U.S. patent application number 13/269697 was filed with the patent office on 2012-08-16 for compounds useful as antagonists of ccr2.
This patent application is currently assigned to Millennium Pharmaceuticals, Inc.. Invention is credited to Amy M. Elder, Shomir Ghosh, Sian Griffiths, Prakash Raman, Francois Soucy, Kevin Sprott, Qing Ye.
Application Number | 20120208818 13/269697 |
Document ID | / |
Family ID | 37897354 |
Filed Date | 2012-08-16 |
United States Patent
Application |
20120208818 |
Kind Code |
A1 |
Elder; Amy M. ; et
al. |
August 16, 2012 |
COMPOUNDS USEFUL AS ANTAGONISTS OF CCR2
Abstract
The present invention provides compounds of general formula I:
##STR00001## or a pharmaceutically acceptable salt thereof, wherein
X, n, Y, and R.sup.1 are defined generally and in subsets herein.
Compounds of the invention are inhibitors of CCR2 and accordingly
are useful for the treatment of a variety of inflammatory,
allergic, and autoimmune diseases, disorders, or conditions.
Inventors: |
Elder; Amy M.; (Arlington,
MA) ; Ghosh; Shomir; (Brookline, MA) ;
Griffiths; Sian; (Watertown, MA) ; Raman;
Prakash; (Acton, MA) ; Soucy; Francois;
(Stoneham, MA) ; Sprott; Kevin; (Boston, MA)
; Ye; Qing; (Westborough, MA) |
Assignee: |
Millennium Pharmaceuticals,
Inc.
Cambridge
MA
|
Family ID: |
37897354 |
Appl. No.: |
13/269697 |
Filed: |
October 10, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12084353 |
Feb 19, 2009 |
8067415 |
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PCT/US2006/042181 |
Oct 26, 2006 |
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13269697 |
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60732344 |
Nov 1, 2005 |
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Current U.S.
Class: |
514/237.2 ;
514/249; 514/266.21; 514/299; 514/309; 514/338; 514/394; 514/406;
544/141; 544/293; 544/349; 546/112; 546/141; 546/275.7; 548/306.1;
548/362.1 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
29/00 20180101; A61P 9/10 20180101; C07D 409/04 20130101; C07D
413/14 20130101; C07D 417/14 20130101; C07D 207/14 20130101; C07D
409/14 20130101; A61P 19/02 20180101; C07D 403/14 20130101; C07D
471/04 20130101; A61P 25/00 20180101; A61P 17/00 20180101; C07D
401/14 20130101; C07D 405/14 20130101 |
Class at
Publication: |
514/237.2 ;
546/112; 514/299; 544/293; 514/266.21; 546/275.7; 514/338; 514/394;
548/306.1; 548/362.1; 514/406; 514/249; 544/349; 546/141; 514/309;
544/141 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 405/14 20060101 C07D405/14; A61K 31/517 20060101
A61K031/517; A61K 31/4439 20060101 A61K031/4439; A61K 31/4184
20060101 A61K031/4184; A61K 31/416 20060101 A61K031/416; A61K
31/502 20060101 A61K031/502; C07D 471/04 20060101 C07D471/04; A61K
31/4725 20060101 A61K031/4725; C07D 401/14 20060101 C07D401/14;
C07D 403/14 20060101 C07D403/14; C07D 413/14 20060101 C07D413/14;
A61P 29/00 20060101 A61P029/00; A61P 19/02 20060101 A61P019/02;
A61P 25/00 20060101 A61P025/00; A61P 9/10 20060101 A61P009/10; A61P
3/10 20060101 A61P003/10; A61K 31/435 20060101 A61K031/435 |
Claims
1. A compound of formula I: ##STR00184## or a pharmaceutically
acceptable salt thereof, wherein: Y is --Y.sub.1--Y.sub.2--,
wherein: Y.sub.1 is --SO.sub.2N(R')--, --C(O)N(R')--;
--C(O)N(R')C(O)--, --N(R')SO.sub.2--, --N(R')SO.sub.2N(R')--,
--N(R')C(O)--, --NR'C(O)N(R')--, or --N(R')C(O)O--; and Y.sub.2 is
absent or is an optionally substituted C.sub.1-6 alkylene chain,
wherein one or two methylene units of Y.sub.2 are optionally and
independently interrupted by --O--, --S--, --N(R')--, --C(O)--,
--OC(O)--, --C(O)O--, --S(O)--, --S(O).sub.2--, --C(O)N(R')--,
--N(R')C(O)--, --N(R')C(O)N(R')--, --N(R')C(O)O--, --OC(O)N(R')--,
--N(R')S(O).sub.2--, or --S(O).sub.2N(R')--, or wherein Y.sub.2, or
a portion thereof, is an optionally substituted ring selected from
3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; each R' is independently hydrogen or optionally substituted
C.sub.1-6aliphatic; R.sup.1 is an optionally substituted group
selected from 3-10-membered cycloaliphatic, 3-10-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; ring A is substituted at one or more
carbon atoms with m independent occurrences of R.sup.2; m is 0-6;
each occurrence of R.sup.2 is independently halogen, .dbd.O,
.dbd.S, --CN, --R.sup.2b, --N(R.sup.2a).sub.2, --OR.sup.2a,
--SR.sup.2b, --S(O).sub.2R.sup.2b, --C(O)R.sup.2a, --C(O)OR.sup.2a,
--C(O)N(R.sup.2a).sub.2, --S(O).sub.2N(R.sup.2a).sub.2,
--OC(O)N(R.sup.2a).sub.2, --N(R')C(O)R.sup.2a,
--N(R')SO.sub.2R.sup.2b, --N(R')C(O)OR.sup.2a,
--N(R')C(O)N(R.sup.2a).sub.2, or --N(R')SO.sub.2N(R.sup.2a).sub.2,
or two occurences of R.sup.2a or R.sup.2b are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.2a, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.2a is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.2b is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; ring B is substituted
with r independent occurrences of --R.sup.3; r is 0-6; each
occurrence of R.sup.3 is independently --R.sup.3a,
-T.sub.1-R.sup.3d, or --V.sub.1-T.sub.1-R.sup.3d, wherein: each
occurrence of --R.sup.h is independently halogen, --CN, --NO.sub.2,
--R.sup.3c, --N(R.sup.3b).sub.2, --OR.sup.3b, --SR.sup.3c,
--S(O).sub.2R.sup.3c, --C(O)R.sup.3b, --C(O)OR.sup.3b,
--C(O)N(R.sup.3b).sub.2, --S(O).sub.2N(R.sup.3b).sub.2,
--OC(O)N(R.sup.3b).sub.2, --N(R')C(O)R.sup.3b,
--N(R')SO.sub.2R.sup.3c, --N(R')C(O)OR.sup.3b,
--N(R')C(O)N(R.sup.3b).sub.2, or --N(R')SO.sub.2N(R.sup.3b).sub.2,
or two occurences of R.sup.3b or R.sup.3e are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.3b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.3b is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.3c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.3d is independently an optionally substituted group selected
from 3-10-membered cycloaliphatic, 3-10-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; each occurrence of V.sub.1 is independently
--C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R')--,
--S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring; X is
--O--, --S--, --SO.sub.2--, or --N(W--R.sup.4)--; W is absent or is
a group selected from --W.sub.1-L.sub.2-W.sub.2--, wherein W.sub.1
and W.sub.2 are each independently absent or are an optionally
substituted C.sub.1-3alkylene chain, and L.sub.2 is absent or is a
group selected from --N(R)--, --O--, --S--, --S(O)--,
--S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R)--,
--S(O).sub.2N(R)--, --OC(O)N(R)--, --N(R)C(O)--, --N(R)SO.sub.2--,
--N(R)C(O)O--, --N(R)C(O)N(R)--, --N(R)SO.sub.2N(R)--, --OC(O)--,
or --C(O)N(R)--O--, wherein R is hydrogen or C.sub.1-C.sub.4alkyl,
provided that if W.sub.1 is absent then L.sub.2 is selected from
--C(O)--, --C(O)O--, --C(O)O--, --S(O)--, --S(O).sub.2--,
--C(O)N(R)--, or --S(O).sub.2N(R)-- R.sup.4 is an optionally
substituted monocyclic or bicyclic ring selected from 3-10-membered
cycloaliphatic, 3-10-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, provided that the compound is other than: a)
1-Pyrrolidinecarboxamide,
3-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-N-methyl-N-[(-
3S)-1-(tetrahydro-2-oxo-3-furanyl)-3-pyrrolidinyl]-, (3S)--; pcomp
also b) Pentitol,
1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[(-
4-phenoxyphenyl)amino]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyr-
rolidinyl]-pcomp also c) 1-Pyrrolidinecarboxamide,
N-methyl-3-[methyl[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]carbonyl]ami-
no]-N-[(3R)-1'-(phenylmethyl)[1,3'-bipyrrolidin]-3-yl]-, (3S)-pcomp
d) Pentitol,
1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[4-
'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]carbonyl]amino]-1-pyrrolidinyl]car-
bonyl]amino]-1-pyrrolidinyl]-pcomp e)
[1,3'-Bipyrrolidine]-1'-carboxylic acid,
3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]be-
nzoyl]amino]-, 1,1-dimethylethyl ester, (3R,4R)-rel-pcomp and
inflamm; and f) [1,3'-Bipyrrolidine]-3-carboxamide,
N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,
(3R,4R)-rel-pcomp and inflamm
2. The compound of claim 1, wherein the compound has the structure
of formula I-A-I or I-A-ii: ##STR00185##
3. The compound of claim 2, wherein r is 0, 1, or 2.
4. The compound of claim 3, wherein r is 1 and the compound has the
structure of formula I-B: ##STR00186##
5. The compound of claim 3, wherein r is 2 and the compound has the
structure of I-B-i: ##STR00187## wherein the two occurrences of
R.sup.3, taken together, form an optionally substituted
3-6-membered spiro carbocyclic or heterocyclic ring.
6. The compound of claim 4 or 5, wherein R.sup.1 is an optionally
substituted aryl group.
7. The compound of claim 5, wherein R.sup.1 is an optionally
substituted phenyl group.
8. The compound of claim 4 or 5, wherein R.sup.1 is an optionally
substituted 5-8-membered monocyclic or 7-10-membered bicyclic
heterocyclyl or heteroaryl ring having 1-4 heteroatoms
independently selected from N, O, or S.
9. The compound of claim 8, wherein R.sup.1 is an optionally
substituted group selected from: ##STR00188##
10. The compound of claim 8, wherein R.sup.1 is an optionally
substituted group selected from: ##STR00189## ##STR00190##
##STR00191##
11. The compound of claim 4 or 5, wherein: R.sup.1 is an optionally
substituted aryl group or R.sup.1 is an optionally substituted
5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or
heteroaryl ring having 1-4 heteroatoms independently selected from
N, O, or S, and R.sup.1 is optionally substituted with 1-3
occurrences of R.sup.1a, wherein each occurrence of R.sup.1a is
independently halogen, .dbd.O, .dbd.S, --CN, --NO.sub.2,
--R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b, --SR.sup.1c,
--S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein each occurrence of R.sup.1b is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; and each occurrence of
R.sup.1c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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.
12. The compound of claim 11, wherein each occurrence of R.sup.1a
is independently .dbd.O, halogen, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, or --SR.sup.1c.
13. The compound of claim 11, wherein each occurrence of R.sup.1a
is independently C.sub.1-4fluoroalkyl, --O(C.sub.1-4fluoroalkyl),
or --S(C.sub.1-4fluoroallyl).
14. The compound of claim 4 or 5, wherein Y.sub.1 is
--SO.sub.2N(R')--, --C(O)NR'--, or --N(R')S(O).sub.2--.
15. The compound of claim 4 or 5, wherein Y.sub.1 is
--N(R')C(O)--.
16. The compound of claim 4 or 5, wherein Y is selected from:
##STR00192## ##STR00193##
17. The compound of claim 4 or 5, wherein X is O.
18. The compound of claim 4 or 5, wherein X is --N(W--R.sup.4).
19. The compound of claim 4 or 5, wherein X is O, m is 1, and
R.sup.2 is an optionally substituted group selected from a
monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
20. The compound of claim 4 or 5, wherein X is --N(W--R.sup.4) and
R.sup.4 is an optionally substituted group selected from a
monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
21. The compound of claim 4 or 5, wherein X is --N(W--R.sup.4), W
is absent and R.sup.4 is optionally substituted phenyl.
22. The compound of claim 4 or 5, wherein: X is --N(W--R.sup.4) and
R.sup.4 is an optionally substituted group selected from a
monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or X is --N(W--R.sup.4), W is absent
and R.sup.4 is optionally substituted phenyl, wherein: R.sup.4 is
optionally substituted with 1-3 occurrences of R.sup.4a and each
occurrence of R.sup.4a is independently --R.sup.4b,
-T.sub.1-R.sup.4e, --V.sub.1-T.sub.1-R.sup.4e, wherein each
occurrence of --R.sup.4b is independently halogen, --CN,
--NO.sub.2, --R.sup.4d, --N(R.sup.4c).sub.2, --OR.sup.4c,
--SR.sup.4d, --S(O).sub.2R.sup.4d, --C(O)R.sup.4c, --C(O)OR.sup.4c,
--C(O)N(R.sup.4c).sub.2, --S(O).sub.2N(R.sup.4c).sub.2,
--OC(O)N(R.sup.4e).sub.2, --N(R')C(O)R.sup.4c,
--N(R')SO.sub.2R.sup.4d, --N(R')C(O)OR.sup.4c,
--N(R')C(O)N(R.sup.4c).sub.2, or --N(R')SO.sub.2N(R.sup.4c).sub.2,
or two occurences of R.sup.4b, R.sup.4c or R.sup.4d are optionally
taken together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.4c, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.4c is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.4d is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.4e is independently an optionally substituted group selected
from 3-10-membered cycloaliphatic, 3-10-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; each occurrence of V.sub.1 is independently
--C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R')--,
--S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring;
23. The compound of claim 21, wherein the phenyl group is
substituted with 1 or 2 occurrences of R.sup.4a, wherein each
occurrence of R.sup.4a is independently halogen, --CN,
--C(O)N(R.sup.4c).sub.2, --O(R.sup.4c), --S(R.sup.4d),
--N(R.sup.4c).sub.2, --C(O)O-T.sub.1-R.sup.4e, --R.sup.4d, or
wherein two occurrences of R.sup.4b, taken together with their
intervening atoms, form a 5-6-membered spiro or fused carbocyclic
or heterocyclyl ring.
24. The compound of claim 4 or 5, wherein R.sup.3 is --OR.sup.3b,
--SR.sup.3c, --V.sub.1-T.sub.1-R.sup.3d, or T.sub.1-R.sup.3d,
wherein V.sub.1 is O or S, and T.sub.1 is --CH.sub.2-- or
--CH.sub.2--CH.sub.2--.
25. The compound of claim 24, wherein R.sup.3b, R.sup.3c, and
R.sup.3d are each independently an optionally substituted group
selected from C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl,
5-10-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.
26. The compound of claim 25, wherein R.sup.3b, R.sup.3c, and
R.sup.3d are each independently optionally substituted
C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl, or an
optionally substituted group selected from: ##STR00194##
27. The compound of claim 24, wherein R.sup.3b, R.sup.3c, and
R.sup.3d are each independently an optionally substituted ring
selected from bicyclic 8-10-membered heterocyclyl having 1-5
heteroatoms independently selected from nitrogen, oxygen, or sulfur
or 8-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
28. The compound of claim 27, wherein R.sup.3b, R.sup.3c, and
R.sup.3d are each independently optionally substituted with 1-3
occurrences of R.sup.3e, wherein R.sup.3e is R.sup.f, halogen,
--N(R.sup.g).sub.2, --OR.sup.g, --SR.sup.f, --S(O).sub.2R.sup.f,
--COR.sup.f, --COOR.sup.g, --CON(R.sup.g).sub.2,
--CON(R.sup.g).sub.2, --S(O).sub.2N(R.sup.g).sub.2,
--CC(O)N(R.sup.g).sub.2, --NR'C(O)R.sup.f, --NR'S(O).sub.2R.sup.f,
wherein R.sup.f is an optionally substituted C.sub.1-6 aliphatic
group and R.sup.g is hydrogen or an optionally substituted
C.sub.1-6 aliphatic group.
