Benzylamine-containing 5,6-heteroaromatic compounds useful for combating mycobacterial infections

Abstract

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

[0001] This application is a divisional application of Chinese patent application No. 202080062740.1 (application date: September 10, 2020, invention name: 5,6-heteroaromatic compounds containing benzylamine that can be used to fight mycobacterial infections).

[0002] [Related applications]

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 898,066, filed on September 10, 2019, the entire contents of which are incorporated herein by reference. [Technical field]

[0004] The present invention relates to novel compounds. The present invention also relates to such compounds for use as pharmaceutical compositions, and further for use in treating bacterial diseases, including diseases caused by pathogenic mycobacteria such as non-tuberculous mycobacteria. Such compounds can act by interfering with ATP synthesis of pathogenic mycobacteria, with inhibition of cytochrome bc1 activity as the main mode of action. [Background Technology]

[0005] There are 95 well-characterized species of the genus Mycobacterium. For centuries, two well-known mycobacterial species, Mycobacterium tuberculosis and Mycobacterium leprae, have been known causes of great human suffering. Most other mycobacteria exist in the environment, and their pathogenic potential has been recognized since the last century. These mycobacteria are called non-tuberculous mycobacteria (NTM). Although the incidence of tuberculosis (TB) is decreasing, new health problems have arisen worldwide due to NTM. Pulmonary diseases caused by NTM are characterized by progressive, irreversible lung damage and increased mortality. About 80% of pulmonary NTM diseases are caused by the Mycobacterium avium complex (MAC: Mycobacterium avium (M.avium), Mycobacterium intracellulare (M.intracellulare) and Mycobacterium chimaera (M.chimaera)).

[0006] The annual prevalence of NTM lung disease varies by region, ranging from 0.2 / 100,000 to 14.7 / 100,000, with an overall alarming increase. The disease is more common after age 60, with an estimated prevalence in the United States increasing from 19.6 / 100,000 in 1994-1996 to 26.7 / 100,000 in 2004-2006.

[0007] Unlike TB, NTM are opportunistic pathogens that primarily cause TB-like lung disease in immunocompromised patients or those with pre-existing lung conditions such as cystic fibrosis (CF), bronchiectasis, or chronic obstructive pulmonary disease (COPD). In addition, postmenopausal women without pre-existing structural lung disease represent another risk group for NTM lung disease. These women, primarily older women of Caucasian or Asian descent, present with NTM lung disease as nodular bronchiectasis.

[0008] Agents that can treat one or both of TB and NTM infections are described herein. There is an unmet medical need for compounds that are effective against one or both of TB and NTM pathogens, and the compounds of the invention are believed to be effective as single agents or in combination therapy against drug-resistant strains.

[0009] Patent Document 1 discloses various compounds having cytochrome bc1 inhibitory activity. For example, the following compounds are disclosed.

[0010]

[0011] Patent Documents 2 to 12 disclose various compounds having cytochrome bc1 inhibitory activity. For example, Patent Document 12 discloses the following compounds.

[0012]

[0013] [Patent document]

[0014] Patent document 1: WO 2017 / 049321

[0015] Patent document 2: WO 2011 / 057145

[0016] Patent document 3: WO 2014 / 015167

[0017] Patent document 4: WO 2011 / 113606

[0018] Patent Document 5: WO 2015 / 014993

[0019] Patent Document 6: WO 2017 / 001660

[0020] Patent Document 7: WO 2017 / 001661

[0021] Patent Document 8: WO 2017 / 216281

[0022] Patent Document 9: WO 2017 / 216283

[0023] Patent document 10: WO 2018 / 158280

[0024] Patent Document 11: US 2017 / 0313697

[0025] Patent Document 12: WO 2019 / 175737 [Summary of the invention]

[0026] [Problems to be Solved by the Invention]

[0027] An object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof, which can be used for treating or preventing bacterial diseases, including diseases caused by pathogenic mycobacteria such as nontuberculous mycobacteria, and a pharmaceutical composition containing the same.

[0028] [Methods of solving the problem]

[0029] In order to solve the above problems, after in-depth research, the present invention successfully synthesized excellent compounds for preventing and / or treating mycobacterial infections, especially non-tuberculous mycobacterial infections.

[0030] [Brief description of several embodiments of the present invention]

[0031] (1) A compound represented by formula (I):

[0032]

[0033] or a pharmaceutically acceptable salt thereof,

[0034] in

[0035] A group represented by the formula:

[0036]

[0037] is a group represented by the following formula:

[0038]

[0039] R 1 each is 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;

[0040] m is 0, 1, 2, 3 or 4;

[0041] R 2 is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group;

[0042] R 3a , R 3b , R 3c and R 3d are each independently a hydrogen atom, a halogen, 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 Not all hydrogen atoms at the same time;

[0043] Ring C is represented as follows:

[0044]

[0045] X is CH or N;

[0046] Y is CH or N;

[0047] R 4 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

[0048] Two R attached to adjacent carbon atoms 4 The group may form, together with the carbon atom to which it is attached, 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;

[0049] Two R attached to the same carbon atom 4 The group may form, together with the carbon atom to which it is attached, 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;

[0050] Two R's 4 The groups may together form a (C2-C4) bridge in which one of the carbon atoms of the bridge may optionally be replaced by an oxygen atom or a nitrogen atom; the carbon atoms of the bridge are each independently selected from R 4C and the nitrogen atom of the bridge, if present, is selected from R 4N Substituents are substituted;

[0051] R 4C are each independently a hydrogen atom, a halogen, a hydroxyl group, a cyano group, or a substituted or unsubstituted alkyl group;

[0052] R 4N are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0053] p is 0 or 1;

[0054] q is 0, 1, 2, 3, or 4;

[0055] R 5 CR 5C or N;

[0056] R 6 CR 6C or N;

[0057] R 7 CR 7C or N;

[0058] R 8 CR 8C or N;

[0059] R 9 CR 9C or N;

[0060] Condition R 5 , R 6 , R 7 , R 8 and R 9 Not all are N;

[0061] R 5C , R 6C , R 7C , R 8C and R 9C each independently represents a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted aromatic carbocyclyloxy group, a substituted or unsubstituted non-aromatic carbocyclyloxy group, a substituted or unsubstituted aromatic heterocyclyloxy group, a substituted or unsubstituted non-aromatic heterocyclyloxy group, or a pentafluorothio group;

[0062] The conditions are as follows except for the following compounds:

[0063]

[0064] (2) The compound according to (1) above or a pharmaceutically acceptable salt thereof, wherein the group represented by the following formula:

[0065]

[0066] is a group represented by the following formula:

[0067]

[0068] wherein each symbol is as defined in (1) above.

[0069] (3) The compound according to (1) above or a pharmaceutically acceptable salt thereof, wherein the group represented by the following formula:

[0070]

[0071] is a group represented by the following formula:

[0072]

[0073] wherein each symbol is as defined in (1) above.

[0074] (4) The compound according to (2) above or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen or substituted or unsubstituted alkyl.

[0075] (5) The compound according to (3) above or a pharmaceutically acceptable salt thereof, wherein R 1 is a substituted or unsubstituted alkyloxy group or a substituted or unsubstituted alkyl group.

[0076] (6) The compound according to any one of (1) to (5) above, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0077] (7) The compound according to any one of (1) to (6) above, or a pharmaceutically acceptable salt thereof, wherein R 2 is a substituted or unsubstituted alkyl group.

[0078] (8) The compound according to any one of (1) to (7) above, or a pharmaceutically acceptable salt thereof, wherein R 3b It is a halogen.

[0079] (9) The compound according to any one of (1) to (8) above, or a pharmaceutically acceptable salt thereof, wherein R 3b and R 3c are each independently halogen.

[0080] (10) The compound according to any one of (1) to (7) above, or a pharmaceutically acceptable salt thereof, wherein R 3a It is a halogen.

[0081] (11) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (10) above, wherein Ring C represents the following:

[0082]

[0083] wherein each symbol is as defined in (1) above.

[0084] (12) The compound according to any one of (1) to (11) above, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0085] (13) The compound according to any one of (1) to (12) above, or a pharmaceutically acceptable salt thereof, wherein q is 0.

[0086] (14) The compound according to any one of (1) to (12) above, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0087] (15) The compound according to any one of (1) to (12) above, or a pharmaceutically acceptable salt thereof, wherein q is 2.

[0088] (16) The compound according to (14) above or a pharmaceutically acceptable salt thereof, wherein Ring C is represented as follows:

[0089]

[0090] wherein each symbol is as defined in (1) above.

[0091] (17) The compound according to (15) above or a pharmaceutically acceptable salt thereof, wherein Ring C is represented as follows:

[0092]

[0093] wherein each symbol is as defined in (1) above.

[0094] (18) The compound according to any one of (1) to (17) above, or a pharmaceutically acceptable salt thereof, wherein X and Y are N.

[0095] (19) The compound according to any one of (1) to (17) above, or a pharmaceutically acceptable salt thereof, wherein one of X and Y is N, and the other of X and Y is CH.

[0096] (20) The compound according to any one of (1) to (12) or (14) to (19) above, or a pharmaceutically acceptable salt thereof, wherein R 4 Each is independently a substituted or unsubstituted alkyl group.

[0097] (21) The compound according to any one of (1) to (20) above, or a pharmaceutically acceptable salt thereof, wherein R 7 CR7C , and R 7C is a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkyloxy group.

[0098] (22) The compound according to (21) above or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R 8 and R 9 For CH.

[0099] (23) The compound according to (21) above or a pharmaceutically acceptable salt thereof, wherein R 5 CR 5C , R 5C is a halogen, and R 6 , R 8 and R 9 For CH.

[0100] (24) A compound according to (1) above or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 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).

[0101] (25) The compound according to (1) above or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds (I-1-144), (I-1-149) and (I-2-6).

[0102] (26) A pharmaceutical composition comprising the compound according to any one of (1) to (25) above or a pharmaceutically acceptable salt thereof.

[0103] (27) The pharmaceutical composition according to (26) above, which is used for treating and / or preventing mycobacterium infection.

[0104] (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 pharmaceutically acceptable salt thereof.

[0105] (29) The compound according to any one of (1) to (25) above or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing mycobacterial infection.

[0106] (1A) A compound represented by formula (I):

[0107]

[0108] or a pharmaceutically acceptable salt thereof,

[0109] in

[0110] Ring A and Ring B are represented as follows:

[0111]

[0112] R 1 each is 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;

[0113] m is 0, 1, 2, 3 or 4;

[0114] R 2 is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group;

[0115] R 3a , R 3b , R 3c and R 3d are each independently a hydrogen atom, a halogen, 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 Not all hydrogen atoms at the same time;

[0116] Ring C is represented as follows:

[0117]

[0118] X is CH or N;

[0119] Y is CH or N;

[0120] R 4 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

[0121] Two R attached to adjacent carbon atoms4 may form, together with the carbon atom to which it is attached, 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;

[0122] Two R attached to the same carbon atom 4 may form, together with the carbon atom to which it is attached, 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;

[0123] Two R's 4 The groups may together form a (C2-C4) bridge in which one of the carbon atoms of the bridge may optionally be replaced by an oxygen atom or a nitrogen atom; the carbon atoms of the bridge are each independently selected from R 4C and the nitrogen atom of the bridge, if present, is selected from R 4N Substituents are substituted;

[0124] R 4C are each independently a hydrogen atom, a halogen, a hydroxyl group, a cyano group, or a substituted or unsubstituted alkyl group;

[0125] R 4N are each independently a hydrogen atom, or a substituted or unsubstituted alkyl group;

[0126] p is 0 or 1;

[0127] q is 0, 1, 2, 3, or 4;

[0128] R 5 CR 5C or N;

[0129] R 6 CR 6C or N;

[0130] R 7 CR 7C or N;

[0131] R 8 CR 8C or N;

[0132] R 9 CR 9C or N;

[0133] Condition R 5 , R 6 , R 7 , R 8 and R 9 Not all are N;

[0134] R 5C , R 6C , R7C , R 8C and R 9C each independently represents a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted aromatic carbocyclyloxy group, a substituted or unsubstituted non-aromatic carbocyclyloxy group, a substituted or unsubstituted aromatic heterocyclyloxy group, a substituted or unsubstituted non-aromatic heterocyclyloxy group, or a pentafluorothio group;

[0135] The conditions are as follows except for the following compounds:

[0136]

[0137] (2A) The compound according to (1A) above or a pharmaceutically acceptable salt thereof, wherein Ring A and Ring B are represented as follows:

[0138]

[0139] (3A) The compound according to (1A) above or a pharmaceutically acceptable salt thereof, wherein Ring A and Ring B are represented as follows:

[0140]

[0141] (4A) The compound according to (2A) above or a pharmaceutically acceptable salt thereof, wherein R 1 is halogen or substituted or unsubstituted alkyl.

[0142] (5A) The compound according to (3A) above or a pharmaceutically acceptable salt thereof, wherein R 1 is a substituted or unsubstituted alkyloxy group or a substituted or unsubstituted alkyl group.

[0143] (6A) The compound according to any one of (1A) to (5A) above, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0144] (7A) The compound according to any one of (1A) to (6A) above, or a pharmaceutically acceptable salt thereof, wherein R 2 is a substituted or unsubstituted alkyl group.

[0145] (8A) The compound according to any one of (1A) to (7A) above, or a pharmaceutically acceptable salt thereof, wherein R 3b It is a halogen.

[0146] (9A) The compound according to any one of (1A) to (8A) above, or a pharmaceutically acceptable salt thereof, wherein R3b and R 3c are each independently halogen.

[0147] (10A) The compound according to any one of (1A) to (9A) above, or a pharmaceutically acceptable salt thereof, wherein Ring C represents the following:

[0148]

[0149] (11A) The compound according to any one of (1A) to (10A) above, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0150] (12A) The compound according to any one of (1A) to (11A) above, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0151] (13A) The compound according to any one of (1A) to (12A) above, or a pharmaceutically acceptable salt thereof, wherein Ring C represents the following:

[0152]

[0153] (14A) The compound according to any one of (1A) to (13A) above, or a pharmaceutically acceptable salt thereof, wherein X and Y are N.

[0154] (15A) The compound according to any one of (1A) to (13A) above, or a pharmaceutically acceptable salt thereof, wherein one of X and Y is N, and the other of X and Y is CH.

[0155] (16A) The compound according to any one of (1A) to (15A) above, or a pharmaceutically acceptable salt thereof, wherein R 4 is a substituted or unsubstituted alkyl group.

[0156] (17A) The compound according to any one of (1A) to (16A) above, or a pharmaceutically acceptable salt thereof, wherein R 7 CR 7C , and R 7C is a substituted or unsubstituted alkyloxy group.

