Novel anti-mycobacterial heterocyclic amides

文档序号：913525 发布日期：2021-02-26 浏览：11次中文

阅读说明：本技术 新型抗分枝杆菌杂环酰胺 (Novel anti-mycobacterial heterocyclic amides ) 是由 J·达伊 J·格雷哈姆 T·贾维斯 E·麦克法丁 U·奥克斯纳孙喜成 C·翁于 2019-02-28 设计创作，主要内容包括：本发明提供具有有用的抗分枝杆菌活性的新型杂环酰胺化合物。还提供这些化合物作为药物组合物的用途及其制备方法。(The present invention provides novel heterocyclic amide compounds having useful antimycobacterial activity. Also provided are uses of these compounds as pharmaceutical compositions and methods of making the same.)

1. A compound of formula (I):

wherein:

x is selected from C or N,

y is selected from the group consisting of N, O or S,

n＝1-6

r1, R2, R3 and R4 are independently selected from H, halogen, small alkyl (C1-C6), small alkoxy (C1-C6), halogenated small alkyl (C1-C6), halogenated small alkoxy (C1-C6) and carboxylic ester,

when X is carbon, R5 is selected from H, alkyl, halogen and cyano; when X is nitrogen, R5 is absent,

when Y is N, R6 is selected from H, alkyl, and substituted alkyl; when Y is O or S, R6 is absent,

r7 is selected from H, small alkyl (C1-C6), halogenated small alkyl (C1-C6), when n < 3, R7 can not be H;

each R8 is independently selected from H, small alkyl (C1-C6), halogenated small alkyl (C1-C6), m is 1-6,

when R7 and R8 are alkyl or haloalkyl, they may be joined together to form a ring, provided thatExcluding:

4-propylcyclohexane-1-carbonyl, 1, 2, 2, 3, 3, 4, 4,5, 5, 6, 6-undefluorocyclohexane-1-carbonyl, 4-methylcyclohexane-1-carbonyl, 4-butylcyclohexane-1-carbonyl, cyclohexanecarbonyl, cyclopentanecarbonyl, cyclobutanecarbonyl, cycloheptanecarbonyl, 3- (trifluoromethyl) cyclohexane-1-carbonyl, 4, 4-difluorocyclohexane-1-carbonyl, bicyclo [3.1.0] hexane-3-carbonyl, 1-methylcyclopentane-1-carbonyl, bicyclo [2.2.1] heptane-2-carbonyl, adamantane-1-carbonyl, 3-bromoadamantane-1-carbonyl, 3-chloroadamantane-1-carbonyl, and mixtures thereof, 3, 5-dimethyladamantane-1-carbonyl, 3-methyladamantane-1-carbonyl, 5, 6-trifluoro-6- (trifluoromethyl) bicyclo [2.2.1] heptane-2-carbonyl, adamantane-2-carbonyl.

2. The compound of claim 1, whereinComprises the following steps:

5-trifluoromethyl-benzo [ d ] thiazol-2-amine; 6-isopropyl-benzo [ d ] thiazol-2-amine; 6-butyl-benzo [ d ] thiazol-2-amine, 6-dimethylamino-benzo [ d ] thiazol-2-amine, [1, 3] dioxolo [4 ', 5': 4, 5] benzo [1, 2-d ] thiazol-6-amine, 6-ethoxybenzo [ d ] thiazol-2-amine, 6-isopropoxybenzo [ d ] thiazol-2-amine, 5, 7-difluorobenzo [ d ] thiazol-2-amine, 5, 7-dichlorobenzo [ d ] thiazol-2-amine, 5, 7-dimethylbenzo [ d ] thiazol-2-amine, 6- (methylthio) benzo [ d ] thiazol-2-amine, 6- (difluoromethoxy) benzo [ d ] thiazol-2-amine, 6- (trifluoromethoxy) benzo [ d ] thiazol-2-amine, 6- (tert-butyl) benzo [ d ] thiazol-2-amine, 7-fluorobenzo [ d ] thiazol-2-amine, 6-bromo-4-fluoro-benzo [ d ] thiazol-2-amine, 5-bromo-benzo [ d ] thiazol-2-amine, 5-chloro-benzo [ d ] thiazol-2-amine, 2-aminobenzo [ d ] thiazole-6-carboxylic acid ethyl ester, 6-bromo-benzo [ d ] thiazol-2-amine, 5-fluoro-benzo [ d ] thiazol-2-amine, 4-fluoro-benzo [ d ] thiazol-2-amine, 5, 6-difluoro-benzo [ d ] thiazol-2-amine, 4,5, 6-trifluoro-benzo [ d ] thiazol-2-amine, 4, 6-dichloro-benzo [ d ] thiazol-2-amine, 2-amino, 6-methyl-benzo [ d ] thiazol-2-amine, 6-fluoro-benzo [ d ] thiazol-2-amine, 4-fluoro-benzo [ d ] thiazol-2-amine, 6-chloro-benzo [ d ] thiazol-2-amine, 6-methoxy-benzo [ d ] thiazol-2-amine, 6-trifluoromethyl-benzo [ d ] thiazol-2-amine, 4, 6-difluoro-benzo [ d ] thiazol-2-amine, 4-trifluoromethyl-benzo [ d ] thiazol-2-amine, or 6-trifluoromethyl-benzo [ d ] thiazol-2-amine.

3. The compound of claim 1, whereinComprises the following steps:

(1R, 2R, 4R) -2-methylbicyclo [2.2.1] hept-5-ene-2-carbonyl, (1R, 2S, 4R) -2-methylbicyclo [2.2.1] hept-5-ene-2-carbonyl, decahydronaphthalene-2-carbonyl, (1R, 3S) -1, 2, 2, 3-tetramethylcyclopentane-1-carbonyl, 3-difluoro-1-methylcyclopentane-1-carbonyl, 3-dimethylcyclopentane-1-carbonyl, 1-ethylcyclopentane-1-carbonyl, 3-methylcyclopentane-1-carbonyl, cyclopentanecarbonyl, 1-methylcycloheptane-1-carbonyl, 1, 2-dimethylcyclopentane-1-carbonyl, 2-methyldicyclo [2.2.1] heptane-2-carbonyl, 1, 3-dimethylcyclopentane-1-carbonyl, 1-isobutylcyclopentane-1-carbonyl, pivaloyl, 2-methyl-7-oxabicyclo [2.2.1] heptane-2-carbonyl, 5-methylbicyclo [3.3.1] nonane-1-carbonyl, 3-methylbicyclo [3.1.0] hexane-3-carbonyl, 1-ethylcyclohexane-1-carbonyl, 1-methylcyclohexane-1-carbonyl, bicyclo [3.3.1] nonane-3-carbonyl, cyclohexanecarbonyl, cyclooctanecarbonyl or 3, 3, 5-trimethylcyclohexane-1-carbonyl.