29. The compound of claim 28, wherein R.sup.3b, R.sup.3c, and
R.sup.3d are each independently optionally substituted with 1-3
occurrences of R.sup.3e, wherein R.sup.3e is C.sub.1-4aliphatic,
C.sub.1-4haloaliphatic, or halogen.
30. The compound of claim 5, wherein r is 2 and two occurrences of
R.sup.3, taken together, form an optionally substituted
3-6-membered spiro carbocyclic or heterocyclic ring selected from:
##STR00195##
31. The compound of claim 4, wherein the compound has the structure
of formula I-C: ##STR00196##
32. The compound of claim 31, wherein X is O and the compound has
the structure of formula I-D: ##STR00197## wherein: a) R.sup.1 is
an optionally substituted 5-8-membered monocyclic or 7-10-membered
bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms
independently selected from N, O, or S, wherein R.sup.1 is
optionally substituted with 1-3 occurrences of R.sup.1a, wherein
each occurrence of R.sup.1a is independently halogen, .dbd.O,
.dbd.S, --CN, --NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, --SR.sup.1c, --S(O).sub.2R.sup.1c, --C(O)R.sup.1b,
C(O)OR.sup.1b, --C(O)N(R.sup.1b).sub.2,
--S(O).sub.2N(R.sup.1b).sub.2, --OC(O)N(R.sup.1b).sub.2,
--N(R')C(O)R.sup.1b, --N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: each occurrence of R.sup.1b
is independently hydrogen or an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; and each occurrence of
R.sup.1c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; b) Y is
--NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2, --NHC(O)--,
--NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--; c) m is 0 or 1, and when
m is 1 R.sup.2 is an optionally substituted group selected from a
monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; and d) R.sup.3 is --OR.sup.3b,
--SR.sup.3c, --V.sub.1-T.sub.1-R.sup.3d, or T.sub.1-R.sup.3d,
wherein V.sub.1 is O or S, and T.sub.1 is --CH.sub.2-- or
--CH.sub.2--CH.sub.2--, wherein R.sup.3b, R.sup.3c, and R.sup.3d
are each independently an optionally substituted group selected
from C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl,
5-10-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.
33. The compound of claim 32, wherein: a) R.sup.1 is an optionally
substituted group selected from: ##STR00198## ##STR00199##
##STR00200## ##STR00201## and each occurrence of R.sup.1a is
independently .dbd.O, halogen, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, or --SR.sup.1c; and b) R.sup.3b, R.sup.3c, and
R.sup.3d are each independently optionally substituted
C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl, or an
optionally substituted group selected from: ##STR00202## wherein
R.sup.3b, R.sup.3c, and R.sup.3d are each independently optionally
substituted with 1-3 occurrences of R.sup.3e, wherein R.sup.3e is
C.sub.1-4aliphatic, C.sub.1-4haloaliphatic, or halogen.
34. The compound of claim 31, wherein X is N(W--R.sup.4), and the
compound has the structure of formula I-E: ##STR00203## wherein: a)
R.sup.1 is an optionally substituted 5-8-membered monocyclic or
7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4
heteroatoms independently selected from N, O, or S, wherein R.sup.1
is optionally substituted with 1-3 occurrences of R.sup.1a, wherein
each occurrence of R.sup.1a is independently halogen, .dbd.O, --CN,
--NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b,
--S(O).sub.2R.sup.1c, --C(O)R.sup.1b, C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: each occurrence of R.sup.1b
is independently hydrogen or an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; and each occurrence of
R.sup.1c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; b) Y is
--NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2, --NHC(O)--,
--NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--; c) m is 0; d) R.sup.3 is
--OR.sup.3b, --SR.sup.3c, --V.sub.1-T.sub.1-R.sup.3d, or
T.sub.1-R.sup.3d, wherein V.sub.1 is O or S, and T.sub.1 is
--CH.sub.2-- or --CH.sub.2--CH.sub.2--, wherein R.sup.3b, R.sup.3c,
and R.sup.3d are each independently an optionally substituted group
selected from C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl,
5-10-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; e) W is absent, and f)
R.sup.4 is an optionally substituted group selected from a
monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
35. The compound of claim 31, wherein X is N(W--R.sup.4), and the
compound has the structure of formula I-E: ##STR00204## wherein: a)
R.sup.1 is an optionally substituted 5-8-membered monocyclic or
7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4
heteroatoms independently selected from N, O, or S, wherein R.sup.1
is optionally substituted with 1-3 occurrences of R.sup.1% wherein
each occurrence of R.sup.1a is independently halogen, .dbd.O, --CN,
--NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b,
--SR.sup.1', --S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: each occurrence of R.sup.1b
is independently hydrogen or an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; and each occurrence of
R.sup.1c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; b) Y is
--NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2, --NHC(O)--,
--NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--; c) m is 0; d) R.sup.3 is
--OR.sup.3b, --SR.sup.3c, --V.sub.1-T.sub.1-R.sup.3d, or
T.sub.1-R.sup.3d, wherein V.sub.1 is O or S, and T.sub.1 is
--CH.sub.2-- or --CH.sub.2--CH.sub.2--, wherein R.sup.3b, R.sup.3c,
and R.sup.3d are each independently an optionally substituted group
selected from C.sub.1-4 alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl,
5-10-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; e) W is absent, and f)
R.sup.4 is optionally substituted phenyl.
36. The compound of claim 34 or 35, wherein R.sup.4 is optionally
substituted with 1-3 occurrences of R.sup.4a each occurrence of
R.sup.4a is independently --R.sup.4b, -T.sub.1-R.sup.4c, or
--V.sub.1-T.sub.1-R.sup.4e, wherein: each occurrence of --R.sup.4b
is independently halogen, --CN, --NO.sub.2, --R.sup.4d,
--N(R.sup.4c).sub.2, --OR.sup.4c, --SR.sup.4d,
--S(O).sub.2R.sup.4d, --C(O)R.sup.4c, --C(O)OR.sup.4c,
--C(O)N(R.sup.4c).sub.2, --S(O).sub.2N(R.sup.4c).sub.2,
--OC(O)N(R.sup.4c).sub.2, --N(R')C(O)R.sup.4c,
--N(R')SO.sub.2R.sup.4d, --N(R')C(O)OR.sup.4c,
--N(R')C(O)N(R.sup.4).sub.2, or --N(R)SO.sub.2N(R.sup.4c).sub.2, or
two occurences of R.sup.4b, R.sup.4c or R.sup.4d are optionally
taken together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.4c, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.4c is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.4d is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.4e is independently an optionally substituted group selected
from 3-10-membered cycloaliphatic, 3-10-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; each occurrence of V.sub.1 is independently
--C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R')--,
--S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; and each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring.
37. The compound of claim 34 or 35, wherein: a) R.sup.1 is an
optionally substituted group selected from: ##STR00205##
##STR00206## ##STR00207## ##STR00208## and each occurrence of
R.sup.1a is independently .dbd.O, halogen, --R.sup.1c,
--N(R.sup.1b).sub.2, --OR.sup.1b, or --SR.sup.1c; and b) R.sup.3b,
R.sup.3c, and R.sup.3d are each independently optionally
substituted C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl, or
an optionally substituted group selected from: ##STR00209## wherein
R.sup.3b, R.sup.3c, and R.sup.3d are each independently optionally
substituted with 1-3 occurrences of R.sup.3e, wherein R.sup.3e is
C.sub.1-4aliphatic, C.sub.1-4haloaliphatic, or halogen.
38. The compound of claim 5, having the structure of formula I-F:
##STR00210## or a pharmaceutically acceptable salt thereof, wherein
the two occurrences of R.sup.3, taken together, form an optionally
substituted 3-6-membered spiro carbocyclic or heterocyclic
ring.
39. The compound of claim 38, wherein X is O and the compound has
the structure of formula I-G: ##STR00211## or a pharmaceutically
acceptable salt thereof, wherein: a) R.sup.1 is an optionally
substituted 5-8-membered monocyclic or 7-10-membered bicyclic
heterocyclyl or heteroaryl ring having 1-4 heteroatoms
independently selected from N, O, or S, wherein R.sup.1 is
optionally substituted with 1-3 occurrences of R.sup.1a, wherein
each occurrence of R.sup.1a is independently halogen, .dbd.O,
.dbd.S, --CN, --NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, --SR.sup.1c, --S(O).sub.2R.sup.1c, --C(O)R.sup.1b,
C(O)OR.sup.1b, --C(O)N(R.sup.1b).sub.2,
--S(O).sub.2N(R.sup.1b).sub.2, --OC(O)N(R.sup.1b).sub.2,
--N(R')C(O)R.sup.1b, --N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: each occurrence of R.sup.1b
is independently hydrogen or an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; and each occurrence of
R.sup.1c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; b) Y is
--NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2, --NHC(O)--,
--NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--; c) m is 0 or 1, and when
m is 1 R.sup.2 is an optionally substituted group selected from a
monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur; and d) wherein the two occurrences of
R.sup.3, taken together, form an optionally substituted
3-6-membered spiro carbocyclic or heterocyclic ring.
40. The compound of claim 39, wherein: a) R.sup.1 is an optionally
substituted group selected from: ##STR00212## ##STR00213##
##STR00214## and each occurrence of R.sup.1a is independently
.dbd.O, halogen, --R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b, or
--SR.sup.1c; and b) the spiro ring formed from the two occurrences
of R.sup.3 is an optionally substituted ring selected from:
##STR00215##
41. The compound of claim 38, wherein X is N(W--R.sup.4), and the
compound has the structure of formula I-H: ##STR00216## or a
pharmaceutically acceptable salt thereof, wherein: a) R.sup.1 is an
optionally substituted 5-8-membered monocyclic or 7-10-membered
bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms
independently selected from N, O, or S, wherein R.sup.1 is
optionally substituted with 1-3 occurrences of R.sup.1a, wherein
each occurrence of R.sup.1a is independently halogen, .dbd.O, --CN,
--NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b,
--SR.sup.1c, --S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: each occurrence of R.sup.1b
is independently hydrogen or an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; and each occurrence of
R.sup.1c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; b) Y is
--NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2, --NHC(O)--,
--NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--; c) m is 0; d) wherein
the two occurrences of R.sup.3, taken together, form an optionally
substituted 3-6-membered spiro carbocyclic or heterocyclic ring; e)
W is absent, and f) R.sup.4 is an optionally substituted group
selected from a monocyclic 3-7-membered heterocyclyl having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a
7-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
42. The compound of claim 38, wherein X is N(W--R.sup.4), and the
compound has the structure of formula I-H: ##STR00217## or a
pharmaceutically acceptable salt thereof, wherein: a) R.sup.1 is an
optionally substituted 5-8-membered monocyclic or 7-10-membered
bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms
independently selected from N, O, or S, wherein R.sup.1 is
optionally substituted with 1-3 occurrences of R.sup.1a, wherein
each occurrence of R.sup.1a is independently halogen, .dbd.O, --CN,
--NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b,
--S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: each occurrence of R.sup.1b
is independently hydrogen or an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; and each occurrence of
R.sup.1c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; b) Y is
--NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2, --NHC(O)--,
--NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--; c) m is 0; d) the spiro
ring formed from the two occurrences of R.sup.3 is an optionally
substituted ring selected from: ##STR00218## e) W is absent, and f)
R.sup.4 is optionally substituted phenyl.
43. The compound of claim 41 or 42, wherein R.sup.4 is optionally
substituted with 1-3 occurrences of R.sup.4a and each occurrence of
R.sup.4a is independently --R.sup.4b, -T.sub.1-R.sup.4e, or
--V.sub.1-T.sub.1-R.sup.4e, wherein: each occurrence of --R.sup.4b
is independently halogen, --CN, --NO.sub.2, --R.sup.4d,
--N(R.sup.4c).sub.2, --OR.sup.4c, --SR.sup.4d,
--S(O).sub.2R.sup.4d, --C(O)R.sup.4c, --C(O)OR.sup.4c,
--C(O)N(R.sup.4c).sub.2, --S(O).sub.2N(R.sup.4c).sub.2,
--OC(O)N(R.sup.4c).sub.2, --N(R')C(O)R.sup.4c,
--N(R')SO.sub.2R.sup.4d, --N(R')C(O)OR.sup.4c,
--N(R')C(O)N(R.sup.4c).sub.2, or --N(R')SO.sub.2N(R.sup.4c).sub.2,
or two occurences of R.sup.4b, R.sup.4c or R.sup.4d are optionally
taken together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.4c, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.4c is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.4d is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.4e is independently an optionally substituted group selected
from 3-10-membered cycloaliphatic, 3-10-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; each occurrence of V.sub.1 is independently
--C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R')--,
--S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; and each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring.
