U.S. patent application number 12/167038 was filed with the patent office on 2009-07-16 for kinase inhibitory phosphonate analogs.
Invention is credited to Carina Cannizzaro, James M. Chen, Xiaowu Chen, Aesop Cho, Lee S. Chong, Manoj Desai, Maria Fardis, Thorsten Kirschberg, Richard L. Mackman, Sundaramoorthi Swaminathan, William J. Watkins.
Application Number | 20090181930 12/167038 |
Document ID | / |
Family ID | 33425953 |
Filed Date | 2009-07-16 |
United States Patent
Application |
20090181930 |
Kind Code |
A1 |
Cannizzaro; Carina ; et
al. |
July 16, 2009 |
KINASE INHIBITORY PHOSPHONATE ANALOGS
Abstract
The invention is related to phosphorus substituted kinase
inhibitory compounds, compositions containing such compounds, and
therapeutic methods that include the administration of such
compounds, as well as to processes and intermediates useful for
preparing such compounds.
Inventors: |
Cannizzaro; Carina; (San
Mateo, CA) ; Chen; James M.; (San Ramon, CA) ;
Chen; Xiaowu; (San Mateo, CA) ; Cho; Aesop;
(Mountain View, CA) ; Chong; Lee S.; (Newark,
CA) ; Desai; Manoj; (Pleasant Hill, CA) ;
Fardis; Maria; (San Carlos, CA) ; Kirschberg;
Thorsten; (Belmont, CA) ; Mackman; Richard L.;
(Millbrae, CA) ; Swaminathan; Sundaramoorthi;
(Burlingame, CA) ; Watkins; William J.;
(Sunnyvale, CA) |
Correspondence
Address: |
VIKSNINS HARRIS & PADYS PLLP
P.O BOX 111098
St. Paul
MN
55111-1098
US
|
Family ID: |
33425953 |
Appl. No.: |
12/167038 |
Filed: |
July 2, 2008 |
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Current U.S.
Class: |
514/80 ;
544/232 |
Current CPC
Class: |
A61K 47/548 20170801;
A61P 9/00 20180101; C07F 9/6561 20130101; A61P 37/06 20180101; A61P
17/06 20180101; A61P 1/04 20180101; A61P 35/00 20180101; A61P 27/02
20180101; A61P 35/04 20180101; A61P 19/02 20180101; A61K 47/54
20170801; A61P 29/00 20180101; C07F 9/58 20130101; A61P 43/00
20180101; A61P 35/02 20180101; A61P 3/00 20180101; A61K 31/662
20130101 |
Class at
Publication: |
514/80 ;
544/232 |
International
Class: |
C07F 9/6512 20060101
C07F009/6512; A61K 31/675 20060101 A61K031/675 |
Claims
1. A conjugate of formula: [DRUG]-(A.sup.0).sub.nn; wherein: DRUG
is a compound of formula 502: ##STR00675## wherein: nn is 1, 2 or
3; A.sup.0 is A.sup.1, A.sup.2 or W.sup.3 with the proviso that the
conjugate includes at least one A.sup.1; A.sup.1 is: ##STR00676##
A.sup.2 is: ##STR00677## A.sup.3 is: ##STR00678## Y.sup.1 is
independently O, S, N(R.sup.x), N(O)(R.sup.x), N(OR.sup.x),
N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x)); Y.sup.2 is independently
a bond, O, N(R.sup.x), N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x),
N(N(R.sup.x)(R.sup.x)), --S(O).sub.M2--, or
--S(O).sub.M2--S(O).sub.M2--; and when Y.sup.2 joins two
phosphorous atoms Y.sup.2 can also be C(R.sup.2)(R.sup.2); R.sup.x
is H, R.sup.1, R.sup.2, W.sup.3, a protecting group, or the
formula; ##STR00679## wherein: R.sup.y is independently H, W.sup.3,
R.sup.2 or a protecting group; R.sup.1 is independently H or alkyl
of 1 to 18 carbon atoms; R.sup.2 is independently H, R.sup.1,
R.sup.3 or R.sup.4 wherein each R.sup.4 is independently
substituted with 0 to 3 R.sup.3 groups or taken together at a
carbon atom, two R.sup.2 groups form a ring of 3 to 8 carbons and
the ring may be substituted with 0 to 3 R.sup.3 groups; R.sup.3 is
R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d, provided that when
R.sup.3 is bound to a heteroatom, then R.sup.3 is R.sup.3c or
R.sup.3d; R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
R.sup.3b is Y.sup.1; R.sup.3c is --R.sup.x, --N(R.sup.x)(R.sup.x),
--SR.sup.x, --S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
--N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x)); R.sup.3d is
--C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x)); R.sup.4 is an alkyl of 1 to 18
carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to
18 carbon atoms; R.sup.5 is R.sup.4 wherein each R.sup.4 is
substituted with 0 to 3 R.sup.3 groups; W.sup.3 is W.sup.4 or
W.sup.5; W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.M2R.sup.5, or --SO.sub.M2W.sup.5;
W.sup.5 is carbocycle wherein W.sup.5 is independently substituted
with 0 to 3 R.sup.2 groups; W.sup.6 is W.sup.3 independently
substituted with 1, 2, or 3 A3 groups; M2 is 0, 1 or 2; M12a is 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d are independently 0 or 1;
and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. or a
pharmaceutically acceptable salt or solvate thereof.
2. The conjugate of claim 1 wherein each A.sup.3 is of the formula:
##STR00680##
3. The conjugate of claim 1 wherein each A.sup.3 is of the formula:
##STR00681## wherein Y.sup.2b is O or N(R.sup.x).
4. The conjugate of claim 1 wherein each A.sup.3 is of the formula:
##STR00682##
5. The conjugate of claim 1 wherein each A.sup.3 is of the formula:
##STR00683## wherein the phenyl carbocycle is substituted with 0,
1, 2, or 3 R.sup.1 groups.
6. The conjugate of claim 1 wherein each A.sup.3 is of the formula:
##STR00684## wherein: Y.sup.1a is O or S; Y.sup.2b is O or
N(R.sup.2); and Y.sup.2c is O, N(R.sup.y) or S.
7. The conjugate of claim 1 wherein A.sup.0 is of the formula:
##STR00685## wherein each R is independently alkyl.
8. A pharmaceutical composition comprising a pharmaceutical
excipient and a conjugate as described in claim 1, or a
pharmaceutically acceptable salt or solvate thereof.
Description
PRIORITY OF INVENTION
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119(e) to U.S. Provisional Patent Application Ser.
Nos. 60/465,588, 60/465,594, 60/465,465, and 60/465,569, all filed
Apr. 25, 2003; and to U.S. Provisional Patent Application Ser. Nos.
60/495,382, 60/495,685, 60/495,527, and 60/495,686, all filed Aug.
15, 2003; and to U.S. Provisional Patent Application Ser. Nos.
60/513,956, 60/513,925, 60/514,368, 60/514,207, 60/514,115,
60/514,324, 60/514,330, and 60/513,974, all filed Oct. 24, 2003;
and to U.S. Provisional Patent Application Ser. No. 60/531,932,
filed Dec. 22, 2003; and to U.S. Provisional Patent Application
Ser. No. 60/536,054, filed Jan. 12, 2004. The entirety of all
Provisional Applications listed above are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The invention relates generally to phosphonate-containing
compounds with kinase-inhibitory activity, i.e., compounds that are
kinase inhibitors.
BACKGROUND OF THE INVENTION
[0003] Improving the delivery of drugs and other agents to target
cells and tissues has been the focus of considerable research for
many years. Though many attempts have been made to develop
effective methods for importing biologically active molecules into
cells, both in vivo and in vitro, none has proved to be entirely
satisfactory. Optimizing the association of the inhibitory drug
with its intracellular target, while minimizing intercellular
redistribution of the drug, e.g., to neighboring cells, is often
difficult or inefficient.
[0004] Most agents currently administered to a patient parenterally
are not targeted, resulting in systemic delivery of the agent to
cells and tissues of the body where it is unnecessary, and often
undesirable. This may result in adverse drug side effects, and
often limits the dose of a drug (e.g., glucocorticoids and other
anti-inflammatory drugs) that can be administered. By comparison,
although oral administration of drugs is generally recognized as a
convenient and economical method of administration, oral
administration can result in either (a) uptake of the drug through
the cellular and tissue barriers, e.g., blood/brain, epithelial,
cell membrane, resulting in undesirable systemic distribution, or
(b) temporary residence of the drug within the gastrointestinal
tract. Accordingly, a major goal has been to develop methods for
specifically targeting agents to cells and tissues. Benefits of
such treatment includes avoiding the general physiological effects
of inappropriate delivery of such agents to other cells and
tissues, such as uninfected cells.
[0005] Many of the current treatment regimes for cell proliferation
diseases such as psoriasis and cancer utilize compounds which
inhibit DNA synthesis. Such compounds are toxic to cells generally
but their toxic effect on rapidly dividing cells such as tumor
cells can be beneficial. Alternative approaches to
anti-proliferative agents which act by mechanisms other than the
inhibition of DNA synthesis have the potential to display enhanced
selectivity of action.
[0006] In recent years it has been discovered that a cell may
become cancerous by virtue of the transformation of a portion of
its DNA into an oncogene i.e. a gene that, on activation, leads to
the formation of malignant tumor cells (Bradshaw, Mutagenesis 1986,
1, 91). Several such oncogenes give rise to the production of
peptides which are receptors for growth factors. The growth factor
receptor complex subsequently leads to an increase in cell
proliferation. It is known, for example, that several oncogenes
encode tyrosine kinase enzymes and that certain growth factor
receptors are also tyrosine kinase enzymes (Yarden et al., Ann.
Rev. Biochem., 1988, 57, 443; Larsen et al., Ann. Reports in Med.
Chem. 1989, Chpt. 13).
[0007] Receptor tyrosine kinases are important in the transmission
of biochemical signals that initiate cell replication. They are
large enzymes that span the cell membrane and possess an
extracellular binding domain for growth factors such as epidermal
growth factor (EGF), and an intracellular portion that functions as
a kinase to phosphorylate tyrosine amino acids in proteins and
hence influence cell proliferation. Various classes of receptor
tyrosine kinases are known (Wilks, Advances in Cancer Research,
1993, 60, 43-73) based on families of growth factors that bind to
different receptor tyrosine kinases. The classification includes
Class I receptor tyrosine kinases comprising the EGF family of
receptor tyrosine kinases such as the EGF, TGF.alpha., NEU, erbB,
Xmrk, HER and let23 receptors, Class II receptor tyrosine kinases
comprising the insulin family of receptor tyrosine kinases such as
the insulin, IGFI and insulin-related receptor (IRR) receptors and
Class III receptor tyrosine kinases comprising the platelet-derived
growth factor (PDGF) family of receptor tyrosine kinases such as
the PDGF.alpha., PDGF.beta. and colony-stimulating factor 1 (CSF1)
receptors.
[0008] It is known that Class I kinases such as the EGF family of
receptor tyrosine kinases are frequently present in common human
cancers such as breast cancer (Sainsbury et al., Brit. J Cancer,
1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21 and Klijn
et al., Breast Cancer Res. Treat., 1994, 29, 73), non-small cell
lung cancers (NSCLCs) including adenocarcinomas (Cerny et al.,
Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990,
45, 269; and Rusch et al., Cancer Research, 1993, 53, 2379) and
squamous cell cancer of the lung (Hendler et al., Cancer Cells,
1989, 7, 347), bladder cancer (Neal et al., Lancet, 1985, 366),
oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142),
gastrointestinal cancer such as colon, rectal or stomach cancer
(Bolen et al., Oncogene Res., 1987, 1, 149), cancer of the prostate
(Visakorpi et al., Histochem. J., 1992, 24, 481), leukaemia (Konaka
et al., Cell, 1984, 37, 1035) and ovarian, bronchial or pancreatic
cancer (European Patent Specification No. 0400586). As further
human tumor tissues are tested for the EGF family of receptor
tyrosine kinases, it is expected that their widespread prevalence
will be established in further cancers such as thyroid and uterine
cancer. It is also known that EGF type tyrosine kinase activity is
rarely detected in normal cells, whereas it is more frequently
detectable in malignant cells (Hunter, Cell, 1987, 50, 823). It has
been shown more recently (W. J. Gullick, Brit. Med. Bull., 1991,
47, 87) that EGF receptors that possess tyrosine kinase activity
are overexpressed in many human cancers such as brain, lung
squamous cell, bladder, gastric, breast, head and neck,
oesophageal, gynaecological and thyroid tumors.
[0009] Accordingly, an inhibitor of receptor tyrosine kinases
should be of value as a selective inhibitor of the growth of
mammalian cancer cells (Yaish et al. Science, 1988, 242, 933).
Support for this view is provided by the demonstration that
erbstatin, an EGF receptor tyrosine kinase inhibitor, specifically
attenuates the growth in athymic nude mice of a transplanted human
mammary carcinoma that expresses EGF receptor tyrosine kinase but
is without effect on the growth of another carcinoma that does not
express EGF receptor tyrosine kinase (Toi et al., Eur. J. Cancer
Clin. Oncol., 1990, 26, 722.) Various derivatives of styrene are
also stated to possess tyrosine kinase inhibitory properties
(European Patent Application Nos. 0 211 363, 0 304 493 and 0 322
738) and to be of use as anti-tumor agents. The in vivo inhibitory
effect of two such styrene derivatives that are EGF receptor
tyrosine kinase inhibitors has been demonstrated against the growth
of human squamous cell carcinoma inoculated into nude mice (Yoneda
et al., Cancer Research, 1991, 51, 4430). Various known tyrosine
kinase inhibitors are disclosed in a more recent review by T. R.
Burke Jr. (Drugs of the Future, 1992, 17, 119).
[0010] Kinase inhibitors have valuable pharmacological properties
and can be used, for example, as anti-tumoral drugs and as drugs
against atherosclerosis. The phosphorylation of proteins has long
been known as an important step in the differentiation and
proliferation of cells. Phosphorylation is catalyzed by protein
kinases that are divided into serine/threonine kinases and tyrosine
kinases. The serine/threonine kinases include protein kinase C and
the tyrosine kinases include PDGF (platelet-derived growth
factor)-receptor tyrosine kinase and Bcr-Abl kinase.
[0011] Kinase inhibitors inhibit cellular kinases that are involved
in disease states, for example, Bcr-Abl. Chronic myelogenous
Leukemia (CML) is a hematological stem cell disorder associated
with a specific chromosomal translocation known as the Philadelphia
chromosome that is detected in 95% of patients with CML and 20%
with acute lymphocytic leukemia (ALL). The molecular consequences
of the translocation is the fusion of the abl protooncogene to the
bcr gene resulting in the production of an activated from of Abl
tyrosine protein kinase. The Bcr-Abl protein is capable of inducing
leukemias in mice, thus implicating the protein as the cause of
these diseases. As the tyrosine kinase activity of the Bcr-Abl
protein is essential to its transforming ability, an inhibitor
would be useful therapy for these disorders.
[0012] In addition, kinase inhibitors prevent the development of
resistance (multi-drug resistance) in cancer treatment with other
chemotherapeutic drugs or remove existing resistance to other
chemotherapeutic drugs.
[0013] Two processes, the de novo formation of vessels from
differentiating endothelial cells or angioblasts in the developing
embryo (vasculogenesis) and the growth of new capillary vessels
from existing blood vessels (angiogenesis), are involved in the
development of the vascular systems of animal organs and tissues.
Transient phases of new vessel formation (neovascularization) also
occur in the adult body, for example, during the menstrual cycle,
pregnancy or wound healing. On the other hand, a number of diseases
are known to be associated with deregulated angiogenesis, for
example, retinopathies, psoriasis, hemangioblastoma, hemangioma,
and neoplastic diseases (solid tumors). The complex processes of
vasculogenesis and angiogenesis have been found to involve a whole
range of molecules, especially angiogenic growth factors and their
endothelial receptors, as well as cell adhesion molecules.
[0014] Recent findings show that at the center of the network
regulating the growth and differentiation of the vascular system
and its components, both during embryonic development and normal
growth and in a wide number of pathological anomalies and diseases,
lies the angiogenic factor known as vascular endothelial growth
factor (VEGF), along with its cellular receptors (see Breier, G.,
et al., Trends in Cell Biology 6, 454-6 (1996) and the references
cited therein).
[0015] VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein and
is related to platelet-derived growth factor (PDGF). It is produced
by normal cell lines and tumor cell lines, is an endothelial
cell-specific mitogen, shows angiogenic activity in in vivo test
systems (e.g. rabbit cornea), is chemotactic for endothelial cells
and monocytes, and induces plasminogen activators in endothelial
cells, which are then involved in the proteolytic degradation of
extracellular matrix during the formation of capillaries. A number
of isoforms of VEGF are known that show comparable biological
activity, but differ in the type of cells that secrete them and in
their heparin-binding capacity. In addition, there are other
members of the VEGF family, such as placenta growth factor (PLGF)
and VEGF-C.
[0016] VEGF receptors are transmembranous receptor tyrosine
kinases. They are characterized by an extracellular domain with
seven immunoglobulin-like domains and an intracellular tyrosine
kinase domain. Various types of VEGF receptor are known, e.g.
VEGFR-1, VEGFR-2, and VEGFR-3.
[0017] A large number of human tumors, especially gliomas and
carcinomas, express high levels of VEGF and its receptors. This has
led to the hypothesis that the VEGF released by tumor cells could
stimulate the growth of blood capillaries and the proliferation of
tumor endothelium in a paracrine manner and thus, through the
improved blood supply, accelerate tumor growth. Increased VEGF
expression could explain the occurrence of cerebral edema in
patients with glioma. Direct evidence of the role of VEGF as a
tumor angiogenesis factor in vivo has been obtained from studies in
which VEGF expression or VEGF activity was inhibited. This was
achieved with antibodies that inhibit VEGF activity, with
dominant-negative VEGFR-2 mutants that inhibited signal
transduction, or with the use of antisense-VEGF RNA techniques. All
approaches led to a reduction in the growth of glioma cell lines or
other tumor cell lines in vivo as a result of inhibited tumor
angiogenesis.
[0018] In addition, hypoxia, a large number of growth factors and
cytokines, e.g. Epidermal Growth Factor, Transforming Growth Factor
a, Transforming Growth Factor A, Interleukin 1, and Interleukin 6,
induce the expression of VEGF in cell experiments. Angiogenesis is
regarded as an absolute prerequisite for those tumors that grow
beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen
and nutrients may be supplied to the tumor cells by diffusion.
Every tumor, regardless of its origin and its cause, is thus
dependent on angiogenesis for its growth after it has reached a
certain size.
[0019] Three principal mechanisms play an important part in the
activity of angiogenesis inhibitors against tumors: 1) inhibition
of the growth of vessels, especially capillaries, into avascular
resting tumors, with the result that there is no net tumor growth
owing to the balance that is achieved between apoptosis and
proliferation; 2) prevention of the migration of tumor cells owing
to the absence of bloodflow to and from tumors; and 3) inhibition
of endothelial cell proliferation, thus avoiding the paracrine
growth-stimulating effect exerted on the surrounding tissue by the
endothelial cells that normally line the vessels.
[0020] Inhibitors of cyclin-dependent kinases, e.g., Alvocidib
(U.S. Pat. No. 4,900,727; also known as flavopiridol) have been
identified as a potentially useful therapeutic agents for a variety
of cancers, including gastrointestinal and colon tumors, leukemias
and myelomas (see, for example, Intl. J. Oncol., 1996, 9,
1143).
[0021] Inhibitors of tyrosine kinases, including Bcr-Abl, e.g.,
Gleevec, are useful for the treatment of chronic myeloid leukemia
(CML), and potentially for treatment of other cancers that express
these kinases, including acute lymphocytic leukemia (ALL) and
certain solid tumors. Gleevec was approved for the treatment of
inoperable and/or metastatic malignant gastrointestinal stromal
tumors (GISTs).
[0022] Inhibitors of Flt3 tyrosine kinase, e.g., CEP-701 (U.S. Pat.
No. 4,923,986) and Midostaurin (U.S. Pat. No. 5,093,330), have
potential utility for the treatment of a variety of cancers (Cancer
Res., 1999, 59, 10).
[0023] Inhibitors of MAP Erk kinase, e.g., PD-184352 (U.S. Pat. No.
6,251,943), have been identified as potentially useful therapeutic
agents for a variety of oncological disorders, including colon,
breast, pancreatic and non-small-cell lung cancers (see, for
example, Proc. Am. Soc. Clin. Oncol., 2003, 22, abstract 816).
[0024] Other kinase inhibitors, e.g., doramapimod (U.S. Pat. No.
6,319,921), have been identified as potentially useful therapeutic
agents for the treatment of inflammatory diseases such as
rheumatoid arthritis, psoriasis and Crohn's disease.
[0025] Other kinase inhibitors, e.g., BAY-43-9006 (U.S. Publication
No. 2002/0165394) have been identified as potentially useful
therapeutic agents for a variety of cancers including
gastrointestinal and colon tumors, leukemia and carcinoma (Curr.
Pharm. Design, 2002, 8, 2269).
[0026] Cytokine receptors are critical for the development and
homeostasis of immune cells. These receptors all require the
cytoplasmic tyrosine kinase JAK3 for signaling (Changelian, P. S.
et al., Science, 2003, 302, 875). CP-690,550 (WO 02,096,909) is an
orally available Janus kinase (JAK)-3 inhibitor, for the potential
treatment of transplant rejection and psoriasis.
[0027] Thus, there is a need for therapeutic agents that are kinase
inhibitors with improved pharmacological properties, e.g., drugs
having improved kinase-inhibitory activity and pharmacokinetic
properties, including improved oral bioavailability, greater
potency and extended effective half-life in vivo. Such inhibitors
would have therapeutic potential as, e.g., anticancer agents. Such
kinase inhibitory compounds may be used to treat breast cancer,
non-small cell lung cancers (NSCLCs), adenocarcinomas, squamous
cell cancer of the lung, oesophageal cancer, gastrointestinal
cancer, colon cancer, rectal cancer, stomach cancer, prostate
cancer, leukaemia, ovarian cancer, bronchial cancer, pancreatic
cancer, thyroid cancer, uterine cancer, brain cancer, lung squamous
cell cancer, bladder cancer, gastric cancer, head and neck cancer,
gynaecological and thyroid tumors, to prevent the development of
resistance (multi-drug resistance) in cancer treatment with other
chemotherapeutic drugs or remove existing resistance to other
chemotherapeutic drugs, retinopathies, hemangioblastoma,
hemangioma, and neoplastic diseases, gliomas, to inhibit tumor
angiogenesis, myelomas, chronic myeloid leukemia (CML), acute
lymphocytic leukemia (ALL), inoperable and/or metastatic malignant
gastrointestinal stromal tumors (GISTs), treatment of inflammatory
diseases such as rheumatoid arthritis, Crohn's disease, treatment
of cell proliferation diseases, and for the treatment of transplant
rejection and psoriasis.
[0028] New kinase inhibitors should have fewer side effects, less
complicated dosing schedules, and be orally active. In particular,
there is a need for a less onerous dosage regimen, such as one
pill, once per day.
[0029] Assay methods capable of determining the presence, absence
or amounts of kinase inhibition are of practical utility in the
search for inhibitors as well as for diagnosing the presence of
conditions associated with kinase activity.
SUMMARY OF THE INVENTION
[0030] Intracellular targeting may be achieved by methods and
compositions that allow accumulation or retention of biologically
active agents inside cells. The present invention provides novel
analogs of kinase-inhibitory compounds. Such novel
kinase-inhibitory analogs possess all the utilities of the
kinase-inhibitory compounds and optionally provide cellular
accumulation as set forth below. In addition, the present invention
provides compositions and methods for inhibition of kinases or
therapeutic activity against kinases.
[0031] The present invention relates generally to the accumulation
or retention of therapeutic compounds inside cells. The invention
is more particularly related to attaining high concentrations of
phosphonate-containing molecules in target cells. Such effective
targeting may be applicable to a variety of therapeutic
formulations and procedures.
[0032] Compositions of the invention include kinase-inhibitory
compounds having at least one phosphonate group. Accordingly, in
one embodiment the invention provides a conjugate comprising a
kinase inhibiting compound linked to one or more phosphonate
groups; or a pharmaceutically acceptable salt or solvate
thereof.
[0033] In another embodiment, the invention provides a compound of
any one of formulae 500-511:
##STR00001## ##STR00002## ##STR00003##
that is substituted with one or more groups A.sup.0, wherein:
[0034] A.sup.0 is A.sup.1, A.sup.2 or W.sup.3 with the proviso that
the conjugate includes at least one A.sup.1;
[0035] A.sup.1 is:
##STR00004##
[0036] A.sup.2 is:
##STR00005##
[0037] A.sup.3 is:
##STR00006##
[0038] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0039] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--; and when Y.sup.2
joins two phosphorous atoms Y.sup.2 can also be
C(R.sup.2)(R.sup.2);
[0040] R.sup.x is independently H, R.sup.1, R.sup.2, W.sup.3, a
protecting group, or the formula:
##STR00007##
[0041] wherein:
[0042] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0043] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0044] R.sup.2 is independently H, R.sup.1, R.sup.3 or R.sup.4
wherein each R.sup.4 is independently substituted with 0 to 3
R.sup.3 groups or taken together at a carbon atom, two R.sup.2
groups form a ring of 3 to 8 carbons and the ring may be
substituted with 0 to 3 R.sup.3 groups;
[0045] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0046] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0047] R.sup.3b is Y.sup.1;
[0048] R.sup.3c is R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.x)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
--N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0049] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0050] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0051] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0052] W.sup.3 is W.sup.4 or W.sup.5;
[0053] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.M2R.sup.5, or --SO.sub.M2W.sup.5;
[0054] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0055] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0056] M2 is 0, 1 or 2;
[0057] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0058] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0059] M1a, M1c, and M1d are independently 0 or 1; and
[0060] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0061] In another embodiment, the invention provides a compound of
the formula:
[DRUG]-(A.sup.0).sub.nn
or a pharmaceutically acceptable salt thereof wherein,
[0062] DRUG is a compound of any one of formulae 500-511;
[0063] nn is 1, 2, or 3;
[0064] A.sup.0 is A.sup.1, A.sup.2 or W.sup.3 with the proviso that
the conjugate includes at least one A.sup.1;
[0065] A.sup.1 is:
##STR00008##
[0066] A.sup.2 is:
##STR00009##
[0067] A.sup.3 is:
##STR00010##
[0068] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0069] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--; and when Y.sup.2
joins two phosphorous atoms Y.sup.2 can also be
C(R.sup.2)(R.sup.2);
[0070] R.sup.x is independently H, R.sup.1, R.sup.2, W.sup.3, a
protecting group, or the formula:
##STR00011##
[0071] wherein:
[0072] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0073] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0074] R.sup.2 is independently H, R.sup.1, R.sup.3 or R.sup.4
wherein each R.sup.4 is independently substituted with 0 to 3
R.sup.3 groups or taken together at a carbon atom, two R.sup.2
groups form a ring of 3 to 8 carbons and the ring may be
substituted with 0 to 3 R.sup.3 groups;
[0075] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0076] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0077] R.sup.3b is Y;
[0078] R.sup.3c is R.sup.x, --N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0079] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0080] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0081] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0082] W.sup.3 is W.sup.4 or W.sup.5;
[0083] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.M2R.sup.5, or --SO.sub.M2W.sup.5;
[0084] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0085] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0086] M2 is 0, 1 or 2;
[0087] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0088] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0089] M1a, M1c, and M1d are independently 0 or 1; and
[0090] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0091] In another embodiment, the invention provides a compound of
any one of formulae 1-36:
##STR00012## ##STR00013## ##STR00014## ##STR00015## ##STR00016##
##STR00017## ##STR00018##
wherein:
[0092] A.sup.0 is A.sup.1;
[0093] A.sup.1 is:
##STR00019##
[0094] A.sup.3 is:
##STR00020##
[0095] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0096] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--; and when Y.sup.2
joins two phosphorous atoms Y.sup.2 can also be
C(R.sup.2)(R.sup.2);
[0097] R.sup.x is independently H, R.sup.2, W.sup.3, a protecting
group, or the formula:
##STR00021##
[0098] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0099] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0100] R.sup.2 is independently H, R.sup.3 or R.sup.4 wherein each
R.sup.4 is independently substituted with 0 to 3 R.sup.3
groups;
[0101] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0102] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0103] R.sup.3b is Y.sup.1;
[0104] R.sup.3c is R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
--N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0105] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0106] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0107] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0108] R.sup.5a is independently alkylene of 1 to 18 carbon atoms,
alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.3 groups;
[0109] W.sup.3 is W.sup.4 or W.sup.5;
[0110] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0111] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0112] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0113] M2 is 0, 1 or 2;
[0114] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0115] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0116] M1a, M1c, and M1d are independently 0 or 1;
[0117] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0118] X.sup.50 is H F, or Cl; and
[0119] X.sup.51 is H or Cl.
[0120] The invention provides a pharmaceutical composition
comprising an effective amount of a compound of the invention, or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable diluent or carrier.
[0121] This invention provides a method of increasing cellular
accumulation and retention of drug compounds, thus improving their
therapeutic and diagnostic value, comprising linking the compound
to one or more (e.g., 1, 2, 3, or 4) phosphonate groups.
[0122] The invention also provides a method of inhibiting a kinase,
comprising administering to a mammal an amount of a compound of the
invention.
[0123] The invention also provides a compound of the invention for
use in medical therapy (preferably for use in treating a condition
associated with kinase activity), as well as the use of a compound
of the invention for the manufacture of a medicament useful for the
treatment of a condition associated with kinase activity.
[0124] The invention also provides processes and novel
intermediates disclosed herein which are useful for preparing
compounds of the invention. Some of the compounds of the invention
are useful to prepare other compounds of the invention.
[0125] In another aspect of the invention, the activity of a kinase
is inhibited by a method comprising the step of treating a sample
suspected of containing a kinase with a compound or composition of
the invention.
DETAILED DESCRIPTION OF EXEMPLARY CLAIMS
[0126] Reference will now be made in detail to certain claims of
the invention, examples of which are illustrated in the
accompanying structures and formulas. While the invention will be
described in conjunction with the enumerated claims, it will be
understood that they are not intended to limit the invention to
those claims. On the contrary, the invention is intended to cover
all alternatives, modifications, and equivalents, which may be
included within the scope of the present invention as defined by
the claims.
DEFINITIONS
[0127] Unless stated otherwise, the following terms and phrases as
used herein are intended to have the following meanings:
[0128] When tradenames are used herein, applicants intend to
independently include the tradename product and the active
pharmaceutical ingredient(s) of the tradename product.
[0129] "Bioavailability" is the degree to which the
pharmaceutically active agent becomes available to the target
tissue after the agent's introduction into the body. Enhancement of
the bioavailability of a pharmaceutically active agent can provide
a more efficient and effective treatment for patients because, for
a given dose, more of the pharmaceutically active agent will be
available at the targeted tissue sites.
[0130] The terms "phosphonate" and "phosphonate group" include
functional groups or moieties within a molecule that comprises a
phosphorous that is 1) single-bonded to a carbon, 2) double-bonded
to a heteroatom, 3) single-bonded to a heteroatom, and 4)
single-bonded to another heteroatom, wherein each heteroatom can be
the same or different. The terms "phosphonate" and "phosphonate
group" also include functional groups or moieties that comprise a
phosphorous in the same oxidation state as the phosphorous
described above, as well as functional groups or moieties that
comprise a prodrug moiety that can separate from a compound so that
the compound retains a phosphorous having the characteristics
described above. For example, the terms "phosphonate" and
"phosphonate group" include phosphonic acid, phosphonic monoester,
phosphonic diester, phosphonamidate, and phosphonthioate functional
groups. In one specific embodiment of the invention, the terms
"phosphonate" and "phosphonate group" include functional groups or
moieties within a molecule that comprises a phosphorous that is 1)
single-bonded to a carbon, 2) double-bonded to an oxygen, 3)
single-bonded to an oxygen, and 4) single-bonded to another oxygen,
as well as functional groups or moieties that comprise a prodrug
moiety that can separate from a compound so that the compound
retains a phosphorous having such characteristics. In another
specific embodiment of the invention, the terms "phosphonate" and
"phosphonate group" include functional groups or moieties within a
molecule that comprises a phosphorous that is 1) single-bonded to a
carbon, 2) double-bonded to an oxygen, 3) single-bonded to an
oxygen or nitrogen, and 4) single-bonded to another oxygen or
nitrogen, as well as functional groups or moieties that comprise a
prodrug moiety that can separate from a compound so that the
compound retains a phosphorous having such characteristics.
[0131] The term "prodrug" as used herein refers to any compound
that when administered to a biological system generates the drug
substance, i.e. active ingredient, as a result of spontaneous
chemical reaction(s), enzyme catalyzed chemical reaction(s),
photolysis, and/or metabolic chemical reaction(s). A prodrug is
thus a covalently modified analog or latent form of a
therapeutically-active compound.
[0132] "Prodrug moiety" refers to a labile functional group that
separates from the active inhibitory compound during metabolism,
systemically, inside a cell, by hydrolysis, enzymatic cleavage, or
by some other process (Bundgaard, Hans, "Design and Application of
Prodrugs" in A Textbook of Drug Design and Development (1991), P.
Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic
Publishers, pp. 113-191). Enzymes that are capable of an enzymatic
activation mechanism with the phosphonate prodrug compounds of the
invention include, but are not limited to, amidases, esterases,
microbial enzymes, phospholipases, cholinesterases, and phosphases.
Prodrug moieties can serve to enhance solubility, absorption and
lipophilicity to optimize drug delivery, bioavailability and
efficacy. A prodrug moiety may include an active metabolite or drug
itself.
[0133] Exemplary prodrug moieties include the hydrolytically
sensitive or labile acyloxymethyl esters --CH.sub.2C(.dbd.O)R.sup.9
and acyloxymethyl carbonates --CH.sub.2C(.dbd.O)OR.sup.9 where
R.sup.9 is C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 substituted
alkyl, C.sub.6-C.sub.20 aryl or C.sub.6-C.sub.20 substituted aryl.
The acyloxyalkyl ester was first used as a prodrug strategy for
carboxylic acids and then applied to phosphates and phosphonates by
Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
4,816,570, 4,968,788, 5,663,159 and 5,792,756. Subsequently, the
acyloxyalkyl ester was used to deliver phosphonic acids across cell
membranes and to enhance oral bioavailability. A close variant of
the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester
(carbonate), may also enhance oral bioavailability as a prodrug
moiety in the compounds of the combinations of the invention. An
exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM)
--CH.sub.2C(.dbd.O)C(CH.sub.3).sub.3. An exemplary acyloxymethyl
carbonate prodrug moiety is pivaloyloxymethylcarbonate
(POC)--CH.sub.2C(.dbd.O)OC(CH.sub.3).sub.3.
[0134] The phosphonate group may be a phosphonate prodrug moiety.
The prodrug moiety may be sensitive to hydrolysis, such as, but not
limited to a pivaloyloxymethyl carbonate (POC) or POM group.
Alternatively, the prodrug moiety may be sensitive to enzymatic
potentiated cleavage, such as a lactate ester or a
phosphonamidate-ester group.
[0135] Aryl esters of phosphorus groups, especially phenyl esters,
are reported to enhance oral bioavailability (De Lombaert et al.
(1994) J. Med. Chem. 37: 498). Phenyl esters containing a
carboxylic ester ortho to the phosphate have also been described
(Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl
esters are reported to generate the parent phosphonic acid. In some
cases, substituents at the ortho- or para-position may accelerate
the hydrolysis. Benzyl analogs with an acylated phenol or an
alkylated phenol may generate the phenolic compound through the
action of enzymes, e.g., esterases, oxidases, etc., which in turn
undergoes cleavage at the benzylic C--O bond to generate the
phosphoric acid and the quinone methide intermediate. Examples of
this class of prodrugs are described by Mitchell et al. (1992) J.
Chem. Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other
benzylic prodrugs have been described containing a carboxylic
ester-containing group attached to the benzylic methylene (Glazier
WO 91/19721). Thio-containing prodrugs are reported to be useful
for the intracellular delivery of phosphonate drugs. These
proesters contain an ethylthio group in which the thiol group is
either esterified with an acyl group or combined with another thiol
group to form a disulfide. Deesterification or reduction of the
disulfide generates the free thio intermediate which subsequently
breaks down to the phosphoric acid and episulfide (Puech et al.
(1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med.
Chem. 39: 4958). Cyclic phosphonate esters have also been described
as prodrugs of phosphorus-containing compounds (Erion et al., U.S.
Pat. No. 6,312,662).
[0136] "Protecting group" refers to a moiety of a compound that
masks or alters the properties of a functional group or the
properties of the compound as a whole. Chemical protecting groups
and strategies for protection/deprotection are well known in the
art. See e.g., Protective Groups in Organic Chemistry, Theodora W.
Greene, John Wiley & Sons, Inc., New York, 1991. Protecting
groups are often utilized to mask the reactivity of certain
functional groups, to assist in the efficiency of desired chemical
reactions, e.g., making and breaking chemical bonds in an ordered
and planned fashion. Protection of functional groups of a compound
alters other physical properties besides the reactivity of the
protected functional group, such as the polarity, lipophilicity
(hydrophobicity), and other properties which can be measured by
common analytical tools. Chemically protected intermediates may
themselves be biologically active or inactive.
[0137] Protected compounds may also exhibit altered, and in some
cases, optimized properties in vitro and in vivo, such as passage
through cellular membranes and resistance to enzymatic degradation
or sequestration. In this role, protected compounds with intended
therapeutic effects may be referred to as prodrugs. Another
function of a protecting group is to convert the parental drug into
a prodrug, whereby the parental drug is released upon conversion of
the prodrug in vivo. Because active prodrugs may be absorbed more
effectively than the parental drug, prodrugs may possess greater
potency in vivo than the parental drug. Protecting groups are
removed either in vitro, in the instance of chemical intermediates,
or in vivo, in the case of prodrugs. With chemical intermediates,
it is not particularly important that the resulting products after
deprotection, e.g., alcohols, be physiologically acceptable,
although in general it is more desirable if the products are
pharmacologically innocuous.
[0138] Any reference to any of the compounds of the invention also
includes a reference to a physiologically acceptable salt thereof.
Examples of physiologically acceptable salts of the compounds of
the invention include salts derived from an appropriate base, such
as an alkali metal (for example, sodium), an alkaline earth (for
example, magnesium), ammonium and NX.sub.4.sup.+ (wherein X is
C.sub.1-C.sub.4 alkyl). Physiologically acceptable salts of an
hydrogen atom or an amino group include salts of organic carboxylic
acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic,
malonic, malic, isethionic, lactobionic and succinic acids; organic
sulfonic acids, such as methanesulfonic, ethanesulfonic,
benzenesulfonic and p-toluenesulfonic acids; and inorganic acids,
such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
Physiologically acceptable salts of a compound of an hydroxy group
include the anion of said compound in combination with a suitable
cation such as Na.sup.+ and NX.sub.4.sup.+ (wherein X is
independently selected from H or a C.sub.1-C.sub.4 alkyl
group).
[0139] For therapeutic use, salts of active ingredients of the
compounds of the invention will be physiologically acceptable, i.e.
they will be salts derived from a physiologically acceptable acid
or base. However, salts of acids or bases which are not
physiologically acceptable may also find use, for example, in the
preparation or purification of a physiologically acceptable
compound. All salts, whether or not derived form a physiologically
acceptable acid or base, are within the scope of the present
invention.
[0140] "Alkyl" is C.sub.1-C.sub.18 hydrocarbon containing normal,
secondary, tertiary or cyclic carbon atoms. Examples are methyl
(Me, --CH.sub.3), ethyl (Et, --CH.sub.2CH.sub.3), 1-propyl (n-Pr,
n-propyl, --CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3.
[0141] "Alkenyl" is C.sub.2-C.sub.18 hydrocarbon containing normal,
secondary, tertiary or cyclic carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp.sup.2 double bond.
Examples include, but are not limited to, ethylene or vinyl
(--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
cyclopentenyl (--C.sub.5H.sub.7), and 5-hexenyl (--CH.sub.2
CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2).
[0142] "Alkynyl" is C.sub.2-C.sub.18 hydrocarbon containing normal,
secondary, tertiary or cyclic carbon atoms with at least one site
of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples
include, but are not limited to, acetylenic (--C.ident.CH) and
propargyl (--CH.sub.2C.ident.CH).
[0143] "Alkylene" refers to a saturated, branched or straight chain
or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two
monovalent radical centers derived by the removal of two hydrogen
atoms from the same or two different carbon atoms of a parent
alkane. Typical alkylene radicals include, but are not limited to,
methylene (--CH.sub.2--) 1,2-ethyl (--CH.sub.2CH.sub.2--),
1,3-propyl (--CH.sub.2CH.sub.2CH.sub.2--), 1,4-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0144] "Alkenylene" refers to an unsaturated, branched or straight
chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and
having two monovalent radical centers derived by the removal of two
hydrogen atoms from the same or two different carbon atoms of a
parent alkene. Typical alkenylene radicals include, but are not
limited to, 1,2-ethylene (--CH.dbd.CH--).
[0145] "Alkynylene" refers to an unsaturated, branched or straight
chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and
having two monovalent radical centers derived by the removal of two
hydrogen atoms from the same or two different carbon atoms of a
parent alkyne. Typical alkynylene radicals include, but are not
limited to, acetylene (--C.ident.C--), propargyl
(--CH.sub.2C.ident.C--), and 4-pentynyl
(--CH.sub.2CH.sub.2CH.sub.2C.ident.CH--).
[0146] "Aryl" means a monovalent aromatic hydrocarbon radical of
6-20 carbon atoms derived by the removal of one hydrogen atom from
a single carbon atom of a parent aromatic ring system. Typical aryl
groups include, but are not limited to, radicals derived from
benzene, substituted benzene, naphthalene, anthracene, biphenyl,
and the like.
[0147] "Arylalkyl" refers to an acyclic alkyl radical in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
or sp.sup.3 carbon atom, is replaced with an aryl radical. Typical
arylalkyl groups include, but are not limited to, benzyl,
2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
naphthobenzyl, 2-naphthophenylethan-1-yl and the like. The
arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl
moiety, including alkanyl, alkenyl or alkynyl groups, of the
arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to
14 carbon atoms.
[0148] "Substituted alkyl", "substituted aryl", and "substituted
arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which
one or more hydrogen atoms are each independently replaced with a
non-hydrogen substituent. Typical substituents include, but are not
limited to, --X, --R, --O.sup.-, --OR, --SR, --S.sup.-, --NR.sub.2,
--NR.sub.3, .dbd.NR, --CX.sub.3, --CN, --OCN, --SCN,
--N.dbd.C.dbd.O, --NCS, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3,
NC(.dbd.O)R, --C(.dbd.O)R, --C(.dbd.O)NRR--S(.dbd.O).sub.2O--,
--S(.dbd.O).sub.2OH, --S(.dbd.O).sub.2R, --OS(.dbd.O).sub.2OR,
--S(.dbd.O).sub.2NR, --S(.dbd.O)R, --OP(.dbd.O)O.sub.2R,
--P(.dbd.O)O.sub.2RRR--P(.dbd.O)(O.sup.-).sub.2,
--P(.dbd.O)(OH).sub.2, --C(.dbd.O)R, --C(.dbd.O)X, --C(S)R,
--C(O)OR, --C(O)O.sup.-, --C(S)OR, --C(O)SR, --C(S)SR, --C(O)NRR,
--C(S)NRR, --C(NR)NRR, where each X is independently a halogen: F,
Cl, Br, or I; and each R is independently --H, alkyl, aryl,
heterocycle, protecting group or prodrug moiety. Alkylene,
alkenylene, and alkynylene groups may also be similarly
substituted.
[0149] "Heterocycle" as used herein includes, by way of example and
not limitation, those heterocycles described in Paquette, Leo A.;
Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New
York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The
Chemistry of Heterocyclic Compounds, A Series of Monographs" (John
Wiley & Sons, New York, 1950 to present), in particular Volumes
13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In
one specific embodiment of the invention "heterocycle" includes a
"carbocycle" as defined herein, wherein one or more (e.g., 1, 2, 3,
or 4) carbon atoms have been replaced with a heteroatom (e.g., O,
N, or S).
[0150] Examples of heterocycles include, by way of example and not
limitation, pyridyl, dihydroypyridyl, tetrahydropyridyl
(piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized
tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,
indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,
piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl,
pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,
phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,
isatinoyl, and bis-tetrahydrofuranyl:
##STR00022##
[0151] By way of example and not limitation, carbon bonded
heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine,
position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a
pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4,
or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or
isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4
of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or
position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more
typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,
4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,
5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,
5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or
5-thiazolyl.
[0152] By way of example and not limitation, nitrogen bonded
heterocycles are bonded at position 1 of an aziridine, azetidine,
pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,
2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole,
indoline, 1H-indazole, position 2 of a isoindole, or isoindoline,
position 4 of a morpholine, and position 9 of a carbazole, or
.beta.-carboline. Still more typically, nitrogen bonded
heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,
1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
[0153] "Carbocycle" refers to a saturated, unsaturated or aromatic
ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon
atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
Monocyclic carbocycles have 3 to 6 ring atoms, still more typically
5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms,
e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or
9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl,
cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,
1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,
1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and
naphthyl.
[0154] "Linker" or "link" refers to a chemical moiety comprising a
covalent bond or a chain or group of atoms that covalently attaches
a phosphonate group to a drug. Linkers include portions of
substituents A.sup.1 and A.sup.3, which include moieties such as:
repeating units of alkyloxy (e.g., polyethylenoxy, PEG,
polymethyleneoxy) and alkylamino (e.g., polyethyleneamino,
Jeffamine.TM.); and diacid ester and amides including succinate,
succinamide, diglycolate, malonate, and caproamide.
[0155] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0156] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0157] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties,
e.g., melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0158] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0159] The term "treatment" or "treating," to the extent it relates
to a disease or condition includes preventing the disease or
condition from occurring, inhibiting the disease or condition,
eliminating the disease or condition, and/or relieving one or more
symptoms of the disease or condition.
[0160] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and l or (+) and (-) are employed
to designate the sign of rotation of plane-polarized light by the
compound, with (-) or l meaning that the compound is levorotatory.
A compound prefixed with (+) or d is dextrorotatory. For a given
chemical structure, these stereoisomers are identical except that
they are mirror images of one another. A specific stereoisomer may
also be referred to as an enantiomer, and a mixture of such isomers
is often called an enantiomeric mixture. A 50:50 mixture of
enantiomers is referred to as a racemic mixture or a racemate,
which may occur where there has been no stereoselection or
stereospecificity in a chemical reaction or process. The terms
"racemic mixture" and "racemate" refer to an equimolar mixture of
two enantiomeric species, devoid of optical activity.
Protecting Groups
[0161] In the context of the present invention, protecting groups
include prodrug moieties and chemical protecting groups.
[0162] Protecting groups are available, commonly known and used,
and are optionally used to prevent side reactions with the
protected group during synthetic procedures, i.e. routes or methods
to prepare the compounds of the invention. For the most part the
decision as to which groups to protect, when to do so, and the
nature of the chemical protecting group "PG" will be dependent upon
the chemistry of the reaction to be protected against (e.g.,
acidic, basic, oxidative, reductive or other conditions) and the
intended direction of the synthesis. The PG groups do not need to
be, and generally are not, the same if the compound is substituted
with multiple PG. In general, PG will be used to protect functional
groups such as carboxyl, hydroxyl, thio, or amino groups and to
thus prevent side reactions or to otherwise facilitate the
synthetic efficiency. The order of deprotection to yield free,
deprotected groups is dependent upon the intended direction of the
synthesis and the reaction conditions to be encountered, and may
occur in any order as determined by the artisan.
[0163] Various functional groups of the compounds of the invention
may be protected. For example, protecting groups for --OH groups
(whether hydroxyl, carboxylic acid, phosphonic acid, or other
functions) include "ether- or ester-forming groups". Ether- or
ester-forming groups are capable of functioning as chemical
protecting groups in the synthetic schemes set forth herein.
However, some hydroxyl and thio protecting groups are neither
ether- nor ester-forming groups, as will be understood by those
skilled in the art, and are included with amides, discussed
below.
[0164] A very large number of hydroxyl protecting groups and
amide-forming groups and corresponding chemical cleavage reactions
are described in Protective Groups in Organic Synthesis, Theodora
W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN
0-471-62301-6) ("Greene"). See also Kocienski, Philip J.;
Protecting Groups (Georg Thieme Verlag Stuttgart, N.Y., 1994),
which is incorporated by reference in its entirety herein. In
particular Chapter 1, Protecting Groups: An Overview, pages 1-20,
Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol
Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting
Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages
155-184. For protecting groups for carboxylic acid, phosphonic
acid, phosphonate, sulfonic acid and other protecting groups for
acids see Greene as set forth below. Such groups include by way of
example and not limitation, esters, amides, hydrazides, and the
like.
Ether- and Ester-Forming Protecting Groups
[0165] Ester-forming groups include: (1) phosphonate ester-forming
groups, such as phosphonamidate esters, phosphorothioate esters,
phosphonate esters, and phosphon-bis-amidates; (2) carboxyl
ester-forming groups, and (3) sulphur ester-forming groups, such as
sulphonate, sulfate, and sulfinate.
[0166] The phosphonate moieties of the compounds of the invention
may or may not be prodrug moieties, i.e. they may or may be
susceptible to hydrolytic or enzymatic cleavage or modification.
Certain phosphonate moieties are stable under most or nearly all
metabolic conditions. For example, a dialkylphosphonate, where the
alkyl groups are two or more carbons, may have appreciable
stability in vivo due to a slow rate of hydrolysis.
[0167] Within the context of phosphonate prodrug moieties, a large
number of structurally-diverse prodrugs have been described for
phosphonic acids (Freeman and Ross in Progress in Medicinal
Chemistry 34: 112-147 (1997) and are included within the scope of
the present invention. An exemplary phosphonate ester-forming group
is the phenyl carbocycle in substructure A.sub.3 having the
formula:
##STR00023##
[0168] wherein R.sub.1 may be H or C.sub.1-C.sub.12 alkyl; m1 is 1,
2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted
with 0 to 3 R.sub.2 groups. Where Y.sub.1 is O, a lactate ester is
formed, and where Y.sub.1 is N(R.sub.2), N(OR.sub.2) or
N(N(R.sub.2).sub.2, a phosphonamidate ester results.
[0169] In its ester-forming role, a protecting group typically is
bound to any acidic group such as, by way of example and not
limitation, a --CO.sub.2H or --C(S)OH group, thereby resulting in
--CO.sub.2R.sup.x where R.sup.x is defined herein. Also, R.sup.x
for example includes the enumerated ester groups of WO
95/07920.
[0170] Examples of protecting groups include:
[0171] C.sub.3-C.sub.12 heterocycle (described above) or aryl.
These aromatic groups optionally are polycyclic or monocyclic.
Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and
3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and
4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3-
and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and
5-pyrimidinyl,
[0172] C.sub.3-C.sub.12 heterocycle or aryl substituted with halo,
R.sup.1, R.sup.1--O--C.sub.1-C.sub.12 alkylene, C.sub.1-C.sub.12
alkoxy, CN, NO.sub.2, OH, carboxy, carboxyester, thiol, thioester,
C.sub.1-C.sub.12 haloalkyl (1-6 halogen atoms), C.sub.2-C.sub.12
alkenyl or C.sub.2-C.sub.12 alkynyl. Such groups include 2-, 3- and
4-alkoxyphenyl (C.sub.1-C.sub.12 alkyl), 2-, 3- and
4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-,
3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl,
2- and 3-ethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl,
2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-,
3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl,
2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and
2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and
3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and
3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and
3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and
3,5-dihalophenyl (including 2,4-difluorophenyl and
3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen
atoms, C.sub.1-C.sub.12 alkyl including 4-trifluoromethylphenyl),
2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and
4-haloalkylbenzyl (1 to 5 halogen atoms, C.sub.1-C.sub.12 alkyl
including 4-trifluoromethylbenzyl and 2-, 3- and
4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl),
4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl,
benzyl, alkylsalicylphenyl (C.sub.1-C.sub.4 alkyl, including 2-, 3-
and 4-ethylsalicylphenyl), 2-, 3- and 4-acetylphenyl,
1,8-dihydroxynaphthyl (--C.sub.10H.sub.6--OH) and aryloxy ethyl
[C.sub.6-C.sub.9 aryl (including phenoxy ethyl)],
2,2'-dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol,
--C.sub.6H.sub.4CH.sub.2--N(CH.sub.3).sub.2, trimethoxybenzyl,
triethoxybenzyl, 2-alkyl pyridinyl (C.sub.1-4 alkyl);
##STR00024##
esters of 2-carboxyphenyl; and C.sub.1-C.sub.4
alkylene-C.sub.3-C.sub.6 aryl (including benzyl,
--CH.sub.2-pyrrolyl, --CH.sub.2-thienyl, --CH.sub.2-imidazolyl,
--CH.sub.2-oxazolyl, --CH.sub.2-isoxazolyl, --CH.sub.2-thiazolyl,
--CH.sub.2-isothiazolyl, --CH.sub.2-pyrazolyl, --CH.sub.2-pyridinyl
and --CH.sub.2-pyrimidinyl) substituted in the aryl moiety by 3 to
5 halogen atoms or 1 to 2 atoms or groups selected from halogen,
C.sub.1-C.sub.12 alkoxy (including methoxy and ethoxy), cyano,
nitro, OH, C.sub.1-C.sub.12 haloalkyl (1 to 6 halogen atoms;
including --CH.sub.2CCl.sub.3), C.sub.1-C.sub.12 alkyl (including
methyl and ethyl), C.sub.2-C.sub.12 alkenyl or C.sub.2-C.sub.12
alkynyl; alkoxy ethyl [C.sub.1-C.sub.6 alkyl including
--CH.sub.2--CH.sub.2--O--CH.sub.3 (methoxy ethyl)]; alkyl
substituted by any of the groups set forth above for aryl, in
particular OH or by 1 to 3 halo atoms (including --CH.sub.3,
--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --CH.sub.2CH.sub.3,
--(CH.sub.2).sub.2CH.sub.3, --(CH.sub.2).sub.3CH.sub.3,
--(CH.sub.2).sub.4CH.sub.3, --(CH.sub.2).sub.5CH.sub.3,
--CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2Cl, --CH.sub.2CF.sub.3, and
--CH.sub.2CCl.sub.3);
##STR00025##
propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol
monoester, --CH.sub.2--C(O)--N(R.sup.1).sub.2,
--CH.sub.2--S(O)(R.sup.1), --CH.sub.2--S(O).sub.2(R.sup.1),
--CH.sub.2--CH(OC(O)CH.sub.2R.sup.1)--CH.sub.2(OC(O)CH.sub.2R.sup.1),
cholesteryl, enolpyruvate (HOOC--C(.dbd.CH.sub.2)--), glycerol;
[0173] a 5 or 6 carbon monosaccharide, disaccharide or
oligosaccharide (3 to 9 monosaccharide residues);
[0174] triglycerides such as .alpha.-D-.beta.-diglycerides (wherein
the fatty acids composing glyceride lipids generally are naturally
occurring saturated or unsaturated C.sub.6-26, C.sub.6-18 or
C.sub.6-10 fatty acids such as linoleic, lauric, myristic,
palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty
acids) linked to acyl of the parental compounds herein through a
glyceryl oxygen of the triglyceride;
[0175] phospholipids linked to the carboxyl group through the
phosphate of the phospholipid;
[0176] phthalidyl (shown in FIG. 1 of Clayton et al., Antimicrob.
Agents Chemo. (1974) 5(6):670-671;
[0177] cyclic carbonates such as
(5-R.sub.d-2-oxo-1,3-dioxolen-4-yl)methyl esters (Sakamoto et al.,
Chem. Pharm. Bull. (1984) 32(6)2241-2248) where R.sub.d is R.sub.1,
R.sub.4 or aryl; and
##STR00026##
[0178] The hydroxyl groups of the compounds of this invention
optionally are substituted with one of groups III, IV or V
disclosed in WO 94/21604, or with isopropyl.
[0179] Table A lists examples of protecting group ester moieties
that for example can be bonded via oxygen to --C(O)O-- and
--P(O)(O--).sub.2 groups. Several amidates also are shown, which
are bound directly to --C(O)-- or --P(O).sub.2. Esters of
structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting
the compound herein having a free hydroxyl with the corresponding
halide (chloride or acyl chloride and the like) and
N,N-dicyclohexyl-N-morpholine carboxamidine (or another base such
as DBU, triethylamine, CsCO.sub.3, N,N-dimethylaniline and the
like) in DMF (or other solvent such as acetonitrile or
N-methylpyrrolidone). When the compound to be protected is a
phosphonate, the esters of structures 5-7, 11, 12, 21, and 23-26
are synthesized by reaction of the alcohol or alkoxide salt (or the
corresponding amines in the case of compounds such as 13, 14 and
15) with the monochlorophosphonate or dichlorophosphonate (or
another activated phosphonate).
TABLE-US-00001 TABLE A 1. --CH.sub.2--C(O)--N(R.sub.1).sub.2* 2.
--CH.sub.2--S(O)(R.sub.1) 3. --CH.sub.2--S(O).sub.2(R.sub.1) 4.
--CH.sub.2--O--C(O)--CH.sub.2--C.sub.6H.sub.5 5. 3-cholesteryl 6.
3-pyridyl 7. N-ethylmorpholino 8.
--CH.sub.2--O--C(O)--C.sub.6H.sub.5 9.
--CH.sub.2--O--C(O)--CH.sub.2CH.sub.3 10.
--CH.sub.2--O--C(O)--C(CH.sub.3).sub.3 11. --CH.sub.2--CCl.sub.3
12. --C.sub.6H.sub.5 13. --NH--CH.sub.2--C(O)O--CH.sub.2CH.sub.3
14. --N(CH.sub.3)--CH.sub.2--C(O)O--CH.sub.2CH.sub.3 15.
--NHR.sub.1 16. --CH.sub.2--O--C(O)--C.sub.10H.sub.15 17.
--CH.sub.2--O--C(O)--CH(CH.sub.3).sub.2 18.
--CH.sub.2--C#H(OC(O)CH.sub.2R.sub.1)--CH.sub.2--
--(OC(O)CH.sub.2R.sub.1)* 19. ##STR00027## 20. ##STR00028## 21.
##STR00029## 22. ##STR00030## 23. ##STR00031## 24. ##STR00032## 25.
##STR00033## 26. ##STR00034## #-chiral center is (R), (S) or
racemate.
[0180] Other esters that are suitable for use herein are described
in EP 632048.
[0181] Protecting groups also includes "double ester" forming
profunctionalities
such as --CH.sub.2OC(O)OCH.sub.3,
##STR00035##
--CH.sub.2SCOCH.sub.3, --CH.sub.2OCON(CH.sub.3).sub.2, or alkyl- or
aryl-acyloxyalkyl groups of the structure --CH(R.sup.1 or
W.sup.5)O((CO)R.sup.37) or --CH(R.sup.1 or W.sup.5)((CO)OR.sup.38)
(linked to oxygen of the acidic group) wherein R.sup.37 and
R.sup.38 are alkyl, aryl, or alkylaryl groups (see U.S. Pat. No.
4,968,788). Frequently R.sup.37 and R.sup.38 are bulky groups such
as branched alkyl, ortho-substituted aryl, meta-substituted aryl,
or combinations thereof, including normal, secondary, iso- and
tertiary alkyls of 1-6 carbon atoms. An example is the
pivaloyloxymethyl group. These are of particular use with prodrugs
for oral administration. Examples of such useful protecting groups
are alkylacyloxymethyl esters and their derivatives, including
--CH(CH.sub.2CH.sub.2OCH.sub.3)OC(O)C(CH.sub.3).sub.3,
##STR00036##
CH.sub.2OC(O)C.sub.10H.sub.15, --CH.sub.2OC(O)C(CH.sub.3).sub.3,
--CH(CH.sub.2OCH.sub.3)OC(O)C(CH.sub.3).sub.3,
--CH(CH(CH.sub.3).sub.2)OC(O)C(CH.sub.3).sub.3,
--CH.sub.2OC(O)CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2OC(O)C.sub.6H.sub.11, --CH.sub.2OC(O)C.sub.6H.sub.5,
--CH.sub.2OC(O)C.sub.10H.sub.15, --CH.sub.2OC(O)CH.sub.2CH.sub.3,
--CH.sub.2OC(O)CH(CH.sub.3).sub.2, --CH.sub.2OC(O)C(CH.sub.3).sub.3
and --CH.sub.2OC(O)CH.sub.2C.sub.6H.sub.5.
[0182] In some claims the protected acidic group is an ester of the
acidic group and is the residue of a hydroxyl-containing
functionality. In other claims, an amino compound is used to
protect the acid functionality. The residues of suitable hydroxyl
or amino-containing functionalities are set forth above or are
found in WO 95/07920. Of particular interest are the residues of
amino acids, amino acid esters, polypeptides, or aryl alcohols.
Typical amino acid, polypeptide and carboxyl-esterified amino acid
residues are described on pages 11-18 and related text of WO
95/07920 as groups L1 or L2. WO 95/07920 expressly teaches the
amidates of phosphonic acids, but it will be understood that such
amidates are formed with any of the acid groups set forth herein
and the amino acid residues set forth in WO 95/07920.
[0183] Typical esters for protecting acidic functionalities are
also described in WO 95/07920, again understanding that the same
esters can be formed with the acidic groups herein as with the
phosphonate of the '920 publication. Typical ester groups are
defined at least on WO 95/07920 pages 89-93 (under R.sup.31 or
R.sup.35), the table on page 105, and pages 21-23 (as R). Of
particular interest are esters of unsubstituted aryl such as phenyl
or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy-
and/or alkylestercarboxy-substituted aryl or alkylaryl, especially
phenyl, ortho-ethoxyphenyl, or C.sub.1-C.sub.4
alkylestercarboxyphenyl (salicylate C.sub.1-C.sub.12
alkylesters).
[0184] The protected acidic groups, particularly when using the
esters or amides of WO 95/07920, are useful as prodrugs for oral
administration. However, it is not essential that the acidic group
be protected in order for the compounds of this invention to be
effectively administered by the oral route. When the compounds of
the invention having protected groups, in particular amino acid
amidates or substituted and unsubstituted aryl esters are
administered systemically or orally they are capable of hydrolytic
cleavage in vivo to yield the free acid.
[0185] One or more of the acidic hydroxyls are protected. If more
than one acidic hydroxyl is protected then the same or a different
protecting group is employed, e.g., the esters may be different or
the same, or a mixed amidate and ester may be used.
[0186] Typical hydroxy protecting groups described in Greene (pages
14-118) include substituted methyl and alkyl ethers, substituted
benzyl ethers, silyl ethers, esters including sulfonic acid esters,
and carbonates. For example: [0187] Ethers (methyl, t-butyl,
allyl); [0188] Substituted Methyl Ethers (Methoxymethyl,
Methylthiomethyl, t-Butylthiomethyl,
(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,
p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,
t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,
2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,
Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,
Tetrahydropyranyl, 3-Bromotetrahydropyranyl,
Tetrahydropthiopyranyl, 1-Methoxycyclohexyl,
4-Methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl,
4-Methoxytetrahydropthiopyranyl S,S-Dioxido,
1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,
1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));
[0189] Substituted Ethyl Ethers (1-Ethoxyethyl,
1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl,
1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-Trichloroethyl, 2-Trimethylsilylethyl,
2-(Phenylselenyl)ethyl, [0190] p-Chlorophenyl, p-Methoxyphenyl,
2,4-Dinitrophenyl, Benzyl); [0191] Substituted Benzyl Ethers
(p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl,
p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl,
p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido,
Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosuberyl,
Triphenylmethyl, .alpha.-Naphthyldiphenylmethyl,
p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl,
Tri(p-methoxyphenyl)methyl,
4-(4'-Bromophenacyloxy)phenyldiphenylmethyl,
4,4',4''-Tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-Tris(levulinoyloxyphenyl)methyl,
4,4',4''-Tris(benzoyloxyphenyl)methyl,
3-(Imidazol-1-ylmethyl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-Bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl,
9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,
1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); [0192]
Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,
Dimethylisopropylsilyl, Diethylisopropylsilyl, Dimethylthexylsilyl,
t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl,
Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl,
t-Butylmethoxyphenylsilyl); [0193] Esters (Formate, Benzoylformate,
Acetate, Choroacetate, Dichloroacetate, Trichloroacetate,
Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate,
Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-Phenylacetate,
3-Phenylpropionate, 4-Oxopentanoate (Levulinate),
4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate,
4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,
2,4,6-Trimethylbenzoate (Mesitoate)); [0194] Carbonates (Methyl,
9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl,
2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl,
2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl,
p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,
o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate,
4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); [0195] Groups With
Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate,
4-Nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate,
2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate,
4-(Methylthiomethoxy)butyrate,
2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters
(2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3
tetramethylbutyl)phenoxyacetate,
2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chlorodiphenylacetate,
Isobutyrate, Monosuccinate, (E)-2-Methyl-2-butenoate (Tigloate),
o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, .alpha.-Naphthoate,
Nitrate, Alkyl N,N,N',N'-Tetramethylphosphorodiamidate,
N-Phenylcarbamate, Borate, Dimethylphosphinothioyl,
2,4-Dinitrophenylsulfenate); and [0196] Sulfonates (Sulfate,
Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
[0197] Typical 1,2-diol protecting groups (thus, generally where
two OH groups are taken together with the protecting functionality)
are described in Greene at pages 118-142 and include Cyclic Acetals
and Ketals (Methylene, Ethylidene, 1-t-Butylethylidene,
1-Phenylethylidene, (4-Methoxyphenyl)ethylidene,
2,2,2-Trichloroethylidene, Acetonide (Isopropylidene),
Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene,
p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,
3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters
(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,
1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,
.alpha.-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene
Derivative, .alpha.-(N,N-Dimethylamino)benzylidene Derivative,
2-Oxacyclopentylidene); Silyl Derivatives (Di-t-butylsilylene
Group, 1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), and
Tetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, Cyclic
Boronates, Ethyl Boronate and Phenyl Boronate.
[0198] More typically, 1,2-diol protecting groups include those
shown in Table B, still more typically, epoxides, acetonides,
cyclic ketals and aryl acetals.
TABLE-US-00002 TABLE B ##STR00037## ##STR00038## ##STR00039##
##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046## ##STR00047##
wherein R.sup.9 is C.sub.1-C.sub.6 alkyl.
Amino Protecting Groups
[0199] Another set of protecting groups include any of the typical
amino protecting groups described by Greene at pages 315-385. They
include: [0200] Carbamates: (methyl and ethyl, 9-fluorenylmethyl,
9(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,
4-methoxyphenacyl); [0201] Substituted Ethyl:
(2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl,
1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,
1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,
1-methyl-1-(4-biphenylyl)ethyl,
1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and
4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,
1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,
4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,
benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,
p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,
9-anthrylmethyl, diphenylmethyl); [0202] Groups With Assisted
Cleavage: (2-methylthioethyl, 2-methylsulfonylethyl,
2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl,
4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl,
2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,
m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,
5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl);
[0203] Groups Capable of Photolytic Cleavage: (m-nitrophenyl,
3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,
phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives
(phenothiazinyl-(10)-carbonyl, N'-p-toluenesulfonylaminocarbonyl,
N'-phenylaminothiocarbonyl); [0204] Miscellaneous Carbamates:
(t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl,
cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl,
diisopropylmethyl, 2,2-dimethoxycarbonylvinyl,
o-(N,N-dimethylcarboxamido)benzyl,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,
2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl,
p-(p'-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,
1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl,
1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,
1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,
2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,
2,4,6-trimethylbenzyl); [0205] Amides: (N-formyl, N-acetyl,
N-choroacetyl, N-trichoroacetyl, N-trifluoroacetyl, N-phenylacetyl,
N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide,
N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); [0206] Amides
With Assisted Cleavage: (N-o-nitrophenylacetyl,
N-o-nitrophenoxyacetyl, N-acetoacetyl,
(N'-dithiobenzyloxycarbonylamino)acetyl,
N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,
N-2-methyl-2-(o-nitrophenoxy)propionyl,
N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,
N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine,
N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl,
4,5-diphenyl-3-oxazolin-2-one); [0207] Cyclic Imide Derivatives:
(N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,
N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,
5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexan-2-one,
1-substituted 3,5-dinitro-4-pyridonyl); [0208] N-Alkyl and N-Aryl
Amines: (N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,
N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),
Quaternary Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl,
N-5-dibenzosuberyl, N-triphenylmethyl,
N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,
N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl,
N-2-picolylamine N'-oxide); [0209] Imine Derivatives:
(N-1,1-dimethylthiomethylene, N-benzylidene,
N-p-methoxybenzylidene, N-diphenylmethylene,
N-[(2-pyridyl)mesityl]methylene, N(N',N'-dimethylaminomethylene,
N,N'-isopropylidene, N-p-nitrobenzylidene, N-salicylidene,
N-5-chlorosalicylidene,
N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene);
[0210] Enamine Derivatives:
(N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); [0211] N-Metal Derivatives
(N-borane derivatives, N-diphenylborinic acid derivatives,
N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenzyl, N-copper
or N-zinc chelate); [0212] N--N Derivatives: (N-nitro, N-nitroso,
N-oxide); [0213] N--P Derivatives: (N-diphenylphosphinyl,
N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl
phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl); [0214]
N--Si Derivatives, N--S Derivatives, and N-Sulfenyl Derivatives:
(N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,
N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,
N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,
N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives
(N-p-toluenesulfonyl, N-benzenesulfonyl,
N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,
N-2,4,6-trimethoxybenzenesulfonyl,
N-2,6-dimethyl-4-methoxybenzenesulfonyl,
N-pentamethylbenzenesulfonyl,
N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,
N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,
N-2,6-dimethoxy-4-methylbenzenesulfonyl,
N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,
N-.beta.-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,
N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl,
N-benzylsulfonyl, N-trifluoromethylsulfonyl,
N-phenacylsulfonyl).
[0215] More typically, protected amino groups include carbamates
and amides, still more typically, --NHC(O)R.sup.1 or
--N.dbd.CR.sup.1N(R.sup.1).sub.2. Another protecting group, also
useful as a prodrug for amino or --NH(R.sup.5), is:
##STR00048##
See for example Alexander, J. et al. (1996) J. Med. Chem.
39:480-486.
Amino Acid and Polypeptide Protecting Group and Conjugates
[0216] An amino acid or polypeptide protecting group of a compound
of the invention has the structure R.sup.15NHCH(R.sup.16)C(O)--,
where R.sup.15 is H, an amino acid or polypeptide residue, or
R.sup.5, and R.sup.16 is defined below.
[0217] R.sup.16 is lower alkyl or lower alkyl (C.sub.1-C.sub.6)
substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl,
C.sub.6-C.sub.7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl,
sulfoxide, and/or alkylphosphate. R.sup.10 also is taken together
with the amino acid a N to form a proline residue
(R.sup.10=--CH.sub.2).sub.3--). However, R.sup.10 is generally the
side group of a naturally-occurring amino acid such as H,
--CH.sub.3, --CH(CH.sub.3).sub.2, --CH.sub.2--CH(CH.sub.3).sub.2,
--CHCH.sub.3--CH.sub.2--CH.sub.3, --CH.sub.2--C.sub.6H.sub.5,
--CH.sub.2CH.sub.2--S--CH.sub.3, --CH.sub.2OH, --CH(OH)--CH.sub.3,
--CH.sub.2--SH, --CH.sub.2--C.sub.6H.sub.40H,
--CH.sub.2--CO--NH.sub.2, --CH.sub.2--CH.sub.2--CO--NH.sub.2,
--CH.sub.2--COOH, --CH.sub.2--CH.sub.2--COOH,
--(CH.sub.2).sub.4--NH.sub.2 and
--(CH.sub.2).sub.3--NH--C(NH.sub.2)--NH.sub.2. R.sub.10 also
includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl,
imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
[0218] Another set of protecting groups include the residue of an
amino-containing compound, in particular an amino acid, a
polypeptide, a protecting group, --NHSO.sub.2R, NHC(O)R,
--N(R).sub.2, NH.sub.2 or --NH(R)(H), whereby for example a
carboxylic acid is reacted, i.e. coupled, with the amine to form an
amide, as in C(O)NR.sub.2. A phosphonic acid may be reacted with
the amine to form a phosphonamidate, as in
--P(O)(OR)(NR.sub.2).
[0219] In general, amino acids have the structure
R.sup.17C(O)CH(R.sup.16)NH--, where R.sup.17 is --OH, --OR, an
amino acid or a polypeptide residue. Amino acids are low molecular
weight compounds, on the order of less than about 1000 MW and which
contain at least one amino or imino group and at least one carboxyl
group. Generally the amino acids will be found in nature, i.e., can
be detected in biological material such as bacteria or other
microbes, plants, animals or man. Suitable amino acids typically
are alpha amino acids, i.e. compounds characterized by one amino or
imino nitrogen atom separated from the carbon atom of one carboxyl
group by a single substituted or unsubstituted alpha carbon atom.
Of particular interest are hydrophobic residues such as mono- or
di-alkyl or aryl amino acids, cycloalkylamino acids and the like.
These residues contribute to cell permeability by increasing the
partition coefficient of the parental drug. Typically, the residue
does not contain a sulfhydryl or guanidino substituent.
[0220] Naturally-occurring amino acid residues are those residues
found naturally in plants, animals or microbes, especially proteins
thereof. Polypeptides most typically will be substantially composed
of such naturally-occurring amino acid residues. These amino acids
are glycine, alanine, valine, leucine, isoleucine, serine,
threonine, cysteine, methionine, glutamic acid, aspartic acid,
lysine, hydroxylysine, arginine, histidine, phenylalanine,
tyrosine, tryptophan, proline, asparagine, glutamine and
hydroxyproline. Additionally, unnatural amino acids, for example,
valanine, phenylglycine and homoarginine are also included.
Commonly encountered amino acids that are not gene-encoded may also
be used in the present invention. All of the amino acids used in
the present invention may be either the D- or L-optical isomer. In
addition, other peptidomimetics are also useful in the present
invention. For a general review, see Spatola, A. F., in Chemistry
and Biochemistry of Amino Acids, Peptides and Proteins, B.
Weinstein, eds., Marcel Dekker, New York, p. 267 (1983).
[0221] When protecting groups are single amino acid residues or
polypeptides they optionally are substituted at R.sup.3 of
substituents A.sup.1, A.sup.2 or A.sup.3 in a compound of the
invention. These conjugates are produced by forming an amide bond
between a carboxyl group of the amino acid (or C-terminal amino
acid of a polypeptide for example). Similarly, conjugates are
formed between R.sup.3 and an amino group of an amino acid or
polypeptide. Generally, only one of any site in the parental
molecule is amidated with an amino acid as described herein,
although it is within the scope of this invention to introduce
amino acids at more than one permitted site. Usually, a carboxyl
group of R.sup.3 is amidated with an amino acid. In general, the
.alpha.-amino or .alpha.-carboxyl group of the amino acid or the
terminal amino or carboxyl group of a polypeptide are bonded to the
parental functionalities, i.e., carboxyl or amino groups in the
amino acid side chains generally are not used to form the amide
bonds with the parental compound (although these groups may need to
be protected during synthesis of the conjugates as described
further below).
[0222] With respect to the carboxyl-containing side chains of amino
acids or polypeptides it will be understood that the carboxyl group
optionally will be blocked, e.g., by R.sup.1, esterified with
R.sup.5 or amidated. Similarly, the amino side chains R.sup.16
optionally will be blocked with R.sup.1 or substituted with
R.sup.5.
[0223] Such ester or amide bonds with side chain amino or carboxyl
groups, like the esters or amides with the parental molecule,
optionally are hydrolyzable in vivo or in vitro under acidic
(pH<3) or basic (pH>10) conditions. Alternatively, they are
substantially stable in the gastrointestinal tract of humans but
are hydrolyzed enzymatically in blood or in intracellular
environments. The esters or amino acid or polypeptide amidates also
are useful as intermediates for the preparation of the parental
molecule containing free amino or carboxyl groups. The free acid or
base of the parental compound, for example, is readily formed from
the esters or amino acid or polypeptide conjugates of this
invention by conventional hydrolysis procedures.
[0224] When an amino acid residue contains one or more chiral
centers, any of the D, L, meso, threo or erythro (as appropriate)
racemates, scalemates or mixtures thereof may be used. In general,
if the intermediates are to be hydrolyzed non-enzymatically (as
would be the case where the amides are used as chemical
intermediates for the free acids or free amines), D isomers are
useful. On the other hand, L isomers are more versatile since they
can be susceptible to both non-enzymatic and enzymatic hydrolysis,
and are more efficiently transported by amino acid or dipeptidyl
transport systems in the gastrointestinal tract.
[0225] Examples of suitable amino acids whose residues are
represented by R.sup.x or R.sup.y include the following:
[0226] Glycine;
[0227] Aminopolycarboxylic acids, e.g., aspartic acid,
.beta.-hydroxyaspartic acid, glutamic acid, .beta.-hydroxyglutamic
acid, .beta.-methylaspartic acid, .beta.-methylglutamic acid,
.beta.,.beta.-dimethylaspartic acid, .gamma.-hydroxyglutamic acid,
.beta.,.gamma.-dihydroxyglutamic acid, .beta.-phenylglutamic acid,
.gamma.-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic
acid, 2-aminosuberic acid and 2-aminosebacic acid;
[0228] Amino acid amides such as glutamine and asparagine;
[0229] Polyamino- or polybasic-monocarboxylic acids such as
arginine, lysine, .beta.-aminoalanine, .gamma.-aminobutyrine,
ornithine, citruline, homoarginine, homocitrulline, hydroxylysine,
allohydroxylsine and diaminobutyric acid;
[0230] Other basic amino acid residues such as histidine;
[0231] Diaminodicarboxylic acids such as
.alpha.,.alpha.'-diaminosuccinic acid,
.alpha.,.alpha.'-diaminoglutaric acid,
.alpha.,.alpha.'-diaminoadipic acid,
.alpha.,.alpha.'-diaminopimelic acid,
.alpha.,.alpha.'-diamino-.beta.-hydroxypimelic acid,
.alpha.,.alpha.'-diaminosuberic acid,
.alpha.,.alpha.'-diaminoazelaic acid, and
.alpha.,.alpha.'-diaminosebacic acid;
[0232] Imino acids such as proline, hydroxyproline,
allohydroxyproline, .gamma.-methylproline, pipecolic acid,
5-hydroxypipecolic acid, and azetidine-2-carboxylic acid;
[0233] A mono- or di-alkyl (typically C.sub.1-C.sub.8 branched or
normal) amino acid such as alanine, valine, leucine, allylglycine,
butyrine, norvaline, norleucine, heptyline, .alpha.-methylserine,
.alpha.-amino-.alpha.-methyl-.gamma.-hydroxyvaleric acid,
.alpha.-amino-.alpha.-methyl-.delta.-hydroxyvaleric acid,
.alpha.-amino-.alpha.-methyl-.epsilon.-hydroxycaproic acid,
isovaline, .alpha.-methylglutamic acid, .alpha.-aminoisobutyric
acid, .alpha.-aminodiethylacetic acid,
.alpha.-aminodiisopropylacetic acid, .alpha.-aminodi-n-propylacetic
acid, .alpha.-aminodiisobutylacetic acid,
.alpha.-aminodi-n-butylacetic acid,
.alpha.-aminoethylisopropylacetic acid,
.alpha.-amino-n-propylacetic acid, .alpha.-aminodiisoamyacetic
acid, .alpha.-methylaspartic acid, .alpha.-methylglutamic acid,
1-aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine,
tert-leucine, .alpha.-methyltryptophan and
.alpha.-amino-.beta.-ethyl-.beta.-phenylpropionic acid;
[0234] .beta.-phenylserinyl;
[0235] Aliphatic .alpha.-amino-.beta.-hydroxy acids such as serine,
.beta.-hydroxylcucine, .beta.-hydroxynorleucine,
.beta.-hydroxynorvaline, and .alpha.-amino-.beta.-hydroxystearic
acid;
[0236] .alpha.-Amino, .alpha.-, .gamma.-, .delta.- or
.epsilon.-hydroxy acids such as homoserine,
.delta.-hydroxynorvaline, .gamma.-hydroxynorvaline and
.epsilon.-hydroxynorleucine residues; canavine and canaline;
.gamma.-hydroxyornithine;
[0237] 2-hexosaminic acids such as D-glucosaminic acid or
D-galactosaminic acid;
[0238] .alpha.-Amino-.beta.-thiols such as penicillamine,
.beta.-thiolnorvaline or .beta.-thiolbutyrine;
[0239] Other sulfur containing amino acid residues including
cysteine; homocystine, .beta.-phenylmethionine, methionine,
S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and
thiol ethers of cysteine or homocysteine;
[0240] Phenylalanine, tryptophan and ring-substituted .alpha.-amino
acids such as the phenyl- or cyclohexylamino acids
.alpha.-aminophenylacetic acid, .alpha.-aminocyclohexylacetic acid
and .alpha.-amino-.beta.-cyclohexylpropionic acid; phenylalanine
analogues and derivatives comprising aryl, lower alkyl, hydroxy,
guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl
(e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-,
3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-,
2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p-nitro-phenylalanine);
furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or
naphthyl-alanines; and tryptophan analogues and derivatives
including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and
4-carboxytryptophan;
[0241] .alpha.-Amino substituted amino acids including sarcosine
(N-methylglycine), N-benzylglycine, N-methylalanine,
N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine,
N-methylvaline and N-benzylvaline; and
[0242] .alpha.-Hydroxy and substituted .alpha.-hydroxy amino acids
including serine, threonine, allothreonine, phosphoserine and
phosphothreonine.
[0243] .alpha.-Hydroxy and substituted .alpha.-hydroxy amino acids
including serine, threonine, allothreonine, phosphoserine and
phosphothreonine.
[0244] Polypeptides are polymers of amino acids in which a carboxyl
group of one amino acid monomer is bonded to an amino or imino
group of the next amino acid monomer by an amide bond. Polypeptides
include dipeptides, low molecular weight polypeptides (about
1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10,
50, 75, 100 or more residues, and suitably are substantially
sequence-homologous with human, animal, plant or microbial
proteins. They include enzymes (e.g., hydrogen peroxidase) as well
as immunogens such as KLH, or antibodies or proteins of any type
against which one wishes to raise an immune response. The nature
and identity of the polypeptide may vary widely.
[0245] The polypeptide amidates are useful as immunogens in raising
antibodies against either the polypeptide (if it is not immunogenic
in the animal to which it is administered) or against the epitopes
on the remainder of the compound of this invention.
[0246] Antibodies capable of binding to the parental non-peptidyl
compound are used to separate the parental compound from mixtures,
for example in diagnosis or manufacturing of the parental compound.
The conjugates of parental compound and polypeptide generally are
more immunogenic than the polypeptides in closely homologous
animals, and therefore make the polypeptide more immunogenic for
facilitating raising antibodies against it. Accordingly, the
polypeptide or protein may not need to be immunogenic in an animal
typically used to raise antibodies, e.g., rabbit, mouse, horse, or
rat, but the final product conjugate should be immunogenic in at
least one of such animals. The polypeptide optionally contains a
peptidolytic enzyme cleavage site at the peptide bond between the
first and second residues adjacent to the acidic heteroatom. Such
cleavage sites are flanked by enzymatic recognition structures,
e.g., a particular sequence of residues recognized by a
peptidolytic enzyme.
[0247] Peptidolytic enzymes for cleaving the polypeptide conjugates
of this invention are well known, and in particular include
carboxypeptidases. Carboxypeptidases digest polypeptides by
removing C-terminal residues, and are specific in many instances
for particular C-terminal sequences. Such enzymes and their
substrate requirements in general are well known. For example, a
dipeptide (having a given pair of residues and a free carboxyl
terminus) is covalently bonded through its .alpha.-amino group to
the phosphorus or carbon atoms of the compounds herein. In claims
where W.sub.1 is phosphonate it is expected that this peptide will
be cleaved by the appropriate peptidolytic enzyme, leaving the
carboxyl of the proximal amino acid residue to autocatalytically
cleave the phosphonoamidate bond.
[0248] Suitable dipeptidyl groups (designated by their single
letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK,
AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH,
RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE,
NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NR, NY, NV, DA, DR, DN,
DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV,
CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT,
CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF,
EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL,
QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG,
GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC,
HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR,
IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY,
IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS,
LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM,
KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI,
ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ,
FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD,
PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA,
SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW,
SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP,
TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK,
WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH,
YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE,
VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.
[0249] Tripeptide residues are also useful as protecting groups.
When a phosphonate is to be protected, the sequence
--X.sup.4-pro-X.sup.5-- (where X.sup.4 is any amino acid residue
and X.sup.5 is an amino acid residue, a carboxyl ester of proline,
or hydrogen) will be cleaved by luminal carboxypeptidase to yield
X.sup.4 with a free carboxyl, which in turn is expected to
autocatalytically cleave the phosphonoamidate bond. The carboxy
group of X.sup.5 optionally is esterified with benzyl.
[0250] Dipeptide or tripeptide species can be selected on the basis
of known transport properties and/or susceptibility to peptidases
that can affect transport to intestinal mucosal or other cell
types. Dipeptides and tripeptides lacking an .alpha.-amino group
are transport substrates for the peptide transporter found in brush
border membrane of intestinal mucosal cells (Bai, J. P. F., (1992)
Pharm Res. 9:969-978). Transport competent peptides can thus be
used to enhance bioavailability of the amidate compounds. Di- or
tripeptides having one or more amino acids in the D configuration
are also compatible with peptide transport and can be utilized in
the amidate compounds of this invention. Amino acids in the D
configuration can be used to reduce the susceptibility of a di- or
tripeptide to hydrolysis by proteases common to the brush border
such as aminopeptidase N. In addition, di- or tripeptides
alternatively are selected on the basis of their relative
resistance to hydrolysis by proteases found in the lumen of the
intestine. For example, tripeptides or polypeptides lacking asp
and/or glu are poor substrates for aminopeptidase A, di- or
tripeptides lacking amino acid residues on the N-terminal side of
hydrophobic amino acids (leu, tyr, phe, val, trp) are poor
substrates for endopeptidase, and peptides lacking a pro residue at
the penultimate position at a free carboxyl terminus are poor
substrates for carboxypeptidase P. Similar considerations can also
be applied to the selection of peptides that are either relatively
resistant or relatively susceptible to hydrolysis by cytosolic,
renal, hepatic, serum or other peptidases. Such poorly cleaved
polypeptide amidates are immunogens or are useful for bonding to
proteins in order to prepare immunogens.
SPECIFIC EMBODIMENTS OF THE INVENTION
[0251] Specific values described for radicals, substituents, and
ranges, as well as specific embodiments of the invention described
herein, are for illustration only; they do not exclude other
defined values or other values within defined ranges.
[0252] In one specific embodiment of the invention, the conjugate
is a compound that is substituted with one or more phosphonate
groups either directly or indirectly through a linker; and that is
optionally substituted with one or more groups A.sup.0; or a
pharmaceutically acceptable salt thereof, wherein:
[0253] A.sup.0 is A.sup.1, A.sup.2 or W.sup.3;
[0254] A.sup.1 is:
##STR00049##
[0255] A.sup.2 is:
##STR00050##
[0256] A.sup.3 is:
##STR00051##
[0257] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0258] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--;
[0259] R.sup.x is independently H, R.sup.1, W.sup.3, a protecting
group, or the formula:
##STR00052##
[0260] wherein:
[0261] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0262] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0263] R.sup.2 is independently H, R.sup.1, R.sup.3 or R.sup.4
wherein each R.sup.4 is independently substituted with 0 to 3
R.sup.3 groups or taken together at a carbon atom, two R.sup.2
groups form a ring of 3 to 8 carbons and the ring may be
substituted with 0 to 3 R.sup.3 groups;
[0264] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0265] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0266] R.sup.3b is Y.sup.1;
[0267] R.sup.3c is R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0268] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0269] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0270] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0271] R.sup.5a is independently alkylene of 1 to 18 carbon atoms,
alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.3 groups;
[0272] W.sup.3 is W.sup.4 or W.sup.5;
[0273] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0274] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0275] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0276] M2 is 0, 1 or 2;
[0277] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0278] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0279] M1a, M1c, and M1d are independently 0 or 1; and
[0280] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0281] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00053##
[0282] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00054##
[0283] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00055##
[0284] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00056##
[0285] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00057##
and W.sup.5a is a carbocycle or a heterocycle where W.sup.5a is
independently substituted with 0 or 1 R.sup.2 groups. A specific
value for M12a is 1.
[0286] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00058##
[0287] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00059##
[0288] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00060##
wherein W.sup.5a is a carbocycle independently substituted with 0
or 1 R.sup.2 groups;
[0289] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00061##
wherein Y.sup.2b is O or N(R.sup.2); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0290] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00062##
wherein W.sup.5a is a carbocycle independently substituted with 0
or 1 R.sup.2 groups;
[0291] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00063##
wherein W.sup.5a is a carbocycle or heterocycle where W.sup.5a is
independently substituted with 0 or 1 R.sup.2 groups.
[0292] In another specific embodiment of the invention A.sup.1 is
of the formula:
##STR00064##
wherein Y.sup.2b is O or N(R.sup.2); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0293] In a specific embodiment of the invention A.sup.2 is of the
formula:
##STR00065##
[0294] In another specific embodiment of the invention A.sup.2 is
of the formula:
##STR00066##
[0295] In another specific embodiment of the invention M12b is
1.
[0296] In another specific embodiment of the invention M12b is 0,
Y.sup.2 is a bond and W.sup.5 is a carbocycle or heterocycle where
W.sup.5 is optionally and independently substituted with 1, 2, or 3
R.sup.2 groups.
[0297] In another specific embodiment of the invention A.sup.2 is
of the formula:
##STR00067##
wherein W.sup.5a is a carbocycle or heterocycle where W.sup.5a is
optionally and independently substituted with 1, 2, or 3 R.sup.2
groups.
[0298] In another specific embodiment of the invention M12a is
1.
[0299] In another specific embodiment of the invention A.sup.2 is
selected from phenyl, substituted phenyl, benzyl, substituted
benzyl, pyridyl and substituted pyridyl.
[0300] In another specific embodiment of the invention A.sup.2 is
of the formula:
##STR00068##
[0301] In another specific embodiment of the invention A.sup.2 is
of the formula:
##STR00069##
[0302] In another specific embodiment of the invention M12b is
1.
[0303] In a specific embodiment of the invention A.sup.3 is of the
formula:
##STR00070##
[0304] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00071##
[0305] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00072##
wherein Y.sup.1a is O or S; and Y.sup.2a is O, N(R.sup.x) or S.
[0306] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00073##
wherein Y.sup.2b is O or N(R.sup.x).
[0307] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00074##
wherein Y.sup.2b is O or N(R.sup.x); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0308] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00075##
wherein Y.sup.2b is O or N(R.sup.x); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0309] In another specific embodiment of the invention M12d is
1.
[0310] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00076##
[0311] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00077##
[0312] In another specific embodiment of the invention W.sup.5 is a
carbocycle.
[0313] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00078##
[0314] In another specific embodiment of the invention W.sup.5 is
phenyl.
[0315] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00079##
wherein Y.sup.1a is O or S; and Y.sup.2a is O, N(R.sup.x) or S.
[0316] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00080##
wherein Y.sup.2b is O or N(R.sup.x).
[0317] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00081##
wherein Y.sup.2b is O or N(R.sup.x); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0318] In another specific embodiment of the invention R.sup.1 is
H.
[0319] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00082##
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3
R.sup.2 groups.
[0320] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00083##
[0321] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00084##
[0322] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00085##
[0323] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00086##
[0324] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00087##
wherein Y.sup.1a is O or S; and Y.sup.2a is O, N(R.sup.2) or S.
[0325] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00088##
wherein Y.sup.1a is O or S; Y.sup.2b is O or N(R.sup.2); and
Y.sup.2c is O, N(R.sup.y) or S.
[0326] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00089##
wherein Y.sup.1a is O or S; Y.sup.2b is O or N(R.sup.2); Y.sup.2d
is O or N(R.sup.y); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
[0327] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00090##
wherein Y.sup.2b is O or N(R.sup.2); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0328] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00091##
wherein Y.sup.2b is O or N(R.sup.2).
[0329] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00092##
[0330] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00093##
[0331] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00094##
wherein Y.sup.1a is O or S; and Y.sup.2a is O, N(R.sup.2) or S.
[0332] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00095##
wherein Y.sup.1a is O or S; Y.sup.2b is O or N(R.sup.2); and
Y.sup.2c is O, N(R.sup.y) or S.
[0333] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00096##
wherein Y.sup.1a is O or S; Y.sup.2b is O or N(R.sup.2); Y.sup.2d
is O or N(R.sup.y); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
[0334] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00097##
wherein Y.sup.2b is O or N(R.sup.2); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0335] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00098##
wherein Y.sup.2b is O or N(R.sup.2).
[0336] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00099##
wherein: Y.sup.2b is O or N(R.sup.x); and M12d is 1, 2, 3, 4, 5, 6,
7 or 8.
[0337] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00100##
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3
R.sup.2 groups.
[0338] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00101##
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3
R.sup.2 groups.
[0339] In another specific embodiment of the invention A.sup.3 is
of the formula:
##STR00102##
[0340] In a specific embodiment of the invention A.sup.0 is of the
formula:
##STR00103##
wherein each R is independently (C.sub.1-C.sub.6)alkyl.
[0341] In a specific embodiment of the invention R.sup.x is
independently H, R.sup.1, W.sup.3, a protecting group, or the
formula:
##STR00104##
[0342] wherein:
[0343] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0344] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0345] R.sup.2 is independently H, R.sup.1, R.sup.3 or R.sup.4
wherein each R.sup.4 is independently substituted with 0 to 3
R.sup.3 groups or taken together at a carbon atom, two R.sup.2
groups form a ring of 3 to 8 carbons and the ring may be
substituted with 0 to 3 R.sup.3 groups;
[0346] In a specific embodiment of the invention R.sup.x is of the
formula:
##STR00105##
wherein Y.sup.1a is O or S; and Y.sup.2c is O, N(R.sup.y) or S.
[0347] In a specific embodiment of the invention R.sup.x is of the
formula:
##STR00106##
wherein Y.sup.1a is O or S; and Y.sup.2d is O or N(R.sup.y).
[0348] In a specific embodiment of the invention R.sup.x is of the
formula:
##STR00107##
[0349] In a specific embodiment of the invention R.sup.y is
hydrogen or alkyl of 1 to 10 carbons.
[0350] In a specific embodiment of the invention R.sup.x is of the
formula:
##STR00108##
[0351] In a specific embodiment of the invention R.sup.x is of the
formula:
##STR00109##
[0352] In a specific embodiment of the invention R.sup.x is of the
formula:
##STR00110##
[0353] In a specific embodiment of the invention Y.sup.1 is O or
S.
[0354] In a specific embodiment of the invention Y.sup.2 is O,
N(R.sup.y) or S.
[0355] In one specific embodiment of the invention R.sup.x is a
group of the formula:
##STR00111##
wherein:
[0356] m1a, m1b, m1c, m1d and m1e are independently 0 or 1;
[0357] m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0358] R.sup.y is H, W.sup.3, R.sup.2 or a protecting group;
provided that:
[0359] if m1a, m12c, and m1d are 0, then m1b, m1c and m1e are
0;
[0360] if m1a and m12c are 0 and m1d is not 0, then m1b and m1c are
0;
[0361] if m1a and m1d are 0 and m12c is not 0, then m1b and at
least one of m1c and m1e are 0;
[0362] if m1a is 0 and m12c and m1d are not 0, then m1b is 0;
[0363] if m12c and m1d are 0 and m1a is not 0, then at least two of
m1b, m1c and m1e are 0;
[0364] if m12c is 0 and m1a and m1d are not 0, then at least one of
m1b and m1c are 0; and
[0365] if m1d is 0 and m1a and m12c are not 0, then at least one of
m1c and m1e are 0.
