U.S. patent application number 14/097447 was filed with the patent office on 2014-11-06 for substituted hydroxamic acids and uses thereof.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. The applicant listed for this patent is Millennium Pharmaceuticals, Inc.. Invention is credited to Christopher Blackburn, Kenneth M. Gigstad, He Xu.
Application Number | 20140329836 14/097447 |
Document ID | / |
Family ID | 43386814 |
Filed Date | 2014-11-06 |
United States Patent
Application |
20140329836 |
Kind Code |
A1 |
Blackburn; Christopher ; et
al. |
November 6, 2014 |
SUBSTITUTED HYDROXAMIC ACIDS AND USES THEREOF
Abstract
This invention provides compounds of formula (I): ##STR00001##
wherein R.sup.1, R.sup.2, G, n, p and q 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) ; Xu; He; (Needham, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Millennium Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Millennium Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
43386814 |
Appl. No.: |
14/097447 |
Filed: |
December 5, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12803170 |
Jun 21, 2010 |
8624040 |
|
|
14097447 |
|
|
|
|
61219103 |
Jun 22, 2009 |
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Current U.S.
Class: |
514/255.05 ;
514/256; 514/269; 514/301; 514/412; 514/414; 544/319; 544/333;
544/405; 546/114; 548/453 |
Current CPC
Class: |
A61P 35/02 20180101;
A61P 35/00 20180101; A61K 31/38 20130101; C07D 495/04 20130101 |
Class at
Publication: |
514/255.05 ;
546/114; 514/301; 544/405; 544/319; 514/269; 544/333; 514/256;
548/453; 514/412; 514/414 |
International
Class: |
C07D 495/04 20060101
C07D495/04 |
Claims
1. A compound of formula (I): ##STR00428## or a pharmaceutically
acceptable salt thereof; wherein: p is 0-2; q is 1-3; provided that
the total of p and q is 1-3; G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.1-V.sub.2--R.sup.3,
-L.sub.1-R.sup.3, or -L.sub.1-V.sub.2-L.sub.2-R.sup.3; L.sub.1 and
L.sub.2 are each independently unsubstituted or substituted
C.sub.1-3 alkylene, where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--. V.sub.1 is --C(O)--, --C(S)--,
--C(O)--N(R.sup.4a)--, --C(O)--O--, or --S(O).sub.2--; V.sub.2 is
--C(O)--, --C(S)--, --N(R.sup.4a)--, --C(O)--N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--, --SO.sub.2--N(R.sup.4a)--,
--N(R.sup.4a)--SO.sub.2--, --C(O)--O--, --O--C(O)--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --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 1-4 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, halo, or unsubstituted or
substituted C.sub.1-4 aliphatic; each occurrence of R.sup.4a is
independently hydrogen, or unsubstituted or substituted C.sub.1-4
aliphatic; R.sup.1 is hydrogen, halo, --CN, C.sub.1-3 alkyl,
C.sub.1-3haloalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3 haloalkyl,
--NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
NHS(O).sub.2C.sub.1-3 alkyl; ring A is optionally further
substituted with n occurrences of R.sup.2; each occurrence of
R.sup.2 is independently halo, C.sub.1-4 aliphatic, --CN,
--OR.sup.B, --SR.sup.C, --N(R.sup.B).sub.2, --NR.sup.BC(O)R.sup.B,
--NR.sup.BC(O)N(R.sup.B).sub.2, --NR.sup.BCO.sub.2R.sup.C,
--CO.sub.2R.sup.B, --C(O)R.sup.B, --C(O)N(R.sup.B).sub.2,
--OC(O)N(R.sup.B).sub.2, --S(O).sub.2R.sup.C,
--SO.sub.2N(R.sup.B).sub.2, --S(O)R.sup.C,
--NR.sup.BSO.sub.2N(R.sup.B).sub.2, --NR.sup.BSO.sub.2R.sup.C, or a
C.sub.1-4 aliphatic substituted with R.sup.D, halo, --CN,
--OR.sup.B, --SR.sup.C, --N(R.sup.B).sub.2, --NR.sup.BC(O)R.sup.B,
--NR.sup.BC(O)N(R.sup.B).sub.2, --NR.sup.BCO.sub.2R.sup.C,
--CO.sub.2R.sup.B, --C(O)R.sup.B, --C(O)N(R.sup.B).sub.2,
--OC(O)N(R.sup.B).sub.2, --S(O).sub.2R.sup.C,
--SO.sub.2N(R.sup.B).sub.2, --S(O)R.sup.B,
--NR.sup.BSO.sub.2N(R.sup.B).sub.2, or --NR.sup.BSO.sub.2R.sup.C;
or two R.sup.2 are taken together to form a 3-6 membered
cycloaliphatic ring; each occurrence of R.sup.B is independently H
or C.sub.1-4 aliphatic; or two R.sup.B on the same nitrogen atom
taken together with the nitrogen atom form a 5-8 membered aromatic
or non-aromatic ring having in addition to the nitrogen atom 0-2
ring heteroatoms selected from N, O and S; each occurrence of
R.sup.C is independently C.sub.1-4 aliphatic; each occurrence of
R.sup.D is independently 6-10-membered aryl, or 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; and n is 0-4.
2. A compound of formula (I): ##STR00429## or a pharmaceutically
acceptable salt thereof; wherein: p is 0-2; q is 1-3; provided that
the total of p and q is 1-3; G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.1-V.sub.1--R.sup.3,
-L.sub.2-V.sub.2--R.sup.3, --V.sub.1-L.sub.1-V.sub.2--R.sup.3, or
-L.sub.1-R.sup.3; L.sub.1 is unsubstituted or substituted C.sub.1-3
alkylene chain, where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--; L.sub.2 is unsubstituted or substituted
C.sub.2-3 alkylene chain, where one carbon atom may be replaced
with --CR.sup.A.dbd.CR.sup.A--; V.sub.1 is --C(O)--, --C(S)--,
--C(O)--N(R.sup.4a)--, --C(O)--O--, or --S(O).sub.2--; V.sub.2 is
--C(O)--, --C(S)--, --N(R.sup.4a)--, --C(O)--N(R.sup.4a)--,
--N(R.sup.4a)--C(O)--, --SO.sub.2--N(R.sup.4a)--,
--N(R.sup.4a)--SO.sub.2--, --C(O)--O--, --O--C(O)--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --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 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, unsubstituted or
substituted 6-10-membered aryl, or unsubstituted or substituted
5-10-membered heteroaryl having 1-4 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; each occurrence of R.sup.4a is
independently hydrogen, or an optionally substituted C.sub.1-4
aliphatic group; R.sup.1 is hydrogen, chloro, fluoro,
--O--C.sub.1-4 alkyl, cyano, hydroxy, C.sub.1-4 alkyl, or C.sub.1-4
fluoroalkyl; ring A is optionally further substituted with n
occurrences of R.sup.2; each occurrence of R.sup.2 is independently
fluoro, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or R.sup.D; or two
R.sup.2 are taken together to form a 3-6 membered cycloaliphatic
ring; each occurrence of R.sup.D is independently 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; and n is 0-4.
3. The compound of claim 2, wherein: R.sup.1 is hydrogen or methyl;
each occurrence of R.sup.2 is independently fluoro, methyl, or
trifluoromethyl; V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a), or
--S(O).sub.2--; V.sub.2 is --N(R.sup.4a)--,
--C(O)--NR.sup.4a--N(R.sup.4a)--C(O)--, --SO.sub.2--N(R.sup.4a)--,
--N(R.sup.4a)--SO.sub.2--, --O--, or --S--; and n is 0-2.
4. The compound of claim 2, represented by formulas (II-A)-(II-F):
##STR00430##
5. The compound of claim 2, wherein: R.sup.3 when substituted is
substituted with 1-4 independent occurrences of --R.sup.5, wherein
R.sup.5 is --R.sup.5a, --R.sup.5d, -L.sub.3-R.sup.5d, or
--V.sub.3-L.sub.3-R.sup.5d; each occurrence of R.sup.5a is
independently halogen, C.sub.1-4 aliphatic, --CN, --NO.sub.2,
--N(R.sup.5).sub.2, --OR.sup.5b, --SR.sup.5b, --S(O).sub.2R.sup.5c,
--S(O)R.sup.5c--C(O)R.sup.5b, --C(O)OR.sup.5b,
--C(O)N(R.sup.5b).sub.2, --S(O).sub.2N(R.sup.5b).sub.2,
--OC(O)N(R.sup.5b).sub.2, --N(R.sup.5e)C(O)R.sup.5b,
--N(R.sup.5e)SO.sub.2R.sup.5e, --N(R.sup.5e)C(O)OR.sup.5b,
--N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2, or a C.sub.1-4 aliphatic
substituted with R.sup.5dd, halogen, --CN, --NO.sub.2,
--N(R.sup.5b).sub.2, --OR.sup.5b, --SR.sup.5c,
--S(O).sub.2R.sup.5c, --S(O)R.sup.5c--C(O)R.sup.5b,
--C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5e,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2; each occurrence of R.sup.5b
is independently hydrogen or an optionally substituted group
selected from C.sub.1-6 aliphatic, 3-10-membered cycloaliphatic,
4-10-membered heterocyclyl having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or two occurrences of
R.sup.5b on the same nitrogen atom can be taken together with the
nitrogen atom to which they are bound to form an optionally
substituted 4-7-membered heterocyclyl ring having 0-1 additional
heteroatoms selected from nitrogen, oxygen, and sulfur; each
occurrence of R.sup.5c is independently an optionally substituted
group selected from C.sub.1-6 aliphatic, 3-10-membered
cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
6-10-membered aryl, or 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; each occurrence of R.sup.5d is an optionally substituted
group selected from 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, and sulfur; each occurrence of R.sup.5dd is an optionally
substituted group selected from 6-10-membered aryl, or
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; each occurrence of
R.sup.5e is independently hydrogen or an optionally substituted
C.sub.1-6 aliphatic group; each occurrence of V.sub.3 is
independently --N(R.sup.5e), --O--, --S--, --S(O)--,
--S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R.sup.5e)--,
--S(O).sub.2N(R.sup.5e)--, --OC(O)N(R.sup.5e)--,
--N(R.sup.5e)C(O)--, --N(R.sup.5e)SO.sub.2--, --N(R.sup.5e)C(O)O--,
--N(R.sup.5e)C(O)N(R.sup.5e)--, --N(R.sup.5e)SO.sub.2N(R.sup.5e)--,
--OC(O)--, or --C(O)N(R.sup.3e)O--; and L.sub.3 is an optionally
substituted C.sub.1-3 alkylene chain, where one carbon atom may be
replaced with CR.sup.A.dbd.CR.sup.A--.
6. The compound of claim 5, wherein: G is --R.sup.3,
--C(R.sup.6)(R.sup.6')--R.sup.3, --C(O)--R.sup.3, or
--S(O).sub.2--R.sup.3; R.sup.6 is hydrogen, C.sub.1-4 aliphatic,
C.sub.3-6 cycloaliphatic, or 6-10-membered aryl; R.sup.6' is
hydrogen, C.sub.1-4 aliphatic, C.sub.3-6 cycloaliphatic, or
6-10-membered aryl; or R.sup.6 and R.sup.6' are taken together to
form a C.sub.3-6 cycloaliphatic group; R.sup.3 is --R.sup.3a; and
R.sup.3a is 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 R.sup.3a if substituted is substituted with 0-1
occurrences of --R.sup.5a, and one occurrence of --R.sup.5d.
7. The compound of claim 6, represented by formulas (II-A)-(II-C):
##STR00431## wherein: R.sup.1 is hydrogen, chloro, fluoro, methoxy,
cyano, or methyl; each occurrence of R.sup.2 is independently
fluoro, methyl, or trifluoromethyl; n is 0-2; R.sup.5a is chloro,
fluoro, C.sub.1-4 alkyl, C.sub.1-6 fluoroalkyl, --O--C.sub.1-6
alkyl, --O--C.sub.1-6 fluoroalkyl, cyano, hydroxy,
--NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl, --C(O)N(C.sub.1-6
alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl, --NHC(O)N(C.sub.1-6
alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6 alkyl; R.sup.5d if
substituted is substituted with 0-2 occurrences of --R.sup.7a; and
each occurrence of R.sup.7a is independently chloro, fluoro, bromo,
iodo, C.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, --O--C.sub.1-6 alkyl,
--O--C.sub.1-6 fluoroalkyl, cyano, hydroxy, --NHC(O)C.sub.1-6
alkyl, --NHC.sub.1-6 alkyl, --N(C.sub.1-6 alkyl).sub.2,
--C(O)NHC.sub.1-6 alkyl, --C(O)N(C.sub.1-6 alkyl).sub.2,
--NHC(O)NHC.sub.1-6 alkyl, --NHC(O)N(C.sub.1-6 alkyl).sub.2, or
--NHS(O).sub.2C.sub.1-6 alkyl.
8. The compound of claim 7, represented by formulas (II-A)-(II-B):
##STR00432##
9. The compound of claim 7, wherein: R.sup.1 is hydrogen or methyl;
and n is 0.
10. The compound of claim 7, wherein: R.sup.5d is thienyl,
pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl,
pyrimidinyl, or benzothienyl.
11. The compound of claim 5, wherein: G is
--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--NH--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--S(O).sub.2--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--[C(R.sup.6)(R.sup.6')].sub.z--V.sub.2a--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.y--V.sub.2a--R.sup.3,
--C(R.sup.6)(R.sup.6')--V.sub.2a'--R.sup.3, or
--C(O)--C(R.sup.6)(R.sup.6')--V.sub.2a--R.sup.3; R.sup.6 is
hydrogen, C.sub.1-4 aliphatic, C.sub.3-6 cycloaliphatic, or
6-10-membered aryl; R.sup.6' is hydrogen, C.sub.1-4 aliphatic,
C.sub.3-6 cycloaliphatic, or 6-10-membered aryl; or R.sup.6 and
R.sup.6' are taken together to form a C.sub.3-6 cycloaliphatic
group; V.sub.2a is --C(O)--, --O--, --S--, --N(R.sup.4a)--, or
--C(O)N(R.sup.4a)--; V.sub.2a' is --O--, --S--, or --N(R.sup.4a)--;
R.sup.3 is --R.sup.3d; R.sup.3d is unsubstituted or substituted
C.sub.1-6 aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 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 R.sup.3d if substituted is
substituted with 0-2 independent occurrences of --R.sup.5a; z is
0-3; and y is 1-2.
12. The compound of claim 11, represented by formula (II-A)-(II-C):
##STR00433## wherein: R.sup.1 is hydrogen, chloro, fluoro, methoxy,
cyano, or methyl; each occurrence of R.sup.2 is independently
fluoro, methyl, or trifluoromethyl; n is 0-2; R.sup.3d is
unsubstituted or substituted with 0-1 occurrences of --R.sup.5a;
and R.sup.5a is chloro, fluoro, C.sub.1-4 alkyl, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl,
cyano, hydroxy, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl.
13. The compound of claim 12, represented by formulas
(II-A)-(II-B): ##STR00434##
14. The compound of claim 12, wherein: R.sup.1 is hydrogen or
methyl; and n is 0.
15. The compound of claim 12, wherein: R.sup.5a is chloro, fluoro,
methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy,
cyano, or hydroxy.
16. The compound of claim 12, wherein: G is
--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3, or
--S(O).sub.2--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3.
17. A pharmaceutical composition comprising a compound of claim 1
or 2, and a pharmaceutically acceptable carrier.
18. 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 or 2.
19. The method of claim 18, wherein the proliferative disorder is
breast cancer, lung cancer, ovarian cancer, multiple myeloma, acute
myeloid leukemia, or acute lymphoblastic leukemia.
20. A method for inhibiting HDAC6 activity in a patient comprising
administering a pharmaceutical composition comprising an amount of
a compound of claim 1 or 2 effective to inhibit HDAC6 activity in
the patient.
Description
PRIORITY CLAIM
[0001] The present application is a continuation of U.S. patent
application Ser. No. 12/803,170, filed Jun. 21, 2010 (pending),
which claims the benefit under 35 U.S.C. .sctn.119(e) of U.S.
Provisional Patent Application No. 61/219,103, filed Jun. 22, 2009,
which are hereby incorporated by reference in their 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 to as histone or lysine
deacetylases (HDACs or KDACs) as they catalyze the removal of
acetyl groups from the .epsilon.-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. Mol. 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. ScL 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. E-pub Feb. 4, 2010) 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 inhibitors
of HDAC6, and are useful for the treatment of proliferative
diseases or disorders. In one aspect the compounds of the invention
are represented by formula (I):
##STR00002##
[0009] or a pharmaceutically acceptable salt thereof; wherein:
[0010] p is 0-2;
[0011] q is 1-3;
[0012] provided that the total of p and q is 1-3;
[0013] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.1-V.sub.2--R.sup.3,
-L.sub.1-R.sup.3, or -L.sub.1-V.sub.2-L.sub.2-R.sup.3;
[0014] L.sub.1 and L.sub.2 are each independently unsubstituted or
substituted C.sub.1-3 alkylene, where one carbon atom may be
replaced with --CR.sup.A.dbd.CR.sup.A--.
[0015] V.sub.1 is --C(O)--, --C(S)--, --C(O)--N(R.sup.4a)--,
--C(O)--O--, or --S(O).sub.2--;
[0016] V.sub.2 is --C(O)--, --C(S)--, --N(R.sup.4a)--,
--C(O)--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--,
--SO.sub.2--N(R.sup.4a)--, --N(R.sup.4a)--SO.sub.2--, --C(O)--O--,
--O--C(O)--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--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)--;
[0017] 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 1-4
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;
[0018] each occurrence of R.sup.A is independently hydrogen, halo,
or unsubstituted or substituted C.sub.1-4 aliphatic;
[0019] each occurrence of R.sup.4a is independently hydrogen, or
unsubstituted or substituted C.sub.1-4 aliphatic;
[0020] R.sup.1 is hydrogen, halo, --CN, C.sub.1-3 alkyl,
C.sub.1-3haloalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3 haloalkyl,
--NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
NHS(O).sub.2C.sub.1-3 alkyl;
[0021] ring A is optionally further substituted with n occurrences
of R.sup.2;
[0022] each occurrence of R.sup.2 is independently halo, C.sub.1-4
aliphatic, --CN, --OR.sup.B, --SR.sup.C, --N(R.sup.B).sub.2,
--NR.sup.BC(O)R.sup.B, --NR.sup.BC(O)N(R.sup.B).sub.2,
--NR.sup.BCO.sub.2R.sup.C, --CO.sub.2R.sup.B, --C(O)R.sup.B,
--C(O)N(R.sup.B).sub.2, --OC(O)N(R.sup.B).sub.2,
--S(O).sub.2R.sup.C, --SO.sub.2N(R.sup.B).sub.2, --S(O)R.sup.C,
--NR.sup.BSO.sub.2N(R.sup.B).sub.2, --NR.sup.BSO.sub.2R.sup.C, or a
C.sub.1-4 aliphatic substituted with R.sup.D, halo, --CN,
--OR.sup.B, --SR.sup.C, --N(R.sup.B).sub.2, --NR.sup.BC(O)R.sup.B,
--NR.sup.BC(O)N(R.sup.B).sub.2, --NR.sup.BCO.sub.2R.sup.C,
--CO.sub.2R.sup.B, --C(O)R.sup.B, --C(O)N(R.sup.B).sub.2,
--OC(O)N(R.sup.B).sub.2, --S(O).sub.2R.sup.C,
--SO.sub.2N(R.sup.B).sub.2, --S(O)R.sup.B,
--NR.sup.BSO.sub.2N(R.sup.B).sub.2, or --NR.sup.BSO.sub.2R.sup.C;
or two R.sup.2 are taken together to form a 3-6 membered
cycloaliphatic ring;
[0023] each occurrence of R.sup.B is independently H or C.sub.1-4
aliphatic; or two R.sup.B on the same nitrogen atom taken together
with the nitrogen atom form a 5-8 membered aromatic or non-aromatic
ring having in addition to the nitrogen atom 0-2 ring heteroatoms
selected from N, O and S;
[0024] each occurrence of R.sup.C is independently C.sub.1-4
aliphatic;
[0025] each occurrence of R.sup.D is independently 6-10-membered
aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and
[0026] n is 0-4.
[0027] In another aspect the compounds of the invention are
represented by formula (I):
##STR00003##
[0028] or a pharmaceutically acceptable salt thereof;
[0029] wherein:
[0030] p is 0-2;
[0031] q is 1-3;
[0032] provided that the total of p and q is 1-3;
[0033] G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.1-V.sub.1--R.sup.3,
-L.sub.2-V.sub.2--R.sup.3, --V.sub.1-L.sub.1-V.sub.2--R.sup.3, or
-L.sub.1-R.sup.3;
[0034] L.sub.1 is unsubstituted or substituted C.sub.1-3 alkylene,
where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--;
[0035] L.sub.2 is unsubstituted or substituted C.sub.2-3 alkylene,
where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--;
[0036] V.sub.1 is --C(O)--, --C(S)--, --C(O)--N(R.sup.4a)--,
--C(O)--O--, or --S(O).sub.2--;
[0037] V.sub.2 is --C(O)--, --C(S)--, --N(R.sup.4a)--,
--C(O)--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--,
--SO.sub.2--N(R.sup.4a)--, --N(R.sup.4a)--SO.sub.2--, --C(O)--O--,
--O--C(O)--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--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)--,
[0038] 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 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur;
[0039] each occurrence of R.sup.A is independently hydrogen,
fluoro, or unsubstituted or substituted C.sub.1-4 aliphatic;
[0040] each occurrence of R.sup.4a is independently hydrogen, or
unsubstituted or substituted C.sub.1-4 aliphatic;
[0041] R.sup.1 is hydrogen, chloro, fluoro, --O--C.sub.1-4 alkyl,
cyano, hydroxy, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl;
[0042] ring A is optionally further substituted with n occurrences
of R.sup.2;
[0043] each occurrence of R.sup.2 is independently fluoro,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or R.sup.D; or two R.sup.2
are taken together to form a 3-6 membered cycloaliphatic ring;
[0044] each occurrence of R.sup.D is independently 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; and
[0045] n is 0-4.
2. Compounds and Definitions
[0046] 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.
[0047] 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.
[0048] 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., 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.
[0049] 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.
[0050] 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.
[0051] As used herein, the term "aromatic" includes aryl and
heteroaryl groups as described generally below and herein.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] 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.
[0060] 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)).
[0061] 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 C6-14aromatic hydrocarbon moiety
comprising one to three aromatic rings. Preferably, the aryl group
is a C6-10aryl 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".
[0062] 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 C6-10 arylC1-6alkyl, including, without limitation,
benzyl, phenethyl, and naphthylmethyl.
[0063] 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. In some embodiments,
the heteroaryl group has 5-10 ring atoms, 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.
[0064] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used
interchangeably and refer to a stable 4-10 membered ring,
preferably a 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).
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.+).sub.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.+,
--C(R.sup.o).dbd.N--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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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,
##STR00004##
for example where a phenyl group is substituted with two
occurrences of OR 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:
##STR00005##
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.
[0075] 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.
[0076] 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.
[0077] 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%.
[0078] 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.
[0079] 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%.
[0080] 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).
[0081] 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.
[0082] 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.
[0083] 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
[0084] In some embodiments, for compounds of formula (I):
[0085] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a), or
--S(O).sub.2--;
[0086] V.sub.2 is --N(R.sup.4a)--, --C(O)--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--, or --S--; and
[0087] n is 0-2.
