HK1194368A - Isoxazole derivatives useful as antibacterial agents - Google Patents
Isoxazole derivatives useful as antibacterial agents Download PDFInfo
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- HK1194368A HK1194368A HK14107786.7A HK14107786A HK1194368A HK 1194368 A HK1194368 A HK 1194368A HK 14107786 A HK14107786 A HK 14107786A HK 1194368 A HK1194368 A HK 1194368A
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Description
Technical Field
The present invention relates to novel hydroxamic acid derivatives. The invention also relates to methods of using such compounds in the treatment of bacterial infections, particularly gram-negative bacterial infections, and to pharmaceutical compositions comprising such compounds.
Background
Infections caused by gram-negative bacteria such as Pseudomonas aeruginosa (Pseudomonas-aeruginosa), Enterobacteriaceae (Enterobacteriaceae) and Acinetobacter baumannii (Acinetobacter-baumannii) which produce β -lactamase (ESBL) in a broad spectrum are major health problems, especially in the case of nosocomial acquired infections. Furthermore, the level of resistance to current antibiotic therapies is increasing, which severely limits treatment options. For example, in 2002, 33% of Pseudomonas aeruginosa infections from intensive care units were resistant to fluoroquinolones, while resistance to imipenem was 22% (CID-42: 657-68, 2006). In addition, Multiple Drug Resistant (MDR) infections are also increasing; for P.aeruginosa, MDR increased from 4% in 1992 to 14% in 2002 (Biochem Pharm 71: 991, 2006).
A unique aspect of gram-negative bacteria is that their outer membrane contains Lipopolysaccharides (LPS), which are critical for maintaining the integrity of the membrane and are essential for bacterial viability (reviewed in ann. rev. biochem 76: 295329, 2007). The main lipid component of LPS is lipid a, and inhibition of lipid a biosynthesis is lethal to the bacteria. Lipid a is synthesized on the cytoplasmic surface of the bacterial inner membrane by a pathway consisting of 9 different enzymes. These enzymes are highly conserved in most gram-negative bacteria. LpxC [ UDP-3-O- (R-3-hydroxymyristoyl) -N-acetylglucosamine deacetylase]Is an enzyme that catalyzes the first committed step in the lipid A biosynthetic pathway, i.e., the removal of the N-acetyl group from UDP-3-O- (R-3-hydroxymyristoyl) -N-acetylglucosamine. LpxC is Zn without mammalian homologues2+The dependent enzyme makes it a good target for the development of new antibiotics. Several LpxC inhibitors with low nM affinity have been reported (Biochemistry-45: 7940-48, 2006).
Summary of The Invention
A new class of LpxC inhibitors has been discovered. These compounds, or pharmaceutically acceptable salts thereof, may be represented by formula I and formula II as follows:
wherein
R1Is (C)1-C3) An alkyl group;
R2is hydrogen or (C)1-C3) An alkyl group;
R3is hydrogen, (C)1-C3) Alkoxy group, (C)1-C3) Alkyl radicalCyano, (C)1-C3) Haloalkoxy, (C)1-C3) Haloalkyl, halogen, or hydroxy;
l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nNR4SO2(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；
R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyl group, (C)3-C8) Cycloalkyl group, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl or formyl;
n is 0, 1,2, 3 or 4;
p is 0, 1,2, 3 or 4;
R6is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylcarbonyl group, (C)1-C6) alkyl-NR4-(C1-C6) Alkyl, (C)1-C6) Alkylthio (C)1-C6) Alkyl, (C)1-C6) Alkylthio carbonyl group, (C)6-C12) Aryl group, (C)6-C12) Aryloxy group, (C)6-C12) Arylthio, (C)6-C12) aryl-NR4-、(C3-C8) Cycloalkyl group, (C)3-C8) Cycloalkyloxy, (C)3-C8) Cycloalkylthio, (C)3-C8) cycloalkyl-NR4-、(C5-C12) Heteroaryl, (C)5-C12) Heteroaryloxy, (C)5-C12) Heteroarylthio group, (C)5-C12) heteroaryl-NR4-、(C3-C13) Heterocycle, (C)3-C13) Heterocycloxy, (C)3-C13) Heterocyclic thio group, (C)3-C13) Heterocyclic ring-NR4-, hydroxy (C)1-C10) Alkyl, mercapto (C)1-C6) Alkyl group, (NR)4R5) Alkyl or (NR)4R5) A carbonyl group; and is
R7Is absent, or is (C)6-C12) Aryl group, (C)6-C12) Aryl radical (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl, (C)5-C12) Heteroaryl, (C)5-C12) Heteroaryl (C)1-C6) Alkyl, (C)3-C13) Heterocycle or (C)3-C13) Heterocycle (C)1-C6) An alkyl group.
The compounds of formula I and formula II exhibit antibacterial activity, particularly against gram-negative organisms. They may be used to treat bacterial infections in mammals, particularly humans. The compounds may also be used in veterinary applications, such as the treatment of infections in livestock and companion animals.
The compounds of formula I and formula II are useful in the treatment of a variety of infections; in particular gram-negative bacterial infections, including nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intra-abdominal infections, lung infections (including infections in patients with cystic fibrosis), Helicobacter pylori (Helicobacter pylori) (and relief of associated gastric complications, such as peptic ulcers, gastric carcinogenesis, etc.), endocarditis, diabetic foot infections, osteomyelitis and central nervous system infections.
To simplify administration, the compounds are typically mixed with at least one excipient and formulated into a pharmaceutical dosage form. Examples of such dosage forms include tablets, capsules, injectable solutions/suspensions, aerosols for inhalation, creams/ointments for topical, otic or ophthalmic application and solutions/suspensions for oral ingestion.
Detailed Description
The headings in this document are only used to speed up the reader's reading. They should not be construed as limiting the invention or the claims in any way.
In one embodiment, the present invention provides compounds of formula I and formula II wherein R is1Is (C)1-C3) An alkyl group; r2Is (C)1-C3) An alkyl group; r3Is hydrogen; l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p--or- (CH)2)nNR4CO(CH2)p-；R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group; n is 0, 1 or 2; p is 0, 1 or 2; r6Is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylthio carbonyl group, (C)6-C12) Aryl group, (C)6-C12) Aryloxy group, (C)3-C8) Cycloalkyl group, (C)5-C12) Heteroaryl, hydroxy (C)1-C10) Alkyl or (NR)4R5) A carbonyl group; and R7Is absent or is (C)3-C13) A heterocyclic ring.
In another embodiment, the invention provides a compound of formula I and formula IIA compound of formula (I) wherein R1Is methyl; r2Is methyl; r3Is hydrogen; l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；R4Is hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group; n is 0, 1 or 2; p is 0, 1 or 2; r6Is (C)6-C12) Aryl or (C)6-C12) Aryloxy group of each (C)6-C12) Aryl is phenyl optionally substituted with 1,2 or 3 substituents independently being (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo, or methylenedioxy; r7Is absent or is (C)3-C13) Heterocycle wherein said (C)3-C13) The heterocycle is morpholino.
In another embodiment, the invention provides compounds of formula I and formula II wherein R1Is methyl; r2Is methyl; r3Is hydrogen; l is a bond, - (CH)2)2-、-O(CH2)-、-(CH2)O(CH2)-、-S(CH2)-、-(CH2)2NR4(CH2)-、-SO2NR4(CH2) -or-CONR4(CH2)-；R4Is hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group; r6Is (C)6-C12) Aryl or (C)6-C12) Aryloxy group of each (C)6-C12) Aryl is phenyl optionally substituted with 1,2 or 3 substituents independently being (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo, or methylenedioxy; r7Is absent or is (C)3-C13) Heterocycle wherein said (C)3-C13) The heterocycle is morpholino.
In another embodiment, the invention provides compounds of formula I and formula II wherein R1Is methyl; r2Is methyl; r3Is hydrogen; l is a bond, - (CH)2)2-、-O(CH2)-、-(CH2)O(CH2)-、-S(CH2)-、-(CH2)2NR4(CH2)-、-SO2NR4(CH2) -or-CONR4(CH2)-；R4Is hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group; r6Is (C)6-C12) Aryl or (C)6-C12) Aryloxy group of each (C)6-C12) Aryl is phenyl optionally substituted with 1,2 or 3 substituents independently being (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo, or methylenedioxy; r7Is absent.
In another embodiment, the invention provides compounds of formula I and formula II wherein R1Is methyl; r2Is methyl; r3Is hydrogen; l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；R4Is hydrogen, (C)1-C6) Alkyl or (C)3-C8) CycloalkanesA group; n is 0, 1 or 2; p is 0, 1 or 2; r6Is (C)5-C12) Heteroaryl group, wherein (C)5-C12) Heteroaryl is pyridyl, quinolyl or thienyl, each of which is optionally substituted with 1 substituent which is (C)1-C6) Alkyl or halogen; r7Is absent.
In another embodiment, the invention provides compounds of formula I and formula II wherein R1Is methyl; r2Is methyl; r3Is hydrogen; l is a bond; r6Is (C)5-C12) Heteroaryl group, wherein (C)5-C12) Heteroaryl is pyridyl, quinolyl or thienyl, each of which is optionally substituted with 1 substituent which is (C)1-C6) Alkyl or halogen; r7Is absent.
In another embodiment, the invention provides compounds of formula I and formula II wherein R1Is methyl; r2Is methyl; r3Is hydrogen; l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group; n is 0, 1 or 2; p is 0, 1 or 2; r6Is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylthio carbonyl group, (C)3-C8) Cycloalkyl, hydroxy (C)1-C10) Alkyl or (NR)4R5) A carbonyl group, wherein (C)3-C8) Cycloalkyl being cyclohexylA group optionally substituted with 1 substituent which is hydroxyl; r7Is absent.
In another embodiment, the invention provides compounds of formula I and formula II wherein R1Is methyl; r2Is methyl; r3Is hydrogen; l is a bond, - (CH)2)-、-O(CH2)-、-NR4(CH2) -or-NR4CO-；R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group; r6Is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylthio carbonyl group, (C)3-C8) Cycloalkyl, hydroxy (C)1-C10) Alkyl or (NR)4R5) A carbonyl group, wherein (C)3-C8) Cycloalkyl is cyclohexyl, optionally substituted with 1 substituent, which is hydroxy; r7Is absent.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or formula II in admixture with at least one pharmaceutically acceptable excipient.
In another embodiment, the present invention provides a method of treating a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or formula II.
In another embodiment, the present invention provides the use of a compound of formula I or formula II for the manufacture of a medicament for bacterial infection.
Definition of
As used throughout this application (including the claims), the following terms have the meanings defined below, unless otherwise specifically indicated. The plural and singular should be treated as interchangeable, rather than representing a quantity.
As used hereinLanguage "(C)2-C6) Alkenyl "refers to a straight or branched chain hydrocarbon containing 2 to 6 carbons and containing at least one carbon-carbon double bond. (C)2-C6) Representative examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
The term "(C) as used herein1-C6) Alkoxy "means (C) as defined herein attached to the parent molecular moiety through an oxygen atom1-C6) An alkyl group. (C)1-C6) Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentoxy, and hexoxy.
The term "(C) as used herein1-C3) Alkoxy "means (C) as defined herein attached to the parent molecular moiety through an oxygen atom1-C3) An alkyl group. (C)1-C3) Examples of alkoxy groups include methoxy, ethoxy, propoxy, and 2-propoxy (isopropoxy).