[0157] (18A) The compound according to (17A) above or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R 8 and R 9 For CH.

[0158] (19A) The compound according to (17A) above or a pharmaceutically acceptable salt thereof, wherein R 5 CR5C , R 5C is a halogen, and R 6 , R 8 and R 9 For CH.

[0159] (20A) A compound according to (1A) above or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 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).

[0160] (21A) A pharmaceutical composition comprising the compound according to any one of (1A) to (20A) above or a pharmaceutically acceptable salt thereof.

[0161] (22A) The pharmaceutical composition according to (21A) above, which is used for treating and / or preventing mycobacterium infection.

[0162] (23A) A method for preventing or treating mycobacterium infection, comprising administering to a subject the compound according to any one of (1A) to (20A) above or a pharmaceutically acceptable salt thereof.

[0163] (24A) The compound according to any one of (1A) to (20A) above, or a pharmaceutically acceptable salt thereof, for use in treating and / or preventing mycobacterium infection.

[0164] [Effects of the invention]

[0165] The compounds of the present invention are useful for treating or preventing mycobacterial infections, especially nontuberculous mycobacterial infections. [Specific implementation method]

[0166] Each term used in this specification will be described as follows. In this specification, even when each term is used alone or together with other terms, the term has the same meaning.

[0167] The term "consisting of" means having only the stated components or elements.

[0168] The term "comprising" means not to be limited to the components and does not exclude undescribed factors.

[0169] In the claims and / or the specification, the use of the words "a" or "an" when used in conjunction with the term "comprising" may mean "one", but is also consistent with the meaning of "one or more", "at least one" and "one or more than one".

[0170] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is as described above and below.

[0171] The term "halogen" includes fluorine, chlorine, bromine and iodine atoms. Fluorine and chlorine atoms are particularly preferred.

[0172] The term "alkyl" includes C1 to C15, preferably C1 to C10, more preferably C1 to C6, and further preferably C1 to C4 straight or branched chain hydrocarbon groups. 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.

[0173] A preferred embodiment of "alkyl" is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. A more preferred embodiment is methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0174] The term "alkenyl" includes C2 to C15, preferably C2 to C10, more preferably C2 to C6, and further preferably C2 to C4 straight or branched hydrocarbon groups having one or more double bonds at any position. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl and pentadecenyl.

[0175] Preferred embodiments of the "alkenyl group" are vinyl, allyl, propenyl, isopropenyl or butenyl.

[0176] The term "alkynyl" includes C2 to C8 straight or branched alkynyl groups having one or more triple bonds in the above "alkyl", and examples thereof include ethynyl, propynyl, butynyl, etc. In addition, the "alkynyl" may have a double bond.

[0177] 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.

[0178] Preferred embodiments of the "alkyloxy group" are methyloxy, ethyloxy, n-propyloxy, isopropyloxy or tert-butyloxy.

[0179] 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.

[0180] 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.

[0181] The term "aromatic carbocycle" refers to a cyclic aromatic hydrocarbon as a single ring or a polycyclic ring having two or more rings. For example, it includes a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and the like.

[0182] A preferred embodiment of the "aromatic carbocyclic ring" is a benzene ring.

[0183] The term "aromatic carbocyclic group" refers to a cyclic aromatic hydrocarbon group which is a monocyclic ring or a polycyclic ring having two or more rings. For example, it includes phenyl, naphthyl, anthracenyl, phenanthryl and the like.

[0184] A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0185] The term "non-aromatic carbocycle" refers to a cyclic saturated hydrocarbon ring or a cyclic unsaturated non-aromatic hydrocarbon ring, which is a monocyclic ring or a polycyclic ring having two or more rings. The "non-aromatic carbocycle" as a polycyclic ring having two or more rings includes a condensed ring in which a non-aromatic carbocycle which is a monocyclic ring or a polycyclic ring having two or more rings is condensed with the ring of the above "aromatic carbocycle".

[0186] Furthermore, the "non-aromatic carbocyclic ring" also includes the following rings having a bridge or a ring having a spiro ring.

[0187]

[0188] The non-aromatic carbocyclic ring as a monocyclic ring is preferably a C3 to C16 carbocyclic ring, more preferably a C3 to C12 carbocyclic ring, and further preferably a C3 to C6 carbocyclic ring. For example, it includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, etc.

[0189] Examples of the polycyclic non-aromatic carbocyclic ring having two or more rings include indane, indene, acenaphthene, tetralin, fluorene and the like.

[0190] The term "non-aromatic carbocyclic group" refers to a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group, which is a monocyclic ring or a polycyclic ring having two or more rings. The "non-aromatic carbocyclic group" as a polycyclic ring having two or more rings includes a condensed ring group in which the non-aromatic carbocyclic group as a monocyclic ring or a polycyclic ring having two or more rings is condensed with the ring of the above "aromatic carbocyclic group".

[0191] In addition, the "non-aromatic carbocyclic group" also includes the following groups having a bridge or forming a spiro ring:

[0192]

[0193] The monocyclic non-aromatic carbocyclic group is preferably C3 to C16, more preferably C3 to C12, and further preferably C3 to C6 carbocyclic group. For example, it includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, etc.

[0194] As the polycyclic non-aromatic carbocyclic group having two or more rings, there are included, for example, indanyl, indenyl, acenaphthenyl, tetralinyl, fluorenyl and the like.

[0195] The term "aromatic heterocycle" refers to an aromatic ring containing one or more heteroatoms independently selected from O, S and N which may be the same or different and which is a monocyclic ring or a polycyclic ring having two or more rings.

[0196] The "aromatic heterocycle" as a polycyclic ring having two or more rings includes a condensed ring in which the aromatic heterocycle as a monocyclic ring or a polycyclic ring having two or more rings is condensed with the ring of the above "aromatic carbocycle".

[0197] The monocyclic aromatic heterocyclic ring is preferably a 5- to 8-membered ring and more preferably a 5- to 6-membered ring. For example, it includes a "5-membered aromatic heterocyclic ring" such as pyrrole, imidazole, pyrazole, triazole, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, etc.; and a "6-membered aromatic heterocyclic ring" such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.

[0198] The bicyclic aromatic heterocycle includes, for example, 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, thiazolopyridine and the like.

[0199] Examples of the polycyclic aromatic heterocyclic ring having three or more rings include carbazole, acridine, xanthene, phenothiazine, phenoxathiol, phenoxazine, dibenzofuran and the like.

[0200] The term "aromatic heterocyclic group" refers to an aromatic ring group containing one or more heteroatoms independently selected from O, S and N which may be the same or different, and which is a monocyclic ring or a polycyclic ring having two or more rings.

[0201] The "aromatic heterocyclic group" as a polycyclic ring having two or more rings includes a condensed ring group in which the aromatic heterocyclic group as a monocyclic ring or a polycyclic ring having two or more rings is condensed with the ring of the above "aromatic carbocyclic group".

[0202] The monocyclic aromatic heterocyclic group is preferably a 5- to 8-membered ring and more preferably a 5- to 6-membered ring. For example, it includes pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.

[0203] The bicyclic aromatic heterocyclic group includes, for example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridinyl, thiazolylpyridinyl and the like.

[0204] As the polycyclic aromatic heterocyclic group having three or more rings, there are included, for example, a carbazolyl group, an acridinyl group, a xanthenyl group, a phenothiazinyl group, a phenoxathiyl group, a phenoxazinyl group, a dibenzofuranyl group and the like.

[0205] The term "non-aromatic heterocycle" refers to a non-aromatic ring containing one or more heteroatoms independently selected from O, S and N which may be the same or different and which is a monocyclic ring or a polycyclic ring having two or more rings.

[0206] The “non-aromatic heterocycle” as a polycyclic ring having two or more rings includes a condensed ring in which a non-aromatic heterocycle as a monocyclic ring or a polycyclic ring having two or more rings is condensed with a ring of the above “aromatic carbocycle”, “non-aromatic carbocycle” and / or “aromatic heterocycle”. The “non-aromatic heterocycle” as a polycyclic ring having two or more rings further includes a condensed ring in which an aromatic heterocycle as a monocyclic ring or a polycyclic ring having two or more rings is condensed with a ring of the above “non-aromatic carbocycle”.

[0207] Furthermore, the "non-aromatic heterocycle" also includes the following rings having a bridge or forming a spiro ring.

[0208]

[0209] The non-aromatic heterocyclic ring which is a monocyclic ring is preferably 3 to 8-membered, more preferably 3 to 6-membered, and more preferably 5 to 6-membered. For example, it includes

[0210] "5-membered non-aromatic heterocycle" such as thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydrofuran, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dioxolane, dioxoline, etc.,

[0211] "6-membered non-aromatic heterocycle" such as dioxane, thioxane, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydropyran, dihydrooxazine, tetrahydropyridazine, hexahydropyrimidine, thiazine, and the like, and

[0212] Thiirane, oxirane, oxetane, oxathiolane, azetidine, hexahydroazepine, tetrahydrodiazepine, dioxazine, aziridine, oxepane, thiolane, thiine, and the like.

[0213] Examples of the polycyclic non-aromatic heterocycle having two or more rings include indoline, isoindoline, chroman, isochroman, dihydrobenzofuran, dihydroisobenzofuran, dihydroquinoline, dihydroisoquinoline, tetrahydroquinoline, tetrahydroisoquinoline and the like.

[0214] The term "non-aromatic heterocyclic group" refers to a non-aromatic ring group containing one or more heteroatoms independently selected from O, S and N which are the same or different and which is monocyclic or polycyclic having two or more rings.

[0215] The “non-aromatic heterocyclic group” as a polycyclic ring having two or more rings includes a condensed ring group in which a non-aromatic heterocyclic ring as a monocyclic ring or a polycyclic ring having two or more rings is condensed with a ring of the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.

[0216] In addition, the “non-aromatic heterocyclic group” also includes the following groups having a bridge or forming a spiro ring:

[0217]

[0218] The non-aromatic heterocyclic group which is a monocyclic ring is preferably a 3- to 8-membered ring and more preferably a 5- to 6-membered ring. For example, it includes dioxanyl, thiirane, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholino, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazolyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl, aziridine, dioxolenyl, oxepanyl, thiolanyl, thiinyl, thiazinyl and the like.

[0219] Examples of the polycyclic non-aromatic heterocyclic group having two or more rings include indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.

[0220] The term "aromatic carbocyclyloxy" refers to a group in which an "aromatic carbocyclic ring" is bonded to an oxygen atom. Examples include phenyloxy and naphthyloxy.

[0221] The term "non-aromatic carbocyclyloxy" refers to a group in which a "non-aromatic carbocyclic ring" is bonded to an oxygen atom. Examples include cyclopropyloxy, cyclohexyloxy, and cyclohexenyloxy.

[0222] The term "aromatic heterocyclyloxy" refers to a group in which an "aromatic heterocycle" is bonded to an oxygen atom. Examples include pyridyloxy and oxazolyloxy.

[0223] The term "non-aromatic heterocyclyloxy" refers to a group in which a "non-aromatic heterocycle" is bonded to an oxygen atom. Examples include piperidinyloxy and tetrahydrofuranyloxy.

[0224] Substituents of "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.

[0225] Substituents: halogen, hydroxy, carboxyl, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, aminosulfonyl, sulfanyl, sulfinyl, sulfo, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, urea, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkyl 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, alkylamino formyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl, non-aromatic heterocyclyl, aromatic carbocyclyloxy, non-aromatic carbocyclyloxy, aromatic heterocyclyloxy, non-aromatic heterocyclyloxy, aromatic carbocyclylcarbonyl, non-aromatic carbocyclylcarbonyl, aromatic heterocyclylcarbonyl, non-aromatic heterocyclylcarbonyl, aromatic carbocyclyloxycarbonyl, non-aromatic carbocyclyloxycarbonyl, aromatic heterocyclyloxycarbonyl, non-aromatic heterocyclyloxycarbonyl, aromatic carbocyclylalkyloxy, non-aromatic carbocyclyl The invention also comprises the following: an aromatic alkyloxy group, an aromatic heterocyclylalkyloxy group, a non-aromatic heterocyclylalkyloxy group, an aromatic carbocyclylalkyloxycarbonyl group, a non-aromatic carbocyclylalkyloxycarbonyl group, an aromatic heterocyclylalkyloxycarbonyl group, a non-aromatic heterocyclylalkyloxycarbonyl group, an aromatic carbocyclylalkylamino group, a non-aromatic carbocyclylalkylamino group, an aromatic heterocyclylalkylamino group, a non-aromatic heterocyclylalkylamino group, an aromatic carbocyclylsulfanyl group, a non-aromatic carbocyclylsulfanyl group, an aromatic heterocyclylsulfanyl group, a non-aromatic heterocyclylsulfanyl group, a non-aromatic carbocyclylsulfonyl group, an aromatic heterocyclylsulfonyl group, a non-aromatic heterocyclylsulfonyl group, a non-aromatic carbocyclylsulfonyl group, an aromatic heterocyclylsulfonyl group, and a non-aromatic heterocyclylsulfonyl group.

[0226] Preferred substituents: halogen, hydroxy, carboxyl, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, aminosulfonyl, sulfanyl, sulfinyl, sulfo, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, urea, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyl The invention also includes but is not limited to: an alkylsulfonylamino group, an alkylsulfonylamino group, an alkenylsulfonylamino group, an alkynylsulfonylamino group, an alkylimino group, an alkenylimino group, an alkynylimino group, an alkylcarbonylimino group, an alkenylcarbonylimino group, an alkynylcarbonylimino group, an alkyloxyimino group, an alkenyloxyimino group, an alkynyloxyimino group, an alkylcarbonyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an alkylsulfanyl group, an alkenylsulfanyl group, an alkynylsulfanyl group, an alkylsulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, an alkylcarbamoyl group, an alkenylcarbamoyl group, an alkynylcarbamoyl group, an alkylaminosulfonyl group, an alkenylaminosulfonyl group and an alkynylaminosulfonyl group.

[0227] More preferred substituents are: halogen, hydroxy, amino, cyano, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylamino, alkenylamino and alkynylamino.

[0228] Particularly preferred substituents are: halogen and non-aromatic carbocyclic groups.