[0088] In some embodiments, for compounds of formula (I):
[0089] R.sup.1 is hydrogen or methyl;
[0090] each occurrence of R.sup.2 is independently fluoro, methyl,
or trifluoromethyl;
[0091] V.sub.1 is --C(O)--, --C(O)--N(R.sup.4a), or
--S(O).sub.2--;
[0092] V.sub.2 is --C(O)--, --N(R.sup.4a)--, --C(O)--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--, or --S--; and
[0093] n is 0-2.
[0094] In some embodiments, for compounds of formula (I):
[0095] 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 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, unsubstituted or substituted 6-10-membered aryl, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; wherein R.sup.3 when substituted is substituted with 1-4
independent occurrences of --R.sup.5, wherein R.sup.5 is
--R.sup.5a, --R.sup.5d, -T.sub.1-R.sup.5d, or
--V.sub.3-L.sub.3-R.sup.5d;
[0096] each occurrence of R.sup.5a is independently halogen,
C.sub.1-4 aliphatic, --CN, --NO.sub.2, --N(R.sup.5b).sub.2,
--OR.sup.5b, --SR.sup.5c, --S(O).sub.2R.sup.5c,
--S(O)R.sup.5c--C(O)R.sup.5b, --C(O)OR.sup.5b,
--C(O)N(R.sup.5b).sub.2, --S(O).sub.2N(R.sup.5b).sub.2,
--OC(O)N(R.sup.5b).sub.2, --N(R.sup.5e)C(O)R.sup.5b,
--N(R.sup.5e)SO.sub.2R.sup.5c, --N(R.sup.5e)C(O)OR.sup.5b,
--N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2, or a C.sub.1-4 aliphatic
substituted with R.sup.5dd, halogen, --CN, --NO.sub.2,
--N(R.sup.5b).sub.2, --OR.sup.5b, --SR.sup.5c,
--S(O).sub.2R.sup.5c, --S(O)R.sup.5c--C(O)R.sup.5b,
--C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5c,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2;
[0097] each occurrence of R.sup.5b is independently hydrogen or an
optionally substituted group selected from C.sub.1-6 aliphatic,
3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-4
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur; or two occurrences of R.sup.5b on the same nitrogen atom
can be taken together with the nitrogen atom to which they are
bound to form an optionally substituted 4-7-membered heterocyclyl
ring having 0-1 additional heteroatoms selected from nitrogen,
oxygen, and sulfur;
[0098] each occurrence of R.sup.5c is independently an optionally
substituted group selected from C.sub.1-6 aliphatic, 3-10-membered
cycloaliphatic, 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur,
6-10-membered aryl, or 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur;
[0099] each occurrence of R.sup.5d is an optionally substituted
group selected from 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, and sulfur;
[0100] each occurrence of R.sup.5dd is an optionally substituted
group selected from 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, and sulfur;
[0101] each occurrence of R.sup.5e is independently hydrogen or an
optionally substituted C.sub.1-6 aliphatic group;
[0102] each occurrence of V.sub.3 is independently --N(R.sup.5e),
--O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--,
--C(O)N(R.sup.5e)--, --S(O).sub.2N(R.sup.5e)--,
--OC(O)N(R.sup.5e)--, --N(R.sup.5e)C(O)--, --N(R.sup.5e)SO.sub.2--,
--N(R.sup.5e)C(O)O--, --N(R.sup.5e)C(O)N(R.sup.5e)--,
--N(R.sup.5e)SO.sub.2N(R.sup.5e)--, --OC(O)--, or
--C(O)N(R.sup.5e)O--; and
[0103] L.sub.3 is an optionally substituted C.sub.1-3 alkylene
chain, where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--.
[0104] In some embodiments, compounds of formula (I) are
represented by formulas (II-A)-(II-F):
##STR00006##
[0105] wherein R.sup.1, R.sup.2, G, and n have the values described
herein.
[0106] In some embodiments, compounds of formula (I) are
represented by formulas (II-A), (II-B), or (II-C). In some
embodiments, compounds of formula (I) are represented by formulas
(II-A), or (II-B). In certain embodiments, compounds of formula (I)
are represented by formula (II-A). In certain embodiments,
compounds of formula (I) are represented by formula (II-B).
[0107] In some embodiments, compounds of formula (I) are
represented by formulas (III-A)-(III-F):
##STR00007##
[0108] wherein G, and R.sup.1 have the values described herein.
[0109] In some embodiments, compounds of formula (I) are
represented by formulas (III-A), (III-B), or (III-C). In some
embodiments, compounds of formula (I) are represented by formulas
(III-A), or (III-B). In certain embodiments, compounds of formula
(I) are represented by formula (III-A). In certain embodiments,
compounds of formula (I) are represented by formula (III-B).
[0110] In some embodiments, compounds of formula (I) are
represented by formulas (IV-A)-(IV-C):
##STR00008##
[0111] wherein G has the values described herein.
[0112] In certain embodiments, compounds of formula (I) are
represented by formula (IV-A). In certain embodiments, compounds of
formula (I) are represented by formula (IV-B). In certain
embodiments, compounds of formula (I) are represented by formula
(IV-C).
[0113] In some embodiments, compounds of formula (I) are
represented by formulas (V-A)-(V-G):
##STR00009##
[0114] wherein R.sup.3, R.sup.6, R.sup.6', p, q, and V.sub.2a have
the values described herein.
[0115] In certain embodiments, compounds of formula (I) are
represented by formula (V-A). In certain embodiments, compounds of
formula (I) are represented by formula (V-B). In certain
embodiments, compounds of formula (I) are represented by formula
(V-C). In certain embodiments, compounds of formula (I) are
represented by formula (V-D). In certain embodiments, compounds of
formula (I) are represented by formula (V-E). In certain
embodiments, compounds of formula (I) are represented by formula
(V-F). In certain embodiments, compounds of formula (I) are
represented by formula (V-G).
[0116] The values described below are with respect to any of
formulas (I), (II-A)-(II-G), (III-A)-(III-G), (IV-A)-(IV-B) and
(V-A)-(V-G).
[0117] In some embodiments:
[0118] p is 0-2;
[0119] q is 1-3;
[0120] provided that the total of p and q is 1-3.
[0121] In certain embodiments, p is 1 and q is 1. In certain
embodiments, p is 0 and q is 1. In certain embodiments, p is 0 and
q is 2. In certain embodiments, p is 1 and q is 2. In certain
embodiments, p is 2 and q is 1. In certain embodiments, p is 0 and
q is 3.
[0122] In some embodiments, R.sup.1 is hydrogen, halo, --CN,
C.sub.1-3 alkyl, C.sub.1-3haloalkyl, --O--C.sub.1-3 alkyl,
--O--C.sub.1-3 haloalkyl, --NHC(O)C.sub.1-3 alkyl,
--NHC(O)NHC.sub.1-3 alkyl, or NHS(O).sub.2C.sub.1-3 alkyl. In some
embodiments, R.sup.1 is hydrogen, chloro, fluoro, --O--C.sub.1-4
alkyl, cyano, hydroxy, C.sub.1-4 alkyl, or C.sub.1-4 fluoroalkyl.
In certain embodiments, R.sup.1 is hydrogen, chloro, fluoro,
methoxy, ethoxy, propoxy, cyano, trifluoromethyl, methyl, ethyl,
n-propyl, isopropyl, or tert-butyl. In certain embodiments, R.sup.1
is hydrogen, chloro, fluoro, methoxy, cyano, or methyl. In certain
embodiments, R.sup.1 is hydrogen or methyl. In certain embodiments,
R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is methyl.
[0123] In some embodiments, ring A is optionally further
substituted with n occurrences of R.sup.2 wherein, each occurrence
of R.sup.2 is independently halo, C.sub.1-4 aliphatic, --CN,
--OR.sup.B, --SR.sup.C, --N(R.sup.B).sub.2, --NR.sup.BC(O)R.sup.B,
--NR.sup.BC(O)N(R.sup.B).sub.2, --NR.sup.BCO.sub.2R.sup.C,
--CO.sub.2R.sup.B, --C(O)R.sup.B, --C(O)N(R.sup.B).sub.2,
--OC(O)N(R.sup.B).sub.2, --S(O).sub.2R.sup.C,
--SO.sub.2N(R.sup.B).sub.2, --S(O)R.sup.C,
--NR.sup.BSO.sub.2N(R.sup.B).sub.2, --NR.sup.BSO.sub.2R.sup.C, or a
C.sub.1-4 aliphatic substituted with R.sup.D, halo, --CN,
--OR.sup.B, --SR.sup.C, --N(R.sup.B).sub.2, --NR.sup.BC(O)R.sup.B,
--NR.sup.BC(O)N(R.sup.B).sub.2, --NR.sup.BCO.sub.2R.sup.C,
--CO.sub.2R.sup.B, --C(O)R.sup.B, --C(O)N(R.sup.B).sub.2,
--OC(O)N(R.sup.B).sub.2, --S(O).sub.2R.sup.C,
--SO.sub.2N(R.sup.B).sub.2, --S(O)R.sup.C,
--NR.sup.BSO.sub.2N(R.sup.B).sub.2, or --NR.sup.BSO.sub.2R.sup.C.
In some embodiments, two R.sup.2 are, taken together to form a 3-6
membered cyclaliphatic ring. In some embodiments, each occurrence
of R.sup.2 is independently halo, C.sub.1-3 alkyl,
C.sub.1-3haloalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3 haloalkyl,
--NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl,
NHS(O).sub.2C.sub.1-3 alkyl; or C.sub.1-4aliphatic optionally
substituted with R.sup.D. In certain embodiments, each occurrence
of R.sup.2 is independently chloro, fluoro, methoxy, ethoxy,
propoxy, trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, or
tert-butyl.
[0124] In some embodiments, each occurrence of R.sup.2 is
independently fluoro, C.sub.1-4 alkyl, C.sub.1-4haloalkyl,
--NHC(O)C.sub.1-6 alkyl, --NHC(O)NHC.sub.1-6 alkyl,
NHS(O).sub.2C.sub.1-6 alkyl, or R.sup.D, wherein R.sup.D has the
values contained herein. In some embodiments, each occurrence of
R.sup.2 is independently fluoro, C.sub.1-4 alkyl,
C.sub.1-4haloalkyl, or R.sup.D, wherein R.sup.D has the values
contained herein. In some embodiments each occurrence of R.sup.2 is
independently fluoro, C.sub.1-4 alkyl, C.sub.1-4haloalkyl, or
phenyl, wherein the phenyl ring is unsubstituted or substituted
with one occurrence of fluoro, chloro, or methyl. In some
embodiments, each occurrence of R.sup.2 is independently fluoro,
methyl, or trifluoromethyl. In certain embodiments, each occurrence
of R.sup.2 is independently methyl or fluoro. In certain
embodiments, R.sup.2 is methyl.
[0125] In some embodiments, each occurrence of R.sup.B is
independently H or C.sub.1-4 aliphatic; or two R.sup.B on the same
nitrogen atom taken together with the nitrogen atom form a 5-8
membered aromatic or non-aromatic ring having in addition to the
nitrogen atom 0-2 ring heteroatoms selected from N, O and S.
[0126] In some embodiments, each occurrence of R.sup.C is
independently C.sub.1-4 aliphatic.
[0127] In some embodiments, each occurrence of R.sup.D is
independently 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, and sulfur.
[0128] In some embodiments, n is 0-4. In some embodiments, n is
0-2. In certain embodiments, n is 2. In certain embodiments, n is
1. In certain embodiments, n is 0.
[0129] In some embodiments, G is --R.sup.3, --V.sub.1--R.sup.3,
--V.sub.1-L.sub.1-R.sup.3, -L.sub.1-V.sub.2--R.sup.3,
-L.sub.1-R.sup.3, or -L.sub.1-V.sub.2-L.sub.2-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 --R.sup.3,
--V.sub.1--R.sup.3, --V.sub.1-L.sub.1-R.sup.3,
-L.sub.1-V.sub.1--R.sup.3, -L.sub.2-V.sub.2--R.sup.3,
--V.sub.1-L.sub.1-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 --R.sup.3,
--V.sub.1--R.sup.3, or -L.sub.1-R.sup.3, wherein L.sub.1, V.sub.1,
and R.sup.3 have the values described herein.
[0130] In certain embodiments, G is --R.sup.3,
--C(R.sup.6)(R.sup.6')--R.sup.3, --C(O)--R.sup.3, or
--S(O).sub.2--R.sup.3, wherein R.sup.3, R.sup.6, and R.sup.6' have
the values described herein. In certain embodiments, G is
--R.sup.3, wherein R.sup.3 has the values described herein. In
certain embodiments, G is --(CH.sub.2).sub.t--R.sup.3, or
--(CH.sub.2).sub.t--X.sub.3--R.sup.3, wherein R.sup.3, X.sub.3 and
t have the values described herein. In certain embodiments, G is
--C(O)--R.sup.3, --C(R.sup.6)(R.sup.6')--R.sup.3,
--C(O)--C(R.sup.6)(R.sup.6')--R.sup.3, --S(O).sub.2--R.sup.3,
--S(O).sub.2--C(R.sup.6)(R.sup.6')--R.sup.3, or
--C(O)--NH--R.sup.3, wherein R.sup.3, R.sup.6 and R.sup.6' have the
values described herein. In certain embodiments, G is
--CH.sub.2--CH.dbd.CH--R.sup.3, wherein R.sup.3 has the values
described herein.
[0131] In certain embodiments, G is
--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--N(R.sup.4a)--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--S(O).sub.2--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--[C(R.sup.6)(R.sup.6')].sub.y--V.sub.2a--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.y--V.sub.2a--R.sup.3,
--C(R.sup.6)(R.sup.6')--V.sub.2a'--R.sup.3, or
--C(O)--C(R.sup.6)(R.sup.6')--V.sub.2a'--R.sup.3, wherein R.sup.6,
R.sup.6', V.sub.2a, V.sub.2a', R.sup.3, R.sup.4a, z, and y have the
values described herein. In certain embodiments, G is
--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--NH--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--S(O).sub.2--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--[C(R.sup.6)(R.sup.6')].sub.y--V.sub.2a--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.y--V.sub.2a--R.sup.3,
--C(R.sup.6)(R.sup.6')--V.sub.2a'--R.sup.3, or
--C(O)--C(R.sup.6)(R.sup.6')--V.sub.2a'--R.sup.3, wherein R.sup.6,
R.sup.6', V.sub.2a, V.sub.2a', R.sup.3, z, and y have the values
described herein. In certain embodiments, G is
--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3, or
--S(O).sub.2--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3, wherein
R.sup.6, R.sup.6', R.sup.3, and z have the values described
herein.
[0132] In some embodiments, L.sub.1 and L.sub.2 are each
independently unsubstituted or substituted C.sub.1-3 alkylene,
where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--. In some embodiments, L.sub.1 and L.sub.2
are each independently --CH.sub.2--, CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, or --CH.dbd.CH--. In some
embodiments, L.sub.1 and L.sub.2 are each independently
--CH.sub.2--. In some embodiments, L.sub.1 and L.sub.2 are each
independently a C.sub.1-3 alkylene chain, where one carbon atom may
be replaced with --CR.sup.A.dbd.CR.sup.A--, optionally substituted
with 0-2 occurrences of R.sup.8a wherein each occurrence of
R.sup.8a is independently halogen, C.sub.1-4 aliphatic, --CN,
--NO.sub.2, --N(R.sup.5b).sub.2, --OR.sup.5b, --SR.sup.5c,
--S(O).sub.2R.sup.5c, --S(O)R.sup.5c, --C(O)R.sup.5b,
--C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5e,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2; or a C.sub.1-4 aliphatic
substituted with halogen, --CN, --NO.sub.2, --N(R.sup.5b).sub.2,
--OR.sup.5b, --SR.sup.5c, --S(O).sub.2R.sup.5c, --S(O)R.sup.5c,
--C(O)R.sup.5b, --C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5c,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2. In some embodiments,
L.sub.1 and L.sub.2 are each independently a C.sub.1-3 alkylene
chain, where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--, optionally substituted with 0-2
occurrences of R.sup.8a wherein each occurrence of R.sup.8a is
independently fluoro or C.sub.1-4 aliphatic.
[0133] In some embodiments, L.sub.2 is unsubstituted or substituted
C.sub.2-3 alkylene, where one carbon atom may be replaced with
--CR.sup.A.dbd.CR.sup.A--. In some embodiments, L.sub.2 is
--CH.sub.2CH.sub.2-- or --CH.sub.2CH.sub.2CH.sub.2--. In certain
embodiments, L.sub.2 is --CH.sub.2CH.sub.2--. In certain
embodiments, L.sub.2 is --CH.sub.2CH.sub.2CH.sub.2--.
[0134] In some embodiments, V.sub.1 is --C(O)--, --C(S)--,
--C(O)--N(R.sup.4a)--, --C(O)--O--, or --S(O).sub.2--, wherein
R.sup.4a has 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
certain embodiments, V.sub.1 is --C(O)--, or S(O).sub.2--.
[0135] In some embodiments, V.sub.2 is --C(O)--, --C(S)--,
--N(R.sup.4a)--, --C(O)--N(R.sup.4a)--, --N(R.sup.4a)--C(O)--,
--SO.sub.2--N(R.sup.4a)--, --N(R.sup.4a)--SO.sub.2--, --C(O)--O--,
--O--C(O)--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--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 --C(O)--,
--N(R.sup.4a)--, --C(O)--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--, or
--S--. In certain embodiments, V.sub.2 is --C(O)--,
--N(R.sup.4a)--, --O--, or --S--. In certain embodiments, V.sub.2
is --NH--, or --O--.
[0136] In some embodiments, each occurrence of R.sup.A is
independently hydrogen, halo, or an unsubstituted or substituted
C.sub.1-4aliphatic. In some embodiments, each occurrence of R.sup.A
is independently hydrogen, fluoro, or unsubstituted or substituted
C.sub.1-4 aliphatic. In certain embodiments, each occurrence of
R.sup.A is independently hydrogen, fluoro or methyl. In certain
embodiments, each occurrence of R.sup.A is hydrogen.
[0137] In some embodiments, each occurrence of R.sup.4a is
independently hydrogen, or unsubstituted or substituted
C.sub.1-4aliphatic. In some other embodiments, each occurrence of
R.sup.4a is independently hydrogen.
[0138] In some embodiments, G is represented by formulas
(VI-a-i)-(VI-n-v):
##STR00010## ##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024##
[0139] 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 1-4 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.
[0140] In certain embodiments, R.sup.3 is methyl, ethyl, propyl,
isopropyl, tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl,
propenyl, pentenyl, hexenyl, 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, tetrahydronaphthyridinyl,
tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrothienyl, indanyl, tetrahydroindazolyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,
quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,
benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or
adamantyl, wherein each of the foregoing groups are unsubstituted
or substituted.
[0141] 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 1-4 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 if R.sup.3 is substituted, it
is substituted with 1-4 independent occurrences of --R.sup.5,
wherein R.sup.5 is --R.sup.5a, --R.sup.5d, -L.sub.3-R.sup.5d,
--V.sub.3-L.sub.3-R.sup.5d; and R.sup.5a, R.sup.5d, L.sub.3, and
V.sub.3 have the values described herein.
[0142] In certain embodiments, R.sup.3 is methyl, ethyl, propyl,
isopropyl, tert-butyl, butyl, iso-butyl, pentyl, hexyl, butenyl,
propenyl, pentenyl, hexenyl, 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, tetrahydronaphthyridinyl,
tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, pteridinyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrothienyl, indanyl, tetrahydroindazolyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, thiomorpholinyl,
quinuclidinyl, phenanthridinyl, tetrahydronaphthyl, indolinyl,
benzodioxanyl, chromanyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or
adamantyl, wherein each of the foregoing groups are unsubstituted
or substituted with 1-4 independent occurrences of --R.sup.5,
wherein R.sup.5 is --R.sup.5a, --R.sup.5d, -L.sub.3-R.sup.5d, or
--V.sub.3-L.sub.3-R.sup.5d; and R.sup.5a, R.sup.5d, L.sub.3, and
V.sub.3 have the values described herein.
[0143] In some embodiments, R.sup.3 is --R.sup.3a, wherein R.sup.3a
is 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 R.sup.3a if substituted is substituted with 0-1
occurrences of --R.sup.5a, and one occurrence of --R.sup.5d,
wherein R.sup.5a and R.sup.5d have the values described herein.
[0144] In some embodiments, R.sup.3a is furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl,
benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,
benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,
2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl,
isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, or pteridinyl, wherein each of the foregoing groups
is unsubstituted or substituted with 0-1 occurrences of --R.sup.5a,
and 1 occurrence of --R.sup.5d, wherein R.sup.5a and R.sup.5d have
the values described herein. In certain embodiments, R.sup.3a is
thienyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl,
4H-furo[3,2-b]pyrrolyl, or phenyl, wherein each of the foregoing
groups is unsubstituted or substituted with 0-1 occurrences of
--R.sup.5a, and 1 occurrence of --R.sup.5d, wherein R.sup.5a and
R.sup.5d have the values described herein.
[0145] In some embodiments, R.sup.3 is --R.sup.3b, wherein R.sup.3b
is 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 R.sup.3b if substituted is substituted with 0-2
independent occurrences of --R.sup.5a, wherein R.sup.5a has the
values described herein. In some embodiments, R.sup.3b is furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,
phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl,
benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,
benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,
2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl,
isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, or pteridinyl, wherein each of the foregoing groups
is unsubstituted or substituted with 0-1 occurrence of --R.sup.5a,
wherein R.sup.5a has the values described herein.
[0146] In some embodiments, R.sup.3 is --R.sup.3c, wherein R.sup.3c
is unsubstituted or substituted 6-10-membered aryl, unsubstituted
or substituted 4-10-membered heterocyclyl having 1-4 heteroatoms
independently selected from nitrogen, oxygen, and sulfur, or
unsubstituted or substituted 5-10-membered heteroaryl having 1-5
heteroatoms independently selected from nitrogen, oxygen, and
sulfur, wherein R.sup.3c if substituted is substituted with 0-2
independent occurrences of --R.sup.5a, wherein R.sup.5a has the
values described herein. In some embodiments, R.sup.3c is furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,
phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl,
benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,
benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,
2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl,
isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,
thiamorpholinyl, quinuclidinyl, indanyl, phenanthridinyl,
tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl, or
chromanyl, wherein each of the foregoing groups is unsubstituted or
substituted with 0-2 independent occurrences of --R.sup.5a, wherein
R.sup.5a has the values described herein. In certain embodiments,
R.sup.3c is phenyl, naphthyl or indolyl, wherein each of the
foregoing groups is unsubstituted or substituted with 0-1
independent occurrences of --R.sup.5a, wherein R.sup.5a has the
values described herein.
[0147] In some embodiments, R.sup.3 is --R.sup.3d, wherein R.sup.3d
is unsubstituted or substituted C.sub.1-6 aliphatic, unsubstituted
or substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 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
R.sup.3d if substituted is substituted with 0-2 independent
occurrences of --R.sup.5a, wherein R.sup.5a has the values
described herein.
[0148] In some embodiments, R.sup.3d is unsubstituted or
substituted C.sub.1-6 aliphatic, wherein R.sup.3d if substituted is
substituted with 0-1 independent occurrences of --R.sup.5a, wherein
R.sup.5a has the values described herein. In certain embodiments,
R.sup.3d is methyl, ethyl, propyl, isopropyl, tert-butyl, butyl,
iso-butyl, pentyl, hexyl, butenyl, propenyl, pentenyl, or
hexenyl.
