U.S. patent application number 14/932508 was filed with the patent office on 2019-10-24 for antimicrobial compounds and methods of making and using the same.
The applicant listed for this patent is Melinta Therapeutics, Inc.. Invention is credited to Ashoke Bhattacharjee, Shili Chen, Erin M. Duffy, Zoltan F. Kanyo, Matthew H. Scheideman, Yuanqing Tang.
Application Number | 20190322668 14/932508 |
Document ID | / |
Family ID | 47357660 |
Filed Date | 2019-10-24 |
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United States Patent
Application |
20190322668 |
Kind Code |
A1 |
Duffy; Erin M. ; et
al. |
October 24, 2019 |
ANTIMICROBIAL COMPOUNDS AND METHODS OF MAKING AND USING THE
SAME
Abstract
The present invention relates generally to the field of
antimicrobial compounds and to methods of making and using them.
These compounds are useful for treating, preventing, and reducing
the risk of microbial infections in humans and animals.
Inventors: |
Duffy; Erin M.; (Deep River,
CT) ; Bhattacharjee; Ashoke; (Cheshire, CT) ;
Chen; Shili; (Cheshire, CT) ; Kanyo; Zoltan F.;
(North Haven, CT) ; Scheideman; Matthew H.; (New
Haven, CT) ; Tang; Yuanqing; (Cheshire, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Melinta Therapeutics, Inc. |
New Haven |
CT |
US |
|
|
Family ID: |
47357660 |
Appl. No.: |
14/932508 |
Filed: |
November 4, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14112027 |
Feb 7, 2014 |
9221827 |
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PCT/US2012/032994 |
Apr 11, 2012 |
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14932508 |
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61476138 |
Apr 15, 2011 |
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61535118 |
Sep 15, 2011 |
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61610363 |
Mar 13, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 17/00 20180101; C07D 403/12 20130101; A61P 31/04 20180101;
A61P 31/06 20180101; A61P 31/00 20180101; C07D 239/36 20130101;
C07D 487/04 20130101; A61P 19/08 20180101; C07D 401/14 20130101;
A61P 13/02 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 239/36 20060101 C07D239/36; C07D 403/12 20060101
C07D403/12; C07D 401/14 20060101 C07D401/14 |
Claims
1-60. (canceled)
61. A method of treating, preventing, or reducing a microbial
infection in a human or animal comprising administering to the
human or animal an effective amount of a compound according to the
formula: ##STR01095## or a tautomer thereof, or a pharmaceutically
acceptable salt, ester, or prodrug of said compound or tautomer,
wherein X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or N; X.sub.3
is CR.sup.3 or N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or
N; with the proviso that X.sub.1, X.sub.2, X.sub.3, X.sub.4, and
X.sub.5 are not all N; Y.sub.6 is CR.sup.6 or N; Y.sub.7 is
CR.sup.7 or N; Y.sub.8 is CR.sup.8 or N; Y.sub.9 is CR.sup.9 or N;
Y.sub.10 is CR.sup.10 or N; with the proviso that Y.sub.6, Y.sub.7,
Y.sub.8, Y.sub.9, and Y.sub.10 are not all N; wherein R.sup.1,
R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.10
are each independently selected from (a) hydrogen, (b) F, (c) Cl,
(d) Br, (e) I, (f) --CF.sub.3, (g) --CF.sub.2H, (h) --CFH.sub.2,
(i) --OCF.sub.3, (j) --OCF.sub.2H, (k) --OCFH.sub.2, (l)
--OCH.sub.3, (m) --CN, (n) --N.sub.3, (o) --NO.sub.2, (p)
--NR.sup.11R.sup.11, (q) --NR.sup.11C(O)R.sup.11, (r)
--C(O)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2)R.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur); wherein each
(ff) through (nn) is optionally substituted with one or more
R.sup.12; alternatively, wherein two substituents selected from
R.sup.6, R.sup.7, and R.sup.8 are taken together with the carbon
atom to which they are attached to form (a) -3-7 membered saturated
or unsaturated carbocyclic or (b) -3-7 membered saturated or
unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12; each is independently selected from (a) hydrogen,
(b) halogen, (c) --OH, (d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH,
(f) --OCF.sub.3, (g) --OCF.sub.2H, (h) --OCFH.sub.2, (i)
--OCH.sub.3, --OR.sup.12, (k) --COR.sup.12, (l) --CN, (m)
--NO.sub.2, (n) --CONH.sub.2, (o) --CONR.sup.12R.sup.12,(p)
--COCH.sub.3, (q) --S(O).sub.pCH.sub.3, (r)
--S(O).sub.pNR.sup.12R.sup.12, (s) --SR.sup.12, (t) C(O)OH, (u)
C(O)OR.sup.12, (v) --N.sub.3, (w) NH.sub.2, (x)
--NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8 alkyl), (z)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (aa) C.sub.1-C.sub.8 alkyl, (bb)
C.sub.2-C.sub.8 alkenyl, (cc) --C.sub.2-C.sub.8 alkenyl, (dd)
haloalkyl, (ee) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (ff) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (gg) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (hh) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, and (ii)
--(C.dbd.NH)NR.sup.12R.sup.12; wherein each (y) through (hh) is
optionally substituted with one or more R.sup.12; alternatively two
R.sup.11 substituents are taken together to form (a) -3-7 membered
saturated or unsaturated carbocyclic or (b) -3-7 membered saturated
or unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12; R.sup.3 is selected from: ##STR01096## wherein
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.31 are
each independently selected from (a) hydrogen, (b) halogen, (c)
--CN, (d) --N.sub.3, (e) NO.sub.2, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.11,
(k) --C(O)R.sup.11, (l) --C(O)NR.sup.11R.sup.11, (m) NH.sub.2, (n)
--NR.sup.11R.sup.11, (o) --NR.sup.11C(O)R.sup.11,
--S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle; wherein each (s) through (x) is optionally
substituted with one or more R.sup.12; alternatively, one or more
pairs of substituents selected from R.sup.3a and R.sup.3b, R.sup.3c
and R.sup.3d, R.sup.3e and R.sup.3f, R.sup.3g and R.sup.3h,
R.sup.3i and R.sup.3j, and R.sup.3k and R.sup.3l are taken together
with the carbon atom to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic, (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, (c) an exo carbon-carbon double bond, (d) carbonyl
group, or (e) thiocarbonyl group; wherein each (a) through (b) is
optionally substituted with one or more R.sup.12; alternatively,
wherein two substituents selected from R.sup.3a, R.sup.3b,
R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g, R.sup.3h,
R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on different carbon
atoms are taken together with the intervening atoms to which they
are attached to form (a) 3-7 membered saturated or unsaturated
carbocyclic or (b) 3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h,R.sup.3i R.sup.3j, R.sup.3k, and R.sup.3l on two
adjacent carbon atoms are taken together with the bond between said
adjacent carbon atoms form a carbon-carbon triple bond; U is
selected from --O--, --S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11NR.sup.11S(O).sub.pNR.sup.11S(O).sub.pNR.sup.11--,
and NR.sup.11C(O)NR.sup.11--, T is selected from
--NR.sup.11R.sup.11, --NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11R.sup.11, and OR.sup.11; alternatively,
one R.sup.11 and one substituent selected from R.sup.3a, R.sup.3b,
R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g, R.sup.3h,
R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.9 is selected from: ##STR01097##
wherein R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are each independently
selected from (a) hydrogen, (b) halogen, (c) --CN, (d) --N.sub.3,
(e) --NO.sub.2, (f) --OCF.sub.3--, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH, (j) --OR.sup.11, (k) --NH.sub.2, (l)
--NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n) --C(O)OR.sup.11, (o)
--C(O)NR.sup.11R.sup.11, (p) --NR.sup.11C(O)R.sup.11, (q)
--S(O).sub.pR.sup.11, (r) --C.sub.1-C.sub.8 alkyl, (s)
--C.sub.2-C.sub.8 alkenyl, (t) --C.sub.1-C.sub.8 alkynyl, (u)
haloalkyl, (v) -3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur, and (w) -3-14
membered saturated, unsaturated, or aromatic carbocycle, wherein
each (r) through (w) is optionally substituted with one or more
R.sup.12; alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group; wherein each (a) through
(c) is optionally substituted with one or more R.sup.12;
alternatively, two substituents selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t on different carbon atoms are taken together
with the intervening atoms to which they are attached to form (a)
-3-7 membered saturated or unsaturated carbocyclic or (b) -3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur; wherein each (a) through (b) is optionally
substituted with one or more R.sup.12; alternatively, two
substituents selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n,
R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or four substituents selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a carbon-carbon triple bond; Z is selected from --O--,
--S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(.dbd.O)--, --(.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11, --NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and --NR.sup.11C(O)NR.sup.11--; W
is selected from --NR.sup.11R.sup.11, --NR.sup.11(CO)OR.sup.11,
NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.12 is independently selected from
(a) hydrogen, (b) halogen, (c) --OH, (d) --SH, (e)
--(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH.sub.2, (j) --O(C.sub.1-C.sub.8 alkyl), (k)
--CN, (l) --NO.sub.2, (m) --CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8
alkyl), (o) C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q)
--COCH.sub.3, (r) --S(O).sub.pCH.sub.3, (s)
--S(O).sub.pN(C.sub.1-C.sub.8 alkyl).sub.2, (t) --S(C.sub.1-C.sub.8
(u) --C(O)OH, (v) --C(O)O(C.sub.1-C.sub.8 alkyl), (w) --N.sub.3,
(x) --NHC(O)(C.sub.1-C.sub.8 alkyl), (y) --N(C.sub.1-C.sub.8
alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z) --NH.sub.2, (aa)
--NH(C.sub.1-C.sub.8 alkyl), (bb) --N(C.sub.1-C.sub.8 alkyl).sub.2,
(cc) --C.sub.1-C.sub.8 alkyl, (dd) --C.sub.2-C.sub.8 alkenyl, (ee)
C.sub.2-C.sub.8 alkynyl, (ff) haloalkyl, (gg) (C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (hh)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (ii) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (jj)
3-14 membered saturated, unsaturated, or aromatic carbocycle, (kk)
--(C.dbd.NH)NH.sub.2, (ll) --C(.dbd.NH)NH.sub.2, (mm)
--C(O)R.sup.13, (nn) .dbd.O, and (oo) .dbd.NR.sup.13; wherein each
(aa) through (jj) is optionally substituted with one or more
R.sup.13; R.sup.13 is independently selected from (a) hydrogen, (b)
halogen, (c) --C.sub.1-C.sub.8 alkyl, (d) --C.sub.2-C.sub.8
alkenyl, (e) --C.sub.2-C.sub.8 alkynyl, (f) haloalkyl, (g) --OH,
(h) --OC.sub.1-C.sub.8 alkyl, (i) --OC.sub.2-C.sub.8 alkenyl, (j)
--OC.sub.2-C.sub.8 alkynyl, (k) --OCF.sub.3, (l) --OCH.sub.3, (m)
--OCF.sub.2H, (n) --OCFH.sub.2, (o) --NH.sub.2, (p) --CN, (q)
--N.sub.3, (r) --S(O).sub.pC.sub.1-C.sub.8 alkyl, (s) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, and (t) -3-14 membered saturated,
unsaturated, or aromatic carbocycle; p is 0,1, or 2; and t is 0,1,
or 2, or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer.
62. (canceled)
63. (canceled)
64. A method of treating, preventing, or reducing the risk of a
microbial infection in a human or animal comprising administering
to the human or animal an effective amount of a compound according
to the formula: ##STR01098## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein X.sub.1 is CR.sup.1 or N; X.sub.2 is
CR.sup.2 or N; X.sub.3 is CR.sup.3 or N; X.sub.4 is CR.sup.4 or N;
Xs is CR.sup.5 or N; with the proviso that X.sub.1, X.sub.2,
X.sub.3, X.sub.4, and X.sub.5 are not all N; Y6 is CR.sup.6 or N;
Y.sub.7 is CR.sup.7 or N; Y.sub.8 is CR.sup.8 or N; Y.sub.9 is
CR.sup.9 or N; Yio is CR.sup.10 or N; with the proviso that
Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, and Y.sub.10 are not all N;
wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.10 are each independently selected from (a)
hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g)
--CF.sub.2H, (h) --CFH.sub.2, (i) --OCF.sub.3, (j) --OCF.sub.2H,
(k) --OCFH.sub.2, (l) --OCH.sub.3, (m) --CN, (n) --N.sub.3, (o)
--NO.sub.2, (p) --NR.sup.11R.sup.11, (q) --NR.sup.11C(O)R.sup.11,
(r) --C(O)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2).sub.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) -(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur); wherein each
(ff) through (nn) is optionally substituted with one or more
R.sup.12; alternatively, wherein two substituents selected from
R.sup.6, R.sup.7, and R.sup.8 are taken together with the carbon
atom to which they are attached to form (a) -3-7 membered saturated
or unsaturated carbocyclic or (b) -3-7 membered saturated or
unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12; each R.sup.11 is independently selected from (a)
hydrogen, (b) halogen, (c) --OH, (d) --SH, (e) --(C.sub.1-C.sub.8
alkyl)OH, (f) (g) --OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3,
(j) --OR.sup.12, (k) --COR.sup.12, (l) --CN, (m) --NO.sub.2, (n)
--CONH.sub.2, (o) --CONR.sup.12R.sup.12, (p) --COCH.sub.3, (q)
--S(O).sub.pCH.sub.3, (r) --S(O).sub.pNR.sup.12R.sup.12, (s)
--SR.sup.12, (t) --C(O)OH, (u) --C(O)OR.sup.12, (v) --N.sub.3, (w)
--NH.sub.2, (x) --NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8
alkyl), (z) --N(C.sub.1-C.sub.8 alkyl).sub.2, (aa)
--C.sub.1-C.sub.8 alkyl, (bb) --C.sub.2-C.sub.8 alkenyl, (cc)
--C.sub.2-C.sub.8 alkenyl, (dd) -haloalkyl, (ee) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (ff)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (gg) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (hh)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, and
(ii) --(C.dbd.NH)NR.sup.12R.sup.12; wherein each (y) through (hh)
is optionally substituted with one or more R.sup.12; alternatively
two R.sup.11 substituents are taken together to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.3 is selected from: ##STR01099##
wherein R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
each independently selected from (a) hydrogen, (b) halogen, (c)
--CN, (d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.11,
(k) --C(O)R.sup.11, (l) --C(O)NR.sup.11R.sup.11, (m) --NH.sub.2,
(n) --NR.sup.11R.sup.11, (o) --NR.sup.11C(O)R.sup.11, (p)
--S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle; wherein each (s) through (x) is optionally
substituted with one or more R.sup.12; alternatively, one or more
pairs of substituents selected from R.sup.3a and R.sup.3b, R.sup.3c
and R.sup.3d, R.sup.3e and R.sup.3f, R.sup.3g and R.sup.3h,
R.sup.3i and R.sup.3j, and R.sup.3k and R.sup.3l are taken together
with the carbon atom to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic, (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, (c) an exo carbon-carbon double bond, (d) carbonyl
group, or (e) thiocarbonyl group; wherein each (a) through (b) is
optionally substituted with one or more R.sup.12; alternatively,
wherein two substituents selected from R.sup.3a, R.sup.3b,
R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g, R.sup.3h,
R.sup.3i, R.sup.3k, and R.sup.3l on different carbon atoms are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3k, and R.sup.3l on two
adjacent carbon atoms are taken together with the bond between said
adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i,R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a carbon-carbon triple bond; U is
selected from --O--, --S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11 and --NR.sup.11C(O)NR.sup.11--; T is
selected from --NR.sup.11R.sup.11, --NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; R.sup.9 is selected from: ##STR01100## wherein R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t are each independently selected
from (a) hydrogen, (b) halogen, (c) --CN, (d) --N.sub.3, (e)
--NO.sub.2, (f) --OCF.sub.3--, (g) --OCH.sub.3, (h) --OCF.sub.2H,
(i) --OCFH.sub.2, (j) --OR.sup.11, NH.sub.2, (l)
--NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n) --C(O)OR.sup.11, (o)
--C(O)NR.sup.11R.sup.11, (p) --NR11C(O)R.sup.11, (q)
--S(O).sub.pR.sup.11, (r) --C.sub.1-C.sub.8 alkyl, (s)
--C.sub.2-C.sub.8 alkenyl, (t) --C.sub.1-C.sub.8 alkynyl, (u)
haloalkyl, (v) -3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur, and (w) -3-14
membered saturated, unsaturated, or aromatic carbocycle; wherein
each (r) through (w) is optionally substituted with one or more
R.sup.12; alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group; wherein each (a) through
(c) is optionally substituted with one or more R.sup.12;
alternatively, two substituents selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t on different carbon atoms are taken together
with the intervening atoms to which they are attached to form (a)
-3-7 membered saturated or unsaturated carbocyclic or (b) -3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur; wherein each (a) through (b) is optionally
substituted with one or more R.sup.12; alternatively, two
substituents selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n,
R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or four substituents selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a carbon-carbon triple bond: Z is selected from --O--,
--S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sup.pNR.sup.11--, NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and --NR.sup.11C(O)NR.sup.11--; W
is selected from --NR.sup.11R.sup.11, --NR.sup.11(CO)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.12 is independently selected from
(a) hydrogen, (b) halogen, (c) --OH, (d) --SH, (e)
--(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH.sub.2, (j) --O(C.sub.1-C.sub.8 alkyl), (k)
--CN, (l) --NO.sub.2, (m) --CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8
alkyl), (o) C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q)
--COCH.sub.3, (r) --S(O).sub.pCH.sub.3, (s)
--S(O).sub.pN(C.sub.1-C.sub.8 alkyl).sub.2, (t) --S(C.sub.1-C.sub.8
alkyl), (u) --C(O)OH, (v) --C(O)O(C.sub.1-C.sub.8 alkyl), (w)
--N.sub.3, (x) --NHC(O)(C.sub.1-C.sub.8 alkyl), (y)
--N(C.sub.1-C.sub.8 alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z)
--NH.sub.2, (aa) --NH(C.sub.1-C.sub.8 alkyl), (bb)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (cc) --C.sub.1-C.sub.8 alkyl,
(dd) --C.sub.2-C.sub.8 alkenyl, (ee) --C.sub.2-C.sub.8 alkynyl,
(ff) -haloalkyl, (gg) --(C.sub.1-C.sub.8 alkyl)(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (hh) --(C.sub.1-C.sub.8 alkyl)(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (ii) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (jj) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, (kk) --(C.dbd.NH)NH.sub.2,
(ll) --C(.dbd.NH)NH.sub.2, (mm) --C(O)R.sup.13, (nn) .dbd.O, and
(oo) .dbd.NR.sup.13; wherein each (aa) through (jj) is optionally
substituted with one or more R.sup.13; R.sup.13 is independently
selected from (a) hydrogen, (b) halogen, (c) --C.sub.1-C.sub.8
alkyl, (d) --C.sub.2-C.sub.8 alkenyl, (e) --C.sub.2-C.sub.8
alkynyl, (f) -haloalkyl, (g) --OH, (h) --OC.sub.1-C.sub.8 alkyl,
(i) --OC.sub.2-C.sub.8 alkenyl, (j) --OC.sub.2-C.sub.8 alkynyl, (k)
--OCF.sub.3, (l) --OCH.sub.3, (m) --OCF.sub.2H, (n) --OCFH.sub.2,
(o) --NH.sub.2, (p) --CN, (q) --N, (r) S(O).sub.pC.sub.1-C.sub.8
alkyl, (s) 3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur, and (t) -3-14
membered saturated, unsaturated, or aromatic carbocycle, p is 0,1,
or 2; and t is 0,1, or 2, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein the microbial infection is selected
from the group consisting of: a skin infection, a Gram positive
infection, a Gram negative infection, nosocomial pneumonia,
community acquired pneumonia, postviral pneumonia, hospital
acquired pneumonia/ventilator associated pneumonia, a respiratory
tract infection such as chronic respiratory tract infection (CRTI),
acute pelvic infection, a skin infection including an acute
bacterial skin and skin structure infection (AB SSSI) and an
uncomplicated skin and skin structure infection (uSSSI), a
complicated intra-abdominal infection, a urinary tract infection,
bacteremia, septicemia, endocarditis, an atrioventricular shunt
infection, a vascular access infection, meningitis, surgical
prophylaxis, a peritoneal infection, a bone infection, a joint
infection, a methicillinresistant
Staphylococcus aureus infection, a vancomycin-resistant Enterococci
infection, a linezolid-resistant organism infection, a Bacillus
anthracis infection, a Francisella tularensis infection, a Yersinia
pestis infection, and tuberculosis.
65. A method according to claim 64, wherein the microbial infection
is a Gram positive infection.
66. A method according to claim 64, wherein the microbial infection
is a Gram negative infection.
67. A method of treating, preventing, or reducing the risk of a
microbial infection in a human or animal comprising administering
to the human or animal an effective amount of a compound according
to the formula: ##STR01101## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein X.sub.1 is CR.sup.1 or N; X.sub.2 is
CR.sup.2 or N; X.sub.3 is CR.sup.3 or N; X.sub.4 is CR.sup.4 or N;
X.sub.5 is CR.sup.5 or N; with the proviso that X.sub.1, X.sub.2,
X.sub.3, X.sub.4, and X.sub.5 are not all N; Y.sub.6 is CR.sup.6 or
N; Y.sub.7 is CR.sup.7 or N; Y.sub.8 is CR.sup.8 or N; Y.sub.9 is
CR.sup.9 or N; Y.sub.10 is CR.sup.10 or N; with the proviso that
Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, and Y.sub.10 are not all N;
wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.10 are each independently selected from (a)
hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g)
--CF.sub.2H, (h) --CFH, (i) (j) --OCF.sub.2H, (k) --OCFH, (l)
--OCH.sub.3, (m) --CN, (n) --N.sub.3, (o) --NO.sub.2, (p)
--NR.sup.11R.sup.11, (q) --NR.sup.11C(O)R.sup.11, (r)
--C(O)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2).sup.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) C.sub.2-C.sub.8 alkynyl, (ii)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur), (jj)
(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (kk) -haloalkyl, (ll) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (mm) -3-14 membered saturated, unsaturated, or
aromatic carbocycle, and (nn) --CHR.sup.11--NH-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one of
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur); wherein each (ff) through (nn) is optionally
substituted with one or more R.sup.12; alternatively, wherein two
substituents selected from R.sup.6, R.sup.7, and R.sup.8 are taken
together with the carbon atom to which they are attached to form
(a) 3-7 membered saturated or unsaturated carbocyclic or (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur; wherein each (a) through (b) is optionally
substituted with one or more R.sup.12; each R.sup.11 is
independently selected from (a) hydrogen, (b) halogen, (c) --OH,
(d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.12,
(k) --COR.sup.12, (l) --CN, (m) --NO.sub.2, (n) --CONH.sub.2, (o)
--CONR.sup.12R.sup.12, (p) --COCH.sub.3, (q) --S(O).sub.pCH.sub.3,
(r) --S(O).sub.pNR.sup.12R.sup.12, (s) --SR.sup.12, (t) --C(O)OH,
(u) --C(O)OR.sup.12, (v) --N.sub.3, (w) --NH.sub.2, (x)
--NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8 alkyl), (z)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (aa) --C.sub.1-C.sub.8 alkyl,
(bb) --C.sub.2-C.sub.8 alkenyl, (cc) --C.sub.2-C.sub.8 alkynyl,
(dd) haloalkyl, (ee) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (ff) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (gg) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (hh) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, and (ii)
--(C.dbd.NH)NR.sup.12R.sup.12; wherein each (y) through (hh) is
optionally substituted with one or more R.sup.12; alternatively two
R.sup.11 substituents are taken together to form (a) -3-7 membered
saturated or unsaturated carbocyclic or (b) -3-7 membered saturated
or unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12; R.sup.3 is selected from: ##STR01102## wherein
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3j, R.sup.3k, and R.sup.3l are each
independently selected from (a) hydrogen, (b) halogen, (c) --CN,
(d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3, (g) --OCF.sub.2H,
(h) --OCFH.sub.2, (i) --OCH.sub.3, --OR.sup.11, (k) --C(O)R.sup.11,
(l) --C(O)NR.sup.11R.sup.11, (m) --NH.sub.2, (n)
--NR.sup.11R.sup.11, (o) --NR.sup.11C(O)R.sup.11, (p)
--S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle; wherein each (s) through (x) is optionally
substituted with one or more R.sup.12; alternatively, one or more
pairs of substituents selected from R.sup.3a and R.sup.3b, R.sup.3c
and R.sup.3d, R.sup.3e and R.sup.3f, R.sup.3g and R.sup.3h,
R.sup.3i and R.sup.3j, and R.sup.3k and R.sup.3l are taken together
with the carbon atom to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic, (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, (c) an exo carbon-carbon double bond, (d) carbonyl
group, or (e) thiocarbonyl group; wherein each (a) through (b) is
optionally substituted with one or more R.sup.12; alternatively,
wherein two substituents selected from R.sup.3a, R.sup.3b,
R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g, R.sup.3h,
R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on different carbon
atoms are taken together with the intervening atoms to which they
are attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a carbon-carbon triple bond; U is
selected from --O--, --S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and NR.sup.11C(O)NR.sup.11--; T
is selected from --NR.sup.11R.sup.11,
--NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; R.sup.9 is selected from: ##STR01103## wherein R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t are each independently selected
from (a) hydrogen, (b) halogen, (c) --CN, (d) --N.sub.3, (e)
--NO.sub.2, (f) --OCF.sub.3, (g) --OCH.sub.3, (h) --OCF.sub.2H, (i)
--OCFH.sub.2, (j) --OR.sup.11, (k) --NH.sub.2, (l)
--NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n) --C(O)OR.sup.11, (o)
--C(O)NR.sup.11R.sup.11, (p) --NR.sup.11C(O)R.sup.11, (q)
--S(O).sub.pR.sup.11, (r) --C.sub.1-C.sub.8 alkyl, (s)
--C.sub.2-C.sub.8 alkenyl, (t) --C.sub.1-C.sub.8 alkynyl, (u)
haloalkyl, (v) -3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur, and (w) -3-14
membered saturated, unsaturated, or aromatic carbocycle, wherein
each (r) through (w) is optionally substituted with one or more
R.sup.12; alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group; wherein each (a) through
(c) is optionally substituted with one or more R.sup.12;
alternatively, two substituents selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t on different carbon atoms are taken together
with the intervening atoms to which they are attached to form (a)
-3-7 membered saturated or unsaturated carbocyclic or (b) -3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur; wherein each (a) through (b) is optionally
substituted with one or more R.sup.12; alternatively, two
substituents selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n,
R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or four substituents selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a carbon-carbon triple bond; Z is selected from --O--,
--S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and --NR.sup.11C(O)NR.sup.11--; W
is selected from --NR.sup.11R.sup.11, --NR.sup.11(CO)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.12 is independently selected from
(a) hydrogen, (b) halogen, (c) --OH, (d) --SH, (e)
--(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH.sub.2, (j) --O(C.sub.1-C.sub.8 alkyl), (k)
--CN, (l) --NO.sub.2, (m) --CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8
alkyl), (o) C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q)
--COCH.sub.3, (r) --S(O).sub.pCH.sub.3, (s)
--S(O).sub.pN(C.sub.1-C.sub.8 alkyl).sub.2, (t) --S(C.sub.1-C.sub.8
(u) --C(O)OH, (v) --C(O)O(C.sub.1-C.sub.8 (w) --N.sub.3, (x)
--NHC(O)(C.sub.1-C.sub.8 (y) --N(C.sub.1-C.sub.8
alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z) --NH.sub.2, (aa)
--NH(C.sub.1-C.sub.8 alkyl), (bb) --N(C.sub.1-C.sub.8 alkyl).sub.2,
(cc) --C.sub.1-C.sub.8 alkyl, (dd) --C.sub.2-C.sub.8 alkenyl, (ee)
--C.sub.2-C.sub.8 alkynyl, (ff) -haloalkyl, (gg) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (hh)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (ii) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (jj)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, (kk)
--(C.dbd.NH)NH.sub.2, (ll) --C(.dbd.NH)NH.sub.2, (mm)
--C(O)R.sup.13, (nn) .dbd.O, and (oo) .dbd.NR.sup.13; wherein each
(aa) through (jj) is optionally substituted with one or more
R.sup.13; R.sup.13 is independently selected from (a) hydrogen, (b)
halogen, (c) --C.sub.1-C.sub.8 alkyl, (d) --C.sub.2-C.sub.8
alkenyl, (e) --C.sub.2-C.sub.8 alkynyl, (f) -haloalkyl, (g) --OH,
(h) --OC.sub.1-C.sub.8 alkyl, (i) --OC.sub.2-C.sub.8 alkenyl, (j)
--OC.sub.2-C.sub.8 alkynyl, (k) --OCF.sub.3, (l) --OCH.sub.3, (m)
--OCF.sub.2H, (n) --OCFH.sub.2, (o) --NH.sub.2, (p) --CN, (q)
--N.sub.3, (r) --S(O).sub.pC.sub.1-C.sub.8 alkyl, (s) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, and (t) -3-14 membered saturated,
unsaturated, or aromatic carbocycle; p is 0,1, or 2; and t is 0,1,
or 2, or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein said
infection is caused by or involves one or more microorganisms
selected from: Acinetobacter spp. (Acinetobacter baumanni),
Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus,
Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides
vulgatus, Citrobacter freundii, Citrobacter koser, Clostridium
clostridioforme, Clostridium perfringens, Enterobacter aerogenes,
Enterobacter cloacae, Enterococcus faecalis, Enterococcus spp.,
Escherichia coli, Eubacterium lentum, Fusobacterium spp.,
Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella
pneumoniae, Klebsiella oxytoca, Legionella pneumophilia, Moraxella
catarrhalis, Morganella morganii, Mycoplasma
spp., Peptostreptococcus spp., Porphyromonas asaccharolytica,
Prevotella bivia, Proteus mirabilis, Proteus vulgaris, Providencia
rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Serratia
marcescens, Streptococcus anginosus, Staphylococcus aureus,
Staphylococcus epidermidis, Stenotrophomonas maltophilia,
Streptococcus agalactiae, Streptococcus constellatus, Streptococcus
pneumoniae, Streptococcus pyogenes, and Streptococcus pyogenes.
68. The method of claim 67, wherein said infection is caused by or
involves one or more of aerobic and facultative gram-positive
microorganism selected from: Staphylococcus aureus, Streptococcus
pneumoniae, Enterococcus spp., Streptococcus agalactiae,
Streptococcus pyogenes, and Staphylococcus epidermidis.
69. The method of claim 67, wherein said infection is caused by or
involves one or more of aerobic and facultative gram-negative
microorganism selected from: Escherichia coli, Haemophilus
influenzae, Klebsiella pneumoniae, Citrobacter freundii,
Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii,
Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter
baumanni, Moraxella catarrhalis, Proteus mirabilis, Citrobacter
koseri, Haemophilus parainfluenzae, Klebsiella oxytoca, Proteus
vulgaris, Providencia rettgeri, and Providencia stuartii
70. The method of claim 67, wherein said infection is caused by or
involves one or more of anaerobic microorganism: Bacteroides
fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides
thetaiotaomicron, Bacteroides uniformis, Clostridium
clostridioforme, Eubacterium lentum, Peptostreptococcus spp.,
Porphyromonas asaccharolytica, Prevotella bivia, Bacteroides
vulgatus, Clostridium perfringens, and Fusobacterium spp.
71. The method according to claim 67, wherein the microorganism
Enterococcus spp. is selected from vancomycin susceptible isolate
and vancomycin resistant isolate.
72. The method according to claim 67, wherein the microorganism
Escherichia coli is selected from extended spectrum beta-lactamase
(ESBL) producing isolate and Klebsiella pneumoniae carbapenemase
(KPC) producing isolate.
73. The method according to claim 67, wherein the microorganism
Haemophilus influenzae is a beta-lactamase positive isolate.
74. The method according to claim 67, wherein the microorganism
Klebsiella pneumoniae is selected from extended spectrum
beta-lactamase (ESBL) producing isolate and Klebsiella pneumoniae
carbapenemase (KPC) producing isolate.
75. The method according to claim 67, wherein the microorganism
Klebsiella oxytoca selected from extended spectrum beta-lactamase
(ESBL) producing isolate and Klebsiella pneumoniae carbapenemase
(KPC) producing isolate.
76. The method according to claim 67, wherein the microorganism
Staphylococcus aureus is selected from methicillin susceptible
isolate and methicillin resistant isolate.
77. The method according to claim 67, wherein the microorganism
Staphylococcus epidermidis is selected from methicillin susceptible
isolate and methicillin resistant isolate.
78. The method according to claim 67, wherein the microorganism
Streptococcus pneumoniae is selected from penicillin susceptible
isolate and penicillin resistant isolate.
79. The method according to claim 61, wherein the amount of
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer comprises from
0.1 mg to 1500 mg.
80. The method according to claim 79, wherein the amount of
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer comprises
about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or
about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or
about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or
about 325, or about 350 mg, or about 375 mg, or about 400 mg, or
about 425 mg, or about 450 mg, or about 475 mg, or about 500 mg, or
about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or
about 625 mg, or about 650 mg, or about 675 mg, or about 700 mg, or
about 725 mg, or about 750 mg, or about 775 mg, or about 800 mg, or
about 825 mg, or about 850 mg, or about 875 mg, or about 900 mg, or
about 925 mg, or about 950 mg, or about 975 mg, or about 1000 mg,
or about 1025 mg, or about 1050, mg, or about 1075 mg, or about
1100 mg, or about 1125 mg, or about 1150 mg, or about 1175 mg, or
about 1200 mg, or about 1225 mg, or about 1250 mg, or about 1275
mg, or about 1300 mg, or about 1325 mg, or about 1350 mg, or about
1375 mg, or about 1400 mg, or about 1425 mg, or about 1450 mg, or
about 1475 mg, or about 1500 mg.
81. The method according to claim 61 wherein the compound, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, is administered otically,
ophthalmically, nasally, orally, parenterally, topically, or
intravenously.
82. (canceled)
83. (canceled)
84. (canceled)
85. The method according to claim 64 wherein the compound, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, is administered otically,
ophthalmically, nasally, orally, parenterally, topically, or
intravenously.
86. The method according to claim 67 wherein the compound, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, is administered otically,
ophthalmically, nasally, orally, parenterally, topically, or
intravenously.
87. The method according to claim 61, wherein the compound is a
compound of the formula: ##STR01104## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer.
88. The method according to claim 64, wherein the compound is a
compound of the formula: ##STR01105## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer.
89. The method according to claim 67, wherein the compound is a
compound of the formula: ##STR01106## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer.
90. The method according to claim 87, wherein the compound is a
compound of the formula: ##STR01107## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer.
91. The method according to claim 88, wherein the compound is a
compound of the
91. The method according to claim 88, wherein the compound is a
compound of the formula: ##STR01108## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer.
92. The method according to claim 89, wherein the compound is a
compound of the formula: ##STR01109## or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer.
93. The method according to claim 61, wherein the compound is a
compound having the formula: ##STR01110## or a tautomer thereof, or
a pharmaceutically acceptable salt, or ester of said compound or
tautomer, wherein X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or
N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or N; R.sup.1,
R.sup.2, R.sup.4, and R.sup.5 are each independently selected from
(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g)
--CF.sub.2H, (h) --CFH.sub.2, (i) --OCF.sub.3, (j) --OCF.sub.2H,
(k) --OCFH.sub.2, (l) --OCH.sub.3, (m) --CN, (n) --N.sub.3, (o)
--NO.sub.2, (p) --NR.sup.11R.sup.11, (q) --NR.sup.11C(O)R.sup.11,
(r) --C(O)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2)R.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur); wherein each
(ff) through (nn) is optionally substituted with one or more
R.sup.12; wherein: ##STR01111## is selected from the group
consisting of: ##STR01112## ##STR01113## ##STR01114## ##STR01115##
##STR01116## each is independently selected from (a) hydrogen, (b)
halogen, (c) --OH, (d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH, (f)
--OCF.sub.3, (g) --OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH3, (j)
--OR.sup.12, (k) --COR.sup.12, (l) --CN, (m) --NO.sub.2, (n)
--CONH.sub.2, (o) --CONR.sup.12R.sup.12, --COCH.sub.3, (q)
--S(O).sub.pCH.sub.3, (r) --S(O).sub.pNR.sup.12R.sup.12, (s)
--SR.sup.12, (t) --C(O)OH, (u) --C(O)OR.sup.12, (v) --N.sub.3, (w)
--NH.sub.2, (x) --NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8
alkyl), (z) --N(C.sub.1-C.sub.8 alkyl).sub.2, (aa)
--C.sub.1-C.sub.8 alkyl, (bb) --C.sub.2-C.sub.8 alkenyl, (cc)
--C.sub.2-C.sub.8 alkynyl, (dd) -haloalkyl, (ee) (C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (ff)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (gg) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (hh)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, and
(ii) --(C.dbd.NH)NR.sup.12R.sup.12; wherein each (y) through (hh)
is optionally substituted with one or more R.sup.12; alternatively
two R.sup.11 substituents are taken together to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.3 is selected from: ##STR01117##
wherein R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
each independently selected from (a) hydrogen, (b) halogen, (c)
--CN, (d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.11,
(k) --C(O)R.sup.11, (l) --C(O)NR.sup.11R.sup.11, (m) --NH.sub.2,
(n) --NR.sup.11R.sup.11 (o) --NR.sup.11C(O)R.sup.11, (p)
--S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle; wherein each (s) through (x) is optionally
substituted with one or more R.sup.12; alternatively, one or more
pairs of substituents selected from R.sup.3a and R.sup.3b, R.sup.3c
and R.sup.3d, R.sup.3e and R.sup.3f, R.sup.3g and R.sup.3h,
R.sup.3i and R.sup.3j, and R.sup.3k and R.sup.3l are taken together
with the carbon atom to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic, (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, (c) an exo carbon-carbon double bond, (d) carbonyl
group, or (e) thiocarbonyl group; wherein each (a) through (b) is
optionally substituted with one or more R.sup.12; alternatively,
wherein two substituents selected from R.sup.3a, R.sup.3b,
R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g, R.sup.3h,
R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on different carbon
atoms are taken together with the intervening atoms to which they
are attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a carbon-carbon triple bond; U is
selected from --O--, --S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11,
--S(O).sub.pNR.sup.11--,
--NR.sup.11S(O).sub.p----NR.sup.11S(O).sub.pNR.sup.11--, and
--NR.sup.11C(O)NR.sup.11--; T is selected from --NR.sup.11R.sup.11,
NR.sup.11(C.dbd.O)OR.sup.11,
NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; R.sup.9 is selected from: ##STR01118## wherein R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t are each independently selected
from (a) hydrogen, (b) halogen, (c) --CN, (d) --N.sub.3, (e)
--NO.sub.2, (f) --OCF.sub.3, (g) --OCH.sub.3, (h) --OCF.sub.2H, (i)
--OCFH.sub.2, (j) --OR.sup.11, (k) --NH.sub.2, (l)
--NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n) --C(O)OR.sup.11, (o)
--C(O)NR.sup.11R.sup.11, (p) --NR.sup.11C(O)R.sup.11, (q)
--S(O).sub.pR.sup.11, (r) 13 C.sub.1-C.sub.8 alkyl, (s)
--C.sub.2-C.sub.8 alkenyl, (t) --C.sub.1-C.sub.8 alkynyl, (u)
haloalkyl, (v) -3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur, and (w) -3-14
membered saturated, unsaturated, or aromatic carbocycle; wherein
each (r) through (w) is optionally substituted with one or more
R.sup.12; alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group; wherein each (a) through
(c) is optionally substituted with one or more R.sup.12;
alternatively, two substituents selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t on different carbon atoms are taken together
with the intervening atoms to which they are attached to form (a)
-3-7 membered saturated or unsaturated carbocyclic or (b) -3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur; wherein each (a) through (b) is optionally
substituted with one or more R.sup.12; alternatively, two
substituents selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n,
R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or four substituents selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a carbon-carbon triple bond; Z is selected from --O--,
--S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p;
--NR.sup.11S(O).sub.pNR.sup.11--, and --NR.sup.11C(O)NR.sup.11--; W
is selected from --NR.sup.11R.sup.11, --NR.sup.11(CO)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.12 is independently selected from
(a) hydrogen, (b) halogen, (c) --OH, (d) --SH, (e)
--(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH.sub.2, (j) --O(C.sub.1-C.sub.8 alkyl), (k)
--CN, (l) --NO.sub.2, (m) --CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8
alkyl), (o) C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q)
--COCH.sub.3, (r) --S(O).sub.pCH.sub.3, (s)
--S(O).sub.pN(C.sub.1-C.sub.8 alkyl).sub.2, (t) --S(C.sub.1-C.sub.8
alkyl), (u) --C(O)OH, (v) --C(O)O(C.sub.1-C.sub.8 alkyl), (w)
--N.sub.3, (x) --NHC(O)(C.sub.1-C.sub.8 alkyl), (y)
--N(C.sub.1-C.sub.8 alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z)
--NH.sub.2, (aa) --NH(C.sub.1-C.sub.8 alkyl), (bb)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (cc) --C.sub.1-C.sub.8 alkyl,
(dd) --C.sub.2-C.sub.8 alkenyl, (ee) --C.sub.2-C.sub.8 alkynyl,
(ff) -haloalkyl, (gg) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (hh) --(C.sub.1-C.sub.8 alkyl)(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (ii) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (jj) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, (kk) --(C.dbd.NH)NH.sub.2,
(ll) --C(.dbd.NH)NH.sub.2, (mm) --C(O)R.sup.13, (nn) .dbd.O, and
(oo) .dbd.NR.sup.13; wherein each (aa) through (jj) is optionally
substituted with one or more R.sup.13; R.sup.13 is independently
selected from (a) hydrogen, (b) halogen, (c) --C.sub.1-C.sub.8
alkyl, (d) --C.sub.2-C.sub.8 alkenyl, (e) --C.sub.2-C.sub.8
alkynyl, (f) -haloalkyl, (g) --OH, (h) --OC.sub.1-C.sub.8 alkyl,
(i) --OC.sub.2-C.sub.8 alkenyl, (j) --OC.sub.2-C.sub.8 alkynyl, (k)
--OCF.sub.3, (l) --OCH.sub.3, (m) --OCF.sub.2H, (n) --OCFH.sub.2,
(o) --NH.sub.2, (p) --CN, (q) --N.sub.3, (r)
--S(O).sub.pC.sub.1-C.sub.8 alkyl, (s) -3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, and (t) -3-14 membered saturated, unsaturated, or
aromatic carbocycle; p is 0,1, or 2; and t is 0,1, or 2; and
wherein the nitrogen and sulfur heteroatoms in any heterocycle in
the compound are unoxidized or oxidized (N.fwdarw.O and S(O).sub.p,
wherein p=1 or 2).
