U.S. patent application number 13/683967 was filed with the patent office on 2013-08-15 for enhanced treatment regimens using mtor inhibitors.
This patent application is currently assigned to Intellikine LLC. The applicant listed for this patent is Intellikine LLC. Invention is credited to Lynne Bui, Yi Liu, Michael Martin, Christian Rommel, Troy Edward Wilson.
Application Number | 20130209543 13/683967 |
Document ID | / |
Family ID | 48470426 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130209543 |
Kind Code |
A1 |
Liu; Yi ; et al. |
August 15, 2013 |
ENHANCED TREATMENT REGIMENS USING MTOR INHIBITORS
Abstract
The present invention provides for methods and pharmaceutical
compositions comprising inhibitors of mTorC1 and/or mTorC2. In some
aspects, the invention provides for treatment regimens resulting in
enhanced treatment efficacy and better tolerability.
Inventors: |
Liu; Yi; (San Diego, CA)
; Bui; Lynne; (Saratoga, CA) ; Martin;
Michael; (Carlsbad, CA) ; Wilson; Troy Edward;
(San Marino, CA) ; Rommel; Christian; (La Jolla,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Intellikine LLC; |
|
|
US |
|
|
Assignee: |
Intellikine LLC
La Jolla
CA
|
Family ID: |
48470426 |
Appl. No.: |
13/683967 |
Filed: |
November 21, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61563516 |
Nov 23, 2011 |
|
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|
Current U.S.
Class: |
424/450 ;
514/234.2; 514/252.16; 514/262.1; 514/265.1; 514/303; 544/118;
544/262; 544/280; 546/119 |
Current CPC
Class: |
A61K 31/496 20130101;
A61P 29/00 20180101; A61P 35/00 20180101; A61K 31/535 20130101;
A61P 13/12 20180101; A61P 43/00 20180101; A61K 31/437 20130101;
A61P 17/00 20180101; A61P 37/06 20180101; A61K 31/4965 20130101;
A61K 31/519 20130101; A61K 31/5377 20130101; C07D 487/04 20130101;
C07D 519/00 20130101 |
Class at
Publication: |
424/450 ;
514/262.1; 514/265.1; 514/303; 514/234.2; 514/252.16; 544/262;
544/280; 546/119; 544/118 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61K 31/5377 20060101 A61K031/5377; A61K 31/496
20060101 A61K031/496; A61K 31/437 20060101 A61K031/437 |
Claims
1. A method of treating a disorder in a subject in need thereof,
comprising administering an mTorC1/mTorC2 inhibitor to said subject
according to an intermittent regimen effective to achieve an
mTorC1/mTorC2 inhibitor plasma concentration at or above about 100
nM for a duration of time that is longer than that achieved by
administering an equivalent dose of the mTorC1/mTorC2 inhibitor
once daily.
2. The method of claim 1, wherein the intermittent regimen is
effective to achieve an mTorC1/mTorC2 inhibitor plasma
concentration of greater than about 100 nM for a duration longer
than about 20 hours during a 7-day period of administration.
3. The method of claim 1, wherein the intermittent regimen is
effective to achieve an mTorC1/mTorC2 inhibitor plasma
concentration of greater than about 100 nM for a duration of at
least about 30 hours during a 7-day period of administration.
4. A method of treating a disorder in a subject in need thereof,
comprising administering an mTorC1/mTorC2 inhibitor to said subject
according to an intermittent regimen, such that the achieved Cmax
is greater than that achieved by administering an equivalent dose
of the mTorC1/mTorC2 inhibitor once daily.
5. The method of claim 4, wherein the intermittent regimen is
effective to achieve a Cmax which is greater by about 10%, 20%,
30%, 40%, 50%, 100%, 200%, or 300% than the Cmax achieved by
administering an equivalent dose of the mTorC1/mTorC2 inhibitor
once daily.
6. The method of claim 4, wherein the intermittent regimen is
effective to achieve a Cmax of greater than about 200, 250, 300,
350, 400, 450, 500, 550 or 600 nM.
7. The method of claim 4, wherein the intermittent regimen is
effective to achieve a Cmax of greater than about 300 nM.
8. The method of any preceding claim, wherein the intermittent
regimen achieves similar or better pathway inhibition than
administering an equivalent dose of the mTorC1/mTorC2 once
daily.
9. The method of claim 8, wherein the pathway inhibition is
measured as percentage of decrease in phosphorylation of a protein
chosen from p4EBP1, pS6, and pRAS40.
10. The method of any preceding claim, wherein the intermittent
regimen achieves similar or better therapeutic efficacy than
administering an equivalent dose of the mTorC1/mTorC2 once
daily.
11. The method of any preceding claim, wherein the intermittent
regimen achieves at least the same level of tolerability as
compared to administering an equivalent dose of the mTorC1/mTorC2
inhibitor once daily.
12. The method of claim 11, wherein the level of tolerability is
measured as the occurrence or lack of occurrence in the subject of
a grade 3 or higher adverse event.
13. The method of claim 11, wherein the adverse event is rash.
14. The method of claim any preceding claim, wherein the
intermittent regimen comprises at least one cycle in which the
mTorC1/mTorC2 inhibitor is administered for at least 1 day,
followed by an intermission in which the mTorC1/mTorC2 inhibitor is
not administered for at least 1 day.
15. The method of claim 14, wherein the mTorC1/mTorC2 inhibitor is
administered for 2, 3, 4, 5, 6 or 7 consecutive days followed by an
intermission in which the mTorC1/mTorC2 inhibitor is not
administered for at least 1 day.
16. The method of claim 14, wherein the regimen comprises at least
one cycle in which the mTorC1/mTorC2 inhibitor is administered for
2, 3, 4, 5, 6 or 7 consecutive days followed by an intermission in
which the mTorC1/mTorC2 inhibitor is not administered for at least
3, 4, or 5 consecutive days.
17. The method of claim 14, wherein the regimen comprises at least
one cycle in which the mTorC1/mTorC2 inhibitor is administered for
1 day followed by an intermission in which the mTorC1/mTorC2
inhibitor is not administered for 6 consecutive days.
18. The method of claim 14, wherein the regimen comprises at least
one 7-day cycle in which the mTorC1/mTorC2 inhibitor is
administered for 3 consecutive days followed by an intermission of
4 consecutive days.
19. The method of claim 14, wherein the regimen comprises at least
one 7-day cycle in which the mTorC1/mTorC2 inhibitor is
administered for 5 consecutive days followed by an intermission of
2 consecutive days.
20. The method of claim 14, wherein the regimen comprises at least
one 7-day cycle in which the mTorC1/mTorC2 inhibitor is
administered at least 3 times on alternate days within the 7
days.
21. A dosage form for administration to a subject comprising an
mTorC1/mTorC2 inhibitor, wherein the dosage form is formulated to
provide a Cmax of greater than about 200 nM when administered to
the subject.
22. The dosage form of claim 21, wherein the dosage form is capable
of providing a plasma concentration of said mTorC1/mTorC2 inhibitor
of greater than about 100 nM for a duration of time longer than
about 20 hours during a 7-day period of administration.
23. The dosage form of claim 21, wherein the dosage form is capable
of providing a plasma concentration of greater than 100 nM for a
duration of time that is at least about 30 hours during a 7-day
period of administration.
24. The dosage form of claim 21, comprising about 45, 50, 55, 60,
70, 75 mg or less of the mTorC1/mTorC2 inhibitor.
25. A method of treating a disorder in a subject in need thereof,
comprising administering a dosage form of any of claims 21-24.
26. A kit comprising the dosage form of claim 21 and additionally
comprising instructions for administration to a subject in need
thereof.
27. The kit of claim 26, wherein the instructions provide for at
least one 7-day cycle of administration to the subject for 2, 3, 4,
or 5 consecutive days followed by an intermission of 5, 4, 3, or 2
days, respectively.
28. The kit of claim 26, wherein the instructions provide for
administration of the mTorC1/mTorC2 inhibitor to the subject for 3
consecutive days followed by an intermission of 4 consecutive
days.
29. A pharmaceutical regimen for the treatment of a disorder, the
regimen comprising an mTorC1/mTorC2 inhibitor, wherein the regimen
provides an area under the curve that is similar to that obtained
by administering the mTorC1/mTorC2 inhibitor once daily, and
wherein the regimen results in higher therapeutic efficacy as
compared to administering said inhibitor once daily.
30. The method of claim 1, wherein the disorder is a neoplastic
condition, autoimmune disease, inflammatory disease, fibrotic
disease or kidney disease.
31. The method of claim 30, wherein the disorder is a neoplastic
condition.
32. The method of claim 31, wherein the neoplastic condition is
cancer.
33. A method of treating a disorder in a subject in need thereof,
comprising administering an mTorC1/mTorC2 inhibitor to said subject
according to an intermittent regimen effective to achieve (a)
higher therapeutic efficacy, (b) similar or better tolerability of
the mTorC1/mTorC2 inhibitor, and (c) similar or smaller area under
the curve, as compared to administering an equivalent dose of the
mTorC1/mTorC2 inhibitor once daily.
34. The method, dosage form, or pharmaceutical regimen of any
preceding claim, wherein the mTorC1/mTorC2 inhibitor is
administered parenterally, orally, intraperitoneally,
intravenously, intraarterially, transdermally, intramuscularly,
liposomally, via local delivery by catheter or stent,
subcutaneously, intraadiposally, or intrathecally.
35. The method, dosage form, or pharmaceutical regimen of claim 34,
wherein the mTorC1/mTorC2 inhibitor is administered orally.
36. The method, dosage form, or pharmaceutical regimen of any
preceding claim, wherein the mTorC1/mTorC2 inhibitor inhibits both
mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as
ascertained in an in vitro kinase assay.
37. The method, dosage form, or pharmaceutical regimen of any
preceding claim, wherein the mTorC1/mTorC2 inhibitor inhibits both
mTORC1 and mTORC2 with an IC50 value of about 10 nM or less as
ascertained in an in vitro kinase assay.
38. The method, dosage form, or pharmaceutical regimen of any
preceding claim, wherein the mTorC1/mTorC2 inhibitor inhibits both
mTORC1 and mTORC2 with an IC50 value of about 10 nM or less as
ascertained in an in vitro kinase assay, and that the mTorC1/mTorC2
inhibitor is substantially inactive against one or more types I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta..
39. The method, dosage form, or pharmaceutical regimen of any
preceding claim, wherein the mTorC1/mTorC2 inhibitor inhibits both
mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as
ascertained in an in vitro kinase assay, and said IC50 value is at
least 5 times less than its IC50 value against all other type I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta..
40. The method, dosage form, or pharmaceutical regimen of any
preceding claim, wherein the mTorC1/mTorC2 inhibitor is a compound
of Formula I: ##STR00430## or a pharmaceutically acceptable salt
thereof, wherein: X.sub.1 is N or C-E.sup.1, X.sub.2 is N or C,
X.sub.3 is N or C, X.sub.4 is C--R.sup.9 or N, X.sub.5 is N or
C-E.sup.1, X.sub.6 is C or N, and X.sub.7 is C or N; and wherein no
more than two nitrogen ring atoms are adjacent; R.sub.1 is H,
-L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, -L-aryl, -L-heteroaryl,
-L-C.sub.1-10alkylaryl, -L-C.sub.1-10alkylhetaryl,
-L-C.sub.1-10alkylheterocylyl, -L-C.sub.2-10alkenyl,
-L-C.sub.2-10alkynyl, -L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3;
L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--; E.sup.1 and E.sup.2
are independently --(W.sup.1).sub.j--R.sup.4; M.sub.1 is a 5, 6, 7,
8, 9, or -10 membered ring system, wherein the ring system is
monocyclic or bicyclic, substituted with R.sub.5 and additionally
optionally substituted with one or more --(W.sup.2).sub.k--R.sup.2;
each k is 0 or 1; j in E.sup.1 or j in E.sup.2, is independently 0
or 1; W.sup.1 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--; W.sup.2 is --O--,
--NR.sup.7--, --S(O).sub.0-2--, --C(O)--, --C(O)N(R.sup.7)--,
--N(R.sup.7)C(O)--, --N(R.sup.7)C(O)N(R.sup.8)--,
--N(R.sup.7)S(O)--, --N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--; R.sup.2 is hydrogen, halogen,
--OH, --R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl (e.g. bicyclic aryl,
unsubstituted aryl, or substituted monocyclic aryl), hetaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl (e.g.
C.sub.2-10alkyl-monocyclic aryl, C.sub.1-10alkyl-substituted
monocyclic aryl, or C.sub.1-10alkylbicycloaryl),
C.sub.1-10alkylhetaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylhetaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylhetaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocylyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl (e.g.
monocyclic aryl-C.sub.2-10alkyl, substituted monocyclic
aryl-C.sub.1-10alkyl, or bicycloaryl-C.sub.1-10alkyl),
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, hetaryl-C.sub.3-8cycloalkyl,
hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said
bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein
each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety
is substituted with one or more independent alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32; R.sup.3 and R.sup.4 are
independently hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32 aryl, hetaryl, C.sub.1-4alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl,
C.sub.1-10alkylhetaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylhetaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylhetaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocylyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, hetaryl-C.sub.3-8cycloalkyl,
heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein
each of said aryl or heteroaryl moiety is unsubstituted or is
substituted with one or more independent halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
R.sup.5 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32; each of R.sup.31, R.sup.32, and
R.sup.33 is independently H or C.sub.1-10alkyl, wherein the
C.sub.1-10alkyl is unsubstituted or is substituted with one or more
aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each of
said aryl, heteroalkyl, heterocyclyl, or hetaryl group is
unsubstituted or is substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2-aryl,
--C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35;
R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, hetaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen atom; each of R.sup.7 and
R.sup.8 is independently hydrogen, C.sub.1-10alkyl,
C.sub.2-10alkenyl, aryl, heteroaryl, heterocyclyl or
C.sub.3-10cycloalkyl, each of which except for hydrogen is
unsubstituted or is substituted by one or more independent R.sup.6;
R.sup.6 is halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.1-10alkyl,
hetaryl-C.sub.2-10alkenyl, hetaryl-C.sub.2-10alkynyl, wherein each
of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,
or hetaryl group is unsubstituted or is substituted with one or
more independent halo, cyano, nitro, --OC.sub.1-10alkyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R'',
--SO.sub.2NR.sup.34R'', --SO.sub.2NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35; and R.sup.9 is H,
halo, --OR.sup.31, --SH, --NH.sub.2, --NR.sup.34R.sup.35,
--NR.sup.31R.sup.32, --CO.sub.2R.sup.31, --CO.sub.2aryl,
--C(.dbd.O)NR.sup.31R.sup.32, C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2C.sub.1-10alkyl,
--S(O).sub.0-2aryl, --SO.sub.2NR.sup.34R.sup.35,
--SO.sub.2NR.sup.31R.sup.32, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl; aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.1-10alkyl,
hetaryl-C.sub.2-10alkenyl, hetaryl-C.sub.2-10alkynyl, wherein each
of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,
or hetaryl group is unsubstituted or is substituted with one or
more independent halo, cyano, nitro, --OC.sub.1-10alkyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35.
41. The method, dosage form, or pharmaceutical regimen of claim 40,
wherein the mTorC1/mTorC2 inhibitor has the Formula: ##STR00431##
or a pharmaceutically acceptable salt thereof, wherein: E.sup.2 is
--H; X.sub.1 is N; X.sub.2 is N; W.sup.2 is --NH; and k is 1.
42. The method, dosage form, or pharmaceutical regimen of claim 41,
wherein R.sub.2 is H.
43. The method, dosage form, or pharmaceutical regimen of claim 42,
wherein R.sub.1 is isopropyl.
44. The method, dosage form, or pharmaceutical regimen of claim 42,
wherein R.sub.1 is ##STR00432##
45. The method, dosage form, or pharmaceutical regimen of claim 42,
wherein R.sub.1 is ##STR00433##
46. The method, dosage form, or pharmaceutical regimen of claim 42,
wherein R.sub.1 ##STR00434##
47. The method, dosage form, or pharmaceutical regimen of claim 40,
wherein E.sup.2 is --H; X.sub.1 is CH; X.sub.2 is N; W.sup.2 is
--NH; R.sub.2 is H; k is 1; and R.sub.1 is isopropyl or
##STR00435##
Description
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/563,516, filed Nov. 23, 2011, which is
incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The activity of cells can be regulated by external signals
that stimulate or inhibit intracellular events. The process by
which stimulatory or inhibitory signals are transmitted into and
within a cell to elicit an intracellular response is referred to as
signal transduction. Over the past decades, cascades of signal
transduction events have been elucidated and found to play a
central role in a variety of biological responses. Defects in
various components of signal transduction pathways have been found
to account for a vast number of diseases, including numerous forms
of cancer, inflammatory disorders, metabolic disorders, vascular
and neuronal diseases (Gaestel et al. Current Medicinal Chemistry
(2007) 14:2214-2234).
[0003] Kinases represent a class of important signaling molecules.
Kinases can generally be classified into protein kinases and lipid
kinases, and certain kinases exhibit dual specificities. Protein
kinases are enzymes that phosphorylate other proteins and/or
themselves (i.e., autophosphorylation). Protein kinases can be
generally classified into three major groups based upon their
substrate utilization: tyrosine kinases which predominantly
phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF
receptor, EGF receptor, VEGF receptor, src, abl), serine/threonine
kinases which predominantly phosphorylate substrates on serine
and/or threonine residues (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK,
Akt), and dual-specificity kinases which phosphorylate substrates
on tyrosine, serine and/or threonine residues.
[0004] Lipid kinases are enzymes that catalyze the phosphorylation
of lipids. These enzymes, and the resulting phosphorylated lipids
and lipid-derived biologically active organic molecules, play a
role in many different physiological processes, including cell
proliferation, migration, adhesion, and differentiation. Certain
lipid kinases are membrane associated and they catalyze the
phosphorylation of lipids contained in or associated with cell
membranes. Examples of such enzymes include phosphoinositide(s)
kinases (such as PI3-kinases, PI4-Kinases), diacylglycerol kinases,
and sphingosine kinases.
[0005] The phosphoinositide 3-kinases (PI3Ks) signaling pathway is
one of the most highly mutated systems in human cancers. PI3K
signaling is also a key factor in many other diseases in humans.
PI3K signaling is involved in many disease states including
allergic contact dermatitis, rheumatoid arthritis, osteoarthritis,
inflammatory bowel diseases, chronic obstructive pulmonary
disorder, psoriasis, multiple sclerosis, asthma, disorders related
to diabetic complications, and inflammatory complications of the
cardiovascular system such as acute coronary syndrome.
[0006] PI3Ks are members of a unique and conserved family of
intracellular lipid kinases that phosphorylate the 3'-OH group on
phosphatidylinositols or phosphoinositides. The PI3K family
comprises 15 kinases with distinct substrate specificities,
expression patterns, and modes of regulation (Katso et al., 2001).
The class I PI3Ks (p110.quadrature., p110.quadrature.,
p110.quadrature., and p110.quadrature.) are typically activated by
tyrosine kinases or G-protein coupled receptors to generate
phosphatidylinositol-3,4,5-trisphosphate (PIP.sub.3), which engages
downstream effectors such as those in the Akt/PDK1 pathway, mTOR,
the Tec family kinases, and the Rho family GTPases. The class II
and III PI3-Ks play a key role in intracellular trafficking through
the synthesis of PI(3)P and PI(3,4)P2. The PIKKs are protein
kinases that control cell growth (mTORC1) or monitor genomic
integrity (ATM, ATR, DNA-PK, and hSmg-1).
[0007] The production of PIP.sub.3 initiates potent growth and
survival signals. In some epithelial cancers the PI3K pathway is
activated by direct genetic mutation. As PI3K signaling pathway
plays a pivotal role in cell proliferation and differentiation,
inhibition of this pathway is believed to be beneficial in
hyperproliferative diseases.
[0008] Downstream mediators of the PI3K signal transduction pathway
include Akt and mammalian target of rapamycin (mTOR). Akt possesses
a plckstrin homology (PH) domain that bind PIP3, leading to Akt
kinase activation. Akt phosphorylates many substrates and is a
central downstream effector of PI3K for diverse cellular responses.
Full activation of Akt typically requires phosphorylation of T308
in the activation loop and S473 in a hydrophobic motif One
important function of Akt is to augment the activity of mTOR,
through phosphorylation of TSC2 and other mechanisms.
[0009] mTOR is a serine-threonine kinase related to the lipid
kinases of the PI3K family. mTOR has been implicated in a wide
range of biological processes including cell growth, cell
proliferation, cell motility and survival. Disregulation of the
mTOR pathway has been reported in various types of cancer. mTOR is
a multifunctional kinase that integrates growth factor and nutrient
signals to regulate protein translation, nutrient uptake,
autophagy, and mitochondrial function.
[0010] mTOR exists in two complexes, mTORC1 and mTORC2. mTORC1
contains the raptor subunit and mTORC2 contains rictor. These
complexes are differentially regulated, and have distinct substrate
specificities and rapamycin sensitivity. For example, mTORC1
phosphorylates S6 kinase (S6K) and 4EBP1, promoting increased
translation and ribosome biogenesis to facilitate cell growth and
cell cycle progression. S6K also acts in a feedback pathway to
attenuate PI3K/Akt activation. mTORC2 is generally insensitive to
rapamycin. mTORC2 is though to modulate growth factor signaling by
phosphorylating the C-terminal hydrophobic motif of some AGC
kinases such as Akt. In many cellular contexts, mTORC2 is required
for phosphorylation of the S473 site of Akt.
[0011] Over the past decade, mTOR has drawn considerable attention
due to its role in cell growth control and its involvement in human
diseases. mTor has been implicated in a wide range of disorders
including but not limited to cancer, diabetes, obesity,
cardiovascular diseases and neurological disorders. It has been
shown that mTOR modulates many fundamental biological processes
including transcription, translation, autophagy, actin organization
and ribosome biogenesis by integrating intracellular and
extracellular signals, such as signals mediated by growth factors,
nutrients, energy levels and cellular stress.
[0012] As such, kinases particularly protein kinases such as mTor
and Akt, as well as lipid kinases such as PI3Ks are prime targets
for drug development.
[0013] At the same time, tolerability and prevalence of side
effects are important considerations in structuring courses of
treatment for many diseases. For example, treatments which require
the use of therapeutic agents which result in severe adverse events
may become ineffective due to insufficient patient compliance or
because an effective therapeutic dose cannot be administered to the
patient. Similarly, treatments which result in a higher effective
concentration of the drug being present in the blood stream for a
longer period of time may provide better therapeutic efficacy. The
present invention addresses this need in the art by providing
methods and compositions for mTor inhibition and treatment regimens
utilizing such methods and compositions.
SUMMARY OF THE INVENTION
[0014] The invention provides a method of treating a disorder in a
subject in need thereof, comprising administering an mTorC1/mTorC2
inhibitor to said subject according to an intermittent regimen
effective to achieve an mTorC1/mTorC2 inhibitor plasma
concentration at or above about 100 nM for a duration of time that
is longer than that achieved by administering an equivalent dose of
the mTorC1/mTorC2 inhibitor once daily. In some embodiments, the
intermittent regimen is effective to achieve an mTorC1/mTorC2
inhibitor plasma concentration of greater than about 100 nM for a
duration longer than about 20 hours during a 7-day period of
administration. In other embodiments, the intermittent regimen is
effective to achieve an mTorC1/mTorC2 inhibitor plasma
concentration of greater than about 100 nM for a duration of at
least about 30 hours during a 7-day period of administration.
[0015] The invention further provides a method of treating a
disorder in a subject in need thereof, comprising administering an
mTorC1/mTorC2 inhibitor to said subject according to an
intermittent regimen, such that the achieved Cmax is greater than
that achieved by administering an equivalent dose of the
mTorC1/mTorC2 inhibitor once daily. For example, the intermittent
regimen is effective to achieve a Cmax which is greater by about
10%, 20%, 30%, 40%, 50%, 100%, 200%, or 300% than the Cmax achieved
by administering an equivalent dose of the mTorC1/mTorC2 inhibitor
once daily. In some embodiments, the intermittent regimen is
effective to achieve a Cmax of greater than about 200, 250, 300,
350, 400, 450, 500, 550 or 600 nM. For example, the intermittent
regimen is effective to achieve a Cmax of greater than about 300
nM.
[0016] The intermittent regimens of the invention may achieve
similar or better pathway inhibition than administering an
equivalent dose of the mTorC1/mTorC2 once daily. In some
embodiments, the pathway inhibition is measured as percentage of
decrease in phosphorylation of a protein chosen from p4EBP1, pS6,
and pRAS40.
[0017] The intermittent regimens of the invention may also achieve
similar or better therapeutic efficacy than administering an
equivalent dose of the mTorC1/mTorC2 once daily. Further, the
intermittent regimens of the invention may achieve at least the
same level of tolerability as compared to administering an
equivalent dose of the mTorC1/mTorC2 inhibitor once daily. In some
embodiments, the level of tolerability is measured as the
occurrence or lack of occurrence in the subject of a grade 3 or
higher adverse event. For example, the adverse event is rash.
[0018] In some embodiments, an intermittent regimen of the
invention comprises at least one cycle in which the mTorC1/mTorC2
inhibitor is administered for at least 1 day, followed by an
intermission in which the mTorC1/mTorC2 inhibitor is not
administered for at least 1 day. For instance, the mTorC1/mTorC2
inhibitor is administered for 2, 3, 4, 5, 6 or 7 consecutive days
followed by an intermission in which the mTorC1/mTorC2 inhibitor is
not administered for at least 1 day. Alternatively, the regimen
comprises at least one cycle in which the mTorC1/mTorC2 inhibitor
is administered for 1 day followed by an intermission in which the
mTorC1/mTorC2 inhibitor is not administered for 6 consecutive days.
Alternatively, the regimen comprises at least one cycle in which
the mTorC1/mTorC2 inhibitor is administered for 2, 3, 4, 5, 6 or 7
consecutive days followed by an intermission in which the
mTorC1/mTorC2 inhibitor is not administered for at least 3, 4, or 5
consecutive days. In some embodiments, the regimen comprises at
least one 7-day cycle in which the mTorC1/mTorC2 inhibitor is
administered for 3 consecutive days followed by an intermission of
4 consecutive days. In other embodiments, the regimen comprises at
least one 7-day cycle in which the mTorC1/mTorC2 inhibitor is
administered for 5 consecutive days followed by an intermission of
2 consecutive days. In still other embodiments, the regimen
comprises at least one 7-day cycle in which the mTorC1/mTorC2
inhibitor is administered at least 3 times on alternate days within
the 7 days.
[0019] Also provided herein is a dosage form for administration to
a subject comprising an mTorC1/mTorC2 inhibitor, wherein the dosage
form is formulated to provide a Cmax of greater than about 200 nM
when administered to the subject. In some embodiments, the dosage
form is capable of providing a plasma concentration of said
mTorC1/mTorC2 inhibitor of greater than about 100 nM for a duration
of time longer than about 20 hours during a 7-day period of
administration. For example, the dosage form is capable of
providing a plasma concentration of greater than 100 nM for a
duration of time that is at least about 30 hours during a 7-day
period of administration. In some embodiments, the dosage form
comprises about 45, 50, 55, 60, 70, 75 mg or less of the
mTorC1/mTorC2 inhibitor.
[0020] The invention also provides a method of treating a disorder
in a subject in need thereof, comprising administering a dosage
form of the invention.
[0021] Further provided herein is a kit comprising a dosage form as
described and additionally comprising instructions for
administration to a subject in need thereof. For example, the
instructions provide for at least one 7-day cycle of administration
to the subject for 2, 3, 4, or 5 consecutive days followed by an
intermission of 5, 4, 3, or 2 days, respectively. In some
embodiments, the instructions provide for administration of the
mTorC1/mTorC2 inhibitor to the subject for 3 consecutive days
followed by an intermission of 4 consecutive days.
[0022] The invention further provides a pharmaceutical regimen for
the treatment of a disorder, the regimen comprising an
mTorC1/mTorC2 inhibitor, wherein the regimen provides an area under
the curve that is similar to that obtained by administering the
mTorC1/mTorC2 inhibitor once daily, and wherein the regimen results
in higher therapeutic efficacy as compared to administering said
inhibitor once daily.
[0023] For any method of treatment provided by the invention, the
disorders to be treated include, but are not limited to, a
neoplastic condition, autoimmune disease, inflammatory disease,
fibrotic disease or kidney disease. For example, the disorder is a
neoplastic condition such as cancer.
[0024] Also provided is a method of treating a disorder in a
subject in need thereof, comprising administering an mTorC1/mTorC2
inhibitor to said subject according to an intermittent regimen
effective to achieve (a) higher therapeutic efficacy, (b) similar
or better tolerability of the mTorC1/mTorC2 inhibitor, and (c)
similar or smaller area under the curve, as compared to
administering an equivalent dose of the mTorC1/mTorC2 inhibitor
once daily.
[0025] In any method, dosage form, or pharmaceutical regimen of the
invention, the mTorC1/mTorC2 inhibitor may be administered
parenterally, orally, intraperitoneally, intravenously,
intraarterially, transdermally, intramuscularly, liposomally, via
local delivery by catheter or stent, subcutaneously,
intraadiposally, or intrathecally. In some embodiments, the
mTorC1/mTorC2 inhibitor is administered orally.
[0026] In some embodiments of the invention, the mTorC1/mTorC2
inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of
about 100 nM or less as ascertained in an in vitro kinase assay.
For example, the mTorC1/mTorC2 inhibitor inhibits both mTORC1 and
mTORC2 with an IC50 value of about 10 nM or less as ascertained in
an in vitro kinase assay. In some embodiments, the mTorC1/mTorC2
inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of
about 10 nM or less as ascertained in an in vitro kinase assay, and
that the mTorC1/mTorC2 inhibitor is substantially inactive against
one or more types I PI3-kinases selected from the group consisting
of PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase .gamma., and
PI3-kinase .delta.. In other embodiments, the mTorC1/mTorC2
inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of
about 100 nM or less as ascertained in an in vitro kinase assay,
and said IC50 value is at least 5 times less than its IC50 value
against all other type I PI3-kinases selected from the group
consisting of PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase
.gamma., and PI3-kinase .delta..
[0027] In some embodiments of the invention, the mTorC1/mTorC2
inhibitor is a compound of Formula I:
##STR00001##
or a pharmaceutically acceptable salt thereof, wherein: X.sub.1 is
N or C-E.sup.1, X.sub.2 is N or C, X.sub.3 is N or C, X.sub.4 is
C--R.sup.9 or N, X.sub.5 is N or C-E.sup.1, X.sub.6 is C or N, and
X.sub.7 is C or N; and wherein no more than two nitrogen ring atoms
are adjacent; R.sub.1 is H, -L-C.sub.1-10alkyl,
-L-C.sub.3-8cycloalkyl, -L-C.sub.1-10alkyl, --C.sub.3-8cycloalkyl,
-L-aryl, -L-heteroaryl, -L-C.sub.1-10alkylaryl,
-L-C.sub.1-10alkylhetaryl, -L-C.sub.1-10alkylheterocylyl,
-L-C.sub.2-10alkenyl, -L-C.sub.2-10alkynyl,
-L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3;
L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--; E.sup.1 and E.sup.2
are independently --(W.sup.1).sub.j--R.sup.4; M.sub.1 is a 5, 6, 7,
8, 9, or -10 membered ring system, wherein the ring system is
monocyclic or bicyclic, substituted with R.sub.5 and additionally
optionally substituted with one or more --(W.sup.2).sub.k--R.sup.2;
each k is 0 or 1; j in E.sup.1 or j in E.sup.2, is independently 0
or 1; W.sup.1 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--; W.sup.2 is --O--,
--NR.sup.7--, --S(O).sub.0-2--, --C(O)--, --C(O)N(R.sup.7)--,
--N(R.sup.7)C(O)--, --N(R.sup.7)C(O)N(R.sup.8)--,
--N(R.sup.7)S(O)--, --N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--; R.sup.2 is hydrogen, halogen,
--OH, --R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl (e.g. bicyclic aryl,
unsubstituted aryl, or substituted monocyclic aryl), hetaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl (e.g.
C.sub.2-10alkyl-monocyclic aryl, C.sub.1-10alkyl-substituted
monocyclic aryl, or C.sub.1-10alkylbicycloaryl),
C.sub.1-10alkylhetaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylhetaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylhetaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocylyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl (e.g.
monocyclic aryl-C.sub.2-10alkyl, substituted monocyclic
aryl-C.sub.1-10alkyl, or bicycloaryl-C.sub.1-10alkyl),
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, hetaryl-C.sub.3-8cycloalkyl,
hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said
bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein
each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety
is substituted with one or more independent alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32; R.sup.3 and R.sup.4 are
independently hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl, hetaryl, C.sub.1-4alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl,
C.sub.1-10alkylhetaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylhetaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylhetaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocylyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, hetaryl-C.sub.3-8cycloalkyl,
heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein
each of said aryl or heteroaryl moiety is unsubstituted or is
substituted with one or more independent halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
R.sup.5 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32; each of R.sup.31, R.sup.32, and
R.sup.33 is independently H or C.sub.1-10alkyl, wherein the
C.sub.1-10alkyl is unsubstituted or is substituted with one or more
aryl, heteroalkyl, heterocyclyl, or hetaryl group, wherein each of
said aryl, heteroalkyl, heterocyclyl, or hetaryl group is
unsubstituted or is substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(--NO.sub.2, --CN, --S(O).sub.0-2C.sub.1-10alkyl,
--S(O).sub.0-2C.sub.1-10alkylaryl, --S(O).sub.0-2aryl,
--SO.sub.2N(aryl), --SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35;
R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, hetaryl,
C.sub.1-6 alkyl, or O-aryl, and wherein said 3-10 membered
saturated or unsaturated ring independently contains 0, 1, or 2
more heteroatoms in addition to the nitrogen atom; each of R.sup.7
and R.sup.8 is independently hydrogen, C.sub.1-10alkyl,
C.sub.2-10alkenyl, aryl, heteroaryl, heterocyclyl or
C.sub.3-10cycloalkyl, each of which except for hydrogen is
unsubstituted or is substituted by one or more independent R.sup.6;
R.sup.6 is halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.1-10alkyl,
hetaryl-C.sub.2-10alkenyl, hetaryl-C.sub.2-10alkynyl, wherein each
of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,
or hetaryl group is unsubstituted or is substituted with one or
more independent halo, cyano, nitro, --OC.sub.1-10alkyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2 NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35; and R.sup.9 is H,
halo, --OR.sup.31, --SH, --NH.sub.2, --NR.sup.34R.sup.35,
--NR.sup.31R.sup.32, --CO.sub.2R.sup.31, --CO.sub.2aryl,
--C(.dbd.O)NR.sup.31R.sup.32, C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2C.sub.1-10alkyl,
--S(O).sub.0-2aryl, --SO.sub.2NR.sup.34R.sup.35,
--SO.sub.2NR.sup.31R.sup.32, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl; aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.1-10alkyl,
hetaryl-C.sub.2-10alkenyl, hetaryl-C.sub.2-10alkynyl, wherein each
of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,
or hetaryl group is unsubstituted or is substituted with one or
more independent halo, cyano, nitro, --OC.sub.1-10alkyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2 NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35.
[0028] In some embodiments, the mTorC1/mTorC2 inhibitor has the
Formula:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein: E.sup.2 is
--H; X.sub.1 is N; X.sub.2 is N; W.sup.2 is --NH; and k is 1.
[0029] In some embodiments, R.sub.2 is H. In other embodiments,
R.sub.1 is isopropyl. In other embodiments, R.sub.1 is
##STR00003##
In yet other embodiments, R.sub.1 is
##STR00004##
In still other embodiments, R.sub.1 is
##STR00005##
[0030] In some embodiments of the compound of Formula I, E.sup.2 is
--H; X.sub.1 is CH; X.sub.2 is N; W.sup.2 is --NH; R.sub.2 is H; k
is 1; and R.sub.1 is isopropyl or
##STR00006##
INCORPORATION BY REFERENCE
[0031] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0033] FIG. 1 shows the Cmax observed upon administration of
compound A at various dose levels.
[0034] FIG. 2 shows the area under the curve (AUC) upon
administration of compound A at various dose levels.
[0035] FIG. 3 shows plasma concentration-time profiles for compound
A administered at various dose levels.
[0036] FIG. 4 shows modeled pharmacokinetic properties of compound
A.
[0037] FIG. 5 shows mTor C pathway inhibition in peripheral blood
mono-nucleocytes by an intermittent dosing regimen using compound
A.
[0038] FIG. 6 shows mTor C pathway inhibition (p4EBP1) in skin
biopsies by an intermittent dosing regimen using compound A.
[0039] FIG. 7 shows mTor C pathway inhibition (pS6) in skin
biopsies by an intermittent dosing regimen using compound A.
[0040] FIG. 8 shows mTor C pathway inhibition (pPRAS40) in skin
biopsies by an intermittent dosing regimen using compound A.
DETAILED DESCRIPTION OF THE INVENTION
[0041] Several aspects of the invention are described below with
reference to example applications for illustration. It should be
understood that numerous specific details, relationships, and
methods are set forth to provide a full understanding of the
invention. One having ordinary skill in the relevant art, however,
will readily recognize that the invention can be practiced without
one or more of the specific details or with other methods. Unless
stated otherwise, the present invention is not limited by the
illustrated ordering of acts or events, as some acts may occur in
different orders and/or concurrently with other acts or events.
Furthermore, not all illustrated acts or events are required to
implement a methodology in accordance with the present
invention.
[0042] The terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
the invention. As used herein, the singular forms "a", "an" and
"the" are intended to include the plural forms as well, unless the
context clearly indicates otherwise. Furthermore, to the extent
that the terms "including", "includes", "having", "has", "with", or
variants thereof are used in either the detailed description and/or
the claims, such terms are intended to be inclusive in a manner
similar to the term "comprising".
[0043] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 1 or more
than 1 standard deviation, per the practice in the art.
Alternatively, "about" can mean a range of up to 20%, up to 10%, up
to 5%, or up to 1% of a given value. Alternatively, particularly
with respect to biological systems or processes, the term can mean
within an order of magnitude, preferably within 5-fold, and more
preferably within 2-fold, of a value. Where particular values are
described in the application and claims, unless otherwise stated
the term "about" meaning within an acceptable error range for the
particular value should be assumed.
[0044] "Treatment", "treating", "palliating" and "ameliorating", as
used herein, are used interchangeably. These terms refer to an
approach for obtaining beneficial or desired results including but
not limited to therapeutic benefit and/or a prophylactic benefit.
By therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a patient at risk of developing a particular
disease, or to a patient reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made.
[0045] As used herein, the term "neoplastic condition" refers to
the presence of cells possessing abnormal growth characteristics,
such as uncontrolled proliferation, immortality, metastatic
potential, rapid growth and proliferation rate, perturbed oncogenic
signaling, and certain characteristic morphological features. This
includes but is not limited to the growth of: (1) benign or
malignant cells (e.g., tumor cells) that correlates with
overexpression of a tyrosine or serine/threonine kinase; (2) benign
or malignant cells (e.g., tumor cells) that correlates with
abnormally high level of tyrosine or serine/threonine kinase
activity. Exemplary tyrosine kinases implicated in a neoplastic
condition include but are not limited to receptor tyrosine kinases
such as epidermal growth factor receptors (EGF receptor), platelet
derived growth factor (PDGF) receptors, and cyotsolic tyrosine
kinases such as src and abl kinase. Non-limiting serine/threonine
kinases implicated in neoplastic condition include but are not
limited to raf and mek.
[0046] The term "effective amount" or "therapeutically effective
amount" refers to that amount of an inhibitor described herein that
is sufficient to effect the intended application including but not
limited to disease treatment, as defined below. The therapeutically
effective amount may vary depending upon the intended application
(in vitro or in vivo), or the subject and disease condition being
treated, e.g., the weight and age of the subject, the severity of
the disease condition, the manner of administration and the like,
which can readily be determined by one of ordinary skill in the
art. The term also applies to a dose that will induce a particular
response in target cells, e.g., reduction of proliferation or
downregulation of activity of a target protein. The specific dose
will vary depending on the particular compounds chosen, the dosing
regimen to be followed, whether it is administered in combination
with other compounds, timing of administration, the tissue to which
it is administered, and the physical delivery system in which it is
carried.
[0047] A "sub-therapeutic amount" of an agent or therapy is an
amount less than the effective amount for that agent or therapy,
but when combined with an effective or sub-therapeutic amount of
another agent or therapy can produce a result desired by the
physician, due to, for example, synergy in the resulting
efficacious effects, or reduced side effects.
[0048] A "synergistically effective" therapeutic amount or
"synergistically effective" amount of an agent or therapy is an
amount which, when combined with an effective or sub-therapeutic
amount of another agent or therapy, produces a greater effect than
when either of the two agents are used alone. In some embodiments,
a syngergistically effective therapeutic amount of an agent or
therapy produces a greater effect when used in combination than the
additive effects of each of the two agents or therapies when used
alone. The term "greater effect" encompasses not only a reduction
in symptoms of the disorder to be treated, but also an improved
side effect profile, improved tolerability, improved patient
compliance, improved efficacy, or any other improved clinical
outcome.
[0049] As used herein, "agent" or "biologically active agent"
refers to a biological, pharmaceutical, or chemical compound or
other moiety. Non-limiting examples include simple or complex
organic or inorganic molecule, a peptide, a protein, an
oligonucleotide, an antibody, an antibody derivative, antibody
fragment, a vitamin derivative, a carbohydrate, a toxin, or a
chemotherapeutic compound. Various compounds can be synthesized,
for example, small molecules and oligomers (e.g., oligopeptides and
oligonucleotides), and synthetic organic compounds based on various
core structures. In addition, various natural sources can provide
compounds for screening, such as plant or animal extracts, and the
like. A skilled artisan can readily recognize that there is no
limit as to the structural nature of the agents of the present
invention.
[0050] The term "agonist" as used herein refers to a compound
having the ability to initiate or enhance a biological function of
a target protein, whether by inhibiting the activity or expression
of the target protein. Accordingly, the term "agonist" is defined
in the context of the biological role of the target polypeptide.
While preferred agonists herein specifically interact with (e.g.,
bind to) the target, compounds that initiate or enhance a
biological activity of the target polypeptide by interacting with
other members of the signal transduction pathway of which the
target polypeptide is a member are also specifically included
within this definition.
[0051] The terms "antagonist" and "inhibitor" are used
interchangeably, and they refer to a compound having the ability to
inhibit a biological function of a target protein, whether by
inhibiting the activity or expression of the target protein.
Accordingly, the terms "antagonist" and "inhibitors" are defined in
the context of the biological role of the target protein. While
preferred antagonists herein specifically interact with (e.g., bind
to) the target, compounds that inhibit a biological activity of the
target protein by interacting with other members of the signal
transduction pathway of which the target protein is a member are
also specifically included within this definition. A preferred
biological activity inhibited by an antagonist is associated with
the development, growth, or spread of a tumor, or an undesired
immune response as manifested in autoimmune disease.
[0052] The phrases "mTorC1/C2 inhibitor", "mTorC1/mTorC2
inhibitor", or "mTOR inhibitor that binds to and directly inhibits
both mTORC1 and mTORC2 kinases" are used interchangeably and refer
to an mTOR inhibitor that interacts with and reduces the kinase
activity of both mTORC1 and mTORC2 complexes.
[0053] An "anti-neoplastic", "anti-cancer agent", "anti-tumor
agent" or "chemotherapeutic agent" refers to any agent useful in
the treatment of a neoplastic condition. One class of anti-cancer
agents comprises chemotherapeutic agents. "Chemotherapy" means the
administration of one or more chemotherapeutic drugs and/or other
agents to a cancer patient by various methods, including
intravenous, oral, intramuscular, intraperitoneal, intravesical,
subcutaneous, transdermal, buccal, or inhalation or in the form of
a suppository.
[0054] As used herein, the term "antiangiogenic" refers to the
ability to inhibit or impair the formation of blood vessels,
including but not limited to inhibiting endothelial cell
proliferation, endothelial cell migration, and capillary tube
formation.
[0055] The term "cell proliferation" refers to a phenomenon by
which the cell number has changed as a result of division. This
term also encompasses cell growth by which the cell morphology has
changed (e.g., increased in size) consistent with a proliferative
signal.
[0056] The terms "co-administration," "administered in combination
with," and their grammatical equivalents, encompass administration
of two or more agents to an animal so that both agents and/or their
metabolites are present in the animal at the same time.
Co-administration includes simultaneous administration in separate
compositions, administration at different times in separate
compositions, or administration in a composition in which both
agents are present. Co-administered agents may be in the same
formulation. Co-administered agents may also be in different
formulations.
[0057] A "therapeutic effect," as used herein, encompasses a
therapeutic benefit and/or a prophylactic benefit as described
above. A prophylactic effect includes delaying or eliminating the
appearance of a disease or condition, delaying or eliminating the
onset of symptoms of a disease or condition, slowing, halting, or
reversing the progression of a disease or condition, or any
combination thereof.
[0058] The term "pharmaceutically acceptable salt" refers to salts
derived from a variety of organic and inorganic counter ions well
known in the art. Pharmaceutically acceptable acid addition salts
can be formed with inorganic acids and organic acids. Inorganic
acids from which salts can be derived include, for example,
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like. Organic acids from which salts can
be derived include, for example, acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic
acid, succinic acid, fumaric acid, tartaric acid, citric acid,
benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and
the like. Pharmaceutically acceptable base addition salts can be
formed with inorganic and organic bases. Inorganic bases from which
salts can be derived include, for example, sodium, potassium,
lithium, ammonium, calcium, magnesium, iron, zinc, copper,
manganese, aluminum, and the like. Organic bases from which salts
can be derived include, for example, primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines, basic ion exchange resins, and
the like, specifically such as isopropylamine, trimethylamine,
diethylamine, triethylamine, tripropylamine, and ethanolamine. In
some embodiments, the pharmaceutically acceptable base addition
salt is chosen from ammonium, potassium, sodium, calcium, and
magnesium salts.
[0059] "Pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" includes any and all solvents, dispersion
media, coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents and the like. The use of such media and
agents for pharmaceutically active substances is well known in the
art. Except insofar as any conventional media or agent is
incompatible with the active ingredient, its use in the therapeutic
compositions of the invention is contemplated. Supplementary active
ingredients can also be incorporated into the compositions.
[0060] "Signal transduction" is a process during which stimulatory
or inhibitory signals are transmitted into and within a cell to
elicit an intracellular response. A modulator of a signal
transduction pathway refers to a compound that modulates the
activity of one or more cellular proteins mapped to the same
specific signal transduction pathway. A modulator may augment
(agonist) or suppress (antagonist) the activity of a signaling
molecule.
[0061] The term "selective inhibition" or "selectively inhibit" as
applied to a biologically active agent refers to the agent's
ability to selectively reduce the target signaling activity as
compared to off-target signaling activity, via direct or interact
interaction with the target.
[0062] "Subject" refers to an animal, such as a mammal, for example
a human. The methods described herein can be useful in both human
therapeutics, pre-clinical, and veterinary applications. In some
embodiments, the subject is a mammal, and in some embodiments, the
subject is human.
[0063] The term "in vivo" refers to an event that takes place in a
subject's body.
[0064] The term "in vitro" refers to an event that takes places
outside of a subject's body. For example, an in vitro assay
encompasses any assay run outside of a subject assay. In vitro
assays encompass cell-based assays in which cells alive or dead are
employed. In vitro assays also encompass a cell-free assay in which
no intact cells are employed.
[0065] Unless otherwise stated, the connections of compound name
moieties are at the rightmost recited moiety. That is, the
substituent name starts with a terminal moiety, continues with any
linking moieties, and ends with the linking moiety. For example,
heteroarylthio C.sub.1-4 alkyl has a heteroaryl group connected
through a thio sulfur to a C.sub.1-4 alkyl radical that connects to
the chemical species bearing the substituent. This condition does
not apply where a formula such as, for example "-L-C.sub.1-10
alkyl-C.sub.3-8cycloalkyl" is represented. In such case, the
terminal group is a C.sub.3-8cycloalkyl group attached to a linking
C.sub.1-10 alkyl moiety which is attached to an element L, which is
itself connected to the chemical species bearing the
substituent.
[0066] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to ten carbon atoms (e.g.,
C.sub.1-C.sub.10 alkyl). Whenever it appears herein, a numerical
range such as "1 to 10" refers to each integer in the given range;
e.g., "1 to 10 carbon atoms" means that the alkyl group may consist
of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 10 carbon atoms, although the present definition also
covers the occurrence of the term "alkyl" where no numerical range
is designated. In some embodiments, it is a C.sub.1-C.sub.4 alkyl
group. Typical alkyl groups include, but are in no way limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl
isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl,
septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to
the rest of the molecule by a single bond, for example, methyl
(Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl,
n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,
2-methylhexyl, and the like. Unless stated otherwise specifically
in the specification, an alkyl group is optionally substituted by
one or more of substituents which independently are: alkyl,
heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2 where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0067] The term "halo" or "halogen" refers to fluoro, chloro,
bromo, or iodo.
[0068] The term "haloalkyl" refers to an alkyl group substituted
with one or more halo groups, for example chloromethyl,
2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl,
8-chlorononyl, and the like.