[0149] In some embodiments, R.sup.3d is unsubstituted or
substituted 3-10-membered cycloaliphatic, unsubstituted or
substituted 4-10-membered heterocyclyl having 1-4 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
R.sup.3d if substituted is substituted with 0-2 independent
occurrences of --R.sup.5a, wherein R.sup.5a has the values
described herein. In certain embodiments, R.sup.3d is furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,
phenyl, naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl,
benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,
benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,
2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl,
isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, pteridinyl, tetrahydrofuranyl, tetrahydrothienyl,
pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,
decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl,
dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,
thiamorpholinyl, quinuclidinyl, indanyl, phenanthridinyl,
tetrahydronaphthyl, indolinyl, benzodioxanyl, benzodioxolyl,
chromanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, bicycloheptanyl, bicyclooctanyl, or
adamantyl, wherein each of the foregoing groups is unsubstituted or
substituted with 0-2 independent occurrences of --R.sup.5a, wherein
R.sup.5a has the values described herein.
[0150] In certain embodiments, R.sup.3d is pyrrolyl, thiazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
phenyl, pyridyl, indolyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,
2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzofuranyl, purinyl, quinolyl, cinnolinyl, naphthyl,
piperidinyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclohexenyl, or adamantyl, wherein each of the foregoing groups is
unsubstituted or substituted with 0-1 independent occurrences of
--R.sup.5a, wherein R.sup.5a has the values described herein.
[0151] In some embodiments, each occurrence of R.sup.5a is
independently halogen, C.sub.1-4 aliphatic, --CN, --NO.sub.2,
--N(R.sup.5b).sub.2, --OR.sup.5b, --SR.sup.5c,
--S(O).sub.2R.sup.5c, --S(O)R.sup.5c, --C(O)R.sup.5b,
--C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5c,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2, or a C.sub.1-4 aliphatic
substituted with R.sup.5dd, halogen, --CN, --NO.sub.2,
--N(R.sup.5b).sub.2, --OR.sup.5b, --SR.sup.5c,
--S(O).sub.2R.sup.5c, --S(O)R.sup.5c, --C(O)R.sup.5b,
--C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5c,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2, wherein R.sup.5b, R.sup.5c,
R.sup.5dd, and R.sup.5e have the values described herein.
[0152] In some embodiments, R.sup.5a is halo, C.sub.1-3alkyl,
C.sub.1-3haloalkyl, --O--C.sub.1-3alkyl, --O--C.sub.1-3 haloalkyl,
--C(O)C.sub.1-3 alkyl, --NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3
alkyl, or NHS(O).sub.2C.sub.1-3 alkyl. In some embodiments,
R.sup.5a is --CH.sub.2--R.sup.5dd, wherein R.sup.5dd is phenyl,
pyridyl, naphthyl or thienyl optionally substituted with 0-1
occurrence of R.sup.7a, wherein R.sup.7a has the values described
herein. In certain embodiments, R.sup.5a is chloro, fluoro,
methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl,
trifluoromethoxy, methyl, ethyl, propyl, butyl, isopropyl,
--NHC(O)CH.sub.3, --NHC(O)CH.sub.2CH.sub.3, --NHC(O)NHCH.sub.3, or
--NHS(O).sub.2CH.sub.3.
[0153] In some embodiments, each occurrence of R.sup.5a is
independently chloro, fluoro, C.sub.1-4 alkyl, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl,
cyano, hydroxy, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6 alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6 alkyl.
In certain embodiments, each occurrence of R.sup.5a is chloro,
fluoro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy,
trifluoromethoxy, cyano, or hydroxy.
[0154] In some embodiments, each occurrence of R.sup.5b is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6 aliphatic, 3-10-membered cycloaliphatic,
4-10-membered heterocyclyl having 1-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur; or two occurrences of
R.sup.5b on the same nitrogen atom can be taken together with the
nitrogen atom to which they are bound to form an optionally
substituted 4-7-membered heterocyclyl ring having 0-1 additional
heteroatoms selected from nitrogen, oxygen, and sulfur.
[0155] In some embodiments, each occurrence of R.sup.5c is
independently an optionally substituted group selected from
C.sub.1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, and sulfur.
[0156] In some embodiments, each occurrence of R.sup.5e is
independently hydrogen or an optionally substituted C.sub.1-6
aliphatic group. In some other embodiments, each occurrence of
R.sup.5e is independently hydrogen.
[0157] In some embodiments, the variable R.sup.6 is hydrogen,
C.sub.1-4 aliphatic, C.sub.3-6 cycloaliphatic, or 6-10-membered
aryl. In some embodiments, R.sup.6 is hydrogen, C.sub.1-4
aliphatic, or C.sub.3-6 cycloaliphatic. In certain embodiments,
R.sup.6 is hydrogen, methyl, ethyl, phenyl, cyclopropyl,
cyclobutyl, or cyclopentyl. In certain embodiments, R.sup.6 is
hydrogen or methyl. In certain embodiments, R.sup.6 is
hydrogen.
[0158] In some embodiments, the variable R.sup.6' is hydrogen,
C.sub.1-4 aliphatic, C.sub.3-6 cycloaliphatic, or 6-10-membered
aryl. In some embodiments, R.sup.6' is hydrogen, C.sub.1-4
aliphatic, or C.sub.3-6 cycloaliphatic. In certain embodiments,
R.sup.6' is hydrogen, methyl, ethyl, phenyl, cyclopropyl,
cyclobutyl, or cyclopentyl. In certain embodiments, R.sup.6' is
hydrogen or methyl. In certain embodiments, R.sup.6' is
hydrogen.
[0159] In some embodiments, R.sup.6 and R.sup.6' are taken together
to form a C.sub.3-6 cycloaliphatic group. In certain embodiments,
R.sup.6 and R.sup.6' are taken together to form a cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl group.
[0160] In some embodiments, V.sub.2a is --C(O)--, --O--, --S--,
--N(R.sup.4a)--, or --C(O)N(R.sup.4a)--. In certain embodiments,
V.sub.2a is --NH-- or --O--.
[0161] In some embodiments, V.sub.2a' is --O--, --S--, or
--N(R.sup.4a)--, wherein R.sup.4a has the values described herein.
In certain embodiments, V.sub.2a' is --O-- or --NH--.
[0162] In some embodiments, t is 2-3. In certain embodiments, t is
2. In certain embodiments, t is 3.
[0163] In some embodiments, u is 2-3. In certain embodiments, u is
2. In certain embodiments, u is 3.
[0164] In some embodiments, z is 0-3. In some embodiments, z is
0-1. In certain embodiments, z is 0. In certain embodiments, z is
1. In certain embodiments, z is 2. In certain embodiments, z is
3.
[0165] In some embodiments, y is 2-3. In certain embodiments, y is
2. In certain embodiments, y is 3.
[0166] In some embodiments, V.sub.3 is --N(R.sup.5e), --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R.sup.5e)--,
--S(O).sub.2N(R.sup.5e)--, --OC(O)N(R.sup.5e)--,
--N(R.sup.5e)C(O)--, --N(R.sup.5e)SO.sub.2--, --N(R.sup.5e)C(O)O--,
--N(R.sup.5e)C(O)N(R.sup.5e)--, --N(R.sup.5e)SO.sub.2N(R.sup.5e)--,
--OC(O)--, or --C(O)N(R.sup.5e)O--. In some embodiments, V.sub.3 is
--N(R.sup.5e), --O--, --S--, --C(O)--, --C(O)O--,
--C(O)N(R.sup.5e)--, or --S(O).sub.2N(R.sup.5e). In some
embodiments, V.sub.3 is --NH--, --O--, --S--, or --C(O)--.
[0167] In some embodiments, L.sub.3 is an optionally substituted
C.sub.1-3 alkylene chain, where one carbon atom may be replaced
with --CR.sup.A.dbd.CR.sup.A--. In some embodiments, L.sub.3 is
--CH.sub.2--, CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CH.dbd.CH--. In some embodiments, L.sub.3 is --CH.sub.2--. In
some embodiments, L.sub.3 is a C.sub.1-3 alkylene chain, where one
carbon atom may be replaced with --CR.sup.A.dbd.CR.sup.A--,
optionally substituted with 0-2 occurrences of R.sup.8a, wherein
each occurrence of R.sup.8a is independently halogen, C.sub.1-4
aliphatic, --CN, --NO.sub.2, --N(R.sup.5b).sub.2, --OR.sup.5b,
--SR.sup.5c, --S(O).sub.2R.sup.5c, --S(O)R.sup.5c, --C(O)R.sup.5b,
--C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5c,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2, or a C.sub.1-4 aliphatic
substituted with halogen, --CN, --NO.sub.2, --N(R.sup.5b).sub.2,
--OR.sup.5b, --SR.sup.5c, --S(O).sub.2R.sup.5c, --S(O)R.sup.5c,
--C(O)R.sup.5b, --C(O)OR.sup.5b, --C(O)N(R.sup.5b).sub.2,
--S(O).sub.2N(R.sup.5b).sub.2, --OC(O)N(R.sup.5b).sub.2,
--N(R.sup.5e)C(O)R.sup.5b, --N(R.sup.5e)SO.sub.2R.sup.5c,
--N(R.sup.5e)C(O)OR.sup.5b, --N(R.sup.5e)C(O)N(R.sup.5b).sub.2, or
--N(R.sup.5e)SO.sub.2N(R.sup.5b).sub.2; or two occurrences of
R.sup.5b on the same nitrogen atom taken together with the nitrogen
atom to which they are bound, form an optionally substituted
4-7-membered heterocyclyl ring having 0-1 additional heteroatoms
selected from nitrogen, oxygen, and sulfur; wherein R.sup.5b,
R.sup.5c and R.sup.5e have the values described herein. In some
embodiments, L.sub.3 is a C.sub.1-3 alkylene chain, where one
carbon atom may be replaced with --CR.sup.A.dbd.CR.sup.A--,
optionally substituted with 0-2 occurrences of R.sup.8a, wherein
each occurrence of R.sup.8a is independently fluoro or C.sub.1-4
aliphatic.
[0168] In some embodiments, R.sup.5d is an optionally substituted
group selected from 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, and sulfur. In some embodiments, R.sup.5d is an optionally
substituted group selected from 6-10-membered aryl, or
5-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, and sulfur, wherein R.sup.5d if
substituted, is substituted with 0-2 independent occurrences of
--R.sup.7a, wherein R.sup.7a has the values described herein. In
some embodiments, R.sup.5d is an optionally substituted group
selected from 6-10-membered aryl, or 5-10-membered heteroaryl
having 1-5 heteroatoms independently selected from nitrogen,
oxygen, and sulfur, wherein R.sup.5d if substituted is substituted
with 0-1 independent occurrences of R.sup.7a, wherein R.sup.7a has
the values described herein.
[0169] In some embodiments, R.sup.5d is furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,
naphthyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, indolizinyl, indolyl, isoindolyl, indazolyl,
benzimidazolyl, benzthiazolyl, benzothienyl, benzofuranyl,
benzoxazolyl, benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]thiadiazolyl, benzo[d]oxazol-2(3H)-one,
2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzofuranyl, 4H-furo[3,2-b]pyrrolyl, purinyl, quinolyl,
isoquinolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, or pteridinyl, wherein each of the foregoing groups
is unsubstituted or substituted with 0-2 independent occurrences of
--R.sup.7a, wherein R.sup.7a has the values described herein. In
certain embodiments, R.sup.5d is thienyl, pyrrolyl, pyrazolyl,
isoxazolyl, triazolyl, phenyl, pyridyl, or benzothienyl, wherein
each of the foregoing groups is unsubstituted or substituted with
0-1 occurrences of --R.sup.7a, wherein R.sup.7a has the values
described herein. In certain embodiments, R.sup.5d is thienyl,
pyrrolyl, pyrazolyl, isoxazolyl, triazolyl, phenyl, pyridyl,
pyrimidinyl, or benzothienyl, wherein each of the foregoing groups
is unsubstituted or substituted with 0-1 occurrences of --R.sup.7a,
wherein R.sup.7a has the values described herein.
[0170] In some embodiments, R.sup.5dd is R.sup.5d. In some other
embodiments, R.sup.5dd is phenyl, pyridyl, naphthyl or thienyl,
wherein each of the foregoing groups is unsubstituted or
substituted with 0-1 occurrence of R.sup.7a, wherein R.sup.7a has
the values described herein.
[0171] In some embodiments, R.sup.7a is halo, C.sub.1-3 alkyl,
C.sub.1-3haloalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3haloalkyl,
--NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
NHS(O).sub.2C.sub.1-3 alkyl. In some embodiments, R.sup.7a is
chloro, fluoro, methoxy, ethoxy, propoxy, isopropoxy,
trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl,
isopropyl, --NHC(O)CH.sub.3, --NHC(O)CH.sub.2CH.sub.3,
--NHC(O)NHCH.sub.3, or --NHS(O).sub.2CH.sub.3. In some embodiments,
each occurrence of R.sup.7a is chloro, fluoro, bromo, iodo,
C.sub.1-6 alkyl, C.sub.1-6fluoroalkyl, --O--C.sub.1-6 alkyl,
--O--C.sub.1-6fluoroalkyl, cyano, hydroxy, --NHC(O)C.sub.1-6 alkyl,
--NHC.sub.1-6 alkyl, --N(C.sub.1-6alkyl).sub.2, --C(O)NHC.sub.1-6
alkyl, --C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6 alkyl.
In certain embodiments, R.sup.7a is chloro, fluoro, methyl, ethyl,
trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, cyano, or
hydroxy.
[0172] In certain embodiments:
[0173] G is --R.sup.3, --C(R.sup.6)(R.sup.6')--R.sup.3,
--C(O)--R.sup.3, or --S(O).sub.2--R.sup.3;
[0174] R.sup.6 is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl;
[0175] R.sup.6' is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl; or
[0176] R.sup.6 and R.sup.6' are taken together to form a C.sub.3-6
cycloaliphatic group;
[0177] R.sup.3 is --R.sup.3a; and
[0178] R.sup.3a is 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 R.sup.3a if substituted is substituted with 0-1
occurrences of --R.sup.5a, and one occurrence of --R.sup.5d;
[0179] wherein R.sup.5a and R.sup.5d have the values described
herein.
[0180] In certain embodiments:
[0181] G is --R.sup.3;
[0182] R.sup.3 is --R.sup.3b; and
[0183] R.sup.3b is 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 R.sup.3b if substituted is substituted with 0-2
independent occurrences of --R.sup.5a;
[0184] wherein R.sup.5a has the values described herein.
[0185] In certain embodiments:
[0186] G is --(CH.sub.2).sub.t--R.sup.3 or
--(CH.sub.2).sub.t--V.sub.2a--R.sup.3;
[0187] R.sup.3 is --R.sup.3c;
[0188] R.sup.3c is unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, unsubstituted or substituted
6-10-membered aryl, or unsubstituted or substituted 5-10-membered
heteroaryl having 1-4 heteroatoms independently selected from
nitrogen, oxygen, and sulfur, wherein R.sup.3a if substituted is
substituted with 0-2 independent occurrences of --R.sup.5a;
[0189] V.sub.2a is --C(O)--, --O--, --S--, --N(R.sup.4a)--, or
--C(O)N(R.sup.4a)--; and
[0190] t is 2-3;
[0191] wherein R.sup.5a and R.sup.4a have the values described
herein.
[0192] In certain embodiments:
[0193] G is --C(R.sup.6)(R.sup.6')--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.u--R.sup.3,
--S(O).sub.2--[C(R.sup.6)(R.sup.6')].sub.u--R.sup.3, or
--C(O)--NH--[(R.sup.6)(R.sup.6')].sub.u--R.sup.3;
[0194] R.sup.6 is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl;
[0195] R.sup.6' is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl; or
[0196] R.sup.6 and R.sup.6' are taken together to form a C.sub.3-6
cycloaliphatic group;
[0197] R.sup.3 is --R.sup.3d;
[0198] R.sup.3d is unsubstituted or substituted C.sub.1-6
aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 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 R.sup.3d if substituted is
substituted with 0-2 independent occurrences of --R.sup.5a; and
[0199] u is 1-2;
[0200] wherein R.sup.5a has the values described herein.
[0201] In certain embodiments, the compound of formula (I) is
represented by formulas (II-A)-(II-B):
##STR00025##
wherein:
[0202] each occurrence of R.sup.1 is independently chloro, fluoro,
methoxy, ethoxy, propoxy, cyano, trifluoromethyl, methyl, ethyl,
n-propyl, isopropyl, or tert-butyl;
[0203] each occurrence of R.sup.2 is independently chloro, fluoro,
methoxy, ethoxy, propoxy, trifluoromethyl, methyl, ethyl, n-propyl,
isopropyl, or tert-butyl;
[0204] n is 0-2;
[0205] R.sup.5a is halo, C.sub.1-3 alkyl, C.sub.1-3haloalkyl,
--O--C.sub.1-3 alkyl, --O--C.sub.1-3 haloalkyl, --NHC(O)C.sub.1-3
alkyl, --NHC(O)NHC.sub.1-3 alkyl, or NHS(O).sub.2C.sub.1-3
alkyl;
[0206] R.sup.5d is optionally substituted with 0-2 occurrences of
--R.sup.7a; and
[0207] each occurrence of R.sup.7a is independently halo, C.sub.1-3
alkyl, C.sub.1-3haloalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3
haloalkyl, --NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
NHS(O).sub.2C.sub.1-3 alkyl;
[0208] wherein G has the values described herein.
[0209] In certain embodiments, the compound of formula (I) is
represented by formula (II-C):
##STR00026##
[0210] wherein:
[0211] each occurrence of R.sup.1 is independently chloro, fluoro,
methoxy, ethoxy, propoxy, cyano, trifluoromethyl, methyl, ethyl,
n-propyl, isopropyl, or tert-butyl;
[0212] each occurrence of R.sup.2 is independently chloro, fluoro,
methoxy, ethoxy, propoxy, trifluoromethyl, methyl, ethyl, n-propyl,
isopropyl, or tert-butyl;
[0213] n is 0-2;
[0214] R.sup.3d is optionally substituted with 0-1 occurrences of
--R.sup.5a; and
[0215] each occurrence of R.sup.5a is independently halo, C.sub.1-3
alkyl, C.sub.1-3haloalkyl, --O--C.sub.1-3 alkyl, --O--C.sub.1-3
haloalkyl, --NHC(O)C.sub.1-3 alkyl, --NHC(O)NHC.sub.1-3 alkyl, or
NHS(O).sub.2C.sub.1-3 alkyl;
[0216] wherein G has the values described herein.
[0217] In certain embodiments, the compound of formula (I) is
represented by formula (II-A)-(II-C):
##STR00027##
[0218] wherein:
[0219] G is --R.sup.3, --C(R.sup.6)(R.sup.6')--R.sup.3,
--C(O)--R.sup.3, or --S(O).sub.2--R.sup.3;
[0220] R.sup.6 is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl;
[0221] R.sup.6' is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl; or
[0222] R.sup.6 and R.sup.6' are taken together to form a C.sub.3-6
cycloaliphatic group;
[0223] R.sup.3 is --R.sup.3a; and
[0224] R.sup.3a is 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 R.sup.3a if substituted is substituted with 0-1
occurrences of --R.sup.5a, and one occurrence of --R.sup.5d;
[0225] wherein R.sup.1, R.sup.2, R.sup.5a, R.sup.5d, and n have the
values described herein.
[0226] In certain embodiments, described directly above:
[0227] R.sup.1 is hydrogen, chloro, fluoro, methoxy, cyano, or
methyl;
[0228] each occurrence of R.sup.2 is independently fluoro, methyl,
or trifluoromethyl;
[0229] n is 0-2;
[0230] R.sup.5a is chloro, fluoro, C.sub.1-4 alkyl, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl,
cyano, hydroxy, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6 alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl;
[0231] R.sup.5d if substituted is substituted with 0-2 occurrences
of --R.sup.7a; and
[0232] each occurrence of R.sup.7a is independently chloro, fluoro,
bromo, iodo, C.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, --O--C.sub.1-6
alkyl, --O--C.sub.1-6 fluoroalkyl, cyano, hydroxy,
--NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl, --C(O)N(C.sub.1-6
alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl, --NHC(O)N(C.sub.1-6
alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6 alkyl;
[0233] wherein R.sup.5d has the values described herein.
[0234] In certain embodiments, the compound of formula (I) is
represented by formula (II-A)-(II-C):
##STR00028##
[0235] wherein:
[0236] G is --[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--C(O)--NH--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--S(O).sub.2--[C(R.sup.6)(R.sup.6')].sub.z--R.sup.3,
--[C(R.sup.6)(R.sup.6')].sub.y--V.sub.2a--R.sup.3,
--C(O)--[C(R.sup.6)(R.sup.6')].sub.y--V.sub.2a--R.sup.3,
--C(R.sup.6)(R.sup.6')--V.sub.2a'--R.sup.3, or
--C(O)--C(R.sup.6)(R.sup.6')--V.sub.2a'--R.sup.3,
[0237] R.sup.6 is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl;
[0238] R.sup.6' is hydrogen, C.sub.1-4 aliphatic, C.sub.3-6
cycloaliphatic, or 6-10-membered aryl; or
[0239] R.sup.6 and R.sup.6' are taken together to form a C.sub.3-6
cycloaliphatic group;
[0240] V.sub.2a is --C(O)--, --O--, --S--, --N(R.sup.4a)--, or
--C(O)N(R.sup.4a)--;
[0241] V.sub.2a' is --O--, --S--, or --N(R.sup.4a)--;
[0242] R.sup.3 is --R.sup.3d;
[0243] R.sup.3d is unsubstituted or substituted C.sub.1-6
aliphatic, unsubstituted or substituted 3-10-membered
cycloaliphatic, unsubstituted or substituted 4-10-membered
heterocyclyl having 1-4 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 R.sup.3d if substituted is
substituted with 0-2 independent occurrences of --R.sup.5a;
[0244] z is 0-3; and
[0245] y is 1-2;
[0246] wherein R.sup.1, R.sup.2, R.sup.5a, and n have the values
described herein.
[0247] In certain embodiments, described directly above:
[0248] R.sup.1 is hydrogen, chloro, fluoro, methoxy, cyano, or
methyl;
[0249] each occurrence of R.sup.2 is independently fluoro, methyl,
or trifluoromethyl;
[0250] n is 0-2;
[0251] R.sup.3d is unsubstituted or substituted with 0-1
occurrences of --R.sup.5a; and
[0252] R.sup.5a is chloro, fluoro, C.sub.1-4 alkyl, C.sub.1-6
fluoroalkyl, --O--C.sub.1-6 alkyl, --O--C.sub.1-6 fluoroalkyl,
cyano, hydroxy, --NHC(O)C.sub.1-6 alkyl, --NHC.sub.1-6 alkyl,
--N(C.sub.1-6 alkyl).sub.2, --C(O)NHC.sub.1-6 alkyl,
--C(O)N(C.sub.1-6 alkyl).sub.2, --NHC(O)NHC.sub.1-6 alkyl,
--NHC(O)N(C.sub.1-6 alkyl).sub.2, or --NHS(O).sub.2C.sub.1-6
alkyl;
[0253] wherein R.sup.5d has the values described herein.
