CN1314813A - Novel isoxazolinone antibacterial agent - Google Patents

Novel isoxazolinone antibacterial agent Download PDF

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CN1314813A
CN1314813A CN99809894A CN99809894A CN1314813A CN 1314813 A CN1314813 A CN 1314813A CN 99809894 A CN99809894 A CN 99809894A CN 99809894 A CN99809894 A CN 99809894A CN 1314813 A CN1314813 A CN 1314813A
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alkyl
optional
phenyl
alkoxyl
replaces
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L·B·斯尼德尔
Z·郑
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/12—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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Abstract

This invention describes isoxazolinone derivatives which possess antibacterial activity and are useful in the treatment of bacterial diseases. More particularly, new isoxazolinones are provided having general formula (I), wherein A and R1 are as described in the specification.

Description

New De isoxazolinone antibacterial agent
Background of the present invention
Invention field
The present invention relates to new De isoxazolinone, use their method and their method of preparation.The invention provides chemical compound or its pharmaceutically acceptable salt by following general formula representative
Figure A9980989400361
Wherein: R 1Be
a)H,
B) C 1-8Alkyl is by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8Acyloxy is optional to be replaced,
C) C 3-6Cycloalkyl, or
D) C 1-8Alkoxyl; L is oxygen or sulfur; A is
a)
b)
C) have 1-3 the first heteroaromatic moiety of heteroatomic 5-that is selected from S, N and O, the first heteroaromatic moiety of wherein said 5-is by carbon atom bonding and can have the benzene of condensing or naphthyl ring in addition, and wherein heteroaromatic moiety is by 1-3 R 8The optional replacement,
D) have the 6-unit heteroaromatic moiety of at least one nitrogen-atoms, wherein said heteroaromatic moiety is by carbon atom bonding, and wherein said 6-unit heteroaromatic moiety can have the benzene of condensing or naphthyl ring in addition, and wherein said heteroaromatic moiety is by 1-3 R 9The optional replacement,
E) B-carboline-3-base or the indolizine base that closes by 6-unit ring key are by 1-3 R 9The optional replacement,
F) Or
G)
Figure A9980989400372
R wherein 2And R 3Each independently is
a)H,
b)F,
c)Cl,
d)Br,
E) C 1-6Alkyl,
f)NO 2,
g)I,
H) C 1-6Alkoxyl,
I)OH,
J) amino,
K) cyano group, or
L) R 2And R 3Be together-O (CH 2) h-O; R wherein 4Be
a)H,
B) C 1-2Alkyl,
C) F, or
D) OH; R 5Be
a)H,
b)CF 3,
C) by the optional C that replaces of one or more halos 1-3Alkyl,
D) by the optional phenyl that replaces of one or more halos,
E) R 5And R 6Be 5-, 6-or the 7-unit ring of following formula together,
F) Wherein D is S, O or NR 86, R wherein 86Be H or C 1-6Alkyl, or
G) work as R 7When being electron withdraw group, R 5And R 6Be together-(CH 2) K-; R 6And R 7Be identical or different in all cases, be
A) electron withdraw group,
b)H,
c)CF 3,
D) by the optional C that replaces of a halo 1-3Alkyl,
E) phenyl, condition are R 6And R 7In at least one is an electron withdraw group, or
F) R 6And R 7Be 5-, 6-or the 7-unit ring of following formula together, U is
a)CH 2,
b)O,
C) S or
D) NR 16R 16Be
A) H or
B) C 1-5Alkyl; R wherein 8Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
l)-NR 17R 18,
M)
Figure A9980989400392
R wherein 87Be H or C 1-6Alkyl,
N) C 1-6Alkyl is by OH, sulfonamides, C 1-5Alkoxyl, C 1-5Acyl group or-NR 17R 18The optional replacement,
O) C 2-8Alkyl is by one or two R 19The optional replacement,
P) phenyl is by one or two R 19The optional replacement,
Q) have 1-3 the saturated or unsaturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N and O, by one or two R 19The optional replacement, or R 17And R 18Be identical or different in all cases, be
a)H,
B) C 1-4Alkyl,
C) C 5-6Cycloalkyl, or
D) R 17And R 18With nitrogen-atoms is the saturated or unsaturated heterocyclic moiety of 5-or 6-unit, and this part is optional to have the another one hetero atom that is selected from S, N, O, can choose wantonly by following group to replace (being included on the another one nitrogen-atoms): C 1-3The heteroaromatic moiety of alkyl, formoxyl, the 5-that contains 1-3 O, N or S or 6-unit, R wherein 88And R 89Each independently is hydrogen or C 1-6Alkyl, SO 2R 90, R wherein 90Be H or C 1-6Alkyl or by the optional C that replaces of one or more F, Cl or OH 1-3Acyl group; R 19Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2，
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
L) C 1-6Alkyl is by OH, C 1-5Alkoxyl, C 1-5Acyl group or-NR 17R 18The optional replacement,
M) phenyl,
n)-C(=O)NR 20R 21,
o)-NR 17R 18,
p)-N(R 20)(-SO 2R 22),
Q)-SO 2-NR 20R 21, or
R)-S (=O) iR 22R 20And R 21Be identical or different in all cases, be
a)H,
B) C 1-6Alkyl, or
C) phenyl; R 22Be
A) C 1-4Alkyl, or
B) by C 1-4The optional phenyl that replaces of alkyl; R wherein 9Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3
g)NO 2
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
l)-NR 23R 24,
M) C 1-6Alkyl is by OH, C 1-5Alkoxyl, C 1-5Acyl group or-NR 23R 24The optional replacement,
N) by one or two R 25The optional C that replaces 2-8The alkenyl phenyl,
O) by one or two R 25The optional phenyl that replaces,
P) have 1-3 the saturated or undersaturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N and O, by one or two R 25The optional replacement, or
Q) R 23And R 24Be identical or different in all cases, be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl, or
G) R 23And R 24With nitrogen-atoms is the saturated heterocyclic moiety of 5-or 6-unit, and this part can be chosen wantonly has the hetero atom that another is selected from S, N, O, equally also can replace (being included on another nitrogen-atoms) by following substituent group: phenyl, pyrimidine radicals, C 1-3Alkyl or C 1-3Acyl group; R 25Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group
K) C 1-6Acyl group,
L) phenyl,
M) C 1-6Alkyl is by OH, azido, C 1-5Alkoxyl, C 1-5Acyl group ,-NR 32R 33,-SR 34,-O-SO 2R 35Or
Figure A9980989400431
The optional replacement,
n)-C(=O)NR 26R 27,
o)-NR 23R 24,
p)-N(R 26)(-SO 2R 22),
Q)-SO 2-NR 26R 27, or
r)-S(=O) iR 22,
S)-CH=N-R 28, or
T)-CH (OH)-SO 3R 31R 22As defined above; R 26And R 27Be identical or different in all cases, be
a)H,
B) C 1-6Alkyl,
C) phenyl, or
D) tolyl;
R 28Be
a)OH,
B) benzyloxy,
c)-NH-C(=O)-NH 2,
D)-NH-C (=S)-NH 2, or
E)-NH-C (=NH)-NR 29R 30R 29And R 30Be identical or different in all cases, be
A) H, or
B) by phenyl or the optional C that replaces of pyridine radicals 1-4Alkyl; R 31Be
A) H, or
B) sodium ion; R 32And R 33Be identical or different in all cases, be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl,
G) R 32And R 33Be to have 1-3 the saturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N, O together, optional by following substituent group replacement (being included on the described nitrogen-atoms): phenyl, pyrimidine radicals, C 1-3Alkyl or C 1-3Acyl group,
H)-P (O) (OR 37) (OR 38), or
I)-SO 2-R 39R 34Be
Figure A9980989400441
R 35Be C 1-3Alkyl; R 36Be
A) C 1-6Alkoxy carbonyl, or
B) carboxyl; R 37And R 38Be identical or different in all cases, be
A) H, or
B) C 1-3Alkyl; R 39Be
A) methyl,
B) phenyl, or
C) tolyl; Wherein K is
a)O,
B) S, or
C) NR 40, R wherein 40Be hydrogen, formoxyl, C 1-4Alkyl, C 1-4Acyl group, phenyl, C 3-6Cycloalkyl ,-P (O) (OR 37) (OR 38) or-SO 2-R 39, R wherein 37, R 38And R 39As defined above; R 10, R 11, R 12, R 13, R 14And R 15Be identical or different in all cases, be
a)H,
B) formoxyl,
C) carboxyl,
D) C 1-6Alkoxy carbonyl,
E) C 1-8Alkyl,
F) C 2-8Alkenyl, wherein substituent group (e) and (f) can be by OH, halo, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl or by the optional phenyl that replaces of halo optional replacement,
G) have 6-10 carbon atom, the optional aromatics part that replaces by following substituent group: carboxyl, halo ,-CN, formoxyl, CF 3, NO 2, C 1-6Alkyl, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl;
h)-NR 42R 43,
i)OR 44,
j)-S(=O) i-R 45,
K)-SO 2-N (R 46) (R 47), or
L) group of following formula:
Figure A9980989400461
R 19As defined above; T is
a)O,
B) S, or
C) SO 2R 42And R 43Be identical or different in all cases, be
a)H,
B) C 3-6Cycloalkyl,
C) phenyl,
D) C 1-6Acyl group,
E) by OH, C 1-6Alkoxyl (this alkoxyl can be by OH, have 1-3 is selected from the 5-of atom of S, N and O or the aromatic heterocycle of 6-unit partly replaces), by OH, CF 3, halo ,-NO 2, C 1-4Alkoxyl ,-NR 48R 49The optional phenyl that replaces or
Figure A9980989400462
The optional C that replaces 1-8Alkyl, or f)
Figure A9980989400463
Or g)
Figure A9980989400464
V is
a)O,
B) CH 2, or
C) NR 56R 48And R 49Be identical or different in all cases, be
A) H, or
B) C 1-4Alkyl; R 54Be
a)OH,
B) C 1-4Alkoxyl, or
C)-NR 57R 58R 55Be
A) H, or
B) by indyl, OH, sulfydryl, imidazole radicals, methyl mercapto, amino, by OH ,-C (=O)-NH 2,-CO 2H or-C (=NH)-NH 2The optional C that replaces of the optional phenyl that replaces 1-7Alkyl; R 56Be
a)H,
B) phenyl, or
C) by the optional C that replaces of OH 1-6Alkyl; R 57And R 58Be identical or different in all cases, be
a)H,
B) C 1-5Alkyl,
C) C 1-3Cycloalkyl, or
D) phenyl; R 44Be
A) by C 1-6Alkoxyl or C 1-6Hydroxyl, C 3-6Cycloalkyl, has the partly optional C that replaces of the optional benzo-condensed heterocycle of 6-unit aromatics of 1-3 nitrogen-atoms 1-8Alkyl, this benzo-fused heterocycle part can by one or two-NO 2, CF 3, halo ,-CN, OH, C 1-5Alkyl, C 1-5Alkoxyl or C 1-5Acyl substituted,
b)
C) phenyl, or
D) pyridine radicals; R 45Be
A) C 1-16Alkyl,
B) C 2-16Alkenyl, wherein substituent group (a) and (b) can be by C 1-6Alkoxy carbonyl or have that 1-3 is selected from 5-, the 6-of the atom of S, N and O or 7-unit aromatic heterocycle is partly optional replaces,
C) have the aromatics part of 6-10 carbon atom, or
D) have 5-, 6-or the 7-unit aromatic heterocycle part that 1-3 is selected from the atom of S, N and O, wherein substituent group (c) and (d) can by carboxyl, halo ,-CN, formoxyl, CF 3,-NO 2, C 1-6Alkyl, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl is optional to be replaced; R 46And R 47In all cases can be identical or different, be
a)H,
B) phenyl,
C) C 1-6Alkyl, or
D) benzyl; R 50And R 51Be identical or different in all cases, be
a)H,
b)OH,
C) by-NR 48R 49The optional C that replaces 1-6Alkyl, wherein R 48And R 49As defined above,
D) R 50And R 51Be together=O; R 52Be
A) have the aromatics part of 6-10 carbon atom,
B) have 1-3 and be selected from the 5-of atom of S, N and O or the optional benzo of aromatics-condensed heterocycle part of 6-unit, wherein substituent group (a) and (b) equally can-NO individual by 1-3 2, CF 3, halo ,-CN, OH, phenyl, C 1-5Alkyl, C 1-5Alkoxyl or C 1-5Acyl group is optional to be replaced,
C) morpholinyl,
d)OH,
E) C 1-6Alkoxyl,
F)-NR 48R 49, R wherein 48And R 49As defined above,
G)-C (=O)-R 59, or
H)
Figure A9980989400491
R 53Be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl,
G)-P (O) (OR 37) (OR 38), or
H)-SO 2R 39, R wherein 37, R 38And R 39As defined above; R 59Be
A) morpholinyl,
B) OH, or
C) C 1-6Alkoxyl; H is 1,2 or 3; I is 0,1 or 2; J is 0 or 1; K is 3,4 or 5; R is 1,2,3,4,5 or 6; T is 0,1,2,3,4,5 or 6; U is 1 or 2; With Q be
A) hydrogen;
B) halo;
c)NO 2,
d)N 3,
E) C 1-6Alkylthio group,
f)
Figure A9980989400501
g)
Figure A9980989400502
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
Figure A9980989400503
l)
Figure A9980989400504
M)-sulfonamides (H 2NSO 2-),
n)-NHOH,
o)
Figure A9980989400505
P) heteroaryl
Figure A9980989400506
Wherein heteroaryl is to have 1-3 heteroatomic 5-or 6-unit aromatic heterocyclic group that is selected from O, N or S, q) R) amino, s) C 1-C 6Alkyl amino-, t) two (C 1-C 6Alkyl) amino-u)
Figure A9980989400512
R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl,
v)OH,
W) cyano group,
X) hydroxyl (C 1-C 6Alkyl),
y)
Figure A9980989400513
Z)
Figure A9980989400514
Wherein r is 1-6,
aa)
Figure A9980989400515
bb)
Cc)
Figure A9980989400517
R wherein 84Be hydrogen or C 1-6Alkyl,
Dd)
Figure A9980989400518
R wherein 85Be hydrogen, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl;
Ee)
Figure A9980989400519
R wherein 84Be hydrogen or C 1-6Alkyl, ff) replace or unsubstituted C 6-C 10Aryl moiety gg) has 1-3 atom, that replace or unsubstituted monocycle or dicyclo, saturated or undersaturated heterocyclic moiety that is selected from O, N or S, and described ring is bonded on the phenyl substituent by ring carbon or nitrogen,
Hh) have 1-3 and be selected from the heteroatomic monocycle of O, N or S or the replacement or the unsubstituted heteroaromatic moiety of dicyclo, described ring is bonded on the phenyl substituent by ring carbon or nitrogen, and wherein this heteroaromatic moiety can have condensed benzene or naphthalene nucleus in addition; Described substituent group for example p, q, ff, gg and hh partly is selected from following 1 or 2 group: 1) halo, 2) C 1-6Alkyl, 3) NO 2, 4) and N 3, 5) 6)
Figure A9980989400522
7) formoxyl, 8) 9)
Figure A9980989400524
10) heteroaryl
Figure A9980989400525
Wherein heteroaryl is to have 1-3 to be selected from the heteroatomic 5-of O, N or S or the aromatic heterocyclic group of 6-unit, 11) 12) R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl, 13) OH, 14) hydroxyl (C 1-C 6Alkyl), 15)
Figure A9980989400531
16)
Figure A9980989400532
Wherein r is 1-6,17) 18)-CH 2-R 80, R wherein 80Be
A)-OR 32, R wherein 32As defined above,
B)-SR 32, R wherein 32As defined above,
C)-NR 32R 33, R wherein 32And R 33As defined above, or
D) contain the 5-of 1-4 O, S or N atom or the heteroaromatic of 6-unit, 19) R wherein 84 as defined above, and 20) cyano group, 21) carboxyl, 22) CF 3, 23)
Figure A9980989400535
24) Wherein phenyl moiety can be by halo or (C 1-C 6) the optional replacement of alkyl, 25) R wherein 60And R 61As defined above, 26) Or
Figure A9980989400539
, R wherein 91Be to have the 5-of 1-3 O, N or S or the aromatic heterocyclic group of 6-unit, 27)
Figure A99809894005310
28) R wherein 85As defined above, 29)
Figure A9980989400541
R wherein 99, R 100And R 101Each independently is C 1-6Alkyl; Or Q and R 1And R 2One of formation-O-CH 2-O.
These derivants are as antibacterial, can have the pathogen of imitating anti-many mankind and beasts, comprise gram positive bacteria for example staphylococcus, streptococcus and the enterococcus of multiple resistance, for example enterococcus faecalis of the staphylococcus aureus of methicillin-resistant or anti-Lyphocin (Fujisawa).
The explanation of prior art
Herbicide De isoxazolinone before being used on a small quantity emerge is arranged in the document.For example in U.S. patent 4,065, open 2-methyl-4-in 463 (trifluoro acute pyogenic infection of nails base--tolyl)-3-isoxazoline-5-ketone and 2-methyl-4-(chloro--tolyl)-3-isoxazoline-5-ketone is used to prevent the growth of weeds, and this grass has injurious effects to crop growth.
Figure A9980989400542
U.S. patent 4,000, and 155 disclose relevant chemical compound 1, and 2-dimethyl-4-(trichlorine acute pyogenic infection of nails base--tolyl)-3-pyrazolin-5-one is used for same purposes.
