U.S. patent application number 13/034974 was filed with the patent office on 2011-09-01 for substituted hydroxamic acids and uses thereof.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Christopher Blackburn, Kenneth M. Gigstad, Sean J. Harrison, He Xu.
Application Number | 20110212969 13/034974 |
Document ID | / |
Family ID | 44505600 |
Filed Date | 2011-09-01 |
United States Patent
Application |
20110212969 |
Kind Code |
A1 |
Blackburn; Christopher ; et
al. |
September 1, 2011 |
SUBSTITUTED HYDROXAMIC ACIDS AND USES THEREOF
Abstract
This invention provides compounds of formula (I): ##STR00001##
wherein ring A, X.sub.1, X.sub.2, X.sub.3, R.sup.2, R.sup.4b,
R.sup.10, and G have values as described in the specification,
useful as inhibitors of HDAC6. The invention also provides
pharmaceutical compositions comprising the compounds of the
invention, and methods of using the compositions in the treatment
of proliferative, inflammatory, infectious, neurological or
cardiovascular diseases or disorders.
Inventors: |
Blackburn; Christopher;
(Natick, MA) ; Gigstad; Kenneth M.; (Westford,
MA) ; Harrison; Sean J.; (Belmont, MA) ; Xu;
He; (Needham, MA) |
Assignee: |
Millennium Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
44505600 |
Appl. No.: |
13/034974 |
Filed: |
February 25, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61339138 |
Feb 26, 2010 |
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61426314 |
Dec 22, 2010 |
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Current U.S.
Class: |
514/249 ;
514/248; 514/255.06; 514/256; 514/300; 514/419; 514/421; 514/443;
514/469; 514/471; 514/575; 544/235; 544/335; 544/355; 544/407;
546/121; 548/453; 548/492; 549/467; 549/487; 549/57; 562/622 |
Current CPC
Class: |
A61K 31/437 20130101;
C07D 491/048 20130101; C07C 2601/04 20170501; C07D 311/14 20130101;
A61K 31/407 20130101; C07C 259/08 20130101; C07D 209/42 20130101;
C07D 237/28 20130101; C07C 275/26 20130101; C07D 207/34 20130101;
C07D 241/44 20130101; A61K 31/341 20130101; A61P 35/00 20180101;
C07C 275/28 20130101; C07D 233/84 20130101; C07D 285/14 20130101;
C07D 491/04 20130101; C07D 417/04 20130101; A61K 31/381 20130101;
C07C 2601/06 20170501; C07D 307/85 20130101; C07C 259/10 20130101;
C07C 311/06 20130101; C07C 275/34 20130101; C07D 277/56 20130101;
A61K 31/166 20130101; C07D 231/14 20130101; A61K 31/505 20130101;
C07D 211/62 20130101; C07D 239/28 20130101; C07D 277/64 20130101;
A61K 31/498 20130101; A61K 31/502 20130101; C07D 307/84 20130101;
A61K 31/404 20130101; C07D 333/68 20130101; A61K 31/343 20130101;
A61K 31/4965 20130101; C07C 311/19 20130101; C07D 333/70
20130101 |
Class at
Publication: |
514/249 ;
562/622; 514/575; 549/467; 514/469; 548/453; 514/421; 549/487;
514/471; 548/492; 514/419; 549/57; 514/443; 544/335; 514/256;
546/121; 514/300; 544/235; 514/248; 544/407; 514/255.06;
544/355 |
International
Class: |
A61K 31/166 20060101
A61K031/166; C07C 259/10 20060101 C07C259/10; C07D 307/85 20060101
C07D307/85; A61K 31/343 20060101 A61K031/343; C07D 491/048 20060101
C07D491/048; A61K 31/407 20060101 A61K031/407; C07D 307/68 20060101
C07D307/68; A61K 31/341 20060101 A61K031/341; C07D 209/42 20060101
C07D209/42; A61K 31/404 20060101 A61K031/404; C07D 333/70 20060101
C07D333/70; A61K 31/381 20060101 A61K031/381; C07D 239/28 20060101
C07D239/28; A61K 31/505 20060101 A61K031/505; C07D 471/04 20060101
C07D471/04; A61K 31/437 20060101 A61K031/437; C07D 237/28 20060101
C07D237/28; A61K 31/502 20060101 A61K031/502; C07D 241/24 20060101
C07D241/24; A61K 31/4965 20060101 A61K031/4965; C07D 241/44
20060101 C07D241/44; A61K 31/498 20060101 A61K031/498; A61P 35/00
20060101 A61P035/00 |
Claims
1. A compound of formula (I): ##STR00620## or a pharmaceutically
acceptable salt thereof; wherein: ring A is an aromatic 6-membered
ring connected through one of positions (a) or (b); X.sub.1 is
CR.sup.1 or N; (i) when ring A is connected through position (a),
X.sub.2 is C; and X.sub.3 is CR.sup.1 or N; or (ii) when ring A is
connected through position (b), X.sub.3 is C; and X.sub.2 is
CR.sup.1 or N; each occurrence of R.sup.1 is independently
hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-3 fluoroalkyl,
--O--C.sub.1-3 alkyl, --O--C.sub.1-3 fluoroalkyl, cyano, hydroxy,
--NHC(O)C.sub.1-3 alkyl, --C(O)NHC.sub.1-3 alkyl,
--NHC(O)NHC.sub.1-3 alkyl, or --NHS(O).sub.2C.sub.1-3 alkyl. each
occurrence of R.sup.10 is independently hydrogen, halogen, hydroxy,
--O--C.sub.1-3 alkyl, or --O--C.sub.1-3 fluoroalkyl; R.sup.2 is
C.sub.1-6 aliphatic, C.sub.1-6 fluoroaliphatic, or unsubstituted or
substituted 6-10-membered aryl; R.sup.4b is hydrogen, or C.sub.1-4
aliphatic; G is --R.sup.3, --V.sub.1--R.sup.3,
-L.sub.2-V.sub.1--R.sup.3, -L.sub.2-V.sub.2--R.sup.3, or
-L.sub.1-R.sup.3; L, is an unsubstituted or substituted C.sub.1-3
alkylene chain; L.sub.2 is an unsubstituted or substituted
C.sub.2-3 alkylene chain; V.sub.1 is --C(O)--,
--C(O)--CR.sup.A.dbd.CR.sup.A--, --C(O)--N(R.sup.4a)--,
--C(O)--O--, or --S(O).sub.2--; V.sub.2 is --C(S)--,
--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--, --SO.sub.2--N(R.sup.4a)--,
--N(R.sup.4a)--SO.sub.2--, --O--, --S--, --S(O)--,
--N(R.sup.4a)--C(O)--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--O--,
--O--C(O)--N(R.sup.4a)--, or
--N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--; R.sup.3 is unsubstituted or
substituted C.sub.1-6 aliphatic, unsubstituted or substituted
3-10-membered cycloaliphatic, unsubstituted or substituted
4-10-membered heterocyclyl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; each occurrence of
R.sup.A is independently hydrogen, fluoro, or unsubstituted or
substituted C.sub.1-4 aliphatic; and each occurrence of R.sup.4a is
independently hydrogen, or unsubstituted or substituted
aliphatic.
2. The compound of claim 1, wherein: X.sub.1 is CR.sup.1; and (i)
when ring A is connected through position (a), X.sub.2 is C; and
X.sub.3 is CR.sup.1; or (ii) when ring A is connected through
position (b), X.sub.3 is C; and X.sub.2 is CR.sup.1.
3. The compound of claim 1, wherein: R.sup.4b is H; and R.sup.2 is
methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, tert-butyl,
cyclopropyl, or phenyl.
4. The compound of claim 1, wherein: G is --V.sub.1--R.sup.3; and
V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or --S(O).sub.2--.
5. The compound of claim 1, wherein: R.sup.1 is hydrogen, chloro,
fluoro, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyano,
trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl;
and R.sup.10 is hydrogen.
6. The compound of claim 1, represented by formula (II-a):
##STR00621## wherein ring A is an aromatic 6-membered ring
connected through one of positions (a) or (b); X.sub.1 is CR.sup.1
or N; (i) when ring A is connected through position (a), X.sub.2 is
C; and X.sub.3 is CR.sup.1 or N; or (ii) when ring A is connected
through position (b), X.sub.3 is C; and X.sub.2 is CR.sup.1 or N;
each occurrence of R.sup.1 is independently hydrogen, halogen,
C.sub.1-4 alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3 alkyl,
--O--C.sub.1-3 fluoroalkyl, cyano, hydroxy, --NHC(O)C.sub.1-3
alkyl, --C(O)NHC.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
--NHS(O).sub.2C.sub.1-3alkyl. each occurrence of R.sup.10 is
independently hydrogen, halogen, hydroxy, --O--C.sub.1-3alkyl, or
--O--C.sub.1-3-fluoroalkyl; R.sup.2 is C.sub.1-6 aliphatic,
C.sub.1-6 fluoroaliphatic, or unsubstituted or substituted
6-10-membered aryl; R.sup.4b is hydrogen, or C.sub.1-4 aliphatic; G
is --R.sup.3, --V.sub.1--R.sup.3, -L.sub.2-V.sub.1--R.sup.3,
-L.sub.2-V.sub.2--R.sup.3, or -L.sub.1-R.sup.3; L, is an
unsubstituted or substituted C.sub.1-3 alkylene chain; L.sub.2 is
an unsubstituted or substituted C.sub.2-3 alkylene chain; V, is
--C(O)--, --C(O)--CR.sup.A.dbd.CR.sup.A--, --C(O)--N(R.sup.4a)--,
--C(O)--O--, or --S(O).sub.2--; V.sub.2 is --C(S)--,
--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--, --SO.sub.2--N(R.sup.4a)--,
--N(R.sup.4a)--SO.sub.2--, --O--, --S--, --S(O)--,
--N(R.sup.4a)--C(O)--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--O--,
--O--C(O)--N(e)-, or --N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--;
R.sup.3 is unsubstituted or substituted C.sub.1-6 aliphatic,
unsubstituted or substituted 3-10-membered cycloaliphatic,
unsubstituted or substituted 4-10-membered heterocyclyl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; each occurrence of R.sup.A is independently hydrogen,
fluoro, or unsubstituted or substituted C.sub.1-4 aliphatic; and
each occurrence of R.sup.4a is independently hydrogen, or
unsubstituted or substituted C.sub.1-4 aliphatic.
7. The compound of claim 6, wherein: X.sub.1 is CR.sup.1; and (i)
when ring A is connected through position (a), X.sub.2 is C; and
X.sub.3 is CR.sup.1; or (ii) when ring A is connected through
position (b), X.sub.3 is C; and X.sub.2 is CR.sup.1.
8. The compound of claim 6, wherein: R.sup.4b is H; and R.sup.2 is
methyl, ethyl, isopropyl, n-propyl, trifluoromethyl, tert-butyl,
cyclopropyl, or phenyl.
9. The compound of claim 6, wherein: G is --V.sub.1--R.sup.3; and
V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)--, or --S(O).sub.2--.
10. The compound of claim 6, wherein: R.sup.1 is hydrogen, chloro,
fluoro, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, cyano,
trifluoromethyl, methyl, ethyl, isopropyl, n-propyl, or tert-butyl;
and R.sup.10 is hydrogen.
11. The compound of claim 6, wherein: each substitutable carbon
chain atom in R.sup.3 is unsubstituted or substituted with 1-2
occurrences of --R.sup.5dd; each substitutable saturated ring
carbon atom in R.sup.3 is unsubstituted or substituted with .dbd.O,
.dbd.S, .dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2,
.dbd.N--OR.sup.5, .dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or --R.sup.5a; each
substitutable unsaturated ring carbon atom in R.sup.3 is
unsubstituted or is substituted with --R.sup.5a; each substitutable
ring nitrogen atom in R.sup.3 is unsubstituted or substituted with
--R.sup.9b; each R.sup.5a is independently halogen, --NO.sub.2,
--CN, --C(R.sup.5).dbd.C(R.sup.5).sub.2,
--C(R.sup.5).dbd.C(R.sup.5)(R.sup.10), --C.ident.--R.sup.5,
--OR.sup.5, --SR.sup.6, --S(O)R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, --N(R.sup.4).sub.2,
--NR.sup.4C(O)R.sup.5, --NR.sup.4C(O)N(R.sup.4).sub.2,
--NR.sup.4CO.sub.2R.sup.6, --OC(O)N(R.sup.4).sub.2,
--C(O)--C(O)R.sup.5, --C(O)R.sup.5, --C(O)N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--OR.sup.5,
--N(R.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6, --N(R.sup.4)SO.sub.2N(R.sup.4).sub.2,
--P(O)(R.sup.5).sub.2, --P(O)(OR.sup.5).sub.2, unsubstituted or
substituted C.sub.1-6 aliphatic, unsubstituted or substituted
3-10-membered cycloaliphatic, unsubstituted or substituted
4-10-membered heterocyclyl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or two adjacent
R.sup.5a, taken together with the intervening ring atoms, form an
unsubstituted or substituted fused aromatic ring or an
unsubstituted or substituted non-aromatic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; each occurrence of R.sup.5dd is independently halogen,
--OH, --O(C.sub.1-3 alkyl), --CN, --N(R.sup.4).sub.2,
--C(O)(C.sub.1-3 alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-3 alkyl),
--C(O)NH.sub.2, or --C(O)NH(C.sub.1-3 alkyl); each R.sup.4 is
independently hydrogen, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; or two R.sup.4 on the same nitrogen
atom, taken together with the nitrogen atom, form an unsubstituted
or substituted 5- to 6-membered heteroaryl or an unsubstituted or
substituted 4- to 8-membered heterocyclyl having, in addition to
the nitrogen atom, 0-2 ring heteroatoms selected from nitrogen,
oxygen, and sulfur; each R.sup.5 is independently hydrogen,
unsubstituted or substituted C.sub.1-6 aliphatic, unsubstituted or
substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
unsubstituted or substituted 6-10-membered aryl, or unsubstituted
or substituted 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur. each
R.sup.6 is independently unsubstituted or substituted C.sub.1-6
aliphatic, or unsubstituted or substituted 6-10-membered aryl; each
R.sup.7 is independently unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; each R.sup.9b is independently
--C(O)R.sup.5, --C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6,
--SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2, unsubstituted
C.sub.1-4 aliphatic, or C.sub.1-4 aliphatic substituted with 1-2
occurrences of R.sup.7 or R.sup.8; and each R.sup.8 is
independently halogen, --OH, --O(C.sub.1-3 alkyl), --CN,
--N(R.sup.4).sub.2, --C(O)(C.sub.1-3 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-3 alkyl), --C(O)NH.sub.2, or --C(O)NH(C.sub.1-3
alkyl).
12. The compound of claim 11, wherein: each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
--R.sup.5a; the total number of R.sup.5a substituents is p; p is
1-2; each R.sup.5a is independently halogen, --CN, --OH, C.sub.1-4
alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3 alkyl, fluoroalkyl,
--NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl,
--NHS(O).sub.2C.sub.1-3 alkyl, --NHC.sub.1-3 alkyl, --N(C.sub.1-3
alkyl).sub.2, 3-10-membered cycloaliphatic substituted with 0-2
occurrences of --R.sup.7a, 4-10-membered heterocyclyl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur substituted with 0-2 occurrences of --R.sup.7a,
6-10-membered aryl substituted with 0-2 occurrences of --R.sup.7a,
or 5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur substituted with 0-2
occurrences of --R.sup.7a; and each occurrence of R.sup.7a is
independently halogen, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl,
--O--C.sub.1-3 alkyl, --O--C.sub.1-3 fluoroalkyl, --NHC(O)C.sub.1-3
alkyl, --C(O)NHC.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
--NHS(O).sub.2C.sub.1-3 alkyl.
13. The compound of claim 11, represented by formula (III-a-i):
##STR00622## wherein: each occurrence of R.sup.1 is independently
hydrogen, chloro, fluoro, hydroxy, trifluoromethyl, or methyl;
R.sup.10 is hydrogen; G is --V.sub.1--R.sup.3; and V.sub.1 is
--C(O)--, --C(O)--N(R.sup.4a)-- or --S(O).sub.2--.
14. The compound of claim 13, wherein R.sup.1 is hydrogen.
15. The compound of claim 13, wherein R.sup.2 is methyl, ethyl,
isopropyl, n-propyl, trifluoromethyl, tert-butyl, cyclopropyl, or
phenyl.
16. The compound of claim 13, wherein R.sup.2 is methyl, ethyl,
isopropyl, or n-propyl.
17. The compound of claim 13, wherein: each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
--R.sup.5a; the total number of R.sup.5a substituents is p; p is
1-2; each R.sup.5a is independently halogen, --CN, --OH, C.sub.1-4
alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3
fluoroalkyl, --NHC(O)C.sub.1-3 alkyl, --C(O)NHC.sub.1-3 alkyl,
--NHC(O)NHC.sub.1-3 alkyl, --NHS(O).sub.2C.sub.1-3 alkyl,
3-10-membered cycloaliphatic substituted with 0-2 occurrences of
--R.sup.7a, 4-10-membered heterocyclyl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur
substituted with 0-2 occurrences of --R.sup.7a, 6-10-membered aryl
substituted with 0-2 occurrences of --R.sup.7a, or 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of
--R.sup.7a; and each occurrence of R.sup.7a is independently
halogen, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3
alkyl, --O--C.sub.1-3 fluoroalkyl, --NHC(O)C.sub.1-3 alkyl,
--C(O)NHC.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
--NHS(O).sub.2C.sub.1-3 alkyl.
18. The compound of claim 11, represented by formula (III-a-v):
##STR00623## wherein: each occurrence of R.sup.1 is independently
hydrogen, chloro, fluoro, hydroxy, trifluoromethyl, or methyl;
R.sup.10 is hydrogen; G is --V.sub.1--R.sup.3; and V.sub.1 is
--C(O)--, --C(O)--N(R.sup.4a)-- or --S(O).sub.2--.
19. The compound of claim 18, wherein R.sup.1 is hydrogen.
20. The compound of claim 18, wherein R.sup.2 is methyl, ethyl,
isopropyl, n-propyl, trifluoromethyl, tert-butyl, cyclopropyl, or
phenyl.
21. The compound of claim 18, wherein R.sup.2 is methyl, ethyl,
isopropyl, or n-propyl.
22. The compound of claim 18, wherein: each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
--R.sup.5a; the total number of Rya substituents is p; p is 1-2;
each R.sup.5a is independently halogen, --CN, --OH, C.sub.1-4
alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3
fluoroalkyl, --NHC(O)C.sub.1-3 alkyl, --C(O)NHC.sub.1-3 alkyl,
--NHC(O)NHC.sub.1-3 alkyl, --NHS(O).sub.2C.sub.1-3 alkyl,
3-10-membered cycloaliphatic substituted with 0-2 occurrences of
--R.sup.7a, 4-10-membered heterocyclyl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur
substituted with 0-2 occurrences of --R.sup.7a, 6-10-membered aryl
substituted with 0-2 occurrences of --R.sup.7a, or 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of
--R.sup.7a; and each occurrence of R.sup.7a is independently
halogen, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3
alkyl, --O--C.sub.1-3 fluoroalkyl, --NHC(O)C.sub.1-3 alkyl,
--C(O)NHC.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
--NHS(O).sub.2C.sub.1-3 alkyl.
23. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
24. A method of treating a proliferative disorder in a patient
comprising administering to said patient a therapeutically
effective amount of a compound of claim 1.
25. The method of claim 24, wherein the proliferative disorder is
breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute
myelogenous leukemia, or acute lymphoblastic leukemia.
26. A method for inhibiting HDAC6 activity in a patient comprising
administering a pharmaceutical composition comprising an amount of
a compound of claim 1 effective to inhibit HDAC6 activity in the
patient.
Description
PRIORITY CLAIM
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of U.S. Provisional Patent Application Ser. No.
61/339,138, filed Feb. 26, 2010, incorporated by reference in its
entirety, and U.S. Provisional Patent Application Ser. No.
61/426,314, filed Dec. 22, 2010, incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The invention relates to compounds and methods for the
selective inhibition of HDAC6. The present invention relates to
compounds useful as HDAC6 inhibitors. The invention also provides
pharmaceutical compositions comprising the compounds of the
invention and methods of using the compositions in the treatment of
various diseases.
BACKGROUND OF THE INVENTION
[0003] Histone deacetylase 6 (HDAC6) is a member of a family of
amidohydrolases commonly referred as histone or lysine deacetylases
(HDACs or KDACs) as they catalyze the removal of acetyl groups from
the s-amino group of lysine residues from proteins. The family
includes 18 enzymes which can be divided in 3 main classes based on
their sequence homology to yeast enzymes Rpd3 (Class I), Hda1
(Class II) and Sir2 (Class III). A fourth class was defined with
the finding of a distinct mammalian enzyme--HDAC11 (reviewed in
Yang, et al., Nature Rev. Mot Cell Biol. 2008, 9:206-218 and in
Saunders and Verdin, Oncogene 2007, 26 (37):5489-5504).
Biochemically, Class I (HDAC1, 2, 3, 8) and Class II (HDAC4, 5, 6,
7, 9, 10) and Class IV (HDAC11) are Zn.sup.2+-dependent enzymes,
while Class III (SIRT1-7) are dependent on nicotinamide adenine
dinucleotide (NAD.sup.+) for activity. Unlike all other HDACs,
HDAC6 resides primarily in the cytosol. It has 2 functional
catalytic domains and a carboxy-terminal Zn.sup.2+-finger ubiquitin
binding domain that binds ubiquitinated misfolded proteins
(Kawaguchi et al., Cell 2003, 115(6):727-738), ubiquitin (Boyaullt
et al., EMBO J. 2006, 25(14): 3357-3366), as well as ubiquitin-like
FAT10 modifier (Kalveram et al., J Cell Sci. 2008,
121(24):4079-4088). Known substrates of HDAC6 include cytoskeletal
proteins .alpha.-tubulin and cortactin; .beta.-catenin which forms
part of adherens junctions and anchors the actin cytoskeleton; the
chaperone Hsp90; and the redox regulatory proteins peroxiredoxin
(Prx) I and Prx II (reviewed in Boyault et al., Oncogene 2007,
26(37):5468-5476; Matthias et al., Cell Cycle 2008, 7(1):7-10; Li
et al., J Biol. Chem. 2008, 283(19):12686-12690; Parmigiani et al.,
Proc. Natl. Acad. Sci. USA 2009, 105(28):9633-9638). Thus, HDAC6
mediates a wide range of cellular functions including
microtubule-dependent trafficking and signaling, membrane
remodeling and chemotactic motility, involvement in control of
cellular adhesion, ubiquitin level sensing, regulation of chaperone
levels and activity, and responses to oxidative stress. All of
these functions may be important in tumorigenesis, tumor growth and
survival as well as metastasis (Simms-Waldrip et al., Mol. Genet.
Metabolism 2008, 94(3):283-286; Rodriguez-Gonzalez et al., Cancer
Res. 2008, 68(8):2557-2560; Kapoor, Int. J. Cancer 2009, 124:509;
Lee et al., Cancer Res. 2008, 68(18):7561-7569). Recent studies
have shown HDAC6 to be important in autophagy, an alternative
pathway for protein degradation that compensates for deficiencies
in the activity of the ubiquitin proteasome system or expression of
proteins prone to form aggregates and can be activated following
treatment with a proteasome inhibitor (Kawaguchi et al., Cell 2003,
115(6):727-738; Iwata et al., J. Biol. Chem. 2005, 280(48):
40282-40292; Ding et al., Am. J. Pathol. 2007, 171:513-524, Pandey
et al., Nature 2007, 447(7146):860-864). Although the molecular
mechanistic details are not completely understood, HDAC6 binds
ubiquitinated or ubiquitin-like conjugated misfolded proteins which
would otherwise induce proteotoxic stress and then serves as an
adaptor protein to traffic the ubiquitinated cargo to the
microtubule organizing center using the microtubule network via its
known association with dynein motor protein. The resulting
perinuclear aggregates, known as aggresomes, are then degraded by
fusion with lysosomes in an HDAC6- and cortactin-dependent process
which induces remodeling of the actin cytoskeleton proximal to
aggresomes (Lee et al., EMBO J. 2010, 29:969-980). In addition,
HDAC6 regulates a variety of biological processes dependent on its
association with the microtubular network including cellular
adhesion (Tran et al., J. Cell Sci. 2007, 120(8):1469-1479) and
migration (Zhang et al., Mol. Cell. 2007, 27(2):197-213; reviewed
in Valenzuela-Fernandez et al., Trends Cell. Biol. 2008,
18(6):291-297), epithelial to mesenchymal transition (Shan et al.,
J. Biol. Chem. 2008, 283(30):21065-21073), resistance to anoikis
(Lee et al., Cancer Res. 2008, 68(18):7561-7569), epithelial growth
factor-mediated Wnt signaling via .beta.-catenin deacetylation (Li
et al., J. Biol. Chem. 2008, 283(19):12686-12690) and epithelial
growth factor receptor stabilization by endocytic trafficking
(Lissanu Deribe et al., Sci. Signal. 2009, 2(102): ra84; Gao et
al., J. Biol. Chem. 2010, 285:11219-11226); all events that promote
oncogenesis and metastasis (Lee et al., Cancer Res. 2008,
68(18):7561-7569). HDAC6 activity is known to be upregulated by
Aurora A kinase in cilia formation (Pugacheva et al., Cell 2007,
129(7):1351-1363) and indirectly by farnesyl transferase with which
HDAC6 forms a complex with microtubules (Zhou et al., J. Biol.
Chem. 2009, 284(15): 9648-9655). Also, HDAC6 is negatively
regulated by tau protein (Perez et al., J. Neurochem. 2009, 109(6):
1756-1766).
[0004] Diseases in which selective HDAC6 inhibition could have a
potential benefit include cancer (reviewed in Simms-Waldrip et al.,
Mol. Genet. Metabolism 2008, 94(3):283-286 and Rodriguez-Gonzalez
et al., Cancer Res. 2008, 68(8):2557-2560), specifically: multiple
myeloma (Hideshima et al., Proc. Natl. Acad. Sci. USA 2005,
102(24):8567-8572); lung cancer (Kamemura et al., Biochem. Biophys.
Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro et al.,
Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et
al., Cancer Res. 2008, 68(18):7561-7569); prostate cancer (Mellado
et al., Clin. Trans. Onco. 2009, 11(1):5-10); pancreatic cancer
(Nawrocki et al., Cancer Res. 2006, 66(7):3773-3781); renal cancer
(Cha et al., Clin. Cancer Res. 2009, 15(3):840-850); and leukemias
such as acute myeloid leukemia (AML) (Fiskus et al., Blood 2008,
112(7):2896-2905) and acute lymphoblastic leukemia (ALL)
(Rodriguez-Gonzalez et al., Blood 2008, 112(11): Abstract
1923).
[0005] Inhibition of HDAC6 may also have a role in cardiovascular
disease, i.e. cardiovascular stress, including pressure overload,
chronic ischemia, and infarction-reperfusion injury (Tannous et
al., Circulation 2008, 117(24):3070-3078); bacterial infection,
including those caused by uropathogenic Escherichia coli (Dhakal
and Mulve, J. Biol. Chem. 2008, 284(1):446-454); neurological
diseases caused by accumulation of intracellular protein aggregates
such as Huntington's disease (reviewed in Kazantsev et al., Nat.
Rev. Drug Disc. 2008, 7(10):854-868; see also Dompierre et al., J.
Neurosci. 2007, 27 (13):3571-3583; Kozikowski et al., J. Med. Chem.
2007, 50:3054-3061) or central nervous system trauma caused by
tissue injury, oxidative-stress induced neuronal or axomal
degeneration (Rivieccio et al., Proc. Natl. Acad. Sci. USA 2009,
106(46):19599-195604); and inflammation, including reduction of
pro-inflammatory cytokine IL-1.beta. (Carta et al., Blood 2006,
108(5):1618-1626), increased expression of the FOXP3 transcription
factor, which induces immunosuppressive function of regulatory
T-cells resulting in benefits in chronic diseases such as
rheumatoid arthritis, psoriasis, multiple sclerosis, lupus and
organ transplant rejection (reviewed in Wang et al., Nat. Rev. Drug
Disc. 2009, 8(12):969-981).
[0006] Given the complex function of HDAC6, selective inhibitors
could have potential utility when used alone or in combination with
other chemotherapeutics such as microtubule destabilizing agents
(Zhou et al., J. Biol. Chem. 2009, 284(15): 9648-9655); Hsp90
inhibitors (Rao et al., Blood 2008, 112(5) 1886-1893); inhibitors
of Hsp90 client proteins, including receptor tyrosine kinases such
as Her-2 or VEGFR (Bhalla et al., J. Clin. Oncol. 2006, 24 (18S):
Abstract 1923; Park et al., Biochem. Biophys. Res. Commun. 2008,
368(2):318-322), and signaling kinases such as Bcr-Abl, Akt, mutant
FLT-3, c-Raf, and MEK (Bhalla et al., J. Clin. Oncol. 2006, 24
(18S): Abstract 1923; Kamemura et al., Biochem. Biophys. Res.
Commun. 2008, 374(1):84-89); inhibitors of cell cycle kinases
Aurora A and Aurora B (Pugacheva et al., Cell 2007,
129(7):1351-1363; Park et al., J. Mol. Med. 2008, 86(1):117-128;
Cha et al., Clin. Cancer Res. 2009, 15(3):840-850); EGFR inhibitors
(Lissanu Deribe et al., Sci. Signal. 2009, 2 (102): ra84; Gao et
al., J. Biol. Chem. 2010, 285:11219-11226) and proteasome
inhibitors (Hideshima et al., Proc. Natl. Acad. Sci. USA 2005,
102(24):8567-8572) or other inhibitors of the ubiquitin proteasome
system such as ubiquitin and ubiqutin-like activating (E1),
conjugation (E2), ligase enzymes (E3, E4) and deubiquitinase
enzymes (DUBs) as well as modulators of autophagy and protein
homeostasis pathways. In addition, HDAC6 inhibitors could be
combined with radiation therapy (Kim et al., Radiother. Oncol.
2009, 92(1): 125-132.
[0007] Clearly, it would be beneficial to provide novel HDAC6
inhibitors that possess good therapeutic properties, especially for
the treatment of proliferative diseases or disorders.
DETAILED DESCRIPTION OF THE INVENTION
1. General Description of Compounds of the Invention
[0008] The present invention provides compounds that are effective
inhibitors of HDAC6. These compounds are useful for inhibiting
HDAC6 activity in vitro and in vivo, and are especially useful for
the treatment of various cell proliferative diseases or disorders.
The compounds of the invention are represented by formula (I):
##STR00002##
[0009] or a pharmaceutically acceptable salt thereof; wherein:
[0010] ring A is an aromatic 6-membered ring connected through one
of positions (a) or (b); [0011] X.sub.1 is CR.sup.1 or N; [0012]
(i) when ring A is connected through position (a), X.sub.2 is C;
and X.sub.3 is CR.sup.1 or N; or [0013] (ii) when ring A is
connected through position (b), X.sub.3 is C; and X.sub.2 is
CR.sup.1 or N;
[0014] each occurrence of R.sup.1 is independently hydrogen,
halogen, C.sub.1-4 alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3
alkyl, --O--C.sub.1-3 fluoroalkyl, cyano, hydroxy,
--NHC(O)C.sub.1-3 alkyl, --NHC.sub.1-3 alkyl,
--N(C.sub.1-3alkyl).sub.2, --C(O)NHC.sub.1-3 alkyl,
--NHC(O)NHC.sub.1-3 alkyl, or --NHS(O).sub.2C.sub.1-3 alkyl;
[0015] each occurrence of R.sup.10 is independently hydrogen,
halogen, hydroxy, --O--C.sub.1-3alkyl, or --O--C.sub.1-3
fluoroalkyl;
[0016] R.sup.2 is C.sub.1-6 aliphatic, C.sub.1-6 fluoroaliphatic,
or unsubstituted or substituted 6-10-membered aryl;
[0017] R.sup.4b is hydrogen, or C.sub.1-4 aliphatic;
[0018] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.2-V.sub.1--R.sup.3,
-L.sub.2-V.sub.2--R.sup.3, or -L.sub.1-R.sup.3;
[0019] L.sub.1 is an unsubstituted or substituted C.sub.1-3
alkylene chain;
[0020] L.sub.2 is an unsubstituted or substituted C.sub.2-3
alkylene chain;
[0021] V.sub.1 is --C(O)--, --C(S)--,
--C(O)--CR.sup.A.dbd.CR.sup.A--, --C(O)--N(R.sup.4a)--,
--C(O)--O--, or --S(O).sub.2--;
[0022] V.sub.2 is --N(R.sup.4a)--, --N(R.sup.4a)--C(O)--,
--SO.sub.2--N(R.sup.4a)--, --N(R.sup.4a)--SO.sub.2--, --O--, --S--,
--S(O)--, --N(R.sup.4a)--C(O)--N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--O--, --O--C(O)--N(R.sup.4a)--, or
--N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--;
[0023] R.sup.3 is unsubstituted or substituted C.sub.1-6 aliphatic,
unsubstituted or substituted 3-10-membered cycloaliphatic,
unsubstituted or substituted 4-10-membered heterocyclyl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur;
[0024] each occurrence of R.sup.A is independently hydrogen,
fluoro, or unsubstituted or substituted C.sub.1-4 aliphatic;
and
[0025] each occurrence of R.sup.4a is independently hydrogen, or
unsubstituted or substituted C.sub.1-4 aliphatic.
2. Compounds and Definitions
[0026] Compounds of this invention include those described
generally for formula (I) above, and are further illustrated by the
classes, subclasses, and species disclosed herein. As used herein,
the following definitions shall apply unless otherwise
indicated.
[0027] As described herein, compounds of the invention may be
optionally substituted with one or more substituents, such as are
illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the invention. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted", whether preceded by the term
"optionally" or not, means that a hydrogen radical of the
designated moiety is replaced with the radical of a specified
substituent, provided that the substitution results in a stable or
chemically feasible compound. The term "substitutable", when used
in reference to a designated atom, means that attached to the atom
is a hydrogen radical, which hydrogen atom can be replaced with the
radical of a suitable substituent. Unless otherwise indicated, an
"optionally substituted" group may have a substituent at each
substitutable position of the group, and when more than one
position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent
may be either the same or different at every position. Combinations
of substituents envisioned by this invention are preferably those
that result in the formation of stable or chemically feasible
compounds.
[0028] A stable compound or chemically feasible compound is one in
which the chemical structure is not substantially altered when kept
at a temperature from about -80.degree. C. to about +40.degree. C.,
in the absence of moisture or other chemically reactive conditions,
for at least a week, or a compound which maintains its integrity
long enough to be useful for therapeutic or prophylactic
administration to a patient.
[0029] The phrase "one or more substituents", as used herein,
refers to a number of substituents that equals from one to the
maximum number of substituents possible based on the number of
available bonding sites, provided that the above conditions of
stability and chemical feasibility are met.
[0030] As used herein, the term "independently selected" means that
the same or different values may be selected for multiple instances
of a given variable in a single compound.
[0031] As used herein, the term "aromatic" includes aryl and
heteroaryl groups as described generally below and herein.
[0032] The term "aliphatic" or "aliphatic group", as used herein,
means an optionally substituted straight-chain or branched
C.sub.1-12 hydrocarbon, or a cyclic C.sub.1-12 hydrocarbon which is
completely saturated or which contains one or more units of
unsaturation, but which is not aromatic (also referred to herein as
"carbocycle", "cycloaliphatic", "cycloalkyl", or "cycloalkenyl").
For example, suitable aliphatic groups include optionally
substituted linear, branched or cyclic alkyl, alkenyl, alkynyl
groups and hybrids thereof, such as (cycloalkyl)alkyl,
(cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. Unless otherwise
specified, in various embodiments, aliphatic groups have 1-12,
1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.
[0033] The term "alkyl", used alone or as part of a larger moiety,
refers to an optionally substituted straight or branched chain
hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2
carbon atoms.
[0034] The term "alkenyl", used alone or as part of a larger
moiety, refers to an optionally substituted straight or branched
chain hydrocarbon group having at least one double bond and having
2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
[0035] The term "alkynyl", used alone or as part of a larger
moiety, refers to an optionally substituted straight or branched
chain hydrocarbon group having at least one triple bond and having
2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
[0036] The terms "cycloaliphatic", "carbocycle", "carbocyclyl",
"carbocyclo", or "carbocyclic", used alone or as part of a larger
moiety, refer to an optionally substituted saturated or partially
unsaturated cyclic aliphatic ring system having from 3 to about 14
ring carbon atoms. In some embodiments, the cycloaliphatic group is
an optionally substituted monocyclic hydrocarbon having 3-8 or 3-6
ring carbon atoms. Cycloaliphatic groups include, without
limitation, optionally substituted cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl. The
terms "cycloaliphatic", "carbocycle", "carbocyclyl", "carbocyclo",
or "carbocyclic" also include optionally substituted bridged or
fused bicyclic rings having 6-12, 6-10, or 6-8 ring carbon atoms,
wherein any individual ring in the bicyclic system has 3-8 ring
carbon atoms.
[0037] The term "cycloalkyl" refers to an optionally substituted
saturated ring system of about 3 to about 10 ring carbon atoms.
Exemplary monocyclic cycloalkyl rings include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
[0038] The term "cycloalkenyl" refers to an optionally substituted
non-aromatic monocyclic or multicyclic ring system containing at
least one carbon-carbon double bond and having about 3 to about 10
carbon atoms. Exemplary monocyclic cycloalkenyl rings include
cyclopentyl, cyclohexenyl, and cycloheptenyl.