4. A compound selected from: n- (1-benzothien-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, 5-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-1-carboxamide, 1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cycloheptane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl group]Adamantane-2-carboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, 5-methyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-5-methylbicyclo [3.3.1]Nonane-1-carboxamide, (3R, 5S, 7S) -N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-3-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Decahydronaphthalene-2-carboxamide, (1R, 3S) -1, 2, 2, 3-tetramethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazole-2-yl) -1-methylcycloheptane-1-carboxamide, N- (1-benzothien-2-yl) adamantane-2-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, 5-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-1-carboxamide, 1, 3-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (5-bromo-1-benzothien-2-yl) -3, 5-dimethyladamantane-1-carboxamide, 3, 5-trimethyl-N- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- (1-benzothien-2-yl) adamantane-1-carboxamide, 1-ethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Tricyclic [3.3.1.0^3，7]Nonane-3-carboxamide, (3R, 5S, 7S) -N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclooctanecarboxamide, N- (5-chloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, (1R, 3R, 7R) -3, 5-dimethyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- (1-benzothien-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (1-benzothien-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (7-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 6-difluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, 3, 5-dimethyladamantane-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, 3, 5-trimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- (1-benzothien-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -1-methylcyclopentane-1-carboxamide, (1R, 2R, 4R) -2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [2.2.1]Hept-5-ene-2-carboxamide, 3-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 1-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cycloheptane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -1-methylcycloheptane-1-carboxamide, N- (1-benzothien-2-yl) -1-methylcycloheptane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-2-carboxamide, 1, 2-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 3, 5-dimethyl-N- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-3-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, 3, 5-dimethyl-N- {6- [ (trifluoromethyl) sulfanyl]-1, 3-benzothiazol-2-yl } adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-3, 5-dimethyladamantane-1-carboxamide, N- (6-bromo-4-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -3,5-Dimethyladamantane-1-carboxamide, N- (7-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3, 5-trimethyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cyclohexane-1-carboxamide, 3, 5-dimethyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, 3, 5-trimethyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3-difluoro-1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, 1-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 1- (2-methylpropyl) -N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- (5, 6-difluoro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1-benzothien-2-yl) cyclooctanecarboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-bromo-4-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4-chloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, and pharmaceutically acceptable salts thereof, N- (6-methoxy-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4, 6-dichloro-1, 3-benzothiazol-2-yl) -3, 5-dimethylgoldAdamantane-1-carboxamide, 3, 5-dimethyl-N- (6-methyl-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, 3, 5-dimethyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 2- (3, 5-dimethyladamantane-1-carboxamido) -1, 3-benzothiazole-6-carboxylic acid ethyl ester, 1-ethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 3-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 1-methyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cycloheptane-1-carboxamide, 2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [2.2.1]Heptane-2-carboxamide, N- (1-benzothien-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-bromo-5, 7-dimethyl-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclooctanecarboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-ethoxy-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 6-dichloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (5, 6, N- (5-chloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-bromo-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-chloro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-chloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 6-difluoro-1H-1, 3-benzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-fluoro-1H-1, 3-benzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, pharmaceutical compositions containing these compounds, and pharmaceutical compositions containing these compounds, N- (6-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-methoxy-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamideAmides, N- (1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3- (trifluoromethyl) -N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 3-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 1-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, (1R, 2S, 4R) -2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [2.2.1]Hept-5-ene-2-carboxamides, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentanecarboxamide, N- (1, 3-benzoxazol-2-yl) adamantane-2-carboxamide, 5-methyl-N- [6- (trifluoromethyl) -1, 3-benzoxazol-2-yl]Bicyclo [3.3.1]Nonane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, 1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 3-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.1.0]Hexane-3-carboxamide, N- (6-ethoxy-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cycloheptanecarboxamide, N- (5-chloro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cycloheptanecarboxamide, N- (5, 7-dichloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 7-dimethyl-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4-fluoro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-methoxy-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1H-1, 3-benzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Spiro [2.5 ]]Octane-5-carboxamide, 1- (3-methylcyclohexyl) -3- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Urea, 3, 5-dimethyl-N- [6- (trifluoromethyl) -1, 3-benzoxazol-2-yl]Adamantane-1-carboxamide, N- (5, 6-dichloro-1H-1, 3-benzimidazol-2-yl) -3,5-trimethylcyclohexane-1-carboxamide, 3-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -1-methylcyclopentane-1-carboxamide, 1-methyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cyclohexane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexanecarboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cyclohexanecarboxamide, N- (6-bromo-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (1-benzothien-2-yl) cycloheptanecarboxamide, N- (5, 7-dimethyl-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-methoxy-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3, 5-trimethyl-N- [6- (trifluoromethyl) -1, 3-benzoxazol-2-yl]Cyclohexane-1-carboxamide, N- (5, 6-dichloro-1H-1, 3-benzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzothiazol-2-yl) -2-methylcyclohexane-1-carboxamide, N- (4-chloro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, processes for their preparation and their use, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (6-fluoro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-1-methylcyclohexane-1-carboxamide, 2-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Propionamide, N- (7-hydroxy-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 6-difluoro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1-benzothien-2-yl) cyclohexanecarboxamide, 3, 5-trimethyl-N- {6- [ (trifluoromethyl) sulfanyl]-1, 3-benzothiazol-2-yl } cyclohexane-1-carboxamide, N- (6-fluoro-1H-1, 3-benzimidazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4-chloro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexaneCyclohexane-1-carboxamide, 3-methyl-N- (4-methyl-1, 3-benzothiazol-2-yl) cyclohexane-1-carboxamide, N- (6-methoxy-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (4-methyl-1, 3-benzothiazol-2-yl) bicyclo [2.2.1]Heptane-2-carboxamide, N- (5, 7-dichloro-1, 3-benzoxazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, 2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]-7-oxabicyclo [2.2.1]Heptane-2-carboxamide, N- [6- (dimethylamino) -1, 3-benzothiazol-2-yl]-3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) cyclooctanecarboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexanecarboxamide, N- (4, 6-difluoro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3-methoxycyclohexane-1-carboxamide and N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Spiro [2.5 ]]Octane-6-carboxamide.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of a compound of claim 1.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt of a compound of claim 4.

7. A method of protecting a patient from a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of a compound of claim 1.

8. A method of protecting a patient from a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt of a compound of claim 4.

Technical Field

The present disclosure relates to novel heterocyclic amide compounds useful for the treatment of infections caused by mycobacteria (such as nontuberculous mycobacteria and tuberculous mycobacteria). The disclosure also relates to processes for preparing the novel compounds and pharmaceutical compositions comprising the novel compounds useful for treating mycobacterial infections.

Background

Mycobacteria remain important and are generally drug-resistant human pathogens worldwide, including mycobacterium tuberculosis (m.tuberculosis) and non-tuberculous mycobacteria (NTM) that have historically been less identified. Pulmonary NTM disease steadily increased in the united states from 86,000 cases in 2010 to the predicted 181,000 cases in 2014, with an associated direct medical cost of $ 17 billion (Strollo, s.e. et al, Ann Am Thorac Soc 12, 1458-. Potential pulmonary disorders that lead to increased susceptibility include bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis (Marras, T.K. et al, Clin Chest Med 23, 553-. Other risk factors are primary immunodeficiency involving abnormalities in the IL-12, TNFa or IFN- γ pathways (Lake, M.A. et al, BMC Med 14, 54, 2016), reduced immunocompetence due to HIV infection (Vinnard, C. et al, Ann Am Thorac Soc 13, 1951-. Epidemiology also reflects demographic risk factors such as age > 60 years and female gender ((Prevots, d.r. et al, Am J Respir Crit Care Med 182, 970) 976, 2010; Lake, m.a. et al, BMC Med 14, 54, 2016.) Tuberculosis (TB) remains a persistent global public health threat, with over 20 billions of people worldwide carrying the infection, mycobacterium tuberculosis (Mtb) bacteria can remain latent for extended periods of time, although the vast pool of latent infections drives an ever-increasing population with active disease, with 1,040 million new TB and 170 ten thousand death cases (WHO, 2017) being expected in total in 2016. most TB cases occur in 30 high-load countries (WHO, 2017.) total 9,287 new TB cases (Schmit, k.tuber-United states, early sport and 66) being reported in the United states, 2016, 289-294, 2017). From 1999 to 2014, TB-related mortality decreased by more than 50% in the united states and decreased to 1,021 deaths in 2014, which corresponded to 3.3 TB-related deaths per 1,000,000-year (Vinnard, c. et al, Ann Am Thorac Soc 13, 1951-. In contrast, NTM-related deaths remained essentially unchanged during this period, with a mortality rate of 2.3 NTM-related deaths per 1,000,000 people-year. In some countries, the prevalence of NTM infection has now exceeded TB (Low, j.l. et al, Front Microbiol 8, 1539, 2016). Notably, the epidemiology of fatal NTM infections is changing, the number of cases of HIV-infected individuals is decreasing, and death in older white women is increasing (Vinnard, C. et al, Ann Am Thorac Soc 13, 1951-K1955, 2016).

Mycobacterial pathogens are inherently resistant to many antibiotics and constitute a huge human health problem and a major threat to disease control worldwide (Fonseca, j.d. et al, Int J Infect Dis 32, 94-100, 2015). The mechanisms of antibiotic resistance in mycobacterium tuberculosis are fairly well understood and include 1) intrinsic resistance through low permeability of the cell wall, acquired resistance through chromosomal mutations, specific resistance mechanisms based on target changes, 2) target simulation, or direct impact on the drug through its modification, degradation, or efflux, and 3) phenotypic tolerance due to epigenetic responses to metabolic or physiological changes that can lead to persistence (Nguyen, L. (2016) (Arch Toxicol 90, 1585-); gold, b. et al, Microbiol Spectr 5, 2017; jansen, R.S. et al, Trends Pharmacol Sci 38, 393-405, 2017). Continued selective pressure has led to the cumulative resistance to first and second line drugs seen in multi-drug resistance (MDR), broad drug resistance (XDR), and ultimately complete drug resistance (TDR) Mycobacterium tuberculosis (Dorman, S.E. et al, Nat Med 13, 295-. Infection with XDR mycobacterium tuberculosis strains puts global TB control programs at risk. XDR-TB cases do occur in the united states and are associated with an estimated average cost of $ 483,000 per case, and XDR-TB mortality reminds of that of the previous antibiotic age (CDC, 2009).