[0366] In another specific embodiment, the invention provides a
compound of the formula:
[DRUG]-(A.sup.0).sub.nn
or a pharmaceutically acceptable salt thereof wherein,
[0367] DRUG is a compound of any one of formulae 500-511
[0368] nn is 1, 2, or 3;
[0369] A.sup.0 is A.sup.1, A.sup.2 or W.sup.3 with the proviso that
the compound includes at least one A.sup.1;
[0370] A.sup.1 is:
##STR00112##
[0371] A.sup.2 is:
##STR00113##
[0372] A.sup.3 is:
##STR00114##
[0373] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0374] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--;
[0375] R.sup.x is independently H, R.sup.1, W.sup.3, a protecting
group, or the formula:
##STR00115##
[0376] wherein:
[0377] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0378] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0379] R.sup.2 is independently H, R.sup.1, R.sup.3 or R.sup.4
wherein each R.sup.4 is independently substituted with 0 to 3
R.sup.3 groups or taken together at a carbon atom, two R.sup.2
groups form a ring of 3 to 8 carbons and the ring may be
substituted with 0 to 3 R.sup.3 groups;
[0380] R.sup.3 is R.sup.3a, R.sup.3h, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0381] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0382] R.sup.3b is Y.sup.1;
[0383] R.sup.3c is R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
--N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)((R.sup.x)(R.sup.x));
[0384] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0385] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0386] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0387] R.sup.5a is independently alkylene of 1 to 18 carbon atoms,
alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.3 groups;
[0388] W.sup.3 is W.sup.4 or W.sup.5;
[0389] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0390] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0391] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0392] M2 is 0, 1 or 2;
[0393] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0394] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0395] M1a, M1c, and M1d are independently 0 or 1; and
[0396] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0397] In another specific embodiment, the invention provides a
compound of the formula 1-36:
[0398] A.sup.0 is A.sup.1;
[0399] A.sup.1 is
##STR00116##
[0400] A.sup.3 is:
##STR00117##
[0401] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0402] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--;
[0403] R.sup.x is independently H, W.sup.3, a protecting group, or
the formula:
##STR00118##
[0404] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0405] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0406] R.sup.2 is independently H, R.sup.3 or R.sup.4 wherein each
R.sup.4 is independently substituted with 0 to 3 R.sup.3
groups;
[0407] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0408] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0409] R.sup.3b is Y.sup.1;
[0410] R.sup.3c is --R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0411] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0412] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0413] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0414] R.sup.5a is independently alkylene of 1 to 18 carbon atoms,
alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.3 groups;
[0415] W.sup.3 is W.sup.4 or W.sup.5;
[0416] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0417] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0418] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0419] M2 is 0, 1 or 2;
[0420] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0421] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0422] M1a, M1c, and M1d are independently 0 or 1; and
[0423] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0424] X.sup.50 is H F, or Cl; and
[0425] X.sup.51 is H or Cl.
[0426] The present invention also provides a compound of any one of
formulae 1-36 wherein:
[0427] A.sup.0 is A.sup.1;
[0428] A.sup.1 is
##STR00119##
[0429] A.sup.3 is:
##STR00120##
[0430] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0431] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--;
[0432] R.sup.x is independently H, W.sup.3, a protecting group, or
the formula:
##STR00121##
[0433] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0434] R.sup.1 is independently H or alkyl of 1 to 18 carbon
atoms;
[0435] R.sup.2 is independently H, R.sup.3 or R.sup.4 wherein each
R.sup.4 is independently substituted with 0 to 3 R.sup.3
groups;
[0436] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0437] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0438] R.sup.3b is Y.sup.1;
[0439] R.sup.3c is --R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x), --OC(Y.sup.1)R.sup.x,
--OC(Y.sup.1)OR.sup.x, --OC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--SC(Y.sup.1)R.sup.x, --SC(Y.sup.1)OR.sup.x,
--SC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --N(R.sup.x)C(Y.sup.1)R.sup.x,
N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0440] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0441] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0442] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0443] R.sup.5a is independently alkylene of 1 to 18 carbon atoms,
alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.3 groups;
[0444] W.sup.3 is W.sup.4 or W.sup.5;
[0445] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0446] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0447] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0448] M2 is 0, 1 or 2;
[0449] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0450] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0451] M1a, M1c, and M1d are independently 0 or 1;
[0452] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0453] X.sup.50 is H F, or Cl; and
[0454] X.sup.51 is H or Cl.
[0455] In another specific embodiment, the invention provides a
compound of the formula:
[DRUG]-[L-P(.dbd.Y.sup.1)--Y.sup.2--R.sup.x].sub.nn
[0456] or a pharmaceutically acceptable salt thereof wherein,
[0457] DRUG is a compound of any one of formulae 500-547;
[0458] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0459] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--;
[0460] R.sup.x is independently H, W.sup.3, a protecting group, or
the formula:
##STR00122##
[0461] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0462] R.sup.2 is independently H, R.sup.3 or R.sup.4 wherein each
R.sup.4 is independently substituted with 0 to 3 R.sup.3
groups;
[0463] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d
[0464] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0465] R.sup.3b is Y.sup.1;
[0466] R.sup.3c is R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x),
--OC(Y.sup.1)R.sup.x, --OC(Y.sup.1)OR.sup.x,
--OC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --SC(Y.sup.1)R.sup.x,
SC(Y.sup.1)OR.sup.x, --SC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--N(R.sup.x)C(Y.sup.1)R.sup.x, --N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0467] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0468] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0469] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0470] W.sup.3 is W.sup.4 or W.sup.5;
[0471] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0472] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0473] M2 is 1, 2, or 3;
[0474] M1a, M1c, and M1d are independently 0 or 1;
[0475] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0476] nn is 1, 2, or 3; and
[0477] L is a linking group.
[0478] In another specific embodiment, the invention provides a
compound of which is a compound of the formula:
[DRUG]-(A.sup.0).sub.nn
or a pharmaceutically acceptable salt thereof wherein,
[0479] DRUG is a compound of any one of formulae 500-511;
[0480] nn is 1, 2, or 3;
[0481] A.sup.0 is A.sup.1, A.sup.2, or W.sup.3 with the proviso
that the compound includes at least one A.sup.1;
[0482] A.sup.1 is:
##STR00123##
[0483] A.sup.2 is:
##STR00124##
[0484] A.sup.3 is:
##STR00125##
[0485] Y.sup.1 is independently O, S, N(R.sup.x), N(O)(R.sup.x),
N(OR.sup.x), N(O)(OR.sup.x), or N(N(R.sup.x)(R.sup.x));
[0486] Y.sup.2 is independently a bond, O, N(R.sup.x),
N(O)(R.sup.x), N(OR.sup.x), N(O)(OR.sup.x), N(N(R.sup.x)(R.sup.x)),
--S(O).sub.M2--, or --S(O).sub.M2--S(O).sub.M2--;
[0487] R.sup.x is independently H, W.sup.3, a protecting group, or
the formula:
##STR00126##
[0488] R.sup.y is independently H, W.sup.3, R.sup.2 or a protecting
group;
[0489] R.sup.2 is independently H, R.sup.3 or R.sup.4 wherein each
R.sup.4 is independently substituted with 0 to 3 R.sup.3
groups;
[0490] R.sup.3 is R.sup.3a, R.sup.3b, R.sup.3c or R.sup.3d,
provided that when R.sup.3 is bound to a heteroatom, then R.sup.3
is R.sup.3c or R.sup.3d;
[0491] R.sup.3a is F, Cl, Br, I, --CN, N.sub.3 or --NO.sub.2;
[0492] R.sup.3b is Y.sup.1;
[0493] R.sup.3c is R.sup.x, N(R.sup.x)(R.sup.x), --SR.sup.x,
--S(O)R.sup.x, --S(O).sub.2R.sup.x, --S(O)(OR.sup.x),
--S(O).sub.2(OR.sup.x),
--OC(Y.sup.1)R.sup.x, --OC(Y.sup.1)OR.sup.x,
--OC(Y.sup.1)(N(R.sup.x)(R.sup.x)), --SC(Y.sup.1)R.sup.x,
--SC(Y.sup.1)OR.sup.x, --SC(Y.sup.1)(N(R.sup.x)(R.sup.x)),
--N(R.sup.x)C(Y.sup.1)R.sup.x, --N(R.sup.x)C(Y.sup.1)OR.sup.x, or
--N(R.sup.x)C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0494] R.sup.3d is --C(Y.sup.1)R.sup.x, --C(Y.sup.1)OR.sup.x or
--C(Y.sup.1)(N(R.sup.x)(R.sup.x));
[0495] R.sup.4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to
18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
[0496] R.sup.5 is R.sup.4 wherein each R.sup.4 is substituted with
0 to 3 R.sup.3 groups;
[0497] W.sup.3 is W.sup.4 or W.sup.5;
[0498] W.sup.4 is R.sup.5, --C(Y.sup.1)R.sup.5,
--C(Y.sup.1)W.sup.5, --SO.sub.2R.sup.5, or --SO.sub.2W.sup.5;
[0499] W.sup.5 is carbocycle or heterocycle wherein W.sup.5 is
independently substituted with 0 to 3 R.sup.2 groups;
[0500] W.sup.6 is W.sup.3 independently substituted with 1, 2, or 3
A.sup.3 groups;
[0501] M2 is 0, 1 or 2;
[0502] M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0503] M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
[0504] M1a, M1e, and M1d are independently 0 or 1; and
[0505] M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
[0506] In compounds of the invention W.sup.5 carbocycles and
W.sup.5 heterocycles may be independently substituted with 0 to 3
R.sup.2 groups. W.sup.5 may be a saturated, unsaturated or aromatic
ring comprising a mono- or bicyclic carbocycle or heterocycle.
W.sup.5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms. The
W.sup.5 rings are saturated when containing 3 ring atoms, saturated
or mono-unsaturated when containing 4 ring atoms, saturated, or
mono- or di-unsaturated when containing 5 ring atoms, and
saturated, mono- or di-unsaturated, or aromatic when containing 6
ring atoms.
[0507] A W.sup.5 heterocycle may be a monocycle having 3 to 7 ring
members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from
N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9
carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
W.sup.5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5
carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or
5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms
selected from N and S). W.sup.5 heterocyclic bicycles have 7 to 10
ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected
from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or
[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2
hetero atoms selected from N and S) arranged as a bicyclo [5,6] or
[6,6] system. The W.sup.5 heterocycle may be bonded to Y.sup.2
through a carbon, nitrogen, sulfur or other atom by a stable
covalent bond.
[0508] W.sup.5 heterocycles include for example, pyridyl,
dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl,
pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl,
isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl,
and pyrrolyl. W.sup.5 also includes, but is not limited to,
examples such as:
##STR00127##
[0509] W.sup.5 carbocycles and heterocycles may be independently
substituted with 0 to 3 R.sup.2 groups, as defined above. For
example, substituted W.sup.5 carbocycles include:
##STR00128##
[0510] Examples of substituted phenyl carbocycles include:
##STR00129##
Linking Groups and Linkers
[0511] The invention provides conjugates that comprise a kinase
inhibiting compound that is linked to one or more phosphonate
groups either directly (e.g. through a covalent bond) or through a
linking group (i.e. a linker). The nature of the linker is not
critical provided it does not interfere with the ability of the
phosphonate containing compound to function as a therapeutic agent.
The phosphonate or the linker can be linked to the compound (e.g. a
compound of 500-511) at any synthetically feasible position on the
compound by removing a hydrogen or any portion of the compound to
provide an open valence for attachment of the phosphonate or the
linker.
[0512] In one embodiment of the invention the linking group or
linker (which can be designated "L") can include all or a portions
of the group A.sup.0, A.sup.1, A.sup.2, or W.sup.3 described
herein.
[0513] In another embodiment of the invention the linking group or
linker has a molecular weight of from about 20 daltons to about 400
daltons.
[0514] In another embodiment of the invention the linking group or
linker has a length of about 5 angstroms to about 300
angstroms.
[0515] In another embodiment of the invention the linking group or
linker separates the DRUG and a P(.dbd.Y.sup.1) residue by about 5
angstroms to about 200 angstroms, inclusive, in length.
[0516] In another embodiment of the invention the linking group or
linker is a divalent, branched or unbranched, saturated or
unsaturated, hydrocarbon chain, having from 2 to 25 carbon atoms,
wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is
optionally replaced by (--O--), and wherein the chain is optionally
substituted on carbon with one or more (e.g. 1, 2, 3, or 4)
substituents selected from (C.sub.1-C.sub.6)alkoxy,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkanoyl,
(C.sub.1-C.sub.6)alkanoyloxy, (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo
(.dbd.O), carboxy, aryl, aryloxy, heteroaryl, and
heteroaryloxy.
[0517] In another embodiment of the invention the linking group or
linker is of the formula W-A wherein A is (C.sub.1-C.sub.24)alkyl,
(C.sub.2-C.sub.24)alkenyl, (C.sub.2-C.sub.24)alkynyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.6-C.sub.10)aryl or a
combination thereof, wherein W is --N(R)C(.dbd.O)--,
--C(.dbd.O)N(R)--, --OC(.dbd.O)--, --C(.dbd.O)O--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --N(R)--, --C(.dbd.O)--, or a direct
bond; wherein each R is independently H or
(C.sub.1-C.sub.6)alkyl.
[0518] In another embodiment of the invention the linking group or
linker is a divalent radical formed from a peptide.
[0519] In another embodiment of the invention the linking group or
linker is a divalent radical formed from an amino acid.
[0520] In another embodiment of the invention the linking group or
linker is a divalent radical formed from poly-L-glutamic acid,
poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine,
poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine,
poly-L-lysine-L-phenylalanine, poly-L-lysine or
poly-L-lysine-L-tyrosine.
[0521] In another embodiment of the invention the linking group or
linker is of the formula W--(CH.sub.2).sub.n wherein, n is between
about 1 and about 10; and W is --N(R)C(.dbd.O)--,
--C(.dbd.O)N(R)--, --OC(.dbd.O)--, --C(.dbd.O)O--, --O--, --S--,
--S(O)--, --S(O).sub.2--, --C(.dbd.O)--, --N(R)--, or a direct
bond; wherein each R is independently H or
(C.sub.1-C.sub.6)alkyl.
[0522] In another embodiment of the invention the linking group or
linker is methylene, ethylene, or propylene.
[0523] In another embodiment of the invention the linking group or
linker is attached to the phosphonate group through a carbon atom
of the linker.
Intracellular Targeting
[0524] The phosphonate group of the compounds of the invention may
cleave in vivo in stages after they have reached the desired site
of action, i.e. inside a cell. One mechanism of action inside a
cell may entail a first cleavage, e.g. by esterase, to provide a
negatively-charged "locked-in" intermediate. Cleavage of a terminal
ester grouping in a compound of the invention thus affords an
unstable intermediate which releases a negatively charged "locked
in" intermediate.
[0525] After passage inside a cell, intracellular enzymatic
cleavage or modification of the phosphonate or prodrug compound may
result in an intracellular accumulation of the cleaved or modified
compound by a "trapping" mechanism. The cleaved or modified
compound may then be "locked-in" the cell by a significant change
in charge, polarity, or other physical property change which
decreases the rate at which the cleaved or modified compound can
exit the cell, relative to the rate at which it entered as the
phosphonate prodrug. Other mechanisms by which a therapeutic effect
are achieved may be operative as well. Enzymes which are capable of
an enzymatic activation mechanism with the phosphonate prodrug
compounds of the invention include, but are not limited to,
amidases, esterases, microbial enzymes, phospholipases,
cholinesterases, and phosphatases.
[0526] From the foregoing, it will be apparent that many different
drugs can be derivatized in accord with the present invention.
Numerous such drugs are specifically mentioned herein. However, it
should be understood that the discussion of drug families and their
specific members for derivatization according to this invention is
not intended to be exhaustive, but merely illustrative.
Kinase-Inhibitory Compounds
[0527] The compounds of the invention include those with
kinase-inhibitory activity. The compounds of the inventions bear
one or more (e.g. 1, 2, 3, or 4) phosphonate groups, which may be a
prodrug moiety.
[0528] The term "kinase-inhibitory compound" includes those
compounds that inhibit the activity of at least one kinase. In
particular, the compounds include Gefitinib, imatinib, erlotinib,
vatalanib, alvocidib, CEP-701, GLEEVEC, midostaurin, MLN-518,
PD-184352, doramapimod, BAY-43-9006, and CP-690,550.
[0529] Typically, compounds of the invention have a molecular
weight of from about 400 amu to about 10,000 amu; in a specific
embodiment of the invention, compounds have a molecular weight of
less than about 5000 amu; in another specific embodiment of the
invention, compounds have a molecular weight of less than about
2500 amu; in another specific embodiment of the invention,
compounds have a molecular weight of less than about 1000 amu; in
another specific embodiment of the invention, compounds have a
molecular weight of less than about 800 amu; in another specific
embodiment of the invention, compounds have a molecular weight of
less than about 600 amu; and in another specific embodiment of the
invention, compounds have a molecular weight of less than about 600
amu and a molecular weight of greater than about 400 amu.
[0530] The compounds of the invention also typically have a
logD(polarity) less than about 5. In one embodiment the invention
provides compounds having a logD less than about 4; in another one
embodiment the invention provides compounds having a logD less than
about 3; in another one embodiment the invention provides compounds
having a logD greater than about -5; in another one embodiment the
invention provides compounds having a logD greater than about -3;
and in another one embodiment the invention provides compounds
having a logD greater than about 0 and less than about 3.
[0531] Selected substituents within the compounds of the invention
are present to a recursive degree. In this context, "recursive
substituent" means that a substituent may recite another instance
of itself. Because of the recursive nature of such substituents,
theoretically, a large number may be present in any given claim.
For example, R.sup.x contains a R.sup.y substituent. R.sup.y can be
R.sup.2, which in turn can be R.sup.3. If R.sup.3 is selected to be
R.sup.3c, then a second instance of R.sup.x can be selected. One of
ordinary skill in the art of medicinal chemistry understands that
the total number of such substituents is reasonably limited by the
desired properties of the compound intended. Such properties
include, by of example and not limitation, physical properties such
as molecular weight, solubility or log P, application properties
such as activity against the intended target, and practical
properties such as ease of synthesis.
[0532] By way of example and not limitation, W.sup.3, R.sup.y and
R.sup.3 are all recursive substituents in certain claims.
Typically, each of these may independently occur 20, 19, 18, 17,
16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times
in a given claim. More typically, each of these may independently
occur 12 or fewer times in a given claim. More typically yet,
W.sup.3 will occur 0 to 8 times, R.sup.y will occur 0 to 6 times
and R.sup.3 will occur 0 to 10 times in a given claim. Even more
typically, W.sup.3 will occur 0 to 6 times, R.sup.y will occur 0 to
4 times and R.sup.3 will occur 0 to 8 times in a given claim.
[0533] Recursive substituents are an intended aspect of the
invention. One of ordinary skill in the art of medicinal chemistry
understands the versatility of such substituents. To the degree
that recursive substituents are present in an claim of the
invention, the total number will be determined as set forth
above.
[0534] Whenever a compound described herein is substituted with
more than one of the same designated group, e.g., "R.sup.1" or
"R.sup.6a", then it will be understood that the groups may be the
same or different, i.e., each group is independently selected. Wavy
lines indicate the site of covalent bond attachments to the
adjoining groups, moieties, or atoms.
[0535] In one embodiment of the invention, the compound is in an
isolated and purified form. Generally, the term "isolated and
purified" means that the compound is substantially free from
biological materials (e.g. blood, tissue, cells, etc.). In one
specific embodiment of the invention, the term means that the
compound or conjugate of the invention is at least about 50 wt. %
free from biological materials; in another specific embodiment, the
term means that the compound or conjugate of the invention is at
least about 75 wt. % free from biological materials; in another
specific embodiment, the term means that the compound or conjugate
of the invention is at least about 90 wt. % free from biological
materials; in another specific embodiment, the term means that the
compound or conjugate of the invention is at least about 98 wt. %
free from biological materials; and in another embodiment, the term
means that the compound or conjugate of the invention is at least
about 99 wt. % free from biological materials. In another specific
embodiment, the invention provides a compound or conjugate of the
invention that has been synthetically prepared (e.g., ex vivo).
[0536] In one embodiment of the invention, the compound is not an
anti-inflammatory compound; in another embodiment the compound is
not an anti-infective; in another embodiment the compound is not a
compound that is active against immune-mediated conditions; in
another embodiment the compound is not a compound that is active
against metabolic diseases; in another embodiment the compound is
not an antiviral agent; in another embodiment the compound is not a
nucleoside; in another embodiment the compound is not a IMPDH
inhibitor; in another embodiment the compound is not an
antimetabolite; in another embodiment the compound is not a PNP
inhibitor; in another embodiment the compound inhibits a
serine/threonine kinase, tyrosine kinase, Bcr-Abl kinase,
cyclin-dependent kinase, Flt3 tyrosine kinase, MAP Erk kinase, JAK3
kinase, VEGF receptor kinase, PDGF receptor tyrosine kinase,
protein kinase C, insulin receptor tyrosine kinase, or an EGF
receptor tyrosine kinase; in another embodiment the compound is not
Gefitinib, imatinib, erlotinib, vatalanib, alvocidib, CEP-701,
GLEEVEC, midostaurin, MLN-518, PD-184352, doramapimod, BAY-43-9006,
or CP-690,550; in another embodiment the compound is not a
substituted compound of any one of formulae 500-510; in another
embodiment the compound is not a substituted compound of formula
511; in another embodiment the compound is not a compound of any
one of formulae 1-33; in another embodiment the compound is not a
compound of formula 34 or 35.
Cellular Accumulation
[0537] In one embodiment, the invention is provides compounds
capable of accumulating in human PBMC (peripheral blood mononuclear
cells). PBMC refer to blood cells having round lymphocytes and
monocytes. Physiologically, PBMC are critical components of the
mechanism against infection. PBMC may be isolated from heparinized
whole blood of normal healthy donors or buffy coats, by standard
density gradient centrifugation and harvested from the interface,
washed (e.g. phosphate-buffered saline) and stored in freezing
medium. PBMC may be cultured in multi-well plates. At various times
of culture, supernatant may be either removed for assessment, or
cells may be harvested and analyzed (Smith R. etal (2003) Blood
102(7):2532-2540). The compounds of this claim may further comprise
a phosphonate or phosphonate prodrug. More typically, the
phosphonate or phosphonate prodrug can have the structure A.sup.3
as described herein.
[0538] Typically, compounds of the invention demonstrate improved
intracellular half-life of the compounds or intracellular
metabolites of the compounds in human PBMC when compared to analogs
of the compounds not having the phosphonate or phosphonate prodrug.
Typically, the half-life is improved by at least about 50%, more
typically at least in the range 50-100%, still more typically at
least about 100%, more typically yet greater than about 100%.
[0539] In one embodiment of the invention the intracellular
half-life of a metabolite of the compound in human PBMCs is
improved when compared to an analog of the compound not having the
phosphonate or phosphonate prodrug. In such claims, the metabolite
may be generated intracellularly, e.g. generated within human PBMC.
The metabolite may be a product of the cleavage of a phosphonate
prodrug within human PBMCs. The phosphonate prodrug may be cleaved
to form a metabolite having at least one negative charge at
physiological pH. The phosphonate prodrug may be enzymatically
cleaved within human PBMC to form a phosphonate having at least one
active hydrogen atom of the form P--OH.
Stereoisomers
[0540] The compounds of the invention may have chiral centers,
e.g., chiral carbon or phosphorus atoms. The compounds of the
invention thus include racemic mixtures of all stereoisomers,
including enantiomers, diastereomers, and atropisomers. In
addition, the compounds of the invention include enriched or
resolved optical isomers at any or all asymmetric, chiral atoms. In
other words, the chiral centers apparent from the depictions are
provided as the chiral isomers or racemic mixtures. Both racemic
and diastereomeric mixtures, as well as the individual optical
isomers isolated or synthesized, substantially free of their
enantiomeric or diastereomeric partners, are all within the scope
of the invention. The racemic mixtures are separated into their
individual, substantially optically pure isomers through well-known
techniques such as, for example, the separation of diastereomeric
salts formed with optically active adjuncts, e.g., acids or bases
followed by conversion back to the optically active substances. In
most instances, the desired optical isomer is synthesized by means
of stereospecific reactions, beginning with the appropriate
stereoisomer of the desired starting material.
[0541] The compounds of the invention can also exist as tautomeric
isomers in certain cases. All though only one delocalized resonance
structure may be depicted, all such forms are contemplated within
the scope of the invention. For example, ene-amine tautomers can
exist for purine, pyrimidine, imidazole, guanidine, amidine, and
tetrazole systems and all their possible tautomeric forms are
within the scope of the invention.
Salts and Hydrates
[0542] The compositions of this invention optionally comprise salts
of the compounds herein, especially pharmaceutically acceptable
non-toxic salts containing, for example, Na.sup.+, Li.sup.+,
K.sup.+, Ca.sup.+2 and Mg.sup.+2. Such salts may include those
derived by combination of appropriate cations such as alkali and
alkaline earth metal ions or ammonium and quaternary amino ions
with an acid anion moiety, typically a carboxylic acid. Monovalent
salts are preferred if a water soluble salt is desired.
[0543] Metal salts typically are prepared by reacting the metal
hydroxide with a compound of this invention. Examples of metal
salts which are prepared in this way are salts containing Li.sup.+,
Na.sup.+, and K.sup.+. A less soluble metal salt can be
precipitated from the solution of a more soluble salt by addition
of the suitable metal compound.
[0544] In addition, salts may be formed from acid addition of
certain organic and inorganic acids, e.g., HCl, HBr,
H.sub.2SO.sub.4, H.sub.3PO.sub.4 or organic sulfonic acids, to
basic centers, typically amines, or to acidic groups. Finally, it
is to be understood that the compositions herein comprise compounds
of the invention in their un-ionized, as well as zwitterionic form,
and combinations with stoichiometric amounts of water as in
hydrates.
[0545] Also included within the scope of this invention are the
salts of the parental compounds with one or more amino acids. Any
of the amino acids described above are suitable, especially the
naturally-occurring amino acids found as protein components,
although the amino acid typically is one bearing a side chain with
a basic or acidic group, e.g., lysine, arginine or glutamic acid,
or a neutral group such as glycine, serine, threonine, alanine,
isoleucine, or leucine.
Methods of Kinase Inhibition
[0546] Another aspect of the invention relates to methods of
inhibiting the activity of at least one kinase comprising the step
of treating a sample suspected of containing a kinase with a
composition of the invention.
[0547] Compositions of the invention may act as kinase inhibitors,
as intermediates for such inhibitors, or have other utilities as
described below. The inhibitors will bind to locations on the
surface or in a cavity of at least one kinase. Compositions binding
the kinase may bind with varying degrees of reversibility. Those
compounds binding substantially irreversibly are ideal candidates
for use in this method of the invention. Once labeled, the
substantially irreversibly binding compositions are useful as
probes for the detection of a kinase. Accordingly, the invention
relates to methods of detecting kinase in a sample suspected of
containing kinase comprising the steps of: treating a sample
suspected of containing kinase with a composition comprising a
compound of the invention bound to a label; and observing the
effect of the sample on the activity of the label. Suitable labels
are well known in the diagnostics field and include stable free
radicals, fluorophores, radioisotopes, enzymes, chemiluminescent
groups and chromogens. The compounds herein are labeled in
conventional fashion using functional groups such as hydroxyl or
amino.
[0548] Within the context of the invention samples suspected of
containing at least one kinase include natural or man-made
materials such as living organisms; tissue or cell cultures;
biological samples such as biological material samples (blood,
serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue
samples, and the like); laboratory samples; food, water, or air
samples; bioproduct samples such as extracts of cells, particularly
recombinant cells synthesizing a desired glycoprotein; and the
like. Typically the sample will be suspected of containing a
kinase. Samples can be contained in any medium including water and
organic solvent/water mixtures. Samples include living organisms
such as humans, and man made materials such as cell cultures.
[0549] The treating step of the invention comprises adding the
composition of the invention to the sample or it comprises adding a
precursor of the composition to the sample. The addition step
comprises any method of administration as described above.
[0550] If desired, the activity of the kinase after application of
the composition can be observed by any method including direct and
indirect methods of detecting kinase activity. Quantitative,
qualitative, and semiquantitative methods of determining kinase
activity are all contemplated. Typically one of the screening
methods described above are applied, however, any other method such
as observation of the physiological properties of a living organism
are also applicable.
[0551] Many organisms contain kinases. The compounds of this
invention are useful in the treatment or prophylaxis of conditions
associated with kinase activation in animals or in man.
[0552] However, in screening compounds capable of inhibiting kinase
it should be kept in mind that the results of enzyme assays may not
correlate with cell culture assays. Thus, a cell based assay should
be the primary screening tool.
Screens for Kinase Inhibitors
[0553] Compositions of the invention are screened for inhibitory
activity against a kinase by any of the conventional techniques for
evaluating enzyme activity. Within the context of the invention,
typically compositions are first screened for inhibition of kinase
in vitro and compositions showing inhibitory activity are then
screened for activity in vivo. Compositions having in vitro Ki
(inhibitory constants) of less then about 5.times.10.sup.-6 M,
typically less than about 1.times.10.sup.-7 M and preferably less
than about 5.times.10.sup.-8 M are preferred for in vivo use.
[0554] Useful in vitro screens have been described in detail, e.g.,
Bioorg. Med. Chem. Lett., 2001, 11, 2775).
Pharmaceutical Formulations
[0555] The compounds of this invention are formulated with
conventional carriers and excipients, which will be selected in
accord with ordinary practice. Tablets will contain excipients,
glidants, fillers, binders and the like. Aqueous formulations are
prepared in sterile form, and when intended for delivery by other
than oral administration generally will be isotonic. All
formulations will optionally contain excipients such as those set
forth in the Handbook of Pharmaceutical Excipients (1986).
Excipients include ascorbic acid and other antioxidants, chelating
agents such as EDTA, carbohydrates such as dextrin,
hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid
and the like. The pH of the formulations ranges from about 3 to
about 11, but is ordinarily about 7 to 10.
[0556] While it is possible for the active ingredients to be
administered alone it may be preferable to present them as
pharmaceutical formulations. The formulations, both for veterinary
and for human use, of the invention comprise at least one active
ingredient, as above defined, together with one or more acceptable
carriers therefor and optionally other therapeutic ingredients. The
carrier(s) must be "acceptable" in the sense of being compatible
with the other ingredients of the formulation and physiologically
innocuous to the recipient thereof.
[0557] The formulations include those suitable for the foregoing
administration routes. The formulations may conveniently be
presented in unit dosage form and may be prepared by any of the
methods well known in the art of pharmacy. Techniques and
formulations generally are found in Remington's Pharmaceutical
Sciences (Mack Publishing Co., Easton, Pa.). Such methods include
the step of bringing into association the active ingredient with
the carrier which constitutes one or more accessory ingredients. In
general the formulations are prepared by uniformly and intimately
bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both, and then, if
necessary, shaping the product.
[0558] Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient; as a powder or granules; as a solution or a
suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The
active ingredient may also be administered as a bolus, electuary or
paste.
[0559] A tablet is made by compression or molding, optionally with
one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with a binder, lubricant, inert diluent, preservative,
surface active or dispersing agent. Molded tablets may be made by
molding in a suitable machine a mixture of the powdered active
ingredient moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and optionally are formulated so as
to provide slow or controlled release of the active ingredient
therefrom.
[0560] For administration to the eye or other external tissues
e.g., mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w (including active
ingredient(s) in a range between 0.1% and 20% in increments of 0.1%
w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w
and most preferably 0.5 to 10% w/w. When formulated in an ointment,
the active ingredients may be employed with either a paraffinic or
a water-miscible ointment base. Alternatively, the active
ingredients may be formulated in a cream with an oil-in-water cream
base.
[0561] If desired, the aqueous phase of the cream base may include,
for example, at least 30% w/w of a polyhydric alcohol, i.e. an
alcohol having two or more hydroxyl groups such as propylene
glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and
polyethylene glycol (including PEG 400) and mixtures thereof. The
topical formulations may desirably include a compound which
enhances absorption or penetration of the active ingredient through
the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethyl sulphoxide and related
analogs.
[0562] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier (otherwise known as an
emulgent), it desirably comprises a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Preferably, a hydrophilic emulsifier is included together with a
lipophilic emulsifier which acts as a stabilizer. It is also
preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called
emulsifying wax, and the wax together with the oil and fat make up
the so-called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations.
[0563] Emulgents and emulsion stabilizers suitable for use in the
formulation of the invention include Tween.RTM. 60, Span.RTM. 80,
cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl
mono-stearate and sodium lauryl sulfate.
[0564] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties. The cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters known as Crodamol CAP may be
used, the last three being preferred esters. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils are used.
[0565] Pharmaceutical formulations according to the present
invention comprise one or more compounds of the invention together
with one or more pharmaceutically acceptable carriers or excipients
and optionally other therapeutic agents. Pharmaceutical
formulations containing the active ingredient may be in any form
suitable for the intended method of administration. When used for
oral use for example, tablets, troches, lozenges, aqueous or oil
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, syrups or elixirs may be prepared. Compositions
intended for oral use may be prepared according to any method known
to the art for the manufacture of pharmaceutical compositions and
such compositions may contain one or more agents including
sweetening agents, flavoring agents, coloring agents and preserving
agents, in order to provide a palatable preparation. Tablets
containing the active ingredient in admixture with non-toxic
pharmaceutically acceptable excipient which are suitable for
manufacture of tablets are acceptable. These excipients may be, for
example, inert diluents, such as calcium or sodium carbonate,
lactose, lactose monohydrate, croscarmellose sodium, povidone,
calcium or sodium phosphate; granulating and disintegrating agents,
such as maize starch, or alginic acid; binding agents, such as
cellulose, microcrystalline cellulose, starch, gelatin or acacia;
and lubricating agents, such as magnesium stearate, stearic acid or
talc. Tablets may be uncoated or may be coated by known techniques
including microencapsulation to delay disintegration and adsorption
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 alone or with
a wax may be employed.
[0566] Formulations for oral use may be also presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example calcium phosphate or kaolin, or as soft
gelatin capsules wherein the active ingredient is mixed with water
or an oil medium, such as peanut oil, liquid paraffin or olive
oil.
[0567] Aqueous suspensions of the invention contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropyl methylcelluose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0568] Oil suspensions may be formulated by suspending the active
ingredient in a vegetable oil, such as arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oral suspensions may contain a thickening agent, such
as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such
as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an antioxidant such as ascorbic
acid.
[0569] Dispersible powders and granules of the invention suitable
for preparation of an aqueous suspension by the addition of water
provide the active ingredient in admixture with a dispersing or
wetting agent, a suspending agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional excipients, for
example sweetening, flavoring and coloring agents, may also be
present.
[0570] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, such as olive oil or arachis oil, a mineral oil,
such as liquid paraffin, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum
acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids and hexitol anhydrides, such as sorbitan monooleate, and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan monooleate. The emulsion may also
contain sweetening and flavoring agents. Syrups and elixirs may be
formulated with sweetening agents, such as glycerol, sorbitol or
sucrose. Such formulations may also contain a demulcent, a
preservative, a flavoring or a coloring agent.
[0571] The pharmaceutical compositions of the invention may be in
the form of a sterile injectable preparation, such as a sterile
injectable aqueous or oleaginous suspension. This suspension may be
formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0572] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0573] Formulations suitable for administration to the eye include
eye drops wherein the active ingredient is dissolved or suspended
in a suitable carrier, especially an aqueous solvent for the active
ingredient. The active ingredient is preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously 0.5
to 10% particularly about 1.5% w/w.
[0574] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0575] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0576] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns (including particle sizes in a range between 0.1 and
500 microns in increments microns such as 0.5, 1, 30 microns, 35
microns, etc.), which is administered by rapid inhalation through
the nasal passage or by inhalation through the mouth so as to reach
the alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration may be prepared according to
conventional methods and may be delivered with other therapeutic
agents such as compounds heretofore used in the treatment or
prophylaxis of conditions associated with kinase activity.
[0577] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0578] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0579] The formulations are presented in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water for
injection, immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0580] It should be understood that in addition to the ingredients
particularly mentioned above the formulations of this invention may
include other agents conventional in the art having regard to the
type of formulation in question, for example those suitable for
oral administration may include flavoring agents.
[0581] The invention further provides veterinary compositions
comprising at least one active ingredient as above defined together
with a veterinary carrier therefor.
[0582] Veterinary carriers are materials useful for the purpose of
administering the composition and may be solid, liquid or gaseous
materials which are otherwise inert or acceptable in the veterinary
art and are compatible with the active ingredient. These veterinary
compositions may be administered orally, parenterally or by any
other desired route.
[0583] Compounds of the invention can also be formulated to provide
controlled release of the active ingredient to allow less frequent
dosing or to improve the pharmacokinetic or toxicity profile of the
active ingredient. Accordingly, the invention also provided
compositions comprising one or more compounds of the invention
formulated for sustained or controlled release.
[0584] Effective dose of active ingredient depends at least on the
nature of the condition being treated, toxicity, whether the
compound is being used prophylactically (lower doses), the method
of delivery, and the pharmaceutical formulation, and will be
determined by the clinician using conventional dose escalation
studies. It can be expected to be from about 0.0001 to about 100
mg/kg body weight per day. Typically, from about 0.01 to about 10
mg/kg body weight per day. More typically, from about 0.01 to about
5 mg/kg body weight per day. More typically, from about 0.05 to
about 0.5 mg/kg body weight per day. For example, the daily
candidate dose for an adult human of approximately 70 kg body
weight will range from 1 mg to 1000 mg, preferably between 5 mg and
500 mg, and may take the form of single or multiple doses.
Routes of Administration
[0585] One or more compounds of the invention (herein referred to
as the active ingredients) are administered by any route
appropriate to the condition to be treated. Suitable routes include
oral, rectal, nasal, topical (including buccal and sublingual),
vaginal and parenteral (including subcutaneous, intramuscular,
intravenous, intradermal, intrathecal and epidural), and the like.
It will be appreciated that the preferred route may vary with for
example the condition of the recipient. An advantage of the
compounds of this invention is that they are orally bioavailable
and can be dosed orally.
Combination Therapy
[0586] Active ingredients of the invention are also used in
combination with other active ingredients. Such combinations are
selected based on the condition to be treated, cross-reactivities
of ingredients and pharmaco-properties of the combination.
[0587] It is also possible to combine any compound of the invention
with one or more other active ingredients in a unitary dosage form
for simultaneous or sequential administration to a patient. The
combination therapy may be administered as a simultaneous or
sequential regimen. When administered sequentially, the combination
may be administered in two or more administrations.
[0588] The combination therapy may provide "synergy" and
"synergistic effect", i.e. the effect achieved when the active
ingredients used together is greater than the sum of the effects
that results from using the compounds separately. A synergistic
effect may be attained when the active ingredients are: (1)
co-formulated and administered or delivered simultaneously in a
combined formulation; (2) delivered by alternation or in parallel
as separate formulations; or (3) by some other regimen. When
delivered in alternation therapy, a synergistic effect may be
attained when the compounds are administered or delivered
sequentially, e.g., in separate tablets, pills or capsules, or by
different injections in separate syringes. In general, during
alternation therapy, an effective dosage of each active ingredient
is administered sequentially, i.e. serially, whereas in combination
therapy, effective dosages of two or more active ingredients are
administered together.
Metabolites of the Compounds of the Invention
[0589] Also falling within the scope of this invention are the in
vivo metabolic products of the compounds described herein. Such
products may result for example from the oxidation, reduction,
hydrolysis, amidation, esterification and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes compounds produced by a process
comprising contacting a compound of this invention with a mammal
for a period of time sufficient to yield a metabolic product
thereof. Such products typically are identified by preparing a
radiolabelled (e.g., C.sup.14 or H.sup.3) compound of the
invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS or
NMR analysis. In general, analysis of metabolites is done in the
same way as conventional drug metabolism studies well-known to
those skilled in the art. The conversion products, so long as they
are not otherwise found in vivo, are useful in diagnostic assays
for therapeutic dosing of the compounds of the invention even if
they possess no kinase inhibitory activity of their own.
[0590] Recipes and methods for determining stability of compounds
in surrogate gastrointestinal secretions are known. Compounds are
defined herein as stable in the gastrointestinal tract where less
than about 50 mole percent of the protected groups are deprotected
in surrogate intestinal or gastric juice upon incubation for 1 hour
at 37.degree. C. Simply because the compounds are stable to the
gastrointestinal tract does not mean that they cannot be hydrolyzed
in vivo. The phosphonate prodrugs of the invention typically will
be stable in the digestive system but are substantially hydrolyzed
to the parental drug in the digestive lumen, liver or other
metabolic organ, or within cells in general.
Exemplary Methods of Making the Compounds of the Invention.
[0591] The invention also relates to methods of making the
compositions of the invention. The compositions are prepared by any
of the applicable techniques of organic synthesis. Many such
techniques are well known in the art. However, many of the known
techniques are elaborated in Compendium of Organic Synthetic
Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison
and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen
Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol.
4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and
Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic
Chemistry, Third Edition, (John Wiley & Sons, New York, 1985),
Comprehensive Organic Synthesis. Selectivity, Strategy &
Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M.
Trost, Editor-in-Chief (Pergamon Press, New York, 1993
printing).
[0592] A number of exemplary methods for the preparation of the
compositions of the invention are provided below. These methods are
intended to illustrate the nature of such preparations are not
intended to limit the scope of applicable methods.
[0593] Generally, the reaction conditions such as temperature,
reaction time, solvents, work-up procedures, and the like, will be
those common in the art for the particular reaction to be
performed. The cited reference material, together with material
cited therein, contains detailed descriptions of such conditions.
Typically the temperatures will be -100.degree. C. to 200.degree.
C., solvents will be aprotic or protic, and reaction times will be
10 seconds to 10 days. Work-up typically consists of quenching any
unreacted reagents followed by partition between a water/organic
layer system (extraction) and separating the layer containing the
product.
[0594] Oxidation and reduction reactions are typically carried out
at temperatures near room temperature (about 20.degree. C.),
although for metal hydride reductions frequently the temperature is
reduced to 0.degree. C. to -100.degree. C., solvents are typically
aprotic for reductions and may be either protic or aprotic for
oxidations. Reaction times are adjusted to achieve desired
conversions.
[0595] Condensation reactions are typically carried out at
temperatures near room temperature, although for non-equilibrating,
kinetically controlled condensations reduced temperatures
(0.degree. C. to -100.degree. C.) are also common. Solvents can be
either protic (common in equilibrating reactions) or aprotic
(common in kinetically controlled reactions).
[0596] Standard synthetic techniques such as azeotropic removal of
reaction by-products and use of anhydrous reaction conditions
(e.g., inert gas environments) are common in the art and will be
applied when applicable.
SCHEMES AND EXAMPLES
[0597] General aspects of these exemplary methods are described
below and in the Examples. Each of the products of the following
processes is optionally separated, isolated, and/or purified prior
to its use in subsequent processes.
[0598] Generally, the reaction conditions such as temperature,
reaction time, solvents, work-up procedures, and the like, will be
those common in the art for the particular reaction to be
performed. The cited reference material, together with material
cited therein, contains detailed descriptions of such conditions.
Typically the temperatures will be -100.degree. C. to 200.degree.
C., solvents will be aprotic or protic, and reaction times will be
10 seconds to 10 days. Work-up typically consists of quenching any
unreacted reagents followed by partition between a water/organic
layer system (extraction) and separating the layer containing the
product.
[0599] Oxidation and reduction reactions are typically carried out
at temperatures near room temperature (about 20.degree. C.),
although for metal hydride reductions frequently the temperature is
reduced to 0.degree. C. to -100.degree. C., solvents are typically
aprotic for reductions and may be either protic or aprotic for
oxidations. Reaction times are adjusted to achieve desired
conversions.
[0600] Condensation reactions are typically carried out at
temperatures near room temperature, although for non-equilibrating,
kinetically controlled condensations reduced temperatures
(0.degree. C. to -100.degree. C.) are also common. Solvents can be
either protic (common in equilibrating reactions) or aprotic
(common in kinetically controlled reactions).
[0601] Standard synthetic techniques such as azeotropic removal of
reaction by-products and use of anhydrous reaction conditions
(e.g., inert gas environments) are common in the art and will be
applied when applicable.
[0602] The terms "treated", "treating", "treatment", and the like,
when used in connection with a chemical synthetic operation, mean
contacting, mixing, reacting, allowing to react, bringing into
contact, and other terms common in the art for indicating that one
or more chemical entities is treated in such a manner as to convert
it to one or more other chemical entities. This means that
"treating compound one with compound two" is synonymous with
"allowing compound one to react with compound two", "contacting
compound one with compound two", "reacting compound one with
compound two", and other expressions common in the art of organic
synthesis for reasonably indicating that compound one was
"treated", "reacted", "allowed to react", etc., with compound two.
For example, treating indicates the reasonable and usual manner in
which organic chemicals are allowed to react. Normal concentrations
(0.01M to 10M, typically 0.1M to 1M), temperatures (-100.degree. C.
to 250.degree. C., typically -78.degree. C. to 150.degree. C., more
typically -78.degree. C. to 100.degree. C., still more typically
0.degree. C. to 100.degree. C.), reaction vessels (typically glass,
plastic, metal), solvents, pressures, atmospheres (typically air
for oxygen and water insensitive reactions or nitrogen or argon for
oxygen or water sensitive), etc., are intended unless otherwise
indicated. The knowledge of similar reactions known in the art of
organic synthesis are used in selecting the conditions and
apparatus for "treating" in a given process. In particular, one of
ordinary skill in the art of organic synthesis selects conditions
and apparatus reasonably expected to successfully carry out the
chemical reactions of the described processes based on the
knowledge in the art.
[0603] Modifications of each of the exemplary schemes and in the
examples (hereafter "exemplary schemes") leads to various analogs
of the specific exemplary materials produce. The above-cited
citations describing suitable methods of organic synthesis are
applicable to such modifications.
[0604] In each of the exemplary schemes it may be advantageous to
separate reaction products from one another and/or from starting
materials. The desired products of each step or series of steps is
separated and/or purified (hereinafter separated) to the desired
degree of homogeneity by the techniques common in the art.
Typically such separations involve multiphase extraction,
crystallization from a solvent or solvent mixture, distillation,
sublimation, or chromatography. Chromatography can involve any
number of methods including, for example: reverse-phase and normal
phase; size exclusion; ion exchange; high, medium, and low pressure
liquid chromatography methods and apparatus; small scale
analytical; simulated moving bed (SMB) and preparative thin or
thick layer chromatography, as well as techniques of small scale
thin layer and flash chromatography.
[0605] Another class of separation methods involves treatment of a
mixture with a reagent selected to bind to or render otherwise
separable a desired product, unreacted starting material, reaction
by product, or the like. Such reagents include adsorbents or
absorbents such as activated carbon, molecular sieves, ion exchange
media, or the like. Alternatively, the reagents can be acids in the
case of a basic material, bases in the case of an acidic material,
binding reagents such as antibodies, binding proteins, selective
chelators such as crown ethers, liquid/liquid ion extraction
reagents (LIX), or the like.
[0606] Selection of appropriate methods of separation depends on
the nature of the materials involved. For example, boiling point,
and molecular weight in distillation and sublimation, presence or
absence of polar functional groups in chromatography, stability of
materials in acidic and basic media in multiphase extraction, and
the like. One skilled in the art will apply techniques most likely
to achieve the desired separation.
[0607] A single stereoisomer, e.g., an enantiomer, substantially
free of its stereoisomer may be obtained by resolution of the
racemic mixture using a method such as formation of diastereomers
using optically active resolving agents (Stereochemistry of Carbon
Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H.,
(1975) J. Chromatogr., 113:(3) 283-302). Racemic mixtures of chiral
compounds of the invention can be separated and isolated by any
suitable method, including: (1) formation of ionic, diastereomeric
salts with chiral compounds and separation by fractional
crystallization or other methods, (2) formation of diastereomeric
compounds with chiral derivatizing reagents, separation of the
diastereomers, and conversion to the pure stereoisomers, and (3)
separation of the substantially pure or enriched stereoisomers
directly under chiral conditions.
[0608] Under method (1), diastereomeric salts can be formed by
reaction of enantiomerically pure chiral bases such as brucine,
quinine, ephedrine, strychnine,
.alpha.-methyl-.beta.-phenylethylamine (amphetamine), and the like
with asymmetric compounds bearing acidic functionality, such as
carboxylic acid and sulfonic acid. The diastereomeric salts may be
induced to separate by fractional crystallization or ionic
chromatography. For separation of the optical isomers of amino
compounds, addition of chiral carboxylic or sulfonic acids, such as
camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid
can result in formation of the diastereomeric salts.
[0609] Alternatively, by method (2), the substrate to be resolved
is reacted with one enantiomer of a chiral compound to form a
diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry
of Organic Compounds, John Wiley & Sons, Inc., p. 322).
Diastereomeric compounds can be formed by reacting asymmetric
compounds with enantiomerically pure chiral derivatizing reagents,
such as menthyl derivatives, followed by separation of the
diastereomers and hydrolysis to yield the free, enantiomerically
enriched xanthene. A method of determining optical purity involves
making chiral esters, such as a menthyl ester, e.g., (-) menthyl
chloroformate in the presence of base, or Mosher ester,
.alpha.-methoxy-.alpha.-(trifluoromethyl)phenyl acetate (Jacob III.
(1982) J. Org. Chem. 47:4165), of the racemic mixture, and
analyzing the NMR spectrum for the presence of the two
atropisomeric diastereomers. Stable diastereomers of atropisomeric
compounds can be separated and isolated by normal- and
reverse-phase chromatography following methods for separation of
atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). By
method (3), a racemic mixture of two enantiomers can be separated
by chromatography using a chiral stationary phase (Chiral Liquid
Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York;
Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or
purified enantiomers can be distinguished by methods used to
distinguish other chiral molecules with asymmetric carbon atoms,
such as optical rotation and circular dichroism.
EXAMPLES GENERAL SECTION
[0610] A number of exemplary methods for the preparation of
compounds of the invention are provided herein, for example, in the
Examples hereinbelow. These methods are intended to illustrate the
nature of such preparations are not intended to limit the scope of
applicable methods. Certain compounds of the invention can be used
as intermediates for the preparation of other compounds of the
invention. For example, the interconversion of various phosphonate
compounds of the invention is illustrated below.
Interconversions of the Phosphonates R-Link-P(O)(OR.sup.1).sub.2,
R-Link-P(O)(OR.sup.1)(OH) and R-Link-P(O)(OH).sub.2.
[0611] The following schemes 32-38 described the preparation of
phosphonate esters of the general structure
R-link-P(O)(OR.sup.1).sub.2, in which the groups R.sup.1 may be the
same or different. The R.sup.1 groups attached to a phosphonate
ester, or to precursors thereto, may be changed using established
chemical transformations. The interconversion reactions of
phosphonates are illustrated in Scheme S32. The group R in Scheme
32 represents the substructure, i.e. the drug "scaffold, to which
the substituent link-P(O)(OR.sup.1).sub.2 is attached, either in
the compounds of the invention, or in precursors thereto. At the
point in the synthetic route of conducting a phosphonate
interconversion, certain functional groups in R may be protected.
The methods employed for a given phosphonate transformation depend
on the nature of the substituent R.sup.1, and of the substrate to
which the phosphonate group is attached. The preparation and
hydrolysis of phosphonate esters is described in Organic Phosphorus
Compounds, G. M. Kosolapoff, L. Macir, eds, Wiley, 1976, p.
9ff.
[0612] In general, synthesis of phosphonate esters is achieved by
coupling a nucleophile amine or alcohol with the corresponding
activated phosphonate electrophilic precursor. For example,
chlorophosphonate addition on to 5'-hydroxy of nucleoside is a well
known method for preparation of nucleoside phosphate monoesters.
The activated precursor can be prepared by several well known
methods. Chlorophosphonates useful for synthesis of the prodrugs
are prepared from the substituted-1,3-propanediol (Wissner, et al,
(1992) J. Med. Chem. 35:1650). Chlorophosphonates are made by
oxidation of the corresponding chlorophospholanes (Anderson, et al,
(1984) J. Org. Chem. 49:1304) which are obtained by reaction of the
substituted diol with phosphorus trichloride. Alternatively, the
chlorophosphonate agent is made by treating substituted-1,3-diols
with phosphorusoxychloride (Patois, et al, (1990) J. Chem. Soc.
Perkin Trans. I, 1577). Chlorophosphonate species may also be
generated in situ from corresponding cyclic phosphites (Silverburg,
et al., (1996) Tetrahedron lett., 37:771-774), which in turn can be
either made from chlorophospholane or phosphoramidate intermediate.
Phosphoroflouridate intermediate prepared either from pyrophosphate
or phosphoric acid may also act as precursor in preparation of
cyclic prodrugs (Watanabe et al., (1988) Tetrahedron lett.,
29:5763-66).
[0613] Phosphonate prodrugs of the present invention may also be
prepared from the free acid by Mitsunobu reactions (Mitsunobu,
(1981) Synthesis, 1; Campbell, (1992) J. Org. Chem. 57:6331), and
other acid coupling reagents including, but not limited to,
carbodiimides (Alexander, et al, (1994) Collect. Czech. Chem.
Commun. 59:1853; Casara et al, (1992) Bioorg. Med. Chem. Lett.
2:145; Ohashi et al, (1988) Tetrahedron Lett., 29:1189), and
benzotriazolyloxytris-(dimethylamino)phosphonium salts (Campagne et
al (1993) Tetrahedron Lett. 34:6743).
[0614] Aryl halides undergo Ni.sup.+2 catalyzed reaction with
phosphite derivatives to give aryl phosphonate containing compounds
(Balthazar, et al (1980) J. Org. Chem. 45:5425). Phosphonates may
also be prepared from the chlorophosphonate in the presence of a
palladium catalyst using aromatic triflates (Petrakis et al (1987)
J. Am. Chem. Soc. 109:2831; Lu et al (1987) Synthesis 726). In
another method, aryl phosphonate esters are prepared from aryl
phosphates under anionic rearrangement conditions (Melvin (1981)
Tetrahedron Lett. 22:3375; Casteel et al (1991) Synthesis, 691).
N-Alkoxy aryl salts with alkali met al derivatives of cyclic alkyl
phosphonate provide general synthesis for heteroaryl-2-phosphonate
linkers (Redmore (1970) J. Org. Chem. 35:4114). These above
mentioned methods can also be extended to compounds where the
W.sup.5 group is a heterocycle. Cyclic-1,3-propanyl prodrugs of
phosphonates are also synthesized from phosphonic diacids and
substituted propane-1,3-diols using a coupling reagent such as
1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g.,
pyridine). Other carbodiimide based coupling agents like
1,3-disopropylcarbodiimide or water soluble reagent,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
can also be utilized for the synthesis of cyclic phosphonate
prodrugs.
[0615] The conversion of a phosphonate diester S32.1 into the
corresponding phosphonate monoester S32.2 (Scheme 32, Reaction 1)
is accomplished by a number of methods. For example, the ester
S32.1 in which R.sup.1 is an aralkyl group such as benzyl, is
converted into the monoester compound S32.2 by reaction with a
tertiary organic base such as diazabicyclooctane (DABCO) or
quinuclidine, as described in J. Org. Chem. (1995) 60:2946. The
reaction is performed in an inert hydrocarbon solvent such as
toluene or xylene, at about 110.degree. C. The conversion of the
diester S32.1 in which R.sup.1 is an aryl group such as phenyl, or
an alkenyl group such as allyl, into the monoester S32.2 is
effected by treatment of the ester S32.1 with a base such as
aqueous sodium hydroxide in acetonitrile or lithium hydroxide in
aqueous tetrahydrofuran. Phosphonate diesters S32.1 in which one of
the groups R.sup.1 is aralkyl, such as benzyl, and the other is
alkyl, is converted into the monoesters S32.2 in which R.sup.1 is
alkyl by hydrogenation, for example using a palladium on carbon
catalyst. Phosphonate diesters in which both of the groups R.sup.1
are alkenyl, such as allyl, is converted into the monoester S32.2
in which R.sup.1 is alkenyl, by treatment with
chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in
aqueous ethanol at reflux, optionally in the presence of
diazabicyclooctane, for example by using the procedure described in
J. Org. Chem. (1973) 38:3224, for the cleavage of allyl
carboxylates.
[0616] The conversion of a phosphonate diester S32.1 or a
phosphonate monoester S32.2 into the corresponding phosphonic acid
S32.3 (Scheme 32, Reactions 2 and 3) can be effected by reaction of
the diester or the monoester with trimethylsilyl bromide, as
described in J. Chem. Soc., Chem. Comm., (1979) 739. The reaction
is conducted in an inert solvent such as, for example,
dichloromethane, optionally in the presence of a silylating agent
such as bis(trimethylsilyl)trifluoroacetamide, at ambient
temperature. A phosphonate monoester S32.2 in which R.sup.1 is
aralkyl such as benzyl, is converted into the corresponding
phosphonic acid S32.3 by hydrogenation over a palladium catalyst,
or by treatment with hydrogen chloride in an ethereal solvent such
as dioxane. A phosphonate monoester S32.2 in which R.sup.1 is
alkenyl such as, for example, allyl, is converted into the
phosphonic acid S32.3 by reaction with Wilkinson's catalyst in an
aqueous organic solvent, for example in 15% aqueous acetonitrile,
or in aqueous ethanol, for example using the procedure described in
Helv. Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis
of phosphonate esters S32.1 in which R.sup.1 is benzyl is described
in J. Org. Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis
of phosphonate esters S32.1 in which R.sup.1 is phenyl is described
in J. Am. Chem. Soc. (1956) 78:2336.
[0617] The conversion of a phosphonate monoester S32.2 into a
phosphonate diester S32.1 (Scheme 32, Reaction 4) in which the
newly introduced R.sup.1 group is alkyl, aralkyl, haloalkyl such as
chloroethyl, or aralkyl is effected by a number of reactions in
which the substrate S32.2 is reacted with a hydroxy compound
R.sup.1OH, in the presence of a coupling agent. Typically, the
second phosphonate ester group is different than the first
introduced phosphonate ester group, i.e. R.sup.1 is followed by the
introduction of R.sup.2 where each of R.sup.1 and R.sup.2 is alkyl,
aralkyl, haloalkyl such as chloroethyl, or aralkyl (Scheme 32,
Reaction 4a) whereby S32.2 is converted to S32.1a. Suitable
coupling agents are those employed for the preparation of
carboxylate esters, and include a carbodiimide such as
dicyclohexylcarbodiimide, in which case the reaction is preferably
conducted in a basic organic solvent such as pyridine, or
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PYBOP, Sigma), in which case the reaction is performed in a polar
solvent such as dimethylformamide, in the presence of a tertiary
organic base such as diisopropylethylamine, or Aldrithiol-2
(Aldrich) in which case the reaction is conducted in a basic
solvent such as pyridine, in the presence of a triaryl phosphine
such as triphenylphosphine. Alternatively, the conversion of the
phosphonate monoester S32.2 to the diester S32.1 is effected by the
use of the Mitsunobu reaction, as described above (Scheme 7). The
substrate is reacted with the hydroxy compound R.sup.1OH, in the
presence of diethyl azodicarboxylate and a triarylphosphine such as
triphenyl phosphine. Alternatively, the phosphonate monoester S32.2
is transformed into the phosphonate diester S32.1, in which the
introduced R.sup.1 group is alkenyl or aralkyl, by reaction of the
monoester with the halide R.sup.1Br, in which R.sup.1 is as alkenyl
or aralkyl. The alkylation reaction is conducted in a polar organic
solvent such as dimethylformamide or acetonitrile, in the presence
of a base such as cesium carbonate. Alternatively, the phosphonate
monoester is transformed into the phosphonate diester in a two step
procedure. In the first step, the phosphonate monoester S32.2 is
transformed into the chloro analog RP(O)(OR.sup.1)Cl by reaction
with thionyl chloride or oxalyl chloride and the like, as described
in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds,
Wiley, 1976, p. 17, and the thus-obtained product RP(O)(OR.sup.1)Cl
is then reacted with the hydroxy compound R.sup.1OH, in the
presence of a base such as triethylamine, to afford the phosphonate
diester S32.1.
[0618] A phosphonic acid R-link-P(O)(OH).sub.2 is transformed into
a phosphonate monoester RP(O)(OR.sup.1)(OH) (Scheme 32, Reaction 5)
by means of the methods described above of for the preparation of
the phosphonate diester R-link-P(O)(OR.sup.1).sub.2 S32.1, except
that only one molar proportion of the component R.sup.1OH or
R.sup.1Br is employed. Dialkyl phosphonates may be prepared
according to the methods of: Quast et al (1974) Synthesis 490;
Stowell et al (1990) Tetrahedron Lett. 3261; U.S. Pat. No.
5,663,159.
[0619] A phosphonic acid R-link-P(O)(OH).sub.2 S32.3 is transformed
into a phosphonate diester R-link-P(O)(OR.sup.1).sub.2 S32.1
(Scheme 32, Reaction 6) by a coupling reaction with the hydroxy
compound R OH, in the presence of a coupling agent such as
Aldrithiol-2 (Aldrich) and triphenylphosphine. The reaction is
conducted in a basic solvent such as pyridine. Alternatively,
phosphonic acids S32.3 are transformed into phosphonic esters S32.1
in which R.sup.1 is aryl, by means of a coupling reaction
employing, for example, dicyclohexylcarbodiimide in pyridine at ca
70.degree. C. Alternatively, phosphonic acids S32.3 are transformed
into phosphonic esters S32.1 in which R.sup.1 is alkenyl, by means
of an alkylation reaction. The phosphonic acid is reacted with the
alkenyl bromide R.sup.1Br in a polar organic solvent such as
acetonitrile solution at reflux temperature, the presence of a base
such as cesium carbonate, to afford the phosphonic ester S32.1.
##STR00130##
Preparation of Phosphonate Carbamates.
[0620] Phosphonate esters may contain a carbamate linkage. The
preparation of carbamates is described in Comprehensive Organic
Functional Group Transformations, A. R. Katritzky, ed., Pergamon,
1995, Vol. 6, p. 416ff, and in Organic Functional Group
Preparations, by S. R. Sandler and W. Karo, Academic Press, 1986,
p. 260ff. The carbamoyl group may be formed by reaction of a
hydroxy group according to the methods known in the art, including
the teachings of Ellis, US 2002/0103378 A1 and Hajima, U.S. Pat.
No. 6,018,049.
[0621] Scheme 33 illustrates various methods by which the carbamate
linkage is synthesized. As shown in Scheme 33, in the general
reaction generating carbamates, an alcohol S33.1, is converted into
the activated derivative S33.2 in which Lv is a leaving group such
as halo, imidazolyl, benztriazolyl and the like, as described
herein. The activated derivative S33.2 is then reacted with an
amine S33.3, to afford the carbamate product S33.4. Examples 1-7 in
Scheme 33 depict methods by which the general reaction is effected.
Examples 8-10 illustrate alternative methods for the preparation of
carbamates.
[0622] Scheme 33, Example 1 illustrates the preparation of
carbamates employing a chloroformyl derivative of the alcohol
S33.5. In this procedure, the alcohol S33.5 is reacted with
phosgene, in an inert solvent such as toluene, at about 0.degree.
C., as described in Org. Syn. Coll. Vol. 3, 167, 1965, or with an
equivalent reagent such as trichloromethoxy chloroformate, as
described in Org. Syn. Coll. Vol. 6, 715, 1988, to afford the
chloroformate S33.6. The latter compound is then reacted with the
amine component S33.3, in the presence of an organic or inorganic
base, to afford the carbamate S33.7. For example, the chloroformyl
compound S33.6 is reacted with the amine S33.3 in a water-miscible
solvent such as tetrahydrofuran, in the presence of aqueous sodium
hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to
yield the carbamate S33.7. Alternatively, the reaction is performed
in dichloromethane in the presence of an organic base such as
diisopropylethylamine or dimethylaminopyridine.
[0623] Scheme 33, Example 2 depicts the reaction of the
chloroformate compound S33.6 with imidazole to produce the
imidazolide S33.8. The imidazolide product is then reacted with the
amine S33.3 to yield the carbamate S33.7. The preparation of the
imidazolide is performed in an aprotic solvent such as
dichloromethane at 0.degree., and the preparation of the carbamate
is conducted in a similar solvent at ambient temperature,
optionally in the presence of a base such as dimethylaminopyridine,
as described in J. Med. Chem., 1989, 32, 357.
[0624] Scheme 33 Example 3, depicts the reaction of the
chloroformate S33.6 with an activated hydroxyl compound R''OH, to
yield the mixed carbonate ester S33.10. The reaction is conducted
in an inert organic solvent such as ether or dichloromethane, in
the presence of a base such as dicyclohexylamine or triethylamine.
The hydroxyl component R''OH is selected from the group of
compounds S33.19-S33.24 shown in Scheme 33, and similar compounds.
For example, if the component R''OH is hydroxybenztriazole S33.19,
N-hydroxysuccinimide S33.20, or pentachlorophenol, S33.21, the
mixed carbonate S33.10 is obtained by the reaction of the
chloroformate with the hydroxyl compound in an ethereal solvent in
the presence of dicyclohexylamine, as described in Can. J. Chem.,
1982, 60, 976. A similar reaction in which the component R''OH is
pentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed
in an ethereal solvent in the presence of triethylamine, as
described in Syn., 1986, 303, and Chem. Ber. 118, 468, 1985.
[0625] Scheme 33 Example 4 illustrates the preparation of
carbamates in which an alkyloxycarbonylimidazole S33.8 is employed.
In this procedure, an alcohol S33.5 is reacted with an equimolar
amount of carbonyl diimidazole S33.11 to prepare the intermediate
S33.8. The reaction is conducted in an aprotic organic solvent such
as dichloromethane or tetrahydrofuran. The acyloxyimidazole S33.8
is then reacted with an equimolar amount of the amine R'NH.sub.2 to
afford the carbamate S33.7. The reaction is performed in an aprotic
organic solvent such as dichloromethane, as described in Tet.
Lett., 42, 2001, 5227, to afford the carbamate S33.7.
[0626] Scheme 33, Example 5 illustrates the preparation of
carbamates by means of an intermediate alkoxycarbonylbenztriazole
S33.13. In this procedure, an alcohol ROH is reacted at ambient
temperature with an equimolar amount of benztriazole carbonyl
chloride S33.12, to afford the alkoxycarbonyl product S33.13. The
reaction is performed in an organic solvent such as benzene or
toluene, in the presence of a tertiary organic amine such as
triethylamine, as described in Synthesis., 1977, 704. The product
is then reacted with the amine R'NH.sub.2 to afford the carbamate
S33.7. The reaction is conducted in toluene or ethanol, at from
ambient temperature to about 80.degree. C. as described in
Synthesis., 1977, 704.
[0627] Scheme 33, Example 6 illustrates the preparation of
carbamates in which a carbonate (R'O).sub.2CO, S33.14, is reacted
with an alcohol S33.5 to afford the intermediate alkyloxycarbonyl
intermediate S33.15. The latter reagent is then reacted with the
amine R'NH.sub.2 to afford the carbamate S33.7. The procedure in
which the reagent S33.15 is derived from hydroxybenztriazole S33.19
is described in Synthesis, 1993, 908; the procedure in which the
reagent S33.15 is derived from N-hydroxysuccinimide S33.20 is
described in Tet. Lett., 1992, 2781; the procedure in which the
reagent S33.15 is derived from 2-hydroxypyridine S33.23 is
described in Tet. Lett., 1991, 4251; the procedure in which the
reagent S33.15 is derived from 4-nitrophenol S33.24 is described in
Synthesis. 1993, 103. The reaction between equimolar amounts of the
alcohol ROH and the carbonate S33.14 is conducted in an inert
organic solvent at ambient temperature.
[0628] Scheme 33, Example 7 illustrates the preparation of
carbamates from alkoxycarbonyl azides S33.16. In this procedure, an
alkyl chloroformate S33.6 is reacted with an azide, for example
sodium azide, to afford the alkoxycarbonyl azide S33.16. The latter
compound is then reacted with an equimolar amount of the amine
R'NH.sub.2 to afford the carbamate S33.7. The reaction is conducted
at ambient temperature in a polar aprotic solvent such as
dimethylsulfoxide, for example as described in Synthesis., 1982,
404.
[0629] Scheme 33, Example 8 illustrates the preparation of
carbamates by means of the reaction between an alcohol ROH and the
chloroformyl derivative of an amine S33.17. In this procedure,
which is described in Synthetic Organic Chemistry, R. B. Wagner, H.
D. Zook, Wiley, 1953, p. 647, the reactants are combined at ambient
temperature in an aprotic solvent such as acetonitrile, in the
presence of a base such as triethylamine, to afford the carbamate
S33.7.
[0630] Scheme 33, Example 9 illustrates the preparation of
carbamates by means of the reaction between an alcohol ROH and an
isocyanate S33.18. In this procedure, which is described in
Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953,
p. 645, the reactants are combined at ambient temperature in an
aprotic solvent such as ether or dichloromethane and the like, to
afford the carbamate S33.7.
[0631] Scheme 33, Example 10 illustrates the preparation of
carbamates by means of the reaction between an alcohol ROH and an
amine R'NH.sub.2. In this procedure, which is described in Chem.
Lett. 1972, 373, the reactants are combined at ambient temperature
in an aprotic organic solvent such as tetrahydrofuran, in the
presence of a tertiary base such as triethylamine, and selenium.
Carbon monoxide is passed through the solution and the reaction
proceeds to afford the carbamate S33.7.
##STR00131## ##STR00132##
Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,
Monoamidates, Diesters and Monoesters.
[0632] A number of methods are available for the conversion of
phosphonic acids into amidates and esters. In one group of methods,
the phosphonic acid is either converted into an isolated activated
intermediate such as a phosphoryl chloride, or the phosphonic acid
is activated in situ for reaction with an amine or a hydroxy
compound.
[0633] The conversion of phosphonic acids into phosphoryl chlorides
is accomplished by reaction with thionyl chloride, for example as
described in J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim.,
1958, 28, 1063, or J. Org. Chem., 1994, 59, 6144, or by reaction
with oxalyl chloride, as described in J. Am. Chem. Soc., 1994, 116,
3251, or J. Org. Chem., 1994, 59, 6144, or by reaction with
phosphorus pentachloride, as described in J. Org. Chem., 2001, 66,
329, or in J. Med. Chem., 1995, 38, 1372. The resultant phosphoryl
chlorides are then reacted with amines or hydroxy compounds in the
presence of a base to afford the amidate or ester products.
[0634] Phosphonic acids are converted into activated imidazolyl
derivatives by reaction with carbonyl diimidazole, as described in
J. Chem. Soc., Chem. Comm. (1991) 312, or Nucleosides &
Nucleotides (2000) 19:1885. Activated sulfonyloxy derivatives are
obtained by the reaction of phosphonic acids with
trichloromethylsulfonyl chloride or with
triisopropylbenzenesulfonyl chloride, as described in Tet. Lett.
(1996) 7857, or Bioorg. Med. Chem. Lett. (1998) 8:663. The
activated sulfonyloxy derivatives are then reacted with amines or
hydroxy compounds to afford amidates or esters.
[0635] Alternatively, the phosphonic acid and the amine or hydroxy
reactant are combined in the presence of a diimide coupling agent.
The preparation of phosphonic amidates and esters by means of
coupling reactions in the presence of dicyclohexyl carbodiimide is
described, for example, in J. Chem. Soc., Chem. Comm. (1991) 312 or
Coll. Czech. Chem. Comm. (1987) 52:2792. The use of ethyl
dimethylaminopropyl carbodiimide for activation and coupling of
phosphonic acids is described in Tet. Lett., (2001) 42:8841, or
Nucleosides & Nucleotides (2000) 19:1885.
[0636] A number of additional coupling reagents have been described
for the preparation of amidates and esters from phosphonic acids.
The agents include Aldrithiol-2, and PYBOP and BOP, as described in
J. Org. Chem., 1995, 60, 5214, and J. Med. Chem. (1997) 40:3842,
mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described
in J. Med. Chem. (1996) 39:4958, diphenylphosphoryl azide, as
described in J. Org. Chem. (1984) 49:1158,
1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT)
as described in Bioorg. Med. Chem. Lett. (1998) 8:1013,
bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), as
described in Tet. Lett., (1996) 37:3997,
2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described in
Nucleosides Nucleotides 1995, 14, 871, and diphenyl
chlorophosphate, as described in J. Med. Chem., 1988, 31, 1305.
[0637] Phosphonic acids are converted into amidates and esters by
means of the Mitsunobu reaction, in which the phosphonic acid and
the amine or hydroxy reactant are combined in the presence of a
triaryl phosphine and a dialkyl azodicarboxylate. The procedure is
described in Org. Lett., 2001, 3, 643, or J. Med. Chem., 1997, 40,
3842.
[0638] Phosphonic esters are also obtained by the reaction between
phosphonic acids and halo compounds, in the presence of a suitable
base. The method is described, for example, in Anal. Chem., 1987,
59, 1056, or J. Chem. Soc. Perkin Trans., 1, 1993, 19, 2303, or J.
Med. Chem., 1995, 38, 1372, or Tet. Lett., 2002, 43, 1161.
[0639] Schemes 34-37 illustrate the conversion of phosphonate
esters and phosphonic acids into carboalkoxy-substituted
phosphonbisamidates (Scheme 34), phosphonamidates (Scheme 35),
phosphonate monoesters (Scheme 36) and phosphonate diesters,
(Scheme 37). Scheme 38 illustrates synthesis of gem-dialkyl amino
phosphonate reagents.
[0640] Scheme 34 illustrates various methods for the conversion of
phosphonate diesters S34.1 into phosphonbisamidates S34.5. The
diester S34.1, prepared as described previously, is hydrolyzed,
either to the monoester S34.2 or to the phosphonic acid S34.6. The
methods employed for these transformations are described above. The
monoester S34.2 is converted into the monoamidate S34.3 by reaction
with an aminoester S34.9, in which the group R.sup.2 is H or alkyl;
the group R.sup.4b is a divalent alkylene moiety such as, for
example, CHCH.sub.3, CHCH.sub.2CH.sub.3, CH(CH(CH.sub.3).sub.2),
CH(CH.sub.2Ph), and the like, or a side chain group present in
natural or modified aminoacids; and the group R.sup.5b is
C.sub.1-C.sub.12 alkyl, such as methyl, ethyl, propyl, isopropyl,
or isobutyl; C.sub.6-C.sub.20 aryl, such as phenyl or substituted
phenyl; or C.sub.6-C.sub.20 arylalkyl, such as benzyl or
benzyhydryl. The reactants are combined in the presence of a
coupling agent such as a carbodiimide, for example dicyclohexyl
carbodiimide, as described in J. Am. Chem. Soc., (1957) 79:3575,
optionally in the presence of an activating agent such as
hydroxybenztriazole, to yield the amidate product S34.3. The
amidate-forming reaction is also effected in the presence of
coupling agents such as BOP, as described in J. Org. Chem. (1995)
60:5214, Aldrithiol, PYBOP and similar coupling agents used for the
preparation of amides and esters. Alternatively, the reactants
S34.2 and S34.9 are transformed into the monoamidate S34.3 by means
of a Mitsunobu reaction. The preparation of amidates by means of
the Mitsunobu reaction is described in J. Med. Chem. (1995)
38:2742. Equimolar amounts of the reactants are combined in an
inert solvent such as tetrahydrofuran in the presence of a triaryl
phosphine and a dialkyl azodicarboxylate. The thus-obtained
monoamidate ester S34.3 is then transformed into amidate phosphonic
acid S34.4. The conditions used for the hydrolysis reaction depend
on the nature of the R.sup.1 group, as described previously. The
phosphonic acid amidate S34.4 is then reacted with an aminoester
S34.9, as described above, to yield the bisamidate product S34.5,
in which the amino substituents are the same or different.
Alternatively, the phosphonic acid S34.6 may be treated with two
different amino ester reagents simulataneously, i.e. S34.9 where
R.sup.2, R.sup.4b or R.sup.5b are different. The resulting mixture
of bisamidate products S34.5 may then be separable, e.g., by
chromatography.
##STR00133##
[0641] An example of this procedure is shown in Scheme 34, Example
1. In this procedure, a dibenzyl phosphonate S34.14 is reacted with
diazabicyclooctane (DABCO) in toluene at reflux, as described in J.
Org. Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate
S34.15. The product is then reacted with equimolar amounts of ethyl
alaninate S34.16 and dicyclohexyl carbodiimide in pyridine, to
yield the amidate product S34.17. The benzyl group is then removed,
for example by hydrogenolysis over a palladium catalyst, to give
the monoacid product S34.18 which may be unstable according to J.
Med. Chem. (1997) 40(23):3842. This compound S34.18 is then reacted
in a Mitsunobu reaction with ethyl leucinate S34.19, triphenyl
phosphine and diethylazodicarboxylate, as described in J. Med.
Chem., 1995, 38, 2742, to produce the bisamidate product
S34.20.
[0642] Using the above procedures, but employing in place of ethyl
leucinate S34.19 or ethyl alaninate S34.16, different aminoesters
S34.9, the corresponding products S34.5 are obtained.
[0643] Alternatively, the phosphonic acid S34.6 is converted into
the bisamidate S34.5 by use of the coupling reactions described
above. The reaction is performed in one step, in which case the
nitrogen-related substituents present in the product S34.5 are the
same, or in two steps, in which case the nitrogen-related
substituents can be different.
[0644] An example of the method is shown in Scheme 34, Example 2.
In this procedure, a phosphonic acid S34.6 is reacted in pyridine
solution with excess ethyl phenylalaninate S34.21 and
dicyclohexylcarbodiimide, for example as described in J. Chem.
Soc., Chem. Comm., 1991, 1063, to give the bisamidate product
S34.22.
[0645] Using the above procedures, but employing, in place of ethyl
phenylalaninate, different aminoesters S34.9, the corresponding
products S34.5 are obtained.
[0646] As a further alternative, the phosphonic acid S34.6 is
converted into the mono or bis-activated derivative S34.7, in which
Lv is a leaving group such as chloro, imidazolyl,
triisopropylbenzenesulfonyloxy etc. The conversion of phosphonic
acids into chlorides S34.7 (Lv=Cl) is effected by reaction with
thionyl chloride or oxalyl chloride and the like, as described in
Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds,
Wiley, 1976, p. 17. The conversion of phosphonic acids into
monoimidazolides S34.7 (Lv=imidazolyl) is described in J. Med.
Chem., 2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.
Alternatively, the phosphonic acid is activated by reaction with
triisopropylbenzenesulfonyl chloride, as described in Nucleosides
and Nucleotides, 2000, 10, 1885. The activated product is then
reacted with the aminoester S34.9, in the presence of a base, to
give the bisamidate S34.5. The reaction is performed in one step,
in which case the nitrogen substituents present in the product
S34.5 are the same, or in two steps, via the intermediate S34.11,
in which case the nitrogen substituents can be different.
[0647] Examples of these methods are shown in Scheme 34, Examples 3
and 5. In the procedure illustrated in Scheme 34, Example 3, a
phosphonic acid S34.6 is reacted with ten molar equivalents of
thionyl chloride, as described in Zh. Obschei Khim., 1958, 28,
1063, to give the dichloro compound S34.23. The product is then
reacted at reflux temperature in a polar aprotic solvent such as
acetonitrile, and in the presence of a base such as triethylamine,
with butyl serinate S34.24 to afford the bisamidate product
S34.25.
[0648] Using the above procedures, but employing, in place of butyl
serinate S34.24, different aminoesters S34.9, the corresponding
products S34.5 are obtained.
[0649] In the procedure illustrated in Scheme 34, Example 5, the
phosphonic acid S34.6 is reacted, as described in J. Chem. Soc.
Chem. Comm., 1991, 312, with carbonyl diimidazole to give the
imidazolide S34.32. The product is then reacted in acetonitrile
solution at ambient temperature, with one molar equivalent of ethyl
alaninate S34.33 to yield the monodisplacement product S34.34. The
latter compound is then reacted with carbonyl diimidazole to
produce the activated intermediate S34.35, and the product is then
reacted, under the same conditions, with ethyl N-methylalaninate
S34.33a to give the bisamidate product S34.36.
[0650] Using the above procedures, but employing, in place of ethyl
alaninate S34.33 or ethyl N-methylalaninate S34.33a, different
aminoesters S34.9, the corresponding products S34.5 are
obtained.
[0651] The intermediate monoamidate S34.3 is also prepared from the
monoester S34.2 by first converting the monoester into the
activated derivative S34.8 in which Lv is a leaving group such as
halo, imidazolyl etc, using the procedures described above. The
product S34.8 is then reacted with an aminoester S34.9 in the
presence of a base such as pyridine, to give an intermediate
monoamidate product S34.3. The latter compound is then converted,
by removal of the R.sup.1 group and coupling of the product with
the aminoester S34.9, as described above, into the bisamidate
S34.5.
[0652] An example of this procedure, in which the phosphonic acid
is activated by conversion to the chloro derivative S34.26, is
shown in Scheme 34, Example 4. In this procedure, the phosphonic
monobenzyl ester S34.15 is reacted, in dichloromethane, with
thionyl chloride, as described in Tet. Letters., 1994, 35, 4097, to
afford the phosphoryl chloride S34.26. The product is then reacted
in acetonitrile solution at ambient temperature with one molar
equivalent of ethyl 3-amino-2-methylpropionate S34.27 to yield the
monoamidate product S34.28. The latter compound is hydrogenated in
ethylacetate over a 5% palladium on carbon catalyst to produce the
monoacid product S34.29. The product is subjected to a Mitsunobu
coupling procedure, with equimolar amounts of butyl alaninate
S34.30, triphenyl phosphine, diethylazodicarboxylate and
triethylamine in tetrahydrofuran, to give the bisamidate product
S34.31.
[0653] Using the above procedures, but employing, in place of ethyl
3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30,
different aminoesters S34.9, the corresponding products S34.5 are
obtained.
[0654] The activated phosphonic acid derivative S34.7 is also
converted into the bisamidate S34.5 via the diamino compound
S34.10. The conversion of activated phosphonic acid derivatives
such as phosphoryl chlorides into the corresponding amino analogs
S34.10, by reaction with ammonia, is described in Organic
Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976.
The bisamino compound S34.10 is then reacted at elevated
temperature with a haloester S34.12 (Hal=halogen, i.e. F, Cl, Br,
I), in a polar organic solvent such as dimethylformamide, in the
presence of a base such as 4,4-dimethylaminopyridine (DMAP) or
potassium carbonate, to yield the bisamidate S34.5. Alternatively,
S34.6 may be treated with two different amino ester reagents
simulataneously, i.e. S34.12 where R.sup.4b or R.sup.5b are
different. The resulting mixture of bisamidate products S34.5 may
then be separable, e.g., by chromatography.
[0655] An example of this procedure is shown in Scheme 34, Example
6. In this method, a dichlorophosphonate S34.23 is reacted with
ammonia to afford the diamide S34.37. The reaction is performed in
aqueous, aqueous alcoholic or alcoholic solution, at reflux
temperature. The resulting diamino compound is then reacted with
two molar equivalents of ethyl 2-bromo-3-methylbutyrate S34.38, in
a polar organic solvent such as N-methylpyrrolidinone at ca.
150.degree. C., in the presence of a base such as potassium
carbonate, and optionally in the presence of a catalytic amount of
potassium iodide, to afford the bisamidate product S34.39.
[0656] Using the above procedures, but employing, in place of ethyl
2-bromo-3-methylbutyrate S34.38, different haloesters S34.12 the
corresponding products S34.5 are obtained.
[0657] The procedures shown in Scheme 34 are also applicable to the
preparation of bisamidates in which the aminoester moiety
incorporates different functional groups. Scheme 34, Example 7
illustrates the preparation of bisamidates derived from tyrosine.
In this procedure, the monoimidazolide S34.32 is reacted with
propyl tyrosinate S34.40, as described in Example 5, to yield the
monoamidate S34.41. The product is reacted with carbonyl
diimidazole to give the imidazolide S34.42, and this material is
reacted with a further molar equivalent of propyl tyrosinate to
produce the bisamidate product S34.43.
[0658] Using the above procedures, but employing, in place of
propyl tyrosinate S34.40, different aminoesters S34.9, the
corresponding products S34.5 are obtained. The aminoesters employed
in the two stages of the above procedure can be the same or
different, so that bisamidates with the same or different amino
substituents are prepared.
[0659] Scheme 35 illustrates methods for the preparation of
phosphonate monoamidates.
[0660] In one procedure, a phosphonate monoester S34.1 is
converted, as described in Scheme 34, into the activated derivative
S34.8. This compound is then reacted, as described above, with an
aminoester S34.9, in the presence of a base, to afford the
monoamidate product S35.1.
[0661] The procedure is illustrated in Scheme 35, Example 1. In
this method, a monophenyl phosphonate S35.7 is reacted with, for
example, thionyl chloride, as described in J. Gen. Chem. USSR.,
1983, 32, 367, to give the chloro product S35.8. The product is
then reacted, as described in Scheme 34, with ethyl alaninate, to
yield the amidate S35.10.
[0662] Using the above procedures, but employing, in place of ethyl
alaninate S35.9, different aminoesters S34.9, the corresponding
products S35.1 are obtained.
[0663] Alternatively, the phosphonate monoester S34.1 is coupled,
as described in Scheme 34, with an aminoester S34.9 to produce the
amidate S35.1. If necessary, the R.sup.1 substituent is then
altered, by initial cleavage to afford the phosphonic acid S35.2.
The procedures for this transformation depend on the nature of the
R.sup.1 group, and are described above. The phosphonic acid is then
transformed into the ester amidate product S35.3, by reaction with
the hydroxy compound R.sup.3OH, in which the group R.sup.3 is aryl,
heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the same
coupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobu
reaction etc) described in Scheme 34 for the coupling of amines and
phosphonic acids.
##STR00134##
##STR00135##
##STR00136##
##STR00137##
##STR00138##
##STR00139##
##STR00140##
[0664] Examples of this method are shown in Scheme 35, Examples
1-3. In the sequence shown in Example 2, a monobenzyl phosphonate
S35.11 is transformed by reaction with ethyl alaninate, using one
of the methods described above, into the monoamidate S35.12. The
benzyl group is then removed by catalytic hydrogenation in
ethylacetate solution over a 5% palladium on carbon catalyst, to
afford the phosphonic acid amidate S35.13. The product is then
reacted in dichloromethane solution at ambient temperature with
equimolar amounts of 1-(dimethylaminopropyl)-3-ethylcarbodiimide
and trifluoroethanol S35.14, for example as described in Tet.
Lett., 2001, 42, 8841, to yield the amidate ester S35.15.
[0665] In the sequence shown in Scheme 35, Example 3, the
monoamidate S35.13 is coupled, in tetrahydrofuran solution at
ambient temperature, with equimolar amounts of dicyclohexyl
carbodiimide and 4-hydroxy-N-methylpiperidine S35.16, to produce
the amidate ester product S35.17.
[0666] Using the above procedures, but employing, in place of the
ethyl alaninate product S35.12 different monoacids S35.2, and in
place of trifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine
S35.16, different hydroxy compounds R.sup.3OH, the corresponding
products S35.3 are obtained.
[0667] Alternatively, the activated phosphonate ester S34.8 is
reacted with ammonia to yield the amidate S35.4. The product is
then reacted, as described in Scheme 34, with a haloester S35.5, in
the presence of a base, to produce the amidate product S35.6. If
appropriate, the nature of the R.sup.1 group is changed, using the
procedures described above, to give the product S35.3. The method
is illustrated in Scheme 35, Example 4. In this sequence, the
monophenyl phosphoryl chloride S35.18 is reacted, as described in
Scheme 34, with ammonia, to yield the amino product S35.19. This
material is then reacted in N-methylpyrrolidinone solution at
170.degree. with butyl 2-bromo-3-phenylpropionate S35.20 and
potassium carbonate, to afford the amidate product S35.21.
[0668] Using these procedures, but employing, in place of butyl
2-bromo-3-phenylpropionate S35.20, different haloesters S35.5, the
corresponding products S35.6 are obtained.
[0669] The monoamidate products S35.3 are also prepared from the
doubly activated phosphonate derivatives S34.7. In this procedure,
examples of which are described in Synlett., 1998, 1, 73, the
intermediate S34.7 is reacted with a limited amount of the
aminoester S34.9 to give the mono-displacement product S34.11. The
latter compound is then reacted with the hydroxy compound R.sup.3OH
in a polar organic solvent such as dimethylformamide, in the
presence of a base such as diisopropylethylamine, to yield the
monoamidate ester S35.3.
[0670] The method is illustrated in Scheme 35, Example 5. In this
method, the phosphoryl dichloride S35.22 is reacted in
dichloromethane solution with one molar equivalent of ethyl
N-methyl tyrosinate S35.23 and dimethylaminopyridine, to generate
the monoamidate S35.24. The product is then reacted with phenol
S35.25 in dimethylformamide containing potassium carbonate, to
yield the ester amidate product S35.26.
[0671] Using these procedures, but employing, in place of ethyl
N-methyl tyrosinate S35.23 or phenol S35.25, the aminoesters S34.9
and/or the hydroxy compounds R.sup.3OH, the corresponding products
S35.3 are obtained.
##STR00141##
##STR00142##
##STR00143##
##STR00144##
##STR00145##
##STR00146##
[0672] Scheme 36 illustrates methods for the preparation of
carboalkoxy-substituted phosphonate diesters in which one of the
ester groups incorporates a carboalkoxy substituent.
[0673] In one procedure, a phosphonate monoester S34.1, prepared as
described above, is coupled, using one of the methods described
above, with a hydroxyester S36.1, in which the groups R.sup.4b and
R.sup.5b are as described in Scheme 34. For example, equimolar
amounts of the reactants are coupled in the presence of a
carbodiimide such as dicyclohexyl carbodiimide, as described in
Aust. J. Chem., 1963, 609, optionally in the presence of
dimethylaminopyridine, as described in Tet., 1999, 55, 12997. The
reaction is conducted in an inert solvent at ambient
temperature.
[0674] The procedure is illustrated in Scheme 36, Example 1. In
this method, a monophenyl phosphonate S36.9 is coupled, in
dichloromethane solution in the presence of dicyclohexyl
carbodiimide, with ethyl 3-hydroxy-2-methylpropionate S36.10 to
yield the phosphonate mixed diester S36.11.
[0675] Using this procedure, but employing, in place of ethyl
3-hydroxy-2-methylpropionate S36.10, different hydroxyesters S33.1,
the corresponding products S33.2 are obtained.
[0676] The conversion of a phosphonate monoester S34.1 into a mixed
diester S36.2 is also accomplished by means of a Mitsunobu coupling
reaction with the hydroxyester S36.1, as described in Org. Lett.,
2001, 643. In this method, the reactants S34.1 and S36.1 are
combined in a polar solvent such as tetrahydrofuran, in the
presence of a triarylphosphine and a dialkyl azodicarboxylate, to
give the mixed diester S36.2. The R.sup.1 substituent is varied by
cleavage, using the methods described previously, to afford the
monoacid product S36.3. The product is then coupled, for example
using methods described above, with the hydroxy compound R.sup.3OH,
to give the diester product S36.4.
[0677] The procedure is illustrated in Scheme 36, Example 2. In
this method, a monoallyl phosphonate S36.12 is coupled in
tetrahydrofuran solution, in the presence of triphenylphosphine and
diethylazodicarboxylate, with ethyl lactate S36.13 to give the
mixed diester S36.14. The product is reacted with
tris(triphenylphosphine) rhodium chloride (Wilkinson catalyst) in
acetonitrile, as described previously, to remove the allyl group
and produce the monoacid product S36.15. The latter compound is
then coupled, in pyridine solution at ambient temperature, in the
presence of dicyclohexyl carbodiimide, with one molar equivalent of
3-hydroxypyridine S36.16 to yield the mixed diester S36.17.
[0678] Using the above procedures, but employing, in place of the
ethyl lactate S36.13 or 3-hydroxypyridine, a different hydroxyester
S36.1 and/or a different hydroxy compound R.sup.3OH, the
corresponding products S36.4 are obtained.
[0679] The mixed diesters S36.2 are also obtained from the
monoesters S34.1 via the intermediacy of the activated monoesters
S36.5. In this procedure, the monoester S34.1 is converted into the
activated compound S36.5 by reaction with, for example, phosphorus
pentachloride, as described in J. Org. Chem., 2001, 66, 329, or
with thionyl chloride or oxalyl chloride (Lv=Cl), or with
triisopropylbenzenesulfonyl chloride in pyridine, as described in
Nucleosides and Nucleotides, 2000, 19, 1885, or with carbonyl
diimidazole, as described in J. Med. Chem., 2002, 45, 1284. The
resultant activated monoester is then reacted with the hydroxyester
S36.1, as described above, to yield the mixed diester S36.2.
[0680] The procedure is illustrated in Scheme 36, Example 3. In
this sequence, a monophenyl phosphonate S36.9 is reacted, in
acetonitrile solution at 70.degree. C., with ten equivalents of
thionyl chloride, so as to produce the phosphoryl chloride S36.19.
The product is then reacted with ethyl
4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containing
triethylamine, to give the mixed diester S36.21.
[0681] Using the above procedures, but employing, in place of ethyl
4-carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters
S36.1, the corresponding products S36.2 are obtained.
[0682] The mixed phosphonate diesters are also obtained by an
alternative route for incorporation of the R.sup.3O group into
intermediates S36.3 in which the hydroxyester moiety is already
incorporated. In this procedure, the monoacid intermediate S36.3 is
converted into the activated derivative S36.6 in which Lv is a
leaving group such as chloro, imidazole, and the like, as
previously described. The activated intermediate is then reacted
with the hydroxy compound R.sup.3OH, in the presence of a base, to
yield the mixed diester product S36.4.
[0683] The method is illustrated in Scheme 36, Example 4. In this
sequence, the phosphonate monoacid S36.22 is reacted with
trichloromethanesulfonyl chloride in tetrahydrofuran containing
collidine, as described in J. Med. Chem., 1995, 38, 4648, to
produce the trichloromethanesulfonyloxy product S36.23. This
compound is reacted with 3-(morpholinomethyl)phenol S36.24 in
dichloromethane containing triethylamine, to yield the mixed
diester product S36.25.
[0684] Using the above procedures, but employing, in place of with
3-(morpholinomethyl)phenol S36.24, different alcohols R.sup.3OH,
the corresponding products S36.4 are obtained.
[0685] The phosphonate esters S36.4 are also obtained by means of
alkylation reactions performed on the monoesters S34.1. The
reaction between the monoacid S34.1 and the haloester S36.7 is
performed in a polar solvent in the presence of a base such as
diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056,
or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or
in a non-polar solvent such as benzene, in the presence of
18-crown-6, as described in Syn. Comm., 1995, 25, 3565.
[0686] The method is illustrated in Scheme 36, Example 5. In this
procedure, the monoacid S36.26 is reacted with ethyl
2-bromo-3-phenylpropionate S36.27 and diisopropylethylamine in
dimethylformamide at 80.degree. C. to afford the mixed diester
product S36.28.
[0687] Using the above procedure, but employing, in place of ethyl
2-bromo-3-phenylpropionate S36.27, different haloesters S36.7, the
corresponding products S36.4 are obtained.
##STR00147##
##STR00148##
##STR00149##
##STR00150##
##STR00151##
##STR00152##
[0688] Scheme 37 illustrates methods for the preparation of
phosphonate diesters in which both the ester substituents
incorporate carboalkoxy groups.
[0689] The compounds are prepared directly or indirectly from the
phosphonic acids S34.6. In one alternative, the phosphonic acid is
coupled with the hydroxyester S37.2, using the conditions described
previously in Schemes 34-36, such as coupling reactions using
dicyclohexyl carbodiimide or similar reagents, or under the
conditions of the Mitsunobu reaction, to afford the diester product
S37.3 in which the ester substituents are identical.