44. The compound of claim 41 or 42, wherein: a) R.sup.1 is an
optionally substituted group selected from: ##STR00219##
##STR00220## ##STR00221## and each occurrence of R.sup.1a is
independently .dbd.O, halogen, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, or --SR.sup.1c; and b) the spiro ring formed from the
two occurrences of R.sup.3 is an optionally substituted ring
selected from: ##STR00222##
45. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier or diluent and a ##STR00223## or a
pharmaceutically acceptable salt thereof, wherein: Y is
--Y.sub.1--Y.sub.2--, wherein: Y.sub.1 is --SO.sub.2N(R')--,
--C(O)N(R')--; --C(O)N(R')C(O)--, --N(R')SO.sub.2--,
--N(R')SO.sub.2N(R')--, --N(R')C(O)--, --NR'C(O)N(R')--, or
--N(R')C(O)O--; and Y.sub.2 is absent or is an optionally
substituted C.sub.1-6 alkylene chain, wherein one or two methylene
units of Y.sub.2 are optionally and independently interrupted by
--O--, --S--, --N(R')--, --C(O)--, --OC(O)--, --C(O)O--, --S(O)--,
--S(O).sub.2--, --C(O)N(R')--, --N(R')C(O)--, --N(R')C(O)N(R')--,
--N(R')C(O)O--, --OC(O)N(R')--, --N(R')S(O).sub.2--, or
--S(O).sub.2N(R')--, or wherein Y.sub.2, or a portion thereof, is
an optionally substituted ring selected from 3-6-membered
cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, 6-membered
aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; each R' is
independently hydrogen or optionally substituted
C.sub.1-6aliphatic; R.sup.1 is an optionally substituted group
selected from 3-10-membered cycloaliphatic, 3-10-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; ring A is substituted at one or more
carbon atoms with m independent occurrences of R.sup.2; m is 0-6;
each occurrence of R.sup.2 is independently halogen, .dbd.O,
.dbd.S, --CN, --R.sup.2b, --N(R.sup.2a).sub.2, --OR.sup.2a,
--SR.sup.2b, --S(O).sub.2R.sup.2b, C(O)R.sup.2a, --C(O)OR.sup.2a,
--C(O)N(R.sup.2a).sub.2, --S(O).sub.2N(R.sup.2a).sub.2,
--OC(O)N(R.sup.2a).sub.2, --N(R')C(O)R.sup.2a,
--N(R')SO.sub.2R.sup.2b, --N(R')C(O)OR.sup.2a,
--N(R')C(O)N(R.sup.2a).sub.2, or --N(R')SO.sub.2N(R.sup.2a).sub.2,
or two occurences of R.sup.2a or R.sup.2b are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.2a, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.2a is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.2b is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; ring B is substituted
with r independent occurrences of --R.sup.3; r is 0-6; each
occurrence of R.sup.3 is independently --R.sup.3a,
-T.sub.1-R.sup.3d, or --V.sub.1-T.sub.1-R.sup.3d, wherein: each
occurrence of --R.sup.3a is independently halogen, --CN,
--NO.sub.2, --R.sup.3c, --N(R.sup.3b).sub.2, --OR.sup.3b,
--SR.sup.3c, --S(O).sub.2R.sup.3c, --C(O)R.sup.3b, --C(O)OR.sup.3b,
--C(O)N(R.sup.3b).sub.2, --S(O).sub.2N(R.sup.3b).sub.2,
--OC(O)N(R.sup.3b).sub.2, --N(R')C(O)R.sup.3b,
--N(R')SO.sub.2R.sup.3c, --N(R')C(O)OR.sup.3b,
--N(R')C(O)N(R.sup.3b).sub.2, or --N(R')SO.sub.2N(R.sup.3b).sub.2,
or two occurences of R.sup.3b or R.sup.3c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.3b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.3b is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.3c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.3d is independently an optionally substituted group selected
from 3-10-membered cycloaliphatic, 3-10-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; each occurrence of V.sub.1 is independently
--C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R')--,
--S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring; X is
--O--, --S--, --SO.sub.2--, or --N(W--R.sup.4)--; W is absent or is
a group selected from --W.sub.1-L.sub.2-W.sub.2--, wherein W.sub.1
and W.sub.2 are each independently absent or are an optionally
substituted C.sub.1-3alkylene chain, and L.sub.2 is absent or is a
group selected from --N(R)--, --O--, --S--, --S(O)--,
--S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R)--,
--S(O).sub.2N(R)--, --OC(O)N(R)--, --N(R)C(O)--, --N(R)SO.sub.2--,
--N(R)C(O)O--, --N(R)C(O)N(R)--, --N(R)SO.sub.2N(R)--, --OC(O)--,
or --C(O)N(R)--O--, wherein R is hydrogen or C.sub.1-C.sub.4alkyl,
provided that if W.sub.1 is absent then L.sub.2 is selected from
--C(O)--, --C(O)O--, --C(O)O--, --S(O)--, --S(O).sub.2--,
--C(O)N(R)--, or --S(O).sub.2N(R)-- R.sup.4 is an optionally
substituted monocyclic or bicyclic ring selected from 3-10-membered
cycloaliphatic, 3-10-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, provided that the compound is other than: a)
1-Pyrrolidinecarboxamide,
3-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-N-methyl-N-[(-
3S)-1-(tetrahydro-2-oxo-3-furanyl)-3-pyrrolidinyl]-, (3S)--; b)
Pentitol,
1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[(4-phenoxyp-
henyl)amino]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyrrolidinyl]-
-; c) 1-Pyrrolidinecarboxamide,
N-methyl-3-[methyl[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]carbonyl]ami-
no]-N-[(3R)-1'-(phenylmethyl)[1,3'-bipyrrolidin]-3-yl]-, (3S)--; d)
Pentitol,
1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[4-
'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]carbonyl]amino]-1-pyrrolidinyl]car-
bonyl]amino]-1-pyrrolidinyl]-; e)
[1,3'-Bipyrrolidine]-1'-carboxylic acid,
3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-
amino]-, 1,1-dimethylethyl ester, (3R,4R)-rel-; and f)
[1,3'-Bipyrrolidine]-3-carboxamide,
N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,
(3R,4R)-rel-.
46. A method for treating an inflammatory disorder comprising
administering to a subject an effective amount of a compound of
formula I ##STR00224## or a pharmaceutically acceptable salt
thereof, wherein: Y is --Y.sub.1--Y.sub.2--, wherein: Y.sub.1 is
--SO.sub.2N(R')--, --C(O)N(R')--; --C(O)N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')SO.sub.2N(R')--, --N(R')C(O)--,
--NR'C(O)N(R')--, or --N(R')C(O)O--; and Y.sub.2 is absent or is an
optionally substituted C.sub.1-6 alkylene chain, wherein one or two
methylene units of Y.sub.2 are optionally and independently
interrupted by --O--, --S--, --N(R')--, --C(O)--, --OC(O)--,
--C(O)O--, --S(O)--, --S(O).sub.2--, --C(O)N(R')--, --N(R')C(O)--,
--N(R')C(O)N(R')--, --N(R')C(O)O--, --OC(O)N(R')--,
--N(R')S(O).sub.2--, or --S(O).sub.2N(R')--, or wherein Y.sub.2, or
a portion thereof, is an optionally substituted ring selected from
3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; each R' is independently hydrogen or optionally substituted
C.sub.1-6aliphatic; R.sup.1 is an optionally substituted group
selected from 3-10-membered cycloaliphatic, 3-10-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; ring A is substituted at one or more
carbon atoms with m independent occurrences of R.sup.2; m is 0-6;
each occurrence of R.sup.2 is independently halogen, .dbd.O,
.dbd.S, --CN, --R.sup.2b, --N(R.sup.2a).sub.2, --OR.sup.2a,
--SR.sup.2b, --S(O).sub.2R.sup.2b, --C(O)R.sup.2a, --C(O)OR.sup.2a,
--C(O)N(R.sup.2a).sub.2, --S(O).sub.2N(R.sup.2a).sub.2,
--OC(O)N(R.sup.2a).sub.2, --N(R')C(O)R.sup.2a,
--N(R')SO.sub.2R.sup.2b, --N(R')C(O)OR.sup.2a,
--N(R')C(O)N(R.sup.2a).sub.2, or --N(R')SO.sub.2N(R.sup.2a).sub.2,
or two occurences of R.sup.2a or R.sup.2b are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.2a, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.2a is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.2'' is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; ring B is substituted
with r independent occurrences of --R.sup.3; r is 0-6; each
occurrence of R.sup.3 is independently --R.sup.3a,
-T.sub.1-R.sup.3d, or --V.sub.1-T.sub.1-R.sup.3d, wherein: each
occurrence of --R.sup.3a is independently halogen, --CN,
--NO.sub.2, --R.sup.3c, --N(R.sup.3b).sub.2, --OR.sup.3b,
--SR.sup.3c, --S(O).sub.2R.sup.3c, --C(O)R.sup.3b, --C(O)OR.sup.3b,
--C(O)N(R.sup.3b).sub.2, --S(O).sub.2N(R.sup.3b).sub.2,
--OC(O)N(R.sup.3b).sub.2, --N(R')C(O)R.sup.3b,
--N(R')SO.sub.2R.sup.3c, --N(R')C(O)OR.sup.3b,
--N(R')C(O)N(R.sup.3b).sub.2, or --N(R')SO.sub.2N(R.sup.3b).sub.2,
or two occurences of R.sup.3b or R.sup.3c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.3b, taken together with the nitrogen atom to
which they are hound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; each occurrence of R.sup.3b is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.3c is independently an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; each occurrence of
R.sup.3d is independently an optionally substituted group selected
from 3-10-membered cycloaliphatic, 3-10-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; each occurrence of V.sub.1 is independently
--C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R')--,
--S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring; X is
--O--, --S--, --SO.sub.2--, or --N(W--R.sup.4)--; W is absent or is
a group selected from --W.sub.1-L.sub.2-W.sub.2--, wherein W.sub.1
and W.sub.2 are each independently absent or are an optionally
substituted C.sub.1-3alkylene chain, and L.sub.2 is absent or is a
group selected from --N(R)--, --O--, --S--, --S(O)--,
--S(O).sub.2--, --C(O)--, --C(O)O--, --C(O)N(R)--,
--S(O).sub.2N(R)--, --OC(O)N(R)--, --N(R)C(O)--, --N(R)SO.sub.2--,
--N(R)C(O)O--, --N(R)C(O)N(R)--, --N(R)SO.sub.2N(R)--, --OC(O)--,
or --C(O)N(R)--O--, wherein R is hydrogen or C.sub.1-C.sub.4alkyl,
provided that if W.sub.1 is absent then L.sub.2 is selected from
--C(O)--, --C(O)O--, --C(O)O--, --S(O)--, --S(O).sub.2--,
--C(O)N(R)--, or --S(O).sub.2N(R)-- R.sup.4 is an optionally
substituted monocyclic or bicyclic ring selected from 3-10-membered
cycloaliphatic, 3-10-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, provided that the compound is other than: a)
[1,3'-Bipyrrolidine]-1'-carboxylic acid,
3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-
amino]-, 1,1-dimethylethyl ester, (3R,4R)-rel-; and b)
[1,3'-Bipyrrolidine]-3-carboxamide,
N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,
(3R,4R)-rel-.
47. The method of claim 46, wherein the disorder is rheumatoid
arthritis, multiple sclerosis, scleroderma, atherosclerosis,
neuropathic pain, and type II diabetes.
48. The method of claim 47, wherein the disorder is rheumatoid
arthritis or multiple sclerosis.
Description
PRIORITY INFORMATION
[0001] The present application is a Continuation of U.S. Ser. No.
12/084,353, which is a national stage application under 35 U.S.C.
371 of PCT Application Serial No. PCT/US2006/042181, filed Oct. 26,
2006, which claims priority under 35 U.S.C. .sctn.119(e) to U.S.
Provisional Application No. 60/732,344, filed Nov. 1, 2005, the
entire contents of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Chemoattractant cytokines, Chemoattractant cytokines or
chemokines are a family of proinflammatory mediators that are
released by a wide variety of cells to promote recruitment and
activation of cells such as T and B lymphocytes, eosinophils,
basophils, and neutrophils (Luster et al. New Eng. J. Med, 1998,
338, 436). The chemokines are related in primary structure and
contain four conserved cysteines, which form disulfide bonds. The
chemokine family includes the C--X--C chemokines
(.alpha.-chemokines), and the C--C chemokines (.beta.-chemokines),
in which the first two conserved cysteines are separated by an
intervening residue, or are adjacent, respectively (Baggiolini, M.
and Dahinden, C. A., Immunology Today, 1994, 15, 127).
[0003] Chemokines exert their biological activity by binding to
specific cell-surface receptors belonging to the family of
G-protein-coupled seven-transmembrane-domain proteins (Horuk,
Trends Pharm. Sci. 1994, 15, 159) which are termed "chemokine
receptors". On binding their cognate ligands, chemokine receptors
then transduce signals important for the development and
trafficking of specific leukocyte subsets (Baggiolini, et. al.,
Nature 1994, 15, 365). The chemokines and their cognate receptors
have been implicated as being important mediators of inflammatory,
and allergic diseases, disorders, and conditions, as well as
autoimmune pathologies such as rheumatoid arthritis and
atherosclerosis (see, Carter, Current Opinion in Chemical Biology
2002, 6, 510; Trivedi et al., Ann. Reports Med. Chem. 2000, 35,
191; Saunders et al., Drug Disc. Today 1999, 4, 80; and Premack et
al., Nature Medicine, 1996, 2, 1174). Accordingly, agents that
block the interaction of chemokines with their cognate receptors
would be useful in treating inflammatory, allergic, and autoimmune
diseases, disorders, or conditions caused by aberrant activation of
leukocytes or lymphocytes.
[0004] CCR2 is a chemokine receptor expressed on monocytes which
recognizes the ligands MCP-1, MCP-2, MCP-3, and MCP-4 (see,
Berkhout, et al., J. Biol. Chem. 1997, 272, 16404. It has been
implicated that the interaction of monocyte chemoattractant
protein-1 (MCP-1) and its receptor (CCR2) plays a role in the
pathogenesis of inflammatory, allergic, and autoimmune diseases
(for example rheumatoid arthritis, multiple sclerosis, COPD,
neuropathic pain, asthma, and atherosclerosis) by attracting
leukocytes to sites of inflammation and subsequently activating
these cells. When the chemokine MCP-1 binds to CCR2, it induces a
rapid increase in intracellular calcium concentration, increased
expression of cellular adhesion molecules, cellular degranulation,
and the promotion of leukocyte migration. (see Dawson, et al.,
Expert Opin. Ther. Targets, 2003, 7, 35; Gongh et al., J. Exp. Med.
1997, 181, 131; Izikson, et al., Clin. Immunol. 2002, 103, 125;
Donnelly et al., Drugs, 2003, 63, 1973; Leonard, E. J. Challenges
Mod. Med., 1994, 3, 25; and Ross, R. New Engl. J. Med. 1999, 147,
213). In particular, monocyte chemoattractant protein-1 (MCP-1) is
believed to be primarily responsible for the selective recruitment
of leukocytes to the site of inflammation by binding to its
receptor CCR2 on the surface of monocytes and macrophages (Rollins
et al., Blood, 1997, 90, 909; Howard et al., Trends Biotechnol.
1996, 14, 46; Saunders et al., Drug Discovery Today, 1999, 4, 80;
Murphy et al., Pharmacologic Rev., 2000, 52, 145; and Horuk, R.
Cytokine Growth Factor Rev., 2001, 12, 313). The importance of the
MCP-1/CCR2 interaction has been demonstrated by experiments with
genetically modified mice (see, Bao, et al., J. Exp. Med. 1998,
187, 601; Boring et al., J. Clin. Invest. 1997, 100, 2552; Kuziel
et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 12053; and Kurihara
et al., J. Exp. Med. 1997, 186, 1757). Several studies have also
been published indicating that therapeutic intervention at the CCR2
receptor via inhibition of the interaction between MCP-1 and CCR2
may have beneficial effects in a variety of inflammatory, allergic,
and autoimmune diseases. For example, studies completed to date
have indicated that the antagonisum of the MCP-1/CCR2 interaction
may be useful in treating rheumatoid arthritis; ameliorate chronic
polyadjuvant-induced arthritis (Youssef et al., J. Clin. Invest.
2000, 106, 361); collagen-induced arthritis (Ogata et al., J.
Pathol. 1997, 182, 106); streptococcal cell wall-induced arthritis
(Schimmer et al., J. Immunol. 1998, 160, 1466); MRL-1pr mouse model
of arthritis (Gong et al., J. Exp. Med. 1997, 186, 131);
atherosclerosis (Rezaie-Majd et al, Arterioscler. Thromb. Vasc.
Biol. 2002, 22, 1194-1199; Gu et al., Mol. Cell. 1998, 2, 275;
Gosling et al., J. Clin. Invest. 1999, 103, 773; Boring et al,
Nature 1998, 394, 894; and Ni et al. Circulation 2001, 103,
2096-2101); multiple sclerosis (Iarlori et al., J. Neuroimmunol.
2002, 123, 170-179; Kennedy et al., J. Neuroimmunol. 1998, 92, 98;
Fife et al., J. Exp. Med. 2000, 192, 899; and Izikson et al., J.
Exp. Med. 2000, 192, 1075); organ transplant rejection
(Reynaud-Gaubert et al., J. of Heart and Lung Transplant., 2002,
21, 721-730; Belperio et al., J. Clin. Invest. 2001, 108, 547-556;
and Belperio et al., J. Clin. Invest. 2001, 108, 547-556); asthma
(Gonzalo et al., J. Exp. Med. 1998, 188, 157; Lukacs, et al., J.
Immunol. 1997, 158, 4398; and Lu et al., J. Exp. Med. 1998, 187,
601); kidney disease (Lloyd et al., J. Exp. Med. 1997, 185, 1371;
and Tesch et al., J. Clin. Invest. 1999, 103, 73); lupus
erythematosus (Tesch et al., J. Exp. Med. 1999, 190, 1813); colitis
(Andres et al., J. Immunol. 2000, 164, 6303); alveolitis (Jones, et
al., J. Immunol. 1992, 149, 2147); cancer (Conti, et al., Seminars
in Cancer Biology 2004, 14, 149; Salcedo et al., Blood 2000, 96,
34-40); restinosis (Roque et al. Arterioscler. Thromb. Vasc. Biol.
2002, 22, 554-559); inflammatory bowel disease (Reinecker et al.,
Gastroenterology 1995, 108, 40; and Grimm et al., J. Leukoc. Biol.
1996, 59, 804); brain trauma (King et al., J. Neuroimmunol. 1994,
56, 127; and Berman et al., J. Immunol. 1996, 156, 3017);
transplant arteriosclerosis (Russell et al., Proc. Natl. Acad. Sci.