Although the development of therapeutics for the treatment of Mtb infections generally lack activity against NTM, by screening a TB active compound library against NTM, which does result in a high hit rate, remains an attractive approach to start a new NTM drug discovery program (Low, j.l. et al, Front Microbiol 8, 1539, 2016). Among older drugs, the potential role of clofazimine in NTM treatment regimens has been suggested because this agent shows bactericidal activity and synergy with amikacin or clarithromycin, both commonly used antibiotics to treat NTM infections (Ferro, b.e. et al, Antimicrob Agents chemicother, 60, 1097-. NTM treatment regimens vary from species to species, particularly between fast-growing bacteria (RGM) (including mycobacterium abscessus (Mabs) complex (mycobacterium abscessus subsp., bordetella (bolett) and mosaic (masseliensis)), mycobacterium cheloniae (m.chelonae), mycobacterium fortuitum (m.fortuitum), and the like) and slow-growing bacteria (represented by mycobacterium avium (m.avium), mycobacterium intracellulare (m.intracell), and mycobacterium marmorale (m.chimaera complex or MAC)). Generally, Drug treatments are long, costly, and often associated with Drug-related toxicity and poor prognosis (van Ingen, J. et al, Drug resistance Updat 15, 149-. Treatment options for NTM are severely limited, which has prompted proposals for the development of novel anti-mycobacterial agents. The Mycobacterium abscessus complex is particularly an emerging NTM infection for which effective treatment is often difficult to obtain, cumbersome and expensive (Balalino, G.J. et al, Respir Med 103, 1448-. Treatment of Mabs infections typically involves the use of 1-2 parenteral agents such as amikacin, cefoxitin, imipenem or tigecycline (Kasperbauer, s.h. et al, Clin Chest Med 36, 67-78, 2015) in combination with an oral macrolide such as clarithromycin or azithromycin. Unfortunately, recent monitoring showed that only 16% of Mabs strains were sensitive to clarithromycin, while 24% were resistant and 59% expressed erm-induced macrolide resistance (Lee, m. et al, N Engl J Med 367, 1508-. Therefore, not surprisingly, the overall clinical and microbial cure rate for Mabs infection was only 41% (die, R. et al, Chest 152, 120-.

Acquisition of NTM infection occurs by environmental sources (Falkinham, j.o.j Appl Microbiol 107, 356-367, 2009), although human transmission of mycobacterium abscessus mosaic subspecies has been described in patients with cystic fibrosis (Bryant, j.m. et al, Science 354, 751-757, 2016). The prevalence of NTM has occurred in hospitals due to contaminated equipment or water supply lines (Aitken, M.L. et al, Am J Respir Crit Care Med 185, 231-. One large scale skin and soft tissue infection outbreak in brazil was caused by laparoscopy contaminated with strains of mycobacterium abscessus mosaic subspecies that were resistant to 2% glutaraldehyde for disinfection (Lorena, n.s. et al, Rev Col brass Cir 36, 266-. Outbreaks of RGM infections unrelated to medical procedures have also been reported, including epidemics caused by Mabs (Dytoc, M.T. et al, Diagn Microbiol infection Dis 53, 39-45, 2005) in recreational water, Mycobacterium gordonae (M.gordonae) in drinking water (Lalande, V. et al, J Hosp infection 48, 76-79, 2001) or tattoo inks contaminated with Mycobacterium cheloniae (Kedynen, B.S. et al, N Engl J Med 367, 1020-.

Summary of The Invention

It has now been found that substituted heterocyclic amide compounds are useful in the treatment of mycobacterial infections. The present invention relates to these antimycobacterial compounds and salts thereof, pharmaceutical compositions comprising these compounds and methods of use thereof in the treatment of mycobacterial infections, including drug resistant mycobacterial infections.

In one aspect, the invention provides compounds of formula (I):

wherein:

x is selected from C or N,

y is selected from the group consisting of N, O or S,

n＝1-6

r1, R2, R3 and R4 are independently selected from H, halogen, small alkyl (C1-C6), small alkoxy (C1-C6), halogenated small alkyl (C1-C6), halogenated small alkoxy (C1-C6), carboxylic ester and the like,

when X is carbon, R5 is selected from H, alkyl, halogen and cyano; when X is N, R5 is absent,

when Y is N, R6 is selected from H, alkyl, and substituted alkyl; when Y is O or S, R6 is absent,

r7 is selected from H, small alkyl (C1-C6), halogenated small alkyl (C1-C6), when n < 3, R7 can not be H,

each R8 is independently selected from H, small alkyl (C1-C6), halogenated small alkyl (C1-C6), m is 1-6,

when R7 and R8 are alkyl or haloalkyl, they may be linked together to form a ring.

These and various other features as well as advantages, which characterize the present invention, will be apparent from a reading of the following detailed description and a review of the appended claims.

Detailed Description

The present invention relates to antimycobacterial compounds and salts thereof, pharmaceutical compositions comprising these compounds and methods of use thereof. The compounds of the invention are useful for protecting patients from bacterial infections, including antibiotic resistant bacterial infections.

In particular, the antimycobacterial compounds of the invention include heterocyclic amide compounds.

In one embodiment, the present invention provides a compound of formula (I):

in one embodiment of the process of the present invention,

x is selected from C or N,

y is selected from the group consisting of N, O or S,

n＝1-6，

r1, R2, R3 and R4 are independently selected from H, halogen, small alkyl (C1-C6), small alkoxy (C1-C6), halogenated small alkyl (C1-C6), halogenated small alkoxy (C1-C6) and carboxylic ester,

when X is carbon, R5 is selected from H, alkyl, halogen and cyano; when X is nitrogen, R5 is absent,

when Y is N, R6 is selected from H, alkyl, and substituted alkyl; when Y is O or S, R6 is absent,

r7 is selected from H, small alkyl (C1-C6), halogenated small alkyl (C1-C6), when n < 3, R7 can not be H,

each R8 is independently selected from H, small alkyl (C1-C6), halogenated small alkyl (C1-C6), m is 1-6,

when R7 and R8 are alkyl or haloalkyl, they may be joined together to form a ring, provided thatExcluding:

4-propylcyclohexane-1-carbonyl, 1, 2, 2, 3, 3, 4, 4,5, 5, 6, 6-undefluorocyclohexane-1-carbonyl, 4-methylcyclohexane-1-carbonyl, 4-butylcyclohexane-1-carbonyl, cyclohexanecarbonyl, cyclopentanecarbonyl, cyclobutanecarbonyl, cycloheptanecarbonyl, 3- (trifluoromethyl) cyclohexane-1-carbonyl, 4, 4-difluorocyclohexane-1-carbonyl, bicyclo [3.1.0] hexane-3-carbonyl, 1-methylcyclopentane-1-carbonyl, bicyclo [2.2.1] heptane-2-carbonyl, adamantane-1-carbonyl, 3-bromoadamantane-1-carbonyl, 3-chloroadamantane-1-carbonyl, 3, 5-dimethyladamantane-1-carbonyl, 3-methyladamantane-1-carbonyl, 5, 6-trifluoro-6- (trifluoromethyl) bicyclo [2.2.1] heptane-2-carbonyl, adamantane-2-carbonyl.

Suitable identifiers of (a) include, but are not limited to:

As used herein, the term "alkyl" and similar terms such as "alkoxy" include all straight chain, branched chain and cyclic isomers. Alkyl refers to a saturated branched, straight chain, or cyclic monovalent hydrocarbon radical having the indicated number of carbon atoms (i.e., C1-C6 represents 1-6 carbon atoms) resulting from the removal of one, two, or three hydrogen atoms from a parent alkane. Representative examples thereof include methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, methylene andalkyl optionally substituted with fluorine may have 1 or more F substitutions to H on the alkyl chain. A representative example of an alkyl group optionally substituted with fluorine is trifluoromethyl.

