CN1742009A - Oxazolidinones as antibacterial agents - Google Patents

Oxazolidinones as antibacterial agents Download PDF

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CN1742009A
CN1742009A CN 200380109183 CN200380109183A CN1742009A CN 1742009 A CN1742009 A CN 1742009A CN 200380109183 CN200380109183 CN 200380109183 CN 200380109183 A CN200380109183 A CN 200380109183A CN 1742009 A CN1742009 A CN 1742009A
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M·B·格雷夫斯托克
N·J·哈尔斯
F·雷克
F·周
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AstraZeneca AB
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AstraZeneca AB
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Abstract

A compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, wherein C is selected from (D) and (E), R2a, R6a, and R3a are independently selected from for example H, CF3, Me and Et; R2b and R6b are independently selected from for example H, F, CF3, Me and Et; R1b is for example optionally substituted diazolyl, triazolyl or tetrazolyl; R4 is for example an optionally substituted 5- or 6-membered heterocyclic ring system. Methods for making compounds of the formula (I), compositions containing them and their use as antibacterial agents are also described.

Description

As antibacterials De oxazolidone
The present invention relates to antimicrobial compounds, especially contain the antimicrobial compounds that replaces De oxazolidone ring.The invention further relates to they the preparation method, be used for its preparation intermediate, they are as the purposes of medicine and the medicinal compositions that comprises them.
International microorganism association all the time to microbiotic chemical sproof development represent to pay close attention to, resistance cause bacterial strain at present effectively antimicrobial drug produce resistance, make antimicrobial drug invalid.In general, bacterial pathogen can be divided into Gram-positive or gram-negative pathogens.It has been generally acknowledged that the antimicrobial compounds that Gram-positive and gram-negative pathogens are all had an effective active has broad spectrum of activity.The compounds of this invention is considered to effectively resisting gram-positive pathogenic agent and some gram-negative pathogens.
The particularly important is the Gram-positive pathogenic agent, for example staphylococcus (Staphylococci), faecalis (Enterococci), suis (Streptococci) and mycobacterium, because their endurance strain in case form, just is difficult to treatment and is difficult to eradicate from hospital environment.Such bacterial strain example has methicillin-resistant staphylococcus (MRSA), methicillin-resistant coagulase negative staphylococcus (MRCNS), penicillin resistant streptococcus pneumoniae (Streptococcus pneumoniae) and multidrug resistance faecium (Enterococcus faecium).
The main clinical effective microbiotic that is used for the treatment of such resistance Gram-positive pathogenic agent is a vancomycin.Vancomycin is a glycopeptide, comprises renal toxicity with multiple toxicity.In addition, the most important thing is that antibiotic resistance is also just appearring in vancomycin and other glycopeptide.This resistance just increases with stable speed, makes that the curative effect of these pharmacological agent Gram-positive pathogenic agent is more and more lower.Nowadays, the resistance that is used for the treatment of the medicine (for example beta-lactam, quinolone and macrolide) of upper respiratory tract infection is also increasing, upper respiratory tract infection also is to be caused by some gram negative strain, comprises hemophilus influenzae (H.influenzae) and moraxelle catarrhalis (M.catarrhalis).
The antimicrobial compounds of existing some the Han oxazolidone ring in this area (Walter A.Gregory et al for example, J.Med.Chem.1990,33,2569-2578 and 1989,32 (8), 1673-81; Chung-Ho Park et al, J.Med.Chem.1992,35,1156-1165).May form the bacterium of anti-known antibacterials by some mode, the for example differentiation of active binding site on (i) bacterium, cause former active pharmacophore effect reduction or become unnecessary, and/or (ii) form the mode of the specific pharmacophore of chemical ablation, and/or (iii) form outer pump mechanism.Therefore, need constantly to seek antimicrobial drug, especially comprise the compound of more efficiently novel pharmacophore with useful pharmacological characteristic.
Therefore, the invention provides acceptable salt or the interior hydrolyzable ester of body on a kind of formula (I) compound or its pharmacology,
Wherein group C is selected from group D and E,
Wherein, the benzyl ring among D and the E is with (I) Zhong De oxazolidone is connected;
R 1B is HET1 or HET2, wherein
I) HET1 is a N connection 5-unit unsaturated or part unsaturated heterocycle fully, comprises (i) 1-3 other nitrogen heteroatom or (ii) other heteroatoms and optional other nitrogen heteroatom that is selected from O and S; This ring is chosen wantonly on the C atom beyond the connectivity N atom adjacent C atom and is replaced by oxo or thio group; And/or this ring chooses the RT substituting group that is selected from hereinafter definition on any effective C atom beyond the connectivity N atom adjacent C atom wantonly and replaces, and/or on the available nitrogen atom beyond the adjacent N atom of connectivity N atom (precondition is that this ring is not therefore by quaternized) by the replacement of (1-4C) alkyl;
Ii) HET2 is a N connection 6-unit dihydro heteroaryl ring, comprises altogether (comprise and connect heteroatoms) 3 nitrogen heteroatoms at the most, and this ring is replaced by oxo or thio group on the suitable C atom beyond the connectivity N atom adjacent C atom; And/or this ring chooses wantonly on any effective C atom beyond the connectivity N atom adjacent C atom and replaced by 1-2 RT substituting group that independently is selected from hereinafter definition, and/or (precondition is that this ring is not so by quaternized) quilt (1-4C) alkyl replacement on the available nitrogen atom beyond the adjacent N atom of connectivity N atom;
The RT substituting group is selected from following group: (RTal) hydrogen, halogen, (1-4C) alkoxyl group, (2-4C) alkenyl oxy, (2-4C) alkenyl, (2-4C) alkynyl group, (3-6C) cycloalkyl, (3-6C) cycloalkenyl group, (1-4C) alkylthio, amino, azido-, cyano group and nitro; Or (RTa2) (1-4C) alkylamino, two-(1-4C) alkylaminos and (2-4C) alkenyl amino;
Perhaps RT is selected from following group
(RTb1) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: hydroxyl, (1-4C) alkoxyl group, (1-4C) alkylthio, cyano group and azido-; Or
(RTb2) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: (2-4C) alkenyl oxy, (3-6C) cycloalkyl and (3-6C) cycloalkenyl group;
Perhaps RT is selected from following group
(RTc) the first monocycle of complete saturated 4-, it comprises 1-2 heteroatoms that independently is selected from O, N and S (optional oxidation), and connects through ring nitrogen or ring carbon atom;
As (RTa1) or (RTa2), (RTb1) or (RTb2) or the RT substituting group (RTc) when comprising alkyl, alkenyl, alkynyl group, cycloalkyl or cycloalkenyl group part, described group is partly chosen wantonly on effective carbon atom by 1-3 or more independently is selected from the substituting group replacement of F, Cl, Br, OH and CN;
R 2A and R 6A independently is selected from H, CF 3, OMe, SMe, Me and Et;
R 2B and R 6B independently is selected from H, F, Cl, CF 3, OMe, SMe, Me and Et;
R 3A be selected from H, (1-4C) alkyl, cyano group, Br, F, Cl, OH, (1-4C) alkoxyl group ,-S (O) n(1-4C) alkyl (wherein n=0,1 or 2), amino, (1-4C) alkyl-carbonyl-amino, nitro ,-CHO ,-CO (1-4C) alkyl ,-CONH 2With-CONH (1-4C) alkyl;
R 4Be selected from R 4A and R 4B, wherein
R 4A be selected from azido-,-NR 7R 8, OR 10, (1-4C) alkyl, (1-4C) alkoxyl group, (3-6C) cycloalkyl ,-(CH 2) k-R 9, AR1, AR2, (1-4C) alkyloyl ,-CS (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-(C=O) 1-R 6,-COO (1-4C) alkyl ,-C=OAR1 ,-C=OAR2 ,-COOAR1, S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-S (O) pAR1 ,-S (O) pAR2 and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl chain can be chosen wantonly by (1-4C) alkyl, cyano group, hydroxyl or halogen and replace; P=0,1 or 2;
R 4B is selected from HET-3;
R 6Be selected from hydrogen, (1-4C) alkoxyl group, amino, (1-4C) alkylamino and hydroxyl (1-4C) alkylamino;
K is 1 or 2;
L is 1 or 2;
R 7And R 8Independently be selected from H and (1-4C) alkyl, perhaps R 7And R 8Nitrogen with their connections can form 5-7 unit ring, and this ring is chosen wantonly has 11 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n (wherein n=1 or 2); Wherein this ring can be chosen wantonly and independently is selected from following group by 1-2 and replace: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2), AR1, AR2 ,-C=OAR1 ,-C=OAR2 ,-COOAR1 ,-CS (1-4C) alkyl ,-C (=S) O (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-S (O) pAR1 and-S (O) pAR2; Wherein any (1-4C) alkyl, (3-6C) cycloalkyl or (1-4C) alkyloyl can choose wantonly and be selected from following substituting group by 1-2 and replace (except the contiguous heteroatomic carbon atom): (1-4C) alkyl, cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino; P=0,1 or 2;
R 9Independently be selected from following R 9A-R 9D:
R 9a：AR1、AR2、AR2a、AR2b、AR3、AR3a、AR3b、AR4、AR4a、CY1、CY2；
R 9B: cyano group, carboxyl, (1-4C) alkoxy carbonyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form 5-7 unit ring with Rw with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly has 11 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and is selected from following group replace on another nitrogen: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-COOAR1 ,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl, (3-6C) cycloalkyl or (1-4C) alkyloyl self can choose wantonly by cyano group, hydroxyl or halogen replace)], vinyl, 2-(1-4C) alkyl vinyl, 2-cyano group vinyl, 2-cyano group-2-((1-4C) alkyl) vinyl, 2-nitroethylene base, 2-nitro-2-((1-4C) alkyl) vinyl, 2-((1-4C) alkyl amino-carbonyl) vinyl, 2-((1-4C) alkoxy carbonyl) vinyl, 2-(AR1) vinyl, 2-(AR2) vinyl, 2-(AR2a) vinyl;
R 9C:(1-6C) alkyl
{ optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy (phosphoryl), and [O-P (O) (OH) 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy (phosphiryl) [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: [phosphono-P (O) (OH) for carboxyl, phosphoryl (phosphonate) 2And single-and two-(1-4C) alkoxy derivative], inferior phosphoryl (phosphinate) [P (OH) 2And single-and two-(1-4C) alkoxy derivative], cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein w be O or S, the definition of Rv and Rw is the same], (=NORv), wherein the definition of Rv is the same, (1-4C) alkyl S (O) pNH, (1-4C) alkyl S (O) p-((1-4C) alkyl) N-, fluoro (1-4C) alkyl S (O) pNH-, fluoro (1-4C) alkyl S (O) p ((1-4C) alkyl) N-, (1-4C) alkyl S (O) q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O-, AR3-O-, AR1-S (O) q-, AR2-S (O) q-, AR3-S (O) q-, AR1-NH-, AR2-NH-, (p is 1 or 2 to AR3-NH-, and q is 0,1 or 2) and comprise AR2a, AR2b, the group of AR3a and AR3b type AR2 and AR3 }; R wherein 9Any (1-4C) alkyl self in any substituting group of c can independently be selected from following group by 1-2 and replace: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;
R 9D:R 14C (O) O (1-6C) alkyl-, R wherein 14Be AR1, AR2, (1-4C) alkylamino, benzyloxy-(1-4C) alkyl or (1-10C) alkyl { optional replacement as (R 9C) definition };
R 10Be selected from hydrogen, R 9C (with above definition), (1-4C) acyl group and (1-4C) alkyl sulphonyl;
HET-3 is selected from:
A) comprise the 5-unit heterocycle of at least 1 nitrogen and/or oxygen, wherein any carbon atom is C=O, C=N or C=S, and wherein said ring is with following formula HET3-A-HET3-E:
Figure A20038010918300261
B) comprise 1-4 and independently be selected from N, O and heteroatomic carbon connection 5-of S or 6-unit hetero-aromatic ring, it is selected from following HET3-F-HET3-Y:
Figure A20038010918300271
C) comprise 1-4 and independently be selected from N, O and heteroatomic nitrogen connection 5-of S or 6-unit hetero-aromatic ring, it is selected from following HET3-Z-HET3-AH:
Figure A20038010918300281
Wherein, the R of HET-3 1A is the substituting group on the carbon;
R 1A independently is selected from following R 1A1-R 1A5:
R 1a1：AR1、AR2、AR2a、AR2b、AR3、AR3a、AR3b、AR4、AR4a、CY1、CY2；
R 1A2: cyano group, carboxyl, (1-4C) alkoxy carbonyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form 5-7 unit ring with Rw with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly has 11 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and is selected from following group replace on another nitrogen: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-COOAR1 ,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl, (1-4C) alkyloyl is with (3-4C) naphthenic substituent self can be by cyano group, hydroxyl or halogen replace, and precondition is that such substituting group is not on the carbon of contiguous piperazine ring nitrogen-atoms], vinyl, 2-(1-4C) alkyl vinyl, 2-cyano group vinyl, 2-cyano group-2-((1-4C) alkyl) vinyl, 2-nitroethylene base, 2-nitro-2-((1-4C) alkyl) vinyl, 2-((1-4C) alkyl amino-carbonyl) vinyl, 2-((1-4C) alkoxy carbonyl) vinyl, 2-(AR1) vinyl, 2-(AR2) vinyl, 2-(AR2a) vinyl;
R 1A3:(1-10C) alkyl
{ optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy, and [O-P (O) (OH) 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: [phosphono-P (O) (OH) for carboxyl, phosphoryl (phosphonate) 2And single-and two-(1-4C) alkoxy derivative], inferior phosphoryl [P (OH) 2And single-and two-(1-4C) alkoxy derivative], cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv and Rw can form 5-7 unit ring with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly to have 1 and be selected from N, O, 1 carbon atom of the ring that the other heteroatoms displacement of S (O) n so forms; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and be selected from following group replacement on another nitrogen: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl,-COO (1-4C) alkyl,-S (O) n (1-4C) alkyl (wherein n=1 or 2),-COOAR1,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl], (=NORv), wherein the definition of Rv is the same, (1-4C) alkyl S (O) pNH-, (1-4C) alkyl S (O) p-((1-4C) alkyl) N-, fluoro (1-4C) alkyl S (O) pNH-, fluoro (1-4C) alkyl S (O) p ((1-4C) alkyl) N-, (1-4C) alkyl S (O) q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O-, AR3-O-, AR1-S (O) q-, AR2-S (O) q-, AR3-S (O) q-, AR1-NH-, AR2-NH-, (p is 1 or 2 to AR3-NH-, and q is 0,1 or 2) and comprise AR2a, AR2b, the group of AR3a and AR3b type AR2 and AR3 }; R wherein 1Any (1-4C) alkyl in any substituting group of a3, (1-4C) alkyloyl and (3-6C) cycloalkyl self can independently be selected from following group replacement by 1-2: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;
R 1A4:R 14C (O) O (1-6C) alkyl-, R wherein 14Be AR1, AR2, AR2a, AR2b, (1-4C) alkylamino, benzyloxy-(1-4C) alkyl or (1-10C) alkyl { optional replacement as (R 1A3) definition };
R 1A5:F, Cl, hydroxyl, sulfydryl, (1-4C) alkyl S (O) p-(p=0,1 or 2) ,-NR 7R 8(R wherein 7And R 8Definition the same) or-OR 10(R wherein 10Definition the same);
M is 0,1 or 2;
R 21Be selected from hydrogen, methyl [optionally replaced by following group: cyano group, trifluoromethyl ,-(wherein W, Rv and Rw are with R above for C=WNRvRw 1The definition of a3), alkoxy carbonyl, CY1, CY2, AR1, AR2, AR2a, AR2b (connecting) or the AR3 of the alkoxyl group of the alkoxy carbonyl of (1-4C) alkoxy carbonyl, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) without nitrogen], (2-10C) alkyl [chooses wantonly on the carbon except carbon that HET-3 ring nitrogen is connected and independently is selected from R by 1-2 1The optional substituent group of a3 definition replaces] and R 14C (O) O (2-6C) alkyl-, R wherein 14Same above R 1The definition of a4, wherein R 14C (O) O connects with the carbon carbon in addition that is connected HET-3 ring nitrogen);
R 22For cyano group ,-COR 12,-COOR 12,-CONHR 12,-CON (R 12) (R 13) ,-SO 2R 12(precondition is R 12Be not hydrogen) ,-SO 2NHR 12,-SO 2N (R 12) (R 13) or NO 2, R wherein 12And R 13With hereinafter define identical;
R 12And R 13Independently be selected from hydrogen, phenyl (optionally be selected from following substituting group by one or more and replace: halogen, (1-4C) alkyl and (1-4C) alkyl that is replaced by 1-3 or more halogen atom) and (1-4C) alkyl (optional) by 1-3 or more halogen atom replacement, or for any N (R 12) (R 13) group, R 12And R 13Can form 5-7 unit ring with the nitrogen that they connect, this ring is chosen wantonly has 1 carbon atom that the other heteroatoms that is selected from N, O, S (O) n is replaced the ring that so forms; Wherein said ring can be chosen wantonly and independently is selected from following group by 1-2 and replace: (1-4C) alkyl (choose wantonly on not adjacent carbon and replaced), (3-6C) cycloalkyl, (1-4C) alkyloyl by cyano group, hydroxyl or halogen with nitrogen ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2), AR1, AR2 ,-C=OAR1 ,-C=OAR2 ,-COOAR1 ,-CS (1-4C) alkyl ,-C (=S) O (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-S (O) pAR1 and-S (O) pAR2; Wherein any (1-4C) alkyl chain can be chosen wantonly by (1-4C) alkyl, cyano group, hydroxyl or halogen and replace; P=0,1 or 2;
AR1 is optional phenyl that replaces or the optional naphthyl that replaces;
AR2 is optional 5-or 6-unit unsaturated fully (promptly having maximum degree of unsaturation) the bicyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and connect by ring carbon atom, if perhaps should encircle, can connect by theheterocyclic nitrogen atom not therefore by quaternized;
AR2a is partial hydrogenation type AR2 (is AR2 ring system retained part but not whole degrees of unsaturation), connect by ring carbon atom, if perhaps should ring not therefore by quaternized, can connect by theheterocyclic nitrogen atom;
AR2b is complete hydrogenation type AR2 (being that the AR2 ring system does not have unsaturation), connects by ring carbon atom or theheterocyclic nitrogen atom;
AR3 is optional 8-, 9-or 10-unit unsaturated fully (promptly having maximum degree of unsaturation) the bicyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and passes through the ring carbon atom connection of arbitrary ring of formation second cycle line;
AR3a is partial hydrogenation type AR3 (is AR3 ring system retained part but not fully degree of unsaturation), and the ring carbon atom of the arbitrary ring by constituting second cycle line connects, if perhaps should ring not have therefore by quaternized then can be by the theheterocyclic nitrogen atom connection of arbitrary ring;
AR3b is complete hydrogenation type AR3 (being that the AR3 ring system does not have unsaturation), and the ring carbon atom or the theheterocyclic nitrogen atom of the arbitrary ring by constituting second cycle line connect;
AR4 is optional 13-or 14-unit unsaturated fully (promptly having maximum degree of unsaturation) the tricyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and passes through the ring carbon atom connection of any ring of formation three ring systems;
AR4a is partial hydrogenation type AR4 (is AR4 ring system retained part but not whole degrees of unsaturation), and the ring carbon atom of any ring by constituting three ring systems connects, if perhaps should ring not have therefore by quaternized then can be by the theheterocyclic nitrogen atom connection of any ring;
CY1 is optional cyclobutyl, cyclopentyl or the cyclohexyl ring that replaces;
CY2 is optional cyclopentenyl or the tetrahydrobenzene basic ring that replaces;
Wherein: AR1; AR2; AR2a; AR2b; AR3; AR3a; AR3b; AR4; AR4a; the optional substituting group of CY1 and CY2 for (on effective carbon atom) at the most 3 independently be selected from following substituting group: (1-4C) alkyl { optionally independently is selected from following substituting group replacement: hydroxyl; trifluoromethyl; (1-4C) (q is 0 to alkyl S (O) q-; 1 or 2); (1-4C) alkoxyl group; (1-4C) alkoxy carbonyl; cyano group; nitro; (1-4C) alkanoylamino;-CONRvRw or-NRvRw}; trifluoromethyl; hydroxyl; halogen; nitro; cyano group; sulfydryl; (1-4C) alkoxyl group; (1-4C) alkanoyloxy; dimethylamino methene amido carbonyl; two (N-(1-4C) alkyl) amino methyl imino-; carboxyl; (1-4C) alkoxy carbonyl; (1-4C) alkyloyl; (1-4C) alkyl SO 2Amino, (2-4C) alkenyl { optional } by carboxyl or (1-4C) alkoxy carbonyl replacement, (2-4C) alkynyl group, (1-4C) alkanoylamino, oxo (=O), sulfo-(=S), (1-4C) alkanoylamino { (1-4C) alkyloyl is optional is replaced by hydroxyl }, (1-4C) (q is 0 to alkyl S (O) q-, 1 or 2) { (1-4C) alkyl is optional by one or more cyano group that independently are selected from, hydroxyl and (1-4C) the group replacement of alkoxyl group },-CONRvRw or-NRvRw[wherein Rv be hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl];
At AR1; AR2; AR2a; AR2b; AR3; AR3a; AR3b; AR4; AR4a; CY1 and CY2 (on effective carbon atom) and alkyl (except as otherwise noted) go up other optional substituting group at the most 3 independently be selected from following substituting group: trifluoromethoxy; benzoyl-amido; benzoyl; phenyl optional by at the most 3 independently be selected from following substituting group and replace: halogen; (1-4C) alkoxyl group or cyano group }; furans; the pyrroles; pyrazoles; imidazoles; triazole; pyrimidine; pyridazine; pyridine isoxazole oxazole; isothiazole; thiazole; thiophene; oxyimino (1-4C) alkyl; (1-4C) Alkoximino (1-4C) alkyl; the alkyl of halogen-(1-4C); (1-4C) alkane sulfonamido;-SO 2NRvRw[wherein Rv is hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl]; And
AR2, AR2a, AR2b, AR3, AR3a, AR3b, the optional substituting group of AR4 and AR4a has (on the available nitrogen atom, such replacement can not cause quaternized) (1-4C) alkyl, (1-4C) { wherein (1-4C) alkyl independently is selected from following substituting group replacement with (1-4C) alkyl-carbonyl is optional by (preferred one) to alkyl-carbonyl: cyano group, hydroxyl, nitro, trifluoromethyl, (1-4C) (q is 0 to alkyl S (O) q-, 1 or 2), (1-4C) alkoxyl group, (1-4C) alkoxy carbonyl, (1-4C) alkanoylamino,-CONRvRw or-NRvRw[wherein Rv be hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl] }, (2-4C) alkenyl, (2-4C) alkynyl group, (1-4C) alkoxy carbonyl or oxo (constituting the N-oxide compound).
