Benzylamine-containing 5,6-heteroaromatic compounds useful against mycobacterial infections

Abstract

Formula (I): [Formula 1] TIFF2022547228000163.tif60117In formula, formula: [chemical 2] The group represented by TIFF2022547228000164.tif2426 has the formula: [C3] The group represented by TIFF2022547228000165.tif26129; R 1 are each independently halogen, hydroxy, cyano, etc.; m is 0, 1, 2, 3 or 4; R 2 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, etc.; R 3a , R 3b , R 3c and R 3d are each independently a hydrogen atom, a halogen atom, or the like, provided that R 3a , R 3b , R 3c and R 3d is not a hydrogen atom at the same time; Ring C is represented as follows: [C4] TIFF2022547228000166.tif62161X is CH or N; Y is CH or N; R 4 are each independently halogen, hydroxy, cyano, etc.; p is 0 or 1; q is 0, 1, 2, 3 or 4; R 5 is CR 5C or N;R 6 is CR 6C or N;R 7 is CR 7C or N;R 8 is CR 8C or N;R 9 is CR 9C or N; However, R 5 , R 6 , R 7 , R 8 and R 9 is not N at the same time; R 5C , R 6C , R 7C , R 8C and R 9C are each independently a hydrogen atom, etc. or a pharmaceutically acceptable salt thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 898,066, filed Sep. 10, 2019, the entire contents of which are incorporated herein by reference. [Technical field]

[0002] The present invention relates to novel compounds. The present invention also relates to such compounds for use as pharmaceutical compositions and for use in the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria, such as nontuberculous mycobacteria. Such compounds may act by inhibiting the synthesis of ATP in pathogenic mycobacteria, with the inhibition of cytochrome bc1 activity as the primary mode of action. [Background technology]

[0003] The genus Mycobacterium has 95 well-characterized species. For centuries, two well-known mycobacterial species, Mycobacterium tuberculosis and M. Leprae, have been known causes of immense suffering to humans. Many other mycobacteria are present in the environment and their pathogenic potential has been recognized since the beginning of the last century. These mycobacteria are called nontuberculous mycobacteria (NTM). Although the incidence of tuberculosis (TB) is decreasing, NTM is creating new health concerns worldwide. Pulmonary disease caused by NTM is characterized by progressive irreversible lung damage and increased mortality. Approximately 80% of pulmonary NTM disease is caused by the Mycobacterium avium complex (MAC: M. avium, M. intracellulare, and M. chimaera). The annual prevalence of NTM lung disease varies in various regions, ranging from 0.2 / 100,000 to 14.7 / 100,000, with an overall alarmingly increasing rate. The disease is more prevalent after age 60, In the United States, estimated prevalence ranged from 19.6 / 100,000 in 1994-1996 to 26.7 / 100,000 in 2004-2006. Unlike TB, NTM is an opportunistic pathogen that causes TB-like lung disease mostly in immunocompromised patients or those with pre-existing pulmonary conditions such as cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD). In addition, postmenopausal women without pre-existing structural lung disease are another risk group for NTM lung disease. These women, mainly older women of Caucasian or Asian descent, present with nodular bronchiectasis as NTM lung disease.

[0004] Described herein is an active agent that can be a treatment for either or both of TB and NTM infections.There is an unmet medical need for a compound that is effective against either or both of TB and NTM pathogens, and the compound is believed to be effective as a single agent or in combination therapy against drug-resistant strains.

[0005] Patent Document 1 discloses various compounds having cytochrome bc1 inhibitory activity. For example, the following compounds are disclosed: [ka] Patent Documents 2 to 12 disclose various compounds having cytochrome bc1 inhibitory activity. For example, Patent Document 12 discloses the following compound: [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2017 / 049321 [Patent Document 2] International Publication No. 2011 / 057145 [Patent Document 3] International Publication No. 2014 / 015167 [Patent Document 4] International Publication No. 2011 / 113606 [Patent Document 5] International Publication No. 2015 / 014993 [Patent Document 6] International Publication No. 2017 / 001660 [Patent Document 7] International Publication No. 2017 / 001661 [Patent Document 8] International Publication No. 2017 / 216281 [Patent Document 9] International Publication No. 2017 / 216283 [Patent Document 10] International Publication No. 2018 / 158280 [Patent Document 11] US Patent Application Publication No. 2017 / 0313697 [Patent Document 12] International Publication No. 2019 / 175737 Summary of the Invention [Problem to be solved by the invention]

[0007] It is an object of the present invention to provide compounds or pharma- ceutically acceptable salts thereof that are useful for treating or preventing bacterial diseases, including diseases caused by pathogenic mycobacteria, such as nontuberculous mycobacteria, and pharmaceutical compositions containing the same. [Means for solving the problem]

[0008] As a result of intensive research aimed at solving the above problems, the present inventors have succeeded in synthesizing an excellent compound for preventing and / or treating mycobacterial infections, particularly nontuberculous mycobacterial infections.

[0009] BRIEF DESCRIPTION OF SOME EMBODIMENTS OF THE INVETION (1) Formula (I): [ka] During the ceremony, formula: [ka] The group represented by formula: [ka] is a group represented by: R 1 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl; m is 0, 1, 2, 3 or 4; R 2 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 3a , R 3b , R 3c and R 3d are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, provided that R 3a , R 3b , R 3c and R 3dis not a hydrogen atom at the same time; Ring C is represented as follows: [ka] X is CH or N; Y is CH or N; R 4 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; Two R's attached to adjacent carbon atoms 4 The groups, together with the carbon atoms to which they are attached, may form a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 5- to 6-membered non-aromatic heterocyclic ring; Two R's attached to the same carbon atom 4 The groups, together with the carbon atoms to which they are attached, may form a substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 3- to 6-membered non-aromatic heterocyclic ring; The Two R's 4 The groups together may form a (C2-C4) bridge, one of the carbon atoms of the bridge may be optionally replaced by an oxygen atom or a nitrogen atom; each carbon atom of the bridge may be independently selected from the group consisting of R 4C and the nitrogen atom of said bridge, if present, is substituted with a substituent selected from R 4N and is substituted with a substituent selected from R 4C are each independently a hydrogen atom, halogen, hydroxy, cyano, or substituted or unsubstituted alkyl; R 4N are each independently a hydrogen atom or a substituted or unsubstituted alkyl; p is 0 or 1; q is 0, 1, 2, 3 or 4; R 5 CR 5C or N; R 6 CR 6C or N; R 7 CR 7C or N; R 8 CR 8C or N; R 9 CR 9C or N; However, R 5 , R 6 , R 7 , R 8 and R 9 is not N at the same time; R 5C , R 6C , R 7C , R 8C and R 9C are each independently a hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, or pentafluorothio; However, the compounds shown below: [ka] Excluding or a pharma- ceutically acceptable salt thereof. (2) formula: [ka] The group represented by formula: [ka] (wherein each symbol is as defined in (1) above), or a pharma- ceutically acceptable salt thereof. (3) formula: [ka] The group represented by formula: [ka] (wherein each symbol is as defined in (1) above), or a pharma- ceutically acceptable salt thereof. (4)R 1 is halogen or substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof. (5)R 1 is substituted or unsubstituted alkyloxy or substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof. (6) The compound according to any one of the above (1) to (5), wherein m is 1, or a pharma- ceutically acceptable salt thereof. (7)R 2 The compound according to any one of the above (1) to (6), or a pharma- ceutically acceptable salt thereof, wherein is substituted or unsubstituted alkyl. (8)R 3b The compound according to any one of the above (1) to (7) or a pharma- ceutically acceptable salt thereof, wherein is halogen. (9)R 3b and R 3c is each independently a halogen, or a pharma- ceutically acceptable salt thereof. (10)R 3a The compound according to any one of the above (1) to (7) or a pharma- ceutically acceptable salt thereof, wherein is halogen. (11) Ring C is represented as follows: [ka] The compound according to any one of the above (1) to (10), wherein each symbol is as defined in the above (1), or a pharma- ceutically acceptable salt thereof. (12) The compound according to any one of the above (1) to (11), wherein p is 1, or a pharma- ceutically acceptable salt thereof. (13) The compound according to any one of the above (1) to (12), wherein q is 0, or a pharma- ceutically acceptable salt thereof. (14) The compound according to any one of the above (1) to (12), wherein q is 1, or a pharma- ceutically acceptable salt thereof. (15) The compound according to any one of the above (1) to (12) or a pharma- ceutically acceptable salt thereof, wherein q is 2. (16) Ring C is represented as follows: [ka] The compound according to the above (14), wherein each symbol is as defined in the above (1), or a pharma- ceutically acceptable salt thereof. (17) Ring C is represented as follows: [ka] The compound according to the above (15), wherein each symbol is as defined in the above (1), or a pharma- ceutically acceptable salt thereof. (18) The compound according to any one of the above (1) to (17) or a pharma- ceutically acceptable salt thereof, wherein X and Y are N. (19) The compound according to any one of the above (1) to (17), wherein one of X and Y is N, and the other of X and Y is CH, or a pharma- ceutically acceptable salt thereof. (20)R 4 is each independently substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof. (21)R 7 CR 7C and R 7Cis substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, or a pharma- ceutically acceptable salt thereof according to any one of the above (1) to (20). (22)R 5 , R 6 , R 8 and R 9 The compound according to (21) above, wherein is CH, or a pharma- ceutically acceptable salt thereof. (23)R 5 CR 5C and R 5C is a halogen, and R 6 , R 8 and R 9 The compound according to (21) above, wherein is CH, or a pharma- ceutically acceptable salt thereof. (24) The compound according to (1) above, wherein the compound is selected from the group consisting of compounds (I-1-3), (I-1-25), (I-1-29), (I-1-38), (I-1-39), (I-1-42), (I-1-43), (I-1-45), (I-1-95) and (I-1-118), or a pharma- ceutically acceptable salt thereof. (25) The compound according to the above (1) or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds (I-1-144), (I-1-149) and (I-2-6). (26) A pharmaceutical composition comprising the compound according to any one of (1) to (25) above or a pharma- ceutically acceptable salt thereof. (27) The pharmaceutical composition according to (26) above for the treatment and / or prevention of mycobacterial infection. (28) A method for preventing or treating mycobacterial infection, comprising administering to a subject the compound according to any one of (1) to (25) above or a pharma- ceutically acceptable salt thereof. (29) The compound according to any one of (1) to (25) above or a pharma- ceutically acceptable salt thereof for the treatment and / or prevention of mycobacterial infection. (1A) Formula (I): [ka] During the ceremony, Ring A and ring B are represented as follows: [ka] R 1 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl; m is 0, 1, 2, 3 or 4; R 2 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 3a , R 3b , R 3c and R 3d are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, provided that R 3a , R 3b , R 3c and R 3d is not a hydrogen atom at the same time; Ring C is represented as follows: [ka] X is CH or N; Y is CH or N; R 4are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; Two R's attached to adjacent carbon atoms 4 may, together with the carbon atom to which they are attached, form a substituted or unsubstituted 5- to 6-membered non-aromatic carbocycle or a substituted or unsubstituted 5- to 6-membered non-aromatic heterocycle; Two R's attached to the same carbon atom 4 may, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3- to 6-membered non-aromatic carbocycle or a substituted or unsubstituted 3- to 6-membered non-aromatic heterocycle; The Two R's 4 The groups together may form a (C2-C4) bridge, one of the carbon atoms of the bridge may be optionally replaced by an oxygen atom or a nitrogen atom; each carbon atom of the bridge may be independently selected from the group consisting of R 4C and the nitrogen atom of said bridge, if present, is substituted with a substituent selected from R 4N and is substituted with a substituent selected from R 4C are each independently a hydrogen atom, halogen, hydroxy, cyano, or substituted or unsubstituted alkyl; R 4N are each independently a hydrogen atom or a substituted or unsubstituted alkyl; p is 0 or 1; q is 0, 1, 2, 3 or 4; R 5 CR 5C or N; R 6 CR 6C or N; R 7 CR 7C or N; R 8 CR 8C or N; R 9 CR 9C or N; However, R 5, R 6 , R 7 , R 8 and R 9 is not N at the same time; R 5C , R 6C , R 7C , R 8C and R 9C are each independently a hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, or pentafluorothio; However, the compounds shown below: [ka] Excluding or a pharma- ceutically acceptable salt thereof. (2A) Ring A and ring B are represented as follows: [ka] The compound according to the above (1A) or a pharma- ceutically acceptable salt thereof. (3A) Ring A and ring B are represented as follows: [ka] The compound according to the above (1A) or a pharma- ceutically acceptable salt thereof. (4A)R 1 is halogen or substituted or unsubstituted alkyl, or a pharma- ceutically acceptable salt thereof. (5A)R 1 The compound according to the above (3A) or a pharma- ceutically acceptable salt thereof, wherein is substituted or unsubstituted alkyloxy or substituted or unsubstituted alkyl. (6A) The compound according to any one of the above (1A) to (5A), wherein m is 1, or a pharma- ceutically acceptable salt thereof. (7A)R 2 The compound according to any one of the above (1A) to (6A) or a pharma- ceutically acceptable salt thereof, wherein is substituted or unsubstituted alkyl. (8A)R 3b The compound according to any one of the above (1A) to (7A) or a pharma- ceutically acceptable salt thereof, wherein is halogen. (9A)R 3b and R 3c is each independently a halogen, or a pharma- ceutically acceptable salt thereof. (10A) Ring C is represented as follows: [ka] The compound according to any one of the above (1A) to (9A) or a pharma- ceutically acceptable salt thereof. (11A) The compound according to any one of the above (1A) to (10A), wherein p is 1, or a pharma- ceutically acceptable salt thereof. (12A) The compound according to any one of the above (1A) to (11A), wherein q is 1, or a pharma- ceutically acceptable salt thereof. (13A) Ring C is represented as follows: [ka] The compound according to any one of the above (1A) to (12A) or a pharma- ceutically acceptable salt thereof. (14A) The compound according to any one of the above (1A) to (13A) or a pharma- ceutically acceptable salt thereof, wherein X and Y are N. (15A) The compound according to any one of the above (1A) to (13A) or a pharma- ceutically acceptable salt thereof, wherein one of X and Y is N, and the other of X and Y is CH. (16A)R 4The compound according to any one of the above (1A) to (15A) or a pharma- ceutically acceptable salt thereof, wherein is substituted or unsubstituted alkyl. (17A)R 7 CR 7C and R 7C The compound according to any one of the above (1A) to (16A) or a pharma- ceutically acceptable salt thereof, wherein is substituted or unsubstituted alkyloxy. (18A)R 5 , R 6 , R 8 and R 9 The compound according to (17A) above, wherein is CH, or a pharma- ceutically acceptable salt thereof. (19A)R 5 CR 5C and R 5C is a halogen, and R 6 , R 8 and R 9 The compound according to (17A) above, wherein is CH, or a pharma- ceutically acceptable salt thereof. (20A) The compound according to (1A) above, wherein the compound is selected from the group consisting of compounds (I-1-3), (I-1-25), (I-1-29), (I-1-38), (I-1-39), (I-1-42), (I-1-43), (I-1-45), (I-1-95) and (I-1-118), or a pharma- ceutically acceptable salt thereof. (21A) A pharmaceutical composition comprising the compound according to any one of (1A) to (20A) above or a pharma- ceutically acceptable salt thereof. (22A) A pharmaceutical composition according to (21A) above for the treatment and / or prevention of mycobacterial infection. (23A) A method for preventing or treating a mycobacterial infection, comprising administering to a subject a compound according to any one of (1A) to (20A) above or a pharma- ceutically acceptable salt thereof. (24A) The compound according to any one of (1A) to (20A) above or a pharma- ceutically acceptable salt thereof for the treatment and / or prevention of mycobacterial infection. Effect of the Invention