As used herein, the terms "alkenyl" and "alkynyl" include all straight chain, branched chain and cyclic isomers. Representative examples thereof include vinyl, ethynyl and 1-propynyl. Alkenyl optionally substituted with fluorine may have 1 or more F substitutions to H on the alkenyl chain. A representative example of alkenyl optionally substituted with fluorine is fluorovinyl.

For thePreferred substituents for alkyl and alkenyl groups include, for example (unless otherwise specified) halogen, cyano, azido, nitro, carboxy, (C)_1-6) Alkoxycarbonyl, carbamoyl, mono-or di- (C)_1-6) Alkylcarbamoyl, sulfo, sulfamoyl, mono-or di- (C)_1-6) Alkylsulfamoyl, amino, mono-or di- (C)_1-6) Alkylamino, acylamino (e.g. pyridyloxy), ureido, (C)_1-6) Alkoxycarbonylamino, 2, 2, 2-trichloroethoxycarbonylamino, aryl, heteroaryl, heterocyclyl, hydroxy, (C)_1-6) Alkoxy (e.g., ethoxy, isopropoxy), acyloxy (e.g., phenyloxy, benzyloxy, phenethyloxy), oxo, acyl, 2-thiophenoyl (thienoyl), (C)_1-6) Alkylthio group, (C)_1-6) Alkylsulfinyl group, (C)_1-6) Alkylsulfonyl, oximino, (C)_1-6) Alkoxyimino, hydrazino, hydrazono, phenyloxime acyl, guanidino, amidino and iminoalkylamino groups. Also preferred are 4-formyl-piperazin-1-yl, 4-methylpiperazin-1-yl-, 4-ethylpiperazin-1-yl-, 4-phenylpiperazin-1-yl-, 4-pyrimidin-2-yl-piperazin-1-yl, hexahydroxy-pyrrolo [1, 2-a []Imidazol-1-yl, morpholin-4-yl, 3- (2-methoxy-ethyl) -methyl-amino, and 3- (2-methoxy-ethyl) -methyl-amino. Other suitable substituents include alkylthio (meaning an alkyl-S-group, wherein the alkyl group is as described above). Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. Bonded to the parent moiety through sulfur. Substituents also include alkoxycarbonyl (meaning an alkyl-O-CO-group). Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl group. Other suitable substituents are alkylsulfonyl (meaning alkyl-SO)₂A group). Preferred alkylsulfonyl groups are those wherein the alkyl group is lower alkyl. Bonded to the parent moiety through the sulfonyl group.

As used herein, the term "aryl" means an aromatic monocyclic or polycyclic ring system, each ring containing from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl group may be optionally substituted by one or more "ring system substituents" and is optionally substituted by up to five, preferably up to three substituents which may be the same or different and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, and the like. Aryl moieties are well known and described, for example, in Hawley's Condensed Chemical Dictionary (13ed.), R.J.Lewis, ed., J.Wiley & Sons, Inc., New York (1997). The aryl group may be substituted or unsubstituted.

When substituted, the aryl group may have up to three substituents. Preferred substituents (ring system substituents) for aryl groups include, for example (unless otherwise specified) halogen, cyano, (C)_1-6) Alkyl, mono-to perfluoro (C)_1-3) Alkyl, (C)_3-7) Cycloalkyl group, (C)_2-6) Alkenyl, (C)_1-6) Alkoxy group, (C)_2-6) Alkenyloxy, aryl C: (_1-6) Alkoxy, halo (C)_1-6) Alkyl, hydroxy, amino, mono-or di- (C)_1-6) Alkylamino, acylamino, nitro, carboxyl, (C)_1-6) Alkoxycarbonyl, (C)_1-6) Alkenyloxycarbonyl radical, (C)_1-6) Alkoxycarbonyl (C)_1-6) Alkyl, carboxyl (C)_1-6) Alkyl, (C)_1-6) Alkylcarbonyloxy, carboxy (C)_1-6) Alkyloxy, (C)_1-6) Alkoxycarbonyl (C)_1-6) Alkoxy group, (C)_1-6) Alkylthio group, (C)_1-6) Alkylsulfinyl group, (C)_1-6) Alkylsulfonyl, sulfamoyl, mono-and di- (C)_1-6) -alkylsulfamoyl, carbamoyl, mono-and di- (C)_1-6) Alkylcarbamoyl, heteroaryl and heterocyclyl. Other preferred aryl groups include arylalkyl (meaning an alkyl-substituted aryl group). Other preferred aryl groups include aryloxy (meaning aryl-O-groups, wherein the aryl group is as described above). Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. Bonded to the parent moiety through the ether oxygen. Arylalkoxy means an arylalkyl-O-group, wherein the arylalkyl group is as described above. Non-limiting examples of suitable arylalkoxy groups includeIncluding benzyloxy and phenethyloxy. Bonded to the parent moiety through the ether oxygen. Other preferred aryl groups are arylthio (meaning aryl-S-groups, wherein the aryl group is as described above). Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. Bonded to the parent moiety through sulfur. Other preferred aryl groups include arylalkylthio (meaning arylalkyl-S-groups wherein the arylalkyl group is as described above). A non-limiting example of a suitable arylalkylthio group is benzylthio. Bonded to the parent moiety through sulfur. Other preferred aryl groups are aryloxycarbonyl (meaning aryl-O-c (O) -groups). Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthyloxycarbonyl. The bond to the parent moiety is through the carbonyl group. Other such groups are arylalkoxycarbonyl (meaning arylalkyl-O-C (O) -groups). A non-limiting example of a suitable arylalkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl group. Other such groups are arylsulfonyl (meaning aryl-SO)₂-a group). Bonded to the parent moiety through the sulfonyl group.

As used herein, the term "heteroaryl" means monocyclic and polycyclic aromatic hydrocarbons containing at least one heteroatom ring member (e.g., sulfur, oxygen, or nitrogen, alone or in combination). Preferably, the heteroaryl ring comprises 4 to 7, and preferably 5 to 6 ring atoms. Non-limiting examples of suitable heteroaryl groups include pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1, 2, 4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1, 2-a ] pyridyl, imidazo [2, 1-b ] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridinyl, isoquinolyl, benzoazaindolyl, 1, 2, 4-triazinyl, benzothiazolyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, quinoxalyl, pyridazinyl, quinoxalinyl, and the like, Thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, 2, 3-dihydrobenzofuranyl, 2, 3-dihydrobenzothienyl-S-oxide, 2, 3-dihydrobenzothienyl-S-dioxide, benzoxazolin-2-one-yl, dihydroindolyl, benzodioxolanyl, benzodioxane, and the like. Heteroaryl groups may be substituted or unsubstituted. Fused heteroaryl ring systems may comprise carbocyclic rings and need only comprise one heterocyclic ring.

The term "heterocyclyl" as used herein, means an aromatic or non-aromatic saturated monocyclic or polycyclic (preferably bicyclic) ring system containing from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms, wherein one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, or sulfur, alone or in combination. Suitable heterocycles contain 4 to 7, preferably 5 to 6 ring atoms. A fused heterocyclic ring system may contain carbocyclic rings and need only contain one heterocyclic ring. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclic groups contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom is present as a ring atom, respectively. any-NH in the heterocyclyl ring may be present in protected form (e.g. in the form of n (boc), -n (cbz), -n (tos) groups etc.), and such protected groups are also considered part of the present invention. The heterocyclyl group may be optionally substituted by one or more "ring system substituents" which may be the same or different and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl group may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrimidinyl, oxazolidinyl, and the like.

When substituted, the heteroaryl or heterocyclyl group may have up to three substituents. Preferred such substituents include those mentioned above for aryl groups as well as oxo.

As used herein, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.

As used herein, the term "acyl" means an H-C (O) -, alkyl-C (O) -or cycloalkyl-C (O) -group, wherein the various groups are as described above. The bond to the parent moiety is through the carbonyl group. Preferred acyl groups contain lower alkyl groups. Non-limiting examples of suitable acyl groups include formyl, acetyl and propionyl.

As used herein, the term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the designated group, provided that the designated atom's normal valency is not exceeded in the present case, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently stable that it can withstand isolation to a useful degree of purity from the reaction mixture and formulation as an effective therapeutic agent. The term "optionally substituted" means optionally substituted with the indicated group, radical or moiety.