On the other hand, the present invention relates to acceptable salt on formula defined above (1) compound or the pharmacology.
On the one hand, the present invention relates to formula defined above (1) compound or its prodrug again.The suitable example of the prodrug of formula (1) compound is the interior hydrolyzable ester of the body of formula (1) compound.Therefore, more on the one hand, the present invention relates to hydrolyzable ester in formula defined above (1) compound or its body.
On the one hand, provide formula defined above (I) compound again, wherein HET3 is selected from:
a)HET3-A-HET3-E；
B) HET3-F-HET3-Y; With
c)HET3-Z-HET3-AE。
When optional substituting group is selected from " 0,1,2 or 3 " individual group, should be understood that this definition comprises that all substituting groups all are selected from one of them special groups group, perhaps substituting group is selected from the special groups group more than 2 or 2.Similarly convention is applicable to that substituting group is selected from " 0,1 or 2 " individual group group and " 1 or 2 " individual group group.
In this manual, term ' alkyl ' comprises straight chain and branched structure.For example (1-4C) alkyl comprises propyl group and sec.-propyl.But mention that concrete alkyl for example only refers to the straight chain type group when " propyl group ", mention that concrete branched-chain alkyl for example only refers to the branched chain type group when " sec.-propyl ".In this manual, term ' alkenyl ' and ' cycloalkenyl group ' comprise all positional isomerss and geometrical isomer.In this manual, term ' aryl ' is unsubstituted isocyclic aryl, especially phenyl, 1-and 2-naphthyl.
For fear of ambiguity, when in HET1 or HET2, mentioning carbon atom, be meant CH by oxo or thio group replacement 2Replaced respectively by C=O or C=S.
In this manual, use the explanation of compound term to comprise the group of an above functional group, for example the alkyl of the alkoxyl group of (1-4C) alkoxyl group-(1-4C)-(1-4C).This class term should be explained the understanding of each composition group according to those skilled in the art.For example (1-4C) alkoxyl group-(1-4C) alkoxyl group-(1-4C) alkyl comprises methoxymethoxy methyl, oxyethyl group methoxy base propyl group and propoxy-ethoxyl methyl.
Should be understood that when the definition group is optional when being replaced by an above substituting group, replace so to form chemically stable compound.For example, can be trifluoromethyl, but can not be trihydroxy methyl.This convention is applicable to the optional substituting group of definition in any case.
Below be some substituting group and the suitable concrete suitable example of group group that relates in this specification sheets.These groups to above or hereinafter disclosed any definition and embodiment all can use when suitable.For fear of ambiguity, every kind of explanation representative concrete independent aspects of the present invention.
(1-4C) alkyl and (1-5C) example of alkyl comprise methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl; (1-6C) example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, amyl group and hexyl; (1-10C) example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, amyl group, hexyl, heptyl, octyl group and nonyl; (1-4C) alkanoylamino-(1-4C) example of alkyl comprises formamido-methyl, acetamidomethyl and acetamido ethyl; The example of hydroxyl (1-4C) alkyl and hydroxyl (1-6C) alkyl comprises hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; (1-4C) example of alkoxy carbonyl comprises methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl; (1-4C) alkoxyl group-(1-4C) example of alkoxy carbonyl comprises methoxymethoxy carbonyl, methoxy ethoxy carbonyl and propoxy-methoxycarbonyl; (1-4C) alkoxyl group-(1-4C) alkoxyl group-(1-4C) example of alkoxy carbonyl comprises methoxymethoxy methoxycarbonyl, methoxy ethoxy methoxycarbonyl and propoxy-oxyethyl group methoxy base carbonyl; The example of 2-((1-4C) alkoxy carbonyl) vinyl comprises 2-(methoxycarbonyl) vinyl and 2-(ethoxy carbonyl) vinyl; The example of 2-cyano group-2-((1-4C) alkyl) vinyl comprises 2-cyano group-2-methyl ethylene and 2-cyano group-2-ethyl vinyl; The example of 2-nitro-2-((1-4C) alkyl) vinyl comprises 2-nitro-2-methyl ethylene and 2-nitro-2-ethyl vinyl; The example of 2-((1-4C) alkyl amino-carbonyl) vinyl comprises 2-(methylamino carbonyl) vinyl and 2-(ethylamino carbonyl) vinyl; (2-4C) non-limiting examples of alkenyls comprises allyl group and vinyl; (2-4C) example of alkenyl oxy comprises allyl group oxygen base and vinyl oxygen base; (2-4C) example of alkynyl group comprises ethynyl and 2-propynyl; (2-4C) example of alkynyl group oxygen base comprises ethynyl oxygen base and 2-propynyl oxygen base; (1-4C) example of alkyloyl comprises formyl radical, ethanoyl and propionyl; (1-4C) example of alkyl-carbonyl comprises ethanoyl and propionyl; (1-4C) example of alkoxyl group comprises methoxyl group, oxyethyl group and propoxy-; (1-6C) alkoxyl group and (1-10C) example of alkoxyl group comprise methoxyl group, oxyethyl group, propoxy-and pentyloxy; (1-4C) example of alkylthio comprises methylthio group and ethylmercapto group; (1-4C) example of alkylamino comprises methylamino, ethylamino and propyl group amino; (2-4C) example of alkenyl amino comprises vinyl amino and allyl amino; The example of hydroxyl (1-4C) alkylamino comprises 2-hydroxyethyl amino, 2-hydroxypropyl amino and 3-hydroxypropyl amino; Two-((1-4C) alkyl) amino examples comprise dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propyl group amino and dipropyl amino; The example of halogen comprises fluorine, chlorine and bromine; (1-4C) example of alkyl sulphonyl comprises methyl sulphonyl and ethylsulfonyl; (1-4C) alkoxyl group of alkoxyl group-(1-4C) and (1-6C) alkoxyl group-(1-6C) example of alkoxyl group comprises methoxymethoxy, 2-methoxy ethoxy, 2-ethoxy ethoxy and 3-methoxy propoxy; (1-4C) alkoxyl group-(1-4C) alkoxyl group-(1-4C) example of alkoxyl group comprises 2-(methoxymethoxy) oxyethyl group, 2-(2-methoxy ethoxy) oxyethyl group; 3-(2-methoxy ethoxy) propoxy-and 2-(2-ethoxy ethoxy) oxyethyl group; (1-4C) alkyl S (O) 2Amino example comprises the amino and ethylsulfonyl amino of methyl sulphonyl; (1-4C) alkanoylamino and (1-6C) example of alkanoylamino comprise formamido-, acetamido and propionyl amino; (1-4C) example of alkoxycarbonyl amino comprises the amino and ethoxy carbonyl amino of methoxycarbonyl; The example of N-(1-4C) alkyl-N-(1-6C) alkanoylamino comprises N-methylacetamide base, N-ethyl acetamide base and N-methyl-prop amido; (1-4C) example of alkyl S (O) pNH-(wherein p is 1 or 2) comprises methylsulfinyl amino, methyl sulphonyl amino, ethyl sulfinyl amino and ethylsulfonyl amino; (1-4C) example of alkyl S (O) p ((1-4C) alkyl) N-(wherein p is 1 or 2) comprises methylsulfinyl methylamino, methyl sulphonyl methylamino, 2-(ethyl sulfinyl) ethylamino and 2-(ethylsulfonyl) ethylamino; The example of fluoro (1-4C) alkyl S (O) pNH-(wherein p is 1 or 2) comprises the amino and trifluoromethyl sulfonyl amino of trifluoromethyl sulphinyl base; The example of fluoro (1-4C) alkyl S (O) p ((1-4C) alkyl) NH-(wherein p is 1 or 2) comprises the amino and trifluoromethyl sulfonyl methylamino of trifluoromethyl sulphinyl ylmethyl; (1-4C) example of alkoxyl group (hydroxyl) phosphorus acyloxy comprises methoxyl group (hydroxyl) phosphorus acyloxy and oxyethyl group (hydroxyl) phosphorus acyloxy; The example of two-(1-4C) alkoxyl group phosphorus acyloxy comprises two-methoxyl group phosphorus acyloxy, two-oxyethyl group phosphorus acyloxy and oxyethyl group (methoxyl group) phosphorus acyloxy; (1-4C) alkyl S (O) q-(wherein q is 0,1 or 2) and-example of S (O) n (1-4C) alkyl (wherein n=1 or 2) comprises methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methyl sulphonyl and ethylsulfonyl; Phenyl S (O) q and naphthyl S (O) qThe example of-(wherein q is 0,1 or 2) is respectively phenyl sulfenyl, phenyl sulfinyl, phenyl sulfonyl and naphthyl sulfenyl and naphthyl sulfinyl and naphthyl alkylsulfonyl; Benzyloxy-(1-4C) example of alkyl comprises benzyloxymethyl and benzyloxy ethyl; (3-4C) example of alkylidene chain is trimethylene or tetramethylene; (1-6C) alkoxyl group-(1-6C) example of alkyl comprises methoxymethyl, ethoxyl methyl and 2-methoxy ethyl; Hydroxyl-(2-6C) example of alkoxyl group comprises 2-hydroxyl-oxethyl and 3-hydroxyl propoxy-; (1-4C) alkylamino-(2-6C) example of alkoxyl group comprises 2-methyl amino ethoxy and 2-ethylamino oxyethyl group; Two-(1-4C) alkylaminos-(2-6C) example of alkoxyl group comprises 2-dimethylamino ethoxy and 2-diethyl amino base oxethyl; The example of phenyl (1-4C) alkyl comprises benzyl and styroyl; (1-4C) example of alkyl-carbamoyl comprises methylamino formyl radical and ethylamino formyl radical; The example of two ((1-4C) alkyl) formamyl comprises two (methyl) formamyls and two (ethyl) formamyl; The example of oxyimino (1-4C) alkyl comprises oxyimino methyl, 2-(oxyimino) ethyl and 1-(oxyimino) ethyl; (1-4C) Alkoximino-(1-4C) example of alkyl comprises methoxyimino methyl, ethoxy imino methyl, 1-(methoxyimino) ethyl and 2-(methoxyimino) ethyl; The example of halo (1-4C) alkyl comprises halogenated methyl, 1-halogenated ethyl, 2-halogenated ethyl and 3-halopropyl; The example of nitro (1-4C) alkyl comprises nitro methyl, 1-nitro-ethyl, 2-nitro-ethyl and 3-nitro propyl group; The example of amino (1-4C) alkyl comprises amino methyl, 1-amino-ethyl, 2-amino-ethyl and 3-aminopropyl; The example of cyano group (1-4C) alkyl comprises cyano methyl, 1-cyano ethyl, 2-cyano ethyl and 3-cyano group propyl group; (1-4C) example of alkane sulfonamido comprises methylsulfonyl amido and ethanesulfonamide group; (1-4C) example of alkyl amino sulfonyl comprises methylamino alkylsulfonyl and ethylamino alkylsulfonyl; The example of two-(1-4C) alkyl amino sulfonyls comprises dimethylamino alkylsulfonyl, diethylamino alkylsulfonyl and N-methyl-N-ethylamino alkylsulfonyl; (1-4C) example of alkanesulfonyl oxygen base comprises methyl sulphonyl oxygen base, ethylsulfonyl oxygen base and sulfonyl propyl base oxygen base; (1-4C) example of alkyloyl oxygen base comprises acetoxyl group, propionyloxy; (1-4C) example of alkyl amino-carbonyl comprises methylamino carbonyl and ethylamino carbonyl; The aminocarboxy example of two ((1-4C) alkyl) comprises dimethylamino carbonyl and diethylamino carbonyl; (3-6C) example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (3-6C) example of cycloalkenyl group comprises cyclopropenyl radical, cyclobutene base, cyclopentenyl and cyclohexenyl; (4-7C) example of cycloalkyl comprises cyclobutyl, cyclopentyl and cyclohexyl; The example of two (N-(1-4C) alkyl) amino methyl imino-comprises dimethylaminomethyl imino-and diethylamino methyl imino-.
The specific examples of AR2 comprises that the example that for example contains a heteroatomic AR2 has furans, pyrroles, thiophene; The example that contains the AR2 of 1-4 N atom has pyrazoles, imidazoles, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3-and 1,2,4-triazole and tetrazolium; The example You oxazole, isoxazole of AR2 that contains a N atom and an O atom is with oxazine; The example that contains the AR2 of a N atom and a S atom has thiazole and isothiazole; The example that contains the AR2 of two N atoms and a S atom has 1,2,4-and 1,3,4-thiadiazoles.
The specific examples of AR2a for example comprises pyrrolin (especially 2,5-pyrrolin-4-yl) and tetrahydropyridine (especially 1,2,5,6-tetrahydropyridine-4-yl).
The specific examples of AR2b comprises for example tetrahydrofuran (THF), tetramethyleneimine, morpholine (preferred morpholino), parathiazan (preferred parathiazan-4-yl), piperazine (preferred Piperazino), tetrahydroglyoxaline and piperidines, 1,3-dioxolane-4-base, 1,3-dioxane-4-base, 1,3-dioxane-5-base and 1,4-dioxane-2-base.
The specific examples of AR3 comprises the benzo-fused system of two rings that for example contains 5-or 6-unit hetero-aromatic ring, and described 5-or 6-unit hetero-aromatic ring contain a nitrogen-atoms and optional 1-3 other heteroatoms that is selected from oxygen, sulphur and nitrogen.The specific examples of such ring system comprises for example indoles, cumarone, thionaphthene, benzoglyoxaline, benzothiazole, benzisothiazole, benzoxazole, benzoisoxazole, quinoline, quinoxaline, quinazoline, phthalazines and cinnoline.
Other specific examples of AR3 is included in and all contains heteroatomic 5/5-, 5/6 and 6/6 second cycle line in two rings.The specific examples of such ring system comprises for example purine and naphthyridines.
More specific exampless of AR3 comprise two ring hetero-aromatic ring systems, wherein contain at least one bridgehead nitrogen and optional 1-3 other heteroatoms that is selected from oxygen, sulphur and nitrogen.The specific examples of such ring system comprises for example 3H-pyrrolo-[1,2-a] pyrroles, pyrrolo-[2,1-b] thiazole, 1H-imidazo [1,2-a] pyrroles, 1H-imidazo [1,2-a] imidazoles, 1H, and the 3H-pyrrolo-[1,2-c] oxazole, 1H-imidazo [1,5-a] pyrroles, pyrrolo-[1,2-b] isoxazole, imidazo [5,1-b] thiazole, imidazo [2,1-b] thiazole, indolizine, imidazo [1,2-a] pyridine, imidazo [1,5-a] pyridine, pyrazolo [1,5-a] pyridine, pyrrolo-[1,2-b] pyridazine, pyrrolo-[1,2-c] pyrimidine, pyrrolo-[1,2-a] pyrazine, pyrrolo-[1,2-a] pyrimidine, pyrido [2,1-c]-s-triazole, s-triazole [1,5-a] pyridine, imidazo [1,2-c] pyrimidine, imidazo [1,2-a] pyrazine, imidazo [1,2-a] pyrimidine, imidazo [1,5-a] pyrazine, imidazo [1,5-a] pyrimidine, imidazo [1,2-b]-pyridazine, s-triazolo [4,3-a] pyrimidine, imidazo [5,1-b] oxazole and imidazo [2,1-b] oxazole.Other specific examples of such ring system for example comprise [1H]-pyrrolo-[2,1-c] oxazine, [3H]-oxazoles also [3,4-a] pyridine, [6H]-pyrrolo-[2,1-c] oxazine and pyrido [2,1-c] [1,4] oxazine.Other specific examples of 5/5-second cycle line have Mi Zuo Bing oxazole or Imidazothiazole, particularly imidazo [5,1-b] thiazole, imidazo [2,1-b] thiazole, imidazo [5,1-b] oxazole or imidazo [2,1-b] oxazole.
The specific examples of AR3a and AR3b comprises for example indoline, 1,3,4,6,9,9a-hexahydropyridine also [2,1c] [1,4] oxazine-8-base, 1,2,3,5,8,8a-six hydrogen imidazos [1,5a] pyridine-7-base, 1,5,8,8a-Si Qing oxazole is [3,4a] pyridine-7-base also, 1,5,6,7,8,8a-Liu Qing oxazole is [3,4a] pyridine-7-base also, (7aS) [3H, 5H]-1, the 7a-pyrrolin also [1,2c] oxazole-6-base, (7aS) [5H]-1,2,3,7a-Pyrrolidine also [1,2c] imidazoles-6-base, (7aR) [3H, 5H]-1,7a-pyrrolin also [1,2c] oxazole-6-base, [3H, 5H]-pyrrolo-[1,2-c] oxazole-6-base, [5H]-2, the 3-pyrrolin is [1,2-c] imidazoles-6-base also, [3H, 5H]-pyrrolo-[1,2-c] thiazole-6-base, [3H, 5H]-1,7a-pyrrolin also [1,2-c] thiazole-6-base, [5H]-pyrrolo-[1,2-c] imidazoles-6-base, [1H]-3,4,8, the 8a-Pyrrolidine also [2,1-c] oxazine-7-base, [3H]-1,5,8,8a-Si Qing oxazole is [3,4-a] pyridine-7-base also, [3H]-5,8-dihydro-oxazole also [3,4-a] pyridine-7-base and 5, the 8-glyoxalidine is [1,5-a] pyridine-7-base also.
The specific examples of AR4 comprises for example pyrrolo-[a] quinoline, 2,3-pyrrolo-isoquinoline 99.9, pyrrolo-[a] isoquinoline 99.9,1H-pyrrolo-[1,2-a] benzoglyoxaline, 9H-imidazo [1,2-a] indoles, 5H-imidazo [2,1-a] isoindole, 1H-imidazo [3,4-a] indoles, imidazo [1,2-a] quinoline, imidazo [2,1-a] isoquinoline 99.9, imidazo [1,5-a] quinoline and imidazo [5,1-a] isoquinoline 99.9.
Employed nomenclature referring to for example " Heterocyclic Compounds (Systems withbridgehead nitrogen), W.L.Mosby (Interscience Publishers Inc., NewYork), 1961, the 1 and part 2.
Except as otherwise noted, otherwise when listing optional substituting group, such replacement preferably is not together with two replacements.If do not indicate in addition, the suitable optional substituting group of a certain concrete group is the substituting group of the similar group of this paper regulation.
Ar2b is 1; 3-dioxolane-4-base, 1; 3-dioxane-4-base, 1; 3-dioxane-5-base or 1, the preferred optional substituting group on 4-dioxane-2-base is replaced or two replacement for independently being selected from following substituting group list: (1-4C) alkyl (comprising together with two replacements), (1-4C) alkoxyl group, (1-4C) alkylthio, kharophen, (1-4C) alkyloyl, cyano group, trifluoromethyl and phenyl.
Preferred optional substituting group on CY1 and the CY2 replaces or two replacement for independently being selected from following substituting group list: (1-4C) alkyl (comprising together with two replacements), hydroxyl, (1-4C) alkoxyl group, (1-4C) alkylthio, kharophen, (1-4C) alkyloyl, cyano group and trifluoromethyl.
Acceptable salt comprises acid salt for example mesylate, fumarate, hydrochloride, Citrate trianion, maleate, tartrate and (inferior choosing) hydrobromate on the suitable pharmacology.Suitable salt also comprises the salt that forms with phosphoric acid and sulfuric acid.On the other hand, suitable salt is for example an alkali metal salt of alkali salt, for example sodium salt; Alkaline earth salt, for example calcium salt or magnesium salts; Organic amine salt, for example with triethylamine, morpholine, N-Methyl piperidine, N-Ethyl piperidine, PROCAINE HCL, PHARMA GRADE, dibenzylamine, N, N-The salt of dibenzyl ethamine, three-(2-hydroxyethyl) amine, N-methyl d-glycosamine and amino acid (for example Methionin).Have an above positively charged ion or negatively charged ion, this depends on charged functional groups quantity and positively charged ion or anionic valency.Acceptable salt is sodium salt on the preferred pharmacology.
Yet, in order to help separated salt in preparation, no matter whether be can accept on the pharmacology, all possible preferably less salt of solvability in selected solvent.
The compounds of this invention can the prodrug form administration, and it will decompose in human or animal body and produce The compounds of this invention.Prodrug can be used for changing or improving the physics and/or the characteristics of pharmacokinetics of parent compound, when proper group that comprises the formation prodrug of can deriving in the parent compound or substituting group, just can prepare prodrug.The example of prodrug comprises acceptable salt on the interior hydrolyzable ester of The compounds of this invention body or its pharmacology.
Various forms of prodrugs are well known in the art, for example referring to:
A) Design of Prodrugs, chief editor H.Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.309-396, (Academic Press, 1985) such as chief editor K.Widder;
B) A Textbook of Drug Design and Development, chief editor Krogsgaard-Larsen and H.Bundgaard, the 5th chapter " Design and Application ofProdrugs ", H.Bundgaard, p.113-191 (1991);
c)H.Bundgaard，Advanced?Drug?Delivery?Reviews， 8，1-38(1992)；
D) H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77, 285 (1988); With
E) N.Kakeya etc., Chem Pharm Bull, 32, 692 (1984).
The appropriate precursors medicine of pyridine or triazole derivative comprises acyloxy picoline or triazolium salt, for example halogenide; For example following prodrug:
(reference: T.Yamazaki etc., 42 NdInterscience Conference on AntimicrobialAgents and Chemotherapy, San Diego, 2002; Abstract F820).
The appropriate precursors medicine of hydroxyl is the acyl ester of acetal-carbonic ether of formula RCOOC (R, R ') OCO-, and wherein R is (1-4C) alkyl and R ' is (1-4C) alkyl or H.Further the suitable precursor medicine is carbonic ether and carbamate RCOO-and RNHCOO-.
Comprise acceptable salt on hydrolyzable ester in the body of The compounds of this invention of carboxyl or hydroxyl or its pharmacology for for example can be in human or animal body hydrolysis produce acceptable ester on the pharmacology of parent alcohol.