[0010] The compounds of the present invention are useful in the treatment or prevention of mycobacterial infections, particularly non-tuberculous mycobacterial infections. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Each term used in this specification will be explained below. In this specification, each term has the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the listed components or elements. The term "comprising" means that it is not limited by the components and does not exclude unrecited factors. The use of the terms "a" or "an" when used in conjunction with the term "comprising" in the claims and / or specification may mean "one," but is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0012] Compounds represented by formula (I) or pharma- ceutically acceptable salts thereof are described above and below.

[0013] The term "halogen" includes fluorine, chlorine, bromine and iodine atoms, with fluorine and chlorine atoms being particularly preferred.

[0014] The term "alkyl" includes linear or branched hydrocarbon groups of C1 to C15, preferably C1 to C10, more preferably C1 to C6, and even more preferably C1 to C4. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Preferred embodiments of "alkyl" are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. More preferred embodiments are methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0015] The term "alkenyl" includes linear or branched hydrocarbon groups of C2 to C15, preferably C2 to C10, more preferably C2 to C6, and even more preferably C2 to C4, having one or more double bonds at any position(s). Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferred embodiments of "alkenyl" are vinyl, allyl, propenyl, isopropenyl or butenyl.

[0016] The term "alkynyl" includes C2-C8 linear or branched alkynyl having one or more triple bonds in the above "alkyl", and examples thereof include ethynyl, propynyl, butynyl, etc. Furthermore, "alkynyl" may have a double bond.

[0017] The term "alkyloxy" refers to a group in which the above "alkyl" is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy and hexyloxy. Preferred embodiments of "alkyloxy" are methyloxy, ethyloxy, n-propyloxy, isopropyloxy or tert-butyloxy.

[0018] The term "alkenyloxy" refers to a group in which the above "alkenyl" is bonded to an oxygen atom. Examples include vinyloxy, allyloxy, 1-n-propenyloxy, 2-n-butenyloxy, 2-n-pentenyloxy, 2-n-hexenyloxy, 2-n-heptenyloxy, and 2-n-octenyloxy.

[0019] The term "alkynyloxy" refers to a group in which the above "alkynyl" is bonded to an oxygen atom. Examples include ethynyloxy, 1-n-propynyloxy, 2-n-propynyloxy, 2-n-butynyloxy, 2-n-pentynyloxy, 2-n-hexynyloxy, 2-n-heptynyloxy, and 2-n-octynyloxy.

[0020] The term "aromatic carbocycle" refers to a cyclic aromatic hydrocarbon ring that is monocyclic or polycyclic having two or more rings. For example, aromatic carbocycles include a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and the like. A preferred embodiment of an "aromatic carbocycle" is a benzene ring.

[0021] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group that is monocyclic or polycyclic having two or more rings. For example, aromatic carbocyclic groups include phenyl, naphthyl, anthryl, phenanthryl, and the like. A preferred embodiment of an "aromatic carbocyclic group" is phenyl.

[0022] The term "non-aromatic carbocycle" refers to a cyclic saturated or unsaturated non-aromatic hydrocarbon ring, which may be monocyclic or polycyclic having two or more rings. A "non-aromatic carbocycle" which is polycyclic having two or more rings includes a fused ring in which a non-aromatic carbocycle, which may be monocyclic or polycyclic having two or more rings, is fused to a ring of the above-mentioned "aromatic carbocycle". Additionally, "non-aromatic carbocycle" also includes rings that form bridged or spiro rings as described below. [ka] The monocyclic non-aromatic carbocycle is preferably a C3 to C16 carbocycle, more preferably a C3 to C12 carbocycle, and even more preferably a C3 to C6 carbocycle. For example, examples of the monocyclic non-aromatic carbocycle include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclohexadiene. Non-aromatic carbocycles that are polycyclic, having two or more rings, include, for example, indane, indene, acenaphthalene, tetrahydronaphthalene, fluorene, and the like.

[0023] The term "non-aromatic carbocyclic group" refers to a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group which is monocyclic or polycyclic having two or more rings. A "non-aromatic carbocyclic group" which is polycyclic having two or more rings includes a fused ring group in which a non-aromatic carbocyclic group which is monocyclic or polycyclic having two or more rings is fused to a ring of the above "aromatic carbocyclic group". Additionally, "non-aromatic carbocyclic groups" also include groups that have bridged or spiro rings, as follows: [ka] The monocyclic non-aromatic carbocyclic group is preferably a C3 to C16, more preferably a C3 to C12, and even more preferably a C3 to C6 carbocyclyl. For example, examples of the monocyclic non-aromatic carbocyclic group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Non-aromatic carbocyclic groups that are polycyclic, having two or more rings, include, for example, indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, and the like.

[0024] The term "aromatic heterocycle" means an aromatic ring that is monocyclic or polycyclic having two or more rings, containing one or more identical or different heteroatoms independently selected from O, S and N. An "aromatic heterocycle" having two or more rings and being polycyclic includes a fused ring in which a monocyclic or polycyclic aromatic heterocycle having two or more rings is fused with a ring of the above-mentioned "aromatic carbocycle". The monocyclic aromatic heterocycle is preferably a 5- to 8-membered ring, more preferably a 5- to 6-membered ring. For example, examples of the monocyclic aromatic heterocycle include "5-membered aromatic heterocycles" such as pyrrole, imidazole, pyrazole, triazole, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, and thiadiazole, and "6-membered aromatic heterocycles" such as pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Examples of bicyclic aromatic heterocycles include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, pyrazolopyridine, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, and thiazolopyridine. Examples of polycyclic aromatic heterocycles having three or more rings include carbazole, acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, dibenzofuran, and the like.

[0025] The term "aromatic heterocyclic group" means an aromatic cyclic group which is monocyclic or polycyclic having two or more rings, containing one or more identical or different heteroatoms independently selected from O, S and N. An "aromatic heterocyclic group" which is polycyclic having two or more rings includes a fused ring group in which a monocyclic or polycyclic aromatic heterocyclic group having two or more rings is fused with a ring of the above-mentioned "aromatic carbocyclic group". The monocyclic aromatic heterocyclic group is preferably a 5- to 8-membered ring, more preferably a 5- to 6-membered ring. Examples of the monocyclic aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl. Examples of bicyclic aromatic heterocyclic groups include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzoisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl. Aromatic heterocyclic groups that are polycyclic, having three or more rings, include, for example, carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, and the like.

[0026] The term "non-aromatic heterocycle" means a non-aromatic ring that is monocyclic or polycyclic having two or more rings, containing one or more identical or different heteroatoms independently selected from O, S and N. A "non-aromatic heterocycle" that is polycyclic having two or more rings includes a fused ring in which a monocyclic or polycyclic non-aromatic heterocycle having two or more rings is fused with a ring of the above-mentioned "aromatic carbocycle", "non-aromatic carbocycle" and / or "aromatic heterocycle". A non-aromatic heterocycle that is polycyclic having two or more rings further includes a fused ring in which a monocyclic or polycyclic aromatic heterocycle having two or more rings is fused with a ring of the above-mentioned "non-aromatic carbocycle". Additionally, "non-aromatic heterocycle" also includes rings that form bridged or spiro rings as described below. [ka] The monocyclic non-aromatic heterocycle is preferably a 3- to 8-membered ring, more preferably a 3- to 6-membered ring, and more preferably a 5- or 6-membered ring. For example, examples of the monocyclic non-aromatic heterocycle include: "Five-membered non-aromatic heterocycles" such as thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydrofuran, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dioxolane, and dioxoline; "6-membered non-aromatic heterocycles" such as dioxane, thiane, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydropyran, dihydrooxazine, tetrahydropyridazine, hexahydropyrimidine, thiazine, and the like; and Examples of such an alkyl group include thiirane, oxirane, oxetane, oxathiolane, azetidine, hexahydroazepine, tetrahydrodiazepine, dioxazine, aziridine, oxepane, thiolane, and thiine. Non-aromatic heterocycles that are polycyclic, having two or more rings, include, for example, indoline, isoindoline, chroman, isochroman, dihydrobenzofuran, dihydroisobenzofuran, dihydroquinoline, dihydroisoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, and the like.

[0027] The term "non-aromatic heterocyclic group" means a non-aromatic cyclic group that is monocyclic or polycyclic having two or more rings, containing one or more identical or different heteroatoms independently selected from O, S and N. A "non-aromatic heterocyclic group" which is polycyclic having two or more rings includes a fused ring group in which a monocyclic or polycyclic non-aromatic heterocycle having two or more rings is fused to a ring of the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group" and / or "aromatic heterocyclic group". Furthermore, "non-aromatic heterocyclic group" also includes groups having bridges or forming spiro rings, as follows: [ka] The monocyclic non-aromatic heterocyclic group is preferably a 3- to 8-membered ring, more preferably a 5- or 6-membered ring. For example, non-aromatic monocyclic heterocyclic groups include dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl, aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thiinyl, thiazinyl, and the like. Non-aromatic heterocyclic groups that are polycyclic, having two or more rings, include, for example, indolinyl, isoindolinyl, chromanyl, isochromanyl dihydrobenzofuryl, dihydroisobenzofuryl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and the like.

[0028] The term "aromatic carbocycle-oxy" refers to a group in which an "aromatic carbocycle" is bonded to an oxygen atom. Examples include phenyloxy and naphthyloxy.

[0029] The term "non-aromatic carbocycle-oxy" refers to a group in which a "non-aromatic carbocycle" is attached to an oxygen atom. Examples include cyclopropyloxy, cyclohexyloxy, and cyclohexenyloxy.

[0030] The term "heteroaromatic ring-oxy" refers to a group in which a "heteroaromatic ring" is bonded to an oxygen atom. Examples include pyridyloxy and oxazolyloxy.

[0031] The term "non-aromatic heterocycle-oxy" refers to a group in which a "non-aromatic heterocycle" is bonded to an oxygen atom. Examples include piperidinyloxy and tetrahydrofuryloxy.

[0032] Substituents for "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy" and "substituted alkynyloxy" include the following substituents. Carbon atoms at any position may be bonded to one or more groups selected from the following substituents. Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino , alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenyl

[0043] Examples of the alkynylcarbonyloxy include alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylsulfamoyl, alkenylsulfamoyl, alkynylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl,Aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl and non-aromatic heterocyclic sulfonyl. Preferred substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkylsulfonylamino. , alkenylsulfonylamino, alkynylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylsulfamoyl, alkenylsulfamoyl and alkynylsulfamoyl. More preferred substituents are: halogen, hydroxy, amino, cyano, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylamino, alkenylamino and alkynylamino. Particularly preferred substituents: halogens and non-aromatic carbocyclic groups.

[0033] "Two R's attached to adjacent carbon atoms 4 "A substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring formed by two R 4 "A substituted or unsubstituted 5- to 6-membered non-aromatic heterocycle formed by two R 4 "A substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic ring formed by the carbon atom to which they are attached" and "two R 4 Substituents on the ring of the "aromatic carbocycle", "non-aromatic carbocycle", "aromatic heterocycle" and "non-aromatic heterocycle" portion of "substituted or unsubstituted 3- to 6-membered non-aromatic heterocycle formed by", "substituted or unsubstituted aromatic carbocycle-oxy", "substituted or unsubstituted non-aromatic carbocycle-oxy", "substituted or unsubstituted aromatic heterocycle-oxy" and "substituted or unsubstituted non-aromatic heterocycle-oxy" include the following substituents. An atom at any (one or more) position on the ring may be bonded to one or more groups selected from the following substituents. Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyl alkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkynylcarbonylimino , alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylsulfamoyl, alkenylsulfamoyl, alkynylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl,Aromatic carbocycle alkyloxy, non-aromatic carbocycle alkyloxy, aromatic heterocycle alkyloxy, non-aromatic heterocycle alkyloxy, aromatic carbocycle alkyloxycarbonyl, non-aromatic carbocycle alkyloxycarbonyl, aromatic heterocycle alkyloxycarbonyl, non-aromatic heterocycle alkyloxycarbonyl, aromatic carbocycle alkyloxyalkyl, non-aromatic carbocycle alkyloxyalkyl, aromatic heterocycle alkyloxyalkyl, non-aromatic heterocycle alkyloxyalkyl, aromatic carbocycle alkylamino, non-aromatic carbocycle alkylamino, aromatic heterocycle alkylamino, non-aromatic heterocycle alkylamino, aromatic carbocycle sulfanyl, non-aromatic carbocycle sulfanyl, aromatic heterocycle sulfanyl, non-aromatic heterocycle sulfanyl, non-aromatic carbocycle sulfonyl, aromatic carbocycle sulfonyl, aromatic heterocycle sulfonyl and non-aromatic heterocycle sulfonyl. Preferred substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkylsulfonylamino. , alkenylsulfonylamino, alkynylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylsulfamoyl, alkenylsulfamoyl and alkynylsulfamoyl. More preferred substituents are: halogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyl and haloalkyloxy. Particularly preferred substituents: halogen, alkyl, haloalkyl and haloalkyloxy.