It should also be noted that in the text, flow diagrams, examples and tables herein, any heteroatom with an unsaturated valence is considered to have a hydrogen atom to satisfy its valence. When a functional group in a compound is said to be "protected", this means that the group is in a modified form to prevent unwanted side reactions at the protected site when the compound is reacted. Suitable protecting Groups are those of ordinary skill in the art and are recognized by reference to standard textbooks, such as T.W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, N.Y.

When any variable (e.g. aryl, heterocycle, R)₂Etc.) in any constituent or in formula (I) occurring more than one time, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The compounds according to the invention are suitably provided in substantially pure form (e.g. at least 50% pure, suitably at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight). Impure or less pure forms of the compounds according to the invention may be used, for example, to prepare more pure forms of the same or related compounds (e.g. corresponding derivatives) suitable for pharmaceutical use.

It will be appreciated that certain compounds of the invention may contain one or more chiral centers, such that the compounds may exist as stereoisomers (including diastereomers and enantiomers). The present invention encompasses all such stereoisomers and mixtures thereof, including racemates.

Accordingly, the present disclosure provides the following compounds:

n- (1-benzothien-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, 5-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-1-carboxamide, 1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cycloheptane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl group]Adamantane-2-carboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, 5-methyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-5-methylbicyclo [3.3.1]Nonane-1-carboxamide, (3R, 5S, 7S) -N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-3-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Decahydronaphthalene-2-carboxamide, (1R, 3S) -1, 2, 2, 3-tetramethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -1-methylcycloheptane-1-carboxamide, N- (1-benzothien-2-yl) adamantane-2-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, 5-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-1-carboxamide, 1, 3-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (5-bromo-1-benzothien-2-yl) -3, 5-dimethyladamantane-1-carboxamide, 3, 5-trimethyl-N- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- (1-benzothien-2-yl) adamantane-1-carboxamide, 1-ethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Tricyclic [3.3.1.0^3，7]Nonane-3-carboxamide, (3R, 5S, 7S) -N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclooctanecarboxamide, N- (5-chloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, (1R, 3R, 7R) -3, 5-dimethyl-N- [6- (tris-benzothiazol-2-yl) -3, 5-dimethyl-N- [ 1- (trifluoromethyl) carbamic acidFluoromethyl) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- (1-benzothien-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (1-benzothien-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (7-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 6-difluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, 3, 5-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, 3, 5-trimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- (1-benzothien-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzothiazol-2-yl) -1-methylcyclopentane-1-carboxamide, (1R, 2R, 4R) -2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [2.2.1]Hept-5-ene-2-carboxamide, 3-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 1-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cycloheptane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -1-methylcycloheptane-1-carboxamide, N- (1-benzothien-2-yl) -1-methylcycloheptane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-2-carboxamide, 1, 2-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 3, 5-dimethyl-N- [5- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.3.1]Nonane-3-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 7-dichloro-1, 3-benzoxazole-2-carboxamide-yl) -3, 5-dimethyladamantane-1-carboxamide, 3, 5-dimethyl-N- {6- [ (trifluoromethyl) sulfanyl]-1, 3-benzothiazol-2-yl } adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-3, 5-dimethyladamantane-1-carboxamide, N- (6-bromo-4-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (7-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, and pharmaceutically acceptable salts thereof, N- (6-bromo-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3, 5-trimethyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cyclohexane-1-carboxamide, 3, 5-dimethyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, 3, 5-trimethyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3-difluoro-1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) adamantane-2-carboxamide, 1-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 1- (2-methylpropyl) -N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Adamantane-1-carboxamide, N- (5, 6-difluoro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1-benzothien-2-yl) cyclooctanecarboxamide, N- (5, 7-dimethyl-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-bromo-4-fluoro-1,3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4-chloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-methoxy-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, processes for their preparation, and their use, N- (4, 6-dichloro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, 3, 5-dimethyl-N- (6-methyl-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, 3, 5-dimethyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 2- (3, 5-dimethyladamantane-1-carboxamido) -1, 3-benzothiazole-6-carboxylic acid ethyl ester, 1-ethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 3-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 1-methyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cycloheptane-1-carboxamide, 2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [2.2.1]Heptane-2-carboxamide, N- (1-benzothien-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-bromo-5, 7-dimethyl-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclooctanecarboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-ethoxy-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (5, 6-dichloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (5, 6, N- (5-chloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-bromo-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cyclooctanecarboxamide, N- (6-chloro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-chloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 6-difluoro-1H-1, 3-benzeneBenzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-fluoro-1H-1, 3-benzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4-fluoro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-fluoro-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, pharmaceutical compositions comprising the same, and methods of use thereof, N- (6-methoxy-1, 3-benzothiazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3- (trifluoromethyl) -N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 3-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclohexane-1-carboxamide, 1-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, (1R, 2S, 4R) -2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [2.2.1]Hept-5-ene-2-carboxamides, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentanecarboxamide, N- (1, 3-benzoxazol-2-yl) adamantane-2-carboxamide, 5-methyl-N- [6- (trifluoromethyl) -1, 3-benzoxazol-2-yl]Bicyclo [3.3.1]Nonane-1-carboxamide, N- (5, 7-difluoro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-bromo-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, 1-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, 3-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Bicyclo [3.1.0]Hexane-3-carboxamide, N- (6-ethoxy-1, 3-benzothiazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cycloheptanecarboxamide, N- (5-chloro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cycloheptanecarboxamide, N- (5, 7-dichloro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 7-dimethyl-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4-fluoro-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-methoxy-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamideAmines, N- (1H-1, 3-benzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Spiro [2.5 ]]Octane-5-carboxamide, 1- (3-methylcyclohexyl) -3- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Urea, 3, 5-dimethyl-N- [6- (trifluoromethyl) -1, 3-benzoxazol-2-yl]Adamantane-1-carboxamide, N- (5, 6-dichloro-1H-1, 3-benzimidazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3-methyl-N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Cyclopentane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -1-methylcyclopentane-1-carboxamide, 1-methyl-N- (4, 5, 6-trifluoro-1, 3-benzothiazol-2-yl) cyclohexane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) adamantane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexanecarboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) cyclohexanecarboxamide, N- (6-bromo-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) bicyclo [3.3.1]Nonane-3-carboxamide, N- (1-benzothien-2-yl) cycloheptanecarboxamide, N- (5, 7-dimethyl-1, 3-benzoxazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (6-methoxy-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3, 5-trimethyl-N- [6- (trifluoromethyl) -1, 3-benzoxazol-2-yl]Cyclohexane-1-carboxamide, N- (5, 6-dichloro-1H-1, 3-benzimidazol-2-yl) -3, 5-dimethyladamantane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzothiazol-2-yl) -2-methylcyclohexane-1-carboxamide, N- (4-chloro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, processes for their preparation and their use, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (6-fluoro-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (4, 6-difluoro-1, 3-benzothiazol-2-yl) -1-methylcyclohexane-1-carboxamide, N- [6- (difluoromethoxy) -1, 3-benzothiazol-2-yl]-1-methylcyclohexane-1-carboxamide, 2-dimethyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Propionamide, N- (7-hydroxy-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5, 6-difluoro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1-benzothien-2-yl) cyclohexanecarboxamide, 3, 5-trimethyl-N- {6- [ (trifluoromethyl) sulfanyl]-1, 3-benzothiazol-2-yl } cyclohexane-1-carboxamide, N- (6-fluoro-1H-1, 3-benzimidazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (4-chloro-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, 3-methyl-N- (4-methyl-1, 3-benzothiazol-2-yl) cyclohexane-1-carboxamide, N- (6-methoxy-1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, methods of preparation thereof, pharmaceutical compositions containing the compounds, and methods of use thereof, N- (1, 3-benzothiazol-2-yl) -3-methylcyclohexane-1-carboxamide, N- (4-methyl-1, 3-benzothiazol-2-yl) bicyclo [2.2.1]Heptane-2-carboxamide, N- (5, 7-dichloro-1, 3-benzoxazol-2-yl) -5-methylbicyclo [3.3.1]Nonane-1-carboxamide, 2-methyl-N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]-7-oxabicyclo [2.2.1]Heptane-2-carboxamide, N- [6- (dimethylamino) -1, 3-benzothiazol-2-yl]-3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (1, 3-benzoxazol-2-yl) cyclooctanecarboxamide, N- [6- (trifluoromethoxy) -1, 3-benzothiazol-2-yl]Cyclohexanecarboxamide, N- (4, 6-difluoro-1, 3-benzoxazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (5-bromo-1, 3-benzothiazol-2-yl) -3, 3, 5-trimethylcyclohexane-1-carboxamide, N- (6-chloro-1, 3-benzothiazol-2-yl) -3-methoxycyclohexane-1-carboxamide, N- [6- (trifluoromethyl) -1, 3-benzothiazol-2-yl]Spiro [2.5 ]]Octane-6-carboxamide.