USA 1993, 90, 6086); idiopathic pulmonary fibrosis (Antoniades et
al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371); psoriasis
(Deleuran et al., J. Dermatol. Sci. 1996, 13, 228; and Gillitzer et
al., J. Invest. Dermatol. 1993, 101, 127); HIV and HIV-1-associated
dementia (Garzino-Demo, WO 99/46991; Doranz et al., Cell 1996, 85,
1149; Connor et al., J. Exp. Med. 1997, 185, 621; and Smith et al.,
Science 1997, 277, 959); and neuropathic pain (Abbadie, et al.,
Proc. Natl. Acad. Sci. USA 2003, 100, 7947). Similarly,
demonstration of the importance of the MCP-1/CCR-2 interaction has
been reported in the literature. For example, Lu et al., J. Exp.
Med. 1998, 187, 601; Boring et al., J. Clin. Invest. 1997, 100,
2552; Kuziel et al., Proc. Natl. Acad. Sci. USA 1997, 94, 12053;
and Kurihara et al., J. Exp. Med. 1997, 186, 1757.
[0005] Accordingly, agents that inhibit the interaction of MCP-1
and CCR2 would be useful in the treatment of a variety of
inflammatory, allergic and autoimmune diseases, disorders, or
conditions.
DETAILED DESCRIPTION OF THE INVENTION
[0006] 1. General Description of Compounds of the Invention:
[0007] The present invention provides compounds that are effective
inhibitors of CCR2. Accordingly, these compounds are useful for the
treatment of various cell inflammatory, allergic and autoimmune
diseases, disorders, or conditions.
[0008] The present invention relates to a compound of formula
I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein: [0009] Y is
--Y.sub.1--Y.sub.2--, wherein: [0010] Y.sub.1 is --SO.sub.2N(R')--,
--C(O)N(R')--; --C(O)N(R')C(O)--, --N(R')SO.sub.2--,
--N(R')SO.sub.2N(R')--, --N(R')C(O)--, --NR'C(O)N(R')--, or
--N(R')C(O)O--; and [0011] Y.sub.2 is absent or is an optionally
substituted C.sub.1-6 alkylene chain, wherein one or two methylene
units of Y.sub.2 are optionally and independently interrupted by
--O--, --S--, --N(R')--, --C(O)--, --OC(O)--, --C(O)O--, --S(O)--,
--S(O).sub.2--, --C(O)N(R')--, --N(R')C(O)--, --N(R')C(O)N(R')--,
--N(R')C(O)O--, --OC(O)N(R')--, --N(R')S(O).sub.2--, or
--S(O).sub.2N(R')--, or wherein Y.sub.2, or a portion thereof, is
an optionally substituted ring selected from 3-6-membered
cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, 6-membered
aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; [0012]
each R' is independently hydrogen or optionally substituted
C.sub.1-6aliphatic; [0013] R.sup.1 is an optionally substituted
group selected from 3-10-membered cycloaliphatic, 3-10-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; [0014] ring A is substituted at one or
more carbon atoms with m independent occurrences of R.sup.2; [0015]
m is 0-6; [0016] each occurrence of R.sup.2 is independently
halogen, .dbd.O, .dbd.S, --CN, --R.sup.2b, --N(R.sup.2a).sub.2,
--OR.sup.2a, --SR.sup.2b, --S(O).sub.2R.sup.2b, --C(O)R.sup.2a,
--C(O)OR.sup.2a, --C(O)N(R.sup.2a).sub.2,
--S(O).sub.2N(R.sup.2a).sub.2, --OC(O)N(R.sup.2a).sub.2,
--N(R')C(O)R.sup.2a, --N(R')SO.sub.2R.sup.2b, --N(R')C(O)OR.sup.2a,
--N(R')C(O)N(R.sup.2a).sub.2, or --N(R)SO.sub.2N(R.sup.2a).sub.2,
or two occurences of R.sup.2a or R.sup.2b are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.2a, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; [0017] each occurrence of R.sup.2a is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0018] each occurrence
of R.sup.2b is independently an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0019] ring B is
substituted with r independent occurrences of --R.sup.3; [0020] r
is 0-6; [0021] each occurrence of R.sup.3 is independently
--R.sup.3a, -T.sub.1-R.sup.3d, or --V.sub.1-T.sub.1-R.sup.3d,
wherein: [0022] each occurrence of --R.sup.3a is independently
halogen, --CN, --NO.sub.2, --R.sup.3c, --N(R.sup.3b).sub.2,
--OR.sup.3b, --SR.sup.3c, --S(O).sub.2R.sup.3c, --C(O)R.sup.3b,
--C(O)OR.sup.3b, --C(O)N(R.sup.3b).sub.2,
--S(O).sub.2N(R.sup.3b).sub.2, --OC(O)N(R.sup.3b).sub.2,
--N(R')C(O)R.sup.3b, --N(R')SO.sub.2R.sup.3c, --N(R')C(O)OR.sup.3b,
--N(R')C(O)N(R.sup.3b).sub.2, or --N(R')SO.sub.2N(R.sup.3b).sub.2,
or two occurences of R.sup.3b or R.sup.3c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.3b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; [0023] each occurrence of R.sup.3b is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0024] each occurrence
of R.sup.3c is independently an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0025] each occurrence
of R.sup.3d is independently an optionally substituted group
selected from 3-10-membered cycloaliphatic, 3-10-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; [0026] each occurrence of V.sub.1 is
independently --C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--,
--S--, --S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--,
--C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; [0027] each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring;
[0028] X is --O--, --S--, --SO.sub.2--, or --N(W--R.sup.4)--;
[0029] W is absent or is a group selected from
--W.sub.1-L.sub.2-W.sub.2--, wherein W.sub.1 and W.sub.2 are each
independently absent or are an optionally substituted
C.sub.1-3alkylene chain, and L.sub.2 is absent or is a group
selected from --N(R)--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--C(O)--, --C(O)O--, --C(O)N(R)--, --S(O).sub.2N(R)--,
--OC(O)N(R)--, --N(R)C(O)--, --N(R)SO.sub.2--, --N(R)C(O)O--,
--N(R)C(O)N(R)--, --N(R)SO.sub.2N(R)--, --OC(O)--, or
--C(O)N(R)--O--, wherein R is hydrogen or C.sub.1-C.sub.4alkyl,
provided that if W.sub.1 is absent then L.sub.2 is selected from
--C(O)--, --C(O)O--, --C(O)O--, --S(O)--, --S(O).sub.2--,
--C(O)N(R)--, or --S(O).sub.2N(R)-- [0030] R.sup.4 is an optionally
substituted monocyclic or bicyclic ring selected from 3-10-membered
cycloaliphatic, 3-10-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.
[0031] In some embodiments, a compound of the invention is other
than one or more of: [0032] a) 1-Pyrrolidinecarboxamide,
3-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-N-methyl-N-[(-
3S)-1-(tetrahydro-2-oxo-3-furanyl)-3-pyrrolidinyl]-, (3S)--; [0033]
b) Pentitol,
1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[(-
4-phenoxyphenyl)amino]carbonyl]amino]-1-pyrrolidinyl]carbonyl]amino]-1-pyr-
rolidinyl]-; [0034] c) 1-Pyrrolidinecarboxamide,
N-methyl-3-[methyl[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]carbonyl]ami-
no]-N-[(3R)-1'-(phenylmethyl)[1,3'-bipyrrolidin]-3-yl]-, (3S)--;
[0035] d) Pentitol,
1,4-anhydro-2,3,5-trideoxy-3-[(3R)-3-[methyl[[(3S)-3-[methyl[[4-
'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]carbonyl]amino]-1-pyrrolidinyl]car-
bonyl]amino]-1-pyrrolidinyl]-; [0036] e)
[1,3'-Bipyrrolidine]-1'-carboxylic acid,
3-[(hydroxyamino)carbonyl]-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]-
amino]-, 1,1-dimethylethyl ester, (3R,4R)-rel-; and [0037] f)
[1,3'-Bipyrrolidine]-3-carboxamide,
N-hydroxy-4-[[4-[(2-methyl-4-quinolinyl)methoxy]benzoyl]amino]-,
(3R,4R)-rel-.
[0038] 2. Compounds and Definitions:
[0039] Compounds of this invention include those described
generally above, and are further illustrated by the classes,
subclasses, and species disclosed herein. As used herein, the
following definitions shall apply unless otherwise indicated.
[0040] 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 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.
[0041] 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. 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.
[0042] 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. By way of example, in a
compound of formula (I), if Ring B is substituted with two
substituents --R.sup.b, each substituent is selected from the group
of defined values for R.sup.b, and the two values selected may be
the same or different.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.sup.+ (as in N-substituted
pyrrolidinyl)).
[0052] The terms "aryl" and "ar-", used alone or as part of a
larger moiety, e.g., "aralkyl", "aralkoxy", or "aryloxyalkyl",
refer to an optionally substituted C.sub.6-14 aromatic hydrocarbon
moiety comprising one to three aromatic rings. Preferably, the aryl
group is a C.sub.6-10 aryl 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".
[0053] An "aralkyl" or "arylalkyl" group comprises an aryl group
covalently attached to an alkyl group, either of which
independently is optionally substituted. Preferably, the aralkyl
group is C.sub.6-10 arylC.sub.1-6alkyl, including, without
limitation, benzyl, phenethyl, and naphthylmethyl.
[0054] The terms "heteroaryl" and "heteroar-", used alone or as
part of a larger moiety, e.g., "heteroaralkyl", or
"heteroaralkoxy", refer to groups having 5 to 14 ring atoms,
preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 .pi.
electrons shared in a cyclic array; and having, in addition to
carbon atoms, from one to five heteroatoms. A heteroaryl group may
be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or
tricyclic, more preferably mono- or bicyclic. The term "heteroatom"
refers to nitrogen, oxygen, or sulfur, and includes any oxidized
form of nitrogen or sulfur, and any quaternized form of a basic
nitrogen. For example, a nitrogen atom of a heteroaryl may be a
basic nitrogen atom and may also be optionally oxidized to the
corresponding N-oxide. When a heteroaryl is substituted by a
hydroxy group, it also includes its corresponding tautomer. The
terms "heteroaryl" and "heteroar-", as used herein, also include
groups in which a heteroaromatic ring is fused to one or more aryl,
cycloaliphatic, or heterocycloaliphatic rings. Nonlimiting examples
of heteroaryl groups include thienyl, furanyl, pyrrolyl,
imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,
oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,
naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl,
benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,
benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
The term "heteroaryl" may be used interchangeably with the terms
"heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of
which terms include rings that are optionally substituted. The term
"heteroaralkyl" refers to an alkyl group substituted by a
heteroaryl, wherein the alkyl and heteroaryl portions independently
are optionally substituted.
[0055] As used herein, the terms "heterocycle", "heterocyclyl",
"heterocyclic radical", and "heterocyclic ring" are used
interchangeably and refer to a stable 3- to 8-membered monocyclic
or 7-10-membered bicyclic heterocyclic moiety that is either
saturated or partially unsaturated, and having, in addition to
carbon atoms, one or more, preferably one to four, heteroatoms, as
defined above. When used in reference to a ring atom of a
heterocycle, the term "nitrogen" includes a substituted nitrogen.
As an example, in a saturated or partially unsaturated ring having
0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the
nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in
pyrrolidinyl), or NR.sup.+ (as in N-substituted pyrrolidinyl).
[0056] 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.
[0057] 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 aryl or heteroaryl moieties, as herein
defined.
[0058] 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 replaced with a
substituent. Suitable substituents include those described below
for a substituted aliphatic group. An alkylene chain also may be
substituted at one or more positions with an aliphatic group or a
substituted aliphatic group.
[0059] 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 replaced with
the functional group. Examples of suitable "interrupting functional
groups" include --C(R.sup.+).dbd.C(R.sup.+)--, --C.ident.C--,
--O--, --S--, --S(O)--, --S(O).sub.2--, --S(O).sub.2N(R.sup.+)--,
--N(R.sup.+)--, --N(R.sup.+)CO--, --N(R.sup.+)C(O)N(R.sup.+)--,
--N(R.sup.+)C(.dbd.NR.sup.+)--N(R.sup.+)--,
--N(R.sup.+)--C(.dbd.NR.sup.+)--, --N(R.sup.+)CO.sub.2--,
--N(R.sup.+)SO.sub.2--, --N(R.sup.+)SO.sub.2N(R.sup.+)--,
--OC(O)--, --OC(O)O--, --OC(O)N(R.sup.+)--, --C(O)--, --CO.sub.2--,
--C(O)N(R.sup.+)--, --C(O)--C(O)--,
--C(.dbd.NR.sup.+)--N(R.sup.+)--, --C(NR.sup.+).dbd.N--,
--C(.dbd.NR.sup.+)--O--, --C(OR.sup.+).dbd.N--,
--C(R.sup.o).dbd.N--O--, or --N(R.sup.+)--N(R.sup.+)--. Each
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.
[0060] Examples of C.sub.3-6 alkylene chains that have been
"interrupted" with --O-- include --CH.sub.2OCH.sub.2--,
--CH.sub.2O(CH.sub.2).sub.2--, --CH.sub.2O(CH.sub.2).sub.3--,
--CH.sub.2O(CH.sub.2).sub.4--, --(CH.sub.2).sub.2OCH.sub.2--,
--(CH.sub.2).sub.2O(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2O(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3O(CH.sub.2)--,
--(CH.sub.2).sub.3O(CH.sub.2).sub.2--, and
--(CH.sub.2).sub.4O(CH.sub.2)--. Other examples of alkylene chains
that are "interrupted" with functional groups include
--CH.sub.2ZCH.sub.2--, --CH.sub.2Z(CH.sub.2).sub.2--,
--CH.sub.2Z(CH.sub.2).sub.3--, --CH.sub.2Z(CH.sub.2).sub.4--,
--(CH.sub.2).sub.2ZCH.sub.2--,
--(CH.sub.2).sub.2Z(CH.sub.2).sub.2--,
--(CH.sub.2).sub.2Z(CH.sub.2).sub.3--,
--(CH.sub.2).sub.3Z(CH.sub.2)--,
--(CH.sub.2).sub.3Z(CH.sub.2).sub.2--, and
--(CH.sub.2).sub.4Z(CH.sub.2)--, wherein Z is one of the
"interrupting" functional groups listed above. One of ordinary
skill in the art will recognize that when an alkylene chain having
an interruption is attached to a functional group, certain
combinations are not sufficiently stable for pharmaceutical use.
Only stable or chemically feasible compounds are within the scope
of the present invention.
[0061] 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.
[0062] 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.o and R.sup.+ are
as defined above.
[0063] 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 each R* and R.sup.o is defined above.
[0064] 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.
[0065] 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.
[0066] Exemplary rings that are formed when two independent
occurrences of R.sup.+ (or any other variable similarly defined in
the specification and claims herein), are taken together with their
intervening atom(s) include, but are not limited to the following:
a) two independent occurrences of R.sup.+ (or any other variable
similarly defined in the specification or claims herein) that are
bound to the same atom and are taken together with that atom to
form a ring, for example, N(R.sup.+).sub.2, where both occurrences
of R.sup.+ are taken together with the nitrogen atom to form a
piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two
independent occurrences of R.sup.+ (or any other variable similarly
defined in the specification or claims herein) that are bound to
different atoms and are taken together with both of those atoms to
form a ring, for example where a phenyl group is substituted with
two occurrences of OR
##STR00003##
these two occurrences of R.sup.+ are taken together with the oxygen
atoms to which they are bound to form a fused 6-membered oxygen
containing ring:
##STR00004##
It will be appreciated that a variety of other rings (e.g., Spiro
and bridged rings) can be formed when two independent occurrences
of R.sup.+ (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.
[0067] 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 .sup.13C- or .sup.14C-enriched carbon are within the scope of
this invention. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
[0068] It is to be understood that, when a disclosed compound has
at least one chiral center, the present invention encompasses one
enantiomer of inhibitor free from the corresponding optical isomer,
racemic mixture of the inhibitor and mixtures enriched in one
enantiomer relative to its corresponding optical isomer. When a
mixture is enriched in one enantiomer relative to its optical
isomers, the mixture contains, for example, an enantiomeric excess
of at least 50%, 75%, 90%, 95% 99% or 99.5%.