[0039] The terms "haloaliphatic", "haloalkyl", "haloalkenyl" and
"haloalkoxy" refer to an aliphatic, alkyl, alkenyl or alkoxy group,
as the case may be, which is substituted with one or more halogen
atoms. As used herein, the term "halogen" or "halo" means F, Cl,
Br, or I. The term "fluoroaliphatic" refers to a haloaliphatic
wherein the halogen is fluoro, including perfluorinated aliphatic
groups. Examples of fluoroaliphatic groups include, without
limitation, fluoromethyl, difluoromethyl, trifluoromethyl,
2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl,
1,2,2-trifluoroethyl, and pentafluoroethyl.
[0040] The term "heteroatom" refers to one or more of oxygen,
sulfur, nitrogen, phosphorus, or silicon (including, any oxidized
form of nitrogen, sulfur, phosphorus, or silicon; the quaternized
form of any basic nitrogen or; a substitutable nitrogen of a
heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl),
NH (as in pyrrolidinyl) or NR+ (as in N-substituted
pyrrolidinyl)).
[0041] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to an optionally substituted C.sub.6-14aromatic hydrocarbon
moiety comprising one to three aromatic rings. Preferably, the aryl
group is a C.sub.6-10aryl group. Aryl groups include, without
limitation, optionally substituted phenyl, naphthyl, or
anthracenyl. The terms "aryl" and "ar-", as used herein, also
include groups in which an aryl ring is fused to one or more
cycloaliphatic rings to form an optionally substituted cyclic
structure such as a tetrahydronaphthyl, indenyl, or indanyl ring.
The term "aryl" may be used interchangeably with the terms "aryl
group", "aryl ring", and "aromatic ring".
[0042] An "aralkyl" or "arylalkyl" group comprises an aryl group
covalently attached to an alkyl group, either of which
independently is optionally substituted. Preferably, the aralkyl
group is C.sub.6-10arylC.sub.1-6alkyl, including, without
limitation, benzyl, phenethyl, and naphthylmethyl.
[0043] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., "heteroaralkyl", or
"heteroaralkoxy", refer to groups having 5 to 14 ring atoms,
preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 .pi.
electrons shared in a cyclic array; and having, in addition to
carbon atoms, from one to five heteroatoms. A heteroaryl group may
be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term "heteroatom"
refers to nitrogen, oxygen, or sulfur, and includes any oxidized
form of nitrogen or sulfur, and any quaternized form of a basic
nitrogen. For example, a nitrogen atom of a heteroaryl may be a
basic nitrogen atom and may also be optionally oxidized to the
corresponding N-oxide. When a heteroaryl is substituted by a
hydroxy group, it also includes its corresponding tautomer. The
terms "heteroaryl" and "heteroar-", as used herein, also include
groups in which a heteroaromatic ring is fused to one or more aryl,
cycloaliphatic, or heterocycloaliphatic rings. Nonlimiting examples
of heteroaryl groups include thienyl, furanyl, pyrrolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
The term "heteroaryl" may be used interchangeably with the terms
"heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of
which terms include rings that are optionally substituted. The term
"heteroaralkyl" refers to an alkyl group substituted by a
heteroaryl, wherein the alkyl and heteroaryl portions independently
are optionally substituted.
[0044] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used
interchangeably and refer to a stable 3- to 8-membered monocyclic
or 7-10-membered bicyclic heterocyclic moiety that is either
saturated or partially unsaturated, and having, in addition to
carbon atoms, one or more, preferably one to four, heteroatoms, as
defined above. When used in reference to a ring atom of a
heterocycle, the term "nitrogen" includes a substituted nitrogen.
As an example, in a saturated or partially unsaturated ring having
0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the
nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl).
[0045] A heterocyclic ring can be attached to its pendant group at
any heteroatom or carbon atom that results in a stable structure
and any of the ring atoms can be optionally substituted. Examples
of such saturated or partially unsaturated heterocyclic radicals
include, without limitation, tetrahydrofuranyl, tetrahydrothienyl,
piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,
dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl,
morpholinyl, and thiamorpholinyl. A heterocyclyl group may be
mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term
"heterocyclylalkyl" refers to an alkyl group substituted by a
heterocyclyl, wherein the alkyl and heterocyclyl portions
independently are optionally substituted. Additionally, a
heterocyclic ring also includes groups in which the heterocyclic
ring is fused to one or more aryl rings.
[0046] As used herein, the term "partially unsaturated" refers to a
ring moiety that includes at least one double or triple bond
between ring atoms. The term "partially unsaturated" is intended to
encompass rings having multiple sites of unsaturation, but is not
intended to include aromatic (e.g., aryl or heteroaryl) moieties,
as herein defined.
[0047] The term "alkylene" refers to a bivalent alkyl group. An
"alkylene chain" is a polymethylene group, i.e.,
--(CH.sub.2).sub.n'--, wherein n' is a positive integer, preferably
from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
An optionally substituted alkylene chain is a polymethylene group
in which one or more methylene hydrogen atoms is optionally
replaced with a substituent. Suitable substituents include those
described below for a substituted aliphatic group and also include
those described in the specification herein. It will be appreciated
that two substituents of the alkylene group may be taken together
to form a ring system. In certain embodiments, two substituents can
be taken together to form a 3-7-membered ring. The substituents can
be on the same or different atoms.
[0048] An alkylene chain also can be optionally interrupted by a
functional group. An alkylene chain is "interrupted" by a
functional group when an internal methylene unit is interrupted by
the functional group. Examples of suitable "interrupting functional
groups" are described in the specification and claims herein.
[0049] For purposes of clarity, all bivalent groups described
herein, including, e.g., the alkylene chain linkers described
above, are intended to be read from left to right, with a
corresponding left-to-right reading of the formula or structure in
which the variable appears.
[0050] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the
like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy
and the like) group may contain one or more substituents and thus
may be "optionally substituted". In addition to the substituents
defined above and herein, suitable substituents on the unsaturated
carbon atom of an aryl or heteroaryl group also include and are
generally selected from -halo, --NO.sub.2, --CN, --R.sup.+,
--C(R.sup.+).dbd.C(R.sup.+).sub.2, --C.ident.C--R.sup.+,
--OR.sup.+, --SR.sup.o, --S(O)R.sup.o, --SO.sub.2R.sup.o,
--SO.sub.3R.sup.+, --SO.sub.2N(R.sup.+).sub.2, --N(R.sup.+).sub.2,
--NR.sup.+C(O)R.sup.+, --NR.sup.+C(S)R.sup.+,
--NR.sup.+C(O)N(R.sup.+).sub.2, --NR.sup.+C(S)N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--R.sup.o, --NR.sup.+CO.sub.2R.sup.+,
--NR.sup.+SO.sub.2R.sup.o, --NR.sup.+SO.sub.2N(R.sup.+).sup.2,
--O--C(O)R.sup.+, --O--CO.sub.2R.sup.+, --OC(O)N(R.sup.+).sub.2,
--C(O)R.sup.+, --C(S)R.sup.o, --CO.sub.2R.sup.+,
--C(O)--C(O)R.sup.+, --C(O)N(R.sup.+).sub.2,
--C(S)N(R.sup.+).sub.2, --C(O)N(R.sup.+)--OR.sup.+,
--C(O)N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+).sub.2,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+)--C(O)R.sup.+,
--C(.dbd.NR.sup.+)--N(R.sup.+).sub.2, --C(.dbd.NR.sup.+)--OR.sup.+,
--N(R.sup.+)--N(R.sup.+).sub.2,
--C(.dbd.NR.sup.+)--N(R.sup.+)--OR.sup.+, --P(O)(R.sup.+).sub.2,
--P(O)(OR.sup.+).sub.2, --O--P(O)--OR.sup.+, and
--P(O)(NR.sup.+)--N(R.sup.+).sub.2, wherein R.sup.+, independently,
is hydrogen or an optionally substituted aliphatic, aryl,
heteroaryl, cycloaliphatic, or heterocyclyl group, or two
independent occurrences of R.sup.+ are taken together with their
intervening atom(s) to form an optionally substituted 5-7-membered
aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring. Each
R.sup.o is an optionally substituted aliphatic, aryl, heteroaryl,
cycloaliphatic, or heterocyclyl group.
[0051] An aliphatic or heteroaliphatic group, or a non-aromatic
carbycyclic or heterocyclic ring may contain one or more
substituents and thus may be "optionally substituted". Unless
otherwise defined above and herein, suitable substituents on the
saturated carbon of an aliphatic or heteroaliphatic group, or of a
non-aromatic carbocyclic or heterocyclic ring are selected from
those listed above for the unsaturated carbon of an aryl or
heteroaryl group and additionally include the following: .dbd.O,
.dbd.S, .dbd.C(R*).sub.2, .dbd.N--N(R*).sub.2, .dbd.N--OR*,
.dbd.N--NHC(O)R*,
.dbd.N--NHCO.sub.2R.sup.o.dbd.N--NHSO.sub.2R.sup.o or .dbd.N--R*
where R.sup.o is defined above, and each R* is independently
selected from hydrogen or an optionally substituted C.sub.1-6
aliphatic group.
[0052] In addition to the substituents defined above and herein,
optional substituents on the nitrogen of a non-aromatic
heterocyclic ring also include and are generally selected from
--R.sup.+, --N(R.sup.+).sub.2, --C(O)R.sup.+, --C(O)OR.sup.+,
--C(O)C(O)R.sup.+, --C(O)CH.sub.2C(O)R.sup.+, --S(O).sub.2R.sup.+,
--S(O).sub.2N(R.sup.+).sub.2, --C(S)N(R.sup.+).sub.2,
--C(.dbd.NH)--N(R.sup.+).sub.2, or --N(R.sup.+)S(O).sub.2R.sup.+;
wherein each R.sup.+ is defined above. A ring nitrogen atom of a
heteroaryl or non-aromatic heterocyclic ring also may be oxidized
to form the corresponding N-hydroxy or N-oxide compound. A
nonlimiting example of such a heteroaryl having an oxidized ring
nitrogen atom is N-oxidopyridyl.
[0053] As detailed above, in some embodiments, two independent
occurrences of R.sup.+ (or any other variable similarly defined in
the specification and claims herein), are taken together with their
intervening atom(s) to form a monocyclic or bicyclic ring selected
from 3-13-membered cycloaliphatic, 3-12-membered heterocyclyl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, or sulfur.
[0054] Exemplary rings that are formed when two independent
occurrences of R.sup.+ (or any other variable similarly defined in
the specification and claims herein), are taken together with their
intervening atom(s) include, but are not limited to the following:
a) two independent occurrences of R.sup.+ (or any other variable
similarly defined in the specification or claims herein) that are
bound to the same atom and are taken together with that atom to
form a ring, for example, N(R.sup.+).sub.2, where both occurrences
of R.sup.+ are taken together with the nitrogen atom to form a
piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two
independent occurrences of R.sup.+ (or any other variable similarly
defined in the specification or claims herein) that are bound to
different atoms and are taken together with both of those atoms to
form a ring, for example where a phenyl group is substituted with
two occurrences of OR.sup.+
##STR00003##
these two occurrences of R.sup.+ are taken together with the oxygen
atoms to which they are bound to form a fused 6-membered oxygen
containing ring:
##STR00004##
It will be appreciated that a variety of other rings (e.g., spiro
and bridged rings) can be formed when two independent occurrences
of R+ (or any other variable similarly defined in the specification
and claims herein) are taken together with their intervening
atom(s) and that the examples detailed above are not intended to be
limiting.
[0055] Unless otherwise stated, structures depicted herein are also
meant to include all isomeric (e.g., enantiomeric, diastereomeric,
and geometric (or conformational)) forms of the structure; for
example, the R and S configurations for each asymmetric center, (Z)
and (E) double bond isomers, and (Z) and (E) conformational
isomers. Therefore, single stereochemical isomers as well as
enantiomeric, diastereomeric, and geometric (or conformational)
mixtures of the present compounds are within the scope of the
invention. Unless otherwise stated, all tautomeric forms of the
compounds of the invention are within the scope of the invention.
Additionally, unless otherwise stated, structures depicted herein
are also meant to include compounds that differ only in the
presence of one or more isotopically enriched atoms. For example,
compounds having the present structures except for the replacement
of hydrogen by deuterium or tritium, or the replacement of a carbon
by a 13C- or 14C-enriched carbon are within the scope of this
invention. Such compounds are useful, for example, as analytical
tools or probes in biological assays.
[0056] The terms "stereoisomer", "enantiomer", "diastereomer",
"epimer", and "chiral center", are used herein in accordance with
the meaning each is given in ordinary usage by those of ordinary
skill in the art. Thus, stereoisomers are compounds that have the
same atomic connectivity, but differ in the spatial arrangement of
the atoms. Enantiomers are stereoisomers that have a mirror image
relationship, that is, the stereochemical configuration at all
corresponding chiral centers is opposite. Diastereomers are
stereoisomers having more than one chiral center, which differ from
one another in that the stereochemical configuration of at least
one, but not all, of the corresponding chiral centers is opposite.
Epimers are diastereomers that differ in stereochemical
configuration at only one chiral center.
[0057] It is to be understood that, when a disclosed compound has
at least one chiral center, the present invention encompasses one
enantiomer of the compound, substantially free from the
corresponding optical isomer, a racemic mixture of both optical
isomers of the compound, and mixtures enriched in one enantiomer
relative to its corresponding optical isomer. When a mixture is
enriched in one enantiomer relative to its optical isomer, the
mixture contains, for example, an enantiomeric excess of at least
50%, 75%, 90%, 95%, 99%, or 99.5%.
[0058] The enantiomers of the present invention may be resolved by
methods known to those skilled in the art, for example by formation
of diastereoisomeric salts which may be separated, for example, by
crystallization; formation of diastereoisomeric derivatives or
complexes which may be separated, for example, by crystallization,
gas-liquid or liquid chromatography; selective reaction of one
enantiomer with an enantiomer-specific reagent, for example
enzymatic esterification; or gas-liquid or liquid chromatography in
a chiral environment, for example on a chiral support for example
silica with a bound chiral ligand or in the presence of a chiral
solvent. Where the desired enantiomer is converted into another
chemical entity by one of the separation procedures described
above, a further step is required to liberate the desired
enantiomeric form. Alternatively, specific enantiomers may be
synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0059] When a disclosed compound has at least two chiral centers,
the present invention encompasses a diastereomer substantially free
of other diastereomers, an enantiomeric pair of diastereomers
substantially free of other stereoisomers, mixtures of
diastereomers, mixtures of enantiomeric pairs of diastereomers,
mixtures of diastereomers in which one diastereomer is enriched
relative to the other diastereomer(s), and mixtures of enantiomeric
pairs of diastereomers in which one enantiomeric pair of
diastereomers is enriched relative to the other stereoisomers. When
a mixture is enriched in one diastereomer or enantiomeric pair of
diastereomers pairs relative to the other stereoisomers, the
mixture is enriched with the depicted or referenced diastereomer or
enantiomeric pair of diastereomers relative to other stereoisomers
for the compound, for example, by a molar excess of at least 50%,
75%, 90%, 95%, 99%, or 99.5%.
[0060] As used herein, the term "diastereomeric ratio" refers to
the ratio between diastereomers which differ in the stereochemical
configuration at one chiral center, relative to a second chiral
center in the same molecule. By way of example, a chemical
structure with two chiral centers provides four possible
stereoisomers: R*R, R*S, S*R, and S*S, wherein the asterisk denotes
the corresponding chiral center in each stereoisomer. The
diastereomeric ratio for such a mixture of stereoisomers is the
ratio of one diastereomer and its enantiomer to the other
diastereomer and its enantiomer=(R*R S*S):(R*S S*R).
[0061] One of ordinary skill in the art will recognize that
additional stereoisomers are possible when the molecule has more
than two chiral centers. For purposes of the present invention, the
term "diastereomeric ratio" has identical meaning in reference to
compounds with multiple chiral centers as it does in reference to
compounds having two chiral centers. Thus, the term "diastereomeric
ratio" refers to the ratio of all compounds having R*R or S*S
configuration at the specified chiral centers to all compounds
having R*S or S*R configuration at the specified chiral centers.
For convenience, this ratio is referred to herein as the
diastereomeric ratio at the asterisked carbon, relative to the
second specified chiral center.
[0062] The diastereomeric ratio can be measured by any analytical
method suitable for distinguishing between diastereomeric compounds
having different relative stereochemical configurations at the
specified chiral centers. Such methods include, without limitation,
nuclear magnetic resonance (NMR), gas chromatography (GC), and high
performance liquid chromatography (HPLC) methods.
[0063] The diastereoisomeric pairs may be separated by methods
known to those skilled in the art, for example chromatography or
crystallization and the individual enantiomers within each pair may
be separated as described above. Specific procedures for
chromatographically separating diastereomeric pairs of precursors
used in the preparation of compounds disclosed herein are provided
the examples herein.
3. Description of Exemplary Compounds
[0064] In some embodiments, the compound of formula (I) is
represented by:
##STR00005##
[0065] wherein R.sup.1, R.sup.10, R.sup.2, R.sup.4b, K and G have
the values described herein. In certain embodiments, the compound
of formula (I) is represented by formulas (I-i) or (I-v), wherein
R.sup.1, R.sup.10, R.sup.2, R.sup.4b, and G have the values
described herein.
[0066] In some embodiments, the compound of formula (I) is
represented by formula (II-a):
##STR00006##
[0067] wherein:
[0068] ring A is an aromatic 6-membered ring connected through one
of positions (a) or (b); [0069] X.sub.1 is CR.sup.1 or N; [0070]
(i) when ring A is connected through position (a), X.sub.2 is C;
and X.sub.3 is CR.sup.1 or N; or [0071] (ii) when ring A is
connected through position (b), X.sub.3 is C; and X.sub.2 is
CR.sup.1 or N; and R.sup.1, R.sup.10, R.sup.2, R.sup.4b, and G have
the values described herein.
[0072] In some embodiments, the compound of formula (II-a) is
represented by:
##STR00007##
[0073] wherein R.sup.1, R.sup.10, R.sup.2, R.sup.4b, and G have the
values described herein. In certain embodiments, the compound of
formula (II-a) is represented by formulas (II-a-i) or (II-a-v),
wherein R.sup.1, R.sup.10, R.sup.2, R.sup.4b, and G have the values
described herein.
[0074] In some embodiments, the compound of formula (I) is
represented by formula (II-b):
##STR00008##
[0075] wherein:
[0076] ring A is an aromatic 6-membered ring connected through one
of positions (a) or (b);
[0077] wherein: [0078] X.sub.1 is CR.sup.1 or N; [0079] (i) when
ring A is connected through position (a), X.sub.2 is C; and X.sub.3
is CR.sup.1 or N; or [0080] (ii) when ring A is connected through
position (b), X.sub.3 is C; and X.sub.2 is CR.sup.1 or N;
[0081] and R.sup.1, R.sup.10, R.sup.2, R.sup.4b, and G have the
values described herein.
[0082] In some embodiments, the compound of formula (II-b) is
represented by:
##STR00009##
[0083] wherein R.sup.1, R.sup.10, R.sup.2, R.sup.4b, and G have the
values described herein. In certain embodiments, the compound of
formula (II) is represented by formulas (II-b-i) or (II-b-v),
wherein R.sup.1, R.sup.10, R.sup.2, R.sup.4b, and G have the values
described herein.
[0084] In some embodiments, the compound of formula (I) is
represented by:
##STR00010##
[0085] wherein R.sup.1, R.sup.10, R.sup.2, and G have the values
described herein. In certain embodiments, the compound of formula
(I) is represented by formulas (III-a-i) or (III-a-v), wherein
R.sup.1, R.sup.10, R.sup.2, and G have the values described
herein.
[0086] The values described below for each variable are with
respect to any of formulas (I), (H), (III), (IV), (V), (VI), or
their sub-formulas as described herein.
[0087] Each occurrence of the variable R.sup.1 is independently
hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-3 fluoroalkyl,
--O--C.sub.1-3 alkyl, --O--C.sub.1-3 fluoroalkyl, cyano, hydroxy,
--NHC(O)C.sub.1-3 alkyl, --NHC.sub.1-3 alkyl, --N(C.sub.1-3
alkyl).sub.2, --C(O)NHC.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl,
or --NHS(O).sub.2C.sub.1-3 alkyl. In some embodiments, each
occurrence of R.sup.1 is independently hydrogen, chloro, fluoro,
C.sub.1-4 alkyl, --O--C.sub.1-3 alkyl, trifluoromethyl, hydroxy, or
cyano. In certain embodiments, each occurrence of R.sup.1 is
independently hydrogen, chloro, fluoro, hydroxy, methoxy, ethoxy,
n-propoxy, isopropoxy, cyano, trifluoromethyl, methyl, ethyl,
isopropyl, n-propyl, or tert-butyl. In certain embodiments, each
occurrence of R.sup.1 is independently hydrogen, chloro, fluoro,
hydroxy, trifluoromethyl, or methyl. In certain embodiments,
R.sup.1 is hydrogen.
[0088] Each occurrence of the variable R.sup.10 is independently
hydrogen, halogen, hydroxy, --O--C.sub.1-3 alkyl, or --O--C.sub.1-3
fluoroalkyl. In some embodiments, R.sup.10 is hydrogen, chloro,
fluoro, hydroxy, methoxy, or ethoxy. In some embodiments, R.sup.10
is hydrogen.
[0089] The variable R.sup.2 is C.sub.1-6 aliphatic, C.sub.1-6
fluoroaliphatic, or unsubstituted or substituted 6-10-membered
aryl. In some embodiments, R.sup.2 is methyl, ethyl, isopropyl,
n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl,
or phenyl. In certain embodiments, R.sup.2 is methyl, ethyl,
isopropyl, n-propyl, trifluoromethyl, tert-butyl, cyclopropyl, or
phenyl. In certain embodiments, R.sup.2 is methyl, ethyl,
isopropyl, or n-propyl.
[0090] The variable R.sup.4b is hydrogen, or C.sub.1-4 aliphatic.
In some embodiments, R.sup.4b is hydrogen.
[0091] The variable G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.2-V.sub.1--R.sup.3,
-L.sub.2-V.sub.2--R.sup.3, or -L.sub.1-R.sup.3, wherein L.sub.1,
L.sub.2, V.sub.1, V.sub.2, and R.sup.3 have the values described
herein. In some embodiments, G is --V.sub.1--R.sup.3, or
--V.sub.1-L.sub.1-R.sup.3, wherein L.sub.1, V.sub.1, and R.sup.3
have the values described herein. In certain embodiments, G is
--V.sub.1--R.sup.3, wherein V.sub.1, and R.sup.3 have the values
described herein.
[0092] The variable L.sub.1 is an unsubstituted or substituted
C.sub.1-3 alkylene chain. In some embodiments, L.sub.1 is
--CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--. In certain embodiments, L.sub.1 is
--CH.sub.2--.
[0093] The variable L.sub.2 is an unsubstituted or substituted
C.sub.2-3 alkylene chain. In some embodiments, L.sub.2 is
--CH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2CH.sub.2--.
[0094] The variable V.sub.1 is --C(O)--, --C(S)--,
--C(O)--CR.sup.A.dbd.CR.sup.A--, --C(O)--N(R.sup.4a)--,
--C(O)--O--, or --S(O).sub.2--, wherein R.sup.A and R.sup.4a have
the values described herein. In some embodiments, V.sub.1 is
--C(O)--, --C(O)--N(R.sup.4a)--, or --S(O).sub.2--, wherein
R.sup.4a has the values described herein. In certain embodiments,
V.sub.1 is --C(O)--, --C(O)--NH--, or --S(O).sub.2--. In other
certain embodiments, V.sub.1 is --C(O)--.
[0095] Each occurrence of the variable R.sup.A is independently
hydrogen, halo, or an optionally substituted C.sub.1-4aliphatic
group. In some embodiments, each occurrence of R.sup.A is
independently hydrogen, fluoro or methyl. In certain embodiments,
each occurrence of R.sup.A is hydrogen.
[0096] Each occurrence of the variable R.sup.4a is independently
hydrogen, or unsubstituted or substituted C.sub.1-4 aliphatic. In
certain embodiments, R.sup.4a is hydrogen.
[0097] The variable V.sub.2 is --N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--, --SO.sub.2--N(R.sup.4a)--,
--N(R.sup.4a)--SO.sub.2--, --O--, --S--,
--N(R.sup.4a)--C(O)--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--O--,
--O--C(O)--N(R.sup.4a)--, or
--N(R.sup.4a)--SO.sub.2--N(R.sup.4a)--, wherein R.sup.4a has the
values described herein. In some embodiments, V.sub.2 is
--N(R.sup.4a)--, --NR.sup.4a--C(O)--, --SO.sub.2--N(R.sup.4a)--,
--N(R.sup.4a)--SO.sub.2--, --O--, or --S--, wherein R.sup.4a has
the values described herein. In certain embodiments, V.sub.2 is
--N(R.sup.4a)--, --O--, or --S--, wherein R.sup.4a has the values
described herein. In certain embodiments, V.sub.2 is --NH--, or
--O--.
[0098] The variable R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur.
[0099] In some embodiments, R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; wherein: [0100] each substitutable
carbon chain atom in R.sup.3 is unsubstituted or substituted with
1-2 occurrences of --R.sup.5dd; [0101] each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
.dbd.O, .dbd.S, .dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2,
.dbd.N--OR.sup.5, .dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or --R.sup.5a; [0102]
each substitutable unsaturated ring carbon atom in R.sup.3 is
unsubstituted or is substituted with --R.sup.5a; and [0103] each
substitutable ring nitrogen atom in R.sup.3 is unsubstituted or
substituted with --R.sup.9b; [0104] wherein R.sup.5dd, R.sup.4,
R.sup.5, R.sup.6, R.sup.5a, and R.sup.9b have the values described
herein.
[0105] In some embodiments, R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; wherein: [0106] each substitutable
carbon chain atom in R.sup.3 is unsubstituted or substituted with
1-2 occurrences of --R.sup.5dd; [0107] each substitutable saturated
ring carbon atom in R.sup.3 is unsubstituted or substituted with
.dbd.O, .dbd.S, .dbd.C(R.sup.5).sub.2, .dbd.N--R.sup.5 or
--R.sup.5a; [0108] each substitutable unsaturated ring carbon atom
in R.sup.3 is unsubstituted or is substituted with --R.sup.5a; and
[0109] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b; [0110] wherein
R.sup.5dd, R.sup.5, R.sup.5a, and R.sup.9b have the values
described herein.
[0111] In certain embodiments, R.sup.3 is unsubstituted or
substituted C.sub.1-6 aliphatic, unsubstituted or substituted
3-10-membered cycloaliphatic, unsubstituted or substituted
4-10-membered heterocyclyl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; wherein: [0112] each
substitutable carbon chain atom in R.sup.3 is unsubstituted or
substituted with 1-2 occurrences of --R.sup.5dd; [0113] each
substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with --R.sup.5a; [0114] each
substitutable unsaturated ring carbon atom in R.sup.3 is
unsubstituted or is substituted with --R.sup.5a; [0115] the total
number of R.sup.5a substituents is p; and [0116] each substitutable
ring nitrogen atom in R.sup.3 is unsubstituted or substituted with
--R.sup.9b; [0117] wherein R.sup.5dd, R.sup.5a, R.sup.9b, and p
have the values described herein.
[0118] In some embodiments, R.sup.3 is unsubstituted or substituted
C.sub.1-6 aliphatic. In certain embodiments, each substitutable
carbon chain atom in R.sup.3 is unsubstituted or substituted with
1-2 occurrences of --R.sup.5dd, wherein R.sup.5dd has the values
described herein. In certain embodiments, R.sup.3 is methyl, ethyl,
n-propyl, isopropyl, tert-butyl, n-butyl, iso-butyl, pentyl, hexyl,
butenyl, propenyl, pentenyl, or hexenyl, wherein each of the
forementioned groups is unsubstituted or substituted. In certain
embodiments, R.sup.3 is methyl, ethyl, n-propyl, isopropyl,
tert-butyl, n-butyl, iso-butyl, pentyl, hexyl, butenyl, propenyl,
pentenyl, or hexenyl, wherein each substitutable carbon chain atom
in R.sup.3 is unsubstituted or substituted with 1-2 occurrences of
--R.sup.5dd, wherein R.sup.5dd has the values described herein.
[0119] In some embodiments, R.sup.3 is unsubstituted or substituted
unsubstituted or substituted 3-10-membered cycloaliphatic,
unsubstituted or substituted 4-10-membered heterocyclyl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur.
[0120] In certain embodiments, R.sup.3 is unsubstituted or
substituted unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, wherein:
[0121] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with .dbd.O, .dbd.S,
.dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2, .dbd.N--OR.sup.5,
.dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or
--R.sup.5a;
[0122] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a; and
[0123] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0124] wherein R.sup.4, R.sup.5, R.sup.6, R.sup.5a, and R.sup.9b
have the values described herein.
[0125] In certain embodiments, R.sup.3 is unsubstituted or
substituted unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, wherein:
[0126] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with .dbd.O, .dbd.S,
.dbd.C(R.sup.5).sub.2, .dbd.N--R.sup.5 or --R.sup.5a;
[0127] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a; and
[0128] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0129] wherein R.sup.5, R.sup.5a, and R.sup.9b have the values
described herein.
[0130] In certain embodiments, R.sup.3 is unsubstituted or
substituted unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, wherein: [0131] each substitutable
saturated ring carbon atom in R.sup.3 is unsubstituted or
substituted with --R.sup.5a; [0132] each substitutable unsaturated
ring carbon atom in R.sup.3 is unsubstituted or is substituted with
--R.sup.5a; [0133] the total number of R.sup.5a substituents is p;
and [0134] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b; [0135] wherein
R.sup.5a, R.sup.9b, and p have the values described herein.
[0136] In certain embodiments, R.sup.3 is furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl,
indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,
benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,
pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
pteridinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothienyl, indanyl, tetrahydroindazolyl, pyrrolidinyl,
pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl,
oxazolidinyl, piperazinyl, dioxanyl, diazepinyl, oxazepinyl,
thiazepinyl, morpholinyl, thiamorpholinyl, quinuclidinyl,
phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl,
chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or
adamantyl; wherein:
[0137] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with .dbd.O, .dbd.S,
.dbd.C(R.sup.5).sub.2, .dbd.N--N(R.sup.4).sub.2, .dbd.N--OR.sup.5,
.dbd.N--NHC(O)R.sup.5, .dbd.N--NHCO.sub.2R.sup.6,
.dbd.N--NHSO.sub.2R.sup.6, .dbd.N--R.sup.5 or
--R.sup.5a;
[0138] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a; and
[0139] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0140] wherein R.sup.4, R.sup.5, R.sup.6, R.sup.5a, and R.sup.9b
have the values described herein.
[0141] In certain embodiments, R.sup.3 is furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl,
indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,
benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,
pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
pteridinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothienyl, indanyl, tetrahydroindazolyl, pyrrolidinyl,
pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl,
oxazolidinyl, piperazinyl, dioxanyl, diazepinyl, oxazepinyl,
thiazepinyl, morpholinyl, thiamorpholinyl, quinuclidinyl,
phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl,
chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or
adamantyl; wherein:
[0142] each substitutable saturated ring carbon atom in R.sup.3 is
unsubstituted or substituted with .dbd.O, .dbd.S,
.dbd.C(R.sup.5).sub.2, .dbd.N--R.sup.5, or --R.sup.5a;
[0143] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a; and
[0144] each substitutable ring nitrogen atom in R.sup.3 is
unsubstituted or substituted with --R.sup.9b;
[0145] wherein R.sup.5, R.sup.5a, and R.sup.9b have the values
described herein.
[0146] In certain embodiments, R.sup.3 is furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolizinyl, imidazopyridyl, indolyl, isoindolyl,
indazolyl, benzimidazolyl, benzthiazolyl, benzothienyl,
benzofuranyl, benzoxazolyl, benzodioxolyl, benzthiadiazolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl,
pyrazolopyrimidinyl, purinyl, quinolyl, isoquinolyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl,
phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
pteridinyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothienyl, indanyl, tetrahydroindazolyl, pyrrolidinyl,
pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl,
oxazolidinyl, piperazinyl, dioxanyl, diazepinyl, oxazepinyl,
thiazepinyl, morpholinyl, thiamorpholinyl, quinuclidinyl,
phenanthridinyl, tetrahydronaphthyl, indolinyl, benzodioxanyl,
chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or
adamantyl; wherein: [0147] each substitutable saturated ring carbon
atom in R.sup.3 is unsubstituted or substituted with --R.sup.5a;
[0148] each substitutable unsaturated ring carbon atom in R.sup.3
is unsubstituted or is substituted with --R.sup.5a; [0149] the
total number of R.sup.5a substituents is p; and [0150] each
substitutable ring nitrogen atom in R.sup.3 is unsubstituted or
substituted with --R.sup.9b; [0151] wherein R.sup.5a, R.sup.9b, and
p have the values described herein.
[0152] In some embodiments, each occurrence of R.sup.5dd is
independently halogen, hydroxy, --O(C.sub.1-3 alkyl), cyano,
--N(R.sup.4).sub.2, --C(O)(C.sub.1-3 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-3 alkyl), --C(O)NH.sub.2, or --C(O)NH(C.sub.1-3
alkyl). In certain embodiments, each occurrence of R.sup.5dd is
independently fluoro, hydroxy, methoxy, ethoxy, or
--C(O)NHCH.sub.3.
[0153] Each R.sup.4 is independently hydrogen, unsubstituted or
substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
unsubstituted or substituted 6-10-membered aryl, or unsubstituted
or substituted 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur; or two
R.sup.4 on the same nitrogen atom, taken together with the nitrogen
atom, form an unsubstituted or substituted 5- to 6-membered
heteroaryl or an unsubstituted or substituted 4- to 8-membered
heterocyclyl having, in addition to the nitrogen atom, 0-2 ring
heteroatoms selected from nitrogen, oxygen, and sulfur.
[0154] Each R.sup.5 is independently hydrogen, unsubstituted or
substituted C.sub.1-6 aliphatic, unsubstituted or substituted
3-10-membered cycloaliphatic, unsubstituted or substituted
4-10-membered heterocyclyl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur.
[0155] Each R.sup.6 is independently unsubstituted or substituted
C.sub.1-6 aliphatic, or unsubstituted or substituted 6-10-membered
aryl.
[0156] Each R.sup.7 is independently unsubstituted or substituted
4-10-membered heterocyclyl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur.
[0157] Each R.sup.9b is independently --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --CO.sub.2R.sup.6, --SO.sub.2R.sup.6,
--SO.sub.2N(R.sup.4).sub.2, unsubstituted C.sub.1-4 aliphatic, or
C.sub.1-4 aliphatic substituted with 1-2 independent occurrences of
R.sup.7 or R.sup.8, wherein R.sup.7 and R.sup.8 have the values
described herein.
[0158] Each R.sup.8 is independently halogen, --OH, --O(C.sub.1-3
alkyl), --CN, --N(R.sup.4).sub.2, --C(O)(C.sub.1-3 alkyl),
--CO.sub.2H, --CO.sub.2(C.sub.1-3 alkyl), --C(O)NH.sub.2, or
--C(O)NH(C.sub.1-3 alkyl), wherein R.sup.4 has the values described
herein.
[0159] Each R.sup.5a is independently halogen, --NO.sub.2, --CN,
--C(R.sup.5).dbd.C(R.sup.5).sub.2, --OR.sup.5, --SR.sup.6,
--S(O)R.sup.6, --SO.sub.2R.sup.6, --SO.sub.2N(R.sup.4).sub.2,
--N(R.sup.4).sub.2, --NR.sup.4C(O)R.sup.5,
--NR.sup.4C(O)N(R.sup.4).sub.2, --NR.sup.4CO.sub.2R.sup.6,
--OC(O)N(R.sup.4).sub.2, --C(O)--C(O)R.sup.5, --C(O)R.sup.5,
--C(O)N(R.sup.4).sub.2, --C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--C(.dbd.NR.sup.4)--OR.sup.5, --N(R.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)C(.dbd.NR.sup.4)--N(R.sup.4).sub.2,
--N(R.sup.4)SO.sub.2R.sup.6,
--N(R.sup.4)SO.sub.2N(R.sup.4).sub.2)--P(O)(R.sup.5).sub.2,
--P(O)(OR.sup.5).sub.2, unsubstituted or substituted C.sub.1-6
aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur; or two adjacent R.sup.5a, taken
together with the intervening ring atoms, form an unsubstituted or
substituted fused aromatic ring or an unsubstituted or substituted
non-aromatic ring having 0-3 heteroatoms independently selected
from nitrogen, oxygen, and sulfur, wherein R.sup.5, R.sup.6, and
R.sup.4 have the values described herein.
[0160] In some embodiments, each R.sup.5a is independently halogen,
--CN, --OH, C.sub.1-4 alkyl, C.sub.1-3 fluoroalkyl, --O--C.sub.1-3
alkyl, --O--C.sub.1-3 fluoroalkyl, --NHC(O)C.sub.1-3 alkyl,
--C(O)NHC.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl,
--NHS(O).sub.2C.sub.1-3 alkyl, 3-10-membered cycloaliphatic
substituted with 0-2 occurrences of --R.sup.7a, 4-10-membered
heterocyclyl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur substituted with 0-2 occurrences of
--R.sup.7a, 6-10-membered aryl substituted with 0-2 occurrences of
--R.sup.7a, or 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, and sulfur
substituted with 0-2 occurrences of --R.sup.7a wherein R.sup.7a has
the values described herein.
[0161] In certain embodiments, each R.sup.5a is independently
chloro, fluoro, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy,
cyano, trifluoromethyl, methyl, ethyl, isopropyl, n-propyl,
tert-butyl or phenyl.
[0162] Each occurrence of the variable R.sup.7a is independently
halogen, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl, C.sub.1-3 alkyl,
--O--C.sub.1 fluoroalkyl, --NHC(O)C.sub.1-3 alkyl,
--C(O)NHC.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
--NHS(O).sub.2C.sub.1-3 alkyl.