Prodrugs and solvates of the compounds of the present invention are also encompassed herein. The term "prodrug" as used herein refers to a compound that is a drug precursor that, upon administration to a subject, undergoes a chemical transformation, either metabolic or chemical, to yield a compound of formula (I) or a salt and/or solvate thereof. Discussion of prodrugs is provided in t.higuchi and v.stella, Pro-drugs as Novel Delivery Systems (1987)14 of the a.c.s.symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward b.roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference.

As used herein, the term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are introduced into the crystal lattice of the crystalline solid. "solvate" includes both solution phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

As used herein, the term "hydrate" is where the solvent molecule is H₂A solvate of O.

As used herein, the phrase "effective amount" or "therapeutically effective amount" is intended to describe an amount of a compound or composition of the present invention that is effective to inhibit bacterial replication and thereby produce a desired therapeutic, ameliorative, inhibitory or prophylactic effect.

The compounds of formula (I), as defined herein for formula (I), may form salts that are also within the scope of the invention. Unless otherwise indicated, reference to a compound of formula (I) should be understood to include reference to a salt thereof. The term "salt" as used herein refers to both acidic salts formed with inorganic and/or organic acids and basic salts formed with inorganic and/or organic bases. Furthermore, when a compound of formula (I) contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety, such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are also included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of compounds of formula (I) may be formed, for example, by: the compound of formula (I) is reacted with an amount of acid or base, such as one equivalent, in a medium, such as the medium in which the salt precipitates, or in an aqueous medium which is subsequently freeze-dried.

Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate (also known as tosylate), and the like. In addition, acids which are generally considered suitable for forming pharmaceutically acceptable salts from basic pharmaceutical compounds are discussed in, for example, the following documents: berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 119; gould, International J.of pharmaceuticals (1986) 33201217; anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, d.c. on their website). These disclosures are incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts (such as sodium, lithium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts with organic bases (e.g., organic amines, such as dicyclohexylamine, t-butylamine), salts with amino acids (such as arginine, lysine), and the like. Basic nitrogen-containing groups may be quaternized with such materials as: lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long chain halides (e.g., decyl, dodecyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.

All such acid and base salts are pharmaceutically acceptable salts within the scope of the present invention and are considered equivalent to the free forms of the corresponding compounds for the purposes of the present invention.

The compounds of formula (I), and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example as an amide or imino ether). All such tautomeric forms are intended to be encompassed herein as part of the present invention. All stereoisomers (e.g., geometric isomers, optical isomers, etc.) (including those of salts, solvates and prodrugs of the compounds, and salts and solvates of prodrugs) of the compounds of the present invention, such as those existing due to asymmetric carbon atoms on various substituents, including enantiomeric forms (which may exist even if no asymmetric carbon atom), rotameric forms, atropisomers, and diastereomeric forms, are encompassed within the scope of the invention, and positional isomers (e.g., 4-pyridyl and 3-pyridyl) are also encompassed within the scope of the invention. Individual stereoisomers of the compounds of the invention may be, for example, substantially free of the other isomers, or may be mixed, for example, as racemates, or with all of the other stereoisomers, or with other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by IUPAC1974 Recommendation. The use of the terms "salt", "solvate", "prodrug" and the like are equally applicable to the salts, solvates and prodrugs of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the compounds of the present invention.

Another aspect of the invention is a method of protecting a patient from mycobacterial infection. The patient may be an animal, preferably a mammal, even more preferably a human, suffering from or susceptible to a disease or condition associated with a bacterial infection. The protection may be prophylactic, i.e. the compound of the invention is administered without a diagnosed bacterial infection, or therapeutic, i.e. the compound of the invention is administered after a bacterial infection has been diagnosed. Protection may be achieved by administering to the patient a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate of said compound. Preferred dosages are from about 0.001 to 500mg/kg body weight/day of a compound of formula (I) or a pharmaceutically acceptable salt or solvate of said compound. Particularly preferred doses are from about 0.01 to 25mg/kg body weight/day of a compound of formula (I) or a pharmaceutically acceptable salt or solvate of said compound.

Methods for diagnosing bacterial infections in patients are known in the art. Preferred bacterial infections to be treated include bacterial infections caused by any bacterial type or species against which the compounds of the present invention have an antimycobacterial effect. Particularly preferred bacterial types or species include gram positive and gram negative bacteria, with the most preferred bacterial types including gram positive bacteria.

To protect an animal from bacterial infection, a therapeutic or prophylactic composition of the invention is administered to the animal in an effective manner such that bacterial infection is minimized and/or reduced. Preferably, the bacterial infection and/or bacterial load of the infectious bacteria is reduced by at least about 50%, at least about 70%, more preferably at least about 90%, 95% or 97%.

Suitable patients to be treated include humans; poultry, such as chickens, ostriches, quails and turkeys; other mammals such as companion animals (including dogs, cats and rodents) and food-economic and/or fur or other production animals such as horses, cattle, llamas, chinchillas, ferrets, goats, sheep, rodents, minks, rabbits, raccoons and pigs.

The compounds of the invention may also be used in combination (together or sequentially) with one or more antimycobacterial therapeutic agents, for example treatment with other known classes of antibacterial drugs (e.g. β -lactams, glycopeptides, oxazolidinones, macrolides, ketolides, quinolones, fluoroquinolones, aminoglycosides, tetracyclines and lipopeptides). If formulated as a fixed dose, such combination products employ the compounds of the present invention within the dosage ranges described herein and the other pharmaceutically active or therapeutic agents within their dosage ranges. When the combined preparation is not appropriate, the compound of formula (I) may also be administered sequentially with known antibacterial agents. The present invention does not limit the order of administration; the compounds of formula (I) may be administered before or after the administration of known antibacterial agents. These techniques are within the skill of the skilled artisan and the attending physician.

Thus, in one aspect, the invention includes combinations comprising an amount of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more of the antibacterial or therapeutic agents listed above, wherein the amounts of the compounds/therapeutic agents produce the desired therapeutic effect. The pharmacological properties of the compounds of the invention may be confirmed by a number of pharmacological assays. The exemplary pharmacological assays described herein have been performed with compounds and/or salts thereof according to the present invention.

In another aspect, the invention includes a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate of said compound, and at least one pharmaceutically acceptable carrier. Accordingly, the present invention also includes compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.

As used herein, the phrase "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivering biologically active agents to a patient, particularly a mammal. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art depending on a variety of factors. These factors include, but are not limited to: the type and nature of the active agent formulated; a subject to whom a composition comprising the agent is to be administered; a predetermined route of administration of the composition; and the therapeutic indications for which it is intended. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, and various solid and semi-solid dosage forms. Such carriers may include a variety of different ingredients and additives in addition to the active agent, and inclusion of such additional ingredients in the formulation is for a variety of reasons known to those of ordinary skill in the art, such as stabilization of the active agent, binder, and the like. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources, e.g., Remington's Pharmaceutical Sciences, 17 th edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference in its entirety.

The preparation of the pharmaceutical compositions of the present invention includes inclusion of inert, solid or liquid pharmaceutically acceptable carriers. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets (cachets), and suppositories. The powders and tablets may contain from about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, silica, sucrose, lactic acid, starch or cellulose derivatives. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparation for various compositions can be found in a.gennaro (ed.), Remington's Pharmaceutical Sciences, 18 th edition, (1990), Mack Publishing co.