[0254] Representative examples of compounds of formula (I) are
shown in Table 1:
TABLE-US-00001 ##STR00029## 1 ##STR00030## 2 ##STR00031## 3
##STR00032## 4 ##STR00033## 5 ##STR00034## 6 ##STR00035## 7
##STR00036## 8 ##STR00037## 9 ##STR00038## 10 ##STR00039## 11
##STR00040## 12 ##STR00041## 13 ##STR00042## 14 ##STR00043## 15
##STR00044## 16 ##STR00045## 17 ##STR00046## 18 ##STR00047## 19
##STR00048## 20 ##STR00049## 21 ##STR00050## 22 ##STR00051## 23
##STR00052## 24 ##STR00053## 25 ##STR00054## 26 ##STR00055## 27
##STR00056## 28 ##STR00057## 29 ##STR00058## 30 ##STR00059## 31
##STR00060## 32 ##STR00061## 33 ##STR00062## 34 ##STR00063## 35
##STR00064## 36 ##STR00065## 37 ##STR00066## 38 ##STR00067## 39
##STR00068## 40 ##STR00069## 41 ##STR00070## 42 ##STR00071## 43
##STR00072## 44 ##STR00073## 45 ##STR00074## 46 ##STR00075## 47
##STR00076## 48 ##STR00077## 49 ##STR00078## 50 ##STR00079## 51
##STR00080## 52 ##STR00081## 53 ##STR00082## 54 ##STR00083## 55
##STR00084## 56 ##STR00085## 57 ##STR00086## 58 ##STR00087## 59
##STR00088## 60 ##STR00089## 61 ##STR00090## 62 ##STR00091## 63
##STR00092## 64 ##STR00093## 65 ##STR00094## 66 ##STR00095## 67
##STR00096## 68 ##STR00097## 69 ##STR00098## 70 ##STR00099## 71
##STR00100## 72 ##STR00101## 73 ##STR00102## 74 ##STR00103## 75
##STR00104## 76 ##STR00105## 77 ##STR00106## 78 ##STR00107## 79
##STR00108## 80 ##STR00109## 81 ##STR00110## 82 ##STR00111## 83
##STR00112## 84 ##STR00113## 85 ##STR00114## 86 ##STR00115## 87
##STR00116## 88 ##STR00117## 89 ##STR00118## 90 ##STR00119## 91
##STR00120## 92 ##STR00121## 93 ##STR00122## 94 ##STR00123## 95
##STR00124## 96 ##STR00125## 97 ##STR00126## 98 ##STR00127## 99
##STR00128## 100 ##STR00129## 101 ##STR00130## 102 ##STR00131## 103
##STR00132## 104 ##STR00133## 105 ##STR00134## 106 ##STR00135## 107
##STR00136## 108 ##STR00137## 109 ##STR00138## 110 ##STR00139## 111
##STR00140## 112 ##STR00141## 113 ##STR00142## 114 ##STR00143## 115
##STR00144## 116 ##STR00145## 117 ##STR00146## 118 ##STR00147## 119
##STR00148## 120 ##STR00149## 121 ##STR00150## 122 ##STR00151## 123
##STR00152## 124 ##STR00153## 125
##STR00154## 126 ##STR00155## 127 ##STR00156## 128 ##STR00157## 129
##STR00158## 130 ##STR00159## 131 ##STR00160## 132 ##STR00161## 133
##STR00162## 134 ##STR00163## 135 ##STR00164## 136 ##STR00165## 137
##STR00166## 138 ##STR00167## 139 ##STR00168## 140 ##STR00169## 141
##STR00170## 142 ##STR00171## 143 ##STR00172## 144 ##STR00173## 145
##STR00174## 146 ##STR00175## 147 ##STR00176## 148 ##STR00177## 149
##STR00178## 150 ##STR00179## 151 ##STR00180## 152 ##STR00181## 153
##STR00182## 154 ##STR00183## 155 ##STR00184## 156 ##STR00185## 157
##STR00186## 158 ##STR00187## 159 ##STR00188## 160 ##STR00189## 161
##STR00190## 162 ##STR00191## 163 ##STR00192## 164 ##STR00193## 165
##STR00194## 166 ##STR00195## 167 ##STR00196## 168 ##STR00197## 169
##STR00198## 170 ##STR00199## 171 ##STR00200## 172 ##STR00201## 173
##STR00202## 174 ##STR00203## 175 ##STR00204## 176 ##STR00205## 177
##STR00206## 178 ##STR00207## 179 ##STR00208## 180 ##STR00209## 181
##STR00210## 182 ##STR00211## 183 ##STR00212## 184 ##STR00213## 185
##STR00214## 186 ##STR00215## 187 ##STR00216## 188 ##STR00217## 189
##STR00218## 190 ##STR00219## 191 ##STR00220## 192 ##STR00221## 193
##STR00222## 194 ##STR00223## 195 ##STR00224## 196 ##STR00225## 197
##STR00226## 198 ##STR00227## 199 ##STR00228## 200 ##STR00229## 201
##STR00230## 202 ##STR00231## 203 ##STR00232## 204 ##STR00233## 205
##STR00234## 206 ##STR00235## 207 ##STR00236## 208 ##STR00237## 209
##STR00238## 210 ##STR00239## 211 ##STR00240## 212 ##STR00241## 213
##STR00242## 214 ##STR00243## 215 ##STR00244## 216 ##STR00245## 217
##STR00246## 218 ##STR00247## 219 ##STR00248## 220 ##STR00249## 221
##STR00250## 222 ##STR00251## 223 ##STR00252## 224 ##STR00253## 225
##STR00254## 226 ##STR00255## 227 ##STR00256## 228 ##STR00257## 229
##STR00258## 230 ##STR00259## 231 ##STR00260## 232 ##STR00261## 233
##STR00262## 234 ##STR00263## 235 ##STR00264## 236 ##STR00265## 237
##STR00266## 238 ##STR00267## 239 ##STR00268## 240
[0255] The compounds in Table 1 above may also be identified by the
following chemical names:
TABLE-US-00002 1
6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyri-
dine-2-carboxamide 2
6-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
-2-carboxamide 3
N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 4
6-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydrothi-
eno[2,3-c]pyridine-2- carboxamide 5
N-hydroxy-6-(3-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine--
2-carboxamide 6
N-hydroxy-6-(2-phenoxybutanoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine--
2-carboxamide 7
6-[(5-chloro-4-methoxy-3-thienyl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrot-
hieno[2,3-c]pyridine-2- carboxamide 8
N-hydroxy-6-(4,5,6,7-tetrahydro-2H-indazol-3-ylcarbonyl)-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-2- carboxamide 9
6-(2,2-diphenylbutanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide 10
6-(dicyclohexylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-
e-2-carboxamide 11
N-hydroxy-6-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-4-
,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 12
6-[(2,4-dimethylphenoxy)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 13
6-{[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}-N-hydroxy-4,5,6,7--
tetrahydrothieno[2,3- c]pyridine-2-carboxamide 14
6-[1-adamantylcarbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide 15
N-hydroxy-6-{[1-(phenylsulfonyl)piperidin-2-yl]carbonyl}-4,5,6,7-tetrah-
ydrothieno[2,3-c]pyridine-2- carboxamide 16
N-hydroxy-6-[2-methyl-5-(piperidin-1-ylsulfonyl)-3-furoyl]-4,5,6,7-tetr-
ahydrothieno[2,3-c]pyridine-2- carboxamide 17
6-(9H-fluoren-9-ylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyri-
dine-2-carboxamide 18
6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 19
6-(butylsulfonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-c-
arboxamide 20
6-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothi-
eno[2,3-c]pyridine-2- carboxamide 21
N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothi-
eno[2,3-c]pyridine-2- carboxamide 22
6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tefra-
hydrothieno[2,3-c]pyridine-2- carboxamide 23
N-hydroxy-6-[4-(1H-pyrazol-1-yl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-2-carboxamide 24
N-hydroxy-6-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-4,5,6,7-t-
etrahydrothieno[2,3- c]pyridine-2-carboxamide 25
6-(2,1,3-benzothiadiazol-4-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno-
[2,3-c]pyridine-2-carboxamide 26
5-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyri-
dine-2-carboxamide 27
N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothien-
o[3,2-c]pyridine-2-carboxamide 28
N-hydroxy-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[3,2-
-c]pyridine-2-carboxamide 29
N-hydroxy-5-[(5-methylpyrazin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[3-
,2-c]pyridine-2-carboxamide 30
N-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyri-
dine-2-carboxamide 31
5-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-
e-2-carboxamide 32
5-[4-(4,6-dimethoxypyrimidin-2-yl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine-2- carboxamide 33
5-(1-adamantylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridi-
ne-2-carboxamide 34
N-hydroxy-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothi-
eno[3,2-c]pyridine-2- carboxamide 35
5-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrahy-
drothieno[3,2-c]pyridine-2- carboxamide 36
6-[3,5-bis(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[-
2,3-c]pyridine-2-carboxamide 37
N-hydroxy-5-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c-
]pyridine-2-carboxamide 38
N-hydroxy-5-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetrah-
ydrothieno[3,2-c]pyridine-2- carboxamide 39
5-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indol-2-yl}carbonyl)-N-h-
ydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 40
N.sup.2-hydroxy-N.sup.6-(5-phenyl-2-thienyl)-4,7-dihydrothieno[2,3-c]py-
ridine-2,6(5H)-dicarboxamide 41
N-hydroxy-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-te-
trahydrothieno[2,3-c]pyridine- 2-carboxamide 42
6-(2-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carbox-
amide 43
N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-3-methyl-
-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 44
6-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,-
3-c]pyridine-2-carboxamide 45
N.sup.5-[4-chloro-3-(trifluoromethyl)phenyl]-N.sup.2-hydroxy-6,7-dihydr-
othieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 46
5-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothi-
eno[3,2-c]pyridine-2- carboxamide 47
6-[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrot-
hieno[2,3-c]pyridine-2- carboxamide 48
N-hydroxy-6-[(2-methyl-4-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-2- carboxamide 49
N-hydroxy-4-methyl-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothie-
no[2,3-c]pyridine-2- carboxamide 50
N-hydroxy-5-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-5,6-dihydr-
o-4H-thieno[2,3-c]pyrrole-2- carboxamide 51
6-(4-fluoro-3-methylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]p-
yridine-2-carboxamide 52
6-[(3,5-difluorophenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c-
]pyridine-2-carboxamide 53
N-hydroxy-5-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydroth-
ieno[3,2-c]pyridine-2- carboxamide 54
N.sup.2-hydroxy-N.sup.6-[3-(trifluoromethyl)phenyl]-4,7-dihydrothieno[2-
,3-c]pyridine-2,6(5H)-dicarboxamide 55
N.sup.2-hydroxy-N.sup.5-(3-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyrid-
ine-2,5(4H)-dicarboxamide 56
6-({3-[(2-amino-2-oxoethyl)sulfanyl]-2-thienyl}carbonyl)-N-hydroxy-4,5,-
6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 57
6-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]p-
yridine-2-carboxamide 58
6-({5-[(cyclopropylcarbonyl)amino]-1-methyl-1H-indol-2-yl}carbonyl)-N-h-
ydroxy-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide 59
N-hydroxy-6-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[-
2,3-c]pyridine-2-carboxamide 60
N.sup.5-(4-chlorobenzyl)-N.sup.2-hydroxy-6,7-dihydrothieno[3,2-c]pyridi-
ne-2,5(4H)-dicarboxamide 61
N.sup.5-[(1S)-1-(4-chlorophenyl)ethyl]-N.sup.2-hydroxy-6,7-dihydrothien-
o[3,2-c]pyridine-2,5(4H)-dicarboxamide 62
6-[(3,5-dimethylisoxazol-4-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide 63
N.sup.2-hydroxy-N.sup.6-(4-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyrid-
ine-2,6(5H)-dicarboxamide 64
6-(4-tert-butylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide 65
N-hydroxy-6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-2- carboxamide 66
5-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]car-
bonyl}-N-hydroxy-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine-2-carboxamide 67
6-(5-tert-butyl-2-methyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2-
,3-c]pyridine-2-carboxamide 68
N-hydroxy-3-methyl-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothie-
no[3,2-c]pyridine-2- carboxamide 69
6-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-t-
etrahydrothieno[2,3- c]pyridine-2-carboxamide 70
N-hydroxy-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridi-
ne-2-carboxamide 71
6-[(4'-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno-
[2,3-c]pyridine-2- carboxamide 72
6-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine-2- carboxamide 73
N-hydroxy-5-(5-pyridin-4-yl-1,3-thiazol-2-yl)-4,5,6,7-tetrahydrothieno[-
3,2-c]pyridine-2-carboxamide 74
N.sup.5-[2-fluoro-5-(trifluoromethyl)phenyl]-N.sup.2-hydroxy-6,7-dihydr-
othieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 75
N-hydroxy-6-[(2-methyl-1,3-thiazol-4-yl)acetyl]-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide 76
N.sup.6-cyclohexyl-N.sup.2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6-
(5H)-dicarboxamide 77
N-hydroxy-6-[3-(trifluoromethoxy)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c-
]pyridine-2-carboxamide 78
5-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine-2- carboxamide 79
N.sup.2-hydroxy-N.sup.6-(3-methoxybenzyl)-4,7-dihydrothieno[2,3-c]pyrid-
ine-2,6(5H)-dicarboxamide 80
N.sup.2-hydroxy-N.sup.6-(3-methylphenyl)-4,7-dihydrothieno[2,3-c]pyridi-
ne-2,6(5H)-dicarboxamide 81
N-hydroxy-6-[(6-hydroxypyridin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[-
2,3-c]pyridine-2-carboxamide 82
5-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-te-
trahydrothieno[3,2-c]pyridine- 2-carboxamide 83
5-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-
-c]pyridine-2-carboxamide 84
N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetra-
hydrothieno[2,3-c]pyridine-2- carboxamide 85
N-hydroxy-6-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2--
carboxamide 86
N.sup.6-[2-fluoro-4-(trifluoromethyl)phenyl]-N.sup.2-hydroxy-4-methyl-4-
,7-dihydrothieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 87
6-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-7-methyl-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide 88
6-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-t-
etrahydrothieno[2,3- c]pyridine-2-carboxamide 89
N-hydroxy-6-({[3-(trifluoromethyl)phenyl]sulfanyl}acetyl)-4,5,6,7-tetra-
hydrothieno[2,3-c]pyridine-2- carboxamide 90
N.sup.10-[4-chloro-3-(trifluoromethyl)phenyl]-N.sup.2-hydroxy-4,5,6,7,8-
,9-hexahydro-4,8- epiminocycloocta[b]thiophene-2,10-dicarboxamide
91
N-hydroxy-6-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide 92
10-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7,8,9-hexah-
ydro-4,8- epiminocycloocta[b]thiophene-2-carboxamide 93
N-hydroxy-6-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}-4,5,-
6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 94
N-hydroxy-6-(3-methyl-2-furoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
-2-carboxamide 95
N-hydroxy-6-(quinolin-6-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyri-
dine-2-carboxamide 96
N-hydroxy-5-({5-[3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)-4,5,6,7-
-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 97
5-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahy-
drothieno[3,2-c]pyridine-2- carboxamide 98
N-hydroxy-6-[(4-methyl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothi-
eno[2,3-c]pyridine-2- carboxamide 99
N-hydroxy-6-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyri-
dine-2-carboxamide 100
6-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine-2- carboxamide 101
N-hydroxy-5-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7--
tetrahydrothieno[3,2-c]pyridine-
2-carboxamide 102
N-hydroxy-6-({5-{3-(trifluoromethyl)phenyl]-3-thienyl}sulfonyl)4,5,6,7-
-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 103
N.sup.2-hydroxy-N.sup.6-(4-methylbenzyl)-4,7-dihydrothieno[2,3-c]pyrid-
ine-2,6(5H)-dicarboxamide 104
10-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7,8,9-hexahydro-4,8-epim-
inocycloocta[b]thiophene-2- carboxamide 105
N-hydroxy-5-[4-(trifluoromethyl)benzyl]-5,6-dihydro-4H-thieno[2,3-c]py-
rrole-2-carboxamide 106
N.sup.6-[2-fluoro-5-(trifluoromethyl)phenyl]-N.sup.2-hydroxy-4,7-dihyd-
rothieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 107
N-hydroxy-6-[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-2- carboxamide 108
6-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrah-
ydrothieno[2,3-c]pyridine-2- carboxamide 109
N.sup.2-hydroxy-N.sup.5-(4-methoxybenzyl)-6,7-dihydrothieno[3,2-c]pyri-
dine-2,5(4H)-dicarboxamide 110
6-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-N-hydroxy-4,5,6,7-tetrahydroth-
ieno[2,3-c]pyridine-2- carboxamide 111
N-hydroxy-6-(4-methoxybenzyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine--
2-carboxamide 112
6-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl-
}-N-hydroxy-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide
113
5-[2-(benzylamino)pyrimidin-4-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3-
,2-c]pyridine-2-carboxamide 114
6-{[2-(4-chloro-2-methoxyphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]ca-
rbonyl}-N-hydroxy-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-2-carboxamide 115
5-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-
-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide
116
N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothie-
no[2,3-c]pyridine-2- carboxamide 117
N.sup.6-[4-chloro-3-(trifluoromethyl)phenyl]-N.sup.2-hydroxy-4,7-dihyd-
rothieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 118
6-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 119
N-hydroxy-7,7-dimethyl-5-(quinolin-2-ylmethyl)-4,5,6,7-tetrahydrothien-
o[3,2-c]pyridine-2- carboxamide 120
N-hydroxy-6-[(4'-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothie-
no[2,3-c]pyridine-2- carboxamide 121
6-[(4-tert-butylphenyl)sulfonyl]-7-(2-fluorophenyl)-N-hydroxy-4,5,6,7--
tetrahydrothieno[2,3-c]pyridine- 2-carboxamide 122
6-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-4,5,6,7-tetrah-
ydrothieno[2,3-c]pyridine-2- carboxamide 123
6-{[2-(5-cyano-2-thienyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl}-
-N-hydroxy-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-2-carboxamide
124
5-[(4'-fluorobiphenyl-3-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothien-
o[3,2-c]pyridine-2-carboxamide 125
6-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrot-
hieno[2,3-c]pyridine-2- carboxamide 126
N-hydroxy-5-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4,5,6,7-t-
etrahydrothieno[3,2-c]pyridine- 2-carboxamide 127
N-hydroxy-6-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothi-
eno[2,3-c]pyridine-2- carboxamide 128
6-[(1-cyclopropyl-1H-pyrrol-2-yl)carbonyl]-7-(2-fluorophenyl)-N-hydrox-
y-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 129
N-hydroxy-5-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-
-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 130
N-hydroxy-6-{[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-4,5,6,7-
-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 131
6-[3,5-bis(acetylamino)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-
-c]pyridine-2-carboxamide 132
N.sup.2-hydroxy-N.sup.6-(5-methyl-3-phenylisoxazol-4-yl)-4,7-dihydroth-
ieno[2,3-c]pyridine-2,6(5H)- dicarboxamide 133
N-hydroxy-6-[3-(1H-pyrazol-1-yl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 134
6-[3-(2,3-dihydro-1H-indol-1-yl)-3-oxopropyl]-N-hydroxy-7-methyl-4,5,6-
,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 135
N-hydroxy-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-
-carboxamide 136
6-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2-
,3-c]pyridine-2-carboxamide 137
N.sup.6-[(1S)-1-(4-chlorophenyl)ethyl]-N.sup.2-hydroxy-4,7-dihydrothie-
no[2,3-c]pyridine-2,6(5H)-dicarboxamide 138
N-hydroxy-7-methyl-6-{5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}--
4,5,6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 139
N.sup.2-hydroxy-N.sup.6-(4-isopropylphenyl)-4,7-dihydrothieno[2,3-c]py-
ridine-2,6(5H)-dicarboxamide 140
6-(3,5-difluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyrid-
ine-2-carboxamide 141
5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrol-
e-2-carboxamide 142
5-{[2-(4-tert-butylphenyl)-4-methyl-4H-furo[3,2-b]pyrrol-5-yl]carbonyl-
}-N-hydroxy-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide
143
7-(2-fluorophenyl)-N-hydroxy-6-[3-(trifluoromethoxy)benzyl]-4,5,6,7-te-
trahydrothieno[2,3- c]pyridine-2-carboxamide 144
N-hydroxy-6-[5-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4,5,6,7-tetrahydrot-
hieno[2,3-c]pyridine-2- carboxamide 145
N-hydroxy-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyr-
rol-5-yl}carbonyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine-2-carboxamide 146
N-hydroxy-6-(1,3-thiazol-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-2-carboxamide 147
N.sup.6-[(1R)-1-(4-chlorophenyl)ethyl]-N.sup.2-hydroxy-4,7-dihydrothie-
no[2,3-c]pyridine-2,6(5H)-dicarboxamide 148
5-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-5,6-dihyd-
ro-4H-thieno[2,3-c]pyrrole-2- carboxamide 149
6-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetra-
hydrothieno[2,3-c]pyridine-2- carboxamide 150
5-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]-
pyridine-2-carboxamide 151
N-hydroxy-5-[(4'-methoxybiphenyl-4-yl)sulfonyl]-4,5,6,7-tetrahydrothie-
no[3,2-c]pyridine-2- carboxamide 152
N-hydroxy-6-[(4-methyl-2-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrah-
ydrothieno[2,3-c]pyridine-2- carboxamide 153
N-hydroxy-3-methyl-5-(propylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]p-
yridine-2-carboxamide 154
N.sup.5-[(1R)-1-(4-chlorophenyl)ethyl]-N.sup.2-hydroxy-6,7-dihydrothie-
no[3,2-c]pyridine-2,5(4H)-dicarboxamide 155
N.sup.6-(4-chlorobenzyl)-N.sup.2-hydroxy-4,7-dihydrothieno[2,3-c]pyrid-
ine-2,6(5H)-dicarboxamide 156
N-hydroxy-6-(2,3,5,6-tetrafluorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 157
5-[4-(benzylamino)pyrimidin-2-yl]-N-hydroxy-4,5,6,7-tetrahydrothieno[3-
,2-c]pyridine-2-carboxamide 158
N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4,5,6,7-tetra-
hydrothieno[2,3-c]pyridine-2- carboxamide 159
6-[(5-amino-1H-pyrazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothie-
no[2,3-c]pyridine-2- carboxamide 160
6-[(4-tert-butylphenyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,-
3-c]pyridine-2-carboxamide 161
5-[2-(4-chlorophenoxy)ethyl]-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyr-
role-2-carboxamide 162
N-hydroxy-7,7-dimethyl-5-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-f-
uro[3,2-b]pyrrol-5-
yl}carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide
163
N.sup.2-hydroxy-N.sup.6-(4-iodophenyl)-4,7-dihydrothieno[2,3-c]pyridin-
e-2,6(5H)-dicarboxamide 164
6-[3-fluoro-5-(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydroth-
ieno[2,3-c]pyridine-2- carboxamide 165
N-hydroxy-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[3,2-c-
]pyridine-2-carboxamide 166
N-hydroxy-5-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetr-
ahydrothieno[3,2-c]pyridine- 2-carboxamide 167
N-hydroxy-6-[5-(3-methyl-1-benzothien-2-yl)-1,3-thiazol-2-yl]-4,5,6,7--
tetrahydrothieno[2,3-c]pyridine- 2-carboxamide 168
5-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrah-
ydrothieno[3,2-c]pyridine-2- carboxamide 169
N.sup.6-(4-butylphenyl)-N.sup.2-hydroxy-4,7-dihydrothieno[2,3-c]pyridi-
ne-2,6(5H)-dicarboxamide 170
5-[(3-chloro-1-methyl-1H-indol-2-yl)carbonyl]-N-hydroxy-5,6-dihydro-4H-
-thieno[2,3-c]pyrrole-2- carboxamide 171
N-hydroxy-6-[4-(trifluoromethyl)benzoyl]-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 172
N-hydroxy-5-(propylsulfonyl)-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-car-
boxamide 173 tert-butyl
2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxy-
late 174
N-hydroxy-6-[(3-methoxy-1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetr-
ahydrothieno[2,3-c]pyridine- 2-carboxamide 175
N-hydroxy-6-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]-4-methyl-4,5,-
6,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 176
N.sup.2-hydroxy-N.sup.6-mesityl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5-
H)-dicarboxamide 177
6-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydroth-
ieno[2,3-c]pyridine-2- carboxamide 178
6-(2,5-dimethyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyr-
idine-2-carboxamide 179
N-hydroxy-6-(quinolin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyr-
idine-2-carboxamide 180
N-hydroxy-6-({4-methyl-2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyr-
rol-5-yl}carbonyl)-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-2-carboxamide 181