[0229] "Two R attached to adjacent carbon atoms 4 a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring formed together with the carbon atoms to which it is attached, "two R attached to adjacent carbon atoms" 4 a substituted or unsubstituted 5- to 6-membered non-aromatic heterocyclic ring formed together with the carbon atom to which it is attached, "two R 4 a substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic ring formed together with the carbon atom to which it is attached, "two R 4 The substituents on the ring of the “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle” and “non-aromatic heterocycle” moieties of the “substituted or unsubstituted 3- to 6-membered non-aromatic heterocycle”, “substituted or unsubstituted aromatic carbocyclyloxy”, “substituted or unsubstituted non-aromatic carbocyclyloxy”, “substituted or unsubstituted aromatic heterocyclyloxy” and “substituted or unsubstituted non-aromatic heterocyclyloxy”, include the following substituents. Atoms at any position of the ring may be bonded to one or more groups selected from the following substituents.

[0230] Substituents: halogen, hydroxy, carboxyl, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, aminosulfonyl, sulfanyl, sulfinyl, sulfo, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, urea, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, 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, alkylaminosulfonyl , alkenylaminosulfonyl, alkynylaminosulfonyl, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl, non-aromatic heterocyclyl, aromatic carbocyclyloxy, non-aromatic carbocyclyloxy, aromatic heterocyclyloxy, non-aromatic heterocyclyloxy, aromatic carbocyclylcarbonyl, non-aromatic carbocyclylcarbonyl, aromatic heterocyclylcarbonyl, non-aromatic heterocyclylcarbonyl, aromatic carbocyclyloxycarbonyl, non-aromatic carbocyclyloxycarbonyl, aromatic heterocyclyloxycarbonyl, non-aromatic heterocyclyloxycarbonyl, aromatic carbocyclylalkyl, non-aromatic carbocyclylalkyl, aromatic heterocyclylalkyl, non-aromatic heterocyclylalkyl, aromatic carbocyclylalkyloxy, non-aromatic carbocyclylalkyloxy, aromatic heterocyclylalkyloxy, non-aromatic heterocyclyl The invention also includes an aromatic alkyloxy radical, an aromatic carbocyclylalkyloxycarbonyl, a non-aromatic carbocyclylalkyloxycarbonyl, an aromatic heterocyclylalkyloxycarbonyl, a non-aromatic heterocyclylalkyloxycarbonyl, an aromatic carbocyclylalkyloxyalkyl, a non-aromatic carbocyclylalkyloxyalkyl, an aromatic heterocyclylalkyloxyalkyl, a non-aromatic heterocyclylalkyloxyalkyl, an aromatic carbocyclylalkylamino, a non-aromatic carbocyclylalkylamino, an aromatic heterocyclylalkylamino, a non-aromatic heterocyclylalkylamino, an aromatic carbocyclylsulfanyl, a non-aromatic carbocyclylsulfanyl, an aromatic heterocyclylsulfanyl, a non-aromatic heterocyclylsulfanyl, a non-aromatic carbocyclylsulfonyl, an aromatic carbocyclylsulfonyl, an aromatic heterocyclylsulfonyl and a non-aromatic heterocyclylsulfonyl.

[0231] Preferred substituents: halogen, hydroxy, carboxyl, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, aminosulfonyl, sulfanyl, sulfinyl, sulfo, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, urea, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkyl The invention also includes but is not limited to: an alkylsulfonylamino group, an alkylsulfonylamino group, an alkenylsulfonylamino group, an alkynylsulfonylamino group, an alkylimino group, an alkenylimino group, an alkynylimino group, an alkylcarbonylimino group, an alkenylcarbonylimino group, an alkynylcarbonylimino group, an alkyloxyimino group, an alkenyloxyimino group, an alkynyloxyimino group, an alkylcarbonyloxy group, an alkenylcarbonyloxy group, an alkynylcarbonyloxy group, an alkyloxycarbonyl group, an alkenyloxycarbonyl group, an alkynyloxycarbonyl group, an alkylsulfanyl group, an alkenylsulfanyl group, an alkynylsulfanyl group, an alkylsulfinyl group, an alkenylsulfinyl group, an alkynylsulfinyl group, an alkylcarbamoyl group, an alkenylcarbamoyl group, an alkynylcarbamoyl group, an alkylaminosulfonyl group, an alkenylaminosulfonyl group and an alkynylaminosulfonyl group.

[0232] More preferred substituents are: halogen, hydroxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyl and haloalkyloxy.

[0233] Particularly preferred substituents are: halogen, alkyl, haloalkyl and haloalkyloxy.

[0234] The term "haloalkyl" includes groups in which one or more hydrogen atoms attached to the carbon atom of the above "alkyl" are replaced by the above "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-prop-2-yl.

[0235] Preferred embodiments of "haloalkyl" are trifluoromethyl and trichloromethyl.

[0236] 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.

[0237] Preferred embodiments of "haloalkoxy" are trifluoromethoxy and trichloromethoxy.

[0238] 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.

[0239] Preferred embodiments of the "alkylcarbonyl group" are methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.

[0240] 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.

[0241] The term "alkynylcarbonyl" refers to a group in which the above "alkynyl" is bonded to a carbonyl group. Examples include ethynylcarbonyl and n-propynylcarbonyl.

[0242] The term "alkylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the amino group are replaced by the above "alkyl". Examples include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino and N-methyl-N-ethylamino.

[0243] Preferred embodiments of "alkylamino" are methylamino and ethylamino.

[0244] 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.

[0245] Preferred embodiments of the "alkylsulfonyl group" are methylsulfonyl and ethylsulfonyl.

[0246] The term "alkenylsulfonyl group" refers to a group in which the above "alkenyl" is bonded to a sulfonyl group. Examples include vinylsulfonyl, allylsulfonyl and n-propenylsulfonyl.

[0247] The term "alkynylsulfonyl" refers to a group in which the above "alkynyl" is bonded to a sulfonyl group. Examples include ethynylsulfonyl and n-propynylsulfonyl.

[0248] The term "alkylcarbonylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the amino group are replaced by the above "alkylcarbonyl". Examples include methylcarbonylamino, dimethylcarbonylamino, ethylcarbonylamino, diethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, N,N-diisopropylcarbonylamino, n-butylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino and sec-butylcarbonylamino.

[0249] The term "alkylsulfonylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the amino group are replaced by the above "alkylsulfonyl". Examples include methylsulfonylamino, dimethylsulfonylamino, ethylsulfonylamino, diethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, N,N-diisopropylsulfonylamino, n-butylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino and sec-butylsulfonylamino.

[0250] Preferred embodiments of the "alkylsulfonylamino group" are methylsulfonylamino and ethylsulfonylamino.

[0251] The term "alkylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkyl". Examples include methylimino, ethylimino, n-propylimino and isopropylimino.

[0252] The term "alkenylimino group" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkenyl group". Examples include vinylimino and n-propenylimino.

[0253] The term "alkynylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkynyl". Examples include ethynylimino and n-propynylimino.

[0254] The term "alkylcarbonylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkylcarbonyl". Examples include methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino and isopropylcarbonylimino.

[0255] The term "alkenylcarbonylimino group" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkenylcarbonyl group". Examples include vinylcarbonylimino group and n-propenylcarbonylimino group.

[0256] The term "alkynylcarbonylimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkynylcarbonyl". Examples include ethynylcarbonylimino and n-propynylcarbonylimino.

[0257] The term "alkyloxyimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkyloxy". Examples include methyloxyimino, ethyloxyimino, n-propyloxyimino and isopropyloxyimino.

[0258] The term "alkenyloxyimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkenyloxy". Examples include vinyloxyimino and n-propenyloxyimino.

[0259] The term "alkynyloxyimino" refers to a group in which the hydrogen atom attached to the nitrogen atom of the imino group is replaced with the above "alkynyloxy". Examples include ethynyloxyimino and n-propynyloxyimino.

[0260] 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.

[0261] Preferred embodiments of the "alkylcarbonyloxy group" are methylcarbonyloxy and ethylcarbonyloxy.

[0262] The term "alkenylcarbonyloxy" refers to a group in which the above "alkenylcarbonyl" is bonded to an oxygen atom. Examples include vinylcarbonyloxy and n-propenylcarbonyloxy.

[0263] The term "alkynylcarbonyloxy" refers to a group in which the above "alkynylcarbonyl" is bonded to an oxygen atom. Examples include ethynylcarbonyloxy and n-propynylcarbonyloxy.

[0264] 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.

[0265] Preferred embodiments of the "alkyloxycarbonyl group" are methyloxycarbonyl, ethyloxycarbonyl and n-propyloxycarbonyl.

[0266] The term "alkenyloxycarbonyl" refers to a group in which the above "alkenyloxy" is bonded to a carbonyl group. Examples include vinyloxycarbonyl and n-propenyloxycarbonyl.

[0267] The term "alkynyloxycarbonyl" refers to a group in which the above "alkynyloxy" is bonded to a carbonyl group. Examples include ethynyloxycarbonyl and n-propynyloxycarbonyl.

[0268] The term "alkylsulfanyl" refers to a group in which the hydrogen atom attached to the sulfur atom of the sulfanyl group is replaced with the above "alkyl". Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl and isopropylsulfanyl.

[0269] The term "alkenylsulfanyl group" refers to a group in which a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above "alkenyl group". Examples include vinylsulfanyl and n-propenylsulfanyl.

[0270] The term "alkynylsulfanyl group" refers to a group in which a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above "alkynyl group". Examples include ethynylsulfanyl and n-propynylsulfanyl.

[0271] The term "alkylsulfinyl group" refers to a group in which the above "alkyl" is bonded to a sulfinyl group. Examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and isopropylsulfinyl.

[0272] The term "alkenylsulfinyl group" refers to a group in which the above "alkenyl group" is bonded to a sulfinyl group. Examples include vinylsulfinyl and n-propenylsulfinyl.

[0273] The term "alkynylsulfinyl" refers to a group in which the above "alkynyl" is bonded to a sulfinyl group. Examples include ethynylsulfinyl and n-propynylsulfinyl.

[0274] The term "alkylcarbamoyl" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the carbamoyl group are replaced by the above "alkyl". Examples include methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl and diethylcarbamoyl.

[0275] The term "alkylaminosulfonyl" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the aminosulfonyl group are replaced with the above "alkyl". Examples include methylaminosulfonyl, dimethylaminosulfonyl, ethylaminosulfonyl and diethylaminosulfonyl.

[0276] The term "aromatic carbocyclylcarbonyl" refers to a group in which an "aromatic carbocyclic ring" is bonded to a carbonyl group. Examples include phenylcarbonyl and naphthylcarbonyl.

[0277] The term "non-aromatic carbocyclylcarbonyl" refers to a group in which a "non-aromatic carbocyclic ring" is bonded to a carbonyl group. Examples include cyclopropylcarbonyl, cyclohexylcarbonyl, and cyclohexenylcarbonyl.

[0278] The term "non-aromatic carbocyclylcarbonyloxy" refers to a group in which a "non-aromatic carbocyclylcarbonyl" is bonded to an oxygen atom. Examples include cyclopropylcarbonyloxy, cyclohexylcarbonyloxy and cyclohexenylcarbonyloxy.

[0279] The term "aromatic heterocyclylcarbonyl" refers to a group in which an "aromatic heterocycle" is bonded to a carbonyl group. Examples include pyridylcarbonyl and oxazolylcarbonyl.

[0280] The term "non-aromatic heterocyclylcarbonyl" refers to a group in which a "non-aromatic heterocycle" is bonded to a carbonyl group. Examples include piperidinylcarbonyl and tetrahydrofuranylcarbonyl.

[0281] The term "aromatic carbocyclyloxycarbonyl" refers to a group in which an "aromatic carbocyclyloxy" is bonded to a carbonyl group. Examples include phenyloxycarbonyl and naphthyloxycarbonyl.

[0282] The term "non-aromatic carbocyclyloxycarbonyl" refers to a group in which a "non-aromatic carbocyclyloxy" is bonded to a carbonyl group. Examples include cyclopropyloxycarbonyl, cyclohexyloxycarbonyl and cyclohexenyloxycarbonyl.

[0283] The term "aromatic heterocyclyloxycarbonyl" refers to a group in which an "aromatic heterocyclyloxy" is bonded to a carbonyl group. Examples include a pyridyloxycarbonyl group and an oxazolyloxycarbonyl group.

[0284] The term "non-aromatic heterocyclyloxycarbonyl" refers to a group in which a "non-aromatic heterocyclyloxy" is bonded to a carbonyl group. Examples include piperidinyloxycarbonyl and tetrahydrofuranyloxycarbonyl.

[0285] The term "aromatic carbocyclylalkyloxy" refers to an alkyloxy group substituted with one or more of the above-mentioned "aromatic carbocyclyl groups". Examples include benzyloxy, phenethyloxy, phenyl-n-propyloxy, diphenylmethyloxy, triphenylmethyloxy, naphthylmethyloxy, and the following groups having R or S stereochemistry or racemates:

[0286]

[0287] The term "non-aromatic carbocyclylalkyloxy" refers to an alkyloxy group substituted by one or more of the above-mentioned "non-aromatic carbocyclyl groups". "Non-aromatic carbocyclylalkyloxy" also includes "non-aromatic carbocyclylalkyloxy" in which the alkyl portion is substituted by the above-mentioned "aromatic carbocyclyl groups". Examples include cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, and the following groups having R or S stereochemistry or racemates:

[0288]

[0289] The term "aromatic heterocyclylalkyloxy" refers to an alkyloxy group substituted by one or more of the above-mentioned "aromatic heterocyclyl groups". "Aromatic heterocyclylalkyloxy" also includes "aromatic heterocyclylalkyloxy" groups in which the alkyl portion is substituted by the above-mentioned "aromatic carbocyclyl" and / or "non-aromatic carbocyclyl". Examples include pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothienylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, and the following groups having R or S stereochemistry or racemates:

[0290]

[0291] The term "non-aromatic heterocyclylalkyloxy" refers to an alkyloxy group substituted by one or more of the above-mentioned "non-aromatic heterocyclyl groups". "Non-aromatic heterocyclylalkyloxy" also includes "non-aromatic heterocyclylalkyloxy" groups in which the alkyl portion is substituted by the above-mentioned "aromatic carbocyclyl", "non-aromatic carbocyclyl" and / or "aromatic heterocyclyl". Examples include tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy and the following groups having R or S stereochemistry or racemates:

[0292]

[0293] The term "aromatic carbocyclylalkyloxycarbonyl" refers to an alkyloxycarbonyl group substituted with one or more of the above-mentioned "aromatic carbocyclyl groups". Examples include benzyloxycarbonyl, phenethyloxycarbonyl, phenyl-n-propyloxycarbonyl, diphenylmethyloxycarbonyl, triphenylmethyloxycarbonyl, naphthylmethyloxycarbonyl, and the following groups having R or S stereochemistry or racemates:

[0294]

[0295] The term "non-aromatic carbocyclylalkyloxycarbonyl" refers to an alkyloxycarbonyl substituted by one or more of the above-mentioned "non-aromatic carbocyclyls". "Non-aromatic carbocyclylalkyloxycarbonyl" also includes "non-aromatic carbocyclylalkyloxycarbonyl" in which the alkyl portion is substituted by the above "aromatic carbocyclyl". Examples include cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, and the following groups having R or S stereochemistry or racemates:

[0296]

[0297] The term "aromatic heterocyclylalkyloxycarbonyl" refers to an alkyloxycarbonyl substituted by one or more of the above-mentioned "aromatic heterocyclyls". "Aromatic heterocyclylalkyloxycarbonyl" also includes "aromatic heterocyclylalkyloxycarbonyl" in which the alkyl portion is substituted by the above "aromatic carbocyclyl" and / or "non-aromatic carbocyclyl". Examples include pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothienylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyloxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl and the following groups having R or S stereochemistry or racemates:

[0298]

[0299] The term "non-aromatic heterocyclylalkyloxycarbonyl" refers to an alkyloxycarbonyl substituted by one or more of the above-mentioned "non-aromatic heterocyclyls". "Non-aromatic heterocyclylalkyloxycarbonyl" also includes "non-aromatic heterocyclylalkyloxycarbonyl" in which the alkyl portion is substituted by the above-mentioned "aromatic carbocyclyl", "non-aromatic carbocyclyl" and / or "aromatic heterocyclyl". Examples include tetrahydropyranylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, piperazinylmethyloxycarbonyl and the following groups having R or S stereochemistry or racemates:

[0300]

[0301] The term "aromatic carbocyclylalkylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the amino group are replaced by the above "aromatic carbocyclylalkyl". Examples include benzylamino, phenethylamino, phenylpropylamino, dibenzylamino, tritylamino, naphthylmethylamino and dibenzylamino.