[0163] The variable p is 1-2. In some embodiments, p is 1.
[0164] In some embodiments, G is:
##STR00011##
[0165] wherein X and Ring C have the values described herein.
[0166] In certain embodiments, G is:
##STR00012##
[0167] wherein Ring C has the values described herein.
[0168] The variable X is --C(O)-- or
-L.sub.2a-R.sup.3aa--V.sub.2a--, wherein L.sub.2a, R.sup.3aa, and
V.sub.2a have the values described herein. In some embodiments, X
is --C(O)--. In some embodiments, X is
-L.sub.2a-R.sup.3aa--V.sub.2a--, wherein L.sub.2a, R.sup.3aa, and
V.sub.2a have the values described herein. In some embodiments, X
is --C(O)--,
##STR00013##
[0169] wherein V.sub.2a and t have the values described herein.
[0170] In certain embodiments, X is --C(O)--,
##STR00014## ##STR00015## ##STR00016##
[0171] In certain embodiments, X is --C(O)--, X-ii, X-xi, X-xii,
X-xxii, X-xxiv, or X-xxv.
[0172] Ring C is a 4-7 membered heterocyclic ring containing one
nitrogen atom, wherein the nitrogen atom is not the atom bound to
X, and wherein the nitrogen atom in Ring C is substituted with
R.sup.9bb and Ring C is unsubstituted or substituted by 1-4
occurrences of R.sup.5b; wherein R.sup.9bb, X, and R.sup.5b have
the values described herein. In some embodiments, Ring C is a 4-7
membered heterocyclic ring containing one nitrogen atom, wherein
the nitrogen atom is not the atom bound to X, and wherein the
nitrogen atom in Ring C is substituted with R.sup.9bb and Ring C is
unsubstituted or substituted by 1-2 occurrences of R.sup.5b;
wherein R.sup.9bb, X, and R.sup.5b have the values described
herein.
[0173] In certain embodiments, Ring C is:
##STR00017##
[0174] wherein Ring C is unsubstituted or substituted with 1
occurrence of R.sup.5b, wherein R.sup.9bb and R.sup.5b have the
values described herein. In certain embodiments, Ring C is:
##STR00018##
[0175] wherein R.sup.9bb, z and R.sup.5bb have the values described
herein.
[0176] The variable V.sub.2a is a bond, --NH--C(O)--,
--NH--S(O).sub.2--, or --NH--C(O)--NH--. In some embodiments,
V.sub.2a is a bond or --NH--C(O)--. In certain embodiments,
V.sub.2a is a bond. In certain embodiments, V.sub.2a is
--NH--C(O)--.
[0177] The variable t is 0-2. In some embodiments, t is 0-1. In
certain embodiments, t is 0. In certain embodiments, t is 1. In
certain embodiments, t is 2.
[0178] The variable L.sub.2a is a bond or unsubstituted or
substituted C.sub.1-3 alkylene chain. In some embodiments, L.sub.2a
is a bond, --CH.sub.2--, --CH.sub.2CH.sub.2--, or
--CH.sub.2CH.sub.2CH.sub.2--. In certain embodiments, L.sub.2a is a
bond. In certain embodiments, L.sub.2a is --CH.sub.2--. In certain
embodiments, L.sub.2a is .beta.CH.sub.2CH.sub.2--.
[0179] The variable R.sup.3aa is a 6-membered aromatic ring
containing 0-2 nitrogen atoms which is unsubstituted or substituted
with 1-2 independent occurrences of R.sup.4c, wherein R.sup.4c has
the values described herein. In some embodiments, R.sup.3aa is
phenyl or pyridyl, each of which is unsubstituted or substituted
with 1-2 independent occurrences of R.sup.4c, wherein R.sup.4c has
the values described herein. In some embodiments, R.sup.3aa is:
##STR00019##
[0180] wherein each ring is unsubstituted or substituted with 1-2
independent occurrences of R.sup.4c.
[0181] The variable R.sup.4c is chloro, fluoro, cyano, hydroxy,
methoxy, ethoxy, trifluoromethoxy, trifluoromethyl, methyl, or
ethyl. In some embodiments, R.sup.4c is chloro, fluoro, methyl or
ethyl.
[0182] The variable z is 0-1. In some embodiments, z is 0. In some
embodiments, z is 1.
[0183] Each occurrence of the variable R.sup.5b is independently
chloro, fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy,
trifluoromethyl, trifluoromethoxy, --C(O)NH.sub.2, or --CO.sub.2H.
In some embodiments, each occurrence of the variable R.sup.5b is
independently chloro, fluoro, hydroxy, methyl, or ethyl. In certain
embodiments, each occurrence of the variable R.sup.5b is
methyl.
[0184] The variable R.sup.5bb is hydrogen or methyl. In some
embodiments, R.sup.5bb is hydrogen. In some embodiments, R.sup.5bb
is methyl.
[0185] The variable R.sup.9bb is hydrogen, unsubstituted
C(O)--O--C.sub.1-6 aliphatic, unsubstituted C(O)--C.sub.1-6
aliphatic, unsubstituted C(O)--C.sub.3-10 cycloaliphatic, or
unsubstituted C.sub.1-6 aliphatic. In some embodiments, R.sup.9bb
is hydrogen, methyl, ethyl, isopropyl, or tert-butoxycarbonyl. In
some embodiments, R.sup.9bb is methyl, ethyl, or isopropyl. In
certain embodiments, R.sup.9bb is hydrogen.
[0186] In certain embodiments, the compound of formula (I) is
represented by:
##STR00020##
[0187] wherein:
[0188] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, hydroxy, trifluoromethyl, or methyl;
[0189] R.sup.10 is hydrogen;
[0190] G is --V.sub.1--R.sup.3; and
[0191] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)-- or
--S(O).sub.2--;
[0192] wherein R.sup.2, R.sup.3, and R.sup.4a have the values
described herein.
[0193] In certain embodiments, the compound of formula (I) is
represented by:
##STR00021##
[0194] wherein:
[0195] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, hydroxy, trifluoromethyl, or methyl;
[0196] R.sup.10 is hydrogen;
[0197] G is --V.sub.1--R.sup.3; and
[0198] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a)-- or
--S(O).sub.2--;
[0199] wherein R.sup.2, R.sup.3, and R.sup.4a have the values
described herein.
[0200] In certain embodiments, the compound of formula (I) is
represented by:
##STR00022##
wherein:
[0201] ring A is an aromatic 6-membered ring connected through one
of positions (a) or (b); [0202] X.sub.1 is CR.sup.1 or N; [0203]
(i) when ring A is connected through position (a), X.sub.2 is C;
and X.sub.3 is CR.sup.1 or N; or [0204] (ii) when ring A is
connected through position (b), X.sub.3 is C; and X.sub.2 is
CR.sup.1 or N;
[0205] R.sup.4b is hydrogen, or C.sub.1-4 aliphatic;
[0206] R.sup.2 is methyl, ethyl, isopropyl, n-propyl,
trifluoromethyl, tert-butyl, cyclopropyl, or phenyl; [0207] R.sup.1
is hydrogen, chloro, fluoro, hydroxy, methoxy, ethoxy, n-propoxy,
isopropoxy, cyano, trifluoromethyl, methyl, ethyl, isopropyl,
n-propyl, or tert-butyl;
[0208] R.sup.10 is hydrogen; and
[0209] wherein Ring C and X have the values described herein.
[0210] In such embodiments:
[0211] R.sup.2 is methyl, ethyl, isopropyl, or n-propyl; [0212]
R.sup.1 is hydrogen; and
[0213] R.sup.4b is hydrogen.
[0214] In certain embodiments, the compound of formula (I) is
represented by:
##STR00023##
wherein:
[0215] ring A is an aromatic 6-membered ring connected through one
of positions (a) or (b); [0216] X.sub.1 is CR.sup.1 or N; [0217]
(i) when ring A is connected through position (a), X.sub.2 is C;
and X.sub.3 is CR.sup.1 or N; or [0218] (ii) when ring A is
connected through position (b), X.sub.3 is C; and X.sub.2 is
CR.sup.1 or N;
[0219] R.sup.4b is hydrogen;
[0220] R.sup.2 is methyl, ethyl, isopropyl, n-propyl,
trifluoromethyl, tert-butyl, cyclopropyl, or phenyl; each
occurrence of R.sup.1 is independently hydrogen, chloro, fluoro,
hydroxy, trifluoromethyl, or methyl;
[0221] R.sup.10 is hydrogen;
[0222] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0223] X is --C(O)--, X-a, X-b, X-c, X-d, X-e, X-f, or X-g;
[0224] Ring C is unsubstituted or substituted with one occurrence
of R.sup.5b; and z, R.sup.5b, t, and V.sub.2a have the values
described herein.
[0225] In such embodiments:
[0226] R.sup.2 is methyl, ethyl, isopropyl, or n-propyl;
[0227] R.sup.1 is hydrogen; and
[0228] R.sup.5b is methyl.
[0229] In certain embodiments, the compound of formula (I) is
represented by:
##STR00024##
[0230] wherein:
[0231] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, hydroxy, trifluoromethyl, or methyl;
[0232] R.sup.2 is methyl, ethyl, isopropyl, n-propyl,
trifluoromethyl, tert-butyl, cyclopropyl, or phenyl;
[0233] R.sup.10 is hydrogen;
[0234] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0235] X is --C(O)--, X-ii, X-xi, X-xii, X-xxii, X-xxiv, or
X-xxv;
[0236] R.sup.5bb is hydrogen or methyl; and
[0237] z has the values described herein.
[0238] In certain such embodiments,
[0239] R.sup.1 is hydrogen;
[0240] R.sup.2 is methyl, ethyl, isopropyl, or n-propyl;
[0241] R.sup.5bb is methyl; and
[0242] z is 1.
[0243] In certain embodiments, the compound of formula (I) is
represented by:
##STR00025##
[0244] wherein:
[0245] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, hydroxy, trifluoromethyl, or methyl;
[0246] R.sup.2 is methyl, ethyl, isopropyl, n-propyl,
trifluoromethyl, tert-butyl, cyclopropyl, or phenyl;
[0247] R.sup.10 is hydrogen;
[0248] R.sup.9bb is hydrogen, methyl, ethyl, isopropyl, or
tert-butoxycarbonyl;
[0249] X is --C(O)--, X-ii, X-xi, X-xii, X-xxii, X-xxiv, or
X-xxv;
[0250] R.sup.5bb is hydrogen or methyl; and
[0251] z has the values described herein.
[0252] In certain such embodiments,
[0253] R.sup.1 is hydrogen;
[0254] R.sup.2 is methyl, ethyl, isopropyl, or n-propyl;
[0255] R.sup.5bb is methyl; and
[0256] z is 1.
[0257] In certain embodiments, the compound of formula (I) is
represented by:
##STR00026##
[0258] wherein:
[0259] each occurrence of R.sup.1 is independently hydrogen,
chloro, fluoro, hydroxy, trifluoromethyl, or methyl;
[0260] R.sup.10 is hydrogen;
[0261] G is --V.sub.1--R.sup.3;
[0262] V.sub.1 is --C(O)--, --C(O)--NH-- or --S(O).sub.2--;
[0263] R.sup.2 is methyl, ethyl, isopropyl, or n-propyl; and
[0264] wherein R.sup.3 has the values described herein.
[0265] In certain such embodiments, the compound of formula (I) is
represented by formula (III-a-i).
[0266] In certain such embodiments, the compound of formula (I) is
represented by formula (III-a-ii). In certain such embodiments, the
compound of formula (I) is represented by formula (III-a-iii). In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-iv). In certain such embodiments, the
compound of formula (I) is represented by formula (III-a-v). In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-vi). In certain such embodiments, the
compound of formula (I) is represented by formula (III-a-vii). In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-viii).
[0267] In certain such embodiments, the compound of formula (I) is
represented by formula (III-a-i), wherein R.sup.1 is hydrogen. In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-ii), wherein R.sup.1 is hydrogen. In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-iii), wherein R.sup.1 is hydrogen. In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-iv), wherein R.sup.1 is hydrogen. In
certain such embodiments, the compound of formula (I) is
represented by formula (III-a-v), wherein R.sup.1 is hydrogen. In
certain such embodiments, the compound of formula (I) is
represented by formula wherein R.sup.1 is hydrogen. In certain such
embodiments, the compound of formula (I) is represented by formula
wherein R.sup.1 is hydrogen. In certain such embodiments, the
compound of formula (I) is represented by formula wherein R.sup.1
is hydrogen.
[0268] Representative examples of compounds of formula (I) are
shown in Table 1.
TABLE-US-00001 ##STR00027## I-1 ##STR00028## I-2 ##STR00029## I-3
##STR00030## I-4 ##STR00031## I-5 ##STR00032## I-6 ##STR00033## I-7
##STR00034## I-8 ##STR00035## I-9 ##STR00036## I-10 ##STR00037##
I-11 ##STR00038## I-12 ##STR00039## I-13 ##STR00040## I-14
##STR00041## I-15 ##STR00042## I-16 ##STR00043## I-17 ##STR00044##
I-18 ##STR00045## I-19 ##STR00046## I-20 ##STR00047## I-21
##STR00048## I-22 ##STR00049## I-23 ##STR00050## I-24 ##STR00051##
I-25 ##STR00052## I-26 ##STR00053## I-27 ##STR00054## I-28
##STR00055## I-29 ##STR00056## I-30 ##STR00057## I-31 ##STR00058##
I-32 ##STR00059## I-33 ##STR00060## I-34 ##STR00061## I-35
##STR00062## I-36 ##STR00063## I-37 ##STR00064## I-38 ##STR00065##
I-39 ##STR00066## I-40 ##STR00067## I-41 ##STR00068## I-42
##STR00069## I-43 ##STR00070## I-44 ##STR00071## I-45 ##STR00072##
I-46 ##STR00073## I-47 ##STR00074## I-48 ##STR00075## I-49
##STR00076## I-50 ##STR00077## I-51 ##STR00078## I-52 ##STR00079##
I-53 ##STR00080## I-54 ##STR00081## I-55 ##STR00082## I-56
##STR00083## I-57 ##STR00084## I-58 ##STR00085## I-59 ##STR00086##
I-60 ##STR00087## I-61 ##STR00088## I-62 ##STR00089##
I-63 ##STR00090## I-64 ##STR00091## I-65 ##STR00092## I-66
##STR00093## I-67 ##STR00094## I-68 ##STR00095## I-69 ##STR00096##
I-70 ##STR00097## I-71 ##STR00098## I-72 ##STR00099## I-73
##STR00100## I-74 ##STR00101## I-75 ##STR00102## I-76 ##STR00103##
I-77 ##STR00104## I-78 ##STR00105## I-79 ##STR00106## I-80
##STR00107## I-81 ##STR00108## I-82 ##STR00109## I-83 ##STR00110##
I-84 ##STR00111## I-85 ##STR00112## I-86 ##STR00113## I-87
##STR00114## I-88 ##STR00115## I-89 ##STR00116## I-90 ##STR00117##
I-91 ##STR00118## I-92 ##STR00119## I-93 ##STR00120## I-94
##STR00121## I-95 ##STR00122## I-96 ##STR00123## I-97 ##STR00124##
I-98 ##STR00125## I-99 ##STR00126## I-100 ##STR00127## I-101
##STR00128## I-102 ##STR00129## I-103 ##STR00130## I-104
##STR00131## I-105 ##STR00132## I-106 ##STR00133## I-107
##STR00134## I-108 ##STR00135## I-109 ##STR00136## I-110
##STR00137## I-111 ##STR00138## I-112 ##STR00139## I-113
##STR00140## I-114 ##STR00141## I-115 ##STR00142## I-116
##STR00143## I-117 ##STR00144## I-118 ##STR00145## I-119
##STR00146## I-120 ##STR00147## I-121 ##STR00148## I-122
##STR00149## I-123 ##STR00150## I-124 ##STR00151## I-125
##STR00152## I-126 ##STR00153## I-127 ##STR00154## I-128
##STR00155## I-129 ##STR00156## I-130 ##STR00157## I-131
##STR00158## I-132 ##STR00159## I-133 ##STR00160## I-134
##STR00161## I-135 ##STR00162## I-136 ##STR00163## I-137
##STR00164## I-138 ##STR00165## I-139 ##STR00166## I-140
##STR00167## I-141 ##STR00168## I-142 ##STR00169## I-143
##STR00170## I-144 ##STR00171## I-145 ##STR00172## I-146
##STR00173## I-147 ##STR00174## I-148 ##STR00175## I-149
##STR00176## I-150 ##STR00177## I-151 ##STR00178## I-152
##STR00179## I-153 ##STR00180## I-154 ##STR00181## I-155
##STR00182## I-156 ##STR00183## I-157 ##STR00184## I-158
##STR00185## I-159 ##STR00186## I-160 ##STR00187## I-161
##STR00188## I-162 ##STR00189## I-163 ##STR00190## I-164
##STR00191## I-165 ##STR00192## I-166 ##STR00193## I-167
##STR00194## I-168 ##STR00195## I-169 ##STR00196## I-170
##STR00197## I-171 ##STR00198## I-172 ##STR00199## I-173
##STR00200## I-174 ##STR00201## I-175 ##STR00202## I-176
##STR00203## I-177 ##STR00204## I-178 ##STR00205## I-179
##STR00206## I-180 ##STR00207## I-181 ##STR00208## I-182
##STR00209## I-183 ##STR00210## I-184 ##STR00211## I-185
##STR00212## I-186 ##STR00213## I-187 ##STR00214## I-188
##STR00215## I-189 ##STR00216## I-190 ##STR00217## I-191
##STR00218## I-192 ##STR00219## I-193 ##STR00220## I-194
##STR00221## I-195 ##STR00222## I-196 ##STR00223## I-197
##STR00224## I-198 ##STR00225## I-199 ##STR00226## I-200
##STR00227## I-201 ##STR00228## I-202 ##STR00229## I-203
##STR00230## I-204 ##STR00231## I-205 ##STR00232## I-206
##STR00233## I-207 ##STR00234## I-208 ##STR00235## I-209
##STR00236## I-210 ##STR00237## I-211 ##STR00238## I-212
##STR00239## I-213 ##STR00240## I-214 ##STR00241## I-215
##STR00242## I-216 ##STR00243## I-217 ##STR00244## I-218
##STR00245## I-219 ##STR00246## I-220 ##STR00247## I-221
##STR00248## I-222 ##STR00249## I-223 ##STR00250## I-224
##STR00251## I-225 ##STR00252## I-226 ##STR00253## I-227
##STR00254## I-228 ##STR00255## I-229 ##STR00256## I-230
##STR00257## I-231 ##STR00258## I-232 ##STR00259## I-233
##STR00260## I-234 ##STR00261## I-235 ##STR00262## I-236
##STR00263## I-237 ##STR00264## I-238 ##STR00265## I-239
##STR00266## I-240 ##STR00267## I-241 ##STR00268## I-242
##STR00269## I-243 ##STR00270## I-244 ##STR00271## I-245
##STR00272## I-246 ##STR00273## I-247 ##STR00274## I-248
##STR00275## I-249 ##STR00276## I-250 ##STR00277##
I-251 ##STR00278## I-252 ##STR00279## I-253 ##STR00280## I-254
##STR00281## I-255 ##STR00282## I-256 ##STR00283## I-257
##STR00284## I-258 ##STR00285## I-259 ##STR00286## I-260
##STR00287## I-261 ##STR00288## I-262 ##STR00289## I-263
##STR00290## I-264 ##STR00291## I-265 ##STR00292## I-266
##STR00293## I-267 ##STR00294## I-268 ##STR00295## I-269
##STR00296## I-270 ##STR00297## I-271 ##STR00298## I-272
##STR00299## I-273 ##STR00300## I-274 ##STR00301## I-275
##STR00302## I-276 ##STR00303## I-277 ##STR00304## I-278
##STR00305## I-279 ##STR00306## I-280 ##STR00307## I-281
##STR00308## I-282 ##STR00309## I-283 ##STR00310## I-284
##STR00311## I-285 ##STR00312## I-286 ##STR00313## I-287
##STR00314## I-288 ##STR00315## I-289 ##STR00316## I-290
##STR00317## I-291 ##STR00318## I-292 ##STR00319## I-293
##STR00320## I-294 ##STR00321## I-295 ##STR00322## I-296
##STR00323## I-297 ##STR00324## I-298 ##STR00325## I-299
##STR00326## I-300 ##STR00327## I-301 ##STR00328## I-302
##STR00329## I-303 ##STR00330## I-304 ##STR00331## I-305
##STR00332## I-306 ##STR00333## I-307 ##STR00334## I-308
##STR00335## I-309 ##STR00336## I-310 ##STR00337## I-311
##STR00338## I-312 ##STR00339## I-313 ##STR00340##
I-314 ##STR00341## I-315 ##STR00342## I-316 ##STR00343## I-317
##STR00344## I-318 ##STR00345## I-319 ##STR00346## I-320
##STR00347## I-321 ##STR00348## I-322 ##STR00349## I-323
##STR00350## I-324 ##STR00351## I-325 ##STR00352## I-326
##STR00353## I-327 ##STR00354## I-328 ##STR00355## I-329
##STR00356## I-330 ##STR00357## I-331 ##STR00358## I-332
##STR00359## I-333 ##STR00360## I-334 ##STR00361## I-335
##STR00362## I-336 ##STR00363## I-337 ##STR00364## I-338
##STR00365## I-339 ##STR00366## I-340 ##STR00367## I-341
##STR00368## I-342 ##STR00369## I-343 ##STR00370## I-344
##STR00371## I-345 ##STR00372## I-346 ##STR00373## I-347
##STR00374## I-348 ##STR00375## I-349 ##STR00376## I-350
##STR00377## I-351 ##STR00378## I-352 ##STR00379## I-353
##STR00380## I-354 ##STR00381## I-355 ##STR00382## I-356
##STR00383## I-357 ##STR00384## I-358 ##STR00385## I-359
##STR00386## I-360 ##STR00387## I-361 ##STR00388## I-362
##STR00389## I-363 ##STR00390## I-364 ##STR00391## I-365
##STR00392## I-366 ##STR00393## I-367 ##STR00394## I-368
##STR00395## I-369 ##STR00396## I-370 ##STR00397## I-371
##STR00398## I-372 ##STR00399## I-373 ##STR00400## I-374
##STR00401## I-375 ##STR00402## I-376
##STR00403## I-377 ##STR00404## I-378 ##STR00405## I-379
##STR00406## I-380 ##STR00407## I-381 ##STR00408## I-382
##STR00409## I-383 ##STR00410## I-384 ##STR00411## I-385
##STR00412## I-386 ##STR00413## I-387 ##STR00414## I-388
##STR00415## I-389 ##STR00416## I-390 ##STR00417## I-391
##STR00418## I-392 ##STR00419## I-393 ##STR00420## I-394
##STR00421## I-395 ##STR00422## I-396 ##STR00423## I-397
##STR00424## I-398 ##STR00425## I-399 ##STR00426## I-400
##STR00427## I-401 ##STR00428## I-402 ##STR00429## I-403
##STR00430## I-404 ##STR00431## I-405 ##STR00432## I-406
##STR00433## I-407 ##STR00434## I-408 ##STR00435## I-409
##STR00436## I-410 ##STR00437## I-411 ##STR00438## I-412
##STR00439## I-413 ##STR00440## I-414 ##STR00441## I-415
##STR00442## I-416 ##STR00443## I-417 ##STR00444## I-418
##STR00445## I-419 ##STR00446## I-420 ##STR00447## I-421
##STR00448## I-422 ##STR00449## I-423 ##STR00450## I-424
##STR00451## I-425 ##STR00452## I-426 ##STR00453## I-427
##STR00454## I-428 ##STR00455## I-429 ##STR00456## I-430
##STR00457## I-431 ##STR00458## I-432 ##STR00459## I-433
##STR00460## I-434 ##STR00461## I-435 ##STR00462## I-436
##STR00463## I-437 ##STR00464## I-438 ##STR00465## I-439
##STR00466## I-440 ##STR00467## I-441 ##STR00468## I-442
##STR00469## I-443 ##STR00470## I-444 ##STR00471## I-445
##STR00472## I-446 ##STR00473## I-447 ##STR00474## I-448
##STR00475## I-449 ##STR00476## I-450 ##STR00477## I-451
##STR00478## I-452 ##STR00479## I-453 ##STR00480## I-454
##STR00481## I-455 ##STR00482## I-456 ##STR00483## I-457
##STR00484## I-458 ##STR00485## I-459 ##STR00486## I-460
##STR00487## I-461 ##STR00488## I-462 ##STR00489## I-463
##STR00490## I-464 ##STR00491## I-465 ##STR00492## I-466
##STR00493## I-467 ##STR00494## I-468 ##STR00495## I-469
##STR00496## I-470 ##STR00497## I-471 ##STR00498## I-472
##STR00499## I-473 ##STR00500## I-474 ##STR00501## I-475
##STR00502## I-476 ##STR00503## I-477 ##STR00504## I-478
##STR00505## I-479 ##STR00506## I-480 ##STR00507## I-481
##STR00508## I-482 ##STR00509## I-483 ##STR00510## I-484
##STR00511## I-485 ##STR00512## I-486 ##STR00513## I-487
##STR00514## I-488 ##STR00515## I-489 ##STR00516## I-490
##STR00517## I-491 ##STR00518## I-492 ##STR00519## I-493
##STR00520## I-494 ##STR00521## I-495 ##STR00522## I-496
##STR00523## I-497 ##STR00524## I-498 ##STR00525## I-499
##STR00526## I-500 ##STR00527## I-501 ##STR00528##
I-502 ##STR00529## I-503 ##STR00530## I-504 ##STR00531## I-505
##STR00532## I-506 ##STR00533## I-507 ##STR00534## I-508
##STR00535## I-509 ##STR00536## I-510 ##STR00537## I-511
##STR00538## I-512 ##STR00539## I-513 ##STR00540## I-514
##STR00541## I-515 ##STR00542## I-516 ##STR00543## I-517
##STR00544## I-518 ##STR00545## I-519 ##STR00546## I-520
##STR00547## I-521 ##STR00548## I-522 ##STR00549## I-523
##STR00550## I-524 ##STR00551## I-525 ##STR00552## I-526
##STR00553## I-527 ##STR00554## I-528 ##STR00555## I-529
##STR00556## I-530 ##STR00557## I-531 ##STR00558## I-532
##STR00559## I-533 ##STR00560## I-534 ##STR00561## I-535
##STR00562## I-536
[0269] The compounds in Table 1 above may also be identified by the
following chemical names:
TABLE-US-00002 I-1
4-{1-[(ethylsulfonyl)amino]ethyl}-N-hydroxybenzamide I-2
4-(1-{[(4-fluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide I-3
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)adamantane-1-carboxamide
I-4
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-benzofur-
an-2-carboxamide I-5
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methyl-2-phenyl-4-
H-furo[3,2- b]pyrrole-5-carboxamide I-6
N-hydroxy-4-(1-{[(1-naphthylamino)carbonyl]amino}ethyl)benzamide
I-7
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzofuran-2--
carboxamide I-8
2-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-methylbenzami-
de I-9
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2,5-dimeth-
yl-3-furamide I-10
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1H-indole-3-carboxamide
I-11
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)biphenyl-4-car-
boxamide I-12
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzoth-
iophene-2- carboxamide I-13
3-(1-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}ethyl)-N-hydroxybenza-
mide I-14
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
I-15
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)adamantane-1-carbox-
amide I-16
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methyl-2-phenyl--
4H-furo[3,2- b]pyrrole-5-carboxamide I-17
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-4-methyl-2-ph-
enylpyrimidine-5- carboxamide I-18
4-[(1R)-1-({[1-adamantylamino]carbonyl}amino)butyl]-N-hydroxybenzamid-
e I-19
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-4-methox-
ybenzamide I-20
N-hydroxy-4-[1-({[(4-phenoxyphenyl)amino]carbonyl}amino)ethyl]benzami-
de I-21 4-{1-[(cyclobutylcarbonyl)amino]ethyl}-N-hydroxybenzamide
I-22
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzof-
uran-2-carboxamide I-23
N-hydroxy-4-(1-{[(3-methoxyphenyl)sulfonyl]amino}ethyl)benzamide
I-24
4-(1-{[(2-chloro-6-fluorophenyl)acetyl]amino}ethyl)-N-hydroxybenzamid-
e I-25
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrrol-
e-2-carboxamide I-26
N-hydroxy-4-((1R)-1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benzam-
ide I-27
4-[1-({[(3-fluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e I-28
N-hydroxy-4-{1-[(mesitylacetyl)amino]-2-methylpropyl}benzamide I-29
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-1,3-thiazole-4-
-carboxamide I-30
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-methyl-1H-p-
yrrole-2- carboxamide I-31
N-hydroxy-4-[1-({[(2-phenoxyphenyl)amino]carbonyl}amino)ethyl]benzami-
de I-32
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzofuran--
2-carboxamide I-33
N-hydroxy-4-{1-[(propylsulfonyl)amino]ethyl}benzamide I-34
N-hydroxy-4-(1-{[(2-methoxyphenyl)acetyl]amino}ethyl)benzamide I-35
6-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)imidazo[1,2-a]p-
yridine-2-carboxamide I-36
N-hydroxy-4-[1-(isobutyrylamino)ethyl]benzamide I-37
4-[1-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e I-38
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-isopropoxybenzamide
I-39
4,5-dichloro-N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1-
H-pyrrole-2- carboxamide I-40
4-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)benza-
mide I-41
4-[1-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2,2-dimethylpro-
pyl]-N- hydroxybenzamide I-42
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2-methyl--
1,3-thiazole-4- carboxamide I-43
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1,3-benzothia-
zole-6-carboxamide I-44
4-[1-({[(2,4-dimethoxyphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-45
N-hydroxy-4-{1-[(3-phenylpropanoyl)amino]ethyl}benzamide I-46
N-((R)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)adamantane-
-1-carboxamide I-47
N-hydroxy-4-(1-{[(4-methoxyphenyl)sulfonyl]amino}ethyl)benzamide
I-48
N-hydroxy-4-(2-methyl-1-{[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]a-
mino}propyl)benzamide I-49
N-hydroxy-4-(1-{[(2-oxo-2H-chromen-6-yl)sulfonyl]amino}ethyl)benzamid-
e I-50
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]-2,2,2-trifluoroethyl}-N-hydr-
oxybenzamide I-51
4-(1-{[(2,5-dimethylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-52
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-
bis(trifluoromethyl)benzamide I-53
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-2-
-carboxamide I-54
4-(1-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-N-hydroxy-
benzamide I-55
4-[1-({[(3,4-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenz-
amide I-56
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)cinnoline-4-carboxamide
I-57
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-(trifluoromethyl)benz-
amide I-58
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)adamantane-1-c-
arboxamide I-59
4-{1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxybenzamide I-60
N-hydroxy-4-(1-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethy-
l)benzamide I-61
4-(1-{[(4-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzam-
ide I-62
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-3-methyl-1-benzoth-
iophene-2- carboxamide I-63
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-(1H-pyrrol-1-yl)benza-
mide I-64
4-(1-{[(4-chlorobenzyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-65
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-methyl-
-1H-pyrrole-2- carboxamide I-66
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl--
1H-pyrazole-3- carboxamide I-67
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzot-
hiophene-2- carboxamide I-68
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1H-indol-
e-2-carboxamide I-69
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-5-methyl-1H-i-
ndole-2-carboxamide I-70
N-hydroxy-4-(1-{[4-(4-methoxyphenyl)butanoyl]amino}ethyl)benzamide
I-71
4-(1-{[(1,3-benzodioxol-5-ylamino)carbonyl]amino}ethyl)-N-hydroxybenz-
amide I-72
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methyl-2-[4-(trifluor-
omethyl)phenyl]-4H- furo[3,2-b]pyrrole-5-carboxamide I-73
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxybenzamide
I-74
4-[1-({[(2-fluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e I-75
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3-(methyl-
sulfonyl)benzamide I-76
N-hydroxy-4-[1-({[(2-methylbenzyl)amino]carbonyl}amino)ethyl]benzamid-
e I-77
1-benzyl-3-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methy-
lpropyl)-1H-pyrazole- 5-carboxamide I-78
4-(1-{[(2,4-dimethylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-79
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-benzofuran-2-car-
boxamide I-80
4-(2,2-dimethyl-1-{[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]amino}p-
ropyl)-N- hydroxybenzamide I-81
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrazole-3--
carboxamide I-82
4-{1-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]ethyl}-N-hydrox-
ybenzamide I-83
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)adamantane-1-carboxamide
I-84
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,5-dimethyl-1H-pyrazol-
e-3-carboxamide I-85
N-hydroxy-4-[1-({[(3-methylphenyl)amino]carbonyl}amino)ethyl]benzamid-
e I-86
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1,3-dimet-
hyl-1H-pyrazole-4- carboxamide I-87
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)pyrazine-2-
-carboxamide I-88
4-{1-[(cyclopentylcarbonyl)amino]ethyl}-N-hydroxybenzamide I-89
4-[1-({[(2,5-dichlorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenz-
amide I-90
4-(1-{[(3,4-difluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-91
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3,5-dimethyl-1H-pyrrole-
-2-carboxamide I-92
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-4-carboxam-
ide I-93
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3-methyl-1-be-
nzofuran-2- carboxamide I-94
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzothioph-
ene-2-carboxamide I-95
N-hydroxy-4-{1-[(1-naphthylsulfonyl)amino]ethyl}benzamide I-96
4,5-dichloro-N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpro-
pyl)-1-methyl-1H- pyrrole-2-carboxamide I-97
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-2-carb-
oxamide I-98
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indole-2-ca-
rboxamide I-99
N-[(R)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]-1-benzothiop-
hene-2-carboxamide I-100
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-benzimidaz-
ole-2-carboxamide I-101
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-4,5,6,7-tetra-
hydro-2H-indazole-3- carboxamide I-102
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrro-
le-2-carboxamide I-103
4-[1-({[(3-chloro-4-methylphenyl)amino]carbonyl}amino)ethyl]-N-hydro-
xybenzamide I-104
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-2,5-dimethyl-3-furamid-
e I-105
4-((1R)-1-{[(1-adamantylamino)carbonyl]amino}-2,2,2-trifluoroethyl)--
N-hydroxybenzamide I-106
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-methyl-1H-indol-
e-2-carboxamide I-107
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-
-1H-indole-3- carboxamide I-108
4,5-dichloro-1-methyl-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)ca-
rbonyl]phenyl}ethyl)-1H- pyrrole-2-carboxamide I-109
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-phenyl-1H-pyrazole-5-
-carboxamide I-110
4-[1-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)ethyl]-N-hydroxy-
benzamide I-111
N-hydroxy-4-{1-[(3-methylbutanoyl)amino]ethyl}benzamide I-112
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)thiophene-2-c-
arboxamide I-113
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzot-
hiophene-2- carboxamide I-114
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-4,5,6,7-tetra-
hydro-2H-indazole-3- carboxamide I-115
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indol-
e-2-carboxamide I-116
2,4,5-trifluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylprop-
yl)benzamide I-117
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-3-car-
boxamide I-118
4-(1-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenza-
mide I-119
1-methyl-N-((1R)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl-
}ethyl)-1H-pyrrole-2- carboxamide I-120
4-[1-({[(3-fluoro-4-methylphenyl)amino]carbonyl}amino)ethyl]-N-hydro-
xybenzamide I-121
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-4-carboxa-
mide I-122
4-methoxy-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]pheny-
l}ethyl)benzamide I-123
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1,3-thia-
zole-4-carboxamide I-124
N-[(S)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]-1-benzothio-
phene-2-carboxamide I-125
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)imidazo[1,2-a]pyridine--
2-carboxamide I-126
N-hydroxy-4-((1R)-2-methyl-1-{[(1-methylcyclohexyl)carbonyl]amino}pr-
opyl)benzamide I-127
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1H-indol-
e-2-carboxamide I-128
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)quinoline-2-carboxamide
I-129
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-5-methyl-
-1H-indole-2- carboxamide I-130
5-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-b-
enzofuran-2- carboxamide I-131
4-(1-{[(4-tert-butylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-132
N-hydroxy-4-(1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benzamide
I-133
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-
-1H-pyrrole-2- carboxamide I-134
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2,3-dihydro-1-benzofur-
an-7-carboxamide I-135
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2,1,3-benzot-
hiadiazole-5- carboxamide I-136
4-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
I-137
3,5-difluoro-N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
I-138
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-(1,3-oxazol-5-yl)ben-
zamide I-139
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2-methyl-4-(-
trifluoromethyl)-1,3- thiazole-5-carboxamide I-140
4-[1-({[(4-tert-butylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-141
N-hydroxy-4-{1-[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]e-
thyl}benzamide I-142
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-4-carboxamide
I-143
4'-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)bip-
henyl-4-carboxamide I-144
4-{1-[(3,3-dimethylbutanoyl)amino]ethyl}-N-hydroxybenzamide I-145
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-
-1H-indole-5- carboxamide I-146
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-4-methoxybenzamid-
e I-147
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-methylthiophene-2-ca-
rboxamide I-148
4-(1-{[(2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]amino}ethyl)-N-h-
ydroxybenzamide I-149
3-{1-[(cyclohexylcarbonyl)amino]ethyl}-N-hydroxybenzamide I-150
4-{1-[({[4-(difluoromethoxy)phenyl]amino}carbonyl)amino]ethyl}-N-hyd-
roxybenzamide I-151
N-hydroxy-3-(1-{[4-(trifluoromethyl)benzoyl]amino}ethyl)benzamide
I-152
4-(1-{[(2,5-difluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-153
4-(1-{[(3-fluoro-4-methoxyphenyl)sulfonyl]amino}ethyl)-N-hydroxybenz-
amide I-154
N-hydroxy-4-(1-{[(1-methylcyclopropyl)carbonyl]amino}ethyl)benzamide
I-155
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2,5-bis(trif-
luoromethyl)benzamide I-156
4-[1-({[(2,6-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-157