The term "(C) as used herein1-C6) Alkoxy (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety1-C6) An alkoxy group. (C)1-C6) Alkoxy (C)1-C6) Representative examples of alkyl groups include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
The term "(C) as used herein1-C6) Alkoxycarbonyl "means (C), as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein1-C6) An alkoxy group. (C)1-C6) Representative examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term "(C) as used herein1-C6) Alkoxycarbonyl (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety1-C6) An alkoxycarbonyl group. (C)1-C6) Alkoxycarbonyl (C)1-C6) Representative examples of alkyl groups include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl and 2-tert-butoxycarbonylethyl.
The term "(C) as used herein1-C6) (ii) alkoxysulfonyl "means (C), as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein1-C6) An alkoxy group. (C)1-C6) Representative examples of alkoxysulfonyl groups include, but are not limited to, methoxysulfonyl, ethoxysulfonyl, and propoxysulfonyl.
The term "(C) as used herein1-C3) Alkyl "refers to a straight or branched chain hydrocarbon containing 1 to 3 carbon atoms. (C)1-C3) Examples of alkyl groups include methyl, ethyl, n-propyl and isopropyl.
The term "(C) as used herein1-C6) Alkyl "refers to a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. (C)1-C6) Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
The term "(C) as used herein1-C10) Alkyl "refers to a straight or branched chain hydrocarbon containing 1 to 10 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-butylA decyl group.
The term "(C) as used herein1-C6) Alkylcarbonyl "means (C), as defined herein, attached to the parent molecular moiety through a carbonyl group, as defined herein1-C6) An alkyl group. (C)1-C6) Representative examples of alkylcarbonyl groups include, but are not limited to, acetyl, 1-oxopropyl, 2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term "(C) as used herein1-C6) Alkylcarbonyl (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety1-C6) An alkylcarbonyl group. (C)1-C6) Alkylcarbonyl (C)1-C6) Representative examples of alkyl groups include, but are not limited to, 2-oxopropyl, 3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
The term "(C) as used herein1-C6) (ii) alkylcarbonyloxy "means (C), as defined herein, attached to the parent molecular moiety through an oxygen atom, as defined herein1-C6) An alkylcarbonyl group. (C)1-C6) Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and t-butylcarbonyloxy.
The term "(C) as used herein1-C6) (ii) alkylsulfinyl "means (C), as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein1-C6) An alkyl group. (C)1-C6) Representative examples of alkylsulfinyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl.
The term "(C) as used herein1-C6) Alkylsulfonyl "means (C), as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein1-C6) An alkyl group. (C)1-C6) Representative examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl and ethylsulfonyl.
The term "(C) as used herein1-C6) Alkylsulfonyl (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety1-C6) An alkylsulfonyl group.
The term "(C) as used herein1-C6) Alkylthio "means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom, as defined herein (C)1-C6) An alkyl group. (C)1-C6) Representative examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
The term "(C) as used herein1-C6) Alkylthio (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety1-C6) An alkylthio group. (C)1-C6) Alkylthio (C)1-C6) Representative examples of alkyl groups include, but are not limited to, methylthiomethyl and 2- (ethylthio) ethyl.
The term "(C) as used herein2-C6) Alkynyl "refers to a straight or branched chain hydrocarbon containing 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. (C)2-C6) Representative examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "(C) as used herein6-C12) Aryl "refers to phenyl or bicyclic aryl. The bicyclic aryl is naphthyl or phenyl fused to a cycloalkyl or phenyl fused to a cycloalkenyl. Said bicyclic aryl passing through any carbon contained in said bicyclic arylThe atom is attached to the parent molecule. Representative examples of said bicyclic aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, dihydronaphthyl and tetrahydronaphthyl.
(C) of the present invention6-C12) Aryl is optionally substituted with 1,2, 3,4 or 5 groups which are independently (C)2-C6) Alkenyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkoxysulfonyl group, (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyl group, (C)1-C6) Alkylcarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyloxy, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylthio group, (C)1-C6) Alkylthio (C)1-C6) Alkyl, (C)2-C6) Alkynyl, carboxyl (C)1-C6) Alkyl, cyano (C)1-C6) Alkyl, ethylenedioxy, formyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl, halogen, hydroxy (C)1-C6) Alkyl, mercapto, methylenedioxy, nitro, oxo, -NZ1Z2、(NZ1Z2) Carbonyl group, (NZ)1Z2) Carbonyloxy, (NZ)1Z2) Sulfonyl or (NZ)1Z2) Sulfonyl (C)1-C6) An alkyl group. Representative examples of substituted aryl groups include, but are not limited to, benzo [1,3 ]]Dioxolyl, 2, 3-dihydrobenzo [1,4 ]]Dioxinyl, 2-chloro-4-methoxyphenyl, cyanophenyl, 2, 3-difluorophenyl, 2,3, 4-trifluorophenyl, 2, 3-dichlorophenyl, 2, 6-dichlorophenyl, 2, 4-dichlorophenyl, 3, 4-dichlorophenyl, 2, 4-difluorophenyl, 3, 4-difluorophenyl, 2, 6-dimethoxyphenylPhenyl, 3, 4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-difluoromethoxy-3-methylphenyl and 2,3, 4-trifluorophenyl.
The term "(C) as used herein6-C12) Aryl radical (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety6-C12) And (4) an aryl group. (C)6-C12) Aryl radical (C)1-C6) Representative examples of alkyl groups include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphthalen-2-ylethyl.
The term "(C) as used herein6-C12) aryl-NR5- "means a through-NR5(C) the group attached to the parent molecular moiety as defined herein6-C12) And (4) an aryl group.
The term "(C) as used herein6-C12) Aryloxy "means an aryl group as defined herein attached to the parent molecular moiety through an oxygen atom (C)6-C12) And (4) an aryl group. (C)6-C12) Representative examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.
The term "(C) as used herein6-C12) Arylthio "means (C) as defined herein attached to the parent molecular moiety through a sulfur atom6-C12) And (4) an aryl group. (C)6-C12) Representative examples of arylthio groups include, but are not limited to, phenylthio and naphthylthio.
The term "carbonyl" as used herein refers to the group-C (O) -.
The term "carboxy" as used herein means-CO2And (4) an H group.
The term "carboxy (C) as used herein1-C6) Alkyl "refers to a compound having a structure represented by the formula (C)1-C6) The alkyl group is attached to the carboxyl group, as defined herein, on the parent molecule.
The term "cyano" as used herein refers to the group-CN.
The term "cyano (C) as used herein1-C6) Alkyl "refers to a compound having a structure represented by the formula (C)1-C6) The alkyl group is attached to the parent molecule through a cyano group as defined herein. Representative examples of cyanoalkyl groups include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.
The term "(C) as used herein5-C8) Cycloalkenyl "refers to cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups containing at least one carbon-carbon double bond. (C)5-C8) Representative examples of cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclohexadienyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl.
The term "(C) as used herein3-C8) Cycloalkyl "means a saturated cyclic hydrocarbon group containing 3 to 8 carbons, (C)3-C8) Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
(C) of the present invention3-C8) Cycloalkyl is optionally substituted with 1,2, 3 or 4 groups independently being (C)2-C6) Alkenyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkoxysulfonyl group, (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyl group, (C)1-C6) Alkylcarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyloxy, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylthio group, (C)1-C6) Alkylthio (C)1-C6) Alkyl, (C)2-C6) Alkynyl, carboxyl (C)1-C6) Alkyl, cyano (C)1-C6) Alkyl, ethylenedioxy, formyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl, halogen, hydroxy (C)1-C6) Alkyl, mercapto, nitro, oxo, -NZ1Z2、(NZ1Z2) Carbonyl group, (NZ)1Z2) Carbonyloxy, (NZ)1Z2) Sulfonyl or (NZ)1Z2) Sulfonyl (C)1-C6) An alkyl group.
The term "(C) as used herein3-C8) Cycloalkyl (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) as defined herein wherein the alkyl group is attached to the parent molecule3-C8) A cycloalkyl group. (C)3-C8) Cycloalkyl (C)1-C6) Representative examples of alkyl groups include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
The term "(C) as used herein3-C8) cycloalkyl-NR5- "means a through-NR5-the group attached to the parent molecule is (C) as defined herein3-C8) A cycloalkyl group.
The term "(C) as used herein3-C8) Cycloalkyloxy "means (C), as defined herein, attached to the parent molecule through an oxygen atom3-C8) A cycloalkyl group. (C)3-C8) Representative examples of cycloalkyloxy groups include, but are not limited to, cyclopropyloxy, 2-cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and 4-cycloheptyloxy.
The term "(C) as used herein3-C8) Cycloalkylthio "means (C), as defined herein, attached to the parent molecule through a sulfur atom3-C8) A cycloalkyl group. (C)3-C8) Representative examples of cycloalkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and cycloheptylthio.
The term "ethylenedioxy" as used herein means-O (CH)2)2An O-group wherein the oxygen atom of the ethylenedioxy group is connected to the parent molecular moiety through 1 carbon atom to form a 5-membered ring; or an ethylenedioxy group is attached to the parent molecular moiety through two adjacent carbon atoms to form a 6-membered ring.
The term "formyl" as used herein refers to the-C (O) H group.
The term "halo" or "halogen" as used herein refers to-Cl, -Br, -I or-F.
The term "halo (C) as used herein1-C3) Alkoxy "refers to a compound formed by (C) as defined herein1-C3) The alkoxy group is attached to at least one halogen, as defined herein, on the parent molecular moiety. Halo (C)1-C3) Representative examples of alkoxy groups include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term "halo (C) as used herein1-C6) Alkyl "is defined as through (C) as defined herein1-C6) The alkyl group is attached to at least one halogen, as defined herein, on the parent molecular moiety. Halo (C)1-C6) Representative examples of alkyl groups include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "halo (C) as used herein1-C3) Alkyl "is defined as through (C) as defined herein1-C3) Attachment of alkyl groups toAt least one halogen as defined herein on the parent molecular moiety. Halo (C)1-C3) Representative examples of alkyl groups include, but are not limited to, chloromethyl, difluoromethyl, 2-fluoroethyl, 2-difluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "(C) as used herein5-C12) Heteroaryl "refers to a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 membered ring. The 5-membered ring consists of 2 double bonds and 1,2, 3 or 4 nitrogen atoms and/or optionally 1 oxygen or sulfur atom. The 6-membered ring consists of 3 double bonds and 1,2, 3 or 4 nitrogen atoms. The 5-or 6-membered heteroaryl is attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl. Representative examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, iso-heteroarylAzolyl, isothiazolyl, thiazolyl,A diazolyl group,Oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl or a monocyclic heteroaryl fused to a cycloalkyl or a monocyclic heteroaryl fused to a cycloalkenyl or a monocyclic heteroaryl fused to a monocyclic heteroaryl. The monocyclic heteroaryl and bicyclic heteroaryl are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heteroaryl or bicyclic heteroaryl. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienylOxadiazolyl, cinnolinyl, oxazolyl, cinnolinyl, cinnolin,Dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, tetrahydroquinolinyl, and thienopyridinyl.
(C) of the present invention5-C12) Heteroaryl is optionally substituted with 1,2, 3 or 4 groups which are independently (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkoxysulfonyl group, (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyl group, (C)1-C6) Alkylcarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyloxy, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylthio group, (C)1-C6) Alkylthio (C)1-C6) Alkyl, (C)2-C6) Alkynyl, carboxyl (C)1-C6) Alkyl, cyano (C)1-C6) Alkyl, ethylenedioxy, formyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl, halogen, hydroxy (C)1-C6) Alkyl, mercapto, nitro, -NZ1Z2、(NZ1Z2) Carbonyl group, (NZ)1Z2) Carbonyloxy, (NZ)1Z2) Sulfonyl or (NZ)1Z2) Sulfonyl (C)1-C6) An alkyl group. Substituted heteroaryl groups of the present invention may exist in the form of tautomers. The present invention includes all tautomers, including non-aromatic tautomers.