Figure A9980989400543
The applicant does not also know any document that discloses these chemical compounds as the broad spectrum antimicrobicide purposes.Different member ring systems is disclosed in WO98/07708, its open purposes as antibacterial De isoxazoline derivative,
Figure A9980989400544
Wherein W is that the aryl that replaces or heteroaryl system and V are H or by F, Cl, OH, C 1-C 4The optional C that replaces of alkoxyl or acyloxy 1-C 4Alkyl.
Show that below De oxazolidone II is a well-known class Orally active antibacterial.Prior art comprises the relevant a large amount of document of these chemical compounds, and wherein Y and Z can comprise various substituent groups.Concrete substituted oxazolidinone is disclosed in following document: the U.S patent No. 4,705,799 and 5,523,403 (the phenyl 2-oxazolidones of replacement), the U.S. patent No. 4,948,801; 5,254,577; With 5,130,316 (aryl Ben oxazolidine chemical compound) and european patent applications 0,697,412; 0,694,544; 0694,543; With 0,693,491 (5-9 unit heteroaryl replaces the De oxazolidone).
Figure A9980989400551
In addition, reported that also some have the chemical compound of furanone ring antibacterial activity, that contain replacement.WO97/14690 is open
Figure A9980989400552
Wherein T is hydroxyl or NHC (O) C 1-C 4Alkyl, each independently is hydrogen or fluoro for M and L, and each independently is hydrogen or methyl for G and H, and K-J is formula C=CH, CHCH 2Or C (OH) CH 2, I is O, SO, SO 2Or the nitrogen that replaces, Q-R is CH 2-CH 2Or CH=CH 2The furanone of other replacement is open in U.S. patent 5,708,169, WO97/43280 and WO97/10235.
The present invention's general introduction
Have now found that some replacement De isoxazolinones are effective antibacterial.The present invention especially comprises formula I chemical compound or its pharmaceutically acceptable salt: Wherein: R 1Be
a)H,
B) by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl,
C) C 3-6Cycloalkyl, or
D) C 1-8Alkoxyl; L is oxygen or sulfur; A is
a)
b)
Figure A9980989400563
C) have 1-3 the first heteroaromatic moiety of heteroatomic 5-that is selected from S, N and O, the first heteroaromatic moiety of wherein said 5-is by carbon atom bonding and can have the benzene of condensing or naphthyl ring in addition, and wherein heteroaromatic moiety is by 1-3 R 8The optional replacement,
D) have the 6-unit heteroaromatic moiety of at least one nitrogen-atoms, wherein said heteroaromatic moiety is by carbon atom bonding, and wherein said 6-unit heteroaromatic moiety can have the benzene of condensing or naphthyl ring in addition, and wherein said heteroaromatic moiety is by 1-3 R 9The optional replacement,
E) B-carboline-3-base or the indolizine base that closes by 6-unit ring key are by 1-3 R 9The optional replacement, f) Or g) R wherein 2And R 3Each independently is
a)H,
b)F,
c)Cl,
d)Br,
E) C 1-6Alkyl,
f)NO 2,
g)I,
H) C 1-6Alkoxyl,
i)OH,
J) amino,
K) cyano group, or
L) R 2And R 3Be together-O (CH 2) h-O; R wherein 4Be
a)H,
B) C 1-2Alkyl,
C) F, or
D) OH, R 5Be
a)H,
b)CF 3,
C) by the optional C that replaces of one or more halos 1-3Alkyl,
D) by the optional phenyl that replaces of one or more halos,
E) R 5And R 6Be 5-, 6-or the 7-unit ring of following formula together,
Figure A9980989400581
F)
Figure A9980989400582
Wherein D is S, O or NR 86, R wherein 86Be H or C 1-6Alkyl, or
G) work as R 7When being electron withdraw group, R 5And R 6Be together-(CH 2) k-; R 6And R 7Be identical or different in all cases, be
A) electron withdraw group,
b)H,
c)CF 3,
D) by the optional C that replaces of a halo 1-3Alkyl,
E) phenyl, condition are R 6And R 7In at least one is an electron withdraw group, or
F) R 6And R 7Be 5-, 6-or the 7-unit ring of following formula together,
Figure A9980989400583
U is
a)CH 2,
b)O,
C) S or,
D) NR 16R 16Be
A) H or
B) C 1-5Alkyl; R wherein 8Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
l)-NR 17R 18,
M) R wherein 87Be H or C 1-6Alkyl,
N) by OH, sulfonamides, C 1-5Alkoxyl, C 1-5Acyl group or-NR 17R 18The optional C that replaces 1-6Alkyl,
O) by one or two R 19The optional C that replaces 2-8Alkyl,
P) by one or two R 19The optional phenyl that replaces,
Q) have 1-3 the saturated or unsaturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N and O, by one or two R 19The optional replacement, or R 17And R 18Be identical or different in all cases, be
a)H,
B) C 1-4Alkyl,
C) C 5-6Cycloalkyl, or
D) R 17And R 18With nitrogen-atoms is the saturated or unsaturated heterocyclic moiety of 5-or 6-unit, and this part is optional to have the another one hetero atom that is selected from S, N, O, can choose wantonly equally by following group to replace (being included on the another one nitrogen-atoms): C 1-3The heteroaromatic moiety of alkyl, formoxyl, the 5-that contains 1-3 O, N or S or 6-unit, R wherein 88And R 89Each independently is hydrogen or C 1-6Alkyl, SO 2R 90, R wherein 90Be H or C 1-6Alkyl or by the optional C that replaces of one or more F, Cl or OH 1-3Acyl group; R 19Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
L) by OH, C 1-5Alkoxyl, C 1-5Acyl group or-NR 17R 18The optional C that replaces 1-6Alkyl,
M) phenyl,
n)-C(=O)NR 20R 21,
o)-NR 17R 18,
p)-N(R 20)(-SO 2R 22),
Q)-SO 2-NR 20R 21, or
R)-S (=O) iR 22R 20And R 21Be identical or different in all cases, be
a)H,
B) C 1-6Alkyl, or
C) phenyl; R 22Be
A) C 1-4Alkyl, or
B) by C 1-4The optional phenyl that replaces of alkyl; R wherein 9Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
l)-NR 23R 24,
M) by OH, C 1-5Alkoxyl, C 1-5Acyl group or-NR 23R 24The optional C that replaces 1-6Alkyl,
N) by one or two R 25The optional C that replaces 2-8The alkenyl phenyl,
O) by one or two R 25The optional phenyl that replaces,
P) have 1-3 the saturated or undersaturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N and O, by one or two R 25The optional replacement, or
Q)
Figure A9980989400611
R 23And R 24Be identical or different in all cases, be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl, or
G) R 23And R 24With nitrogen-atoms is the saturated heterocyclic moiety of 5-or 6-unit, and this part can be chosen wantonly has the hetero atom that another is selected from S, N, O, equally also can replace (being included on another nitrogen-atoms) by following substituent group: phenyl, pyrimidine radicals, C 1-3Alkyl or C 1-3Acyl group; R 25Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group
K) C 1-6Acyl group,
L) phenyl,
M) C 1-6Alkyl is by OH, azido, C 1-5Alkoxyl, C 1-5Acyl group ,-NR 32R 33,-SR 34,-O-SO 2R 35Or The optional replacement,
n)-C(=O)NR 26R 27,
o)-NR 23R 24,
p)-N(R 26)(-SO 2R 22),
Q)-SO 2-NR 26R 27, or
r)-S(=O) iR 22,
S)-CH=N-R 28, or
T)-CH (OH)-SO 3R 31R 22As defined above; R 26And R 27Be identical or different in all cases, be
a)H,
B) C 1-6Alkyl,
C) phenyl, or
D) tolyl; R 28Be
a)OH,
B) benzyloxy,
c)-NH-C(=O)-NH 2,
D)-NH-C (=S)-NH 2, or
E)-NH-C (=NH)-NR 29R 30R 29And R 30Be identical or different in all cases, be
A) H, or
B) by phenyl or the optional C that replaces of pyridine radicals 1-4Alkyl; R 31Be
A) H, or
B) sodium ion; R 32And R 33Be identical or different in all cases, be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl,
G) R 32And R 33Be to have 1-3 the saturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N, O together, optional by following substituent group replacement (being included on the described nitrogen-atoms): phenyl, pyrimidine radicals, C 1-3Alkyl or C 1-3Acyl group,
H)-P (O) (OR 37) (OR 38), or
I)-SO 2-R 39R 34Be
Figure A9980989400641
R 35Be C 1-3Alkyl; R 36Be
A) C 1-6Alkoxy carbonyl, or
B) carboxyl; R 37And R 38Be identical or different in all cases, be
A) H, or
B) C 1-3Alkyl; R 39Be
A) methyl,
B) phenyl, or
C) tolyl; Wherein K is
a)O,
B) S, or
C) NR 40, R wherein 40Be hydrogen, formoxyl, C 1-4Alkyl, C 1-4Acyl group, phenyl, C 3-6Cycloalkyl ,-P (O) (OR 37) (OR 38) or-SO 2-R 39, R wherein 37, R 38And R 39As defined above; R 10, R 11, R 12, R 13, R 14And R 15Be identical or different in all cases, be
a)H,
B) formoxyl,
C) carboxyl,
D) C 1-6Alkoxy carbonyl,
E) C 1-8Alkyl,
F) C 2-8Alkenyl, wherein substituent group (e) and (f) can be by OH, halo, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Oxygen base carbonyl or by the optional phenyl that replaces of halo optional replacement,
G) have 6-10 carbon atom, the optional aromatics part that replaces by following substituent group: carboxyl, halo ,-CN, formoxyl, CF 3, NO 2, C 1-6Alkyl, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl;
h)-NR 42R 43,
i)OR 44,
j)-S(=O) i-R 45,
K)-SO 2-N (R 46) (R 47), or
L) group of following formula:
Figure A9980989400651
R 19As defined above; T is
a)O,
B) S, or
C) SO 2R 42And R 43Be identical or different in all cases, be
a)H,
B) C 3-6Cycloalkyl,
C) phenyl,
D) C 1-6Acyl group,
E) by OH, C 1-6Alkoxyl (this alkoxyl can be by OH, have 1-3 is selected from the 5-of atom of S, N and O or the aromatic heterocycle of 6-unit partly replaces), by OH, CF 3, halo ,-NO 2, C 1-4Alkoxyl ,-NR 48R 49The optional phenyl that replaces or
Figure A9980989400661
The optional C that replaces 1-8Alkyl,
F) Or
G)
Figure A9980989400663
V is
a)O,
B) CH 2, or
C) NR 56R 48And R 49Be identical or different in all cases, be
A) H, or
B) C 1-4Alkyl; R 54Be
a)OH,
B) C 1-4Alkoxyl, or
C)-NR 57R 58R 55Be
A) H, or
B) by indyl, OH, sulfydryl, imidazole radicals, methyl mercapto, amino, by OH ,-C (=O)-NH 2,-CO 2H or-C (=NH)-NH 2The optional C that replaces of the optional phenyl that replaces 1-7Alkyl; R 56Be
a)H,
B) phenyl, or
C) by the optional C that replaces of OH 1-6Alkyl; R 57And R 58Be identical or different in all cases, be
a)H,
B) C 1-5Alkyl,
C) C 1-3Cycloalkyl, or
D) phenyl; R 44Be
A) by C 1-6Alkoxyl or C 1-6Hydroxyl, C 3-6Cycloalkyl, has the partly optional C that replaces of the optional benzo-condensed heterocycle of 6-unit aromatics of 1-3 nitrogen-atoms 1-8Alkyl, this benzo-fused heterocycle part equally can by one or two-NO 2, CF 3, halo ,-CN, OH, C 1-5Alkyl, C 1-5Alkoxyl or C 1-5Acyl substituted,
b)
Figure A9980989400671
C) phenyl, or
D) pyridine radicals; R 45Be
A) C 1-16Alkyl,
B) C 2-16Alkenyl, wherein substituent group (a) and (b) can be by C 1-6Alkoxy carbonyl or have that 1-3 is selected from 5-, the 6-of the atom of S, N and O or 7-unit aromatic heterocycle is partly optional replaces,
C) have the aromatics part of 6-10 carbon atom, or
D) have 5-, 6-or the 7-unit aromatic heterocycle part that 1-3 is selected from the atom of S, N and O, wherein substituent group (c) and (d) can by carboxyl, halo ,-CN, formoxyl, CF 3,-NO 2, C 1-6Alkyl, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl is optional to be replaced; R 46And R 47In all cases can be identical or different, be
a)H,
B) phenyl,
C) C 1-6Alkyl, or
D) benzyl; R 50And R 51Be identical or different in all cases, be
a)H,
b)OH,
C) by-NR 48R 49The optional C that replaces 1-6Alkyl, wherein R 48And R 49As defined above,
D) R 50And R 51Be together=O; R 52Be
A) have the aromatics part of 6-10 carbon atom,
B) have 1-3 and be selected from the 5-of atom of S, N and O or the optional benzo of aromatics-condensed heterocycle part of 6-unit, wherein substituent group (a) and (b) can be selected from-NO by 1-3 is individual equally 2, CF 3, halo ,-CN, OH, phenyl, C 1-5Alkyl, C 1-5Alkoxyl or C 1-5The group of acyl group is optional to be replaced,
C) morpholinyl,
d)OH,
E) C 1-6Alkoxyl,
F)-NR 48R 49, R wherein 48And R 49As defined above,
G)-C (=O)-R 59, or
H)
Figure A9980989400691
R 53Be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl,
G)-P (O) (OR 37) (OR 38), or
H)-SO 2R 39, R wherein 37, R 38And R 39As defined above; R 59Be
A) morpholinyl,
B) OH, or
C) C 1-6Alkoxyl; H is 1,2 or 3; I is 0,1 or 2; J is 0 or 1; K is 3,4 or 5; R is 1,2,3,4,5 or 6; T is 0,1,2,3,4,5 or 6; U is 1 or 2; With Q be
A) hydrogen;
B) halo;
c)NO 2,
d)N 3,
E) C 1-6Alkylthio group,
f)
g)
Figure A9980989400702
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
Figure A9980989400703
l)
M)-sulfonamides (H 2NSO 2-),
n)-NHOH,
o)
Figure A9980989400705
P) heteroaryl
Figure A9980989400706
Wherein heteroaryl is to have heteroatomic 5-or a 6-unit aromatic heterocyclic group that 1-3 is selected from O, N or S,
q)
Figure A9980989400707
R) amino,
S) C 1-C 6Alkyl amino-,
T) two (C 1-C 6Alkyl) amino-
U) R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl,
v)OH,
W) cyano group,
X) hydroxyl (C 1-C 6Alkyl),
y)
Figure A9980989400711
Z)
Figure A9980989400712
Wherein r is 1-6,
aa)
Figure A9980989400713
bb)
Figure A9980989400714
Cc) R wherein 84Be hydrogen or C 1-6Alkyl,
Dd)
Figure A9980989400716
R wherein 85Be hydrogen, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl;
Ee) R wherein 84Be hydrogen or C 1-6Alkyl,
Ff) replace or unsubstituted C 6-C 10Aryl moiety,
Gg) have 1-3 atom, that replace or unsubstituted monocycle or dicyclo, saturated or undersaturated heterocyclic moiety that is selected from O, N or S, described ring is bonded on the phenyl substituent by ring carbon or nitrogen,
Hh) have 1-3 and be selected from the heteroatomic monocycle of O, N or S or the replacement or the unsubstituted heteroaromatic moiety of dicyclo, described ring is bonded on the phenyl substituent by ring carbon or nitrogen, and wherein this heteroaromatic moiety can have condensed benzene or naphthalene nucleus in addition; Described substituent group for example p, q, ff, gg and hh partly is selected from following 1 or 2 group: 1) halo, 2) C 1-6Alkyl, 3) NO 2, 4) and N 3, 5)
Figure A9980989400721
6) 7) formoxyl, 8)
Figure A9980989400723
9)
Figure A9980989400724
10) heteroaryl
Figure A9980989400725
Wherein heteroaryl is to have 1-3 to be selected from the heteroatomic 5-of O, N or S or the aromatic heterocyclic group of 6-unit, 11)
Figure A9980989400726
12) R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl, 13) OH, 14) hydroxyl (C 1-C 6Alkyl), 15) 16) Wherein r is 1-6,17)
Figure A99809894007210
18)-CH 2-R 80, R wherein 80Be
A)-OR 32, R wherein 32As defined above,
B)-SR 32, R wherein 32As defined above,
C)-NR 32R 33, R wherein 32And R 33As defined above, or
D) contain the 5-of 1-4 O, S or N atom or the heteroaromatic of 6-unit, 19)
Figure A9980989400731
R wherein 84As defined above, 20) cyano group, 21) carboxyl, 22) CF 3, 23) 24)
Figure A9980989400733
Wherein phenyl moiety can be by halo or (C 1-C 6) the optional replacement of alkyl, 25) R wherein 60And R 61As defined above, 26) Or R wherein 91Be to have the 5-of 1-3 O, N or S or the aromatic heterocyclic group of 6-unit, 27) 28)
Figure A9980989400738
R wherein 85As defined above, 29) R wherein 99, R 100And R 101Each independently is C 1-6Alkyl; Or Q and R 1And R 2One of formation-O-CH 2-O.
The compounds of this invention is new and represents the antibacterial of newtype.They were with report De oxazolidone was different with the isoxazoline antibiotic in the past, because they contain the isoxazolinone member ring systems.They are different with the isoxazoline herbicides of prior art, must be by amide moieties replacement as defined above because should encircle nitrogen.
