U.S. patent application number 13/893163 was filed with the patent office on 2014-05-08 for benzoxazole kinase inhibitors and methods of use.
This patent application is currently assigned to Intellikine LLC. The applicant listed for this patent is Intellikine LLC La Jolla. Invention is credited to Katrina Chan, Liansheng Li, Yi Liu, Pingda Ren, Troy Edward Wilson.
Application Number | 20140128599 13/893163 |
Document ID | / |
Family ID | 42337454 |
Filed Date | 2014-05-08 |
United States Patent
Application |
20140128599 |
Kind Code |
A1 |
Ren; Pingda ; et
al. |
May 8, 2014 |
BENZOXAZOLE KINASE INHIBITORS AND METHODS OF USE
Abstract
The present invention provides chemical entities or compounds
and pharmaceutical compositions thereof that are capable of
modulating certain protein kinases such as mTor, tyrosine kinases,
and/or lipid kinases such as PI3 kinase. Also provided in the
present invention are methods of using these compositions to
modulate activities of one or more of these kinases, especially for
therapeutic applications.
Inventors: |
Ren; Pingda; (San Diego,
CA) ; Liu; Yi; (San Diego, CA) ; Li;
Liansheng; (San Diego, CA) ; Chan; Katrina;
(Fremont, CA) ; Wilson; Troy Edward; (San Marino,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Intellikine LLC La Jolla |
La Jolla |
CA |
US |
|
|
Assignee: |
Intellikine LLC
La Jolla
CA
|
Family ID: |
42337454 |
Appl. No.: |
13/893163 |
Filed: |
May 13, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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12586241 |
Sep 17, 2009 |
8476431 |
|
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13893163 |
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61198200 |
Nov 3, 2008 |
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61201923 |
Dec 16, 2008 |
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61214261 |
Apr 20, 2009 |
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61230655 |
Jul 31, 2009 |
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Current U.S.
Class: |
544/118 ;
544/262 |
Current CPC
Class: |
A61K 9/0078 20130101;
A61K 39/3955 20130101; A61K 31/7068 20130101; A61P 35/00 20180101;
C07F 5/025 20130101; A61K 31/275 20130101; A61K 9/0014 20130101;
A61K 45/06 20130101; A61K 9/0053 20130101; A61K 31/5377 20130101;
C07D 413/14 20130101; A61K 9/0019 20130101; C07D 487/04 20130101;
C07D 413/04 20130101; A61K 31/455 20130101; A61K 31/337 20130101;
A61K 31/519 20130101; A61K 31/275 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
544/118 ;
544/262 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1-55. (canceled)
56. A compound of the formula: ##STR00385## or a pharmaceutically
acceptable salt thereof.
57. A composition comprising the compound or pharmaceutically
acceptable salt of claim 56 and a pharmaceutically acceptable
carrier.
58. A method of ameliorating a disorder comprising administering to
a subject in need thereof an effective amount of the compound,
pharmaceutically acceptable salt or composition of claims 56 or
57.
59. The method according to claim 58, wherein said disorder is
selected from the group consisting of hyperproliferative disorder,
bone disorder, inflammatory disease, immune disease, nervous system
disease, metabolic disease, angiogenic disease, ophthalmic disease,
respiratory disease, and cardiac disease.
60. The method according to claim 59, wherein said disorder is
cancer.
61. The method according to claim 60, wherein said cancer is
selected from the group consisting of fibrosarcoma, pancreatic
cancer, kidney cancer, liver cancer, osteosarcoma melanoma,
nasopharyngeal cancer, gastric cancer, ovarian cancer, leukemia,
myeloma, breast cancer, prostate cancer, colorectal cancer, lung
cancer, glioblastoma, endometrial cancer, neuroendocrine cancer,
bladder cancer, mesothelioma, head and neck cancer, and cervical
cancer.
Description
[0001] This application is a Continuation application which claims
the benefit of U.S. application Ser. No. 12/586,241, filed Sep. 17,
2009, which claims the benefit of U.S. Provisional Application Ser.
No. 61/198,200, filed on Nov. 3, 2008; U.S. Provisional Application
Ser. No. 61/201,923, filed Dec. 16, 2008; U.S. Provisional
Application Ser. No. 61/214,261, filed Apr. 20, 2009; and U.S.
Provisional Application Ser. No. 61/230,655, filed Jul. 31, 2009,
each of which is hereby incorporated 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.alpha., p110k, p110.delta., and
p110.gamma.) 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 posseses
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 wid 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. The present invention addresses this need in
the art by providing a new class of kinase inhibitors.
SUMMARY OF THE INVENTION
[0013] In one aspect of the invention, compounds are provided of
the Formula I'-A':
##STR00001##
[0014] or a pharmaceutically acceptable salt thereof wherein:
[0015] 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; and wherein no
more than two nitrogen ring atoms are adjacent;
[0016] R.sub.1 is H, -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkcyl,
-L-C.sub.1-10alkyl-C.sub.3-8-cycloalkyl, -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.3-8cycloalkcyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkcyl, -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;
[0017] 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)--;
[0018] M.sub.1 is benzoxazolyl substituted with
--(W.sup.2).sub.k--R.sup.2;
[0019] k is 0 or 1;
[0020] E.sup.1 and E.sup.2 are independently --(W).sub.j--R.sup.4;
j in E.sup.1 or j in E.sup.2, is independently 0 or 1; [0021]
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--;
[0022] 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--;
[0023] 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.3-8cycloalkcyl-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.3-8cycloalkcyl, 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.3-8-cycloalkyl,
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(O)NR.sup.31R.sup.32;
[0024] 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(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;
[0025] 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(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;
[0026] 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0027] 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;
[0028] 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;
[0029] 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.0-2
C.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; and
[0030] 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(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.
[0031] In some embodiments, X.sub.4 is C--R.sup.9. In other
embodiments, X.sub.4 is N.
[0032] The invention also provides a compound as defined above,
wherein the compound is of Formula I-A:
##STR00002##
or a pharmaceutically acceptable salt thereof, and wherein the
substituents are as defined above.
[0033] In some embodiments of the compounds of Formula I'-A' or
I-A, X.sub.3 is N.
[0034] In a second aspect, the invention provides a compound of
Formula II-A-1:
##STR00003##
[0035] or a pharmaceutically acceptable salt thereof wherein:
[0036] X.sub.1 is N or C-E.sup.1 and X.sub.2 is N; or X.sub.1 is NH
or CH-E.sup.1 and X.sub.2 is C;
[0037] R.sub.1 is H, -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkcyl,
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkcyl, -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.3-8cycloalkcyl,
-L-C.sub.2-10alkynyl-C.sub.3-8cycloalkcyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C.sub.3-8cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3;
and 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);
[0038] k is 0 or 1;
[0039] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0040] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0041] 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--;
[0042] 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--;
[0043] 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.31,
--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.2-10-alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.1-10alkyl (e.g.
monocyclic aryl-C.sub.2-10alkcyl, 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;
[0044] 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(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.1-10alkyl,
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.3-10cycloalkyl,
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.34, --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;
[0045] 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;
[0046] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(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;
[0047] 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;
and
[0048] 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; or R.sup.6
is 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, 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,
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.
[0049] In a third aspect, the invention provides a compound of
Formula III:
##STR00004##
[0050] or a pharmaceutically acceptable salt thereof wherein:
[0051] X.sub.1 is N or C-E.sup.1 and X.sub.2 is N; or X.sub.1 is NH
or CH-E.sup.1 and X.sub.2 is C;
[0052] 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;
[0053] 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)--;
[0054] M.sub.1 is benzoxazolyl substituted with
--(W.sup.2).sub.k--R.sup.2;
[0055] k is 0 or 1;
[0056] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0057] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0058] 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--;
[0059] 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--;
[0060] 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.33, --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.33, 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;
[0061] 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.31CR.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, 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.3-8cycloakyl-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.1-10allyl, 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(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.34NR.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;
[0062] each of R.sup.31, R.sup.32, and R.sup.33 is 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 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;
[0063] 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;
[0064] 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;
[0065] 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.0-2
C.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; and
[0066] 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.0-2
C.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.
[0067] In yet another aspect, the invention provides a compound of
Formula IV-A-1:
##STR00005##
[0068] or a pharmaceutically acceptable salt thereof wherein:
[0069] X.sub.1 is N or C-E.sup.1 and X.sub.2 is N; or X.sub.1 is NH
or CH-E.sup.1 and X.sub.2 is C;
[0070] R.sub.1 is --H, -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkcyl,
-L-C.sub.1-10alkyl-C.sub.3-8cycloalkcyl, -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.3-8cycloalkcyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C.sub.3-8cycloalkcyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0071] 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)--;
[0072] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0073] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0074] 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--;
[0075] 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--;
[0076] k is 0 or 1;
[0077] R.sup.2, 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(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.3-8cycloalkcyl,
C.sub.1-10alkyl-C.sub.3-8cycloalkcyl,
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.3-8cycloalkcyl, 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
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;
[0078] each of R.sup.31, R.sup.32, and R.sup.33 is 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 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0079] 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;
[0080] 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;
[0081] 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.2NR.sup.31R.sup.32,
--NR.sup.31R.sup.32, or --NR.sup.34R.sup.35; and
[0082] 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.0-2
C.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.
[0083] In another aspect, the invention provides a compound of
Formula IV-A or Formula IV-B:
##STR00006##
or pharmaceutically acceptable salt thereof wherein:
[0084] 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 CR.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 CR.sup.9 or N;
[0085] 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.3-8cycloalkcyl, -L-heteroalkyl,
-L-heteroalkylaryl, -L-heteroalkylheteroaryl,
-L-heteroalkyl-heterocylyl, -L-heteroalkyl-C.sub.3-8cycloalkcyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0086] 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);
[0087] k is 0 or 1;
[0088] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0089] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0090] 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--;
[0091] 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--;
[0092] 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(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.1-10alkyl,
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.3-8cycloakyl-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.3-8cycloalkcyl, 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;
[0093] 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;
[0094] 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;
[0095] 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 alkyl, 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0096] 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;
[0097] 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;
[0098] 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.0-2
C.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.34R.sup.35, or --NR.sup.34R.sup.35; and
[0099] 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.0-2
C.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.
[0100] In one embodiment of the compounds of the invention, X.sub.4
is CR.sup.9. In another embodiment, X.sub.4 is N.
[0101] In some embodiments of the compounds of the invention,
E.sup.2 is --H. In some embodiments of the compounds of the
invention, X.sub.1 is N and X.sub.2 is N. In other embodiments of
the compounds of the invention, X.sub.1 is C-E.sup.1 and X.sub.2 is
N. In one embodiment of the compounds of the invention, X.sub.1 is
NH and X.sub.2 is C.
[0102] In some embodiments of the compounds of the invention,
R.sub.31 and R.sub.32 are --H.
[0103] In some embodiments of the compounds of Formula I'-A', I-A,
I-B, III (including III-A and III-B), C, or C'', 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. In some embodiments, M.sub.1 is
either a 5-benzoxazolyl or a 6-benzoxazolyl moiety, optionally
substituted at its 2-position with --(W.sub.2).sub.k--R.sub.2.
[0104] In some embodiments of the compounds of the invention,
M.sub.1 is a moiety having one of the following structures:
##STR00007##
[0105] In some embodiments of the compounds of the invention,
--(W.sup.2)k- is --NR.sup.7--, --N(R.sup.7)C(O)--,
--N(R.sup.7)C(O)N(R.sup.8)--, or --N(R.sup.7)S(O).sub.2--. In other
embodiments of the compounds of the invention, --(W.sup.2).sub.k--
is --NH--. In another embodiment of the compounds of the invention,
--(W.sup.2).sub.k-- is --(CH).sub.2--. In yet another embodiment of
the compounds of the invention, --(W.sup.2).sub.k-- is --NHC(O)--.
In yet another embodiment of the compounds of the invention,
--(W.sup.2).sub.k-- is --N(R.sup.7)C(O)N(R.sup.8)--. In a further
embodiment of the compounds of the invention, --(W.sup.2).sub.k--
is --NHS(O).sub.2--.
[0106] In some embodiments of the compounds of the invention,
R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3,
wherein R.sup.3 is hydrogen, --OH, --OR.sup.31, --C(O)R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35, aryl,
hetaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, or heterocyclyl,
wherein each of said aryl, heteroaryl, alkyl, cycloalkyl, or
heterocyclyl moiety is unsubstituted or is substituted with one or
more alkyl or --OH. In some embodiments of the compounds of the
invention, R.sub.1 is unsubstituted or is substituted with
C.sub.1-10alkyl or cycloC.sub.3-10alkyl.
[0107] In some embodiments of the compounds of the invention,
R.sup.2 is --H. In other embodiments of the compounds of the
invention, R.sup.2 is alkyl. In yet other embodiments of the
compounds of the invention, R.sup.2 is methyl. In other embodiments
of the compounds of the invention, R.sup.2 is isopropyl. In some
embodiments of the compounds of the invention, R.sup.2 is
cycloalkyl. In other embodiments of the compounds of the invention,
R.sup.2 is cyclopropyl.
[0108] In some embodiments of the compounds of the invention,
E.sup.2 is --H; X.sub.1 and X.sub.2 are N; R.sub.1 is
-L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3;
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, hetaryl, 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.2)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.31R.sup.32, or
--SC(.dbd.O)NR.sup.31R.sup.32 s, 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; and wherein --(W.sup.2).sub.k-- is
--NR.sup.7--, --N(R.sup.7)C(O)-- or --N(R.sup.7)S(O).sub.2--.
[0109] The invention also provides a process for synthesizing a
compound of Formula C:
##STR00008##
[0110] comprising the step of allowing a compound of Formula A to
react with a compound of Formula B under conditions that are
effective for synthesizing a compound of Formula C; wherein:
[0111] T.sub.1 is halo;
[0112] 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;
wherein no more than two ring nitrogen atoms of the compound of
Formula A are adjacent; and wherein no more than two ring nitrogen
atoms of the compound of Formula C are adjacent;
[0113] R.sub.1 is hydrogen, -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;
[0114] 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)--;
each of G is independently H or R.sub.G1; and R.sub.G1 is alkyl,
alkenyl, or aryl; or the G groups of
##STR00009##
join together to form a 5- or 6-membered cyclic moiety;
[0115] M of Formula B is a M.sub.1 moiety, and wherein M.sub.1
moiety of Formula B and M.sub.1 moiety of Formula C are identical,
having one of the following structures:
##STR00010##
[0116] E.sup.1 is --(W.sup.1).sub.j--R wherein j is 0 or 1;
[0117] 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)S(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--;
[0118] k is 0 or 1;
[0119] 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--;
[0120] R.sup.2 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --R.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, bicyclic aryl, substituted
monocyclic aryl, hetaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkcyl,
C.sub.1-10allyl-C.sub.3-8cycloalkcyl,
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.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.1-10alkylhetaryl,
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.1-10alkoxyC.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl, or
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-C.sub.2-10alkynyl, hetaryl-C.sub.3-8, 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 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.31R.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,
[0121] 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, --CO)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.33, --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.1-10alkyl,
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.2-10alynyl-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(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;
[0122] R.sup.5 is hydrogen;
[0123] 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0124] 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; [0125] 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;
and
[0126] 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.0-2
C.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, or hetaryl-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, 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
[0127] M.sub.1 of Formula B and M.sub.1 of Formula C are the same;
R.sub.1 of Formula A and R.sub.1 of Formula C are the same;
R.sub.31 of Formula A and R.sub.31 of Formula C are the same;
R.sub.32 of Formula A and R.sub.32 of Formula C are the same;
X.sub.1 of Formula A and X.sub.1 of Formula C are the same; X.sub.2
of Formula A and X.sub.2 of Formula C are the same; and X.sub.3 of
Formula A and X.sub.3 of Formula C are the same.
[0128] In some embodiments of the process for synthesizing a
compound of Formula C, T.sub.1 is iodo or bromo.
[0129] In other embodiments of the process for synthesizing a
compound of Formula C, the compound of Formula B is a compound
having one of the following formulae:
##STR00011## ##STR00012##
[0130] In some embodiments of the process for synthesizing a
compound of Formula C, each of the compound of Formula B and the
compound of Formula C is the compound wherein:
[0131] X.sub.1 and X.sub.2 are N;
[0132] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3
substituents;
[0133] 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, hetaryl, 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, --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; and wherein --(W.sup.2).sub.k-- is
--NR.sup.7--, --N(R.sup.7)C(O)-- or --N(R.sup.7)S(O).sub.2--.
[0134] In some embodiments, the compound of Formula A reacts with
the compound of Formula B in the presence of palladium tetrakis
(triphenylphosphine). In some embodiments, when the compound of
Formula A reacts with the compound of Formula B in the presence of
palladium tetrakis (triphenylphosphine), the palladium tetrakis
(triphenylphosphine) is present in an amount from about 0.07 molar
equivalents to about 0.15 molar equivalents of the compound of
Formula A.
[0135] In another aspect, the invention provides a composition
comprising a compound of Formula A and a compound of Formula B:
##STR00013##
[0136] or a salt thereof, wherein: T is halo; 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; wherein no more than two
ring nitrogen atoms of the compound of Formula A are adjacent; and
wherein no more than two ring nitrogen atoms of the compound of
Formula C are adjacent;
[0137] each of G is independently H or R.sub.G1; and R.sub.G1 is
alkyl, alkenyl, or aryl;
[0138] or the G groups of
##STR00014##
join together to form a 5- or 6-membered cyclic moiety;
[0139] M of Formula B is a M.sub.1 moiety, and wherein M.sub.1 of
Formula B has one of the following structures:
##STR00015##
[0140] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0141] 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--;
[0142] k is 0 or 1;
[0143] 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)--,
--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--;
[0144] R.sub.1 is hydrogen, -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;
[0145] 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)--;
[0146] R.sup.2 is hydrogen, halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --R.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, bicyclic aryl, 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.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.1-10alkylhetaryl,
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.1-10alkoxyC.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl, or
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 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.31R.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 --(.dbd.O)NR.sup.31R.sup.32;
[0147] 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.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10ally-C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloakyl-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.3-8-cycloalkenyl, 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;
[0148] R.sup.5 is hydrogen;
[0149] 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;
[0150] 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.0-2
C.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, or hetaryl-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, 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;
[0151] 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 alkyl, 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
and
[0152] 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.
[0153] In some embodiments of the compositions of the invention,
each of the compound of Formula A and the compound of Formula B is
the compound wherein:
[0154] X.sub.1 and X.sub.2 are N; R.sub.1 is -L-C.sub.1-10alkyl,
-L-C.sub.3-8cycloalkyl, -L-C.sub.1-10alkylheterocylyl, or
-L-heterocyclyl, each of which is unsubstituted or is substituted
by one or more independent R.sup.3 substituents; 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,
hetaryl, 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, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.34R.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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32; and wherein --(W.sup.2).sub.k-- is
--NR.sup.7--, --N(R.sup.7)C(O)-- or --N(R.sup.7)S(O).sub.2--.
[0155] In some embodiments of the compositions of the invention,
the composition further comprises a compound of Formula C:
##STR00016##
or a salt thereof, wherein:
[0156] M.sub.1 of Formula B and M.sub.1 of Formula C are the same;
R.sub.1 of Formula A and R.sub.1 of Formula C are the same;
R.sub.31 of Formula A and R.sub.31 of Formula C are the same;
R.sub.32 of Formula A and R.sub.32 of Formula C are the same;
X.sub.1 of Formula A and X.sub.1 of Formula C are the same; X.sub.2
of Formula A and X.sub.2 of Formula C are the same; and X.sub.3 of
Formula A and X.sub.3 of Formula C are the same.
[0157] In some embodiments of the compositions of the invention,
the composition further comprises an organic solvent.
[0158] In another aspect, the invention provides a process for
synthesizing a compound of Formula G-6-B:
##STR00017##
comprising the step of allowing a compound of Formula G-6 to react
with an acid under conditions effective for synthesizing a compound
of Formula G-6-B.
[0159] In some embodiments of the process for synthesizing a
compound of Formula G-6-B, the acid is hydrochloric acid.
[0160] In another aspect, the invention provides a process for
synthesizing a compound of Formula G-6:
##STR00018##
comprising the step of allowing a compound of Formula 1-2 to react
with bis(pinacolato)diboron under conditions effective for
synthesis of the compound of Formula G-6.
[0161] In yet another aspect, the invention provides a process for
synthesizing a compound of Formula 1-2:
##STR00019##
comprising the step of allowing a compound of Formula 1-1 to react
with a cyanogen halide under conditions effective to synthesize the
compound of Formula 1-2.
[0162] In some embodiments of the process for synthesizing a
compound of Formula 1-2, the cyanogen halide is cyanogen
bromide.
[0163] In a further aspect, the invention provides a process for
synthesizing a compound of Formula B:
##STR00020##
comprising the step of allowing a compound of Formula D to react
with a base and a trialkyl borate under conditions effective to
synthesize a compound of Formula B; wherein: G is alkyl; T.sub.2 is
halo, triflate, tosylate or mesylate; each of M of Formula D and M
of Formula B is a M.sub.1 moiety, and wherein M.sub.1 moiety of
Formula D and M.sub.1 moiety of Formula B are identical, having one
of the following structures:
##STR00021##
[0164] R.sup.5 is hydrogen; k is 1; --W.sup.2--R.sup.2 is
--NH-G.sub.p;
[0165] G.sub.p is acetyl, tert-butyl carbamate (Boc),
carbobenzyloxy (Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl
(FMOC), or p-methoxybenzyl (PMB); and wherein G.sub.p of Formula D
and G.sub.p of Formula B are the same.
[0166] In other embodiments of the process for synthesizing a
compound of Formula B, the base is n-butyllithium. In yet other
embodiments, the trialkyl borate is triisopropyl borate. In some
embodiments of the process for synthesizing a compound of Formula
B, each of the compound of Formula D and the compound of Formula B
is the compound wherein --(W.sup.2).sub.k-- is --NR.sup.7--,
--N(R.sup.7)C(O)-- or --N(R.sup.7)S(O).sub.2--.
[0167] In some embodiments, the process further comprises the step
of allowing the compound of Formula B wherein --W.sup.2--R.sup.2 is
--NH-G.sub.p and G.sub.p is tert-butyl carbamate to react with a
reagent under conditions effective to yield a compound of Formula
B, wherein --W.sup.2--R.sup.2 is --NH.sub.2. In some embodiments,
the reagent is hydrochloric acid.
[0168] In yet another aspect, the invention provides a process for
synthesizing a compound of Formula 3-4:
##STR00022##
[0169] comprising the step of allowing a compound of Formula 3-3 to
react with a cyanogen halide under conditions effective for
synthesizing a compound of Formula 3-4; wherein:
[0170] 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;
wherein no more than two ring nitrogen atoms of the compound of
Formula 3-3 are adjacent; and wherein no more than two ring
nitrogen atoms of the compound of Formula 3-4 are adjacent;
[0171] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0172] 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--;
[0173] R.sub.1 is hydrogen, -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.3-8-cycloalkyl,
-L-aralkyl, -L-heteroaralkyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0174] 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)--;
[0175] 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.33, --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.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.1-10alkyl-C.sub.3-8-cycloalkyl,
C.sub.3-8cycloalkyl-C.sub.1-10alkyl,
C.sub.3-8cycloalkyl-C.sub.2-10alkenyl,
C.sub.3-8cycloakyl-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(O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0176] 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 alkyl, 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(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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0177] 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; [0178] 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;
and
[0179] R.sup.6 is halo, --OR.sup.31, --SH, NH.sub.2,
--NR.sup.34R.sup.31, --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.0-2
C.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, or hetaryl-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, 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
[0180] wherein R.sub.1 of Formula 3-3 and R.sub.1 of Formula 3-4
are the same; R.sub.31 of Formula 3-3 and R.sub.31 of Formula 3-4
are the same; R.sub.32 of Formula 3-3 and R.sub.32 of Formula 3-4
are the same; X.sub.1 of Formula 3-3 and X.sub.1 of Formula 3-4 are
the same; X.sub.2 of Formula 3-3 and X.sub.2 of Formula 3-4 are the
same; and X.sub.3 of Formula 3-3 and X.sub.3 of Formula 3-4 are the
same.
[0181] In some embodiments of the process of the invention, each of
the compound of Formula 3-3 and the compound of Formula 3-4 is the
compound wherein:
[0182] X.sub.1 and X.sub.2 are N;
[0183] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3
substituents; and wherein
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, hetaryl, 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, --OC(.dbd.O)OR.sup.33,
--OC(.dbd.O)NR.sup.34R.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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32.
[0184] In some embodiments for synthesizing a compound of Formula
3-4, the cyanogen halide is cyanogen bromide.
[0185] In another aspect, the invention provides a process for
synthesizing a compound of Formula 3-3:
##STR00023##
[0186] comprising the step of allowing a compound of Formula 3-2 to
react with a reagent under conditions effective to synthesize a
compound of Formula 3-3; wherein;
[0187] 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;
wherein no more than two ring nitrogen atoms of the compound of
Formula 3-3 are adjacent; and wherein no more than two ring
nitrogen atoms of the compound of Formula 3-4 are adjacent;
[0188] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0189] 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--;
[0190] R.sub.1 is hydrogen, -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;
[0191] 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)--;
[0192] 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)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.1-10alkyl,
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;
[0193] 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 alkyl, 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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.31;
[0194] 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; [0195] 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;
and
[0196] 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.0-2
C.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, or hetaryl-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, haloC.sub.2-10alkenyl, haloC.sub.2-10alkynyl,
--COOH, --C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.31R.sup.32,
--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
[0197] wherein R.sub.1 of Formula 3-2 and R.sub.1 of Formula 3-3
are the same; R.sub.31 of Formula 3-2 and R.sub.31 of Formula 3-3
are the same; R.sub.32 of Formula 3-2 and R.sub.32 of Formula 3-3
are the same; X.sub.1 of Formula 3-2 and X.sub.1 of Formula 3-3 are
the same; X.sub.2 of Formula 3-2 and X.sub.2 of Formula 3-3 are the
same; and X.sub.3 of Formula 3-2 and X.sub.3 of Formula 3-3 are the
same.
[0198] In some embodiments of the process for synthesizing a
compound of Formula 3-3, the reagent is (a) sodium dithionite or
(b) palladium on carbon in the presence of hydrogen gas.