94. The method according to claim 64, wherein the compound is a
compound having the formula: ##STR01119## or a tautomer thereof, or
a pharmaceutically acceptable salt, or ester of said compound or
tautomer, wherein X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or
N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or N; R.sup.1,
R.sup.2, R.sup.4, and R.sup.5 are each independently selected from
(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g)
--CF.sub.2H, (h) --CFH.sub.2, (i) --OCF.sub.3, (j) --OCF.sub.2H,
(k) --OCFH.sub.2, (l) --OCH.sub.3, (m) --CN, (n) --N.sub.3, (o)
--NO.sub.2, (p) --NR.sup.11R.sup.11, (q) --NR.sup.11C(O)R.sup.11,
(r) --C(O)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2)R.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) -(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur); wherein each
(ff) through (nn) is optionally substituted with one or more
R.sup.12; wherein: ##STR01120## is selected from the group
consisting of: ##STR01121## ##STR01122## ##STR01123## ##STR01124##
##STR01125## ##STR01126## ##STR01127## each R.sup.11 is
independently selected from (a) hydrogen, (b) halogen, (c) --OH,
(d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.12,
(k) --COR.sup.12, (l) --CN, (m) --NO.sub.2, (n) --CONH.sub.2, (o)
--CONR.sup.12R.sup.12, (p) --COCH.sub.3, (q) --S(O).sub.pCH.sub.3,
(r) --S(O).sub.pNR.sup.12R.sup.12, (s) --SR.sup.12, (t) --C(O)OH,
(u) --C(O)OR.sup.12, (v) --N.sub.3, (w) --NH.sub.2, (x)
--NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8 alkyl), (z)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (aa) --C.sub.1-C.sub.8 alkyl,
(bb) --C.sub.2-C.sub.8 alkenyl, (cc) --C.sub.2-C.sub.8 alkynyl,
(dd) -haloalkyl, (ee) (C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (ff) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (gg) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (hh) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, and (ii)
--(C.dbd.NH)NR.sup.12R.sup.12; wherein each (y) through (hh) is
optionally substituted with one or more R.sup.12; alternatively two
R.sup.11 substituents are taken together to form (a) -3-7 membered
saturated or unsaturated carbocyclic or (b) -3-7 membered saturated
or unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12; R.sup.3 is selected from: ##STR01128## wherein
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
each independently selected from (a) hydrogen, (b) halogen, (c)
--CN, (d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.11,
(k) --C(O)R.sup.11, (l) --C(O)NR.sup.11R.sup.11, (m) --NH.sub.2,
(n) --NR.sup.11R.sup.11 (o) --NR.sup.11C(O)R.sup.11, (p)
--S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle; wherein each (s) through (x) is optionally
substituted with one or more R.sup.12; alternatively, one or more
pairs of substituents selected from R.sup.3a and R.sup.3b, R.sup.3c
and R.sup.3d, R.sup.3e and R.sup.3f, R.sup.3g and R.sup.3h,
R.sup.3i and R.sup.3j, and R.sup.3k and R.sup.3l are taken together
with the carbon atom to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic, (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, (c) an exo carbon-carbon double bond, (d) carbonyl
group, or (e) thiocarbonyl group; wherein each (a) through (b) is
optionally substituted with one or more R.sup.12; alternatively,
wherein two substituents selected from R.sup.3a, R.sup.3b,
R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g, R.sup.3h,
R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on different carbon
atoms are taken together with the intervening atoms to which they
are attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a carbon-carbon triple bond; U is
selected from --O--, --S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--,
--NR.sup.11S(O).sub.pNR.sup.11S(O).sub.pNR.sup.11--,
--NR.sup.11(O)NR.sup.11--; T is selected from --NR.sup.11R.sup.11,
--NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; R.sup.9 is selected from: ##STR01129## wherein R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t are each independently selected
from (a) hydrogen, (b) halogen, (c) --CN, (d) --N.sub.3, (e)
--NO.sub.2, (f) --OCF.sub.3, (g) --OCH.sub.3, (h) --OCF.sub.2H, (i)
--OCFH.sub.2, (j) --OR.sup.11, (k) --NH.sub.2, (l)
--NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n) --C(O)OR.sup.11, (o)
--C(O)NR.sup.11R.sup.11, (p) --NR.sup.11C(O)R.sup.11, (q)
--S(O).sub.pR.sup.11, (r) --C.sub.1-C.sub.8 alkyl, (s)
--C.sub.2-C.sub.8 alkenyl, (t) --C.sub.1-C.sub.8 alkynyl, (u)
haloalkyl, (v) -3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur, and (w) -3-14
membered saturated, unsaturated, or aromatic carbocycle; wherein
each (r) through (w) is optionally substituted with one or more
R.sup.12; alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group; wherein each (a) through
(c) is optionally substituted with one or more R.sup.12;
alternatively, two substituents selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t on different carbon atoms are taken together
with the intervening atoms to which they are attached to form (a)
-3-7 membered saturated or unsaturated carbocyclic or (b) -3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur; wherein each (a) through (b) is optionally
substituted with one or more R.sup.12; alternatively, two
substituents selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n,
R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or four substituents selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a carbon-carbon triple bond; Z is selected from --O--,
--S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sup.pNR.sup.11--, NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and --NR.sup.11C(O)NR.sup.11--; W
is selected from --NR.sup.11R.sup.11, --NR.sup.11(CO)OR.sup.11,
--NR.sup.1(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.12 is independently selected from
(a) hydrogen, (b) halogen, (c) --OH, (d) ---SH, (e)
--(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH.sub.2, (j) --O(C.sub.1-C.sub.8 alkyl), (k)
--CN, (l) --NO.sub.2, (m) --CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8
alkyl), (o) C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q)
--COCH.sub.3, (r) --S(O).sub.pCH.sub.3, (s)
--S(O).sub.pN(C.sub.1-C.sub.8 alkyl).sub.2, (t) --S(C.sub.1-C.sub.8
alkyl), (u) --C(O)OH, (v) --C(O)O(C.sub.1-C.sub.8 alkyl), (w)
--N.sub.3, (x) --NHC(O)(C.sub.1-C.sub.8 alkyl), (y)
--N(C.sub.1-C.sub.8 alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z)
--NH.sub.2, (aa) --NH(C.sub.1-C.sub.8 alkyl), (bb)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (cc) --C.sub.1-C.sub.8 alkyl,
(dd) --C.sub.2-C.sub.8 alkenyl, (ee) --C.sub.2-C.sub.8 alkynyl,
(ff) -haloalkyl, (gg) -(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (hh) -(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (ii) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (jj) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, (kk) --(C.dbd.NH)NH.sub.2,
(ll) --C(.dbd.NH)NH.sub.2, (mm) --C(O)R.sup.13, (nn) .dbd.O, and
(oo) .dbd.NR.sup.13; wherein each (aa) through (jj) is optionally
substituted with one or more R.sup.13; R.sup.13 is independently
selected from (a) hydrogen, (b) halogen, (c) --C.sub.1-C.sub.8
alkyl, (d) -C.sub.2-C.sub.8 alkenyl, (e) --C.sub.2-C.sub.8 alkynyl,
(f) -haloalkyl, (g) --OH, (h) --OC.sub.1-C.sub.8 alkyl, (i)
--OC.sub.2-C.sub.8 alkenyl, (j) --OC.sub.2-C.sub.8 alkynyl, (k)
--OCF.sub.3, (l) --OCH.sub.3, (m) --OCF.sub.2H, (n) --OCFH.sub.2,
(o) --NH.sub.2, (p) --CN, (q) --N.sub.3, (r)
--S(O).sub.pC.sub.1-C.sub.8 alkyl, (s) -3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, and (t) -3-14 membered saturated, unsaturated, or
aromatic carbocycle; p is 0, 1, or 2; and t is 0, 1, or 2; and
wherein the nitrogen and sulfur heteroatoms in any heterocycle in
the compound are unoxidized or oxidized (N.fwdarw.O and S(O).sub.p,
wherein p=1 or 2).
95. The method according to claim 67, wherein the compound is a
compound having the formula: ##STR01130## or a tautomer thereof, or
a pharmaceutically acceptable salt, or ester of said compound or
tautomer, wherein X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or
N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or N; R.sup.1,
R.sup.2, R.sup.4, and R.sup.5 are each independently selected from
(a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g)
--CF.sub.2H, (h) --CFH.sub.2, (i) --OCF.sub.3, (j) --OCF.sub.2H,
(k) --OCFH.sub.2, (l) --OCH.sub.3, (m) CN, (n) --N.sub.3, (o)
--NO.sub.2, (p) --NR.sup.11R.sup.11, (q) --NR.sup.11C(O)R.sup.11,
(r) C(O)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2).sub.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur); wherein each
(ff) through (nn) is optionally substituted with one or more
R.sup.12; wherein: ##STR01131## is selected from the group
consisting of: ##STR01132## ##STR01133## ##STR01134## ##STR01135##
##STR01136## ##STR01137## ##STR01138## each R.sup.11 is
independently selected from (a) hydrogen, (b) halogen, (c) --OH,
(d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.12,
(k) --COR.sup.12, (l) --CN, (m) --NO.sub.2, (n) --CONH.sub.2, (o)
--CONR.sup.12R.sup.12, (p) --COCH.sub.3, (q) --S(O).sub.pCH.sub.3,
(r) --S(O).sub.pNR.sup.12R.sup.12, (s) --SR.sup.12, (t) --C(O)OH,
(u) --C(O)OR.sup.12, (v) --N.sub.3, (w) --NH.sub.2, (x)
--NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8 alkyl), (z)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (aa) --C.sub.1-C.sub.8 alkyl,
(bb) --C.sub.2-C.sub.8 alkenyl, (cc) --C.sub.2-C.sub.8 alkynyl,
(dd) -haloalkyl, (ee) (C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (ff) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (gg) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (hh) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, and (ii)
--(C.dbd.NH)NR.sup.12R.sup.12; wherein each (y) through (hh) is
optionally substituted with one or more R.sup.12; alternatively two
R.sup.11 sub stituents are taken together to form (a) -3-7 membered
saturated or unsaturated carbocyclic or (b) -3-7 membered saturated
or unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur,
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12; R.sup.3 is selected from: ##STR01139## wherein
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
each independently selected from (a) hydrogen, (b) halogen, (c)
--CN, (d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3, (g)
--OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j) --OR.sup.11,
(k) --C(O)R.sup.11, (l) --C(O)NR.sup.11R.sup.11, (m) --NH.sub.2,
(n) NR.sup.11R.sup.11 (o) --NR.sup.11C(O)R.sup.11, (p)
--S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle; wherein each (s) through (x) is optionally
substituted with one or more R.sup.12; alternatively, one or more
pairs of sub stituents selected from R.sup.3a and R.sup.3b,
R.sup.3c and R.sup.3d, R.sup.3e and R.sup.3f, R.sup.3g and
R.sup.3h, R.sup.3i and R.sup.3j, and R.sup.3k and R.sup.3l are
taken together with the carbon atom to which they are attached to
form (a) -3-7 membered saturated or unsaturated carbocyclic, (b)
-3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (c) an exo carbon-carbon double bond,
(d) carbonyl group, or (e) thiocarbonyl group; wherein each (a)
through (b) is optionally substituted with one or more R.sup.12;
alternatively, wherein two substituents selected from R.sup.3a,
R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g,
R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on different
carbon atoms are taken together with the intervening atoms to which
they are attached to form (a) -3-7 membered saturated or
unsaturated carbocyclic or (b) -3-7 membered saturated or
unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12; alternatively, wherein two substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3iR.sup.3j, R.sup.3k, and R.sup.3l on two
adjacent carbon atoms are taken together with the bond between said
adjacent carbon atoms form a carbon-carbon triple bond; U is
selected from --O--, --S(O).sub.p--, --NR.sup.11, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and --NR.sup.11C(O)NR.sup.11--; T
is selected from --NR.sup.11R.sup.11,
--NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; wherein each
(a) through (b) is optionally substituted with one or more
R.sup.12; R.sup.9 is selected from: ##STR01140## wherein R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t are each independently selected
from (a) hydrogen, (b) halogen, (c) --CN, (d) --N.sub.3, (e)
--NO.sub.2, (f) --OCF.sub.3, (g) --OCH.sub.3, (h) --OCF.sub.2H, (i)
--OCFH.sub.2, (j) --OR.sup.11, (k) --NH.sub.2, (l)
--NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n) --C(O)OR.sup.11, (o)
--C(O)NR.sup.11R.sup.11, (p) --NR.sup.11C(O)R.sup.11, (q)
--S(O).sub.pR.sup.11, (r) --C.sub.1-C.sub.8 alkyl, (s)
--C.sub.2-C.sub.8 alkenyl, (t) --C.sub.1-C.sub.8 alkynyl, (u)
haloalkyl, (v) -3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur, and (w) -3-14
membered saturated, unsaturated, or aromatic carbocycle; wherein
each (r) through (w) is optionally substituted with one or more
R.sup.12; alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group; wherein each (a) through
(c) is optionally substituted with one or more R.sup.12;
alternatively, two substituents selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t on different carbon atoms are taken together
with the intervening atoms to which they are attached to form (a)
-3-7 membered saturated or unsaturated carbocyclic or (b) -3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur; wherein each (a) through (b) is optionally
substituted with one or more R.sup.12; alternatively, two
substituents selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n,
R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or four substituents selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a carbon-carbon triple bond; Z is selected from --O--,
--S(O).sub.p--, --NR.sup.11--, --(C.dbd.O)--,
--NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and --NR.sup.11C(O)NR.sup.11--; W
is selected from --NR.sup.11R.sup.11, --NR.sup.11(CO)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
alternatively, one R.sup.11 and one substituent selected from
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12; R.sup.12 is independently selected from
(a) hydrogen, (b) halogen, (c) --OH, (d) --SH, (e)
--(C.sub.1-C.sub.8 alkyl)OH, (f) --OCF.sub.3, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH.sub.2, (j) --O(C.sub.1-C.sub.8 alkyl), (k)
--CN, (l) --NO.sub.2, (m) --CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8
alkyl), (o) C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q)
--COCH.sub.3, (r) --S(O).sub.pCH.sub.3, (s)
--S(O).sub.pN(C.sub.1-C.sub.8 alkyl).sub.2, (t) --S(C.sub.1-C.sub.8
alkyl), (u) --C(O)OH, (v) --C(O)O(C.sub.1-C.sub.8 alkyl), (w)
--N.sub.3, (x) --NHC(O)(C.sub.1-C.sub.8 alkyl), (y)
--N(C.sub.1-C.sub.8 alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z)
--NH.sub.2, (aa) --NH(C.sub.1-C.sub.8 alkyl), (bb)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (cc) --C.sub.1-C.sub.8 alkyl,
(dd) --C.sub.2-C.sub.8 alkenyl, (ee) --C.sub.2-C.sub.8 alkynyl,
(ff) -haloalkyl, (gg) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (hh) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (ii) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (jj) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, (kk) --(C.dbd.NH)NH.sub.2,
(ll) --C(.dbd.NH)NH.sub.2, (mm) --C(O)R.sup.13, (nn) .dbd.O, and
(oo) .dbd.NR.sup.13; wherein each (aa) through (jj) is optionally
substituted with one or more R.sup.13; R.sup.13 is independently
selected from (a) hydrogen, (b) halogen, (c) --C.sub.1-C.sub.8
alkyl, (d) --C.sub.2-C.sub.8 alkenyl, (e) --C.sub.2-C.sub.8
alkynyl, (f) haloalkyl, (g) --OH, (h) --OC.sub.1-C.sub.8 alkyl, (i)
--OC.sub.2-C.sub.8 alkenyl, (j) --OC.sub.2-C.sub.8 alkynyl, (k)
--OCF.sub.3, (l) --OCH.sub.3, (m) --OCF.sub.2H, (n) --OCFH.sub.2,
(o) --NH.sub.2, (p) --CN, (q) --N.sub.3, (r)
--S(O).sub.pC.sub.1-C.sub.8 alkyl, (s) -3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, and (t) -3-14 membered saturated, unsaturated, or
aromatic carbocycle; p is 0,1, or 2; and t is 0,1, or 2; and
wherein the nitrogen and sulfur heteroatoms in any heterocycle in
the compound are unoxidized or oxidized (N.fwdarw.O and S(O).sub.p,
wherein p=1 or 2).
96. The method according to claim 61, wherein the compound is a
compound according to any of the compounds in Table 1, Table 2,
Table 2a and Table 2aa or a tautomer thereof, or a pharmaceutically
acceptable salt, ester, or prodrug of said compound or
tautomer.
97. The method according to claim 64, wherein the compound is a
compound according to any of the compounds in Table 1, Table 2,
Table 2a and Table 2aa or a tautomer thereof, or a pharmaceutically
acceptable salt, ester, or prodrug of said compound or
tautomer.
98. The method according to claim 67, wherein the compound is a
compound according to any of the compounds in Table 1, Table 2,
Table 2a and Table 2aa or a tautomer thereof, or a pharmaceutically
acceptable salt, ester, or prodrug of said compound or tautomer.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 14/112,027, filed Feb. 7, 2014 (now allowed),
which is a national stage application, filed under 35 U.S.C. .sctn.
371, of International Application No. PCT/US2012/032994, filed on
Apr. 11, 2012, which claims priority to and the benefit of U.S.
provisional application No. 61/476,138, filed Apr. 15, 2011, U.S.
provisional application No. 61/535,118, filed Sep. 15, 2011, and
U.S. provisional application No. 61/610,363, filed Mar. 13, 2012.
The contents of the aforementioned applications are hereby
incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
antimicrobial compounds and to methods of making and using them.
These compounds are useful for treating, preventing, and reducing
the risk of microbial infections in humans and animals.
BACKGROUND
[0003] Since the discovery of penicillin in the 1920s and
streptomycin in the 1940s, many new compounds have been discovered
or specifically designed for use as antibiotic agents. It was once
thought that infectious diseases could be completely controlled or
eradicated with the use of such therapeutic agents. However, such
views have been challenged because strains of cells or
microorganisms resistant to currently effective therapeutic agents
continue to evolve. Almost every antibiotic agent developed for
clinical use has ultimately encountered problems with the emergence
of resistant bacteria. For example, resistant strains of
Gram-positive bacteria such as methicillin-resistant staphylococci,
penicillin-resistant streptococci, and vancomycin-resistant
enterococci have developed. Resistant bacteria can cause serious
and even fatal results for infected patients. See, e.g., Lowry, F.
D. "Antimicrobial Resistance: The Example of Staphylococcus
aureus," J. Clin. Invest., vol. 111, no. 9, pp. 1265-1273 (2003);
and Gold, H. S. and Moellering, R. C., Jr., "Antimicrobial Drug
Resistance," N Engl. J. Med., vol. 335, pp. 1445-53 (1996).
[0004] The discovery and development of new antibacterial agents
have been for decades a major focus in many pharmaceutical
companies. Nonetheless, in more recent years there has been an
exodus of pharmaceutical companies from this area of research and
drug development. As a consequence of this exodus, there have been
very few new antibiotics entering the market. This lack of new
antibiotics is particularly disturbing, especially at a time when
bacterial resistance to current therapies is increasing both in the
hospital and community settings.
[0005] In the search for new antibiotic agents, researchers have
tried combining or linking various portions of antibiotic molecules
to create multifunctional or hybrid compounds Other researchers
have tried making derivatives of known classes of antibiotics,
e.g., telithromycin, which is sold under the trade name Ketek.RTM.,
is a derivative of erythromycin. However, these approaches have met
with limited success.
[0006] An approach to developing new antimicrobial compounds is to
design modulators, for example, inhibitors, of bacterial ribosome
function. By modulating or inhibiting bacterial ribosome function
such antimicrobial compounds could interfere with essential
processes such as RNA translation and protein synthesis, thereby
providing an antimicrobial effect. In fact, some antibiotic
compounds such as erythromycin, clindamycin, and linezolid are
known to bind to the ribosome.
[0007] The present invention utilizes a structure based drug design
approach for discovering and developing new antimicrobial agents.
This approach starts with the high resolution X ray crystal of the
ribosome to design new classes of antimicrobial compounds having
specific chemical structures, ribosome binding characteristics, and
antimicrobial activity. This structure based drug discovery
approach is described in the following publication: Franceschi, F.
and Duffy, E. M., "Structure-based drug design meets the ribosome",
Biochemical Pharmacology, vol. 71, pp. 1016-1025 (2006).
[0008] Based on this structure based drug design approach, the
present invention describes new chemical classes of antimicrobial
compounds useful for treating bacterial infections in humans and
animals. Without being limited by theories, these compounds are
believed to inhibit bacterial ribosome function by binding to the
ribosome. By taking advantage of these ribosome binding sites, the
antimicrobial compounds of the present invention can provide better
activity, especially against resistant strains of bacteria, than
current antibiotic compounds.
[0009] The present invention therefore fills an important ongoing
need for providing new antimicrobial agents, particularly for
antimicrobial agents, having activity against resistant pathogenic
bacterial organisms.
SUMMARY OF THE INVENTION
[0010] The present invention relates generally to the field of
antimicrobial compounds and to methods of making and using them.
These compounds and tautomers thereof are useful for treating,
preventing, and reducing the risk of microbial infections in humans
and animals. The present invention also provides pharmaceutically
acceptable salts, esters, and prodrugs of these compounds and
tautomers.
[0011] In one aspect, the present invention relates to a compound
having the formula:
##STR00001##
[0012] or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
[0013] X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or N; X.sub.3
is CR.sup.3 or N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or
N; with the proviso that X.sub.1, X.sub.2, X.sub.3, X.sub.4, and
X.sub.5 are not all N;
[0014] Y.sub.6 is CR.sup.6 or N; Y.sub.2 is CR.sup.2 or N; Y.sub.8
is CR.sup.8 or N; Y.sub.9 is CR.sup.9 or N; Y.sub.10 is CR.sup.10
or N; with the proviso that Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, and
Y.sub.10 are not all N; wherein R.sup.1, R.sup.2, R.sup.4, R.sup.5,
R.sup.6, R.sup.2, R.sup.8 and R.sup.10 are each independently
selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f)
--CF.sub.3, (g) --CF.sub.2H, (h) --CFH.sub.2, (i) --OCF.sub.3, (j)
--OCF.sub.2H, (k) --OCFH.sub.2, (l) --OCH.sub.3, (m) --CN, (n)
--N.sub.3, (o) --NO.sub.2, (p) --NR.sup.11R.sup.11, (q)
--NR.sup.11C(O)R.sup.11, (r) --C(O)NR.sup.11R.sup.11, (s)
--OR.sup.11, (t) --COH, (u) --CO(C.sub.1-C.sub.8 alkyl), (v)
--COR.sup.11, (w) --NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x)
--S(O).sub.pR.sup.11, (y) --NR.sup.11S(O).sub.pR.sup.11, (z)
--SR.sup.11, (aa) --S CF .sub.3, (bb)
--C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc) --COOR.sup.11, (dd)
--(OCH.sub.2CH.sub.2).sub.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) 3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur);
[0015] wherein each (ff) through (nn) is optionally substituted
with one or more R.sup.12; alternatively, wherein two substituents
selected from R.sup.6, R.sup.7, and R.sup.8 are taken together with
the carbon atom to which they are attached to form (a) 3-7 membered
saturated or unsaturated carbocyclic or (b) 3-7 membered saturated
or unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or
more R.sup.12;
[0016] each R.sup.11 is independently selected from (a) hydrogen,
(b) halogen, (c) --OH, (d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH,
(f) --OCF.sub.3, (g) --OCF.sub.2H, (h) --OCFH.sub.2, (i)
--OCH.sub.3, (j) --OR.sup.12, (k) --COR.sup.12, (l) --CN, (m)
--NO.sub.2, (n) --CONH.sub.2, (o) --CONR.sup.12R.sup.12, (p)
--COCH.sub.3, (q) --S(O).sub.pCH.sub.3, (r)
--S(O).sub.pNR.sup.12R.sup.12, (s) --SR.sup.12, (t) --C(O)OH, (u)
--C(O)OR.sup.12, (v) --N.sub.3, (w) --NH.sub.2, (x)
--NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8 alkyl), (z)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (aa) --C.sub.1-C.sub.8 alkyl,
(bb) --C.sub.2-C.sub.8 alkenyl, (cc) --C.sub.2-C.sub.8 alkynyl,
(dd) haloalkyl, (ee) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur), (ff) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (gg) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (hh) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, and (ii)
--(C.dbd.NH)NR.sup.12R.sup.12;
[0017] wherein each (y) through (hh) is optionally substituted with
one or more R.sup.12;
[0018] alternatively two R.sup.11 substituents are taken together
to form (a) -3-7 membered saturated or unsaturated carbocyclic or
(b) -3-7 membered saturated or unsaturated heterocyclic ring
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, wherein each (a)
through (b) is optionally substituted with one or more
R.sup.12;
[0019] R.sup.3 is selected from:
##STR00002##
[0020] wherein R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e,
R.sup.3f, R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and
R.sup.3l are each independently selected from (a) hydrogen, (b)
halogen, (c) --CN, (d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3,
(g) --OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j)
--OR.sup.11, (k) --C(O)R.sup.11, (l) --C(O)NR.sup.11R.sup.11, (m)
--NH.sub.2, (n) --NR.sup.11R.sup.11, (o) --NR.sup.11C(O)R.sup.11,
(p) --S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle;
[0021] wherein each (s) through (x) is optionally substituted with
one or more R.sup.12;
[0022] alternatively, one or more pairs of substituents selected
from R.sup.3a and R.sup.3b, R.sup.3c and R.sup.3d, R.sup.3e and
R.sup.3f, R.sup.3g and R.sup.3h, R.sup.3i and R.sup.3j, and
R.sup.3k and R.sup.3l are taken together with the carbon atom to
which they are attached to form (a) -3-7 membered saturated or
unsaturated carbocyclic, (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur, (c) an exo
carbon-carbon double bond, (d) carbonyl group, or (e) thiocarbonyl
group;
[0023] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0024] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3k, and R.sup.3l on different
carbon atoms are taken together with the intervening atoms to which
they are attached to form (a) -3-7 membered saturated or
unsaturated carbocyclic or (b) -3-7 membered saturated or
unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and
sulfur;
[0025] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0026] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a carbon-carbon triple bond;
[0027] U is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O)--,
--NR.sup.11S(O).sub.pNR.sup.11--, and
--NR.sup.11C(O)NR.sup.11--;
[0028] T is selected from --NR.sup.11R.sup.11,
--N.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
[0029] alternatively, one R.sup.11 and one substituent selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0030] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0031] R.sup.9 is selected from:
##STR00003##
[0032] wherein R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are each
independently selected from (a) hydrogen, (b) halogen, (c) --CN,
(d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3, (g) --OCH.sub.3,
(h) --OCF.sub.2H, (i) --OCFH.sub.2, (j) --OR.sup.11, (k)
--NH.sub.2, (l) --NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n)
--C(O)OR.sup.11, (o) --C(O)NR.sup.11R.sup.11, (p)
--NR.sup.11C(O)R.sup.11, (q) --S(O).sub.pR.sup.11, (r)
--C.sub.1-C.sub.8 alkyl, (s) --C.sub.2-C.sub.8 alkenyl, (t)
--C.sub.1-C.sub.8 alkynyl, (u) haloalkyl, (v) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (w) -3-14 membered saturated, unsaturated,
or aromatic carbocycle;
[0033] wherein each (r) through (w) is optionally substituted with
one or more R.sup.12;
[0034] alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group;
[0035] wherein each (a) through (c) is optionally substituted with
one or more R.sup.12;
[0036] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t on different carbon atoms are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0037] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0038] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon atoms are
taken together with the bond between said adjacent carbon atoms
form a substituted or unsubstituted carbon-carbon double bond, or
four substituents selected from R.sup.9k, R.sup.9l, R.sup.9m,
R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and
R.sup.9t on two adjacent carbon atoms are taken together with the
bond between said adjacent carbon atoms form a carbon-carbon triple
bond;
[0039] Z is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p--,
--NR.sup.11S(O).sub.pNR.sup.11--, and
--NR.sup.11C(O)NR.sup.11--;
[0040] W is selected from --NR.sup.11R.sup.11,
--NR.sup.11(CO)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
[0041] alternatively, one R.sup.11 and one substituent selected
from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur;
[0042] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0043] R.sup.12 is independently selected from (a) hydrogen, (b)
halogen, (c) --OH, (d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH, (f)
--OCF.sub.3, (g) --OCH.sub.3, (h) --OCF.sub.2H, (i) --OCFH.sub.2,
(j) --O(C.sub.1-C.sub.8 alkyl), (k) --CN, (l) --NO.sub.2, (m)
--CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8 alkyl), (o)
C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q) --COCH.sub.3,
(r) --S(O).sub.pCH.sub.3, (s) --S(O).sub.pN(C.sub.1-C.sub.8
alkyl).sub.2, (t) --S(C.sub.1-C.sub.8 alkyl), (u) --C(O)OH, (v)
--C(O)O(C.sub.1-C.sub.8 alkyl), (w) --N.sub.3, (x)
--NHC(O)(C.sub.1-C.sub.8 alkyl), (y) --N(C.sub.1-C.sub.8
alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z) --NH.sub.2, (aa)
--NH(C.sub.1-C.sub.8 alkyl), (bb) --N(C.sub.1-C.sub.8 alkyl).sub.2,
(cc) --C.sub.1-C.sub.8 alkyl, (dd) --C.sub.2-C.sub.8 alkenyl, (ee)
--C.sub.2-C.sub.8 alkynyl, (ff) haloalkyl, (gg) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (hh)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (ii) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (jj)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, (kk)
--(C.dbd.NH)NH.sub.2, (ll) --C(.dbd.NH)NH.sub.2, (mm)
--C(O)R.sup.13, (nn) .dbd.O, and (oo) .dbd.NR.sup.13;
[0044] wherein each (aa) through (jj) is optionally substituted
with one or more R.sup.13; R.sup.13 is independently selected from
(a) hydrogen, (b) halogen, (c) --C.sub.1-C.sub.8 alkyl, (d)
--C.sub.2-C.sub.8 alkenyl, (e) --C.sub.2-C.sub.8 alkynyl, (f)
haloalkyl, (g) --OH, (h) --OC.sub.1-C.sub.8 alkyl, (i)
--OC.sub.2C.sub.8 alkenyl, (j) --OC.sub.2-C.sub.8 alkynyl, (k)
--OCF.sub.3, (l) --OCH.sub.3, (m) --OCF.sub.2H, (n) --OCFH.sub.2,
(o) --NH.sub.2, (p) --CN, (q) --N.sub.3, (r)
--S(O).sub.pC.sub.1-C.sub.8 alkyl, (s) -3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur, and (t) 3-14 membered saturated, unsaturated, or
aromatic carbocycle;
[0045] p is 0,1, or 2; and
[0046] t is 0,1, or 2.
[0047] In one aspect, the present invention relates to a compound
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, having the
formula:
##STR00004##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein
[0048] X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or N; X.sub.3
is CR.sup.3 or N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or
N; with the proviso that X.sub.1, X.sub.2, X.sub.3, X.sub.4, and
X.sub.5 are not all N;
[0049] Y.sub.6 is CR.sup.6 or N; Y.sub.7 is CR.sup.7 or N; Y.sub.8
is CR.sup.8 or N; Y.sub.9 is CR.sup.9 or N; Y.sub.10 is CR.sup.10
or N; with the proviso that Y.sub.6, Y.sub.2, Y.sub.8, Y.sub.9, and
Y.sub.10 are not all N; wherein
[0050] R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.10 are each independently selected from (a)
hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g) --CFH,
(h) --CFH.sub.2, (i) --OCF.sub.3, (j) --OCF.sub.2H, (k)
--OCFH.sub.2, (l) --OCH.sub.3, (m) --CN, (n) --N.sub.3, (o)
--NO.sub.2, (p) --NR.sup.11R.sup.11, (q) --NR.sup.11(CO)R.sup.11,
(r) --(CO)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2).sub.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur);
[0051] wherein each (ff) through (nn) is optionally substituted
with one or more R.sup.12;
[0052] each R.sup.11 is independently selected from (a) hydrogen,
(b) halogen, (c) --CF.sub.3, (d) --CF.sub.2H, (e) --CFH.sub.2, (f)
--OH, (g) --SH, (h) --(C.sub.1-C.sub.8 alkyl)OH, (i) --OCF.sub.3,
(j) --OCF.sub.2H, (k) --OCFH.sub.2, (l) --OCH.sub.3, (m)
--OR.sup.12, (n) --COR.sup.12, (o) --CN, (p) --NO.sub.2, (q)
-CONH.sub.2, (r) --CONR.sup.12R.sup.12, (s) --C(O)CH.sub.3, (t)
--S(O).sub.pCH.sub.3, (u) --S(O).sub.pNR.sup.12R.sup.12, (v)
--SR.sup.12, (w) --C(O)OH, (x) --C(O)OR.sup.12, (y) --N.sub.3, (z)
--NH.sub.2, (aa) --NR.sup.12C(O)R.sup.12, (bb) --NH(C.sub.1-C.sub.8
alkyl), (cc) --N(C.sub.1-C.sub.8 alkyl).sub.2, (dd)
--C.sub.1-C.sub.8 alkyl, (ee) --C.sub.2-C.sub.8 alkenyl, (ff)
--C.sub.2-C.sub.8 alkynyl, (gg) -haloalkyl, (hh) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (ii)
--(C.sub.1-C.sub.8 alkyl)(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (jj) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (kk)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, and
(11) --(C.dbd.NH)NR.sup.12R.sup.12;
[0053] wherein each (bb) through (kk) is optionally substituted
with one or more R.sup.12;
[0054] alternatively two R.sup.11 subsituents are taken together to
form (a) 3-7 membered saturated or unsaturated carbocyclic or (b)
3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, wherein each (a) through (b) is
optionally substituted with one or more R.sup.12;
[0055] R.sup.3 is selected from:
##STR00005##
[0056] wherein R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e,
R.sup.3f, R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j are each
independently selected from (a) hydrogen, (b) halogen, (c)
--CH.sub.3, (d) --CF.sub.3, (e) --CF.sub.2H, (f) --CFH.sub.2, (g)
--OCF.sub.3, (h) --OCF.sub.2H, (i) --OCFH.sub.2, (j) --OCH.sub.3,
(k) --OR.sup.11, (l) --C.sub.1-C.sub.8 alkyl, (m) haloalkyl, (n)
-3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, and (o) -3-14 membered
saturated, unsaturated, or aromatic carbocycle;
[0057] wherein each (1) through (o) is optionally substituted with
one or more R.sup.12;
[0058] alternatively, one or more pairs of substituents selected
from R.sup.3a and R.sup.3b, R.sup.3c and R.sup.3d, R.sup.3e and
R.sup.3f, R.sup.3g and R.sup.3h, and R.sup.3i and R.sup.3j are
taken together with the carbon atom to which they are attached to
form (a) -3-7 membered saturated or unsaturated carbocyclic, (b)
-3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (c) an exo carbon-carbon double bond,
(d) carbonyl group, or (e) thiocarbonyl group;
[0059] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0060] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j on different carbon
atoms are taken together with the intervening atoms to which they
are attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0061] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0062] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a substituted or unsubstituted carbon-carbon double
bond, or wherein four substituents selected from R.sup.3a,
R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g,
R.sup.3h,R.sup.3i and R.sup.3j on two adjacent carbon atoms are
taken together with the bond between said adjacent carbon atoms
form a carbon-carbon triple bond;
[0063] U is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p-- and
--NR.sup.11S(O).sub.pNR.sup.11--;
[0064] T is selected from --NR.sup.11R.sup.11,
--NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
[0065] alternatively, one R.sup.11 and one substituent selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f
R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur;
[0066] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0067] R.sup.9 is selected from:
##STR00006##
[0068] wherein R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are each
independently selected from (a) hydrogen, (b) halogen, (c)
--CH.sub.3, (d) --CF.sub.3, (e) --CF.sub.2H, (f) --CFH.sub.2, (g)
--OCF.sub.3, (h) --OCH.sub.3, (i) --OCF.sub.2H, (j) --OCFH.sub.2,
(k) --OR.sup.11, --(l) --C.sub.1-C.sub.8 alkyl, (m) haloalkyl, (n)
-3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, and (o) -3-14 membered
saturated, unsaturated, or aromatic carbocycle;
[0069] wherein each (l) through (o) is optionally substituted with
one or more R.sup.12;
[0070] alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) -3-7 membered saturated or unsaturated carbocyclic, (b)
3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (c) an exo carbon-carbon double bond,
(d) carbonyl group, and (e) thiocarbonyl group;
[0071] wherein each (a) through (c) is optionally substituted with
one or more R.sup.12;
[0072] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t on different carbon atoms are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0073] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0074] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon atoms are
taken together with the bond between said adjacent carbon atoms
form a substituted or unsubstituted carbon-carbon double bond, or
four substituents selected from R.sup.9k, R.sup.9l, R.sup.9m,
R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and
R.sup.9t on two adjacent carbon atoms are taken together with the
bond between said adjacent carbon atoms form a carbon-carbon triple
bond;
[0075] Z is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, NR.sup.11S(O).sub.p-- and
--NR.sup.11S(O).sub.pNR.sup.11--;
[0076] W is selected from --NR.sup.11R.sup.11, --NR.sup.11
(CO)OR.sup.11, --NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and
--OR.sup.11;
[0077] alternatively, one R.sup.11 and one substituent selected
from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur;
[0078] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0079] R.sup.12 is independently selected from (a) hydrogen, (b)
halogen, (c) --CF.sub.3, (d) --CF.sub.2H, (e) --CFH.sub.2, (f)
--OH, (g) --SH, (h) --(C.sub.1-C.sub.8 alkyl)OH, (i) --OCF.sub.3,
(j) --OCH.sub.3, (k) --OCF.sub.2H, (l) --OCFH.sub.2, (m)
--O(C.sub.1-C.sub.8 alkyl), (n) --CN, (o) --NO.sub.2, (p)
--CONH.sub.2, (q) --C(O)H, (r) --C(O)CH.sub.3, (s)
--S(O).sub.pCH.sub.3, (t) --S(O).sub.pN(C.sub.1-C.sub.8
alkyl).sub.2, (u) --S(C.sub.1-C.sub.8 alkyl), (v) --C(O)OH, (w)
--C(O)O(C.sub.1-C.sub.8 alkyl), (x) --N.sub.3, (y)
--NHC(O)(C.sub.1-C.sub.8 alkyl), (z) --N(C.sub.1-C.sub.8
alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (aa) --NH.sub.2, (bb)
--NH(C.sub.1-C.sub.8 alkyl), (cc) --N(C.sub.1-C.sub.8 alkyl).sub.2,
(dd) --C.sub.1-C.sub.8 alkyl, (ee) --C.sub.2-C.sub.8 alkenyl, (ff)
--C.sub.2-C.sub.8 alkynyl, (gg) -haloalkyl, (hh) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (ii)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (jj) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (kk)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, (ll)
(C.dbd.NH)NH.sub.2, (mm) C(O)NH(C.sub.1-C.sub.8 alkyl), (nn)
C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, and (oo)
C(.dbd.NH)NH.sub.2;
[0080] p is 0, 1, or 2; and
[0081] t is 0, 1, or 2.