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)adamanta-
ne-1-carboxamide I-158
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-benzot-
hiophene-3- carboxamide I-159
N-hydroxy-4-(1-{[(4-methoxyphenyl)acetyl]amino}ethyl)benzamide
I-160
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5,7-dimethylpyrazolo[1-
,5-a]pyrimidine-2- carboxamide I-161
4-{1-[(2,1,3-benzoxadiazol-4-ylsulfonyl)amino]ethyl}-N-hydroxybenzam-
ide I-162
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)adamantan-
e-1-carboxamide I-163
4-{1-[({[2-chloro-4-(trifluoromethyl)phenyl]amino}carbonyl)amino]eth-
yl}-N- hydroxybenzamide I-164
4-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methoxybenz-
amide I-165
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)pyrazine-2-carboxamide
I-166
N-hydroxy-4-[1-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]ben-
zamide I-167
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-dimethyl-1H-pyrazo-
le-4-carboxamide I-168
N-hydroxy-4-[1-({[(3-methyl-5-phenylisoxazol-4-yl)amino]carbonyl}ami-
no)ethyl]benzamide I-169
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzof-
uran-2-carboxamide I-170
N-hydroxy-4-{1-[(isoquinolin-5-ylsulfonyl)amino]ethyl}benzamide
I-171
N-hydroxy-4-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)buty-
l]benzamide I-172
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2-phenyl-1,3-
-thiazole-4- carboxamide I-173
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3,5-bis(trif-
luoromethyl)benzamide I-174
N-hydroxy-4-(2-methyl-1-{[(2-methyl-1H-indol-3-yl)acetyl]amino}propy-
l)benzamide I-175
4-[1-({[(2,3-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-176 N-hydroxy-4-{1-[(mesitylsulfonyl)amino]ethyl}benzamide
I-177
3-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxybenzamide
I-178
N-hydroxy-4-[1-({[4-(1,3-oxazol-5-yl)phenyl]sulfonyl}amino)ethyl]ben-
zamide I-179
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-thiazole-4-carboxa-
mide I-180
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methyl-2-phenyl-4H-f-
uro[3,2-b]pyrrole-5- carboxamide I-181
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-2,5-dimethyl-1H-pyrrol-
e-3-carboxamide I-182
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-5-methyl-
-1-phenyl-1H- pyrazole-4-carboxamide I-183
3-[1-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)ethyl]-N-hydrox-
ybenzamide I-184
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene--
2-carboxamide I-185
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-(1H-pyrazol-1-yl)ben-
zamide I-186
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-isopropyl-1-methyl-1-
H-pyrazole-5- carboxamide I-187
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3-methy-
l-1-benzofuran-2- carboxamide I-188
4-(1-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenza-
mide I-189
N-hydroxy-4-[(1R)-2-methyl-1-({[4-(trifluoromethyl)phenyl]sulfonyl}a-
mino)propyl]benzamide I-190
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)quinoxaline-2-
-carboxamide I-191
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1,3-benzothi-
azole-2-carboxamide I-192
4-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-
benzamide I-193
N-hydroxy-3-{(1R)-1-[(4-methoxybenzoyl)amino]ethyl}benzamide I-194
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzofuran-
-5-carboxamide I-195
N-hydroxy-4-[2-methyl-1-({[3-(trifluoromethyl)phenyl]acetyl}amino)pr-
opyl]benzamide I-196
N-hydroxy-4-[1-({[(1-phenylethyl)amino]carbonyl}amino)ethyl]benzamid-
e I-197
4-(1-{[(3-chlorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-198
4-(1-{[(4-fluorobenzyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-199
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-(methylsulfonyl)benz-
amide I-200
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-dime-
thylisoxazole-4- carboxamide I-201
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-ca-
rboxamide I-202
N-hydroxy-3-{1-[(4-methoxybenzoyl)amino]ethyl}benzamide I-203
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)pyrazine-2-ca-
rboxamide I-204
4-{1-[(diphenylacetyl)amino]-2-methylpropyl}-N-hydroxybenzamide
I-205
4-(1-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenza-
mide I-206
4-(1-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-2-methylpropyl)-N-h-
ydroxybenzamide I-207
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-carboxa-
mide I-208
4-{1-[(cyclohexylcarbonyl)amino]ethyl}-N-hydroxybenzamide I-209
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)adamantane-1-carbo-
xamide I-210
N-hydroxy-4-[1-({[(2-phenylethyl)amino]carbonyl}amino)ethyl]benzamid-
e I-211
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2-methyl-
-4,5,6,7-tetrahydro- 2H-indazole-3-carboxamide I-212
4-(1-{[(1-adamantylacetyl]amino}ethyl)-N-hydroxybenzamide I-213
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)cycloheptanecarboxamide
I-214
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzo-
thiophene-2- carboxamide I-215
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)thiophene-
-2-carboxamide I-216
3-ethyl-N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-py-
razole-5-carboxamide I-217
4-(1-{[(2,5-dimethyl-1,3-thiazol-4-yl)acetyl]amino}ethyl)-N-hydroxyb-
enzamide I-218
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3,5-dimethylisoxazole--
4-carboxamide I-219
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indole-2-c-
arboxamide I-220
N-hydroxy-4-(2-methyl-1-{[(2,4,7-trimethyl-1H-indol-3-yl)acetyl]amin-
o}propyl)benzamide I-221
N-hydroxy-4-(1-{[(4-isopropylphenyl)sulfonyl]amino}ethyl)benzamide
I-222
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-4-methyl-2-phenyl-
-4H-furo[3,2- b]pyrrole-5-carboxamide I-223
3-hydroxy-N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropy-
l)adamantane-1- carboxamide I-224
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2H-chromene-3-carboxam-
ide I-225
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methoxybenzamide
I-226
5-chloro-N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran--
2-carboxamide I-227
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1H-indole-2-carboxamid-
e I-228
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-(1H-pyrrol-1-yl)thio-
phene-2-carboxamide I-229
N-((R)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)-1-benzot-
hiophene-2- carboxamide I-230
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-1,3-benzothia-
zole-5-carboxamide I-231
4-methyl-2-phenyl-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbon-
yl]phenyl}ethyl)-4H- furo[3,2-b]pyrrole-5-carboxamide I-232
N-hydroxy-4-(1-{[(2-methylphenyl)sulfonyl]amino}ethyl)benzamide
I-233
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2,1,3-benzothiadiazole-
-5-carboxamide I-234
N-hydroxy-3-(1-{[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]amino}eth-
yl)benzamide I-235
4-(1-{[(2-chloro-4-fluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenza-
mide I-236
4-[1-({[(4-cyanophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e I-237
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzof-
uran-2-carboxamide I-238
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3,5-dimethyl-
isoxazole-4- carboxamide I-239
4-{1-[(cyclopropylcarbonyl)amino]ethyl}-N-hydroxybenzamide I-240
N-((1S)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene--
2-carboxamide I-241
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,5-dimethyl-1H-pyrazo-
le-3-carboxamide I-242
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-methy-
l-1H-indole-2- carboxamide I-243
4-[1-(butyrylamino)ethyl]-N-hydroxybenzamide I-244
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-3-car-
boxamide I-245
4,5-dichloro-N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-me-
thyl-1H-pyrrole-2- carboxamide I-246
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)quinoline-4-c-
arboxamide I-247
5-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1H--
indole-2-carboxamide I-248
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-4-methyl-
-2-[4- (trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole-5-carboxamide
I-249
N-((S)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)-1-benzot-
hiophene-2- carboxamide I-250
4-[1-({[3,5-bis(trifluoromethyl)phenyl]acetyl}amino)-2-methylpropyl]-
-N-hydroxybenzamide
I-251
3,5-difluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpro-
pyl)benzamide I-252
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2,5-dimethyl-
-3-furamide I-253
N-hydroxy-4-[1-({[(2-methoxy-5-methylphenyl)amino]carbonyl}amino)eth-
yl]benzamide I-254
4-(1-{[(2-chloro-4-cyanophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzam-
ide I-255
4-{1-[(cyclopentylcarbonyl)amino]-2-methylpropyl}-N-hydroxybenzamide
I-256
4-(1-{[(2,5-dimethyl-3-thienyl)sulfonyl]amino}ethyl)-N-hydroxybenzam-
ide I-257
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-methyl-1-phenyl-1H-p-
yrazole-4- carboxamide I-258
N-hydroxy-4-(2-methyl-1-{[(1-phenylcyclopentyl)carbonyl]amino}propyl-
)benzamide I-259
N-[(S)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]adamantane-1-
-carboxamide I-260
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1,5-dime-
thyl-1H-pyrazole-3- carboxamide I-261
4-[1-({[(2,6-difluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-262
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-dime-
thyl-1H-pyrrole-2- carboxamide I-263
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrrole-2--
carboxamide I-264
N-hydroxy-4-[1-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)ethyl-
]benzamide I-265
4-{1-[(cyclohexylcarbonyl)amino]-2,2-dimethylpropyl}-N-hydroxybenzam-
ide I-266
N-hydroxy-4-(1-{[(4-methylphenyl)sulfonyl]amino}ethyl)benzamide
I-267
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)thiophene-2-carboxamide
I-268 3-{1-[(4-tert-butylbenzoyl)amino]ethyl}-N-hydroxybenzamide
I-269
2-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
I-270
5-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-
-1-benzofuran-2- carboxamide I-271
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrro-
le-2-carboxamide I-272
4-{1-[(2,1,3-benzothiadiazol-5-ylsulfonyl)amino]ethyl}-N-hydroxybenz-
amide I-273
N-hydroxy-4-((1S)-1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benza-
mide I-274
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)biphenyl-4-carboxa-
mide I-275
4-[1-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-276
1-methyl-N-((1R)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl-
}ethyl)-1H-indole-2- carboxamide I-277
N-hydroxy-4-[1-({[(4-methylbenzyl)amino]carbonyl}amino)ethyl]benzami-
de I-278
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-1,3-thiazole--
4-carboxamide I-279
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1H-indo-
le-2-carboxamide I-280
4-{1-[(1,3-benzodioxol-5-ylacetyl)amino]ethyl}-N-hydroxybenzamide
I-281
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-methyl-1H-pyrro-
le-2-carboxamide I-282
3,5-bis(acetylamino)-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methy-
lpropyl)benzamide I-283
N-hydroxy-3-((1R)-1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benza-
mide I-284
N-hydroxy-4-(1-{[(2,3,4-trifluorophenyl)sulfonyl]amino}ethyl)benzami-
de I-285
N-hydroxy-4-(1-{[(4-isopropylphenyl)acetyl]amino}ethyl)benzamide
I-286
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-isobutylisoxazole-3--
carboxamide I-287
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]-2-methylpropyl}-N-hydroxybe-
nzamide I-288
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-dimethyl-1H-pyrazo-
le-5-carboxamide I-289
N-hydroxy-4-{2-methyl-1-[(3-methyl-2-phenylbutanoyl)amino]propyl}ben-
zamide I-290
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}-2,2,2-trifluoroethyl)-N-
-hydroxybenzamide I-291
3-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpro-
pyl)-1-methyl-1H- pyrazole-5-carboxamide I-292
4-(1-{[(2-chlorophenyl)acetyl]amino}ethyl)-N-hydroxybenzamide I-293
4-(1-{[(2,1,3-benzothiadiazol-4-ylamino)carbonyl]amino}ethyl)-N-hydr-
oxybenzamide I-294
N-((1S)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indol-
e-2-carboxamide I-295
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methylbenzamide
I-296
N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)bi-
phenyl-4-carboxamide I-297
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-benzodioxole-5-car-
boxamide I-298
N-hydroxy-4-(1-{[(1-phenylcyclopentyl)carbonyl]amino}ethyl)benzamide
I-299
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-benzothiophene--
2-carboxamide I-300
4-[1-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2-methylpropyl-
]-N-hydroxybenzamide I-301
4,5-dichloro-N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-me-
thyl-1H-pyrrole-2- carboxamide I-302
4-(1-{[(4-chlorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-303
4-(2,2-dimethyl-1-{[4-(trifluoromethyl)benzoyl]amino}propyl)-N-hydro-
xybenzamide I-304
3-methyl-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl-
}ethyl)-1-benzofuran-2- carboxamide I-305
N-hydroxy-4-[1-({[(5-methyl-3-phenylisoxazol-4-yl)amino]carbonyl}ami-
no)ethyl]benzamide I-306
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-7-methoxy-1--
benzofuran-2- carboxamide I-307
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3-methy-
l-1-benzothiophene-2- carboxamide I-308
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-benzot-
hiophene-2- carboxamide I-309
3-tert-butyl-N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl--
1H-pyrazole-5- carboxamide I-310
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2,5-dime-
thyl-1H-pyrrole-3- carboxamide I-311
3-{1-[(cyclopentylcarbonyl)amino]ethyl}-N-hydroxybenzamide I-312
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)adamantane-1-carbo-
xamide I-313
N-hydroxy-4-{1-[(tetrahydro-2H-pyran-4-ylacetyl)amino]ethyl}benzamid-
e I-314
N-hydroxy-3-[1-({[3-(trifluoromethyl)phenyl]acetyl}amino)ethyl]benza-
mide I-315 N-hydroxy-4-{1-[(phenylsulfonyl)amino]ethyl}benzamide
I-316
N-hydroxy-4-[1-({[(3-methylbenzyl)amino]carbonyl}amino)ethyl]benzami-
de I-317
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-ca-
rboxamide I-318
3-ethyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)--
1-methyl-1H-pyrazole- 5-carboxamide I-319
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1H-indol-
e-3-carboxamide I-320
3-((1R)-1-{[(tert-butylamino)carbonyl]amino}ethyl)-N-hydroxybenzamid-
e I-321
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene--
2-carboxamide I-322
N-((S)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)adamantan-
e-1-carboxamide I-323
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)biphenyl-4-ca-
rboxamide I-324
2-(4-tert-butylphenyl)-N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-
-4-methyl-4H-furo[3,2- b]pyrrole-5-carboxamide I-325
4-{1-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]eth-
yl}-N- hydroxybenzamide I-326
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3,5-dimethylisoxazole--
4-carboxamide I-327
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-naphthamide I-328
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)adamanta-
ne-1-carboxamide I-329
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-dime-
thyl-1H-indole-2- carboxamide I-330
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indol-
e-2-carboxamide I-331
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-naphthamid-
e I-332
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-4-methy-
l-2-phenyl-4H- furo[3,2-b]pyrrole-5-carboxamide I-333
3-{1-[(3,3-dimethylbutanoyl)amino]ethyl}-N-hydroxybenzamide I-334
4-{1-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]eth-
yl}-N-hydroxybenzamide I-335
N-hydroxy-4-(1-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)ben-
zamide I-336
N-[(R)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]adamantane-1-
-carboxamide I-337
2-(4-tert-butylphenyl)-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-d-
imethylpropyl)-4- methyl-4H-furo[3,2-b]pyrrole-5-carboxamide I-338
4-{1-[(benzylsulfonyl)amino]ethyl}-N-hydroxybenzamide I-339
4-(1-{[(tert-butylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
I-340
4-(1-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-341
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)biphenyl-
-4-carboxamide I-342
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-methyl-1H-indole-2-c-
arboxamide I-343
3-[(1R)-1-({[1-adamantylamino]carbonyl}amino)ethyl]-N-hydroxybenzami-
de I-344
4-{1-[(cyclohexylcarbonyl)amino]-2-methylpropyl}-N-hydroxybenzamide
I-345
4-(1-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-2,2-dimethylpropyl)-
-N-hydroxybenzamide I-346
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-4-methoxyben-
zamide I-347
4-(1-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}ethyl)-N-hydroxybenz-
amide I-348
4-{1-[(cyclohex-3-en-1-ylcarbonyl)amino]ethyl}-N-hydroxybenzamide
I-349
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-5-carboxa-
mide I-350
4-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
I-351
N-hydroxy-4-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethy-
l]benzamide I-352
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-4-methox-
ybenzamide I-353
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indole-3-c-
arboxamide I-354
4-[(1R)-1-({[1-adamantylamino]carbonyl}amino)-2-methylpropyl]-N-hydr-
oxybenzamide I-355
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)biphenyl--
4-carboxamide I-356
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrrole-2--
carboxamide I-357
4-{1-[(2,3-dihydro-1H-inden-2-ylacetyl)amino]ethyl}-N-hydroxybenzami-
de I-358
4-[1-({[(3-acetylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzami-
de I-359
4,5-dichloro-N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-me-
thyl-1H-pyrrole-2- carboxamide I-360
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-benzothiazole-6-ca-
rboxamide I-361
4-(1-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
I-362
3-[1-({[3,5-bis(trifluoromethyl)phenyl]acetyl}amino)ethyl]-N-hydroxy-
benzamide I-363
N-hydroxy-4-{1-[(quinolin-8-ylsulfonyl)amino]ethyl}benzamide I-364
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-
-1H-indole-2- carboxamide I-365
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]butyl}-N-hydroxybenzamide
I-366
2,6-dichloro-N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
I-367
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-3-methyl-1-benzof-
uran-2-carboxamide I-368
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}-2-methylpropyl)-N-hydro-
xybenzamide I-369
4-{1-[(1-benzothien-2-ylsulfonyl)amino]ethyl}-N-hydroxybenzamide
I-370 4-{1-[(cyclopentylacetyl)amino]ethyl}-N-hydroxybenzamide
I-371
N-hydroxy-4-{1-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]et-
hyl}benzamide I-372
N-hydroxy-4-(1-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino}ethy-
l)benzamide I-373
4-{1-[(cyclopentylcarbonyl)amino]-2,2-dimethylpropyl}-N-hydroxybenza-
mide I-374
4-[(1R)-1-({[1-adamantylamino]carbonyl}amino)ethyl]-N-hydroxybenzami-
de I-375
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2-oxo-6-phen-
yl-1,2- dihydropyridine-3-carboxamide I-376
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3,5-dimethyl-1H-indole-
-2-carboxamide I-377
4-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpro-
pyl)benzamide I-378
4-(1-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}ethyl)-N-hydroxybe-
nzamide I-379
4-{1-[(cyclopropylacetyl)amino]ethyl}-N-hydroxybenzamide I-380
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}butyl)-N-hydroxybenzamid-
e I-381
4-[1-({[(4-ethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e I-382
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)cycloheptanec-
arboxamide I-383
4-[1-({[(2,4-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-384
4-(1-{[(biphenyl-2-ylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
I-385 4-[1-(benzoylamino)ethyl]-N-hydroxybenzamide I-386
4,5-dichloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpro-
pyl)-1-methyl-1H- pyrrole-2-carboxamide I-387
N-hydroxy-4-((1R)-1-{[(1-methylcyclohexyl)carbonyl]amino}butyl)benza-
mide I-388
4-[1-({[(3,5-dichlorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-389
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-methyl-1H--
pyrazole-3- carboxamide I-390
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzothiop-
hene-2-carboxamide I-391
N-hydroxy-4-[1-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]ben-
zamide I-392
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-4-methyl-
-2-phenyl-4H-furo[3,2- b]pyrrole-5-carboxamide I-393
N-((1S)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-4-carboxa-
mide I-394
N-hydroxy-4-[1-({[(2-methylphenyl)amino]carbonyl}amino)ethyl]benzami-
de I-395
4-(1-{[(cyclohexylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
I-396
4-{1-[(3,3-dimethylbutanoyl)amino]-2,2-dimethylpropyl}-N-hydroxybenz-
amide I-397
4-[1-({[(3,5-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-398
4-[1-({[(4-acetylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzami-
de I-399
N-hydroxy-4-{1-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)amino]et-
hyl}benzamide I-400
N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-
-benzofuran-2- carboxamide I-401
N-(1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-carboxa-
mide I-402
4-(1-{[(2,4-difluorophenyl)acetyl]amino}ethyl)-N-hydroxybenzamide
I-403
N-hydroxy-3-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethy-
l]benzamide I-404
6-{(1S)-1-[(1-benzothien-2-ylcarbonyl)amino]-2,2-dimethylpropyl}-N-h-
ydroxynicotinamide I-405
5-{(1S)-1-[(2,2-dimethylpropanoyl)amino]propyl}-N-hydroxynicotinamid-
e I-406
5-{(1S)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxy-6-methoxyni-
cotinamide I-407
2-{(1S)-1-[(cyclopentylacetyl)amino]butyl}-N-hydroxyisonicotinamide
I-408
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}propyl)-1-methylpiperidi-
ne-4-carboxamide I-409
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}propyl)-1-methyl-1H-indo-
le-2-carboxamide I-410
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]propyl}-N-hydroxy-3-methoxyb-
enzamide I-411
N-((1S)-1-{5-[(hydroxyamino)carbonyl]pyridin-2-yl}-2,2-dimethylpropy-
l)-1-methyl-1H-indole- 2-carboxamide I-412
6-{(1S)-1-[(2,2-dimethylpropanoyl)amino]-2,2-dimethylpropyl}-N-hydro-
xynicotinamide I-413
N-((1S)-1-{4-[(hydroxyamino)carbonyl]pyridin-2-yl}butyl)-1-methyl-1H-
-indole-2-carboxamide I-414
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-b-
enzothiophene-2- carboxamide I-415
N-hydroxy-2-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)prop-
yl]isonicotinamide I-416
6-((1S)-2,2-dimethyl-1-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}pro-
pyl)-N- hydroxynicotinamide I-417
6-((1S)-2,2-dimethyl-1-{[(1-methylpiperidin-4-yl)carbonyl]amino}prop-
yl)-N- hydroxynicotinamide I-418
4-{(1S)-1-[(2,2-dimethylpropanoyl)amino]-2,2-dimethylpropyl}-N-hydro-
xybenzamide I-419
N-hydroxy-6-methoxy-5-((1S)-1-{[(1-methyl-1H-pyrrol-2-
yl)carbonyl]amino}ethyl)nicotinamide I-420
6-((1S)-1-{[(dimethylamino)acetyl]amino}-2,2-dimethylpropyl)-N-hydro-
xynicotinamide I-421
6-((1S)-1-{[(dimethylamino)acetyl]amino}ethyl)-N-hydroxynicotinamide
I-422
4-{(1S)-1-[(cyclopentylacetyl)amino]propyl}-N-hydroxybenzamide
I-423
5-{(1S)-1-[(1-benzothien-2-ylcarbonyl)amino]propyl}-N-hydroxynicotin-
amide I-424
5-{(1S)-1-[(cyclopentylacetyl)amino]ethyl}-N-hydroxy-6-methoxynicoti-
namide I-425
N-hydroxy-5-((1S)-1-{[(1-methylpiperidin-4-yl)carbonyl]amino}propyl)-
nicotinamide I-426
2-{(1S)-1-[(2,2-dimethylpropanoyl)amino]butyl}-N-hydroxyisonicotinam-
ide I-427
3-fluoro-N-hydroxy-4-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}a-
mino)ethyl]benzamide I-428
5-{(1S)-1-[(1-adamantylcarbonyl)amino]propyl}-N-hydroxynicotinamide
I-429
6-{(1S)-1-[(1-adamantylcarbonyl)amino]-2,2-dimethylpropyl}-N-hydroxy-
nicotinamide I-430
2-{(1S)-1-[(cyclopentylacetyl)amino]-2-methylpropyl}-N-hydroxypyrimi-
dine-5-carboxamide I-431
N-hydroxy-6-methoxy-5-((1S)-1-{[(1-methylpiperidin-4-yl)carbonyl]ami-
no}ethyl)nicotinamide I-432
6-{(1S)-1-[(cyclopentylacetyl)amino]-2,2-dimethylpropyl}-N-hydroxyni-
cotinamide I-433
N-hydroxy-6-((1S)-1-{[(1-methylpiperidin-4-yl)carbonyl]amino}ethyl)n-
icotinamide I-434
6-{(1S)-1-[(biphenyl-4-ylcarbonyl)amino]ethyl}-N-hydroxynicotinamide
I-435
N-hydroxy-6-((1S)-1-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}ethyl)-
nicotinamide I-436
2-{(1S)-1-[(1-adamantylcarbonyl)amino]-2-methylpropyl}-N-hydroxypyri-
midine-5-carboxamide I-437
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-m-
ethylpiperidine-4- carboxamide I-438
N-hydroxy-2-((1S)-1-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}butyl)-
isonicotinamide I-439
N-((1R)-1-{2-fluoro-4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl-
)biphenyl-4- carboxamide I-440
N-hydroxy-2-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethy-
l]pyrimidine-5- carboxamide I-441
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}propyl)-1-benzothiophene-
-2-carboxamide I-442
5-{(1S)-1-[(cyclopentylacetyl)amino]propyl}-N-hydroxynicotinamide
I-443
6-{(1S)-1-[(biphenyl-4-ylcarbonyl)amino]-2,2-dimethylpropyl}-N-hydro-
xynicotinamide I-444
N-((1S)-1-{5-[(hydroxyamino)carbonyl]-2-methoxypyridin-3-yl}ethyl)-1-
-methyl-1H-indole-2- carboxamide I-445
6-{(1S)-1-[(1-benzothien-2-ylcarbonyl)amino]ethyl}-N-hydroxynicotina-
mide I-446
6-{(1S)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxynicotinamide
I-447
5-((1S)-1-{[(dimethylamino)acetyl]amino}ethyl)-N-hydroxy-6-methoxyni-
cotinamide I-448
2-{(1S)-1-[(1-benzothien-2-ylcarbonyl)amino]-2-methylpropyl}-N-hydro-
xypyrimidine-5- carboxamide I-449
2-{(1S)-1-[(biphenyl-4-ylcarbonyl)amino]butyl}-N-hydroxyisonicotinam-
ide I-450
2-{(1S)-1-[(biphenyl-4-ylcarbonyl)amino]-2-methylpropyl}-N-hydroxypy-
rimidine-5- carboxamide I-451
2-((1S)-1-{[(dimethylamino)acetyl]amino}butyl)-N-hydroxyisonicotinam-
ide I-452
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-m-
ethyl-1H-indole-2- carboxamide I-453
5-((1S)-1-{[(dimethylamino)acetyl]amino}propyl)-N-hydroxynicotinamid-
e I-454 N-hydroxy-2-[(1R)-2-methyl-1-({[4-
(trifluoromethyl)phenyl]sulfonyl}amino)propyl]isonicotinamide I-455
N-((1S)-1-{5-[(hydroxyamino)carbonyl]pyridin-3-yl}propyl)-1-methyl-1-
H-indole-2- carboxamide I-456
2-((1S)-1-{[(dimethylamino)acetyl]amino}-2-methylpropyl)-N-hydroxypy-
rimidine-5- carboxamide I-457
N-((1S)-1-{5-[(hydroxyamino)carbonyl]pyridin-2-yl}ethyl)-1-methyl-1H-
-indole-2-carboxamide I-458
2-{(1S)-1-[(1-benzothien-2-ylcarbonyl)amino]butyl}-N-hydroxyisonicot-
inamide I-459
4-{(1S)-1-[(cyclopentylacetyl)amino]-2,2-dimethylpropyl}-N-hydroxybe-
nzamide I-460
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}propyl)-1-methyl-1H-pyrr-
ole-2-carboxamide I-461
N-hydroxy-5-((1S)-1-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}propyl-
)nicotinamide I-462
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-m-
ethyl-1H-pyrrole-2- carboxamide I-463
5-((1R)-1-{[(tert-butylamino)carbonyl]amino}propyl)-N-hydroxynicotin-
amide I-464
5-{(1S)-1-[(biphenyl-4-ylcarbonyl)amino]ethyl}-N-hydroxy-6-methoxyni-
cotinamide I-465
2-{(1S)-1-[(1-adamantylcarbonyl)amino]butyl}-N-hydroxyisonicotinamid-
e I-466
N-((1S)-1-{5-[(hydroxyamino)carbonyl]pyrimidin-2-yl}-2-methylpropyl)-
-1-methyl-1H-indole-2- carboxamide I-467
5-{(1S)-1-[(biphenyl-4-ylcarbonyl)amino]propyl}-N-hydroxynicotinamid-
e I-468
N-hydroxy-2-((1S)-1-{[(1-methylpiperidin-4-yl)carbonyl]amino}butyl)i-
sonicotinamide I-469
6-{(1S)-1-[(1-adamantylcarbonyl)amino]ethyl}-N-hydroxynicotinamide
I-470
4-((1S)-1-{[(dimethylamino)acetyl]amino}propyl)-N-hydroxybenzamide
I-471
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)biph-
enyl-4-carboxamide I-472
5-{(1S)-1-[(1-adamantylcarbonyl)amino]ethyl}-N-hydroxy-6-methoxynico-
tinamide I-473
2-{(1S)-1-[(2,2-dimethylpropanoyl)amino]-2-methylpropyl}-N-hydroxypy-
rimidine-5- carboxamide I-474
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}propyl)biphenyl-4-carbox-
amide I-475
4-{(1S)-1-[(2,2-dimethylpropanoyl)amino]propyl}-N-hydroxybenzamide
I-476
N-hydroxy-2-((1S)-2-methyl-1-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]ami-
no}propyl)pyrimidine- 5-carboxamide I-477
N-hydroxy-2-((1S)-2-methyl-1-{[(1-methylpiperidin-4-yl)carbonyl]amin-
o}propyl)pyrimidine-5- carboxamide I-478
4-((1S)-1-{[(dimethylamino)acetyl]amino}-2,2-dimethylpropyl)-N-hydro-
xybenzamide I-479
5-{(1S)-1-[(1-benzothien-2-ylcarbonyl)amino]ethyl}-N-hydroxy-6-metho-
xynicotinamide I-480
N-(1-{4-[(hydroxyamino)carbonyl]-2-methoxyphenyl}ethyl)-1-benzothiop-
hene-2-carboxamide I-481
N-(1-{4-[(hydroxyamino)carbonyl]-2-methoxyphenyl}ethyl)-1-methyl-1H--
pyrrole-2- carboxamide I-482
4-((1R)-1-{[(benzylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
I-483
N-(1-{4-[(hydroxyamino)carbonyl]-2-methoxyphenyl}ethyl)adamantane-1--
carboxamide I-484
4-{1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxy-3-methoxybenzami-
de I-485
N-(1-{4-[(hydroxyamino)carbonyl]-2-methylphenyl}ethyl)-1-benzothioph-
ene-2-carboxamide I-486
N-(1-{4-[(hydroxyamino)carbonyl]-2-methylphenyl}ethyl)-1-methyl-1H-p-
yrrole-2-carboxamide I-487
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methylpiperidin-
e-4-carboxamide I-488
N-hydroxy-4-[1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]ben-
zamide I-489
N-hydroxy-4-((1R)-1-{[(1-methylcyclohexyl)methyl]amino}ethyl)benzami-
de I-490
4-{1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxy-3-methylbenzamid-
e I-491
N-(1-{4-[(hydroxyamino)carbonyl]-2-methylphenyl}ethyl)adamantane-1-c-
arboxamide I-492
N-hydroxy-4-[(1R)-2-methyl-1-({[(5-phenyl-2-thienyl)amino]carbonyl}a-
mino)propyl]benzamide I-493
4-((1R)-1-{[(biphenyl-2-ylamino)carbonyl]amino}-2-methylpropyl)-N-hy-
droxybenzamide I-494
4-((1R)-1-{[(biphenyl-2-ylamino)carbonyl]amino}ethyl)-N-hydroxybenza-
mide I-495 N-hydroxy-4-{(1R)-2-methyl-1-[({[(1S)-1-
phenylethyl]amino}carbonyl)amino]propyl}benzamide I-496
4-((1R)-1-{[(2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]amino}ethyl-
)-N-hydroxybenzamide I-497
4-[(1R)-1-({[(3,4-dimethylphenyl)amino]carbonyl}amino)-2-methylpropy-
l]-N-
hydroxybenzamide I-498
4-[(1R)-1-({[(4-cyanophenyl)amino]carbonyl}amino)-2-methylpropyl]-N--
hydroxybenzamide I-499
N-hydroxy-4-{(1R)-1-[({[(1S)-1-phenylethyl]amino}carbonyl)amino]ethy-
l}benzamide I-500
4-[(1R)-1-({[(3,4-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydro-
xybenzamide I-501
N-hydroxy-4-[(1R)-2-methyl-1-({[(2-phenylethyl)amino]carbonyl}amino)-
propyl]benzamide I-502
N-hydroxy-4-{(1R)-1-[({[(1R)-1-phenylethyl]amino}carbonyl)amino]ethy-
l}benzamide I-503
N-hydroxy-4-((1R)-1-{[(1-naphthylamino)carbonyl]amino}ethyl)benzamid-
e I-504
4-[(1R)-1-({[(4-cyanophenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-505
4-[(1R)-1-({[(2,6-difluorophenyl)amino]carbonyl}amino)-2-methylpropy-
l]-N-hydroxybenzamide I-506
N-hydroxy-4-[(1R)-1-({[(2-phenylethyl)amino]carbonyl}amino)ethyl]ben-
zamide I-507 N-hydroxy-4-{(1R)-2-methyl-1-[({[(1R)-1-
phenylethyl]amino}carbonyl)amino]propyl}benzamide I-508
4-[(1R)-1-({[(2,6-difluorophenyl)amino]carbonyl}amino)ethyl]-N-hydro-
xybenzamide I-509
4-((1R)-1-{[(2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]amino}-2-me-
thylpropyl)-N- hydroxybenzamide I-510
N-hydroxy-4-((1R)-2-methyl-1-{[(1-naphthylamino)carbonyl]amino}propy-
l)benzamide I-511
N-hydroxy-4-[(1R)-1-({[(5-phenyl-2-thienyl)amino]carbonyl}amino)ethy-
l]benzamide I-512
4-[(1R)-1-({[(3,4-dimethylphenyl)amino]carbonyl}amino)-2-methylpropy-
l]-N- hydroxybenzamide I-513
N-hydroxy-4-[(1R)-1-({[(1S)-1-phenylethyl]carbamoyl}amino)ethyl]benz-
amide I-514
N-hydroxy-4-[(1R)-2-methyl-1-({[(1R)-1-phenylethyl]carbamoyl}amino)p-
ropyl]benzamide I-515
4-((1R)-1-{[(biphenyl-2-ylamino)carbonyl]amino}-2-methylpropyl)-N-hy-
droxybenzamide I-516 N-hydroxy-4-{(1R)-2-methyl-1-[({[(1S)-1-
phenylethyl]amino}carbonyl)amino]propyl}benzamide I-517
N-hydroxy-4-[(1R)-1-({[(1R)-1-phenylethyl]carbamoyl}amino)ethyl]benz-
amide I-518
4-[(1R)-1-({[(2,6-difluorophenyl)amino]carbonyl}amino)ethyl]-N-hydro-
xybenzamide I-519
N-hydroxy-4-((1R)-2-methyl-1-{[4-(3-phenylisoxazol-5-yl)-1,3-thiazol-
-2- yl]amino}propyl)benzamide I-520
4-[(1R)-1-({[(4-cyanophenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide I-521
4-[(1R)-1-({[(2,6-difluorophenyl)amino]carbonyl}amino)-2-methylpropy-
l]-N-hydroxybenzamide I-522
N-hydroxy-4-[(1R)-2-methyl-1-({[(2-phenylethyl)amino]carbonyl}amino)-
propyl]benzamide I-523
4-((1R)-1-{[(biphenyl-2-ylamino)carbonyl]amino}ethyl)-N-hydroxybenza-
mide I-524
N-hydroxy-4-((1R)-2-methyl-1-{[(1-naphthylamino)carbonyl]amino}propy-
l)benzamide I-525
4-[(1R)-1-({[(4-cyanophenyl)amino]carbonyl}amino)-2-methylpropyl]-N--
hydroxybenzamide I-526
4-((1R)-1-{[(2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]amino}-2-me-
thylpropyl)-N- hydroxybenzamide I-527
N-hydroxy-4-((1R)-1-{[(1-naphthylamino)carbonyl]amino}ethyl)benzamid-
e I-528
4-((1R)-1-{[(2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]amino}ethyl-
)-N-hydroxybenzamide I-529
N-hydroxy-4-((1R)-2-methyl-1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]-
amino}propyl)benzamide I-530
N-hydroxy-4-((1R)-1-{[(1-isopropylpiperidin-4-yl)methyl]amino}butyl)-
benzamide I-531
3-{[((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)amino]methyl}-N--
pyrrolidin-3- ylbenzamide I-532
N-(4-{[((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)ami-
no]methyl}pyridin-2- yl)-4-methylpiperidine-4-carboxamide I-533
N-(4-{[((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)ami-
no]methyl}phenyl)-1- methylpiperidine-4-carboxamide I-534
4-((1R)-1-{[(1-ethylpiperidin-4-yl)methyl]amino}ethyl)-N-hydroxybenz-
amide I-535
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2-(trifl-
uoromethyl)benzamide I-536
4-{(1S)-1-[(2,2-dimethylpropanoyl)amino]butyl}-N-hydroxybenzamide
4. General Synthetic Methods and Intermediates
[0270] The compounds of the present invention can be prepared by
methods known to one of ordinary skill in the art and/or by
reference to the schemes shown below and the synthetic examples.
Exemplary synthetic routes are set forth in Schemes below, and in
the Examples.
[0271] As shown in Scheme 1 below. condensation of commercially
available methyl 4-acetylbenzoate (xlviii) with hydroxylamine
(Method X) affords the resulting oxime xlix which can be reduced by
catalytic hydrogenoylsis in the presence of acid (Method Y) to
generate racemic compound of formula l. The amine can be further
elaborated according to Methods D, H or I, or those described in
Scheme 13, followed by treatment with hydroxylamine hydrochloride
in the presence of base to generate the corresponding substituted
hydroxamate.