[0034] The term "haloalkyl" includes groups in which one or more hydrogen atoms bonded to the carbon atom of the "alkyl" are replaced with the "halogen". Examples include monofluoromethyl, monofluoroethyl, monofluoro-n-propyl, 2,2,3,3,3-n-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl and 1,1,1-trifluoro-n-propan-2-yl. Preferred embodiments of "haloalkyl" are trifluoromethyl and trichloromethyl.

[0035] The term "haloalkyloxy" refers to a group in which the above "haloalkyl" is bonded to an oxygen atom. Examples include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy and trichloroethoxy. Preferred embodiments of "haloalkyloxy" are trifluoromethoxy and trichloromethoxy.

[0036] The term "alkylcarbonyl" refers to a group in which the above "alkyl" is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and n-hexylcarbonyl. Preferred embodiments of "alkylcarbonyl" are methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.

[0037] The term "alkenylcarbonyl" refers to a group in which the above "alkenyl" is bonded to a carbonyl group. Examples include vinylcarbonyl, allylcarbonyl, and n-propenylcarbonyl.

[0038] The term "alkynylcarbonyl" refers to a group in which the above "alkynyl" is bonded to a carbonyl group. Examples include ethynylcarbonyl and n-propynylcarbonyl.

[0039] The term "alkylamino" refers to a group in which one or two hydrogen atoms bonded to the nitrogen atom of an amino group are replaced with the above-mentioned "alkyl." Examples include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino, and N-methyl-N-ethylamino. Preferred embodiments of "alkylamino" are methylamino and ethylamino.

[0040] The term "alkylsulfonyl" refers to a group in which the above "alkyl" is bonded to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl and sec-butylsulfonyl. Preferred embodiments of "alkylsulfonyl" are methylsulfonyl and ethylsulfonyl.

[0041] The term "alkenylsulfonyl" refers to a group in which the above "alkenyl" is bonded to a sulfonyl group. Examples include vinylsulfonyl, allylsulfonyl, and n-propenylsulfonyl.

[0042] The term "alkynylsulfonyl" refers to a group in which the above "alkynyl" is linked to a sulfonyl group. Examples include ethynylsulfonyl and n-propynylsulfonyl.

[0043] The term "alkylcarbonylamino" refers to a group in which one or two hydrogen atoms bonded to the nitrogen atom of an amino group are replaced with the above-mentioned "alkylcarbonyl". Examples include methylcarbonylamino, dimethylcarbonylamino, ethylcarbonylamino, diethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, N,N-diisopropylcarbonylamino, n-butylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino and sec-butylcarbonylamino.

[0044] The term "alkylsulfonylamino" refers to a group in which one or two hydrogen atoms bonded to the nitrogen atom of an amino group are replaced with the above-mentioned "alkylsulfonyl." Examples include methylsulfonylamino, dimethylsulfonylamino, ethylsulfonylamino, diethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, N,N-diisopropylsulfonylamino, n-butylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, and sec-butylsulfonylamino. Preferred embodiments of "alkylsulfonylamino" are methylsulfonylamino and ethylsulfonylamino.

[0045] The term "alkylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of an imino group is replaced with the above-mentioned "alkyl." Examples include methylimino, ethylimino, n-propylimino, and isopropylimino.

[0046] The term "alkenylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of an imino group is replaced with the above-mentioned "alkenyl." Examples include ethylenylimino and n-propenylimino.

[0047] The term "alkynyl imino" refers to a group in which the hydrogen atom attached to the nitrogen atom of an imino group is replaced with the above-mentioned "alkynyl." Examples include ethynyl imino and n-propynyl imino.

[0048] The term "alkylcarbonylimino" refers to a group in which the hydrogen atom bonded to the nitrogen atom of an imino group is replaced with the above-mentioned "alkylcarbonyl." Examples include methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, and isopropylcarbonylimino.

[0049] The term "alkenylcarbonylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of an imino group is replaced with the above-mentioned "alkenylcarbonyl." Examples include ethylenylcarbonylimino and n-propenylcarbonylimino.

[0050] The term "alkynylcarbonylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of an imino group is replaced with the above-mentioned "alkynylcarbonyl." Examples include ethynylcarbonylimino and n-propynylcarbonylimino.

[0051] The term "alkyloxyimino" refers to a group in which the hydrogen atom bonded to the nitrogen atom of an imino group is replaced with the above-mentioned "alkyloxy." Examples include methyloxyimino, ethyloxyimino, n-propyloxyimino, and isopropyloxyimino.

[0052] The term "alkenyloxyimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of an imino group is replaced with the above-mentioned "alkenyloxy." Examples include ethylenyloxyimino and n-propenyloxyimino.

[0053] The term "alkynyloxyimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of an imino group is replaced with the above-mentioned "alkynyloxy." Examples include ethynyloxyimino and n-propynyloxyimino.

[0054] The term "alkylcarbonyloxy" refers to a group in which the above "alkylcarbonyl" is bonded to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy and sec-butylcarbonyloxy. Preferred embodiments of "alkylcarbonyloxy" are methylcarbonyloxy and ethylcarbonyloxy.

[0055] The term "alkenylcarbonyloxy" refers to a group in which the above "alkenylcarbonyl" is bonded to an oxygen atom. Examples include ethylenylcarbonyloxy and n-propenylcarbonyloxy.

[0056] The term "alkynylcarbonyloxy" refers to a group in which the above "alkynylcarbonyl" is bonded to an oxygen atom. Examples include ethynylcarbonyloxy and n-propynylcarbonyloxy.

[0057] The term "alkyloxycarbonyl" refers to a group in which the above "alkyloxy" is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl and n-hexyloxycarbonyl. Preferred embodiments of "alkyloxycarbonyl" are methyloxycarbonyl, ethyloxycarbonyl and n-propyloxycarbonyl.

[0058] The term "alkenyloxycarbonyl" refers to a group in which the above "alkenyloxy" is bonded to a carbonyl group. Examples include ethylenyloxycarbonyl and n-propenyloxycarbonyl.

[0059] The term "alkynyloxycarbonyl" refers to a group in which the above "alkynyloxy" is bonded to a carbonyl group. Examples include ethynyloxycarbonyl and n-propynyloxycarbonyl.

[0060] The term "alkylsulfanyl" refers to a group in which the hydrogen atom bonded to the sulfur atom of a sulfanyl group is replaced with the above-mentioned "alkyl." Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, and isopropylsulfanyl.

[0061] The term "alkenylsulfanyl" refers to a group in which the hydrogen atom attached to the sulfur atom of a sulfanyl group is replaced with the above-mentioned "alkenyl." Examples include ethylenylsulfanyl and n-propenylsulfanyl.

[0062] The term "alkynylsulfanyl" refers to a group in which the hydrogen atom attached to the sulfur atom of a sulfanyl group is replaced with the above-mentioned "alkynyl." Examples include ethynylsulfanyl and n-propynylsulfanyl.

[0063] The term "alkylsulfinyl" refers to a group in which the above "alkyl" is linked to a sulfinyl group. Examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and isopropylsulfinyl.

[0064] The term "alkenylsulfinyl" refers to a group in which the above "alkenyl" is linked to a sulfinyl group. Examples include ethylenylsulfinyl and n-propenylsulfinyl.

[0065] The term "alkynylsulfinyl" refers to a group in which the above "alkynyl" is linked to a sulfinyl group. Examples include ethynylsulfinyl and n-propynylsulfinyl.

[0066] The term "alkylcarbamoyl" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of a carbamoyl group are replaced with the above-mentioned "alkyl." Examples include methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, and diethylcarbamoyl.

[0067] The term "alkylsulfamoyl" refers to a group in which one or two hydrogen atoms bonded to the nitrogen atom of a sulfamoyl group are replaced with the above-mentioned "alkyl." Examples include methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, and diethylsulfamoyl.

[0068] The term "aromatic carbocyclecarbonyl" refers to a group in which an "aromatic carbocycle" is bonded to a carbonyl group. Examples include phenylcarbonyl and naphthylcarbonyl.

[0069] The term "non-aromatic carbocyclic carbonyl" refers to a group in which a "non-aromatic carbocyclic ring" is attached to a carbonyl group. Examples include cyclopropylcarbonyl, cyclohexylcarbonyl, and cyclohexenylcarbonyl.

[0070] The term "non-aromatic carbocyclic carbonyloxy" refers to a group in which a "non-aromatic carbocyclic carbonyl" is attached to an oxygen atom. Examples include cyclopropylcarbonyloxy, cyclohexylcarbonyloxy, and cyclohexenylcarbonyloxy.

[0071] The term "aromatic heterocyclecarbonyl" refers to a group in which an "aromatic heterocycle" is bonded to a carbonyl group. Examples include pyridylcarbonyl and oxazolylcarbonyl.

[0072] The term "non-aromatic heterocycle carbonyl" refers to a group in which a "non-aromatic heterocycle" is bonded to a carbonyl group. Examples include piperidinylcarbonyl and tetrahydrofurylcarbonyl.

[0073] The term "aromatic carbocycleoxycarbonyl" refers to a group in which an "aromatic carbocycleoxy" is attached to a carbonyl group. Examples include phenyloxycarbonyl and naphthyloxycarbonyl.

[0074] The term "non-aromatic carbocyclic oxycarbonyl" refers to a group in which a "non-aromatic carbocyclic oxy" is bonded to a carbonyl group. Examples include cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, and cyclohexenyloxycarbonyl.

[0075] The term "aromatic heterocycle-oxycarbonyl" refers to a group in which an "aromatic heterocycle-oxy" is bonded to a carbonyl group. Examples include pyridyloxycarbonyl and oxazolyloxycarbonyl.

[0076] The term "non-aromatic heterocycle-oxycarbonyl" refers to a group in which a "non-aromatic heterocycle-oxy" is bonded to a carbonyl group. Examples include piperidinyloxycarbonyl and tetrahydrofuryloxycarbonyl.

[0077] The term "aromatic carbocyclic alkyloxy" means alkyloxy substituted with one or more of the above "aromatic carbocyclic groups". Examples include benzyloxy, phenethyloxy, phenyl-n-propyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, and groups of the following formulae having either R or S stereochemistry or racemic. [ka]

[0078] The term "non-aromatic carbocyclic alkyloxy" refers to an alkyloxy substituted with one or more of the above "non-aromatic carbocyclic groups". "Non-aromatic carbocyclic alkyloxy" also includes "non-aromatic carbocyclic alkyloxy" in which the alkyl portion is substituted with the above "aromatic carbocyclic group". Examples include cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, and groups of the following formulae having either R or S stereochemistry or racemic. [ka]

[0079] The term "aromatic heterocycle alkyloxy" refers to an alkyloxy substituted with one or more of the above-mentioned "aromatic heterocycle groups". "Aromatic heterocycle alkyloxy" also includes "aromatic heterocycle alkyloxy" in which the alkyl portion is substituted with the above-mentioned "aromatic carbocyclic group" and / or "non-aromatic carbocyclic group". Examples include pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, and the following formula groups with either R or S stereochemistry or racemic form. [ka]

[0080] The term "non-aromatic heterocycle alkyloxy" refers to an alkyloxy substituted with one or more of the above "non-aromatic heterocyclic groups". "Non-aromatic heterocycle alkyloxy" also includes "non-aromatic heterocycle alkyloxy" in which the alkyl portion is substituted with the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and / or "aromatic heterocyclic group". Examples include tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, and groups of the following formulae having either R or S stereochemistry or racemic form. [ka]

[0081] The term "aromatic carbocyclic alkyloxycarbonyl" refers to alkyloxycarbonyl substituted with one or more of the above "aromatic carbocyclic groups". Examples include benzyloxycarbonyl, phenethyloxycarbonyl, phenyl-n-propyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, and groups of the following formulae having either R or S stereochemistry or racemic form. [ka]

[0082] The term "non-aromatic carbocyclic alkyloxycarbonyl" refers to an alkyloxycarbonyl substituted with one or more of the above "non-aromatic carbocyclic groups". "Non-aromatic carbocyclic alkyloxycarbonyl" also includes "non-aromatic carbocyclic alkyloxycarbonyl" in which the alkyl portion is substituted with the above "aromatic carbocyclic group". Examples include cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, and groups of the following formulae having either R or S stereochemistry or racemic form. [ka]

[0083] The term "aromatic heterocycle alkyloxycarbonyl" refers to an alkyloxycarbonyl substituted with one or more of the above-mentioned "aromatic heterocycle groups". "Aromatic heterocycle alkyloxycarbonyl" also includes "aromatic heterocycle alkyloxycarbonyl" in which the alkyl portion is substituted with the above-mentioned "aromatic carbocyclic group" and / or "non-aromatic carbocyclic group". Examples include pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyloxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, and the following formula groups with either R or S stereochemistry or racemic form. [ka]

[0084] The term "non-aromatic heterocyclic alkyloxycarbonyl" refers to an alkyloxycarbonyl substituted with one or more of the above "non-aromatic heterocyclic groups". "Non-aromatic heterocyclic alkyloxycarbonyl" also includes "non-aromatic heterocyclic alkyloxycarbonyl" in which the alkyl portion is substituted with the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and / or "aromatic heterocyclic group". Examples include tetrahydropyranylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, piperazinylmethyloxycarbonyl, and groups of the following formulae having either R or S stereochemistry or racemic form. [ka]

[0085] The term "aromatic carbocyclic alkylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of an amino group are replaced with the above-mentioned "aromatic carbocyclic alkyl." Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, and dibenzylamino.