The formula I chemical compound is to be used for the treatment of the infection by the enterococcus faecalis of the staphylococcus aureus of various antibacterials, especially anti--methicillin and anti--vancomycin of human and other animal.
The present invention also comprises preparation and contains the method for the Pharmaceutical composition of above-claimed cpd and pharmaceutically acceptable carrier or diluent.
Definition
Here used term " pharmaceutically acceptable salt " expression comprises nontoxic and inorganic or organic acid acid-addition salts, for example with the salt of sour example hydrochloric acid, phosphoric acid, sulphuric acid, maleic acid, acetic acid, citric acid, succinic acid, benzoic acid, fumaric acid, mandelic acid, right-toluene-sulfonic acid, methanesulfonic acid, ascorbic acid, lactic acid, gluconic acid, three fluoro acetic acid, hydroiodic acid, hydrobromic acid etc.These salt can be hydrated forms.
Term " halo " or " halogen " comprise chloro, bromo, fluoro and iodo, preferred chloro or fluoro.
Here used aliphatic series " alkyl " is meant the straight or branched of the carbon atom of specific quantity, for example with regard to C 1-C 6Alkyl, this alkyl group can have 1 to 6 carbon atom.
Equally, as term " C 2-C 8Alkenyl " refer to have at least two kiki alkenyl group key, that the specific quantity carbon atom is arranged, " C 2-C 8Alkynyl group " refer to have a triple-linked alkynyl group group that the specific quantity carbon atom is arranged etc. at least.
Term " acyloxy " removes explanation in addition, refers to The group of type, wherein this alkyl can have the carbon atom of specific quantity, for example C 1-C 6Alkoxyl has 1-6 carbon atom.When unlimited timing, the length of carbon is 1-6 carbon atom.
Remove explanation in addition, term " aryl " refers to aromatic carbocyclic, for example phenyl and naphthyl.
Here used " heteroaromatic " refers to have one or more O of being selected from, N, the aromatic heterocycle part of the atom of S, pyridine for example, thiophene, furan, pyrimidine, the 2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, the 2-pyrimidine radicals, the 4-pyrimidine radicals, the 5-pyrimidine radicals, the 3-pyridazinyl, the 4-pyridazinyl, the 3-pyrazinyl, the 2-quinolyl, the 3-quinolyl, the 1-isoquinolyl, the 3-isoquinolyl, the 2-imidazole radicals, the 4-imidazole radicals, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 3-pyrazolyl, the 4-pyrazolyl, the 5-pyrazolyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 2-indyl, the 3-indyl, the 3-indazolyl, the 2-benzoxazolyl, the 2-[4-morpholinodithio base, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyrrole radicals, the 3-pyrrole radicals, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,4-thiadiazoles 3-base, 1,2,4-thiadiazoles-5-base, 1,2,4-thiazole-3-base, 1,2,4-thiazole-5-base, 1,2,3,4-tetrazolium-5-base, the 5-oxazolyl, the 1-pyrrole radicals, the 1-pyrazolyl, 1,2, the 3-triazol-1-yl, 1,2, the 4-triazol-1-yl, the 1-tetrazole radical, the 1-indyl, the 1-indazolyl, the 2-isoindolyl, the 1-purine radicals, the 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl.
Saturated or unsaturated heterocyclic group can have 1-3 atom that is selected from O, N and S, for example dioxolanes, imidazolidine, dithiolane, oxathiolane, oxazolidine, piperidyl, piperazinyl, morpholinyl or thio-morpholinyl or corresponding unsaturated heterocycle group.
In described heterocyclic moiety, possible nitrogen and/or sulphur atom can be oxidized, and the chemical compound of these oxidations is included in the formula I chemical compound.
Describe in detail
The preferred embodiment of the invention is the formula I chemical compound, and wherein A is
Figure A9980989400751
Q wherein 1, R 2And R 3As defined above.
The preferred embodiment of the present invention comprises following formula: compound or its pharmaceutically acceptable salt,
Figure A9980989400752
R wherein 1Be H, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl; R 2And R 3Each independently is
a)H,
b)F,
c)Cl,
d)Br,
E) C 1-6Alkyl,
f)NO 2,
g)I,
H) C 1-6Alkoxyl,
i)OH,
J) amino, or
K) cyano group; With Q be
A) hydrogen,
B) halo,
c)NO 2,
d)N 3,
E) C 1-C 6Alkylthio group,
f)
g)
Figure A9980989400762
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
Figure A9980989400763
l)
m)
Figure A9980989400771
N) heteroaryl Wherein heteroaryl is to have 1-3 heteroatomic 5-or 6-unit aromatic heterocyclic group that is selected from O, N or S, o)
Figure A9980989400773
P) amino, q) C 1-C 6Alkyl amino-, r) two (C 1-C 6Alkyl) amino-, s)
Figure A9980989400774
R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl,
t)OH,
U) cyano group,
V) hydroxyl (C 1-C 6Alkyl),
w)
Figure A9980989400775
X)
Figure A9980989400776
Wherein r is 1-6,
y)
Figure A9980989400777
z)
Aa)
Figure A9980989400779
R wherein 84Be hydrogen or C 1-6Alkyl,
Bb) R wherein 85Be hydrogen, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl,
Cc)
Figure A9980989400781
R wherein 84As defined above,
dd)
Figure A9980989400782
ee)
Figure A9980989400783
ff)
Figure A9980989400784
gg)
Figure A9980989400785
hh)
Figure A9980989400786
ii)
jj)
Figure A9980989400788
kk)
ll)
mm)
nn)
Figure A9980989400794
Oo) R wherein 92Be H or C 1-6Alkyl,
pp)
Figure A9980989400796
qq)
rr)
Figure A9980989400798
ss)
tt)
uu)
vv)
Figure A9980989400804
ww)
Figure A9980989400805
xx)
Figure A9980989400806
yy)
Figure A9980989400807
zz)
Aaa) by X and the optional diazine that replaces of Y,
Bbb) by X and the optional triazine radical that replaces of Y,
Ccc) by X and the optional quinolyl that replaces of Y,
Ddd) by X and the optional quinoxalinyl that replaces of Y,
Eee) by X and the optional phthalazinyl that replaces of Y,
fff)
ggg)
Figure A9980989400812
Hhh) Or
Iii)
Figure A9980989400814
B is the unsaturated 4-atom connector with a nitrogen and three carbon; M is
a)H,
B) C 1-8Alkyl,
C) C 3-8Cycloalkyl,
D)-(CH 2) mOR 66, or
E)-(CH 2) nNR 67R 68Z is
a)O,
B) S, or
C) NM; W is
a)CH,
B) N or
C) S or O are when Z is NM; X and Y each independently be
A) hydrogen,
B) halo,
c)NO 2,
d)N 3,
E) C 1-6Alkylthio group,
f)
Figure A9980989400821
g)
Figure A9980989400822
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
Figure A9980989400823
l)
Figure A9980989400824
M) heteroaryl
Figure A9980989400825
Wherein heteroaryl is to have heteroatomic 5-or a 6-unit aromatic heterocyclic group that 1-3 is selected from O, N or S,
n)
Figure A9980989400826
O) amino,
P) C 1-C 6Alkyl amino-,
Q) two (C 1-C 6Alkyl) amino-,
R)
Figure A9980989400831
R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl,
s)OH,
T) hydroxyl (C 1-C 6Alkyl),
u)
Figure A9980989400832
V)
Figure A9980989400833
Wherein r is 1-6,
w)
x)
Figure A9980989400835
Y)
Figure A9980989400836
R wherein 84As defined above,
Z) cyano group,
Aa) carboxyl,
bb)CF 3,
Cc) sulfydryl,
dd)
Figure A9980989400837
Ee)
Figure A9980989400838
Wherein phenyl moiety can be by halo or C 1-C 6Alkyl is optional to be replaced,
ff)
Figure A9980989400839
Gg)
Figure A99809894008310
Wherein R85 as defined above, or
Hh)
Figure A99809894008311
R wherein 99, R 100And R 101Each independently is C 1-6Alkyl; Or Q and R 1And R 3One of formation-O-CH 2-O; R 62Be
a)H,
B) by the optional C that replaces of one or more halos 1-8Alkyl, or
C) by one or more OH, or C 1-8The optional C that replaces of alkoxyl 1-8Alkyl, E is
a)NR 69,
B)-S (=O) i, wherein i is 0,1 or 2, or
C) O; R 63Be
a)H,
B) C 1-6Alkyl,
C)-(CH 2) q-aryl, or
D) halo; R 66Be H or C 1-4Alkyl; R 67And R 68Each independently is H or C 1-4Alkyl, or NR 67R 68Be together-(CH 2) m-; R 69Be
a)H,
B) C 1-6Alkyl,
C)-(CH 2) q-aryl,
d)-CO 2R 81,
e)COR 82,
f)-C(=O)-(CH 2) q-C(=O)R 81,
G)-S (=O) z-C 1-6Alkyl,
H)-S (=O) z-(CH 2) q-aryl, or
I)-(C=O) j-Het, wherein j is 0 or 1; Z 1Be
A)-CH 2-, or
B)-CH (R 70)-CH 2-; Z 2Be
a)-O 2S-,
b)-O-,
c)-S-,
D)-SO-, or
E)-N (R 71)-; Z 3Be
a)S,
b)SO,
C) SO 2, or
D) O; A 1Be H or CH 3A 2Be
a)H,
b)OH-,
c)CH 3CO 2-,
d)CH 3-,
e)CH 3O-,
f)R 72O-CH 2-C(O)-NH-,
g)R 73O-C(O)-NH-,
h)R 73-C(O)-NH-,
I) (C 1-C 2) alkyl-O-C (O)-, or
J) HO-CH 2Or A 1And A 2Be together
A) Or
B) O=; R 64Be H or CH 3
M is 4 or 5;
N is 0,1,2,3,4 or 5;
Y is 0 or 1;
P is 0,1,2,3,4 or 5;
W is 1,2 or 3;
Q is 1,2,3 or 4;
Z is 0 or 1; R 65Be
a)R 74OC(R 75)(R 76)-C(O)-，
b)R 77OC(O)-，
c)R 78(O)-,
D) R 79-SO 2-, or
E) R 80-NH-C (O)-; R 70Be H or (C 1-C 3) alkyl; R 71Be
a)R 74OC(R 75)(R 76)-C(O)-,
b)R 77O-C(O)-,
c)R 78-C(O)-,
d)
e)
f)H 3C-C(O)-(CH 2) 2-C(O)-,
g)R 79-SO 2-,
h)
Figure A9980989400871
I) R 80-NH-C (O)-, R 72Be
a)H,
b)CH 3,
C) phenyl-CH 2-, or
D) CH 3C (O)-; R 73Be (C 1-C 3) alkyl or phenyl; R 74Be H, CH 3, phenyl-CH 2-or CH 3-C (O)-; R 75And R 76Each independently is H or CH 3, or R 75And R 76Be together-CH 2CH 2-; R 77Be (C 1-C 3) alkyl or phenyl; R 78Be H, (C 1-C 4) alkyl, aryl-(CH 2) n 1, ClH 2C, Cl 2HC, FH 2C-, F 2HC-or (C 3-C 6) cycloalkyl; R 79Be CH 3,-CH 2Cl ,-CH 2CH=CH 2, aryl or-CH 2CN; R 80Be-(CH 2) n 1-aryl, wherein n 1Be 0 or 1; R 81Be
a)H,
B) by the optional C that replaces of one or more OH, halo or CN 1-6Alkyl,
C)-(CH 2) q-aryl, wherein q as defined above, or
D)-(CH 2) q-OR 83, wherein q as defined above; R 82Be
A) by the optional C that replaces of one or more OH, halo or CN 1-6Alkyl,
B)-(CH 2) q-aryl, wherein q as defined above, or
C)-(CH 2) q-OR 83, wherein q as defined above; R 83Be
a)H,
B) C 1-6Alkyl,
C)-(CH 2) q-aryl, wherein q as defined above, or
D)-C (=O) C 1-6Alkyl; With
Aryl is phenyl, pyridine radicals or naphthyl, described phenyl, pyridine radicals or naphthyl moiety by one or more halos ,-CN, OH, SH, C 1-6Alkoxyl or C 1-6Alkylthio group is optional to be replaced.
Another preferred embodiment of the present invention comprises following formula: compound
Figure A9980989400881
Or its pharmaceutically acceptable salt, wherein R 1Be H, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl; R 2And R 3Each independently is H or F; Or R 2And R 3Representative together
Figure A9980989400882
Q is
A) hydrogen,
B) halo,
c)N 3,
d)NO 2,
E) C 1-C 6Alkylthio group,
f)
Figure A9980989400883
g)
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
Figure A9980989400891
l)
m)
Figure A9980989400893
N) (C 1-C 6Alkoxyl) 2N-,
O) contain 1-3 O, N or S and be connected to the 5-on the phenyl substituent or the heterocycle of 6-unit by carbon or nitrogen, described heterocyclic moiety is by R 96The optional replacement,
p)
Figure A9980989400894
Q) by R 96The optional phenyl that replaces, or
R) comprise 1-3 O, N or S and be connected to the saturated or undersaturated heterocycle of 5-on the phenyl substituent or 6-unit by carbon or nitrogen, described heterocyclic moiety is by R 96The optional replacement, and R 96Be
A) C 1-C 6Alkyl-OH,
b)
c)
D) cyano group,
E) formoxyl,
f)
g)
Figure A9980989400898
H)
Figure A9980989400901
R wherein 99, R 100And R 101Each independently is C 1-6Alkyl,
i)
Figure A9980989400902
j)
Figure A9980989400903
K)
Figure A9980989400904
Wherein phenyl can replace by halo is optional,
l)
M) (C 1-C 6Alkyl) 2N-,
N) C 1-C 6Alkyl-NH-,
O) amino,
p)
Figure A9980989400906
Q)
Figure A9980989400907
Or
R)
Figure A9980989400908
R wherein 98Be phenyl, contain 1-3 O, N or S and be connected to the 5-on the phenyl substituent or the heteroaryl of 6-unit, or contain 1-4 O, N or S and be connected to the saturated or undersaturated heterocycle of 5-or 6-unit on the phenyl substituent by a ring carbon atom by a ring carbon atom.
Some particularly preferred embodiments of the present invention are listed in following table.
Figure A9980989400911
Figure A9980989400931
Figure A9980989401001
Figure A9980989401011
The compounds of this invention also can be by the method preparation of following general introduction.
Obviously to those skilled in the art, method as described herein is actually representational, also available other method.
Isoxazolinone 5 of the present invention is the order preparation by listing in the flow process 1 preferably.Arylacetic acids 1 can be bought and obtain or by the preparation of one of many known methods in the Chemistry Literature, include but not limited to the order shown in flow process 2 or 3.Isoxazolinone 3 is by Marchesini[J.Org.Chem.1984,49,4287-4290 page or leaf] described method preparation.1 obtains 2,2 with the reaction of sodium hydride and Ethyl formate obtains 3 with azanol reaction.With mild alkaline treatment 3, preferred potassium carbonate, in suitable solvent, preferred dichloromethane or N, dinethylformamide adds 4 (with the method preparation of descriptions in US patent 5,284,863 such as Barnes) subsequently and obtains isoxazolinone 5.Flow process 1
Figure A9980989401021
Be used to prepare the another kind of method of aryl acetate 1 of the present invention shown in the flow process 2.Use Buchwald[Tet.Lett., 1997,38, the 6363-6366 page or leaf] the middle method of describing, use N, the N-dialkylamine is handled triflate 6 (using method known to those skilled in the art, by the preparation of 4-hydroxyphenyl acetic acid methyl ester), produces the ester shown in 7.Aryl-bromide ,-iodide and-chloride also is suitable as the substitute of triflate 6 in the flow process 2.Used N in flow process 2, N-dialkylamine can buy and obtain or synthetic by the method in the document.Many cyclic n nitroso compounds, the preparation method of the document of N-dialkylamine are described in detail by Gadwood (WO97/10223), and other is well known to those skilled in the art.Flow process 2
Figure A9980989401022
Another alternative method for preparing aryl acetate 1 of the present invention is shown in the flow process 3.With the preferred potassium carbonate of weak base, uncle or secondary amine or mercaptides, at suitable solvent, preferred acetonitrile or N in the dinethylformamide, handle 8 between 25 ℃ and 100 ℃ of temperature, obtain 9.Chemical compound 8 can be bought and obtain.The method that proposes by Gravestock (international monopoly 97/14690) is converted into 11 or 12 with chemical compound chemical compound 9.Reaction also is well known to those skilled in the art to this program as Willgerodt.Transform 11 be 12 process also can be by known the whole bag of tricks in Chemistry Literature, include but not limited in hot alcohol, finish with acid treatment.Flow process 3
With method [J.Med.Chem., 1996,39,680-685] well known by persons skilled in the art and that give an example by Barbachyn, by for example m-chloro benzoic acid or Osmic acid. are handled sulfide 13 and 15, preparation sulfoxide and sulfone 14 and 16 with oxidant respectively.Flow process 4
The another kind of method of preparation The compounds of this invention 18 is shown in the flow process 5.Handle 17 with suitable organic stannane and obtain 18.This method is well known by persons skilled in the art, is called Stille intersection-coupling reaction.Flow process 5
The present invention 21,22,23 and 24 preparation are described in flow process 6.Obtain 20 with three fluoro acetic acid treatment 19.With acyl chlorides, chloro-formate, sulfonyl halogen or isocyanates, in the presence of triethylamine, handle chemical compound 20 with known method in the Chemistry Literature, obtain chemical compound 21,22,23 and 24 respectively.Flow process 6
Figure A9980989401051
The chemical compound 27 and 28 of triazole-replacement is by the cyclisation preparation of azide 25 with acetylene 26 (flow process 7).This is the 3+2 cycloaddition of standard, and this has many data to prove in Chemistry Literature.Acetylene 26 can be bought the method that obtains or pass through in the document and prepare.For example, cyanoacetylene is according to Murahashi[J.Chem.Soc.Jap., 1956,77,1689] method preparation.This cyclization carries out between 25 ℃ and 80 ℃ of temperature usually in suitable solvent such as DMF.Other suitable solvent includes but not limited to DMSO, NMP and DMA.The addition product 27 of these two cyclisation and 28 adopts preparation HPLC or separates with solvent that is fit to such as ethyl acetate grinding.Other solvent that is suitable for grinding includes but not limited to methanol, ethanol, ether and acetone.Flow process 7:1,2, the 3-triazole
Triazobenzene isoxazoline ketone 25 is reduced to aminophenyl isoxazolinone 29 by one of method of having known in many Chemistry Literatures, includes but not limited to, handles with stannous chloride in as 2: 1 ethyl acetate and methanol mixture at the solvent that is fit to.In acetic acid, with 2,5-dimethoxy-tetrahydrofuran 30 is handled aminophenyl isoxazolinone 29 and is obtained pyrroles-replacement De isoxazolinone 31 (flow process 8).May transform pyrroles (R=CHO) subsequently, for example corresponding oxime can by with methanol in the preparation that refluxes of 50% moisture azanol.Flow process 8: pyrroles
Figure A9980989401071
N-thiacetate 33 can with the method for knowing in the various documents, for example be prepared by the method that refluxes with Lawesson ' s reagent in benzene by corresponding N-acetas 32.Other solvent also is suitable as toluene and dimethylbenzene.Flow process 9: thiacetate
Figure A9980989401072
Be appreciated that substituent group used in above reaction contains the functional group of some reaction-sensitivities, this group can cause that not meeting paying of needing reacts, and these groups can be protected by the blocking group of routine well known by persons skilled in the art.The suitable blocking group and the method for removing them be for example, the blocking group in the organic synthesis, Theodora W.Greene (John Wiley﹠amp; Sons, 1991) be described in.These " protection " intermediate and end product are included in the scope of the present invention and claims.
