyl-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-56 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(2-morpholinothiazol-4-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-57 (3R,6S,9aS)-6-(4-(benzylamino)butyl)-3-isobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-58 (4S,11aS)-11-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-4-isobutyl-2-(1-methylpiperidin-4-yl)-1,2,11,11a-tetrahydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ID-59 tert-Butyl 4-((4-((4S,11aS)-11-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-fluoro-2-(1-methylpiperidin-4-yl)-3,6-dioxo-1,3,4,6,11,11a-hexahydro-2H-pyrazino[2,1-b]quinazolin-4-yl)butyl)(methyl)amino)piperidine-1-carboxylate ID-60 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-methylpiperidin-4-yl)-6-(2-(methylthio)ethyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0558] ID-61 (3R,6S,9aS)-6-(4-hydroxybenzyl)-3-isobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-62 (3R,6S,9aS)-3,6-Diisobutyl-1-((E)-3-(pyridin-2-yl)acryloyl)-8-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-63 (3R,6S,9aS)-8-(1-cyclohexylpiperidin-4-yl)-3,6-diisobutyl-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-64 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3,6-diisobutyl-8-(tetrahydro-2H-pyran-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-65 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-3-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-66 (3R,6S,9aS)-6-Benzyl-3-isobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-67 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylazepan-4-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-68 (3R,6S,9aS)-8-(4-aminocyclohexyl)-3,6-diisobutyl-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-69 (3R,6S,9aS)-8-(4-(dimethylamino)cyclohexyl)-3,6-diisobutyl-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-70 (3R,6S,9aS)-3,6-Diisobutyl-8-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1-((E)-3-(pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0559] ID-71 (3R,6S,9aS)-3,6-Diisobutyl-8-(1-methylpiperidin-4-yl)-1-((E)-3-(5-(trifluoromethyl)pyridin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-72 (3R,6S,9aS)-3,6-Diisobutyl-1-((E)-3-(5-methoxypyridin-2-yl)acryloyl)-8-(1-methylpiperidin-4-yl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-73 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-isopropylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-74 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-methylpiperidin-4-yl)-6-(2-(methylsulfonyl)ethyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-75 (3R,6S,9aS)-8-(1-(3-aminopropyl)piperidin-4-yl)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-76 4-(4-((3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyl-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-8(1H)-yl)piperidin-1-yl)butyric acid ID-77 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-(1-(2-(2-hydroxyethoxy)ethyl)piperidin-4-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-78 (3R,6S,9aS)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-1-((E)-3-(2-(methylthio)pyrimidin-4-yl)acryloyl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-79 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-(1-(3-hydroxypropyl)piperidin-4-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-80 (3R,6S,9aS)-8-(1-(4-hydroxybutyl)piperidin-4-yl)-1-((E)-3-(5-(3-hydroxyphenyl)pyridin-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0560] ID-81 (3R,6S,9aS)-1-((E)-3-(4-ethynylthiazol-2-yl)acryloyl)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-82 (3R,6S,9aS)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyl-1-((E)-3-(4-(pyridin-3-yl)thiazol-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-83 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-(1-(4-hydroxy-3-(hydroxymethyl)butyl)piperidin-4-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-84 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-(1-(4-hydroxybutyl)azetidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-85 (3R,6S,9aS)-1-((E)-3-(4-hydroxybenzo[d]thiazol-2-yl)acryloyl)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-86 (2R,5S,8aR)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-5-benzyl-2-isobutyl-7-(1-methylpiperidin-4-yl)tetrahydroimidazo[1,2-a]pyrazine-3,6(2H,5H)-dione ID-87 (3R,6S,9aS)-1-((E)-3-(4-((1-aminocyclopropyl)ethynyl)thiazol-2-yl)acryloyl)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-88 (3R,6S,9aS)-1-((E)-3-(4-(3-(dimethylamino)prop-1-yn-1-yl)thiazol-2-yl)acryloyl)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-89 (3R,6S,9aS)-1-((E)-3-(5-ethynylthiazol-2-yl)acryloyl)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-90 (3R,6S,9aS)-3-(cyclohexylmethyl)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-6-neopentyl-1-((E)-3-(quinoxalin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0561] ID-91 (3R,6S,9aS)-8-(1-(4-hydroxybutyl)azetidin-3-yl)-1-((E)-3-(4-(7-hydroxyhept-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-92 (3R,6S,9aS)-8-(1-(4-hydroxybutyl)azetidin-3-yl)-1-((E)-3-(4-(6-hydroxyhex-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-93 6-(2-((E)-3-((3R,6S,9aS)-8-((S)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyl-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazin-1(6H)-yl)-3-oxoprop-1-en-1-yl)thiazol-4-yl)-N-methylhex-5-ynamide ID-94 (3R,6S,9aS)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyl-1-((E)-3-(4-((tetrahydro-2H-pyran-4-yl)ethynyl)thiazol-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-95 (3S,6S,9aR)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-96 (3S,6S,9aR)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-3-isobutyl-6-neopentylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione ID-97 (3R,6S,9aS)-1-((E)-3-(4-(3-(2-hydroxyethoxy)prop-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-isopropylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-98 (3R,6S,9aS)-1-((E)-3-(5-hydroxybenzo[d]thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-isopropylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-99 (3R,6S,9aS)-3-(cyclopropylmethyl)-1-((E)-3-(4-(6-hydroxyhex-1-yn-1-yl)thiazol-2-yl)acryloyl)-8-(1-isopropylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-100 (3R,6S,9aS)-1-((E)-3-(5-ethynyl-4-(5-hydroxypent-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-isopropylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0562] ID-101 (3R,6S,9aS)-1-((E)-3-(5-(3-hydroxypropoxy)benzo[d]thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-isopropylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-102 (3R,6S,9aS)-8-(1-cyclopropylpiperidin-4-yl)-1-((E)-3-(4-(5-hydroxypent-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-103 (3R,6S,9aS)-1-((E)-3-(5-ethynyl-4-(5-hydroxypent-1-yn-1-yl)thiazol-2-yl)acryloyl)-3-isobutyl-8-(1-methylpiperidin-4-yl)-6-neopentyltetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-104 (3R,6S,9aS)-1-((E)-3-(benzo[d]thiazol-2-yl)acryloyl)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-6-neopentyl-3-(((1R,2S)-2-phenethylcyclopropyl)methyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-105 Benzyl (4-((3R,6S,9aS)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-6-neopentyl-4,7-dioxo-1-((E)-3-(quinoxalin-2-yl)acryloyl)octahydropyrazino[2,1-c][1,2,4]oxadiazin-3-yl)butyl)carbamate ID-106 (3R,6S,9aS)-3-(Cyclohexylmethyl)-8-(1-isopropylpiperidin-4-yl)-6-neopentyl-1-((E)-3-(quinoxalin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione ID-107 (3R,6S,9aS)-3-(2-ethylbutyl)-8-((R)-1-(4-hydroxybutyl)pyrrolidin-3-yl)-6-neopentyl-1-((E)-3-(quinoxalin-2-yl)acryloyl)tetrahydropyrazino[2,1-c][1,2,4]oxadiazine-4,7(3H,6H)-dione