N-hydroxy-6-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c-
]pyridine-2-carboxamide 182
6-(4-fluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine--
2-carboxamide 183
6-[(4,5-dichloro-1-methyl-1H-pyrrol-2-yl)carbonyl]-N-hydroxy-4,5,6,7-t-
etrahydrothieno[2,3- c]pyridine-2-carboxamide 184
6-{[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}-N-hydroxy-4,5,6-
,7-tetrahydrothieno[2,3- c]pyridine-2-carboxamide 185
N-hydroxy-6-{[4-(trifluoromethyl)phenyl]acetyl}-4,5,6,7-tetrahydrothie-
no[2,3-c]pyridine-2- carboxamide 186
6-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetra-
hydrothieno[2,3-c]pyridine-2- carboxamide 187
N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetr-
ahydrothieno[2,3-c]pyridine- 2-carboxamide 188
6-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3--
c]pyridine-2-carboxamide 189
N.sup.5-(2,6-difluorophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno-
[3,2-c]pyridine-2,5(4H)- dicarboxamide 190
5-(4-tert-butylbenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothien-
o[3,2-c]pyridine-2-carboxamide 191
N.sup.5-benzyl-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2-c]pyridin-
e-2,5(4H)-dicarboxamide 192
5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,-
7-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 193
5-(4-chlorobenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]-
pyridine-2-carboxamide 194
N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetra-
hydrothieno[3,2-c]pyridine-2- carboxamide 195
5-(1-benzothien-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydr-
othieno[3,2-c]pyridine-2- carboxamide 196
N.sup.5-(4-cyanophenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno[3,2--
c]pyridine-2,5(4H)-dicarboxamide 197
N-hydroxy-3-methyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-tet-
rahydrothieno[3,2-c]pyridine- 2-carboxamide 198
5-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylcarbonyl)-N-hydroxy-7,7-dimeth-
yl-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine-2-carboxamide 199
N-hydroxy-3-methyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)carbon-
yl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 200
N.sup.5-(3,4-dimethylphenyl)-N2-hydroxy-7,7-dimethyl-6,7-dihydrothieno-
[3,2-c]pyridine-2,5(4H)- dicarboxamide 201
N.sup.2-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno-
[3,2-c]pyridine-2,5(4H)- dicarboxamide 202
N.sup.2-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno-
[3,2-c]pyridine-2,5(4H)- dicarboxamide 203
5-[(3S,5S,7S)-1-adamantylcarbonyl]-N-hydroxy-3-methyl-4,5,6,7-tetrahyd-
rothieno[3,2-c]pyridine-2- carboxamide 204
5-(2,2-dimethylpropanoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[-
3,2-c]pyridine-2-carboxamide 205
5-(1-benzothien-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothi-
eno[3,2-c]pyridine-2- carboxamide 206
N.sup.5-(2,3-dihydro-1-benzofuran-5-yl)-N.sup.2-hydroxy-7,7-dimethyl-6-
,7-dihydrothieno[3,2-c]pyridine- 2,5(4H)-dicarboxamide 207
5-(biphenyl-4-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothi-
eno[3,2-c]pyridine-2- carboxamide 208
N-hydroxy-7,7-dimethyl-5-[(3-phenyl-1H-indol-2-yl)carbonyl]-4,5,6,7-te-
trahydrothieno[3,2-c]pyridine- 2-carboxamide 209
N-hydroxy-5-(4-methoxybenzoyl)-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c-
]pyridine-2-carboxamide 210
N-hydroxy-7,7-dimethyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-t-
etrahydrothieno[3,2-c]pyridine- 2-carboxamide 211
N-hydroxy-7,7-dimethyl-5-[(5-pyridin-2-yl-2-thienyl)carbonyl]-4,5,6,7--
tetrahydrothieno[3,2-c]pyridine- 2-carboxamide 212 tert-butyl
2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxy-
late 213
N.sup.2-hydroxy-7,7-dimethyl-N.sup.5-(2-phenylethyl)-6,7-dihydrothieno-
[3,2-c]pyridine-2,5(4H)-dicarboxamide 214
N-hydroxy-5-(4-methoxybenzoyl)-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3-
,2-c]pyridine-2-carboxamide 215
5-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydr-
othieno[3,2-c]pyridine-2- carboxamide 216
5-(1-benzofuran-2-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothi-
eno[3,2-c]pyridine-2- carboxamide 217
N-hydroxy-3-methyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3-
,2-c]pyridine-2-carboxamide 218
5-(4-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,-
2-c]pyridine-2-carboxamide 219
N-hydroxy-3-methyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyr-
idine-2-carboxamide 220
N-hydroxy-7,7-dimethyl-5-(pyridin-2-ylcarbonyl)-4,5,6,7-tetrahydrothie-
no[3,2-c]pyridine-2- carboxamide 221
5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-3-methyl-4,5,6,7-te-
trahydrothieno[3,2-c]pyridine- 2-carboxamide 222
N-hydroxy-7,7-dimethyl-5-[(2-methyl-1,3-thiazol-4-yl)carbonyl]-4,5,6,7-
-tetrahydrothieno[3,2- c]pyridine-2-carboxamide 223
5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrol-
e-2-carboxamide 224
N-hydroxy-7,7-dimethyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrah-
ydrothieno[3,2-c]pyridine-2- carboxamide 225
5-(4-tert-butylbenzoyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,-
2-c]pyridine-2-carboxamide 226
N-hydroxy-7,7-dimethyl-5-(2-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[-
3,2-c]pyridine-2-carboxamide 227
N-hydroxy-7,7-dimethyl-5-(phenylacetyl)-4,5,6,7-tetrahydrothieno[3,2-c-
]pyridine-2-carboxamide 228
N-hydroxy-7,7-dimethyl-5-[(4-methyl-2-pyridin-2-yl-1,3-thiazol-5-yl)ca-
rbonyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-carboxamide 229
5-butyryl-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-
-carboxamide 230
5-(1-adamantylcarbonyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole--
2-carboxamide 231
5-(1-benzothien-2-ylcarbonyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]py-
rrole-2-carboxamide 232
N-hydroxy-3-methyl-5-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine-2- carboxamide 233
5-(biphenyl-4-ylcarbonyl)-N-hydroxy-3-methyl-4,5,6,7-tetrahydrothieno[-
3,2-c]pyridine-2-carboxamide 234
5-(2-chlorobenzoyl)-N-hydroxy-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,-
2-c]pyridine-2-carboxamide 235
N-hydroxy-6-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide 236
N.sup.5-[2-(dimethylamino)ethyl]-N.sup.2-hydroxy-7,7-dimethyl-6,7-dihy-
drothieno[3,2-c]pyridine-2,5(4H)- dicarboxamide 237
N-hydroxy-3-methyl-5-[(4-methylpiperidin-4-yl)carbonyl]-4,5,6,7-tetrah-
ydrothieno[3,2-c]pyridine-2- carboxamide 238
N-hydroxy-6-(piperidin-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]py-
ridine-2-carboxamide 239
N-hydroxy-5-[(2S)-3-methyl-2-(methylamino)butanoyl]-4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine-2- carboxamide
4. General Synthetic Methods and Intermediates
[0256] 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
that follow. Exemplary synthetic routes are set forth in Schemes
below, and in the Examples.
[0257] One of ordinary skill in the art will appreciate that the
transformations shown below in Schemes can also be carried out on
analogous compounds containing one or more substituents on Ring A
and at the R.sup.1 position, or on analogous compounds with
different Ring A ring sizes.
##STR00269##
[0258] Scheme 1 shows a general route for preparing compounds of
formula iii. As shown in Scheme 1, methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i, is treated
with a carboxylic acid, R.sup.3--CO.sub.2H, using a coupling agent
in the presence of a base (Method A). 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 A include,
but are not limited to, triethylamine, N,N'-diisopropylethylamine
and N-methylmorpholine. Suitable solvents for Method A include, but
are not limited to, dichloromethane (DCM), tetrahydrofuran (THF),
N,N'-dimethylformamide (DMF), N-methylpyrrolidone (NMP) or
N,N'-dimethylacetamide. Conversion of ii to the corresponding
hydroxamate iii is achieved by heating ii in the presence of
hydroxylamine hydrochloride and potassium hydroxide in an
appropriate solvent such as methanol (Method B). Conversion to the
corresponding hydroxamate can also be achieved using the potassium
salt of hydroxylamine (Huang et al., J. Med. Chem. 2009,
52(21):675).
##STR00270##
[0259] Scheme 2 shows a general route for preparing compounds of
formula vi. Amides of formula iv, where v is 1-2, are prepared by
Method A, using either chloroacetic acid or 3-chloropropionic acid,
and are then reacted with oxygen (R.sup.3--OH) or nitrogen
nucleophiles (R.sup.3--NH.sub.2) in a solvent such as
CH.sub.2Cl.sub.2 or DMF, in the presence of a base, such as
N,N'-diisopropylethylamine (Method C; see Takikawa et al., Organic
Lett. 2007, 9(14):2713-2716; Slee et al., J. Med. Chem. 2008,
51(6):1730-1739) to give compounds of formula vi where X is --O--
or --NH--. Subsequent conversion of compounds of formula v to the
corresponding hydroxamates vi is carried out as described in Scheme
1 using Method B.
##STR00271##
[0260] Scheme 3 shows a general route for preparing compounds of
formula viii. As shown in Scheme 3, methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated
with the appropriate sulfonyl chloride, R.sup.3--SO.sub.2Cl, and
DMAP in DMF at ambient temperature (Method D). Method D may also be
carried out in a solvent such as DCM or N,N'-dimethylacetamide.
Subsequent conversion of the resulting compounds of formula vii to
the corresponding hydroxamates viii is carried out as described in
Scheme 1 using Method B.
##STR00272##
[0261] Scheme 4 shows a general route for preparing compounds of
formula xi. Sulfonamides of formula ix bearing a pendant aromatic
bromide can be prepared as described in Scheme 3, and are then
subjected to a Suzuki coupling with a boronic acid,
R.sup.5d'--B(OH).sub.2, in the presence of a Pd-catalyst such as
Pd(PPh.sub.3).sub.4, and a base such as Na.sub.2CO.sub.3 (see
Weinstein et al., Bioorg. Med Chem. Lett. 2005 15(5): 1435-1440) to
afford sulfonamides of formula x. Other Pd-mediated coupling
conditions such as the reaction of an organo-stannane compound with
an aromatic halide, or reaction with amines in a Buchwald-Hartiwig
type coupling may be employed to generate compounds of formula x
where R.sup.5d' is for example an aromatic ring, a heteroaromatic
ring or an amine containing moiety. Subsequent conversion of
compounds of formula x to the corresponding hydroxamates of formula
xi is carried out as described in Scheme 1 using Method B.
##STR00273##
[0262] Scheme 5 shows a general route for preparing compounds of
formula xiii. As shown in Scheme 5, methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated
with an appropriate alkyl halide (R.sup.3--CH.sub.2--Br or
R.sup.3--CH.sub.2--Cl), in the presence of a suitable base such as
Et.sub.3N in a solvent such as DMF (Method F) to afford compounds
of formula xii. Alternatively, a reductive alkylation with an
aldehyde in the presence of a reducing agent can be used to
generate compounds of formula xii. Subsequent conversion of
compounds of formula xii to the corresponding hydroxamate xiii is
carried out as described in Scheme 1 (Method B).
##STR00274##
[0263] Scheme 6 shows a general route for preparing compounds of
formula xv. As shown in Scheme 6, a solution of methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i, and
optionally a base in a solvent is treated with an isocyanate
(R.sup.3--NCO), at ambient or elevated temperature to afford
compounds of formula xiv (Method G). Suitable bases for Method G
include, but are not limited to triethylamine,
N,N'-diisopropylethylamine and N-methylmorpholine. Suitable
solvents for Method G include, but are not limited to, DCM, THF,
DMF, NMP and N,N'-dimethylacetamide. Subsequent conversion of
compounds of formula xiv to the corresponding hydroxamates of
formula xv is carried out as described in Scheme 1 using Method
B.
##STR00275##
[0264] Scheme 7 shows a general route for preparing compounds of
formula xviii As shown in Scheme 7, methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate i is treated
with ammonium thiocyanate in a solvent such as THF at an elevated
temperature (Method H). Cyclization of the resulting thiourea xvi
to the aminothiazole xvii is accomplished upon treatment with an
alpha-haloketone, (for example; R.sup.5--C(O)--CH.sub.2Cl) in a
solvent such as 1,4-dioxane at ambient or elevated temperature
(Method I). Subsequent conversion of compounds of formula xvii to
the corresponding hydroxamates of formula xviii is carried out as
described in Scheme 1 using Method B.
##STR00276##
[0265] Scheme 8 shows a general route for preparing compounds of
formula xxvi and xxvii. Ring expansion of compound xix, (prepared
as described by Padwa et. al., J. Org. Chem. 1989, 54(2): 299-308)
via a Schmidt rearrangement (Method J) followed by reduction of the
resulting amides with borane (Method K) affords amines xx and xxi
(in a fashion analogous to that described in PCT Int. Appl. Pub. WO
08/076954). Subsequent protection of the amines with Boc-anhydride
provides compounds xxii and xxiii (Method L). Bromination of xxii
and xxiii followed by Pd-catalyzed carbonylation with carbon
monoxide provides intermediates xxiv and xxv (Method M; as
exemplified in Janetka et al., Bioorg. Med. Chem. Lett. 2008,
18(14): 4242-4248; and PCT Int. Appl. Pub. WO 05/037214).
Subsequent removal of the Boc-protecting group (Method N) under
acidic conditions yields compounds xxvi and xxvii. It will be
appreciated that analogous transformations to those described in
Scheme 1-7 above can be achieved starting from the compounds
formula xxvi and xxvii.
##STR00277##
[0266] Scheme 9 shows a general route for the preparation of
compounds of formula xxxiii from commercially available
halo-pyridines. Reaction of pyridine xxviii with LDA followed by
quenching with DMF gives pyridine aldehyde xxix (Method O, see Ondi
et al., Tetrahedron 2005, 61(3), 717-725). Palladium catalyzed
reaction of xxix with Ar-boronic acids or Ar-boronates (where Ar is
substituted or unsubstituted aryl or heteroaryl) affords compounds
of formula XXX (Method P, see Fujihara et al., Organic Letters
2009, 11(10): 2121-2124; Rocca et al., J. Org. Chem. 1993, 58(27):
7831; and Rocca et al., Tetrahedron 1993, 49(1): 49). Treatment
with methyl 2-mercaptoacetate affects cyclization to the compound
of formula xxxi (Method Q; see PCT Int. Appl. Pub. WO 05/110410).
The pyridine ring is reduced followed by de-methylation to yields
compounds of formula xxxiii (Methods R, S). It will be appreciated
that analogous transformations to those described in Schemes 1-7
above can be achieved starting from the compounds of formula
xxxiii.
##STR00278##
[0267] Scheme 10 shows the methods described in Scheme 9 above
applied to generate substituted compounds of formulas xxxv and
xxxvii starting from commercially available halo-pyridines xxxiv
and xxxvi. It will be appreciated that analogous transformations to
those described in Schemes 1-7 above can be achieved starting from
the compounds of formula xxxv and xxxvii.
##STR00279##
[0268] Scheme 11 shows a general route for the preparation of
compounds of formula xxxxii. Cyclocondensation of 1,5-dicarbonyl
compounds of formula xxxviii with ammonia, followed by
dehydrogenation gives compounds of formula xxxix (Method T, see Kim
et al., Tetrahedron Lett. 2008, 49(41): 5863-5866). Nitration of
the compound of formula xxxix affords the compound of formula xxxx
(Method U, see Katritzky et al., Organic & Biomolecular
Chemistry 2005, 3(3): 538-541). Reduction of the nitro group
followed by conversion of the aniline intermediate to fluorine
gives compounds of formula xxxxi (Method V, see Motoyama et al.,
Organic Letters 2009, 11(6): 1345-1348; Clark et al., Bioorg. Med.
Chem. 2008, 16(6): 3163-3170). Conversion of the compound of
formula xxxxi to compounds of formula xxxxii can be achieved with
the methods described above (Methods O, Q, R, S). It will be
appreciated that analogous transformations to those described in
Schemes 1-7 above can be achieved starting from the compounds of
formula xxxxii.
##STR00280##
[0269] Scheme 12 above shows an extension of the chemistry
described in Schemes 9 and 11 to generate compounds of formula
xxxxv. Bromination of pyridine xxxx with NBS gives compounds of
formula xxxxiii (Method W, see Carroll et al., J. Med. Chem. 2002,
45(21): 4755-4761). The pyridine of formula xxxxiii can be
converted to compounds of formula xxxxiv by a palladium catalyzed
coupling reaction in a similar manner as described in Scheme 9
(Method P). The conversion of the compounds of formula xxxxiv to
xxxxv can be achieved as described above in Schemes 9 and 11
(Methods V, O, Q, R, S). It will be appreciated that analogous
transformations to those described in Schemes 1-7 above can be
achieved starting from the compounds of formula xxxxv.
##STR00281##
[0270] Scheme 13 shows another general route for the preparation of
the compound of formula xxxxviii. Condensation of
ethylmercaptoacetate with commercially available compound xxxxvi in
the presence of base (Method X, see Pessoa-Mahana et al.
Heterocycles 2008, 75(8), 1913-1929; PCT Int. Appl. Pub. WO
05/110410) affords the compound of formula xxxxvii. Reduction of
the pyridyl ring can be achieved using hydrogen over Adam's
catalyst (Method Y, see Wang et al., J. Med. Chem. 2007, 50,
199-210) to give compounds of formula xxxxviii. It will be
appreciated that analogous transformations to those described in
Schemes 1-7 above can be achieved starting from the compounds of
formula xxxxviii.
##STR00282##
[0271] Scheme 14 above shows a general route for the preparation of
compounds of formula Lii. Protected piperidones xxxxix (where each
R.sup.2 may be the same or different; derived from commercial
sources or accessed through literature routes) can be
chloroformylated using a Vilsmer-Hack reaction to afford compounds
of formula L (Method Z, see Grunewald et al., Bioorg. Med. Chem.
2008, 16(1), 542-559). Treatment with ethylmercaptoacetate in the
presence of excess triethylamine provides compounds of formula Li
(Method AA, see Venkatesan et al., J. Med. Chem. 2006, 45(15),
4623). Subsequent removal of the Boc-protecting group (Method N)
under acidic conditions yields compounds of formula Lii. It will be
appreciated that analogous transformations to those described in
Schemes 1-7 above can be achieved starting from the compounds of
formula Lii.
##STR00283##
[0272] Scheme 15 above shows a general route for the preparation of
the compound of formula Lv. Condensation of Liii (prepared as
described by Tucker et al., J. Med. Chem. 2008, 51(20), 6503-6511)
with ethylmercaptoacetate in the presence of a base affords the
bicyclic compound of formula Liv (Method BB; see PCT Int. Appl.
Pub. WO 05/077926). The pyridyl ring can then be reduced with
hydrogen over Adam's catalyst (Method Y). It will be appreciated
that analogous transformations to those described in Schemes 1-7
above can be achieved starting from the compound of formula Lv.
##STR00284##
[0273] Scheme 16 above shows a general route for the preparation of
the compound of formula Lx. Protection of the secondary amine of
compound xxxxviii can be achieved employing standard Boc anhydride
in the presence of a suitable base (Method L; see Wang et al., J.
Med. Chem. 2007, 50(2):199-210). Saponificiation of the ester of
Lvi with sodium hydroxide (Method CC) provides the free acid of
compound Lvii which assists in the ortho-metallation at C-3 with
t-BuLi which, upon quenching with N-fluorobenzenesulfonimide,
generates compound Lviii (Method DD, see Torrado et al., Bioorg.
Med. Chem. 2004, 12(20): 5277-5295). Re-esterfication is
accomplished with TMS-diazomethane (Method EE) followed by removal
of the Boc protecting group under acidic conditions (Method N) to
generate compound Lx. It will be appreciated that analogous
transformations to those described in Schemes 1-7 above can be
achieved starting from the compound of formula Lx.
##STR00285##
[0274] Scheme 17 above shows a general route for the preparation of
the compound of formula Lxiii. Starting from the compound of
formula Lvii (prepared as described above in Scheme 16), the
compound of formula Lxi can be achieved through the carboxylic acid
assisted ortho-metallation of Lvii with sec-BuLi/TMEDA followed by
quenching with N-chloro succinimide (Method DD, see Torrado et al.,
Bioorg. Med. Chem. 2004, 12(20): 5277-5295). Subsequent
modification of the protecting groups is achieved though
esterification with TMS-diazomethane (Method EE) followed by
removal of the Boc group under acidic conditions (Method N) to
provide the compound of formula Lxiii. It will be appreciated that
analogous transformations to those described in Schemes 1-7 above
can be achieved starting from the compound of formula Lxiii.
##STR00286##
[0275] Scheme 18 above shows a general route for the preparation of
the compound of formula Lxvii. Condensation of commercially
available Lxiv with ethylmercaptoacetate, followed by subsequent
cyclization under basic conditions provides the compound of formula
Lxv (Method FF, see U.S. App. Pub. No. 2006/0003990; Donoso et al.
Synthesis 1992, (6):526-8). Methylation of the free hydroxyl,
accomplished upon treatment with diazo((trimethylsilyl))methane
(Method GG, see U.S. App. Pub. No. 2006/0003990) followed by
removal of the Boc protecting group under acidic conditions (Method
N) affords the compound of formula Lxvii. It will be appreciated
that analogous transformations to those described in Schemes 1-7
above can be achieved starting from the compound of formula
Lxvii.
5. Uses, Formulation and Administration
[0276] As discussed above, the present invention provides compounds
and pharmaceutical compositions that are useful as inhibitors of
MAC enzymes, particularly HDAC6, and thus the present compounds are
useful for treating proliferative, inflammatory, infectious,
neurological or cardiovascular disorders.
[0277] In some embodiments, the invention provides the compound of
formula (I), or a pharmaceutically acceptable salt thereof, for use
in treating a proliferative disorder. In some embodiments, the
invention provides a pharmaceutical composition for the treatment
of a proliferative disorder comprising the compound of formula (I),
or a pharmaceutically acceptable salt thereof. In some embodiments,
the invention provides the use of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, for the preparation of a
pharmaceutical composition for the treatment of a proliferative
disorder. In some embodiments, the invention provides the use of an
effective amount of the compound of formula (I), or a
pharmaceutically acceptable salt thereof, for the treatment of a
proliferative disorder.
[0278] 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.
[0279] 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.
[0280] 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.
[0281] 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.
[0282] 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.
[0283] 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.
[0284] 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.
[0285] 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.
[0286] 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.
[0287] 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.
[0288] 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.
[0289] 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.
[0290] 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.
[0291] 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.
[0292] 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.
[0293] 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.
[0294] 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.
[0295] 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.