The term "(C) as used herein5-C12) Heteroaryl (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety5-C12) A heteroaryl group. (C)5-C12) Heteroaryl (C)1-C6) Representative examples of alkyl groups include, but are not limited to, furan-3-ylmethyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1- (pyridin-4-yl) ethyl, pyridin-3-ylmethyl, 6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl, (6- (trifluoromethyl) pyridin-3-yl) methyl, (6- (cyano) pyridin-3-yl) methyl, (2- (cyano) pyridin-4-yl) methyl, (5- (cyano) pyridin-2-yl) methyl, (2- (chloro) pyridin-4-yl) methyl, pyrimidin-5-ylmethyl, methyl, ethyl, propyl, butyl, pentyl, 2- (pyrimidin-2-yl) propyl, thien-2-ylmethyl, and thien-3-ylmethyl.
The term "(C) as used herein3-C12) heteroaryl-NR5- "denotes the general formula NR5(C) as defined herein, wherein a diradical is attached to the parent molecule5-C12) A heteroaryl group.
The term "(C) as used herein5-C12) Heteroaryloxy "means (C), as defined herein, appended to the parent molecular moiety through an oxygen atom5-C12) A heteroaryl group. (C)5-C12) Representative examples of heteroaryloxy include, but are not limited to, furan-3-yloxy, 1H-imidazol-2-yloxy, 1H-imidazol-4-yloxy, pyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4-yloxy, (6- (trifluoromethyl) pyridin-3-yl) oxy, (6- (cyano) pyridin-3-yl) -oxy, (2- (cyano) pyridin-4-yl) oxy, (5- (cyano) pyridin-2-yl) oxy, (2- (chloro) pyridin-4-yl) oxy, pyrimidin-5-yloxy, pyrimidin-2-yloxy, pyridinyloxy, and pyridinyloxy, Thien-2-yloxy and thien-3-yloxy.
The term "(C) as used herein5-C12) Heteroarylthio "means (C), as defined herein, appended to the parent molecular moiety through a sulfur atom5-C12) A heteroaryl group. (C)5-C12) Representative examples of heteroarylthio include, but are not limited to, pyridin-3-ylthio and quinolin-3-ylthio.
The term "(C) as used herein3-C13) Heterocyclic ring "or" heterocyclic group "Refers to a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring comprising at least one heteroatom independently selected from O, N and S. The 3 or 4 membered ring contains 1 heteroatom selected from O, N and S. The 5-membered ring contains 0 or 1 double bond and 1,2 or 3 heteroatoms selected from O, N and S. The 6 or 7 membered ring contains 0, 1 or 2 double bonds and 1,2 or 3 heteroatoms selected from O, N and S. The bicyclic heterocycle consists of a monocyclic heterocycle fused to a phenyl group or a monocyclic heterocycle fused to a cycloalkyl group or a monocyclic heterocycle fused to a cycloalkenyl group. The monocyclic heterocycle and bicyclic heterocycle are attached to the parent molecular moiety through any carbon atom or any nitrogen atom within the heterocycle. (C)5-C13) Representative examples of heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1, 3-dinaphthylAlkyl, 1, 3-dioxolanyl, 1, 3-dithiolyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isovaleryl, and their use as pesticidesAzolinyl, isoOxazolidinyl, morpholinyl,diazolinyl group,Diazolidinyl group,An azolinyl group,Oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranylTetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1-thiomorpholinyl (thiomorpholinyl sulfone), thiopyranyl and trithianyl.
(C) of the present invention3-C13) The heterocyclyl is optionally substituted with 1,2, 3,4 or 5 groups which are independently (C)2-C6) Alkenyl, (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkoxycarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkoxysulfonyl group, (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyl group, (C)1-C6) Alkylcarbonyl (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyloxy, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl group, (C)1-C6) Alkylthio group, (C)1-C6) Alkylthio (C)1-C6) Alkyl, (C)2-C6) Alkynyl, carboxyl (C)1-C6) Alkyl, cyano (C)1-C6) Alkyl, ethylenedioxy, formyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl, halogen, hydroxy (C)1-C6) Alkyl, mercapto, nitro, oxo, -NZ1Z2、(NZ1Z2) Carbonyl group, (NZ)1Z2) Carbonyloxy, (NZ)1Z2) Sulfonyl or (NZ)1Z2) Sulfonyl (C)1-C6) An alkyl group.
The term "(C) as used herein3-C13) Heterocycle (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (C) alkyl as defined herein attached to the parent molecular moiety5-C13) A heterocyclic ring.
The term "(C) as used herein3-C13) Heterocyclic ring-NR5- "means by NR5(C) attached to the parent molecular moiety as defined herein5-C13) A heterocyclic ring.
The term "(C) as used herein3-C13) Heterocyclyloxy "means (C), as defined herein, appended to the parent molecular moiety through an oxygen atom5-C13) A heterocyclic ring.
The term "(C) as used herein3-C13) (ii) heterocyclylthio "means as defined herein attached to the parent molecular moiety through a sulfur atom (C)5-C13) A heterocyclic ring. Representative examples of heteroarylthio include, but are not limited to, pyridin-3-ylthio and quinolin-3-ylthio.
The term "hydroxy" as used herein refers to an-OH group.
The term "hydroxy (C) as used herein1-C10) Alkyl "is defined as through (C) as defined herein1-C10) The alkyl group is attached to at least one hydroxyl group, as defined herein, on the parent molecular moiety. Hydroxy (C)1-C10) Representative examples of alkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2, 3-dihydroxypentyl, 2-ethyl-4-hydroxyheptyl, 5, 6-dihydroxyoctyl, and 9-hydroxynonyl.
The term "hydroxy (C) as used herein1-C6) Alkylthio "refers to a hydroxy group (C), as defined herein, appended to the parent molecular moiety through a sulfur atom1-C6) An alkyl group.
The term "mercapto" as used herein refers to the-SH group.
The term "mercapto (C)" as used herein1-C10) Alkyl "is defined as through (C) as defined herein1-C10) Alkyl attached to the parent molecular moiety as defined hereinAt least one mercapto group.
The term "methylenedioxy" as used herein refers to-O (CH)2) An O-group wherein the oxygen atom of the methylenedioxy group is attached to the parent molecular moiety through 2 adjacent carbon atoms to form a 5-membered ring.
The term "nitro" as used herein means-NO2A group.
The term "NZ" as used herein1Z2"refers to 2 groups Z attached to the parent molecular moiety through a nitrogen atom1And Z2。Z1And Z2Each independently of the others is hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyl or formyl. NZ1Z2Representative examples of (a) include, but are not limited to, amino, methylamino, acetylamino, acetylmethylamino, butylamino, diethylamino, dimethylamino, ethylmethylamino, and formylamino.
The term "(NZ) as used herein1Z2) Carbonyl "means an NZ group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein1Z2A group. (NZ)1Z2) Representative examples of carbonyl groups include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, and (ethylmethylamino) carbonyl.
The term "NZ" as used herein1Z2(C1-C6) Alkyl "is defined as through (C) as defined herein1-C6) NZ as defined herein with alkyl attached to the parent molecular moiety1Z2A group.
The term "(NZ) as used herein1Z2) Carbonyloxy "means (NZ) as defined herein attached to the parent molecular moiety through an oxygen atom1Z2) A carbonyl group.
The term "(NZ) as used herein1Z2) By "sulfonyl" is meant NZ, as defined herein, attached to the parent molecular moiety through a sulfonyl group, as defined herein1Z2A group. (NZ)1Z2) Representative examples of sulfonyl groups include, but are not limited to, aminosulfonyl, (methylamino) sulfonyl, (dimethylamino) sulfonyl, and (ethylmethylamino) sulfonyl.
The term "(NZ) as used herein1Z2) Carbonyl (C)1-C6) Alkyl "is defined as through (C) as defined herein1-C6) (NZ) as defined herein, with alkyl attached to the parent molecular moiety1Z2) A carbonyl group.
The term "(NZ) as used herein1Z2) "Thiocarbonyloxy" means an oxygen atom attached to the parent molecular moiety through an oxygen atom (NZ) as defined herein1Z2) A thiocarbonyl group.
The term "oxo" as used herein refers to the = O moiety.
The term "sulfinyl" as used herein refers to the group-S (O) -or-S.
The term "sulfonyl" as used herein refers to-SO2-a group.
The term "isomer" as used herein refers to "stereoisomers" and "geometric isomers" as defined below.
The term "stereoisomer" as used herein refers to a compound having one or more chiral centers, each of which may exist in either the (R) or (S) configuration. Stereoisomers include all diastereoisomeric, enantiomeric and epimeric forms as well as racemates and mixtures thereof.
The term "geometric isomer" as used herein refers to compounds that may exist in cis, trans, entgegen (e) and zusammen (z) forms.
The terms "compound of formula I", "compound of formula II" and "compound of the invention" are used interchangeably throughout this application and shall be treated as synonyms.
The term "patient" as used herein refers to a warm-blooded animal, such as livestock, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, monkeys, chimpanzees, and humans.
The phrase "pharmaceutically acceptable" as used herein means that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients included in the formulation and/or the mammal being treated therewith.
The phrase "therapeutically effective amount" as used herein refers to an amount of a compound of formula I or formula II which, when administered to a patient, provides a desired effect of reducing the severity of symptoms associated with a bacterial infection, reducing the number of bacteria in the affected tissue, and/or preventing an increase in the number of bacteria in the affected tissue (local or systemic).
The term "treatment" as used herein refers to the ability of the compound to reduce, ameliorate or slow the progression of a bacterial infection (or condition) or any tissue damage associated with the disease in a patient.
The phrase "pharmaceutically acceptable salt" as used herein, unless otherwise specified, includes salts of acid or base groups that may be present in the compounds of the present invention. The compounds of the present invention, which are basic in nature, are capable of forming a wide variety of salts with various inorganic and organic acids. Acids which can be used for the preparation of pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, i.e. salts comprising a pharmaceutically acceptable anion, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, gluconate, formate, benzoate, glutamate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate [ i.e. 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate) ]. In addition to the acids mentioned above, the compounds of the invention comprising a basic moiety, such as an amino group, may also form pharmaceutically acceptable salts with different amino acids.
The invention also relates to base addition salts of the compounds of the invention. Chemical bases that can be used to prepare such pharmaceutically acceptable base salts are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from the pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine- (meglumine) and lower alkanolammonium and other pharmaceutically acceptable base salts of organic amines.
Suitable base salts are formed from bases which form non-toxic salts. Non-limiting examples of suitable base salts include aluminum, arginine, N' -bis (benzyl) ethane-1, 2-diamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For a review of suitable salts, see Stahl and WermuthHandbook of Pharmaceutical Salts：Properties，Selection，and Use(Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are well known to those skilled in the art.
Certain compounds of formula I and formula II may exist as geometric isomers. The compounds of formula I and formula II may have one or more asymmetric centers and thus exist in two or more stereoisomeric forms. The present invention includes all individual stereoisomers and geometric isomers of the compounds of formula I and formula II and mixtures thereof. The individual enantiomers may be obtained in the synthesis by chiral separation or by using the relevant enantiomers.
In addition, the compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are equivalent to unsolvated forms for the purposes of the present invention. The compounds may also exist in one or more crystalline (i.e., polymorphic) forms, or they may exist as amorphous solids. All of these forms are encompassed by the claims.