[0086] The term "non-aromatic carbocyclic alkylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of an amino group are replaced with the above-mentioned "non-aromatic carbocyclic alkyl." Examples include cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, and cyclohexylmethylamino.

[0087] The term "aromatic heterocycle alkylamino" refers to a group in which one or two hydrogen atoms bonded to the nitrogen atom of an amino group are replaced with the above-mentioned "aromatic heterocycle alkyl". Examples include pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolylmethylamino and benzoxazolylmethylamino.

[0088] The term "non-aromatic heterocyclic alkylamino" refers to a group in which one or two hydrogen atoms bonded to the nitrogen atom of an amino group are replaced with the above-mentioned "non-aromatic heterocyclic alkyl". Examples include tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino and piperazinylmethylamino.

[0089] The term "aromatic carbocycle sulfanyl" refers to a group in which the hydrogen atom bonded to the sulfur atom of a sulfanyl group is replaced with an "aromatic carbocycle." Examples include phenylsulfanyl and naphthylsulfanyl.

[0090] The term "non-aromatic carbocyclic sulfanyl" refers to a group in which the hydrogen atom bonded to the sulfur atom of a sulfanyl group is replaced with a "non-aromatic carbocyclic ring." Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, and cyclohexenylsulfanyl.

[0091] The term "heteroaromatic sulfanyl" refers to a group in which the hydrogen atom bonded to the sulfur atom of a sulfanyl group is replaced with a "heteroaromatic ring." Examples include pyridylsulfanyl and oxazolylsulfanyl.

[0092] The term "non-aromatic heterocycle sulfanyl" refers to a group in which the hydrogen atom bonded to the sulfur atom of a sulfanyl group is replaced with a "non-aromatic heterocycle." Examples include piperidinylsulfanyl and tetrahydrofurylsulfanyl.

[0093] The term "non-aromatic carbocycle sulfonyl" refers to a group in which a "non-aromatic carbocycle" is attached to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclohexenylsulfonyl.

[0094] The term "aromatic carbocycle sulfonyl" refers to a group in which an "aromatic carbocycle" is attached to a sulfonyl group. Examples include phenylsulfonyl and naphthylsulfonyl.

[0095] The term "aromatic heterocycle sulfonyl" refers to a group in which a "heteroaromatic cycle" is bonded to a sulfonyl group. Examples include pyridylsulfonyl and oxazolylsulfonyl.

[0096] The term "non-aromatic heterocycle sulfonyl" refers to a group in which a "non-aromatic heterocycle" is bonded to a sulfonyl group. Examples include piperidinylsulfonyl and tetrahydrofurylsulfonyl.

[0097] The term "alkyloxyalkyl" refers to a group in which the "alkyloxy" is bonded to the "alkyl." Examples include methoxymethyl, methoxyethyl, and ethoxymethyl.

[0098] The term "alkyloxyalkyloxy" refers to a group in which the "alkyloxy" is bonded to the "alkyloxy". Examples include methoxymethoxy, methoxyethoxy, ethoxymethoxy and ethoxyethoxy.

[0099] The term "aromatic carbocyclic alkyl" means an alkyl substituted with one or more of the above "aromatic carbocyclic groups". Examples include benzyl, phenethyl, phenyl-n-propyl, benzhydryl, trityl, naphthylmethyl, and groups of the following formulae having either R or S stereochemistry or racemic. [ka] Preferred embodiments of "aromatic carbocyclic alkyl" are benzyl, phenethyl or benzhydryl.

[0100] The term "non-aromatic carbocyclic alkyl" refers to an alkyl substituted with one or more of the above "non-aromatic carbocyclic groups". "Non-aromatic carbocyclic alkyl" also includes "non-aromatic carbocyclic alkyl" in which the alkyl portion is substituted with an above "aromatic carbocyclic group". Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and groups of the following formulae having either R or S stereochemistry or racemic: [ka]

[0101] The term "aromatic heterocycloalkyl" refers to an alkyl substituted with one or more of the above "aromatic heterocyclic groups". "Aromatic heterocycloalkyl" also includes "aromatic heterocycloalkyl" in which the alkyl portion is substituted with the above "aromatic carbocyclic group" and / or "non-aromatic carbocyclic group". Examples include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl, and groups of the following formulae having either R or S stereochemistry or racemic form: [ka]

[0102] The term "non-aromatic heterocycloalkyl" refers to an alkyl substituted with one or more of the above "non-aromatic heterocyclic groups". "Non-aromatic heterocycloalkyl" also includes "non-aromatic heterocycloalkyl" in which the alkyl portion is substituted with the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and / or "aromatic heterocyclic group". Examples include tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, and groups of the following formulae having either R or S stereochemistry or racemic form: [ka]

[0103] The term "aromatic carbocyclic alkyloxyalkyl" refers to alkyloxyalkyl substituted with one or more of the above "aromatic carbocyclic groups". Examples include benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, and groups of the following formulae having either R or S stereochemistry or racemic. [ka]

[0104] The term "non-aromatic carbocyclic alkyloxyalkyl" refers to alkyloxyalkyl substituted with one or more of the above "non-aromatic carbocyclic groups". "Non-aromatic carbocyclic alkyloxyalkyl" also includes "non-aromatic carbocyclic alkyloxyalkyl" in which the alkyl moiety attached to the non-aromatic carbocyclic ring is substituted with the above "aromatic carbocyclic group". Examples include cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, and groups of the following formulae having either R or S stereochemistry or racemic form. [ka]

[0105] The term "aromatic heterocycle alkyloxyalkyl" refers to an alkyloxyalkyl substituted with one or more of the above-mentioned "aromatic heterocycle groups". "Aromatic heterocycle alkyloxyalkyl" also includes "aromatic heterocycle alkyloxyalkyl" in which the alkyl moiety attached to the aromatic heterocycle is substituted with the above-mentioned "aromatic carbocyclic group" and / or "non-aromatic carbocyclic group". Examples include pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyloxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, and the following formula groups with either R or S stereochemistry or racemic form. [ka]

[0106] The term "non-aromatic heterocycle alkyloxyalkyl" refers to alkyloxyalkyl substituted with one or more of the above "non-aromatic heterocyclic groups". "Non-aromatic heterocycle alkyloxyalkyl" also includes "non-aromatic heterocycle alkyloxyalkyl" in which the alkyl moiety attached to the non-aromatic heterocycle is substituted with the above "aromatic carbocyclic group", "non-aromatic carbocyclic group" and / or "aromatic heterocyclic group". Examples include tetrahydropyranylmethyloxymethyl, morpholinylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, and groups of the following formulae having either R or S stereochemistry or racemic form. [ka]

[0107] Ring A, Ring B, R 1 , m, R 2 , R 3a , R 3b , R 3c , R 3d , ring C, X, Y, R 4 , R 4C , R 4N , p, q, R 5 , R 6 , R 7 , R 8 , R 9 , R 5C , R 6C , R 7C , R 8C and R 9C Preferred embodiments of are in the compounds represented by formula (I) and are described below: Compounds having any possible combination of those described below are preferred.

[0108] In formula (I), the formula: [ka] The group represented by formula: [ka] It is a group represented by:

[0109] R 1 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl. Preferably, R 1 are each independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. More preferably, R 1 are each independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. In formula (I): [ka] is a group represented as follows: [ka] If Preferably, R 1 is each independently halogen or substituted or unsubstituted alkyl. More preferably, R 1 are each independently a halogen. In formula (I): [ka] is a group represented as follows: [ka] If Preferably, R 1 Each is independently substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.

[0110] R 1 When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino, and the like. R 1 When is a substituted group, more preferred substituents on said substituted group are selected from halogen, and the like.

[0111] m is 0, 1, 2, 3 or 4. Preferably, m is 0, 1 or 2. More preferably, m is 1 or 2. Especially preferably, m is 1.

[0112] When m is 1, in formula (I), the formula: [ka] The group represented by is preferably [ka] It is.

[0113] When m is 1, in formula (I), the formula: [ka] The group represented by is preferably [ka] It is.

[0114] When m is 2, in formula (I), [ka] The group represented by is preferably [ka] It is.

[0115] When m is 2, in formula (I), [ka] The group represented by is preferably [ka] It is.

[0116] R 2 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Preferably, R 2 is halogen or substituted or unsubstituted alkyl. More preferably, R 2 is a substituted or unsubstituted alkyl.

[0117] R 2 When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino, and the like. R 2 When is a substituted group, more preferred substituents on said substituted group are selected from halogen, and the like.

[0118] R 3a , R 3b , R 3c and R 3d are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, provided that R 3a , R3b , R 3c and R 3d is not a hydrogen atom at the same time.

[0119] Preferably, R 3a is a hydrogen atom or a halogen atom. More preferably, R 3a is a hydrogen atom.

[0120] Preferably, R 3b is a hydrogen atom or a halogen atom. More preferably, R 3b is a halogen.

[0121] Preferably, R 3c is a hydrogen atom or a halogen atom. More preferably, R 3c is a hydrogen atom.

[0122] Preferably, R 3d is a hydrogen atom or a halogen atom. More preferably, R 3d is a hydrogen atom.

[0123] R 3b is a halogen, and R 3a , R 3c and R 3d Also preferred are embodiments in which is a hydrogen atom.

[0124] R 3a is a halogen, and R 3b , R 3c and R 3d Also preferred are embodiments in which is a hydrogen atom.

[0125] R 3b and R 3c are each independently a halogen; R 3a and R 3d Also preferred are embodiments in which is a hydrogen atom.

[0126] R 3a and R 3b are each independently a halogen; R 3c and R 3dAlso preferred are embodiments in which is a hydrogen atom.

[0127] R 3a and R 3c are each independently a halogen; R 3b and R 3d Also preferred are embodiments in which is a hydrogen atom.

[0128] R 3a When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, alkyloxy, and the like.

[0129] R 3b When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, alkyloxy, and the like.

[0130] R 3c When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, alkyloxy, and the like.

[0131] R 3d When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, alkyloxy, and the like.

[0132] Ring C is represented as follows: [ka] where the left bond is of the formula: [ka] and is bonded to a group represented by The right bond is of the form: [ka] The compound is bonded to a group represented by the formula: Preferably, ring C is represented as follows: [ka] More preferably, ring C is represented as follows: [ka] Particularly preferably, ring C is represented as follows: [ka] Most preferably, ring C is represented as follows: [ka] Embodiments in which Ring C is represented as follows: [ka] Also preferred are embodiments in which Ring C is represented as follows: [ka] is also preferred.

[0133] X is CH or N.

[0134] Y is CH or N.

[0135] Also preferred is the embodiment where X is N and Y is N.

[0136] Also preferred is the embodiment where X is N and Y is CH.

[0137] Also preferred is the embodiment where X is CH and Y is N.

[0138] R 4 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; Two R's attached to adjacent carbon atoms 4The groups, together with the carbon atoms to which they are attached, may form a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 5- to 6-membered non-aromatic heterocyclic ring; Two R's attached to the same carbon atom 4 The groups, together with the carbon atoms to which they are attached, may form a substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic ring or a substituted or unsubstituted 3- to 6-membered non-aromatic heterocyclic ring; The Two R's 4 The groups together may form a (C2-C4) bridge, one of the carbon atoms of the bridge may be optionally replaced by an oxygen atom or a nitrogen atom; each carbon atom of the bridge may be independently selected from the group consisting of R 4C and the nitrogen atom of said bridge, if present, is substituted with a substituent selected from R 4N is substituted with a substituent selected from:

[0139] Preferably, R 4 is each independently halogen or substituted or unsubstituted alkyl. More preferably, R 4 Each is independently substituted or unsubstituted alkyl. The Two R's 4 Also preferred are embodiments in which the groups together form a (C2-C4) bridge. For example, such embodiments include the following: [ka] Two R's attached to adjacent carbon atoms 4 Also preferred are embodiments in which groups, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted 5-6 membered non-aromatic carbocyclic ring. For example, such embodiments include the following (as racemic or stereodefined cis or trans fused isomers): [ka] Two R's attached to the same carbon atom 4Also preferred are embodiments in which groups, taken together with the carbon atom to which they are attached, form a substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic ring. For example, such embodiments include the following: [ka]

[0140] R 4 When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino, and the like.

[0141] R 4C are each independently a hydrogen atom, halogen, hydroxy, cyano, or substituted or unsubstituted alkyl. Preferably, R 4C are each independently a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl. More preferably, R 4C are each independently a hydrogen atom.

[0142] R 4C When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, amino, alkyloxy, alkylamino, and the like.

[0143] R 4N are each independently a hydrogen atom or a substituted or unsubstituted alkyl. Preferably, R 4N Each is independently substituted or unsubstituted alkyl.

[0144] R 4N When is a substituted group, preferred substituents on said substituted group are selected from halogen, and the like.

[0145] p is 0 or 1. Preferably, p is 1.

[0146] q is 0, 1, 2, 3 or 4. Preferably, q is 0, 1 or 2. More preferably, q is 1 or 2. Especially preferably, q is 1.

[0147] R 5 is CR 5C or N;R 6 is CR 6C or N;R 7 is CR 7C or N;R 8 is CR 8C or N;R 9 is CR 9C or N; where R 5 , R 6 , R 7 , R 8 and R 9 is not N at the same time. Preferably, R 5 is CR 5C It is. Preferably, R 6 is CR 6C It is. Preferably, R 7 is CR 7C It is. Preferably, R 8 is CR 8C It is. Preferably, R 9 is CR 9C It is.

[0148] R 5C , R 6C , R 7C , R 8C and R 9Care each independently a hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, or pentafluorothio.

[0149] Preferably, R 5C and R 9C are each independently a hydrogen atom or a halogen atom. More preferably, R 5C and R 9C is a hydrogen atom.

[0150] R 5C When is a substituted group, preferred substituents on said substituted group are selected from halogen, and the like.

[0151] R 9C When is a substituted group, preferred substituents on said substituted group are selected from halogen, and the like.