Acceptable ester comprises (1-6C) alkoxy methyl ester (for example methoxymethyl), (1-6C) alkanoyloxy methyl ester (for example oxy acid methyl neopentyl), peptidyl ester, (3-8C) cyclo alkoxy carbonyl oxygen base (1-6C) alkyl ester (for example 1-cyclohexyl-carbonyl oxygen base ethyl) on the suitable pharmacology of carboxyl; 1,3-dioxolane-2-ylmethyl ester (for example 5-methyl isophthalic acid, 3-dioxolane-2-ylmethyl); (1-6C) alkoxy-carbonyl oxy ethyl ester (for example 1-methoxycarbonyl oxygen base ethyl) can form described ester on any carboxyl of The compounds of this invention.
Comprise in the body of The compounds of this invention of one or more hydroxyls that acceptable salt comprises inorganic ester for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and alpha-acyloxy alkyl oxide on hydrolyzable ester or its pharmacology, and owing to the related compound that obtains parent hydroxy is decomposed in the interior hydrolysis of the body of ester.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.Selection be used for group that hydroxyl generates hydrolyzable ester in the body comprise the benzoyl of (1-10C) alkyloyl, benzoyl, phenylacetyl and replacement and phenylacetyl, (1-10C) alkoxy carbonyl (acquisition alkyl carbonate), two-(1-4C) alkyl-carbamoyls and N-(two-(1-4C) alkylamino ethyls)- N-(1-4C) alkyl-carbamoyl (acquisition carbamate), two-(1-4C) alkylamino ethanoyl, carboxyl (2-5C) alkyl-carbonyl and carboxyl ethanoyl.The example of ring substituents comprises chloromethyl or amino methyl, (1-4C) alkylamino methyl and two-((1-4C) alkyl) amino methyl and morpholino or Piperazino (being connected 3-or the 4-position that base is connected to the benzoyl basic ring through methylene radical by theheterocyclic nitrogen atom) on phenylacetyl and the benzoyl.Hydrolyzable ester comprises for example R in other relevant body AC (O) O (1-6C) alkyl-CO-(R wherein ABe for example optional benzyloxy that replaces-(1-4C) alkyl or the optional phenyl that replaces; The suitable substituent of phenyl for example comprises the alkyl of the alkyl of the alkyl of 4-(1-4C) Piperazino-(1-4C), Piperazino-(1-4C) and morpholino-(1-4C) in such ester.
Hydrolyzable ester is described below in the suitable body of formula (I) compound.For example 1, the 2-glycol can cyclisation production (PD1) cyclic ester or formula (PD2) pyrophosphate, and 1, the 3-glycol can cyclisation production (PD3) cyclic ester:
Figure A20038010918300421
The ester of formula (I) compound (wherein at (PD1), (PD2) and (PD3) HO-functional group by (1-4C) alkyl, phenyl or benzyl protection) can be used as the intermediate of the such prodrug of preparation.
Hydrolyzable ester comprises phosphoramidate in the more body, and also comprise The compounds of this invention: wherein any free hydroxyl group independently forms phosphoric acid ester (npd is 1) or the phosphorous acid ester (npd is 0) of formula (PD4):
Figure A20038010918300422
For fear of ambiguity, phosphono is-P (O) is (OH) 2(1-4C) alkoxyl group (hydroxyl)-phosphoryl be-O-P (O) (OH) 2The alkoxy derivative of list-(1-4C); Two-(1-4C) alkoxy phosphoryls are-O-P (O) is (OH) 2Two-(1-4C) alkoxy derivative.
The intermediate that can be used for preparing such ester comprises the compound that contains one or more formulas (PD4) group, and wherein the 1-2 of (PD1)-OH is independent of the alkyl (such phenyl is optional independently to be selected from (1-4C) alkyl, nitro, halogen and (1-4C) the group replacement of alkoxyl group by 1-2) of (1-4C) alkyl protection (such compound itself also is the purpose compound), phenyl or phenyl-(1-4C).
Therefore; comprise for example (PD1), (PD2), (PD3) and (PD4) etc. the prodrug of group can be prepared as follows: contain the The compounds of this invention of suitable hydroxyl and the phosphoric acid agent of due care (for example chloride or dialkyl amido leavings group) reaction, carry out oxidizing reaction (if desired) and protective reaction then.
Other suitable precursor medicine comprises the salt of phosphono oxygen ylmethyl ether and they, for example the prodrug of R-OH as:
Figure A20038010918300431
When The compounds of this invention comprises a plurality of free hydroxyl group, can earlier the hydroxyl that need not be converted into prodrug functional group be protected (for example using the tertiary butyl-dimetylsilyl), and then go protection.In addition, enzymatic process can be used for selectivity phosphorylation or dephosphorylation alcohol functional group.
When on the pharmacology that can generate hydrolyzable ester in the body during acceptable salt, can finish by routine techniques.Thus, for example contain formula (PD1), (PD2), (PD3) and/or (PD4) compound of group can ionization (partly or entirely) generate the salt of the counter ion that contains proper amt.Therefore, for instance, if hydrolyzable ester comprises two (PD4) groups in the prodrug body of The compounds of this invention, have in the then whole molecule 4 HO-P-functional groups, each functional group can generate suitable salt (to be that whole molecule can generate for example single-, two-, three-or four-sodium salt).
There is a chiral centre C-5 position of The compounds of this invention Zai oxazolidone ring.This pharmacologic activity diastereomer is formula (Ia):
It typically is (5R) configuration, depend on R 1The characteristic of b and C.
The present invention includes the mixture of pure diastereomer or diastereomer, for example racemic mixture.If the use enantiomeric mixture needs bigger consumption (ratio that depends on each enantiomer) to realize the effect of the pharmaceutical active enantiomer of same weight.
In addition, the part The compounds of this invention may contain other chiral centre, for example on the substituting group of group C.Should be understood that and the present invention includes all such optically active isomer and diastereomer and racemic mixtures with anti-microbial activity.It all is well known in the art how preparing optically active form (for example synthetic by recrystallization technology resolution of racemic form, chirality, enzyme process fractionation, bio-transformation or chromatography) and the anti-microbial activity that how to detect as hereinafter introducing.
The present invention relates to have all tautomeric forms of the The compounds of this invention of anti-microbial activity.
It is to be further understood that some The compounds of this invention may exist solvate and non-solvent compound form, for example hydrate forms.Should be understood that and the present invention includes all such solvate forms with anti-microbial activity.
It is to be further understood that may there be polymorph in some The compounds of this invention, and the present invention includes all such forms with anti-microbial activity.
As mentioned above, we have found that a series of compounds with excellent activity, they can be used for many Gram-positive pathogenic agent, comprise and known the most frequently used microbiotic is had chemical sproof Gram-positive pathogenic agent, and the gram-negative pathogens that is difficult to cultivate, for example hemophilus influenzae, moraxelle catarrhalis, Mycoplasma and chlamydozoan bacterial strain.Following compounds has good pharmacology and/or physics and/or pharmaco-kinetic properties.
One embodiment of the invention provide formula (I) compound, alternate embodiment provides acceptable salt on the pharmacology of formula (I) compound, another alternate embodiment provides hydrolyzable ester in the body of formula (I) compound, and another alternate embodiment provides acceptable salt on the pharmacology of hydrolyzable ester in the body of formula (I) compound.
On the one hand, hydrolyzable ester is phosphoric acid ester (definition of cotype (PD4), npd is 1) in the body of formula (I) compound.
Wherein C is selected from formula (I) compound of group D or E or its pharmacology in acceptable salt or the body hydrolyzable ester and represents the concrete independent aspects of the present invention.
Particularly preferred The compounds of this invention constitutes acceptable salt or body interior hydrolyzable ester, wherein substituent R on The compounds of this invention or its pharmacology 1A, R 1B, R 2A, R 2B, R 3A, R 6A and R 6B and above-mentioned other substituting group have above disclosed value or any following value (above or hereinafter disclosed any definition and embodiment is suitable all can use):
An embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (I) compound or its pharmacology, and wherein group C is group D.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (I) compound or its pharmacology, and wherein group C is group E.
One side R 2A and R 6A is a hydrogen.
One side R 2B and R 6One is another hydrogen of fluorine among the b.Again on the one hand, R 2B and R 6B is a fluorine.Another aspect, R 2B is fluorine and R 6B is selected from Cl, CF 3, Me, Et, OMe and SMe.
On the one hand, R 2B and R 6Among the b one for chlorine another is a hydrogen.
On the other hand, R 2B and R 6One is CF among the b 3And another is a hydrogen.
Again on the one hand, R 2B and R 6Among the b one for Me another is a hydrogen.
Again on the one hand, R 2B and R 6Among the b one for Et another is a hydrogen.
Again on the one hand, R 2B and R 6Among the b one for OMe another is a hydrogen.
Again on the one hand, R 2B and R 6Among the b one for SMe another is a hydrogen.
One side R 3A be selected from H, (1-4C) alkyl, cyano group, Br, F, Cl, OH, (1-4C) alkoxyl group ,-S (1-4C) alkyl, amino, nitro and-CHO.Advance on the one hand R 3A is selected from H, Cl, Br, F, Me, Et, OMe and SMe.
In one embodiment, R 1B is for to use HET1, and wherein HET1 is selected from following structure (Za)-(Zf):
Figure A20038010918300451
Wherein u and v independently are 0 or 1, and RT is with any embodiment of above or hereinafter definition or the definition in the aspect.
In one embodiment, R 1B is HET1, wherein HET1 is selected from 1,2,3-triazoles (especially 1,2,3-triazol-1-yl (Zd)), 1,2,4-triazole (especially 1,2,4-triazol-1-yl (Zc)) and tetrazolium (preferred tetrazolium-2-base (Zf)), wherein u and v independently are 0 or 1, and RT is with above or any embodiment of hereinafter definition or the definition in the aspect.
In a further embodiment, R 1B is HET1, and wherein HET1 is selected from 1,2,3-triazoles-1-base (Zd) and tetrazolium-2-base (Zf), and wherein u and v independently are 0 or 1, and RT is with any embodiment of above or hereinafter definition or the definition in the aspect.
In a further embodiment, R 1B is HET1, and wherein HET1 is 1,2,3-triazoles-1-base (Zd), and wherein u and v independently are 0 or 1, and RT is with any embodiment of above or hereinafter definition or the definition in the aspect.
In one embodiment, R 1B is HET2, and wherein HET2 is two-Hydrogen pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2, and 4-triazine, 1,3,5-triazines and pyridine, wherein RT is with any embodiment of above or hereinafter definition or the definition in the aspect.
In a further embodiment, R 1B is HET2, and wherein HET2 is pyrimidone, pyridazinone, pyrazine ketone, 1,2,3-triazone, 1,2, and 4-triazone, 1,3,5-triazines ketone and pyridone, wherein RT is with any embodiment of above or hereinafter definition or the definition in the aspect.
In a further embodiment, R 1B is HET2, and wherein HET2 is selected from sulfo-pyrimidone, sulfo-pyridazinone, sulfo-pyrazine ketone, sulfo--1,2,3-triazone, sulfo--1,2,4-triazone, sulfo--1,3,5-triazone and sulfo-pyridone, wherein RT is with any embodiment of above or hereinafter definition or the definition in the aspect.
On the one hand, the RT substituting group is preferably from RTa1-RTb2 group group substituting group, wherein:
(RTa1) hydrogen, halogen, (1-4C) alkoxyl group, (2-4C) alkenyl oxy, (2-4C) alkenyl, (2-4C) alkynyl group, (3-6C) cycloalkyl, (3-6C) cycloalkenyl group, (1-4C) alkylthio, amino, azido-, cyano group and nitro;
(RTa2) (1-4C) alkylamino, two-(1-4C) alkylaminos and (2-4C) alkenyl amino;
(RTb1) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: hydroxyl, (1-4C) alkoxyl group, (1-4C) alkylthio, cyano group and azido-;
(RTb2) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: (2-4C) alkenyl oxy, (3-6C) cycloalkyl and (3-6C) cycloalkenyl group;
Wherein, (RTa1) or (RTa2) or (RTb1) or the RT substituting group (RTb2) when comprising alkyl, alkenyl, alkynyl group, cycloalkyl or cycloalkenyl group part, described group is partly chosen wantonly and is effectively being replaced by the individual or more substituting group of 1-3 on the carbon atom, and described substituting group independently is selected from F, Cl, Br, OH and CN.
Again on the one hand, the RT substituting group is preferably from RTa1-RTb1 group group, wherein: (RTa1) hydrogen, halogen, (1-4C) alkoxyl group, (2-4C) alkenyl oxy, (2-4C) alkenyl, (2-4C) alkynyl group, (3-6C) cycloalkyl, (3-6C) cycloalkenyl group, (1-4C) alkylthio, amino, azido-, cyano group and nitro;
(RTb1) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: hydroxyl, (1-4C) alkoxyl group, (1-4C) alkylthio, cyano group and azido-; And (RTa1) or the RT substituting group (RTb1) when comprising alkyl, alkenyl, alkynyl group, cycloalkyl or cycloalkenyl group part, described group is partly chosen wantonly and is effectively being replaced by the individual or more substituting group of 1-3 on the carbon atom, and described substituting group independently is selected from F, Cl, Br and CN.
Another aspect, most preferably RT is
(a) hydrogen; Or
(b) halogen, especially fluorine, chlorine or bromine; Or
(c) cyano group; Or
(d) (1-4C) alkyl, especially methyl; Or
(e) mono-substituted (1-4C) alkyl, especially methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl; Or
(f) dibasic (1-4C) alkyl, difluoromethyl for example, or
(g) trisubstituted (1-4C) alkyl, for example trifluoromethyl.
One side R 4Be selected from R 4A.Again on the one hand, R 4Be selected from R 4B.
One side R 4A be selected from (1-4C) alkyl, (3-6C) cycloalkyl, AR1, AR2, (1-4C) alkyloyl ,-CS (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-COO (1-4C) alkyl ,-C=OAR1 ,-C=OAR2 ,-COOAR1 ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-S (O) pAR1 ,-S (O) pAR2 and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl chain can be chosen wantonly by (1-4C) alkyl, cyano group, hydroxyl or halogen and replace; P=0,1 or 2).
Another aspect, R 4A be selected from azido-,-NR 7R 8,-OR 10(1-4C) alkoxyl group ,-(CH2) m-R 9With-(C=O) 1-R 6
HET-3 is selected from HET3-A, HET3-B, HET3-C, HET3-D and HET3-E on the one hand.
On the other hand, HET-3 is selected from HET3-F, HET3-G, HET3-H and HET3-I.
On the one hand, HET-3 is selected from HET3-J, HET3-K, HET3-L, HET3-M, HET3-N, HET3-O, HET3-P, HET3-Q, HET3-R and HET3-S again.
Another aspect, HET-3 is selected from HET3-J, HET3-L, HET3-M, HET3-N, HET3-P, HET3-Q, HET3-R and HET3-S.
Another aspect, HET-3 is selected from HET3-L and HET3-M.
Another aspect, HET-3 is selected from HET3-P and HET3-Q.
Another aspect, HET-3 is selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y.
Another aspect, HET-3 is selected from HET3-T, HET3-V, HET3-Y and HET-3-W.
Another aspect, HET-3 is selected from HET3-V and HET3-Y.
Another aspect, HET-3 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH.
When m=1, one side R 1A is selected from R 1A1; R on the other hand 1A is selected from R 1A2; R on the one hand again 1A is selected from R 1A3, another aspect R 1A is selected from R 1A4, another aspect, R 1A is selected from R 1A5.
When m=2, two R of one side 1A independently is selected from identical group group R 1A1-R 1A5.On the other hand when m=2, each R 1A independently is selected from different group group R 1A1-R 1A5.
Usually, m is 1 or 2.On the one hand preferred m is 1.Preferred on the other hand m is 2.
Work as R 1A is selected from R 1During a1, R 1The concrete group of a is AR1 and AR2, more preferably AR2.
Work as R 1A is selected from R 1During a2, R 1The concrete group of a be cyano group and-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form 5-7 unit ring with Rw with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly has 1 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein when described ring is piperazine ring, this ring can be chosen wantonly being selected from following group by one on another nitrogen and replace: (1-4C) alkyl (choose wantonly on not adjacent carbon and replace), (3-6C) cycloalkyl, (1-4C) alkyloyl with described nitrogen ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-COOAR1 ,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl, (1-4C) alkyloyl are replaced by cyano group, hydroxyl or halogen with (3-6C) cycloalkyl is optional].Work as R 1The more specifically group of a is selected from R 1During a2, R 1A2 be cyano group, formyl radical ,-COO (1-4C) alkyl ,-C (=O) NH 2The piperazine of ,-(C=O) and-(C=O) morpholine.
Work as R 1A is selected from R 1During a3, R 1The concrete group of a is that { optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy, and [O-P (O) (OH) for (1-10C) alkyl 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: carboxyl, cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein W be O, Rv and Rw independently are H or (1-4C) alkyl, and wherein Rv can form morpholine with Rw with the amide nitrogen that they are connected, tetramethyleneimine, piperidines or piperazine ring; Wherein when described ring is piperazine ring, this ring can choose wantonly on another nitrogen by one be selected from (1-4C) alkyl and (1-4C) group of alkyloyl replace], (1-4C) alkyl S (O) q-(q is 0,1 or 2), AR2, AR2-O-, AR2-NH-and the group that comprises AR2a, AR2b type AR2; R wherein 1(1-4C) alkyl that exists in any substituting group on the a3 and (1-4C) acyl group self can independently be selected from the replacement of following group by 1-2: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;
Work as R 1A is selected from R 1During a3, R 1The more specifically group of a is that { optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, phosphorus acyloxy, and [O-P (O) (OH) for (1-10C) alkyl 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative], carboxyl, amino, (1-4C) alkylamino, two (1-4C) alkylamino, (1-4C) alkyl S (O) q (preferred q=2), AR2 and AR2b.Work as R 1A is selected from R 1During a3, R 1The more specifically group of a is (1-6C) alkyl of replacement mentioned above.Work as R 1The further concrete group of a is selected from R 1During a3, it is (1-4C) alkyl of replacement mentioned above.
Constitute R 1(1-10C) alkyl of a3, (1-6C) alkyl or (1-4C) the concrete substituting group of alkyl be that [O-P (O) (OH) for the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, phosphorus acyloxy 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and carboxyl.Preferred R 1A3 is by (1-4C) alkyl of 1-2 hydroxyl replacement.
Work as R 1The concrete group of a is selected from R 1During a4, it is R 14C (O) O (1-6C) alkyl-, R wherein 14Be selected from AR1, AR2, AR2a, AR2b and (1-10C) alkyl (optional replaced) by one or more substituting groups that independently are selected from OH and two (1-4C) alkylamino.R 14More specifically group be AR2a, AR2b and (1-6C) alkyl of being replaced by hydroxyl.R 14More specifically group be AR2a, AR2b and (1-4C) alkyl of being replaced by hydroxyl.
Work as R 1The concrete group of a is selected from R 1During a5, it is fluorine, chlorine and hydroxyl.
Other substituent concrete group (when above or hereinafter disclosed any definition and embodiment where applicable all can use) be :-
A) one side R 7And R 8Independent is H or (1-4C) alkyl
B) another aspect, R 7And R 8Connected nitrogen forms 5-7 unit ring together, chooses wantonly and defines replacement as mentioned or hereinafter
C) preferred R 7And R 8Connected nitrogen forms pyrrolidyl, piperidyl, piperazinyl or morpholine basic ring together
D) R 7And R 8During for pyrrolidyl, piperidyl, piperazinyl or morpholine basic ring; preferred optional substituting group on its ring be (1-4C) alkyl and (1-4C) alkyloyl, wherein said (1-4C) alkyl or (1-4C) alkyloyl self can choose wantonly by 1-2 and be selected from following substituting group replacement: hydroxyl, amino, (1-4C) alkylamino and two (1-4C) alkylamino
E) on the one hand, R 9Be selected from R 9A is preferably from AR2, AR2a and AR2b
F) more on the one hand, R 9Be selected from R 9B, preferably from-C (=W) NRvRw, wherein w is O, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form morpholine, tetramethyleneimine, piperidines or piperazine ring with Rw with the amide nitrogen that they are connected; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and be selected from following group replacement on another nitrogen: (1-4C) alkyl and (1-4C) alkyloyl, wherein any (1-4C) alkyl and (1-4C) alkyloyl self can independently be selected from the replacement of following group by 1-2: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if substituting group exists like this, and it is not on contiguous heteroatomic carbon;
G) another aspect, R 9Be selected from R 9C, wherein R 9C is that { optional by 1-3 group replacement (comprising together with two replacements), each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy, and [O-P (O) (OH) for (1-6C) alkyl 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: carboxyl, cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein W be O, Rv and Rw independently are H or (1-4C) alkyl, and wherein Rv can form morpholine with Rw with the amide nitrogen that they are connected, tetramethyleneimine, piperidines or piperazine ring; Wherein when described ring is piperazine ring, this ring can choose wantonly on another nitrogen, be selected from (1-4C) alkyl and (1-4C) group of alkyloyl replace], (1-4C) alkyl S (O) q-(q is 0,1 or 2), AR2, AR2-O-, AR2-NH-and the group that comprises AR2a, AR2b type AR2; R wherein 9Any (1-4C) alkyl in any substituting group on the c and (1-4C) alkyloyl self can independently be selected from the replacement of following group by 1-2: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;
H) another aspect, R 9Be selected from R 9C, wherein R 9C is that { optional by 1-3 group replacement (comprising together with two replacements), each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, phosphorus acyloxy, and [O-P (O) (OH) for (1-6C) alkyl 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative], carboxyl, amino, (1-4C) alkylamino, two (1-4C) alkylamino, (1-4C) alkyl S (O) q (preferred q=2), AR2 and AR2b.R 9The more specifically group of c is (1-4C) alkyl, optional replacement as mentioned before.
I) another aspect, R 9Be selected from R 9D, wherein R 9D is R 14C (O) O (1-6C) alkyl-, R 14Be selected from AR1, AR2, AR2a, AR2b and (1-10C) alkyl (optional) by 1-2 substituting group replacement that independently is selected from OH and two (1-4C) alkylamino.R 14Concrete group be AR2a, AR2b and (1-6C) alkyl of being replaced by hydroxyl.R 14More specifically group be AR2a, AR2b and (1-4C) alkyl of being replaced by hydroxyl.
J) R 21Concrete group be R 14C (O) O (2-6C) alkyl-, R wherein 14Preferably alkyl is (optional by 1-2 substituting group replacement that independently is selected from OH and two (1-4C) alkylamino from AR1, AR2, AR2a, AR2b with (1-10C).