[0563] Experimental example: MTS assay in Panc-1 (human pancreatic carcinoma cell line) (material and method) 1.Cells Cell line name: PANC-1 Source: Human pancreatic adenocarcinoma Purchased from: ATCC Product code: CRL-1469 2.Cell culture 2.1 Reagents for cell culture D-MEM (high glucose) containing L-glutamine and phenol red (Wako, Cat. No.: 044-29765) Fetal bovine serum (FBS; Life Technologies, Cat. No.: 26140-079) Penicillin-streptomycin solution (x100) (Wako, Cat. No.: 168-23191) 10×D-PBS(-)(Wako,Cat.No.:048-29805) 0.25 w / v% trypsin-1 mmol / l EDTA·4Na solution containing phenol red (Wako, Cat. No.: 201-16945) 2.2 Culture conditions Each cell line was cultured under the following conditions. Subculture was carried out as necessary. Growth medium: D-MEM + 10% FBS Culture environment: 37℃, 5%CO2 Seeding density: 5.0×10 5 Cell / 25cm 2 2.3 Measurement sample Solvent control substance: DMSO (HYBRI-MAX®, Sigma-Aldrich Corp.) Test substance: Example compounds (ID-1 - ID-13) Each test substance was serially diluted with DMSO (common ratio 2) to prepare a DMSO solution of the test substance. 2.4 Measurement and Analysis A human pancreatic cancer cell line (PANC-1) was exposed to a sample of the solvent control substance and a sample of the test substance, and the cell viability after 6 days was measured using the MTS method. Measurements were performed three times, and the average value was used. The cell viability in each test substance sample was calculated using the following formula 1, with the value after exposure to the solvent control substance being 100% viability. Viability (%) = 100 × absorbance of each test substance sample / absorbance of solvent control substance sample formula 1 A normalized value calculated from the absorbance at 492 nm and 630 nm of each sample and the absorbance of the blank using the following formula 2 was used as the absorbance in formula 1 above. Normalized value (ABS492nm-630nm) = (ABSsa 492nm-ABSsa 630nm)-(ABSbl 492nm-ABSbl 630nm) ABSsa 492: absorbance of each sample at a wavelength of 492 nm ABSsa 630: absorbance of each sample at a wavelength of 630 nm ABSbl 492: Absorbance of blank corresponding to each sample at a wavelength of 492 nm ABSbl 630: Absorbance of blank corresponding to each sample at a wavelength of 630 nm formula 2 The analysis was performed by estimating a logistic regression curve (four parameters) using the nplr package in R (The R Foundation for Statistical Computing). The results are shown in Table 14.