The end product of the formula I that some are required comprises amine.In these cases, the form that this end product can pharmaceutically-acceptable acid addition reclaims, for example by suitable acid such as HCl, HI or methanesulfonic acid are added in the amine.
Be appreciated that some product in the formula I scope can have substituted radical, this group can cause the formation of optical isomer.All these class optical isomers and epimerism mixture thereof be R-or S-or racemic form all within the scope of the invention.
The compounds of this invention is useful, because they are animal, especially comprise mammal and have pharmacologically active especially in human body.The new isoxazoline ketone derivatives of formula I, or its pharmaceutically acceptable salt or its prodrug are the active effective antibiotics of resisting gram-positive bacteria.They also can be used as simultaneously, for example promote the additive, food preservative of growth of animal, the antibacterial that in industry, uses, for example in water base coating and in the plain boiled water in paper mill to suppress the growth of noxious bacteria, destroying or to suppress the growth of harmful bacterium on medical treatment and tooth glassware tool, they are particularly useful for treating the bacterial infection that people and other animal are caused by the gram positive bacteria to new derivant sensitivity as disinfectant.
Medicinal activity compound of the present invention can use separately or as the Pharmaceutical composition preparation, except that Huo isoxazolinone composition, said composition comprises pharmaceutically acceptable carrier or diluent.This chemical compound can be by many mode administrations, for example oral, part or parenteral (intravenous or intramuscular injection).This Pharmaceutical composition can be solid form such as capsule, tablet, powder etc., or liquid form such as solution, suspension or emulsion.The compositions that is used to inject can prepare by unit dosage form, at ampoule or in the multidose container, can contain additive for example suspending agent, stabilizing agent and dispersant.Said composition also can be matching while using system form or powder form, prepares again with suitable solvent such as sterilized water in use.
Therefore, according to another aspect of the present invention, provide the method for treatment bacterial infection, this method comprises and gives host, especially mammalian hosts and the particularly chemical compound of patient effective dose.Purposes and The compounds of this invention the purposes during being used for the treatment of the medication preparation of bacterial infection of The compounds of this invention as medicine also is provided.
The dosage of administration is decided according to the specific part and the organism of the approach of the concrete compositions of employed particular compound, preparation, administration, host's character and the state of an illness, treatment basically.Yet particularly preferred dosage and route of administration are by doctor or veterinarian's decision.But, usually through the amount of the chemical compound of parenteral or orally give mammalian hosts for every day approximately 25mg to 2g every day approximately.
The preparation of pyrazoles substituted compound is listed in flow process 10.By a kind of method in many known methods in the Chemistry Literature, include but not limited to handle with sodium nitrite and stannous chloride, with chemical compound 29 diazotising, reduction forms hydrazonium salt hydrochlorate 34 then.With ethoxy carbonyl malonaldehyde (malondiadehyde), cyano group malonaldehyde [according to Bertz, S.H.Dabbagh, G. and Cotte, P. at J.Org.Chem, 1982,47,2216 pages method preparation] or malonaldehyde [according to Martinez, A.M., Cushmac, G.E., Rocek, J. is at J.Amer.Chem.Soc, 1975,97,6502 pages method preparation], in the presence of sodium bicarbonate, at room temperature handle 34 and obtain chemical compound 35.Flow process 10: pyrazoles
Figure A9980989401091
External activity
The sample of the chemical compound that will in following examples 1-97, prepare, water-soluble and with after the nutrient broth dilution, find to present the scope of the indicator microoraganism that following minimum inhibitory concentration (MIC) contrast determines through the test tube dilution.According to the suggestion of the international committee of clinical experiment standard (NCCLS), with culture fluid Microdilution test determines MICs.Except the streptococcus of in Todd Hewitt meat soup, testing, use the Mueller-Hinton culture medium.Final bacterial inoculum contains about 5 * 10 5Cfu/ml, at 35 ℃, (streptococcus is at 5%CO under the surrounding air with flat board 2In) hatched 18 hours.MIC is defined as the lowest concentration of drug that prevents the visible growth.
Microorganism MIC value ug/ml
Streptococcus pneumoniae A9585≤8
Enterococcus faecalis A20688≤16
Staphylococcus aureus A15090, the penicillinase positive≤16
The embodiment explanation
Following examples explanation the present invention, but be not limited to this.The abbreviation of using in described embodiment is conventional abbreviation well known to those skilled in the art.Some used abbreviations are as follows:
H=hour
The mol=mole
The mmol=mM
The g=gram
The min=branch
The rt=room temperature
The THF=oxolane
The L=liter
The mL=milliliter
Et 2The O=ether
The EtOAc=ethyl acetate
MeOH=methanol
The DMF=dimethyl formamide
In following examples, all temperature are Celsius temperature.Fusing point is measured on the electric heating instrument and is not proofreaied and correct.Proton and 13C-NMR ( 1H and 13CNMR) spectrum is recorded on BrukerAM-300 or the Varian Gemini300 spectrometer.Unless otherwise indicated, all spectrum are all at CDCl 3, DMSO-d 6, CD 3OD or D 2Measure among the O.Is the chemical shift of unit with respect to tetramethylsilane (TMS) or reference solvent peak record with δ, and coupling constant is unit record with hertz (Hz) between proton.The following expression of cracking mode: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; Br, broad peak; Dd, double doublet; Dt, Shuan Sanfeng; And appd, apparent bimodal etc.Infrared spectrogram is recorded on the Perkin-Elmer1800FT-IR spectrometer, from 4000cm -1To 400cm -1, be calibrated to the 1601cm of polystyrene film -1Absorb, with reciprocal centimetre (cm -1) record.Utilize direct chemical ionization (DCl, isobutene .), fast atom bombardment (FAB) or electron ionization spraying (ESI), mass spectrum is recorded on Kratos MS-50 or Finnegan 4500 instruments, use direct chemical ionizing (DCI, isobutene .), fast atom bombardment (FAB) or electronic and ionic spraying (ESI).In indicated solvent, ultraviolet spectrogram is recorded on Hewlett Packard 8452 diode array spectrophotometers.
Analytical type thin layer chromatography (TLC) (60F-254) on the silica gel plate of precoating carries out, and with the colour developing of UV light, iodine vapor and/or by the phosphomolybdic acid temper tiniting with methanol system.Column chromatography also refers to flash chromatography, a little more than carrying out under the atmospheric pressure, adopts specified solvent with silica gel in small, broken bits in glass column.Anti-phase analytical type thin layer chromatography carries out on the anti-phase plate of pre-bag quilt, and develops the color with UV light or iodine vapor.
Embodiment 1
N-[[4-(4-methyl mercapto phenyl)-5-oxo-2-isoxazoline-3-yl] methyl] acetamide
Figure A9980989401111
A.4-methylthio phenyl guanidine-acetic acid ethyl ester
To 4-methylthio phenyl guanidine-acetic acid (1.0g, the slow concentrated sulphuric acid that adds catalytic amount in 55ml alcoholic solution 5.48mmol).At room temperature stir this mixture overnight, under reduced pressure concentrate then.Residue is distributed between dichloromethane and the sodium bicarbonate.With salt water washing organic layer, use dried over mgso, filter and the concentrated colourless grease of 1.1g (96%) that obtains. 1H?NMR(300MHz,CDCl 3)δ7.22(s,4H),4.15(q,J=6Hz,2H),3.57(s,2H),2.47(s,3H),1.25(t,J=6Hz,3H)。B.4-methyl mercapto-α-formoxyl-phenylacetic acid ethyl ester
At room temperature, (0.84g, suspension 20.8mmol) join 4-methylthio phenyl guanidine-acetic acid ethyl ester, and (1.1g is in Ethyl formate 5.2mmol) (20mL) solution with NaH.At room temperature, mixture was stirred 1 hour, slowly add cold 0.5N HCl (20mL) then.With the rough reactant of extracted with diethyl ether, with sodium bicarbonate, salt water washing organic layer,, filter and concentrate and obtain 1.2g4-methyl mercapto-α-formoxyl-phenylacetic acid ethyl ester through dried over mgso, be colourless grease, this grease not purification is used for that next step is poly-.C.4-(4-methyl mercapto)-phenyl-isoxazole azoles quinoline-5-ketone
In the 20mL methanol of 4-methyl mercapto-α-formoxyl-phenylacetic acid ethyl ester and 1mL aqueous solution, add hydroxylamine hydrochloride (0.54g, 7.8mmol).With mixture heated to refluxing 1 hour.Evaporating solvent and water grinding residues obtain precipitate, further grind with ether then and obtain 0.48g (two steps, 44%) product, are faint yellow solid. 1H?NMR(300MHz,MeOH-d 4)δ8.74(s,1H),7.66(d,J=8Hz,2H),7.25(d,J=8Hz,2H),2.46(s,3H)。D.N-[[4-(4-methyl mercapto phenyl)-5-oxo-2-isoxazoline-3-yl] methyl] acetamide
To 4-(4-methyl mercapto)-phenyl-isoxazole azoles quinoline-5-ketone (0.2g, add in 10mL dichloromethane solution 0.97mmol) potassium carbonate (0.67g, 4.85mmol) and N-(methylol) acetamide acetate (0.64g, 4.85mmol).At room temperature mixture was stirred 18 hours.Be poured into then among the HCl of 10mL 1N and with chloroform extraction three times.With sodium bicarbonate, salt water washing organic layer,, filter and the concentrated brown solid that obtains, with this solid of hexane/chloroform recrystallization through dried over mgso.Be further purified the solid that obtains with the ether grinding, obtain 0.186g (69%) product, be brown solid. 1H?NMR(300MHz,DMSO-d 6)δ8.93(s,1H),7.72(d,J=9Hz,2H),7.28(d,J=9Hz,2H),5.02(d,J=6Hz,2H),2.48(s,3H),1.84(s,3H)。
Embodiment 2N-{[4-(3-fluoro-4-oxygen-4-morpholine-4-base phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401131
To N-{[4-(3-fluoro-4-morpholine-4-base phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide (200mg, and adding monoperphthalic acid magnesium in 50mL methanol solution 0.60mmol) (300mg, 0.60mmol).After following 2 hours of the room temperature, filter the precipitate and the concentrated filtrate of white.Use the dichloromethane eluting, make the residue that obtains by the alkali alumina stick harness.Concentrate eluant and from dichloromethane/hexane recrystallization, obtain 162mg (44%) title compound, be brown solid. 1H?NMR(DMSO-d 6；300MHz)δ9.19(s,1H),9.02(t,J=6.1Hz,1H),8.62-8.55(m,2H),7.82-7.75(m,2H),5.09(d,J=6.0Hz,2H),4.44(appt,J=11.1Hz,2H),4.08(appt,J=9.6Hz,2H),3.78(appd,J=11.1Hz,2H),2.89(appd,J=10.5Hz,2H),1.86(s,3H)；ESI(M+H) +=352。
Embodiment 3N-(4-[4-(methyl sulfinyl) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
Figure A9980989401132
Under 0 ℃, to N-{[4-(4-methyl mercapto phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } (1.0g is in 50mL chloroformic solution 3.6mmol), in 2 hours for acetamide, add m-CPBA (1.12g, 30mL chloroformic solution 3.6mmol) by syringe pump.Added saturated sodium bicarbonate and vigorous stirring reactant mixture 10 minutes, pour it into saturated sodium bicarbonate and 4: 1 chloroforms this moment: in the methanol.With salt water washing organic layer,, filter and concentrate through dried over mgso.Use the ether grinding residues, obtain 800mg (79%) title compound, be colourless solid. 1H?NMR(DMSO-d 6；300MHz)δ9.11(s,1H),8.96(t,J=6.1Hz,1H),7.96(d,J=6.6Hz,2H),7.67(d,J=6.6Hz,2H),5.03(d,J=6.1Hz,2H),2.73(s,3H),1.84(s,3H)；ESI(M+H) +=295。
Embodiment 4N-(4-[4-(methyl sulphonyl) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
Figure A9980989401141
Under 0 ℃, to N-{[4-(4-methyl mercapto phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } (200mg adds m-CPBA (450mg, 5mL chloroformic solution 1.44mmol) to acetamide in 20mL chloroformic solution 0.72mmol).After 30 minutes, add saturated sodium bicarbonate and use the chloroform extraction reactant mixture.With salt water washing organic layer,, filter and concentrate through dried over mgso.From acetone/1: 1 hexane: the precipitation residue obtains 112mg (50%) title compound the ether, is colourless solid. 1H?NMR(DMSO-d 6；300MHz)δ9.24(s,1H),9.01(t,J=6.1Hz,1H),8.02(d,J=8.6Hz,2H),7.91(d,J=8.6Hz,2H),5.11(d,J=6.2Hz,2H),3.20(s,3H),1.86(s,3H)；ESI(M+H) +=311。
Embodiment 5N-(4-[4-(1,1-dioxo (1, the 4-thiazaperhydroin-4-yl))-3-fluoro phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
To N-{[4-(3-fluoro-4-(1, the 4-thiazaperhydroin-4-yl) phenyl)-and 5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide (100mg, 0.29mmol) 2mL water and the 8mL acetone soln in add N-methylmorpholine N-oxide (98mg, 0.85mmol), (2.5wt% is in isopropyl alcohol to add Osmic acid. subsequently; 7 μ l; 0.07mmol).After at room temperature 18 hours, add saturated sodium sulfite also with 4: 1 chloroforms: the methanol extraction reactant mixture.Concentrated organic layer obtains 85mg (77%) title compound, is colourless solid. 1H?NMR(DMSO-d 6；300MHz)δ8.95(s,1H),8.92(t,J=6.2Hz,1H),7.62-7.51(m,2H),7.17(appt,J=9.2Hz,1H),4.99(d,J=6.2Hz,2H),3.52-3.48(m,4H),3.27-3.23(m,4H),1.82(s,3H)；ESI(M+H) +=384。
Embodiment 64-(3-fluoro-4-morpholine-4-base phenyl)-2-{[(thio-ethyl) amino] methyl }-2-dihydrogen isoxazole-5-ketone
Figure A9980989401152
With N-{[4-3-fluoro-4-morpholinyl phenyl-5-oxo-2-isoxazoline-3-yl] methyl } acetamide (0.25g, 0.75mmol) and (0.4g, the mixture in the 10mL benzene 1.0mmol) heating 3 hours under refluxing of Lawesson ' s reagent.Under reduced pressure concentrate this mixture then.With silica gel column chromatography (with dichloromethane and eluent ethyl acetate) purification residue, obtain colorless solid (80mg, 30%): 1H NMR (300MHz, CDCl 3) δ 8.61 (brs, 1H), 8.49 (s, 1H), 7.50 (dd, J=1.5 and 13.8Hz, 1H), 7.40 (dd, J=1.5 and 10.2Hz, 1H), 7.12 (t, J=10.2Hz, 1H), 5.56 (d, J=6.3Hz, 2H), 3.94 (m, 4H), 3.17 (m, 4H), 2.57 (s, 3H).