[0082] In addition, the invention provides methods of synthesizing
the foregoing compounds and tautomers thereof, and pharmaceutically
acceptable salts, esters and prodrugs of said compounds and
tautomers. Following synthesis, an effective amount of one or more
of the compounds or tautomers thereof, or pharmaceutically
acceptable salts, esters or prodrugs of said compounds or tautomers
can be formulated with a pharmaceutically acceptable carrier for
administration to a human or animal for use as antimicrobial
agents, particularly as antibacterial agents. In certain
embodiments, the compounds of the present invention are useful for
treating, preventing, or reducing the risk of microbial infections
or for the manufacture of a medicament for treating, preventing, or
reducing the risk of microbial infections. Accordingly, the
compounds or tautomers thereof, or pharmaceutically acceptable
salts, esters, or prodrugs of said compounds or tautomers or their
formulations can be administered, for example, via oral,
parenteral, intravenous, otic, ophthalmic, nasal, or topical
routes, to provide an effective amount of the compound or tautomer
thereof, or pharmaceutically acceptable salt, ester or prodrug of
said compound or tautomer to the human or animal.
[0083] The foregoing and other aspects and embodiments of the
invention can be more fully understood by reference to the
following detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
[0084] The present invention provides a family of compounds or
tautomers thereof that can be used as antimicrobial agents, more
particularly as antibacterial agents.
[0085] The present invention also includes pharmaceutically
acceptable salts, esters, and prodrugs of said compounds and
tautomers.
[0086] The compounds or tautomers thereof, or pharmaceutically
acceptable salts, esters, or prodrugs of said compounds or
tautomers described herein can have asymmetric centers. Compounds
or tautomers thereof or pharmaceutically acceptable salts, esters,
or prodrugs of said compounds or tautomers of the present invention
containing an asymmetrically substituted atom can be isolated in
optically active or racemic forms. It is well known in the art how
to prepare optically active forms, such as by resolution of racemic
forms or by synthesis from optically active starting materials.
Many geometric isomers of olefins, C.dbd.N double bonds, and the
like can also be present in the compounds or tautomers thereof, or
pharmaceutically acceptable salts, esters, or prodrugs of said
compounds or tautomers described herein, and all such stable
isomers are contemplated in the present invention. Cis and trans
geometric isomers of the compounds or tautomers thereof, or
pharmaceutically acceptable salts, esters, or prodrugs of said
compounds or tautomers of the present invention are described and
can be isolated as a mixture of isomers or as separate isomeric
forms. All chiral, diastereomeric, racemic, and geometric isomeric
forms of a structure are intended, unless specific stereochemistry
or isomeric form is specifically indicated. All processes used to
prepare compounds or tautomers thereof, or pharmaceutically
acceptable salts, esters, or prodrugs of said compounds or
tautomers of the present invention and intermediates made therein
are considered to be part of the present invention. All tautomers
of shown or described compounds are also considered to be part of
the present invention. Furthermore, the invention also includes
metabolites of the compounds described herein.
[0087] The invention also comprehends isotopically-labeled
compounds or tautomers thereof, or pharmaceutically acceptable
salts, esters, or prodrugs of said compounds or tautomers, which
are identical to those recited in formulae of the invention and
following, but for the fact that one or more atoms are replaced by
an atom having an atomic mass or mass number different from the
atomic mass or mass number most commonly found in nature. Examples
of isotopes that can be incorporated into compounds or tautomers
thereof, or pharmaceutically acceptable salts, esters, or prodrugs
of said compounds or tautomers of the invention include isotopes of
hydrogen, carbon, nitrogen, fluorine, such as .sup.3H, .sup.11C,
.sup.14C and .sup.18F.
[0088] Compounds or tautomers thereof, or pharmaceutically
acceptable salts, esters, or prodrugs of said compounds or
tautomers of the present invention that contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of the present invention. Isotopically-labeled compounds or
tautomers thereof, or pharmaceutically acceptable salts, esters, or
prodrugs of said compounds or tautomers of the present invention,
for example those into which radioactive isotopes such as .sup.3H,
.sup.14C are incorporated, are useful in drug and/or substrate
tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. .sup.11C and .sup.8F
isotopes are particularly useful in PET (positron emission
tomography). PET is useful in brain imaging. Further, substitution
with heavier isotopes such as deuterium, i.e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances, isotopically labeled compounds or tautomers thereof,
or pharmaceutically acceptable salts, esters, or prodrugs of said
compounds or tautomers having a formula of the invention can
generally be prepared by carrying out the procedures disclosed in
the Schemes and/or in the Examples below, by substituting a readily
available isotopically labeled reagent for a non-isotopically
labeled reagent. In one embodiment, the compounds or tautomers
thereof, or pharmaceutically acceptable salts, esters, or prodrugs
of said compounds or tautomers of the invention are not
isotopically labelled.
[0089] When any variable (e.g., R.sup.12) occurs more than one time
in any constituent or formulae of the invention, its definition at
each occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with one or more R.sup.12 moieties, then R.sup.12 at
each occurrence is selected independently from the definition of
R.sup.12. Also, combinations of substituents and/or variables are
permissible, but only if such combinations result in stable
compounds within a designated atom's normal valency.
[0090] A chemical structure showing a dotted line representation
for a chemical bond indicates that the bond is optionally present.
For example, a dotted line drawn next to a solid single bond
indicates that the bond can be either a single bond or a double
bond.
[0091] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent can be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom via which such substituent is bonded to the
rest of the compound of a given formula, then such substituent can
be bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible, but only if such
combinations result in stable compounds.
[0092] In cases wherein there are nitrogen atoms in the compounds
or tautomers thereof, or pharmaceutically acceptable salts, esters,
or prodrugs of said compounds or tautomers of the present
invention, these, where appropriate, can be converted to N-oxides
by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen
peroxides). Thus, shown and claimed nitrogen atoms are considered
to cover both the shown nitrogen and its N-oxide (N.fwdarw.O)
derivative, as appropriate. In some embodiments, the present
invention relates to N-oxides of the compounds or tautomers
thereof, or pharmaceutically acceptable salts, esters, or prodrugs
of said compounds or tautomers disclosed herein.
[0093] One approach to developing improved antiproliferative and
antiinfective agents is to provide modulators (for example,
inhibitors) of ribosome function.
[0094] Ribosomes are ribonucleoproteins, which are present in both
prokaryotes and eukaryotes. Ribosomes are the cellular organelles
responsible for protein synthesis. During gene expression,
ribosomes translate the genetic information encoded in a messenger
RNA into protein (Garrett et al. (2000) "The Ribosome: Structure,
Function, Antibiotics and Cellular Interactions," American Society
for Microbiology, Washington, D.C.).
[0095] Ribosomes comprise two nonequivalent ribonucleoprotein
subunits. The larger subunit (also known as the "large ribosomal
subunit") is about twice the size of the smaller subunit (also
known as the "small ribosomal subunit"). The small ribosomal
subunit binds messenger RNA (mRNA) and mediates the interactions
between mRNA and transfer RNA (tRNA) anticodons on which the
fidelity of translation depends. The large ribosomal subunit
catalyzes peptide bond formation, i.e. the peptidyl-transferase
reaction of protein synthesis, and includes, at least, three
different tRNA binding sites known as the aminoacyl, peptidyl, and
exit sites. The aminoacyl site or A-site accommodates the incoming
aminoacyl-tRNA that is to contribute its amino acid to the growing
peptide chain. Also, the A space of the A-site is important. The
peptidyl site or P-site accommodates the peptidyltRNA complex,
i.e., the tRNA with its amino acid that is part of the growing
peptide chain. The exit or Esite accommodates the deacylated tRNA
after it has donated its amino acid to the growing polypeptide
chain.
1. Definitions
[0096] "Isomerism" means compounds that have identical molecular
formulae but that differ in the nature or the sequence of bonding
of their atoms or in the arrangement of their atoms in space.
Isomers that differ in the arrangement of their atoms in space are
termed "stereoisomers". Stereoisomers that are not mirror images of
one another are termed "diastereoisomers", and stereoisomers that
are non-superimposable mirror images are termed "enantiomers", or
sometimes optical isomers. A carbon atom bonded to four
nonidentical substituents is termed a "chiral center".
[0097] "Chiral isomer" means a compound with at least one chiral
center. A compound with one chiral center has two enantiomeric
forms of opposite chirality and may exist either as an individual
enantiomer or as a mixture of enantiomers. A mixture containing
equal amounts of individual enantiomeric forms of opposite
chirality is termed a "racemic mixture". A compound that has more
than one chiral center has 2.sup.n-1 enantiomeric pairs, where n is
the number of chiral centers. Compounds with more than one chiral
center may exist as either an individual diastereomer or as a
mixture of diastereomers, termed a "diastereomeric mixture". When
one chiral center is present, a stereoisomer may be characterized
by the absolute configuration (R or S) of that chiral center.
Absolute configuration refers to the arrangement in space of the
substituents attached to the chiral center. The substituents
attached to the chiral center under consideration are ranked in
accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn
et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et
al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc.
1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn,
J., Chem. Educ. 1964, 41, 116).
[0098] "Geometric Isomers" means the diastereomers that owe their
existence to hindered rotation about double bonds. These
configurations are differentiated in their names by the prefixes
cis and trans, or Z and E, which indicate that the groups are on
the same or opposite side of the double bond in the molecule
according to the Cahn-Ingold-Prelog rules.
[0099] Further, the compounds discussed in this application include
all atropic isomers thereof "Atropic isomers" are a type of
stereoisomer in which the atoms of two isomers are arranged
differently in space. Atropic isomers owe their existence to a
restricted rotation caused by hindrance of rotation of large groups
about a central bond. Such atropic isomers typically exist as a
mixture, however as a result of recent advances in chromatography
techniques, it has been possible to separate mixtures of two
atropic isomers in select cases.
[0100] "Tautomers" refers to compounds whose structures differ
markedly in arrangement of atoms, but which exist in easy and rapid
equilibrium. It is to be understood that compounds of present
invention may be depicted as different tautomers. It should also be
understood that when compounds have tautomeric forms, all
tautomeric forms are intended to be within the scope of the
invention, and the naming of the compounds does not exclude any
tautomer form.
[0101] Some compounds of the present invention can exist in a
tautomeric form which is also intended to be encompassed within the
scope of the present invention.
[0102] The compounds, pharmaceutically acceptable salts, esters and
prodrugs of the present invention can exist in several tautomeric
forms, including the enol and imine form, and the keto and enamine
form and geometric isomers and mixtures thereof. All such
tautomeric forms are included within the scope of the present
invention. Tautomers exist as mixtures of a tautomeric set in
solution. In solid form, usually one tautomer predominates. Even
though one tautomer may be described, the present invention
includes all tautomers of the present compounds.
[0103] A tautomer is one of two or more structural isomers that
exist in equilibrium and are readily converted from one isomeric
form to another. This reaction results in the formal migration of a
hydrogen atom accompanied by a switch of adjacent conjugated double
bonds.
[0104] In solutions where tautomerization is possible, a chemical
equilibrium of the tautomers can be reached. The exact ratio of the
tautomers depends on several factors, including temperature,
solvent, and pH. The concept of tautomers that are interconvertable
by tautomerizations is called tautomerism.
[0105] Of the various types of tautomerism that are possible, two
are commonly observed. In keto-enol tautomerism a simultaneous
shift of electrons and a hydrogen atom occurs. Ring-chain
tautomerism, is exhibited by glucose. It arises as a result of the
aldehyde group (--CHO) in a sugar chain molecule reacting with one
of the hydroxy groups (--OH) in the same molecule to give it a
cyclic (ring-shaped) form.
[0106] Tautomerizations are catalyzed by: Base: 1. deprotonation;
2. formation of a delocalized anion (e.g. an enolate); 3.
protonation at a different position of the anion; Acid: 1.
protonation; 2. formation of a delocalized cation; 3. deprotonation
at a different position adjacent to the cation.
[0107] Common tautomeric pairs are: ketone-enol, amide-nitrile,
lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings
(e.g. in the nucleobases guanine, thymine, and cytosine),
amine-enamine and enamine-enamine. An example below is included for
illustrative purposes, and the present invention is not limited to
this example:
##STR00007##
[0108] The terms "crystal polymorphs" or "polymorphs" or "crystal
forms" means crystal structures in which a compound (or salt or
solvate thereof) can crystallize in different crystal packing
arrangements, all of which have the same elemental composition.
Different crystal forms usually have different X-ray diffraction
patterns, infrared spectral, melting points, density hardness,
crystal shape, optical and electrical properties, stability and
solubility. Recrystallization solvent, rate of crystallization,
storage temperature, and other factors may cause one crystal form
to dominate. Crystal polymorphs of the compounds can be prepared by
crystallization under different conditions.
[0109] The term "substituted," as used herein, means that any one
or more hydrogens on the designated atom, usually a carbon, oxygen,
or nitrogen atom, is replaced with a selection from the indicated
group, provided that the designated atom's normal valency is not
exceeded, and that the substitution results in a stable compound.
When a substituent is keto (i.e., .dbd.O), then 2 hydrogens on the
atom are replaced. Ring double bonds, as used herein, are double
bonds that are formed between two adjacent ring atoms (e.g.,
C.dbd.C, C.dbd.N, N.dbd.N, etc.).
[0110] As used herein, the term "anomeric carbon" means the acetal
carbon of a glycoside.
[0111] As used herein, the term "glycoside" is a cyclic acetal.
[0112] As used herein, "alkyl" is intended to include both branched
and straight-chain saturated aliphatic hydrocarbon groups having
the specified number of carbon atoms. For example C.sub.1-4 is
intended to include C.sub.1, C.sub.2, C.sub.3, and C.sub.4
C.sub.1-6 alkyl is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, and C.sub.6 alkyl groups and C.sub.1-8 is
intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
C.sub.6, C.sub.7, and C.sub.8. Some examples of alkyl include, but
are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl,
s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and
n-octyl.
[0113] As used herein, "alkenyl" is intended to include hydrocarbon
chains of either straight or branched configuration and one or more
unsaturated carbon-carbon bonds that can occur in any stable point
along the chain, such as ethenyl and propenyl. For example
C.sub.2-6 alkenyl is intended to include C.sub.2, C.sub.3, C.sub.4,
C.sub.5, and C.sub.6 alkenyl groups and C.sub.2-8 alkenyl is
intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6,
C.sub.7, and C.sub.8.
[0114] As used herein, "alkynyl" is intended to include hydrocarbon
chains of either straight or branched configuration and one or more
triple carbon-carbon bonds that can occur in any stable point along
the chain, such as ethynyl and propynyl. For example, C.sub.2-6
alkynyl is intended to include C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6 alkynyl groups and C.sub.2-8 alkynyl is intended to
include C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8.
[0115] Furthermore, "alkyl", "alkenyl", and "alkynyl" are intended
to include moieties which are diradicals, i.e., having two points
of attachment. A nonlimiting example of such an alkyl moiety that
is a diradical is --CH.sub.2CH.sub.2--, i.e., a C.sub.2 alkyl group
that is covalently bonded via each terminal carbon atom to the
remainder of the molecule. The alkyl diradicals are also known as
"alkylenyl" radicals. The alkenyl diradicals are also known as
"alkenylenyl" radicals. The alkynyl diradicals are also known as
"alkynylenyl" radicals..
[0116] As used herein, "cycloalkyl" is intended to include
saturated ring groups, such as cyclopropyl, cyclobutyl, or
cyclopentyl. C.sub.3-8 cycloalkyl is intended to include C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.7, and C.sub.8 cycloalkyl
groups.
[0117] As used herein "counterion" is used to mean a positively or
negatively charged species present in conjunction with an ion of
opposite charge. A nonlimiting example of a counterion is an ion or
ions present to counterbalance the charge or charges on an organic
compound. Nonlimiting examples of counterions include chloride,
bromide, hydroxide, acetate, sulfate, and ammonium.
[0118] As used herein, "halo" or "halogen" refers to fluoro,
chloro, bromo, and iodo substituents.
[0119] As used herein, "haloalkyl" is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms, substituted with 1 or
more halogen (for example --C.sub.vF.sub.w wherein v=1 to 3 and w=1
to (2v+1)). Examples of haloalkyl include, but are not limited to,
trifluoromethyl, trichloromethyl, pentafluoroethyl, and
pentachloroethyl.
[0120] As used herein, "alkoxy" refers to an alkyl group as defined
above with the indicated number of carbon atoms attached through an
oxygen bridge. C.sub.1-6 alkoxy, is intended to include C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6 alkoxy groups.
C.sub.1-8 alkoxy, is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.7, and C.sub.8 alkoxy groups.
Examples of alkoxy include, but are not limited to, methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,
n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.
[0121] As used herein, "alkylthio" refers to an alkyl group as
defined above with the indicated number of carbon atoms attached
through a sulfur bridge. C.sub.1-6 alkylthio, is intended to
include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, and C.sub.6
alkylthio groups. C.sub.1-8 alkylthio, is intended to include
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, and
C.sub.8 alkylthio groups.
[0122] As used herein, "carbocycle" or "carbocyclic ring" is
intended to mean, unless otherwise specified, any stable 3, 4, 5,
6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or
tricyclic ring, any of which can be saturated, unsaturated
(including partially and fully unsaturated), or aromatic and said
ring consists of carbon atoms in its core ring structure. Examples
of such carbocycles or carbocyclic rings include, but are not
limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl,
cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,
[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl,
naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown
above, bridged rings are also included in the definition of
carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when
one or more carbon atoms link two nonadjacent carbon atoms.
Preferred bridges are one or two carbon atoms. It is noted that a
bridge always converts a monocyclic ring into a tricyclic ring.
When a ring is bridged, the substituents recited for the ring can
also be present on the bridge. Fused (e.g., naphthyl and
tetrahydronaphthyl) and spiro rings are also included.
[0123] As used herein, the term "heterocycle" or "heterocyclic"
ring means, unless otherwise stated, a stable 3, 4, 5, 6, 7, 8, 9,
10, 11, or 12membered monocyclic, bicyclic or tricyclic ring which
is saturated, unsaturated (including partially and fully
unsaturated), or aromatic, and said ring consists of carbon atoms
and one or more heteroatoms in its core ring structure, e.g., 1 or
1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected
from nitrogen, oxygen, and sulfur, and including any bicyclic or
tricyclic group in which any of the above defined heterocyclic
rings is fused or attached to a second ring (e.g., a benzene ring).
The nitrogen and sulfur heteroatoms can optionally be oxidized
(i.e., N.fwdarw.O and S(O).sub.p, wherein p=1 or 2). When a
nitrogen atom is included in the ring it is either N or NH,
depending on whether or not it is attached to a double bond in the
ring (i.e., a hydrogen is present if needed to maintain the
trivalency of the nitrogen atom). The nitrogen atom can be
substituted or unsubstituted (i.e., N or NR wherein R is H or
another substituent, as defined). The heterocycle or heterocyclic
ring can be attached to its pendant group at any heteroatom or
carbon atom that results in a stable structure. The heterocycle or
heterocyclic rings described herein can be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. A nitrogen
in the heterocycle or heterocyclic ring can optionally be
quaternized. Bridged rings are also included in the definition of
heterocycle or heterocyclic ring. A bridged ring occurs when one or
more atoms (i.e., C, O, N, or S) link two nonadjacent carbon or
nitrogen atoms. Preferred bridges include, but are not limited to,
one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen
atoms, and a carbonnitrogen group. When a ring is bridged, the
substituents recited for the ring can also be present on the
bridge. Spiro and fused rings are also included.
[0124] As used herein, the term "aromatic heterocycle", "aromatic
heterocylic" or "heteroaryl" ring is intended to mean a stable 5,
6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic
ring which consists of carbon atoms and one or more heteroatoms,
e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms,
independently selected from nitrogen, oxygen, and sulfur. In the
case of bicyclic aromatic heterocyclic or heterocycle or heteroaryl
rings, only one of the two rings needs to be aromatic (e.g.,
2,3-dihydroindole), though both can be (e.g., quinoline). The
second ring can also be fused or bridged as defined above for
heterocycles. The nitrogen atom can be substituted or unsubstituted
(i.e., N or NR wherein R is H or another substituent, as defined).
The nitrogen and sulfur heteroatoms can optionally be oxidized
(i.e., N.fwdarw.O and S(O).sub.p, wherein p=1 or 2). In certain
compounds, the total number of S and 0 atoms in the aromatic
heterocycle is not more than 1.
[0125] Examples of aromatic heterocycles, aromatic heterocyclics or
heteroaryls include, but are not limited to, acridinyl,
azabicyclooctanonyl, azepanyl, azetidinyl, azocinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,
benzodioxoly, benzooxadiazoly, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, cycloheptyl,
decahydroquinolinyl, dihydrobenzodioxinyl, 2H,6H-1,5,2dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolidinylimine, imidazolinyl, imidazolyl,
imidazolonyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl,
indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,
isothiazolyl, isoxazolyl, methylenedioxyphenyl,
methylbenztriazolyl, methylfuranyl, methylimidazolyl,
methylthiazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolidinonyl, oxazolyl, oxindolyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperazinonyl,
piperidinyl, piperidenyl, piperidonyl, 4-piperidonyl, piperonyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,
pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridinonyl, pyridyl,
pyrimidinyl, pyrroldionyl, pyrrolidinyl, pyrrolidinonyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, thiomorpholinyldioxidyl, triazinyl,
triazolopyrimidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
[0126] As used herein, the phrase "pharmaceutically acceptable"
refers to those compounds or tautomers thereof, or salts, esters,
or prodrugs thereof, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication, commensurate with a reasonable benefit/risk
ratio.
[0127] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds or tautomers thereof,
wherein the parent compound or a tautomer thereof, is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional nontoxic salts or the quaternary ammonium salts of the
parent compound or a tautomer thereof formed, for example, from
nontoxic inorganic or organic acids. For example, such conventional
non toxic salts include, but are not limited to, those derived from
inorganic and organic acids selected from 2-acetoxybenzoic,
2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic,
benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic,
ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic,
glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,
hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,
hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,
maleic, malic, mandelic, methane sulfonic, napsylic, nitric,
oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
polygalacturonic, propionic, salicylic, stearic, subacetic,
succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and
toluene sulfonic.
[0128] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound or a tautomer
thereof that contains a basic or acidic moiety by conventional
chemical methods. Generally, such pharmaceutically acceptable salts
can be prepared by reacting the free acid or base forms of these
compounds or tautomers thereof with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two; generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
18th ed., Mack Publishing Company, Easton, Pa., USA, p. 1445
(1990).
[0129] Since prodrugs are known to enhance numerous desirable
qualities of pharmaceuticals (e.g., solubility, bioavailability,
manufacturing, etc.) the compounds or tautomers thereof of the
present invention can be delivered in prodrug form. Thus, the
present invention is intended to cover prodrugs of the presently
claimed compounds or tautomers thereof, methods of delivering the
same and compositions containing the same. "Prodrugs" are intended
to include any covalently bonded carriers that release an active
parent drug of the present invention in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of the present
invention are prepared by modifying functional groups present in
the compound or a tautomer thereof in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compound or a tautomer thereof. Prodrugs
include compounds or tautomers thereof of the present invention
wherein a hydroxy, amino, or sulfhydryl group is bonded to any
group that, when the prodrug of the present invention is
administered to a mammalian subject, it cleaves to form a free
hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
formate, and benzoate derivatives of alcohol and amine functional
groups in the compounds of the present invention.
[0130] As used herein, "stable compound" and "stable structure" are
meant to indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0131] As used herein, the term "patient", as used herein, means
the human or animal (in the case of an animal, more typically a
mammal) subject that would be subjected to a surgical or invasive
medical procedure. Such patient or subject could be considered to
be in need of the methods of treating, reducing the risk of or
preventing the infection due to a surgical procedure or an invasive
medical procedure. Such patient or subject can also be considered
to be in need of perioperative prophylaxis.
[0132] As used herein, the term "treating" means to provide a
therapeutic intervention to cure or ameliorate an infection.
[0133] As used herein, the term "preventing", as used herein means,
to completely or almost completely stop an infection from
occurring, for example when the patient or subject is predisposed
to an infection or at risk of contracting an infection. Preventing
can also include inhibiting, i.e. arresting the development, of an
infection.
[0134] As used herein, the term "reducing the risk of", as used
herein, means to lower the likelihood or probability of an
infection occurring, for example when the patient or subject is
predisposed to an infection or at risk of contracting an
infection.
[0135] As used herein, "unsaturated" refers to compounds having at
least one degree of unsaturation (e.g., at least one multiple bond)
and includes partially and fully unsaturated compounds.
[0136] As used herein, the term "effective amount" refers to an
amount of a compound or a tautomer thereof, or a pharmaceutically
acceptable salt, ester, or prodrug of said compound or tautomer,
(including combinations of compounds and/or tautomers thereof,
and/or pharmaceutically acceptable salts, esters, or prodrugs of
said compound or tautomer), of the present invention that is
effective when administered alone or in combination as an
antimicrobial agent. For example, an effective amount refers to an
amount of the compound or tautomer thereof, or a pharmaceutically
acceptable salt, ester, or prodrug said compound or tautomer that
is present in a composition, a formulation or on a medical device
given to a recipient patient or subject sufficient to elicit
biological activity, for example, anti-infective activity, such as
e.g., anti-microbial activity, anti-bacterial activity, anti-fungal
activity, anti-viral activity, or anti-parasitic activity.
[0137] The term "prophylactically effective amount" means an amount
of a compound or a tautomer of said compound or tautomer, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer (including combinations of compounds and/or
tautomers thereof, and/or pharmaceutically acceptable salts,
esters, or prodrugs thereof), of the present invention that is
effective prophylactically when administered alone or in
combination as an antimicrobial agent. For example, a
prophylactically effective amount refers to an amount of the
compound or tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer that is
present in a composition, a formulation, or on a medical device
given to a recipient patient or subject sufficient to prevent or
reduce the risk of an infection due to a surgical procedure or an
invasive medical procedure.
[0138] It is to be further understood that the representations for
"Hydrogen Bond Acceptor--Hydrogen Bond Acceptor--Hydrogen Bond
Donor" and "Hydrogen Bond Acceptor--Hydrogen Bond
Acceptor--Hydrogen Bond Acceptor" are meant to indicate the
relative orientation of the hydrogen bond acceptors and donor and
not meant to limit that such groups are directly connected together
as it is contemplated that additional atoms or groups of atoms can
be included between such groups.
[0139] In the specification, the singular forms also include the
plural, unless the context clearly dictates otherwise. Unless
defined otherwise, all technical and scientific terms used herein
have the same meaning as commonly understood by one of ordinary
skill in the art to which this invention belongs. In the case of
conflict, the present specification will control. As used herein,
"mammal" refers to human and non-human patients.
[0140] As used herein, the term "therapeutically effective amount"
refers to an amount of a compound or a tautomer thereof or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, (also including combinations of compounds
and/or tautomers thereof, and/or pharmaceutically acceptable salts,
esters, or prodrugs or said compounds or tautomers), of the present
invention that is effective when administered alone or in
combination as an antimicrobial agent. For example, a
therapeutically effective amount refers to an amount of the
compound or tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer that is
present in a composition, a formulation, or on a medical device
given to a recipient patient or subject in an amount sufficient to
elicit biological activity, for example, anti-microbial activity,
antifungal activity, anti-viral activity, anti-parasitic activity,
anti-diarrheal activity, and/or anti-proliferative activity. In one
aspect, the combination of compounds and/or tautomers thereof,
and/or pharmaceutically acceptable salts, esters, or prodrugs or
said compounds or tautomers is a synergistic combination. Synergy,
as described, for example, by Chou and Talalay, Adv. Enzyme Regul.
vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds
or tautomers thereof or pharmaceutically acceptable salts, esters,
or prodrugs of said compounds or tautomers when administered in
combination is greater than the additive effect of the compounds or
tautomers thereof, or pharmaceutically acceptable salts, esters, or
prodrugs of said compounds or tautomers when administered alone as
a single agent. In general, a synergistic effect is most clearly
demonstrated at sub-optimal concentrations of the compounds or
tautomers thereof, or pharmaceutically acceptable salts, esters, or
prodrugs of said compounds or tautomers. Synergy can be in terms of
lower cytotoxicity, increased anti proliferative and/or
antiinfective effect, or some other beneficial effect of the
combination compared with the individual components.
[0141] As used herein, the term "RNA microhelix binding site"
refers to the ribofunctional locus of the large ribosomal subunit
occupied by the RNA microhelix of Formula III. The RNA microhelix
binding site defines at least a portion of or overlaps with the
E-site.
[0142] As used herein, the term "A-site" refers to the
ribofunctional locus occupied by an aminoacyl-tRNA molecule
immediately prior to its participation in the peptidebond forming
reaction.
[0143] As used herein, the term "E-site" refers to the
ribofunctional locus occupied by a deacylated tRNA molecule
following its participation in the peptidebond forming
reaction.
[0144] As used herein, the term "P-site" refers to the
ribofunctional locus occupied by a peptidyl-tRNA at the time it
participates in the peptidebond forming reaction.
[0145] As used herein, the term "A-space" refers to the portion of
the Asite within the peptidyl transferase center in which the amino
acid portion of the aminoacylated tRNA binds, or alternatively the
portion of the A-site in which the oxazolidinone ring of linezolid
binds.
[0146] As used herein and in reference to a ribosome or ribosomal
subunit, the terms "a portion of" or "a portion of the
three-dimensional structure of" are understood to mean a portion of
the three-dimensional structure of a ribosome or ribosomal subunit,
including charge distribution and hydrophilicity/hydrophobicity
characteristics, formed by at least three, more preferably at least
three to ten, and most preferably at least ten amino acid residues
and/or nucleotide residues of the ribosome or ribosomal subunit.
The residues forming such a portion can be, for example, (i)
contiguous residues based upon, for example, a primary sequence of
a ribosomal RNA or ribosomal protein, (ii) residues which form a
contiguous portion of the threedimensional structure of the
ribosome or ribosomal subunit, or (c) a combination thereof. As
used herein and in reference to the RNA microhelix, the terms "a
portion of" or "a portion of the threedimensional structure of" are
understood to mean a portion of the threedimensional structure of
RNA microhelix, including charge distribution and
hydrophilicity/hydrophobicity characteristics, formed by at least
three, more preferably at least three to ten atoms of one or more
core residues of Formula III. The atoms forming such a portion can
be, for example, (i) solvent inaccessible atoms buried within the
core of the RNA microhelix, (ii) solvent accessible atoms of the
RNA microhelix, or (iii) a combination thereof.
[0147] As used herein, the term ESBL is extended spectrum
beta-lactamase. The term KPC is Klebsiella pneumonia
carbapenemase.
[0148] As used herein, the term acute bacterial skin and skin
structure infection (ABSSSI) encompasses complicated skin and skin
structure infections (cSSSI) and complication skin and soft tissue
infections (cSSTI), which have been used interchangeably. The terms
uncomplicated skin and skin structure infections (uCSSSI) and
uncomplicated skin and soft tissue infections (uCSSTI) have been
used interchangeably.
[0149] As used herein, the term "spp." is the abbreviation for
species.
[0150] As used herein, the term "formulae of the invention"
includes one or more of the formulae: [0151] IA, I, II, III, IV, V,
VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, Va,
VIa, VIIa, VIIIa, IXa, Xa, XIa, XIIa, XIIIa, XIVa, XVa, XVIa,
XVIIa, XVIIIa, XXa, XXa1, XXb, XXb1, [0152] A1, A2, A3, A4, A5, A6,
A7, B1, B2, B3, B4, B5, B6, B7, C1, C2, C3, C4, C5, C6, C7, D1, D2,
D3, D4, D5, D6, D7, E1, E2, E3, E4, E5, E6, E7, [0153] A1a, A2a,
A3a, A4a, ASa, Aha, Ala, A8a, A9a, B1a, B2a, B3a, B4a, BSa, B6a,
B7a, B8a, B9a, C1a, C2a, C3a, C4a, CSa, Cha, C7a, C8a, C9a, [0154]
D1a, D2a, D3a, D4a, D5a, D6a, D7a, D8a, D9a, E1a, E2a, E3a, E4a,
E5a, E6a, E1a, E8a, F1, F2, G1, G2, G3, G4, [0155] H1, H2, H3, H4,
H5, H6, H7, H8, H9, H10, H11, H12, [0156] I1, I2, I3, I4, I5, I6,
I7, I8, I9, I10, I11, and I12.
[0157] As used herein, the term "compound of the invention"
includes one or more compounds of the formulae of the invention or
a compound explicitly disclosed herein.
[0158] All percentages and ratios used herein, unless otherwise
indicated, are by weight.
[0159] Throughout the description, where compositions are described
as having, including, or comprising specific components, or where
processes are described as having, including, or comprising
specific process steps, it is contemplated that compositions of the
present invention also consist essentially of, or consist of, the
recited components, and that the processes of the present invention
also consist essentially of, or consist of, the recited processing
steps. Further, it should be understood that the order of steps or
order for performing certain actions are immaterial so long as the
invention remains operable. Moreover, two or more steps or actions
can be conducted simultaneously.
2. Compounds of the Invention
[0160] In some embodiments, the present invention relates to a
compound having the formula:
##STR00008##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein
[0161] X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or N; X.sub.3
is CR.sup.3 or N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or
N; with the proviso that X.sub.1, X.sub.2, X.sub.3, X.sub.4, and
X.sub.5 are not all N;
[0162] Y.sub.6 is CR.sup.6 or N; Y.sub.7 is CR.sup.7 or N; Y.sub.8
is CR.sup.8 or N; Y.sub.9 is CR.sup.9 or N; Y.sub.10 is CR.sup.10
or N; with the proviso that Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, and
Y.sub.10 are not all N; wherein [0163] R.sup.1, R.sup.2, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.10 are each
independently selected from (a) hydrogen, (b) F, (c) Cl, (d) Br,
(e) I, (f) --CF.sub.3, (g) --CF.sub.2H, (h) --CFH.sub.2, (i)
--OCF.sub.3, (j) --OCF.sub.2H, (k) --OCFH.sub.2, (l) --OCH.sub.3,
(m) --CN, (n) --N.sub.3, (o) --NO.sub.2, (p) --NR.sup.11R.sup.11,
(q) --NR.sup.11C(O)R.sup.11, (r) --C(O)NR.sup.11R.sup.11, (s)
--OR.sup.11, (t) --COH, (u) --CO(C.sub.1-C.sub.8 alkyl), (v)
--COR.sup.11, (w) --NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x)
--S(O).sub.pR.sup.11, (y) --NR.sup.11S(O).sub.pR.sup.11, (z)
--SR.sup.11, (aa) --SCF.sub.3, (bb)
-C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc) --COOR.sup.11, (dd)
--(OCH.sub.2CH.sub.2).sub.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one of more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur);
[0164] wherein each (ff) through (nn) is optionally substituted
with one or more R.sup.12; alternatively, wherein two substituents
selected from R.sup.6, R.sup.7, and R.sup.8 are taken together with
the carbon atom to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; wherein each (a) through (b) is optionally substituted
with one or more R.sup.12;
[0165] each R.sup.11 is independently selected from (a) hydrogen,
(b) halogen, (c) --OH, (d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH,
(f) --OCF.sub.3, (g) --OCF.sub.2H, (h) --OCFH.sub.2, (i)
--OCH.sub.3, (j) --OR.sup.12, (k) --COR.sup.12, (l) --CN, (m)
--NO.sub.2, (n) --CONH.sub.2, (o) --CONR.sup.12R.sup.12, (p)
--COCH.sub.3, (q) --S(O).sub.pCH.sub.3, (r)
--S(O).sub.pNR.sup.12R.sup.12, (s) --SR.sup.12, (t) --C(O)OH, (u)
--C(O)OR.sup.12, (v) --N.sub.3, (w) --NH.sub.2, (x)
--NR.sup.12C(O)R.sup.12, (y) --NH(C.sub.1-C.sub.8 alkyl), (z)
--N(C.sub.1-C.sub.8 alkyl).sub.2, (aa) --C.sub.IC.sub.s alkyl, (bb)
--C.sub.2-C.sub.8 alkenyl, (cc) --C.sub.2-C.sub.8 alkynyl, (dd)
haloalkyl, (ee) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (ff) --(C.sub.1-C.sub.8 alkyl)(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (gg) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (hh) -3-14 membered saturated,
unsaturated, or aromatic carbocycle, and (ii)
--(C.dbd.NH)NR.sup.12R.sup.12;
[0166] wherein each (y) through (hh) is optionally substituted with
one or more R.sup.12;
[0167] alternatively two R.sup.11 substituents are taken together
to form (a) -3-7 membered saturated or unsaturated carbocyclic or
(b) -3-7 membered saturated or unsaturated heterocyclic ring
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, wherein each (a)
through (b) is optionally substituted with one or more
R.sup.12;
[0168] R.sup.3 is selected from:
##STR00009##
[0169] wherein R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e,
R.sup.3f, R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and
R.sup.3l are each independently selected from (a) hydrogen, (b)
halogen, (c) --CN, (d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3,
(g) --OCF.sub.2H, (h) --OCFH.sub.2, (i) --OCH.sub.3, (j)
--OR.sup.11, (k) --C(O)R.sup.11, (l) --C(O)NR.sup.11R.sup.11, (m)
--NH.sub.2, (n)---NR.sup.11R.sup.11, (o) --NR.sup.11C(O)R.sup.11,
(p) --S(O).sub.pR.sup.11, (q) --C(O)OH, (r) --C(O)OR.sup.11, (s)
--C.sub.1-C.sub.8 alkyl, (t) --C.sub.2-C.sub.8 alkenyl, (u)
--C.sub.2-C.sub.8 alkynyl, (v) haloalkyl, (w) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated,
or aromatic carbocycle;
[0170] wherein each (s) through (x) is optionally substituted with
one or more R.sup.12;
[0171] alternatively, one or more pairs of substituents selected
from R.sup.3a and R.sup.3b, R.sup.3c and R.sup.3d, R.sup.3e and
R.sup.3f, R.sup.3g and R.sup.3h, R.sup.3i and R.sup.3j, and
R.sup.3k and R.sup.3l are taken together with the carbon atom to
which they are attached to form (a) -3-7 membered saturated or
unsaturated carbocyclic, (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur, (c) an exo
carbon-carbon double bond, (d) carbonyl group, or (e) thiocarbonyl
group;
[0172] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0173] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3k, and R.sup.3l on different
carbon atoms are taken together with the intervening atoms to which
they are attached to form (a) -3-7 membered saturated or
unsaturated carbocyclic or (b) -3-7 membered saturated or
unsaturated heterocyclic ring containing one or more heteroatoms
selected from the group consisting of nitrogen, oxygen, and
sulfur;
[0174] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0175] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a substituted or unsubstituted
carbon-carbon double bond, or wherein four substituents selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l on
two adjacent carbon atoms are taken together with the bond between
said adjacent carbon atoms form a carbon-carbon triple bond;
[0176] U is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O)--,
--NR.sup.11S(O).sub.pNR.sup.11--, and
--NR.sup.11C(O)NR.sup.11--;
[0177] T is selected from --NR.sup.11R.sup.11,
--NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
[0178] alternatively, one R.sup.11 and one substituent selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, R.sup.3j, R.sup.3k, and R.sup.3l are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0179] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0180] R.sup.9 is selected from:
##STR00010##
[0181] wherein R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are each
independently selected from (a) hydrogen, (b) halogen, (c) --CN,
(d) --N.sub.3, (e) --NO.sub.2, (f) --OCF.sub.3, (g) --OCH.sub.3,
(h) --OCF.sub.2H, (i) --OCFH.sub.2, (j) --OR.sup.11, (k)
--NH.sub.2, (l) --NR.sup.11R.sup.11, (m) --C(O)R.sup.11, (n)
--C(O)OR.sup.11, (o) --C(O)NR.sup.11R.sup.11, (p)
--NR.sup.11C(O)R.sup.11, (q) --S(O).sub.pR.sup.11, (r)
--C.sub.1-C.sub.8 alkyl, (s) --C.sub.2-C.sub.8 alkenyl, (t)
--C.sub.1-C.sub.8 alkynyl, (u) haloalkyl, (v) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (w) -3-14 membered saturated, unsaturated,
or aromatic carbocycle;
[0182] wherein each (r) through (w) is optionally substituted with
one or more R.sup.12;
[0183] alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7
membered saturated or unsaturated heterocyclic ring containing one
or more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d)
carbonyl group, or (e) thiocarbonyl group;
[0184] wherein each (a) through (c) is optionally substituted with
one or more R.sup.12;
[0185] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t on different carbon atoms are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0186] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0187] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon atoms are
taken together with the bond between said adjacent carbon atoms
form a substituted or unsubstituted carbon-carbon double bond, or
four substituents selected from R.sup.9k, R.sup.9l, R.sup.9m,
R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and
R.sup.9t on two adjacent carbon atoms are taken together with the
bond between said adjacent carbon atoms form a carbon-carbon triple
bond;
[0188] Z is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11NR.sup.11S(O)--,
--NR.sup.11S(O).sub.pNR.sup.11--, and
--NR.sup.11C(O)NR.sup.11--;
[0189] W is selected from --NR.sup.11R.sup.11,
--NR.sup.11(CO)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
[0190] alternatively, one R.sup.11 and one substituent selected
from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur;
[0191] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0192] R.sup.12 is independently selected from (a) hydrogen, (b)
halogen, (c) --OH, (d) --SH, (e) --(C.sub.1-C.sub.8 alkyl)OH, (f)
--OCF.sub.3, (g) --OCH.sub.3, (h) --OCF.sub.2H, (i) --OCFH.sub.2,
(j) --O(C.sub.1-C.sub.8 alkyl), (k) --CN, (l) --NO.sub.2, (m)
--CONH.sub.2, (n) C(O)NH(C.sub.1-C.sub.8 alkyl), (o)
C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, (p) --COH, (q) --COCH.sub.3,
(r) --S(O).sub.pCH.sub.3, (s) --S(O).sub.pN(C.sub.1-C.sub.8
alkyl).sub.2, (t) --S(C.sub.1-C.sub.8 alkyl), (u) --C(O)OH, (v)
--C(O)O(C.sub.1-C.sub.8 alkyl), (w) --N.sub.3, (x)
--NHC(O)(C.sub.1-C.sub.8 alkyl), (y) --N(C.sub.1-C.sub.8
alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (z) --NH.sub.2, (aa)
--NH(C.sub.1-C.sub.8 alkyl), (bb) --N(C.sub.1-C.sub.8 alkyl).sub.2,
(cc) --C.sub.1-C.sub.8 alkyl, (dd) --C.sub.2-C.sub.8 alkenyl, (ee)
--C.sub.2-C.sub.8 alkynyl, (ff) haloalkyl, (gg) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (hh)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (ii) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (jj)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, (kk)
--(C.dbd.NH)NH.sub.2, (ll) --C(.dbd.NH)NH.sub.2, (mm)
--C(O)R.sup.13, (nn) .dbd.O, and (oo) .dbd.NR.sup.13;
[0193] wherein each (aa) through (jj) is optionally substituted
with one or more R.sup.13;
[0194] R.sup.13 is independently selected from (a) hydrogen, (b)
halogen, (c) --C.sub.1-C.sub.8 alkyl, (d) --C.sub.2-C.sub.8
alkenyl, (e) --C.sub.2-C.sub.8 alkynyl, (f) haloalkyl, (g) --OH,
(h) --OC.sub.1-C.sub.8 alkyl, (i) --OC.sub.2-C.sub.8 alkenyl, (j)
--OC.sub.2-C.sub.8 alkynyl, (k) --OCF.sub.3, (l) --OCH.sub.3, (m)
--OCF.sub.2H, (n) --OCFH.sub.2, (o) --NH.sub.2, (p) --CN, (q)
--N.sub.3, (r) --S(O).sub.pC.sub.1-C.sub.8 alkyl, (s) -3-14
membered saturated, unsaturated, or aromatic heterocycle containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, and (t) -3-14 membered saturated,
unsaturated, or aromatic carbocycle;
[0195] p is 0,1, or 2; and
[0196] t is 0,1, or 2.