[0069] "Acyl" refers to the groups (alkyl)-C(O)--, (aryl)-C(O)--,
(heteroaryl)-C(O)--, (heteroalkyl)-C(O)--, and
(heterocycloalkyl)-C(O)--, wherein the group is attached to the
parent structure through the carbonyl functionality. In some
embodiments, it is a C.sub.1-C.sub.10 acyl radical which refers to
the total number of chain or ring atoms of the alkyl, aryl,
heteroaryl or heterocycloalkyl portion of the acyloxy group plus
the carbonyl carbon of acyl, i.e three other ring or chain atoms
plus carbonyl. If the R radical is heteroaryl or heterocycloalkyl,
the hetero ring or chain atoms contribute to the total number of
chain or ring atoms. Unless stated otherwise specifically in the
specification, the "R" of an acyloxy group is optionally
substituted by one or more substituents which independently are:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,
--OR.sup.a, SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0070] "Cycloalkyl" refers to a monocyclic or polycyclic radical
that contains only carbon and hydrogen, and may be saturated, or
partially unsaturated. Cycloalkyl groups include groups having from
3 to 10 ring atoms (i.e., C.sub.2-C.sub.10 cycloalkyl). Whenever it
appears herein, a numerical range such as "3 to 10" refers to each
integer in the given range; e.g., "3 to 10 carbon atoms" means that
the cycloalkyl group may consist of 3 carbon atoms, etc., up to and
including 10 carbon atoms. In some embodiments, it is a
C.sub.3-C.sub.8 cycloalkyl radical. In some embodiments, it is a
C.sub.3-C.sub.5 cycloalkyl radical. Illustrative examples of
cycloalkyl groups include, but are not limited to the following
moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl,
cyclodecyl, norbornyl, and the like. Unless stated otherwise
specifically in the specification, a cycloalkyl group is optionally
substituted by one or more substituents which independently are:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0071] The term "C.sub.1-10alkyl-C.sub.3-8cycloalkyl" is used to
describe an alkyl group, branched or straight chain and containing
1 to 10 carbon atoms, attached to a linking cycloalkyl group which
contains 3 to 8 carbons, such as for example, 2-methyl cyclopropyl,
and the like. Either portion of the moiety is unsubstituted or
substituted.
[0072] The term "bicycloalkyl" refers to a structure consisting of
two cycloalkyl moieties, unsubstituted or substituted, that have
two or more atoms in common If the cycloalkyl moieties have exactly
two atoms in common they are said to be "fused". Examples include,
but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and
the like. If the cycloalkyl moieties have more than two atoms in
common they are said to be "bridged". Examples include, but are not
limited to, bicyclo[3.2.1]heptyl ("norbornyl"),
bicyclo[2.2.2]octyl, and the like.
[0073] As used herein, the term "heteroatom" or "ring heteroatom"
is meant to include oxygen (O), nitrogen (N), sulfur (S),
phosphorus (P), and silicon (Si).
[0074] "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include
optionally substituted alkyl, alkenyl and alkynyl radicals and
which have one or more skeletal chain atoms selected from an atom
other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or
combinations thereof A numerical range may be given, e.g.,
C.sub.1-C.sub.4 heteroalkyl which refers to the chain length in
total, which in this example is 4 atoms long. For example, a
--CH.sub.2OCH.sub.2CH.sub.3 radical is referred to as a "C.sub.4"
heteroalkyl, which includes the heteroatom center in the atom chain
length description. Connection to the rest of the molecule may be
through either a heteroatom or a carbon in the heteroalkyl chain. A
heteroalkyl group may be substituted with one or more substituents
which independently are: alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0075] The term "heteroalkylaryl" refers to a heteroalkyl group as
defined above which is attached to an aryl group, and may be
attached at a terminal point or through a branched portion of the
heteroalkyl, for example, an benzyloxymethyl moiety. Either portion
of the moiety is unsubstituted or substituted.
[0076] The term "heteroalkylheteroaryl" refers likewise to a
heteroalkyl group which is attached to a heteroaryl moiety, for
example, an ethoxymethylpyridyl group. Either portion of the moiety
is unsubstituted or substituted.
[0077] The term "heteroalkyl-heterocyclyl" refers to a heteroalkyl
group as defined above, which is attached to a heterocyclic group,
for example, 4(3-aminopropyl)-N-piperazinyl. Either portion of the
moiety is unsubstituted or substituted.
[0078] The term "heteroalkyl-C.sub.3-8cycloalkyl" refers to a
heteroalkyl group as defined above, which is attached to a cyclic
alkyl containing 3 to 8 carbons, for example,
1-aminobutyl-4-cyclohexyl. Either portion of the moiety is
unsubstituted or substituted.
[0079] The term "heterobicycloalkyl" refers to a bicycloalkyl
structure, which is unsubstituted or substituted, in which at least
one carbon atom is replaced with a heteroatom independently
selected from oxygen, nitrogen, and sulfur.
[0080] The term "heterospiroalkyl" refers to a spiroalkyl
structure, which is unsubstituted or substituted, in which at least
one carbon atom is replaced with a heteroatom independently
selected from oxygen, nitrogen, and sulfur.
[0081] An "alkene" moiety refers to a group consisting of at least
two carbon atoms and at least one carbon-carbon double bond, and an
"alkyne" moiety refers to a group consisting of at least two carbon
atoms and at least one carbon-carbon triple bond. The alkyl moiety,
whether saturated or unsaturated, may be branched, straight chain,
or cyclic.
[0082] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one double bond, and having from two to ten
carbon atoms (i.e., C.sub.2-C.sub.10 alkenyl). Whenever it appears
herein, a numerical range such as "2 to 10" refers to each integer
in the given range; e.g., "2 to 10 carbon atoms" means that the
alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc.,
up to and including 10 carbon atoms. In certain embodiments, an
alkenyl comprises two to eight carbon atoms. In other embodiments,
an alkenyl comprises two to five carbon atoms (e.g.,
C.sub.2-C.sub.5 alkenyl). The alkenyl is attached to the rest of
the molecule by a single bond, for example, ethenyl (i.e., vinyl),
prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl,
penta-1,4-dienyl, and the like. Unless stated otherwise
specifically in the specification, an alkenyl group is optionally
substituted by one or more substituents which independently are:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a,
N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0083] The term "C.sub.2-10 alkenyl-heteroalkyl" refers to a group
having an alkenyl moiety, containing 2 to 10 carbon atoms and is
branched or straight chain, which is attached to a linking
heteroalkyl group, such as, for example, allyloxy, and the like.
Either portion of the moiety is unsubstituted or substituted.
[0084] The term "C.sub.2-10 alkynyl-heteroalkyl" refers to a group
having an alkynyl moiety, which is unsubstituted or substituted,
containing 2 to 10 carbon atoms and is branched or straight chain,
which is attached to a linking heteroalkyl group, such as, for
example, 4-but-1-ynoxy, and the like. Either portion of the moiety
is unsubstituted or substituted.
[0085] The term "haloalkenyl" refers to an alkenyl group
substituted with one or more halo groups.
[0086] Unless otherwise specified, the term "cycloalkenyl" refers
to a cyclic aliphatic 3 to 8 membered ring structure, optionally
substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic
bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl,
cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl, and the like.
[0087] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one triple bond, having from two to ten carbon
atoms (i.e., C.sub.2-C.sub.10 alkynyl). Whenever it appears herein,
a numerical range such as "2 to 10" refers to each integer in the
given range; e.g., "2 to 10 carbon atoms" means that the alkynyl
group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to
and including 10 carbon atoms. In certain embodiments, an alkynyl
comprises two to eight carbon atoms. In other embodiments, an
alkynyl has two to five carbon atoms (e.g., C.sub.2-C.sub.5
alkynyl). The alkynyl is attached to the rest of the molecule by a
single bond, for example, ethynyl, propynyl, butynyl, pentynyl,
hexynyl, and the like. Unless stated otherwise specifically in the
specification, an alkynyl group is optionally substituted by one or
more substituents which independently are: alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0088] The term C.sub.2-10 alkynyl-C.sub.3-8 cycloalkyl refers to a
group containing an alkynyl group, containing 2 to 10 carbons and
branched or straight chain, which is attached to a linking
cycloalkyl group containing 3 to 8 carbons, such as, for example
3-prop-3-ynyl-cyclopent-lyl, and the like. Either portion of the
moiety is unsubstituted or substituted.
[0089] The term "haloalkynyl" refers to an alkynyl group
substituted with one or more independent halo groups.
[0090] "Amino" or "amine" refers to a --N(R.sup.a).sub.2 radical
group, where each R.sup.a is independently hydrogen, alkyl,
fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,
heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl, unless stated otherwise specifically in the
specification. When a --N(R.sup.a).sub.2 group has two R.sup.a
other than hydrogen they can be combined with the nitrogen atom to
form a 4-, 5-, 6-, or 7-membered ring. For example,
--N(R.sup.a).sub.2 is meant to include, but not be limited to,
1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise
specifically in the specification, an amino group is optionally
substituted by one or more substituents which independently are:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl and each of these moieties may be optionally
substituted as defined herein.
[0091] "Amide" or "amido" refers to a chemical moiety with formula
--C(O)N(R).sub.2 or --NHC(O)R, where R is selected from the group
consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded
through a ring carbon) and heteroalicyclic (bonded through a ring
carbon), each of which moiety may itself be optionally substituted.
In some embodiments it is a C.sub.1-C.sub.4 amido or amide radical,
which includes the amide carbonyl in the total number of carbons in
the radical. The R.sup.2' of --N(R).sub.2 of the amide may
optionally be taken together with the nitrogen to which it is
attached to form a 4-, 5-, 6-, or 7-membered ring. Unless stated
otherwise specifically in the specification, an amido group is
optionally substituted independently by one or more of the
substituents as described herein for alkyl, cycloalkyl, aryl,
heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a
peptide molecule attached to a compound of Formula (I), thereby
forming a prodrug. Any amine, hydroxy, or carboxyl side chain on
the compounds described herein can be amidified. The procedures and
specific groups to make such amides are known to those of skill in
the art and can readily be found in reference sources such as
Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd
Ed., John Wiley & Sons, New York, N.Y., 1999, which is
incorporated herein by reference in its entirety.
[0092] "Aromatic" or "aryl" refers to an aromatic radical with six
to ten ring atoms (e.g., C.sub.6-C.sub.10 aromatic or
C.sub.6-C.sub.10 aryl) which has at least one ring having a
conjugated pi electron system which is carbocyclic (e.g., phenyl,
fluorenyl, and naphthyl). Bivalent radicals formed from substituted
benzene derivatives and having the free valences at ring atoms are
named as substituted phenylene radicals. Bivalent radicals derived
from univalent polycyclic hydrocarbon radicals whose names end in
"-yl" by removal of one hydrogen atom from the carbon atom with the
free valence are named by adding "-idene" to the name of the
corresponding univalent radical, e.g., a naphthyl group with two
points of attachment is termed naphthylidene. Whenever it appears
herein, a numerical range such as "6 to 10" refers to each integer
in the given range; e.g., "6 to 10 ring atoms" means that the aryl
group may consist of 6 ring atoms, 7 ring atoms, etc., up to and
including 10 ring atoms. The term includes monocyclic or fused-ring
polycyclic (i.e., rings which share adjacent pairs of ring atoms)
groups. Unless stated otherwise specifically in the specification,
an aryl moiety is optionally substituted by one or more
substituents which are independently: alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --OC(O)N(R.sup.a).sub.2, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)C(O)N(R.sup.a).sub.2,
N(R.sup.a)C(NR.sup.a)N(R.sup.a).sub.2,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0093] "Heteroaryl" or, alternatively, "heteroaromatic" refers to a
5- to 18-membered aromatic radical (e.g., C.sub.5-C.sub.13
heteroaryl) that includes one or more ring heteroatoms selected
from nitrogen, oxygen and sulfur, and which may be a monocyclic,
bicyclic, tricyclic or tetracyclic ring system. Whenever it appears
herein, a numerical range such as "5 to 18" refers to each integer
in the given range; e.g., "5 to 18 ring atoms" means that the
heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc.,
up to and including 18 ring atoms. Bivalent radicals derived from
univalent heteroaryl radicals whose names end in "-yl" by removal
of one hydrogen atom from the atom with the free valence are named
by adding "-idene" to the name of the corresponding univalent
radical, e.g., a pyridyl group with two points of attachment is a
pyridylidene. An N-containing "heteroaromatic" or "heteroaryl"
moiety refers to an aromatic group in which at least one of the
skeletal atoms of the ring is a nitrogen atom. The polycyclic
heteroaryl group may be fused or non-fused. The heteroatom(s) in
the heteroaryl radical is optionally oxidized. One or more nitrogen
atoms, if present, are optionally quaternized. The heteroaryl is
attached to the rest of the molecule through any atom of the
ring(s). Examples of heteroaryls include, but are not limited to,
azepinyl, acridinyl, benzimidazolyl, benzindolyl,
1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl,
benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl,
benzothiazolyl, benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl,
imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,
thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated
otherwise specifically in the specification, a heteraryl moiety is
optionally substituted by one or more substituents which are
independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or
heteroarylalkyl.
[0094] The terms "aryl-alkyl", "arylalkyl" and "aralkyl" are used
to describe a group wherein the alkyl chain can be branched or
straight chain forming a linking portion with the terminal aryl, as
defined above, of the aryl-alkyl moiety. Examples of aryl-alkyl
groups include, but are not limited to, optionally substituted
benzyl, phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl,
2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl,
2-(4-methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl,
2-(2-methoxyphenyl)ethyl, 2-(3-nitrophenyl)ethyl,
2-(2,4-dichlorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl,
3-phenylpropyl, 3-(3-chlorophenyl)propyl, 3-(2-methylphenyl)propyl,
3-(4-methoxyphenyl)propyl, 3-(4-(trifluoromethyl)phenyl)propyl,
3-(2,4-dichlorophenyl)propyl, 4-phenylbutyl,
4-(4-chlorophenyl)butyl, 4-(2-methylphenyl)butyl,
4-(2,4-dichlorophenyl)butyl, 4-(2-methoxphenyl)butyl, and
10-phenyldecyl. Either portion of the moiety is unsubstituted or
substituted.
[0095] The term "C.sub.1-10alkylaryl" as used herein refers to an
alkyl group, as defined above, containing 1 to 10 carbon atoms,
branched or unbranched, wherein the aryl group replaces one
hydrogen on the alkyl group, for example, 3-phenylpropyl. Either
portion of the moiety is unsubstituted or substituted.
[0096] The term C.sub.2-10 alkyl monocycloaryl" refers to a group
containing a terminal alkyl group, branched or straight chain and
containing 2 to 10 atoms attached to a linking aryl group which has
only one ring, such as for example, 2-phenyl ethyl. Either portion
of the moiety is unsubstituted or substituted.
[0097] The term "C.sub.1-10 alkyl bicycloaryl" refers to a group
containing a terminal alkyl group, branched or straight chain and
containing 2 to 10 atoms attached to a linking aryl group which is
bicyclic, such as for example, 2-(1-naphthyl)-ethyl. Either portion
of the moiety is unsubstituted or substituted.
[0098] The terms "aryl-cycloalkyl" and "arylcycloalkyl" are used to
describe a group wherein the terminal aryl group is attached to a
cycloalkyl group, for example phenylcyclopentyl and the like.
Either portion of the moiety is unsubstituted or substituted.
[0099] The terms "heteroaryl-C.sub.3-8cycloalkyl" and
"heteroaryl-C.sub.3-8cycloalkyl" are used to describe a group
wherein the terminal heteroaryl group is attached to a cycloalkyl
group, which contains 3 to 8 carbons, for example
pyrid-2-yl-cyclopentyl and the like. Either portion of the moiety
is unsubstituted or substituted.
[0100] The term "heteroaryl-heteroalkyl" refers to a group wherein
the terminal heteroaryl group is attached to a linking heteroalkyl
group, such as for example, pyrid-2-yl methylenoxy, and the like.
Either portion of the moiety is unsubstituted or substituted.
[0101] The terms "aryl-alkenyl", "arylalkenyl" and "aralkenyl" are
used to describe a group wherein the alkenyl chain can be branched
or straight chain forming a linking portion of the aralkenyl moiety
with the terminal aryl portion, as defined above, for example
styryl (2-phenylvinyl), phenpropenyl, and the like. Either portion
of the moiety is unsubstituted or substituted.
[0102] The term "aryl-C.sub.2-10alkenyl" means an arylalkenyl as
described above wherein the alkenyl moiety contains 2 to 10 carbon
atoms such as for example, styryl (2-phenylvinyl), and the like.
Either portion of the moiety is unsubstituted or substituted.
[0103] The term "C.sub.2-10alkenyl-aryl" is used to describe a
group wherein the terminal alkenyl group, which contains 2 to 10
carbon atoms and can be branched or straight chain, is attached to
the aryl moiety which forms the linking portion of the alkenyl-aryl
moiety, such as for example, 3-propenyl-naphth-1-yl, and the like.
Either portion of the moiety is unsubstituted or substituted.
[0104] The terms "aryl-alkynyl", "arylalkynyl" and "aralkynyl" are
used to describe a group wherein the alkynyl chain can be branched
or straight chain forming a linking portion of the aryl-alkynyl
moiety with the terminal aryl portion, as defined above, for
example 3-phenyl-1-propynyl, and the like. Either portion of the
moiety is unsubstituted or substituted.
[0105] The term "aryl-C.sub.2-10alkynyl" means an arylalkynyl as
described above wherein the alkynyl moiety contains two to ten
carbons, such as, for example 3-phenyl-1-propynyl, and the like.
Either portion of the moiety is unsubstituted or substituted.
[0106] The term "C.sub.2-10alkynyl-aryl" means a group containing
an alkynyl moiety attached to an aryl linking group, both as
defined above, wherein the alkynyl moiety contains two to ten
carbons, such as, for example 3-propynyl-naphth-1-yl. Either
portion of the moiety is unsubstituted or substituted.
[0107] The terms "aryl-oxy", "aryloxy" and "aroxy" are used to
describe a terminal aryl group attached to a linking oxygen atom.
Typical aryl-oxy groups include phenoxy, 3,4-dichlorophenoxy, and
the like. Either portion of the moiety is unsubstituted or
substituted.
[0108] The terms "aryl-oxyalkyl", "aryloxyalkyl" and "aroxyalkyl"
are used to describe a group wherein an alkyl group is substituted
with a terminal aryl-oxy group, for example
pentafluorophenoxymethyl and the like. Either portion of the moiety
is unsubstituted or substituted.
[0109] The term "C.sub.1-10alkoxy-C.sub.1-10alkyl" refers to a
group wherein an alkoxy group, containing 1 to 10 carbon atoms and
an oxygen atom within the branching or straight chain, is attached
to a linking alkyl group, branched or straight chain which contains
1 to 10 carbon atoms, such as, for example methoxypropyl, and the
like. Either portion of the moiety is unsubstituted or
substituted.
[0110] The term "C.sub.1-10alkoxy-C.sub.2-10alkenyl" refers to a
group wherein an alkoxy group, containing 1 to 10 carbon atoms and
an oxygen atom within the branching or straight chain, is attached
to a linking alkenyl group, branched or straight chain which
contains 1 to 10 carbon atoms, such as, for example
3-methoxybut-2-en-1-yl, and the like. Either portion of the moiety
is unsubstituted or substituted.
[0111] The term "C.sub.1-10alkoxy-C.sub.2-10alkynyl" refers to a
group wherein an alkoxy group, containing 1 to 10 carbon atoms and
an oxygen atom within the branching or straight chain, is attached
to a linking alkynyl group, branched or straight chain which
contains 1 to 10 carbon atoms, such as, for example
3-methoxybut-2-in-1-yl, and the like. Either portion of the moiety
is unsubstituted or substituted.
[0112] The term "heterocycloalkenyl" refers to a cycloalkenyl
structure, which is unsubstituted or substituted in which at least
one carbon atom is replaced with a heteroatom selected from oxygen,
nitrogen, and sulfur.
[0113] The terms "heteroaryl-oxy", "heteroaryl-oxy",
"heteroaryloxy", "heteroaryloxy", "hetaroxy" and "heteroaroxy" are
used to describe a terminal heteroaryl group, which is
unsubstituted or substituted, attached to a linking oxygen atom.
Typical heteroaryl-oxy groups include
4,6-dimethoxypyrimidin-2-yloxy and the like.
[0114] The terms "heteroarylalkyl", "heteroarylalkyl",
"heteroaryl-alkyl", "heteroaryl-alkyl", "hetaralkyl" and
"heteroaralkyl" are used to describe a group wherein the alkyl
chain can be branched or straight chain forming a linking portion
of the heteroaralkyl moiety with the terminal heteroaryl portion,
as defined above, for example 3-furylmethyl, thenyl, furfuryl, and
the like. Either portion of the moiety is unsubstituted or
substituted.
[0115] The term "heteroaryl-C.sub.1-10alkyl" is used to describe a
heteroaryl alkyl group as described above where the alkyl group
contains 1 to 10 carbon atoms. Either portion of the moiety is
unsubstituted or substituted.
[0116] The term "C.sub.1-10alkyl-heteroaryl" is used to describe a
alkyl attached to a hetary group as described above where the alkyl
group contains 1 to 10 carbon atoms. Either portion of the moiety
is unsubstituted or substituted.
[0117] The terms "heteroarylalkenyl", "heteroarylalkenyl",
"heteroaryl-alkenyl", "heteroaryl-alkenyl", "hetaralkenyl" and
"heteroaralkenyl" are used to describe a heteroarylalkenyl group
wherein the alkenyl chain can be branched or straight chain forming
a linking portion of the heteroaralkenyl moiety with the terminal
heteroaryl portion, as defined above, for example
3-(4-pyridyl)-1-propenyl. Either portion of the moiety is
unsubstituted or substituted.
[0118] The term "heteroaryl-C.sub.2-10alkenyl" group is used to
describe a group as described above wherein the alkenyl group
contains 2 to 10 carbon atoms. Either portion of the moiety is
unsubstituted or substituted.
[0119] The term "C.sub.2-10alkenyl-heteroaryl" is used to describe
a group containing an alkenyl group, which is branched or straight
chain and contains 2 to 10 carbon atoms, and is attached to a
linking heteroaryl group, such as, for example 2-styryl-4-pyridyl,
and the like. Either portion of the moiety is unsubstituted or
substituted.
[0120] The terms "heteroarylalkynyl", "heteroarylalkynyl",
"heteroaryl-alkynyl", "heteroaryl-alkynyl", "hetaralkynyl" and
"heteroaralkynyl" are used to describe a group wherein the alkynyl
chain can be branched or straight chain forming a linking portion
of the heteroaralkynyl moiety with the heteroaryl portion, as
defined above, for example 4-(2-thienyl)-1-butynyl, and the like.
Either portion of the moiety is unsubstituted or substituted.
[0121] The term "heteroaryl-C.sub.2-10alkynyl" is used to describe
a heteroarylalkynyl group as described above wherein the alkynyl
group contains 2 to 10 carbon atoms. Either portion of the moiety
is unsubstituted or substituted.
[0122] The term "C.sub.2-10alkynyl-heteroaryl" is used to describe
a group containing an alkynyl group which contains 2 to 10 carbon
atoms and is branched or straight chain, which is attached to a
linking heteroaryl group such as, for example, 4(but-1-ynyl)
thien-2-yl, and the like. Either portion of the moiety is
unsubstituted or substituted.
[0123] The term "heterocyclyl" refers to a four-, five-, six-, or
seven-membered ring containing one, two, three or four heteroaroms
independently selected from nitrogen, oxygen and sulfur. The
four-membered ring has zero double bonds, the five-membered ring
has zero to two double bonds, and the six- and seven-membered rings
have zero to three double bonds. The term "heterocyclyl" also
includes bicyclic groups in which the heterocyclyl ring is fused to
another monocyclic heterocyclyl group, or a four- to se-membered
aromatic or nonaromatic carbocyclic ring. The heterocyclyl group
can be attached to the parent molecular moiety through any carbon
atom or nitrogen atom in the group.
[0124] "Heterocycloalkyl" refers to a stable 3- to 18-membered
non-aromatic ring radical that comprises two to twelve carbon atoms
and from one to six heteroatoms selected from nitrogen, oxygen and
sulfur. Whenever it appears herein, a numerical range such as "3 to
18" refers to each integer in the given range; e.g., "3 to 18 ring
atoms" means that the heterocycloalkyl group may consist of 3 ring
atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In
some embodiments, it is a C.sub.5-C.sub.10 heterocycloalkyl. In
some embodiments, it is a C.sub.4-C.sub.10 heterocycloalkyl. In
some embodiments, it is a C.sub.3-C.sub.10 heterocycloalkyl. Unless
stated otherwise specifically in the specification, the
heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems. The heteroatoms in the heterocycloalkyl radical may be
optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heterocycloalkyl radical is partially
or fully saturated. The heterocycloalkyl may be attached to the
rest of the molecule through any atom of the ring(s). Examples of
such heterocycloalkyl radicals include, but are not limited to,
dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,
imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl,
pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,
tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,
thiamorpholinyl, 1-oxo-thiomorpholinyl, and
1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in
the specification, a heterocycloalkyl moiety is optionally
substituted by one or more substituents which independently are:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
nitro, oxo, thioxo, trimethylsilanyl, --OR.sup.a, SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), or
PO.sub.3(R.sup.a).sub.2, where each R.sup.a is independently
hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl,
aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[0125] "Heterocycloalkyl" also includes bicyclic ring systems
wherein one non-aromatic ring, usually with 3 to 7 ring atoms,
contains at least 2 carbon atoms in addition to 1-3 heteroatoms
independently selected from oxygen, sulfur, and nitrogen, as well
as combinations comprising at least one of the foregoing
heteroatoms; and the other ring, usually with 3 to 7 ring atoms,
optionally contains 1-3 heteroatoms independently selected from
oxygen, sulfur, and nitrogen and is not aromatic.
[0126] The terms "heterocyclylalkyl", "heterocyclyl-alkyl",
"hetcyclylalkyl", and "hetcyclyl-alkyl" are used to describe a
group wherein the alkyl chain can be branched or straight chain
forming a linking portion of the heterocyclylalkyl moiety with the
terminal heterocyclyl portion, as defined above, for example
3-piperidinylmethyl and the like. The term "heterocycloalkylene"
refers to the divalent derivative of heterocycloalkyl.
[0127] The term "C.sub.1-10alkyl-heterocycyl" refers to a group as
defined above where the alkyl moiety contains 1 to 10 carbon atoms.
Either portion of the moiety is unsubstituted or substituted.
[0128] The term "heterocycyl-C.sub.1-10alkyl" refers to a group
containing a terminal heterocyclic group attached to a linking
alkyl group which contains 1 to 10 carbons and is branched or
straight chain, such as, for example, 4-morpholinyl ethyl, and the
like. Either portion of the moiety is unsubstituted or
substituted.
[0129] The terms "heterocyclylalkenyl", "heterocyclyl-alkenyl",
"hetcyclylalkenyl" and "hetcyclyl-alkenyl" are used to describe a
group wherein the alkenyl chain can be branched or straight chain
forming a linking portion of the heterocyclylalkenyl moiety with
the terminal heterocyclyl portion, as defined above, for example
2-morpholinyl-1-propenyl and the like. The term
"heterocycloalkenylene" refers to the divalent derivative of
heterocyclylalkenyl. Either portion of the moiety is unsubstituted
or substituted.
[0130] The term "heterocycyl-C.sub.2-10 alkenyl" refers to a group
as defined above where the alkenyl group contains 2 to 10 carbon
atoms and is branched or straight chain, such as, for example,
4-(N-piperazinyl)-but-2-en-1-yl, and the like. Either portion of
the moiety is unsubstituted or substituted.
[0131] The terms "heterocyclylalkynyl", "heterocyclyl-alkynyl",
"hetcyclylalkynyl" and "hetcyclyl-alkynyl" are used to describe a
group wherein the alkynyl chain can be branched or straight chain
forming a linking portion of the heterocyclylalkynyl moiety with
the terminal heterocyclyl portion, as defined above, for example
2-pyrrolidinyl-1-butynyl and the like. Either portion of the moiety
is unsubstituted or substituted.
[0132] The term "heterocycyl-C.sub.2-10 alkynyl" refers to a group
as defined above where the alkynyl group contains 2 to 10 carbon
atoms and is branched or straight chain, such as, for example,
4-(N-piperazinyl)-but-2-yn-1-yl, and the like.
[0133] The term "aryl-heterocycyl" refers to a group containing a
terminal aryl group attached to a linking heterocyclic group, such
as for example, N4-(4-phenyl)-piperazinyl, and the like. Either
portion of the moiety is unsubstituted or substituted.
[0134] The term "heteroaryl-heterocycyl" refers to a group
containing a terminal heteroaryl group attached to a linking
heterocyclic group, such as for example,
N4-(4-pyridyl)-piperazinyl, and the like. Either portion of the
moiety is unsubstituted or substituted.
[0135] The term "carboxylalkyl" refers to a terminal carboxyl
(--COOH) group attached to branched or straight chain alkyl groups
as defined above.
[0136] The term "carboxylalkenyl" refers to a terminal carboxyl
(--COOH) group attached to branched or straight chain alkenyl
groups as defined above.
[0137] The term "carboxylalkynyl" refers to a terminal carboxyl
(--COOH) group attached to branched or straight chain alkynyl
groups as defined above.
[0138] The term "carboxylcycloalkyl" refers to a terminal carboxyl
(--COOH) group attached to a cyclic aliphatic ring structure as
defined above.
[0139] The term "carboxylcycloalkenyl" refers to a terminal
carboxyl (--COOH) group attached to a cyclic aliphatic ring
structure having ethylenic bonds as defined above.
[0140] The terms "cycloalkylalkyl" and "cycloalkyl-alkyl" refer to
a terminal cycloalkyl group as defined above attached to an alkyl
group, for example cyclopropylmethyl, cyclohexylethyl, and the
like. Either portion of the moiety is unsubstituted or
substituted.
[0141] The terms "cycloalkylalkenyl" and "cycloalkyl-alkenyl" refer
to a terminal cycloalkyl group as defined above attached to an
alkenyl group, for example cyclohexylvinyl, cycloheptylallyl, and
the like. Either portion of the moiety is unsubstituted or
substituted.
[0142] The terms "cycloalkylalkynyl" and "cycloalkyl-alkynyl" refer
to a terminal cycloalkyl group as defined above attached to an
alkynyl group, for example cyclopropylpropargyl,
4-cyclopentyl-2-butynyl, and the like. Either portion of the moiety
is unsubstituted or substituted.
[0143] The terms "cycloalkenylalkyl" and "cycloalkenyl-alkyl" refer
to a terminal cycloalkenyl group as defined above attached to an
alkyl group, for example 2-(cyclopenten-1-yl)ethyl and the like.
Either portion of the moiety is unsubstituted or substituted.
[0144] The terms "cycloalkenylalkenyl" and "cycloalkenyl-alkenyl"
refer to terminal a cycloalkenyl group as defined above attached to
an alkenyl group, for example 1-(cyclohexen-3-yl)allyl and the
like.
[0145] The terms "cycloalkenylalkynyl" and "cycloalkenyl-alkynyl"
refer to terminal a cycloalkenyl group as defined above attached to
an alkynyl group, for example 1-(cyclohexen-3-yl)propargyl and the
like. Either portion of the moiety is unsubstituted or
substituted.
[0146] The term "alkoxy" refers to the group --O-alkyl, including
from 1 to 8 carbon atoms of a straight, branched, cyclic
configuration and combinations thereof attached to the parent
structure through an oxygen. Examples include methoxy, ethoxy,
propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
"Lower alkoxy" refers to alkoxy groups containing one to six
carbons. In some embodiments, C.sub.1-C.sub.4 alkyl, is an alkyl
group which encompasses both straight and branched chain alkyls of
from 1 to 4 carbon atoms.
[0147] The term "haloalkoxy" refers to an alkoxy group substituted
with one or more halo groups, for example chloromethoxy,
trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy, and the
like.
[0148] The term "alkoxyalkoxyalkyl" refers to an alkyl group
substituted with an alkoxy moiety which is in turn is substituted
with a second alkoxy moiety, for example methoxymethoxymethyl,
isopropoxymethoxyethyl, and the like. This moiety is substituted
with further substituents or not substituted with other
substituents.
[0149] The term "alkylthio" includes both branched and straight
chain alkyl groups attached to a linking sulfur atom, for example
methylthio and the like.
[0150] The term "alkoxyalkyl" refers to an alkyl group substituted
with an alkoxy group, for example isopropoxymethyl and the like.
Either portion of the moiety is unsubstituted or substituted.
[0151] The term "alkoxyalkenyl" refers to an alkenyl group
substituted with an alkoxy group, for example 3-methoxyallyl and
the like. Either portion of the moiety is unsubstituted or
substituted.
[0152] The term "alkoxyalkynyl" refers to an alkynyl group
substituted with an alkoxy group, for example 3-methoxypropargyl
and the like. Either portion of the moiety is unsubstituted or
substituted.
[0153] The term "C.sub.2-10alkenylC.sub.3-8cycloalkyl" refers to an
alkenyl group as defined above substituted with a three to eight
membered cycloalkyl group, for example, 4-(cyclopropyl)-2-butenyl
and the like. Either portion of the moiety is unsubstituted or
substituted.
[0154] The term "C.sub.2-10alkynylC.sub.3-8cycloalkyl" refers to an
alkynyl group as defined above substituted with a three to eight
membered cycloalkyl group, for example, 4-(cyclopropyl)-2-butynyl
and the like. Either portion of the moiety is unsubstituted or
substituted.
[0155] The term "heterocyclyl-C.sub.1-10alkyl" refers to a
heterocyclic group as defined above substituted with an alkyl group
as defined above having 1 to 10 carbons, for example,
4-(N-methyl)-piperazinyl, and the like. Either portion of the
moiety is unsubstituted or substituted.
[0156] The term "heterocyclyl-C.sub.2-10alkenyl" refers to a
heterocyclic group as defined above, substituted with an alkenyl
group as defined above, having 2 to 10 carbons, for example,
4-(N-allyl) piperazinyl, and the like. Moieties wherein the
heterocyclic group is substituted on a carbon atom with an alkenyl
group are also included. Either portion of the moiety is
unsubstituted or substituted.
[0157] The term "heterocyclyl-C.sub.2-10alkynyl" refers to a
heterocyclic group as defined above, substituted with an alkynyl
group as defined above, having 2 to 10 carbons, for example,
4-(N-propargyl) piperazinyl, and the like. Moieties wherein the
heterocyclic group is substituted on a carbon atom with an alkenyl
group are also included. Either portion of the moiety is
unsubstituted or substituted.
[0158] The term "oxo" refers to an oxygen that is double bonded to
a carbon atom. One in the art understands that an "oxo" requires a
second bond from the atom to which the oxo is attached.
Accordingly, it is understood that oxo cannot be subststituted onto
an aryl or heteroaryl ring, unless it forms part of the aromatic
system as a tautomer.
[0159] The term "oligomer" refers to a low-molecular weight
polymer, whose number average molecular weight is typically less
than about 5000 g/mol, and whose degree of polymerization (average
number of monomer units per chain) is greater than one and
typically equal to or less than about 50.
[0160] "Sulfonamidyl" or "sulfonamido" refers to a
S(.dbd.O).sub.2--NR'R' radical, where each R' is selected
independently from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
heteroalicyclic (bonded through a ring carbon). The R' groups in
NR'R' of the S(.dbd.O).sub.2--NR'R' radical may be taken together
with the nitrogen to which it is attached to form a 4-, 5-, 6-, or
7-membered ring. A sulfonamido group is optionally substituted by
one or more of the substituents described for alkyl, cycloalkyl,
aryl, heteroaryl respectively.
[0161] Compounds described can contain one or more asymmetric
centers and may thus give rise to diastereomers and optical
isomers. The present invention includes all such possible
diastereomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric
isomers, and pharmaceutically acceptable salts thereof. Compounds
may be shown without a definitive stereochemistry at certain
positions. The present invention includes all stereoisomers of the
disclosed compounds and pharmaceutically acceptable salts thereof.
Further, mixtures of stereoisomers as well as isolated specific
stereoisomers are also included. During the course of the synthetic
procedures used to prepare such compounds, or in using racemization
or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers.
[0162] The present invention includes all manner of rotamers and
conformationally restricted states of an inhibitor of the
invention.
[0163] Substituents for alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl monovalent and divalent derivative radicals
(including those groups often referred to as alkylene, alkenyl,
heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one
or more of a variety of groups selected from, but not limited to:
alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, --OR.sup.a, .dbd.O,
.dbd.NR', .dbd.N--OR.sup.a, --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --C(O)NR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''', --NR''C(O)OR',
--NR--C(NR'R'').dbd.NR''', --S(O)R', --S(O).sub.2R',
--S(O).sub.2NR'R'', --NRSO.sub.2R', --CN and NO.sub.2 in a number
ranging from zero to (2 m'+1), where m' is the total number of
carbon atoms in such radical. R', R'', R''' and R''' each
preferably independently refer to hydrogen, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl (e.g., aryl substituted with 1-3 halogens),
substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or
arylalkyl groups. When an inhibitor of the invention includes more
than one R group, for example, each of the R groups is
independently selected as are each R', R'', R''' and R''' groups
when more than one of these groups is present.
[0164] When R' and R'' or R'' and R''' are attached to the same
nitrogen atom, they can be combined with the nitrogen atom to form
a 4-, 5-, 6-, or 7-membered ring. For example, --NR'R'' is meant to
include, but not be limited to, 1-pyrrolidinyl, 4 piperazinyl, and
4-morpholinyl. From the above discussion of substituents, one of
skill in the art will understand that the term "alkyl" is meant to
include groups including carbon atoms bound to groups other than
hydrogen groups, such as haloalkyl (e.g., --CF.sub.3 and
--CH.sub.2CF.sub.3) and acyl (e.g., --C(O)CH.sub.3, --C(O)CF.sub.3,
--C(O)CH.sub.2OCH.sub.3, and the like).
[0165] Similar to the substituents described for alkyl radicals
above, exemplary substituents for aryl and heteroaryl groups (as
well as their divalent derivatives) are varied and are selected
from, for example: halogen, alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, --OR.sup.a, --NR'R'', --SR', -halogen,
--SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --C(O)NR'R'',
--OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''', --NR''C(O)OR',
--NR--C(NR'R''R''').dbd.NR'''', --NR--C(NR'R'').dbd.NR''',
--S(O)R', --S(O).sub.2R', --S(O).sub.2NR'R'', --NRSO.sub.2R', --CN
and --NO.sub.2, --R', --N.sub.3, --CH(Ph).sub.2,
fluoro(C.sub.1-C.sub.4)alkoxo, and fluoro(C.sub.1-C.sub.4)alkyl, in
a number ranging from zero to the total number of open valences on
aromatic ring system; and where R', R'', R''' and R''' are
preferably independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl
and substituted or unsubstituted heteroaryl. When an inhibitor of
the invention includes more than one R group, for example, each of
the R groups is independently selected as are each R', R'', R'''
and R'''' groups when more than one of these groups is present.
[0166] As used herein, 0-2 in the context of --S(O).sub.(0-2)-- are
integers of 0, 1, and 2.
[0167] Two of the substituents on adjacent atoms of aryl or
heteroaryl ring may optionally form a ring of the formula
-T-C(O)--(CRR').sub.q--U--, wherein T and U are independently NR--,
--O--, --CRR'-- or a single bond, and q is an integer of from 0 to
3. Alternatively, two of the substituents on adjacent atoms of aryl
or heteroaryl ring may optionally be replaced with a substituent of
the formula -A-(CH.sub.2).sub.r--B--, wherein A and B are
independently --CRR'--, --O--, --NR--, --S--, --S(O)--,
--S(O).sub.2--, --S(O).sub.2NR'-- or a single bond, and r is an
integer of from 1 to 4. One of the single bonds of the new ring so
formed may optionally be replaced with a double bond.
Alternatively, two of the substituents on adjacent atoms of aryl or
heteroaryl ring may optionally be replaced with a substituent of
the formula --(CRR').sub.s--X'--(C''R''').sub.d--, where s and d
are independently integers of from 0 to 3, and X' is --O--,
--NR'--, --S--, --S(O)--, --S(O).sub.2--, or --S(O).sub.2NR'--. The
substituents R, R', R'' and R''' are preferably independently
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
[0168] Unless otherwise stated, structures depicted herein are also
meant to include compounds which differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structures except for the replacement of a hydrogen by
a deuterium or tritium, or the replacement of a carbon by
.sup.13C-- or .sup.14C-enriched carbon are within the scope of this
invention.
[0169] The compounds of the present invention may also contain
unnatural proportions of atomic isotopes at one or more of atoms
that constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C). All
isotopic variations of the compounds of the present invention,
whether radioactive or not, are encompassed within the scope of the
present invention.
Treatment Regimens
[0170] The invention provides an intermittent treatment regimen in
which an mTorC1/mTorC2 inhibitor is administered to a subject and
where the intermittent regimen is effective to achieve an
mTorC1/mTorC2 inhibitor plasma concentration at or above about 100
nM for a duration of time that is longer than that achieved by
administering an equivalent dose of the mTorC1/mTorC2 inhibitor
once daily. As used herein, the term "equivalent dose" refers to a
single or multiple dose administered to a subject over a period of
time, including a day, several days, a week, a month or longer. In
some embodiments, equivalence is evaluated during the length of a
treatment cycle, e.g. a week. The term equivalent dose is not
limited to identical amounts of a compound administered of a
specified period of time, but also refers to dose amounts which
result in a similar level of tolerability. By way of example, when
comparing a regimen of the invention in which an mTorC1/mTorC2
inhibitor is administered intermittently at a weekly cumulative
dose of 50 mg, with a regimen in which the mTorC1/mTorC2 inhibitor
is administered daily, it may only possible to achieve a weekly
cumulative dose of less than 50 mg (e.g. about 40-45 mg) using
daily administration due to dose-limiting toxicity and/or limited
tolerability. In such a case, administration of the weekly
cumulative 50 mg dose in the intermittent regimen is "equivalent"
to the about 40-45 mg weekly cumulative dose administered
daily.
[0171] For example, the intermittent regimen is effective to
achieve an mTorC1/mTorC2 inhibitor plasma concentration of greater
than about 80, 90, 100, 100, 120, 130, 140, 150, or 160 nM for a
duration longer than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,
33, 34, or 35 hours during a 7-day period of administration. In
some instances, the intermittent regimen is effective to achieve an
mTorC1/mTorC2 inhibitor plasma concentration of greater than about
100 nM for a duration longer than about 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33, 34, or 35 hours during a 7-day period
of administration. In other instances, the intermittent regimen is
effective to achieve an mTorC1/mTorC2 inhibitor plasma
concentration of greater than about 100 nM for a duration longer
than about 20 or about 30 hours during a 7-day period of
administration.
[0172] The invention also provides a treatment regimen which is
effective to achieve a Cmax which is greater by about 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150%,
200%, 250%, or 300% than the Cmax achieved by administering an
equivalent dose of the mTorC1/mTorC2 inhibitor once daily. For
example, the Cmax achieved is greater than about 100, 200, 250,
300, 350, 400, 450, 500, 550 or 600 nM. In some instances, the Cmax
achieved is greater than about 200, 250, 300, 350, 400, 450, 500,
550 or 600 nM. For example, the Cmax is greater than 200 nM.
Alternatively, the Cmax is greater than 300 nM. In other instances,
the Cmax achieved is between 200 and 600 nM. In yet other
instances, the Cmax achieved is between 200 and 500 nM. In yet
other instances, the Cmax achieved is between 200 and 500 nM.
[0173] In some embodiments, an intermittent treatment regimen of
the invention achieves similar or better pathway inhibition than
administering an equivalent dose of the mTorC1/mTorC2 inhibitor
once daily. Pathway inhibition may be measured, for example, as a
percentage decrease in phosphorylation of a protein chosen from
p4EBP1, pS6, and pRAS40. In some embodiments, pathway inhibition is
measured as a 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, 95% or greater decrease in phosphorylation of p4EBP1. For
example, phosphorylation of p4EBP1 is reduced by at least 60%. In
other embodiments, pathway inhibition is measured as a 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or greater
decrease in phosphorylation of pS6. For example, phosphorylation of
pS6 is reduced by at least 60%. In yet other embodiments, pathway
inhibition is measured as a 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, 85%, 90%, 95% or greater decrease in phosphorylation of
pRAS40. For example, phosphorylation of pRAS40 is reduced by at
least 60%. In yet other embodiments, pathway inhibition is measured
as a 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or
greater decrease in phosphorylation of p4EBP1, pS6, and pRAS40. For
example, phosphorylation of p4EBP1, pS6, and pRAS40 is reduced by
at least 60%. In some embodiments, pathway inhibition is measured
in peripheral blood cells. In other embodiments, pathway inhibition
is measured in a biopsy, for example a skin biopsy.
[0174] In some embodiments, an intermittent treatment regimen of
the invention achieves similar or better level of tolerability as
compared to administering an equivalent dose of the mTorC1/mTorC2
inhibitor once daily. The level of tolerability may be measured,
for example, as the occurrence or lack of occurrence of a grade 3
or higher adverse event. In some embodiments, the adverse event is
rash, hyperglycaemia, lymphopenia, diarrhoea,
gamma-glutamyltransferase increase, hypokalaemia, hyponatraemia,
pruritus, thrombocytopenia, upper abdominal pain, anaemia,
aspartate aminotransferase increase, asthenia, catheter related
infection, cellulitis, disease progression, enterocutaneous
fistula, gastroenteritis, acute pancreatitis, pleural effusion,
macular rash, somnolence, or urinary tract infection. For example,
the adverse event is rash.
[0175] In some embodiments, a given dosing schedule comprises one
or more administrations of an mTorC1/mTorC2 inhibitor, wherein at
least one administration of an mTorC1/mTorC2 inhibitor, such as
described herein, may be repeated or cycled on a daily, weekly,
biweekly, monthly, bimonthly, annually, semi-annually, or any other
period. A repeated dosing schedule or cycle may be repeated for a
fixed period of time determined at the start of the schedule; may
be terminated, extended, or otherwise adjusted based on a measure
of therapeutic effect, such as a level of reduction in the presence
of detectable disease tissue (e.g. a reduction of at least 50%,
60%, 70%, 80%, 90%, 95%, 99%, or 100%); or may be terminated,
extended, or otherwise adjusted for any other reason as determined
by a medical professional.
[0176] In some embodiments, the intermittent regimen comprises at
least one cycle in which the mTorC1/mTorC2 inhibitor is
administered for at least 1 day, followed by an intermission in
which the mTorC1/mTorC2 inhibitor is not administered for at least
1 day. For example, the mTorC1/mTorC2 inhibitor is administered for
2, 3, 4, 5, 6 or 7 consecutive days followed by an intermission in
which the mTorC1/mTorC2 inhibitor is not administered for at least
1 day, for example not administered for at least 1, 2, 3, 4, 5, 6,
or 7 days. In some embodiments, the mTorC1/mTorC2 inhibitor is
administered for 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days,
followed by an intermission where the mTorC1/mTorC2 inhibitor is
not administered for at least 2, 3, 4, 5, 6, or 7 days. In other
embodiments, the mTorC1/mTorC2 inhibitor is administered for 2, 3,
4, 5, 6 or 7 consecutive days followed by an intermission in which
the mTorC1/mTorC2 inhibitor is not administered for at least 3, 4,
or 5 consecutive days. In yet other embodiments, the regimen
comprises at least one 7-day cycle in which the mTorC1/mTorC2
inhibitor is administered for 3 consecutive days followed by an
intermission of 4 consecutive days. In yet other embodiments, the
regimen comprises at least one 7-day cycle in which the
mTorC1/mTorC2 inhibitor is administered for 4 consecutive days
followed by an intermission of 3 consecutive days. In yet other
embodiments, the regimen comprises at least one 7-day cycle in
which the mTorC1/mTorC2 inhibitor is administered for 5 consecutive
days followed by an intermission of 2 consecutive days. In yet
other embodiments, the regimen comprises at least one 7-day cycle
in which the mTorC1/mTorC2 inhibitor is administered for 6
consecutive days followed by an intermission of 1 day.
[0177] In some embodiments, an mTorC1/mTorC2 inhibitor, and/or any
additional therapeutic compound of the invention is administered in
multiple doses. Dosing may be about once, twice, three times, four
times, five times, six times, or more than six times per day or per
week. Dosing may be about once a month, once every two weeks, once
a week, or once every other day. In some embodiments, cycles of
administering an mTorC1/mTorC2 inhibitor followed by periods of
rest (intermission) are repeated for more than about 6, 10, 14, 28
days, two months, six months, or one year. In some cases,
repetition of a dosing cycle comprising administration of an
mTorC1/mTorC2 inhibitor followed by rest are continued as long as
necessary. Administration of the treatment regimens of the
invention may continue as long as necessary. In some embodiments,
an mTorC1/mTorC2 inhibitor of the invention is administered for
more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments,
an mTorC1/mTorC2 inhibitor of the invention is administered for
less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments,
an mTorC1/mTorC2 inhibitor of the invention is administered
chronically on an ongoing basis, e.g., for the treatment of chronic
effects.
[0178] The amount of the mTorC1/mTorC2 inhibitor administered
herein may vary depending upon the intended application (in vitro
or in vivo), or the subject and disease condition being treated,
e.g., the weight and age of the subject, the severity of the
disease condition, the manner of administration and the like, which
can readily be determined by one of ordinary skill in the art.