[0564] [Table 14-1]

[0565] [Table 14-2]

[0566] [Table 14-3]

[0567] [Table 14-4] [Industrial Applicability]

[0568] The compounds of the present invention can be used to treat diseases such as cancer because they inhibit the proliferation of cancer cells. Although only a few exemplary embodiments of the present invention have been described in detail above, those skilled in the art will readily appreciate that many changes may be made in the exemplary embodiments without substantially departing from the novel teachings and advantages of the present invention. Accordingly, all such modifications are intended to be included within the scope of this invention. This application is based on U.S. Provisional Application No. 63 / 052,587 filed in the United States (filing date: July 16, 2020), the contents of which are incorporated herein in their entirety.

Claims

Claim 1 A compound represented by the following formula (I): 【Chemical 1】 [wherein, Q is a hydrogen atom or is represented by any one of the following formulas (II-1) to (II-8): 【Chemical Formula 2】 R １ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, or -(CO)-R １ａ wherein; R １ａ is alkyl optionally substituted, alkoxy optionally substituted, aryl optionally substituted, or heteroaryl optionally substituted; R １ｂ is a hydrogen atom or 1 to 3 identical or different alkyl groups; Q １ａ is a single bond or an alkylene optionally substituted; Q １ｂ is a hydrogen atom, hydroxy, halogen, cyano, -Q １ｃ , -COQ １ｃ , -CONQ １ｃ Q １ｄ , CONQ １ｃ -OQ １ｄ , -NQ １ｃ Q １ｄ , or -OQ １ｃ ; Q １ｃ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; Q １ｄ is a hydrogen atom or an optionally substituted alkyl; Q ２ａ is a cycloalkylene optionally substituted; Q ２ｂ and Q ２ｃ are the same or different and are each a hydrogen atom or an optionally substituted alkyl; U is -CO- or -CH ２ -; R ２ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkylalkyl, or -X-N(R ２ａ )(R ２ｂ ); X is an alkylene group; R ２ａ and R ２ｂ are the same or different and each is a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, or an optionally substituted cycloalkylalkyl; V is an optionally substituted aryl ring, an optionally substituted heteroaryl ring, an optionally substituted partially saturated heteroaryl ring, or an optionally substituted heterocycloalkyl ring; R ３ is a hydrogen atom, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C≡C-R ３ａ or -COOR ３ｂ ; R ３ａ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl, R ３ｂ is a hydrogen atom, an alkyl optionally substituted, 【Chemical Formula 3】 represents any one of the following formulas (III-1) to (III-4): 【Chemical Formula 4】 R ４ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted heterocycloalkylalkyl, Ar ２ is an aryl ring optionally substituted or a heteroaryl ring optionally substituted; and R ５ is a hydrogen atom or an optionally substituted alkyl; and R ６ and R ７ are each, independently of one another, a hydrogen atom or a halogen, where R and R may be the same or different]] or a pharmaceutically acceptable salt thereof. Claim 2 The compound according to Claim 1, which is a compound represented by the following formula (I-a): 【Chemical Formula 5】 [wherein, R １ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted heterocycloalkylalkyl, or -(CO)-R １ａ wherein; R １ａ is alkyl optionally substituted, alkoxy optionally substituted, aryl optionally substituted, or heteroaryl optionally substituted; 【Chemical Formula 6】 represents any one of the following formulas (II-1-a) to (II-6-a): 【Chemical Formula 7】 R １ｂ is a hydrogen atom or 1 to 3 identical or different alkyl groups; R ２ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkylalkyl, or -X-N(R ２ａ )(R ２ｂ ); X is an alkylene group; R ２ａ and R ２ｂ are the same or different and are each a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkylalkyl; Ar １ is an optionally substituted aryl ring or an optionally substituted heteroaryl ring; R ３ is a hydrogen atom, hydroxy, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C≡C—R ３ａ or —COOR ３ｂ ; R ３ａ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl, R ３ｂ is a hydrogen atom or an optionally substituted alkyl, 【Chemical 8】 represents any one of the following formulas (III-1) to (III-3): 【Chemical Formula 9】 R ４ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted arylalkyl, an optionally substituted heteroarylalkyl, an optionally substituted cycloalkylalkyl, or an optionally substituted heterocycloalkylalkyl, Ar ２ is an aryl ring optionally substituted or a heteroaryl ring optionally substituted; and R ５ is a hydrogen atom or an optionally substituted alkyl] or a pharmaceutically acceptable salt thereof. Claim 3 The compound according to Claim 1, which is a compound represented by the following formula (IV): 【Chemical Formula 10】 [wherein each symbol is as defined in Claim 1] or a pharmaceutically acceptable salt thereof. Claim 4 The compound according to any one of Claims 1 to 3, which is a compound represented by the following formula (IV-a): 【Chemical Formula 11】 [wherein each symbol is as defined in Claim 2] or a pharmaceutically acceptable salt thereof. Claim 5 The compound according to Claim 1 or 3, wherein Q is represented by any one of the following formulas (VI-1) to (VI-3): 【Chemical Formula 12】 [wherein each symbol is as defined in Claim 1] or a pharmaceutically acceptable salt thereof. Claim 6 The compound according to any one of Claims 1, 3 and 5, wherein Q is represented by the following formula (II-7): 【Chemical 13】 Q １ａ is an alkylene, Q １ｂ is -CONH-Q １ｃ , -Q １ｄ , -CO-Q １ｄ、 -N(Q １ｃ )-Q １ｄ (wherein Q １ｃ is a hydrogen atom or alkyl, and Q １ｄ is a hydrogen atom or a heterocycloalkyl optionally substituted with alkyl). or a pharmaceutically acceptable salt thereof.