The invention also relates to prodrugs of the compounds of the invention. Thus, certain derivatives of the compounds of the invention that have little or no pharmacological activity themselves may be converted (e.g., by hydrolytic cleavage) to compounds of the invention having the desired activity when administered into or on the body. Such derivatives are referred to as "prodrugs". Additional information on prodrug use can be found in Pro drugs as Novel Delivery Systems, vol.14, ACS symposium series (t.higuchi and w.stella) and Bioreversible Carriers in drug design, Pergamon Press, 1987(ed.e.b.roche, american pharmaceutical Association).
The invention also includes compounds of the invention containing protecting groups. It will also be appreciated by those skilled in the art that compounds of the invention may also be prepared with some protecting groups which are useful for purification or storage and which may be removed prior to administration to a patient. Protection and deprotection of functional Groups is described in J.W.F.McOmie, editors "Protective Groups in Organic Chemistry", Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3 rd edition, T.W.Greene and P.G.M.Wuts, Wiley Interscience (1999).
The invention also includes isotopically-labeled compounds, which are identical to those recited in formula I and formula II, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, but not limited toLimited to respectively2H、3H、13C、14C、15N、17O、18O、31P、32P、35S、18F and36and (4) Cl. Compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Certain isotopically-labelled compounds of the present invention, for example, those into which a radioactive isotope is incorporated, for example3H and14the compounds of C are useful in drug and/or substrate tissue distribution assays. Tritiated (i.e. tritiated)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detection. In addition, heavier isotopes such as deuterium (i.e., deuterium) are used2H) Substitutions may be made which may provide some therapeutic advantage due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and are therefore preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
All compounds of formula I and formula II contain a sulfonyl moiety as shown below:
the sulfonyl moiety is always substituted with a lower alkyl moiety. Typically, it is methyl. Such as R2The carbon atom adjacent to the sulfonyl group may be optionally substituted. Typically, R1And R2Both are methyl.
It will be readily apparent to those skilled in the art that the carbon adjacent to the sulfonyl moiety is a chiral center. Thus, the compounds may exist as racemates, (S) enantiomers or (R) enantiomers. In another embodiment, the compounds may be prepared and administered as the (R) enantiomer as shown below:
it is very obvious to the person skilled in the art that the compounds synthesized are rarely present completely in the form of a single enantiomer. The opposite enantiomer (i.e., the (S) enantiomer) may be present in small amounts (i.e., "substantially pure"). The minor amount may be up to 10w/w%, more typically not more than 5w/w%, and in another embodiment not more than 1w/w% or more specifically not more than 0.5 w/w%.
Synthesis of
The compounds of formula I and formula II can be prepared by different methods similarly known in the art. The reaction schemes provided below illustrate two general methods for preparing these compounds. Other methods, including modifications thereof, will be readily apparent to those skilled in the art.
Reaction scheme 1
Scheme 1 illustrates the general preparation of compounds of formula II wherein the initial step (step A) comprises the construction of a heterocompoundOxazole 3 wherein R1、R2、R6、R7And L is as defined in formula II in the summary of the invention section herein. Starting materials were an aldoxime derivative of structure 1 and an alkynyl sulfone of structure 2. Many of these aldoximes 1 are known, commercially available, and/or can be prepared using standard synthetic techniques. Using criteria known to those skilled in the artSynthetic techniques and methods prepare alkynyl sulfones 2. R1、R2、R6、R7And L represents the same moiety as expected in the final product. The ethyl protecting group (ethyl ester) of carboxylic acids is described, but any standard protecting group as described in j. org. chem. (1980) vol.45, 1486 and "preparation 1" may be used.
In step A, the nitrile oxide formed in situ by oxidative dehydrogenation of the acetaldoxime 1 is subjected to a1, 3-dipolar cycloaddition with an alkyne 2 in a manner analogous to that described in Synthesis (1982) Vol.6, 508. Typically, equal amounts of an aldoxime and an alkyne are mixed together in the presence of an oxidizing agent, such as sodium hypochlorite, to give an isoximeAnd (3) azole. A variety of oxidants, solvent systems, temperatures and protocols can be used for this reaction, using standard techniques to isolate and purify the desired product.
In step B, carboxylic acid 4 is obtained. Typically, this step is performed by basic hydrolysis of the ester, but the manner in which this step is performed will vary depending on the identity of the protecting group and is well known to those skilled in the art.
In step C, the hydroxamic acid is incorporated into a molecule. Typically, the protected hydroxylamine is used in a standard amidation reaction to give the protected hydroxamic acid, which is then subjected to suitable deprotection conditions to give the desired hydroxamic acid. In some cases. Deprotection may be carried out under the reaction conditions used for the amidation reaction. In either case, the protected intermediate and/or the desired end product is isolated and purified from the reaction medium using techniques well known in the art.
Reaction scheme 2
Reaction ofScheme 2 illustrates the general preparation of compounds of formula I, which is carried out according to the same reaction sequence as the preparation of compounds of formula II (steps A-C), wherein R1、R2、R6、R7And L is as defined in formula II in the summary of the invention section herein. Because of the analogous procedure, the skilled person is able to prepare compounds of formula I by reference to the description of scheme 1. Starting materials were alkyne derivatives of Structure 5 and aldoxime sulfones of Structure 6, which yield iso-forms in a1, 3-dipolar cycloaddition (scheme 2)Oxazole 7, a regioisomer of structure 3 (scheme 1). Many of these alkynes 5 are known, commercially available, and/or can be prepared using standard synthetic techniques. Acetaldoxime sulfone 6 can be prepared using standard synthetic techniques and methods. R1、R2、R6、R7And L represents the same moiety as expected in the final product. The ethyl protecting group (ethyl ester) of a carboxylic acid is described, but any standard protecting group as described in j. org. chem. (1980) vol.45, 1486, "preparation 2" and "preparation 3" may be used.
Medical and veterinary applications
The compounds may be used for the treatment or prevention of infectious diseases, in particular due to susceptible and multi-drug resistant (MDR) gram-negative bacteria. Examples of the gram-negative bacteria include Acinetobacter baumannii, Acinetobacter sp, Achromobacter sp, Aeromonas sp, Bacteroides fragilis, Bordetella sp, Brucella sp, Campylobacter sp, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Thermomyces terrestris, Fusobacter sp, Clostridium sp, Salmonella typhimurium, Salmonella typhi, Salmonella, and Salmonella, Salmonella, Klebsiella pneumoniae (Klebsiella pneumoniae) (including those encoding ultra-broad-spectrum beta-lactamases (hereinafter "ESBLs"), Legionella pneumophila (Legionella pneumophila), Moraxella catarrhalis (Moraxella catarrhalis) (beta-lactamase positive and negative), Morganella morganii (Morganella morganii), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Neisseria meningitidis (Neisseria meningitidis), Proteus vulgaris (Proteus vulgaris), Porphyromonas (Porphyromonas spp.), Proteus spp (Prevotella spp.), Mannheimia halmolyticus, Pasteurella spp (Pasteurella spp.), Pseudomonas sp., Pseudomonas aeruginosa (Pseudomonas sp.), Pseudomonas sp., burkholderia cepacia (Burkholderia cepacia), species of the genus Vibrio (Vibrio spp.), species of the genus Yersinia (Yersinia spp.), and stenotrophomonas maltophilia (Stenotrophoron). Examples of other gram-negative microorganisms include members of the Enterobacteriaceae (Enterobacteriaceae) family which express ESBLs, KPCs, CTX-M, metallo beta-lactamases (e.g., NDM-1), and AmpC-type beta-lactamases, which confer resistance to currently available cephalosporins, carbapenems, beta-lactams, and beta-lactam/beta-lactamase inhibitor combinations.
In a more specific embodiment, the gram-negative bacteria are selected from the group consisting of acinetobacter baumannii, acinetobacter species, Citrobacter species (Citrobacter spp.), enterobacter aerogenes, enterobacter cloacae, escherichia coli, klebsiella oxcicola, klebsiella pneumoniae, serratia marcescens, stenotrophomonas maltophilia, pseudomonas aeruginosa, and members of the enterobacteriaceae and pseudomonas genera that express ESBLs, KPCs, CTX-M, metallo beta-lactamases, and AmpC-type beta-lactamases that confer resistance to currently available cephalosporins, carbapenems, beta-lactams, and beta-lactam/beta-lactamase inhibitor combinations.
Examples of infections that can be treated with the compounds of formula I and formula II include nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intra-abdominal infections, pulmonary infections (including those in patients with cystic fibrosis), helicobacter pylori (and alleviating associated gastric complications such as peptic ulcers, gastric carcinogenesis, etc.), endocarditis, diabetic foot infections, osteomyelitis or central nervous system infections.
Furthermore, the compounds may be used to treat helicobacter pylori infections in the gastrointestinal tract of humans (and other mammals). Elimination of these bacteria is associated with improved health outcomes including fewer symptoms of dyspepsia, reduced recurrence and re-bleeding of peptic ulcers, reduced risk of gastric cancer, and the like. A more detailed discussion of eradication of H.pylori and its effect on gastrointestinal disease can be found at the following website: www.informahealthcare.com, Expert opin. drug saf. (2008) -7 (3).
In order to exhibit this anti-infective activity, the compounds need to be administered in a therapeutically effective amount. By "therapeutically effective amount" is meant a sufficient amount to describe the compound to treat the infection at a reasonable benefit/risk ratio appropriate for any such medical treatment. However, it will be understood that the attending physician will determine the total dosage of the compounds within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the particular compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed, and the like, are well known in the medical arts. However, as a general guideline, the total daily dose is typically in the range of about 0.1 mg/kg/day to about 5000 mg/kg/day, given in single or divided doses. Typically, the dosage for human use ranges from about 10mg to about 3000mg per day, in single or multiple doses.
Any route typically used to treat infectious diseases may be used to administer the compounds, including oral, parenteral, topical, transmucosal, and intestinal. Parenteral administration includes injection to produce a systemic effect or direct injection into the affected area. Examples of parenteral administration are subcutaneous, intravenous, intramuscular, intradermal, intrathecal and intraocular, intranasal, intraventricular injection or infusion techniques. Topical administration includes treatment of areas susceptible to entry by topical application, for example, the eye, ear including outer and middle ear infections, vagina, open wounds, skin including the epidermis and the lower or lower intestinal tract of dermal structures. Transmucosal administration includes nasal spray or inhalation administration.
Preparation
The compounds of the invention may be formulated for administration in any manner useful in human or veterinary medicine in a manner analogous to other biologically active agents, such as antibiotics. Such methods are well known in the art and are summarized below.
The compositions may be formulated for administration by any route known in the art, e.g., subcutaneously, by inhalation, orally, topically or parenterally. The compositions may be in any form known in the art, including, but not limited to, tablets, capsules, powders, granules, lozenges, creams, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
For example, the topical formulations of the present invention may be formulated as ointments, creams or lotions, ophthalmic ointments/drops and low-ear drops, impregnated dressings and aerosols and may contain suitable conventional additives such as preservatives, solvents and emollients to assist drug penetration and the like. Such topical formulations may also contain conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers can be present, for example, in an amount of about 1% to about 98% of the formulation.
Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binding agents, for example, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example, magnesium stearate, talc, polyethylene glycol or silicon dioxide; disintegrants, for example, potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in standard pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as co-solvents, for example, sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (including use oils), for example, almond oil; oil esters, such as glycerol, propylene glycol or ethanol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid; if desired, conventional flavoring or coloring agents are included.