[0179] A dosage form of the invention refers to the physical
formulation of a drug for administration to the patient. When the
dosage form is a solid, the dosage form can be a single capsule,
tablet, or pill, or alternatively can be comprised of multiple
capsules, tablets or pills. A dosage form may be administered to a
subject once or multiple times per day. Methods of determining the
most effective means and dosage of administration are well known to
those of skill in the art and will vary with the composition used
for therapy, the purpose of the therapy, the target cell or tissue
being treated, and the subject being treated. Single or multiple
administrations (e.g. about or more than about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or more
doses) can be carried out with the dose level and pattern being
selected by the treating physician.
[0180] An inhibitor may be administered in any suitable amount. In
some embodiments, an inhibitor is administered to a subject within
a range of about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,
50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,
67, 68, 69, or 70 mg per week. For example, the inhibitor is
administered to a subject within a range of about 35, 36, 37, 38,
39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or
55 mg per week. In some embodiments, the inhibitor is administered
to a subject within a range of about 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, 50, 51, 52, 53, 54, or 55 mg per week.
[0181] In some embodiments, an inhibitor is administered to a
subject in an amount greater than 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5,
or 10 mg per day on average over the course of a treatment cycle.
For example, the inhibitor is administered to a subject in an
amount between about 6 and 10 mg, between about 6.5 and 9.5 mg,
between about 6.5 and 8.5 mg, between about 6.5 and 8 mg, or
between about 7 and 9 mg on average over the course of a treatment
cycle.
[0182] In some embodiments, an inhibitor is administered to a
subject within a range of about 0.1 mg/kg-50 mg/kg per day, such as
about, less than about, or more than about, 0.1 mg/kg, 0.2 mg/kg,
0.3 mg/kg, 0.4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg,
10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16
mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg,
35 mg/kg, 40 mg/kg, 45 mg/kg, or 50 mg/kg per day. In some
embodiments, an inhibitor is administered to a subject within a
range of about 0.1 mg/kg-400 mg/kg per week, such as about, less
than about, or more than about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15
mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg,
50 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg,
350 mg/kg, or 400 mg/kg per week. In some embodiments, an inhibitor
is administered to a subject within a range of about 0.1 mg/kg-1500
mg/kg per month, such as about, less than about, or more than about
50 mg/kg, 100 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg,
350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg,
650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg,
950 mg/kg, or 1000 mg/kg per month. In some embodiments, an
inhibitor is administered to a subject within a range of about 0.1
mg/m.sup.2-200 mg/m.sup.2 per week, such as about, less than about,
or more than about 5 mg/m.sup.2, 10 mg/m.sup.2, 15 mg/m.sup.2, 20
mg/m.sup.2, 25 mg/m.sup.2, 30 mg/m.sup.2, 35 mg/m.sup.2, 40
mg/m.sup.2, 45 mg/m.sup.2, 50 mg/m.sup.2, 55 mg/m.sup.2, 60
mg/m.sup.2, 65 mg/m.sup.2, 70 mg/m.sup.2, 75 mg/m.sup.2, 100
mg/m.sup.2, 125 mg/m.sup.2, 150 mg/m.sup.2, 175 mg/m.sup.2, or 200
mg/m.sup.2 per week. The target dose may be administered in a
single dose. Alternatively, the target dose may be administered in
about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 25, 30, or more doses. For example, a
dose of about 20 mg/kg per week may be delivered weekly at a dose
of about 20 mg/kg, or may be delivered at a dose of about 6.67
mg/kg administered on each of three days over the course of the
week, which days may or may not be consecutive. The administration
schedule may be repeated according to any regimen according to the
invention, including any administration schedule described herein.
In some embodiments, an inhibitor is administered to a subject in
the range of about 0.1 mg/m.sup.2-500 mg/m.sup.2, such as about,
less than about, or more than about 5 mg/m.sup.2, 10 mg/m.sup.2,15
mg/m.sup.2, 20 mg/m.sup.2, 25 mg/m.sup.2, 30 mg/m.sup.2, 35
mg/m.sup.2, 40 mg/m.sup.2, 45 mg/m.sup.2, 50 mg/m.sup.2, 55
mg/m.sup.2, 60 mg/m.sup.2, 65 mg/m.sup.2, 70 mg/m.sup.2, 75
mg/m.sup.2, 100 mg/m.sup.2, 130 mg/m.sup.2, 135 mg/m.sup.2, 155
mg/m.sup.2, 175 mg/m.sup.2, 200 mg/m.sup.2, 225 mg/m.sup.2, 250
mg/m.sup.2, 300 mg/m.sup.2, 350 mg/m.sup.2, 400 mg/m.sup.2, 420
mg/m.sup.2, 450 mg/m.sup.2, or 500 mg/m.sup.2.
[0183] A dose of mTorC1/mTorC2 inhibitor may be about, at least
about, or at most about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400,
425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725,
750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000 mg or mg/kg,
or any range derivable therein. It is contemplated that a dosage of
mg/kg refers to the mg amount of inhibitor per kg of total body
weight of the subject. It is contemplated that when multiple doses
are given to a patient, the doses may vary in amount or they may be
the same.
[0184] The amount of each inhibitor administered will be dependent
on the mammal being treated, the severity of the disorder or
condition, the rate of administration, the disposition of the
compound and the discretion of the prescribing physician.
[0185] mTORC1/mTORC2 Inhibitor Compounds
[0186] An mTorC1/mTorC2 inhibitor for use in the present invention
can be any mTorC1/mTorC2 inhibitor that is known in the art, and
can include any chemical entity that, upon administration to a
patient, results in inhibition of mTOR in the patient. An
mTorC1/mTorC2 inhibitor can inhibit mTorC1/mTorC2 by any
biochemical mechanism, including competition at the ATP binding
site, competition elsewhere at the catalytic site of mTOR kinase,
non-competitive inhibition, irreversible inhibition (e.g. covalent
protein modification), or modulation of the interactions of other
protein subunits or binding proteins with mTOR kinase in a way that
results in inhibition of mTOR kinase activity (e.g. modulation of
the interaction of mTOR with FKBP12, G.beta.L, (mLST8), RAPTOR
(mKOG1), or RICTOR (mAVO3)). Such inhibitors useful in the
invention described herein include those disclosed and claimed in
U.S. Pat. No. 7,700,594 and in U.S. Pat. No. 7,651,687, a series of
compounds that inhibit mTOR by binding to and directly inhibiting
both mTORC1 and mTORC2 kinases. Similar results can be obtained
with any compound that inhibits mTOR by binding to and directly
inhibiting both mTORC1 and mTORC2 kinases, such as those whose
structures are disclosed herein. Additional such compounds can
readily be identified by determining their ability to inhibit both
mTORC1 and mTORC2 kinase activities using
immunoprecipitation-kinase assays with antibodies specific to
either the raptor or rictor proteins of the mTORC1 and mTORC2
complexes (for an example of such assays, see Jacinto, E. et al.
(2004) Nature Cell Biol. 6(11): 1122-1128). Also useful in the
invention described herein are mTorC1/mTorC2 inhibitors that are
dual PI3K/mTOR kinase inhibitors, such as for example the compound
PI-103 as described in Fan, Q-W et al (2006) Cancer Cell 9:341-349
and Knight, Z. A. et al. (2006) Cell 125:733-747.
[0187] In some embodiments, the capacity of an mTorC1/mTorC2
inhibitor to inhibit mTorC1/mTorC2 is expressed in terms of an IC50
value. As used herein, the term "IC50" refers to the half maximal
inhibitory concentration of an inhibitor in inhibiting biological
or biochemical function. This quantitative measure indicates how
much of a particular inhibitor is needed to inhibit a given
biological process (or component of a process, i.e. an enzyme,
cell, cell receptor or microorganism) by half. In other words, it
is the half maximal (50%) inhibitory concentration (IC) of a
substance (50% IC, or IC50). EC50 refers to the plasma
concentration required for obtaining 50% of a maximum effect in
vivo.
[0188] Determination of IC50 can be made by determining and
constructing a dose-response curve and examining the effect of
different concentrations of an inhibitor on reversing agonist
activity. In vitro assays that are useful in making these
determinations are referred to as "in vitro kinase assays."
[0189] In some embodiments, an in vitro kinase assay includes the
use of labeled ATP as phosphodonor, and following the kinase
reaction the substrate peptide is captured on an appropriate
filter. Unreacted labeled ATP and metabolites are resolved from the
radioactive peptide substrate by various techniques, such as
involving trichloroacetic acid precipitation and extensive washing.
Addition of several positively charged residues allows capture on
phosphocellulose paper followed by washing. Radioactivity
incorporated into the substrate peptide is detected by
scintillation counting. This assay is relatively simple, reasonably
sensitive, and the peptide substrate can be adjusted both in terms
of sequence and concentration to meet the assay requirements. Other
exemplary kinase assays are detailed in U.S. Pat. No. 5,759,787 and
U.S. application Ser. No. 12/728,926, both of which are
incorporated herein by reference.
[0190] The ability of an mTorC1/mTorC2 inhibitor utilized in the
subject methods to bind to and directly inhibit both mTORC1 and
mTORC2 can be ascertained using any method known in the art or
described herein. For example, inhibition of mTorC1 and/or mTorC2
activity can be determined by a reduction in signal transduction of
the PI3K/Akt/mTor pathway. A wide variety of readouts can be
utilized to establish a reduction of the output of such signaling
pathway. Some non-limiting exemplary readouts include (1) a
decrease in phosphorylation of Akt at residues, including but not
limited to S473 and T308; (2) a decrease in activation of Akt as
evidenced by a reduction of phosphorylation of Akt substrates
including but not limited to FoxO1/O3a T24/32,
GSK3.alpha./.beta.S21/9, and TSC2 T1462; (3) a decrease in
phosphorylation of signaling molecules downstream of mTor,
including but not limited to ribosomal S6 S240/244, 70S6K T389, and
4EBP1 T37/46; (4) inhibition of proliferation of cells including
but not limited to normal or neoplastic cells, mouse embryonic
fibroblasts, leukemic blast cells, cancer stem cells, and cells
that mediate autoimmune reactions; (5) induction of apoptosis of
cells or cell cycle arrest (e.g. accumulation of cells in G1
phase); (6) reduction of cell chemotaxis; and (7) an increase in
binding of 4EBP1 to eIF4E.
[0191] mTOR exists in two types of complexes, mTorC1 containing the
raptor subunit and mTorC2 containing rictor. As known in the art,
"rictor" refers to a cell growth regulatory protein having human
gene locus 5p13.1. These complexes are regulated differently and
have a different spectrum of substrates. For instance, mTor Cl
phosphorylates S6 kinase (S6K) and 4EBP1, promoting increased
translation and ribosome biogenesis to facilitate cell growth and
cell cycle progression. S6K also acts in a feedback pathway to
attenuate PI3K/Akt activation. Thus, inhibition of mTor C.sub.1
(e.g. by a biologically active agent as discussed herein) results
in activation of 4EBP1, resulting in inhibition of (e.g. a decrease
in) RNA translation.
[0192] mTorC2 is generally insensitive to rapamycin and selective
inhibitors and is thought to modulate growth factor signaling by
phosphorylating the C-terminal hydrophobic motif of some AGC
kinases such as Akt. In many cellular contexts, mTorC2 is required
for phosphorylation of the S473 site of Akt. Thus, mTor Cl activity
is partly controlled by Akt whereas Akt itself is partly controlled
by mTorC2.
[0193] Growth factor stimulation of PI3K causes activation of Akt
by phosphorylation at the two key sites, S473 and T308. It has been
reported that full activation of Akt requires phosphorylation of
both S473 and T308Active. Akt promotes cell survival and
proliferation in many ways including suppressing apoptosis,
promoting glucose uptake, and modifying cellular metabolism. Of the
two phosphorylation sites on Akt, activation loop phosphorylation
at T308, mediated by PDK1, is believed to be indispensable for
kinase activity, while hydrophobic motif phosphorylation at S473
enhances Akt kinase activity.
[0194] Inhibition of Akt phosphorylation can be determined using
any methods known in the art or described herein. Representative
assays include but are not limited to immunoblotting and
immunoprecipitation with antibodies such as anti-phosphotyrosine
antibodies that recognize the specific phosphorylated proteins.
Cell-based ELISA kit quantifies the amount of activated
(phosphorylated at S473) Akt relative to total Akt protein is also
available (SuperArray Biosciences).
[0195] Selective mTor inhibition may also be determined by
expression levels of the mTor genes, its downstream signaling genes
(for example by RT-PCR), or expression levels of the proteins (for
example by immunocytochemistry, immunohistochemistry, Western
blots) as compared to other PI3-kinases or protein kinases.
[0196] Cell-based assays for establishing selective inhibition of
mTorC1 and/or mTorC2 can take a variety of formats. This generally
will depend on the biological activity and/or the signal
transduction readout that is under investigation. For example, the
ability of the agent to inhibit mTorC1 and/or mTorC2 to
phosphorylate downstream substrate(s) can be determined by various
types of kinase assays known in the art. Representative assays
include but are not limited to immunoblotting and
immunoprecipitation with antibodies such as anti-phosphotyrosine,
anti-phosphoserine or anti-phosphothreonine antibodies that
recognize phosphorylated proteins. Alternatively, antibodies that
specifically recognize a particular phosphorylated form of a kinase
substrate (e.g. anti-phospho AKT S473 or anti-phospho AKT T308) can
be used. In addition, kinase activity can be detected by high
throughput chemiluminescent assays such as AlphaScreen.TM.
(available from Perkin Elmer) and eTag.TM. assay (Chan-Hui, et al.
(2003) Clinical Immunology 111: 162-174). In another aspect, single
cell assays such as flow cytometry as described in the phosflow
experiment can be used to measure phosphorylation of multiple
downstream mTOR substrates in mixed cell populations.
[0197] One advantage of the immunoblotting and phosflow methods is
that the phosphorylation of multiple kinase substrates can be
measured simultaneously. This provides the advantage that efficacy
and selectivity can be measured at the same time. For example,
cells may be contacted with an mTorC1/mTorC2 inhibitor at various
concentrations and the phosphorylation levels of substrates of both
mTOR and other kinases can be measured. In one aspect, a large
number of kinase substrates are assayed in what is termed a
"comprehensive kinase survey." Selective mTorC1/mTorC2 inhibitors
are expected to inhibit phosphorylation of mTOR substrates without
inhibiting phosphorylation of the substrates of other kinases.
Alternatively, selective mTorC1/mTorC2 inhibitors may inhibit
phosphorylation of substrates of other kinases through anticipated
or unanticipated mechanisms such as feedback loops or
redundancy.
[0198] Effect of inhibition of mTorC1 and/or mTorC2 can be
established by cell colony formation assay or other forms of cell
proliferation assay. A wide range of cell proliferation assays are
available in the art, and many of which are available as kits.
Non-limiting examples of cell proliferation assays include testing
for tritiated thymidine uptake assays, BrdU
(5'-bromo-2'-deoxyuridine) uptake (kit marketed by Calibochem), MTS
uptake (kit marketed by Promega), MTT uptake (kit marketed by
Cayman Chemical), CyQUANT.RTM. dye uptake (marketed by
Invitrogen).
[0199] Apoptosis and cell cycle arrest analysis can be performed
with any methods exemplified herein as well other methods known in
the art. Many different methods have been devised to detect
apoptosis. Exemplary assays include but are not limited to the
TUNEL (TdT-mediated dUTP Nick-End Labeling) analysis, ISEL (in situ
end labeling), and DNA laddering analysis for the detection of
fragmentation of DNA in populations of cells or in individual
cells, Annexin-V analysis that measures alterations in plasma
membranes, detection of apoptosis related proteins such p53 and
Fas.
[0200] A cell-based assay typically proceeds with exposing the
target cells (e.g., in a culture medium) to a test compound which
is a potential mTorC1 and/or mTorC2 selective inhibitor, and then
assaying for readout under investigation. Depending on the nature
of the candidate mTorC1/mTorC2 inhibitors, they can directly be
added to the cells or in conjunction with carriers. For instance,
when the agent is nucleic acid, it can be added to the cell culture
by methods well known in the art, which include without limitation
calcium phosphate precipitation, microinjection or electroporation.
Alternatively, the nucleic acid can be incorporated into an
expression or insertion vector for incorporation into the cells.
Vectors that contain both a promoter and a cloning site into which
a polynucleotide can be operatively linked are well known in the
art. Such vectors are capable of transcribing RNA in vitro or in
vivo, and are commercially available from sources such as
Stratagene (La Jolla, Calif.) and Promega Biotech (Madison, Wis.).
In order to optimize expression and/or in vitro transcription, it
may be necessary to remove, add or alter 5' and/or 3' untranslated
portions of the clones to eliminate extra, potential inappropriate
alternative translation initiation codons or other sequences that
may interfere with or reduce expression, either at the level of
transcription or translation. Alternatively, consensus ribosome
binding sites can be inserted immediately 5' of the start codon to
enhance expression. Examples of vectors are viruses, such as
baculovirus and retrovirus, bacteriophage, adenovirus,
adeno-associated virus, cosmid, plasmid, fungal vectors and other
recombination vehicles typically used in the art which have been
described for expression in a variety of eukaryotic and prokaryotic
hosts, and may be used for gene therapy as well as for simple
protein expression. Among these are several non-viral vectors,
including DNA/liposome complexes, and targeted viral protein DNA
complexes. To enhance delivery to a cell, the nucleic acid or
proteins of this invention can be conjugated to antibodies or
binding fragments thereof which bind cell surface antigens.
Liposomes that also comprise a targeting antibody or fragment
thereof can be used in the methods of this invention. Other
biologically acceptable carriers can be utilized, including those
described in, for example, REMINGTON'S PHARMACEUTICAL SCIENCES,
19th Ed. (2000), in conjunction with the subject compounds.
Additional methods for cell-based assays for determining effects of
agents on cell-cycle progression are described in U.S. Pat. No.
7,612,189, incorporated herein by reference.
[0201] In practicing the subject methods, any cells that express
PI3-kinase .alpha., mTorC1, mTorC2 and/or Akt can be target cells.
Non-limiting examples of specific cell types whose proliferation
can be inhibited include fibroblast, cells of skeletal tissue (bone
and cartilage), cells of epithelial tissues (e.g. liver, lung,
breast, skin, bladder and kidney), cardiac and smooth muscle cells,
neural cells (glia and neurones), endocrine cells (adrenal,
pituitary, pancreatic islet cells), melanocytes, and many different
types of haemopoietic cells (e.g., cells of B-cell or T-cell
lineage, and their corresponding stem cells, lymphoblasts). Also of
interest are cells exhibiting a neoplastic propensity or phenotype.
Of particular interest is the type of cells that differentially
expresses (over-expresses or under-expresses) a disease-causing
gene. The types of diseases involving abnormal functioning of genes
include but are not limited to autoimmune diseases, cancer,
obesity, hypertension, diabetes, neuronal and/or muscular
degenerative diseases, cardiac diseases, endocrine disorders, and
any combinations thereof.
[0202] In some embodiments, the mTorC1/mTorC2 inhibitor utilized in
the subject methods inhibits one of mTORC1 and mTORC2 selectively
with an IC50 value of about 1000, 500, 100, 75, 50, 25, 10, 5, 1,
or 0.5 nM or less as ascertained in an in vitro kinase. For
example, an mTorC1/mTorC2 inhibitor utilized in the subject methods
inhibits mTORC1 selectively with an IC50 value of about 1000, 500,
100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an
in vitro kinase assay.
[0203] In some embodiments, the mTorC1/mTorC2 inhibitor inhibits
one of mTORC1 and mTORC2 with an IC50 value of about 1 nM, 2 nM, 5
nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM,
90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190
nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM,
400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700
nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 .mu.M, 1.2 .mu.M, 1.3
.mu.M, 1.4 .mu.M, 1.5 .mu.M, 1.6 .mu.M, 1.7 .mu.M, 1.8 .mu.M, 1.9
.mu.M, 2 .mu.M, 5 .mu.M, 10 .mu.M, 15 .mu.M, 20 .mu.M, 25 .mu.M, 30
.mu.M, 40 .mu.M, 50 .mu.M, 60 .mu.M, 70 .mu.M, 80 .mu.M, 90 .mu.M,
100 .mu.M, 200 .mu.M, 300 .mu.M, 400 .mu.M, or 500 .mu.M or less as
ascertained in an in vitro kinase assay, and said IC50 value is at
least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50,
100, or 1000 times less than its IC50 value against all other type
I PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta.. For example, the mTorC1/mTorC2 inhibitor inhibits one of
mTORC1 and mTORC2 with an IC50 value of about 200, 100, 75, 50, 25,
10, 5, 1 or 0.5 nM or less as ascertained in an in vitro kinase
assay. In one instance, the mTorC1/mTorC2 inhibitor inhibits one of
mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as
ascertained in an in vitro kinase assay. As another example, the
mTorC1/mTorC2 inhibitor inhibits one of mTORC1 and mTORC2 with an
IC50 value of about 10 nM or less as ascertained in an in vitro
kinase assay.
[0204] In some embodiments, the mTorC1/mTorC2 inhibitor inhibits
both mTORC1 and mTORC2 with an IC50 value of about 1 nM, 2 nM, 5
nM, 7 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM,
90 nM, 100 nM, 120 nM, 140 nM, 150 nM, 160 nM, 170 nM, 180 nM, 190
nM, 200 nM, 225 nM, 250 nM, 275 nM, 300 nM, 325 nM, 350 nM, 375 nM,
400 nM, 425 nM, 450 nM, 475 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700
nM, 750 nM, 800 nM, 850 nM, 900 nM, 950 nM, 1 .mu.M, 1.2 .mu.M, 1.3
.mu.M, 1.4 .mu.M, 1.5 .mu.M, 1.6 .mu.M, 1.7 .mu.M, 1.8 .mu.M, 1.9
.mu.M, 2 .mu.M, 5 .mu.M, 10 .mu.M, 15 .mu.M, 20 .mu.M, 25 .mu.M, 30
.mu.M, 40 .mu.M, 50 .mu.M, 60 .mu.M, 70 .mu.M, 80 .mu.M, 90 .mu.M,
100 .mu.M, 200 .mu.M, 300 .mu.M, 400 .mu.M, or 500 .mu.M or less as
ascertained in an in vitro kinase assay, and said IC50 value is at
least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50,
100, or 1000 times less than its IC50 value against all other type
I PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta.. For example, the mTorC1/mTorC2 inhibitor inhibits both
mTORC1 and mTORC2 with an IC50 value of about 200, 100, 75, 50, 25,
10, 5, 1 or 0.5 nM or less as ascertained in an in vitro kinase
assay. In one instance, the mTorC1/mTorC2 inhibitor inhibits both
mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as
ascertained in an in vitro kinase assay. As another example, the
mTorC1/mTorC2 inhibitor inhibits both mTORC1 and mTORC2 with an
IC50 value of about 10 nM or less as ascertained in an in vitro
kinase assay.
[0205] In some embodiments, the present invention provides the use
of an mTorC1/mTorC2 inhibitor, wherein the mTorC1/mTorC2 inhibitor
directly binds to and inhibits one of mTORC1 and mTORC2 with an
IC50 value of about or less than a predetermined value, as
ascertained in an in vitro kinase assay. In some embodiments, the
mTorC1/mTorC2 inhibitor inhibits one of mTORC1 and mTORC2 with an
IC50 value of about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM
or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nM or
less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less,
90 nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150
nM or less, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM
or less, 200 nM or less, 225 nM or less, 250 nM or less, 275 nM or
less, 300 nM or less, 325 nM or less, 350 nM or less, 375 nM or
less, 400 nM or less, 425 nM or less, 450 nM or less, 475 nM or
less, 500 nM or less, 550 nM or less, 600 nM or less, 650 nM or
less, 700 nM or less, 750 nM or less, 800 nM or less, 850 nM or
less, 900 nM or less, 950 nM or less, 1 .mu.M or less, 1.2 .mu.M or
less, 1.3 .mu.M or less, 1.4 .mu.M or less, 1.5 .mu.M or less, 1.6
.mu.M or less, 1.7 .mu.M or less, 1.8 .mu.M or less, 1.9 .mu.M or
less, 2 .mu.M or less, 5 .mu.M or less, 10 .mu.M or less, 15 .mu.M
or less, 20 .mu.M or less, 25 .mu.M or less, 30 .mu.M or less, 40
.mu.M or less, 50 .mu.M or less, 60 .mu.M or less, 70 .mu.M or
less, 80 .mu.M or less, 90 .mu.M or less, 100 .mu.M or less, 200
.mu.M or less, 300 .mu.M or less, 400 .mu.M or less, or 500 .mu.M
or less.
[0206] In some embodiments, the present invention provides the use
of an mTorC1/mTorC2 inhibitor, wherein the mTorC1/mTorC2 inhibitor
directly binds to and inhibits both mTORC1 and mTORC2 with an IC50
value of about or less than a predetermined value, as ascertained
in an in vitro kinase assay. In some embodiments, the mTorC1/mTorC2
inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of
about 1 nM or less, 2 nM or less, 5 nM or less, 7 nM or less, 10 nM
or less, 20 nM or less, 30 nM or less, 40 nM or less, 50 nM or
less, 60 nM or less, 70 nM or less, 80 nM or less, 90 nM or less,
100 nM or less, 120 nM or less, 140 nM or less, 150 nM or less, 160
nM or less, 170 nM or less, 180 nM or less, 190 nM or less, 200 nM
or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nM or
less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or
less, 425 nM or less, 450 nM or less, 475 nM or less, 500 nM or
less, 550 nM or less, 600 nM or less, 650 nM or less, 700 nM or
less, 750 nM or less, 800 nM or less, 850 nM or less, 900 nM or
less, 950 nM or less, 1 .mu.M or less, 1.2 .mu.M or less, 1.3 .mu.M
or less, 1.4 .mu.M or less, 1.5 .mu.M or less, 1.6 .mu.M or less,
1.7 .mu.M or less, 1.8 .mu.M or less, 1.9 .mu.M or less, 2 .mu.M or
less, 5 .mu.M or less, 10 .mu.M or less, 15 .mu.M or less, 20 .mu.M
or less, 25 .mu.M or less, 30 .mu.M or less, 40 .mu.M or less, 50
.mu.M or less, 60 .mu.M or less, 70 .mu.M or less, 80 .mu.M or
less, 90 .mu.M or less, 100 .mu.M or less, 200 .mu.M or less, 300
.mu.M or less, 400 .mu.M or less, or 500 .mu.M or less.
[0207] In some embodiments, the mTorC1/mTorC2 inhibitor inhibits
one of mTORC1 and mTORC2 with an IC50 value of about 1 nM or less,
2 nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or
less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less,
70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM
or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or
less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or
less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or
less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or
less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or
less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or
less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or
less, 1 .mu.M or less, 1.2 .mu.M or less, 1.3 .mu.M or less, 1.4
.mu.M or less, 1.5 .mu.M or less, 1.6 .mu.M or less, 1.7 .mu.M or
less, 1.8 .mu.M or less, 1.9 .mu.M or less, 2 .mu.M or less, 5
.mu.M or less, 10 .mu.M or less, 15 .mu.M or less, 20 .mu.M or
less, 25 .mu.M or less, 30 .mu.M or less, 40 .mu.M or less, 50
.mu.M or less, 60 .mu.M or less, 70 .mu.M or less, 80 .mu.M or
less, 90 .mu.M or less, 100 .mu.M or less, 200 .mu.M or less, 300
.mu.M or less, 400 .mu.M or less, or 500 .mu.M or less, and the
mTorC1/mTorC2 inhibitor is substantially inactive against one or
more types I PI3-kinases selected from the group consisting of
PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase .gamma., and
PI3-kinase .delta.. In some embodiments, the mTorC1/mTorC2
inhibitor inhibits one of mTORC1 and mTORC2 with an IC50 value of
about 10 nM or less as ascertained in an in vitro kinase assay, and
the mTorC1/mTorC2 inhibitor is substantially inactive against one
or more types I PI3-kinases selected from the group consisting of
PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase .gamma., and
PI3-kinase .delta..
[0208] In some embodiments, the mTorC1/mTorC2 inhibitor inhibits
both mTORC1 and mTORC2 with an IC50 value of about 1 nM or less, 2
nM or less, 5 nM or less, 7 nM or less, 10 nM or less, 20 nM or
less, 30 nM or less, 40 nM or less, 50 nM or less, 60 nM or less,
70 nM or less, 80 nM or less, 90 nM or less, 100 nM or less, 120 nM
or less, 140 nM or less, 150 nM or less, 160 nM or less, 170 nM or
less, 180 nM or less, 190 nM or less, 200 nM or less, 225 nM or
less, 250 nM or less, 275 nM or less, 300 nM or less, 325 nM or
less, 350 nM or less, 375 nM or less, 400 nM or less, 425 nM or
less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nM or
less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or
less, 800 nM or less, 850 nM or less, 900 nM or less, 950 nM or
less, 1 .mu.M or less, 1.2 .mu.M or less, 1.3 .mu.M or less, 1.4
.mu.M or less, 1.5 .mu.M or less, 1.6 .mu.M or less, 1.7 .mu.M or
less, 1.8 .mu.M or less, 1.9 .mu.M or less, 2 .mu.M or less, 5
.mu.M or less, 10 .mu.M or less, 15 .mu.M or less, 20 .mu.M or
less, 25 .mu.M or less, 30 .mu.M or less, 40 .mu.M or less, 50
.mu.M or less, 60 .mu.M or less, 70 .mu.M or less, 80 .mu.M or
less, 90 .mu.M or less, 100 .mu.M or less, 200 .mu.M or less, 300
.mu.M or less, 400 .mu.M or less, or 500 .mu.M or less, and the
mTorC1/mTorC2 inhibitor is substantially inactive against one or
more types I PI3-kinases selected from the group consisting of
PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase .gamma., and
PI3-kinase .delta.. In some embodiments, the mTorC1/mTorC2
inhibitor inhibits both mTORC1 and mTORC2 with an IC50 value of
about 10 nM or less as ascertained in an in vitro kinase assay, and
the mTorC1/mTorC2 inhibitor is substantially inactive against one
or more types I PI3-kinases selected from the group consisting of
PI3-kinase .alpha., PI3-kinase PI3-kinase .gamma., and PI3-kinase
.delta..
[0209] As used herein, the terms "substantially inactive" refers to
an inhibitor that inhibits the activity of its target by less than
approximately 1%, 5%, 10%, 15% or 20% of its maximal activity in
the absense of the inhibitor, as determined by an in vitro
enzymatic assay (e.g. in vitro kinase assay).
[0210] In some embodiments, the mTorC1/mTorC2 inhibitor inhibits
one of mTORC1 and mTORC2 with an IC50 value of about 1000, 500,
100, 75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an
in vitro kinase assay, and said IC50 value is at least 2, 5, 10,
15, 20, 50, 100 or 100 times less than its IC50 value against all
other type I PI3-kinases selected from the group consisting of
PI3-kinase .alpha., PI3-kinase PI3-kinase .gamma., and PI3-kinase
.delta.. For example, the mTorC1/mTorC2 inhibitor inhibits one of
mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as
ascertained in an in vitro kinase assay, and said IC50 value is at
least 5 times less than its IC50 value against all other type I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase PI3-kinase .gamma., and PI3-kinase .delta..
[0211] In other embodiments, the mTorC1/mTorC2 inhibitor inhibits
both mTORC1 and mTORC2 with an IC50 value of about 1000, 500, 100,
75, 50, 25, 10, 5, 1, or 0.5 nM or less as ascertained in an in
vitro kinase assay, and said IC50 value is at least 2, 5, 10, 15,
20, 50, 100 or 100 times less than its IC50 value against all other
type I PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta.. For example, the mTorC1/mTorC2 inhibitor inhibits both
mTORC1 and mTORC2 with an IC50 value of about 100 nM or less as
ascertained in an in vitro kinase assay, and said IC50 value is at
least 5 times less than its IC50 value against all other type I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta..
[0212] In some embodiments, the mTorC1/mTorC2 inhibitor inhibits
one of mTORC1 and mTORC2 with an IC50 value of about 100 nM or less
as ascertained in an in vitro kinase assay, and said IC50 value is
at least 5 times less than its IC50 value against all other type I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta.. In other embodiments, the mTorC1/mTorC2 inhibitor inhibits
one of mTORC1 and mTORC2 with an IC50 value of about 50 nM or less
as ascertained in an in vitro kinase assay, and said IC50 value is
at least 5 times less than its IC50 value against all other type I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta..
[0213] In other embodiments, the mTorC1/mTorC2 inhibitor inhibits
both mTORC1 and mTORC2 with an IC50 value of about 100 nM or less
as ascertained in an in vitro kinase assay, and said IC50 value is
at least 5 times less than its IC50 value against all other type I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta.. In other embodiments, the mTorC1/mTorC2 inhibitor inhibits
both mTORC1 and mTORC2 with an IC50 value of about 50 nM or less as
ascertained in an in vitro kinase assay, and said IC50 value is at
least 5 times less than its IC50 value against all other type I
PI3-kinases selected from the group consisting of PI3-kinase
.alpha., PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase
.delta..
[0214] mTorC1/mTorC2 inhibitors suitable for use in the subject
methods can be selected from a variety types of molecules. For
example, an inhibitor can be biological or chemical compound such
as a simple or complex organic or inorganic molecule, peptide,
peptide mimetic, protein (e.g. antibody), liposome, or a
polynucleotide (e.g. small interfering RNA, microRNA, anti-sense,
aptamer, ribozyme, or triple helix). Some exemplary classes of
chemical compounds suitable for use in the subject methods are
detailed in the sections below.
[0215] The advantages of selective inhibition of a cellular target
as a way of treating a disease condition mediated by such target
are manifold. Because healthy cells depend on the signaling
pathways that are activated in cancers for survival, inhibition of
these pathways during cancer treatment can cause harmful side
effects. In order for a method of treating cancer to be successful
without causing excessive damage to healthy cells, a very high
degree of specificity in targeting the aberrant signaling component
or components is desirable. Moreover, cancer cells may depend on
overactive signaling for their survival (known as the oncogene
addiction hypothesis). In this way, cancer cells are frequently
observed to adapt to drug inhibition of an aberrant signaling
component by selecting for mutations in the same pathway that
overcome the effect of the drug. Therefore, cancer therapies may be
more successful in overcoming the problem of drug resistance if
they target a signaling pathway as a whole, or target more than one
component within a signaling pathway.
[0216] One major downstream effector of mTOR signaling is the Akt
serine/threonine kinase. Akt possesses a protein domain known as a
PH domain, or Pleckstrin Homology domain, which binds to
phosphoinositides with high affinity. In the case of the PH domain
of Akt, it binds either PIP3 (phosphatidylinositol
(3,4,5)-trisphosphate, PtdIns(3,4,5)P3) or PIP2
(phosphatidylinositol (3,4)-bisphosphate, PtdIns(3,4)P2). PI3K
phosphorylates PIP2 in response to signals from chemical
messengers, such as ligand binding to G protein-coupled receptors
or receptor tyrosine kinases. Phosphorylation by PI3K converts PIP2
to PIP3, recruiting Akt to the cell membrane where it is
phosphorylated at serine 473 (S473) by mTORC2. Phosphorylation of
Akt at another site, threonine 308 (T308), is not directly
dependent on mTORC2, but requires PI3K activity. Therefore, PI3K
activity towards Akt can be isolated from mTOR activity by
examining Akt threonine 308 phosphorylation status in cells lacking
mTORC2 activity.
[0217] In one aspect, the invention provides a compound which is an
inhibitor of mTorC1/mTorC2 of the Formula I:
##STR00007##
[0218] or a pharmaceutically acceptable salt thereof, wherein:
[0219] X.sub.1 is N or C-E.sup.1, X.sub.2 is N or C, X.sub.3 is N
or C, X.sub.4 is C--R.sup.9 or N, X.sub.5 is N or C-E.sup.1,
X.sub.6 is C or N, and X.sub.7 is C or N; and wherein no more than
two nitrogen ring atoms are adjacent;
[0220] R.sub.1 is H, -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkyl, --C.sub.3-8cycloalkyl, -L-aryl, -L-heteroaryl,
-L-C.sub.1-10alkylaryl, -L-C.sub.1-10alkylhetaryl,
-L-C.sub.1-10alkylheterocylyl, -L-C.sub.2-10alkenyl,
-L-C.sub.2-10alkynyl, -L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0221] L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--;
[0222] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0223] M.sub.1 is a 5, 6, 7, 8, 9, or -10 membered ring system,
wherein the ring system is monocyclic or bicyclic, substituted with
R.sub.5 and additionally optionally substituted with one or more
(W.sup.2).sub.k--R.sup.2;
[0224] each k is 0 or 1;
[0225] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0226] W.sup.1 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0227] W.sup.2 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--,
--N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0228] R.sup.2 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl (e.g. bicyclic aryl,
unsubstituted aryl, or substituted monocyclic aryl), hetaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl (e.g.
C.sub.2-10alkyl-monocyclic aryl, C.sub.1-10alkyl-substituted
monocyclic aryl, or C.sub.1-10alkylbicycloaryl),
C.sub.1-10alkylhetaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylhetaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylhetaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocylyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl (e.g.
monocyclic aryl-C.sub.2-10alkyl, substituted monocyclic
aryl-C.sub.1-10alkyl, or bicycloaryl-C.sub.1-10alkyl),
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, hetaryl-C.sub.3-8cycloalkyl,
hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein each of said
bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein
each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety
is substituted with one or more independent alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0229] R.sup.3 and R.sup.4 are independently hydrogen, halogen,
--OH, --R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.3)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl, hetaryl, C.sub.1-4alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl,
C.sub.1-10alkylhetaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylhetaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylhetaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocylyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, hetaryl-C.sub.3-8cycloalkyl,
heteroalkyl, hetaryl-heteroalkyl, or hetaryl-heterocyclyl, wherein
each of said aryl or heteroaryl moiety is unsubstituted or is
substituted with one or more independent halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0230] R.sup.5 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32;
[0231] each of R.sup.31, R.sup.32, and R.sup.33 is independently H
or C.sub.1-10alkyl, wherein the C.sub.1-10alkyl is unsubstituted or
is substituted with one or more aryl, heteroalkyl, heterocyclyl, or
hetaryl group, wherein each of said aryl, heteroalkyl,
heterocyclyl, or hetaryl group is unsubstituted or is substituted
with one or more halo, --OH, --C.sub.1-10alkyl, --CF.sub.3,
--O-aryl, --OCF.sub.3, --OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2 aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35;
[0232] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, hetaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen atom;
[0233] each of R.sup.7 and R.sup.8 is independently hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, aryl, heteroaryl, heterocyclyl
or C.sub.3-10cycloalkyl, each of which except for hydrogen is
unsubstituted or is substituted by one or more independent
R.sup.6;
[0234] R.sup.6 is halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, wherein each of said alkyl, alkenyl,
alkynyl, aryl, heteroalkyl, heterocyclyl, or hetaryl group is
unsubstituted or is substituted with one or more independent halo,
cyano, nitro, --OC.sub.1-10alkyl, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, haloC.sub.1-10alkyl,
haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl, --COOH,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35; and
[0235] R.sup.9 is H, halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.1-10alkyl,
hetaryl-C.sub.2-10alkenyl, hetaryl-C.sub.2-10alkynyl, wherein each
of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heterocyclyl,
or hetaryl group is unsubstituted or is substituted with one or
more independent halo, cyano, nitro, --OC.sub.1-10alkyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35.
[0236] M.sub.1 is a 5, 6, 7, 8, 9, or -10 membered ring system,
wherein the ring system is monocyclic or bicyclic. The monocyclic
M.sub.1 ring is unsubstituted or substituted with one or more
R.sup.5 substituents (including 0, 1, 2, 3, 4, or 5 R.sup.5
substituents). In some embodiments, the monocyclic M.sub.1 ring is
aromatic (including phenyl) or heteroaromatic (including but not
limited to pyridinyl, pyrrolyl, imidazolyl, thiazolyl, or
pyrimidinyl). The monocyclic M.sub.1 ring may be a 5 or 6 membered
ring (including but not limited to pyridinyl, pyrrolyl, imidazolyl,
thiazolyl, or pyrimidinyl). In some embodiments, M.sub.2 is a five
membered heteroaromatic group with one heteroatom, wherein the
heteroatom is N, S, or O. In another embodiment, M.sub.2 is a five
membered heteroaromatic group with two heteroatoms, wherein the
heteroatoms are nitrogen and oxygen or nitrogen and sulfur.
[0237] The bicyclic M.sub.1 ring is unsubstituted or substituted
with one or more R.sup.5 substituents (including 0, 1, 2, 3, 4, 5,
6 or 7 R.sup.5 substituents). Bicyclic M.sub.1 ring is a 7, 8, 9,
or 10 membered aromatic or heteroaromatic. Examples of an aromatic
bicyclic M.sub.1 ring include naphthyl. In other embodiments the
bicyclic M.sub.1 ring is heteroaromatic and includes but is not
limited to benzothiazolyl, quinolinyl, quinazolinyl, benzoxazolyl,
and benzoimidazolyl.
[0238] The invention also provides compounds wherein M.sub.1 is a
moiety having a structure of Formula M1-A or Formula M1-B:
##STR00008##
wherein W.sub.1, W.sub.2, and W.sub.7 are independently N or
C--R.sup.5; W.sub.4 and W.sub.10 are independently N--R.sup.5, O,
or S; W.sub.6 and W.sub.8 are independently N or C--R.sup.5;
W.sub.5 and W.sub.9 are independently N or C--R.sup.2; and W.sub.3
is C or N, provided no more than two N and/or N--R.sup.5 are
adjacent and no two O or S are adjacent.
[0239] In some embodiments of the invention, the M.sub.1 moiety of
Formula M1-A is a moiety of Formula M1-A1, Formula M1-A2, Formula
M1-A3, or Formula M1-A4:
##STR00009##
wherein W.sub.4 is N--R.sup.5, O, or S; W.sub.6 is N or C--R.sup.5
and W.sub.5 is N or C--R.sup.2.
[0240] Some nonlimiting examples of the M.sub.1 moiety of Formula
M1-A include:
##STR00010##
wherein R.sup.5 is (W.sup.1).sub.k--R.sup.53 or R.sup.55; each k is
independently 0 or 1, n is 0, 1, 2, or 3, and
(W.sup.1).sub.k--R.sup.53 and R.sup.55 are as defined above.
[0241] In other embodiments of the invention, the M.sub.1 moiety of
Formula M1-B is a moiety of Formula M1-B1, Formula M1-B2, Formula
M1-B3, or Formula M1-B4:
##STR00011##
wherein W.sub.10 is N--R.sup.5, O, or S, W.sub.8 is N or
C--R.sup.5, and W.sub.5 is N or C--R.sup.2.
[0242] Some nonlimiting examples of the M.sub.1 moiety of Formula
M1-B include:
##STR00012##
wherein R'.sup.5 is (W.sup.1).sub.k--R.sup.53 or R.sup.55; k is 0
or 1, n is 0, 1, 2, or 3, and (W.sup.1).sub.k--R.sup.53 and
R.sup.55 are as defined above.
[0243] The invention also provides compounds wherein M.sub.1 is a
moiety having a structure of Formula M1-C or Formula M1-D:
##STR00013##
wherein W.sub.12, W.sub.13, W.sub.14, and W.sub.15 are
independently N or C--R.sup.5; W.sub.11 and W.sub.18 are
independently N--R.sup.5, O, or S; W.sub.16 and W.sub.17 are
independently N or C--R.sup.5; provided no more than two N are
adjacent.
[0244] In other embodiments of the invention, the M.sub.1 moiety of
Formula M1-C or Formula M1-D is a moiety of Formula M1-C1 or
Formula M1-D1:
##STR00014##
wherein W.sub.11 and W.sub.18 are N--R.sup.5, O, or S; and W.sub.16
and W.sub.17 are N or C--R.sup.5.
[0245] Some nonlimiting examples of the M.sub.1 moiety of Formula
M1-C and Formula M1-D include:
##STR00015##
wherein R'.sup.5 is (W.sup.1).sub.k--R.sup.53 or R.sup.55; k is 0
or 1, and (W.sup.1).sub.k--R.sup.53 and R.sup.55 are as defined
above.
[0246] The invention also provides compounds wherein M.sub.1 is a
moiety having a structure of Formula M1-E:
##STR00016##
wherein X.sub.11, X.sub.12, X.sub.13, X.sub.14, X.sub.15, X.sub.16,
and X.sub.17 are independently N, or C--R.sup.5; provided that no
more than two N are adjacent.
[0247] In some embodiments of the invention, the M.sub.1 moiety
having a structure of Formula M1-E, is a moiety having a structure
of Formula M1-E1, M1-E2, M1-E3, M1-E4, M1-E5, M1-E6, M1-E7, or
M1-E8:
##STR00017##
[0248] In some embodiments of the invention, the M.sub.1 moiety
having a structure of Formula M1-E, is a moiety having a
structure:
##STR00018##
[0249] Some nonlimiting examples of the M.sub.1 moiety of Formula
M1-E include:
##STR00019##
wherein R'.sup.5 is (W.sup.1).sub.k--R.sup.53 or R.sup.55; k is 0
or 1, n is 0, 1, 2, or 3, and (W.sup.1).sub.k--R.sup.53 or R.sup.55
are as defined above. In some embodiments, k is 0, and R.sup.5 is
R.sup.53.
[0250] In some embodiments, R.sup.53 is hydrogen, unsubstituted or
substituted C.sub.1-C.sub.10alkyl (which includes but is not
limited to --CH.sub.3, --CH.sub.2CH.sub.3, n-propyl, isopropyl,
n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or
unsubstituted or substituted C.sub.3-C.sub.8cycloalkyl (which
includes but is not limited to cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl). In other embodiments, R.sup.53 is
monocyclic or bicyclic aryl, wherein the R.sup.53 aryl is
unsubstituted or substituted. Some examples of aryl include but are
not limited to phenyl, naphthyl or fluorenyl. In some other
embodiments, R.sup.53 is unsubstituted or substituted heteroaryl,
including but not limited to monocyclic and bicyclic heteroaryl.
Monocyclic heteroaryl R.sup.53 includes but is not limited to
pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, imidazolyl,
thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R.sup.53
includes but is not limited to benzothiophenyl, benzofuryl,
indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, and
purinyl. Additionally, R.sup.53 may be alkylcycloalkyl (including
but not limited to cyclopropylethyl, cyclopentylethyl, and
cyclobutylpropyl), -alkylaryl (including but not limited to benzyl,
phenylethyl, and phenylnaphthyl), -alkylhetaryl (including but not
limited to pyridinylmethyl, pyrrolylethyl, and imidazolylpropyl),
or -alkylheterocyclyl (non-limiting examples are morpholinylmethyl,
1-piperazinylmethyl, and azetidinylpropyl). For each of
alkylcycloalkyl, alkylaryl, alkylhetaryl, or alkylheterocyclyl, the
moiety is connected to M.sub.1 through the alkyl portion of the
moiety In other embodiments, R.sup.53 is unsubstituted or
substituted C.sub.2-C.sub.10alkenyl (including but not limited to
alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl,
butenyl, or pentenyl) or unsubstituted or substituted alkynyl
(including but not limited to unsubstituted or substituted
C.sub.2-C.sub.10alkynyl such as acetylenyl, propargyl, butynyl, or
pentynyl).
[0251] Further embodiments provide R.sup.53 wherein R.sup.53 is
alkenylaryl, alkenylheteroaryl, alkenylheteroalkyl, or
alkenylheterocyclcyl, wherein each of alkenyl, aryl, heteroaryl,
heteroalkyl, and heterocyclyl is as described herein and wherein
the alkenylaryl, alkenylhetaryl, alkenylheteroalkyl, or
alkenylheterocyclcyl moiety is attached to M.sub.1 through the
alkenyl. Some nonlimiting examples in include styryl,
3-pyridinylallyl, 2-methoxyethoxyvinyl, and 3-morpholinlylallyl In
other embodiments, R.sup.53 is -alkynylaryl, -alkynylhetaryl,
-alkynylheteroalkyl, -alkynylheterocylyl, -alkynylcycloalkyl, or
-alkynylC.sub.3-8cycloalkenyl, wherein each of alkynyl, aryl,
heteroaryl, heteroalkyl, and heterocyclyl is as described herein
and wherein the alkynylaryl, alkynylhetaryl, alkynylheteroalkyl, or
alkynylheterocycicyl moiety is attached to M.sub.1 through the
alkynyl. Alternatively, R.sup.53 is -alkoxyalkyl, -alkoxyalkenyl,
or -alkoxyalkynyl, wherein each of alkoxy, alkyl, alkenyl, and
alkynyl is as described herein and wherein the -alkoxyalkyl,
-alkoxyalkenyl, or -alkoxyalkynyl moiety is attached to M.sub.1
through the alkoxy. In yet other embodiments, R.sup.53 is
-heterocyclylalkyl, -heterocyclylalkenyl, or -heterocyclylalkynyl,
wherein the heterocyclyl, alkyl, alkenyl, or alkynyl is as
described herein and wherein the -heterocyclylalkyl,
-heterocyclylalkenyl, or -heterocyclylalkynyl is attached to
M.sub.1 through the heterocyclyl portion of the moiety. Further,
R.sup.53 may be aryl-alkenyl, aryl-alkynyl, or aryl-heterocyclyl,
wherein the aryl, alkenyl, alkynyl, or heterocyclyl is as described
herein and wherein the aryl-alkenyl, aryl-alkynyl, or
aryl-heterocyclyl moiety is attached to M.sub.1 through the aryl
portion of the moiety. In some other embodiments, R.sup.53 is
heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl,
heteroaryl-cycloalkyl, heteroaryl-heteroalkyl, or heteroaryl
-heterocyclyl, wherein each of heteroaryl, alkyl, alkenyl, alkynyl,
cycloalkyl, heteroalkyl, and heterocyclyl is as described herein
and wherein the heteroaryl-alkyl, heteroaryl-alkenyl,
heteroaryl-alkynyl, heteroaryl-cycloalkyl, heteroaryl-heteroalkyl,
or heteroaryl-heterocyclyl moiety is attached to M.sub.1 through
the heteroaryl portion of the moiety.