Embodiment 7N-{[4-(4-acetylphenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
With 10 fens clockwise N-{[4-phenyl-5-oxo-2-dihydrogen isoxazole-2-yls] methyl acetamide (3.0g, 12.9mmol) and aluminum chloride (III) (13.8g, 150mL1 103.4mmol), dripping acetyl chloride in the 2-dichloro-ethane solution (7.3mL, 103.4mmol).With the red mixture heated to 80 that generated ℃ 3.5 hours, be cooled to room temperature, in the mixture that was poured into the 20% methanol/chloroform that immerses the quick stirring in the ice bath and 1N hydrochloric acid in 10 minutes.Mixture is poured in the separatory funnel, carried out layer and separate.With 20% methanol/chloroform extraction water-bearing layer twice, wash the organic layer of merging continuously with 1N sodium hydroxide, saturated sodium bicarbonate and saline then.Through the dried over mgso organic layer, filter and the amorphous yellow solid of simmer down to then, this solid is dissolved in 20% methanol/chloroform.Add ether and with mixture be placed on 0 ℃ following 18 hours.The sedimentation and filtration that generates is obtained the title compound of 2.48g (70%), be the pale pink solid. 1H?NMR(DMSO-d 6；300MHz)δ9.18(s,1H),9.00(t,J=6.1Hz,1H),7.96(d,J=6.7Hz,2H),7.91(d,J=6.6Hz,2H),5.10(t,J=6.2Hz,2H),2.56(s,3H),1.86(s,3H)；ESI(M+H) +=275。
Embodiment 8N-(4-[4-((oxyimino) ethyl) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
Figure A9980989401171
With N-{[4-(4-acetylphenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } (2.0g, 7.3mmol) (1.0mL, mixture heated 14.6mmol) is to refluxing 1.5 hours with 50% aqueous hydroxylamine solution for acetamide.Being concentrated into nearly drying also is dissolved in 20% methanol/chloroform again.Add hexane up to solution becomes muddy and with mixture be placed on 0 ℃ 3 hours.Filtering precipitate obtains the title compound of 1.42g (67%), is faint yellow solid. 1H?NMR(DMSO-d 6；300MHz)δ11.21(s,1H),9.01(s,1H),8.96(t,J=6.2Hz,1H),7.78(d,J=8.6Hz,2H),7.66(d,J=8.6Hz,2H),5.04(d,J=6.2Hz,2H),2.19(s,3H),1.84(s,3H)；ESI(M+H) +=290。
Embodiment 9N-{[4-(4-(2-furyl) phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401172
Nitrogen bubble is fed N-{[4-(4-iodine substituted phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide (300mg, 0.84mmol), 2-tributyl stannyl furan (0.26mL, 0.84mmol), three (dibenzalacetones), two palladiums (0) (77mg, 0.08mmol), triphenylarsine (51mg, 0.17mmol) and lithium chloride (106mg is in 5mL DMF mixture 2.51mmol).Reactant mixture was sealed and at room temperature stirs 8 hours, during this period with 20% methanol/chloroform dilution, through diatomite filtration and concentrated.Residue is suspended in the chloroform, application of sample is on the chromatography assembly (12M) of the Biotage flash 40i on the frit, obtain a kind of solid with 50% hexane/ethyl acetate eluting, grind the title compound that this solid obtains 132mg (53%), be colourless solid with chloroform/ether. 1H?NMR(DMSO-d 6；300MHz)δ9.00(s,1H),8.94(t,J=6.0Hz,1H),7.82(d,J=8.4Hz,2H),7.74-7.70(m,2H),6.95(d,J=3.2Hz,1H),6.60-6.59(m,1H),5.04(d,J=6.1Hz,2H),1.85(s,3H)；ESI(M+H) +=299。
Embodiment 10N-{[5-oxo-4-(4-(2-thienyl) phenyl)-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401181
Nitrogen bubble is fed N-{[4-(4-iodine substituted phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide (300mg, 0.84mmol), 2-tributyl stannyl thiophene (0.27mL, 0.84mmol), three (dibenzalacetones), two palladiums (0) (77mg, 0.08mmol), triphenylarsine (51mg, 0.17mmol) and lithium chloride (106mg is in 5mL DMF mixture 2.51mmol).Reactant mixture was sealed and at room temperature stirs 8 hours, dilute this mixture with 20% methanol/chloroform during this period, through diatomite filtration and concentrated.Residue is suspended in the chloroform, application of sample is on the chromatography assembly (12M) of the Biotage flash 40i on the frit, obtain a kind of solid with 15% acetone/chloroform eluting, grind this solid with chloroform/ether and obtain 165mg (63%) title compound, be colourless solid. 1H?NMR(DMSO-d 6；300MHz)δ9.00(s,1H),8.95(t,J=6.0Hz,1H),7.81(d,J=7.3Hz,2H),7.68(d,J=7.4Hz,2H),7.54-7.52(m,2H),7.15-7.11(m,1H),5.04(d,J=6.1Hz,2H),1.85(s,3H)；ESI(M+H) +=315。
Embodiment 11N-{[4-(4-(2H, 3H-1,4-dioxin-5-yl) phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Nitrogen bubble is fed N-{[4-(4-iodine substituted phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide (300mg, 0.84mmol), 2-(tributyl stannyl)-5,6-dihydro-[1,4]-dioxin (346mg, 0.92mmol), three (dibenzalacetones), two palladiums (0) (77mg, 0.08mmol), triphenylarsine (51mg, 0.17mmol) and lithium chloride (106mg is in 5mLDMF mixture 2.51mmol).Reactant mixture was sealed and at room temperature stirs 16 hours, dilute this mixture with 20% methanol/chloroform during this period, add 10% potassium fluoride aqueous solution and also this mixture was stirred 1 hour fast.Through this reactant mixture of diatomite filtration and concentrated.The dark oil thing that produces is dissolved in 20% methanol/chloroform, absorb on the silica gel and application of sample to the chromatography assembly S1M of Biotageflash 40i.Carry out chromatography with 12M silica gel cylinder, obtain amber oily thing, grind the title compound that obtains 115mg (44%), be the solid of brown with ether with 20% acetone/chloroform eluting. 1H?NMR(DMSO-d 6；300MHz)δ8.93-8.88(m,2H),7.70(d,J=8.5Hz,2H),7.41(d,J=8.4Hz,2H),6.96(s,1H),5.01(d,J=6.2Hz,2H),4.22-4.19(m,2H),4.10-4.07(m,2H),1.85(s,3H)；ESI(M+H) +=317。
Embodiment 12N-{[5-oxo-4-(4-pyrazine-2-base phenyl)-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401192
Nitrogen bubble is fed N-{[4-(4-iodine substituted phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide (300mg, 0.84mmol), 2-(tributyl stannyl) pyrazine (340mg, 0.92mmol), three (dibenzalacetones), two palladiums (0) (77mg, 0.08mmol), triphenylarsine (51mg, 0.17mmol) and lithium chloride (106mg is in 5mL DMF mixture 2.51mmol).Reactant mixture was sealed and at room temperature stirs 16 hours, dilute this mixture with 20% methanol/chloroform during this period, the aqueous solution that adds 10% potassium fluoride also stirs this mixture 1 hour fast.Through this reactant mixture of diatomite filtration and concentrated.The dark oil thing that generates is dissolved in 20% methanol/chloroform, absorb on the silica gel and application of sample to the chromatography assembly S1M of Biotage flash 40i.Carry out chromatography with 12M silica gel cylinder, obtain amber oily thing, this grease is ground with ether obtain 52mg (44%) title compound, be colourless solid with 25% acetone/chloroform eluting. 1HNMR(DMSO-d 6；300MHz)δ9.28(d,J=1.4Hz,1H),9.11(s,1H),8.97(t,J=6.1Hz,2H),8.71(appt,J=1.9Hz,1H),8.59(d,J=2.5Hz,1H),8.17(d,J=8.5Hz,2H),7.94(d,J=8.5Hz,2H),5.07(d,J=6.2Hz,2H),1.86(s,3H)；ESI(M+H) +=311。
Embodiment 13N-{[5-oxo-4-(4-{4-[2-(1,1,2,2-tetramethyl-1-sila propoxyl group) acetyl group] piperazinyl } phenyl)-2-dihydrogen isoxazole-2-yl] methyl } acetamide
To N-{[5-oxo-4-(piperazinyl phenyl)-2-dihydrogen isoxazole-2-yl] methyl } acetamide three fluoro acetate (0.43g, 1.0mmol) the 2mL dimethyl formamide and the solution of 10mL dichloromethane in add triethylamine (0.7mL, 0.5mmol), add subsequently (t-butyl dimethyl silane oxygen base) chloroacetic chloride (1.0g, 4.8mmol).Reactant mixture at room temperature stirred be distributed in then between dichloromethane and the water in 1.5 hours.With saturated sodium bicarbonate, salt water washing organic layer,, filter and concentrate through dried over mgso.Residue is obtained 0.24g (49%) title compound with the ether grinding. 1H NMR (methanol-d 4300MHz) δ 8.49 (s, 1H), 7.66 (d, J=8.8Hz, 2H), 7.00 (d, J=8.8Hz, 2H), 5.07 (s, 2H), 4.42 (s, 2H), 3.73 (t, J=4.9Hz, 4H), 3.24 (t, J=4.9Hz, 4H), 1.94 (s, 3H), 0.95 (s, 9H); ESI (M+H) +=489.
Embodiment 14N-[(4-{4-[4-(2-hydroxyacetyl) piperazinyl] phenyl }-5-oxo-2-dihydrogen isoxazole-2-yl) methyl] acetamide
To N-{[5-oxo-4-(4-{4-[2-(1,1,2,2-tetramethyl-1-sila propoxyl group) acetyl group] piperazinyl } phenyl)-2-dihydrogen isoxazole-2-yl] methyl } (0.3g adds 4mL three chloro acetic acid to acetamide in the solution of 4mL dichloromethane 0.6mmol).After 1 hour, the concentration response thing is distributed in residue in dichloromethane and the saturated sodium bicarbonate solution.With salt water washing organic layer,, filter and concentrate through dried over mgso.Residue is obtained 92mg (40%) title compound with the ether grinding. 1H?NMR(DMSO-d 6；300MHz)δ8.87(t,J=6.2Hz,1H),8.74(s,1H),7.63(d,J=8.7Hz,2H),6.97(d,J=8.9Hz,2H),4.95(d,J=6.2Hz,2H),4.64(t,J=5.6Hz,1H),4.13(d,J=5.6Hz,2H),3.60(brs,2H),3.48(brs,2H),3.17(brs,4H),1.83(s,3H)；ESI(M+H) +=375。
Embodiment 15N-{[4-(4-azido phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401212
Prepare 4-triazobenzene guanidine-acetic acid ethyl ester according to the general way of listing in the flow process 1.Being prepared as follows of starting material: 4-triazobenzene guanidine-acetic acid ethyl ester
Figure A9980989401221
According to Marchesini (J.Org.Chem.49, the 4287-4290 page or leaf, 1984) conventional method is with sodium nitrite (38g, 0.56mol) (25g is in the TFA mixture of 700mL 0.14mol) to join the 4-aminophenyl ethyl acetate that is stirring and cooling off (0 ℃) lentamente.Add finish after, with reactant 0 ℃ of following restir 0.5 hour, in 0.5 hour, slowly add then Hydrazoic acid,sodium salt (27g, 0.42mol).Under 0 ℃ with mixture restir 2 hours, with the frozen water quencher and use the EtOAc extraction product.Wash organic layer with water,, filter and concentrate and obtain 26.5g (90%) title compound, be white solid through dried over mgso. 1H?NMR(300MHz,DMSO-d 6)δ7.31(d,J=8Hz,2H),7.07(d,J=7Hz,2H),4.07(q,J=7Hz,2H),3.66(s,2H),1.17(t,J=7Hz,3H)。
Embodiment 16N-[(4-{4-[4-(hydroxymethyl) (1,2,3-triazoles base)] phenyl }-5-oxo-2-dihydrogen isoxazole-2-yl) methyl] acetamide
With N-{[4-(4-azido phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl acetamide (80mg, 0.29mmol) and propargyl alcohol (0.1mL, the mixed liquor of 3mL DMF 1.71mmol) is 100 ℃ of down heating 10 hours.Concentrate this reactant mixture then in a vacuum and through flash chromatography (silica gel; Use the 10%MeOH/EtOAc eluting subsequently with EtOAc) purification, obtain the 62mg yellow solid. 1H NMR spectrum shows that this raw product is two kinds of triazole mixture of isomers.Through preparation HPLC (H 2O/MeOH) separate these isomers and obtain 10mg (10%) title compound, be white solid. 1HNMR(300MHz,DMSO-d 6)δ9.11(s,1H),8.96(t,J=6Hz,1H),8.69(s,1H),7.96(m,4H),5.07(d,J=6Hz,2H),4.61(s,2H),1.86(s,3H)。
Embodiment 171-(4-{2-[(acetylamino) methyl]-5-oxo-2-dihydrogen isoxazole-4-yl } phenyl)-1,2,3-triazoles-4-carboxylate methyl ester
Figure A9980989401231
With N-{[4-(4-azido phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl acetamide (80mg, 0.29mmol) and methyl propionate (0.05mL, 3mL DMF mixed liquor 0.58mmol) is 50 ℃ of down heating 24 hours.Concentrate this reactant mixture then in a vacuum and obtain 25mg (24%) title compound, be yellow solid with the EtOAc grinding.(a kind of more reliable alternative relates to and at room temperature carries out this reaction 10 days, as above separates then). 1H?NMR(300MHz,DMSO-d 6)δ9.52(s,1H),9.15(s,1H),8.96(t,J=6Hz,1H),8.02(s,4H),5.08(d,J=6Hz,2H),3.90(s,3H),1.87(s,3H)。
Embodiment 18N-(4-[4-(4-acetyl group) (1,2,3-triazoles base)) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
Figure A9980989401232
With N-{[4-(4-azido phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } (100mg, 0.36mmol) (0.035mL, 3mL DMF mixed liquor 0.72mmol) heated 24 hours down at 50 ℃ acetamide with 3-crotonylene-ketone.Concentrated reaction mixture and grind with EtOAc and to obtain 60mg (49%) title compound in a vacuum is yellow solid then. 1H?NMR(300MHz,DMSO-d 6)δ9.47(s,1H),9.35(s,1H),8.98(t,J=6Hz,1H),8.02(s,4H),5.08(d,J=6Hz,2H),3.32(s,3H),1.85(s,3H)。
Embodiment 19N-(4-[4-(4-cyano group (1,2,3-triazoles base)) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
With N-{[4-(4-azido phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl acetamide (500mg, 1.83mmol) and the cyanoacetylene of 0.8mL [according to Murahashi, S.; Takizawa, T.; Kurioka, S.; Maekawa, S.; At J.Chem.Soc.Jap., 77,1689 pages, 1956 preparations] 5mL DMF mixed liquor 50 ℃ of down heating 48 hours.After the cooling, the solid of collecting precipitation and obtain 375mg (63%) title compound with DMF washing is white solid after filtration. 1H?NMR(300MHz,DMSO-d 6)δ9.75(s,1H),9.17(s,1H),9.00(t,J=6Hz,1H),8.05(d,J=9Hz,2H),7.95(d,J=9Hz,2H),5.10(d,J=6Hz,2H),1.85(s,3H)。
Embodiment 20N-{[4-(4-aminophenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
To N-{[4-(4-azido phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } (3g adds SnCl in 40mL EtOAc 10.98mmol) and the mixed liquor of 20mL MeOH to acetamide 2.2H 2O (12.5g, 54.9mmol).After all solids dissolving, concentrated reaction mixture is also with saturated sodium bicarbonate aqueous solution neutralization in a vacuum.Concentrate this mixture in a vacuum once more and residue is dissolved in 4: 1CHCl 3Among/the MeOH.Through the solution that diatomite filtration obtains, abandoning does not have dissolved substances.Concentrated filtrate obtains 3g (100%) title compound in a vacuum then, is yellow solid. 1H NMR (300MHz, DMSO-d 6) δ 8.83 (t, J=6Hz, 1H), 8.55 (s, 1H), 7.43 (d, J=9Hz, 2H), 6.56 (d, J=9Hz, 2H), 5.21 (broadband s, 2H), 4.91 (d, J=6Hz, 2H), 1.82 (s, 3H).