For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, which is typically water. The compounds may be suspended or dissolved in a vehicle or other suitable solvent, depending on all vehicles and concentrations. In preparing solutions, the compounds may be dissolved in water for injection, sterile filtered, filled into suitable vials or ampoules, and sealed. Advantageously, active agents such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To enhance stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The lyophilized dry powder is then sealed in a vial, and the accompanying vial may be provided with water for injection to redissolve the liquid prior to use. Parenteral suspensions are prepared in essentially the same manner as the compounds are suspended in the vehicle rather than dissolved therein, and cannot be sterilized by filtration. The compounds were sterilized by exposure to ethylene oxide and then suspended in sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain, for example, from about 0.1% to about 100% by weight of the active agent, depending on the method of administration. If the composition comprises dosage units, each unit will contain, for example, about 0.5 to 1000mg of active ingredient. The dosage used for adult treatment will range, for example, from about 10 to 3000 mg/day, depending on the route and frequency of administration.
If desired, the compounds of the present invention may be administered in combination with one or more additional antibacterial agents ("additional active agents"). Such combined use of the compounds of the present invention with additional active agents may be carried out in a simultaneous, separate or sequential manner.
The examples and preparations provided below further illustrate the compounds of the present invention and methods of making such compounds and are illustrative. It should be understood that the scope of the present invention is not limited in any way by the following examples and preparations. In the following examples, molecules with a single chiral center exist as a racemic mixture unless otherwise noted. Unless otherwise noted, those molecules having two or more chiral centers exist as racemic mixtures of diastereomers. The single enantiomers/diastereomers may be obtained by methods well known to those skilled in the art.
Experimental methods
The experiments are generally carried out in an inert gas (nitrogen or argon) atmosphere, in particular in the case of oxygen-and moisture-sensitive reagents or intermediates. Commercial solvents and reagents are generally used without further purification, including, if appropriate, anhydrous solvents(generally, Sure Seal from Aldrich chemical Company, Milwaukee, WisconsinTMProduct). Mass spectral data were reported according to liquid chromatography-mass spectrometry (LCMS) or Atmospheric Pressure Chemical Ionization (APCI). Nuclear magnetic resonance chemical shifts (NMR) are expressed in parts per million (ppm, δ) with reference to the residual peak of the deuterated solvent used. The melting points are not calibrated. Using a Hewlett PackardLow Resolution Mass Spectra (LRMS) were recorded using a chemical ionization (ammonium) or Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform using an 50/50 mixture of acetonitrile/water containing 0.1% formic acid as the ionizing agent. The room temperature or the ambient temperature is 20-25 ℃.
For the synthesis, the reference methods, reaction conditions (reaction time length and temperature) in the other examples were varied. In general, the reaction is carried out by thin layer chromatography or mass spectrometry and, where appropriate, work-up. Purification can be performed between two experiments: in general, the solvent and solvent ratio for the eluent/gradient are selected to give the appropriate Rfs or retention time.
In the above discussion and in the examples below, the following abbreviations have the following meanings. An abbreviation has a generally accepted meaning if it is not defined.
aq. = water
bm = broad multimodal
bd = broad doublet
bs = broad singlet
d = doublet
dd = doublet in doublet
dq = doublet of quartets
dt = doublet of triplets
DIAD = diisopropyl azocarboxylate
DMF = dimethylformamide
DMSO = dimethyl sulfoxide
equ. = equivalent
g = gram
h = hour
HPLC = -high pressure liquid chromatography
m = multiplet
M = molarity
mg = mg
mL = mL
mm = mm
mmol = mmol
q = quartet
s = single peak
t or tr = triplet peak
=2, 4, 6-tripropyl-1, 3,5,2,4, 6-trioxatriphosphetane 2,4, 6-trioxide
TBS = tert-butyldimethylsilyl group
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
MeOH = methanol
DCM = dichloromethane
HCl = hydrochloric acid
MS = mass spectrometry
rt = room temperature
EtOAc = ethyl acetate
EtO = ethoxy
μ L = microliter
J = coupling constant
NMR = nuclear magnetic resonance
MHz = megahertz
Hz = Hertz
m/z = mass to charge ratio
min = min
H2N-OTHP = O-tetrahydro-2H-pyran-2-yl-hydroxylamine
Et2O = ethyl ether
sat. = saturated
Preparation of the starting Material
Preparation 1
2-methyl-2- (methylsulfonyl) hex-5-ynoic acid ethyl ester and the individual enantiomers (R) and (S)
Step A)
2- (methylsulfonyl) propionic acid ethyl ester
Sodium methanesulfinate (103g, 937mmol) and ethyl 2-chloropropionate (109g, 892mmol) were combined in ethanol (350mL) in a 500mL one-necked round-bottom flask. The reaction was heated to 77 ℃ for 20h and then cooled to room temperature. The solids were removed by filtration through celite and the filter pad was washed with ethanol. The combined filtrates were concentrated under reduced pressure. The crude product was suspended in diethyl ether (250mL) and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound as a pale yellow oil (51g, 73%).1H NMR (400MHz, chloroform-d) δ 1.32(t, J =7.05-Hz, 3H)1.67(d, J =7.47Hz, 3H)3.05(s, 3H)3.83-3.92(m, 1H)4.18-4.37(m, 2H).
Step B)
2-methyl-2- (methylsulfonyl) hex-5-ynoic acid ethyl ester
Sodium hydride (60% dispersion in mineral oil, 3.9g, 17.2mmol, 1.2equiv) was added to a solution of ethyl 2- (methylsulfonyl) propionate (14.8g, 82.0mmol, 1.0equiv) in N, N-dimethylformamide (180mL) at room temperature. After the evolved gas had subsided (about 30min), a stirred mixture of potassium iodide (2.89g, 17.2mmol, 0.2equiv) and 4-bromobut-1-yne (10.9g, 82.0mmol, 1.0equiv) in N, N-dimethylformamide (20mL) (about 2H) was added dropwise via cannula. After 3h, the reaction was stopped with water (200mL) and the reaction was quenched with 1: the resulting solution was extracted with 1 ethyl acetate-hexanes (2 × 200 mL). The combined organic phases were washed with water (2 × 50mL), brine (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (340g silica gel column, 0-25% gradient of ethyl acetate in hexanes) to give the title compound as a colorless clear oil (6.63g, 35%). MS (GCMS) m/z233(m + 1).1H NMR (400MHz, chloroform)-d)δ1.33(t，J=7.12Hz，3H)1.64(s，3H)2.00(t，J=2.63Hz，1H)2.11-2.22(m，1H)2.22-2.32(m，1H)2.33-2.45(m，1H)2.46-2.58(m，1H)3.05(s，3H)4.28(q，J=7.16Hz，2H)。
Chiral separation of ethyl 2-methyl-2- (methylsulfonyl) hex-5-ynoate
Using flash chromatography, the racemic material (20.0g) was resolved under the conditions provided in Table 1 (below) to give enantiomer 1(5.7g, [ alpha ], (R))]589 20= +15.5 °, 99% enantiomeric purity) and enantiomer 2(4.7g, ([ α')]589 20= 14.7 °, 99% enantiomeric purity). Enantiomer 1 was determined to be ethyl (2R) -2-methyl-2- (methylsulfonyl) hex-5-ynoate.
TABLE 1
| Preparation instrument | Multigramlll-1 |
| Column | Chiralpak AD-H |
| Size of | 30mm x250mm |
| Mobile phase | 95：5CO2-methanol |
| Modifying agent | Is free of |
| Flow rate of flow | 120g/min |
| Back pressure | 100 bar |
| Wavelength of light | 210nm |
| Dissolving solvent | Methanol |
| Sample volume | 500mL |
| Concentration of sample | 22.0mg/mL |
| Injection volume | 1.0mL |
| Sample loading capacity | 22.0mg |
| Load rate | 0.264 g/hr |
| Injection interval | 5min |
Preparation 2
5- (hydroxyimino) -2-methyl-2- (methylsulfonyl) pentanoic acid ethyl ester
And the individual enantiomers (R) and (S)
Step A)
2-methyl-2- (methylsulfonyl) hex-5-enoic acid ethyl ester
The title compound (8.0g, 46%) was prepared from ethyl 2- (methylsulfonyl) propionate (13.3g, 74.1mmol) and 4-bromobut-1-ene (10.0g, 74.1mmol) by the method described for the synthesis of ethyl 2-methyl-2- (methylsulfonyl) hex-5-ynoate (preparation 1, step B). MS (GCMS) m/z-235(m + 1).1H NMR (400MHz, chloroform-d) δ 1.33(t, J =7.17Hz, 3H)1.63(s, 3H)1.91-2.08(m, 2H)2.13-2.29(m, 1H)2.32(d, J =7.51Hz, 1H)3.05(s, 3H)4.29(q, J =7.06Hz, 2H)4.95-5.16(m, 2H)5.67-5.93(m, 1-H)
Chiral separation of ethyl-2-methyl-2- (methylsulfonyl) hex-5-enoate
Resolution of the racemic material (12.2g) using flash chromatography under the conditions provided in table 2 (below) gave enantiomer 1(4.2g, [ alpha ], (R))]589 20= -3.7 °, 99% enantiomeric purity) and enantiomer 2(4.9g, ([ α')]589 20=2.9 °, 99% enantiomeric purity). Enantiomer 2 was determined to be (2R) -2-methyl-2- (methylsulfonyl) hex-5-enoic acid ethyl ester.
TABLE 2
| Preparation instrument | Multigramlll-1 |
| Column | Chiralpak AS H |
| Size of | 30mm x250mm |
| Mobile phase | 95：5CO2-propanol (E-propanol) |
| Modifying agent | Is free of |
| Flow rate of flow | 120g/min |
| Back pressure | 100 bar |
| Wavelength of light | 210nm |
| Dissolving solvent | Propanol(s) |
| Sample volume | 300mL |
| Concentration of sample | 22.0mg/mL |
| Injection volume | 2.0mL |
| Sample loading capacity | 53.33mg |
| Load rate | 0.961 g/h |
| Injection interval | 3.33min |
Step B)
2-methyl-2- (methylsulfonyl) -5-oxopentanoic acid ethyl ester
2, 6-lutidine (6.1mL, 52.9mmol, 2.0equiv), osmium tetroxide (2.5% w/v in t-butanol, 6.6mL, 0.53mmol, 0.02equiv) and sodium periodate (23.1g, 106mmol, 4.0equiv) were added sequentially to ethyl 2-methyl-2- (methylsulfonyl) hex-5-enoate (6.2g, 26.0mmol, 1.0equiv) at room temperature in 1, 4-bisAlkane-water (3: 1, 0.27L). After vigorous stirring overnight (about 18h), the reaction was partitioned between dichloromethane (0.2L) and water (0.2L). The aqueous phase was extracted with dichloromethane (0.2L). The combined organic phases were washed with brine (30mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as an oil (6.2 g). MS (GCMS) m/z237(m + 1).1H NMR (400MHz, chloroform-d) δ 1.34(t, J =7.22Hz, 3H)1.63(s, 3H)2.21-2.39(m, 1H)2.56(s, 2H)2.65-2.81(m, 1H)3.05-3.17(m, 3H)4.30(q, J =7.15Hz, 2H)9.79(s, 1H).