##STR00563##
[0272] As shown in Scheme 2, aryl bromide li can be acylated via a
Heck coupling (Method Z) to afford lii. Application of Methods X-Y
as shown in Scheme 1 provides lii which can then be further
elaborated as described herein.
##STR00564##
[0273] Scheme 3 below shows a general route for the preparation of
substituted aminomethyl benzoate compounds of formula iv.
Conversion of tert-butyl 4-formylbenzoate i (prepared as described
in Adlington et al., J. Med. Chem. 2001, 44:1491) to the
N-(tert-butanesulfinyl)imine ii is carried out by reaction with one
enantiomer of 2-methyl-2-propanesulfinamide under dehydrative
conditions (Method A; Ti(OEt).sub.4 or Ti(O.sup.iPr).sub.4, DCM;
Ellman et al., Acc. Chem. Res. 2002, 35:984; Ellman et al., J. Org.
Chem. 1999, 64:1278; Ellman et al., J. Am. Chem. Soc. 1999,
121:268; Davis et al., J. Org. Chem. 1999, 64:1403).
Diastereoselective addition of the R.sup.2 group by the use of the
appropriate Grignard reagent (Method B; as described by Liu et al.,
J. Am. Chem. Soc. 1997, 119:9913) provides a-branched sulfinamides
iii in high diastereomeric ratios. Isolation of single
diastereomers by chromatography followed by removal of the chiral
auxiliary (1 equiv. HCl; Method C) provides enantiomerically pure
amine iv. When R.sup.2 is trifluoromethyl,
tetra-n-butylammoniumdifluorotriphenylsilicate and
(trifluoromethyl)trimethylsilane can be used instead of a Grignard
reagent to introduce the trifluoromethyl group to the compound of
formula ii, resulting in the compound of formula iii wherein
R.sup.2 is trifluoromethyl. The synthetic sequence can be repeated
with the opposite enantiomer of the 2-methyl-2-propanesulfinamide
to generate the other enantiomer of the compound of formula iv. It
will also be appreciated that this method can be used to generate
the meta-regioisomer of the compounds of formula iv starting from
the appropriate starting materials.
[0274] The absolute stereochemistry of the chiral primary amines is
established by comparison of the .sup.1H-NMR spectra of the
corresponding Mosher amides as described by Priest et al., J. Chem.
Ed., 2008, 85:698.
##STR00565##
[0275] Scheme 4 shows a general route for the elaboration of
compounds of formula iv to compounds of formula vii. The primary
amine of iv is acylated with a carboxylic acid (R.sup.3--CO.sub.2H)
in the presence of a coupling agent (Method D). Suitable coupling
agents include, but are not limited to,
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU), or
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU). Suitable bases for Method D include,
but are not limited to, triethylamine (Et.sub.3N),
N,N'-diisopropylethylamine (DIPEA) and N-methylmorpholine. Suitable
solvents for Method D include, but are not limited to,
dichloromethane (DCM), tetrahydrofuran (THF),
N,N'-dimethylformamide (DMF), N-methylpyrrolidone (NMP) or
N,N'-dimethylacetamide. Deprotection of the tert-butyl ester to
give compounds of formula vi is achieved under acidic conditions,
using for example, trifluoracetic acid in DCM or dichloroethane
(Method E). Conversion of the acid of formula vi to the
corresponding hydroxamate of formula vii (Method F) is achieved by
activation of the acid with a coupling reagent such as HATU, in the
presence of base such as Et.sub.3N, in a solvent such as DMF,
followed by treatment with
O-(tert-butyldimethylsilyl)hydroxylamine. The silyl protecting
group can then be removed by treatment under acidic conditions such
as 1% HCl in isopropyl alcohol. Alternatively, the hydroxamate can
be introduced by treatment of the acid of formula vi with cyanuric
chloride, base and catalytic DMAP followed by hydroxylamine
hydrochloride (Method G; Giacomelli et al., Org. Lett. 2003,
5:2715).
##STR00566##
[0276] Scheme 5 shows a route for the preparation of substituted
aminomethyl benzoate compounds of formula x. The primary amine of
formula iv is treated with the appropriate sulfonyl chloride,
R.sup.3--SO.sub.2Cl, and DMAP in DMF at ambient temperature to give
compounds of formula viii (Method H). Method H may also be carried
out in a solvent such as DCM or N,N'-dimethylacetamide.
Deprotection of the tert-butyl ester (Method E), and conversion of
the acid to the corresponding hydroxamate (Method F or G) can be
carried out as described in Scheme 3 above to generate compounds of
formula x.
##STR00567##
[0277] Scheme 6 shows a route for the preparation of substituted
aminomethyl benzoate compounds of formula xiii. The primary amine
of formula iv is treated with the appropriate isocyanate,
(R.sup.3--NCO), and base in solvent overnight at ambient or
elevated temperature to afford compounds of formula xi (Method I).
Suitable bases for Method I include, but are not limited to
Et.sub.3N, DIPEA, and N-methylmorpholine. Suitable solvents for
Method I include, but are not limited to, DCM, THF, DMF, NMP or
N,N'-dimethylacetamide. Deprotection of the tert-butyl ester
(Method E), and conversion of the acid to the corresponding
hydroxamate (Method F or G) can be carried out as described in
Scheme 4 above to give compounds of formula xiii. It will be
appreciated that the methods described in Schemes 4, 5 and 6 can be
carried out on amines with different substitution at the R.sup.2
position and differing ring A structures.
##STR00568##
[0278] Scheme 7 below shows a route for the preparation of
tert-butyl substituted compounds of formula xxiv and xxv. Ketone xv
is prepared by reaction of the arylzinc reagent xiv with pivaloyl
chloride (Method J; WO 08/156,721). Conversion of xv to the
sufinimines xvi and xvii is carried out by reaction with the
appropriate sulfinamide under dehydrative conditions (Method A;
Ellman et al., Acc. Chem. Res. 2002, 35:984; Ellman et al., J. Org.
Chem. 1999, 64:1278; Ellman et al., J. Am. Chem. Soc. 1999,
121:268; Davis et al., J. Org. Chem. 1999, 64:1403). Reduction
using NaBH.sub.4 (Method K; Ellman et al., Tetrahedron Lett. 1999,
40:6709; Coyler et al., J. Org. Chem. 2006, 71:6859) and subsequent
separation of pairs of diastereomers xviii and xix or xx and xxi by
normal phase chromatography is followed by removal of the chiral
auxiliary (Method C) to give enantiomerically pure amines xxii and
xxiii. Further elaboration of the compounds of formula xxiv and xxv
is accomplished by reaction with a carboxylic acid as described
above in Scheme 4 (Method D), and then conversion to the
hydroxamate by treatment with hydroxylamine hydrochloride (Method
L; KOH, MeOH). Alternatively, the compounds of formula xxii and
xxiii can be further elaborated as described in Schemes 5, 6 or 13
followed by conversion to the corresponding hydroxamates.
##STR00569##
[0279] Alternatively, sulfinimine xxvi is prepared as shown in
Scheme 8 by condensation of the appropriate sulfinamide with
tert-butyl 4-formylbenzoate i (Method M; Yim and Wong, J. Org.
Chem. 2004, 69:2892); treated with tert-butyllithium in THF (Method
N) to give xxvii after separation of the resulting diastereomers.
Removal of the chiral auxiliary (Method C) followed by elaboration
of the resulting amine as described above in Scheme 2 (Method D),
and removal of the tert-butyl ester using TFA (Method E) yields the
compound of formula xxviii. The compound of formula xxviii is
converted to the corresponding hydroxamate of formula xxv using
cyanuric chloride, base and catalytic DMAP followed by
hydroxylamine hydrochloride (Method G) (Giacomelli, G., et. al.
Org. Lett. 2003, 5, 2715). Alternatively, following removal of the
chiral auxiliary the compound of formula xxvii can be further
elaborated as described in Schemes 5, 6 or 13 followed by
conversion to the corresponding hydroxamates.
##STR00570##
[0280] Alternatively, as shown in Scheme 9, condensation of
pivaloyl aldehyde with S-2-methyl-2-sulfinimide xxix (Method P)
gives xxx which can be treated with the aryllithium reagent xxxi
(Knochel, Science of Synthesis 2004, 3:5-90) in THF at reflux to
give compound xxxii (Method Q; Ellman et al J. Am. Chem. Soc. 1997,
119:913; J. Org. Chem. 2001, 66:8772; WO 02/070492; WO 07/145,568).
Compound xxxii can then be further elaborated as described
above.
##STR00571##
[0281] Scheme 10 shows another alternative route to
enantiomerically pure tert-butyl derivatives. Treatment of pivaloyl
chloride xxxiii with 4-carboxymethylphenylmagnesium iodide
(prepared according to Wang et al., Org. Lett. 2006, 8:305) in the
presence of vanadium chloride in DCM affords ketone xxxiv (Method
R). Treatment with N-amino-4-benzyl-2-oxazolidinone, and TsOH
affords acylhydrazone xxxv (Method S; Friestad et al., J. Am. Chem.
Soc. 2000, 122:8329). The acylhydrazone is reduced using
Bu.sub.3SnH and BF.sub.3 in DCM (Method T; Friestad et al.,
Tetrahedron 2003, 59: 6393) to give the compound of formula xxxvi.
The compound of formula xxxvi is then acylated using n-BuLi,
R.sup.3COCl; the chiral auxiliary is removed with SmI.sub.2 and
HMPA in THF (Method U; Friestad et al., J. Am. Chem. Soc. 2000,
122:8329) to afford the compound of formula xxxvii which can then
be transformed to the corresponding hydroxamate as described
above.
##STR00572##
[0282] Compounds of formula xxxix, xl and xli can be prepared
starting from the commercially available 6-formylnicotinic acid,
5-formylnicotinic acid, and 2-formylisonicotinic acid respectively
as shown in FIG. 1 below. Elaboration using Methods A-C as outlined
in Scheme 3 provides access to the corresponding enantomerically
pure products xxxix, xl and xli. The compounds of formula xlii can
be prepared starting from methyl 5-fluoro-6-formylnicotinate (as
described by Locardi et al., WO 09/036,996). Elaboration using
Methods A-C as outlined in Scheme 3 provides access to
enantomerically pure xlii. Compounds of formula xliii can be
prepared starting from methyl 2-chloro-6-formylisonicotinate
(prepared as described in Augustine et al., Tetrahedron 2008,
64(4):688-695). Elaboration using Methods A-C as outlined in Scheme
3 provides access to enantomerically pure xliii. The compound of
formula xliv can be prepared starting from methyl
2-formylpyrimidine-5-carboxylate
[0283] (as described by Hunt et. al. WO 08/156,715). Elaboration
using Methods A-C as outlined in Scheme 3 provides access to
enantomerically pure xliv. It will be appreciated that the other
optical isomer of each of the amines shown in FIG. 1 will be
isolated following column chromatography of the diastereomers prior
to removal of the chiral auxiliary. The amines can be further
elaborated according to Methods D, H or I, or those described in
Scheme 13, followed by treatment with hydroxylamine hydrochloride
in the presence of base to generate the substituted
hydroxamate.
FIG. 1: Examples of enantiomerically pure amines accessible via
route outlined in Scheme 3
##STR00573##
[0284] Scheme 11 shows a general route for the elaboration of
compounds of formula xlv to compounds of formula xlvii.
Carbonylation of xlv employing carbon monoxide in the presence of a
Pd catalyst, as described in WO 05/037214 (Method V) provides xlvi.
Elaboration using methods A-C as outlined in Scheme 3 provides
access to enantomerically pure xlvii which can be further
elaborated according to Methods D, H or I, or those described in
Scheme 13 followed by treatment with hydroxylamine hydrochloride in
the presence of base to generate corresponding substituted
hydroxamates.
##STR00574##
[0285] Scheme 12 shows a route for the preparation of substituted
(aminomethyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamides
representated by formula lviii. The primary nitrogen of 11v can be
orthogonally protected with a Fmoc group employing standard
conditions using reagents such as Fmoc-Cl (Method Z). Removal of
the t-butyl ester under acidic conditions (Method E) followed by
coupling of the liberated acid of formula lvi with
O-(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of an
appropriate coupling agent (Method CC) provides lvii. Removal of
the Fmoc group is accomplished with piperidine in an appropriate
solvent (Method DD) to give compound of formula lviii. The compound
of formula lviii can be further functionalized employing
transformations such as described in Methods D, H or I or those
described in Scheme 13 followed by removal of the THP group under
acidic conditions.
##STR00575##
[0286] Scheme 13 shows a route for the preparation of substituted
(R)-4-(1-ethylamino)-N-hydroxybenzamides representated by formula
lxii. The compound of formula lix can be selectively converted to
the corresponding ester using acid catalyzed Fisher esterification
conditions (Method EE). Reductive alkylation resulting from the
reaction of an aldehyde (R'CHO) in the presence of an appropriate
borohydride such as, but not limited to, sodium cyanoborohydride
(Method FF; Jones et al., Bioorg. & Med. Chem. Lett. 2008,
18(11):3456-3461) provides the compound of formula lxi. Amine lx
may also be arylated using standard nucleophilic aromatic
substitution of a suitable electrophile such as
2-chloro-nitropyridine, in the presence of suitable base, such as
DIPEA at elevated temperatures (Method HH). Amine lx may also be
N-arylated through a copper(II)-acetate mediated coupling with a
suitable arylboronic acid (Method II; Chan et al. Tetrahedron Lett.
1998, 39(19):2933). Reaction of the compound of formula lxi with
the potassium salt of hydroxylamine (Method GG; Huang et al., Med.
Chem. 2009, 52(21):6757) leads to the formation of the
corresponding hydroxamate lxii.
##STR00576##
4. Uses, Formulation and Administration
[0287] As discussed above, the present invention provides compounds
and pharmaceutical compositions that are useful as inhibitors of
HDAC enzymes, particularly HDAC6, and thus the present compounds
are useful for treating proliferative, inflammatory, infectious,
neurological or cardiovascular disorders.
[0288] The compounds and pharmaceutical compositions of the
invention are particularly useful for the treatment of cancer. As
used herein, the term "cancer" refers to a cellular disorder
characterized by uncontrolled or disregulated cell proliferation,
decreased cellular differentiation, inappropriate ability to invade
surrounding tissue, and/or ability to establish new growth at
ectopic sites. The term "cancer" includes, but is not limited to,
solid tumors and bloodborne tumors, The term "cancer" encompasses
diseases of skin, tissues, organs, bone, cartilage, blood, and
vessels. The term "cancer" further encompasses primary and
metastatic cancers.
[0289] Non-limiting examples of solid tumors that can be treated
with the disclosed inhibitors include pancreatic cancer; bladder
cancer; colorectal cancer; breast cancer, including metastatic
breast cancer; prostate cancer, including androgen-dependent and
androgen-independent prostate cancer; renal cancer, including,
e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung
cancer, including, e.g., non-small cell lung cancer (NSCLC),
bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung;
ovarian cancer, including, e.g., progressive epithelial or primary
peritoneal cancer; cervical cancer; gastric cancer; esophageal
cancer; head and neck cancer, including, e.g., squamous cell
carcinoma of the head and neck; melanoma; neuroendocrine cancer,
including metastatic neuroendocrine tumors; brain tumors,
including, e.g., glioma, anaplastic oligodendroglioma, adult
glioblastoma multiforme, and adult anaplastic astrocytoma; bone
cancer; and soft tissue sarcoma.
[0290] Non-limiting examples of hematologic malignancies that can
be treated with the disclosed inhibitors include acute myeloid
leukemia (AML); chronic myelogenous leukemia (CML), including
accelerated CML and CML blast phase (CML-BP); acute lymphoblastic
leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's
disease (HD); non-Hodgkin's lymphoma (NHL), including follicular
lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell
lymphoma; multiple myeloma (MM); Waldenstrom's macroglobulinemia;
myelodysplastic syndromes (MDS), including refractory anemia (RA),
refractory anemia with ringed siderblasts (RARS), (refractory
anemia with excess blasts (RAEB), and RAEB in transformation
(RAEB-T); and myeloproliferative syndromes.
[0291] In some embodiments, compounds of the invention are suitable
for the treatment of breast cancer, lung cancer, ovarian cancer,
multiple myeloma, acute myeloid leukemia or acute lymphoblastic
leukemia.
[0292] In other embodiments, compounds of the invention are
suitable for the treatment of inflammatory and cardiovascular
disorders including, but not limited to, allergies/anaphylaxis,
acute and chronic inflammation, rheumatoid arthritis; autoimmunity
disorders, thrombosis, hypertension, cardiac hypertrophy, and heart
failure.
[0293] Accordingly, in another aspect of the present invention,
pharmaceutical compositions are provided, wherein these
compositions comprise any of the compounds as described herein, and
optionally comprise a pharmaceutically acceptable carrier, adjuvant
or vehicle. In certain embodiments, these compositions optionally
further comprise one or more additional therapeutic agents.
[0294] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable prodrugs, salts, esters, salts of such esters, or any
other adduct or derivative which upon administration to a patient
in need is capable of providing, directly or indirectly, a compound
as otherwise described herein, or a metabolite or residue
thereof.
[0295] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof. As used herein,
the term "inhibitorily active metabolite or residue thereof" means
that a metabolite or residue thereof is also an inhibitor of
HDAC6.
[0296] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0297] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0298] In yet another aspect, a method for treating a
proliferative, inflammatory, infectious, neurological or
cardiovascular disorder is provided comprising administering an
effective amount of a compound, or a pharmaceutical composition to
a subject in need thereof. In certain embodiments of the present
invention an "effective amount" of the compound or pharmaceutical
composition is that amount effective for treating a proliferative,
inflammatory, infectious, neurological or cardiovascular disorder,
or is that amount effective for treating cancer. In other
embodiments, an "effective amount" of a compound is an amount which
inhibits binding of HDAC6, and thereby blocks the resulting
signaling cascades that lead to the abnormal activity of growth
factors, receptor tyrosine kinases, protein serine/threonine
kinases, G protein coupled receptors and phospholipid kinases and
phosphatases.
[0299] The compounds and compositions, according to the method of
the present invention, may be administered using any amount and any
route of administration effective for treating the disease. The
exact amount required will vary from subject to subject, depending
on the species, age, and general condition of the subject, the
severity of the infection, the particular agent, its mode of
administration, and the like. The compounds of the invention are
preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the
disease being treated and the severity of the disease; the activity
of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed, and like factors well known in the
medical arts. The term "patient", as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0300] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0301] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0302] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0303] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0304] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0305] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0306] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia,
[0307] c) humectants such as glycerol, d) disintegrating agents
such as agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain silicates, and sodium carbonate, e) solution
retarding agents such as paraffin, 0 absorption accelerators such
as quaternary ammonium compounds, g) wetting agents such as, for
example, cetyl alcohol and glycerol monostearate, h) absorbents
such as kaolin and bentonite clay, and i) lubricants such as talc,
calcium stearate, magnesium stearate, solid polyethylene glycols,
sodium lauryl sulfate, and mixtures thereof. In the case of
capsules, tablets and pills, the dosage form may also comprise
buffering agents.
[0308] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols and the like.
[0309] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0310] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0311] In some embodiments, a compound of formula (I) or a
pharmaceutical composition thereof is administered in conjunction
with an anticancer agent. As used herein, the term "anticancer
agent" refers to any agent that is administered to a subject with
cancer for purposes of treating the cancer. Combination therapy
includes administration of the therapeutic agents concurrently or
sequentially. Alternatively, the therapeutic agents can be combined
into one composition which is administered to the patient.
[0312] Non-limiting examples of DNA damaging chemotherapeutic
agents include topoisomerase I inhibitors (e.g., irinotecan,
topotecan, camptothecin and analogs or metabolites thereof, and
doxorubicin); topoisomerase II inhibitors (e.g., etoposide,
teniposide, and daunorubicin); alkylating agents (e.g., melphalan,
chlorambucil, busulfan, thiotepa, ifosfamide, carmustine,
lomustine, semustine, streptozocin, decarbazine, methotrexate,
mitomycin C, and cyclophosphamide); DNA intercalators (e.g.,
cisplatin, oxaliplatin, and carboplatin); DNA intercalators and
free radical generators such as bleomycin; and nucleoside mimetics
(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,
cytarabine, mercaptopurine, thioguanine, pentostatin, and
hydroxyurea).
[0313] Chemotherapeutic agents that disrupt cell replication
include: paclitaxel, docetaxel, and related analogs; vincristine,
vinblastin, and related analogs; thalidomide, lenalidomide, and
related analogs (e.g., CC-5013 and CC-4047); protein tyrosine
kinase inhibitors (e.g., imatinib mesylate and gefitinib);
proteasome inhibitors (e.g., bortezomib); NF-.kappa.B inhibitors,
including inhibitors of NB kinase; antibodies which bind to
proteins overexpressed in cancers and thereby downregulate cell
replication (e.g., trastuzumab, rituximab, cetuximab, and
bevacizumab); and other inhibitors of proteins or enzymes known to
be upregulated, over-expressed or activated in cancers, the
inhibition of which down-regulates cell replication. In certain
embodiments, a compound of the invention is administered in
conjunction with a proteasome inhibitor.
[0314] Another aspect of the invention relates to inhibiting HDAC6,
activity in a biological sample or a patient, which method
comprises administering to the patient, or contacting said
biological sample with a compound of formula (I), or a composition
comprising said compound. The term "biological sample", as used
herein, generally includes in vivo, in vitro, and ex vivo
materials, and also includes, without limitation, cell cultures or
extracts thereof; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen, tears, or
other body fluids or extracts thereof.
[0315] Still another aspect of this invention is to provide a kit
comprising separate containers in a single package, wherein the
inventive pharmaceutical compounds, compositions and/or salts
thereof are used in combination with pharmaceutically acceptable
carriers to treat disorders, symptoms and diseases where HDAC6
plays a role.
Experimental Procedures
I. Preparation of Exemplary Compounds
DEFINITIONS
[0316] ATP adenosine triphosphate DCE dichloroethane DCM
dichloromethane DIPEA diisopropylethyl amine
DMF N,N-dimethylformamide
[0317] DMFDMA N,N-dimethylformamide dimethyl acetal DMSO
dimethylsulfoxide EDCI
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDTA
ethylenediaminetetraacetic acid EtOAc ethyl acetate EtOH ethanol FA
formic acid FBS fetal bovine serum h hours HATU
N,N,N',N'-tetramethyl-o-(7-azabenzotriazole-1-yl)uronium
hexafluorophosphate HBTU
o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate HEPES
N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) HOBT
1-hydroxybenztriazole hydrate HRMS high resolution mass spectrum
IPA isopropyl alcohol LAH lithium aluminum hydride LC-MS liquid
chromatography mass spectrum m/z mass to charge Me methyl MEM
minimum essential media MeOH methanol min minutes MS mass spectrum
MWI microwave irradiation NMM N-methyl morpholine PBS phosphate
buffered saline rt room temperature TEA triethylamine TFA
trifluoroacetic acid TFAA trifluoroacetic anhydride THF
tetrahydrofuran
[0318] Analytical Methods
[0319] NMR: 1H NMR spectra are run on a 400 MHz Bruker unless
otherwise stated.
[0320] LCMS: LC-MS spectra are run using an Agilent 1100 LC
interfaced to a micromass Waters.RTM. Micromass.RTM. Zspray.TM.
Mass Detector (ZMD).
[0321] HPLC: Preparative HPLC are conducted using 18.times.150 mm
Sunfire C-18 columns eluting with water-MeCN gradients using a
Gilson instrument operated by 322 pumps with the UV/visible 155
detector triggered fraction collection set to between 200 nm and
400 nm. Mass gated fraction collection is conducted on an Agilent
1100 LC/MSD instrument.
Example 1
tert-Butyl 4-formylbenzoate
##STR00577##
[0323] To a 250-mL round-bottom flask was added 4-formylbenzoic
acid (5.0 g, 33 mmol), di-tert-butyldicarbonate (14.54 g, 66.6
mmol), N,N-dimethylaminopyridine (0.814 g, 6.66 mmol), and THF (100
mL). The mixture was stirred at rt for 16 h. The solvent was then
removed to give a solid. To the residue was added EtOAc (150 mL),
sat. NaHCO.sub.3 solution (25 mL), and water (25 mL). After
separation, the aqueous layer was extracted with EtOAc (2.times.100
mL). The combined organic phases were washed with brine (50 mL),
dried (MgSO.sub.4), and concentrated. Purification via flash
chromatography (hexanes to 10% EtOAc-hexanes) afforded tert-butyl
4-formylbenzoate (1.90 g, 28%) as a white solid. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 10.10 (s, 1H), 8.14 (d, J=8.3 Hz,
2H), 7.93 (d, J=8.5 Hz, 2H), 1.61 (s, 9H).
Example 2
tert-Butyl 3-formylbenzoate
##STR00578##
[0325] The title compound was prepared in an analogous fashion to
that described in Example 1 starting from commercially available
3-formylbenzoic acid. Yield: 92.4%; NMR (CDCl.sub.3, 400 MHz)
510.08 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 8.25 (dd, J=7.6, 1.5 Hz,
1H), 8.05 (dd, J=7.6, 1.5 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 1.62 (s,
9H).
Example 3
4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate
##STR00579##
[0327] To a 500-mL round-bottom flask was added
(S)-(-)-2-methyl-2-propanesulfinamide (1.41 g, 11.6 mmol),
tert-butyl 4-formylbenzoate (2.00 g, 9.70 mmol) and DCM (90 mL).
The mixture was cooled to 0.degree. C. then titanium
tetraisopropoxide (17.2 mL, 58.2 mmol) was added. After the
solution was warmed to rt and stirred for 6 h, the reaction mixture
was diluted with DCM (200 mL). To the flask was added water (17.2
mL) slowly. The mixture was vigorously stirred at rt for 30 min,
then filtered through a pad of Celite. The filtrate was
concentrated to give a solid. Purification via flash chromatography
(hexanes to 10% EtOAc-hexanes) afforded
4-[(E)-{[(5)-tert-butylsulfinyl]imino}methyl]benzoate (2.42 g, 81%)
as a white solid. [.alpha.].sub.D.sup.20=+52.0 (c=1.0, CHCl.sub.3);
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.63 (s, 1H), 8.08 (d,
J=8.5 Hz, 2H), 7.89 (d, J=8.5 Hz, 2H), 1.61 (s, 9H), 1.28 (s,
9H).
Example 4
3-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate
##STR00580##
[0329] The title compound was prepared in an analogous fashion to
that described in Example 3 starting from tert-butyl
3-formylbenzoate. Yield: 83%; .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.63 (s, 1H), 8.43 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 8.03
(dt, J=8.0, 3.0 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 1.62 (s, 9H), 1.28
(s, 9H).
Example 5
4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate
##STR00581##
[0331] To a 250-mL round-bottom flask was added
(R)-(+)-2-methyl-2-propanesulfinamide (0.360 g, 2.97 mmol),
tert-butyl 4-formylbenzoate (0.51 g, 2.47 mmol), DCM (20 mL). The
mixture was cooled to 0.degree. C., then titanium tetraisopropoxide
(4.40 mL, 14.8 mmol) was added. The solution was warmed to rt and
stirred overnight. After the reaction was diluted with DCM (100
mL), water (4.4 mL) was added slowly. The mixture was vigorously
stirred at rt for 30 min, filtered through a pad of Celite. The
filtrate was concentrated to give a solid. Purification via flash
chromatography (hexanes to 10% EtOAc-hexanes) afforded
4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate (0.52 g, 68%)
as a white solid. [.alpha.].sub.D.sup.20=-49.6 (c=1.0, CHCl.sub.3);
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.63 (s, 1H), 8.08 (d,
J=8.3 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 1.61 (s, 9H), 1.28 (s,
9H).
Example 6
4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate
##STR00582##
[0333] The title compound was prepared in an analogous fashion to
that described in Example 5 starting from tert-butyl
3-formylbenzoate. Yield: 83%; [.alpha.].sub.D.sup.20=-83.6 (c=1.0,
CHCl.sub.3); .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.63 (s,
1H), 8.43 (s, 1H), 8.13 (dd, J=8.0, 3.0 Hz, 1H), 8.03 (d, J=7.8 Hz,
1H), 7.54 (t, J=7.8 Hz, 1H), 1.57 (s, 9H), 1.28 (s, 9H).
Example 7
tert-butyl 4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate
and tert-butyl
4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate
##STR00583##
[0335] To an oven-dried 100-mL round-bottom flask was added
4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate (0.83 g, 2.68
mmol), and DCM (13.4 mL). The solution was cooled to -45.degree. C.
then methylmagnesium bromide (1.78 mL, 5.35 mmol, 3.0 M in ether)
was slowly added via syringe. The resulting reaction mixture was
stirred at -45.degree. C. for 4 h, then gradually warmed to rt and
stirred for 16 h. To the reaction was added DCM (50 mL) and sat.
NH.sub.4Cl solution (10 mL). After separation, the aqueous layer
was extracted with DCM (2.times.30 mL). The combined organic layers
were washed with brine, dried (MgSO.sub.4), and concentrated.
Purification via flash chromatography (20% EtOAc-hexanes to 50%
EtOAc-hexanes) afforded major diastereomer tert-butyl
4-[(1R)-1-{[(5)-tert-butylsulfinyl]amino}ethyl]benzoate (0.656 g,
75%) as a white solid. [.alpha.].sub.D.sup.20=+86.1 (c=1.0,
CHCl.sub.3); .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (d,
J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 4.62 (m, 1H), 3.33 (d, J=3.0
Hz, 1H), 1.58 (s, 9H), 1.52 (d, J=6.8 Hz, 3H), 1.20 (s, 9H). The
minor diastereomer tert-butyl
4-[(15)-1-{[(5)-tert-butylsulfinyl]amino}ethyl]benzoate (0.065 g,
7.5%) was isolated as a white solid.
Example 8
tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate
##STR00584##
[0337] The title compound was prepared in an analogous fashion to
that described in Example 7 starting from
3-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate. Yield: 74%
[.alpha.].sub.D.sup.20+90.9 (c=1.0, CHCl.sub.3); .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.96 (s, 1H), 7.89 (d, J=7.8 Hz, 1H),
7.48 (d, J=7.8, 1H), 7.38 (t, J=7.8 Hz, 1H), 4.63 (m, 1H), 3.35 (d,
J=3.3 Hz, 1H), 1.58 (s, 9H), 1.54 (d, J=6.8 Hz, 3H), 1.21 (s,
9H).
Example 9
tert-butyl
3-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]benzoate
##STR00585##
[0339] The title compound was prepared in an analogous fashion to
that described in Example 7 starting from
3-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate. Yield: 58%;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.95 (s, 1H), 7.89 (d,
J=7.8 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 4.63
(m, 1H), 3.35 (d, J=3.3 Hz, 1H), 1.58 (s, 9H), 1.54 (d, J=6.8 Hz,
3H), 1.21 (s, 9H).
Example 10
tert-butyl 4-((R)-1-(S)-1,1-dimethylethylsulfinamido)butyl)benzoate
and tert-butyl
4-((S)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate
##STR00586##
[0341] The title compounds were prepared in an analogous fashion to
that described in Example 7 starting from
4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate.
[0342] tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate Yield:
39%; [.alpha.].sub.D.sup.20=.sub.+75.2 (c=1.0, CHCl.sub.3); .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 7.95 (d, J=8.1 Hz, 2H), 7.34 (d,
J=8.3 Hz, 2H), 4.43 (dt, J=7.1, 2.0 Hz, 1H), 3.38 (d, J=2.0 Hz,
1H), 1.77 (m, 2H), 1.59 (s, 9H), 1.26 (m, 2H), 1.17 (s, 9H), 0.88
(t, J=7.4 Hz, 3H).
[0343] tert-butyl
4-((S)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate Yield:
39%; [.alpha.].sub.D.sup.20=.sub.+34.2 (c=1.0, CHCl.sub.3); NMR
(CDCl.sub.3, 400 MHz) .delta. 7.96 (d, J=8.4 Hz, 2H), 7.36 (d,
J=8.1 Hz, 2H), 4.39 (m, 1H), 3.37 (d, J=4.0 Hz, 1H), 2.00 (m, 1H),
1.71 (m, 1H), 1.58 (s, 9H), 1.22 (s, 9H), 1.17 (m, 2H), 0.87 (t,
J=7.4 Hz, 3H).
Example 11
tert-butyl-4-[(R)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benzo-
ate and tent-butyl
4-[(S)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benzoate
##STR00587##
[0345] The title compounds were prepared in an analogous fashion to
that described in Example 7 starting from
4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate.
[0346]
tert-butyl-4-[(R)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methy-
l]benzoate: Yield: 36%; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
7.97 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 3.72 (dd, J=8.8,
3.3 Hz, 1H), 3.54 (d, J=3.0 Hz, 1H), 1.58 (s, 9H), 1.24 (s, 9H),
1.14 (m, 1H), 0.80 (m, 1H), 0.64 (m, 1H), 0.48 (m, 1H), 0.23 (m,
1H).
[0347]
tert-butyl-4-[(S)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methy-
l]benzoate: Yield: 53%; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
7.96 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 3.61 (m, 1H), 3.58
(d, J=1.8 Hz, 1H), 1.57 (s, 9H), 1.20 (s, 9H), 1.17 (m, 1H), 0.67
(m, 1H), 0.48 (m, 2H), 0.38 (m, 1H).
Example 12
tert-butyl
4-[(R)-{[(S)-tert-butylsulfinyl]amino}(phenyl)methyl]benzoate
##STR00588##
[0349] The title compound (dr, 6.0:1) was prepared in an analogous
fashion to that described in Example 7 starting from
4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate. Yield: 84%;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (d, J=8.3 Hz, 2H),
7.48 (d, J=8.5 Hz, 2H), 7.37-7.27 (m, 5H), 5.69 (d, J=2.3 Hz, 1H),
3.71 (d, J=2.3 Hz, 1H), 1.57 (s, 9H), 1.27 (s, 9H).
Example 13
tert-butyl
4-[(S)-{[(R)-tert-butylsulfinyl]amino}(phenyl)methyl]benzoate
##STR00589##
[0351] The title compound (dr, 6.3:1) was prepared in an analogous
fashion to that described in Example 7 starting from
4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate Yield: 75%;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (d, J=8.5 Hz, 2H),
7.48 (d, J=8.1 Hz, 2H), 7.37-7.27 (m, 5H), 5.69 (d, J=2.3 Hz, 1H),
3.72 (d, J=2.3 Hz, 1H), 1.57 (s, 9H), 1.27 (s, 9H).
Example 14
tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoa-
te
##STR00590##
[0353] To an oven-dried 50-mL round-bottom flask was added
tert-butyl 4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate
(3.00 g, 9.70 mmol) and THF (48 mL). The solution was cooled to
-78.degree. C. then isopropyllithium (55.4 mL, 38.8 mmol, 0.70 M of
in pentane) was slowly added via a syringe pump over 15 min. The
resulting reaction mixture was stirred at -78.degree. C. After 1 h,
EtOAc (100 mL), sat. NH.sub.4Cl solution (20 mL), and water (10 mL)
were added to the flask at this temperature. After separation, the
aqueous layer was extracted with EtOAc (2.times.60 mL). Combined
organic layers were washed with brine (20 mL), dried (MgSO.sub.4),
and concentrated. Purification via flash chromatography (20%
EtOAc-hexanes to 50% EtOAc-hexanes) afforded major diastereomer
tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate
(1.59 g, 46%) as a white solid. [.alpha.].sub.D.sup.20=-18.9
(c=1.0, CHCl.sub.3); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.96
(d, J=8.5 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 4.18 (d, J=6.0 Hz, 1H),
3.45 (d, J=6.0 Hz, 1H), 2.22 (m, 1H), 1.58 (s, 9H), 1.24 (s, 9H),
0.94 (d, J=6.8 Hz, 3 H), 0.80 (d, J=6.8 Hz, 3H).
Example 15
tert-butyl
4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoa-
te
##STR00591##
[0355] The title compound was prepared in an analogous fashion to
that described in Example 14 starting from
4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate. Yield: 47%;
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (d, J=8.3 Hz, 2H),
7.31 (d, J=8.3 Hz, 2H), 4.18 (d, J=6.0 Hz, 1H), 3.45 (d, J=5.8 Hz,
1H), 2.22 (m, 1H), 1.58 (s, 9H), 1.24 (s, 9H), 0.94 (d, J=6.8 Hz,
3H), 0.80 (d, J=6.6 Hz, 3H),
Example 16
tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]-
benzoate
##STR00592##
[0357] To a 50-mL oven-dried round-bottom flask charged with
tert-butyl 4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate
(0.16 g, 0.5 mmol), tetra-n-butylammoniumdifluoro-triphenylsilicate
(0.30 g, 0.55 mmol), THF (8 mL) was slowly added
(trifluoromethyl)trimethylsilane (0.94 mL, 0.60 mmol) in THF (2 mL)
slowly at -45.degree. C. The mixture was stirred at this
temperature for 2 h, then warmed to -30.degree. C. and stirred for
1 h. The reaction was quenched with addition of sat. NH.sub.4Cl (5
mL) and EtOAc (10 mL) at -30.degree. C. After warming to rt, the
mixture was extracted with EtOAc (2.times.20 mL). The combined
organic phases were washed with brine (10 mL), dried (MgSO.sub.4),
and concentrated. Purification via flash chromatography (10%
EtOAc-hexanes to 20% EtOAc-hexanes) afforded tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate
(0.136 g, 72%) as a white solid. .sup.1H NMR (Methanol-d.sub.4, 300
MHz) .delta. 7.98 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 5.15
(d, J=7.9 Hz, 1H), 1.59 (s, 9H), 1.23 (s, 9H).