[0302] The term "non-aromatic carbocyclylalkylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the amino group are replaced by the above "non-aromatic carbocyclylalkyl". Examples include cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino and cyclohexylmethylamino.

[0303] The term "aromatic heterocyclylalkylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the amino group are replaced by the above "aromatic heterocyclylalkyl". Examples include pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothienylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolylmethylamino and benzoxazolylmethylamino.

[0304] The term "non-aromatic heterocyclylalkylamino" refers to a group in which one or two hydrogen atoms attached to the nitrogen atom of the amino group are replaced by the above "non-aromatic heterocyclylalkyl". Examples include tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino and piperazinylmethylamino.

[0305] The term "aromatic carbocyclylsulfanyl" refers to a group in which a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with an "aromatic carbocyclic ring." Examples include phenylsulfanyl and naphthylsulfanyl.

[0306] The term "non-aromatic carbocyclylsulfanyl" refers to a group in which the hydrogen atom attached to the sulfur atom of the sulfanyl group is replaced by a "non-aromatic carbocyclic ring." Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, and cyclohexenylsulfanyl.

[0307] The term "aromatic heterocyclylsulfanyl group" refers to a group in which a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with an "aromatic heterocycle." Examples include pyridylsulfanyl and oxazolylsulfanyl.

[0308] The term "non-aromatic heterocyclylsulfanyl group" refers to a group in which a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with a "non-aromatic heterocycle". Examples include piperidinylsulfanyl and tetrahydrofuranylsulfanyl.

[0309] The term "non-aromatic carbocyclic sulfonyl group" refers to a group in which a "non-aromatic carbon ring" is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl and cyclohexenylsulfonyl.

[0310] The term "aromatic carbocyclic sulfonyl group" refers to a group in which an "aromatic carbocyclic ring" is bonded to a sulfonyl group. Examples include phenylsulfonyl and naphthylsulfonyl.

[0311] The term "aromatic heterocyclic sulfonyl group" refers to a group in which an "aromatic heterocyclic ring" is bonded to a sulfonyl group. Examples include pyridylsulfonyl and oxazolylsulfonyl.

[0312] The term "non-aromatic heterocyclic sulfonyl group" refers to a group in which a "non-aromatic heterocyclic ring" is bonded to a sulfonyl group. Examples include piperidinylsulfonyl and tetrahydrofuranylsulfonyl.

[0313] The term "alkyloxyalkyl" refers to a group in which the above "alkyloxy" is bonded to the above "alkyl." Examples include methoxymethyl, methoxyethyl and ethoxymethyl.

[0314] The term "alkyloxyalkyloxy" refers to a group in which the above "alkyloxy" is bonded to the above "alkyloxy". Examples include methoxymethoxy, methoxyethoxy, ethoxymethoxy and ethoxyethoxy.

[0315] The term "aromatic carbocyclylalkyl" refers to an alkyl group substituted with one or more of the above "aromatic carbocyclyls". Examples include benzyl, phenethyl, phenyl-n-propyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, and the following radicals having R or S stereochemistry or racemates:

[0316]

[0317] A preferred embodiment of the "aromatic carbocyclylalkyl group" is benzyl, phenethyl or benzhydryl.

[0318] The term "non-aromatic carbocyclylalkyl" refers to an alkyl group substituted by one or more of the above-mentioned "non-aromatic carbocyclyl groups". "Non-aromatic carbocyclylalkyl" also includes "non-aromatic carbocyclylalkyl" in which the alkyl portion is substituted by the above-mentioned "aromatic carbocyclyl groups". Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the following radicals having R or S stereochemistry or racemates:

[0319]

[0320] The term "aromatic heterocyclylalkyl" refers to an alkyl group substituted by one or more of the above-mentioned "aromatic heterocyclyls". "Aromatic heterocyclylalkyl" also includes "aromatic heterocyclylalkyl" in which the alkyl portion is substituted by the above-mentioned "aromatic carbocyclyl" and / or "non-aromatic carbocyclyl". Examples include pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothienylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benzoxazolylmethyl and the following groups having R or S stereochemistry or racemates:

[0321]

[0322] The term "non-aromatic heterocyclylalkyl" refers to an alkyl group substituted by one or more of the above-mentioned "non-aromatic heterocyclyl groups". "Non-aromatic heterocyclylalkyl" also includes "non-aromatic heterocyclylalkyl" in which the alkyl portion is substituted by the above-mentioned "aromatic carbocyclyl", "non-aromatic carbocyclyl" and / or "aromatic heterocyclyl". Examples include tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl and the following groups having R or S stereochemistry or racemates:

[0323]

[0324] The term "aromatic carbocyclylalkyloxyalkyl" refers to an alkyloxyalkyl substituted with one or more of the above-mentioned "aromatic carbocyclyls". Examples include benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, diphenylmethyloxymethyl, triphenylmethyloxymethyl, naphthylmethyloxymethyl, and the following radicals having R or S stereochemistry or racemates:

[0325]

[0326] The term "non-aromatic carbocyclylalkyloxyalkyl" refers to an alkyloxyalkyl substituted by one or more of the above-mentioned "non-aromatic carbocyclyls". The term "non-aromatic carbocyclylalkyloxyalkyl" also includes "non-aromatic carbocyclylalkyloxyalkyl" in which the alkyl portion bonded to the non-aromatic carbocyclic ring is substituted by the above-mentioned "aromatic carbocyclyl". Examples include cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl and the following radicals having R or S stereochemistry or racemates:

[0327]

[0328] The term "aromatic heterocyclylalkyloxyalkyl" refers to an alkyloxyalkyl group substituted by one or more of the above-mentioned "aromatic heterocyclyl groups". "Aromatic heterocyclylalkyloxyalkyl" also includes "aromatic heterocyclylalkyloxyalkyl" groups in which the alkyl portion bonded to the aromatic heterocycle is substituted by the above-mentioned "aromatic carbocyclyl" and / or "non-aromatic carbocyclyl". Examples include pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothienylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyloxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl and the following groups having R or S stereochemistry or racemates:

[0329]

[0330] The term "non-aromatic heterocyclylalkyloxyalkyl" refers to an alkyloxyalkyl group substituted by one or more of the above-mentioned "non-aromatic heterocyclyl groups". "Non-aromatic heterocyclylalkyloxyalkyl" also includes "non-aromatic heterocyclylalkyloxyalkyl" groups in which the alkyl moiety bonded to the non-aromatic heterocycle is substituted by the above-mentioned "aromatic carbocyclyl", "non-aromatic carbocyclyl" and / or "aromatic heterocyclyl". Examples include tetrahydropyranylmethyloxymethyl, morpholinylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl and the following groups having R or S stereochemistry or racemates:

[0331]

[0332] In the compound represented by formula (I), ring A, ring B, and 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 described below. Compounds having any possible combination described below are preferred.

[0333] In formula (I), the group represented by the following formula:

[0334]

[0335] is a group represented by the following formula:

[0336]

[0337] R 1 and wherein the at least one alkyl radical is independently halogen, hydroxyl, 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.

[0338] Preferably, R 1 Each is independently halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.

[0339] More preferably, R 1 Each is independently halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.

[0340] In formula (I), the group represented by the following formula:

[0341]

[0342] In the case of a group represented by the following formula:

[0343]

[0344] Preferably, R 1Each is independently halogen or substituted or unsubstituted alkyl.

[0345] More preferably, R 1 are each independently halogen.

[0346] In formula (I), the group represented by the following formula:

[0347]

[0348] In the case of a group represented by the following formula:

[0349]

[0350] Preferably, R 1 Each is independently a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group.

[0351] When R 1 In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.

[0352] When R 1 In the case of a substituted group, further preferred substituents on the substituted group are selected from halogen and the like.

[0353] m is 0, 1, 2, 3 or 4. Preferably, m is 0, 1 or 2. Further preferably, m is 1 or 2. Particularly preferably, m is 1.

[0354] In the case where m is 1, in formula (I), the group represented by the following formula:

[0355]

[0356] Preferably

[0357]

[0358] In the case where m is 1, in formula (I), the group represented by the following formula:

[0359]

[0360] Preferably

[0361]

[0362] In the case where m is 2, in formula (I), the group represented by the following formula:

[0363]

[0364] Preferably

[0365]

[0366] In the case where m is 2, in formula (I), the group represented by the following formula:

[0367]

[0368] Preferably

[0369]

[0370] R 2 is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group.

[0371] Preferably, R 2 is halogen or substituted or unsubstituted alkyl.

[0372] More preferably, R 2 is a substituted or unsubstituted alkyl group.

[0373] When R 2 In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.

[0374] When R 2 In the case of a substituted group, further preferred substituents on the substituted group are selected from halogen and the like.

[0375] R 3a , R 3b , R 3c and R 3d are each independently a hydrogen atom, a halogen, 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 Not all are hydrogen atoms.

[0376] Preferably, R 3a is a hydrogen atom or a halogen. Further preferably, R 3a A hydrogen atom.

[0377] Preferably, R 3b is a hydrogen atom or a halogen. Further preferably, R 3b It is a halogen.

[0378] Preferably, R 3c is a hydrogen atom or a halogen. Further preferably, R 3c A hydrogen atom.

[0379] Preferably, R 3d is a hydrogen atom or a halogen. Further preferably, R 3d A hydrogen atom.

[0380] Where R 3b is a halogen, and R 3a , R 3c and R 3d An embodiment in which it is a hydrogen atom is also preferred.

[0381] Where R 3a is a halogen, and R 3b , R 3c and R 3d An embodiment in which it is a hydrogen atom is also preferred.

[0382] Where R 3b and R 3c are each independently halogen, and R 3a and R 3d An embodiment in which it is a hydrogen atom is also preferred.

[0383] Where R 3a and R 3b are each independently halogen, and R 3c and R 3d An embodiment in which it is a hydrogen atom is also preferred.

[0384] Where R 3a and R 3c are each independently halogen, and R 3b and R 3d An embodiment in which it is a hydrogen atom is also preferred.

[0385] When R 3a In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxyl, alkyloxy and the like.

[0386] When R 3b In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxyl, alkyloxy and the like.

[0387] When R 3c In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxyl, alkyloxy and the like.

[0388] When R 3d In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxyl, alkyloxy and the like.

[0389] Ring C is represented as follows:

[0390]

[0391] wherein the left bond is to a group represented by the formula:

[0392]

[0393] and is right-bonded to a group represented by the following formula:

[0394]

[0395] Preferably, ring C is represented as follows:

[0396]

[0397] Further preferably, ring C is represented as follows:

[0398]

[0399] Particularly preferably, ring C represents the following:

[0400]

[0401] Most preferably, Ring C is represented as follows:

[0402]

[0403] Wherein ring C is represented as follows:

[0404] The embodiment of wherein ring C is represented as follows:

[0405] The embodiment of is also preferred.

[0406] X is CH or N.

[0407] Y is CH or N.

[0408] The embodiment wherein X is N and Y is N is also preferred.

[0409] Also preferred are embodiments wherein X is N and Y is CH.

[0410] The embodiment wherein X is CH and Y is N is also preferred.

[0411] R 4 are each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

[0412] Two R attached to adjacent carbon atoms 4The group may form, together with the carbon atom to which it is attached, 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;

[0413] Two R attached to the same carbon atom 4 The group may form, together with the carbon atom to which it is attached, 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;

[0414] Two R's 4 The groups may together form a (C2-C4) bridge in which one of the carbon atoms of the bridge may optionally be replaced by an oxygen atom or a nitrogen atom; the carbon atoms of the bridge are each independently selected from R 4C and the nitrogen atom of the bridge, if present, is selected from R 4N substituted by a substituent.

[0415] Preferably, R 4 Each is independently halogen or substituted or unsubstituted alkyl.

[0416] More preferably, R 4 Each is independently a substituted or unsubstituted alkyl group.

[0417] Two of the R 4 An embodiment in which the groups together form a (C2-C4) bridge is also preferred. For example, it includes the following:

[0418]

[0419] where two R attached to adjacent carbon atoms 4 The embodiment in which the group together with the carbon atom to which it is attached forms a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring is also preferred. For example, it includes the following (in the form of racemic or stereo-defined cis- or trans-fused isomers):

[0420]

[0421] The two R attached to the same carbon atom 4 The embodiment in which the group together with the carbon atom to which it is attached forms a substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic ring is also preferred. For example, it includes the following:

[0422]

[0423] When R 4 In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.

[0424] R 4C Each is independently a hydrogen atom, a halogen, a hydroxyl group, a cyano group, or a substituted or unsubstituted alkyl group.

[0425] Preferably, R 4C Each is independently a hydrogen atom, a halogen, or a substituted or unsubstituted alkyl group.

[0426] More preferably, R 4C are each independently a hydrogen atom.

[0427] When R 4C In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, amino, alkyloxy, alkylamino, and the like.