[0199] In some embodiments of the process for synthesizing a
compound of Formula 3-3, each of the compound of Formula 3-2 and
the compound of Formula 3-3 is a compound wherein: X.sub.1 and
X.sub.2 are N; R.sub.1 is -L-C.sub.1-10alkyl,
-L-C.sub.3-8cycloalkyl, -L-C.sub.1-10alkylheterocylyl, or
-L-heterocyclyl, each of which is unsubstituted or is substituted
by one or more independent R.sup.3 substituents; and wherein
[0200] 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, hetaryl, 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, --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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32.
[0201] In another aspect, the invention provides a process for
synthesizing a compound of Formula 3-2:
##STR00024##
[0202] comprising the step of allowing a compound of Formula 3-1 to
react with a reagent under conditions effective to synthesize the
compound of Formula 3-2; wherein:
[0203] 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;
wherein no more than two ring nitrogen atoms of the compound of
Formula 3-1 are adjacent; and wherein no more than two ring
nitrogen atoms of the compound of Formula 3-2 are adjacent;
[0204] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0205] 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)S(O).sub.2--;
[0206] R.sub.1 is hydrogen, -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;
[0207] 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)--;
[0208] 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(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.1-10alkyl,
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;
[0209] 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 alkyl, 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0210] 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;
[0211] 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;
and
[0212] 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.0-2
C.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, or hetaryl-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, 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
[0213] wherein R.sub.1 of Formula 3-1 and R.sub.1 of Formula 3-23
are the same; R.sub.31 of Formula 3-1 and R.sub.31 of Formula 3-2
are the same; R.sub.32 of Formula 3-1 and R.sub.32 of Formula 3-2
are the same; X.sub.1 of Formula 3-1 and X.sub.1 of Formula 3-2 are
the same; X.sub.2 of Formula 3-1 and X.sub.2 of Formula 3-2 are the
same; and X.sub.3 of Formula 3-1 and X.sub.3 of Formula 3-2 are the
same.
[0214] In some embodiments of the process for synthesizing a
compound of Formula 3-2, the reagent is nitric acid.
[0215] In some embodiments of the process for synthesizing a
compound of Formula 3-2, each of the compound of Formula 3-1 and
the compound of Formula 3-2 is a compound wherein:
[0216] X.sub.1 and X.sub.2 are N; R.sub.1 is -L-C.sub.1-10alkyl,
-L-C.sub.3-8cycloalkyl, -L-C.sub.1-10alkylheterocylyl, or
-L-heterocyclyl, each of which is unsubstituted or is substituted
by one or more independent R.sup.3 substituents; and wherein
[0217] 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, hetaryl, 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, --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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32.
[0218] The invention also provides a compound of Formula E:
##STR00025##
[0219] or a salt thereof, wherein:
[0220] G is H or R.sub.G1; and R.sub.G1 is alkyl, alkenyl, or
aryl;
[0221] or the G groups of
##STR00026##
join together to form a 5- or 6-membered cyclic moiety; and
[0222] R.sub.G2 is H, acetyl, tert-butyl carbamate (Boc),
carbobenzyloxy (Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl
(FMOC), or p-methoxybenzyl (PMB).
[0223] In some embodiments, the compound of Formula E is:
##STR00027##
[0224] In some embodiments, a compound of the invention is a
compound of Formula F:
##STR00028##
[0225] or a salt thereof, wherein R.sub.G2 is H, tert-butyl
carbamate, acetyl, tert-butyl carbamate (Boc), carbobenzyloxy
(Cbz), benzyl (Bz), fluorenylmethyloxycarbonyl (FMOC), or
p-methoxybenzyl (PMB).
[0226] In some embodiments, the invention provides a compound of
Formula 3-3':
##STR00029##
[0227] or a salt thereof wherein:
[0228] 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;
wherein no more than two ring nitrogen atoms are adjacent;
[0229] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0230] 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--;
[0231] R.sub.1 is hydrogen, -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-heteroalkly-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;
[0232] 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)--;
[0233] 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.3S, --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.1-10alkyl,
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.3-8cycloakyl-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.2-10alynyl-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(O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0234] 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0235] 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; [0236] 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;
[0237] 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.0-2
C.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, or hetaryl-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, 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
[0238] R.sup.36 is NH.sub.2 or NO.sub.2.
[0239] In some embodiments, the compound of Formula 3-3' is the
compound wherein:
[0240] X.sub.1 and X.sub.2 are N;
[0241] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3
substituents;
[0242] 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(O)NR.sup.34R.sup.35, aryl, hetaryl, 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(O)NR.sup.31R.sup.32,
--C(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(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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32; and wherein
(W.sup.2).sub.k-- is --NR.sup.7--, --N(R.sup.7)(O)-- or
--N(R.sup.7)S(O).sub.2--.
[0243] In another aspect, the invention provides a composition
comprising a compound of Formula 3-3:
##STR00030##
[0244] or a salt thereof, and a cyanogen halide wherein:
[0245] 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;
wherein no more than two nitrogen ring atoms are adjacent;
[0246] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0247] 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--;
[0248] R.sub.1 is hydrogen, -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;
[0249] 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)--;
[0250] 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.1-10alkyl,
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.3-8cycloakyl-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.2-10alynyl-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;
[0251] 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;
[0252] 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.0-2
C.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, or hetaryl-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, 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;
[0253] 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
and
[0254] 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.
[0255] In some embodiments of the composition comprising a compound
of Formula 3-3 and cyanogen halide, the cyanogen halide is cyanogen
bromide.
[0256] In some embodiments of the composition comprising a compound
of Formula 3-3 and cyanogen halide, the compound of Formula 3-3 is
the compound wherein:
[0257] X.sub.1 and X.sub.2 are N;
[0258] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3
substituents; and wherein
[0259] 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, hetaryl, 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, --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.
[0260] In some embodiments of the composition comprising a compound
of Formula 3-3 and cyanogen halide, the composition further
comprises a compound of Formula 3-4:
##STR00031##
[0261] or a salt thereof, wherein: R.sub.1 of Formula 3-3 and
R.sub.1 of Formula 3-4 are the same; R.sub.31 of Formula 3-3 and
R.sub.31 of Formula 3-4 are the same; R.sub.32 of Formula 3-3 and
R.sub.32 of Formula 3-4 are the same; X.sub.1 of Formula 3-3 and
X.sub.1 of Formula 3-4 are the same; X.sub.2 of Formula 3-3 and
X.sub.2 of Formula 3-4 are the same; and X.sub.3 of Formula 3-3 and
X.sub.3 of Formula 3-4 are the same.
[0262] In another aspect, the invention provides a composition
comprising a compound of Formula 3-1:
##STR00032##
[0263] or a salt thereof, and a nitrating reagent wherein:
[0264] 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;
wherein no more than two nitrogen ring atoms are adjacent;
[0265] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0266] 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)S(O).sub.2--;
[0267] R.sub.1 is hydrogen, -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;
[0268] 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)--;
[0269] 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(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.1-10alkyl,
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(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;
[0270] 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;
[0271] 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.0-2
C.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, or hetaryl-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, 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;
[0272] 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
and
[0273] 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.
[0274] In some embodiments of the composition comprising a compound
of Formula 3-1 and a nitrating agent, the compound of Formula 3-1
is the compound wherein:
[0275] X.sub.1 and X.sub.2 are N;
[0276] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.1-10cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3
substituents;
[0277] 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, hetaryl, 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, --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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32; and wherein
--(W.sup.2).sub.k-- is --NR.sup.7--, --N(R.sup.7)C(O)-- or
--N(R.sup.7)S(O).sub.2--.
[0278] In some embodiments, the nitrating agent is nitric acid.
[0279] In some embodiments of the composition comprising a compound
of Formula 3-1 and a nitrating agent, the composition further
comprises a compound of Formula 3-2:
##STR00033##
[0280] or a salt thereof, wherein:
[0281] R.sub.1 of Formula 3-1 and R.sub.1 of Formula 3-2 are the
same; R.sub.3, of Formula 3-1 and R.sub.31 of Formula 3-2 are the
same; R.sub.32 of Formula 3-1 and R.sub.32 of Formula 3-2 are the
same; X.sub.1 of Formula 3-1 and X.sub.1 of Formula 3-2 are the
same; X.sub.2 of Formula 3-1 and X.sub.2 of Formula 3-2 are the
same, and X.sub.3 of Formula 3-1 and X.sub.3 of Formula 3-2 are the
same.
[0282] In another aspect, the invention provides a process for
synthesizing a compound of Formula C:
##STR00034##
[0283] comprising the step of allowing a compound of Formula A to
react with a compound of Formula B under conditions that are
effective for synthesizing a compound of Formula C; wherein;
[0284] T.sub.1 is halo;
[0285] 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;
wherein no more than two ring nitrogen atoms of the compound of
Formula A are adjacent; and wherein no more than two ring nitrogen
atoms of the compound of Formula C are adjacent;
[0286] R.sub.1 is hydrogen, -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;
[0287] 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)--;
each of G is independently H or R.sub.G1; and R.sub.G1 is alkyl,
alkenyl, or aryl;
[0288] or the G groups of
##STR00035##
join together to form a 5- or 6-membered cyclic moiety;
[0289] M of Formula B is a M.sub.1 moiety, and wherein M.sub.1
moiety of Formula B and M.sub.1 moiety of Formula C are identical,
having one of the following structures:
##STR00036##
[0290] E.sup.1 is --(W.sup.1).sub.j--R.sup.4 wherein j is 0 or
1;
[0291] 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--;
[0292] k is 0 or 1;
[0293] 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--;
[0294] 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.2,
--NR.sup.31C(.dbd.O)OR.sup.2,
--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, bicyclic aryl, 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.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.1-10alkylhetaryl,
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.1-10alkoxyC.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl, or
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 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(O.dbd.)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;
[0295] 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(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.1-10alkyl,
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(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;
[0296] R.sup.5 is halogen, --OH, --R.sup.31, --CF.sub.3,
--OCF.sub.3, --OR.sup.31, --NR.sup.31R.sup.32, --NR.sup.31R.sup.32,
--C(O)R.sup.31, --CO.sub.2R.sup.31, --C(.dbd.O)NR.sup.31R.sup.32,
--C(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(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;
[0297] 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.31R.sup.32, --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.1-10alkaryl,
--CO.sub.2-aryl, --C(.dbd.O)N(C.sub.1-10allyl)(C.sub.1-10alkyl),
--C(.dbd.O)NH(C.sub.1-10alkyl), --C(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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0298] 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; [0299] 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;
and
[0300] 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.0-2
C.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, or hetaryl-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, 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
[0301] M.sub.1 of Formula B and M.sub.1 of Formula C are the same;
R.sub.5 of Formula B and R.sub.5 of Formula C are the same; R.sub.1
of Formula A and R.sub.1 of Formula C are the same; R.sub.31 of
Formula A and R.sub.31 of Formula C are the same; R.sub.32 of
Formula A and R.sub.32 of Formula C are the same; X.sub.1 of
Formula A and X.sub.1 of Formula C are the same; X.sub.2 of Formula
A and X.sub.2 of Formula C are the same; and X.sub.3 of Formula A
and X.sub.3 of Formula C are the same.
[0302] In some of the embodiments of the process for synthesizing a
compound of Formula C, each of the compound of Formula A and the
compound of Formula C is the compound wherein:
[0303] X.sub.1 and X.sub.2 are N;
[0304] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3
substituents;
[0305] 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, hetaryl, 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, --OC(.dbd.O)OR.sup.33,
--OC(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; and wherein
[0306] --(W.sup.2).sub.k-- is --NR.sup.7--, --N(R.sup.7)C(O)-- or
--N(R.sup.7)S(O).sub.2--.
[0307] In some of the embodiments of the process for synthesizing a
compound of Formula C, the compound of Formula B has one of the
following structures:
##STR00037## ##STR00038##
[0308] In another aspect, the invention provides a composition
comprising a compound of Formula A and a compound of Formula B:
##STR00039##
[0309] or a salt thereof, wherein:
[0310] T is halo;
[0311] 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;
wherein no more than two ring nitrogen atoms of the compound of
Formula A are adjacent; and wherein no more than two ring nitrogen
atoms of the compound of Formula C are adjacent;
[0312] each of G is independently H or R.sub.G1; and R.sub.G1 is
alkyl, alkenyl, or aryl;
[0313] or the G groups of
##STR00040##
join together to form a 5- or 6-membered cyclic moiety;
[0314] M of Formula B is a M.sub.1 moiety, and wherein M.sub.1
moiety of Formula B has one of the following structures:
##STR00041##
[0315] E.sup.1 is (W.sup.1).sub.j--R wherein j is 0 or 1;
[0316] 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--;
[0317] k is 0 or 1;
[0318] 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--;
[0319] R.sub.1 is hydrogen, -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;
[0320] 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)--;
[0321] 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, bicyclic aryl, 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.3-8cycloakyl-C.sub.2-10alkynyl,
C.sub.1-10alkyl-C.sub.2-10alkenyl,
C.sub.1-10alkyl-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.1-10alkylhetaryl,
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.1-10alkoxyC.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl, or
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 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.31R.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;
[0322] 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(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.31,
--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.1-10alkyl,
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(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.31R.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.3, --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;
[0323] R.sup.5 is 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(O)NR.sup.31R.sup.32,
--C(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; [0324] 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;
[0325] R.sup.6 is halo, --OR.sup.31, --SH, NH.sub.2,
--NR.sup.34NR.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.0-2
C.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, or hetaryl-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, 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;
[0326] 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 alkyl, 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
and
[0327] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(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.
[0328] In some embodiments of the composition comprising a compound
of Formula A and a compound of Formula B, the compound of Formula A
is the compound wherein:
[0329] X.sub.1 and X.sub.2 are N;
[0330] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3
substituents;
[0331] 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, hetaryl, 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.33R.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, 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; and wherein
--(W.sup.2).sub.k-- is --NR.sup.7--, --N(R.sup.7)C(O)-- or
--N(R.sup.7)S(O).sub.2--.
[0332] In some embodiments of the composition comprising a compound
of Formula A and a compound of Formula B, the compound of Formula B
is a compound having one of the following formulae:
##STR00042## ##STR00043##
[0333] In some embodiments of the composition comprising a compound
of Formula A and a compound of Formula B, the composition further
comprises a compound of Formula C:
##STR00044##
[0334] or a salt thereof, wherein:
[0335] M.sub.1 of Formula B and M.sub.1 of Formula C are the same;
R.sub.5 of Formula B and R.sub.5 of Formula C are the same; R.sub.1
of Formula A and R.sub.1 of Formula C are the same; R.sub.1 of
Formula A and R.sub.1 of Formula C are the same; R.sub.31 of
Formula A and R.sub.31 of Formula C are the same; R.sub.32 of
Formula A and R.sub.32 of Formula C are the same; X.sub.1 of
Formula A and X.sub.1 of Formula C are the same; X.sub.2 of Formula
A and X.sub.2 of Formula C are the same; and X.sub.3 of Formula A
and X.sub.3 of Formula C are the same.
[0336] In a further aspect the invention provides a compound of
Formula I-B:
##STR00045##
[0337] or a pharmaceutically acceptable salt thereof wherein:
[0338] X.sub.1 is N and X.sub.2 is C, or X.sub.1 is C-E.sup.1 and
X.sub.2 is C;
[0339] R.sub.1 is hydrogen, -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;
[0340] 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)--;
[0341] M.sub.1 is a moiety having one of the following
structures:
##STR00046##
[0342] k is 0 or 1;
[0343] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0344] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0345] 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--;
[0346] 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--;
[0347] 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(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,
--SC(.dbd.O)NR.sup.31R.sup.32, 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.3-8cycloakyl-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;
[0348] R.sup.3 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(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;
[0349] 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(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, -bicyclic aryl, 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.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.1-10alkylhetaryl,
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.1-10alkoxyC.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl, or
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 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(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;
[0350] 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 alkyl, 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(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.0-2 C.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;
[0351] 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;
[0352] 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;
and
[0353] 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.0-2
C.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.2-10alkyl,
hetaryl-C.sub.2-10alkenyl, or hetaryl-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, 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.
[0354] In some embodiments the compound Formula I-B, is the
compound wherein M.sub.1 is:
##STR00047##
[0355] In yet another aspect, the invention provides a compound of
Formula IV-A or Formula IV-B:
##STR00048##
[0356] or a pharmaceutically acceptable salt thereof wherein:
[0357] 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, X.sub.3 is N, and
X.sub.4 is CR.sup.9 or N;
[0358] 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;
[0359] 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)--;
[0360] k is 0 or 1;
[0361] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0362] j in E.sup.1 or j in E.sup.2, is independently 0 or 11;
[0363] 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--;
[0364] 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--;
[0365] 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.1-10alkyl,
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;
[0366] 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(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, bicyclic aryl, 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.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.1-10alkylhetaryl,
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.1-10alkoxyC.sub.2-10alkenyl,
C.sub.1-10alkoxyC.sub.2-10alkynyl, heterocyclyl, heteroalkyl,
heterocyclyl-C.sub.1-10alkyl, heterocyclyl-C.sub.2-10alkenyl,
heterocyclyl-C.sub.2-10alkynyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, aryl-heterocyclyl, or
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 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)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;
[0367] 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(O)SR.sup.31, --NR.sup.31C(.dbd.NR)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;
[0368] 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.0-2 C.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;
[0369] 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;
[0370] 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;
[0371] 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.0-2
C.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; and
[0372] 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.0-2
C.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.
[0373] In some embodiments of the compound of Formula IV-A or
Formula IV-B, X.sub.4 is CR.sup.9. In other embodiments, X.sub.4 is
N.
[0374] The compounds of the invention inhibit a protein kinase. In
some embodiments of the compounds of the invention, the compound
inhibits a lipid kinase. In other embodiments of the compounds of
the invention, the compound inhibits a protein kinase and a lipid
kinase. In some embodiments of the compounds of the invention, the
compound inhibits a kinase selected from the group consisting of
PI3 kinase .alpha., PI3 kinase .beta., PI3 kinase .gamma., PI3
kinase .delta., DNA-PK, mTor C (including mTorC1 and mTorC2), Abl.
VEGFR, EphB4, Tie2, Flt3, PDGFR, RET, InsR, ATM, ATR, hSmg-1, and
IGFR.
[0375] In some embodiments, a compound of the invention or a
pharmaceutically acceptable salt thereof inhibits mTor at an IC50
value of less than about 100 nM. In other embodiments, a compound
of the invention or a pharmaceutically acceptable salt thereof
inhibits mTor at an IC50 value of less than about 10 nM.
[0376] In a further aspect, the invention provides a composition
comprising a compound of Formula I'-A', I (including I-A and I-B),
II-A (including II-A-1, II-A-1a, and II-A-2), II-B (including
II-B-1 and II-B-2), III (including III-A and III-B), IV-A
(including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and IV-B-2),
C, 3-6, or N-3, or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
[0377] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
E.sup.2 is --H; X.sub.1 and X.sub.2 are N; R.sub.1 is
-L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3;
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, hetaryl, 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(.dbd.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.32s, 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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32; and wherein --(W.sup.2).sub.k-- is
--NR.sup.7--, --N(R.sup.7)C(O)-- or --N(R.sup.7)S(O).sub.2--.
[0378] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
X.sub.4 is CR.sup.9. In another embodiment, X.sub.4 is N.
[0379] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
E.sup.2 is --H. In some embodiments of the compounds of the
invention, X.sub.1 is N and X.sub.2 is N. In other embodiments of
the compounds of the invention, X.sub.1 is C-E.sup.1 and X.sub.2 is
N. In one embodiment of the compounds of the invention, X.sub.1 is
NH and X.sub.2 is C.
[0380] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
R.sub.31 and R.sub.32 are --H.
[0381] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
--(W.sup.2).sub.k-- is --NR.sup.7--, --N(R.sup.7)C(O)--,
--N(R)C(O)N(R.sup.8)--, or --N(R.sup.7)S(O).sub.2--. In other
embodiments, --(W.sup.2).sub.k-- is --NH--. In another embodiment,
--(W.sup.2).sub.k-- is --(CH).sub.2--. In yet another embodiment,
--(W.sup.2).sub.k-- is --NHC(O)--. In a further embodiment of the
compounds of the invention, --(W.sup.2).sub.k-- is
--N(R.sup.7)C(O)N(R.sup.8)--. In another embodiment of the
compounds of the invention, --(W.sup.2).sub.k-- is
--NHS(O).sub.2--.
[0382] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3,
wherein R.sup.3 is hydrogen, --OH, --OR.sup.31, --C(O)R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35, aryl,
hetaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, or heterocyclyl,
wherein each of said aryl, heteroaryl, alkyl, cycloalkyl, or
heterocyclyl moiety is unsubstituted or is substituted with one or
more alkyl or --OH. In some embodiments of the compounds of the
invention, R.sub.1 is unsubstituted or is substituted with
C.sub.1-10alkyl or cycloC.sub.3-10alkyl.
[0383] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
R.sup.2 is alkyl. In yet other embodiments, R.sup.2 is methyl. In
other embodiments of the compounds of the invention, R.sup.2 is
isopropyl. In some embodiments, R.sup.2 is cycloalkyl. In other
embodiments, R.sup.2 is cyclopropyl.
[0384] In another aspect of the invention, a method is provided of
inhibiting activity of a protein kinase and/or a lipid kinase
present in a cell, comprising contacting said cell with an
effective amount of a compound of Formula I'-A', I (including I-A
and I-B), II-A (including II-A-1, II-A-1a, and II-A-2), II-B
(including II-B-1 and II-B-2), III (including III-A and III-B),
IV-A (including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and
IV-B-2), C, 3-6, or N-3.
[0385] In some embodiments of the methods of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof, is a compound wherein
E.sup.2 is --H; X.sub.1 and X.sub.2 are N; R.sub.1 is
-L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3;
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, hetaryl, 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.3S(O).sub.0-2R.sup.32, --C(.dbd.S)OR.sup.31,
--C(.dbd.O)SR.sup.31, --NR.sup.31C(.dbd.NR.sup.2)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.2, or
--SC(.dbd.O)NR.sup.31R.sup.32s, 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(O)NR.sup.34R.sup.35, or
--C(.dbd.O)NR.sup.31R.sup.32; and wherein --(W.sup.2).sub.k-- is
--NR.sup.7--, --N(R.sup.7)C(O)-- or --N(R.sup.7)S(O).sub.2--.
[0386] In some embodiments of the methods of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof, is a compound wherein
X.sub.4 is CR.sup.9. In another embodiment, X.sub.4 is N.
[0387] In some embodiments of the methods of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof, is a compound wherein
E.sup.2 is --H. In some embodiments of the compounds of the
invention, X.sub.1 is N and X.sub.2 is N. In other embodiments of
the compounds of the invention, X.sub.1 is C-E.sup.1 and X.sub.2 is
N. In one embodiment of the compounds of the invention, X.sub.1 is
NH and X.sub.2 is C.
[0388] In some embodiments of the methods of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof, is a compound wherein
R.sub.31 and R.sub.32 are --H.
[0389] In some embodiments of the methods of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof, is a compound wherein
--(W.sup.2)k- is --NR.sup.7--, --N(R.sup.7)C(O)--,
--N(R.sup.7)C(O)N(R.sup.8)--, or --N(R.sup.7)S(O).sub.2--. In other
embodiments, --(W.sup.2).sub.k-- is --NH--. In another embodiment,
--(W.sup.2).sub.k-- is --(CH).sub.2--. In yet another embodiment,
--(W.sup.2).sub.k-- is --NHC(O)--. In a further embodiment of the
compounds of the invention, --(W.sup.2).sub.k-- is
--N(R.sup.7)C(O)N(R.sup.8)--. In another embodiment of the
compounds of the invention, --(W.sup.2).sub.k-- is
--NHS(O).sub.2--.
[0390] In some embodiments of the methods of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof, is a compound wherein
R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent R.sup.3,
wherein R.sup.3 is hydrogen, --OH, --OR.sup.31, --C(O)R.sup.31,
--C(.dbd.O)NR.sup.31R.sup.32, --C(.dbd.O)NR.sup.34R.sup.35, aryl,
hetaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl, or heterocyclyl,
wherein each of said aryl, heteroaryl, alkyl, cycloalkyl, or
heterocyclyl moiety is unsubstituted or is substituted with one or
more alkyl or --OH. In some embodiments of the compounds of the
invention, R.sub.1 is unsubstituted or is substituted with
C.sub.1-10alkyl or cycloC.sub.3-10alkyl.
[0391] In some embodiments of the compositions of the invention, a
compound of Formula I'-A', I (including I-A and I-B), II-A
(including II-A-1, II-A-1a, and II-A-2), II-B (including II-B-1 and
II-B-2), III (including III-A and III-B), IV-A (including IV-A-1
and IV-A-2), IV-B (including IV-B-1 and IV-B-2), C, 3-6, or N-3, or
a pharmaceutically acceptable salt thereof is a compound wherein
R.sup.2 is alkyl. In yet other embodiments, R.sup.2 is methyl. In
other embodiments of the compounds of the invention, R.sup.2 is
isopropyl. In some embodiments, R.sup.2 is cycloalkyl. In other
embodiments, R.sup.2 is cyclopropyl.
[0392] In some of the embodiments of the methods of the invention,
the inhibiting takes place in a subject suffering from a disorder
selected from the group consisting of cancer, bone disorder,
inflammatory disease, immune disease, nervous system disease,
metabolic disease, respiratory disease, and cardiac disease.
Further, in some embodiments of the method of the invention a
second therapeutic agent is administered.
[0393] In some embodiments, one or more compounds of the invention
yield selective inhibition of mTor-mediated signal transduction as
compared to PI3K. In some other embodiments, the compounds provided
herein can inhibit mTor-mediated activity more effectively than
rapamycin, hence providing an alternative treatment for
rapamycin-resistant conditions.
[0394] In some embodiments, one or more compounds of the invention
selectively inhibits both mTorC1 and mTorC2 activity relative to
all type I phosphatidylinositol 3-kinases (PI3-kinase) consisting
of PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase .gamma., and
PI3-kinase .delta.. In some embodiments, one or more compounds of
the invention selectively inhibits both mTor activity with an IC50
value of about 100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or even 1
pM, or less as ascertained in an in vitro kinase assay. In some
embodiments, one or more compounds of the invention is
substantially ineffective in inhibiting a type I PI3-kinase at a
concentration of 100 nM, 200 nM, 500 nM, or 1 uM, 5 uM or 10 uM, or
higher in an in vitro kinase assay.