[0069] 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.
[0070] When a disclosed compound has at least two chiral centers,
the present invention encompasses a diastereomer free of other
diastereomers, a pair of diastereomers free from other
diasteromeric pairs, mixtures of diasteromers, mixtures of
diasteromeric pairs, mixtures of diasteromers in which one
diastereomer is enriched relative to the other diastereomer(s) and
mixtures of diasteromeric pairs in which one diastereomeric pair is
enriched relative to the other diastereomeric pair(s). When a
mixture is enriched in one diastereomer or diastereomeric pair(s)
relative to the other diastereomers or diastereomeric pair(s), the
mixture is enriched with the depicted or referenced diastereomer or
diastereomeric pair(s) relative to other diastereomers or
diastereomeric pair(s) for the compound, for example, by a molar
excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.
[0071] 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.
[0072] 3. Description of Exemplary Compounds:
[0073] In certain exemplary embodiments n is 1 and the compound has
the structure of formula I-A-I or I-A-ii:
##STR00005##
[0074] In certain embodiments r is 0 or 1. In other embodiments, r
is 1 and the compound has the structure of formula I-B:
##STR00006##
[0075] In yet other embodiments, r is 2 and the compound has the
structure of I-B-i:
##STR00007##
[0076] wherein the two occurrences of R.sup.3, taken together, form
an optionally substituted 3-6-membered spiro carbocyclic or
heterocyclic ring.
[0077] In certain embodiments, R.sup.1 is an optionally substituted
aryl group. In other embodiments, R.sup.1 is an optionally
substituted phenyl group. In still other embodiments, R.sup.1 is an
optionally substituted 5-8-membered monocyclic or 7-10-membered
bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms
independently selected from N, O, or S. In yet other embodiments,
R.sup.1 is an optionally substituted group selected from:
##STR00008##
In still other embodiments, R.sup.1 is an optionally substituted
group selected from:
##STR00009## ##STR00010## ##STR00011##
[0078] In some embodiments, R.sup.1 is optionally substituted with
1-3 occurrences of R.sup.1a, wherein each occurrence of R.sup.1a is
independently halogen, .dbd.O, .dbd.S, --CN, --NO.sub.2,
--R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b, --SR.sup.1c,
--S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: [0079] each occurrence of
R.sup.1b is independently hydrogen or an optionally substituted
group selected from C.sub.1-6aliphatic, 3-10-membered
cycloaliphatic, 3-10-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; and [0080] each occurrence of R.sup.1c is independently an
optionally substituted group selected from C.sub.1-6aliphatic,
3-10-membered cycloaliphatic, 3-10-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.
[0081] In some embodiments, each occurrence of R.sup.1a is
independently .dbd.O, halogen, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, or --SR.sup.1c. In other embodiments, each occurrence
of R.sup.1a is independently C.sub.1-4fluoroalkyl,
--O(C.sub.1-4fluoroalkyl), or --S(C.sub.1-4fluoroallyl).
[0082] In still other embodiments, Y.sub.1 is --SO.sub.2N(R')--,
--C(O)NR'--, or --N(R')S(O).sub.2--.
[0083] In yet other embodiments, Y.sub.1 is --N(R')C(O)--. In still
other embodiments, Y is selected from:
##STR00012## ##STR00013##
[0084] In other embodiments, for compounds of the invention X is O.
In still other embodiments, X is --N(W--R.sup.4).
[0085] In still other embodiments, for compounds of the invention,
X is O, m is 1, and R.sup.2 is an optionally substituted group
selected from a monocyclic 3-8-membered heterocyclyl having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a
7-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0086] In yet other embodiments, for compounds of the invention, X
is --N(W--R.sup.4) and R.sup.4 is an optionally substituted group
selected from a monocyclic 3-8-membered heterocyclyl having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or a
7-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0087] In yet other embodiments, R.sup.4 is optionally substituted
with 1-3 occurrences of R.sup.4a and each occurrence of R.sup.4a is
independently --R.sup.4b, -T.sub.1-R.sup.4e, or
--V.sub.1-T.sub.1-R.sup.4e, wherein: [0088] each occurrence of
--R.sup.4b is independently halogen, --CN, --NO.sub.2, --R.sup.4d,
--N(R.sup.4c).sub.2, --OR.sup.4c, --SR.sup.4d,
--S(O).sub.2R.sup.4d, --C(O)R.sup.4c, --C(O)OR.sup.4c,
--C(O)N(R.sup.4c).sub.2, --S(O).sub.2N(R.sup.4c).sub.2,
--OC(O)N(R.sup.4c).sub.2, --N(R')C(O)R.sup.4c,
--N(R')SO.sub.2R.sup.4d, --N(R')C(O)OR.sup.4c,
--N(R')C(O)N(R.sup.4e).sub.2, or --N(R')SO.sub.2N(R.sup.4c).sub.2,
or two occurences of R.sup.4b, R.sup.4c or R.sup.4d are optionally
taken together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.4c, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; [0089] each occurrence of R.sup.4c is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0090] each occurrence
of R.sup.4d is independently an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0091] each occurrence
of R.sup.4e is independently an optionally substituted group
selected from 3-10-membered cycloaliphatic, 3-10-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; [0092] each occurrence of V.sub.1 is
independently --C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--,
--S--, --S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--,
--C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; [0093] each
occurrence of T.sub.1 is independently C.sub.1-6 alkylene chain
optionally substituted with R.sup.3a, wherein the alkylene chain
optionally is interrupted by --C(R').dbd.C(R')--, --C.ident.C--,
--N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--,
--N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O-- or wherein
T.sup.1 or a portion thereof optionally forms part of an optionally
substituted 3-7 membered cycloaliphatic or heterocyclyl ring;
[0094] In still other embodiments, X is --N(W--R.sup.4), W is
absent and R.sup.4 is optionally substituted phenyl, wherein the
phenyl group is substituted with 1 or 2 occurrences of R.sup.4a,
wherein each occurrence of R.sup.4a is independently halogen, --CN,
--C(O)N(R.sup.4c).sub.2, --O(R.sup.4c), --S(R.sup.4d),
--N(R.sup.4c).sub.2, --C(O)O-T.sub.1-R.sup.4e, --R.sup.4d, or
wherein two occurrences of R.sup.4b, taken together with their
intervening atoms, form a 5-6-membered spiro or fused carbocyclic
or heterocyclyl ring.
[0095] In yet other embodiments, for compounds of the invention,
R.sup.3 is --OR.sup.3b, --SR.sup.3c, --V.sub.1-T.sub.1-R.sup.3d, or
T.sub.1-R.sup.3d, wherein V.sub.1 is O or S, and T.sub.1 is
--CH.sub.2-- or --CH.sub.2--CH.sub.2--.
[0096] In some embodiments, R.sup.3b, R.sup.3c, and R.sup.3d are
each independently an optionally substituted group selected from
C.sub.1-4alkenyl, C.sub.1-4alkynyl, C.sub.1-4alkyl, 5-10-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.
[0097] In other embodiments, R.sup.3b, R.sup.3c, and R.sup.3d are
each independently optionally substituted C.sub.1-4alkenyl,
C.sub.1-4alkynyl, C.sub.1-4alkyl, or an optionally substituted
group selected from:
##STR00014##
[0098] In still other embodiments, R.sup.3b, R.sup.3c, and R.sup.3d
are each independently an optionally substituted ring selected from
bicyclic 8-10-membered heterocyclyl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or
8-10-membered heteroaryl having 1-5 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0099] In yet other embodiments, R.sup.3b, R.sup.3c, and R.sup.3d
are each independently optionally substituted with 1-3 occurrences
of R.sup.3e, wherein R.sup.3e is R.sup.f, halogen,
--N(R.sup.g).sub.2, --OR.sup.g, --SR.sup.f, --S(O).sub.2R.sup.f,
--COR.sup.f, --COOR.sup.g, --CON(R.sup.g).sub.2,
--CON(R.sup.g).sub.2, --S(O).sub.2N(R.sup.g).sub.2,
--CC(O)N(R.sup.g).sub.2, --NR'C(O)R.sup.f, --NR'S(O).sub.2R.sup.f,
wherein R.sup.f is an optionally substituted C.sub.1-6 aliphatic
group and R.sup.g is hydrogen or an optionally substituted
C.sub.1-6 aliphatic group.
[0100] In still other embodiments, R.sup.3b, R.sup.3c, and R.sup.3d
are each independently optionally substituted with 1-3 occurrences
of R.sup.3e, wherein R.sup.3e is C.sub.1-4aliphatic,
C.sub.1-4haloaliphatic, or halogen.
[0101] In still other embodiments, r is 2 and two occurrences of
R.sup.3, taken together, form an optionally substituted
3-6-membered spiro carbocyclic or heterocyclic ring. In some
embodiments, the spiro ring is an optionally substituted ring
selected from:
##STR00015##
[0102] Certain additional subsets of interest include those
compounds having the structure of formula I-C:
##STR00016##
or a pharmaceutically acceptable salt thereof.
[0103] In some embodiments, for compounds of general formula I-C, X
is O and the compound has the structure of formula I-D:
##STR00017##
[0104] or a pharmaceutically acceptable salt thereof, wherein:
[0105] a) R.sup.1 is an optionally substituted 5-8-membered
monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl
ring having 1-4 heteroatoms independently selected from N, O, or S,
wherein R.sup.1 is optionally substituted with 1-3 occurrences of
R.sup.1a, wherein each occurrence of R.sup.1a is independently
halogen, .dbd.O, .dbd.S, --CN, --NO.sub.2, --R.sup.1c,
--N(R.sup.1b).sub.2, --OR.sup.1b, --SR.sup.1c,
--S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: [0106] each occurrence of
R.sup.1b is independently hydrogen or an optionally substituted
group selected from C.sub.1-6aliphatic, 3-10-membered
cycloaliphatic, 3-10-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; and [0107] each occurrence of R.sup.1c is independently an
optionally substituted group selected from C.sub.1-6aliphatic,
3-10-membered cycloaliphatic, 3-10-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;
[0108] b) Y is --NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2,
--NHC(O)--, --NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--;
[0109] c) m is 0 or 1, and when m is 1 R.sup.2 is an optionally
substituted group selected from a monocyclic 3-7-membered
heterocyclyl having 1-2 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and
[0110] d) R.sup.3 is --OR.sup.3b, --SR.sup.3e,
--V.sub.1-T.sub.1-R.sup.3d, or T.sub.1-R.sup.3d, wherein V.sub.1 is
O or S, and T.sub.1 is --CH.sub.2-- or --CH.sub.2--CH.sub.2--,
wherein R.sup.3b, R.sup.3c, and R.sup.3d are each independently an
optionally substituted group selected from C.sub.1-4alkenyl,
C.sub.1-4alkynyl, C.sub.1-4alkyl, 5-10-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.
[0111] In other embodiments, for compounds of general formula
I-D:
a) R.sup.1 is an optionally substituted group selected from:
##STR00018## ##STR00019## ##STR00020##
and each occurrence of R.sup.1a is independently .dbd.O, halogen,
--R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b, or --SR.sup.1c; and
b) R.sup.3b, R.sup.3c, and R.sup.3d are each independently
optionally substituted C.sub.1-4alkenyl, C.sub.1-4alkynyl,
C.sub.1-4alkyl, or an optionally substituted group selected
from:
##STR00021##
wherein R.sup.3b, R.sup.3c, and R.sup.3d are each independently
optionally substituted with 1-3 occurrences of R.sup.3e, wherein
R.sup.3e is C.sub.1-4aliphatic, C.sub.1-4haloaliphatic, or
halogen.
[0112] In some embodiments, for compounds of general formula I-C, X
is N(W--R.sup.4), and the compound has the structure of formula
I-E:
##STR00022##
[0113] or a pharmaceutically acceptable salt thereof, wherein:
[0114] a) R.sup.1 is an optionally substituted 5-8-membered
monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl
ring having 1-4 heteroatoms independently selected from N, O, or S,
wherein R.sup.1 is optionally substituted with 1-3 occurrences of
R.sup.1a, wherein each occurrence of R.sup.1a is independently
halogen, .dbd.O, --CN, --NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, --SR.sup.1c, --S(O).sub.2R.sup.1c, --C(O)R.sup.1b,
--C(O)OR.sup.1b, --C(O)N(R.sup.1b).sub.2,
--S(O).sub.2N(R.sup.1b).sub.2, --OC(O)N(R.sup.1b).sub.2,
--N(R')C(O)R.sup.1b, --N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: [0115] each occurrence of
R.sup.1b is independently hydrogen or an optionally substituted
group selected from C.sub.1-6aliphatic, 3-10-membered
cycloaliphatic, 3-10-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; and [0116] each occurrence of R.sup.1c is independently an
optionally substituted group selected from C.sub.1-6aliphatic,
3-10-membered cycloaliphatic, 3-10-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;
[0117] b) Y is --NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2,
--NHC(O)--, --NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--;
[0118] c) m is 0;
[0119] d) R.sup.3 is --OR.sup.3b, --SR.sup.3c,
--V.sub.1-T.sub.1-R.sup.3d, or T.sub.1-R.sup.3d, wherein V.sub.1 is
O or S, and T.sub.1 is --CH.sub.2-- or --CH.sub.2--CH.sub.2--,
wherein R.sup.3b, R.sup.3c, and R.sup.3d are each independently an
optionally substituted group selected from C.sub.1-4alkenyl,
C.sub.1-4alkynyl, C.sub.1-4alkyl, 5-10-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;
[0120] e) W is absent, and
[0121] f) R.sup.4 is an optionally substituted group selected from
a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
[0122] In some embodiments, for compounds of general formula I-C, X
is N(W--R.sup.4), and the compound has the structure of formula
I-E:
##STR00023##
[0123] or a pharmaceutically acceptable salt thereof, wherein:
[0124] a) R.sup.1 is an optionally substituted 5-8-membered
monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl
ring having 1-4 heteroatoms independently selected from N, O, or S,
wherein R.sup.1 is optionally substituted with 1-3 occurrences of
R.sup.1a, wherein each occurrence of R.sup.1a is independently
halogen, .dbd.O, --CN, --NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, --S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: [0125] each occurrence of
R.sup.1b is independently hydrogen or an optionally substituted
group selected from C.sub.1-6aliphatic, 3-10-membered
cycloaliphatic, 3-10-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; and [0126] each occurrence of R.sup.1c is independently an
optionally substituted group selected from C.sub.1-6aliphatic,
3-10-membered cycloaliphatic, 3-10-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;
[0127] b) Y is --NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2,
--NHC(O)--, --NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--;
[0128] c) m is 0;
[0129] d) R.sup.3 is --OR.sup.3b, --SR.sup.3c,
--V.sub.1-T.sub.1-R.sup.3d, or T.sub.1-R.sup.3d, wherein V.sub.1 is
O or S, and T.sub.1 is --CH.sub.2-- or --CH.sub.2--CH.sub.2--,
wherein R.sup.3b, R.sup.3c, and R.sup.3d are each independently an
optionally substituted group selected from C.sub.1-4alkenyl,
C.sub.1-4alkynyl, C.sub.1-4alkyl, 5-10-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;
[0130] e) W is absent, and
[0131] f) R.sup.4 is optionally substituted phenyl.