[0252] For each of the aryl or heteroaryl moieties forming part or
all of R.sup.53, the aryl or heteroaryl is unsubstituted or is
substituted with one or more independent halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NNR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32 substituents. Additionally, each of
the alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moieties
forming part of all of R.sup.53 is unsubstituted or substituted
with one or more halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NNR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32 substituents.
[0253] In other embodiments, R.sup.5 is --W.sup.1--R.sup.53. In
some embodiments, R.sup.5 is --OR.sup.53, including but not limited
to Oalkyl (including but not limited to methoxy or ethoxy), --Oaryl
(including but not limited to phenoxy), --O-heteroaryl (including
but not limited to pyridinoxy) and --O-heterocycloxy(including but
not limited to 4-N-piperidinoxy). In some embodiments R.sup.5 is
--NR.sup.6R.sup.53 including but not limited to anilinyl,
diethylamino, and 4-N-piperidinylamino. In yet other embodiments
R.sup.5 is --S(O).sub.0-2R.sup.53, including but not limited to
phenylsulfonyl and pyridinylsulfonyl. The invention also provides
compounds wherein R.sup.5 is --C(O) (including but not limited to
acetyl, benzoyl, and pyridinoyl) or --C(O)O R.sup.53 (including but
not limited to carboxyethyl, and carboxybenzyl). In other
embodiments, R.sup.5 is --C(O)N(R.sup.6)R.sup.53 (including but not
limited to C(O)NH(cyclopropyl) and C(O)N(Me)(phenyl)) or
--CH(R.sup.6)N(R.sup.7)R.sup.53 (including but not limited to
--CH.sub.2--NH-pyrrolidinyl, CH.sub.2--NHcyclopropyl, and
CH.sub.2-anilinyl). Alternatively, R.sup.5 is
--N(R.sup.6)C(O)R.sup.53 (including but not limited to
--NHC(O)phenyl, --NHC(O)cyclopentyl, and to --NHC(O)piperidinyl) or
--N(R.sup.6)S(O).sub.2R.sup.53 (including but not limited to
--NHS(O).sub.2phenyl, --NHS(O).sub.2piperazinyl, and
--NHS(O).sub.2methyl. Additionally, R.sup.5 is
--N(R.sup.6)S(O)R.sup.53, --CH(R.sup.6)N(C(O)OR.sup.7) R.sup.53,
--CH(R.sup.7)N(C(O)R.sup.7) R.sup.53,
--CH(R.sup.6)N(SO.sub.2R.sup.7)R.sup.53,
--CH(R.sup.6)N(R.sup.7)R.sup.53,
--CH(R.sup.6)C(O)N(R.sup.7)R.sup.53,
--CH(R.sup.6)N(R.sup.7)C(O)R.sup.53,
--CH(R.sup.6)N(R.sup.7)S(O)R.sup.53, or
--CH(R.sup.6)N(R.sup.7)S(O).sub.2R.sup.53.
[0254] Alternatively, R.sup.5 is R.sup.55. R.sup.55 is halo, --OH,
--NO.sub.2, --CF.sub.3, --OCF.sub.3, or --CN. In some other
embodiments, R.sup.55 is --R.sup.31, --OR.sup.31 (including but not
limited to methoxy, ethoxy, and butoxy)-C(O)R.sup.31 (non-limiting
examples include acetyl, propionyl, and pentanoyl), or
--CO.sub.2R.sup.31 (including but not limited to carboxymethyl,
carboxyethyl and carboxypropyl). In further embodiments, R.sup.55
is --NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.31R.sup.32,
--SO.sub.2NR.sup.31R.sup.32, or --S(O).sub.0-2R.sup.31. In other
embodiments, R.sup.55 is --NR.sup.34R.sup.35 or --SO.sub.2
NR.sup.34R.sup.35, wherein R.sup.34R.sup.35 are taken together with
the nitrogen to which R.sup.34R.sup.35 are attached to form a
cyclic moiety. The cyclic moiety so formed may be unsubstituted or
substituted, wherein the substituents are selected from the group
consisting of alkyl, --C(O)alkyl, --S(O).sub.2alkyl, and
--S(O).sub.2aryl. Examples include but are not limited to
morpholinyl, piperazinyl, or --SO.sub.2-(4-N-methyl-piperazin-1-yl.
Additionally, R.sup.55 is --NR.sup.31C(.dbd.O)R.sup.32,
NR.sup.31C(.dbd.O)OR.sup.32, NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
C(.dbd.O)SR.sup.31, NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NNR.sup.34R.sup.35,
--OC(.dbd.O)SR.sup.31, --SC(.dbd.O)OR.sup.31,
--P(O)OR.sup.31OR.sup.32, or --SC(.dbd.O)NR.sup.31R.sup.32. In yet
another embodiment, R.sup.55 is --O-aryl, including but not limited
to phenoxy, and naphthyloxy.
[0255] The invention further provides a compound which is an
mTorC1/mTorC2 inhibitor, wherein the compound has the Formula
I-A:
##STR00020##
[0256] or a pharmaceutically acceptable salt thereof, wherein:
[0257] X.sub.1 is N or C-E.sup.1, X.sub.2 is N, X.sub.3 is C.sub.1
and X.sub.4 is C--R.sup.9 or N; or X.sub.1 is N or C-E.sup.1,
X.sub.2 is C, X.sub.3 is N, and X.sub.4 is C--R.sup.9 or N;
[0258] R.sub.1 is H, L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, -L-aryl, -L-heteroaryl,
-L-C.sub.1-10alkylaryl, -L-C.sub.1-10alkylheteroaryl,
-L-C.sub.1-10alkylheterocyclyl, -L-C.sub.2-10alkenyl,
-L-C.sub.2-10alkynyl, -L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0259] L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--;
[0260] M.sub.1 is a moiety having the structure of Formula M1-F1 or
M1-F2:
##STR00021##
[0261] k is 0 or 1;
[0262] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0263] j, in each instance (i.e., in E.sup.1 or j in E.sup.2), is
independently 0 or 1
[0264] W.sup.1 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0265] W.sup.2 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--,
--N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0266] R.sup.2 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl (e.g. bicyclic aryl,
unsubstituted aryl, or substituted monocyclic aryl), heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl (e.g.
C.sub.2-10alkyl-monocyclic aryl, C.sub.1-10alkyl-substituted
monocyclic aryl, or C.sub.1-10alkylbicycloaryl),
C.sub.1-10alkylheteroaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl (e.g.
monocyclic aryl-C.sub.2-10alkyl, substituted monocyclic
aryl-C.sub.1-10alkyl, or bicycloaryl-C.sub.1-10alkyl),
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of
said bicyclic aryl or heteroaryl moiety is unsubstituted, or
wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl
moiety is substituted with one or more independent alkyl,
heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.3)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.3)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0267] R.sup.3 and R.sup.4 are independently hydrogen, halogen,
--OH, --R.sup.31, --CF.sub.3, --OCF, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl, heteroaryl, C.sub.1-4alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl,
C.sub.1-10alkylheteroaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl,
wherein each of said aryl or heteroaryl moiety is unsubstituted or
is substituted with one or more independent halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--S(O).sub.0-2R.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0268] R.sup.5 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32;
[0269] R.sup.31, R.sup.32, and R.sup.33, in each instance, are
independently H or C.sub.1-10alkyl, wherein the C.sub.1-10alkyl is
unsubstituted or is substituted with one or more aryl, heteroalkyl,
heterocyclyl, or heteroaryl group, wherein each of said aryl,
heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or
is substituted with one or more halo, --OH, --C.sub.1-10alkyl,
--CF.sub.3, --O-aryl, --OCF.sub.3, --OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35;
[0270] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, heteroaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen atom;
[0271] R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, aryl, heteroaryl, heterocyclyl
or C.sub.3-10cycloalkyl, each of which except for hydrogen is
unsubstituted or is substituted by one or more independent
R.sup.6;
[0272] R.sup.6 is halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-C.sub.2-10alkenyl, heteroaryl-C.sub.2-10alkynyl, wherein
each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl,
heterocyclyl, or heteroaryl group is unsubstituted or is
substituted with one or more independent halo, cyano, nitro,
--OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2 NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35; and
[0273] R.sup.9 is H, halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
[0274] C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-C.sub.2-10alkenyl, heteroaryl-C.sub.2-10alkynyl, wherein
each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl,
heterocyclyl, or heteroaryl group is unsubstituted or is
substituted with one or more independent halo, cyano, nitro,
--OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2 NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35.
[0275] In some embodiments, X.sub.4 is C--R.sup.9.
[0276] The invention also provides an inhibitor as defined above,
wherein the compound is of Formula I:
##STR00022##
or a pharmaceutically acceptable salt thereof, and wherein the
substituents are as defined above.
[0277] In various embodiments the compound of Formula I-B or its
pharmaceutically acceptable salt thereof, is a compound having the
structure of Formula I-B1 or Formula I-B2:
##STR00023##
or a pharmaceutically acceptable salt thereof.
[0278] In various embodiments of Formula I-B1, X.sub.1 is N and
X.sub.2 is N. In other embodiments, X.sub.1 is C-E.sup.1 and
X.sub.2 is N. In yet other embodiments, X.sub.1 is NH and X.sub.2
is C. In further embodiments, X.sub.1 is CH-E.sup.1 and X.sub.2 is
C.
[0279] In various embodiments of Formula I-B2, X.sub.1 is N and
X.sub.2 is C. In further embodiments, X.sub.1 is C-E.sup.1
and X.sub.2 is C.
[0280] In various embodiments, X.sub.1 is
C--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0281] In another embodiment, X.sub.1 is CH. In yet another
embodiment, X.sub.1 is C-halogen, where halogen is Cl, F, Br, or
I.
[0282] In various embodiments of X.sub.1, it is
C--(W.sup.1).sub.j--R.sup.4. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --O--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --NR.sup.7--. In various embodiments of X.sub.1,
j is 1, and W.sup.1 is --NH--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of X.sub.1, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of X.sub.1, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of X.sub.1, j is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In
various embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0283] In another embodiment, X.sub.1 is CH.sub.2. In yet another
embodiment, X.sub.1 is CH-halogen, where halogen is Cl, F, Br, or
I.
[0284] In another embodiment, X.sub.1 is N.
[0285] In various embodiments, X.sub.2 is N. In other embodiments,
X.sub.2 is C.
[0286] In various embodiments, E.sup.2 is
--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0287] In another embodiment, E.sup.2 is CH. In yet another
embodiment, E.sup.2 is C-halogen, where halogen is Cl, F, Br, or
I.
[0288] In various embodiments of E.sup.2, it is
--(W.sup.1).sub.j--R.sup.4. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --O--. In various embodiments of E.sup.2, j is 1,
and W.sup.1 is --NR.sup.7--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --NH--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of E.sup.2, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of E.sup.2, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of E.sup.2, j is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In
various embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0289] In various embodiments when M.sub.1 is a moiety of Formula
M1-F1, M.sub.1 is benzoxazolyl substituted with
--(W.sub.2).sub.k--R.sub.2. In some embodiments, M.sub.1 is a
benzoxazolyl substituted at the 2-position with
--(W.sup.2).sub.j--R.sup.2. In some embodiments, M.sub.1 is either
a 5-benzoxazolyl or a 6-benzoxazolyl moiety, optionally substituted
at the 2-position with --(W.sup.2).sub.j--R.sup.2. Exemplary
Formula M1-F1 M.sub.1 moieties include but are not limited to the
following:
##STR00024##
[0290] In various embodiments when M.sub.1 is a moiety of Formula
M1-F2, Formula M1-F2 is an aza-substituted benzoxazolyl moiety
having a structure of one of the following formulae:
##STR00025##
[0291] Exemplary Formula M1-F2 M.sub.1 moieties include but are not
limited to the following:
##STR00026##
[0292] In various embodiments of M.sub.1, k is 0. In other
embodiments of M.sub.1, k is 1, and W.sup.2 is selected from one of
the following: --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O) --, or
--N(R.sup.7)C(O)N(R.sup.8) --. In yet another embodiment of
M.sub.1, k is 1, and W.sup.2 is --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--, --CH(R.sup.7)N(C(O)OR.sup.8)
--, --CH(R.sup.7)N(C(O)R.sup.8) --, or
--CH(R.sup.7)N(SO.sub.2R.sup.8) --. In a further embodiment of
M.sub.1, k is 1, and W.sup.2 is --CH(R.sup.7)N(R.sup.8) --,
--CH(R.sup.7)C(O)N(R.sup.8) --, --CH(R.sup.7)N(R.sup.8)C(O) --, or
--CH(R.sup.7)N(R.sup.8)S(O) --. In yet another embodiment of
M.sub.1, k is 1, and W.sup.2 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0293] The invention provides an inhibitor of mTor which is a
compound of Formula I-C or Formula I-D:
##STR00027##
or a pharmaceutically acceptable salt thereof, wherein X.sub.1 is N
or C-E.sup.1, X.sub.2 is N, and X.sub.3 is C; or X.sub.1 is N or
C-E.sup.1, X.sub.2 is C, and X.sub.3 is N;
[0294] R.sub.1 is H, L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, -L-aryl, -L-heteroaryl,
-L-C.sub.1-10alkylaryl, -L-C.sub.1-10alkylheteroaryl,
-L-C.sub.1-10alkylheterocyclyl, -L-C.sub.2-10alkenyl,
-L-C.sub.2-10alkynyl, -L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0295] L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--;
[0296] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0297] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0298] W.sup.1 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0299] W.sup.2 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--,
--N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0300] k is 0 or 1;
[0301] R.sup.2 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl (e.g. bicyclic aryl,
unsubstituted aryl, or substituted monocyclic aryl), heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl (e.g.
C.sub.2-10alkyl-monocyclic aryl, C.sub.1-10alkyl-substituted
monocyclic aryl, or C.sub.1-10alkylbicycloaryl),
C.sub.1-10alkylheteroaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl-C.sub.1-10alkyl,
heterocyclyl-C.sub.2-10alkenyl, heterocyclyl-C.sub.2-10alkynyl,
aryl-C.sub.1-10alkyl (e.g. monocyclic aryl-C.sub.2-10alkyl,
substituted monocyclic aryl-C.sub.1-10alkyl, or
bicycloaryl-C.sub.1-10alkyl), aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of
said bicyclic aryl or heteroaryl moiety is unsubstituted, or
wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl
moiety is substituted with one or more independent alkyl,
heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32 s, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0302] R.sup.3 and R.sup.4 are independently hydrogen, halogen,
--OH, --R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl,
C.sub.1-10alkylheteroaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl-C.sub.1-10alkyl,
heterocyclyl-C.sub.2-10alkenyl, heterocyclyl-C.sub.2-10alkynyl,
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of
said aryl or heteroaryl moiety is unsubstituted or is substituted
with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0303] R.sup.5 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32;
[0304] R.sup.31, R.sup.32, and R.sup.33, in each instance, are
independently H or C.sub.1-10alkyl, wherein the C.sub.1-10alkyl is
unsubstituted or is substituted with one or more aryl, heteroalkyl,
heterocyclyl, or heteroaryl group, wherein each of said aryl,
heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or
is substituted with one or more halo, --OH, --C.sub.1-10alkyl,
--CF.sub.3, --O-aryl, --OCF.sub.3, --OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35;
[0305] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, heteroaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen atom; and
[0306] R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, aryl, heteroaryl, heterocyclyl
or C.sub.3-10cycloalkyl, each of which except for hydrogen is
unsubstituted or is substituted by one or more independent R.sup.6;
and R.sup.6 is halo, --OR.sup.31, --SH, NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, or C.sub.2-10alkynyl; or
R.sup.6 is aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-C.sub.2-10alkenyl, heteroaryl-C.sub.2-10alkynyl, each of
which is unsubstituted or is substituted with one or more
independent halo, cyano, nitro, --OC.sub.1-10alkyl,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
haloC.sub.1-10alkyl, halo C.sub.2-10alkenyl, halo
C.sub.2-10alkynyl, --COOH, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --SO.sub.2NR.sup.34R.sup.35,
--SO.sub.2NR.sup.31R.sup.32, --NR.sup.31R.sup.32, or
--NR.sup.34R.sup.35.
[0307] In various embodiments of the compound of Formula I-C, the
compound has a structure of Formula I-C1 or Formula I-C2:
##STR00028##
or a pharmaceutically acceptable salt thereof
[0308] In some embodiments of Formula I-C1, X.sub.1 is N and
X.sub.2 is N. In other embodiments, X.sub.1 is C-E.sup.1 and
X.sub.2 is N. In yet other embodiments, X.sub.1 is NH and X.sub.2
is C. In further embodiments, X.sub.1 is CH-E.sup.1 and X.sub.2 is
C.
[0309] In several embodiments of Formula I-C2, X.sub.1 is N and
X.sub.2 is C. In yet other embodiments, X.sub.1 is NH
and X.sub.2 is C. In further embodiments, X.sub.1 is CH-E.sup.1 and
X.sub.2 is C.
[0310] In various embodiments of the compound of Formula I-D, the
compound has a structure of Formula I-D1 or Formula I-D2:
##STR00029##
or a pharmaceutically acceptable salt thereof.
[0311] In some embodiments of Formula I-D1, X.sub.1 is N and
X.sub.2 is N. In other embodiments, X.sub.1 is C-E.sup.1 and
[0312] X.sub.2 is N. In yet other embodiments, X.sub.1 is NH and
X.sub.2 is C. In further embodiments, X.sub.1 is CH-E.sup.1 and
X.sub.2 is C.
[0313] In several embodiments of Formula I-D2, X.sub.1 is N and
X.sub.2 is C. In further embodiments, X.sub.1 is C-E.sup.1
and X.sub.2 is C.
[0314] In various embodiments, X.sub.1 is
C--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0315] In another embodiment, X.sub.1 is CH. In yet another
embodiment, X.sub.1 is C-halogen, where halogen is Cl, F, Br, or
I.
[0316] In various embodiments of X.sub.1, it is
C--(W.sup.1).sub.j--R.sup.4. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --O--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --NR.sup.7--. In various embodiments of X.sub.1,
j is 1, and W.sup.1 is --NH--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of X.sub.1, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of X.sub.1, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of X.sub.1, j is 1, and W.sup.1 is --CH(R.sup.7)N(C(O)OR.sup.8)--.
In various embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0317] In various embodiments, X.sub.1 is
CH--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0318] In another embodiment, X.sub.1 is CH.sub.2. In yet another
embodiment, X.sub.1 is CH-halogen, where halogen is Cl, F, Br, or
I.
[0319] In various embodiments of X.sub.1, it is
CH--(W.sup.1).sub.j--R.sup.4. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --O--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --NR.sup.7--. In various embodiments of X.sub.1,
j is 1, and W.sup.1 is --NH--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of X.sub.1, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of X.sub.1, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of X.sub.1, j is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In
various embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0320] In another embodiment, X.sub.1 is N.
[0321] In various embodiments, X.sub.2 is N. In other embodiments,
X.sub.2 is C.
[0322] In various embodiments, E.sup.2 is
--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0323] In another embodiment, E.sup.2 is CH. In yet another
embodiment, E.sup.2 is C-halogen, where halogen is Cl, F, Br, or
I.
[0324] In various embodiments of E.sup.2, it is
--(W.sup.1).sub.j--R.sup.4. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --O--. In various embodiments of E.sup.2, j is 1,
and W.sup.1 is --NR.sup.7--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --NH--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of E.sup.2, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of E.sup.2, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of E.sup.2, j is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In
various embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0325] In various embodiments, k is 0. In other embodiments, k is 1
and W.sup.2 is --O--. In another embodiment, k is 1 and W.sup.2 is
--NR.sup.7--. In yet another embodiment of, k is 1, and W.sup.2 is
--S(O).sub.0-2--. In another embodiment of, k is 1 and W.sup.2 is
--C(O)--. In a further embodiment, k is 1 and W.sup.2 is
--C(O)N(R.sup.7) --. In another embodiment, k is 1, and W.sup.2 is
--N(R.sup.7)C(O)--. In another embodiment, k is 1 and W.sup.2 is
--N(R.sup.7)C(O)N(R.sup.8)--. In yet another embodiment, k is 1 and
W.sup.2 is --N(R.sup.7)S(O)--. In still yet another embodiment, k
is 1 and W.sup.2 is --N(R.sup.7)S(O).sub.2--. In a further
embodiment, k is 1 and W.sup.2 is --C(O)O--. In another embodiment,
k is 1 and W.sup.2 is --CH(R.sup.7)N(C(O)OR.sup.8)--. In another
embodiment, k is 1 and W.sup.2 is --CH(R.sup.7)N(C(O)R.sup.8)--. In
another embodiment, k is 1 and W.sup.2 is
--CH(R.sup.7)N(SO.sub.2R.sup.8)--. In a further embodiment, k is 1
and W.sup.2 is --CH(R.sup.7)N(R.sup.8)--. In another embodiment, k
is 1 and W.sup.2 is --CH(R.sup.7)C(O)N(R.sup.8)--. In yet another
embodiment, k is 1 and W.sup.2 is --CH(R.sup.7)N(R.sup.8)C(O)--. In
another embodiment, k is 1 and W.sup.2 is
--CH(R.sup.7)N(R.sup.8)S(O)--. In yet another embodiment, k is 1
and W.sup.2 is --CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0326] The invention also provides a compound which is an
mTorC1/mTorC2 inhibitor of Formula I-E:
##STR00030##
[0327] or a pharmaceutically acceptable salt thereof, wherein:
X.sub.1 is N or C-E.sup.1, X.sub.2 is N, and X.sub.3 is C; or
X.sub.1 is N or C-E.sup.1, X.sub.2 is C, and X.sub.3 is N;
[0328] R.sub.1 is --H, L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, -L-aryl, -L-heteroaryl,
-L-C.sub.1-10alkylaryl, -L-C.sub.1-10alkylheteroaryl,
-L-C.sub.1-10alkylheterocyclyl, -L-C.sub.2-10alkenyl,
-L-C.sub.2-10alkynyl, -L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0329] L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--;
[0330] M.sub.1 is a moiety having the structure of Formula M1-F1 or
Formula M1-F2:
##STR00031##
[0331] k is 0 or 1;
[0332] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0333] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0334] W.sup.1 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0335] W.sup.2 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--,
--N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0336] R.sup.2 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl (e.g. bicyclic aryl,
unsubstituted aryl, or substituted monocyclic aryl), heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl (e.g.
C.sub.2-10alkyl-monocyclic aryl, C.sub.1-10alkyl-substituted
monocyclic aryl, or C.sub.1-10alkylbicycloaryl),
C.sub.1-10alkylheteroaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl-C.sub.1-10alkyl,
heterocyclyl-C.sub.2-10alkenyl, heterocyclyl-C.sub.2-10alkynyl,
aryl-C.sub.1-10alkyl (e.g. monocyclic aryl-C.sub.2-10alkyl,
substituted monocyclic aryl-C.sub.1-10alkyl, or
bicycloaryl-C.sub.1-10alkyl), aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of
said bicyclic aryl or heteroaryl moiety is unsubstituted, or
wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl
moiety is substituted with one or more independent alkyl,
heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0337] R.sup.3 and R.sup.4 are independently hydrogen, halogen,
--OH, --R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl, heteroaryl, C.sub.1-4 alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl,
C.sub.1-10alkylheteroaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl,
wherein each of said aryl or heteroaryl moiety is unsubstituted or
is substituted with one or more independent halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0338] R.sup.5 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32;
[0339] R.sup.31, R.sup.32, and R.sup.33, in each instance, are
independently H or C.sub.1-10alkyl, wherein the C.sub.1-10alkyl is
unsubstituted or is substituted with one or more aryl, heteroalkyl,
heterocyclyl, or heteroaryl group wherein each of said aryl,
heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or
is substituted with one or more halo, --OH, --C.sub.1-10alkyl,
--CF.sub.3, --O-aryl, --OCF.sub.3, --OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35;
[0340] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, heteroaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen atom;
[0341] R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, aryl, heteroaryl, heterocyclyl
or C.sub.3-10cycloalkyl, each of which except for hydrogen is
unsubstituted or is substituted by one or more independent
R.sup.6;
[0342] R.sup.6 is halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-C.sub.2-10alkenyl, heteroaryl-C.sub.2-10alkynyl, wherein
each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl,
heterocyclyl, or heteroaryl group is unsubstituted or is
substituted with one or more independent halo, cyano, nitro,
--OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl,
haloC.sub.2-10alkynyl, --COOH, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --SO.sub.2NR.sup.34R.sup.35,
--SO.sub.2 NR.sup.31R.sup.32, --NR.sup.31R.sup.32, or
--NR.sup.34R.sup.35; and
[0343] R.sup.9 is H, halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-C.sub.2-10alkenyl, heteroaryl-C.sub.2-10alkynyl, wherein
each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl,
heterocyclyl, or heteroaryl group is unsubstituted or is
substituted with one or more independent halo, cyano, nitro,
--OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl,
haloC.sub.2-10alkynyl, --COOH, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --SO.sub.2NR.sup.34R.sup.35,
--SO.sub.2 NR.sup.31R.sup.32, --NR.sup.31R.sup.32, or
--NR.sup.34R.sup.35.
[0344] In various embodiments of the compound of Formula I-E, the
compound has a structure of Formula I-E1 or Formula I-E2:
##STR00032##
or a pharmaceutically acceptable salt thereof.
[0345] In some embodiments of Formula I-E1, X.sub.1 is N and
X.sub.2 is N. In other embodiments, X.sub.1 is C-E.sup.1 and
X.sub.2 is N. In yet other embodiments, X.sub.1 is NH and X.sub.2
is C. In further embodiments, X.sub.1 is CH-E.sup.1 and X.sub.2 is
C.
[0346] In several embodiments of Formula I-E2, X.sub.1 is N and
X.sub.2 is C. In further embodiments, X.sub.1 is C-E.sup.1
and X.sub.2 is C.
[0347] In various embodiments, X.sub.1 is
C--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0348] In another embodiment, X.sub.1 is CH. In yet another
embodiment, X.sub.1 is C-halogen, where halogen is Cl, F, Br, or
I.
[0349] In various embodiments of X.sub.1, it is
C--(W.sup.1).sub.j--R.sup.4. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --O--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --NR.sup.7--. In various embodiments of X.sub.1,
j is 1, and W.sup.1 is --NH--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of X.sub.1, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of X.sub.1, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of X.sub.1, j is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In
various embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O) --. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0350] In another embodiment, X.sub.1 is N.
[0351] In various embodiments, X.sub.2 is N. In other embodiments,
X.sub.2 is C.
[0352] In various embodiments, E.sup.2 is
--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0353] In another embodiment, E.sup.2 is CH. In yet another
embodiment, E.sup.2 is C-halogen, where halogen is Cl, F, Br, or
I.
[0354] In various embodiments of E.sup.2, it is
--(W.sup.1).sub.j--R.sup.4. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --O--. In various embodiments of E.sup.2, j is 1,
and W.sup.1 is --NR.sup.7--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --NH--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of E.sup.2, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of E.sup.2, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of E.sup.2, j is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In
various embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0355] In various embodiments when M.sub.1 is a moiety of Formula
I-E1, M.sub.1 is benzoxazolyl substituted with
--(W.sub.2).sub.k--R.sub.2. In some embodiments, M.sub.1 is a
benzoxazolyl moiety, substituted at the 2-position with
--(W.sub.2).sub.k--R.sub.2. In some embodiments, M.sub.1 is either
a 5-benzoxazolyl or a 6-benzoxazolyl moiety, optionally substituted
with --(W.sub.2).sub.k--R.sub.2. Exemplary Formula I-E1 M.sub.1
moieties include but are not limited to the following:
##STR00033##
[0356] In various embodiments when M.sub.1 is a moiety of Formula
I-E2, Formula I-E2 is an aza-substituted benzoxazolyl moiety having
a structure of one of the following formulae:
##STR00034##
[0357] Exemplary Formula I-E2 M.sub.1 moieties include but are not
limited to the following:
##STR00035##
[0358] In various embodiments of M.sub.1, k is 0. In other
embodiments of M.sub.1, k is 1 and W.sup.2 is --O--. In another
embodiment of M.sub.1, k is 1 and W.sup.2 is --NR.sup.7--. In yet
another embodiment of M.sub.1, k is 1 and W.sup.2 is
--S(O).sub.0-2--. In another embodiment of M.sub.1, k is 1 and
W.sup.2 is --C(O)--. In a further embodiment of M.sub.1, k is 1 and
W.sup.2 is --C(O)N(R.sup.7) --. In another embodiment of M.sub.1, k
is 1 and W.sup.2 is --N(R.sup.7)C(O)--. In another embodiment, k is
1 and W.sup.2 is --N(R.sup.7)C(O)N(R.sup.8) --. In yet another
embodiment of M.sub.1, k is 1 and W.sup.2 is --N(R.sup.7)S(O) --.
In still yet another embodiment of M.sub.1, k is 1 and W.sup.2 is
--N(R.sup.7)S(O).sub.2--. In a further embodiment of M.sub.1, k is
1 and W.sup.2 is --C(O)O--. In another embodiment of M.sub.1, k is
1 and W.sup.2 is --CH(R.sup.7)N(C(O)OR.sup.8) --. In another
embodiment of M.sub.1, k is 1 and W.sup.2 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In another embodiment of M.sub.1, k
is 1 and W.sup.2 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In a further
embodiment of M.sub.1, k is 1 and W.sup.2 is
--CH(R.sup.7)N(R.sup.8)--. In another embodiment of M.sub.1, k is 1
and W.sup.2 is --CH(R.sup.7)C(O)N(R.sup.8)--. In yet another
embodiment of M.sub.1, k is 1 and W.sup.2 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In another embodiment of M.sub.1, k
is 1 and W.sup.2 is --CH(R.sup.7)N(R.sup.8)S(O) --. In yet another
embodiment of M.sub.1, k is 1 and W.sup.2 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0359] Additional embodiments of compounds of Formula I, including
I-A, I-B, I-C, I-D, I-E and others are described below.
[0360] In various embodiments of compounds of Formula I, L is
absent. In another embodiment, L is (C.dbd.O)--. In another
embodiment, L is C(.dbd.O)O--. In a further embodiment, L is
--C(.dbd.O)NR.sup.31--. In yet another embodiment, L is --S--. In
one embodiment, L is --S(O)--. In another embodiment, L is
--S(O).sub.2--. In yet another embodiment, L is
--S(O).sub.2NR.sup.31--. In another embodiment, L is
--NR.sup.31--.
[0361] In various embodiments of compounds of Formula I, R.sub.1 is
L-C.sub.1-10alkyl, which is unsubstituted. In another embodiment,
R.sub.1 is L-C.sub.1-10alkyl, which is substituted by one or more
independent R.sup.3. In yet another embodiment, R.sub.1 is
L-unsubstituted C.sub.1-10alkyl, where L is absent. In another
embodiment, R.sub.1 is L-C.sub.1-10alkyl, which is substituted by
one or more independent R.sup.3, and L is absent.
[0362] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.3-8cycloalkyl, which is unsubstituted. In another
embodiment, R.sub.1 is L-C.sub.3-8cycloalkyl, which is substituted
by one or more independent R.sup.3. In yet another embodiment,
R.sub.1 is -L-C.sub.3-8cycloalkyl, which is unsubstituted, and L is
absent. In a further embodiment, R.sub.1 is -L-C.sub.3-8cycloalkyl
which is substituted by one or more independent R.sup.3, and L is
absent.
[0363] In various embodiments of compounds of Formula I, R.sub.1 is
H.
[0364] In various embodiments of compounds of Formula I, R.sub.1 is
-L-aryl, which is unsubstituted. In another embodiment, R.sub.1 is
-L-aryl, which is substituted by one or more independent R.sup.3.
In another embodiment, R.sub.1 is -L-aryl which is unsubstituted,
and L is absent. In yet another embodiment, R.sub.1 is -L-aryl,
which is substituted by one or more independent R.sup.3, and L is
absent.
[0365] In various embodiments of compounds of Formula I, R.sub.1 is
-L-heteroaryl, which is unsubstituted. In another embodiment,
R.sub.1 is -L-heteroaryl, which is substituted by one or more
independent R.sup.3. In a further embodiment, R.sub.1 is
-L-heteroaryl which is unsubstituted and L is absent. In yet
another embodiment, R.sub.1 is -L-heteroaryl, which is substituted
by one or more independent R.sup.3, and L is absent.
[0366] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, which is unsubstituted. In
another embodiment, R.sub.1 is
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, which is substituted by one
or more independent R.sup.3. In a further embodiment, R.sub.1 is
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl which is unsubstituted and L
is absent. In yet another embodiment, R.sub.1 is
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, which is substituted by one
or more independent R.sup.3, and L is absent.
[0367] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.1-10alkylaryl, which is unsubstituted.
[0368] In another embodiment, R.sub.1 is -L-C.sub.1-10alkylaryl,
which is substituted by one or more independent R.sup.3. In a
further embodiment, R.sub.1 is -L-C.sub.1-10alkylaryl which is
unsubstituted and L is absent. In yet another embodiment, R.sub.1
is -L-C.sub.1-10alkylaryl, which is substituted by one or more
independent R.sup.3, where L is absent.
[0369] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.1-10alkylheteroaryl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-C.sub.1-10alkylheteroaryl, which is
substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-C.sub.1-10alkylheteroaryl which is
unsubstituted and L is absent. In yet another embodiment, R.sub.1
is -L-C.sub.1-10alkylheteroaryl, which is substituted by one or
more independent R.sup.3, where L is absent.
[0370] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.1-10alkylheterocyclyl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-C.sub.1-10alkylheterocyclyl, which is
substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-C.sub.1-10alkylheterocyclyl which is
unsubstituted and L is absent. In yet another embodiment, R.sub.1
is -L-C.sub.1-10alkylheterocyclyl, which is substituted by one or
more independent R.sup.3, where L is absent.
[0371] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.2-10alkenyl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-C.sub.2-10alkenyl which is substituted by
one or more independent R.sup.3. In a further embodiment, R.sub.1
is -L-C.sub.2-10alkenyl which is unsubstituted and L is absent. In
yet another embodiment, R.sub.1 is -L-C.sub.2-10alkenyl, which is
substituted by one or more independent R.sup.3, where L is
absent.
[0372] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.2-10alkynyl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-C.sub.2-10alkynyl which is substituted by
one or more independent R.sup.3. In a further embodiment, R.sub.1
is -L-C.sub.2-10alkynyl which is unsubstituted and L is absent. In
yet another embodiment, R.sub.1 is -L-C.sub.2-10alkynyl, which is
substituted by one or more independent R.sup.3, where L is
absent.
[0373] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, which is unsubstituted.
In another embodiment, R.sub.1 is
-L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl which is substituted by
one or more independent R.sup.3. In a further embodiment, R.sub.1
is -L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl which is unsubstituted
and L is absent. In yet another embodiment, R.sub.1 is
-L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, which is substituted by
one or more independent R.sup.3, where L is absent.
[0374] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, which is unsubstituted.
In another embodiment, R.sub.1 is
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl which is substituted by
one or more independent R.sup.3. In a further embodiment, R.sub.1
is -L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl which is unsubstituted
and L is absent. In yet another embodiment, R.sub.1 is
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, which is substituted by
one or more independent R.sup.3, where L is absent.
[0375] In various embodiments of compounds of Formula I, R.sub.1 is
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, which is unsubstituted.
In another embodiment, R.sub.1 is
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl which is substituted by
one or more independent R.sup.3. In a further embodiment, R.sub.1
is -L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl which is unsubstituted
and L is absent. In yet another embodiment, R.sub.1 is
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, which is substituted by
one or more independent R.sup.3, where L is absent.
[0376] In various embodiments of compounds of Formula I, R.sub.1 is
-L-heteroalkyl, which is unsubstituted. In another embodiment,
R.sub.1 is -L-heteroalkyl which is substituted by one or more
independent R.sup.3. In a further embodiment, R.sub.1 is
-L-heteroalkyl which is unsubstituted and L is absent. In yet
another embodiment, R.sub.1 is -L-heteroalkyl, which is substituted
by one or more independent R.sup.3, where L is absent.
[0377] In various embodiments of compounds of Formula I, R.sub.1 is
-L-heteroalkylaryl, which is unsubstituted.
[0378] In another embodiment, R.sub.1 is -L-heteroalkylaryl which
is substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-heteroalkylaryl which is unsubstituted
and L is absent. In yet another embodiment, R.sub.1 is
-L-heteroalkylaryl, which is substituted by one or more independent
R.sup.3, where L is absent.
[0379] In various embodiments of compounds of Formula I, R.sub.1 is
-L-heteroalkylheteroaryl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-heteroalkylheteroaryl, which is
substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-heteroalkylheteroaryl which is
unsubstituted and L is absent. In yet another embodiment, R.sub.1
is -L-heteroalkylheteroaryl, which is substituted by one or more
independent R.sup.3, where L is absent.
[0380] In various embodiments of compounds of Formula, R.sub.1 is
-L-heteroalkyl-heterocyclyl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-heteroalkyl-heterocyclyl, which is
substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-heteroalkyl-heterocyclyl which is
unsubstituted, and L is absent. In yet another embodiment, R.sub.1
is -L-heteroalkyl-heterocyclyl, which is substituted by one or more
independent R.sup.3, where L is absent.
[0381] In various embodiments of compounds of Formula I, R.sub.1 is
-L-heteroalkyl-C.sub.3-8cycloalkyl, which is unsubstituted. In
another embodiment, R.sub.1 is -L-heteroalkyl-C.sub.3-8cycloalkyl,
which is substituted by one or more independent R.sup.3. In a
further embodiment, R.sub.1 is -L-heteroalkyl-C.sub.3-8cycloalkyl
which is unsubstituted and L is absent. In yet another embodiment,
R.sub.1 is -L-heteroalkyl-C.sub.3-8cycloalkyl, which is substituted
by one or more independent R.sup.3, where L is absent.
[0382] In various embodiments of compounds of Formula I, R.sub.1 is
-L-aralkyl, which is unsubstituted. In another embodiment, R.sub.1
is -L-aralkyl, which is substituted by one or more independent
R.sup.3. In a further embodiment, R.sub.1 is -L-aralkyl which is
unsubstituted. In yet another embodiment, R.sub.1 is -L-aralkyl,
which is substituted by one or more independent R.sup.3, where L is
absent.
[0383] In various embodiments of compounds of Formula I, R.sub.1 is
-L-heteroaralkyl, which is unsubstituted. In another embodiment,
R.sub.1 is -L-heteroaralkyl, which is substituted by one or more
independent R.sup.3. In a further embodiment, R.sub.1 is
-L-heteroaralkyl which is unsubstituted and L is absent. In yet
another embodiment, R.sub.1 is -L-heteroaralkyl, which is
substituted by one or more independent R.sup.3, where L is
absent.
[0384] In various embodiments of compounds of Formula I, R.sub.1 is
-L-heterocyclyl, which is unsubstituted. In another embodiment,
R.sub.1 is -L-heterocyclyl, which is substituted by one or more
independent R.sup.3. In a further embodiment, R.sub.1 is
-L-heterocyclyl which is unsubstituted and L is absent. In yet
another embodiment, R.sub.1 is -L-heterocyclyl, which is
substituted by one or more independent R.sup.3, where L is
absent.
[0385] In various embodiments of compounds of Formula I, R.sub.1 is
a substituent as shown below:
##STR00036## ##STR00037## ##STR00038##
[0386] In various embodiments of compounds of Formula I, R.sup.2 is
hydrogen. In another embodiment, R.sup.2 is halogen. In another
embodiment, R.sup.2 is --OH. In another embodiment, R.sup.2 is
--R.sup.31. In another embodiment, R.sup.2 is --CF.sub.3. In
another embodiment, R.sup.2 is --OCF.sub.3. In another embodiment,
R.sup.2 is --OR.sup.31. In another embodiment, R.sup.2 is
--NR.sup.31R.sup.32. In another embodiment, R.sup.2 is
--NR.sup.34R.sup.35. In another embodiment, R.sup.2 is
--C(O)R.sup.31. In another embodiment, R.sup.2 is
--CO.sub.2R.sup.31. In another embodiment, R.sup.2 is
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.2 is
--C(.dbd.O)NR.sup.34R.sup.35. In another embodiment, R.sup.2 is
--NO.sub.2. In another embodiment, R.sup.2 is --CN. In another
embodiment, R.sup.2 is --S(O).sub.0-2R.sup.3. In another
embodiment, R.sup.2 is --SO.sub.2NR.sup.31R.sup.32. In another
embodiment, R.sup.2 is --SO.sub.2NR.sup.34R.sup.35. In another
embodiment, R.sup.2 is --NR.sup.31C(.dbd.O)R.sup.32. In another
embodiment, R.sup.2 is --NR.sup.31C(.dbd.O)OR.sup.32. In another
embodiment, R.sup.2 is --NR.sup.31C(.dbd.O)NR.sup.32R.sup.33. In
another embodiment, R.sup.2 is --NR.sup.31S(O).sub.0-2R.sup.32. In
another embodiment, R.sup.2 is --C(.dbd.S)OR.sup.31. In another
embodiment, R.sup.2 is --C(.dbd.O)SR.sup.31. In another
embodiment,
[0387] R.sup.2 is --NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32. In
another embodiment, R.sup.2 is
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33. In another embodiment,
R.sup.2 is --NR.sup.31C(.dbd.NR.sup.32)SR.sup.33. In another
embodiment, R.sup.2 is --OC(.dbd.O)OR.sup.33. In another
embodiment, R.sup.2 is --OC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, R.sup.2 is --OC(.dbd.O)SR.sup.31. In another
embodiment, R.sup.2 is --SC(.dbd.O)OR.sup.31. In another
embodiment, R.sup.2 is --P(O)OR.sup.31OR.sup.32. In another
embodiment, R.sup.2 is --SC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, R.sup.2 is monocyclic aryl. In another embodiment,
R.sup.2 is bicyclic aryl. In another embodiment, R.sup.2 is
substituted monocyclic aryl. In another embodiment, R.sup.2 is
heteroaryl. In another embodiment, R.sup.2 is C.sub.1-4alkyl. In
another embodiment, R.sup.2 is C.sub.1-10alkyl. In another
embodiment, R.sup.2 is C.sub.3-8cycloalkyl. In another embodiment,
R.sup.2 is C.sub.3-8cycloalkyl-C.sub.1-10alkyl. In another
embodiment, R.sup.2 is C.sub.1-10alkyl-C.sub.3-8cycloalkyl. In
another embodiment, R.sup.2 is C.sub.1-10alkyl-monocyclic aryl. In
another embodiment, R.sup.2 is C.sub.2-10alkyl-monocyclic aryl. In
another embodiment, R.sup.2 is monocyclic aryl-C.sub.2-10alkyl. In
another embodiment, R.sup.2 is C.sub.1-10alkyl-bicyclicaryl. In
another embodiment, R.sup.2 is bicyclicaryl-C.sub.1-10alkyl. In
another embodiment, R.sup.2 is --C.sub.1-10alkylheteroaryl. In
another embodiment, R.sup.2 is --C.sub.1-10alkylheterocyclyl. In
another embodiment, R.sup.2 is --C.sub.2-10alkenyl. In another
embodiment, R.sup.2 is --C.sub.2-10alkynyl. In another embodiment,
R.sup.2 is C.sub.2-10alkenylaryl. In another embodiment, R.sup.2 is
C.sub.2-10alkenylheteroaryl. In another embodiment, R.sup.2 is
C.sub.2-10alkenylheteroalkyl. In another embodiment, R.sup.2 is
C.sub.2-10alkenylheterocyclcyl. In another embodiment, R.sup.2 is
--C.sub.2-10alkynylaryl. In another embodiment, R.sup.2 is
--C.sub.2-10alkynylheteroaryl. In another embodiment, R.sup.2 is
C.sub.2-10alkynylheteroalkyl. In another embodiment, R.sup.2 is
C.sub.2-10alkynylheterocyclyl. In another embodiment, R.sup.2 is
C.sub.2-10alkynylC.sub.3-8cycloalkyl. In another embodiment,
R.sup.2 is C.sub.2-10alkynylC.sub.3-8cycloalkenyl. In another
embodiment, R.sup.2 is C.sub.1-10alkoxy-C.sub.1-10alkyl. In another
embodiment, R.sup.2 is C.sub.1-10alkoxy-C.sub.2-10alkenyl. In
another embodiment, R.sup.2 is C.sub.1-10alkoxy-C.sub.2-10alkynyl.
In another embodiment, R.sup.2 is -heterocyclyl C.sub.1-10alkyl. In
another embodiment, R.sup.2 is heterocyclylC.sub.2-10alkenyl. In
another embodiment, R.sup.2 is heterocyclylC.sub.2-10alkynyl. In
another embodiment, R.sup.2 is arylC.sub.2-10alkyl. In another
embodiment, R.sup.2 is arylC.sub.1-10alkyl. In another embodiment,
R.sup.2 is arylC.sub.2-10alkenyl. In another embodiment, R.sup.2 is
arylC.sub.2-10alkynyl. In another embodiment, R.sup.2 is
aryl-heterocyclyl. In another embodiment, R.sup.2 is heteroaryl
C.sub.1-10alkyl. In another embodiment, R.sup.2 is
heteroarylC.sub.2-10alkenyl. In another embodiment, R.sup.2 is
heteroarylC.sub.2-10alkynyl. In another embodiment, R.sup.2 is
heteroaryl C.sub.3-8cycloalkyl. In another embodiment, R.sup.2 is
heteroaryl heteroalkyl. In another embodiment, R.sup.2 is
heteroaryl-heterocyclyl.
[0388] In various embodiments of compounds of Formula I, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is unsubstituted. In
various embodiments, when R.sup.2 is bicyclic aryl, monocyclic
aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
monocyclic aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent halo. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent --OH. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --R.sup.31. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent --CF.sub.3. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OCF. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent --OR.sup.31. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31R.sup.32. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.34R.sup.35. In another embodiment, when
R.sup.4 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(O)R.sup.31. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --CO.sub.2R.sup.31. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.O)NR.sup.34R.sup.35. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NO.sub.2. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent --CN. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --S(O).sub.0-2R.sup.31. In another embodiment,
when R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SO.sub.2NR.sup.31R.sup.32. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SO.sub.2NR.sup.34R.sup.35. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.O)R.sup.32. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.O)OR.sup.32. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.O)NR.sup.32R.sup.33. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31S(O).sub.0-2R.sup.32. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.S)OR.sup.31. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.O)SR.sup.31. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32. In
another embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent, --NR.sup.31C(.dbd.NR.sup.32)OR.sup.33. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.NR.sup.32)SR.sup.33. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OC(.dbd.O)OR.sup.33. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OC(.dbd.O)SR.sup.31. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SC(.dbd.O)OR.sup.31. In another embodiment, when
R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --P(O)OR.sup.31OR.sup.32. In another embodiment,
when R.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent alkyl. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent heteroalkyl. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent alkenyl. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent alkynyl. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent cycloalkyl. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent heterocycloalkyl. In
another embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent aryl. In another embodiment, when R.sup.2 is
bicyclic aryl, monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, monocyclic aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent arylalkyl. In another
embodiment, when R.sup.2 is bicyclic aryl, monocyclic aryl,
heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent heteroaryl. In another embodiment, when R
.sup.2 is bicyclic aryl, monocyclic aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, monocyclic
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent heteroarylalkyl.