K) R 21More specifically group be (2-10C) alkyl, choose wantonly with carbon that HET-3 ring nitrogen is connected beyond carbon on by 1-2 R that independently is selected from above or hereinafter defines 1The optional substituent group of a3 replaces; R 21More specifically group be optional (2-6C) alkyl that replaces, more preferably optional (2-4C) alkyl that replaces.
L) constitute R 21(2-6C) alkyl or (2-4C) the concrete substituting group of alkyl be 1-2 and independently be selected from following substituting group: [O-P (O) is (OH) for the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, phosphorus acyloxy 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative], carboxyl, amino, (1-4C) alkylamino, two (1-4C) alkylamino, (1-4C) alkyl S (O) q (preferably wherein q=2), AR2 and AR2bm) constitute R 21(2-6C) alkyl or (2-4C) the how concrete replacement base value of alkyl be 1-2 and independently be selected from following substituting group: [O-P (O) is (OH) for the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, phosphorus acyloxy 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and carboxyl.Preferred formation R 21(2-6C) alkyl or (2-4C) substituting group of alkyl be 1-2 hydroxyl.
N) preferred R 22Be cyano group.
O) especially preferred AR2, AR2a and AR2b group are the group that comprises basic nitrogen, and for example pyridine, tetramethyleneimine, piperazine and piperidines are chosen replacement as mentioned before wantonly.
An embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology,
Figure A20038010918300531
Wherein group C is group D; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine;
R 4Be selected from HET-3.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group D; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group D; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group D; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; M=1 and R 1A is selected from R 1A3.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; M=1 and R 1A is selected from R 1A3.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group D; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y, R1b is selected from Zd and Zf, u and v independently be 0 or 1 and RT be selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group D; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, R 1B is selected from Zd and Zf, u and v independently be 0 or 1 and RT be selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group D; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; M=1, R 1A is selected from R 1A3, R 1B is selected from Zd and Zf, u and v independently be 0 or 1 and RT be selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y, R 1B is selected from Zd and Zf, u and v independently be 0 or 1 and RT be selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, R 1B is selected from Zd and Zf, u and v independently be 0 or 1 and RT be selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; M=1, R 1A is selected from R 1A3, R 1B is selected from Zd and Zf, u and v independently be 0 or 1 and RT be selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be HET3-V, R 1B is selected from Zd and Zf, u and v independently be 0 or 1 and RT be selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be HET3-V, R 1B is Zd or Zf, and u and v independently are 0 or 1, R 21For methyl or (2-4C) alkyl (optional independently be selected from following substituting group replacement by 1-2: [O-P (O) (OH) for the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, phosphorus acyloxy 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and carboxyl), and RT is selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be HET3-V, R 1B is Zd, and u and v independently are 0 or 1, R 21Be methyl or (2-4C) alkyl (optional by 1-2 hydroxyl replacement), and RT is selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be HET3-V, R 1B is Zd, and u and v independently are 0 or 1, R 21Be methyl or (2-4C) alkyl (optional by 1-2 hydroxyl replacement), and RT is selected from hydrogen, halogen, methyl, methyl fluoride, chloromethyl, brooethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be HET3-V, R 1B is Zd, and u and v independently are 0 or 1, R 21Be methyl or (2-4C) alkyl (optional by 1-2 hydroxyl replacement), and RT is selected from hydrogen, fluorine, chlorine, methyl, methyl fluoride, chloromethyl, difluoromethyl and trifluoromethyl.
Another embodiment provides acceptable salt or the interior hydrolyzable ester of body on formula (Ia) compound or its pharmacology, and wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; R 4Be HET3-V, R 1B is Zd, and u and v independently are 0 or 1, R 21Be methyl or (2-4C) alkyl (optional by 1-2 hydroxyl replacement), and RT is selected from hydrogen, chlorine, methyl fluoride and difluoromethyl.
In above-mentioned all definition, preferred compound is the compound shown in the formula (Ia).
Particular compound of the present invention comprises each compound that embodiment introduces, and each compound provides an aspect independently of the present invention.Especially preferred compound is embodiment 1 compound.
The method part:
Again on the one hand, the invention provides the method that prepare acceptable salt on The compounds of this invention or its pharmacology or the interior hydrolyzable ester of body.Should be understood that in following some preparation method, some substituting group may need protection to prevent unwanted reaction.Skilled chemical technology personnel know when need such protecting group, and how in position to add such protection, and go protection subsequently.
About the example of blocking group, a kind of referring in the some general document of related topics, for example " Protective Groups in Organic Synthesis ", Theodora Green (publisher: John Wiley and Sons).Blocking group can by in the document or the known any proper method that is fit to slough related blocking group of skilled chemical technology personnel slough, method selected should make blocking group slough and disturb minimum to other group in the molecule.
Therefore, if reactant comprises for example amino, carboxyl or hydroxyl etc., just may in some reaction mentioned in this article, protect such group.
The appropriate protection group of amino or alkylamino is for example acyl group, for example alkyloyl (for example ethanoyl); Alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl or tert-butoxycarbonyl; Aryl methoxy carbonyl, for example benzyloxycarbonyl; Or aroyl, for example benzoyl.The protective condition that goes that is used for above-mentioned blocking group must be according to the difference of selected blocking group and difference.Therefore, for example acyl group (for example alkyloyl or alkoxy carbonyl) or aroyl can be sloughed by for example following method: with suitable alkali (for example alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide) hydrolysis.Perhaps; acyl group (for example tert-butoxycarbonyl) can be sloughed by for example following method: it is handled with suitable acid (hydrochloric acid, sulfuric acid, phosphoric acid or trifluoracetic acid); aryl methoxy carbonyl (for example benzyloxycarbonyl) can be sloughed by for example following method: with catalyzer (for example carbon carries palladium) hydrogenation, perhaps use Lewis acid (for example three (trifluoracetic acid) boron) to handle.The blocking group that suitably substitutes of primary amino is for example phthaloyl, can handle with alkylamine (for example dimethylaminopropyl amine) or with hydrazine it is sloughed.
The appropriate protection group of hydroxyl is for example acyl group, for example alkyloyl (for example ethanoyl); Aroyl, for example benzoyl; Or arylmethyl, for example benzyl.The protective condition that goes of above blocking group must be according to the difference of selected blocking group and difference.Thus, for example acyl group (for example alkyloyl or aroyl) can be sloughed by for example following method: with suitable alkali (for example alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide) hydrolysis.Perhaps, arylmethyl (for example benzyl) can be sloughed by for example following method: with catalyzer (for example carbon carries palladium) hydrogenation.
The appropriate protection group of carboxyl is esterified group for example for example methyl or ethyl, and it can be by sloughing with alkali (for example sodium hydroxide) hydrolysis; The perhaps tertiary butyl for example, it can be sloughed by for example using acid (for example organic acid, for example trifluoracetic acid) to handle; Perhaps benzyl for example, it can be sloughed by for example using catalyzer (for example carbon carries palladium) hydrogenation.Resin also can be used as blocking group.
Blocking group can be sloughed by the known routine techniques of chemical field in any suitable stage in synthetic.
Hydrolyzable ester can be by being suitable for preparing any currently known methods preparation of chemofacies related compounds in acceptable salt or the body on The compounds of this invention or its pharmacology.During hydrolyzable ester, such method provides as another feature of the present invention, by following representative embodiment explanation in being used to prepare on The compounds of this invention or its pharmacology acceptable salt or body.Essential starting raw material can obtain (referring to for example AdvancedOrganic Chemistry (Wiley-Interscience) by vitochemical standard method, Jerry March or Houben-Weyl, Methoden der Organischen Chemie).Non-limiting example has subsequently been introduced the preparation method of such starting raw material.Perhaps, essential starting raw material can be by obtaining with the similar method of exemplary illustration, and this belongs to the routine techniques that the organic chemistry personnel grasp.The information (can improve and be used to prepare essential starting raw material) for preparing essential starting raw material or related compound can be consulted following patent application openly, and the content of methods involving part is attached to this paper by reference: for example WO 94/13649; WO 98/54161; WO 99/64416; WO99/64417; WO 00/21960; WO 01/40222.
We have wherein provided the ordinary method of Zhi oxazolidinones compound especially with reference to our PCT patent application WO 99/64417 and WO00/21960.
Skilled technique of organic chemistry personnel can use and improve above reference and embodiment and this paper embodiment information that comprises and relate to wherein, be convenient to obtain essential starting raw material and product.For example, the instruction that skilled chemical technology personnel can use formula (I) compound that wherein has pyrimidyl-phenyl (promptly when group C is group D) herein is to prepare the compound that has pyridyl-phenyl (when group C is group E) defined above, and vice versa.
Therefore, the present invention also provides, and the interior hydrolyzable ester of acceptable salt and body can pass through method (a)-(j) preparation on The compounds of this invention and the pharmacology thereof; Carry out the following step then if desired:
I) slough any protecting group;
Ii) generate prodrug (for example hydrolyzable ester in the body); And/or
Iii) generate acceptable salt on the pharmacology;
Wherein said method (a)-(j) following (except as otherwise noted, otherwise wherein the definition of each variable is the same):
A) modify the substituting group on the another kind of compound of the present invention or substituting group is incorporated into the another kind of compound of the present invention (referring to for example by the standard chemical method, Comprehensive OrganicFunctional Group Transformations (Pergamon), Katritzky, Meth-Cohn and Rees or Advanced Organic Chemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden der Organischen Chemie)); For example:
Acyl amino can be converted into the sulfo-acyl amino;
Acyl amino or sulfo-acyl amino can be converted into other acyl amino or sulfo-acyl amino; Heterocyclic radical is tetrazyl or thiazolyl for example, or heterocyclic radical amino (choose wantonly and replace on amino-nitrogen-atoms or protection);
Acyloxy can be converted into hydroxyl or be converted into can be by the group (directly transform or transform by the intersexes hydroxyl) of hydroxyl acquisition;
Alkylogen for example alkyl bromide or alkyl iodide can be converted into alkyl fluoride RF or nitrile;
Alkyl sulfonic ester for example methylsulfonic acid alkyl ester can be converted into alkyl fluoride RF or nitrile;
Alkylthio for example methylthio group can be converted into methanesulfinyl or methylsulfonyl;
Arylthio for example thiophenyl (phentlthio) can be converted into benzenesulfinyl or benzenesulfonyl;
Amidino groups or guanidine radicals can be converted into 1 of 2-replacement, 3-diazole and 1,3-diazines;
Amino can be converted into acyl amino for example or sulfo-acyl amino for example ethanamide (the optional replacement), alkyl-or dialkyl-7-amino and be converted into thus that other N-alkyl-sulfonamide derivatives, sulfuryl amino, sulfinyl amino, amidino groups, guanidine radicals, arylamino, heteroaryl amino, for example optional 4-of N connection heterocycle replace 1,2, the 3-triazol-1-yl;
Aryl-or heteroaryl-halogen roll into a ball aryl for example-or assorted-aryl chloride or bromine or iodine can be converted into by the coupled reaction (the especially coupled reaction of Pd (0) mediation) of transition metal mediation aryl-, heteroaryl, alkenyl, alkynyl group, acyl group, alkylthio or alkyl-or dialkyl-7-amino aryl or heteroaryl of replacing;
Aryl-or heteroaryl-sulfonate group for example aryl-or assorted-aryl triflate can be converted into by the coupled reaction (the especially coupled reaction of Pd (0) mediation) of transition metal mediation aryl-, heteroaryl, alkenyl, alkynyl group, acyl group, alkylthio or alkyl-or dialkyl-7-amino aryl or heteroaryl of replacing;
Aryl-or heteroaryl-halogen roll into a ball aryl for example-or assorted-aryl chloride or bromine or iodine can be converted into trialkyltin, boric acid dialkyl, the trialkoxysilyl of the intermediate that is used for synthetic The compounds of this invention, the aryl or the heteroaryl of replacement by the coupled reaction (the especially coupled reaction of Pd (0) mediation) of transition metal mediation;
Azido-can be converted into for example 1,2,3-triazoles base or amine, and therefore is converted into any common sulfonamide derivatives, for example acyl amino (for example acetamido) by means commonly known in the art;
The carboxylic acid group can be converted into trifluoromethyl, hydroxymethyl, alkoxy carbonyl, chooses the aminocarboxyl, formyl radical or the acyl group that replace wantonly on nitrogen;
Cyano group can be converted into tetrazolium or imido acid ester group (imidate), amidine, amidrazone, N-hydroxyl amino hydrazone, acid amides, thioamides, ester or acid, and therefore is converted into any heterocycle that is derived from this class carbonitrile derivatives by methods known in the art;
Hydroxyl for example can be converted into alkoxyl group, cyano group, azido-, alkylthio, ketone group and oximido, fluorine, bromine, chlorine, iodine, alkyl-or aryl-alkylsulfonyl oxygen base for example triflate, methanesulfonates or tosylate, siloxy-; Acyl amino or sulfo-acyl amino, for example ethanamide (choose wantonly and on amido-nitrogen-atoms, replace or protection); Acyloxy, for example acetoxyl group; Phosphono oxygen base, heterocyclic radical amino (choose wantonly and on amino-nitrogen-atoms, replace or protection), for example isoxazole-3-base is amino or 1,2, and 5-thiadiazoles-3-base is amino; By the heterocyclic radical (choose wantonly on the carbon atom of non-contiguous connection azo-cycle atom and replace) that nitrogen connects, 1,2,3-triazoles-1-base that for example optional 4-replaces; Or amidino groups, for example 1-(N-cyanoimino) ethylamino; This class of hydroxyl transforms one or more derivatives (for example methanesulfonates or trinitride) conversion that can directly transform (for example by acidylate or Mitsunobu reaction) or pass through intersexes;
Siloxy-can be converted into hydroxyl or be converted into can be by the group that obtains on the hydroxyl (directly transform or transform by the intersexes hydroxyl);
Ketone group can be converted into hydroxyl, thiocarbonyl, oximido or difluoro;
Nitro can be converted into amino, and therefore is converted into any common sulfonamide derivatives, for example acyl amino (as acetamido) by means commonly known in the art;
2-, 4-or 6-pyridyl or 2-, 4-or 6-pyrimidyl halogenide for example muriate or sulphonate (for example methanesulfonates) substituting group can be converted into alkoxyl group, alkylthio, amino, alkylamino, dialkyl amido or N connection heterocyclic substituent;
In addition, optional heteroaromatic rings D that replaces or E can be by introducing new substituting group (R 2A, R 3A or R 6A) or functionalized again existing substituting group (R 2A, R 3A or R 6A) be converted into other heteroaromatic rings D or E
Heterocyclic radical amino (choosing wantonly in replacement on amino-nitrogen-atoms or protection) can be converted into other heterocyclic radical amino (choose wantonly and replace or protection) by the following method on amino-nitrogen-atoms: functionalized again (for example protect or go and protect) amino-nitrogen-atoms, new ring substituents or the functionalized again existing ring substituents of introducing;
Heterocyclic radical (choose wantonly and replacing on the carbon atom of non-contiguous connection azo-cycle atom) by the nitrogen connection can be converted into other heterocyclic radical (choose wantonly on the carbon atom of non-contiguous connection azo-cycle atom and replace) that connects by nitrogen by the following method: introduce new ring substituents or functionalized again existing ring substituents, for example modify 1 of 4-replacement, 2, the 4-substituting group of 3-triazol-1-yl;
For example, following flow process illustrates the method that hydroxyl is converted into the optional triazolyl that replaces:
Method (h), (i) and (j) illustrate and under condition as mild as a dove, carry out the regioselectivity method;
B) make formula (IIa) compound molecule [wherein X be the leavings group (for example muriate, bromide, iodide, trifyl oxygen base, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) that is used for the palladium coupling and in this case A be N or C-R 3A] (wherein X ' is for being used for the leavings group of palladium coupling with formula (IIb) compound molecule; for example muriate, bromide, iodide, trifyl oxygen base, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) reaction, wherein X and X ' select to make and replace aryl-X (or heteroaryl-X) and aryl-X ' (or heteroaryl-X ') key with aryl-aryl, heteroaryl-aryl or heteroaryl-heteroaryl key.Such method now has been well-known, referring to for example J.K.Stille, AngewChem.Int.Ed.Eng., 1986,25,509-524; N.Miyaura and A Suzuki, Chem.Rev., 1995,95,2457-2483, D.Baranano, G.Mann, and J.F.Hartwig, Current Org.Chem., 1997,1,287-305, S.P.Stanforth, Tetrahedron, 541998,263-303; P.R.Parry, C.Wang, A.S.Batsanov, M.R.Bryce, and B.Tarbit, J. Org.Chem., 2002,67,7541-7543;
Figure A20038010918300631
Leavings group X can select different groups with X ' and produce required formula (I) cross-linking products;
For example
Figure A20038010918300641
As the reagent of method (b) or be used for required pyridine, pyrimidine and the Fang oxazolidinone of intermediate of preparation method (b) reagent can be by the organic method preparation of standard, for example similar approach preparation by introducing in method part (c)-(j), the introducing of radicals X known in this field and X ' and the method for change;
C) make the heterobiaryl derivative carbamate of formula (III) Cheng the oxazolidone ring with the reacting ethylene oxide Sheng of suitable replacement;
The change of this method known in this field, wherein carbamate is replaced by isocyanic ester or is replaced by amine, or/and wherein said oxyethane is equal to reagent X-CH 2CH (the optional protection of O-) CH 2R 1B (wherein X is replaceable group) displacement.
For example
(d) make the reaction of formula (VI) compound and formula (VII) compound:
Wherein X is muriate, bromide, iodide, trifyl oxygen base, trimethylammonium stannyl, trialkoxysilyl or the boric acid residue of replaceable substituting group-for example, below is formula (VII):
T-X’
(VII)
Wherein to be HET3 defined above and X ' be replaceable C connection substituting group-for example muriate, bromide, iodide, trifyl oxygen base, trimethylammonium stannyl, trialkoxysilyl or boric acid residue to T-X '; Wherein said substituent X and X ' select substituting group complementary pair well known in the art, so that be suitable as the complementary interaction thing of coupled reaction, this coupled reaction is with for example palladium (0) catalysis of transition metal;
(d (i)) makes formula (VIII) compound and formula (IX) compound pass through for example palladium (0) catalyzed reaction of transition metal:
Wherein X is muriate, bromide, iodide, trifyl oxygen base, trimethylammonium stannyl, trialkoxysilyl or the boric acid residue of replaceable substituting group-for example; Below be formula (IX) (Tetrahedron Letts., 2001,42 (22), 3681-3684);
Figure A20038010918300661
(d is (ii)) makes formula (X) compound and the reaction of formula (XI) compound:
Figure A20038010918300662
X is muriate, bromide, iodide, the trifyl oxygen base of replaceable substituting group-for example, below is formula (XI):
T-H
(XI)
Wherein T-H is amine R 7R 8NH, pure R 10OH or contain the azoles of effective ring-NH part obtains compound (XIIa), (XIIb) or (XIIc), wherein A is nitrogen or C-R in this case 3A and A ' are optional nitrogen or the carbon that is replaced by one or more radicals R la;
Figure A20038010918300663
(e) make the reaction of formula (XIII) compound and formula (XIV) compound:
Figure A20038010918300671
X wherein 1And X 2Be the independent optional heteroatoms combination that is selected from O, N and S that replaces, make C (X 1) X 2Constituting carboxylic acid derivation substituting group, below is formula (XIV), wherein X 3And X 4Be the independent optional heteroatoms combination that is selected from O, N and S that replaces:
Figure A20038010918300672
C (X 1) X 2And C (X 3) X 4In one constitute optional hydrazides, thio-hydrazide or amidrazone, hydroximic acid base (hydroximidate) or the hydroxyl amidine (hydroxamidine) that replaces, and C (X 1) X 2And C (X 3) X 4In another constitutes optional acylating agent, sulfo-acylating agent or imido acylating agent, the such C (X of replacing 1) X 2And C (X 3) X 4Can condense by method well-known in the art and form 1,2 together, 4-heteroatoms 5-unit heterocycle, it comprises 3 the heteroatoms combinations that are selected from O, N and S, for example thiadiazoles;
(e (i)) makes for example reaction of sodium azide of formula (XV) compound and nitrine negative ion source:
Figure A20038010918300673
X wherein 2Be replaceable group, for example oxyethyl group or diphenylphosphine acyloxy obtain tetrazolium (XVI)
The perhaps nitrile of formula (XVII)
Can with trinitride for example ammonium azide or trialkyl stannyl trinitride direct reaction, (XVI Rla=H), uses radicals R la ≠ H alkanisation then, obtains tetrazolium (XVIIIa) and (XVIIIb) to obtain tetrazolium;
Figure A20038010918300682
(f) make formula (XIX) compound:
Figure A20038010918300683
React with formula (XX) compound:
Figure A20038010918300684
C (X 5) X 6And C (X 7) X 8In one constitute optional α-(leavings group replacement) ketone that replaces, wherein leavings group for for example halogen or (alkyl or aryl)-alkylsulfonyl oxygen base-, and C (X 5) X 6And C (X 7) X 8In another constitutes optional acid amides, thioamides or the amidine that replaces, C (X like this 5) X 6And C (X 7) X 8Can condense by method well-known in the art and form 1 together, 3-heteroatoms 5-unit heterocycle, it comprises 2 heteroatomss that are selected from O, N and S, for example thiazoles;
(g) can prepare HET like this and be 1 of optional replacement, 2, the formula of 3-triazole (I) compound: make trinitride (wherein for example the Y in (II) is an azido-) cycloaddition to for example optional hexamethylene-1 that replaces of acetylene or acetylene equivalent, the 4-diene or optional replace carry the ethene that can remove substituting group (for example aryl sulfonyl);
(h) can prepare formula (I) compound that HET is the 1,2,3-triazoles of 4-replacement like this: make amino methyloxazolidinonesas and 1,1-dihalo ketone alkylsulfonyl hydrazone reaction (Sakai, Kunihazu; Hida, Nobuko; Kondo, Kiyosi; Bull.Chem.Soc.Jpn., 59,1986,179-183; Sakai, Kunikazu; Tsunemoto, Daiei; Kobori, Takeo; Kondo, Kiyoshi; Hido, Noboko EP 103840 A2 19840328);
(i) also can prepare formula (I) compound that HET is the 1,2,3-triazoles of 4-replacement like this: make azido methyl oxazolidinone and terminal alkyne reaction with Cu (I) catalysis, this for example is reflected in the alcohol solution and under the room temperature and carries out, obtain that 4-replaces 1,2,3-triazole (V.V.Rostovtsev, L.G.Green, V.V.Fokin, and K.B.Sharpless, Angew.Chem.Int.Ed., 2002,41,2596-2599);
Figure A20038010918300692
(j) also can prepare HET like this is 4-halogenated 1,2, the formula of 3-triazole (I) compound: the azido methyl oxazolidinone is reacted with vinyl halides base SULPHURYL CHLORIDE in 0 ℃-100 ℃, and this reaction can not have thinner or carries out in inert diluent (for example chlorobenzene, chloroform or dioxane).