Step C)
5- (hydroxyimino) -2-methyl-2- (methylsulfonyl) pentanoic acid ethyl ester
Sodium bicarbonate (2.29g, 27.3mmol, 1.05equiv) was added to a solution of hydroxylamine hydrochloride (1.94g, 27.3mmol, 1.05equiv) in water (100mL) at room temperature. Gas evolution ceasesAfter (about 30min), a solution of ethyl 2-methyl-2- (methylsulfonyl) -5-oxopentanoate (6.14g, 26.0mmol, 1.0equiv) in ethanol (100mL) was added dropwise over 30min, and the reaction was stirred overnight (about 15 h). The reaction mixture was concentrated under reduced pressure to half volume (about 100mL) and partitioned between dichloromethane (200mL) and water (100 mL). The aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (6.4g, 97%, about 1: 1E/Z isomer mixture). MS (LCMS) m/z252.1(m + 1).1H NMR (400MHz, chloroform-d) δ 1.34(td, J =7.12, 1.17Hz, 6H)1.56-1.72(m, 6H)2.11-2.19(m, 2H)2.19-2.29(m, 1H)2.44(d, J =3.71Hz, 4H)2.51-2.63(m, 1H)3.06(d, J =2.93Hz, 6H)4.30(qd, J =7.12, 3.22Hz, 4H)6.66-6.88(m, 1H)7.43(d, J =5.07Hz, 1H).
Preparation 3
1-ethynyl-2-fluoro-3-methoxybenzene
Potassium carbonate (3.6g, 26.0mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (2.4mL, 15.6mmol) were added in succession to a solution of 2-fluoro-3-methoxybenzaldehyde (2.0g, 13.0mmol) in methanol (100mL) and the reaction was stirred at room temperature for 16 h. After concentrating the reaction mixture under reduced pressure, the crude material was purified by flash chromatography (40g silica gel column, 0-40% gradient of ethyl acetate in hexane) to give a clear colorless oil (1.8g, 92%). MS (GCMS) m/z 150.1H NMR (400MHz, chloroform-d) δ 3.31(d, J =0.78Hz, 1H)3.90(s, 3H)6.93-7.11(m, 3H).
Example 1
(2R) -4- [3- (2-fluoro-3-methoxyphenyl) iso
Azol-5-yl]-N-hydroxy-2-methyl-
2- (methylsulfonyl) butanamide
Step A)
(2R) -4- [3- (2-fluoro-3-methoxyphenyl) iso
Azol-5-yl]-2-methyl-2- (methylsulfonyl)
Butyric acid ethyl ester
Sodium hypochlorite (6% aqueous solution, 5.7mL, 4.6mmol, 2.0equiv) was added dropwise over 20min to a cooled (0-5 ℃) and vigorously stirred solution of 2-fluoro-3-methoxybenzaldehyde oxime (0.39g, 2.3mmol, 1.0equiv) and ethyl (2R) -2-methyl-2- (methylsulfonyl) hex-5-ynoate (0.53g, 2.3mmol, 1.0equiv) in dichloromethane (30 mL). The biphasic mixture was stirred vigorously at room temperature overnight (15 h). Water (20mL) was added and the mixture was extracted with dichloromethane (3 × 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25g silica gel column, 0-90% gradient of ethyl acetate in hexanes) to give a clear colorless oil (0.49g, 53%). MS (LCMS) m/z400.1(m + 1).1H NMR (400MHz, chloroform-d) δ 1.35(t, J =7.12Hz, 3H)1.72(s, 3H)2.29-2.47(m, 1H)2.60-2.76(m, 1H)2.80-2.94(m, 1H)2.98(s, 1H)3.09(s, 3H)3.86-3.99(m, 3H)4.30(q, J =7.09Hz, 2H)6.52(d, J =3.71Hz, 1H)7.05(d, J =1.56Hz, 1H)7.11-7.22(m, 1H)7.51(s, 1H).
Step B)
(2R) -4- [3- (2-fluoro-3-methoxyphenyl) iso
Azol-5-yl]-2-methyl-2- (methylsulfonyl)
Butyric acid
Sodium hydroxide (1.0M aqueous solution, 4.7mL, 4.7mmol, 4.0equiv) was added to (2R) -4- [3- (2-fluoro-3-methoxyphenyl) isoAzol-5-yl]Ethyl-2-methyl-2- (methylsulfonyl) butyrate (0.47g, 1.2mmol, 1.0equiv) in 1, 4-bisTo a solution in alkane (10mL), the reaction was stirred overnight (18h) at room temperature. Water (5mL) was added and the mixture was extracted with ether (25 mL). The aqueous phase was acidified with 1.0M hydrochloric acid to pH =3 and then extracted with ethyl acetate (2 × 50 mL). The combined ethyl acetate phases were dried over potassium carbonate, filtered, and concentrated under reduced pressure to give a light tan solid (0.42g, 96%). MS (LCMS) m/z372.1(m + 1).1H NMR (400MHz, methanol-d)4)δ1.68(s，3H)2.26-2.41(m，1H)2.61-2.74(m，1H)2.85-3.00(m，1H)3.04-3.15(m，1H)3.16(s，3H)3.92(s，3H)6.65(d，J=3.12Hz，1H)7.18-7.24(m，2H)7.36-7.44(m，1H)。
Step C)
(2R) -4- [3- (2-fluoro-3-methoxyphenyl) iso
Azol-5-yl]-N-hydroxy-2-methyl-2- (methyl)
Sulfonyl) butanamides
Mixing N, N-dimethyl-4-aminopyridine (0.04g, 0.3mmol, 0.3equiv), N-ethyl-N-isopropylpropan-2-amine (0.89mL, 5.2mmol, 4.5equiv),(50% w/w in ethyl acetate, 2.7mL, 4.5mmol, 4.0 equiv.) and (2R) -4- [3- (2-fluoro-3-methoxyphenyl) isoAzol-5-yl]-2-methyl-2- (methylsulfonyl) butyric acid (0.42g, 1.1mmol, 1.0equiv) was stirred at room temperature for 30 min. A solution of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.15g, 1.2mmol, 1.2equiv) in ethyl acetate (12mL) was added and the reaction was stirred at room temperature overnight (18H). Water (40mL) was added and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25g silica gel column, 0-100% gradient of ethyl acetate in hexane) to give (2R) -4- [3- (2-fluoro-3-methoxyphenyl) isoAzol-5-yl]-2-methyl-2- (methylsulfonyl) -N- (tetrahydro-2H-pyran-2-yloxy) butanamide as a tan solid (0.23g, 42-%). MS (LCMS) m/z469.1 (m-1).
Hydrochloric acid (4.0M of 1, 4-bisAlkane solution, 0.49mL, 1.9mmol, 4.0equiv) was added to (2R) -4- [3- (2-fluoro-3-methoxyphenyl) isoAzol-5-yl]-2-methyl-2- (methylsulfonyl) -N- (tetrahydro-2H-pyran-2-yloxy) butanamide (0.23g, 0.49mmol, 1.0equiv) in 1, 4-bisTo a solution in alkane-dichloromethane-water (2: 2: 1, 5mL), the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the resulting crude material was purified by flash chromatography (30g-C18 reverse phase column, 5-60% gradient acetonitrile in water) to give (2R) -4- [3- (2-fluoro-3-methoxyphenyl) iso-isomerAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide as pale brownA colored solid (0.09g, 48%). MS (LCMS) m/z387.1(m + 1).1H NMR (400MHz, methanol-d)4)δ1.67(s，3H)2.20-2.38(m，1H)2.80(s，2H)2.95-3.09(m，1H)3.10(s，3H)3.94(s，3H)6.68(d，J=3.12Hz，1H)7.22(dd，J=5.95，1.17Hz，2H)7.33-7.51(m，1H)。
Example 2
(2R) -4- [5- (2-fluoro-3-methoxyphenyl) iso
Azol-3-yl]-N-hydroxy-2-
Methyl-2- (methylsulfonyl) butanamide
Step A)
(2R) -4- [5- (2-fluoro-3-methoxyphenyl) iso
Azol-3-yl]-2-methyl-2- (methylsulfonyl)
Butyric acid ethyl ester
Sodium hypochlorite (6% aqueous solution, 6.0mL, 4.8mmol, 2.0equiv) was added dropwise to a cooled (0-5 ℃ C.) and vigorously stirred solution of 1-ethynyl-2-fluoro-3-methoxybenzene (0.36g, 2.4mmol, 1.0equiv) and ethyl (2R) -5- (hydroxyimino) -2-methyl-2- (methylsulfonyl) pentanoate (0.60g, 2.4mmol, 1.0equiv) in dichloromethane (20 mL). The biphasic mixture was stirred vigorously at room temperature overnight (15 h). Water (50mL) was added and the mixture was extracted with dichloromethane (2 × 75 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25g silica gel column, 0-20% gradient ethyl acetate in hexanes) to afford a light tan oil (0.50g, 52%). MS (Mass Spectrometry)(LCMS)m/z400.3(m+1)。1H NMR (400MHz, methanol-d)4)δ1.26(t，J=7.17Hz，3H)1.71(s，2H)2.24-2.42(m，2H)3.09-3.20(m，5-H)-3.95(s，3H)4.12(d，J=7.12Hz，2H)6.74-6.85(m，1H)7.18-7.34(m，2H)7.41-7.54(m，1H)。
Step B)
(2R) -4- [5- (2-fluoro-3-methoxyphenyl) iso
Azol-3-yl]-2-methyl-2- (methylsulfonyl)
Butyric acid
According to the synthesis (2R) -4- [3- (2-fluoro-3-methoxyphenyl) isoAzol-5-yl]-2-methyl-2- (methylsulfonyl) butanoic acid (example 1, step B) from (2R) -4- [5- (2-fluoro-3-methoxyphenyl) isoAzol-3-yl]Ethyl-2-methyl-2- (methylsulfonyl) butyrate (0.50g, 1.25mmol) the title compound was prepared (0.46g, 95%). MS (GCMS) m/z372.1(m + 1).1H NMR (400MHz, methanol-d)4)δ1.69(s，3H)2.45-2.56(m，2H)3.14(d，J=9.95Hz，5-H)-3.93(s，3H)6.70-6.82(m，1H)7.19-7.30(m，2H)7.37-7.52(m，1H)。
Step C)
(2R) -4- [5- (2-fluoro-3-methoxyphenyl) iso
Azol-3-yl]-N-hydroxy-2-methyl-2- (methyl)
Sulfonyl) butanamides
N, N-dimethyl-4-aminopyridine (0.04g, 0.3mmol, 0.2equiv), N-ethyl-N-isopropylpropan-2-amine (0.97mL,5.8mmol，4.5equiv)、(50% w/w in ethyl acetate, 3.0mL, 4.96mmol, 4.0 equiv.) and (2R) -4- [5- (2-fluoro-3-methoxyphenyl) isoAzol-3-yl]2-methyl-2- (methylsulfonyl) butyric acid (0.46g, 1.24mmol, 1.0equiv) was stirred at room temperature for 30 min. A solution of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.16g, 1.3mmol, 1.2equiv) in ethyl acetate (15mL) was added and the reaction was stirred at room temperature overnight (18H). Water (40mL) was added and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (25g silica gel column, 0-100% gradient of ethyl acetate in hexane) to give (2R) -4- [5- (2-fluoro-3-methoxyphenyl) isoAzol-3-yl]-2-methyl-2- (methylsulfonyl) -N- (tetrahydro-2H-pyran-2-yloxy) butanamide (0.60g, 10%). MS (LCMS) m/z469.1 (m-1).