[0389] In various embodiments of compounds of Formula I, R.sup.3 is
hydrogen. In another embodiment, R.sup.3 is halogen. In another
embodiment, R.sup.3 is --OH. In another embodiment, R.sup.3 is
--R.sup.31. In another embodiment, R.sup.3 is --CF.sub.3. In
another embodiment, R.sup.3 is --OCF.sub.3. In another embodiment,
R.sup.3 is --OR.sup.31. In another embodiment, R.sup.3 is
--NR.sup.31R.sup.32. In another embodiment, R.sup.3 is
--NR.sup.34R.sup.35. In another embodiment, R.sup.3 is
--C(O)R.sup.31. In another embodiment, R.sup.3 is
--CO.sub.2R.sup.31. In another embodiment, R.sup.3 is
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.3 is
--C(.dbd.O)NR.sup.34R.sup.35. In another embodiment, R.sup.3 is
--NO.sub.2. In another embodiment, R.sup.3 is --CN. In another
embodiment, R.sup.3 is --S(O).sub.0-2R.sup.31. In another
embodiment, R.sup.3 is --SO.sub.2NR.sup.31R.sup.32. In another
embodiment, R.sup.3 is --SO.sub.2NR.sup.34R.sup.35. In another
embodiment, R.sup.3 is --NR.sup.31C(.dbd.O)R.sup.32. In another
embodiment, R.sup.3 is --NR.sup.31C(.dbd.O)OR.sup.32. In another
embodiment, R.sup.3 is --NR.sup.31C(.dbd.O)NR.sup.32R.sup.33. In
another embodiment, R.sup.3 is --NR.sup.31S(O).sub.0-2R.sup.32. In
another embodiment, R.sup.3 is --C(.dbd.S)OR.sup.31. In another
embodiment, R.sup.3 is --C(.dbd.O)SR.sup.31. In another embodiment,
R.sup.3 is --NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32. In
another embodiment, R.sup.3 is
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33. In another embodiment,
R.sup.3 is --NR.sup.31C(.dbd.NR.sup.32)SR.sup.33. In another
embodiment, R.sup.3 is --OC(.dbd.O)OR.sup.33. In another
embodiment, R.sup.3 is --OC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, R.sup.3 is --OC(.dbd.O)SR.sup.31. In another
embodiment, R.sup.3 is --SC(.dbd.O)OR.sup.31. In another
embodiment, R.sup.3 is --P(O)OR.sup.31OR.sup.32. In another
embodiment, R.sup.3 is --SC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, R.sup.3 is aryl. In another embodiment, R.sup.2 is
heteroaryl. In another embodiment, R.sup.3 is C.sub.1-4alkyl. In
another embodiment, R.sup.3 is C.sub.1-10alkyl. In another
embodiment, R.sup.3 is C.sub.3-8cycloalkyl. In another embodiment,
R.sup.3 is C.sub.3-8cycloalkyl-C.sub.1-10alkyl. In another
embodiment, R.sup.3 is --C.sub.1-10alkyl-C.sub.3-8cycloalkyl. In
another embodiment, R.sup.3 is C.sub.2-10alkyl-monocyclic aryl. In
another embodiment, R.sup.3 is monocyclic aryl-C.sub.2-10alkyl. In
another embodiment, R.sup.3 is C.sub.1-10alkyl-bicyclicaryl. In
another embodiment, R.sup.3 is bicyclicaryl-C.sub.1-10alkyl. In
another embodiment, R.sup.3 is C.sub.1-10alkylheteroaryl. In
another embodiment, R.sup.3 is C.sub.1-10alkylheterocyclyl. In
another embodiment, R.sup.3 is C.sub.2-10alkenyl. In another
embodiment, R.sup.3 is C.sub.2-10alkynyl. In another embodiment,
R.sup.3 is C.sub.2-10alkenylaryl. In another embodiment, R.sup.3 is
C.sub.2-10alkenylheteroaryl. In another embodiment, R.sup.3 is
C.sub.2-10alkenylheteroalkyl. In another embodiment, R.sup.3 is
C.sub.2-10alkenylheterocyclcyl. In another embodiment, R.sup.3 is
--C.sub.2-10alkynylaryl. In another embodiment, R.sup.3 is
--C.sub.2-10alkynylheteroaryl. In another embodiment, R.sup.3 is
--C.sub.2-10alkynylheteroalkyl. In another embodiment, R.sup.3 is
C.sub.2-10alkynylheterocyclyl. In another embodiment, R.sup.3 is
--C.sub.2-10alkynylC.sub.3-8cycloalkyl. In another embodiment,
R.sup.3 is C.sub.2-10alkynylC.sub.3-8cycloalkenyl. In another
embodiment, R.sup.3 is --C.sub.1-10alkoxy-C.sub.1-10alkyl. In
another embodiment, R.sup.3 is C.sub.1-10alkoxy-C.sub.2-10alkenyl.
In another embodiment, R.sup.3 is
--C.sub.1-10alkoxy-C.sub.2-10alkynyl. In another embodiment,
R.sup.3 is heterocyclyl-C.sub.1-10alkyl. In another embodiment,
R.sup.3 is -heterocyclylC.sub.2-10alkenyl. In another embodiment,
R.sup.3 is heterocyclyl-C.sub.2-10alkynyl. In another embodiment,
R.sup.3 is aryl-C.sub.1-10alkyl. In another embodiment, R.sup.3 is
aryl-C.sub.2-10alkenyl. In another embodiment, R.sup.3 is
aryl-C.sub.2-10alkynyl. In another embodiment, R.sup.3 is
aryl-heterocyclyl. In another embodiment, R.sup.3 is
heteroaryl-C.sub.1-10alkyl. In another embodiment, R.sup.3 is
heteroaryl-C.sub.2-10alkenyl. In another embodiment, R.sup.3 is
heteroaryl-C.sub.2-10alkynyl. In another embodiment, R.sup.3 is
heteroaryl-C.sub.3-8cycloalkyl. In another embodiment, R.sup.3 is
heteroaryl heteroalkyl. In another embodiment, R.sup.3 is
heteroaryl-heterocyclyl.
[0390] In various embodiments of compounds of Formula I, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is unsubstituted. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent halo. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --OH. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent R.sup.31. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --CF.sub.3. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --OCF. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent OR.sup.31. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --NR.sup.31R.sup.32. In
another embodiment, when R.sup.3 is aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --NR.sup.34R.sup.35. In another embodiment, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --C(O)R.sup.31. In another embodiment, when R.sup.3 is
aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --CO.sub.2R.sup.31. In another embodiment, when R.sup.3
is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --C(.dbd.O)NR.sup.31R.sup.32. In another embodiment,
when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.O)NR.sup.34R.sup.35. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --NO.sub.2. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --CN. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --S(O).sub.0-2R.sup.31. In
another embodiment, when R.sup.3 is aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --SO.sub.2NR.sup.31R.sup.32. In another embodiment,
when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent
--SO.sub.2NR.sup.34R.sup.35. In another embodiment, when R.sup.3 is
aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent NR.sup.31C(.dbd.O)R.sup.32. In another embodiment,
when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.O)OR.sup.32. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33. In another embodiment, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31S(O).sub.0-2R.sup.32. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent --C(.dbd.S)OR.sup.31. In
another embodiment, when R.sup.3 is aryl, heteroaryl,
C.sub.1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl,
heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.O)SR.sup.31. In another embodiment, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32. In
another embodiment, when R.sup.3 is aryl, heteroaryl,
C.sub.1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl,
heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent, --NR.sup.31C(.dbd.NR.sup.32)OR.sup.33. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33. In another embodiment, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OC(.dbd.O)OR.sup.33. In another embodiment, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, when R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent --OC(.dbd.O)SR.sup.31. In
another embodiment, when R.sup.3 is aryl, heteroaryl,
C.sub.1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl,
heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SC(.dbd.O)OR.sup.31. In another embodiment, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --P(O)OR.sup.31OR.sup.32. In another embodiment, when
R.sup.3 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SC(.dbd.O)NR.sup.31R.sup.32.
[0391] In various embodiments of compounds of Formula I, R.sup.4 is
hydrogen. In another embodiment, R.sup.4 is halogen. In another
embodiment, R.sup.4 is --OH. In another embodiment, R.sup.4 is
--R.sup.31. In another embodiment, R.sup.4 is --CF.sub.3. In
another embodiment, R.sup.4 is --OCF.sub.3. In another embodiment,
R.sup.4 is --OR.sup.31. In another embodiment, R.sup.4 is
--NR.sup.31R.sup.32. In another embodiment, R.sup.4 is
--NR.sup.34R.sup.35. In another embodiment, R.sup.4 is
--C(O)R.sup.31. In another embodiment, R.sup.4 is
--CO.sub.2R.sup.31. In another embodiment, R.sup.4 is
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.4 is
--C(.dbd.O)NR.sup.34R.sup.35. In another embodiment, R.sup.4 is
--NO.sub.2. In another embodiment, R.sup.4 is --CN. In another
embodiment, R.sup.4 is --S(O).sub.0-2R.sup.31. In another
embodiment, R.sup.4 is --SO.sub.2NR.sup.31R.sup.32. In another
embodiment, R.sup.4 is --SO.sub.2NR.sup.34R.sup.35. In another
embodiment, R.sup.4 is --NR.sup.31C(.dbd.O)R.sup.32. In another
embodiment, R.sup.4 is --NR.sup.31C(.dbd.O)OR.sup.32. In another
embodiment, R.sup.4 is --NR.sup.31C(.dbd.O)NR.sup.32R.sup.33. In
another embodiment, R.sup.4 is --NR.sup.31S(O).sub.0-2R.sup.32. In
another embodiment, R.sup.4 is --C(.dbd.S)OR.sup.31. In another
embodiment, R.sup.4 is --C(.dbd.O)SR.sup.31. In another embodiment,
R.sup.4 is --NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32. In
another embodiment, R.sup.4 is
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33. In another embodiment,
R.sup.4 is --NR.sup.31C(.dbd.NR.sup.32)SR.sup.33. In another
embodiment, R.sup.4 is --OC(.dbd.O)OR.sup.33. In another
embodiment, R.sup.4 is --OC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, R.sup.4 is --OC(.dbd.O)SR.sup.31. In another
embodiment, R.sup.4 is --SC(.dbd.O)OR.sup.31. In another
embodiment, R.sup.4 is --P(O)OR.sup.31OR.sup.32. In another
embodiment, R.sup.4 is --SC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, R.sup.4 is aryl. In another embodiment, R.sup.4 is
heteroaryl. In another embodiment, R.sup.4 is C.sub.1-4alkyl. In
another embodiment, R.sup.4 is C.sub.1-10alkyl. In another
embodiment, R.sup.4 is C.sub.3-8cycloalkyl. In another embodiment,
R.sup.4 is C.sub.1-10alkyl-C.sub.3-8cycloalkyl. In another
embodiment, R.sup.4 is C.sub.1-10alkylaryl. In another embodiment,
R.sup.4 is C.sub.1-10alkylheteroaryl. In another embodiment,
R.sup.4 is C.sub.1-10alkylheterocyclyl. In another embodiment,
R.sup.4 is C.sub.2-10alkenyl. In another embodiment, R.sup.4 is
C.sub.2-10alkynyl. In another embodiment, R.sup.4 is
C.sub.2-10alkynyl-C.sub.3-8cycloalkyl. R.sup.4 is
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl. In another embodiment,
R.sup.4 is C.sub.2-10alkenylaryl. In another embodiment, R.sup.4 is
C.sub.2-10alkenyl-heteroaryl. In another embodiment, R.sup.4 is
C.sub.2-10alkenylheteroalkyl. In another embodiment, R.sup.4 is
C.sub.2-10alkenylheterocyclcyl. In another embodiment, R.sup.4 is
--C.sub.2-10alkynylaryl. In another embodiment, R.sup.4 is
C.sub.2-10alkynylheteroaryl. In another embodiment, R.sup.4 is
C.sub.2-10alkynylheteroalkyl. In another embodiment, R.sup.4 is
C.sub.2-10alkynylheterocyclyl. In another embodiment, R.sup.4 is
C.sub.2-10alkynylC.sub.3-8cycloalkyl. In another embodiment,
R.sup.4 is heterocyclyl C.sub.1-10alkyl. In another embodiment,
R.sup.4 is heterocyclylC.sub.2-10alkenyl. In another embodiment,
R.sup.4 is heterocyclyl-C.sub.2-10alkynyl. In another embodiment,
R.sup.4 is aryl-C.sub.1-10alkyl. In another embodiment, R.sup.4 is
arylC.sub.2-10alkenyl. In another embodiment, R.sup.4 is
arylC.sub.2-10alkynyl. In another embodiment, R.sup.4 is
aryl-heterocyclyl. In another embodiment, R.sup.4 is heteroaryl
C.sub.1-10alkyl. In another embodiment, R.sup.4 is
heteroarylC.sub.2-10alkenyl. In another embodiment, R.sup.4 is
heteroarylC.sub.2-10alkynyl. In another embodiment, R.sup.4 is
C.sub.3-8cycloalkyl-C.sub.1-10alkyl. In another embodiment, R.sup.4
is C.sub.3-8cycloalkyl-C.sub.2-10alkenyl. In another embodiment,
R.sup.4 is C.sub.3-8cycloalkyl-C.sub.2-10alkynyl.
[0392] In various embodiments of compounds of Formula I, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is unsubstituted. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent halo. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --OH. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent R.sup.31. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --CF.sub.3. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --OCF. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --OR.sup.31. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --NR.sup.31R.sup.32. In
another embodiment, when R.sup.4 is aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --NR.sup.34R.sup.35. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --C(O)R.sup.31. In another embodiment, when R.sup.4 is
aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --CO.sub.2R.sup.31. In another embodiment, when R.sup.4
is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --C(.dbd.O)NR.sup.31R.sup.32. In another embodiment,
when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.O)NR.sup.34R.sup.35. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --NO.sub.2. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --CN. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl, or heteroalkyl, it is
substituted with one or more independent --S(O).sub.0-2R.sup.31. In
another embodiment, when R.sup.4 is aryl, heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent SO.sub.2NR.sup.31R.sup.32. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --SO.sub.2NR.sup.34R.sup.35. In another embodiment,
when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.O)R.sup.32. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent
--NR.sup.31C(.dbd.O)OR.sup.32. In another embodiment, when R.sup.4
is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl, heterocyclyl,
heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --NR.sup.31C(.dbd.O)NR.sup.32R.sup.33. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent
--NR.sup.31S(O).sub.0-2R.sup.32. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.S)OR.sup.31. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --C(.dbd.O)SR.sup.31. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32. In
another embodiment, when R.sup.4 is aryl, heteroaryl,
C.sub.1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl,
heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent, --NR.sup.31C(.dbd.NR.sup.32)OR.sup.33. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OC(.dbd.O)OR.sup.33. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --OC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, when R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl,
cycloalkyl, heterocyclyl, heteroalkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl, heterocyclyl
C.sub.1-10alkyl, or C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is
substituted with one or more independent --OC(.dbd.O)SR.sup.31. In
another embodiment, when R.sup.4 is aryl, heteroaryl,
C.sub.1-10alkyl, cycloalkyl, heterocyclyl, heteroalkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, aryl-C.sub.2-10alkyl,
heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SC(.dbd.O)OR.sup.31. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, or heteroalkyl, it is substituted with one or more
independent --P(O)OR.sup.31OR.sup.32. In another embodiment, when
R.sup.4 is aryl, heteroaryl, C.sub.1-10alkyl, cycloalkyl,
heterocyclyl, heteroalkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
aryl-C.sub.2-10alkyl, heterocyclyl C.sub.1-10alkyl, or
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, it is substituted with one or
more independent --SC(.dbd.O)NR.sup.31R.sup.32.
[0393] In various embodiments of compounds of Formula I, R.sup.5 is
hydrogen. In another embodiment, R.sup.5 is halogen. In another
embodiment, R.sup.5 is --OH. In another embodiment, R.sup.5 is
--R.sup.31. In another embodiment, R.sup.5 is --CF.sub.3. In
another embodiment, R.sup.5 is --OCF.sub.3. In another embodiment,
R.sup.5 is --OR.sup.31. In another embodiment, R.sup.5 is
--NR.sup.31R.sup.32. In another embodiment, R.sup.5 is
--NR.sup.34R.sup.35. In another embodiment, R.sup.5 is
--C(O)R.sup.31. In another embodiment, R.sup.5 is
--CO.sub.2R.sup.31. In another embodiment, R.sup.5 is
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.5 is
--C(.dbd.O)NR.sup.34R.sup.35. In another embodiment, R.sup.5 is
--NO.sub.2. In another embodiment, R.sup.5 is --CN. In another
embodiment, R.sup.5 is --S(O).sub.0-2R.sup.31. In another
embodiment, R.sup.5 is --SO.sub.2NR.sup.31R.sup.32. In another
embodiment, R.sup.5 is --SO.sub.2NR.sup.34R.sup.35. In another
embodiment, R.sup.5 is --NR.sup.31C(.dbd.O)R.sup.32. In another
embodiment, R.sup.5 is --NR.sup.31C(.dbd.O)OR.sup.32. In another
embodiment, R.sup.5 is --NR.sup.31C(.dbd.O)NR.sup.32R.sup.33. In
another embodiment, R.sup.5 is --NR.sup.31S(O).sub.0-2R.sup.32. In
another embodiment, R.sup.5 is --C(.dbd.S)OR.sup.31. In another
embodiment, R.sup.5 is --C(.dbd.O)SR.sup.31. In another embodiment,
R.sup.5 is --NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32. In
another embodiment, R.sup.5 is
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33. In another embodiment,
R.sup.5 is --NR.sup.31C(.dbd.NR.sup.32)SR.sup.33. In another
embodiment, R.sup.5 is --OC(.dbd.O)OR.sup.33. In another
embodiment, R.sup.5 is --OC(.dbd.O)NR.sup.31R.sup.32. In another
embodiment, R.sup.5 is --OC(.dbd.O)SR.sup.31. In another
embodiment, R.sup.5 is --SC(.dbd.O)OR.sup.31. In another
embodiment, R.sup.5 is --P(O)OR.sup.31OR.sup.32. In another
embodiment, R.sup.5 is or --SC(.dbd.O)NR.sup.31R.sup.32.
[0394] In various embodiments of compounds of Formula I, R.sup.7 is
hydrogen. In another embodiment, R.sup.7 is unsubstituted
C.sub.1-10alkyl. In another embodiment, R.sup.7 is unsubstituted
C.sub.2-10alkenyl. In another embodiment, R.sup.7 is unsubstituted
aryl. In another embodiment, R.sup.7 is unsubstituted heteroaryl.
In another embodiment, R.sup.7 is unsubstituted heterocyclyl. In
another embodiment, R.sup.7 is unsubstituted C.sub.3-10cycloalkyl.
In another embodiment, R.sup.7 is C.sub.1-10alkyl substituted by
one or more independent R.sup.6. In another embodiment, R.sup.7 is
C.sub.2-10alkenyl substituted by one or more independent R.sup.6.
In another embodiment, R.sup.7 is aryl substituted by one or more
independent R.sup.6. In another embodiment, R.sup.7 is heteroaryl
substituted by one or more independent R.sup.6. In another
embodiment, R.sup.7 is heterocyclyl substituted by one or more
independent R.sup.6. In another embodiment, R.sup.7 is
C.sub.3-10cycloalkyl substituted by one or more independent
R.sup.6.
[0395] In various embodiments of compounds of Formula I, R.sup.8 is
hydrogen. In another embodiment, R.sup.8 is unsubstituted
C.sub.1-10alkyl. In another embodiment, R.sup.8 is unsubstituted
C.sub.2-10alkenyl. In another embodiment, R.sup.8 is unsubstituted
aryl. In another embodiment, R.sup.8 is unsubstituted heteroaryl.
In another embodiment, R.sup.8 is unsubstituted heterocyclyl. In
another embodiment, R.sup.8 is unsubstituted C.sub.3-10cycloalkyl.
In another embodiment, R.sup.8 is C.sub.1-10alkyl substituted by
one or more independent R.sup.6. In another embodiment, R.sup.8 is
C.sub.2-10alkenyl substituted by one or more independent R.sup.6.
In another embodiment, R.sup.8 is aryl substituted by one or more
independent R.sup.6. In another embodiment, R.sup.8 is heteroaryl
substituted by one or more independent R.sup.6. In another
embodiment, R.sup.8 is heterocyclyl substituted by one or more
independent R.sup.6. In another embodiment, leis
C.sub.3-10cycloalkyl substituted by one or more independent
R.sup.6.
[0396] In various embodiments of compounds of Formula I, R.sup.6 is
halo, In another embodiment, R.sup.6 is --OR.sup.31. In another
embodiment, R.sup.6 is --SH. In another embodiment, R.sup.6 is
NH.sub.2. In another embodiment, R.sup.6 is --NR.sup.34R.sup.35. In
another embodiment, R.sup.6 is --NR.sup.31R.sup.32. In another
embodiment, R.sup.6 is --CO.sub.2R.sup.31. In another embodiment,
R.sup.6 is --CO.sub.2aryl. In another embodiment, R.sup.6 is
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.6 is
C(.dbd.O)NR.sup.34R.sup.35. In another embodiment, R.sup.6 is
--NO.sub.2. In another embodiment, R.sup.6 is --CN. In another
embodiment, R.sup.6 is --S(O).sub.0-2C.sub.1-10alkyl. In another
embodiment, R.sup.6 is --S(O).sub.0-2aryl. In another embodiment,
R.sup.6 is --SO.sub.2NR.sup.34R.sup.35. In another embodiment,
R.sup.6 is --SO.sub.2NR.sup.31R.sup.32. In another embodiment,
R.sup.6 is C.sub.1-10alkyl. In another embodiment, R.sup.6 is
C.sub.2-10alkenyl. In another embodiment, R.sup.6 is
C.sub.2-10alkynyl. In another embodiment, R.sup.6 is unsubstituted
aryl-C.sub.1-10alkyl. In another embodiment, R.sup.6 is
unsubstituted aryl-C.sub.2-10alkenyl. In another embodiment,
R.sup.6 is unsubstituted aryl-C.sub.2-10alkynyl. In another
embodiment, R.sup.6 is unsubstituted heteroaryl-C.sub.1-10alkyl. In
another embodiment, R.sup.6 is unsubstituted
heteroaryl-C.sub.2-10alkenyl. In another embodiment, R.sup.6 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
halo. In another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent cyano. In another
embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent nitro. In another
embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent --OC.sub.1-10alkyl. In
another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent --C.sub.1-10alkyl. In
another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent --C.sub.2-10alkenyl. In
another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent --C.sub.2-10alkynyl. In
another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent -(halo)C.sub.1-10alkyl. In
another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent -(halo)C.sub.2-10alkenyl. In
another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent -(halo)C.sub.2-10alkynyl. In
another embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent --COOH. In another
embodiment, R.sup.6 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.6 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--C(.dbd.O) NR.sup.34R.sup.35. In another embodiment, R.sup.6 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--SO.sub.2NR.sup.34R.sup.35. In another embodiment, R.sup.6 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--SO.sub.2 NR.sup.31R.sup.32. In another embodiment, R.sup.6 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--NR.sup.31R.sup.32. In another embodiment, R.sup.6 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--NR.sup.34R.sup.35.
[0397] In various embodiments of compounds of Formula I, R.sup.9 is
H. In another embodiment, R.sup.9 is halo. In another embodiment,
R.sup.9 is --OR.sup.31. In another embodiment, R.sup.9 is --SH. In
another embodiment, R.sup.9 is NH.sub.2. In another embodiment,
R.sup.9 is --NR.sup.34R.sup.35. In another embodiment, R.sup.9 is
--NR.sup.31R.sup.32. In another embodiment, R.sup.9 is
--CO.sub.2R.sup.31. In another embodiment, R.sup.9 is
--CO.sub.2aryl. In another embodiment, R.sup.9 is
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.9 is
--C(.dbd.O)NR.sup.34R.sup.35. In another embodiment, R.sup.9 is
--NO.sub.2. In another embodiment, R.sup.9 is --CN. In another
embodiment, R.sup.9 is --S(O).sub.0-2C.sub.1-10alkyl. In another
embodiment, R.sup.9 is --S(O).sub.0-2aryl. In another embodiment,
R.sup.9 is --SO.sub.2NR.sup.34R.sup.35. In another embodiment,
R.sup.9 is --SO.sub.2NR.sup.31R.sup.32. In another embodiment,
R.sup.9 is C.sub.1-10alkyl. In another embodiment, R.sup.9 is
C.sub.2-10alkenyl. In another embodiment, R.sup.9 is
C.sub.2-10alkynyl. In another embodiment, R.sup.9 is unsubstituted
aryl-C.sub.1-10alkyl. In another embodiment, R.sup.9 is
unsubstituted aryl-C.sub.2-10alkenyl. In another embodiment,
R.sup.9 is unsubstituted aryl-C.sub.2-10alkynyl. In another
embodiment, R.sup.9 is unsubstituted heteroaryl-C.sub.1-10alkyl. In
another embodiment, R.sup.9 is unsubstituted
heteroaryl-C.sub.2-10alkenyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
halo. In another embodiment, R.sup.9 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent cyano. In another
embodiment, R.sup.9 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent nitro. In another
embodiment, R.sup.9 is aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--OC.sub.1-10alkyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--C.sub.1-10alkyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--C.sub.2-10alkenyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--C.sub.2-10alkynyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
-(halo)C.sub.1-10alkyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
-(halo)C.sub.2-10alkenyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
-(halo)C.sub.2-10alkynyl. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--COOH. In another embodiment, R.sup.9 is aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl,
heteroaryl-C.sub.1-10alkyl, or heteroaryl-C.sub.2-10alkenyl
substituted by one or more independent
--C(.dbd.O)NR.sup.31R.sup.32. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--C(.dbd.O)NR.sup.34R.sup.35. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--SO.sub.2NR.sup.34R.sup.35. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--SO.sub.2 NR.sup.31R.sup.32. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--NR.sup.31R.sup.32. In another embodiment, R.sup.9 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl, or
heteroaryl-C.sub.2-10alkenyl substituted by one or more independent
--NR.sup.34R.sup.35.
[0398] In various embodiments of compounds of Formula I, R.sup.31
is H. In some embodiments, R.sup.31 is unsubstituted
C.sub.1-10alkyl. In some embodiments, R.sup.31 is substituted
C.sub.1-10alkyl. In some embodiments, R.sup.31 is C.sub.1-10alkyl
substituted with one or more aryl. In some embodiments, R.sup.31 is
C.sub.1-10alkyl substituted with one or more heteroalkyl. In some
embodiments, R.sup.31 is C.sub.1-10alkyl substituted with one or
more heterocyclyl. In some embodiments, R.sup.31 is C.sub.1-10alkyl
substituted with one or more heteroaryl. In some embodiments, when
R.sup.31 is C.sub.1-10alkyl substituted with one or more aryl, each
of said aryl substituents is unsubstituted or substituted with one
or more halo, --OH, --C.sub.1-10alkyl, --CF.sub.3, --O-aryl,
--OCF.sub.3, --OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.31 is C.sub.1-10alkyl substituted with
one or more heteroalkyl, each of said heteroalkyl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35
subtituents. In some embodiments, when R.sup.31 is C.sub.1-10alkyl
substituted with one or more heterocyclyl, each of said
heterocyclyl group is unsubstituted or substituted with one or more
halo, --OH, --C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.31 is C.sub.1-10alkyl substituted with
one or more heteroaryl, each of said heteroaryl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.31 is substituted C.sub.1-10alkyl, it
is substituted by a combination of aryl, heteroalkyl, heterocyclyl,
or heteroaryl groups.
[0399] In various embodiments of compounds of Formula I, R.sup.32
is H. In some embodiments, R.sup.32 is unsubstituted
C.sub.1-10alkyl. In some embodiments, R.sup.32 is substituted
C.sub.1-10alkyl. In some embodiments, R.sup.32 is C.sub.1-10alkyl
substituted with one or more aryl. In some embodiments, R.sup.32 is
C.sub.1-10alkyl substituted with one or more heteroalkyl. In some
embodiments, R.sup.32 is C.sub.1-10alkyl substituted with one or
more heterocyclyl. In some embodiments, R.sup.32 is C.sub.1-10alkyl
substituted with one or more heteroaryl. In some embodiments, when
R.sup.32 is C.sub.1-10alkyl substituted with one or more aryl, each
of said aryl group is unsubstituted or substituted with one or more
halo, --OH, --C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.32 is C.sub.1-10alkyl substituted with
one or more heteroalkyl, each of said heteroalkyl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.32 is C.sub.1-10alkyl substituted with
one or more heterocyclyl, each of said heterocyclyl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.32 is C.sub.1-10alkyl substituted with
one or more heteroaryl, each of said heteroaryl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.32 is substituted C.sub.1-10alkyl, it
is substituted by a combination of aryl, heteroalkyl, heterocyclyl,
or heteroaryl groups.
[0400] In various embodiments of compounds of Formula I, R.sup.33
is unsubstituted C.sub.1-10alkyl. In some embodiments, R.sup.33 is
substituted C.sub.1-10alkyl. In some embodiments, R.sup.33 is
C.sub.1-10alkyl substituted with one or more aryl. In some
embodiments, R.sup.33 is C.sub.1-10alkyl substituted with one or
more heteroalkyl. In some embodiments, R.sup.33 is C.sub.1-10alkyl
substituted with one or more heterocyclyl. In some embodiments,
R.sup.33 is C.sub.1-10alkyl substituted with one or more
heteroaryl. In some embodiments, when R.sup.33 is C.sub.1-10alkyl
substituted with one or more aryl, each of said aryl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.33 is C.sub.1-10alkyl substituted with
one or more heteroalkyl, each of said heteroalkyl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.33 is C.sub.1-10alkyl substituted with
one or more heterocyclyl, each of said heterocyclyl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.33 is C.sub.1-10alkyl substituted with
one or more heteroaryl, each of said heteroaryl group is
unsubstituted or substituted with one or more halo, --OH,
--C.sub.1-10alkyl, --CF.sub.3, --O-aryl, --OCF.sub.3,
--OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35. In
some embodiments, when R.sup.33 is substituted C.sub.1-10alkyl, it
is substituted by a combination of aryl, heteroalkyl, heterocyclyl,
or heteroaryl groups.
[0401] In various embodiments of compounds of Formula I, R.sup.34
and R.sup.35 in --NR.sup.34R.sup.35, --C(.dbd.O)NR.sup.34R.sup.35,
or --SO.sub.2NR.sup.34R.sup.35, are taken together with the
nitrogen atom to which they are attached to form a 3-10 membered
saturated or unsaturated ring; wherein said ring is independently
unsubstituted or is substituted by one or more --NR.sup.31R.sup.32,
hydroxyl, halogen, oxo, aryl, heteroaryl, C.sub.1-6alkyl, or
O-aryl, and wherein said 3-10 membered saturated or unsaturated
ring independently contains 0, 1, or 2 more heteroatoms in addition
to the nitrogen.
[0402] In some embodiments, the R.sup.34 and R.sup.35 in
--NR.sup.34R.sup.35, --C(.dbd.O)NR.sup.34R.sup.35, or
--SO.sub.2NR.sup.34R.sup.35, are taken together with the nitrogen
atom to which they are attached to form:
##STR00039##
[0403] In another embodiment, X.sub.1 is --C--NH.sub.2.
[0404] In various embodiments, X.sub.1 is C--NH--R.sup.4, where
--NH--R.sup.4 is:
##STR00040## ##STR00041##
[0405] In one embodiment, the invention provides an inhibitor of
Formula I-C1 where R.sup.5 is H. In another embodiment, the
invention provides an inhibitor of Formula I-C2 where R.sup.5 is
H.
[0406] In some embodiments, the invention provides an inhibitor of
Formula I-C1a:
##STR00042##
[0407] or a pharmaceutically acceptable salt thereof wherein:
[0408] E.sup.2 is --H;
[0409] X.sub.1 and X.sub.2 are N;
[0410] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocyclyl, or -L-heterocyclyl, each of which
is unsubstituted or is substituted by one or more independent
R.sup.3;
[0411] L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--(C.dbd.O)N(R.sup.31)--, --S--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--;
[0412] R.sup.3 is hydrogen, --OH, --OR.sup.31, --NR.sup.31R.sup.32,
--C(O)R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, aryl, heteroaryl, C.sub.1-4alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, or heterocyclyl, wherein each
of said aryl or heteroaryl moiety is unsubstituted or is
substituted with one or more independent alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --S(O).sub.0-2R.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, or heterocyclyl moiety is unsubstituted or is
substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0413] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0414] R.sup.2 is hydrogen, halogen, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35, bicyclic
aryl, substituted monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl, C.sub.2-10alkyl-monocyclic
aryl, monocyclic aryl-C.sub.2-10alkyl, C.sub.1-10alkylbicycloaryl,
bicycloaryl-C.sub.1-10alkyl, substituted C.sub.1-10alkylaryl,
substituted aryl-C.sub.1-10alkyl, C.sub.1-10alkylheteroaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylheteroaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylheteroaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxyC.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.2-10alkynyl, heterocyclyl, heterocyclyl
C.sub.1-10alkyl, heterocyclylC.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of
said bicyclic aryl or heteroaryl moiety is unsubstituted, or
wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl
moiety is substituted with one or more independent halo, --OH,
--R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0415] R.sup.31, R.sup.32, and R.sup.33, in each instance, are
independently H or C.sub.1-10alkyl, wherein the C.sub.1-10alkyl is
unsubstituted; and
[0416] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, heteroaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen.
[0417] In another aspect, an inhibitor of Formula I-C1 is a
compound of Formula I-C1a:
##STR00043##
[0418] or a pharmaceutically acceptable salt thereof, wherein:
E.sup.2 is --H; X.sub.1 is CH and X.sub.2 is N;
[0419] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocyclyl, or -L-heterocyclyl, each of which
is unsubstituted or is substituted by one or more independent
R.sup.3;
[0420] L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--;
[0421] R.sup.3 is hydrogen, --OH, --OR.sup.31, --NR.sup.31R.sup.32,
--C(O)R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, aryl, heteroaryl, C.sub.1-4alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl, or heterocyclyl, wherein each
of said aryl or heteroaryl moiety is unsubstituted or is
substituted with one or more independent alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, halo, --OH, R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --C(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, or heterocyclyl moiety is unsubstituted or is
substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0422] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0423] R.sup.2 is hydrogen, halogen, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35, bicyclic
aryl, substituted monocyclic aryl, heteroaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl, C.sub.2-10alkyl-monocyclic
aryl, monocyclic aryl-C.sub.2-10alkyl, C.sub.1-10alkylbicycloaryl,
bicycloaryl-C.sub.1-10alkyl, substituted C.sub.1-10alkylaryl,
substituted aryl-C.sub.1-10alkyl, C.sub.1-10alkylheteroaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
heterocyclyl, heterocyclyl C.sub.1-10alkyl,
heterocyclyl-C.sub.2-10alkenyl, heterocyclyl-C.sub.2-10alkynyl,
aryl-heterocyclyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of
said bicyclic aryl or heteroaryl moiety is unsubstituted, or
wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl
moiety is substituted with one or more independent halo, --OH,
--R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0424] R.sup.31, R.sup.32, and R.sup.33, in each instance, are
independently H or C.sub.1-10alkyl, wherein the C.sub.1-10alkyl is
unsubstituted; and
[0425] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, heteroaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen.
[0426] The invention further provides a compound which is an
mTorC1/mTorC2 inhibitor, wherein the compound has the Formula
I-A:
##STR00044##
[0427] or a pharmaceutically acceptable salt thereof, wherein:
[0428] X.sub.1 is N or C-E.sup.1, X.sub.2 is N, X.sub.3 is C, and
X.sub.4 is C--R.sup.9 or N; or X.sub.1 is N or C-E.sup.1, X.sub.2
is C, X.sub.3 is N, and X.sub.4 is C--R.sup.9 or N;
[0429] R.sub.1 is --H, -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkyl, -L-aryl, -L-heteroaryl,
-L-C.sub.1-10alkylaryl, -L-C.sub.1-10alkylheteroaryl,
-L-C.sub.1-10alkylheterocyclyl, -L-C.sub.2-10alkenyl,
-L-C.sub.2-10alkynyl, -L-C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocyclyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0430] L is absent, --(C.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.31)--, --S--, --S(O)--, --S(O).sub.2--,
--S(O).sub.2N(R.sup.31)--, or --N(R.sup.31)--;
[0431] M.sub.1 is benzothiazolyl substituted with
--(W.sup.2).sub.k--R.sup.2;
[0432] k is 0 or 1;
[0433] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0434] j, in each instance (i.e., in E.sup.1 or j in E.sup.2), is
independently 0 or 1
[0435] W.sup.1 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0436] W.sup.2 is --O--, --NR.sup.7--, --S(O).sub.0-2--, --C(O)--,
--C(O)N(R.sup.7)--, --N(R.sup.7)C(O)--,
--N(R.sup.7)C(O)N(R.sup.8)--, --N(R.sup.7)S(O)--,
--N(R.sup.7)S(O).sub.2--, --C(O)O--,
--CH(R.sup.7)N(C(O)OR.sup.8)--, --CH(R.sup.7)N(C(O)R.sup.8)--,
--CH(R.sup.7)N(SO.sub.2R.sup.8)--, --CH(R.sup.7)N(R.sup.8)--,
--CH(R.sup.7)C(O)N(R.sup.8)--, --CH(R.sup.7)N(R.sup.8)C(O)--,
--CH(R.sup.7)N(R.sup.8)S(O)--, or
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--;
[0437] R.sup.2 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl (e.g. bicyclic aryl,
unsubstituted aryl, or substituted monocyclic aryl), heteroaryl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylaryl (e.g.
C.sub.2-10alkyl-monocyclic aryl, C.sub.1-10alkyl-substituted
monocyclic aryl, or C.sub.1-10alkylbicycloaryl),
C.sub.1-10alkylheteroaryl, C.sub.1-10alkylheterocyclyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl (e.g.
monocyclic aryl-C.sub.2-10alkyl, substituted monocyclic
aryl-C.sub.1-10alkyl, or bicycloaryl-C.sub.1-10alkyl),
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of
said bicyclic aryl or heteroaryl moiety is unsubstituted, or
wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl
moiety is substituted with one or more independent alkyl,
heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more alkyl, heteroalkyl, alkenyl,
alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, halo, --OH, --R.sup.31, --CF.sub.3, --OCF.sub.3,
--OR.sup.31, --O-aryl, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.34R.sup.35,
or --C(.dbd.O)NR.sup.31R.sup.32;
[0438] R.sup.3 and R.sup.4 are independently hydrogen, halogen,
--OH, --R.sup.31, --CF.sub.3, --OCF.sub.3, --OR.sup.31,
--NR.sup.31R.sup.32, --NR.sup.34R.sup.35, --C(O)R.sup.31,
--CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, aryl, heteroaryl, C.sub.1-4alkyl,
C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-C.sub.2-10alkynyl, C.sub.1-10alkylheteroaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenyl-C.sub.1-10alkyl,
C.sub.2-10alkynyl-C.sub.1-10alkyl, C.sub.2-10alkenylaryl,
C.sub.2-10alkenylheteroaryl, C.sub.2-10alkenylheteroalkyl,
C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynylaryl,
C.sub.2-10alkynylheteroaryl, C.sub.2-10alkynylheteroalkyl,
C.sub.2-10alkynylheterocyclyl,
C.sub.2-10alkynyl-C.sub.3-8cycloalkenyl, C.sub.1-10alkoxy
C.sub.1-10alkyl, C.sub.1-10alkoxy-C.sub.2-10alkenyl,
C.sub.1-10alkoxy-C.sub.2-10alkynyl, heterocyclyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl,
aryl-C.sub.2-10alkenyl, aryl-C.sub.2-10alkynyl, aryl-heterocyclyl,
heteroaryl-C.sub.1-10alkyl, heteroaryl-C.sub.2-10alkenyl,
heteroaryl-C.sub.2-10alkynyl, heteroaryl-C.sub.3-8cycloalkyl,
heteroalkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl,
wherein each of said aryl or heteroaryl moiety is unsubstituted or
is substituted with one or more independent halo, --OH, --R.sup.31,
--CF.sub.3, --OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35,
--NO.sub.2, --CN, --S(O).sub.0-2R.sup.31,
--SO.sub.2NR.sup.31R.sup.32, --SO.sub.2NR.sup.34R.sup.35,
--NR.sup.31C(.dbd.O)R.sup.32, --NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32, and wherein each of said alkyl,
cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or
is substituted with one or more halo, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --O-aryl, --NR.sup.31R.sup.32,
--NR.sup.34R.sup.35, --C(O)R.sup.31, --CO.sub.2R.sup.31,
--C(.dbd.O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0439] R.sup.5 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.34R.sup.35,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2R.sup.31, --SO.sub.2NR.sup.31R.sup.32,
--SO.sub.2NR.sup.34R.sup.35, --NR.sup.31C(.dbd.O)R.sup.32,
--NR.sup.31C(.dbd.O)OR.sup.32,
--NR.sup.31C(.dbd.O)NR.sup.32R.sup.33,
--NR.sup.31S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)NR.sup.33R.sup.32,
--NR.sup.31C(.dbd.NR.sup.32)OR.sup.33,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.31R.sup.32, --OC(.dbd.O)SR.sup.31,
--SC(.dbd.O)OR.sup.31, --P(O)OR.sup.31OR.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32;
[0440] R.sup.31, R.sup.32, and R.sup.33, in each instance, are
independently H or C.sub.1-10alkyl, wherein the C.sub.1-10alkyl is
unsubstituted or is substituted with one or more aryl, heteroalkyl,
heterocyclyl, or heteroaryl group, wherein each of said aryl,
heteroalkyl, heterocyclyl, or heteroaryl group is unsubstituted or
is substituted with one or more halo, --OH, --C.sub.1-10alkyl,
--CF.sub.3, --O-aryl, --OCF.sub.3, --OC.sub.1-10alkyl, --NH.sub.2,
--N(C.sub.1-10alkyl)(C.sub.1-10alkyl), --NH(C.sub.1-10alkyl),
--NH(aryl), --NR.sup.34R.sup.35, --C(O)(C.sub.1-10alkyl),
--C(O)(C.sub.1-10alkyl-aryl), --C(O)(aryl),
--CO.sub.2--C.sub.1-10alkyl, --CO.sub.2--C.sub.1-10alkylaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(.dbd.O)NR.sup.34R.sup.35,
--C(.dbd.O)NH.sub.2, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10alkylaryl,
--S(O).sub.0-2aryl, --SO.sub.2N(aryl),
--SO.sub.2N(C.sub.1-10alkyl)(C.sub.1-10alkyl),
--SO.sub.2NH(C.sub.1-10alkyl) or --SO.sub.2NR.sup.34R.sup.35;
[0441] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(.dbd.O)NR.sup.34R.sup.35, or --SO.sub.2NR.sup.34R.sup.35, are
taken together with the nitrogen atom to which they are attached to
form a 3-10 membered saturated or unsaturated ring; wherein said
ring is independently unsubstituted or is substituted by one or
more --NR.sup.31R.sup.32, hydroxyl, halogen, oxo, aryl, heteroaryl,
C.sub.1-6alkyl, or O-aryl, and wherein said 3-10 membered saturated
or unsaturated ring independently contains 0, 1, or 2 more
heteroatoms in addition to the nitrogen atom;
[0442] R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, aryl, heteroaryl, heterocyclyl
or C.sub.3-10cycloalkyl, each of which except for hydrogen is
unsubstituted or is substituted by one or more independent
R.sup.6;
[0443] R.sup.6 is halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-C.sub.2-10alkenyl, heteroaryl-C.sub.2-10alkynyl, wherein
each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl,
heterocyclyl, or heteroaryl group is unsubstituted or is
substituted with one or more independent halo, cyano, nitro,
--OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl,
haloC.sub.2-10alkynyl, --COOH, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --SO.sub.2NR.sup.34R.sup.35,
--SO.sub.2 NR.sup.31R.sup.32, --NR.sup.31R.sup.32, or
--NR.sup.34R.sup.35; and
[0444] R.sup.9 is H, halo, --OR.sup.31, --SH, --NH.sub.2,
--NR.sup.34R.sup.35, --NR.sup.31R.sup.32, --CO.sub.2R.sup.31,
--CO.sub.2aryl, --C(.dbd.O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN,
--S(O).sub.0-2C.sub.1-10alkyl, --S(O).sub.0-2aryl,
--SO.sub.2NR.sup.34R.sup.35, --SO.sub.2NR.sup.31R.sup.32,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl;
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, heteroaryl-C.sub.1-10alkyl,
heteroaryl-C.sub.2-10alkenyl, heteroaryl-C.sub.2-10alkynyl, wherein
each of said alkyl, alkenyl, alkynyl, aryl, heteroalkyl,
heterocyclyl, or heteroaryl group is unsubstituted or is
substituted with one or more independent halo, cyano, nitro,
--OC.sub.1-10alkyl, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.2-10alkynyl, haloC.sub.1-10alkyl, haloC.sub.2-10alkenyl,
haloC.sub.2-10alkynyl, --COOH, --C(.dbd.O)NR.sup.31R.sup.32,
--C(.dbd.O)NR.sup.34R.sup.35, --SO.sub.2NR.sup.34R.sup.35,
--SO.sub.2NR.sup.31R.sup.32, --NR.sup.31R.sup.32, or
--NR.sup.34R.sup.35.
[0445] In some embodiments, X.sub.4 is C--R.sup.9.
[0446] The invention also provides an inhibitor as defined above,
wherein the compound is of Formula I-B:
##STR00045##
or a pharmaceutically acceptable salt thereof, and wherein the
substituents are as defined above.
[0447] In various embodiments the compound of Formula I-B or its
pharmaceutically acceptable salt thereof, is an inhibitor having
the structure of Formula I-B1 or Formula I-B2:
##STR00046##
or a pharmaceutically acceptable salt thereof.
[0448] In various embodiments of Formula I-B1, X.sub.1 is N and
X.sub.2 is N. In other embodiments, X.sub.1 is C-E.sup.1 and
X.sub.2 is N. In yet other embodiments, X.sub.1 is NH and X.sub.2
is C. In further embodiments, X.sub.1 is CH-E.sup.1 and X.sub.2 is
C.
[0449] In various embodiments of Formula I-B2, X.sub.1 is N and
X.sub.2 is C. In further embodiments, X.sub.1 is C-E.sup.1
and X.sub.2 is C.
[0450] In various embodiments, X.sub.1 is
C--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0451] In another embodiment, X.sub.1 is CH. In yet another
embodiment, X.sub.1 is C-halogen, where halogen is Cl, F, Br, or
I.
[0452] In various embodiments of X.sub.1, it is C--(W.sup.1),
--R.sup.4. In various embodiments of X.sub.1, j is 1, and W.sup.1
is --O--. In various embodiments of X.sub.1, j is 1, and W.sup.1 is
--NR.sup.7--. In various embodiments of X.sub.1, j is 1, and
W.sup.1 is --NH--. In various embodiments of X.sub.1, j is 1, and
W.sup.1 is --S(O).sub.0-2--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --C(O)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various embodiments of
X.sub.1, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is --N(R.sup.7)S(O)--.
In various embodiments of X.sub.1, j is 1, and W.sup.1 is
--N(R.sup.7)S(O).sub.2--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --C(O)O--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of X.sub.1, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of X.sub.1, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of X.sub.1, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0453] In another embodiment, X.sub.1 is CH.sub.2. In yet another
embodiment, X.sub.1 is CH-halogen, where halogen is Cl, F, Br, or
I.
[0454] In another embodiment, X.sub.1 is N.
[0455] In various embodiments, X.sub.2 is N. In other embodiments,
X.sub.2 is C.
[0456] In various embodiments, E.sup.2 is
--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0457] In another embodiment, E.sup.2 is CH. In yet another
embodiment, E.sup.2 is C-halogen, where halogen is Cl, F, Br, or
I.
[0458] In various embodiments of E.sup.2, it is
--(W.sup.1).sub.j--R.sup.4. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --O--. In various embodiments of E.sup.2, j is 1,
and W.sup.1 is --NR.sup.7--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --NH--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --S(O).sub.0-2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)N(R.sup.7)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is --N(R.sup.7)C(O)--.
In various embodiments of E.sup.2, j is 1, and W.sup.1 is
--N(R.sup.7)S(O)--. In various embodiments of E.sup.2, j is 1, and
W.sup.1 is --N(R.sup.7)S(O).sub.2--. In various embodiments of
E.sup.2, j is 1, and W.sup.1 is --C(O)O--. In various embodiments
of E.sup.2, j is 1, and W.sup.1 is CH(R.sup.7)N(C(O)OR.sup.8)--. In
various embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(C(O)R.sup.8)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(SO.sub.2R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)--. In various embodiments of E.sup.2, j is
1, and W.sup.1 is --CH(R.sup.7)C(O)N(R.sup.8)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)C(O)--. In various embodiments of E.sup.2, j
is 1, and W.sup.1 is --CH(R.sup.7)N(R.sup.8)S(O)--. In various
embodiments of E.sup.2, j is 1, and W.sup.1 is
--CH(R.sup.7)N(R.sup.8)S(O).sub.2--.
[0459] In various embodiments of Formula I-A, I-B, I-B1 and I-B2,
M.sub.1 is:
##STR00047##
[0460] In some embodiments of the invention, M.sub.1 is
benzothiazolyl substituted with --(W.sup.2).sub.k--R.sup.2. W.sup.2
can be --O--, --S(O).sub.0-2-- (including but not limited to S--,
--S(O)--, and S(O).sub.2--), --C(O), or C(O)O--. In other
embodiments, W.sup.1 is --NR.sup.6-- or --CH(R.sup.6)N(R.sup.7)--,
wherein R.sup.6 and R.sup.7 are each independently hydrogen,
unsubstituted or substituted C.sub.1-C.sub.10alkyl (which includes
but is not limited to --CH.sub.3, --CH.sub.2CH.sub.3, n-propyl,
isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and
heptyl), unsubstituted or substituted C.sub.2-C.sub.10alkenyl
(including but not limited to alkenyl such as, for example, vinyl,
allyl, 1-methyl propen-1-yl, butenyl, or pentenyl). Additionally
when W.sup.2 is --NR.sup.6-- or --CH(R.sup.6)N(R.sup.7)--, R.sup.6
and R.sup.7 are each independently unsubstituted or substituted
aryl (including phenyl and naphthtyl). In yet other embodiments,
when W.sup.2 is --NR.sup.6-- or --CH(R.sup.6)N(R.sup.7)--, R.sup.6
and R.sup.7 are each independently heteroaryl, wherein the
heteroaryl is unsubstituted or substituted. R.sup.6 and R.sup.7
heteroaryl is monocyclic heteroaryl, and includes but is not
limited to imidazolyl, pyrrolyl, oxazolyl, thiazolyl, and
pyridinyl. In some other embodiments, when W.sup.2 is --NR.sup.6--
or --CH(R.sup.6)N(R.sup.7)--, R.sup.6 and R.sup.7 are each
independently unsubstituted or substituted heterocyclyl (which
includes but is not limited to pyrrolidinyl, tetrahydrofuranyl,
piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl,
morpholinyl, and piperazinyl) or unsubstituted or substituted
C.sub.3-8cycloalkyl (including but not limited to cyclopropyl,
cyclobutyl, and cyclopentyl). Non limiting exemplary W.sup.2
include --NH--, --N(cyclopropyl), and --N(4-N-piperidinyl).