Figure A20038010918300693
The loop-like addition reaction that document discloses compound shown in (j) obtains incoherent triazole with incoherent trinitride, and halogen is bromine (C.S.Rondestvedt, Jr. and P.K.Chang in above-mentioned vinyl SULPHURYL CHLORIDE reagent, J.Amer.Chem.Soc., 77,1955,6532-6540; By C.S.Rondestvedt, Jr., J.Amer.Chem.Soc., 76,1954, the described method of 1926-1929 prepares 1-bromo-1-ethene SULPHURYL CHLORIDE).Yet the reaction of vinyl SULPHURYL CHLORIDE can not stop when obtaining required product and generate unwanted by product.In addition, openly in the document how not control following reaction key element: with intermediate ring adducts form unwanted triazole by cancellation H-halogenic ingredient or with intermediate ring adducts by cancellation HCl and SO 2Composition forms required triazole.
We find unexpectedly, when described halogen is chlorine, and promptly when reagent is compound 1-chloro-1-ethene SULPHURYL CHLORIDE,
Figure A20038010918300701
Described cycloaddition reaction be height location optionally, obtain the required product of high yield.Reagent 1-chloro-1-ethene SULPHURYL CHLORIDE is a novel cpd in addition.Therefore, another aspect of the invention comprises compound 1-chloro-1-ethene SULPHURYL CHLORIDE.Further aspect of the present invention comprises that 1-chloro-1-ethene SULPHURYL CHLORIDE forms the purposes of 4-chloro-1,2,3-triazoles with trinitride in cycloaddition reaction.Another aspect of the invention comprises that 1-chloro-1-ethene SULPHURYL CHLORIDE forms formula (I) compound (R wherein with azide derivatives on stream 1B is a 4-chloro-1,2,3-triazoles, and R4 is 4-chloro-HET3-AB) purposes.
Form formula (I) compound (R wherein with 1-chloro-1-ethene SULPHURYL CHLORIDE and azide derivatives on stream 1B is 4-chloro-1,2,3-triazoles and or R 4Be 4-chloro-HET3-AB) cycloaddition reaction carry out in 0 ℃-100 ℃ (preferred room temperatures), this reaction can be in inert solvent (preferred chlorobenzene, chloroform or dioxane) or more preferably do not have solvent to carry out.
The organic chemistry those of ordinary skill can use standard technique to slough any blocking group, generates acceptable salt and/or the interior hydrolyzable ester of generation body on the pharmacology.In addition, for example prepare the detail of the steps such as prodrug of hydrolyzable ester in the body referring to above part about such ester.
When needing the opticity form of The compounds of this invention, can use opticity starting raw material (for example the asymmetric induction by the appropriate reaction step generates) to obtain by more than one methods, perhaps split the racemic form acquisition of compound or intermediate, perhaps obtain by chromatographic separation diastereomer (if generation) with standard method.The enzymatic technology also can be used to prepare optically active compounds and/or intermediate.
Similarly, when needing the pure positional isomers of The compounds of this invention, available pure positional isomers obtains by more than one methods as starting raw material, perhaps splits the mixture acquisition of positional isomers or intermediate with standard method.
The another feature according to the present invention provides hydrolyzable ester in acceptable salt on The compounds of this invention or its pharmacology or the body to be used for the treatment of the method for human or animal body.
The another feature according to the present invention, the invention provides in a kind of warm-blooded animal in this treatment of needs (for example people) body the method that produces antibacterial effect, this method comprises and gives on described animal effective dose The compounds of this invention or its pharmacology hydrolyzable ester in acceptable salt or the body.
The present invention also provides as hydrolyzable ester in acceptable salt or the body on the The compounds of this invention of medicine or its pharmacology; On The compounds of this invention or its pharmacology in acceptable salt or the body hydrolyzable ester in preparation is used for warm-blooded animal (for example people) body, produce purposes on the medicine of antibacterial effect.
In order to use in The compounds of this invention, its body acceptable salt on hydrolyzable ester or the pharmacology, comprise being used for the treatment of property of acceptable salt (part that relates to medicinal compositions below is called " The compounds of this invention ") (comprising preventative) treatment Mammals (comprising the people) on the pharmacology of hydrolyzable ester in the body, particularly treatment is infected, and practice is formulated as medicinal compositions with it according to standard drug usually.
Therefore on the other hand, the invention provides medicinal compositions, it comprises acceptable diluent or carrier on acceptable salt on hydrolyzable ester in the The compounds of this invention, its body or the pharmacology (comprising acceptable salt on the pharmacology of hydrolyzable ester in the body) and the pharmacology.
The present composition can be fit to the formulation of following administering mode: oral (tablet for example, lozenge, hard or soft balsam wafer, water-based or oiliness suspensoid, emulsion, dispersible powder or granula, syrup or elixir), topical (emulsifiable paste for example, ointment, gel or water-based or oily solution agent or suspensoid), dosing eyes (drops), inhalation (for example fines or liquid aerosol), be blown into (for example sterile aqueous or the oily solution agent of administration (for example fines) or administered parenterally, be used for intravenously, subcutaneous, the hypogloeeis, intramuscular or intramuscular administration), or the suppository of rectal administration.
Except that The compounds of this invention, medicinal compositions of the present invention can also comprise (promptly passing through co-formulated) or unite and give (simultaneously, sequential or independent) one or more known drugs, and described medicine is selected from other clinical effective antibacterials (for example beta-lactam, macrolide, quinolone or Glucosaminitol) and/or other anti-infective (for example anti-fungal triazole or amphotericin).These medicines can comprise that carbapenems (for example meropenem or imipenum) is to increase curative effect.The compounds of this invention also can co-formulated or is united and give bactericidal and increase albumen (BPI) product or outer pump inhibitor with the activity of improvement to gram negative bacterium and anti-antiseptic-germicide bacterium.The compounds of this invention also can or be united with VITAMIN (for example vitamins B, as Wei ShengsuB2, vitamin B6, vitamin B12 and folic acid) co-formulated and given.The compounds of this invention also can or be united with cyclooxygenase (COX) inhibitor (especially cox 2 inhibitor) co-formulated and given.
In one aspect of the invention, The compounds of this invention and effectively the antibacterials co-formulated of resisting gram-positive bacterium.
In one side more of the present invention, the antibacterials co-formulated of The compounds of this invention and effective anti-gram negative bacterium.
Of the present invention more on the one hand, The compounds of this invention is united with effective antibacterials of resisting gram-positive bacterium and is given.
Of the present invention more on the one hand, the antibacterials of The compounds of this invention and effective anti-gram negative bacterium are united and are given.
The present composition can obtain by ordinary method with conventional pharmaceutical excipient, and this is well known in the art.Therefore, be used for oral composition and can comprise for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.The medicinal compositions of intravenous administration can comprise favourable (for example enhanced stability) suitably sterilant, oxidation inhibitor, reductive agent or suitable sequestrant.
When being used for tablet formulation, acceptable vehicle comprises for example inert diluent (for example lactose, yellow soda ash, calcium phosphate or lime carbonate), granulation and disintegrating agent (for example W-Gum or Lalgine) on the suitable pharmacology; Tackiness agent is starch for example; Lubricant is Magnesium Stearate, stearic acid or talcum powder for example; Sanitas is ethyl p-hydroxybenzoate or propylparaben for example; And antioxidant, for example xitix.Tablet is dressing not, and perhaps dressing to be improving it in GI disintegration and the absorption of activeconstituents subsequently, or improves their stability and/or outward appearance, in either case, uses conventional Drug coating and method well-known in the art.
Oral compositions can be hard gelatine capsule agent form, wherein activeconstituents mixes with inert solid diluent (for example lime carbonate, calcium phosphate or kaolin), perhaps be soft gelatin capsule agent form, wherein activeconstituents mixes with water or oil (for example peanut oil, whiteruss or sweet oil).
Aqueous suspension comprises activeconstituents and one or more suspension agents of fines form, for example Xylo-Mucine, methylcellulose gum, HYDROXY PROPYL METHYLCELLULOSE, sodiun alginate, polyvinylpyrrolidone, tragacanth and Sudan Gum-arabic usually; Dispersion agent or wetting agent, for example condensation product of Yelkin TTS or alkylene oxide and lipid acid (for example polyoxyethylene stearic acid ester), the condensation product of ethylene oxide and long chain aliphatic alcohol (for example heptadecene oxygen base hexadecanol), ethylene oxide and condensation product (for example polyoxyethylene sorbitol monooleate) derived from the partial ester of lipid acid and hexitol, the condensation product of ethylene oxide and long chain aliphatic alcohol (for example heptadecene oxygen base hexadecanol), ethylene oxide and condensation product (for example polyoxyethylene sorbitol monooleate) derived from the partial ester of lipid acid and hexitol, or ethylene oxide and derived from the condensation product (for example polyethylene anhydro sorbitol monooleate) of the partial ester of lipid acid and hexitol acid anhydrides.Aqueous suspension can also comprise one or more sanitass (for example ethyl p-hydroxybenzoate or propylparaben), antioxidant (for example xitix), tinting material, seasonings and/or sweeting agent (for example sucrose, asccharin or aspartame).
The oiliness suspensoid can followingly be prepared: activeconstituents is suspended in vegetables oil (for example peanut oil, sweet oil, sesame oil or Oleum Cocois) or mineral oil (for example whiteruss).The oiliness suspensoid can also comprise thickening material for example beeswax, solid paraffin or hexadecanol.Can add sweeting agent (for example above-mentioned sweeting agent) and seasonings so that agreeable to the taste oral preparations to be provided.Can add oxidation inhibitor (for example xitix) in these compositions preserves.
Be fit to comprise activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitass usually by adding disperseed powder and the granula that entry prepares aqueous suspension.The example explanation hereinbefore of suitable dispersion agent or wetting agent and suspension agent.Also can comprise other vehicle for example sweeting agent, seasonings and tinting material.
Medicinal compositions of the present invention also can be oil-in-water emulsion.Oil phase can be the mixture of vegetables oil (for example sweet oil or peanut oil), mineral oil (for example whiteruss) or any above-mentioned oil.Suitable emulsifying agent can be for for example naturally occurring natural gum (for example Sudan Gum-arabic or tragacanth), naturally occurring phosphatide (for example soybean lecithin), derived from the ester of lipid acid and hexitol acid anhydrides or the condensation product (for example polyethenoxy sorbitan monooleate) of partial ester (for example anhydro sorbitol monooleate) and described partial ester and ethylene oxide.Emulsion also can comprise sweeting agent, seasonings and sanitas.
Syrup and elixir can be used sweeting agent (for example glycerine, propylene glycol, Sorbitol Powder, aspartame or sucrose) preparation, can also comprise negative catalyst, sanitas, seasonings and/or tinting material.
Medicinal compositions also can be the water-based or the oiliness suspensoid of aseptic injection, and it can be prepared according to currently known methods with one or more suitable above-mentioned dispersion agents or wetting agent and suspensoid.Aseptic injection preparation can also be the aseptic injectable solution or the suspension of nontoxic parenteral acceptable diluent or solvent, for example solution of 1,3 butylene glycol.Can use for example cyclodextrin of solubility enhancing agent.
The composition of inhalation can be conventional pressurised aerosol, makes activeconstituents loose for comprising the smog or the small droplets of micro-solid.Can use conventional aerosol propellant for example volatility fluoridize hydro carbons or hydro carbons, the aerosol device is generally used for the distribution and computation activeconstituents.
About the further information of preparation, can consult Comprehensive MedicinalChemistry, the 5th volume, 25.2 chapters, (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990.
The activeconstituents consumption for preparing single formulation with one or more mixed with excipients must be according to main body of being treated and specific route of administration variation.The preparation that for example is used for the orally give people comprises for example 50mg-5g active medicine and the suitably vehicle of consumption usually, and vehicle can account for about 5-98% of whole composition weight.Unit dosage comprises the about 2g activeconstituents of about 200mg-usually.About the further information of route of administration and dosage, can consult Comprehensive Medicinal Chemistry, the 5th volume, 25.3 chapters, (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
Suitable medicinal compositions of the present invention is a kind of unit dosage of suitable oral administration, for example comprises the tablet or the capsule of 1mg-1g The compounds of this invention, preferred 100mg-1g compound.Especially preferably comprise 50mg-800mg, particularly the tablet of 100mg-500mg The compounds of this invention or capsule.
Again on the one hand, medicinal compositions of the present invention is the composition of a kind of suitable intravenously, subcutaneous or intramuscularly, for example comprises the injection of 0.1%w/v-50%w/v (1mg/ml-500mg/ml) The compounds of this invention.
Each patient every day can be by for example intravenously, subcutaneous or intramuscularly 0.5mgkg -1-20mgkg -1The compounds of this invention gives composition 1-4 time every day.In another embodiment, give 5mgkg every day -1-20mgkg -1The compounds of this invention.Intravenously, subcutaneous and intramuscular administration can give by heavy dose of bolus injection mode.Perhaps, intravenous administration can give by continuous infusion within a certain period of time.Perhaps, each patient can accept roughly to be equivalent to the day oral dosage of parenteral dosage every day, gives composition 1-4 time every day.
In above other medicinal compositions, processing, method, purposes and medication preparation feature, also be useful in the substituting and embodiment preferred of The compounds of this invention of this introduction.
Anti-microbial activity:
Acceptable The compounds of this invention is effective antibacterials on the pharmacology, and it has the excellent activity spectrum external to being used to screen the active standard gram-positive microorganism of anti-malignant bacteria.Acceptable The compounds of this invention has shown that especially faecalis, streptococcus pneumoniae, methicillin-resistant staphylococcus aureus bacterial strain (S.aureus) and coagulase negative staphylococcus and hemophilus bacterial strain and Moraxella bacterial strain are had activity on the pharmacology.The antimicrobial spectrum of specific compound and usefulness can detect with the standard testing system.
(antibiotic) characteristic of The compounds of this invention can also prove and estimates, for example utilize standard technique to give warm-blooded mammals by oral and/or intravenous injection with compound with conventionally test in the body.
Following result is obtained by the outer test system of standard body.Active in minimum inhibition concentration (MIC) expression, use the agar dilution technology with 10 4The inoculum density that CFU/ is ordered detects MIC.Usually, the field of activity of compound is 0.01-256 μ g/ml.
On agar, detect staphylococcus, adopt the standard test condition of expressing methicillin resistance: inoculation 10 4The CFU/ point, 37 ℃ of inoculation temps, incubation 24 hours.
Detection of streptococcus and faecalis on agar are replenished 5% defibrinated horse blood, inoculation 10 in the agar 4The CFU/ point, 37 ℃ of culture temperature, 5% carbon dioxide atmosphere, 48 hours, blood was the requirement that part is tried microorganism growth.The difficult gram-negative micro-organism of cultivating is tested in the Mueller-Hinton substratum, wherein replenishes protohemine and NAD, 37 ℃ of grow aerobicallies 24 hours, and inoculates 5 * 10 4The CFU/ hole.
For example, below be the test result of embodiment 1 compound:
Microorganism MIC (μ g/ml)
Streptococcus aureus: MSQS 0.25
MRQR 0.25
Streptococcus pneumoniae＜0.06
Faecium 0.25
Hemophilus influenzae 2
Moraxelle catarrhalis (Moraxella catarrhalis) 0.25
Anti-Linezolid streptococcus pneumoniae 0.5
MSQS=methicillin-sensitivity and quinolone sensitivity
MRQR=methicillin-resistant and anti-quinolone
Following some intermediate and/or the reference example that belongs to the scope of the invention also may have effective activity, and another feature of the present invention is provided.
Below by the present invention of embodiment non-limitative illustration, except as otherwise noted, otherwise wherein :-
(i) evaporation is finished by rotary evaporation in vacuo, carries out subsequent processing steps after removing by filter residual solid;
(ii) various operations are at room temperature carried out, and are generally 18-26 ℃, except as otherwise noted, unless perhaps those of skill in the art need operate, otherwise need not exhausted air under inert atmosphere;
(iii) column chromatography (by quick operation) is used for the purification compound, and except as otherwise noted, otherwise on Merck Kieselgel silicon-dioxide (Art.9385), carry out;
The output that (iv) provides only is used as and illustrates, not necessarily obtainable maximum production;
(v) common, the structure of final product of the present invention confirms that by NMR and mass-spectrometric technique [the proton resonance spectrum is used DMSO-d usually 6Detect, except as otherwise noted, otherwise use VarianGemini 2000 spectrometers, the intensity of field 300MHz of operation perhaps uses Bruker AM250 spectrometer, the intensity of field 250MHz of operation; Chemical shift is interior mark with tetramethylsilane, is expressed as ppm (δ scale), and the multiplicity at peak is expressed as: s, and unimodal; D, bimodal; AB or dd, double doublet; Dt, Shuan Sanfeng; Dm, two multimodals; T, triplet, m, multiplet; Br, broad peak; Fast atom bombardment (FAB) mass-spectrometric data uses Platform spectrometer (Micromass) to obtain usually, and electron spray(ES) is used in the time of suitably and collected positively charged ion or negatively charged ion data]; Specific rotation is measured with Perkin ElmerPolarimeter 341 in 589nm in 20 ℃ in the 0.1M methanol solution;
(vi) each intermediate purifies to the subsequent stage required standard, and with enough concrete data characterizations to confirm that specified structure is correct; HPLC, TLC or NMR detect purity, determine compound by infrared spectra (IR), mass spectrum or NMR spectrum as required; NOE is an Overhauser effect;
(vii) wherein may use following abbreviation :-
DMF N, dinethylformamide; The DMA N,N-dimethylacetamide; The TLC tlc; The HPLC high pressure lipuid chromatography (HPLC); The MPLC medium pressure liquid chromatography; The NMP N-Methyl pyrrolidone; The DMSO methyl-sulphoxide; CDCl 3The deuterate chloroform; The MS mass spectrum; The ESP electron spray(ES); The EI electron impact; The CI chemi-ionization; The ionization of APCI atmospheric pressure chemical; The EtOAc ethyl acetate; MeOH methyl alcohol; Phosphorus acyloxy (HO) 2-P (O)-O-; Inferior phosphorus acyloxy (HO) 2-P-O-; SYNTHETIC OPTICAL WHITNER " Clorox " 6.15% clorox; The THF tetrahydrofuran (THF);
(viii) temperature is ℃.
Embodiment 1:(5R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazolium-5-yl) pyridin-3-yl) phenyl)-5- (1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone
With (5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone (370mg, 0.95mmol), two valeryl two boron (605mg, 2.4mmol) and potassium acetate (326mg, 3.3mmol) mixture in methyl-sulphoxide (5mL), outgas, with nitrogen flushing back dichloro [1,1 '] two (diphenylphosphino) ferrocene] (69mg 10mol%) handles palladium (II) methylene dichloride adducts.Mixture heating up to 80 ℃ is continued 1.5 hours, be cooled to room temperature, filter, use ethyl acetate extraction through Celite.Organic phase is washed through aqueous ammonium chloride solution, is evaporated to dried after the dried over mgso.Nonvolatile resistates is purified [use hexane: ethyl acetate (3: 2) wash-out] through silica gel chromatography, acquisition mixture (5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,2-oxazolidine-2-ketone and corresponding boric acid (210mg ,～0.54mmol, 57%), it directly uses no longer further and purifies.
With the boric acid ester of previous step preparation and mixture, 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine (160mg of boric acid, 0.67mmol) and salt of wormwood (448mg, 3.24mmol) at N, dinethylformamide and water (10mL, 7: 1) in the mixture degassing, with the nitrogen flushing, (62mg 0.054mmol) handles with tetrakis triphenylphosphine palladium (0).Reaction mixture is cooled to room temperature in 80 ℃ of heating 1.5 hours, filters through Celite, uses ethyl acetate extraction, is evaporated to dried after the dried over mgso.Nonvolatile resistates is purified [use ethyl acetate: hexane (3: 2) wash-out] through silica gel chromatography, obtains colourless amorphous body product (140mg, 61%).
MS(ESP)：422.47(MH +)C 19H 16FN 9O 2
1 H-NMR(DMSO-d 6 )δ：3.98(dd，1H)；4.31(dd，1H)；4.47(s，3H)；4.86(m，2H)；5.18(m，1H)；7.45(m，1H)；7.61(m，1H)；7.74(m，1H)；7.77(brs，1H)；8.12-8.27(m，3H)；8.93(s，1H)。
The intermediate of embodiment 1 is prepared as follows:
Acetate (5R)-3-(3-fluorophenyl)-1,3-Evil Azoles alkane-2-ketone-5-ylmethyl ester
Figure A20038010918300791
With (5R)-3-(3-fluorophenyl)-5-hydroxymethyl-1,3-oxazolidine-2-ketone (40g, 0.189M is referring to Upjohn WO 94-13649) under nitrogen atmosphere stirring suspension in dry methylene chloride (400mL).Add triethylamine (21g, 0.208M) and 4-dimethylaminopyridine (0.6g, 4.9mM), in 30 minutes, be added dropwise to then diacetyl oxide (20.3g, 0.199M), in stirring at room 18 hours.Add saturated sodium bicarbonate aqueous solution (250mL), separate organic phase, through the washing of 2% SODIUM PHOSPHATE, MONOBASIC, dry (sal epsom) filters the back evaporation, obtains required oily product (49.6g).