[0395] In some embodiments, one or more compounds of the invention
inhibits phosphorylation of Akt (S473) and Akt (T308) more
effectively than rapamycin when tested at a comparable molar
concentration in an in vitro kinase assay.
[0396] In some embodiments, one or more compounds of the invention
competes with ATP for binding to ATP-binding site on mTorC1 and/or
mTorC2.
[0397] In some embodiments, one or more compounds of the invention
causes apoptosis of said cell or cell cycle arrest.
[0398] The present invention provides methods and composition for
inhibiting cell proliferation. In one embodiment, the method
comprises contacting a cell with one or more compounds of the
invention that selectively inhibits mTorC1 and/or mTorC2 activity
relative to one or more type I phosphatidylinositol 3-kinases
(PI3-kinase) ascertained by an in vitro kinase assay, wherein the
one or more type I PI3-kinase is selected from the group consisting
of PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase .gamma., and
PI3-kinase .delta.. In some embodiment, the inhibition of
cell-proliferation is evidenced by an assay selected from the group
consisting of an MTS cell proliferation assay, a resazurin assay, a
colony formation assay, flow cytometry, and a cell division tracker
dye assay.
[0399] In a separate and related embodiment, the present invention
provides a method of inhibiting phosphorylation of both Akt (S473)
and Akt (T308) in a cell, comprising contacting a cell with an
effective amount of one or more compounds of the invention that
selectively inhibits both mTorC1 and mTorC2 activity relative to
one or more type I phosphatidylinositol 3-kinases (PI3-kinase) as
ascertained by a cell-based assay or an in vitro kinase assay,
wherein the one or more type I PI3-kinase is selected from the
group consisting of PI3-kinase .alpha., PI3-kinase .beta.,
PI3-kinase .gamma., and PI3-kinase .delta., thereby Akt
phosphorylation at residues S473 and T308 is simultaneously
inhibited.
[0400] In another embodiment, the present invention provies a
method of substantially inhibiting proliferation of a neoplastic
cell comprising contacting the cell with an effective amount of one
or more compounds of the invention that inhibits full activation of
Akt in a cell and an anti-cancer agent, wherein said inhibition of
cell proliferation is enhanced through a synergistic effect of said
compound and said anti-cancer agent.
[0401] In yet another embodiment, the present invention provides a
method of ameliorating a medical condition mediated by mTorC1
and/or mTorC2, comprising administering to a subject in need
thereof a therapeutically effective amount of one or more compounds
of the invention that selectively inhibits mTorC1 and/or mTorC2
activity relative to one or more type I phosphatidylinositol
3-kinases (PI3-kinase) as ascertained in a cell-based assay or an
in vitro kinase assay, wherein the one or more type I PI3-kinase is
selected from the group consisting of PI3-kinase .alpha.,
PI3-kinase .beta., PI3-kinase .gamma., and PI3-kinase .delta..
[0402] Also provided in the present invention is a combination
treatment for a subject diagnosed with or at risk of a neoplastic
condition, comprising administering to said subject a
therapeutically effective amount of one or more compounds of the
invention that substantially inhibits full activation of Akt in a
cell and an anti-cancer agent, wherein the efficacy of said
treatment is enhanced through a synergistic effect of said compound
and said anti-cancer agent.
[0403] In some embodiment, the compound utilized in the subject
methods is a compound that selectively inhibits both mTorC1 and
mTORC2 activity relative to all type I phosphatidylinositol
3-kinases (PI3-kinase) consisting of PI3-kinase .alpha., PI3-kinase
.beta., PI3-kinase .gamma., and PI3-kinase .delta..
[0404] In some other embodiments, the anti-cancer agent utlized in
the subject methods can include but are not limited to rapamycin,
Gleevec, or derivative thereof, which inhibits a mammalian target
of rapamycin or Gleevec.
[0405] A wide variety of neoplastic conditions can be treated using
one or more of the subject compositions. Such conditions include
but are not limited to neoplastic condition such as restenosis,
cancer selected from B cell lymphoma, T cell lymphoma, non small
cell lung carcinoma, and leukemia, or an autoimmune disorder.
[0406] The compound of the invention and/or the anti-cancer agent
can be administered parenterally, orally, intraperitoneally,
intravenously, intraarterially, transdermally, intramuscularly,
liposomally, via local delivery by catheter or stent,
subcutaneously, intraadiposally, or intrathecally.
INCORPORATION BY REFERENCE
[0407] All publications and patent applications mentioned in this
specification are herein incorporated by reference in their
entirety as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0408] 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:
[0409] FIG. 1A-1B summarizes the results of cell proliferation
inhibition assays performed with a wide range of neoplastic cell
lines in vitro using conventional anti-cancer drugs or a compound
of the present invention such as a compound of Table 1. The
experimental procedure is described herein, e.g., in Example 17.
The degree of inhibition is reported in the Figure herein as +, ++,
+++, ++++, or +++++ in the order of increased magnitude in
inhibiting cell proliferation. The results demonstrate that one or
more compounds of the invention yields 50% inhibition of cell
proliferation at a concentration that is one or two orders of
magnitude less than that of the conventional anti-cancer drugs when
tested under the same condition.
[0410] FIG. 2 is a western blot illustrating the dose dependent
effect of a compound of Table 1 in inhibiting pAKT phosphorylation
at residue 47 as well as other signalling molecules downstream of
mTOR including p4EBP1 and pRAS40. The results demonstrate that the
subject mTOR inhibitor of the invention is more effective in
inhibiting Akt phosphorylation as compared to rapamycin.
[0411] FIG. 3A depicts the in vivo effect of a compound of Table 1
of the subject invention in inhibiting tumor growth in a tumor
model such as the U87 human glioblastoma xenograft mouse model over
a course of about 14 study days upon administration of the compound
at the dose of 3 mg/kg, 1 mg/kg, or 0.3 mg/kg. FIG. 3B shows the
test animals and the size of the tumor taken from the negative
control animal (PEG400 treated) or from the test animals treated
with 0.3 mg/kg, 1 mg/kg, or 3 mg/kg of a compound of Table 1. FIG.
3C is a plot of body weight of the negative control and test
animals measured over the course of treatment. The results
demonstrate that the compound is well tolerated and no significant
weight loss is detected during the treatment period, and that tumor
growth is significantly inhibited by administration of one or more
compounds of the present invention under the conditions tested.
[0412] FIG. 4A illustrates an experimental procedure for assessing
the ability of the compounds of the invention to inhibit mTOR
signalling, especially phosphorylation of AKT(473), PRAS40,
S6(240), and 4EBP-1. The phosphorylation pattern of these
signalling molecules are shown in FIG. 4B.
[0413] FIG. 5 depicts the results of lipid and protein kinase
selectivity assays with a compound of Table 1.
[0414] FIG. 6 depicts the effects of a compound of Table 1 of the
present invention on PC3 cell proliferation, PC3 pAKT activation,
and primary tumor cell line proliferation. Additionally, the
specificity of a compound of Table 1 was tested by culturing Jurakt
cells in whole blood to test for non-specific binding/inactivation
of the one or more compounds by components of whole blood.
[0415] FIG. 7A-7B depict the effect of a compound of Table 1 of the
present invention on cellular proliferation and PI3K pathway
activation as compared to rapamycin. FIG. 7A depicts a graph
showing the dose response curve of PC3 cell proliferation in
response to rapamcyin and a compound of the invention from Table 1.
FIG. 7B depicts a western blot analysis of inhibition of
phosphorylation of PI3K pathway targets by one or more compounds
selected from Table 1 as compared to rapamycin.
[0416] FIG. 8A-8B depicts a comparison of the effect of a compound
of Table 1 of the present invention on the proliferation of the
indicated cell lines. FIG. 8A depicts the IC.sub.50 of the compound
for inhibition of cell lines derived from lung and colon and lists
the respective proliferation activating mutations associated with
those cell lines. FIG. 8B depicts the effects of a compound of
Table 1 of the present invention on proliferation of cell lines
comprising the various activating mutations indicated in comparison
to the inhibition provided by a Pan PI3 kinase inhibitor or a Pan
PI3 kinase inhibitor that also inhibits mTOR.
[0417] FIG. 9A-9B depict the effects of a compound of Table 1 of
the present invention on cell cycle progression in HCT116 and SW620
cells as compared to various other compounds. FIG. 9A depicts the
inhibiting effect of the compound at 500 nM on cell cycle
progression as compared to DMSO vehicle control and as compared to
10 uM doxorubicin. FIG. 9B depicts the effect of the indicated
compounds on the population of cells residing in G.sub.0/G.sub.1
phase during culture for two different cell lines.
[0418] FIG. 10 depicts a western blot analysis of the effect of a
compound of Table 1 of the present invention on phosphorylation in
tumor cells from a U87-MG xenograft tumor mouse model.
[0419] FIGS. 11A-11D depicts the efficacy of oral administration of
a compound of Table 1 of the present invention for inhibiting
growth of U87-MG, A549, ZR-75-1, and 786-O xenograft tumors in
female athymic nude mice.
[0420] FIG. 12 depicts the results of TUNEL staining of the tumor
mass of U87-MG xenograft tumors excised from mice, which were
administered vehicle, 1 mg/kg, or 3 mg/kg of the compound of the
invention orally. These results show increased in vivo apoptosis in
the presence of a compound of Table 1 of the present invention.
FIG. 12 further depicts the size of the excised U87 tumors which
decreases with an increasing dose of a compound of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0421] 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 may
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 appended claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby
[0422] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which this invention belongs. All patents
and publications referred to herein are incorporated by
reference.
[0423] As used in the specification and claims, the singular form
"a", "an" and "the" include plural references unless the context
clearly dictates otherwise.
[0424] The term "effective amount" or "therapeutically effective
amount" refers to that amount of a compound 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 platelet adhesion
and/or cell migration. 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.
[0425] As used herein, "treatment" or "treating," or "palliating"
or "ameliorating" is used interchangeably herein. These terms refer
to an approach for obtaining beneficial or desired results
including but not limited to a 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 subject, notwithstanding that the subject may still
be afflicted with the underlying disorder. For prophylactic
benefit, the compositions may be administered to a subject at risk
of developing a particular disease, or to a subject reporting one
or more of the physiological symptoms of a disease, even though a
diagnosis of this disease may not have been made.
[0426] A "therapeutic effect," as that term is 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.
[0427] The term "co-administration," "administered in combination
with," and their grammatical equivalents, as used herein, encompass
administration of two or more agents to an animal so that both
agents and/or their metabolites are present in the subject 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.
[0428] The term "pharmaceutically acceptable salt" refers to salts
derived from a variety of organic and inorganic counter ions well
known in the art and include, by way of example only, sodium,
potassium, calcium, magnesium, ammonium, tetraalkylammonium, and
the like, when the molecule contains an acidic functionality; and
when the molecule contains a basic functionality, salts of organic
or inorganic acids, such as hydrochloride, hydrobromide, tartrate,
mesylate (methane sulfonate), ethane sulfonate, acetate, maleate,
oxalate, phosphate, and the like. In a compound with more than one
basic moiety, more than one of the basic moieties may be converted
to the salt form, including but not limited to a bis- or tris-salt.
Alternatively, a compound having more than one basic moiety may
form a salt at only one of the basic moieties.
[0429] 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.
[0430] 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.
[0431] As used herein, "agent" or "biologically active agent"
refers to a biological, pharmaceutical, or chemical compound or
other moiety. Non-limiting examples include a 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.
[0432] "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 which 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.
[0433] An "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.
[0434] 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.
[0435] The term "selective inhibition" or "selectively inhibit"
refers to a biologically active agent refers to the agent's ability
to preferentially reduce the target signaling activity as compared
to off-target signaling activity, via direct or indirect
interaction with the target.
[0436] "mTorC1 and/or mTorC2 activity" as applied to a biologically
active agent refers to the agent's ability to modulate signal
transduction mediated by mTorC1 and/or mTorC2. For example,
modulation of mTorC1 and/or mTorC2 activity is evidenced by
alteration in signaling output from the PI3K/Akt/mTor pathway.
[0437] The term "B-ALL" as used herein refers to B-cell Acute
Lymphoblastic Leukemia.
[0438] "Subject" refers to an animal, such as a mammal, for example
a human. The methods described herein can be useful in both human
therapeutics and veterinary applications. In some embodiments, the
subject is a mammal, and in some embodiments, the subject is
human.
[0439] "Radiation therapy" means exposing a subject, using routine
methods and compositions known to the practitioner, to radiation
emitters such as alpha-particle emitting radionuclides (e.g.,
actinium and thorium radionuclides), low linear energy transfer
(LET) radiation emitters (i.e. beta emitters), conversion electron
emitters (e.g. strontium-89 and samarium-153-EDTMP, or high-energy
radiation, including without limitation x-rays, gamma rays, and
neutrons.
[0440] An "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.
[0441] "Prodrug" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound described herein. Thus, the term
"prodrug" refers to a precursor of a biologically active compound
that is pharmaceutically acceptable. A prodrug may be inactive when
administered to a subject, but is converted in vivo to an active
compound, for example, by hydrolysis. The prodrug compound often
offers advantages of solubility, tissue compatibility or delayed
release in a mammalian organism (see, e.g., Bundgard, H., Design of
Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion
of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel
Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated in full by reference herein. The term
"prodrug" is also meant to include any covalently bonded carriers,
which release the active compound in vivo when such prodrug is
administered to a mammalian subject. Prodrugs of an active
compound, as described herein, may be prepared by modifying
functional groups present in the active compound in such a way that
the modifications are cleaved, either in routine manipulation or in
vivo, to the parent active compound. Prodrugs include compounds
wherein a hydroxy, amino or mercapto group is bonded to any group
that, when the prodrug of the active compound is administered to a
mammalian subject, cleaves to form a free hydroxy, free amino or
free mercapto group, respectively. Examples of prodrugs include,
but are not limited to, acetate, formate and benzoate derivatives
of a hydroxy functional group, or acetamide, formamide and
benzamide derivatives of an amine functional group in the active
compound and the like.
[0442] The term "in vivo" refers to an event that takes place in a
subject's body.
[0443] 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.
[0444] 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,
hetarylthio C.sub.1-4alkyl has a heteroaryl group connected through
a thio sulfur to a C.sub.1-4alkyl 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.3-8 cycloalkyl" is represented. In such case, the
terminal group is a C.sub.3-8 cycloalkyl 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.
[0445] 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.
[0446] 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.
[0447] As used herein, for example, "C.sub.1-4alkyl" is used to
mean an alkyl having 1-4 carbons--that is, 1, 2, 3, or 4 carbons in
a straight or branched configuration. In all embodiments of this
invention, the term "alkyl" includes both branched and straight
chain alkyl groups, or cyclic hydrocarbon groups, or a combination
thereof. Alkyl groups are fully saturated, unsubstituted or
substituted, and can include di- and multivalent radicals, having
the number of carbon atoms designated (i.e. C.sub.1-C.sub.10 means
one to ten carbons and C.sub.2-C.sub.10 means two to ten carbons).
Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,
n-hexyl, n-heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl,
tetradecyl, hexadecyl, octadecyl, eicosyl, and the like.
[0448] The term "halo" or "halogen" refers to fluoro, chloro,
bromo, or iodo.
[0449] 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.
[0450] The term "acyl" refers to the structure --C(.dbd.O)--R, in
which R is a general substituent variable such as, for example
R.sup.1 described above. Examples include, but are not limited to,
alkylketo, (bi)cyclo)alkylketo, (cyclo)alkenylketo, alkynylketo,
arylketo, hetarylketo, heterocyclylketo, heterobicycloalkylketo,
spiroalkylketo. An acyl moiety is unsubstituted or is substituted
on R.
[0451] Unless otherwise specified, the term "cycloalkyl" refers to
a 3-8 carbon cyclic aliphatic ring structure that is unsubstituted
or substituted with, for example, alkyl, hydroxy, oxo, or halo,
such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl,
2-hydroxycyclopentyl, cyclohexyl, 4-chlorocyclohexyl, cycloheptyl,
cyclooctyl, and the like.
[0452] 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.
[0453] 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.
[0454] As used herein, the term "heteroatom" or "ring heteroatom"
is meant to include oxygen (O), nitrogen (N), sulfur (S),
phosphorus (P), and silicon (Si).
[0455] The term "heteroalkyl," by itself or in combination with
another term, means, unless otherwise stated, a straight or
branched chain, or cyclic hydrocarbon radical, or combinations
thereof, consisting of at least one carbon atoms and at least one
heteroatom selected from the group consisting of O, N, P, Si and S,
and wherein the nitrogen, phosphorus, and sulfur atoms may
optionally be oxidized and the nitrogen heteroatom may optionally
be quaternized. The heteroatom(s) O, N, P and S and Si may be
placed at any interior position of the heteroalkyl group or at the
position at which alkyl group is attached to the remainder of the
molecule. The alkyl portion of the moiety is unsubstituted or
substituted. Examples include, but are not limited to,
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2,
--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3,
--CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3,
--CH.sub.2--CH.dbd.N--OCH.sub.3,
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3, O--CH.sub.3,
--O--CH.sub.2--CH.sub.3, and --CN. Up to two or three heteroatoms
may be consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3
and --CH.sub.2--O--Si(CH.sub.3).sub.3. Similarly, the term
"heteroalkylene" by itself or as part of another substituent means
a divalent radical derived from heteroalkyl, as exemplified, but
not limited by, --CH.sub.2--CH.sub.2--S--CH.sub.2--CH.sub.2-- and
--CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For
heteroalkylene groups, heteroatoms can also occupy either or both
of the chain termini (e.g., alkyleneoxo, alkylenedioxo,
alkyleneamino, alkylenediamino, and the like). Still further, for
alkylene and heteroalkylene linking groups, no orientation of the
linking group is implied by the direction in which the formula of
the linking group is written. For example, the formula --C(O)OR'--
represents both --C(O)OR'-- and --R'OC(O)--. As described above,
heteroalkyl groups, as used herein, include those groups that are
attached to the remainder of the molecule through a heteroatom,
such as --C(O)R', --C(O)NR', --NR'R'', --OR', --SR', and/or
--SO.sub.2R'. Where "heteroalkyl" is recited, followed by
recitations of specific heteroalkyl groups, such as --NR'R'' or the
like, it will be understood that the terms heteroalkyl and --NR'R''
are not redundant or mutually exclusive. Rather, the specific
heteroalkyl groups are recited to add clarity. Thus, the term
"heteroalkyl" should not be interpreted herein as excluding
specific heteroalkyl groups, such as --NR'R'' or the like.
[0456] 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.
[0457] The term "heteroalkylheteroaryl" refers likewise to a
heteroalkyl group which is attached to a hetaryl moiety, for
example, an ethoxymethylpyridyl group. Either portion of the moiety
is unsubstituted or substituted.
[0458] The term "heteroalkyl-heterocylyl" 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.
[0459] 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.
[0460] 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.
[0461] 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.
[0462] "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 (ie. 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. The alkenyl is unsubstituted or
substituted. The term "C.sub.2-10 alkenyl-C.sub.3-8 cycloalkyl"
refers to a group containing an alkenyl 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-enyl-cyclopent-1yl, and the like. Either portion
of the moiety is unsubstituted or substituted.
[0463] 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.
[0464] 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.
[0465] The term "haloalkenyl" refers to an alkenyl group
substituted with one or more halo groups.
[0466] 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.
[0467] "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 (ie. 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. The alkynyl is unsubstituted or
substituted.
[0468] 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-1yl, and the like. Either portion of the
moiety is unsubstituted or substituted.
[0469] The term, "haloalkynyl" refers to an alkynyl group
substituted with one or more independent halo groups.
[0470] "Amino" or "amine" refers to a --NR'R'' moiety, where each
R' is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl,
cycloaklylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl, unless stated otherwise specifically
in the specification. When both R' and R'' of a --NR'R'' moiety are
not hydrogen, R' and R'' 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 and
4-morpholinyl. Unless stated otherwise specifically in the
specification, an amino group is optionally substituted by one or
more substituent which independently is: alkyl, heteroalkyl,
alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,
trifluoromethoxy, nitro, trimethylsilanyl, --OR', --SR',
--OC(O)--R', --N(R').sub.2, --C(O)R', --C(O)OR',
--OC(O)N(R').sub.2, --C(O)N(R').sub.2, --N(R)C(O)OR', --N(R)C(O)R',
--N(R')C(O)N(R').sub.2, N(R')C(NR')N(R').sub.2, --N(R')S(O).sub.tR'
(where t is 1 or 2), --S(O).sub.tOR' (where t is 1 or 2),
--S(O).sub.tN(R').sub.2 (where t is 1 or 2), or PO.sub.3(R').sub.2,
where each R' is independently hydrogen, alkyl, fluoroalkyl,
carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0471] "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). 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'.sub.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 heterocyclyl. An amide may be an amino acid or a
peptide molecule attached to a compound of Formula (I'-A'), 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.
[0472] "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). 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. Examples of
aryl include, but are not limited to, phenyl, 4-chlorophenyl,
4-fluorophenyl, 4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl,
2-methylphenyl, 3-methyphenyl, 4-methylphenyl, 4-ethylphenyl,
2-methyl-3-methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl,
3,5-dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl,
naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl,
4-(trifluoromethyl)phenyl, and 2-iodo-4-methylphenyl. An aryl
moiety is unsubstituted or substituted.
[0473] "Heteroaryl" or, alternatively, "heteroaromatic", "hetaryl",
"heteroar" or "hetar" refers to a 5- to 18-membered aromatic
radical (e.g., C.sub.3-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. 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). A heteroaryl
moiety is unsubstituted or substituted.
[0474] 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.
[0475] 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.
[0476] 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.
[0477] 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.
[0478] 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.
[0479] The terms "hetaryl-C.sub.3-8cycloalkyl" and
"heteroaryl-C.sub.3-8cycloalkyl" are used to describe a group
wherein the terminal hetaryl 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.
[0480] The term "hetaryl-heteroalkyl" refers to a group wherein the
terminal hetaryl 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.
[0481] 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.
[0482] 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.
[0483] 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.
[0484] 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.
[0485] 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.
[0486] 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.
[0487] 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.
[0488] 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.
[0489] 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.
[0490] 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.
[0491] 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.
[0492] 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.
[0493] The terms "hetaryl-oxy", "heteroaryl-oxy", "hetaryloxy",
"heteroaryloxy", "hetaroxy" and "heteroaroxy" are used to describe
a terminal hetaryl group, which is unsubstituted or substituted,
attached to a linking oxygen atom. Typical hetaryl-oxy groups
include 4,6-dimethoxypyrimidin-2-yloxy and the like.
[0494] The terms "hetarylalkyl", "heteroarylalkyl",
"hetaryl-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.
[0495] The term "hetaryl-C.sub.1-10alkyl" is used to describe a
hetaryl alkyl group as described above where the alkyl group
contains 1 to 10 carbon atoms. Either portion of the moiety is
unsubstituted or substituted.
[0496] The term "C.sub.1-10alkyl-hetaryl" 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.
[0497] The terms "hetarylalkenyl", "heteroarylalkenyl",
"hetaryl-alkenyl", "heteroaryl-alkenyl", "hetaralkenyl" and
"heteroaralkenyl" are used to describe a hetarylalkenyl 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.
[0498] The term "hetaryl-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.
[0499] The term "C.sub.2-10alkenyl-hetaryl" 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 hetaryl group, such as, for example 2-styryl-4-pyridyl, and
the like. Either portion of the moiety is unsubstituted or
substituted.
[0500] The terms "hetarylalkynyl", "heteroarylalkynyl",
"hetaryl-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.
[0501] The term "hetaryl-C.sub.2-10alkynyl" is used to describe a
hetarylalkynyl group as described above wherein the alkynyl group
contains 2 to 10 carbon atoms. Either portion of the moiety is
unsubstituted or substituted.
[0502] The term "C.sub.2-10alkynyl-hetaryl" 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 hetaryl group such as, for example, 4(but-1-ynyl)
thien-2-yl, and the like. Either portion of the moiety is
unsubstituted or substituted.
[0503] The term "heterocyclyl", "hetcyclyl", or "heterocycloalkyl"
refers to a substituted or unsubstituted 3-, 4-, 5-, or 6-membered
saturated or partially unsaturated ring containing one, two, or
three heteroatoms, preferably one or two heteroatoms independently
selected from oxygen, nitrogen and sulfur; or to a bicyclic ring
system containing up to 10 atoms including at least one heteroatom
independently selected from oxygen, nitrogen, and sulfur wherein
the ring containing the heteroatom is saturated. Examples of
heterocyclyls include, but are not limited to, tetrahydrofuranyl,
tetrahydrofuryl, pyrrolidinyl, piperidinyl, 4-pyranyl,
tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl, dioxolanyl,
dioxanyl, indolinyl, and 5-methyl-6-chromanyl.
[0504] 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.
[0505] 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.
[0506] 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.
[0507] 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.
[0508] 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.
[0509] 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.
[0510] 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.
[0511] 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.
[0512] The term "hetaryl-heterocycyl" refers to a group containing
a terminal hetaryl 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.
[0513] The term "carboxylalkyl" refers to a terminal carboxyl
(--COOH) group attached to branched or straight chain alkyl groups
as defined above.
[0514] The term "carboxylalkenyl" refers to a terminal carboxyl
(--COOH) group attached to branched or straight chain alkenyl
groups as defined above.
[0515] The term "carboxylalkynyl" refers to a terminal carboxyl
(--COOH) group attached to branched or straight chain alkynyl
groups as defined above.
[0516] The term "carboxylcycloalkyl" refers to a terminal carboxyl
(--COOH) group attached to a cyclic aliphatic ring structure as
defined above.
[0517] The term "carboxylcycloalkenyl" refers to a terminal
carboxyl (--COOH) group attached to a cyclic aliphatic ring
structure having ethylenic bonds as defined above.
[0518] 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.
[0519] 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.
[0520] 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.
[0521] 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.
[0522] 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.
[0523] 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.
[0524] The term "alkoxy" includes both branched and straight chain
terminal alkyl groups attached to a linking oxygen atom. Typical
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy,
tert-butoxy and the like. An alkoxy moiety is unsubstituted or
substituted.
[0525] The term "haloalkoxy" refers to an alkoxy group substituted
with one or more halo groups, for example chloromethoxy,
trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy, and the
like.
[0526] 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.
[0527] The term "alkylthio" includes both branched and straight
chain alkyl groups attached to a linking sulfur atom, for example
methylthio and the like.
[0528] 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.
[0529] 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.
[0530] 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.
[0531] 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.
[0532] 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.
[0533] 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.