[0296] 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, 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, f) 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.
[0297] 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 polethylene
glycols and the like.
[0298] 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.
[0299] 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.
[0300] 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.
[0301] 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).
[0302] 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 I.kappa.B 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 downregulates cell replication. In certain
embodiments, a compound of the invention is administered in
conjunction with a proteasome inhibitor.
[0303] 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.
[0304] 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
Definitions
[0305] AcOH acetic acid [0306] ACN acetonitrile [0307] ATP
adenosine triphosphate [0308] BOC tert-butoxycarbonyl [0309] DCE
dichloroethane [0310] DCM dichloromethane [0311] DIPEA
diisopropylethyl amine [0312] DMF N,N-dimethylformamide [0313]
DMFDMA N,N-dimethylformamide dimethyl acetal [0314] DMAP
N,N-dimethylaminopyridine [0315] DMSO dimethylsulfoxide [0316] DPPA
diphenylphosphoryl azide [0317] DTT dithiothreitol [0318] EDCI
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0319]
EDTA ethylenediaminetetraacetic acid [0320] EtOAc ethyl acetate
[0321] EtOH ethanol [0322] FA formic acid [0323] FBS fetal bovine
serum [0324] h hours [0325] HATU
N,N,N',N'-tetramethyl-o-(7-azabenzotriazole-1-yl)uronium
hexafluorophosphate [0326] HBTU
o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0327] HEPES
N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) [0328] HOBT
1-hydroxybenztriazole hydrate [0329] HRMS high resolution mass
spectrum [0330] LAH lithium aluminum hydride [0331] LCMS liquid
chromatography mass spectrum [0332] m/z mass to charge [0333] Me
methyl [0334] MeOH methanol [0335] min minutes [0336] MS mass
spectrum [0337] MTT methylthiazoletetrazolium [0338] MOM-Cl methyl
chloromethyl ether [0339] MWI microwave irradiation [0340] NMM
N-methyl morpholine [0341] PBS phosphate buffered saline [0342] PKA
cAMP-dependent protein kinase [0343] rt room temperature [0344] TEA
triethylamine [0345] TFFA trifluoroacetic anhydride [0346] THF
tetrahydrofuran [0347] TMB 3,3',5,5'-Tetramethylbenzidine [0348]
WST
(4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene
disulfonate sodium salt)
[0349] Analytical Methods
[0350] NMR
[0351] 1H NMR Spectra were run on a 300 MHZ or 400 MHz Bruker NMR
unless otherwise stated.
[0352] LCMS
[0353] LCMS spectra were run on a Phenominex Luna 5 .mu.m C18
50.times.4.6 mm column on a Hewlett-Packard HP1100 using one of the
following gradients unless otherwise stated
(1) Method Formic Acid (FA): Acetonitrile containing 0 to 100
percent 0.1% formic acid in water (2.5 ml/min for a 3 minute run).
(2) Method Ammonium Acetate (AA): Acetonitrile containing 0 to 100
percent 10 mM ammonium acetate in water (2.5 ml/min for a 3 minute
run).
[0354] HPLC
[0355] Reverse phase preparative purification were performed on
either a Gilson HPLC or Agilent A2Prep LCMS system employing a
Waters Sunfire C18 10 mm 19.times.150 mm column unless otherwise
stated.
Example 1
Synthesis of methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate
##STR00287##
[0356] Step 1: Methyl thieno[2,3-c]pyridine-2-carboxylate
[0357] To a 50-mL round-bottom flask was added
3-fluoro-4-pyridinecarboxaldehyde (0.8 mL, 8.02 mmol) and
N,N-dimethylformamide (14 mL) and the solution was cooled to
0.degree. C. To this solution was added potassium carbonate (1.22
g, 8.828 mmol) and methyl 2-mercaptoacetate (0.754 mL, 8.427 mmol).
The solution turned to a clear yellow solution after stirring for
10 min. After 30 min at 0.degree. C., the reaction was warmed to
room temperature and stirred over the weekend by which time a solid
precipitate was formed. Water was added provide a homogeneous
solution, which was cooled to 0.degree. C., the solid was collected
via vacuum filtration, and washed with cold water until clear and
colorless affording methyl thieno[2,3-c]pyridine-2-carboxylate
(1.55 g, 82%) as a white solid. LCMS: (FA) ES+ 194; .sup.1H NMR
(d.sub.6-DMSO, 300 MHz) 59.37 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 8.26
(d, J=0.6 Hz, 1H), 7.97 (dd, J=5.4 Hz, 1.2 Hz, 1H), 3.92 (s,
3H).
Step 2: Methyl
6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate
[0358] A solution of methyl thieno[2,3-c]pyridine-2-carboxylate
(370 mg, 1.9 mmol) and acetonitrile (7.3 mL) was stirred at
42.degree. C. for 6 h over which time the formation of a
precipitate was observed. Upon cooling to room temperature, the
solvent was removed in vacuo. To the material thus obtained was
added methanol (10 mL) and platinum dioxide (100 mg, 0.4 mmol). The
mixture was stirred under a balloon H.sub.2 atmosphere pressure for
4 h. The solvent was then removed under reduced pressure and the
residue obtained was partitioned between EtOAc and saturated
aqueous NaHCO.sub.3. Upon separation, the aqueous layer was
extracted with EtOAc three additional times. The combined organic
phases were further washed with saturated aqueous NaHCO.sub.3,
water and brine, dried over anhydrous MgSO.sub.4 and concentrated
to give methyl
6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (0.4
g, 95%) as an off-white solid. LCMS: (FA) ES+ 212; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.7.50 (s, 1H), 3.85 (s, 3H), 3.64 (m,
2H), 2.73 (m, 4H), 2.48 (s, 3H).
Step 3: Methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate
[0359] Into a 1000-mL round-bottom flask containing methyl
6-methyl-4,5,6,7-tetrahydrothieno[2,3c]pyridine-2-carboxylate (9.84
g, 46.6 mmol), and 1,4-dioxane (466 mL) was added
N,N-diisopropylethylamine (81.1 mL, 466 mmol). The solution was
cooled to 0.degree. C. whereupon .alpha.-chloroethyl chloroformate
(50.2 mL, 466 mmol) was added dropwise. Upon complete addition, the
solution was warmed to room temperature and stirred for 3 h. The
solvent was removed in vacuo and the residue obtained was dissolved
in methanol (466 mL). The clear yellow solution heated to reflux
for 3 h. Removal of the solvent under reduced pressure afforded a
solid which was partitioned between dichloromethane and saturated
aqueous NaHCO.sub.3. The aqueous layer was further extracted with
dichloromethane three times. The combined organic phases were
washed with brine, dried over anhydrous MgSO.sub.4 and
concentrated. Purification via flash chromatography (50%
EtOAc-hexanes to 1% triethylamine-99% EtOAc to 1% MeOH-1%
triethylamine-98% EtOAc) afforded methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (5.08 g, 55%)
as a brown solid. LCMS: (FA) ES+ 198; .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta.7.50 (s, 1H), 4.04 (s, 2H), 3.86 (s, 3H), 3.12 (t,
J=6.0 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H).
Example 2
Synthesis of
6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridin-
e-2 carboxamide (Compound 1)
##STR00288##
[0361] To a solution of HBTU (38.4 mg, 0.101 mmol) and
trimethylacetic acid (10.4 mg, 0.101 mmol) in DCM (2 mL) was then
added triethylamine (28.3 .mu.L, 0.203 mmol). The reaction solution
was stirred at room temperature for 30 min. A solution of methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (20 mg, 0.101
mmol) in DCM was added in one portion. The solution was then
stirred at room temperature overnight then further heated at
36.degree. C. for 1 h. Upon cooling to room temperature, the
reaction was diluted with DCM and washed with saturated aqueous
NaHCO.sub.3. The aqueous layer was extracted with methylene
chloride twice, the combined organic phases were additionally
washed with water, brine, dried over anhydrous MgSO.sub.4 and
concentrated to afford an oil residue. To the material obtained was
added methanol (1 mL), hydroxylamine hydrochloride (28.2 mg, 0.406
mmol), and potassium hydroxide (45.5 mg, 0.811 mmol). The reaction
mixture was heated at 80.degree. C. for 2 h, cooled to room
temperature and the solvent removed in vacuo. To the solid residue
obtained was dissolved in DMSO (1.4 mL) and purified with Gilson
prep-HPLC [202 nm, rt=5.13 (12 min), 15-45% MeCN--H.sub.2O] to
afforded
6-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3c]pyridin-
e-2 carboxamide (3.51 mg, 12%) as a white solid. LCMS: (FA) ES+
283; .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.8.13 (s, 1H), 6.91
(s, 1H), 4.44 (s, 2H), 3.52 (t, J=5.9 Hz, 2H), 2.37 (t, J=5.9 Hz,
2H), 0.92 (s, 9H).
Example 3
Synthesis of
6-(cyclohexylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine--
2 carboxamide (Compound 2)
##STR00289##
[0363] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 36.2%; Purification with Gilson
prep-HPLC [198 nm, rt=5.64 (12 min), 20-50% MeCN--H.sub.2O]. LCMS:
(FA) ES+ 309; .sup.1H NMR (MeOD, 300 MHz) 87.30 (s, 1H), 4.75 (s,
2H), 3.83 (t, J=6.0 Hz, 2H), 2.65 (m, 3H), 1.74 (m, 6H), 1.41 (m,
4H).
Example 4
Synthesis of
N-hydroxy-6-[(1-methylcyclohexyl)carbonyl]-4,5,6,7-tetrahydrothieno[2,3-c-
]pyridine-2-carboxamide (Compound 3)
##STR00290##
[0365] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 22.9%; Purification with Gilson
prep-HPLC [204 nm, rt=6.69 (12 min), 25-50% MeCN--H.sub.2O]. LCMS:
(FA) ES+ 323; .sup.1H NMR (d.sub.6-DMSO, 400 MHz) 89.08 (s, 1H),
7.31 (s, 1H), 4.73 (s, 2H), 3.78 (t, J=6.0 Hz, 2H), 2.63 (t, J=6.0
Hz, 2H), 1.96 (m, 2H), 1.45 (m, 2H), 1.33 (m, 6H).
Example 5
Synthesis of
6-[2-(4-chlorophenyl)-2-methylpropanoyl]-N-hydroxy-4,5,6,7-tetrahydrothie-
no[2,3-c]pyridine-2-carboxamide (Compound 4)
##STR00291##
[0367] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 35.9%; Purification with Gilson
prep-HPLC [202 nm, rt=6.68 (12 min), 25-55% MeCN--H.sub.2O]; LCMS:
(FA) ES+ 379.
Example 6
Synthesis of
N-hydroxy-6-(3-thienylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2
carboxamide (Compound 5)
##STR00292##
[0369] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 12%; Purification with Gilson
prep-HPLC [212 nm, rt=4.73 (12 min), 15-40% MeCN--H.sub.2O]; LCMS:
(FA) ES+ 309; .sup.1H NMR (d.sub.6-DMSO, 400 MHz) 88.72 (s, 1H),
7.50 (q, J=1.0 Hz, 1H), 7.26 (q, J=2.0 Hz, 1H), 6.97 (s, 1H), 6.87
(d, J=5.2 Hz, 1H), 4.40 (s, 2H), 3.31 (m, 2H), 2.35 (m, 2H).
Example 7
Synthesis of
N-hydroxy-6-(2-phenoxybutanoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-
-carboxamide (Compound 6)
##STR00293##
[0371] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 12%; LCMS: (FA) ES+ 361.
Example 8
Synthesis of
6-[(5-chloro-4-methoxy-3-thienyl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydroth-
ieno[2,3-c]pyridine-2-carboxamide (Compound 7)
##STR00294##
[0373] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 1.9%; LCMS: (FA) ES+ 373.
Example 9
Synthesis of
N-hydroxy-6-(4,5,6,7-tetrahydro-2H-indazol-3-ylcarbonyl)-4,5,6,7-tetrahyd-
rothieno[2,3-c]pyridine-2-carboxamide (Compound 8)
##STR00295##
[0375] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 8.5%; LCMS: (FA) ES+ 347.
Example 10
Synthesis of
6-(2,2-diphenylbutanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-
e-2-carboxamide (Compound 9)
##STR00296##
[0377] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 5%; LCMS: (FA) ES+ 421.
Example 11
Synthesis of
6-(dicyclohexylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine--
2-carboxamide (Compound 10)
##STR00297##
[0379] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 8.5%; LCMS: (FA) ES+ 347.
Example 12
Synthesis of
N-hydroxy-6-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]carbonyl}-4,5-
,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound
11)
##STR00298##
[0381] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 6.2%; LCMS: (FA) ES+ 405.
Example 13
Synthesis of
6-[(2,4-dimethylphenoxy)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-2-carboxamide (Compound 12)
##STR00299##
[0383] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 3.3%; LCMS: (FA) ES+ 361.
Example 14
Synthesis of
6-{[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}-N-hydroxy-4,5,6,7-te-
trahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 13)
##STR00300##
[0385] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 2.4%; LCMS: (FA) ES+ 423.
Example 15
Synthesis of
6-[1-adamantylcarbonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
-2-carboxamide (Compound 14)
##STR00301##
[0387] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 1.8%; LCMS: (FA) ES+ 361.
Example 16
Synthesis of
N-hydroxy-6-{[1-(phenylsulfonyl)piperidin-2-yl]carbonyl}-4,5,6,7-tetrahyd-
rothieno[2,3-c]pyridine-2-carboxamide (Compound 15)
##STR00302##
[0389] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 3.1%; LCMS: (FA) ES+ 436.
Example 17
Synthesis of
N-hydroxy-6-[2-methyl-5-(piperidin-1-ylsulfonyl)-3-furoyl]-4,5,6,7-tetrah-
ydrothieno[2,3-c]pyridine-2-carboxamide (Compound 16)
##STR00303##
[0391] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 9.8%; LCMS: (FA) ES+ 454.
Example 18
Synthesis of
6-(9H-fluoren-9-ylacetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide (Compound 17)
##STR00304##
[0393] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 7.6%; LCMS: (FA) ES+ 405.
Example 19
Synthesis of
6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-2-carboxamide (Compound 18)
##STR00305##
[0395] A solution of
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (40 mg, 0.203
mmol), 2,2-diphenylethanesulfonylchloride (114 mg, 0.406 mmol),
N,N-dimethylaminopyridine (2.48 mg, 0.02 mmol), and triethylamine
(56.5 uL, 0.406 mmol) in 1,2-dichloroethane (0.5 mL) was stirred at
room temperature overnight. The reaction was diluted with
dichloroethane and the solution was washed with saturated aqueous
NaHCO.sub.3. The aqueous layer was extracted with twice with
dichloroethane, the combined organic phases were washed with brine,
dried over anhydrous MgSO.sub.4 and concentrated to give a solid
residue.
[0396] To the solid obtained was added hydroxylamine hydrochloride
(56.4 mg, 0.811 mmol), potassium hydroxide (91 mg, 1.62 mmol), and
methanol (2 mL, 49 mmol). The mixture was heated at 80.degree. C.
for 3 h, cooled to room temperature and the solvent removed under
reduced pressure. To the residue was dissolved in DMSO (1.5 mL)
purified via Gilson prep-HPLC [208 nm, rt=7.30 (12 min), 30-60%
MeCN--H.sub.2O] to afford 32.3 mg (32.4%)
6-[(2,2-diphenylethyl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-2 carboxamide as a white solid. LCMS: (FA) ES+ 443;
.sup.1H NMR (MeOD, 400 MHz) .delta. 7.35-7.12 (m, 11H), 4.51 (t,
J=7.0 Hz, 1H), 4.20 (s, 2H), 3.96 (d, J=7.2 Hz, 2H), 3.28 (d, J=5.2
Hz, 2H), 2.59 (d, J=6.0 Hz, 2H).
Example 20
Synthesis of
6-(butylsulfonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2
carboxamide (Compound 19)
##STR00306##
[0398] The title compound was prepared in an analogous fashion to
that described in Example 19 Yield: 5.4%; Purification with Gilson
prep-HPLC [282 nm, rt=5.74 (12 min), 20-50% MeCN--H.sub.2O]; LCMS:
(FA) ES+ 319; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.10 (s, 1H),
6.92 (s, 1H), 4.17 (s, 2H), 3.22 (t, J=6.0 Hz, 2H), 2.69 (t, J=7.8
Hz, 2H), 2.42 (t, J=5.8 Hz, 2H), 1.35 (m, 2H), 1.07 (m, 2H), 0.55
(t, J=7.4 Hz, 3H).
Example 21
Synthesis of
6-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-N-hydroxy-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide (Compound 20)
##STR00307##
[0400] The title compound was prepared in an analogous fashion to
that described in Example 19. Yield: 5.6%; Purification with Gilson
prep-HPLC [196 nm, rt=5.71 (12 min), 20-45% MeCN--H.sub.2O]; LCMS:
(FA) ES+ 358; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.47 (s, 1H),
7.26 (s, 1H), 4.51 (s, 2H), 3.57 (t, J=6.0 Hz, 2H), 2.69 (q, J=7.3
Hz, 2H), 2.65 (s, 3H), 2.36 (s, 3H).
Example 22
Synthesis of
N-hydroxy-6-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide (Compound 21)
##STR00308##
[0402] The title compound was prepared in an analogous fashion to
that described in Example 19. Yield: 53.2%; Purification with
Gilson prep-HPLC [232 nm, rt=7.41 (12 min), 30-65% MeCN--H.sub.2O].
LCMS: (FA) ES+ 407; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.04 (d,
J=8.0 Hz, 2H), 7.98 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 4.40 (s, 2H),
3.42 (t, J=6.0 Hz, 2H), 2.65 (t, J=6.0 Hz, 2H).
Example 23
Synthesis of
6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-2-carboxamide (Compound 22)
##STR00309##
[0404] A solution of
7-(chloromethyl)-3,4-dihydro-2H-1,5-benzodioxepine (0.06 g, 0.3
mmol) and methyl thieno[2,3-c]pyridine-2-carboxylate (0.046 g, 0.24
mmol) in acetonitrile (2 mL) was heated at 40.degree. C. overnight
then at 60.degree. C. for 4 h. Upon cooling to room temperature,
the solvent was removed under reduced pressure to afford a solid
residue. The material thus obtained was dissolved in methanol (2
mL, 49 mmol), was cooled to -78.degree. C. under an N.sub.2
atmosphere and sodium borohydride (54.5 mg, 1.44 mmol) was added
slowly in portions. Upon complete addition, the reaction mixture
was allowed to warm to room temperature. The solvent was removed
under reduced pressure and the residue obtained was partitioned
between dichloroethane and water. The aqueous layer was extracted
with dichloroethane (2.times.), the combined organic phases were
dried over anhydrous MgSO.sub.4, and concentrated to give an
oil.
[0405] To the material obtained was added potassium hydroxide (108
mg, 1.92 mmol), hydroxylamine hydrochloride (66.7 mg, 0.96 mmol)
and methanol (2 mL, 49 mmol). The reaction mixture was heated at
80.degree. C. for 3 h. Upon cooling to room temperature, the
solvent was removed under reduced pressure and the residue obtained
was dissolved in DMSO (1.5 mL) and purified via Gilson prep-HPLC
[274 nm, rt=3.25 (12 min), 2-25% MeCN--H.sub.2O] to give 17.9 mg
(20.7%)
6-(3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-hydroxy-4,5,6,7-tetrahy-
dro thieno[2,3-c]pyridine-2-carboxamide as a white solid. LCMS:
(FA) ES+ 361; .sup.1H NMR (d.sub.6-DMSO, 400 MHz) .delta. 8.21 (s,
1H), 7.31 (s, 1H), 6.91 (m, 3H), 4.10 (m, 4H), 3.56 (s, 4H), 2.67
(m, 2H), 2.61 (m, 2H), 2.07 (m, 2H).
Example 24
Synthesis of
N-hydroxy-6-[4-(1H-pyrazol-1-yl)benzyl]-4,5,6,7-tetrahydrothieno[2,3-c]py-
ridine-2-carboxamide (Compound 23)
##STR00310##
[0407] The title compound was prepared in an analogous fashion to
that described in Example 23. Yield: 2.6%; Purification with Gilson
prep-HPLC [260 nm, rt=3.26 (12 min), 2-25% MeCN--H.sub.2O]; LCMS:
(FA) ES+ 355; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.36 (s, 1H),
8.22 (m, 1H), 7.72 (m, 3H), 7.52 (m, 2H), 7.28 (s, 1H), 6.52 (m,
1H), 3.83 (s, 2H), 3.75 (s, 2H), 2.88 (t, J=5.8 Hz, 2H), 2.77 (t,
J=5.8 Hz, 2H).
Example 25
Synthesis of
N-hydroxy-6-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-4,5,6,7
tetrahydro thieno[2,3-c]pyridine-2-carboxamide (Compound 24)
##STR00311##
[0409] The title compound was prepared in an analogous fashion to
that described in Example 23. Yield: 9.5%; Purification with Gilson
prep-HPLC [272 nm, rt=4.03 (12 min), 10-30% MeCN--H.sub.2O]; LCMS:
(FA) ES+ 370; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.22 (s, 1H),
8.00 (d, J=8.8 Hz, 2H), 7.48 (m, 1H), 7.32 (tt, J=7.6, 1.2 Hz, 2H),
3.92 (s, 2H), 3.84 (s, 2H), 2.95 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.8
Hz, 2H), 2.40 (s, 3H).
Example 26
Synthesis of
6-(2,1,3-benzothiadiazol-4-ylmethyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2-
,3c]pyridine-2-carboxamide (Compound 25)
##STR00312##
[0411] The title compound was prepared in an analogous fashion to
that described in Example 23. Yield: 5.6%; Purification with Gilson
prep-HPLC [306 nm, rt=3.02 (12 min), 2-22% MeCN--H.sub.2O]; LCMS:
(FA) ES+ 347; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.32 (s, 1H),
7.97 (m, 1H), 7.70 (m, 2H), 7.28 (s, 1H), 4.35 (s, 2H), 3.86 (s,
2H), 2.98 (t, J=5.8 Hz, 2H), 2.78 (t, J=5.8 Hz, 2H).
Example 27
Synthesis of ethyl
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
##STR00313##
[0413] Into a 100-mL round-bottom flask charged with 5-tert-butyl
2-ethyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (1
g, 3.21 mmol; prepared as described in J. Med. Chem. 2006,
49(15):4623-4637) and DCM (16 mL) was slowly added trifluoroacetic
acid (1.48 mL, 19.3 mmol) at 0.degree. C. The solution was then
stirred at room temperature for 60 min. To the reaction mixture was
then added saturated aqueous NaHCO.sub.3 solution (10 mL) and DCM
(10 mL). Upon separation of the layers, the aqueous solution was
further extracted with DCM (20 mL) twice. The combined organic
layers were washed with brine, dried over anhydrous MgSO.sub.4, and
concentrated to give ethyl
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.547 g,
81%) as an oil. LCMS: (FA) ES+ 212.