MS(ESP)：254(MH +)C 12H 12FNO 4
NMR(CDCl 3 )δ：2.02(s，3H)；3.84(dd，1H)；4.16(t，1H)；4.25(dd，1H)；4.32(dd，1H)；4.95(m，1H)；6.95(td，1H)；7.32(d，1H)；7.43(t，1H)；7.51(d，1H)。
Acetate (5R)-3-(3-fluoro-4-iodo-phenyl)-1,3-Evil Azoles alkane-2-ketone-5-ylmethyl ester
Figure A20038010918300792
With acetate (5R)-3-(3-fluoro-phenyl)-1,3-oxazolidine-2-ketone-5-ylmethyl ester (15.2g 60mM) is dissolved in mixture chloroform (100mL) and acetonitrile (100mL) under nitrogen atmosphere, and the adding Silver Trifluoroacetate (16.96g, 77mM).(18.07g 71mM) added the solution of vigorous stirring in batches, in stirring at room 18 hours with iodine in 30 minutes.When reacting imperfect tense, (2.64g 12mM), stirred 18 hours to add Silver Trifluoroacetate again.After the filtration, with mixture add hypo solution (3%, 200mL) and methylene dichloride (200mL), separate organic phase, through Sulfothiorine (200mL), saturated sodium bicarbonate aqueous solution (200mL), salt solution (200mL) washing, dry (sal epsom) filters the back evaporation.Crude product is suspended in isohexane (100mL), and the diethyl ether that adds capacity stirred 1 hour with stripping brown impurity the time.Filter and obtain required emulsifiable paste shape solid product (24.3g).
MS(ESP)：380(MH +)C 12H 11FINO 4
NMR(DMSO-d 6 )δ：2.03(s，3H)；3.82(dd，1H)；4.15(t，1H)；4.24(dd，1H)；4.30(dd，1H)；4.94(m，1H)；7.19(dd，1H)；7.55(dd，1H)；7.84(t，1H)。
(5R)-and 3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-1,3-Evil Azoles alkane-2-ketone
With acetate (5R)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidine-2-ketone-5-ylmethyl ester (30g, 79mM) in room temperature salt of wormwood (16.4g, 0.119mM) in mixture methyl alcohol (800mL) and methylene dichloride (240mL), handled 25 minutes, add the neutralization of acetate (10mL) and water (500mL) then immediately.Filtering precipitate is dissolved in methylene dichloride (1.2L) after washing with water, solution washs through saturated sodium bicarbonate solution, dry (sal epsom).Filter the back evaporation, obtain required product (23g).
MS(ESP)：338(MH +)C 10H 9FINO 3
NMR(DMSO-d 6 )δ：3.53(m，1H)；3.67(m，1H)；3.82(dd，1H)；4.07(t，1H)；4.70(m，1H)；5.20(t，1H)；7.21(dd，1H)；7.57(dd，1H)；7.81(t，1H)。
(5R)-and 5-azido methyl-3-(3-fluoro-4-iodophenyl)-1,3-Evil Azoles alkane-2-ketone
Methylsulfonyl chloride (17.9mL) is added dropwise to (5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-1 under dry nitrogen atmosphere, 3-oxazolidine-2-ketone (55.8g) and triethylamine (46.1mL) are dissolved in the stirred solution in the dry methylene chloride (800mL), and ice bath keeps below room temperature.Allow the reaction mixture that stirs rise to room temperature in 3 hours, water and salt solution wash after drying (Na successively 2SO 4).Removal of solvent under reduced pressure obtains yellow solid intermediate methanesulfonates (68g), and it directly uses no longer further and purifies.
With the stirred solution of mixture in DMF (800mL) of intermediate methanesulfonates (68g) and sodiumazide (32.3g) in 75 ℃ of heated overnight.Allow mixture be cooled to room temperature, dilute with water is used ethyl acetate extraction 2 times.The extract that merges washs after drying (Na successively through water and salt solution 2SO 4).Removal of solvent under reduced pressure obtains yellow oil, and it purifies acquisition Off-white solid trinitride product (49g) through silica gel column chromatography [use ethyl acetate: hexane (1: 1) wash-out].Product and ethyl acetate/hexane are ground further purification.
1H-NMR(DMSO-d 6)δ：3.57-3.64(dd，1H)；3.70-3.77(dd，1H)；3.81-3.87(dd，1H)；4.06(t，1H)；4.78-4.84(m，1H)；7.05-7.09(ddd，1H)；7.45(dd，1H)；7.68-7.74(dd，1H)。
(5R)-and 3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2-ketone
Figure A20038010918300812
With mixture (5R)-5-azido methyl-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidine-2-ketone (30g) and the stirred solution reflux of two ring [2.2.1] heptadiene (30mL) in dioxane (300mL) spend the night.Allow mixture be cooled to room temperature, reduction vaporization obtains brown solid to doing.Brown solid is purified through silica gel column chromatography [usefulness gradient 98: 2-95: 5 methyl alcohol: chloroform wash-out], obtains faint yellow solid triazole product (20g).Product and dichloromethane/hexane (1: 1) are ground further purification, obtain Off-white solid.
1H-NMR(DMSO-d 6)δ：3.86-3.92(dd，1H)；4.23(t，1H)；4.83(d，2H)；5.11-5.19(m，1H)；7.12-7.16(dd，1H)；7.47-7.51(dd，1H)；7.76(s，1H)；7.79-7.85(dd，1H)；8.16(s，1H)。
3-bromo-6-cyano group-pyridine
Figure A20038010918300821
With 2, (39.465g, 0.17mol) (14.42g 0.17mol) handled 20 hours the stirred solution that is dissolved in anhydrous NMP (100mL) the 5-dibromo pyridine with CuCN in 110 ℃ under the nitrogen atmosphere.After reaction mixture is cooled to 40 ℃ with aqueous sodium hydroxide solution (2M; 200mL) and ethyl acetate (200mL) handle successively.Stirred the mixture 1 hour, and removed by filter the precipitation of generation then through Celite.Remaining solid is through aqueous sodium hydroxide solution (2M; 600mL) and ethyl acetate (600mL) wash successively.Use ammonium hydroxide aqueous solution (5M after merging organic layer; 800mL) washing, dried over mgso, reduction vaporization is to doing.Nonvolatile resistates is purified through silica gel chromatography [gradient 1%-7% ethyl acetate/hexane], obtains colourless amorphous body title compound (8.538g, 28%).
1 H-NMR(DMSO-d 6 )(300MHz)δ8.05(d，1H)；8.40(dd，1H)；8.95(d，1H)。
5-bromo-2-tetrazolium-5-yl pyridines
Figure A20038010918300822
With 3-bromo-6-cyano group-pyridine (2g, 10.9mmol), sodiumazide (0.85g, 13mmol) and ammonium chloride (0.59g, 11mmol) at N, the mixture in the N dimethyl formamide (20mL) in 120 ℃ the heating 1 hour.(～100mL) dilution, filtering separation product with the ethyl acetate washing, obtain oyster white amorphous body title compound to reaction mixture then, and it is directly used in next step and no longer further purifies through ethyl acetate.
5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine and 5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyrrole Pyridine
Figure A20038010918300831
The method preparation that 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine and 5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine are introduced according to Dong A Pharmaceuticals (WO 01/94342).
5-bromo-2-tetrazolium-5-yl pyridines [Dong APharmaceuticals (WO 01/94342)] that 6.5g is not purified (～28mmol) and sodium hydroxide (9g, 125mmol) the mixture reduction vaporization in dry DMF is to doing.The stirred solution that nonvolatile resistates is dissolved in dry DMF (50mL) splashes into methyl iodide in the ice bath temperature, and (3.0mL 48mmol) handles.Allow the reaction mixture that stirs heat up, kept 2 hours in room temperature then.Reaction mixture distributes between frozen water and ethyl acetate.Organic phase is through water washing, reduction vaporization after the dried over mgso, and the resistates of acquisition is purified through silica gel chromatography [use methylene dichloride: ethyl acetate (60: 1) wash-out], obtains:
1. 5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine (1.397g), colorless solid, (TLC: silica gel, hexane: ethyl acetate (4: 1), Rf:0.3), 1 H-NMR (DMSO-d 6 ) (300MHz)
δ：4.38(s，3H)；8.17(d，1H)；8.35(dd，1H)；8.96(d，1H)。
2. 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine (1.07g), colorless solid, (TLC: silica gel, hexane: ethyl acetate (4: 1), Rf:0.1). 1 H-NMR(DMSO-d 6 )(300MHz)
δ：4.46(s，3H)；8.09(d，1H)；8.28(dd，1H)；8.88(d，1H)。Structure, wherein CH are determined in experiment based on nmr HMBC (Heteronuclear Multiple Bond Correlation) 3The long-range coupling of the C5 of proton-tetrazole ring occurs in the 1-methyl isophthalic acid H-isomer of Rf0.3, but not at the 2-of Rf0.1 methyl-2H-isomer).Therefore compound 5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine is that therefore isomer and compound 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine of Rf0.3 be the isomer of Rf0.1
Embodiment 2:(5R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazolium-5-yl) pyridin-3-yl) phenyl)-5- (4-methyl fluoride-1H-1,2,3-triazol-1-yl methyl)-13-Evil Azoles alkane-2-ketone
Figure A20038010918300841
With (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-methyl fluoride-1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone (1.5g, 3.57mmol), two valeryl two boron (2.26g, 8.9mmol) and potassium acetate (1.22g, 12.5mmol) mixture in methyl-sulphoxide (15mL) is with dichloro [1,1 '] two (diphenylphosphino) ferrocene] (261mg 10mol%) handles palladium (II) methylene dichloride adducts, then as reaction as described in the embodiment 1.Reaction mixture is purified through silica gel chromatography [use hexane: ethyl acetate (3: 2) wash-out], acquisition contains corresponding boric acid and (5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl)-5-(4-methyl fluoride-1H-1,2,3-triazol-1-yl methyl)-1, the mixture of 3-oxazolidine-2-ketone (562mg ,～37%), its purity is enough to continue next step.
With the boric acid ester of previous step preparation and the mixture (337mg of boric acid, 0.8mmol), 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine (175mg, 0.73mmol) and salt of wormwood (504mg, 3.65mmol) at N, dinethylformamide: water (10mL, 7: 1) in mixture with tetrakis triphenylphosphine palladium (0) (84mg, 10mol%) handle after with it as reaction as described in the embodiment 1.Reaction mixture is purified through silica gel chromatography [use ethyl acetate: hexane (1: 2) wash-out], obtains colourless amorphous body product (180mg, 49%).
MS(ESP)：454.45(MH +)
1 H-NMR(DMSO-d 6 )δ：3.98(dd，1H)；4.32(dd，1H)；4.47(s，3H)；4.88(m，2H)；5.19(m，1H)；5.46(d，2H，J H，F?48Hz)；7.45(m，1H)；7.63(m，1H)；7.75(m，1H)；8.15-8.24(m，2H)；8.38(d，1H)；8.93(s，1H)。
The intermediate of embodiment 2 is prepared as follows:
(5R)-and 3-(3-fluoro-4-iodophenyl)-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2-ketone
Figure A20038010918300851
With (5R)-3-(3-fluoro-4-iodophenyl)-5-azido methyl-1,3-oxazolidine-2-ketone (10g, 28mmol) and propargyl alcohol (3.2mL, 56mmol) (526mg 2.8mmol) handles the mixture in acetonitrile (80mL), stirs then and spends the night with CuI.With solidified reaction mixture ethyl acetate: the acetonitrile extraction, through water washing, reduction vaporization after the dried over mgso obtains the enough stand-by crude product of purity (12.3g, quantitative).
MS(ESP)：41913(MH +)C 13H 12FIN 4O 3
1 H-NMR(DMSO-d 6 )δ：3.88(dd，1H)；423(dd，1H)；451(d，2H)；4.80(m，2H)；5.14(m，1H)；5.22(dd，1H)；7.16(m，1H)；7.51(m，1H)；7.83(m，1H)；8.01(d，1H)。
(5R)-and 3-(3-fluoro-4-iodophenyl)-5-(4-brooethyl-1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles Alkane-2-ketone
Figure A20038010918300852
With (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone (14.7g, 35.1mmol) and carbon tetrabromide (12.16g, 36.7mmol) in methylene dichloride (1L), stir the mixture that (12.34g 61.2mmol) handles with triphenylphosphine in 0 ℃.In 0 ℃ of stirred reaction mixture after 30 minutes in stirred overnight at room temperature.Use hexane after reaction mixture is added on silicagel column: ethyl acetate (1: 1) and ethyl acetate: methyl alcohol (95: 5) is wash-out successively, and the product of acquisition is purified through re-crystallizing in ethyl acetate, obtains colorless solid title compound (14g).
MS(ESP)：482.69(MH +，Br 81)C 13H 11BrFIN 4O 2
1 H-NMR(DMSO-d 6 )δ：3.87(dd，1H)；4.23(dd，1H)；4.74(s，2H)；4.81(m，2H)；5.12(m，1H)；7.14(m，1H)；7.49(m，1H)；7.81(m，1H)；8.22(d，1H)。
(5R)-and 3-(3-fluoro-4-iodophenyl)-5-[(4-methyl fluoride-1H-1,2, the 3-triazol-1-yl) methyl]Evil Azoles alkane- 2-ketone
Figure A20038010918300861
With (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-brooethyl-1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone (6.94g, 14.4mmol), Potassium monofluoride (4.19g, 72.1mmol) and the mixture heating up to 90 of 1-butyl-3-methyl imidazolium tetrafluoroborate (18.4mL) in acetonitrile (250mL) and water (1.5mL) ℃ spend the night.Reaction mixture dilutes through ethyl acetate, washes with water, is evaporated to dried after the dried over mgso.Nonvolatile resistates is purified through silica gel chromatography [using eluent ethyl acetate], obtains oyster white amorphous body title compound (2.7g, 45%).
MS(ESP)：421.34(MH +)C 13H 11F 2IN 4O 2
1 H-NMR(DMSO-d 6 )δ：3.88(dd，1H)；4.23(dd，1H)；4.84(m，2H)；5.14(m，1H)；5.45(d，2H，J H，F?52Hz)；7.14(m，1H)；7.49(m，1H)；7.81(m，1H)；8.34(d，1H)。
Embodiment 3:(5R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazolium-5-yl) pyridin-3-yl) phenyl)-5- (4-chloro-1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2-ketone
(3-fluoro-4-(4 with (5R)-3-, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl)-5-(4-chloro-1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone (300mg, 0.71mmol), 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine (170mg, 0.71mmol) and yellow soda ash (226mg, 2.13mmol) at N, dinethylformamide: the mixture degassing in the water (5mL, 10: 1), wash with nitrogen, (82mg 10mol%) handles with tetrakis triphenylphosphine palladium (0).In 70 ℃ of reacting by heating mixtures 3 hours, be cooled to room temperature, reduction vaporization is to doing.Nonvolatile resistates is purified through silica gel chromatography [use methylene dichloride: N, dinethylformamide (25: 1-20: 1) wash-out].Enriched product part to smaller size smaller (～3mL), with methylene dichloride (5mL) and hexane (15mL) processing to precipitate colourless amorphous body product (229mg, 71%).
MS(ESP)：456.27(MH +)C 19H 15FN 9O 2
1 H-NMR(DMSO-d 6 )δ：3.98(dd，1H)；4.32(dd，1H)；4.47(s，3H)；4.86(m，2H)；5.19(m，1H)；7.46(m，1H)；7.63(m，1H)；7.76(m，1H)；8.15-8.27(m，2H)；8.47(s，1H)；8.93(s，1H)。
The intermediate of embodiment 3 is prepared as follows:
The ethene SULPHURYL CHLORIDE
Under the nitrogen atmosphere with 2-chloro-ethane-sulfonyl chloride (50g, 0.307mol) stirred solution that is dissolved in dry ether (400mL) in-60 ℃ to-50 ℃ with 2, (42.2mL 0.36mol) is dissolved in the solution-treated of dry ether (60mL) to the 6-lutidine, and then handles with dry ether (200mL).Allow the reaction mixture that stirs rise to room temperature, be cooled to after 0 ℃ with the aqueous sulfuric acid (1% that dilutes; 125mL) slowly handle.Separate the ether phase, with the aqueous sulfuric acid (1% of dilution; 125mL) and salt solution (2 * 120mL) washing, concentrating under reduced pressure after the dried over mgso (500mmHg) obtains rough oily matter, it is purified through distillation method, obtain ethene SULPHURYL CHLORIDE (C.S.Rondestveldt, J.Amer.Chem.Soc., 76,1954,1926) (24.6g, 63%)
b.p.?27.2℃/0.2mmHg。
1H-nmr (CDCl 3) δ 7.20 (dd, J=16.2 and 9.4Hz, 1H), 6.55 (dd, J=16.2 and 1.7Hz, 1H), 6.24 (dd, J=9.4 and 1.7Hz, 1H).
1,2-two chloro-ethane-sulfonyl chlorides
(32g, the stirred solution in carbon tetrachloride solution 0.25mol) was in about room temperature (200W lamp) irradiation 5 hours in the ethene SULPHURYL CHLORIDE with chlorine.Decompression (50mmHg) concentrated reaction mixture, the nonvolatile resistates of fractionation obtains 1,2-two chloro-ethane-sulfonyl chlorides (Goldstein et al.Zh.Obshch.Khim., 28,1958,2107) (15,5g, 31%), b.p.75 ℃/0.7mmHg.
1H-nmr (CDCl 3) δ 5.29 (dd, J=8.9 and 3.3Hz, 1H), 4.40 (dd, J=12.4 and 3.3Hz, 1H), 3.97 (dd, J=12.4 and 8.9Hz, 1H).
1-chloro-1-ethene SULPHURYL CHLORIDE
Under the nitrogen atmosphere with 1,2-two chloro-ethane-sulfonyl chlorides (14.54g, 73.62mmol) stirred solution that is dissolved in dry ether (140mL) in-60 ℃ to-50 ℃ with 2, (10.30mL 88.34mmol) handles the 6-lutidine.Allow the reaction mixture that stirs rise to room temperature, be cooled to after 0 ℃ with the aqueous sulfuric acid (1% that dilutes; 50mL) slowly handle.Separate the ether phase, diluted aqueous sulfuric acid (1%; 2 * 60mL) and salt solution (3 * 60mL) washings, decompression (60mmHg) concentrates after the dried over mgso, the oily matter of acquisition is purified through distillation method, obtains 1-chloro-1-ethene SULPHURYL CHLORIDE (7.2g, 61%), b.p.26 ℃/2mmHg.
1H-nmr (CDCl 3) δ 6.70 (and d, J=3.8Hz, 1H) and 6.22 (d, J=3.8Hz, 1H).
(5R)-and 3-(3-fluoro-4-iodophenyl)-5-(4-chloro-1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2- Ketone
With (5R)-3-(3-fluoro-4-iodophenyl)-5-azido methyl-1,3-oxazolidine-2-ketone (1g, 28mmol) (1g, heated 1 hour in 80 ℃ in penstock with 1-chloro-1-ethene SULPHURYL CHLORIDE by stirring the mixture 6.2mmol).Allow reaction mixture be cooled to room temperature, with chloroform (15mL) dilution, in 80 ℃ of reheat 4 hours.Allow reaction mixture be cooled to room temperature, filter the collecting precipitation thing,, obtain colourless amorphous body title compound (725mg, 62%) through a little washed with dichloromethane.
MS(ESP)：423.3(MH +)C 12H 9FIN 4O 2
1 H-NMR(DMSO-d 6 )δ：3.89(dd，1H)；4.22(dd，1H)；4.82(m，2H)；5.15(m，1H)；7.15(m，1H)；7.49(m，1H)；7.82(m，1H)；8.44(s，1H)。
(5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl)-5- (4-chloro-1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2-ketone
With (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-chloro-1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone (725mg, 1.7mmol), two valeryl two boron (1.09g, 4.3mmol) and potassium acetate (590mg, 6mmol) the dichloro [1 of the mixture in methyl-sulphoxide (10mL), 1 '] two (diphenylphosphino) ferrocene] (90mg 0.11mmol) handles palladium (II) methylene dichloride adducts, then as reaction as described in the embodiment 1.Behind 45 minute hands, allow reaction mixture be cooled to room temperature, wash with aqueous ammonium chloride solution with ethyl acetate dilution back.Water layer is through ethyl acetate extraction 2 times, and the organic layer of merging is evaporated to dried through water washing after the dried over sodium sulfate.Nonvolatile resistates is purified through silica gel chromatography [use hexane: acetone (2: 1) wash-out], separates out further purification with methylene dichloride and hexane, obtains colourless amorphous body product (590mg, 81%), and its purity is enough to carry out ensuing reaction.
MS(ESP)：423(MH +)C 18H 21BFN 4O 4
1 H-NMR(DMSO-d 6 )δ：1.28(s，12H)；3.92(dd，1H)；4.24(dd，1H)；4.83(m，2H)；5.16(m，1H)；7.30(m，1H)；7.39(m，1H)；7.63(m，1H)；8.45(s，1H)。
Embodiment 4:(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazolium-5-yl)-1-pyridine oxide-3-yl] Phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2-ketone
Figure A20038010918300901
(175mg, 0.73mM) (nominal weight in wet base, 70%:0.50g 2.05mM) are dissolved in 1, and 2-ethylene dichloride (5ml) back was in 80 ℃ of heating 1.5 hours with 3-chlorine peroxybenzoic acid with 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine.Mixture is directly purified through silica gel chromatography, with 25% acetonitrile/methylene dichloride wash-out.Therefore obtain white solid 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine 1-oxide compound (165mg).Analyzing this material through tlc is homogeneity, and it is directly used in next step and no longer further characterizes or purify.
With above-mentioned sample pyridine oxide with (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-oxazolidine-2-ketone (335mg, 0.86mMol is as embodiment 1 preparation), salt of wormwood (400mg, 2.9mMol) and four (triphenylphosphinyl) palladium (0) (80mg 0.07mMol) is suspended in THF (10ml) and water (1ml) after merging.In 75 ℃ of heated mixt 2 hours, dilute with water.Precipitated solid on the de-entrainment filter, water, ether and 1: 1 methylene dichloride: the hexane flushing, vacuum-drying obtains the Off-white solid clean product, 134mg.
MS (electron spray(ES)): 438 (M+1) C 19H 16FN 9O 3
1 H-NMR(300MHz，DMSO-d 6 )δ：3.97(dd，1H)；4.30(t，1H)；4.49(s，3H)；4.86(d，2H)；5.19(m，1H)；7.43(dd，1H)；7.61(dd，1H)；7.68(dd，1H)；7.77(t，2H)；8.06(d，1H)；8.18(s，1H)；8.68(s，1H)。
Embodiment 5:(5R)-3-[3-fluoro-4-[6-(2-(2-hydroxyethyl)-2H-1,2,3,4-tetrazolium-5-yl)-3- Pyridyl] phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)Evil Azoles alkane-2-ketone
Figure A20038010918300911
With 2-[5-(5-bromopyridine-2-yl)-2H-tetrazolium-2-yl] and ethanol (167mg, 0.62mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] oxazolidine-2-ketone (240mg, 0.62mmol) and yellow soda ash (262mg 2.47mmol) is dissolved in/is suspended in N, dinethylformamide/water (5ml, 10: 1).With its degassing, with nitrogen flushing back add tetrakis triphenylphosphine palladium (0) (71mg, 0.061mmol).In 70 ℃ of heating 3 hours, be cooled to room temperature, evaporating solvent.Purify through silica gel chromatography (methylene dichloride/DMF (20: 1)), obtain the required product of colorless solid (198mg, 71%).