Embodiment 21N-(4-[4-(3-formoxyl pyrrole radicals) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
Figure A9980989401251
To N-{[4-(4-aminophenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide (200mg adds 2 in 3ml acetic acid solution 0.81mmol), and 5-dimethoxy-3-oxolane formaldehyde (184mg, 1.27mmol).Mixture was refluxed 0.5 hour, concentrate in a vacuum then and obtain raw product.Obtain 240mg (91%) title compound through silica gel column chromatography purification (use the EtOAc eluting, use the EtOAc eluant solution of 8%MeOH then), be yellow solid. 1H?NMR(300MHz,DMSO-d 6)δ9.79(s,1H),9.08(s,1H),9.00(t,J=6Hz,1H),8.29(m,1H),7.93(d,J=9Hz,2H),7.74(d,J=9Hz,2H),7.58(m,1H),6.71(m,1H),5.06(d,J=6Hz,2H),1.86(s,3H)。
Embodiment 22N-{[5-oxo-4-(4-pyrrole radicals phenyl)-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Except with 2; 5-dimethoxy-3-oxolane replaces 2; outside 5-dimethoxy-3-oxolane formaldehyde; the method that is used for N-({ 4-[4-(3-formoxyl pyrrole radicals) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide as described above is from N-{[4-(4-aminophenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide prepares this chemical compound. 1H?NMR(300MHz,DMSO-d 6)δ8.92(s,1H),8.94(t,J=6Hz,1H),7.85(d,J=9Hz,2H),7.62(d,J=9Hz,2H),7.40(t,J=2Hz,2H),6.27(t,J=2Hz,2H),5.04(d,J=6Hz,2H),1.86(s,3H)。
Embodiment 23N-[(4{4-[3-((oxyimino) methyl) pyrrole radicals] phenyl }-5-oxo-2-dihydrogen isoxazole-2-yl) methyl] acetamide
Figure A9980989401261
With N-({ 4-[4-(3-formoxyl pyrrole radicals) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide (100mg, 0.30mmol) and 50% moisture NH 2(40mg, the mixture of 3mL MeOH 0.60mmol) heated 2 hours under refluxing OH.In a vacuum reactant mixture is concentrated then and use the ether grinding residues, obtain 96mg (94%) title compound, be xanchromatic solid. 1H?NMR(300MHz,DMSO-d 6)δ10.6(s,1H),9.02(s,1H),8.95(t,J=6Hz,1H),8.00(s,1H),7.87(d,J=9Hz,2H),7.66(s,1H),7.63(d,J=9Hz,2H),7.45(m,1H),6.50(m,1H),5.04(d,J=6Hz,2H),1.85(s,3H)。
Embodiment 244-(4{2-[(acetylamino) methyl]-5-oxo-2-dihydrogen isoxazole-4-yl } phenyl) the piperazine carboxylic acid tert-butyl ester
Figure A9980989401271
To 4-[4-(5-oxo-2-dihydrogen isoxazole-4-yl] phenyl] the piperazine carboxylic acid tert-butyl ester (1.5g, 4.3mmol) the 35mL dimethyl formamide solution in add N-(methylol) acetamide acetas (2.9g, 22.0mmol), add subsequently potassium carbonate (3.0g, 22.0mmol).After 5 hours, reactant mixture is poured in the frozen water.After 18 hours, filtering-depositing is also dry in a vacuum, obtains 1.4g (77%) title compound. 1H NMR (methanol-d 4, 300MHz) δ 8.48 (s, 1H), 7.66 (d, J=8.8Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 5.07 (s, 2H), 3.58 (t, J=4.8Hz, 4H), 3.17 (t, J=5.2Hz, 4H), 1.94 (s, 3H), 1.50 (s, 9H); ESI (M+H) +=417.
Be prepared as follows starting material: 2-(4-{4-[(t-butyl) oxygen base carbonyl] piperazinyl } phenyl) methyl acetate
To be equipped with cesium carbonate (4.6g, 14.0mmol), acid chloride (II) (0.07g, 0.3mmol) and (S)-BINAP (0.28g, 4.5mmol) flask evacuation and with exsiccant nitrogen purge.Add 2-{4-[(trifluoro acute pyogenic infection of nails base by syringe) sulfonyl oxygen base] phenyl } methyl acetate (3.0g; 10.0mmol) and t-butyl-1-piperazine carboxylic acid ester (2.3g; 12.0mmol) the 20mL toluene solution, the mixture that obtains at room temperature stirred 30 minutes and stirred 16 hours down at 80 ℃.Reactant mixture is shifted out from heating bath, concentrate, chromatography on silica gel (0-30% ethyl acetate/hexane) obtains 1.7g (50%) title compound. 1H?NMR(300MHz,CDCl 3)δ7.20(d,J=8.5Hz,2H),6.89(d,J=8.4Hz,2H),3.70(s,3H),3.59(t,J=5.0Hz,4H),3.57(s,2H),3.12(t,J=5.2Hz,4H),1.50(s,9H)；ESI(M+H) +=335。2-(4-{4-[(t-butyl) oxygen base carbonyl] piperazinyl }) phenyl)-3-oxo ethyl propionate
To 2-(4-{4-[(t-butyl) oxygen base carbonyl] piperazinyl phenyl) methyl acetate (and 0.67g, add in 8mL Ethyl formate 2.0mmol) in batches sodium hydride (60% in mineral oil dispersion liquid) (0.32g, 8.0mmol).1.5 after hour, reactant mixture is poured in the saturated sodium bicarbonate, is used extracted with diethyl ether three times.Organic layer with the salt water washing merges through dried over mgso, filters and concentrates.In next step, directly use rough product and be not further purified.4-[4-(5-oxo-2-dihydrogen isoxazole-4-yl) phenyl] the piperazine carboxylic acid tert-butyl ester
Figure A9980989401282
To 2-(4-{4-[(t-butyl) oxygen base carbonyl] piperazinyl) phenyl)-3-oxo ethyl propionate (7.8g, add in 140mL methanol 20.7mmol) and the 40mL water azanol (50% in water, 3.0mL, 49.0mmol).Reactant mixture is heated to backflow 3 hours, and cooling also concentrates.Water grinding residues and filtering precipitate, dry and obtain the 4.3g title compound with the ether washing.This aqueous solution lyophilization is obtained other 1.5g title compound. 1H NMR (methanol-d 4300MHz) δ 8.35 (s, 1H), 7.58 (brd, J=, 2H), 6.96 (d, J=8.2Hz, 2H), 3.58 (t, J=4.6Hz, 4H), 3.10 (brs, 4H), 1.50 (s, 9H); ESI (M+H) +=345.
Embodiment 25N-{[5-oxo-4-(piperazinyl phenyl)-2-dihydrogen isoxazole-2-yl] methyl } acetamide three fluoro acetates
Figure A9980989401291
To 4-(4-{2-[(acetylamino) methyl]-5-oxo-2-dihydrogen isoxazole-4-yl } phenyl) (0.3g adds 2mL three fluoro acetic acid to the piperazine carboxylic acid tert-butyl ester in 5mL dichloromethane solution 0.7mmol).After 30 minutes, reactant mixture concentrated and grind and obtain 0.3g (97%) title compound with ether. 1HNMR (methanol-d 4300MHz) δ 9.00 (t, J=6.0Hz, 1H), 8.23 (s, 1H), 7.70 (d, J=8.8Hz, 2H), 7.05 (d, J=8.7Hz, 2H), 5.08 (d, J=6.2Hz, 2H), 3.45-3.38 (m, 8H), 1.95 (s, 3H); ESI (M+H) +=317.
Embodiment 264-(4-{2-[(acetyl-amino) methyl]-5-oxo (2-dihydrogen isoxazole-4-yl) }-2-fluoro phenyl) the piperazine carboxylic acid tert-butyl ester
Figure A9980989401292
Prepare according to the conventional method shown in flow process 1,3 and 6.Be prepared as follows initial substance: 2-(4-{4-[(t-butyl) oxygen base carbonyl] piperazinyl }-3-fluoro phenyl) acetic acid
Figure A9980989401293
Under 0 ℃, to 4-[2-fluoro-4-(2-morpholine-4-base-2-thio-ethyl) phenyl] the piperazine carboxylic acid tert-butyl ester (4.2g, 10mmol) the middle 22mL concentrated hydrochloric acid that adds.The mixture heated that obtains to refluxing 1.5 hours, is cooled to 0 ℃ and add 23ml 10N sodium hydroxide to make pH be 14.Add 50mL water then, add Bis(tert-butoxycarbonyl)oxide (5.6g, 5mL tetrahydrofuran solution 26.0mmol) subsequently.Under 0 ℃, the mixture that obtains was stirred 30 minutes, at room temperature stirred then 1 hour, simultaneously with the dilution of 200mL water.Add the 5mL sodium hydroxide pH is transferred to 14, use the extracted with diethyl ether reactant mixture.Hcl acidifying water-bearing layer by careful adding 6N makes pH reach 3, uses ethyl acetate extraction then three times.With salt water washing organic layer, through dried over mgso and concentrated.Be dissolved in the residue that obtains in the dichloromethane again and add hexane and make and produce precipitation, collect this precipitate after filtration, obtain 3.0g (89%) title product. 1H?NMR(CDCl 3；300MHz)δ7.04-6.98(m,2H),6.90(t,J=8.3Hz,1H),3.60(m,6H),3.02(t,J=5.0Hz,4H),1.50(s,3H)；ESI(M+H) +=339。2-(4-{4-[(t-butyl) oxygen base carbonyl] piperazinyl }-3-fluoro phenyl) methyl acetate
Figure A9980989401301
To 2-(4-{4-[(t-butyl) oxygen base carbonyl] piperazinyl }-3-fluoro phenyl) acetic acid (0.3g, and adding trimethyl silyl Azimethylene. in 2mL methanol 1.0mmol) and the 7mL toluene (0.65mL, 1.30mmol).After at room temperature stirring 1 hour, concentrated reaction mixture obtains 0.36g (99%) title compound. 1H?NMR(CDCl 3；300MHz)δ7.00(m,2H),6.90(t,J=8.3Hz,1H),3.71(s,3H),3.61(t,J=4.9Hz,4H),3.57(s,2H),3.02(t,J=5.0Hz,4H),1.50(s,9H)；ESI(M+H) +=353。
Embodiment 27N-{[4-(4-morpholinyl phenyl)-5-oxo-2-isoxazoline-3-yl] methyl } acetamide
Figure A9980989401302
Prepare according to the conventional method shown in flow process 1 and 2.Be prepared as follows initial substance: 4-(trifluoro acute pyogenic infection of nails base sulfonyl oxygen base) phenylacetic acid methyl ester
Figure A9980989401311
Under 0 ℃, to 4-hydroxyphenyl acetic acid methyl ester (20g, 120mmol) and pyridine (20mL, (23mL 132mmol) continues 30 minutes to drip trifluoro acute pyogenic infection of nails sulphonic acid anhydride in 100mL dichloromethane 240mmool).Under 0 ℃ again through 30 minutes after, then at room temperature again through 30 minutes, add the hydrochloric acid of 1N and reactant mixture be extracted in the dichloromethane.With the hydrochloric acid of 1N, saturated sodium bicarbonate, salt water washing organic layer, through dried over mgso, filter and concentrate and obtain 32g (90%) title compound, be yellow solid. 1H?NMR(CDCl 3；300MHz)δ7.38(d,J=8.4Hz,2H),7.24(d,J=8.5Hz,2H),3.72(s,3H),3.66(s,2H)。4-morpholino phenylacetic acid methyl ester
Figure A9980989401312
Nitrogen bubble is fed 4-(trifluoro acute pyogenic infection of nails base sulfonyl oxygen base) phenylacetic acid methyl ester (1.0g; 3.35mmol), cesium carbonate (1.6g; 4.69mmol), acid chloride (II) (22mg; 0.10mmol), (S)-BINAP (93mg; 0.15mmol) and morpholine (0.35mL; 4.02mmol) the 8mL toluene solution in, and with reactant mixture be heated to 80 ℃ 6 hours.Cool off reactant then, add kieselguhr and enriched mixture.On Biotage fiash40i chromatography assembly (exsiccant kieselguhr is added SIM), carry out chromatography, obtain the title compound of 250mg (37%), be yellow oil with 20% ethyl acetate/hexane eluting (40S cylinder). 1H?NMR(CDCl 3；300MHz)δ7.19(d,J=8.4Hz,2H),6.87(d,J=8.3Hz,2H),3.89-3.85(m,4H),3.69(s,3H),3.56(s,2H),3.17-3.13(m,4H)。
Embodiment 28
N-{[4-(4-(1, the 4-thjazaperhydroin-4-yl) phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401321
Prepare according to the conventional method shown in flow process 1 and 3.Be prepared as follows initial substance: the 4-thiomorpholine is for 1-Phenylethanone.
Figure A9980989401322
To 4-fluorobenzene ethyl ketone (20g, add in 100mL dimethyl formamide 145mmol) potassium carbonate (39g, 580mmol), add subsequently thiomorpholine (87mL, 870mmol).Reactant mixture is heated to backflow, after 24 hours, it is cooled to room temperature and be distributed in water and dichloromethane in.Through the dried over mgso organic layer, filter and concentrate.Residue is dissolved in the ether again, obtains 3lg (96%) title compound, be yellow solid with the hexane precipitation. 1H?NMR(CDCl 3；300MHz)δ7.87(d,J=9.0Hz,2H),6.82(d,J=9.0Hz,2H),3.81-3.78(m,4H),2.73-2.69(m,4H),2.53(s,3H)。The 4-thiomorpholine is for phenyl thioacetyl morpholine
With the 4-thiomorpholine for 1-Phenylethanone. (30g, 136mmol), morpholine (16mL, 180mmol) and sulfur (6g, mixture heated 180mmol) is cooled to 50 ℃ to refluxing 6 hours, adds 1: 1 hexane of 100mL: ethyl acetate.Reactant mixture was refluxed 30 minutes again, and the precipitation that produces is collected in cooling after filtration.Wash this precipitation with additional 1: 1 ether/hexane and obtain 31g (73%) title compound, be the yellowish orange solid. 1H?NMR(CDCl 3；300MHz)δ7.21(d,J=8.7Hz,2H),6.86(d,J=8.1Hz,2H),4.35(t,J=4.8Hz,2H),4.27(s,2H),3.74(t,J=4.8Hz,2H),3.65(t,J=4.2Hz,2H),3.52(t,J=5.1Hz,4H),3.41(t,J=5.4Hz,2H),2.77-2.71(m,2H)。The 4-thiomorpholine is for the phenylacetic acid ethyl ester
Figure A9980989401331
With the 4-thiomorpholine for phenyl thioacetyl morpholine (30g, 1: 1 ethanol of 70mL 93.2mmol): sulfuric acid solution is heated to and refluxed 18 hours, being cooled to room temperature and solid sodium bicarbonate is slowly joined in the reactant up to its pH is 7.Use the chloroform extraction reactant mixture,,, filter and be condensed into yellow residue through dried over mgso with salt water washing organic layer.Then this residue is dissolved in the chloroform again, application of sample (40M cylinder) and with 10% ethyl acetate/hexane chromatography in the Biotage flash 40i chromatography assembly obtains 12g (51%) title compound, is yellow oil. 1H?NMR(CDCl 3；300MHz)δ7.18(d,J=8.7Hz,2H),6.86(d,J=8.6Hz,2H),4.14(q,J=7.2Hz,2H),3.54-3.50(m,6H),2.76-2.73(m,4H),1.25(t,J=7.2Hz,3H)。
Embodiment 29N-{[4-(3-fluoro-4-methyl thio-phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401332
Prepare according to the conventional method shown in flow process 1 and 3.Be prepared as follows initial substance: 3-fluoro-4-methyl thioacetophenone
To 3,4-difluoro-benzene ethyl ketone (30g, and adding sulfo-Feldalat NM in 200mL dimethyl sulfoxide 192mmol) (15g, 211mmol).With reactant mixture be heated to 150 ℃ 2 hours, be distributed in then between ethyl acetate and the sodium bicarbonate.With salt water washing organic layer,, filter and concentrate through dried over mgso.Residue is dissolved in the ethyl acetate and with hexane precipitates.The collecting precipitation thing obtains 25g (70%) title compound after filtration, is yellow solid.3-fluoro-4-methyl thio-phenyl thioacetyl morpholine
With 3-fluoro-4-methyl thioacetophenone (9.0g, 48.9mmol), morpholine (5.7mL, 65.0mmol) and sulfur (2.1g, mixture heated 65.0mmol) is to refluxing 4 hours, is cooled to 50 ℃ and add 1: 1 hexane: ethyl acetate.The reactant mixture reheat to refluxing 30 minutes, is cooled to room temperature, collects the orange precipitate that produces after filtration.With 1: 1 hexane: ether washed this precipitate and obtains 10.1g (73%) title compound, is the yellowish orange solid. 1H?NMR(DMSO-d 6；300MHz)δ7.36-7.29(m,1H),7.20-7.15(m,2H),4.27(s,2H),4.22(t,J=4.8Hz,2H),3.73(t,J=4.5Hz,2H),3.65(t,J=4.8Hz,2H),3.47(t,J=5.1Hz,2H),2.47(s,3H)。3-fluoro-4-methyl thio-phenyl acetic acid
Figure A9980989401343
To 3-fluoro-4-methyl thio-phenyl thioacetyl morpholine (2.6g, 90.9mmol) middle 500mL 10% potassium hydroxide that adds.Reactant mixture is heated to backflow 3 hours, is cooled to room temperature, carefully add 2N hydrochloric acid pH value is transferred to 4.Also extract this organic layer with the aqueous solution of dichloromethane extraction with 200mL l0% potassium hydroxide.Add 2N hydrochloric acid to make water-bearing layer pH be 4 and use dichloromethane extraction through careful.Through the dried over mgso organic layer, filter and concentrate and obtain 10.0g (55%) title compound, be brown oil. 1H?NMR(CDCl 3；300MHz)δ7.24-7.21(m,1H),7.04-6.99(m,2H),3.63(s,2H),2.46(s,3H)。