Example 28
Synthesis of
5-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridi-
ne-2-carboxamide (Compound 26)
##STR00314##
[0415] To a solution of HATU (104 mg, 0.274 mmol) and
trimethylacetic acid (28 mg, 0.274 mmol) in DCM (2 mL) was added
triethylamine (104 .mu.L, 0.203 mmol). The reaction solution was
stirred at room temperature for 30 min. A solution of ethyl
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20 mg, 0.101
mmol; prepared as described in J. Med. Chem. 2006,
49(15):4623-4637) in DMF (0.5 mL) was added in one portion. The
solution was then stirred at room temperature overnight. The
solution was then diluted with DCM and washed with saturated
aqueous NaHCO.sub.3. The aqueous layer was extracted with DCM
twice, the combined organic phases were additionally washed with
water, brine, dried over anhydrous MgSO.sub.4 and concentrated to
afford an oil residue. To the material thus obtained was added
methanol (2 mL), hydroxylamine hydrochloride (52.1 mg, 0.75 mmol),
and potassium hydroxide (84.2 mg, 1.5 mmol). The reaction mixture
was heated at 80.degree. C. for 3 h, cooled to room temperature and
the solvent removed in vacuo. The solid residue obtained was
dissolved in DMSO (1.4 mL) and purified with Gilson prep-HPLC [282
nm, rt=5.2 (12 min), 15-40% MeCN--H.sub.2O] to afforded white solid
(16.1 mg, 24%) as a white solid. LCMS: (FA) ES+ 283; .sup.1H NMR
(d.sub.6,DMSO, 400 MHz) .delta. 11.13 (s, 1H), 9.08 (s, 1H), 7.37
(s, 1H), 4.56 (s, 2H), 3.83 (t, J=5.8 Hz, 2H), 2.83 (t, J=5.4 Hz,
2H), 1.22 (s, 9H).
Example 29
Synthesis of
N-hydroxy-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[-
3,2-c]pyridine-2-carboxamide (Compound 27)
##STR00315##
[0417] The title compound was prepared in an analogous fashion to
that described in Example 28. (18.3 mg, 24%). LCMS: (FA) ES+
306.
Example 30
Synthesis of
N-hydroxy-5-(1-methylcyclohexanecarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]-
pyridine-2-carboxamide (Compound 28)
##STR00316##
[0419] The title compound was prepared in an analogous fashion to
that described in Example 28. (21.0 mg, 26%). LCMS: (FA) ES+
323.
Example 31
Synthesis of
N-hydroxy-5-(5-methylpyrazine-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]-
pyridine-2-carboxamide (Compound 29)
##STR00317##
[0421] The title compound was prepared in an analogous fashion to
that described in Example 28. (10.3 mg, 12.9%). LCMS: (FA) ES+
319.
Example 32
Synthesis of
N-hydroxy-5-(quinolin-8-ylcarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridi-
ne-2-carboxamide (Compound 30)
##STR00318##
[0423] The title compound was prepared in an analogous fashion to
that described in Example 28. (14.9 mg, 16.9%). LCMS: (FA) ES+
354.
Example 33
Synthesis of
5-(cyclohexanecarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-
-2-carboxamide (Compound 31)
##STR00319##
[0425] The title compound was prepared in an analogous fashion to
that described in Example 28. (14.5 mg, 18.8%). LCMS: (FA) ES+
309.
Example 34
Synthesis of
5-(4-(4,6-dimethoxypyrimidin-2-yl)benzoyl)-N-hydroxy-4,5,6,7-tetrahydroth-
ieno[3,2-c]pyridine-2-carboxamide (Compound 32)
##STR00320##
[0427] The title compound was prepared in an analogous fashion to
that described in Example 28. (18.7 mg, 20.6%). LCMS: (FA) ES+
309.
Example 35
Synthesis of
5-(adamantan-1-ylcarbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyrid-
ine-2-carboxamide (Compound 33)
##STR00321##
[0429] The title compound was prepared in an analogous fashion to
that described in Example 28. (26.7, 41.1%); LCMS: (FA) ES+
361.
Example 36
Synthesis of
N-hydroxy-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5,6,7-tetrahydrothien-
o[3,2-c]pyridine-2-carboxamide (Compound 34)
##STR00322##
[0431] The title compound was prepared in an analogous fashion to
that described in Example 28. Yield: 49.9%; Purification with
Gilson prep-HPLC [228 nm, rt=7.39 (12 min), 30-65% MeCN--H.sub.2O].
LCMS: (FA) ES+ 407; .sup.1H NMR (MeOD, 400 MHz) .delta. 8.04 (d,
J=8.0 Hz, 2H), 7.91 (d, J=8.0 Hz, 2H), 7.25 (s, 1H), 4.26 (s, 2H),
3.51 (t, J=6.0 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H).
Example 37
Synthesis of
6-{[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}-N-hydroxy-4,5,6,7--
tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 184)
##STR00323##
[0433] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 10.5%; LCMS: (FA) ES+ 402.
Example 38
Synthesis of
N-hydroxy-3-methyl-5-[4-(trifluoromethyl)benzyl]-4,5,6,7-tetrahydrothieno-
[3,2-c]pyridine-2-carboxamide (Compound 68)
##STR00324##
[0435] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 4.2%; LCMS: (FA) ES+ 385.
Example 39
Synthesis of
6-[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothi-
eno[2,3-c]pyridine-2-carboxamide (Compound 47)
##STR00325##
[0437] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 11.9%; LCMS: (FA) ES+ 352.
Example 40
Synthesis of
N-hydroxy-6-[(6-hydroxypyridin-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[2,-
3-c]pyridine-2-carboxamide (Compound 81)
##STR00326##
[0439] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 11.8%; LCMS: (FA) ES+ 320.
Example 41
Synthesis of
N-hydroxy-6-(2-(2-methylthiazol-4-yl)acetyl)-4,5,6,7-tetrahydrothieno[2,3-
-c]pyridine-2-carboxamide (Compound 75)
##STR00327##
[0441] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 7.4%; LCMS: (FA) ES+ 338.
Example 42
Synthesis of
6-(furan-2-carbonyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2--
carboxamide (Compound 42)
##STR00328##
[0443] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 17.7%; LCMS: (FA) ES+ 293.
Example 43
Synthesis of
6-(2,5-dimethyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide (Compound 178)
##STR00329##
[0445] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 22.9%; LCMS: (FA) ES+ 321.
Example 44
Synthesis of
6-({3-[(2-amino-2-oxoethyl)sulfanyl]-2-thienyl}carbonyl)-N-hydroxy-4,5,6,-
7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 56)
##STR00330##
[0447] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 7.0%; LCMS: (FA) ES+ 398.
Example 45
Synthesis of
M-[2-fluoro-5-(trifluoromethyl)phenyl]-N.sup.2-hydroxy-4,7-dihydrothieno[-
2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 106)
##STR00331##
[0449] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 5.2%; LCMS: (FA) ES+ 389.
Example 46
Synthesis of
N-hydroxy-6-(quinolin-2-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridi-
ne-2-carboxamide (Compound 179)
##STR00332##
[0451] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 7.1%; LCMS: (FA) ES+ 354.
Example 47
Synthesis of
N-hydroxy-6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetyl]-4,5,6,7-tetrahydr-
othieno[2,3-c]pyridine-2-carboxamide (Compound 65)
##STR00333##
[0453] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 398.
Example 48
Synthesis of
6-(3,5-difluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
-2-carboxamide (Compound 140)
##STR00334##
[0455] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 7.7%; LCMS: (FA) ES+ 339.
Example 49
Synthesis of
N-hydroxy-6-(2-methyl-4-phenylpyrimidine-5-carbonyl)-4,5,6,7-tetrahydroth-
ieno[2,3-c]pyridine-2-carboxamide (Compound 48)
##STR00335##
[0457] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 16.8%; LCMS: (FA) ES+ 395.
Example 50
Synthesis of
N-hydroxy-6-(2,3,5,6-tetrafluorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]p-
yridine-2-carboxamide (Compound 156)
##STR00336##
[0459] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 5.8%; LCMS: (FA) ES+ 375.
Example 51
Synthesis of
6-[(4,6-dimethoxypyrimidin-2-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothi-
eno[2,3-c]pyridine-2-carboxamide (Compound 100)
##STR00337##
[0461] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 5.8%; LCMS: (FA) ES+ 365.
Example 53
Synthesis of
6-[(4-tert-butylphenyl)acetyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]p-
yridine-2-carboxamide (Compound 118)
##STR00338##
[0463] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 12.7%; LCMS: (FA) ES+ 373.
Example 54
Synthesis of
6-(2-(3,5-dimethyl-1H-pyrazol-1-yl)acetyl)-N-hydroxy-4,5,6,7-tetrahydroth-
ieno[2,3-c]pyridine-2-carboxamide (Compound 125)
##STR00339##
[0465] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 6.3%; LCMS: (FA) ES+ 335.
Example 55
Synthesis of
N-hydroxy-6-[(4-methyl-1,3-thiazol-5-yl)carbonyl]-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide (Compound 98)
##STR00340##
[0467] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 14.6%; LCMS: (FA) ES+ 324.
Example 56
Synthesis of
N-hydroxy-6-(quinoline-6-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-
e-2-carboxamide (Compound 95)
##STR00341##
[0469] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 11.6%; LCMS: (FA) ES+ 354.
Example 57
Synthesis of
N-hydroxy-6-[(1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahydrothieno-
[2,3-c]pyridine-2-carboxamide (Compound 127)
##STR00342##
[0471] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 6.3%; LCMS: (FA) ES+ 369.
Example 58
Synthesis of
6-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahyd-
rothieno[2,3-c]pyridine-2-carboxamide (Compound 149)
##STR00343##
[0473] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 22.4%; LCMS: (FA) ES+ 335.
Example 59
Synthesis of
6-[(3,5-dimethylisoxazol-4-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide (Compound 177)
##STR00344##
[0475] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 21.3%; LCMS: (FA) ES+ 322.
Example 60
Synthesis of
N-hydroxy-6-[(5-methyl-3-phenylisoxazol-4-yl)carbonyl]-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine-2-carboxamide (Compound 107)
##STR00345##
[0477] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 5.5%; LCMS: (FA) ES+ 384.
Example 61
Synthesis of
N-hydroxy-6-(3-methyl-2-furoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-
-carboxamide (Compound 94)
##STR00346##
[0479] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 18.3%; LCMS: (FA) ES+ 307.
Example 62
Synthesis of
6-[(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tet-
rahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 69)
##STR00347##
[0481] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 16.7%; LCMS: (FA) ES+ 363.
Example 63
Synthesis of
6-[3,5-bis(trifluoromethyl)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,-
3-c]pyridine-2-carboxamide (Compound 36)
##STR00348##
[0483] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 5.7%; LCMS: (FA) ES+ 439.
Example 64
Synthesis of
6-(2-(3,5-dimethylisoxazol-4-yl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothien-
o[2,3-c]pyridine-2-carboxamide (Compound 62)
##STR00349##
[0485] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 8.3%; LCMS: (FA) ES+ 336.
Example 65
Synthesis of
N-hydroxy-6-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahydrothieno[-
2,3-c]pyridine-2-carboxamide (Compound 116)
##STR00350##
[0487] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 19.5%; LCMS: (FA) ES+ 306.
Example 66
Synthesis of
6-(2-(3,5-difluorophenyl)acetyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c-
]pyridine-2-carboxamide (Compound 52)
##STR00351##
[0489] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 4.6%; LCMS: (FA) ES+ 353.
Example 67
Synthesis of
6-(4-fluoro-3-methylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyr-
idine-2-carboxamide (Compound 51)
##STR00352##
[0491] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 20.1%; LCMS: (FA) ES+ 335.
Example 68
Synthesis of
6-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tet-
rahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 88)
##STR00353##
[0493] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 24.5%; LCMS: (FA) ES+ 363.
Example 69
Synthesis of
N-hydroxy-6-(2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)-4,5,-
6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (Compound 93)
##STR00354##
[0495] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 7.7%; LCMS: (FA) ES+ 389.
Example 70
Synthesis of
6-(4-tert-butylbenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
-2-carboxamide (Compound 64)
##STR00355##
[0497] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 20.9%; LCMS: (FA) ES+ 359.
Example 71
Synthesis of
6-(5-tert-butyl-2-methyl-3-furoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-
-c]pyridine-2-carboxamide (Compound 67)
##STR00356##
[0499] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 20.2%; LCMS: (FA) ES+ 363.
Example 72
Synthesis of
6-[3,5-bis(acetylamino)benzoyl]-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-2-carboxamide (Compound 131)
##STR00357##
[0501] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 8.0%; LCMS: (FA) ES+ 417.
Example 73
Synthesis of
6-[(3-ethyl-1-methyl-1H-pyrazol-5-yl)carbonyl]-N-hydroxy-4,5,6,7-tetrahyd-
rothieno[2,3-c]pyridine-2-carboxamide (Compound 186)
##STR00358##
[0503] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 335.
Example 74
Synthesis of
6-(3-(1H-pyrazol-1-yl)benzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]p-
yridine-2-carboxamide (Compound 133)
##STR00359##
[0505] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 7.2%; LCMS: (FA) ES+ 369.
Example 75
Synthesis of
6-(4-fluorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-c-
arboxamide (Compound 182)
##STR00360##
[0507] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 19.3%; LCMS: (FA) ES+ 321.
Example 76
Synthesis of
N-hydroxy-6-(4-(trifluoromethyl)benzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]p-
yridine-2-carboxamide (Compound 171)
##STR00361##
[0509] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 8.4%; LCMS: (FA) ES+ 371.
Example 77
Synthesis of
N-hydroxy-6-(quinoline-8-carbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-
e-2-carboxamide (Compound 99)
##STR00362##
[0511] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 10.1%; LCMS: (FA) ES+ 354.
Example 78
Synthesis of
N-hydroxy-6-({[3-(trifluoromethyl)phenyl]sulfanyl}acetyl)-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-2-carboxamide (Compound 89)
##STR00363##
[0513] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 11.0%; LCMS: (FA) ES+ 417.
Example 79
Synthesis of
N-hydroxy-6-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)carbonyl]-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-2-carboxamide (Compound 84)
##STR00364##
[0515] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 22.7%; LCMS: (FA) ES+ 383.
Example 80
Synthesis of
N-hydroxy-6-(1,3-thiazol-4-ylcarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyr-
idine-2-carboxamide (Compound 146)
##STR00365##
[0517] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 12.8%; LCMS: (FA) ES+ 310.
Example 81
Synthesis of
N-hydroxy-6-[(4-methyl-2-phenylpyrimidin-5-yl)carbonyl]-4,5,6,7-tetrahydr-
othieno[2,3-c]pyridine-2-carboxamide (Compound 152)
##STR00366##
[0519] The title compound was prepared in an analogous fashion to
that described in Example 2. Yield: 17.2%; LCMS: (FA) ES+ 395.
Example 82
Synthesis of
N2-hydroxy-N6-(4-methylbenzyl)-4,5-dihydrothieno[2,3-c]pyridine-2,6(5H)-d-
icarboxamide (Compound 103)
##STR00367##
[0521] To a vial charged with 1-(isocyanatomethyl)-4-methylbenzene
(0.032 g, 0.22 mmol) was added methyl
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylate (0.0434 g,
0.22 mmol) in 1,2-dichloroethane (2 mL). The solution was stirred
at rt for 2 h. The solvent was evaporated. To the residue was added
potassium hydroxide (0.099 g, 1.76 mmol), hydroxylamine
hydrochloride (0.046 g 0.66 mmol), and methanol (2 mL). The vial
was capped and heated at 80.degree. C. with vigorous shaking for 1
h, then cooled to rt. To the vial was added acetic acid (0.1 mL)
and the solution was shaken at rt for 15 min. The solvent was
completed removed. To the residue was added DMSO (1.3 mL) and the
solution was filtered and purified by Gilson prep-HPLC to afford
0.007 g (11.2%) of a white solid. LCMS: (FA) ES+346.
Example 83
Synthesis of
N.sup.2-hydroxy-N.sup.6-(5-methyl-3-phenylisoxazol-4-yl)-4,7-dihydrothien-
o[2,3-c]pyridine-2,6(5H)-dicarboxamide (Compound 132)
##STR00368##
[0523] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 20.4%; LCMS: (FA) ES+ 399.
Example 84
Synthesis of
N.sup.2-hydroxy-N.sup.6-(3-methylphenyl)-4,7-dihydrothieno[2,3-c]pyridine-
-2,6(5H)-dicarboxamide (Compound 80)
##STR00369##
[0525] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 4.8%; LCMS: (FA) ES+ 332.
Example 85
Synthesis of
N.sup.2-hydroxy-N.sup.6-[3-(trifluoromethyl)phenyl]-4,7-dihydrothieno[2,3-
-c]pyridine-2,6(5H)-dicarboxamide (Compound 54)
##STR00370##
[0527] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 3.6%; LCMS: (FA) ES+ 386.
Example 86
Synthesis of
N.sup.6-(4-butylphenyl)-N.sup.2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine--
2,6(5H)-dicarboxamide (Compound 169)
##STR00371##
[0529] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 12.1%; LCMS: (FA) ES+ 374.
Example 87
Synthesis of
N.sup.2-hydroxy-N.sup.6-(5-phenyl-2-thienyl)-4,7-dihydrothieno[2,3-c]pyri-
dine-2,6(5H)-dicarboxamide (Compound 40)
##STR00372##
[0531] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 6.8%; LCMS: (FA) ES+ 400.
Example 88
Synthesis of
N.sup.2-hydroxy-N.sup.6-mesityl-4,7-dihydrothieno[2,3-c]pyridine-2,6(5H)--
dicarboxamide (Compound 176)
##STR00373##
[0533] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 26.3%; LCMS: (FA) ES+ 360.
Example 89
Synthesis of
N.sup.2-hydroxy-N.sup.6-(4-isopropylphenyl)-4,7-dihydrothieno[2,3-c]pyrid-
ine-2,6(5H)-dicarboxamide (Compound 139)
##STR00374##
[0535] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 5.2%; LCMS: (FA) ES+ 360.
Example 90
Synthesis of
N.sup.6-cyclohexyl-N.sup.2-hydroxy-4,7-dihydrothieno[2,3-c]pyridine-2,6(5-
H)-dicarboxamide (Compound 76)
##STR00375##
[0537] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 20.1%; LCMS: (FA) ES+ 324.
Example 91
Synthesis of
N.sup.2-hydroxy-N.sup.6-(4-iodophenyl)-4,7-dihydrothieno[2,3-c]pyridine-2-
,6(5H)-dicarboxamide (Compound 163)
##STR00376##
[0539] The title compound was prepared in an analogous fashion to
that described in Example 82. Yield: 13.2%; LCMS: (FA) ES+ 444.
Example 92
Synthesis of ethyl
3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
##STR00377##
[0540] Step 1: ethyl
3-methylthieno[3,2-c]pyridine-2-carboxylate
[0541] To a solution of ethyl 2-mercaptoacetate (5.52 g, 0.046 mol)
and triethylamine (5.52 g, 0.055 mol) in acetonitrile (100 mL) at
room temperature was added 1-(4-chloropyridin-3-yl)ethanone (6.5 g,
0.042 mol). The reaction mixture was heated at reflux for 18 hours.
Upon cooling to room temperature, the solvent was evaporated and
the residue obtained partitioned between ethyl acetate and water.
The organic layer was dried over anhydrous NaHSO.sub.4, filtered
and concentrated. The oily residue was passed through a pad of
silica (ethyl acetate/hexane: 5/1) to afford ethyl
3-methylthieno[3,2-c]pyridine-2-carboxylate (1.6 g, 22%). LCMS (FA)
ES+ 222; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.10 (s, 1H),
8.50 (d, J=5.6 Hz, 1H), 7.98 (d, J=17.6 Hz, 1H), 4.37 (d, J=7.2 Hz,
2H), 3.58 (t, J=5.9 Hz, 2H), 1.38 (d, J=7.2 Hz, 3H).
Step 2: ethyl
3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
[0542] A mixture of ethyl
3-methylthieno[3,2-c]pyridine-2-carboxylate (4 g, 0.018 mol) and
PtO.sub.2 (0.5 g, 0.002 mol) in ethanol (100 mL) was stirred under
an H.sub.2 atmosphere (3 atmospheres) for 72 hours at room
temperature. The PtO.sub.2 was removed by filtration, the filtrate
was concentrated under reduced pressure and the residue obtained
was purified by silica gel chromatography (DCM/EtOH=10:1) to afford
ethyl
3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (1.6
g, 40%). ES+ 226; .sup.1H NMR (400 MHz, DMSO) .delta. 4.24 (q,
J=7.1 Hz, 2H), 3.93 (s, 2H), 3.21 (t, J=5.9 Hz, 2H), 2.89 (t, J=5.7
Hz, 2H), 2.55 (s, 1H), 2.34 (s, 3H), 1.26 (t, J=6.0 Hz, 3H).
Example 93
Synthesis of
7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-
-c]pyridine-2-carboxamide
##STR00378##
[0543] Step 1:
1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde
[0544] A solution of anhydrous DMF (142 mL, 1.85 mol) in anhydrous
DCM (670 mL) was cooled to 0.degree. C. A solution of POCl.sub.3
(121 mL, 1.3 mol) in anhydrous DCM (87 mL) was added dropwise. Upon
complete addition, the solution was warmed to room temperature and
further to reflux for 30 minutes. A solution of
1-benzyl-3,3-dimethylpiperidin-4-one (75 g, 0.35 mol) in anhydrous
DCM (133 mL) was added all at once to the boiling solution and the
mixture was further refluxed overnight. The reaction was cooled to
room temperature and added dropwise to a biphasic mixture of 4.0 M
aqueous sodium acetate (1000 mL) and DCM (300 mL). Upon separation
of the layers, the organic layer was washed with water, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated to dryness to afford
1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde
(75 g, 82% crude yield).
Step 2: ethyl
5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxyla-
te
[0545] To a solution of
1-benzyl-4-chloro-5,5-dimethyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde
(75 g, 0.28 mol) in DCM (1.2 L) was added ethyl 2-mercaptoacetate
(67 g, 0.56 mol) and triethylamine (85 g, 0.84 mol) was added
slowly at room temperature. Upon complete addition, the reaction
mixture was heated at reflux overnight. Upon cooling to room
temperature, the reaction was quenched with the addition of water.
The organic layer was washed with water, dried over anhydrous
Na.sub.2SO.sub.4, concentrated and purified by silica gel
chromatography (0-20% EtOAc/hexane) to afford the title compound
(31.7 g, 27.5% over two steps).
Step 3: ethyl
7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
hydrochloride
[0546] A solution of ethyl
5-benzyl-7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxyla-
te (14.6 g, 0.044 mol) in anhydrous DCM was cooled to 0.degree. C.
whereupon K.sub.2CO.sub.3 (6.1 g, 0.044 mmol) and
.alpha.-chloroethyl chloroformate (6.97 g, 0.049 mol) were added.
Upon complete addition, the reaction was heated at reflux
overnight. The reaction was cooled to room temperature and diluted
with DCM, then washed with saturated aqueous NaHCO.sub.3 and brine
respectively. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and evaporated to afford an oily residue which was
taken up in EtOH and refluxed for 2 hours. The solvent was
evaporated to dryness and the residue was washed with ethyl acetate
to afford the desired product (9.6 g, 79%). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.82 (s, 2H), 7.64 (s, 1H), 4.28 (q, J=7.2 Hz, 2H),
4.15 (s, 2H), 3.26 (s, 2H), 1.42 (s, 6H), 1.28 (t, J=7.2 Hz,
3H).