[0690] This method is illustrated in Scheme 37, Example 1. In this
procedure, the phosphonic acid S34.6 is reacted with three molar
equivalents of butyl lactate S37.5 in the presence of Aldrithiol-2
and triphenyl phosphine in pyridine at ca. 70.degree. C., to afford
the diester S37.6.
[0691] Using the above procedure, but employing, in place of butyl
lactate S37.5, different hydroxyesters S37.2, the corresponding
products S37.3 are obtained.
[0692] Alternatively, the diesters S37.3 are obtained by alkylation
of the phosphonic acid S34.6 with a haloester S37.1. The alkylation
reaction is performed as described in Scheme 36 for the preparation
of the esters S36.4.
[0693] This method is illustrated in Scheme 37, Example 2. In this
procedure, the phosphonic acid S34.6 is reacted with excess ethyl
3-bromo-2-methylpropionate S37.7 and diisopropylethylamine in
dimethylformamide at ca. 80.degree. C., as described in Anal.
Chem., 1987, 59, 1056, to produce the diester S37.8.
[0694] Using the above procedure, but employing, in place of ethyl
3-bromo-2-methylpropionate S37.7, different haloesters S37.1, the
corresponding products S37.3 are obtained.
[0695] The diesters S37.3 are also obtained by displacement
reactions of activated derivatives S34.7 of the phosphonic acid
with the hydroxyesters S37.2. The displacement reaction is
performed in a polar solvent in the presence of a suitable base, as
described in Scheme 36. The displacement reaction is performed in
the presence of an excess of the hydroxyester, to afford the
diester product S37.3 in which the ester substituents are
identical, or sequentially with limited amounts of different
hydroxyesters, to prepare diesters S37.3 in which the ester
substituents are different.
[0696] The methods are illustrated in Scheme 37, Examples 3 and 4.
As shown in Example 3, the phosphoryl dichloride S35.22 is reacted
with three molar equivalents of ethyl
3-hydroxy-2-(hydroxymethyl)propionate S37.9 in tetrahydrofuran
containing potassium carbonate, to obtain the diester product
S37.10.
[0697] Using the above procedure, but employing, in place of ethyl
3-hydroxy-2-(hydroxymethyl)propionate S37.9, different
hydroxyesters S37.2, the corresponding products S37.3 are
obtained.
[0698] Scheme 37, Example 4 depicts the displacement reaction
between equimolar amounts of the phosphoryl dichloride S35.22 and
ethyl 2-methyl-3-hydroxypropionate S37.11, to yield the monoester
product S37.12. The reaction is conducted in acetonitrile at
70.degree. in the presence of diisopropylethylamine. The product
S37.12 is then reacted, under the same conditions, with one molar
equivalent of ethyl lactate S37.13, to give the diester product
S37.14.
[0699] Using the above procedures, but employing, in place of ethyl
2-methyl-3-hydroxypropionate S37.11 and ethyl lactate S37.13,
sequential reactions with different hydroxyesters S37.2, the
corresponding products S37.3 are obtained.
##STR00153##
##STR00154##
##STR00155##
##STR00156##
##STR00157##
[0700] 2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can
be prepared by the route in Scheme 5. Condensation of
2-methyl-2-propanesulfinamide with acetone give sulfinyl imine
S38.11 (J. Org. Chem. 1999, 64, 12). Addition of dimethyl
methylphosphonate lithium to S38.11 afford S38.12. Acidic
methanolysis of S38.12 provide amine S38.13. Protection of amine
with Cbz group and removal of methyl groups yield phosphonic acid
S38.14, which can be converted to desired S38.15 (Scheme 38a) using
methods reported earlier on. An alternative synthesis of compound
S38.14 is also shown in Scheme 38b. Commercially available
2-amino-2-methyl-1-propanol is converted to aziridines S38.16
according to literature methods (J. Org. Chem. 1992, 57, 5813; Syn.
Lett. 1997, 8, 893). Aziridine opening with phosphite give S38.17
(Tetrahedron Lett. 1980, 21, 1623). Reprotection) of S38.17 affords
S38.14.
##STR00158##
##STR00159##
[0701] The invention will now be illustrated by the following
non-limiting Examples.
Example 1
Synthesis of Representative Compounds of Formulae 1-3
[0702] Generally, compounds of the invention can be made as
illustrated below:
##STR00160## ##STR00161##
Phosphonate Interconversions
[0703] Phosphonate interconversions of representative compounds of
the invention can be prepared as discussed hereinbelow. The final
compounds, described above as 1.1, 1.2 and 1.3, are synthesized
according to the methods described herein. The intermediate
phosphonate esters, shown as 1.4, 1.5 and 1.6, can be used to
prepare the final compounds by one skilled in the art using known
methods for synthesis of substituted phosphonates. These methods
are similar to those described for the synthesis of amides. The
preparation of amides from carboxylic acids and derivatives is
described, for example, in "Organic Functional Group Preparations,"
by S. R. Sandier and W. Karo, Academic Press, 1968, p. 274. Further
methods are described below for the synthesis of the phosphonate
diesters and can, in some cases, be applied to the synthesis of
phosphor-amides.
[0704] The conversion of various substituents into the group
link-P(O)(OR.sup.1).sub.2, where R.sup.1 is defined above as 1.4,
1.5 and 1.6, or indeed the final stage of P(O)RR.sup.o, as defined
above, can be effected at any convenient stage of the synthetic
sequence, or in the final step. The selection of an appropriate
step for the introduction of the phosphonate substituent is made
after consideration of the chemical procedures required, and the
stability of the substrates to those procedures. It may be
necessary to protect reactive groups, for example hydroxyl, amino,
during the introduction of the group link-P(O)(OR.sup.1).sub.2 or
P(O)RR.sup.o.
[0705] In the succeeding examples, the nature of the phosphonate
ester group P(O)(OR.sup.1).sub.2 can be varied, either before or
after incorporation into the scaffold, by means of chemical
transformations. The transformations, and the methods by which they
are accomplished, are described below.
Protection of Reactive Substituents.
[0706] Depending on the reaction conditions employed, it may be
necessary to protect certain reactive substituents from unwanted
reactions by protection before the sequence described, and to
deprotect the substituents afterwards, according to the knowledge
of one skilled in the art. Protection and deprotection of
functional groups are described, for example, in "Protective Groups
in Organic Synthesis," by T. W. Greene and P. G. M Wuts, Wiley,
Third Edition 1996. Reactive substituents that may be protected are
shown in the accompanying schemes as, for example, [OH], [SH],
etc.
General Applicability of Methods for Introduction of Phosphonate
Substituents.
[0707] The procedures described herein for the introduction of
phosphonate moieties are, with appropriate modifications known to
one skilled in the art, transferable to different chemical
substrates. Thus, the methods described herein below for the
introduction of phosphonate groups onto compounds of the invention
are also applicable to the introduction of phosphonate moieties
onto anilines of the invention and the reverse is also true.
Example 2
Synthesis of Representative Compounds of Formulae 1-3
[0708] Intermediate phosphonates of representative compounds of the
invention can be made as described herein. For example, the
synthesis of target molecules such as 1.4 (Example 1), in which the
link is a heteroatom and carbon chain can be illustrated as
follows:
##STR00162##
[0709] The preparation of 2.1 is described in U.S. Pat. No.
5,770,596. Diether 2.1 is converted into mono ether 2.2 as
described in "Protective Groups in Organic Synthesis," by T. W.
Greene and P. G. M Wuts, Wiley, 3rd Edition, 1999, p. 246, or by
the method described in U.S. Pat. No. 5,770,596. In one embodiment,
diether 2.1 in methanesulfonic acid is treated with L-methionine at
reflux to give the phenol 2.2. Phenol 2.2 is then protected as the
acetyl compound 2.3 and then converted to the chloride 2.4. These
procedures are described in U.S. Pat. No. 5,770,596. The acetoxy
compound is then treated with the aniline 2.4a to give the amine
2.5 followed by deprotection of the acetyl group to give 2.6 as
described in U.S. Pat. No. 5,770,596. Treatment of 2.6 with
epibromohydrin 2.7 (Aldrich) in DMF with potassium carbonate
present then affords the epoxide 2.8. Treatment of epoxide 2.8 with
morpholine in a non-protic solvent as reflux in the presence of a
base such as triethylamine affords the alcohol 2.9. The alcohol 2.9
is treated with one equivalent of the phosphonate alkylating agent,
in which Lv is a group such as mesyl, trifluoromethanesulfonyl, Br,
I, Cl, tosyl, etc., in the presence of base e.g., potassium or
cesium carbonate in DMF, to give the ether 2.13 in which the link
is an oxygen and carbon chain. Alternatively, the alcohol 2.9 is
oxidized to the ketone 2.11, as described in "Comprehensive Organic
Transformations," by R. C. Larock, 2.sup.nd Edition, 1999, p.
1234ff. Preferably, the alcohol 2.9 is treated with Dess-martin
periodinone to give the ketone 2.11. Ketone 2.11 is then reacted
with an amino alkyl phosphonate 2.12 under reductive amination
conditions to give the phosphonate 2.14 in which the link is a
nitrogen and carbon chain. The preparation of amines by means of
reductive amination procedures is described, for example, in
"Comprehensive Organic Transformations," by R. C. Larock, 2.sup.nd
edition, p. 835. In this procedure, the amine component and the
aldehyde component are reacted together in the presence of a
reducing agent such as, for example, borane, sodium
cyanoborohydride or diisobutylaluminum hydride, to yield the amine
product.
[0710] Specific compounds of the invention can be prepared as
follows.
##STR00163##
[0711] The alcohol 2.9 is treated with triflate 2.17, prepared as
described in Tet. Lett., 27:1497 (1986), and potassium carbonate in
DMF, to give the ether 2.15. Alternatively, for example, the ketone
2.11 is treated with amine 2.18 (Acros) in methanol. After a period
of time, sodium borohydride is added to give the amine 2.16. Using
the above procedures, but employing in place of the triflate 2.17
or the amine 2.18, additional compounds of the invention are
obtained.
Example 3
Synthesis of Representative Compounds of Formulae 1-3
[0712] Representative compounds of the invention can be prepared as
follows:
##STR00164## ##STR00165##
[0713] The reactions shown above illustrate the preparation of the
compounds 3.9 of the invention in which the phosphonate is linked
through a carbon chain and a heteroatom.
[0714] Phenol 3.6 (See also phenol 2.6 in Example 2) is treated
with dibromide 3.1 using the conditions described in Example 2 for
the preparation of 2.8 from 2.6, to give bromide 3.2. Bromide 3.2
is then treated with the dialkyl hydroxy, thio or amino-substituted
alkylphosphonate 3.3 to give the product 3.9. The reaction is
performed in the presence of a base, in a polar aprotic solvent
such as dioxan or N-methylpyrrolidinone. The base employed in the
reaction depends on the nature of the reactant 3.3. For example, if
X is O, a strong base such as, for example, lithium
hexamethyldisilylazide or potassium tert. butoxide is employed. If
X is S, NH or N-alkyl, an inorganic base such as cesium carbonate
and the like is employed.
[0715] A specific compound of the invention can be prepared as
follows. 3.6 is treated with dibromoethane 3.4a to give the bromide
3.4. Bromide 3.4 is then treated with amine 3.5, prepared as
described in J. Org. Chem., 65:676 (2000), in DMF and potassium
carbonate at about 80.degree. C. to give the phosphonate 3.7.
[0716] Alternatively, bromide 3.4 is then heated at reflux with an
equimolar amount of a dialkyl 2-mercaptoethylphosphonate 3.7, the
preparation of which is described in Aust. J. Chem., 43:1123
(1990), in the presence of sodium carbonate, to afford the
thioether product 3.8.
[0717] Using the above procedures, but employing, in place of the
dibromoethane 3.4a, different dibromo compounds 3.1 and/or
different alkyl phosphonates 3.3 in place of 3.5 or 3.7 the
corresponding products 3.8 are obtained.
Example 4
Synthesis of Representative Compounds of Formulae 1-3
##STR00166##
[0719] The synthesis of target molecules 1.6 (see Example 1), in
which A is Br, Cl, [OH], [NH], or the group
link-P(O)(OR.sup.1).sub.2 is illustrated above. The preparation of
4.4 is described in Example 2. Treatment of chloride 4.4 with amine
4.1 in reluxing isopropanol gives amine 4.2. The preparation of 4.1
in which A is group link-P(O)(OR.sup.1).sub.2 is described below.
Treatment of amine 4.2 according to conditions described in U.S.
Pat. No. 5,770,599 then affords the final product 4.3.
Example 5
Synthesis of Representative Compounds of Formulae 1-3
##STR00167##
[0721] The preparation of the compounds 5.3 in which the
substituent A is either the group link-P(O)(OR.sup.1).sub.2 or a
precursor such as [OH], [SH], [NH], Br, etc., is shown. The
conversion of the compounds 5.3 in which A is [OH], [SH], [NH], Br,
etc., into the phosphonate esters 5.4 is illustrated. In this
procedure, the compounds 5.3 are converted, using the procedures
described herein into the compounds 5.4.
Example 6
Synthesis of Representative Compounds of Formulae 1-3
[0722] The preparation of phosphonate-containing derivatives which
are employed in the preparation of the phosphonate ester
intermediates of the invention is described herein.
##STR00168## ##STR00169##
[0723] The preparation of representative compounds of the invention
in which the phosphonate is attached through a heteroatom, e.g., O,
S, or N, and a carbon linker is illustrated. In this procedure an
optionally protected aniline is reacted with an alkylphosphonate
6.2 in which Lv is a leaving group such as triflate, Br, Cl, Mesyl,
etc., in the presence of a suitable base. The base required for
this transformation depends on the nature of the heteroatom X. For
example, if X is N or S, an excess of an inorganic base such as,
for example, potassium carbonate, in the presence of an organic
solvent such as dimethylformamide, is suitable. The reaction
proceeds at from ambient temperature to about 80.degree. to afford
the displacement products 6.3. If X is O, an equimolar amount of a
strong base, such as, for example, lithium hexamethyldisilylazide
and the like, is employed in the presence of a solvent such as
tetrahydrofuran. Deprotection of the amine group, as described in
"Protective Groups in Organic Synthesis," by T. W. Greene and P. G.
M Wuts, Wiley, Third Edition 1999 ch 7. affords the amine 6.4.
[0724] A specific compound of the invention can be prepared as
follows. The diamine 6.5 (Aldrich), protected as the CBZ carbamate
(see "Protective Groups in Organic Synthesis," by T. W. Greene and
P. G. M Wuts, Wiley, Third Edition 1999, p 531 ff) is treated with
an equimolar amount of triflate 6.6, the preparation of which is
described in Tet. Lett., 27:1497 (1986) in dimethylformamide
containing excess potassium carbonate, at about 60.degree. C. to
afford the phosphonate product 6.7. Deprotection by reduction over
palladium on carbon in the presence of hydrogen then affords the
amine 6.8.
[0725] Alternatively, the aminophenol 6.9, protected as the CBZ
carbamate as described above, is reacted with one equivalent of
triflate 6.6 to give phosphonate 6.10. Removal of the CBZ group by
catalytic reduction over palladium on carbon in the presence of
hydrogen, as described above, then affords the amine 6.11.
[0726] Using the above procedures, but employing, in place of the
aniline 6.5 or phenol 6.9, different anilines 6.1, and/or different
alkylphosphonates 6.2, in place of 6.6, the corresponding products
6.4 are obtained.
Example 7
Synthesis of Representative Compounds of Formulae 1-3
##STR00170##
[0728] The preparation of compounds of the invention in which the
phosphonate is attached through a unsaturated or saturated carbon
linker is illustrated. In this procedure, an optionally protected
halo-substituted aniline 7.0 is coupled, by means of a
palladium-catalyzed Heck reaction with a dialkyl alkenyl
phosphonate 7.1, to afford the coupled product 7.2. The coupling of
aryl halides with olefins by means of the Heck reaction is
described, for example, in "Advanced Organic Chemistry," by F. A.
Carey and R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem.
Res., 12:146 (1979). The aryl bromide and the olefin are coupled in
a polar solvent such as dimethylformamide or dioxane, in the
presence of a palladium(0) catalyst such as
tetrakis(triphenylphosphine)palladium(0) or a palladium(II)
catalyst such as palladium(II) acetate, and optionally in the
presence of a base such as triethylamine or potassium carbonate, to
afford the coupled product 7.2. Protection of anilines is described
in "Protective Groups in Organic Synthesis," by T. W. Greene and P.
G. M Wuts, Wiley, Third Edition 1999, ch 7. Preferably, the aniline
is treated with a BOC reagent such as BOC chloride or BOC anhydride
in the presence of DMAP and a base, e.g., triethylamine, to afford
the protected aniline. Optionally, the product 7.2 can be reduced
to afford the saturated phosphonate 7.3. Methods for the reduction
of carbon-carbon double bonds are described, for example, in
"Comprehensive Organic Transformations," by R. C. Larock, VCH,
1989, p. 6. The methods include catalytic reduction, and chemical
reduction, the latter for example employing diborane or
diimide.
[0729] For example, BOC protected 3-chloro-4-fluoro aniline 7.6
(Aldrich) is reacted with a dialkyl propenyl phosphonate 7.7, the
preparation of which is described in J. Med. Chem., 39:949 (1996);
in the presence of bis(triphenylphosphine) palladium(II) chloride,
as described in J. Med. Chem., 35:1371 (1992), to afford the
coupled product 7.8. The BOC protection of the aniline is performed
by treating the corresponding aniline with BOC anhydride in the
presence of DMAP. The product 7.8 is reduced, for example by
reaction with diimide, as described in J. Org. Chem., 30:3965
(1965), to afford the saturated product 7.9. Boc removal by
treatment of 7.8 and 7.9 with TFA in THF or dioxane affords the
products 7.10 and 7.11, respectively. Using the above procedures
but employing in place of the halo pyridine compound 7.6, different
pyridines 7.0 and/or different phosphonates 7.1, the corresponding
products 7.4 and 7.5 are obtained.
Example 8
Synthesis of Representative Compounds of Formulae 4-7
[0730] In general, the compounds of the invention described herein
can be synthesized as follows:
##STR00171## ##STR00172##
Phosphonate Interconversions
[0731] In general, phosphonate conversions of the representative
compounds of the invention, e.g., as illustrated above, can be as
follows: The intermediate phosphonate esters shown above (8.4, 8.5,
8.6) can be used to prepare the final compounds illustrated above
(8.1, 8.2, 8.3), by one skilled in the art, using known methods for
synthesis of substituted phosphonates. These methods are similar to
those described for the synthesis of amides. The preparation of
amides from carboxylic acids and derivatives is described, for
example, in "Organic Functional Group Preparations," by S. R.
Sandler and W. Karo, Academic Press, 1968, p. 274. Further methods
are described below for the synthesis of the phosphonate diesters
and can in some cases be applied to the synthesis of
phosphor-amides.
[0732] The conversion of various substituents into the group
link-P(O)(OR.sup.1).sub.2, where R.sup.1 is defined above, e.g.,
see 8.4, 8.5, 8.6, or indeed the final stage of P(O)RR.sup.o, as
defined above, can be effected at any convenient stage of the
synthetic sequence, or in the final step. The selection of an
appropriate step for the introduction of the phosphonate
substituent is made after consideration of the chemical procedures
required, and the stability of the substrates to those procedures.
It may be necessary to protect reactive groups, for example
hydroxyl, amino, during the introduction of the group
link-P(O)(OR.sup.1).sub.2 or P(O)RR.sup.o.
[0733] In the succeeding examples, the nature of the phosphonate
ester group P(O)(OR.sup.1).sub.2 can be varied, either before or
after incorporation into the scaffold, by means of chemical
transformations. The transformations, and the methods by which they
are accomplished, are described below.
Protection of Reactive Substituents.
[0734] Depending on the reaction conditions employed, it may be
necessary to protect certain reactive substituents from unwanted
reactions by protection before the sequence described, and to
deprotect the substituents afterwards, according to the knowledge
of one skilled in the art. Protection and deprotection of
functional groups are described, for example, in "Protective Groups
in Organic Synthesis," by T. W. Greene and P. G. M Wuts, Wiley,
Third Edition 1999. Reactive substituents which may be protected
are shown in the accompanying schemes as, for example, [OH], [SH],
etc.
Example 9
Preparation of Representative Compounds of Formulae 4-7
[0735] Representative compounds of the invention can be synthesized
as follows:
##STR00173##
[0736] The preparation of compounds of the invention in which A is
Br, I, [SH], [NH], etc., or the group link-P(O)(OR.sup.1).sub.2 is
illustrated above. Amine 9.1 is coupled with the acid 9.2 to give
the amide 9.3. The preparation of amides from carboxylic acids and
derivatives is described, for example, in "Organic Functional Group
Preparations," by S. R. Sandler and W. Karo, Academic Press, 1968,
p. 274. The carboxylic acid is reacted with the amine in the
presence of an activating agent, such as, for example,
dicyclohexylcarbodiimide or diisopropylcarbodiimide, optionally in
the presence of, for example, hydroxybenztriazole, in a non-protic
solvent such as, for example, pyridine, DMF or dichloromethane, to
afford the amide.
[0737] Alternatively, the carboxylic acid may first be converted
into an activated derivative, such as the acid chloride or
anhydride, and then reacted with the amine in the presence of an
organic base such as, for example, pyridine, to afford the
amide.
[0738] The conversion of a carboxylic acid into the corresponding
acid chloride is effected by treatment of the carboxylic acid with
a reagent such as, for example, thionyl chloride or oxalyl chloride
in an inert organic solvent such as dichloromethane. Preferably,
the acid 9.2 is treated with oxalyl chloride in an inert solvent
such as dichloromethane followed by the addition of a few drops of
DMF and then treated with the amine 9.1 to give the amide 9.3. The
acid, 9.2 is prepared according to the methods described
herein.
Example 10
Synthesis of Representative Compounds of Formulae 4-7
[0739] Preparations of representative compounds of the invention
can be made as follows:
##STR00174##
[0740] The reactions shown in Example 9 illustrate the preparation
of the compounds 10.3 in which the substituent A is either the
group link-P(O)(OR.sup.1).sub.2 or a precursor such as [OH], [SH],
[NH], Br, etc. The conversion of the compounds 10.3 in which A is
[OH], [SH], [NH], Br, etc., into the phosphonate esters 10.4 is
described herein. In this procedure, the compounds 10.3 are
converted, using the procedures described hereinbelow, into the
compounds 10.4.
Example 11
Synthesis of Representative Compounds of Formulae 4-7
[0741] Preparations of representative compounds of Formulae 4-7 can
be made as follows:
##STR00175##
[0742] The preparation of representative compounds of the invention
in which A is Br, I, [SH], [NH], etc., or the group
link-P(O)(OR.sup.1).sub.2 is illustrated. The amine 11.1 is treated
with acid 11.3 as described above to give the amide 11.2. The
preparation of acid 11.3 is described hereinbelow.
Example 12
Synthesis of Representative Compounds of Formulae 4-7
[0743] Preparations of representative compounds of the invention
can be made as follows:
##STR00176##
[0744] The reactions shown in Example 11 illustrate the preparation
of the compounds of the invention in which the substituent A is
either the group link-P(O)(OR.sup.1).sub.2 or a precursor such as
[OH], [SH], [NH], Br, etc. The conversion of the compounds 12.2 in
which A is [OH], [SH], [NH], Br, etc., into the phosphonate esters
12.3 is described herein. In this procedure, the compounds 12.2 are
converted, using the procedures described below, into the compounds
12.3.
Example 13
Synthesis of Representative Compounds of Formulae 4-7
[0745] Preparations of representative compounds of Formulae 4-7 can
be made as follows:
##STR00177##
[0746] The preparation of compounds of the invention in which A is
Br, I, [SH], [NH], etc., or the group link-P(O)(OR.sup.1).sub.2.
The amine 13.1 is treated with acid 13.2 as described above, to
give the amide 13.3. The preparation of acid 13.2 is described
below.
[0747] The reactions shown above illustrate the preparation of the
compounds 13.3 in which the substituent A is either the group
link-P(O)(OR.sup.1).sub.2 or a precursor such as [OH], [SH], [NH],
Br, etc. The conversion of the compounds 13.3 in which A is [OH],
[SH], [NH], Br, etc., into the phosphonate esters 13.4. In this
procedure, the compounds 13.3 are converted, using the procedures
described below is also shown above.
Example 14
Preparation of Representative Compounds of Formulae 4-7
[0748] The preparation of phosphonate-containing derivatives of
compounds of the invention in which A is Br, Cl, [OH], [NH], or the
group link-P(O)(OR.sup.1).sub.2 that are employed in the
preparation of the phosphonate ester intermediates of the invention
is illustrated below.
##STR00178##
[0749] Piperazine 14.1 is protected with a BOC group according to
methods described in "Protective Groups in Organic Synthesis," by
T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999 p. 518ff.
In one embodiment, piperazine is treated with 1 equivalent of BOC
anhydride in methanol or DMF and one equivalent of triethylamine to
give the BOC amine 14.2. Treatment of 14.2 with an alkylphosphonate
14.3 in which Lv is a leaving group such as triflate, Br, Cl,
Mesyl, etc., in the presence of a suitable base, affords the
product 14.4. The base required for this transformation is
typically an inorganic base such as, for example, potassium
carbonate, in the presence of an organic solvent such as
dimethylformamide. The reaction proceeds at from ambient
temperature to about 80.degree. to afford the displacement products
14.4. Deprotection, of the BOC-amine group as described in
"Protective Groups in Organic Synthesis," by T. W. Greene and P. G.
M Wuts, Wiley, Third Edition 1999 p 520ff, affords the amine 14.5.
The amine 14.5 is then reacted with the acid 14.6 (Aldrich) in the
presence of a base to give the product acid 14.7.
##STR00179##
[0750] For example, as illustrated above, 14.2 prepared from
piperazine as described above, is treated with bromophosphonate
14.8, prepared as described in Syn, 9:909 (1999), and potassium
carbonate in THF to give the amine 14.9. The BOC amine 14.9 is then
deprotected by treatment with trifluoroacetic acid in
dichloromethane to give the amine 14.10. The amine 14.10 is then
reacted with the bromomethyl benzoic acid 14.6 in THF or dioxane in
the presence of triethylamine, or aqueous potassium carbonate, to
give the acid 14.11. Using the above procedures, but employing, in
place of the bromo phosphonate compound 14.8, different
phosphonates 14.3, the corresponding products 14.7 are
obtained.
Example 15
Synthesis of Representative Compounds of Formulae 4-7
[0751] Preparations of representative compounds of the invention
can be made as follows:
##STR00180##
[0752] The preparation of acids of the compounds of the invention
in which the phosphonate is attached to the scaffold through a
heteroatom and carbon linker is shown below. The benzyl protected
ketone 15.1, prepared from the corresponding acid by treatment with
benzyl alcohol in the presence of DCC and DMAP in DMF, as described
in "Protective Groups in Organic Synthesis," by T. W. Greene and P.
G. M Wuts, Wiley, Third Edition 1999 p. 373ff., is treated with a
brominating agent to give the bromo ketone 15.2.
[0753] Protection of the ketone as the cyclic dioxalone as
described at p. 312ff in "Protective Groups in Organic Synthesis"
gives 15.3. Dioxalone 15.3 is then treated with the dialkyl
hydroxy, thio or amino-substituted alkylphosphonate 15.4 to give
the dioxalone 15.5. The reaction is performed in the presence of a
base, in a polar aprotic solvent such as dioxane or
N-methylpyrrolidinone. The base employed in the reaction depends on
the nature of the reactant 15.4. For example, if X is O, a strong
base such as, for example, lithium hexamethyldisilylazide or
potassium tert. butoxide is employed. If X is S, NH or N-alkyl, an
inorganic base such as cesium carbonate and the like is employed.
Deprotection of the dioxalone as described at p. 317ff of
"Protective Groups in Organic Synthesis," gives ketone 15.6. Ketone
17.6 is then treated under reductive amination conditions with
N-methyl piperazine to give the amine 15.7.
[0754] The preparation of amines by means of reductive amination
procedures is described, for example, in "Comprehensive Organic
Transformations," by R. C. Larock, 2.sup.nd edition, p. 835. In
this procedure, the amine component and the aldehyde component are
reacted together in the presence of a reducing agent such as, for
example, borane, sodium cyanoborohydride or diisobutylaluminum
hydride, to yield the amine product.
[0755] Deprotection of the ester group as described at p. 373ff of
"Protective Groups in Organic Synthesis" then affords the acid
15.8.
##STR00181##
[0756] For example, the preparation of a specific compound of the
invention is shown above. 4-acetyl benzoic acid is treated with
benzyl bromide in the presence of potassium carbonate in aqueous
THF to give the ester 15.1. Treatment of the ester 15.1 with
bromine in acetic acid, or NBS and AIBN in CCl.sub.4 affords the
bromide 15.2. Bromide 15.2 is then reacted with 1,2-ethane diol in
toluene at reflux under a dean stark head with a catalytic amount
of p-TsOH present to give the dioxalone 15.3. Dioxalone 15.3 is
reacted with dialkyl 2-aminoethyl phosphonate 15.9, prepared as
described in J. Org. Chem., 65:676 (2000), in dimethylformamide at
ca 80.degree., in the presence of potassium carbonate, to afford
the amine 15.10. Treatment of the dioxalone 15.10 with 1N
hydrochloric acid in THF then yields the ketone 15.11. Ketone 15.11
is reacted with N-methyl piperazine in the presence of
triethylamine followed 30 minutes later by the addition of sodium
cyanoborohydride to give the amine 15.12. Removal of the benzyl
ester by hydrolysis using sodium hydroxide in aqueous THF gives the
acid 15.13.
[0757] Using the above procedures, but employing, in place of the
amino phosphonate compound 15.9, different phosphonates 15.4, the
corresponding products 15.8 are obtained.
Example 16
Synthesis of Representative Compounds of Formulae 4-7
[0758] Preparations of representative compounds of the invention
can be made as follows:
##STR00182##
[0759] The preparation of an acid of the invention in which the
phosphonate is attached through a unsaturated or saturated carbon
linker, is shown above. In this procedure, the acid 14.6 (Aldrich)
is treated with N-methyl piperazine as described in Example 14 for
the preparation of 14.7, to give the acid 16.1. Acid 16.1 is then
brominated with bromine or NBS to give the bromide 16.2. Bromide
16.2 is optionally protected as the benzyl or t-butyl ester, as
described in "Protective Groups in Organic Synthesis," by T. W.
Greene and P. G. M Wuts, Wiley, Third Edition 1999 p 373ff to give
16.2a.
[0760] Ester 16.2a is then coupled, by means of a
palladium-catalyzed Heck reaction with a dialkyl alkenyl
phosphonate 16.3, to afford the coupled product 16.4. The coupling
of aryl halides with olefins by means of the Heck reaction is
described, for example, in "Advanced Organic Chemistry," by F. A.
Carey and R. J. Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem.
Res., 12:146 (1979). The aryl bromide and the olefin are coupled in
a polar solvent such as dimethylformamide or dioxane, in the
presence of a palladium(0) catalyst such as
tetrakis(triphenylphosphine)palladium(0) or a palladium(II)
catalyst such as palladium(II) acetate, and optionally in the
presence of a base such as triethylamine or potassium carbonate, to
afford the coupled product 16.4. Optionally, the product 16.4 can
be reduced to afford the saturated phosphonate 16.5. Methods for
the reduction of carbon-carbon double bonds are described, for
example, in "Comprehensive Organic Transformations," by R. C.
Larock, VCH, 1989, p. 6. The methods include catalytic reduction,
and chemical reduction, the latter for example employing diborane
or diimide.
[0761] For example, the preparation of a specific compound of the
invention is illustrated below.
##STR00183##
[0762] Amine 16.1 is then treated with NBS and AIBN in carbon
tetrachloromethane at reflux to give the bromide 16.8. Bromide 16.8
is then reacted in t-butanol with DCC and DMAP to give the t-butyl
ester 16.9. Ester 16.9 is then reacted with dialkyl propenyl
phosphonate 16.10, the preparation of which is described in J. Med.
Chem., 39:949 (1996), in the presence of bis(triphenylphosphine)
palladium(II) chloride, as described in J. Med. Chem., 35:1371
(1992), to afford the coupled product 16.11. This product 16.11 is
then treated with aqueous HCl in dioxane to give the acid 16.13.
Optionally, the alkene 16.11 can be reduced by reaction with
diimide, as described in J. Org. Chem., 30:3965 (1965), to afford
the saturated product 16.12. Hydrolysis of the ester as described
above through treatment with aqueous HCl in dioxane gives the acid
16.14.
[0763] Using the above procedures, but employing, in place of the
phosphonate compound 16.10, different phosphonates 16.3, the
corresponding products 16.6 and 16.7 are obtained.
Examples 17-26
Preparation of Representative Compounds of Formulae 8-11
##STR00184## ##STR00185##
[0765] Representative compounds of the invention, e.g., as shown
above, can be synthesized according to the following methods.
Phosphonate Interconversions
[0766] The final compounds described above are synthesized
according to the methods described herein. The intermediate
phosphonate esters are shown above (17.1, 17.2, 17.3 and 17.4) and
these compounds can be used to prepare the final compounds above
(17.1a, 17.2a, 17.3a and 17.4a), by one skilled in the art, using
known methods for synthesis of substituted phosphonates. These
methods are similar to those described for the synthesis of amides.
The preparation of amides from carboxylic acids and derivatives is
described, for example, in "Organic Functional Group Preparations,"
by S. R. Sandler and W. Karo, Academic Press, 1968, p. 274. Further
methods are described below for the synthesis of the phosphonate
diesters and can in some cases be applied to the synthesis of
phosphor-amides.
[0767] In the following schemes, the conversion of various
substituents into the group link-P(O)(OR.sup.1).sub.2, where
R.sup.1 is defined above, or indeed the final stage of
P(O)RR.sup.o, as defined above, can be effected at any convenient
stage of the synthetic sequence, or in the final step. The
selection of an appropriate step for the introduction of the
phosphonate substituent is made after consideration of the chemical
procedures required, and the stability of the substrates to those
procedures. It may be necessary to protect reactive groups, for
example hydroxyl, amino, during the introduction of the group
link-P(O)(OR.sup.1).sub.2 or P(O)RR.sup.o
[0768] In the succeeding examples, the nature of the phosphonate
ester group P(O)(OR.sup.1).sub.2 can be varied, either before or
after incorporation into the scaffold, by means of chemical
transformations. The transformations, and the methods by which they
are accomplished, are described below.
Protection of Reactive Substituents.
[0769] Depending on the reaction conditions employed, it may be
necessary to protect certain reactive substituents from unwanted
reactions by protection before the sequence described, and to
deprotect the substituents afterwards, according to the knowledge
of one skilled in the art. Protection and deprotection of
functional groups are described, for example, in "Protective Groups
in Organic Synthesis," by T. W. Greene and P. G. M Wuts, Wiley,
Third Edition 1999. Reactive substituents which may be protected
are shown in the accompanying schemes as, for example, [OH], [SH],
etc.
[0770] The procedures described in Examples 17-26 for the
introduction of phosphonate moieties are, with appropriate
modifications known to one skilled in the art, transferable to
different chemical substrates. Thus, for example, the methods
described herein for the introduction of phosphonate groups onto
the aryl ring of 25.6 are also applicable to the introduction of
phosphonate moieties onto the alkyne 26.8, and the reverse is also
true.
Example 17
Preparation of Representative Compounds of Formulae 8-11
##STR00186##
[0772] Illustrated above is the synthesis of target molecules of
the invention, in which A is Br, Cl, [OH], [NH], or the group
link-P(O)(OR.sup.1).sub.2. The preparation of 17.5 in which is A is
a phosphonate is described below. Conversion of 17.5 into 17.11 in
which A is methoxymethyl is described in EP 0817775 B1 and similar
conditions are used to convert 17.5 to 17.11 in which A is the
group link-P(O)(OR.sup.1).sub.2. Nitration of the diether 17.5
gives nitro compound 7.6, which, followed by reduction under
standard reducing conditions as described in "Comprehensive Organic
Transformations," by R. C. Larock, 2.sup.nd Edition, 1999, p 821,
affords the amine 17.7. For example, 17.5 is treated with cold
nitric acid in acetic acid, followed by catalytic hydrogenolysis of
the nitro product in acidic ethanol over platinum oxide at high
pressure to give the amine 17.7. The hydrochloride salt that is
isolated is then heated at ca 160.degree. C. with ammonium formate
and formamide to generate the quinazoline 17.8. The quianzoline is
converted to the chloride, 17.9, as described in EP 0817775 B1. In
one embodiment, the quinazoline 17.8 is treated with oxalyl
chloride in chloroform and DMF to give the chloride 17.9.
Displacement of the chloride by the amine, 17.10, then affords the
product 17.11. For example, heating the chloride 17.9 with
3-ethynyl-aniline in isopropanol at reflux gives 17.11.
[0773] The reactions shown above illustrate the preparation of the
compounds 17.11 in which the substituent A is either the group
link-P(O)(OR.sup.1).sub.2 or a precursor such as [OH], [SH], [NH],
Br, etc. The conversion of the compounds 17.11 in which A is [OH],
[SH], [NH], Br, etc., into the phosphonate esters 17.12 is also
depicted above. In this procedure, the compounds 17.11 are
converted, using the procedures described in Examples 17-26 into
the compounds 17.12.
Example 18
Preparation of Representative Compounds of Formulae 8-11
##STR00187##
[0775] Illustrated above is the synthesis of target molecules of
the invention in which A is Br, Cl, [OH], [NH], or the group
link-P(O)(OR.sup.1).sub.2. Conversion of 18.1 into 18.2 is
completed using the conditions described above in Example 17 for
the conversion of 17.5 into 17.11. The preparation of 18.1 in which
is A is a phosphonate is described below in Example 23.
[0776] The reactions shown above illustrate the preparation of the
compounds 18.2 in which the substituent A is either the group
link-P(O)(OR.sup.1).sub.2 or a precursor such as [OH], [SH], [NH],
Br, etc. Also depicted above is the conversion of the compounds
18.2 in which A is [OH], [SH], [NH], Br, etc., into the phosphonate
esters 18.3. In this procedure, the compounds 18.2 are converted,
using the procedures described herein into the compounds 18.3.
Example 20
Preparation of Representative Compounds of Formulae 8-11
##STR00188##
[0778] Illustrated above is the synthesis of target molecules of
the invention, in which A is Br, Cl, [OH], [NH], or the group
link-P(O)(OR.sup.1).sub.2. The preparation of 20.1 is described in
EP 0817775 B1. Diether 20.1 is converted to the chloride 20.2 using
conditions described in EP 0817775 B1 or as described in Example
17. Treatment of chloride 20.2 with amine 20.4 in refluxing
isopropanol gives 20.3. The preparation of 20.4 in which A is group
link-P(O)(OR.sup.1).sub.2 is shown in Example 25.
[0779] The reactions shown above illustrate the preparation of the
compounds 20.3 in which the substituent A is either the group
link-P(O)(OR.sup.1).sub.2 or a precursor such as [OH], [SH], [NH],
Br, etc. Also depicted above is the conversion of the compounds
20.3 in which A is [OH], [SH], [NH], Br, etc., into the phosphonate
esters 20.4. In this procedure, the compounds 20.3 are converted,
using the procedures described in Examples 17-26, into the
compounds 20.4.
Example 21
Preparation of Representative Compounds of Formulae 8-11
##STR00189##
[0781] Illustrated above is the synthesis of target molecules of
the invention, in which A is Br, Cl, [OH], [NH], or the group
link-P(O)(OR.sup.1).sub.2. The preparation of 20.2 is described in
Example 20. Chloride 20.2 is converted to the amine 21.2 by
treatment with amine 21.1 in refluxing isopropanol. The preparation
of 21.1 in which A is group link-P(O)(OR.sup.1).sub.2 is shown in
Example 26.
[0782] The reactions shown above illustrate the preparation of the
compounds 21.2 in which the substituent A is either the group
link-P(O)(OR.sup.1).sub.2 or a precursor such as [OH], [SH], [NH],
Br, etc. Also depicted above is the conversion of the compounds
21.2 in which A is [OH], [SH], [NH], Br, etc., into the phosphonate
esters 21.3. In this procedure, the compounds 21.2 are converted,
using the procedures described in Examples 17-26, into the
compounds 21.3.
Example 22
Preparation of Representative Compounds of Formulae 8-11
##STR00190##
[0784] Described herein is the preparation of
phosphonate-containing derivatives 22.11 and 22.12 that are
employed in the preparation of the phosphonate ester intermediates
17.1. The dihydroxybenzoic acid 22.1 is treated with one equivalent
of the phosphonate alkylating agent, in which Lv is a leaving group
such as mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc., in
the presence of base as described in EP 0817775 B1, to give the
ether 22.2. The ether is then subjected to the same alkylating
conditions in the presence of 2-bromoethylmethyl ether (Aldrich) to
give the diether 12.12.
[0785] For example, as shown above, ester 22.1, prepared from the
corresponding acid (Aldrich) by refluxing in concentrated HCl and
ethanol, in acetone is treated with dialkyl 4-bromobutylphosphonate
22.4, prepared as described in Syn, 9:909 (1999), potassium
carbonate and tetrabutylammonium iodide to give the ether 22.6.
Ether 22.6 is then treated with 2-bromoethylmethyl ether (Aldrich),
potassium carbonate and tetrabutyl ammonium iodide to give the
diether 22.7. Using the above procedures, but employing, in place
of the bromobutylphosphonate 22.5, different phosphonates 22.3, the
corresponding products are obtained.
##STR00191##
[0786] The preparation of phosphonate-containing derivatives 22.11
and 22.12 is shown above. The dihydroxybenzoic acid 22.1 is treated
with one equivalent of alcohol 22.8 as described above to give
ether 22.9. This ether 22.9 is then further treated with one
equivalent of 2-bromoethylmethyl ether (Aldrich), and one
equivalent of base as described above to give the diether 22.10.
Treatment, once again with an phosphonate alkylating agent 22.3, in
which Lv is a group such as mesyl, trifluoromethanesulfonyl, Br, I,
Cl, tosyl, etc., in the presence of base then affords ether
22.11.
[0787] For example, 22.1 in acetone is treated with 2-bromoethanol,
as described above for the preparation of 22.2 from 22.1, to give
22.13. Reaction with 2-bromoethylmethyl ether (Aldrich), and one
equivalent of sodium hydride in DMF, then affords the diether
22.14. Reaction of diether 22.14 with triflate 22.15, prepared as
described in Tet. Lett., 27:1497 (1986), and potassium carbonate in
DMF, gives the ether 22.12. Using the above procedures, but
employing, in place of the bromobutylphosphonate 22.15, different
phosphonates 22.3, and in place of alcohol 22.12, different
alcohols 22.8, the corresponding products are obtained.
Example 23
Preparation of Representative Compounds of Formulae 8-11
##STR00192##
[0789] Described above is the preparation of phosphonate-containing
derivatives of compounds of the invention that are employed in the
preparation of the phosphonate ester intermediates 17.2. The
dihydroxybenzoic acid 22.1 is first treated with 2-bromoethylmethyl
ether (Aldrich), as described in Example 22, to give the ether
23.1. Ether 23.1 is then treated with one equivalent of the
phosphonate alkylating agent, in which Lv is a group such as mesyl,
trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc., in the presence
of base, as described in EP 0817775 B1, to give the ether 23.2. For
example, as shown above, ether 23.1 is treated with triflate 22.15,
prepared as described in Tet. Lett., 27:1497 (1986), and potassium
carbonate in DMF, to give the ether 23.3.
[0790] Using the above procedures, but employing in place of the
phosphonate 22.5 different phosphonates 22.3, the corresponding
products 23.2 are obtained.
##STR00193##
[0791] Described above is the preparation of phosphonate-containing
derivatives 23.5 that are employed in the preparation of the
phosphonate ester intermediates 17.1. Ether 23.1 is reacted with
2-bromoethanol, as described in Example 22 for the preparation of
23.2 from 22.1, to give 23.4. Treatment of diether 23.4 with a
phosphonate alkylating agent 22.3, in which Lv is a group such as
mesyl, trifluoromethanesulfonyl, Br, I, Cl, tosyl, etc., in the
presence of base then affords ether 23.5.
[0792] For example, 23.1 in acetone is treated 2-bromoethanol,
22.1, as described in Example 22 for the preparation of 22.2 from
22.1, to give 23.6. Reaction with bromobutylphosphonate 22.5, as
described above then affords 23.7.
[0793] Using the above procedures, but employing, in place of the
bromobutylphosphonate 22.5, different phosphonates 22.3, and in
place of alcohol 22.12, different alcohols 22.8, the corresponding
products 23.5 are obtained.
Example 25
Preparation of Representative Compounds of Formulae 8-11
##STR00194##
[0795] The preparation of phosphonate-containing derivatives is
depicted above. Aniline 25.1 is first protected using methods
described in "Protective Groups in Organic Synthesis," by T. W.
Greene and P. G. M Wuts, Wiley, Third Edition 1999 ch 7.
Bromination of 25.2 by treatment with bromine in acetic acid or NBS
in tetrachloromethane at reflux, in the presence of AIBN then
affords the bromophenol 25.3. Alkylation with a phosphonate
alkylating agent 22.3 as described in Example 22 then affords the
phosphonate 25.4. Coupling with TMS acetylene by palladium mediated
reaction affords the alkyne 25.5 which can then be deprotected
using conditions described in "Protective Groups in Organic
Synthesis," by T. W. Greene and P. G. M Wuts, Wiley, Third Edition
1999 ch7 gives the amine 25.6. The coupling of aryl halides with
alkynes is described, for example, in "Comprehensive Organic
Synthesis," Eds. Trost and Fleming, Oxford, 1991, 3, part 2.4, p
521.
[0796] For example, as shown above, 3-aminophenol, 25.6, is treated
with one equivalent of mesyl chloride in the presence of pyridine
to afford 25.7. The mesyl compound 25.7 is then treated with
bromine in acetic acid to give the bromide 25.8. Bromide 25.8 is
alkylated with 22.15 as described in Example 23 to give the
phosphonate 25.9. Treatment of 25.9 with TMS-acetylene in a polar
solvent such as dimethylformamide or acetonitrile, in the presence
of a palladium(0) catalyst such as
tetrakis(triphenylphosphine)palladium(0) or a palladium(II)
catalyst such as palladium(II) acetate, and optionally in the
presence of a base such as triethylamine or potassium carbonate and
copper (I) iodide, affords the coupled product 25.10. Deprotection
of the mesyl group by treatment with potassium hydroxide in THF and
water gives the amine 25.11. Using the above procedures, but
employing, in place of the phosphonate 22.15, different
phosphonates 22.3, and in place of alcohol 25.6, different alcohols
25.1, the corresponding products 25.6 are obtained.
Example 26
Preparation of Representative Compounds of Formulae 8-11
##STR00195## ##STR00196##
[0798] The preparation of phosphonate-containing derivatives 26.8
is shown above. 3-Iodoaniline is first protected using methods
described in "Protective Groups in Organic Synthesis," by T. W.
Greene and P. G. M Wuts, Wiley, Third Edition 1999 ch 7. Coupling
with propargyl alcohol by palladium mediated reaction, as described
in Example 25 affords the alkyne 26.2. Alkylation with a
phosphonate alkylating agent 22.3 as described in Example 22
affords the phosphonate 26.3. Finally, deprotection using
conditions described in "Protective Groups in Organic Synthesis,"
by T. W. Greene and P. G. M Wuts, Wiley, Third Edition 1999 ch 7
gives the amine 26.8. For example, 3-iodoaniline (Aldrich) is
treated with BOC anhydride in the presence of pyridine and DMAP to
afford 26.4. Treatment of 26.4 with propargyl alcohol in a polar
solvent such as dimethylformamide or acetonitrile, in the presence
of a palladium(0) catalyst such as
tetrakis(triphenylphosphine)palladium(0) or a palladium(II)
catalyst such as palladium(II) acetate, and optionally in the
presence of a base such as triethylamine or potassium carbonate and
copper (I) iodide, affords the coupled product 26.5. Alkylation of
26.5 with triflate 22.15, as described in Example 22 then affords
the phosphonate 26.6. Deprotection of the BOC group by treatment
with TFA in THF or dioxane gives the amine 26.7.
[0799] Using the above procedures, but employing, in place of the
phosphonate 22.15, different phosphonates 22.3, and in place of
iodoaniline 26.4, different anilines, 26.1, the corresponding
products 26.8 are obtained.
Examples 27-33
Preparation of Representative Compounds of Formulae 12-13
[0800] Generally, for Examples 27-33, representation compounds of
the invention can be prepared as follows:
##STR00197## ##STR00198##
Phosphonate Interconversions
[0801] The final compounds described above are generally
synthesized according to the methods described in Examples 27-33.
The intermediate phosphonate esters 27.1 and 27.2 and these
compounds can be used to prepare the final compounds 27.1a and
27.2a, by one skilled in the art, using known methods for synthesis
of substituted phosphonates. These methods are similar to those
described for the synthesis of amides. The preparation of amides
from carboxylic acids and derivatives is described, for example, in
"Organic Functional Group Preparations," by S. R. Sandler and W.
Karo, Academic Press, 1968, p. 274. Further methods are described
below for the synthesis of the phosphonate diesters and can in some
cases be applied to the synthesis of phosphor-amides.
[0802] In the following schemes, the conversion of various
substituents into the group link-P(O)(OR.sup.1).sub.2, where
R.sup.1 is defined as above, or indeed the final stage of
P(O)RR.sup.o, as defined above, can be effected at any convenient
stage of the synthetic sequence, or in the final step. The
selection of an appropriate step for the introduction of the
phosphonate substituent is made after consideration of the chemical
procedures required, and the stability of the substrates to those
procedures. It may be necessary to protect reactive groups, for
example hydroxyl, amino, during the introduction of the group
link-P(O)(OR.sup.1).sub.2 or P(O)RR.sup.o.
[0803] In the succeeding examples, the nature of the phosphonate
ester group P(O)(OR.sup.1).sub.2 can be varied, either before or
after incorporation into the scaffold, by means of chemical
transformations. The transformations, and the methods by which they
are accomplished, are described below.
Protection of Reactive Substituents
[0804] Depending on the reaction conditions employed, it may be
necessary to protect certain reactive substituents from unwanted
reactions by protection before the sequence described, and to
deprotect the substituents afterwards, according to the knowledge
of one skilled in the art. Protection and deprotection of
functional groups are described, for example, in "Protective Groups
in Organic Synthesis," by T. W. Greene and P. G. M Wuts, Wiley,
Third Edition 1999. Reactive substituents which may be protected
are shown in Examples 27-33 as, for example, [OH], [SH], etc.
Example 27
Preparation of Representative Compounds of Formulae 12-13
##STR00199##
[0806] Illustrated above is the preparation of compounds 27.1 in
which A is Br, I, [SH], [NH], etc., or the group
link-P(O)(OR.sup.1).sub.2. The preparation of these compounds
follows procedures described in J. Med. Chem., 43(12):2310 (2000).
The phthalic anhydride 27.8 is melted with a methylpyridine 27.9 in
which A is Br, I, [SH], [NH], etc., or the group
link-P(O)(OR.sup.1).sub.2, under high temperature to give 27.3 (the
synthesis of 27.9 is described below). The product 27.3 on
treatment with hydrazine in water and optionally ethanol, then
rearranges to afford the pyridinone 27.4. Pyridinone 27.4 is then
converted to the chloride 27.5 by treatment with a phosphorous
oxychloride in an inert solvent such as acetonitrile at ca
50.degree. C. The amine, 27.7, is introduced by heating the
chloride 27.5 in the presence of the amine, optionally in a high
boiling solvent such as xylenes or DMF to give the amine 27.6.
[0807] Alternatively the pyridinone 27.4 can be directly converted
to the product 27.6 in a one step procedure involving melting the
aniline, 27.7, with the pyridinone in the presence of a dehydrating
agent such as phosphorus pentoxide as described in J. Med. Chem.,
43(12):2310 (2000).
[0808] The reactions shown above illustrate the preparation of the
compounds 27.6 in which the substituent A is either the group
link-P(O(OR.sup.1).sub.2 or a precursor such as [OH], [SH], [NH],
Br, etc. Depicted below is the conversion of the compounds 27.6 in
which A is [OH], [SH], [NH], Br, etc., into the phosphonate esters
27.1.
##STR00200##
[0809] In this procedure, the compounds 27.6 are converted, using
the procedures described herein into the compounds 27.1.
Example 28
Preparation of Representative Compounds of Formulae 12-13
##STR00201##
[0811] Illustrated above is the preparation of compounds 27.2 in
which A is Br, I, [SH], [NH], etc., or the group
link-P(O)(OR.sup.1).sub.2. The chloride 28.1, described in J. Med.
Chem., 43(12):2310 (2000), is treated with an aniline 28.2, in
which A is Br, I, [SH], [NH], etc. or the group
link-P(O)(OR.sup.1).sub.2, as described in Example 27, to give
amine 28.3. Alternatively the pyridinone 28.4, described in J. Med.
Chem., 43(12):2310 (2000) is treated with an aniline 28.2 in which
A is Br, I, [SH], [NH], etc., or the group
link-P(O)(OR.sup.1).sub.2 as described in Example 27 to give amine
28.3.
[0812] The reactions shown above illustrate the preparation of the
compounds 28.3 in which the substituent A is either the group
link-P(O)(OR.sup.1).sub.2 or a precursor such as [OH], [SH], [NH],
Br, etc. Depicted below is the conversion of the compounds 28.3 in
which A is [OH], [SH], [NH], Br, etc., into the phosphonate esters
27.2. In this procedure, the compounds 28.3 are converted, using
the procedures described below into the compounds 27.2.
##STR00202##
Examples 29-31
[0813] Generally, for Examples 29-31, the reagents used in the
synthesis of representative compounds of the invention is as
follows:
General Applicability of Methods for Introduction of Phosphonate
Substituents
[0814] The procedures described for the introduction of phosphonate
moieties (Examples 29-33) are, with appropriate modifications known
to one skilled in the art, transferable to different chemical
substrates. Thus, the methods described above for the introduction
of phosphonate groups onto the pyridyl ring of 27.9 are applicable
to the introduction of phosphonate moieties onto the aniline 28.2
and the reverse is also true.
[0815] Described generally in Examples 29-31 is the preparation of
phosphonate-containing derivatives 27.9, in which A is Br, Cl,
[OH], [NH], and the group link-P(O)(OR.sup.1).sub.2 that are
employed in the preparation of the phosphonate ester intermediates
27.1.
Example 29
Preparation of Representative Compounds of Formulae 12-13
##STR00203##
[0817] Described above is the preparation of 27.9 in which the
phosphonate is attached directly to the ring. The halo pyridine
29.1 is treated with a dialkyl phosphite 29.2 to give the
phosphonate 29.3. The coupling reaction is conducted in the
presence of a palladium (0) catalyst, for example as described in
J. Med. Chem., 35:1371 (1992). For example,
2-bromo-4-methylpyridine (Aldrich) 29.4 is reacted with an
equimolar amount of a dialkyl sodium phosphite 29.2, in the
presence of tetrakis(triphenylphosphine)palladium(0) and
triethylamine, in toluene at reflux, to yield the phosphonate 29.5.
Using the above procedures, but employing, in place of the halo
pyridine bis(chloromethyl) compound 29.4, different pyridines 29.1,
and/or different dialkyl sodium phosphites 29.2 the corresponding
products 29.3 are obtained.
Example 30
Preparation of Representative Compounds of Formulae 12-13
##STR00204##
[0819] Illustrated above is the preparation of 27.9 in which the
phosphonate is attached through a unsaturated or saturated carbon
linker. In this procedure, a halo-substituted pyridine 29.1 is
coupled, by means of a palladium-catalyzed Heck reaction with a
dialkyl alkenyl phosphonate 30.1. The coupling of aryl halides with
olefins by means of the Heck reaction is described, for example, in
"Advanced Organic Chemistry," by F. A. Carey and R. J. Sundberg,
Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12:146 (1979). The
aryl bromide and the olefin are coupled in a polar solvent such as
dimethylformamide or dioxane, in the presence of a palladium(0)
catalyst such as tetrakis(triphenylphosphine)palladium(0) or a
palladium(II) catalyst such as palladium(II) acetate, and
optionally in the presence of a base such as triethylamine or
potassium carbonate, to afford the coupled product 30.2.
[0820] Optionally, the product 30.2 can be reduced to afford the
saturated phosphonate 30.3. Methods for the reduction of
carbon-carbon double bonds are described, for example, in
"Comprehensive Organic Transformations," by R. C. Larock, VCH,
1989, p. 6. The methods include catalytic reduction and chemical
reduction, the latter, for example, employing diborane or
diimide.
[0821] For example, as shown above, 2-bromo-4-methylpyridine 29.4
is reacted with a dialkyl butenyl phosphonate 30.4, the preparation
of which is described in J. Med. Chem., 39:949 (1996) in the
presence of bis(triphenylphosphine) palladium(I) chloride as
described in J. Med. Chem., 35:1371 (1992), to afford the coupled
product 30.5. Optionally, the product 30.5 is reduced, for example,
by reaction with diimide as described in J. Org. Chem., 30:3965
(1965), to afford the saturated product 30.6. Using the above
procedures, but employing, in place of the halo pyridine compound
29.4, different pyridines 29.1, and/or different phosphonates 30.1
the corresponding products 30.2 and 30.3 are obtained.
Example 31
Preparation of Representative Compounds of Formulae 12-13
##STR00205##
[0823] Illustrated above is the preparation of 27.9 in which the
phosphonate is attached through a heteroatom, e.g., O, S or N, and
a carbon chain. In this procedure, a halo-substituted pyridine 29.1
is reacted with a dialkyl hydroxy- or thio-alkylphosphonate 31.1.
The preparation of alkoxypyridines by the reaction of alkoxides
with halopyridines is described, for example, in J. Am. Chem. Soc.,
82:4414 (1960). The preparation of pyridine thioethers by reaction
of halopyridines with thiols is described, for example, in
"Chemistry of Heterocyclic Compounds, Pyridine and its
Derivatives," E. Klingsberg, Ed, part 4, p. 358. The alcohols and
thiols are transformed into metal salts, for example sodium or
potassium salts, and then reacted with the halopyridine substrates
at elevated temperatures, optionally in the presence of copper
powder catalyst, to afford the ether or thioether products 31.2.
For example, a tetrahydrofuran solution of 3-bromo-4-methylpyridine
31.3 (Aldrich) is heated at reflux with an equimolar amount of a
dialkyl 2-mercaptoethylphosphonate 31.4, the preparation of which
is described in Aust. J. Chem., 43:1123 (1990), in the presence of
sodium carbonate, to afford the thioether product 31.5.
[0824] Using the above procedures, but employing, in place of the
halopyridines 31.3, different halopyridines 29.1, and/or different
hydroxy or thio-alkyl phosphonates 31.1, the corresponding products
31.2 are obtained.
Examples 32-33
[0825] Described generally in Examples 32-33 is the preparation of
phosphonate-containing derivatives 28.3, in which A is Br, Cl,
[OH], [NH], and the group link-P(O)(OR.sup.1).sub.2 that are
employed in the preparation of the phosphonate ester intermediates
27.2.
Example 32
##STR00206## ##STR00207##
[0827] Illustrated above is the preparation of 28.2 (see Example
28) in which the phosphonate is attached through a heteroatom,
e.g., O, S, or N, and a carbon linker. In this procedure, an
optionally protected aniline is reacted with an alkylphosphonate
32.2 in which Lv is a leaving group such as triflate, Br, Cl,
Mesyl, etc., in the presence of a suitable base. The base required
for this transformation depends on the nature of the heteroatom X.
For example, if X is N or S, an excess of an inorganic base such
as, for example, potassium carbonate, in the presence of an organic
solvent such as dimethylformamide, is suitable. The reaction
proceeds at from ambient temperature to about 80.degree. to afford
the displacement products 32.3. If X is O, an equimolar amount of a
strong base, such as, for example, lithium hexamethyldisilylazide
and the like, is employed, in the presence of a solvent such as
tetrahydrofuran. Deprotection, of the amine group as described in
"Protective Groups in Organic Synthesis," by T. W. Greene and P. G.
M Wuts, Wiley, Third Edition 1999 ch 7. then affords the amine
32.4.
[0828] For example, the diamine 32.5 (Aldrich), mono-protected as
the CBZ carbamate as described in "Protective Groups in Organic
Synthesis," by T. W. Greene and P. G. M Wuts, Wiley, Third Edition
1999 p 531ff, is treated with an equimolar amount of triflate 32.6,
the preparation of which is described in Tet. Lett., 27:1497
(1986), in dimethylformamide containing excess potassium carbonate,
at ca 60.degree. to afford the phosphonate product 32.7.
Deprotection by reduction over palladium on carbon in the presence
of hydrogen then affords the amine 32.8. Using the above
procedures, but employing, in place of the aniline 32.5, different
anilines 32.1, and/or different alkylphosphonates 32.2, the
corresponding products 32.4 are obtained.
[0829] Alternatively, the aminophenol 32.9, protected as the CBZ
carbamate as described above, is reacted with one equivalent of an
alkylphosphonate 32.6, as described above, to give phosphonate
32.10. Removal of the CBZ group by catalytic reduction over
palladium on carbon in the presence of hydrogen then affords the
amine 32.11.
Example 33
##STR00208##
[0831] Illustrated above is the preparation of 28.2 (see Example
28) in which the phosphonate is attached through a unsaturated or
saturated carbon linker. In this procedure, an optionally protected
halo-substituted aniline 33.1 is coupled, by means of a
palladium-catalyzed Heck reaction with a dialkyl alkenyl
phosphonate 30.1, as described in Example 30, to afford the coupled
product 33.2. Protection of anilines is described in "Protective
Groups in Organic Synthesis," by T. W. Greene and P. G. M Wuts,
Wiley, Third Edition 1999 ch 7. Preferably the aniline is treated
with a BOC reagent such as BOC chloride, or BOC anhydride in the
presence of DMAP and a base, e.g., triethylamine to afford the
protected aniline.
[0832] Optionally, the coupled product 33.2 can be reduced, as
described in Example 30, to afford the saturated phosphonate 33.3.
Removal of the protecting groups, as described in "Protective
Groups in Organic Synthesis," by T. W. Greene and P. G. M Wuts,
Wiley, Third Edition 1999 ch 7., affords the anilines 33.4 and
33.5.
[0833] For example, BOC protected 3-bromo-4-fluoro aniline 33.6
(Aldrich) is reacted with a dialkyl propenyl phosphonate 33.7, the
preparation of which is described in J. Med. Chem., 39:949 (1996),
in the presence of bis(triphenylphosphine) palladium(II) chloride,
as described in J. Med. Chem., 35:1371 (1992), to afford the
coupled product 33.8. The BOC protection of the aniline is
performed by treating the aniline with BOC anhydride in the
presence of DMAP. The product 33.8 is reduced, for example by
reaction with diimide, as described in J. Org. Chem., 30:3965
(1965), to afford the saturated product 33.9. Treatment of 33.8 and
33.9 with TFA in THF or dioxane, then affords the products 33.10
and 33.11, respectively. Using the above procedures, but employing,
in place of the halo pyridine compound 33.6, different pyridines
33.1, and/or different phosphonates 30.1 the corresponding products
33.4 and 33.5 are obtained.
Example 34
Preparation of Representative Compounds of Formulae 14-15
[0834] Representative compounds of the invention can be prepared
according to the following methods.
##STR00209##
[0835] The bis-anisole derivative of flavopiridol (see Bioorg. Med.
Chem. Lett., 10:1037 (2000)) serves as an ideal starting point for
attachment of a phosphonate moiety to the piperidine nitrogen.
Following protection of the alcohol, the tertiary amine is
demethylated and derivatized with the reagent of choice. Removal of
the methyl ethers and the protecting group on the alcohol gives the
desired analogs.
[0836] The synthesis of a specific compound of the invention, an
alvocidib analog with a phosphonate moiety linked to the piperidine
nitrogen, is illustrated below.
##STR00210##
[0837] The alcohol is protected as the acetate under standard
conditions (see Greene, T., "Protective groups in Organic
Synthesis," Wiley-Interscience, 1999). Demethylation of the
N-methylpiperidine is achieved through reaction with
.alpha.-chloroethyl chloroformate in the presence of a base such as
N,N-diisopropylethylamine (DIEA) followed by brief heating in
acidic methanol. The liberated secondary amine is condensed with
(2-oxo-ethyl)-phosphonic acid diethyl ester under reductive
conditions such as those achieved through the use of sodium
cyanoborohydride in a solvent such as methanol or dimethylformamide
(see Tet. Lett., 31:5595 (1990)). The alcohol is de-acetylated by
treatment with sodium ethoxide in ethanol. Finally,
bis-demethylation is achieved by heating with pyridinium
hydrochloride (see Bioorg. Med. Chem. Lett., 10:1037 (2000)).
##STR00211##
[0838] The 2-hydroxyacetophenone (see Bioorg. Med. Chem. Lett.,
10:1037 (2000)) is treated with a suitable phosphonate-bearing
benzoyl chloride derivative. The flavone ring system is formed by
cyclization, and the methyl groups are removed. Such a synthesis is
exemplified below.
##STR00212##
[0839] Condensation with
[4-(2-chlorocarbonyl-phenoxy)-but-2-enyl]-phosphonic acid diethyl
ester (synthesis below) is followed by successive treatment with
sodium hydride, hydrochloric acid and sodium carbonate, generating
the 5,7-dimethoxyflavone. Demethylation to provide the
5,7-dihydroxyflavone final product is achieved as above (see also
Bioorg. Med. Chem. Lett., 10:1037 (2000)).
[0840] The synthesis of another specific compound of the invention
[4-(2-chlorocarbonyl-phenoxy)-but-2-enyl]-phosphonic acid diethyl
ester, is illustrated below.
##STR00213##
[0841] Salicylic acid methyl ester is treated in a solvent such as
dimethylformamide or tetrahydrofuran with a base such as sodium
hydride. When bubbling ceases, E-1,4-dibromobutene is added in
excess. After quenching the reaction with aqueous ammonium chloride
and extracting the product with an organic solvent such as ethyl
acetate, the mono-alkylated product is isolated by chromatography.
The resulting monobromide is heated with triethylphosphite in a
solvent such as toluene (or other Arbuzov reaction conditions: see
Engel, R., "Synthesis of Carbon-phosphorus Bonds," CRC press, 1988)
to generate the diethyl ester of the desired phosphonic acid. The
methyl ester is saponified with lithium hydroxide and the acid
chloride generated by treatment with oxalyl chloride in a solvent
such as dichloromethane in the presence of a catalytic amount of
dimethylformamide.
[0842] Syntheses of another specific compound of the invention is
shown below.
##STR00214##
[0843] The phenol is treated in a solvent such as tetrahydrofuran
or dimethylformamide with a base such as sodium hydride. When
bubbling ceases, diethyl phosphonomethyltriflate (prepared
according to Tetrahedron Lett., 27:1477 (1986)) is added, yielding
the desired phosphonate diester.
[0844] Similarly, a reagent suitable for generating an analog with
a phosphonate moiety attached to the 4-position of the phenyl ring
at the flavone 2-position may be generated from 4-hydroxybenzoic
acid methyl ester.
Example 35
Preparation of Representative Compounds of Formulae 16-18
[0845] In general, representative compounds of the invention can be
prepared as follows:
##STR00215## ##STR00216##
[0846] The preparation of a specific compound of the invention is
shown below:
##STR00217##
[0847] CEP-701 can be treated in a solvent such as
dimethylformamide or tetrahydrofuran with two equivalents of a base
such as sodium hydride. When bubbling ceases, benzyl bromide is
added in excess, yielding the doubly-protected intermediate. After
further treatment with a base such as magnesium tert-butoxide,
diethyl phosphonomethyltriflate (prepared according to Tetrahedron
Lett., 27:1477 (1986)) is added, yielding the desired phosphonate
diester. Final deprotection by hydrogenation over a catalyst such
as palladium on charcoal in a solvent such as methanol as described
in Greene, T., "Protective Groups in Organic Synthesis,"
Wiley-Interscience, 1999, provides the desired product.
[0848] Another specific compound of the invention can be prepared
as follows:
##STR00218##
[0849] CEP-701 can be treated in a solvent such as
dimethylformamide or tetrahydrofuran with one equivalent of a base
such as sodium hydride or cesium carbonate. Benzyl bromide is
added, yielding the N-benzylated product. After further treatment
with a base such as magnesium tert-butoxide, diethyl
phosphonomethyltriflate is added, yielding the desired phosphonate
diester. Final deprotection by hydrogenation over a catalyst such
as palladium on charcoal in a solvent such as methanol utilizing
the method described in Greene (see above) provides the desired
product.
[0850] Another specific compound of the invention can be
synthesized as follows:
##STR00219##
[0851] (4-Formyl-phenoxymethyl)-phosphonic acid diethyl ester is
generated by treatment of 4-hydroxybenzaldehyde, in a solvent such
as dimethylformamide or tetrahydrofuran, with a base such as sodium
hydride and diethyl phosphonomethyltriflate. The product is
condensed with CEP-701 in a solvent such as toluene, in the
presence of a catalytic amount of p-toluenesulfonic acid, with
azeotropic removal of the water so formed, yielding the desired
acetal.
Example 36
Preparation of Representative Compounds of Formulae 19-21
[0852] Representative compounds of the invention can be made
according to the following:
##STR00220##
[0853] Staurosporin is acylated with activated benzoic acid
derivatives such as benzoyl chlorides in a solvent such as
chloroform, in the presence of a base such as
N,N-diisopropylethylamine (DIEA) (Bioorg. Med. Chem. Lett., 4:399
(1994)). Specifically, examples of benzoyl chlorides for use in the
synthesis of suitable phosphonate-containing midostaurin analogs
are illustrated below.
##STR00221##
[0854] 4-Hydroxybenzoic acid methyl ester is treated with magnesium
tert-butoxide and diethyl phosphonomethyltriflate (prepared
according to Tetrahedron Lett., 27:1477 (1986)) in a solvent such
as tetrahydrofuran. The resulting
4-(diethoxyphosphorylmethoxy)benzoic acid methyl ester is
saponified with lithium hydroxide in ethanol, and the acid chloride
is generated from the benzoic acid by reaction with oxalyl chloride
in a solvent such as dichloromethane, catalyzed by
dimethylformamide.
##STR00222##
[0855] 3-Hydroxybenzoic acid methyl ester is treated in a solvent
such as dimethylformamide or tetrahydrofuran with a base such as
sodium hydride. When bubbling ceases, E-1,4-dibromobutene is added
in excess. After quenching the reaction with aqueous ammonium
chloride and extracting the product with an organic solvent such as
ethyl acetate, the mono-alkylated product is isolated by
chromatography. The bromide is heated with triethylphosphite in a
solvent such as toluene (or other Arbuzov reaction conditions: see
Engel, R., "Synthesis of Carbon-phosphorus Bonds," CRC press, 1988)
to generate 3-[4-(diethoxy-phosphoryl)-but-2-enyloxy]-benzoic acid
methyl ester. The remaining steps are similar to those described
above.
[0856] In addition, representative compounds of the invention can
be prepared as follows:
##STR00223##
[0857] Alkylations on the secondary amine of staurosporine have
been carried out under a variety of standard conditions: see
Bioorg. Med. Chem. Lett., 4:399 (1994). An example of the synthesis
of a phosphonate-containing alkyl derivative, which is another
specific compound of the invention, is shown below:
##STR00224##
[0858] Staurosporin is alkylated with diethyl
phosphonomethyltriflate in the presence of a base such as DIEA.
Example 37
Preparation of Representative Compounds of Formulae 22-24
[0859] Representative compounds of the invention can be prepared as
generally described below.
##STR00225##
[0860] Introduction of the phosphonate-bearing entity at the
quinazoline 7-position is most conveniently achieved by alkylation
of a suitably-protected 4-piperazinylquinazoline, prior to urea
formation.
[0861] A specific compound of the invention can be prepared as
follows:
##STR00226##
[0862] 6,7-Dimethoxy-3,4-dihydroquinazolin-4-one is reacted with
boron tribromide to give a mixture of mono-demethylated products.
Although these may be separated by chromatography at this stage,
the separation may be more conveniently achieved on the mixture of
acetates that arises from reaction with and acetylating reagent
such as acetyl chloride in the presence of a base such as pyridine.
The desired isomer is reacted with thionyl chloride (see Bioorg.
Med. Chem. Lett., 11:1911 (2001)) and the resulting
4-chloroquinazoline is treated with piperazine-1-carboxylic acid
benzyl ester. The acetyl protecting group is removed under standard
conditions such as by treatment with ammonia in methanol (see
Greene, T., "Protective Groups in Organic Synthesis,"
Wiley-Interscience, 1999) to generate Intermediate A.
[0863] Upon treatment with a base such as magnesium tert-butoxide
and diethyl phosphonomethyltriflate (prepared according to
Tetrahedron Lett., 27:1477 (1986)), the phosphonate-bearing moiety
is introduced at the quinazoline 7-position. Thereafter, removal of
the benzyl carbamate protecting group by hydrogenation over a
catalyst such as palladium on charcoal in a solvent such as
methanol (see Greene, ibid) and condensation with
4-isopropoxyaniline (commercially available) and 4-nitrophenyl
chloroformate provides the desired compound.
[0864] Another specific compound of the invention is prepared as
follows:
##STR00227##
[0865] Intermediate A may be alkylated on the phenol by reaction
with 4-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl
ester in the presence of an azodicarboxylate diester such as
diisopropyl azodicarboxylate and triphenylphosphine, as described
by Mitsunobu (Bull. Chem. Soc. Japan., 44:3427 (1971)). Following
deprotection with trifluoroacetic acid, the liberated secondary
amine is condensed with (2-oxo-ethyl)-phosphonic acid diethyl ester
under reductive conditions such as those achieved through the use
of sodium cyanoborohydride in a solvent such as methanol or
dimethylformamide (see Tet. Lett., 31:5595 (1990)). The remaining
steps are similar to those described above.
Example 38
Preparation of Representative Compounds of Formulae 22=24
[0866] Representative compounds of the invention can be prepared as
follows:
##STR00228##
[0867] The route is similar to that shown in Example 37, but
exploits a selective demethylation at the 6-position of
6,7-dimethoxy-3,4-dihydroquinazolin-4-one (see Bioorg. Med. Chem.
Lett., 11:1911 (2001)). A specific example of such a synthesis is
shown below.
##STR00229##
[0868] Following the selective demethylation, the steps are similar
to those discussed in previous examples up to the point where a
phenol is alkylated. In this example, however, the alkylation is
performed with E-1,4-dibromobutene, and the monobromide product is
reacted with triethylphosphite in a solvent such as toluene toluene
(or other Arbuzov reaction conditions: see Engel, R., "Synthesis of
Carbon-phosphorus Bonds," CRC press, 1988) to generate the diethyl
ester of the desired phosphonic acid. Thereafter, the steps are
again similar to those described in previous examples.
Example 39
Preparation of Representative Compounds of Formulae 25-26
[0869] Compounds of the invention can be prepared as generally
described below.
##STR00230##
[0870] The coupling of an aniline with 2,3,4-trifluorobenzoic acid
is performed in the presence of a large excess of a base such as
lithium diisopropylamide in a solvent such as tetrahydrofuran, and
at temperatures at or below ambient, as described in patent
application WO 2001-US22948. The subsequent introduction of a
phosphonate moeity may be achieved by a variety of means, such as
those illustrated below. Thereafter, the hydroxamic ester is
generated by treatment of the benzoic acid with
O-(tetrahydro-2H-pyran-2-yl)hydroxylamine and diisopropylethylamine
in the presence of a coupling reagent such as
benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate (PyBOP) in a solvent such as tetrahydrofuran or
dichloromethane, as described in patent application WO 2000-US18347
20000705, followed by treatment with ethanolic hydrochloric
acid.
[0871] A specific compound of the invention can be synthesized as
follows:
##STR00231##
[0872] Having coupled 2,3,4-trifluorobenzoic acid with
2-iodo-5-nitroanisole (commercially available), the methyl ether is
removed under standard conditions such as by treatment with
hydrobromic acid in acetic acid (see Greene, T., "Protective Groups
in Organic Synthesis," Wiley-Interscience, 1999). The benzoic acid
is esterified by dissolution in acidic methanol. The phenol is then
treated in a solvent such as tetrahydrofuran or dimethylformamide
with a base such as sodium hydride. When bubbling ceases, diethyl
phosphonomethyltriflate (prepared according to Tetrahedron Lett.,
27:1477 (1986)) is added, yielding the desired phosphonate diester.
Saponification of the benzoic acid (ready for coupling to form the
hydroxamate ester; see above) is achieved with lithium hydroxide in
a solvent such as tetrahydrofuran or ethanol.
[0873] In addition, representative compounds of the invention are
prepared as follows:
##STR00232##
[0874] The iodo substituent present in PD-184352 may be used for
the introduction of a phosphonate-bearing moiety, as illustrated
below.
##STR00233##
[0875] 5-Chloro-1-pentyne is treated with triethylphosphite in a
solvent such as toluene (or other Arbuzov reaction conditions: see
Engel, R., "Synthesis of Carbon-phosphorus Bonds," CRC press, 1988)
to generate the diethyl ester of the desired phosphonic acid. This
acetylene is coupled with PD-184352 under conditions such as those
pioneered by Sonagashira (Sonogashira et al., Tetrahedron Lett.
4467 (1975)).
Example 40
Preparation of Representative Compounds of Formulae 27-30
[0876] Compounds of the invention can be prepared as generally
outlined below.
##STR00234##
[0877] The aryl hydrazine is condensed with
4,4-dimethyl-3-oxo-pentanenitrile to form an aminopyrazole (as
described in J. Med. Chem., 45:2994 (2002)). Urea formation is
accomplished by sequential condensation with 4-nitrophenyl
chloroformate and the requisite aniline. The latter is generated
from 4-nitro-naphthalen-1-ol by reaction with
2-morpholin-4-yl-ethanol using a method such as that described by
Mitsunobu (Bull. Chem. Soc. Japan, 44:3427 (1971)), followed by
tin(II)-mediated reduction of the nitro group to reveal the
aniline.
[0878] The synthesis of a specific compound of the invention, e.g.,
suitable phosphonate-containing arylhydrazine, is illustrated
below.
##STR00235##
[0879] 5-Methyl-2-nitrophenol is alkylated with
E-1,4-dibromobutene. The resulting monobromide is heated with
triethylphosphite in a solvent such as toluene (or other Arbuzov
reaction conditions: see Engel, R., "Synthesis of Carbon-phosphorus
Bonds," CRC press, 1988) to generate the diethyl ester of the
desired phosphonic acid. The nitro group is converted to the aryl
hydrazine by diazotization and reduction with sodium sulfite (Chem.
Ber, 93:540 (1960)) or tin(II) chloride (J. Med. Chem., 44:4031
(2001)).
[0880] The syntheses of suitable phosphonate-containing aryl
hydrazines in which link is attached to the 3- or 4-positions of
the phenyl ring are analogous to that shown above, starting from
2-methyl-5-nitrophenol and 4-nitrophenol, respectively.
[0881] In addition, representative compounds of the invention can
be synthesized as shown below:
##STR00236##
[0882] Following the synthesis of the urea through condensation of
5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine and
1-isocyanato-4-methoxy-naphthalene, the product is demethylated by
treatment with a Lewis acid such as boron tribromide. The resulting
phenol is coupled with a suitable morpholine derivative using a
method such as that described by Mitsunobu (Bull. Chem. Soc.
Japan., 44:3427 (1971)).
[0883] The synthesis of a specific compound of the invention, e.g.,
suitable phosphonate-containing morpholine derivative, is
illustrated below.
##STR00237##
[0884] Morpholine-2,4-dicarboxylic acid 4-benzyl ester (generated
from morpholine-2,4-dicarboxylic acid by reaction with benzyl
chloroformate under standard protection conditions (such as those
described in Greene, T., "Protective Groups in Organic Synthesis,"
Wiley-interscience, 1999)) is coupled with 2-aminoethylphosphonic
acid diethyl ester (commercially available) using standard reagents
for the formation of a secondary amide such as
dicyclohexylcarbodiimide (DCC) and hydroxybenztriazole (HOBT), in a
solvent such as dimethylformamide. Removal of the benzyl carbamate
protecting group by hydrogenation over palladium in a solvent such
as methanol (as described in Greene, T. ibid.) provides the desired
product.
Example 41
Preparation of Representative Compounds of Formulae 31-34
[0885] Representative compounds of the invention can be prepared as
follows.
##STR00238##
[0886] A specific compound of the invention can be prepared as
follows:
##STR00239##
[0887] The acid is coupled with 2-aminoethylphosphonic acid diethyl
ester (commercially available) using standard reagents for the
formation of a secondary amide such as dicyclohexylcarbodiimide
(DCC) and hydroxybenztriazole (HOBT), in a solvent such as
dimethylformamide.
[0888] Representative compounds of the invention may also be
prepared as follows:
##STR00240##
[0889] An aniline bearing a phosphonate moiety is coupled with
4-(4-aminophenoxy)-pyridine-2-carboxylic acid methylamide (US
2002/0165394) in the presence of a reagent such as phosgene, in a
solvent such as toluene to form a urea (see Bioorg. Med. Chem.
Lett., 11:2775 (2001)).
[0890] 4-(4-Aminophenoxy)-pyridine-2-carboxylic acid methylamide is
formed by alkylation of (4-hydroxypyridine-2-carboxylic acid
methylamide with 4-fluoronitrobenzene with a base such as cesium
carbonate in a solvent such as dimethylformamide, followed by
reduction of the nitro group with tin(II) chloride in a solvent
such as ethanol.
[0891] The synthesis of a specific compound of the invention, e.g.,
a suitable phosphonate-bearing aniline, is illustrated below.
##STR00241##
[0892] 2-Chloro-5-nitrophenol is alkylated with an excess of
E-1,4-dibromobutene in a solvent such as dimethylformamide in the
presence of a base such as potassium carbonate. The monobromide
product is heated with triethylphosphite in a solvent such as
toluene (or other Arbuzov reaction conditions: see Engel, R.,
"Synthesis of Carbon-phosphorus Bonds," CRC press, 1988). Finally,
the nitro group is reduced with tin(II) chloride in a solvent such
as ethanol.
[0893] Synthesis of representative compounds of the invention is
shown below.
##STR00242##
[0894] 4-Chloro-3-trifluoromethylaniline is coupled with a
4-phenoxy-substituted aniline bearing a phosphonate moiety in a
manner similar to that shown in Scheme 2 to form a urea. The
synthesis of a specific compound of the invention, e.g., suitable
phosphonate-bearing aniline is illustrated below.
##STR00243##
[0895] (3-Benzyloxy)phenol is treated with magnesium t-butoxide and
diethyl phosphonomethyltriflate (prepared according to Tetrahedron
Lett., 27:1477 (1986)) in a solvent such as tetrahydrofuran. The
benzyl group is removed by hydrogenation over a catalyst such as
palladium on charcoal in a solvent such as methanol as described in
Greene, T., "Protective Groups in Organic Synthesis,"
Wiley-Interscience, 1999, and the resulting phenol is alkylated
with 4-fluoronitrobenzene with a base such as potassium carbonate
in a solvent such as dimethylformamide. Finally, the nitro group is
reduced.
[0896] In addition, a representative compound of the invention can
be prepared as follows:
##STR00244##
[0897] 4-Chloro-3-trifluoromethylaniline is coupled with a
4-phenoxy-substituted aniline bearing a phosphonate moiety in a
manner similar to that shown hereinabove to form a urea. The
synthesis of a suitable phosphonate-bearing aniline, which is a
specific compound of the invention, is illustrated below.
##STR00245##
[0898] 2-Chloro-5-nitrobenzoyl chloride is reacted with
2-aminoethylphosphonic acid diethyl ester. Thereafter, displacement
of the chloride by reaction with
4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide in the
presence of a base such as potassium carbonate in a solvent such as
tetrahydrofuran generates the biaryl ether motif, and reduction of
the nitro group as in previous examples reveals the aniline ready
for coupling in the urea-forming step.
Example 42
Preparation of Representative Compounds of Formulae 35-36
[0899] Representative compounds of the invention can be made
according to the following:
##STR00246##
[0900] CP-690, 550,
3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin--
1-yl}-3-oxo-propionitrile, can be prepared as described in WO
02,096,909 and WO 03,048,162. Enolate formation at the
.alpha.-cyanoamide position using over 2 equivalents of base
followed by addition of diethyl phosphonomethyltriflate (prepared
according to Tetrahedron Lett., 27:1477 (1986)) yields the desired
compound 42.1. A solvent such as THF, DMF or other anhydrous
solvents may be used for this reaction. In case the pyrrole
nitrogen interferes with the desired alkylation, a protecting group
such as BOC may be introduced before the alkylation reaction.
Removal of the BOC group can be accomplished by exposure of the
reaction product to TFA as described in Greene, T., "Protective
Groups in Organic Synthesis," Wiley-Interscience, 1999.
[0901] A second series of pro-drugs can be prepared by attaching
the phosphonate group on to the pyrrole ring at the 2-position.
Compounds such as 42.9 can be made according to the general route
outlined below.
##STR00247##
[0902] Compound 42.4 is prepared according to WO 02,096,909.
Protection of the pyrrole nitrogen using a tosyl group is achieved
as described in Sakamoto et al., Tetrahedron Lett., 35(18):2919
(1994). Ortho lithiation using t-BuLi and quenching with
formaldehyde as described in the above reference as well as Seela
et al., Chem. Ber., 110(4): 1462 (1977) introduces a substituent at
the requisite site. The primary alcohol so formed may be used for
attachment of the phosphonate moiety via ether formation using base
and diethyl phosphonomethyltriflate (prepared according to
Tetrahedron Lett., 27:1477 (1986)) in an anhydrous solvent. Removal
of the benzyl protecting group is achieved using hydrogenolysis
conditions. The piperidine nitrogen is then coupled with
cyano-acetic acid 2,5-dioxo-pyrrolidine-1-yl ester to provide
compound 42.8. Removal of the tosyl protecting group can be
achieved using basic conditions to provide the desired product
42.9.
##STR00248##
[0903] Specifically, as shown above,
(1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-y-
l)-amine, compound 42.4 (prepared as described in WO 02,096,909) is
first protected on the pyrrole nitrogen using a tosyl group.
Subsequent formylation using the procedure reported by Sakamoto et
al., (Tetrahedron Lett. 35:2919 (1994)) provides compound 42.6. The
primary alcohol is then treated in a solvent such as
tetrahydrofuran or dimethylformamide with a base such as sodium
hydride. When bubbling ceases, diethyl phosphonomethyltriflate
(prepared according to Tetrahedron Lett., 27:1477 (1986)) is added,
yielding the desired product 42.10. Debenzylation of the piperidine
nitrogen following by coupling to cyano-acetic acid
2,5-dioxo-pyrrolidine-1-yl ester gives compound 42.4. Removal of
the tosyl protecting group provides the desired pro-drug 42.12.
Example 43
Preparation of Representative Compounds of Formulae 4-7
[0904] Representative compounds of the invention may be prepared as
follows:
[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-
-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acid diethyl ester
[0905] A mixture of
N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1--
ylmethyl-benzamide (30 mg, 0.06 mmol, Zimmermann et al., Bioorg.
Med. Chem. Lett. 1996, 6, 1221), diethyl 2-bromoethylphosphonate
(30 .mu.L, 0.12 mmol) and K.sub.2CO3 (20 mg, 0.16 mmol) in 2.5 mL
of DMF was heated at 110.degree. C. for 8 hours when most of the
starting materials were consumed as judged by LCMS analysis. The
solid material was filtered off. The filtrate was diluted with
water and then extracted with EtOAc. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated to dryness. The crude
material was purified by silica gel chromatography using 10%
MeOH/CH.sub.2Cl.sub.2 to provide 28 mg (55%) of the desired
product. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.32 (t, 6H),
1.92-20.3 (m, 4H), 2.35 (s, 3H), 2.5 (bs, 6H), 2.64 (m, 2H), 3.56
(s, 2H), 4.05-4.14 (m, 4H), 7.07 (s, 1H), 7.18 (d, 2H, J=5 Hz),
7.30 (dd, 1H, J=6, 8 Hz), 7.33-7.45 (m, 3H), 7.84 (d, 2H, J=8 Hz),
8.01 (s, 1H), 8.51 (dd, 2H, J=4, 9 Hz), 8.58 (d, 1H, J=2 Hz), 8.70
(dd, 1H, J=2, 5 Hz), 9.25 (s, 1H); .sup.31P (121.4 MHz, CDCl.sub.3)
.delta. 30.5; MS (m/z) 644 [M+H].sup.+.
##STR00249##
[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl-
]-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acid
[0906] To a solution of
[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl-
]-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acid diethyl ester (8
mg, 0.012 mmol) in DMF (1 mL) was added TMSBr (15 .mu.L, 0.12 mmol)
at room temperature. The reaction was allowed to proceed at room
temperature for 14 hours. Another portion of TMSBr (20 .mu.L) was
added and heated at 110.degree. C. for 12 hours when completion of
the reaction was detected by LCMS. The reaction was cooled down to
room temperature and quenched with addition of MeOH. The reaction
mixture was dried under reduced pressure and the residue was
purified by RP HPLC using a C18 column with a gradient of
H.sub.2O--Acetonitrile (5-100%) over 20 minutes to provide 4.2 mg
(50%) of the product as mono-TFA salt. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.80-1.84 (m, 2H), 2.08-2.02 (m, 2H), 2.23 (s,
3H), 3.07 (bs, 4H), 3.30-3.32 (2H, possible overlap with solvent),
3.89 (m, 2H), 4.01 (s, 2H), 6.87 (s, 1H), 7.23-7.3 (m, 3H),
7.52-7.60 (m, 3H), 8.01 (d, 2H, J=8 Hz), 8.08 (dd, 1H, J=2, 5 Hz),
8.30 (s, 1H), 8.58 (d, 1H, J=5 Hz), 8.89 (d, 1H, J=2 Hz), 9.22 (dd,
1H, J=2, 5 Hz), 9.63 (s, 1H); .sup.31P (121.4 MHz, CD.sub.3OD)
.delta. 21.9; MS (m/z) 588 [M+H].sup.+.
##STR00250##
2-{[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbam-
oyl]-benzyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-propionic
acid ethyl ester
[0907] A solution of
N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-piperazin-1--
ylmethyl-benzamide (20 mg, 0.04 mmol) and
2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester
(60 mg, 0.2 mmol) in 1% Acetic Acid/DMF (1.5 mL) solution was
stirred at room temperature for 7 hours followed by an addition of
NaCNBH.sub.3 (30 mg, 0.24 mmol). The resulting mixture was stirred
for additional 30 min when completion of the reaction was observed
by LCMS. After evaporation of solvent, the residue was taken up in
CH.sub.2Cl.sub.2 and then extracted with saturated aqueous
NaHCO.sub.3. The organic extracts were dried in vacuo and the
residue was purified by silica gel chromatography using
MeOH--CH.sub.2Cl.sub.2 (7%) to afford 8 mg (26%) of the product.
.sup.31P NMR (121.4 MHz, CDCl.sub.3) .delta. 27.2, 28.6; MS (m/z)
764 [M+H].sup.+.
##STR00251##
2-{Hydroxy-[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phen-
ylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphinoyloxy}-propionic
acid
[0908] To a solution of
2-{[2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbam-
oyl]-benzyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-propionic
acid ethyl ester (6 mg, 0.008 mmol) in 2:1 acetonitrile/water (0.3
mL) was added 1N NaOH (50 .mu.L, 0.048 mmol). The solution was
allowed to stir at room temperature for 1 hour when completion of
the reaction was observed by LCMS. The reaction was acidified by 1N
HCl (50 .mu.L) solution and purified by RP HPLC using a C18 column
with a gradient of H.sub.2O--Acetonitrile (5-100%) over 20 minutes
to provide 2 mg (38%) of the product. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 1.51 (d, 3H, J=7 Hz), 2.04 (m, 2H), 2.33 (s,
3H), 2.96 (bs, 4H), 3.31 (m, 2H), 3.4 (bs, 4H), 3.89 (s, 2H), 4.88
(1H, possible overlap with solvent), 7.30 (m, 2H), 7.48-7.57 (m,
4H), 7.96-7.99 (m, 4H), 8.32 (s, 1H), 8.56 (d, 1H, J=5 Hz), 8.86
(d, 1H, J=2 Hz), 9.10 (dd, 1H, J=2, 5 Hz), 9.59 (s, 1H); .sup.31P
(121.4 MHz, CD.sub.3OD) .delta. 20.0; MS (m/z) 660 [M+H].sup.+.
Example 44
Preparation of Representative Compounds of Formulae 31-34
[0909] Preparation of Representative Compounds of the Invention can
be as Discussed below.
##STR00252##
In addition, representative compounds of the invention can be
synthesized as follows:
##STR00253##
Example 45
[0910] By way of example and not limitation, embodiments of the
invention are named below in tabular format (Table 106). These
embodiments are of the general formula "MBF":
##STR00254##
Each embodiment of MBF is depicted as a substituted nucleus (Sc).
Sc is described in formula 1-36 herein, wherein A.sup.0 is the
point of covalent attachment of Sc to Lg, as well as in Tables 1.1
to 1.5 below. For those embodiments described in Table 106, Sc is a
nucleus designated by a number and each substituent is designated
in order by letter or number. Tables 1.1 to 1.5 are a schedule of
nuclei used in forming the embodiments of Table 106. Each nucleus
(Sc) is given a number designation from Tables 1.1 to 1.5, and this
designation appears first in each embodiment name. Similarly,
Tables 10.1 to 10.19 and 20.1 to 20.36 list the selected linking
groups (Lg) and prodrug (Pd.sup.1 and Pd.sup.2) substituents, again
by letter or number designation, respectively. Accordingly, a
compound of the formula MBF includes compounds having Sc groups
based on formula 1-36 herein as well as compounds according to
Table 100 below. In all cases, compounds of the formula MBF have
groups Lg, Pd.sup.1 and Pd.sup.2 setforth in the Tables below.
[0911] Accordingly, each named embodiment of Table 106 is depicted
by a number designating the nucleus from Table 1.1-1.5, followed by
a letter designating the linking group (Lg) from Table 10.1-10.19,
and two numbers designating the two prodrug groups (Pd.sup.1 and
Pd.sup.2) from Table 20.1-20.36. In graphical tabular form, each
embodiment of Table 106 appears as a name having the syntax:
Sc.Lg.Pd.sup.1.Pd.sup.2
[0912] Each Sc group is shown having a tilda (".about."). The tilda
is the point of covalent attachment of Sc to Lg. Q.sup.1 and
Q.sup.2 of the linking groups (Lg), it should be understood, do not
represent groups or atoms but are simply connectivity designations.
Q.sup.1 is the site of the covalent bond to the nucleus (Sc) and
Q.sup.2 is the site of the covalent bond to the phosphorous atom of
formula MBF. Each prodrug group (Pd.sup.1 and Pd.sup.2) are
covalently bonded to the phosphorous atom of MBF at the tilda
symbol (".about."). Some embodiments of Tables 10.1-10.19 and
20.1-20.36 may be designated as a combination of letters and
numbers (Table 10.1-10.19) or number and letter (Table 20.1-20.36).
For example there are Table 10 entries for BJ1 and BJ2. In any
event, entries of Table 10.1-10.19 always begin with a letter and
those of Table 20.1-20.36 always begin with a number. When a
nucleus (Sc) is shown enclosed within square brackets ("[ ]") and a
covalent bond extends outside the brackets, the point of covalent
attachment of Sc to Lg may be at any substitutable site on SC.
Selection of the point of attachment is described herein. By way of
example and not limitation, the point of attachment is selected
from those depicted in the schemes and examples.