[0534] 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.
[0535] 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.
[0536] 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.
[0537] 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.
[0538] "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.
[0539] 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. The above
Formula I is shown without a definitive stereochemistry at certain
positions. The present invention includes all stereoisomers of
Formula I 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.
[0540] The present invention includes all manner of rotamers and
conformationally restricted states of a compound of the
invention.
[0541] 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', .dbd.O,
.dbd.NR', .dbd.N--OR', --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 (2m'+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 a compound 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.
[0542] 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).
[0543] 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', --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 a compound 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.
[0544] As used herein, 0-2 in the context of --S(O).sub.(0-2)-- are
integers of 0, 1, and 2.
[0545] 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.
[0546] A. Generic Formulas and Detailed Description
[0547] 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.
[0548] 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.
[0549] A compound or a pharmaceutically acceptable salt thereof is
provided, wherein the compound has the Formula I'-A':
##STR00049##
[0550] or a pharmaceutically acceptable salt thereof wherein:
[0551] 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;
[0552] wherein no more than two nitrogen ring atoms are
adjacent;
[0553] 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;
[0554] 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)--;
[0555] M.sub.1 is a moiety having the structure of Formula A-1 or
Formula A-2:
##STR00050##
[0556] k is 0 or 1;
[0557] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0558] j, in each instance (i.e., in E.sup.1 or j in E.sup.2), is
independently 0 or 1
[0559] 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--;
[0560] 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--;
[0561] 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(--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.3-8cycloakyl-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,
--C(.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
--(.dbd.O)NR.sup.32,
[0562] 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.3-8cycloakyl-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',
--NR.sup.31C(.dbd.NR.sup.2)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;
[0563] 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;
[0564] 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 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2C.sub.1-10, --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;
[0565] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(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;
[0566] 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;
[0567] 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.0-2
C.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; and
[0568] 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2aryl, --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.2-10alynyl, 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(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.
[0569] In some embodiments, X.sub.4 is C--R.sup.9.
[0570] The invention also provides a compound as defined above,
wherein the compound is of Formula I:
##STR00051##
or a pharmaceutically acceptable salt thereof and wherein the
substituents are as defined above.
[0571] In various embodiments the compound of Formula I or its
pharmaceutically acceptable salt thereof, is a compound having the
structure of Formula I-A or Formula I-B:
##STR00052##
or a pharmaceutically acceptable salt thereof.
[0572] In various embodiments of Formula I-A, 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.
[0573] In various embodiments of Formula I-B, 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.
[0574] In various embodiments, X.sub.1 is
C--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0575] 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.
[0576] 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--.
[0577] In various embodiments, X.sub.1 is
CH--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0578] 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.
[0579] 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)S(O).sub.2--.
[0580] In another embodiment, X.sub.1 is N.
[0581] In various embodiments, X.sub.2 is N. In other embodiments,
X.sub.2 is C.
[0582] In various embodiments, E.sup.2 is
--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0583] 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.
[0584] 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')--. 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--.
[0585] In various embodiments when M.sub.1 is a moiety of Formula
A-1, 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 A-I M.sub.1 moieties include but are not limited to the
following:
##STR00053##
[0586] In various embodiments when M.sub.1 is a moiety of Formula
A-2, Formula A-2 is an aza-substituted benzoxazolyl moiety having a
structure of one of the following formulae:
##STR00054##
[0587] Exemplary Formula A-2 M.sub.1 moieties include but are not
limited to the following:
##STR00055##
[0588] 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--.
[0589] In some embodiments, the compound of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1 and II-A-2), II-B
(including II-B-1 and II-B-2), C, 3-6, C'', or 3-6''' is not a
compound having one of the following structures:
##STR00056##
[0590] The invention provides a compound of Formula II-A or Formula
II-B:
##STR00057##
[0591] 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;
[0592] 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;
[0593] 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)--;
[0594] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0595] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0596] 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--;
[0597] 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--;
[0598] k is 0 or 1;
[0599] 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.3-8cycloakyl-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-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.32s, 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(O)NR.sup.31R.sup.32;
[0600] 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(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.32R.sup.33,
--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.1-10alkyl,
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.2-10alkynylaryl,
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-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, hetaryl-heteroalkyl, or
hetaryl-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(O)NR.sup.31R.sup.32;
[0601] 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;
[0602] 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 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(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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0603] 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; and
[0604] 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.0-2
C.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,
hetaryl-C.sub.1-10alkyl, hetaryl-C.sub.2-10alkenyl,
hetaryl-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, 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.
[0605] In various embodiments of the compound of Formula II-A, the
compound has a structure of Formula II-A-1 or Formula II-A-2:
##STR00058##
or a pharmaceutically acceptable salt thereof.
[0606] In some embodiments of Formula II-A-1, 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.
[0607] In several embodiments of Formula II-A-2, 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.
[0608] In various embodiments of the compound of Formula II-B, the
compound has a structure of Formula II-B-1 or Formula II-B-2:
##STR00059##
or a pharmaceutically acceptable salt thereof.
[0609] In some embodiments of Formula II-B-1, 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.
[0610] In several embodiments of Formula II-B-2, 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.
[0611] In various embodiments, X.sub.1 is
C--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0612] 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.
[0613] 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--.
[0614] In various embodiments, X.sub.1 is
CH--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0615] 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.
[0616] 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--.
[0617] In another embodiment, X.sub.1 is N.
[0618] In various embodiments, X.sub.2 is N. In other embodiments,
X.sub.2 is C.
[0619] In various embodiments, E.sup.2 is
--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0620] 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.
[0621] 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--.
[0622] 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--.
[0623] The invention also provides a compound of Formula III:
##STR00060##
[0624] 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.sub.1 and X.sub.3 is N;
[0625] 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;
[0626] 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 --NR.sup.31)--;
[0627] M.sub.1 is a moiety having the structure of Formula A-1 or
Formula A-2:
##STR00061##
[0628] k is 0 or 1;
[0629] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0630] j in E.sup.1 or j in E.sup.2, is independently 0 or 1;
[0631] 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--;
[0632] 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--;
[0633] 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.33, --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.3-8cycloakyl-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-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(O)NR.sup.31R.sup.32;
[0634] 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(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(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.32,
--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(O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0635] 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;
[0636] 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 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(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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0637] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(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;
[0638] 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;
[0639] 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(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(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
[0640] 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(O)NR.sup.31R.sup.32,
C(.dbd.O)NR.sup.34R.sup.35, --NO.sub.2, --CN, --S(O).sub.0-2
C.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(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.
[0641] In various embodiments of the compound of Formula III, the
compound has a structure of Formula III-A or Formula III-B:
##STR00062##
or a pharmaceutically acceptable salt thereof.
[0642] In some embodiments of Formula III-A, 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.
[0643] In several embodiments of Formula III-B, 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.
[0644] In various embodiments, X.sub.1 is
C--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0645] 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.
[0646] 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--.
[0647] In various embodiments, X.sub.1 is
CH--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0648] 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.
[0649] 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--.
[0650] In another embodiment, X.sub.1 is N.
[0651] In various embodiments, X.sub.2 is N. In other embodiments,
X.sub.2 is C.
[0652] In various embodiments, E.sup.2 is
--(W.sup.1).sub.j--R.sup.4, where j is 0.
[0653] 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.
[0654] 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--.
[0655] In various embodiments when M.sub.1 is a moiety of Formula
A-1, M.sub.1 is benzoxazolyl substituted with --(W.sub.2)--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 A-1 M.sub.1 moieties include but are not limited
to the following:
##STR00063##
[0656] In various embodiments when M.sub.1 is a moiety of Formula
A-2, Formula A-2 is an aza-substituted benzoxazolyl moiety having a
structure of one of the following formulae:
##STR00064##
[0657] Exemplary Formula A-2 M.sub.1 moieties include but are not
limited to the following:
##STR00065##
[0658] 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--.
[0659] In some aspects of the invention, a compound of Formula
I'-A' is a compound of Formula IV-A or Formula IV-B:
##STR00066##
or a pharmaceutically acceptable salt thereof.
[0660] In various embodiments of the compound of Formula IV-A, the
compound has a structure of Formula IV-A-1 or Formula IV-A-2:
##STR00067##
or a pharmaceutically acceptable salt thereof.
[0661] In some embodiments of Formula IV-A-1, 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. In several embodiments of Formula IV-A-2, 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.
[0662] In some embodiments, X.sub.4 is CR.sup.9. In other
embodiments, X.sub.4 is N.
[0663] In various embodiments of the compound of Formula II-B, the
compound has a structure of Formula II-B-1 or Formula II-B-2:
##STR00068##
or a pharmaceutically acceptable salt thereof.
[0664] In some embodiments of Formula IV-B-1, 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.
[0665] In several embodiments of Formula IV-B-2, 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.
[0666] In some embodiments, X.sub.4 is CR.sup.9. In other
embodiments, X.sub.4 is N.
[0667] Additional embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, B (including B' and B''), C, 3-1, 3-3, 3-4,
3-5, 3-6, C'', 3-1'', 3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'',
or N-3'' are described below.
[0668] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'',
3-1'', 3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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--.
[0669] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0670] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0671] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', R.sub.1 is
H.
[0672] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (IV-B-1 and
IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'', 3-3'', 3-4'',
3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0673] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0674] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0675] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', R.sub.1 is
-L-C.sub.1-10alkylaryl, which is unsubstituted. 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.
[0676] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', R.sub.1 is
-L-C.sub.1-10alkylhetaryl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-C.sub.1-10alkylhetaryl, which is
substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-C.sub.1-10alkylhetaryl which is
unsubstituted and L is absent. In yet another embodiment, R.sub.1
is -L-C.sub.1-10alkylhetaryl, which is substituted by one or more
independent R.sup.3, where L is absent.
[0677] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', R.sub.1 is
-L-C.sub.1-10alkylheterocylyl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-C.sub.1-10alkylheterocylyl, which is
substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-C.sub.1-10alkylheterocylyl which is
unsubstituted and L is absent. In yet another embodiment, R.sub.1
is -L-C.sub.1-10alkylheterocylyl, which is substituted by one or
more independent R.sup.3, where L is absent.
[0678] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0679] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0680] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0681] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0682] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0683] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0684] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', R.sub.1 is
-L-heteroalkylaryl, which is unsubstituted. 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.
[0685] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0686] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', R.sub.1 is
-L-heteroalkyl-heterocylyl, which is unsubstituted. In another
embodiment, R.sub.1 is -L-heteroalkyl-heterocylyl, which is
substituted by one or more independent R.sup.3. In a further
embodiment, R.sub.1 is -L-heteroalkyl-heterocylyl which is
unsubstituted, and L is absent. In yet another embodiment, R.sub.1
is -L-heteroalkyl-heterocylyl, which is substituted by one or more
independent R.sup.3, where L is absent.
[0687] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0688] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0689] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0690] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1 and II-A-2), II-B
(including II-B-1 and II-B-2), III (including III-A and III-B),
IV-A (including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and
IV-B-2), A, C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'', 3-3'', 3-4'',
3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0691] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', R.sub.1 is a
substituent as shown below:
##STR00069## ##STR00070## ##STR00071##
[0692] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), B (including B' and B''), C, 3-6,C'', or 3-6'',
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(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.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,
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
hetaryl. 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.1-10alkylhetaryl. 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.2-10alkenylhetaryl. 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.2-10alkynylhetaryl. In another embodiment, R.sup.2 is
--C.sub.2-10alkynylheteroalkyl. In another embodiment, R.sup.2 is
--C.sub.2-10alkynylheterocylyl. 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 aryl-C.sub.2-10alkyl. In another embodiment,
R.sup.2 is aryl-C.sub.1-10alkyl. In another embodiment, R.sup.2 is
aryl-C.sub.2-10alkenyl. In another embodiment, R.sup.2 is
aryl-C.sub.2-10alkynyl. In another embodiment, R.sup.2 is
aryl-heterocyclyl. In another embodiment, R.sup.2 is
hetaryl-C.sub.1-10alkyl. In another embodiment, R.sup.2 is
hetaryl-C.sub.2-10alkenyl. In another embodiment, R.sup.2 is
hetaryl-C.sub.2-10alkynyl. In another embodiment, R.sup.2 is
hetaryl-C.sub.3-8cycloalkyl. In another embodiment, R.sup.2 is
hetaryl-heteroalkyl. In another embodiment, R.sup.2 is
hetaryl-heterocyclyl.
[0693] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), C, 3-6,C'', or 3-6'', when R.sup.2 is bicyclic
aryl, monocyclic aryl, hetaryl, 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, hetaryl, C.sub.1-10 alkyl,
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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl,
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, hetaryl,
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, hetaryl,
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,
hetaryl, 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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl,
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,
hetaryl, 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,
hetaryl, 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, hetaryl,
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,
hetaryl, 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,
hetaryl, 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,
hetaryl, 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, hetaryl,
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, hetaryl,
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,
hetaryl, 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,
hetaryl, 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,
hetaryl, 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, hetaryl,
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,
hetaryl, 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, hetaryl,
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, hetaryl,
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, hetaryl,
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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl, 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,
hetaryl, 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, hetaryl, 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.
[0694] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.3. 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.1 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
hetaryl. 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.1-10alkylhetaryl. 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.2-10alkenylhetaryl. 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.2-10alkynylhetaryl. In another embodiment, R.sup.3 is
--C.sub.2-10alkynylheteroalkyl. In another embodiment, R.sup.3 is
C.sub.2-10alkynylheterocylyl. 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
hetaryl-C.sub.1-10alkyl. In another embodiment, R.sup.3 is
hetaryl-C.sub.2-10alkenyl. In another embodiment, R.sup.3 is
hetaryl-C.sub.2-10alkynyl. In another embodiment, R.sup.3 is
hetaryl-C.sub.3-8cycloalkyl. In another embodiment, R.sup.3 is
hetaryl-heteroalkyl. In another embodiment, R.sup.3 is
hetaryl-heterocyclyl.
[0695] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', when R.sup.3
is aryl, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, C.sub.1-10alkyl,
C.sub.3-8cycloalkyl, C.sub.3-5cycloalkyl-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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, C.sub.1-10alkyl, C.sub.3-8cycloalkyl,
C.sub.3-5cycloalkyl-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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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.
[0696] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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(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.3. 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
hetaryl. 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.1-10alkylhetaryl. 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-hetaryl. 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.2-10alkynylhetaryl. In another embodiment, R.sup.4 is
C.sub.2-10alkynylheteroalkyl. In another embodiment, R.sup.4 is
C.sub.2-10alkynylheterocylyl. 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
aryl-C.sub.2-10alkenyl. In another embodiment, R.sup.4 is
aryl-C.sub.2-10alkynyl. In another embodiment, R.sup.4 is
aryl-heterocyclyl. In another embodiment, R.sup.4 is
hetaryl-C.sub.1-10alkyl. In another embodiment, R.sup.4 is
hetaryl-C.sub.2-10alkenyl. In another embodiment, R.sup.4 is
hetaryl-C.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.
[0697] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'' when R.sup.4
is aryl, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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, hetaryl, 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.
[0698] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), B, C, or C'', 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.
[0699] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.
[0700] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'''', 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, R.sup.8 is
C.sub.3-10cycloalkyl substituted by one or more independent
R.sup.6.
[0701] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1, II-A-1a, and
II-A-2), II-B (including II-B-1 and II-B-2), III (including III-A
and III-B), IV-A (including IV-A-1 and IV-A-2), IV-B (including
IV-B-1 and IV-B-2), A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'',
3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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.24. 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.0-2 C.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 hetaryl-C.sub.1-10alkyl. In
another embodiment, R.sup.6 is unsubstituted
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-C.sub.2-10alkenyl substituted by one or more independent
--C(.dbd.O)NR.sup.34R.sup.32. In another embodiment, R.sup.5 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.1-10alkyl, or
hetaryl-C.sub.2-10alkenyl substituted by one or more independent
--C(.dbd.O)NR.sup.14R.sup.35. In another embodiment, R.sup.6 is
aryl-C.sub.1-10alkyl, aryl-C.sub.2-10alkenyl,
aryl-C.sub.2-10alkynyl, hetaryl-C.sub.1-10alkyl, or
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-C.sub.2-10alkenyl substituted by one or more independent
--SO.sub.2NR.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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-C.sub.2-10alkenyl substituted by one or more independent
--NR.sup.34R.sup.35.
[0702] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), III (including III-A and III-B), IV-A
(including IV-A-I and IV-A-2), or IV-B (including IV-B-1 and
IV-B-2) A, A'', C, 3-1, 3-3, 3-4, 3-5, 3-6, C'', 3-1'', 3-3'',
3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'', 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(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.0-2 C.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 hetaryl-C.sub.1-10alkyl. In
another embodiment, R.sup.9 is unsubstituted
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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,
hetaryl-C.sub.1-10alkyl, or hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-C.sub.2-10alkenyl substituted by one or more independent
--SO.sub.2NR.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, hetaryl-C.sub.1-10alkyl, or
hetaryl-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, hetaryl-C.sub.1-10alkyl, or
hetaryl-C.sub.2-10alkenyl substituted by one or more independent
--NR.sup.34R.sup.35.
[0703] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1 and II-A-2), II-B
(including II-B-1 and II-B-2), III (including III-A and III-B),
IV-A (including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and
IV-B-2), A, B (including B' and B''), C, C, 3-1, 3-3, 3-4, 3-5,
3-6, C'', 3-1'', 3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or
N-3'', or N-3, 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 hetaryl.
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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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
substituents. 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. In
some embodiments, when R.sup.31 is C.sub.1-10alkyl substituted with
one or more hetaryl, each of said hetaryl 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. In
some embodiments, when R.sup.31 is substituted C.sub.1-10alkyl, it
is substituted by a combination of aryl, heteroalkyl, heterocyclyl,
or hetaryl groups.
[0704] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1 and II-A-2), II-B
(including II-B-1 and II-B-2), III (including III-A and III-B),
IV-A (including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and
IV-B-2), A, B (including B' and B''), C, 3-1, 3-2, 3-3, 3-4, 3-5,
3-6, N-1, or N-3, 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 hetaryl.
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, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN, --S(O).sub.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. 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, --OCF.sub.3, --O(C.sub.1-10alkyl), --O-aryl,
--N(aryl)(C.sub.1-10alkyl), --NO.sub.2, --CN, --S(O).sub.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. In
some embodiments, when R.sup.32 is C.sub.1-10alkyl substituted with
one or more hetaryl, each of said hetaryl 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. In
some embodiments, when R.sup.32 is substituted C.sub.1-10alkyl, it
is substituted by a combination of aryl, heteroalkyl, heterocyclyl,
or hetaryl groups.
[0705] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1 and II-A-2), II-B
(including II-B-1 and II-B-2), III (including III-A and III-B),
IV-A (including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and
IV-B-2), A, B (including B' and B''), C, 3-1, 3-3, 3-4, 3-5, 3-6,
C'', 3-1'', 3-3'', 3-4'', 3-5'', 3-6'', N-1, N-3, N-1'', or N-3'',
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 hetaryl. 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. In
some embodiments, when R.sup.33 is C.sub.1-10alkyl substituted with
one or more hetaryl, each of said hetaryl 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(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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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. In
some embodiments, when R.sup.33 is substituted C.sub.1-10alkyl, it
is substituted by a combination of aryl, heteroalkyl, heterocyclyl,
or hetaryl groups.
[0706] In various embodiments of compounds of Formula I'-A', I
(including I-A and I-B), II-A (including II-A-1 and II-A-2), II-B
(including II-B-1 and II-B-2), III (including III-A and III-B),
IV-A (including IV-A-1 and IV-A-2), IV-B (including IV-B-1 and
IV-B-2), A, B (including B' and B''), C, 3-1, 3-3, 3-4, 3-5, 3-6,
C'', 3-1'', 3-3'', 3-4'', 3-5'', or 3-6'', N-1, N-3, N-1'', or
N-3'', 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.
[0707] 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:
##STR00072##
[0708] In another embodiment, X.sub.1 is C--NH.sub.2.
[0709] In various embodiments, X.sub.1 is C--NH--R.sup.4,where
--NH--R.sup.4 is:
##STR00073##
[0710] In one aspect, the invention provides a compound of Formula
II-A-1:
##STR00074##
[0711] or a pharmaceutically acceptable salt thereof wherein:
[0712] X.sub.1 is N or C-E.sup.1 and X.sub.2 is N; or X.sub.1 is NH
or CH-E.sup.1 and X.sub.2 is C;
[0713] R.sub.1 is hydrogen, -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 substituted by one or more independent
R.sup.3;
[0714] 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.3)--;
[0715] M.sub.1 is benzoxazolyl substituted with
--(W.sup.2).sub.k--R.sup.2;
[0716] k is 0 or 1;
[0717] E.sup.1 and E.sup.2 are independently
--(W.sup.1).sub.j--R.sup.4;
[0718] j in E.sup.1 or j in E.sup.2, is independently 0 or 11;
[0719] 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--;
[0720] 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--;
[0721] 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.1-10alkyl,
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.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
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;
[0722] 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, bicyclic aryl, 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.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.1-10alkylhetaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylhetaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylhetaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocylyl,
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, 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 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.35s, or --C(.dbd.O)NR.sup.31R.sup.32;
[0723] 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 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0724] 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;
[0725] 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
[0726] 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.0-2
C.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, or hetaryl-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, 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.
[0727] In another aspect, the invention provides a compound of
Formula II-A-1 or a pharmaceutically acceptable salt thereof
wherein:
[0728] E.sup.2 is --H; X.sub.1 and X.sub.2 are N;
[0729] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0730] 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)--;
[0731] 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, hetaryl, 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.34R.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, 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;
[0732] --(W.sup.2).sub.k-- is --NR.sup.7--, --N(R.sup.7)C(O)-- or
--N(R.sup.7)S(O).sub.2--;
[0733] k is 0 or 1;
[0734] 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.31R.sup.32,
--SC(.dbd.O)NR.sup.31R.sup.32, bicyclic aryl, 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.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.1-10alkylhetaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylhetaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylhetaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocylyl,
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, 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 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;
[0735] 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 hetaryl group, wherein each of said alkyl, 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.0-2
C.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;
[0736] 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;
[0737] R.sup.7 is 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
[0738] 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.0-2
C.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, or hetaryl-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, 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.
[0739] In yet another aspect, the invention provides a compound of
Formula II-A-1 or a pharmaceutically acceptable salt thereof
wherein:
[0740] E.sup.2 is --H; X.sub.1 and X.sub.2 are N;
[0741] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0742] 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)--;
[0743] 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, hetaryl, 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, --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.31R.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.34R.sup.32;
[0744] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0745] 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, bicyclic aryl, 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.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.1-10alkylhetaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylhetaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylhetaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocylyl,
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, 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 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(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.32R.sup.33,
--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.31R.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(O)NR.sup.34R.sup.35, or --C(.dbd.O)NR.sup.31R.sup.32;
[0746] 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
[0747] 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.
[0748] In a further aspect, the invention provides a compound of
Formula II-A-1 or a pharmaceutically acceptable salt thereof
wherein:
[0749] E.sup.2 is --H;
[0750] X.sub.1 and X.sub.2 are N;
[0751] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0752] 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)--;
[0753] 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, hetaryl, 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.13C(.dbd.NR.sup.32)OR.sup.31,
--NR.sup.31C(.dbd.NR.sup.32)SR.sup.33, --OC(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.31R.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;
[0754] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0755] 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, 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.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.1-10alkylhetaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylhetaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylhetaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocylyl,
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, 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 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;
[0756] 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
[0757] 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.
[0758] In another aspect, the compound of Formula II-A-1 is a
compound of Formula II-A-1a:
##STR00075##
[0759] or a pharmaceutically acceptable salt thereof wherein:
[0760] E.sup.2 is --H; X.sub.1 and X.sub.2 are N;
[0761] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0762] 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)--;
[0763] 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, hetaryl, 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, --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;
[0764] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0765] 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, 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.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.1-10alkylhetaryl,
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, hetaryl-C.sub.1-10alkyl, 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 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.31R.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;
[0766] 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
[0767] 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.
[0768] In another aspect, the invention provides a compound of
Formula II-A-1:
##STR00076##
[0769] or a pharmaceutically acceptable salt thereof wherein:
[0770] E.sup.2 is --H; X.sub.1 is CH and X.sub.2 is N;
[0771] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0772] 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)--;
[0773] 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, hetaryl, 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(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;
[0774] --(W.sup.2).sub.k-- is --NR.sup.7--, --N(R.sup.7)C(O)-- or
--N(R.sup.7)S(O).sub.2--;
[0775] k is 0 or 1;
[0776] 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(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, bicyclic aryl, 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.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.1-10alkylhetaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylhetaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylhetaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocylyl,
C.sub.2-10alkenyl-C.sub.3-8cycloalkyl, C.sub.2-10alkynyl-C
cycloalkenyl, 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, 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 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;
[0777] 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 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.0-2
C.sub.1-10alkyl, --S(O).sub.0-2 C.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;
[0778] 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;
[0779] R.sup.7 is 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
[0780] 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.0-2
C.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, or hetaryl-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, 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.
[0781] In yet another aspect, the invention provides a compound of
Formula II-A-1 or a pharmaceutically acceptable salt thereof
wherein:
[0782] E.sup.2 is --H; X.sub.1 is CH and X.sub.2 is N;
[0783] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0784] 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)--;
[0785] 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(O)NR.sup.34R.sup.35, aryl, hetaryl, 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, --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;
[0786] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0787] 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(.dbd.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, bicyclic aryl, 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.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.1-10alkylhetaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylhetaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylhetaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocylyl,
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, 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 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', --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;
[0788] 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
[0789] R.sup.34 and R.sup.35 in --NR.sup.34R.sup.35,
--C(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.1-4alkyl, 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.
[0790] In a further aspect, the invention provides a compound of
Formula II-A-1 or a pharmaceutically acceptable salt thereof
wherein:
[0791] E.sup.2 is --H; X.sub.1 is CH and X.sub.2 is N;
[0792] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0793] 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)--;
[0794] 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, hetaryl, 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, --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.31R.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;
[0795] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0796] 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, 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.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.1-10alkylhetaryl,
C.sub.1-10alkylheterocyclyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.2-10alkenylaryl, C.sub.2-10alkenylhetaryl,
C.sub.2-10alkenylheteroalkyl, C.sub.2-10alkenylheterocyclcyl,
C.sub.2-10alkynylaryl, C.sub.2-10alkynylhetaryl,
C.sub.2-10alkynylheteroalkyl, C.sub.2-10alkynylheterocylyl,
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, 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 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;
[0797] 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
[0798] 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.