Hydrochloric acid (4.0M of 1, 4-bisAlkane solution, 0.13mL, 0.51mmol, 4equiv) was added to (2R) -4- [5- (2-fluoro-3-methoxyphenyl) isoAzol-3-yl]-2-methyl-2- (methylsulfonyl) -N- (tetrahydro-2H-pyran-2-yloxy) butanamide (0.60g, 0.13mmol, 1.0equiv) in 1, 4-bisTo a solution in alkane-dichloromethane-water (2: 2: 1, 2.5mL), the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the resulting crude material was purified by preparative HPLC (Sepax 2-ethylpyridine 250X21.2mm5 μm, heptane-ethanolSolvent system as eluent) to obtain (2R) -4- [5- (2-fluoro-3-methoxyphenyl) isoAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide (0.01g, 20-%). MS (LCMS) m/z385.0 (m-1).1H NMR (400MHz, methanol-d)4)δ1.59-1.71(m，3H)2.13-2.29(m，1H)2.61-2.81(m，2H)2.80-2.99(m，1H)3.07(s，3H)3.92(s，3H)6.65-6.84(m，1H)7.16-7.30(m，2H)7.37-7.52(m，1H)。
Examples 3 to 6
The compounds in table 3 were prepared using similar methods/conditions as described in examples 1 and 2 and using the appropriate starting materials. The starting materials were prepared using synthetic methods well known to those skilled in the art.
TABLE 3
Example 7
4- [3- (5-ethyl-2-thienyl) iso
Azol-5-yl]-N-hydroxy-2-methyl-
2- (methylsulfonyl) butanamide
Sodium hypochlorite (6% aqueous solution, 0.25mL, 0.2mmol, 1.3equiv) was added dropwise to a vigorously stirred solution of 5-ethylthiophene-2-carbaldehyde oxime (23mg, 0.15mmol, 1.0equiv) and ethyl 2-methyl-2- (methylsulfonyl) hex-5-ynoate (35mg, 0.15mmol, 1.0equiv) in dichloromethane (1.0 mL). The reaction was stirred at 30 ℃ for 16 h. Water (1.0mL) was added to the reaction, the phases were separated, and the aqueous phase was extracted with dichloromethane (1.0 mL). The combined organic phases were concentrated under reduced pressure (SpeedVac).
The crude material was dissolved in tetrahydrofuran (0.7 mL). Lithium hydroxide (1.0M aqueous, 0.7mL) was added and the reaction was shaken at 30 ℃ for 16 h. The solution (SpeedVac) was concentrated under reduced pressure to remove tetrahydrofuran, and the resulting aqueous portion was acidified with citric acid (4.0M aqueous, 0.1mL) to pH = 4-5. The mixture was extracted with ethyl acetate (2X1.0 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure (SpeedVac).
The crude material was dissolved in dichloromethane (1.0 mL). (aminooxy) (tert-butyl) dimethylsilane (14mg, 0.1mmol), N-ethyl-N-isopropylpropan-2-amine (35-uL, 0.2mmol) and [ bis (dimethylamino) methylene ] hexafluorophosphate were added successively](3H-[1,2,3]Triazolo [4,5-b]Pyridin-3-yl) oxy- (38mg, 0.1mmol), the reaction was shaken at 30 ℃ for 16 h. Hydrochloric acid (4.0M of 1, 4-bis) was addedAlkane solution, 40uL), the reaction was shaken at 30 ℃ for 30 min. The solvent was removed under reduced pressure (SpeedVac) and the crude material was purified by reverse phase preparative HPLC to give the title compound. MS (LCMS) m/z373.0(m + 1).
Example 8
4- [5- (2-fluorophenyl) iso-phenyl
Azol-3-yl]-N-hydroxy-2-methyl-
2- (methylsulfonyl) butanamide
A solution of N-chlorosuccinimide (29mg, 0.22mmol, 1.8equiv) and ethyl 5- (hydroxyimino) -2-methyl-2- (methylsulfonyl) pentanoate (51mg, 0.2mmol, 1.6equiv) in N, N-dimethylformamide (0.5mL) was shaken at 60 ℃. After 4h, the reaction mixture was cooled to 0-5 ℃. A solution of 1-ethynyl-2-fluorobenzene (15mg, 0.13mmol, 1.0equiv) in N, N-dimethylformamide (0.25mL) was added, triethylamine (36-uL, 0.25mmol, 2.0equiv) was added, and the mixture was shaken at 0 ℃ for 1 h. The reaction was heated to 60 ℃ with shaking for 16h and then concentrated under reduced pressure (SpeedVac).
The crude material was dissolved in methanol (1.0mL), treated with lithium hydroxide (1.0M aqueous, 0.5mL) and shaken at 30 ℃ for 16 h. The reaction was concentrated under reduced pressure (SpeedVac) and the resulting residue was dissolved in acetonitrile- (1.0mL) and water (0.5 mL). After acidification to pH =6 with 2.0M hydrochloric acid (about 0.1mL), the crude material was purified by preparative HPLC.
The purified carboxylic acid intermediate was dissolved in (aminooxy) (tert-butyl) dimethylsilane solution (0.4M in N, N-dimethylformamide, 0.25mL, 0.1 mmol). Triethylamine (21-uL, 0.15mmol) and [ bis (dimethylamino) methylene ] hexafluorophosphate were added successively](3H-[1,2,3]Triazolo [4,5-b]Pyridin-3-yl) oxy- (0.4M in N, N-dimethylformamide, 0.25mL, 0.1mmol), the reaction was shaken at 30 ℃ for 16 h. The solvent was removed under pressure (SpeedVac) and the crude material was purified by reverse phase preparative HPLC to give the title compound. MS (LCMS) m/z357.1(m + 1).
Biological examples
To evaluate the biological activity of the selected compounds, in vitro assays were performed on the selected compounds. One of the tests measures the ability of a compound to disrupt the synthesis of Lipopolysaccharide (LPS), an outer membrane component of gram-negative bacteria. This disruption of synthesis is lethal to the bacteria. This assay measures the ability of a compound to inhibit LpxC, the first enzyme in the biosynthetic pathway of LPS (determined as IC)50). In addition, MICs (minimum inhibitory concentration) against several bacteria was determined. The specific scheme is as follows:
A)IC of LpxC enzyme from Pseudomonas aeruginosa 50 Assay (labeled PA LpxC enzyme) IC 50 )：
IC was performed in the LpxC enzyme assay in a manner similar to that described by Malikzay et al, 2006 potter, Screening LpxC (UDP-3-O- (R-3-hydroxyiminoctaloy) -GlcNAc-deacylase) using BioTrove Rapid FireHTS Mass Spectrometry (aNew Lead Discovery and bIndeflection and induced leakage-Disease, cStrural-Chemistry, Schering Plough research institute, Kenilworth, NJ07033, (BioTrove, Inc.12ll Gi St., Su4000, Woburn, MA01801)50And (4) measuring. Briefly, Pseudomonas aeruginosa LpxC enzyme (0.1nM) purified from bacteria overexpressing E.coli (E. -coli) was incubated at 25 ℃ in a final volume of 50ul, in the presence and absence of inhibitor compounds, containing 0.5uM UDP-3-O- (R-3-hydroxydecanoyl) -N-acetylglucosamine, 1mg/mL BSA and 50mM sodium phosphate buffer pH 8.0. After 1 hour was complete, 5ul of 1N HCl was added to stop the enzymatic reaction, the plates were centrifuged and then treated with a BioTroveRapidfire HTMS mass spectrometry system. Enzyme-free control for calculating IC from percent conversion values50The value is obtained.
B)MIC assay: the compounds described in the examples were evaluated for their in vitro antibacterial activity by the Minimal Inhibitory Concentration (MIC) of Clinical and Laboratory Standards Institute (CLSI). See: method for Dilution of chemical and Laboratory instituteslittle Tests for Bacteria that growing aerobically; approved Standard-eighth edition. CLSI file M7-A8[ ISBN-1-56238-689-1-]. Clinical and Laboratory Standards Institute, 940WestValley Road, Suite1400, Wayne, Pennsylvania190871898USA, 2006; also Clinical and Laboratory Standards institute, Performance Standards for analytical compliance Testing; TwentiethInformational Supplement. CLSI file M100-S20[ ISBN1-56238-716-2 ]]。Clinical and Laboratory Standards Institute。
MIC assays are standard laboratory methods for evaluating the antibacterial activity of compounds. The MIC represents the lowest drug concentration that inhibited visible bacterial growth after overnight incubation. To determine MIC values, a range of drug concentrations (e.g., 0.06. mu.g/mL to 64. mu.g/mL) are incubated with the defined bacterial strains. Typically, the drug concentration range is divided into 2-fold increments (e.g., 0.06. mu.g/mL, 0.12. mu.g/mL, 0.25. mu.g/mL, 0.50. mu.g/mL, 1.0. mu.g/mL, etc.), with each of the different drug concentrations being incubated overnight with the same number of bacteria as appropriate. The MIC was then determined by visually examining the effect at each concentration and identifying the lowest concentration of drug that inhibited bacterial growth compared to the drug-free control group. Typically, bacteria continue to grow at drug concentrations below the MIC, but do not grow at MIC and at concentrations above the MIC.
MIC values described in tables 4 and 5 below were derived from experiments in which each test compound was evaluated in duplicate. In the case of 0-2 fold changes in duplicate values, the lower of the two values is reported below. In general, if the change in duplicate values is greater than 2-fold, the assay is considered invalid and the assay is repeated until the change between duplicate assay runs is ≦ 2-fold. Consistent with the above mentioned CLSI guidelines, both control organism and reference compounds were used for each MIC determination, resulting in suitable quality control. The MIC values generated using these control biological and reference compounds are required to fall within certain ranges of the assay to be considered effective and are included herein. Those skilled in the art recognize that MIC values may vary from experiment to experiment. In general, it is believed that MIC values will typically vary between +/-2-fold from experiment to experiment. Although a single MIC was reported for each compound and each organism, the reader should not conclude that each compound was tested only once. Several compounds were tested in multiple runs. The data reported in tables 4 and 5 are a reflection of the relative activity of the compounds and, consistent with the guidelines above, may lead to different MICs for these reasons.
The following strains were used in these MIC assays:
1) pseudomonas aeruginosa UC12120- (mouse strain), labeled PA-UC12120 in tables 4 and 5;
2) escherichia coli EC-1: VOGEL, the mouse strain marked EC-1 in tables 4 and 5;
3) acinetobacter baumannii/acinetobacter haemolyticus: the multi-drug resistant clinical isolate labeled AB-3167 in tables 4 and 5;
tables 4 and 5 below show the results obtained using the end products described in examples 1 to 50. If a particular form entry is blank, then the data is not available at that time.
Column 1 corresponds to the example number, column 2 provides the compound name, column 3 provides the results from the LpxC enzyme assay described above, and columns 4-6 provide MIC data as described above.
TABLE 4
Examples 7 to 50
Examples 7-50 in table 5 were prepared using similar methods/conditions as outlined in examples 7 and 8. As described in the synthesis section (schemes 1 and 2), the products result from 1, 3-dipolar cycloaddition of alkynes to oxygenated nitriles (generated in situ).
In table 5 (below), column 2 provides the compound name, columns 3-6 provide in vitro biological data generated in the same manner as in table 4, columns 7 and 8 provide the mass and retention time of the generation determined using LCMS, using method A, B or C (column 9).