TABLE-US-00003 TABLE 1.1 1 ##STR00255## 2 ##STR00256## 3
##STR00257## 4 ##STR00258##
TABLE-US-00004 TABLE 1.2 ##STR00259## ##STR00260##
TABLE-US-00005 TABLE 1.3 ##STR00261## ##STR00262## ##STR00263##
##STR00264##
TABLE-US-00006 TABLE 1.4 ##STR00265## ##STR00266##
TABLE-US-00007 TABLE 1.5 ##STR00267## ##STR00268##
TABLE-US-00008 TABLE 10.1 ##STR00269## ##STR00270## ##STR00271##
##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276##
##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281##
##STR00282## ##STR00283##
TABLE-US-00009 TABLE 10.2 ##STR00284## ##STR00285## ##STR00286##
##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291##
##STR00292## ##STR00293## ##STR00294## ##STR00295##
TABLE-US-00010 TABLE 10.3 ##STR00296## ##STR00297## ##STR00298##
##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303##
##STR00304## ##STR00305## ##STR00306## ##STR00307##
TABLE-US-00011 TABLE 10.4 ##STR00308## ##STR00309## ##STR00310##
##STR00311## ##STR00312## ##STR00313## ##STR00314## ##STR00315##
##STR00316## ##STR00317## ##STR00318## ##STR00319##
TABLE-US-00012 TABLE 10.5 ##STR00320## ##STR00321## ##STR00322##
##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327##
##STR00328## ##STR00329## ##STR00330## ##STR00331##
TABLE-US-00013 TABLE 10.6 ##STR00332## ##STR00333## ##STR00334##
##STR00335## ##STR00336## ##STR00337##
TABLE-US-00014 TABLE 10.7 ##STR00338## ##STR00339## ##STR00340##
##STR00341## ##STR00342## ##STR00343##
TABLE-US-00015 TABLE 10.8 ##STR00344## ##STR00345## ##STR00346##
##STR00347## ##STR00348## ##STR00349##
TABLE-US-00016 TABLE 10.9 ##STR00350## ##STR00351## ##STR00352##
##STR00353## ##STR00354## ##STR00355##
TABLE-US-00017 TABLE 10.10 ##STR00356## ##STR00357## ##STR00358##
##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363##
##STR00364## ##STR00365## ##STR00366## ##STR00367##
TABLE-US-00018 TABLE 10.11 ##STR00368## ##STR00369## ##STR00370##
##STR00371## ##STR00372## ##STR00373##
TABLE-US-00019 TABLE 10.12 ##STR00374## DA ##STR00375## DB
##STR00376## DC ##STR00377## DD ##STR00378## DE ##STR00379## DF
TABLE-US-00020 TABLE 10.13 ##STR00380## DG ##STR00381## DH
##STR00382## DI ##STR00383## DJ ##STR00384## DK ##STR00385## DL
TABLE-US-00021 TABLE 10.14 ##STR00386## DM ##STR00387## DN
##STR00388## DO ##STR00389## DP ##STR00390## DQ ##STR00391## DR
TABLE-US-00022 TABLE 10.15 ##STR00392## DS ##STR00393## DT
##STR00394## DU ##STR00395## DV ##STR00396## DW ##STR00397## DX
##STR00398## DY ##STR00399## DZ ##STR00400## EA ##STR00401## EB
##STR00402## EC ##STR00403## ED
TABLE-US-00023 TABLE 10.16 ##STR00404## EE ##STR00405## EF
##STR00406## EG ##STR00407## EH ##STR00408## EI ##STR00409## EJ
TABLE-US-00024 TABLE 10.17 ##STR00410## EK ##STR00411## EL
##STR00412## EM ##STR00413## EN ##STR00414## EO ##STR00415## EP
TABLE-US-00025 TABLE 10.18 ##STR00416## EQ ##STR00417## ER
##STR00418## ES ##STR00419## ET ##STR00420## EU ##STR00421## EV
TABLE-US-00026 TABLE 10.19 ##STR00422## EW ##STR00423## EX
##STR00424## EY ##STR00425## EZ ##STR00426## FA ##STR00427## FB
TABLE-US-00027 TABLE 20.1 ##STR00428## 1 ##STR00429## 2
##STR00430## 3 ##STR00431## 4 ##STR00432## 5 ##STR00433## 6
##STR00434## 7 ##STR00435## 8
TABLE-US-00028 TABLE 20.2 ##STR00436## 9 ##STR00437## 10
##STR00438## 11
TABLE-US-00029 TABLE 20.3 ##STR00439## 12 ##STR00440## 13
##STR00441## 14 ##STR00442## 15 ##STR00443## 16 ##STR00444## 17
##STR00445## 18 ##STR00446## 19
TABLE-US-00030 TABLE 20.4 ##STR00447## 20 ##STR00448## 21
##STR00449## 22
TABLE-US-00031 TABLE 20.5 ##STR00450## 23 ##STR00451## 24
##STR00452## 25 ##STR00453## 26 ##STR00454## 27 ##STR00455## 28
##STR00456## 29 ##STR00457## 30
TABLE-US-00032 TABLE 20.6 ##STR00458## 31 ##STR00459## 32
##STR00460## 33
TABLE-US-00033 TABLE 20.7 ##STR00461## 34 ##STR00462## 35
##STR00463## 36 ##STR00464## 37 ##STR00465## 38 ##STR00466## 39
##STR00467## 40 ##STR00468## 41
TABLE-US-00034 TABLE 20.8 ##STR00469## ##STR00470## 42 43
##STR00471## ##STR00472## 44 45 ##STR00473## ##STR00474## 46 47
##STR00475## ##STR00476## 48 49
TABLE-US-00035 TABLE 20.9 ##STR00477## 50 ##STR00478## 51
##STR00479## 52 ##STR00480## 53 ##STR00481## 54 ##STR00482## 55
##STR00483## 56 ##STR00484## 57
TABLE-US-00036 TABLE 20.10 ##STR00485## 58 ##STR00486## 59
##STR00487## 60
TABLE-US-00037 TABLE 20.11 ##STR00488## 61 ##STR00489## 62
##STR00490## 63 ##STR00491## 64 ##STR00492## 65 ##STR00493## 66
##STR00494## 67 ##STR00495## 68
TABLE-US-00038 TABLE 20.12 ##STR00496## 69 ##STR00497## 70
##STR00498## 71
TABLE-US-00039 TABLE 20.13 ##STR00499## 72 ##STR00500## 73
##STR00501## 74 ##STR00502## 75 ##STR00503## 76 ##STR00504## 77
##STR00505## 78 ##STR00506## 79
TABLE-US-00040 TABLE 20.14 ##STR00507## 80 ##STR00508## 81
##STR00509## 82
TABLE-US-00041 TABLE 20.15 ##STR00510## ##STR00511## 83 84
##STR00512## ##STR00513## 85 86 ##STR00514## ##STR00515## 87 88
##STR00516## ##STR00517## 89 90
TABLE-US-00042 TABLE 20.16 ##STR00518## ##STR00519## 91 92
##STR00520## ##STR00521## 93 94 ##STR00522## ##STR00523## 95 96
##STR00524## ##STR00525## 97 98
TABLE-US-00043 TABLE 20.17 ##STR00526## 99 ##STR00527## 100
##STR00528## 101 ##STR00529## 102 ##STR00530## 103 ##STR00531## 104
##STR00532## 105 ##STR00533## 106
TABLE-US-00044 TABLE 20.18 ##STR00534## 107 ##STR00535## 108
##STR00536## 109
TABLE-US-00045 TABLE 20.19 ##STR00537## 110 ##STR00538## 111
##STR00539## 112 ##STR00540## 113 ##STR00541## 114 ##STR00542## 115
##STR00543## 116 ##STR00544## 117
TABLE-US-00046 TABLE 20.20 ##STR00545## 118 ##STR00546## 119
##STR00547## 120
TABLE-US-00047 TABLE 20.21 ##STR00548## 121 ##STR00549## 122
##STR00550## 123 ##STR00551## 124 ##STR00552## 125 ##STR00553## 126
##STR00554## 127 ##STR00555## 128
TABLE-US-00048 TABLE 20.22 ##STR00556## 129 ##STR00557## 130
##STR00558## 131
TABLE-US-00049 TABLE 20.23 ##STR00559## 132 ##STR00560## 133
##STR00561## 134 ##STR00562## 135 ##STR00563## 136 ##STR00564## 137
##STR00565## 138 ##STR00566## 139
TABLE-US-00050 TABLE 20.24 ##STR00567## 140 ##STR00568## 141
##STR00569## 142 ##STR00570## 143 ##STR00571## 144 ##STR00572## 145
##STR00573## 146 ##STR00574## 147
TABLE-US-00051 TABLE 20.25 ##STR00575## 148 ##STR00576## 149
##STR00577## 150 ##STR00578## 151 ##STR00579## 152 ##STR00580## 153
##STR00581## 154 ##STR00582## 155 ##STR00583## 156 ##STR00584## 157
##STR00585## 158 ##STR00586## 159
TABLE-US-00052 TABLE 20.26 ##STR00587## 160 ##STR00588## 161
##STR00589## 162 ##STR00590## 163 ##STR00591## 164 ##STR00592## 165
##STR00593## 166 ##STR00594## 167 ##STR00595## 168 ##STR00596## 169
##STR00597## 170 ##STR00598## 171
TABLE-US-00053 TABLE 20.27 ##STR00599## 172 ##STR00600## 173
##STR00601## 174 ##STR00602## 175 ##STR00603## 176 ##STR00604## 177
##STR00605## 178 ##STR00606## 179
TABLE-US-00054 TABLE 20.28 ##STR00607## 180 ##STR00608## 181
##STR00609## 182 ##STR00610## 183 ##STR00611## 184 ##STR00612##
185
TABLE-US-00055 TABLE 20.29 ##STR00613## 186 ##STR00614## 187
##STR00615## 188 ##STR00616## 189 ##STR00617## 190 ##STR00618## 191
##STR00619## 192 ##STR00620## 193
TABLE-US-00056 TABLE 20.30 ##STR00621## 194 ##STR00622## 195
##STR00623## 196 ##STR00624## 197 ##STR00625## 198 ##STR00626##
199
TABLE-US-00057 TABLE 20.31 ##STR00627## 200 ##STR00628## 201
##STR00629## 202 ##STR00630## 203 ##STR00631## 204 ##STR00632## 205
##STR00633## 206 ##STR00634## 207
TABLE-US-00058 TABLE 20.32 ##STR00635## 208 ##STR00636## 209
##STR00637## 210 ##STR00638## 211 ##STR00639## 212 ##STR00640##
213
TABLE-US-00059 TABLE 20.33 ##STR00641## 214 ##STR00642## 215
##STR00643## 216 ##STR00644## 217 ##STR00645## 218 ##STR00646## 219
##STR00647## 220 ##STR00648## 221
TABLE-US-00060 TABLE 20.34 ##STR00649## 222 ##STR00650## 223
##STR00651## 224 ##STR00652## 225 ##STR00653## 226 ##STR00654##
227
TABLE-US-00061 TABLE 20.35 ##STR00655## 228 ##STR00656## 229
##STR00657## 230 ##STR00658## 231 ##STR00659## 232 ##STR00660## 233
##STR00661## 234 ##STR00662## 235
TABLE-US-00062 TABLE 20.36 ##STR00663## 236 ##STR00664## 237
##STR00665## 238 ##STR00666## 239 ##STR00667## 240 ##STR00668## 241
##STR00669## 242 ##STR00670## 243
TABLE-US-00063 TABLE 20.37 ##STR00671## 244 ##STR00672## 245
##STR00673## 246 ##STR00674## 247
TABLE-US-00064 TABLE 106 Prodrugs of 1.B 1.B.228.228; 1.B.228.229;
1.B.228.230; 1.B.228.231; 1.B.228.236; 1.B.228.237; 1.B.228.238;
1.B.228.239; 1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169;
1.B.228.172; 1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228;
1.B.229.229; 1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237;
1.B.229.238; 1.B.229.239; 1.B.229.154; 1.B.229.157; 1.B.229.166;
1.B.229.169; 1.B.229.172; 1.B.229.175; 1.B.229.240; 1.B.229.244;
1.B.230.228; 1.B.230.229; 1.B.230.230; 1.B.230.231; 1.B.230.236;
1.B.230.237; 1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157;
1.B.230.166; 1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240;
1.B.230.244; 1.B.231.228; 1.B.231.229; 1.B.231.230; 1.B.231.231;
1.B.231.236; 1.B.231.237; 1.B.231.238; 1.B.231.239; 1.B.231.154;
1.B.231.157; 1.B.231.166; 1.B.231.169; 1.B.231.172; 1.B.231.175;
1.B.231.240; 1.B.231.244; 1.B.236.228; 1.B.236.229; 1.B.236.230;
1.B.236.231; 1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239;
1.B.236.154; 1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172;
1.B.236.175; 1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229;
1.B.237.230; 1.B.237.231; 1.B.237.236; 1.B.237.237; 1.B.237.238;
1.B.237.239; 1.B.237.154; 1.B.237.157; 1.B.237.166; 1.B.237.169;
1.B.237.172; 1.B.237.175; 1.B.237.240; 1.B.237.244; 1.B.238.228;
1.B.238.229; 1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237;
1.B.238.238; 1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166;
1.B.238.169; 1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244;
1.B.239.228; 1.B.239.229; 1.B.239.230; 1.B.239.231; 1.B.239.236;
1.B.239.237; 1.B.239.238; 1.B.239.239; 1.B.239.154; 1.B.239.157;
1.B.239.166; 1.B.239.169; 1.B.239.172; 1.B.239.175; 1.B.239.240;
1.B.239.244; 1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231;
1.B.154.236; 1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154;
1.B.154.157; 1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175;
1.B.154.240; 1.B.154.244; 1.B.157.228; 1.B.157.229; 1.B.157.230;
1.B.157.231; 1.B.157.236; 1.B.157.237; 1.B.157.238; 1.B.157.239;
1.B.157.154; 1.B.157.157; 1.B.157.166; 1.B.157.169; 1.B.157.172;
1.B.157.175; 1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B.166.229;
1.B.166.230; 1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238;
1.B.166.239; 1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169;
1.B.166.172; 1.B.166.175; 1.B.166.240; 1.B.166.244; 1.B.169.228;
1.B.169.229; 1.B.169.230; 1.B.169.231; 1.B.169.236; 1.B.169.237;
1.B.169.238; 1.B.169.239; 1.B.169.154; 1.B.169.157; 1.B.169.166;
1.B.169.169; 1.B.169.172; 1.B.169.175; 1.B.169.240; 1.B.169.244;
1.B.172.228; 1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236;
1.B.172.237; 1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157;
1.B.172.166; 1.B.172.169; 1.B.172.172; 1.B.172.175; 1.B.172.240;
1.B.172.244; 1.B.175.228; 1.B.175.229; 1.B.175.230; 1.B.175.231;
1.B.175.236; 1.B.175.237; 1.B.175.238; 1.B.175.239; 1.B.175.154;
1.B.175.157; 1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175;
1.B.175.240; 1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230;
1.B.240.231; 1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239;
1.B.240.154; 1.B.240.157; 1.B.240.166; 1.B.240.169; 1.B.240.172;
1.B.240.175; 1.B.240.240; 1.B.240.244; 1.B.244.228; 1.B.244.229;
1.B.244.230; 1.B.244.231; 1.B.244.236; 1.B.244.237; 1.B.244.238;
1.B.244.239; 1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169;
1.B.244.172; 1.B.244.175; 1.B.244.240; 1.B.244.244; Prodrugs of 1.D
1.D.228.228; 1.D.228.229; 1.D.228.230; 1.D.228.231; 1.D.228.236;
1.D.228.237; 1.D.228.238; 1.D.228.239; 1.D.228.154; 1.D.228.157;
1.D.228.166; 1.D.228.169; 1.D.228.172; 1.D.228.175; 1.D.228.240;
1.D.228.244; 1.D.229.228; 1.D.229.229; 1.D.229.230; 1.D.229.231;
1.D.229.236; 1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154;
1.D.229.157; 1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175;
1.D.229.240; 1.D.229.244; 1.D.230.228; 1.D.230.229; 1.D.230.230;
1.D.230.231; 1.D.230.236; 1.D.230.237; 1.D.230.238; 1.D.230.239;
1.D.230.154; 1.D.230.157; 1.D.230.166; 1.D.230.169; 1.D.230.172;
1.D.230.175; 1.D.230.240; 1.D.230.244; 1.D.231.228; 1.D.231.229;
1.D.231.230; 1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238;
1.D.231.239; 1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169;
1.D.231.172; 1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228;
1.D.236.229; 1.D.236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237;
1.D.236.238; 1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166;
1.D.236.169; 1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244;
1.D.237.228; 1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236;
1.D.237.237; 1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157;
1.D.237.166; 1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240;
1.D.237.244; 1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231;
1.D.238.236; 1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154;
1.D.238.157; 1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175;
1.D.238.240; 1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230;
1.D.239.231; 1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239;
1.D.239.154; 1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172;
1.D.239.175; 1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229;
1.D.154.230; 1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238;
1.D.154.239; 1.D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169;
1.D.154.172; 1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228;
1.D.157.229; 1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237;
1.D.157.238; 1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166;
1.D.157.169; 1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244;
1.D.166.228; 1.D.166.229; 1.D.166.230; 1.D.166.231; 1.D.166.236;
1.D.166.237; 1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157;
1.D.166.166; 1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240;
1.D.166.244; 1.D.169.228; 1.D.169.229; 1.D.169.230; 1.D.169.231;
1.D.169.236; 1.D.169.237; 1.D.169.238; 1.D.169.239; 1.D.169.154;
1.D.169.157; 1.D.169.166; 1.D.169.169; 1.D.169.172; 1.D.169.175;
1.D.169.240; 1.D.169.244; 1.D.172.228; 1.D.172.229; 1.D.172.230;
1.D.172.231; 1.D.172.236; 1.D.172.237; 1.D.172.238; 1.D.172.239;
1.D.172.154; 1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172;
1.D.172.175; 1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D.175.229;
1.D.175.230; 1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238;
1.D.175.239; 1.D.175.154; 1.D.175.157; 1.D.175.166; 1.D.175.169;
1.D.175.172; 1.D.175.175; 1.D.175.240; 1.D.175.244; 1.D.240.228;
1.D.240.229; 1.D.240.230; 1.D.240.231; 1.D.240.236; 1.D.240.237;
1.D.240.238; 1.D.240.239; 1.D.240.154; 1.D.240.157; 1.D.240.166;
1.D.240.169; 1.D.240.172; 1.D.240.175; 1.D.240.240; 1.D.240.244;
1.D.244.228; 1.D.244.229; 1.D.244.230; 1.D.244.231; 1.D.244.236;
1.D.244.237; 1.D.244.238; 1.D.244.239; 1.D.244.154; 1.D.244.157;
1.D.244.166; 1.D.244.169; 1.D.244.172; 1.D.244.175; 1.D.244.240;
1.D.244.244; Prodrugs of 1.E 1.E.228.228; 1.E.228.229; 1.E.228.230;
1.E.228.231; 1.E.228.236; 1.E.228.237; 1.E.228.238; 1.E.228.239;
1.E.228.154; 1.E.228.157; 1.E.228.166; 1.E.228.169; 1.E.228.172;
1.E.228.175; 1.E.228.240; 1.E.228.244; 1.E.229.228; 1.E.229.229;
1.E.229.230; 1.E.229.231; 1.E.229.236; 1.E.229.237; 1.E.229.238;
1.E.229.239; 1.E.229.154; 1.E.229.157; 1.E.229.166; 1.E.229.169;
1.E.229.172; 1.E.229.175; 1.E.229.240; 1.E.229.244; 1.E.230.228;
1.E.230.229; 1.E.230.230; 1.E.230.231; 1.E.230.236; 1.E.230.237;
1.E.230.238; 1.E.230.239; 1.E.230.154; 1.E.230.157; 1.E.230.166;
1.E.230.169; 1.E.230.172; 1.E.230.175; 1.E.230.240; 1.E.230.244;
1.E.231.228; 1.E.231.229; 1.E.231.230; 1.E.231.231; 1.E.231.236;
1.E.231.237; 1.E.231.238; 1.E.231.239; 1.E.231.154; 1.E.231.157;
1.E.231.166; 1.E.231.169; 1.E.231.172; 1.E.231.175; 1.E.231.240;
1.E.231.244; 1.E.236.228; 1.E.236.229; 1.E.236.230; 1.E.236.231;
1.E.236.236; 1.E.236.237; 1.E.236.238; 1.E.236.239; 1.E.236.154;
1.E.236.157; 1.E.236.166; 1.E.236.169; 1.E.236.172; 1.E.236.175;
1.E.236.240; 1.E.236.244; 1.E.237.228; 1.E.237.229; 1.E.237.230;
1.E.237.231; 1.E.237.236; 1.E.237.237; 1.E.237.238; 1.E.237.239;
1.E.237.154; 1.E.237.157; 1.E.237.166; 1.E.237.169; 1.E.237.172;
1.E.237.175; 1.E.237.240; 1.E.237.244; 1.E.238.228; 1.E.238.229;
1.E.238.230; 1.E.238.231; 1.E.238.236; 1.E.238.237; 1.E.238.238;
1.E.238.239; 1.E.238.154; 1.E.238.157; 1.E.238.166; 1.E.238.169;
1.E.238.172; 1.E.238.175; 1.E.238.240; 1.E.238.244; 1.E.239.228;
1.E.239.229; 1.E.239.230; 1.E.239.231; 1.E.239.236; 1.E.239.237;
1.E.239.238; 1.E.239.239; 1.E.239.154; 1.E.239.157; 1.E.239.166;
1.E.239.169; 1.E.239.172; 1.E.239.175; 1.E.239.240; 1.E.239.244;
1.E.154.228; 1.E.154.229; 1.E.154.230; 1.E.154.231; 1.E.154.236;
1.E.154.237; 1.E.154.238; 1.E.154.239; 1.E.154.154; 1.E.154.157;
1.E.154.166; 1.E.154.169; 1.E.154.172; 1.E.154.175; 1.E.154.240;
1.E.154.244; 1.E.157.228; 1.E.157.229; 1.E.157.230; 1.E.157.231;
1.E.157.236; 1.E.157.237; 1.E.157.238; 1.E.157.239; 1.E.157.154;
1.E.157.157; 1.E.157.166; 1.E.157.169; 1.E.157.172; 1.E.157.175;
1.E.157.240; 1.E.157.244; 1.E.166.228; 1.E.166.229; 1.E.166.230;
1.E.166.231; 1.E.166.236; 1.E.166.237; 1.E.166.238; 1.E.166.239;
1.E.166.154; 1.E.166.157; 1.E.166.166; 1.E.166.169; 1.E.166.172;
1.E.166.175; 1.E.166.240; 1.E.166.244; 1.E.169.228; 1.E.169.229;
1.E.169.230; 1.E.169.231; 1.E.169.236; 1.E.169.237; 1.E.169.238;
1.E.169.239; 1.E.169.154; 1.E.169.157; 1.E.169.166; 1.E.169.169;
1.E.169.172; 1.E.169.175; 1.E.169.240; 1.E.169.244; 1.E.172.228;
1.E.172.229; 1.E.172.230; 1.E.172.231; 1.E.172.236; 1.E.172.237;
1.E.172.238; 1.E.172.239; 1.E.172.154; 1.E.172.157; 1.E.172.166;
1.E.172.169; 1.E.172.172; 1.E.172.175; 1.E.172.240; 1.E.172.244;
1.E.175.228; 1.E.175.229; 1.E.175.230; 1.E.175.231; 1.E.175.236;
1.E.175.237; 1.E.175.238; 1.E.175.239; 1.E.175.154; 1.E.175.157;
1.E.175.166; 1.E.175.169; 1.E.175.172; 1.E.175.175; 1.E.175.240;
1.E.175.244; 1.E.240.228; 1.E.240.229; 1.E.240.230; 1.E.240.231;
1.E.240.236; 1.E.240.237; 1.E.240.238; 1.E.240.239; 1.E.240.154;
1.E.240.157; 1.E.240.166; 1.E.240.169; 1.E.240.172; 1.E.240.175;
1.E.240.240; 1.E.240.244; 1.E.244.228; 1.E.244.229; 1.E.244.230;
1.E.244.231; 1.E.244.236; 1.E.244.237; 1.E.244.238; 1.E.244.239;
1.E.244.154; 1.E.244.157; 1.E.244.166; 1.E.244.169; 1.E.244.172;
1.E.244.175; 1.E.244.240; 1.E.244.244; Prodrugs of 1.G 1.G.228.228;
1.G.228.229; 1.G.228.230; 1.G.228.231; 1.G.228.236; 1.G.228.237;
1.G.228.238; 1.G.228.239; 1.G.228.154; 1.G.228.157; 1.G.228.166;
1.G.228.169; 1.G.228.172; 1.G.228.175; 1.G.228.240; 1.G.228.244;
1.G.229.228; 1.G.229.229; 1.G.229.230; 1.G.229.231; 1.G.229.236;
1.G.229.237; 1.G.229.238; 1.G.229.239; 1.G.229.154; 1.G.229.157;
1.G.229.166; 1.G.229.169; 1.G.229.172; 1.G.229.175; 1.G.229.240;
1.G.229.244; 1.G.230.228; 1.G.230.229; 1.G.230.230; 1.G.230.231;
1.G.230.236; 1.G.230.237; 1.G.230.238; 1.G.230.239; 1.G.230.154;
1.G.230.157; 1.G.230.166; 1.G.230.169; 1.G.230.172; 1.G.230.175;
1.G.230.240; 1.G.230.244; 1.G.231.228; 1.G.231.229; 1.G.231.230;
1.G.231.231; 1.G.231.236; 1.G.231.237; 1.G.231.238; 1.G.231.239;
1.G.231.154; 1.G.231.157; 1.G.231.166; 1.G.231.169; 1.G.231.172;
1.G.231.175; 1.G.231.240; 1.G.231.244; 1.G.236.228; 1.G.236.229;
1.G.236.230; 1.G.236.231; 1.G.236.236; 1.G.236.237; 1.G.236.238;
1.G.236.239; 1.G.236.154; 1.G.236.157; 1.G.236.166; 1.G.236.169;
1.G.236.172; 1.G.236.175; 1.G.236.240; 1.G.236.244; 1.G.237.228;
1.G.237.229; 1.G.237.230; 1.G.237.231; 1.G.237.236; 1.G.237.237;
1.G.237.238; 1.G.237.239; 1.G.237.154; 1.G.237.157; 1.G.237.166;
1.G.237.169; 1.G.237.172; 1.G.237.175; 1.G.237.240; 1.G.237.244;
1.G.238.228; 1.G.238.229; 1.G.238.230; 1.G.238.231; 1.G.238.236;
1.G.238.237; 1.G.238.238; 1.G.238.239; 1.G.238.154; 1.G.238.157;
1.G.238.166; 1.G.238.169; 1.G.238.172; 1.G.238.175; 1.G.238.240;
1.G.238.244; 1.G.239.228; 1.G.239.229; 1.G.239.230; 1.G.239.231;
1.G.239.236; 1.G.239.237; 1.G.239.238; 1.G.239.239; 1.G.239.154;
1.G.239.157; 1.G.239.166; 1.G.239.169; 1.G.239.172; 1.G.239.175;
1.G.239.240; 1.G.239.244; 1.G.154.228; 1.G.154.229; 1.G.154.230;
1.G.154.231; 1.G.154.236; 1.G.154.237; 1.G.154.238; 1.G.154.239;
1.G.154.154; 1.G.154.157; 1.G.154.166; 1.G.154.169; 1.G.154.172;
1.G.154.175; 1.G.154.240; 1.G.154.244; 1.G.157.228; 1.G.157.229;
1.G.157.230; 1.G.157.231; 1.G.157.236; 1.G.157.237; 1.G.157.238;
1.G.157.239; 1.G.157.154; 1.G.157.157; 1.G.157.166; 1.G.157.169;
1.G.157.172; 1.G.157.175; 1.G.157.240; 1.G.157.244; 1.G.166.228;
1.G.166.229; 1.G.166.230; 1.G.166.231; 1.G.166.236; 1.G.166.237;
1.G.166.238; 1.G.166.239; 1.G.166.154; 1.G.166.157; 1.G.166.166;
1.G.166.169; 1.G.166.172; 1.G.166.175; 1.G.166.240; 1.G.166.244;
1.G.169.228; 1.G.169.229; 1.G.169.230; 1.G.169.231; 1.G.169.236;
1.G.169.237; 1.G.169.238; 1.G.169.239; 1.G.169.154; 1.G.169.157;
1.G.169.166; 1.G.169.169; 1.G.169.172; 1.G.169.175; 1.G.169.240;
1.G.169.244; 1.G.172.228; 1.G.172.229; 1.G.172.230; 1.G.172.231;
1.G.172.236; 1.G.172.237; 1.G.172.238; 1.G.172.239; 1.G.172.154;
1.G.172.157; 1.G.172.166; 1.G.172.169; 1.G.172.172; 1.G.172.175;
1.G.172.240; 1.G.172.244; 1.G.175.228; 1.G.175.229; 1.G.175.230;
1.G.175.231; 1.G.175.236; 1.G.175.237; 1.G.175.238; 1.G.175.239;
1.G.175.154; 1.G.175.157; 1.G.175.166; 1.G.175.169; 1.G.175.172;
1.G.175.175; 1.G.175.240; 1.G.175.244; 1.G.240.228; 1.G.240.229;
1.G.240.230; 1.G.240.231; 1.G.240.236; 1.G.240.237; 1.G.240.238;
1.G.240.239; 1.G.240.154; 1.G.240.157; 1.G.240.166; 1.G.240.169;
1.G.240.172; 1.G.240.175; 1.G.240.240; 1.G.240.244; 1.G.244.228;
1.G.244.229; 1.G.244.230; 1.G.244.231; 1.G.244.236; 1.G.244.237;
1.G.244.238; 1.G.244.239; 1.G.244.154; 1.G.244.157; 1.G.244.166;
1.G.244.169; 1.G.244.172; 1.G.244.175; 1.G.244.240; 1.G.244.244;
Prodrugs of 1.I 1.I.228.228; 1.I.228.229; 1.I.228.230; 1.I.228.231;
1.I.228.236; 1.I.228.237; 1.I.228.238; 1.I.228.239; 1.I.228.154;
1.I.228.157; 1.I.228.166; 1.I.228.169; 1.I.228.172; 1.I.228.175;
1.I.228.240; 1.I.228.244; 1.I.229.228; 1.I.229.229; 1.I.229.230;
1.I.229.231; 1.I.229.236; 1.I.229.237; 1.I.229.238; 1.I.229.239;
1.I.229.154; 1.I.229.157; 1.I.229.166; 1.I.229.169; 1.I.229.172;
1.I.229.175; 1.I.229.240; 1.I.229.244; 1.I.230.228; 1.I.230.229;
1.I.230.230; 1.I.230.231; 1.I.230.236; 1.I.230.237; 1.I.230.238;
1.I.230.239; 1.I.230.154; 1.I.230.157; 1.I.230.166; 1.I.230.169;
1.I.230.172; 1.I.230.175; 1.I.230.240; 1.I.230.244; 1.I.231.228;
1.I.231.229; 1.I.231.230; 1.I.231.231; 1.I.231.236; 1.I.231.237;
1.I.231.238; 1.I.231.239; 1.I.231.154; 1.I.231.157; 1.I.231.166;
1.I.231.169; 1.I.231.172; 1.I.231.175; 1.I.231.240; 1.I.231.244;
1.I.236.228; 1.I.236.229; 1.I.236.230; 1.I.236.231; 1.I.236.236;
1.I.236.237; 1.I.236.238; 1.I.236.239; 1.I.236.154; 1.I.236.157;
1.I.236.166; 1.I.236.169; 1.I.236.172; 1.I.236.175; 1.I.236.240;
1.I.236.244; 1.I.237.228; 1.I.237.229; 1.I.237.230; 1.I.237.231;
1.I.237.236; 1.I.237.237; 1.I.237.238; 1.I.237.239; 1.I.237.154;
1.I.237.157; 1.I.237.166; 1.I.237.169; 1.I.237.172; 1.I.237.175;
1.I.237.240; 1.I.237.244; 1.I.238.228; 1.I.238.229; 1.I.238.230;
1.I.238.231; 1.I.238.236; 1.I.238.237; 1.I.238.238; 1.I.238.239;
1.I.238.154; 1.I.238.157; 1.I.238.166; 1.I.238.169; 1.I.238.172;
1.I.238.175; 1.I.238.240; 1.I.238.244; 1.I.239.228; 1.I.239.229;
1.I.239.230; 1.I.239.231; 1.I.239.236; 1.I.239.237; 1.I.239.238;
1.I.239.239; 1.I.239.154; 1.I.239.157; 1.I.239.166; 1.I.239.169;
1.I.239.172; 1.I.239.175; 1.I.239.240; 1.I.239.244; 1.I.154.228;
1.I.154.229; 1.I.154.230; 1.I.154.231; 1.I.154.236; 1.I.154.237;
1.I.154.238; 1.I.154.239; 1.I.154.154; 1.I.154.157; 1.I.154.166;
1.I.154.169; 1.I.154.172; 1.I.154.175; 1.I.154.240; 1.I.154.244;
1.I.157.228; 1.I.157.229; 1.I.157.230; 1.I.157.231; 1.I.157.236;
1.I.157.237; 1.I.157.238; 1.I.157.239; 1.I.157.154; 1.I.157.157;
1.I.157.166; 1.I.157.169; 1.I.157.172; 1.I.157.175; 1.I.157.240;
1.I.157.244; 1.I.166.228; 1.I.166.229; 1.I.166.230; 1.I.166.231;
1.I.166.236; 1.I.166.237; 1.I.166.238; 1.I.166.239; 1.I.166.154;
1.I.166.157; 1.I.166.166; 1.I.166.169; 1.I.166.172; 1.I.166.175;
1.I.166.240;
1.I.166.244; 1.I.169.228; 1.I.169.229; 1.I.169.230; 1.I.169.231;
1.I.169.236; 1.I.169.237; 1.I.169.238; 1.I.169.239; 1.I.169.154;
1.I.169.157; 1.I.169.166; 1.I.169.169; 1.I.169.172; 1.I.169.175;
1.I.169.240; 1.I.169.244; 1.I.172.228; 1.I.172.229; 1.I.172.230;
1.I.172.231; 1.I.172.236; 1.I.172.237; 1.I.172.238; 1.I.172.239;
1.I.172.154; 1.I.172.157; 1.I.172.166; 1.I.172.169; 1.I.172.172;
1.I.172.175; 1.I.172.240; 1.I.172.244; 1.I.175.228; 1.I.175.229;
1.I.175.230; 1.I.175.231; 1.I.175.236; 1.I.175.237; 1.I.175.238;
1.I.175.239; 1.I.175.154; 1.I.175.157; 1.I.175.166; 1.I.175.169;
1.I.175.172; 1.I.175.175; 1.I.175.240; 1.I.175.244; 1.I.240.228;
1.I.240.229; 1.I.240.230; 1.I.240.231; 1.I.240.236; 1.I.240.237;
1.I.240.238; 1.I.240.239; 1.I.240.154; 1.I.240.157; 1.I.240.166;
1.I.240.169; 1.I.240.172; 1.I.240.175; 1.I.240.240; 1.I.240.244;
1.I.244.228; 1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236;
1.I.244.237; 1.I.244.238; 1.I.244.239; 1.I.244.154; 1.I.244.157;
1.I.244.166; 1.I.244.169; 1.I.244.172; 1.I.244.175; 1.I.244.240;
1.I.244.244; Prodrugs of 1.J 1.J.228.228; 1.J.228.229; 1.J.228.230;
1.J.228.231; 1.J.228.236; 1.J.228.237; 1.J.228.238; 1.J.228.239;
1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169; 1.J.228.172;
1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229;
1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238;
1.J.229.239; 1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169;
1.J.229.172; 1.J.229.175; 1.J.229.240; 1.J.229.244; 1.J.230.228;
1.J.230.229; 1.J.230.230; 1.J.230.231; 1.J.230.236; 1.J.230.237;
1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157; 1.J.230.166;
1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244;
1.J.231.228; 1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236;
1.J.231.237; 1.J.231.238; 1.J.231.239; 1.J.231.154; 1.J.231.157;
1.J.231.166; 1.J.231.169; 1.J.231.172; 1.J.231.175; 1.J.231.240;
1.J.231.244; 1.J.236.228; 1.J.236.229; 1.J.236.230; 1.J.236.231;
1.J.236.236; 1.J.236.237; 1.J.236.238; 1.J.236.239; 1.J.236.154;
1.J.236.157; 1.J.236.166; 1.J.236.169; 1.J.236.172; 1.J.236.175;
1.J.236.240; 1.J.236.244; 1.J.237.228; 1.J.237.229; 1.J.237.230;
1.J.237.231; 1.J.237.236; 1.J.237.237; 1.J.237.238; 1.J.237.239;
1.J.237.154; 1.J.237.157; 1.J.237.166; 1.J.237.169; 1.J.237.172;
1.J.237.175; 1.J.237.240; 1.J.237.244; 1.J.238.228; 1.J.238.229;
1.J.238.230; 1.J.238.231; 1.J.238.236; 1.J.238.237; 1.J.238.238;
1.J.238.239; 1.J.238.154; 1.J.238.157; 1.J.238.166; 1.J.238.169;
1.J.238.172; 1.J.238.175; 1.J.238.240; 1.J.238.244; 1.J.239.228;
1.J.239.229; 1.J.239.230; 1.J.239.231; 1.J.239.236; 1.J.239.237;
1.J.239.238; 1.J.239.239; 1.J.239.154; 1.J.239.157; 1.J.239.166;
1.J.239.169; 1.J.239.172; 1.J.239.175; 1.J.239.240; 1.J.239.244;
1.J.154.228; 1.J.154.229; 1.J.154.230; 1.J.154.231; 1.J.154.236;
1.J.154.237; 1.J.154.238; 1.J.154.239; 1.J.154.154; 1.J.154.157;
1.J.154.166; 1.J.154.169; 1.J.154.172; 1.J.154.175; 1.J.154.240;
1.J.154.244; 1.J.157.228; 1.J.157.229; 1.J.157.230; 1.J.157.231;
1.J.157.236; 1.J.157.237; 1.J.157.238; 1.J.157.239; 1.J.157.154;
1.J.157.157; 1.J.157.166; 1.J.157.169; 1.J.157.172; 1.J.157.175;
1.J.157.240; 1.J.157.244; 1.J.166.228; 1.J.166.229; 1.J.166.230;
1.J.166.231; 1.J.166.236; 1.J.166.237; 1.J.166.238; 1.J.166.239;
1.J.166.154; 1.J.166.157; 1.J.166.166; 1.J.166.169; 1.J.166.172;
1.J.166.175; 1.J.166.240; 1.J.166.244; 1.J.169.228; 1.J.169.229;
1.J.169.230; 1.J.169.231; 1.J.169.236; 1.J.169.237; 1.J.169.238;
1.J.169.239; 1.J.169.154; 1.J.169.157; 1.J.169.166; 1.J.169.169;
1.J.169.172; 1.J.169.175; 1.J.169.240; 1.J.169.244; 1.J.172.228;
1.J.172.229; 1.J.172.230; 1.J.172.231; 1.J.172.236; 1.J.172.237;
1.J.172.238; 1.J.172.239; 1.J.172.154; 1.J.172.157; 1.J.172.166;
1.J.172.169; 1.J.172.172; 1.J.172.175; 1.J.172.240; 1.J.172.244;
1.J.175.228; 1.J.175.229; 1.J.175.230; 1.J.175.231; 1.J.175.236;
1.J.175.237; 1.J.175.238; 1.J.175.239; 1.J.175.154; 1.J.175.157;
1.J.175.166; 1.J.175.169; 1.J.175.172; 1.J.175.175; 1.J.175.240;
1.J.175.244; 1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231;
1.J.240.236; 1.J.240.237; 1.J.240.238; 1.J.240.239; 1.J.240.154;
1.J.240.157; 1.J.240.166; 1.J.240.169; 1.J.240.172; 1.J.240.175;
1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229; 1.J.244.230;
1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239;
1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172;
1.J.244.175; 1.J.244.240; 1.J.244.244; Prodrugs of 1.L 1.L.228.228;
1.L.228.229; 1.L.228.230; 1.L.228.231; 1.L.228.236; 1.L.228.237;
1.L.228.238; 1.L.228.239; 1.L.228.154; 1.L.228.157; 1.L.228.166;
1.L.228.169; 1.L.228.172; 1.L.228.175; 1.L.228.240; 1.L.228.244;
1.L.229.228; 1.L.229.229; 1.L.229.230; 1.L.229.231; 1.L.229.236;
1.L.229.237; 1.L.229.238; 1.L.229.239; 1.L.229.154; 1.L.229.157;
1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175; 1.L.229.240;
1.L.229.244; 1.L.230.228; 1.L.230.229; 1.L.230.230; 1.L.230.231;
1.L.230.236; 1.L.230.237; 1.L.230.238; 1.L.230.239; 1.L.230.154;
1.L.230.157; 1.L.230.166; 1.L.230.169; 1.L.230.172; 1.L.230.175;
1.L.230.240; 1.L.230.244; 1.L.231.228; 1.L.231.229; 1.L.231.230;
1.L.231.231; 1.L.231.236; 1.L.231.237; 1.L.231.238; 1.L.231.239;
1.L.231.154; 1.L.231.157; 1.L.231.166; 1.L.231.169; 1.L.231.172;
1.L.231.175; 1.L.231.240; 1.L.231.244; 1.L.236.228; 1.L.236.229;
1.L.236.230; 1.L.236.231; 1.L.236.236; 1.L.236.237; 1.L.236.238;
1.L.236.239; 1.L.236.154; 1.L.236.157; 1.L.236.166; 1.L.236.169;
1.L.236.172; 1.L.236.175; 1.L.236.240; 1.L.236.244; 1.L.237.228;
1.L.237.229; 1.L.237.230; 1.L.237.231; 1.L.237.236; 1.L.237.237;
1.L.237.238; 1.L.237.239; 1.L.237.154; 1.L.237.157; 1.L.237.166;
1.L.237.169; 1.L.237.172; 1.L.237.175; 1.L.237.240; 1.L.237.244;
1.L.238.228; 1.L.238.229; 1.L.238.230; 1.L.238.231; 1.L.238.236;
1.L.238.237; 1.L.238.238; 1.L.238.239; 1.L.238.154; 1.L.238.157;
1.L.238.166; 1.L.238.169; 1.L.238.172; 1.L.238.175; 1.L.238.240;
1.L.238.244; 1.L.239.228; 1.L.239.229; 1.L.239.230; 1.L.239.231;
1.L.239.236; 1.L.239.237; 1.L.239.238; 1.L.239.239; 1.L.239.154;
1.L.239.157; 1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175;
1.L.239.240; 1.L.239.244; 1.L.154.228; 1.L.154.229; 1.L.154.230;
1.L.154.231; 1.L.154.236; 1.L.154.237; 1.L.154.238; 1.L.154.239;
1.L.154.154; 1.L.154.157; 1.L.154.166; 1.L.154.169; 1.L.154.172;
1.L.154.175; 1.L.154.240; 1.L.154.244; 1.L.157.228; 1.L.157.229;
1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237; 1.L.157.238;
1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169;
1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L.166.228;
1.L.166.229; 1.L.166.230; 1.L.166.231; 1.L.166.236; 1.L.166.237;
1.L.166.238; 1.L.166.239; 1.L.166.154; 1.L.166.157; 1.L.166.166;
1.L.166.169; 1.L.166.172; 1.L.166.175; 1.L.166.240; 1.L.166.244;
1.L.169.228; 1.L.169.229; 1.L.169.230; 1.L.169.231; 1.L.169.236;
1.L.169.237; 1.L.169.238; 1.L.169.239; 1.L.169.154; 1.L.169.157;
1.L.169.166; 1.L.169.169; 1.L.169.172; 1.L.169.175; 1.L.169.240;
1.L.169.244; 1.L.172.228; 1.L.172.229; 1.L.172.230; 1.L.172.231;
1.L.172.236; 1.L.172.237; 1.L.172.238; 1.L.172.239; 1.L.172.154;
1.L.172.157; 1.L.172.166; 1.L.172.169; 1.L.172.172; 1.L.172.175;
1.L.172.240; 1.L.172.244; 1.L.175.228; 1.L.175.229; 1.L.175.230;
1.L.175.231; 1.L.175.236; 1.L.175.237; 1.L.175.238; 1.L.175.239;
1.L.175.154; 1.L.175.157; 1.L.175.166; 1.L.175.169; 1.L.175.172;
1.L.175.175; 1.L.175.240; 1.L.175.244; 1.L.240.228; 1.L.240.229;
1.L.240.230; 1.L.240.231; 1.L.240.236; 1.L.240.237; 1.L.240.238;
1.L.240.239; 1.L.240.154; 1.L.240.157; 1.L.240.166; 1.L.240.169;
1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244; 1.L.244.228;
1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237;
1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166;
1.L.244.169; 1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;
Prodrugs of 1.O 1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231;
1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1.O.228.154;
1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.O.228.175;
1.O.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230;
1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239;
1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172;
1.O.229.175; 1.O.229.240; 1.O.229.244; 1.O.230.228; 1.O.230.229;
1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238;
1.O.230.239; 1.O.230.154; 1.O.230.157; 1.O.230.166; 1.O.230.169;
1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228;
1.O.231.229; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237;
1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166;
1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244;
1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236;
1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157;
1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240;
1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231;
1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154;
1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175;
1.O.237.240; 1.O.237.244; 1.O.238.228; 1.O.238.229; 1.O.238.230;
1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.O.238.239;
1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172;
1.O.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229;
1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238;
1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169;
1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; 1.O.154.228;
1.O.154.229; 1.O.154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237;
1.O.154.238; 1.O.154.239; 1.O.154.154; 1.O.154.157; 1.O.154.166;
1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244;
1.O.157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236;
1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154; 1.O.157.157;
1.O.157.166; 1.O.157.169; 1.O.157.172; 1.O.157.175; 1.O.157.240;
1.O.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231;
1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154;
1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175;
1.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230;
1.O.169.231; 1.O.169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239;
1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172;
1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229;
1.O.172.230; 1.O.172.231; 1.O.172.236; 1.O.172.237; 1.O.172.238;
1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169;
1.O.172.172; 1.O.172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228;
1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237;
1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166;
1.O.175.169; 1.O.175.172; 1.O.175.175; 1.O.175.240; 1.O.175.244;
1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236;
1.O.240.237; 1.O.240.238; 1.O.240.239; 1.O.240.154; 1.O.240.157;
1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240;
1.O.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231;
1.O.244.236; 1.O.244.237; 1.O.244.238; 1.O.244.239; 1.O.244.154;
1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175;
1.O.244.240; 1.O.244.244; Prodrugs of 1.P 1.P.228.228; 1.P.228.229;
1.P.228.230; 1.P.228.231; 1.P.228.236; 1.P.228.237; 1.P.228.238;
1.P.228.239; 1.P.228.154; 1.P.228.157; 1.P.228.166; 1.P.228.169;
1.P.228.172; 1.P.228.175; 1.P.228.240; 1.P.228.244; 1.P.229.228;
1.P.229.229; 1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237;
1.P.229.238; 1.P.229.239; 1.P.229.154; 1.P.229.157; 1.P.229.166;
1.P.229.169; 1.P.229.172; 1.P.229.175; 1.P.229.240; 1.P.229.244;
1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231; 1.P.230.236;
1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157;
1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240;
1.P.230.244; 1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231;
1.P.231.236; 1.P.231.237; 1.P.231.238; 1.P.231.239; 1.P.231.154;
1.P.231.157; 1.P.231.166; 1.P.231.169; 1.P.231.172; 1.P.231.175;
1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229; 1.P.236.230;
1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239;
1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172;
1.P.236.175; 1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229;
1.P.237.230; 1.P.237.231; 1.P.237.236; 1.P.237.237; 1.P.237.238;
1.P.237.239; 1.P.237.154; 1.P.237.157; 1.P.237.166; 1.P.237.169;
1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244; 1.P.238.228;
1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237;
1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166;
1.P.238.169; 1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244;
1.P.239.228; 1.P.239.229; 1.P.239.230; 1.P.239.231; 1.P.239.236;
1.P.239.237; 1.P.239.238; 1.P.239.239; 1.P.239.154; 1.P.239.157;
1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175; 1.P.239.240;
1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231;
1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154;
1.P.154.157; 1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175;
1.P.154.240; 1.P.154.244; 1.P.157.228; 1.P.157.229; 1.P.157.230;
1.P.157.231; 1.P.157.236; 1.P.157.237; 1.P.157.238; 1.P.157.239;
1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169; 1.P.157.172;
1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P.166.229;
1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238;
1.P.166.239; 1.P.166.154; 1.P.166.157; 1.P.166.166; 1.P.166.169;
1.P.166.172; 1.P.166.175; 1.P.166.240; 1.P.166.244; 1.P.169.228;
1.P.169.229; 1.P.169.230; 1.P.169.231; 1.P.169.236; 1.P.169.237;
1.P.169.238; 1.P.169.239; 1.P.169.154; 1.P.169.157; 1.P.169.166;
1.P.169.169; 1.P.169.172; 1.P.169.175; 1.P.169.240; 1.P.169.244;
1.P.172.228; 1.P.172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236;
1.P.172.237; 1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P.172.157;
1.P.172.166; 1.P.172.169; 1.P.172.172; 1.P.172.175; 1.P.172.240;
1.P.172.244; 1.P.175.228; 1.P.175.229; 1.P.175.230; 1.P.175.231;
1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239; 1.P.175.154;
1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175;
1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230;
1.P.240.231; 1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239;
1.P.240.154; 1.P.240.157; 1.P.240.166; 1.P.240.169; 1.P.240.172;
1.P.240.175; 1.P.240.240; 1.P.240.244; 1.P.244.228; 1.P.244.229;
1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237; 1.P.244.238;
1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169;
1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244; Prodrugs of 1.U
1.U.228.228; 1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236;
1.U.228.237; 1.U.228.238; 1.U.228.239; 1.U.228.154; 1.U.228.157;
1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240;
1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231;
1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154;
1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175;
1.U.229.240; 1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230;
1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239;
1.U.230.154; 1.U.230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172;
1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229;
1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238;
1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169;
1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228;
1.U.236.229; 1.U.236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237;
1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166;
1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244;
1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236;
1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157;
1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240;
1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231;
1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239;
1.U.238.154;
1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175;
1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230;
1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239;
1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172;
1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229;
1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238;
1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169;
1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228;
1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237;
1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166;
1.U.157.169; 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244;
1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1.U.166.236;
1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154; 1.U.166.157;
1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240;
1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231;
1.U.169.236; 1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154;
1.U.169.157; 1.U.169.166; 1.U.169.169; 1.U.169.172; 1.U.169.175;
1.U.169.240; 1.U.169.244; 1.U.172.228; 1.U.172.229; 1.U.172.230;
1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238; 1.U.172.239;
1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172;
1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229;
1.U.175.230; 1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238;
1.U.175.239; 1.U.175.154; 1.U.175.157; 1.U.175.166; 1.U.175.169;
1.U.175.172; 1.U.175.175; 1.U.175.240; 1.U.175.244; 1.U.240.228;
1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236; 1.U.240.237;
1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166;
1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244;
1.U.244.228; 1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236;
1.U.244.237; 1.U.244.238; 1.U.244.239; 1.U.244.154; 1.U.244.157;
1.U.244.166; 1.U.244.169; 1.U.244.172; 1.U.244.175; 1.U.244.240;
1.U.244.244; Prodrugs of 1.W 1.W.228.228; 1.W.228.229; 1.W.228.230;
1.W.228.231; 1.W.228.236; 1.W.228.237; 1.W.228.238; 1.W.228.239;
1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169; 1.W.228.172;
1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229;
1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238;
1.W.229.239; 1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169;
1.W.229.172; 1.W.229.175; 1.W.229.240; 1.W.229.244; 1.W.230.228;
1.W.230.229; 1.W.230.230; 1.W.230.231; 1.W.230.236; 1.W.230.237;
1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157; 1.W.230.166;
1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244;
1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236;
1.W.231.237; 1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157;
1.W.231.166; 1.W.231.169; 1.W.231.172; 1.W.231.175; 1.W.231.240;
1.W.231.244; 1.W.236.228; 1.W.236.229; 1.W.236.230; 1.W.236.231;
1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239; 1.W.236.154;
1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175;
1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230;
1.W.237.231; 1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239;
1.W.237.154; 1.W.237.157; 1.W.237.166; 1.W.237.169; 1.W.237.172;
1.W.237.175; 1.W.237.240; 1.W.237.244; 1.W.238.228; 1.W.238.229;
1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237; 1.W.238.238;
1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169;
1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228;
1.W.239.229; 1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237;
1.W.239.238; 1.W.239.239; 1.W.239.154; 1.W.239.157; 1.W.239.166;
1.W.239.169; 1.W.239.172; 1.W.239.175; 1.W.239.240; 1.W.239.244;
1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231; 1.W.154.236;
1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157;
1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240;
1.W.154.244; 1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231;
1.W.157.236; 1.W.157.237; 1.W.157.238; 1.W.157.239; 1.W.157.154;
1.W.157.157; 1.W.157.166; 1.W.157.169; 1.W.157.172; 1.W.157.175;
1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229; 1.W.166.230;
1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239;
1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172;
1.W.166.175; 1.W.166.240; 1.W.166.244; 1.W.169.228; 1.W.169.229;
1.W.169.230; 1.W.169.231; 1.W.169.236; 1.W.169.237; 1.W.169.238;
1.W.169.239; 1.W.169.154; 1.W.169.157; 1.W.169.166; 1.W.169.169;
1.W.169.172; 1.W.169.175; 1.W.169.240; 1.W.169.244; 1.W.172.228;
1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237;
1.W.172.238; 1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166;
1.W.172.169; 1.W.172.172; 1.W.172.175; 1.W.172.240; 1.W.172.244;
1.W.175.228; 1.W.175.229; 1.W.175.230; 1.W.175.231; 1.W.175.236;
1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154; 1.W.175.157;
1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240;
1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231;
1.W.240.236; 1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154;
1.W.240.157; 1.W.240.166; 1.W.240.169; 1.W.240.172; 1.W.240.175;
1.W.240.240; 1.W.240.244; 1.W.244.228; 1.W.244.229; 1.W.244.230;
1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238; 1.W.244.239;
1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172;
1.W.244.175; 1.W.244.240; 1.W.244.244; Prodrugs of 1.Y 1.Y.228.228;
1.Y.228.229; 1.Y.228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237;
1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166;
1.Y.228.169; 1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244;
1.Y.229.228; 1.Y.229.229; 1.Y.229.230; 1.Y.229.231; 1.Y.229.236;
1.Y.229.237; 1.Y.229.238; 1.Y.229.239; 1.Y.229.154; 1.Y.229.157;
1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175; 1.Y.229.240;
1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231;
1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154;
1.Y.230.157; 1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175;
1.Y.230.240; 1.Y.230.244; 1.Y.231.228; 1.Y.231.229; 1.Y.231.230;
1.Y.231.231; 1.Y.231.236; 1.Y.231.237; 1.Y.231.238; 1.Y.231.239;
1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169; 1.Y.231.172;
1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229;
1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238;
1.Y.236.239; 1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169;
1.Y.236.172; 1.Y.236.175; 1.Y.236.240; 1.Y.236.244; 1.Y.237.228;
1.Y.237.229; 1.Y.237.230; 1.Y.237.231; 1.Y.237.236; 1.Y.237.237;
1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157; 1.Y.237.166;
1.Y.237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244;
1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236;
1.Y.238.237; 1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157;
1.Y.238.166; 1.Y.238.169; 1.Y.238.172; 1.Y.238.175; 1.Y.238.240;
1.Y.238.244; 1.Y.239.228; 1.Y.239.229; 1.Y.239.230; 1.Y.239.231;
1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239; 1.Y.239.154;
1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175;
1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230;
1.Y.154.231; 1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239;
1.Y.154.154; 1.Y.154.157; 1.Y.154.166; 1.Y.154.169; 1.Y.154.172;
1.Y.154.175; 1.Y.154.240; 1.Y.154.244; 1.Y.157.228; 1.Y.157.229;
1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237; 1.Y.157.238;
1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169;
1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228;
1.Y.166.229; 1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237;
1.Y.166.238; 1.Y.166.239; 1.Y.166.154; 1.Y.166.157; 1.Y.166.166;
1.Y.166.169; 1.Y.166.172; 1.Y.166.175; 1.Y.166.240; 1.Y.166.244;
1.Y.169.228; 1.Y.169.229; 1.Y.169.230; 1.Y.169.231; 1.Y.169.236;
1.Y.169.237; 1.Y.169.238; 1.Y.169.239; 1.Y.169.154; 1.Y.169.157;
1.Y.169.166; 1.Y.169.169; 1.Y.169.172; 1.Y.169.175; 1.Y.169.240;
1.Y.169.244; 1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231;
1.Y.172.236; 1.Y.172.237; 1.Y.172.238; 1.Y.172.239; 1.Y.172.154;
1.Y.172.157; 1.Y.172.166; 1.Y.172.169; 1.Y.172.172; 1.Y.172.175;
1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229; 1.Y.175.230;
1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239;
1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172;
1.Y.175.175; 1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229;
1.Y.240.230; 1.Y.240.231; 1.Y.240.236; 1.Y.240.237; 1.Y.240.238;
1.Y.240.239; 1.Y.240.154; 1.Y.240.157; 1.Y.240.166; 1.Y.240.169;
1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244; 1.Y.244.228;
1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237;
1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166;
1.Y.244.169; 1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;
Prodrugs of 2.B 2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231;
2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154;
2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175;
2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230;
2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239;
2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172;
2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229;
2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238;
2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169;
2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228;
2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237;
2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166;
2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244;
2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236;
2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157;
2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240;
2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231;
2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154;
2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175;
2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230;
2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239;
2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172;
2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229;
2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238;
2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169;
2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228;
2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236; 2.B.154.237;
2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166;
2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244;
2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236;
2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157;
2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240;
2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231;
2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154;
2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175;
2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230;
2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239;
2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172;
2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229;
2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238;
2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169;
2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228;
2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237;
2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166;
2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244;
2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236;
2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157;
2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240;
2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231;
2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154;
2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175;
2.B.244.240; 2.B.244.244; Prodrugs of 2.D 2.D.228.228; 2.D.228.229;
2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238;
2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169;
2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228;
2.D.229.229; 2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237;
2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166;
2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244;
2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236;
2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157;
2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240;
2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231;
2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154;
2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175;
2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230;
2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239;
2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172;
2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229;
2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238;
2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169;
2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228;
2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237;
2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166;
2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244;
2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236;
2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157;
2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240;
2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231;
2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154;
2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175;
2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230;
2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239;
2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172;
2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229;
2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238;
2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169;
2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D.169.228;
2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237;
2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166;
2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244;
2.D.172.228; 2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236;
2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157;
2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240;
2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231;
2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154;
2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175;
2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230;
2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239;
2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172;
2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229;
2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238;
2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169;
2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244; Prodrugs of 2.E
2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236;
2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157;
2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240;
2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231;
2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154;
2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175;
2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229;
2.E.230.230;
2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239;
2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172;
2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229;
2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238;
2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169;
2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228;
2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237;
2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166;
2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244;
2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236;
2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157;
2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240;
2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231;
2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154;
2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175;
2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230;
2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239;
2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172;
2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229;
2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238;
2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169;
2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228;
2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237;
2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166;
2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244;
2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236;
2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157;
2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240;
2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231;
2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154;
2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175;
2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230;
2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239;
2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172;
2.E.172.175; 2.E.172.240; 2.E.172.244; 2.E.175.228; 2.E.175.229;
2.E.175.230; 2.E.175.231; 2.E.175.236; 2.E.175.237; 2.E.175.238;
2.E.175.239; 2.E.175.154; 2.E.175.157; 2.E.175.166; 2.E.175.169;
2.E.175.172; 2.E.175.175; 2.E.175.240; 2.E.175.244; 2.E.240.228;
2.E.240.229; 2.E.240.230; 2.E.240.231; 2.E.240.236; 2.E.240.237;
2.E.240.238; 2.E.240.239; 2.E.240.154; 2.E.240.157; 2.E.240.166;
2.E.240.169; 2.E.240.172; 2.E.240.175; 2.E.240.240; 2.E.240.244;
2.E.244.228; 2.E.244.229; 2.E.244.230; 2.E.244.231; 2.E.244.236;
2.E.244.237; 2.E.244.238; 2.E.244.239; 2.E.244.154; 2.E.244.157;
2.E.244.166; 2.E.244.169; 2.E.244.172; 2.E.244.175; 2.E.244.240;
2.E.244.244; Prodrugs of 2.G 2.G.228.228; 2.G.228.229; 2.G.228.230;
2.G.228.231; 2.G.228.236; 2.G.228.237; 2.G.228.238; 2.G.228.239;
2.G.228.154; 2.G.228.157; 2.G.228.166; 2.G.228.169; 2.G.228.172;
2.G.228.175; 2.G.228.240; 2.G.228.244; 2.G.229.228; 2.G.229.229;
2.G.229.230; 2.G.229.231; 2.G.229.236; 2.G.229.237; 2.G.229.238;
2.G.229.239; 2.G.229.154; 2.G.229.157; 2.G.229.166; 2.G.229.169;
2.G.229.172; 2.G.229.175; 2.G.229.240; 2.G.229.244; 2.G.230.228;
2.G.230.229; 2.G.230.230; 2.G.230.231; 2.G.230.236; 2.G.230.237;
2.G.230.238; 2.G.230.239; 2.G.230.154; 2.G.230.157; 2.G.230.166;
2.G.230.169; 2.G.230.172; 2.G.230.175; 2.G.230.240; 2.G.230.244;
2.G.231.228; 2.G.231.229; 2.G.231.230; 2.G.231.231; 2.G.231.236;
2.G.231.237; 2.G.231.238; 2.G.231.239; 2.G.231.154; 2.G.231.157;
2.G.231.166; 2.G.231.169; 2.G.231.172; 2.G.231.175; 2.G.231.240;
2.G.231.244; 2.G.236.228; 2.G.236.229; 2.G.236.230; 2.G.236.231;
2.G.236.236; 2.G.236.237; 2.G.236.238; 2.G.236.239; 2.G.236.154;
2.G.236.157; 2.G.236.166; 2.G.236.169; 2.G.236.172; 2.G.236.175;
2.G.236.240; 2.G.236.244; 2.G.237.228; 2.G.237.229; 2.G.237.230;
2.G.237.231; 2.G.237.236; 2.G.237.237; 2.G.237.238; 2.G.237.239;
2.G.237.154; 2.G.237.157; 2.G.237.166; 2.G.237.169; 2.G.237.172;
2.G.237.175; 2.G.237.240; 2.G.237.244; 2.G.238.228; 2.G.238.229;
2.G.238.230; 2.G.238.231; 2.G.238.236; 2.G.238.237; 2.G.238.238;
2.G.238.239; 2.G.238.154; 2.G.238.157; 2.G.238.166; 2.G.238.169;
2.G.238.172; 2.G.238.175; 2.G.238.240; 2.G.238.244; 2.G.239.228;
2.G.239.229; 2.G.239.230; 2.G.239.231; 2.G.239.236; 2.G.239.237;
2.G.239.238; 2.G.239.239; 2.G.239.154; 2.G.239.157; 2.G.239.166;
2.G.239.169; 2.G.239.172; 2.G.239.175; 2.G.239.240; 2.G.239.244;
2.G.154.228; 2.G.154.229; 2.G.154.230; 2.G.154.231; 2.G.154.236;
2.G.154.237; 2.G.154.238; 2.G.154.239; 2.G.154.154; 2.G.154.157;
2.G.154.166; 2.G.154.169; 2.G.154.172; 2.G.154.175; 2.G.154.240;
2.G.154.244; 2.G.157.228; 2.G.157.229; 2.G.157.230; 2.G.157.231;
2.G.157.236; 2.G.157.237; 2.G.157.238; 2.G.157.239; 2.G.157.154;
2.G.157.157; 2.G.157.166; 2.G.157.169; 2.G.157.172; 2.G.157.175;
2.G.157.240; 2.G.157.244; 2.G.166.228; 2.G.166.229; 2.G.166.230;
2.G.166.231; 2.G.166.236; 2.G.166.237; 2.G.166.238; 2.G.166.239;
2.G.166.154; 2.G.166.157; 2.G.166.166; 2.G.166.169; 2.G.166.172;
2.G.166.175; 2.G.166.240; 2.G.166.244; 2.G.169.228; 2.G.169.229;
2.G.169.230; 2.G.169.231; 2.G.169.236; 2.G.169.237; 2.G.169.238;
2.G.169.239; 2.G.169.154; 2.G.169.157; 2.G.169.166; 2.G.169.169;
2.G.169.172; 2.G.169.175; 2.G.169.240; 2.G.169.244; 2.G.172.228;
2.G.172.229; 2.G.172.230; 2.G.172.231; 2.G.172.236; 2.G.172.237;
2.G.172.238; 2.G.172.239; 2.G.172.154; 2.G.172.157; 2.G.172.166;
2.G.172.169; 2.G.172.172; 2.G.172.175; 2.G.172.240; 2.G.172.244;
2.G.175.228; 2.G.175.229; 2.G.175.230; 2.G.175.231; 2.G.175.236;
2.G.175.237; 2.G.175.238; 2.G.175.239; 2.G.175.154; 2.G.175.157;
2.G.175.166; 2.G.175.169; 2.G.175.172; 2.G.175.175; 2.G.175.240;
2.G.175.244; 2.G.240.228; 2.G.240.229; 2.G.240.230; 2.G.240.231;
2.G.240.236; 2.G.240.237; 2.G.240.238; 2.G.240.239; 2.G.240.154;
2.G.240.157; 2.G.240.166; 2.G.240.169; 2.G.240.172; 2.G.240.175;
2.G.240.240; 2.G.240.244; 2.G.244.228; 2.G.244.229; 2.G.244.230;
2.G.244.231; 2.G.244.236; 2.G.244.237; 2.G.244.238; 2.G.244.239;
2.G.244.154; 2.G.244.157; 2.G.244.166; 2.G.244.169; 2.G.244.172;
2.G.244.175; 2.G.244.240; 2.G.244.244; Prodrugs of 2.I 2.I.228.228;
2.I.228.229; 2.I.228.230; 2.I.228.231; 2.I.228.236; 2.I.228.237;
2.I.228.238; 2.I.228.239; 2.I.228.154; 2.I.228.157; 2.I.228.166;
2.I.228.169; 2.I.228.172; 2.I.228.175; 2.I.228.240; 2.I.228.244;
2.I.229.228; 2.I.229.229; 2.I.229.230; 2.I.229.231; 2.I.229.236;
2.I.229.237; 2.I.229.238; 2.I.229.239; 2.I.229.154; 2.I.229.157;
2.I.229.166; 2.I.229.169; 2.I.229.172; 2.I.229.175; 2.I.229.240;
2.I.229.244; 2.I.230.228; 2.I.230.229; 2.I.230.230; 2.I.230.231;
2.I.230.236; 2.I.230.237; 2.I.230.238; 2.I.230.239; 2.I.230.154;
2.I.230.157; 2.I.230.166; 2.I.230.169; 2.I.230.172; 2.I.230.175;
2.I.230.240; 2.I.230.244; 2.I.231.228; 2.I.231.229; 2.I.231.230;
2.I.231.231; 2.I.231.236; 2.I.231.237; 2.I.231.238; 2.I.231.239;
2.I.231.154; 2.I.231.157; 2.I.231.166; 2.I.231.169; 2.I.231.172;
2.I.231.175; 2.I.231.240; 2.I.231.244; 2.I.236.228; 2.I.236.229;
2.I.236.230; 2.I.236.231; 2.I.236.236; 2.I.236.237; 2.I.236.238;
2.I.236.239; 2.I.236.154; 2.I.236.157; 2.I.236.166; 2.I.236.169;
2.I.236.172; 2.I.236.175; 2.I.236.240; 2.I.236.244; 2.I.237.228;
2.I.237.229; 2.I.237.230; 2.I.237.231; 2.I.237.236; 2.I.237.237;
2.I.237.238; 2.I.237.239; 2.I.237.154; 2.I.237.157; 2.I.237.166;
2.I.237.169; 2.I.237.172; 2.I.237.175; 2.I.237.240; 2.I.237.244;
2.I.238.228; 2.I.238.229; 2.I.238.230; 2.I.238.231; 2.I.238.236;
2.I.238.237; 2.I.238.238; 2.I.238.239; 2.I.238.154; 2.I.238.157;
2.I.238.166; 2.I.238.169; 2.I.238.172; 2.I.238.175; 2.I.238.240;
2.I.238.244; 2.I.239.228; 2.I.239.229; 2.I.239.230; 2.I.239.231;
2.I.239.236; 2.I.239.237; 2.I.239.238; 2.I.239.239; 2.I.239.154;
2.I.239.157; 2.I.239.166; 2.I.239.169; 2.I.239.172; 2.I.239.175;
2.I.239.240; 2.I.239.244; 2.I.154.228; 2.I.154.229; 2.I.154.230;
2.I.154.231; 2.I.154.236; 2.I.154.237; 2.I.154.238; 2.I.154.239;
2.I.154.154; 2.I.154.157; 2.I.154.166; 2.I.154.169; 2.I.154.172;
2.I.154.175; 2.I.154.240; 2.I.154.244; 2.I.157.228; 2.I.157.229;
2.I.157.230; 2.I.157.231; 2.I.157.236; 2.I.157.237; 2.I.157.238;
2.I.157.239; 2.I.157.154; 2.I.157.157; 2.I.157.166; 2.I.157.169;
2.I.157.172; 2.I.157.175; 2.I.157.240; 2.I.157.244; 2.I.166.228;
2.I.166.229; 2.I.166.230; 2.I.166.231; 2.I.166.236; 2.I.166.237;
2.I.166.238; 2.I.166.239; 2.I.166.154; 2.I.166.157; 2.I.166.166;
2.I.166.169; 2.I.166.172; 2.I.166.175; 2.I.166.240; 2.I.166.244;
2.I.169.228; 2.I.169.229; 2.I.169.230; 2.I.169.231; 2.I.169.236;
2.I.169.237; 2.I.169.238; 2.I.169.239; 2.I.169.154; 2.I.169.157;
2.I.169.166; 2.I.169.169; 2.I.169.172; 2.I.169.175; 2.I.169.240;
2.I.169.244; 2.I.172.228; 2.I.172.229; 2.I.172.230; 2.I.172.231;
2.I.172.236; 2.I.172.237; 2.I.172.238; 2.I.172.239; 2.I.172.154;
2.I.172.157; 2.I.172.166; 2.I.172.169; 2.I.172.172; 2.I.172.175;
2.I.172.240; 2.I.172.244; 2.I.175.228; 2.I.175.229; 2.I.175.230;
2.I.175.231; 2.I.175.236; 2.I.175.237; 2.I.175.238; 2.I.175.239;
2.I.175.154; 2.I.175.157; 2.I.175.166; 2.I.175.169; 2.I.175.172;
2.I.175.175; 2.I.175.240; 2.I.175.244; 2.I.240.228; 2.I.240.229;
2.I.240.230; 2.I.240.231; 2.I.240.236; 2.I.240.237; 2.I.240.238;
2.I.240.239; 2.I.240.154; 2.I.240.157; 2.I.240.166; 2.I.240.169;
2.I.240.172; 2.I.240.175; 2.I.240.240; 2.I.240.244; 2.I.244.228;
2.I.244.229; 2.I.244.230; 2.I.244.231; 2.I.244.236; 2.I.244.237;
2.I.244.238; 2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166;
2.I.244.169; 2.I.244.172; 2.I.244.175; 2.I.244.240; 2.I.244.244;
Prodrugs of 2.J 2.J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231;
2.J.228.236; 2.J.228.237; 2.J.228.238; 2.J.228.239; 2.J.228.154;
2.J.228.157; 2.J.228.166; 2.J.228.169; 2.J.228.172; 2.J.228.175;
2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229; 2.J.229.230;
2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239;
2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172;
2.J.229.175; 2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229;
2.J.230.230; 2.J.230.231; 2.J.230.236; 2.J.230.237; 2.J.230.238;
2.J.230.239; 2.J.230.154; 2.J.230.157; 2.J.230.166; 2.J.230.169;
2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244; 2.J.231.228;
2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237;
2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166;
2.J.231.169; 2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244;
2.J.236.228; 2.J.236.229; 2.J.236.230; 2.J.236.231; 2.J.236.236;
2.J.236.237; 2.J.236.238; 2.J.236.239; 2.J.236.154; 2.J.236.157;
2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175; 2.J.236.240;
2.J.236.244; 2.J.237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231;
2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154;
2.J.237.157; 2.J.237.166; 2.J.237.169; 2.J.237.172; 2.J.237.175;
2.J.237.240; 2.J.237.244; 2.J.238.228; 2.J.238.229; 2.J.238.230;
2.J.238.231; 2.J.238.236; 2.J.238.237; 2.J.238.238; 2.J.238.239;
2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169; 2.J.238.172;
2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229;
2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238;
2.J.239.239; 2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169;
2.J.239.172; 2.J.239.175; 2.J.239.240; 2.J.239.244; 2.J.154.228;
2.J.154.229; 2.J.154.230; 2.J.154.231; 2.J.154.236; 2.J.154.237;
2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157; 2.J.154.166;
2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244;
2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236;
2.J.157.237; 2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157;
2.J.157.166; 2.J.157.169; 2.J.157.172; 2.J.157.175; 2.J.157.240;
2.J.157.244; 2.J.166.228; 2.J.166.229; 2.J.166.230; 2.J.166.231;
2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239; 2.J.166.154;
2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175;
2.J.166.240; 2.J.166.244; 2.J.169.228; 2.J.169.229; 2.J.169.230;
2.J.169.231; 2.J.169.236; 2.J.169.237; 2.J.169.238; 2.J.169.239;
2.J.169.154; 2.J.169.157; 2.J.169.166; 2.J.169.169; 2.J.169.172;
2.J.169.175; 2.J.169.240; 2.J.169.244; 2.J.172.228; 2.J.172.229;
2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237; 2.J.172.238;
2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169;
2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228;
2.J.175.229; 2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237;
2.J.175.238; 2.J.175.239; 2.J.175.154; 2.J.175.157; 2.J.175.166;
2.J.175.169; 2.J.175.172; 2.J.175.175; 2.J.175.240; 2.J.175.244;
2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231; 2.J.240.236;
2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157;
2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240;
2.J.240.244; 2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231;
2.J.244.236; 2.J.244.237; 2.J.244.238; 2.J.244.239; 2.J.244.154;
2.J.244.157; 2.J.244.166; 2.J.244.169; 2.J.244.172; 2.J.244.175;
2.J.244.240; 2.J.244.244; Prodrugs of 2.L 2.L.228.228; 2.L.228.229;
2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238;
2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169;
2.L.228.172; 2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228;
2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237;
2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166;
2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244;
2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236;
2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157;
2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240;
2.L.230.244; 2.L.231.228; 2.L.231.229; 2.L.231.230; 2.L.231.231;
2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154;
2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175;
2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230;
2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239;
2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172;
2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L.237.228; 2.L.237.229;
2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238;
2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166; 2.L.237.169;
2.L.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228;
2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237;
2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166;
2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244;
2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236;
2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157;
2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240;
2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231;
2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154;
2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175;
2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L.157.229; 2.L.157.230;
2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239;
2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172;
2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229;
2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238;
2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169;
2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L.169.228;
2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236; 2.L.169.237;
2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166;
2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244;
2.L.172.228; 2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236;
2.L.172.237; 2.L.172.238; 2.L.172.239; 2.L.172.154; 2.L.172.157;
2.L.172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240;
2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230; 2.L.175.231;
2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154;
2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175;
2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230;
2.L.240.231; 2.L.240.236; 2.L.240.237;
2.L.240.238; 2.L.240.239; 2.L.240.154; 2.L.240.157; 2.L.240.166;
2.L.240.169; 2.L.240.172; 2.L.240.175; 2.L.240.240; 2.L.240.244;
2.L.244.228; 2.L.244.229; 2.L.244.230; 2.L.244.231; 2.L.244.236;
2.L.244.237; 2.L.244.238; 2.L.244.239; 2.L.244.154; 2.L.244.157;
2.L.244.166; 2.L.244.169; 2.L.244.172; 2.L.244.175; 2.L.244.240;
2.L.244.244; Prodrugs of 2.O 2.O.228.228; 2.O.228.229; 2.O.228.230;
2.O.228.231; 2.O.228.236; 2.O.228.237; 2.O.228.238; 2.O.228.239;
2.O.228.154; 2.O.228.157; 2.O.228.166; 2.O.228.169; 2.O.228.172;
2.O.228.175; 2.O.228.240; 2.O.228.244; 2.O.229.228; 2.O.229.229;
2.O.229.230; 2.O.229.231; 2.O.229.236; 2.O.229.237; 2.O.229.238;
2.O.229.239; 2.O.229.154; 2.O.229.157; 2.O.229.166; 2.O.229.169;
2.O.229.172; 2.O.229.175; 2.O.229.240; 2.O.229.244; 2.O.230.228;
2.O.230.229; 2.O.230.230; 2.O.230.231; 2.O.230.236; 2.O.230.237;
2.O.230.238; 2.O.230.239; 2.O.230.154; 2.O.230.157; 2.O.230.166;
2.O.230.169; 2.O.230.172; 2.O.230.175; 2.O.230.240; 2.O.230.244;
2.O.231.228; 2.O.231.229; 2.O.231.230; 2.O.231.231; 2.O.231.236;
2.O.231.237; 2.O.231.238; 2.O.231.239; 2.O.231.154; 2.O.231.157;
2.O.231.166; 2.O.231.169; 2.O.231.172; 2.O.231.175; 2.O.231.240;
2.O.231.244; 2.O.236.228; 2.O.236.229; 2.O.236.230; 2.O.236.231;
2.O.236.236; 2.O.236.237; 2.O.236.238; 2.O.236.239; 2.O.236.154;
2.O.236.157; 2.O.236.166; 2.O.236.169; 2.O.236.172; 2.O.236.175;
2.O.236.240; 2.O.236.244; 2.O.237.228; 2.O.237.229; 2.O.237.230;
2.O.237.231; 2.O.237.236; 2.O.237.237; 2.O.237.238; 2.O.237.239;
2.O.237.154; 2.O.237.157; 2.O.237.166; 2.O.237.169; 2.O.237.172;
2.O.237.175; 2.O.237.240; 2.O.237.244; 2.O.238.228; 2.O.238.229;
2.O.238.230; 2.O.238.231; 2.O.238.236; 2.O.238.237; 2.O.238.238;
2.O.238.239; 2.O.238.154; 2.O.238.157; 2.O.238.166; 2.O.238.169;
2.O.238.172; 2.O.238.175; 2.O.238.240; 2.O.238.244; 2.O.239.228;
2.O.239.229; 2.O.239.230; 2.O.239.231; 2.O.239.236; 2.O.239.237;
2.O.239.238; 2.O.239.239; 2.O.239.154; 2.O.239.157; 2.O.239.166;
2.O.239.169; 2.O.239.172; 2.O.239.175; 2.O.239.240; 2.O.239.244;
2.O.154.228; 2.O.154.229; 2.O.154.230; 2.O.154.231; 2.O.154.236;
2.O.154.237; 2.O.154.238; 2.O.154.239; 2.O.154.154; 2.O.154.157;
2.O.154.166; 2.O.154.169; 2.O.154.172; 2.O.154.175; 2.O.154.240;
2.O.154.244; 2.O.157.228; 2.O.157.229; 2.O.157.230; 2.O.157.231;
2.O.157.236; 2.O.157.237; 2.O.157.238; 2.O.157.239; 2.O.157.154;
2.O.157.157; 2.O.157.166; 2.O.157.169; 2.O.157.172; 2.O.157.175;
2.O.157.240; 2.O.157.244; 2.O.166.228; 2.O.166.229; 2.O.166.230;
2.O.166.231; 2.O.166.236; 2.O.166.237; 2.O.166.238; 2.O.166.239;
2.O.166.154; 2.O.166.157; 2.O.166.166; 2.O.166.169; 2.O.166.172;
2.O.166.175; 2.O.166.240; 2.O.166.244; 2.O.169.228; 2.O.169.229;
2.O.169.230; 2.O.169.231; 2.O.169.236; 2.O.169.237; 2.O.169.238;
2.O.169.239; 2.O.169.154; 2.O.169.157; 2.O.169.166; 2.O.169.169;
2.O.169.172; 2.O.169.175; 2.O.169.240; 2.O.169.244; 2.O.172.228;
2.O.172.229; 2.O.172.230; 2.O.172.231; 2.O.172.236; 2.O.172.237;
2.O.172.238; 2.O.172.239; 2.O.172.154; 2.O.172.157; 2.O.172.166;
2.O.172.169; 2.O.172.172; 2.O.172.175; 2.O.172.240; 2.O.172.244;
2.O.175.228; 2.O.175.229; 2.O.175.230; 2.O.175.231; 2.O.175.236;
2.O.175.237; 2.O.175.238; 2.O.175.239; 2.O.175.154; 2.O.175.157;
2.O.175.166; 2.O.175.169; 2.O.175.172; 2.O.175.175; 2.O.175.240;
2.O.175.244; 2.O.240.228; 2.O.240.229; 2.O.240.230; 2.O.240.231;
2.O.240.236; 2.O.240.237; 2.O.240.238; 2.O.240.239; 2.O.240.154;
2.O.240.157; 2.O.240.166; 2.O.240.169; 2.O.240.172; 2.O.240.175;
2.O.240.240; 2.O.240.244; 2.O.244.228; 2.O.244.229; 2.O.244.230;
2.O.244.231; 2.O.244.236; 2.O.244.237; 2.O.244.238; 2.O.244.239;
2.O.244.154; 2.O.244.157; 2.O.244.166; 2.O.244.169; 2.O.244.172;
2.O.244.175; 2.O.244.240; 2.O.244.244; Prodrugs of 2.P 2.P.228.228;
2.P.228.229; 2.P.228.230; 2.P.228.231; 2.P.228.236; 2.P.228.237;
2.P.228.238; 2.P.228.239; 2.P.228.154; 2.P.228.157; 2.P.228.166;
2.P.228.169; 2.P.228.172; 2.P.228.175; 2.P.228.240; 2.P.228.244;
2.P.229.228; 2.P.229.229; 2.P.229.230; 2.P.229.231; 2.P.229.236;
2.P.229.237; 2.P.229.238; 2.P.229.239; 2.P.229.154; 2.P.229.157;
2.P.229.166; 2.P.229.169; 2.P.229.172; 2.P.229.175; 2.P.229.240;
2.P.229.244; 2.P.230.228; 2.P.230.229; 2.P.230.230; 2.P.230.231;
2.P.230.236; 2.P.230.237; 2.P.230.238; 2.P.230.239; 2.P.230.154;
2.P.230.157; 2.P.230.166; 2.P.230.169; 2.P.230.172; 2.P.230.175;
2.P.230.240; 2.P.230.244; 2.P.231.228; 2.P.231.229; 2.P.231.230;
2.P.231.231; 2.P.231.236; 2.P.231.237; 2.P.231.238; 2.P.231.239;
2.P.231.154; 2.P.231.157; 2.P.231.166; 2.P.231.169; 2.P.231.172;
2.P.231.175; 2.P.231.240; 2.P.231.244; 2.P.236.228; 2.P.236.229;
2.P.236.230; 2.P.236.231; 2.P.236.236; 2.P.236.237; 2.P.236.238;
2.P.236.239; 2.P.236.154; 2.P.236.157; 2.P.236.166; 2.P.236.169;
2.P.236.172; 2.P.236.175; 2.P.236.240; 2.P.236.244; 2.P.237.228;
2.P.237.229; 2.P.237.230; 2.P.237.231; 2.P.237.236; 2.P.237.237;
2.P.237.238; 2.P.237.239; 2.P.237.154; 2.P.237.157; 2.P.237.166;
2.P.237.169; 2.P.237.172; 2.P.237.175; 2.P.237.240; 2.P.237.244;
2.P.238.228; 2.P.238.229; 2.P.238.230; 2.P.238.231; 2.P.238.236;
2.P.238.237; 2.P.238.238; 2.P.238.239; 2.P.238.154; 2.P.238.157;
2.P.238.166; 2.P.238.169; 2.P.238.172; 2.P.238.175; 2.P.238.240;
2.P.238.244; 2.P.239.228; 2.P.239.229; 2.P.239.230; 2.P.239.231;
2.P.239.236; 2.P.239.237; 2.P.239.238; 2.P.239.239; 2.P.239.154;
2.P.239.157; 2.P.239.166; 2.P.239.169; 2.P.239.172; 2.P.239.175;
2.P.239.240; 2.P.239.244; 2.P.154.228; 2.P.154.229; 2.P.154.230;
2.P.154.231; 2.P.154.236; 2.P.154.237; 2.P.154.238; 2.P.154.239;
2.P.154.154; 2.P.154.157; 2.P.154.166; 2.P.154.169; 2.P.154.172;
2.P.154.175; 2.P.154.240; 2.P.154.244; 2.P.157.228; 2.P.157.229;
2.P.157.230; 2.P.157.231; 2.P.157.236; 2.P.157.237; 2.P.157.238;
2.P.157.239; 2.P.157.154; 2.P.157.157; 2.P.157.166; 2.P.157.169;
2.P.157.172; 2.P.157.175; 2.P.157.240; 2.P.157.244; 2.P.166.228;
2.P.166.229; 2.P.166.230; 2.P.166.231; 2.P.166.236; 2.P.166.237;
2.P.166.238; 2.P.166.239; 2.P.166.154; 2.P.166.157; 2.P.166.166;
2.P.166.169; 2.P.166.172; 2.P.166.175; 2.P.166.240; 2.P.166.244;
2.P.169.228; 2.P.169.229; 2.P.169.230; 2.P.169.231; 2.P.169.236;
2.P.169.237; 2.P.169.238; 2.P.169.239; 2.P.169.154; 2.P.169.157;
2.P.169.166; 2.P.169.169; 2.P.169.172; 2.P.169.175; 2.P.169.240;
2.P.169.244; 2.P.172.228; 2.P.172.229; 2.P.172.230; 2.P.172.231;
2.P.172.236; 2.P.172.237; 2.P.172.238; 2.P.172.239; 2.P.172.154;
2.P.172.157; 2.P.172.166; 2.P.172.169; 2.P.172.172; 2.P.172.175;
2.P.172.240; 2.P.172.244; 2.P.175.228; 2.P.175.229; 2.P.175.230;
2.P.175.231; 2.P.175.236; 2.P.175.237; 2.P.175.238; 2.P.175.239;
2.P.175.154; 2.P.175.157; 2.P.175.166; 2.P.175.169; 2.P.175.172;
2.P.175.175; 2.P.175.240; 2.P.175.244; 2.P.240.228; 2.P.240.229;
2.P.240.230; 2.P.240.231; 2.P.240.236; 2.P.240.237; 2.P.240.238;
2.P.240.239; 2.P.240.154; 2.P.240.157; 2.P.240.166; 2.P.240.169;
2.P.240.172; 2.P.240.175; 2.P.240.240; 2.P.240.244; 2.P.244.228;
2.P.244.229; 2.P.244.230; 2.P.244.231; 2.P.244.236; 2.P.244.237;
2.P.244.238; 2.P.244.239; 2.P.244.154; 2.P.244.157; 2.P.244.166;
2.P.244.169; 2.P.244.172; 2.P.244.175; 2.P.244.240; 2.P.244.244;
Prodrugs of 2.U 2.U.228.228; 2.U.228.229; 2.U.228.230; 2.U.228.231;
2.U.228.236; 2.U.228.237; 2.U.228.238; 2.U.228.239; 2.U.228.154;
2.U.228.157; 2.U.228.166; 2.U.228.169; 2.U.228.172; 2.U.228.175;
2.U.228.240; 2.U.228.244; 2.U.229.228; 2.U.229.229; 2.U.229.230;
2.U.229.231; 2.U.229.236; 2.U.229.237; 2.U.229.238; 2.U.229.239;
2.U.229.154; 2.U.229.157; 2.U.229.166; 2.U.229.169; 2.U.229.172;
2.U.229.175; 2.U.229.240; 2.U.229.244; 2.U.230.228; 2.U.230.229;
2.U.230.230; 2.U.230.231; 2.U.230.236; 2.U.230.237; 2.U.230.238;
2.U.230.239; 2.U.230.154; 2.U.230.157; 2.U.230.166; 2.U.230.169;
2.U.230.172; 2.U.230.175; 2.U.230.240; 2.U.230.244; 2.U.231.228;
2.U.231.229; 2.U.231.230; 2.U.231.231; 2.U.231.236; 2.U.231.237;
2.U.231.238; 2.U.231.239; 2.U.231.154; 2.U.231.157; 2.U.231.166;
2.U.231.169; 2.U.231.172; 2.U.231.175; 2.U.231.240; 2.U.231.244;
2.U.236.228; 2.U.236.229; 2.U.236.230; 2.U.236.231; 2.U.236.236;
2.U.236.237; 2.U.236.238; 2.U.236.239; 2.U.236.154; 2.U.236.157;
2.U.236.166; 2.U.236.169; 2.U.236.172; 2.U.236.175; 2.U.236.240;
2.U.236.244; 2.U.237.228; 2.U.237.229; 2.U.237.230; 2.U.237.231;
2.U.237.236; 2.U.237.237; 2.U.237.238; 2.U.237.239; 2.U.237.154;
2.U.237.157; 2.U.237.166; 2.U.237.169; 2.U.237.172; 2.U.237.175;
2.U.237.240; 2.U.237.244; 2.U.238.228; 2.U.238.229; 2.U.238.230;
2.U.238.231; 2.U.238.236; 2.U.238.237; 2.U.238.238; 2.U.238.239;
2.U.238.154; 2.U.238.157; 2.U.238.166; 2.U.238.169; 2.U.238.172;
2.U.238.175; 2.U.238.240; 2.U.238.244; 2.U.239.228; 2.U.239.229;
2.U.239.230; 2.U.239.231; 2.U.239.236; 2.U.239.237; 2.U.239.238;
2.U.239.239; 2.U.239.154; 2.U.239.157; 2.U.239.166; 2.U.239.169;
2.U.239.172; 2.U.239.175; 2.U.239.240; 2.U.239.244; 2.U.154.228;
2.U.154.229; 2.U.154.230; 2.U.154.231; 2.U.154.236; 2.U.154.237;
2.U.154.238; 2.U.154.239; 2.U.154.154; 2.U.154.157; 2.U.154.166;
2.U.154.169; 2.U.154.172; 2.U.154.175; 2.U.154.240; 2.U.154.244;
2.U.157.228; 2.U.157.229; 2.U.157.230; 2.U.157.231; 2.U.157.236;
2.U.157.237; 2.U.157.238; 2.U.157.239; 2.U.157.154; 2.U.157.157;
2.U.157.166; 2.U.157.169; 2.U.157.172; 2.U.157.175; 2.U.157.240;
2.U.157.244; 2.U.166.228; 2.U.166.229; 2.U.166.230; 2.U.166.231;
2.U.166.236; 2.U.166.237; 2.U.166.238; 2.U.166.239; 2.U.166.154;
2.U.166.157; 2.U.166.166; 2.U.166.169; 2.U.166.172; 2.U.166.175;
2.U.166.240; 2.U.166.244; 2.U.169.228; 2.U.169.229; 2.U.169.230;
2.U.169.231; 2.U.169.236; 2.U.169.237; 2.U.169.238; 2.U.169.239;
2.U.169.154; 2.U.169.157; 2.U.169.166; 2.U.169.169; 2.U.169.172;
2.U.169.175; 2.U.169.240; 2.U.169.244; 2.U.172.228; 2.U.172.229;
2.U.172.230; 2.U.172.231; 2.U.172.236; 2.U.172.237; 2.U.172.238;
2.U.172.239; 2.U.172.154; 2.U.172.157; 2.U.172.166; 2.U.172.169;
2.U.172.172; 2.U.172.175; 2.U.172.240; 2.U.172.244; 2.U.175.228;
2.U.175.229; 2.U.175.230; 2.U.175.231; 2.U.175.236; 2.U.175.237;
2.U.175.238; 2.U.175.239; 2.U.175.154; 2.U.175.157; 2.U.175.166;
2.U.175.169; 2.U.175.172; 2.U.175.175; 2.U.175.240; 2.U.175.244;
2.U.240.228; 2.U.240.229; 2.U.240.230; 2.U.240.231; 2.U.240.236;
2.U.240.237; 2.U.240.238; 2.U.240.239; 2.U.240.154; 2.U.240.157;
2.U.240.166; 2.U.240.169; 2.U.240.172; 2.U.240.175; 2.U.240.240;
2.U.240.244; 2.U.244.228; 2.U.244.229; 2.U.244.230; 2.U.244.231;
2.U.244.236; 2.U.244.237; 2.U.244.238; 2.U.244.239; 2.U.244.154;
2.U.244.157; 2.U.244.166; 2.U.244.169; 2.U.244.172; 2.U.244.175;
2.U.244.240; 2.U.244.244; Prodrugs of 2.W 2.W.228.228; 2.W.228.229;
2.W.228.230; 2.W.228.231; 2.W.228.236; 2.W.228.237; 2.W.228.238;
2.W.228.239; 2.W.228.154; 2.W.228.157; 2.W.228.166; 2.W.228.169;
2.W.228.172; 2.W.228.175; 2.W.228.240; 2.W.228.244; 2.W.229.228;
2.W.229.229; 2.W.229.230; 2.W.229.231; 2.W.229.236; 2.W.229.237;
2.W.229.238; 2.W.229.239; 2.W.229.154; 2.W.229.157; 2.W.229.166;
2.W.229.169; 2.W.229.172; 2.W.229.175; 2.W.229.240; 2.W.229.244;
2.W.230.228; 2.W.230.229; 2.W.230.230; 2.W.230.231; 2.W.230.236;
2.W.230.237; 2.W.230.238; 2.W.230.239; 2.W.230.154; 2.W.230.157;
2.W.230.166; 2.W.230.169; 2.W.230.172; 2.W.230.175; 2.W.230.240;
2.W.230.244; 2.W.231.228; 2.W.231.229; 2.W.231.230; 2.W.231.231;
2.W.231.236; 2.W.231.237; 2.W.231.238; 2.W.231.239; 2.W.231.154;
2.W.231.157; 2.W.231.166; 2.W.231.169; 2.W.231.172; 2.W.231.175;
2.W.231.240; 2.W.231.244; 2.W.236.228; 2.W.236.229; 2.W.236.230;
2.W.236.231; 2.W.236.236; 2.W.236.237; 2.W.236.238; 2.W.236.239;
2.W.236.154; 2.W.236.157; 2.W.236.166; 2.W.236.169; 2.W.236.172;
2.W.236.175; 2.W.236.240; 2.W.236.244; 2.W.237.228; 2.W.237.229;
2.W.237.230; 2.W.237.231; 2.W.237.236; 2.W.237.237; 2.W.237.238;
2.W.237.239; 2.W.237.154; 2.W.237.157; 2.W.237.166; 2.W.237.169;
2.W.237.172; 2.W.237.175; 2.W.237.240; 2.W.237.244; 2.W.238.228;
2.W.238.229; 2.W.238.230; 2.W.238.231; 2.W.238.236; 2.W.238.237;
2.W.238.238; 2.W.238.239; 2.W.238.154; 2.W.238.157; 2.W.238.166;
2.W.238.169; 2.W.238.172; 2.W.238.175; 2.W.238.240; 2.W.238.244;
2.W.239.228; 2.W.239.229; 2.W.239.230; 2.W.239.231; 2.W.239.236;
2.W.239.237; 2.W.239.238; 2.W.239.239; 2.W.239.154; 2.W.239.157;
2.W.239.166; 2.W.239.169; 2.W.239.172; 2.W.239.175; 2.W.239.240;
2.W.239.244; 2.W.154.228; 2.W.154.229; 2.W.154.230; 2.W.154.231;
2.W.154.236; 2.W.154.237; 2.W.154.238; 2.W.154.239; 2.W.154.154;
2.W.154.157; 2.W.154.166; 2.W.154.169; 2.W.154.172; 2.W.154.175;
2.W.154.240; 2.W.154.244; 2.W.157.228; 2.W.157.229; 2.W.157.230;
2.W.157.231; 2.W.157.236; 2.W.157.237; 2.W.157.238; 2.W.157.239;
2.W.157.154; 2.W.157.157; 2.W.157.166; 2.W.157.169; 2.W.157.172;
2.W.157.175; 2.W.157.240; 2.W.157.244; 2.W.166.228; 2.W.166.229;
2.W.166.230; 2.W.166.231; 2.W.166.236; 2.W.166.237; 2.W.166.238;
2.W.166.239; 2.W.166.154; 2.W.166.157; 2.W.166.166; 2.W.166.169;
2.W.166.172; 2.W.166.175; 2.W.166.240; 2.W.166.244; 2.W.169.228;
2.W.169.229; 2.W.169.230; 2.W.169.231; 2.W.169.236; 2.W.169.237;
2.W.169.238; 2.W.169.239; 2.W.169.154; 2.W.169.157; 2.W.169.166;
2.W.169.169; 2.W.169.172; 2.W.169.175; 2.W.169.240; 2.W.169.244;
2.W.172.228; 2.W.172.229; 2.W.172.230; 2.W.172.231; 2.W.172.236;
2.W.172.237; 2.W.172.238; 2.W.172.239; 2.W.172.154; 2.W.172.157;