[0152] Preferably, R 6C and R 8C are each independently a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkyloxy. More preferably, R 6C and R 8C are each independently a hydrogen atom, a halogen, or a substituted or unsubstituted alkyloxy. Particularly preferably, R 6C and R 8C Each of the groups independently is a hydrogen atom or a substituted or unsubstituted alkyloxy. Most preferably, R 6C and R 8C is a hydrogen atom.

[0153] R6C When is a substituted group, preferred substituents on said substituted group are selected from halogen, and the like.

[0154] R 8C When is a substituted group, preferred substituents on said substituted group are selected from halogen, and the like.

[0155] Preferably, R 7C is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted non-aromatic carbocyclic oxy. More preferably, R 7C is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. Particularly preferably, R 7C is substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. Most preferably, R 7C is a substituted or unsubstituted alkyloxy, including trihaloalkyloxy (such as OCF3).

[0156] R 7C When is a substituted group, preferred substituents on said substituted group are selected from halogen, hydroxy, amino, alkyloxy, alkylamino, non-aromatic carbocyclic groups, and the like. R 7C When is a substituted group, more preferred substituents on said substituted group are selected from halogen, and the like.

[0157] Preferable combinations of substituents in the compound represented by formula (I) include the following 1) to 6). 1) Formula: [ka] is a group represented as follows: [ka] and; R 1 are each independently halogen or substituted or unsubstituted alkyl; R 2 are each independently halogen or substituted or unsubstituted alkyl; R 3b is a halogen; R 3a , R 3c and R 3d is a hydrogen atom; ring C is represented as follows, in either R or S stereochemistry or racemic: [ka] R 4 is a substituted or unsubstituted alkyl; R 5 , R 6 , R 8 and R 9 is CH; R 7 CR 7C ;R 7C is a substituted or unsubstituted alkyloxy, including trihaloalkyloxy (such as OCF3), 2) Formula: [ka] is a group represented as follows: [ka] and; R 1 are each independently a halogen; R 2 are each independently substituted or unsubstituted alkyl; R 3b is a halogen; R 3a , R 3c and R 3d is a hydrogen atom; ring C is represented as follows, in either R or S stereochemistry or racemic: [ka] R 4 is a substituted or unsubstituted alkyl; R 5 , R6 , R 8 and R 9 is CH; R 7 CR 7C ;R 7C is a substituted or unsubstituted alkyloxy, including trihaloalkyloxy (such as OCF3), 3) Formula: [ka] is a group represented as follows: [ka] and; R 1 are each independently a halogen; R 2 are each independently substituted or unsubstituted alkyl; R 3a is a halogen; R 3b , R 3c and R 3d is a hydrogen atom; ring C is represented as follows: [ka] R 5 , R 6 , R 8 and R 9 is CH;R 7 is CR 7C ;R 7C is a substituted or unsubstituted alkyl, 4) Formula: [ka] is a group represented as follows: [ka] and; R 1 are each independently a halogen; R 2 are each independently substituted or unsubstituted alkyl; R 3bis a halogen; R 3a , R 3c and R 3d is a hydrogen atom; ring C is represented as follows, in either R or S stereochemistry or racemic: [ka] R 4 is a substituted or unsubstituted alkyl; R 5 , R 6 , R 8 and R 9 is CH; R 7 CR 7C ;R 7C is a substituted or unsubstituted alkyloxy, including trihaloalkyloxy (such as OCF3), 5) Formula: [ka] is a group represented as follows: [ka] and; R 1 are each independently substituted or unsubstituted alkyl; R 2 are each independently substituted or unsubstituted alkyl; R 3b is a halogen; R 3a , R 3c and R 3d is a hydrogen atom; ring C is represented as follows, in either R or S stereochemistry or racemic: [ka] R 4 is a substituted or unsubstituted alkyl; R 5 , R 6 , R 8 and R 9 is CH; R 7 CR 7C ;R 7Cis a substituted or unsubstituted alkyloxy, including trihaloalkyloxy (such as OCF3), 6) Ring A and ring B are represented as follows: [ka] R 1 are each independently substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy; R 2 are each independently halogen or substituted or unsubstituted alkyl; R 3b is a halogen; R 3a , R 3c and R 3d is a hydrogen atom; ring C is represented as follows: [ka] R 4 is a substituted or unsubstituted alkyl; R 5 , R 6 , R 8 and R 9 is CH; R 7 CR 7C ;R 7C is a substituted or unsubstituted alkyloxy, including trihaloalkyloxy (such as OCF3).

[0158] The compounds of formula (I) are not limited to a particular isomer, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers or rotamers), racemates or mixtures thereof.

[0159] One or more hydrogen, carbon and / or other atoms in the compounds of formula (I) may be replaced by isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, e.g., 2 H, 3 H, 11 C. 13 C.14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl. The compounds of formula (I) include compounds replaced with these isotopes. The compounds replaced with the above isotopes are useful as pharmaceuticals, and include all radiolabeled compounds of the compounds of formula (I). The "radiolabeling method" in the manufacture of the "radiolabeled compound" is encompassed by the present invention, and the "radiolabeled compound" is useful for research on the pharmacokinetics of metabolized drugs, research on binding assays, and / or diagnostic tools.

[0160] Radiolabeled compounds of the compound of formula (I) can be prepared using methods well known in the art of the present invention. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a compound of formula (I) through catalytic dehalogenation reaction with tritium. This method involves reacting a suitable halogenated precursor of the compound of formula (I) with tritium gas in the presence of a suitable catalyst such as Pd / C and in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol.1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 By using raw materials containing C, 14 C-labeled compounds can be prepared.

[0161] Pharmaceutically acceptable salts of the compounds of formula (I) include, for example, salts with alkali metals (e.g., lithium, sodium or potassium), alkaline earth metals (e.g., calcium or barium), magnesium, transition metals (e.g., zinc or iron), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline or quinoline), amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid or hydroiodic acid) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid). These salts can be formed by conventional methods.

[0162] The compound of formula (I) or its pharma- ceutically acceptable salt may form a solvate (e.g., hydrate), cocrystal, and / or crystalline polymorph. The present invention encompasses these various solvates, cocrystals, and crystalline polymorphs. A "solvate" may be one in which any number of solvent molecules (e.g., water molecules) are coordinated with the compound of formula (I). When the compound of formula (I) or its pharma- ceutically acceptable salt is left in the air, the compound may absorb water, resulting in the attachment of the adsorbed water or the formation of a hydrate. Recrystallization of the compound of formula (I) or its pharma- ceutically acceptable salt may produce a crystalline polymorph. "Cocrystal" means that the compound of formula (I) or its salt and a paired molecule are present in the same crystal lattice, and the cocrystal may be formed with any number of paired molecules.

[0163] The compound of formula (I) of the present invention or its pharma- ceutically acceptable salt may form a prodrug. The present invention also includes such various prodrugs. Prodrugs are derivatives of the compounds of the present invention that have a chemically or metabolically decomposable group, and compounds that are converted to the pharma- ceutical active compounds of the present invention through solvolysis in vivo or under physiological conditions. Prodrugs include compounds that are converted to the compounds of formula (I) through enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, compounds that are converted to the compounds of formula (I) through hydrolysis by gastric acid, etc. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs themselves may have some activity.

[0164] When the compound of formula (I) or a pharma- ceutically acceptable salt thereof has hydroxyl group(s), prodrugs include, for example, acyloxy and sulfonyloxy derivatives prepared by reacting the compound having hydroxyl group(s) with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride and mixed anhydride, or with a condensing agent. For example, these include CHCOO-, C2H5COO-, tert-BuCOO-, C2H5 ... 15 H 31 These include COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O-PhSO3-, PhSO3- and p-CH3PhSO3-.

[0165] The term "pharmaceutically acceptable" means prophylactically or therapeutically harmless.

[0166] The general synthetic procedures of the compounds of the present invention are described below. The starting materials and reaction reagents used in such synthesis are commercially available, or can be synthesized according to methods well known in the art using commercially available compounds. In addition, extraction, purification, etc. can be carried out according to methods practiced in the art. In all the following steps, when the reaction has a substituent such as hydroxy, mercapto, amino, formyl, carbonyl, or carboxy, the substituent can be protected in advance by the method described in Protective Groups in organic Synthesis, and Theodora W Greene (John Wiley & Sons, hereinafter referred to as Document A), and the protective group can be removed at a desired stage. Furthermore, in all the steps, the order of the steps to be performed can be changed as appropriate, and each intermediate can be isolated and used in the next step. All of the reaction time, reaction temperature, solvent, reagent, protective group, etc. are merely examples and are not limited as long as they do not adversely affect the reaction.

[0167] For example, the compounds of the present invention represented by formula (I) can be prepared according to the general procedures described below. The compounds of the present invention can also be prepared according to other methods based on knowledge in organic chemistry.

[0168] Preparation of compound a3 [ka] During the ceremony, PG is an amino protecting group such as Boc or Cbz, and R a1 is halogen, triflate, nonaflate, mesylate or tosylate, and the other symbols are as defined above. Compound a1 is reacted with a2 in the presence of a base to give compound a3. Examples of solvents include toluene, DMF, DMA, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane, and the like, which can be used alone or in combination. Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a1. The reaction temperature can be from room temperature to 200° C., preferably from 50° C. to 150° C., and the reaction can be carried out in a closed tube, if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0169] Preparation of compound a5 [ka] In the formula, each symbol is as defined above. Compound a5 can be obtained by reacting compound a3 with a deprotecting agent, followed by reaction with a4 in the presence of palladium, a ligand and a base. Examples of reaction solvents for the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, etc., and these solvents may be used alone or in combination. Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum trichloride, bromocatecholborane, trimethylsilyl chloride, trimethylsilyl triflate, etc. The amount of the deprotecting agent can be 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents, of compound a4. Examples of palladium include palladium acetate, Pd(PPh3)4, PdCl2(PPh3)2, Pd2(dba)3, etc. The amount of palladium can be 0.01 to 5 molar equivalents of compound a4, preferably 0.01 to 1 molar equivalents. Examples of the ligand include 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), etc. The amount of the ligand can be 0.01 to 5 molar equivalents of compound a3, preferably 0.01 to 1 molar equivalents. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a4. Examples of reaction solvents include methanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200° C., preferably from 50° C. to 150° C., and the reaction can be carried out in a closed tube, if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0170] Preparation of compound a6 [ka] In the formula, each symbol is as defined above. Compound a6 can be obtained by reacting a1 and a4 in the presence of palladium, a ligand and a base. Examples of palladium include palladium acetate, Pd(PPh3)4, PdCl2(PPh3)2, Pd2(dba)3, etc. The amount of palladium can be 0.01 to 5 molar equivalents of compound a1, preferably 0.01 to 1 molar equivalents. Examples of the ligand include 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), etc. The amount of the ligand can be 0.01 to 5 molar equivalents of compound a1, preferably 0.01 to 1 molar equivalents. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a1. Examples of reaction solvents include methanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200° C., preferably from 50° C. to 150° C., and the reaction can be carried out in a closed tube, if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0171] Preparation of compound a5 [ka] In the formula, each symbol is as defined above. Compound a5 can be obtained by reacting compound a6 with a deprotecting agent, followed by reaction with a2 in the presence of a base. Examples of reaction solvents for the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, etc., and these solvents may be used alone or in combination. Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum trichloride, bromocatecholborane, trimethylsilyl chloride, trimethylsilyl triflate, etc. The amount of the deprotecting agent can be 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents, of compound a2. Examples of solvents include toluene, DMF, DMA, dimethylsulfoxide, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane, etc., and these solvents may be used alone or in combination. Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU, etc. The amount of the base can be 1 to 10 molar equivalents of compound a2, preferably 1 to 5 molar equivalents. The reaction temperature can be from room temperature to 200° C., preferably from 50° C. to 150° C., and the reaction can be carried out in a closed tube, if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0172] Preparation of compound a7 [ka] In the formula, each symbol is as defined above. Compound a7 can be obtained by reacting compound a5 with a reducing agent. Examples of reaction solvents include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene, etc., and these solvents may be used alone or in combination. Examples of the reducing agent include Pd on carbon and hydrogen, Pd(OH)2 and hydrogen, NiCl2(H2O)6 and sodium borohydride, lithium aluminum hydride, etc. The amount of the reducing agent can be 1 to 100 molar equivalents of compound a5, preferably 1 to 10 molar equivalents. The reaction temperature may be from 0°C to 200°C, preferably from 0°C to 100°C. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0173] Preparation of compound a9 [ka] During the ceremony, R a2 is a halogen, triflate, nonaflate, mesylate, tosylate, bornic acid or boronate; R a3 is triflate, nonaflate, mesylate, tosylate, bornic acid or boronate, and the other symbols are as defined above. Compound a1 is reacted with a8 in the presence of palladium and a base to give compound a9. Examples of palladium include palladium acetate, Pd(PPh3)4, PdCl2(PPh3)2, Pd2(dba)3, PdCl2(dppf), etc. The amount of palladium can be 0.01 to 5 molar equivalents of compound a1, preferably 0.01 to 1 molar equivalents. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a1. Examples of reaction solvents include water, DMF, DMA, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200° C., preferably from 50° C. to 150° C., and the reaction can be carried out in a closed tube, if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0174] Preparation of compound a10 [ka] In the formula, each symbol is as defined above. Compound A10 can be obtained by reacting compound A4 with a deprotecting agent, followed by reaction with compound A9 in the presence of palladium, a ligand and a base. Examples of reaction solvents for the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, etc., and these solvents may be used alone or in combination. Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum trichloride, bromocatecholborane, trimethylsilyl chloride, trimethylsilyl triflate, etc. The amount of the deprotecting agent can be 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents, of compound a4. Examples of palladium include palladium acetate, Pd(PPh3)4, PdCl2(PPh3)2, Pd2(dba)3, etc. The amount of palladium can be 0.01 to 5 molar equivalents of compound a4, preferably 0.01 to 1 molar equivalents. Examples of the ligand include 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), etc. The amount of the ligand can be 0.01 to 5 molar equivalents of compound a4, preferably 0.01 to 1 molar equivalent. Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a4. Examples of reaction solvents include methanol, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, and the like, and these solvents may be used alone or in combination. The reaction temperature can be from room temperature to 200° C., preferably from 50° C. to 150° C., and the reaction can be carried out in a closed tube, if necessary. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0175] Preparation of compound a11 [ka] In the formula, each symbol is as defined above. Compound a11 can be obtained by reacting compound a10 with a reducing agent. Examples of reaction solvents include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene, etc., and these solvents may be used alone or in combination. Examples of the reducing agent include NiCl2(H2O)6 and sodium borohydride, lithium aluminum hydride, borane tetrahydrofuran, borane dimethyl sulfide, etc. The amount of the reducing agent can be 1 to 100 molar equivalents of compound a10, preferably 1 to 10 molar equivalents. The reaction temperature may be from 0°C to 200°C, preferably from 0°C to 100°C. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0176] Preparation of compound a13 [ka] In the formula, each symbol is as defined above. Compound a13 can be obtained by reacting compound a7 with a carbocyclic acid (compound a12) in the presence of a condensing agent and a base. Examples of reaction solvents include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, etc., and these solvents may be used alone or in combination. Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12. Examples of the condensing agent include HATU, WSC, DCC, HOBt, etc. The amount of the condensing agent can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of the compound a12. The carboxylic acid can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a7. The reaction temperature may be from ice-cooling to reflux temperature, preferably room temperature. The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