Embodiment 30N-{[4-(3-fluoro-4-methoxyphenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401351
Prepare according to the conventional method shown in the flow process 1.Be prepared as follows initial substance: (3-fluoro-4-methoxyl group) phenylacetic acid ethyl ester
Figure A9980989401352
To (3-fluoro-4-hydroxyl) phenylacetic acid ethyl ester (2.5g, add in 20mL acetone 8.9mmol) potassium carbonate (3.4g, 24.2mmol) and iodomethane (1.5mL, 24.2mmol).Reactant mixture is heated to refluxed 2 hours, cool off and be distributed between the saturated sodium bicarbonate and ether.With salt water washing organic layer, through dried over mgso, filter and concentrate and obtain 2.3g (88%) title compound, be yellow oil. 1H?NMR(CDCl 3；300MHz)δ7.06-6.88(m,3H),4.15(q,J=7.2Hz,2H),3.88(s,3H),3.54(s,2H),1.26(t,J=7.2Hz,3H)。
Embodiment 31
N-(4-[4-(3-cyanopyrrole base) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
Figure A9980989401353
To N-[(4-{4-[3-((oxyimino) methyl) pyrrole radicals] phenyl }-5-oxo-2-dihydrogen isoxazole-2-yl) methyl] acetamide (100mg, 3ml CH 0.29mmol) 3CN and 1ml CCl 4Mixture in add the polymer combination triphenyl phasphine (400mg, 1.2mmol), and with mixture heating 8 hours under refluxing.Then it is dissolved in the ethyl acetate again, filters and the concentrated yellow solid that obtains.Grind this solid with ether and obtain 30mg (32%) title compound, be yellow solid. 1H?NMR(300MHz,DMSO-d 6)δ9.08(s,1H),8.97(t,J=6Hz,1H),8.28(s,1H),7.92(d,J=9Hz,2H),7.70(d,J=9Hz,2H),7.59(m,1H),6.74(m,1H),5.06(d,J=6Hz,2H),1.86(s,3H)。
Embodiment 32
N-[(4-{4-[3-((1E) 2-azepine-2-methoxy-ethylene base) pyrrole radicals] phenyl }-5-oxo-2-dihydrogen isoxazole-2-yl) methyl] acetamide
With N-({ 4-[4-(3-formylpyrrole base) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide (100mg, 0.3mmol), HCl.NH 2OCH 3(31mg, 0.37mmol) and sodium carbonate (20mg, mixture 0.19mmol) are dissolved in 3mL MeOH and the 2mL water.In this mixture, add acetic acid pH is transferred to 5.Reactant is heated to backflow 1 hour.Reactant is cooled to room temperature, collects yellow mercury oxide after filtration, obtain 40mg (36%) title compound, be yellow solid.(M+H +)=355。
Embodiment 33
N-{[4-(4-{3-[(1E)-2-(acetylamino)-2-azepine vinyl] pyrrole radicals } phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide
Figure A9980989401371
To be dissolved in N-among the 3mL EtOH (4-[4-(3-formylpyrrole base) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl] methyl) acetamide (100mg, 0.3mmol) and acetic acid hydrazides (28mg, mixture 0.38mmol) heated in backflow 1 hour.Reactant is cooled to room temperature, collects yellow mercury oxide after filtration, obtain 80mg (36%) title compound.(M+H +)=382。
Embodiment 34
1-(4-{2-[(acetylamino) methyl]-5-oxo-2-dihydrogen isoxazole-4-yl } phenyl) pyrazoles-4-carboxylic acid, ethyl ester
Figure A9980989401372
N-{[4-in being dissolved in 3mL methanol (4-diazanyl phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide hydrochloride (150mg, 0.5mmol) mixture in add sodium bicarbonate (50mg, 0.6mmol) and the ethoxycarbonyl malonaldehyde (75mg, 0.52mmol).Mixture at room temperature stirred spend the night.Collect solid after filtration, wash with water then, drying obtains 140mg reddish violet solid.This raw product is obtained 123mg (66%) title compound through silica gel column chromatography (using 5% methanol/ethyl acetate eluting subsequently with ethyl acetate), be yellow solid. 1H?NMR(300MHz,DMSO-d 6)δ9.11(s,1H),9.08(s,1H),8.96(t,J=6Hz,1H),8.15(s,1H),7.95(m,4H),5.06(d,J=6Hz,2H),4.28(q,J=7Hz,2H),1.86(s,3H),1.31(t,J=7Hz,3H)。
Starting material, N-{[4-(4-diazanyl phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl } acetamide hydrochloride is prepared as follows.Under 0 ℃, with 5 minutes, will be dissolved in sodium nitrite in the 2mL water (112mg 1.6mmol) joins N-{[4-(4-aminophenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl (400mg is in concentrated hydrochloric acid solution 1.6mmol) for acetamide.Under 0 ℃,, add SnCl then with reactant restir 10 minutes 22H 2O (720mg, 2mL concentrated hydrochloric acid solution 3.2mmol).Mixture was at room temperature stirred 3 hours.Then reactant mixture is filtered to collect yellow solid, obtain 260mg (55%) title compound with this solid of 3mL water washing and drying. 1H?NMR(300MHz,DMSO-d 6)δ10.2(s,2H),8.94(t,J=6Hz,1H),8.82(s,1H),8.35(s,1H),7.70(d,J=9,2H),6.99(d,J=9,2H),4.99(d,J=6Hz,2H),1.84(s,3H)。
Embodiment 35
N-(4-[4-(4-cyano pyrazole base) phenyl]-5-oxo-2-dihydrogen isoxazole-2-yl } methyl) acetamide
Figure A9980989401381
To N-{[4-(4-diazanyl phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl acetamide hydrochloride (50mg, add in 2mL methanol solution 0.17mmol) 20mg (0.24mmol) sodium bicarbonate and cyano group malonaldehyde (30mg, 0.3mmol).At room temperature stir this mixture overnight.Then it is concentrated and obtain a kind of solid, water, obtain 42mg (76%) title compound with this solid of methanol wash then, be yellow solid. 1H?NMR(300MHz,DMSO-d 6)δ9.35(s,1H),9.10(s,1H),8.98(t,J=6Hz,1H),8.37(s,1H),7.93(m,4H),5.07(d,J=6Hz,2H),1.86(s,3H)。
The preparation of cyano group malonaldehyde.(0.82g, 50% is suspended in the mineral oil, 17mmol) to add sodium hydride in exsiccant flask.Ether with 15mL washs sodium hydride three times, and the ether with 15mL joins in the flask then.After this slurry is cooled to 0 ℃, add Ethyl formate (10.4g, 140mmol).In this mixture, add and be dissolved in 3 in the 10mL ether, 3-diethoxy propionitrile (2g, 14mmol) lasting 2 hours (syringe pump).At room temperature mixture was stirred 20 hours, pour into then in the 100mL frozen water.With this solution of extracted with diethyl ether three times, then ether extraction liquid is discarded.The water-bearing layer is acidified to pH3 and uses dichloromethane extraction with concentrated hydrochloric acid.Through the dried over mgso organic layer, filter and concentrate and obtain 0.3g cyano group malonaldehyde, be yellow solid.From the water-bearing layer of pH3, obtain other product: the water-bearing layer is concentrated into drying, is dissolved in then in the 5mL methanol.Remove inorganic salt after filtration, concentrated filtrate obtains 1g cyano group malonaldehyde, is yellow solid. 1H?NMR(300MHz,DMSO-d 6)δ8.94(s,2H),4.95(brs,1H)。
Embodiment 36
N-{[5-oxo-4-(4-pyrazolyl phenyl)-2-Qingization isoxazole-2-yl] methyl } acetamide
Figure A9980989401391
To N-{[4-(4-diazanyl phenyl)-5-oxo-2-dihydrogen isoxazole-2-yl] methyl acetamide hydrochloride (100mg, add in 3mL methanol solution 0.33mmol) sodium bicarbonate (28mg, 0.33mmol) and malonaldehyde (50mg, 0.35mmol).At room temperature mixture is stirred and spend the night.Then it is concentrated and obtain the 120mg yellow oil, obtain 30mg (30%) title compound through silica gel column chromatography (using eluent ethyl acetate) purification then, be yellow solid. 1H?NMR(300MHz,DMSO-d 6)δ9.03(s,1H),8.95(t,J=6Hz,1H),8.52(s,1H),7.88(m,4H),7.75(s,1H),6.56(s,1H),5.05(d,J=6Hz,2H),1.86(s,3H)。
Show some representative compounds of the present invention in the following table, comprise chemical constitution, characteristic property (MS data) and the preparation method of above embodiment 1-36 chemical compound.
Figure A9980989401411
Figure A9980989401421
Figure A9980989401431
Figure A9980989401441
Figure A9980989401461
Figure A9980989401471
Figure A9980989401481
Figure A9980989401501
Figure A9980989401521

Claims (7)

1. following formula: compound or its pharmaceutically acceptable salt, Wherein: R 1Be
a)H，
B) C 1-8Alkyl is by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8Acyloxy is optional to be replaced,
C) C 3-6Cycloalkyl, or
D) C 1-8Alkoxyl; L is oxygen or sulfur; A is
a)
Figure A9980989400022
b)
C) have 1-3 the first heteroaromatic moiety of heteroatomic 5-that is selected from S, N and O, the first heteroaromatic moiety of wherein said 5-is by carbon atom bonding and can have the benzene of condensing or naphthyl ring in addition, and wherein heteroaromatic moiety is by 1-3 R 8The optional replacement,
D) have the 6-unit heteroaromatic moiety of at least one nitrogen-atoms, wherein said heteroaromatic moiety is by carbon atom bonding, and wherein said 6-unit heteroaromatic moiety can have the benzene of condensing or naphthyl ring in addition, and wherein said heteroaromatic moiety is by 1-3 R 9The optional replacement,
E) B-carboline-3-base or the indolizine base that closes by 6-unit ring key are by 1-3 R 9The optional replacement,
F)
Figure A9980989400031
Or
G)
Figure A9980989400032
R wherein 2And R 3Each independently is
a)H,
b)F,
c)Cl,
d)Br,
E) C 1-6Alkyl,
f)NO 2,
g)I,
H) C 1-6Alkoxyl,
I)OH,
J) amino,
K) cyano group, or
L) R 2And R 3Be together-O (CH 2) h-O; R wherein 4Be
a)H,
B) C 1-2Alkyl,
C) F, or
D) OH; R 5Be
a)H,
b)CF 3,
C) by the optional C that replaces of one or more halos 1-3Alkyl,
D) by the optional phenyl that replaces of one or more halos,
E) R 5And R 6Be 5-, 6-or the 7-unit ring of following formula together,
Figure A9980989400041
F) Wherein D is S, O or NR 86, R wherein 86Be H or C 1-6Alkyl, or
G) work as R 7When being electron withdraw group, R 5And R 6Be together-(CH 2) K-; R 6And R 7Be identical or different in all cases, be
A) electron withdraw group,
b)H,
c)CF 3,
D) by the optional C that replaces of a halo 1-3Alkyl,
E) phenyl, condition are R 6And R 7In at least one is an electron withdraw group, or
F) R 6And R 7Be 5-, 6-or the 7-unit ring of following formula together,
Figure A9980989400043
U is
a)CH 2,
b)O,
C) S or
D) NR 16R 16Be
A) H or
B) C 1-5Alkyl; R wherein 8Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
l)-NR 17R 18,
M)
Figure A9980989400051
R wherein 87Be H or C 1-6Alkyl,
N) C 1-6Alkyl is by OH, sulfonamides, C 1-5Alkoxyl, C 1-5Acyl group or-NR 17R 18The optional replacement,
O) C 2-8Alkyl is by one or two R 19The optional replacement,
P) phenyl is by one or two R 19The optional replacement,
Q) have 1-3 the saturated or unsaturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N and O, by one or two R 19The optional replacement, or
Figure A9980989400052
R 17And R 18Be identical or different in all cases, be
a)H,
B) C 1-4Alkyl,
C) C 5-6Cycloalkyl, or
D) R 17And R 18With nitrogen-atoms is the saturated or unsaturated heterocyclic moiety of 5-or 6-unit, and this part is optional to have the another one hetero atom that is selected from S, N, O, can choose wantonly by following group to replace (being included on the another one nitrogen-atoms): C 1-3The heteroaromatic moiety of alkyl, formoxyl, the 5-that contains 1-3 O, N or S or 6-unit, R wherein 88And R 89Each independently is hydrogen or C 1-6Alkyl, SO 2R 90, R wherein 90Be H or C 1-6Alkyl or by the optional C that replaces of one or more F, Cl or OH 1-3Acyl group; R 19Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
L) C 1-6Alkyl is by OH, C 1-5Alkoxyl, C 1-5Acyl group or-NR 17R 18The optional replacement,
M) phenyl,
n)-C(=O)NR 20R 21,
o)-NR 17R 18,
p)-N(R 20)(-SO 2R 22),
Q)-SO 2-NR 20R 21, or
R)-S (=O) iR 22R 20And R 21Be identical or different in all cases, be
a)H,
B) C 1-6Alkyl, or
C) phenyl; R 22Be
A) C 1-4Alkyl, or
B) by C 1-4The optional phenyl that replaces of alkyl; R wherein 9Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3
g)NO 2
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group,
K) C 1-6Acyl group,
l)-NR 23R 24,
M) C 1-6Alkyl is by OH, C 1-5Alkoxyl, C 1-5Acyl group or-NR 23R 24The optional replacement,
N) by one or two R 25The optional C that replaces 2-8The alkenyl phenyl,
O) by one or two R 25The optional phenyl that replaces,
P) have 1-3 the saturated or undersaturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N and O, by one or two R 25The optional replacement, or
Q)
Figure A9980989400081
R 23And R 24Be identical or different in all cases, be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl, or
G) R 23And R 24With nitrogen-atoms is the saturated heterocyclic moiety of 5-or 6-unit, and this part can be chosen wantonly has the hetero atom that another is selected from S, N, O, equally also can replace (being included on another nitrogen-atoms) by following substituent group: phenyl, pyrimidine radicals, C 1-3Alkyl or C 1-3Acyl group; R 25Be
A) carboxyl,
B) halo,
c)-CN,
D) sulfydryl,
E) formoxyl,
f)CF 3,
g)NO 2,
H) C 1-6Alkoxyl,
I) C 1-6Alkoxy carbonyl,
J) C 1-6Alkylthio group
K) C 1-6Acyl group,
L) phenyl,
M) C 1-6Alkyl is by OH, azido, C 1-5Alkoxyl, C 1-5Acyl group ,-NR 32R 33,-SR 34,-O-SO 2R 35Or
Figure A9980989400091
The optional replacement,
n)-C(=O)NR 26R 27,
o)-NR 23R 24,
p)-N(R 26)(-SO 2R 22),
Q)-SO 2-NR 26R 27, or
r)-S(=O) iR 22,
S)-CH=N-R 28, or
T)-CH (OH)-SO 3R 31R 22As defined above; R 26And R 27Be identical or different in all cases, be
a)H,
B) C 1-6Alkyl,
C) phenyl, or
D) tolyl; R 28Be
a)OH,
B) benzyloxy,
c)-NH-C(=O)-NH 2,
D)-NH-C (=S)-NH 2, or
E)-NH-C (=NH)-NR 29R 30R 29And R 30Be identical or different in all cases, be
A) H, or
B) by phenyl or the optional C that replaces of pyridine radicals 1-4Alkyl; R 31Be
A) H, or
B) sodium ion; R 32And R 33Be identical or different in all cases, be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl,
G) R 32And R 33Be to have 1-3 the saturated heterocyclic moiety of 5-or 6-unit that is selected from the atom of S, N, O together, optional by following substituent group replacement (being included on the described nitrogen-atoms): phenyl, pyrimidine radicals, C 1-3Alkyl or C 1-3Acyl group,
H)-P (O) (OR 37) (OR 38), or
I)-SO 2-R 39R 34Be R 35Be C 1-3Alkyl; R 36Be
A) C 1-6Alkoxy carbonyl, or
B) carboxyl; R 37And R 38Be identical or different in all cases, be
A) H, or
B) C 1-3Alkyl; R 39Be
A) methyl,
B) phenyl, or
C) tolyl; Wherein K is
a)O,
B) S, or
C) NR 40, R wherein 40Be hydrogen, formoxyl, C 1-4Alkyl, C 1-4Acyl group, phenyl, C 3-6Cycloalkyl ,-P (O) (OR 37) (OR 38) or-SO 2-R 39, R wherein 37, R 38And R 39As defined above; R 10, R 11, R 12, R 13, R 14And R 15Be identical or different in all cases, be
a)H,
B) formoxyl,
C) carboxyl,
D) C 1-6Alkoxy carbonyl,
E) C 1-8Alkyl,
F) C 2-8Alkenyl, wherein substituent group (e) and (f) can be by OH, halo, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl or by the optional phenyl that replaces of halo optional replacement,