[0132] In other embodiments, for compounds of general formula I-E,
R.sup.4 is optionally substituted with 1-3 occurrences of R.sup.4a
and each occurrence of R.sup.4a is independently --R.sup.4b,
-T.sub.1-R.sup.4e, or --V.sub.1-T.sub.1-R.sup.4e, wherein: [0133]
each occurrence of --R.sup.4b is independently halogen, --CN,
--NO.sub.2, --R.sup.4d, --N(R.sup.4c).sub.2, OR.sup.4c,
--SR.sup.4d, --S(O).sub.2R.sup.4d, --C(O)R.sup.4c, --C(O)OR.sup.4c,
--C(O)N(R.sup.4c).sub.2, --S(O).sub.2N(R.sup.4c).sub.2,
--OC(O)N(R.sup.4c).sub.2, --N(R')C(O)R.sup.4c,
--N(R')SO.sub.2R.sup.4d, --N(R')C(O)OR.sup.4c,
--N(R')C(O)N(R.sup.4c).sub.2, or --N(R')SO.sub.2N(R.sup.4c).sub.2,
or two occurences of R.sup.4b, R.sup.4c or R.sup.4d are optionally
taken together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.4c, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; [0134] each occurrence of R.sup.4c is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0135] each occurrence
of R.sup.4d is independently an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0136] each occurrence
of R.sup.4e is independently an optionally substituted group
selected from 3-10-membered cycloaliphatic, 3-10-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; [0137] each occurrence of V.sub.1 is
independently --C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--,
--S--, --S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--,
--C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; and [0138]
each occurrence of T.sub.1 is independently C.sub.1-6 alkylene
chain optionally substituted with R.sup.3a, wherein the alkylene
chain optionally is interrupted by --C(R').dbd.C(R')--,
--C.ident.C--, --N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--C(O)--, --C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--,
--OC(O)N(R')--, --N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--,
--NR'C(O)N(R')--, --N(R')SO.sub.2N(R')--, --OC(O)--, or
--C(O)N(R')--O-- or wherein T.sup.1 or a portion thereof optionally
forms part of an optionally substituted 3-7 membered cycloaliphatic
or heterocyclyl ring. In other embodiments, for compounds of
general formula I-E: a) R.sup.1 is an optionally substituted group
selected from:
##STR00024## ##STR00025## ##STR00026##
[0138] and each occurrence of R.sup.1a is independently .dbd.O,
halogen, --R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b, or
--SR.sup.1c; and b) R.sup.3b, R.sup.3c, and R.sup.3d are each
independently optionally substituted C.sub.1-4alkenyl,
C.sub.1-4alkynyl, C.sub.1-4alkyl, or an optionally substituted
group selected from:
##STR00027##
wherein R.sup.3b, R.sup.1c, and R.sup.3d are each independently
optionally substituted with 1-3 occurrences of R.sup.3e, wherein
R.sup.3e is C.sub.1-4aliphatic, C.sub.1-4haloaliphatic, or
halogen.
[0139] Still other subsets of interest include those compounds
having the structure of formula I-F:
##STR00028##
[0140] or a pharmaceutically acceptable salt thereof,
[0141] wherein the two occurrences of R.sup.3, taken together, form
an optionally substituted 3-6-membered spiro carbocyclic or
heterocyclic ring.
[0142] In some embodiments, for compounds of general formula I-F, X
is O and the compound has the structure of formula I-G:
##STR00029##
[0143] or a pharmaceutically acceptable salt thereof, wherein:
[0144] a) R.sup.1 is an optionally substituted 5-8-membered
monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl
ring having 1-4 heteroatoms independently selected from N, O, or S,
wherein R.sup.1 is optionally substituted with 1-3 occurrences of
R.sup.1a, where in each occurrence of R.sup.1a is independently
halogen, .dbd.O, .dbd.S, --CN, --NO.sub.2, --R.sup.1c,
--N(R.sup.1b).sub.2, --OR.sup.1b, --SR.sup.1c,
--S(O).sub.2R.sup.1c, --C(O)R.sup.1b, --C(O)OR.sup.1b,
--C(O)N(R.sup.1b).sub.2, --S(O).sub.2N(R.sup.1b).sub.2,
--OC(O)N(R.sup.1b).sub.2, --N(R')C(O)R.sup.1b,
--N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: [0145] each occurrence of
R.sup.1b is independently hydrogen or an optionally substituted
group selected from C.sub.1-6aliphatic, 3-10-membered
cycloaliphatic, 3-10-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; and [0146] each occurrence of R.sup.1c is independently an
optionally substituted group selected from C.sub.1-6aliphatic,
3-10-membered cycloaliphatic, 3-10-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;
[0147] b) Y is --NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2,
--NHC(O)--, --NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--;
[0148] c) m is 0 or 1, and when m is 1 R.sup.2 is an optionally
substituted group selected from a monocyclic 3-7-membered
heterocyclyl having 1-2 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl
having 1-2 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms
independently selected from nitrogen, oxygen, or sulfur; and
[0149] d) wherein the two occurrences of R.sup.3, taken together,
form an optionally substituted 3-6-membered spiro carbocyclic or
heterocyclic ring.
[0150] In other embodiments, for compounds of general formula
I-G:
a) R.sup.1 is an optionally substituted group selected from:
##STR00030## ##STR00031## ##STR00032##
and each occurrence of R.sup.1a is independently .dbd.O, halogen,
--R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b, or --SR.sup.1c; and
b) the spiro ring formed from the two occurrences of R.sup.3 is an
optionally substituted ring selected from:
##STR00033##
[0151] In some embodiments, for compounds of general formula I-F, X
is N(W--R.sup.4), and the compound has the structure of formula
I-H:
##STR00034##
[0152] or a pharmaceutically acceptable salt thereof, wherein:
[0153] a) R.sup.1 is an optionally substituted 5-8-membered
monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl
ring having 1-4 heteroatoms independently selected from N, O, or S,
wherein R.sup.1 is optionally substituted with 1-3 occurrences of
R.sup.1a, wherein each occurrence of R.sup.1a is independently
halogen, .dbd.O, --CN, --NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, --SR.sup.1c, --S(O).sub.2R.sup.1c, --C(O)R.sup.1b,
--C(O)OR.sup.1b, --C(O)N(R.sup.1b).sub.2,
--S(O).sub.2N(R.sup.1b).sub.2, --OC(O)N(R.sup.1b).sub.2,
--N(R')C(O)R.sup.1b, --N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: [0154] each occurrence of
R.sup.1b is independently hydrogen or an optionally substituted
group selected from C.sub.1-6aliphatic, 3-10-membered
cycloaliphatic, 3-10-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; and [0155] each occurrence of R.sup.1c is independently an
optionally substituted group selected from C.sub.1-6aliphatic,
3-10-membered cycloaliphatic, 3-10-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;
[0156] b) Y is --NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2,
--NHC(O)--, --NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--;
[0157] c) m is 0;
[0158] d) wherein the two occurrences of R.sup.3, taken together,
form an optionally substituted 3-6-membered spiro carbocyclic or
heterocyclic ring;
[0159] e) W is absent, and
[0160] f) R.sup.4 is an optionally substituted group selected from
a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, a bicyclic
7-10-membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, a monocyclic
5-6-membered heteroaryl having 1-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 7-10-membered
heteroaryl having 1-5 heteroatoms independently selected from
nitrogen, oxygen, or sulfur.
[0161] In some embodiments, for compounds of general formula I-F, X
is N(W--R.sup.4), and the compound has the structure of formula
I-H:
##STR00035##
[0162] or a pharmaceutically acceptable salt thereof, wherein:
[0163] a) R.sup.1 is an optionally substituted 5-8-membered
monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl
ring having 1-4 heteroatoms independently selected from N, O, or S,
wherein R.sup.1 is optionally substituted with 1-3 occurrences of
R.sup.1a, wherein each occurrence of R.sup.1a is independently
halogen, .dbd.O, --CN, --NO.sub.2, --R.sup.1c, --N(R.sup.1b).sub.2,
--OR.sup.1b, --SR.sup.1c, --S(O).sub.2R.sup.1c, --C(O)R.sup.1b,
--C(O)OR.sup.1b, --C(O)N(R.sup.1b).sub.2,
--S(O).sub.2N(R.sup.1b).sub.2, --OC(O)N(R.sup.1b).sub.2,
--N(R')C(O)R.sup.1b, --N(R')SO.sub.2R.sup.1c, --N(R')C(O)OR.sup.1b,
--N(R')C(O)N(R.sup.1b).sub.2, or --N(R')SO.sub.2N(R.sup.1b).sub.2,
or two occurences of R.sup.1b or R.sup.1c are optionally taken
together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur or two
occurrences of R.sup.1b, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur, wherein: [0164] each occurrence of
R.sup.1b is independently hydrogen or an optionally substituted
group selected from C.sub.1-6aliphatic, 3-10-membered
cycloaliphatic, 3-10-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; and [0165] each occurrence of R.sup.1c is independently an
optionally substituted group selected from C.sub.1-6aliphatic,
3-10-membered cycloaliphatic, 3-10-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;
[0166] b) Y is --NH(CO)CH.sub.2--, --NHS(O).sub.2CH.sub.2,
--NHC(O)--, --NH(CO)CH.sub.2NH--, or --NHS(O).sub.2--;
[0167] c) m is 0;
[0168] d) the spiro ring formed from the two occurrences of R.sup.3
is an optionally substituted ring selected from:
##STR00036##
[0169] e) W is absent, and
[0170] f) R.sup.4 is optionally substituted phenyl.
[0171] In other embodiments, for compounds of general formula I-H,
R.sup.4 is optionally substituted with 1-3 occurrences of R.sup.4a
and each occurrence of R.sup.4a is independently --R.sup.4b,
-T.sub.1-R.sup.4e, or --V.sub.1-T.sub.1-R.sup.4e, wherein: [0172]
each occurrence of --R.sup.4b is independently halogen, --CN,
--NO.sub.2, --R.sup.4d, --N(R.sup.4c).sub.2, --OR.sup.4c,
--SR.sup.4d, --S(O).sub.2R.sup.4d, --C(O)R.sup.4c, --C(O)OR.sup.4c,
--C(O)N(R.sup.4c).sub.2, --S(O).sub.2N(R.sup.4c).sub.2,
--OC(O)N(R.sup.4c).sub.2, --N(R')C(O)R.sup.4c,
--N(R')SO.sub.2R.sup.4d, --N(R')C(O)OR.sup.4c,
--N(R')C(O)N(R.sup.4c).sub.2, or --N(R')SO.sub.2N(R.sup.4c).sub.2,
or two occurences of R.sup.4b, R.sup.4c or R.sup.4d are optionally
taken together with their intervening atom(s) to form an optionally
substituted spiro, fused, or bridged ring selected from 6-membered
aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having
1-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms
independently selected from nitrogen, oxygen, or sulfur, or two
occurrences of R.sup.4c, taken together with the nitrogen atom to
which they are bound, form an optionally substituted 3-7-membered
heterocyclyl ring having 1-3 additional heteroatoms selected from
nitrogen, oxygen, or sulfur; [0173] each occurrence of R.sup.4c is
independently hydrogen or an optionally substituted group selected
from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0174] each occurrence
of R.sup.4d is independently an optionally substituted group
selected from C.sub.1-6aliphatic, 3-10-membered cycloaliphatic,
3-10-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; [0175] each occurrence
of R.sup.4e is independently an optionally substituted group
selected from 3-10-membered cycloaliphatic, 3-10-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; [0176] each occurrence of V.sub.1 is
independently --C(R').dbd.C(R')--, --C.ident.C--, --N(R')--, --O--,
--S--, --S(O)--, --S(O).sub.2--, --C(O)--, --C(O)O--,
--C(O)N(R')--, --S(O).sub.2N(R')--, --OC(O)N(R')--, --N(R')C(O)--,
--N(R')SO.sub.2--, --N(R')C(O)O--, --NR'C(O)N(R')--,
--N(R')SO.sub.2N(R')--, --OC(O)--, or --C(O)N(R')--O--; and [0177]
each occurrence of T.sub.1 is independently C.sub.1-6 alkylene
chain optionally substituted with R.sup.3a, wherein the alkylene
chain optionally is interrupted by --C(R').dbd.C(R')--,
--C.ident.C--, --N(R')--, --O--, --S--, --S(O)--, --S(O).sub.2--,
--C(O)--, --C(O)O--, --C(O)N(R')--, --S(O).sub.2N(R')--,
--OC(O)N(R')--, --N(R')C(O)--, --N(R')SO.sub.2--, --N(R')C(O)O--,
--NR'C(O)N(R')--, --N(R')SO.sub.2N(R')--, --OC(O)--, or
--C(O)N(R')--O-- or wherein T.sup.1or a portion thereof optionally
forms part of an optionally substituted 3-7 membered cycloaliphatic
or heterocyclyl ring.
[0178] In other embodiments, for compounds of general formula
I-H:
a) R.sup.1 is an optionally substituted group selected from:
##STR00037## ##STR00038## ##STR00039##
and each occurrence of R.sup.1a is independently .dbd.O, halogen,
--R.sup.1c, --N(R.sup.1b).sub.2, --OR.sup.1b, or --SR.sup.1c; and
b) the spiro ring formed from the two occurrences of R.sup.3 is an
optionally substituted ring selected from:
##STR00040##
[0179] 4. Uses, Formulation, and Administration:
[0180] As discussed above, the present invention provides compounds
that are inhibitors of chemokine receptor activity. In some
embodiments, the present invention provides compounds that are
inhibitors of CCR2 activity. The compounds can be assayed in vitro
or in vivo for their ability to bind to and/or inhibit chemokine
receptor activity, preferably CCR2. Assays are described in the
Examples and/or are known in the art.
[0181] In another aspect, therefore, the invention provides a
method for inhibiting CCR2 activity in biological sample or a
subject, which method comprises administering to the subject, or
contacting said biological sample with a compound of formula I or a
composition comprising said compound. The term "biological sample",
as used herein, 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. Inhibition of CCR2 activity
in a biological sample is useful for a variety of purposes that are
known to one of skill in the art. Examples of such purposes
include, but are not limited to, blood transfusion,
organ-transplantation, biological specimen storage, and biological
assays.
[0182] In some embodiments, the compound of formula I interacts
with and reduces the activity of more than one chemokine receptor
in the biological sample, preferably a cell. By way of example,
when assayed against CCR2, some compounds of formula I show
inhibition of more than one chemokine receptor, for example CCR5.
In some embodiments, the compound of formula I is selective for the
inhibition of CCR2, i.e., the concentration of the compound that is
required for inhibition of CCR2 is lower, preferably at least
2-fold, 5-fold, 10-fold, or 50-fold lower, than the concentration
of the compound required for inhibition of another chemokine
receptor (e.g., CCR5). In some embodiments of the invention,
compounds of the invention are selective for the inhibition of
CCR2. As used herein, the term "selective" means that a compound
binds to or inhibits a chemokine receptor with greater affinity or
potency, respectively, compared to at least one other chemokine
receptor, or preferably compared to all other chemokine receptors
of the same class (e.g., all of the CC-type receptors). In some
embodiments, the compounds of the invention have binding or
inhibition selectivity for CCR2 or CCR5 over any other chemokine
receptor. Selectivity can be at least about 10-fold, at least about
20-fold, at least about 50-fold, at least about 100-fold, at least
about 200-fold, at least about 500-fold, or at least about
1000-fold. Binding affinity and inhibitor potency can be measured
according to routine methods in the art, such as according to the
assays provided herein.
[0183] As used herein the term "contacting" refers to the bringing
together of indicated moieties in an in vitro or an in vivo system.
For example, "contacting" the chemokine receptor with a compound of
the invention includes the administration of a compound of the
present invention to a subject, such as a human, having a chemokine
receptor, as well as, for example, introducing a compound of the
invention into a sample containing a cellular or purified
preparation containing the chemokine receptor.
[0184] In another aspect, the invention provides a pharmaceutical
composition comprising a compound of formula (I) as defined above,
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
[0185] If pharmaceutically acceptable salts of the compounds of the
invention are utilized in these compositions, the salts preferably
are derived from inorganic or organic acids and bases. For reviews
of suitable salts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19
(1977) and Remington: The Science and Practice of Pharmacy, 20th
Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000.
[0186] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, 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 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 active
metabolite or residue thereof. As used herein, the term "active
metabolite or residue thereof" means that a metabolite or residue
thereof is useful for the treatment of inflammatory or allergic
disorders. In some embodiments, without wishing to be bound by any
particular theory, a "pharmaceutically acceptable salt" means any
non-toxic salt of a compound of this invention that, upon
administration to a recipient, is capable of providing, either
directly or indirectly, an inhibitorily active compound of the
invention or an inhibitorily active metabolite or residue thereof.