[0799] In another aspect, the compound of Formula II-A-1 is a
compound of Formula II-A-1a:
##STR00077##
[0800] or a pharmaceutically acceptable salt thereof wherein:
E.sup.2 is --H; X.sub.1 is CH and X.sub.2 is N;
[0801] R.sub.1 is -L-C.sub.1-10alkyl, -L-C.sub.3-8cycloalkyl,
-L-C.sub.1-10alkylheterocylyl, or -L-heterocyclyl, each of which is
unsubstituted or is substituted by one or more independent
R.sup.3;
[0802] 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)--;
[0803] 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, hetaryl, 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.13C(.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.2)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.31R.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;
[0804] --(W.sup.2).sub.k-- is --NH--, --N(H)C(O)-- or
--N(H)S(O).sub.2--;
[0805] 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, 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.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.1-10alkylhetaryl,
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, hetaryl-C.sub.1-10alkyl, 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 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;
[0806] 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
[0807] 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.
[0808] B. Reaction Schemes
[0809] The 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 illustratrative purposes.
Numbering does not necessarily correspond to that of claims or
other tables.
##STR00078##
[0810] 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,
[0811] The substituents corresponding to M.sub.1 are thereafter
introduced by reacting aryl or hetaryl boronic acids with the
compound of Formula A-4 to obtain compound A-5.
##STR00079##
[0812] 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.
##STR00080##
[0813] 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.
[0814] 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.
[0815] 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:
##STR00081##
[0816] wherein G is H or R.sub.G1; R.sub.G1 is alkyl, alkenyl, or
aryl. Alternatively,
##STR00082##
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.
##STR00083##
[0817] 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.
[0818] 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.
[0819] 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.
[0820] 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.
[0821] 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.
[0822] Some exemplary compounds of Formula B that can be
synthesized via Scheme C include but are not limited to compounds
of the following formulae:
##STR00084## ##STR00085## ##STR00086##
[0823] 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:
##STR00087##
[0824] 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.
[0825] 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.
[0826] 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
[0827] 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.
[0828] Some exemplary compounds with such protecting groups,
include but are not limited to compounds of the following
formulae:
##STR00088##
[0829] An exemplary transformation of M.sub.2 to M.sub.1 can be
carried out via Scheme D as shown below.
##STR00089## ##STR00090##
[0830] 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.
[0831] 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.
[0832] 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'.
[0833] Exemplary compounds having a pyrazolopyrimidine core can be
synthesized via Scheme E.
##STR00091##
[0834] 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.
[0835] 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.
[0836] 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.
##STR00092##
##STR00093##
##STR00094##
##STR00095##
##STR00096##
##STR00097##
##STR00098##
##STR00099##
##STR00100##
[0837] 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.
[0838] 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'.
[0839] 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.
##STR00101##
[0840] 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.
[0841] 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.
[0842] 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'.
[0843] 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.
[0844] 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 0.25 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 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''.
[0845] 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''.
[0846] 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 (ie., 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.
##STR00102##
##STR00103## ##STR00104##
##STR00105##
##STR00106##
[0847] 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.1has 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.1moiety are well known in the art, as well as the methods of
incorporation and removal, and the reagents suitable for such
transformations.
[0848] 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.
[0849] C. Illustrative Subclasses of Compounds of the Invention
[0850] Some illustrative compounds of the invention are described
below. The compounds of the invention are not limited in any way to
the compounds illustrated herein.
##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111##
##STR00112## ##STR00113##
[0851] 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.
[0852] 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.
[0853] 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, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe, or
NHSO.sub.2Me. In other embodiments, when R.sub.1 is
##STR00129##
ad 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. 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.2NHCOH, 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. 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.
[0854] 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##
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. In other embodiments, when R.sub.1 is
##STR00204##
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
##STR00205##
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
##STR00206##
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
##STR00207##
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
##STR00208##
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
##STR00209##
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.
[0855] In other embodiments, when R.sub.1 is
##STR00210##
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
##STR00211##
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
##STR00212##
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
##STR00213##
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
##STR00214##
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
##STR00215##
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
##STR00216##
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
##STR00217##
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
##STR00218##
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
##STR00219##
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
##STR00220##
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
##STR00221##
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
##STR00222##
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
##STR00223##
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
##STR00224##
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
##STR00225##
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
##STR00226##
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
##STR00227##
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
##STR00228##
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
##STR00229##
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.
[0856] In the noted embodiments, pyridin-2-yl is
##STR00230##
N-methylaminocyclohex-4-yl
##STR00231##
[0858] N-methylpiperidin-4-yl is
##STR00232##
and N-methylaminocyclobut-3-yl is
##STR00233##
[0860] 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
##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. 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 propylamino,
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. In other
embodiments, when R.sub.1 is
##STR00304##
aan 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.
[0861] 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. In other
embodiments, when R.sub.1 is
##STR00324##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00325##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00326##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00327##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino In other
embodiments, when R.sub.1 is
##STR00328##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00329##
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.
[0862] In other embodiments, when R.sub.1 is
##STR00330##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00331##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00332##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00333##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00334##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00335##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00336##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00337##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00338##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00339##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00340##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00341##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00342##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00343##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00344##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00345##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00346##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00347##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00348##
and X.sub.1 is CH, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino. In other
embodiments, when R.sub.1 is
##STR00349##
and X.sub.1 is N, V is cyclopropanecarboxamido, cyclopropylamino,
morpholinoethylamino, hydroxyethylamino, or N-morpholino.
[0863] In the noted embodiments, cyclopropanecarboxamido is
##STR00350##
cyclopropylamino is
##STR00351##
2-morpholinoethylamino is
##STR00352##
hydroxyethylamino is
##STR00353##
N-morpholino is
##STR00354##
TABLE-US-00001 [0864] TABLE 1 Biological activity of several
illustrative 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 ##STR00355## ++++ +++ ++ ++++ +++ ++++ 2 ##STR00356## ++++
++ + +++ +++ +++ 3 ##STR00357## ++ + ++ ++ ++ 4 ##STR00358## +++ ++
++ +++ +++ ++ 5 ##STR00359## ++++ +++ ++ ++++ +++ ++++ 6
##STR00360## ++++ ++ + ++ +++ +++ 7 ##STR00361## ++++ +++ ++ ++ +++
++ 8 ##STR00362## ++++ +++ + +++ +++ ++++ 9 ##STR00363## ++++ ++ +
+++ +++ ++++ 10 ##STR00364## ++ + 11 ##STR00365## +++ + 12
##STR00366## +++ + 13 ##STR00367## ++ ++ +++ +++ 14 ##STR00368## ++
++ +++ ++ 15 ##STR00369## + + + + 16 ##STR00370## + + ++ + 17
##STR00371## + + + + 18 ##STR00372## + + + + 19 ##STR00373## ++ + +
+ 20 ##STR00374## ++ ++ + ++ 21 ##STR00375## +++ + + + + 22
##STR00376## ++++ ++++ ++ +++ +++ ++ 23 ##STR00377## ++++ ++ + ++
++ 24 ##STR00378## + + + + 25 ##STR00379## +++ ++ ++++ +++ 26
##STR00380## ++++ +++ ++++ +++ 27 ##STR00381## ++ + + +++
[0865] 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.
[0866] In other embodiments, the present invention provides the
following compounds:
##STR00382## ##STR00383## ##STR00384##
[0867] 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 M (IC.sub.50).
[0868] In some embodiments, one or more compounds of the invention
may bind specifically to a PI3 kinase or a protein kinase selected
from the group consisting of mTor, DNA-dependent protein kinase
DNA-dependent protein kinase (Pubmed protein accession number
(PPAN) AAA79184), Abl tyrosine kinase (CAA52387), Bcr-Abl,
hemopoietic cell kinase (PPAN CA119695), Src (PPAN CAA24495),
vascular endothelial growth factor receptor 2 (PPAN ABB82619),
vascular endothelial growth factor receptor-2 (PPAN ABB82619),
epidermal growth factor receptor (PPAN AG43241), EPH receptor B4
(PPAN EAL23820), stem cell factor receptor (PPAN AAF22141),
Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fins-related
tyrosine kinase 3 (PPAN NP.sub.--004110), platelet-derived growth
factor receptor alpha (PPAN NP.sub.--990080), RET (PPAN CAA73131),
and any other protein kinases listed in the appended tables and
figures, as well as any functional mutants thereof. In some
embodiments, the IC50 of a compound of the invention for
p110.alpha., p110.beta., p110.gamma., or p110.delta. is less than
about 1 uM, less than about 100 nM, less than about 50 nM, less
than about 10 nM, less than 1 nM or even less than about 0.5 nM. In
some embodiments, the IC50 of a compound of the invention for mTor
is less than about 1 uM, less than about 100 nM, less than about 50
nM, less than about 10 nM, less than 1 nM or even less than about
0.5 nM. In some other embodiments, one or more compounds of the
invention exhibit dual binding specificity and are capable of
inhibiting a PI3 kinase (e.g., a class I PI3 kinease) as well as a
protein kinase (e.g., mTor) with an IC50 value less than about 1
uM, less than about 100 nM, less than about 50 nM, less than about
10 nM, less than 1 nM or even less than about 0.5 nM. In some
embodiments, one or more compounds of the invention may be capable
of inhibiting tyrosine kinases including, for example,
DNA-dependent protein kinase DNA-dependent protein kinase (Pubmed
protein accession number (PPAN) AAA79184), Abl tyrosine kinase
(CAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CAI19695), Src
(PPAN CAA24495), vascular endothelial growth factor receptor 2
(PPAN ABB82619), vascular endothelial growth factor receptor-2
(PPAN ABB82619), epidermal growth factor receptor (PPAN AG43241),
EPH receptor B4 (PPAN EAL23820), stem cell factor receptor (PPAN
AAF22141), Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858),
fins-related tyrosine kinase 3 (PPAN NP.sub.--004110),
platelet-derived growth factor receptor alpha (PPAN
NP.sub.--990080), RET (PPAN CAA73131), and functional mutants
thereof. In some embodiments, the tyrosine kinase is Abl, Bcr-Abl,
EGFR, or Flt-3, and any other kinases listed in the Tables
herein.
[0869] In some embodiments, one or more compounds of the invention
yield selective inhibition of mTor-mediated signal transduction as
compared to upstream PI3K. In some other embodiments, the compounds
provided herein can inhibit mTor-mediated activity more effectively
than rapamycin, hence providing an alternative treatment for
rapamycin-resistant conditions.
[0870] In some embodiments, the compounds of the invention
including but not limited to those shown in Table 1 selectively
inhibit both mTorC1 and mTorC2 activity relative to one, two, three
or all type I phosphatidylinositol 3-kinases (PI3-kinase). As noted
above type I PI3-kinases are PI3-kinase .alpha., PI3-kinase .beta.,
PI3-kinase .gamma., and PI3-kinase .delta.. For instance, one or
more compounds of the invention may inhibit mTORC1 and mTORC2 with
an IC.sub.50 that is 1/10.sup.th, 1/20.sup.th, 1/25.sup.th,
1/50.sup.th, 1/100.sup.th, 1/200.sup.th, 1/300.sup.th,
1/400.sup.th, 1/500.sup.th, 1/1000.sup.th, 1/2000.sup.th or less
than the IC.sub.50 for one or more type I PI3-kinases consisting of
PI3-kinase .alpha., PI3-kinase .beta., PI3-kinase .gamma., and
PI3-kinase .delta.. In some embodiments, one or more compounds of
the invention are substantially ineffective in inhibiting a type I
PI3-kinase at a concentration of 100 nM, 200 nM, 500 nM, or 1 uM, 5
uM or 10 uM, or higher in an in vitro kinase assay.
[0871] In other embodiments, the compounds of the invention
including but not limited to compound 1 and others shown in Table 1
selectively inhibit both mTORC1 and mTORC2 activity relative to
one, two, three or all type II or III PI3-kinases, for example,
PI3KC2.alpha., PI3KC2.beta., and VPS34. In particular, one or more
of the compounds of the invention may inhibit mTORC1 and mTORC2
with an IC.sub.50 that is 1/10.sup.th, 1/20.sup.th, 1/25.sup.th,
1/50.sup.th, 1/100.sup.th, 1/200.sup.th, 1/300.sup.th,
1/400.sup.th, 1/500.sup.th, 1/1000.sup.th, 1/2000.sup.th or less
than the IC.sub.50 for one or more type II or III PI3-kinases.
[0872] In yet another embodiment, compounds of the invention
including but not limited to compound 1 and others shown in Table 1
selectively inhibit both mTORC1 and mTORC2 activity relative to one
or more PI4-kinases such as PI4K.alpha. and PI4K.beta.. For
instance, one or more compounds of the invention may inhibit mTORC1
and mTORC2 with an IC.sub.50 that is 1/10.sup.th, 1/20.sup.th,
1/25.sup.th, 1/50.sup.th, 1/100.sup.th, 1/200.sup.th, 1/300.sup.th,
1/400.sup.th, 1/500.sup.th, 1/1000.sup.th, 1/2000.sup.th or less
than the IC.sub.50 for one or more PI4-kinases.
[0873] In still another embodiment, the compounds of the invention
including but not limited to those shown in Table 1 selectively
inhibit both mTORC1 and mTORC2 activity relative to one or more
protein kinases including serine/threonine kinase such as DNA-PK.
Such selective inhibition can be evidenced by, e.g., the IC.sub.50
value of the compound of the invention that can be 1/2, 1/3.sup.rd,
1/4.sup.th, 1/5.sup.th, 1/7.sup.th, 1/10.sup.th, 1/15.sup.th,
1/20.sup.th, 1/25.sup.th, 1/30.sup.th, 1/40.sup.th, 1/50.sup.th,
1/100.sup.th, 1/150.sup.th, 1/200.sup.th, 1/300.sup.th,
1/400.sup.th, 1/500.sup.th, 1/1000.sup.th, 1/2000.sup.th or less as
compared to that of a reference protein kinase. In some instances,
the compounds of the invention including but not limited to those
shown in Table 1 lack substantial cross-reactivity with at least
about 100, 200, 300, or more protein kinases other than mTORC1 or
mTORC2. The lack of substantial cross-reactivity with other
non-mTor protein kinases can be evidenced by, e.g., at least 50%,
60%, 70%, 80%, 90% or higher kinase activity retained when the
compound of the invention is applied to the protein kinase at a
concentration of 1 .mu.M, 5 .mu.M, 10 .mu.M or higher.
[0874] In some embodiments, one or more compounds of the invention
selectively inhibits both mTor activity with an IC50 value of about
100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or even 1 pM, or less as
ascertained in an in vitro kinase assay.
[0875] In some embodiments, one or more compounds of the invention
inhibits phosphorylation of Akt (S473) and Akt (T308) more
effectively than rapamycin when tested at a comparable molar
concentration in an in vitro kinase assay.
[0876] In some embodiments, one or more compounds of the invention
competes with ATP for binding to ATP-binding site on mTorC1 and/or
mTorC2.
[0877] In some embodiments, one or more compounds of the invention
are capable of inhibiting and/or otherwise modulating cellular
signal transduction via one or more protein kinases or lipid
kianses disclosed herein. For example, one or more compounds of the
invention are capable of inhibiting or modulating the output of a
signal transduction pathway. Output of signaling transduction of a
given pathway can be measured by the level of phosphorylation,
dephosphorylation, fragmentation, reduction, oxidation of a
signaling molecule in the pathway of interest. In another specific
embodiment, the output of the pathway may be a cellular or
phenotypic output (e.g. modulating/inhibition of cellular
proliferation, cell death, apoptosis, autophagy, phagocytocis, cell
cycle progression, metastases, cell invasion, angiogenesis,
vascularization, ubiquitination, translation, transcription,
protein trafficking, mitochondrial function, golgi function,
enodplasmic reticular function, etc). In some embodiments, one or
more compounds of the invention are capable of, by way of example,
causing apoptosis, causing cell cycle arrest, inhibiting cellular
proliferation, inhibiting tumor growth, inhibiting angiogenesis,
inhibiting vascularization, inhibiting metastases, and/or
inhibiting cell invasion.
[0878] In some embodiments, one or more compounds of the invention
causes apoptosis of said cell or cell cycle arrest. Cell cyle can
be arrested at the G0/G1 phase, S phase, and/or G2/M phase by the
subject compounds.
[0879] In some embodiments, one or more compounds of the invention
including but not limited to the compounds listed in Table 1 are
capable of inhibiting cellular proliferation. For example, in some
cases, one or more compounds of the invention listed in Table 1 may
inhibit proliferation of tumor cells or tumor cell lines with a
wide range of genetic makeup. In some cases, the compounds of the
invention may inhibit PC3 cell proliferation in vitro or in an in
vivo model such as a xenograft mouse model. In some cases, in vitro
cultured PC3 cell proliferation may be inhibited with an IC.sub.50
of less than 100 nM, 75 nM, 500 nM, 25 nM, 15 nM, 10 nM, 5 nM, 3
nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM or less by one or more compounds of
the invention listed in Table 1.
[0880] In some cases, phosphorylation of AKT may be inhibited with
an IC.sub.50 of less than 100 nM, 75 nM, 500 nM, 25 nM, 15 nM, 10
nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM or less by one or more
compounds of the invention listed in Table 1. Inhibition of
phosphorylation of AKT may be a partially or completely blocked by
the addition of human whole blood. In some cases, the one or more
compounds of the invention listed in Table 1 exhibit specific
binding and/or inhibition of mTOR as evidenced by a small (e.g.
less than about 0.5-fold, 1-fold, 2-fold, or 3-fold) increase in
IC.sub.50 for inhibition of AKT phosphorylation of cells cultured
in whole blood as compared to standard culture media (e.g. DMEM 10%
FBS).
[0881] In some cases, proliferation of primary tumors derived from
subjects (e.g. cancer patients) can be inhibited by a compound of
the invention as shown by in vitro assays, or in vivo models (e.g.
using the subjects' tumor cells for generating a xenograft mode).
In some cases primary tumor cell line proliferation may be
inhibited with an IC.sub.50 of less than 100 nM, 75 nM, 500 nM, 25
nM, 15 nM, 10 nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM or even
less by one or more compounds of the invention listed in Table 1.
In some cases, the average IC.sub.50 of a compound of the invention
for inhibiting a panel 10, 20, 30, 40, 50, 100 or more primary
tumor cells may be about 200 nM, 100 nM, 75 nM, 500 nM, 25 nM, 15
nM, 10 nM, 5 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM or even less. The
tumor cells that can be inhibited by the compounds of the present
invention include but are not limited to pancreatic, renal
(kidney), bone, nasopharyngeal, gastric, stomach, ovarian, oral,
breast, blood, prostate, rectal, colon, colorectal, blial, neural,
lung, and dermal cells.
[0882] In some embodiments, the compounds of the invention are
effective in blocking cell proliferation signals in cells deficient
in PTEN activity but expressing PI3K.alpha.. In some cases, cell
proliferation signalling may be inhibited by one or more compounds
of the invention including but not limited to those shown in Table
1 as evidenced by Western blot analysis of phosphorylation of
proteins such as AKT (phosphorylation at T308 or S473), 4EBP1
(phosphorylation at S65), S6 (phosphorylation at S240/244), FOXO1
(phosphorylation at T24/3a T32), GSK3.beta. (phosphorylation at
S9), PRAS40 (phosphorylation at T246), or MAPK phosphorylation. In
some cases, the compounds of the invention can inhibit
phosphorylation of any one of these targets to a greater degree
than rapamycin under the conditions tested. In other cases, the
compounds of the invention can inhibit phosphorylation of signaling
proteins and suppress proliferation of cells containing these
signaling proteins but are resistant to existing chemotherapeutic
agents including but not limited to rapamycin, Gleevec, dasatinib,
alkylating agents, antimetabolites, anthracyclines, plant
alkaloids, topoisomerase inhibitors and other antitumor agents
disclosed herein.
[0883] In some embodiments, the compounds of the invention
including but not limited to those shown in Table 1, may inhibit
tumor cells comprising a wide range of activating or tumor-causing
mutations. Such mutations include but are not limited to mutations
in KRAS, PI3KC.alpha., BRAF, TSC1/2, PBKclass A, LAT1, and PTEN.
For example, one or more compounds of the invention such as the
compounds in Table 1, including but not limited to compound 1 may
inhibit proliferation of tumor cells comprising mutations in KRAS
at G12, G13, or mutations in Q61 including but not limited to the
G12V, G12S, G13D, Q61K, and Q61H mutations. In another example, one
or more compounds of the invention may inhibit proliferation of
tumor cells comprising mutations in BRAF at V600 including but not
limited to the mutation V600E. In another example, one or more
compounds of the invention such as the compounds in Table 1 may
inhibit proliferation of tumor cells comprising a mutation in
PI3KC.alpha. at E545, P449, or H1047 including but not limited to
the E545K, H1047R, and P449T mutations. In yet another example, one
or more compounds of the invention such as the compounds in Table
1, may inhibit proliferation of tumor cells comprising activating
mutations in one or more combinations of genes such as for example
activating mutations in PTEN and KRAS, PTEN and BRAF, or PTEN and
PI3KC.alpha.. In yet another example, one or more compounds of the
invention such as the compounds in Table 1 may inhibit tumor cells
or tumor cell lines comprising activating mutations in one or more
combinations of genes such as for example activating mutations in
BRAF and PI3KC.alpha..
[0884] In some embodiments, one or more compounds of the invention
including those in Table 1 may cause cell cyle arrest. In some
cases, cells treated with one or more compounds of the invention
including compound 1 and others in Table 1, may arrest or take
longer to proceed through one or more cell cycle stages such as
G.sub.0/G.sub.1, S, or G.sub.2/M. For example, cells treated with
one or more compounds of the invention may arrest or take longer to
proceed through the G.sub.0G.sub.1 cell cycle stage. In some cases,
about 35%, 40%, 50%, 55%, 60%, 65%, 70% or more of cells treated
with one or more compounds of the invention may be in the
G.sub.0/G.sub.1 cell cycle stage. In some cases, cells exhibiting
cell cycle arrest in the G.sub.0/G.sub.1 cell cycle stage in
response to treatment with the compounds of the invention are tumor
cells or rapidly dividing cells. In some cases, cells exhibiting
cell cycle arrest in the G.sub.0/G.sub.1 cell cycle stage in
response to treatment with one or more compounds of the present
invention are HCT116 cells or SW620 cells. In some cases, one or
more compounds of the invention such as the compounds in Table 1,
including but not limited to compound 1 exhibit a comparable or a
greater degree of G.sub.0/G.sub.1 arrest as compared to an
inhibitor that inhibits one or more PI3-kinases. In some cases, the
compounds of the invention effect a comparable or a greater degree
of G.sub.0/G.sub.1 arrest as compared to an inhibitor that inhibits
both mTOR and one or more PI3Ks in tumor cells. In some cases, the
compounds of the invention effect a comparable or a greater degree
of G.sub.0/G.sub.1 arrest as compared to rapamycin or
doxorubicin.
[0885] In some embodiments, cell signalling in tumor cells
xenografted into female athymic nude mice may be inhibited by one
or more compounds of the invention such as the compounds in Table
1, including but not limited to compound 1. In some cases, cell
signalling may be inhibited by one or more compounds of the
invention as evidenced by western blot detection of phosphorylation
of proteins extracted from homogenized tumors, such as AKT
phosphorylation at T308 or S473, 4EBP1 phosphorylation at S65, S6
phosphorylation at S240/244. In some cases, inhibition of
phosphorylation may be comparable to or greater than that provided
by known inhibitors of phosphorylation such as a Pan PI3K inhibitor
that also inhibits one or more isoforms of mTOR (Pan PI3K/mTor
inhibitor) under the conditions tested. In other cases, one or more
compounds of the invention may inhibit phosphorylation of proteins
that other inhibitors such as Pan PI3K/mTor inhibitors do not
affect, or have little effect on, e.g., phosphorylation of AKT at
T308 and S473.
[0886] In some embodiments, the compounds of the invention
including but not limited to compound 1 and others shown in Table
1, cause a reduction in tumor volume of xenograft tumors in female
nude athymic mice. For example, treatment with one or more
compounds of the invention results in a reduction in the growth or
tumor volume caused by engraftment of U87-MG, A549, ZR-75-1, or
786-0 tumor cells in nude mice. The compounds of the invention may
be administered orally, subcutaneously, or intravenously, or any
other compound administration methods provided herein. In some
cases, the compounds are administered once a week, every other day,
once a day, twice a day, three times a day, four times a day or
more. In some cases, 0.01 mg/kg of compound is administered, 0.05
mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5
mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 100
mg/kg or more compound is administered at a time. In some cases, a
significant reduction in tumor volume may be detected within 5, 10,
15, 20, 25, or 30 days of tumor engraftment.
[0887] The invention provides a pharmaceutical composition
comprising one or more compounds disclosed herein. In some
embodiments the invention provides pharmaceutical compositions for
the treatment of disorders such as hyperproliferative disorders
including but not limited to cancers such as acute myeloid
leukemia, lymphoma, thymus, brain, lung, squamous cell skin, eye,
retinoblastoma, intraocular melanoma, mesothelioma, mediastinum,
oral cavity and oropharyngeal, bladder, gastric, stomach,
pancreatic, bladder, breast, cervical head, neck, renal, kidney,
liver, hepatobiliary system, small intestine, colon, rectum, anus,
prostate, colorectal, urethra, esophageal, testicular,
gynecological, penis, testis, ovarian, endocrine system, skin,
thyroid, CNS, PNS, AIDS related AIDS-Related (e.g. Lymphoma and
Kaposi's Sarcoma), other viral-nduced cancers, sarcomas of the soft
tissue and bone, and melanomas of cutaneous and intraocular origin.
Cancers includes solid tumors as well as hematological
malignancies. In addition, a cancer at any stage of progression can
be treated, such as primary, metastatic, and recurrent cancers.
[0888] In some embodiments, said pharmaceutical composition is for
the treatment of a non-cancerous hyperproliferative disorder such
as a benign tumor, for example but not limited to, for the
treatment of a benign hyperplasia of the skin (e.g., psoriasis),
breast, lung, kidney, pancreas, restenosis, or prostate (e.g.,
benign prostatic hypertrophy (BPH)).