[0428] R 4N Each is independently a hydrogen atom or a substituted or unsubstituted alkyl group.

[0429] Preferably, R 4N Each is independently a substituted or unsubstituted alkyl group.

[0430] When R 4N In the case of a substituted group, preferred substituents on the substituted group are selected from halogen and the like.

[0431] p is 0 or 1. Preferably, p is 1.

[0432] q is 0, 1, 2, 3 or 4. Preferably, q is 0, 1 or 2. Further preferably, q is 1 or 2. Particularly preferably, q is 1.

[0433] 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; if R 5 , R 6 , R 7 , R 8 and R 9 Not N at the same time.

[0434] Preferably, R 5 CR 5C .

[0435] Preferably, R 6 CR 6C .

[0436] Preferably, R 7 CR 7C .

[0437] Preferably, R 8 CR 8C .

[0438] Preferably, R 9 CR 9C .

[0439] R 5C , R 6C , R 7C , R 8C and R 9C each is independently a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted alkenyloxy group, a substituted or unsubstituted alkynyloxy group, a substituted or unsubstituted aromatic carbocyclyloxy group, a substituted or unsubstituted non-aromatic carbocyclyloxy group, a substituted or unsubstituted aromatic heterocyclyloxy group, a substituted or unsubstituted non-aromatic heterocyclyloxy group, or a pentafluorosulfenyl group.

[0440] Preferably, R 5C and R 9C Each is independently a hydrogen atom or a halogen. Further preferably, R 5C and R 9C A hydrogen atom.

[0441] When R 5C In the case of a substituted group, preferred substituents on the substituted group are selected from halogen and the like.

[0442] When R 9C In the case of a substituted group, preferred substituents on the substituted group are selected from halogen and the like.

[0443] Preferably, R 6C and R 8C Each is independently a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group.

[0444] More preferably, R 6C and R 8C Each is independently a hydrogen atom, a halogen, or a substituted or unsubstituted alkyloxy group. 6C and R 8C Each is independently a hydrogen atom or a substituted or unsubstituted alkyloxy group.

[0445] Most preferably, R 6C and R 8C A hydrogen atom.

[0446] When R 6C In the case of a substituted group, preferred substituents on the substituted group are selected from halogen and the like.

[0447] When R 8C In the case of a substituted group, preferred substituents on the substituted group are selected from halogen and the like.

[0448] Preferably, R 7C is a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, or a substituted or unsubstituted non-aromatic carbocyclyloxy group.

[0449] More preferably, R 7C is halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.

[0450] Particularly preferably, R 7C is a substituted or unsubstituted alkyl group or a substituted or unsubstituted alkyloxy group.

[0451] Most preferably, R 7C is a substituted or unsubstituted alkyloxy group, including a trihaloalkyloxy group (e.g., OCF 3 ).

[0452] When R 7C In the case of a substituted group, preferred substituents on the substituted group are selected from halogen, hydroxy, amino, alkyloxy, alkylamino, non-aromatic carbocyclic group and the like.

[0453] When R 7C In the case of a substituted group, more preferably the substituent on the substituted group is selected from halogen and the like.

[0454] Preferred combinations of substituents of the compound represented by formula (I) include the following 1) to 6):

[0455] 1) A compound wherein a group represented by the following formula:

[0456]

[0457] is a group represented by:

[0458]

[0459] 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 halogen; R 3a , R3c and R 3d is a hydrogen atom; Ring C is represented as follows, having R or S stereochemistry or a racemate:

[0460]

[0461] R 4 is a substituted or unsubstituted alkyl group; R 5 , R 6 , R 8 and R 9 CH; R 7 CR 7C ; R 7C is a substituted or unsubstituted alkyloxy group, including a trihaloalkyloxy group (eg, OCF 3 ):

[0462] 2) A compound wherein a group represented by the following formula:

[0463]

[0464] is a group represented by:

[0465]

[0466] R 1 are each independently halogen; R 2 are each independently a substituted or unsubstituted alkyl group; R 3b is halogen; R 3a , R 3c and R 3d is a hydrogen atom; Ring C is represented as follows, having R or S stereochemistry or a racemate:

[0467]

[0468] R 4 is a substituted or unsubstituted alkyl group; R 5 , R 6 , R 8 and R 9 CH; R 7 CR 7C ; R 7C is a substituted or unsubstituted alkyloxy group, including a trihaloalkyloxy group (eg, OCF 3 ):

[0469] 3) A compound wherein the group represented by the following formula:

[0470]

[0471] is a group represented by:

[0472]

[0473] R 1 are each independently halogen; R 2 are each independently a substituted or unsubstituted alkyl group; R 3a is halogen; R 3b , R 3c and R 3d is a hydrogen atom; Ring C is represented as follows:

[0474]

[0475] R 5 , R 6 , R 8 and R 9 CH; R 7 CR 7C ; R 7C is a substituted or unsubstituted alkyl group:

[0476] 4) A compound wherein the group represented by the following formula:

[0477]

[0478] is a group represented by:

[0479]

[0480] R 1 are each independently halogen; R 2 are each independently a substituted or unsubstituted alkyl group; R 3b is halogen; R 3a , R 3c and R 3d is a hydrogen atom; Ring C is represented as follows, having R or S stereochemistry or a racemate:

[0481]

[0482] R 4 is a substituted or unsubstituted alkyl group; R 5 , R 6 , R 8 and R 9 CH; R 7 CR 7C ; R 7C is a substituted or unsubstituted alkyloxy group, including a trihaloalkyloxy group (eg, OCF 3 ):

[0483] 5) A compound wherein the group represented by the following formula:

[0484]

[0485] is a group represented by:

[0486]

[0487] R 1 are each independently a substituted or unsubstituted alkyl group; R 2 are each independently a substituted or unsubstituted alkyl group; R 3b is halogen; R 3a , R 3c and R 3d is a hydrogen atom; Ring C is represented as follows, having R or S stereochemistry or a racemate:

[0488]

[0489] R 4 is a substituted or unsubstituted alkyl group; R 5 , R 6 , R 8 and R 9 CH; R 7 CR 7C ; R 7C is a substituted or unsubstituted alkyloxy group, including a trihaloalkyloxy group (eg, OCF 3 ):

[0490] 6) A compound, wherein ring A and ring B are represented as follows:

[0491]

[0492] R 1 are each independently a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group; R 2 are each independently a substituted or unsubstituted alkyl group; R 3b is halogen; R 3a , R 3c and R 3d is a hydrogen atom; Ring C is represented as follows:

[0493]

[0494] R 4 is a substituted or unsubstituted alkyl group; R 5 , R 6 , R 8 and R 9 CH; R 7 CR 7C ; R 7Cis a substituted or unsubstituted alkyloxy group, including a trihaloalkyloxy group (eg, OCF 3 ).

[0495] The compounds of formula (I) are not limited to specific isomers, but include all possible isomers (eg, keto-enol isomers, imine-enamine isomers, diastereomers, enantiomers or rotational isomers), racemates or mixtures thereof.

[0496] One or more hydrogen, carbon and / or other atoms in the compound 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, such as 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 substituted with these isotopes. The compounds substituted with the above isotopes can be used as drugs, and include all radiolabeled compounds of the compounds of formula (I). The present invention covers the "radiolabeling method" in the manufacture of "radiolabeled compounds", and the "radiolabeled compounds" can be used for metabolic drug pharmacokinetic studies, binding assays and / or diagnostic tool studies.

[0497] Radiolabeled compounds of the compound of formula (I) can be prepared using methods well known in the field of the present invention. For example, tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a compound of formula (I) by using a catalytic dehalogenation reaction of tritium. The method includes reacting a suitably halogenated compound precursor 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 preparation methods for tritium-labeled compounds of formula (I) can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be used with 14 Preparation of raw materials of C.

[0498] Pharmaceutically acceptable salts of compounds of formula (I) include, for example, salts formed 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 salts formed with 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.

[0499] The compound of formula (I) or its pharmaceutically acceptable salt may form a solvate (e.g., a hydrate), a co-crystal and / or a crystalline polymorph. The present invention encompasses those various solvates, co-crystals and / or crystalline polymorphs. "Solvates" may be those 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 pharmaceutically acceptable salt is allowed to stand in the atmosphere, the compound may absorb moisture, causing the adsorbed water to attach or form a hydrate. Recrystallization of the compound of formula (I) or its pharmaceutically acceptable salt may produce a crystalline polymorph. "Co-crystal" refers to a compound of formula (I) or its salt and a counter-molecule present in the same crystal lattice, and it may be formed with any number of counter-molecules.

[0500] The compound of formula (I) of the present invention or its pharmaceutically acceptable salt can form a prodrug. The present invention also covers various prodrugs of this type. Prodrugs are derivatives of compounds of the present invention having chemically degradable groups or metabolically degradable groups, and compounds that are converted into pharmaceutically active compounds of the present invention by solvent decomposition in vivo or under physiological conditions. Prodrugs include compounds that are converted into compounds of formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. in vivo under physiological conditions, compounds that are converted into compounds of formula (I) by hydrolysis by gastric acid, etc. The method of selecting and preparing suitable prodrug derivatives is described in, for example, "Design of Prodrugs, Elsevier, Amsterdam, 1985". The prodrug itself may have a certain activity.

[0501] When the compound of formula (I) or a pharmaceutically acceptable salt thereof has one or more hydroxyl groups, the prodrugs include acyloxy derivatives and sulfonyloxy derivatives, which are prepared, for example, by reacting a compound having one or more hydroxyl groups with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride and a mixed anhydride, or with a condensing agent. For example, they include CH 3 COO-, C 2 H 5 COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-、CH 3 CH(NH 2 )COO-、CH 2 N(CH 3 ) 2 COO-、CH 3 SO 3 -、CH 3 CH 2 SO 3 -、CF 3 SO 3 -、CH 2 FSO 3 -、CF 3 CH 2 SO 3 -、p-CH 3 O-PhSO 3 -、PhSO 3 - and p-CH 3 PhSO 3 -.

[0502] The term "pharmaceutically acceptable" means prophylactically or therapeutically harmless.

[0503] The general procedure for synthesizing the compounds of the present invention is described below. The starting materials and reagents used in this synthesis are commercially available, or can be synthesized using commercially available compounds according to methods well known in the art. Further, extraction, purification, etc. can be carried out according to methods performed in the art.

[0504] In all the following steps, when there is a substituent that hinders the reaction, for example, a hydroxyl, a thiol, an amino, a formyl, a carbonyl, a carboxyl, 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 Reference A), and the protecting group can be removed at a desired stage. In addition, in all the steps, the order of the steps to be performed can be appropriately changed, and each intermediate can be separated and used in the next step. Reaction time, reaction temperature, solvent, reagent, protecting group, etc. are only exemplary and not limited, as long as they do not adversely affect the reaction.

[0505] For example, the compound represented by formula (I) of the present invention can be produced according to the general procedure described below. In addition, the compound of the present invention can be prepared according to other methods based on the knowledge of organic chemistry.

[0506] Preparation of compound a3

[0507]

[0508] in

[0509] PG is an amino protecting group, such as Boc, Cbz, etc.; R a1 is halogen, trifluoromethanesulfonate, perfluorobutanesulfonate, methanesulfonate or toluenesulfonate, etc.; other symbols are as defined above.

[0510] In the presence of a base, compound a1 reacts with a2 to obtain compound a3.

[0511] Examples of the solvent include toluene, DMF, DMA, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane, and the like, and these solvents may be used alone or in combination.

[0512] Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a1.

[0513] The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction may be performed in a sealed tube as necessary.

[0514] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0515] Preparation of compound a5

[0516]

[0517] where each symbol is as defined above.

[0518] Compound a5 can be obtained by reacting compound a3 with a deprotecting agent and then reacting compound a4 in the presence of palladium, a ligand and a base.

[0519] Examples of the reaction solvent for the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.

[0520] Examples of deprotecting agents include hydrochloric acid / ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum chloride, bromocatechol borane, trimethylsilyl chloride, trifluoromethanesulfonic acid trimethylsilyl ester, etc. The deprotecting agent can be used in an amount of 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents of compound a4.

[0521] Examples of palladium include palladium acetate, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 etc. The amount of palladium used may be 0.01 to 5 molar equivalents, preferably 0.01 to 1 molar equivalent of compound a4.

[0522] Examples of ligands 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, preferably 0.01 to 1 molar equivalent of compound a3.

[0523] Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents of compound a4.

[0524] Examples of the reaction solvent 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.

[0525] The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction may be performed in a sealed tube as necessary.

[0526] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0527] Preparation of compound a6

[0528]

[0529] where each symbol is as defined above.

[0530] Compound a6 can be obtained by reacting a1 with a4 in the presence of palladium, a ligand and a base.

[0531] Examples of palladium include palladium acetate, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 etc. The amount of palladium used may be 0.01 to 5 molar equivalents, preferably 0.01 to 1 molar equivalent of compound a1.

[0532] Examples of ligands 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 used can be 0.01 to 5 molar equivalents, preferably 0.01 to 1 molar equivalent of compound a1.

[0533] Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a1.

[0534] Examples of the reaction solvent 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.

[0535] The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction may be performed in a sealed tube as necessary.

[0536] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0537] Preparation of compound a5

[0538]

[0539] where each symbol is as defined above.

[0540] Compound a5 can be obtained by reacting compound a6 with a deprotecting agent and then reacting compound a2 in the presence of a base.

[0541] Examples of the reaction solvent for the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.

[0542] Examples of deprotecting agents include hydrochloric acid / ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum chloride, bromocatechol borane, trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate, etc. The deprotecting agent can be used in an amount of 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents of compound a2.

[0543] Examples of the solvent include toluene, DMF, DMA, dimethyl sulfoxide, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane, and the like, and these solvents may be used alone or in combination.

[0544] Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a2.

[0545] The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction may be performed in a sealed tube as necessary.

[0546] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0547] Preparation of compound a7

[0548]

[0549] where each symbol is as defined above.

[0550] Compound a7 can be obtained by reacting compound a5 with a reducing agent.

[0551] Examples of the reaction solvent include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.

[0552] Examples of reducing agents include hydrogen and Pd on carbon, hydrogen and Pd(OH) 2 , sodium borohydride and NiCl 2 (H 2 O) 6, lithium aluminum hydride, etc. The amount of the reducing agent used can be 1 to 100 molar equivalents, preferably 1 to 10 molar equivalents of compound a5.

[0553] The reaction temperature may be 0°C to 200°C, preferably 0°C to 100°C.