[0461] For example, exemplary mTorC1/mTorC2 inhibitors of the
invention have the Formulas:
##STR00048##
[0462] In specific embodiments, the compounds for use in the
invention are chosen from the group consisting of:
##STR00049## ##STR00050##
Reaction Schemes--mTorC1/mTorC2 Inhibitor Compounds
[0463] The mTorC1/mTorC2 inhibitor compounds disclosed herein may
be prepared by the routes described below. Materials used herein
are either commercially available or prepared by synthetic methods
generally known in the art. These schemes are not limited to the
compounds listed or by any particular substituents employed for
illustrative purposes. Numbering does not necessarily correspond to
that of claims or other tables.
##STR00051##
[0464] In one embodiment, compounds are synthesized by condensing a
functionalized heterocycle A-1 with formamide, to provide a
pyrazolopyrimidine A-2. The pyrazolopyrimidine is treated with
N-iodosuccinimide, which introduces an iodo substituent in the
pyrazole ring as in A-3. The R.sub.1 substituent is introduced by
reacting the pyrazolopyrimidine A3 with a compound of Formula
R.sub.1-Lg in the presence of a base such as potassium carbonate to
produce a compound of Formula A-4. Other bases that are suitable
for use in this step include but are not limited to sodium hydride
and potassium t-butoxide. The compound of Formula R.sub.1-Lg has a
moiety R.sub.1 as defined for R.sub.1 of a compound of Formula I-A,
and wherein Lg is an appropriate leaving group such as halide
(including bromo, iodo, and chloro), tosylate, or other suitable
leaving group,
[0465] The substituents corresponding to M.sub.1 are thereafter
introduced by reacting aryl or heteroaryl boronic acids with the
compound of Formula A-4 to obtain compound A-5.
##STR00052##
[0466] Alternatively, Mitsunobu chemistry can be used to obtain
alkylated pyrazolopyrimidine A-4, as shown in Scheme A-1.
Iodopyrazolopyrimidine A-3 is reacted with a suitable alcohol, in
the presence of triphenylphosphine and diisopropylazodicarboxylate
(DIAD) to produce pyrazolopyrimidine A-4.
##STR00053##
[0467] The compounds of the invention may be synthesized via a
reaction scheme represented generally in Scheme B. The synthesis
proceeds via coupling a compound of Formula A with a compound of
Formula B to yield a compound of Formula C. The coupling step is
typically catalyzed by using, e.g., a palladium catalyst, including
but not limited to palladium tetrakis (triphenylphosphine). The
coupling is generally performed in the presence of a suitable base,
a nonlimiting example being sodium carbonate. One example of a
suitable solvent for the reaction is aqueous dioxane.
[0468] A compound of Formula A for use in Scheme B has a structure
of Formula A, wherein T.sub.1 is triflate or halo (including bromo,
chloro, and iodo), and wherein R.sub.1, X.sub.1, X.sub.2, X.sub.3,
R.sub.31 and R.sub.32 are defined as for a compound of Formula I-A.
For boronic acids and acid derivatives as depicted in Formula B, M
is either M.sub.1 or M.sub.2. M.sub.1 is defined as for a compound
of Formula I-A. For example, M.sub.1 can be a 5-benzoxazolyl or a
6-benzoxazolyl moiety, including but not limited to those M.sub.1
moieties disclosed herein. M.sub.2 is a moiety which is
synthetically transformed to form M.sub.1, after the M.sub.2 moiety
has been coupled to the bicyclic core of the compound of Formula
A.
[0469] For a compound of Formula B, G is hydrogen or R.sub.G1,
wherein R.sub.G1 is alkyl, alkenyl, or aryl. Alternatively,
B(OG).sub.2 is taken together to form a 5- or 6-membered cyclic
moiety. In some embodiments, the compound of Formula B is a
compound having a structure of Formula E:
##STR00054##
[0470] wherein G is H or R.sub.G1; R.sub.G1 is alkyl, alkenyl, or
aryl. Alternatively,
##STR00055##
forms a 5- or 6-membered cyclic moiety; and R.sub.2 is a R.sub.G2
moiety, wherein the R.sub.G2 moiety is H, acyl, or an amino
protecting group including but not limited to tert-butyl carbamate
(Boc), carbobenzyloxy (Cbz), benzyl (Bz),
fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyl (PMB), and the
like.
##STR00056##
[0471] In some embodiments, a compound of Formula B is a compound
of Formula B', wherein G is R.sub.G1. or a compound of Formula B'',
wherein G is hydrogen. Scheme C depicts an exemplary scheme for
synthesizing a compound of Formula B' or, optionally, Formula B''
for use in Reaction Scheme C. This reaction proceeds via reacting a
compound of Formula D with a trialkyl borate or a boronic acid
derivative to produce a compound of Formula B'. The reaction is
typically run a solvent such as dioxane or tetrahydrofuran. The
trialkyl borate includes but is not limited to triisopropyl borate
and the boronic acid derivative includes but is not limited to
bis(pinacolato)diboron.
[0472] When the reaction is performed with trialkyl borate, a base
such as n-butyllithium is first added to the compound of Formula D
to generate an anion, prior to the addition of the borate. When the
reaction is performed with a boronic acid derivative such as
bis(pinacolato)diboron, a palladium catalyst and a base is used.
Typical palladium catalysts include but is not limited to palladium
chloride (diphenylphosphino)ferrocene). A suitable base includes
but is not limited to potassium acetate.
[0473] A compound of Formula D for use in Scheme C is a compound
wherein T.sub.2 is halo or another leaving group, and M is as
defined above in Scheme B. The compound of Formula B' may further
be converted to a compound of Formula B'' by treatment with an acid
such as hydrochloric acid.
[0474] In one embodiment of a compound of Formula B, B', B'', or E,
the G groups are hydrogen. In another of a compound of Formula B,
B', B'', or E, the G groups are R.sub.G1.
[0475] In some embodiments, no further synthetic transformation of
M.sub.1 moiety is performed after the coupling reaction when, e.g.
M.sub.1 is 2-N-acetyl-benzoxazol-5-yl.
[0476] Some exemplary compounds of Formula B that can be
synthesized via Scheme C include but are not limited to compounds
of the following formulae:
##STR00057## ##STR00058##
[0477] In other embodiments of the invention, a compound of Formula
E is synthesized from a compound of Formula F, as shown in Scheme
C-1:
##STR00059##
[0478] Scheme C-1 depicts an exemplary scheme for synthesizing a
compound of Formula E. This reaction proceeds via reacting a
compound of Formula F with a trialkyl borate or a boronic acid
derivative to produce a compound of Formula E. The conditions of
the reaction are as described above in Scheme C.
[0479] A compound of Formula F for use in Scheme C-1 is a compound
wherein T.sub.2 is halo (including Br, Cl, and I) or another
leaving group (including but not limited to triflate, tosylate, and
mesylate), and the G.sub.p moiety is H, acyl, or an amino
protecting group including but not limited to tert-butyl carbamate
(Boc), carbobenzyloxy (Cbz), benzyl (Bz),
fluorenylmethyloxycarbonyl (FMOC), p-methoxybenzyl (PMB), and the
like.
[0480] The compound of Formula E, wherein G is alkyl, may further
be converted to a compound of Formula E, wherein G is hydrogen, by
treatment with an acid such as hydrochloric acid
[0481] Where desired, deprotection of a substituent (e.g., removal
of Boc protection from an amino substituent) on the benzoxazolyl
moiety (i.e. M.sub.1 of Formula C) is performed after coupling the
compound of Formula B to the compound of Formula A.
[0482] Some exemplary compounds with such protecting groups,
include but are not limited to compounds of the following
formulae:
##STR00060##
[0483] An exemplary transformation of M.sub.2 to M.sub.1 can be
carried out via Scheme D as shown below.
##STR00061##
[0484] In Step 1, a compound of Formula 3-1 is reacted with boronic
acid 3-2, in the presence of palladium tetrakis
(triphenylphosphine) and a suitable base, such as sodium carbonate
in an aqueous/organic solvent mixture to produce a compound of
Formula 3-3. In Step 2, the compound of Formula 3-3 is reacted with
about 2 equivalents of nitric acid in acetic acid as solvent to
produce a compound of Formula 3-4. Two alternative transformations
may be used to effect the next transformation of Step 3. In the
first method, the compound of Formula 3-4 is treated with sodium
dithionite and sodium hydroxide in water to produce a compound of
Formula 3-5. Alternatively, the compound of Formula 3-4 is reduced
using palladium on carbon in a suitable solvent under a hydrogen
atmosphere to yield a compound of Formula 3-5.
[0485] In Step 4, compound 3-5 is reacted with about 1.2
equivalents of cyanogen bromide in a solvent such as
methanol/tetrahydrofuran mixture to produce a compound of Formula
3-6. The compound of Formula 3-6 may be further transformed by
other substitution or derivatization.
[0486] A compound of Formula 3-1 useful in the method of Scheme D
is a compound having a structure of Formula 3-1, wherein T.sub.1 is
triflate or halo (including bromo, chloro, and iodo), and wherein
R.sub.1, X.sub.1, X.sub.2, X.sub.3, R.sub.31 and R.sub.32 are
defined as for a compound of Formula I-A.
[0487] Exemplary compounds having a pyrazolopyrimidine core can be
synthesized via Scheme E.
##STR00062##
[0488] In Step 1 of Scheme E, compound A-2 in dimethylformamide
(DMF), is reacted with an N-halosuccinimide (NT.sub.1S) at about
80.degree. C., to provide compound 4-1, where T.sub.1 is iodo or
bromo. In Step 2, compound 4-1 in DMF is reacted with a compound
R.sub.1T.sub.x, in the presence of potassium carbonate, to provide
compound 4-2. In Step 4, compound 4-2 is coupled with a compound of
Formula B using palladium catalysis such as palladium tetrakis
(triphenylphosphine), and in the presence of sodium carbonate, to
yield a pyrazolopyrimidine compound as shown.
[0489] A compound of Formula R.sub.1T.sub.x suitable for use in
Reaction Scheme E is the compound wherein R.sub.1 is cycloalkyl or
alkyl and T.sub.x is halo (including bromo, iodo, or chloro) or a
leaving group, including but not limited to mesylate or
tosylate.
[0490] Reaction Schemes F-M illustrate methods of synthesis of
borane reagents useful in preparing intermediates of use in
synthesis of the compounds of the invention as described in
Reaction Schemes A, B, and E above, to introduce M.sub.1
substituents.
##STR00063##
##STR00064##
##STR00065##
##STR00066##
##STR00067##
##STR00068##
##STR00069##
##STR00070##
##STR00071##
[0491] In an alternative method of synthesis, a compound of Formula
N-1 and a compound of N-2 are coupled to produce a compound of
Formula C. The coupling step is typically catalyzed by using, e.g.,
a palladium catalyst, including but not limited to palladium
tetrakis (triphenylphosphine). The coupling is generally performed
in the presence of a suitable base, a nonlimiting example being
sodium carbonate. One example of a suitable solvent for the
reaction is aqueous dioxane.
[0492] A compound of Formula N-1 for use in Scheme N has a
structure of Formula N-1, wherein G is hydrogen or R.sub.G1,
wherein R.sub.G1 is alkyl, alkenyl, or aryl. Alternatively,
B(OG).sub.2 of the compound of Formula N-1 is taken together to
form a 5- or 6-membered cyclic moiety. R.sub.1, X.sub.1, X.sub.2,
X.sub.3, R.sub.31 and R.sub.32 of the compound of Formula N-1 are
defined as for a compound of Formula I-A.
[0493] A compound of Formula N-2 for use in Scheme N has a
structure of Formula N-2 wherein T.sub.1 is triflate or halo
(including bromo, chloro, and iodo). M of the compound of Formula
N-2 is either M.sub.1 or M.sub.2. M.sub.1 is defined as for a
compound of Formula I For example, M.sub.1 can be a 5-benzoxazolyl
or a 6-benzoxazolyl moiety, including but not limited to those
M.sub.1 moieties disclosed herein. M.sub.2 is a moiety which is
synthetically transformed to form M.sub.1, after the M.sub.2 moiety
has been coupled to the bicyclic core of the compound of Formula
N-1.
##STR00072##
[0494] A compound of Formula N-1 may be synthesized as shown in
Scheme N-1. A compound of Formula N-1 is reacted with a trialkyl
borate or a boronic acid derivative to produce a compound of
Formula N-1. The reaction is typically run a solvent such as
dioxane or tetrahydrofuran. The trialkyl borate includes but is not
limited to triisopropyl borate and the boronic acid derivative
includes but is not limited to bis(pinacolato)diboron.
[0495] When the reaction is performed with trialkyl borate, a base
such as n-butyllithium is first added to the compound of Formula
N-3 to generate an anion, prior to the addition of the borate. When
the reaction is performed with a boronic acid derivative such as
bis(pinacolato)diboron, a palladium catalyst and a base is used.
Typical palladium catalysts include but is not limited to palladium
chloride (diphenylphosphino)ferrocene). A suitable base includes
but is not limited to potassium acetate.
[0496] A compound of Formula N-3 suitable for use in Scheme N-1 is
a compound wherein T.sub.2 is halo or another leaving group such as
mesylate, tosylate, or triflate. X.sub.1, X.sub.2, X.sub.3,
R.sub.1, R.sub.31, and R.sub.32 of the compound of Formula N-3 is
as defined for a compound of Formula I-A.
[0497] In some embodiments of the invention, a compound of Formula
A, B, B', B'', C, C'', D, E, E'', 3-1,3-2, 3-3,3-4, 3-5, 3-6,
N-1'', N-3'', 3-1'', 3-3'', 3-4'', 3-5'', 3-6'', N-1'', or N-3'' is
provided as its salt, including but not limited to hydrochloride,
acetate, formate, nitrate, sulfate, and boronate.
[0498] In some embodiments of the invention, a palladium compound,
including but not limited to palladium chloride
(diphenylphosphino)ferrocene) and palladium tetrakis
(triphenylphosphine), is used in the synthesis of a compound of
Formula A, B, B', B'', C, C'', D, E, E'', 3-1,3-2, 3-3,3-4, 3-5,
3-6, N-1'', N-3'', 3-1'', 3-3'', 3-4'', 3-5'', 3-6'', N-1'', or
N-3''. When a palladium compound is present in the synthesis of a
compound of Formula A, B, B', B'', C, C'', D, E, E'', 3-1,3-2,
3-3,3-4, 3-5, 3-6, N-1'', N-3'', 3-1'', 3-3'', 3-4'', 3-5'', 3-6'',
N-1'', or N-3'', it is present in an amount ranging from about
0.005 molar equivalents to about 0.5 molar equivalents, from about
0.05 molar equivalents to about 0.20 molar equivalents, from about
0.05 molar equivalents to about 0.25 molar equivalents, from about
0.07 molar equivalents to about 0.15 molar equivalents, or about
0.8 molar equivalents to about 0.1 molar equivalents of the
compound of Formula A, B, B', B'', C, D, E, 3-1,3-2, 3-3,3-4, 3-5,
3-6, N-1, or N-3. In some embodiments, a palladium compound,
including but not limited to palladium chloride
(diphenylphosphino)ferrocene) and palladium tetrakis
(triphenylphosphine) is present in the synthesis of a compound of
Formula A, B, B', B'', C, C'', D, E, E'', 3-1,3-2, 3-3,3-4, 3-5,
3-6, N-1'', N-3'', 3-1'', 3-3'', 3-4'', 3-5'', 3-6'', N-1'', or
N-3'' in about 0.07, about 0.08, about 0.09, about 0.10, about
0.11, about 0.12, about 0.13, about 0.14, or about 0.15 molar
equivalents of a starting material of Formula A, B, B', B'', C,
C'', D, E, E'', 3-1,3-2, 3-3,3-4, 3-5, 3-6, N-1'', N-3'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1'', or N-3'' that is used to
synthesize a compound of Formula A, B, B', B'', C, C'', D, E, E'',
3-1,3-2, 3-3,3-4, 3-5, 3-6, N-1'', N-3'', 3-1'', 3-3'', 3-4'',
3-5'', 3-6'', N-1'', or N-3''.
[0499] In some embodiments of the above reaction schemes B, D, E, N
or N-1, another embodiment of the compounds of Formula A, C,
3-1,3-3, 3-4,3-5, 3-6, A-2,4-1, 4-2, N-1 and N-3 is as shown in
Schemes B'. D'. E', N' or N-1' below. In these alternative
syntheses, producing a compound of Formula C, 3-1,3-3, 3-4,3-5,
3-6, A-2,4-1, 4-2, N-1 or N-3, use compounds that comprise an amino
moiety having a R.sub.G2 moiety present during one or more of the
synthetic steps, wherein R.sub.G2 is an amino protecting group
including but not limited to tert-butyl carbamate (Boc),
carbobenzyloxy (Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl
(FMOC), p-methoxybenzyl (PMB), and the like. These compounds
include a compound of Formula A'', C'', 3-1'', 3-3'', 3-4'', 3-5'',
3-6'', A-2'', 4-1'', 4-2'', N-1'' or N-3''.
[0500] The R.sub.G2 moiety is removed, using suitable methods, at
any point desired, whereupon the compound of Formula C, 3-1,3-3,
3-4,3-5, 3-6, A-2,4-1, 4-2, N-1 or N-3 has a R.sub.31 hydrogen
replacing the R.sub.G2 moiety on the amino moiety. This
transformation is specifically illustrated for the conversion of a
compound of Formula C'' to a compound of C (i.e., as in Step 4 of
Scheme E') and for the conversion of a compound of Formula 3-6'' to
a compound of Formula 3-6 (i.e., as in Step 5 of Scheme D'). This
illustration is in no way limiting as to the choice of steps
wherein a compound comprising a NR.sub.31R.sub.G2 moiety may be
converted to a compound comprising a NR.sub.31R.sub.32 moiety
wherein the R.sub.32 moiety is hydrogen.
##STR00073##
##STR00074## ##STR00075##
##STR00076##
##STR00077##
[0501] Additionally, the invention encompasses methods of synthesis
of the compounds of A, B, B', B'', C, E, 3-1,3-2, 3-3,3-4, 3-5,
3-6, N-1 or N-3, wherein one or more of M, M.sub.1, or R.sub.1 has
a protecting group present during one or more steps of the
synthesis. Protecting groups suitable for use for a M, M.sub.1, or
R.sub.1 moiety are well known in the art, as well as the methods of
incorporation and removal, and the reagents suitable for such
transformations.
[0502] Compounds of the invention where X.sub.4 is C--R.sup.9 may
be prepared by methods analogous to the ones described in the
Schemes illustrated above.
Reaction Schemes O, P and Q illustrate methods of synthesis of
borane reagents useful in preparing intermediates of use in
synthesis of the compounds of the invention as described in
Reaction Schemes 1 and 2 above, to introduce benzothiazolyl
substituents.
##STR00078##
A compound of Formula O-1 is treated with, for example, nitric acid
to produce a compound of Formula O-2. The compound of Formula O-2
is treated with a reducing agent such as stannous chloride to
produce a compound of Formula O-3. The compound of O-3 is treated
with sodium nitrate in acide and cupric bromide to produce a
compound of Formula O-4. The compound of O-4 is treated a base such
as butyl lithium and boron tris-isopropoxide to produce a compound
of Formula O-5.
##STR00079##
A compound of Formula P-1 is treated with, for example, potassium
thiocyanate and bromine in acetic acid to produce a compound of
Formula P-2. The compound of Formula P-2 is treated with an
acetylating reagent such as acetyl chloride to produce a compound
of Formula P-3. The compound of P-3 is reacted with, for example,
bis(pinacolato)diboron (compound P-4) in the presence of a catalyst
such as palladium chloride to produce a compound of Formula
P-5.
##STR00080##
[0503] The compound of Formula P-2 is reacted with, for example,
methyl carbamic acid chloride to produce a compound of Formula Q-1.
The compound of Formula Q-1 is reacted with bis(pinacolato)diboron
(compound P-4) in the presence of a catalyst such as
Pd.sub.2(dba).sub.3,
2-chlorohexylphosphino-2,4,6-triisopropylbiphenyl, a base suchy as
potassium acetate, to produce the compound of Formula Q-2.
[0504] Some illustrative compounds of the invention which are
mTorC1/mTorC2 inhibitors are described below. The compounds of the
invention are not limited in any way to the compounds illustrated
herein.
##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085##
##STR00086## ##STR00087##
[0505] Illustrative compounds of the invention include those of
subclass 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b,
8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b,
15a, 15b, 16a, or 16b, where the substituents R.sub.1, X.sub.1, and
V are as described below.
[0506] In some embodiments, when R.sub.1 is H and X.sub.1 is CH, V
is phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH,
NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other
embodiments, when R.sub.1 is H and X.sub.1 is N, V is phenylamino,
benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt,
NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other embodiments,
when R.sub.1 is CH.sub.3 and X.sub.1 is CH, V is phenylamino,
benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt,
NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other embodiments,
when R.sub.1 is CH.sub.3 and X.sub.1 is N, V is phenylamino,
benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt,
NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other embodiments,
when R.sub.1 is Et and X.sub.1 is CH, V is phenylamino, benzyl,
phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr,
NHCOOMe, CONHMe, or NHSO.sub.2Me. In other embodiments, when
R.sub.1 is Et and X.sub.1 is N, V is phenylamino, benzyl, phenyl,
NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe,
CONHMe, or NHSO.sub.2Me. In other embodiments, when R.sub.1 is iPr
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is iPr and X.sub.1
is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt,
NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me.
In one embodiment, R.sub.1 is iPr, X.sub.1 is N, and V is NH.sub.2.
In another embodiment, R.sub.1 is iPr, X.sub.1 is N, and V is
NHCOMe. In other embodiments, when R.sub.1 is cyclobutyl and
X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is cyclobutyl and
X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is cyclopentyl and
X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is cyclopentyl and
X.sub.1 is N V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is phenyl and
X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is phenyl and
X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is pyridin-2-yl
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is pyridin-2-yl
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
N-methylaminocyclohex-4-yl and X.sub.1 is CH, V is phenylamino,
benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt,
NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other embodiments,
when R.sub.1 is N-methylaminocyclohex-4-yl and X.sub.1 is N, V is
phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe,
NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other
embodiments, when R.sub.1 is N-methylpiperidin-4-yl and X.sub.1 is
CH, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH,
NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other
embodiments, when R.sub.1 is N-methylpiperidin-4-yl and X.sub.1 is
N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH,
NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other
embodiments, when R.sub.1 is N-methylaminocyclobut-3-yl and X.sub.1
is CH, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt,
NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me.
In other embodiments, when R.sub.1 is N-methylaminocyclobut-3-yl
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is tert-butyl and
X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is tert-butyl and
X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
1-cyano-but-4-yl and X.sub.1 is CH, V is phenylamino, benzyl,
phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr,
NHCOOMe, CONHMe, or NHSO.sub.2Me. In other embodiments, when
R.sub.1 is 1-cyano-but-4-yl and X.sub.1 is N, V is phenylamino,
benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt,
NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other embodiments,
when R.sub.1 is 1-cyano-prop-3-yl and X.sub.1 is CH, V is
phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe,
NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other
embodiments, when R.sub.1 is 1-cyano-prop-3-yl and X.sub.1 is N, V
is phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH,
NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other
embodiments, when R.sub.1 is 3-azetidinyl and X.sub.1 is CH, V is
phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe,
NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me. In other
embodiments, when R.sub.1 is 3-azetidinyl and X.sub.1 is N, V is
phenylamino, benzyl, phenyl, NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe,
NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or NHSO.sub.2Me.
[0507] In other embodiments, when R.sub.1 is
##STR00088##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00089##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00090##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00091##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00092##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00093##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00094##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00095##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00096##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00097##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00098##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00099##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00100##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00101##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00102##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00103##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00104##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00105##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00106##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00107##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00108##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00109##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00110##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00111##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00112##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00113##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00114##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00115##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00116##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00117##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00118##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00119##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00120##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00121##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00122##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00123##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00124##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00125##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00126##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00127##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00128##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00129##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00130##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00131##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00132##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00133##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00134##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00135##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00136##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00137##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00138##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00139##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00140##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00141##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00142##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00143##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00144##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00145##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00146##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00147##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00148##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00149##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00150##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00151##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00152##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00153##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00154##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00155##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00156##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00157##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00158##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00159##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00160##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00161##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00162##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00163##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00164##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00165##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00166##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00167##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00168##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00169##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me.
[0508] In other embodiments, when R.sub.1 is
##STR00170##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00171##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00172##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00173##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00174##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00175##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00176##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00177##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00178##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00179##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00180##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00181##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00182##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00183##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. and X.sub.1 is CH, V is phenylamino, benzyl, phenyl,
NHMe, NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe,
CONHMe, or NHSO.sub.2Me.
[0509] In other embodiments, when R.sub.1 is
##STR00184##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00185##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00186##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00187##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00188##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00189##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00190##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00191##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00192##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00193##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00194##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00195##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00196##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00197##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00198##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00199##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00200##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00201##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00202##
and X.sub.1 is CH, V is phenylamino, benzyl, phenyl, NHMe,
NH.sub.2, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00203##
and X.sub.1 is N, V is phenylamino, benzyl, phenyl, NHMe, NH.sub.2,
NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me.
[0510] In the noted embodiments, pyridin-2-yl is
##STR00204##
N-methylaminocyclohex-4-yl is
##STR00205##
[0511] N-methylpiperidin-4-yl is
##STR00206##
[0512] and N-methylaminocyclobut-3-yl is
##STR00207##
[0514] Illustrative compounds of the invention include those of
subclass 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b,
8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b,
15a, 15b, 16a, or 16b, where the substituents R.sub.1, X.sub.1, and
V are as described below. In some embodiments, when R.sub.1 is
H
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is H and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In some embodiments, when
R.sub.1 is CH.sub.3 and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is CH.sub.3 and X.sub.1 is N, V is cyclopropanecarboxamido,
cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or
N-morpholino. In some embodiments, when R.sub.1 is Et and X.sub.1
is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is Et and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In some embodiments, when
R.sub.1 is iPr and X.sub.1 is CH, V is cyclopropanecarboxamido,
cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or
N-morpholino. In other embodiments, when R.sub.1 is iPr and X.sub.1
is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some
embodiments, when R.sub.1 is cyclobutyl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is cyclobutyl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In some embodiments, when
R.sub.1 is cyclopentyl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is cyclopentyl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In some embodiments, when
R.sub.1 is phenyl and X.sub.1 is CH, V is cyclopropanecarboxamido,
cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or
N-morpholino. In other embodiments, when R.sub.1 is phenyl and
X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In some
embodiments, when R.sub.1 is pyridin-2-yl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is pyridin-2-yl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In some embodiments, when
R.sub.1 is N-methylaminocyclohex-4-yl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is N-methylaminocyclohex-4-yl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In some embodiments, when
R.sub.1 is N-methylpiperidin-4-yl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is N-methylpiperidin-4-yl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In some embodiments, when
R.sub.1 is N-methylaminocyclobut-3-yl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is N-methylaminocyclobut-3-yl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is tert-butyl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is tert-butyl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is 1-cyano-but-4-yl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is 1-cyano-but-4-yl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is 1-cyano-prop-3-yl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is 1-cyano-prop-3-yl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is 3-azetidinyl and X.sub.1 is CH, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is 3-azetidinyl and X.sub.1 is N, V is
cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino,
hydroxyethylamino, or N-morpholino. In other embodiments, when
R.sub.1 is
##STR00208##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00209##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00210##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00211##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00212##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00213##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00214##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00215##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00216##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00217##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00218##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00219##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00220##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00221##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00222##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00223##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00224##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00225##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00226##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00227##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00228##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00229##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00230##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00231##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00232##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00233##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00234##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00235##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00236##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00237##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00238##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00239##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00240##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00241##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00242##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00243##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00244##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00245##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00246##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00247##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00248##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00249##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00250##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00251##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00252##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00253##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00254##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00255##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00256##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00257##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00258##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00259##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00260##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00261##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00262##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00263##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00264##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00265##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00266##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00267##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00268##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00269##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00270##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00271##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00272##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00273##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00274##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00275##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00276##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00277##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00278##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00279##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00280##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00281##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00282##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00283##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00284##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00285##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00286##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00287##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00288##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00289##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino.
[0515] In other embodiments, when R.sub.1 is
##STR00290##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00291##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00292##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00293##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00294##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00295##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00296##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00297##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00298##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00299##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00300##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00301##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino In other
embodiments, when R.sub.1 is
##STR00302##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00303##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. and
X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino.
[0516] In other embodiments, when R.sub.1 is
##STR00304##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00305##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00306##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00307##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00308##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00309##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00310##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00311##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00312##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00313##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00314##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00315##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00316##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00317##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00318##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00319##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00320##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00321##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00322##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00323##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino.
[0517] In the noted embodiments, cyclopropanecarboxamido is
cyclopropylamino is
##STR00324##
cyclopropylamino is
##STR00325##
morpholinoethylamino is
##STR00326##
hydroxyethylamino is
##STR00327##
and N-morpholino is
##STR00328##
TABLE-US-00001 [0518] TABLE 1 Biological activity of several
illustrative mTorC1/mTorC2 inhibitor compounds of the invention.
mTOR PI3K .alpha. PI3K .beta. PI3K .gamma. PI3K .delta. PC3
Structure IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50
(nM) IC.sub.50 (nM) EC50 (nM) 1 ##STR00329## ++++ +++ ++ ++++ +++
++++ 2 ##STR00330## ++++ ++ + +++ +++ +++ 3 ##STR00331## ++ + ++ ++
++ 4 ##STR00332## +++ ++ ++ +++ +++ ++ 5 ##STR00333## ++++ +++ ++
++++ +++ ++++ 6 ##STR00334## ++++ ++ + ++ +++ +++ 7 ##STR00335##
++++ +++ ++ ++ +++ ++ 8 ##STR00336## ++++ +++ + +++ +++ ++++ 9
##STR00337## ++++ ++ + +++ +++ ++++ 10 ##STR00338## ++ + 11
##STR00339## +++ + 12 ##STR00340## +++ + 13 ##STR00341## ++ ++ +++
+++ 14 ##STR00342## ++ ++ +++ ++ 15 ##STR00343## + + + + 16
##STR00344## + + ++ + 17 ##STR00345## + + + + 18 ##STR00346## + + +
+ 19 ##STR00347## ++ + + + 20 ##STR00348## ++ ++ + ++ 21
##STR00349## +++ + + + + 22 ##STR00350## ++++ ++++ ++ +++ +++ ++ 23
##STR00351## ++++ ++ + ++ ++ 24 ##STR00352## + + + + 25
##STR00353## +++ ++ ++++ +++ 26 ##STR00354## ++++ +++ ++++ +++ 27
##STR00355## ++ + + +++
[0519] Table 1 shows the biological activity in mTOR and PI3K
kinase assays of several compounds of the invention. The scale
utilized in Table 1 is as follows: ++++ less than 100 nM; +++ less
than 1.0 .mu.M; ++ less than 10 .mu.M; and +greater than 10
.mu.M.
[0520] In other embodiments, the present invention provides the
following compounds:
##STR00356## ##STR00357## ##STR00358##
[0521] Any of the compounds shown above may show a biological
activity in an mTOR or PI3K inhibition assay of between about 0.5
nM and 25 .mu.M (IC.sub.50).
[0522] Additional compounds which are mTorC1/mTorC2 inhibitors of
the invention are shown in Table 2.
TABLE-US-00002 TABLE 2 In vitro IC.sub.50 values for Illustrative
mTor Inhibitor Compounds of the Invention. PC3 mTORC PI3K .alpha.
PI3K .beta. PI3K .gamma. PI3K .delta. prolifera- # Structure
IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM)
IC.sub.50 (nM) tion (nM) 1 ##STR00359## ++++ + + ++ ++ +++ 2
##STR00360## + - - - - - 3 ##STR00361## ++ + - - - - 4 ##STR00362##
+ + - 5 ##STR00363## + + + 6 ##STR00364## + + + 7 ##STR00365## +++
+ + 8 ##STR00366## + + + 9 ##STR00367## ++++ + + 10 ##STR00368##
+++++ + + + + + 11 ##STR00369## +++++++ + + ++ ++ ++++ 12
##STR00370## ++++++ + + ++ + ++++ 13 ##STR00371## + + + 14
##STR00372## + + - 15 ##STR00373## +++++++ + + ++++ ++++ ++++ 16
##STR00374## +++++++ + + ++ +++ ++ 17 ##STR00375## + + + 18
##STR00376## + * * 19 ##STR00377## + + - 20 ##STR00378## + + - 21
##STR00379## ++++ ++ + ++ ++ + 22 ##STR00380## +++++++ + + - + ++
23 ##STR00381## + + - 24 ##STR00382## + + + 25 ##STR00383## ++ + +
26 ##STR00384## ++++++ + + ++ +++ ++ 27 ##STR00385## +++++ ++ 28
##STR00386## ++ + + - + + 29 ##STR00387## + - 30 ##STR00388## +++++
+ + - + + 31 ##STR00389## +++++ + + - ++ + 32 ##STR00390## ++ + - +
+ + 33 ##STR00391## ++ + - + + + 34 ##STR00392## + + - + + - 35
##STR00393## + + - + + - 36 ##STR00394## ++++++ + - +++ ++ +++ 37
##STR00395## + ++ - ++ ++ - 38 ##STR00396## ++ + - + + + 39
##STR00397## ++++++ + - + + + 40 ##STR00398## +++ + - + + + 41
##STR00399## ++++++ + + ++++ + + 42 ##STR00400## +++++++ + + - +++
+ 43 ##STR00401## + + + - + - 44 ##STR00402## +++ + + - + - 45
##STR00403## + 46 ##STR00404## - 47 ##STR00405## - 48 ##STR00406##
++++ + + + + 49 ##STR00407## ++++++ + + ++ ++ 50 ##STR00408## ++++
+ + ++ ++ 51 ##STR00409## ++++ + + ++ ++ 52 ##STR00410## ++ + + +
++ 53 ##STR00411## +++ + + + - 54 ##STR00412## +++++ + + + - 55
##STR00413## ++ + + + - 56 ##STR00414## + + + + - 57 ##STR00415##
+++++ + + + - 58 ##STR00416## + + + + - 59 ##STR00417## + + + + -
60 ##STR00418## +++ + + +++ - 61 ##STR00419## +++++ + + + + 62
##STR00420## +++++++ + + + +++ 63 ##STR00421## +++++++ ++ + +++++
+++++ 64 ##STR00422## +++++ + + ++ ++ 65 ##STR00423## ++++++ ++++ +
+++++ +++++ 66 ##STR00424## + + + + + 67 ##STR00425## + + + + + 68
##STR00426## +++++++ ++ + ++++ +++++ 69 ##STR00427## +++++++ + + +
++ 70 ##STR00428## +++++++ ++ + +++ +++++ 71 ##STR00429## +++ + + +
+
[0523] In Table 2 above, a +++++++ indicates an IC.sub.50 of 5 nM
or less; a ++++++ indicates an IC.sub.50 of 10 nM or less; a +++++
indicates an IC.sub.50 of 25 nM or less; an ++++ indicates an
IC.sub.50 of 50 nm or less, a +++ indicates an IC.sub.50 of 100 nM
or less, a ++ indicates an IC.sub.50 of 500 nM or less, and a +
indicates an IC.sub.50 of more than 500 nM.
[0524] In some embodiments, the mTorC1/mTorC2 inhibitor is a
compound of Formula I, Formula I-A, Formula I-B1, Formula I-C,
Formula I-C1a, or a compound of Table 1 or Table 2. For example,
the mTorC1/mTorC2 inhibitor is a compound of Formula I where M1 is
a bicyclic heteroaryl system, including, for instance,
benzothiazolyl, quinolinyl, quinazolinyl, benzoxazolyl, and
benzoimidazolyl. In other embodiments, the mTorC1/mTorC2 inhibitor
is a compound of Formula I where M1 is of formula M1-A, M1-B, M1-C
or M1-D. In yet other embodiments, the mTorC1/mTorC2 inhibitor is
of Formula I-B1 and M1 is of formula M1-F1. In still other
embodiments, the mTorC1/mTorC2 inhibitor is of Formula I-C. In
still other embodiments, the mTorC1/mTorC2 inhibitor is of Formula
I-C1a.
Disease Targets
[0525] The subject methods are useful for treating any disease
conditions, for example diseases for which current treatment
regimens result in adverse events, limited tolerability, or patient
non-compliance. In some embodiments, the disease condition is a
proliferative disorder, such as described herein, including but not
limited to cancer. In other embodiments, the disorder is diabetes.
In still other embodiments, the disorder is an autoimmune
disorder.
[0526] In some embodiments, the disease condition is associated
with mTor and/or PI3-kinase. A vast diversity of disease conditions
associated with mTOR and/or PI3-kinase have been reported.
PI3-kinase .alpha., one of the four isoforms of type I PI3-kinases
has been implicated, for example, in a variety of human
proliferative disorders, such as cancers. Angiogenesis has been
shown to selectively require the a isoform of PI3K in the control
of endothelial cell migration. (Graupera et al, Nature 2008; 453;
662-6). Mutations in the gene coding for PI3K .alpha. or mutations
which lead to upregulation of PI3K .alpha. are believed to occur in
many human cancers such as lung, stomach, endometrial, ovarian,
bladder, breast, colon, brain and skin cancers. Often, mutations in
the gene coding for PI3K .alpha. are point mutations clustered
within several hotspots in helical and kinase domains, such as
E542K, E545K, and H1047R. Many of these mutations have been shown
to be oncogenic gain-of-function mutations. Because of the high
rate of PI3K .alpha. mutations, targeting of this pathway provides
valuable therapeutic opportunities. While other PI3K isoforms such
as PI3K .delta. or PI3K .gamma. are expressed primarily in
hematopoietic cells, PI3K .alpha., along with PI3K .beta., is
expressed constitutively.
[0527] Disease conditions associated with PI3-kinase and/or mTOR
can also be characterized by abnormally high level of activity
and/or expression of downstream messengers of mTOR and PI3-kinase.
For example, proteins or messengers such as PIP2, PIP3, PDK, Akt,
PTEN, PRAS40, GSK-3.beta., p21, p27 may be present in abnormal
amounts which can be identified by any assays known in the art.
[0528] Deregulation of the mTOR pathway is emerging as a common
theme in diverse human diseases and as a consequence drugs that
target mTOR have therapeutic value. The diseases associated with
deregulation of mTORC1 include, but are not limited to, tuberous
sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), both of
which are caused by mutations in TSC1 or TSC2 tumor suppressors.
Patients with TSC develop benign tumors that when present in brain,
however, can cause seizures, mental retardation and death. LAM is a
serious lung disease Inhibition of mTORC1 may help patients with
Peutz-Jeghers cancer-prone syndrome caused by the LKB 1 mutation.
mTORC1 may also have role in the genesis of sporadic cancers.
Inactivation of several tumor suppressors, in particular PTEN, p53,
VHL and NF1, has been linked to mTORC1 activation. Rapamycin and
its analogues (eg CCI-779, RAD001 and AP23573) inhibit TORC1 and
have shown moderate anti-cancer activity in phase II clinical
trials. However, due to the negative signal from S6K1 to the
insulin/PI3K/Akt pathway, it is important to note that inhibitors
of mTORC1, like rapalogs, can activate PKB/Akt. If this effect
persists with chronic rapamycin treatment, it may provide cancer
cells with an increased survival signal that may be clinically
undesirable. The PI3K/Akt pathway is activated in many cancers.
Activated Akt regulates cell survival, cell proliferation and
metabolism by phosphorylating proteins such as BAD, FOXO, NF-KB,
p21Cip1, p27Kip1, GSK313 and others. Akt might also promote cell
growth by phosphorylating TSC2. Akt activation may promote cellular
transformation and resistance to apoptosis by collectively
promoting growth, proliferation and survival, while inhibiting
apoptotic pathways.
[0529] Where desired, the subject to be treated is tested prior to
treatment using a diagnostic assay to determine the sensitivity of
tumor cells to an mTorC1/mTorC2 inhibitor. Any method known in the
art that can determine the sensitivity of the tumor cells of a
subject to an mTorC1/mTorC2 inhibitor can be employed. In these
methods one or more additional anti-cancer agents or treatments can
be co-administered according to a treatment regimen of the
invention using the mTorC1/mTorC2 inhibitor, as judged to be
appropriate by the administering physician given the prediction of
the likely responsiveness of the subject to the combination of
mTorC1/mTorC2 inhibitor, in combination with any additional
circumstances pertaining to the individual subject.
[0530] The data presented in the Examples herein below demonstrate
that the anti-tumor effects of an intermittent regimen of the
invention involving an agent which is an mTorC1/mTorC2 inhibitor
(where the mTorC1/mTorC2 inhibitor is administered according to a
treatment regimen) are superior to the anti-tumor effects of the
agent administered daily. As such, the subject methods are
particularly useful for treating a proliferative disorder, such as
a neoplastic condition. Non-limiting examples of such conditions
include but are not limited to Acanthoma, Acinic cell carcinoma,
Acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, Acute
eosinophilic leukemia, Acute lymphoblastic leukemia, Acute
megakaryoblastic leukemia, Acute monocytic leukemia, Acute
myeloblastic leukemia with maturation, Acute myeloid dendritic cell
leukemia, Acute myeloid leukemia, Acute promyelocytic leukemia,
Adamantinoma, Adenocarcinoma, Adenoid cystic carcinoma, Adenoma,
Adenomatoid odontogenic tumor, Adrenocortical carcinoma, Adult
T-cell leukemia, Aggressive NK-cell leukemia, AIDS-Related Cancers,
AIDS-related lymphoma, Alveolar soft part sarcoma, Ameloblastic
fibroma, Anal cancer, Anaplastic large cell lymphoma, Anaplastic
thyroid cancer, Angioimmunoblastic T-cell lymphoma, Angiomyolipoma,
Angiosarcoma, Appendix cancer, Astrocytoma, Atypical teratoid
rhabdoid tumor, Basal cell carcinoma, Basal-like carcinoma, B-cell
leukemia, B-cell lymphoma, Bellini duct carcinoma, Biliary tract
cancer, Bladder cancer, Blastoma, Bone Cancer, Bone tumor, Brain
Stem Glioma, Brain Tumor, Breast Cancer, Brenner tumor, Bronchial
Tumor, Bronchioloalveolar carcinoma, Brown tumor, Burkitt's
lymphoma, Cancer of Unknown Primary Site, Carcinoid Tumor,
Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinoma of
Unknown Primary Site, Carcinosarcoma, Castleman's Disease, Central
Nervous System Embryonal Tumor, Cerebellar Astrocytoma, Cerebral
Astrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma,
Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus
papilloma, Chronic Lymphocytic Leukemia, Chronic monocytic
leukemia, Chronic myelogenous leukemia, Chronic Myeloproliferative
Disorder, Chronic neutrophilic leukemia, Clear-cell tumor, Colon
Cancer, Colorectal cancer, Craniopharyngioma, Cutaneous T-cell
lymphoma, Degos disease, Dermatofibrosarcoma protuberans, Dermoid
cyst, Desmoplastic small round cell tumor, Diffuse large B cell
lymphoma, Dysembryoplastic neuroepithelial tumor, Embryonal
carcinoma, Endodermal sinus tumor, Endometrial cancer, Endometrial
Uterine Cancer, Endometrioid tumor, Enteropathy-associated T-cell
lymphoma, Ependymoblastoma, Ependymoma, Epithelioid sarcoma,
Erythroleukemia, Esophageal cancer, Esthesioneuroblastoma, Ewing
Family of Tumor, Ewing Family Sarcoma, Ewing's sarcoma,
Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor,
Extrahepatic Bile Duct Cancer, Extramammary Paget's disease,
Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma,
Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer,
Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer,
Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal
Carcinoid Tumor, Gastrointestinal Stromal Tumor, Gastrointestinal
stromal tumor, Germ cell tumor, Germinoma, Gestational
choriocarcinoma, Gestational Trophoblastic Tumor, Giant cell tumor
of bone, Glioblastoma multiforme, Glioma, Gliomatosis cerebri,
Glomus tumor, Glucagonoma, Gonadoblastoma, Granulosa cell tumor,
Hairy Cell Leukemia, Hairy cell leukemia, Head and Neck Cancer,
Head and neck cancer, Heart cancer, Hemangioblastoma,
Hemangiopericytoma, Hemangiosarcoma, Hematological malignancy,
Hepatocellular carcinoma, Hepatosplenic T-cell lymphoma, Hereditary
breast-ovarian cancer syndrome, Hodgkin Lymphoma, Hodgkin's
lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Inflammatory
breast cancer, Intraocular Melanoma, Islet cell carcinoma, Islet
Cell Tumor, Juvenile myelomonocytic leukemia, Sarcoma, Kaposi's
sarcoma, Kidney Cancer, Klatskin tumor, Krukenberg tumor, Laryngeal
Cancer, Laryngeal cancer, Lentigo maligna melanoma, Leukemia,
Leukemia, Lip and Oral Cavity Cancer, Liposarcoma, Lung cancer,
Luteoma, Lymphangioma, Lymphangiosarcoma, Lymphoepithelioma,
Lymphoid leukemia, Lymphoma, Macroglobulinemia, Malignant Fibrous
Histiocytoma, Malignant fibrous histiocytoma, Malignant Fibrous
Histiocytoma of Bone, Malignant Glioma, Malignant Mesothelioma,
Malignant peripheral nerve sheath tumor, Malignant rhabdoid tumor,
Malignant triton tumor, MALT lymphoma, Mantle cell lymphoma, Mast
cell leukemia, Mediastinal germ cell tumor, Mediastinal tumor,
Medullary thyroid cancer, Medulloblastoma, Medulloblastoma,
Medulloepithelioma, Melanoma, Melanoma, Meningioma, Merkel Cell
Carcinoma, Mesothelioma, Mesothelioma, Metastatic Squamous Neck
Cancer with Occult Primary, Metastatic urothelial carcinoma, Mixed
Mullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor,
Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiple
myeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplastic
Disease, Myelodysplastic Syndromes, Myeloid leukemia, Myeloid
sarcoma, Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer,
Nasopharyngeal Cancer, Nasopharyngeal carcinoma, Neoplasm,
Neurinoma, Neuroblastoma, Neuroblastoma, Neurofibroma, Neuroma,
Nodular melanoma, Non-Hodgkin Lymphoma, Non-Hodgkin lymphoma,
Nonmelanoma Skin Cancer, Non-Small Cell Lung Cancer, Ocular
oncology, Oligoastrocytoma, Oligodendroglioma, Oncocytoma, Optic
nerve sheath meningioma, Oral Cancer, Oral cancer, Oropharyngeal
Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer, Ovarian cancer,
Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low
Malignant Potential Tumor, Paget's disease of the breast, Pancoast
tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroid
cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer,
Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell
tumor, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal
Tumor of Intermediate Differentiation, Pineoblastoma, Pituicytoma,
Pituitary adenoma, Pituitary tumor, Plasma Cell Neoplasm,
Pleuropulmonary blastoma, Polyembryoma, Precursor T-lymphoblastic
lymphoma, Primary central nervous system lymphoma, Primary effusion
lymphoma, Primary Hepatocellular Cancer, Primary Liver Cancer,
Primary peritoneal cancer, Primitive neuroectodermal tumor,
Prostate cancer, Pseudomyxoma peritonei, Rectal Cancer, Renal cell
carcinoma, Respiratory Tract Carcinoma Involving the NUT Gene on
Chromosome 15, Retinoblastoma, Rhabdomyoma, Rhabdomyosarcoma,
Richter's transformation, Sacrococcygeal teratoma, Salivary Gland
Cancer, Sarcoma, Schwannomatosis, Sebaceous gland carcinoma,
Secondary neoplasm, Seminoma, Serous tumor, Sertoli-Leydig cell
tumor, Sex cord-stromal tumor, Sezary Syndrome, Signet ring cell
carcinoma, Skin Cancer, Small blue round cell tumor, Small cell
carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Small
intestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart,
Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma,
Squamous cell carcinoma, Stomach cancer, Superficial spreading
melanoma, Supratentorial Primitive Neuroectodermal Tumor, Surface
epithelial-stromal tumor, Synovial sarcoma, T-cell acute
lymphoblastic leukemia, T-cell large granular lymphocyte leukemia,
T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia,
Teratoma, Terminal lymphatic cancer, Testicular cancer, Thecoma,
Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid cancer,
Transitional Cell Cancer of Renal Pelvis and Ureter, Transitional
cell carcinoma, Urachal cancer, Urethral cancer, Urogenital
neoplasm, Uterine sarcoma, Uveal melanoma, Vaginal Cancer, Verner
Morrison syndrome, Verrucous carcinoma, Visual Pathway Glioma,
Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor,
Wilms' tumor, or any combination thereof.
[0531] In some embodiments, a treatment regimen involves
administering an mTorC1/mTorC2 inhibitor for the treatment of a
cancer which is lung cancer, breast cancer, endometrial cancer,
ovarian cancer, bladder cancer, prostate cancer, neuroendocrine
cancer, renal cancer, lyphoma, myeloma or leukemia.