2.W.172.166; 2.W.172.169; 2.W.172.172; 2.W.172.175; 2.W.172.240;
2.W.172.244; 2.W.175.228; 2.W.175.229; 2.W.175.230; 2.W.175.231;
2.W.175.236; 2.W.175.237; 2.W.175.238; 2.W.175.239; 2.W.175.154;
2.W.175.157; 2.W.175.166; 2.W.175.169; 2.W.175.172; 2.W.175.175;
2.W.175.240; 2.W.175.244; 2.W.240.228; 2.W.240.229; 2.W.240.230;
2.W.240.231; 2.W.240.236; 2.W.240.237; 2.W.240.238; 2.W.240.239;
2.W.240.154; 2.W.240.157; 2.W.240.166; 2.W.240.169; 2.W.240.172;
2.W.240.175; 2.W.240.240; 2.W.240.244; 2.W.244.228; 2.W.244.229;
2.W.244.230; 2.W.244.231; 2.W.244.236; 2.W.244.237; 2.W.244.238;
2.W.244.239; 2.W.244.154; 2.W.244.157; 2.W.244.166; 2.W.244.169;
2.W.244.172; 2.W.244.175; 2.W.244.240; 2.W.244.244; Prodrugs of 2.Y
2.Y.228.228; 2.Y.228.229; 2.Y.228.230; 2.Y.228.231; 2.Y.228.236;
2.Y.228.237; 2.Y.228.238; 2.Y.228.239; 2.Y.228.154; 2.Y.228.157;
2.Y.228.166; 2.Y.228.169; 2.Y.228.172; 2.Y.228.175; 2.Y.228.240;
2.Y.228.244; 2.Y.229.228; 2.Y.229.229; 2.Y.229.230; 2.Y.229.231;
2.Y.229.236; 2.Y.229.237; 2.Y.229.238; 2.Y.229.239; 2.Y.229.154;
2.Y.229.157; 2.Y.229.166; 2.Y.229.169; 2.Y.229.172; 2.Y.229.175;
2.Y.229.240; 2.Y.229.244; 2.Y.230.228; 2.Y.230.229; 2.Y.230.230;
2.Y.230.231; 2.Y.230.236; 2.Y.230.237; 2.Y.230.238; 2.Y.230.239;
2.Y.230.154; 2.Y.230.157; 2.Y.230.166; 2.Y.230.169; 2.Y.230.172;
2.Y.230.175; 2.Y.230.240; 2.Y.230.244; 2.Y.231.228; 2.Y.231.229;
2.Y.231.230; 2.Y.231.231; 2.Y.231.236; 2.Y.231.237; 2.Y.231.238;
2.Y.231.239; 2.Y.231.154; 2.Y.231.157; 2.Y.231.166; 2.Y.231.169;
2.Y.231.172; 2.Y.231.175; 2.Y.231.240; 2.Y.231.244; 2.Y.236.228;
2.Y.236.229; 2.Y.236.230; 2.Y.236.231; 2.Y.236.236; 2.Y.236.237;
2.Y.236.238; 2.Y.236.239; 2.Y.236.154; 2.Y.236.157; 2.Y.236.166;
2.Y.236.169; 2.Y.236.172; 2.Y.236.175; 2.Y.236.240; 2.Y.236.244;
2.Y.237.228; 2.Y.237.229; 2.Y.237.230; 2.Y.237.231; 2.Y.237.236;
2.Y.237.237; 2.Y.237.238; 2.Y.237.239; 2.Y.237.154; 2.Y.237.157;
2.Y.237.166; 2.Y.237.169; 2.Y.237.172; 2.Y.237.175; 2.Y.237.240;
2.Y.237.244; 2.Y.238.228; 2.Y.238.229; 2.Y.238.230; 2.Y.238.231;
2.Y.238.236; 2.Y.238.237; 2.Y.238.238; 2.Y.238.239; 2.Y.238.154;
2.Y.238.157; 2.Y.238.166; 2.Y.238.169; 2.Y.238.172; 2.Y.238.175;
2.Y.238.240; 2.Y.238.244; 2.Y.239.228; 2.Y.239.229; 2.Y.239.230;
2.Y.239.231; 2.Y.239.236; 2.Y.239.237; 2.Y.239.238; 2.Y.239.239;
2.Y.239.154; 2.Y.239.157; 2.Y.239.166; 2.Y.239.169; 2.Y.239.172;
2.Y.239.175; 2.Y.239.240; 2.Y.239.244; 2.Y.154.228; 2.Y.154.229;
2.Y.154.230; 2.Y.154.231; 2.Y.154.236; 2.Y.154.237; 2.Y.154.238;
2.Y.154.239; 2.Y.154.154; 2.Y.154.157; 2.Y.154.166; 2.Y.154.169;
2.Y.154.172; 2.Y.154.175; 2.Y.154.240; 2.Y.154.244; 2.Y.157.228;
2.Y.157.229; 2.Y.157.230; 2.Y.157.231; 2.Y.157.236; 2.Y.157.237;
2.Y.157.238; 2.Y.157.239; 2.Y.157.154; 2.Y.157.157; 2.Y.157.166;
2.Y.157.169; 2.Y.157.172; 2.Y.157.175; 2.Y.157.240;
2.Y.157.244;
2.Y.166.228; 2.Y.166.229; 2.Y.166.230; 2.Y.166.231; 2.Y.166.236;
2.Y.166.237; 2.Y.166.238; 2.Y.166.239; 2.Y.166.154; 2.Y.166.157;
2.Y.166.166; 2.Y.166.169; 2.Y.166.172; 2.Y.166.175; 2.Y.166.240;
2.Y.166.244; 2.Y.169.228; 2.Y.169.229; 2.Y.169.230; 2.Y.169.231;
2.Y.169.236; 2.Y.169.237; 2.Y.169.238; 2.Y.169.239; 2.Y.169.154;
2.Y.169.157; 2.Y.169.166; 2.Y.169.169; 2.Y.169.172; 2.Y.169.175;
2.Y.169.240; 2.Y.169.244; 2.Y.172.228; 2.Y.172.229; 2.Y.172.230;
2.Y.172.231; 2.Y.172.236; 2.Y.172.237; 2.Y.172.238; 2.Y.172.239;
2.Y.172.154; 2.Y.172.157; 2.Y.172.166; 2.Y.172.169; 2.Y.172.172;
2.Y.172.175; 2.Y.172.240; 2.Y.172.244; 2.Y.175.228; 2.Y.175.229;
2.Y.175.230; 2.Y.175.231; 2.Y.175.236; 2.Y.175.237; 2.Y.175.238;
2.Y.175.239; 2.Y.175.154; 2.Y.175.157; 2.Y.175.166; 2.Y.175.169;
2.Y.175.172; 2.Y.175.175; 2.Y.175.240; 2.Y.175.244; 2.Y.240.228;
2.Y.240.229; 2.Y.240.230; 2.Y.240.231; 2.Y.240.236; 2.Y.240.237;
2.Y.240.238; 2.Y.240.239; 2.Y.240.154; 2.Y.240.157; 2.Y.240.166;
2.Y.240.169; 2.Y.240.172; 2.Y.240.175; 2.Y.240.240; 2.Y.240.244;
2.Y.244.228; 2.Y.244.229; 2.Y.244.230; 2.Y.244.231; 2.Y.244.236;
2.Y.244.237; 2.Y.244.238; 2.Y.244.239; 2.Y.244.154; 2.Y.244.157;
2.Y.244.166; 2.Y.244.169; 2.Y.244.172; 2.Y.244.175; 2.Y.244.240;
2.Y.244.244; Prodrugs of 3.B 3.B.228.228; 3.B.228.229; 3.B.228.230;
3.B.228.231; 3.B.228.236; 3.B.228.237; 3.B.228.238; 3.B.228.239;
3.B.228.154; 3.B.228.157; 3.B.228.166; 3.B.228.169; 3.B.228.172;
3.B.228.175; 3.B.228.240; 3.B.228.244; 3.B.229.228; 3.B.229.229;
3.B.229.230; 3.B.229.231; 3.B.229.236; 3.B.229.237; 3.B.229.238;
3.B.229.239; 3.B.229.154; 3.B.229.157; 3.B.229.166; 3.B.229.169;
3.B.229.172; 3.B.229.175; 3.B.229.240; 3.B.229.244; 3.B.230.228;
3.B.230.229; 3.B.230.230; 3.B.230.231; 3.B.230.236; 3.B.230.237;
3.B.230.238; 3.B.230.239; 3.B.230.154; 3.B.230.157; 3.B.230.166;
3.B.230.169; 3.B.230.172; 3.B.230.175; 3.B.230.240; 3.B.230.244;
3.B.231.228; 3.B.231.229; 3.B.231.230; 3.B.231.231; 3.B.231.236;
3.B.231.237; 3.B.231.238; 3.B.231.239; 3.B.231.154; 3.B.231.157;
3.B.231.166; 3.B.231.169; 3.B.231.172; 3.B.231.175; 3.B.231.240;
3.B.231.244; 3.B.236.228; 3.B.236.229; 3.B.236.230; 3.B.236.231;
3.B.236.236; 3.B.236.237; 3.B.236.238; 3.B.236.239; 3.B.236.154;
3.B.236.157; 3.B.236.166; 3.B.236.169; 3.B.236.172; 3.B.236.175;
3.B.236.240; 3.B.236.244; 3.B.237.228; 3.B.237.229; 3.B.237.230;
3.B.237.231; 3.B.237.236; 3.B.237.237; 3.B.237.238; 3.B.237.239;
3.B.237.154; 3.B.237.157; 3.B.237.166; 3.B.237.169; 3.B.237.172;
3.B.237.175; 3.B.237.240; 3.B.237.244; 3.B.238.228; 3.B.238.229;
3.B.238.230; 3.B.238.231; 3.B.238.236; 3.B.238.237; 3.B.238.238;
3.B.238.239; 3.B.238.154; 3.B.238.157; 3.B.238.166; 3.B.238.169;
3.B.238.172; 3.B.238.175; 3.B.238.240; 3.B.238.244; 3.B.239.228;
3.B.239.229; 3.B.239.230; 3.B.239.231; 3.B.239.236; 3.B.239.237;
3.B.239.238; 3.B.239.239; 3.B.239.154; 3.B.239.157; 3.B.239.166;
3.B.239.169; 3.B.239.172; 3.B.239.175; 3.B.239.240; 3.B.239.244;
3.B.154.228; 3.B.154.229; 3.B.154.230; 3.B.154.231; 3.B.154.236;
3.B.154.237; 3.B.154.238; 3.B.154.239; 3.B.154.154; 3.B.154.157;
3.B.154.166; 3.B.154.169; 3.B.154.172; 3.B.154.175; 3.B.154.240;
3.B.154.244; 3.B.157.228; 3.B.157.229; 3.B.157.230; 3.B.157.231;
3.B.157.236; 3.B.157.237; 3.B.157.238; 3.B.157.239; 3.B.157.154;
3.B.157.157; 3.B.157.166; 3.B.157.169; 3.B.157.172; 3.B.157.175;
3.B.157.240; 3.B.157.244; 3.B.166.228; 3.B.166.229; 3.B.166.230;
3.B.166.231; 3.B.166.236; 3.B.166.237; 3.B.166.238; 3.B.166.239;
3.B.166.154; 3.B.166.157; 3.B.166.166; 3.B.166.169; 3.B.166.172;
3.B.166.175; 3.B.166.240; 3.B.166.244; 3.B.169.228; 3.B.169.229;
3.B.169.230; 3.B.169.231; 3.B.169.236; 3.B.169.237; 3.B.169.238;
3.B.169.239; 3.B.169.154; 3.B.169.157; 3.B.169.166; 3.B.169.169;
3.B.169.172; 3.B.169.175; 3.B.169.240; 3.B.169.244; 3.B.172.228;
3.B.172.229; 3.B.172.230; 3.B.172.231; 3.B.172.236; 3.B.172.237;
3.B.172.238; 3.B.172.239; 3.B.172.154; 3.B.172.157; 3.B.172.166;
3.B.172.169; 3.B.172.172; 3.B.172.175; 3.B.172.240; 3.B.172.244;
3.B.175.228; 3.B.175.229; 3.B.175.230; 3.B.175.231; 3.B.175.236;
3.B.175.237; 3.B.175.238; 3.B.175.239; 3.B.175.154; 3.B.175.157;
3.B.175.166; 3.B.175.169; 3.B.175.172; 3.B.175.175; 3.B.175.240;
3.B.175.244; 3.B.240.228; 3.B.240.229; 3.B.240.230; 3.B.240.231;
3.B.240.236; 3.B.240.237; 3.B.240.238; 3.B.240.239; 3.B.240.154;
3.B.240.157; 3.B.240.166; 3.B.240.169; 3.B.240.172; 3.B.240.175;
3.B.240.240; 3.B.240.244; 3.B.244.228; 3.B.244.229; 3.B.244.230;
3.B.244.231; 3.B.244.236; 3.B.244.237; 3.B.244.238; 3.B.244.239;
3.B.244.154; 3.B.244.157; 3.B.244.166; 3.B.244.169; 3.B.244.172;
3.B.244.175; 3.B.244.240; 3.B.244.244; Prodrugs of 3.D 3.D.228.228;
3.D.228.229; 3.D.228.230; 3.D.228.231; 3.D.228.236; 3.D.228.237;
3.D.228.238; 3.D.228.239; 3.D.228.154; 3.D.228.157; 3.D.228.166;
3.D.228.169; 3.D.228.172; 3.D.228.175; 3.D.228.240; 3.D.228.244;
3.D.229.228; 3.D.229.229; 3.D.229.230; 3.D.229.231; 3.D.229.236;
3.D.229.237; 3.D.229.238; 3.D.229.239; 3.D.229.154; 3.D.229.157;
3.D.229.166; 3.D.229.169; 3.D.229.172; 3.D.229.175; 3.D.229.240;
3.D.229.244; 3.D.230.228; 3.D.230.229; 3.D.230.230; 3.D.230.231;
3.D.230.236; 3.D.230.237; 3.D.230.238; 3.D.230.239; 3.D.230.154;
3.D.230.157; 3.D.230.166; 3.D.230.169; 3.D.230.172; 3.D.230.175;
3.D.230.240; 3.D.230.244; 3.D.231.228; 3.D.231.229; 3.D.231.230;
3.D.231.231; 3.D.231.236; 3.D.231.237; 3.D.231.238; 3.D.231.239;
3.D.231.154; 3.D.231.157; 3.D.231.166; 3.D.231.169; 3.D.231.172;
3.D.231.175; 3.D.231.240; 3.D.231.244; 3.D.236.228; 3.D.236.229;
3.D.236.230; 3.D.236.231; 3.D.236.236; 3.D.236.237; 3.D.236.238;
3.D.236.239; 3.D.236.154; 3.D.236.157; 3.D.236.166; 3.D.236.169;
3.D.236.172; 3.D.236.175; 3.D.236.240; 3.D.236.244; 3.D.237.228;
3.D.237.229; 3.D.237.230; 3.D.237.231; 3.D.237.236; 3.D.237.237;
3.D.237.238; 3.D.237.239; 3.D.237.154; 3.D.237.157; 3.D.237.166;
3.D.237.169; 3.D.237.172; 3.D.237.175; 3.D.237.240; 3.D.237.244;
3.D.238.228; 3.D.238.229; 3.D.238.230; 3.D.238.231; 3.D.238.236;
3.D.238.237; 3.D.238.238; 3.D.238.239; 3.D.238.154; 3.D.238.157;
3.D.238.166; 3.D.238.169; 3.D.238.172; 3.D.238.175; 3.D.238.240;
3.D.238.244; 3.D.239.228; 3.D.239.229; 3.D.239.230; 3.D.239.231;
3.D.239.236; 3.D.239.237; 3.D.239.238; 3.D.239.239; 3.D.239.154;
3.D.239.157; 3.D.239.166; 3.D.239.169; 3.D.239.172; 3.D.239.175;
3.D.239.240; 3.D.239.244; 3.D.154.228; 3.D.154.229; 3.D.154.230;
3.D.154.231; 3.D.154.236; 3.D.154.237; 3.D.154.238; 3.D.154.239;
3.D.154.154; 3.D.154.157; 3.D.154.166; 3.D.154.169; 3.D.154.172;
3.D.154.175; 3.D.154.240; 3.D.154.244; 3.D.157.228; 3.D.157.229;
3.D.157.230; 3.D.157.231; 3.D.157.236; 3.D.157.237; 3.D.157.238;
3.D.157.239; 3.D.157.154; 3.D.157.157; 3.D.157.166; 3.D.157.169;
3.D.157.172; 3.D.157.175; 3.D.157.240; 3.D.157.244; 3.D.166.228;
3.D.166.229; 3.D.166.230; 3.D.166.231; 3.D.166.236; 3.D.166.237;
3.D.166.238; 3.D.166.239; 3.D.166.154; 3.D.166.157; 3.D.166.166;
3.D.166.169; 3.D.166.172; 3.D.166.175; 3.D.166.240; 3.D.166.244;
3.D.169.228; 3.D.169.229; 3.D.169.230; 3.D.169.231; 3.D.169.236;
3.D.169.237; 3.D.169.238; 3.D.169.239; 3.D.169.154; 3.D.169.157;
3.D.169.166; 3.D.169.169; 3.D.169.172; 3.D.169.175; 3.D.169.240;
3.D.169.244; 3.D.172.228; 3.D.172.229; 3.D.172.230; 3.D.172.231;
3.D.172.236; 3.D.172.237; 3.D.172.238; 3.D.172.239; 3.D.172.154;
3.D.172.157; 3.D.172.166; 3.D.172.169; 3.D.172.172; 3.D.172.175;
3.D.172.240; 3.D.172.244; 3.D.175.228; 3.D.175.229; 3.D.175.230;
3.D.175.231; 3.D.175.236; 3.D.175.237; 3.D.175.238; 3.D.175.239;
3.D.175.154; 3.D.175.157; 3.D.175.166; 3.D.175.169; 3.D.175.172;
3.D.175.175; 3.D.175.240; 3.D.175.244; 3.D.240.228; 3.D.240.229;
3.D.240.230; 3.D.240.231; 3.D.240.236; 3.D.240.237; 3.D.240.238;
3.D.240.239; 3.D.240.154; 3.D.240.157; 3.D.240.166; 3.D.240.169;
3.D.240.172; 3.D.240.175; 3.D.240.240; 3.D.240.244; 3.D.244.228;
3.D.244.229; 3.D.244.230; 3.D.244.231; 3.D.244.236; 3.D.244.237;
3.D.244.238; 3.D.244.239; 3.D.244.154; 3.D.244.157; 3.D.244.166;
3.D.244.169; 3.D.244.172; 3.D.244.175; 3.D.244.240; 3.D.244.244;
Prodrugs of 3.E 3.E.228.228; 3.E.228.229; 3.E.228.230; 3.E.228.231;
3.E.228.236; 3.E.228.237; 3.E.228.238; 3.E.228.239; 3.E.228.154;
3.E.228.157; 3.E.228.166; 3.E.228.169; 3.E.228.172; 3.E.228.175;
3.E.228.240; 3.E.228.244; 3.E.229.228; 3.E.229.229; 3.E.229.230;
3.E.229.231; 3.E.229.236; 3.E.229.237; 3.E.229.238; 3.E.229.239;
3.E.229.154; 3.E.229.157; 3.E.229.166; 3.E.229.169; 3.E.229.172;
3.E.229.175; 3.E.229.240; 3.E.229.244; 3.E.230.228; 3.E.230.229;
3.E.230.230; 3.E.230.231; 3.E.230.236; 3.E.230.237; 3.E.230.238;
3.E.230.239; 3.E.230.154; 3.E.230.157; 3.E.230.166; 3.E.230.169;
3.E.230.172; 3.E.230.175; 3.E.230.240; 3.E.230.244; 3.E.231.228;
3.E.231.229; 3.E.231.230; 3.E.231.231; 3.E.231.236; 3.E.231.237;
3.E.231.238; 3.E.231.239; 3.E.231.154; 3.E.231.157; 3.E.231.166;
3.E.231.169; 3.E.231.172; 3.E.231.175; 3.E.231.240; 3.E.231.244;
3.E.236.228; 3.E.236.229; 3.E.236.230; 3.E.236.231; 3.E.236.236;
3.E.236.237; 3.E.236.238; 3.E.236.239; 3.E.236.154; 3.E.236.157;
3.E.236.166; 3.E.236.169; 3.E.236.172; 3.E.236.175; 3.E.236.240;
3.E.236.244; 3.E.237.228; 3.E.237.229; 3.E.237.230; 3.E.237.231;
3.E.237.236; 3.E.237.237; 3.E.237.238; 3.E.237.239; 3.E.237.154;
3.E.237.157; 3.E.237.166; 3.E.237.169; 3.E.237.172; 3.E.237.175;
3.E.237.240; 3.E.237.244; 3.E.238.228; 3.E.238.229; 3.E.238.230;
3.E.238.231; 3.E.238.236; 3.E.238.237; 3.E.238.238; 3.E.238.239;
3.E.238.154; 3.E.238.157; 3.E.238.166; 3.E.238.169; 3.E.238.172;
3.E.238.175; 3.E.238.240; 3.E.238.244; 3.E.239.228; 3.E.239.229;
3.E.239.230; 3.E.239.231; 3.E.239.236; 3.E.239.237; 3.E.239.238;
3.E.239.239; 3.E.239.154; 3.E.239.157; 3.E.239.166; 3.E.239.169;
3.E.239.172; 3.E.239.175; 3.E.239.240; 3.E.239.244; 3.E.154.228;
3.E.154.229; 3.E.154.230; 3.E.154.231; 3.E.154.236; 3.E.154.237;
3.E.154.238; 3.E.154.239; 3.E.154.154; 3.E.154.157; 3.E.154.166;
3.E.154.169; 3.E.154.172; 3.E.154.175; 3.E.154.240; 3.E.154.244;
3.E.157.228; 3.E.157.229; 3.E.157.230; 3.E.157.231; 3.E.157.236;
3.E.157.237; 3.E.157.238; 3.E.157.239; 3.E.157.154; 3.E.157.157;
3.E.157.166; 3.E.157.169; 3.E.157.172; 3.E.157.175; 3.E.157.240;
3.E.157.244; 3.E.166.228; 3.E.166.229; 3.E.166.230; 3.E.166.231;
3.E.166.236; 3.E.166.237; 3.E.166.238; 3.E.166.239; 3.E.166.154;
3.E.166.157; 3.E.166.166; 3.E.166.169; 3.E.166.172; 3.E.166.175;
3.E.166.240; 3.E.166.244; 3.E.169.228; 3.E.169.229; 3.E.169.230;
3.E.169.231; 3.E.169.236; 3.E.169.237; 3.E.169.238; 3.E.169.239;
3.E.169.154; 3.E.169.157; 3.E.169.166; 3.E.169.169; 3.E.169.172;
3.E.169.175; 3.E.169.240; 3.E.169.244; 3.E.172.228; 3.E.172.229;
3.E.172.230; 3.E.172.231; 3.E.172.236; 3.E.172.237; 3.E.172.238;
3.E.172.239; 3.E.172.154; 3.E.172.157; 3.E.172.166; 3.E.172.169;
3.E.172.172; 3.E.172.175; 3.E.172.240; 3.E.172.244; 3.E.175.228;
3.E.175.229; 3.E.175.230; 3.E.175.231; 3.E.175.236; 3.E.175.237;
3.E.175.238; 3.E.175.239; 3.E.175.154; 3.E.175.157; 3.E.175.166;
3.E.175.169; 3.E.175.172; 3.E.175.175; 3.E.175.240; 3.E.175.244;
3.E.240.228; 3.E.240.229; 3.E.240.230; 3.E.240.231; 3.E.240.236;
3.E.240.237; 3.E.240.238; 3.E.240.239; 3.E.240.154; 3.E.240.157;
3.E.240.166; 3.E.240.169; 3.E.240.172; 3.E.240.175; 3.E.240.240;
3.E.240.244; 3.E.244.228; 3.E.244.229; 3.E.244.230; 3.E.244.231;
3.E.244.236; 3.E.244.237; 3.E.244.238; 3.E.244.239; 3.E.244.154;
3.E.244.157; 3.E.244.166; 3.E.244.169; 3.E.244.172; 3.E.244.175;
3.E.244.240; 3.E.244.244; Prodrugs of 3.G 3.G.228.228; 3.G.228.229;
3.G.228.230; 3.G.228.231; 3.G.228.236; 3.G.228.237; 3.G.228.238;
3.G.228.239; 3.G.228.154; 3.G.228.157; 3.G.228.166; 3.G.228.169;
3.G.228.172; 3.G.228.175; 3.G.228.240; 3.G.228.244; 3.G.229.228;
3.G.229.229; 3.G.229.230; 3.G.229.231; 3.G.229.236; 3.G.229.237;
3.G.229.238; 3.G.229.239; 3.G.229.154; 3.G.229.157; 3.G.229.166;
3.G.229.169; 3.G.229.172; 3.G.229.175; 3.G.229.240; 3.G.229.244;
3.G.230.228; 3.G.230.229; 3.G.230.230; 3.G.230.231; 3.G.230.236;
3.G.230.237; 3.G.230.238; 3.G.230.239; 3.G.230.154; 3.G.230.157;
3.G.230.166; 3.G.230.169; 3.G.230.172; 3.G.230.175; 3.G.230.240;
3.G.230.244; 3.G.231.228; 3.G.231.229; 3.G.231.230; 3.G.231.231;
3.G.231.236; 3.G.231.237; 3.G.231.238; 3.G.231.239; 3.G.231.154;
3.G.231.157; 3.G.231.166; 3.G.231.169; 3.G.231.172; 3.G.231.175;
3.G.231.240; 3.G.231.244; 3.G.236.228; 3.G.236.229; 3.G.236.230;
3.G.236.231; 3.G.236.236; 3.G.236.237; 3.G.236.238; 3.G.236.239;
3.G.236.154; 3.G.236.157; 3.G.236.166; 3.G.236.169; 3.G.236.172;
3.G.236.175; 3.G.236.240; 3.G.236.244; 3.G.237.228; 3.G.237.229;
3.G.237.230; 3.G.237.231; 3.G.237.236; 3.G.237.237; 3.G.237.238;
3.G.237.239; 3.G.237.154; 3.G.237.157; 3.G.237.166; 3.G.237.169;
3.G.237.172; 3.G.237.175; 3.G.237.240; 3.G.237.244; 3.G.238.228;
3.G.238.229; 3.G.238.230; 3.G.238.231; 3.G.238.236; 3.G.238.237;
3.G.238.238; 3.G.238.239; 3.G.238.154; 3.G.238.157; 3.G.238.166;
3.G.238.169; 3.G.238.172; 3.G.238.175; 3.G.238.240; 3.G.238.244;
3.G.239.228; 3.G.239.229; 3.G.239.230; 3.G.239.231; 3.G.239.236;
3.G.239.237; 3.G.239.238; 3.G.239.239; 3.G.239.154; 3.G.239.157;
3.G.239.166; 3.G.239.169; 3.G.239.172; 3.G.239.175; 3.G.239.240;
3.G.239.244; 3.G.154.228; 3.G.154.229; 3.G.154.230; 3.G.154.231;
3.G.154.236; 3.G.154.237; 3.G.154.238; 3.G.154.239; 3.G.154.154;
3.G.154.157; 3.G.154.166; 3.G.154.169; 3.G.154.172; 3.G.154.175;
3.G.154.240; 3.G.154.244; 3.G.157.228; 3.G.157.229; 3.G.157.230;
3.G.157.231; 3.G.157.236; 3.G.157.237; 3.G.157.238; 3.G.157.239;
3.G.157.154; 3.G.157.157; 3.G.157.166; 3.G.157.169; 3.G.157.172;
3.G.157.175; 3.G.157.240; 3.G.157.244; 3.G.166.228; 3.G.166.229;
3.G.166.230; 3.G.166.231; 3.G.166.236; 3.G.166.237; 3.G.166.238;
3.G.166.239; 3.G.166.154; 3.G.166.157; 3.G.166.166; 3.G.166.169;
3.G.166.172; 3.G.166.175; 3.G.166.240; 3.G.166.244; 3.G.169.228;
3.G.169.229; 3.G.169.230; 3.G.169.231; 3.G.169.236; 3.G.169.237;
3.G.169.238; 3.G.169.239; 3.G.169.154; 3.G.169.157; 3.G.169.166;
3.G.169.169; 3.G.169.172; 3.G.169.175; 3.G.169.240; 3.G.169.244;
3.G.172.228; 3.G.172.229; 3.G.172.230; 3.G.172.231; 3.G.172.236;
3.G.172.237; 3.G.172.238; 3.G.172.239; 3.G.172.154; 3.G.172.157;
3.G.172.166; 3.G.172.169; 3.G.172.172; 3.G.172.175; 3.G.172.240;
3.G.172.244; 3.G.175.228; 3.G.175.229; 3.G.175.230; 3.G.175.231;
3.G.175.236; 3.G.175.237; 3.G.175.238; 3.G.175.239; 3.G.175.154;
3.G.175.157; 3.G.175.166; 3.G.175.169; 3.G.175.172; 3.G.175.175;
3.G.175.240; 3.G.175.244; 3.G.240.228; 3.G.240.229; 3.G.240.230;
3.G.240.231; 3.G.240.236; 3.G.240.237; 3.G.240.238; 3.G.240.239;
3.G.240.154; 3.G.240.157; 3.G.240.166; 3.G.240.169; 3.G.240.172;
3.G.240.175; 3.G.240.240; 3.G.240.244; 3.G.244.228; 3.G.244.229;
3.G.244.230; 3.G.244.231; 3.G.244.236; 3.G.244.237; 3.G.244.238;
3.G.244.239; 3.G.244.154; 3.G.244.157; 3.G.244.166; 3.G.244.169;
3.G.244.172; 3.G.244.175; 3.G.244.240; 3.G.244.244; Prodrugs of 3.I
3.I.228.228; 3.I.228.229; 3.I.228.230; 3.I.228.231; 3.I.228.236;
3.I.228.237; 3.I.228.238; 3.I.228.239; 3.I.228.154; 3.I.228.157;
3.I.228.166; 3.I.228.169; 3.I.228.172; 3.I.228.175; 3.I.228.240;
3.I.228.244; 3.I.229.228; 3.I.229.229; 3.I.229.230; 3.I.229.231;
3.I.229.236; 3.I.229.237; 3.I.229.238; 3.I.229.239; 3.I.229.154;
3.I.229.157; 3.I.229.166; 3.I.229.169; 3.I.229.172; 3.I.229.175;
3.I.229.240; 3.I.229.244; 3.I.230.228; 3.I.230.229; 3.I.230.230;
3.I.230.231; 3.I.230.236; 3.I.230.237; 3.I.230.238; 3.I.230.239;
3.I.230.154; 3.I.230.157; 3.I.230.166; 3.I.230.169; 3.I.230.172;
3.I.230.175; 3.I.230.240; 3.I.230.244; 3.I.231.228; 3.I.231.229;
3.I.231.230; 3.I.231.231; 3.I.231.236; 3.I.231.237; 3.I.231.238;
3.I.231.239; 3.I.231.154; 3.I.231.157; 3.I.231.166; 3.I.231.169;
3.I.231.172; 3.I.231.175; 3.I.231.240; 3.I.231.244; 3.I.236.228;
3.I.236.229; 3.I.236.230; 3.I.236.231; 3.I.236.236; 3.I.236.237;
3.I.236.238; 3.I.236.239; 3.I.236.154; 3.I.236.157; 3.I.236.166;
3.I.236.169; 3.I.236.172; 3.I.236.175; 3.I.236.240; 3.I.236.244;
3.I.237.228; 3.I.237.229; 3.I.237.230; 3.I.237.231; 3.I.237.236;
3.I.237.237; 3.I.237.238; 3.I.237.239; 3.I.237.154;
3.I.237.157;
3.I.237.166; 3.I.237.169; 3.I.237.172; 3.I.237.175; 3.I.237.240;
3.I.237.244; 3.I.238.228; 3.I.238.229; 3.I.238.230; 3.I.238.231;
3.I.238.236; 3.I.238.237; 3.I.238.238; 3.I.238.239; 3.I.238.154;
3.I.238.157; 3.I.238.166; 3.I.238.169; 3.I.238.172; 3.I.238.175;
3.I.238.240; 3.I.238.244; 3.I.239.228; 3.I.239.229; 3.I.239.230;
3.I.239.231; 3.I.239.236; 3.I.239.237; 3.I.239.238; 3.I.239.239;
3.I.239.154; 3.I.239.157; 3.I.239.166; 3.I.239.169; 3.I.239.172;
3.I.239.175; 3.I.239.240; 3.I.239.244; 3.I.154.228; 3.I.154.229;
3.I.154.230; 3.I.154.231; 3.I.154.236; 3.I.154.237; 3.I.154.238;
3.I.154.239; 3.I.154.154; 3.I.154.157; 3.I.154.166; 3.I.154.169;
3.I.154.172; 3.I.154.175; 3.I.154.240; 3.I.154.244; 3.I.157.228;
3.I.157.229; 3.I.157.230; 3.I.157.231; 3.I.157.236; 3.I.157.237;
3.I.157.238; 3.I.157.239; 3.I.157.154; 3.I.157.157; 3.I.157.166;
3.I.157.169; 3.I.157.172; 3.I.157.175; 3.I.157.240; 3.I.157.244;
3.I.166.228; 3.I.166.229; 3.I.166.230; 3.I.166.231; 3.I.166.236;
3.I.166.237; 3.I.166.238; 3.I.166.239; 3.I.166.154; 3.I.166.157;
3.I.166.166; 3.I.166.169; 3.I.166.172; 3.I.166.175; 3.I.166.240;
3.I.166.244; 3.I.169.228; 3.I.169.229; 3.I.169.230; 3.I.169.231;
3.I.169.236; 3.I.169.237; 3.I.169.238; 3.I.169.239; 3.I.169.154;
3.I.169.157; 3.I.169.166; 3.I.169.169; 3.I.169.172; 3.I.169.175;
3.I.169.240; 3.I.169.244; 3.I.172.228; 3.I.172.229; 3.I.172.230;
3.I.172.231; 3.I.172.236; 3.I.172.237; 3.I.172.238; 3.I.172.239;
3.I.172.154; 3.I.172.157; 3.I.172.166; 3.I.172.169; 3.I.172.172;
3.I.172.175; 3.I.172.240; 3.I.172.244; 3.I.175.228; 3.I.175.229;
3.I.175.230; 3.I.175.231; 3.I.175.236; 3.I.175.237; 3.I.175.238;
3.I.175.239; 3.I.175.154; 3.I.175.157; 3.I.175.166; 3.I.175.169;
3.I.175.172; 3.I.175.175; 3.I.175.240; 3.I.175.244; 3.I.240.228;
3.I.240.229; 3.I.240.230; 3.I.240.231; 3.I.240.236; 3.I.240.237;
3.I.240.238; 3.I.240.239; 3.I.240.154; 3.I.240.157; 3.I.240.166;
3.I.240.169; 3.I.240.172; 3.I.240.175; 3.I.240.240; 3.I.240.244;
3.I.244.228; 3.I.244.229; 3.I.244.230; 3.I.244.231; 3.I.244.236;
3.I.244.237; 3.I.244.238; 3.I.244.239; 3.I.244.154; 3.I.244.157;
3.I.244.166; 3.I.244.169; 3.I.244.172; 3.I.244.175; 3.I.244.240;
3.I.244.244; Prodrugs of 3.J 3.J.228.228; 3.J.228.229; 3.J.228.230;
3.J.228.231; 3.J.228.236; 3.J.228.237; 3.J.228.238; 3.J.228.239;
3.J.228.154; 3.J.228.157; 3.J.228.166; 3.J.228.169; 3.J.228.172;
3.J.228.175; 3.J.228.240; 3.J.228.244; 3.J.229.228; 3.J.229.229;
3.J.229.230; 3.J.229.231; 3.J.229.236; 3.J.229.237; 3.J.229.238;
3.J.229.239; 3.J.229.154; 3.J.229.157; 3.J.229.166; 3.J.229.169;
3.J.229.172; 3.J.229.175; 3.J.229.240; 3.J.229.244; 3.J.230.228;
3.J.230.229; 3.J.230.230; 3.J.230.231; 3.J.230.236; 3.J.230.237;
3.J.230.238; 3.J.230.239; 3.J.230.154; 3.J.230.157; 3.J.230.166;
3.J.230.169; 3.J.230.172; 3.J.230.175; 3.J.230.240; 3.J.230.244;
3.J.231.228; 3.J.231.229; 3.J.231.230; 3.J.231.231; 3.J.231.236;
3.J.231.237; 3.J.231.238; 3.J.231.239; 3.J.231.154; 3.J.231.157;
3.J.231.166; 3.J.231.169; 3.J.231.172; 3.J.231.175; 3.J.231.240;
3.J.231.244; 3.J.236.228; 3.J.236.229; 3.J.236.230; 3.J.236.231;
3.J.236.236; 3.J.236.237; 3.J.236.238; 3.J.236.239; 3.J.236.154;
3.J.236.157; 3.J.236.166; 3.J.236.169; 3.J.236.172; 3.J.236.175;
3.J.236.240; 3.J.236.244; 3.J.237.228; 3.J.237.229; 3.J.237.230;
3.J.237.231; 3.J.237.236; 3.J.237.237; 3.J.237.238; 3.J.237.239;
3.J.237.154; 3.J.237.157; 3.J.237.166; 3.J.237.169; 3.J.237.172;
3.J.237.175; 3.J.237.240; 3.J.237.244; 3.J.238.228; 3.J.238.229;
3.J.238.230; 3.J.238.231; 3.J.238.236; 3.J.238.237; 3.J.238.238;
3.J.238.239; 3.J.238.154; 3.J.238.157; 3.J.238.166; 3.J.238.169;
3.J.238.172; 3.J.238.175; 3.J.238.240; 3.J.238.244; 3.J.239.228;
3.J.239.229; 3.J.239.230; 3.J.239.231; 3.J.239.236; 3.J.239.237;
3.J.239.238; 3.J.239.239; 3.J.239.154; 3.J.239.157; 3.J.239.166;
3.J.239.169; 3.J.239.172; 3.J.239.175; 3.J.239.240; 3.J.239.244;
3.J.154.228; 3.J.154.229; 3.J.154.230; 3.J.154.231; 3.J.154.236;
3.J.154.237; 3.J.154.238; 3.J.154.239; 3.J.154.154; 3.J.154.157;
3.J.154.166; 3.J.154.169; 3.J.154.172; 3.J.154.175; 3.J.154.240;
3.J.154.244; 3.J.157.228; 3.J.157.229; 3.J.157.230; 3.J.157.231;
3.J.157.236; 3.J.157.237; 3.J.157.238; 3.J.157.239; 3.J.157.154;
3.J.157.157; 3.J.157.166; 3.J.157.169; 3.J.157.172; 3.J.157.175;
3.J.157.240; 3.J.157.244; 3.J.166.228; 3.J.166.229; 3.J.166.230;
3.J.166.231; 3.J.166.236; 3.J.166.237; 3.J.166.238; 3.J.166.239;
3.J.166.154; 3.J.166.157; 3.J.166.166; 3.J.166.169; 3.J.166.172;
3.J.166.175; 3.J.166.240; 3.J.166.244; 3.J.169.228; 3.J.169.229;
3.J.169.230; 3.J.169.231; 3.J.169.236; 3.J.169.237; 3.J.169.238;
3.J.169.239; 3.J.169.154; 3.J.169.157; 3.J.169.166; 3.J.169.169;
3.J.169.172; 3.J.169.175; 3.J.169.240; 3.J.169.244; 3.J.172.228;
3.J.172.229; 3.J.172.230; 3.J.172.231; 3.J.172.236; 3.J.172.237;
3.J.172.238; 3.J.172.239; 3.J.172.154; 3.J.172.157; 3.J.172.166;
3.J.172.169; 3.J.172.172; 3.J.172.175; 3.J.172.240; 3.J.172.244;
3.J.175.228; 3.J.175.229; 3.J.175.230; 3.J.175.231; 3.J.175.236;
3.J.175.237; 3.J.175.238; 3.J.175.239; 3.J.175.154; 3.J.175.157;
3.J.175.166; 3.J.175.169; 3.J.175.172; 3.J.175.175; 3.J.175.240;
3.J.175.244; 3.J.240.228; 3.J.240.229; 3.J.240.230; 3.J.240.231;
3.J.240.236; 3.J.240.237; 3.J.240.238; 3.J.240.239; 3.J.240.154;
3.J.240.157; 3.J.240.166; 3.J.240.169; 3.J.240.172; 3.J.240.175;
3.J.240.240; 3.J.240.244; 3.J.244.228; 3.J.244.229; 3.J.244.230;
3.J.244.231; 3.J.244.236; 3.J.244.237; 3.J.244.238; 3.J.244.239;
3.J.244.154; 3.J.244.157; 3.J.244.166; 3.J.244.169; 3.J.244.172;
3.J.244.175; 3.J.244.240; 3.J.244.244; Prodrugs of 3.L 3.L.228.228;
3.L.228.229; 3.L.228.230; 3.L.228.231; 3.L.228.236; 3.L.228.237;
3.L.228.238; 3.L.228.239; 3.L.228.154; 3.L.228.157; 3.L.228.166;
3.L.228.169; 3.L.228.172; 3.L.228.175; 3.L.228.240; 3.L.228.244;
3.L.229.228; 3.L.229.229; 3.L.229.230; 3.L.229.231; 3.L.229.236;
3.L.229.237; 3.L.229.238; 3.L.229.239; 3.L.229.154; 3.L.229.157;
3.L.229.166; 3.L.229.169; 3.L.229.172; 3.L.229.175; 3.L.229.240;
3.L.229.244; 3.L.230.228; 3.L.230.229; 3.L.230.230; 3.L.230.231;
3.L.230.236; 3.L.230.237; 3.L.230.238; 3.L.230.239; 3.L.230.154;
3.L.230.157; 3.L.230.166; 3.L.230.169; 3.L.230.172; 3.L.230.175;
3.L.230.240; 3.L.230.244; 3.L.231.228; 3.L.231.229; 3.L.231.230;
3.L.231.231; 3.L.231.236; 3.L.231.237; 3.L.231.238; 3.L.231.239;
3.L.231.154; 3.L.231.157; 3.L.231.166; 3.L.231.169; 3.L.231.172;
3.L.231.175; 3.L.231.240; 3.L.231.244; 3.L.236.228; 3.L.236.229;
3.L.236.230; 3.L.236.231; 3.L.236.236; 3.L.236.237; 3.L.236.238;
3.L.236.239; 3.L.236.154; 3.L.236.157; 3.L.236.166; 3.L.236.169;
3.L.236.172; 3.L.236.175; 3.L.236.240; 3.L.236.244; 3.L.237.228;
3.L.237.229; 3.L.237.230; 3.L.237.231; 3.L.237.236; 3.L.237.237;
3.L.237.238; 3.L.237.239; 3.L.237.154; 3.L.237.157; 3.L.237.166;
3.L.237.169; 3.L.237.172; 3.L.237.175; 3.L.237.240; 3.L.237.244;
3.L.238.228; 3.L.238.229; 3.L.238.230; 3.L.238.231; 3.L.238.236;
3.L.238.237; 3.L.238.238; 3.L.238.239; 3.L.238.154; 3.L.238.157;
3.L.238.166; 3.L.238.169; 3.L.238.172; 3.L.238.175; 3.L.238.240;
3.L.238.244; 3.L.239.228; 3.L.239.229; 3.L.239.230; 3.L.239.231;
3.L.239.236; 3.L.239.237; 3.L.239.238; 3.L.239.239; 3.L.239.154;
3.L.239.157; 3.L.239.166; 3.L.239.169; 3.L.239.172; 3.L.239.175;
3.L.239.240; 3.L.239.244; 3.L.154.228; 3.L.154.229; 3.L.154.230;
3.L.154.231; 3.L.154.236; 3.L.154.237; 3.L.154.238; 3.L.154.239;
3.L.154.154; 3.L.154.157; 3.L.154.166; 3.L.154.169; 3.L.154.172;
3.L.154.175; 3.L.154.240; 3.L.154.244; 3.L.157.228; 3.L.157.229;
3.L.157.230; 3.L.157.231; 3.L.157.236; 3.L.157.237; 3.L.157.238;
3.L.157.239; 3.L.157.154; 3.L.157.157; 3.L.157.166; 3.L.157.169;
3.L.157.172; 3.L.157.175; 3.L.157.240; 3.L.157.244; 3.L.166.228;
3.L.166.229; 3.L.166.230; 3.L.166.231; 3.L.166.236; 3.L.166.237;
3.L.166.238; 3.L.166.239; 3.L.166.154; 3.L.166.157; 3.L.166.166;
3.L.166.169; 3.L.166.172; 3.L.166.175; 3.L.166.240; 3.L.166.244;
3.L.169.228; 3.L.169.229; 3.L.169.230; 3.L.169.231; 3.L.169.236;
3.L.169.237; 3.L.169.238; 3.L.169.239; 3.L.169.154; 3.L.169.157;
3.L.169.166; 3.L.169.169; 3.L.169.172; 3.L.169.175; 3.L.169.240;
3.L.169.244; 3.L.172.228; 3.L.172.229; 3.L.172.230; 3.L.172.231;
3.L.172.236; 3.L.172.237; 3.L.172.238; 3.L.172.239; 3.L.172.154;
3.L.172.157; 3.L.172.166; 3.L.172.169; 3.L.172.172; 3.L.172.175;
3.L.172.240; 3.L.172.244; 3.L.175.228; 3.L.175.229; 3.L.175.230;
3.L.175.231; 3.L.175.236; 3.L.175.237; 3.L.175.238; 3.L.175.239;
3.L.175.154; 3.L.175.157; 3.L.175.166; 3.L.175.169; 3.L.175.172;
3.L.175.175; 3.L.175.240; 3.L.175.244; 3.L.240.228; 3.L.240.229;
3.L.240.230; 3.L.240.231; 3.L.240.236; 3.L.240.237; 3.L.240.238;
3.L.240.239; 3.L.240.154; 3.L.240.157; 3.L.240.166; 3.L.240.169;
3.L.240.172; 3.L.240.175; 3.L.240.240; 3.L.240.244; 3.L.244.228;
3.L.244.229; 3.L.244.230; 3.L.244.231; 3.L.244.236; 3.L.244.237;
3.L.244.238; 3.L.244.239; 3.L.244.154; 3.L.244.157; 3.L.244.166;
3.L.244.169; 3.L.244.172; 3.L.244.175; 3.L.244.240; 3.L.244.244;
Prodrugs of 3.O 3.O.228.228; 3.O.228.229; 3.O.228.230; 3.O.228.231;
3.O.228.236; 3.O.228.237; 3.O.228.238; 3.O.228.239; 3.O.228.154;
3.O.228.157; 3.O.228.166; 3.O.228.169; 3.O.228.172; 3.O.228.175;
3.O.228.240; 3.O.228.244; 3.O.229.228; 3.O.229.229; 3.O.229.230;
3.O.229.231; 3.O.229.236; 3.O.229.237; 3.O.229.238; 3.O.229.239;
3.O.229.154; 3.O.229.157; 3.O.229.166; 3.O.229.169; 3.O.229.172;
3.O.229.175; 3.O.229.240; 3.O.229.244; 3.O.230.228; 3.O.230.229;
3.O.230.230; 3.O.230.231; 3.O.230.236; 3.O.230.237; 3.O.230.238;
3.O.230.239; 3.O.230.154; 3.O.230.157; 3.O.230.166; 3.O.230.169;
3.O.230.172; 3.O.230.175; 3.O.230.240; 3.O.230.244; 3.O.231.228;
3.O.231.229; 3.O.231.230; 3.O.231.231; 3.O.231.236; 3.O.231.237;
3.O.231.238; 3.O.231.239; 3.O.231.154; 3.O.231.157; 3.O.231.166;
3.O.231.169; 3.O.231.172; 3.O.231.175; 3.O.231.240; 3.O.231.244;
3.O.236.228; 3.O.236.229; 3.O.236.230; 3.O.236.231; 3.O.236.236;
3.O.236.237; 3.O.236.238; 3.O.236.239; 3.O.236.154; 3.O.236.157;
3.O.236.166; 3.O.236.169; 3.O.236.172; 3.O.236.175; 3.O.236.240;
3.O.236.244; 3.O.237.228; 3.O.237.229; 3.O.237.230; 3.O.237.231;
3.O.237.236; 3.O.237.237; 3.O.237.238; 3.O.237.239; 3.O.237.154;
3.O.237.157; 3.O.237.166; 3.O.237.169; 3.O.237.172; 3.O.237.175;
3.O.237.240; 3.O.237.244; 3.O.238.228; 3.O.238.229; 3.O.238.230;
3.O.238.231; 3.O.238.236; 3.O.238.237; 3.O.238.238; 3.O.238.239;
3.O.238.154; 3.O.238.157; 3.O.238.166; 3.O.238.169; 3.O.238.172;
3.O.238.175; 3.O.238.240; 3.O.238.244; 3.O.239.228; 3.O.239.229;
3.O.239.230; 3.O.239.231; 3.O.239.236; 3.O.239.237; 3.O.239.238;
3.O.239.239; 3.O.239.154; 3.O.239.157; 3.O.239.166; 3.O.239.169;
3.O.239.172; 3.O.239.175; 3.O.239.240; 3.O.239.244; 3.O.154.228;
3.O.154.229; 3.O.154.230; 3.O.154.231; 3.O.154.236; 3.O.154.237;
3.O.154.238; 3.O.154.239; 3.O.154.154; 3.O.154.157; 3.O.154.166;
3.O.154.169; 3.O.154.172; 3.O.154.175; 3.O.154.240; 3.O.154.244;
3.O.157.228; 3.O.157.229; 3.O.157.230; 3.O.157.231; 3.O.157.236;
3.O.157.237; 3.O.157.238; 3.O.157.239; 3.O.157.154; 3.O.157.157;
3.O.157.166; 3.O.157.169; 3.O.157.172; 3.O.157.175; 3.O.157.240;
3.O.157.244; 3.O.166.228; 3.O.166.229; 3.O.166.230; 3.O.166.231;
3.O.166.236; 3.O.166.237; 3.O.166.238; 3.O.166.239; 3.O.166.154;
3.O.166.157; 3.O.166.166; 3.O.166.169; 3.O.166.172; 3.O.166.175;
3.O.166.240; 3.O.166.244; 3.O.169.228; 3.O.169.229; 3.O.169.230;
3.O.169.231; 3.O.169.236; 3.O.169.237; 3.O.169.238; 3.O.169.239;
3.O.169.154; 3.O.169.157; 3.O.169.166; 3.O.169.169; 3.O.169.172;
3.O.169.175; 3.O.169.240; 3.O.169.244; 3.O.172.228; 3.O.172.229;
3.O.172.230; 3.O.172.231; 3.O.172.236; 3.O.172.237; 3.O.172.238;
3.O.172.239; 3.O.172.154; 3.O.172.157; 3.O.172.166; 3.O.172.169;
3.O.172.172; 3.O.172.175; 3.O.172.240; 3.O.172.244; 3.O.175.228;
3.O.175.229; 3.O.175.230; 3.O.175.231; 3.O.175.236; 3.O.175.237;
3.O.175.238; 3.O.175.239; 3.O.175.154; 3.O.175.157; 3.O.175.166;
3.O.175.169; 3.O.175.172; 3.O.175.175; 3.O.175.240; 3.O.175.244;
3.O.240.228; 3.O.240.229; 3.O.240.230; 3.O.240.231; 3.O.240.236;
3.O.240.237; 3.O.240.238; 3.O.240.239; 3.O.240.154; 3.O.240.157;
3.O.240.166; 3.O.240.169; 3.O.240.172; 3.O.240.175; 3.O.240.240;
3.O.240.244; 3.O.244.228; 3.O.244.229; 3.O.244.230; 3.O.244.231;
3.O.244.236; 3.O.244.237; 3.O.244.238; 3.O.244.239; 3.O.244.154;
3.O.244.157; 3.O.244.166; 3.O.244.169; 3.O.244.172; 3.O.244.175;
3.O.244.240; 3.O.244.244; Prodrugs of 3.P 3.P.228.228; 3.P.228.229;
3.P.228.230; 3.P.228.231; 3.P.228.236; 3.P.228.237; 3.P.228.238;
3.P.228.239; 3.P.228.154; 3.P.228.157; 3.P.228.166; 3.P.228.169;
3.P.228.172; 3.P.228.175; 3.P.228.240; 3.P.228.244; 3.P.229.228;
3.P.229.229; 3.P.229.230; 3.P.229.231; 3.P.229.236; 3.P.229.237;
3.P.229.238; 3.P.229.239; 3.P.229.154; 3.P.229.157; 3.P.229.166;
3.P.229.169; 3.P.229.172; 3.P.229.175; 3.P.229.240; 3.P.229.244;
3.P.230.228; 3.P.230.229; 3.P.230.230; 3.P.230.231; 3.P.230.236;
3.P.230.237; 3.P.230.238; 3.P.230.239; 3.P.230.154; 3.P.230.157;
3.P.230.166; 3.P.230.169; 3.P.230.172; 3.P.230.175; 3.P.230.240;
3.P.230.244; 3.P.231.228; 3.P.231.229; 3.P.231.230; 3.P.231.231;
3.P.231.236; 3.P.231.237; 3.P.231.238; 3.P.231.239; 3.P.231.154;
3.P.231.157; 3.P.231.166; 3.P.231.169; 3.P.231.172; 3.P.231.175;
3.P.231.240; 3.P.231.244; 3.P.236.228; 3.P.236.229; 3.P.236.230;
3.P.236.231; 3.P.236.236; 3.P.236.237; 3.P.236.238; 3.P.236.239;
3.P.236.154; 3.P.236.157; 3.P.236.166; 3.P.236.169; 3.P.236.172;
3.P.236.175; 3.P.236.240; 3.P.236.244; 3.P.237.228; 3.P.237.229;
3.P.237.230; 3.P.237.231; 3.P.237.236; 3.P.237.237; 3.P.237.238;
3.P.237.239; 3.P.237.154; 3.P.237.157; 3.P.237.166; 3.P.237.169;
3.P.237.172; 3.P.237.175; 3.P.237.240; 3.P.237.244; 3.P.238.228;
3.P.238.229; 3.P.238.230; 3.P.238.231; 3.P.238.236; 3.P.238.237;
3.P.238.238; 3.P.238.239; 3.P.238.154; 3.P.238.157; 3.P.238.166;
3.P.238.169; 3.P.238.172; 3.P.238.175; 3.P.238.240; 3.P.238.244;
3.P.239.228; 3.P.239.229; 3.P.239.230; 3.P.239.231; 3.P.239.236;
3.P.239.237; 3.P.239.238; 3.P.239.239; 3.P.239.154; 3.P.239.157;
3.P.239.166; 3.P.239.169; 3.P.239.172; 3.P.239.175; 3.P.239.240;
3.P.239.244; 3.P.154.228; 3.P.154.229; 3.P.154.230; 3.P.154.231;
3.P.154.236; 3.P.154.237; 3.P.154.238; 3.P.154.239; 3.P.154.154;
3.P.154.157; 3.P.154.166; 3.P.154.169; 3.P.154.172; 3.P.154.175;
3.P.154.240; 3.P.154.244; 3.P.157.228; 3.P.157.229; 3.P.157.230;
3.P.157.231; 3.P.157.236; 3.P.157.237; 3.P.157.238; 3.P.157.239;
3.P.157.154; 3.P.157.157; 3.P.157.166; 3.P.157.169; 3.P.157.172;
3.P.157.175; 3.P.157.240; 3.P.157.244; 3.P.166.228; 3.P.166.229;
3.P.166.230; 3.P.166.231; 3.P.166.236; 3.P.166.237; 3.P.166.238;
3.P.166.239; 3.P.166.154; 3.P.166.157; 3.P.166.166; 3.P.166.169;
3.P.166.172; 3.P.166.175; 3.P.166.240; 3.P.166.244; 3.P.169.228;
3.P.169.229; 3.P.169.230; 3.P.169.231; 3.P.169.236; 3.P.169.237;
3.P.169.238; 3.P.169.239; 3.P.169.154; 3.P.169.157; 3.P.169.166;
3.P.169.169; 3.P.169.172; 3.P.169.175; 3.P.169.240; 3.P.169.244;
3.P.172.228; 3.P.172.229; 3.P.172.230; 3.P.172.231; 3.P.172.236;
3.P.172.237; 3.P.172.238; 3.P.172.239; 3.P.172.154; 3.P.172.157;
3.P.172.166; 3.P.172.169; 3.P.172.172; 3.P.172.175; 3.P.172.240;
3.P.172.244; 3.P.175.228; 3.P.175.229; 3.P.175.230; 3.P.175.231;
3.P.175.236; 3.P.175.237; 3.P.175.238; 3.P.175.239; 3.P.175.154;
3.P.175.157; 3.P.175.166; 3.P.175.169; 3.P.175.172; 3.P.175.175;
3.P.175.240; 3.P.175.244; 3.P.240.228; 3.P.240.229; 3.P.240.230;
3.P.240.231; 3.P.240.236; 3.P.240.237; 3.P.240.238; 3.P.240.239;
3.P.240.154; 3.P.240.157; 3.P.240.166; 3.P.240.169; 3.P.240.172;
3.P.240.175; 3.P.240.240; 3.P.240.244; 3.P.244.228; 3.P.244.229;
3.P.244.230; 3.P.244.231; 3.P.244.236; 3.P.244.237; 3.P.244.238;
3.P.244.239; 3.P.244.154; 3.P.244.157; 3.P.244.166; 3.P.244.169;
3.P.244.172; 3.P.244.175; 3.P.244.240; 3.P.244.244; Prodrugs of 3.U
3.U.228.228; 3.U.228.229; 3.U.228.230; 3.U.228.231; 3.U.228.236;
3.U.228.237; 3.U.228.238; 3.U.228.239; 3.U.228.154; 3.U.228.157;
3.U.228.166; 3.U.228.169; 3.U.228.172; 3.U.228.175; 3.U.228.240;
3.U.228.244; 3.U.229.228; 3.U.229.229; 3.U.229.230;
3.U.229.231;
3.U.229.236; 3.U.229.237; 3.U.229.238; 3.U.229.239; 3.U.229.154;
3.U.229.157; 3.U.229.166; 3.U.229.169; 3.U.229.172; 3.U.229.175;
3.U.229.240; 3.U.229.244; 3.U.230.228; 3.U.230.229; 3.U.230.230;
3.U.230.231; 3.U.230.236; 3.U.230.237; 3.U.230.238; 3.U.230.239;
3.U.230.154; 3.U.230.157; 3.U.230.166; 3.U.230.169; 3.U.230.172;
3.U.230.175; 3.U.230.240; 3.U.230.244; 3.U.231.228; 3.U.231.229;
3.U.231.230; 3.U.231.231; 3.U.231.236; 3.U.231.237; 3.U.231.238;
3.U.231.239; 3.U.231.154; 3.U.231.157; 3.U.231.166; 3.U.231.169;
3.U.231.172; 3.U.231.175; 3.U.231.240; 3.U.231.244; 3.U.236.228;
3.U.236.229; 3.U.236.230; 3.U.236.231; 3.U.236.236; 3.U.236.237;
3.U.236.238; 3.U.236.239; 3.U.236.154; 3.U.236.157; 3.U.236.166;
3.U.236.169; 3.U.236.172; 3.U.236.175; 3.U.236.240; 3.U.236.244;
3.U.237.228; 3.U.237.229; 3.U.237.230; 3.U.237.231; 3.U.237.236;
3.U.237.237; 3.U.237.238; 3.U.237.239; 3.U.237.154; 3.U.237.157;
3.U.237.166; 3.U.237.169; 3.U.237.172; 3.U.237.175; 3.U.237.240;
3.U.237.244; 3.U.238.228; 3.U.238.229; 3.U.238.230; 3.U.238.231;
3.U.238.236; 3.U.238.237; 3.U.238.238; 3.U.238.239; 3.U.238.154;
3.U.238.157; 3.U.238.166; 3.U.238.169; 3.U.238.172; 3.U.238.175;
3.U.238.240; 3.U.238.244; 3.U.239.228; 3.U.239.229; 3.U.239.230;
3.U.239.231; 3.U.239.236; 3.U.239.237; 3.U.239.238; 3.U.239.239;
3.U.239.154; 3.U.239.157; 3.U.239.166; 3.U.239.169; 3.U.239.172;
3.U.239.175; 3.U.239.240; 3.U.239.244; 3.U.154.228; 3.U.154.229;
3.U.154.230; 3.U.154.231; 3.U.154.236; 3.U.154.237; 3.U.154.238;
3.U.154.239; 3.U.154.154; 3.U.154.157; 3.U.154.166; 3.U.154.169;
3.U.154.172; 3.U.154.175; 3.U.154.240; 3.U.154.244; 3.U.157.228;
3.U.157.229; 3.U.157.230; 3.U.157.231; 3.U.157.236; 3.U.157.237;
3.U.157.238; 3.U.157.239; 3.U.157.154; 3.U.157.157; 3.U.157.166;
3.U.157.169; 3.U.157.172; 3.U.157.175; 3.U.157.240; 3.U.157.244;
3.U.166.228; 3.U.166.229; 3.U.166.230; 3.U.166.231; 3.U.166.236;
3.U.166.237; 3.U.166.238; 3.U.166.239; 3.U.166.154; 3.U.166.157;
3.U.166.166; 3.U.166.169; 3.U.166.172; 3.U.166.175; 3.U.166.240;
3.U.166.244; 3.U.169.228; 3.U.169.229; 3.U.169.230; 3.U.169.231;
3.U.169.236; 3.U.169.237; 3.U.169.238; 3.U.169.239; 3.U.169.154;
3.U.169.157; 3.U.169.166; 3.U.169.169; 3.U.169.172; 3.U.169.175;
3.U.169.240; 3.U.169.244; 3.U.172.228; 3.U.172.229; 3.U.172.230;
3.U.172.231; 3.U.172.236; 3.U.172.237; 3.U.172.238; 3.U.172.239;
3.U.172.154; 3.U.172.157; 3.U.172.166; 3.U.172.169; 3.U.172.172;
3.U.172.175; 3.U.172.240; 3.U.172.244; 3.U.175.228; 3.U.175.229;
3.U.175.230; 3.U.175.231; 3.U.175.236; 3.U.175.237; 3.U.175.238;
3.U.175.239; 3.U.175.154; 3.U.175.157; 3.U.175.166; 3.U.175.169;
3.U.175.172; 3.U.175.175; 3.U.175.240; 3.U.175.244; 3.U.240.228;
3.U.240.229; 3.U.240.230; 3.U.240.231; 3.U.240.236; 3.U.240.237;
3.U.240.238; 3.U.240.239; 3.U.240.154; 3.U.240.157; 3.U.240.166;
3.U.240.169; 3.U.240.172; 3.U.240.175; 3.U.240.240; 3.U.240.244;
3.U.244.228; 3.U.244.229; 3.U.244.230; 3.U.244.231; 3.U.244.236;
3.U.244.237; 3.U.244.238; 3.U.244.239; 3.U.244.154; 3.U.244.157;
3.U.244.166; 3.U.244.169; 3.U.244.172; 3.U.244.175; 3.U.244.240;
3.U.244.244; Prodrugs of 3.W 3.W.228.228; 3.W.228.229; 3.W.228.230;
3.W.228.231; 3.W.228.236; 3.W.228.237; 3.W.228.238; 3.W.228.239;
3.W.228.154; 3.W.228.157; 3.W.228.166; 3.W.228.169; 3.W.228.172;
3.W.228.175; 3.W.228.240; 3.W.228.244; 3.W.229.228; 3.W.229.229;
3.W.229.230; 3.W.229.231; 3.W.229.236; 3.W.229.237; 3.W.229.238;
3.W.229.239; 3.W.229.154; 3.W.229.157; 3.W.229.166; 3.W.229.169;
3.W.229.172; 3.W.229.175; 3.W.229.240; 3.W.229.244; 3.W.230.228;
3.W.230.229; 3.W.230.230; 3.W.230.231; 3.W.230.236; 3.W.230.237;
3.W.230.238; 3.W.230.239; 3.W.230.154; 3.W.230.157; 3.W.230.166;
3.W.230.169; 3.W.230.172; 3.W.230.175; 3.W.230.240; 3.W.230.244;
3.W.231.228; 3.W.231.229; 3.W.231.230; 3.W.231.231; 3.W.231.236;
3.W.231.237; 3.W.231.238; 3.W.231.239; 3.W.231.154; 3.W.231.157;
3.W.231.166; 3.W.231.169; 3.W.231.172; 3.W.231.175; 3.W.231.240;
3.W.231.244; 3.W.236.228; 3.W.236.229; 3.W.236.230; 3.W.236.231;
3.W.236.236; 3.W.236.237; 3.W.236.238; 3.W.236.239; 3.W.236.154;
3.W.236.157; 3.W.236.166; 3.W.236.169; 3.W.236.172; 3.W.236.175;
3.W.236.240; 3.W.236.244; 3.W.237.228; 3.W.237.229; 3.W.237.230;
3.W.237.231; 3.W.237.236; 3.W.237.237; 3.W.237.238; 3.W.237.239;
3.W.237.154; 3.W.237.157; 3.W.237.166; 3.W.237.169; 3.W.237.172;
3.W.237.175; 3.W.237.240; 3.W.237.244; 3.W.238.228; 3.W.238.229;
3.W.238.230; 3.W.238.231; 3.W.238.236; 3.W.238.237; 3.W.238.238;
3.W.238.239; 3.W.238.154; 3.W.238.157; 3.W.238.166; 3.W.238.169;
3.W.238.172; 3.W.238.175; 3.W.238.240; 3.W.238.244; 3.W.239.228;
3.W.239.229; 3.W.239.230; 3.W.239.231; 3.W.239.236; 3.W.239.237;
3.W.239.238; 3.W.239.239; 3.W.239.154; 3.W.239.157; 3.W.239.166;
3.W.239.169; 3.W.239.172; 3.W.239.175; 3.W.239.240; 3.W.239.244;
3.W.154.228; 3.W.154.229; 3.W.154.230; 3.W.154.231; 3.W.154.236;
3.W.154.237; 3.W.154.238; 3.W.154.239; 3.W.154.154; 3.W.154.157;
3.W.154.166; 3.W.154.169; 3.W.154.172; 3.W.154.175; 3.W.154.240;
3.W.154.244; 3.W.157.228; 3.W.157.229; 3.W.157.230; 3.W.157.231;
3.W.157.236; 3.W.157.237; 3.W.157.238; 3.W.157.239; 3.W.157.154;
3.W.157.157; 3.W.157.166; 3.W.157.169; 3.W.157.172; 3.W.157.175;
3.W.157.240; 3.W.157.244; 3.W.166.228; 3.W.166.229; 3.W.166.230;
3.W.166.231; 3.W.166.236; 3.W.166.237; 3.W.166.238; 3.W.166.239;
3.W.166.154; 3.W.166.157; 3.W.166.166; 3.W.166.169; 3.W.166.172;
3.W.166.175; 3.W.166.240; 3.W.166.244; 3.W.169.228; 3.W.169.229;
3.W.169.230; 3.W.169.231; 3.W.169.236; 3.W.169.237; 3.W.169.238;
3.W.169.239; 3.W.169.154; 3.W.169.157; 3.W.169.166; 3.W.169.169;
3.W.169.172; 3.W.169.175; 3.W.169.240; 3.W.169.244; 3.W.172.228;
3.W.172.229; 3.W.172.230; 3.W.172.231; 3.W.172.236; 3.W.172.237;
3.W.172.238; 3.W.172.239; 3.W.172.154; 3.W.172.157; 3.W.172.166;
3.W.172.169; 3.W.172.172; 3.W.172.175; 3.W.172.240; 3.W.172.244;
3.W.175.228; 3.W.175.229; 3.W.175.230; 3.W.175.231; 3.W.175.236;
3.W.175.237; 3.W.175.238; 3.W.175.239; 3.W.175.154; 3.W.175.157;
3.W.175.166; 3.W.175.169; 3.W.175.172; 3.W.175.175; 3.W.175.240;
3.W.175.244; 3.W.240.228; 3.W.240.229; 3.W.240.230; 3.W.240.231;
3.W.240.236; 3.W.240.237; 3.W.240.238; 3.W.240.239; 3.W.240.154;
3.W.240.157; 3.W.240.166; 3.W.240.169; 3.W.240.172; 3.W.240.175;
3.W.240.240; 3.W.240.244; 3.W.244.228; 3.W.244.229; 3.W.244.230;
3.W.244.231; 3.W.244.236; 3.W.244.237; 3.W.244.238; 3.W.244.239;
3.W.244.154; 3.W.244.157; 3.W.244.166; 3.W.244.169; 3.W.244.172;
3.W.244.175; 3.W.244.240; 3.W.244.244; Prodrugs of 3.Y 3.Y.228.228;
3.Y.228.229; 3.Y.228.230; 3.Y.228.231; 3.Y.228.236; 3.Y.228.237;
3.Y.228.238; 3.Y.228.239; 3.Y.228.154; 3.Y.228.157; 3.Y.228.166;
3.Y.228.169; 3.Y.228.172; 3.Y.228.175; 3.Y.228.240; 3.Y.228.244;
3.Y.229.228; 3.Y.229.229; 3.Y.229.230; 3.Y.229.231; 3.Y.229.236;
3.Y.229.237; 3.Y.229.238; 3.Y.229.239; 3.Y.229.154; 3.Y.229.157;
3.Y.229.166; 3.Y.229.169; 3.Y.229.172; 3.Y.229.175; 3.Y.229.240;
3.Y.229.244; 3.Y.230.228; 3.Y.230.229; 3.Y.230.230; 3.Y.230.231;
3.Y.230.236; 3.Y.230.237; 3.Y.230.238; 3.Y.230.239; 3.Y.230.154;
3.Y.230.157; 3.Y.230.166; 3.Y.230.169; 3.Y.230.172; 3.Y.230.175;
3.Y.230.240; 3.Y.230.244; 3.Y.231.228; 3.Y.231.229; 3.Y.231.230;
3.Y.231.231; 3.Y.231.236; 3.Y.231.237; 3.Y.231.238; 3.Y.231.239;
3.Y.231.154; 3.Y.231.157; 3.Y.231.166; 3.Y.231.169; 3.Y.231.172;
3.Y.231.175; 3.Y.231.240; 3.Y.231.244; 3.Y.236.228; 3.Y.236.229;
3.Y.236.230; 3.Y.236.231; 3.Y.236.236; 3.Y.236.237; 3.Y.236.238;
3.Y.236.239; 3.Y.236.154; 3.Y.236.157; 3.Y.236.166; 3.Y.236.169;
3.Y.236.172; 3.Y.236.175; 3.Y.236.240; 3.Y.236.244; 3.Y.237.228;
3.Y.237.229; 3.Y.237.230; 3.Y.237.231; 3.Y.237.236; 3.Y.237.237;
3.Y.237.238; 3.Y.237.239; 3.Y.237.154; 3.Y.237.157; 3.Y.237.166;
3.Y.237.169; 3.Y.237.172; 3.Y.237.175; 3.Y.237.240; 3.Y.237.244;
3.Y.238.228; 3.Y.238.229; 3.Y.238.230; 3.Y.238.231; 3.Y.238.236;
3.Y.238.237; 3.Y.238.238; 3.Y.238.239; 3.Y.238.154; 3.Y.238.157;
3.Y.238.166; 3.Y.238.169; 3.Y.238.172; 3.Y.238.175; 3.Y.238.240;
3.Y.238.244; 3.Y.239.228; 3.Y.239.229; 3.Y.239.230; 3.Y.239.231;
3.Y.239.236; 3.Y.239.237; 3.Y.239.238; 3.Y.239.239; 3.Y.239.154;
3.Y.239.157; 3.Y.239.166; 3.Y.239.169; 3.Y.239.172; 3.Y.239.175;
3.Y.239.240; 3.Y.239.244; 3.Y.154.228; 3.Y.154.229; 3.Y.154.230;
3.Y.154.231; 3.Y.154.236; 3.Y.154.237; 3.Y.154.238; 3.Y.154.239;
3.Y.154.154; 3.Y.154.157; 3.Y.154.166; 3.Y.154.169; 3.Y.154.172;
3.Y.154.175; 3.Y.154.240; 3.Y.154.244; 3.Y.157.228; 3.Y.157.229;
3.Y.157.230; 3.Y.157.231; 3.Y.157.236; 3.Y.157.237; 3.Y.157.238;
3.Y.157.239; 3.Y.157.154; 3.Y.157.157; 3.Y.157.166; 3.Y.157.169;
3.Y.157.172; 3.Y.157.175; 3.Y.157.240; 3.Y.157.244; 3.Y.166.228;
3.Y.166.229; 3.Y.166.230; 3.Y.166.231; 3.Y.166.236; 3.Y.166.237;
3.Y.166.238; 3.Y.166.239; 3.Y.166.154; 3.Y.166.157; 3.Y.166.166;
3.Y.166.169; 3.Y.166.172; 3.Y.166.175; 3.Y.166.240; 3.Y.166.244;
3.Y.169.228; 3.Y.169.229; 3.Y.169.230; 3.Y.169.231; 3.Y.169.236;
3.Y.169.237; 3.Y.169.238; 3.Y.169.239; 3.Y.169.154; 3.Y.169.157;
3.Y.169.166; 3.Y.169.169; 3.Y.169.172; 3.Y.169.175; 3.Y.169.240;
3.Y.169.244; 3.Y.172.228; 3.Y.172.229; 3.Y.172.230; 3.Y.172.231;
3.Y.172.236; 3.Y.172.237; 3.Y.172.238; 3.Y.172.239; 3.Y.172.154;
3.Y.172.157; 3.Y.172.166; 3.Y.172.169; 3.Y.172.172; 3.Y.172.175;
3.Y.172.240; 3.Y.172.244; 3.Y.175.228; 3.Y.175.229; 3.Y.175.230;
3.Y.175.231; 3.Y.175.236; 3.Y.175.237; 3.Y.175.238; 3.Y.175.239;
3.Y.175.154; 3.Y.175.157; 3.Y.175.166; 3.Y.175.169; 3.Y.175.172;
3.Y.175.175; 3.Y.175.240; 3.Y.175.244; 3.Y.240.228; 3.Y.240.229;
3.Y.240.230; 3.Y.240.231; 3.Y.240.236; 3.Y.240.237; 3.Y.240.238;
3.Y.240.239; 3.Y.240.154; 3.Y.240.157; 3.Y.240.166; 3.Y.240.169;
3.Y.240.172; 3.Y.240.175; 3.Y.240.240; 3.Y.240.244; 3.Y.244.228;
3.Y.244.229; 3.Y.244.230; 3.Y.244.231; 3.Y.244.236; 3.Y.244.237;
3.Y.244.238; 3.Y.244.239; 3.Y.244.154; 3.Y.244.157; 3.Y.244.166;
3.Y.244.169; 3.Y.244.172; 3.Y.244.175; 3.Y.244.240; 3.Y.244.244;
Prodrugs of 4.B 4.B.228.228; 4.B.228.229; 4.B.228.230; 4.B.228.231;
4.B.228.236; 4.B.228.237; 4.B.228.238; 4.B.228.239; 4.B.228.154;
4.B.228.157; 4.B.228.166; 4.B.228.169; 4.B.228.172; 4.B.228.175;
4.B.228.240; 4.B.228.244; 4.B.229.228; 4.B.229.229; 4.B.229.230;
4.B.229.231; 4.B.229.236; 4.B.229.237; 4.B.229.238; 4.B.229.239;
4.B.229.154; 4.B.229.157; 4.B.229.166; 4.B.229.169; 4.B.229.172;
4.B.229.175; 4.B.229.240; 4.B.229.244; 4.B.230.228; 4.B.230.229;
4.B.230.230; 4.B.230.231; 4.B.230.236; 4.B.230.237; 4.B.230.238;
4.B.230.239; 4.B.230.154; 4.B.230.157; 4.B.230.166; 4.B.230.169;
4.B.230.172; 4.B.230.175; 4.B.230.240; 4.B.230.244; 4.B.231.228;
4.B.231.229; 4.B.231.230; 4.B.231.231; 4.B.231.236; 4.B.231.237;
4.B.231.238; 4.B.231.239; 4.B.231.154; 4.B.231.157; 4.B.231.166;
4.B.231.169; 4.B.231.172; 4.B.231.175; 4.B.231.240; 4.B.231.244;
4.B.236.228; 4.B.236.229; 4.B.236.230; 4.B.236.231; 4.B.236.236;
4.B.236.237; 4.B.236.238; 4.B.236.239; 4.B.236.154; 4.B.236.157;
4.B.236.166; 4.B.236.169; 4.B.236.172; 4.B.236.175; 4.B.236.240;
4.B.236.244; 4.B.237.228; 4.B.237.229; 4.B.237.230; 4.B.237.231;
4.B.237.236; 4.B.237.237; 4.B.237.238; 4.B.237.239; 4.B.237.154;
4.B.237.157; 4.B.237.166; 4.B.237.169; 4.B.237.172; 4.B.237.175;
4.B.237.240; 4.B.237.244; 4.B.238.228; 4.B.238.229; 4.B.238.230;
4.B.238.231; 4.B.238.236; 4.B.238.237; 4.B.238.238; 4.B.238.239;
4.B.238.154; 4.B.238.157; 4.B.238.166; 4.B.238.169; 4.B.238.172;
4.B.238.175; 4.B.238.240; 4.B.238.244; 4.B.239.228; 4.B.239.229;
4.B.239.230; 4.B.239.231; 4.B.239.236; 4.B.239.237; 4.B.239.238;
4.B.239.239; 4.B.239.154; 4.B.239.157; 4.B.239.166; 4.B.239.169;
4.B.239.172; 4.B.239.175; 4.B.239.240; 4.B.239.244; 4.B.154.228;
4.B.154.229; 4.B.154.230; 4.B.154.231; 4.B.154.236; 4.B.154.237;
4.B.154.238; 4.B.154.239; 4.B.154.154; 4.B.154.157; 4.B.154.166;
4.B.154.169; 4.B.154.172; 4.B.154.175; 4.B.154.240; 4.B.154.244;
4.B.157.228; 4.B.157.229; 4.B.157.230; 4.B.157.231; 4.B.157.236;
4.B.157.237; 4.B.157.238; 4.B.157.239; 4.B.157.154; 4.B.157.157;
4.B.157.166; 4.B.157.169; 4.B.157.172; 4.B.157.175; 4.B.157.240;
4.B.157.244; 4.B.166.228; 4.B.166.229; 4.B.166.230; 4.B.166.231;
4.B.166.236; 4.B.166.237; 4.B.166.238; 4.B.166.239; 4.B.166.154;
4.B.166.157; 4.B.166.166; 4.B.166.169; 4.B.166.172; 4.B.166.175;
4.B.166.240; 4.B.166.244; 4.B.169.228; 4.B.169.229; 4.B.169.230;
4.B.169.231; 4.B.169.236; 4.B.169.237; 4.B.169.238; 4.B.169.239;
4.B.169.154; 4.B.169.157; 4.B.169.166; 4.B.169.169; 4.B.169.172;
4.B.169.175; 4.B.169.240; 4.B.169.244; 4.B.172.228; 4.B.172.229;
4.B.172.230; 4.B.172.231; 4.B.172.236; 4.B.172.237; 4.B.172.238;
4.B.172.239; 4.B.172.154; 4.B.172.157; 4.B.172.166; 4.B.172.169;
4.B.172.172; 4.B.172.175; 4.B.172.240; 4.B.172.244; 4.B.175.228;
4.B.175.229; 4.B.175.230; 4.B.175.231; 4.B.175.236; 4.B.175.237;
4.B.175.238; 4.B.175.239; 4.B.175.154; 4.B.175.157; 4.B.175.166;
4.B.175.169; 4.B.175.172; 4.B.175.175; 4.B.175.240; 4.B.175.244;
4.B.240.228; 4.B.240.229; 4.B.240.230; 4.B.240.231; 4.B.240.236;
4.B.240.237; 4.B.240.238; 4.B.240.239; 4.B.240.154; 4.B.240.157;
4.B.240.166; 4.B.240.169; 4.B.240.172; 4.B.240.175; 4.B.240.240;
4.B.240.244; 4.B.244.228; 4.B.244.229; 4.B.244.230; 4.B.244.231;
4.B.244.236; 4.B.244.237; 4.B.244.238; 4.B.244.239; 4.B.244.154;
4.B.244.157; 4.B.244.166; 4.B.244.169; 4.B.244.172; 4.B.244.175;
4.B.244.240; 4.B.244.244; Prodrugs of 4.D 4.D.228.228; 4.D.228.229;
4.D.228.230; 4.D.228.231; 4.D.228.236; 4.D.228.237; 4.D.228.238;
4.D.228.239; 4.D.228.154; 4.D.228.157; 4.D.228.166; 4.D.228.169;
4.D.228.172; 4.D.228.175; 4.D.228.240; 4.D.228.244; 4.D.229.228;
4.D.229.229; 4.D.229.230; 4.D.229.231; 4.D.229.236; 4.D.229.237;
4.D.229.238; 4.D.229.239; 4.D.229.154; 4.D.229.157; 4.D.229.166;
4.D.229.169; 4.D.229.172; 4.D.229.175; 4.D.229.240; 4.D.229.244;
4.D.230.228; 4.D.230.229; 4.D.230.230; 4.D.230.231; 4.D.230.236;
4.D.230.237; 4.D.230.238; 4.D.230.239; 4.D.230.154; 4.D.230.157;
4.D.230.166; 4.D.230.169; 4.D.230.172; 4.D.230.175; 4.D.230.240;
4.D.230.244; 4.D.231.228; 4.D.231.229; 4.D.231.230; 4.D.231.231;
4.D.231.236; 4.D.231.237; 4.D.231.238; 4.D.231.239; 4.D.231.154;
4.D.231.157; 4.D.231.166; 4.D.231.169; 4.D.231.172; 4.D.231.175;
4.D.231.240; 4.D.231.244; 4.D.236.228; 4.D.236.229; 4.D.236.230;
4.D.236.231; 4.D.236.236; 4.D.236.237; 4.D.236.238; 4.D.236.239;
4.D.236.154; 4.D.236.157; 4.D.236.166; 4.D.236.169; 4.D.236.172;
4.D.236.175; 4.D.236.240; 4.D.236.244; 4.D.237.228; 4.D.237.229;
4.D.237.230; 4.D.237.231; 4.D.237.236; 4.D.237.237; 4.D.237.238;
4.D.237.239; 4.D.237.154; 4.D.237.157; 4.D.237.166; 4.D.237.169;
4.D.237.172; 4.D.237.175; 4.D.237.240; 4.D.237.244; 4.D.238.228;
4.D.238.229; 4.D.238.230; 4.D.238.231; 4.D.238.236; 4.D.238.237;
4.D.238.238; 4.D.238.239; 4.D.238.154; 4.D.238.157; 4.D.238.166;
4.D.238.169; 4.D.238.172; 4.D.238.175; 4.D.238.240; 4.D.238.244;
4.D.239.228; 4.D.239.229; 4.D.239.230; 4.D.239.231; 4.D.239.236;
4.D.239.237; 4.D.239.238; 4.D.239.239; 4.D.239.154; 4.D.239.157;
4.D.239.166; 4.D.239.169; 4.D.239.172; 4.D.239.175; 4.D.239.240;
4.D.239.244; 4.D.154.228; 4.D.154.229; 4.D.154.230; 4.D.154.231;
4.D.154.236; 4.D.154.237; 4.D.154.238; 4.D.154.239; 4.D.154.154;
4.D.154.157; 4.D.154.166; 4.D.154.169; 4.D.154.172; 4.D.154.175;
4.D.154.240; 4.D.154.244; 4.D.157.228; 4.D.157.229; 4.D.157.230;
4.D.157.231; 4.D.157.236; 4.D.157.237; 4.D.157.238; 4.D.157.239;
4.D.157.154; 4.D.157.157; 4.D.157.166; 4.D.157.169; 4.D.157.172;
4.D.157.175; 4.D.157.240; 4.D.157.244; 4.D.166.228; 4.D.166.229;
4.D.166.230; 4.D.166.231; 4.D.166.236; 4.D.166.237; 4.D.166.238;
4.D.166.239; 4.D.166.154; 4.D.166.157; 4.D.166.166; 4.D.166.169;
4.D.166.172; 4.D.166.175; 4.D.166.240; 4.D.166.244; 4.D.169.228;
4.D.169.229; 4.D.169.230; 4.D.169.231; 4.D.169.236; 4.D.169.237;
4.D.169.238; 4.D.169.239; 4.D.169.154; 4.D.169.157; 4.D.169.166;
4.D.169.169; 4.D.169.172; 4.D.169.175; 4.D.169.240; 4.D.169.244;
4.D.172.228; 4.D.172.229; 4.D.172.230; 4.D.172.231; 4.D.172.236;
4.D.172.237; 4.D.172.238; 4.D.172.239; 4.D.172.154; 4.D.172.157;
4.D.172.166; 4.D.172.169; 4.D.172.172; 4.D.172.175; 4.D.172.240;
4.D.172.244; 4.D.175.228; 4.D.175.229; 4.D.175.230; 4.D.175.231;
4.D.175.236; 4.D.175.237; 4.D.175.238;
4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166; 4.D.175.169;
4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244; 4.D.240.228;
4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236; 4.D.240.237;
4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157; 4.D.240.166;
4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240; 4.D.240.244;
4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231; 4.D.244.236;
4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154; 4.D.244.157;
4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175; 4.D.244.240;
4.D.244.244; Prodrugs of 4.E 4.E.228.228; 4.E.228.229; 4.E.228.230;
4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238; 4.E.228.239;
4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169; 4.E.228.172;
4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228; 4.E.229.229;
4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237; 4.E.229.238;
4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166; 4.E.229.169;
4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244; 4.E.230.228;
4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236; 4.E.230.237;
4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157; 4.E.230.166;
4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240; 4.E.230.244;
4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231; 4.E.231.236;
4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154; 4.E.231.157;
4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175; 4.E.231.240;
4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230; 4.E.236.231;
4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239; 4.E.236.154;
4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172; 4.E.236.175;
4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229; 4.E.237.230;
4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238; 4.E.237.239;
4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169; 4.E.237.172;
4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228; 4.E.238.229;
4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237; 4.E.238.238;
4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166; 4.E.238.169;
4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244; 4.E.239.228;
4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236; 4.E.239.237;
4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157; 4.E.239.166;
4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240; 4.E.239.244;
4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231; 4.E.154.236;
4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154; 4.E.154.157;
4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175; 4.E.154.240;
4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230; 4.E.157.231;
4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239; 4.E.157.154;
4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172; 4.E.157.175;
4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229; 4.E.166.230;
4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238; 4.E.166.239;
4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169; 4.E.166.172;
4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228; 4.E.169.229;
4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237; 4.E.169.238;
4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166; 4.E.169.169;
4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244; 4.E.172.228;
4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236; 4.E.172.237;
4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157; 4.E.172.166;
4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240; 4.E.172.244;
4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231; 4.E.175.236;
4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154; 4.E.175.157;
4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175; 4.E.175.240;
4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230; 4.E.240.231;
4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239; 4.E.240.154;
4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172; 4.E.240.175;
4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229; 4.E.244.230;
4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238; 4.E.244.239;
4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169; 4.E.244.172;
4.E.244.175; 4.E.244.240; 4.E.244.244; Prodrugs of 4.G 4.G.228.228;
4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236; 4.G.228.237;
4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157; 4.G.228.166;
4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240; 4.G.228.244;
4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231; 4.G.229.236;
4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154; 4.G.229.157;
4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175; 4.G.229.240;
4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230; 4.G.230.231;
4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239; 4.G.230.154;
4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172; 4.G.230.175;
4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229; 4.G.231.230;
4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238; 4.G.231.239;
4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169; 4.G.231.172;
4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228; 4.G.236.229;
4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237; 4.G.236.238;
4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166; 4.G.236.169;
4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244; 4.G.237.228;
4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236; 4.G.237.237;
4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157; 4.G.237.166;
4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240; 4.G.237.244;
4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231; 4.G.238.236;
4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154; 4.G.238.157;
4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175; 4.G.238.240;
4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230; 4.G.239.231;
4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239; 4.G.239.154;
4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172; 4.G.239.175;
4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229; 4.G.154.230;
4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238; 4.G.154.239;
4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169; 4.G.154.172;
4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228; 4.G.157.229;
4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237; 4.G.157.238;
4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166; 4.G.157.169;
4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244; 4.G.166.228;
4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236; 4.G.166.237;
4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157; 4.G.166.166;
4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240; 4.G.166.244;
4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231; 4.G.169.236;
4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154; 4.G.169.157;
4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175; 4.G.169.240;
4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230; 4.G.172.231;
4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239; 4.G.172.154;
4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172; 4.G.172.175;
4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229; 4.G.175.230;
4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238; 4.G.175.239;
4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169; 4.G.175.172;
4.G.175.175; 4.G.175.240; 4.G.175.244; 4.G.240.228; 4.G.240.229;
4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237; 4.G.240.238;
4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166; 4.G.240.169;
4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244; 4.G.244.228;
4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236; 4.G.244.237;
4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157; 4.G.244.166;
4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240; 4.G.244.244;
Prodrugs of 4.I 4.I.228.228; 4.I.228.229; 4.I.228.230; 4.I.228.231;
4.I.228.236; 4.I.228.237; 4.I.228.238; 4.I.228.239; 4.I.228.154;
4.I.228.157; 4.I.228.166; 4.I.228.169; 4.I.228.172; 4.I.228.175;
4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229; 4.I.229.230;
4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238; 4.I.229.239;
4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169; 4.I.229.172;
4.I.229.175; 4.I.229.240; 4.I.229.244; 4.I.230.228; 4.I.230.229;
4.I.230.230; 4.I.230.231; 4.I.230.236; 4.I.230.237; 4.I.230.238;
4.I.230.239; 4.I.230.154; 4.I.230.157; 4.I.230.166; 4.I.230.169;
4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244; 4.I.231.228;
4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236; 4.I.231.237;
4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157; 4.I.231.166;
4.I.231.169; 4.I.231.172; 4.I.231.175; 4.I.231.240; 4.I.231.244;
4.I.236.228; 4.I.236.229; 4.I.236.230; 4.I.236.231; 4.I.236.236;
4.I.236.237; 4.I.236.238; 4.I.236.239; 4.I.236.154; 4.I.236.157;
4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175; 4.I.236.240;
4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230; 4.I.237.231;
4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239; 4.I.237.154;
4.I.237.157; 4.I.237.166; 4.I.237.169; 4.I.237.172; 4.I.237.175;
4.I.237.240; 4.I.237.244; 4.I.238.228; 4.I.238.229; 4.I.238.230;
4.I.238.231; 4.I.238.236; 4.I.238.237; 4.I.238.238; 4.I.238.239;
4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169; 4.I.238.172;
4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228; 4.I.239.229;
4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237; 4.I.239.238;
4.I.239.239; 4.I.239.154; 4.I.239.157; 4.I.239.166; 4.I.239.169;
4.I.239.172; 4.I.239.175; 4.I.239.240; 4.I.239.244; 4.I.154.228;
4.I.154.229; 4.I.154.230; 4.I.154.231; 4.I.154.236; 4.I.154.237;
4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157; 4.I.154.166;
4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240; 4.I.154.244;
4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231; 4.I.157.236;
4.I.157.237; 4.I.157.238; 4.I.157.239; 4.I.157.154; 4.I.157.157;
4.I.157.166; 4.I.157.169; 4.I.157.172; 4.I.157.175; 4.I.157.240;
4.I.157.244; 4.I.166.228; 4.I.166.229; 4.I.166.230; 4.I.166.231;
4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239; 4.I.166.154;
4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172; 4.I.166.175;
4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229; 4.I.169.230;
4.I.169.231; 4.I.169.236; 4.I.169.237; 4.I.169.238; 4.I.169.239;
4.I.169.154; 4.I.169.157; 4.I.169.166; 4.I.169.169; 4.I.169.172;
4.I.169.175; 4.I.169.240; 4.I.169.244; 4.I.172.228; 4.I.172.229;
4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237; 4.I.172.238;
4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166; 4.I.172.169;
4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244; 4.I.175.228;
4.I.175.229; 4.I.175.230; 4.I.175.231; 4.I.175.236; 4.I.175.237;
4.I.175.238; 4.I.175.239; 4.I.175.154; 4.I.175.157; 4.I.175.166;
4.I.175.169; 4.I.175.172; 4.I.175.175; 4.I.175.240; 4.I.175.244;
4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231; 4.I.240.236;
4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154; 4.I.240.157;
4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175; 4.I.240.240;
4.I.240.244; 4.I.244.228; 4.I.244.229; 4.I.244.230; 4.I.244.231;
4.I.244.236; 4.I.244.237; 4.I.244.238; 4.I.244.239; 4.I.244.154;
4.I.244.157; 4.I.244.166; 4.I.244.169; 4.I.244.172; 4.I.244.175;
4.I.244.240; 4.I.244.244; Prodrugs of 4.J 4.J.228.228; 4.J.228.229;
4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237; 4.J.228.238;
4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166; 4.J.228.169;
4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244; 4.J.229.228;
4.J.229.229; 4.J.229.230; 4.J.229.231; 4.J.229.236; 4.J.229.237;
4.J.229.238; 4.J.229.239; 4.J.229.154; 4.J.229.157; 4.J.229.166;
4.J.229.169; 4.J.229.172; 4.J.229.175; 4.J.229.240; 4.J.229.244;
4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231; 4.J.230.236;
4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154; 4.J.230.157;
4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175; 4.J.230.240;
4.J.230.244; 4.J.231.228; 4.J.231.229; 4.J.231.230; 4.J.231.231;
4.J.231.236; 4.J.231.237; 4.J.231.238; 4.J.231.239; 4.J.231.154;
4.J.231.157; 4.J.231.166; 4.J.231.169; 4.J.231.172; 4.J.231.175;
4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229; 4.J.236.230;
4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238; 4.J.236.239;
4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169; 4.J.236.172;
4.J.236.175; 4.J.236.240; 4.J.236.244; 4.J.237.228; 4.J.237.229;
4.J.237.230; 4.J.237.231; 4.J.237.236; 4.J.237.237; 4.J.237.238;
4.J.237.239; 4.J.237.154; 4.J.237.157; 4.J.237.166; 4.J.237.169;
4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244; 4.J.238.228;
4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236; 4.J.238.237;
4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157; 4.J.238.166;
4.J.238.169; 4.J.238.172; 4.J.238.175; 4.J.238.240; 4.J.238.244;
4.J.239.228; 4.J.239.229; 4.J.239.230; 4.J.239.231; 4.J.239.236;
4.J.239.237; 4.J.239.238; 4.J.239.239; 4.J.239.154; 4.J.239.157;
4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175; 4.J.239.240;
4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230; 4.J.154.231;
4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239; 4.J.154.154;
4.J.154.157; 4.J.154.166; 4.J.154.169; 4.J.154.172; 4.J.154.175;
4.J.154.240; 4.J.154.244; 4.J.157.228; 4.J.157.229; 4.J.157.230;
4.J.157.231; 4.J.157.236; 4.J.157.237; 4.J.157.238; 4.J.157.239;
4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169; 4.J.157.172;
4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228; 4.J.166.229;
4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237; 4.J.166.238;
4.J.166.239; 4.J.166.154; 4.J.166.157; 4.J.166.166; 4.J.166.169;
4.J.166.172; 4.J.166.175; 4.J.166.240; 4.J.166.244; 4.J.169.228;
4.J.169.229; 4.J.169.230; 4.J.169.231; 4.J.169.236; 4.J.169.237;
4.J.169.238; 4.J.169.239; 4.J.169.154; 4.J.169.157; 4.J.169.166;
4.J.169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240; 4.J.169.244;
4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231; 4.J.172.236;
4.J.172.237; 4.J.172.238; 4.J.172.239; 4.J.172.154; 4.J.172.157;
4.J.172.166; 4.J.172.169; 4.J.172.172; 4.J.172.175; 4.J.172.240;
4.J.172.244; 4.J.175.228; 4.J.175.229; 4.J.175.230; 4.J.175.231;
4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239; 4.J.175.154;
4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172; 4.J.175.175;
4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229; 4.J.240.230;
4.J.240.231; 4.J.240.236; 4.J.240.237; 4.J.240.238; 4.J.240.239;
4.J.240.154; 4.J.240.157; 4.J.240.166; 4.J.240.169; 4.J.240.172;
4.J.240.175; 4.J.240.240; 4.J.240.244; 4.J.244.228; 4.J.244.229;
4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237; 4.J.244.238;
4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166; 4.J.244.169;
4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244; Prodrugs of 4.L
4.L.228.228; 4.L.228.229; 4.L.228.230; 4.L.228.231; 4.L.228.236;
4.L.228.237; 4.L.228.238; 4.L.228.239; 4.L.228.154; 4.L.228.157;
4.L.228.166; 4.L.228.169; 4.L.228.172; 4.L.228.175; 4.L.228.240;
4.L.228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230; 4.L.229.231;
4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239; 4.L.229.154;
4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172; 4.L.229.175;
4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229; 4.L.230.230;
4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238; 4.L.230.239;
4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169; 4.L.230.172;
4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228; 4.L.231.229;
4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237; 4.L.231.238;
4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166; 4.L.231.169;
4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244; 4.L.236.228;
4.L.236.229; 4.L.236.230; 4.L.236.231; 4.L.236.236; 4.L.236.237;
4.L.236.238; 4.L.236.239; 4.L.236.154; 4.L.236.157; 4.L.236.166;
4.L.236.169; 4.L.236.172; 4.L.236.175; 4.L.236.240; 4.L.236.244;
4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231; 4.L.237.236;
4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154; 4.L.237.157;
4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175; 4.L.237.240;
4.L.237.244; 4.L.238.228; 4.L.238.229; 4.L.238.230; 4.L.238.231;
4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239; 4.L.238.154;
4.L.238.157; 4.L.238.166; 4.L.238.169; 4.L.238.172; 4.L.238.175;
4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229; 4.L.239.230;
4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238; 4.L.239.239;
4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169; 4.L.239.172;
4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L.154.228; 4.L.154.229;
4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237; 4.L.154.238;
4.L.154.239; 4.L.154.154; 4.L.154.157; 4.L.154.166; 4.L.154.169;
4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244;
4.L.157.228;
4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236; 4.L.157.237;
4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157; 4.L.157.166;
4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240; 4.L.157.244;
4.L.166.228; 4.L.166.229; 4.L.166.230; 4.L.166.231; 4.L.166.236;
4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154; 4.L.166.157;
4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175; 4.L.166.240;
4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230; 4.L.169.231;
4.L.169.236; 4.L.169.237; 4.L.169.238; 4.L.169.239; 4.L.169.154;
4.L.169.157; 4.L.169.166; 4.L.169.169; 4.L.169.172; 4.L.169.175;
4.L.169.240; 4.L.169.244; 4.L.172.228; 4.L.172.229; 4.L.172.230;
4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238; 4.L.172.239;
4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169; 4.L.172.172;
4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228; 4.L.175.229;
4.L.175.230; 4.L.175.231; 4.L.175.236; 4.L.175.237; 4.L.175.238;
4.L.175.239; 4.L.175.154; 4.L.175.157; 4.L.175.166; 4.L.175.169;
4.L.175.172; 4.L.175.175; 4.L.175.240; 4.L.175.244; 4.L.240.228;
4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236; 4.L.240.237;
4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157; 4.L.240.166;
4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240; 4.L.240.244;
4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231; 4.L.244.236;
4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154; 4.L.244.157;
4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175; 4.L.244.240;
4.L.244.244; Prodrugs of 4.O 4.O.228.228; 4.O.228.229; 4.O.228.230;
4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238; 4.O.228.239;
4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169; 4.O.228.172;
4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228; 4.O.229.229;
4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237; 4.O.229.238;
4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166; 4.O.229.169;
4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244; 4.O.230.228;
4.O.230.229; 4.O.230.230; 4.O.230.231; 4.O.230.236; 4.O.230.237;
4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O.230.157; 4.O.230.166;
4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.230.240; 4.O.230.244;
4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231; 4.O.231.236;
4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154; 4.O.231.157;
4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175; 4.O.231.240;
4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230; 4.O.236.231;
4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239; 4.O.236.154;
4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172; 4.O.236.175;
4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229; 4.O.237.230;
4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238; 4.O.237.239;
4.O.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169; 4.O.237.172;
4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228; 4.O.238.229;
4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237; 4.O.238.238;
4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166; 4.O.238.169;
4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244; 4.O.239.228;
4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236; 4.O.239.237;
4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157; 4.O.239.166;
4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240; 4.O.239.244;
4.O.154.228; 4.O.154.229; 4.O.154.230; 4.O.154.231; 4.O.154.236;
4.O.154.237; 4.O.154.238; 4.O.154.239; 4.O.154.154; 4.O.154.157;
4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175; 4.O.154.240;
4.O.154.244; 4.O.157.228; 4.O.157.229; 4.O.157.230; 4.O.157.231;
4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239; 4.O.157.154;
4.O.157.157; 4.O.157.166; 4.O.157.169; 4.O.157.172; 4.O.157.175;
4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229; 4.O.166.230;
4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238; 4.O.166.239;
4.O.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169; 4.O.166.172;
4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228; 4.O.169.229;
4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237; 4.O.169.238;
4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166; 4.O.169.169;
4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244; 4.O.172.228;
4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236; 4.O.172.237;
4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157; 4.O.172.166;
4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240; 4.O.172.244;
4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231; 4.O.175.236;
4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154; 4.O.175.157;
4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175; 4.O.175.240;
4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230; 4.O.240.231;
4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239; 4.O.240.154;
4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172; 4.O.240.175;
4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229; 4.O.244.230;
4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238; 4.O.244.239;
4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169; 4.O.244.172;
4.O.244.175; 4.O.244.240; 4.O.244.244; Prodrugs of 4.P 4.P.228.228;
4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236; 4.P.228.237;
4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157; 4.P.228.166;
4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240; 4.P.228.244;
4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231; 4.P.229.236;
4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154; 4.P.229.157;
4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175; 4.P.229.240;
4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230; 4.P.230.231;
4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239; 4.P.230.154;
4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172; 4.P.230.175;
4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229; 4.P.231.230;
4.P.231.231; 4.P.231.236; 4.P.231.237; 4.P.231.238; 4.P.231.239;
4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169; 4.P.231.172;
4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228; 4.P.236.229;
4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237; 4.P.236.238;
4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166; 4.P.236.169;
4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244; 4.P.237.228;
4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236; 4.P.237.237;
4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157; 4.P.237.166;
4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240; 4.P.237.244;
4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231; 4.P.238.236;
4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154; 4.P.238.157;
4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175; 4.P.238.240;
4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230; 4.P.239.231;
4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239; 4.P.239.154;
4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172; 4.P.239.175;
4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229; 4.P.154.230;
4.P.154.231; 4.P.154.236; 4.P.154.237; 4.P.154.238; 4.P.154.239;
4.P.154.154; 4.P.154.157; 4.P.154.166; 4.P.154.169; 4.P.154.172;
4.P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228; 4.P.157.229;
4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237; 4.P.157.238;
4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166; 4.P.157.169;
4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244; 4.P.166.228;
4.P.166.229; 4.P.166.230; 4.P.166.231; 4.P.166.236; 4.P.166.237;
4.P.166.238; 4.P.166.239; 4.P.166.154; 4.P.166.157; 4.P.166.166;
4.P.166.169; 4.P.166.172; 4.P.166.175; 4.P.166.240; 4.P.166.244;
4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231; 4.P.169.236;
4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154; 4.P.169.157;
4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175; 4.P.169.240;
4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230; 4.P.172.231;
4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239; 4.P.172.154;
4.P.172.157; 4.P.172.166; 4.P.172.169; 4.P.172.172; 4.P.172.175;
4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229; 4.P.175.230;
4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238; 4.P.175.239;
4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169; 4.P.175.172;
4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228; 4.P.240.229;
4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237; 4.P.240.238;
4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166; 4.P.240.169;
4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244; 4.P.244.228;
4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236; 4.P.244.237;
4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157; 4.P.244.166;
4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240; 4.P.244.244;
Prodrugs of 4.U 4.U.228.228; 4.U.228.229; 4.U.228.230; 4.U.228.231;
4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239; 4.U.228.154;
4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172; 4.U.228.175;
4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229; 4.U.229.230;
4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238; 4.U.229.239;
4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169; 4.U.229.172;
4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228; 4.U.230.229;
4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237; 4.U.230.238;
4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166; 4.U.230.169;
4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244; 4.U.231.228;
4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236; 4.U.231.237;
4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157; 4.U.231.166;
4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240; 4.U.231.244;
4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231; 4.U.236.236;
4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154; 4.U.236.157;
4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175; 4.U.236.240;
4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230; 4.U.237.231;
4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239; 4.U.237.154;
4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172; 4.U.237.175;
4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229; 4.U.238.230;
4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238; 4.U.238.239;
4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169; 4.U.238.172;
4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228; 4.U.239.229;
4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237; 4.U.239.238;
4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166; 4.U.239.169;
4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244; 4.U.154.228;
4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236; 4.U.154.237;
4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157; 4.U.154.166;
4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240; 4.U.154.244;
4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231; 4.U.157.236;
4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154; 4.U.157.157;
4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175; 4.U.157.240;
4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230; 4.U.166.231;
4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239; 4.U.166.154;
4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172; 4.U.166.175;
4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229; 4.U.169.230;
4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238; 4.U.169.239;
4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169; 4.U.169.172;
4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228; 4.U.172.229;
4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237; 4.U.172.238;
4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166; 4.U.172.169;
4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244; 4.U.175.228;
4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236; 4.U.175.237;
4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157; 4.U.175.166;
4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240; 4.U.175.244;
4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231; 4.U.240.236;
4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154; 4.U.240.157;
4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175; 4.U.240.240;
4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230; 4.U.244.231;
4.U.244.236; 4.U.244.237; 4.U.244.238; 4.U.244.239; 4.U.244.154;
4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172; 4.U.244.175;
4.U.244.240; 4.U.244.244; Prodrugs of 4.W 4.W.228.228; 4.W.228.229;
4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237; 4.W.228.238;
4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166; 4.W.228.169;
4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244; 4.W.229.228;
4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236; 4.W.229.237;
4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157; 4.W.229.166;
4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240; 4.W.229.244;
4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231; 4.W.230.236;
4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154; 4.W.230.157;
4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175; 4.W.230.240;
4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230; 4.W.231.231;
4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239; 4.W.231.154;
4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172; 4.W.231.175;
4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229; 4.W.236.230;
4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238; 4.W.236.239;
4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169; 4.W.236.172;
4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228; 4.W.237.229;
4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237; 4.W.237.238;
4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166; 4.W.237.169;
4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244; 4.W.238.228;
4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236; 4.W.238.237;
4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157; 4.W.238.166;
4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240; 4.W.238.244;
4.W.239.228; 4.W.239.229; 4.W.239.230; 4.W.239.231; 4.W.239.236;
4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154; 4.W.239.157;
4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175; 4.W.239.240;
4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230; 4.W.154.231;
4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239; 4.W.154.154;
4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172; 4.W.154.175;
4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W.157.229; 4.W.157.230;
4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238; 4.W.157.239;
4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169; 4.W.157.172;
4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228; 4.W.166.229;
4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237; 4.W.166.238;
4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166; 4.W.166.169;
4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244; 4.W.169.228;
4.W.169.229; 4.W.169.230; 4.W.169.231; 4.W.169.236; 4.W.169.237;
4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157; 4.W.169.166;
4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240; 4.W.169.244;
4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231; 4.W.172.236;
4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154; 4.W.172.157;
4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175; 4.W.172.240;
4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230; 4.W.175.231;
4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239; 4.W.175.154;
4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172; 4.W.175.175;
4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229; 4.W.240.230;
4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238; 4.W.240.239;
4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169; 4.W.240.172;
4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228; 4.W.244.229;
4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237; 4.W.244.238;
4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166; 4.W.244.169;
4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244; Prodrugs of 4.Y
4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231; 4.Y.228.236;
4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154; 4.Y.228.157;