[0197] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, having the
formula:
##STR00011##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein
[0198] X.sub.1 is CR.sup.1 or N; X.sub.2 is CR.sup.2 or N; X.sub.3
is CR.sup.3 or N; X.sub.4 is CR.sup.4 or N; X.sub.5 is CR.sup.5 or
N; with the proviso that X.sub.1, X.sub.2, X.sub.3, X.sub.4, and
X.sub.5 are not all N;
[0199] Y.sub.6 is CR.sup.6 or N; Y.sub.7 is CR.sup.7 or N; Y.sub.8
is CR.sup.8 or N; Y.sub.9 is CR.sup.9 or N; Y.sub.10 is CR.sup.10
or N; with the proviso that Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.9, and
Y.sub.10 are not all N; wherein
[0200] R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.10 are each independently selected from (a)
hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g) --CFH,
(h) --CFH.sub.2, (i) --OCF.sub.3, (j) --OCF.sub.2H, (k)
--OCFH.sub.2, (l) --OCH.sub.3, (m) --CN, (n) --N.sub.3, (o)
--NO.sub.2, (p) --NR.sup.11R.sup.11, (q) --NR.sup.11(CO)R.sup.11,
(r) --(CO)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --(OS (y)
--NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa) --SCF.sub.3,
(bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc) --COOR.sup.11,
(dd) --(OCH.sub.2CH.sub.2).sub.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, (hh) --C.sub.2-C.sub.8 alkynyl,
(ii) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated,
unsaturated, or aromatic heterocycle containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur), (jj) --(C.sub.1-C.sub.8 alkyl)-(3-14 membered
saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl,
(ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered
saturated, unsaturated, or aromatic carbocycle, and (nn)
--CHR.sup.11--NH--(3-14 membered saturated, unsaturated, or
aromatic heterocycle containing one of more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur);
[0201] wherein each (ff) through (nn) is optionally substituted
with one or more R.sup.12;
[0202] each R.sup.11 is independently selected from (a) hydrogen,
(b) halogen, (c) --CF.sub.3, (d) --CF.sub.2H, (e) --CFH.sub.2, (f)
--OH, (g) --SH, (h) --(C.sub.1-C.sub.8 alkyl)OH, (i) --OCF.sub.3,
(j) --OCF.sub.2H, (k) --OCFH.sub.2, (l) --OCH.sub.3, (m)
--OR.sup.12, (n) --COR.sup.12, (o) --CN, (p) --NO.sub.2, (q)
--CONH.sub.2, (r) --CONR.sup.12R.sup.12, (s) --C(O)CH.sub.3, (t)
--S(O).sub.pCH.sub.3, (u) --S(O).sub.pNR.sup.12R.sup.12, (v)
--SR.sup.12, (w) --C(O)OH, (x) --C(O)OR.sup.12, (y) --N.sub.3, (z)
--NH.sub.2, (aa) --NR.sup.12C(O)R.sup.12, (bb) --NH(C.sub.1-C.sub.8
alkyl), (cc) --N(C.sub.1-C.sub.8 alkyl).sub.2, (dd)
--C.sub.1-C.sub.8 alkyl, (ee) --C.sub.2-C.sub.8 alkenyl, (ff)
--C.sub.2-C.sub.8 alkynyl, (gg) haloalkyl, (hh) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (ii)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (jj) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (kk)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, and
(ll) --(C.dbd.NH)NR.sup.12R.sup.12;
[0203] wherein each (bb) through (kk) is optionally substituted
with one or more R.sup.12;
[0204] alternatively two R.sup.11 subsituents are taken together to
form (a) 3-7 membered saturated or unsaturated carbocyclic or (b)
3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, wherein each (a) through (b) is
optionally substituted with one or more R.sup.12;
[0205] R.sup.3 is selected from:
##STR00012##
[0206] wherein R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e,
R.sup.3f, R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j are each
independently selected from (a) hydrogen, (b) halogen, (c)
--CH.sub.3, (d) --CF.sub.3, (e) --CF.sub.2H, (f) --CFH.sub.2, (g)
--OCF.sub.3, (h) --OCF.sub.2H, (i) --OCFH.sub.2, (j)--OCH.sub.3,
(k) --OR.sup.11, (l) --C.sub.1-C.sub.8 alkyl, (m) haloalkyl, (n)
--3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, and (o) -3-14 membered
saturated, unsaturated, or aromatic carbocycle;
[0207] wherein each (l) through (o) is optionally substituted with
one or more R.sup.12;
[0208] alternatively, one or more pairs of substituents selected
from R.sup.3a and R.sup.3b, R.sup.3c and R.sup.3d, R.sup.3e and
R.sup.3f, R.sup.3g and R.sup.3h, and R.sup.3i and R.sup.3j are
taken together with the carbon atom to which they are attached to
form (a) -3-7 membered saturated or unsaturated carbocyclic, (b)
-3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (c) an exo carbon-carbon double bond,
(d) carbonyl group, or (e) thiocarbonyl group;
[0209] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0210] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j on different carbon
atoms are taken together with the intervening atoms to which they
are attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0211] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0212] alternatively, wherein two substituents selected from
R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j on two adjacent carbon
atoms are taken together with the bond between said adjacent carbon
atoms form a substituted or unsubstituted carbon-carbon double
bond, or wherein four substituents selected from R.sup.3a,
R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f, R.sup.3g,
R.sup.3h, R.sup.3i and R.sup.3j on two adjacent carbon atoms are
taken together with the bond between said adjacent carbon atoms
form a carbon-carbon triple bond;
[0213] U is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p-- and
--NR.sup.11S(O).sub.pNR.sup.11--;
[0214] T is selected from --NR.sup.11R.sup.11,
--NR.sup.11(C.dbd.O)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and OR.sup.11;
[0215] alternatively, one R.sup.11 and one substituent selected
from R.sup.3a, R.sup.3b, R.sup.3c, R.sup.3d, R.sup.3e, R.sup.3f,
R.sup.3g, R.sup.3h, R.sup.3i, and R.sup.3j are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur;
[0216] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0217] R.sup.9 is selected from:
##STR00013##
[0218] wherein R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are each
independently selected from (a) hydrogen, (b) halogen, (c)
--CH.sub.3, (d) --CF.sub.3, (e) --CF.sub.2H, (f) --CFH.sub.2, (g)
--OCF.sub.3, (h) --OCH.sub.3, (i) --OCF.sub.2H, (j) --OCFH.sub.2,
(k) --OR.sup.11, (l) --C.sub.1-C.sub.8 alkyl, (m) haloalkyl, (n)
-3-14 membered saturated, unsaturated, or aromatic heterocycle
containing one or more heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, and (o) -3-14 membered
saturated, unsaturated, or aromatic carbocycle;
[0219] wherein each (l) through (o) is optionally substituted with
one or more R.sup.12;
[0220] alternatively, one or more pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) -3-7 membered saturated or unsaturated carbocyclic, (b)
-3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur, (c) an exo carbon-carbon double bond,
(d) carbonyl group, and (e) thiocarbonyl group;
[0221] wherein each (a) through (c) is optionally substituted with
one or more R.sup.12;
[0222] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t on different carbon atoms are
taken together with the intervening atoms to which they are
attached to form (a) -3-7 membered saturated or unsaturated
carbocyclic or (b) -3-7 membered saturated or unsaturated
heterocyclic ring containing one or more heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur;
[0223] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0224] alternatively, two substituents selected from R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9n,
R.sup.9r, R.sup.9s, and R.sup.9t on two adjacent carbon atoms are
taken together with the bond between said adjacent carbon atoms
form a substituted or unsubstituted carbon-carbon double bond, or
four substituents selected from R.sup.9k, R.sup.9l, R.sup.9m,
R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and
R.sup.9t on two adjacent carbon atoms are taken together with the
bond between said adjacent carbon atoms form a carbon-carbon triple
bond;
[0225] Z is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p-- and
--NR.sup.11S(O).sub.pNR.sup.11--;
[0226] W is selected from --NR.sup.11R.sup.11,
--NR.sup.11(CO)OR.sup.11,
--NR.sup.11(C.dbd.NR.sup.11)NR.sup.11R.sup.11, and --OR.sup.11;
[0227] alternatively, one R.sup.11 and one substituent selected
from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are taken together with
the intervening atoms to which they are attached to form (a) -3-7
membered saturated or unsaturated carbocyclic or (b) -3-7 membered
saturated or unsaturated heterocyclic ring containing one or more
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur;
[0228] wherein each (a) through (b) is optionally substituted with
one or more R.sup.12;
[0229] R.sup.12 is independently selected from (a) hydrogen, (b)
halogen, (c) --CF.sub.3, (d) --CF.sub.2H, (e) --CFH.sub.2, (f)
--OH, (g) --SH, (h) --(C.sub.1-C.sub.8 alkyl)OH, (i) --OCF.sub.3,
(j) --OCH.sub.3, (k) --OCF.sub.2H, (l) --OCFH.sub.2, (m)
--O(C.sub.1-C.sub.8 alkyl), (n) --CN, (o) --NO.sub.2, (p)
--CONH.sub.2, (q) --C(O)H, (r) --C(O)CH.sub.3, (s)
--S(O).sub.pCH.sub.3, (t) --S(O).sub.pN(C.sub.1-C.sub.8
alkyl).sub.2, (u) --S(C.sub.1-C.sub.8 alkyl), (v) --C(O)OH, (w)
--C(O)O(C.sub.1-C.sub.8 alkyl), (x) --N.sub.3, (y)
--NHC(O)(C.sub.1-C.sub.8 alkyl), (z) --N(C.sub.1-C.sub.8
alkyl)C(O)(C.sub.1-C.sub.8 alkyl), (aa) --NH.sub.2, (bb)
--NH(C.sub.1-C.sub.8 alkyl), (cc) --N(C.sub.1-C.sub.8 alkyl).sub.2,
(dd) --C.sub.1-C.sub.8 alkyl, (ee) --C.sub.2-C.sub.8 alkenyl, (ff)
--C.sub.2-C.sub.8 alkynyl, (gg) -haloalkyl, (hh) --(C.sub.1-C.sub.8
alkyl)-(3-14 membered saturated, unsaturated, or aromatic
heterocycle containing one or more heteroatoms selected from the
group consisting of nitrogen, oxygen, and sulfur), (ii)
--(C.sub.1-C.sub.8 alkyl)-(3-14 membered saturated, unsaturated, or
aromatic carbocycle), (jj) -3-14 membered saturated, unsaturated,
or aromatic heterocycle containing one or more heteroatoms selected
from the group consisting of nitrogen, oxygen, and sulfur, (kk)
-3-14 membered saturated, unsaturated, or aromatic carbocycle, (ll)
--(C.dbd.NH)NH.sub.2, (mm) --C(O)NH(C.sub.1-C.sub.8 alkyl), (nn)
--C(O)N(C.sub.1-C.sub.8 alkyl).sub.2, and (oo)
--C(.dbd.NH)NH.sub.2;
[0230] p is 0, 1, or 2; and
[0231] t is 0, 1, or 2.
[0232] In some embodiments, the present invention relates to a
compound having the formula:
##STR00014##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein X.sub.1,
X.sub.2, X.sub.4, X.sub.5, Y.sub.6, Y.sub.7, Y.sub.8, Y.sub.10,
R.sup.3 and R.sup.9 are as defined herein.
[0233] In some embodiments, the present invention relates to a
compound having the formula:
##STR00015##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, and R.sup.10 are as defined herein.
[0234] In some embodiments, the present invention relates to a
compound having the formula:
##STR00016##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.8 ,
R.sup.9, and R.sup.10 are as defined herein.
[0235] In some embodiments, the present invention relates to a
compound having formula:
##STR00017##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, and R.sup.10 are as defined herein.
[0236] In some embodiments, the present invention relates to a
compound having formula:
##STR00018##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, and
R.sup.10 are as defined herein.
[0237] In some embodiments, the present invention relates to a
compound having formula:
##STR00019##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, and
R.sup.10 are as defined herein.
[0238] In some embodiments, the present invention relates to a
compound having formula:
##STR00020##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, and
R.sup.10 are as defined herein.
[0239] In some embodiments, the present invention relates to a
compound having formula:
##STR00021##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n ,R.sup.9o, R.sup.9p, and R.sup.10 are
as defined herein.
[0240] In some embodiments, the present invention relates to a
compound having formula:
##STR00022##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9p, and R.sup.10 are as defined
herein.
[0241] In some embodiments, the present invention relates to a
compound having formula:
##STR00023##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.8, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, and R.sup.10 are
as defined herein.
[0242] In some embodiments, the present invention relates to a
compound having formula:
##STR00024##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, and R.sup.10 are as defined
herein.
[0243] In some embodiments, the present invention relates to a
compound having formula:
##STR00025##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, and R.sup.9 are as defined
herein.
[0244] In some embodiments, the present invention relates to a
compound having formula:
##STR00026##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, and
R.sup.9p are as defined herein.
[0245] In some embodiments, the present invention relates to a
compound having formula:
##STR00027##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, and R.sup.9p are
as defined herein.
[0246] In some embodiments, the present invention relates to a
compound having formula:
##STR00028##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, and R.sup.9p are
as defined herein.
[0247] In some embodiments, the present invention relates to a
compound having formula:
##STR00029##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, and R.sup.9p are
as defined herein.
[0248] In some embodiments, the present invention relates to a
compound having formula:
##STR00030##
[0249] or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.1, R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, and R.sup.9p are
as defined herein.
[0250] In some embodiments, the present invention relates to a
compound having formula:
##STR00031##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, and R.sup.9p are as defined
herein.
[0251] In some embodiments, the present invention relates to a
compound having formula:
##STR00032##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.8, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, and R.sup.9p are as defined
herein.
[0252] In some embodiments, the present invention relates to a
compound having formula:
##STR00033##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, R.sup.9r, and R.sup.10 are as defined
herein.
[0253] In some embodiments, the present invention relates to a
compound having formula:
##STR00034##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, and R.sup.10 are as defined herein.
[0254] In some embodiments, the present invention relates to a
compound having formula:
##STR00035##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, and R.sup.10 are as defined herein.
[0255] In some embodiments, the present invention relates to a
compound having formula:
##STR00036##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, and R.sup.10 are as defined herein.
[0256] In some embodiments, the present invention relates to a
compound having formula:
##STR00037##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, and R.sup.10 are as defined herein.
[0257] In some embodiments, the present invention relates to a
compound having formula:
##STR00038##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, and R.sup.10 are as defined herein.
[0258] In some embodiments, the present invention relates to a
compound having formula:
##STR00039##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.8, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, and R.sup.10 are as defined herein.
[0259] In some embodiments, the present invention relates to a
compound having formula:
##STR00040##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r, and
R.sup.10 are as defined herein.
[0260] In some embodiments, the present invention relates to a
compound having formula:
##STR00041##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q and R.sup.9r are
as defined herein.
[0261] In some embodiments, the present invention relates to a
compound having formula:
##STR00042##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, and R.sup.9r are as defined herein.
[0262] In some embodiments, the present invention relates to a
compound having formula:
##STR00043##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, and R.sup.9r are as defined herein.
[0263] In some embodiments, the present invention relates to a
compound having formula:
##STR00044##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, and R.sup.9r are as defined herein.
[0264] In some embodiments, the present invention relates to a
compound having formula:
##STR00045##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.8,
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, and R.sup.9r are as defined herein.
[0265] In some embodiments, the present invention relates to a
compound having formula:
##STR00046##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.6, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are as defined herein.
[0266] In some embodiments, the present invention relates to a
compound having formula:
##STR00047##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.7, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are as defined herein.
[0267] In some embodiments, the present invention relates to a
compound having formula:
##STR00048##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer wherein R.sup.1,
R.sup.2, R.sup.3a, R.sup.3b, R.sup.4, R.sup.5, R.sup.8, R.sup.9k,
R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are as defined herein.
[0268] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, according to
any formulae of the invention, wherein at least one substituent
selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t is not
hydrogen.
[0269] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, according to
any formulae of the invention, wherein at least two substituents
selected from R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o,
R.sup.9p, R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are not
hydrogen.
[0270] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, according to
any formulae of the invention, wherein R.sup.1, R.sup.2, R.sup.4
and R.sup.5 are each independently selected from hydrogen and F. In
some embodiments, R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are each
hydrogen.
[0271] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, according to
any formulae of the invention, wherein R.sup.3a and R.sup.3b are
each independently selected from (a) hydrogen, (b) F, (c) Cl, (d)
--CH.sub.3, (e) --CF.sub.3, (f) --CF.sub.2H, (g) --CFH.sub.2, (h)
--OCF.sub.3, (i) --OCF.sub.2H, (j) --OCFH.sub.2, (k) --OCH.sub.3,
and (l) --OH. In some embodiments, R.sup.3a and R.sup.3b are each
hydrogen. In some embodiments, R.sup.3a and R.sup.3b are each
hydrogen. In some embodiments, the stereochemistry of R.sup.3a and
R.sup.3b is
##STR00049##
and R.sup.3a is methyl and R.sup.3b is hydrogen. In some
embodiments, the stereochemistry of R.sup.3a and R.sup.3b is
##STR00050##
and R.sup.3a is methyl and R.sup.3b is hydrogen. In some
embodiments, the stereochemistry of R.sup.3a and R.sup.3b is
##STR00051##
and R.sup.3a is hydrogen and R.sup.3b is methyl. In some
embodiments, the stereochemistry of R.sup.3a and R.sup.3b is
##STR00052##
and R.sup.3a is hydrogen and R.sup.3b is methyl.
[0272] In some embodiments, the present invention relates to a
compound having formula:
##STR00053##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9k, R.sup.9l, and R.sup.10 are as defined
herein.
[0273] In some embodiments, the present invention relates to a
compound having formula:
##STR00054##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9k, R.sup.9l, and R.sup.10 are as defined
herein.
[0274] In some embodiments, the present invention relates to a
compound having formula:
##STR00055##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9k, R.sup.9l, and R.sup.10 are as defined
herein.
[0275] In some embodiments, the present invention relates to a
compound having formula:
##STR00056##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9k, R.sup.9l, and R.sup.10 are as defined
herein.
[0276] In some embodiments, the present invention relates to a
compound having formula:
##STR00057##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9k, R.sup.9l, and R.sup.10 are as defined herein.
[0277] In some embodiments, the present invention relates to a
compound having formula:
##STR00058##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9k, R.sup.9l, and R.sup.10 are as defined herein.
[0278] In some embodiments, the present invention relates to a
compound having formula:
##STR00059##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9k, R.sup.9l, and R.sup.10 are as defined herein.
[0279] In some embodiments, the present invention relates to a
compound having formula:
##STR00060##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9m, R.sup.9n, and R.sup.10 are as defined
herein.
[0280] In some embodiments, the present invention relates to a
compound having formula:
##STR00061##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9m , R.sup.9n, and R.sup.10 are as defined
herein.
[0281] In some embodiments, the present invention relates to a
compound having formula:
##STR00062##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9m, R.sup.9n, and R.sup.10 are as defined
herein.
[0282] In some embodiments, the present invention relates to a
compound having formula:
##STR00063##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9m, R.sup.9n, and R.sup.10 are as defined
herein.
[0283] In some embodiments, the present invention relates to a
compound having formula:
##STR00064##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9m, R.sup.9n, and R.sup.10 are as defined herein.
[0284] In some embodiments, the present invention relates to a
compound having formula:
##STR00065##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9m, R.sup.9p, and R.sup.10 are as defined herein.
[0285] In some embodiments, the present invention relates to a
compound having formula:
##STR00066##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9m, R.sup.9p, and R.sup.10 are as defined herein.
[0286] In some embodiments, the present invention relates to a
compound having formula:
##STR00067##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9o, R.sup.9p, and R.sup.10 are as defined
herein.
[0287] In some embodiments, the present invention relates to a
compound having formula:
##STR00068##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9o, R.sup.9p, and R.sup.10 are as defined
herein.
[0288] In some embodiments, the present invention relates to a
compound having formula:
##STR00069##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9o, R.sup.9p, and R.sup.10 are as defined
herein.
[0289] In some embodiments, the present invention relates to a
compound having formula:
##STR00070##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9o, R.sup.9p, and R.sup.10 are as defined
herein.
[0290] In some embodiments, the present invention relates to a
compound having formula:
##STR00071##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9o, R.sup.9p, and R.sup.10 are as defined herein.
[0291] In some embodiments, the present invention relates to a
compound having formula:
##STR00072##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9o, R.sup.9p, and R.sup.10 are as defined herein.
[0292] In some embodiments, the present invention relates to a
compound having formula:
##STR00073##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9o, R.sup.9p, and R.sup.10 are as defined herein.
[0293] In some embodiments, the present invention relates to a
compound having formula:
##STR00074##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9q, R.sup.9r, and R.sup.10 are as defined
herein.
[0294] In some embodiments, the present invention relates to a
compound having formula:
##STR00075##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9q, R.sup.9r, and R.sup.10 are as defined
herein.
[0295] In some embodiments, the present invention relates to a
compound having formula:
##STR00076##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9q, R.sup.9r, and R.sup.10 are as defined
herein.
[0296] In some embodiments, the present invention relates to a
compound having formula:
##STR00077##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9q, R.sup.9r, and R.sup.10 are as defined
herein.
[0297] In some embodiments, the present invention relates to a
compound having formula:
##STR00078##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9q, R.sup.9r, and R.sup.10 are as defined herein.
[0298] In some embodiments, the present invention relates to a
compound having formula:
##STR00079##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9q, R.sup.9r, and R.sup.10 are as defined herein.
[0299] In some embodiments, the present invention relates to a
compound having formula:
##STR00080##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9q, R.sup.9r, and R.sup.10 are as defined herein.
[0300] In some embodiments, the present invention relates to a
compound having formula:
##STR00081##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, and R.sup.10 are as defined herein.
[0301] In some embodiments, the present invention relates to a
compound having formula:
##STR00082##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, and R.sup.10 are as defined herein.
[0302] In some embodiments, the present invention relates to a
compound having formula:
##STR00083##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, and R.sup.10 are as defined herein.
[0303] In some embodiments, the present invention relates to a
compound having formula:
##STR00084##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, and R.sup.10 are as defined herein.
[0304] In some embodiments, the present invention relates to a
compound having formula:
##STR00085##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6 and
R.sup.10 are as defined herein.
[0305] In some embodiments, the present invention relates to a
compound having formula:
##STR00086##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7 and
R.sup.10 are as defined herein.
[0306] In some embodiments, the present invention relates to a
compound having formula:
##STR00087##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8 and
R.sup.10 are as defined herein.
[0307] In some embodiments, the present invention relates to a
compound having formula:
##STR00088##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9k and R.sup.9l are as defined herein.
[0308] In some embodiments, the present invention relates to a
compound having formula:
##STR00089##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9k and R.sup.9l are as defined herein.
[0309] In some embodiments, the present invention relates to a
compound having formula:
##STR00090##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9k and R.sup.9l are as defined herein.
[0310] In some embodiments, the present invention relates to a
compound having formula:
##STR00091##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9k and R.sup.9l are as defined herein.
[0311] In some embodiments, the present invention relates to a
compound having formula:
##STR00092##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9k and R.sup.9l are as defined herein.
[0312] In some embodiments, the present invention relates to a
compound having formula:
##STR00093##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9k and R.sup.9l are as defined herein.
[0313] In some embodiments, the present invention relates to a
compound having formula:
##STR00094##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9k and R.sup.9l are as defined herein.
[0314] In some embodiments, the present invention relates to a
compound having formula:
##STR00095##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9k,
R.sup.9l and R.sup.10 are as defined herein.
[0315] In some embodiments, the present invention relates to a
compound having formula:
##STR00096##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9k
and R.sup.9l are as defined herein.
[0316] In some embodiments, the present invention relates to a
compound having formula:
##STR00097##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9m and R.sup.9n are as defined herein.
[0317] In some embodiments, the present invention relates to a
compound having formula:
##STR00098##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9m and R.sup.9n are as defined herein.
[0318] In some embodiments, the present invention relates to a
compound having formula:
##STR00099##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9m and R.sup.9n are as defined herein.
[0319] In some embodiments, the present invention relates to a
compound having formula:
##STR00100##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9m and R.sup.9n are as defined herein.
[0320] In some embodiments, the present invention relates to a
compound having formula:
##STR00101##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9m and R.sup.9n are as defined herein.
[0321] In some embodiments, the present invention relates to a
compound having formula:
##STR00102##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9m and R.sup.9n are as defined herein.
[0322] In some embodiments, the present invention relates to a
compound having formula:
##STR00103##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9m and R.sup.9n are as defined herein.
[0323] In some embodiments, the present invention relates to a
compound having formula:
##STR00104##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9m,
R.sup.9n and R.sup.10 are as defined herein.
[0324] In some embodiments, the present invention relates to a
compound having formula:
##STR00105##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9m
and R.sup.9n are as defined herein.
[0325] In some embodiments, the present invention relates to a
compound having formula:
##STR00106##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9o and R.sup.9p are as defined herein.
[0326] In some embodiments, the present invention relates to a
compound having formula:
##STR00107##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9o and R.sup.9p are as defined herein.
[0327] In some embodiments, the present invention relates to a
compound having formula:
##STR00108##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9o and R.sup.9p are as defined herein.
[0328] In some embodiments, the present invention relates to a
compound having formula:
##STR00109##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9o and R.sup.9p are as defined herein.
[0329] In some embodiments, the present invention relates to a
compound having formula:
##STR00110##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9o and R.sup.9p are as defined herein.
[0330] In some embodiments, the present invention relates to a
compound having formula:
##STR00111##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9o and R.sup.9p are as defined herein.
[0331] In some embodiments, the present invention relates to a
compound having formula:
##STR00112##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9o and R.sup.9p are as defined herein.
[0332] In some embodiments, the present invention relates to a
compound having formula:
##STR00113##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9o,
R.sup.9p and R.sup.10 are as defined herein.
[0333] In some embodiments, the present invention relates to a
compound having formula:
##STR00114##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9o
and R.sup.9p are as defined herein.
[0334] In some embodiments, the present invention relates to a
compound having formula:
##STR00115##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.8, R.sup.9q, and R.sup.9r are as defined herein.
[0335] In some embodiments, the present invention relates to a
compound having formula:
##STR00116##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, R.sup.9q, and R.sup.9r are as defined herein.
[0336] In some embodiments, the present invention relates to a
compound having formula:
##STR00117##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.8, R.sup.9q, and R.sup.9r are as defined herein.
[0337] In some embodiments, the present invention relates to a
compound having formula:
##STR00118##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.8, R.sup.9q, and R.sup.9r are as defined herein.
[0338] In some embodiments, the present invention relates to a
compound having formula:
##STR00119##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.9q, and R.sup.9r are as defined herein.
[0339] In some embodiments, the present invention relates to a
compound having formula:
##STR00120##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7,
R.sup.9q, and R.sup.9r are as defined herein.
[0340] In some embodiments, the present invention relates to a
compound having formula:
##STR00121##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8,
R.sup.9q, and R.sup.9r are as defined herein.
[0341] In some embodiments, the present invention relates to a
compound having formula:
##STR00122##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9q,
R.sup.9r, and R.sup.10 are as defined herein.
[0342] In some embodiments, the present invention relates to a
compound having formula:
##STR00123##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.9q
and R.sup.9r are as defined herein.
[0343] In some embodiments, the present invention relates to a
compound having formula:
##STR00124##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6,
R.sup.7, and R.sup.8 are as defined herein.
[0344] In some embodiments, the present invention relates to a
compound having formula:
##STR00125##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6 and
R.sup.7 are as defined herein.
[0345] In some embodiments, the present invention relates to a
compound having formula:
##STR00126##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6 and
R.sup.8 are as defined herein.
[0346] In some embodiments, the present invention relates to a
compound having formula:
##STR00127##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7 and
R.sup.8 are as defined herein.
[0347] In some embodiments, the present invention relates to a
compound having formula:
##STR00128##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.6 is
as defined herein.
[0348] In some embodiments, the present invention relates to a
compound having formula:
##STR00129##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.7 is
as defined herein.
[0349] In some embodiments, the present invention relates to a
compound having formula:
##STR00130##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.8 is
as defined herein.
[0350] In some embodiments, the present invention relates to a
compound having formula:
##STR00131##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.10 is
as defined herein.
[0351] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.10 is selected from hydrogen, F and Cl.
[0352] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.6, R.sup.7, and R.sup.8 are each independently selected from
(a) F, (b) Cl, (c) --CF.sub.3, (d) --CF.sub.2H, (e) --CFH.sub.2,
(f) --OCF.sub.3, (g) --OCF.sub.2H, (h) --OCFH.sub.2, (i)
--OCH.sub.3, (j) --CN, (k) --OR.sup.11, (l) --S(O).sub.pR.sup.11,
(m) --SCF.sub.3, (n) --C.sub.1-C.sub.8 alkyl, (o) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, (p) -3-14 membered saturated, unsaturated, or
aromatic carbocycle, (q) --CHCHCN and (r)
--CHCH--C(O)NH-t-butyl.
[0353] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.6, R.sup.7, and R.sup.8 are each independently selected from
(a) F, (b) Cl, (c) --CF.sub.3, (d) --CF.sub.2H, (e) --CFH.sub.2,
(f) --OCF.sub.3, (g) --OCF.sub.2H, (h) --OCFH.sub.2, (i)
--OCH.sub.3, (j) --CN, (k) --OR.sup.11, (l) --S(O).sub.pR.sup.11,
(m) --SCF.sub.3, (n) --C.sub.1-C.sub.8 alkyl, (o) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (p) -3-14 membered saturated, unsaturated,
or aromatic carbocycle.
[0354] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.6, R.sup.7, and R.sup.8 are each independently selected from
are each independently selected from (a) F; (b) Cl; (c) --CF.sub.3;
(d) --CF.sub.2H; (e) --CFH.sub.2; (f) --OCF.sub.3; (g)
--OCF.sub.2H; (h) --OCFH.sub.2; (i) --OCH.sub.3; (j)
--O(C.sub.1-C.sub.4 alkyl); (k) --S(O)CH.sub.3; (l) --S(O)CF.sub.3;
(m) --S(O).sub.2CH.sub.3; (n) --S(O).sub.2CF.sub.3; (o)
--SCF.sub.3;
[0355] (p) --C.sub.1-C.sub.4 alkyl selected from methyl, ethyl,
isopropyl, and t-butyl;
[0356] (q) -3-7 membered saturated, unsaturated, or aromatic
heterocycle selected from oxetanyl, azepanyl, pyridyl,
dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl,
azetidinyl, pyrrolidinyl, piperidinyl, and piperidenyl; and
[0357] (r) -3-7 membered saturated, unsaturated, or aromatic
carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, phenyl, cyclohexenyl, and
cyclohexadienyl.
[0358] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.6, R.sup.7, and R.sup.8 are each independently selected from
are each independently selected from (a) F, (b) Cl, (c) --CF.sub.3,
(d) --OCF.sub.3, (e) --OCH.sub.3, (f) methyl, (g) ethyl, (h)
isopropyl, (i) t-butyl, (j) azepanyl, (k) cyclopropyl, (l)
cyclobutyl, (m) cyclohexyl, (n) phenyl, (o) pyridyl, (p)
azetidinyl, (q) pyrrolidinyl, (r) piperidinyl, and (s)
piperidenyl.
[0359] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are each independently
selected from (a) hydrogen, (b) halogen, (c) --CF.sub.3, (d)
--CF.sub.2H, (e) --CFH.sub.2, (f) --OCF.sub.3, (g) --OCH.sub.3, (h)
--OCF.sub.2H, (i) --OCFH.sub.2, (j) --OR.sup.11, (k)
--C.sub.1-C.sub.8 alkyl, (l) haloalkyl, (m) -3-14 membered
saturated, unsaturated, or aromatic heterocycle containing one or
more heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur, and (n) -3-14 membered saturated, unsaturated,
or aromatic carbocycle;
[0360] alternatively, one or more of pairs of substituents selected
from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n, R.sup.9o and
R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and R.sup.9t are
taken together with the carbon atom to which they are attached to
form (a) 3-7 membered saturated or unsaturated carbocyclic or (b)
3-7 membered saturated or unsaturated heterocyclic ring containing
one or more heteroatoms selected from the group consisting of
nitrogen, oxygen, and sulfur; and
[0361] at least one substituent selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t is not hydrogen.
[0362] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9nR.sup.9o, R.sup.9p, R.sup.9q,
R.sup.9r, R.sup.9s, and R.sup.9t are each independently selected
from (a) hydrogen; (b) halogen; (c) --CF.sub.3; (d) --CF.sub.2H;
(e) --CFH.sub.2; (f) --OCF.sub.3; (g) --OCH.sub.3; (h)
--OCF.sub.2H; (i) --OCFH.sub.2; (j) --OH; (k) --O(C.sub.1-C.sub.4
alkyl);
[0363] (l) -C.sub.1-C.sub.4 alkyl selected from methyl, ethyl,
isopropyl, and t-butyl;
[0364] (m) -3-7 membered saturated, unsaturated, or aromatic
heterocycle selected from oxetanyl, azepanyl, pyridyl,
dihydropyridyl, furanyl, tetrahydrofuranyl, tetrahydropyridyl,
azetidinyl, pyrrolidinyl, piperidinyl, and piperidenyl; and
[0365] (n) -3-7 membered saturated, unsaturated, or aromatic
carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, phenyl, cyclohexenyl, and
cyclohexadienyl;
[0366] alternatively, one or more of pairs of substituents are
selected from R.sup.9k and R.sup.9l, R.sup.9m and R.sup.9n,
R.sup.9o and R.sup.9p, R.sup.9q and R.sup.9r, and R.sup.9s and
R.sup.9t are taken together with the carbon atom to which they are
attached form cyclopropyl, cyclobutyl, or oxetanyl; and
[0367] at least one substituent selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t is not hydrogen;
[0368] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.9k, R.sup.9l, R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p,
R.sup.9q, R.sup.9r, R.sup.9s, and R.sup.9t are each independently
selected from (a) hydrogen, (b) halogen, (d) --CF.sub.3, (e)
--CF.sub.2H, (f) --CFH.sub.2, (g) --OCF.sub.3, (h) --OCH.sub.3, (i)
--OCF.sub.2H, (j) --OCFH.sub.2, (k) --OH, (l) --OCH.sub.3, (l)
methyl, (m) ethyl, (n) isopropyl, and (o) t-butyl; and
[0369] at least one substituent selected from R.sup.9k, R.sup.9l,
R.sup.9m, R.sup.9n, R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9r,
R.sup.9s, and R.sup.9t is not hydrogen.
[0370] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
##STR00132##
is selected from:
##STR00133## ##STR00134## ##STR00135## ##STR00136## ##STR00137##
##STR00138## ##STR00139## ##STR00140## ##STR00141##
##STR00142##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer.
[0371] In some embodiments,
##STR00143##
is selected from
##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148##
##STR00149##
[0372] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.3 is selected from:
##STR00150## ##STR00151## ##STR00152## ##STR00153##
[0373] In some embodiments, the present invention relates to a
compound having the formula:
##STR00154##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.3b, R.sup.6, R.sup.7, R.sup.8, Z, R.sup.9o, R.sup.9p,
R.sup.9q, and R.sup.9r are as defined herein.
[0374] In some embodiments, the present invention relates to a
compound having the formula:
##STR00155##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.3b, R.sup.6, R.sup.7, R.sup.8, R.sup.9o, R.sup.9p, R.sup.9q,
and R.sup.9r are as defined herein.
[0375] In some embodiments, the present invention relates to a
compound of formula F1 or F2, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein
[0376] Z is selected from --O--, --S(O).sub.p--, --NR.sup.11--,
--(C.dbd.O)--, --NR.sup.11(C.dbd.O)--, --(C.dbd.O)NR.sup.11--,
--S(O).sub.pNR.sup.11--, --NR.sup.11S(O).sub.p--, and
--NR.sup.11S(O).sub.pNR.sup.11--;
[0377] R.sup.3a is selected from halogen and --C.sub.1-C.sub.6
alkyl;
[0378] R.sup.3b is selected from hydrogen, halogen, --OCF.sub.3,
--OCF.sub.2H, --OCFH.sub.2, --OCH.sub.3, --OR.sup.11--,
--C.sub.l-C.sub.6 alkyl, and haloalkyl; [0379] R.sup.6, R.sup.7,
and R.sup.8 are each independently selected from (a) hydrogen, (b)
F, (c) Cl, (d) Br, (e) I, (f) --CF.sub.3, (g) --CF.sub.2H, (h)
--CFH.sub.2, (i) --OCF.sub.3, (j) --OCF.sub.2H, (k) --OCFH.sub.2,
(l) --OCH.sub.3, (m) --CN, (n) --N.sub.3, (o) --NO.sub.2, (p)
--NR.sup.11R.sup.11, (q) --NR.sup.11(CO)R.sup.11, (r)
--(CO)NR.sup.11R.sup.11, (s) --OR.sup.11, (t) --COH, (u)
--CO(C.sub.1-C.sub.8 alkyl), (v) --COR.sup.11, (w)
--NR.sup.11(CNR.sup.11)NR.sup.11R.sup.11, (x) --S(O).sub.pR.sup.11,
(y) --NR.sup.11S(O).sub.pR.sup.11, (z) --SR.sup.11, (aa)
--SCF.sub.3, (bb) --C(CF.sub.3)H--NH--CHR.sup.11R.sup.11, (cc)
--COOR.sup.11, (dd) --(OCH.sub.2CH.sub.2).sub.tR.sup.11, (ee)
--(OCH.sub.2CH.sub.2).sub.tOR.sup.11, (ff) --C.sub.1-C.sub.8 alkyl,
(gg) --C.sub.2-C.sub.8 alkenyl, and (hh) --C.sub.2-C.sub.8
alkynyl;
[0380] R.sup.9o, R.sup.9p, R.sup.9q, and R.sup.9r are each
independently selected from (a) hydrogen, (b) halogen, (c)
--OCF.sub.3, (d) --OCH.sub.3, (e) --OCF.sub.2H, (f) --OCFH.sub.2,
(g) --OR.sup.11, (h) --C.sub.1-C.sub.8 alkyl, and (i)
haloalkyl;
[0381] R.sup.11 is selected from hydrogen, --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.2-C.sub.6 alkynyl, and
haloalkyl;
[0382] p is 0, 1, or 2; and
[0383] t is 0, 1, or 2.
[0384] In some embodiments, the present invention relates to a
compound of formula F1, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein Z is O; [0385] R.sup.9o, R.sup.9p,
R.sup.9q, and R.sup.9r are each independently selected from
C.sub.1-C.sub.6 alkyl and hydrogen; [0386] R.sup.6 and R.sup.8 are
each independently selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and --CF.sub.3;
[0387] R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; and [0388]
R.sup.3a is selected from halogen and --C.sub.1-C.sub.6 alkyl;
[0389] R.sup.3b is selected from hydrogen, halogen, --CF.sub.3,
--CF.sub.2H, --CFH.sub.2, --C.sub.1-C.sub.6 alkyl, and haloalkyl;
and [0390] p is 0, 1, or 2.