[0889] In some embodiments, the invention provides pharmaceutical
compositions for treating diseases or conditions related to an
undesirable, over-active, harmful or deleterious immune response in
a mammal. Such undesirable immune response can be associated with
or result in e.g. asthma, emphysema, bronchitis, psoriasis,
allergy, anaphylaxsis, autoimmune diseases, rhuematoid arthritis,
graft versus host diseas, and lupus erythematosus. The
pharmaceutical compositions of the present invention can be used to
treat other respiratory diseases including but not limited to
disease affecting the lobes of the lung, the pleural cavity,
bronchial tubes, trachea, upper respiratory tract, or the nerves
and muscle responsible for breathing.
[0890] The invention also provides compositions for the treatment
of multiorgan failure.
[0891] The invention also provides compositions for the treatment
of liver diseases (including diabetes), pancreatitis, gall bladder
disease (including gallstones), or kidney disease (including
proliferative glomerulonephritis and diabetes-induced renal
disease) or pain in a mammal.
[0892] The invention further provides a composition for the
prevention of blastocyte implantation in a mammal.
[0893] The invention also relates to a composition 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, Kaposi's sarcoma and ovarian, breast, lung, pancreatic,
prostate, colon and epidermoid cancer.
[0894] The invention further provides compositions 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.
[0895] In some embodiments, compositions are provided for treating
a disease which is skeletal muscle atrophy, skeletal or muscle
hypertrophy. The invention further provides compositions for the
treatment of disorders that include but are not limited to cancers
as discussed herein, transplantation-related disorders (e.g.,
lowering rejection rates, graft-versus-host disease, etc.),
muscular sclerosis (MS), allergic disorders (e.g. arthritis,
allergic encephalomyelitis) and other immunosuppressive-related
disorders, metabolic disorders (e.g., diabetes), reducing intimal
thickening following vascular injury, and misfolded protein
disorders (e.g., Alzheimer's Disease, Gaucher's Disease,
Parkinson's Disease, Huntington's Disease, cystic fibrosis, macular
degeneration, retinitis pigmentosa, and prion disorders) (as mTOR
inhibition can alleviate the effects of misfolded protein
aggregates). The disorders also include hamartoma syndromes, such
as tuberous sclerosis and Cowden Disease (also termed Cowden
syndrome and multiple hamartoma syndrome)
[0896] In some embodiments, the invention provides a pharmaceutical
composition for treating ophthalmic disorders. The composition is
formulated for ocular administration and it contains an effective
amount of a compound of the present invention and a pharmaceutical
excipient suitable for ocular administration. Pharmaceutical
compositions of the invention suitable for ocular administration
can be presented as discrete dosage forms, such as drops or sprays
each containing a predetermined amount of an active ingredient a
solution, or a suspension in an aqueous or non-aqueous liquid, an
oil-in-water emulsion, or a water-in-oil liquid emulsion. Eye drops
may be prepared by dissolving the active ingredient in a sterile
aqueous solution such as physiological saline, buffering solution,
etc., or by combining powder compositions to be dissolved before
use. Other vehicles may be chosen, as is known in the art,
including but not limited to: balance salt solution, saline
solution, water soluble polyethers such as polyethyene glycol,
polyvinyls, such as polyvinyl alcohol and povidone, cellulose
derivatives such as methylcellulose and hydroxypropyl
methylcellulose, petroleum derivatives such as mineral oil and
white petrolatum, animal fats such as lanolin, polymers of acrylic
acid such as carboxypolymethylene gel, vegetable fats such as
peanut oil and polysaccharides such as dextrans, and
glycosaminoglycans such as sodium hyaluronate. If desired,
additives ordinarily used in the eye drops can be added. Such
additives include isotonizing agents (e.g., sodium chloride, etc.),
buffer agent (e.g., boric acid, sodium monohydrogen phosphate,
sodium dihydrogen phosphate, etc.), preservatives (e.g.,
benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.),
thickeners (e.g., saccharide such as lactose, mannitol, maltose,
etc.; e.g., hyaluronic acid or its salt such as sodium hyaluronate,
potassium hyaluronate, etc.; e.g., mucopolysaccharide such as
chondroitin sulfate, etc.; e.g., sodium polyacrylate, carboxyvinyl
polymer, crosslinked polyacrylate, polyvinyl alcohol, polyvinyl
pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,
hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl
cellulose or other agents known to those skilled in the art).
[0897] 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.
[0898] 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.
[0899] 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.
[0900] 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.
[0901] 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.
[0902] 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.
[0903] 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.
[0904] 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.
[0905] 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.
[0906] 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.
[0907] 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.
[0908] Described below are non-limiting exemplary pharmaceutical
compositions and methods for preparing the same.
[0909] Pharmaceutical Compositions for Oral Administration.
[0910] 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.
[0911] 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.
[0912] 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.
[0913] 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.
[0914] 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.
[0915] 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.
[0916] 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.
[0917] 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.
[0918] 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.
[0919] 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.
[0920] 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.
[0921] 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.
[0922] 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.
[0923] 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.
[0924] 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.
[0925] 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.
[0926] 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.
[0927] 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.
[0928] 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.
[0929] 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.
[0930] 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
tetrahydrofiurfuryl 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.
[0931] 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.
[0932] 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.
[0933] 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.
[0934] 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.
[0935] 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.
[0936] Pharmaceutical Compositions for Injection.
[0937] 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.
[0938] 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.
[0939] 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.
[0940] 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.
[0941] Pharmaceutical Compositions for Topical (e.g. Transdermal)
Delivery.
[0942] 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.
[0943] 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.
[0944] 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.
[0945] 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.
[0946] 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.
[0947] Pharmaceutical Compositions for Inhalation.
[0948] 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.
[0949] Other Pharmaceutical Compositions.
[0950] 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.
[0951] 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 abe administered intraadiposally or intrathecally.
[0952] 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.
[0953] 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.
[0954] 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.
[0955] 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.
[0956] 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.
[0957] 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.
[0958] 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.
[0959] 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.
[0960] 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.
[0961] 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.
[0962] 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.
[0963] 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.
[0964] The invention also provides methods of using the compounds
or pharmaceutical compositions of the present invention to treat
disease conditions, including but not limited to conditions
implicated by mTORC1, mTORC2 and/or PI3-kinases malfunction.
[0965] The invention also relates to a method of treating a
hyperproliferative disorder in a mammal that comprises
administering to said mammal a therapeutically effective amount of
a compound of the present invention, or a pharmaceutically
acceptable salt, ester, prodrug, solvate, hydrate or derivative
thereof. In some embodiments, said method relates to the treatment
of cancer such as acute myeloid leukemia, thymus, brain, lung,
squamous cell, skin, eye, retinoblastoma, intraocular melanoma,
oral cavity and oropharyngeal, bladder, gastric, stomach,
pancreatic, bladder, breast, cervical, head, neck, renal, kidney,
liver, ovarian, prostate, colorectal, esophageal, testicular,
gynecological, thyroid, CNS, PNS, AIDS related (e.g. Lymphoma and
Kaposi's Sarcoma) or Viral-Induced cancer. In some embodiments,
said method relates to the treatment of a non-cancerous
hyperproliferative disorder such as benign hyperplasia of the skin
(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic
hypertrophy (BPH)).
[0966] The treatment methods provided herein comprise administering
to the subject a therapeutically effective amount of a compound of
the invention. In one embodiment, the present invention provides a
method of treating an inflammation disorder, including autoimmune
diseases in a mammal. The method comprises administering to said
mammal a therapeutically effective amount of a compound of the
present invention, or a pharmaceutically acceptable salt, ester,
prodrug, solvate, hydrate or derivative thereof. diseases
associated with malfunctioning of one or more types of mTOR
(including Examples of autoimmune diseases includes but is are not
limited to acute disseminated encephalomyelitis (ADEM), Addison's
disease, antiphospholipid antibody syndrome (APS), aplastic anemia,
autoimmune hepatitis, coeliac disease, Crohn's disease, Diabetes
mellitus (type 1), Goodpasture's syndrome, Graves' disease,
Guillain-Barre syndrome (GBS), Hashimoto's disease, lupus
erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus
myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis,
oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis,
rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis,
temporal arteritis (also known as "giant cell arteritis"), warm
autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia
universalis, Chagas' disease, chronic fatigue syndrome,
dysautonomia, endometriosis, hidradenitis suppurativa, interstitial
cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative
colitis, vitiligo, and vulvodynia. Other disorders include
bone-resorption disorders and thromobsis.
[0967] In some embodiments, the method of treating inflammatory or
autoimmune diseases comprises administering to a subject (e.g. a
mammal) a therapeutically effective amount of one or more compounds
of the present invention that selectively inhibit PI3K-.delta.
and/or PI3K-.gamma. as compared to all other type I PI3 kinases.
Such selective inhibition of PI3K-.delta. and/or PI3K-.gamma. may
be advantageous for treating any of the diseases or conditions
described herein. For example, selective inhibition of PI3K-.delta.
may inhibit inflammatory responses associated with inflammatory
diseases, autoimmune disease, or diseases related to an undesirable
immune response including but not limited to asthma, emphysema,
allergy, dermatitis, rhuematoid arthritis, psoriasis, lupus
erythematosus, or graft versus host disease. Selective inhibition
of PI3K-.delta. may further provide for a reduction in the
inflammatory or undesirable immune response without a concomittant
reduction in the ability to reduce a bacterial, viral, and/or
fungal infection. Selective inhibition of both PI3K-.delta. and
PI3K-.gamma. may be advantageous for inhibiting the inflammatory
response in the subject to a greater degree than that would be
provided for by inhibitors that selectively inhibit PI3K-.delta. or
PI3K-.gamma. alone. In one aspect, one or more of the subject
methods are effective in reducing antigen specific antibody
production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold,
7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold,
750-fold, or about 1000-fold or more. In another aspect, one or
more of the subject methods are effective in reducing antigen
specific IgG3 and/or IgGM production in vivo by about 2-fold,
3-fold, 4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold,
100-fold, 250-fold, 500-fold, 750-fold, or about 1000-fold or
more.
[0968] In one aspect, one of more of the subject methods are
effective in ameliorating symptoms associated with rhuematoid
arthritis including but not limited to a reduction in the swelling
of joints, a reduction in serum anti-collagen levels, and/or a
reduction in joint pathology such as bone resorption, cartilage
damage, pannus, and/or inflammation. In another aspect, the subject
methods are effective in reducing ankle inflammation by at least
about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75% to
90%. In another aspect, the subject methods are effective in
reducing knee inflammation by at least about 2%, 5%, 10%, 15%, 20%,
25%, 30%, 50%, 60%, or about 75% to 90% or more. In still another
aspect, the subject methods are effective in reducing serum
anti-type II collagen levels by at least about 10%, 12%, 15%, 20%,
24%, 25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or
more. In another aspect, the subject methods are effective in
reducing ankle histopathology scores by about 5%, 10%, 15%, 20%,
25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more. In still another
aspect, the subject methods are effective in reducing knee
histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%,
50%, 60%, 75%, 80%, 90% or more.
[0969] In other embodiments, the present invention provides methods
of using the compounds or pharmaceutical compositions to treat
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. For example, methods are provided to treat obstructive
pulmonary disease. Chronic obstructive pulmonary disease (COPD) is
an umbrella term for a group of respiratory tract diseases that are
characterized by airflow obstruction or limitation. Conditions
included in this umbrella term are: chronic bronchitis, emphysema,
and bronchiectasis.
[0970] In another embodiment, the compounds described herein are
used for the treatment of asthma. Also, the compounds or
pharmaceutical compositions described herein may be used for the
treatment of endotoxemia and sepsis. In one embodiment, the
compounds or pharmaceutical compositions described herein are used
to for the treatment of rheumatoid arthritis (RA). In yet another
embodiment, the compounds or pharmaceutical compositions described
herein is used for the treatment of contact or atopic dermatitis.
Contact dermatitis includes irritant dermatitis, phototoxic
dermatitis, allergic dermatitis, photoallergic dermatitis, contact
urticaria, systemic contact-type dermatitis and the like. Irritant
dermatitis can occur when too much of a substance is used on the
skin of when the skin is sensitive to certain substance. Atopic
dermatitis, sometimes called eczema, is a kind of dermatitis, an
atopic skin disease.
[0971] The invention also relates to a method of treating diseases
related to vasculogenesis or angiogenesis in a mammal that
comprises administering to said mammal a therapeutically effective
amount of a compound of the invention, or a pharmaceutically
acceptable salt, ester, prodrug, solvate, hydrate or derivative
thereof. 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, Kaposi's sarcoma and ovarian, breast,
lung, pancreatic, prostate, colon and epidermoid cancer.
[0972] Subjects that can be treated with compounds of the
invention, or pharmaceutically acceptable salt, ester, prodrug,
solvate, hydrate or derivative of said compounds, according to the
methods of this invention include, for example, subjects that have
been diagnosed as having psoriasis; restenosis; atherosclerosis;
BPH; breast cancer such as a ductal carcinoma in duct tissue in a
mammary gland, medullary carcinomas, colloid carcinomas, tubular
carcinomas, and inflammatory breast cancer; ovarian cancer,
including epithelial ovarian tumors such as adenocarcinoma in the
ovary and an adenocarcinoma that has migrated from the ovary into
the abdominal cavity; uterine cancer; cervical cancer such as
adenocarcinoma in the cervix epithelial including squamous cell
carcinoma and adenocarcinomas; prostate cancer, such as a prostate
cancer selected from the following: an adenocarcinoma or an
adenocarinoma that has migrated to the bone; pancreatic cancer such
as epitheliod carcinoma in the pancreatic duct tissue and an
adenocarcinoma in a pancreatic duct; bladder cancer such as a
transitional cell carcinoma in urinary bladder, urothelial
carcinomas (transitional cell carcinomas), tumors in the urothelial
cells that line the bladder, squamous cell carcinomas,
adenocarcinomas, and small cell cancers; leukemia such as acute
myeloid leukemia (AML), acute lymphocytic leukemia, chronic
lymphocytic leukemia, chronic myeloid leukemia, hairy cell
leukemia, myelodysplasia, myeloproliferative disorders, acute
myelogenous leukemia (AML), chronic myelogenous leukemia (CML),
mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma
(MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer
such as non-small cell lung cancer (NSCLC), which is divided into
squamous cell carcinomas, adenocarcinomas, and large cell
undifferentiated carcinomas, and small cell lung cancer; skin
cancer such as basal cell carcinoma, melanoma, squamous cell
carcinoma and actinic keratosis, which is a skin condition that
sometimes develops into squamous cell carcinoma; eye
retinoblastoma; cutaneous or intraocular (eye) melanoma; primary
liver cancer (cancer that begins in the liver); kidney cancer;
thyroid cancer such as papillary, follicular, medullary and
anaplastic; AIDS-related lymphoma such as diffuse large B-cell
lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell
lymphoma; Kaposi's Sarcoma; viral-induced cancers including
hepatitis B virus (HBV), hepatitis C virus (HCV), and
hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1)
and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV)
and cervical cancer; central nervous system cancers (CNS) such as
primary brain tumor, which includes gliomas (astrocytoma,
anaplastic astrocytoma, or glioblastoma multiforme),
Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma,
and Medulloblastoma; peripheral nervous system (PNS) cancers such
as acoustic neuromas and malignant peripheral nerve sheath tumor
(MPNST) including neurofibromas and schwannomas, malignant fibrous
cytoma, malignant fibrous histiocytoma, malignant meningioma,
malignant mesothelioma, and malignant mixed Miillerian tumor; oral
cavity and oropharyngeal cancer such as, hypopharyngeal cancer,
laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer;
stomach cancer such as lymphomas, gastric stromal tumors, and
carcinoid tumors; testicular cancer such as germ cell tumors
(GCTs), which include seminomas and nonseminomas, and gonadal
stromal tumors, which include Leydig cell tumors and Sertoli cell
tumors; thymus cancer such as to thymomas, thymic carcinomas,
Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid
tumors; rectal cancer; and colon cancer
[0973] The invention also relates to a method of treating diabetes
in a mammal that comprises administering to said mammal a
therapeutically effective amount of a compound of the invention, or
a pharmaceutically acceptable salt, ester, prodrug, solvate,
hydrate or derivative thereof.
[0974] In addition, the compounds described herein may be used to
treat acne.
[0975] In addition, the compounds described herein may be used for
the treatment of arteriosclerosis, including atherosclerosis.
Arteriosclerosis is a general term describing any hardening of
medium or large arteries. Atherosclerosis is a hardening of an
artery specifically due to an atheromatous plaque.
[0976] Further the compounds described herein may be used for the
treatment of glomerulonephritis. Glomerulonephritis is a primary or
secondary autoimmune renal disease characterized by inflammation of
the glomeruli. It may be asymptomatic, or present with hematuria
and/or proteinuria. There are many recognized types, divided in
acute, subacute or chronic glomerulonephritis. Causes are
infectious (bacterial, viral or parasitic pathogens), autoimmune or
paraneoplastic.
[0977] Additionally, the compounds described herein may be used for
the treatment of bursitis, lupus, acute disseminated
encephalomyelitis (ADEM), addison's disease, antiphospholipid
antibody syndrome (APS), aplastic anemia, autoimmune hepatitis,
coeliac disease, crohn's disease, diabetes mellitus (type 1),
goodpasture's syndrome, graves' disease, guillain-barre syndrome
(GBS), hashimoto's disease, inflammatory bowel disease, lupus
erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome
(OMS), optic neuritis, ord's thyroiditis, ostheoarthritis,
uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,
reiter's syndrome, takayasu's arteritis, temporal arteritis, warm
autoimmune hemolytic anemia, wegener's granulomatosis, alopecia
universalis, chagas' disease, chronic fatigue syndrome,
dysautonomia, endometriosis, hidradenitis suppurativa, interstitial
cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative
colitis, vitiligo, vulvodynia, appendicitis, arteritis, arthritis,
blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,
cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis,
dacryoadenitis, dermatomyositis, endocarditis, endometritis,
enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,
fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis,
hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis,
myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis,
orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,
peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis,
proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis,
sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis,
vaginitis, vasculitis, or vulvitis.
[0978] The invention also relates to a method of treating a
cardiovascular disease in a mammal that comprises administering to
said mammal a therapeutically effective amount of a compound of the
invention, or a pharmaceutically acceptable salt, ester, prodrug,
solvate, hydrate or derivative thereof. Examples of cardiovascular
conditions include, but are not limited to, atherosclerosis,
restenosis, vascular occlusion and carotid obstructive disease.
[0979] In another aspect, the invention provides methods of
disrupting the function of a leukocyte or disrupting a function of
an osteoclast. The method includes contacting the leukocyte or the
osteoclast with a function disrupting amount of a compound of the
invention.
[0980] In another aspect of the present invention, methods are
provided for treating ophthalmic disease by administering one or
more compounds of the invention or pharmaceutical compositions to
the eye of a subject.
[0981] Methods are further provided for administering the compounds
of the present invention via eye drop, intraocular injection,
intravitreal injection, topically, or through the use of a drug
eluting device, microcapsule, implant, or microfluidic device. In
some cases, the compounds of the present invention are administered
with a carrier or excipient that increases the intraocular
penetrance of the compound such as an oil and water emulsion with
colloid particles having an oily core surrounded by an interfacial
film. It is contemplated that all local routes to the eye may be
used including topical, subconjunctival, periocular, retrobulbar,
subtenon, intracameral, intravitreal, intraocular, subretinal,
juxtascleral and suprachoroidal administration. Systemic or
parenteral administration may be feasible including but not limited
to intravenous, subcutaneous, and oral delivery. An exemplary
method of administration will be intravitreal or subtenon injection
of solutions or suspensions, or intravitreal or subtenon placement
of bioerodible or non-bioerodible devices, or by topical ocular
administration of solutions or suspensions, or posterior
juxtascleral administration of a gel or cream formulation.
[0982] In some cases, the colloid particles include at least one
cationic agent and at least one non-ionic sufactant such as a
poloxamer, tyloxapol, a polysorbate, a polyoxyethylene castor oil
derivative, a sorbitan ester, or a polyoxyl stearate. In some
cases, the cationic agent is an alkylamine, a tertiary alkyl amine,
a quarternary ammonium compound, a cationic lipid, an amino
alcohol, a biguanidine salt, a cationic compound or a mixture
thereof. In some cases the cationic agent is a biguanidine salt
such as chlorhexidine, polyaminopropyl biguanidine, phenformin,
alkylbiguanidine, or a mixture thereof. In some cases, the
quaternary ammonium compound is a benzalkonium halide, lauralkonium
halide, cetrimide, hexadecyltrimethylammonium halide,
tetradecyltrimethylammonium halide, dodecyltrimethylammonium
halide, cetrimonium halide, benzethonium halide, behenalkonium
halide, cetalkonium halide, cetethyldimonium halide,
cetylpyridinium halide, benzododecinium halide, chlorallyl
methenamine halide, rnyristylalkonium halide, stearalkonium halide
or a mixture of two or more thereof. In some cases, cationic agent
is a benzalkonium chloride, lauralkonium chloride, benzododecinium
bromide, benzethenium chloride, hexadecyltrimethylammonium bromide,
tetradecyltrimethylammonium bromide, dodecyltrimethylammonium
bromide or a mixture of two or more thereof. In some cases, the oil
phase is mineral oil and light mineral oil, medium chain
triglycerides (MCT), coconut oil; hydrogenated oils comprising
hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate
castor oil or hydrogenated soybean oil; polyoxyethylene
hydrogenated castor oil derivatives comprising poluoxyl-40
hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or
polyoxyl-100 hydrogenated castor oil.
[0983] The invention further provides methods of modulating a PI3K
and/or mTor kinase activity by contacting the kinase with an
effective amount of a compound of the invention. Modulation can be
inhibiting or activating kinase activity. In some embodiments, the
invention provides methods of inhibiting kinase activity by
contacting the kinase with an effective amount of a compound of the
invention in solution. In some embodiments, the invention provides
methods of inhibiting the kinase activity by contacting a cell,
tissue, organ that express the kinase of interest. In some
embodiments, the invention provides methods of inhibiting kinase
activity in subject including but not limited to rodents and mammal
(e.g., human) by administering into the subject an effective amount
of a compound of the invention. In some embodiments, the percentage
of inhibiting exceeds 25%, 300%, 40%, 50%, 60%, 70%, 80%, or
90%.
[0984] In some embodiments, the kinase is selected from the group
consisting of mTor, including different isoforms such as mTORC1 and
mTORC2; PI3 kinase including different isorforms such as PI3 kinase
.alpha., PI3 kinase .beta., PI3 kinase .gamma., PI3 kinase .delta.;
DNA-PK; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEK receptor
tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3);
Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR;
hSmg-1; Hck; Src; Epidermal growth factor receptor (EGFR); KIT;
Inulsin Receptor (IR) and IGFR.
[0985] The invention further provides methods of modulating mTOR
activity by contacting mTOR with an amount of a compound of the
invention sufficient to modulate the activity of mTOR. Modulate can
be inhibiting or activating mTOR activity. In some embodiments, the
invention provides methods of inhibiting mTOR by contacting mTOR
with an amount of a compound of the invention sufficient to inhibit
the activity of mTOR. In some embodiments, the invention provides
methods of inhibiting mTOR activity in a solution by contacting
said solution with an amount of a compound of the invention
sufficient to inhibit the activity of mTOR in said solution. In
some embodiments, the invention provides methods of inhibiting mTOR
activity in a cell by contacting said cell with an amount of a
compound of the invention sufficient to inhibit the activity of
mTOR in said cell. In some embodiments, the invention provides
methods of inhibiting mTOR activity in a tissue by contacting said
tissue with an amount of a compound of the invention sufficient to
inhibit the activity of mTOR in said tissue. In some embodiments,
the invention provides methods of inhibiting mTOR activity in an
organism by contacting said organism with an amount of a compound
of the invention sufficient to inhibit the activity of mTOR in said
organism. In some embodiments, the invention provides methods of
inhibiting mTOR activity in an animal by contacting said animal
with an amount of a compound of the invention sufficient to inhibit
the activity of mTOR in said animal. In some embodiments, the
invention provides methods of inhibiting mTOR activity in a mammal
by contacting said mammal with an amount of a compound of the
invention sufficient to inhibit the activity of mTOR in said
mammal. In some embodiments, the invention provides methods of
inhibiting mTOR activity in a human by contacting said human with
an amount of a compound of the invention sufficient to inhibit the
activity of mTOR in said human. The present invention provides
methods of treating a disease mediated by mTOR activity in a
subject in need of such treatment.
[0986] The present invention also provides methods for combination
therapies in which an agent known to modulate other pathways, or
other components of the same pathway, or even overlapping sets of
target enzymes are used in combination with a compound of the
present invention, 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 one
or more compounds of the invention with chemotherapeutic agents,
therapeutic antibodies, and radiation treatment, to provide a
synergistic or additive therapeutic effect.
[0987] In one aspect, the compounds or pharmaceutical compositions
of the invention may present synergistic or additive efficacy when
administered in combination with agents that inhibit IgE production
or activity. Such combination can reduce the undesired effect of
high level of IgE associated with the use of one or more
PI3K.delta. inhibitors, if such effect occurs. This may be
particularly useful in treatment of autoimmune and inflammatory
disorders (AIID) such as rheumatoid arthritis. Additionally, the
administration of PI3K.delta. or PI3K.delta./.gamma.inhibitors of
the invention in combination with inhibitors of mTOR may also
exhibit synergy through enhanced inhibition of the PI3K
pathway.
[0988] In a separate but related aspect, the invention provides a
combination treatment of a disease associated with PI3K.delta.
comprising administering to a PI3K.delta. .quadrature.inhibitor and
an agent that inhibits IgE production or activity. Other exemplary
PI3K.delta. .quadrature.inhibitors are applicable and they are
described, e.g., U.S. Pat. No. 6,800,620. Such combination
treatment is particularly useful for treating autoimmune and
inflammatory diseases (AIID) including but not limited to
rheumatoid arthritis.
[0989] Agents that inhibit IgE production are known in the art and
they include but are not limited to one or more of TEI-9874,
2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid,
rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors,
TORC2 inhibitors, and any other compounds that inhibit mTORC1 and
mTORC2. Agents that inhibit IgE activity include, for example,
anti-IgE antibodies such as for example Omalizumab and TNX-901.