[0532] In some embodiments, a treatment regimen involves
administering an mTorC1/mTorC2 inhibitor for the treatment of solid
tumors. Solid tumors include malignancies (e.g., sarcomas,
adenocarcinomas, and carcinomas) of the various organ systems, such
as those of lung, breast, lymphoid, gastrointestinal (e.g., colon),
and genitourinary (e.g., renal, urothelial, or testicular tumors)
tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas
include colorectal cancers, renal-cell carcinoma, liver cancer,
non-small cell carcinoma of the lung, and cancer of the small
intestine. Additional exemplary solid tumors include: fibrosarcoma,
myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma,
chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's
tumor, leiomyosarcoma, rhabdomyosarcoma, gastrointestinal system
carcinomas, colon carcinoma, pancreatic cancer, breast cancer,
genitourinary system carcinomas, ovarian cancer, prostate cancer,
squamous cell carcinoma, basal cell carcinoma, adenocarcinoma,
sweat gland carcinoma, sebaceous gland carcinoma, papillary
carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary
carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma,
bile duct carcinoma, choriocarcinoma, seminoma, embryonal
carcinoma, Wilms' tumor, cervical cancer, endocrine system
carcinomas, testicular tumor, lung carcinoma, small cell lung
carcinoma, non-small cell lung carcinoma, bladder carcinoma,
epithelial carcinoma, glioma, astrocytoma, medulloblastoma,
craniopharyngioma, ependymoma, pinealoma, hemangioblastoma,
acoustic neuroma, oligodendroglioma, meningioma, melanoma,
neuroblastoma, and retinoblastoma.
[0533] In some embodiments, a treatment regimen of the invention
involves administering an mTorC1/mTorC2 inhibitor for the treatment
of multiple myeloma and/or Waldenstrom's macroglobulinemia.
[0534] In some embodiments, a treatment regimen involves
administering an mTorC1/mTorC2 inhibitor for the treatment of renal
cell carcinoma (also known as RCC or hypernephroma). Renal cell
carcinoma is a kidney cancer that originates in the lining of the
proximal convoluted tubule. Any known type of renal cell carcinoma
may be treated using the treatment regimens of the invention,
including clear renal cell carcinoma, papillary renal cell
carcinoma, chromophobe renal cell carcinoma and collecting duct
carcinoma. Any stage of the disease may be treated using the
methods of the invention, including early stage as well as later
stages (e.g. metastatic renal cell carcinoma).
[0535] In other embodiments, the treatment regimen involves
administering an mTorC1/mTorC2 inhibitor for treatment of heart
conditions including atherosclerosis, heart hypertrophy, cardiac
myocyte dysfunction, elevated blood pressure and vasoconstriction.
The invention also relates to a method of treating diseases related
to vasculogenesis or angiogenesis in a mammal that comprises
subjecting said mammal to a therapeutically effective regimen using
an mTorC1/mTorC2 inhibitor of the present invention, or any
pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate
or derivative thereof.
[0536] In some embodiments, said method is for treating a disease
selected from the group consisting of tumor angiogenesis, chronic
inflammatory disease such as rheumatoid arthritis, atherosclerosis,
inflammatory bowel disease, skin diseases such as psoriasis,
eczema, and scleroderma, diabetes, diabetic retinopathy,
retinopathy of prematurity, age-related macular degeneration,
hemangioma, glioma, melanoma, sarcoma and ovarian, breast, lung,
pancreatic, prostate, colon and epidermoid cancer.
[0537] In some embodiments, the invention provides a treatment
regimen involving administering an mTorC1/mTorC2 inhibitor for
treating a disease condition associated with PI3-kinase .alpha.
and/or mTOR, including, but not limited to, conditions related to
an undesirable, over-active, harmful or deleterious immune response
in a mammal, collectively termed "autoimmune disease." Autoimmune
disorders include, but are not limited to, Crohn's disease,
ulcerative colitis, psoriasis, psoriatic arthritis, juvenile
arthritis and ankylosing spondilitis, Other non-limiting examples
of autoimmune disorders include autoimmune diabetes, multiple
sclerosis, systemic lupus erythematosus (SLE), rheumatoid
spondylitis, gouty arthritis, allergy, autoimmune uveitis,
nephrotic syndrome, multisystem autoimmune diseases, autoimmune
hearing loss, adult respiratory distress syndrome, shock lung,
chronic pulmonary inflammatory disease, pulmonary sarcoidosis,
pulmonary fibrosis, silicosis, idiopathic interstitial lung
disease, chronic obstructive pulmonary disease, asthma, restenosis,
spondyloarthropathies, Reiter's syndrome, autoimmune hepatitis,
inflammatory skin disorders, vasculitis of large vessels, medium
vessels or small vessels, endometriosis, prostatitis and Sjogren's
syndrome. Undesirable immune response can also be associated with
or result in, e.g., asthma, emphysema, bronchitis, psoriasis,
allergy, anaphylaxsis, auto-immune diseases, rhuematoid arthritis,
graft versus host disease, transplantation rejection, lung
injuries, and lupus erythematosus. The pharmaceutical compositions
of the present invention can be used to treat other respiratory
diseases including but not limited to diseases affecting the lobes
of lung, pleural cavity, bronchial tubes, trachea, upper
respiratory tract, or the nerves and muscle for breathing. The
methods of the invention can be further used to treat multiorgan
failure.
[0538] The invention also provides a treatment regimen involving
administering an mTorC1/mTorC2 inhibitor for treating liver
diseases (including diabetes), pancreatitis or kidney disease
(including proliferative glomerulonephritis and diabetes-induced
renal disease) or pain in a mammal.
[0539] The invention further provides a treatment regimen involving
administering an mTorC1/mTorC2 inhibitor for treating sperm
motility. The invention also provides a treatment regimen involving
administering a an mTorC1/mTorC2 inhibitor for treating
neurological or neurodegenerative diseases including, but not
limited to, Alzheimer's disease, Huntington's disease, CNS trauma,
and stroke.
[0540] The invention further provides a treatment regimen involving
administering an mTorC1/mTorC2 inhibitor for the prevention of
blastocyte implantation in a mammal.
[0541] The invention also relates to a treatment regimen involving
administering an mTorC1/mTorC2 inhibitor for treating a disease
related to vasculogenesis or angiogenesis in a mammal which can
manifest as tumor angiogenesis, chronic inflammatory disease such
as rheumatoid arthritis, inflammatory bowel disease,
atherosclerosis, skin diseases such as psoriasis, eczema, and
scleroderma, diabetes, diabetic retinopathy, retinopathy of
prematurity, age-related macular degeneration, hemangioma, glioma,
melanoma, sarcoma and ovarian, breast, lung, pancreatic, prostate,
colon and epidermoid cancer.
[0542] The invention further provides a treatment regimen involving
administering an mTorC1/mTorC2 inhibitor for the treatment of
disorders involving platelet aggregation or platelet adhesion,
including but not limited to Bernard-Soulier syndrome, Glanzmann's
thrombasthenia, Scott's syndrome, von Willebrand disease,
Hermansky-Pudlak Syndrome, and Gray platelet syndrome.
[0543] In some embodiments, a treatment regimen is provided
involving administering an mTorC1/mTorC2 inhibitor to treat disease
which is skeletal muscle atrophy, skeletal muscle hypertrophy,
leukocyte recruitment in cancer tissue, invasion metastasis,
melanoma, sarcoma, acute and chronic bacterial and viral
infections, sepsis, glomerulo sclerosis, glomerulo, nephritis, or
progressive renal fibrosis.
[0544] Certain embodiments contemplate a human subject such as a
subject that has been diagnosed as having or being at risk for
developing or acquiring a proliferative disorder condition. Certain
other embodiments contemplate a non-human subject, for example a
non-human primate such as a macaque, chimpanzee, gorilla, vervet,
orangutan, baboon or other non-human primate, including such
non-human subjects that can be known to the art as preclinical
models, including preclinical models for inflammatory disorders.
Certain other embodiments contemplate a non-human subject that is a
mammal, for example, a mouse, rat, rabbit, pig, sheep, horse,
bovine, goat, gerbil, hamster, guinea pig or other mammal. There
are also contemplated other embodiments in which the subject or
biological source can be a non-mammalian vertebrate, for example,
another higher vertebrate, or an avian, amphibian or reptilian
species, or another subject or biological source. In certain
embodiments of the present invention, a transgenic animal is
utilized. A transgenic animal is a non-human animal in which one or
more of the cells of the animal includes a nucleic acid that is
non-endogenous (i.e., heterologous) and is present as an
extrachromosomal element in a portion of its cell or stably
integrated into its germ line DNA (i.e., in the genomic sequence of
most or all of its cells).
Therapeutic Efficacy
[0545] In some embodiments, therapeutic efficacy is measured based
on an effect of treating a proliferative disorder, such as cancer.
In general, therapeutic efficacy of the methods and compositions of
the invention, with regard to the treatment of a proliferative
disorder (e.g. cancer, whether benign or malignant), may be
measured by the degree to which the methods and compositions
promote inhibition of tumor cell proliferation, the inhibition of
tumor vascularization, the eradication of tumor cells, and/or a
reduction in the size of at least one tumor such that a human is
treated for the proliferative disorder. Several parameters to be
considered in the determination of therapeutic efficacy are
discussed herein. The proper combination of parameters for a
particular situation can be established by the clinician. The
progress of the inventive method in treating cancer (e.g., reducing
tumor size or eradicating cancerous cells) can be ascertained using
any suitable method, such as those methods currently used in the
clinic to track tumor size and cancer progress. The primary
efficacy parameter used to evaluate the treatment of cancer by the
inventive method and compositions preferably is a reduction in the
size of a tumor. Tumor size can be figured using any suitable
technique, such as measurement of dimensions, or estimation of
tumor volume using available computer software, such as FreeFlight
software developed at Wake Forest University that enables accurate
estimation of tumor volume. Tumor size can be determined by tumor
visualization using, for example, CT, ultrasound, SPECT, spiral CT,
MRI, photographs, and the like. In embodiments where a tumor is
surgically resected after completion of the therapeutic period, the
presence of tumor tissue and tumor size can be determined by gross
analysis of the tissue to be resected, and/or by pathological
analysis of the resected tissue.
[0546] In some embodiments, tumor size is reduced as a result of
the inventive method preferably without significant adverse events
in the subject. Adverse events are categorized or "graded" by the
Cancer Therapy Evaluation Program (CTEP) of the National Cancer
Institute (NCI), with Grade 0 representing minimal adverse side
effects and Grade 4 representing the most severe adverse events.
The NCI toxicity scale (published April 1999) and Common Toxicity
Criteria Manual (updated August 1999) is available through the NCI,
e.g., through the NCI internet website at www.ctep.info.nih.gov or
in the Investigator's Handbook for participants in clinical trials
of investigational agents sponsored by the Division of Cancer
Treatment and Diagnosis, NCI. Desirably, the inventive method is
associated with minimal adverse events, e.g. Grade 0, Grade 1, or
Grade 2 adverse events, as graded by the CTEP/NCI.
[0547] As discussed herein, reduction of tumor size, although
preferred, is not required in that the actual size of tumor may not
shrink despite the eradication of tumor cells. Eradication of
cancerous cells is sufficient to realize a therapeutic effect.
Likewise, any reduction in tumor size is sufficient to realize a
therapeutic effect.
[0548] Desirably, the growth of a tumor is stabilized (i.e., one or
more tumors do not increase more than 1%, 5%, 10%, 15%, or 20% in
size, and/or do not metastasize) as a result of the inventive
method and compositions. Such stabilization may be evidenced by a
longer period of stable disease as characterized by the RECIST
guidelines. In some embodiments, a tumor is stabilized for at least
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks. In some
embodiments, a tumor is stabilized for at least about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, or more months. In some embodiments, a
tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, or more years. Preferably, the inventive method reduces the
size of a tumor at least about 5% (e.g., at least about 10%, 15%,
20%, or 25%). More preferably, tumor size is reduced at least about
30% (e.g., at least about 35%, 40%, 45%, 50%, 55%, 60%, or 65%).
Even more preferably, tumor size is reduced at least about 70%
(e.g., at least about 75%, 80%, 85%, 90%, or 95%). Most preferably,
the tumor is completely eliminated, or reduced below a level of
detection. In some embodiments, a subject remains tumor free (e.g.
in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, or more weeks following treatment. In some embodiments, a
subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, or more months following treatment. In some
embodiments, a subject remains tumor free for at least about 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, or more years after treatment.
[0549] When a tumor is subject to surgical resection following
completion of the therapeutic period, the efficacy of the inventive
method in reducing tumor size can be determined by measuring the
percentage of resected tissue that is necrotic (i.e., dead). In
some embodiments, a treatment is therapeutically effective if the
necrosis percentage of the resected tissue is greater than about
20% (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
100%), more preferably about 90% or greater (e.g., about 90%, 95%,
or 100%). Most preferably, the necrosis percentage of the resected
tissue is 100%, that is, no tumor tissue is present or
detectable.
[0550] A number of secondary parameters can be employed to
determine the efficacy of the inventive method. Examples of
secondary parameters include, but are not limited to, detection of
new tumors, detection of tumor antigens or markers (e.g., CEA, PSA,
or CA-125), biopsy, surgical downstaging (i.e., conversion of the
surgical stage of a tumor from unresectable to resectable), PET
scans, survival, disease progression-free survival, time to disease
progression, quality of life assessments such as the Clinical
Benefit Response Assessment, and the like, all of which can point
to the overall progression (or regression) of cancer in a human.
Biopsy is particularly useful in detecting the eradication of
cancerous cells within a tissue. Radioimmunodetection (RAID) is
used to locate and stage tumors using serum levels of markers
(antigens) produced by and/or associated with tumors ("tumor
markers" or "tumor-associated antigens"), and can be useful as a
pre-treatment diagnostic predicate, a post-treatment diagnostic
indicator of recurrence, and a post-treatment indicator of
therapeutic efficacy. Examples of tumor markers or tumor-associated
antigens that can be evaluated as indicators of therapeutic
efficacy include, but are not limited to, carcinembryonic antigen
(CEA) prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside
molecules (e.g., GM2, GD2, and GD3), MART-1, heat shock proteins
(e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2/neu,
c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100. Other
tumor-associated antigens are known in the art. RAID technology in
combination with endoscopic detection systems also efficiently
distinguishes small tumors from surrounding tissue (see, for
example, U.S. Pat. No. 4,932,412).
[0551] Desirably, in accordance with the inventive method, the
treatment of cancer in a human patient is evidenced by one or more
of the following results: (a) the complete disappearance of a tumor
(i.e., a complete response), (b) about a 25% to about a 50%
reduction in the size of a tumor for at least four weeks after
completion of the therapeutic period as compared to the size of the
tumor before treatment, (c) at least about a 50% reduction in the
size of a tumor for at least four weeks after completion of the
therapeutic period as compared to the size of the tumor before the
therapeutic period, (d) at least a 2% decrease (e.g., about a 5%,
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) in a
specific tumor-associated antigen level at about 4-12 weeks after
completion of the therapeutic period as compared to the
tumor-associated antigen level before the therapeutic period or (e)
a longer period of stable disease, for example longer by 1, 2, 3,
4, or 5 months. While at least a 2% decrease in a tumor-associated
antigen level is preferred, any decrease in the tumor-associated
antigen level is evidence of treatment of a cancer in a patient by
the inventive method. For example, with respect to unresectable,
locally advanced pancreatic cancer, treatment can be evidenced by
at least a 10% decrease in the CA19-9 tumor-associated antigen
level at 4-12 weeks after completion of the therapeutic period as
compared to the CA19-9 level before the therapeutic period.
Similarly, with respect to locally advanced rectal cancer,
treatment can be evidenced by at least a 10% decrease in the CEA
tumor-associated antigen level at 4-12 weeks after completion of
the therapeutic period as compared to the CEA level before the
therapeutic period.
[0552] With respect to quality of life assessments, such as the
Clinical Benefit Response Criteria, the therapeutic benefit of the
treatment in accordance with the invention can be evidenced in
terms of pain intensity, analgesic consumption, and/or the
Karnofsky Performance Scale score. The Karnofsky Performance Scale
allows patients to be classified according to their functional
impairment. The Karnofsky Performance Scale is scored from 0-100.
In general, a lower Karnofsky score is predictive of a poor
prognosis for survival. Thus, the treatment of cancer in a human
patient alternatively, or in addition, is evidenced by (a) at least
a 50% decrease (e.g., at least a 60%, 70%, 80%, 90%, or 100%
decrease) in pain intensity reported by a patient, such as for any
consecutive four week period in the 12 weeks after completion of
treatment, as compared to the pain intensity reported by the
patient before treatment, (b) at least a 50% decrease (e.g., at
least a 60%, 70%, 80%, 90%, or 100% decrease) in analgesic
consumption reported by a patient, such as for any consecutive four
week period in the 12 weeks after completion of treatment as
compared to the analgesic consumption reported by the patient
before treatment, and/or (c) at least a 20 point increase (e.g., at
least a 30 point, 50 point, 70 point, or 90 point increase) in the
Karnofsky Performance Scale score reported by a patient, such as
for any consecutive four week period in the 12 weeks after
completion of the therapeutic period as compared to the Karnofsky
Performance Scale score reported by the patient before the
therapeutic period.
[0553] The treatment of a proliferative disorder (e.g. cancer,
whether benign or malignant) in a human patient desirably is
evidenced by one or more (in any combination) of the foregoing
results, although alternative or additional results of the
referenced tests and/or other tests can evidence treatment
efficacy.
[0554] Detection, monitoring, and rating of various cancers in a
human are further described in Cancer Facts and Figures 2001,
American Cancer Society, New York, N.Y., and International Patent
Application WO 01/24684. Accordingly, a clinician can use standard
tests to determine the efficacy of the various embodiments of the
inventive method in treating cancer. However, in addition to tumor
size and spread, the clinician also may consider quality of life
and survival of the subject in evaluating efficacy of
treatment.
[0555] In some embodiments, administration of an mTorC1/mTorC2
inhibitor according to an intermittent regiment of the invention
provides improved therapeutic efficacy over a treatment where the
inhibitor is administered daily. Improved efficacy may be measured
using any method known in the art, including but not limited to
those described herein. In some embodiments, the improved
therapeutic efficacy is an improvement of at least about 10%, 20%,
30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%,
150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000%, 10000% or more,
using an appropriate measure (e.g. tumor size reduction, duration
of tumor size stability, duration of time free from metastatic
events, duration of disease-free survival). Improved efficacy may
also be expressed as fold improvement, such as at least about
2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold,
10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold,
80-fold, 90-fold, 100-fold, 1000-fold, 10000-fold, or more, using
an appropriate measure (e.g. tumor size reduction, duration of
tumor size stability, duration of time free from metastatic events,
duration of disease-free survival).
Pharmaceutical Compositions and Administration
[0556] The subject pharmaceutical compositions are typically
formulated to provide a therapeutically effective amount of a
compound of the present invention as the active ingredient, or a
pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate
or derivative thereof. Where desired, the pharmaceutical
compositions contain pharmaceutically acceptable salt and/or
coordination complex thereof, and one or more pharmaceutically
acceptable excipients, carriers, including inert solid diluents and
fillers, diluents, including sterile aqueous solution and various
organic solvents, permeation enhancers, solubilizers and
adjuvants.
[0557] The subject pharmaceutical compositions can be administered
alone or in combination with one or more other agents, which are
also typically administered in the form of pharmaceutical
compositions. Where desired, the one or more compounds of the
invention and other agent(s) may be mixed into a preparation or
both components may be formulated into separate preparations to use
them in combination separately or at the same time.
[0558] In some embodiments, the concentration of one or more
compounds provided in the pharmaceutical compositions of the
present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%,
30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%,
7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%,
0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,
0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%,
0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%,
0.0002%, or 0.0001% w/w, w/v or v/v.
[0559] In some embodiments, the concentration of one or more
compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%,
40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25%
18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%,
15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%,
13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%,
11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%,
8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25%
6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%,
3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%,
0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,
0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,
0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,
0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or
v/v.
[0560] In some embodiments, the concentration of one or more
compounds of the invention is in the range from approximately
0.0001% to approximately 50%, approximately 0.001% to approximately
40%, approximately 0.01% to approximately 30%, approximately 0.02%
to approximately 29%, approximately 0.03% to approximately 28%,
approximately 0.04% to approximately 27%, approximately 0.05% to
approximately 26%, approximately 0.06% to approximately 25%,
approximately 0.07% to approximately 24%, approximately 0.08% to
approximately 23%, approximately 0.09% to approximately 22%,
approximately 0.1% to approximately 21%, approximately 0.2% to
approximately 20%, approximately 0.3% to approximately 19%,
approximately 0.4% to approximately 18%, approximately 0.5% to
approximately 17%, approximately 0.6% to approximately 16%,
approximately 0.7% to approximately 15%, approximately 0.8% to
approximately 14%, approximately 0.9% to approximately 12%,
approximately 1% to approximately 10% w/w, w/v or v/v.
[0561] In some embodiments, the concentration of one or more
compounds of the invention is in the range from approximately
0.001% to approximately 10%, approximately 0.01% to approximately
5%, approximately 0.02% to approximately 4.5%, approximately 0.03%
to approximately 4%, approximately 0.04% to approximately 3.5%,
approximately 0.05% to approximately 3%, approximately 0.06% to
approximately 2.5%, approximately 0.07% to approximately 2%,
approximately 0.08% to approximately 1.5%, approximately 0.09% to
approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v
or v/v.
[0562] In some embodiments, the amount of one or more compounds of
the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g,
8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5
g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g,
0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g,
0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06
g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007
g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g,
0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002
g, or 0.0001 g.
[0563] In some embodiments, the amount of one or more compounds of
the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g,
0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015
g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005
g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085
g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g,
0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g,
0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g 0.15 g, 0.2 g 0.25
g, 0.3 g 0.35 g, 0.4 g 0.45 g, 0.5 g, 0.55 g, 0.6 g 0.65 g, 0.7 g,
0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g,
3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9
g, 9.5 g, or 10 g.
[0564] In some embodiments, the amount of one or more compounds of
the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8
g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
[0565] The compounds according to the invention are effective over
a wide dosage range. For example, in the treatment of adult humans,
dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg
per day, and from 5 to 40 mg per day are examples of dosages that
may be used. An exemplary dosage is 10 to 30 mg per day. The exact
dosage will depend upon the route of administration, the form in
which the compound is administered, the subject to be treated, the
body weight of the subject to be treated, and the preference and
experience of the attending physician.
[0566] A pharmaceutical composition of the invention typically
contains an active ingredient (e.g., a compound) of the present
invention or a pharmaceutically acceptable salt and/or coordination
complex thereof, and one or more pharmaceutically acceptable
excipients, carriers, including but not limited to inert solid
diluents and fillers, diluents, sterile aqueous solution and
various organic solvents, permeation enhancers, solubilizers and
adjuvants.
[0567] Described below are non-limiting exemplary pharmaceutical
compositions and methods for preparing the same.
[0568] Pharmaceutical Compositions for Oral Administration.
[0569] In some embodiments, the invention provides a pharmaceutical
composition for oral administration containing a compound of the
invention, and a pharmaceutical excipient suitable for oral
administration.
[0570] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of a compound of the invention; optionally (ii)
an effective amount of a second agent; and (iii) a pharmaceutical
excipient suitable for oral administration. In some embodiments,
the composition further contains: (iv) an effective amount of a
third agent.
[0571] In some embodiments, the pharmaceutical composition may be a
liquid pharmaceutical composition suitable for oral consumption.
Pharmaceutical compositions of the invention suitable for oral
administration can be presented as discrete dosage forms, such as
capsules, cachets, or tablets, or liquids or aerosol sprays each
containing a predetermined amount of an active ingredient as a
powder or in granules, a solution, or a suspension in an aqueous or
non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil
liquid emulsion. Such dosage forms can be prepared by any of the
methods of pharmacy, but all methods include the step of bringing
the active ingredient into association with the carrier, which
constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation. For example, a tablet can be prepared by
compression or molding, optionally with one or more accessory
ingredients. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as powder or granules, optionally mixed with an excipient such as,
but not limited to, a binder, a lubricant, an inert diluent, and/or
a surface active or dispersing agent. Molded tablets can be made by
molding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent.
[0572] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising an active ingredient,
since water can facilitate the degradation of some compounds. For
example, water may be added (e.g., 5%) in the pharmaceutical arts
as a means of simulating long-term storage in order to determine
characteristics such as shelf-life or the stability of formulations
over time. Anhydrous pharmaceutical compositions and dosage forms
of the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms of the invention which
contain lactose can be made anhydrous if substantial contact with
moisture and/or humidity during manufacturing, packaging, and/or
storage is expected. An anhydrous pharmaceutical composition may be
prepared and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions may be packaged using materials
known to prevent exposure to water such that they can be included
in suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastic or the
like, unit dose containers, blister packs, and strip packs.
[0573] An active ingredient can be combined in an intimate
admixture with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier can take a wide
variety of forms depending on the form of preparation desired for
administration. In preparing the compositions for an oral dosage
form, any of the usual pharmaceutical media can be employed as
carriers, such as, for example, water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, and the like in
the case of oral liquid preparations (such as suspensions,
solutions, and elixirs) or aerosols; or carriers such as starches,
sugars, micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, and disintegrating agents can be used in the
case of oral solid preparations, in some embodiments without
employing the use of lactose. For example, suitable carriers
include powders, capsules, and tablets, with the solid oral
preparations. If desired, tablets can be coated by standard aqueous
or nonaqueous techniques.
[0574] Binders suitable for use in pharmaceutical compositions and
dosage forms include, but are not limited to, corn starch, potato
starch, or other starches, gelatin, natural and synthetic gums such
as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl
cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
microcrystalline cellulose, and mixtures thereof.
[0575] Examples of suitable fillers for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof.
[0576] Disintegrants may be used in the compositions of the
invention to provide tablets that disintegrate when exposed to an
aqueous environment. Too much of a disintegrant may produce tablets
which may disintegrate in the bottle. Too little may be
insufficient for disintegration to occur and may thus alter the
rate and extent of release of the active ingredient(s) from the
dosage form. Thus, a sufficient amount of disintegrant that is
neither too little nor too much to detrimentally alter the release
of the active ingredient(s) may be used to form the dosage forms of
the compounds disclosed herein. The amount of disintegrant used may
vary based upon the type of formulation and mode of administration,
and may be readily discernible to those of ordinary skill in the
art. About 0.5 to about 15 weight percent of disintegrant, or about
1 to about 5 weight percent of disintegrant, may be used in the
pharmaceutical composition. Disintegrants that can be used to form
pharmaceutical compositions and dosage forms of the invention
include, but are not limited to, agar-agar, alginic acid, calcium
carbonate, microcrystalline cellulose, croscarmellose sodium,
crospovidone, polacrilin potassium, sodium starch glycolate, potato
or tapioca starch, other starches, pre-gelatinized starch, other
starches, clays, other algins, other celluloses, gums or mixtures
thereof.
[0577] Lubricants which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, calcium stearate, magnesium stearate, mineral oil,
light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures
thereof. Additional lubricants include, for example, a syloid
silica gel, a coagulated aerosol of synthetic silica, or mixtures
thereof A lubricant can optionally be added, in an amount of less
than about 1 weight percent of the pharmaceutical composition.
[0578] When aqueous suspensions and/or elixirs are desired for oral
administration, the active ingredient therein may be combined with
various sweetening or flavoring agents, coloring matter or dyes
and, if so desired, emulsifying and/or suspending agents, together
with such diluents as water, ethanol, propylene glycol, glycerin
and various combinations thereof.
[0579] The tablets can be uncoated or coated by known techniques to
delay disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
also be presented as hard gelatin capsules wherein the active
ingredient is mixed with an inert solid diluent, for example,
calcium carbonate, calcium phosphate or kaolin, or as soft gelatin
capsules wherein the active ingredient is mixed with water or an
oil medium, for example, peanut oil, liquid paraffin or olive
oil.
[0580] Surfactant which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, hydrophilic surfactants, lipophilic surfactants, and
mixtures thereof. That is, a mixture of hydrophilic surfactants may
be employed, a mixture of lipophilic surfactants may be employed,
or a mixture of at least one hydrophilic surfactant and at least
one lipophilic surfactant may be employed.
[0581] A suitable hydrophilic surfactant may generally have an HLB
value of at least 10, while suitable lipophilic surfactants may
generally have an HLB value of or less than about 10. An empirical
parameter used to characterize the relative hydrophilicity and
hydrophobicity of non-ionic amphiphilic compounds is the
hydrophilic-lipophilic balance ("HLB" value). Surfactants with
lower HLB values are more lipophilic or hydrophobic, and have
greater solubility in oils, while surfactants with higher HLB
values are more hydrophilic, and have greater solubility in aqueous
solutions. Hydrophilic surfactants are generally considered to be
those compounds having an HLB value greater than about 10, as well
as anionic, cationic, or zwitterionic compounds for which the HLB
scale is not generally applicable. Similarly, lipophilic (i.e.,
hydrophobic) surfactants are compounds having an HLB value equal to
or less than about 10. However, HLB value of a surfactant is merely
a rough guide generally used to enable formulation of industrial,
pharmaceutical and cosmetic emulsions.
[0582] Hydrophilic surfactants may be either ionic or non-ionic.
Suitable ionic surfactants include, but are not limited to,
alkylammonium salts; fusidic acid salts; fatty acid derivatives of
amino acids, oligopeptides, and polypeptides; glyceride derivatives
of amino acids, oligopeptides, and polypeptides; lecithins and
hydrogenated lecithins; lysolecithins and hydrogenated
lysolecithins; phospholipids and derivatives thereof;
lysophospholipids and derivatives thereof; carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acyl lactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[0583] Within the aforementioned group, ionic surfactants include,
by way of example: lecithins, lysolecithin, phospholipids,
lysophospholipids and derivatives thereof; carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acylactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[0584] Ionic surfactants may be the ionized forms of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine,
lysophosphatidylcholine, lysophosphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid,
lysophosphatidylserine, PEG-phosphatidylethanolamine,
PVP-phosphatidylethanolamine, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholylsarcosine, caproate, caprylate, caprate, laurate, myristate,
palmitate, oleate, ricinoleate, linoleate, linolenate, stearate,
lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines,
palmitoyl carnitines, myristoyl carnitines, and salts and mixtures
thereof.
[0585] Hydrophilic non-ionic surfactants may include, but are not
limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides;
lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as
polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such
as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol
fatty acid esters such as polyethylene glycol fatty acids
monoesters and polyethylene glycol fatty acids diesters;
polyethylene glycol glycerol fatty acid esters; polyglycerol fatty
acid esters; polyoxyalkylene sorbitan fatty acid esters such as
polyethylene glycol sorbitan fatty acid esters; hydrophilic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids, and sterols; polyoxyethylene sterols,
derivatives, and analogues thereof; polyoxyethylated vitamins and
derivatives thereof; polyoxyethylene-polyoxypropylene block
copolymers; and mixtures thereof; polyethylene glycol sorbitan
fatty acid esters and hydrophilic transesterification products of a
polyol with at least one member of the group consisting of
triglycerides, vegetable oils, and hydrogenated vegetable oils. The
polyol may be glycerol, ethylene glycol, polyethylene glycol,
sorbitol, propylene glycol, pentaerythritol, or a saccharide.
[0586] Other hydrophilic-non-ionic surfactants include, without
limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32
laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20
oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400
oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate,
PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate,
PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,
PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl
oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40
palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil,
PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor
oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6
caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,
polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol,
PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate,
PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9
lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl
ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24
cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose
monostearate, sucrose monolaurate, sucrose monopalmitate, PEG
10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and
poloxamers.
[0587] Suitable lipophilic surfactants include, by way of example
only: fatty alcohols; glycerol fatty acid esters; acetylated
glycerol fatty acid esters; lower alcohol fatty acids esters;
propylene glycol fatty acid esters; sorbitan fatty acid esters;
polyethylene glycol sorbitan fatty acid esters; sterols and sterol
derivatives; polyoxyethylated sterols and sterol derivatives;
polyethylene glycol alkyl ethers; sugar esters; sugar ethers;
lactic acid derivatives of mono- and di-glycerides; hydrophobic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids and sterols; oil-soluble
vitamins/vitamin derivatives; and mixtures thereof. Within this
group, preferred lipophilic surfactants include glycerol fatty acid
esters, propylene glycol fatty acid esters, and mixtures thereof,
or are hydrophobic transesterification products of a polyol with at
least one member of the group consisting of vegetable oils,
hydrogenated vegetable oils, and triglycerides.
[0588] In one embodiment, the composition may include a solubilizer
to ensure good solubilization and/or dissolution of the compound of
the present invention and to minimize precipitation of the compound
of the present invention. This can be especially important for
compositions for non-oral use, e.g., compositions for injection. A
solubilizer may also be added to increase the solubility of the
hydrophilic drug and/or other components, such as surfactants, or
to maintain the composition as a stable or homogeneous solution or
dispersion.
[0589] Examples of suitable solubilizers include, but are not
limited to, the following: alcohols and polyols, such as ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins and
cyclodextrin derivatives; ethers of polyethylene glycols having an
average molecular weight of about 200 to about 6000, such as
tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG;
amides and other nitrogen-containing compounds such as
2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam,
N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,
N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone;
esters such as ethyl propionate, tributylcitrate, acetyl
triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl
oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene
glycol monoacetate, propylene glycol diacetate,
.epsilon.-caprolactone and isomers thereof, .delta.-valerolactone
and isomers thereof, .beta.-butyrolactone and isomers thereof; and
other solubilizers known in the art, such as dimethyl acetamide,
dimethyl isosorbide, N-methylpyrrolidones, monooctanoin, diethylene
glycol monoethyl ether, and water.
[0590] Mixtures of solubilizers may also be used. Examples include,
but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl
caprylate, dimethylacetamide, N-methylpyrrolidone,
N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl
methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene
glycol 200-100, glycofurol, transcutol, propylene glycol, and
dimethyl isosorbide. Particularly preferred solubilizers include
sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol
and propylene glycol.
[0591] The amount of solubilizer that can be included is not
particularly limited. The amount of a given solubilizer may be
limited to a bioacceptable amount, which may be readily determined
by one of skill in the art. In some circumstances, it may be
advantageous to include amounts of solubilizers far in excess of
bioacceptable amounts, for example to maximize the concentration of
the drug, with excess solubilizer removed prior to providing the
composition to a subject using conventional techniques, such as
distillation or evaporation. Thus, if present, the solubilizer can
be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by
weight, based on the combined weight of the drug, and other
excipients. If desired, very small amounts of solubilizer may also
be used, such as 5%, 2%, 1% or even less. Typically, the
solubilizer may be present in an amount of about 1% to about 100%,
more typically about 5% to about 25% by weight.
[0592] The composition can further include one or more
pharmaceutically acceptable additives and excipients. Such
additives and excipients include, without limitation, detackifiers,
anti-foaming agents, buffering agents, polymers, antioxidants,
preservatives, chelating agents, viscomodulators, tonicifiers,
flavorants, colorants, odorants, opacifiers, suspending agents,
binders, fillers, plasticizers, lubricants, and mixtures
thereof.
[0593] In addition, an acid or a base may be incorporated into the
composition to facilitate processing, to enhance stability, or for
other reasons. Examples of pharmaceutically acceptable bases
include amino acids, amino acid esters, ammonium hydroxide,
potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,
aluminum hydroxide, calcium carbonate, magnesium hydroxide,
magnesium aluminum silicate, synthetic aluminum silicate, synthetic
hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine,
ethanolamine, ethylenediamine, triethanolamine, triethylamine,
triisopropanolamine, trimethylamine,
tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable
are bases that are salts of a pharmaceutically acceptable acid,
such as acetic acid, acrylic acid, adipic acid, alginic acid,
alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid,
boric acid, butyric acid, carbonic acid, citric acid, fatty acids,
formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,
isoascorbic acid, lactic acid, maleic acid, oxalic acid,
para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic
acid, salicylic acid, stearic acid, succinic acid, tannic acid,
tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid,
and the like. Salts of polyprotic acids, such as sodium phosphate,
disodium hydrogen phosphate, and sodium dihydrogen phosphate can
also be used. When the base is a salt, the cation can be any
convenient and pharmaceutically acceptable cation, such as
ammonium, alkali metals, alkaline earth metals, and the like.
Example may include, but not limited to, sodium, potassium,
lithium, magnesium, calcium and ammonium.
[0594] Suitable acids are pharmaceutically acceptable organic or
inorganic acids. Examples of suitable inorganic acids include
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,
nitric acid, boric acid, phosphoric acid, and the like. Examples of
suitable organic acids include acetic acid, acrylic acid, adipic
acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic
acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric
acid, fatty acids, formic acid, fumaric acid, gluconic acid,
hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic
acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic
acid, propionic acid, p-toluenesulfonic acid, salicylic acid,
stearic acid, succinic acid, tannic acid, tartaric acid,
thioglycolic acid, toluenesulfonic acid, uric acid and the
like.
[0595] Pharmaceutical Compositions for Injection.
[0596] In some embodiments, the invention provides a pharmaceutical
composition for injection containing a compound of the present
invention and a pharmaceutical excipient suitable for injection.
Components and amounts of agents in the compositions are as
described herein.
[0597] The forms in which the novel compositions of the present
invention may be incorporated for administration by injection
include aqueous or oil suspensions, or emulsions, with sesame oil,
corn oil, cottonseed oil, or peanut oil, as well as elixirs,
mannitol, dextrose, or a sterile aqueous solution, and similar
pharmaceutical vehicles.
[0598] Aqueous solutions in saline are also conventionally used for
injection. Ethanol, glycerol, propylene glycol, liquid polyethylene
glycol, and the like (and suitable mixtures thereof), cyclodextrin
derivatives, and vegetable oils may also be employed. The proper
fluidity can be maintained, for example, by the use of a coating,
such as lecithin, for the maintenance of the required particle size
in the case of dispersion and by the use of surfactants. The
prevention of the action of microorganisms can be brought about by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
[0599] Sterile injectable solutions are prepared by incorporating
the compound of the present invention in the required amount in the
appropriate solvent with various other ingredients as enumerated
above, as required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, certain desirable
methods of preparation are vacuum-drying and freeze-drying
techniques which yield a powder of the active ingredient plus any
additional desired ingredient from a previously sterile-filtered
solution thereof.
[0600] Pharmaceutical Compositions for Topical (e.g., Transdermal)
Delivery.
[0601] In some embodiments, the invention provides a pharmaceutical
composition for transdermal delivery containing a compound of the
present invention and a pharmaceutical excipient suitable for
transdermal delivery.
[0602] Compositions of the present invention can be formulated into
preparations in solid, semi-solid, or liquid forms suitable for
local or topical administration, such as gels, water soluble
jellies, creams, lotions, suspensions, foams, powders, slurries,
ointments, solutions, oils, pastes, suppositories, sprays,
emulsions, saline solutions, dimethylsulfoxide (DMSO)-based
solutions. In general, carriers with higher densities are capable
of providing an area with a prolonged exposure to the active
ingredients. In contrast, a solution formulation may provide more
immediate exposure of the active ingredient to the chosen area.
[0603] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients, which are compounds that
allow increased penetration of, or assist in the delivery of,
therapeutic molecules across the stratum corneum permeability
barrier of the skin. There are many of these penetration-enhancing
molecules known to those trained in the art of topical formulation.
Examples of such carriers and excipients include, but are not
limited to, humectants (e.g., urea), glycols (e.g., propylene
glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid),
surfactants (e.g., isopropyl myristate and sodium lauryl sulfate),
pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g.,
menthol), amines, amides, alkanes, alkanols, water, calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0604] Another exemplary formulation for use in the methods of the
present invention employs transdermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or
discontinuous infusion of a compound of the present invention in
controlled amounts, either with or without another agent.
[0605] The construction and use of transdermal patches for the
delivery of pharmaceutical agents is well known in the art. See,
e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such
patches may be constructed for continuous, pulsatile, or on demand
delivery of pharmaceutical agents.
[0606] Pharmaceutical Compositions for Inhalation.
[0607] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. Preferably the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in preferably
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be inhaled directly from the
nebulizing device or the nebulizing device may be attached to a
face mask tent, or intermittent positive pressure breathing
machine. Solution, suspension, or powder compositions may be
administered, preferably orally or nasally, from devices that
deliver the formulation in an appropriate manner.
[0608] Other Pharmaceutical Compositions.
[0609] Pharmaceutical compositions may also be prepared from
compositions described herein and one or more pharmaceutically
acceptable excipients suitable for sublingual, buccal, rectal,
intraosseous, intraocular, intranasal, epidural, or intraspinal
administration. Preparations for such pharmaceutical compositions
are well-known in the art. See, e.g., See, e.g., Anderson, Philip
O.; Knoben, James E.; Troutman, William G, eds., Handbook of
Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and
Taylor, eds., Principles of Drug Action, Third Edition, Churchill
Livingston, New York, 1990; Katzung, ed., Basic and Clinical
Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and
Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth
Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences,
20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The
Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical
Press, London, 1999); all of which are incorporated by reference
herein in their entirety.
[0610] Administration of the compounds or pharmaceutical
composition of the present invention can be effected by any method
that enables delivery of the compounds to the site of action. These
methods include oral routes, intraduodenal routes, parenteral
injection (including intravenous, intraarterial, subcutaneous,
intramuscular, intravascular, intraperitoneal or infusion), topical
(e.g. transdermal application), rectal administration, via local
delivery by catheter or stent or through inhalation. Compounds can
also be administered intraadiposally or intrathecally.
[0611] The amount of the compound administered will be dependent on
the subject being treated, the severity of the disorder or
condition, the rate of administration, the disposition of the
compound and the discretion of the prescribing physician. However,
an effective dosage is in the range of about 0.001 to about 100 mg
per kg body weight per day, preferably about 1 to about 35
mg/kg/day, in single or divided doses. For a 70 kg human, this
would amount to about 0.05 to 7 g/day, preferably about 0.05 to
about 2.5 g/day. In some instances, dosage levels below the lower
limit of the aforesaid range may be more than adequate, while in
other cases still larger doses may be employed without causing any
harmful side effect, e.g. by dividing such larger doses into
several small doses for administration throughout the day.
[0612] In some embodiments, a compound of the invention is
administered in a single dose. Typically, such administration will
be by injection, e.g., intravenous injection, in order to introduce
the agent quickly. However, other routes may be used as
appropriate. A single dose of a compound of the invention may also
be used for treatment of an acute condition.
[0613] In some embodiments, a compound of the invention is
administered in multiple doses. Dosing may be about once, twice,
three times, four times, five times, six times, or more than six
times per day. Dosing may be about once a month, once every two
weeks, once a week, or once every other day. In another embodiment
a compound of the invention and another agent are administered
together about once per day to about 6 times per day. In another
embodiment the administration of a compound of the invention and an
agent continues for less than about 7 days. In yet another
embodiment the administration continues for more than about 6, 10,
14, 28 days, two months, six months, or one year. In some cases,
continuous dosing is achieved and maintained as long as
necessary.
[0614] Administration of the compounds of the invention may
continue as long as necessary. In some embodiments, a compound of
the invention is administered for more than 1, 2, 3, 4, 5, 6, 7,
14, or 28 days. In some embodiments, a compound of the invention is
administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In
some embodiments, a compound of the invention is administered
chronically on an ongoing basis, e.g., for the treatment of chronic
effects.
[0615] An effective amount of a compound of the invention may be
administered in either single or multiple doses by any of the
accepted modes of administration of agents having similar
utilities, including rectal, buccal, intranasal and transdermal
routes, by intra-arterial injection, intravenously,
intraperitoneally, parenterally, intramuscularly, subcutaneously,
orally, topically, or as an inhalant.
[0616] The compositions of the invention may also be delivered via
an impregnated or coated device such as a stent, for example, or an
artery-inserted cylindrical polymer. Such a method of
administration may, for example, aid in the prevention or
amelioration of restenosis following procedures such as balloon
angioplasty. Without being bound by theory, compounds of the
invention may slow or inhibit the migration and proliferation of
smooth muscle cells in the arterial wall which contribute to
restenosis. A compound of the invention may be administered, for
example, by local delivery from the struts of a stent, from a stent
graft, from grafts, or from the cover or sheath of a stent. In some
embodiments, a compound of the invention is admixed with a matrix.
Such a matrix may be a polymeric matrix, and may serve to bond the
compound to the stent. Polymeric matrices suitable for such use,
include, for example, lactone-based polyesters or copolyesters such
as polylactide, polycaprolactonglycolide, polyorthoesters,
polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes,
poly (ether-ester) copolymers (e.g. PEO-PLLA);
polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based
polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate,
polyvinyl pyrrolidinone), fluorinated polymers such as
polytetrafluoroethylene and cellulose esters. Suitable matrices may
be nondegrading or may degrade with time, releasing the compound or
compounds. Compounds of the invention may be applied to the surface
of the stent by various methods such as dip/spin coating, spray
coating, dip-coating, and/or brush-coating. The compounds may be
applied in a solvent and the solvent may be allowed to evaporate,
thus forming a layer of compound onto the stent. Alternatively, the
compound may be located in the body of the stent or graft, for
example in microchannels or micropores. When implanted, the
compound diffuses out of the body of the stent to contact the
arterial wall. Such stents may be prepared by dipping a stent
manufactured to contain such micropores or microchannels into a
solution of the compound of the invention in a suitable solvent,
followed by evaporation of the solvent. Excess drug on the surface
of the stent may be removed via an additional brief solvent wash.
In yet other embodiments, compounds of the invention may be
covalently linked to a stent or graft. A covalent linker may be
used which degrades in vivo, leading to the release of the compound
of the invention. Any bio-labile linkage may be used for such a
purpose, such as ester, amide or anhydride linkages. Compounds of
the invention may additionally be administered intravascularly from
a balloon used during angioplasty. Extravascular administration of
the compounds via the pericard or via advential application of
formulations of the invention may also be performed to decrease
restenosis.
[0617] A variety of stent devices which may be used as described
are disclosed, for example, in the following references, all of
which are hereby incorporated by reference: U.S. Pat. No.
5,451,233; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273; U.S.
Pat. No. 5,496,346; U.S. Pat. No. 5,292,331; U.S. Pat. No.
5,674,278; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S.
Pat. No. 5,195,984; U.S. Pat. No. 5,292,331; U.S. Pat. No.
5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053.
[0618] The compounds of the invention may be administered in
dosages. It is known in the art that due to intersubject
variability in compound pharmacokinetics, individualization of
dosing regimen is necessary for optimal therapy. Dosing for a
compound of the invention may be found by routine experimentation
in light of the instant disclosure.
[0619] When a compound of the invention is administered in a
composition that comprises one or more agents, and the agent has a
shorter half-life than the compound of the invention unit dose
forms of the agent and the compound of the invention may be
adjusted accordingly.
[0620] The subject pharmaceutical composition may, for example, be
in a form suitable for oral administration as a tablet, capsule,
pill, powder, sustained release formulations, solution, suspension,
for parenteral injection as a sterile solution, suspension or
emulsion, for topical administration as an ointment or cream or for
rectal administration as a suppository. The pharmaceutical
composition may be in unit dosage forms suitable for single
administration of precise dosages. The pharmaceutical composition
will include a conventional pharmaceutical carrier or excipient and
a compound according to the invention as an active ingredient. In
addition, it may include other medicinal or pharmaceutical agents,
carriers, adjuvants, etc.
[0621] Exemplary parenteral administration forms include solutions
or suspensions of active compound in sterile aqueous solutions, for
example, aqueous propylene glycol or dextrose solutions. Such
dosage forms can be suitably buffered, if desired.
[0622] The invention also provides kits. The kits include a
compound or compounds of the present invention as described herein,
in suitable packaging, and written material that can include
instructions for use, discussion of clinical studies, listing of
side effects, and the like. Such kits may also include information,
such as scientific literature references, package insert materials,
clinical trial results, and/or summaries of these and the like,
which indicate or establish the activities and/or advantages of the
composition, and/or which describe dosing, administration, side
effects, drug interactions, or other information useful to the
health care provider. Such information may be based on the results
of various studies, for example, studies using experimental animals
involving in vivo models and studies based on human clinical
trials. The kit may further contain another agent. In some
embodiments, the compound of the present invention and the agent
are provided as separate compositions in separate containers within
the kit. In some embodiments, the compound of the present invention
and the agent are provided as a single composition within a
container in the kit. Suitable packaging and additional articles
for use (e.g., measuring cup for liquid preparations, foil wrapping
to minimize exposure to air, and the like) are known in the art and
may be included in the kit. Kits described herein can be provided,
marketed and/or promoted to health providers, including physicians,
nurses, pharmacists, formulary officials, and the like. Kits may
also, in some embodiments, be marketed directly to the
consumer.