[0391] In some embodiments, the present invention relates to a
compound of formula F2, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are each independently selected from --C.sub.1-C.sub.6
alkyl and hydrogen; [0392] R.sup.6 and R.sup.8 are each
independently selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and --CF.sub.3;
[0393] R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; and [0394]
R.sup.3a is selected from halogen and --C.sub.1-C.sub.6 alkyl;
[0395] R.sup.3b is selected from hydrogen, halogen, --CF.sub.3,
--CF.sub.2H, --CFH.sub.2, --C.sub.1-C.sub.6 alkyl, and haloalkyl;
and [0396] p is 0, 1, or 2.
[0397] In some embodiments, the present invention relates to a
compound having the formula:
##STR00156##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are as defined herein.
[0398] In some embodiments, the present invention relates to a
compound having the formula:
##STR00157##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are as defined herein.
[0399] In some embodiments, the present invention relates to a
compound having the formula:
##STR00158##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are as defined herein.
[0400] In some embodiments, the present invention relates to a
compound having the formula:
##STR00159##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are as defined herein.
[0401] In some embodiments, the present invention relates to a
compound of formulae G1, G2, G3, or G4, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are each independently selected from C.sub.1-C.sub.6 alkyl
and hydrogen; [0402] R.sup.6 and R.sup.8 are each independently
selected from hydrogen, F, Cl, Br, I, --C.sub.1-C.sub.6 alkyl,
--CH.sub.2F, --CHF.sub.2, and --CF.sub.3; [0403] R.sup.7 is
selected from hydrogen, F, Cl, Br, I, --C.sub.1-C.sub.6 alkyl,
--CH.sub.2F, --CHF.sub.2, --CF.sub.3, --OC.sub.1-C.sub.6 alkyl,
--S(O).sub.p--C.sub.1-C.sub.6 alkyl, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, --S(O).sub.p--CH.sub.3, --S(O).sub.p--CH.sub.2F, and
--S(O).sub.p--CF.sub.3; and [0404] R.sup.3a is selected from
halogen and -C.sub.1-C.sub.6 alkyl; and [0405] p is 0, 1, or 2.
[0406] In some embodiments, the present invention relates to a
compound of formulae G1, G2, G3, or G4, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein R.sup.9o, R.sup.9p, R.sup.9q, and
R.sup.9r are each independently selected from --C.sub.1-C.sub.6
alkyl and hydrogen; [0407] R.sup.6 is selected from hydrogen, F,
Cl, Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and
--CF.sub.3; [0408] R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; [0409] R.sup.8
is hydrogen; [0410] R.sup.3a is selected from halogen and
--C.sub.1-C.sub.6 alkyl; and [0411] p is 0, 1, or 2.
[0412] In some embodiments, the present invention relates to a
compound having the formula:
##STR00160##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9q, and R.sup.9r are as defined
herein.
[0413] In some embodiments, the present invention relates to a
compound having the formula:
##STR00161##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9q, and R.sup.9r are as defined
herein.
[0414] In some embodiments, the present invention relates to a
compound having the formula:
##STR00162##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9q, and R.sup.9r are as defined
herein.
[0415] In some embodiments, the present invention relates to a
compound having the formula:
##STR00163##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9(.sup.1, and R.sup.9r are as
defined herein.
[0416] In some embodiments, the present invention relates to a
compound having the formula:
##STR00164##
[0417] or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein
R.sup.3a, R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as defined
herein.
[0418] In some embodiments, the present invention relates to a
compound having the formula:
##STR00165##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as defined herein.
[0419] In some embodiments, the present invention relates to a
compound having the formula:
##STR00166##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as defined herein.
[0420] In some embodiments, the present invention relates to a
compound having the formula:
##STR00167##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as defined herein.
[0421] In some embodiments, the present invention relates to a
compound having the formula:
##STR00168##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as defined herein.
[0422] In some embodiments, the present invention relates to a
compound having the formula:
##STR00169##
wherein R.sup.3a, R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as
defined herein, or a tautomer thereof, or a pharmaceutically
acceptable salt, ester, or prodrug of said compound or
tautomer.
[0423] In some embodiments, the present invention relates to a
compound having the formula:
##STR00170##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as defined herein.
[0424] In some embodiments, the present invention relates to a
compound having the formula:
##STR00171##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9r are as defined herein.
[0425] In some embodiments, the present invention relates to a
compound of formulae H1, H2, H3, or H4, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein R.sup.9q and R.sup.9r are each
independently selected from --C.sub.l-C.sub.6 alkyl and hydrogen;
[0426] R.sup.6 and R.sup.8 are each independently selected from
hydrogen, F, Cl, Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F,
--CHF.sub.2, and --CF.sub.3; [0427] R.sup.7 is selected from
hydrogen, F, Cl, Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OC.sub.1-C.sub.6 alkyl,
--S(O).sub.p--C.sub.1-C.sub.6 alkyl, --OCH.sub.2F, --OCHF.sub.2,
--OCF.sub.3, --S(O).sub.p--CH.sub.3, --S(O).sub.p--CH.sub.2F, and
--S(O).sub.p--CF.sub.3; and [0428] R.sup.3a is selected from
halogen and --C.sub.1-C.sub.6 alkyl; and [0429] p is 0, 1, or
2.
[0430] In some embodiments, the present invention relates to a
compound of formulae H1, H2, H3, or H4, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein R.sup.9q and R.sup.9r are each
independently selected from --C.sub.1-C.sub.6 alkyl and hydrogen;
[0431] R.sup.6 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and --CF.sub.3;
[0432] R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; [0433] R.sup.8
is hydrogen; [0434] R.sup.3a is selected from halogen and
--C.sub.1-C.sub.6 alkyl; and [0435] p is 0, 1, or 2.
[0436] In some embodiments, the present invention relates to a
compound of formulae H5, H6, H7, H8, H9, H10, H11, or H12, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, wherein R.sup.9r is
--C.sub.1-C.sub.6 alkyl; R.sup.6 is selected from hydrogen, F, Cl,
Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and
--CF.sub.3; R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; [0437] R.sup.8
is hydrogen; [0438] R.sup.3a is selected from halogen and
--C.sub.1-C.sub.6 alkyl; and [0439] p is 0, 1, or 2.
[0440] In some embodiments, the present invention relates to a
compound of formulae H5, H6, H7, H8, H9, H10, H11, or H12, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, wherein R.sup.9r is
--CH.sub.3; [0441] R.sup.6 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and --CF.sub.3;
[0442] R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, ---S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; [0443] R.sup.8
is hydrogen; [0444] R.sup.3a is --CH.sub.3; and [0445] p is 0, 1,
or 2.
[0446] In some embodiments, the present invention relates to a
compound having the formula:
##STR00172##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, and R.sup.9p are as defined
herein.
[0447] In some embodiments, the present invention relates to a
compound having the formula:
##STR00173##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, and R.sup.9p are as defined
herein.
[0448] In some embodiments, the present invention relates to a
compound having the formula:
##STR00174##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, and R.sup.9p are as defined
herein.
[0449] In some embodiments, the present invention relates to a
compound having the formula:
##STR00175##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, R.sup.9o, and R.sup.9p are as defined
herein.
[0450] In some embodiments, the present invention relates to a
compound having the formula:
##STR00176##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0451] In some embodiments, the present invention relates to a
compound having the formula:
##STR00177##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0452] In some embodiments, the present invention relates to a
compound having the formula:
##STR00178##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0453] In some embodiments, the present invention relates to a
compound having the formula:
##STR00179##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0454] In some embodiments, the present invention relates to a
compound having the formula:
##STR00180##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0455] In some embodiments, the present invention relates to a
compound having the formula:
##STR00181##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0456] In some embodiments, the present invention relates to a
compound having the formula:
##STR00182##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0457] In some embodiments, the present invention relates to a
compound having the formula:
##STR00183##
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, wherein R.sup.3a,
R.sup.6, R.sup.7, R.sup.8, and R.sup.9o are as defined herein.
[0458] In some embodiments, the present invention relates to a
compound of formulae I1, I2, I3, or I4, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein R.sup.9o and R.sup.9p are each
independently selected from --C.sub.1-C.sub.6 alkyl and hydrogen;
[0459] R.sup.6 and R.sup.8 are each independently selected from
hydrogen, F, Cl, Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F,
--CHF.sub.2, and --CF.sub.3; [0460] R.sup.7 is selected from
hydrogen, F, Cl, Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --OC.sub.1--C.sub.6 alkyl,
--S(O).sub.p--C.sub.1-C.sub.6 alkyl, --OCH.sub.2F, OCHF.sub.2,
--OCF.sub.3, S(O).sub.p--CH.sub.3, --S(O).sub.p--CH.sub.2F, and
--S(O).sub.p--CF.sub.3; and [0461] R.sup.3a is selected from
halogen and --C.sub.1-C.sub.6 alkyl; and [0462] p is 0, 1, or
2.
[0463] In some embodiments, the present invention relates to a
compound of formulae I1, I2, I3, or I4, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, wherein R.sup.9o and R.sup.9p are each
independently selected from --C.sub.1-C.sub.6 alkyl and hydrogen;
[0464] R.sup.6 is selected from hydrogen, F, Cl, Br, I,
C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and --CF.sub.3;
[0465] R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; [0466] R.sup.8
is hydrogen; [0467] R.sup.3a is selected from halogen and
--C.sub.1-C.sub.6 alkyl; and [0468] p is 0, 1, or 2.
[0469] In some embodiments, the present invention relates to a
compound of formulae I5, I6, I7, I8, I9, I10, I11, or I12, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, wherein R.sup.9o is
--C.sub.1-C.sub.6 alkyl; [0470] R.sup.6 is selected from hydrogen,
F, Cl, Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2,
and --CF.sub.3; [0471] R.sup.7 is selected from hydrogen, F, Cl,
Br, I, --C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2,
--CF.sub.3, --OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6
alkyl, --OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3,
--S(O).sub.p--CH.sub.3, --S(O).sub.p--CH.sub.2F, and
--S(O).sub.p--CF.sub.3; [0472] R.sup.8 is hydrogen; [0473] R.sup.3a
is selected from halogen and --C.sub.1-C.sub.6 alkyl; and [0474] p
is 0, 1, or 2.
[0475] In some embodiments, the present invention relates to a
compound of formulae I5, I6, I7, I8, I9, I10, I11, or I12, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, wherein R.sup.9o is
--CH.sub.3; [0476] R.sup.6 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, and --CF.sub.3;
[0477] R.sup.7 is selected from hydrogen, F, Cl, Br, I,
--C.sub.1-C.sub.6 alkyl, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--OC.sub.1-C.sub.6 alkyl, --S(O).sub.p--C.sub.1-C.sub.6 alkyl,
--OCH.sub.2F, --OCHF.sub.2, --OCF.sub.3, --S(O).sub.p--CH.sub.3,
--S(O).sub.p--CH.sub.2F, and --S(O).sub.p--CF.sub.3; [0478] R.sup.8
is hydrogen; [0479] R.sup.3a is CH.sub.3; and [0480] p is 0, 1, or
2.
[0481] In some embodiments, the present invention relates to a
compound of formulae IV, V, VI, VII, VIII, IX, X, XI, XXa, XXa1,
Va, VIa, VIIa, VIIIa, IXa, Xa, XIa, XII, XIII, XIV, XV, XVI, XVII,
XVIII, XXb, XXb1, XIIa, XIIIa, XIVa, XVa, XVIa, XVIIa, XVIIIa, F1,
or F2, or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, wherein the
moiety
##STR00184##
and R.sup.3b is H, is selected from:
##STR00185## ##STR00186## ##STR00187## ##STR00188##
##STR00189##
[0482] In some embodiments, the present invention relates to a
compound of formulae F1 (R.sup.3b is H), F2 (R.sup.3b is H), G2,
G4, H2, H4, H6, H8, H10, H12, I12, I4, I6, I8, I10, or I12, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, wherein the moiety
##STR00190##
is selected from:
##STR00191## ##STR00192## ##STR00193## ##STR00194##
[0483] In some embodiments, the present invention relates to a
compound of formulae Fl (R.sup.3b is H), F2 (R.sup.3b is H), G1,
G3, H1, H3, F15, H7, H9, H11, I1, I3, I5, I7, I9, or I11, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer, wherein the moiety
##STR00195##
is selected from:
##STR00196## ##STR00197## ##STR00198## ##STR00199##
[0484] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, according to
any one the compounds in Table 1, Table 2, Table 2a, and Table
2aa.
[0485] In some embodiments, the present invention relates to a
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer that binds the
ribosome. In some embodiments, the ribosome is a bacterial
ribosome.
[0486] In some embodiments, the present invention relates to a
pharmaceutical composition comprising a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, and a
pharmaceutically acceptable carrier. In some embodiments, the
present invention relates to a compound or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer of the invention and a means for delivery.
[0487] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a disease
state in a human or animal comprising administering to the human or
animal in need thereof an effective amount of a compound of the
invention, or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer.
[0488] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing a microbial infection
in a human or animal comprising administering to the human or
animal an effective amount of a compound of the invention, or a
tautomer thereof, or a pharmaceutically acceptable salt, ester, or
prodrug of said compound or tautomer.
[0489] In some embodiments, the present invention relates to use of
a compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, in the manufacture of a medicament for
treating, preventing, or reducing a microbial infection in a human
or animal. In some embodiments, the present invention relates to a
compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, for use in treating, preventing, or reducing
a microbial infection in a human or animal.
[0490] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a microbial
infection in a human or animal comprising administering to the
human or animal an effective amount of a compound or a tautomer
thereof, or a pharmaceutically acceptable salt, ester, or prodrug
of said compound or tautomer, wherein said microbial infection is
caused by one or more of the following microorganisms:
Acinetobacter spp. (Acinetobacter baumanni), Bacteroides
distasonis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides
thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus,
Citrobacter freundii, Citrobacter koser, Clostridium
clostridioforme, Clostridium perfringens, Enterobacter aerogenes,
Enterobacter cloacae, Enterococcus faecalis, Enterococcus spp.
(vancomycin susceptible and resistant isolates), Escherichia coli
(including ESBL and KPC producing isolates), Eubacterium lentum,
Fusobacterium spp., Haemophilus influenzae (including
beta-lactamase positive isolates), Haemophilus parainfluenzae,
Klebsiella pneumoniae (including ESBL and KPC producing isolates),
Klebsiella oxytoca (including ESBL and KPC producing isolates),
Legionella pneumophilia Moraxella catarrhalis, Morganella morganii,
Mycoplasma spp., Peptostreptococcus spp., Porphyromonas
asaccharolytica, Prevotella bivia, Proteus mirabilis, Proteus
vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas
aeruginosa, Serratia marcescens, Streptococcus anginosus,
Staphylococcus aureus (methicillin susceptible and resistant
isolates), Staphylococcus epidermidis (methicillin susceptible and
resistant isolates), Stenotrophomonas maltophilia, Streptococcus
agalactiae, Streptococcus constellatus, Streptococcus pneumoniae
(penicillin susceptible and resistant isolates), Streptococcus
pyogenes, or Streptococcus pyogenes.
[0491] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a microbial
infection in a human or animal comprising administering to the
human or animal an effective amount of a compound or a tautomer
thereof, or a pharmaceutically acceptable salt, ester, or prodrug
of said compound or tautomer, wherein said infection is caused by
or involves one or more microorganisms selected from: Acinetobacter
spp. (Acinetobacter baumanni), Bacteroides distasonis, Bacteroides
fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron,
Bacteroides uniformis, Bacteroides vulgatus, Citrobacter freundii,
Citrobacter koser, Clostridium clostridioforme, Clostridium
perfringens, Enterobacter aerogenes, Enterobacter cloacae,
Enterococcus faecalis, Enterococcus spp., Escherichia coli,
Eubacterium lentum, Fusobacterium spp., Haemophilus influenzae,
Haemophilus parainfluenzae, Klebsiella pneumoniae, Klebsiella
oxytoca, Legionella pneumophilia, Moraxella catarrhalis, Morganella
morganii, Mycoplasma spp., Peptostreptococcus spp., Porphyromonas
asaccharolytica, Prevotella bivia, Proteus mirabilis, Proteus
vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas
aeruginosa, Serratia marcescens, Streptococcus anginosus,
Staphylococcus aureus, Staphylococcus epidermidis, Stenotrophomonas
maltophilia, Streptococcus agalactiae, Streptococcus constellatus,
Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus
pyogenes.
[0492] In some embodiments, the present invention relates to a
method wherein said infection is caused by or involves one or more
of aerobic and facultative gram-positive microorganism selected
from: Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus
spp., Streptococcus agalactiae, Streptococcus pyogenes, and
Staphylococcus epidermidis.
[0493] In some embodiments, the present invention relates to a
method wherein said infection is caused by or involves one or more
of aerobic and facultative gram-negative microorganism selected
from: Escherichia coli, Haemophilus influenzae, Klebsiella
pneumoniae, Citrobacter freundii, Enterobacter aerogenes,
Enterobacter cloacae, Morganella morganii, Serratia marcescens ,
Pseudomonas aeruginosa, Acinetobacter baumanni, Moraxella
catarrhalis, Proteus mirabilis, Citrobacter koseri, Haemophilus
parainfluenzae, Klebsiella oxytoca, Proteus vulgaris, Providencia
rettgeri, and Providencia stuartii.
[0494] In some embodiments, the present invention relates to a
method wherein, said infection is caused by or involves one or more
of anaerobic microorganism: Bacteroides fragilis, Bacteroides
distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron,
Bacteroides uniformis, Clostridium clostridioforme, Eubacterium
lentum, Peptostreptococcus spp., Porphyromonas asaccharolytica,
Prevotella bivia, Bacteroides vulgatus, Clostridium perfringens,
and Fusobacterium spp.
[0495] In some embodiments, the present invention relates to a
method, wherein the microorganism Enterococcus spp. is selected
from vancomycin susceptible isolate and vancomycin resistant
isolate.
[0496] In some embodiments, the present invention relates to a
method wherein, the microorganism Escherichia coli is selected from
extended spectrum beta-lactamase (ESBL) producing isolate and
Klebsiella pneumoniae carbapenemase (KPC) producing isolate.
[0497] In some embodiments, the present invention relates to a
method wherein, the microorganism Haemophilus influenzae is a
beta-lactamase positive isolate.
[0498] In some embodiments, the present invention relates to a
method wherein, the microorganism Klebsiella pneumoniae is selected
from extended spectrum beta-lactamase (ESBL) producing isolate and
Klebsiella pneumoniae carbapenemase (KPC) producing isolate.
[0499] In some embodiments, the present invention relates to a
method wherein, the microorganism Klebsiella oxytoca selected from
extended spectrum beta-lactamase (ESBL) producing isolate and
Klebsiella pneumoniae carbapenemase (KPC) producing isolate. In
some embodiments, the present invention relates to a method
wherein, the microorganism Staphylococcus aureus is selected from
methicillin susceptible isolate and methicillin resistant
isolate.
[0500] In some embodiments, the present invention relates to a
method wherein, the microorganism Staphylococcus epidermidis is
selected from methicillin susceptible isolate and methicillin
resistant isolate.
[0501] In some embodiments, the present invention relates to a
method wherein, the microorganism Streptococcus pneumoniae is
selected from penicillin susceptible isolate and penicillin
resistant isolate.
[0502] In some embodiments, the present invention relates to a
method of treating, preventing or reducing the risk of a microbial
infection in a human or animal comprising administering to the
human or animal an effective amount of a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, or use of a
compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, in the manufacture of a medicament for
treating, preventing, or reducing the risk of a microbial infection
in a human or animal, [0503] wherein the microbial infection is
selected from the group consisting of: a skin infection, a Gram
positive infection, a Gram negative infection, nosocomial
pneumonia, community acquired pneumonia, postviral pneumonia,
hospital acquired pneumonia/ventilator associated pneumonia, a
respiratory tract infection such as chronic respiratory tract
infection (CRTI), acute pelvic infection, a complicated skin and
skin structure infection, a skin and soft tissue infection (SSTI)
including uncomplicated skin and soft tissue infections (uSSTI)s
and complicated skin and soft tissue infections, an abdominal
infection, a complicated intra-abdominal infection, a urinary tract
infection, bacteremia, septicemia, endocarditis, an
atrioventricular shunt infection, a vascular access infection,
meningitis, surgical prophylaxis, a peritoneal infection, a bone
infection, a joint infection, a methicillinresistant Staphylococcus
aureus infection, a vancomycinresistant Enterococci infection, a
linezolidresistant organism infection, a Bacillus anthracis
infection, a Francisella tularensis infection, a Yersinia pestis
infection, and tuberculosis.
[0504] The compounds of the present invention can be used, for
example for the treatment of patients with moderate to severe
infections, which may be caused by susceptible isolates of the
indicated microorganisms:
[0505] In some embodiments, the present invention relates to a
method of treating, preventing or reducing the risk of a
complicated intra-abdominal infection in a human or animal
comprising administering to the human or animal an effective amount
of a compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, or to the use of a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, in the manufacture
of a medicament for treating, preventing or reducing the risk of a
complicated intra-abdominal infection in a human or animal,
[0506] In some embodiments, the complicated intra-abdominal
infection is selected from polymicrobial infections such as abscess
due to Escherichia coli, Clostridium clostridioforme, Eubacterium
lentum, Peptostreptococcus spp., Bacteroides fragilis, Bacteroides
distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron,
Bacteroides uniformis , Streptococcus anginosus, Streptococcus
constellatus , Enterococcus faecalis, Proteus mirabilis, or
Clostridium perfringens.
[0507] In some embodiments, the present invention relates to a
method of treating, preventing or reducing the risk of a
complicated skin and skin structure infection (cSSSI, also known as
acute bacterial skin and skin structure infections or ABSSSI) in a
human or animal comprising administering to the human or animal an
effective amount of a compound of the invention, or a tautomer
thereof, or a pharmaceutically acceptable salt, ester, or prodrug
of said compound or tautomer, or to the use of a compound of the
invention, or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, in the
manufacture of a medicament for treating, preventing or reducing
the risk of a complicated skin and skin structure infection,
[0508] In some embodiments, the complicated skin and skin structure
infection is selected from diabetic foot infections without
osteomyelitis due to Staphylococcus aureus (methicillin susceptible
and resistant isolates), Streptococcus agalactiae, Streptococcus
pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus
mirabilis, Bacteroides fragilis, Peptostreptococcus species,
Porphyromonas asaccharolytica, or Prevotella bivia.
[0509] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a community
acquired pneumonia (CAP) in a human or animal comprising
administering to the human or animal an effective amount of a
compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, or to the use of a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, in the manufacture
of a medicament for treating, preventing or reducing the risk of
community acquired pneumonia,
[0510] In some embodiment, the community acquired pneumonia is due
to Streptococcus pneumoniae (penicillin susceptible and resistant
isolates) including cases with concurrent bacteremia, Haemophilus
influenzae (including beta-lactamase positive isolates), Moraxella
catarrhalis, or atypical bacteria like Mycoplasma spp.
[0511] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a
complicated urinary tract infection (cUTI) in a human or animal
comprising administering to the human or animal an effective amount
of a compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, or to the use of a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, in the manufacture
of a medicament for treating, preventing or reducing the risk of a
complicated urinary tract infection,
[0512] In some embodiment, the complicated urinary tract infection
is selected from pyelonephritis due to Escherichia coli, concurrent
bacteremia, or Klebsiella pneumoniae.
[0513] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of an acute
pelvic infection in a human or animal comprising administering to
the human or animal an effective amount of a compound of the
invention, or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, or to the use
of a compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, in the manufacture of a medicament for
treating, preventing or reducing the risk of an cute pelvic
infection,
[0514] In some embodiments, the acute pelvic infection is selected
from postpartum endomyometritis, septic abortion and post surgical
gynecologic infections and the infection is due to a microorganism
selected from Streptococcus agalactiae, Escherichia colt,
Bacteroides fragilis, Porphyromonas asaccharolytica,
Peptostreptococcus spp., and Prevotella bivia.
[0515] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a hospital
acquired pneumonia (HAP)/ventilator associated pneumonia (VAP) in a
human or animal comprising administering to the human or animal an
effective amount of a compound of the invention, or a tautomer
thereof, or a pharmaceutically acceptable salt, ester, or prodrug
of said compound or tautomer, or to the use of a compound of the
invention, or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, in the
manufacture of a medicament for treating, preventing or reducing
the risk of hospital acquired pneumonia/ventilator associated
pneumonia,
[0516] In some embodiments, the hospital acquired
pneumonia/ventilator associated pneumonia is due to a microorganism
selected from Streptococcus pneumoniae (penicillin susceptible and
resistant isolates), Staphylococcus aureus (methicillin susceptible
and resistant isolates), Klebsiella pneumoniae, Pseudomonas
aeruginosa, Acinetobacter spp., Stenotrophomonas maltophilia,
Haemophilus influenzae (including beta-lactamase positive
isolates), and Legionella pneumophilia.
[0517] The compounds or tautomers or pharmaceutically acceptable
salts, esters or prodrugs of said compounds or tautomers of the
present invention may also be useful for the prevention,
prophylaxis, or reduction of surgical site infections. In some
embodiments, the compounds or tautomers or pharmaceutically
acceptable salts, esters or prodrugs of said compounds or tautomers
of the present invention are useful following elective colorectal
surgery.
[0518] Appropriate specimens for bacteriological examination should
be obtained in order to isolate and identify the causative
organisms and to determine their susceptibility to the compounds of
the present invention. Therapy with the compounds or tautomers or
pharmaceutically acceptable salts, esters or prodrugs of said
compounds or tautomers of the present invention may be initiated
empirically before results of these tests are known; once results
become available, antimicrobial therapy should be adjusted
accordingly.
[0519] To reduce the development of drug-resistant bacteria and
maintain the effectiveness of the compounds or tautomers or
pharmaceutically acceptable salts, esters or prodrugs of said
compounds or tautomers of the present invention and other
antibacterial drugs, the compounds or tautomers or pharmaceutically
acceptable salts, esters or prodrugs of said compounds or tautomers
should be used only to treat or prevent infections that are proven
or strongly suspected to be caused by susceptible bacteria. When
culture and susceptibility information are available, they should
be considered in selecting or modifying antibacterial therapy. In
the absence of such data, local epidemiology and susceptibility
patterns may contribute to the empiric selection of therapy.
[0520] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a microbial
infection due to an aerobic or facultative gram-positive
microorganism in a human or animal comprising administering to the
human or animal an effective amount of a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, or to the use of a
compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, in the manufacture of a medicament for
treating, preventing or reducing the risk of a microbial infection
due to an aerobic or facultative gram-positive microorganism.
[0521] In some embodiments, the aerobic or facultative
gram-positive microorganism is selected from: [0522] Staphylococcus
aureus (methicillin susceptible and resistant isolates),
Streptococcus pneumoniae (penicillin susceptible and resistant
isolates), Enterococcus spp. (vancomycin susceptible and resistant
isolates), Streptococcus agalactiae, Streptococcus pyogenes, and
Staphylococcus epidermidis (methicillin susceptible and resistant
isolates).
[0523] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a microbial
infection due to an aerobic and facultative gram-negative
microorganism in a human or animal comprising administering to the
human or animal an effective amount of a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, or to the use of a
compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, in the manufacture of a medicament for
treating, preventing or reducing the risk of a microbial infection
due to an aerobic or facultative gram-positive microorganism.
[0524] In some embodiments, the aerobic and facultative
gram-negative microorganism is selected from: Escherichia coli
[including extended spectrum beta-lactamase (ESBL) and Klebsiella
pneumonia (KPC) producing isolates), Haemophilus influenzae
(including Beta-lactamase positive isolates), Klebsiella pneumoniae
(including ESBL and KPC producing isolates), Citrobacter freundii,
Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii,
Serratia marcescens , Pseudomonas aeruginosa, Acinetobacter
baumanni, Moraxella catarrhalis, Proteus mirabilis, Citrobacter
koseri, Haemophilus parainfluenzae, Klebsiella oxytoca (including
ESBL and KPC producing isolates), Proteus vulgaris, Providencia
rettgeri, and Providencia stuartii.
[0525] In some embodiments, the present invention relates to a
method of treating, preventing, or reducing the risk of a microbial
infection due to an anaerobic microorganism in a human or animal
comprising administering to the human or animal an effective amount
of a compound of the invention, or a tautomer thereof, or a
pharmaceutically acceptable salt, ester, or prodrug of said
compound or tautomer, or to the use of a compound of the invention,
or a tautomer thereof, or a pharmaceutically acceptable salt,
ester, or prodrug of said compound or tautomer, in the manufacture
of a medicament for treating, preventing or reducing the risk of a
microbial infection due to an anaerobic microorganism.
[0526] In some embodiments, the anaerobic microorganism is selected
from: Bacteroides fragilis, Bacteroides distasonis, Bacteroides
ovatus , Bacteroides thetaiotaomicron, Bacteroides uniformis,
Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus
species, Porphyromonas asaccharolytica, Prevotella bivia,
Bacteroides vulgates, Clostridium perfringens, and Fusobacterium
spp.
[0527] In some embodiments, the present invention relates to a
method of treating or reducing the risk of a microbial infection in
a human or animal comprising administering to the human or animal
an effective amount of a compound of the invention, or a tautomer
thereof, or a pharmaceutically acceptable salt, ester, or prodrug
of said compound or tautomer, or to the use of a compound of the
invention, or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer, in the
manufacture of a medicament for treating, preventing or reducing
the risk of a microbial infection.
[0528] In some embodiments, the microorganism is Legionella
pneumophilia.
[0529] In some embodiments, the microorganism Enterococcus spp. is
selected from vancomycin susceptible isolate and vancomycin
resistant isolate. In some embodiments, the microorganism
Escherichia coli is selected from extended spectrum beta-lactamase
(ESBL) producing isolate and Klebsiella pneumoniae carbapenemase
(KPC) producing isolate. In some embodiments, the microorganism
Haemophilus influenzae is a beta-lactamase positive isolate. In
some embodiments, the microorganism Klebsiella pneumoniae is
selected from extended spectrum beta-lactamase (ESBL) producing
isolate and Klebsiella pneumoniae carbapenemase (KPC) producing
isolate. In some embodiments, the microorganism Klebsiella oxytoca
selected from extended spectrum beta-lactamase (ESBL) producing
isolate and Klebsiella pneumoniae carbapenemase (KPC) producing
isolate. In some embodiments, the microorganism Staphylococcus
aureus is selected from methicillin susceptible isolate and
methicillin resistant isolate. In some embodiments,the
microorganism Staphylococcus epidermidis is selected from
methicillin susceptible isolate and methicillin resistant isolate.
In some embodiments, the microorganism Streptococcus pneumoniae is
selected from penicillin susceptible isolate and penicillin
resistant isolate.
[0530] In some embodiments, the present invention relates to a
method, use, or compound of the invention, wherein the amount of
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer comprises from
0.1 mg to 1500 mg.
[0531] In some embodiments, the present invention relates to a
method, use, or compound of the invention wherein the amount of
compound or a tautomer thereof, or a pharmaceutically acceptable
salt, ester, or prodrug of said compound or tautomer comprises
about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or
about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or
about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or
about 325, or about 350 mg, or about 375 mg, or about 400 mg, or
about 425 mg, or about 450 mg, or about 475 mg, or about 500 mg, or
about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or
about 625 mg, or about 650 mg, or about 675 mg, or about 700 mg, or
about 725 mg, or about 750 mg, or about 775 mg, or about 800 mg, or
about 825 mg, or about 850 mg, or about 875 mg, or about 900 mg, or
about 925 mg, or about 950 mg, or about 975 mg, or about 1000 mg,
or about 1025 mg, or about 1050, mg, or about 1075 mg, or about
1100 mg, or about 1125 mg, or about 1150 mg, or about 1175 mg, or
about 1200 mg, or about 1225 mg, or about 1250 mg, or about 1275
mg, or about 1300 mg, or about 1325 mg, or about 1350 mg, or about
1375 mg, or about 1400 mg, or about 1425 mg, or about 1450 mg, or
about 1475 mg, or about 1500 mg.
[0532] In some embodiments, the present invention relates to a
method, use, or compound of the invention wherein the compound, or
a tautomer thereof, or a pharmaceutically acceptable salt, ester,
or prodrug of said compound or tautomer, is administered otically,
ophthalmically, nasally, orally, parenterally, topically, or
intravenously.
[0533] In some embodiments, the present invention relates to a
method of synthesizing a compound of the invention, or a tautomer
thereof, or a pharmaceutically acceptable salt, ester, or prodrug
of said compound or tautomer.
[0534] In some embodiments, the present invention relates to a
medical device containing a compound of the invention or a tautomer
thereof, or a pharmaceutically acceptable salt, ester, or prodrug
of said compound or tautomer. In some embodiments, the device is a
stent.
3. Synthesis of the Compounds of the Invention
[0535] Compounds of the invention can be prepared according to
methods known in the art. More specifically, compounds of the
invention can be prepared according to the procedures and examples
described herein. In one aspect, a compound of the invention can be
synthesized by coupling two fragments A and B:
##STR00200##
[0536] In one aspect, a compound of the invention can be
synthesized as outlined Scheme 1.
##STR00201##
[0537] In one aspect, a compound of the invention can be
synthesized as outlined in Scheme 2. The scheme depicts the
preparation of a compound of formula I having certain values where
X.sub.3 is CR.sup.3 and Y.sup.9 is CR.sup.9. It is understood that
one skilled in the art would be able to readily apply this scheme
for the synthesis of compounds having other R.sup.3 and R.sup.9
groups as described herein.
##STR00202##
[0538] In one aspect, the transformation of step 1 of the synthesis
described above is based on a coupling reaction of Fragments A and
B to form the core pyrrolocytosine ring. See e.g., Wojciechowski,
F., Hudson, R. H. E. "Peptide Nucleic Acid Containing a
Meta-Substituted Phenylpyrrolocytosine Exhibits a Fluorescence
Response and Increased Binding Affinity toward RNA." Org. Lett.
2009, 11(21), 4878-4881 and Wojciechowski, F., Hudson, R. H. E.
"Fluorescence and Hybridization Properties of Peptide Nucleic Acid
Containing a Substituted Phenylpyrrolocytosine Designed to Engage
Guanine with an Additional H-Bond" J. Am. Chem. Soc., 2008,
130(38), 12574-12575. In one aspect, X in Fragment A is I or Br and
R.sup.3a, R.sup.3b, R.sup.3e, R.sup.3f, R.sup.3g, R.sup.3h,
R.sup.3i, R.sup.3j, R.sup.6, R.sup.7, R.sup.8, R.sup.9k, R.sup.9l,
R.sup.9o, R.sup.9p, R.sup.9q, R.sup.9p, R.sup.9q, R.sup.9r, and Z
are as described herein.
[0539] Fragments A and B can be coupled using a variety of methods
known in the art. Step 2 of the synthesis involves the installation
of a guanidine functional group using methods known in the art. In
one aspect, the protected terminal amine on the left-hand side of
the molecule can be deprotected to afford the primary amine.
Guanidine can then be installed by selective addition to the
primary amine on the basis of steric factors and the diminished
reactivity of the benzylic nitrogen. Global deprotection then
produces the final compound in the form of a polyamine salt.
[0540] In one aspect, a compound of the invention can be
synthesized as shown in the Scheme 3. The scheme depicts the
preparation of a compound having certain values defined, however
one skilled in the art would understand that the methodology
outlined below could be readily applied for the preparation of
other compounds of the invention described herein.
##STR00203## ##STR00204##
[0541] Although Scheme 3 shown above is depicted with certain
values for R.sup.3a, R.sup.9o, R.sup.9r, and Z, it is understood
that one skilled in the art would be able to readily apply this
scheme for the synthesis of compounds having other R.sup.3a,
R.sup.9o, R.sup.9r, and Z groups. Furthermore, it is understood
that Scheme 3 above is applicable for the variety of aryl groups
described herein e.g.,
##STR00205##
Preparation of Fragment A
[0542] Fragment A intermediates can be prepared according to
methods known in the art. The schemes below outline strategies that
can be applied for the synthesis of Fragment A intermediates and
used to prepare compounds of the invention. Procedures for the
preparation of Fragment A intermediates are also found in the
examples provided herein. In one aspect, Fragment A can be
synthesized using a 4 step process as outlined below.
[0543] Step 1 uses a reductive amination strategy to form a benzyl
amine intermediate. The amine and aldehyde groups can be on either
one of the compounds involved in the reductive amination reaction.
Reductive amination is a well known procedure in the chemical arts
and thus, the skilled person would be able to optimize Step 1 for
the preparation of a compound of the invention.
##STR00206##
Following formation of the benzyl amine intermediate, Step 2 is a
coupling reaction to form a pinacol borane compound, which is then
coupled in Step 3 with an iodocytosine moiety. Step 4 involves
acylation of the amine group of the pyrimidinone to form a Fragment
A intermediate.
##STR00207##
[0544] Scheme 6 and Scheme 7 below show a 4-step for the synthesis
of the Fragment A intermediate:
##STR00208##
[0545] Although the schemes depict the preparation of compounds
having certain values defined, one skilled in the art would
understand that the methodology outlined below could be readily
applied for the preparation of other compounds of the invention
described herein. The scheme below shows two alternative procedures
for Step 1 in the synthesis of the Fragment A intermediate above.
In the first procedure, the resulting benzyl amine intermediate
does not have a substituent at the benzylic position (i.e.,
R.sup.3a.dbd.H). In the second procedure, the resulting benzyl
amine intermediate has at least one substituent (R.sup.3a is not H)
in the benzylic position. It is understood that the second
procedure can be used to prepare a variety of different benzyl
amine intermediates e.g., intermediates with R.sup.3a selected from
ethyl, propyl, alkenyl, cyclopropyl, CO.sub.2H, CO.sub.2Me, alkyl
substituted with CO.sub.2Me, CO.sub.2H, etc.
##STR00209##
[0546] Steps 2-4 are shown below for the preparation of Fragment A.
The steps are the same for compounds having R.sup.3a as H or
CH.sub.3. Although the steps are depicted with compounds having
R.sup.3a defined as H or CH.sub.3, one skilled in the art could
readily apply the procedures described herein and in the examples
for the preparation of a different Fragment A e.g., a Fragment A
with R.sup.3a selected from ethyl, propyl, alkenyl, cyclopropyl,
CO.sub.2H, CO.sub.2Me, alkyl substituted with CO.sub.2Me,
CO.sub.2H, etc.
##STR00210##
Preparation of Fragment B
[0547] Fragment B intermediates can be prepared according to
methods known in the art. The schemes below outline strategies that
can be applied for the synthesis of Fragment B intermediates and
used to prepare compounds of the invention. Procedures for the
preparation of Fragment B intermediates are also found in the
examples provided herein. Scheme 8 below is a retro-synthetic
analysis which shows the strategy for attaching a R.sup.9 group to
the aryl moiety. The strategy involves the coupling of an aryl
halide with an aminoalkene moiety. This strategy is applicable for
the synthesis of Fragment B intermediates where the R.sup.9 group
is an all carbon chain (i.e., Z is CH.sub.2). Although the Scheme 8
illustrates a transformation to form a Fragment B intermediate with
a certain R.sup.9 group, it is understood that the strategy can be
applied to prepare different Fragment B intermediates with a
different R.sup.9 group as described herein, where Z is
CH.sub.2.
##STR00211##
[0548] An example of the preparation of the aminoalkene compound is
shown below. Further details regarding the preparation of this
aminoalkene compound are found in the examples herein.
##STR00212##
[0549] Alternatively, Scheme 9 below depicts a retro-synthetic
strategy for the synthesis of Fragment B intermediates that have an
oxygen atom in the R.sup.9 chain. In one aspect, the synthesis of
the Fragment B intermediate begins with a dibromide or dihalide (Br
and I) aryl compound (labeled A and B below). The synthesis
involves conversion of an aryl bromide or iodide to an aldehyde
group, reduction of the aldehyde to a primary alcohol, which is
next converted to a leaving group (LG). The R.sup.9 chain is then
elaborated by the displacement of the OLG group with a primary
alcohol. The primary alcohol has functionality that can be unmasked
and elaborated to a nitrogen group using chemistry known in the
art.
##STR00213##
[0550] Alternatively, the R.sup.9 chain can be installed to produce
a Fragment B intermediate starting with an aldehyde aryl compound
(labeled C in Scheme 9). The synthesis can involve a Wittig
olefination reaction to install the R.sup.9 chain as shown in
Scheme 10, which depicts the retro-synthesis of fragment B.
##STR00214##
[0551] It is understood that the synthetic procedures described
above and in the examples can be used to prepare compounds of the
invention having a variety of different aryl groups.
[0552] Some representative aryl groups include e.g.,
##STR00215##
[0553] It is understood that the synthetic procedures described
above and in the examples can be used to prepare compounds of the
invention having a variety of different R.sup.9 chains. Some
representative R.sup.9 chains include e.g.,
##STR00216##
In the last R.sup.9 chain, there is no CH.sub.2 group between the
aryl group and cyclic group.