4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175; 4.Y.228.240;
4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230; 4.Y.229.231;
4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239; 4.Y.229.154;
4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172; 4.Y.229.175;
4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229; 4.Y.230.230;
4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238; 4.Y.230.239;
4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169; 4.Y.230.172;
4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228; 4.Y.231.229;
4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237; 4.Y.231.238;
4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166; 4.Y.231.169;
4.Y.231.172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244; 4.Y.236.228;
4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236; 4.Y.236.237;
4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157;
4.Y.236.166;
4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240; 4.Y.236.244;
4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231; 4.Y.237.236;
4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154; 4.Y.237.157;
4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175; 4.Y.237.240;
4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230; 4.Y.238.231;
4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239; 4.Y.238.154;
4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172; 4.Y.238.175;
4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229; 4.Y.239.230;
4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238; 4.Y.239.239;
4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169; 4.Y.239.172;
4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228; 4.Y.154.229;
4.Y.154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237; 4.Y.154.238;
4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166; 4.Y.154.169;
4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244; 4.Y.157.228;
4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236; 4.Y.157.237;
4.Y.157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157; 4.Y.157.166;
4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240; 4.Y.157.244;
4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231; 4.Y.166.236;
4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154; 4.Y.166.157;
4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175; 4.Y.166.240;
4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230; 4.Y.169.231;
4.Y.169.236; 4.Y.169.237; 4.Y.169.238; 4.Y.169.239; 4.Y.169.154;
4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172; 4.Y.169.175;
4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229; 4.Y.172.230;
4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238; 4.Y.172.239;
4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169; 4.Y.172.172;
4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228; 4.Y.175.229;
4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237; 4.Y.175.238;
4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166; 4.Y.175.169;
4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244; 4.Y.240.228;
4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236; 4.Y.240.237;
4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157; 4.Y.240.166;
4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240; 4.Y.240.244;
4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231; 4.Y.244.236;
4.Y.244.237; 4.Y.244.238; 4.Y.244.239; 4.Y.244.154; 4.Y.244.157;
4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175; 4.Y.244.240;
4.Y.244.244; Prodrugs of 5.B 5.B.228.228; 5.B.228.229; 5.B.228.230;
5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238; 5.B.228.239;
5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169; 5.B.228.172;
5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228; 5.B.229.229;
5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237; 5.B.229.238;
5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166; 5.B.229.169;
5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244; 5.B.230.228;
5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236; 5.B.230.237;
5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157; 5.B.230.166;
5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240; 5.B.230.244;
5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231; 5.B.231.236;
5.B.231.237; 5.B.231.238; 5.B.231.239; 5.B.231.154; 5.B.231.157;
5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175; 5.B.231.240;
5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230; 5.B.236.231;
5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239; 5.B.236.154;
5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172; 5.B.236.175;
5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229; 5.B.237.230;
5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238; 5.B.237.239;
5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169; 5.B.237.172;
5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228; 5.B.238.229;
5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237; 5.B.238.238;
5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166; 5.B.238.169;
5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244; 5.B.239.228;
5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236; 5.B.239.237;
5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157; 5.B.239.166;
5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240; 5.B.239.244;
5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231; 5.B.154.236;
5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154; 5.B.154.157;
5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175; 5.B.154.240;
5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230; 5.B.157.231;
5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239; 5.B.157.154;
5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172; 5.B.157.175;
5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229; 5.B.166.230;
5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238; 5.B.166.239;
5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169; 5.B.166.172;
5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228; 5.B.169.229;
5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237; 5.B.169.238;
5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166; 5.B.169.169;
5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244; 5.B.172.228;
5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236; 5.B.172.237;
5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157; 5.B.172.166;
5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240; 5.B.172.244;
5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231; 5.B.175.236;
5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154; 5.B.175.157;
5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175; 5.B.175.240;
5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230; 5.B.240.231;
5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239; 5.B.240.154;
5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172; 5.B.240.175;
5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229; 5.B.244.230;
5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238; 5.B.244.239;
5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169; 5.B.244.172;
5.B.244.175; 5.B.244.240; 5.B.244.244; Prodrugs of 5.D 5.D.228.228;
5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236; 5.D.228.237;
5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157; 5.D.228.166;
5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240; 5.D.228.244;
5.D.229.228; 5.D.229.229; 5.D.229.230; 5.D.229.231; 5.D.229.236;
5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154; 5.D.229.157;
5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175; 5.D.229.240;
5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230; 5.D.230.231;
5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239; 5.D.230.154;
5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172; 5.D.230.175;
5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229; 5.D.231.230;
5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238; 5.D.231.239;
5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169; 5.D.231.172;
5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228; 5.D.236.229;
5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237; 5.D.236.238;
5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166; 5.D.236.169;
5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244; 5.D.237.228;
5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236; 5.D.237.237;
5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157; 5.D.237.166;
5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240; 5.D.237.244;
5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231; 5.D.238.236;
5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154; 5.D.238.157;
5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175; 5.D.238.240;
5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230; 5.D.239.231;
5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239; 5.D.239.154;
5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172; 5.D.239.175;
5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229; 5.D.154.230;
5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238; 5.D.154.239;
5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169; 5.D.154.172;
5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228; 5.D.157.229;
5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237; 5.D.157.238;
5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166; 5.D.157.169;
5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244; 5.D.166.228;
5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236; 5.D.166.237;
5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157; 5.D.166.166;
5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240; 5.D.166.244;
5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231; 5.D.169.236;
5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154; 5.D.169.157;
5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175; 5.D.169.240;
5.D.169.244; 5.D.172.228; 5.D.172.229; 5.D.172.230; 5.D.172.231;
5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239; 5.D.172.154;
5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172; 5.D.172.175;
5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229; 5.D.175.230;
5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238; 5.D.175.239;
5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169; 5.D.175.172;
5.D.175.175; 5.D.175.240; 5.D.175.244; 5.D.240.228; 5.D.240.229;
5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237; 5.D.240.238;
5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166; 5.D.240.169;
5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244; 5.D.244.228;
5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236; 5.D.244.237;
5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157; 5.D.244.166;
5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240; 5.D.244.244;
Prodrugs of 5.E 5.E.228.228; 5.E.228.229; 5.E.228.230; 5.E.228.231;
5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239; 5.E.228.154;
5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172; 5.E.228.175;
5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229; 5.E.229.230;
5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238; 5.E.229.239;
5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169; 5.E.229.172;
5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228; 5.E.230.229;
5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237; 5.E.230.238;
5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166; 5.E.230.169;
5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244; 5.E.231.228;
5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236; 5.E.231.237;
5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157; 5.E.231.166;
5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240; 5.E.231.244;
5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231; 5.E.236.236;
5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154; 5.E.236.157;
5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175; 5.E.236.240;
5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230; 5.E.237.231;
5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239; 5.E.237.154;
5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172; 5.E.237.175;
5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229; 5.E.238.230;
5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238; 5.E.238.239;
5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169; 5.E.238.172;
5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228; 5.E.239.229;
5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237; 5.E.239.238;
5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166; 5.E.239.169;
5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244; 5.E.154.228;
5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236; 5.E.154.237;
5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157; 5.E.154.166;
5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240; 5.E.154.244;
5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231; 5.E.157.236;
5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154; 5.E.157.157;
5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175; 5.E.157.240;
5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230; 5.E.166.231;
5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239; 5.E.166.154;
5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172; 5.E.166.175;
5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229; 5.E.169.230;
5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238; 5.E.169.239;
5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169; 5.E.169.172;
5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228; 5.E.172.229;
5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237; 5.E.172.238;
5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166; 5.E.172.169;
5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244; 5.E.175.228;
5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236; 5.E.175.237;
5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157; 5.E.175.166;
5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240; 5.E.175.244;
5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231; 5.E.240.236;
5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154; 5.E.240.157;
5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175; 5.E.240.240;
5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230; 5.E.244.231;
5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239; 5.E.244.154;
5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172; 5.E.244.175;
5.E.244.240; 5.E.244.244; Prodrugs of 5.G 5.G.228.228; 5.G.228.229;
5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237; 5.G.228.238;
5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166; 5.G.228.169;
5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244; 5.G.229.228;
5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236; 5.G.229.237;
5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157; 5.G.229.166;
5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240; 5.G.229.244;
5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231; 5.G.230.236;
5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154; 5.G.230.157;
5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175; 5.G.230.240;
5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230; 5.G.231.231;
5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239; 5.G.231.154;
5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172; 5.G.231.175;
5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229; 5.G.236.230;
5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238; 5.G.236.239;
5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169; 5.G.236.172;
5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228; 5.G.237.229;
5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237; 5.G.237.238;
5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166; 5.G.237.169;
5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244; 5.G.238.228;
5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236; 5.G.238.237;
5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157; 5.G.238.166;
5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240; 5.G.238.244;
5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231; 5.G.239.236;
5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154; 5.G.239.157;
5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175; 5.G.239.240;
5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230; 5.G.154.231;
5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239; 5.G.154.154;
5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172; 5.G.154.175;
5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229; 5.G.157.230;
5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238; 5.G.157.239;
5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169; 5.G.157.172;
5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228; 5.G.166.229;
5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237; 5.G.166.238;
5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166; 5.G.166.169;
5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244; 5.G.169.228;
5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236; 5.G.169.237;
5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157; 5.G.169.166;
5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240; 5.G.169.244;
5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231; 5.G.172.236;
5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154; 5.G.172.157;
5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175; 5.G.172.240;
5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230; 5.G.175.231;
5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239; 5.G.175.154;
5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172; 5.G.175.175;
5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229; 5.G.240.230;
5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238; 5.G.240.239;
5.G.240.154; 5.G.240.157; 5.G.240.166; 5.G.240.169; 5.G.240.172;
5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228; 5.G.244.229;
5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237; 5.G.244.238;
5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166; 5.G.244.169;
5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244; Prodrugs of 5.I
5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231;
5.I.228.236;
5.I.228.237; 5.I.228.238; 5.I.228.239; 5.I.228.154; 5.I.228.157;
5.I.228.166; 5.I.228.169; 5.I.228.172; 5.I.228.175; 5.I.228.240;
5.I.228.244; 5.I.229.228; 5.I.229.229; 5.I.229.230; 5.I.229.231;
5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239; 5.I.229.154;
5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172; 5.I.229.175;
5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229; 5.I.230.230;
5.I.230.231; 5.I.230.236; 5.I.230.237; 5.I.230.238; 5.I.230.239;
5.I.230.154; 5.I.230.157; 5.I.230.166; 5.I.230.169; 5.I.230.172;
5.I.230.175; 5.I.230.240; 5.I.230.244; 5.I.231.228; 5.I.231.229;
5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237; 5.I.231.238;
5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166; 5.I.231.169;
5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244; 5.I.236.228;
5.I.236.229; 5.I.236.230; 5.I.236.231; 5.I.236.236; 5.I.236.237;
5.I.236.238; 5.I.236.239; 5.I.236.154; 5.I.236.157; 5.I.236.166;
5.I.236.169; 5.I.236.172; 5.I.236.175; 5.I.236.240; 5.I.236.244;
5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231; 5.I.237.236;
5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154; 5.I.237.157;
5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175; 5.I.237.240;
5.I.237.244; 5.I.238.228; 5.I.238.229; 5.I.238.230; 5.I.238.231;
5.I.238.236; 5.I.238.237; 5.I.238.238; 5.I.238.239; 5.I.238.154;
5.I.238.157; 5.I.238.166; 5.I.238.169; 5.I.238.172; 5.I.238.175;
5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229; 5.I.239.230;
5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238; 5.I.239.239;
5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169; 5.I.239.172;
5.I.239.175; 5.I.239.240; 5.I.239.244; 5.I.154.228; 5.I.154.229;
5.I.154.230; 5.I.154.231; 5.I.154.236; 5.I.154.237; 5.I.154.238;
5.I.154.239; 5.I.154.154; 5.I.154.157; 5.I.154.166; 5.I.154.169;
5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244; 5.I.157.228;
5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236; 5.I.157.237;
5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157; 5.I.157.166;
5.I.157.169; 5.I.157.172; 5.I.157.175; 5.I.157.240; 5.I.157.244;
5.I.166.228; 5.I.166.229; 5.I.166.230; 5.I.166.231; 5.I.166.236;
5.I.166.237; 5.I.166.238; 5.I.166.239; 5.I.166.154; 5.I.166.157;
5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175; 5.I.166.240;
5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230; 5.I.169.231;
5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239; 5.I.169.154;
5.I.169.157; 5.I.169.166; 5.I.169.169; 5.I.169.172; 5.I.169.175;
5.I.169.240; 5.I.169.244; 5.I.172.228; 5.I.172.229; 5.I.172.230;
5.I.172.231; 5.I.172.236; 5.I.172.237; 5.I.172.238; 5.I.172.239;
5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169; 5.I.172.172;
5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228; 5.I.175.229;
5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237; 5.I.175.238;
5.I.175.239; 5.I.175.154; 5.I.175.157; 5.I.175.166; 5.I.175.169;
5.I.175.172; 5.I.175.175; 5.I.175.240; 5.I.175.244; 5.I.240.228;
5.I.240.229; 5.I.240.230; 5.I.240.231; 5.I.240.236; 5.I.240.237;
5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157; 5.I.240.166;
5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240; 5.I.240.244;
5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231; 5.I.244.236;
5.I.244.237; 5.I.244.238; 5.I.244.239; 5.I.244.154; 5.I.244.157;
5.I.244.166; 5.I.244.169; 5.I.244.172; 5.I.244.175; 5.I.244.240;
5.I.244.244; Prodrugs of 5.J 5.J.228.228; 5.J.228.229; 5.J.228.230;
5.J.228.231; 5.J.228.236; 5.J.228.237; 5.J.228.238; 5.J.228.239;
5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169; 5.J.228.172;
5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228; 5.J.229.229;
5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237; 5.J.229.238;
5.J.229.239; 5.J.229.154; 5.J.229.157; 5.J.229.166; 5.J.229.169;
5.J.229.172; 5.J.229.175; 5.J.229.240; 5.J.229.244; 5.J.230.228;
5.J.230.229; 5.J.230.230; 5.J.230.231; 5.J.230.236; 5.J.230.237;
5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157; 5.J.230.166;
5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240; 5.J.230.244;
5.J.231.228; 5.J.231.229; 5.J.231.230; 5.J.231.231; 5.J.231.236;
5.J.231.237; 5.J.231.238; 5.J.231.239; 5.J.231.154; 5.J.231.157;
5.J.231.166; 5.J.231.169; 5.J.231.172; 5.J.231.175; 5.J.231.240;
5.J.231.244; 5.J.236.228; 5.J.236.229; 5.J.236.230; 5.J.236.231;
5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239; 5.J.236.154;
5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172; 5.J.236.175;
5.J.236.240; 5.J.236.244; 5.J.237.228; 5.J.237.229; 5.J.237.230;
5.J.237.231; 5.J.237.236; 5.J.237.237; 5.J.237.238; 5.J.237.239;
5.J.237.154; 5.J.237.157; 5.J.237.166; 5.J.237.169; 5.J.237.172;
5.J.237.175; 5.J.237.240; 5.J.237.244; 5.J.238.228; 5.J.238.229;
5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237; 5.J.238.238;
5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166; 5.J.238.169;
5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244; 5.J.239.228;
5.J.239.229; 5.J.239.230; 5.J.239.231; 5.J.239.236; 5.J.239.237;
5.J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157; 5.J.239.166;
5.J.239.169; 5.J.239.172; 5.J.239.175; 5.J.239.240; 5.J.239.244;
5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231; 5.J.154.236;
5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154; 5.J.154.157;
5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175; 5.J.154.240;
5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230; 5.J.157.231;
5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239; 5.J.157.154;
5.J.157.157; 5.J.157.166; 5.J.157.169; 5.J.157.172; 5.J.157.175;
5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J.166.229; 5.J.166.230;
5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238; 5.J.166.239;
5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169; 5.J.166.172;
5.J.166.175; 5.J.166.240; 5.J.166.244; 5.J.169.228; 5.J.169.229;
5.J.169.230; 5.J.169.231; 5.J.169.236; 5.J.169.237; 5.J.169.238;
5.J.169.239; 5.J.169.154; 5.J.169.157; 5.J.169.166; 5.J.169.169;
5.J.169.172; 5.J.169.175; 5.J.169.240; 5.J.169.244; 5.J.172.228;
5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236; 5.J.172.237;
5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157; 5.J.172.166;
5.J.172.169; 5.J.172.172; 5.J.172.175; 5.J.172.240; 5.J.172.244;
5.J.175.228; 5.J.175.229; 5.J.175.230; 5.J.175.231; 5.J.175.236;
5.J.175.237; 5.J.175.238; 5.J.175.239; 5.J.175.154; 5.J.175.157;
5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175; 5.J.175.240;
5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230; 5.J.240.231;
5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239; 5.J.240.154;
5.J.240.157; 5.J.240.166; 5.J.240.169; 5.J.240.172; 5.J.240.175;
5.J.240.240; 5.J.240.244; 5.J.244.228; 5.J.244.229; 5.J.244.230;
5.J.244.231; 5.J.244.236; 5.J.244.237; 5.J.244.238; 5.J.244.239;
5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169; 5.J.244.172;
5.J.244.175; 5.J.244.240; 5.J.244.244; Prodrugs of 5.L 5.L.228.228;
5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236; 5.L.228.237;
5.L.228.238; 5.L.228.239; 5.L.228.154; 5.L.228.157; 5.L.228.166;
5.L.228.169; 5.L.228.172; 5.L.228.175; 5.L.228.240; 5.L.228.244;
5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231; 5.L.229.236;
5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154; 5.L.229.157;
5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175; 5.L.229.240;
5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230; 5.L.230.231;
5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239; 5.L.230.154;
5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172; 5.L.230.175;
5.L.230.240; 5.L.230.244; 5.L.231.228; 5.L.231.229; 5.L.231.230;
5.L.231.231; 5.L.231.236; 5.L.231.237; 5.L.231.238; 5.L.231.239;
5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169; 5.L.231.172;
5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L.236.228; 5.L.236.229;
5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237; 5.L.236.238;
5.L.236.239; 5.L.236.154; 5.L.236.157; 5.L.236.166; 5.L.236.169;
5.L.236.172; 5.L.236.175; 5.L.236.240; 5.L.236.244; 5.L.237.228;
5.L.237.229; 5.L.237.230; 5.L.237.231; 5.L.237.236; 5.L.237.237;
5.L.237.238; 5.L.237.239; 5.L.237.154; 5.L.237.157; 5.L.237.166;
5.L.237.169; 5.L.237.172; 5.L.237.175; 5.L.237.240; 5.L.237.244;
5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231; 5.L.238.236;
5.L.238.237; 5.L.238.238; 5.L.238.239; 5.L.238.154; 5.L.238.157;
5.L.238.166; 5.L.238.169; 5.L.238.172; 5.L.238.175; 5.L.238.240;
5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230; 5.L.239.231;
5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239; 5.L.239.154;
5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172; 5.L.239.175;
5.L.239.240; 5.L.239.244; 5.L.154.228; 5.L.154.229; 5.L.154.230;
5.L.154.231; 5.L.154.236; 5.L.154.237; 5.L.154.238; 5.L.154.239;
5.L.154.154; 5.L.154.157; 5.L.154.166; 5.L.154.169; 5.L.154.172;
5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228; 5.L.157.229;
5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237; 5.L.157.238;
5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166; 5.L.157.169;
5.L.157.172; 5.L.157.175; 5.L.157.240; 5.L.157.244; 5.L.166.228;
5.L.166.229; 5.L.166.230; 5.L.166.231; 5.L.166.236; 5.L.166.237;
5.L.166.238; 5.L.166.239; 5.L.166.154; 5.L.166.157; 5.L.166.166;
5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240; 5.L.166.244;
5.L.169.228; 5.L.169.229; 5.L.169.230; 5.L.169.231; 5.L.169.236;
5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154; 5.L.169.157;
5.L.169.166; 5.L.169.169; 5.L.169.172; 5.L.169.175; 5.L.169.240;
5.L.169.244; 5.L.172.228; 5.L.172.229; 5.L.172.230; 5.L.172.231;
5.L.172.236; 5.L.172.237; 5.L.172.238; 5.L.172.239; 5.L.172.154;
5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172; 5.L.172.175;
5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229; 5.L.175.230;
5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238; 5.L.175.239;
5.L.175.154; 5.L.175.157; 5.L.175.166; 5.L.175.169; 5.L.175.172;
5.L.175.175; 5.L.175.240; 5.L.175.244; 5.L.240.228; 5.L.240.229;
5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237; 5.L.240.238;
5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166; 5.L.240.169;
5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244; 5.L.244.228;
5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236; 5.L.244.237;
5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157; 5.L.244.166;
5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240; 5.L.244.244;
Prodrugs of 5.O 5.O.228.228; 5.O.228.229; 5.O.228.230; 5.O.228.231;
5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239; 5.O.228.154;
5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172; 5.O.228.175;
5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229; 5.O.229.230;
5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238; 5.O.229.239;
5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169; 5.O.229.172;
5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228; 5.O.230.229;
5.O.230.230; 5.O.230.231; 5.O.230.236; 5.O.230.237; 5.O.230.238;
5.O.230.239; 5.O.230.154; 5.O.230.157; 5.O.230.166; 5.O.230.169;
5.O.230.172; 5.O.230.175; 5.O.230.240; 5.O.230.244; 5.O.231.228;
5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236; 5.O.231.237;
5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157; 5.O.231.166;
5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240; 5.O.231.244;
5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231; 5.O.236.236;
5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154; 5.O.236.157;
5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175; 5.O.236.240;
5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230; 5.O.237.231;
5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239; 5.O.237.154;
5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172; 5.O.237.175;
5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229; 5.O.238.230;
5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238; 5.O.238.239;
5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169; 5.O.238.172;
5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228; 5.O.239.229;
5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237; 5.O.239.238;
5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166; 5.O.239.169;
5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244; 5.O.154.228;
5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236; 5.O.154.237;
5.O.154.238; 5.O.154.239; 5.O.154.154; 5.O.154.157; 5.O.154.166;
5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.154.240; 5.O.154.244;
5.O.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231; 5.O.157.236;
5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154; 5.O.157.157;
5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175; 5.O.157.240;
5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230; 5.O.166.231;
5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239; 5.O.166.154;
5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172; 5.O.166.175;
5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229; 5.O.169.230;
5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238; 5.O.169.239;
5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169; 5.O.169.172;
5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228; 5.O.172.229;
5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237; 5.O.172.238;
5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166; 5.O.172.169;
5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244; 5.O.175.228;
5.O.175.229; 5.O.175.230; 5.O.175.231; 5.O.175.236; 5.O.175.237;
5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157; 5.O.175.166;
5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240; 5.O.175.244;
5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231; 5.O.240.236;
5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154; 5.O.240.157;
5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175; 5.O.240.240;
5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230; 5.O.244.231;
5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239; 5.O.244.154;
5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172; 5.O.244.175;
5.O.244.240; 5.O.244.244; Prodrugs of 5.P 5.P.228.228; 5.P.228.229;
5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237; 5.P.228.238;
5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166; 5.P.228.169;
5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244; 5.P.229.228;
5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236; 5.P.229.237;
5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157; 5.P.229.166;
5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240; 5.P.229.244;
5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231; 5.P.230.236;
5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154; 5.P.230.157;
5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175; 5.P.230.240;
5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230; 5.P.231.231;
5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239; 5.P.231.154;
5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172; 5.P.231.175;
5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229; 5.P.236.230;
5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238; 5.P.236.239;
5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169; 5.P.236.172;
5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228; 5.P.237.229;
5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237; 5.P.237.238;
5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166; 5.P.237.169;
5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244; 5.P.238.228;
5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236; 5.P.238.237;
5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157; 5.P.238.166;
5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240; 5.P.238.244;
5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231; 5.P.239.236;
5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154; 5.P.239.157;
5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175; 5.P.239.240;
5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230; 5.P.154.231;
5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239; 5.P.154.154;
5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172; 5.P.154.175;
5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P.157.229; 5.P.157.230;
5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238; 5.P.157.239;
5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169; 5.P.157.172;
5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228; 5.P.166.229;
5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237; 5.P.166.238;
5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166; 5.P.166.169;
5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244; 5.P.169.228;
5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236; 5.P.169.237;
5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157; 5.P.169.166;
5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240; 5.P.169.244;
5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231; 5.P.172.236;
5.P.172.237; 5.P.172.238; 5.P.172.239;
5.P.172.154; 5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172;
5.P.172.175; 5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229;
5.P.175.230; 5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238;
5.P.175.239; 5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169;
5.P.175.172; 5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228;
5.P.240.229; 5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237;
5.P.240.238; 5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166;
5.P.240.169; 5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244;
5.P.244.228; 5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236;
5.P.244.237; 5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157;
5.P.244.166; 5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240;
5.P.244.244; Prodrugs of 5.U 5.U.228.228; 5.U.228.229; 5.U.228.230;
5.U.228.231; 5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239;
5.U.228.154; 5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172;
5.U.228.175; 5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229;
5.U.229.230; 5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238;
5.U.229.239; 5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169;
5.U.229.172; 5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228;
5.U.230.229; 5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237;
5.U.230.238; 5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166;
5.U.230.169; 5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244;
5.U.231.228; 5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236;
5.U.231.237; 5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157;
5.U.231.166; 5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240;
5.U.231.244; 5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231;
5.U.236.236; 5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154;
5.U.236.157; 5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175;
5.U.236.240; 5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230;
5.U.237.231; 5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239;
5.U.237.154; 5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172;
5.U.237.175; 5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229;
5.U.238.230; 5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238;
5.U.238.239; 5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169;
5.U.238.172; 5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228;
5.U.239.229; 5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237;
5.U.239.238; 5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166;
5.U.239.169; 5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244;
5.U.154.228; 5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236;
5.U.154.237; 5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157;
5.U.154.166; 5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240;
5.U.154.244; 5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231;
5.U.157.236; 5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154;
5.U.157.157; 5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175;
5.U.157.240; 5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230;
5.U.166.231; 5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239;
5.U.166.154; 5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172;
5.U.166.175; 5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229;
5.U.169.230; 5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238;
5.U.169.239; 5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169;
5.U.169.172; 5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228;
5.U.172.229; 5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237;
5.U.172.238; 5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166;
5.U.172.169; 5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244;
5.U.175.228; 5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236;
5.U.175.237; 5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157;
5.U.175.166; 5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240;
5.U.175.244; 5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231;
5.U.240.236; 5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154;
5.U.240.157; 5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175;
5.U.240.240; 5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230;
5.U.244.231; 5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239;
5.U.244.154; 5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172;
5.U.244.175; 5.U.244.240; 5.U.244.244; Prodrugs of 5.W 5.W.228.228;
5.W.228.229; 5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237;
5.W.228.238; 5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166;
5.W.228.169; 5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244;
5.W.229.228; 5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236;
5.W.229.237; 5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157;
5.W.229.166; 5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240;
5.W.229.244; 5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231;
5.W.230.236; 5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154;
5.W.230.157; 5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175;
5.W.230.240; 5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230;
5.W.231.231; 5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239;
5.W.231.154; 5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172;
5.W.231.175; 5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229;
5.W.236.230; 5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238;
5.W.236.239; 5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169;
5.W.236.172; 5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228;
5.W.237.229; 5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237;
5.W.237.238; 5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166;
5.W.237.169; 5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244;
5.W.238.228; 5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236;
5.W.238.237; 5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157;
5.W.238.166; 5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240;
5.W.238.244; 5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231;
5.W.239.236; 5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154;
5.W.239.157; 5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175;
5.W.239.240; 5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230;
5.W.154.231; 5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239;
5.W.154.154; 5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172;
5.W.154.175; 5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229;
5.W.157.230; 5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238;
5.W.157.239; 5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169;
5.W.157.172; 5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228;
5.W.166.229; 5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237;
5.W.166.238; 5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166;
5.W.166.169; 5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244;
5.W.169.228; 5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236;
5.W.169.237; 5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157;
5.W.169.166; 5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240;
5.W.169.244; 5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231;
5.W.172.236; 5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154;
5.W.172.157; 5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175;
5.W.172.240; 5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230;
5.W.175.231; 5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239;
5.W.175.154; 5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172;
5.W.175.175; 5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229;
5.W.240.230; 5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238;
5.W.240.239; 5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169;
5.W.240.172; 5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228;
5.W.244.229; 5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237;
5.W.244.238; 5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166;
5.W.244.169; 5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244;
Prodrugs of 5.Y 5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231;
5.Y.228.236; 5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154;
5.Y.228.157; 5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175;
5.Y.228.240; 5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230;
5.Y.229.231; 5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239;
5.Y.229.154; 5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172;
5.Y.229.175; 5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229;
5.Y.230.230; 5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238;
5.Y.230.239; 5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169;
5.Y.230.172; 5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228;
5.Y.231.229; 5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237;
5.Y.231.238; 5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166;
5.Y.231.169; 5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244;
5.Y.236.228; 5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236;
5.Y.236.237; 5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157;
5.Y.236.166; 5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240;
5.Y.236.244; 5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231;
5.Y.237.236; 5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154;
5.Y.237.157; 5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175;
5.Y.237.240; 5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230;
5.Y.238.231; 5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239;
5.Y.238.154; 5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172;
5.Y.238.175; 5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229;
5.Y.239.230; 5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238;
5.Y.239.239; 5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169;
5.Y.239.172; 5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228;
5.Y.154.229; 5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237;
5.Y.154.238; 5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166;
5.Y.154.169; 5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244;
5.Y.157.228; 5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236;
5.Y.157.237; 5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157;
5.Y.157.166; 5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240;
5.Y.157.244; 5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231;
5.Y.166.236; 5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154;
5.Y.166.157; 5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175;
5.Y.166.240; 5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230;
5.Y.169.231; 5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239;
5.Y.169.154; 5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172;
5.Y.169.175; 5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229;
5.Y.172.230; 5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238;
5.Y.172.239; 5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169;
5.Y.172.172; 5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228;
5.Y.175.229; 5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237;
5.Y.175.238; 5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166;
5.Y.175.169; 5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244;
5.Y.240.228; 5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236;
5.Y.240.237; 5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157;
5.Y.240.166; 5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240;
5.Y.240.244; 5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231;
5.Y.244.236; 5.Y.244.237; 5.Y.244.238; 5.Y.244.239; 5.Y.244.154;
5.Y.244.157; 5.Y.244.166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175;
5.Y.244.240; 5.Y.244.244; Prodrugs of 6.B 6.B.228.228; 6.B.228.229;
6.B.228.230; 6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238;
6.B.228.239; 6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169;
6.B.228.172; 6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228;
6.B.229.229; 6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237;
6.B.229.238; 6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166;
6.B.229.169; 6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244;
6.B.230.228; 6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236;
6.B.230.237; 6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157;
6.B.230.166; 6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240;
6.B.230.244; 6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231;
6.B.231.236; 6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154;
6.B.231.157; 6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175;
6.B.231.240; 6.B.231.244; 6.B.236.228; 6.B.236.229; 6.B.236.230;
6.B.236.231; 6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239;
6.B.236.154; 6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172;
6.B.236.175; 6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229;
6.B.237.230; 6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238;
6.B.237.239; 6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169;
6.B.237.172; 6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228;
6.B.238.229; 6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237;
6.B.238.238; 6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166;
6.B.238.169; 6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244;
6.B.239.228; 6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236;
6.B.239.237; 6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157;
6.B.239.166; 6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240;
6.B.239.244; 6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231;
6.B.154.236; 6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154;
6.B.154.157; 6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175;
6.B.154.240; 6.B.154.244; 6.B.157.228; 6.B.157.229; 6.B.157.230;
6.B.157.231; 6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239;
6.B.157.154; 6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172;
6.B.157.175; 6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229;
6.B.166.230; 6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238;
6.B.166.239; 6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169;
6.B.166.172; 6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B.169.228;
6.B.169.229; 6.B.169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237;
6.B.169.238; 6.B.169.239; 6.B.169.154; 6.B.169.157; 6.B.169.166;
6.B.169.169; 6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244;
6.B.172.228; 6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236;
6.B.172.237; 6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157;
6.B.172.166; 6.B.172.169; 6.B.172.172; 6.B.172.175; 6.B.172.240;
6.B.172.244; 6.B.175.228; 6.B.175.229; 6.B.175.230; 6.B.175.231;
6.B.175.236; 6.B.175.237; 6.B.175.238; 6.B.175.239; 6.B.175.154;
6.B.175.157; 6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175;
6.B.175.240; 6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230;
6.B.240.231; 6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239;
6.B.240.154; 6.B.240.157; 6.B.240.166; 6.B.240.169; 6.B.240.172;
6.B.240.175; 6.B.240.240; 6.B.240.244; 6.B.244.228; 6.B.244.229;
6.B.244.230; 6.B.244.231; 6.B.244.236; 6.B.244.237; 6.B.244.238;
6.B.244.239; 6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169;
6.B.244.172; 6.B.244.175; 6.B.244.240; 6.B.244.244; Prodrugs of 6.D
6.D.228.228; 6.D.228.229; 6.D.228.230; 6.D.228.231; 6.D.228.236;
6.D.228.237; 6.D.228.238; 6.D.228.239; 6.D.228.154; 6.D.228.157;
6.D.228.166; 6.D.228.169; 6.D.228.172; 6.D.228.175; 6.D.228.240;
6.D.228.244; 6.D.229.228; 6.D.229.229; 6.D.229.230; 6.D.229.231;
6.D.229.236; 6.D.229.237; 6.D.229.238; 6.D.229.239; 6.D.229.154;
6.D.229.157; 6.D.229.166; 6.D.229.169; 6.D.229.172; 6.D.229.175;
6.D.229.240; 6.D.229.244; 6.D.230.228; 6.D.230.229; 6.D.230.230;
6.D.230.231; 6.D.230.236; 6.D.230.237; 6.D.230.238; 6.D.230.239;
6.D.230.154; 6.D.230.157; 6.D.230.166; 6.D.230.169; 6.D.230.172;
6.D.230.175; 6.D.230.240; 6.D.230.244; 6.D.231.228; 6.D.231.229;
6.D.231.230; 6.D.231.231; 6.D.231.236; 6.D.231.237; 6.D.231.238;
6.D.231.239; 6.D.231.154; 6.D.231.157; 6.D.231.166; 6.D.231.169;
6.D.231.172; 6.D.231.175; 6.D.231.240; 6.D.231.244; 6.D.236.228;
6.D.236.229; 6.D.236.230; 6.D.236.231; 6.D.236.236; 6.D.236.237;
6.D.236.238; 6.D.236.239; 6.D.236.154; 6.D.236.157; 6.D.236.166;
6.D.236.169; 6.D.236.172; 6.D.236.175; 6.D.236.240; 6.D.236.244;
6.D.237.228; 6.D.237.229; 6.D.237.230; 6.D.237.231; 6.D.237.236;
6.D.237.237; 6.D.237.238; 6.D.237.239; 6.D.237.154; 6.D.237.157;
6.D.237.166; 6.D.237.169; 6.D.237.172; 6.D.237.175; 6.D.237.240;
6.D.237.244; 6.D.238.228; 6.D.238.229; 6.D.238.230; 6.D.238.231;
6.D.238.236; 6.D.238.237; 6.D.238.238; 6.D.238.239; 6.D.238.154;
6.D.238.157; 6.D.238.166; 6.D.238.169; 6.D.238.172; 6.D.238.175;
6.D.238.240; 6.D.238.244; 6.D.239.228; 6.D.239.229; 6.D.239.230;
6.D.239.231; 6.D.239.236; 6.D.239.237; 6.D.239.238; 6.D.239.239;
6.D.239.154; 6.D.239.157; 6.D.239.166; 6.D.239.169; 6.D.239.172;
6.D.239.175; 6.D.239.240; 6.D.239.244; 6.D.154.228;
6.D.154.229;
6.D.154.230; 6.D.154.231; 6.D.154.236; 6.D.154.237; 6.D.154.238;
6.D.154.239; 6.D.154.154; 6.D.154.157; 6.D.154.166; 6.D.154.169;
6.D.154.172; 6.D.154.175; 6.D.154.240; 6.D.154.244; 6.D.157.228;
6.D.157.229; 6.D.157.230; 6.D.157.231; 6.D.157.236; 6.D.157.237;
6.D.157.238; 6.D.157.239; 6.D.157.154; 6.D.157.157; 6.D.157.166;
6.D.157.169; 6.D.157.172; 6.D.157.175; 6.D.157.240; 6.D.157.244;
6.D.166.228; 6.D.166.229; 6.D.166.230; 6.D.166.231; 6.D.166.236;
6.D.166.237; 6.D.166.238; 6.D.166.239; 6.D.166.154; 6.D.166.157;
6.D.166.166; 6.D.166.169; 6.D.166.172; 6.D.166.175; 6.D.166.240;
6.D.166.244; 6.D.169.228; 6.D.169.229; 6.D.169.230; 6.D.169.231;
6.D.169.236; 6.D.169.237; 6.D.169.238; 6.D.169.239; 6.D.169.154;
6.D.169.157; 6.D.169.166; 6.D.169.169; 6.D.169.172; 6.D.169.175;
6.D.169.240; 6.D.169.244; 6.D.172.228; 6.D.172.229; 6.D.172.230;
6.D.172.231; 6.D.172.236; 6.D.172.237; 6.D.172.238; 6.D.172.239;
6.D.172.154; 6.D.172.157; 6.D.172.166; 6.D.172.169; 6.D.172.172;
6.D.172.175; 6.D.172.240; 6.D.172.244; 6.D.175.228; 6.D.175.229;
6.D.175.230; 6.D.175.231; 6.D.175.236; 6.D.175.237; 6.D.175.238;
6.D.175.239; 6.D.175.154; 6.D.175.157; 6.D.175.166; 6.D.175.169;
6.D.175.172; 6.D.175.175; 6.D.175.240; 6.D.175.244; 6.D.240.228;
6.D.240.229; 6.D.240.230; 6.D.240.231; 6.D.240.236; 6.D.240.237;
6.D.240.238; 6.D.240.239; 6.D.240.154; 6.D.240.157; 6.D.240.166;
6.D.240.169; 6.D.240.172; 6.D.240.175; 6.D.240.240; 6.D.240.244;
6.D.244.228; 6.D.244.229; 6.D.244.230; 6.D.244.231; 6.D.244.236;
6.D.244.237; 6.D.244.238; 6.D.244.239; 6.D.244.154; 6.D.244.157;
6.D.244.166; 6.D.244.169; 6.D.244.172; 6.D.244.175; 6.D.244.240;
6.D.244.244; Prodrugs of 6.E 6.E.228.228; 6.E.228.229; 6.E.228.230;
6.E.228.231; 6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239;
6.E.228.154; 6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172;
6.E.228.175; 6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229;
6.E.229.230; 6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238;
6.E.229.239; 6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169;
6.E.229.172; 6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228;
6.E.230.229; 6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237;
6.E.230.238; 6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166;
6.E.230.169; 6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244;
6.E.231.228; 6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236;
6.E.231.237; 6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157;
6.E.231.166; 6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240;
6.E.231.244; 6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231;
6.E.236.236; 6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154;
6.E.236.157; 6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175;
6.E.236.240; 6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230;
6.E.237.231; 6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239;
6.E.237.154; 6.E.237.157; 6.E.237.166; 6.E.237.169; 6.E.237.172;
6.E.237.175; 6.E.237.240; 6.E.237.244; 6.E.238.228; 6.E.238.229;
6.E.238.230; 6.E.238.231; 6.E.238.236; 6.E.238.237; 6.E.238.238;
6.E.238.239; 6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169;
6.E.238.172; 6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228;
6.E.239.229; 6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237;
6.E.239.238; 6.E.239.239; 6.E.239.154; 6.E.239.157; 6.E.239.166;
6.E.239.169; 6.E.239.172; 6.E.239.175; 6.E.239.240; 6.E.239.244;
6.E.154.228; 6.E.154.229; 6.E.154.230; 6.E.154.231; 6.E.154.236;
6.E.154.237; 6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157;
6.E.154.166; 6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240;
6.E.154.244; 6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231;
6.E.157.236; 6.E.157.237; 6.E.157.238; 6.E.157.239; 6.E.157.154;
6.E.157.157; 6.E.157.166; 6.E.157.169; 6.E.157.172; 6.E.157.175;
6.E.157.240; 6.E.157.244; 6.E.166.228; 6.E.166.229; 6.E.166.230;
6.E.166.231; 6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239;
6.E.166.154; 6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172;
6.E.166.175; 6.E.166.240; 6.E.166.244; 6.E.169.228; 6.E.169.229;
6.E.169.230; 6.E.169.231; 6.E.169.236; 6.E.169.237; 6.E.169.238;
6.E.169.239; 6.E.169.154; 6.E.169.157; 6.E.169.166; 6.E.169.169;
6.E.169.172; 6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228;
6.E.172.229; 6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237;
6.E.172.238; 6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166;
6.E.172.169; 6.E.172.172; 6.E.172.175; 6.E.172.240; 6.E.172.244;
6.E.175.228; 6.E.175.229; 6.E.175.230; 6.E.175.231; 6.E.175.236;
6.E.175.237; 6.E.175.238; 6.E.175.239; 6.E.175.154; 6.E.175.157;
6.E.175.166; 6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240;
6.E.175.244; 6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231;
6.E.240.236; 6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154;
6.E.240.157; 6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175;
6.E.240.240; 6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230;
6.E.244.231; 6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239;
6.E.244.154; 6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172;
6.E.244.175; 6.E.244.240; 6.E.244.244; Prodrugs of 6.G 6.G.228.228;
6.G.228.229; 6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237;
6.G.228.238; 6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166;
6.G.228.169; 6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244;
6.G.229.228; 6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236;
6.G.229.237; 6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157;
6.G.229.166; 6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240;
6.G.229.244; 6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231;
6.G.230.236; 6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154;
6.G.230.157; 6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175;
6.G.230.240; 6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230;
6.G.231.231; 6.G.231.236; 6.G.231.237; 6.G.231.238; 6.G.231.239;
6.G.231.154; 6.G.231.157; 6.G.231.166; 6.G.231.169; 6.G.231.172;
6.G.231.175; 6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G.236.229;
6.G.236.230; 6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238;
6.G.236.239; 6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169;
6.G.236.172; 6.G.236.175; 6.G.236.240; 6.G.236.244; 6.G.237.228;
6.G.237.229; 6.G.237.230; 6.G.237.231; 6.G.237.236; 6.G.237.237;
6.G.237.238; 6.G.237.239; 6.G.237.154; 6.G.237.157; 6.G.237.166;
6.G.237.169; 6.G.237.172; 6.G.237.175; 6.G.237.240; 6.G.237.244;
6.G.238.228; 6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236;
6.G.238.237; 6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157;
6.G.238.166; 6.G.238.169; 6.G.238.172; 6.G.238.175; 6.G.238.240;
6.G.238.244; 6.G.239.228; 6.G.239.229; 6.G.239.230; 6.G.239.231;
6.G.239.236; 6.G.239.237; 6.G.239.238; 6.G.239.239; 6.G.239.154;
6.G.239.157; 6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175;
6.G.239.240; 6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230;
6.G.154.231; 6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239;
6.G.154.154; 6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172;
6.G.154.175; 6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G.157.229;
6.G.157.230; 6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238;
6.G.157.239; 6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169;
6.G.157.172; 6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228;
6.G.166.229; 6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237;
6.G.166.238; 6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166;
6.G.166.169; 6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244;
6.G.169.228; 6.G.169.229; 6.G.169.230; 6.G.169.231; 6.G.169.236;
6.G.169.237; 6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157;
6.G.169.166; 6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240;
6.G.169.244; 6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231;
6.G.172.236; 6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154;
6.G.172.157; 6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175;
6.G.172.240; 6.G.172.244; 6.G.175.228; 6.G.175.229; 6.G.175.230;
6.G.175.231; 6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239;
6.G.175.154; 6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172;
6.G.175.175; 6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229;
6.G.240.230; 6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238;
6.G.240.239; 6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169;
6.G.240.172; 6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228;
6.G.244.229; 6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237;
6.G.244.238; 6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166;
6.G.244.169; 6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244;
Prodrugs of 6.I 6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231;
6.I.228.236; 6.I.228.237; 6.I.228.238; 6.I.228.239; 6.I.228.154;
6.I.228.157; 6.I.228.166; 6.I.228.169; 6.I.228.172; 6.I.228.175;
6.I.228.240; 6.I.228.244; 6.I.229.228; 6.I.229.229; 6.I.229.230;
6.I.229.231; 6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239;
6.I.229.154; 6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172;
6.I.229.175; 6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229;
6.I.230.230; 6.I.230.231; 6.I.230.236; 6.I.230.237; 6.I.230.238;
6.I.230.239; 6.I.230.154; 6.I.230.157; 6.I.230.166; 6.I.230.169;
6.I.230.172; 6.I.230.175; 6.I.230.240; 6.I.230.244; 6.I.231.228;
6.I.231.229; 6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237;
6.I.231.238; 6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166;
6.I.231.169; 6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244;
6.I.236.228; 6.I.236.229; 6.I.236.230; 6.I.236.231; 6.I.236.236;
6.I.236.237; 6.I.236.238; 6.I.236.239; 6.I.236.154; 6.I.236.157;
6.I.236.166; 6.I.236.169; 6.I.236.172; 6.I.236.175; 6.I.236.240;
6.I.236.244; 6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231;
6.I.237.236; 6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154;
6.I.237.157; 6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175;
6.I.237.240; 6.I.237.244; 6.I.238.228; 6.I.238.229; 6.I.238.230;
6.I.238.231; 6.I.238.236; 6.I.238.237; 6.I.238.238; 6.I.238.239;
6.I.238.154; 6.I.238.157; 6.I.238.166; 6.I.238.169; 6.I.238.172;
6.I.238.175; 6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229;
6.I.239.230; 6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238;
6.I.239.239; 6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169;
6.I.239.172; 6.I.239.175; 6.I.239.240; 6.I.239.244; 6.I.154.228;
6.I.154.229; 6.I.154.230; 6.I.154.231; 6.I.154.236; 6.I.154.237;
6.I.154.238; 6.I.154.239; 6.I.154.154; 6.I.154.157; 6.I.154.166;
6.I.154.169; 6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244;
6.I.157.228; 6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236;
6.I.157.237; 6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157;
6.I.157.166; 6.I.157.169; 6.I.157.172; 6.I.157.175; 6.I.157.240;
6.I.157.244; 6.I.166.228; 6.I.166.229; 6.I.166.230; 6.I.166.231;
6.I.166.236; 6.I.166.237; 6.I.166.238; 6.I.166.239; 6.I.166.154;
6.I.166.157; 6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175;
6.I.166.240; 6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230;
6.I.169.231; 6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239;
6.I.169.154; 6.I.169.157; 6.I.169.166; 6.I.169.169; 6.I.169.172;
6.I.169.175; 6.I.169.240; 6.I.169.244; 6.I.172.228; 6.I.172.229;
6.I.172.230; 6.I.172.231; 6.I.172.236; 6.I.172.237; 6.I.172.238;
6.I.172.239; 6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169;
6.I.172.172; 6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228;
6.I.175.229; 6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237;
6.I.175.238; 6.I.175.239; 6.I.175.154; 6.I.175.157; 6.I.175.166;
6.I.175.169; 6.I.175.172; 6.I.175.175; 6.I.175.240; 6.I.175.244;
6.I.240.228; 6.I.240.229; 6.I.240.230; 6.I.240.231; 6.I.240.236;
6.I.240.237; 6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157;
6.I.240.166; 6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240;
6.I.240.244; 6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231;
6.I.244.236; 6.I.244.237; 6.I.244.238; 6.I.244.239; 6.I.244.154;
6.I.244.157; 6.I.244.166; 6.I.244.169; 6.I.244.172; 6.I.244.175;
6.I.244.240; 6.I.244.244; Prodrugs of 6.J 6.J.228.228; 6.J.228.229;
6.J.228.230; 6.J.228.231; 6.J.228.236; 6.J.228.237; 6.J.228.238;
6.J.228.239; 6.J.228.154; 6.J.228.157; 6.J.228.166; 6.J.228.169;
6.J.228.172; 6.J.228.175; 6.J.228.240; 6.J.228.244; 6.J.229.228;
6.J.229.229; 6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237;
6.J.229.238; 6.J.229.239; 6.J.229.154; 6.J.229.157; 6.J.229.166;
6.J.229.169; 6.J.229.172; 6.J.229.175; 6.J.229.240; 6.J.229.244;
6.J.230.228; 6.J.230.229; 6.J.230.230; 6.J.230.231; 6.J.230.236;
6.J.230.237; 6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J.230.157;
6.J.230.166; 6.J.230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240;
6.J.230.244; 6.J.231.228; 6.J.231.229; 6.J.231.230; 6.J.231.231;
6.J.231.236; 6.J.231.237; 6.J.231.238; 6.J.231.239; 6.J.231.154;
6.J.231.157; 6.J.231.166; 6.J.231.169; 6.J.231.172; 6.J.231.175;
6.J.231.240; 6.J.231.244; 6.J.236.228; 6.J.236.229; 6.J.236.230;
6.J.236.231; 6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239;
6.J.236.154; 6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172;
6.J.236.175; 6.J.236.240; 6.J.236.244; 6.J.237.228; 6.J.237.229;
6.J.237.230; 6.J.237.231; 6.J.237.236; 6.J.237.237; 6.J.237.238;
6.J.237.239; 6.J.237.154; 6.J.237.157; 6.J.237.166; 6.J.237.169;
6.J.237.172; 6.J.237.175; 6.J.237.240; 6.J.237.244; 6.J.238.228;
6.J.238.229; 6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237;
6.J.238.238; 6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J.238.166;
6.J.238.169; 6.J.238.172; 6.J.238.175; 6.J.238.240; 6.J.238.244;
6.J.239.228; 6.J.239.229; 6.J.239.230; 6.J.239.231; 6.J.239.236;
6.J.239.237; 6.J.239.238; 6.J.239.239; 6.J.239.154; 6.J.239.157;
6.J.239.166; 6.J.239.169; 6.J.239.172; 6.J.239.175; 6.J.239.240;
6.J.239.244; 6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231;
6.J.154.236; 6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154;
6.J.154.157; 6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175;
6.J.154.240; 6.J.154.244; 6.J.157.228; 6.J.157.229; 6.J.157.230;
6.J.157.231; 6.J.157.236; 6.J.157.237; 6.J.157.238; 6.J.157.239;
6.J.157.154; 6.J.157.157; 6.J.157.166; 6.J.157.169; 6.J.157.172;
6.J.157.175; 6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J.166.229;
6.J.166.230; 6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238;
6.J.166.239; 6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169;
6.J.166.172; 6.J.166.175; 6.J.166.240; 6.J.166.244; 6.J.169.228;
6.J.169.229; 6.J.169.230; 6.J.169.231; 6.J.169.236; 6.J.169.237;
6.J.169.238; 6.J.169.239; 6.J.169.154; 6.J.169.157; 6.J.169.166;
6.J.169.169; 6.J.169.172; 6.J.169.175; 6.J.169.240; 6.J.169.244;
6.J.172.228; 6.J.172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236;
6.J.172.237; 6.J.172.238; 6.J.172.239; 6.J.172.154; 6.J.172.157;
6.J.172.166; 6.J.172.169; 6.J.172.172; 6.J.172.175; 6.J.172.240;
6.J.172.244; 6.J.175.228; 6.J.175.229; 6.J.175.230; 6.J.175.231;
6.J.175.236; 6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154;
6.J.175.157; 6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175;
6.J.175.240; 6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230;
6.J.240.231; 6.J.240.236; 6.J.240.237; 6.J.240.238; 6.J.240.239;
6.J.240.154; 6.J.240.157; 6.J.240.166; 6.J.240.169; 6.J.240.172;
6.J.240.175; 6.J.240.240; 6.J.240.244; 6.J.244.228; 6.J.244.229;
6.J.244.230; 6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238;
6.J.244.239; 6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169;
6.J.244.172; 6.J.244.175; 6.J.244.240; 6.J.244.244; Prodrugs of 6.L
6.L.228.228; 6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236;
6.L.228.237; 6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157;
6.L.228.166; 6.L.228.169; 6.L.228.172; 6.L.228.175; 6.L.228.240;
6.L.228.244; 6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231;
6.L.229.236; 6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154;
6.L.229.157; 6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175;
6.L.229.240; 6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230;
6.L.230.231; 6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239;
6.L.230.154; 6.L.230.157; 6.L.230.166; 6.L.230.169; 6.L.230.172;
6.L.230.175; 6.L.230.240; 6.L.230.244; 6.L.231.228; 6.L.231.229;
6.L.231.230; 6.L.231.231; 6.L.231.236; 6.L.231.237; 6.L.231.238;
6.L.231.239; 6.L.231.154; 6.L.231.157; 6.L.231.166;
6.L.231.169;
6.L.231.172; 6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228;
6.L.236.229; 6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237;
6.L.236.238; 6.L.236.239; 6.L.236.154; 6.L.236.157; 6.L.236.166;
6.L.236.169; 6.L.236.172; 6.L.236.175; 6.L.236.240; 6.L.236.244;
6.L.237.228; 6.L.237.229; 6.L.237.230; 6.L.237.231; 6.L.237.236;
6.L.237.237; 6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157;
6.L.237.166; 6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240;
6.L.237.244; 6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231;
6.L.238.236; 6.L.238.237; 6.L.238.238; 6.L.238.239; 6.L.238.154;
6.L.238.157; 6.L.238.166; 6.L.238.169; 6.L.238.172; 6.L.238.175;
6.L.238.240; 6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230;
6.L.239.231; 6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239;
6.L.239.154; 6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172;
6.L.239.175; 6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229;
6.L.154.230; 6.L.154.231; 6.L.154.236; 6.L.154.237; 6.L.154.238;
6.L.154.239; 6.L.154.154; 6.L.154.157; 6.L.154.166; 6.L.154.169;
6.L.154.172; 6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L.157.228;
6.L.157.229; 6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237;
6.L.157.238; 6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166;
6.L.157.169; 6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244;
6.L.166.228; 6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236;
6.L.166.237; 6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157;
6.L.166.166; 6.L.166.169; 6.L.166.172; 6.L.166.175; 6.L.166.240;
6.L.166.244; 6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231;
6.L.169.236; 6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154;
6.L.169.157; 6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175;
6.L.169.240; 6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230;
6.L.172.231; 6.L.172.236; 6.L.172.237; 6.L.172.238; 6.L.172.239;
6.L.172.154; 6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172;
6.L.172.175; 6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229;
6.L.175.230; 6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238;
6.L.175.239; 6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169;
6.L.175.172; 6.L.175.175; 6.L.175.240; 6.L.175.244; 6.L.240.228;
6.L.240.229; 6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237;
6.L.240.238; 6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166;
6.L.240.169; 6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244;
6.L.244.228; 6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236;
6.L.244.237; 6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157;
6.L.244.166; 6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240;
6.L.244.244; Prodrugs of 6.O 6.O.228.228; 6.O.228.229; 6.O.228.230;
6.O.228.231; 6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239;
6.O.228.154; 6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172;
6.O.228.175; 6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229;
6.O.229.230; 6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238;
6.O.229.239; 6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169;
6.O.229.172; 6.O.229.175; 6.O.229.240; 6.O.229.244; 6.O.230.228;
6.O.230.229; 6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237;
6.O.230.238; 6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166;
6.O.230.169; 6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244;
6.O.231.228; 6.O.231.229; 6.O.231.230; 6.O.231.231; 6.O.231.236;
6.O.231.237; 6.O.231.238; 6.O.231.239; 6.O.231.154; 6.O.231.157;
6.O.231.166; 6.O.231.169; 6.O.231.172; 6.O.231.175; 6.O.231.240;
6.O.231.244; 6.O.236.228; 6.O.236.229; 6.O.236.230; 6.O.236.231;
6.O.236.236; 6.O.236.237; 6.O.236.238; 6.O.236.239; 6.O.236.154;
6.O.236.157; 6.O.236.166; 6.O.236.169; 6.O.236.172; 6.O.236.175;
6.O.236.240; 6.O.236.244; 6.O.237.228; 6.O.237.229; 6.O.237.230;
6.O.237.231; 6.O.237.236; 6.O.237.237; 6.O.237.238; 6.O.237.239;
6.O.237.154; 6.O.237.157; 6.O.237.166; 6.O.237.169; 6.O.237.172;
6.O.237.175; 6.O.237.240; 6.O.237.244; 6.O.238.228; 6.O.238.229;
6.O.238.230; 6.O.238.231; 6.O.238.236; 6.O.238.237; 6.O.238.238;
6.O.238.239; 6.O.238.154; 6.O.238.157; 6.O.238.166; 6.O.238.169;
6.O.238.172; 6.O.238.175; 6.O.238.240; 6.O.238.244; 6.O.239.228;
6.O.239.229; 6.O.239.230; 6.O.239.231; 6.O.239.236; 6.O.239.237;
6.O.239.238; 6.O.239.239; 6.O.239.154; 6.O.239.157; 6.O.239.166;
6.O.239.169; 6.O.239.172; 6.O.239.175; 6.O.239.240; 6.O.239.244;
6.O.154.228; 6.O.154.229; 6.O.154.230; 6.O.154.231; 6.O.154.236;
6.O.154.237; 6.O.154.238; 6.O.154.239; 6.O.154.154; 6.O.154.157;
6.O.154.166; 6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240;
6.O.154.244; 6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231;
6.O.157.236; 6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154;
6.O.157.157; 6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175;
6.O.157.240; 6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230;
6.O.166.231; 6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239;
6.O.166.154; 6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172;
6.O.166.175; 6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229;
6.O.169.230; 6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238;
6.O.169.239; 6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169;
6.O.169.172; 6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228;
6.O.172.229; 6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237;
6.O.172.238; 6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166;
6.O.172.169; 6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244;
6.O.175.228; 6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236;
6.O.175.237; 6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157;
6.O.175.166; 6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240;
6.O.175.244; 6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231;
6.O.240.236; 6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154;
6.O.240.157; 6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175;
6.O.240.240; 6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230;
6.O.244.231; 6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239;
6.O.244.154; 6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172;
6.O.244.175; 6.O.244.240; 6.O.244.244; Prodrugs of 6.P 6.P.228.228;
6.P.228.229; 6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237;
6.P.228.238; 6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166;
6.P.228.169; 6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244;
6.P.229.228; 6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236;
6.P.229.237; 6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157;
6.P.229.166; 6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240;
6.P.229.244; 6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231;
6.P.230.236; 6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154;
6.P.230.157; 6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175;
6.P.230.240; 6.P.230.244; 6.P.231.228; 6.P.231.229; 6.P.231.230;
6.P.231.231; 6.P.231.236; 6.P.231.237; 6.P.231.238; 6.P.231.239;
6.P.231.154; 6.P.231.157; 6.P.231.166; 6.P.231.169; 6.P.231.172;
6.P.231.175; 6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229;
6.P.236.230; 6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238;
6.P.236.239; 6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169;
6.P.236.172; 6.P.236.175; 6.P.236.240; 6.P.236.244; 6.P.237.228;
6.P.237.229; 6.P.237.230; 6.P.237.231; 6.P.237.236; 6.P.237.237;
6.P.237.238; 6.P.237.239; 6.P.237.154; 6.P.237.157; 6.P.237.166;
6.P.237.169; 6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244;
6.P.238.228; 6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236;
6.P.238.237; 6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157;
6.P.238.166; 6.P.238.169; 6.P.238.172; 6.P.238.175; 6.P.238.240;
6.P.238.244; 6.P.239.228; 6.P.239.229; 6.P.239.230; 6.P.239.231;
6.P.239.236; 6.P.239.237; 6.P.239.238; 6.P.239.239; 6.P.239.154;
6.P.239.157; 6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175;
6.P.239.240; 6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230;
6.P.154.231; 6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239;
6.P.154.154; 6.P.154.157; 6.P.154.166; 6.P.154.169; 6.P.154.172;
6.P.154.175; 6.P.154.240; 6.P.154.244; 6.P.157.228; 6.P.157.229;
6.P.157.230; 6.P.157.231; 6.P.157.236; 6.P.157.237; 6.P.157.238;
6.P.157.239; 6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169;
6.P.157.172; 6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228;
6.P.166.229; 6.P.166.230; 6.P.166.231; 6.P.166.236; 6.P.166.237;
6.P.166.238; 6.P.166.239; 6.P.166.154; 6.P.166.157; 6.P.166.166;
6.P.166.169; 6.P.166.172; 6.P.166.175; 6.P.166.240; 6.P.166.244;
6.P.169.228; 6.P.169.229; 6.P.169.230; 6.P.169.231; 6.P.169.236;
6.P.169.237; 6.P.169.238; 6.P.169.239; 6.P.169.154; 6.P.169.157;
6.P.169.166; 6.P.169.169; 6.P.169.172; 6.P.169.175; 6.P.169.240;
6.P.169.244; 6.P.172.228; 6.P.172.229; 6.P.172.230; 6.P.172.231;
6.P.172.236; 6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154;
6.P.172.157; 6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175;
6.P.172.240; 6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230;
6.P.175.231; 6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239;
6.P.175.154; 6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172;
6.P.175.175; 6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229;
6.P.240.230; 6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238;
6.P.240.239; 6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169;
6.P.240.172; 6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228;
6.P.244.229; 6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237;
6.P.244.238; 6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166;
6.P.244.169; 6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244;
Prodrugs of 6.U 6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231;
6.U.228.236; 6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154;
6.U.228.157; 6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175;
6.U.228.240; 6.U.228.244; 6.U.229.228; 6.U.229.229; 6.U.229.230;
6.U.229.231; 6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239;
6.U.229.154; 6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172;
6.U.229.175; 6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229;
6.U.230.230; 6.U.230.231; 6.U.230.236; 6.U.230.237; 6.U.230.238;
6.U.230.239; 6.U.230.154; 6.U.230.157; 6.U.230.166; 6.U.230.169;
6.U.230.172; 6.U.230.175; 6.U.230.240; 6.U.230.244; 6.U.231.228;
6.U.231.229; 6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237;
6.U.231.238; 6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166;
6.U.231.169; 6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244;
6.U.236.228; 6.U.236.229; 6.U.236.230; 6.U.236.231; 6.U.236.236;
6.U.236.237; 6.U.236.238; 6.U.236.239; 6.U.236.154; 6.U.236.157;
6.U.236.166; 6.U.236.169; 6.U.236.172; 6.U.236.175; 6.U.236.240;
6.U.236.244; 6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231;
6.U.237.236; 6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154;
6.U.237.157; 6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175;
6.U.237.240; 6.U.237.244; 6.U.238.228; 6.U.238.229; 6.U.238.230;
6.U.238.231; 6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239;
6.U.238.154; 6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172;
6.U.238.175; 6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229;
6.U.239.230; 6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238;
6.U.239.239; 6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169;
6.U.239.172; 6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228;
6.U.154.229; 6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237;
6.U.154.238; 6.U.154.239; 6.U.154.154; 6.U.154.157; 6.U.154.166;
6.U.154.169; 6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244;
6.U.157.228; 6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236;
6.U.157.237; 6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157;
6.U.157.166; 6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240;
6.U.157.244; 6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231;
6.U.166.236; 6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154;
6.U.166.157; 6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175;
6.U.166.240; 6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230;
6.U.169.231; 6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239;
6.U.169.154; 6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172;
6.U.169.175; 6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229;
6.U.172.230; 6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238;
6.U.172.239; 6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169;
6.U.172.172; 6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228;
6.U.175.229; 6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237;
6.U.175.238; 6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166;
6.U.175.169; 6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244;
6.U.240.228; 6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236;
6.U.240.237; 6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157;
6.U.240.166; 6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240;
6.U.240.244; 6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231;
6.U.244.236; 6.U.244.237; 6.U.244.238; 6.U.244.239; 6.U.244.154;
6.U.244.157; 6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175;
6.U.244.240; 6.U.244.244; Prodrugs of 6.W 6.W.228.228; 6.W.228.229;
6.W.228.230; 6.W.228.231; 6.W.228.236; 6.W.228.237; 6.W.228.238;
6.W.228.239; 6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169;
6.W.228.172; 6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228;
6.W.229.229; 6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237;
6.W.229.238; 6.W.229.239; 6.W.229.154; 6.W.229.157; 6.W.229.166;
6.W.229.169; 6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244;
6.W.230.228; 6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236;
6.W.230.237; 6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157;
6.W.230.166; 6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240;
6.W.230.244; 6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231;
6.W.231.236; 6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154;