MS(ESP)：452.18(MH +)C 20H 18FN 9O 3
1 H-NMR(DMSO-d 6 )δ：3.97(m，3H)；4.31(dd，1H)；4.70-4.90(m，4H)；5.05-5.25(m，2H)；7.40-7.80(m，4H)；8.15-8.30(m，3H)；8.93(s，1H)。
The intermediate of embodiment 5 is prepared as follows:
(5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]- [(1H-1,2,3-triazol-1-yl) methyl]Evil Azoles alkane-2-ketone
Figure A20038010918300912
(with embodiment 1)
2-[5-(5-bromopyridine-2-yl)-2H-tetrazolium-2-yl] ethanol
With 5-bromo-2-(2H-tetrazolium-5-yl) pyridine (WO 0194342 A1) (1.2g 5.3mmol) is dissolved in/is suspended in 1-propyl alcohol (15ml), add potassium hydroxide (250mg 4.5mmol) is dissolved in the solution of 1-propyl alcohol (15ml), with it in 80 ℃ of heating 1 hour.(0.344ml, 4.8mmol) refluxed 1 day in the back to add ethylene bromohyrin.Add potassium hydroxide (270mg) and ethylene bromohyrin (0.35ml) again, the reflux mixture is 4 hours again.Added behind potassium hydroxide and the ethylene bromohyrin backflow mixture once more 14 hours.Reaction mixture is through 0.45 μ M membrane filtration, with ethanol and washed with dichloromethane filter cake.Through silica gel chromatography (hexane/ethyl acetate 1: the 1-ethyl acetate) purify, obtain title compound (0.342g, 24%) and corresponding 1H-tetrazolium positional isomers (0.225g).
1 H-NMR(DMSO-d 6 )δ：3.90-4.02(dt，2H)；4.78(t，2H)；5.091H)；8.10(m，1H)；8.27(dd，1H)；8.88(d，1H)。
The structure of positional isomers is determined in the HMBC NMR experiment of 1H-tetrazolium isomer.
Embodiment 6:(5R)-3-[3-fluoro-4-[6-(1-(propane-1,3-glycol-2-yl)-1H-1,2,3, the 4-tetrazolium- The 5-yl)-and the 3-pyridyl] phenyl]-5-[(4-methyl fluoride-1H-1,2, the 3-triazol-1-yl) methyl]Evil Azoles alkane- 2-ketone
Figure A20038010918300922
With 2-[5-(5-bromopyridine-2-yl)-1H-tetrazolium-1-yl] propane-1, the 3-glycol (170mg, 0.57mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidine-2-ketone (220mg, 0.57mmol) and yellow soda ash (240mg, 2.27mmol) be dissolved in/be suspended in N, dinethylformamide/water (5mL, 10: 1).With its degassing, with nitrogen flushing back add tetrakis triphenylphosphine palladium (0) (65mg, 0.056mmol).In 70 ℃ of heating 3 hours, be cooled to room temperature, evaporating solvent.Purify through silica gel chromatography (methylene dichloride/DMF (20: 1)), obtain colorless solid product 189mg (69%).
MS(ESP)：482.17(MH +)C 20H 18FN 9O 3
1 H-NMR(DMSO-d 6 )δ：3.85-4.00(m，5H)；4.31(dd，1H)；4.86(m，2H)；5.03(dd，2H)；5.19(m，1H)；5.84(m，1H)；7.46(dd，1H)；7.62(dd，1H)；7.73-7.82(m，2H)；8.19(s，1H)；8.22-8.35(m，2H)；8.98(s，1H)。
The intermediate of embodiment 6 is prepared as follows:
2-[5-(5-bromopyridine-2-yl)-1H-tetrazolium-1-yl] propane-1, the 3-glycol
With 5-bromo-2-(2H-tetrazolium-5-yl) pyridine (0.56g, 2.5mmol) (WO 0194342 Al prepares free acid: the material (1g) of the method preparation that will introduce according to WO 0194342 Al is dissolved in hot water (70mL, 90 ℃); Then add the HCl (aqueous solution, 1M, 4mL) postcooling is to room temperature, filter the free acid of collecting precipitation, wash back high vacuum drying with water, obtain the 0.56g free acid), triphenylphosphine (0.65g, 2.5mmol) with 1,3-two-(tertiary butyl-dimethyl-siloxy-)-propan-2-ol (0.79g, 2.5mmol) (D.P.Curran and J.-C.Chao, Synth.Commun.20, No 22,1990,3575-3584) be dissolved in/be suspended in dry THF (25mL), (0.49mL 2.5mmol), allows reaction mixture rise to ambient temperature overnight to add diisopropyl azodiformate after it is cooled to 0 ℃.Solvent evaporated under reduced pressure, resistates is purified through silica gel chromatography (hexane/ethyl acetate (30: 1)), obtains mixture two-silyl ether title compound and corresponding 2H-tetrazolium positional isomers (809mg).This mixture is dissolved in dry THF (10mL), be cooled to be added dropwise to after 0 ℃ tetrabutyl ammonium fluoride (the THF solution of 1M, 5mL, 5mmol).Evaporating solvent after 1 hour, (purify, and the 2H-that obtains title compound (318mg) and corresponding position isomerism replaces tetrazolium (69mg) by methylene dichloride/acetone (3: 1-2: 1)) through silica gel chromatography for resistates.The title compound structure is determined in the NOE-NMR experiment.
1 H-NMR(DMSO-d 6 )δ：3.80-3.95(m，4H)；5.01(t，2H)；5.69(m，1H)；8.14(m，1H)；8.35(m，1H)；8.94(m，1H)。
Embodiment 7:(5R)-and 5-{[4-(difluoromethyl)-1H-1,2, the 3-triazol-1-yl] methyl }-3-{3-fluoro-4- [6-(2-methyl-2H-tetrazolium-5-yl) pyridin-3-yl] phenyl }-1,3-Evil Azoles alkane-2-ketone
With (5R)-5-{[4-(difluoromethyl)-1H-1,2, the 3-triazol-1-yl] methyl }-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-1,3-oxazolidine-2-ketone (0.25g, 0.586mmol) and 5-bromo-[2-(2-methyl-2H-1,2,3,4-tetrazolium-5-yl)] pyridine (155mg, 0.645mmol) and salt of wormwood (404mg, 2.93mmol) be dissolved in/be suspended in N, dinethylformamide/water (10mL, 7: 1) together, (67mg 10mol%) makes catalyzer as reaction as described in the embodiment 1 with tetrakis triphenylphosphine palladium (0).(ethyl acetate/hexane (1: 2) is purified, and obtains the colourless amorphous body product of 200mg through silica gel chromatography.
MS(ESP)：472.15(MH +)C 20H 16F 3N 9O 2
1 H-NMR(DMSO-d 6 )δ：3.98(dd，1H)；4.32(dd，1H)；4.47(s，3H)；4.88(d，2H)；5.22(m，1H)；7.05～7.42(t，br，1H)；7.46(m，1H)；7.60(m，1H)；7.75(m，1H)；8.15-8.24(m，2H)；8.65(s，1H)；8.93(s，1H)。
The intermediate of embodiment 7 is prepared as follows:
(5R)-and 5-{[4-(difluoromethyl)-1H-1,2, the 3-triazol-1-yl] methyl }-(4,4,5,5-four for 3-[3-fluoro-4- Methyl isophthalic acid, 3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-1,3-Evil Azoles alkane-2-ketone
Figure A20038010918300951
With (5R)-5-{[4-(difluoromethyl)-1H-1,2, the 3-triazol-1-yl] methyl }-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidine-2-ketone (2.56g, 5.84mmol), two valeryl two boron (3.71g, 14.6mmol), potassium acetate (2.0g, 20.44mmol) and 1,1 '-(0.427g 0.584mmol) is suspended in DMSO (10ml) to [two (diphenylphosphino) ferrocene] dichloro palladium (II) methylene dichloride complex compound.In 80 ℃ of heated mixt 90 minutes, obtain clarifying dark solution.After being cooled to room temperature, add ethyl acetate (150ml), mixture filters through Celite, and (2 * 100ml) washings are concentrated into dried after the dried over sodium sulfate with saturated brine solution.Dark resistates is dissolved in methylene dichloride (20ml), slowly adds hexane (100ml) then, filter the gained post precipitation and wash with 5% dichloromethane/hexane, collect required product (1.73g), it directly uses no longer further as intermediate and purifies.
1 H-NMR(DMSO-d 6 )δ：1.12(s，12H)；3.88(dd，1H)；4.23(dd，1H)；4.84(m，2H)；5.14(m，1H)；6.80～7.20(t，br，1H)；7.14(m，1H)；7.28(m，1H)；7.51(m，1H)；8.45(s，1H)。
(5R)-and 5-{[4-(difluoromethyl)-1H-1,2, the 3-triazol-1-yl] methyl }-3-(3-fluoro-4-iodophenyl)- 1,3-Evil Azoles alkane-2-ketone
Figure A20038010918300952
With 1-{[(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidine-5-yl] methyl }-1H-1,2,3-triazole-4-formaldehyde (3.6g, 8.65mmol) (2.3g 10.38mmol) mixes in dry methylene chloride (20ml) with [two (2-methoxy ethyl) amino]-sulfur trifluoride, add ethanol (20ul) then, reaction mixture refluxed 14 hours is cooled to room temperature, washs after anhydrous magnesium sulfate drying with saturated sodium bicarbonate aqueous solution.Spissated crude samples is purified through column chromatography, with hexane/ethyl acetate (1.5: 1) wash-out, obtains title compound (2.58g).
MS(ESP)：439.02(MH +)C 13H 10F 3IN 4O 2
1 H-NMR(DMSO-d 6 )δ：4.02(dd，1H)；4.40(dd，1H)；5.03(d，2H)；5.30(m，1H)；7.15～7.53(t，br，1H)；7.28(dd，1H)；7.6(dd，1H)；7.95(t，1H)；8.70(s，1H)。
1-{[(5R)-and 3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidine-5-yl] methyl }-1H-1,2,3-three Azoles-4-formaldehyde
With (5R)-3-(3-fluoro-4-iodophenyl)-5-[(4-hydroxymethyl-1H-1,2, the 3-triazol-1-yl) methyl] oxazolidine-2-ketone (5.7g, 13.6mmol) and manganese oxide (3.56g, 40.9mmol) mix, in drying 1, be heated to 100 ℃ in the 4-dioxane and continue 48 hours, cooling mixture to 70 ℃ filters through Celite then.Be dissolved in 5% ethanol/methylene behind the concentrated filtrate, add hexane, filter the post precipitation that generates and collect title compound (3.6g).
MS(ESP)：416.91(MH +)C 13H 10FIN 4O 3
1 H-NMR(DMSO-d 6 )δ：3.87(m，1H)；4.18(dd，1H)；4.85(d，2H)；5.15(m，1H)；7.12(d，1H)；7.42(d，1H)；7.8(dd，1H)；8.88(s，1H)；10.01(s，1H)。
(5R)-and 3-(3-fluoro-4-iodophenyl)-5-[(4-hydroxymethyl-1H-1,2, the 3-triazol-1-yl) methyl]Evil Azoles Alkane-2-ketone
Figure A20038010918300971
((10g 28mmol) is dissolved in acetonitrile (80mL) to azido methyl) oxazolidine-2-ketone with (5R)-3-(3-fluoro-4-iodophenyl)-5-.Add successively propargyl alcohol (3.2mL, 56mmol) and CuI (526mg, 2.8mmol), stirring is spent the night.The solidified reaction mixture extracts through ethylacetate/acetonitrile, washes with water after dried over mgso.Vacuum evaporating solvent obtains 12.3g crude product (quantitatively).
MS(ESP)：419.13(MH +)C 13H 12FIN 4O 3
1 H-NMR(DMSO-d 6 )δ：3.88(dd，1H)；4.23(dd，1H)；4.51(d，2H)；4.80(m，2H)；5.14(m，1H)；5.22(dd，1H)；7.16(m，1H)；7.51(m，1H)；7.83(m，1H)；8.01(d，1H)。
Embodiment 8:(5R)-3-{3-fluoro-4-[2-methyl-6-(4-methyl isophthalic acid H-1,2,3-triazol-1-yl) pyridine- The 3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2-ketone
Figure A20038010918300972
With 3-bromo-2-methyl-6-(4-methyl isophthalic acid H-1,2,3-triazol-1-yl) pyridine (196mg, 0.773mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1, and 3-oxazolidine-2-ketone (300mg, 0.773mmol), salt of wormwood (320mg, 2.31mmol) and four (triphenylphosphinyl) palladium (0) (89mg 0.077mmol) is suspended in DMF (3ml) and water (0.3ml) after merging.In 80 ℃ of heated mixt 2 hours, be diluted with water to 7ml then.Collect solid, water flushing back resuspending is in the DMSO of tepor (3ml).Suspension is through methylene dichloride (5ml) and ether (4ml) dilution.Collect solid,, obtain white solid clean product (110mg) with ether and washed with methanol, vacuum-drying.
MS(APCI)：435(M+1)C 21H 19N 8O 2F
NMR(DMSO-d 6 )δ：2.36(s，3H)；2.41(s，3H)；3.95(dd，1H)；4.31(t，1H)；4.88(d，2H)；5.15-5.24(m，1H)；7.44(dd，1H)；7.50(t，1H)；7.62(dd，1H)；7.79(d，1H)；7.95(q，2H)；8.20(d，1H)；8.61(d，1H)。
The intermediate of above-claimed cpd is prepared as follows:
3-bromo-2-methyl-6-(4-methyl isophthalic acid H-1,2,3-triazol-1-yl) pyridine
Figure A20038010918300981
To 6-amino-3-bromo-2-picoline (1.0g, 5.3mmol) solution that is dissolved in methyl alcohol (20ml) in room temperature add diisopropylethylamine (2.8ml, 16.0mmol).Stirred solution 10 minutes, (2.0g, 6.95mmol), reaction mixture weekend is in stirring at room in 4 ℃ of addings [(1E)-2,2-two chloro-1-methyl ethylidene] hydrazides-4-methyl-Phenylsulfonic acid.Vacuum evaporating solvent, resistates is purified through silica gel chromatography, with 25% ethyl acetate/hexane wash-out, obtains title compound (758mg).
MS(APCI)：254(M+1)C 9H 9BrN 4
1 H-NMR(DMSO-d 6 )δ：2.34(s，3H)；2.64(s，3H)；7.83(d，2H)；8.26(d，1H)；8.56(s，1H)。
(5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5- (1H-1,2,3-triazol-1-yl methyl)-1,3-Evil Azoles alkane-2-ketone
Referring to embodiment 1.

Claims (25)

1. hydrolyzable ester in acceptable salt or the body on formula (I) compound or its pharmacology,
Figure A2003801091830002C1
Wherein C is selected from D and E,
Wherein (I) De oxazolidone is connected the benzyl ring among D and the E with formula;
R 1B is HET1 or HET2, wherein
I) HET1 is a N connection 5-unit unsaturated or part unsaturated heterocycle fully, and it comprises (i) 1-3 other nitrogen heteroatom or (ii) an other heteroatoms that is selected from O and S and an optional other nitrogen heteroatom; This ring is chosen wantonly on the C atom beyond the connectivity N atom adjacent C atom and is replaced by oxo or thio group; And/or this ring chooses wantonly and is selected from hereinafter on any effective C atom beyond the connectivity N atom adjacent C atom that the substituting group of the RT of definition replaces, and/or on the available nitrogen atom beyond the adjacent N atom of connectivity N atom (precondition is that this ring is not therefore by quaternized) by the replacement of (1-4C) alkyl;
Ii) HET2 is a N connection 6-unit dihydro heteroaryl ring, comprises sum (comprising the connectivity heteroatoms) 3 nitrogen heteroatoms at the most, and this ring is replaced by oxo or thio group on the suitable C atom beyond the connectivity N atom adjacent C atom; And/or this ring chooses wantonly and is selected from independently hereinafter by 1-2 on any effective C atom beyond the connectivity N atom adjacent C atom that the substituting group of the RT of definition replaces, and/or (precondition is that this ring is not so by quaternized) quilt (1-4C) alkyl replacement on the available nitrogen atom beyond the adjacent N atom of connectivity N atom;
The RT substituting group is selected from following group:
(RTa1) hydrogen, halogen, (1-4C) alkoxyl group, (2-4C) alkenyl oxy, (2-4C) alkenyl, (2-4C) alkynyl group, (3-6C) cycloalkyl, (3-6C) cycloalkenyl group, (1-4C) alkylthio, amino, azido-, cyano group and nitro; Or
(RTa2) (1-4C) alkylamino, two-(1-4C) alkylaminos and (2-4C) alkenyl amino;
Perhaps RT is selected from following group
(RTb1) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: hydroxyl, (1-4C) alkoxyl group, (1-4C) alkylthio, cyano group and azido-; Or
(RTb2) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: (2-4C) alkenyl oxy, (3-6C) cycloalkyl and (3-6C) cycloalkenyl group;
Perhaps RT is selected from following group
(RTc) the first monocycle of complete saturated 4-comprises 1-2 heteroatoms (optional oxidation) that independently is selected from O, N and S, and connects through ring nitrogen or ring carbon atom;
As (RTa1) or (RTa2), (RTb1) or (RTb2) or the RT substituting group (RTc) when comprising alkyl, alkenyl, alkynyl group, cycloalkyl or cycloalkenyl group part, described group is partly chosen wantonly on effective carbon atom by 1-3 or more independently is selected from the substituting group replacement of F, Cl, Br, OH and CN;
R 2A and R 6A independently is selected from H, CF 3, OMe, SMe, Me and Et;
R 2B and R 6B independently is selected from H, F, Cl, CF 3, OMe, SMe, Me and Et;
R 3A be selected from H, (1-4C) alkyl, cyano group, Br, F, Cl, OH, (1-4C) alkoxyl group ,-S (O) n(1-4C) alkyl (wherein n=0,1 or 2), amino, (1-4C) alkyl-carbonyl-amino, nitro ,-CHO ,-CO (1-4C) alkyl ,-CONH 2With-CONH (1-4C) alkyl;
R 4Be selected from R 4A and R 4B, wherein
R 4A be selected from azido-,-NR 7R 8, OR 10, (1-4C) alkyl, (1-4C) alkoxyl group, (3-6C) cycloalkyl ,-(CH 2) k-R 9, AR1, AR2, (1-4C) alkyloyl ,-CS (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-(C=O) 1-R 6,-COO (1-4C) alkyl ,-C=OAR1 ,-C=OAR2 ,-COOAR1, S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-S (O) pAR1 ,-S (O) pAR2 and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl chain can be chosen wantonly by (1-4C) alkyl, cyano group, hydroxyl or halogen and replace; P=0,1 or 2;
R 4B is selected from HET-3;
R 6Be selected from hydrogen, (1-4C) alkoxyl group, amino, (1-4C) alkylamino and hydroxyl (1-4C) alkylamino;
K is 1 or 2;
L is 1 or 2;
R 7And R 8Independently be selected from H and (1-4C) alkyl, perhaps R 7And R 8The nitrogen that connects with their can form 5-7 unit ring, and this ring is chosen wantonly to have 1 and be selected from N, O, S (O) n1 carbon atom of the ring that the other heteroatoms displacement of (wherein n=1 or 2) so forms; Wherein this ring can be chosen wantonly and independently is selected from following group by 1-2 and replace: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2), AR1, AR2 ,-C=OAR1 ,-C=OAR2 ,-COOAR1 ,-CS (1-4C) alkyl ,-C (=S) O (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-S (O) pAR1 and-S (O) pAR2; Wherein any (1-4C) alkyl, (3-6C) cycloalkyl or (1-4C) alkyloyl can choose wantonly and be selected from following substituting group by 1-2 and replace (except the contiguous heteroatomic carbon atom): (1-4C) alkyl, cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino; P=0,1 or 2;
R 9Independently be selected from following R 9A-R 9D:
R 9a：AR1、AR2、AR2a、AR2b、AR3、AR3a、AR3b、AR4、AR4a、CY1、CY2；
R 9B: cyano group, carboxyl, (1-4C) alkoxy carbonyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form 5-7 unit ring with Rw with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly has 11 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and is selected from following group replace on another nitrogen: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-COOAR1 ,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl, (3-6C) cycloalkyl or (1-4C) alkyloyl self can choose wantonly by cyano group, hydroxyl or halogen replace)], vinyl, 2-(1-4C) alkyl vinyl, 2-cyano group vinyl, 2-cyano group-2-((1-4C) alkyl) vinyl, 2-nitroethylene base, 2-nitro-2-((1-4C) alkyl) vinyl, 2-((1-4C) alkyl amino-carbonyl) vinyl, 2-((1-4C) alkoxy carbonyl) vinyl, 2-(AR1) vinyl, 2-(AR2) vinyl, 2-(AR2a) vinyl;
R 9C:(1-6C) alkyl
{ optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy, and [O-P (O) (OH) 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: [phosphono-P (O) (OH) for carboxyl, phosphoryl 2And single-and two-(1-4C) alkoxy derivative], inferior phosphoryl [P (OH) 2And single-and two-(1-4C) alkoxy derivative], cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein W be O or S, the definition of Rv and Rw is the same], (=NORv), wherein the definition of Rv is the same, (1-4C) alkyl S (O) pNH, (1-4C) alkyl S (O) p-((1-4C) alkyl) N-, fluoro (1-4C) alkyl S (O) pNH-, fluoro (1-4C) alkyl S (O) p ((1-4C) alkyl) N-, (1-4C) alkyl S (O) q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O-, AR3-O-, AR1-S (O) q-, AR2-S (O) q-, AR3-S (O) q-, AR1-NH-, AR2-NH-, (p is 1 or 2 to AR3-NH-, and q is 0,1 or 2) and comprise AR2a, AR2b, the group of AR3a and AR3b type AR2 and AR3 }; R wherein 9Any (1-4C) alkyl self in any substituting group of c can independently be selected from following group by 1-2 and replace: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;
R 9D:R 14C (O) O (1-6C) alkyl-, R wherein 14Be AR1, AR2, (1-4C) alkylamino, benzyloxy-(1-4C) alkyl or (1-10C) alkyl { optional as (R 9C) definition replaces };
R 10Be selected from hydrogen, R 9C (definition the same), (1-4C) acyl group and (1-4C) alkyl sulphonyl;
HET-3 is selected from:
A) comprise the 5-unit heterocycle of at least 1 nitrogen and/or oxygen, wherein any carbon atom is C=O, C=N or C=S, and wherein said ring is with following formula HET3-A-HET3-E:
Figure A2003801091830006C1
B) comprise 1-4 and independently be selected from N, O and heteroatomic carbon connection 5-of S or 6-unit hetero-aromatic ring, it is selected from following HET3-F-HET3-Y:
Figure A2003801091830006C2
Figure A2003801091830007C1
C) comprise 1-4 and independently be selected from N, O and heteroatomic nitrogen connection 5-of S or 6-unit hetero-aromatic ring, it is selected from following HET3-Z-HET3-AH:
Figure A2003801091830007C2
The R among the HET-3 wherein 1A is the substituting group on the carbon;
R 1A independently is selected from following R 1A1-R 1A5:
R 1a1：AR1、AR2、AR2a、AR2b、AR3、AR3a、AR3b、AR4、AR4a、CY1、CY2；
R 1A2: cyano group, carboxyl, (1-4C) alkoxy carbonyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form 5-7 unit ring with Rw with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly has 11 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and is selected from following group by one replace on another nitrogen: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-COOAR1 ,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl, (1-4C) alkyloyl is with (3-4C) naphthenic substituent self can be by cyano group, hydroxyl or halogen replace, and precondition is that such substituting group is not on the carbon adjacent with the piperazine ring nitrogen-atoms], vinyl, 2-(1-4C) alkyl vinyl, 2-cyano group vinyl, 2-cyano group-2-((1-4C) alkyl) vinyl, 2-nitroethylene base, 2-nitro-2-((1-4C) alkyl) vinyl, 2-((1-4C) alkyl amino-carbonyl) vinyl, 2-((1-4C) alkoxy carbonyl) vinyl, 2-(AR1) vinyl, 2-(AR2) vinyl, 2-(AR2a) vinyl;
R 1A3:(1-10C) alkyl
{ optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy, and [O-P (O) (OH) 2And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) 2And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: [phosphono-P (O) (OH) for carboxyl, phosphoryl 2And single-and two-(1-4C) alkoxy derivative], inferior phosphoryl [P (OH) 2And single-and two-(1-4C) alkoxy derivative], cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv and Rw can form 5-7 unit ring with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly to have 1 and be selected from N, O, 1 carbon atom of the ring that the other heteroatoms displacement of S (O) n so forms; Wherein when described ring is piperazine ring, this ring can be chosen wantonly on another nitrogen and is selected from following group replacement by one: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl,-COO (1-4C) alkyl,-S (O) n (1-4C) alkyl (wherein n=1 or 2),-COOAR1,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl], (=NORv), wherein the definition of Rv is the same, (1-4C) alkyl S (O) pNH-, (1-4C) alkyl S (O) p-((1-4C) alkyl) N-, fluoro (1-4C) alkyl S (O) pNH-, fluoro (1-4C) alkyl S (O) p ((1-4C) alkyl) N-, (1-4C) alkyl S (O) q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O-, AR3-O-, AR1-S (O) q-, AR2-S (O) q-, AR3-S (O) q-, AR1-NH-, AR2-NH-, (p is 1 or 2 to AR3-NH-, and q is 0,1 or 2) and comprise AR2a, AR2b, the group of AR3a and AR3b type AR2 and AR3 }; R wherein 1Any (1-4C) alkyl in any substituting group of a3, (1-4C) alkyloyl and (3-6C) cycloalkyl self can independently be selected from following group replacement by 1-2: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;
R 1A4:R 14C (O) O (1-6C) alkyl-, R wherein 14Be AR1, AR2, AR2a, AR2b, (1-4C) alkylamino, benzyloxy-(1-4C) alkyl or (1-10C) alkyl { optional as (R 1A3) definition replaces };
R 1A5:F, Cl, hydroxyl, sulfydryl, (1-4C) alkyl S (O) p-(p=0,1 or 2) ,-NR 7R 8(R wherein 7And R 8Definition the same) or-OR 10(R wherein 10Definition the same);
M is 0,1 or 2;
R 21Be selected from hydrogen, methyl [optionally replaced by following group: cyano group, trifluoromethyl ,-(wherein W, Rv and Rw are with R above for C=WNRvRw 1The definition of a3), alkoxy carbonyl, CY1, CY2, AR1, AR2, AR2a, AR2b (connecting) or the AR3 of the alkoxyl group of the alkoxy carbonyl of (1-4C) alkoxy carbonyl, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) without nitrogen], (2-10C) alkyl [chooses wantonly on the carbon beyond HET-3 ring nitrogen connects carbon and independently is selected from R by 1-2 1The optional substituent group of a3 definition replaces] and R 14C (O) O (2-6C) alkyl-, R wherein 14Same above R 1The definition of a4, wherein R 14C (O) O is connected carbon carbon in addition with HET-3 ring nitrogen and connects;
R 22For cyano group ,-COR 12,-COOR 12,-CONHR 12,-CON (R 12) (R 13) ,-SO 2R 12(precondition is R 12Be not hydrogen) ,-SO 2NHR 12,-SO 2N (R 12) (R 13) or NO 2, R wherein 12And R 13With hereinafter definition;
R 12And R 13Independently be selected from hydrogen, phenyl (optionally be selected from following substituting group by one or more and replace: halogen, (1-4C) alkyl and (1-4C) alkyl that is replaced by 1-3 or more halogen atoms) and (1-4C) alkyl (optional) by 1-3 or the replacements of more halogen atoms, or for any N (R 12) (R 13) group, R 12And R 13Can form 5-7 unit ring with the nitrogen of their connections, this ring is chosen wantonly has 1 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein said ring can be chosen wantonly and independently is selected from following group by 1-2 and replace: (1-4C) alkyl (choose wantonly on not adjacent carbon and replaced), (3-6C) cycloalkyl, (1-4C) alkyloyl by cyano group, hydroxyl or halogen with nitrogen ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2), AR1, AR2 ,-C=OAR1 ,-C=OAR2 ,-COOAR1 ,-CS (1-4C) alkyl ,-C (=S) O (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-S (O) pAR1 and-S (O) pAR2; Wherein any (1-4C) alkyl chain can be chosen wantonly by (1-4C) alkyl, cyano group, hydroxyl or halogen and replace; P=0,1 or 2;
AR1 is optional phenyl that replaces or the optional naphthyl that replaces;
AR2 is optional 5-or 6-unit unsaturated fully (promptly having maximum degree of unsaturation) the bicyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and connect by ring carbon atom, if perhaps should encircle, can connect by theheterocyclic nitrogen atom not therefore by quaternized;
AR2a is partial hydrogenation type AR2 (is AR2 ring system retained part degree of unsaturation but not fully degree of unsaturation), connect by ring carbon atom, if perhaps should ring not therefore by quaternized, can connect by theheterocyclic nitrogen atom;
AR2b is complete hydrogenation type AR2 (being that the AR2 ring system does not have unsaturation), connects by ring carbon atom or theheterocyclic nitrogen atom;
AR3 is optional 8-, 9-or 10-unit unsaturated fully (promptly having maximum degree of unsaturation) the bicyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and passes through the ring carbon atom connection of arbitrary ring of formation second cycle line;
AR3a is partial hydrogenation type AR3 (is AR3 ring system retained part degree of unsaturation but not fully degree of unsaturation), and the ring carbon atom of the arbitrary ring by constituting second cycle line connects, if perhaps should ring not have therefore by quaternized then can be by the theheterocyclic nitrogen atom connection of arbitrary ring;
AR3b is complete hydrogenation type AR3 (being that the AR3 ring system does not have unsaturation), and the ring carbon atom or the theheterocyclic nitrogen atom of the arbitrary ring by constituting second cycle line connect;
AR4 is optional 13-or 14-unit unsaturated fully (promptly having maximum degree of unsaturation) the tricyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and passes through the ring carbon atom connection of any ring of formation three ring systems;
AR4a is partial hydrogenation type AR4 (is AR4 ring system retained part degree of unsaturation but not fully degree of unsaturation), and the ring carbon atom of any ring by constituting three ring systems connects, if perhaps should ring not have therefore by quaternized then can be by the theheterocyclic nitrogen atom connection of any ring;
CY1 is optional cyclobutyl, cyclopentyl or the cyclohexyl ring that replaces;
CY2 is optional cyclopentenyl or the tetrahydrobenzene basic ring that replaces;
Wherein: AR1; AR2; AR2a; AR2b; AR3; AR3a; AR3b; AR4; AR4a; the optional substituting group of CY1 and CY2 for (on effective carbon atom) at the most 3 independently be selected from following substituting group: (1-4C) alkyl { optionally independently is selected from following substituting group replacement: hydroxyl; trifluoromethyl; (1-4C) (q is 0 to alkyl S (O) q-; 1 or 2); (1-4C) alkoxyl group; (1-4C) alkoxy carbonyl; cyano group; nitro; (1-4C) alkanoylamino;-CONRvRw or-NRvRw}; trifluoromethyl; hydroxyl; halogen; nitro; cyano group; sulfydryl; (1-4C) alkoxyl group; (1-4C) alkanoyloxy; dimethylamino methene amido carbonyl; two (N-(1-4C) alkyl) amino methyl imino-; carboxyl; (1-4C) alkoxy carbonyl; (1-4C) alkyloyl; (1-4C) alkyl SO 2Amino, (2-4C) alkenyl { optional } by carboxyl or (1-4C) alkoxy carbonyl replacement, (2-4C) alkynyl group, (1-4C) alkanoylamino, oxo (=O), sulfo-(=S), (1-4C) alkanoylamino { (1-4C) alkyloyl is optional is replaced by hydroxyl }, (1-4C) (q is 0 to alkyl S (O) q-, 1 or 2) { (1-4C) alkyl is optional by one or more cyano group that independently are selected from, hydroxyl and (1-4C) the group replacement of alkoxyl group },-CONRvRw or-NRvRw[wherein Rv be hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl];
At AR1; AR2; AR2a; AR2b; AR3; AR3a; AR3b; AR4; AR4a; CY1 and CY2 (on effective carbon atom) and alkyl (except as otherwise noted) go up other optional substituting group at the most 3 independently be selected from following substituting group: trifluoromethoxy; benzoyl-amido; benzoyl; phenyl optional by at the most 3 independently be selected from following substituting group and replace: halogen; (1-4C) alkoxyl group or cyano group }; furans; the pyrroles; pyrazoles; imidazoles; triazole; pyrimidine; pyridazine; pyridine isoxazole oxazole; isothiazole; thiazole; thiophene; oxyimino (1-4C) alkyl; (1-4C) Alkoximino (1-4C) alkyl; the alkyl of halogen-(1-4C); (1-4C) alkane sulfonamido;-SO 2NRvRw[wherein Rv is hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl]; And
AR2, AR2a, AR2b, AR3, AR3a, AR3b, the optional substituting group of AR4 and AR4a has (on the available nitrogen atom, such replacement can not cause quaternized) (1-4C) alkyl, (1-4C) alkyl-carbonyl { (1-4C) alkyl and (1-4C) alkyl-carbonyl is optional independently is selected from following substituting group (preferred) replacement: cyano group wherein, hydroxyl, nitro, trifluoromethyl, (1-4C) (q is 0 to alkyl S (O) q-, 1 or 2), (1-4C) alkoxyl group, (1-4C) alkoxy carbonyl, (1-4C) alkanoylamino,-CONRvRw or-NRvRw[wherein Rv be hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl] }, (2-4C) alkenyl, (2-4C) alkynyl group, (1-4C) alkoxy carbonyl or oxo (constituting the N-oxide compound).
2. hydrolyzable ester, wherein R in acceptable salt or the body on claimed formula (I) compound of claim 1 or its pharmacology 1B is HET1, and wherein HET1 is selected from following structure (Za)-(Zf):
Figure A2003801091830013C1
Wherein u and v are 0 or 1 independently, and RT is selected from:
(a) hydrogen;
(b) halogen;
(c) cyano group;
(d) (1-4C) alkyl;
(e) single (1-4C) alkyl that replaces;
(f) two replace (1-4C) alkyl and
(g) three replace (1-4C) alkyl.
3. hydrolyzable ester, wherein R in acceptable salt or the body on claim 1 or 2 claimed formula (I) compounds or its pharmacology 4Be R 4B.
4. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein HET-3 is selected from HET3-T, HET3-V, HET3-Y and HET-3-W.
5. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein HET-3 is selected from HET3-V and HET3-Y.
6. hydrolyzable ester, wherein R in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology 1A is R 1A3.
7. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein group C is group D.
8. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein group C is group E.
9. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of claim 1 or its pharmacology, wherein group C is group E; R 2A and R 6A is a hydrogen; R 2B and R 6B independently is hydrogen or fluorine; And R 4Be HET3-V, R 1B is selected from Zd and Zf, and u and v independently are 0 or 1, and RT is selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.
Each aforementioned claim claimed with hydrolyzable ester in acceptable salt or the body on following formula (Ia) compound or its pharmacology
11. the prodrug of the compound that each aforementioned claim is claimed.
12. a method that produces anti-microbial effect in the warm-blooded animal body, this method comprise on each claimed The compounds of this invention of claim 1-11 of giving described animal effective dose or its pharmacology hydrolyzable ester in acceptable salt or the body.
13. as hydrolyzable ester in acceptable salt or the body on each claimed The compounds of this invention of claim 1-11 of medicine or its pharmacology.
14. the purposes of hydrolyzable ester on the preparation medicine in acceptable salt or the body on each claimed The compounds of this invention of claim 1-11 or its pharmacology, described medicine is used for producing anti-microbial effect in the warm-blooded animal body.
15. a medicinal compositions, said composition comprise on each claimed The compounds of this invention of claim 1-11 or its pharmacology in acceptable salt or the body acceptable diluent or carrier on hydrolyzable ester and the pharmacology.
16. a method for preparing hydrolyzable ester in acceptable salt on the claimed formula of claim 1 (I) compound or its pharmacology or the body, described method comprises the method for a kind of (a)-(i); Then if desired, carry out following steps:
I) slough any protecting group;
Ii) form prodrug (for example hydrolyzable ester in the body); And/or
Iii) form acceptable salt on the pharmacology;
Wherein said method (a)-(i) is:
A) substituting group on another compound of modification the present invention is perhaps introduced substituting group on another compound of the present invention;
B) [wherein X is the leavings group that is used for the palladium coupling, and A is N or C-R to make formula (IIa) compound molecule 3A] with formula (IIb) compound molecule [wherein X ' is for being used for the leavings group of palladium coupling] reaction, wherein X and X ' make and replace aryl-X (or heteroaryl-X) and aryl-X ' (or heteroaryl-X ') key with aryl-aryl, heteroaryl-aryl or heteroaryl-heteroaryl key; And select different X and X ' so that produce required formula (I) cross-linking products;
Figure A2003801091830015C1
C) make heterobiaryl derivative (III) carbamate Cheng the oxazolidone ring with the reacting ethylene oxide Xing of suitable replacement;
Figure A2003801091830015C2
(d) make the reaction of formula (VI) compound and formula (VII) compound:
Wherein X is replaceable substituting group, below is formula (VII):
T-X’
(VII)
Wherein T-X ' is HET1 defined above or HET2, and X ' is that replaceable C connects substituting group; Wherein said substituent X and X ' are chosen as the substituting group complementary pair of the complementary substrate that is suitable as coupled reaction, and this coupled reaction is with for example palladium (O) catalysis of transition metal;
(d (i)) makes formula (VIII) compound react with formula (IX) compound by transition metal-catalyzed:
Figure A2003801091830016C1
Wherein X is replaceable substituting group, below is formula (IX);
(d is (ii)) makes formula (X) compound and the reaction of formula (XI) compound:
Figure A2003801091830016C3
X is replaceable substituting group, below is formula (XI):
T-H
(XI)
Wherein T-H is amine R 7R 8NH, pure R 10OH or contain the azoles of effective ring-NH obtains compound (XIIa), (XIIb) or (XIIc), A is nitrogen or C-R in this case 3A and A ' are optional nitrogen or the carbon that is replaced by one or more radicals R 1a;
(e) make the reaction of formula (XIII) compound and formula (XIV) compound:
Figure A2003801091830017C2
X wherein 1And X 2Be the independent optional heteroatoms combination that is selected from O, N and S that replaces, make C (X 1) X 2Constituting the carboxylic acid derivative substituting group, below is formula (XIV), wherein X 3And X 4Be the independent optional heteroatoms combination that is selected from O, N and S that replaces:
C (X wherein 1) X 2And C (X 3) X 4In one constitute optional hydrazides, thio-hydrazide or amidrazone, hydroximic acid base or the hydroxyl amidine that replaces, and C (X 1) X 2And C (X 3) X 4In another constitutes optional acylating agent, sulfo-acylating agent or the imido acylating agent that replaces, make C (X 1) X 2And C (X 3) X 4Can condense and form 1,2 together, 4-heteroatoms 5-unit heterocycle, it comprises 3 the heteroatoms combinations that are selected from O, N and S, for example thiadiazoles;
(e (i)) makes formula (XV) compound and the reaction of trinitride negative ion source:
Figure A2003801091830018C1
X wherein 2Be replaceable group, obtain tetrazolium (XVI);
Figure A2003801091830018C2
The perhaps nitrile of formula (XVII)
Figure A2003801091830018C3
Can with the trinitride direct reaction, (XVI R1a=H), uses radicals R 1a ≠ H alkanisation then, obtains tetrazolium (XVIIIa) and (XVIIIb) to obtain tetrazolium;
Figure A2003801091830018C4
(f) make the reaction of formula (XIX) compound and formula (XX) compound:
Below be formula (XX):
Figure A2003801091830019C1
C (X wherein 5) X 6And C (X 7) X 8In one constitute optional α-(leavings group replacement) ketone that replaces, wherein leavings group for for example halogen or (alkyl or aryl)-alkylsulfonyl oxygen base-, and C (X 5) X 6And C (X 7) X 8In another constitutes optional acid amides, thioamides or the amidine that replaces, make C (X 5) X 6And C (X 7) X 8Can condense and form 1 together, 3-heteroatoms 5-unit heterocycle, it comprises 2 the heteroatoms combinations that are selected from O, N and S, for example thiazoles;
(g) preparation HET is 1 of optional replacement, 2, the method of the formula of 3-triazole (I) compound is: make the trinitride cycloaddition to acetylene or acetylene equivalent, and for example optional hexamethylene-1 that replaces, 4-diene or optional carrying of replacing can be removed for example ethene of aryl sulfonyl of substituting group;
(h) be formula (I) compound of the 1,2,3-triazoles of 4-replacement for HET, can make amino methyloxazolidinonesas and 1, the preparation of 1-dihalo ketone alkylsulfonyl hydrazone reaction;
Figure A2003801091830019C2
(i) preparation HET is that the method for formula (I) compound of the 1,2,3-triazoles that replaces of 4-is: make azido methyl oxazolidinone and terminal alkyne reaction with Cu (I), the 1,2,3-triazoles of acquisition 4-replacement.
17. method for preparing hydrolyzable ester in acceptable salt on the claimed formula of claim 1 (I) compound or its pharmacology or the body; wherein HET-1 is 4-halogenated 1; 2; the 3-triazole; this method comprises makes the azido methyl oxazolidinone react with vinyl halides base SULPHURYL CHLORIDE in 0 ℃-100 ℃, and this reaction can not have thinner or carries out in inert diluent
18. the method for claim 17, wherein vinyl halides base SULPHURYL CHLORIDE is a 1-chloro-1-ethene SULPHURYL CHLORIDE.
19. compound 1-chloro-1-ethene SULPHURYL CHLORIDE
Figure A2003801091830020C1
20.1-chloro-1-ethene SULPHURYL CHLORIDE is forming purposes in the cycloaddition reaction of 4-chloro-1,2,3-triazoles with trinitride.
21.1-chloro-1-ethene SULPHURYL CHLORIDE is forming purposes in the method for formula (I) compound, wherein R with azide derivatives 1B is 4-chloro-1,2,3-triazoles, perhaps R 4Be 4-chloro-HET3-AB.
22. the medicinal compositions that claim 15 is claimed, wherein said composition comprises VITAMIN.
23. the medicinal compositions that claim 22 is claimed, wherein said VITAMIN are vitamins B.
24. the medicinal compositions that claim 15 is claimed, wherein said composition comprise formula (I) compound combined and effective antibacterials of resisting gram-positive bacterium.
25. the medicinal compositions that claim 15 is claimed, wherein said composition comprise formula (I) compound combined and the antibacterials of effective anti-gram negative bacterium.
CN 200380109183 2002-11-28 2003-11-24 Oxazolidinones as antibacterial agents Pending CN1742009A (en)

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WO2011107019A1 (en) * 2010-03-03 2011-09-09 本溪瑞圣康药物开发有限公司 Antibacterial compounds, preparation methods and uses thereof
CN102803256A (en) * 2010-03-08 2012-11-28 乐高化工生物科学株式会社 Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives
CN103582631A (en) * 2011-06-01 2014-02-12 罗地亚经营管理公司 Method for preparing a fluorinated organic compound
CN106083994A (en) * 2016-04-18 2016-11-09 南京曼杰生物科技有限公司 Substituted oxazolidone soluble derivative and application thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107019A1 (en) * 2010-03-03 2011-09-09 本溪瑞圣康药物开发有限公司 Antibacterial compounds, preparation methods and uses thereof
CN102803256A (en) * 2010-03-08 2012-11-28 乐高化工生物科学株式会社 Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives
CN102803256B (en) * 2010-03-08 2015-03-18 乐高化工生物科学株式会社 Method for preparing (r)-3-(3-fluoro-4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1h)-yl)phenyl)-5-(substituted methyl)oxazolidin-2-one derivatives
CN103582631A (en) * 2011-06-01 2014-02-12 罗地亚经营管理公司 Method for preparing a fluorinated organic compound
CN103582631B (en) * 2011-06-01 2017-10-24 罗地亚经营管理公司 The method for preparing the organic compound of fluorination
CN106083994A (en) * 2016-04-18 2016-11-09 南京曼杰生物科技有限公司 Substituted oxazolidone soluble derivative and application thereof
CN106083994B (en) * 2016-04-18 2019-12-06 南京曼杰生物科技有限公司 Substituted oxazolidinone water-soluble derivatives and uses thereof

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