[0554] Precursors for the preparation of the R.sup.9 chain include
e.g.,
##STR00217##
[0555] The three schemes (Schemes 11-13) below illustrate several
general strategies for preparing Fragment B intermediates. Scheme
11 illustrates how the dihalide aryl comopund (labelled compound 8)
is a key intermediate which can be coupled with a variety of
different R.sup.9 chains to synthesize a Fragment B intermediate
and used to prepare many of the compounds of the invention.
Synthetic procedures for the preparation of dihalide aryl
intermediates used to prepare compounds of the invention are found
in the examples herein.
##STR00218##
[0556] Scheme 12 shows a key transformation of the dihalide aryl
intermediate compound 8 to compound 21, which can be elaborated to
many different Fragment B intermediates.
##STR00219##
[0557] Scheme 13 emphasizes the utility of the aniline moiety for
the regioselective installation of either iodide or bromide either
in a stepwise manner (eg. 2.fwdarw.6.fwdarw.7) or in one pot
(2.fwdarw.3). The diversity of aniline compounds, either
commercially available or prepared from other starting materials
(eg. 1.fwdarw.2), allows access to a variety of substitution
patterns.
##STR00220## ##STR00221##
[0558] Scheme 14 below shows the preparation of a Fragment B
intermediate having a ring in the R.sup.9 chain. In one aspect, the
process of attaching the R.sup.9 group to the aryl moiety includes
coupling of a dihalide aryl intermediate compound 8 with an
aminoalkene moiety having a ring structure e.g.,
##STR00222##
[0559] Scheme 14 illustrates a strategy for preparing R.sup.9
chains having any size ring incorporated into the chain e.g., a 3-,
4-, 5-, 6-, etc. membered ring. In one aspect, the amino group can
be installed via either a Curtius rearrangement (2.fwdarw.3) or a
nitrile reduction (1.fwdarw.7). In one aspect, the aminoalkene
moiety can be attached to the aryl moiety via the Suzuki-coupling
reaction. For example, the aminoalkene can first be converted to a
alkylborane by treatment with 9-BBN and then reacted with compound
8, replacing the more reactive iodide first. The terminal alkyne
can be installed by a variety of methods know in the art. Reagents
such as trimethylsilyl acetylene can be employed to generate
fragment B.
##STR00223##
4. Characterization of Compounds of the Invention
[0560] Compounds designed, selected and/or optimized by methods
described above, once produced, can be characterized using a
variety of assays known to those skilled in the art to determine
whether the compounds have biological activity. For example, the
molecules can be characterized by conventional assays, including
but not limited to those assays described below, to determine
whether they have a predicted activity, binding activity and/or
binding specificity.
[0561] Furthermore, highthroughput screening can be used to speed
up analysis using such assays. As a result, it can be possible to
rapidly screen the molecules described herein for activity, for
example, as anticancer, antibacterial, antifungal, antiparasitic or
antiviral agents. Also, it can be possible to assay how the
compounds interact with a ribosome or ribosomal subunit and/or are
effective as modulators (for example, inhibitors) of protein
synthesis using techniques known in the art. General methodologies
for performing high throughput screening are described, for
example, in Devlin (1998) High Throughput Screening, Marcel Dekker;
and U.S. Pat. No. 5,763,263. Highthroughput assays can use one or
more different assay techniques including, but not limited to,
those described below.
[0562] (1) Surface Binding Studies. A variety of binding assays can
be useful in screening new molecules for their binding activity.
One approach includes surface plasmon resonance (SPR) that can be
used to evaluate the binding properties of molecules of interest
with respect to a ribosome, ribosomal subunit or a fragment
thereof.
[0563] SPR methodologies measure the interaction between two or
more macromolecules in realtime through the generation of a
quantummechanical surface plasmon. One device, (BIAcore
Biosensor.RTM. from Pharmacia Biosensor, Piscataway, N.J.) provides
a focused beam of polychromatic light to the interface between a
gold film (provided as a disposable biosensor "chip") and a buffer
compartment that can be regulated by the user. A 100 nm thick
"hydrogel" composed of carboxylated dextran that provides a matrix
for the covalent immobilization of analytes of interest is attached
to the gold film. When the focused light interacts with the free
electron cloud of the gold film, plasmon resonance is enhanced. The
resulting reflected light is spectrally depleted in wavelengths
that optimally evolved the resonance. By separating the reflected
polychromatic light into its component wavelengths (by means of a
prism), and determining the frequencies that are depleted, the
BIAcore establishes an optical interface which accurately reports
the behavior of the generated surface plasmon resonance. When
designed as above, the plasmon resonance (and thus the depletion
spectrum) is sensitive to mass in the evanescent field (which
corresponds roughly to the thickness of the hydrogel). If one
component of an interacting pair is immobilized to the hydrogel,
and the interacting partner is provided through the buffer
compartment, the interaction between the two components can be
measured in real time based on the accumulation of mass in the
evanescent field and its corresponding effects of the plasmon
resonance as measured by the depletion spectrum. This system
permits rapid and sensitive realtime measurement of the molecular
interactions without the need to label either component.
[0564] (2) Fluorescence Polarization. Fluorescence polarization
(FP) is a measurement technique that can readily be applied to
proteinprotein, proteinligand, or RNAligand interactions in order
to derive IC.sub.50s and Kds of the association reaction between
two molecules. In this technique one of the molecules of interest
is conjugated with a fluorophore. This is generally the smaller
molecule in the system (in this case, the compound of interest).
The sample mixture, containing both the ligandprobe conjugate and
the ribosome, ribosomal subunit or fragment thereof, is excited
with vertically polarized light. Light is absorbed by the probe
fluorophores, and reemitted a short time later. The degree of
polarization of the emitted light is measured. Polarization of the
emitted light is dependent on several factors, but most importantly
on viscosity of the solution and on the apparent molecular weight
of the fluorophore. With proper controls, changes in the degree of
polarization of the emitted light depends only on changes in the
apparent molecular weight of the fluorophore, which inturn depends
on whether the probeligand conjugate is free in solution, or is
bound to a receptor. Binding assays based on FP have a number of
important advantages, including the measurement of IC.sub.50s and
Kds under true homogenous equilibrium conditions, speed of analysis
and amenity to automation, and ability to screen in cloudy
suspensions and colored solutions.
[0565] (3) Protein Synthesis. It is contemplated that, in addition
to characterization by the foregoing biochemical assays, the
compound of interest can also be characterized as a modulator (for
example, an inhibitor of protein synthesis) of the functional
activity of the ribosome or ribosomal subunit.
[0566] Furthermore, more specific protein synthesis inhibition
assays can be performed by administering the compound to a whole
organism, tissue, organ, organelle, cell, a cellular or subcellular
extract, or a purified ribosome preparation and observing its
pharmacological and inhibitory properties by determining, for
example, its inhibition constant (IC.sub.50) for inhibiting protein
synthesis. Incorporation of .sup.3H leucine or .sup.35S methionine,
or similar experiments can be performed to investigate protein
synthesis activity. A change in the amount or the rate of protein
synthesis in the cell in the presence of a molecule of interest
indicates that the molecule is a modulator of protein synthesis. A
decrease in the rate or the amount of protein synthesis indicates
that the molecule is a inhibitor of protein synthesis.
[0567] (4) Antimicrobial assays and other evaluation. Furthermore,
the compounds can be assayed for antiproliferative or antiinfective
properties on a cellular level. For example, where the target
organism is a microorganism, the activity of compounds of interest
can be assayed by growing the microorganisms of interest in media
either containing or lacking the compound. Growth inhibition can be
indicative that the molecule can be acting as a protein synthesis
inhibitor. More specifically, the activity of the compounds of
interest against bacterial pathogens can be demonstrated by the
ability of the compound to inhibit growth of defined strains of
human pathogens. For this purpose, a panel of bacterial strains can
be assembled to include a variety of target pathogenic species,
some containing resistance mechanisms that have been characterized.
Use of such a panel of organisms permits the determination of
structureactivity relationships not only in regards to potency and
spectrum, but also with a view to obviating resistance
mechanisms.
[0568] The in vitro activity of the compounds of the present
invention can be determined. Antimicrobial testing is typically
performed to determine the minimum inhibitory concentration (MIC).
Minimum inhibitory concentrations (MICs) are determined by the
microdilution method in a final volume of 100 .mu.l according to
protocols outlined by The Clinical and Laboratory Standards
Institute (CLSI). Performance standards for reference strains are
assessed within the same experimental design to maintain quality
control. See, for example, Clinical Laboratory Standards Institute:
Methods for dilution antimicrobial susceptibility tests for
bacteria that grow aerobically M7-A8. Approved Standard-Eighth
Edition. Wayne, Pa.: CLSI; December 2008; and Clinical Laboratory
Standards Institute: Performance Standards for Antimicrobial
Susceptibility Testing M100-S20; Approved Standard-Twentieth
Edition. Wayne, Pa.: CLSI; June 2010.
[0569] The antimicrobial and other drug properties of the compounds
can further be evaluated in various in vivo mammalian assays, such
as a mouse or rat peritonitis infectious models, skin and soft
tissue models (often referred to as the thigh model), or a mouse
pneumonia model. There are septicemia or organ infection models
known to those skilled in the art. These efficacy models can be
used as part of the evaluation process and can be used as a guide
of potential efficacy in humans. Endpoints can vary from reduction
in bacterial burden to lethality. For the latter endpoint, results
are often expressed as a PD.sub.50 value, or the dose of drug that
protects 50% of the animals from mortality.
[0570] To further assess a compound's druglike properties,
measurements of inhibition of cytochrome P450 enzymes and phase II
metabolizing enzyme activity can also be measured either using
recombinant human enzyme systems or more complex systems like human
liver microsomes. Further, compounds can be assessed as substrates
of these metabolic enzyme activities as well. These activities are
useful in determining the potential of a compound to cause drugdrug
interactions or generate metabolites that retain or have no useful
antimicrobial activity.
[0571] To get an estimate of the potential of the compound to be
orally bioavailable, one can also perform solubility and Caco-2
assays. The latter is a cell line from human epithelium that allows
measurement of drug uptake and passage through a Caco-2 cell
monolayer often growing within wells of a 24-well microtiter plate
equipped with a 1 micron membrane. Free drug concentrations can be
measured on the basolateral side of the monolayer, assessing the
amount of drug that can pass through the intestinal monolayer.
Appropriate controls to ensure monolayer integrity and tightness of
gap junctions are needed. Using this same system one can get an
estimate of P-glycoprotein mediated efflux. P-glycoprotein is a
pump that localizes to the apical membrane of cells, forming
polarized monolayers. This pump can abrogate the active or passive
uptake across the Caco-2 cell membrane, resulting in less drug
passing through the intestinal epithelial layer. These results are
often done in conjunction with solubility measurements and both of
these factors are known to contribute to oral bioavailability in
mammals. Measurements of oral bioavailability in animals and
ultimately in man using traditional pharmacokinetic experiments
will determine the absolute oral bioavailability.
[0572] Experimental results can also be used to build models that
help predict physical-chemical parameters that contribute to
drug-like properties. When such a model is verified, experimental
methodology can be reduced, with increased reliance on the model
predictability.
[0573] (5) Animal Pharmacology and Toxicology. The compounds of the
present invention can be evaluated for efficacy in well-known
animal models. The following table provides representative animal
models for various infection indications.
TABLE-US-00001 Target Infection Indication Animal Model of Efficacy
HAP/VAP Efficacy in mouse and/or rat pneumoniae model vs.
respiratory tract infection pathogens of interest (Streptococcus
pneumoniae, including multi-drug resistant Streptococcus
pneumoniae, H. influenzae, methicillin resistant Staphylococcus
aureus (MRSA), and Pseudomonas. aeruginosa) cSSSI Efficacy in mouse
model against pathogens of interest (MRSA, K. pneumoniae) Sepsis
Efficacy in mouse peritonitis model vs. pathogens of interest (E.
coli, K. pneumoniae, E. faecalis, MRSA) cUTI Efficacy in mouse
model against E. coli, K. pneumoniae and/or MRSA) Febrile Efficacy
in mouse peritonitis model against S. aureus, neutropenia S.
epidermidis, S. pneumoniae, S. pyogenes, P. aeruginosa
Animal Model for Complicated Skin and Skin Structure Infections
(cSSSI): Murine Skin and Soft Tissue Infection Model of Klebsiella
pneumoniae 1705966 in Thighs of Neutropenic Female CD-1 Mice
[0574] This model is useful to assess the efficacy of compounds of
the present invention in a Klebsiella pneumoniae 1705966
neutropenic mouse thigh infection model using female ICR (CD-1)
mice.
[0575] Study Design:
[0576] Species: Female ICR (CD-1) Mice, 8 to 9 weeks old, weighting
25-29 g.
[0577] Inoculum: Klebsiella pneumoniae 17059663 was streaked from
frozen stock onto Blood agar (Tryptic Soy Agar +5% Sheep Blood),
BD, #221261) and incubated overnight at 35.degree. C. After
overnight incubation, enough bacteria (approx. 1 full loop) to
measure OD.sub.625=0.990 was transferred from plate and diluted
into 10 ml pre-warmed Mueller-Hinton broth. This culture was
further diluted 1:1000 into pre-warmed MH broth and grown for
approximately 2 hrs at 35.degree. C. with shaking. Each mouse was
given 0.1 mL of 1:1000 dilution culture injected into both caudal
thigh muscles under isoflurane inhalation anesthesia.
Dilution Initial O.D. Final O.D. (after 2 hr. Incubation)
TABLE-US-00002 1:10 0.135 0.424 1:100 0.014 0.215 1:1000 0.001
0.035
Neutropenia is induced by intraperitoneal (I.P.) administration of
Cyclophosphamide monohydrateon Day-4 (150 mg/kg) and Day-1 (100
mg/kg). [0578] Vehicle: 0.9% sodium chloride [0579] Dosing: Each
mouse in the treated groups was given the appropriate dose of the
compound to be tested in a volume of 0.2m1, 2 and 8 hrs. post
bacterial inoculation. [0580] Time points: [0581] Controls: 0, 2,
6, and 24 hrs. [0582] Treated: 24 hrs.
[0583] Sampling: 2 or 3 mice/time point were euthanized via
CO.sub.2, and their caudal thigh muscles excised and homogenized.
The thigh muscles were placed in 5 ml sterile PBS in Stomacher
Filter bag and homogenized with MicroBiomaster80 (Brinkmann) for
60seconds, normal setting and 1:10 dilutions were made per standard
protocol in a 96-well plate. Aliquots of 25 ul for each dilution,
as well as the homogenate, were plated on blood agar plates and
incubated at 35.degree. C. to determine the CFU/mL over the time
course. After overnight incubation, colonies were counted.
Animal Model for Sespsis:
[0584] Murine Peritonitis Model (E. coli, K. pneumoniae, E.
faecalis, MRSA)
[0585] This model is used to evaluate the effect of subcutaneous
(SC) treatment with compounds of the present invention on growth of
Escherichia coli ATCC 25922 in a mouse peritonitis model using
female Swiss Webster mice.
Controls:
[0586] Negative: Inoculum only [0587] Inoculum Vehicle
Intraperitoneal [0588] Positive: Ciprofloxacin
Study Design:
[0589] Species: Female Swiss Webster Mice
[0590] Inoculation: Escherichia coli ATCC 25922 is made by adding 1
ml (4/6/07) stock to 9 ml 0.25% Brewer's Yeast to make (1:10), then
1 ml of the (1:10) will be added to 9 ml 0.25% Brewer's Yeast to
make (1:100), then lml of the (1:100) will be added to 9 ml 0.25%
Brewer's Yeast to make (1:1000), then 2.5 ml of the (1:1000) will
be added to 122.5 ml 0.25% Brewer's Yeast to make (1:50,000), 1
ml/mouse will by inoculated intraperitoneally (IP).
Route of Administration: SC
[0591] Dosing: Vehicle for compounds of the present invention:
Saline or 50 mM Sodium phosphate buffer in 10% Captisol in water,
pH=7.2.
[0592] Dose Administration: Q3H.times.3 beginning at 30 min post
bacterial inoculation
[0593] Study Duration: 24 hrs. 0.25% Brewer's Yeast Extract (BYE):
Dilute 2% prepared on 11/12/09 (Lot.2158K, MP Biomedicals) 25 ml
2%+175 ml 1.times. PBS.
[0594] Outcome Measures: Colony Forming Unit's from peritoneal wash
and spleen homogenate and drug levels from wash, spleen homogenate,
and plasma.
[0595] Blood is collected via cardiac puncture while mouse is under
CO.sub.2 narcosis. The whole blood sample is placed in heparinized
eppendorf tubes and kept on wet ice until centrifuged (4 min @
14,000 rpm). Plasma is transferred to 96 deep-well block on dry ice
and stored at -20.degree. C. Immediately following blood
collection, 2 ml of sterile PBS (phosphate buffered saline) was
injected into the peritoneal cavity with a 25G needle. The abdomen
was gently massaged, and a small incision was made to allow access
to the peritoneal cavity. The peritoneal wash fluid was collected
using sterile technique, serially diluted 1:10, plated on blood
agar plates, and incubated overnight at 35.degree. C.
[0596] Spleens were harvested and placed in 1 ml sterile PBS in
Stomacher bag and homogenized with MicroBiomaster80 (Brinkmann) for
60 seconds, normal setting and 1:10 dilutions were made. 25 ul of
each dilution, as well as the homogenate, was plated on blood agar
plates and incubated at 35.degree. C. to determine the CFU/mL over
the time course. After overnight incubation, colonies were
counted.
Other Animal Models
[0597] Similarly, other animal infection models can be used for
hospital acquired pneumonia (HAP)/ ventilator acquired pneumonia
(VAP), complicated urinary tract infections (cUTI), and febrile
neutropenia.
5. Formulation and Administration
[0598] The compositions and methods of the present invention can be
practiced by delivering the compounds of the present invention
using a means for delivery e.g., any suitable carrier. The dose of
active compound, mode of administration and use of suitable carrier
will depend upon the intended patient or subject and the targeted
microorganism, e.g., the target bacterial organism. The
formulations, both for human medical use and veterinary use, of
compounds according to the present invention typically include such
compounds in association with a pharmaceutically acceptable
carrier.
[0599] The carrier(s) should be "acceptable" in the sense of being
compatible with compounds of the present invention and not
deleterious to the recipient. Pharmaceutically acceptable carriers,
in this regard, are intended to include any and all solvents,
dispersion media, coatings, absorption delaying agents, and the
like, compatible with pharmaceutical administration. The use of
such media and agents for pharmaceutically active substances is
known in the art. Except insofar as any conventional media or agent
is incompatible with the active compound, use thereof in the
compositions is contemplated. Supplementary active compounds
(identified or designed according to the invention and/or known in
the art) also can be incorporated into the compositions. The
formulations can conveniently be presented in dosage unit form and
can be prepared by any of the methods well known in the art of
pharmacy/microbiology. In general, some formulations are prepared
by bringing the compound into association with a liquid carrier or
a finely divided solid carrier or both, and then, if necessary,
shaping the product into the desired formulation.
[0600] A pharmaceutical composition of the invention should be
formulated to be compatible with its intended route of
administration. Solutions or suspensions can include the following
components: a sterile diluent such as water, saline solution, fixed
oils, polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or sodium
bisulfite; chelating agents such as ethylenediaminetetraacetic
acid; buffers such as acetates, citrates or phosphates and agents
for the adjustment of tonicity such as sodium chloride or dextrose.
The pH can be adjusted with acids or bases, such as hydrochloric
acid or sodium hydroxide.
[0601] A wide variety of formulations and administration methods,
including, e.g., intravenous formulations and administration
methods can be found in S. K. Niazi, ed., Handbook of
Pharmaceutical Formulations, Vols. 1-6 [Vol. 1 Compressed Solid
Products, Vol. 2 Uncompressed Drug Products, Vol. 3 Liquid
Products, Vol. 4 Semi-Solid Products, Vol. 5 Over the Counter
Products, and Vol. 6 Sterile Products], CRC Press, Apr. 27,
2004.
[0602] Useful solutions for oral or parenteral administration can
be prepared by any of the methods well known in the pharmaceutical
art, described, for example, in Remington's Pharmaceutical
Sciences, 18th ed. (Mack Publishing Company, 1990). Formulations
for parenteral administration can also include glycocholate for
buccal administration, methoxysalicylate for rectal administration,
or citric acid for vaginal administration. The parenteral
preparation can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass or plastic. Suppositories for
rectal administration also can be prepared by mixing the drug with
a non-irritating excipient such as cocoa butter, other glycerides,
or other compositions which are solid at room temperature and
liquid at body temperatures.
[0603] Formulations also can include, for example, polyalkylene
glycols such as polyethylene glycol, oils of vegetable origin, and
hydrogenated naphthalenes. Formulations for direct administration
can include glycerol and other compositions of high viscosity.
Other potentially useful parenteral carriers for these drugs
include ethylene-vinyl acetate copolymer particles, osmotic pumps,
implantable infusion systems, and liposomes. Formulations for
inhalation administration can contain as excipients, for example,
lactose, or can be aqueous solutions containing, for example,
polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or
oily solutions for administration in the form of nasal drops, or as
a gel to be applied intranasally. Retention enemas also can be used
for rectal delivery.
[0604] Formulations of the present invention suitable for oral
administration can be in the form of: discrete units such as
capsules, gelatin capsules, sachets, tablets, troches, or lozenges,
each containing a predetermined amount of the drug; a powder or
granular composition; a solution or a suspension in an aqueous
liquid or non-aqueous liquid; or an oil-in-water emulsion or a
water-in-oil emulsion. The drug can also be administered in the
form of a bolus, electuary or paste. A tablet can be made by
compressing or molding the drug optionally with one or more
accessory ingredients. Compressed tablets can be prepared by
compressing, in a suitable machine, the drug in a free-flowing form
such as a powder or granules, optionally mixed by a binder,
lubricant, inert diluent, surface active or dispersing agent.
Molded tablets can be made by molding, in a suitable machine, a
mixture of the powdered drug and suitable carrier moistened with an
inert liquid diluent.
[0605] Oral compositions generally include an inert diluent or an
edible carrier. For the purpose of oral therapeutic administration,
the active compound can be incorporated with excipients. Oral
compositions prepared using a fluid carrier for use as a mouthwash
include the compound in the fluid carrier and are applied orally
and swished and expectorated or swallowed. Pharmaceutically
compatible binding agents, and/or adjuvant materials can be
included as part of the composition. The tablets, pills, capsules,
troches and the like can contain any of the following ingredients,
or compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose; a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate or Sterotes;
a glidant such as colloidal silicon dioxide; a sweetening agent
such as sucrose or saccharin; or a flavoring agent such as
peppermint, methyl salicylate, or orange flavoring.
[0606] Pharmaceutical compositions suitable for injectable use
include sterile aqueous solutions (where water soluble) or
dispersions and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersion. For intravenous
administration, suitable carriers include physiological saline,
bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or
phosphate buffered saline (PBS). It should be stable under the
conditions of manufacture and storage and should be preserved
against the contaminating action of microorganisms such as bacteria
and fungi. The carrier can be a solvent or dispersion medium
containing, for example, water, ethanol, polyol (for example,
glycerol, propylene glycol, and liquid polyetheylene glycol), and
suitable mixtures thereof. The proper fluidity can be maintained,
for example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and by the use of surfactants. In many cases, it will be preferable
to include isotonic agents, for example, sugars, polyalcohols such
as manitol, sorbitol, sodium chloride in the composition. Prolonged
absorption of the injectable compositions can be brought about by
including in the composition an agent which delays absorption, for
example, aluminum monostearate and gelatin.
[0607] Sterile injectable solutions can be prepared by
incorporating the active compound in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filter sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle which contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, methods of preparation include vacuum
drying and freeze-drying which yields a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered solution thereof.
[0608] Formulations suitable for intra-articular administration can
be in the form of a sterile aqueous preparation of the drug that
can be in microcrystalline form, for example, in the form of an
aqueous microcrystalline suspension. Liposomal formulations or
biodegradable polymer systems can also be used to present the drug
for both intra-articular and ophthalmic administration.
[0609] Formulations suitable for topical administration, including
eye treatment, include liquid or semi-liquid preparations such as
liniments, lotions, gels, applicants, oil-in-water or water-in-oil
emulsions such as creams, ointments or pastes; or solutions or
suspensions such as drops. Formulations for topical administration
to the skin surface can be prepared by dispersing the drug with a
dermatologically acceptable carrier such as a lotion, cream,
ointment or soap. Useful are carriers capable of forming a film or
layer over the skin to localize application and inhibit removal.
For topical administration to internal tissue surfaces, the agent
can be dispersed in a liquid tissue adhesive or other substance
known to enhance adsorption to a tissue surface. For example,
hydroxypropylcellulose or fibrinogen/thrombin solutions can be used
to advantage. Alternatively, tissue-coating solutions, such as
pectin-containing formulations can be used.
[0610] For inhalation treatments, inhalation of powder
(self-propelling or spray formulations) dispensed with a spray can,
a nebulizer, or an atomizer can be used. Such formulations can be
in the form of a fine powder for pulmonary administration from a
powder inhalation device or self-propelling powder-dispensing
formulations. In the case of self-propelling solution and spray
formulations, the effect can be achieved either by choice of a
valve having the desired spray characteristics (i.e., being capable
of producing a spray having the desired particle size) or by
incorporating the active ingredient as a suspended powder in
controlled particle size. For administration by inhalation, the
compounds also can be delivered in the form of an aerosol spray
from pressured container or dispenser which contains a suitable
propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
[0611] Systemic administration also can be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants generally are known in the art,
and include, for example, for transmucosal administration,
detergents and bile salts. Transmucosal administration can be
accomplished through the use of nasal sprays or suppositories. For
transdermal administration, the active compounds typically are
formulated into ointments, salves, gels, or creams as generally
known in the art.
[0612] The active compounds can be prepared with carriers that will
protect the compound against rapid elimination from the body, such
as a controlled release formulation, including implants and
microencapsulated delivery systems. Biodegradable, biocompatible
polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art. Liposomal suspensions can
also be used as pharmaceutically acceptable carriers. These can be
prepared according to methods known to those skilled in the art,
for example, as described in U.S. Pat. No. 4,522,811.
[0613] Oral or parenteral compositions can be formulated in dosage
unit form for ease of administration and uniformity of dosage.
Dosage unit form refers to physically discrete units suited as
unitary dosages for the subject to be treated; each unit containing
a predetermined quantity of active compound calculated to produce
the desired therapeutic effect in association with the required
pharmaceutical carrier. The specification for the dosage unit forms
of the invention are dictated by and directly dependent on the
unique characteristics of the active compound and the therapeutic
effect to be achieved, and the limitations inherent in the art of
compounding such an active compound for the treatment of
individuals. Furthermore, administration can be by periodic
injections of a bolus, or can be made more continuous by
intravenous, intramuscular or intraperitoneal administration from
an external reservoir (e.g., an intravenous bag).
[0614] Where adhesion to a tissue surface is desired the
composition can include the drug dispersed in a fibrinogen-thrombin
composition or other bioadhesive. The compound then can be painted,
sprayed or otherwise applied to the desired tissue surface.
Alternatively, the drugs can be formulated for parenteral or oral
administration to humans or other mammals, for example, in
effective amounts, e.g., amounts that provide appropriate
concentrations of the drug to target tissue for a time sufficient
to induce the desired effect.
[0615] Where the active compound is to be used as part of a
transplant procedure, it can be provided to the living tissue or
organ to be transplanted prior to removal of tissue or organ from
the donor. The compound can be provided to the donor host.
Alternatively or, in addition, once removed from the donor, the
organ or living tissue can be placed in a preservation solution
containing the active compound. In all cases, the active compound
can be administered directly to the desired tissue, as by injection
to the tissue, or it can be provided systemically, either by oral
or parenteral administration, using any of the methods and
formulations described herein and/or known in the art. Where the
drug comprises part of a tissue or organ preservation solution, any
commercially available preservation solution can be used to
advantage. For example, useful solutions known in the art include
Collins solution, Wisconsin solution, Belzer solution, Eurocollins
solution and lactated Ringer's solution.
[0616] In conjunction with the methods of the present invention,
pharmacogenomics (i.e., the study of the relationship between an
individual's genotype and that individual's response to a foreign
compound or drug) can be considered. Differences in metabolism of
therapeutics can lead to severe toxicity or therapeutic failure by
altering the relation between dose and blood concentration of the
pharmacologically active drug. Thus, a physician or clinician can
consider applying knowledge obtained in relevant pharmacogenomics
studies in determining whether to administer a drug as well as
tailoring the dosage and/or therapeutic regimen of treatment with
the drug.
[0617] Generally, an effective amount of dosage of active compound
will be in the range of from about 0.1 to about 100 mg/kg of body
weight/day, more preferably from about 1.0 to about 50 mg/kg of
body weight/day. The amount administered will also likely depend on
such variables as the type of surgery or invasive medical
procedure, the overall health status of the patient, the relative
biological efficacy of the compound delivered, the formulation of
the drug, the presence and types of excipients in the formulation,
and the route of administration. Also, it is to be understood that
the initial dosage administered can be increased beyond the above
upper level in order to rapidly achieve the desired blood-level or
tissue level, or the initial dosage can be smaller than the
optimum.
[0618] Nonlimiting doses of active compound comprise from about 0.1
to about 1500 mg per dose. Nonlimiting examples of doses, which can
be formulated as a unit dose for convenient administration to a
patient include: about 25 mg, about 50 mg, about 75 mg, about 100
mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about
225 mg, about 250 mg, about 275 mg, about 300 mg, about 325, about
350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg,
about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575
mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg about
700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg,
about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925
mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about
1050, mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150
mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg,
about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about
1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475
mg, and about 1500 mg. The foregoing doses are useful for
administering the compounds of the present invention according to
the methods of the present invention.
[0619] As is understood by one of ordinary skill in the art,
generally, when dosages are described for a pharmaceutical active,
the dosage is given on the basis of the parent or active moiety.
Therefore, if a salt, hydrate, or another form of the parent or
active moiety is used, a corresponding adjustment in the weight of
the compound is made, although the dose is still referred to on the
basis of the parent or active moiety delivered. As a nonlimiting
example, if the parent or active moiety of interest is a
monocarboxylic acid having a molecular weight of 250, and if the
monosodium salt of the acid is desired to be delivered to be
delivered at the same dosage, then an adjustment is made
recognizing that the monosodium salt would have a molecular weight
of approximately 272 (i.e. minus 1H or 1.008 atomic mass units and
plus 1 Na or 22.99 atomic mass units). Therefore, a 250 mg dosage
of the parent or active compound would correspond to about 272 mg
of the monosodium salt, which would also deliver 250 mg of the
parent or active compound. Said another way, about 272 mg of the
monosodium salt would be equivalent to a 250 mg dosage of the
parent or active compound.
Formulation Examples
I. Formulation for Intravenous Administration
TABLE-US-00003 [0620] Ingredients Amount Antimicrobial Compound
0.1-1500 total mg of the present invention Dextrose, USP 50 mg/ml
Sodium citrate, USP 1.60-1.75 mg/ml Citric Acid, USP 0.80-0.90
mg/ml Water, USP q.s
This formulation for intravenous administration is formulated by
heating water for injection to about 60.degree. C. Next the sodium
citrate, citric acid and dextrose are added and stirred until
dissolved. A solution or aqueous slurry of the antimicrobial
compound is added to the previous mixture and stirred until
dissolved. The mixture is cooled to 25.degree. C. with stirring.
The pH is measured and adjusted if necessary. Lastly the mixture is
brought to the desired volume, if necessary, with water for
injection. The mixture is filtered, filled into the desired
container (vial, syringe, infusion container, etc.), over wrapped
and terminally moist heat sterilized.
[0621] This formulation is useful for intravenous administration,
either bolus or infusion, to a patient for treating, preventing, or
reducing the risk of infection.
II. Lyophilisate for Reconstitution
[0622] Alternatively, the antimicrobial compound can be provided as
a lyophilisate which can be reconstituted before intravenous or
intramuscular administration.
TABLE-US-00004 Ingredient mg per injection vial Antimicrobial
Compound 0.1-1500 of the present invention Cyclodextin 1500
[0623] Reconstitution solution for a volume to be administered of
50 ml (infusion): 5% aqueous glucose solution. [0624]
Reconstitution solution for a volume to be administered of 15 ml
(bolus): 3.3% aqueous glucose solution.
[0625] The foregoing lyophilisate is useful for reconstitution and
intravenous administration, either bolus or infusion, to a patient
for treating, preventing, or reducing the risk of infection.
III. Lyophilisate for Reconstitution
TABLE-US-00005 [0626] Ingredient mg per injection vial
Antimicrobial Compound 0.1 -1500 of the present invention soya
lecithin 2250 Sodium cholate 1500
[0627] Reconstitution solution for a volume to be administered of
50 ml (infusion): 4% aqueous glucose solution. [0628]
Reconstitution solution for a volume to be administered of 15 ml
(bolus): 2% aqueous glucose solution
[0629] The foregoing lyophilisate is useful for reconstitution and
intravenous administration, either bolus or infusion, to a patient
for treating, preventing, or reducing the risk of infection.
IV. Lyophilisate for Reconstitution
TABLE-US-00006 [0630] Ingredient mg per injection vial
Antimicrobial Compound 0.1-1500 of the present invetnion soya
lecithin 900 Sodium glycocholate 540
[0631] Reconstitution solution for a volume to be administered of
15 ml (bolus): 3.3% aqueous glucose solution.
[0632] The foregoing lyophilisate is useful for reconstitution and
intravenous administration, either bolus or infusion, to a patient
for treating, preventing, or reducing the risk of infection.
V. Tablet for Oral Administration
TABLE-US-00007 [0633] Ingredients Per Tablet Per 4000 Tablets
Antimicrobial Compound 0.1-1500 mg 0.4-6000 g of the present
invention Anhydrous Lactose, NF 110.45 mg 441.8 g Microcrystalline
80.0 mg 320.0 g Cellulose NF Magnesium Stearate 1.00 mg 4.0 g
Impalpable Powder NF Croscarmellose Sodium 2.00 mg 8.0 g NF Type
A
The antimicrobial compound (any of the compounds equivalent to the
desired delivery strength, e.g., 50 to 1500 mg per tablet) is
premixed with 1/3 of the microcrystalline cellulose NF and 1/2 of
the anhydrous lactose NF in a ribbon blender for 5 minutes at 20
RPM. To the premix is added the remaining 2/3 of the
microcrystalline cellulose NF and the remaining 1/2 of the
anhydrous lactose NF. This is blended for 10 minutes at 20 RPM.
Crosscarmellose sodium is added to the blended powders and mixed
for 5 minutes at 20 RPM. Finally the magnesium stearate is added to
the mixture by passing through a 90 mesh screen and blended for an
additional 5 minutes at 20 RPM. The lubricated mixture is
compressed to provide tablets of 500 mg active ingredient.
[0634] These tablets are useful for oral administration to a
patient for treating, prevention, or reducing the risk of
infection.
6. Examples
[0635] Nuclear magnetic resonance (NMR) spectra were obtained on a
Bruker Avance 300 or Avance 500 spectrometer, or in some cases a
GENicolet 300 spectrometer. Common reaction solvents were either
high performance liquid chromatography (HPLC) grade or American
Chemical Society (ACS) grade, and anhydrous as obtained from the
manufacturer unless otherwise noted. "Chromatography" or "purified
by silica gel" refers to flash column chromatography using silica
gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise
noted.
[0636] The compounds or tautomers thereof, or pharmaceutically
acceptable salts, esters or prodrugs of said compounds or tautomers
of the present invention can be prepared using known chemical
transformations adapted to the particular situation at hand.
[0637] Some of the abbreviations used in the following experimental
details of the synthesis of the examples are defined below: h or
hr=hour(s); min=minute(s); mol=mole(s); mmol=millimole(s); M=molar;
.mu.M=micromolar; g=gram(s); .mu.g=microgram(s); rt=room
temperature; L=liter(s); mL=milliliter(s); Et.sub.2O=diethyl ether;
THF=tetrahydrofuran; DMSO=dimethyl sulfoxide; EtOAc=ethyl acetate;
Et.sub.3N=triethylamine; i-Pr.sub.2NEt or
DIPEA=diisopropylethylamine; CH.sub.2Cl.sub.2=methylene chloride;
CHCl.sub.3=chloroform; CDCl.sub.3=deuterated chloroform;
CCl.sub.4=carbon tetrachloride; MeOH=methanol;
CD.sub.3OD=deuterated methanol; EtOH=ethanol;
DMF=dimethylformamide; BOC=t-butoxycarbonyl; CBZ=benzyloxycarbonyl;
TBS=t butyldimethylsilyl; TBSCl=t-butyldimethylsilyl chloride;
TFA=trifluoroacetic acid; DBU=diazabicycloundecene;
TBDPSCl=t-butyldiphenylchlorosilane; Hunig's
Base=N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine;
CuI=copper (I) iodide; MsCl=methanesulfonyl chloride;
NaN.sub.3=sodium azide; Na.sub.2SO.sub.4=sodium sulfate;
NaHCO.sub.3=sodium bicarbonate; NaOH=sodium hydroxide;
MgSO.sub.4=magnesium sulfate; K.sub.2CO.sub.3=potassium carbonate;
KOH=potassium hydroxide; NH.sub.4OH=ammonium hydroxide;
NH.sub.4Cl=ammonium chloride; SiO.sub.2=silica; PdC=palladium on
carbon;
Pd(dppf)Cl.sub.2=dichloro[1,1'-bis(diphenylphosphino)ferrocene]
palladium (II).
[0638] Exemplary compounds synthesized in accordance with the
invention are listed in Table 1, Table 2, Table 2a and Table 2aa. A
bolded or dashed bond is shown to indicate a particular
stereochemistry at a chiral center, whereas a wavy bond indicates
that the substituent can be in either orientation or that the
compound is a mixture thereof It should also be known that in the
interest of conserving space, the chemical structures of some
compounds have been split into two parts with the two points of
connection each being indicated by a bond crossed by a wavy line.
See, e.g. compound 1, which was drawn in two parts as:
##STR00224##
but corresponds to the complete chemical structure:
##STR00225##
[0639] The compounds of the present invention can be prepared,
formulated, and delivered as salts, esters, and prodrugs. For
convenience, the compounds are generally shown without indicating a
particular salt, ester, or prodrug form.
[0640] Compounds of the present invention are shown in Table 1,
Table 2, Table 2a, and Table 2aa. LCMS (liquid chromatography mass
spectral) data are provided, where available. When data is not
available this is indicated by "NA". The LCMS data are provided
using the convention for m/z in the format, [M+H].sub.+, except
where otherwise indicated.