[0554] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0555] Preparation of compound a9

[0556]

[0557] in

[0558] R a2 is halogen, trifluoromethanesulfonate, perfluorobutanesulfonate, methanesulfonate, toluenesulfonate, boric acid or borate, R a3 is trifluoromethanesulfonate, perfluorobutanesulfonate, methanesulfonate, toluenesulfonate, boric acid or borate, and the other symbols are as defined above.

[0559] In the presence of palladium and a base, compound a1 reacts with a8 to obtain compound a9.

[0560] Examples of palladium include palladium acetate, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , PdCl 2 (dppf), etc. The amount of palladium used may be 0.01 to 5 molar equivalents, preferably 0.01 to 1 molar equivalents of compound a1.

[0561] Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents of compound a1.

[0562] Examples of the reaction solvent 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.

[0563] The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction may be performed in a sealed tube as necessary.

[0564] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0565] Preparation of compound a10

[0566]

[0567] where each symbol is as defined above.

[0568] Compound a10 can be obtained by reacting compound a4 with a deprotecting agent and then reacting compound a9 with compound a9 in the presence of palladium, a ligand and a base.

[0569] Examples of the reaction solvent for the deprotection reaction include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.

[0570] Examples of deprotecting agents include hydrochloric acid / ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum chloride, bromocatechol borane, trimethylsilyl chloride, trifluoromethanesulfonic acid trimethylsilyl ester, etc. The deprotecting agent can be used in an amount of 1 to 100 molar equivalents, preferably 1 to 50 molar equivalents of compound a4.

[0571] Examples of palladium include palladium acetate, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 etc. The amount of palladium used may be 0.01 to 5 molar equivalents, preferably 0.01 to 1 molar equivalent of compound a4.

[0572] Examples of ligands 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, preferably 0.01 to 1 molar equivalent of compound a4.

[0573] Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents of compound a4.

[0574] Examples of the reaction solvent 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.

[0575] The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction may be performed in a sealed tube as necessary.

[0576] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0577] Preparation of compound a11

[0578]

[0579] where each symbol is as defined above.

[0580] Compound a11 can be obtained by reacting compound a10 with a reducing agent.

[0581] Examples of the reaction solvent include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.

[0582] Examples of reducing agents include sodium borohydride and NiCl 2 (H 2 O) 6 , lithium aluminum hydride, borane tetrahydrofuran, borane dimethyl sulfide, etc. The amount of the reducing agent used can be 1 to 100 molar equivalents, preferably 1 to 10 molar equivalents of compound a10.

[0583] The reaction temperature may be 0°C to 200°C, preferably 0°C to 100°C.

[0584] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0585] Preparation of compound a13

[0586]

[0587] where each symbol is as defined above.

[0588] Compound a13 can be obtained by reacting Compound a7 with carboxylic acid (Compound a12) in the presence of a condensing agent and a base.

[0589] Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.

[0590] Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12.

[0591] Examples of the condensing agent include HATU, WSC, DCC, HOBt, etc. The condensing agent may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12.

[0592] The amount of the carboxylic acid used may be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents of compound a7.

[0593] The reaction temperature may be from ice cooling to reflux temperature, preferably room temperature.

[0594] The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

[0595] Preparation of compound a14

[0596]

[0597] where each symbol is as defined above.

[0598] Compound a14 can be obtained by reacting Compound a11 with carboxylic acid (Compound a12) in the presence of a condensing agent and a base.

[0599] Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.

[0600] Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12.

[0601] Examples of the condensing agent include HATU, WSC, DCC, HOBt, etc. The condensing agent may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12.

[0602] The amount of the carboxylic acid used may be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents of compound a11.

[0603] The reaction temperature may be from ice cooling to reflux temperature, preferably room temperature.

[0604] The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

[0605] Preparation of compound a15

[0606]

[0607] where each symbol is as defined above.

[0608] Compound a15 can be obtained by reacting compound a10 with a reducing agent.

[0609] Examples of the reaction solvent include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.

[0610] Examples of reducing agents include hydrogen and palladium on carbon, hydrogen and Pd(OH) 2 The reducing agent may be used in an amount of 1 to 100 molar equivalents, preferably 1 to 10 molar equivalents of compound a10.

[0611] The reaction temperature may be 0°C to 200°C, preferably 0°C to 100°C.

[0612] The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

[0613] Preparation of compound a16

[0614]

[0615] where each symbol is as defined above.

[0616] Compound a16 can be obtained by reacting Compound a15 with carboxylic acid (Compound a12) in the presence of a condensing agent and a base.

[0617] Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.

[0618] Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, etc. The base may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12.

[0619] Examples of the condensing agent include HATU, WSC, DCC, HOBt, etc. The condensing agent may be used in an amount of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, of compound a12.

[0620] The amount of the carboxylic acid used may be 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents of compound a15.

[0621] The reaction temperature may be from ice cooling to reflux temperature, preferably room temperature.

[0622] The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

[0623] The compounds of the present invention can be used to treat or prevent mycobacterial infections, especially non-tuberculous mycobacterial infections. Such compounds can act by interfering with the ATP synthase of pathogenic mycobacteria, with inhibition of cytochrome bc1 as the main mode of action.

[0624] The compounds of the present invention not only have the above-mentioned activities, but can also be used as medicines, and have any or all of the following excellent properties:

[0625] a) The inhibitory activity of CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.

[0626] b) The compound exhibits good pharmacokinetics, such as high bioavailability, moderate clearance, and high dispersion into target tissues.

[0627] c) The compound has high metabolic stability.

[0628] d) The compound has no irreversible inhibitory effect on a CYP enzyme (eg, CYP3A4) when the concentration is within the range described as a measurement condition in the specification of the present invention.

[0629] e) The compound is not mutagenic.

[0630] f) The compound is associated with lower cardiovascular risk.

[0631] g) The compound has high solubility.

[0632] h) Compounds cause less induction of drug metabolizing enzymes

[0633] i) the compound has a lower risk of phototoxicity,

[0634] j) the compound has a low risk of hepatotoxicity,

[0635] k) The compound has a lower risk of nephrotoxicity,

[0636] l) the compound has a lower risk of gastrointestinal dysfunction, and

[0637] m) The compound has a strong effect.

[0638] The administration route of the drug of the present invention may be by oral or parenteral administration without particular limitation.

[0639] In the case of oral administration, it can be administered in the form of a solid preparation for internal use (e.g., tablets, powders, granules, capsules, pills, films), internal solutions (e.g., suspensions, emulsions, elixirs, syrups, lemonades, alcohol solutions, aromatic solutions, extracts, decoctions, tinctures), etc. by common means. 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.

[0640] In the case of parenteral administration, any form of injection, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, coatings, mouthwashes, enemas, ointments, plasters, gels, creams, patches, pastes, external powders, suppositories) commonly used can be appropriately applied. The injection may be an emulsion, such as O / W, W / O, O / W / O or W / O / W type.

[0641] Optionally, the effective amount of the compound used in the medicine of the present invention can be mixed with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrating agents and / or lubricants as needed to obtain a pharmaceutical composition. In addition, by appropriately changing the effective amount, dosage form and / or various pharmaceutical additives of the compound used in the medicine of the present invention, the pharmaceutical composition can be used for children, the elderly, critically ill patients or surgery. The children's pharmaceutical composition is preferably applied to patients under 12 years old or 15 years old. The children's pharmaceutical composition can also be applied to patients less than 4 weeks after birth, 4 weeks after birth to less than 1 year old, 1 year old to less than 7 years old, 7 years old to less than 15 years old, or 15 years old to 18 years old. The elderly pharmaceutical composition is preferably applied to patients over 65 years old.

[0642] Although the dosage of the pharmaceutical composition of the present invention should be determined in consideration of the patient's age and weight, the type and extent of the disease, the route of administration, etc., the commonly used oral dosage is 0.05 to 100 mg / kg / day and preferably 0.1 to 10 mg / kg / day. For parenteral administration, although the dosage is highly variable due to the route of administration, the commonly used dosage is 0.005 to 10 mg / kg / day and preferably 0.01 to 1 mg / kg / day. The dosage can be administered once a day or in several divided doses.

[0643] In general, pharmaceutical compositions contain an effective amount of active compounds to achieve their intended purpose. In one embodiment, a therapeutically effective amount is an amount that effectively prevents or inhibits the development or progression of a disease characterized by mycobacterial infection or activity in a treated subject. Based on the description provided herein, the determination of an effective amount is within the capabilities of those skilled in the art.

[0644] In some embodiments, the medicaments of the present invention are suitable for treating and / or preventing diseases and disorders characterized by mycobacterial activity or infection. Mycobacteria can be pathogenic or non-pathogenic. Mycobacteria can be Gram-positive or Gram-negative.

[0645] In some embodiments, the medicament of the present invention is suitable for treating tuberculous, leprotic and non-tuberculous mycobacteria in humans (either or both immunocompetent and immunocompromised) and animals. Non-limiting examples of these include, but are not limited to, the following species and strains: tuberculous mycobacteria, such as M. tuberculosis, M. bovis, M. africanum, M. microti, M. canetti; leprotic mycobacteria, such as M. leprae, M. lepromatosis; non-tuberculous mycobacteria, such as M. abscessus, M. abscessus complex, M. avium, M. intracellularae, M. avium complex complex), M. kansasii, M. malmoense, M. xenopi, M. malmoense, M. flamences, M. scrofulaceum, M. chelonae, M. peregrinum, M. haemophilum, M. fortuitum, M. marinum, M. ulcerans, M. gordonae, M. haemophilum, M. mucogenicum, M. nonchromogenicum, M. terrae, M. terrae complex complex), Mycobacterium asiaticum, Mycobacterium celatum, Mycobacterium shimoidei, Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium szulgai, Mycobacterium celatum, Mycobacterium conspicuum, Mycobacterium genavense, Mycobacterium immunogenum, Mycobacterium xenopi.

[0646] In some embodiments, the medicaments of the invention are suitable for use in treating non-mycobacterial infectious diseases in humans (both immunocompetent and immunocompromised) and animals.

[0647] In some embodiments, the subject is known or suspected to be in need of treatment for one or more conditions associated with the non-pathogenic mycobacterium strains: M. smegmatis, M. vaccae, M. aurum, or a combination thereof.

[0648] In some embodiments, the subject is a known or suspected subject in need of treatment for one or more conditions associated with Gram-positive bacteria, Staphylococcus aureus (S. aureus), Micrococcus luteus (M. luteus), or a combination thereof.

[0649] In some embodiments, the subject is a known or suspected subject in need of treatment for one or more conditions associated with Gram-negative bacteria, P. aeruginosa, A. baumanii, or a combination thereof.

[0650] In some embodiments, the subject is a subject known or suspected of being in need of treatment for one or more conditions associated with a pathogenic mycobacterium strain: Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, H37Rv, Mycobacterium africanum, Mycobacterium casseri, Mycobacterium caprae, Mycobacterium voles, Mycobacterium mungi, Mycobacterium pinnipedii, Mycobacterium leprae, Mycobacterium avium, Mycobacterium tuberculosis complex, or a combination thereof.

[0651] In some embodiments, the subject is a subject known or suspected of being in need of treatment for one or more conditions associated with non-pathogenic mycobacterial strains (Mycobacterium smegmatis, Mycobacterium vaccae, Mycobacterium aureus), Gram-positive bacteria (Staphylococcus aureus, Micrococcus luteus), Gram-negative bacteria (Pseudomonas aeruginosa, Acinetobacter baumannii), pathogenic mycobacterial strains (Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, H37Rv, Mycobacterium africanum, Mycobacterium casserovar, Mycobacterium capricolum, Mycobacterium microti, Mycobacterium manchifolia, Mycobacterium sealis, Mycobacterium avium, Mycobacterium tuberculosis complex, Mycobacterium tuberculosis), or a combination thereof.

[0652] In some embodiments, a method is provided, the method comprising killing or inhibiting the growth of one or more of the following populations by contacting one or more members of the population with a compound or composition used in the present invention: non-pathogenic mycobacterial strains (Mycobacterium smegmatis, Mycobacterium vaccae, Mycobacterium aureus), Gram-positive bacteria (Staphylococcus aureus, Micrococcus luteus), Gram-negative bacteria (Pseudomonas aeruginosa, Acinetobacter baumannii), pathogenic mycobacterial strains (Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium marinum, Mycobacterium kansasii, H37Rv, Mycobacterium africanum, Mycobacterium casserovar, Mycobacterium caprae, Mycobacterium voles, Mycobacterium mancheene, Mycobacterium seal, Mycobacterium avium, Mycobacterium tuberculosis complex, Mycobacterium tuberculosis) or a combination thereof.

[0653] [Example]

[0654] The present invention is explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0655] The compound represented by formula (I) of the present invention can be prepared by referring 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.

[0656] In addition, the abbreviations used in this document have the following meanings:

[0657] Me:Methyl

[0658] Et: Ethyl

[0659] Bu: Butyl

[0660] Ph: phenyl

[0661] PPh 3 :Triphenylphosphine

[0662] Ac:Acetyl

[0663] EtOAc: ethyl acetate

[0664] DMF: N,N-dimethylformamide

[0665] DMA: N,N-dimethylacetamide

[0666] TFA: trifluoroacetic acid

[0667] DMSO: dimethyl sulfoxide

[0668] THF: Tetrahydrofuran

[0669] WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0670] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium; 3-oxide, hexafluorophosphate

[0671] DCC: N,N'-dicyclohexylcarbodiimide

[0672] HOBt: Hydroxybenzotriazole

[0673] Boc: tert-Butyloxycarbonyl

[0674] t: uncle

[0675] Cbz: benzyloxycarbonyl

[0676] dppf: 1,1'-bis(diphenylphosphino)ferrocene

[0677] Pd 2 (dba) 3 :Tris(dibenzylideneacetone)dipalladium

[0678] PdCl 2 (dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0679] Pd(PPh 3 ) 4 :Tetrakis(triphenylphosphine)palladium(0)

[0680] PdCl 2 (PPh 3 ) 2 :Bis(triphenylphosphine)palladium chloride

[0681] The NMR analysis of each example was performed using deuterated dimethyl sulfoxide (d6-DMSO) or deuterated chloroform (CDCl 3 ), performed at 400 MHz. Where NMR data are indicated, there may be cases where not all measured peaks are described.

[0682] In the specification, "RT" means retention time of LC / MS: liquid chromatography / mass spectrometry, and the measurement conditions are as follows.

[0683] (Method A)

[0684] UHPLC / MS data of the compounds were measured under the following conditions.

[0685] Column: ACQUITY C18(1.7μm,id50x 2.1mm)(Waters)

[0686] Flow rate: 0.8 mL / min

[0687] UV detection wavelength: 254nm

[0688] Mobile phase: [A] an aqueous solution containing 0.1% formic acid, and [B] an acetonitrile solution containing 0.1% formic acid.