Step 4: ethyl
7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyr-
idine-2-carboxylate
[0547] A solution of ethyl
7,7-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
(20.5 g, 0.074 mol) and DIPEA (42.8 g, 0.37 mol) in DCM (400 mL)
was cooled to 0.degree. C. 2-nitrobenzene-1-sulfonyl chloride (17.3
g, 0.078 mol) was then added and the reaction mixture was allowed
to warm to room temperature overnight. The crude reaction solution
was applied directly to a silica gel column and purified (10-20%
EtOAc/hexane) to afford product (27.6 g, 88%). NMR (400 MHz,
CDCl.sub.3) .delta. 7.98 (dd, J=4.8, 2.4 Hz, 1H), 7.64-7.68 (m,
2H), 7.57 (dd, J=4.4, 2.4 Hz, 1H), 7.37 (s, 1H), 7.19 (s, 1H), 4.33
(s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.33 (s, 2H), 1.31 (s, 6H), 1.19
(t, J=7.2 Hz, 3H),
Step 5:
7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,-
2-c]pyridine-2-carboxylic acid
[0548] To a solution of ethyl
7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyr-
idine-2-carboxylate (32.6 g, 76.8 mmol) in THF (853 mL) was added
1.0 M aqueous LiOH (307 mL, 307 mmol) and the reaction mixture
stirred overnight at room temperature. The solution was
concentrated and the residue dissolved in water (100 mL) and
neutralized with 1.0 M, aqueous HCl (307 mL). The resulting
precipitate was collected via vacuum filtration to afford white
solid (29 g, 95%). LCMS (FA) ES+ 397; .sup.1H NMR (400 MHz, DMSO)
.delta. 13.04 (s, 1H), 8.08 (dd, J=7.6, 1.6 Hz, 1H), 8.02 (dd,
J=7.7, 1.5 Hz, 1H), 7.95-7.86 (m, 2H), 7.49 (s, 1H), 4.36 (s, 2H),
3.40 (s, 2H), 1.28 (s, 6H).
Step 6:
7,7-dimethyl-5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yl-
oxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide
[0549] A solution of
7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyr-
idine-2-carboxylic acid (20 g, 50 mmol) was cooled to 0.degree. C.
DIPEA (32.3 g, 250 mmol) was added and the solution was stirred at
0.degree. C. for 30 minutes.
O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (5.8 g, 50 mmol) and HATU
(22.8 g, 60 mmol) were then added and the reaction was allowed to
warm to room temperature overnight. The reaction mixture was washed
with water, brine and dried over anhydrous Na.sub.2SO.sub.4,
concentrated and purified by silica gel chromatography (20-50%
EtOAc/hexane) to afford product (23.5 g, 94%). LCMS (FA) ES+ 496;
.sup.1H NMR (400 MHz, DMSO) .delta. 11.60 (s, 1H), 8.10 (dd, J=7.7,
1.5 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz, 1H), 7.90 (dtd, J=17.6, 7.5,
1.4 Hz, 2H), 7.41 (s, 1H), 4.92 (s, 1H), 4.33 (s, 2H), 4.00 (s,
1H), 3.50 (d, J=11.1 Hz, 1H), 3.38 (s, 2H), 1.72 (d, J=22.2 Hz,
3H), 1.53 (s, 3H), 1.27 (s, 6H).
Step 7:
7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothi-
eno[3,2-c]pyridine-2-carboxamide
[0550] To a mixture of
7,7-dimethyl-5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,-
5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (15.4 g, 31
mmol) and cesium carbonate (20.2 g, 62 mmol) in acetonitrile (800
mL) was added a solution of thiophenol (6.85 g, 62 mmol) in
acetonitrile (70 mL). The reaction mixture was stirred at room
temperature overnight. The solvent was removed in vacuo and the
residue applied to silica gel chromatography (0-20% DCM/MeOH) to
afford the title compound (8.2 g, 85%). LCMS (FA) ES+ 311; .sup.1H
NMR (400 MHz, DMSO) .delta. 11.49 (s, 1H), 7.30 (s, 1H), 4.91 (s,
1H), 4.01 (dd, J=15.6, 8.0 Hz, 1H), 3.71 (s, 2H), 3.55-3.44 (m,
1H), 2.71 (s, 2H), 1.69 (s, 3H), 1.53 (s, 3H), 1.25 (s, 6H).
Example 94
Synthesis of
N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-tetrahyd-
rothieno[3,2-c]pyridine-2-carboxamide (Compound 194)
##STR00379##
[0551] Step 1: ethyl
3-methyl-5-(1-methyl-1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2--
c]pyridine-2-carboxylate
[0552] A solution of N-methylpyrrole-2-carboxylic acid (12.5 mg,
0.1 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (0.048 g, 0.11 mmol) and
N,N-diisopropylethylamine (52.2 .mu.L, 0.3 mmol) in
N,N-dimethylformamide (1 mL, 12.9 mmol) was stirred at room
temperature for 15 minutes. A solution of ethyl
3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
(22.5 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was then added
and the reaction was further stirred at room temperature overnight.
The solution was evaporated to dryness and the residue obtained was
partitioned between DCM (2 mL) and half-saturated aqueous sodium
bicarbonate solution (2 mL). Upon separation of the layers, the
aqueous layer was extracted with additional DCM (2 mL) and the
combined organic layers were concentrated to dryness.
Step 2:
N-hydroxy-3-methyl-5-[(1-methyl-1H-pyrrol-2-yl)carbonyl]-4,5,6,7-t-
etrahydrothieno[3,2-c]pyridine-2-carboxamide
[0553] A mixture of hydroxylamine hydrochloride (2 g, 29 mmol) in
methanol (10 mL) was heated at 90.degree. C. under a dry nitrogen
atmosphere until homogenous. To the heated solution was added a
solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6
mL). The formation of a white precipitate was observed. After
heating at 90.degree. C. for 30 minutes, the mixture was cooled to
room temperature and the solids allowed to settle. The resulting
solution was assumed to have a 1.7 M concentration of
hydroxylamine.potassium salt and was carefully removed by syringe
to exclude solids. An aliquot of the above solution (1 mL, 1.7
mmol) was added to a solution of ethyl
3-methyl-5-(1-methyl-1H-pyrrole-2-carbonyl)-4,5,6,7-tetrahydrothieno[3,2--
c]pyridine-2-carboxylate obtained in the previous step dissolved in
methanol (1 mL). After stirring for 30 minutes at room temperature,
the reaction was quenched with the addition of formic acid (0.1 mL,
3 mmol). The reaction mixture was concentrated to dryness and the
residue obtained redissolved in DMSO (1 mL) and purified by reverse
phase Gilson prep-HPLC to afford the title compound as a white
solid (7.2 mg, 22.5% over two steps). LCMS (FA) ES+ 320; .sup.1H
NMR (400 MHz, DMSO) .delta. 6.93-6.92 (m, 1H), 6.44 (dd, J=3.8, 1.6
Hz, 1H), 6.06 (dd, J=3.7, 2.6 Hz, 1H), 4.55 (s, 2H), 3.88 (t, J=5.6
Hz, 2H), 3.67 (s, 3H), 2.88 (d, J=2.8 Hz, 2H), 2.22 (s, 3H).
Example 95
[0554] The following compounds were prepared in a fashion analogous
to that described in Example 94 starting from the intermediates
which were prepared as described above and the corresponding
carboxylic acids.
TABLE-US-00003 Compound Structure LC-MS (FA) 221 ##STR00380## ES+
407 219 ##STR00381## ES+ 331 233 ##STR00382## ES+ 393 204
##STR00383## ES+ 297 209 ##STR00384## ES+ 347 225 ##STR00385## ES+
373 229 ##STR00386## ES+ 283 217 ##STR00387## ES+ 318 232
##STR00388## ES+ 337 216 ##STR00389## ES+ 357 199 ##STR00390## ES+
415 197 ##STR00391## ES+ 338 205 ##STR00392## ES+ 373 203
##STR00393## ES+ 375 193 ##STR00394## ES+ 351
Example 96
Synthesis of
5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,5,6,7-t-
etrahydrothieno[3,2-c]pyridine-2-carboxamide (Compound 192)
##STR00395##
[0555] Step 1: ethyl
5-(3-chlorobenzo[b]thiophene-2-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrot-
hieno[3,2-c]pyridine-2-carboxylate
[0556] A solution of 3-chloro-1-benzothiophene-2-carboxylic acid
(23.4 mg, 0.11 mmol),
N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (0.048 g, 0.11 mmol) and
N,N-diisopropylethylamine (52.2 pt, 0.3 mmol) in
N,N-dimethylformamide (1 mL, 12.9 mmol) was stirred at room
temperature for 15 minutes. A solution of
7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-
-c]pyridine-2-carboxamide (31 mg, 0.1 mmol) in
N,N-dimethylformamide (1 mL) was then added and the reaction was
further stirred at room temperature overnight. The solution was
evaporated to dryness and the residue obtained was partitioned
between DCM (2 mL) and half-saturated aqueous sodium bicarbonate
solution (2 mL). Upon separation of the layers, the aqueous layer
was extracted with additional DCM (2 mL) and the combined organic
layers were concentrated to dryness to afford the title
compound.
Step 2:
5-[(3-chloro-1-benzothien-2-yl)carbonyl]-N-hydroxy-7,7-dimethyl-4,-
5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide
[0557] To a solution of ethyl
5-(3-chlorobenzo[b]thiophene-2-carbonyl)-7,7-dimethyl-4,5,6,7-tetrahydrot-
hieno[3,2-c]pyridine-2-carboxylate obtained in step 1 in THF (0.5
mL) was added 4.0 M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The
reaction was stirred at room temperature for 2 hours whereupon it
was concentrated to dryness. The residue obtained was redissolved
in DMSO (1 mL) and purified on Gilson prep-HPLC to afford the title
compound (6.7 mg, 16% over two steps). LCMS (FA) ES+ 421; .sup.1H
NMR (400 MHz, DMSO) .delta. 8.16-8.11 (m, 1H), 7.89-7.83 (m, 1H),
7.63-7.55 (m, 2H), 7.46-7.12 (m, 1H), 4.64 (d, J=104.6 Hz, 2H),
3.88-3.49 (m, 2H), 1.36 (br s, 3H), 1.20 (br s, 3H).
Example 97
[0558] The following compounds were prepared in a fashion analogous
to that described in Example 96 starting from the intermediates
which were prepared as described above and the corresponding
carboxylic acids.
TABLE-US-00004 Compound Structure LC-MS (FA) 211 ##STR00396## ES+
414 226 ##STR00397## ES+ 337 220 ##STR00398## ES+ 332 215
##STR00399## ES+ 371 207 ##STR00400## ES+ 407 208 ##STR00401## ES+
446 214 ##STR00402## ES+ 361 234 ##STR00403## ES+ 365 210
##STR00404## ES+ 334 222 ##STR00405## ES+ 352 218 ##STR00406## ES+
365 198 ##STR00407## ES+ 403 228 ##STR00408## ES+ 429 224
##STR00409## ES+ 351 195 ##STR00410## ES+ 387 227 ##STR00411## ES+
445 190 ##STR00412## ES+ 387
Example 98
Synthesis of
N.sup.2-hydroxy-7,7-dimethyl-N5-[(1S)-1-phenylethyl]-6,7-dihydrothieno[3,-
2-c]pyridine-2,5(4H)-dicarboxamide (Compound 201)
##STR00413##
[0560] A solution of
7,7-dimethyl-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-
-c]pyridine-2-carboxamide (31 mg, 0.1 mmol) and triethylamine (41.8
.mu.L, 0.3 mmol) in 1,2-dichloroethane (1 mL) was added
(S)-1-phenylethyl isocyanate (22.1 mg, 0.15 mmol). The reaction was
stirred at room temperature overnight. The solution was evaporated
to dryness and the residue obtained was redissolved in
tetrahydrofuran (1 mL). 4.0 M of hydrochloric acid in 1,4-dioxane
(1 mL, 4 mmol) was added and the reaction solution was stirred at
room temperature for 2 hours. The solution was evaporated to
dryness, redissolved in DMSO (1 mL) and purified on an Agilent 1100
LC/MSD instrument to afford the title compound (17.8 mg, 46%). LCMS
(FA) ES+ 374; .sup.1H NMR (400 MHz, MeOD) .delta. 7.35-7.24 (m,
5H), 7.20-7.15 (m, 1H), 5.01-4.91 (m, 1H), 4.50 (d, J=4.0 Hz, 2H),
3.50 (d, J=4.6 Hz, 2H), 1.47 (d, J=7.1 Hz, 3H), 1.30 (s, 6H).
Example 99
[0561] The following compounds were prepared in a fashion analogous
to that described in Example 98 starting from the intermediates
which were prepared as described above and the corresponding
isocyanates.
TABLE-US-00005 Compound Structure LC-MS (FA) 213 ##STR00414## ES+
374 196 ##STR00415## ES+ 371 189 ##STR00416## ES+ 382 200
##STR00417## ES+ 374 206 ##STR00418## ES+ 387 202 ##STR00419## ES+
374 191 ##STR00420## ES+ 360
Example 100
Synthesis of tert-butyl
2-[(hydroxyamino)carbonyl]-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxy-
late (Compound 212)
##STR00421##
[0563] A mixture of 5-tert-butyl 2-ethyl
6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (0.056 g,
0.18 mmol; prepared as described in J. Med. Chem. 2006, 49(15):
4623), hydroxylamine hydrochloride (0.037 mg, 0.54 mmol) and
potassium hydroxide (0.1 mg, 1.8 mmol) in methanol (2 mL) was
heated at 75.degree. C. for 1 hour. Upon cooling to room
temperature the reaction was quenched by the addition of acetic
acid (100 .mu.L, 1.8 mmol) and the solvent was evaporated to
dryness. The residue was dissolved in DMSO (1 mL) and purified
using a Gilson prep to afford a white solid (26.9 mg, 50%). LCMS
(FA) ES+ 299; .sup.1H NMR (400 MHz, MeOD) .delta. 7.27 (s, 1H),
4.46 (s, 2H), 3.71 (t, J=5.4 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 1.48
(s, 9H).
Example 101
Synthesis of methyl
5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate
##STR00422##
[0564] Step 1: methyl
4,5-bis(chloromethyl)thiophene-2-carboxylate
[0565] A solution of methyl thiophene-2-carboxylate (1 mL, 8.65
mmol) in chloromethyl methyl ether (1 mL, 13 mmol) was added
dropwise to a suspension of zinc chloride (1.179 g, 8.65 mmol) in
chloromethyl methyl ether (8 mL, 104 mmol) under an N.sub.2
atmosphere. After complete addition, the mixture was stirred at
room temperature for 15 minutes over which time the suspension
became a homogenous clear colorless solution. The reaction was
further warmed to 60.degree. C. for 3 hours. The reaction mixture
was cooled to room temperature and poured over ice. The mixture was
stirred for 1 hour then extracted with EtOAc (30 mL). The organic
layer was dried over anhydrous MgSO.sub.4, concentrated and
purified via silica chromatography (5-10% EtOAc/hexane) to afford a
colorless solid (1.272 g, 61%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.71 (s, 1H), 4.78 (s, 2H), 4.59 (s, 2H), 3.89 (s, 3H).
Step 2: methyl
5-[(2-nitrophenyl)sulfonyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxy-
late
[0566] To a solution of methyl
4,5-bis(chloromethyl)thiophene-2-carboxylate (4.106 g, 17.17 mmol)
and 2-nitrobenzenesulfonamide (3.825 g, 18.92 mmol) in acetone (40
mL) was added 2.5 M of potassium carbonate in water (20 mL, 50
mmol). The resulting biphasic mixture was stirred at room
temperature for 1 hour then further heated at 45.degree. C.
overnight resulting in formation of precipitate. The reaction
mixture was cooled to room temperature and the precipitate was
collected by vacuum filtration. The solid obtained was washed with
water followed by cold methanol and dried under vacuum to afford an
off white solid (3.352 g, 53%). LCMS (FA) ES+ 369; .sup.1H NMR (400
MHz, DMSO) .delta. 8.02 (ddd, J=7.8, 4.9, 1.4 Hz, 2H), 7.90 (td,
J=7.7, 1.5 Hz, 1H), 7.84 (td, J=7.7, 1.4 Hz, 1H), 7.63 (s, 1H),
4.79 (t, J=2.9 Hz, 2H), 4.60 (t, J=2.9 Hz, 2H), 3.80 (s, 3H).
Step 3: methyl
5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate
[0567] To a mixture of methyl
5-[(2-nitrophenyl)sulfonyl]-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxy-
late (3.297 g, 8.95 mmol) and cesium carbonate (5.6 g, 17 mmol) in
acetonitrile (95 mL) was added a solution of benzenethiol (1.8 mL,
17 mmol) in acetonitrile (20 mL). The resulting reaction mixture
was stirred at room temperature for 4 hours. The solvent was
removed in vacuo and the residue was washed exhaustively with
Et.sub.2O to afford an off white solid (1.326 g, 80%). LCMS (FA)
ES+ 184; .sup.1H NMR (400 MHz, MeOD) .delta. 7.59 (s, 1H), 4.32 (t,
J=2.0 Hz, 2H), 4.17 (t, J=2.0 Hz, 2H), 3.85 (s, 3H).
Example 102
Synthesis of
5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-
-carboxamide (Compound 223)
##STR00423##
[0568] Step 1: methyl
5-pivaloyl-5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate
[0569] To a mixture of methyl
5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate (0.023 g, 0.127
mmol) and pivalic acid (0.014 g, 0.14 mmol) in methylene chloride
(0.92 mL) was added
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (0.055 g, 0.146 mmol) and N-methylmorpholine
(0.035 mL, 0.32 mmol) respectively. The reaction mixture was
stirred at room temperature overnight. The reaction was diluted
with additional DCM (2 mL) and washed with saturated aqueous
NaHCO.sub.3 (2 mL). The aqueous layer was extracted with additional
DCM (3 mL), and the combined organic layers were concentrated to
afford an oily residue. LCMS (FA) ES+ 268.
Step 2:
5-(2,2-dimethylpropanoyl)-N-hydroxy-5,6-dihydro-4H-thieno[2,3-c]py-
rrole-2-carboxamide
[0570] The residue obtained in the previous step was taken up in
methanol (1.7 mL, 43 mmol) and to the solution was added
hydroxylamine hydrochloride (0.035 g, 0.51 mmol) and potassium
hydroxide (0.086 g, 1.5 mmol). The mixture was heated at 80.degree.
C. for 45 minutes. The reaction was cooled to room temperature and
the solvent evaporated to dryness. The material was dissolved in
DMSO (1 mL), the insolubles removed via filtration and purified by
Gilson prep-HPLC. Lyophilization of fractions containing the
desired product afforded the title compound as a white solid (6.1
mg, 33% over two steps). LCMS (FA) ES+ 267; .sup.1H NMR (400 MHz,
DMSO) .delta. 11.24 (s, 1H), 9.14 (s, 1H), 7.43 (s, 1H), 4.74 (dd,
J=137.5, 64.7 Hz, 4H), 1.22 (s, 9H).
Example 103
[0571] The following compounds were prepared in a fashion analogous
to Example 102 starting from the intermediates which were prepared
as described above and the corresponding carboxylic acids.
TABLE-US-00006 Com- LC-MS pound Structure (FA) 230 ##STR00424## ES+
347 231 ##STR00425## ES+ 345
Example 104
[0572] The following compound was prepared in a fashion analogous
to that described in Example 99 starting from the intermediate
prepared as described in Example 2 employing the corresponding
carboxylic acid.
TABLE-US-00007 Com- LC-MS pound Structure (FA) 159 ##STR00426## ES+
308
Example 105
Synthesis of
5-(4-chlorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-c-
arboxamide (Compound 240)
##STR00427##
[0573] Step 1: ethyl
5-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
[0574] To ethyl
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.237 g,
1.12 mmol), 4-chlorobenzoic acid (0.228 g, 1.46 mmol) in
N,N-dimethylformamide (6 mL) was added a solution of
fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate
(0.444 g, 1.68 mmol) in N,N-diisopropylethylamine (0.6 mL). The
reaction solution was then stirred overnight at room temperature.
Water was then added and the mixture was extracted into ethyl
acetate. The organic layer was washed with brine and evaporated.
Purification of the residue obtained on silica gel (0-10% ethyl
acetate/DCM) afforded a sticky white solid (208 mg, 53%). LCMS (FA)
ES+ 350.
Step 2:
5-(4-chlorobenzoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyrid-
ine-2-carboxamide
[0575] A mixture of hydroxylamine hydrochloride (2 g, 29 mmol) in
methanol (10 mL) was heated at 90.degree. C. under a dry nitrogen
atmosphere until homogenous. To the heated solution was added a
solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6
mL). The formation of a white precipitate was observed. After
heating at 90.degree. C. for 30 minutes, the mixture was cooled to
room temperature and the solids allowed to settle. The resulting
solution was assumed to have a 1.7 M concentration of
hydroxylamine.potassium salt and was carefully removed by syringe
to exclude solids. An aliquot of the above solution (3.5 mL 5.92
mmol) was added to a solution of ethyl
5-(4-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate
obtained in the previous step dissolved in methanol (3.5 mL). After
stirring for 30 minutes at room temperature, the reaction was
quenched with the addition of acetic acid (0.3 mL, 5.86 mmol). The
reaction mixture was concentrated to dryness and purified on a
BioCAD 700E HPLC instrument using Sunfire C-18 (18.times.150 mm)
column to afford a white solid (115 mg, 58%). LCMS (FA) ES+ 337;
.sup.1H NMR (400 MHz, MeOD) .delta. 7.55-7.41 (m, 4H), 7.36 (br s,
0.5H), 7.13 (br s, 0.5H), 4.75 (br s, 1H), 4.52 (br s, 1H), 4.05
(br s, 1H), 3.70 (br s, 1H), 2.95 (br s, 2H).
Example 106
HDAC6 Enzyme Assay
[0576] 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.
1-1925) 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 107
Nuclear Extract HDAC Assay
[0577] 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 108
Western Blot and Immunofluorescence Assays
[0578] 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 (Abcam cat# ab21623) in the
immunofluorescence assay.
Example 109
In Vivo Tumor Efficacy Model
[0579] 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%.
[0580] 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.
[0581] 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.
[0582] 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 50 nM including compounds: 1, 2, 3,
4, 5, 6, 7, 8, 11, 13, 14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 30, 31, 32, 33, 34, 40, 42, 51, 54, 64, 65, 67, 68, 76, 80,
88, 89, 94, 95, 98, 99, 103, 107, 116, 127, 131, 132, 133, 139,
140, 146, 152, 156, 159, 163, 169, 171, 176, 177, 179, 184, 186,
187, 188, 193, 194, 205, 209, 212, 231, 233.
[0583] In certain embodiments, compounds of the invention inhibit
HDAC6 with an IC50 value of greater than 50 nM and less than 100 nM
including compounds: 9, 10, 15, 29, 47, 48, 52, 62, 75, 81, 100,
125, 149, 178, 182, 199, 216, 221, 225, 230.
[0584] In certain embodiments, compounds of the invention inhibit
HDAC6 with an IC50 value of greater than 100 nM and less than 1
.mu.M including compounds: 36, 69, 93, 106, 189, 191, 197, 200,
201, 202, 203, 204, 206, 207, 208, 211, 213, 215, 217, 219, 223,
226, 227, 228, 229, 232.
[0585] In certain embodiments, compounds of the invention inhibit
HDAC6 with an IC50 value of greater than 1 .mu.M including
compounds: 12, 17, 56, 111, 190, 192, 195, 196, 198, 210, 214, 218,
220, 222, 224, 234.
[0586] As detailed above, compounds of the invention are selective
for HDAC6 over other Class I HDAC enzymes. In some embodiments, the
ratio of HDAC IC50 (as obtained in the nuclear extract assay
described above) to HDAC6 IC50 is 10:1. In certain embodiments, the
ratio of HDAC IC50 to HDAC6 IC50 is 100:1. In certain embodiments,
the ratio of HDAC IC50 to HDAC6 IC50 is 1000:1.
[0587] 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.
* * * * *