6.W.231.157; 6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175;
6.W.231.240; 6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230;
6.W.236.231; 6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239;
6.W.236.154; 6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172;
6.W.236.175; 6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229;
6.W.237.230; 6.W.237.231; 6.W.237.236; 6.W.237.237; 6.W.237.238;
6.W.237.239; 6.W.237.154; 6.W.237.157; 6.W.237.166; 6.W.237.169;
6.W.237.172; 6.W.237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228;
6.W.238.229; 6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237;
6.W.238.238; 6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166;
6.W.238.169; 6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244;
6.W.239.228; 6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236;
6.W.239.237; 6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157;
6.W.239.166; 6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240;
6.W.239.244; 6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231;
6.W.154.236; 6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154;
6.W.154.157; 6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175;
6.W.154.240; 6.W.154.244; 6.W.157.228; 6.W.157.229; 6.W.157.230;
6.W.157.231; 6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239;
6.W.157.154; 6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172;
6.W.157.175; 6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229;
6.W.166.230; 6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238;
6.W.166.239; 6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169;
6.W.166.172; 6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W.169.228;
6.W.169.229; 6.W.169.230; 6.W.169.231; 6.W.169.236; 6.W.169.237;
6.W.169.238; 6.W.169.239; 6.W.169.154; 6.W.169.157; 6.W.169.166;
6.W.169.169; 6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244;
6.W.172.228; 6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236;
6.W.172.237; 6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157;
6.W.172.166; 6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240;
6.W.172.244; 6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231;
6.W.175.236; 6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154;
6.W.175.157; 6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175;
6.W.175.240; 6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230;
6.W.240.231; 6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239;
6.W.240.154; 6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172;
6.W.240.175; 6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229;
6.W.244.230; 6.W.244.231; 6.W.244.236; 6.W.244.237; 6.W.244.238;
6.W.244.239; 6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169;
6.W.244.172; 6.W.244.175; 6.W.244.240;
6.W.244.244; Prodrugs of 6.Y 6.Y.228.228; 6.Y.228.229; 6.Y.228.230;
6.Y.228.231; 6.Y.228.236; 6.Y.228.237; 6.Y.228.238; 6.Y.228.239;
6.Y.228.154; 6.Y.228.157; 6.Y.228.166; 6.Y.228.169; 6.Y.228.172;
6.Y.228.175; 6.Y.228.240; 6.Y.228.244; 6.Y.229.228; 6.Y.229.229;
6.Y.229.230; 6.Y.229.231; 6.Y.229.236; 6.Y.229.237; 6.Y.229.238;
6.Y.229.239; 6.Y.229.154; 6.Y.229.157; 6.Y.229.166; 6.Y.229.169;
6.Y.229.172; 6.Y.229.175; 6.Y.229.240; 6.Y.229.244; 6.Y.230.228;
6.Y.230.229; 6.Y.230.230; 6.Y.230.231; 6.Y.230.236; 6.Y.230.237;
6.Y.230.238; 6.Y.230.239; 6.Y.230.154; 6.Y.230.157; 6.Y.230.166;
6.Y.230.169; 6.Y.230.172; 6.Y.230.175; 6.Y.230.240; 6.Y.230.244;
6.Y.231.228; 6.Y.231.229; 6.Y.231.230; 6.Y.231.231; 6.Y.231.236;
6.Y.231.237; 6.Y.231.238; 6.Y.231.239; 6.Y.231.154; 6.Y.231.157;
6.Y.231.166; 6.Y.231.169; 6.Y.231.172; 6.Y.231.175; 6.Y.231.240;
6.Y.231.244; 6.Y.236.228; 6.Y.236.229; 6.Y.236.230; 6.Y.236.231;
6.Y.236.236; 6.Y.236.237; 6.Y.236.238; 6.Y.236.239; 6.Y.236.154;
6.Y.236.157; 6.Y.236.166; 6.Y.236.169; 6.Y.236.172; 6.Y.236.175;
6.Y.236.240; 6.Y.236.244; 6.Y.237.228; 6.Y.237.229; 6.Y.237.230;
6.Y.237.231; 6.Y.237.236; 6.Y.237.237; 6.Y.237.238; 6.Y.237.239;
6.Y.237.154; 6.Y.237.157; 6.Y.237.166; 6.Y.237.169; 6.Y.237.172;
6.Y.237.175; 6.Y.237.240; 6.Y.237.244; 6.Y.238.228; 6.Y.238.229;
6.Y.238.230; 6.Y.238.231; 6.Y.238.236; 6.Y.238.237; 6.Y.238.238;
6.Y.238.239; 6.Y.238.154; 6.Y.238.157; 6.Y.238.166; 6.Y.238.169;
6.Y.238.172; 6.Y.238.175; 6.Y.238.240; 6.Y.238.244; 6.Y.239.228;
6.Y.239.229; 6.Y.239.230; 6.Y.239.231; 6.Y.239.236; 6.Y.239.237;
6.Y.239.238; 6.Y.239.239; 6.Y.239.154; 6.Y.239.157; 6.Y.239.166;
6.Y.239.169; 6.Y.239.172; 6.Y.239.175; 6.Y.239.240; 6.Y.239.244;
6.Y.154.228; 6.Y.154.229; 6.Y.154.230; 6.Y.154.231; 6.Y.154.236;
6.Y.154.237; 6.Y.154.238; 6.Y.154.239; 6.Y.154.154; 6.Y.154.157;
6.Y.154.166; 6.Y.154.169; 6.Y.154.172; 6.Y.154.175; 6.Y.154.240;
6.Y.154.244; 6.Y.157.228; 6.Y.157.229; 6.Y.157.230; 6.Y.157.231;
6.Y.157.236; 6.Y.157.237; 6.Y.157.238; 6.Y.157.239; 6.Y.157.154;
6.Y.157.157; 6.Y.157.166; 6.Y.157.169; 6.Y.157.172; 6.Y.157.175;
6.Y.157.240; 6.Y.157.244; 6.Y.166.228; 6.Y.166.229; 6.Y.166.230;
6.Y.166.231; 6.Y.166.236; 6.Y.166.237; 6.Y.166.238; 6.Y.166.239;
6.Y.166.154; 6.Y.166.157; 6.Y.166.166; 6.Y.166.169; 6.Y.166.172;
6.Y.166.175; 6.Y.166.240; 6.Y.166.244; 6.Y.169.228; 6.Y.169.229;
6.Y.169.230; 6.Y.169.231; 6.Y.169.236; 6.Y.169.237; 6.Y.169.238;
6.Y.169.239; 6.Y.169.154; 6.Y.169.157; 6.Y.169.166; 6.Y.169.169;
6.Y.169.172; 6.Y.169.175; 6.Y.169.240; 6.Y.169.244; 6.Y.172.228;
6.Y.172.229; 6.Y.172.230; 6.Y.172.231; 6.Y.172.236; 6.Y.172.237;
6.Y.172.238; 6.Y.172.239; 6.Y.172.154; 6.Y.172.157; 6.Y.172.166;
6.Y.172.169; 6.Y.172.172; 6.Y.172.175; 6.Y.172.240; 6.Y.172.244;
6.Y.175.228; 6.Y.175.229; 6.Y.175.230; 6.Y.175.231; 6.Y.175.236;
6.Y.175.237; 6.Y.175.238; 6.Y.175.239; 6.Y.175.154; 6.Y.175.157;
6.Y.175.166; 6.Y.175.169; 6.Y.175.172; 6.Y.175.175; 6.Y.175.240;
6.Y.175.244; 6.Y.240.228; 6.Y.240.229; 6.Y.240.230; 6.Y.240.231;
6.Y.240.236; 6.Y.240.237; 6.Y.240.238; 6.Y.240.239; 6.Y.240.154;
6.Y.240.157; 6.Y.240.166; 6.Y.240.169; 6.Y.240.172; 6.Y.240.175;
6.Y.240.240; 6.Y.240.244; 6.Y.244.228; 6.Y.244.229; 6.Y.244.230;
6.Y.244.231; 6.Y.244.236; 6.Y.244.237; 6.Y.244.238; 6.Y.244.239;
6.Y.244.154; 6.Y.244.157; 6.Y.244.166; 6.Y.244.169; 6.Y.244.172;
6.Y.244.175; 6.Y.244.240; 6.Y.244.244; Prodrugs of 7.AH 7.AH.4.157;
7.AH.4.158; 7.AH.4.196; 7.AH.4.223; 7.AH.4.240; 7.AH.4.244;
7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158; 7.AH.5.196;
7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247;
7.AH.7.157; 7.AH.7.158; 7.AH.7.196; 7.AH.7.223; 7.AH.7.240;
7.AH.7.244; 7.AH.7.243; 7.AH.7.247; 7.AH.15.157; 7.AH.15.158;
7.AH.15.196; 7.AH.15.223; 7.AH.15.240; 7.AH.15.244; 7.AH.15.243;
7.AH.15.247; 7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223;
7.AH.16.240; 7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157;
7.AH.18.158; 7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244;
7.AH.18.243; 7.AH.18.247; 7.AH.26.157; 7.AH.26.158; 7.AH.26.196;
7.AH.26.223; 7.AH.26.240; 7.AH.26.244; 7.AH.26.243; 7.AH.26.247;
7.AH.27.157; 7.AH.27.158; 7.AH.27.196; 7.AH.27.223; 7.AH.27.240;
7.AH.27.244; 7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158;
7.AH.29.196; 7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243;
7.AH.29.247; 7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223;
7.AH.54.240; 7.AH.54.244; 7.AH.54.243; 7.AH.54.247; 7.AH.55.157;
7.AH.55.158; 7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244;
7.AH.55.243; 7.AH.55.247; 7.AH.56.157; 7.AH.56.158; 7.AH.56.196;
7.AH.56.223; 7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247;
7.AH.157.157; 7.AH.157.158; 7.AH.157.196; 7.AH.157.223;
7.AH.157.240; 7.AH.157.244; 7.AH.157.243; 7.AH.157.247;
7.AH.196.157; 7.AH.196.158; 7.AH.196.196; 7.AH.196.223;
7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247;
7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223;
7.AH.223.240; 7.AH.223.244; 7.AH.223.243; 7.AH.223.247;
7.AH.240.157; 7.AH.240.158; 7.AH.240.196; 7.AH.240.223;
7.AH.240.240; 7.AH.240.244; 7.AH.240.243; 7.AH.240.247;
7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223;
7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247;
7.AH.247.157; 7.AH.247.158; 7.AH.247.196; 7.AH.247.223;
7.AH.247.240; 7.AH.247.244; 7.AH.247.243; 7.AH.247.247; Prodrugs of
7.AJ 7.AJ.4.157; 7.AJ.4.158; 7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240;
7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247; 7.AJ.5.157; 7.AJ.5.158;
7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244; 7.AJ.5.243;
7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223;
7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157;
7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ.15.240; 7.AJ.15.244;
7.AJ.15.243; 7.AJ.15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196;
7.AJ.16.223; 7.AJ.16.240; 7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247;
7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196; 7.AJ.18.223; 7.AJ.18.240;
7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157; 7.AJ.26.158;
7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243;
7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223;
7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157;
7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244;
7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157; 7.AJ.54.158; 7.AJ.54.196;
7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243; 7.AJ.54.247;
7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240;
7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158;
7.AJ.56.196; 7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243;
7.AJ.56.247; 7.AJ.157.157; 7.AJ.157.158; 7.AJ.157.196;
7.AJ.157.223; 7.AJ.157.240; 7.AJ.157.244; 7.AJ.157.243;
7.AJ.157.247; 7.AJ.196.157; 7.AJ.196.158; 7.AJ.196.196;
7.AJ.196.223; 7.AJ.196.240; 7.AJ.196.244; 7.AJ.196.243;
7.AJ.196.247; 7.AJ.223.157; 7.AJ.223.158; 7.AJ.223.196;
7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243;
7.AJ.223.247; 7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196;
7.AJ.240.223; 7.AJ.240.240; 7.AJ.240.244; 7.AJ.240.243;
7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158; 7.AJ.244.196;
7.AJ.244.223; 7.AJ.244.240; 7.AJ.244.244; 7.AJ.244.243;
7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158; 7.AJ.247.196;
7.AJ.247.223; 7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243;
7.AJ.247.247; Prodrugs of 7.AN 7.AN.4.157; 7.AN.4.158; 7.AN.4.196;
7.AN.4.223; 7.AN.4.240; 7.AN.4.244; 7.AN.4.243; 7.AN.4.247;
7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223; 7.AN.5.240;
7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158;
7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243;
7.AN.7.247; 7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223;
7.AN.15.240; 7.AN.15.244; 7.AN.15.243; 7.AN.15.247; 7.AN.16.157;
7.AN.16.158; 7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244;
7.AN.16.243; 7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196;
7.AN.18.223; 7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247;
7.AN.26.157; 7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240;
7.AN.26.244; 7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158;
7.AN.27.196; 7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243;
7.AN.27.247; 7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223;
7.AN.29.240; 7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157;
7.AN.54.158; 7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244;
7.AN.54.243; 7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196;
7.AN.55.223; 7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247;
7.AN.56.157; 7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240;
7.AN.56.244; 7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158;
7.AN.157.196; 7.AN.157.223; 7.AN.157.240; 7.AN.157.244;
7.AN.157.243; 7.AN.157.247; 7.AN.196.157; 7.AN.196.158;
7.AN.196.196; 7.AN.196.223; 7.AN.196.240; 7.AN.196.244;
7.AN.196.243; 7.AN.196.247; 7.AN.223.157; 7.AN.223.158;
7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244;
7.AN.223.243; 7.AN.223.247; 7.AN.240.157; 7.AN.240.158;
7.AN.240.196; 7.AN.240.223; 7.AN.240.240; 7.AN.240.244;
7.AN.240.243; 7.AN.240.247; 7.AN.244.157; 7.AN.244.158;
7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244;
7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158;
7.AN.247.196; 7.AN.247.223; 7.AN.247.240; 7.AN.247.244;
7.AN.247.243; 7.AN.247.247; Prodrugs of 7.AP 7.AP.4.157;
7.AP.4.158; 7.AP.4.196; 7.AP.4.223; 7.AP.4.240; 7.AP.4.244;
7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158; 7.AP.5.196;
7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247;
7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240;
7.AP.7.244; 7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP.15.158;
7.AP.15.196; 7.AP.15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243;
7.AP.15.247; 7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223;
7.AP.16.240; 7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157;
7.AP.18.158; 7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244;
7.AP.18.243; 7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196;
7.AP.26.223; 7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247;
7.AP.27.157; 7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240;
7.AP.27.244; 7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158;
7.AP.29.196; 7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243;
7.AP.29.247; 7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223;
7.AP.54.240; 7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157;
7.AP.55.158; 7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244;
7.AP.55.243; 7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196;
7.AP.56.223; 7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247;
7.AP.157.157; 7.AP.157.158; 7.AP.157.196; 7.AP.157.223;
7.AP.157.240; 7.AP.157.244; 7.AP.157.243; 7.AP.157.247;
7.AP.196.157; 7.AP.196.158; 7.AP.196.196; 7.AP.196.223;
7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247;
7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223;
7.AP.223.240; 7.AP.223.244; 7.AP.223.243; 7.AP.223.247;
7.AP.240.157; 7.AP.240.158; 7.AP.240.196; 7.AP.240.223;
7.AP.240.240; 7.AP.240.244; 7.AP.240.243; 7.AP.240.247;
7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223;
7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247;
7.AP.247.157; 7.AP.247.158; 7.AP.247.196; 7.AP.247.223;
7.AP.247.240; 7.AP.247.244; 7.AP.247.243; 7.AP.247.247; Prodrugs of
7.AZ 7.AZ.4.157; 7.AZ.4.158; 7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240;
7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247; 7.AZ.5.157; 7.AZ.5.158;
7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244; 7.AZ.5.243;
7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223;
7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ.15.157;
7.AZ.15.158; 7.AZ.15.196; 7.AZ.15.223; 7.AZ.15.240; 7.AZ.15.244;
7.AZ.15.243; 7.AZ.15.247; 7.AZ.16.157; 7.AZ.16.158; 7.AZ.16.196;
7.AZ.16.223; 7.AZ.16.240; 7.AZ.16.244; 7.AZ.16.243; 7.AZ.16.247;
7.AZ.18.157; 7.AZ.18.158; 7.AZ.18.196; 7.AZ.18.223; 7.AZ.18.240;
7.AZ.18.244; 7.AZ.18.243; 7.AZ.18.247; 7.AZ.26.157; 7.AZ.26.158;
7.AZ.26.196; 7.AZ.26.223; 7.AZ.26.240; 7.AZ.26.244; 7.AZ.26.243;
7.AZ.26.247; 7.AZ.27.157; 7.AZ.27.158; 7.AZ.27.196; 7.AZ.27.223;
7.AZ.27.240; 7.AZ.27.244; 7.AZ.27.243; 7.AZ.27.247; 7.AZ.29.157;
7.AZ.29.158; 7.AZ.29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244;
7.AZ.29.243; 7.AZ.29.247; 7.AZ.54.157; 7.AZ.54.158; 7.AZ.54.196;
7.AZ.54.223; 7.AZ.54.240; 7.AZ.54.244; 7.AZ.54.243; 7.AZ.54.247;
7.AZ.55.157; 7.AZ.55.158; 7.AZ.55.196; 7.AZ.55.223; 7.AZ.55.240;
7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ.56.157; 7.AZ.56.158;
7.AZ.56.196; 7.AZ.56.223; 7.AZ.56.240; 7.AZ.56.244; 7.AZ.56.243;
7.AZ.56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196;
7.AZ.157.223; 7.AZ.157.240; 7.AZ.157.244; 7.AZ.157.243;
7.AZ.157.247; 7.AZ.196.157; 7.AZ.196.158; 7.AZ.196.196;
7.AZ.196.223; 7.AZ.196.240; 7.AZ.196.244; 7.AZ.196.243;
7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196;
7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243;
7.AZ.223.247; 7.AZ.240.157; 7.AZ.240.158; 7.AZ.240.196;
7.AZ.240.223; 7.AZ.240.240; 7.AZ.240.244; 7.AZ.240.243;
7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158; 7.AZ.244.196;
7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243;
7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196;
7.AZ.247.223; 7.AZ.247.240; 7.AZ.247.244; 7.AZ.247.243;
7.AZ.247.247; Prodrugs of 7.BF 7.BF.4.157; 7.BF.4.158; 7.BF.4.196;
7.BF.4.223; 7.BF.4.240; 7.BF.4.244; 7.BF.4.243; 7.BF.4.247;
7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223; 7.BF.5.240;
7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158;
7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243;
7.BF.7.247; 7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223;
7.BF.15.240; 7.BF.15.244; 7.BF.15.243; 7.BF.15.247; 7.BF.16.157;
7.BF.16.158; 7.BF.16.196; 7.BF.16.223; 7.BF.16.240; 7.BF.16.244;
7.BF.16.243; 7.BF.16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196;
7.BF.18.223; 7.BF.18.240; 7.BF.18.244; 7.BF.18.243; 7.BF.18.247;
7.BF.26.157; 7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240;
7.BF.26.244; 7.BF.26.243; 7.BF.26.247; 7.BF.27.157; 7.BF.27.158;
7.BF.27.196; 7.BF.27.223; 7.BF.27.240; 7.BF.27.244; 7.BF.27.243;
7.BF.27.247; 7.BF.29.157; 7.BF.29.158; 7.BF.29.196; 7.BF.29.223;
7.BF.29.240; 7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157;
7.BF.54.158; 7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244;
7.BF.54.243; 7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196;
7.BF.55.223; 7.BF.55.240; 7.BF.55.244; 7.BF.55.243; 7.BF.55.247;
7.BF.56.157; 7.BF.56.158; 7.BF.56.196; 7.BF.56.223; 7.BF.56.240;
7.BF.56.244; 7.BF.56.243; 7.BF.56.247; 7.BF.157.157; 7.BF.157.158;
7.BF.157.196; 7.BF.157.223; 7.BF.157.240; 7.BF.157.244;
7.BF.157.243; 7.BF.157.247; 7.BF.196.157; 7.BF.196.158;
7.BF.196.196; 7.BF.196.223; 7.BF.196.240; 7.BF.196.244;
7.BF.196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158;
7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244;
7.BF.223.243; 7.BF.223.247; 7.BF.240.157; 7.BF.240.158;
7.BF.240.196; 7.BF.240.223; 7.BF.240.240; 7.BF.240.244;
7.BF.240.243; 7.BF.240.247; 7.BF.244.157; 7.BF.244.158;
7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244;
7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158;
7.BF.247.196; 7.BF.247.223; 7.BF.247.240; 7.BF.247.244;
7.BF.247.243; 7.BF.247.247; Prodrugs of 7.CI 7.CI.4.157;
7.CI.4.158; 7.CI.4.196; 7.CI.4.223; 7.CI.4.240; 7.CI.4.244;
7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158; 7.CI.5.196;
7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247;
7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240;
7.CI.7.244; 7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158;
7.CI.15.196; 7.CI.15.223; 7.CI.15.240; 7.CI.15.244; 7.CI.15.243;
7.CI.15.247; 7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223;
7.CI.16.240; 7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157;
7.CI.18.158; 7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244;
7.CI.18.243; 7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196;
7.CI.26.223; 7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247;
7.CI.27.157; 7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240;
7.CI.27.244; 7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158;
7.CI.29.196; 7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243;
7.CI.29.247; 7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223;
7.CI.54.240; 7.CI.54.244; 7.CI.54.243; 7.CI.54.247;
7.CI.55.157; 7.CI.55.158; 7.CI.55.196; 7.CI.55.223; 7.CI.55.240;
7.CI.55.244; 7.CI.55.243; 7.CI.55.247; 7.CI.56.157; 7.CI.56.158;
7.CI.56.196; 7.CI.56.223; 7.CI.56.240; 7.CI.56.244; 7.CI.56.243;
7.CI.56.247; 7.CI.157.157; 7.CI.157.158; 7.CI.157.196;
7.CI.157.223; 7.CI.157.240; 7.CI.157.244; 7.CI.157.243;
7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196;
7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243;
7.CI.196.247; 7.CI.223.157; 7.CI.223.158; 7.CI.223.196;
7.CI.223.223; 7.CI.223.240; 7.CI.223.244; 7.CI.223.243;
7.CI.223.247; 7.CI.240.157; 7.CI.240.158; 7.CI.240.196;
7.CI.240.223; 7.CI.240.240; 7.CI.240.244; 7.CI.240.243;
7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196;
7.CI.244.223; 7.CI.244.240; 7.CI.244.244; 7.CI.244.243;
7.CI.244.247; 7.CI.247.157; 7.CI.247.158; 7.CI.247.196;
7.CI.247.223; 7.CI.247.240; 7.CI.247.244; 7.CI.247.243;
7.CI.247.247; Prodrugs of 7.CO 7.CO.4.157; 7.CO.4.158; 7.CO.4.196;
7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;
7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240;
7.CO.5.244; 7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158;
7.CO.7.196; 7.CO.7.223; 7.CO.7.240; 7.CO.7.244; 7.CO.7.243;
7.CO.7.247; 7.CO.15.157; 7.CO.15.158; 7.CO.15.196; 7.CO.15.223;
7.CO.15.240; 7.CO.15.244; 7.CO.15.243; 7.CO.15.247; 7.CO.16.157;
7.CO.16.158; 7.CO.16.196; 7.CO.16.223; 7.CO.16.240; 7.CO.16.244;
7.CO.16.243; 7.CO.16.247; 7.CO.18.157; 7.CO.18.158; 7.CO.18.196;
7.CO.18.223; 7.CO.18.240; 7.CO.18.244; 7.CO.18.243; 7.CO.18.247;
7.CO.26.157; 7.CO.26.158; 7.CO.26.196; 7.CO.26.223; 7.CO.26.240;
7.CO.26.244; 7.CO.26.243; 7.CO.26.247; 7.CO.27.157; 7.CO.27.158;
7.CO.27.196; 7.CO.27.223; 7.CO.27.240; 7.CO.27.244; 7.CO.27.243;
7.CO.27.247; 7.CO.29.157; 7.CO.29.158; 7.CO.29.196; 7.CO.29.223;
7.CO.29.240; 7.CO.29.244; 7.CO.29.243; 7.CO.29.247; 7.CO.54.157;
7.CO.54.158; 7.CO.54.196; 7.CO.54.223; 7.CO.54.240; 7.CO.54.244;
7.CO.54.243; 7.CO.54.247; 7.CO.55.157; 7.CO.55.158; 7.CO.55.196;
7.CO.55.223; 7.CO.55.240; 7.CO.55.244; 7.CO.55.243; 7.CO.55.247;
7.CO.56.157; 7.CO.56.158; 7.CO.56.196; 7.CO.56.223; 7.CO.56.240;
7.CO.56.244; 7.CO.56.243; 7.CO.56.247; 7.CO.157.157; 7.CO.157.158;
7.CO.157.196; 7.CO.157.223; 7.CO.157.240; 7.CO.157.244;
7.CO.157.243; 7.CO.157.247; 7.CO.196.157; 7.CO.196.158;
7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244;
7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158;
7.CO.223.196; 7.CO.223.223; 7.CO.223.240; 7.CO.223.244;
7.CO.223.243; 7.CO.223.247; 7.CO.240.157; 7.CO.240.158;
7.CO.240.196; 7.CO.240.223; 7.CO.240.240; 7.CO.240.244;
7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158;
7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244;
7.CO.244.243; 7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196;
7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;
Prodrugs of 8.AH 8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223;
8.AH.4.240; 8.AH.4.244; 8.AH.4.243; 8.AH.4.247; 8.AH.5.157;
8.AH.5.158; 8.AH.5.196; 8.AH.5.223; 8.AH.5.240; 8.AH.5.244;
8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158; 8.AH.7.196;
8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247;
8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240;
8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158;
8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243;
8.AH.16.247; 8.AH.18.157; 8.AH.18.158; 8.AH.18.196; 8.AH.18.223;
8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157;
8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244;
8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196;
8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247;
8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240;
8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158;
8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243;
8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223;
8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157;
8.AH.56.158; 8.AH.56.196; 8.AH.56.223; 8.AH.56.240; 8.AH.56.244;
8.AH.56.243; 8.AH.56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196;
8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH.157.243;
8.AH.157.247; 8.AH.196.157; 8.AH.196.158; 8.AH.196.196;
8.AH.196.223; 8.AH.196.240; 8.AH.196.244; 8.AH.196.243;
8.AH.196.247; 8.AH.223.157; 8.AH.223.158; 8.AH.223.196;
8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243;
8.AH.223.247; 8.AH.240.157; 8.AH.240.158; 8.AH.240.196;
8.AH.240.223; 8.AH.240.240; 8.AH.240.244; 8.AH.240.243;
8.AH.240.247; 8.AH.244.157; 8.AH.244.158; 8.AH.244.196;
8.AH.244.223; 8.AH.244.240; 8.AH.244.244; 8.AH.244.243;
8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196;
8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243;
8.AH.247.247; Prodrugs of 8.AJ 8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196;
8.AJ.4.223; 8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247;
8.AJ.5.157; 8.AJ.5.158; 8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240;
8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247; 8.AJ.7.157; 8.AJ.7.158;
8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244; 8.AJ.7.243;
8.AJ.7.247; 8.AJ.15.157; 8.AJ.15.158; 8.AJ.15.196; 8.AJ.15.223;
8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247; 8.AJ.16.157;
8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240; 8.AJ.16.244;
8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158; 8.AJ.18.196;
8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243; 8.AJ.18.247;
8.AJ.26.157; 8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223; 8.AJ.26.240;
8.AJ.26.244; 8.AJ.26.243; 8.AJ.26.247; 8.AJ.27.157; 8.AJ.27.158;
8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244; 8.AJ.27.243;
8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196; 8.AJ.29.223;
8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247; 8.AJ.54.157;
8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240; 8.AJ.54.244;
8.AJ.54.243; 8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158; 8.AJ.55.196;
8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243; 8.AJ.55.247;
8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196; 8.AJ.56.223; 8.AJ.56.240;
8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157; 8.AJ.157.158;
8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244;
8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158;
8.AJ.196.196; 8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244;
8.AJ.196.243; 8.AJ.196.247; 8.AJ.223.157; 8.AJ.223.158;
8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240; 8.AJ.223.244;
8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158;
8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244;
8.AJ.240.243; 8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158;
8.AJ.244.196; 8.AJ.244.223; 8.AJ.244.240; 8.AJ.244.244;
8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157; 8.AJ.247.158;
8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244;
8.AJ.247.243; 8.AJ.247.247; Prodrugs of 8.AN 8.AN.4.157;
8.AN.4.158; 8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244;
8.AN.4.243; 8.AN.4.247; 8.AN.5.157; 8.AN.5.158; 8.AN.5.196;
8.AN.5.223; 8.AN.5.240; 8.AN.5.244; 8.AN.5.243; 8.AN.5.247;
8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223; 8.AN.7.240;
8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157; 8.AN.15.158;
8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244; 8.AN.15.243;
8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196; 8.AN.16.223;
8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247; 8.AN.18.157;
8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240; 8.AN.18.244;
8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158; 8.AN.26.196;
8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243; 8.AN.26.247;
8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223; 8.AN.27.240;
8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157; 8.AN.29.158;
8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244; 8.AN.29.243;
8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196; 8.AN.54.223;
8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247; 8.AN.55.157;
8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240; 8.AN.55.244;
8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158; 8.AN.56.196;
8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243; 8.AN.56.247;
8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223;
8.AN.157.240; 8.AN.157.244; 8.AN.157.243; 8.AN.157.247;
8.AN.196.157; 8.AN.196.158; 8.AN.196.196; 8.AN.196.223;
8.AN.196.240; 8.AN.196.244; 8.AN.196.243; 8.AN.196.247;
8.AN.223.157; 8.AN.223.158; 8.AN.223.196; 8.AN.223.223;
8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247;
8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223;
8.AN.240.240; 8.AN.240.244; 8.AN.240.243; 8.AN.240.247;
8.AN.244.157; 8.AN.244.158; 8.AN.244.196; 8.AN.244.223;
8.AN.244.240; 8.AN.244.244; 8.AN.244.243; 8.AN.244.247;
8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223;
8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247; Prodrugs of
8.AP 8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240;
8.AP.4.244; 8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158;
8.AP.5.196; 8.AP.5.223; 8.AP.5.240; 8.AP.5.244; 8.AP.5.243;
8.AP.5.247; 8.AP.7.157; 8.AP.7.158; 8.AP.7.196; 8.AP.7.223;
8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247; 8.AP.15.157;
8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240; 8.AP.15.244;
8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158; 8.AP.16.196;
8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243; 8.AP.16.247;
8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223; 8.AP.18.240;
8.AP.18.244; 8.AP.18.243; 8.AP.18.247; 8.AP.26.157; 8.AP.26.158;
8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244; 8.AP.26.243;
8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196; 8.AP.27.223;
8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247; 8.AP.29.157;
8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240; 8.AP.29.244;
8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158; 8.AP.54.196;
8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243; 8.AP.54.247;
8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223; 8.AP.55.240;
8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157; 8.AP.56.158;
8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244; 8.AP.56.243;
8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196;
8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243;
8.AP.157.247; 8.AP.196.157; 8.AP.196.158; 8.AP.196.196;
8.AP.196.223; 8.AP.196.240; 8.AP.196.244; 8.AP.196.243;
8.AP.196.247; 8.AP.223.157; 8.AP.223.158; 8.AP.223.196;
8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243;
8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196;
8.AP.240.223; 8.AP.240.240; 8.AP.240.244; 8.AP.240.243;
8.AP.240.247; 8.AP.244.157; 8.AP.244.158; 8.AP.244.196;
8.AP.244.223; 8.AP.244.240; 8.AP.244.244; 8.AP.244.243;
8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196;
8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243;
8.AP.247.247; Prodrugs of 8.AZ 8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196;
8.AZ.4.223; 8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247;
8.AZ.5.157; 8.AZ.5.158; 8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240;
8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247; 8.AZ.7.157; 8.AZ.7.158;
8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244; 8.AZ.7.243;
8.AZ.7.247; 8.AZ.15.157; 8.AZ.15.158; 8.AZ.15.196; 8.AZ.15.223;
8.AZ.15.240; 8.AZ.15.244; 8.AZ.15.243; 8.AZ.15.247; 8.AZ.16.157;
8.AZ.16.158; 8.AZ.16.196; 8.AZ.16.223; 8.AZ.16.240; 8.AZ.16.244;
8.AZ.16.243; 8.AZ.16.247; 8.AZ.18.157; 8.AZ.18.158; 8.AZ.18.196;
8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243; 8.AZ.18.247;
8.AZ.26.157; 8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223; 8.AZ.26.240;
8.AZ.26.244; 8.AZ.26.243; 8.AZ.26.247; 8.AZ.27.157; 8.AZ.27.158;
8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244; 8.AZ.27.243;
8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196; 8.AZ.29.223;
8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247; 8.AZ.54.157;
8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240; 8.AZ.54.244;
8.AZ.54.243; 8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158; 8.AZ.55.196;
8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243; 8.AZ.55.247;
8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196; 8.AZ.56.223; 8.AZ.56.240;
8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157; 8.AZ.157.158;
8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244;
8.AZ.157.243; 8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158;
8.AZ.196.196; 8.AZ.196.223; 8.AZ.196.240; 8.AZ.196.244;
8.AZ.196.243; 8.AZ.196.247; 8.AZ.223.157; 8.AZ.223.158;
8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240; 8.AZ.223.244;
8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158;
8.AZ.240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244;
8.AZ.240.243; 8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158;
8.AZ.244.196; 8.AZ.244.223; 8.AZ.244.240; 8.AZ.244.244;
8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157; 8.AZ.247.158;
8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244;
8.AZ.247.243; 8.AZ.247.247; Prodrugs of 8.BF 8.BF.4.157;
8.BF.4.158; 8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244;
8.BF.4.243; 8.BF.4.247; 8.BF.5.157; 8.BF.5.158; 8.BF.5.196;
8.BF.5.223; 8.BF.5.240; 8.BF.5.244; 8.BF.5.243; 8.BF.5.247;
8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223; 8.BF.7.240;
8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF.15.157; 8.BF.15.158;
8.BF.15.196; 8.BF.15.223; 8.BF.15.240; 8.BF.15.244; 8.BF.15.243;
8.BF.15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196; 8.BF.16.223;
8.BF.16.240; 8.BF.16.244; 8.BF.16.243; 8.BF.16.247; 8.BF.18.157;
8.BF.18.158; 8.BF.18.196; 8.BF.18.223; 8.BF.18.240; 8.BF.18.244;
8.BF.18.243; 8.BF.18.247; 8.BF.26.157; 8.BF.26.158; 8.BF.26.196;
8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243; 8.BF.26.247;
8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223; 8.BF.27.240;
8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157; 8.BF.29.158;
8.BF.29.196; 8.BF.29.223; 8.BF.29.240; 8.BF.29.244; 8.BF.29.243;
8.BF.29.247; 8.BF.54.157; 8.BF.54.158; 8.BF.54.196; 8.BF.54.223;
8.BF.54.240; 8.BF.54.244; 8.BF.54.243; 8.BF.54.247; 8.BF.55.157;
8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240; 8.BF.55.244;
8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158; 8.BF.56.196;
8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243; 8.BF.56.247;
8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223;
8.BF.157.240; 8.BF.157.244; 8.BF.157.243; 8.BF.157.247;
8.BF.196.157; 8.BF.196.158; 8.BF.196.196; 8.BF.196.223;
8.BF.196.240; 8.BF.196.244; 8.BF.196.243; 8.BF.196.247;
8.BF.223.157; 8.BF.223.158; 8.BF.223.196; 8.BF.223.223;
8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247;
8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223;
8.BF.240.240; 8.BF.240.244; 8.BF.240.243; 8.BF.240.247;
8.BF.244.157; 8.BF.244.158; 8.BF.244.196; 8.BF.244.223;
8.BF.244.240; 8.BF.244.244; 8.BF.244.243; 8.BF.244.247;
8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223;
8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247; Prodrugs of
8.CI 8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240;
8.CI.4.244; 8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158;
8.CI.5.196; 8.CI.5.223; 8.CI.5.240; 8.CI.5.244; 8.CI.5.243;
8.CI.5.247; 8.CI.7.157; 8.CI.7.158; 8.CI.7.196; 8.CI.7.223;
8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247; 8.CI.15.157;
8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240; 8.CI.15.244;
8.CI.15.243; 8.CI.15.247; 8.CI.16.157; 8.CI.16.158; 8.CI.16.196;
8.CI.16.223; 8.CI.16.240; 8.CI.16.244; 8.CI.16.243; 8.CI.16.247;
8.CI.18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223; 8.CI.18.240;
8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157; 8.CI.26.158;
8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244; 8.CI.26.243;
8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196; 8.CI.27.223;
8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247; 8.CI.29.157;
8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240; 8.CI.29.244;
8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158; 8.CI.54.196;
8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243; 8.CI.54.247;
8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223; 8.CI.55.240;
8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157; 8.CI.56.158;
8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244; 8.CI.56.243;
8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196;
8.CI.157.223; 8.CI.157.240; 8.CI.157.244; 8.CI.157.243;
8.CI.157.247; 8.CI.196.157; 8.CI.196.158; 8.CI.196.196;
8.CI.196.223; 8.CI.196.240; 8.CI.196.244; 8.CI.196.243;
8.CI.196.247; 8.CI.223.157; 8.CI.223.158; 8.CI.223.196;
8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243;
8.CI.223.247; 8.CI.240.157; 8.CI.240.158; 8.CI.240.196;
8.CI.240.223; 8.CI.240.240; 8.CI.240.244; 8.CI.240.243;
8.CI.240.247; 8.CI.244.157; 8.CI.244.158; 8.CI.244.196;
8.CI.244.223; 8.CI.244.240; 8.CI.244.244; 8.CI.244.243;
8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196;
8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243;
8.CI.247.247; Prodrugs of 8.CO 8.CO.4.157; 8.CO.4.158; 8.CO.4.196;
8.CO.4.223; 8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247;
8.CO.5.157; 8.CO.5.158; 8.CO.5.196; 8.CO.5.223; 8.CO.5.240;
8.CO.5.244; 8.CO.5.243; 8.CO.5.247; 8.CO.7.157; 8.CO.7.158;
8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244; 8.CO.7.243;
8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.196; 8.CO.15.223;
8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247; 8.CO.16.157;
8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240; 8.CO.16.244;
8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158; 8.CO.18.196;
8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243; 8.CO.18.247;
8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223; 8.CO.26.240;
8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157; 8.CO.27.158;
8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244; 8.CO.27.243;
8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196; 8.CO.29.223;
8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247; 8.CO.54.157;
8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240; 8.CO.54.244;
8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158; 8.CO.55.196;
8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243; 8.CO.55.247;
8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223; 8.CO.56.240;
8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157; 8.CO.157.158;
8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244;
8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158;
8.CO.196.196; 8.CO.196.223; 8.CO.196.240; 8.CO.196.244;
8.CO.196.243; 8.CO.196.247; 8.CO.223.157; 8.CO.223.158;
8.CO.223.196; 8.CO.223.223; 8.CO.223.240; 8.CO.223.244;
8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.CO.240.158;
8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244;
8.CO.240.243; 8.CO.240.247; 8.CO.244.157; 8.CO.244.158;
8.CO.244.196; 8.CO.244.223; 8.CO.244.240; 8.CO.244.244;
8.CO.244.243; 8.CO.244.247; 8.CO.247.157; 8.CO.247.158;
8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244;
8.CO.247.243; 8.CO.247.247; Prodrugs of 9.AH 9.AH.4.157;
9.AH.4.158; 9.AH.4.196; 9.AH.4.223; 9.AH.4.240; 9.AH.4.244;
9.AH.4.243; 9.AH.4.247; 9.AH.5.157; 9.AH.5.158; 9.AH.5.196;
9.AH.5.223; 9.AH.5.240; 9.AH.5.244; 9.AH.5.243; 9.AH.5.247;
9.AH.7.157; 9.AH.7.158; 9.AH.7.196; 9.AH.7.223; 9.AH.7.240;
9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH.15.157; 9.AH.15.158;
9.AH.15.196; 9.AH.15.223; 9.AH.15.240; 9.AH.15.244; 9.AH.15.243;
9.AH.15.247; 9.AH.16.157; 9.AH.16.158; 9.AH.16.196; 9.AH.16.223;
9.AH.16.240; 9.AH.16.244; 9.AH.16.243; 9.AH.16.247; 9.AH.18.157;
9.AH.18.158; 9.AH.18.196; 9.AH.18.223; 9.AH.18.240; 9.AH.18.244;
9.AH.18.243; 9.AH.18.247; 9.AH.26.157; 9.AH.26.158; 9.AH.26.196;
9.AH.26.223; 9.AH.26.240; 9.AH.26.244; 9.AH.26.243; 9.AH.26.247;
9.AH.27.157; 9.AH.27.158; 9.AH.27.196; 9.AH.27.223; 9.AH.27.240;
9.AH.27.244; 9.AH.27.243; 9.AH.27.247; 9.AH.29.157; 9.AH.29.158;
9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244; 9.AH.29.243;
9.AH.29.247; 9.AH.54.157; 9.AH.54.158; 9.AH.54.196; 9.AH.54.223;
9.AH.54.240; 9.AH.54.244; 9.AH.54.243; 9.AH.54.247; 9.AH.55.157;
9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240; 9.AH.55.244;
9.AH.55.243; 9.AH.55.247; 9.AH.56.157; 9.AH.56.158; 9.AH.56.196;
9.AH.56.223; 9.AH.56.240; 9.AH.56.244; 9.AH.56.243; 9.AH.56.247;
9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH.157.223;
9.AH.157.240; 9.AH.157.244; 9.AH.157.243; 9.AH.157.247;
9.AH.196.157; 9.AH.196.158; 9.AH.196.196; 9.AH.196.223;
9.AH.196.240; 9.AH.196.244; 9.AH.196.243; 9.AH.196.247;
9.AH.223.157; 9.AH.223.158; 9.AH.223.196; 9.AH.223.223;
9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247;
9.AH.240.157; 9.AH.240.158; 9.AH.240.196; 9.AH.240.223;
9.AH.240.240; 9.AH.240.244; 9.AH.240.243; 9.AH.240.247;
9.AH.244.157; 9.AH.244.158; 9.AH.244.196; 9.AH.244.223;
9.AH.244.240; 9.AH.244.244; 9.AH.244.243; 9.AH.244.247;
9.AH.247.157; 9.AH.247.158; 9.AH.247.196; 9.AH.247.223;
9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247; Prodrugs of
9.AJ 9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240;
9.AJ.4.244; 9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158;
9.AJ.5.196; 9.AJ.5.223; 9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243;
9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158; 9.AJ.7.196; 9.AJ.7.223;
9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247; 9.AJ.15.157;
9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; 9.AJ.15.240; 9.AJ.15.244;
9.AJ.15.243; 9.AJ.15.247; 9.AJ.16.157; 9.AJ.16.158; 9.AJ.16.196;
9.AJ.16.223; 9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243; 9.AJ.16.247;
9.AJ.18.157; 9.AJ.18.158; 9.AJ.18.196; 9.AJ.18.223; 9.AJ.18.240;
9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247; 9.AJ.26.157; 9.AJ.26.158;
9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244; 9.AJ.26.243;
9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196; 9.AJ.27.223;
9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247; 9.AJ.29.157;
9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240; 9.AJ.29.244;
9.AJ.29.243; 9.AJ.29.247; 9.AJ.54.157; 9.AJ.54.158; 9.AJ.54.196;
9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244; 9.AJ.54.243; 9.AJ.54.247;
9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223; 9.AJ.55.240;
9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ.56.157; 9.AJ.56.158;
9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244; 9.AJ.56.243;
9.AJ.56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196;
9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ.157.243;
9.AJ.157.247; 9.AJ.196.157; 9.AJ.196.158; 9.AJ.196.196;
9.AJ.196.223; 9.AJ.196.240; 9.AJ.196.244; 9.AJ.196.243;
9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158; 9.AJ.223.196;
9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243;
9.AJ.223.247; 9.AJ.240.157; 9.AJ.240.158; 9.AJ.240.196;
9.AJ.240.223; 9.AJ.240.240; 9.AJ.240.244; 9.AJ.240.243;
9.AJ.240.247; 9.AJ.244.157; 9.AJ.244.158; 9.AJ.244.196;
9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244; 9.AJ.244.243;
9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ.247.196;
9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243;
9.AJ.247.247; Prodrugs of 9.AN 9.AN.4.157; 9.AN.4.158; 9.AN.4.196;
9.AN.4.223; 9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247;
9.AN.5.157; 9.AN.5.158; 9.AN.5.196; 9.AN.5.223; 9.AN.5.240;
9.AN.5.244; 9.AN.5.243; 9.AN.5.247; 9.AN.7.157; 9.AN.7.158;
9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244; 9.AN.7.243;
9.AN.7.247; 9.AN.15.157; 9.AN.15.158; 9.AN.15.196; 9.AN.15.223;
9.AN.15.240; 9.AN.15.244; 9.AN.15.243; 9.AN.15.247; 9.AN.16.157;
9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240; 9.AN.16.244;
9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158; 9.AN.18.196;
9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243; 9.AN.18.247;
9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223; 9.AN.26.240;
9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157; 9.AN.27.158;
9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244; 9.AN.27.243;
9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196; 9.AN.29.223;
9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247; 9.AN.54.157;
9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240; 9.AN.54.244;
9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158; 9.AN.55.196;
9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243; 9.AN.55.247;
9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223; 9.AN.56.240;
9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157; 9.AN.157.158;
9.AN.157.196; 9.AN.157.223; 9.AN.157.240; 9.AN.157.244;
9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158;
9.AN.196.196; 9.AN.196.223; 9.AN.196.240; 9.AN.196.244;
9.AN.196.243; 9.AN.196.247; 9.AN.223.157; 9.AN.223.158;
9.AN.223.196; 9.AN.223.223; 9.AN.223.240; 9.AN.223.244;
9.AN.223.243; 9.AN.223.247; 9.AN.240.157; 9.AN.240.158;
9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244;
9.AN.240.243; 9.AN.240.247; 9.AN.244.157; 9.AN.244.158;
9.AN.244.196; 9.AN.244.223; 9.AN.244.240; 9.AN.244.244;
9.AN.244.243; 9.AN.244.247; 9.AN.247.157; 9.AN.247.158;
9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244;
9.AN.247.243; 9.AN.247.247; Prodrugs of 9.AP 9.AP.4.157;
9.AP.4.158; 9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244;
9.AP.4.243; 9.AP.4.247; 9.AP.5.157; 9.AP.5.158; 9.AP.5.196;
9.AP.5.223; 9.AP.5.240; 9.AP.5.244; 9.AP.5.243; 9.AP.5.247;
9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223; 9.AP.7.240;
9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157; 9.AP.15.158;
9.AP.15.196; 9.AP.15.223; 9.AP.15.240; 9.AP.15.244; 9.AP.15.243;
9.AP.15.247; 9.AP.16.157; 9.AP.16.158; 9.AP.16.196; 9.AP.16.223;
9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247; 9.AP.18.157;
9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240; 9.AP.18.244;
9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158; 9.AP.26.196;
9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243; 9.AP.26.247;
9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223; 9.AP.27.240;
9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157; 9.AP.29.158;
9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244; 9.AP.29.243;
9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196; 9.AP.54.223;
9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247; 9.AP.55.157;
9.AP.55.158; 9.AP.55.196; 9.AP.55.223; 9.AP.55.240; 9.AP.55.244;
9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158; 9.AP.56.196;
9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243; 9.AP.56.247;
9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223;
9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247;
9.AP.196.157; 9.AP.196.158; 9.AP.196.196; 9.AP.196.223;
9.AP.196.240; 9.AP.196.244; 9.AP.196.243; 9.AP.196.247;
9.AP.223.157; 9.AP.223.158; 9.AP.223.196; 9.AP.223.223;
9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247;
9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223;
9.AP.240.240; 9.AP.240.244; 9.AP.240.243; 9.AP.240.247;
9.AP.244.157; 9.AP.244.158; 9.AP.244.196; 9.AP.244.223;
9.AP.244.240; 9.AP.244.244; 9.AP.244.243; 9.AP.244.247;
9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223;
9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247; Prodrugs of
9.AZ 9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240;
9.AZ.4.244; 9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158;
9.AZ.5.196; 9.AZ.5.223; 9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243;
9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158; 9.AZ.7.196; 9.AZ.7.223;
9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247; 9.AZ.15.157;
9.AZ.15.158; 9.AZ.15.196; 9.AZ.15.223; 9.AZ.15.240; 9.AZ.15.244;
9.AZ.15.243; 9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158; 9.AZ.16.196;
9.AZ.16.223; 9.AZ.16.240; 9.AZ.16.244; 9.AZ.16.243; 9.AZ.16.247;
9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196; 9.AZ.18.223; 9.AZ.18.240;
9.AZ.18.244; 9.AZ.18.243; 9.AZ.18.247; 9.AZ.26.157; 9.AZ.26.158;
9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244; 9.AZ.26.243;
9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196; 9.AZ.27.223;
9.AZ.27.240; 9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247; 9.AZ.29.157;
9.AZ.29.158; 9.AZ.29.196; 9.AZ.29.223; 9.AZ.29.240; 9.AZ.29.244;
9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157; 9.AZ.54.158; 9.AZ.54.196;
9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243; 9.AZ.54.247;
9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223; 9.AZ.55.240;
9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157; 9.AZ.56.158;
9.AZ.56.196; 9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244; 9.AZ.56.243;
9.AZ.56.247; 9.AZ.157.157; 9.AZ.157.158; 9.AZ.157.196;
9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243;
9.AZ.157.247; 9.AZ.196.157; 9.AZ.196.158; 9.AZ.196.196;
9.AZ.196.223; 9.AZ.196.240; 9.AZ.196.244; 9.AZ.196.243;
9.AZ.196.247; 9.AZ.223.157; 9.AZ.223.158; 9.AZ.223.196;
9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243;
9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196;
9.AZ.240.223; 9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243;
9.AZ.240.247; 9.AZ.244.157; 9.AZ.244.158; 9.AZ.244.196;
9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244; 9.AZ.244.243;
9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196;
9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243;
9.AZ.247.247; Prodrugs of 9.BF 9.BF.4.157; 9.BF.4.158; 9.BF.4.196;
9.BF.4.223; 9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247;
9.BF.5.157; 9.BF.5.158; 9.BF.5.196; 9.BF.5.223; 9.BF.5.240;
9.BF.5.244; 9.BF.5.243; 9.BF.5.247; 9.BF.7.157; 9.BF.7.158;
9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244; 9.BF.7.243;
9.BF.7.247; 9.BF.15.157; 9.BF.15.158; 9.BF.15.196; 9.BF.15.223;
9.BF.15.240; 9.BF.15.244; 9.BF.15.243; 9.BF.15.247; 9.BF.16.157;
9.BF.16.158; 9.BF.16.196; 9.BF.16.223; 9.BF.16.240; 9.BF.16.244;
9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158; 9.BF.18.196;
9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243; 9.BF.18.247;
9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223; 9.BF.26.240;
9.BF.26.244; 9.BF.26.243; 9.BF.26.247; 9.BF.27.157; 9.BF.27.158;
9.BF.27.196; 9.BF.27.223; 9.BF.27.240; 9.BF.27.244; 9.BF.27.243;
9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196; 9.BF.29.223;
9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247; 9.BF.54.157;
9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240; 9.BF.54.244;
9.BF.54.243; 9.BF.54.247; 9.BF.55.157; 9.BF.55.158; 9.BF.55.196;
9.BF.55.223; 9.BF.55.240; 9.BF.55.244; 9.BF.55.243; 9.BF.55.247;
9.BF.56.157; 9.BF.56.158; 9.BF.56.196; 9.BF.56.223; 9.BF.56.240;
9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157; 9.BF.157.158;
9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244;
9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158;
9.BF.196.196; 9.BF.196.223; 9.BF.196.240; 9.BF.196.244;
9.BF.196.243; 9.BF.196.247; 9.BF.223.157; 9.BF.223.158;
9.BF.223.196; 9.BF.223.223; 9.BF.223.240; 9.BF.223.244;
9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158;
9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244;
9.BF.240.243; 9.BF.240.247; 9.BF.244.157; 9.BF.244.158;
9.BF.244.196; 9.BF.244.223; 9.BF.244.240; 9.BF.244.244;
9.BF.244.243; 9.BF.244.247; 9.BF.247.157; 9.BF.247.158;
9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244;
9.BF.247.243; 9.BF.247.247; Prodrugs of 9.CI 9.CI.4.157;
9.CI.4.158; 9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244;
9.CI.4.243; 9.CI.4.247; 9.CI.5.157; 9.CI.5.158; 9.CI.5.196;
9.CI.5.223; 9.CI.5.240; 9.CI.5.244; 9.CI.5.243; 9.CI.5.247;
9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223; 9.CI.7.240;
9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157; 9.CI.15.158;
9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244; 9.CI.15.243;
9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196; 9.CI.16.223;
9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247; 9.CI.18.157;
9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240; 9.CI.18.244;
9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158; 9.CI.26.196;
9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243; 9.CI.26.247;
9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223; 9.CI.27.240;
9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157; 9.CI.29.158;
9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244; 9.CI.29.243;
9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196; 9.CI.54.223;
9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.247; 9.CI.55.157;
9.CI.55.158; 9.CI.55.196; 9.CI.55.223; 9.CI.55.240; 9.CI.55.244;
9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158; 9.CI.56.196;
9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243; 9.CI.56.247;
9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223;
9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247;
9.CI.196.157; 9.CI.196.158; 9.CI.196.196; 9.CI.196.223;
9.CI.196.240; 9.CI.196.244; 9.CI.196.243; 9.CI.196.247;
9.CI.223.157; 9.CI.223.158; 9.CI.223.196; 9.CI.223.223;
9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247;
9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223;
9.CI.240.240; 9.CI.240.244; 9.CI.240.243; 9.CI.240.247;
9.CI.244.157; 9.CI.244.158; 9.CI.244.196; 9.CI.244.223;
9.CI.244.240; 9.CI.244.244; 9.CI.244.243; 9.CI.244.247;
9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223;
9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247; Prodrugs of
9.CO 9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240;
9.CO.4.244; 9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158;
9.CO.5.196; 9.CO.5.223; 9.CO.5.240; 9.CO.5.244; 9.CO.5.243;
9.CO.5.247; 9.CO.7.157; 9.CO.7.158; 9.CO.7.196; 9.CO.7.223;
9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247; 9.CO.15.157;
9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240; 9.CO.15.244;
9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158; 9.CO.16.196;
9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243;
9.CO.16.247;
9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223; 9.CO.18.240;
9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157; 9.CO.26.158;
9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244; 9.CO.26.243;
9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196; 9.CO.27.223;
9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247; 9.CO.29.157;
9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240; 9.CO.29.244;
9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158; 9.CO.54.196;
9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243; 9.CO.54.247;
9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223; 9.CO.55.240;
9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157; 9.CO.56.158;
9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244; 9.CO.56.243;
9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196;
9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243;
9.CO.157.247; 9.CO.196.157; 9.CO.196.158; 9.CO.196.196;
9.CO.196.223; 9.CO.196.240; 9.CO.196.244; 9.CO.196.243;
9.CO.196.247; 9.CO.223.157; 9.CO.223.158; 9.CO.223.196;
9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243;
9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196;
9.CO.240.223; 9.CO.240.240; 9.CO.240.244; 9.CO.240.243;
9.CO.240.247; 9.CO.244.157; 9.CO.244.158; 9.CO.244.196;
9.CO.244.223; 9.CO.244.240; 9.CO.244.244; 9.CO.244.243;
9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196;
9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243;
9.CO.247.247; Prodrugs of 10.AH 10.AH.4.157; 10.AH.4.158;
10.AH.4.196; 10.AH.4.223; 10.AH.4.240; 10.AH.4.244; 10.AH.4.243;
10.AH.4.247; 10.AH.5.157; 10.AH.5.158; 10.AH.5.196; 10.AH.5.223;
10.AH.5.240; 10.AH.5.244; 10.AH.5.243; 10.AH.5.247; 10.AH.7.157;
10.AH.7.158; 10.AH.7.196; 10.AH.7.223; 10.AH.7.240; 10.AH.7.244;
10.AH.7.243; 10.AH.7.247; 10.AH.15.157; 10.AH.15.158; 10.AH.15.196;
10.AH.15.223; 10.AH.15.240; 10.AH.15.244; 10.AH.15.243;
10.AH.15.247; 10.AH.16.157; 10.AH.16.158; 10.AH.16.196;
10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243;
10.AH.16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196;
10.AH.18.223; 10.AH.18.240; 10.AH.18.244; 10.AH.18.243;
10.AH.18.247; 10.AH.26.157; 10.AH.26.158; 10.AH.26.196;
10.AH.26.223; 10.AH.26.240; 10.AH.26.244; 10.AH.26.243;
10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196;
10.AH.27.223; 10.AH.27.240; 10.AH.27.244; 10.AH.27.243;
10.AH.27.247; 10.AH.29.157; 10.AH.29.158; 10.AH.29.196;
10.AH.29.223; 10.AH.29.240; 10.AH.29.244; 10.AH.29.243;
10.AH.29.247; 10.AH.54.157; 10.AH.54.158; 10.AH.54.196;
10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243;
10.AH.54.247; 10.AH.55.157; 10.AH.55.158; 10.AH.55.196;
10.AH.55.223; 10.AH.55.240; 10.AH.55.244; 10.AH.55.243;
10.AH.55.247; 10.AH.56.157; 10.AH.56.158; 10.AH.56.196;
10.AH.56.223; 10.AH.56.240; 10.AH.56.244; 10.AH.56.243;
10.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH.157.196;
10.AH.157.223; 10.AH.157.240; 10.AH.157.244; 10.AH.157.243;
10.AH.157.247; 10.AH.196.157; 10.AH.196.158; 10.AH.196.196;
10.AH.196.223; 10.AH.196.240; 10.AH.196.244; 10.AH.196.243;
10.AH.196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196;
10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243;
10.AH.223.247; 10.AH.240.157; 10.AH.240.158; 10.AH.240.196;
10.AH.240.223; 10.AH.240.240; 10.AH.240.244; 10.AH.240.243;
10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196;
10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243;
10.AH.244.247; 10.AH.247.157; 10.AH.247.158; 10.AH.247.196;
10.AH.247.223; 10.AH.247.240; 10.AH.247.244; 10.AH.247.243;
10.AH.247.247; Prodrugs of 10.AJ 10.AJ.4.157; 10.AJ.4.158;
10.AJ.4.196; 10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; 10.AJ.4.243;
10.AJ.4.247; 10.AJ.5.157; 10.AJ.5.158; 10.AJ.5.196; 10.AJ.5.223;
10.AJ.5.240; 10.AJ.5.244; 10.AJ.5.243; 10.AJ.5.247; 10.AJ.7.157;
10.AJ.7.158; 10.AJ.7.196; 10.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244;
10.AJ.7.243; 10.AJ.7.247; 10.AJ.15.157; 10.AJ.15.158; 10.AJ.15.196;
10.AJ.15.223; 10.AJ.15.240; 10.AJ.15.244; 10.AJ.15.243;
10.AJ.15.247; 10.AJ.16.157; 10.AJ.16.158; 10.AJ.16.196;
10.AJ.16.223; 10.AJ.16.240; 10.AJ.16.244; 10.AJ.16.243;
10.AJ.16.247; 10.AJ.18.157; 10.AJ.18.158; 10.AJ.18.196;
10.AJ.18.223; 10.AJ.18.240; 10.AJ.18.244; 10.AJ.18.243;
10.AJ.18.247; 10.AJ.26.157; 10.AJ.26.158; 10.AJ.26.196;
10.AJ.26.223; 10.AJ.26.240; 10.AJ.26.244; 10.AJ.26.243;
10.AJ.26.247; 10.AJ.27.157; 10.AJ.27.158; 10.AJ.27.196;
10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243;
10.AJ.27.247; 10.AJ.29.157; 10.AJ.29.158; 10.AJ.29.196;
10.AJ.29.223; 10.AJ.29.240; 10.AJ.29.244; 10.AJ.29.243;
10.AJ.29.247; 10.AJ.54.157; 10.AJ.54.158; 10.AJ.54.196;
10.AJ.54.223; 10.AJ.54.240; 10.AJ.54.244; 10.AJ.54.243;
10.AJ.54.247; 10.AJ.55.157; 10.AJ.55.158; 10.AJ.55.196;
10.AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10.AJ.55.243;
10.AJ.55.247; 10.AJ.56.157; 10.AJ.56.158; 10.AJ.56.196;
10.AJ.56.223; 10.AJ.56.240; 10.AJ.56.244; 10.AJ.56.243;
10.AJ.56.247; 10.AJ.157.157; 10.AJ.157.158; 10.AJ.157.196;
10.AJ.157.223; 10.AJ.157.240; 10.AJ.157.244; 10.AJ.157.243;
10.AJ.157.247; 10.AJ.196.157; 10.AJ.196.158; 10.AJ.196.196;
10.AJ.196.223; 10.AJ.196.240; 10.AJ.196.244; 10.AJ.196.243;
10.AJ.196.247; 10.AJ.223.157; 10.AJ.223.158; 10.AJ.223.196;
10.AJ.223.223; 10.AJ.223.240; 10.AJ.223.244; 10.AJ.223.243;
10.AJ.223.247; 10.AJ.240.157; 10.AJ.240.158; 10.AJ.240.196;
10.AJ.240.223; 10.AJ.240.240; 10.AJ.240.244; 10.AJ.240.243;
10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158; 10.AJ.244.196;
10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244; 10.AJ.244.243;
10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158; 10.AJ.247.196;
10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244; 10.AJ.247.243;
10.AJ.247.247; Prodrugs of 10.AN 10.AN.4.157; 10.AN.4.158;
10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244; 10.AN.4.243;
10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196; 10.AN.5.223;
10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247; 10.AN.7.157;
10.AN.7.158; 10.AN.7.196; 10.AN.7.223; 10.AN.7.240; 10.AN.7.244;
10.AN.7.243; 10.AN.7.247; 10.AN.15.157; 10.AN.15.158; 10.AN.15.196;
10.AN.15.223; 10.AN.15.240; 10.AN.15.244; 10.AN.15.243;
10.AN.15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196;
10.AN.16.223; 10.AN.16.240; 10.AN.16.244; 10.AN.16.243;
10.AN.16.247; 10.AN.18.157; 10.AN.18.158; 10.AN.18.196;
10.AN.18.223; 10.AN.18.240; 10.AN.18.244; 10.AN.18.243;
10.AN.18.247; 10.AN.26.157; 10.AN.26.158; 10.AN.26.196;
10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243;
10.AN.26.247; 10.AN.27.157; 10.AN.27.158; 10.AN.27.196;
10.AN.27.223; 10.AN.27.240; 10.AN.27.244; 10.AN.27.243;
10.AN.27.247; 10.AN.29.157; 10.AN.29.158; 10.AN.29.196;
10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243;
10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196;
10.AN.54.223; 10.AN.54.240; 10.AN.54.244; 10.AN.54.243;
10.AN.54.247; 10.AN.55.157; 10.AN.55.158; 10.AN.55.196;
10.AN.55.223; 10.AN.55.240; 10.AN.55.244; 10.AN.55.243;
10.AN.55.247; 10.AN.56.157; 10.AN.56.158; 10.AN.56.196;
10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243;
10.AN.56.247; 10.AN.157.157; 10.AN.157.158; 10.AN.157.196;
10.AN.157.223; 10.AN.157.240; 10.AN.157.244; 10.AN.157.243;
10.AN.157.247; 10.AN.196.157; 10.AN.196.158; 10.AN.196.196;
10.AN.196.223; 10.AN.196.240; 10.AN.196.244; 10.AN.196.243;
10.AN.196.247; 10.AN.223.157; 10.AN.223.158; 10.AN.223.196;
10.AN.223.223; 10.AN.223.240; 10.AN.223.244; 10.AN.223.243;
10.AN.223.247; 10.AN.240.157; 10.AN.240.158; 10.AN.240.196;
10.AN.240.223; 10.AN.240.240; 10.AN.240.244; 10.AN.240.243;
10.AN.240.247; 10.AN.244.157; 10.AN.244.158; 10.AN.244.196;
10.AN.244.223; 10.AN.244.240; 10.AN.244.244; 10.AN.244.243;
10.AN.244.247; 10.AN.247.157; 10.AN.247.158; 10.AN.247.196;
10.AN.247.223; 10.AN.247.240; 10.AN.247.244; 10.AN.247.243;
10.AN.247.247; Prodrugs of 10.AP 10.AP.4.157; 10.AP.4.158;
10.AP.4.196; 10.AP.4.223; 10.AP.4.240; 10.AP.4.244; 10.AP.4.243;
10.AP.4.247; 10.AP.5.157; 10.AP.5.158; 10.AP.5.196; 10.AP.5.223;
10.AP.5.240; 10.AP.5.244; 10.AP.5.243; 10.AP.5.247; 10.AP.7.157;
10.AP.7.158; 10.AP.7.196; 10.AP.7.223; 10.AP.7.240; 10.AP.7.244;
10.AP.7.243; 10.AP.7.247; 10.AP.15.157; 10.AP.15.158; 10.AP.15.196;
10.AP.15.223; 10.AP.15.240; 10.AP.15.244; 10.AP.15.243;
10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196;
10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243;
10.AP.16.247; 10.AP.18.157; 10.AP.18.158; 10.AP.18.196;
10.AP.18.223; 10.AP.18.240; 10.AP.18.244; 10.AP.18.243;
10.AP.18.247; 10.AP.26.157; 10.AP.26.158; 10.AP.26.196;
10.AP.26.223; 10.AP.26.240; 10.AP.26.244; 10.AP.26.243;
10.AP.26.247; 10.AP.27.157; 10.AP.27.158; 10.AP.27.196;
10.AP.27.223; 10.AP.27.240; 10.AP.27.244; 10.AP.27.243;
10.AP.27.247; 10.AP.29.157; 10.AP.29.158; 10.AP.29.196;
10.AP.29.223; 10.AP.29.240; 10.AP.29.244; 10.AP.29.243;
10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196;
10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243;
10.AP.54.247; 10.AP.55.157; 10.AP.55.158; 10.AP.55.196;
10.AP.55.223; 10.AP.55.240; 10.AP.55.244; 10.AP.55.243;
10.AP.55.247; 10.AP.56.157; 10.AP.56.158; 10.AP.56.196;
10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243;
10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196;
10.AP.157.223; 10.AP.157.240; 10.AP.157.244; 10.AP.157.243;
10.AP.157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196;
10.AP.196.223; 10.AP.196.240; 10.AP.196.244; 10.AP.196.243;
10.AP.196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196;
10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243;
10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196;
10.AP.240.223; 10.AP.240.240; 10.AP.240.244; 10.AP.240.243;
10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196;
10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243;
10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196;
10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243;
10.AP.247.247; Prodrugs of 10.AZ 10.AZ.4.157; 10.AZ.4.158;
10.AZ.4.196; 10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243;
10.AZ.4.247; 10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223;
10.AZ.5.240; 10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157;
10.AZ.7.158; 10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244;
10.AZ.7.243; 10.AZ.7.247; 10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196;
10.AZ.15.223; 10.AZ.15.240; 10.AZ.15.244; 10.AZ.15.243;
10.AZ.15.247; 10.AZ.16.157; 10.AZ.16.158; 10.AZ.16.196;
10.AZ.16.223; 10.AZ.16.240; 10.AZ.16.244; 10.AZ.16.243;
10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196;
10.AZ.18.223; 10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243;
10.AZ.18.247; 10.AZ.26.157; 10.AZ.26.158; 10.AZ.26.196;
10.AZ.26.223; 10.AZ.26.240; 10.AZ.26.244; 10.AZ.26.243;
10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158; 10.AZ.27.196;
10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243;
10.AZ.27.247; 10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196;
10.AZ.29.223; 10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243;
10.AZ.29.247; 10.AZ.54.157; 10.AZ.54.158; 10.AZ.54.196;
10.AZ.54.223; 10.AZ.54.240; 10.AZ.54.244; 10.AZ.54.243;
10.AZ.54.247; 10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196;
10.AZ.55.223; 10.AZ.55.240; 10.AZ.55.244; 10.AZ.55.243;
10.AZ.55.247; 10.AZ.56.157; 10.AZ.56.158; 10.AZ.56.196;
10.AZ.56.223; 10.AZ.56.240; 10.AZ.56.244; 10.AZ.56.243;
10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158; 10.AZ.157.196;
10.AZ.157.223; 10.AZ.157.240; 10.AZ.157.244; 10.AZ.157.243;
10.AZ.157.247; 10.AZ.196.157; 10.AZ.196.158; 10.AZ.196.196;
10.AZ.196.223; 10.AZ.196.240; 10.AZ.196.244; 10.AZ.196.243;
10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158; 10.AZ.223.196;
10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244; 10.AZ.223.243;
10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158; 10.AZ.240.196;
10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244; 10.AZ.240.243;
10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158; 10.AZ.244.196;
10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244; 10.AZ.244.243;
10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158; 10.AZ.247.196;
10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244; 10.AZ.247.243;
10.AZ.247.247; Prodrugs of 10.BF 10.BF.4.157; 10.BF.4.158;
10.BF.4.196; 10.BF.4.223; 10.BF.4.240; 10.BF.4.244; 10.BF.4.243;
10.BF.4.247; 10.BF.5.157; 10.BF.5.158; 10.BF.5.196; 10.BF.5.223;
10.BF.5.240; 10.BF.5.244; 10.BF.5.243; 10.BF.5.247; 10.BF.7.157;
10.BF.7.158; 10.BF.7.196; 10.BF.7.223; 10.BF.7.240; 10.BF.7.244;
10.BF.7.243; 10.BF.7.247; 10.BF.15.157; 10.BF.15.158; 10.BF.15.196;
10.BF.15.223; 10.BF.15.240; 10.BF.15.244; 10.BF.15.243;
10.BF.15.247; 10.BF.16.157; 10.BF.16.158; 10.BF.16.196;
10.BF.16.223; 10.BF.16.240; 10.BF.16.244; 10.BF.16.243;
10.BF.16.247; 10.BF.18.157; 10.BF.18.158; 10.BF.18.196;
10.BF.18.223; 10.BF.18.240; 10.BF.18.244; 10.BF.18.243;
10.BF.18.247; 10.BF.26.157; 10.BF.26.158; 10.BF.26.196;
10.BF.26.223; 10.BF.26.240; 10.BF.26.244; 10.BF.26.243;
10.BF.26.247; 10.BF.27.157; 10.BF.27.158; 10.BF.27.196;
10.BF.27.223; 10.BF.27.240; 10.BF.27.244; 10.BF.27.243;
10.BF.27.247; 10.BF.29.157; 10.BF.29.158; 10.BF.29.196;
10.BF.29.223; 10.BF.29.240; 10.BF.29.244; 10.BF.29.243;
10.BF.29.247; 10.BF.54.157; 10.BF.54.158; 10.BF.54.196;
10.BF.54.223; 10.BF.54.240; 10.BF.54.244; 10.BF.54.243;
10.BF.54.247; 10.BF.55.157; 10.BF.55.158; 10.BF.55.196;
10.BF.55.223; 10.BF.55.240; 10.BF.55.244; 10.BF.55.243;
10.BF.55.247; 10.BF.56.157; 10.BF.56.158; 10.BF.56.196;
10.BF.56.223; 10.BF.56.240; 10.BF.56.244; 10.BF.56.243;
10.BF.56.247; 10.BF.157.157; 10.BF.157.158; 10.BF.157.196;
10.BF.157.223; 10.BF.157.240; 10.BF.157.244; 10.BF.157.243;
10.BF.157.247; 10.BF.196.157; 10.BF.196.158; 10.BF.196.196;
10.BF.196.223; 10.BF.196.240; 10.BF.196.244; 10.BF.196.243;
10.BF.196.247; 10.BF.223.157; 10.BF.223.158; 10.BF.223.196;
10.BF.223.223; 10.BF.223.240; 10.BF.223.244; 10.BF.223.243;
10.BF.223.247; 10.BF.240.157; 10.BF.240.158; 10.BF.240.196;
10.BF.240.223; 10.BF.240.240; 10.BF.240.244; 10.BF.240.243;
10.BF.240.247; 10.BF.244.157; 10.BF.244.158; 10.BF.244.196;
10.BF.244.223; 10.BF.244.240; 10.BF.244.244; 10.BF.244.243;
10.BF.244.247; 10.BF.247.157; 10.BF.247.158; 10.BF.247.196;
10.BF.247.223; 10.BF.247.240; 10.BF.247.244; 10.BF.247.243;
10.BF.247.247; Prodrugs of 10.CI 10.CI.4.157; 10.CI.4.158;
10.CI.4.196; 10.CI.4.223; 10.CI.4.240;
10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158;
10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243;
10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223;
10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157;
10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240;
10.CI.15.244; 10.CI.15.243; 10.CI.15.247; 10.CI.16.157;
10.CI.16.158; 10.CI.16.196; 10.CI.16.223; 10.CI.16.240;
10.CI.16.244; 10.CI.16.243; 10.CI.16.247; 10.CI.18.157;
10.CI.18.158; 10.CI.18.196; 10.CI.18.223; 10.CI.18.240;
10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157;
10.CI.26.158; 10.CI.26.196; 10.CI.26.223; 10.CI.26.240;
10.CI.26.244; 10.CI.26.243; 10.CI.26.247; 10.CI.27.157;
10.CI.27.158; 10.CI.27.196; 10.CI.27.223; 10.CI.27.240;
10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157;
10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240;
10.CI.29.244; 10.CI.29.243; 10.CI.29.247; 10.CI.54.157;
10.CI.54.158; 10.CI.54.196; 10.CI.54.223; 10.CI.54.240;
10.CI.54.244; 10.CI.54.243; 10.CI.54.247; 10.CI.55.157;
10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240;
10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157;
10.CI.56.158; 10.CI.56.196; 10.CI.56.223; 10.CI.56.240;
10.CI.56.244; 10.CI.56.243; 10.CI.56.247; 10.CI.157.157;
10.CI.157.158; 10.CI.157.196; 10.CI.157.223; 10.CI.157.240;
10.CI.157.244; 10.CI.157.243; 10.CI.157.247; 10.CI.196.157;
10.CI.196.158; 10.CI.196.196; 10.CI.196.223; 10.CI.196.240;
10.CI.196.244; 10.CI.196.243; 10.CI.196.247; 10.CI.223.157;
10.CI.223.158; 10.CI.223.196; 10.CI.223.223; 10.CI.223.240;
10.CI.223.244; 10.CI.223.243; 10.CI.223.247; 10.CI.240.157;
10.CI.240.158; 10.CI.240.196; 10.CI.240.223; 10.CI.240.240;
10.CI.240.244; 10.CI.240.243; 10.CI.240.247; 10.CI.244.157;
10.CI.244.158; 10.CI.244.196; 10.CI.244.223; 10.CI.244.240;
10.CI.244.244; 10.CI.244.243; 10.CI.244.247; 10.CI.247.157;
10.CI.247.158; 10.CI.247.196; 10.CI.247.223; 10.CI.247.240;
10.CI.247.244; 10.CI.247.243; 10.CI.247.247; Prodrugs of 10.CO
10.CO.4.157; 10.CO.4.158; 10.CO.4.196; 10.CO.4.223; 10.CO.4.240;
10.CO.4.244; 10.CO.4.243; 10.CO.4.247; 10.CO.5.157; 10.CO.5.158;
10.CO.5.196; 10.CO.5.223; 10.CO.5.240; 10.CO.5.244; 10.CO.5.243;
10.CO.5.247; 10.CO.7.157; 10.CO.7.158; 10.CO.7.196; 10.CO.7.223;
10.CO.7.240; 10.CO.7.244; 10.CO.7.243; 10.CO.7.247; 10.CO.15.157;
10.CO.15.158; 10.CO.15.196; 10.CO.15.223; 10.CO.15.240;
10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157;
10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.CO.16.240;
10.CO.16.244; 10.CO.16.243; 10.CO.16.247; 10.CO.18.157;
10.CO.18.158; 10.CO.18.196; 10.CO.18.223; 10.CO.18.240;
10.CO.18.244; 10.CO.18.243; 10.CO.18.247; 10.CO.26.157;
10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240;
10.CO.26.244; 10.CO.26.243; 10.CO.26.247; 10.CO.27.157;
10.CO.27.158; 10.CO.27.196; 10.CO.27.223; 10.CO.27.240;
10.CO.27.244; 10.CO.27.243; 10.CO.27.247; 10.CO.29.157;
10.CO.29.158; 10.CO.29.196; 10.CO.29.223; 10.CO.29.240;
10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157;
10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240;
10.CO.54.244; 10.CO.54.243; 10.CO.54.247; 10.CO.55.157;
10.CO.55.158; 10.CO.55.196; 10.CO.55.223; 10.CO.55.240;
10.CO.55.244; 10.CO.55.243; 10.CO.55.247; 10.CO.56.157;
10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240;
10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157;
10.CO.157.158; 10.CO.157.196; 10.CO.157.223; 10.CO.157.240;
10.CO.157.244; 10.CO.157.243; 10.CO.157.247; 10.CO.196.157;
10.CO.196.158; 10.CO.196.196; 10.CO.196.223; 10.CO.196.240;
10.CO.196.244; 10.CO.196.243; 10.CO.196.247; 10.CO.223.157;
10.CO.223.158; 10.CO.223.196; 10.CO.223.223; 10.CO.223.240;
10.CO.223.244; 10.CO.223.243; 10.CO.223.247; 10.CO.240.157;
10.CO.240.158; 10.CO.240.196; 10.CO.240.223; 10.CO.240.240;
10.CO.240.244; 10.CO.240.243; 10.CO.240.247; 10.CO.244.157;
10.CO.244.158; 10.CO.244.196; 10.CO.244.223; 10.CO.244.240;
10.CO.244.244; 10.CO.244.243; 10.CO.244.247; 10.CO.247.157;
10.CO.247.158; 10.CO.247.196; 10.CO.247.223; 10.CO.247.240;
10.CO.247.244; 10.CO.247.243; 10.CO.247.247; Prodrugs of 11.AH
11.AH.4.157; 11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240;
11.AH.4.244; 11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158;
11.AH.5.196; 11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243;
11.AH.5.247; 11.AH.7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223;
11.AH.7.240; 11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH.15.157;
11.AH.15.158; 11.AH.15.196; 11.AH.15.223; 11.AH.15.240;
11.AH.15.244; 11.AH.15.243; 11.AH.15.247; 11.AH.16.157;
11.AH.16.158; 11.AH.16.196; 11.AH.16.223; 11.AH.16.240;
11.AH.16.244; 11.AH.16.243; 11.AH.16.247; 11.AH.18.157;
11.AH.18.158; 11.AH.18.196; 11.AH.18.223; 11.AH.18.240;
11.AH.18.244; 11.AH.18.243; 11.AH.18.247; 11.AH.26.157;
11.AH.26.158; 11.AH.26.196; 11.AH.26.223; 11.AH.26.240;
11.AH.26.244; 11.AH.26.243; 11.AH.26.247; 11.AH.27.157;
11.AH.27.158; 11.AH.27.196; 11.AH.27.223; 11.AH.27.240;
11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157;
11.AH.29.158; 11.AH.29.196; 11.AH.29.223; 11.AH.29.240;
11.AH.29.244; 11.AH.29.243; 11.AH.29.247; 11.AH.54.157;
11.AH.54.158; 11.AH.54.196; 11.AH.54.223; 11.AH.54.240;
11.AH.54.244; 11.AH.54.243; 11.AH.54.247; 11.AH.55.157;
11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240;
11.AH.55.244; 11.AH.55.243; 11.AH.55.247; 11.AH.56.157;
11.AH.56.158; 11.AH.56.196; 11.AH.56.223; 11.AH.56.240;
11.AH.56.244; 11.AH.56.243; 11.AH.56.247; 11.AH.157.157;
11.AH.157.158; 11.AH.157.196; 11.AH.157.223; 11.AH.157.240;
11.AH.157.244; 11.AH.157.243; 11.AH.157.247; 11.AH.196.157;
11.AH.196.158; 11.AH.196.196; 11.AH.196.223; 11.AH.196.240;
11.AH.196.244; 11.AH.196.243; 11.AH.196.247; 11.AH.223.157;
11.AH.223.158; 11.AH.223.196; 11.AH.223.223; 11.AH.223.240;
11.AH.223.244; 11.AH.223.243; 11.AH.223.247; 11.AH.240.157;
11.AH.240.158; 11.AH.240.196; 11.AH.240.223; 11.AH.240.240;
11.AH.240.244; 11.AH.240.243; 11.AH.240.247; 11.AH.244.157;
11.AH.244.158; 11.AH.244.196; 11.AH.244.223; 11.AH.244.240;
11.AH.244.244; 11.AH.244.243; 11.AH.244.247; 11.AH.247.157;
11.AH.247.158; 11.AH.247.196; 11.AH.247.223; 11.AH.247.240;
11.AH.247.244; 11.AH.247.243; 11.AH.247.247; Prodrugs of 11.AJ
11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240;
11.AJ.4.244; 11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158;
11.AJ.5.196; 11.AJ.5.223; 11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243;
11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158; 11.AJ.7.196; 11.AJ.7.223;
11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247; 11.AJ.15.157;
11.AJ.15.158; 11.AJ.15.196; 11.AJ.15.223; 11.AJ.15.240;
11.AJ.15.244; 11.AJ.15.243; 11.AJ.15.247; 11.AJ.16.157;
11.AJ.16.158; 11.AJ.16.196; 11.AJ.16.223; 11.AJ.16.240;
11.AJ.16.244; 11.AJ.16.243; 11.AJ.16.247; 11.AJ.18.157;
11.AJ.18.158; 11.AJ.18.196; 11.AJ.18.223; 11.AJ.18.240;
11.AJ.18.244; 11.AJ.18.243; 11.AJ.18.247; 11.AJ.26.157;
11.AJ.26.158; 11.AJ.26.196; 11.AJ.26.223; 11.AJ.26.240;
11.AJ.26.244; 11.AJ.26.243; 11.AJ.26.247; 11.AJ.27.157;
11.AJ.27.158; 11.AJ.27.196; 11.AJ.27.223; 11.AJ.27.240;
11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247; 11.AJ.29.157;
11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240;
11.AJ.29.244; 11.AJ.29.243; 11.AJ.29.247; 11.AJ.54.157;
11.AJ.54.158; 11.AJ.54.196; 11.AJ.54.223; 11.AJ.54.240;
11.AJ.54.244; 11.AJ.54.243; 11.AJ.54.247; 11.AJ.55.157;
11.AJ.55.158; 11.AJ.55.196; 11.AJ.55.223; 11.AJ.55.240;
11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157;
11.AJ.56.158; 11.AJ.56.196; 11.AJ.56.223; 11.AJ.56.240;
11.AJ.56.244; 11.AJ.56.243; 11.AJ.56.247; 11.AJ.157.157;
11.AJ.157.158; 11.AJ.157.196; 11.AJ.157.223; 11.AJ.157.240;
11.AJ.157.244; 11.AJ.157.243; 11.AJ.157.247; 11.AJ.196.157;
11.AJ.196.158; 11.AJ.196.196; 11.AJ.196.223; 11.AJ.196.240;
11.AJ.196.244; 11.AJ.196.243; 11.AJ.196.247; 11.AJ.223.157;
11.AJ.223.158; 11.AJ.223.196; 11.AJ.223.223; 11.AJ.223.240;
11.AJ.223.244; 11.AJ.223.243; 11.AJ.223.247; 11.AJ.240.157;
11.AJ.240.158; 11.AJ.240.196; 11.AJ.240.223; 11.AJ.240.240;
11.AJ.240.244; 11.AJ.240.243; 11.AJ.240.247; 11.AJ.244.157;
11.AJ.244.158; 11.AJ.244.196; 11.AJ.244.223; 11.AJ.244.240;
11.AJ.244.244; 11.AJ.244.243; 11.AJ.244.247; 11.AJ.247.157;
11.AJ.247.158; 11.AJ.247.196; 11.AJ.247.223; 11.AJ.247.240;
11.AJ.247.244; 11.AJ.247.243; 11.AJ.247.247; Prodrugs of 11.AN
11.AN.4.157; 11.AN.4.158; 11.AN.4.196; 11.AN.4.223; 11.AN.4.240;
11.AN.4.244; 11.AN.4.243; 11.AN.4.247; 11.AN.5.157; 11.AN.5.158;
11.AN.5.196; 11.AN.5.223; 11.AN.5.240; 11.AN.5.244; 11.AN.5.243;
11.AN.5.247; 11.AN.7.157; 11.AN.7.158; 11.AN.7.196; 11.AN.7.223;
11.AN.7.240; 11.AN.7.244; 11.AN.7.243; 11.AN.7.247; 11.AN.15.157;
11.AN.15.158; 11.AN.15.196; 11.AN.15.223; 11.AN.15.240;
11.AN.15.244; 11.AN.15.243; 11.AN.15.247; 11.AN.16.157;
11.AN.16.158; 11.AN.16.196; 11.AN.16.223; 11.AN.16.240;
11.AN.16.244; 11.AN.16.243; 11.AN.16.247; 11.AN.18.157;
11.AN.18.158; 11.AN.18.196; 11.AN.18.223; 11.AN.18.240;
11.AN.18.244; 11.AN.18.243; 11.AN.18.247; 11.AN.26.157;
11.AN.26.158; 11.AN.26.196; 11.AN.26.223; 11.AN.26.240;
11.AN.26.244; 11.AN.26.243; 11.AN.26.247; 11.AN.27.157;
11.AN.27.158; 11.AN.27.196; 11.AN.27.223; 11.AN.27.240;
11.AN.27.244; 11.AN.27.243; 11.AN.27.247; 11.AN.29.157;
11.AN.29.158; 11.AN.29.196; 11.AN.29.223; 11.AN.29.240;
11.AN.29.244; 11.AN.29.243; 11.AN.29.247; 11.AN.54.157;
11.AN.54.158; 11.AN.54.196; 11.AN.54.223; 11.AN.54.240;
11.AN.54.244; 11.AN.54.243; 11.AN.54.247; 11.AN.55.157;
11.AN.55.158; 11.AN.55.196; 11.AN.55.223; 11.AN.55.240;
11.AN.55.244; 11.AN.55.243; 11.AN.55.247; 11.AN.56.157;
11.AN.56.158; 11.AN.56.196; 11.AN.56.223; 11.AN.56.240;
11.AN.56.244; 11.AN.56.243; 11.AN.56.247; 11.AN.157.157;
11.AN.157.158; 11.AN.157.196; 11.AN.157.223; 11.AN.157.240;
11.AN.157.244; 11.AN.157.243; 11.AN.157.247; 11.AN.196.157;
11.AN.196.158; 11.AN.196.196; 11.AN.196.223; 11.AN.196.240;
11.AN.196.244; 11.AN.196.243; 11.AN.196.247; 11.AN.223.157;
11.AN.223.158; 11.AN.223.196; 11.AN.223.223; 11.AN.223.240;
11.AN.223.244; 11.AN.223.243; 11.AN.223.247; 11.AN.240.157;
11.AN.240.158; 11.AN.240.196; 11.AN.240.223; 11.AN.240.240;
11.AN.240.244; 11.AN.240.243; 11.AN.240.247; 11.AN.244.157;
11.AN.244.158; 11.AN.244.196; 11.AN.244.223; 11.AN.244.240;
11.AN.244.244; 11.AN.244.243; 11.AN.244.247; 11.AN.247.157;
11.AN.247.158; 11.AN.247.196; 11.AN.247.223; 11.AN.247.240;
11.AN.247.244; 11.AN.247.243; 11.AN.247.247; Prodrugs of 11.AP
11.AP.4.157; 11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240;
11.AP.4.244; 11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158;
11.AP.5.196; 11.AP.5.223; 11.AP.5.240; 11.AP.5.244; 11.AP.5.243;
11.AP.5.247; 11.AP.7.157; 11.AP.7.158; 11.AP.7.196; 11.AP.7.223;
11.AP.7.240; 11.AP.7.244; 11.AP.7.243; 11.AP.7.247; 11.AP.15.157;
11.AP.15.158; 11.AP.15.196; 11.AP.15.223; 11.AP.15.240;
11.AP.15.244; 11.AP.15.243; 11.AP.15.247; 11.AP.16.157;
11.AP.16.158; 11.AP.16.196; 11.AP.16.223; 11.AP.16.240;
11.AP.16.244; 11.AP.16.243; 11.AP.16.247; 11.AP.18.157;
11.AP.18.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240;
11.AP.18.244; 11.AP.18.243; 11.AP.18.247; 11.AP.26.157;
11.AP.26.158; 11.AP.26.196; 11.AP.26.223; 11.AP.26.240;
11.AP.26.244; 11.AP.26.243; 11.AP.26.247; 11.AP.27.157;
11.AP.27.158; 11.AP.27.196; 11.AP.27.223; 11.AP.27.240;
11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157;
11.AP.29.158; 11.AP.29.196; 11.AP.29.223; 11.AP.29.240;
11.AP.29.244; 11.AP.29.243; 11.AP.29.247; 11.AP.54.157;
11.AP.54.158; 11.AP.54.196; 11.AP.54.223; 11.AP.54.240;
11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157;
11.AP.55.158; 11.AP.55.196; 11.AP.55.223; 11.AP.55.240;
11.AP.55.244; 11.AP.55.243; 11.AP.55.247; 11.AP.56.157;
11.AP.56.158; 11.AP.56.196; 11.AP.56.223; 11.AP.56.240;
11.AP.56.244; 11.AP.56.243; 11.AP.56.247; 11.AP.157.157;
11.AP.157.158; 11.AP.157.196; 11.AP.157.223; 11.AP.157.240;
11.AP.157.244; 11.AP.157.243; 11.AP.157.247; 11.AP.196.157;
11.AP.196.158; 11.AP.196.196; 11.AP.196.223; 11.AP.196.240;
11.AP.196.244; 11.AP.196.243; 11.AP.196.247; 11.AP.223.157;
11.AP.223.158; 11.AP.223.196; 11.AP.223.223; 11.AP.223.240;
11.AP.223.244; 11.AP.223.243; 11.AP.223.247; 11.AP.240.157;
11.AP.240.158; 11.AP.240.196; 11.AP.240.223; 11.AP.240.240;
11.AP.240.244; 11.AP.240.243; 11.AP.240.247; 11.AP.244.157;
11.AP.244.158; 11.AP.244.196; 11.AP.244.223; 11.AP.244.240;
11.AP.244.244; 11.AP.244.243; 11.AP.244.247; 11.AP.247.157;
11.AP.247.158; 11.AP.247.196; 11.AP.247.223; 11.AP.247.240;
11.AP.247.244; 11.AP.247.243; 11.AP.247.247; Prodrugs of 11.AZ
11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240;
11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158;
11.AZ.5.196; 11.AZ.5.223; 11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243;
11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158; 11.AZ.7.196; 11.AZ.7.223;
11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247; 11.AZ.15.157;
11.AZ.15.158; 11.AZ.15.196; 11.AZ.15.223; 11.AZ.15.240;
11.AZ.15.244; 11.AZ.15.243; 11.AZ.15.247; 11.AZ.16.157;
11.AZ.16.158; 11.AZ.16.196; 11.AZ.16.223; 11.AZ.16.240;
11.AZ.16.244; 11.AZ.16.243; 11.AZ.16.247; 11.AZ.18.157;
11.AZ.18.158; 11.AZ.18.196; 11.AZ.18.223; 11.AZ.18.240;
11.AZ.18.244; 11.AZ.18.243; 11.AZ.18.247; 11.AZ.26.157;
11.AZ.26.158; 11.AZ.26.196; 11.AZ.26.223; 11.AZ.26.240;
11.AZ.26.244; 11.AZ.26.243; 11.AZ.26.247; 11.AZ.27.157;
11.AZ.27.158; 11.AZ.27.196; 11.AZ.27.223; 11.AZ.27.240;
11.AZ.27.244; 11.AZ.27.243; 11.AZ.27.247; 11.AZ.29.157;
11.AZ.29.158; 11.AZ.29.196; 11.AZ.29.223; 11.AZ.29.240;
11.AZ.29.244; 11.AZ.29.243; 11.AZ.29.247; 11.AZ.54.157;
11.AZ.54.158; 11.AZ.54.196; 11.AZ.54.223; 11.AZ.54.240;
11.AZ.54.244; 11.AZ.54.243; 11.AZ.54.247; 11.AZ.55.157;
11.AZ.55.158; 11.AZ.55.196; 11.AZ.55.223; 11.AZ.55.240;
11.AZ.55.244; 11.AZ.55.243; 11.AZ.55.247; 11.AZ.56.157;
11.AZ.56.158; 11.AZ.56.196; 11.AZ.56.223; 11.AZ.56.240;
11.AZ.56.244; 11.AZ.56.243; 11.AZ.56.247; 11.AZ.157.157;
11.AZ.157.158; 11.AZ.157.196; 11.AZ.157.223; 11.AZ.157.240;
11.AZ.157.244; 11.AZ.157.243; 11.AZ.157.247; 11.AZ.196.157;
11.AZ.196.158; 11.AZ.196.196; 11.AZ.196.223; 11.AZ.196.240;
11.AZ.196.244;
11.AZ.196.243; 11.AZ.196.247; 11.AZ.223.157; 11.AZ.223.158;
11.AZ.223.196; 11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244;
11.AZ.223.243; 11.AZ.223.247; 11.AZ.240.157; 11.AZ.240.158;
11.AZ.240.196; 11.AZ.240.223; 11.AZ.240.240; 11.AZ.240.244;
11.AZ.240.243; 11.AZ.240.247; 11.AZ.244.157; 11.AZ.244.158;
11.AZ.244.196; 11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244;
11.AZ.244.243; 11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158;
11.AZ.247.196; 11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244;
11.AZ.247.243; 11.AZ.247.247; Prodrugs of 11.BF 11.BF.4.157;
11.BF.4.158; 11.BF.4.196; 11.BF.4.223; 11.BF.4.240; 11.BF.4.244;
11.BF.4.243; 11.BF.4.247; 11.BF.5.157; 11.BF.5.158; 11.BF.5.196;
11.BF.5.223; 11.BF.5.240; 11.BF.5.244; 11.BF.5.243; 11.BF.5.247;
11.BF.7.157; 11.BF.7.158; 11.BF.7.196; 11.BF.7.223; 11.BF.7.240;
11.BF.7.244; 11.BF.7.243; 11.BF.7.247; 11.BF.15.157; 11.BF.15.158;
11.BF.15.196; 11.BF.15.223; 11.BF.15.240; 11.BF.15.244;
11.BF.15.243; 11.BF.15.247; 11.BF.16.157; 11.BF.16.158;
11.BF.16.196; 11.BF.16.223; 11.BF.16.240; 11.BF.16.244;
11.BF.16.243; 11.BF.16.247; 11.BF.18.157; 11.BF.18.158;
11.BF.18.196; 11.BF.18.223; 11.BF.18.240; 11.BF.18.244;
11.BF.18.243; 11.BF.18.247; 11.BF.26.157; 11.BF.26.158;
11.BF.26.196; 11.BF.26.223; 11.BF.26.240; 11.BF.26.244;
11.BF.26.243; 11.BF.26.247; 11.BF.27.157; 11.BF.27.158;
11.BF.27.196; 11.BF.27.223; 11.BF.27.240; 11.BF.27.244;
11.BF.27.243; 11.BF.27.247; 11.BF.29.157; 11.BF.29.158;