[0689] Gradient: A linear gradient from 5% to 100% solvent [B] was performed over 3.5 min and 100% solvent [B] was maintained for 0.5 min.

[0690] (Method B)

[0691] UHPLC / MS data of the compounds were measured under the following conditions.

[0692] Column: ACQUITY C18(1.7μm,id50x 2.1mm)(Waters)

[0693] Flow rate: 0.8 mL / min

[0694] UV detection wavelength: 254nm

[0695] Mobile phase: [A] was an aqueous solution containing 10 mM ammonium carbonate, and [B] was acetonitrile.

[0696] Gradient: A linear gradient from 5% to 100% solvent [B] was performed over 3.5 min and 100% solvent [B] was maintained for 0.5 min.

[0697] Hereinafter, MS (m / z) indicates a value observed in a mass spectrum.

[0698] [Example 1]

[0699] Preparation of compound I-1-3

[0700]

[0701] Step 1

[0702] To a solution of compound 1 (1 g, 7.19 mmol) in DMA (5 mL) was added K 2 CO 3(1.49g, 10.78mmol) and compound 2 (0.792g, 7.91mmol), and the solution was stirred at 100°C for 4.5 hours. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate and filtered. After the organic layer was concentrated under reduced pressure, the residue was washed with hexane to obtain compound 3 (1.01g, yield: 64%) as a solid.

[0703] 1H-NMR(CDCl3)δ:7.38-7.33(1H,m),7.27(1H,dd,J=12.9,1.9Hz),6.91(1H,t,J=8.2Hz),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=6.0Hz).

[0704] Step 2

[0705] To a solution of compound 3 (510 mg, 2.33 mmol) in toluene (5.0 mL) were added 1-bromo-4-(trifluoromethyl)benzene 4 (576 mg, 2.56 mmol), Pd(OAc) 2 (52.2mg, 0.233mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (217mg, 0.465mmol) and sodium tert-butoxide (447mg, 4.65mmol), the solution was stirred at 100 ° C for 1 hour. Water and ethyl acetate were added to the reaction solution. The organic layer was washed with water and 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 obtain compound 5 (543mg, yield: 64%) as a yellow solid.

[0706] 1H-NMR (CDCl3) δ: 7.39 (1H, dd, J = 8.4, 1.9Hz), 7.30 (1H, dd, J = 12.5, 1.9Hz), 7.14 (2H, d, J = 8.3Hz), 6.95 (1H, t, J = 9.2Hz), 6.92 (2H ,d,J=8.3Hz),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=6.4Hz)

[0707] Step 3

[0708] 5% Pd-C (320g, 0.150mmol) and concentrated HCl (1.5mL) were added to a solution of compound 5 (546mg, 1.50mmol) in MeOH (15mL), and the solution was stirred for 5 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. NaOH aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure to obtain compound 6 (440mg, yield: 80%) as a yellow solid.

[0709] 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=6.4Hz).

[0710] Step 4

[0711] 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 to a solution of compound 6 (80 mg, 0.209 mmol) in acetonitrile (2.0 mL), and the solution was stirred at 80 ° C for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 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 (CHCl 3 / methanol) to obtain compound I-1-3 (55 mg, yield: 45%) as a white solid.

[0712] LC / MS method A: m / z = 590.2. [M+H]+, retention time: 3.0 min

[0713] [Example 2]

[0714] Preparation of compound 8

[0715]

[0716] To a solution of compound 7 (20 g, 89 mmol) in acetonitrile (200 mL) was added 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), and the solution was stirred at room temperature for more than 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 obtain compound 8 (19.4 g, yield: 64%) as a solid.

[0717] 1H-NMR(CDCl3)δ:9.26(1H,d,J=1.3Hz), 8.14(1H,d,J=8.4Hz), 7.74(1H,d, J=9.4Hz), 7.62-7.44(4H,m), 3.37(2H,q,J=7.5Hz), 1.53(3H,t,J=7.5Hz).

[0718] [Example 3]

[0719] Preparation of compound 10

[0720]

[0721] To a solution of compound 9 (4.9 g, 23.7 mmol) in acetonitrile (99 mL) was added 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), and the solution was stirred at room temperature for more than 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 obtain compound 10 (5.09 g, yield: 66%) as a white solid.

[0722] 1H-NMR(CDCl3)δ:9.18(1H,dd,J=7.5,5.4Hz), 8.14(1H,dt,J=8.4,0.9Hz), 7.59(1H,dd,J=16.1,8. 0Hz), 7.54-7.40 (3H, m), 6.98 (1H, td, J = 7.5, 2.7Hz), 3.35 (2H, q, J = 7.5Hz), 1.52 (3H, t, J = 7.5Hz).

[0723] [Example 4]

[0724] Preparation of compound I-1-38

[0725]

[0726] To a solution of compound 6 (70 mg, 0.183 mmol) in acetonitrile (1.0 mL) were added 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), and the solution was stirred at 50° C. for 1 hour. Saturated NaHCO 3 Aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and 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 obtain compound I-1-38 (78 mg, yield: 75%) as a white solid.

[0727] 1H-NMR(CDCl3)δ:9.44(1H,t,J=5.6Hz),7.22(1H,s),7.14-7.07(4H,m),6.97-6.92(3H,m),6.80(1H,t,J=7.3Hz),6.06(1H,s),4.63(2H ,d,J=3.8Hz),3.95(1H,d,J=2.0Hz),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=4.5Hz).

[0728] LC / MS method B: m / z = 574.25 [M+H] +, retention time: 2.99 min

[0729] [Example 5]

[0730] Preparation of compound I-1-2

[0731]

[0732] Compound 11 (1.32 g, 4.3 mmol) and triethylamine (0.814 mL, 5.87 mmol) were added to a solution of compound 6 (1.5 g, 3.91 mmol) in dichloromethane (1.0 mL), and the solution was stirred at room temperature for 15 hours. The reaction solution was purified by aminosilica gel and silica gel chromatography (CHCl 3 / methanol) to obtain compound I-1-2 (1.76 g, yield: 81%) as a white solid.

[0733] LC / MS method A: m / z = 574.25 [M+H] +, retention time: 2.99 min

[0734] [Example 6]

[0735] Preparation of compound I-1-70

[0736]

[0737] Compound 12 (64 g, 0.209 mmol) and triethylamine (0.087 mL, 0.626 mmol) were added to a solution of compound 6 (80 mg, 0.209 mmol) in dichloromethane (0.8 mL), and the solution was stirred at room temperature for 15 hours. The reaction solution was purified by aminosilica gel and silica gel chromatography (CHCl 3 / methanol) to obtain compound I-1-70 (47 mg, yield: 41%) as a white solid.

[0738] LC / MS method A: m / z = 556.25 [M+H] +, retention time: 2.94 min

[0739] [Example 7]

[0740] Preparation of compound I-1-25

[0741]

[0742] Compound 13 (29.8 g, 0.156 mmol), triethylamine (0.054 mL, 0.391 mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropane-1-amine (30.4 mg, 0.196 mmol) and HOBt (8.8 mg, 0.065 mmol) were added to a solution of compound 6 (50 mg, 0.130 mmol) in dichloromethane (0.8 mL), and the solution was stirred at room temperature for 15 hours. Saturated NaHCO3 aqueous solution was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with water and 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 (CHCl 3 / methanol) to obtain compound I-1-25 (47 mg, yield: 74.5%) as a white solid.

[0743] LC / MS method A: m / z = 556.3 [M+H] +, retention time: 2.73 min

[0744] [Example 8]

[0745] Preparation of compound I-1-1

[0746]

[0747] Step 1

[0748] To a solution of compound 14 (5.05 g, 21.7 mmol) in 1,4-dioxane (76 mL) were added compound 15 (7.37 g, 23.8 mmol), PdCl 2 (PPh 3 ) 2 (1.52 g, 2.17 mmol) and 2M Na 2 CO 3 Aqueous solution (32.5ml, 65mmol). The reaction mixture was stirred at 100°C for 1.5 hours. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-EtOAc) to obtain compound 16 (6.59g, 19.7mmol, 91%) as a white solid.

[0749] 1H-NMR (400MHz, CDCl3) δ: 7.78 (dd, 1H, J = 7.8, 1.3Hz), 7.70 (dd, 1H, 11.6, 1.3Hz), 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)

[0750] Step 2

[0751] To a solution of compound 16 (6.49 g, 19.4 mmol) in THF (100 ml) purged with an inert atmosphere was added 10% Pd(OH) 2 =Toluene-2-yl pyridine ... 4(1.46g, 38.5mmol) in a suspension in THF (100ml). After stirring for 5 minutes, sodium sulfate decahydrate (24.83g, 77mmol) was added to the reaction mixture, and the reaction was stirred for 3 hours. The reaction mixture was filtered through a celite pad. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure to obtain a crude product in the form of an oil. This crude material was used in the next reaction without further purification. Et was added to a solution of the crude material in dichloromethane (100ml) at -78°C. 3 N (7.93 ml, 57.2 mmol) and methanesulfonyl chloride (3.28 g, 28.6 mmol). H 2 The mixture was added into 1% ethyl acetate (60 ml) and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product in the form of an oil. This crude material was used in the next reaction without further purification. NaN was added to a solution of the crude material in DMF (60 ml). 3 (2.47 g, 37.9 mmol), and the mixture was stirred at 80°C for 1 hour. H 2 The mixture was added into 1% ethyl acetate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product in the form of an oil. This crude product was used in the next reaction without further purification. PPh was added to a solution of the crude product in THF (50 ml) 3 (5.55 g, 21.2 mmol) and H 2 O (3.18 ml, 176 mmol), and the mixture was refluxed with stirring for 2 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography (EtOAc-CHCl 3 -MeOH) to obtain compound 17 (4.11 g, 13.3 mmol, 69% for 5 steps) as a white solid.

[0752] 1H-NMR (400MHz, CDCl3) δ: 7.15 (t, 1H, J = 7.7Hz), 7.04 (d, 1H, J = 7.9Hz), 7.00 (d, 1H, J = 11.3Hz), 4, 24 (s, 2 H),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)

[0753] LC / MS method: A, LC-MS: m / z = 253. [M+H]+, retention time: 1.67 min

[0754] Step 3

[0755] To a solution of compound 17 (1.84 g, 5.97 mmol) in dichloromethane (20 ml) were added compound 11 (2.02 g, 6.56 mmol) and Et 3 N (1.24 ml, 8.95 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (CHCl 3 / MeOH) to obtain compound 18 (2.83 g, 5.89 mmol, 99%) as a white solid.

[0756] LC / MS method: A, LC-MS: m / z = 481. [M+H]+, retention time: 2.17 min

[0757] Step 4

[0758] 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 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by amino silica gel chromatography (CHCl 3 / MeOH) to obtain compound 19 (1.83 g, 4.81 mmol, 95%) as an off-white amorphous substance.

[0759] LC / MS method: A, LC-MS: m / z = 381. [M+H]+, retention time: 1.00 min

[0760] Step 5

[0761] To a solution of compound 19 (100 mg, 0.263 mmol) in THF were added compound 4 (95 mg, 0.394 mmol), Pd 2 (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), and then the reaction was stirred at 60° C. for 1 hour. H 2 O, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / EtOAc) to obtain compound I-1-1 (81.7 mg, 0.151 mmol, 57.5%).

[0762] 1H-NMR (400MHz, CDCl3) δ: 9.32 (d, 1H, J = 7.5Hz), 7.33 (s, 1H), 7.28-7.22 (m, 1H), 7.15-7.04 (m, 4H), 6.94 (d, 2H, J = 7.9Hz), 6.77 (d, 1H, J = 6.5 Hz),6.06(s,1H),4.67(d,2H,J=5.3Hz),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)

[0763] LC / MS method: A, LC-MS: m / z = 541. [M+H]+, retention time: 2.42 min

[0764] The following compounds were obtained according to the general synthesis method and examples. The chemical structures and physical properties (LC / MS data) of the compounds are described below.

[0765] [Table 1]

[0766]

[0767] [Table 2]

[0768]

[0769] [Table 3]

[0770]

[0771] [Table 4]

[0772]

[0773] [Table 5]

[0774]

[0775] [Table 6]

[0776]

[0777] [Table 7]

[0778]

[0779] [Table 8]

[0780]

[0781] [Table 9]

[0782]

[0783] [Table 10]

[0784]

[0785] [Table 11]

[0786]

[0787] [Table 12]

[0788]

[0789] [Table 13]

[0790]

[0791] [Table 14]

[0792]

[0793] [Table 15]

[0794]

[0795] [Table 16]

[0796]

[0797] [Table 17]

[0798]

[0799] [Table 18]

[0800]

[0801] [Table 19]

[0802]

[0803] [Table 20]

[0804]

[0805] [Table 21]

[0806]

[0807] [Table 22]

[0808]

[0809] [Table 23]

[0810]

[0811] [Table 24]

[0812]

[0813] [Table 25]

[0814]

[0815] [Table 26]

[0816]

[0817] [Table 27]

[0818]

[0819] [Table 28]

[0820]

[0821] [Table 29]

[0822]

[0823] The following compounds are also preferred and were obtained according to the general synthetic methods and examples. The chemical structures and physical properties (LC / MS data) of the compounds are described below.

[0824] [Table 30]

[0825]

[0826] [Table 31]

[0827]

[0828] [Table 32]

[0829]

[0830] [Table 33]

[0831]

[0832] [Table 34]

[0833]

[0834] [Table 35]

[0835]

[0836] [Table 36]

[0837]

[0838] [Table 37]

[0839]

[0840] [Table 38]

[0841]

[0842] Pharmacological Examples

[0843] (Test Example 1)

[0844] The IC85 of the test compounds against M. avium was determined.

[0845] preparation

[0846] 1 μL of DMSO stock solution of test compound (200x final concentration) was added to a sterile 96-well round-bottom microtiter plate. A series of four-fold dilutions (8 to 0.0000076 μM) were performed directly in the microtiter plate from columns 1 to 11. Untreated control samples with and without inoculum were included in column 12 of each plate.

[0847] A sample of Mycobacterium avium ATCC700898 was taken from a 7H9 (5% OADC) agar plate. This was first diluted with CAMHB medium to obtain an optical density of 0.1 at a wavelength of 600 nm, and then diluted 1 / 20 to produce an inoculum of approximately 5x10 exp6 colony-forming units per mL. The microtiter plate was filled with 200 μL of inoculum solution.