Liquid form preparations include solutions, suspensions, and emulsions. As an example, water or water-polyethylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions may be used. Liquid form preparations may also include solutions for intranasal administration. Gelatin capsules may be used to contain the active ingredient and suitable carriers such as, but not limited to, lactose, starch, magnesium stearate, stearic acid or cellulose derivatives. Compressed tablets may be prepared using similar diluents. Both tablets and capsules can be prepared in the form of sustained release products to provide continuous release of the drug over a period of time. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste, or to protect the active ingredient from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract. Liquid dosage forms for oral administration may also contain coloring or flavoring agents to increase patient acceptance.

Generally, water, pharmaceutically acceptable oils, saline, aqueous dextrose, and related sugar solutions and glycols (such as propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. Solutions for parenteral administration may contain, for example, a water-soluble salt of the active ingredient and one or more suitable stabilizers. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid may act as suitable stabilizers, either alone or in combination. Citric acid and its salts and EDTA are also suitable as stabilizers. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl parabens and chlorobutanol.

Inhalation compositions are preferred and typically comprise an inert diluent or carrier and may be prepared as a dry powder inhaler or a solution/suspension. The inhalation dosage form is administered to the patient weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or 1, 2, 3 or 4 times daily. Preferably, the compounds of the present invention are administered three or less times per day, more preferably once or twice. For the purpose of oral therapeutic administration, one or more active compounds may be mixed with excipients and used in the form of tablets, capsules, lozenges or troches. Pharmaceutically compatible binders and auxiliary materials may be included as part of the composition. Tablets, pills, capsules, lozenges, and the like can contain any of the following ingredients or compounds with similar properties: binders such as, but not limited to, gum tragacanth, acacia, corn starch or gelatin; excipients, such as microcrystalline cellulose, starch, or lactose; disintegrants such as, but not limited to, alginic acid and corn starch; lubricants such as, but not limited to, magnesium stearate; glidants (gildant), such as but not limited to colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; and flavoring agents, such as mint or fruit flavors.

When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, the dosage unit forms may contain various other materials which modify the physical form of the dosage unit, such as coatings of sugars and other enteric materials. The compounds may also be administered as components of elixirs, suspensions, syrups, wafers, chewing gums and the like. Syrups may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes, colorants and flavors. The active material may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action.

Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may contain any of the following components: sterile diluents, such as water for injection, saline solution, fixed oils, natural vegetable oils (such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like), or synthetic fatty vehicles such as ethyl oleate, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol and methyl paraben; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates and phosphates; and substances for regulating the isotonic pressure, such as sodium chloride and glucose. Parenteral preparations may be packaged in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. If necessary, a buffer, a preservative, an antioxidant, etc. may be added.

When administered intravenously, suitable carriers include physiological saline, Phosphate Buffered Saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof. Liposomal suspensions containing tissue-targeting liposomes may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to known methods, for example, as described in U.S. Pat. No. 4,522,811, which is incorporated herein by reference.

The active compound may be formulated with a carrier that protects the compound from rapid elimination from the body, such as a time-release formulation or a coating, such as an enteric coating, that protects the compound of the invention from the acidic environment of the stomach. Enteric coated tablets are well known to those skilled in the art. Additionally, capsules filled with pellets, each coated to protect against the acidic stomach, are also well known to those skilled in the art. Other such carriers include controlled release formulations such as, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparing such formulations are known to those skilled in the art.

The compounds of the invention may be administered via the intrapulmonary route, orally, parenterally (IV, IM, depo-IM, SQ and depo-SQ), sublingually, intranasally (inhalation), intrathecally, topically or rectally. Dosage forms known to those skilled in the art are suitable for delivery of the compounds of the present invention.

When administered via the intrapulmonary route, the compounds of the invention can be administered in conventional dosage forms for inhalation administration well known to those skilled in the art and described more fully herein. These include dry powder inhalers and sprays using solutions or suspensions.

The compounds of the invention may be administered parenterally, for example by IV, IM, depo-IM, SC or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.5 to about 100 mg/day, preferably about 5 to about 50 mg/day should be delivered for humans. When the depot formulation is for monthly or biweekly injections, the dosage for humans should be about 0.5 mg/day to about 50 mg/day, or a monthly dose of about 15mg to about 1,500 mg. The dose for other types of patients can be estimated from the appropriate human dose.

The compounds of the invention may be administered sublingually. When administered sublingually, the compounds of the invention should be administered 1-4 times per day in the amounts described above for IM administration.

The compounds of the invention may also be administered intranasally. When administered by this route, suitable dosage forms are nasal sprays or dry powders known to those skilled in the art. The dose of the compound of the invention for intranasal administration is the amount described above for IM administration.

The compounds of the invention may also be administered intrathecally. When administered by this route, suitable dosage forms are parenteral dosage forms known to those skilled in the art. The dose of the compound of the invention for intrathecal administration is the amount described above for IM administration.

The compounds of the invention may be administered topically. When administered by this route, suitable dosage forms are creams, ointments or patches. When administered topically, the dosage is from about 0.5 mg/day to about 200 mg/day. The compounds of the present invention may be administered rectally by means of suppositories known to those skilled in the art. When administered by suppository, a therapeutically effective amount is from about 0.5mg to about 500mg for humans. The compounds of the invention may be administered by implants known to those skilled in the art. When the compounds of the present invention are administered via an implant, a therapeutically effective amount is that amount described above for depot administration.

In one aspect, the invention herein includes novel compounds and novel methods of using the compounds of the invention. One skilled in the art will know how to prepare and administer the appropriate dosage form in view of the particular compound of the invention and the desired dosage form.

In cases where the compounds of the present invention exhibit insufficient solubility, a solubilization method may be used. Such methods are known and include, but are not limited to, the use of co-solvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as polysorbates (tween. rtm) and dissolution in aqueous sodium bicarbonate. Derivatives, such as salts or prodrugs, of the compounds may also be used to formulate effective pharmaceutical compositions.

The concentration of the compound is effective to deliver, upon administration, an amount that reduces or ameliorates at least one symptom of the condition for which the compound is administered. Typically, the compositions are formulated for single dose administration. A suitable single dose is a dose that is capable of reducing bacterial infection and/or bacterial load of infectious bacteria when administered one or more times over a suitable period of time. For example, a preferred single dose range of the compound of formula (I) is from about 1 microgram to about 10 milligrams, but may be up to 100 milligrams of the composition per kilogram body weight of the patient.

The active compound is typically included in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the patient being treated without undesirable side effects. Therapeutically effective concentrations can be determined empirically by testing the compounds in known in vitro and in vivo model systems for the condition being treated.

The compounds and compositions of the present invention may be packaged in multi-dose or single-dose containers. The packaged compounds and compositions can be provided in a kit, e.g., including component parts that can be assembled for use. For example, a lyophilized form of a compound of the invention and a suitable diluent may be provided as separate components that are combined prior to use. The kit may comprise a compound of the invention and a second therapeutic agent for co-administration. The compound of the invention and the second therapeutic agent may be provided in the form of separate component parts.

The kits herein may comprise a plurality of containers, each container containing one or more unit doses of a compound of the invention. The container is preferably adapted for the desired mode of administration, including but not limited to tablets, gel capsules, sustained release capsules, and the like for oral administration; depot products for parenteral administration, pre-filled syringes, ampoules, vials and the like; and patches, medical pads, creams, ointments and the like for topical administration.

The concentration of the active compound in the pharmaceutical composition depends on the absorption, inactivation and excretion rates of the active compound, the dosing regimen and amount administered, and other factors known to those skilled in the art. The active ingredient may be administered at one time, or may be divided into a number of smaller doses to be administered at intervals. It will be understood that the precise therapeutic dose and duration are a function of the disease to be treated and may be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data.

It is to be noted that the concentration and the dosage value may also vary with the severity of the condition to be ameliorated. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

The compounds of the invention may be prepared as described in the examples below.

The invention disclosed herein is illustrated by the following preparations and examples, which should not be construed as limiting the scope of the disclosure. Other alternative mechanistic pathways and similar structures will be apparent to those skilled in the art.

Examples

The following abbreviations are used throughout the examples section and are not meant to limit the scope of the disclosure.