As used herein, the term "inhibitorily active compound or
inhibitorily active metabolite or residue thereof" means that a
compound or metabolite or residue thereof is also an inhibitor of
CCR2.
[0187] Nonlimiting examples of suitable acid addition salts include
the following: acetate, adipate, alginate, aspartate, benzoate,
benzene sulfonate, bisulfate, butyrate, citrate, camphorate,
camphor sulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, lucoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, methanesulfonate, 2-naphthalenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate,
3-phenyl-propionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, tosylate and undecanoate.
[0188] Suitable base addition salts include, without limitation,
ammonium salts, alkali metal salts, such as sodium and potassium
salts, alkaline earth metal salts, such as calcium and magnesium
salts, salts with organic bases, such as dicyclohexylamine salts,
N-methyl-D-glucamine, and salts with amino acids such as arginine,
lysine, and so forth.
[0189] Also, basic nitrogen-containing groups may be quaternized
with such agents as lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chloride, bromides and iodides; dialkyl sulfates,
such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain
halides such as decyl, lauryl, myristyl and stearyl chlorides,
bromides and iodides, aralkyl halides, such as benzyl and phenethyl
bromides and others. Water or oil-soluble or dispersible products
are thereby obtained.
[0190] As described above, the pharmaceutical compositions of the
present invention additionally comprise a pharmaceutically
acceptable carrier, 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, Mack Publishing Co., a
standard reference text in this field, discloses various carriers
used in formulating pharmaceutical 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 pharmaceutical composition, its use is
contemplated to be within the scope of this invention.
[0191] The pharmaceutical compositions of the invention can be
manufactured by methods well known in the art such as conventional
granulating, mixing, dissolving, encapsulating, lyophilizing, or
emulsifying processes, among others. Compositions may be produced
in various forms, including granules, precipitates, or
particulates, powders, including freeze dried, rotary dried or
spray dried powders, amorphous powders, tablets, capsules, syrup,
suppositories, injections, emulsions, elixirs, suspensions or
solutions. Formulations may optionally contain stabilizers, pH
modifiers, surfactants, bioavailability modifiers and combinations
of these.
[0192] Pharmaceutical formulations may be prepared as liquid
suspensions or solutions using a liquid, such as, but not limited
to, an oil, water, an alcohol, and combinations of these.
Pharmaceutically suitable surfactants, suspending agents, or
emulsifying agents, may be added for oral or parenteral
administration. Suspensions may include oils, such as but not
limited to, peanut oil, sesame oil, cottonseed oil, corn oil and
olive oil. Suspension preparation may also contain esters of fatty
acids such as ethyl oleate, isopropyl myristate, fatty acid
glycerides and acetylated fatty acid glycerides. Suspension
formulations may include alcohols, such as, but not limited to,
ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and
propylene glycol. Ethers, such as but not limited to,
poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil
and petrolatum; and water may also be used in suspension
formulations.
[0193] Pharmaceutically acceptable carriers that may be used in
these compositions 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, 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, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0194] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being. Such pharmaceutical
compositions of the present invention may be administered orally,
parenterally, by inhalation spray, topically, rectally, nasally,
buccally, vaginally or via an implanted reservoir. The term
"parenteral" as used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial, intrasternal,
intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. Preferably, the compositions are
administered orally, intravenously, or subcutaneously. The
formulations of the invention may be designed to be short-acting,
fast-releasing, or long-acting. Still further, compounds can be
administered in a local rather than systemic means, such as
administration (e.g., by injection) at a desired site.
[0195] Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic 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 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 may be employed including synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its
glyceride derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as olive oil
or castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation. Compounds may be formulated for parenteral
administration by injection such as by bolus injection or
continuous infusion. A unit dosage form for injection may be in
ampoules or in multi-dose containers.
[0196] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. In the case of tablets for oral use, carriers that are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried cornstarch. When aqueous suspensions are required for
oral use, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
[0197] Alternatively, the pharmaceutical compositions of this
invention may be administered in the form of suppositories for
rectal administration. These may be prepared by mixing the agent
with a suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0198] The pharmaceutical compositions of this invention may also
be administered topically, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0199] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used. For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions may be formulated in
a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0200] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with our without a preservative
such as benzylalkonium chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated in an
ointment such as petrolatum.
[0201] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques well known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
[0202] The compounds of this invention or pharmaceutical
compositions thereof may also be incorporated into compositions for
coating implantable medical devices, such as prostheses, artificial
valves, vascular grafts, stents and catheters. Accordingly, the
present invention, in another aspect, includes a composition for
coating an implantable device comprising a compound of the present
invention as described generally above, and in classes and
subclasses herein, and a carrier suitable for coating said
implantable device. In still another aspect, the present invention
includes an implantable device coated with a composition comprising
a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for
coating said implantable device.
[0203] Vascular stents, for example, have been used to overcome
restenosis (re-narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk clot
formation or platelet activation. These unwanted effects may be
prevented or mitigated by pre-coating the device with a
pharmaceutically acceptable composition comprising a kinase
inhibitor. Suitable coatings and the general preparation of coated
implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled release
characteristics in the composition.
[0204] The pharmaceutical compositions of the invention preferably
are formulated for administration to a patient having, or at risk
of developing or experiencing a recurrence of, an inflammatory,
allergic or autoimmune disease, condition, or disorder. The term
"patient", as used herein, means an animal, preferably a mammal,
more preferably a human. Preferred pharmaceutical compositions of
the invention are those formulated for oral, intravenous, or
subcutaneous administration. However, any of the above dosage forms
containing a therapeutically effective amount of a compound of the
invention are well within the bounds of routine experimentation and
therefore, well within the scope of the instant invention. In some
embodiments, the pharmaceutical composition of the invention may
further comprise another therapeutic agent. In some embodiments,
such other therapeutic agent is one that is normally administered
to patients with the disease or condition being treated.
[0205] As discussed above, compounds of the invention (including
salts thereof) are useful as inhibitors of CCR2 activity. Several
diseases and disorders have been shown to be mediated at least in
part by the activation of CCR2. Thus, compounds of the invention
are useful for the treatment of (therapeutically or
prophylactically) conditions mediated by CCR2, including, but not
limited to, inflammatory, allergic, or autoimmune diseases,
conditions, or disorders. The disclosed compounds can also be
advantageously used for the treatment of diseases, conditions, or
disorders mediated by esinophils, monocytes, T lymphocytes and
other immune system cells which express CCR2, including
inflammatory, allergic, or autoimmune diseases, conditions, or
disorders mediated by these cells. When activation of CCR2 is
implicated in a particular disease, condition, or disorder, the
disease, condition, or disorder may also be referred to as "a
CCR2-mediated disease, condition, or disorder" or disorder symptom.
Accordingly, in another aspect, the present invention provides a
method for the treatment of an inflammatory, allergic, or
autoimmune disease, condition, or disorder is provided comprising
administering an effective amount of a compound or a pharmaceutical
composition to a subject in need thereof.
[0206] Examples of allergic conditions for which the disclosed
compounds, pharmaceutical compositions and methods are particularly
effective include asthma, atopic dermatitis, allergic rhinitis,
systemic anaphylaxis or hypersensitivity responses, drug allergies
(e.g., to penicillin, cephalosporins), insect sting allergies and
dermatoses such as dermatitis, eczema, atopic dermatitis, allergic
contact dermatitis and urticaria.
[0207] Examples of diseases with an inflammatory component for
which the disclosed compounds, pharmaceutical composition and
methods are effective include rheumatoid arthritis, osteoarthritis,
inflammatory bowel disease [e.g., such as ulcerative colitis,
Crohn's disease, ileitis, Celiac disease, nontropical Sprue,
enteritis, enteropathy associated with seronegative arthropathies,
microscopic or collagenous colitis, eosinophilic gastroenteritis,
or pouchitis resulting after proctocolectomy, and ileoanal
anastomosis] and disorders of the skin [e.g., psoriasis, erythema,
pruritis, and acne].
[0208] Many autoimmune diseases also have an inflammatory
component. Examples include multiple sclerosis, systemic lupus
erythematosus, myasthenia gravis, juvenile onset diabetes,
glomerulonephritis and other nephritides, autoimmune thyroiditis,
Behcet's disease and graft rejection (including allograft rejection
or graft-versus-host disease). The inflammatory component of these
disorders is believed to be mediated, at least in part, by
CCR2.
[0209] Diseases characterized by repurfusion have an inflammatory
component that is believed to be mediated, at least in part by
CCR2. Examples include stroke, cardiac ischemia, and the like. The
disclosed compounds and pharmaceutical compositions also can be
used to treat these disorders.
[0210] Other diseases and conditions with an inflammatory component
believed to be mediated by CCR2 include mastitis (mammary gland),
vaginitis, cholecystitis, cholangitis or pericholangitis (bile duct
and surrounding tissue of the liver), chronic bronchitis, chronic
sinusitis, chronic inflammatory diseases of the lung which result
in interstitial fibrosis, such as interstitial lung diseases (ILD)
(e.g., idiopathic pulmonary fibrosis, or ILD associated with
rheumatoid arthritis, or other autoimmune conditions), cystic
fibrosis, hypersensitivity pneumonitis, collagen diseases,
neuropathic pain, and sarcoidosis.
[0211] Yet other diseases or conditions with inflammatory
components which are amenable to treatment according to methods
disclosed herein include vasculitis (e.g., necrotizing, cutaneous,
and hypersensitivity vasculitis), spondyloarthropathies,
scleroderma, atherosclerosis, restenosis and myositis (including
polymyositis, dermatomyositis), pancreatitis and insulin-dependent
diabetes mellitus.
[0212] Still other diseases or conditions which are amenable to
treatment according to methods disclosed herein include cancer,
preferably breast cancer or multiple myeloma.
[0213] In some embodiments, the present invention provides a method
for treating rheumatoid arthritis, multiple sclerosis, scleroderma,
atherosclerosis, neuropathic pain, type II diabetes, COPD (chronic
obstructive pulmonary disorder), cystic fibrosis, hepatic fibrosis,
inflammatory bowel disease, lung fibrosis, lupus, lupus nephritis,
macular degeneration, cancer (including breast cancer and multiple
myeloma), acute and chronic organ transplant rejection,
inflammatory pain, post MI remodeling, psoriasis, renal fibrosis,
restenosis, stroke, uveitis, endometriosis, acute pancreatitis,
peripheral vascular disease, sarcoidosis, or CIDP/Guillain-Barre
disease comprising administering a therapeutically effective amount
of a compound of formula I.
[0214] In still other embodiments, the present invention provides a
method for treating rheumatoid arthritis, multiple sclerosis,
scleroderma, atherosclerosis, neuropathic pain, or type II diabetes
comprising administering a therapeutically effective amount of a
compound of formula I.
[0215] In yet other embodiments, the present invention provides a
method for treating rheumatoid arthritis or multiple sclerosis
comprising administering a therapeutically effective amount of a
compound of formula I.
[0216] As used herein, "treatment" or "treating" means partial
alleviation, prevention, or cure of a disease, condition, or
disorder as described herein.
[0217] As used herein a "therapeutically effective amount" of the
compound or pharmaceutical composition is that quantity required to
achieve a desired therapeutic and/or prophylactic effect, such as
an amount which results in the prevention of or a decrease in the
symptoms associated with a disease, condition or disorder as
described herein. In some embodiments, a therapeutically effective
amount of a compound is that amount which results in the inhibition
of one or more of the processes mediated by the binding of a
chemokine to a receptor such as CCR2 in a subject with a disease
associated with aberrant leukocyte recruitment and/or activation.
Typical examples of such processes include leukocyte migration,
integrin activation, transient increases in the concentration of
intracellular free calcium and granule release of proinflammatory
mediators.
[0218] Compounds and pharmaceutical compositions, according to the
method of the present invention, may be administered using any
amount and any route of administration effective for treating a
disease, condition, or disorder as described herein. The skilled
artisan will be able to determine appropriate dosages depending on
these and other factors. An "effective amount" typically ranges
between about 0.01 mg/kg/day to about 100 mg/kg/day, preferably
between about 0.5 mg/kg/day to about 50 mg/kg/day. In other
embodiments, an effective amount typically ranges between about 1
mg/kg/day to about 25 mg/kg/day.
[0219] 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
disorder being treated and the severity of the disorder; 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.
[0220] The term "subject", as used herein, is preferably a bird or
mammal, such as a human (Homo sapiens), but can also be an animal
in need of veterinary treatment, e.g., domestic animals (e.g.,
dogs, cats, and the like), farm animals (e.g., cows, sheep, fowl,
pigs, horses, and the like) and laboratory animals (e.g., rats,
mice, guinea pigs, and the like).
[0221] It will also be appreciated that the compounds and
pharmaceutical compositions of the present invention can be
employed in combination therapies, that is, the compounds and
pharmaceutical compositions can be administered concurrently with,
prior to, or subsequent to, one or more other desired therapeutics
or medical procedures. The particular combination of therapies
(therapeutics or procedures) to employ in a combination regimen
will take into account compatibility of the desired therapeutics
and/or procedures and the desired therapeutic effect to be
achieved. It will also be appreciated that the therapies employed
may achieve a desired effect for the same disorder (for example, an
inventive compound may be administered concurrently with another
agent used to treat the same disorder), or they may achieve
different effects (e.g., control of any adverse effects). As used
herein, additional therapeutic agents which are normally
administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated". Exemplary additional therapeutic agents for use
with an antagonist of chemokine receptor function include, but are
not limited to theophylline, .beta.-adrenergic bronchodilators,
corticosteroids, antihistamines, antiallergic agents,
immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone,
methylprednisolone), hormones (e.g., adrenocorticotropic hormone
(ACTH)), cytokines (e.g., interferons (e.g., IFN.beta.-1.alpha.,
IFN.beta.-1.beta.)) and the like.
[0222] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
Examples
[0223] Although certain exemplary embodiments are depicted and
described herein, it will be appreciated that compounds of the
invention can be prepared using appropriate starting materials
according to the methods described generally herein and/or by
methods generally available to one of ordinary skill in the art.
Additional embodiments are exemplified in more detail herein.
Exemplary compounds of formula I are depicted in Table 1 below and
described in the examples below.
[0224] General. All reactions involving air-sensitive reagents were
performed under a nitrogen atmosphere. Reagents were used as
received from commercial suppliers unless otherwise noted. .sup.1H
NMR data were recorded using the Bruker UltraShield 300 MHz/54 mm
instrument equipped with Bruker B-ACS60 Auto Sampler or the Varian
300 MHz instrument. Intermediates and final compounds were purified
by flash chromatography using one of the following instruments: 1.
Biotage 4-channel Quad UV Flash Collector equipped with a Quad 1
Pump Module and the Quad 12/25 Cartridge module. 2. Biotage
12-channel Quad UV Flash Collector equipped with a Quad 3 Pump
Module and a Quad 3 Cartridge module. 3. ISCO combi-flash
chromatography instrument. LC/MS spectra were obtained using a
MicroMass Platform LC (Phenomenx C18 column, 5 micron, 50.times.4.6
mm) equipped with a Gilson 215 Liquid Handler. Standard LC/MS
conditions are as follows. LC-MS data were acquired using the
"Ammonium acetate-standard" method unless otherwise noted.
[0225] Ammonium Acetate-Standard Conditions:
TABLE-US-00001 % A (Water) 95.0 % B (Acetonitrile) 5.0 % Ammonium
acetate 0.1 Flow (ml/min) 2.500 Stop Time (mins) 3.8 Min Pressure
(bar) 0 Max Pressure (bar) 400 Oven Temperature Left (.degree. C.)