11.BF.29.196; 11.BF.29.223; 11.BF.29.240; 11.BF.29.244;
11.BF.29.243; 11.BF.29.247; 11.BF.54.157; 11.BF.54.158;
11.BF.54.196; 11.BF.54.223; 11.BF.54.240; 11.BF.54.244;
11.BF.54.243; 11.BF.54.247; 11.BF.55.157; 11.BF.55.158;
11.BF.55.196; 11.BF.55.223; 11.BF.55.240; 11.BF.55.244;
11.BF.55.243; 11.BF.55.247; 11.BF.56.157; 11.BF.56.158;
11.BF.56.196; 11.BF.56.223; 11.BF.56.240; 11.BF.56.244;
11.BF.56.243; 11.BF.56.247; 11.BF.157.157; 11.BF.157.158;
11.BF.157.196; 11.BF.157.223; 11.BF.157.240; 11.BF.157.244;
11.BF.157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158;
11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244;
11.BF.196.243; 11.BF.196.247; 11.BF.223.157; 11.BF.223.158;
11.BF.223.196; 11.BF.223.223; 11.BF.223.240; 11.BF.223.244;
11.BF.223.243; 11.BF.223.247; 11.BF.240.157; 11.BF.240.158;
11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244;
11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158;
11.BF.244.196; 11.BF.244.223; 11.BF.244.240; 11.BF.244.244;
11.BF.244.243; 11.BF.244.247; 11.BF.247.157; 11.BF.247.158;
11.BF.247.196; 11.BF.247.223; 11.BF.247.240; 11.BF.247.244;
11.BF.247.243; 11.BF.247.247; Prodrugs of 11.CI 11.CI.4.157;
11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244;
11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196;
11.CI.5.223; 11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247;
11.CI.7.157; 11.CI.7.158; 11.CI.7.196; 11.CI.7.223; 11.CI.7.240;
11.CI.7.244; 11.CI.7.243; 11.CI.7.247; 11.CI.15.157; 11.CI.15.158;
11.CI.15.196; 11.CI.15.223; 11.CI.15.240; 11.CI.15.244;
11.CI.15.243; 11.CI.15.247; 11.CI.16.157; 11.CI.16.158;
11.CI.16.196; 11.CI.16.223; 11.CI.16.240; 11.CI.16.244;
11.CI.16.243; 11.CI.16.247; 11.CI.18.157; 11.CI.18.158;
11.CI.18.196; 11.CI.18.223; 11.CI.18.240; 11.CI.18.244;
11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158;
11.CI.26.196; 11.CI.26.223; 11.CI.26.240; 11.CI.26.244;
11.CI.26.243; 11.CI.26.247; 11.CI.27.157; 11.CI.27.158;
11.CI.27.196; 11.CI.27.223; 11.CI.27.240; 11.CI.27.244;
11.CI.27.243; 11.CI.27.247; 11.CI.29.157; 11.CI.29.158;
11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244;
11.CI.29.243; 11.CI.29.247; 11.CI.54.157; 11.CI.54.158;
11.CI.54.196; 11.CI.54.223; 11.CI.54.240; 11.CI.54.244;
11.CI.54.243; 11.CI.54.247; 11.CI.55.157; 11.CI.55.158;
11.CI.55.196; 11.CI.55.223; 11.CI.55.240; 11.CI.55.244;
11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158;
11.CI.56.196; 11.CI.56.223; 11.CI.56.240; 11.CI.56.244;
11.CI.56.243; 11.CI.56.247; 11.CI.157.157; 11.CI.157.158;
11.CI.157.196; 11.CI.157.223; 11.CI.157.240; 11.CI.157.244;
11.CI.157.243; 11.CI.157.247; 11.CI.196.157; 11.CI.196.158;
11.CI.196.196; 11.CI.196.223; 11.CI.196.240; 11.CI.196.244;
11.CI.196.243; 11.CI.196.247; 11.CI.223.157; 11.CI.223.158;
11.CI.223.196; 11.CI.223.223; 11.CI.223.240; 11.CI.223.244;
11.CI.223.243; 11.CI.223.247; 11.CI.240.157; 11.CI.240.158;
11.CI.240.196; 11.CI.240.223; 11.CI.240.240; 11.CI.240.244;
11.CI.240.243; 11.CI.240.247; 11.CI.244.157; 11.CI.244.158;
11.CI.244.196; 11.CI.244.223; 11.CI.244.240; 11.CI.244.244;
11.CI.244.243; 11.CI.244.247; 11.CI.247.157; 11.CI.247.158;
11.CI.247.196; 11.CI.247.223; 11.CI.247.240; 11.CI.247.244;
11.CI.247.243; 11.CI.247.247; Prodrugs of 11.CO 11.CO.4.157;
11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240; 11.CO.4.244;
11.CO.4.243; 11.CO.4.247; 11.CO.5.157; 11.CO.5.158; 11.CO.5.196;
11.CO.5.223; 11.CO.5.240; 11.CO.5.244; 11.CO.5.243; 11.CO.5.247;
11.CO.7.157; 11.CO.7.158; 11.CO.7.196; 11.CO.7.223; 11.CO.7.240;
11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157; 11.CO.15.158;
11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244;
11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158;
11.CO.16.196; 11.CO.16.223; 11.CO.16.240; 11.CO.16.244;
11.CO.16.243; 11.CO.16.247; 11.CO.18.157; 11.CO.18.158;
11.CO.18.196; 11.CO.18.223; 11.CO.18.240; 11.CO.18.244;
11.CO.18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158;
11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244;
11.CO.26.243; 11.CO.26.247; 11.CO.27.157; 11.CO.27.158;
11.CO.27.196; 11.CO.27.223; 11.CO.27.240; 11.CO.27.244;
11.CO.27.243; 11.CO.27.247; 11.CO.29.157; 11.CO.29.158;
11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244;
11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158;
11.CO.54.196; 11.CO.54.223; 11.CO.54.240; 11.CO.54.244;
11.CO.54.243; 11.CO.54.247; 11.CO.55.157; 11.CO.55.158;
11.CO.55.196; 11.CO.55.223; 11.CO.55.240; 11.CO.55.244;
11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158;
11.CO.56.196; 11.CO.56.223; 11.CO.56.240; 11.CO.56.244;
11.CO.56.243; 11.CO.56.247; 11.CO.157.157; 11.CO.157.158;
11.CO.157.196; 11.CO.157.223; 11.CO.157.240; 11.CO.157.244;
11.CO.157.243; 11.CO.157.247; 11.CO.196.157; 11.CO.196.158;
11.CO.196.196; 11.CO.196.223; 11.CO.196.240; 11.CO.196.244;
11.CO.196.243; 11.CO.196.247; 11.CO.223.157; 11.CO.223.158;
11.CO.223.196; 11.CO.223.223; 11.CO.223.240; 11.CO.223.244;
11.CO.223.243; 11.CO.223.247; 11.CO.240.157; 11.CO.240.158;
11.CO.240.196; 11.CO.240.223; 11.CO.240.240; 11.CO.240.244;
11.CO.240.243; 11.CO.240.247; 11.CO.244.157; 11.CO.244.158;
11.CO.244.196; 11.CO.244.223; 11.CO.244.240; 11.CO.244.244;
11.CO.244.243; 11.CO.244.247; 11.CO.247.157; 11.CO.247.158;
11.CO.247.196; 11.CO.247.223; 11.CO.247.240; 11.CO.247.244;
11.CO.247.243; 11.CO.247.247; Prodrugs of 12.AH 12.AH.4.157;
12.AH.4.158; 12.AH.4.196; 12.AH.4.223; 12.AH.4.240; 12.AH.4.244;
12.AH.4.243; 12.AH.4.247; 12.AH.5.157; 12.AH.5.158; 12.AH.5.196;
12.AH.5.223; 12.AH.5.240; 12.AH.5.244; 12.AH.5.243; 12.AH.5.247;
12.AH.7.157; 12.AH.7.158; 12.AH.7.196; 12.AH.7.223; 12.AH.7.240;
12.AH.7.244; 12.AH.7.243; 12.AH.7.247; 12.AH.15.157; 12.AH.15.158;
12.AH.15.196; 12.AH.15.223; 12.AH.15.240; 12.AH.15.244;
12.AH.15.243; 12.AH.15.247; 12.AH.16.157; 12.AH.16.158;
12.AH.16.196; 12.AH.16.223; 12.AH.16.240; 12.AH.16.244;
12.AH.16.243; 12.AH.16.247; 12.AH.18.157; 12.AH.18.158;
12.AH.18.196; 12.AH.18.223; 12.AH.18.240; 12.AH.18.244;
12.AH.18.243; 12.AH.18.247; 12.AH.26.157; 12.AH.26.158;
12.AH.26.196; 12.AH.26.223; 12.AH.26.240; 12.AH.26.244;
12.AH.26.243; 12.AH.26.247; 12.AH.27.157; 12.AH.27.158;
12.AH.27.196; 12.AH.27.223; 12.AH.27.240; 12.AH.27.244;
12.AH.27.243; 12.AH.27.247; 12.AH.29.157; 12.AH.29.158;
12.AH.29.196; 12.AH.29.223; 12.AH.29.240; 12.AH.29.244;
12.AH.29.243; 12.AH.29.247; 12.AH.54.157; 12.AH.54.158;
12.AH.54.196; 12.AH.54.223; 12.AH.54.240; 12.AH.54.244;
12.AH.54.243; 12.AH.54.247; 12.AH.55.157; 12.AH.55.158;
12.AH.55.196; 12.AH.55.223; 12.AH.55.240; 12.AH.55.244;
12.AH.55.243; 12.AH.55.247; 12.AH.56.157; 12.AH.56.158;
12.AH.56.196; 12.AH.56.223; 12.AH.56.240; 12.AH.56.244;
12.AH.56.243; 12.AH.56.247; 12.AH.157.157; 12.AH.157.158;
12.AH.157.196; 12.AH.157.223; 12.AH.157.240; 12.AH.157.244;
12.AH.157.243; 12.AH.157.247; 12.AH.196.157; 12.AH.196.158;
12.AH.196.196; 12.AH.196.223; 12.AH.196.240; 12.AH.196.244;
12.AH.196.243; 12.AH.196.247; 12.AH.223.157; 12.AH.223.158;
12.AH.223.196; 12.AH.223.223; 12.AH.223.240; 12.AH.223.244;
12.AH.223.243; 12.AH.223.247; 12.AH.240.157; 12.AH.240.158;
12.AH.240.196; 12.AH.240.223; 12.AH.240.240; 12.AH.240.244;
12.AH.240.243; 12.AH.240.247; 12.AH.244.157; 12.AH.244.158;
12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244;
12.AH.244.243; 12.AH.244.247; 12.AH.247.157; 12.AH.247.158;
12.AH.247.196; 12.AH.247.223; 12.AH.247.240; 12.AH.247.244;
12.AH.247.243; 12.AH.247.247; Prodrugs of 12.AJ 12.AJ.4.157;
12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244;
12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196;
12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247;
12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240;
12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ.15.157; 12.AJ.15.158;
12.AJ.15.196; 12.AJ.15.223; 12.AJ.15.240; 12.AJ.15.244;
12.AJ.15.243; 12.AJ.15.247; 12.AJ.16.157; 12.AJ.16.158;
12.AJ.16.196; 12.AJ.16.223; 12.AJ.16.240; 12.AJ.16.244;
12.AJ.16.243; 12.AJ.16.247; 12.AJ.18.157; 12.AJ.18.158;
12.AJ.18.196; 12.AJ.18.223; 12.AJ.18.240; 12.AJ.18.244;
12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157; 12.AJ.26.158;
12.AJ.26.196; 12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244;
12.AJ.26.243; 12.AJ.26.247; 12.AJ.27.157; 12.AJ.27.158;
12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240; 12.AJ.27.244;
12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158;
12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244;
12.AJ.29.243; 12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158;
12.AJ.54.196; 12.AJ.54.223; 12.AJ.54.240; 12.AJ.54.244;
12.AJ.54.243; 12.AJ.54.247; 12.AJ.55.157; 12.AJ.55.158;
12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240; 12.AJ.55.244;
12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158;
12.AJ.56.196; 12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244;
12.AJ.56.243; 12.AJ.56.247; 12.AJ.157.157; 12.AJ.157.158;
12.AJ.157.196; 12.AJ.157.223; 12.AJ.157.240; 12.AJ.157.244;
12.AJ.157.243; 12.AJ.157.247; 12.AJ.196.157; 12.AJ.196.158;
12.AJ.196.196; 12.AJ.196.223; 12.AJ.196.240; 12.AJ.196.244;
12.AJ.196.243; 12.AJ.196.247; 12.AJ.223.157; 12.AJ.223.158;
12.AJ.223.196; 12.AJ.223.223; 12.AJ.223.240; 12.AJ.223.244;
12.AJ.223.243; 12.AJ.223.247; 12.AJ.240.157; 12.AJ.240.158;
12.AJ.240.196; 12.AJ.240.223; 12.AJ.240.240; 12.AJ.240.244;
12.AJ.240.243; 12.AJ.240.247; 12.AJ.244.157; 12.AJ.244.158;
12.AJ.244.196; 12.AJ.244.223; 12.AJ.244.240; 12.AJ.244.244;
12.AJ.244.243; 12.AJ.244.247; 12.AJ.247.157; 12.AJ.247.158;
12.AJ.247.196; 12.AJ.247.223; 12.AJ.247.240; 12.AJ.247.244;
12.AJ.247.243; 12.AJ.247.247; Prodrugs of 12.AN 12.AN.4.157;
12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240; 12.AN.4.244;
12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158; 12.AN.5.196;
12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243; 12.AN.5.247;
12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223; 12.AN.7.240;
12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157; 12.AN.15.158;
12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244;
12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158;
12.AN.16.196; 12.AN.16.223; 12.AN.16.240; 12.AN.16.244;
12.AN.16.243; 12.AN.16.247; 12.AN.18.157; 12.AN.18.158;
12.AN.18.196; 12.AN.18.223; 12.AN.18.240; 12.AN.18.244;
12.AN.18.243; 12.AN.18.247; 12.AN.26.157; 12.AN.26.158;
12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244;
12.AN.26.243; 12.AN.26.247; 12.AN.27.157; 12.AN.27.158;
12.AN.27.196; 12.AN.27.223; 12.AN.27.240; 12.AN.27.244;
12.AN.27.243; 12.AN.27.247; 12.AN.29.157; 12.AN.29.158;
12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244;
12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158;
12.AN.54.196; 12.AN.54.223; 12.AN.54.240; 12.AN.54.244;
12.AN.54.243; 12.AN.54.247; 12.AN.55.157; 12.AN.55.158;
12.AN.55.196; 12.AN.55.223; 12.AN.55.240; 12.AN.55.244;
12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158;
12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244;
12.AN.56.243; 12.AN.56.247; 12.AN.157.157; 12.AN.157.158;
12.AN.157.196; 12.AN.157.223; 12.AN.157.240; 12.AN.157.244;
12.AN.157.243; 12.AN.157.247; 12.AN.196.157; 12.AN.196.158;
12.AN.196.196; 12.AN.196.223; 12.AN.196.240; 12.AN.196.244;
12.AN.196.243; 12.AN.196.247; 12.AN.223.157; 12.AN.223.158;
12.AN.223.196; 12.AN.223.223; 12.AN.223.240; 12.AN.223.244;
12.AN.223.243; 12.AN.223.247; 12.AN.240.157; 12.AN.240.158;
12.AN.240.196; 12.AN.240.223; 12.AN.240.240; 12.AN.240.244;
12.AN.240.243; 12.AN.240.247; 12.AN.244.157; 12.AN.244.158;
12.AN.244.196; 12.AN.244.223; 12.AN.244.240; 12.AN.244.244;
12.AN.244.243; 12.AN.244.247; 12.AN.247.157; 12.AN.247.158;
12.AN.247.196; 12.AN.247.223; 12.AN.247.240; 12.AN.247.244;
12.AN.247.243; 12.AN.247.247; Prodrugs of 12.AP 12.AP.4.157;
12.AP.4.158; 12.AP.4.196; 12.AP.4.223; 12.AP.4.240; 12.AP.4.244;
12.AP.4.243; 12.AP.4.247; 12.AP.5.157; 12.AP.5.158; 12.AP.5.196;
12.AP.5.223; 12.AP.5.240; 12.AP.5.244; 12.AP.5.243; 12.AP.5.247;
12.AP.7.157; 12.AP.7.158; 12.AP.7.196; 12.AP.7.223; 12.AP.7.240;
12.AP.7.244; 12.AP.7.243; 12.AP.7.247; 12.AP.15.157; 12.AP.15.158;
12.AP.15.196; 12.AP.15.223; 12.AP.15.240; 12.AP.15.244;
12.AP.15.243; 12.AP.15.247; 12.AP.16.157; 12.AP.16.158;
12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244;
12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158;
12.AP.18.196; 12.AP.18.223; 12.AP.18.240;
12.AP.18.244; 12.AP.18.243; 12.AP.18.247; 12.AP.26.157;
12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240;
12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157;
12.AP.27.158; 12.AP.27.196; 12.AP.27.223; 12.AP.27.240;
12.AP.27.244; 12.AP.27.243; 12.AP.27.247; 12.AP.29.157;
12.AP.29.158; 12.AP.29.196; 12.AP.29.223; 12.AP.29.240;
12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157;
12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240;
12.AP.54.244; 12.AP.54.243; 12.AP.54.247; 12.AP.55.157;
12.AP.55.158; 12.AP.55.196; 12.AP.55.223; 12.AP.55.240;
12.AP.55.244; 12.AP.55.243; 12.AP.55.247; 12.AP.56.157;
12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240;
12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP.157.157;
12.AP.157.158; 12.AP.157.196; 12.AP.157.223; 12.AP.157.240;
12.AP.157.244; 12.AP.157.243; 12.AP.157.247; 12.AP.196.157;
12.AP.196.158; 12.AP.196.196; 12.AP.196.223; 12.AP.196.240;
12.AP.196.244; 12.AP.196.243; 12.AP.196.247; 12.AP.223.157;
12.AP.223.158; 12.AP.223.196; 12.AP.223.223; 12.AP.223.240;
12.AP.223.244; 12.AP.223.243; 12.AP.223.247; 12.AP.240.157;
12.AP.240.158; 12.AP.240.196; 12.AP.240.223; 12.AP.240.240;
12.AP.240.244; 12.AP.240.243; 12.AP.240.247; 12.AP.244.157;
12.AP.244.158; 12.AP.244.196; 12.AP.244.223; 12.AP.244.240;
12.AP.244.244; 12.AP.244.243; 12.AP.244.247; 12.AP.247.157;
12.AP.247.158; 12.AP.247.196; 12.AP.247.223; 12.AP.247.240;
12.AP.247.244; 12.AP.247.243; 12.AP.247.247; Prodrugs of 12.AZ
12.AZ.4.157; 12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240;
12.AZ.4.244; 12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158;
12.AZ.5.196; 12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243;
12.AZ.5.247; 12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223;
12.AZ.7.240; 12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157;
12.AZ.15.158; 12.AZ.15.196; 12.AZ.15.223; 12.AZ.15.240;
12.AZ.15.244; 12.AZ.15.243; 12.AZ.15.247; 12.AZ.16.157;
12.AZ.16.158; 12.AZ.16.196; 12.AZ.16.223; 12.AZ.16.240;
12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157;
12.AZ.18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240;
12.AZ.18.244; 12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157;
12.AZ.26.158; 12.AZ.26.196; 12.AZ.26.223; 12.AZ.26.240;
12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247; 12.AZ.27.157;
12.AZ.27.158; 12.AZ.27.196; 12.AZ.27.223; 12.AZ.27.240;
12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157;
12.AZ.29.158; 12.AZ.29.196; 12.AZ.29.223; 12.AZ.29.240;
12.AZ.29.244; 12.AZ.29.243; 12.AZ.29.247; 12.AZ.54.157;
12.AZ.54.158; 12.AZ.54.196; 12.AZ.54.223; 12.AZ.54.240;
12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157;
12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240;
12.AZ.55.244; 12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157;
12.AZ.56.158; 12.AZ.56.196; 12.AZ.56.223; 12.AZ.56.240;
12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247; 12.AZ.157.157;
12.AZ.157.158; 12.AZ.157.196; 12.AZ.157.223; 12.AZ.157.240;
12.AZ.157.244; 12.AZ.157.243; 12.AZ.157.247; 12.AZ.196.157;
12.AZ.196.158; 12.AZ.196.196; 12.AZ.196.223; 12.AZ.196.240;
12.AZ.196.244; 12.AZ.196.243; 12.AZ.196.247; 12.AZ.223.157;
12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223; 12.AZ.223.240;
12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247; 12.AZ.240.157;
12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223; 12.AZ.240.240;
12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247; 12.AZ.244.157;
12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223; 12.AZ.244.240;
12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247; 12.AZ.247.157;
12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223; 12.AZ.247.240;
12.AZ.247.244; 12.AZ.247.243; 12.AZ.247.247; Prodrugs of 12.BF
12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240;
12.BF.4.244; 12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158;
12.BF.5.196; 12.BF.5.223; 12.BF.5.240; 12.BF.5.244; 12.BF.5.243;
12.BF.5.247; 12.BF.7.157; 12.BF.7.158; 12.BF.7.196; 12.BF.7.223;
12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247; 12.BF.15.157;
12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240;
12.BF.15.244; 12.BF.15.243; 12.BF.15.247; 12.BF.16.157;
12.BF.16.158; 12.BF.16.196; 12.BF.16.223; 12.BF.16.240;
12.BF.16.244; 12.BF.16.243; 12.BF.16.247; 12.BF.18.157;
12.BF.18.158; 12.BF.18.196; 12.BF.18.223; 12.BF.18.240;
12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157;
12.BF.26.158; 12.BF.26.196; 12.BF.26.223; 12.BF.26.240;
12.BF.26.244; 12.BF.26.243; 12.BF.26.247; 12.BF.27.157;
12.BF.27.158; 12.BF.27.196; 12.BF.27.223; 12.BF.27.240;
12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12.BF.29.157;
12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240;
12.BF.29.244; 12.BF.29.243; 12.BF.29.247; 12.BF.54.157;
12.BF.54.158; 12.BF.54.196; 12.BF.54.223; 12.BF.54.240;
12.BF.54.244; 12.BF.54.243; 12.BF.54.247; 12.BF.55.157;
12.BF.55.158; 12.BF.55.196; 12.BF.55.223; 12.BF.55.240;
12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157;
12.BF.56.158; 12.BF.56.196; 12.BF.56.223; 12.BF.56.240;
12.BF.56.244; 12.BF.56.243; 12.BF.56.247; 12.BF.157.157;
12.BF.157.158; 12.BF.157.196; 12.BF.157.223; 12.BF.157.240;
12.BF.157.244; 12.BF.157.243; 12.BF.157.247; 12.BF.196.157;
12.BF.196.158; 12.BF.196.196; 12.BF.196.223; 12.BF.196.240;
12.BF.196.244; 12.BF.196.243; 12.BF.196.247; 12.BF.223.157;
12.BF.223.158; 12.BF.223.196; 12.BF.223.223; 12.BF.223.240;
12.BF.223.244; 12.BF.223.243; 12.BF.223.247; 12.BF.240.157;
12.BF.240.158; 12.BF.240.196; 12.BF.240.223; 12.BF.240.240;
12.BF.240.244; 12.BF.240.243; 12.BF.240.247; 12.BF.244.157;
12.BF.244.158; 12.BF.244.196; 12.BF.244.223; 12.BF.244.240;
12.BF.244.244; 12.BF.244.243; 12.BF.244.247; 12.BF.247.157;
12.BF.247.158; 12.BF.247.196; 12.BF.247.223; 12.BF.247.240;
12.BF.247.244; 12.BF.247.243; 12.BF.247.247; Prodrugs of 12.CI
12.CI.4.157; 12.CI.4.158; 12.CI.4.196; 12.CI.4.223; 12.CI.4.240;
12.CI.4.244; 12.CI.4.243; 12.CI.4.247; 12.CI.5.157; 12.CI.5.158;
12.CI.5.196; 12.CI.5.223; 12.CI.5.240; 12.CI.5.244; 12.CI.5.243;
12.CI.5.247; 12.CI.7.157; 12.CI.7.158; 12.CI.7.196; 12.CI.7.223;
12.CI.7.240; 12.CI.7.244; 12.CI.7.243; 12.CI.7.247; 12.CI.15.157;
12.CI.15.158; 12.CI.15.196; 12.CI.15.223; 12.CI.15.240;
12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157;
12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240;
12.CI.16.244; 12.CI.16.243; 12.CI.16.247; 12.CI.18.157;
12.CI.18.158; 12.CI.18.196; 12.CI.18.223; 12.CI.18.240;
12.CI.18.244; 12.CI.18.243; 12.CI.18.247; 12.CI.26.157;
12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240;
12.CI.26.244; 12.CI.26.243; 12.CI.26.247; 12.CI.27.157;
12.CI.27.158; 12.CI.27.196; 12.CI.27.223; 12.CI.27.240;
12.CI.27.244; 12.CI.27.243; 12.CI.27.247; 12.CI.29.157;
12.CI.29.158; 12.CI.29.196; 12.CI.29.223; 12.CI.29.240;
12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157;
12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240;
12.CI.54.244; 12.CI.54.243; 12.CI.54.247; 12.CI.55.157;
12.CI.55.158; 12.CI.55.196; 12.CI.55.223; 12.CI.55.240;
12.CI.55.244; 12.CI.55.243; 12.CI.55.247; 12.CI.56.157;
12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240;
12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157;
12.CI.157.158; 12.CI.157.196; 12.CI.157.223; 12.CI.157.240;
12.CI.157.244; 12.CI.157.243; 12.CI.157.247; 12.CI.196.157;
12.CI.196.158; 12.CI.196.196; 12.CI.196.223; 12.CI.196.240;
12.CI.196.244; 12.CI.196.243; 12.CI.196.247; 12.CI.223.157;
12.CI.223.158; 12.CI.223.196; 12.CI.223.223; 12.CI.223.240;
12.CI.223.244; 12.CI.223.243; 12.CI.223.247; 12.CI.240.157;
12.CI.240.158; 12.CI.240.196; 12.CI.240.223; 12.CI.240.240;
12.CI.240.244; 12.CI.240.243; 12.CI.240.247; 12.CI.244.157;
12.CI.244.158; 12.CI.244.196; 12.CI.244.223; 12.CI.244.240;
12.CI.244.244; 12.CI.244.243; 12.CI.244.247; 12.CI.247.157;
12.CI.247.158; 12.CI.247.196; 12.CI.247.223; 12.CI.247.240;
12.CI.247.244; 12.CI.247.243; 12.CI.247.247; Prodrugs of 12.CO
12.CO.4.157; 12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240;
12.CO.4.244; 12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158;
12.CO.5.196; 12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.CO.5.243;
12.CO.5.247; 12.CO.7.157; 12.CO.7.158; 12.CO.7.196; 12.CO.7.223;
12.CO.7.240; 12.CO.7.244; 12.CO.7.243; 12.CO.7.247; 12.CO.15.157;
12.CO.15.158; 12.CO.15.196; 12.CO.15.223; 12.CO.15.240;
12.CO.15.244; 12.CO.15.243; 12.CO.15.247; 12.CO.16.157;
12.CO.16.158; 12.CO.16.196; 12.CO.16.223; 12.CO.16.240;
12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157;
12.CO.18.158; 12.CO.18.196; 12.CO.18.223; 12.CO.18.240;
12.CO.18.244; 12.CO.18.243; 12.CO.18.247; 12.CO.26.157;
12.CO.26.158; 12.CO.26.196; 12.CO.26.223; 12.CO.26.240;
12.CO.26.244; 12.CO.26.243; 12.CO.26.247; 12.CO.27.157;
12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240;
12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157;
12.CO.29.158; 12.CO.29.196; 12.CO.29.223; 12.CO.29.240;
12.CO.29.244; 12.CO.29.243; 12.CO.29.247; 12.CO.54.157;
12.CO.54.158; 12.CO.54.196; 12.CO.54.223; 12.CO.54.240;
12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157;
12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240;
12.CO.55.244; 12.CO.55.243; 12.CO.55.247; 12.CO.56.157;
12.CO.56.158; 12.CO.56.196; 12.CO.56.223; 12.CO.56.240;
12.CO.56.244; 12.CO.56.243; 12.CO.56.247; 12.CO.157.157;
12.CO.157.158; 12.CO.157.196; 12.CO.157.223; 12.CO.157.240;
12.CO.157.244; 12.CO.157.243; 12.CO.157.247; 12.CO.196.157;
12.CO.196.158; 12.CO.196.196; 12.CO.196.223; 12.CO.196.240;
12.CO.196.244; 12.CO.196.243; 12.CO.196.247; 12.CO.223.157;
12.CO.223.158; 12.CO.223.196; 12.CO.223.223; 12.CO.223.240;
12.CO.223.244; 12.CO.223.243; 12.CO.223.247; 12.CO.240.157;
12.CO.240.158; 12.CO.240.196; 12.CO.240.223; 12.CO.240.240;
12.CO.240.244; 12.CO.240.243; 12.CO.240.247; 12.CO.244.157;
12.CO.244.158; 12.CO.244.196; 12.CO.244.223; 12.CO.244.240;
12.CO.244.244; 12.CO.244.243; 12.CO.244.247; 12.CO.247.157;
12.CO.247.158; 12.CO.247.196; 12.CO.247.223; 12.CO.247.240;
12.CO.247.244; 12.CO.247.243; 12.CO.247.247. Prodrugs of 13.B
13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231;
13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239;
13.B.228.154; 13.B.228.157; 13.B.228.166; 13.B.228.169;
13.B.228.172; 13.B.228.175; 13.B.228.240; 13.B.228.244;
13.B.229.228; 13.B.229.229; 13.B.229.230; 13.B.229.231;
13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239;
13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169;
13.B.229.172; 13.B.229.175; 13.B.229.240; 13.B.229.244;
13.B.230.228; 13.B.230.229; 13.B.230.230; 13.B.230.231;
13.B.230.236; 13.B.230.237; 13.B.230.238; 13.B.230.239;
13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169;
13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244;
13.B.231.228; 13.B.231.229; 13.B.231.230; 13.B.231.231;
13.B.231.236; 13.B.231.237; 13.B.231.238; 13.B.231.239;
13.B.231.154; 13.B.231.157; 13.B.231.166; 13.B.231.169;
13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244;
13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231;
13.B.236.236; 13.B.236.237; 13.B.236.238; 13.B.236.239;
13.B.236.154; 13.B.236.157; 13.B.236.166; 13.B.236.169;
13.B.236.172; 13.B.236.175; 13.B.236.240; 13.B.236.244;
13.B.237.228; 13.B.237.229; 13.B.237.230; 13.B.237.231;
13.B.237.236; 13.B.237.237; 13.B.237.238; 13.B.237.239;
13.B.237.154; 13.B.237.157; 13.B.237.166; 13.B.237.169;
13.B.237.172; 13.B.237.175; 13.B.237.240; 13.B.237.244;
13.B.238.228; 13.B.238.229; 13.B.238.230; 13.B.238.231;
13.B.238.236; 13.B.238.237; 13.B.238.238; 13.B.238.239;
13.B.238.154; 13.B.238.157; 13.B.238.166; 13.B.238.169;
13.B.238.172; 13.B.238.175; 13.B.238.240; 13.B.238.244;
13.B.239.228; 13.B.239.229; 13.B.239.230; 13.B.239.231;
13.B.239.236; 13.B.239.237; 13.B.239.238; 13.B.239.239;
13.B.239.154; 13.B.239.157; 13.B.239.166; 13.B.239.169;
13.B.239.172; 13.B.239.175; 13.B.239.240; 13.B.239.244;
13.B.154.228; 13.B.154.229; 13.B.154.230; 13.B.154.231;
13.B.154.236; 13.B.154.237; 13.B.154.238; 13.B.154.239;
13.B.154.154; 13.B.154.157; 13.B.154.166; 13.B.154.169;
13.B.154.172; 13.B.154.175; 13.B.154.240; 13.B.154.244;
13.B.157.228; 13.B.157.229; 13.B.157.230; 13.B.157.231;
13.B.157.236; 13.B.157.237; 13.B.157.238; 13.B.157.239;
13.B.157.154; 13.B.157.157; 13.B.157.166; 13.B.157.169;
13.B.157.172; 13.B.157.175; 13.B.157.240; 13.B.157.244;
13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231;
13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239;
13.B.166.154; 13.B.166.157; 13.B.166.166; 13.B.166.169;
13.B.166.172; 13.B.166.175; 13.B.166.240; 13.B.166.244;
13.B.169.228; 13.B.169.229; 13.B.169.230; 13.B.169.231;
13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239;
13.B.169.154; 13.B.169.157; 13.B.169.166; 13.B.169.169;
13.B.169.172; 13.B.169.175; 13.B.169.240; 13.B.169.244;
13.B.172.228; 13.B.172.229; 13.B.172.230; 13.B.172.231;
13.B.172.236; 13.B.172.237; 13.B.172.238; 13.B.172.239;
13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169;
13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244;
13.B.175.228; 13.B.175.229; 13.B.175.230; 13.B.175.231;
13.B.175.236; 13.B.175.237; 13.B.175.238; 13.B.175.239;
13.B.175.154; 13.B.175.157; 13.B.175.166; 13.B.175.169;
13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244;
13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231;
13.B.240.236; 13.B.240.237; 13.B.240.238; 13.B.240.239;
13.B.240.154; 13.B.240.157; 13.B.240.166; 13.B.240.169;
13.B.240.172; 13.B.240.175; 13.B.240.240; 13.B.240.244;
13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231;
13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239;
13.B.244.154; 13.B.244.157; 13.B.244.166; 13.B.244.169;
13.B.244.172; 13.B.244.175; 13.B.244.240; 13.B.244.244; Prodrugs of
13.D 13.D.228.228; 13.D.228.229; 13.D.228.230; 13.D.228.231;
13.D.228.236; 13.D.228.237; 13.D.228.238; 13.D.228.239;
13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169;
13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244;
13.D.229.228; 13.D.229.229; 13.D.229.230; 13.D.229.231;
13.D.229.236; 13.D.229.237; 13.D.229.238; 13.D.229.239;
13.D.229.154; 13.D.229.157; 13.D.229.166; 13.D.229.169;
13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244;
13.D.230.228; 13.D.230.229; 13.D.230.230; 13.D.230.231;
13.D.230.236; 13.D.230.237; 13.D.230.238; 13.D.230.239;
13.D.230.154; 13.D.230.157; 13.D.230.166; 13.D.230.169;
13.D.230.172; 13.D.230.175; 13.D.230.240; 13.D.230.244;
13.D.231.228; 13.D.231.229; 13.D.231.230; 13.D.231.231;
13.D.231.236; 13.D.231.237; 13.D.231.238; 13.D.231.239;
13.D.231.154; 13.D.231.157; 13.D.231.166; 13.D.231.169;
13.D.231.172; 13.D.231.175; 13.D.231.240; 13.D.231.244;
13.D.236.228; 13.D.236.229; 13.D.236.230; 13.D.236.231;
13.D.236.236; 13.D.236.237; 13.D.236.238; 13.D.236.239;
13.D.236.154; 13.D.236.157; 13.D.236.166; 13.D.236.169;
13.D.236.172; 13.D.236.175; 13.D.236.240; 13.D.236.244;
13.D.237.228; 13.D.237.229; 13.D.237.230; 13.D.237.231;
13.D.237.236;
13.D.237.237; 13.D.237.238; 13.D.237.239; 13.D.237.154;
13.D.237.157; 13.D.237.166; 13.D.237.169; 13.D.237.172;
13.D.237.175; 13.D.237.240; 13.D.237.244; 13.D.238.228;
13.D.238.229; 13.D.238.230; 13.D.238.231; 13.D.238.236;
13.D.238.237; 13.D.238.238; 13.D.238.239; 13.D.238.154;
13.D.238.157; 13.D.238.166; 13.D.238.169; 13.D.238.172;
13.D.238.175; 13.D.238.240; 13.D.238.244; 13.D.239.228;
13.D.239.229; 13.D.239.230; 13.D.239.231; 13.D.239.236;
13.D.239.237; 13.D.239.238; 13.D.239.239; 13.D.239.154;
13.D.239.157; 13.D.239.166; 13.D.239.169; 13.D.239.172;
13.D.239.175; 13.D.239.240; 13.D.239.244; 13.D.154.228;
13.D.154.229; 13.D.154.230; 13.D.154.231; 13.D.154.236;
13.D.154.237; 13.D.154.238; 13.D.154.239; 13.D.154.154;
13.D.154.157; 13.D.154.166; 13.D.154.169; 13.D.154.172;
13.D.154.175; 13.D.154.240; 13.D.154.244; 13.D.157.228;
13.D.157.229; 13.D.157.230; 13.D.157.231; 13.D.157.236;
13.D.157.237; 13.D.157.238; 13.D.157.239; 13.D.157.154;
13.D.157.157; 13.D.157.166; 13.D.157.169; 13.D.157.172;
13.D.157.175; 13.D.157.240; 13.D.157.244; 13.D.166.228;
13.D.166.229; 13.D.166.230; 13.D.166.231; 13.D.166.236;
13.D.166.237; 13.D.166.238; 13.D.166.239; 13.D.166.154;
13.D.166.157; 13.D.166.166; 13.D.166.169; 13.D.166.172;
13.D.166.175; 13.D.166.240; 13.D.166.244; 13.D.169.228;
13.D.169.229; 13.D.169.230; 13.D.169.231; 13.D.169.236;
13.D.169.237; 13.D.169.238; 13.D.169.239; 13.D.169.154;
13.D.169.157; 13.D.169.166; 13.D.169.169; 13.D.169.172;
13.D.169.175; 13.D.169.240; 13.D.169.244; 13.D.172.228;
13.D.172.229; 13.D.172.230; 13.D.172.231; 13.D.172.236;
13.D.172.237; 13.D.172.238; 13.D.172.239; 13.D.172.154;
13.D.172.157; 13.D.172.166; 13.D.172.169; 13.D.172.172;
13.D.172.175; 13.D.172.240; 13.D.172.244; 13.D.175.228;
13.D.175.229; 13.D.175.230; 13.D.175.231; 13.D.175.236;
13.D.175.237; 13.D.175.238; 13.D.175.239; 13.D.175.154;
13.D.175.157; 13.D.175.166; 13.D.175.169; 13.D.175.172;
13.D.175.175; 13.D.175.240; 13.D.175.244; 13.D.240.228;
13.D.240.229; 13.D.240.230; 13.D.240.231; 13.D.240.236;
13.D.240.237; 13.D.240.238; 13.D.240.239; 13.D.240.154;
13.D.240.157; 13.D.240.166; 13.D.240.169; 13.D.240.172;
13.D.240.175; 13.D.240.240; 13.D.240.244; 13.D.244.228;
13.D.244.229; 13.D.244.230; 13.D.244.231; 13.D.244.236;
13.D.244.237; 13.D.244.238; 13.D.244.239; 13.D.244.154;
13.D.244.157; 13.D.244.166; 13.D.244.169; 13.D.244.172;
13.D.244.175; 13.D.244.240; 13.D.244.244; Prodrugs of 13.E
13.E.228.228; 13.E.228.229; 13.E.228.230; 13.E.228.231;
13.E.228.236; 13.E.228.237; 13.E.228.238; 13.E.228.239;
13.E.228.154; 13.E.228.157; 13.E.228.166; 13.E.228.169;
13.E.228.172; 13.E.228.175; 13.E.228.240; 13.E.228.244;
13.E.229.228; 13.E.229.229; 13.E.229.230; 13.E.229.231;
13.E.229.236; 13.E.229.237; 13.E.229.238; 13.E.229.239;
13.E.229.154; 13.E.229.157; 13.E.229.166; 13.E.229.169;
13.E.229.172; 13.E.229.175; 13.E.229.240; 13.E.229.244;
13.E.230.228; 13.E.230.229; 13.E.230.230; 13.E.230.231;
13.E.230.236; 13.E.230.237; 13.E.230.238; 13.E.230.239;
13.E.230.154; 13.E.230.157; 13.E.230.166; 13.E.230.169;
13.E.230.172; 13.E.230.175; 13.E.230.240; 13.E.230.244;
13.E.231.228; 13.E.231.229; 13.E.231.230; 13.E.231.231;
13.E.231.236; 13.E.231.237; 13.E.231.238; 13.E.231.239;
13.E.231.154; 13.E.231.157; 13.E.231.166; 13.E.231.169;
13.E.231.172; 13.E.231.175; 13.E.231.240; 13.E.231.244;
13.E.236.228; 13.E.236.229; 13.E.236.230; 13.E.236.231;
13.E.236.236; 13.E.236.237; 13.E.236.238; 13.E.236.239;
13.E.236.154; 13.E.236.157; 13.E.236.166; 13.E.236.169;
13.E.236.172; 13.E.236.175; 13.E.236.240; 13.E.236.244;
13.E.237.228; 13.E.237.229; 13.E.237.230; 13.E.237.231;
13.E.237.236; 13.E.237.237; 13.E.237.238; 13.E.237.239;
13.E.237.154; 13.E.237.157; 13.E.237.166; 13.E.237.169;
13.E.237.172; 13.E.237.175; 13.E.237.240; 13.E.237.244;
13.E.238.228; 13.E.238.229; 13.E.238.230; 13.E.238.231;
13.E.238.236; 13.E.238.237; 13.E.238.238; 13.E.238.239;
13.E.238.154; 13.E.238.157; 13.E.238.166; 13.E.238.169;
13.E.238.172; 13.E.238.175; 13.E.238.240; 13.E.238.244;
13.E.239.228; 13.E.239.229; 13.E.239.230; 13.E.239.231;
13.E.239.236; 13.E.239.237; 13.E.239.238; 13.E.239.239;
13.E.239.154; 13.E.239.157; 13.E.239.166; 13.E.239.169;
13.E.239.172; 13.E.239.175; 13.E.239.240; 13.E.239.244;
13.E.154.228; 13.E.154.229; 13.E.154.230; 13.E.154.231;
13.E.154.236; 13.E.154.237; 13.E.154.238; 13.E.154.239;
13.E.154.154; 13.E.154.157; 13.E.154.166; 13.E.154.169;
13.E.154.172; 13.E.154.175; 13.E.154.240; 13.E.154.244;
13.E.157.228; 13.E.157.229; 13.E.157.230; 13.E.157.231;
13.E.157.236; 13.E.157.237; 13.E.157.238; 13.E.157.239;
13.E.157.154; 13.E.157.157; 13.E.157.166; 13.E.157.169;
13.E.157.172; 13.E.157.175; 13.E.157.240; 13.E.157.244;
13.E.166.228; 13.E.166.229; 13.E.166.230; 13.E.166.231;
13.E.166.236; 13.E.166.237; 13.E.166.238; 13.E.166.239;
13.E.166.154; 13.E.166.157; 13.E.166.166; 13.E.166.169;
13.E.166.172; 13.E.166.175; 13.E.166.240; 13.E.166.244;
13.E.169.228; 13.E.169.229; 13.E.169.230; 13.E.169.231;
13.E.169.236; 13.E.169.237; 13.E.169.238; 13.E.169.239;
13.E.169.154; 13.E.169.157; 13.E.169.166; 13.E.169.169;
13.E.169.172; 13.E.169.175; 13.E.169.240; 13.E.169.244;
13.E.172.228; 13.E.172.229; 13.E.172.230; 13.E.172.231;
13.E.172.236; 13.E.172.237; 13.E.172.238; 13.E.172.239;
13.E.172.154; 13.E.172.157; 13.E.172.166; 13.E.172.169;
13.E.172.172; 13.E.172.175; 13.E.172.240; 13.E.172.244;
13.E.175.228; 13.E.175.229; 13.E.175.230; 13.E.175.231;
13.E.175.236; 13.E.175.237; 13.E.175.238; 13.E.175.239;
13.E.175.154; 13.E.175.157; 13.E.175.166; 13.E.175.169;
13.E.175.172; 13.E.175.175; 13.E.175.240; 13.E.175.244;
13.E.240.228; 13.E.240.229; 13.E.240.230; 13.E.240.231;
13.E.240.236; 13.E.240.237; 13.E.240.238; 13.E.240.239;
13.E.240.154; 13.E.240.157; 13.E.240.166; 13.E.240.169;
13.E.240.172; 13.E.240.175; 13.E.240.240; 13.E.240.244;
13.E.244.228; 13.E.244.229; 13.E.244.230; 13.E.244.231;
13.E.244.236; 13.E.244.237; 13.E.244.238; 13.E.244.239;
13.E.244.154; 13.E.244.157; 13.E.244.166; 13.E.244.169;
13.E.244.172; 13.E.244.175; 13.E.244.240; 13.E.244.244; Prodrugs of
13.G 13.G.228.228; 13.G.228.229; 13.G.228.230; 13.G.228.231;
13.G.228.236; 13.G.228.237; 13.G.228.238; 13.G.228.239;
13.G.228.154; 13.G.228.157; 13.G.228.166; 13.G.228.169;
13.G.228.172; 13.G.228.175; 13.G.228.240; 13.G.228.244;
13.G.229.228; 13.G.229.229; 13.G.229.230; 13.G.229.231;
13.G.229.236; 13.G.229.237; 13.G.229.238; 13.G.229.239;
13.G.229.154; 13.G.229.157; 13.G.229.166; 13.G.229.169;
13.G.229.172; 13.G.229.175; 13.G.229.240; 13.G.229.244;
13.G.230.228; 13.G.230.229; 13.G.230.230; 13.G.230.231;
13.G.230.236; 13.G.230.237; 13.G.230.238; 13.G.230.239;
13.G.230.154; 13.G.230.157; 13.G.230.166; 13.G.230.169;
13.G.230.172; 13.G.230.175; 13.G.230.240; 13.G.230.244;
13.G.231.228; 13.G.231.229; 13.G.231.230; 13.G.231.231;
13.G.231.236; 13.G.231.237; 13.G.231.238; 13.G.231.239;
13.G.231.154; 13.G.231.157; 13.G.231.166; 13.G.231.169;
13.G.231.172; 13.G.231.175; 13.G.231.240; 13.G.231.244;
13.G.236.228; 13.G.236.229; 13.G.236.230; 13.G.236.231;
13.G.236.236; 13.G.236.237; 13.G.236.238; 13.G.236.239;
13.G.236.154; 13.G.236.157; 13.G.236.166; 13.G.236.169;
13.G.236.172; 13.G.236.175; 13.G.236.240; 13.G.236.244;
13.G.237.228; 13.G.237.229; 13.G.237.230; 13.G.237.231;
13.G.237.236; 13.G.237.237; 13.G.237.238; 13.G.237.239;
13.G.237.154; 13.G.237.157; 13.G.237.166; 13.G.237.169;
13.G.237.172; 13.G.237.175; 13.G.237.240; 13.G.237.244;
13.G.238.228; 13.G.238.229; 13.G.238.230; 13.G.238.231;
13.G.238.236; 13.G.238.237; 13.G.238.238; 13.G.238.239;
13.G.238.154; 13.G.238.157; 13.G.238.166; 13.G.238.169;
13.G.238.172; 13.G.238.175; 13.G.238.240; 13.G.238.244;
13.G.239.228; 13.G.239.229; 13.G.239.230; 13.G.239.231;
13.G.239.236; 13.G.239.237; 13.G.239.238; 13.G.239.239;
13.G.239.154; 13.G.239.157; 13.G.239.166; 13.G.239.169;
13.G.239.172; 13.G.239.175; 13.G.239.240; 13.G.239.244;
13.G.154.228; 13.G.154.229; 13.G.154.230; 13.G.154.231;
13.G.154.236; 13.G.154.237; 13.G.154.238; 13.G.154.239;
13.G.154.154; 13.G.154.157; 13.G.154.166; 13.G.154.169;
13.G.154.172; 13.G.154.175; 13.G.154.240; 13.G.154.244;
13.G.157.228; 13.G.157.229; 13.G.157.230; 13.G.157.231;
13.G.157.236; 13.G.157.237; 13.G.157.238; 13.G.157.239;
13.G.157.154; 13.G.157.157; 13.G.157.166; 13.G.157.169;
13.G.157.172; 13.G.157.175; 13.G.157.240; 13.G.157.244;
13.G.166.228; 13.G.166.229; 13.G.166.230; 13.G.166.231;
13.G.166.236; 13.G.166.237; 13.G.166.238; 13.G.166.239;
13.G.166.154; 13.G.166.157; 13.G.166.166; 13.G.166.169;
13.G.166.172; 13.G.166.175; 13.G.166.240; 13.G.166.244;
13.G.169.228; 13.G.169.229; 13.G.169.230; 13.G.169.231;
13.G.169.236; 13.G.169.237; 13.G.169.238; 13.G.169.239;
13.G.169.154; 13.G.169.157; 13.G.169.166; 13.G.169.169;
13.G.169.172; 13.G.169.175; 13.G.169.240; 13.G.169.244;
13.G.172.228; 13.G.172.229; 13.G.172.230; 13.G.172.231;
13.G.172.236; 13.G.172.237; 13.G.172.238; 13.G.172.239;
13.G.172.154; 13.G.172.157; 13.G.172.166; 13.G.172.169;
13.G.172.172; 13.G.172.175; 13.G.172.240; 13.G.172.244;
13.G.175.228; 13.G.175.229; 13.G.175.230; 13.G.175.231;
13.G.175.236; 13.G.175.237; 13.G.175.238; 13.G.175.239;
13.G.175.154; 13.G.175.157; 13.G.175.166; 13.G.175.169;
13.G.175.172; 13.G.175.175; 13.G.175.240; 13.G.175.244;
13.G.240.228; 13.G.240.229; 13.G.240.230; 13.G.240.231;
13.G.240.236; 13.G.240.237; 13.G.240.238; 13.G.240.239;
13.G.240.154; 13.G.240.157; 13.G.240.166; 13.G.240.169;
13.G.240.172; 13.G.240.175; 13.G.240.240; 13.G.240.244;
13.G.244.228; 13.G.244.229; 13.G.244.230; 13.G.244.231;
13.G.244.236; 13.G.244.237; 13.G.244.238; 13.G.244.239;
13.G.244.154; 13.G.244.157; 13.G.244.166; 13.G.244.169;
13.G.244.172; 13.G.244.175; 13.G.244.240; 13.G.244.244; Prodrugs of
13.I 13.I.228.228; 13.I.228.229; 13.I.228.230; 13.I.228.231;
13.I.228.236; 13.I.228.237; 13.I.228.238; 13.I.228.239;
13.I.228.154; 13.I.228.157; 13.I.228.166; 13.I.228.169;
13.I.228.172; 13.I.228.175; 13.I.228.240; 13.I.228.244;
13.I.229.228; 13.I.229.229; 13.I.229.230; 13.I.229.231;
13.I.229.236; 13.I.229.237; 13.I.229.238; 13.I.229.239;
13.I.229.154; 13.I.229.157; 13.I.229.166; 13.I.229.169;
13.I.229.172; 13.I.229.175; 13.I.229.240; 13.I.229.244;
13.I.230.228; 13.I.230.229; 13.I.230.230; 13.I.230.231;
13.I.230.236; 13.I.230.237; 13.I.230.238; 13.I.230.239;
13.I.230.154; 13.I.230.157; 13.I.230.166; 13.I.230.169;
13.I.230.172; 13.I.230.175; 13.I.230.240; 13.I.230.244;
13.I.231.228; 13.I.231.229; 13.I.231.230; 13.I.231.231;
13.I.231.236; 13.I.231.237; 13.I.231.238; 13.I.231.239;
13.I.231.154; 13.I.231.157; 13.I.231.166; 13.I.231.169;
13.I.231.172; 13.I.231.175; 13.I.231.240; 13.I.231.244;
13.I.236.228; 13.I.236.229; 13.I.236.230; 13.I.236.231;
13.I.236.236; 13.I.236.237; 13.I.236.238; 13.I.236.239;
13.I.236.154; 13.I.236.157; 13.I.236.166; 13.I.236.169;
13.I.236.172; 13.I.236.175; 13.I.236.240; 13.I.236.244;
13.I.237.228; 13.I.237.229; 13.I.237.230; 13.I.237.231;
13.I.237.236; 13.I.237.237; 13.I.237.238; 13.I.237.239;
13.I.237.154; 13.I.237.157; 13.I.237.166; 13.I.237.169;
13.I.237.172; 13.I.237.175; 13.I.237.240; 13.I.237.244;
13.I.238.228; 13.I.238.229; 13.I.238.230; 13.I.238.231;
13.I.238.236; 13.I.238.237; 13.I.238.238; 13.I.238.239;
13.I.238.154; 13.I.238.157; 13.I.238.166; 13.I.238.169;
13.I.238.172; 13.I.238.175; 13.I.238.240; 13.I.238.244;
13.I.239.228; 13.I.239.229; 13.I.239.230; 13.I.239.231;
13.I.239.236; 13.I.239.237; 13.I.239.238; 13.I.239.239;
13.I.239.154; 13.I.239.157; 13.I.239.166; 13.I.239.169;
13.I.239.172; 13.I.239.175; 13.I.239.240; 13.I.239.244;
13.I.154.228; 13.I.154.229; 13.I.154.230; 13.I.154.231;
13.I.154.236; 13.I.154.237; 13.I.154.238; 13.I.154.239;
13.I.154.154; 13.I.154.157; 13.I.154.166; 13.I.154.169;
13.I.154.172; 13.I.154.175; 13.I.154.240; 13.I.154.244;
13.I.157.228; 13.I.157.229; 13.I.157.230; 13.I.157.231;
13.I.157.236; 13.I.157.237; 13.I.157.238; 13.I.157.239;
13.I.157.154; 13.I.157.157; 13.I.157.166; 13.I.157.169;
13.I.157.172; 13.I.157.175; 13.I.157.240; 13.I.157.244;
13.I.166.228; 13.I.166.229; 13.I.166.230; 13.I.166.231;
13.I.166.236; 13.I.166.237; 13.I.166.238; 13.I.166.239;
13.I.166.154; 13.I.166.157; 13.I.166.166; 13.I.166.169;
13.I.166.172; 13.I.166.175; 13.I.166.240; 13.I.166.244;
13.I.169.228; 13.I.169.229; 13.I.169.230; 13.I.169.231;
13.I.169.236; 13.I.169.237; 13.I.169.238; 13.I.169.239;
13.I.169.154; 13.I.169.157; 13.I.169.166; 13.I.169.169;
13.I.169.172; 13.I.169.175; 13.I.169.240; 13.I.169.244;
13.I.172.228; 13.I.172.229; 13.I.172.230; 13.I.172.231;
13.I.172.236; 13.I.172.237; 13.I.172.238; 13.I.172.239;
13.I.172.154; 13.I.172.157; 13.I.172.166; 13.I.172.169;
13.I.172.172; 13.I.172.175; 13.I.172.240; 13.I.172.244;
13.I.175.228; 13.I.175.229; 13.I.175.230; 13.I.175.231;
13.I.175.236; 13.I.175.237; 13.I.175.238; 13.I.175.239;
13.I.175.154; 13.I.175.157; 13.I.175.166; 13.I.175.169;
13.I.175.172; 13.I.175.175; 13.I.175.240; 13.I.175.244;
13.I.240.228; 13.I.240.229; 13.I.240.230; 13.I.240.231;
13.I.240.236; 13.I.240.237; 13.I.240.238; 13.I.240.239;
13.I.240.154; 13.I.240.157; 13.I.240.166; 13.I.240.169;
13.I.240.172; 13.I.240.175; 13.I.240.240; 13.I.240.244;
13.I.244.228; 13.I.244.229; 13.I.244.230; 13.I.244.231;
13.I.244.236; 13.I.244.237; 13.I.244.238; 13.I.244.239;
13.I.244.154; 13.I.244.157; 13.I.244.166; 13.I.244.169;
13.I.244.172; 13.I.244.175; 13.I.244.240; 13.I.244.244; Prodrugs of
13.J 13.J.228.228; 13.J.228.229; 13.J.228.230; 13.J.228.231;
13.J.228.236; 13.J.228.237; 13.J.228.238; 13.J.228.239;
13.J.228.154; 13.J.228.157; 13.J.228.166; 13.J.228.169;
13.J.228.172; 13.J.228.175; 13.J.228.240; 13.J.228.244;
13.J.229.228; 13.J.229.229; 13.J.229.230; 13.J.229.231;
13.J.229.236; 13.J.229.237; 13.J.229.238; 13.J.229.239;
13.J.229.154; 13.J.229.157; 13.J.229.166; 13.J.229.169;
13.J.229.172; 13.J.229.175; 13.J.229.240; 13.J.229.244;
13.J.230.228; 13.J.230.229; 13.J.230.230; 13.J.230.231;
13.J.230.236; 13.J.230.237; 13.J.230.238; 13.J.230.239;
13.J.230.154; 13.J.230.157; 13.J.230.166; 13.J.230.169;
13.J.230.172; 13.J.230.175; 13.J.230.240; 13.J.230.244;
13.J.231.228; 13.J.231.229; 13.J.231.230; 13.J.231.231;
13.J.231.236; 13.J.231.237; 13.J.231.238; 13.J.231.239;
13.J.231.154; 13.J.231.157; 13.J.231.166; 13.J.231.169;
13.J.231.172; 13.J.231.175; 13.J.231.240; 13.J.231.244;
13.J.236.228; 13.J.236.229; 13.J.236.230; 13.J.236.231;
13.J.236.236; 13.J.236.237; 13.J.236.238; 13.J.236.239;
13.J.236.154; 13.J.236.157; 13.J.236.166; 13.J.236.169;
13.J.236.172; 13.J.236.175; 13.J.236.240; 13.J.236.244;
13.J.237.228; 13.J.237.229; 13.J.237.230; 13.J.237.231;
13.J.237.236; 13.J.237.237; 13.J.237.238; 13.J.237.239;
13.J.237.154; 13.J.237.157; 13.J.237.166; 13.J.237.169;
13.J.237.172; 13.J.237.175; 13.J.237.240; 13.J.237.244;
13.J.238.228; 13.J.238.229; 13.J.238.230; 13.J.238.231;
13.J.238.236; 13.J.238.237; 13.J.238.238; 13.J.238.239;
13.J.238.154; 13.J.238.157; 13.J.238.166; 13.J.238.169;
13.J.238.172; 13.J.238.175; 13.J.238.240; 13.J.238.244;
13.J.239.228; 13.J.239.229; 13.J.239.230; 13.J.239.231;
13.J.239.236; 13.J.239.237; 13.J.239.238; 13.J.239.239;
13.J.239.154; 13.J.239.157; 13.J.239.166; 13.J.239.169;
13.J.239.172; 13.J.239.175; 13.J.239.240; 13.J.239.244;
13.J.154.228; 13.J.154.229; 13.J.154.230; 13.J.154.231;
13.J.154.236; 13.J.154.237; 13.J.154.238; 13.J.154.239;
13.J.154.154; 13.J.154.157; 13.J.154.166; 13.J.154.169;
13.J.154.172; 13.J.154.175; 13.J.154.240; 13.J.154.244;
13.J.157.228; 13.J.157.229; 13.J.157.230; 13.J.157.231;
13.J.157.236; 13.J.157.237; 13.J.157.238; 13.J.157.239;
13.J.157.154; 13.J.157.157; 13.J.157.166; 13.J.157.169;
13.J.157.172; 13.J.157.175; 13.J.157.240; 13.J.157.244;
13.J.166.228; 13.J.166.229; 13.J.166.230; 13.J.166.231;
13.J.166.236; 13.J.166.237; 13.J.166.238; 13.J.166.239;
13.J.166.154; 13.J.166.157; 13.J.166.166; 13.J.166.169;
13.J.166.172; 13.J.166.175; 13.J.166.240; 13.J.166.244;
13.J.169.228; 13.J.169.229; 13.J.169.230; 13.J.169.231;
13.J.169.236; 13.J.169.237; 13.J.169.238; 13.J.169.239;
13.J.169.154; 13.J.169.157; 13.J.169.166; 13.J.169.169;
13.J.169.172; 13.J.169.175; 13.J.169.240; 13.J.169.244;
13.J.172.228; 13.J.172.229; 13.J.172.230; 13.J.172.231;
13.J.172.236; 13.J.172.237; 13.J.172.238; 13.J.172.239;
13.J.172.154; 13.J.172.157; 13.J.172.166; 13.J.172.169;
13.J.172.172; 13.J.172.175; 13.J.172.240; 13.J.172.244;
13.J.175.228; 13.J.175.229; 13.J.175.230; 13.J.175.231;
13.J.175.236; 13.J.175.237; 13.J.175.238; 13.J.175.239;
13.J.175.154; 13.J.175.157; 13.J.175.166; 13.J.175.169;
13.J.175.172; 13.J.175.175; 13.J.175.240; 13.J.175.244;
13.J.240.228; 13.J.240.229; 13.J.240.230; 13.J.240.231;
13.J.240.236; 13.J.240.237; 13.J.240.238; 13.J.240.239;
13.J.240.154; 13.J.240.157; 13.J.240.166; 13.J.240.169;
13.J.240.172; 13.J.240.175; 13.J.240.240; 13.J.240.244;
13.J.244.228; 13.J.244.229; 13.J.244.230; 13.J.244.231;
13.J.244.236; 13.J.244.237; 13.J.244.238; 13.J.244.239;
13.J.244.154; 13.J.244.157; 13.J.244.166; 13.J.244.169;
13.J.244.172; 13.J.244.175; 13.J.244.240; 13.J.244.244; Prodrugs of
13.L 13.L.228.228; 13.L.228.229; 13.L.228.230; 13.L.228.231;
13.L.228.236; 13.L.228.237; 13.L.228.238; 13.L.228.239;
13.L.228.154; 13.L.228.157; 13.L.228.166; 13.L.228.169;
13.L.228.172; 13.L.228.175; 13.L.228.240;
13.L.228.244; 13.L.229.228; 13.L.229.229; 13.L.229.230;
13.L.229.231; 13.L.229.236; 13.L.229.237; 13.L.229.238;
13.L.229.239; 13.L.229.154; 13.L.229.157; 13.L.229.166;
13.L.229.169; 13.L.229.172; 13.L.229.175; 13.L.229.240;
13.L.229.244; 13.L.230.228; 13.L.230.229; 13.L.230.230;
13.L.230.231; 13.L.230.236; 13.L.230.237; 13.L.230.238;
13.L.230.239; 13.L.230.154; 13.L.230.157; 13.L.230.166;
13.L.230.169; 13.L.230.172; 13.L.230.175; 13.L.230.240;
13.L.230.244; 13.L.231.228; 13.L.231.229; 13.L.231.230;
13.L.231.231; 13.L.231.236; 13.L.231.237; 13.L.231.238;
13.L.231.239; 13.L.231.154; 13.L.231.157; 13.L.231.166;
13.L.231.169; 13.L.231.172; 13.L.231.175; 13.L.231.240;
13.L.231.244; 13.L.236.228; 13.L.236.229; 13.L.236.230;
13.L.236.231; 13.L.236.236; 13.L.236.237; 13.L.236.238;
13.L.236.239; 13.L.236.154; 13.L.236.157; 13.L.236.166;
13.L.236.169; 13.L.236.172; 13.L.236.175; 13.L.236.240;
13.L.236.244; 13.L.237.228; 13.L.237.229; 13.L.237.230;
13.L.237.231; 13.L.237.236; 13.L.237.237; 13.L.237.238;
13.L.237.239; 13.L.237.154; 13.L.237.157; 13.L.237.166;
13.L.237.169; 13.L.237.172; 13.L.237.175; 13.L.237.240;
13.L.237.244; 13.L.238.228; 13.L.238.229; 13.L.238.230;
13.L.238.231; 13.L.238.236; 13.L.238.237; 13.L.238.238;
13.L.238.239; 13.L.238.154; 13.L.238.157; 13.L.238.166;
13.L.238.169; 13.L.238.172; 13.L.238.175; 13.L.238.240;
13.L.238.244; 13.L.239.228; 13.L.239.229; 13.L.239.230;
13.L.239.231; 13.L.239.236; 13.L.239.237; 13.L.239.238;
13.L.239.239; 13.L.239.154; 13.L.239.157; 13.L.239.166;
13.L.239.169; 13.L.239.172; 13.L.239.175; 13.L.239.240;
13.L.239.244; 13.L.154.228; 13.L.154.229; 13.L.154.230;
13.L.154.231; 13.L.154.236; 13.L.154.237; 13.L.154.238;
13.L.154.239; 13.L.154.154; 13.L.154.157; 13.L.154.166;
13.L.154.169; 13.L.154.172; 13.L.154.175; 13.L.154.240;
13.L.154.244; 13.L.157.228; 13.L.157.229; 13.L.157.230;
13.L.157.231; 13.L.157.236; 13.L.157.237; 13.L.157.238;
13.L.157.239; 13.L.157.154; 13.L.157.157; 13.L.157.166;
13.L.157.169; 13.L.157.172; 13.L.157.175; 13.L.157.240;
13.L.157.244; 13.L.166.228; 13.L.166.229; 13.L.166.230;
13.L.166.231; 13.L.166.236; 13.L.166.237; 13.L.166.238;
13.L.166.239; 13.L.166.154; 13.L.166.157; 13.L.166.166;
13.L.166.169; 13.L.166.172; 13.L.166.175; 13.L.166.240;
13.L.166.244; 13.L.169.228; 13.L.169.229; 13.L.169.230;
13.L.169.231; 13.L.169.236; 13.L.169.237; 13.L.169.238;
13.L.169.239; 13.L.169.154; 13.L.169.157; 13.L.169.166;
13.L.169.169; 13.L.169.172; 13.L.169.175; 13.L.169.240;
13.L.169.244; 13.L.172.228; 13.L.172.229; 13.L.172.230;
13.L.172.231; 13.L.172.236; 13.L.172.237; 13.L.172.238;
13.L.172.239; 13.L.172.154; 13.L.172.157; 13.L.172.166;
13.L.172.169; 13.L.172.172; 13.L.172.175; 13.L.172.240;
13.L.172.244; 13.L.175.228; 13.L.175.229; 13.L.175.230;
13.L.175.231; 13.L.175.236; 13.L.175.237; 13.L.175.238;
13.L.175.239; 13.L.175.154; 13.L.175.157; 13.L.175.166;
13.L.175.169; 13.L.175.172; 13.L.175.175; 13.L.175.240;
13.L.175.244; 13.L.240.228; 13.L.240.229; 13.L.240.230;
13.L.240.231; 13.L.240.236; 13.L.240.237; 13.L.240.238;
13.L.240.239; 13.L.240.154; 13.L.240.157; 13.L.240.166;
13.L.240.169; 13.L.240.172; 13.L.240.175; 13.L.240.240;
13.L.240.244; 13.L.244.228; 13.L.244.229; 13.L.244.230;
13.L.244.231; 13.L.244.236; 13.L.244.237; 13.L.244.238;
13.L.244.239; 13.L.244.154; 13.L.244.157; 13.L.244.166;
13.L.244.169; 13.L.244.172; 13.L.244.175; 13.L.244.240;
13.L.244.244; Prodrugs of 13.O 13.O.228.228; 13.O.228.229;
13.O.228.230; 13.O.228.231; 13.O.228.236; 13.O.228.237;
13.O.228.238; 13.O.228.239; 13.O.228.154; 13.O.228.157;
13.O.228.166; 13.O.228.169; 13.O.228.172; 13.O.228.175;
13.O.228.240; 13.O.228.244; 13.O.229.228; 13.O.229.229;
13.O.229.230; 13.O.229.231; 13.O.229.236; 13.O.229.237;
13.O.229.238; 13.O.229.239; 13.O.229.154; 13.O.229.157;
13.O.229.166; 13.O.229.169; 13.O.229.172; 13.O.229.175;
13.O.229.240; 13.O.229.244; 13.O.230.228; 13.O.230.229;
13.O.230.230; 13.O.230.231; 13.O.230.236; 13.O.230.237;
13.O.230.238; 13.O.230.239; 13.O.230.154; 13.O.230.157;
13.O.230.166; 13.O.230.169; 13.O.230.172; 13.O.230.175;
13.O.230.240; 13.O.230.244; 13.O.231.228; 13.O.231.229;
13.O.231.230; 13.O.231.231; 13.O.231.236; 13.O.231.237;
13.O.231.238; 13.O.231.239; 13.O.231.154; 13.O.231.157;
13.O.231.166; 13.O.231.169; 13.O.231.172; 13.O.231.175;
13.O.231.240; 13.O.231.244; 13.O.236.228; 13.O.236.229;
13.O.236.230; 13.O.236.231; 13.O.236.236; 13.O.236.237;
13.O.236.238; 13.O.236.239; 13.O.236.154; 13.O.236.157;
13.O.236.166; 13.O.236.169; 13.O.236.172; 13.O.236.175;
13.O.236.240; 13.O.236.244; 13.O.237.228; 13.O.237.229;
13.O.237.230; 13.O.237.231; 13.O.237.236; 13.O.237.237;
13.O.237.238; 13.O.237.239; 13.O.237.154; 13.O.237.157;
13.O.237.166; 13.O.237.169; 13.O.237.172; 13.O.237.175;
13.O.237.240; 13.O.237.244; 13.O.238.228; 13.O.238.229;
13.O.238.230; 13.O.238.231; 13.O.238.236; 13.O.238.237;
13.O.238.238; 13.O.238.239; 13.O.238.154; 13.O.238.157;
13.O.238.166; 13.O.238.169; 13.O.238.172; 13.O.238.175;
13.O.238.240; 13.O.238.244; 13.O.239.228; 13.O.239.229;
13.O.239.230; 13.O.239.231; 13.O.239.236; 13.O.239.237;
13.O.239.238; 13.O.239.239; 13.O.239.154; 13.O.239.157;
13.O.239.166; 13.O.239.169; 13.O.239.172; 13.O.239.175;
13.O.239.240; 13.O.239.244; 13.O.154.228; 13.O.154.229;
13.O.154.230; 13.O.154.231; 13.O.154.236; 13.O.154.237;
13.O.154.238; 13.O.154.239; 13.O.154.154; 13.O.154.157;
13.O.154.166; 13.O.154.169; 13.O.154.172; 13.O.154.175;
13.O.154.240; 13.O.154.244; 13.O.157.228; 13.O.157.229;
13.O.157.230; 13.O.157.231; 13.O.157.236; 13.O.157.237;
13.O.157.238; 13.O.157.239; 13.O.157.154; 13.O.157.157;
13.O.157.166; 13.O.157.169; 13.O.157.172; 13.O.157.175;
13.O.157.240; 13.O.157.244; 13.O.166.228; 13.O.166.229;
13.O.166.230; 13.O.166.231; 13.O.166.236; 13.O.166.237;
13.O.166.238; 13.O.166.239; 13.O.166.154; 13.O.166.157;
13.O.166.166; 13.O.166.169; 13.O.166.172; 13.O.166.175;
13.O.166.240; 13.O.166.244; 13.O.169.228; 13.O.169.229;
13.O.169.230; 13.O.169.231; 13.O.169.236; 13.O.169.237;
13.O.169.238; 13.O.169.239; 13.O.169.154; 13.O.169.157;
13.O.169.166; 13.O.169.169; 13.O.169.172; 13.O.169.175;
13.O.169.240; 13.O.169.244; 13.O.172.228; 13.O.172.229;
13.O.172.230; 13.O.172.231; 13.O.172.236; 13.O.172.237;
13.O.172.238; 13.O.172.239; 13.O.172.154; 13.O.172.157;
13.O.172.166; 13.O.172.169; 13.O.172.172; 13.O.172.175;
13.O.172.240; 13.O.172.244; 13.O.175.228; 13.O.175.229;
13.O.175.230; 13.O.175.231; 13.O.175.236; 13.O.175.237;
13.O.175.238; 13.O.175.239; 13.O.175.154; 13.O.175.157;
13.O.175.166; 13.O.175.169; 13.O.175.172; 13.O.175.175;
13.O.175.240; 13.O.175.244; 13.O.240.228; 13.O.240.229;
13.O.240.230; 13.O.240.231; 13.O.240.236; 13.O.240.237;
13.O.240.238; 13.O.240.239; 13.O.240.154; 13.O.240.157;
13.O.240.166; 13.O.240.169; 13.O.240.172; 13.O.240.175;
13.O.240.240; 13.O.240.244; 13.O.244.228; 13.O.244.229;
13.O.244.230; 13.O.244.231; 13.O.244.236; 13.O.244.237;
13.O.244.238; 13.O.244.239; 13.O.244.154; 13.O.244.157;
13.O.244.166; 13.O.244.169; 13.O.244.172; 13.O.244.175;
13.O.244.240; 13.O.244.244; Prodrugs of 13.P 13.P.228.228;
13.P.228.229; 13.P.228.230; 13.P.228.231; 13.P.228.236;
13.P.228.237; 13.P.228.238; 13.P.228.239; 13.P.228.154;
13.P.228.157; 13.P.228.166; 13.P.228.169; 13.P.228.172;
13.P.228.175; 13.P.228.240; 13.P.228.244; 13.P.229.228;
13.P.229.229; 13.P.229.230; 13.P.229.231; 13.P.229.236;
13.P.229.237; 13.P.229.238; 13.P.229.239; 13.P.229.154;
13.P.229.157; 13.P.229.166; 13.P.229.169; 13.P.229.172;
13.P.229.175; 13.P.229.240; 13.P.229.244; 13.P.230.228;
13.P.230.229; 13.P.230.230; 13.P.230.231; 13.P.230.236;
13.P.230.237; 13.P.230.238; 13.P.230.239; 13.P.230.154;
13.P.230.157; 13.P.230.166; 13.P.230.169; 13.P.230.172;
13.P.230.175; 13.P.230.240; 13.P.230.244; 13.P.231.228;
13.P.231.229; 13.P.231.230; 13.P.231.231; 13.P.231.236;
13.P.231.237; 13.P.231.238; 13.P.231.239; 13.P.231.154;
13.P.231.157; 13.P.231.166; 13.P.231.169; 13.P.231.172;
13.P.231.175; 13.P.231.240; 13.P.231.244; 13.P.236.228;
13.P.236.229; 13.P.236.230; 13.P.236.231; 13.P.236.236;
13.P.236.237; 13.P.236.238; 13.P.236.239; 13.P.236.154;
13.P.236.157; 13.P.236.166; 13.P.236.169; 13.P.236.172;
13.P.236.175; 13.P.236.240; 13.P.236.244; 13.P.237.228;
13.P.237.229; 13.P.237.230; 13.P.237.231; 13.P.237.236;
13.P.237.237; 13.P.237.238; 13.P.237.239; 13.P.237.154;
13.P.237.157; 13.P.237.166; 13.P.237.169; 13.P.237.172;
13.P.237.175; 13.P.237.240; 13.P.237.244; 13.P.238.228;
13.P.238.229; 13.P.238.230; 13.P.238.231; 13.P.238.236;
13.P.238.237; 13.P.238.238; 13.P.238.239; 13.P.238.154;
13.P.238.157; 13.P.238.166; 13.P.238.169; 13.P.238.172;
13.P.238.175; 13.P.238.240; 13.P.238.244; 13.P.239.228;
13.P.239.229; 13.P.239.230; 13.P.239.231; 13.P.239.236;
13.P.239.237; 13.P.239.238; 13.P.239.239; 13.P.239.154;
13.P.239.157; 13.P.239.166; 13.P.239.169; 13.P.239.172;
13.P.239.175; 13.P.239.240; 13.P.239.244; 13.P.154.228;
13.P.154.229; 13.P.154.230; 13.P.154.231; 13.P.154.236;
13.P.154.237; 13.P.154.238; 13.P.154.239; 13.P.154.154;
13.P.154.157; 13.P.154.166; 13.P.154.169; 13.P.154.172;
13.P.154.175; 13.P.154.240; 13.P.154.244; 13.P.157.228;
13.P.157.229; 13.P.157.230; 13.P.157.231; 13.P.157.236;
13.P.157.237; 13.P.157.238; 13.P.157.239; 13.P.157.154;
13.P.157.157; 13.P.157.166; 13.P.157.169; 13.P.157.172;
13.P.157.175; 13.P.157.240; 13.P.157.244; 13.P.166.228;
13.P.166.229; 13.P.166.230; 13.P.166.231; 13.P.166.236;
13.P.166.237; 13.P.166.238; 13.P.166.239; 13.P.166.154;
13.P.166.157; 13.P.166.166; 13.P.166.169; 13.P.166.172;
13.P.166.175; 13.P.166.240; 13.P.166.244; 13.P.169.228;
13.P.169.229; 13.P.169.230; 13.P.169.231; 13.P.169.236;
13.P.169.237; 13.P.169.238; 13.P.169.239; 13.P.169.154;
13.P.169.157; 13.P.169.166; 13.P.169.169; 13.P.169.172;
13.P.169.175; 13.P.169.240; 13.P.169.244; 13.P.172.228;
13.P.172.229; 13.P.172.230; 13.P.172.231; 13.P.172.236;
13.P.172.237; 13.P.172.238; 13.P.172.239; 13.P.172.154;
13.P.172.157; 13.P.172.166; 13.P.172.169; 13.P.172.172;
13.P.172.175; 13.P.172.240; 13.P.172.244; 13.P.175.228;
13.P.175.229; 13.P.175.230; 13.P.175.231; 13.P.175.236;
13.P.175.237; 13.P.175.238; 13.P.175.239; 13.P.175.154;
13.P.175.157; 13.P.175.166; 13.P.175.169; 13.P.175.172;
13.P.175.175; 13.P.175.240; 13.P.175.244; 13.P.240.228;
13.P.240.229; 13.P.240.230; 13.P.240.231; 13.P.240.236;
13.P.240.237; 13.P.240.238; 13.P.240.239; 13.P.240.154;
13.P.240.157; 13.P.240.166; 13.P.240.169; 13.P.240.172;
13.P.240.175; 13.P.240.240; 13.P.240.244; 13.P.244.228;
13.P.244.229; 13.P.244.230; 13.P.244.231; 13.P.244.236;
13.P.244.237; 13.P.244.238; 13.P.244.239; 13.P.244.154;
13.P.244.157; 13.P.244.166; 13.P.244.169; 13.P.244.172;
13.P.244.175; 13.P.244.240; 13.P.244.244; Prodrugs of 13.U
13.U.228.228; 13.U.228.229; 13.U.228.230; 13.U.228.231;
13.U.228.236; 13.U.228.237; 13.U.228.238; 13.U.228.239;
13.U.228.154; 13.U.228.157; 13.U.228.166; 13.U.228.169;
13.U.228.172; 13.U.228.175; 13.U.228.240; 13.U.228.244;
13.U.229.228; 13.U.229.229; 13.U.229.230; 13.U.229.231;
13.U.229.236; 13.U.229.237; 13.U.229.238; 13.U.229.239;
13.U.229.154; 13.U.229.157; 13.U.229.166; 13.U.229.169;
13.U.229.172; 13.U.229.175; 13.U.229.240; 13.U.229.244;
13.U.230.228; 13.U.230.229; 13.U.230.230; 13.U.230.231;
13.U.230.236; 13.U.230.237; 13.U.230.238; 13.U.230.239;
13.U.230.154; 13.U.230.157; 13.U.230.166; 13.U.230.169;
13.U.230.172; 13.U.230.175; 13.U.230.240; 13.U.230.244;
13.U.231.228; 13.U.231.229; 13.U.231.230; 13.U.231.231;
13.U.231.236; 13.U.231.237; 13.U.231.238; 13.U.231.239;
13.U.231.154; 13.U.231.157; 13.U.231.166; 13.U.231.169;
13.U.231.172; 13.U.231.175; 13.U.231.240; 13.U.231.244;
13.U.236.228; 13.U.236.229; 13.U.236.230; 13.U.236.231;
13.U.236.236; 13.U.236.237; 13.U.236.238; 13.U.236.239;
13.U.236.154; 13.U.236.157; 13.U.236.166; 13.U.236.169;
13.U.236.172; 13.U.236.175; 13.U.236.240; 13.U.236.244;
13.U.237.228; 13.U.237.229; 13.U.237.230; 13.U.237.231;
13.U.237.236; 13.U.237.237; 13.U.237.238; 13.U.237.239;
13.U.237.154; 13.U.237.157; 13.U.237.166; 13.U.237.169;
13.U.237.172; 13.U.237.175; 13.U.237.240; 13.U.237.244;
13.U.238.228; 13.U.238.229; 13.U.238.230; 13.U.238.231;
13.U.238.236; 13.U.238.237; 13.U.238.238; 13.U.238.239;
13.U.238.154; 13.U.238.157; 13.U.238.166; 13.U.238.169;
13.U.238.172; 13.U.238.175; 13.U.238.240; 13.U.238.244;
13.U.239.228; 13.U.239.229; 13.U.239.230; 13.U.239.231;
13.U.239.236; 13.U.239.237; 13.U.239.238; 13.U.239.239;
13.U.239.154; 13.U.239.157; 13.U.239.166; 13.U.239.169;
13.U.239.172; 13.U.239.175; 13.U.239.240; 13.U.239.244;
13.U.154.228; 13.U.154.229; 13.U.154.230; 13.U.154.231;
13.U.154.236; 13.U.154.237; 13.U.154.238; 13.U.154.239;
13.U.154.154; 13.U.154.157; 13.U.154.166; 13.U.154.169;
13.U.154.172; 13.U.154.175; 13.U.154.240; 13.U.154.244;
13.U.157.228; 13.U.157.229; 13.U.157.230; 13.U.157.231;
13.U.157.236; 13.U.157.237; 13.U.157.238; 13.U.157.239;
13.U.157.154; 13.U.157.157; 13.U.157.166; 13.U.157.169;
13.U.157.172; 13.U.157.175; 13.U.157.240; 13.U.157.244;
13.U.166.228; 13.U.166.229; 13.U.166.230; 13.U.166.231;
13.U.166.236; 13.U.166.237; 13.U.166.238; 13.U.166.239;
13.U.166.154; 13.U.166.157; 13.U.166.166; 13.U.166.169;
13.U.166.172; 13.U.166.175; 13.U.166.240; 13.U.166.244;
13.U.169.228; 13.U.169.229; 13.U.169.230; 13.U.169.231;
13.U.169.236; 13.U.169.237; 13.U.169.238; 13.U.169.239;
13.U.169.154; 13.U.169.157; 13.U.169.166; 13.U.169.169;
13.U.169.172; 13.U.169.175; 13.U.169.240; 13.U.169.244;
13.U.172.228; 13.U.172.229; 13.U.172.230; 13.U.172.231;
13.U.172.236; 13.U.172.237; 13.U.172.238; 13.U.172.239;
13.U.172.154; 13.U.172.157; 13.U.172.166; 13.U.172.169;
13.U.172.172; 13.U.172.175; 13.U.172.240; 13.U.172.244;
13.U.175.228; 13.U.175.229; 13.U.175.230; 13.U.175.231;
13.U.175.236; 13.U.175.237; 13.U.175.238; 13.U.175.239;
13.U.175.154; 13.U.175.157; 13.U.175.166; 13.U.175.169;
13.U.175.172; 13.U.175.175; 13.U.175.240; 13.U.175.244;
13.U.240.228; 13.U.240.229; 13.U.240.230; 13.U.240.231;
13.U.240.236; 13.U.240.237; 13.U.240.238; 13.U.240.239;
13.U.240.154; 13.U.240.157; 13.U.240.166; 13.U.240.169;
13.U.240.172; 13.U.240.175; 13.U.240.240; 13.U.240.244;
13.U.244.228; 13.U.244.229; 13.U.244.230; 13.U.244.231;
13.U.244.236; 13.U.244.237; 13.U.244.238; 13.U.244.239;
13.U.244.154; 13.U.244.157; 13.U.244.166; 13.U.244.169;
13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244; Prodrugs of
13.W 13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231;
13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239;
13.W.228.154; 13.W.228.157; 13.W.228.166; 13.W.228.169;
13.W.228.172; 13.W.228.175; 13.W.228.240; 13.W.228.244;
13.W.229.228; 13.W.229.229; 13.W.229.230; 13.W.229.231;
13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239;
13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169;
13.W.229.172; 13.W.229.175; 13.W.229.240; 13.W.229.244;
13.W.230.228; 13.W.230.229; 13.W.230.230; 13.W.230.231;
13.W.230.236; 13.W.230.237; 13.W.230.238; 13.W.230.239;
13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169;
13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244;
13.W.231.228; 13.W.231.229; 13.W.231.230; 13.W.231.231;
13.W.231.236; 13.W.231.237; 13.W.231.238; 13.W.231.239;
13.W.231.154; 13.W.231.157; 13.W.231.166; 13.W.231.169;
13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244;
13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W.236.231;
13.W.236.236; 13.W.236.237; 13.W.236.238; 13.W.236.239;
13.W.236.154; 13.W.236.157; 13.W.236.166; 13.W.236.169;
13.W.236.172; 13.W.236.175; 13.W.236.240; 13.W.236.244;
13.W.237.228; 13.W.237.229; 13.W.237.230; 13.W.237.231;
13.W.237.236; 13.W.237.237; 13.W.237.238; 13.W.237.239;
13.W.237.154; 13.W.237.157; 13.W.237.166; 13.W.237.169;
13.W.237.172; 13.W.237.175; 13.W.237.240; 13.W.237.244;
13.W.238.228; 13.W.238.229; 13.W.238.230; 13.W.238.231;
13.W.238.236; 13.W.238.237; 13.W.238.238; 13.W.238.239;
13.W.238.154; 13.W.238.157; 13.W.238.166; 13.W.238.169;
13.W.238.172; 13.W.238.175; 13.W.238.240; 13.W.238.244;
13.W.239.228; 13.W.239.229; 13.W.239.230; 13.W.239.231;
13.W.239.236; 13.W.239.237; 13.W.239.238; 13.W.239.239;
13.W.239.154; 13.W.239.157; 13.W.239.166; 13.W.239.169;
13.W.239.172; 13.W.239.175; 13.W.239.240; 13.W.239.244;
13.W.154.228; 13.W.154.229; 13.W.154.230; 13.W.154.231;
13.W.154.236; 13.W.154.237; 13.W.154.238; 13.W.154.239;
13.W.154.154; 13.W.154.157; 13.W.154.166; 13.W.154.169;
13.W.154.172; 13.W.154.175; 13.W.154.240; 13.W.154.244;
13.W.157.228; 13.W.157.229; 13.W.157.230; 13.W.157.231;
13.W.157.236; 13.W.157.237; 13.W.157.238; 13.W.157.239;
13.W.157.154; 13.W.157.157; 13.W.157.166; 13.W.157.169;
13.W.157.172; 13.W.157.175; 13.W.157.240; 13.W.157.244;
13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231;
13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239;
13.W.166.154; 13.W.166.157; 13.W.166.166; 13.W.166.169;
13.W.166.172; 13.W.166.175; 13.W.166.240; 13.W.166.244;
13.W.169.228; 13.W.169.229; 13.W.169.230; 13.W.169.231;
13.W.169.236; 13.W.169.237; 13.W.169.238; 13.W.169.239;
13.W.169.154; 13.W.169.157; 13.W.169.166; 13.W.169.169;
13.W.169.172; 13.W.169.175; 13.W.169.240; 13.W.169.244;
13.W.172.228; 13.W.172.229; 13.W.172.230; 13.W.172.231;
13.W.172.236; 13.W.172.237; 13.W.172.238; 13.W.172.239;
13.W.172.154; 13.W.172.157; 13.W.172.166; 13.W.172.169;
13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244;
13.W.175.228; 13.W.175.229;
13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237;
13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157;
13.W.175.166; 13.W.175.169; 13.W.175.172; 13.W.175.175;
13.W.175.240; 13.W.175.244; 13.W.240.228; 13.W.240.229;
13.W.240.230; 13.W.240.231; 13.W.240.236; 13.W.240.237;
13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157;
13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175;
13.W.240.240; 13.W.240.244; 13.W.244.228; 13.W.244.229;
13.W.244.230; 13.W.244.231; 13.W.244.236; 13.W.244.237;
13.W.244.238; 13.W.244.239; 13.W.244.154; 13.W.244.157;
13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175;
13.W.244.240; 13.W.244.244; Prodrugs of 13.Y 13.Y.228.228;
13.Y.228.229; 13.Y.228.230; 13.Y.228.231; 13.Y.228.236;
13.Y.228.237; 13.Y.228.238; 13.Y.228.239; 13.Y.228.154;
13.Y.228.157; 13.Y.228.166; 13.Y.228.169; 13.Y.228.172;
13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228;
13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236;
13.Y.229.237; 13.Y.229.238; 13.Y.229.239; 13.Y.229.154;
13.Y.229.157; 13.Y.229.166; 13.Y.229.169; 13.Y.229.172;
13.Y.229.175; 13.Y.229.240; 13.Y.229.244; 13.Y.230.228;
13.Y.230.229; 13.Y.230.230; 13.Y.230.231; 13.Y.230.236;
13.Y.230.237; 13.Y.230.238; 13.Y.230.239; 13.Y.230.154;
13.Y.230.157; 13.Y.230.166; 13.Y.230.169; 13.Y.230.172;
13.Y.230.175; 13.Y.230.240; 13.Y.230.244; 13.Y.231.228;
13.Y.231.229; 13.Y.231.230; 13.Y.231.231; 13.Y.231.236;
13.Y.231.237; 13.Y.231.238; 13.Y.231.239; 13.Y.231.154;
13.Y.231.157; 13.Y.231.166; 13.Y.231.169; 13.Y.231.172;
13.Y.231.175; 13.Y.231.240; 13.Y.231.244; 13.Y.236.228;
13.Y.236.229; 13.Y.236.230; 13.Y.236.231; 13.Y.236.236;
13.Y.236.237; 13.Y.236.238; 13.Y.236.239; 13.Y.236.154;
13.Y.236.157; 13.Y.236.166; 13.Y.236.169; 13.Y.236.172;
13.Y.236.175; 13.Y.236.240; 13.Y.236.244; 13.Y.237.228;
13.Y.237.229; 13.Y.237.230; 13.Y.237.231; 13.Y.237.236;
13.Y.237.237; 13.Y.237.238; 13.Y.237.239; 13.Y.237.154;
13.Y.237.157; 13.Y.237.166; 13.Y.237.169; 13.Y.237.172;
13.Y.237.175; 13.Y.237.240; 13.Y.237.244; 13.Y.238.228;
13.Y.238.229; 13.Y.238.230; 13.Y.238.231; 13.Y.238.236;
13.Y.238.237; 13.Y.238.238; 13.Y.238.239; 13.Y.238.154;
13.Y.238.157; 13.Y.238.166; 13.Y.238.169; 13.Y.238.172;
13.Y.238.175; 13.Y.238.240; 13.Y.238.244; 13.Y.239.228;
13.Y.239.229; 13.Y.239.230; 13.Y.239.231; 13.Y.239.236;
13.Y.239.237; 13.Y.239.238; 13.Y.239.239; 13.Y.239.154;
13.Y.239.157; 13.Y.239.166; 13.Y.239.169; 13.Y.239.172;
13.Y.239.175; 13.Y.239.240; 13.Y.239.244; 13.Y.154.228;
13.Y.154.229; 13.Y.154.230; 13.Y.154.231; 13.Y.154.236;
13.Y.154.237; 13.Y.154.238; 13.Y.154.239; 13.Y.154.154;
13.Y.154.157; 13.Y.154.166; 13.Y.154.169; 13.Y.154.172;
13.Y.154.175; 13.Y.154.240; 13.Y.154.244; 13.Y.157.228;
13.Y.157.229; 13.Y.157.230; 13.Y.157.231; 13.Y.157.236;
13.Y.157.237; 13.Y.157.238; 13.Y.157.239; 13.Y.157.154;
13.Y.157.157; 13.Y.157.166; 13.Y.157.169; 13.Y.157.172;
13.Y.157.175; 13.Y.157.240; 13.Y.157.244; 13.Y.166.228;
13.Y.166.229; 13.Y.166.230; 13.Y.166.231; 13.Y.166.236;
13.Y.166.237; 13.Y.166.238; 13.Y.166.239; 13.Y.166.154;
13.Y.166.157; 13.Y.166.166; 13.Y.166.169; 13.Y.166.172;
13.Y.166.175; 13.Y.166.240; 13.Y.166.244; 13.Y.169.228;
13.Y.169.229; 13.Y.169.230; 13.Y.169.231; 13.Y.169.236;
13.Y.169.237; 13.Y.169.238; 13.Y.169.239; 13.Y.169.154;
13.Y.169.157; 13.Y.169.166; 13.Y.169.169; 13.Y.169.172;
13.Y.169.175; 13.Y.169.240; 13.Y.169.244; 13.Y.172.228;
13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236;
13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154;
13.Y.172.157; 13.Y.172.166; 13.Y.172.169; 13.Y.172.172;
13.Y.172.175; 13.Y.172.240; 13.Y.172.244; 13.Y.175.228;
13.Y.175.229; 13.Y.175.230; 13.Y.175.231; 13.Y.175.236;
13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154;
13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172;
13.Y.175.175; 13.Y.175.240; 13.Y.175.244; 13.Y.240.228;
13.Y.240.229; 13.Y.240.230; 13.Y.240.231; 13.Y.240.236;
13.Y.240.237; 13.Y.240.238; 13.Y.240.239; 13.Y.240.154;
13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172;
13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228;
13.Y.244.229; 13.Y.244.230; 13.Y.244.231; 13.Y.244.236;
13.Y.244.237; 13.Y.244.238; 13.Y.244.239; 13.Y.244.154;
13.Y.244.157; 13.Y.244.166; 13.Y.244.169; 13.Y.244.172;
13.Y.244.175; 13.Y.244.240; 13.Y.244.244; Prodrugs of 14.AH
14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240;
14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158;
14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243;
14.AH.5.247; 14.AH.7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223;
14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157;
14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240;
14.AH.15.244; 14.AH.15.243; 14.AH.15.247; 14.AH.16.157;
14.AH.16.158; 14.AH.16.196; 14.AH.16.223; 14.AH.16.240;
14.AH.16.244; 14.AH.16.243; 14.AH.16.247; 14.AH.18.157;
14.AH.18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240;
14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157;
14.AH.26.158; 14.AH.26.196; 14.AH.26.223; 14.AH.26.240;
14.AH.26.244; 14.AH.26.243; 14.AH.26.247; 14.AH.27.157;
14.AH.27.158; 14.AH.27.196; 14.AH.27.223; 14.AH.27.240;
14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157;
14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240;
14.AH.29.244; 14.AH.29.243; 14.AH.29.247; 14.AH.54.157;
14.AH.54.158; 14.AH.54.196; 14.AH.54.223; 14.AH.54.240;
14.AH.54.244; 14.AH.54.243; 14.AH.54.247; 14.AH.55.157;
14.AH.55.158; 14.AH.55.196; 14.AH.55.223; 14.AH.55.240;
14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157;
14.AH.56.158; 14.AH.56.196; 14.AH.56.223; 14.AH.56.240;
14.AH.56.244; 14.AH.56.243; 14.AH.56.247; 14.AH.157.157;
14.AH.157.158; 14.AH.157.196; 14.AH.157.223; 14.AH.157.240;
14.AH.157.244; 14.AH.157.243; 14.AH.157.247; 14.AH.196.157;
14.AH.196.158; 14.AH.196.196; 14.AH.196.223; 14.AH.196.240;
14.AH.196.244; 14.AH.196.243; 14.AH.196.247; 14.AH.223.157;
14.AH.223.158; 14.AH.223.196; 14.AH.223.223; 14.AH.223.240;
14.AH.223.244; 14.AH.223.243; 14.AH.223.247; 14.AH.240.157;
14.AH.240.158; 14.AH.240.196; 14.AH.240.223; 14.AH.240.240;
14.AH.240.244; 14.AH.240.243; 14.AH.240.247; 14.AH.244.157;
14.AH.244.158; 14.AH.244.196; 14.AH.244.223; 14.AH.244.240;
14.AH.244.244; 14.AH.244.243; 14.AH.244.247; 14.AH.247.157;
14.AH.247.158; 14.AH.247.196; 14.AH.247.223; 14.AH.247.240;
14.AH.247.244; 14.AH.247.243; 14.AH.247.247; Prodrugs of 14.AJ
14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196; 14.AJ.4.223; 14.AJ.4.240;
14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247; 14.AJ.5.157; 14.AJ.5.158;
14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240; 14.AJ.5.244; 14.AJ.5.243;
14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158; 14.AJ.7.196; 14.AJ.7.223;
14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243; 14.AJ.7.247; 14.AJ.15.157;
14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223; 14.AJ.15.240;
14.AJ.15.244; 14.AJ.15.243; 14.AJ.15.247; 14.AJ.16.157;
14.AJ.16.158; 14.AJ.16.196; 14.AJ.16.223; 14.AJ.16.240;
14.AJ.16.244; 14.AJ.16.243; 14.AJ.16.247; 14.AJ.18.157;
14.AJ.18.158; 14.AJ.18.196; 14.AJ.18.223; 14.AJ.18.240;
14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247; 14.AJ.26.157;
14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240;
14.AJ.26.244; 14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157;
14.AJ.27.158; 14.AJ.27.196; 14.AJ.27.223; 14.AJ.27.240;
14.AJ.27.244; 14.AJ.27.243; 14.AJ.27.247; 14.AJ.29.157;
14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223; 14.AJ.29.240;
14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157;
14.AJ.54.158; 14.AJ.54.196; 14.AJ.54.223; 14.AJ.54.240;
14.AJ.54.244; 14.AJ.54.243; 14.AJ.54.247; 14.AJ.55.157;
14.AJ.55.158; 14.AJ.55.196; 14.AJ.55.223; 14.AJ.55.240;
14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247; 14.AJ.56.157;
14.AJ.56.158; 14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240;
14.AJ.56.244; 14.AJ.56.243; 14.AJ.56.247; 14.AJ.157.157;
14.AJ.157.158; 14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240;
14.AJ.157.244; 14.AJ.157.243; 14.AJ.157.247; 14.AJ.196.157;
14.AJ.196.158; 14.AJ.196.196; 14.AJ.196.223; 14.AJ.196.240;
14.AJ.196.244; 14.AJ.196.243; 14.AJ.196.247; 14.AJ.223.157;
14.AJ.223.158; 14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240;
14.AJ.223.244; 14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157;
14.AJ.240.158; 14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240;
14.AJ.240.244; 14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157;
14.AJ.244.158; 14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240;
14.AJ.244.244; 14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157;
14.AJ.247.158; 14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240;
14.AJ.247.244; 14.AJ.247.243; 14.AJ.247.247; Prodrugs of 14.AN
14.AN.4.157; 14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240;
14.AN.4.244; 14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158;
14.AN.5.196; 14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243;
14.AN.5.247; 14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223;
14.AN.7.240; 14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157;
14.AN.15.158; 14.AN.15.196; 14.AN.15.223; 14.AN.15.240;
14.AN.15.244; 14.AN.15.243; 14.AN.15.247; 14.AN.16.157;
14.AN.16.158; 14.AN.16.196; 14.AN.16.223; 14.AN.16.240;
14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157;
14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240;
14.AN.18.244; 14.AN.18.243; 14.AN.18.247; 14.AN.26.157;
14.AN.26.158; 14.AN.26.196; 14.AN.26.223; 14.AN.26.240;
14.AN.26.244; 14.AN.26.243; 14.AN.26.247; 14.AN.27.157;
14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240;
14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157;
14.AN.29.158; 14.AN.29.196; 14.AN.29.223; 14.AN.29.240;
14.AN.29.244; 14.AN.29.243; 14.AN.29.247; 14.AN.54.157;
14.AN.54.158; 14.AN.54.196; 14.AN.54.223; 14.AN.54.240;
14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157;
14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240;
14.AN.55.244; 14.AN.55.243; 14.AN.55.247; 14.AN.56.157;
14.AN.56.158; 14.AN.56.196; 14.AN.56.223; 14.AN.56.240;
14.AN.56.244; 14.AN.56.243; 14.AN.56.247; 14.AN.157.157;
14.AN.157.158; 14.AN.157.196; 14.AN.157.223; 14.AN.157.240;
14.AN.157.244; 14.AN.157.243; 14.AN.157.247; 14.AN.196.157;
14.AN.196.158; 14.AN.196.196; 14.AN.196.223; 14.AN.196.240;
14.AN.196.244; 14.AN.196.243; 14.AN.196.247; 14.AN.223.157;
14.AN.223.158; 14.AN.223.196; 14.AN.223.223; 14.AN.223.240;
14.AN.223.244; 14.AN.223.243; 14.AN.223.247; 14.AN.240.157;
14.AN.240.158; 14.AN.240.196; 14.AN.240.223; 14.AN.240.240;
14.AN.240.244; 14.AN.240.243; 14.AN.240.247; 14.AN.244.157;
14.AN.244.158; 14.AN.244.196; 14.AN.244.223; 14.AN.244.240;
14.AN.244.244; 14.AN.244.243; 14.AN.244.247; 14.AN.247.157;
14.AN.247.158; 14.AN.247.196; 14.AN.247.223; 14.AN.247.240;
14.AN.247.244; 14.AN.247.243; 14.AN.247.247; Prodrugs of 14.AP
14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240;
14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158;
14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243;
14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223;
14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157;
14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240;
14.AP.15.244; 14.AP.15.243; 14.AP.15.247; 14.AP.16.157;
14.AP.16.158; 14.AP.16.196; 14.AP.16.223; 14.AP.16.240;
14.AP.16.244; 14.AP.16.243; 14.AP.16.247; 14.AP.18.157;
14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240;
14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157;
14.AP.26.158; 14.AP.26.196; 14.AP.26.223; 14.AP.26.240;
14.AP.26.244; 14.AP.26.243; 14.AP.26.247; 14.AP.27.157;
14.AP.27.158; 14.AP.27.196; 14.AP.27.223; 14.AP.27.240;
14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157;
14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240;
14.AP.29.244; 14.AP.29.243; 14.AP.29.247; 14.AP.54.157;
14.AP.54.158; 14.AP.54.196; 14.AP.54.223; 14.AP.54.240;
14.AP.54.244; 14.AP.54.243; 14.AP.54.247; 14.AP.55.157;
14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240;
14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157;
14.AP.56.158; 14.AP.56.196; 14.AP.56.223; 14.AP.56.240;
14.AP.56.244; 14.AP.56.243; 14.AP.56.247; 14.AP.157.157;
14.AP.157.158; 14.AP.157.196; 14.AP.157.223; 14.AP.157.240;
14.AP.157.244; 14.AP.157.243; 14.AP.157.247; 14.AP.196.157;
14.AP.196.158; 14.AP.196.196; 14.AP.196.223; 14.AP.196.240;
14.AP.196.244; 14.AP.196.243; 14.AP.196.247; 14.AP.223.157;
14.AP.223.158; 14.AP.223.196; 14.AP.223.223; 14.AP.223.240;
14.AP.223.244; 14.AP.223.243; 14.AP.223.247; 14.AP.240.157;
14.AP.240.158; 14.AP.240.196; 14.AP.240.223; 14.AP.240.240;
14.AP.240.244; 14.AP.240.243; 14.AP.240.247; 14.AP.244.157;
14.AP.244.158; 14.AP.244.196; 14.AP.244.223; 14.AP.244.240;
14.AP.244.244; 14.AP.244.243; 14.AP.244.247; 14.AP.247.157;
14.AP.247.158; 14.AP.247.196; 14.AP.247.223; 14.AP.247.240;
14.AP.247.244; 14.AP.247.243; 14.AP.247.247; Prodrugs of 14.AZ
14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196; 14.AZ.4.223; 14.AZ.4.240;
14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247; 14.AZ.5.157; 14.AZ.5.158;
14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240; 14.AZ.5.244; 14.AZ.5.243;
14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158; 14.AZ.7.196; 14.AZ.7.223;
14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243; 14.AZ.7.247; 14.AZ.15.157;
14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223; 14.AZ.15.240;
14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157;
14.AZ.16.158; 14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240;
14.AZ.16.244; 14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157;
14.AZ.18.158; 14.AZ.18.196; 14.AZ.18.223; 14.AZ.18.240;
14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247; 14.AZ.26.157;
14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240;
14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157;
14.AZ.27.158; 14.AZ.27.196; 14.AZ.27.223; 14.AZ.27.240;
14.AZ.27.244; 14.AZ.27.243; 14.AZ.27.247; 14.AZ.29.157;
14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223; 14.AZ.29.240;
14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157;
14.AZ.54.158; 14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240;
14.AZ.54.244; 14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157;
14.AZ.55.158; 14.AZ.55.196; 14.AZ.55.223; 14.AZ.55.240;
14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247; 14.AZ.56.157;
14.AZ.56.158; 14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240;
14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157;
14.AZ.157.158; 14.AZ.157.196; 14.AZ.157.223; 14.AZ.157.240;
14.AZ.157.244; 14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157;
14.AZ.196.158; 14.AZ.196.196; 14.AZ.196.223; 14.AZ.196.240;
14.AZ.196.244; 14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157;
14.AZ.223.158; 14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240;
14.AZ.223.244; 14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157;
14.AZ.240.158; 14.AZ.240.196; 14.AZ.240.223; 14.AZ.240.240;
14.AZ.240.244; 14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157;
14.AZ.244.158; 14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240;
14.AZ.244.244; 14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157;
14.AZ.247.158; 14.AZ.247.196; 14.AZ.247.223;
14.AZ.247.240; 14.AZ.247.244; 14.AZ.247.243; 14.AZ.247.247;
Prodrugs of 14.BF 14.BF.4.157; 14.BF.4.158; 14.BF.4.196;
14.BF.4.223; 14.BF.4.240; 14.BF.4.244; 14.BF.4.243; 14.BF.4.247;
14.BF.5.157; 14.BF.5.158; 14.BF.5.196; 14.BF.5.223; 14.BF.5.240;
14.BF.5.244; 14.BF.5.243; 14.BF.5.247; 14.BF.7.157; 14.BF.7.158;
14.BF.7.196; 14.BF.7.223; 14.BF.7.240; 14.BF.7.244; 14.BF.7.243;
14.BF.7.247; 14.BF.15.157; 14.BF.15.158; 14.BF.15.196;
14.BF.15.223; 14.BF.15.240; 14.BF.15.244; 14.BF.15.243;
14.BF.15.247; 14.BF.16.157; 14.BF.16.158; 14.BF.16.196;
14.BF.16.223; 14.BF.16.240; 14.BF.16.244; 14.BF.16.243;
14.BF.16.247; 14.BF.18.157; 14.BF.18.158; 14.BF.18.196;
14.BF.18.223; 14.BF.18.240; 14.BF.18.244; 14.BF.18.243;
14.BF.18.247; 14.BF.26.157; 14.BF.26.158; 14.BF.26.196;
14.BF.26.223; 14.BF.26.240; 14.BF.26.244; 14.BF.26.243;
14.BF.26.247; 14.BF.27.157; 14.BF.27.158; 14.BF.27.196;
14.BF.27.223; 14.BF.27.240; 14.BF.27.244; 14.BF.27.243;
14.BF.27.247; 14.BF.29.157; 14.BF.29.158; 14.BF.29.196;
14.BF.29.223; 14.BF.29.240; 14.BF.29.244; 14.BF.29.243;
14.BF.29.247; 14.BF.54.157; 14.BF.54.158; 14.BF.54.196;
14.BF.54.223; 14.BF.54.240; 14.BF.54.244; 14.BF.54.243;
14.BF.54.247; 14.BF.55.157; 14.BF.55.158; 14.BF.55.196;
14.BF.55.223; 14.BF.55.240; 14.BF.55.244; 14.BF.55.243;
14.BF.55.247; 14.BF.56.157; 14.BF.56.158; 14.BF.56.196;
14.BF.56.223; 14.BF.56.240; 14.BF.56.244; 14.BF.56.243;
14.BF.56.247; 14.BF.157.157; 14.BF.157.158; 14.BF.157.196;
14.BF.157.223; 14.BF.157.240; 14.BF.157.244; 14.BF.157.243;
14.BF.157.247; 14.BF.196.157; 14.BF.196.158; 14.BF.196.196;
14.BF.196.223; 14.BF.196.240; 14.BF.196.244; 14.BF.196.243;
14.BF.196.247; 14.BF.223.157; 14.BF.223.158; 14.BF.223.196;
14.BF.223.223; 14.BF.223.240; 14.BF.223.244; 14.BF.223.243;
14.BF.223.247; 14.BF.240.157; 14.BF.240.158; 14.BF.240.196;
14.BF.240.223; 14.BF.240.240; 14.BF.240.244; 14.BF.240.243;
14.BF.240.247; 14.BF.244.157; 14.BF.244.158; 14.BF.244.196;
14.BF.244.223; 14.BF.244.240; 14.BF.244.244; 14.BF.244.243;
14.BF.244.247; 14.BF.247.157; 14.BF.247.158; 14.BF.247.196;
14.BF.247.223; 14.BF.247.240; 14.BF.247.244; 14.BF.247.243;
14.BF.247.247; Prodrugs of 14.CI 14.CI.4.157; 14.CI.4.158;
14.CI.4.196; 14.CI.4.223; 14.CI.4.240; 14.CI.4.244; 14.CI.4.243;
14.CI.4.247; 14.CI.5.157; 14.CI.5.158; 14.CI.5.196; 14.CI.5.223;
14.CI.5.240; 14.CI.5.244; 14.CI.5.243; 14.CI.5.247; 14.CI.7.157;
14.CI.7.158; 14.CI.7.196; 14.CI.7.223; 14.CI.7.240; 14.CI.7.244;
14.CI.7.243; 14.CI.7.247; 14.CI.15.157; 14.CI.15.158; 14.CI.15.196;
14.CI.15.223; 14.CI.15.240; 14.CI.15.244; 14.CI.15.243;
14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196;
14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243;
14.CI.16.247; 14.CI.18.157; 14.CI.18.158; 14.CI.18.196;
14.CI.18.223; 14.CI.18.240; 14.CI.18.244; 14.CI.18.243;
14.CI.18.247; 14.CI.26.157; 14.CI.26.158; 14.CI.26.196;
14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243;
14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196;
14.CI.27.223; 14.CI.27.240; 14.CI.27.244; 14.CI.27.243;
14.CI.27.247; 14.CI.29.157; 14.CI.29.158; 14.CI.29.196;
14.CI.29.223; 14.CI.29.240; 14.CI.29.244; 14.CI.29.243;
14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196;
14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243;
14.CI.54.247; 14.CI.55.157; 14.CI.55.158; 14.CI.55.196;
14.CI.55.223; 14.CI.55.240; 14.CI.55.244; 14.CI.55.243;
14.CI.55.247; 14.CI.56.157; 14.CI.56.158; 14.CI.56.196;
14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243;
14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196;
14.CI.157.223; 14.CI.157.240; 14.CI.157.244; 14.CI.157.243;
14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196;
14.CI.196.223; 14.CI.196.240; 14.CI.196.244; 14.CI.196.243;
14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196;
14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243;
14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196;
14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243;
14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196;
14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243;
14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196;
14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243;
14.CI.247.247; Prodrugs of 14.CO 14.CO.4.157; 14.CO.4.158;
14.CO.4.196; 14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243;
14.CO.4.247; 14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223;
14.CO.5.240; 14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157;
14.CO.7.158; 14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244;
14.CO.7.243; 14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196;
14.CO.15.223; 14.CO.15.240; 14.CO.15.244; 14.CO.15.243;
14.CO.15.247; 14.CO.16.157; 14.CO.16.158; 14.CO.16.196;
14.CO.16.223; 14.CO.16.240; 14.CO.16.244; 14.CO.16.243;
14.CO.16.247; 14.CO.18.157; 14.CO.18.158; 14.CO.18.196;
14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243;
14.CO.18.247; 14.CO.26.157; 14.CO.26.158; 14.CO.26.196;
14.CO.26.223; 14.CO.26.240; 14.CO.26.244; 14.CO.26.243;
14.CO.26.247; 14.CO.27.157; 14.CO.27.158; 14.CO.27.196;
14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243;
14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.CO.29.196;
14.CO.29.223; 14.CO.29.240; 14.CO.29.244; 14.CO.29.243;
14.CO.29.247; 14.CO.54.157; 14.CO.54.158; 14.CO.54.196;
14.CO.54.223; 14.CO.54.240; 14.CO.54.244; 14.CO.54.243;
14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196;
14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243;
14.CO.55.247; 14.CO.56.157; 14.CO.56.158; 14.CO.56.196;
14.CO.56.223; 14.CO.56.240; 14.CO.56.244; 14.CO.56.243;
14.CO.56.247; 14.CO.157.157; 14.CO.157.158; 14.CO.157.196;
14.CO.157.223; 14.CO.157.240; 14.CO.157.244; 14.CO.157.243;
14.CO.157.247; 14.CO.196.157; 14.CO.196.158; 14.CO.196.196;
14.CO.196.223; 14.CO.196.240; 14.CO.196.244; 14.CO.196.243;
14.CO.196.247; 14.CO.223.157; 14.CO.223.158; 14.CO.223.196;
14.CO.223.223; 14.CO.223.240; 14.CO.223.244; 14.CO.223.243;
14.CO.223.247; 14.CO.240.157; 14.CO.240.158; 14.CO.240.196;
14.CO.240.223; 14.CO.240.240; 14.CO.240.244; 14.CO.240.243;
14.CO.240.247; 14.CO.244.157; 14.CO.244.158; 14.CO.244.196;
14.CO.244.223; 14.CO.244.240; 14.CO.244.244; 14.CO.244.243;
14.CO.244.247; 14.CO.4.157; 14.CO.4.158; 14.CO.4.196; 14.CO.4.223;
14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;
[0913] All literature and patent citations herein are hereby
expressly incorporated by reference at the locations of their
citation. Specifically cited sections or pages of the above cited
works are incorporated by reference with specificity. The invention
has been described in detail sufficient to allow one of ordinary
skill in the art to make and use the subject matter of the
following claims. It is apparent that certain modifications of the
methods and compositions of the following claims can be made within
the scope and spirit of the invention.
[0914] In the claims hereinbelow, the subscript and superscripts of
a given variable are distinct. For example, R.sup.1 is distinct
from R.sup.1.
* * * * *