7. 【Fig. 14】 is represented by any one of the following formulas (VI-1-a) to (VI-3-a), the compound according to Claim 2 or 4: 【Chemical 15】 or a pharmaceutically acceptable salt thereof. Claim 8 Ar １ The compound according to any one of claims 2, 4 and 7, or a pharmaceutically acceptable salt thereof, which is a pyridine ring optionally substituted, a thiazole ring optionally substituted, a benzothiazole ring optionally substituted, or a quinoxaline ring optionally substituted.

9. 【Fig. 16】 is represented by the following formula (VII-1-a), (VII-2-a) or (VII-3-a), the compound according to Claim 8: 【Chemical 17】 or a pharmaceutically acceptable salt thereof. Claim 10 R １ is a hydrogen atom, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or -(CO)-R １ａ wherein; R １ａ is alkyl optionally substituted, alkoxy optionally substituted, aryl optionally substituted, or heteroaryl optionally substituted; R １ｂ is a hydrogen atom; R ２ is alkyl optionally substituted and arylalkyl optionally substituted; R ３ａ is a hydrogen atom, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl, R ４ is alkyl which is optionally substituted, Ar ２ is an aryl ring optionally substituted; and R ５ is a hydrogen atom, The compound according to any one of Claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. 【Fig. 18】 is represented by the following formula (v), the compound according to any one of Claims 1 to 10: 【Chemical Formula 19】 R ４ ' is alkyl optionally substituted or cycloalkyl optionally substituted, or a pharmaceutically acceptable salt thereof. Claim 12 R ４ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R’ is an alkyl group. Claim 13 R ４ The compound or a pharmaceutically acceptable salt thereof according to claim 11 or 12, wherein R' is an isobutyl group. Claim 14 R ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R is alkyl optionally substituted with alkylthio or alkylsulfonyl, or arylalkyl. Claim 15 R ２ The compound or a pharmaceutically acceptable salt thereof according to claim 14, wherein R is isobutyl, neopentyl, sec-butyl, or benzyl. Claim 16 R １ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R is alkyl or alkyl substituted with one or two hydroxy groups. Claim 17 R ３ is a hydrogen atom, hydroxy, or -C≡C-R ３ａ ; R ３ａ is alkyl substituted with hydroxy, the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16. Claim 18 A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

19. The pharmaceutical composition according to claim 18, wherein the composition comprises an effective amount of the compound.

20. An agent for treating or preventing cancer, comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

21. The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or the composition according to claim 18 or 19, for use as a medicament for treating or preventing cancer.

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