Example 17
tert-butyl
4-[(1R)-1-{[(5)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]-
benzoate
##STR00593##
[0359] The title compound was prepared in an analogous fashion to
that described in Example 16 starting from
4-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate. Yield: 47%;
[.alpha.].sub.D.sup.20=+49.3 (c=1.0, CHCl.sub.3); .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.03 (d, J=8.3 Hz, 2H), 7.49 (d,
J=8.3 Hz, 2H), 4.88 (q, J=7.0 Hz, 1H), 3.67 (d, J=6.5 Hz, 1H), 1.59
(s, 9H), 1.25 (s, 9H).
Example 18
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-carboxam-
ide Compound I-317
##STR00594##
[0360] Step 1: tert-butyl-4-[(1R)-1-aminoethyl]benzoate
hydrochloride
[0361] To a 2-dram vial was added tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate (0.0586 g,
0.180 mmol), hydrochloric acid (0.14 mL, 0.54 mmol, 4.0 M in
1,4-dioxane), and methanol (2 mL). The mixture was stirred at rt
for 2 h. The solvent was then completely removed to give
tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride as a white
solid. LC-MS: (FA) ES+222.
Step 2: tert-butyl
4-{(1R)-1-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}benzoate
[0362] To a 2-dram vial was added triethylamine (0.10 mL, 0.72
mmol), HATU (0.068 g, 0.18 mmol), benzofuran-2-carboxylic acid
(0.029 g, 0.18 mmol), and DCM (2 mL). The solution was stirred at
rt for 30 min then transferred to another 2-dram vial containing
solid tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride. The
mixture was stirred at rt for 16 h. To the reaction was then added
DCM (3 mL) and water (1 mL). After separation, the aqueous layer
was extracted with DCM (2.times.3 mL). The combined organic phases
were concentrated to dryness to give crude tert-butyl
4-{(1R)-1-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}benzoate as a
brown solid. LC-MS: (FA) ES+366.
Step 3:
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2--
carboxamide
[0363] To a 2-dram vial containing tert-butyl
4-{(1R)-1-[(1-benzofuran-2-ylcarbonyl)amino]ethyl}benzoate was
added DCM (2.5 mL), and trifluoroacetic acid (0.28 mL, 3.60 mmol).
The mixture was stirred at rt for 6 h then evaporated to give an
oil residue. To the residue was added HATU (0.10 g, 0.27 mmol),
triethylamine (0.25 mL, 1.80 mmol), and DCM (2.5 mL). After
stirring at rt for 30 min, O-(tert-butyldimethylsilyl)hydroxylamine
(0.053 g, 0.360 mmol) was added. The mixture was stirred at rt for
2 h, then the solvent was completely removed to give a sticky brown
oil. To this oil residue was added hydrochloric acid (4.0 mL, 1%
v/v in IPA). After stirring at rt for 30 min, the solvent was
evaporated to dryness to give a solid. To the solid was then added
DMSO (1.1 mL). The solution was filtered and purified by Gilson
prep-HPLC [25-50% MeCN--H.sub.2O] to give
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-carboxa-
mide (0.0148 g, 24%) as a white solid. LC-MS: (FA) ES+325; .sup.1H
NMR (Methanol-d.sub.4, 400 MHz) .delta. 7.71 (m, 3H), 7.60 (d,
J=8.5 Hz, 1H), 7.50 (m, 3H), 7.45 (t, J=7.0 Hz, 1H), 7.31 (t, J=7.8
Hz, 1H), 5.30 (q, J=7.2 Hz, 1H), 1.61 (d, J=7.0 Hz, 3H).
Example 19
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrrole-2-c-
arboxamide Compound I-102
[0364] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
38%; LC-MS: (FA) ES+288; .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta. 8.06 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz,
2H), 6.86 (dd, J=4.0, 1.8 Hz, 1H), 6.80 (t, J=2.3 Hz, 1H), 6.05
(dd, J=4.0, 2.8 Hz, 1H), 5.17 (q, J=7.0 Hz, 1H), 3.82 (s, 3H), 1.52
(d, J=7.3 Hz, 3H).
Example 20
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-2-carb-
oxamide Compound I-184
[0365] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
38%; LC-MS: (FA) ES+341; .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta. 8.04 (s, 1H), 7.88 (m, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.50
(d, J=8.3 Hz, 2H), 7.42 (m, 2H), 5.26 (q, J=7.3 Hz, 1H), 1.60 (d,
J=7.3 Hz, 3H).
Example 21
N-hydroxy-4-((1R)-1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benzamide
Compound I-26
[0366] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
27%; LC-MS: (FA) ES+305; .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta. 7.81 (d, J=7.8 Hz, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.41 (d,
J=8.0 Hz, 2H), 5.08 (q, J=7.3 Hz, 1H), 2.02 (m, 2H), 1.53 (m, 2H),
1.47 (d, J=7.0 Hz, 3H), 1.30 (m, 6H), 1.12 (s, 3H).
Example 22
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-4-carboxamide
Compound I-92
[0367] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+361.
Example 23
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzothiophe-
ne-2-carboxamide Compound I-12
[0368] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+355.
Example 24
4,5-dichloro-N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1-
H-pyrrole-2-carboxamide Compound I-359
[0369] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+356.
Example 25
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methyl-2-phenyl-4H-fu-
ro[3,2-b]pyrrole-5-carboxamide Compound I-5
[0370] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+404.
Example 26
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)adamantane-1-carboxamide
Compound I-209
[0371] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+343.
Example 27
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzofuran-2-
-carboxamide Compound I-237
[0372] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+339.
Example 28
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indole-2-ca-
rboxamide Compound I-115
[0373] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+338.
Example 29
N-hydroxy-4-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benz-
amide Compound I-351
##STR00595##
[0374] Step 1: tert-butyl-4-[(1R)-1-aminoethyl]benzoate
hydrochloride
[0375] To a microwave vial containing tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate (0.052 g,
0.16 mmol) was added hydrochloric acid (0.08 mL, 0.32 mmol, 4.0 M
of in 1,4-dioxane), and methanol (2 mL). This mixture was stirred
at rt for 2 h, and then evaporated to dryness to afford
tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride as a white
solid. LC-MS: (FA) ES+222.
Step 2:
(R)-tert-butyl-4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)be-
nzoate
[0376] To a vial containing
tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride from Step 1
was added N,N-dimethylaminopyridine (3.91 mg, 0.032 mmol),
4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol),
N,N-dimethylformamide (2 mL), and triethylamine (0.18 mL, 1.28
mmol). The mixture was stirred at rt for 16 h, after which the
solvent was fully evaporated. To the residue was added
1,2-dichloroethane (3 mL), sat. NaHCO.sub.3 solution (0.5 mL), and
water (0.5 mL). After separation, the aqueous layer was extracted
with 1,2-dichloroethane (2.times.3 mL). The combined organic phases
were evaporated to dryness to give (R)-tert-butyl
4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)benzoate as a
brown solid. LC-MS: (FA) ES+430.
Step 3:
N-hydroxy-4-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)et-
hyl]benzamide
[0377] To a 2-dram vial containing (R)-tert-butyl
4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)benzoate was added
1,2-dichloroethane (2 mL), and trifluoroacetic acid (0.246 mL, 3.20
mmol). After shaking at rt for 4 h, the mixture was evaporated to
dryness to give a residue which was azetroped with toluene
(2.times.5 mL). To the solid residue in another vial was added HATU
(0.091 g, 0.24 mmol), N,N-dimethylformamide (1.5 mL), triethylamine
(0.18 mL, 1.28 mmol). The mixture was stirred for 10 min then
O-(tert-butyldimethylsilyl)hydroxylamine (0.047 g, 0.32 mmol) in
DCM (0.5 mL) was added. The solution was shaken at rt for 2 h,
after which the solvent was then completely removed to afford a
brown oil. To this oil in another vial was added hydrochloric acid
(3.5 mL, 1% in IPA). After shaking at rt for 30 min, solid
NaHCO.sub.3 was added to quench the excess acid, and the solvent
was then removed. To the solid residue was added DMSO (1.2 mL).
After filtration, the DMSO solution was purified by Gilson
prep-HPLC to give the title compound (0.091 g, 15%) as a white
solid. LC-MS: (FA) ES-387; .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta. 7.79 (d, J=8.3 Hz, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.51 (d,
J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 4.53 (q, J=7.0 Hz, 1H), 1.36
(d, J=7.0 Hz, 3H).
Example 30
4-((1R)-1-{-[(tert-butylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-14
##STR00596##
[0378] Step 1: (R)-4-(1-aminoethyl)benzoic acid hydrochloride
[0379] To a vial containing tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate (0.065 g,
0.20 mmol) was added hydrochloric acid (2.0 mL, 8.0 mmol, 4.0 M in
1,4-dioxane). This vial was capped and heated at 60.degree. C. for
2 h, and then completely evaporated to afford
(R)-4-(1-aminoethyl)benzoic acid hydrochloride as a white solid.
LC-MS: (FA) ES+166.
Step 2:
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}ethyl)-N-hydroxybenzam-
ide
[0380] To the vial containing (R)-4-(1-aminoethyl)benzoic acid
hydrochloride was added tert-butyl isocyanate (0.023 mL, 0.198
mmol), N,N dimethylformamide (3.0 mL), and triethylamine (0.22 mL,
1.59 mmol). After the reaction was stirred at rt for 16 h, HATU
(0.075 g, 0.198 mmol) in N,N-dimethylformamide (0.5 mL) was added,
immediately followed by the addition of
O-(tert-butyldimethylsilyl)hydroxylamine (0.044 g, 0.30 mmol) in
DCM (1 mL). This mixture was shaken at rt for 1 hr, after which the
mixture was evaporated to dryness. To the residue was added
hydrochloric acid (4 mL, 1% in IPA). After shaking at rt for 30
min, solid NaHCO.sub.3 was added to quench the excess acid, and the
mixture was evaporated to dryness to give a solid residue. This
solid was dissolved in DMSO (1.2 mL), and filtered; then purified
via Gilson prep-HPLC [15-38% MeCN--H.sub.2O] to give the title
compound (0.026 g, 47%) as a white solid. LC-MS: (FA) ES+280;
.sup.1H NMR (Methanol-d.sub.4, 400 MHz) 87.69 (d, J=8.3 Hz, 2H),
7.37 (d, J=8.3 Hz, 2H), 4.80 (q, J=7.0 Hz, 1H), 1.37 (d, J=7.0 Hz,
3H), 1.26 (s, 9H).
Example 31
4-[(1R)-1-({[1-adamantylamino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-374
[0381] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butyl sulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+358.
Example 32
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrrole-2-c-
arboxamide Compound I-25
[0382] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
44.8%; LC-MS: (FA) ES+288; .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta. 7.70 (d, J=8.3Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 6.86 (m,
1H), 6.80 (m, 1H), 6.05 (dd, J=4.0, 2.7 Hz, 1H), 5.17 (q, J=7.0 Hz,
1H), 3.82 (s, 3H), 1.52 (d, J=7.3 Hz, 3H).
Example 33
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-2-carb-
oxamide Compound I-53
[0383] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
42.5%; %; LC-MS: (FA) ES+341; .sup.1H NMR (Methanol-d.sub.4, 400
MHz) .delta. 8.04 (s, 1H), 7.88 (m, 2H), 7.73 (d, J=8.0 Hz, 2H),
7.50 (d, J=8.3 Hz, 2H), 7.42 (m, 2H), 5.26 (q, J=7.3 Hz, 1H), 1.60
(d, J=7.3 Hz, 3H).
Example 34
N-hydroxy-4-((1S)-1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benzamide
Compound I-273
[0384] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
18.2%; LC-MS: (FA) ES+305.
Example 35
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-methyl-1H-pyrrole-2-c-
arboxamide Compound I-281
[0385] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+316.
Example 36
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-benzothiophene-2-carb-
oxamide Compound I-299
[0386] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+369.
Example 37
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]butyl}-N-hydroxybenzamide
Compound I-365
[0387] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+293; .sup.1H NMR (Methanol-d.sub.4, 400 MHz) .delta. 7.75
(d, J=8.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H),
4.91 (m, 1H), 1.85-1.69 (m, 2H), 1.45-1.27 (m, 2H), 1.18 (s, 9H),
0.94 (d, J=7.5 Hz, 3H).
Example 38
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-4-methyl-2-phenyl-4H-fu-
ro[3,2-b]pyrrole-5-carboxamide Compound I-222
[0388] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+432.
Example 39
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-3-methyl-1-benzothiophe-
ne-2-carboxamide Compound I-62
[0389] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+383.
Example 40
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)biphenyl-4-carboxamide
Compound I-274
[0390] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+389.
Example 41
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-4-methoxybenzamide
Compound I-146
[0391] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+343.
Example 42
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-methyl-1H-indole-2-ca-
rboxamide Compound I-106
[0392] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+366.
Example 43
N-hydroxy-4-((1R)-1-{[(1-methylcyclohexyl)carbonyl]amino}butyl)benzamide
Compound I-387
[0393] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+333.
Example 44
4,5-dichloro-N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-methyl-1-
H-pyrrole-2-carboxamide Compound I-245
[0394] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+384.
Example 45
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)adamantane-1-carboxamide
Compound I-15
[0395] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+371; .sup.1H NMR (Methanol-d.sub.4, 400 MHz) .delta. 7.68
(d, J=8.3 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 4.91 (m, 1 H), 2.01 (m,
3H), 1.87 (m, 6H), 1.75 (m, 6H), 1.81-1.71 (m, 2H), 1.45-1.27 (m,
2H), 0.94 (d, J=7.5 Hz, 3H).
Example 46
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-3-methyl-1-benzofuran-2-
-carboxamide Compound I-367
[0396] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+367.
Example 47
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}butyl)-1-benzofuran-2-carboxam-
ide Compound I-79
[0397] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+353.
Example 48
N-hydroxy-4-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)butyl]benz-
amide Compound I-171
[0398] The title compound was prepared in an analogous fashion to
that described in Example 29 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES-415; .sup.1H NMR (Methanol-d.sub.4, 400 MHz) .delta. 7.72
(d, J=8.7 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H),
7.11 (d, J=8.3 Hz, 2H), 4.36 (m, 1H), 1.71 (m, 1H), 1.58 (m, 1H),
1.32 (m, 1H), 1.21 (m, 1H), 0.85 (d, J=7.5 Hz, 3H).
Example 49
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}butyl)-N-hydroxybenzamide
Compound I-380
[0399] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+308.
Example 50
4-[(1R)-1-({[(1S,3R,5R,7S)-1-adamantylamino]carbonyl}amino)butyl]-N-hydrox-
ybenzamide Compound I-18
[0400] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
4-((R)-1-((S)-1,1-dimethylethylsulfinamido)butyl)benzoate. LC-MS:
(FA) ES+386.
Example 51
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzothioph-
ene-2-carboxamide Compound I-214
[0401] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
Yield: 17%; LC-MS: (FA) ES+369; .sup.1H NMR (Methanol-d.sub.4, 400
MHz) .delta. 8.03 (s, 1H), 7.89 (m, 2H), 7.73 (d, J=8.3 Hz, 2H),
7.50 (d, J=8.3 Hz, 2H), 7.42 (m, 2H), 4.73 (d, J=10.0 Hz, 1H), 2.25
(m, 1H), 1.30 (t, J=7.3 Hz, 1H), 1.14 (d, J=6.6 Hz, 3H), 0.81 (d,
J=6.8 Hz, 3H).
Example 52
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)adamantane-1-c-
arboxamide Compound I-328
[0402] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
Yield: 27.4%; LC-MS: (FA) ES+371.
Example 53
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1H-indole-2-c-
arboxamide Compound I-68
[0403] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
Yield: 15.0%; LC-MS: (FA) ES+352; .sup.1H NMR (Methanol-d.sub.4,
400 MHz) .delta. 8.63 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 2H),
7.60 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.0 Hz,
1H), 7.19 (m, 2 H), 7.04 (t, J=7.3 Hz, 1H), 4.77 (t, J=9.3 Hz, 1H),
2.23 (m, 1H), 1.12 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H).
Example 54
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3-methyl-1-be-
nzothiophene-2-carboxamide Compound I-307
[0404] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+383.
Example 55
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]-2-methylpropyl}-N-hydroxybenzamid-
e Compound I-287
[0405] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+293.
Example 56
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-4-methyl-2-ph-
enyl-4H-furo[3,2-b]pyrrole-5-carboxamide Compound I-332
[0406] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+432.
Example 57
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3-methyl-1-be-
nzofuran-2-carboxamide Compound I-187
[0407] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+367.
Example 58
N-hydroxy-4-((1R)-2-methyl-1-{[(1-methylcyclohexyl)carbonyl]amino}propyl)b-
enzamide Compound I-126
[0408] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+333.
Example 59
4,5-dichloro-N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)--
1-methyl-1H-pyrrole-2-carboxamide Compound I-96
[0409] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from
tert-butyl-4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzo-
ate. LC-MS: (FA) ES+385.
Example 60
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-methyl-1H-i-
ndole-2-carboxamide Compound I-242
[0410] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+366.
Example 61
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)biphenyl-4-car-
boxamide Compound I-341
[0411] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+389.
Example 62
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-4-methoxybenz-
amide Compound I-19
[0412] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butyl sulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+343.
Example 63
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-methyl-1H-p-
yrrole-2-carboxamide Compound I-65
[0413] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+316.
Example 64
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzofuran--
2-carboxamide Compound I-22
[0414] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butyl sulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+353.
Example 65
N-hydroxy-4-[(1R)-2-methyl-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)p-
ropyl]benzamide Compound I-189
[0415] The title compound was prepared in an analogous fashion to
that described in Example 29 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES-415; .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta.7.68 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.45 (d,
J=8.5 Hz, 2H), 7.06 (d, J=8.1 Hz, 2H), 4.04 (d, J=8.5 Hz, 1H), 1.89
(m, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H).
Example 66
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}-2-methylpropyl)-N-hydroxybenz-
amide Compound I-368
[0416] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+308.
Example 67
4-[(1R)-1-({[1-adamantylamino]carbonyl}amino)-2-methylpropyl]-N-hydroxyben-
zamide Compound I-354
[0417] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+386.
Example 68
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzothioph-
ene-2-carboxamide Compound I-67
[0418] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(S)-tert-butyl sulfinyl]amino}-2-methylpropyl]benzoate.
Yield: 25.3%; LC-MS: (FA) ES+369; .sup.1H NMR (Methanol-d.sub.4,
400 MHz) .delta. 8.03 (s, 1H), 7.89 (m, 2H), 7.73 (d, J=8.3 Hz,
2H), 7.50 (d, J=8.3 Hz, 2H), 7.42 (m, 2H), 4.73 (d, J=10.0 Hz, 1H),
2.25 (m, 1H), 1.30 (t, J=7.3 Hz, 1H), 1.14 (d, J=6.6 Hz, 3H), 0.81
(d, J=6.8 Hz, 3H).
Example 69
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)adamantane-1-c-
arboxamide Compound I-157
[0419] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
Yield: 33.4%; LC-MS: (FA) ES+371.
Example 70
N-((1S)-1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1H-indole-2-c-
arboxamide Compound I-279
[0420] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
Yield: 11%; LC-MS: (FA) ES+352; .sup.1H NMR (Methanol-d.sub.4, 300
MHz) .delta. 8.63 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.60
(d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H),
7.19 (m, 2H), 7.04 (t, J=7.3 Hz, 1H), 4.77 (t, J=9.3 Hz, 1H), 2.23
(m, 1H), 1.12 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H).
Example 71
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indole-2-ca-
rboxamide Compound I-330
[0421] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
31.3%; LC-MS: (FA) ES+338; .sup.1H NMR (Methanol-d.sub.4, 300 MHz)
.delta. 7.82 (s, 1H), 7.61 (m, 3H), 7.42 (m, 2H), 7.27 (t, J=7.8
Hz, 1H), 7.11 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 5.25 (q, J=6.8 Hz,
1H), 3.93 (s, 3H), 1.59 (d, J=7.0 Hz, 3H).
Example 72
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-4-carboxamide
Compound I-121
[0422] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
43.9%; LC-MS: (FA) ES+361; .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta. 7.93 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.71 (d, J=8.3 Hz,
2H), 7.65 (d, J=8.3 Hz, 2H), 7.61 (t, J=7.3 Hz, 2H), 7.45 (q, J=7.8
Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 5.29 (q, J=6.8 Hz, 1H), 1.61 (d,
J=7.0 Hz, 3H).
Example 73
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-2-carb-
oxamide Compound I-321
[0423] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
40.9%; LC-MS: (FA) ES+341.
Example 74
3-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxybenzamide
Compound I-177
[0424] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+265.
Example 75
N-hydroxy-3-((1R)-1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benzamide
Compound I-283
[0425] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+305.
Example 76
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzofuran-2-
-carboxamide Compound I-169
[0426] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+339.
Example 77
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl-1-benzothiophe-
ne-2-carboxamide Compound I-113
[0427] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+355.
Example 78
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrrole-2-c-
arboxamide Compound I-271
[0428] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+288.
Example 79
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-carboxam-
ide Compound I-201
[0429] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+325.
Example 80
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)adamantane-1-carboxamide
Compound I-312
[0430] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+343.
Example 81
N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methyl-2-phenyl-4H-fu-
ro[3,2-b]pyrrole-5-carboxamide Compound I-16
[0431] The title compound was prepared in an analogous fashion to
that described in Example 8 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+404.
Example 82
4,5-dichloro-N-((1R)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1-
H-pyrrole-2-carboxamide Compound I-301
[0432] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+356.
Example 83
N-hydroxy-3-{(1R)-1-[(4-methoxybenzoyl)amino]ethyl}benzamide
Compound I-193
[0433] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+315.
Example 84
N-hydroxy-3-[(1R)-1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benz-
amide Compound I-403
[0434] The title compound was prepared in an analogous fashion to
that described in Example 29 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES-387.
Example 85
3-01R)-1-{[(tert-butylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-320
[0435] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
3-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+280.
Example 86
3-[(1R)-1-({[1-adamantylamino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-343
[0436] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
3-[(1R)-1-{[(5)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate.
LC-MS: (FA) ES+358.
Example 87
N-((1S)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-indole-2-ca-
rboxamide Compound I-294
[0437] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
22.7%; LC-MS: (FA) ES+338; .sup.1H NMR (Methanol-d.sub.4, 300 MHz)
.delta. 7.82 (s, 1H), 7.61 (m, 3H), 7.42 (m, 2H), 7.27 (t, J=7.8
Hz, 1H), 7.11 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 5.25 (q, J=6.8 Hz,
1H), 3.93 (s, 3H), 1.59 (d, J=7.0 Hz, 3H).
Example 88
N-((1S)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-4-carboxamide
Compound I-393
[0438] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(15)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
40.4%; LC-MS: (FA) ES+361; .sup.1H NMR (Methanol-d.sub.4, 300 MHz)
.delta. 7.93 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.71 (d, J=8.3 Hz,
2H), 7.65 (d, J=8.3 Hz, 2H), 7.61 (t, J=7.3 Hz, 2H), 7.45 (q, J=7.8
Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 5.29 (q, J=6.8 Hz, 1H), 1.61 (d,
J=7.0 Hz, 3H).
Example 89
N-((1S)-1-{3-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-2-carb-
oxamide Compound I-240
[0439] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
3-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}ethyl]benzoate. Yield:
48.1%; LC-MS: (FA) ES+341; .sup.1H NMR (Methanol-d.sub.4, 300 MHz)
.delta. 8.04 (s, 1H), 7.88 (m, 2H), 7.82 (s, 1H), 7.60 (m, 2 H),
7.46-7.38 (m, 3H), 5.26 (q, J=7.2 Hz, 1H), 1.61 (d, J=7.2 Hz,
3H).
Example 90
N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)biphenyl-
-4-carboxamide Compound I-296
[0440] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(15)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-413; .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta.
11.26 (s, 1H), 9.59 (d, J=9.5 Hz, 1H), 9.10 (s, 1H), 8.01 (d, J=8.5
Hz, 2H), 7.82-7.75 (m, 4H), 7.73 (m, 2H), 7.50 (m, 2H), 7.41 (m,
1H), 6.15 (d, J=9.2 Hz, 1H).
Example 91
N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzo-
furan-2-carboxamide Compound I-400
[0441] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-377.
Example 92
4,5-dichloro-1-methyl-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl-
]phenyl}ethyl)-1H-pyrrole-2-carboxamide Compound I-108
[0442] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-409.
Example 93
4-methyl-2-phenyl-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phe-
nyl}ethyl)-4H-furo[3,2-b]pyrrole-5-carboxamide Compound I-231
[0443] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(15)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-456.
Example 94
4-methoxy-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethy-
l)benzamide Compound I-122
[0444] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1S)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-367.
Example 95
3-methyl-N-((1S)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl-
)-1-benzofuran-2-carboxamide Compound I-304
[0445] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(15)-1-{[(R)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-391.
Example 96
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]-2,2,2-trifluoroethyl}-N-hydroxybe-
nzamide Compound I-50
[0446] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-317.
Example 97
1-methyl-N-((1R)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl-
)-1H-pyrrole-2-carboxamide Compound I-119
[0447] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(5)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-340.
Example 98
1-methyl-N-((1R)-2,2,2-trifluoro-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl-
)-1H-indole-2-carboxamide Compound I-276
[0448] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-390.
Example 99
4-((1R)-1-{[(tert-butylamino)carbonyl]amino}-2,2,2-trifluoroethyl)-N-hydro-
xybenzamide Compound I-290
[0449] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-332.
Example 100
4-((1R)-1-{[(1-adamantylamino)carbonyl]amino}-2,2,2-trifluoroethyl)-N-hydr-
oxybenzamide Compound I-105
[0450] The title compound was prepared in an analogous fashion to
that described in Example 30 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}-2,2,2-trifluoroethyl]benzoate.
LC-MS: (FA) ES-410.
Example 101
N--((R)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)-1-benzothioph-
ene-2-carboxamide Compound I-229
[0451] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from
tert-butyl-4-[(R)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benz-
oate. Yield: 26.8%; LC-MS: (FA) ES+367.
Example 102
N-((1R)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)adamantane-1-c-
arboxamide Compound I-46
[0452] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from
tert-butyl-4-[(R)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benz-
oate. Yield: 29.6%; LC-MS: (FA) ES+369.
Example 103
N--((S)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)-1-benzothioph-
ene-2-carboxamide Compound I-249
[0453] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from
tert-butyl-4-[(S)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benz-
oate. Yield: 27.8%; LC-MS: (FA) ES+367; .sup.1H NMR
(Methanol-d.sub.4, 300 MHz) .delta. 8.06 (s, 1H), 7.89 (m, 2H),
7.73 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.42 (m, 2H), 4.42
(m, 1H), 1.39 (m, 1H), 0.68 (d, J=7.7 Hz, 2H), 0.49 (t, J=4.5 Hz,
2H).
Example 104
N--((S)-cyclopropyl{4-[(hydroxyamino)carbonyl]phenyl}methyl)adamantane-1-c-
arboxamide Compound I-322
[0454] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from
tert-butyl-4-[(S)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benz-
oate. Yield: 48.1%; LC-MS: (FA) ES+369; .sup.1H NMR
(Methanol-d.sub.4, 300 MHz) .delta.7.69 (d, J=8.3 Hz, 2H), 7.45 (d,
J=8.3 Hz, 2H), 4.21 (m, 1H), 2.02 (m, 3H), 1.89 (m, 6H), 1.76 (m,
6H), 1.26 (m, 1H), 0.61 (d, J=7.9 Hz, 2H), 0.38 (t, J=4.4 Hz,
2H).
Example 105
N--[(R)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]-1-benzothiophene-
-2-carboxamide Compound I-99
[0455] The title compound (er, 6.0:1) was prepared in an analogous
fashion to that described in Example 18 starting from tert-butyl
4-[(R)-{[(S)-tert-butylsulfinyl]amino}(phenyl)methyl]benzoate.
Yield: 32.4%; LC-MS: (FA) ES+403.
Example 106
N--[(R)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]adamantane-1-carb-
oxamide Compound I-336
[0456] The title compound (er, 6.0:1) was prepared in an analogous
fashion to that described in Example 18 starting from tert-butyl
4-[(R)-{[(S)-tert-butylsulfinyl]amino}(phenyl)methyl]benzoate.
Yield: 57.7%; LC-MS: (FA) ES+405.
Example 107
N--[(S)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]-1-benzothiophene-
-2-carboxamide Compound I-124
[0457] The title compound (er, 6.3:1) was prepared in an analogous
fashion to that described in Example 18 starting from
tert-butyl-4-[(S)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benz-
oate. Yield: 31.0%; LC-MS: (FA) ES+403; .sup.1H NMR
(Methanol-d.sub.4, 300 MHz) .delta. 8.09 (s, 1H), 7.89 (m, 2H),
7.74 (d, J=7.9 Hz, 2H), 7.47-7.25 (m, 9H), 6.48 (d, J=8.5 Hz,
1H).
Example 108
N--[(S)-{4-[(hydroxyamino)carbonyl]phenyl}(phenyl)methyl]adamantane-1-carb-
oxamide Compound I-259
[0458] The title compound (er, 6.3:1) was prepared in an analogous
fashion to that described in Example 18 starting from
tert-butyl-4-[(S)-{[(R)-tert-butylsulfinyl]amino}(cyclopropyl)methyl]benz-
oate. Yield: 29.9%; LC-MS: (FA) ES+405; .sup.1H NMR
(Methanol-d.sub.4, 300 MHz) .delta. 8.01 (d, J=8.1 Hz, 1H), 7.70
(d, J=8.3 Hz, 2H), 7.36-7.18 (m, 6H), 6.27 (d, J=8.1 Hz, 1H), 2.01
(m, 3H), 1.91 (m, 6H), 1.76 (m, 6H).
Example 109
4-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxybenzamide
Compound I-73
[0459] The title compound was prepared in an analogous fashion to
that described in Example 18 starting from tert-butyl
4-[(1R)-1-{[(S)-tert-butylsulfinyl]amino}ethyl]benzoate. LC-MS:
(FA) ES+265.
Example 110
ethyl 4-(1-amino-2-methylpropyl)benzoate
##STR00597##
[0460] Step 1: ethyl 4-isobutyrylbenzoate
[0461] To a 100-mL round-bottom flask was added THF (25 mL). The
solvent was bubbled with nitrogen for a few minutes then cooled to
0.degree. C. and added bis(triphenylphosphine)palladium(II)
chloride (0.44 g, 0.63 mmol) followed by
4-(ethoxycarbonyl)phenylzinciodide (25.0 mL, 12.5 mmol; 0.50 M in
THF). After stirred at 0.degree. C. for 15 min, isobutyryl chloride
(1.32 mL, 12.5 mmol) was added and the resulting mixture was
stirred at 0.degree. C. for 2 h. The reaction was quenched with
slow addition of 1 N HCl and extracted with EtOAc (3.times.100 mL).
After separation, combined organic extracts were washed with sat.
NaHCO.sub.3, water, brine, dried (MgSO.sub.4), and concentrated.
Flash column chromatography (EtOAc:hexanes, 0:1 to 1:9) afforded
ethyl 4-isobutyrylbenzoate (2.49 g, 90%) as a slight-brown oil.
LC-MS: (FA) ES+221; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.13
(d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H),
3.56 (m, 1H), 1.42 (t, J=7.2Hz, 3H), 1.23 (d, J=7.2 Hz, 6H).
Step 2: ethyl 4-(1-(hydroxyimino)-2-methylpropyl)benzoate
[0462] A mixture of ethyl 4-isobutyrylbenzoate (0.56 g, 2.54 mmol),
hydroxylamine hydrochloride (1.06 g, 15.2 mmol), and sodium acetate
(1.25 g, 15.2 mmol) in ethanol (36 mL) was heated to 36.degree. C.
for 2 h. The reaction was then concentrated and the residue was
dissolved in EtOAc (200 mL). The organic phase was washed with
water (2.times.20 mL), brine, dried (MgSO.sub.4), and concentrated
to give crude ethyl 4-(1-(hydroxyimino)-2-methylpropyl)benzoate as
a slight-yellow solid. LC-MS: (FA) ES+236.
Step 3: ethyl 4-(1-amino-2-methylpropyl)benzoate
[0463] To the crude ethyl
4-(1-(hydroxyimino)-2-methylpropyl)benzoate in a 100-mL
round-bottom flask was added acetic acid (8 mL) and zinc dust (1.33
g, 20.3 mmol). The mixture was stirred at rt for 1 h, then filtered
through a pad of Celite. The pad was rinsed with ethanol (50 mL).
Combined filtrate was concentrated to give a solid. To the solid
residue was added ammonium hydroxide (20 mL) and DCM (50 mL). The
solution was stirred at rt for 10 min. After separation, the
aqueous layer was extracted with DCM (2.times.50 mL). Combined
organic phases were washed with brine, dried (MgSO.sub.4), and
concentrated to give an oil. Flash column chromatography
(EtOAc:hexanes:TEA, 20:80:2 to 100:0:2) afforded ethyl
4-(1-amino-2-methylpropyl)benzoate (0.563 g, 55%) as a clear oil.
LC-MS: (FA) ES+222; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.99
(d, J=8.3 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 4.37 (q, J=7.2 Hz, 2H),
3.68 (d, J=7.0 Hz, 1H), 1.86 (m, 1H), 1.39 (t, J=7.0 Hz, 3H), 0.96
(d, J=7.0 Hz, 3H), 0.77 (d, J=7.0 Hz, 3H).
Example 111
ethyl 4-(1-amino-2,2-dimethylpropyl)benzoate
##STR00598##
[0465] The title compound was prepared in an analogous fashion to
that described in Example 110 starting from
(4-(ethoxycarbonyl)phenyl)zinc(II) iodide and pivaloyl chloride.
Yield: 63%; LC-MS: (FA) ES+236; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 7.97 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 4.37 (q,
J=7.0 Hz, 2H), 3.77 (s, 1H), 1.86 (m, 1H), 1.39 (t, J=7.3 Hz, 3H),
0.90 (s, 9H).
Example 112
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)adamantane-1-carbox-
amide Compound I-58
##STR00599##
[0466] Step 1: ethyl
4-{1-[(adamantan-1-ylcarbonyl)amino]-2-methylpropyl}benzoate
[0467] To a vial charged with 1-adamantylcarboxylic acid (0.031 g,
0.17 mmol) was added HATU (64.6 mg, 0.17 mmol), triethylamine (0.14
mL, 1.02 mmol) and DMF (1 mL). The solution was shaken at rt for 1
h then ethyl 4-(1-amino-2-methylpropyl)benzoate (0.038 g, 0.17
mmol) in DMF (1 mL) was added. The resulting mixture was shaken at
rt for 16 h. Solvent was then evaporated. To the residue was added
DCE (3 mL) and sat. NaHCO.sub.3 solution (1.5 mL). After
separation, the aqueous layer was extracted with DCE twice.
Combined organic layers were concentrated to give crude ethyl
4-{1-[(adamantan-1-ylcarbonyl)amino]-2-methylpropyl}benzoate as a
solid.
Step 2:
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)adamantane--
1-carboxamide
[0468] To the crude ethyl
4-{1-[(adamantan-1-ylcarbonyl)amino]-2-methylpropyl}benzoate in a
vial was added potassium hydroxide (0.11 g, 1.87 mmol),
hydroxylamine hydrochloride (0.047 g, 0.68 mmol), and methanol (2
mL). The reaction was capped and heated at 80.degree. C. for 1 h.
After cooled to rt, acetic acid (0.097 mL, 1.7 mmol was added to
neutralize the excess base. The solvent was then completely
evaporated. To the solid was added DMSO (1.3 mL). The solution was
then filtered and purified by prep-HPLC purification to give the
title compound (0.009 g, 15%) as a white solid. LC-MS: (FA)
ES+371.
Example 113
5-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzofu-
ran-2-carboxamide Compound I-130
[0469] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+387.
Example 114
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)pyrazine-2-carboxam-
ide Compound I-203
[0470] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+315.
Example 115
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-5-methyl-1H-indole-
-2-carboxamide Compound I-69
[0471] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+366.
Example 116
N-hydroxy-4-[2-methyl-1-{([3-(trifluoromethyl)phenyl]acetyl}amino)propyl]b-
enzamide Compound I-195
##STR00600##
[0473] The title compound was prepared in an analogous fashion to
that described in Example 111 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES-393.
Example 117
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)quinoxaline-2-carbo-
xamide Compound I-190
[0474] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+365.
Example 118
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2,1,3-benzothiadia-
zole-5-carboxamide Compound I-135
[0475] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+371.
Example 119
4'-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)biphenyl--
4-carboxamide Compound I-143
[0476] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES-405.
Example 120
2,4,5-trifluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)ben-
zamide Compound I-116
[0477] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES-365.
Example 121
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzofuran-2-car-
boxamide Compound I-32
[0478] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+353.
Example 122
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-4-methyl-2-phenylp-
yrimidine-5-carboxamide Compound I-17
[0479] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+405.
Example 123
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)cycloheptanecarboxa-
mide Compound I-382
[0480] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+333.
Example 124
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1,3-benzothiazole--
6-carboxamide Compound I-43
[0481] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+370.
Example 125
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3,5-dimethylisoxaz-
ole-4-carboxamide Compound I-238
[0482] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+332.
Example 126
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1,3-benzothiazole--
2-carboxamide Compound I-191
[0483] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+370.
Example 127
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-naphthamide
Compound I-331
[0484] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+363.
Example 128
N-hydroxy-4-(2-methyl-1-{[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]amino}-
propyl)benzamide Compound I-48
[0485] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+408.
Example 129
4-[1-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2-methylpropyl]-N-hy-
droxybenzamide Compound I-300
[0486] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+387.
Example 130
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)thiophene-2-carboxa-
mide Compound I-112
[0487] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+319.