[0177] Preparation of compound a14 [ka] In the formula, each symbol is as defined above. Compound A14 can be obtained by reacting compound A11 with a carbocyclic acid (compound A12) in the presence of a condensing agent and a base. Examples of reaction solvents include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, etc., and these solvents may be used alone or in combination. Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12. Examples of the condensing agent include HATU, WSC, DCC, HOBt, etc. The amount of the condensing agent can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of the compound a12. The carboxylic acid can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a11. The reaction temperature may be from ice-cooling to reflux temperature, preferably room temperature. The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

[0178] Preparation of compound a15 [ka] In the formula, each symbol is as defined above. Compound a15 can be obtained by reacting compound a10 with a reducing agent. Examples of reaction solvents include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene, etc., and these solvents may be used alone or in combination. Examples of the reducing agent include Pd on carbon and hydrogen, Pd(OH)2 and hydrogen, etc. The amount of the reducing agent can be 1 to 100 molar equivalents of the compound a10, preferably 1 to 10 molar equivalents. The reaction temperature may be from 0°C to 200°C, preferably from 0°C to 100°C. The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0179] Preparation of compound a16 [ka] In the formula, each symbol is as defined above. Compound A16 can be obtained by reacting compound A15 with a carbocyclic acid (compound A12) in the presence of a condensing agent and a base. Examples of reaction solvents include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, etc., and these solvents may be used alone or in combination. Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, etc. The amount of the base can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12. Examples of the condensing agent include HATU, WSC, DCC, HOBt, etc. The amount of the condensing agent can be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of the compound a12. The carboxylic acid can be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound a15. The reaction temperature may be from ice-cooling to reflux temperature, preferably room temperature. The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

[0180] The compounds of the present invention are useful in the treatment or prevention of mycobacterial infections, particularly nontuberculous mycobacterial infections. Such compounds may act by interfering with ATP synthase in pathogenic mycobacteria, with inhibition of cytochrome bc1 activity as the primary mode of action. The compounds of the present invention not only have the above-mentioned activity, but also have pharmaceutical utility and have any or all of the following excellent characteristics: a) It has weak inhibitory activity against CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) The compound exhibits excellent pharmacokinetics, including high bioavailability, moderate clearance, and high distribution to targeted tissues. c) The compound has high metabolic stability. d) The compound does not have an irreversible inhibitory effect on CYP enzymes (e.g., CYP3A4) when the concentration is within the range of measurement conditions described herein. e) The compound is not mutagenic. f) The compounds are associated with a lower cardiovascular risk. g) The compound has high solubility. h) The compound is less likely to induce drug metabolizing enzymes i) the compounds have a lower risk of phototoxicity; j) the compounds have a lower risk of hepatotoxicity; k) the compounds have a lower risk of nephrotoxicity; l) the compounds have a lower risk of gastrointestinal disorders; m) The compound has strong potency.

[0181] The administration route of the medicament of the present invention can be either oral or parenteral, and is not particularly limited thereto.

[0182] In the case of oral administration, it can be administered in the form of an oral solid preparation (e.g., tablet, powder, granule, capsule, pill, film), an oral liquid (e.g., suspension, emulsion, elixir, syrup, lemonade, alcohol, fragrance solution, extract, decoction, tincture), etc., by a conventional method. Tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets. Powders and granules can be dry syrups. Capsules can be soft capsules, microcapsules, or sustained-release capsules.

[0183] In the case of parenteral administration, any of the commonly used forms of injections, eye drops, and topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, drops, coatings, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, and suppositories) can be suitably administered. Injections can be in the form of emulsions such as O / W, W / O, O / W / O, or W / O / W types.

[0184] Optionally, the effective amount of the compound used in the medicament of the present invention may be mixed with various pharmaceutical additives, such as excipients, binders, disintegrants and / or lubricants, suitable for the dosage form, as necessary to obtain a pharmaceutical composition. Furthermore, by appropriately changing the effective amount of the compound used in the medicament of the present invention, the dosage form and / or various pharmaceutical additives, the pharmaceutical composition can be used for children, elderly people, critically ill patients or surgery. The pediatric pharmaceutical composition is preferably administered to patients under 12 years old or under 15 years old. The pediatric pharmaceutical composition can also be administered to patients under 4 weeks old, 4 weeks old to under 1 year old, 1 year old to under 7 years old, 7 years old to under 15 years old or 15 years old to 18 years old. The elderly pharmaceutical composition is preferably administered to patients over 65 years old.

[0185] The dosage of the pharmaceutical composition of the present invention should be determined taking into consideration the age and weight of the patient, the type and severity of the disease, the route of administration, etc., and the usual oral dosage is 0.05 to 100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of parenteral administration, the dosage varies greatly depending on the route of administration, but the usual dosage is 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. The dosage can be administered once a day or in divided doses.

[0186] Generally, a pharmaceutical composition contains an active compound in an amount effective to achieve its intended purpose. In one embodiment, a therapeutically effective amount refers to an amount effective to prevent or inhibit the onset or progression of a disease characterized by mycobacterial infection or activity in the subject being treated. Determining an effective amount is within the capabilities of one skilled in the art in light of the description provided herein.

[0187] In some embodiments, the medicaments of the invention are suitable for the treatment and / or prevention of diseases and disorders characterized by mycobacterial activity or infection. The mycobacteria can be pathogenic or non-pathogenic. Mycobacteria can be gram positive or gram negative.

[0188] In some embodiments, the medicaments of the present invention are suitable for the treatment of tuberculous, lepromatous and non-tuberculous mycobacteria in humans (both immunocompetent and immunocompromised) and animals. These non-limiting examples include, but are not limited to, the following species and strains: tuberculous mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, Mycobacterium canetti; lepromatous mycobacteria, such as Mycobacterium leprae, Mycobacterium lepromatosis; non-tuberculous mycobacteria, such as Mycobacterium abscessus, Mycobacterium abscessus complex, Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, Mycobacterium canetti; complex, Mycobacterium avium, Mycobacterium intracellularae, Mycobacterium avium complex, Mycobacterium kansasii, Mycobacterium malmoense, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium flavences, Mycobacterium scrofulaceum, Mycobacterium chelonae, Mycobacterium Mycobacterium peregrinum, Mycobacterium haemophilum, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium ulcerans, Mycobacterium gordonae, Mycobacterium haemophilum, Mycobacterium mucogenicummucogenicum, Mycobacterium nonchromogenicum, Mycobacterium terrae, Mycobacterium terrae complex complex), Mycobacterium asiaticum, Mycobacterium serrata, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium szulgai, Mycobacterium serrata, Mycobacterium conspicuum, Mycobacterium genavense, Mycobacterium immunogenum, Mycobacterium xenopi.

[0189] In some embodiments, the medicaments of the invention are suitable for the treatment of non-mycobacterial infectious diseases in humans (both immunocompetent and immunocompromised) and animals.

[0190] In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with a non-pathogenic mycobacterial strain, Mycobacterium smegmatis, Mycobacterium vaccae, Mycobacterium aurum, or a combination thereof.

[0191] In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with Gram-positive bacteria, Staphylococcus aureus (S. aureus), Micrococcus luteus (M. luteus), or a combination thereof.

[0192] In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with Gram-negative bacteria, Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii (A. baumannii), or a combination thereof.

[0193] In some embodiments, the subject is known or suspected to be in need of treatment for one or more diseases associated with a pathogenic mycobacterial strain, Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, M. kansasaii, H37Rv, M. africanum, M. canettii, M. caprae, M. microti, M. mungi, M. pinnipedii, M. leprae, M. avium, M. tuberculosis complex, M. tuberculosis, or combinations thereof.

[0194] In some embodiments, the subject is infected with a non-pathogenic mycobacterial strain, Mycobacterium smegmatis, Mycobacterium vacciniae, Mycobacterium aurum, gram-positive bacteria, Staphylococcus aureus, Micrococcus luteus, gram-negative bacteria, Pseudomonas aeruginosa, Acinetobacter baumannii, pathogenic mycobacterial strains, Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium purpurea, Mycobacterium purpurea, Mycobacterium tuberculosis ... Known or suspected to require treatment for one or more diseases associated with Um kansasai, H37Rv, Mycobacterium africanum, Mycobacterium canettii, Mycobacterium caprae, Mycobacterium microti, Mycobacterium mungi, Mycobacterium pinipedii, Mycobacterium avium, Mycobacterium tuberculosis complex, tuberculosis or a combination thereof.

[0195] In some embodiments, the non-pathogenic mycobacterial strains include Mycobacterium smegmatis, Mycobacterium vacciniae, Mycobacterium aurum, gram-positive bacteria include Staphylococcus aureus, Micrococcus luteus, gram-negative bacteria include Pseudomonas aeruginosa, Acinetobacter baumannii, pathogenic mycobacterial strains include Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, H37Rv, Mycobacterium africaense, Mycobacterium avium, Mycobacterium spp. In one embodiment, a method is provided for killing or inhibiting the growth of one or more members of the population of Mycobacterium canum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium microti, Mycobacterium mungi, Mycobacterium pinnipedii, Mycobacterium avium, Mycobacterium tuberculosis complex, Mycobacterium tuberculosis, or combinations thereof, by contacting the one or more members of the population with a compound or composition used in the invention. EXAMPLES

[0196] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0197] The compounds represented by formula (I) of the present invention can be prepared by reference to WO 2011 / 057145, WO 2017 / 049321, WO 2011 / 113606, WO 2014 / 015167, the entire contents of each of which are incorporated herein by reference as if set forth in detail.

[0198] Additionally, the abbreviations used herein have the following meanings: Me: Methyl Et: Ethyl Bu: butyl Ph: Phenyl PPh3: Triphenylphosphine Ac: Acetyl EtOAc: ethyl acetate DMF: N,N-dimethylformamide DMA: N,N-Dimethylacetamide TFA: Trifluoroacetic acid DMSO: Dimethyl sulfoxide THF: tetrahydrofuran WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium; 3-oxide, hexafluorophosphate DCC: N,N'-dicyclohexylcarbodiimide HOBt: Hydroxybenzotriazole Boc: t-butoxycarbonyl t:Third class Cbz: benzyloxycarbonyl dppf: 1,1'-bis(diphenylphosphino)ferrocene Pd2(dba)3: Tris(dibezylideneacetone)dipalladium PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) PdCl2(PPh3)2: Bis(triphenylphosphine)palladium J Chloride

[0199] NMR analysis of each example was performed at 400 MHz using deuterated dimethylsulfoxide (d6-DMSO) or deuterated chloroform (CDCl3). When presenting NMR data, not all measured peaks may be listed. In this specification, "RT" means the retention time of LC / MS (liquid chromatography / mass spectrometry), and the measurement conditions are as follows. (Method A) The UHPLC / MS data of the compounds were measured under the following conditions. Column: ACQUITY UPLC® BEH C18 (1.7 μm, inner diameter 50 × 2.1 mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, and [B] is an acetonitrile solution containing 0.1% formic acid. Gradient: A linear gradient from 5% to 100% solvent [B] over 3.5 min was performed, with 100% solvent [B] maintained for 0.5 min. (Method B) The UHPLC / MS data of the compounds were measured under the following conditions. Column: ACQUITY UPLC® BEH C18 (1.7 μm, inner diameter 50 × 2.1 mm) (Waters) Flow rate: 0.8mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, and [B] is acetonitrile. Gradient: A linear gradient from 5% to 100% solvent [B] over 3.5 min was performed, with 100% solvent [B] maintained for 0.5 min. Hereinafter, MS(m / z) indicates the value observed by mass spectrometry. [Example 1]