TABLE-US-00008 TABLE 1 Comp. No. Structure LCMS 1 ##STR00226##
543.1 ##STR00227## 2 ##STR00228## 563.1 ##STR00229## 3 ##STR00230##
531.1 ##STR00231## 4 ##STR00232## 542.1 ##STR00233## 5 ##STR00234##
505.2 ##STR00235## 6 ##STR00236## 541.1 ##STR00237## 7 ##STR00238##
523.1 ##STR00239## 8 ##STR00240## 589.1 ##STR00241## 9 ##STR00242##
501.1 ##STR00243## 10 ##STR00244## 555.1 11 ##STR00245## 561.1
##STR00246## 12 ##STR00247## 589.1 ##STR00248## 13 ##STR00249##
628.2 ##STR00250## 14 ##STR00251## 517.1 ##STR00252## 15
##STR00253## 555.1 ##STR00254## 16 ##STR00255## 621.1 ##STR00256##
17 ##STR00257## 569.1 ##STR00258## 18 ##STR00259## 527.2
##STR00260## 19 ##STR00261## 585.1 ##STR00262## 20 ##STR00263##
627.2 ##STR00264## 21 ##STR00265## 586.1 ##STR00266## 22
##STR00267## 593.1 ##STR00268## 23 ##STR00269## 539.1 ##STR00270##
24 ##STR00271## 507.1 ##STR00272## 25 ##STR00273## 585.1
##STR00274## 26 ##STR00275## 558.3 ##STR00276## 27 ##STR00277##
569.2 ##STR00278## 28 ##STR00279## 628.1 ##STR00280## 29
##STR00281## 571.2 ##STR00282## 30 ##STR00283## 607.1 ##STR00284##
31 ##STR00285## 599.1 ##STR00286## 32 ##STR00287## 549.1
##STR00288## 33 ##STR00289## 565.1 ##STR00290## 34 ##STR00291##
585.1 ##STR00292## 35 ##STR00293## 585.1 ##STR00294## 36
##STR00295## 573.0 ##STR00296## 37 ##STR00297## 539.0 ##STR00298##
38 ##STR00299## 581.1 ##STR00300## 39 ##STR00301## 589.0
##STR00302## 40 ##STR00303## 541.1 ##STR00304## 41 ##STR00305##
544.4 ##STR00306## 42 ##STR00307## 587.1 ##STR00308## 43
##STR00309## 666.9 ##STR00310## 44 ##STR00311## 601.1 ##STR00312##
45 ##STR00313## 659.0 ##STR00314## 46 ##STR00315## 529.1
##STR00316## 47 ##STR00317## 631.1 ##STR00318## 48 ##STR00319##
580.0 ##STR00320## 49 ##STR00321## 545.0 ##STR00322## 50
##STR00323## 571.1 ##STR00324## 51 ##STR00325## 537.0 ##STR00326##
52 ##STR00327## 607.1 ##STR00328## 53 ##STR00329## 541.1
##STR00330## 54 ##STR00331## 523.1 ##STR00332## 55 ##STR00333##
554.1 ##STR00334## 56 ##STR00335## 596.1 ##STR00336## 57
##STR00337## ##STR00338## 58 ##STR00339## 589.0 ##STR00340## 59
##STR00341## 553.0 ##STR00342## 60 ##STR00343## 558.1 ##STR00344##
61 ##STR00345## 564.3 ##STR00346## 62 ##STR00347## 555.1
##STR00348## 63 ##STR00349## 535.0 ##STR00350## 64 ##STR00351##
589.0 ##STR00352## 65 ##STR00353## 605.0 ##STR00354## 66
##STR00355## 474.1 ##STR00356## 67 ##STR00357## 553.1 ##STR00358##
68 ##STR00359## 605.3 ##STR00360## 69 ##STR00361## 601.0
##STR00362## 70 ##STR00363## 587.1 ##STR00364## 71 ##STR00365##
557.0 ##STR00366## 72 ##STR00367## ##STR00368## 73 ##STR00369##
519.1 ##STR00370## 74 ##STR00371## 561.1 ##STR00372## 75
##STR00373## 587.0 ##STR00374## 76 ##STR00375## 587 ##STR00376## 77
##STR00377## 547.1 ##STR00378## 78 ##STR00379## 543.1 ##STR00380##
79 ##STR00381## 503.2 ##STR00382## 80 ##STR00383## 573.1
##STR00384## 81 ##STR00385## 539.0 ##STR00386## 82 ##STR00387##
508.0 ##STR00388## 83 ##STR00389## 535.1 ##STR00390## 84
##STR00391## 523.0 ##STR00392## 85 ##STR00393## 585.1 ##STR00394##
86 ##STR00395## 599.1 ##STR00396## 87 ##STR00397## 603.3
##STR00398## 88 ##STR00399## 587.0 ##STR00400## 89 ##STR00401##
585.0 ##STR00402## 90 ##STR00403## 589.1 ##STR00404## 91
##STR00405## 539.0 ##STR00406## 92 ##STR00407## 621.0 ##STR00408##
93 ##STR00409## 585.1 ##STR00410## 94 ##STR00411## 585.5
##STR00412## 95 ##STR00413## 583.5 ##STR00414## 96 ##STR00415##
611.0 ##STR00416## 97 ##STR00417## 557.0 ##STR00418## 98
##STR00419## 539.0 ##STR00420## 99 ##STR00421## 587.1 ##STR00422##
100 ##STR00423## 583.1 ##STR00424## 101 ##STR00425## 587.1
##STR00426## 102 ##STR00427## 585.0 ##STR00428## 103 ##STR00429##
569.0 ##STR00430## 104 ##STR00431## 599.0 ##STR00432## 105
##STR00433## 553.1 ##STR00434## 106 ##STR00435## 519.1 ##STR00436##
107 ##STR00437## 589.0 ##STR00438## 108 ##STR00439## 535.1
##STR00440## 109 ##STR00441## 535.1 ##STR00442## 110 ##STR00443##
553.1 ##STR00444## 111 ##STR00445## 573.1 ##STR00446## 112
##STR00447## 607.1 ##STR00448## 113 ##STR00449## 519.1 ##STR00450##
114 ##STR00451## 546.0 ##STR00452## 115 ##STR00453## 566.1
##STR00454## 116 ##STR00455## 545.0 ##STR00456## 117 ##STR00457##
533.0 ##STR00458## 118 ##STR00459## 546.0 ##STR00460## 119
##STR00461## 553.1 ##STR00462## 120 ##STR00463## 546.1 ##STR00464##
121 ##STR00465## 546.0 ##STR00466## 122 ##STR00467## 530.1
##STR00468## 123 ##STR00469## 515.1 ##STR00470## 124 ##STR00471##
##STR00472## 125 ##STR00473## 567.0
##STR00474## 126 ##STR00475## 613.1 ##STR00476## 127 ##STR00477##
613.1 ##STR00478## 128 ##STR00479## 553.1 ##STR00480## 129
##STR00481## 552.9 ##STR00482## 130 ##STR00483## 533.1 ##STR00484##
131 ##STR00485## 599.0 ##STR00486## 132 ##STR00487## 553.0
##STR00488## 133 ##STR00489## 519.0 ##STR00490## 134 ##STR00491##
526.1 ##STR00492## 135 ##STR00493## 533.1 ##STR00494## 136
##STR00495## 531.0 ##STR00496## 137 ##STR00497## 597.0 ##STR00498##
138 ##STR00499## 579.0 ##STR00500## 139 ##STR00501## 571.0
##STR00502## 140 ##STR00503## 589.0 ##STR00504## 141 ##STR00505##
529.0 ##STR00506## 142 ##STR00507## 589.0 ##STR00508## 143
##STR00509## 511.0 ##STR00510## 144 ##STR00511## 576.1 ##STR00512##
145 ##STR00513## ##STR00514## 146 ##STR00515## 611.1 ##STR00516##
147 ##STR00517## 519.1 ##STR00518## 148 ##STR00519## 525.0
##STR00520## 149 ##STR00521## 555.0 ##STR00522## 192 ##STR00523##
194 ##STR00524## 195 ##STR00525## 196 ##STR00526## 197 ##STR00527##
198 ##STR00528## 199 ##STR00529## 200 ##STR00530## 201 ##STR00531##
202 ##STR00532## 203 ##STR00533## 204 ##STR00534## 205 ##STR00535##
206 ##STR00536## 207 ##STR00537## 208 ##STR00538## 209 ##STR00539##
210 ##STR00540## 211 ##STR00541## 212 ##STR00542## 569.0
##STR00543## 213 ##STR00544## 568.1 ##STR00545## 214 ##STR00546##
587.1 ##STR00547## 215 ##STR00548## 642.3 ##STR00549## 216
##STR00550## 601.0 ##STR00551## 217 ##STR00552## 549.1 ##STR00553##
218 ##STR00554## 573.0 ##STR00555## 219 ##STR00556## 533.1
##STR00557## 220 ##STR00558## 637.0 ##STR00559## 221 ##STR00560##
570.1 ##STR00561## 222 ##STR00562## 569.0 ##STR00563## 223
##STR00564## 565.0 ##STR00565## 224 ##STR00566## 541.0 ##STR00567##
225 ##STR00568## 591.0 ##STR00569## 226 ##STR00570## 589.0 [M]
##STR00571## 227 ##STR00572## 624.1 ##STR00573## 228 ##STR00574##
525.0 ##STR00575## 229 ##STR00576## 599.1 ##STR00577## 230
##STR00578## 599.0 ##STR00579## 231 ##STR00580## ##STR00581## 232
##STR00582## 657.0 ##STR00583## 233 ##STR00584## 583.1 ##STR00585##
234 ##STR00586## 567.2 ##STR00587## 235 ##STR00588## 601.0
##STR00589## 236 ##STR00590## 583.0 ##STR00591## 237 ##STR00592##
567.1 ##STR00593## 238 ##STR00594## 587.0 ##STR00595## 239
##STR00596## 587.0 ##STR00597## 240 ##STR00598## 587.0
##STR00599## 241 ##STR00600## 571.0 ##STR00601## 242 ##STR00602##
555.0 ##STR00603## 243 ##STR00604## 567.0 ##STR00605## 244
##STR00606## 587.1 ##STR00607## 245 ##STR00608## 549.1 ##STR00609##
246 ##STR00610## 585.1 ##STR00611## 247 ##STR00612## 615.1
##STR00613## 248 ##STR00614## 569.1 ##STR00615## 249 ##STR00616##
569.1 ##STR00617## 250 ##STR00618## 584.3 ##STR00619## 251
##STR00620## 613.1 ##STR00621## 252 ##STR00622## 587.0 ##STR00623##
253 ##STR00624## ##STR00625## 254 ##STR00626## ##STR00627## 255
##STR00628## ##STR00629## 256 ##STR00630## ##STR00631## 257
##STR00632## ##STR00633## 258 ##STR00634## ##STR00635## 259
##STR00636## ##STR00637## 260 ##STR00638## ##STR00639## 261
##STR00640## 577.1 ##STR00641## 262 ##STR00642## 601.1 ##STR00643##
263 ##STR00644## 556.1 ##STR00645## 264 ##STR00646## 613.2
##STR00647## 265 ##STR00648## 585.1 ##STR00649## 266 ##STR00650##
549.1 ##STR00651## 267 ##STR00652## 539.1 ##STR00653## 268
##STR00654## 553.3 ##STR00655## 269 ##STR00656## 567.3 ##STR00657##
270 ##STR00658## ##STR00659## 271 ##STR00660## ##STR00661## 272
##STR00662## ##STR00663## 273 ##STR00664## ##STR00665## 274
##STR00666## 602.2 ##STR00667## 275 ##STR00668## 588.2 ##STR00669##
276 ##STR00670## 625.0 [M/2] + 1 ##STR00671## 277 ##STR00672##
314.4 [M + 1]/2 ##STR00673## 278 ##STR00674## ##STR00675## 279
##STR00676## ##STR00677## 280 ##STR00678## ##STR00679## 281
##STR00680## 310.3 [M + 2H]/2 ##STR00681## 282 ##STR00682## 317.2
[M + 2H]/2 ##STR00683## 283 ##STR00684## 563.1 ##STR00685## 284
##STR00686## 605.1 ##STR00687## 285 ##STR00688## 591.1 ##STR00689##
286 ##STR00690## 603.0 ##STR00691## 287 ##STR00692## 583.0
##STR00693## 288 ##STR00694## 635.2 ##STR00695## 289 ##STR00696##
649.1 ##STR00697## 290 ##STR00698## 597.0 ##STR00699## 291
##STR00700## 553.1 ##STR00701## 292 ##STR00702## 567.2 ##STR00703##
293 ##STR00704## 623.2 ##STR00705## 294 ##STR00706## 615.1
##STR00707## 295 ##STR00708## 567.1 ##STR00709## 296 ##STR00710##
581.1 ##STR00711## 297 ##STR00712## 585.1 ##STR00713## 298
##STR00714## 581.1 ##STR00715## 299 ##STR00716## 599.1 ##STR00717##
300 ##STR00718## 561.4 ##STR00719## 301 ##STR00720## 547.1
##STR00721## 302 ##STR00722## 629.1 ##STR00723## 303 ##STR00724##
615.1
##STR00725## 304 ##STR00726## 629.1 ##STR00727## 305 ##STR00728##
583.0 ##STR00729## 306 ##STR00730## 583.1 ##STR00731## 307
##STR00732## 613.1 (m/e) ##STR00733## 308 ##STR00734## 597.0
##STR00735## 309 ##STR00736## 597.0 ##STR00737## 310 ##STR00738##
627.4 (m/e) ##STR00739## 311 ##STR00740## 587.3 (m/e) ##STR00741##
312 ##STR00742## 551.1 (m/e) ##STR00743## 313 ##STR00744## 549.1
##STR00745## 314 ##STR00746## 571.2 ##STR00747## 315 ##STR00748##
585.1 ##STR00749## 316 ##STR00750## 617.0 ##STR00751## 317
##STR00752## 583.1 ##STR00753## 318 ##STR00754## 597.2 ##STR00755##
319 ##STR00756## 581.1 ##STR00757## 320 ##STR00758## 579.3
##STR00759## 321 ##STR00760## 619.8 ##STR00761## 322 ##STR00762##
585.3 ##STR00763## 323 ##STR00764## 571.3 ##STR00765## 324
##STR00766## 567.0 ##STR00767## 325 ##STR00768## 581.0 ##STR00769##
326 ##STR00770## 603.3 ##STR00771## 327 ##STR00772## 617.3
##STR00773## 328 ##STR00774## 565.5 ##STR00775## 329 ##STR00776##
579.1 ##STR00777## 330 ##STR00778## 543.3 ##STR00779## 331
##STR00780## 557.7 ##STR00781##
TABLE-US-00009 TABLE 2 Comp. No. Structure LCMS 150 ##STR00782##
689.0 151 ##STR00783## 543.0 152 ##STR00784## 587.0 153
##STR00785## 597.0 154 ##STR00786## 598.0 155 ##STR00787## 626.0
156 ##STR00788## 601.0 157 ##STR00789## 693.0 158 ##STR00790##
603.0 159 ##STR00791## 619.0 160 ##STR00792## 585.0 161
##STR00793## 590.0 162 ##STR00794## 652.0 163 ##STR00795## 522.0
164 ##STR00796## 613.0 165 ##STR00797## 522.0 166 ##STR00798##
522.0 167 ##STR00799## 538.0 168 ##STR00800## 633.0 169
##STR00801## 615.0 170 ##STR00802## 526.0 171 ##STR00803## 526.0
172 ##STR00804## 542.0 173 ##STR00805## 526.0 174 ##STR00806##
576.0 175 ##STR00807## 542.0 176 ##STR00808## 550.0 177
##STR00809## 576.0 178 ##STR00810## 538.0 179 ##STR00811## 538.0
180 ##STR00812## 537.0 181 ##STR00813## 548.0 182 ##STR00814##
550.0 183 ##STR00815## 592.0 184 ##STR00816## 548.0 185
##STR00817## 538.0 186 ##STR00818## 550.0 187 ##STR00819## 542.0
188 ##STR00820## 558.0 189 ##STR00821## 548.0 190 ##STR00822##
538.0 332 ##STR00823## 580.3
TABLE-US-00010 TABLE 2a Comp. No. Structure LCMS 333 ##STR00824##
552.0 334 ##STR00825## 566.0 335 ##STR00826## 516.0 336
##STR00827## 619.1 337 ##STR00828## 632.9 338 ##STR00829## 569.3
339 ##STR00830## 583.4 340 ##STR00831## 597.1 341 ##STR00832##
567.2 342 ##STR00833## 569.2 343 ##STR00834## 566.9 344
##STR00835## 603.1 345 ##STR00836## 617.1 346 ##STR00837## 621.4
347 ##STR00838## 695.5 348 ##STR00839## 581.0 349 ##STR00840##
581.0 350 ##STR00841## 595.0 351 ##STR00842## 536.1 352
##STR00843## 550.1 353 ##STR00844## 428.0 354 ##STR00845## 496.3
355 ##STR00846## 486.3 356 ##STR00847## 500.2 357 ##STR00848##
514.1 358 ##STR00849## 528.1 359 ##STR00850## 565.0 360
##STR00851## 579.0 361 ##STR00852## 541.4 362 ##STR00853## 595.4
363 ##STR00854## 555.2 364 ##STR00855## 609.1 365 ##STR00856##
569.0 366 ##STR00857## 552.0 367 ##STR00858## 584.0 368
##STR00859## 621.2 369 ##STR00860## 516.1 370 ##STR00861## 502.1
371 ##STR00862## 530.2 372 ##STR00863## 468.2 373 ##STR00864##
482.2 374 ##STR00865## 581.2 375 ##STR00866## 555.0 376
##STR00867## 569.0 377 ##STR00868## 647.5 378 ##STR00869## 554.6
379 ##STR00870## 568.1 380 ##STR00871## 615.1 381 ##STR00872##
629.5 382 ##STR00873## 567.1 383 ##STR00874## 622.3 384
##STR00875## 579.1 385 ##STR00876## 571.0 386 ##STR00877## 553.1
387 ##STR00878## 530.2 388 ##STR00879## 544.1 389 ##STR00880##
570.1 390 ##STR00881## 584.1 391 ##STR00882## 583.1 392
##STR00883## 581.3 393 ##STR00884## 555.2 394 ##STR00885## 598.1
395 ##STR00886## 581.0 396 ##STR00887## 581.1 397 ##STR00888##
587.6 398 ##STR00889## 601.7 399 ##STR00890## 550.1 400
##STR00891## 597.2 401 ##STR00892## 627.1 402 ##STR00893## 627.1
403 ##STR00894## 627.1 404 ##STR00895## 544.4 405 ##STR00896##
500.1 406 ##STR00897## 468.1 407 ##STR00898## 629.1 408
##STR00899## 561.4 409 ##STR00900## 550.0 410 ##STR00901## 569.1
411 ##STR00902## 553.1 412 ##STR00903## 641.0 413 ##STR00904##
593.1 414 ##STR00905## 579.1 415 ##STR00906## 595.1 416
##STR00907## 643.3 417 ##STR00908## 569.2 418 ##STR00909## 601.0
419 ##STR00910## 615.1 420 ##STR00911## 627.3 421 ##STR00912##
579.2 422 ##STR00913## 599.0 423 ##STR00914## 613.0 424
##STR00915## 631.2 425 ##STR00916## 581.1 426 ##STR00917## 595.1
427 ##STR00918## 611.2 428 ##STR00919## 550.1 429 ##STR00920##
595.1 430 ##STR00921## 609.1 431 ##STR00922## 575.0 432
##STR00923## 589.0 433 ##STR00924## 595.2 434 ##STR00925## 571.2
435 ##STR00926## 599.0 436 ##STR00927## 613.1 437 ##STR00928##
599.1 438 ##STR00929## 613.1 439 ##STR00930## 557.1 440
##STR00931## 641.0 441 ##STR00932## 557.0 442 ##STR00933## 543.1
443 ##STR00934## 557.1 444 ##STR00935## 543.1 445 ##STR00936##
583.1 446 ##STR00937## 557.1 447 ##STR00938## 575.1 448
##STR00939## 579.2 449 ##STR00940## 593.0 450 ##STR00941## 579.0
451 ##STR00942## 593.0 452 ##STR00943## 571.0 453 ##STR00944##
585.0 454 ##STR00945## 585.1 455 ##STR00946## 599.1
456 ##STR00947## 585.2 457 ##STR00948## 553.1 458 ##STR00949##
603.0 459 ##STR00950## 615.0 460 ##STR00951## 629.0 461
##STR00952## 569.1 462 ##STR00953## 551.1 463 ##STR00954## 537.0
464 ##STR00955## 551.1 465 ##STR00956## 537.1 466 ##STR00957##
603.1 467 ##STR00958## 529.1 468 ##STR00959## 543.1
TABLE-US-00011 TABLE 2aa Comp. No. Structure LCMS 469 ##STR00960##
573.1 ##STR00961## 470 ##STR00962## 551.1 ##STR00963## 471
##STR00964## 633.1 ##STR00965## 472 ##STR00966## 593.1 ##STR00967##
473 ##STR00968## 627.2 ##STR00969## 474 ##STR00970## 609.1
##STR00971## 475 ##STR00972## 579.1 ##STR00973## 476 ##STR00974##
613.1 ##STR00975## 477 ##STR00976## 627.2 ##STR00977## 478
##STR00978## 599.2 ##STR00979## 479 ##STR00980## 599.1 ##STR00981##
480 ##STR00982## 613.1 ##STR00983## 481 ##STR00984## 579.1
##STR00985## 482 ##STR00986## 595.1 ##STR00987## 483 ##STR00988##
569.3 ##STR00989## 484 ##STR00990## 583.1 ##STR00991## 485
##STR00992## 595.1 ##STR00993## 486 ##STR00994## 579.1 ##STR00995##
487 ##STR00996## 625.1 ##STR00997## 488 ##STR00998## 641.0
##STR00999## 489 ##STR01000## 611.1 ##STR01001## 490 ##STR01002##
627.1 ##STR01003## 491 ##STR01004## 673.2 ##STR01005## 492
##STR01006## 659.1 ##STR01007## 493 ##STR01008## 585.1 ##STR01009##
494 ##STR01010## 611.1 ##STR01011## 495 ##STR01012## 597.0
##STR01013## 496 ##STR01014## 627.1 ##STR01015## 497 ##STR01016##
613.0 ##STR01017## 498 ##STR01018## 659.2 ##STR01019## 499
##STR01020## 571.0 ##STR01021## 500 ##STR01022## 627.0 ##STR01023##
501 ##STR01024## 595.1 ##STR01025## 502 ##STR01026## 627.1
##STR01027## 503 ##STR01028## 645.1 ##STR01029## 504 ##STR01030##
306.9 [M + 1]/2 ##STR01031## 505 ##STR01032## 613.1 ##STR01033##
506 ##STR01034## 597.1 ##STR01035## 507 ##STR01036## 645.3
##STR01037## 508 ##STR01038## 707.1 ##STR01039##
[0641] In one embodiment, the invention is not the compound
selected from:
TABLE-US-00012 TABLE AA Z1 ##STR01040## Z2 ##STR01041## Z3
##STR01042## Z4 ##STR01043## Z5 ##STR01044## Z6 ##STR01045## Z7
##STR01046## Z8 ##STR01047## Z9 ##STR01048## Z10 ##STR01049## Z11
##STR01050## Z12 ##STR01051## Z13 ##STR01052## Z14 ##STR01053## Z15
##STR01054## Z16 ##STR01055## Z17 ##STR01056## Z18 ##STR01057## Z19
##STR01058## Z20 ##STR01059## Z21 ##STR01060## Z22 ##STR01061## Z23
##STR01062## Z24 ##STR01063## Z25 ##STR01064## Z26 ##STR01065## Z27
##STR01066##
[0642] The compounds of the present invention can be made using
synthetic chemical techniques well known to those of skill in the
art.
EXAMPLES
Example 1
Synthesis of Alkyne Intermediate
[0643] The alkyne intermediate can generally be synthesized
according to the scheme:
##STR01067##
Example 2
Synthesis of Pyrrolocytosines Compound 37 (R.sup.1.dbd.Cl,
R.sup.2.dbd.F) and Compound 91 (R.sup.1.dbd.F, R.sup.2.dbd.Cl)
##STR01068##
[0645] Compounds 37 and 91 can be synthesized according to the
scheme. Compound 37 can be synthesized according to the procedures
detailed below. Similar procedures can be used to synthesize
compound 91. Variables R.sup.1 and R.sup.2 in the scheme are not
the same as in the claims, and they are used in this scheme for
purposes of this particular example.
Synthesis of Compound 31 from 1,5-dibromo-2-chloro-3-fluoro-benzene
(2a)
[0646] A solution of 2,6-dibromo-3-chloro-4-fluoro-phenylamine (la,
4.85 g, 16 mmol, 1 eq.) in DMF (20 mL) was added to a solution of
isoamylnitrite (3.46 mL, 25.6 mmol, 1.6 eq.) in DMF (12 mL) at
70.degree. C. The mixture was heated at 70.degree. C. for 3 h
before it was cooled to room temperature, quenched with 1 N NaOH
aqueous solution (150 mL), and extracted with EtOAc (200 mL). The
EtOAc extract was washed with brine (100 mL.times.2), dried over
MgSO.sub.4, filtered and concentrated. The residue was purified by
flash chromatography (heptane) to give desired product 2a as
colorless oil (3.70 g, 80%).
Synthesis of [4-(3-bromo-4-chloro-5-fluoro-phenyl)-butyl]-carbamic
acid benzyl ester (3a):
[0647] A solution of but-3-enyl-carbamic acid benzyl ester (5.00 g,
24.36 mmol, 1 eq) in anhydrous toluene (60 mL) was cooled under
argon to 0-5.degree. C. 9-BBN (0.50 M, solution in THF; 54.6 mL,
26.80 mmol, 1.1 eq.) was added dropwise, and the mixture was
allowed to reach room temperature. After 24 h, the resulting
solution was added dropwise at room temperature to a mixture of 2a
(7.03 g, 24.36 mmol, 1 eq.), 1N NaOH/H.sub.2O (40 mL, 40 mmol, 1.6
eq.), and toluene (20 mL). The mixture was then degassed with argon
and Pd(PPh.sub.3).sub.4 (1.13 g, 0.98 mmol, 0.04 eq.) was added.
The mixture was rapidly stirred under argon at 60.degree. C. for 24
h, before cooling to room temperature. The mixture was partitioned
between EtOAc (150 mL) and brine (150 mL). The organic phase was
washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude product was purified by flash
chromatography on silica gel (0-50% EtOAc in Heptane) to afford 3a
as a colorless oil (3.54 g, 35%).
Synthesis of
[4-(4-chloro-3-fluoro-5-trimethylsilanylethynyl-phenyl)-butyl]-carbamic
acid benzyl ester (4a)
[0648] A mixture of 3a (4.78 g, 11.51 mmol, 1 eq.), CuI (175 mg,
0.92 mmol, 0.08 eq.), Pd(PPh.sub.3).sub.2Cl.sub.2 (323 mg, 0.46
mmol, 0.04 eq.) and DMF (30 mL) was degassed. Trimethsilylacetylene
(4.23 mL, 21.02 mmol, 2 eq.) was added under argon, followed by
Et.sub.3N (4.81 mL, 34.53 mmol, 3 eq.). The resulting mixture was
heated at 70.degree. C. for 24 h. After cooling to room
temperature, the reaction mixture was diluted with EtOAc (250 mL)
was washed with brine (150 mL.times.2 containing 15 mL 28%
NH.sub.4OH). The EtOAc solution was dried over MgSO.sub.4, filtered
and concentrated. The crude product was purified by flash
chromatography (0-50%, EtOAc in heptane) to afford 4a (4.50 g,
90%).
Synthesis of
[4-(4-Chloro-3-ethynyl-5-fluoro-phenyl)-butyl]-carbamic acid benzyl
ester (5a):
[0649] K.sub.2CO.sub.3 (2.76 g, 20 mmol, 2 eq.) was added to a
solution of 4a (4.50 g, 10.36 mmol, 1 eq.) in degassed MeOH (200
mL). The suspension was stirred at room temperature for 30 min.
before concentration. The residue was partitioned between EtOAc
(200 mL) and brine (200 mL). The EtOAc layer was separated and
washed further with brine (100 mL), dried over MgSO.sub.4, filtered
and concentrated. The crude product was purified by flash
chromatography (0-50%, EtOAc in heptane) to afford 5a as a
colorless oil (3.60 g, 96%).
Synthesis of 6a:
[0650] Intermediate 6a can generally be synthesized according to
the scheme:
##STR01069##
Synthesis of Compound 3b
[0651] Compound 2b (65.0 g, 373 mmol) was dissolved in ethanol (150
mL). The flask was purged with argon. Compound 1b (55.93 g, 373
mmol) was then added and the mixture was stirred at room
temperature for 2 h. The reaction solution was then added via
addition funnel, over 20 minutes, to a suspension of NaBH.sub.4
(14.18 g, 373 mmol) in toluene (150 mL), at 0.degree. C. The ice
bath was removed, and the resulting mixture was stirred at room
temperature for 3 h. 1N HCl (750 mL) was added to the solution, and
the mixture was stirred at room temperature for 30 min.
K.sub.2CO.sub.3 (205.9 g, 1.49 mol), Boc.sub.2O (81.41 g, 373
mmol), and THF (200 mL) were added to the solution, and stirred at
room temperature for 23 h. Reaction solution was partitioned
between EtOAc and 1:1 brine/H.sub.2O. The aqueous layer was washed
with EtOAc (2.times.300 mL). The combined organic layers were
washed with brine (500 mL); dried over Na.sub.2SO.sub.4; filtered,
and concentrated. The crude product was purified by Combi Flash
chromatography, in 3 portions, affording the product as a white
solid (119.43 g, 78%); .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
1.43 (bs, 18H), 1.63 (m, 2H), 2.95-3.30 (m, 4H), 4.45 (m, 2H), 5.93
(bs, 1H), 7.22 (bs, 1H), 7.34 (bs, 1H), 7.78 (d: 8Hz, 1H), 8.19 (d:
8Hz, 1H).
Synthesis Cf compound 5b
[0652] To a mixture of compound 3b (42.28 g, 103.5 mmol) and
compound 4b (24.54 g, 103.5 mmol) were added MeOH (3 L) and
H.sub.2O (750 mL). The mixture was stirred vigorously open to air,
at room temperature, for 30 min. Cu(OAc).sub.2H.sub.2O (20.67g,
103.5 mmol) was then added followed by TMEDA (18.63 mL, 124.3
mmol). The solution was stirred open to air, at room temperature,
for 5 h. Once the reaction was complete, the solution was
concentrated to 0.7 L, and then partitioned between
CH.sub.2Cl.sub.2 (700 mL) and 20% NH.sub.4OH/H.sub.2O saturated
with NH.sub.4Cl (500 mL). The aqueous layer was washed with
CH.sub.2Cl.sub.2 (500 mL, 200 mL). The combined organic layers were
dried over MgSO.sub.4, filtered, and concentrated. The crude
product was purified by Combi Flash chromatography: A:
CH.sub.2Cl.sub.2 B: 15:1 CH.sub.2Cl.sub.2/2N NH.sub.3/MeOH, 0-100%
B over 85 min. (two 330 g columns). This gave the product as a
white solid (35.52 g, 58%); LCMS (ESI): m/e 600 (M+H).sup.+.
Synthesis of Compound 6a:
[0653] Compound 5b (10.0 g, 16.68 mmol) was dissolved in THF (40
mL). The flask was purged with argon. Pyridine (40 mL) was then
added followed by BzCl (3.10 mL, 26.69 mmol). The solution was
stirred at room temperature under argon atmosphere for 3 h. MeOH (4
mL) was added, the mixture was stirred at room temperature for 10
min, and then it was partitioned between EtOAc (200 mL), heptane
(100 mL), and 5% KHCO.sub.3/H.sub.2O (200 mL). The aqueous layer
was washed with EtOAc (100 mL, 50 mL). The combined organic layers
were washed with 5% KHCO.sub.3/H.sub.2O (300 mL); dried over
Na.sub.2SO.sub.4; filtered, and concentrated. The crude product was
purified by Combi Flash chromatography: 0-100% EtOAc/heptane, over
55 min. (330 g column) The product was obtained as an offwhite
powder (9.81 g, 84%); LCMS (ESI): m/e 704 (M+H).sup.+.
##STR01070## ##STR01071##
Synthesis of 7a
[0654] Pyrrolocytosine 7a was prepared from the coupling of common
intermediate 6a and alkyne 5a according to the procedure describing
this type of reaction. For example: compound 6a (1 eq) and compound
5a (1 eq) were placed in a pressure vessel, and anhydrous DMF was
added. The solution was purged with argon, and then CuI (0.1 eq),
Pd(PPh.sub.3).sub.4 (0.05 eq), and Et.sub.3N (6 eq) were added, the
vessel was sealed, and the mixture was stirred at 22.degree. C.,
for 15 min. Subsequently, the temperature was increased to
80-85.degree. C., and the mixture was stirred for 14 h. It was
cooled to ambient temperature, MeOH was added, the vessel was
sealed, and the mixture was stirred at 90.degree. C. for 3 h. After
cooling to ambient temperature, the mixture was partitioned between
sat. KH.sub.2PO.sub.4/H.sub.2O and EtOAc, the organic phase was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by flash
chromatography on silica gel using 5% (2.5M
NH.sub.3/MeOH)/CH.sub.2Cl.sub.2. Starting from 360 mg of 5a, 600 mg
of the desired compound 7a was obtained as an orange-brown solid
(72%); LCMS (ESI) m/e 813.2 (M+1).sup.+.
Synthesis of 8a
[0655] Boc-deprotection of 7a (0.60 g, 0.72 mmol) was accomplished
with 8 mL of 6N HCl in 25 mL EtOH at 60.degree. C. (2 h). Following
solvent evaporation, the crude residue was taken to the next step
without further purification. LCMS (ESI) m/e 613.0 (M+1).sup.+.
Synthesis of 9a
[0656] Guanidine formation was carried out by dissolving 8a in a
5:1 DMF/MeOH (0.1 M) at rt. After treating with
diisopropylethylamine (8 eq), N,N-bis-boc-guanylpyrrazole (1.3 eq)
was added as a solid. The reaction mixture was stirred for 6 h, and
upon completion the solvents were removed by rotary evaporation.
Crude 9a was used without further purification.
Synthesis of 10a (Compound 31)
[0657] Under argon, fully protected guanidine 9a (0.60-0.80 mmol)
was dissolved in 25 mL of trifluoroacetic acid. Thioanisole (0.5
mL) was added dropwise and the solution was stirred at rt for 4 h.
Upon completion, solvent was evaporated affording an oil. Diethyl
ether was added and the liquid layer containing most of the
residual thioanisole was decanted. Crude 10a was then dissolved in
[(20% MeOH-80% H.sub.2O)+0.15%TFA] (10 mL). An aliquot (10 mL) was
injected on a Dynamax 41.4 mm, C-18 prep HPLC Unit (guard+column),
which was eluted with a gradient of solvents of 20%-80%
(MeOH/H.sub.2O+0.15% TFA), over 45 min. The pure fractions were
combined and concentrated with EtOH to dryness. This sample was
treated with 1N HCl/H.sub.2O (5 mL) and EtOH (70 mL), and
concentrated. This operation was repeated; the solid thus obtained
was lyophilized from H.sub.2O-MeCN (4:1), affording compound 10a as
a yellow powder (250 mg); LCMS (ESI) m/e 539.0 (M+1).sup.+; .sup.1H
NMR (300 MHz, D.sub.2O) .delta. 1.50-1.60 (m, 4H), 1.82-1.95 (m,
2H), 2.57 (t, J=6.9 Hz, 2H), 2.86 (t, J=6.9 Hz, 2H), 3.06 (t, J=6.9
Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 4.23 (s, 2H), 6.78 (s, 1H), 7.08
(d, J=8.5 Hz 1H), 7.18 (s, 1H), 7.44 (d, J=8.7, 2H), 7.58 (d, J=8.7
Hz, 2H), 8.48 (s, 1H).
Example 3
Synthesis of a Benzylic Methylated Fragment A Intermediate
##STR01072##
[0659] Pyridine sulfurtrioxide complex (20 g, 125 mmol, 2.5 eq.)
was added to a mixture of (3-hydroxy-propyl)-carbamic acid
tert-butyl ester (8.75 g, 50 mmol, 1 eq.), Et.sub.3N (17.67 g, 175
mmol, 2.5 eq.), DMSO (25 mL) and CH.sub.2Cl.sub.2 (100 mL) at
0.degree. C. The resulted mixture was stirred at 0.degree. C. for
lh and warmed up to room temperature and continuously stirred for 3
h. After concentration, the residue was diluted with EtOAc (200 mL)
and washed with H.sub.2O (200 mL), brine (100 mL), dried over
MgSO.sub.4, filtered and concentrated to give desired aldehyde as
colorless oil (8.60 g, 99%).
##STR01073##
[0660] A mixture of (3-oxo-propyl)-carbamic acid tert-butyl ester
(8.94 g, 51.7 mmol, 1 eq.), (S)-(-)-1-(4-bromo-phenyl)-ethylamine
(10.33 g, 51.7 mmol, 1.0 eq.) and MeOH (50 mL) was stirred at RT
for 18 h. NaBH.sub.4 (1.98 mg, 52.1 mmol, 1.01 eq.) was added
slowly to the above solution. The resulted mixture was stirred at
RT for 1 h, additional (3-oxo-propyl)-carbamic acid tert-butyl
ester (0.8 g, 4.6 mmol) was added and stirred for 2 h. additional
NaBH.sub.4 (0.21 g, 5.53 mmol) was added and stirred for 1 h. EtOAc
(120 mL) was added and washed with 1N NaOH (40 mL.times.2), 1N HCl
(60 mL) and water, dried over MgSO.sub.4, filtered and
concentrated. The crude product was dissolved in EtOAc (120 mL) and
MeOH (20 mL), Et.sub.3N (10.8 mL, 77.52 mmol, 1.5 eq.) was added,
followed by Boc.sub.2O (11.3 g, 51.8 mmol, 1.0 eq.). The resulted
mixture was stirred at RT for 3 days (weekend), washed with
H.sub.2O, dried over MgSO.sub.4, filtered and concentrated. The
crude product was purified by flash chromatography
(EtOAc:Heptane/1:5) to afford
(3-{[1-(4-bromo-phenyl)-ethyl]-tert-butoxycarbonyl-aminol-propyl)-carbami-
c acid tert-butyl ester (17.5 g, 74%).
##STR01074##
[0661] A mixture of
(3-{[1-(4-bromo-phenyl)-ethyl]-tert-butoxycarbonyl-aminol-propyl)-carbami-
c acid tert-butyl ester (15.73 g, 34.42 mmol),
bis(pinacolato)diborane (9.18 g, 36.14 mmol, 1.05 eq.),
Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (843 mg, 1.026 mmol, 0.03 eq.),
KOAc (10.6g, 108.42 mmol, 3.15 eq.) and dioxane (60 mL) was
degassed and heated at 100.degree. C. at Argon atmosphere
overnight. The mixture was diluted with CH.sub.2Cl.sub.2 (150 mL),
washed with H.sub.2O, dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified by chromatography
(EtOAc:Heptane/1:5) to afford
[3-(tert-butoxycarbonyl-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2--
yl)-phenyl]-ethyl}-amino)-propyl]-carbamic acid tert-butyl ester
(16.77 g, 97%).
##STR01075## [0662] References for above rxn: Jacobsen, M. F.;
Knudsen, M. M.; Gothelf, K. V. "Efficient N-Arylation and
N-Alkenylation of the Five DNA/RNA Nucleobases" J. Org. Chem. 2006,
71, 9183-9190. [0663] Dai, Q.; Ran, C.; Harvey, R. G.
"Regioselective Arylation of 2'Deoxyribonucleosides on Amido or
Imino Sites by Copper(II)-Mediated Direct Coupling with Arylboronic
Acids" Tetrahedron 2006, 62, 1764-1771.
[0664] Cu(OAc).sub.2 (6.02 g, 33.13 mmol, 1.1 eq.) was added to a
mixture of
[3-(tert-butoxycarbonyl-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-
-2-yl)-phenyl]-ethyl}-amino)-propyl]-carbamic acid tert-butyl ester
(15.18 g, 30.12 mmol, 1 eq.), 4-amino-5-iodo-1H-pyrimidin-2-one
(7.85 g, 33.13 mmol, 1.1 eq.), MeOH (400 mL) and H.sub.2O (100 mL),
followed by N,N,N,N'-tetramethyl-ethane-1,2-diamine (7.69 g, 66.26
mmol, 2.2 eq.). The Mixture was stirred at RT under air for 48 h
(weekend) before concentrated to a volume ca. 130 mL. The residue
was diluted with CH.sub.2Cl.sub.2 (200 mL). The CH.sub.2Cl.sub.2
extract was washed with brine and concentrated. The crude product
was purified by flash chromatography (CH.sub.2Cl.sub.2
:MeOH:NH.sub.4OH/35:1:0.01) to afford
[3-({1-[4-(4-amino-5-iodo-2-oxo-2H-pyrimidin-1-yl)-phenyl]-ethyl}-tert-bu-
toxycarbonyl-amino)-propyl]-carbamic acid tert-butyl ester (16.06
g, 87%).
##STR01076##
[0665] Benzoic anhydride (5.26 g, 23.25 mmol, 1.05 eq.) was added
to a solution of
[3-({1-[4-(4-amino-5-iodo-2-oxo-2H-pyrimidin-1-yl)-phenyl]-ethyl}-tert-bu-
toxycarbonyl-amino)-propyl]-carbamic acid tert-butyl ester (13.58
g, 22.15 mmol) in DMF (60 mL). The mixture was heated at 70.degree.
C. for 2 h and at RT for 20 h. EtOAc (150 mL) was added to the
mixture and washed with saturated sodium bicarbonate and brine,
dried over MgSO.sub.4, filtered and concentrated. The crude product
was purified by chromatography
(CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH/50:1:0.01) to afford benzoic acid
1-(4-{1-[tert-butoxycarbonyl-(3-tert-butoxycarbonylamino-propyl)-amino]-e-
thyl}-phenyl)-5-iodo-2-oxo-1,2-dihydro-pyrimidin-4-yl ester (15.5
g, 98%).
Example 4
Synthesis of the Fragment B Intermediates
[0666] The preparation of the Fragment B intermediates 5b and 5c
was carried out as described below. The Wittig Olefination can be
performed according to methods known in the art or according to
Gerpe, A., Convenient Route to Primary (Z)-Allyl Amines and
Homologs." Synth. Commun. 2009, 39, 29-47. In one aspect, the
intermediates 5b and 5c were used to prepare compounds 27 and
100.
Synthesis of Phosphonium Bromide XXb
##STR01077##
[0667] Synthesis of Phosphonium Bromide XXc
##STR01078##
[0668] Synthesis of Fragment B intermediates via Wittig
Olefination
##STR01079##
[0669] Example 5
Synthesis of Compound 234
[0670] The preparation of compound 234 was carried out by coupling
Fragment A (5) and Fragment B (H). The preparation of Fragment B
involves the coupling of intermediates 1 and 2.
Synthesis of N-Cbz (S)-4-aminopentene 1 intermediate
##STR01080##
[0672] (R)-4-Hydroxy-1-pentene A (15.00 g, 174.15 mmol) was
dissolved in CH.sub.2Cl.sub.2 (180 mL). To the solution, stirred/Ar
at 0.degree. C. was added triethylamine (30.4 mL, 217.69 mmol),
followed by dropwise addition of methanesulfonyl chloride (14.43
mL, 186.35 mmol), over 10 min. After 5 min, the cold bath was
removed and the mixture was stirred for 75 min, concentrated to 50
mL, and partitioned between heptane (80 mL), EtOAc (200 mL),
H.sub.2O (100 mL) and brine (100 mL). The phases were separated,
the organic phase was washed with H.sub.2O-brine (2:1; 150 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated, affording
intermediate B (28.6 g, yield=100%).