TLC (thin layer chromatography)

eq. -. equivalent

equiv

THF ═ tetrahydrofuran

DIPEA ═ diisopropylethylamine

DIEA is diisopropylethylamine

DCM ═ dichloromethane

MeOH ═ methanol

EtOAc ═ ethyl acetate

BOC₂O-di-tert-butyl dicarbonate

mCPBA ═ 3-chloroperoxybenzoic acid

DMAP ═ 4- (dimethylamino) pyridine

TFA ═ trifluoroacetic acid

DMA ═ N, N-dimethylacetamide

TBTU ═ O- (benzotriazol-1-yl) -N, N' -tetramethyluronium tetrafluoroborate

DMSO ═ dimethyl sulfoxide

Et₂O ═ diethyl ether

MeCN ═ acetonitrile

DMF ═ N, N-dimethylformamide

NMP-1-methyl-2-pyrrolidone

DAST ═ sulfur trifluoride (diethylamino)

DCE ═ 1, 2-dichloroethane

The compounds of examples 1-192 as shown in table 1 below were prepared by the method described in method 1.

Methods of synthesis of the compounds in table 1:

the method comprises the following steps: synthesis of heterocyclic amide analogs

In a microcube equipped with a stir bar, carboxylic acid (2mmol, 1 equiv.) and HATU (76mg, 0.2mmol, 1 equiv.) were dissolved in 1mL DCE. DIPEA (0.1mL, 0.6mmol, 3equiv.) was added and the resulting solution was stirred at RT for 10 min. Amine (0.2mmol, 1 equiv.) was added to the mixture. The reaction solution was heated to 45 ℃ and stirred overnight. Upon completion, the reaction mixture was concentrated and loaded onto a 60g C-18 cartridge and mixed at a ratio of 5-95% ACN: h₂Purification under gradient of O. Fractions containing product were identified by LC-MS and concentrated in vacuo to give the final product.

Similar procedures were used to prepare other heterocyclic amide analogs from commercially available amines and carboxylic acids.

The method portion ends.

Example 193: description of antimycobacterial effects and mechanism of action.

Assays for antimycobacterial activity against a variety of pathogenic organisms including mycobacterium abscessus, mycobacterium cheloniae, mycobacterium fortuitum, mycobacterium exoticus (m.peregrinum), mycobacterium avium, mycobacterium intracellularis, mycobacterium cumulans, and mycobacterium tuberculosis were performed to determine the Minimum Inhibitory Concentration (MIC). All compounds were tested according to the CLSI guidelines (clinical and laboratory standards institute, document M24-a), using standard methods and conditions. For M.abscessus, the compounds described in examples 1-101 had MICs of 0.03-1. mu.g/mL, and example 102-192 had MICs of 2-32. mu.g/mL; but inactive (MIC > 16 μ g/mL) against other pathogens including staphylococcus aureus (s.aureus), streptococcus pneumoniae (s.pneumoconiae), streptococcus pyogenes (s.pyogenenes), enterococcus faecalis (e.faecalis), escherichia coli (e.coli), pseudomonas aeruginosa (p.aeruginosa) and candida albicans (c.albicans). The compound described in example 2 shows bactericidal activity against mycobacterium abscessus and mycobacterium tuberculosis.

The compounds of the invention are not compromised by existing resistance to other drug classes tested, including macrolides, tetracyclines, sulfamethoxazole, isoniazid, rifampin and fluoroquinolones. In particular, the compounds described in examples 2, 5, 45, 46 and 80 are active against azithromycin-, doxycycline-and sulfamethoxazole-resistant mycobacterium abscessus and against isoniazid-, rifampin-and fluoroquinolone-resistant mycobacterium tuberculosis. MIC is comparable in drug-susceptible versus drug-resistant strains, and ranges from 0.03-4. mu.g/mL for clinically relevant drug-resistant strains.

The compounds of the invention show a broad spectrum of antimycobacterial activity against all mycobacteria. The compounds described in examples 2, 5, 45 show MICs of 0.12-1. mu.g/mL against M.abscessus, M.tortoise and M.fortuitum₉₀(concentration of strain inhibited by 90%).

The mechanism of action. Elucidation of the mechanism of action of the benzothiazole amide series is carried out. Evidence was obtained that compounds from this series affect the transfer of mycolic acid to its cellular envelope receptors in Mabs and Mtb, most likely by inhibiting the trehalose monomycolate transporter MmpL 3. This conclusion is supported by the fact that: 1) the Mabs ATCC19977 culture, untreated or treated with cyclohexylamide at 2 and 10 times its MIC, is designated [2 ], [2 ]¹⁴C]Metabolic labeling of acetate leads to the transfer of mycolic acid to arabinogalactan and trehalose dimycolate (marker for MmpL3 inhibitor)(iii) concentration-dependent inhibition of (1); 2) screening a M.smegmatis (M.smegmatis) library expressing 75 different mutant variants of MmpL3 protein from Mtb to obtain 11 mutants, which show that the resistance of the mutants to benzothiazole cyclohexylamide inhibitors is improved by more than 4 times (the resistance of the three mutants is improved by more than 8 times); 3) spontaneous resistance to compounds 79 and 80, Mabs ATCC19977 mutant (isolated on 7H11-ADC agar containing 4x MIC concentration inhibitor) was found to have non-synonymous mutations in its mmpL3 gene (L551S, I306S, a 309P). The involvement of these mutations in the resistance phenotype of spontaneous resistance mutants was confirmed by: it was shown that its introduction into the isogenic background of Mabs ATCC19977 by recombinant engineering was sufficient to increase the resistance to benzothiazole amide compounds by more than 4-fold.

The inhibitory effect of the early lead compound CRS400153 (compound 80) on MmpL3 activity was not due to collapse of proton motive force (its energy was gained from its MmpL 3), as demonstrated by monitoring the effect of CRS400153 treatment on the membrane potential and electrochemical pH gradient of Mtb intact cells and reverse membrane vesicles (data not shown).

Further testing of 16 analogues from the same compound class showed that they all showed reduced activity against CRS400153 resistant mutants carrying mutations in the mmpL3 gene. This data indicates that compounds from the CRS400153 structural class act with mpl3 as their primary biochemical target. In contrast, 8 structurally different compounds from different sublines retained activity against CRS400153 resistant mutants, although some of these non-cross-resistant compounds also inhibited the transfer of mycolic acid to its cell envelope receptors in Mabs. Therefore, these compounds were used as negative controls.

The in vivo efficacy. Several compounds were screened in mouse PK and tolerability studies to evaluate various doses and routes of administration. Although highly tolerated, it is clear that the lipophilicity of the compounds makes it more difficult to achieve efficacy by the oral route of administration. In contrast, intrapulmonary delivery methods for treating pulmonary infections such as NTM and Mtb have been investigated. CRS400226 (compound 45, an earlier lead compound) was synthesized in several grams to support work in-vivo, andfurther developed for this delivery route. While substantially insoluble in water, we found that CRS400226 dissolved in corn oil at concentrations as high as 250 mg/mL. Initial attempts to formulate CRS400226 as a corn oil/saline emulsion (5%) provided the opportunity to obtain in vivo efficacy during the proof of concept phase. Working with doctor Gonzalez-Juarrero (leading edge specialist for intratracheal delivery) in CSU, we evaluated CRS400226 against Mabs #21 in a 28-day mouse model of chronic NTM lung infection. The study used granulocyte macrophage colony stimulating factor knock-out (GM-CSF KO) mice, which represent a clinically relevant model of human infection. Chronic mycobacterium abscessus subspecies (NTM) respiratory tract infections are readily established in these mice with this specific immunodeficiency and pathological changes (Degroote, 2014). 5x10 using Penn Century Mini sprayer⁵To 1x10⁶Bacteria are delivered to the lungs. Starting after 10 days, test compounds were administered once daily by intratracheal microspray administration with a 5% corn oil/saline emulsion over a 4 week period. Bacterial load in the lungs was determined by plating a series of dilutions of the homogenate on 7H11 agar and counting colonies after incubation at 37 ℃. CRS400226 showed a statistically significant reduction in CFU at 25mg/kg compared to vehicle control (fig. 2A) and was very well tolerated at 4 weeks of dosing (fig. 2B).

It is obvious that the present invention is well adapted to attain the ends and advantages mentioned as well as those that are inherent therein. While several presently preferred embodiments have been described for purposes of this disclosure, various changes and modifications may be made within the scope of the invention. Many other modifications may be made which will readily suggest themselves to those skilled in the art and which are encompassed within the spirit of the invention disclosed herein and as defined by the appended claims.

The entire disclosure and all publications cited herein are incorporated by reference.

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