[0200] Preparation of Compound I-1-3 [ka] Process 1 To a solution of compound 1 (1 g, 7.19 mmol) in DMA (5 mL), K2CO3 (1.49 g, 10.78 mmol) and compound 2 (0.792 g, 7.91 mmol) were added, and the solution was stirred at 100° C. for 4.5 h. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over sodium sulfate and filtered. After the organic layer was concentrated under reduced pressure, the residue was washed with hexane to give compound 3 (1.01 g, yield: 64%) as a solid. 1H-NMR(CDCl3)δ:7.38-7.33(1H,m),7.27(1H,dd,J=12.9,1.9 Hz),6.91(1H,t,J=8.2 Hz),3.50-3.41(2H,m),3.12-2.98(3H,m),2.88-2.77(1H,m),2.52-2.44(1H,m),1.12(3H,d,J=6.0 Hz). Process 2 To a solution of compound 3 (510 mg, 2.33 mmol) in toluene (5.0 mL), 1-bromo-4-(trifluoromethyl)benzene 4 (576 mg, 2.56 mmol), Pd(OAc)2 (52.2 mg, 0.233 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (217 mg, 0.465 mmol) and sodium t-butoxide (447 mg, 4.65 mmol) were added, and the solution was stirred at 100°C for 1 h. Water and ethyl acetate were added to the reaction solution. The oranic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give compound 5 (543 mg, yield: 64%) as a yellow solid. 1H-NMR(CDCl3)δ:7.39(1H,dd,J=8.4,1.9 Hz),7.30(1H,dd,J=12.5,1.9 Hz),7.14(2H,d,J=8.3 Hz),6.95(1H,t,J=9.2 Hz),6.92(2H,d,J=8.3 Hz),3.99-3.90(1H,m),3.55-3.50(1H,m),3.42-3.40(1H,m),3.35-3.26(3H,m),3.20-3.11(1H,m),1.16(3H,d,J=6.4 Hz) Process 3 A solution of compound 5 (546 mg, 1.50 mmol) in MeOH (15 mL) was added to 5% Pd-C (320 m g, 0.150 mmol) and concentrated HCl (1.5 mL) were added and the solution was stirred under hydrogen atmosphere at room temperature for 5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the reaction mixture was added aqueous NaOH and ethyl acetate. The oranic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure to give compound 6 (440 mg, yield: 80%) as a yellow solid. 1H-NMR(CDCl3)δ:7.16-7.10(2H,m),7.07-7.00(2H,m),6.98-6.88(3H,m),3.99-3.91(1H,m), 3.86-3.80(2H,m),3.40-3.21(4H,m),3.17-3.10(1H,m),3.05-2.99(1H,m),1.19(3H,d,J=6.4 Hz). Process 4 To a solution of compound 6 (80 mg, 0.209 mmol) in acetonitrile (2.0 mL), compound 7 (52 mg, 0.230 mmol), triethylamine (0.087 mL, 0.626 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (48.6 mg, 0.313 mmol) and HOBt (28.2 mg, 0.209 mmol) were added, and the solution was stirred at 80° C. for 1 h. Water was added to the reaction solution, and it was extracted with ethyl acetate. The oranic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (CHCl3 / methanol) to obtain compound I-1-3 (55 mg, yield: 45%) as a white solid. LC / MS Method A: m / z=590.2. [M+H]+, retention time: 3.0 minutes [Example 2]

[0201] Preparation of compound 8 [ka] To a solution of compound 7 (20 g, 89 mmol) in acetonitrile (200 mL), N-methylmorpholine (19.6 mL, 178 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (18.8 g, 98 mmol) and HOBt (18.01 g, 98 mmol) were added, and the solution was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the reaction mixture was filtered. The residue was washed with water and dried under reduced pressure to give compound 8 (19.4 g, yield: 64%) as a solid. 1H-NMR(CDCl3)δ:9.26(1H,d,J=1.3 Hz),8.14(1H,d,J=8.4 Hz),7.74(1H,d,J=9.4 Hz),7.62-7.44(4H,m),3.37(2H,q,J=7.5 Hz),1.53(3H,t,J=7.5 Hz). [Example 3]

[0202] Preparation of Compound 10 [ka] To a solution of compound 9 (4.9 g, 23.7 mmol) in acetonitrile (99 mL), N-methylmorpholine (2.86 mL, 26 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (4.04 g, 26 mmol) and HOBt (3.2 g, 23.7 mmol) were added, and the solution was stirred at room temperature for 22 hours. Water was added to the reaction solution, and the reaction mixture was filtered. The residue was washed with water and dried under reduced pressure to give compound 10 (5.09 g, yield: 66%) as a white solid. 1H-NMR(CDCl3)δ:9.18(1H,dd,J=7.5,5.4 Hz),8.14(1H,dt,J=8.4,0.9 Hz),7.59(1H,dd,J=16.1,8.0 Hz),7.54-7.40(3H,m),6.98(1H,td,J=7.5,2.7 Hz),3.35(2H,q,J=7.5 Hz),1.52(3H,t,J=7.5 Hz). [Example 4]

[0203] Preparation of Compound I-1-38 [ka] To a solution of compound 6 (70 mg, 0.183 mmol) in acetonitrile (1.0 mL), compound 9 (41.8 mg, 0.201 mmol), triethylamine (0.051 mL, 0.365 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (52.5 mg, 0.274 mmol) and HOBt (24.7 mg, 0.183 mmol) were added, and the solution was stirred at 50 °C for 1 h. Saturated NaHCO3 aqueous solution was added to the reaction solution, and it was extracted with ethyl acetate. The organic (oranic) layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give compound I-1-38 (78 mg, yield: 75%) as a white solid. 1H-NMR(CDCl3)δ:9.44(1H,t,J=5.6 Hz),7.22(1H,s),7.14-7.07(4H,m),6.97-6.92(3H,m),6.80(1H,t,J=7.3 Hz),6.06(1H,s),4.63(2H,d,J=3.8 Hz),3.95(1H,d,J=2.0 Hz),3.38-3.27(4H,m),3.17-3.14(1H,m),3.06-2.95(3H,m),1.44-1.40(3H,m),1.19(3H,d,J=4.5 Hz). LC / MS method B: m / z=574.25[M+H]+, retention time: 2.99 minutes [Example 5]

[0204] Preparation of Compound I-1-2 [ka] To a solution of compound 6 (1.5 g, 3.91 mmol) in dichloromethane (1.0 mL), compound 11 (1.32 g, 4.3 mmol) and triethylamine (0.814 mL, 5.87 mmol) were added, and the solution was stirred at room temperature for 15 hours. The reaction solution was purified by amino silica gel and silica gel chromatography (CHCl3 / methanol) to obtain compound I-1-2 (1.76 g, yield: 81%) as a white solid. LC / MS method A: m / z=574.25[M+H]+, retention time: 2.99 minutes [Example 6]

[0205] Preparation of Compound I-1-70 [ka] To a solution of compound 6 (80 mg, 0.209 mmol) in dichloromethane (0.8 mL), compound 12 (64 m g, 0.209 mmol) and triethylamine (0.087 mL, 0.626 mmol) were added, and the solution was stirred at room temperature for 15 hours. The reaction solution was purified by amino silica gel and silica gel chromatography (CHCl3 / methanol) to give compound I-1-70 (47 mg, yield: 41%) as a white solid. LC / MS method A: m / z=556.25[M+H]+, retention time: 2.94 minutes [Example 7]

[0206] Preparation of Compound I-1-25 [ka] To a solution of compound 6 (50 mg, 0.130 mmol) in dichloromethane (0.8 mL), compound 13 (29.8 m g, 0.156 mmol), triethylamine (0.054 mL, 0.391 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (30.4 mg, 0.196 mmol) and HOBt (8.8 mg, 0.065 mmol) were added and the solution was stirred at room temperature for 15 h. Saturated aqueous NaHCO3 was added to the reaction solution and extracted with dichloromethane. The oranic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3 / methanol) to give compound I-1-25 (47 mg, yield: 74.5%) as a white solid. LC / MS method A: m / z=556.3[M+H]+, retention time: 2.73 minutes [Example 8]

[0207] Preparation of Compound I-1-1 [ka] Process 1 To a solution of compound 14 (5.05 g, 21.7 mmol) in 1,4-dioxane (76 mL), compound 15 (7.37 g, 23.8 mmol), PdCl2(PPh3)2 (1.52 g, 2.17 mmol) and 2M Na2CO3 aqueous solution (32.5 ml, 65 mmol) were added. The reaction mixture was stirred at 100° C. for 1.5 h. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give compound 16 (6.59 g, 19.7 mmol, 91%) as a white solid. 1H-NMR(400 MHz, CDCl3)δ:7.78(dd,1H,J=7.8,1.3 Hz),7.70(dd,1H,11.6,1.3 Hz),6.04(m,1H),4.15-4.05(m,2H),3.92(s,3H),3.62(t,2H,5.4),2.56-2.46(m,2H),1.48(s,9H) Process 2 To a solution of compound 16 (6.49 g, 19.4 mmol) in inert gas-purged THF (100 ml) was added 10% Pd(OH)2 / C (5.44 g, 1.94 mmol). The reaction mixture was flooded with hydrogen gas (1 atm). The resulting suspension was stirred vigorously for 6.5 h. The reaction mixture was purged with inert gas and filtered through Celite. The Celite residue was washed with EtOAc and the filtrate was concentrated under reduced pressure to give the crude material as an oil. This crude material was used in the next reaction without further purification. The crude material was dissolved in THF (100 ml) and added to a suspension of LiAlH4 (1.46 g, 38.5 mmol) in THF (100 ml) at 0° C. After stirring for 5 min, sodium sulfate decahydrate (24.83 g, 77 mmol) was added to the reaction mixture and the reaction was stirred for 3 h. The reaction mixture was filtered through a Celite pad. The celite residue was washed with EtOAc and the filtrate was concentrated under reduced pressure to give the crude product as an oil. This crude material was used in the next reaction without further purification. To a solution of the crude material in dichloromethane (100 ml) was added Et3N (7.93 ml, 57.2 mmol) and methanesulfonyl chloride (3.28 g, 28.6 mmol) at -78 °C. H2O was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude material as an oil. This crude material was used in the next reaction without further purification. To a solution of the crude material in DMF (60 ml) was added NaN3 (2.47 g, 37.9 mmol) and the mixture was stirred at 80 °C for 1 h. H2O was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude material as an oil. This crude product was used in the next reaction without further purification. To a solution of the crude product in THF (50 ml) was added PPh3 (5.55 g, 21.2 mmol) and H2O (3.18 ml, 176 mmol) and the mixture was stirred at reflux for 2 h.The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc-CHCl3-MeOH) to give compound 17 (4.11 g, 13.3 mmol, 69% over five steps) as a white solid. 1H-NMR(400 MHz,CDCl3)δ:7.15(t,1H,J=7.7 Hz),7.04(d,1H,J=7.9 Hz),7.00(d,1H,J=11.3 Hz),4,24(s,2H),3.84(s,2H),2.98-2.89(m,1H),2.84-2.70(m,2H),1.83-1.75(m,2H),1.68-1.55(4H,m),1.48(s,9H) LC / MS method: A, LC-MS: m / z=253. [M+H]+, retention time: 1.67 minutes Process 3 To a solution of compound 17 (1.84 g, 5.97 mmol) in dichloromethane (20 ml) was added compound 11 (2.02 g, 6.56 mmol) and Et3N (1.24 ml, 8.95 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (CHCl3 / MeOH) to give compound 18 (2.83 g, 5.89 mmol, 99%) as a white solid. LC / MS method: A, LC-MS: m / z=481. [M+H]+, retention time: 2.17 minutes Process 4 To a solution of compound 18 (2.44 g, 5.08 mmol) in dichloromethane (20 ml) was added TFA (3.91 ml, 50.8 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by amino silica gel chromatography (CHCl3 / MeOH) to give compound 19 (1.83 g, 4.81 mmol, 95%) as an off-white amorphous solid. LC / MS method: A, LC-MS: m / z=381. [M+H]+, retention time: 1.00 minutes Process 5 To a solution of compound 19 (100 mg, 0.263 mmol) in THF was added compound 4 (95 mg, 0.394 mmol), Pd2(dba)3 (24.1 mg, 0.0026 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (49.1 mg, 0.105 mmol) and NaOtBu (0.789 mmol), then the reaction was stirred at 60 °C for 1 h. H2O was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / EtOAc) to give compound I-1-1 (81.7 mg, 0.151 mmol, 57.5%). 1H-NMR(400 MHz,CDCl3)δ:9.32(d,1H,J=7.5 Hz),7.33(s,1H),7.28-7.22(m,1H),7.15-7.04(m,4H),6.94(d,2H,J=7.9 Hz),6.77(d,1H,J=6.5 Hz),6.06(s,1H),4.67(d,2H,J=5.3 Hz),3.80-3.72(m,2H),3.05-2.95(m,1H),2.90-2.80(m,2H),2.69(s,3H),2.43(s,3H),1.95-1.83(m,4H) LC / MS method: A, LC-MS: m / z=541. [M+H]+, retention time: 2.42 minutes

[0208] According to the general synthesis methods and examples, the following compounds were obtained, whose chemical structures and physical properties (LC / MS data) are described below.

[0209] [Table 1]

[0210] [Table 2]

[0211] [Table 3]

[0212]

Table 4

[0213]

Table 5

[0214]

Table 6

[0215]

Table 7

[0216]

Table 8

[0217]

Table 9

[0218]

Table 10

[0219]

Table 11

[0220]

Table 12

[0221]

Table 13

[0222]

Table 14

[0223]

Table 15

[0224]

Table 16

[0225]

Table 17

[0226]

Table 18

[0227]

Table 19

[0228]

Table 20

[0229]

Table 21

[0230]

Table 22

[0231]

Table 23

[0232] [Table 24]

[0233] [Table 25]

[0234] [Table 26]

[0235] [Table 27]

[0236] [Table 28]

[0237] [Table 29]

[0238] The following compounds are also preferred and were obtained according to the general synthesis methods and examples: The chemical structures and physical properties (LC / MS data) of the compounds are described below.

[0239] [Table 30]

[0240] [Table 31]

[0241] [Table 32]

[0242] [Table 33]

[0243] [Table 34]

[0244] [Table 35]

[0245] [Table 36]

[0246] [Table 37]

[0247] [Table 38]

[0248] Pharmacological Examples (Test Example 1) Determination of IC85 for testing compounds against Mycobacterium avium. preparation One microliter of DMSO stock solution (200x final concentration) of experimental compounds was added to a round-bottom sterile 96-well microtiter plate. Serial 4-fold dilutions (8-0.0000076 μM) were made directly in columns 1-11 in the microtiter plate. Untreated control samples with and without inoculum were included in column 12 of each plate. A sample of Mycobacterium avium ATCC700898 was taken from a 7H9 (5% OADC) agar plate. It was first diluted with CAMHB medium to obtain an optical density of 0.1 at 600 nm wavelength, and then diluted 1 / 20 to obtain an inoculum of approximately 5 x 10exp6 colony forming units / mL. A microtiter plate was filled with 200 μL of the inoculum solution. Plates were incubated at 37°C in a stainless steel tray to prevent evaporation. After 3 days of incubation, resazurin was added to all wells. After 1 day, fluorescence was measured with an EnVision Microplate Reader at an excitation wavelength of 543 nm and an emission wavelength of 590 nm, and IC85 values ​​were calculated.