[0848] The plates were incubated at 37°C in stainless steel strips to prevent evaporation. After 3 days of incubation, resazurin was added to all wells. One day later, fluorescence was measured on an EnVision microplate reader using 543 excitation and 590 nm emission wavelengths and IC85 values ​​were calculated.

[0849] The results of Test Example 1 are shown below.

[0850] [Table 39]

[0851]

[0852] [Table 40]

[0853]

[0854] [Table 41]

[0855]

[0856] (Test Example 2)

[0857] Metabolic stability test

[0858] Using commercially available pooled human liver microsomes, the compounds of the present invention were reacted for a constant time, and by comparing the reacted sample with the unreacted sample, the residual ratio was calculated, thereby evaluating the extent of metabolism in the liver.

[0859] In 0.2mL buffer (50mmol / L Tris-HCl pH 7.4, 150mmol / L potassium chloride, 10mmol / L magnesium chloride) containing 0.5mg protein / mL human liver microsomes, in the presence of 1mmol / L NADPH, the reaction (oxidation reaction) was carried out at 37°C for 0 minutes or 30 minutes. After the reaction, 50μL of the reaction solution was added to 100μL of methanol / acetonitrile=1 / 1 (v / v), mixed and centrifuged at 3000rpm for 15 minutes. The compound of the present invention in the supernatant was quantified 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, and the amount of the compound at 0 minute reaction time was 100%.

[0860] The results of Test Example 2 are shown below.

[0861] [Table 42]

[0862]

[0863] [Table 43]

[0864]

[0865] [Table 44]

[0866]

[0867] The usefulness as a medicine can be checked by the following tests and the like.

[0868] Test Example 3: CYP inhibition test

[0869] Commercially available pooled human liver microsomes were used to assess the extent to which the compounds of the invention inhibited the production of each metabolite as a marker reaction for the five major human CYP isoforms (CYP1A2, 2C9, 2C19, 2D6 and 3A4): 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methylhydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6) and terfenedine hydroxylation (CYP3A4).

[0870] The reaction conditions are as follows: substrate, 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 terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37°C; enzyme, combined human liver microsomes 0.2 mg protein / mL; concentration of the compound of the present invention, 1.0, 5.0, 10, 20 μmol / L (four points).

[0871] Each of the five substrates, human liver microsomes, or compounds of the present invention in 50 mmol / L Hepes buffer was added to a 96-well plate in the composition as described above, and NADPH was added as a cofactor to initiate the metabolic reaction. After incubation at 37°C for 15 minutes, methanol / acetonitrile = 1 / 1 (v / v) solution was added to stop the reaction. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multi-label counter or LC / MS / MS, and hydroxytoluamide (CYP2C9 metabolite), 4'-hydroxymephenytoin (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite) and terfenadine alcohol metabolite (CYP3A4 metabolite) were quantified by LC / MS / MS.

[0872] A sample obtained by adding only DMSO (which is a solvent for dissolving compounds other than the compounds of the present invention) to the reaction mixture was used as a control (100%). Compared with the control, the residual activity (%) at various concentrations of the compounds of the present invention was calculated, and IC 50 The concentrations used and the inhibition rates were calculated by back-calculation using a logistic model.

[0873] Test Example 4: CYP3A4 (MDZ) MBI Test

[0874] The CYP3A4 (MDZ) MBI test is a test to investigate the mechanistic inhibition (MBI) of CYP3A4 inhibition by compounds of the invention by causing an increase in inhibition of the metabolic reactions of the compounds of the invention. CYP3A4 inhibition is assessed using pooled human liver microsomes using the 1-hydroxylation reaction of midazolam (MDZ) as a marker reaction.

[0875] The reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37°C; protein content of combined human liver microsomes, 0.5 mg / mL in pre-reaction, 0.05 mg / mL in reaction (in 10-fold dilution); concentration of the compound of the present invention, 1, 5, 10, 20 μmol / L or 0.83, 5, 10 and 20 μmol / L (four points).

[0876] A solution of combined human liver microsomes and the compound of the present invention in K-Pi buffer (pH 7.4) was added to a 96-well plate as a pre-reaction solution in a pre-reaction composition. A portion of the pre-reaction solution was transferred to another 96-well plate and diluted 1 / 10 by a K-Pi buffer containing a substrate. NADPH was added as a cofactor to start the reaction as a marker reaction (pre-incubation 0 minutes). After the predetermined time of the marker reaction, a solution of methanol / acetonitrile = 1 / 1 (v / v) was added to stop the reaction. In addition, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (pre-incubation 30 minutes). After the predetermined time of the pre-reaction, a portion was transferred to another 96-well plate and diluted 1 / 10 by a K-Pi buffer containing a substrate to start the reaction as a marker reaction. After the predetermined time of the marker reaction, a solution of methanol / acetonitrile = 1 / 1 (v / v) was added to stop the reaction. After centrifugation at 3000rpm for 15 minutes, 1-hydroxymidazolam in the supernatant was quantified by LC / MS / MS.

[0877] The sample obtained by adding only DMSO (which is a solvent for dissolving compounds other than the compounds of the present invention) to the reaction mixture is used as a control (100%). Compared with the control, the residual activity (%) under various concentrations of the compounds of the present invention is calculated, and the IC value is calculated by back-calculation using the concentration and inhibition rate by the logistic model. The shift IC value is calculated as "IC of pre-incubation 0 minutes / IC of pre-incubation 30 minutes". When the shift IC is 1.5 or greater, this is defined as positive. When the shift IC is 1.0 or lower, this is defined as negative.

[0878] Test Example 5: BA Test

[0879] Experimental Materials and Methods for Assessing Oral Absorption

[0880] (1) Animals: Rats

[0881] (2) Housing conditions: Mice or rats were allowed free access to solid food and sterile tap water.

[0882] (3) Dosage and grouping: Oral or intravenous administration at a predetermined dose; grouping is as follows (the dose depends on the compound)

[0883] Oral administration: 2 to 60 μmol / kg or 1 to 30 mg / kg (n=2 to 3)

[0884] Intravenous administration: 1 to 30 μmol / kg or 0.5 to 10 mg / kg (n=2 to 3)

[0885] (4) Preparation of dosing solution: for oral administration, in the form of solution or suspension; for intravenous administration, in the form of solution

[0886] (5) Administration method: For oral administration, the drug is administered by force into the stomach using an oral probe; for intravenous administration, the drug is administered from the tail vein using a syringe equipped with a needle.

[0887] (6) Evaluation items: Blood was collected over time and the plasma concentration of the drug was measured by LC / MS / MS

[0888] (7) Statistical analysis: Regarding the plasma concentration changes of the compounds of the present invention, the area under the plasma concentration-time curve (AUC) was calculated by the nonlinear least squares program WinNonlin (registered trademark), and the bioavailability (BA) was calculated from the AUC of the oral administration group and the intravenous administration group.

[0889] Test Example 6: Fluctuation Ames Test

[0890] The compounds of the invention were evaluated for mutagenicity.

[0891] 20 μL of frozen Salmonella typhimurium (TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and it was incubated at 37°C with shaking for 10 hours. 7.70 to 8.00 mL of TA98 medium was centrifuged (2000×g, 10 minutes). The bacteria were suspended in Micro F buffer (K 2 HPO 4 :3.5g / L,KH 2 PO 4 :1g / L,(NH 4 ) 2 SO 4 : 1g / L, trisodium citrate dihydrate: 0.25g / L, and MgSO 4 7H 20:0.1g / L), the volume of this buffer is the same as the volume of the medium used for centrifugation. The suspension is added to 120mL exposure medium (Micro F buffer containing biotin: 8μg / mL, histidine: 0.2μg / mL and glucose: 8mg / mL). 3.10 to 3.42mL TA100 medium strain is mixed with 120 to 130mL exposure medium. 12 μL each of a DMSO solution of the compound of the present invention (diluted in several stages from a maximum dose of 50 mg / mL at a 2- to 3-fold ratio), DMSO as a negative control; and in the assay without metabolic activation, a 50 μg / mL 4-nitroquinoline 1-oxide DMSO solution for the TA98 strain and a 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain; and in the assay with metabolic activation, a 40 μg / mL 2-aminoanthracene DMSO solution for the TA98 strain and a 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain as positive controls; and 588 μL of the test bacterial suspension (498 μL and 90 μL of the S9 mixture in the case of the metabolic activation assay) were mixed and incubated at 37° C. with shaking for 90 minutes. 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, 37.5 μg / mL bromocresol purple), and 50 μL of each was distributed to 48 wells of the microplate per dose, and incubated at 37°C for 3 days. Since the wells containing bacteria that have acquired the ability to grow by point mutation of the amino acid (histidine) synthetase gene change from purple to yellow due to pH changes, the number of yellow wells in 48 wells was counted per dose and compared with the negative control group. (-) and (+) refer to mutagenicity negative and positive, respectively.

[0892] Test Example 7: hERG test

[0893] For the purpose of evaluating the risk of prolonging the QT interval of the electrocardiogram of the compounds of the present invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels were used to study the effects of the compounds of the present invention on the delayed rectifier K+ current (I Kr ) (which plays an important role in ventricular repolarization).

[0894] The cells were held at a membrane potential of -80 mV and given a -50 mV leak potential by whole-cell patch clamping using an automated patch clamp system (QPatch; Sophion Bioscience A / S). I was recorded after a 2-second depolarizing pulse stimulation at +20 mV and a further 2-second repolarizing pulse stimulation at -50 mV. KrThe extracellular solution (NaCl: 145mmol / L, KCl: 4mmol / L, CaCl) was adjusted to contain 0.1% dimethyl sulfoxide. 2 :2mmol / L,MgCl 2 : 1mmol / L, glucose: 10mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10mmol / L, pH = 7.4) was used as a culture medium. Extracellular fluid (the culture medium and the compound of the present invention had been dissolved therein at respective target concentrations) was applied to the cells at room temperature for 7 minutes or more. From the recording I Kr , using analysis software (QPatch Assay software; Sophion Bioscience A / S), based on the current value at resting membrane potential, the absolute value of the tail peak current was measured. Further, the tail peak current after administration of the compound of the present invention relative to the tail peak current after administration of the culture medium was calculated as % inhibition to evaluate the effect of the compound of the present invention on I Kr impact.

[0895] Test Example 8: Solubility Test

[0896] The solubility of the compound of the present invention is measured under 1% DMSO addition conditions. A solution of 10mmol / L of the compound is prepared with DMSO. 2 μL of the compound solution of the present invention is added to 198 μL of JP-1 fluid or JP-2 fluid, respectively. The mixture is shaken at room temperature for 1 hour, and the mixture is vacuum filtered. The filtrate is diluted 10 times or 100 times with methanol / water=1 / 1 (v / v) or acetonitrile / methanol / water=1 / 1 / 2 (v / v / v), and the compound concentration in the filtrate is measured by absolute calibration method with LC / MS or solid phase extraction (SPE) / MS.

[0897] The composition of JP-1 fluid is as follows.

[0898] Water was added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.

[0899] The composition of JP-2 fluid is as follows.

[0900] 1 volume of water was added to 1 volume of a solution in which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate were dissolved in water to reach 1000 mL.

[0901] Test Example 9: Powder Solubility Test

[0902] An appropriate amount of the compound of the present invention is placed in a suitable container. 200 μL of JP-1 fluid (water is added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL), 200 μL of JP-2 fluid (1 volume of water is added to 1 volume of a solution (in which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate are dissolved in water to reach 1000 mL)) or 20 mmol / L sodium taurocholate (TCA) / JP-2 fluid (JP-2 fluid is added to 1.08 g of TCA to reach 100 mL) is added to each container independently. When the entire amount is dissolved after adding the test reagent, the compound of the present invention is appropriately added. After sealing and shaking at 37° C. for 1 hour, the solution is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to dilute it twice. The dilution rate is changed as needed. After checking that there is no foam and precipitation, the container is sealed and shaken. The compound of the present invention is measured by the absolute calibration curve method using HPLC.

[0903] Test Example 10: P-gp substrate test

[0904] The compound of the present invention is added to one side of Transwell (registered trademark, Corning), where MDR1 expressing cells or parental cells have been cultured in a monolayer. The cells are allowed to react for a constant time. The membrane permeability coefficients of the top surface of the MDR1 expressing cells or parental cells facing the basal side (A→B) and the basal side facing the top surface (B→A) are calculated, and the efflux ratio (ER: ratio of membrane permeability coefficient B→A to A→B) value of the MDR1 expressing cells and parental cells is calculated. The efflux ratio (ER) values ​​of the MDR1 expressing cells and parental cells are compared to confirm whether the compound of the present invention is a P-gp substrate.

[0905] Formulation Example

[0906] The following formulation examples are illustrative only and are not intended to limit the scope of the present invention.

[0907] Formulation Example 1: Tablets

[0908] The compound used in the present invention, lactose and calcium stearate are mixed. The mixture is crushed, granulated and dried to obtain particles of appropriate size. Next, calcium stearate is added to the particles, and the mixture is compressed and molded to obtain tablets.

[0909] Formulation Example 2: Capsules

[0910] The compound used in the present invention, lactose and calcium stearate are uniformly mixed to obtain a powdered drug in the form of powder or fine particles. The powdered drug is filled into a capsule container to obtain a capsule.

[0911] Formulation Example 3: Granules

[0912] The compound used in the present invention, lactose and calcium stearate are uniformly mixed, and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to obtain granules of appropriate size.

[0913] Formulation Example 4: Orally disintegrating tablet

[0914] The compound used in the present invention and crystalline cellulose are mixed, granulated, and tableted to obtain an orally disintegrating tablet.

[0915] Formulation Example 5: Dry Syrup

[0916] The compound used in the present invention and lactose are mixed, crushed, granulated and sieved to obtain a dry syrup of appropriate size.

[0917] Formulation Example 6: Injection

[0918] The compound used in the present invention is mixed with a phosphate buffer to obtain an injection.

[0919] Formulation Example 7: Infusion

[0920] The compound used in the present invention is mixed with a phosphate buffer to obtain an injection.

[0921] Formulation Example 8: Inhalant

[0922] The compound used in the present invention and lactose are mixed and finely crushed to obtain an inhalant.

[0923] Formulation Example 9: Ointment

[0924] The compound used in the present invention is mixed with petrolatum to obtain an ointment.

[0925] Formulation Example 10: Patch

[0926] The compound used in the present invention is mixed with a base such as an adhesive plaster to obtain a patch.

[0927] [Industrial Applicability]

[0928] Based on the above test results, the compound of the present invention may be a drug useful as a therapeutic and / or preventive agent for symptoms and / or diseases induced by mycobacterium infection.

Claims

1. A compound having the formula: or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating and / or preventing mycobacterial infection.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing mycobacterial infection.

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