[0990] For treatment of autoimmune diseases, the compounds of the
invention or pharmaceutical compositions can be used in combination
with commonly prescribed drugs including but not limited to
Enbrel.RTM., Remicade.RTM., Humira.RTM., Avonex.RTM., and
Rebif.RTM.. For treatment of respiratory diseases, the compounds of
the invention or pharmaceutical compositions can be administered in
combination with commonly prescribed drugs including but not
limited to Xolair.RTM., Advair.RTM., Singulair.RTM., and
Spiriva.RTM..
[0991] 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.
[0992] In another aspect, this invention also relates to methods
and pharmaceutical compositions for inhibiting abnormal cell growth
in a mammal which comprises an amount of a compound of the
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.
[0993] In some embodiments, the chemotherapeutic is selected from
the group consisting of mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating antibiotics, growth factor
inhibitors, cell cycle inhibitors, enzymes, topoisomerase
inhibitors, biological response modifiers, anti-hormones,
angiogenesis inhibitors, and anti-androgens.
[0994] Non-limiting examples are chemotherapeutic agents, cytotoxic
agents, and non-peptide small molecules such as Gleevec.RTM.
(Imatinib Mesylate), Velcade.RTM. (bortezomib), Casodex
(bicalutamide), Iressa.RTM. (gefitinib), and Adriamycin as well as
a host of chemotherapeutic agents. Non-limiting examples of
chemotherapeutic agents include alkylating agents such as thiotepa
and cyclosphosphamide (CYTOXAN.TM.); alkyl sulfonates such as
busulfan, improsulfan and piposulfan; aziridines such as benzodopa,
carboquone, meturedopa, and uredopa; ethylenimines and
methylamelamines including altretamine, triethylenemelamine,
trietylenephosphoramide, triethylenethiophosphaoramide and
trimethylolomelamine; nitrogen mustards such as chlorambucil,
chlornaphazine, cholophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, ranimustine; antibiotics such as
aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,
cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin,
Casodex.TM., chromomycins, dactinomycin, daunorubicin, detorubicin,
6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,
idarubicin, marcellomycin, mitomycins, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,
quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,
ubenimex, zinostatin, zorubicin; anti-metabolites such as
methotrexate and 5-fluorouracil (5-FU); folic acid analogues such
as denopterin, methotrexate, pteropterin, trimetrexate; purine
analogs such as fludarabine, 6-mercaptopurine, thiamiprine,
thioguanine; pyrimidine analogs such as ancitabine, azacitidine,
6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,
enocitabine, floxuridine, androgens such as calusterone,
dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine; diaziquone; elfomithine; elliptinium acetate;
etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine;
mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;
phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSK.R.TM.; razoxane; sizofuran; spirogermanium;
tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine;
urethan; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOL.TM.,
Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel
(TAXOTERE, Rhone-Poulenc Rorer, Antony, France); retinoic acid;
esperamicins; capecitabine; and pharmaceutically acceptable salts,
acids or derivatives of any of the above. Also included as suitable
chemotherapeutic cell conditioners are anti-hormonal agents that
act to regulate or inhibit hormone action on tumors such as
anti-estrogens including for example tamoxifen, (Nolvadex.TM.),
raloxifene, aromatase inhibiting 4(5)-imidazoles,
4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone,
and toremifene (Fareston); and anti-androgens such as flutamide,
nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil;
gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum
analogs such as cisplatin and carboplatin; vinblastine; platinum;
etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;
vincristine; vinorelbine; navelbine; novantrone; teniposide;
daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11
(CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine
(DMFO). Where desired, the compounds or pharmaceutical composition
of the present invention can be used in combination with commonly
prescribed anti-cancer drugs such as Herceptin.RTM., Avastin.RTM.,
Erbitux.RTM., Rituxan.RTM., Taxol.RTM., Arimidex.RTM.,
Taxotere.RTM., ABVD, AVICINE, Abagovomab, Acridine carboxamide,
Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin,
Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone,
Amonafide, Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic,
Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine,
Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin,
Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Calyculin,
cell-cycle nonspecific antineoplastic agents, Dichloroacetic acid,
Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,
Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine,
Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod,
Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide,
Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine,
Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone,
Proteasome inhibitor, Rebeccamycin, Resiquimod, Rubitecan, SN-38,
Salinosporamide A, Sapacitabine, Stanford V, Swainsonine,
Talaporfin, Tariquidar, Tegafiur-uracil, Temodar, Tesetaxel,
Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine,
Uramustine, Vadimezan, Vinflunine, ZD6126, and Zosuquidar.
[0995] This invention further relates to a method for using the
compounds or pharmaceutical compositions provided herein, in
combination with radiation therapy for inhibiting abnormal cell
growth or treating the hyperproliferative 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.
[0996] 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, Re-186, Re-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 1-125, 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.
[0997] 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 a compound of the present invention or
pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate
or derivative thereof which amount is effective is 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.
[0998] The compounds or pharmaceutical compositions of the
invention can be used in combination with an amount of one or more
substances selected from anti-angiogenesis agents, signal
transduction inhibitors, antiproliferative agents, glycolysis
inhibitors, or autophagy inhibitors.
[0999] Anti-angiogenesis agents, such as MMP-2
(matrix-metalloproteinase 2) inhibitors, MMP-9
(matrix-metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase
11) inhibitors, can be used in conjunction with a compound of the
invention and pharmaceutical compositions described herein.
Anti-angiogenesis agents include, for example, rapamycin,
temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib,
and bevacizumab. Examples of useful COX-II inhibitors include
CELEBREX.TM. (alecoxib), valdecoxib, and rofecoxib. Examples of
useful matrix metalloproteinase inhibitors are described in WO
96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7,
1996), European Patent Application No. 97304971.1 (filed Jul. 8,
1997), European Patent Application No. 99308617.2 (filed Oct. 29,
1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516
(published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998),
WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug.
6, 1998), WO 98/30566 (published Jul. 16, 1998), European Patent
Publication 606,046 (published Jul. 13, 1994), European Patent
Publication 931, 788 (published Jul. 28, 1999), WO 90/05719
(published May 31, 1990), WO 99/52910 (published Oct. 21, 1999), WO
99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17,
1999), PCT International Application No. PCT/IB98/01113 (filed Jul.
21, 1998), European Patent Application No. 99302232.1 (filed Mar.
25, 1999), Great Britain Patent Application No. 9912961.1 (filed
Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 (filed
Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999),
U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent
Publication 780,386 (published Jun. 25, 1997), all of which are
incorporated herein in their entireties by reference. Preferred
MMP-2 and MMP-9 inhibitors are those that have little or no
activity inhibiting MMP-1. More preferred, are those that
selectively inhibit MMP-2 and/or AMP-9 relative to the other
matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6,
MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific
examples of MMP inhibitors useful in the invention are AG-3340, RO
32-3555, and RS 13-0830.
[1000] Autophagy inhibitors include, but are not limited to
chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil.TM.),
bafilomycin Al, 5-amino-4-imidazole carboxamide riboside (AICAR),
okadaic acid, autophagy-suppressive algal toxins which inhibit
protein phosphatases of type 2A or type 1, analogues of cAMP, and
drugs which elevate cAMP levels such as adenosine, LY204002,
N6-mercaptopurine riboside, and vinblastine. In addition, antisense
or siRNA that inhibits expression of proteins including but not
limited to ATG5 (which are implicated in autophagy), may also be
used.
[1001] The invention also relates to a method of and to a
pharmaceutical composition for treating a cardiovascular disease in
a mammal which comprises an amount of a compound of the invention,
or a pharmaceutically acceptable salt, ester, prodrug, solvate,
hydrate or derivative thereof or an isotopically-labeled derivative
thereof, and an amount of one or more therapeutic agents use for
the treatment of cardiovascular diseases.
[1002] 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.
[1003] The compounds described herein may be formulated or
administered in conjunction with liquid or solid tissue barriers
also known as lubricants. Examples of tissue barriers include, but
are not limited to, polysaccharides, polyglycans, seprafilm,
interceed and hyaluronic acid.
[1004] Medicaments which may be administered in conjunction with
the compounds 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.
[1005] 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.
[1006] 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.
[1007] 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.
[1008] 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.
[1009] Examples of therapeutic antibodies that can be combined with
a compound of the invention 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.
[1010] 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.
[1011] Further therapeutic agents that can be combined with a
compound of the invention 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.
[1012] The compounds described herein can be used in combination
with the agents disclosed herein or other suitable agents,
depending on the condition being treated. Hence, in some
embodiments the one or more compounds of the invention will be
co-administer with other agents as described above. When used in
combination therapy, the compounds described herein may be
administered with the second agent simultaneously or separately.
This administration in combination can include simultaneous
administration of the two agents in the same dosage form,
simultaneous administration in separate dosage forms, and separate
administration. That is, a compound described herein and any of the
agents described above can be formulated together in the same
dosage form and administered simultaneously. Alternatively, a
compound of the invention and any of the agents described above can
be simultaneously administered, wherein both the agents are present
in separate formulations. In another alternative, a compound of the
present invention can be administered just followed by and any of
the agents described above, or vice versa. In the separate
administration protocol, a compound of the invention and any of the
agents described above may be administered a few minutes apart, or
a few hours apart, or a few days apart.
[1013] Administration of the compounds of the present invention can
be effected by any method that enables delivery of the compounds to
the site of action. 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, as an inhalant, or via an impregnated or coated
device such as a stent, for example, or an artery-inserted
cylindrical polymer.
[1014] The amount of the compound 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. 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.
[1015] 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.
[1016] 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.
[1017] Administration of the agents of the invention may continue
as long as necessary. In some embodiments, an agent of the
invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or
28 days. In some embodiments, an agent of the invention is
administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In
some embodiments, an agent of the invention is administered
chronically on an ongoing basis, e.g., for the treatment of chronic
effects.
[1018] 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.
[1019] 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 p110.alpha./p85.alpha.,
p110.beta./p85.alpha., p110.delta./p85.alpha., and p110.gamma.
[1020] Class I PI3-Ks can be either purchased
(p110.alpha./p85.alpha., p110.beta./p85.alpha.,
p110.delta./p85.alpha. from Upstate, and p110.gamma. from Sigma) or
expressed as previously described (Knight et al., 2004). IC50
values are measured using either a standard TLC assay for lipid
kinase activity (described below) or a high-throughput membrane
capture assay. Kinase reactions are performed by preparing a
reaction mixture containing kinase, inhibitor (2% DMSO final
concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2), and
freshly sonicated phosphatidylinositol (100 .mu.g/ml). Reactions
are initiated by the addition of ATP containing 10 .mu.Ci of
.gamma.-32P-ATP to a final concentration 10 or 100 .mu.M and
allowed to proceed for 5 minutes at room temperature. For TLC
analysis, reactions are then terminated by the addition of 105
.mu.l 1N HCl followed by 160 .mu.l CHCl3:MeOH (1:1). The biphasic
mixture is vortexed, briefly centrifuged, and the organic phase is
transferred to a new tube using a gel loading pipette tip precoated
with CHCl.sub.3. This extract is spotted on TLC plates and
developed for 3-4 hours in a 65:35 solution of n-propanol:1M acetic
acid. The TLC plates are then dried, exposed to a phosphorimager
screen (Storm, Amersham), and quantitated. For each compound,
kinase activity is measured at 10-12 inhibitor concentrations
representing two-fold dilutions from the highest concentration
tested (typically, 200 .mu.M). For compounds showing significant
activity, IC50 determinations are repeated two to four times, and
the reported value is the average of these independent
measurements.
[1021] Other commercial kits or systems for assaying PI3-K
activities are available. The commercially available kits or
systems can be used to screen for inhibitors and/or agonists of
PI3-Ks including but not limited to PI 3-Kinase .alpha., .beta.,
.delta., and .gamma.. An exemplary system is PI 3-Kinase (human)
HTRF.TM. Assay from Upstate. The assay can be carried out according
to the procedures suggested by the manufacturer. Briefly, the assay
is a time resolved FRET assay that indirectly measures PIP3 product
formed by the activity of a PI3-K. The kinase reaction is performed
in a microtitre plate (e.g., a 384 well microtitre plate). The
total reaction volume is approximately 20 ul per well. In the first
step, each well receives 2 ul of test compound in 20%
dimethylsulphoxide resulting in a 2% DMSO final concentration.
Next, approximately 14.5 ul of a kinase/PIP2 mixture (diluted in
1.times. reaction buffer) is added per well for a final
concentration of 0.25-0.3 ug/ml kinase and 10 uM PIP2. The plate is
sealed and incubated for 15 minutes at room temperature. To start
the reaction, 3.5 ul of ATP (diluted in 1.times. reaction buffer)
is added per well for a final concentration of 10 uM ATP. The plate
is sealed and incubated for 1 hour at room temperature. The
reaction is stopped by adding 5 ul of Stop Solution per well and
then 5 ul of Detection Mix is added per well. The plate is sealed,
incubated for 1 hour at room temperature, and then read on an
appropriate plate reader. Data is analyzed and IC50s are generated
using GraphPad Prism 5.
Example 2
Expression and Inhibition Assays of Abl
[1022] The cross-activity or lack thereof of one or more compounds
of the invention against Abl kinase can be measured according to
any procedures known in the art or methods disclosed below. For
example, the compounds described herein can be assayed in
triplicate against recombinant full-length Abl or Abl (T315I)
(Upstate) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2,
200 .mu.M ATP (2.5 .mu.Ci of .gamma.-32P-ATP), and 0.5 mg/mL BSA.
The optimized Abl peptide substrate EAIYAAPFAKKK is used as
phosphoacceptor (200 .mu.M). Reactions are terminated by spotting
onto phosphocellulose sheets, which are washed with 0.5% phosphoric
acid (approximately 6 times, 5-10 minutes each). Sheets are dried
and the transferred radioactivity quantitated by
phosphorimaging.
Example 3
Expression and Inhibition Assays of Hck
[1023] The cross-activity or lack thereof of one or more compounds
of the invention against Hck kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be assayed in triplicate against
recombinant full-length Hck in an assay containing 25 mM HEPES, pH
7.4, 10 mM MgCl2, 200 .mu.M ATP (2.5 .mu.Ci of .gamma.-32P-ATP),
and 0.5 mg/mL BSA. The optimized Src family kinase peptide
substrate EIYGEFKKK is used as phosphoacceptor (200 .mu.M).
Reactions are terminated by spotting onto phosphocellulose sheets,
which are washed with 0.5% phosphoric acid (approximately 6 times,
5-10 minutes each). Sheets are dried and the transferred
radioactivity quantitated by phosphorimaging.
Example 4
Expression and Inhibition Assays of Inulsin Receptor (IR)
[1024] The cross-activity or lack thereof of one or more compounds
of the invention against IR receptor kinase can be measured
according to any procedures known in the art or methods disclosed
below. The compounds described herein can be assayed in triplicate
against recombinant insulin receptor kinase domain (Upstate) in an
assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 10 mM MnCl2, 200
.mu.M ATP (2.5 .mu.Ci of .gamma.-32P-ATP), and 0.5 mg/mL BSA. Poly
E-Y (Sigma; 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.
Example 5
Expression and Inhibition Assays of Src
[1025] The cross-activity or lack thereof of one or more compounds
of the invention against Src kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be assayed in triplicate against
recombinant full-length Src or Src (T3381) in an assay containing
25 mM HEPES, pH 7.4, mM MgCl2, 200 .mu.M ATP (2.5 .mu.Ci of
.gamma.-32P-ATP), and 0.5 mg/mL BSA. The optimized Src family
kinase peptide substrate EIYGEFKKK is used as phosphoacceptor (200
.mu.M). Reactions are terminated by spotting onto phosphocellulose
sheets, which are washed with 0.5% phosphoric acid (approximately 6
times, 5-10 minutes each). Sheets were dried and the transferred
radioactivity quantitated by phosphorimaging.
Example 6
Expression and Inhibition Assays of DNA-PK (DNAK)
[1026] The cross-activity or lack thereof of one or more compounds
of the invention against DNAK kinase can be measured according to
any procedures known in the art. DNA-PK can be purchased from
Promega and assayed using the DNA-PK Assay System (Promega)
according to the manufacturer's instructions.
Example 7
Expression and Inhibition Assays mTOR
[1027] The ability of one or more compounds of the invention to
inhibit mTor activity can be measured according to any procedures
known in the art or methods disclosed below. The compounds
described herein can be tested against recombinant mTOR
(Invitrogen) in an assay containing 50 mM HEPES, pH 7.5, 1 mM EGTA,
10 mM MgCl2, 2.5 mM, 0.01% Tween, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 .mu.g/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.
[1028] 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 ul per well and the reaction
buffer composition is 50 mM HEPES pH7.5, 0.01% Polysorbate 20, 1 mM
EGTA, 10 mM MnCl2, 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, 8 ul 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 uM ATP and 0.5 uM 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 8
Expression and Inhibition Assays of Vascular Endothelial Growth
Receptor
[1029] The cross-activity or lack thereof of one or more compounds
of the invention against VEGF receptor can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant KDR
receptor kinase domain (Invitrogen) in an assay containing 25 mM
HEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 .mu.g/mL BSA. Poly E-Y (Sigma; 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.
Example 9
Expression and Inhibition Assays of Ephrin Receptor B4 (EphB4)
[1030] The cross-activity or lack thereof of one or more compounds
of the invention against EphB4 can be measured according to any
procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant Ephrin
receptor B4 kinase domain (Invitrogen) in an assay containing 25 mM
HEPES, pH 7.4, mM MgCl2, 0.1% BME, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 .mu.g/mL BSA. Poly E-Y (Sigma; 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.
Example 10
Expression and Inhibition Assays of Epidermal Growth Factor
Receptor (EGFR)
[1031] The cross-activity or lack thereof of one or more compounds
of the invention against EGFR kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant EGF
receptor kinase domain (Invitrogen) in an assay containing 25 mM
HEPES, pH 7.4, mM MgCl2, 0.1% BME, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 .mu.g/mL BSA. Poly E-Y (Sigma; 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.
Example 11
Expression and Inhibition Assays of KIT Assay
[1032] The cross-activity or lack thereof of one or more compounds
of the invention against KIT kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant KIT
kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH
7.4, 10 mM MgCl2, 1 mM DTT, 10 mM MnCl2, 10 .mu.M ATP (2.5 .mu.Ci
of .mu.-32P-ATP), and 3 .mu.g/mL BSA. Poly E-Y (Sigma; 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.
Example 12
Expression and Inhibition Assays of RET
[1033] The cross-activity or lack thereof of one or more compounds
of the invention against RET kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant RET
kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH
7.4, 10 mM MgCl2, 2.5 mM DTT, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 .mu.g/mL BSA. The optimized Abl peptide
substrate EAIYAAPFAKKK is used as phosphoacceptor (200 .mu.M).
Reactions are terminated by spotting onto phosphocellulose sheets,
which are washed with 0.5% phosphoric acid (approximately 6 times,
5-10 minutes each). Sheets are dried and the transferred
radioactivity quantitated by phosphorimaging.
Example 13
Expression and Inhibition Assays of Platelet Derived Growth Factor
Receptor (PDGFR)
[1034] The cross-activity or lack thereof of one or more compounds
of the invention against PDGFR kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant PDG
receptor kinase domain (Invitrogen) in an assay containing 25 mM
HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 .mu.g/mL BSA. The optimized Abl peptide
substrate EAIYAAPFAKKK is used as phosphoacceptor (200 .mu.M).
Reactions are terminated by spotting onto phosphocellulose sheets,
which are washed with 0.5% phosphoric acid (approximately 6 times,
5-10 minutes each). Sheets are dried and the transferred
radioactivity quantitated by phosphorimaging.
Example 14
Expression and Inhibition Assays of FMS-Related Tyrosine Kinase 3
(FLT-3)
[1035] The cross-activity or lack thereof of one or more compounds
of the invention against FLT-3 kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant FLT-3
kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH
7.4, 10 mM MgCl2, 2.5 mM DTT, 10 .mu.M ATP (2.5 .mu.Ci of
.mu.-32P-ATP), and 3 .mu.g/mL BSA. The optimized Abl peptide
substrate EAIYAAPFAKKK is used as phosphoacceptor (200 .mu.M).
Reactions are terminated by spotting onto phosphocellulose sheets,
which are washed with 0.5% phosphoric acid (approximately 6 times,
5-10 minutes each). Sheets are dried and the transferred
radioactivity quantitated by phosphorimaging.
Example 15
Expression and Inhibition Assays of TEK Receptor Tyrosine Kinase
(TIE2)
[1036] The cross-activity or lack thereof of one or more compounds
of the invention against TIE2 kinase can be measured according to
any procedures known in the art or methods disclosed below. The
compounds described herein can be tested against recombinant TIE2
kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH
7.4, 10 mM MgCl2, 2 mM DTT, 10 mM MnCl2, 10 .mu.M ATP (2.5 .mu.Ci
of .mu.-32P-ATP), and 3 .mu.g/mL BSA. Poly E-Y (Sigma; 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.
Example 16
B Cell Activation and Proliferation Assay
[1037] The ability of one or more compounds of the invention to
inhibit B cell activation and proliferation is determined according
to standard procedures known in the art. For example, an in vitro
cellular proliferation assay is established that measures the
metabolic activity of live cells. The assay is performed in a 96
well microtiter plate using Alamar Blue reduction. Balb/c splenic B
cells are purified over a Ficoll-Paque.TM. PLUS gradient followed
by magnetic cell separation using a MACS B cell Isolation Kit
(Miletenyi). Cells are plated in 90 ul at 50,000 cells/well in B
Cell Media (RPMI+10% FBS+Penn/Strep+50 uM bME+5 mM HEPES). A
compound disclosed herein is diluted in B Cell Media and added in a
10 ul volume. Plates are incubated for 30 min at 37 C and 5%
CO.sub.2 (0.2% DMSO final concentration). A 50 ul B cell
stimulation cocktail is then added containing either 10 ug/ml LPS
or 5 ug/ml F(ab')2 Donkey anti-mouse IgM plus 2 ng/ml recombinant
mouse IL4 in B Cell Media. Plates are incubated for 72 hours at
37.degree. C. and 5% CO.sub.2. A volume of 15 uL of Alamar Blue
reagent is added to each well and plates are incubated for 5 hours
at 37 C and 5% CO.sub.2. Alamar Blue fluoresce is read at
560Ex/590Em, and IC50 or EC50 values are calculated using GraphPad
Prism 5.
Example 17
Tumor Cell Line Proliferation Assay
[1038] The ability of one or more compounds of the invention to
inhibit tumor cell line proliferation is determined according to
standard procedures known in the art. For instance, an in vitro
cellular proliferation assay can be performed to measure the
metabolic activity of live cells. The assay is performed in a 96
well microtiter plate using Alamar Blue reduction. Human tumor cell
lines are obtained from ATCC (e.g., MCF7, U-87 MG, MDA-MB-468,
PC-3, and any other cell lines listed in FIG. 1A-B), grown to
confluency in T75 flasks, trypsinized with 0.25% trypsin, washed
one time with Tumor Cell Media (DMEM+10% FBS), and plated in 90 ul
at 5,000 cells/well in Tumor Cell Media. A compound disclosed
herein is diluted in Tumor Cell Media and added in a 10 ul volume.
Plates are incubated for 72 hours at 37 C and 5% CO.sub.2. A volume
of 10 uL of Alamar Blue reagent is added to each well and plates
are incubated for 3 hours at 37 C and 5% CO.sub.2. Alamar Blue
fluoresce is read at 560Ex/590Em, and IC50 values are calculated
using GraphPad Prism 5. The results depicted in FIG. 1A, FIG. 1B
and FIG. 7A show that a compound of the present invention
effectively inhibits proliferation of a wide range of tumor cells.
In some instance, the compound of the invention yields 50%
inhibition of cell proliferation at a concentration that is one or
two orders of magnitude less than that of a conventional
anti-cancer drug when tested under the same condition.
Example 18
Antitumor Activity In Vivo
[1039] The compounds described herein can be evaluated in a panel
of human and murine tumor models.
[1040] Paclitaxel-Refractory Tumor Models
[1041] 1. Clinically-Derived Ovarian Carcinoma Model.
[1042] This tumor model is established from a tumor biopsy of an
ovarian cancer patient. Tumor biopsy is taken from the patient.
[1043] The compounds described herein are administered to nude mice
bearing staged tumors using an every 2 days.times.5 schedule.
[1044] 2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated
Tubulin).
[1045] A2780Tax is a paclitaxel-resistant human ovarian carcinoma
model. It is derived from the sensitive parent A2780 line by
co-incubation of cells with paclitaxel and verapamil, an
MDR-reversal agent. Its resistance mechanism has been shown to be
non-MDR related and is attributed to a mutation in the gene
encoding the beta-tubulin protein.
[1046] The compounds described herein can be administered to mice
bearing staged tumors on an every 2 days.times.5 schedule.
[1047] 3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug
Resistant).
[1048] HCT116/VM46 is an MDR-resistant colon carcinoma developed
from the sensitive HCT116 parent line. In vivo, grown in nude mice,
HCT116/VM46 has consistently demonstrated high resistance to
paclitaxel.
[1049] The compounds described herein can be administered to mice
bearing staged tumors on an every 2 days.times.5 schedule.
[1050] 5. M5076 Murine Sarcoma Model
[1051] M5076 is a mouse fibrosarcoma that is inherently refractory
to paclitaxel in vivo.
[1052] The compounds described herein can be administered to mice
bearing staged tumors on an every 2 days.times.5 schedule.
[1053] One or more compounds of the invention can be used in
combination other therapeutic agents in vivo in the multidrug
resistant human colon carcinoma xenografts HCT/VM46 or any other
model known in the art including those described herein.
It is expected that one or more compounds of the present invention
are potent inhibitors of tumor growth in vivo under the conditions
tested.
Example 19
Microsome Stability Assay
[1054] The stability of one or more compounds of the invention is
determined according to standard procedures known in the art. For
example, stability of one or more compounds of the invention is
established by an in vitro assay. In particular, an in vitro
microsome stability assay is established that measures stability of
one or more compounds of the invention when reacting with mouse,
rat or human microsomes from liver. The microsome reaction with
compounds is performed in 1.5 mL Eppendorf tube. Each tube contains
0.1 .mu.L of 10.0 mg/ml NADPH; 75 .mu.L of 20.0 mg/ml mouse, rat or
human liver microsome; 0.4 .mu.L of 0.2 M phosphate buffer, and 425
.mu.L of ddH.sub.2O, Negative control (without NADPH) tube contains
75 .mu.L of 20.0 mg/ml mouse, rat or human liver microsome; 0.4
.mu.L of 0.2 M phosphate buffer, and 525 .mu.L of ddH.sub.2O. The
reaction is started by adding 1.0 .mu.L of 10.0 mM tested compound.