Combination Therapies
[0623] The present invention also provides methods for further
combination therapies in which, in addition to an mTorC1/mTorC2
inhibitor, one or more agents known to modulate other pathways, or
other components of the same pathway, or even overlapping sets of
target enzymes is used or a pharmaceutically acceptable salt,
ester, prodrug, solvate, hydrate or derivative thereof. In one
aspect, such therapy includes but is not limited to the combination
of the composition comprising an mTorC1/mTorC2 inhibitor, as
described herein, with chemotherapeutic agents, therapeutic
antibodies, and radiation treatment, to provide, where desired, a
synergistic or additive therapeutic effect. Pathways that my be
targeted by administering another agent include, but are not
limited to, MAP kinase, Akt, NFkB, WNT, RAS/RAF/MEK/ERK, JNK/SAPK,
p38 MAPK, Src Family Kinases, JAK/STAT and/or PKC signaling
pathways. Other agents may target one or more members of one or
more signaling pathways. Representative members of the nuclear
factor-kappaB (NFkB) pathway include but are not limited to RelA
(p65), RelB, c-Rel, p50/p105 (NF-.kappa.B 1), p52/p 100
(NF-.kappa.B2), IkB, and IkB kinase. Non-limiting examples of
receptor tyrosine kinases that are members of the
phosphatidylinositol 3-kinase (PI3K)/AKT pathway that may be
targeted by one or more agents include FLT3 LIGAND, EGFR, IGF-1R,
HER2/neu, VEGFR, and PDGFR. Downstream members of the PI3K/AKT
pathway that may be targeted by agents according to the methods of
the invention include, but are not limited to, forkhead box 0
transcription factors, Bad, GSK-3.beta., I-.kappa.B, mTOR, MDM-2,
and S6 ribosomal subunit.
[0624] Other agents useful in the methods of the invention include
any capable of modulating a target molecule, either directly or
indirectly. Non-limiting examples of target molecules modulated by
other agents include enzymes, enzyme substrates, products of
transitions, antibodies, antigens, membrane proteins, nuclear
proteins, cytosolic proteins, mitochondrial proteins, lysosomal
proteins, scaffold proteins, lipid rafts, phosphoproteins,
glycoproteins, membrane receptors, G-protein-coupled receptors,
nuclear receptors, protein tyrosine kinases, protein
serine/threonine kinases, phosphatases, proteases, hydrolases,
lipases, phospholipases, ligases, reductases, oxidases, synthases,
transcription factors, ion channels, RNA, DNA, RNAse, DNAse,
phospholipids, sphingolipids, nuclear receptors, ion channel
proteins, nucleotide-binding proteins, calcium-binding proteins,
chaperones, DNA binding proteins, RNA binding proteins, scaffold
proteins, tumor suppressors, cell cycle proteins, and histones.
[0625] Other agents may target one or more signaling molecules
including but not limited to the following: HER receptors, PDGF
receptors, Kit receptor, FGF receptors, Eph receptors, Trk
receptors, IGF receptors, Insulin receptor, Met receptor, Ret, VEGF
receptors, TIE1, TIE2, FAK, Jak1, Jak2, Jak3, Tyk2, Src, Lyn, Fyn,
Lck, Fgr, Yes, Csk, Ab1, Btk, ZAP70, Syk, IRAKs, cRaf, ARaf, BRAF,
Mos, Lim kinase, ILK, Tp1, ALK, TGF.beta. receptors, BMP receptors,
MEKKs, ASK, MLKs, DLK, PAKs, Mek 1, Mek 2, MKK3/6, MKK4/7, ASK1,
Cot, NIK, Bub, Myt 1, Wee1, Casein kinases, PDK1, SGK1, SGK2, SGK3,
Akt1, Akt2, Akt3, p90Rsks, p70S6 Kinase, Prks, PKCs, PKAs, ROCK 1,
ROCK 2, Auroras, CaMKs, MNKs, AMPKs, MELK, MARKs, Chk1, Chk2,
LKB-1, MAPKAPKs, Pim1, Pim2, Pim3, IKKs, Cdks, Jnks, Erks, IKKs,
GSK3a, GSK313, Cdks, CLKs, PKR, PI3-Kinase class 1, class 2, class
3, mTor, SAPK/JNK1,2,3, p38s, PKR, DNA-PK, ATM, ATR, Receptor
protein tyrosine phosphatases (RPTPs), LAR phosphatase, CD45, Non
receptor tyrosine phosphatases (NPRTPs), SHPs, MAP kinase
phosphatases (MKPs), Dual Specificity phosphatases (DUSPs), CDC25
phosphatases, Low molecular weight tyrosine phosphatase, Eyes
absent (EYA) tyrosine phosphatases, Slingshot phosphatases (SSH),
serine phosphatases, PP2A, PP2B, PP2C, PP1, PP5, inositol
phosphatases, PTEN, SHIPs, myotubularins, phosphoinositide kinases,
phopsholipases, prostaglandin synthases, 5-lipoxygenase,
sphingosine kinases, sphingomyelinases, adaptor/scaffold proteins,
Shc, Grb2, BLNK, LAT, B cell adaptor for PI3-kinase (BCAP), SLAP,
Dok, KSR, MyD88, Crk, CrkL, GAD, Nck, Grb2 associated binder (GAB),
Fas associated death domain (FADD), TRADD, TRAF2, RIP, T-Cell
leukemia family, IL-2, IL-4, IL-8, IL-6, interferon .beta.,
interferon .alpha., suppressors of cytokine signaling (SOCs), Cb1,
SCF ubiquitination ligase complex, APC/C, adhesion molecules,
integrins, Immunoglobulin-like adhesion molecules, selectins,
cadherins, catenins, focal adhesion kinase, p130CAS, fodrin, actin,
paxillin, myosin, myosin binding proteins, tubulin, eg5/KSP, CENPs,
.beta.-adrenergic receptors, muscarinic receptors, adenylyl cyclase
receptors, small molecular weight GTPases, H-Ras, K-Ras, N-Ras,
Ran, Rac, Rho, Cdc42, Arfs, RABs, RHEB, Vav, Tiam, Sos, Db1, PRK,
TSC1,2, Ras-GAP, Arf-GAPs, Rho-GAPs, caspases, Caspase 2, Caspase
3, Caspase 6, Caspase 7, Caspase 8, Caspase 9, Bcl-2, Mc1-1,
Bcl-XL, Bcl-w, Bcl-B, A1, Bax, Bak, Bok, Bik, Bad, Bid, Bim, Bmf,
Hrk, Noxa, Puma, IAPs, XIAP, Smac, Cdk4, Cdk 6, Cdk 2, Cdk1, Cdk 7,
Cyclin D, Cyclin E, Cyclin A, Cyclin B, Rb, p16, p14Arf, p27KIP,
p21CIP, molecular chaperones, Hsp90s, Hsp70, Hsp27, metabolic
enzymes, Acetyl-CoAa Carboxylase, ATP citrate lyase, nitric oxide
synthase, caveolins, endosomal sorting complex required for
transport (ESCRT) proteins, vesicular protein sorting (Vsps),
hydroxylases, prolyl-hydroxylases PHD-1, 2 and 3, asparagine
hydroxylase FIH transferases, Pin1 prolyl isomerase,
topoisomerases, deacetylases, Histone deacetylases, sirtuins,
histone acetylases, CBP/P300 family, MYST family, ATF2, DNA methyl
transferases, Histone H3K4 demethylases, H3K27, JHDM2A, UTX, VHL,
WT-1, p53, Hdm, ubiquitin proteases, urokinase-type plasminogen
activator (uPA) and uPA receptor (uPAR) system, cathepsins,
metalloproteinases, esterases, hydrolases, separase, potassium
channels, sodium channels, multi-drug resistance proteins,
P-Glycoprotein, nucleoside transporters, Ets, Elk, SMADs, Rel-A
(p65-NFKB), CREB, NFAT, ATF-2, AFT, Myc, Fos, Sp1, Egr-1, T-bet,
.beta.-catenin, HIFs, FOXOs, E2Fs, SRFs, TCFs, Egr-1, {tilde over
(.beta.)}-catenin, FOX(O)STAT1, STAT 3, STAT 4, STAT 5, STAT 6,
p53, WT-1, HMGA, pS6, 4EPB-1, eIF4E-binding protein, RNA
polymerase, initiation factors, and elongation factors.
[0626] The compounds of the invention are also useful as
co-therapeutic compounds for use in combination with other drug
substances such as anti-inflammatory, bronchodilatory or
antihistamine drug substances, particularly in the treatment of
obstructive or inflammatory airways diseases such as those
mentioned herein, for example as potentiators of therapeutic
activity of such drugs or as a means of reducing required dosaging
or potential side effects of such drugs. An inhibitor of the
invention may be mixed with the other drug substance in a fixed
pharmaceutical composition or it may be administered separately,
before, simultaneously with or after the other drug substance.
Accordingly the invention includes a combination of an inhibitor of
the invention as described with an anti-inflammatory,
bronchodilatory, antihistamine or anti-tussive drug substance, said
compound of the invention and said drug substance being in the same
or different pharmaceutical composition. Suitable anti-inflammatory
drugs include steroids, in particular glucocorticosteroids such as
budesonide, beclamethasone dipropionate, fluticasone propionate,
ciclesonide or mometasone furoate, or steroids described in WO
02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those
of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73,
90, 99 and 101), WO 03/035668, WO 03/048181, WO 03/062259, WO
03/064445, WO 03/072592, non-steroidal glucocorticoid receptor
agonists such as those described in WO 00/00531, WO 02/10143, WO
03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4
antagonists such LY29311 1, CGS025019C, CP-195543, SC-53228, BIIL
284, ONO 4057, SB 209247 and those described in U.S. Pat. No.
5,451,700; LTD4 antagonists such as montelukast and zafirlukast;
PDE4 inhibitors such cilomilast (Ariflo.RTM. GlaxoSmithKline),
Roflumilast (Byk Gulden), V-1 1294A (Napp), BAY19-8004 (Bayer),
SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma),
PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801
(Celgene), SeICID.TM. CC-10004 (Celgene), VM554/UM565 (Vernalis),
T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in
WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO
99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO
04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451,
WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO
04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944,
WO 04/019945, WO 04/045607 and WO 04/037805; A2a agonists such as
those disclosed in EP 409595A2, EP 1052264, EP 1241176, WO
94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO
99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO
99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO
00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO
01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO
04/039762, WO 04/039766, WO 04/045618 and WO 04/046083; A2b
antagonists such as those described in WO 02/42298; and beta-2
adrenoceptor agonists such as albuterol (salbutamol),
metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and
especially, formoterol and pharmaceutically acceptable salts
thereof, and compounds (in free or salt or solvate form) of formula
I of WO 0075114, which document is incorporated herein by
reference, preferably compounds of the Examples thereof, as well as
compounds (in free or salt or solvate form) of formula I of WO
04/16601, and also compounds of WO 04/033412. Suitable
bronchodilatory drugs include anticholinergic or antimuscarinic
compounds, in particular ipratropium bromide, oxitropium bromide,
tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but
also those described in WO 01/041 18, WO 02/51841, WO 02/53564, WO
03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP
424021, U.S. Pat. No. 5,171,744, U.S. Pat. No. 3,714,357, WO
03/33495 and WO 04/018422.
[0627] Suitable antihistamine drug substances include cetirizine
hydrochloride, acetaminophen, clemastine fumarate, promethazine,
loratidine, desloratidine, diphenhydramine and fexofenadine
hydrochloride, activastine, astemizole, azelastine, ebastine,
epinastine, mizolastine and tefenadine as well as those disclosed
in WO 03/099807, WO 04/026841 and JP 2004107299.
[0628] Other useful combinations of compounds of the invention with
anti-inflammatory drugs are those with antagonists of chemokine
receptors, e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7,
CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5,
particularly CCR-5 antagonists such as Schering-Plough antagonists
SC-351 125, SCH-55700 and SCH-D, Takeda antagonists such as
TAK-770, and CCR-5 antagonists described in U.S. Pat. No. 6,166,037
(particularly claims 18 and 19), WO 00/66558 (particularly claim
8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO
04/026873.
[0629] The compounds of the invention may be formulated or
administered in conjunction with other agents that act to relieve
the symptoms of inflammatory conditions such as encephalomyelitis,
asthma, and the other diseases described herein. These agents
include non-steroidal anti-inflammatory drugs (NSAIDs), e.g.,
acetylsalicylic acid; ibuprofen; naproxen; indomethacin;
nabumetone; tolmetin; etc. Corticosteroids are used to reduce
inflammation and suppress activity of the immune system. The most
commonly prescribed drug of this type is Prednisone. Chloroquine
(Aralen) or hydroxychloroquine (Plaquenil) may also be very useful
in some individuals with lupus. They are most often prescribed for
skin and joint symptoms of lupus. Azathioprine (Imuran) and
cyclophosphamide (Cytoxan) suppress inflammation and tend to
suppress the immune system. Other agents, e.g., methotrexate and
cyclosporin are used to control the symptoms of lupus.
Anticoagulants are employed to prevent blood from clotting rapidly.
They range from aspirin at very low dose which prevents platelets
from sticking, to heparin/coumadin.
[0630] In one aspect, this invention also relates to methods and
pharmaceutical compositions for inhibiting abnormal cell growth in
a mammal which comprises an amount of an mTorC1/mTorC2 inhibitor of
the present invention, or a pharmaceutically acceptable salt,
ester, prodrug, solvate, hydrate or derivative thereof, in
combination with an amount of an anti-cancer agent (e.g., a
chemotherapeutic agent). Many chemotherapeutics are presently known
in the art and can be used in combination with the compounds of the
invention.
[0631] This invention further relates to a method for using the
compounds or pharmaceutical composition in combination with other
tumor treatment approaches, including surgery, ionizing radiation,
photodynamic therapy, or implants, e.g., with corticosteroids,
hormones, or used as radiosensitizers.
[0632] One such approach may be, for example, radiation therapy in
inhibiting abnormal cell growth or treating the proliferative
disorder in the mammal. Techniques for administering radiation
therapy are known in the art, and these techniques can be used in
the combination therapy described herein. The administration of the
compound of the invention in this combination therapy can be
determined as described herein.
[0633] Radiation therapy can be administered through one of several
methods, or a combination of methods, including without limitation
external-beam therapy, internal radiation therapy, implant
radiation, stereotactic radiosurgery, systemic radiation therapy,
radiotherapy and permanent or temporary interstitial brachytherapy.
The term "brachytherapy," as used herein, refers to radiation
therapy delivered by a spatially confined radioactive material
inserted into the body at or near a tumor or other proliferative
tissue disease site. The term is intended without limitation to
include exposure to radioactive isotopes (e.g., At-211, I-131,
I-125, Y-90, Rel-186, Rel-188, Sm-153, Bi-212, P-32, and
radioactive isotopes of Lu). Suitable radiation sources for use as
a cell conditioner of the present invention include both solids and
liquids. By way of non-limiting example, the radiation source can
be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid
source, I-125 as a solid source, or other radionuclides that emit
photons, beta particles, gamma radiation, or other therapeutic
rays. The radioactive material can also be a fluid made from any
solution of radionuclide(s), e.g., a solution of I-125 or I-131, or
a radioactive fluid can be produced using a slurry of a suitable
fluid containing small particles of solid radionuclides, such as
Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a
gel or radioactive micro spheres.
[0634] Without being limited by any theory, the compounds of the
present invention can render abnormal cells more sensitive to
treatment with radiation for purposes of killing and/or inhibiting
the growth of such cells. Accordingly, this invention further
relates to a method for sensitizing abnormal cells in a mammal to
treatment with radiation which comprises administering to the
mammal an amount of an mTorC1/mTorC2 inhibitor of the present
invention, or a pharmaceutically acceptable salt, ester, prodrug,
solvate, hydrate or derivative thereof, which combined amounts are
effective in sensitizing abnormal cells to treatment with
radiation. The amount of the compound, salt, or solvate in this
method can be determined according to the means for ascertaining
effective amounts of such compounds described herein.
[0635] Photodynamic therapy includes therapy which uses certain
chemicals known as photosensitizing compounds to treat or prevent
cancers. Examples of photodynamic therapy include treatment with
compounds, such as e.g., VISUDYNE and porfimer sodium. Angiostatic
steroids include compounds which block or inhibit angiogenesis,
such as, e.g., anecortave, triamcinolone, hydrocortisone,
11-.alpha.-epihydrocotisol, cortexolone,
17.alpha.-hydroxyprogesterone, corticosterone,
desoxycorticosterone, testosterone, estrone and dexamethasone.
[0636] Implants containing corticosteroids include compounds, such
as e.g., fluocinolone and dexamethasone. Other chemotherapeutic
compounds include, but are not limited to, plant alkaloids,
hormonal compounds and antagonists; biological response modifiers,
preferably lymphokines or interferons; antisense oligonucleotides
or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous
compounds or compounds with other or unknown mechanism of
action.
[0637] The invention also relates to a method of and to a
pharmaceutical composition of treating a cardiovascular disease in
a mammal which comprises administering an amount of an
mTorC1/mTorC2 inhibitor of the present invention, or a
pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate
or derivative thereof, or an isotopically-labeled derivative
thereof, and, separately or in combination with the mTorC1/mTorC2
inhibitor, administering an amount of one or more therapeutic
agents useful for the treatment of cardiovascular diseases.
[0638] Exemplary agents for use in cardiovascular disease
applications are anti-thrombotic agents, e.g., prostacyclin and
salicylates, thrombolytic agents, e.g., streptokinase, urokinase,
tissue plasminogen activator (TPA) and anisoylated
plasminogen-streptokinase activator complex (APSAC), anti-platelets
agents, e.g., acetyl-salicylic acid (ASA) and clopidrogel,
vasodilating agents, e.g., nitrates, calcium channel blocking
drugs, anti-proliferative agents, e.g., colchicine and alkylating
agents, intercalating agents, growth modulating factors such as
interleukins, transformation growth factor-beta and congeners of
platelet derived growth factor, monoclonal antibodies directed
against growth factors, anti-inflammatory agents, both steroidal
and non-steroidal, and other agents that can modulate vessel tone,
function, arteriosclerosis, and the healing response to vessel or
organ injury post intervention. Antibiotics can also be included in
combinations or coatings comprised by the invention. Moreover, a
coating can be used to effect therapeutic delivery focally within
the vessel wall. By incorporation of the active agent in a
swellable polymer, the active agent will be released upon swelling
of the polymer.
[0639] Medicaments which may be administered in conjunction with
the methods described herein include any suitable drugs usefully
delivered by inhalation for example, analgesics, e.g., codeine,
dihydromorphine, ergotamine, fentanyl or morphine; anginal
preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate,
ketotifen or nedocromil; anti-infectives, e.g., cephalosporins,
penicillins, streptomycin, sulphonamides, tetracyclines or
pentamidine; antihistamines, e.g., methapyrilene;
anti-inflammatories, e.g., beclomethasone, flunisolide, budesonide,
tipredane, triamcinolone acetonide or fluticasone; antitussives,
e.g., noscapine; bronchodilators, e.g., ephedrine, adrenaline,
fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine,
phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol,
salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or
(-)-4-amino-3,5-dichloro-.alpha.-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino-
]methyl]benzenemethanol; diuretics, e.g., amiloride;
anticholinergics e.g., ipratropium, atropine or oxitropium;
hormones, e.g., cortisone, hydrocortisone or prednisolone;
xanthines e.g., aminophylline, choline theophyllinate, lysine
theophyllinate or theophylline; and therapeutic proteins and
peptides, e.g., insulin or glucagon. It will be clear to a person
skilled in the art that, where appropriate, the medicaments may be
used in the form of salts (e.g., as alkali metal or amine salts or
as acid addition salts) or as esters (e.g., lower alkyl esters) or
as solvates (e.g., hydrates) to optimize the activity and/or
stability of the medicament.
[0640] Other exemplary therapeutic agents useful for a combination
therapy include but are not limited to agents as described above,
radiation therapy, hormone antagonists, hormones and their
releasing factors, thyroid and antithyroid drugs, estrogens and
progestins, androgens, adrenocorticotropic hormone; adrenocortical
steroids and their synthetic analogs; inhibitors of the synthesis
and actions of adrenocortical hormones, insulin, oral hypoglycemic
agents, and the pharmacology of the endocrine pancreas, agents
affecting calcification and bone turnover: calcium, phosphate,
parathyroid hormone, vitamin D, calcitonin, vitamins such as
water-soluble vitamins, vitamin B complex, ascorbic acid,
fat-soluble vitamins, vitamins A, K, and E, growth factors,
cytokines, chemokines, muscarinic receptor agonists and
antagonists; anticholinesterase agents; agents acting at the
neuromuscular junction and/or autonomic ganglia; catecholamines,
sympathomimetic drugs, and adrenergic receptor agonists or
antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor
agonists and antagonists.
[0641] Therapeutic agents can also include agents for pain and
inflammation such as histamine and histamine antagonists,
bradykinin and bradykinin antagonists, 5-hydroxytryptamine
(serotonin), lipid substances that are generated by
biotransformation of the products of the selective hydrolysis of
membrane phospholipids, eicosanoids, prostaglandins, thromboxanes,
leukotrienes, aspirin, nonsteroidal anti-inflammatory agents,
analgesic-antipyretic agents, agents that inhibit the synthesis of
prostaglandins and thromboxanes, selective inhibitors of the
inducible cyclooxygenase, selective inhibitors of the inducible
cyclooxygenase-2, autacoids, paracrine hormones, somatostatin,
gastrin, cytokines that mediate interactions involved in humoral
and cellular immune responses, lipid-derived autacoids,
eicosanoids, .beta.-adrenergic agonists, ipratropium,
glucocorticoids, methylxanthines, sodium channel blockers, opioid
receptor agonists, calcium channel blockers, membrane stabilizers
and leukotriene inhibitors.
[0642] Additional therapeutic agents contemplated herein include
diuretics, vasopressin, agents affecting the renal conservation of
water, rennin, angiotensin, agents useful in the treatment of
myocardial ischemia, anti-hypertensive agents, angiotensin
converting enzyme inhibitors, .beta.-adrenergic receptor
antagonists, agents for the treatment of hypercholesterolemia, and
agents for the treatment of dyslipidemia.
[0643] Other therapeutic agents contemplated include drugs used for
control of gastric acidity, agents for the treatment of peptic
ulcers, agents for the treatment of gastroesophageal reflux
disease, prokinetic agents, antiemetics, agents used in irritable
bowel syndrome, agents used for diarrhea, agents used for
constipation, agents used for inflammatory bowel disease, agents
used for biliary disease, agents used for pancreatic disease.
Therapeutic agents used to treat protozoan infections, drugs used
to treat Malaria, Amebiasis, Giardiasis, Trichomoniasis,
Trypanosomiasis, and/or Leishmaniasis, and/or drugs used in the
chemotherapy of helminthiasis. Other therapeutic agents include
antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole
quinolones, and agents for urinary tract infections, penicillins,
cephalosporins, and other, .beta.-Lactam antibiotics, an agent
comprising an aminoglycoside, protein synthesis inhibitors, drugs
used in the chemotherapy of tuberculosis, mycobacterium avium
complex disease, and leprosy, antifungal agents, antiviral agents
including nonretroviral agents and antiretroviral agents.
[0644] Examples of therapeutic antibodies that can be combined with
a subject compound include but are not limited to anti-receptor
tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab),
anti CD20 antibodies (rituximab, tositumomab), and other antibodies
such as alemtuzumab, bevacizumab, and gemtuzumab.
[0645] Moreover, therapeutic agents used for immunomodulation, such
as immunomodulators, immunosuppressive agents, tolerogens, and
immunostimulants are contemplated by the methods herein. In
addition, therapeutic agents acting on the blood and the
blood-forming organs, hematopoietic agents, growth factors,
minerals, and vitamins, anticoagulant, thrombolytic, and
antiplatelet drugs.
[0646] Further therapeutic agents that can be combined with a
subject compound may be found in Goodman and Gilman's "The
Pharmacological Basis of Therapeutics" Tenth Edition edited by
Hardman, Limbird and Gilman or the Physician's Desk Reference, both
of which are incorporated herein by reference in their
entirety.
[0647] The examples and preparations provided below further
illustrate and exemplify the compounds of the present invention and
methods of preparing such compounds. It is to be understood that
the scope of the present invention is not limited in any way by the
scope of the following examples and preparations. In the following
examples molecules with a single chiral center, unless otherwise
noted, exist as a racemic mixture. Those molecules with two or more
chiral centers, unless otherwise noted, exist as a racemic mixture
of diastereomers. Single enantiomers/diastereomers may be obtained
by methods known to those skilled in the art.
EXAMPLES
Example 1
Expression and Inhibition Assays of mTOR
[0648] Inhibition of mTor can be measured according to any
procedures known in the art or methods disclosed below. The
compounds described herein and any other mTorC1/mTorC2 inhibitors
known in the art can be tested against recombinant mTOR
(Invitrogen) in an assay containing 50 mM HEPES, pH 7.5, 1 mM EGTA,
10 mM MgCl.sub.2, 2.5 mM, 0.01% Tween, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 mg/mL BSA. Rat recombinant PHAS-1/4EBP1
(Calbiochem; 2 mg/mL) is used as a substrate. Reactions are
terminated by spotting onto nitrocellulose, which is washed with 1M
NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each).
Sheets are dried and the transferred radioactivity quantitated by
phosphorimaging.
[0649] Other kits or systems for assaying mTOR activity are
commercially available. For instance, one can use Invitrogen's
LanthaScreen.TM. Kinase assay to test the inhibitors of mTOR
disclosed herein. This assay is a time resolved FRET platform that
measures the phosphorylation of GFP labeled 4EBP1 by mTOR kinase.
The kinase reaction is performed in a white 384 well microtitre
plate. The total reaction volume is 20 .mu.l per well and the
reaction buffer composition is 50 mM HEPES pH7.5, 0.01% Polysorbate
20, 1 mM EGTA, 10 mM MnCl.sub.2, and 2 mM DTT. In the first step,
each well receives 2 ul of test compound in 20% dimethylsulphoxide
resulting in a 2% DMSO final concentration. Next, 8ul of mTOR
diluted in reaction buffer is added per well for a 60 ng/ml final
concentration. To start the reaction, 10 ul of an ATP/GFP-4EBP1
mixture (diluted in reaction buffer) is added per well for a final
concentration of 10 .mu.M ATP and 0.5 .mu.M GFP-4EBP1. The plate is
sealed and incubated for 1 hour at room temperature. The reaction
is stopped by adding 10 ul per well of a Tb-anti-pT46 4EBP1
antibody/EDTA mixture (diluted in TR-FRET buffer) for a final
concentration of 1.3 nM antibody and 6.7 mM EDTA. The plate is
sealed, incubated for 1 hour at room temperature, and then read on
a plate reader set up for LanthaScreen.TM. TR-FRET. Data is
analyzed and IC50s are generated using GraphPad Prism 5.
Example 2
Kinase Signaling Assays
[0650] PI3K/Akt/mTor signaling is measured in blood cells using the
phosflow method (Methods Enzymol. 2007; 434:131-54). The advantage
of this method is that it is by nature a single cell assay so that
cellular heterogeneity can be detected rather than population
averages. This allows concurrent distinction of signaling states in
different populations defined by other markers. Phosflow is also
highly quantitative. Unfractionated splenocytes, or peripheral
blood mononuclear cells are stimulated with anti-CD3 to initiate
T-cell receptor signaling. The cells are then fixed and stained for
surface markers and intracellular phosphoproteins.
[0651] Human Peripheral Blood Mono-Nucleocyte Biomarker Assay.
[0652] A BD Biosciences Phosflow assay was conducted using human
peripheral blood cells. Whole blood was lysed and fixed using the
provided BD Lyse/Fix buffer and permeabilized with BD Perm III
buffer. Peripheral blood cells were isolated and stained using CD33
and CD20 as extracellular markers and p4E-BP1 (T37/46) as the
intracellular biomarker. Cell type populations were identified as
monocytes (CD33+), granulocytes (CD33 dim), lymphocytes (CD33-),
B-cells (CD33-, CD20+) and T &NK cells (CD33-, CD20-) by FACS
analysis. The median fluorescence intensity (MFI) of each cell type
was analyzed along with the percentage of p4E-BP1 positive cells.
Results are shown in FIG. 5.
[0653] Human Skin Immunohistochemistry Assay.
[0654] Skin tissue was fixed in 10% neutral-buffered formalin
solution for 24 hours and then processed and embedded in paraffin
block. Sections (4 .mu.m) were cut and mounted onto microscopic
slides. Sections were incubated with primary antibodies (p4EBP1,
pS6, or pRAS40) overnight and developed using a chromogenic
substrate.
Example 3
Phase I Clinical Trial
[0655] Adult patients with histologically confirmed advanced solid
tumors were enrolled in a 3+3 dose escalation Phase I study
evaluating 3 intermittent schedules of administration for compound
A: QW (once weekly), QD.times.3d QW (3 days on 4 days off), and
QD.times.5d QW (5 days on 2 days off), in comparison with daily
dosing (QD). Safety, maximum tolerated dose (MTD), pharmacokinetics
(PK) and preliminary antitumor activity were evaluated.
[0656] Comparison of the treatment regimens of the invention showed
consistent and dose-dependent PK as described in FIGS. 1-3.
Compound A was absorbed with a T.sub.max ranging from 0.5 to 4 h
and a mean elimination plasma t.sub.1/2 of 8 h. Plasma exposures
(C.sub.max and AUC.sub.0-24) following oral doses suggest
dose-linear plasma PK. Decreases in p4EBP1 levels were seen in PBC
in all dosing regimens. Skin biopsies showed 60.about.100% pathway
inhibition of TORC1 (p4EBP1 and pS6) and TORC2 (pPRAS40).
Preliminary anti-tumor activity was seen in patients with lung and
renal cancer.
[0657] Pharmacodynamic (PD) endpoints were evaluated in surrogate
(peripheral blood cells [PBCs], skin) and tumor tissues for the
phosphorylation of TORC1-dependent markers (4EBP1/S6), and
TORC2-dependent markers (AKT/PRAS40). 50 patients were treated in 3
intermittent dosing regimens; 21 in 6 cohorts ranging 7-40 mg QW,
20 in 5 cohorts ranging 6-20 mg QD.times.3d QW, and 9 in 3 cohorts
ranging 7-13 mg QD.times.5d QW. Dose limiting toxicities of Grade
(G) 3 asthenia and G3 mucositis were reported in the 40 mg QW, 20
mg QD.times.3d QW; and 13 mg QD.times.5d QW cohorts. The MTD for
intermittent dosing was not reached. All adverse events (AEs)
reported were reversible. The most common (.gtoreq.20%, n=35) AEs
considered possibly related to compound A reported in all 3 dosing
regimens included nausea (51%), hyperglycemia (37%), mucosal
inflammation (29%), rash (23%), asthenia (23%), vomiting (26%), and
diarrhea (20%). The majority of AEs considered possibly related to
compound A in any regimen were Grade 1 or 2. The only reported
Grade.gtoreq.3 AE (.gtoreq.5%) possibly related to compound A in 3
regimens was lymphopenia (6%). Tables 4-9 show summaries of
observed adverse events for various treatment regimens of the
invention.
TABLE-US-00003 TABLE 3 Observed pharmacokinetic and pharmacodynamic
parameters for various treatment regimens using compound A.
Dose/Schedule 6 mg 16 mg 20 mg 10 mg 13 mg 30 mg 40 mg QD Q3D Q3D
Q5D Q5D QW QW Total dose (weekly) 42 48 60 50 65 30 40 C.sub.max
(nM) 150 350 400 250 300 600 700 AUC.sub.wk (h nM) 8000 8000 10000
10000 13000 5000 6500 Time per week (hrs) 20 30 35 25 30 15 20
above 100 nM plasma conc. PD (% inhibition, H score) 60% 80% 80%
80% 80% 80% 80% Skin: 4EBP1/PRAS40 Dose limiting toxicity Rash NA
Mucositis NA NA Asthenia
TABLE-US-00004 TABLE 4 Observed treatment-emergent adverse events
in decreasing order of frequency (daily dosing). Cpd A Cpd A Cpd A
Cpd A Total 2 mg/day 4 mg/day 7 mg/day 6 mg/day QD Dosing Preferred
Term (N = 3) (N = 7) (N = 8) (N = 7) (N = 25) Patients Reporting at
Least 3 (100%) 7 (100%) 8 (100%) 7 (100%) 25 (100%) One Related
TEAE Hyperglycaemia 2 (67%) 5 (71%) 8 (100%) 7 (100%) 22 (88%) Rash
1 (33%) 3 (43%) 4 (50%) 5 (71%) 13 (52%) Nausea 1 (33%) 2 (29%) 3
(38%) 3 (43%) 9 (36%) Pruritus 0 (0%) 2 (29%) 2 (25%) 5 (71%) 9
(36%) Diarrhoea 0 (0%) 0 (0%) 3 (38%) 5 (71%) 8 (32%) Dysgeusia 2
(67%) 3 (43%) 2 (25%) 1 (14%) 8 (32%) Mucosal inflammation 0 (0%) 2
(29%) 4 (50%) 2 (29%) 8 (32%) Asthenia 0 (0%) 0 (0%) 4 (50%) 2
(29%) 6 (24%) Blood creatinine increased 0 (0%) 1 (14%) 4 (50%) 1
(14%) 6 (24%) Decreased appetite 1 (33%) 1 (14%) 3 (38%) 1 (14%) 6
(24%) Fatigue 1 (33%) 2 (29%) 2 (25%) 1 (14%) 6 (24%) Vomiting 0
(0%) 0 (0%) 3 (38%) 3 (43%) 6 (24%) Dry mouth 1 (33%) 1 (14%) 3
(38%) 0 (0%) 5 (20%) Hypercholesterolaemia 0 (0%) 1 (14%) 1 (13%) 3
(43%) 5 (20%) Thrombocytopenia 0 (0%) 1 (14%) 3 (38%) 0 (0%) 4
(16%) Lymphopenia 0 (0%) 1 (14%) 2 (25%) 0 (0%) 3 (12%) Anaemia 0
(0%) 0 (0%) 2 (25%) 0 (0%) 2 (8%) Dehydration 0 (0%) 0 (0%) 2 (25%)
0 (0%) 2 (8%) Coagulopathy 0 (0%) 0 (0%) 1 (13%) 0 (0%) 1 (4%)
Confusional state 0 (0%) 0 (0%) 1 (13%) 0 (0%) 1 (4%) Cough 0 (0%)
0 (0%) 1 (13%) 0 (0%) 1 (4%) Dizziness 0 (0%) 0 (0%) 1 (13%) 0 (0%)
1 (4%) Dry skin 0 (0%) 0 (0%) 1 (13%) 0 (0%) 1 (4%) Dyspepsia 1
(33%) 0 (0%) 0 (0%) 0 (0%) 1 (4%) Dyspnoea 0 (0%) 0 (0%) 1 (13%) 0
(0%) 1 (4%) Dyspnoea exertional 0 (0%) 1 (14%) 0 (0%) 0 (0%) 1 (4%)
Eye infection 0 (0%) 0 (0%) 0 (0%) 1 (14%) 1 (4%) Gastritis 0 (0%)
0 (0%) 1 (13%) 0 (0%) 1 (4%) Gravitational oedema 0 (0%) 0 (0%) 1
(13%) 0 (0%) 1 (4%) Hypocalcaemia 0 (0%) 0 (0%) 1 (13%) 0 (0%) 1
(4%) Insomnia 0 (0%) 0 (0%) 0 (0%) 1 (14%) 1 (4%) Muscle spasms 0
(0%) 0 (0%) 0 (0%) 1 (14%) 1 (4%) Orthostatic hypotension 0 (0%) 0
(0%) 1 (13%) 0 (0%) 1 (4%) Panniculitis 0 (0%) 0 (0%) 1 (13%) 0
(0%) 1 (4%) Polyuria 0 (0%) 1 (14%) 0 (0%) 0 (0%) 1 (4%) Skin
discolouration 0 (0%) 0 (0%) 1 (13%) 0 (0%) 1 (4%) Skin exfoliation
0 (0%) 0 (0%) 1 (13%) 0 (0%) 1 (4%) Weight decreased 0 (0%) 0 (0%)
1 (13%) 0 (0%) 1 (4%)
TABLE-US-00005 TABLE 5 Observed treatment-emergent adverse events
in decreasing order of frequency (weekly dosing). Cpd A Cpd A Cpd A
Cpd A Cpd A Total Preferred 7 mg/week 10 mg/week 15 mg/week 20
mg/week 30 mg/week QW Dosing Term (N = 3) (N = 3) (N = 3) (N = 3)
(N = 3) (N = 15) Patients Reporting at 3 (100%) 2 (67%) 3 (100%) 2
(67%) 3 (100%) 13 (87%) Least One Related TEAE Nausea 1 (33%) 2
(67%) 2 (67%) 2 (67%) 3 (100%) 10 (67%) Hyperglycaemia 1 (33%) 1
(33%) 2 (67%) 1 (33%) 0 (0%) 5 (33%) Vomiting 2 (67%) 1 (33%) 0
(0%) 1 (33%) 1 (33%) 5 (33%) Diarrhoea 1 (33%) 0 (0%) 0 (0%) 2
(67%) 0 (0%) 3 (20%) Mucosal inflammation 0 (0%) 0 (0%) 0 (0%) 2
(67%) 1 (33%) 3 (20%) Aspartate 1 (33%) 1 (33%) 0 (0%) 0 (0%) 0
(0%) 2 (13%) aminotransferase increased Asthenia 0 (0%) 0 (0%) 0
(0%) 2 (67%) 0 (0%) 2 (13%) HYPERGLYCEMIA 0 (0%) 0 (0%) 0 (0%) 0
(0%) 2 (67%) 2 (13%) ASTHENIA 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (33%) 1
(7%) ATHENIA 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (33%) 1 (7%) Alanine 1
(33%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (7%) aminotransferase increased
Blood creatinine 0 (0%) 0 (0%) 1 (33%) 0 (0%) 0 (0%) 1 (7%)
increased Blood triglycerides 0 (0%) 0 (0%) 1 (33%) 0 (0%) 0 (0%) 1
(7%) increased DIARRHEA 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (33%) 1 (7%)
Decreased appetite 0 (0%) 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (7%)
Dysgeusia 1 (33%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (7%) Dyspepsia 0
(0%) 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (7%) Lymphopenia 1 (33%) 0 (0%)
0 (0%) 0 (0%) 0 (0%) 1 (7%) Malaise 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1
(33%) 1 (7%) Muscle spasms 0 (0%) 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1
(7%) Oral discomfort 0 (0%) 1 (33%) 0 (0%) 0 (0%) 0 (0%) 1 (7%)
Pruritus 0 (0%) 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (7%) RASH 0 (0%) 0
(0%) 0 (0%) 0 (0%) 1 (33%) 1 (7%) Rash 0 (0%) 0 (0%) 0 (0%) 1 (33%)
0 (0%) 1 (7%) WEAKNESS 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (33%) 1
(7%)
TABLE-US-00006 TABLE 6 Observed treatment-emergent adverse events
in decreasing order of frequency (3 days on/4 days off dosing). Cpd
A Cpd A Total Cpd A 6 mg/ Cpd A 9 mg/ 12 mg/ 16 mg/ QDx3d 3W 3W 3W
3W QW Preferred Term (N = 3) (N = 5) (N = 3) (N = 3) (N = 14)
Patients Reporting at Least One 3 (100%) 4 (80%) 2 (67%) 2 (67%) 11
(79%) Related TEAE Mucosal inflammation 2 (67%) 2 (40%) 1 (33%) 2
(67%) 7 (50%) Hyperglycaemia 1 (33%) 1 (20%) 2 (67%) 2 (67%) 6
(43%) Nausea 2 (67%) 2 (40%) 2 (67%) 0 (0%) 6 (43%) Pruritus 1
(33%) 2 (40%) 1 (33%) 0 (0%) 4 (29%) Rash 1 (33%) 3 (60%) 0 (0%) 0
(0%) 4 (29%) Asthenia 0 (0%) 1 (20%) 1 (33%) 1 (33%) 3 (21%)
Vomiting 1 (33%) 2 (40%) 0 (0%) 0 (0%) 3 (21%) Diarrhoea 0 (0%) 1
(20%) 0 (0%) 1 (33%) 2 (14%) Asthenia 0 (0%) 0 (0%) 0 (0%) 1 (33%)
1 (7%) Alanine aminotransferase 1 (33%) 0 (0%) 0 (0%) 0 (0%) 1 (7%)
increased Catheter site inflammation 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1
(7%) Catheter site pain 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (7%)
Decreased appetite 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (7%) Dry skin 0
(0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%) Dysgeusia 0 (0%) 0 (0%) 1 (33%) 0
(0%) 1 (7%) Dyspnoea 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%) Fatigue 0
(0%) 0 (0%) 0 (0%) 1 (33%) 1 (7%) Headache 0 (0%) 0 (0%) 0 (0%) 1
(33%) 1 (7%) Hyperbilirubinaemia 1 (33%) 0 (0%) 0 (0%) 0 (0%) 1
(7%) Hypercholesterolaemia 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%)
Hypertransaminasaemia 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%)
Hypertriglyceridaemia 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%)
Hypomagnesaemia 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%) Hypotension 0
(0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%) Low fever 0 (0%) 0 (0%) 0 (0%) 1
(33%) 1 (7%) Lymphopenia 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%)
Palmar-plantar 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%)
erythrodysaesthesia syndrome Platelet count decreased 1 (33%) 0
(0%) 0 (0%) 0 (0%) 1 (7%) Pyrexia 0 (0%) 0 (0%) 0 (0%) 1 (33%) 1
(7%) Rash macular 0 (0%) 0 (0%) 1 (33%) 0 (0%) 1 (7%) Urinary tract
infection 0 (0%) 1 (20%) 0 (0%) 0 (0%) 1 (7%)
TABLE-US-00007 TABLE 7 Observed treatment-emergent adverse events
in decreasing order of frequency (5 days on/2 days off dosing). Cpd
A Cpd A Total 7 mg/5W 10 mg/5W QDx5d QW Preferred Term (N = 3) (N =
3) (N = 6) Patients Reporting at 1 (33%) 1 (33%) 2 (33%) Least One
Related TEAE Diarrhoea 1 (33%) 0 (0%) 1 (17%) Nausea 0 (0%) 1 (33%)
1 (17%) Nausea 1 (33%) 0 (0%) 1 (17%) Rash 1 (33%) 0 (0%) 1 (17%)
Urine tract infection 0 (0%) 1 (33%) 1 (17%) Vomiting 0 (0%) 1
(33%) 1 (17%)
TABLE-US-00008 TABLE 8 Observed treatment-emergent adverse events
in various treatment regimens. Total Total Total Total QD QW QDx3d
QDx5d Dosing Dosing QW QW Total Preferred Term (N = 25) (N = 15) (N
= 14) (N = 6) (N = 60) Catheter site inflammation 0 (0%) 0 (0%) 1
(7%) 0 (0%) 1 (2%) Catheter site pain 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1
(2%) Coagulopathy 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Confusional
state 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Cough 1 (4%) 0 (0%) 0 (0%)
0 (0%) 1 (2%) Diarrhea 0 (0%) 1 (7%) 0 (0%) 0 (0%) 1 (2%) Dizziness
1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Dyspnoea exertional 1 (4%) 0
(0%) 0 (0%) 0 (0%) 1 (2%) Eye infection 1 (4%) 0 (0%) 0 (0%) 0 (0%)
1 (2%) Fatigue 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%) Gastritis 1 (4%)
0 (0%) 0 (0%) 0 (0%) 1 (2%) Gravitational oedema 1 (4%) 0 (0%) 0
(0%) 0 (0%) 1 (2%) Headache 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%)
Hyperbilirubinaemia 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%)
Hypertransaminasaemia 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%)
Hypertriglyceridaemia 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%)
Hypocalcaemia 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Hypomagnesaemia 0
(0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%) Hypotension 0 (0%) 0 (0%) 1 (7%) 0
(0%) 1 (2%) Insomnia 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Low fever 0
(0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%) Malaise 0 (0%) 1 (7%) 0 (0%) 0
(0%) 1 (2%) Nausea 0 (0%) 0 (0%) 0 (0%) 1 (17%) 1 (2%) Oral
discomfort 0 (0%) 1 (7%) 0 (0%) 0 (0%) 1 (2%) Orthostatic
hypotension 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Palmar-plantar
erythrodysaesthesia 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%) syndrome
Panniculitis 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Platelet count
decreased 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%) Polyuria 1 (4%) 0 (0%)
0 (0%) 0 (0%) 1 (2%) Pyrexia 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%)
Rash 0 (0%) 1 (7%) 0 (0%) 0 (0%) 1 (2%) Rash macular 0 (0%) 0 (0%)
1 (7%) 0 (0%) 1 (2%) Skin discolouration 1 (4%) 0 (0%) 0 (0%) 0
(0%) 1 (2%) Skin exfoliation 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%)
Urine tract infection 0 (0%) 0 (0%) 0 (0%) 1 (17%) 1 (2%) Urinary
tract infection 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%) Vomiting 0 (0%)
0 (0%) 0 (0%) 1 (17%) 1 (2%) Weakness 0 (0%) 1 (7%) 0 (0%) 0 (0%) 1
(2%) Weight decreased 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%)
TABLE-US-00009 TABLE 9 Grade 3 or greater treatment-emergent
adverse events for various treatment regimens. Total Total Total
Total QD QW QDx3d QDx5d Dosing Dosing QW QW Total Preferred Term (N
= 25) (N = 15) (N = 14) (N = 6) (N = 60) Patients Reporting at
Least 15 (60%) 3 (20%) 7 (50%) 0 (0%) 25 (42%) One Grade 3 or
Greater TEAE Rash 7 (28%) 0 (0%) 0 (0%) 0 (0%) 7 (12%)
Hyperglycaemia 4 (16%) 0 (0%) 1 (7%) 0 (0%) 5 (8%) Lymphopenia 2
(8%) 1 (7%) 1 (7%) 0 (0%) 4 (7%) Diarrhoea 1 (4%) 1 (7%) 1 (7%) 0
(0%) 3 (5%) Gamma-glutamyltransferase 0 (0%) 1 (7%) 1 (7%) 0 (0%) 2
(3%) increased Hypokalaemia 2 (8%) 0 (0%) 0 (0%) 0 (0%) 2 (3%)
Hyponatraemia 2 (8%) 0 (0%) 0 (0%) 0 (0%) 2 (3%) Pruritus 2 (8%) 0
(0%) 0 (0%) 0 (0%) 2 (3%) Thrombocytopenia 2 (8%) 0 (0%) 0 (0%) 0
(0%) 2 (3%) Abdominal pain upper 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%)
Anaemia 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Aspartate
aminotransferase 0 (0%) 1 (7%) 0 (0%) 0 (0%) 1 (2%) increased
Asthenia 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%) Catheter related
infection 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Cellulitis 1 (4%) 0
(0%) 0 (0%) 0 (0%) 1 (2%) Disease progression 0 (0%) 0 (0%) 1 (7%)
0 (0%) 1 (2%) Enterocutaneous fistula 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1
(2%) Gastroenteritis 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%)
Pancreatitis acute 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Pleural
effusion 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) Rash macular 0 (0%) 0
(0%) 1 (7%) 0 (0%) 1 (2%) Somnolence 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1
(2%) Urinary tract infection 0 (0%) 0 (0%) 1 (7%) 0 (0%) 1 (2%)
TABLE-US-00010 TABLE 10 Results of an additional study showing
grade 3 or greater treatment-emergent adverse events for various
treatment regimens. Total Total Total Total QD QW QDx3d QDx5d
Dosing Dosing QW QW Total Preferred Term (N = 29) (N = 22) (N = 25)
(N = 15) (N = 91) Patients Reporting at least one Grade 3 17 (59%)
10 (45%) 18 (72%) 8 (53%) 53 (58%) or greater TEAE Hyperglycaemia 4
(14%) 0 (0%) 4 (16%) 1 (7%) 9 (10%) Rash 7 (24%) 0 (0%) 1 (4%) 1
(7%) 9 (10%) Mucosal Inflammation 0 (0%) 0 (0%) 4 (16%) 3 (20%) 7
(8%) Anaemia 1 (3%) 2 (9%) 2 (8%) 1 (7%) 6 (7%) Lymphopenia 2 (7%)
1 (5%) 2 (8%) 1 (7%) 6 (7%) Hypophsphataemia 0 (0%) 0 (0%) 3 (12%)
2 (13%) 5 (5%) Asthenia 1 (3%) 1 (5%) 1 (4%) 1 (7%) 4 (4%)
Diarrhoea 1 (3%) 1 (5%) 1 (4%) 0 (0%) 3 (3%) Fatigue 0 (0%) 1 (5%)
0 (0%) 2 (13%) 3 (3%) Gamma-glutamyltransferase increase 0 (0%) 1
(5%) 1 (4%) 1 (7%) 3 (3%) Hypokalaemia 2 (7%) 1 (5%) 0 (0%) 0 (0%)
3 (3%) Pruritus 2 (7%) 0 (0%) 1 (4%) 0 (0%) 3 (3%) Vomiting 0 (0%)
1 (5%) 1 (4%) 1 (7%) 3 (3%) Aspartate aminotransferase increase 0
(0%) 1 (5%) 0 (0%) 1 (7%) 2 (2%) Blood creatinine increase 0 (0%) 0
(0%) 2 (8%) 0 (0%) 2 (2%) Deep vein thrombosis 0 (0%) 1 (5%) 1 (4%)
0 (0%) 2 (2%) Disease progression 0 (0%) 2 (9%) 0 (0%) 0 (0%) 2
(2%) Hyponatraemia 2 (7%) 0 (0%) 0 (0%) 0 (0%) 2 (2%) Muscular
weakness 0 (0%) 1 (5%) 1 (4%) 0 (0%) 2 (2%) Nausea 0 (0%) 0 (0%) 1
(4%) 1 (7%) 2 (2%) Neutropenia 0 (0%) 1 (5%) 0 (0%) 1 (7%) 2 (2%)
Thrombocytopenia 2 (7%) 0 (0%) 0 (0%) 0 (0%) 2 (2%)
[0658] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *
References