Example 131
5-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1H-indole-
-2-carboxamide Compound I-247
[0488] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+386.
Example 132
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzofuran-5-car-
boxamide Compound I-194
[0489] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+353.
Example 133
4-{1-[(cyclohexylcarbonyl)amino]-2-methylpropyl}-N-hydroxybenzamide
Compound I-344
[0490] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+319.
Example 134
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)quinoline-4-carboxa-
mide Compound I-246
[0491] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+364.
Example 135
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)biphenyl-4-carboxam-
ide Compound I-11
[0492] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+389.
Example 136
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2,5-bis(trifluorom-
ethyl)benzamide Compound I-155
[0493] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES-447.
Example 137
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-7-methoxy-1-benzof-
uran-2-carboxamide Compound I-306
[0494] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+383.
Example 138
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-3,5-bis(trifluorom-
ethyl)benzamide Compound I-173
[0495] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES-447.
Example 139
4-{1-[(diphenylacetyl)amino]-2-methylpropyl}-N-hydroxybenzamide
Compound I-204
[0496] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+403.
Example 140
4-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)benzam-
ide Compound I-192
[0497] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+369.
Example 141
3,5-bis(acetylamino)-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropy-
l)benzamide Compound I-282
[0498] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+427.
Example 142
N-hydroxy-4-{2-methyl-1-[(3-methyl-2-phenylbutanoyl)amino]propyl}benzamide
Compound I-289
[0499] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+369.
Example 143
N-(1-(4-(hydroxycarbamoyl)phenyl)-2-methylpropyl)-2,5-dimethylfuran-3-carb-
oxamide Compound I-252
[0500] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+331.
Example 144
N-hydroxy-4-(2-methyl-1-(2-(2,4,7-trimethyl-1H-indol-3-yl)acetamido)propyl-
)benzamide Compound I-220
[0501] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+408.
Example 145
N-hydroxy-4-(1-(4-methoxybenzamido)-2-methylpropyl)benzamide
Compound I-346
[0502] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+343.
Example 146
N-(1-(4-(hydroxycarbamoyl)phenyl)-2-methylpropyl)-2-methyl-4-(trifluoromet-
hyl)thiazole-5-carboxamide Compound I-139
[0503] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES-400.
Example 147
N-(1-(4-(hydroxycarbamoyl)phenyl)-2-methylpropyl)-2-phenylthiazole-4-carbo-
xamide Compound I-172
[0504] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+396.
Example 148
1-benzyl-3-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylprop-
yl)-1H-pyrazole-5-carboxamide Compound I-77
[0505] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+449.
Example 149
N-hydroxy-4-{1-[(mesitylacetyl)amino]-2-methylpropyl}benzamide
Compound I-28
[0506] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+369.
Example 150
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-2-oxo-6-phenyl-1,2-
-dihydropyridine-3-carboxamide Compound I-375
[0507] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+406.
Example 151
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-methyl-1H-pyrazo-
le-3-carboxamide Compound I-389
[0508] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+317.
Example 152
4-[1-({[3,5-bis(trifluoromethyl)phenyl]acetyl}amino)-2-methylpropyl]-N-hyd-
roxybenzamide Compound I-250
[0509] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+461.
Example 153
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)-1-benzothiophene-2-
-carboxamide Compound I-94
[0510] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+369.
Example 154
4-{1-[(cyclopentylcarbonyl)amino]-2-methylpropyl}-N-hydroxybenzamide
Compound I-255
[0511] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+305.
Example 155
N-hydroxy-4-(2-methyl-1-{[(1-phenylcyclopentyl)carbonyl]amino}propyl)benza-
mide Compound I-258
[0512] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+381.
Example 156
N-hydroxy-4-(2-methyl-1-{[(2-methyl-1H-indol-3-yl)acetyl]amino}propyl)benz-
amide Compound I-174
[0513] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+380.
Example 157
4-(1-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-2-methylpropyl)-N-hydroxy-
benzamide Compound I-206
[0514] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES+417.
Example 158
4-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2-methylpropyl)benzamide
Compound I-40
[0515] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2-methylpropyl)benzoate. LC-MS: (FA) ES-329.
Example 159
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)adamantane-1-ca-
rboxamide Compound I-162
[0516] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+385.
Example 160
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-1H-py-
razole-3-carboxamide Compound I-66
[0517] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+331.
Example 161
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-benzothiophe-
ne-2-carboxamide Compound I-308
[0518] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+383.
Example 162
4-(1-{[(5-chloro-1-benzothien-3-yl)acetyl]amino}-2,2-dimethylpropyl)-N-hyd-
roxybenzamide Compound I-345
[0519] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+431.
Example 163
5-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-ben-
zofuran-2-carboxamide Compound I-270
[0520] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+401.
Example 164
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-4-methoxybenza-
mide Compound I-352
[0521] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+357.
Example 165
4-(2,2-dimethyl-1-{[4-(trifluoromethyl)benzoyl]amino}propyl)-N-hydroxybenz-
amide Compound I-303
[0522] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES-393.
Example 166
3-ethyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-meth-
yl-1H-pyrazole-5-carboxamide Compound I-318
[0523] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+359.
Example 167
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-1H-py-
rrole-2-carboxamide Compound I-133
[0524] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+330.
Example 168
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1,3-dimethyl-1-
H-pyrazole-4-carboxamide Compound I-86
[0525] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+345.
Example 169
4-[1-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)-2,2-dimethylpropyl]--
N-hydroxybenzamide Compound I-41
[0526] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+401.
Example 170
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-dimethyl-1-
H-pyrrole-2-carboxamide Compound I-262
[0527] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+344.
Example 171
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-1H-in-
dole-2-carboxamide Compound I-364
[0528] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+385.
Example 172
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)pyrazine-2-carb-
oxamide Compound I-87
[0529] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+329.
Example 173
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2-methyl-4,5,6-
,7-tetrahydro-2H-indazole-3-carboxamide Compound I-211
[0530] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+385.
Example 174
N-(1-(4-(hydroxycarbamoyl)phenyl)-2,2-dimethylpropyl)-2-(trifluoromethyl)b-
enzamide Compound I-535
[0531] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES-393.
Example 175
4-(2,2-dimethyl-1-{[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]amino}propyl-
)-N-hydroxybenzamide Compound I-80
[0532] The title compound was prepared in an analogous fashion to
that described in Example 111 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+422.
Example 176
3,5-difluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)be-
nzamide Compound I-251
[0533] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES-361.
Example 177
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2,5-dimethyl-3-
-furamide Compound I-9
[0534] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES-F 345.
Example 178
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2,5-dimethyl-1-
H-pyrrole-3-carboxamide Compound I-310
[0535] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+344.
Example 179
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)thiophene-2-car-
boxamide Compound I-215
[0536] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+333.
Example 180
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-benzothiophe-
ne-3-carboxamide Compound I-158
[0537] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+383.
Example 181
4-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)be-
nzamide Compound I-377
[0538] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+383.
Example 182
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-dimethyl-1-
H-indole-2-carboxamide Compound I-329
[0539] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+394.
Example 183
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1,5-dimethyl-1-
H-pyrazole-3-carboxamide Compound I-260
[0540] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+345.
Example 184
4-{1-[(3,3-dimethylbutanoyl)amino]-2,2-dimethylpropyl}-N-hydroxybenzamide
Compound I-396
[0541] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+307.
Example 185
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1H-indole-3-ca-
rboxamide Compound I-319
[0542] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+366.
Example 186
3-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-
-methyl-1H-pyrazole-5-carboxamide Compound I-291
[0543] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+387.
Example 187
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-benzofuran-2-
-carboxamide Compound I-4
[0544] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+367.
Example 188
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-dimethylis-
oxazole-4-carboxamide Compound I-200
[0545] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+346.
Example 189
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-5-methyl-1H-in-
dole-2-carboxamide Compound I-129
[0546] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+380.
Example 190
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)biphenyl-4-carb-
oxamide Compound I-355
[0547] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+403.
Example 191
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-1H-in-
dole-5-carboxamide Compound I-145
[0548] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+380.
Example 192
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1,3-thiazole-4-
-carboxamide Compound I-123
[0549] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+334.
Example 193
4-{1-[(cyclohexylcarbonyl)amino]-2,2-dimethylpropyl}-N-hydroxybenzamide
Compound I-265
[0550] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+333.
Example 194
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-2-methyl-1,3-t-
hiazole-4-carboxamide Compound I-42
[0551] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+348.
Example 195
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-5-methyl-1-phe-
nyl-1H-pyrazole-4-carboxamide Compound I-182
[0552] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+407.
Example 196
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1-methyl-1H-in-
dole-3-carboxamide Compound I-107
[0553] The title compound was prepared in an analogous fashion to
that described in Example 112. starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+380.
Example 197
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-1H-indole-2-ca-
rboxamide Compound I-127
[0554] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+366.
Example 198
4-{1-[(cyclopentylcarbonyl)amino]-2,2-dimethylpropyl}-N-hydroxybenzamide
Compound I-373
[0555] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+319.
Example 199
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3,5-bis(triflu-
oromethyl)benzamide Compound I-52
[0556] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES-461.
Example 200
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}-2,2-dimethylpropyl)-3-(methylsulfo-
nyl)benzamide Compound I-75
[0557] The title compound was prepared in an analogous fashion to
that described in Example 112 starting from ethyl
4-(1-amino-2,2-dimethylpropyl)benzoate. LC-MS: (FA) ES+405.
Example 201
methyl 4-(1-(hydroxyimino)ethyl)benzoate
##STR00601##
[0559] A mixture of 4-acetylbenzoic acid methyl ester (1.0 g, 5.6
mmol), hydroxylamine hydrochloride (3.1 g, 45 mmol) and sodium
acetate (3.7 g, 45 mmol) in methanol (50 mL) was heated at
40.degree. C. for 2 hours. The mixture was evaporated to dryness
and the residue partitioned between EtOAc (40 mL) and water (40 mL)
The organic layer was washed with brine (40 mL), dried over
anhydrous MgSO.sub.4 and evaporated to dryness to afford the title
compound as a white solid (1.04 g, 96%). LC-MS: (FA) ES+194;
.sup.1H NMR (400 MHz, MeOD) .delta. 8.02-7.98 (m, 2H), 7.78-7.75
(m, 2H), 3.90 (s, 3H), 2.24 (s, 3H).
Example 202
methyl 4-(1-aminoethyl)benzoate hydrochloride
##STR00602##
[0561] To a degassed solution of methyl
4-(1-(hydroxyimino)ethyl)benzoate (1.1 g, 5.6 mmol) and 12.0 M of
hydrochloric acid in water (0.6 mL, 7.3 mmol) in methanol (50 mL)
was added 10% palladium on carbon (0.20 g, 0.18 mmol). The reaction
mixture was stirred overnight at room temperature. All insolubles
were removed via filtration through celite and subsequent
evaporation of the filtrate to dryness afforded the title compound
as a white solid (1.12 g, 83%). LC-MS: (FA) ES+180; .sup.1H NMR
(400 MHz, MeOD) .delta. 8.09 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.4 Hz,
1H), 4.55 (q, J=6.8 Hz, 1H), 3.91 (s, 3H), 1.65 (d, J=6.9 Hz,
3H).
Example 203
methyl 4-acetyl-3-methylbenzoate
##STR00603##
[0563] Methyl 4-bromo-methylbenzoate (2.146 g, 9.368 mmol),
1,3-bis(diphenylphosphino)propane (0.21 g, 0.52 mmol), sodium
carbonate (2.19 g, 20.6 mmol) and palladium (II) acetate (0.10 g,
0.47 mmol) were combined in a vial and purged with argon. Methanol
(10.7 mL, 265 mmol) and n-butyl vinyl ether (4.83 mL, 37.5 mmol)
were added by syringe. The resulting mixture was further sonicated
under argon flow for several minutes then heated at 90.degree. C.
overnight. Upon cooling to room temperature, the reaction was
diluted with methanol (10 mL). Celite (2 g) was added, the mixture
thoroughly homogenized and filtered. The filter cake was washed
with several mL of methanol. To the red/brown methanolic filtrate
was added 6M aqueous HCl (6.5 mL). The solution turned yellow and
then turbid white over stirring at room temperature (0.3 h). The
solvent was removed under reduced pressure and the residue obtained
was partitioned between ethyl acetate (75 mL) and water (30 mL).
The aqueous phase was extracted with ethyl acetate (30 mL). The
extracts were combined, washed with saturated aqueous sodium
bicarbonate then brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The crude residue was dried in
vacuo to remove butanol. The residue was purified by silica gel
chromatography (5-20% EtOAC/hexanes gradient) to afford the title
compound as an off-white solid (1.49 g, 83%). LC-MS: (FA) ES+193;
.sup.1H NMR (400 MHz, DMSO) .delta. 7.89-7.83 (m, 3H), 3.86 (s,
3H), 2.57 (s, 3H), 2.44 (s, 3H).
Example 204
methyl 4-(1-(hydroxyimino)ethyl)-3-methylbenzoate
##STR00604##
[0565] Methyl 4-acetyl-3-methylbenzoate (1.49 g, 7.76 mmol),
hydroxylamine hydrochloride (4.18 g, 60.1 mmol), and sodium acetate
(4.93 g, 60.1 mmol) were suspended in methanol (40 mL) and the
reaction mixture heated at 40.degree. C. for 2 h. Upon cooling to
room temperature the solvent was removed under reduced pressure.
The residue obtained was partitioned between ethyl acetate (75 mL)
and water (30 mL). The organic extract was washed with water (20
mL) and brine. The washed extract was dried over sodium sulfate,
filtered and concentrated under reduced pressure to afford the
title compound as a solid (1.61 g, 100%). LC-MS: (FA) ES+208;
.sup.1H NMR (300 MHz, MeOD) S 7.91-7.77 (m, 2H), 7.31 (d, J=8.0 Hz,
0.7H), 7.16 (d, J=7.9 Hz, 0.3H), 3.89 (s, 3H), 2.37 (s, 2H), 2.28
(s, 1H), 2.17 (s, 2H), 2.10 (s, 1H).
Example 205
methyl 4-(1-aminoethyl)-3-methylbenzoate hydrochloride
##STR00605##
[0567] To a degassed solution of methyl
4-[N-hydroxyethanimidoyl]-3-methylbenzoate (0.348 g, 1.68 mmol) and
12.0 M aqueous hydrochloric acid (0.35 mL, 4.20 mmol) in methanol
(15 mL) was added 10% palladium on carbon (0.11 g, 0.101 mmol). The
reaction mixture was stirred under a balloon atmosphere of H.sub.2
overnight. All insolubles were then removed via filtration through
celite and the filtrate was evaporated to dryness. The residue was
redissolved in methanol/toluene and concentrated under reduced
pressure to afford a white solid (0.385 g, 100%). LC-MS: (FA)
ES+195; .sup.1H NMR (300 MHz, DMSO) .delta. 7.15 (m Hz, 2H), 6.73
(d, J=8.1 Hz, 1H), 6.45-6.26 (m, 1H), 3.96 (dd, J=13.7, 6.9 Hz,
1H), 3.10 (s, 3H), 1.67 (s, 3H), 0.80 (d, J=6.8 Hz, 3H).
Example 206
methyl 4-acetyl-3-methoxybenzoate
##STR00606##
[0569] Methyl 4-bromo-3-methoxybenzoate (0.53 g, 2.2 mmol),
1,3-bis(diphenylphosphino)propane (0.050 g, 0.12 mmol), sodium
carbonate (0.510 g, 4.81 mmol) and palladium (II) acetate (0.024 g,
0.11 mmol) were combined in a 5 mL microwave vial. The vial was
sealed and purged with argon. Methanol (2.50 mL, 61.7 mmol) and
n-butyl vinyl ether (1.12 mL, 8.74 mmol) were added by syringe, and
the mixture was sonicated under argon flow for several minutes,
then heated to 90.degree. C. over night. Upon cooling to room
temperature, celite (1 g) was added. The mixture was diluted with
methanol (5 mL) and the slurry was then filtered. The filter cake
was washed with methanol and to the pale red/brown methanolic
filtrate was added 6M aqueous HCl (2.5 mL). The solution turned
yellow and then turbid white over stirring at room temperature (0.5
h). The solvent was removed under reduced pressure and the residue
obtained was partitioned between ethyl acetate (50 mL) and
half-saturated aqueous sodium bicarbonate solution (25 mL). The
aqueous phase was extracted with ethyl acetate (30 mL). The organic
extracts were combined, washed with brine, dried over sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (15-85%
EtOAc/hexanes gradient) to afford the title compound (0.396 g,
87%). LC-MS: (FA) ES+209; .sup.1H NMR (300 MHz, DMSO) .delta.
7.69-7.53 (m, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 2.54 (s, 3H).
Example 207
methyl 4-(1-(hydroxyimino)ethyl)-3-methoxybenzoate
##STR00607##
[0571] Methyl 4-acetyl-3-methoxybenzoate (0.396 g, 1.90 mmol),
hydroxylamine hydrochloride (1.02 g, 14.7 mmol), and sodium acetate
(1.21 g, 14.7 mmol) were suspended in methanol (10 mL) and the
reaction mixture heated at 40.degree. C. for 4 h. Upon cooling to
room temperature the solvent was removed under reduced pressure.
The residue obtained was partitioned between ethyl acetate (80 mL)
and water (30 mL). The organic extract was washed with water (25
mL) and brine. The washed extract was dried over sodium sulfate,
filtered and concentrated under reduced pressure to afford the
title compound as a solid (0.417 g, 98%). LC-MS: (FA) ES+224;
.sup.1H NMR (400 MHz, DMSO) .delta. 11.22 (s, 1H), 7.61-7.49 (m,
2H), 7.34 (d, J=7.7 Hz, 1H), 3.86 (s, 6H), 2.05 (s, 3H).
Example 208
methyl 4-(1-aminoethyl)-3-methoxybenzoate hydrochloride
##STR00608##
[0573] To a degassed solution of methyl
4-(1-(hydroxyimino)ethyl)-3-methoxybenzoate (0.417 g, 1.87 mmol) in
methanol (17 mL) was added 12.0 M aqueous hydrochloric acid (0.389
mL, 4.67 mmol) and 10% palladium on carbon (0.120 g, 0.113 mmol).
The reaction mixture was stirred under a balloon atmosphere of
H.sub.2 overnight. The catalyst was removed via filtration through
celite and evaporation of the filtrate to dryness afforded the
title compound (0.471 g, 100%). LC-MS: (FA) ES+209; .sup.1H NMR
(300 MHz, DMSO) .delta. 8.20 (s, 3H), 7.64 (m, 1H), 7.55 (s, 2H),
4.60 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 1.46 (d, J=6.9 Hz,
3H).
Example 209
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-1H-pyrrole-2-carbox-
amide Compound I-356
##STR00609##
[0575] To a solution of N-methylpyrrole-2-carboxylic acid (0.032 g,
0.26 mmol) and methyl 4-(1-aminoethyl)benzoate hydrochloride (50
mg, 0.23 mmol) in methylene chloride (2 mL) was added
N,N,N',N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (0.106 g, 0.278 mmol) and N-methylmorpholine
(0.0586 g, 0.58 mmol) respectively. The resulting mixture was
stirred at room temperature overnight. The reaction was evaporated
to dryness and the residue obtained was partitioned between DCE (3
mL) and saturated aqueous NaHCO.sub.3 (1 mL). The layers were
separated and the aqueous layer was washed with additional DCE (3
mL). The combined organic layers were concentrated. The residue was
taken up in anhydrous methanol (2 mL) to which was added potassium
hydroxide (0.10 g, 1.8 mmol) and hydroxylamine hydrochloride
(0.0805 g, 1.16 mmol). The mixture was stirred at room temperature
for 30 minutes then heated to 80.degree. C. for 5 hours. The
reaction was neutralized by the addition of formic acid (0.0673 mL,
1.78 mmol) and the solution purified using prep-HPLC. Concentration
of fractions containing desired product afforded the title compound
as a white solid (11.3 mg, 17%). LC-MS: (FA) ES+288; .sup.1H NMR
(400 MHz, DMSO) .delta. 11.10 (s, 1H), 9.00 (s, 1H), 8.31 (d, J=8.0
Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 6.92 (dd,
J=3.9, 1.7 Hz, 1H), 6.88 (t, J=2.1 Hz, 1H), 6.01 (dd, J=3.9, 2.5
Hz, 1H), 3.77 (s, 3H), 1.43 (d, J=7.1 Hz, 3H).
[0576] The following compounds were prepared in an analogous
fashion to Example 209. [0577]
4-{1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxybenzamide
Compound I-59: LCMS: (FA) ES+265 [0578]
6-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)imidazo[1,2-a]pyrid-
ine-2-carboxamide Compound I-35: LCMS: (FA) ES+360 [0579]
4-[1-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)ethyl]-N-hydroxybenza-
mide Compound I-110: LCMS: (FA) ES+374 [0580]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-phenyl-1H-pyrazole-5-carb-
oxamide Compound I-109: LCMS: (FA) ES+351 [0581]
N-hydroxy-4-{1-[(3-phenylpropanoyl)amino]ethyl}benzamide Compound
I-45: LCMS: (FA) ES+313
Example 210
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-isopropyl-1-methyl-1H-pyra-
zole-5-carboxamide Compound I-186
##STR00610##
[0583] A solution of
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (41.8 mg, 0.110 mmol),
3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (20.2 mg, 0.12
mmol) and N,N-diisopropylethylamine (52.2 .mu.L, 0.3 mmol) in DMF
(1.0 mL, 13 mmol) was stirred at room temperature for 30 minutes.
Methyl 4-(1-aminoethyl)benzoate hydrochloride (21.6 mg, 0.10 mmol)
and N,N-diisopropylethylamine (17.4 .mu.L, 0.10 mmol) in DMF (1 mL)
was then added and the reaction solution was stirred at room
temperature overnight. The solution was evaporated to dryness and
the residue obtained was partitioned between DCE (2 mL) and
half-saturated aqueous sodium bicarbonate solution (2 mL). The
aqueous layer was washed with additional DCE (2 mL) and the
combined organic layers concentrated. The residue was dissolved in
a mixture of MeOH (0.5 mL) and THF (2 mL); 1.0M aqueous NaOH (0.5
mL) was added and the solution heated to 40.degree. C. overnight.
Upon cooling to room temperature, the solution was neutralized by
the addition of 1.0M aqueous HCl (0.5 mL) and evaporated to
dryness. The residue obtained was taken up in DMF (2.0 mL) and to
the solution was added
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (41.8 mg, 0.11 mmol),
O-(tetrahydropyran-2-yl)hydroxylamine (14.0 mg, 0.120 mmol) and
N,N-diisopropylethylamine (52 .mu.L, 0.3 mmol). The reaction
solution was stirred at room temperature overnight. The solution
was evaporated to dryness and the residue obtained was partitioned
between DCE (2 mL) and half-saturated aqueous sodium bicarbonate
solution (2 mL). The aqueous layer was washed with additional DCE
(2 mL) and the combined organic layers concentrated. The material
obtained was dissolved in MeOH (1 mL), 2.0 M HCl in dioxane (52.2
uL, 0.30 mmol) was added and the solution stirred at room
temperature for 1 hour. The solvents were evaporated and the
resulting material was dissolved in DMSO and purified on Agilent
1100 LC/MSD instrument to afford the title compound as a white
solid (5.3 mg, 16%). LC-MS: (FA) ES+331.
[0584] The following compounds were prepared in an analogous
fashion to Example 210. [0585]
4-(1-{[(2-chlorophenyl)acetyl]amino}ethyl)-N-hydroxybenzamide
Compound I-292: LCMS: (FA) ES+334; [0586]
N-hydroxy-4-(1-{[(1-phenylcyclopentyl)carbonyl]amino}ethyl)benzamide
Compound I-198: LCMS: (FA) ES+353; [0587]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-4,5,6,7-tetrahydro-
-2H-indazole-3-carboxamide Compound I-114: LCMS: (FA) ES+343;
[0588]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-isobutylisoxazole-3-carbo-
xamide Compound I-286: LCMS: (FA) ES+332; [0589]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzothiophene-3-carboxam-
ide Compound I-244: LCMS: (FA) ES+341; [0590]
4-{1-[(2,3-dihydro-1H-inden-2-ylacetyl)amino]ethyl}-N-hydroxybenzamide
Compound I-357: LCMS: (FA) ES+339; [0591]
N-hydroxy-4-(1-{[(4-isopropylphenyl)acetyl]amino}ethyl)benzamide
Compound I-285: LCMS: (FA) ES+341; [0592]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)cinnoline-4-carboxamide
Compound I-56: LCMS: (FA) ES+337; [0593]
N-hydroxy-4-(1-{[4-(4-methoxyphenyl)butanoyl]amino}ethyl)benzamide
Compound I-70: LCMS: (FA) ES+357; [0594]
4-(1-{[(2,5-dimethyl-1,3-thiazol-4-yl)acetyl]amino}ethyl)-N-hydroxybenzam-
ide Compound I-217: LCMS: (FA) ES+334; [0595]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-(1H-pyrazol-1-yl)benzamid-
e Compound I-185: LCMS: (FA) ES+351; [0596]
4-tert-butyl-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
Compound I-350: LCMS: (FA) ES+341; [0597]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-naphthamide
Compound I-327: LCMS: (FA) ES+335; [0598]
4-{1-[(1,3-benzodioxol-5-ylacetyl)amino]ethyl}-N-hydroxybenzamide
Compound I-280: LCMS: (FA) ES+343; [0599]
N-hydroxy-4-[1-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)ethyl]benz-
amide Compound I-264: LCMS: (FA) ES+339; [0600]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methyl
-1-benzofuran-2-carboxamide Compound I-7: LCMS: (FA) ES+339; [0601]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2H-chromene-3-carboxamide
Compound I-224: LCMS: (FA) ES+339; [0602]
4-(1-{[(2,4-difluorophenyl)acetyl]amino}ethyl)-N-hydroxybenzamide
Compound I-402: LCMS: (FA) ES+335; [0603]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)quinoline-2-carboxamide
Compound I-128: LCMS: (FA) ES+336; [0604]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2,1,3-benzothiadiazole-5-ca-
rboxamide Compound I-233: LCMS: (FA) ES+343; [0605]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-(1,3-oxazol-5-yl)benzamid-
e Compound I-138: LCMS: (FA) ES+352; [0606]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-isopropoxybenzamide
Compound I-38: LCMS: (FA) ES+343; [0607]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5,7-dimethylpyrazolo[1,5-a]-
pyrimidine-2-carboxamide Compound I-160: LCMS: (FA) ES+354; [0608]
4-(1-{[(2-chloro-6-fluorophenyl)acetyl]amino}ethyl)-N-hydroxybenzamide
Compound I-24: LCMS: (FA) ES+352; [0609]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)adamantane-1-carboxamide
Compound I-3: LCMS: (FA) ES+343; [0610]
4-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methoxybenzamide
Compound I-164: LCMS: (FA) ES+333; [0611]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-methyl-4H-indole-2-carbox-
amide Compound I-98: LCMS: (FA) ES+338; [0612]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-(1H-pyrrol-1-yl)thiophene-
-2-carboxamide Compound I-228: LCMS: (FA) ES+356; [0613]
4-(1-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}ethyl)-N-hydroxybenzami-
de Compound I-378: LCMS: (FA) ES+362; [0614]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-1,3-benzothiazole--
5-carboxamide Compound I-230: LCMS: (FA) ES+356; [0615]
4-(1-{[1-adamantylacetyl]amino}ethyl)-N-hydroxybenzamide Compound
I-212: LCMS: (FA) ES+357; [0616]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-(1H-pyrrol-1-yl)benzamide
Compound I-63: LCMS: (FA) ES+350; [0617]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-benzothiazole-6-carboxa-
mide Compound I-360: LCMS: (FA) ES+342; [0618]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)imidazo[1,2-a]pyridine-2-car-
boxamide Compound I-125: LCMS: (FA) ES+325; [0619]
4-{1-[(cyclopropylcarbonyl)amino]ethyl}-N-hydroxybenzamide Compound
I-239: LCMS: (FA) ES+249; [0620]
4-{1-[(cyclopropylacetyl)amino]ethyl}-N-hydroxybenzamide Compound
I-379: LCMS: (FA) ES+263; [0621]
N-hydroxy-4-(1-{[(2-methoxyphenyl)acetyl]amino}ethyl)benzamide
Compound I-34: LCMS: (FA) ES+329; [0622]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2,3-dihydro-1-benzofuran-7--
carboxamide Compound I-134: LCMS: (FA) ES+327; [0623]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-dimethyl-1H-pyrazole-5--
carboxamide Compound I-288: LCMS: (FA) ES+303; [0624]
4-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
Compound I-136: LCMS: (FA) ES+320; [0625]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-2-methyl-1,3-thiazole-4-car-
boxamide Compound LCMS: (FA) ES+306; [0626]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,3-benzodioxole-5-carboxam-
ide Compound I-297: LCMS: (FA) ES+329; [0627]
2-chloro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)benzamide
Compound I-269: LCMS: (FA) ES+320; [0628]
4-[1-(butyrylamino)ethyl]-N-hydroxybenzamide Compound I-243: LCMS:
(FA) ES+251; [0629]
N-hydroxy-4-(1-{[(4-methoxyphenyl)acetyl]amino}ethyl)benzamide
Compound I-159: LCMS: (FA) ES+329; [0630]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1,5-dimethyl-1H-pyrazole-3--
carboxamide Compound I-241: LCMS: (FA) ES+303; [0631]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-5-carboxamide
Compound I-349: LCMS: (FA) ES+325; [0632]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3,5-dimethylisoxazole-4-car-
boxamide Compound I-326: LCMS: (FA) ES+304; [0633]
4-{1-[(cyclopentylcarbonyl)amino]ethyl}-N-hydroxybenzamide Compound
I-88: LCMS: (FA) ES+277; [0634]
4-{1-[(cyclobutylcarbonyl)amino]ethyl}-N-hydroxybenzamide Compound
I-21: LCMS: (FA) ES+263; [0635]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-methylthiophene-2-carboxa-
mide Compound I-147: LCMS: (FA) ES+305; [0636]
4-{1-[(3,3-dimethylbutanoyl)amino]ethyl}-N-hydroxybenzamide
Compound I-144: LCMS: (FA) ES+279; [0637]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-1-benzofuran-2-carboxamide
Compound I-207: LCMS: (FA) ES+325; [0638]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methylbenzamide
Compound I-295: LCMS: (FA) ES+299; [0639]
4-{1-[(cyclohexylcarbonyl)amino]ethyl}-N-hydroxybenzamide Compound
I-208: LCMS: (FA) ES+291; [0640]
N-hydroxy-4-[1-(isobutyrylamino)ethyl]benzamide Compound I-36:
LCMS: (FA) ES+251; [0641]
N-hydroxy-4-{1-[(tetrahydro-2H-pyran-4-ylacetyl)amino]ethyl}benzamide
Compound I-313: LCMS: (FA) ES+307; [0642]
N-hydroxy-4-(1-{[(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino}ethyl)ben-
zamide Compound I-372: LCMS: (FA) ES+305; [0643]
4-{1-[(cyclohex-3-en-1-ylcarbonyl)amino]ethyl}-N-hydroxybenzamide
Compound I-348: LCMS: (FA) ES+289; [0644]
4-{1-[(cyclopentylacetyl)amino]ethyl}-N-hydroxybenzamide Compound
I-370: LCMS: (FA) ES+291; [0645]
2-fluoro-N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-5-methylbenzamide
Compound I-8: LCMS: (FA) ES+317; [0646]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)cycloheptanecarboxamide
Compound I-213: LCMS: (FA) ES+305; [0647]
N-hydroxy-4-{1-[(3-methylbutanoyl)amino]ethyl}benzamide Compound
I-111: LCMS: (FA) ES+265; [0648]
N-hydroxy-4-(1-{[(1-methylcyclohexyl)carbonyl]amino}ethyl)benzamide
Compound I-132: LCMS: (FA) ES+305; [0649]
N-hydroxy-4-(1-{[(1-methylcyclopropyl)carbonyl]amino}ethyl)benzamide
Compound I-154: LCMS: (FA) ES+263; [0650]
4-[1-(benzoylamino)ethyl]-N-hydroxybenzamide Compound I-385: LCMS:
(FA) ES+285; [0651]
N-(1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-3-methoxybenzamide
Compound I-225: LCMS: (FA) ES+315;
[0652] The following compounds were prepared in an analogous
fashion to Example 210 using methyl
4-(1-aminoethyl)-3-methoxybenzoate hydrochloride as the starting
material: [0653]
N-(1-{4-[(hydroxyamino)carbonyl]-2-methoxyphenyl}ethyl)-1-methyl-1H-pyrro-
le-2-carboxamide Compound I-481: LCMS: (FA) ES+318; [0654]
4-{1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxy-3-methoxybenzamide
Compound I-484: LCMS: (FA) ES+295; [0655]
N-(1-{4-[(hydroxyamino)carbonyl]-2-methoxyphenyl}ethyl)adamantane-1-carbo-
xamide Compound I-483: LCMS: (FA) ES+373; [0656]
N-(1-{4-[(hydroxyamino)carbonyl]-2-methoxyphenyl}ethyl)-1-benzothiophene--
2-carboxamide Compound I-480: LCMS: (FA) ES+371.
[0657] The following compounds were prepared in an analogous
fashion to Example 210 using methyl
4-(1-aminoethyl)-3-methylbenzoate hydrochloride: as the starting
material: [0658]
N-(1-{4-[(hydroxyamino)carbonyl]-2-methylphenyl}ethyl)-1-benzothiophene-2-
-carboxamide Compound I-485: LCMS: (FA) ES+355; [0659]
N-(1-{4-[(hydroxyamino)carbonyl]-2-methylphenyl}ethyl)-1-methyl-1H-pyrrol-
e-2-carboxamide Compound I-486: LCMS: (FA) ES+302; [0660]
4-{1-[(2,2-dimethylpropanoyl)amino]ethyl}-N-hydroxy-3-methylbenzamide
Compound I-490: LCMS: (FA) ES+279; [0661]
N-(1-{4-[(hydroxyamino)carbonyl]-2-methylphenyl}ethyl)adamantane-1-carbox-
amide Compound I-491: LCMS: (FA) ES+357.
Example 211
4-[1-({[(4-cyanophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-236
##STR00611##
[0663] To a solution of methyl 4-(1-aminoethyl)benzoate
hydrochloride (32.4 mg, 0.15 mmol) and N,N-diisopropylethylamine
(125 .mu.L, 0.718 mmol) in 1,2-dichloroethane (1 mL) was added
4-isocyanatobenzonitrile (32.4 g, 0.23 mmol). The reaction solution
was stirred at room temperature overnight. The solution was
evaporated to dryness and the residue was partitioned between DCE
(2 mL) and half-saturated aqueous sodium bicarbonate solution (2
mL). The aqueous layer was washed with additional DCE (2 mL) and
the combined organic layers concentrated. The material thus
obtained was dissolved in a mixture of MeOH (0.5 mL) and THF (2
mL); 1.0M aqueous NaOH (0.5 mL) was added and the solution heated
at 40.degree. C. overnight. Upon cooling to room temperature, the
solution was neutralized by the addition of 1.0M aqueous HCl (0.5
mL) and evaporated to dryness. The residue was taken up in DMF (2
mL) and to the solution was added
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (62.7 mg, 0.165 mmol),
0-(tetrahydropyran-2-yl)hydroxylamine (14 mg, 0.12 mmol) and
N,N-diisopropylethylamine (104 .mu.L, 0.6 mmol). The reaction
solution was heated at 45.degree. C. overnight. The reaction
mixture was then evaporated to dryness and the residue obtained was
partitioned between DCE (2 mL) and half-saturated aqueous sodium
bicarbonate solution (2 mL). The aqueous layer was washed with
additional DCE (2 mL) and the combined organic layers concentrated.
The residue obtained was dissolved in MeOH (1 mL), and 2.0 M HCl in
dioxane (52.2 .mu.L, 0.30 mmol) was added and the solution stirred
at room temperature for 1 hour. The solvent was evaporated and the
resulting material was dissolved in DMSO and purified using an
Agilent 1100 LC/MSD instrument to afford the title compound as a
white solid (8.1 mg, 25%). LC-MS: (FA) ES+325.