The reaction tubes are incubated at 37.degree. C. 100 .mu.L sample
is collected into new Eppendorf tube containing 300 .mu.L cold
Methanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples
are centrifuged at 15,000 rpm to remove protein. Supernatant of
centrifuged sample is transferred to new tube. Concentration of
stable compound after reaction with microsome in the supernatant is
measured by Liquid Chromatography/Mass Spectrometry (LC-MS). The
microsome stability of one or more compounds of the present
invention when assayed under this condition have T1/2 (min) well
within a range required for clinical development.
Example 20
Plasma Stability Assay
[1055] The stability of one or more compounds of the invention in
plasma is determined according to standard procedures known in the
art. See, e.g., Rapid Commun. Mass Spectrom., 10: 1019-1026. The
following procedure is an HPLC-MS/MS assay using human plasma;
other species including monkey, dog, rat, and mouse are also
available. Frozen, heparinized human plasma is thawed in a cold
water bath and spun for 10 minutes at 2000 rpm at 4.degree. C.
prior to use. A compound of the invention is added from a 400 .mu.M
stock solution to an aliquot of pre-warmed plasma to give a final
assay volume of 400 .mu.L (or 800 .mu.L for half-life
determination), containing 5 .mu.M test compound and 0.5% DMSO.
Reactions are incubated, with shaking, for 0 minutes and 60 minutes
at 37.degree. C., or for 0, 15, 30, 45 and 60 minutes at 37 C for
half life determination. Reactions are stopped by transferring 50
.mu.L of the incubation mixture to 200 .mu.L of ice-cold
acetonitrile and mixed by shaking for 5 minutes. The samples are
centrifuged at 6000.times.g for 15 minutes at 4.degree. C. and 120
.mu.L of supernatant removed into clean tubes. The samples are then
evaporated to dryness and submitted for analysis by HPLC-MS/MS.
[1056] Where desired, one or more control or reference compounds (5
.mu.M) are tested simultaneously with the test compounds: one
compound, propoxycaine, with low plasma stability and another
compound, propantheline, with intermediate plasma stability.
[1057] Samples are reconstituted in acetonitrile/methanol/water
(1/1/2, v/v/v) and analyzed via (RP)HPLC-MS/MS using selected
reaction monitoring (SRM). The HPLC conditions consist of a binary
LC pump with autosampler, a mixed-mode, C12, 2.times.20 mm column,
and a gradient program. Peak areas corresponding to the analytes
are recorded by HPLC-MS/MS. The ratio of the parent compound
remaining after 60 minutes relative to the amount remaining at time
zero, expressed as percent, is reported as plasma stability. In
case of half-life determination, the half-life is estimated from
the slope of the initial linear range of the logarithmic curve of
compound remaining (%) vs. time, assuming first order kinetics.
Example 21
Chemical Stability
[1058] The chemical stability of one or more compounds of the
invention is determined according to standard procedures known in
the art. The following details an exemplary procedure for
ascertaining chemical stability of a subject compound. The default
buffer used for the chemical stability assay is phosphate-buffered
saline (PBS) at pH 7.4; other suitable buffers can be used. A
compound of the invention is added from a 100 .mu.M stock solution
to an aliquot of PBS (in duplicate) to give a final assay volume of
400 .mu.L, containing 5 .mu.M test compound and 1% DMSO (for
half-life determination a total sample volume of 700 .mu.L is
prepared). Reactions are incubated, with shaking, for 0 minutes and
24 hours at 37.degree. C.; for half-life determination samples are
incubated for 0, 2, 4, 6, and 24 hours. Reactions are stopped by
adding immediately 100 .mu.L of the incubation mixture to 100 .mu.L
of acetonitrile and vortexing for 5 minutes. The samples are then
stored at -20.degree. C. until analysis by HPLC-MS/MS. Where
desired, a control compound or a reference compound such as
chlorambucil (5 .mu.M) is tested simultaneously with a compound of
the invention of interest, as this compound is largely hydrolyzed
over the course of 24 hours. Samples are analyzed via
(RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLC
conditions consist of a binary LC pump with autosampler, a
mixed-mode, C12, 2.times.20 mm column, and a gradient program. Peak
areas corresponding to the analytes are recorded by HPLC-MS/MS. The
ratio of the parent compound remaining after 24 hours relative to
the amount remaining at time zero, expressed as percent, is
reported as chemical stability. In case of half-life determination,
the half-life is estimated from the slope of the initial linear
range of the logarithmic curve of compound remaining (%) vs. time,
assuming first order kinetics.
Example 22
Akt Kinase Assay
[1059] Cells comprising components of the Akt/mTOR pathway,
including but not limited to L6 myoblasts, B-ALL cells, B-cells,
T-cells, leukemia cells, bone marrow cells, p190 transduced cells,
philladelphia chromosome positive cells (Ph+), and mouse embryonic
fibroblasts, are typically grown in cell growth media such as DMEM
supplemented with fetal bovine serum and/or antibiotics, and grown
to confluency.
[1060] In order to compare the effect of one or more compounds
disclosed herein on Akt activation, the selected cells are serum
starved overnight and incubated with one or more compounds
disclosed herein or about 0.1% DMSO for approximately 1 minute to
about 1 hour prior to stimulation with insulin (e.g. 100 nM) for
about 1 minutes to about 1 hour. Cells are lysed by scraping into
ice cold lysis buffer containing detergents such as sodium dodecyl
sulfate and protease inhibitors (e.g., PMSF). After contacting
cells with lysis buffer, the solution is briefly sonicated, cleared
by centrifugation, resolved by SDS-PAGE, transferred to
nitrocellulose or PVDF and immunoblotted using antibodies to
phospho-Akt S473, phospho-Akt T308, Akt, and .beta.-actin (Cell
Signaling Technologies).
[1061] The results demonstrate that one or more compounds of the
invention inhibit insulin stimulated phosphorylation of Akt at
S473. Alternatively, some compounds of the invention additionally
inhibit insulin stimulated phosphorylation of Akt at T308. The
class of compounds that can inhibit Akt signalling more effectively
than rapamycin as shown herein include those (e.g., compounds shown
in Table 1) that inhibit mTORC2 and mTORC1.
Example 23
Kinase Signaling in Blood
[1062] 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. To test the effects of one or more compounds
of the invention, 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. It is expected
that inhibitors disclosed herein inhibit anti-CD3 mediated
phosphorylation of Akt-S473 and S6, whereas rapamycin inhibits S6
phosphorylation and enhances Akt phosphorylation under the
conditions tested.
[1063] Similarly, aliquots of whole blood are incubated for 15
minutes with vehicle (e.g. 0.1% DMSO) or kinase inhibitors at
various concentrations, before addition of stimuli to crosslink the
T cell receptor (TCR) (anti-CD3 with secondary antibody) or the B
cell receptor (BCR) using anti-kappa light chain antibody (Fab'2
fragments). After approximately 5 and 15 minutes, samples are fixed
(e.g. with cold 4% paraformaldehyde) and used for phosflow. Surface
staining is used to distinguish T and B cells using antibodies
directed to cell surface markers that are known to the art. The
level of phosphrylation of kinase substrates such as Akt and S6 are
then measured by incubating the fixed cells with labeled antibodies
specific to the phosphorylated isoforms of these proteins. The
population of cells is then analyzed by flow cytometery. The
results are expected to show that one or more of the compounds of
the invention can selectively inhibit signaling of one or more
members of PI3K, mTOR, and Akt in blood cells under the conditions
tested.
Example 24
Colony Formation Assay
[1064] Murine bone marrow cells freshly transformed with a p190
BCR-Abl retrovirus (herein referred to as p190 transduced cells)
are plated in the presence of various drug combinations in M3630
methylcellulose media for about 7 days with recombinant human IL-7
in about 30% serum, and the number of colonies formed is counted by
visual examination under a microscope. It is expected that
compounds of the invention potentiate the effects of a half maximal
concentration of known chemotherapeutic agents such as and without
limitation imatinib, rapamycin, and dasatinib at the concentrations
examined.
[1065] Alternatively, human peripheral blood mononuclear cells are
obtained from Philladelphia chromosome positive (Ph+) and negative
(Ph-) subjects upon initial diagnosis or relapse. Live cells are
isolated and enriched for CD19+CD34+ B cell progenitors. After
overnight liquid culture, cells are plated in methocult GF+H4435,
Stem Cell Tehcnologies) suplemented with cytokines (IL-3, IL-6,
IL-7, G-CSF, GM-CSF, CF, Flt3 ligand, and erythropoietin) and
various concentrations of known chemotherapeutic agents in
combination with either compounds of the invention. Colonies are
counted by microscopy 12-14 days later. This method can be used to
test for the additive or synergistic activity of various
combination therapies utilizing the subject composition. It is
expected that one or more the compounds of the present invention
are potent and selective inhibitors of p190 transduced cell colony
formation under the conditions tested.
Example 25
In Vivo Effect of Kinase Inhibitors on Leukemic Cells
[1066] Female recipient mice are lethally irradiated from a 7
source in two doses about 4 hr apart, with approximately 5Gy each.
About 1 hr after the second radiation dose, mice are injected i.v.
with about 1.times.10.sup.6 leukemic cells (e.g. Ph+ human or
murine cells, or p190 transduced bone marrow cells). These cells
are administered together with a radioprotective dose of about
5.times.10.sup.6 normal bone marrow cells from 3-5 week old donor
mice. Recipients are given antibiotics in the water and monitored
daily. Mice who become sick after about 14 days are euthanized and
lymphoid organs are harvested for analysis. Kinase inhibitor
treatment begins about 10 days after leukemic cell injection and
continues daily until the mice become sick or a maximum of
approximately 35 days post-transplant. Inhibitors are given by oral
lavage.
[1067] Peripheral blood cells are collected approximately on day 10
(pre-treatment) and upon euthanization (post treatment), contacted
with labeled anti-hCD4 antibodies and counted by flow cytometry.
This method can be used to demonstrate that the synergistic effect
of one or more compounds of the invention alone or in combination
with known chemotherapeutic agents significantly reduce leukemic
blood cell counts as compared to treatment with known
chemotherapeutic agents (e.g. Gleevec) alone under the conditions
tested.
Example 26
Inhibition of Proliferation of Tumor Cells Deficient in PTEN
Activity but Expressing PI3-Kinases
[1068] The ability of one or more compounds of the invention to
inhibit proliferation of tumor cells deficient in PTEN Activity but
expressing PI3-kinases is tested according to the procedure
detailed in example 17. As is shown in FIG. 7A, a compound of the
present invention (e.g., a compound of Table 1) yields 50%
inhibition of PC-3 cell proliferation at a concentration that is at
least about two orders of magnitude less as compared to
rapamycin.
[1069] Western blot analysis revealed that the compound of the
invention is capable of inhibiting phosphorylation of AKT (S473)
and AKT (T308) as well as other downstream targets of the mTor
signaling pathway to a greater degree than rapamycin. See FIG. 7B.
In particular, PC-3 cells were plated at about 1.times.10.sup.5
cells/well in 24 well plates in a culture media containing 10% FBS.
The cells were allowed to grow to about 80% confluent. Cells were
treated for 2 hours at 37.degree. C. in CO.sub.2 incubator with
fresh cell culture media (10% FBS) with a compound of the present
invention or rapamycin at indicated concentrations. After
incubation, cells were lysed by adding 1.times. Cell Lysis Buffer
(200 .mu.l per well of 24-well plate of confluent cells). Proteins
were separated via SDS-PAGE on 4-20% gradient gels and standard
semi-dry blotting techniques are used to transfer the protein to
nitrocellulose membranes. p-AKT(473), p-S6K, and p-4EBP1 were
detected by using rabbit anti-human primary antibodies (Cell
Signaling, Danvers, Mass.) followed by an HRP-conjugated
anti-rabbit secondary antibody (Cell Signaling, Danvers, Mass.).
The LumiGLO substrate (KPL, Inc., Gaithersburg, Md.) is used to
detect the phospho-proteins on the Western blot.
Example 27
Treatment of Lupus Disease Model Mice
[1070] Mice lacking the inhibitory receptor Fc.gamma.RIIb that
opposes PI3K signaling in B cells develop lupus with high
penetrance. Fc.gamma.RIIb knockout mice (R2KO, Jackson Labs) are
considered a valid model of the human disease as some lupus
subjects show decreased expression or function of Fc.gamma.RIIb (S.
Bolland and J.V. Ravtech 2000. Immunity 12:277-285).
[1071] The R2KO mice develop lupus-like disease with anti-nuclear
antibodies, glomerulonephritis and proteinurea within about 4-6
months of age. For these experiments, the rapamycin analogue RAD001
(available from LC Laboratories) is used as a benchmark compound,
and administered orally. This compound has been shown to ameliorate
lupus symptoms in the B6.Sle1z.Sle3z model (T. Wu et al. J. Clin
Invest. 117:2186-2196).
[1072] Lupus disease model mice such as R2KO, BXSB or MLR/lpr are
treated at about 2 months old, approximately for about two months.
Mice are given doses of: vehicle, RAD001 at about 10 mg/kg, or
compounds disclosed herein at approximately 10 mg/kg to about 50
mg/kg. Blood and urine samples are obtained at approximately
throughout the testing period, and tested for antinuclear
antibodies (in dilutions of serum) or protein concentration (in
urine). Serum is also tested for anti-ssDNA and anti-dsDNA
antibodies by ELISA. Animals are euthanized at day 60 and tissues
harvested for measuring spleen weight and kidney disease.
Glomerulonephritis is assessed in kidney sections stained with
H&E. Other animals are studied for about two months after
cessation of treatment, using the same endpoints.
[1073] This model established in the art can be employed to test
that the kinase inhibitors disclosed herein can suppress or delay
the onset of lupus symptoms in lupus disease model mice.
Example 28
Murine Bone Marrow Transplant Assay
[1074] Female recipient mice are lethally irradiated from a 7 ray
source. About 1 hr after the radiation dose, mice are injected with
about 1.times.106 leukemic cells from early passage p190 transduced
cultures (e.g. as described in Cancer Genet Cytogenet. 2005 August;
161(1):51-6). These cells are administered together with a
radioprotective dose of approximately 5.times.106 normal bone
marrow cells from 3-5wk old donor mice. Recipients are given
antibiotics in the water and monitored daily. Mice who become sick
after about 14 days are euthanized and lymphoid organs harvested
for flow cytometry and/or magnetic enrichment. Treatment begins on
approximately day 10 and continues daily until mice become sick, or
after a maximum of about 35 days post-transplant. Drugs are given
by oral gavage (p.o.). In a pilot experiment a dose of
chemotherapeutic that is not curative but delays leukemia onset by
about one week or less is identified; controls are vehicle-treated
or treated with chemotherapeutic agent, previously shown to delay
but not cure leukemogenesis in this model (e.g. imatinib at about
70 mg/kg twice daily). For the first phase p190 cells that express
eGFP are used, and postmortem analysis is limited to enumeration of
the percentage of leukemic cells in bone marrow, spleen and lymph
node (LN) by flow cytometry. In the second phase, p190 cells that
express a tailless form of human CD4 are used and the postmortem
analysis includes magnetic sorting of hCD4+ cells from spleen
followed by immunoblot analysis of key signaling endpoints: p
Akt-T308 and S473; pS6 and p4EBP-1. As controls for immunoblot
detection, sorted cells are incubated in the presence or absence of
kinase inhibitors of the present disclosure inhibitors before
lysis. Optionally, "phosflow" is used to detect p Akt --S473 and
pS6-S235/236 in hCD4-gated cells without prior sorting. These
signaling studies are particularly useful if, for example,
drug-treated mice have not developed clinical leukemia at the 35
day time point. Kaplan-Meier plots of survival are generated and
statistical analysis done according to methods known in the art.
Results from p190 cells are analyzed separated as well as
cumulatively.
[1075] Samples of peripheral blood (100-200 .mu.l) are obtained
weekly from all mice, starting on day 10 immediately prior to
commencing treatment. Plasma is used for measuring drug
concentrations, and cells are analyzed for leukemia markers (eGFP
or hCD4) and signaling biomarkers as described herein. It is
expected that the results of the analysis demonstrate effective
therapeutic doses of the compounds disclosed herein for inhibiting
the proliferation of leukemic cells. It is further expected that
combination therapy of the inhibitors disclosed herein with other
chemotherapeutic agents including but not limited to those
disclosed herein (e.g. Gleevec and dasatinib) exhibit a greater
degree of efficacy or decreased toxicity in comparison to the use
of a single chemotherapeutic agent.
Example 29
Rodent Pharmacokinetic Assay
[1076] In order to study the pharmacokinetics of the compounds of
the invention a set of 4-10 week old mice are grouped according to
the following table:
TABLE-US-00002 Compound Administration Mice/ from day-1 to day-7
Group# group (mg/kg) Route Regimen 1 3 1 Po BID for 7 2 3 3 days 3
3 10 4 3 30 5 3 60
[1077] Alternatively, compounds are dosed acutely (e.g. once) and
after a time (e.g. about 0, 30 s, 1 m, 5 m, 10 m, 20 m, 30 m, 1 hr,
2 hr, 3 hr, 5 hr, 8 hr, 10 hr, 12 hr, 1 d, 2 d, etc.) blood is
collected and analyzed as described below.
[1078] Compounds of the invention are dissolved in an appropriate
vehicle (e.g. 5% 1-methyl-2-pyrrolidinone, 85% polyethylene glycol
400, 10% Solutor) and administered orally at 12 hour intervals
daily. All animals are euthanized in CO.sub.2 2 hours after the
final compound is administered. Blood is collected immediately and
kept on ice for plasma isolation. Plasma is isolated by
centrifuging at 5000 rpm for 10 minutes. Harvested plasma is frozen
for pharmacokinetic detection.
[1079] The results are expected to demonstrate the pharmacokinetic
parameters such as absorption, distribution, metabolism, excretion,
and toxicity for the compounds of the invention.
Example 30
Combination Use of PI3K.delta. Inhibitors and Agents that Inhibit
IgE Production or Activity
[1080] The compounds of the invention may present synergistic or
additive efficacy when administered in combination with an
inhibitors selective for one or more PI3-kinase, e.g.,
PI3K.delta..
[1081] PI3K.delta. inhibitors may be efficacious in treatment of
autoimmune and inflammatory disorders (AIID) for example rheumatoid
arthritis. When a PI3K.delta. inhibitor cause an undesired level of
IgE production, one may choose to administer it in combination with
an agent that inhibits IgE production or IgE activity such as an
mTORC1 and/or mTORC2 inhibitor disclosed herein. Additionally, the
administration of PI3K.delta. or PI3K.delta./.gamma. inhibitors in
combination with inhibitors of mTOR may also exhibit synergy
through enhanced inhibition of the PI3K pathway. Various in vivo
and in vitro models may be used to establish the effect of such
combination treatment on AIID including but not limited to (a) in
vitro B-cell antibody production assay, (b) in vivo TNP assay, and
(c) rodent collagen induced arthritis model.
[1082] (a) B-Cell Assay
[1083] Mice are euthanized, and the spleens are removed and
dispersed through a nylon mesh to generate a single-cell
suspension. The splenocytes are washed (following removal of
erythrocytes by osmotic shock) and incubated with anti-CD43 and
anti-Mac-1 antibody-conjugated microbeads (Miltenyi Biotec). The
bead-bound cells are separated from unbound cells using a magnetic
cell sorter. The magnetized column retains the unwanted cells and
the resting B cells are collected in the flow-through. Purified
B-cells are stimulated with lipopolysaccharide or an anti-CD40
antibody and interleukin 4. Stimulated B-cells are treated with
vehicle alone or with a PI3K.delta. inhibitor with and without mTOR
inhibitors such as rapamycin, rapalogs, or mTORC1/C2 inhibitors
disclosed herein. The results are expected to show that in the
presence of mTOR inhibitors alone (e.g., rapamycin as well as the
subject inhibitors capable of inhibiting both mTORC1 and mTORC2),
there is little to no substantial effect on IgG and IgE response.
However, in the presence of PI3K.delta. and mTOR inhibitors, the
B-cells are expected to exhibit a decreased IgG response as
compared to the B-cells treated with vehicle alone, and the B-cells
are expected to exhibit a decreased IgE response as compared to the
response from B-cells treated with PI3K.delta. inhibitors
alone.
[1084] (b) TNP Assay
[1085] Mice are immunized with TNP-Ficoll or TNP-KHL and treated
with: vehicle, a PI3K.delta. inhibitor, an mTOR inhibitor, for
example rapamycin, or a PI3K.delta. inhibitor in combination with
an mTOR inhibitor such as rapamycin. Antigen-specific serum IgE is
measured by ELISA using TNP-BSA coated plates and isotype specific
labeled antibodies. This assay can be used to test that mice
treated with an mTOR inhibitor alone exhibit little or no
substantial effect on antigen specific IgG3 response and no
statistically significant elevation in IgE response as compared to
the vehicle control. This assay can also be used to test that mice
treated with both PI3K.delta. inhibitor and mTOR inhibitor exhibit
a reduction in antigen specific IgG3 response as compared to the
mice treated with vehicle alone. Additionally, this assay can be
employed to test that the mice treated with both PI3K.delta.
inhibitor and mTOR inhibitor exhibit a decrease in IgE response as
compared to the mice treated with PI3K.delta. inhibitor alone.
[1086] (c) Rat Collagen Induced Arthritis Model
[1087] Female Lewis rats are anesthetized and given collagen
injections prepared and administered as described previously on day
0. On day 6, animals are anesthetized and given a second collagen
injection. Caliper measurements of normal (pre-disease) right and
left ankle joints are performed on day 9. On days 10-11, arthritis
typically occurs and rats are randomized into treatment groups.
Randomization is performed after ankle joint swelling is obviously
established and there is good evidence of bilateral disease.
[1088] After an animal is selected for enrollment in the study,
treatment is initiated. Animals are given vehicle, PI3K.delta.
inhibitor, or PI3K.delta. inhibitor in combination with an mTOR
inhibitor. Dosing is administered on days 1-6. Rats are weighed on
days 1-7 following establishment of arthritis and caliper
measurements of ankles taken every day. Final body weights are
taken on day 7 and animals are euthanized.
[1089] This assay can be used to test that the combination
treatment using PI3K.delta. inhibitor and an inhibitor of mTOR
provides greater efficacy than treatment with PI3K.delta. inhibitor
alone.
Example 31
Inhibition of Tumor Growth In Vivo
[1090] Cell Lines:
[1091] Tumor cell lines such as A549, U87, ZR-75-1 and 786-O are
obtained from American Type Culture Collection (ATCC, Manassas,
Va.). Cells are proliferated and preserved cryogenically at early
passage (e.g. passage 3). One aliquot is used for further
proliferation to get enough cells for one TGI study (at about
passage 9).
Animals
[1092] Female athymic nude mice are supplied by Harlan. Mice are
received at 4 to 6 weeks of age. All mice are acclimated for about
one day to two weeks prior to handling. The mice are housed in
microisolator cages and maintained under specific pathogen-free
conditions. The mice are fed with irradiated mouse chow and freely
available autoclaved water is provided.
[1093] Tumor Xenograft Model:
[1094] Mice are inoculated subcutaneously in the right flank with
0.01 to 0.5 ml of tumor cells such as those listed above
(approximately 1.0.times.10.sup.5 to 1.0.times.10.sup.8
cells/mouse). Five to 10 days following inoculation, tumors are
measured using calipers and tumor weight is calculated, for example
using the animal study management software, such as Study Director
V.1.6.70 (Study Log). Mice with tumor sizes of about 120 mg are
pair-matched into desired groups using Study Director (Day 1). Body
weights are recorded when the mice are pair-matched. Tumor volume
and bodyweight measurements are taken one to four times weekly and
gross observations are made at least once daily. On Day 1,
compounds of the present invention and reference compounds as well
as vehicle control are administered by oral gavage or iv as
indicated. At the last day of the experiment, mice are sacrificed
and their tumors are collected 1-4 hours after the final dose. The
tumors are excised and cut into two sections. One third of the
tumor is fixed in formalin and embedded in paraffin blocks and the
remaining two thirds of tumor is snap frozen and stored at
-80.degree. C.
[1095] Data and Statistical Analysis:
[1096] Mean tumor growth inhibition (TGI) is calculated utilizing
the following formula:
[1097] Tumors that regress from the Day 1 starting size are removed
from the calculations. Individual tumor shrinkage (TS) is
calculated using the formula below for tumors that show regression
relative to Day 1 tumor weight. The mean tumor shrinkage of each
group is calculated and reported.
[1098] The model can be employed to show whether the compounds of
the invention can inhibit tumor cell growth including but not
limited to renal carcinomoa cell growth, breast cancer cell growth,
lung cancer cell growth, or glioblastoma cell growth under the
conditions tested.
TS = [ 1 - ( Tumor Weight ( Final ) ) ( Tumor Weight ( Day 1 ) ) ]
.times. 100 % ##EQU00001##
[1099] As shown in FIGS. 3A-3B, a compound of the invention of
Formula I'-A'reduces tumor size in the U87 human glioblastoma
xenograft model in a dose dependent manner over a period of 14-day
treatment. FIG. 3C shows that the compound has no substantial toxic
effect on the animal as there was no significant weight loss during
the treatment. Excised tumors (FIG. 3C) were further examined by
Western blot analysis which revealed inhibition of mTOR/Akt
signalling by the compound of the invention (FIGS. 4B and 10). In
particular, inhibition of mTOR/Akt signalling was evidenced by a
decrease in phosphorylated Akt at residues S473 and T308, pS6,
p4EBP-1, and Cyclin D1. The compound of the invention is more
potent in inhibiting mTOR/Akt signalling as compared to an
inhibitor that is not selective for mTORs, such as one commonly
referred to as PanPI3K/mTor inhibitor. The excised tumors were also
subject to TUNEL staining (FIG. 12) which shows tumor cell death
after the treatment.
[1100] The same experiment was performed with several other tumor
models including tumor cell A549 induced NSCLC (non-small cell lung
cancer), tumor cell ZR-75-1 induced breast cancer, and tumor cell
786-O induced RCC (renal cell carcinoma). FIGS. 11B-11D indicate
that the efficacy of the compound of the invention in treating all
of these tumors became detectable as early as one week after
treatment. The effect of reduction in tumor size in all instances
last at least 1 month.
* * * * *