G) have 6-10 carbon atom, the optional aromatics part that replaces by following substituent group: carboxyl, halo ,-CN, formoxyl, CF 3, NO 2, C 1-6Alkyl, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl;
h)-NR 42R 43,
i)OR 44,
j)-S(=O) i-R 45,
K)-SO 2-N (R 46) (R 47), or
L) group of following formula: R 19As defined above; T is
a)O,
B) S, or
C) SO 2R 42And R 43Be identical or different in all cases, be
a)H,
B) C 3-6Cycloalkyl,
C) phenyl,
D) C 1-6Acyl group,
E) by OH, C 1-6Alkoxyl (this alkoxyl can be by OH, have 1-3 is selected from the 5-of atom of S, N and O or the aromatic heterocycle of 6-unit partly replaces), by OH, CF 3, halo ,-NO 2, C 1-4Alkoxyl ,-NR 48R 49The optional phenyl that replaces or The optional C that replaces 1-8Alkyl, or
F)
Figure A9980989400123
Or
G)
Figure A9980989400124
V is
a)O,
B) CH 2, or
C) NR 56R 48And R 49Be identical or different in all cases, be
A) H, or
B) C 1-4Alkyl; R 54Be
a)OH,
B) C 1-4Alkoxyl, or
C)-NR 57R 58R 55Be
A) H, or
B) by indyl, OH, sulfydryl, imidazole radicals, methyl mercapto, amino, by OH ,-C (=O)-NH 2,-CO 2H or-C (=NH)-NH 2The optional C that replaces of the optional phenyl that replaces 1-7Alkyl; R 56Be
a)H,
B) phenyl, or
C) by the optional C that replaces of OH 1-6Alkyl; R 57And R 58Be identical or different in all cases, be
a)H,
B) C 1-5Alkyl,
C) C 1-3Cycloalkyl, or
D) phenyl; R 44Be
A) by C 1-6Alkoxyl or C 1-6Hydroxyl, C 3-6Cycloalkyl, has the partly optional C that replaces of the optional benzo-condensed heterocycle of 6-unit aromatics of 1-3 nitrogen-atoms 1-8Alkyl, this benzo-fused heterocycle part can by one or two-NO 2, CF 3, halo ,-CN, OH, C 1-5Alkyl, C 1-5Alkoxyl or C 1-5Acyl substituted,
b)
Figure A9980989400141
C) phenyl, or
D) pyridine radicals; R 45Be
A) C 1-16Alkyl,
B) C 2-16Alkenyl, wherein substituent group (a) and (b) can be by C 1-6Alkoxy carbonyl or have that 1-3 is selected from 5-, the 6-of the atom of S, N and O or 7-unit aromatic heterocycle is partly optional replaces,
C) have the aromatics part of 6-10 carbon atom, or
D) have 5-, 6-or the 7-unit aromatic heterocycle part that 1-3 is selected from the atom of S, N and O, wherein substituent group (c) and (d) can by carboxyl, halo ,-CN, formoxyl, CF 3,-NO 2, C 1-6Alkyl, C 1-6Alkoxyl, C 1-6Acyl group, C 1-6Alkylthio group or C 1-6Alkoxy carbonyl is optional to be replaced; R 46And R 47In all cases can be identical or different, be
a)H,
B) phenyl,
C) C 1-6Alkyl, or
D) benzyl; R 50And R 51Be identical or different in all cases, be
a)H,
b)OH,
C) by-NR 48R 49The optional C that replaces 1-6Alkyl, wherein R 48And R 49As defined above,
D) R 50And R 51Be together=O; R 52Be
A) have the aromatics part of 6-10 carbon atom,
B) have 1-3 and be selected from the 5-of atom of S, N and O or the optional benzo of aromatics-condensed heterocycle part of 6-unit, wherein substituent group (a) and (b) equally can-NO individual by 1-3 2, CF 3, halo ,-CN, OH, phenyl, C 1-5Alkyl, C 1-5Alkoxyl or C 1-5Acyl group is optional to be replaced,
C) morpholinyl,
d)OH,
E) C 1-6Alkoxyl,
F)-NR 48R 49, R wherein 48And R 49As defined above,
G)-C (=O)-R 59, or
H) R 53Be
a)H,
B) formoxyl,
C) C 1-4Alkyl,
D) C 1-4Acyl group,
E) phenyl,
F) C 3-6Cycloalkyl,
G)-P (O) (OR 37) (OR 38), or
H)-SO 2R 39, R wherein 37, R 38And R 39As defined above; R 59Be
A) morpholinyl,
B) OH, or
C) C 1-6Alkoxyl; H is 1,2 or 3; I is 0,1 or 2; J is 0 or 1; K is 3,4 or 5; R is 1,2,3,4,5 or 6; T is 0,1,2,3,4,5 or 6; U is 1 or 2; With Q be
A) hydrogen;
B) halo;
c)NO 2,
d)N 3,
E) C 1-6Alkylthio group,
f)
Figure A9980989400161
g)
Figure A9980989400162
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
Figure A9980989400163
Figure A9980989400164
M)-sulfonamides (H 2NSO 2-),
n)-NHOH,
Figure A9980989400165
P) heteroaryl Wherein heteroaryl is to have heteroatomic 5-or a 6-unit aromatic heterocyclic group that 1-3 is selected from O, N or S,
q)
R) amino,
S) C 1-C 6Alkyl amino-,
T) two (C 1-C 6Alkyl) amino-
U)
Figure A9980989400172
R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl,
v)OH,
W) cyano group,
X) hydroxyl (C 1-C 6Alkyl),
y)
Figure A9980989400173
Z) Wherein r is 1-6,
aa)
bb)
Cc)
Figure A9980989400177
R wherein 84Be hydrogen or C 1-6Alkyl,
Dd) R wherein 85Be hydrogen, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl;
Ee)
Figure A9980989400179
R wherein 84Be hydrogen or C 1-6Alkyl,
Ff) replace or unsubstituted C 6-C 10Aryl moiety,
Gg) have 1-3 atom, that replace or unsubstituted monocycle or dicyclo, saturated or undersaturated heterocyclic moiety that is selected from O, N or S, described ring is bonded on the benzene substituent group by ring carbon or nitrogen,
Hh) have 1-3 and be selected from the heteroatomic monocycle of O, N or S or the replacement or the unsubstituted heteroaromatic moiety of dicyclo, described ring is bonded on the phenyl substituent by ring carbon or nitrogen, and wherein this heteroaromatic moiety can have condensed benzene or naphthalene nucleus in addition; Described substituent group for example p, q, ff, gg and hh partly is selected from following 1 or 2 group: 1) halo, 2) C 1-6Alkyl, 3) NO 2, 4) and N 3, 5)
Figure A9980989400181
6) 7) formoxyl, 8) 9)
Figure A9980989400184
10) heteroaryl
Figure A9980989400185
Wherein heteroaryl is to have 1-3 to be selected from the heteroatomic 5-of O, N or S or the aromatic heterocyclic group of 6-unit, 11)
Figure A9980989400186
12)
Figure A9980989400187
R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl, 13) OH, 14) hydroxyl (C 1-C 6Alkyl), 15) 16) Wherein r is 1-6,17) 18)-CH 2-R 80, R wherein 80Be
A)-OR 32, R wherein 32As defined above,
B)-SR 32, R wherein 32As defined above,
C)-NR 32R 33, R wherein 32And R 33As defined above, or
D) contain the 5-of 1-4 O, S or N atom or the heteroaromatic of 6-unit, 19) R wherein 84As defined above, 20) cyano group, 21) carboxyl, 22) CF 3, 23) 24)
Figure A9980989400196
Wherein phenyl moiety can be by halo or (C 1-C 6) the optional replacement of alkyl, 25) R wherein 60And R 61As defined above, 26) Or R wherein 91Be to have the 5-of 1-3 O, N or S or the aromatic heterocyclic group of 6-unit, 27) 28) R wherein 85As defined above, 29)
Figure A9980989400201
R wherein 99, R 100And R 101Each independently is C 1-6Alkyl; Or Q and R 1And R 2One of formation-O-CH together 2-O.
2. the chemical compound of claim 1, wherein A is
Figure A9980989400202
Wherein Q, R 2And R 3Such as in claim 1 definition.
3. following formula: compound or its pharmaceutically acceptable salt,
Figure A9980989400203
R wherein 1Be H, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl; R 2And R 3Each independently is
a)H,
b)F,
c)Cl,
d)Br,
E) C 1-6Alkyl,
f)NO 2,
g)I,
H) C 1-6Alkoxyl,
i)OH,
J) amino, or
K) cyano group; With Q be
A) hydrogen,
B) halo,
c)NO 2,
d)N 3,
E) C 1-C 6Alkylthio group,
f)
g)
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
l)
m)
Figure A9980989400215
N) heteroaryl
Figure A9980989400216
Wherein heteroaryl is to have heteroatomic 5-or a 6-unit aromatic heterocyclic group that 1-3 is selected from O, N or S,
o)
Figure A9980989400217
P) amino,
Q) C 1-C 6Alkyl amino-,
R) two (C 1-C 6Alkyl) amino-,
S)
Figure A9980989400218
R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl,
t)OH,
U) cyano group,
V) hydroxyl (C 1-C 6Alkyl),
w)
Figure A9980989400221
X) Wherein r is 1-6,
y)
z)
Figure A9980989400224
Aa)
Figure A9980989400225
R wherein 84Be hydrogen or C 1-6Alkyl,
Bb)
Figure A9980989400226
R wherein 85Be hydrogen, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl,
Cc) R wherein 84As defined above,
dd)
Figure A9980989400228
ee)
Figure A9980989400229
ff)
Figure A99809894002210
gg)
Figure A9980989400231
hh)
ii)
jj)
Figure A9980989400234
kk)
ll)
mm)
nn)
Figure A9980989400238
Oo)
Figure A9980989400241
R wherein 92Be H or C 1-6Alkyl,
pp)
Figure A9980989400242
qq)
rr)
ss)
tt)
Figure A9980989400246
uu)
Figure A9980989400247
vv)
ww)
xx)
Figure A9980989400252
yy)
Figure A9980989400253
zz)
Figure A9980989400254
Aaa) by X and the optional diazine that replaces of Y,
Bbb) by X and the optional triazine radical that replaces of Y,
Ccc) by X and the optional quinolyl that replaces of Y,
Ddd) by X and the optional quinoxalinyl that replaces of Y,
Eee) by X and the optional phthalazinyl that replaces of Y,
fff)
ggg)
Hhh)
Figure A9980989400261
Or
iii)
Figure A9980989400262
B is the unsaturated 4-atom connector with a nitrogen and three carbon; M is
a)H,
B) C 1-8Alkyl,
C) C 3-8Cycloalkyl,
D)-(CH 2) mOR 66, or
E)-(CH 2) nNR 67R 68Z is
a)O,
B) S, or
C) NM; W is
a)CH,
B) N or
C) S or O are when Z is NM; X and Y each independently be
A) hydrogen,
B) halo,
c)NO 2,
d)N 3,
E) C 1-6Alkylthio group,
f)
Figure A9980989400271
g)
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
l)
Figure A9980989400274
M) heteroaryl
Figure A9980989400275
Wherein heteroaryl is to have heteroatomic 5-or a 6-unit aromatic heterocyclic group that 1-3 is selected from O, N or S,
n)
O) amino,
P) C 1-C 6Alkyl amino-,
Q) two (C 1-C 6Alkyl) amino-,
R) R wherein 60And R 61Each independently is hydrogen or C 1-C 6Alkyl,
s)OH,
T) hydroxyl (C 1-C 6Alkyl),
u)
V) Wherein r is 1-6,
w)
Figure A9980989400281
x)
Y)
Figure A9980989400283
R wherein 84As defined above,
Z) cyano group,
Aa) carboxyl,
bb)CF 3,
Cc) sulfydryl,
dd)
Figure A9980989400284
Ee) Wherein phenyl moiety can be by halo or C 1-C 6Alkyl is optional to be replaced,
ff)
Figure A9980989400286
Gg)
Figure A9980989400287
R wherein 85As defined above, or
Hh)
Figure A9980989400288
R wherein 99, R 100And R 101Each independently is C 1-6Alkyl; Or Q and R 1And R 3One of common formation-O-CH 2-O; R 62Be
a)H,
B) by the optional C that replaces of one or more halos 1-8Alkyl, or
C) by one or more OH, or C 1-8The optional C that replaces of alkoxyl 1-8Alkyl, E is
a)NR 69,
B)-S (=O) i, wherein i is 0,1 or 2, or
C) O; R 63Be
a)H,
B) C 1-6Alkyl,
C)-(CH 2) q-aryl, or
D) halo; R 66Be H or C 1-4Alkyl; R 67And R 68Each independently is H or C 1-4Alkyl, or NR 67R 68Be together-(CH 2) m-; R 69Be
a)H,
B) C 1-6Alkyl,
C)-(CH 2) q-aryl,
d)-CO 2R 81,
e)COR 82,
f)-C(=O)-(CH 2) q-C(=O)R 81,
G)-S (=O) z-C 1-6Alkyl,
H)-S (=O) z-(CH 2) q-aryl, or
I)-(C=O) j-Het, wherein j is 0 or 1; Z 1Be
A)-CH 2-, or
B)-CH (R 70)-CH 2-; Z 2Be
a)-O 2S-,
b)-O-,
c)-S-,
D)-SO-, or
E)-N (R 71)-; Z 3Be
a)S,
b)SO,
C) SO 2, or
D) O; A 1Be H or CH 3A 2Be
a)H,
b)OH-,
c)CH 3CO 2-,
d)CH 3-,
e)CH 3O-,
f)R 72O-CH 2-C(O)-NH-,
g)R 73O-C(O)-NH-,
h)R 73-C(O)-NH-,
I) (C 1-C 2) alkyl-O-C (O)-, or
J) HO-CH 2Or A 1And A 2Be together
A)
Figure A9980989400301
Or
B) O=; R 64Be H or CH 3
M is 4 or 5;
N is 0,1,2,3,4 or 5;
Y is 0 or 1;
P is 0,1,2,3,4 or 5;
W is 1,2 or 3;
Q is 1,2,3 or 4;
Z is 0 or 1; R 65Be
a)R 74OC(R 75)(R 76)-C(O)-,
b)R 77OC(O)-,
c)R 78(O)-,
D) R 79-SO 2-, or
E) R 80-NH-C (O)-; R 70Be H or (C 1-C 3) alkyl; R 71Be
a)R 74OC(R 75)(R 76)-C(O)-,
b)R 77O-C(O)-,
c)R 78-C(O)-,
d)
e)
Figure A9980989400312
f)H 3C-C(O)-(CH 2) 2-C(O)-,
g)R 79-SO 2-,
h)
Figure A9980989400313
I) R 80-NH-C (O)-, R 72Be
a)H,
b)CH 3,
C) phenyl-CH 2-, or
D) CH 3C (O)-; R 73Be (C 1-C 3) alkyl or phenyl; R 74Be H, CH 3, phenyl-CH 2-or CH 3-C (O)-; R 75And R 76Each independently is H or CH 3, or R 75And R 76Be together-CH 2CH 2-; R 77Be (C 1-C 3) alkyl or phenyl; R 78Be H, (C 1-C 4) alkyl, aryl-(CH 2) n 1, ClH 2C, Cl 2HC, FH 2C-, F 2HC-or (C 3-C 6) cycloalkyl; R 79Be CH 3,-CH 2Cl ,-CH 2CH=CH 2, aryl or-CH 2CN; R 80Be-(CH 2) n 1-aryl, wherein n 1Be 0 or 1; R 81Be
a)H,
B) by the optional C that replaces of one or more OH, halo or CN 1-6Alkyl,
C)-(CH 2) q-aryl, wherein q as defined above, or
D)-(CH 2) q-OR 83, wherein q as defined above; R 82Be
A) by the optional C that replaces of one or more OH, halo or CN 1-6Alkyl,
B)-(CH 2) q-aryl, wherein q as defined above, or
C)-(CH 2) q-OR 83, wherein q as defined above; R 83Be
a)H,
B) C 1-6Alkyl,
C)-(CH 2) q-aryl, wherein q as defined above, or
D)-C (=O) C 1-6Alkyl; With aryl be phenyl, pyridine radicals or naphthyl, described phenyl, pyridine radicals or naphthyl moiety by one or more halos ,-CN, OH, SH, C 1-6Alkoxyl or C 1-6Alkylthio group is optional to be replaced.
4. following formula: compound or its pharmaceutically acceptable salt, R wherein 1Be H, by one or more F, Cl, OH, C 1-8Alkoxyl or C 1-8The optional C that replaces of acyloxy 1-8Alkyl, C 3-6Cycloalkyl or C 1-8Alkoxyl; R 2And R 3Each independently is H or F; Or R 2And R 3Representative together
Figure A9980989400331
Q is
A) hydrogen,
B) halo,
c)N 3,
d)NO 2,
E) C 1-C 6Alkylthio group,
f)
g)
Figure A9980989400333
H) C 1-C 6Alkyl,
I) C 1-C 6Alkoxyl,
J) formoxyl,
k)
Figure A9980989400334
l)
Figure A9980989400335
m)
Figure A9980989400336
N) (C 1-C 6Alkoxyl) 2N-,
O) contain 1-3 O, N or S and be connected to the 5-on the phenyl substituent or the heterocycle of 6-unit by carbon or nitrogen, described heterocyclic moiety is by R 96The optional replacement,
p)
Figure A9980989400341
Q) by R 96The optional phenyl that replaces, or
R) contain 1-3 O, N or S and be connected to the saturated or undersaturated heterocycle of 5-on the phenyl substituent or 6-unit by carbon or nitrogen, described heterocyclic moiety is by R 96The optional replacement, and R 96Be
A) C 1-C 6Alkyl-OH,
b)
c)
Figure A9980989400343
D) cyano group,
E) formoxyl,
f)
Figure A9980989400344
g)
Figure A9980989400345
H)
Figure A9980989400346
R wherein 84, R 85And R 86Each independently is C 1-6Alkyl,
I)
j)
Figure A9980989400348
K)
Figure A9980989400349
Wherein phenyl can replace by halo is optional,
l)
M) (C 1-C 6Alkyl) 2N-,
N) C 1-C 6Alkyl-NH-,
O) amino,
p)
Q)
Figure A9980989400352
Or
R)
Figure A9980989400353
R wherein 98Be phenyl, contain 1-3 O, N or S and be connected to 5-or 6-unit heteroaryl on the phenyl substituent, or contain 1-4 O, N or S and be connected to 5-or the first saturated or undersaturated heterocycle of 6-on the phenyl substituent by a ring carbon atom by a ring carbon atom.
5. chemical compound is selected from the chemical compound of the embodiment 1-97 described in the description.
6. Pharmaceutical composition comprises the chemical compound of claim 1 and pharmaceutically acceptable adjuvant, diluent or carrier.
7. treat the method for mammal bacterial infection, this method comprises the chemical compound of the claim 1 of the mammal treatment effective dose that needs this treatment.
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