[0664] The following compounds were prepared in an analogous
fashion to Example 211. [0665]
4-[1-({[(3-fluoro-4-methylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide Compound I-120: LCMS: (FA) ES+332; [0666]
4-[1-({[(3-chloro-4-methylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxyben-
zamide Compound I-103: LCMS: (FA) ES+349; [0667]
N-hydroxy-4-[1-({[(4-phenoxyphenyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-20: LCMS: (FA) ES+392; [0668]
4-[1-({[(2,4-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-383: LCMS: (FA) ES+328; [0669]
4-[1-({[(3,4-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-55: LCMS: (FA) ES+328; [0670]
4-[1-({[(3-acetylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-358: LCMS: (FA) ES+342; [0671]
4-(1-{[(biphenyl-2-ylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-384: LCMS: (FA) ES+376; [0672]
N-hydroxy-4-[1-({[(2-methylbenzyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-76: LCMS: (FA) ES+328; [0673]
4-(1-{[(2,1,3-benzothiadiazol-4-ylamino)carbonyl]amino}ethyl)-N-hydroxybe-
nzamide Compound I-293: LCMS: (FA) ES+358; [0674]
N-hydroxy-4-[1-({[(2-phenoxyphenyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-31: LCMS: (FA) ES+392; [0675]
4-{1-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]ethyl}-N-
-hydroxybenzamide Compound I-334: LCMS: (FA) ES+386; [0676]
4-[1-({[(2,3-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-175: LCMS: (FA) ES+328; [0677]
N-hydroxy-4-{1-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)amino]ethyl}b-
enzamide Compound I-399: LCMS: (FA) ES+368; [0678]
N-hydroxy-4-[1-({[(2-methoxy-5-methylphenyl)amino]carbonyl}amino)ethyl]be-
nzamide Compound I-253: LCMS: (FA) ES+344 [0679]
4-{1-[({[2-chloro-4-(trifluoromethyl)phenyl]amino}carbonyl)amino]ethyl}-N-
-hydroxybenzamide Compound I-163: LCMS: (FA) ES+403; [0680]
4-[1-({[(2,6-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-156: LCMS: (FA) ES+328 [0681]
4-[1-({[(2,6-difluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-261: LCMS: (FA) ES+336 [0682]
N-hydroxy-4-[1-({[(3-methylbenzyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-316: LCMS: (FA) ES+328 [0683]
4-[1-({[(4-ethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-381: LCMS: (FA) ES+328 [0684]
N-hydroxy-4-[1-({[(2-phenylethyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-210: LCMS: (FA) ES+328 [0685]
4-{1-[({[4-(difluoromethoxy)phenyl]amino}carbonyl)amino]ethyl}-N-hydroxyb-
enzamide Compound I-150: LCMS: (FA) ES+366 [0686]
4-[1-({[(2,5-dichlorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-89: LCMS: (FA) ES+369 [0687]
N-hydroxy-4-(1-{[(1-naphthylamino)carbonyl]amino}ethyl)benzamide
Compound I-6: LCMS: (FA) ES+350 [0688]
4-(1-{[(1,3-benzodioxol-5-ylamino)carbonyl]amino}ethyl)-N-hydroxybenzamid-
e Compound I-71: LCMS: (FA) ES+344 [0689]
4-[1-({[(2,4-dimethoxyphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzami-
de Compound I-44: LCMS: (FA) ES+360 [0690]
4-[1-({[(4-fluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-37: LCMS: (FA) ES+318 [0691]
4-[1-({[(4-tert-butylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-140: LCMS: (FA) ES+356 [0692]
4-(1-{[(2,3-dihydro-1-benzofuran-5-ylamino)carbonyl]amino}ethyl)-N-hydrox-
ybenzamide Compound I-148: LCMS: (FA) ES+342 [0693]
4-[1-({[(2-fluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-74: LCMS: (FA) ES+318 [0694]
N-hydroxy-4-[1-({[(3-methylphenyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-85: LCMS: (FA) ES+314 [0695]
4-[1-({[(3,4-difluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-275: LCMS: (FA) ES+336 [0696]
4-[1-({[(3,5-dimethylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-397: LCMS: (FA) ES+328 [0697]
N-hydroxy-4-[1-({[(4-methylbenzyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-277: LCMS: (FA) ES+328 [0698]
4-[1-({[(3,5-dichlorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamid-
e Compound I-388: LCMS: (FA) ES+369 [0699]
N-hydroxy-4-{1-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]ethyl}b-
enzamide Compound I-371: LCMS: (FA) ES+368 [0700]
N-hydroxy-4-[1-({[(3-methyl-5-phenylisoxazol-4-yl)amino]carbonyl}amino)et-
hyl]benzamide Compound I-168: LCMS: (FA) ES+381 [0701]
N-hydroxy-4-[1-[({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]ethyl]-
benzamide Compound I-141: LCMS: (FA) ES+384 [0702]
4-[1-({[(4-acetylphenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-398: LCMS: (FA) ES+342 [0703]
N-hydroxy-4-[1-({[(5-methyl-3-phenylisoxazol-4-yl)amino]carbonyl}amino)et-
hyl]benzamide Compound I-305: LCMS: (FA) ES+381 [0704]
4-{1-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]ethyl}-N-
-hydroxybenzamide Compound I-325: LCMS: (FA) ES+403 [0705]
N-hydroxy-4-[1-({[(1-phenylethyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-196: LCMS: (FA) ES+328 [0706]
N-hydroxy-4-[1-({[(2-methylphenyl)amino]carbonyl}amino)ethyl]benzamide
Compound I-394: LCMS: (FA) ES+314 [0707]
4-(1-{[(cyclohexylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-395: LCMS: (FA) ES+306 [0708]
4-[1-({[(3-fluorophenyl)amino]carbonyl}amino)ethyl]-N-hydroxybenzamide
Compound I-27: LCMS: (FA) ES+318.
Example 212
4-(1-{[(2,4-dimethylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-78
##STR00612##
[0710] To a solution of methyl 4-(1-aminoethyl)benzoate
hydrochloride (32.4 mg, 0.15 mmol) and N,N-diisopropylethylamine
(125 .mu.L, 0.72 mmol) in 1,2-dichloroethane (1 mL) was added
2,4-dimethylbenzenesulfonyl chloride (46 mg, 0.23 mmol). The
reaction was stirred at room temperature overnight. The solution
was evaporated to dryness and the residue was partitioned between
DCE (2 mL) and half-saturated aqueous sodium bicarbonate solution
(2 mL). The aqueous layer was washed with additional DCE (2 mL) and
the combined organic layers concentrated. The residue was dissolved
in a mixture of MeOH (0.5 mL) and THF (2 mL); then 1.0M aqueous
NaOH (0.5 mL) was added and the solution heated at 40.degree. C.
overnight. Upon cooling to room temperature, the solution was
neutralized with 1.0M aqueous HCl (0.5 mL) and evaporated to
dryness. The resulting solid was taken up in DMF (2 mL) and to the
resulting solution was added
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (62.7 mg, 0.165 mmol),
O-(tetrahydropyran-2-yl)hydroxylamine (19.3 mg, 0.165 mmol) and
N,N-diisopropylethylamine (104 .mu.L, 0.60 mmol). The reaction
solution was stirred at 45.degree. C. overnight. The reaction
mixture was evaporated to dryness and the residue obtained was
partitioned between DCE (2 mL) and half-saturated aqueous sodium
bicarbonate solution (2 mL). The aqueous layer was washed with
additional DCE (2 mL) and the combined organic layers concentrated.
The residue obtained was dissolved in MeOH (1 mL), 2.0 M HCl in
dioxane (52 .mu.L, 0.3 mmol) was added and the solution stirred at
room temperature for 1 hour. The solvent was evaporated and the
resulting material was dissolved in DMSO and purified using an
Agilent 1100 LC/MSD instrument to afford the title compounds as a
white solid (23.3 mg, 45%). LC-MS: (FA) ES+349.
[0711] The following compounds were prepared in an analogous
fashion to Example 212. [0712]
N-hydroxy-4-{1-[(propylsulfonyl)amino]ethyl}benzamide Compound
I-33: LCMS: (FA) ES+287; [0713]
4-{1-[(ethylsulfonyl)amino]ethyl}-N-hydroxybenzamide Compound I-1:
LCMS: (FA) ES+273; [0714]
4-{1-[(benzylsulfonyl)amino]ethyl}-N-hydroxybenzamide Compound
I-338: LCMS: (FA) ES+335; [0715]
4-(1-{[(4-fluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-2: LCMS: (FA) ES+339; [0716]
N-hydroxy-4-(1-{[(4-methylphenyl)sulfonyl]amino}ethyl)benzamide
Compound I-266: LCMS: (FA) ES+335; [0717]
N-hydroxy-4-(1-{[(2-methylphenyl)sulfonyl]amino}ethyl)benzamide
Compound I-232: LCMS: (FA) ES+335; [0718]
N-hydroxy-4-(1-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)benzamid-
e Compound I-335: LCMS: (FA) ES+325; [0719]
N-hydroxy-4-{1-[(phenylsulfonyl)amino]ethyl}benzamide Compound
I-315: LCMS: (FA) ES+321; [0720]
N-hydroxy-4-[1-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamid-
e Compound I-488: LCMS: (FA) ES+389; [0721]
4-(1-{[(tert-butylamino)carbonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-339: LCMS: (FA) ES+280; [0722]
N-hydroxy-4-{1-[(mesitylsulfonyl)amino]ethyl}benzamide Compound
I-176: LCMS: (FA) ES+363; [0723]
N-hydroxy-4-[1-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamid-
e Compound I-166: LCMS: (FA) ES+389; [0724]
N-hydroxy-4-[1-({[4-(1,3-oxazol-5-yl)phenyl]sulfonyl}amino)ethyl]benzamid-
e Compound I-178: LCMS: (FA) ES+388; [0725]
4-(1-{[(5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-205: LCMS: (FA) ES+353; [0726]
4-{1-[(1-benzothien-2-ylsulfonyl)amino]ethyl}-N-hydroxybenzamide
Compound I-369: LCMS: (FA) ES+377; [0727]
4-(1-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-340: LCMS: (FA) ES+346; [0728]
N-hydroxy-4-(1-{[(4-isopropylphenyl)sulfonyl]amino}ethyl)benzamide
Compound I-221: LCMS: (FA) ES+363; [0729]
4-(1-{[(2,5-difluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-152: LCMS: (FA) ES+357; [0730]
4-(1-{[(2,5-dimethyl-3-thienyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-256: LCMS: (FA) ES+355; [0731]
4-(1-{[(3-chlorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-197: LCMS: (FA) ES+356; [0732]
4-(1-{[(2-chloro-4-fluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-235: LCMS: (FA) ES+374; [0733]
4-{1-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)amino]ethyl}-N-hydroxyben-
zamide Compound I-82: LCMS: (FA) ES+379; [0734]
N-hydroxy-4-(1-{[(2-oxo-2H-chromen-6-yl)sulfonyl]amino}ethyl)benzamide
Compound I-49: LCMS: (FA) ES+389; [0735]
4-(1-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-347: LCMS: (FA) ES+386; [0736]
4-(1-{[(4-chlorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-302: LCMS: (FA) ES+356; [0737]
N-hydroxy-4-{1-[(isoquinolin-5-ylsulfonyl)amino]ethyl}benzamide
Compound I-170: LCMS: (FA) ES+372; [0738]
N-hydroxy-4-(1-{[(3-methoxyphenyl)sulfonyl]amino}ethyl)benzamide
Compound I-23: LCMS: (FA) ES+351; [0739]
N-hydroxy-4-{1-[(1-naphthylsulfonyl)amino]ethyl}benzamide Compound
I-95: LCMS: (FA) ES+371; [0740]
4-(1-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-N-hydroxybenz-
amide Compound I-54: LCMS: (FA) ES+339; [0741]
4-(1-{[(2-chloro-4-cyanophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-254: LCMS: (FA) ES+381; [0742]
N-hydroxy-4-(1-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)be-
nzamide Compound I-60: LCMS: (FA) ES+353; [0743]
4-(1-{[(3,4-difluorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-90: LCMS: (FA) ES+357; [0744]
4-(1-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-118: LCMS: (FA) ES+370; [0745]
4-(1-{[(4-tert-butylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-131: LCMS: (FA) ES+377; [0746]
4-(1-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-361: LCMS: (FA) ES+356; [0747]
N-hydroxy-4-{1-[(quinolin-8-ylsulfonyl)amino]ethyl}benzamide
Compound I-363: LCMS: (FA) ES+372; [0748]
4-{1-[(2,1,3-benzoxadiazol-4-ylsulfonyl)amino]ethyl}-N-hydroxybenzamide
Compound I-161: LCMS: (FA) ES+363; [0749]
4-(1-{[(4-chlorobenzyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-64: LCMS: (FA) ES+370; [0750]
4-{1-[(2,1,3-benzothiadiazol-5-ylsulfonyl)amino]ethyl}-N-hydroxybenzamide
Compound I-272: LCMS: (FA) ES+379; [0751]
4-(1-{[(4-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-61: LCMS: (FA) ES+353; [0752]
4-(1-{[(3-fluoro-4-methoxyphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-153: LCMS: (FA) ES+369; [0753]
4-(1-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-188: LCMS: (FA) ES+370; [0754]
N-hydroxy-4-[1-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]benzamid-
e Compound I-391: LCMS: (FA) ES+389; [0755]
4-(1-{[(4-fluorobenzyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-198: LCMS: (FA) ES+353; [0756]
N-hydroxy-4-(1-{[(4-methoxyphenyl)sulfonyl]amino}ethyl)benzamide
Compound I-47: LCMS: (FA) ES+351; [0757]
N-hydroxy-4-(1-{[(2,3,4-trifluorophenyl)sulfonyl]amino}ethyl)benzamide
Compound I-284: LCMS: (FA) ES+375; [0758]
4-(1-{[(2,5-dimethylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-51: LCMS: (FA) ES+349; [0759]
4-(1-{[(2,4-dimethylphenyl)sulfonyl]amino}ethyl)-N-hydroxybenzamide
Compound I-78: LCMS: (FA) ES+349.
Example 213
tert-butyl
4-methyl-4-({[(1R)-1-(4-{[(tetrahydro-2H-pyran-2-yloxy)amino]ca-
rbonyl}phenyl)ethyl]amino}carbonyl)piperidine-1-carboxylate
##STR00613##
[0761] To a solution of
4-methyl-4-carboxy-1-N-butoxycarbonyl-piperidine (0.250 g, 1.03
mmol) in N,N-dimethylformamide (1.85 mL) was added
N,N-diisopropylethylamine (0.537 mL, 3.08 mmol) and
fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate
(0.298 g, 1.13 mmol). The reaction mixture was stirred for 15
minutes whereupon (R)-4-(1-amino-ethyl)-benzoic acid hydrochloride
(0.200 g, 0.99 mmol) was added and further stirred at room
temperature overnight. Water was added and the mixture extracted
into ethyl acetate. Upon separation of the layers, the organic
layer was dried over anhydrous MgSO.sub.4 and evaporated to
dryness. LC-MS: (FA) ES+391.
[0762] To a mixture of this material and N,N-diisopropylethylamine
(0.518 mL, 2.97 mmol) in N,N-dimethylformamide (2 mL) was added
fluoro-N,N,N,N'-tetramethylformamidinium hexafluorophosphate (0.288
g, 1.09 mmol) and O-(tetrahydropyran-2-yl)hydroxylamine (0.139 g,
1.19 mmol). The resulting solution was stirred at room temperature
overnight. Upon quenching the reaction with the addition of water,
the solution was extracted into ethyl acetate, the organic layer
washed with brine and the solvent evaporated to dryness. The
residue obtained was purified via silica chromatography (0-5%
MeOH/DCM) to afford the title compound as a white solid (86.0 mg,
18%). LC-MS: (FA) ES+490.
Example 214
N-((1R)-1-{4-[(hydroxyamino)carbonyl]phenyl}ethyl)-4-methylpiperidine-4-ca-
rboxamide Compound I-487
##STR00614##
[0764] To a solution of tert-butyl
4-methyl-4-({[(1R)-1-(4-{[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl}phe-
nyl)ethyl]amino}carbonyl)piperidine-1-carboxylate (0.082 g, 0.17
mmol) in methylene chloride (2 mL) was added 4.0 M hydrochloric
acid in 1,4-dioxane (1 mL). The reaction mixture was stirred at
room temperature for 4 hours. The reaction was concentrated to
dryness. Acetic acid (1.0 mL, 18 mmol), tetrahydrofuran (1 mL),
water (0.50 mL) were added and the resulting mixture was heated at
60.degree. C. for 3 h. The reaction mixture was concentrated to
dryness and co-evaporated with toluene. The crude compound was
purified on a BioCAC 700E HPLC instrument using a Waters Symmetry
(21 mm.times.300 mm) column to afford the title compound (22 mg,
43%). .sup.1H NMR (300 MHz, DMSO) .delta. 8.38 (s, 1H), 8.07 (d,
J=7.8 Hz, 1H), 7.67 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.97
(dd, J=14.4, 7.1 Hz, 1H), 2.97 (d, J=13.1 Hz, 2H), 2.66 (dd,
J=20.6, 10.7 Hz, 2H), 2.08 (s, 2H), 1.52-1.39 (m, 2H), 1.36 (d,
J=7.1 Hz, 3H), 1.12 (s, 3H). LC-MS: (FA) ES+306.
Example 215
(R)-methyl 4-(1-aminoethyl)benzoate
##STR00615##
[0766] To a solution of (R)-4-(1-amino-ethyl)-benzoic acid
hydrochloride (0.20 g, 0.99 mmol) in methanol (3.2 mL) was added
sulfuric acid (5.29 .mu.L, 0.0992 mmol). The resulting solution was
heated at reflux overnight. The methanol was removed under reduced
pressure leaving a light brown oil which was partitioned between
half-saturated sodium bicarbonate solution (50 mL) and ethyl
acetate (75 mL). The aqueous phase was extracted with additional
ethyl acetate (50 mL). The extracts were combined, washed with
saturated aqueous sodium bicarbonate and brine, dried over sodium
sulfate, filtered and concentrated under reduced pressure,
Purification via silica chromatography (0-50% EtOAc/hexane)
afforded product as a white solid (0.124 g, 70%). LC-MS: (FA)
ES+180.
Example 216
(R)-methyl 4-(1-((1-methylcyclohexyl)methylamino)ethyl)benzoate
##STR00616##
[0768] To a solution of (R)-methyl 4-(1-aminoethyl)benzoate (0.12
g, 0.67 mmol) in methanol (2.97 mL, 73.33 mmol) was added
1-methylcyclohexane-1-carboxaldehyde (0.093 g, 0.74 mmol) and
acetic acid (0.152 mL, 2.67 mmol). The reaction was stirred for 1
hour at room temperature whereupon sodium cyanoborohydride (63.1
mg, 1.00 mmol) was added and the mixture further stirred at room
temperature overnight. The solvent was evaporated and the residual
sodium cyanoborohydride quenched with saturated aqueous
NaHCO.sub.3. The mixture was extracted into ethyl acetate, the
organic layer washed with brine and the solvent evaporated to
dryness. The residue obtained was purified via silica
chromatography (0-5% MeOH/DCM) to afford the title compound as a
colorless oil (123.0 mg, 63%). LC-MS: (FA) ES+290.
Example 217
N-hydroxy-4-((1R)-1-{[(1-methylcyclohexyl)methyl]amino}ethyl)benzamide
Compound I-489
##STR00617##
[0770] To a solution of methyl
4-((1R)-1-{[(1-methylcyclohexyl)methyl]amino}ethyl)benzoate (0.12
g, 0.415 mmol) in methanol (1 mL) was added 1.7 M of hydroxylamine
potassium salt in methanol (2.46 mL, 4.19 mmol--prepared as
described in J. Med. Chem. 2009, 52(21):6757-6767). The reaction
mixture was stirred at room temperature for 1 hour. The reaction
was neutralized with the addition of acetic acid (0.24 mL, 4.15
mmol) and was concentrated to dryness. The residue was
co-evaporated with toluene (2.times.). The crude product was
purified on a BioCAD 700E HPLC instrument using a Phenomenex (C18)
Luna (21.2 mm.times.250 mm) column to afford product (85 mg, 70%).
.sup.1H NMR (400 MHz, DMSO) .delta. 11.13 (s, 1H), 8.17 (s, 1H),
7.67 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 3.69 (q, J=6.5 Hz,
1H), 2.19 (d, J=11.5 Hz, 1H), 2.03 (d, J=11.5 Hz, 1H), 1.41-1.09
(m, 13H), 0.83 (s, 3H). LC-MS: (FA) ES+291
Example 218
[0771] The following compounds were prepared in an analogous
fashion to that described in Example 211 starting from appropriate
chiral benzyl amine starting material.
TABLE-US-00003 Compound No LC-MS (FA) I-520 ES+ 325 I-523 ES+ 376
I-527 ES+ 350 I-528 ES+ 342 I-513 ES+ 328 I-518 ES+ 336 I-517 ES+
328 I-512 ES+ 356 I-525 ES+ 353 I-515 ES+ 404 I-524 ES+ 378 I-526
ES+ 370 I-516 ES+ 356 I-521 ES+ 364 I-514 ES+ 356 I-522 ES+ 356
Example 219
4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide
##STR00618##
[0772] Step 1: (S)-tert-butyl
4-(1-(((9-fluoren-9-yl)methoxy)carbonylamino)-2-methylpropyl)benzoate
[0773] To a 2-L round-bottom flask charged with tert-butyl
4-((R)-1-((R)-1,1-dimethylethylsulfinamido)-2-methylpropyl)benzoate
(13.0 g, 0.0368 mol) was added MeOH (650 mL) and hydrochloric acid
(650 mL, 4.0 M in 1,4-dioxane). The mixture was stirred at rt for 2
h. The solvent was then evaporated to give a slightly yellow solid.
To the solid was added 1,4-dioxane (650 mL). sat. NaHCO.sub.3
solution (650 mL), followed by (9H-fluoren-9-yl)methyl
carbonochloridate (10.4 g, 0.0405 mol). The mixture was stirred at
rt for 2 h. The reaction was quenched with EtOAc (800 mL) and water
(200 mL). After separation, the aqueous phase was extracted with
EtOAc (2.times.600 mL). Combined organic phases were washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated. Flash column
chromatography gave (S)-tert-butyl
4-(1-(((9-fluoren-9-yl)methoxy)carbonylamino)-2-methylpropyl)benzoate
(6.5 g, 38%).
Step 2: (9H-fluoren-9-yl)methyl
(1R)-2-methyl-1-(4-(tetrahydro-2H-pyran-2-yloxycarbamoyl)phenyl)propylcar-
bamate
[0774] To a 1-L round-bottom flask was added (S)-tert-butyl
4-(1-(((9-fluoren-9-yl)methoxy)carbonylamino)-2-methylpropyl)benzoate
(6.0 g, 12.7 mmol), DCM (260 mL), and trifluoroacetic acid (28.9 g,
254 mmol). The solution was stirred at rt for 16 h. The solvent
were evaporated to give an oil. To this oil in a 500-mL
round-bottom flask was added diisopropylethyl amine (20.0 g, 155
mmol), DCM (100 mL), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine
(1.78 g, 15.24 mmol), and HBTU (5.79 g, 15.2 mmol). The mixture was
stirred at rt for 4 h, then diluted with DCM (500 mL), and washed
with water (2.times.100 mL), dried (Na.sub.2SO.sub.4), and
concentrated. Flash column chromatography gave
(9H-fluoren-9-yl)methyl
(1R)-2-methyl-1-(4-(tetrahydro-2H-pyran-2-yloxycarbamoyl)phenyl)propylcar-
bamate (4.0 g, 62%).
Step 3:
4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benz-
amide
[0775] To a 1-L round-bottom flask was added
(9H-fluoren-9-yl)methyl
(1R)-2-methyl-1-(4-(tetrahydro-2H-pyran-2-yloxycarbamoyl)phenyl)propylcar-
bamate (10.0 g, 0.0195 mol), ethanol (588 mL), and piperidine (51.7
mL). The solution was stirred at rt for 16 h, then concentrated to
give a solid. Flash column chromatography gave
4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide
(2.3 g, 41%). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.7.59 (d,
J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2 H), 5.00 (m, 1H), 3.95 (m, 1H),
3.59 (m, 2H), 1.83 (m, 4H), 1.57 (m, 3H), 1.20 (m, 1H), 0.90 (t,
J=6.8 Hz, 3H), 0.67 (t, J=6.8 Hz, 3H).
Example 220
(R)--N-hydroxy-4-(2-methyl-1-(4-(3-phenylisoxazol-5-yl)thiazol-2-ylamino)p-
ropyl)benzamide Compound I-519
##STR00619##
[0776] Step 1:
4-((R)-2-methyl-1-thioureidopropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzam-
ide
[0777] A solution of
4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide
(0.1643 g, 0.562 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6
mmol) in DCM (2.5 mL) was cooled in an ice bath and added to a
solution of Fmoc-isothiocyanate (0.173 g, 0.616 mmol) in DCM (2.5
mL, 38 mmol) cooled at 0.degree. C. in an ice bath. The reaction
solution was stirred at rt for 1 h. Piperidine (1.0 mL, 2.0 mmol,
2.0 M in MeOH) was then added and the reaction stirred at rt for an
additional 2 h. The reaction was concentrated and the residue was
purified by flash chromatography (EtOAc:hex, 7:3 to 1:0) to afford
4-((R)-2-methyl-1-thioureidopropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzam-
ide as a white solid. LC-MS: (FA) ES+352.
Step 2:
(R)--N-hydroxy-4-(2-methyl-1-(4-(3-phenylisoxazol-5-yl)thiazol-2-y-
lamino)propyl)benzamide
[0778] A mixture of
4-((R)-2-methyl-1-thioureidopropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzam-
ide (0.0252 g, 0.0717 mmol) and 5-(bromoacetyl)-3-phenylisoxazole
(0.0191 g, 0.0717 mmol) in 1,4-dioxane (0.50 mL) was heated at
40.degree. C. for 1 h. The solution was diluted with DCM (0.50 mL)
and hydrochloric acid (0.20 mL, 0.80 mmol, 4.00 M of in
1,4-dioxane) was added. The reaction was stirred at rt for 3 h. The
mixture was evaporated to dryness, the residue dissolved in DMSO
and the solution purified on prep-HPLC to give
(R)--N-hydroxy-4-(2-methyl-1-(4-(3-phenylisoxazol-5-yl)thiazol-2-ylamino)-
propyl)benzamide as a white solid (0.0173 g, 56%). LC-MS: (FA)
ES+435. .sup.1H NMR (dmso-d.sub.6, 400 MHz) .delta. 11.13 (s, 1H),
9.00 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 7.90 (m, 2H), 7.70 (d, J=8.3
Hz, 2H), 7.51 (dd, J=5.1, 1.9 Hz, 3H), 7.44 (d, J=8.3 Hz, 2H), 7.26
(s, 1H), 7.09 (s, 1H), 4.48 (t, J=8.1 Hz, 1H), 2.10 (m, 1H), 1.00
(d, J=6.6 Hz, 3H), 0.78 (d, J=6.7 Hz, 3H).
Example 221
(R)--N-hydroxy-4-(2-methyl-1-(4-(trifluoromethyl)
thiazol-2-ylamino)propyl)benzamide Compound I-529
[0779] The title compound was prepared in an analogous fashion to
that described in Example 3 starting from appropriate starting
materials. LC-MS: (FA) ES+360. .sup.1H NMR (dmso-d.sub.6, 400 MHz)
.delta. 11.13 (s, 1H), 9.03 (s, 1H), 8.64 (d, J=8.5 Hz, 1H), 7.69
(d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.27 (d, J=0.9 Hz, 1H),
4.39 (t, J=8.0 Hz, 1H), 2.00 (m, 1H), 0.95 (d, J=6.7 Hz, 3H), 0.76
(d, J=6.7 Hz, 3H).
II. Biological Data
Example 222
HDAC6 Enzyme Assay
[0780] To measure the inhibition of HDAC6 activity, purified human
HDAC6 (BPS Bioscience; Cat. No. 5006) is incubated with substrate
Ac-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No.
I-1925) for 1 hour at 30.degree. C. in the presence of test
compounds or vehicle DMSO control. The reaction is stopped with the
HDAC inhibitor trichostatin A (Sigma; Cat. No. T8552) and the
amount of Arg-Gly-Lys-AMC generated is quantitated by digestion
with trypsin (Sigma; Cat. No. T1426) and subsequent measurement of
the amount of AMC released using a fluorescent plate reader
(Pherastar; BMG Technologies) set at Ex 340 nm and Em 460 nm.
Concentration response curves are generated by calculating the
fluorescence increase in test compound-treated samples relative to
DMSO-treated controls, and enzyme inhibition (IC.sub.50) values are
determined from those curves.
Example 223
Nuclear Extract HDAC Assay
[0781] As a screen against Class I HDAC enzymes, HeLa nuclear
extract (BIOMOL; Cat. No. KI-140) is incubated with
Ac-Arg-Gly-Lys(Ac)-AMC peptide (Bachem Biosciences; Cat. No.
1-1925) in the presence of test compounds or vehicle DMSO control.
The Hela nuclear extract is enriched for Class I enzymes HDAC1, -2
and -3. The reaction is stopped with the HDAC inhibitor
Trichostatin A (Sigma; Cat. No. T8552) and the amount of
Arg-Gly-Lys-AMC generated is quantitated by digestion with trypsin
(Sigma; Cat. No. T1426) and subsequent measurement of the amount of
AMC released using a fluorescent plate reader (Pherastar; BMG
Technologies) set at Ex 340 nm and Em 460 nm. Concentration
response curves are generated by calculating the fluorescence
increase in test compound-treated samples relative to DMSO-treated
controls, and enzyme inhibition (IC.sub.50) values are determined
from those curves.
Example 224
Western Blot and Immunofluorescence Assays
[0782] Cellular potency and selectivity of compounds are determined
using a published assay (Haggarty et al., Proc. Natl. Acad. Sci.
USA 2003, 100 (8): 4389-4394) using Hela cells (ATCC cat#
CCL-2.TM.) which are maintained in MEM medium (Invitrogen)
supplemented with 10% FBS; or multiple myeloma cells RPMI-8226
(ATCC cat# CCL-155.TM.) which are maintained in RPMI 1640 medium
(Invitrogen) supplemented with 10% FBS. Briefly, cells are treated
with inhibitors for 6 or 24 h and either lysed for Western
blotting, or fixed for immunofluorescence analyses. HDAC6 potency
is determined by measuring K40 hyperacetylation of alpha-tubulin
with an acetylation selective monoclonal antibody (Sigma cat#
T7451) in IC50 experiments. Selectivity against Class I HDAC
activity is determined similarly using an antibody that recognizes
hyperacetylation of histone H4 (Upstate cat# 06-866) in the Western
blotting assay or nuclear acetylation (Abram cat# ab21623) in the
immunofluorescence assay.
Example 225
In Vivo Tumor Efficacy Model
[0783] Female NCr-Nude mice (age 6-8 weeks, Charles River Labs) are
aseptically injected into the subcutaneous space in the right
dorsal flank with 1.0-5.0.times.10.sup.6 cells (SKOV-3, HCT-116,
BxPC3) in 100 .mu.L of a 1:1 ratio of serum-free culture media
(Sigma Aldrich) and BD Matrigel.TM. (BD Biosciences) using a 1 mL
263/8 gauge needle (Becton Dickinson Ref#309625). Alternatively,
some xenograft models require the use of more immunocompromised
strains of mice such as CB-17 SCID (Charles River Labs) or NOD-SCID
(Jackson Laboratory). Furthermore, some xenograft models require
serial passaging of tumor fragments in which small fragments of
tumor tissue (approximately 1 mm.sup.3) are implanted
subcutaneously in the right dorsal flank of anesthetized (3-5%
isoflourane/oxygen mixture) NCr-Nude, CB-17 SCID or NOD-SCID mice
(age 5-8 weeks, Charles River Labs or Jackson Laboratory) via a
13-ga trocar needle (Popper & Sons 7927). Tumor volume is
monitored twice weekly with Vernier calipers. The mean tumor volume
is calculated using the formula V=W.sup.2.times.L/2. When the mean
tumor volume is approximately 200 mm.sup.3, the animals are
randomized into treatment groups of ten animals each. Drug
treatment typically includes the test compound as a single agent,
and may include combinations of the test compound and other
anticancer agents. Dosing and schedules are determined for each
experiment based on previous results obtained from
pharmacokinetic/pharmacodynamic and maximum tolerated dose studies.
The control group will receive vehicle without any drug. Typically,
test compound (100-200 .mu.L) is administered via intravenous
(27-ga needle), oral (20-ga gavage needle) or subcutaneous (27-ga
needle) routes at various doses and schedules. Tumor size and body
weight are measured twice a week and the study is terminated when
the control tumors reach approximately 2000 mm.sup.3, and/or if
tumor volume exceeds 10% of the animal body weight or if the body
weight loss exceeds 20%.
[0784] The differences in tumor growth trends over time between
pairs of treatment groups are assessed using linear mixed effects
regression models. These models account for the fact that each
animal is measured at multiple time points. A separate model is fit
for each comparison, and the areas under the curve (AUC) for each
treatment group are calculated using the predicted values from the
model. The percent decrease in AUC (dAUC) relative to the reference
group is then calculated. A statistically significant P value
suggests that the trends over time for the two treatment groups are
different.
[0785] The tumor measurements observed on a date pre-specified by
the researcher (typically the last day of treatment) are analyzed
to assess tumor growth inhibition. For this analysis, a T/C ratio
is calculated for each animal by dividing the tumor measurement for
the given animal by the mean tumor measurement across all control
animals. The T/C ratios across a treatment group are compared to
the T/C ratios of the control group using a two-tailed Welch's
t-test. To adjust for multiplicity, a False Discovery Rate (FDR) is
calculated for each comparison using the approach described by
Benjamini and Hochberg, J. R. Stat. Soc. B 1995, 57:289-300.
[0786] As detailed above, compounds of the invention inhibit HDAC6.
In certain embodiments, compounds of the invention inhibit HDAC6
with an IC50 value of less than 100 nM including compounds: I-3,
I-4, I-5, I-6, I-7, I-8, I-11, I-12, I-15, I-18, I-19, I-22, I-25,
I-26, I-30, I-31, I-32, I-35, I-37, I-38, I-44, I-45, I-53, I-55,
I-58, I-59, I-62, I-63, I-65, I-68, I-69, I-71, I-73, I-74, I-79,
I-85, I-88, I-89, I-92, I-94, I-96, I-98, I-99, I-102, I-103,
I-106, I-107, I-109, I-110, I-112, I-115, I-116, I-120, I-122,
I-124, I-125, I-127, I-128, I-129, I-130, I-132, I-134, I-135,
I-136, I-138, I-140, I-141, I-143, I-145, I-146, I-147, I-148,
I-150, I-154, I-160, I-163, I-164, I-172, I-175, I-184, I-185,
I-186, I-187, I-190, I-191, I-194, I-207, I-208, I-209, I-210,
I-213, I-214, I-222, I-223, I-224, I-225, I-228, I-229, I-230,
I-233, I-236, I-237, I-242, I-243, I-245, I-247, I-253, I-261,
I-264, I-269, I-274, I-275, I-278, I-281, I-282, I-286, I-287,
I-288, I-293, I-295, I-296, I-297, I-299, I-304, I-306, I-307,
I-308, I-317, I-319, I-321, I-327, I-328, I-329, I-332, I-334,
I-341, I-346, I-348, I-349, I-350, I-354, I-356, I-357, I-358,
I-359, I-360, I-365, I-367, I-371, I-374, I-375, I-378, I-381,
I-383, I-384, I-385, I-387, I-389, I-397, I-399, I-400, I-512,
I-513, I-514, I-515, I-516, I-518, I-519, I-521, I-522, I-523,
I-524, I-525, I-526, I-527, I-528, I-529.
[0787] In certain embodiments, compounds of the invention inhibit
HDAC6 with an IC50 value of greater than 100 nM and less than 500
nM including compounds: I-1, I-2, I-10, I-16, I-17, I-20, I-21,
I-23, I-40, I-42, I-43, I-46, I-47, I-48, I-66, I-67, I-76, I-77,
I-78, I-84, I-86, I-87, I-97, I-105, I-113, I-114, I-117, I-121,
I-123, I-126, I-133, I-142, I-156, I-158, I-173, I-174, I-176,
I-178, I-182, I-192, I-193, I-196, I-201, I-202, I-203, I-206,
I-215, I-219, I-220, I-226, I-227, I-232, I-239, I-240, I-249,
I-252, I-255, I-258, I-260, I-262, I-266, I-267, I-270, I-277,
I-279, I-290, I-291, I-294, I-298, I-300, I-301, I-302, I-305,
I-310, I-315, I-316, I-318, I-330, I-331, I-336, I-338, I-342,
I-344, I-352, I-353, I-355, I-363, I-364, I-368, I-369, I-372,
I-376, I-377, I-380, I-382, I-388, I-395, I-401, I-480, I-485,
I-487, I-489, I-488, I-517.
[0788] In certain embodiments, compounds of the invention inhibit
HDAC6 with an IC50 value of greater than 500 nM and less than 1
.mu.M including compounds: I-9, I-13, I-28, I-29, I-41, I-52, I-75,
I-81, I-91, I-101, I-108, I-137, I-139, I-151, I-179, I-181, I-183,
I-195, I-199, I-204, I-216, I-246, I-251, I-259, I-268, I-271,
I-272, I-273, I-303, I-309, I-339, I-351, I-393, I-536.
[0789] In certain embodiments, compounds of the invention inhibit
HDAC6 with an IC50 value of greater than 1 .mu.M including
compounds: I-24, I-34, I-36, I-39, I-56, I-57, I-70, I-72, I-80,
I-83, I-93, I-100, I-104, I-111, I-144, I-149, I-155, I-157, I-159,
I-162, I-165, I-167, I-169, I-171, I-177, I-180, I-189, I-200,
I-211, I-212, I-217, I-218, I-231, I-234, I-238, I-241, I-244,
I-248, I-250, I-257, I-263, I-265, I-280, I-283, I-285, I-289,
I-292, I-311, I-312, I-313, I-314, I-320, I-322, I-323, I-324,
I-326, I-333, I-337, I-343, I-345, I-362, I-366, I-370, I-373,
I-379, I-386, I-390, I-392, I-396, I-402, I-403, I-481, I-483,
I-484, I-486, I-488, I-491, I-490.
[0790] As detailed above, compounds of the invention are selective
for HDAC6 over other Class I HDAC enzymes. In certain embodiments,
the ratio of HDAC IC50 (as obtained in the nuclear extract assay
described above) to HDAC6 C50 is less than 5 (HDAC IC50/HDAC6 C50).
In certain embodiments, the ratio of HDAC IC50 to HDAC6 C50 is
between 5 and 10. In certain embodiments, the ratio of HDAC IC50 to
HDAC6 C50 is between 10 and 100.
[0791] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments, which utilize the compounds and methods
of this invention. Therefore, it will be appreciated that the scope
of this invention is to be defined by the appended claims rather
than by the specific embodiments, which have been represented by
way of examples.
* * * * *