[0249] The results of Test Example 1 are shown below.

[0250] [Table 39]

[0251] [Table 40]

[0252] [Table 41]

[0253] (Test Example 2) Metabolic Stability Test The compounds of the present invention were reacted for a certain period of time using commercially available pooled human liver microsomes, and the remaining rate was calculated by comparing the reacted sample with the unreacted sample, thereby evaluating the degree of metabolism in the liver. The reaction was carried out in 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL of human liver microsomes in the presence of 1 mmol / L NADPH at 37°C for 0 or 30 minutes (oxidation reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol / acetonitrile = 1 / 1 (v / v), mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was measured by LC / MS / MS or solid phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention after the reaction was calculated by taking the amount of the compound at 0 minutes of reaction time as 100%.

[0254] The results of Test Example 2 are shown below.

[0255] [Table 42]

[0256] [Table 43]

[0257] [Table 44]

[0258] The usefulness as a pharmaceutical can be examined by the following tests.

[0259] Test Example 3: CYP Inhibition Test Using commercially available pooled human liver microsomes, the degree of inhibition of the production of each metabolite by the compounds of the present invention was evaluated as the marker reactions of the five major human CYP isoforms (CYP1A2, 2C9, 2C19, 2D6 and 3A4), 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6) and terfenezine-hydroxylation (CYP3A4).

[0260] The reaction conditions were as follows: substrates, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenezine (CYP3A4); reaction time, 15 min; reaction temperature, 37°C; enzyme, pooled human liver microsomes, 0.2 mg protein / mL; concentration of the compound of the present invention, 1.0, 5.0, 10, 20 μmol / L (4 points).

[0261] Each of the five substrates, human liver microsomes or the compounds of the present invention in 50 mmol / L Hepes buffer was added to a 96-well plate with the above composition, and NADPH was added as a cofactor to initiate the metabolic reaction. After incubation at 37°C for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescence multilabel counter or LC / MS / MS, and hydroxytolbutamide (CYP2C9 metabolite), 4'hydroxymephenytoin (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite) and terfenadine alcohol metabolite (CYP3A4 metabolite) were quantified by LC / MS / MS.

[0262] A sample obtained by adding only DMSO, a solvent for dissolving the compound, to the reaction mixture instead of the compound of the present invention was used as a control (100%). Compared to the control, the remaining activity (%) was calculated at each concentration of the compound of the present invention, and the IC was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. 50 was calculated.

[0263] Test Example 4: CYP3A4 (MDZ) MBI test The CYP3A4 (MDZ) MBI test is a test to examine the possibility of mechanism based inhibition (MBI) of the compounds of the present invention against CYP3A4 inhibition by the enhancement of the inhibitory effect caused by the metabolic reaction of the compounds of the present invention. CYP3A4 inhibition was evaluated using pooled human liver microsomes by the 1-hydroxylation reaction of midazolam (MDZ) as a marker reaction.

[0264] The reaction conditions were as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 min; substrate metabolism reaction time, 2 min; reaction temperature, 37°C; protein content of pooled human liver microsomes, 0.5 mg / mL in pre-reaction and 0.05 mg / mL in reaction (10-fold dilution); concentration of the compound of the present invention, 1, 5, 10, 20 μmol / L or 0.83, 5, 10, 20 μmol / L (4 points).

[0265] A solution of the compound of the present invention in pooled human liver microsomes and K-Pi buffer (pH 7.4) as a pre-reaction solution was added to a 96-well plate in the pre-reaction composition. A part of the pre-reaction solution was transferred to another 96-well plate and diluted 1 / 10 with K-Pi buffer containing a substrate. NADPH was added as a cofactor to start the reaction as a marker reaction (pre-incubation 0 min). After a predetermined time of the marker reaction, a solution of methanol / acetonitrile = 1 / 1 (V / V) was added to stop the reaction. Furthermore, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (pre-incubation 30 min). After a predetermined time of the pre-reaction, a part was transferred to another 96-well plate and diluted 1 / 10 with K-Pi buffer containing a substrate to start the reaction as a marker reaction. After a predetermined time of the marker reaction, a solution of methanol / acetonitrile = 1 / 1 (V / V) was added to stop the reaction. After centrifugation at 3000 rpm for 15 min, 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS.

[0266] A sample obtained by adding only DMSO, which was a solvent for dissolving the compound, to the reaction mixture instead of the compound of the present invention, was used as a control (100%). The remaining activity (%) was calculated at each concentration of the compound of the present invention compared to the control, and the IC value was calculated by inverse estimation using a logistic model using the concentration and inhibition rate. The shifted IC value was calculated as "IC at 0 minutes preincubation / IC at 30 minutes preincubation". If the shifted IC was 1.5 or higher, it was defined as positive. If the shifted IC was 1.0 or lower, it was defined as negative.

[0267] Test example 5: BA test Materials and methods for experiments to assess oral absorption (1) Animals: Rats were used. (2) Rearing conditions: Mice or rats were allowed to freely consume solid food and sterilized tap water. (3) Dose and grouping: The given doses were administered orally or intravenously; grouping was as follows (dose depends on compound): Oral administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3) Intravenous administration: 1-30 μmol / kg or 0.5-10 mg / kg (n=2-3) (4) Preparation of administration solutions: for oral administration, in solution or suspension form; for intravenous administration, in solubilized form (5) Method of administration: Oral administration is by forcibly administering the drug into the stomach using an oral probe; intravenous administration is by administering the drug into the tail vein using a syringe equipped with a needle. (6) Evaluation items: Blood samples were taken over time, and the plasma drug concentrations were measured by LC / MS / MS. (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) of the compound of the present invention was calculated using the nonlinear least squares program WinNonlin (registered trademark), and the bioavailability (BA) was calculated from the AUC in the oral administration group and the intravenous administration group.

[0268] Test Example 6: Ames test The mutagenicity of the compounds of the present invention was evaluated. 20 μL of frozen Salmonella typhimurium (TA98 and TA100 strains) was inoculated onto 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and incubated at 37 °C for 10 h under shaking. 7.70–8.00 mL of TA98 culture medium was centrifuged (2000 × g, 10 min). Bacteria were suspended in MicroF buffer (K2HPO4: 3.5 g / L, KH2PO4: 1 g / L, (NH4)2SO4: 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO4·7H20: 0.1 g / L) with the same volume as the volume of culture medium used for centrifugation. The suspension was added to 120 mL of Exposure medium (Micro F buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL and glucose: 8 mg / mL). 3.10-3.42 mL of TA100 culture medium strain was mixed with 120-130 mL of Exposure medium. DMSO solutions of the compounds of the present invention (diluted in series at a ratio of 2 to 3 times from the maximum dose of 50 mg / mL), DMSO as a negative control, 50 μg / mL 4-nitroquinoline 1-oxide DMSO solution for TA98 strain and 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for TA100 strain in the assay without metabolic activation, 40 μg / mL 2-aminoanthracene DMSO solution for TA98 strain and 20 μg / mL 2-aminoanthracene DMSO solution for TA100 strain in the assay with metabolic activation as a positive control, were mixed with 12 μL and 588 μL of the test bacteria suspension (498 μL and 90 μL of S9 mixture in the case of metabolic activation assay), and incubated at 37 ° C for 90 minutes under shaking. 460 μL of the mixture was mixed with 2300 μL of Indicator medium (Micro F buffer containing 8 μg / mL biotin, 0.2 μg / mL histidine, 8 mg / mL glucose, and 37.5 μg / mL bromocresol purple) and 50 μL was dispensed per dose into 48 wells of a microplate, which was incubated at 37° C. for 3 days.Wells containing bacteria that have acquired the ability to grow due to a point mutation in the gene for an enzyme that synthesizes the amino acid histidine turn from purple to yellow due to a change in pH, so the number of yellow wells out of 48 wells was counted for each dose and compared with the negative control group. (-) and (+) indicate negative and positive mutagenicity, respectively.

[0269] Test Example 7: hERG Test In order to evaluate the risk of prolonging the electrocardiogram QT interval with the compounds of the present invention, we used CHO cells expressing the human ether-a-go-go related gene (hERG) channel to measure the delayed rectifier K+ current (I Kr The effect of the compound of the present invention on Using an automated patch clamp system (QPatch; Sophion Bioscience A / S), cells were held at a membrane potential of -80 mV and a leak potential of -50 mV was applied. I was induced by a depolarizing pulse of +20 mV for 2 seconds and a repolarizing pulse of -50 mV for 2 seconds. Kr The I was recorded. The extracellular solution adjusted to contain 0.1% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl2: 2 mmol / L, MgCl2: 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH=7.4) was used as a vehicle. The vehicle and the extracellular solution in which the compound of the present invention was dissolved at each desired concentration were applied to the cells at room temperature for 7 minutes or more. The I recorded Kr From the results, the absolute value of the tail peak current was measured based on the current value at the resting membrane potential using analysis software (QPatch Assay software; Sophion Bioscience A / S). Furthermore, the tail peak current after application of the compound of the present invention relative to the tail peak current after application of the vehicle was calculated as % inhibition, and the I Kr The impact on was evaluated.

[0270] Test Example 8: Solubility test The solubility of the compound of the present invention was measured under the condition of adding 1% DMSO. A 10 mmol / L solution of the compound was prepared using DMSO. 2 μL of the solution of the compound of the present invention was added to 198 μL of JP-1 solution or JP-2 solution, respectively. The mixture was shaken at room temperature for 1 hour, and then the mixture was vacuum filtered. The filtrate was diluted 10-fold or 100-fold with methanol / water = 1 / 1 (v / v) or acetonitrile / methanol / water = 1 / 1 / 2 (v / v / v), and the compound concentration in the filtrate was measured by absolute calibration method using LC / MS or solid phase extraction (SPE) / MS.

[0271] The composition of the JP-1 liquid was as follows: 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid were made up to 1000 mL with water. The composition of JP-2 liquid was as follows: To a solution of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in 1 volume of water was added 1 volume of water to make 1000 mL.

[0272] Test Example 9: Powder solubility test An appropriate amount of the compound of the present invention was placed in an appropriate container. 200 μL of JP-1 solution (2.0 g sodium chloride and 7.0 mL hydrochloric acid were added to 1000 mL with water), 200 μL of JP-2 solution (3.40 g potassium dihydrogen phosphate and 3.55 g anhydrous disodium hydrogen phosphate were dissolved in water for 1 volume and added with 1 volume of water to make 1000 mL), or 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (1.08 g TCA was added to JP-2 solution to make 100 mL) were added to each container independently. When the entire amount was dissolved after adding the test reagent, the compound of the present invention was added as appropriate. After sealing and shaking at 37° C. for 1 hour, the solution was filtered and 100 μL of methanol was added to each 100 μL of filtrate to dilute it by 2 times. The dilution factor was changed as necessary. After ensuring the absence of air bubbles and precipitate, the container was sealed and shaken.The compounds of the present invention were measured using HPLC by the absolute calibration method.

[0273] Test Example 10: P-gp substrate test The compound of the present invention is added to one side of Transwell (registered trademark, CORNING) in which human MDR1 expressing cells or parent cells are cultured in monolayer. The cells are reacted for a certain period of time. The membrane permeability coefficients from the apical side to the basolateral side (A→B) and from the basolateral side to the apical side (B→A) of the MDR1 expressing cells or parent cells are calculated, and the efflux ratio (ER; ratio of the membrane permeability coefficients of B→A and A→B) of the MDR1 expressing cells and parent cells is calculated. The efflux ratio (ER) values ​​of the MDR1 expressing cells and parent cells are compared to confirm whether the compound of the present invention is a P-gp substrate.

[0274] Formulation examples The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.

[0275] Formulation Example 1: Tablets The compound used in the present invention is mixed with lactose and calcium stearate. The mixture is milled, granulated and dried to obtain granules of suitable size. Then, calcium stearate is added to the granules, and the mixture is compressed and molded to obtain tablets.

[0276] Formulation Example 2: Capsules The compound used in the present invention, lactose and calcium stearate are mixed uniformly to obtain a powder in the form of powder or granules.The powder is filled into a capsule container to obtain a capsule.

[0277] Formulation Example 3: Granules The compound used in the present invention, lactose and calcium stearate are mixed uniformly, and the mixture is compressed and molded.Then, it is crushed, granulated and sieved to obtain granules of suitable size.

[0278] Formulation Example 4: Orally disintegrating tablet The compound used in the present invention is mixed with crystalline cellulose, granulated, and tableted to obtain an orally disintegrating tablet.

[0279] Formulation Example 5: Dry syrup The compound used in the present invention and lactose are mixed, crushed, granulated and sieved to obtain a dry syrup of suitable size.

[0280] Formulation Example 6: Injection The compound used in the present invention is mixed with a phosphate buffer solution to obtain an injection.

[0281] Formulation Example 7: Infusion The compound used in the present invention is mixed with a phosphate buffer solution to obtain an injection.

[0282] Formulation Example 8: Inhalant The compound used in the present invention is mixed with lactose and pulverized to obtain an inhalant.

[0283] Formulation Example 9: Ointment The compound used in the present invention is mixed with petrolatum to obtain an ointment.

[0284] Formulation Example 10: Patch A patch is obtained by mixing the compound used in the present invention with a base such as an adhesive plaster. [Industrial Applicability]

[0285] From the above test results, the compounds of the present invention can be useful medicines as therapeutic and / or preventive agents for symptoms and / or diseases induced by mycobacterial infection.

Claims

【Request 1】 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

2. A compound comprising the following compound: 【Chemistry 2】 2. The compound of claim 1, wherein:

3. The compound comprising: 【Chemistry 3】 2. The compound of claim 1, wherein:

4. The compound comprising the following compound: 【Chemistry 4】 2. The compound of claim 1, wherein:

5. The compound comprising the following compound: 【Chemistry 5】 2. The compound of claim 1, wherein:

6. The compound comprising the following compound: 【Chemistry 6】 2. The compound of claim 1, wherein:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof.

8. A pharmaceutical composition according to claim 7 for the treatment and / or prevention of mycobacterial infections.

9. A compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof for the treatment and / or prevention of mycobacterial infections.

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