Method A
Method B
Method C
Claims (14)
1. A compound of formula I or formula II
Or a pharmaceutically acceptable salt thereof, wherein
R1Is (C)1-C3) An alkyl group;
R2is hydrogen or (C)1-C3) An alkyl group;
R3is hydrogen, (C)1-C3) Alkoxy group, (C)1-C3) Alkyl, cyano, (C)1-C3) Haloalkoxy, (C)1-C3) Haloalkyl, halogen, or hydroxy;
l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nNR4SO2(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；
R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl, (C)1-C6) Alkylcarbonyl group, (C)3-C8) Cycloalkyl group, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl or formyl;
n is 0, 1,2, 3 or 4;
p is 0, 1,2, 3 or 4;
R6is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylcarbonyl group, (C)1-C6) alkyl-NR4-(C1-C6) Alkyl, (C)1-C6) Alkylthio (C)1-C6) Alkyl, (C)1-C6) Alkylthio carbonyl group, (C)6-C12) Aryl group, (C)6-C12) Aryloxy group, (C)6-C12) Arylthio, (C)6-C12) aryl-NR4-、(C3-C8) Cycloalkyl group, (C)3-C8) Cycloalkyloxy, (C)3-C8) Cycloalkylthio, (C)3-C8) cycloalkyl-NR4-、(C5-C12) Heteroaryl, (C)5-C12) Heteroaryloxy, (C)5-C12) Heteroarylthio group, (C)5-C12) heteroaryl-NR4-、(C3-C13) Heterocycle, (C)3-C13) Heterocycloxy, (C)3-C13) Heterocyclic thio group, (C)3-C13) Heterocyclic ring-NR4-, hydroxy (C)1-C10) Alkyl, mercapto (C)1-C6) Alkyl group, (NR)4R5) Alkyl or (NR)4R5) A carbonyl group; and is
R7Is absent, or is (C)6-C12) Aryl group, (C)6-C12) Aryl radical (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl, (C)5-C12) Heteroaryl, (C)5-C12) Heteroaryl (C)1-C6) Alkyl, (C)3-C13) Heterocycle or (C)3-C13) Heterocycle (C)1-C6) An alkyl group.
2. The compound of claim 1, wherein
R1Is (C)1-C3) An alkyl group;
R2is (C)1-C3) An alkyl group;
R3is hydrogen;
l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；
R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl or(C3-C8) A cycloalkyl group;
n is 0, 1 or 2;
p is 0, 1 or 2;
R6is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylthio carbonyl group, (C)6-C12) Aryl group, (C)6-C12) Aryloxy group, (C)3-C8) Cycloalkyl group, (C)5-C12) Heteroaryl, hydroxy (C)1-C10) Alkyl or (NR)4R5) A carbonyl group; and is
R7Is absent or is (C)3-C13) A heterocyclic ring.
3. The compound of claim 1, wherein
R1Is methyl;
R2is methyl;
R3is hydrogen;
l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；
R4Is hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group;
n is 0, 1 or 2;
p is 0, 1 or 2;
R6is (C)6-C12) Aryl or (C)6-C12) Aryloxy group of each (C)6-C12) Aryl is phenyl optionally substituted with 1,2 or 3 substituents independently being (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo, or methylenedioxy; and is
R7Is absent or is (C)3-C13) Heterocycle wherein said (C)3-C13) The heterocycle is morpholino.
4. The compound of claim 1, wherein
R1Is methyl;
R2is methyl;
R3is hydrogen;
l is a bond, - (CH)2)2-、-O(CH2)-，-(CH2)O(CH2)-、-S(CH2)-，-(CH2)2NR4(CH2)-、-SO2NR4(CH2) -or-CONR4(CH2)-；
R4Is hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group;
R6is (C)6-C12) Aryl or (C)6-C12) Aryloxy group of each (C)6-C12) Aryl is phenyl optionally substituted with 1,2 or 3 substituents independently being (C)1-C6) Alkoxy group, (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo, or methylenedioxy; and is
R7Is absent or is (C)3-C13) Heterocycle wherein said (C)3-C13) The heterocycle is morpholino.
5. The compound of claim 1 which is
(2R) -4- [3- (2-fluoro-3-methoxyphenyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
(2R) -4- [5- (2-fluoro-3-methoxyphenyl) isoAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
(2R) -4- [3- (2-fluoro-4-methoxyphenyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
(2R) -N-hydroxy-2-methyl-2- (methylsulfonyl) -4- (3-phenyliso-phenyl)Oxazol-5-yl) butanamide;
(2R) -4- [5- (2-fluoro-4-methoxyphenyl) isoAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
(2R) -N-hydroxy-2-methyl-2- (methylsulfonyl) -4- (5-phenyliso-phenyl)Oxazol-3-yl) butanamide;
4- [5- (2-fluorophenyl) iso-phenylAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- {5- [ (benzyloxy) methyl]Different from each otherOxazol-3-yl } -N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [5- (2, 6-dichlorophenyl) isoAzol-3-yl]-N-Hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n- ({3- [4- (hydroxyamino) -3-methyl-3- (methylsulfonyl) -4-oxobutyl]Different from each otherOxazol-5-yl } methyl) -4-methoxybenzamide;
n-hydroxy-4- {5- [ (2-methoxyphenoxy) methyl group]Different from each otherOxazol-3-yl } -2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-2-methyl-4- [5- (3-methylphenyl) isoAzol-3-yl]-2- (methylsulfonyl) butanamide;
n-hydroxy-4- [5- (2-methoxyphenyl) isoAzol-3-yl]-2-methyl-2- (methylsulfonyl) butanamide;
4- (5- { [ cyclopropyl (2-phenoxyethyl) amino]Methyl } isoOxazol-3-yl) -N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-4- (5- { [ (2-methoxyphenyl) thio]Methyl } isoOxazol-3-yl) -2-methyl-2- (methylsulfonyl) butanamide;
4- [5- (3, 4-dichlorophenyl) isoAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [5- (3-fluorophenyl) iso-phenylAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- {5- [4- (difluoromethoxy) -3-methylphenyl]Different from each otherOxazol-3-yl } -N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [5- (2, 6-dimethoxyphenyl) isoAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- {5- [ (1, 3-benzodioxol-5-yloxy) methyl]Different from each otherOxazol-3-yl } -N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [5- ({ [ (4-fluorophenyl) sulfonyl group]Amino } methyl) isoAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [5- (2, 4-difluorophenyl) isoAzol-3-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-4- [5- (3-methoxyphenyl) isoAzol-3-yl]-2-methyl-2- (methylsulfonyl) butanamide;
4- [5- (2, 3-dichlorophenyl) isoAzol-3-yl]-N-Hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [3- (2, 6-Dimethoxyphenyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [3- (1, 3-benzodioxol-5-yl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [3- (3-fluorophenyl) iso-phenylAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-2-methyl-2- (methylsulfonyl) -4- [3- (2,3, 4-trifluorophenyl) iso-phenylAzol-5-yl]Butyramide;
n-hydroxy-2-methyl-4- [3- (4-methylphenyl) isoAzol-5-yl]-2- (methylsulfonyl) butanamide;
n-hydroxy-2-methyl-2- (methylsulfonyl) -4- [3- (2-phenylethyl) isoAzol-5-yl]Butyramide;
4- [3- (3, 4-difluorophenyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [3- (3, 4-Dimethoxyphenyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
4- [3- (4-fluorophenyl) iso-phenylAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-4- [3- (4-methoxyphenyl) isoAzol-5-yl]-2-methyl-2- (methylsulfonyl) butanamide;
4- [3- (3-fluoro-4-morpholin-4-ylphenyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-4- [3- (2-methoxyphenyl) isoAzol-5-yl]-2-methyl-2- (methylsulfonyl) butanamide;
4- [3- (2, 4-difluorophenyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1, wherein
R1Is methyl;
R2is methyl;
R3is hydrogen;
l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；
R4Is hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group;
n is 0, 1 or 2;
p is 0, 1 or 2;
R6is (C)5-C12) Heteroaryl group, wherein (C)5-C12) Heteroaryl is pyridyl, quinolyl or thienyl, each of which is optionally substituted with 1 substituent which is (C)1-C6) Alkyl or halogen; and is
R7Is absent.
7. The compound of claim 1, wherein
R1Is methyl;
R2is methyl;
R3is hydrogen;
l is a bond;
R6is (C)5-C12) Heteroaryl group, wherein (C)5-C12) Heteroaryl is pyridyl, quinolyl or thienyl, each of which is optionally substituted with 1 substituent which is (C)1-C6) Alkyl or halogen; and is
R7Is absent.
8. The compound of claim 1 which is
4- [3- (5-ethyl-2-thienyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-2-methyl-2- (methylsulfonyl) -4-(3-quinolin-2-ylisoxazoiinesOxazol-5-yl) butanamide;
4- [3- (3-Fluoropyridin-4-yl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-2-methyl-2- (methylsulfonyl) -4- (3-quinolin-3-ylisoxaz-o-lOxazol-5-yl) butanamide;
4- [3- (3-Fluoropyridin-2-yl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-2-methyl-2- (methylsulfonyl) -4- (3-quinolin-4-ylisoxaz-o-lOxazol-5-yl) butanamide;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1, wherein
R1Is methyl;
R2is methyl;
R3is hydrogen;
l is a bond, - (CH)2)n-、-(CH2)nO(CH2)p-、-(CH2)nS(CH2)p-、-(CH2)nNR4(CH2)p-、-(CH2)nSO2NR4(CH2)p-、-(CH2)nCONR4(CH2)p-or- (CH)2)nNR4CO(CH2)p-；
R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group;
n is 0, 1 or 2;
p is 0, 1 or 2;
R6is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylthio carbonyl group, (C)3-C8) Cycloalkyl, hydroxy (C)1-C10) Alkyl or (NR)4R5) Carbonyl group of which (C)3-C8) Cycloalkyl is cyclohexyl, optionally substituted with 1 substituent, which is hydroxy; and is
R7Is absent.
10. The compound of claim 1, wherein
R1Is methyl;
R2is methyl;
R3is hydrogen;
l is a bond, - (CH)2)-、-O(CH2)-、-NR4(CH2) -or-NR4CO-；
R4And R5Independently of each other, hydrogen, (C)1-C6) Alkyl or (C)3-C8) A cycloalkyl group;
R6is (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxycarbonyl, (C)1-C6) Alkylthio carbonyl group, (C)3-C8) Cycloalkyl, hydroxy (C)1-C10) Alkyl or (NR)4R5) A carbonyl group, wherein (C)3-C8) Cycloalkyl is cyclohexyl, optionally substituted with 1 substituent, which is hydroxy; and is
R7Is absent.
11. The compound of claim 1 which is
S-butyl ({3- [4- (hydroxyamino) -3-methyl-3- (methylsulfonyl) -4-oxobutyl]Different from each otherOxazol-5-yl } methyl) methylthiocarbamate;
n-hydroxy-4- [5- (9-hydroxynonyl) isoAzol-3-yl]-2-methyl-2- (methylsulfonyl) butanamide;
n-hydroxy-4- {5- [ (1-hydroxycyclohexyl) methyl]Different from each otherOxazol-3-yl } -2-methyl-2- (methylsulfonyl) butanamide;
({3- [4- (hydroxyamino) -3-methyl-3- (methylsulfonyl) -4-oxobutyl)]Different from each otherOxazol-5-yl } methyl) isopropyl carbamate;
{3- [4- (hydroxyamino) -3-methyl-3- (methylsulfonyl) -4-oxobutyl]Different from each otherOxazol-5-yl } methylbutylcarbamate;
4- [3- (1-ethoxy-1-methylethyl) isoAzol-5-yl]-N-hydroxy-2-methyl-2- (methylsulfonyl) butanamide;
n-cyclohexyl-5- [4- (hydroxyamino) -3-methyl-3- (methylsulfonyl) -4-oxobutyl]Different from each otherOxazole-3-carboxamide;
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 in admixture with at least one pharmaceutically acceptable excipient.
13. A method of treating a bacterial infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-11.
14. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for use in bacterial infection.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/473,540 | 2011-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1194368A true HK1194368A (en) | 2014-10-17 |
Family
ID=
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