[0673] Compound B (28.6g, 174.15 mmol) was dissolved in anhydrous
DMF (250 mL) and NaN.sub.3 (48.46 g; 745.4 mmol) was added. The
mixture was stirred/Ar at RT for 5 min, and then at 70-75.degree.
C. for 90 min. Afterwards, the mixture was cooled to RT and
partitioned between ice (150 g), water (500 mL) and Et.sub.2O (150
mL). The phases were separated, the aqueous phase was extracted
with Et.sub.2O (3.times.100 mL) (Note: Et.sub.2O could be
substituted by 2-Me-THF). The organic extracts were combined and
washed with brine (2.times.150 mL), resulting in a solution of
compound C, which was used directly in the next step.
[0674] To the solution of C (174.15 mmol) was added THF (100 mL),
followed by H.sub.2O (35 mL). The mixture was stirred at RT/Ar, and
triphenylphosphine 58.65 g, 223.6 mmol) was added in small
portions, over 5 min. Afterwards, the flask was equipped with a
reflux condenser and the mixture was stirred at 40-42.degree. C.,
for 16 hrs. Water (60 mL) was added, followed by dropwise addition
of 3N HCl/H.sub.2O (57 mL) to achieve pH=ca. 2.0. The phases were
separated, and the organic phase was washed with a mixture of
H.sub.2O (40 mL) and 3N HCl/H.sub.2O (3.5 mL). The aqueous phases
were combined and washed with EtOAc (2.times.70 mL), resulting in a
solution of salt D, which was used directly in the next step.
[0675] The aqueous solution of D (174 mmol) was stirred under
argon, while the flask was cooled in a water bath at 20.degree. C.
Na.sub.2CO.sub.3 (18.44 g, 174 mmol) was added in small portions,
followed by KHCO.sub.3 (34.84 g, 348 mmol), and THF (150 mL). To
this mixture, stirred rapidly, was dropwise added benzyl
chloroformate (27.3 mL; 191.4 mmol), over 10 min. The mixture was
stirred for 2 hrs. Next, water (150 mL) and EtOAc (200 mL) were
added, and the mixture was stirred for 10 min. The phases were
separated and the aqueous phase was extracted with EtOAc
(2.times.70 mL). The organic layers were combined, washed with
brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated (50.5 g).This sample was purified by flash
chromatography on Si-gel (230-400 mesh; 750 g), using 5%
EtOAc/heptane (4 L) and then 10% EtOAc/heptane (5 L). This gave a
colorless viscous oil of compound 1, which solidified upon standing
(35.6 g; purity (NMR) 99%--conatins 1% of heptane; yield=93.2% over
4 steps).
Synthesis of 1-bromo-3-chloro-2-fluoro-5-iodo-benzene 2
intermediate
##STR01081##
[0677] N-Iodosuccinimide (286.2 g, 1.272 mol) was slowly added
under argon to rapidly stirred DMF (0.85 L) (Note: It is important
to do it in this order because if DMF is added to NIS, a very
insoluble solid forms), and then methanesulfonic acid (1.90 mL,
29.3 mmol) was added. The mixture was stirred for 5 min and
filtered, which gave a clear solution. Separately,
4-chloro-3-fluoroaniline E (176.3 g, 1.211 mol) was dissolved/Ar in
DMF (1.10 L), the solution was cooled to 0.degree. C., and
methanesulfonic acid (2.03 mL, 31.3 mmol) was added. The mixture
was stirred at 0.degree. C./Ar and the above described solution of
NIS in DMF was added dropwise, at 0-5.degree. C., over lh 20 min.
Subsequently, the mixture was stirred at 0-3.degree. C. for 2.5 h,
and then a solution of monosodium ascorbate (24.0 g, 0.121 mol) in
H.sub.2O (70 mL) was added dropwise at 0-5.degree. C., over 10 min.
The mixture was stirred at 0-5.degree. C. for 20 min, and then
EtOAc (1.3 L) and heptane (0.2 L) are added, followed by 5%
KHCO.sub.3/H.sub.2O (1.4 L). After 5 minutes of stirring, the
phases are separated, and the aqueous phase is extracted with EtOAc
(500 mL). The organic phases are combined, washed with water (1 L),
dried/Na.sub.2SO.sub.4, filtered and concentrated (401 g). This
material is purified by flash chromatography on Si-gel
(230-400mesh; 3.0 kg), using 7%-9% EtOAc/heptane. During the
concentration of fractions, the product F precipitates; the solid
was filtered and dried in vacuo to give aniline F as a crystalline
solid (206.68 g, yield: 77.5%).
[0678] N-Bromosuccinimide (142.29 g, 799.43 mmol) was dissolved
under argon in DMF-AcOH (5:1; 0.40 L), stirred for 5 min, which
resulted in a clear solution.
[0679] Separately, compound F (206.68 g, 761.36 mmol) was dissolved
under argon in DMF-AcOH (5:1; 1.40 L). The solution was cooled to
0-4.degree. C. and the above described solution of NBS was added
dropwise, at 0-4.degree. C., over 20 min. The mixture was stirred
at 0-4.degree. C. for 30 min, and then at 12-14.degree. C. (Note:
it is important not to exceed the specified temperature range due
to a sudden drop in selectivity at higher temperatures), for 5 h,
with HPLC monitoring. Subsequently, the mixture was cooled to
0-5.degree. C. and a solution of monosodium ascorbate (15.08 g,
76.14 mmol) in water (40 mL) is added at 0-10.degree. C., over 10
min. The mixture is stirred at 5-10.degree. C. for 10 min, and then
EtOAc (1.6 L), heptane (0.2 L), H.sub.2O (3.2 L), and brine (0.6 L)
are added, the mixture is stirred for 5 min, and the phases are
separated. The aqueous phase is extracted with EtOAc (0.40 L), the
organic phases are combined and washed with 10% KHCO.sub.3/H.sub.2O
(2.times.1.1 L), dried over Na.sub.2SO4, and concentrated (320 g).
The crude material is dissolved in minimal amount of
CH.sub.2Cl.sub.2, and purified by flash chromatography on Si-gel
(3.0 kg) using 2% EtOAc in heptane. The fractions are concentrated
to ca. 600 g, at which point a solid precipitates. The mixture is
cooled at 10-15.degree. C. and stirred for 1 hr, the product is
filtered, and dried to give aniline G (124.15g, yield: 46.5%).
[0680] A solution of isoamyl nitrite (94.9 mL, 708.7 mmol) in DMF
(500 mL) was stirred and heated under argon, at 65.degree. C. To
this solution was added dropwise a solution of aniline G in DMF
(200 mL), over 40 min, while maintaining the temperature at
65-75.degree. C. The mixture was stirred at 65-70.degree. C. for 30
min, and then cooled to 30-40.degree. C. Heptane (0.80 L), EtOAc
(0.40 L) and 0.5 N HCl/H.sub.2O (1.6 L) were added, after
extraction the phases were separated, and the aqueous phase was
washed with a mixture of heptane (0.20 L) and EtOAc (0.30 L). The
organic phases were combined, washed with 2N HCl/H.sub.2O (0.70 L),
and then with water (0.50 L), dried over Na.sub.2SO.sub.4,
filtered, and concentrated (brown oil, 160 g). This sample was
purified by flash chromatography on Si-gel (3.0 kg) using 100%
heptane as the eluent. This gave a solidifying, thick oil (90.5 g),
which was dissolved at 40.degree. C. in heptane (100 mL), and then
crystallized from the solution at 0.degree. C. After filtration,
the filtrate was recrystallized under similar conditions, and the
crystals were combined. This gave compound 2 (67.0 g, yield: 56.4%;
HPLC purity (PDA) >93%) as colorless crystals (Note: The major
impurity (3-5%) is identified as
1,5-dibromo-3-chloro-2-fluoro-benzene, which is expected to show
utility in the present synthesis, essentially similar to compound
2).
Synthesis of Alkyne Fragment B intermediate 5
##STR01082##
[0682] The Suzuki-coupling reaction is preformed according to
methods known in the art e.g., Al-Hellani, R.; Schluter, A. D. "On
the Synthesis and Selective Deprotection of Low-Generation Dendrons
with Orthogonally Protected Peripheral Amine Groups and a Possible
Impact of the Deprotection Conditions on the Stability of
Dendronized Polymers' Skeletons." Helv. Chim. Acta. 2006, 89,
2745-2763.
[0683] A solution of olefin 1 (18.62g, 84.06 mmol) in dry toluene
(185 mL) was purged with argon, and then cooled to 0.degree. C.
under argon, at which point 9-BBN (11.08 g, 90.80 mmol) was added
in a few portions. The mixture was stirred at 0-5.degree. C. for 20
min, and then at RT for 21 h, which gave a solution of the
trialkylborane.
[0684] To a solution of iodide 2 (28.19 g, 84.06 mmol) in toluene
(65 mL) was added 1N NaOH/H.sub.2O (142.9 mL, 142.9 mmol). The
mixture was purged with argon, and the above described solution of
trialkylborane was added under argon, followed by
tetrakis(triphenylphosphine)Pd(O) (4.86 g, 4.20 mmol). The mixture
was purged with argon, the flask was transferred to an oil bath
(60-64.degree. C.), and the mixture was stirred under argon for 9
h. After cooling to RT, EtOAc (150 mL) and brine (150 mL) were
added, the phases were separated, the organic phase was washed with
1N NaOH/H.sub.2O (100 mL), and with brine (100 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated
(56.1 g). This sample was purified by flash chromatography on
Si-gel (750 g) using 15% EtOAc in heptane as the eluent. The
fractions were combined and concentrated to ca. 300 mL, at which
point crystallization occurred. The solid was filtered and dried.
This gave compound 3 as a white solid (27.9 g; yield: 77.4%).
[0685] The bromide 3 (27.85 g; 64.96 mmol) was dissolved in DMF
(220 mL), the solution was purged with argon. Under a gentle stream
of argon, trimethylsilyl acetylene (27.5 mL, 194.9 mmol) was added,
followed by CuI (990 mg, 5.2 mmol), Pd (PPh.sub.3).sub.4 (3.0 g,
2.6 mmol) and triethylamine (stored under argon; 72.5 mL, 519.7
mmol). The flask was equipped with a reflux condenser, and the
mixture was stirred under argon, at 70.degree. C. for 2.5 h. After
cooling the mixture to RT, brine (300 mL), water (1.0 L) and EtOAc
(0.75 L) were added, and after extraction the phases were
separated. The organic layer was washed with H.sub.2O (0.75 L),
dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude
product was purified by flash chromatography on Si-gel (750 g)
using 15% EtOAc in heptane. This purification was repeated under
the same conditions (Note: due to the potential for ready dimer
formation in the next step, it is essential to eliminate from 4 as
much transition metal residues as possible). This gave compound 4
as a pale-yellow, thick oil (29.8 g).
[0686] This sample was dissolved in MeOH (previously purged with
argon; 350 mL), K.sub.2CO.sub.3 (19 g, 137.47 mmol) was added, the
mixture was stirred under a stream of argon for 5 min, and then it
was stirred in darkness, under argon, at 45.degree. C. After 35 min
the mixture was cooled/Ar to RT, concentrated, and purified by
flash chromatography on Si-gel (750 g) using 17% EtOAc in heptane
(Note: these operations are performed quickly to avoid alkyne
dimerization; after chromatographic purification the alkyne is
stable). This afforded alkyne 5 as a white, crystalline solid
(20.20 g, yield: 83.2%).
Synthesis of Compound 234
##STR01083## ##STR01084##
[0688] The Fragment A intermediate H was prepared according to
methods described herein. H (38.77 g, 54.03 mmol) and alkyne 5
(20.20 g, 54.03 mmol) were dissolved in acetonitrile and the
solution was stirred under gentle stream of argon. Copper(I) iodide
(617 mg, 3.24 mmol) and Pd(PPh.sub.3).sub.4 (1.87 g, 1.62 mmol)
were added, followed by diisopropylethyl amine (26.8 mL, 162.1
mmol). The mixture was stirred under Ar, at RT, for 5 min, and then
it was heated at 72-75.degree. C. for 4.5 h. Afterwards, MeOH (100
mL) was added and the mixture was stirred/Ar, at 72-75.degree. C.,
for 15 h. After cooling to RT, the mixture was concentrated, the
gummy solid thus obtained was dissolved in EtOAc (300 mL), and the
solution was washed with NH.sub.4Cl/NH.sub.4OH (3.times.200 mL).
The organic phase was concentrated and purified by flash
chromatography on Si-gel (750 g) using 5% (2.5M NH.sub.3/MeOH) in
CH.sub.2Cl.sub.2. The chromatography was repeated under similar
conditions, thus affording a red-brown, gummy solid (41.5 g). To a
solution of this sample in MeOH (300 mL), was added charcoal
(Aldrich No. 242276; 45 g) and the mixture was stirred for 2 h at
RT. Afterwards, the mixture was filtered through a silica gel plug
prepared in MeOH, the solids were washed with MeOH (1.0 L),
concentrated, and dried in vacuo to give compound 6 as a
light-brown solid (32.5 g, 70%).
[0689] The pyrrolocytosine 6 (32.5 g, 37.82 mmol) was dissolved
under argon in EtOH (200 proof; 200 mL), 6N HCl/H.sub.2O 75.6 mL,
453.8 mmol) was added, and the mixture was stirred under argon, at
70-72.degree. C., for 1 h 40 min. Afterwards, the mixture was
cooled to 40-45.degree. C., and IPA (200 mL) was added. After 3
min, abundant precipitation occurred more IPA (350 mL) was added,
the mixture was stirred for 10 min, and then filtered. The solid
was washed with IPA (2.times.80 mL), and dried in vacuo overnight,
affording salt 7 as a crystalline solid (20.7 g, yield: 75%).
[0690] Salt 7 (20.7 g, 28.3 mmol) was added under argon to rapidly
stirred MeOH (350 mL), followed by addition of triethylamine (15.8
mL, 113.2 mmol). After the solid dissolved completely (pH ca. 9.5),
N,N'-bis-Boc-1-guanylpyrazole (10.54 g, 33.96 mmol) was added and
the mixture was stirred for 1 h, at which time more
N,N'-bis-Boc-1-guanylpyrazole (0.88 g, 2.83 mmol) was added. The
stirring was continued for 1 h; the mixture was concentrated, and
the thus obtained semi-solid was purified by flash chromatography
on Si-gel (750 g) using 3% MeOH-2% Et.sub.3N-95% CH.sub.2Cl.sub.2.
(Note: it is believed that during this chromatography most of
palladium residues are removed in the form of a complex with the
by-product pyrazole) This gave a partially purified product (29.0
g) which was additionally purified by flash chromatography on
Si-gel (750 g) using 3% (2.5M NH.sub.3/MeOH) in CH.sub.2Cl.sub.2.
This gave compound 8 as a bright-yellow, solid foam (21.6 g, yield:
84.5%); ICP-OES Pd: 8 ppm, Cu<1 ppm.
[0691] Compound 8 (21.30 g) was placed under argon in a 1 L
round-bottom flask. With stirring, a pre-formed mixture of
thioanisole (8.32 mL, 70.9 mmol) and TFA (300 mL) was added. The
reaction mixture was stirred/Ar, at 40-45.degree. C., for 2 h 40
min, and then it was cooled to RT, concentrated, and dried in
vacuo. The thus obtained glassy solid was treated with 6N
HCl/H.sub.2O (50 mL) and EtOH (200 proof, 200 mL), and the mixture
was concentrated to a semi-solid. This material was again treated
with 6N HCl/H.sub.2O (50 mL) and EtOH (200 mL), and the mixture was
concentrated, and dried to a solid. This solid was dissolved in 3N
HCl/H.sub.2O (45 mL), the solution was stirred/Ar, and THF (80 mL)
was added dropwise to precipitate an oil. The mixture was rapidly
stirred for 5 min, and then the phases were separated. The bottom
phase (64.5 g) was placed under argon in a 500 mL flask, stirred at
RT under argon, and then the product was precipitated by addition
of EtOH (150 mL) and isopropanol (50 mL), and the mixture was
stirred at RT for 1 h. The solid was filtered, washed with IPA (4
.times.40 mL), dried with suction, and then dried in vacuo (1 mm
Hg, RT) overnight. This gave the product (14.40 g), which contained
1 equivalent IPA (by .sup.1H-NMR), in addition to some ethanol and
THF. This sample (14.0 g) was dissolved in 1N HCl/H.sub.2O (21 mL),
and solvents (5 mL) were distilled-off. The sample remaining in the
flask was diluted with EtOH (40 mL), and solvents (35 mL) were
distilled-off. The residue was stirred/Ar at RT, EtOH (150 mL) was
added dropwise, the resulting thick suspension was stirred for 1.5
h at RT, and then filtered. The canary-yellow solid was washed with
EtOH (3.times.30 mL), dried in vacuo at RT for 2 h, and then dried
in an oven at 70.degree. C., for 40 h. This gave compound 234 as a
yellow powder (11.94 g; Yield: 75% from 8; HPLC Purity (PDA):
98.9%; Solvents: EtOH 0.3%.sub.wt).
Example 6
Synthesis of Compound 248
[0692] The preparation of compound 248 was carried out by coupling
Fragment A (10) and Fragment B (2).
Synthesis of Fragment B intermediate 9
##STR01085##
[0693] Synthesis of 7
[0694] A solution of (S)-N-Cbz-4-aminopentene (16.425 g, 75 mmol,)
and 9-BBN (dimer, 10.065 g, 41.25 mmol) in toluene was stirred at
RT under argon for 16 hrs. 1N NaOH (120 mL,.), compound 6 (22.79 g,
75 mmol) in toluene (100 mL) and Pd(PPh.sub.3).sub.4 (3.5 g, 3.0
mmol) was added. The mixture was stirred under argon at 60.degree.
C. for 18 hrs, The mixture was diluted with EtOAc (150 mL), washed
with brine (150 mL), dried over MgSO.sub.4, filtered and
concentrated. The crude product was purified by chromatography on
silica gel (0-20% EtOAc in Heptane) to afford 7 as a colorless oil
(31.5 g, 95%). Note the procedure to prepare the starting material
(S)-N-Cbz-4-aminopentene is described herein.
Synthesis of 8
[0695] A mixture of 7 (31.5 g, 70.96 mmol.), CuI (674 mg, 3.55
mmol), PdCl.sub.2 (PPh.sub.3).sub.2 (996mg, 1.42 mmol) and DMF (110
mL) was degassed. Et.sub.3N (19.8 mL, 142.12 mmol) and
trimethsilylacetylene (10.43 g, 106.42 mmol) was added under argon.
The resulting mixture was heated at 70.degree. C. for 24 h. After
cooling to room temperature, the reaction mixture was diluted with
EtOAc (250 mL), washed with 15% NH.sub.4OH and brine (100
mL.times.2). The EtOAc solution was dried over MgSO.sub.4, filtered
and concentrated. The crude product was purified by flash
chromatography (0-10%, EtOAc in heptane) to afford 8 as a light
yellow oil (28.10 g, 86%).
Synthesis of 9
[0696] The suspension of 8 (28.10 g, 60.96 mmol) and
K.sub.2CO.sub.3 (4.4 g, 31.88 mmol) in MeOH (100 mL) was stirred at
room temperature for 1 h. The reaction was diluted with
CH.sub.2Cl.sub.2 (150 mL), washed with water, dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatography (5-20%, EtOAc in heptane) to
afford 9 as a light brown oil (22.60 g, 95%).
##STR01086##
Synthesis of 11
[0697] Compound 9 (13.0 g, 33.38 mmol) and compound 10 (23.47 g,
33.38 mmol) were dissolved in anhydrous DMF (80 mL). The solution
was purged with argon, and then CuI (381 mg, 2.0 mmol),
Pd(PPh.sub.3).sub.4 (1.157g, 1.0 mmol), and Et.sub.3N (13.95 mL,
100.15 mmol) were added. After stirring at 70.degree. C. for 18 h,
MeOH (30 mL) was added, and the mixture was stirred at 90.degree.
C. for 3 h. After cooling to ambient temperature, the mixture was
diluted with EtOAc (200 mL), washed with 15% NH.sub.4OH and brine
(150 mL), dried over MgSO.sub.4, filtered and concentrated. The
crude product was purified by flash chromatography (1-4%, 2.5M
NH.sub.3/MeOH in CH.sub.2Cl.sub.2) to give product 11 (22.94 g,
80%).
Synthesis of 12
[0698] To a solution of 11 (20.94 g, 24.38 mmol) in MeOH (200 mL)
and CH.sub.2Cl.sub.2 (200 mL) was added 4N HCl in dioxane (150 mL)
at 0.degree. C. The reaction was concentrated after stirring at RT
for 16 h. The residue was dissolved in DMF (200 mL).
Diisopropylethyl amine (21 mL) was added, followed by
N,N-bis-boc-guanylpyrrazole (7.56 g, 24.38 mmol). After stirring at
RT for 2 days, the reaction was diluted with EtOAc (250 mL), washed
with brine (100 mL.times.2), The EtOAc solution was dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatography (0-5%, 2.5M NH.sub.3/MeOH in
CH.sub.2Cl.sub.2) to give product 12 (15.76 g, 72%) as a yellow
foam. 12 was further treated with charcoal (1.5 g) in EtOAc (200
mL) at RT for 4 hrs before next step use.
Synthesis of 13
[0699] To a solution of 12 (10.42 g, 11.55 mmol) in
CH.sub.2Cl.sub.2 (70 mL) was added Boc.sub.2O (3.07 g, 14.07 mmol).
The reaction was concentrated after stirring at RT for 3 h. The
residue was purified by flash chromatography (25-90%, EtOAc in
Heptane) to give product 13 (11.08 g, 96%) as a yellow foam.
Synthesis of Compound 248
[0700] To a solution of 13 (10.42 g, 10.40 mmol) in TFA (20 mL) was
added thioanisole (3.9 g, 31.45 mmol). The reaction was
concentrated after stirring at 50.degree. C. for 8 h. MeOH (20 mL)
and 3N HCl/H.sub.2O (40 mL) were added, the resulted solution was
concentrated (this sequence was repeated once). The residue was
dissolved in 1N HCl (120 mL), washed with diethyl ether (80
mL.times.3). The acidic aqueous solution was concentrated and
recrystallized from MeOH/water/ethanol (2 mL/2 mL/20 mL) to afford
the final product 248 (5.8 g, >99% purity, 82% yield).
Example 7
Synthesis of compounds 387 and 388
[0701] Compounds 387 and 388 were prepared according to the
procedure below.
##STR01087##
Example 8
Synthesis of Compounds 389 and 390
[0702] Compounds 389 and 390 were prepared according to the
procedure below.
##STR01088##
Example 9
Synthesis of Compound 399
[0703] Compound 399 was prepared according to the procedure
below.
##STR01089##
Example 10
Synthesis of Compound 404
[0704] Compound 404 was prepared according to the procedure
below.
##STR01090##
Example 11
Synthesis of Compound 390
##STR01091##
[0705] Synthesis of
i1-Methyl-4-(4-trifluoromethyl-pyridin-2-yl)-butyl]-carbamic acid
benzyl ester (2)
[0706] A solution of but-3-enyl-carbamic acid benzyl ester (3.06 g,
14.0 mmol, 1 eq) in anhydrous toluene (40 mL) was cooled under
argon to 0-5.degree. C. 9-BBN (0.50 M, solution in THF; 30.8 mL,
1504 mmol, 1.1 eq.) was added dropwise, the mixture was stirred and
allowed to reach room temperature. After 24 h, 1N NaOH/H.sub.2O
(23.8 mL, 23.8 mmol, 1.7 eq.) was added, followed by
2-bromo-4-trifluoromethyl-pyridine (3.16 g, 14.0 mmol, 1 eq.) and
toluene (25 mL). The resulting mixture was degassed and
Pd(PPh.sub.3).sub.4 (0.89 g, 0.70 mmol, 0.05 eq.) was added. The
mixture was rapidly stirred under argon at 60.degree. C. for 24 h,
and then it was cooled to room temperature. Afterwards, the mixture
was partitioned between EtOAc (100 mL) and brine (100 mL). The
organic phase was washed with brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatography on silica gel (0-50% EtOAc in
Heptane) to afford 2 as colorless oil (5.1 g, 99%).
##STR01092##
Synthesis of
[1-methyl-4-(1-oxy-4-trifluoromethyl-pyridin-2-yl)-butyl]-carbamic
acid benzyl ester (3)
[0707] To a solution of 2 (5.1 g, 13.94 mmol, 1 eq.) in
CH.sub.2Cl.sub.2 (50 ml) was added m-chloroperoxybenzoic acid
(2.88g, 16.72 mmol, 1.2 eq.). The mixture was stirred at room
temperature for 18 h before quenching with NaHCO.sub.3 (sat. 50
ml). The organic solution was washed with brine (50 mL.times.2),
dried over MgSO.sub.4, filtered and concentrated. The crude product
was purified by flash chromatography (0-10%, MeOH in
CH.sub.2Cl.sub.2) to afford 3 (5.30 g, 99%).
Synthesis of
[4-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-1-methyl-butyl]-carbamic
acid benzyl ester (4)
[0708] A solution of 3 (1.52 g, 4.0 mmol) in POCl.sub.3 (6 ml) was
heated at 110.degree. C. for 15 h before cooling to room
temperature. The reaction mixture was quenched with ice, basified
with NaOH to pH ca. 10, and extracted with EtOAc (50 mL.times.2).
The EtOAc solution was washed with brine (50 mL.times.2), dried
over MgSO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatography (0-10%, MeOH in CH.sub.2Cl.sub.2)
to afford the 2-chloropyridine derivative (360 mg). The resulting
product was dissolved in CH.sub.2Cl.sub.2 (10 ml). Hunig's base
(520 mg, 4.03 mmol) was added at 0.degree. C. followed by CbzCl
(343 mg, 2.02 mmol). The mixture was stirred for 3 h at 0.degree.
C., then concentrated and purified by flash chromatography (0-50%,
EtOAc in heptane) to afford 4 (470 mg, 32%).
Synthesis of
[4-(6-Ethynyl-4-trifluoromethyl-pyridin-2-yl)-1-methyl-butyl]-carbamic
acid benzyl ester (5)
[0709] A mixture of 4 (470 mg, 1.17 mmol, 1 eq), CuI (23 mg, 0.117
mmol, 0.1 eq.), Pd(PPh.sub.3).sub.4 (68 mg, 0.058 mmol, 0.05 eq.)
and DMF (8 mL) was degassed. Trimethsilyacetylene (173 mg, 1.760
mmol, 1.5 eq.) was added under Argon, followed by Et.sub.3N (356
mg, 4.81 mL, 3.52 mmol, 3 eq.). The mixture was heated at
70.degree. C. for 24 h. After being cooled to room temperature, the
reaction mixture was diluted with EtOAc (50 mL) and washed with
brine (20 mL.times.2). The EtOAc solution was dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by flash chromatography (0-30%, EtOAc in heptane) to
afford the desired trimethsilyacetylene derivative (500 mg, 92%).
The product was dissolved in MeOH (20 mL), and K.sub.2CO.sub.3 (138
mg, 1 mmol,) was added. The reaction mixture was stirred at room
temperature for 30 min before concentration. The residue was
partitioned between EtOAc (20 mL) and H.sub.2O (20 mL). The EtOAc
layer was washed with brine (10 mL), dried over MgSO.sub.4,
filtered and concentrated. The crude product was purified by flash
chromatography (0-50%, EtOAc in heptane) to afford 5 as colorless
oil (423 mg, 100%).
##STR01093##
Synthesis of 7
[0710] Pyrrolocytosine 7 was prepared from the coupling of common
intermediate 6 and alkyne 5 according to the procedure described
previously. Starting from 230 mg of 5, 320 mg of the desired
compound was obtained as an orange-brown solid (62%); LCMS (ESI)
m/e 876.2 (M+1).sup.+.
Synthesis of Compound 390
[0711] Boc-deprotection of 7 (0.32 g) was accomplished with 2 mL of
4N HCl in dioxane and CH.sub.2Cl.sub.2 (10 mL) at room temperature
(2 h). Following solvent evaporation, the crude residue was taken
to the next step without further purification. LCMS (ESI) m/e 613.0
(M+1).sup.+. Guanidine formation was carried out according to the
protocol used to prepare the other described compounds
(bis-Boc-guanylpyrrazole, Et.sub.3N, MeOH, RT). Deprotection was
found to work best using a stepwise procedure to first remove the
Boc-groups (trifluoroacetic acid in 10 mL of CH.sub.2Cl.sub.2).
Following concentration, the Cbz group was removed by redissolving
the yellow-brown solid in 5 mL of trifluoroacetic acid and adding
thioanisole (0.1 mL) dropwise. The solution was stirred at rt
overnight, and upon completion solvent was evaporated affording the
final compound as a brown oil. Diethyl ether was added and the
liquid layer containing most of the residual thioanisole was
decanted. Crude product was then dissolved in [(20% MeOH-90%
H.sub.2O)+0.15%TFA] (10 mL). An aliquot (10 mL) was injected on a
Dynamax 41.4 mm, C-18 prep HPLC Unit (guard+column), which was
eluted with a gradient of solvents of 15%-70% (MeOH/H.sub.2O+0.15%
TFA), over 45 min. The pure fractions were combined and
concentrated with EtOH to dryness. This sample was treated with 1N
HCl/H.sub.2O (5 mL) and EtOH (10 mL), and concentrated. This
operation was repeated; the solid thus obtained was lyophilized
from H.sub.2O-MeCN (4:1), affording compound 390 as a yellow powder
(86 mg); LCMS (ESI) m/e 584.1 (M+1).sup.+; .sup.1H NMR (300 MHz,
D.sub.2O) .delta. 1.20 (d, J=6.6 Hz, 3H), 1.56 (m, 2H), 1.65 (d,
J=6.8 Hz, 3 H), 1.85 (m, 2H), 2.87 (m, 1H), 2.89 (t, J=6.9 Hz, 2H),
3.00 (m, 1H), 3.15 (t, J=6.9 Hz, 2H), 3.31 (q, J=6.8 Hz, 1H), 4.47
(q, J=6.6 Hz, 1H), 7.05 (s, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.51 (s,
1H), 7.61 (d, J=8.1 Hz, 2H), 7.94 (s, 1H), 8.51 (s, 1H).
Example 12
Syntheis of Compound 322
##STR01094##
[0712] Synthesis of Mesylate 2 from Aldehyde 1
[0713] Aldehyde 1 (11.8 g, 46.6 mmol) was dissolved in MeOH (70 mL)
and the solution was cooled to 0.degree. C. NaBH.sub.4 (2.13 g, 56
mmol) was added slowly as a solid in several portions. After 30
minutes, the mixture was warmed to RT, resulting in the formation
of a clear solution. Stirring for an addition 1.5 h at RT led to
complete consumption of starting material. MeOH was then evaporated
and the residue was partitioned between EtOAc and H.sub.2O. The
organic layer was collected, dried over MgSO.sub.4, and
concentrated to a viscous, colorless oil (12.5 g, 99%). This oil
was then redissolved in CH.sub.2Cl.sub.2 at 0.degree. C., and
Et.sub.3N was added. The dropwise addition of MsCl produced a
slightly yellow solution that was allowed to gradually warm to RT.
Upon completion, the reaction was quenched with NaHCO.sub.3. The
organic layer was separated and the aqueous phase was extracted
2.times. with fresh CH.sub.2Cl.sub.2. The combined organics were
dried over Na.sub.2SO.sub.4 and concentrated to give an oil (8.10
g, 53%) that was used directly in the next step.
Synthesis of Aryl THP Ether 4
[0714] To a flask containing NaH (4.2 g, 105.7 mmol, 60% dispersion
in oil) in 20 mL of THF at 0.degree. C. was added THP-protected
ether 3 (16.9 g, 105.7 mmol) in 30 mL THF. An additional 20 mL of
solvent was added to reduce foaming. After 5 min, the ice bath was
removed and the mixture was brought to RT and stirring was
continued for 1 h. Mesylate 2 (4.4 g, 13.21 mmol) in 50 mL of THF
was then added dropwise at RT and the resulting solution was heated
for 1.5 h at 45-50.degree. C. Complete conversion was observed by
LCMS, so the reaction was quenched with NH.sub.4Cl. EtOAc was added
and the phases were separated. The aqueous layer was extracted
2.times. with fresh EtOAc and the combined organics were dried over
MgSO.sub.4 and concentrated. The crude material was purified by
column chromatography (5-30% EtOAc in heptanes) to provide 2.10 g
of product (40%).
Synthesis of Aryl Alcohol 5
[0715] THP-protected aryl ether 4 (2.10 g, 5.28 mmol) was dissolved
in 35 mL of MeOH and treated with cat. TsOH (0.1 eq). After 5 h at
RT, the reaction was complete as indicated by LCMS and TLC. MeOH
was removed and the mixture was partitioned between EtOAc and
H.sub.2O. The organic layer was separated, dried over MgSO.sub.4,
and concentrated to a slightly yellow-colored oil (1.54 g, 93%).
This material was used without further purification.
Synthesis of Cbz-Protected Aryl Amine 6
[0716] The same procedure for mesylation was used that was part of
the two step conversion starting from aldehyde 1. From 0.86 g (2.73
mmol) of alcohol 5, 1.29 g of crude mesylate was obtained and used
directly for azide formation.
[0717] This residue (1.29 g) was dissolved in DMF (10 mL) and
treated with a single portion of NaN.sub.3 (0.6 g. 9.3 mmol). The
resulting mixture was then allowed to stir overnight at RT. Upon
completion, ether was added and the organic layer was separated.
The aqueous phase was washed 3.times. with additional ether and the
organics were combined, washed 4.times. with H.sub.2O, dried over
MgSO.sub.4, and concentrated. The crude oil (.about.1g) was used
directly in the next step without purification.
[0718] For the reduction to amine, the azide material (.about.3
mmol) was then dissolved in 10 mL THF along with 1 mL of H.sub.2O
and triphenylphosphine (1.6 g, 6.0 mmol). The contents were heated
from 55-60.degree. C. overnight to obtain complete consumption of
starting material. THF was then removed in vacuo.
[0719] Cbz-protection was then accomplished by placing the amine in
15 mL of CH.sub.2Cl.sub.2 and 15 mL of sat. NaHCO.sub.3. The
solution was cooled to 0.degree. C. prior to the addition of CbzCl
(0.64 mL, 4.5 mmol, 1.5 eq). After 4 h at RT, the organic layer was
separated. The aqueous phase was washed 2.times. with fresh
CH.sub.2Cl.sub.2 and the combined organics were dried over
Na.sub.2SO.sub.4 and concentrated. The crude material was purified
by column chromatography (3:1 heptanes/EtOAc) to produce 1.2 g of
desired compound (97% yield from aryl alcohol 5).
[0720] Note: The remainder of the synthesis (i.e. alkyne formation,
Sonogashira/cyclization, and guanidine installation) is according
the procedures described above for compounds 234 and 248).
Example 13
Antimicrobial Activity
[0721] The compounds of the present invention were tested for
antimicrobial activity. These data are presented in Table 3, Table
4, Table 5, and Table 6. The compounds were run against Eschericia
coli strain ATCC25922 using a standard microdilution assay to
determine minimum inhibitory concentrations (MICs). The data is
presented whereby a "+" indicates that the compound has an MIC
value of 16 micrograms/ml or less and a "-" indicates that the
compound has an MIC value greater than 16 micrograms/ml. A "N/A"
means that data is unavailable. It will be recognized by one
skilled in the art that the compounds can be assessed against other
bacterial organisms and that the presentation of data for activity
against Eschericia coli is illustrative and in no way is intended
to limit the scope of the present invention. The compounds of the
present invention can be assayed against a range of other
microorganisms depending upon the performance activity desired to
be gathered.
[0722] Furthermore, the "+", "", and "N/A" representation and the
selection of a cutoff value of 16 micrograms/ml is also
illustrative and in no way is intended to limit the scope of the
present invention. For example, a "-" is not meant to indicate that
the compound necessarily lacks activity or utility, but rather that
its MIC value against the indicated microorganism is greater than
16 micrograms/ml.
TABLE-US-00013 TABLE 3 Compound no. E. coli ATCC25922 MIC 1 + 2 + 3
+ 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 + 12 + 13 + 14 + 15 + 16 + 17 +
18 + 19 + 20 + 21 + 22 + 23 + 24 + 25 + 26 + 27 + 28 + 29 + 30 + 31
+ 32 + 33 + 34 + 35 + 36 + 37 + 38 + 39 + 40 + 41 + 42 + 43 + 44 +
45 + 46 + 47 + 48 + 49 + 50 + 51 + 52 + 53 + 54 + 55 + 56 + 57 + 58
+ 59 + 60 - 61 + 62 + 63 + 64 + 65 + 66 - 67 + 68 + 69 + 70 + 71 +
72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 + 80 + 81 + 82 + 83 + 84 + 85
+ 86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 + 94 + 95 + 96 + 97 + 98 +
99 + 100 + 101 + 102 + 103 + 104 + 105 + 106 + 107 + 108 + 109 +
110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 + 119 + 120 +
121 + 122 + 123 + 124 + 125 + 126 + 127 + 128 + 129 + 130 + 131 +
132 + 133 + 134 + 135 + 136 + 137 + 138 + 139 + 140 + 212 + 213 +
214 + 215 + 216 + 217 + 218 + 219 + 220 + 221 + 222 + 223 + 224 +
225 + 226 + 227 + 228 + 229 + 230 + 231 + 232 + 233 + 234 + 235 +
236 + 237 + 238 + 239 + 240 + 241 + 242 + 243 + 244 + 245 + 246 +
247 + 248 + 249 + 250 + 251 + 252 + 253 + 254 + 255 + 256 + 257 +
258 + 259 + 260 + 261 + 262 + 263 + 264 + 265 + 266 + 267 + 268 +
269 + 270 + 271 + 272 + 273 + 274 + 275 + 276 + 277 + 278 + 279 +
280 + 281 + 282 + 283 + 284 + 285 + 286 + 287 + 288 + 289 + 290 +
291 + 292 + 293 + 294 + 295 + 296 + 297 + 298 + 299 + 300 + 301 +
302 + 303 + 304 + 305 + 306 + 307 + 308 + 309 + 310 + 311 + 312 +
313 + 314 + 315 + 316 +
317 + 318 + 319 + 320 + 321 + 322 + 323 + 324 + 325 + 326 + 327
+
TABLE-US-00014 TABLE 4 Compound no. E. coli ATCC25922 MIC 150 - 151
+ 152 + 153 + 154 + 155 + 156 + 157 + 158 + 159 + 160 + 161 + 162 +
163 + 164 + 165 - 166 + 167 + 168 + 169 + 170 + 171 + 172 + 173 +
174 + 175 + 176 + 177 - 178 + 179 + 180 + 181 + 182 + 183 - 184 +
185 - 186 - 187 - 188 + 189 - 190 -
TABLE-US-00015 TABLE 5 Compound no. E. coli ATCC25922 MIC 333 + 334
+ 335 + 336 + 337 + 338 + 339 + 340 + 341 + 342 + 343 + 344 + 345 +
346 + 347 + 348 + 349 + 350 + 351 - 352 - 353 - 354 - 355 - 356 -
357 - 358 - 359 + 360 + 361 + 362 + 363 + 364 + 365 - 366 - 367 -
368 + 369 + 370 + 371 - 372 - 373 - 374 + 375 + 376 + 377 + 378 +
379 + 380 + 381 + 382 + 383 + 384 + 385 + 386 - 387 + 388 + 389 +
390 + 391 + 392 + 393 + 394 + 395 + 396 + 397 + 398 + 399 + 400 +
401 + 402 + 403 + 404 + 405 - 406 - 407 + 408 + 409 - 410 + 411 +
412 + 413 + 414 + 415 + 416 + 417 + 418 + 419 + 420 + 421 + 522 +
423 + 424 + 425 + 426 + 427 + 428 + 429 + 430 + 431 + 432 + 433 +
434 + 435 + 436 + 437 + 438 + 439 + 440 + 441 + 442 + 443 + 444 +
445 + 446 + 447 + 448 + 449 + 450 + 451 + 452 + 453 + 454 + 455 +
456 + 457 + 458 + 459 + 460 + 461 + 462 + 463 + 464 + 465 + 466 +
467 + 468 +
TABLE-US-00016 TABLE 6 Compound no. E. coli ATCC25922 MIC 469 + 470
+ 471 + 472 + 473 + 474 + 475 + 476 + 477 + 478 + 479 + 480 + 481 +
482 + 483 + 484 + 485 + 486 + 487 + 488 + 489 + 490 - 491 + 492 -
493 + 494 + 495 + 496 + 497 - 498 + 499 + 500 + 501 + 502 + 503 -
504 + 505 + 506 + 507 +
INCORPORATION BY REFERENCE
[0723] The entire disclosure of each of the patent documents and
scientific articles referred to herein is incorporated by reference
for all purposes.
EQUIVALENTS
[0724] The invention can be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The foregoing embodiments are therefore to be considered
in all respects illustrative rather than limiting on the invention
described herein. Scope of the invention is thus indicated by the
appended claims rather than by the foregoing description, and all
changes that come within the meaning and range of equivalency of
the claims are intended to be embraced therein.
* * * * *