10.0 Oven Temperature Right (.degree. C.) 10.0 HP 1100 LC Pump
Gradient Timetable The gradient Timetable contains 4 entries which
are: Time A % B % C % D % Flow Pressure 0.00 95.0 5.0 0.0 0.0 2.500
400 2.00 0.0 100.0 0.0 0.0 2.500 400 3.00 0.0 100.0 0.0 0.0 2.500
400 3.05 95.0 5.0 0.0 0.0 2.000 400
Benzyl
(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipy-
rrolidine-1'-carboxylate (1)
[0226] To a solution of
N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide
(500 mg, 1.59 mmol; prepared according to WO2004/050024A2) in
methanol (5 mL) at room temperature was added benzyl
3-oxopyrrolidine-1-carboxylate (434 mg, 1.98 mmol) followed by
sodium triacetoxyborohydride (470 mg, 2.22 mmol); the reaction
mixture was stirred for 16 hours. To the mixture was added
NaHCO.sub.3 (sat. aq., 10 mL) and dichloromethane (10 mL). The
organic layer was separated and the aqueous layer was washed with
an addition portion of dichloromethane (10 mL). The organic layers
were combined, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The resulting crude product was subjected to flash
chromatography (15% MeOH, 1% NH.sub.4OH in EtOAc) to afford, as a
mixture of diastereomers, benzyl
(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrrolid-
ine-1'-carboxylate (906 mg, 88%) as a white solid. .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.30-1.44 (m, 2H), 1.50-1.68 (m, 2H),
1.80-2.00 (m, 2H), 2.10-3.29 (m, 1H), 2.30-2.43 (m, 1H), 2.55-23.05
(m, 3H), 3.15-3.28 (m, 1H), 3.58-4.20 (m, 3H), 4.30-4.50 (m, 1H),
5.09 (s, 2H), 6.70-6.87 (m, 1H), 7.20-7.50 (m, 6H), 7.52 (t, J=8.7
Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 8.09 (s,
1H). MS m/z: 519 (M+1)
N-(2-{[(3R)-1'-(4-methoxyphenyl)-5'-oxo-1,3'-bipyrrolidin-3-yl]amino}-2-ox-
oethyl)-3-(trifluoromethyl)benzamide (2)
[0227] To a solution of N-allyl-4-methoxyaniline (1.00 g, 6.13
mmol) in methylene chloride (20 mL) was added K.sub.2CO.sub.3 (2.12
mg, 15.3 mmol) and acryloyl chloride (548 .mu.L, 6.74 mmol) at
0.degree. C. After 15 min., the reaction was quenched with
NaHCO.sub.3 (5 mL, sat. aq.) and the organic layer was isolated,
concentrated and subjected to flash chromatography (Hexanes:EtOAc
4:1) to yield N-allyl-N-(4-methoxyphenyl)acrylamide (1.29 mg,
97%).
[0228] To a solution of N-allyl-N-(4-methoxyphenyl)acrylamide (150
mg, 0.69 mmol) in degassed methylene chloride (400 mL) was added
Grubbs catalyst (58 mg, 0.069 mmol) and the mixture was heated to
40.degree. C. overnight. All volatiles were removed and the
resulting material was subjected to flash chromatography
(Hexanes:EtOAc 1:1) to yield
1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (110 mg, 86%).
[0229] A slurry of water (20 .mu.L, 0.10 mmol),
1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (200 mg, 1.06 mmol)
and
N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide
(666 mg, 2.12 mmol) was heated to 90.degree. C. overnight. The
crude mixture was subjected to flash chromatography (1% NH.sub.4OH,
15% MeOH, EtOAc) to afford, as a mixture of diastereomers,
N-(2-{[(3R)-1'-(4-methoxyphenyl)-5'-oxo-1,3'-bipyrrolidin-3-yl]amino}-2-o-
xoethyl)-3-(trifluoromethyl)benzamide as a white solid (115 mg,
21%). .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50-1.82 (m, 1H),
1.83-2.00 (m, 1H), 2.18-2.40 (m, 1H), 2.40-2.58 (m, 1H), 2.56-2.81
(m, 3H), 2.83-3.00 (m, 2H), 3.29-3.33 (m, 2H), 3.60-3.71 (m, 2H),
3.79 (s, 3H), 4.04-4.20 (m, 2H), 4.38-4.47 (m, 1H), 6.94 (m, 2H),
7.19-7.30 (m, 2H), 7.69-7.80 (m, 2H), 7.99 (d, J=7.8 Hz, 1H), 8.18
(s, 1H). MS m/z: 505 (M+1).
Benzyl
4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-b-
ipyrrolidin-1'-yl}benzoate (3)
[0230] In a round-bottom flask, a slurry of benzyl
(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrrolid-
ine-1'-carboxylate (0.765 g, 1.48 mmol) and Palladium (10%) on
Carbon (0.200 g) in methanol (10 mL) was purged with hydrogen gas
for 2 min.; the reaction was then subjected to 1 atm of hydrogen
gas for 3 h. The flask was purged with Argon, then the mixture was
filtered and concentrated to afford
N-{2-[(3R)-1,3'-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)be-
nzamide (0.551 g, 97%) as an off-white solid. .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.32-1.53 (m, 2H), 1.52-2.04 (m, 6H),
2.15-2.40 (m, 2H), 2.40-2.70 (m, 3H), 2.80-3.00 (m, 3H), 4.00-4.20
(m, 2H), 4.42 (bs, 1H), 6.77 (m, 1H), 7.40-7.55 (m, 1H), 7.53 (t,
J=7.8 Hz, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 8.08
(s, 1H). MS m/z: 399 (M+1).
[0231] To a solution of
N-{2-[(3R)-1,3'-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)be-
nzamide (525 mg, 1.36 mmol) in DMSO (3 mL) was added
K.sub.2CO.sub.3 (940 mg, 6.8 mmol) followed by benzyl
4-fluorobenzoate (786 mg, 3.41 mmol). The mixture was heated to
120.degree. C. for 16 hours. The crude mixture was subjected to
column chromatography (15% MeOH, 1% NH.sub.4OH in EtOAc) to afford,
as a mixture of diastereomers,
N-{2-[(3R)-1,3'-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)be-
nzamide (355 mg, 44%) as a white solid. .sup.1H-NMR (MeOD) .delta.:
1.70-1.80 (m, 1H), 1.92-2.04 (m, 1H), 2.20-2.36 (m, 2H), 2.56-2.70
(m, 2H), 2.84-2.96 (m, 2H), 2.96-3.09 (m, 1H), 3.20-3.42 (m, 4H),
3.46-3.62 (m, 2H), 4.03 (s, 2H), 4.37-4.50 (m, 1H), 5.29 (s, 2H),
6.57 (d, J=9.0 Hz, 2H), 7.27-7.46 (m, 5H), 7.68 (t, J=6.9 Hz, 1H),
7.82-7.90 (m, 3H), 8.14 (d, J=8.1 Hz, 1H), 8.22 (s, 1H). MS m/z:
595 (M+1)
N,N-diethyl-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1-
,3'-bipyrrolidin-1'-yl}benzamide (4)
[0232] In a round-bottom flask, a solution of benzyl
4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrro-
lidin-1'-yl}benzoate (258 mg, 0.43 mmol) in methanol (400 .mu.L)
and Palladium (10%) on Carbon (50 mg) was purged with hydrogen gas
for two minutes; the reaction was then subjected to 1 atmosphere of
hydrogen gas for two hours. The flask was purged with Argon, then
the mixture was filtered and concentrated to afford
4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrro-
lidin-1'-yl}benzoic acid (197 mg, 91%) as an off-white solid.
[0233] To a solution of
4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrro-
lidin-1'-yl}benzoic acid (35 mg, 0.069 mmol), HATU (0.032 g, 0.086
mmol), N,N-diisopropylethylamine (30.2 .mu.L, 0.173 mmol),
1-Hydroxybenzotriazole (11.7 mg, 0.0867 mmol) in DMF (3.0 mL) was
added diethylame (8.25 .mu.L, 0.079 mmol). The reaction mixture was
allowed to stir at room temperature overnight. To the mixture was
added NaHCO.sub.3 (sat. aq., 10 mL) and dichloromethane (10 mL).
The organic layer was separated and the aqueous layer was washed
with an addition portion of dichloromethane (10 mL). The organic
layers were combined, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The resulting crude product was subjected to flash
chromatography (15% MeOH, 1% NH.sub.4OH in EtOAc) to afford, as a
mixture of diastereomers,
N,N-diethyl-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]--
1,3'-bipyrrolidin-1'-yl}benzamide (32 mg, 82%) as a white solid.
.sup.1H-NMR (MeOD) .delta.: 1.19 (t, J=6.6 Hz, 6H), 1.66-1.80 (m,
1H), 1.90-2.05 (m, 1H), 2.18-2.40 (m, 2H), 2.50-2.70 (m, 2H),
2.80-3.06 (m, 4H), 3.15-3.40 (m, 4H), 3.38-3.60 (m, 5H), 4.03 (s,
2H), 4.37-4.50 (m, 1H), 6.58 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.1 Hz,
2H), 7.69 (t, J=7.2 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 8.14 (d, J=7.5
Hz, 1H), 8.22 (s, 1H). MS m/z: 560 (M+1)
N-[2-({(3R)-1'-[4-(morpholin-4-ylcarbonyl)phenyl]-1,3'-bipyrrolidin-3-yl}a-
mino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (5)
[0234] The title compound was synthesized in similar fashion to
N,N-diethyl-4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]--
1,3'-bipyrrolidin-1'-yl}benzamide, substituting morpholine for
diethylamine, and was isolated, as a mixture of diastereomers, as a
white solid. .sup.1H-NMR (MeOD) .delta.: 1.55-1.6.5 (m, 1H),
1.67-1.82 (m, 1H), 1.90-2.06 (m, 1H), 2.20-2.36 (m, 2H), 2.56-2.68
(m, 2H), 2.84-2.95 (m, 2H), 2.96-3.06 (m, 1H), 3.18-3.40 (m, 2H),
3.42-3.60 (m, 2H), 3.60-3.74 (m, 10H), 4.03 (s, 2H), 4.39-4.50 (m,
1H), 6.59 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.69 (t, J=8.1
Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 8.22 (s, 1H). MS m/z: 574
(M+1)
N-(2-oxo-2-{[(3R)-1-(tetrahydro-3-thienyl)pyrrolidin-3-yl]amino}ethyl)-3-(-
trifluoromethyl)benzamide (6)
[0235] The title compound was synthesized in similar fashion to
benzyl
(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrrolid-
ine-1'-carboxylate, whereby dihydrothiophen-3(2H)-one was
substituted for benzyl 3-oxopyrrolidine-1-carboxylate, and was
isolated, as a mixture of diastereomers, as a white solid.
.sup.1H-NMR (CDCl.sub.3) .delta.: 1.55-1.66 (m, 1H), 1.71-1.81 (m,
1H), 2.03-2.14 (m, 1H), 2.15-2.26 (m, 1H), 2.33-2.39 (m, 1H),
2.52-2.58 (m, 1H), 2.63-2.73 (m, 3H), 2.74-2.81 (m, 4H), 4.07 (d,
J=4.8 Hz, 2H), 4.36-4.38 (m, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.46 (t,
J=7.9 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.81 (t, J=4.9 Hz, 1H), 7.93
(d, J=8.4 Hz, 1H), 8.03 (s, 1H). MS m/z: 402 (M+1)
Methyl
4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-b-
ipyrrolidin-1'-yl}benzoate (7)
[0236] A slurry of
N-{2-[(3R)-1,3'-bipyrrolidin-3-ylamino]-2-oxoethyl}-3-(trifluoromethyl)be-
nzamide (50 mg, 0.13 mmol), methyl 4-bromobenzoate (35 mg, 0.16
mmol), Pd.sub.2(dba).sub.3 (12 mg, 0.013 mmol), cesium carbonate
(64 mg, 0.19 mmol) and R-BINAP (8 mg, 0.013 mmol) in toluene was
heated at 100.degree. C. overnight. To the mixture was added
NaHCO.sub.3 (sat. aq., 10 mL) and dichloromethane (10 mL). The
organic layer was separated and the aqueous layer was washed with
an addition portion of dichloromethane (10 mL). The organic layers
were combined, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The resulting crude product was subjected to flash
chromatography (15% MeOH, 1% NH.sub.4OH in EtOAc) to afford, as a
mixture of diastereomers, methyl
4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3'-bipyrro-
lidin-1'-yl}benzoate (20 mg, 30%) as a white solid. .sup.1H-NMR
(CDCl.sub.3) .delta.: 1.60-1.76 (m, 1H), 1.86-2.04 (m, 1H),
2.08-2.25 (m, 1H), 2.20-2.44 (m, 2H), 2.60-2.78 (m, 2H), 2.84-3.00
(m, 2H), 3.18 (q, J=8.7 Hz, 1H), 3.32 (q, J=7.5 Hz, 1H), 3.40-3.54
(m, 2H), 3.82 (s, 3H), 4.10 (m, 2H), 4.40-4.56 (m, 1H), 6.44 (d,
J=8.7 Hz, 2H), 6.54 (d, J=2.4 Hz, 1H), 7.20-7.35 (m, 1H), 7.54 (t,
J=7.8 Hz, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.97
(d, J=7.8 Hz, 1H), 8.07 (s, 1H). MS m/z: 519 (M+1)
[0237] Compounds 8-143 can also be prepared by the methods
described herein. Those skilled in the art will be able to
recognize, or be able to ascertain, using no more than routine
experimentation, many equivalents to the specific embodiments of
the invention described herein.
TABLE-US-00002 TABLE 1 ##STR00041## ##STR00042## ##STR00043##
##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058##
##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063##
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083##
##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##
##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093##
##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098##
##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103##
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113##
##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##
##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123##
##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128##
##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133##
##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138##
##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143##
##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148##
##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153##
##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158##
##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163##
##STR00164##
##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169##
##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174##
##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179##
##STR00180## ##STR00181## ##STR00182## ##STR00183##
Biological Testing
[0238] THP-1 FLIPR Assay
[0239] The primary screening assay is a FLIPR (Fluorometric Imaging
Plate Reader) assay using THP-1 cells (ATCC, Catalog No. TIB 202),
a monocytic derived cell line that endogenously expresses CCR2.
[0240] The cells were resuspended at 1.times.10.sup.6cells/ml in
dye loading media (growth media (RPMI+10% FBS (Fetal Bovine
serum)+5.5.times.10.sup.-5M 2-mercaptoethanol)+10 mM HEPES
(N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid)+2.5 mM
probenecid+fluo-3 (1:250)). The cells were incubated for 1 hour at
37.degree. C. and then washed in FLIPR wash buffer (100 mL
10.times.HBSS (Hanks Buffered Saline Solution) (w/Ca++/Mg++)+20 mL
1M HEPES+1 g BSA+10 mL250 mM probenecid+water (to make 1 L)) and
plated at 50,000 cells/well in black/clear 384 well plates. The
plates were transferred to FLIPR where the ability of different
concentrations of compounds to inhibit MCP-1 induced calcium flux
was assessed. Inhibition of the CCR2 response was reflected by a
decrease of the fluorescence signal relative to the positive
controls (MCP-1 alone).
[0241] THP-1 Whole Cell Radioligand Binding Assay
[0242] The cells were washed with PBS (phosphate buffered saline)
and resuspended in binding buffer (10 mM HEPES pH 7.2, 1.times.HBSS
(w/Ca.sup.2+, Mg.sup.2+) 0.5% BSA, 0.02% Na-azide) at
4.times.10.sup.6 cells/ml (for 200,000 cells/well). Cells were
incubated with 0.1 to 0.2 nM [.sup.125I]-labeled MIP-1.alpha. with
or without unlabeled competitor (MIP-1.alpha.) or various
concentrations of compounds for 60 minutes at room temperature. The
assay was terminated by vacuum filtration through glass fiber
filters (GF/B, Packard) which were presoaked in 0.3%
polyethyleneimine. The filters were washed with wash buffer (10 mM
HEPES, pH 7.2, 1 mM CaCl.sub.2, 5 mM MgCl.sub.2 0.5M NaCl), dried
and the amount of bound radioactivity was determined by
scintillation counting.
[0243] Compounds of the invention have been shown to inhibit CCR2,
preferably at a concentration less than 100 nM.
[0244] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
* * * * *